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Challenges and Future
Prospects for Pulmonary
Delivery of Biologics
AAPS Annual Meeting Oct 2015
Sildes Acknowledgement
Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga Ashkan Yazdi
Questions to be addressed
bull Why are biologics important
bull Can inhaled biologics become a reality
bull What evidence is there that inhaled biologics are possible
bull How does one deliver and formulate inhaled biologics
bull What can we expect in the next few years for inhaled biologics
Growth of Biologics
bull Biologics currently represent approximately a
20 share of all global pharmaceutical sales [1]
bull There are more than 300 therapeutic biological
molecules approved worldwide and many more
in product development pipelines
bull Biopharmarsquos current annual growth rate is
approximately 8 and is double that of
conventional pharma [2]
1 httpwwwimshealthcomdeployedfilesimshealthGlobalContentCorporateIMS Health
InstituteReportsGlobal_Use_of_Meds_Outlook_2017Biologics_Marketpdf
2 Ralf Otto AS Ulf Schrader Rapid growth in biopharma Challenges and opportunities 2014 Available from
httpwwwmckinseycominsightshealth_systems_and_servicesrapid_growth_in_biopharma
Alternative Route Inhalation
The inhaled route is an attractive alternative
to the parenteral route of administration for a
multitude of reasons
ndash Local delivery
bull allows high doses of protein drugs to be delivered
while limiting potential systemic side effects
ndash Systemic delivery
Large Surface Area For Absorption
Mild MetabolicEnzymatic
Environment bull Metabolism in lungs differs
substantially from the
intestinalndashhepatic
metabolism
bull Expression levels of
enzymes are generally
lower and the expression
patterns differ
Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance
and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-
6_2
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Questions to be addressed
bull Why are biologics important
bull Can inhaled biologics become a reality
bull What evidence is there that inhaled biologics are possible
bull How does one deliver and formulate inhaled biologics
bull What can we expect in the next few years for inhaled biologics
Growth of Biologics
bull Biologics currently represent approximately a
20 share of all global pharmaceutical sales [1]
bull There are more than 300 therapeutic biological
molecules approved worldwide and many more
in product development pipelines
bull Biopharmarsquos current annual growth rate is
approximately 8 and is double that of
conventional pharma [2]
1 httpwwwimshealthcomdeployedfilesimshealthGlobalContentCorporateIMS Health
InstituteReportsGlobal_Use_of_Meds_Outlook_2017Biologics_Marketpdf
2 Ralf Otto AS Ulf Schrader Rapid growth in biopharma Challenges and opportunities 2014 Available from
httpwwwmckinseycominsightshealth_systems_and_servicesrapid_growth_in_biopharma
Alternative Route Inhalation
The inhaled route is an attractive alternative
to the parenteral route of administration for a
multitude of reasons
ndash Local delivery
bull allows high doses of protein drugs to be delivered
while limiting potential systemic side effects
ndash Systemic delivery
Large Surface Area For Absorption
Mild MetabolicEnzymatic
Environment bull Metabolism in lungs differs
substantially from the
intestinalndashhepatic
metabolism
bull Expression levels of
enzymes are generally
lower and the expression
patterns differ
Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance
and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-
6_2
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Growth of Biologics
bull Biologics currently represent approximately a
20 share of all global pharmaceutical sales [1]
bull There are more than 300 therapeutic biological
molecules approved worldwide and many more
in product development pipelines
bull Biopharmarsquos current annual growth rate is
approximately 8 and is double that of
conventional pharma [2]
1 httpwwwimshealthcomdeployedfilesimshealthGlobalContentCorporateIMS Health
InstituteReportsGlobal_Use_of_Meds_Outlook_2017Biologics_Marketpdf
2 Ralf Otto AS Ulf Schrader Rapid growth in biopharma Challenges and opportunities 2014 Available from
httpwwwmckinseycominsightshealth_systems_and_servicesrapid_growth_in_biopharma
Alternative Route Inhalation
The inhaled route is an attractive alternative
to the parenteral route of administration for a
multitude of reasons
ndash Local delivery
bull allows high doses of protein drugs to be delivered
while limiting potential systemic side effects
ndash Systemic delivery
Large Surface Area For Absorption
Mild MetabolicEnzymatic
Environment bull Metabolism in lungs differs
substantially from the
intestinalndashhepatic
metabolism
bull Expression levels of
enzymes are generally
lower and the expression
patterns differ
Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance
and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-
6_2
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Alternative Route Inhalation
The inhaled route is an attractive alternative
to the parenteral route of administration for a
multitude of reasons
ndash Local delivery
bull allows high doses of protein drugs to be delivered
while limiting potential systemic side effects
ndash Systemic delivery
Large Surface Area For Absorption
Mild MetabolicEnzymatic
Environment bull Metabolism in lungs differs
substantially from the
intestinalndashhepatic
metabolism
bull Expression levels of
enzymes are generally
lower and the expression
patterns differ
Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance
and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-
6_2
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Large Surface Area For Absorption
Mild MetabolicEnzymatic
Environment bull Metabolism in lungs differs
substantially from the
intestinalndashhepatic
metabolism
bull Expression levels of
enzymes are generally
lower and the expression
patterns differ
Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance
and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-
6_2
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Mild MetabolicEnzymatic
Environment bull Metabolism in lungs differs
substantially from the
intestinalndashhepatic
metabolism
bull Expression levels of
enzymes are generally
lower and the expression
patterns differ
Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance
and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-
6_2
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Administration Stability
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Example of the challenge Insulin
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
Ubiquitous biologic formulation issues
+ aerosolization + excipient limitations
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Can inhaled biologics become a
reality bull The withdrawal of Exuberareg remains a
disappointment and has ―muddied the waters for potential investorsdevelopers
bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram
rather than international units very large device)
ndash apparent safety considerations
ndash marketing and sales inadequacies
ndash pricing and sales
1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529
2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113
3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Mixed Perception for Inhaled Biologics
bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics
bull Realityhellip
ndash Pulmozymereg bull Dornase alpha or DNase Genentech
bull Approved in 1993
bull A mainstay of therapy for cystic fibrosis
bull Therefore there is a history of protein delivery to the lungs routinely without adverse events
ndash Afrezza bull Inhaled insulin approved
ndash Many others in the pipeline
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Inhaled Biologics ndash Locally Acting Drug Clinical application
Pitrakinra (recombinant human Interleukin-4) Asthma
vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis
Glutathione Cystic Fibrosis
granulocyte-macrophage colony-stimulating
factor (GM-CSF) pulmonary alveolar proteinosis
DAS181 Influenza virus
INF-γ Cystic fibrosis
Interleukin-2 (IL-2) Cancer
Sargramostin
Metastatic
cancer
sarcoma
α1 -antitrypsin Fibrosis
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Inhaled Proteins ndash Systemically Acting Drug
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Insulin (Exuberareg) Hypoglycemic
effect Type III diabetes
Approved disc2007 Bellary and Barnett (2006)
(NektarPfizer)
Insulin (AIR system) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Muchmore et al (2007)
(AlkermesEli Lilly)
Insulin ( Afrezzareg) Hypoglycemic
effect Type III diabetes
ϕ Approved Steiner et al (2002)
(MannKind)
Insulin (AERx IDMS) Hypoglycemic
effect Type III diabetes
ϕ III disc 2008 Thipphawong et al (2002)
(Aradigm)
Human parathyroid hormone
(PTH)
Bone mineral
metabolism Osteoporosis
Pilot clinical trial
(MannKind) Pfuumltzner et al (2003)
Interferons (INF) Immune system
regulation Multiple sclerosis Pre-clinical
Patton et al (1994) Martin et
al (2002) Vallee et al(2012)
and Agu RU (2001) Niven et
al (1995)
Interleukin-2 (IL-2) Immune system
regulation
Cancer and
immunodeficiency including
HIV
Mayo Clinic
Foundation Ten et al (2002)
Recombinant-methionyl
human granulocyte colony-
stimulating factor( r-huG-
CSF)
Immune system
regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)
Human growth Hormon
(hGH) Bone growth Growth deficiency
ϕ I completed 2008
(AlkermesEli Lilly) Nelson et al (2009) and
Walvoord et al (2009)
EPO-Fc Erythrocyte
production Anaemia
ϕ I completed 2005
(SyntonixBI)
Dumont et al
2005 and Bitonti and
Dumont 2006
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Inhaled Peptides ndash Systemically Acting
Drug Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Calcitonin Bone mineral
metabolism
Osteoporosis Pagets
disease
ϕ I completed 1996
(Dura Pharm) Deftos et al (1997)
Leuprolide
Regulation of
estradiol and
testosterone
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
TAP
Pharmaceuticals
Abbott Laboratories
Adjei A et al
(1990 and 1992)
Cetrorelix Mimetic of
leuprolide
Hormone-responsive
cancers estrogen-
dependent conditions
precocious puberty and in
vitro fertilization
Pre-clinical Lizio et al (2000)
PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)
Glucagon-like peptide-
1 (GLP-1)
Hypoglycemic
effect Type II diabetes
ϕ I completed 2008
ϕ II ongoing
(MannKind)
NCT00642538
Lee et al (2009)
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Inhaled Vaccines Drug
Biological
class
Biological
functions Clinical application
Clinical status
(sponsor)
RefTrial registry
number
Hepatitis B vaccine Immune system
stimulation Hepatitis B Pre-clinical
Thomas et al (2010 and
2011) Muttil et al (2010)
Diphtheria vaccine Immune system
stimulation Diphtheria Pre-clinical Muttil et al (2010)
HPV vaccine Immune system
stimulation Cervical cancer
Department of
Gynecology Centre
Hospitalier
Universitaire
Vaudois
Switzerland
Nardelli-Haefliger et al
(2005)
Influenza vaccine Immune system
stimulation Influenza Pre-clinical
Saluja et al (2010) and
Amorij et al (2007)
HIV vaccine Immune system
stimulation HIV Pre-clinical
Corbett et al (2007) and
Hunter et al (2009)
Live attenuated measles
virus vaccine
Immune system
stimulation Measles vaccine
Early pilot trials in
Mexico and ϕ I
ongoing 2012
(Serum Institute of
India Limited)
Sabin et al (1983 and
1984) Hiremath et al
(2005) Low et al (2007)
Agarkhedkar et al (2014)
NCT01557699
Live attenuated
Mycobacterium
bovis bacillus
vaccine Immune system
stimulation Tuberculosis vaccine
ϕ I ongoing 2012
(University of
Oxford)
NCT01497769
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
ApprovedLate stage Systemically
Acting Brand Name
(Company) Drug
Regulatory
Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs
Exuberareg (Pfizer) Insulin Approved
Withdrawn
1 3 mg (~3 8
units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)
Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-
Adasuve (R) [package Insert]
Afrezzareg
MannKind Insulin Approved
4 8 12 u
cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)
Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom
Semprana
(Allergan)
Dihydro-
ergotamine
Pending
Approval 1 mginh PRN 10 min 67978 2
Cerebral arteries brain
stem Selberstein (2012) Cook
(2009)
Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)
Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)
NA (Vectura) Apomorphine Phase II Multidose
inhaler NA 2-7min 2673 31 CNS Morton (2008)
NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)
NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Enthusiasm
bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics
Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Challenges
Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics
Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
0
90
180
0
90
180
0
90
180
0
90
180
Oropharyngeal
Trachea
Sedimentation 1-5 μm
Diffusion lt 1 μm
Air Velocity Anatomical
Region
Bronchial
Bronchiolar
Alveolar
Effective cross-sectional area
Inertial Impaction
5-30 μm
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153
Aerodynamic Barriers
Sticky Van der Waals world
Gravity dominates
less cohesion
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
So What Happens to ParticlesDrug
After Deposition in the Airways
bull Mechanical
ndash Mucociliary clearance
ndash Cough
bull Cellular
ndash Alveolar macrophages
ndash Epithelial cells
ndash Partitioningabsorption
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Mucocillary Clearance
bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains
bull In effect a combinatorial library
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Phagocytosis
bull Particles penetrating
down to the
respiratory airways
are rapidly cleared
by alveolar
macrophages
bull 12-14
Macrophages05
billion alveoli
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Phagocytosis is complex
bull Phagocytosis requires bull (1) binding of the particle to the macrophage
bull (2) activation of receptors (signal transfer)
bull (3) functional actin and
bull (4) phagosomes engulf material
bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator
bull Influenced by disease (eg incr in asthma)
bull Influence by particle size (Tabata amp Ikada 1988)
bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora
et al 1998)
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Absorption bull 70 ndash 100 m2 surface area for absorption
bull Small hydrophobic molecules are rapidly
absorbed (within seconds) by passive diffusion
bull Transporters tight junctions or via
transcytosis through caveoli
Patton et al Proceedings of the American
Thoracic Society 1338-344 (2004)
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Physicochemical Properties and
Dose
Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery
bull What biologics are susceptible to which
barriers
ndash DEPENDS - need to study each new case
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Airway
anatomy
Disease
state
Breathing
Patterns
Particle
Size
Site of
Deposition
Physicochemical
Properties
Release
Rate
Pulmonary
Absorption
Pulmonary
Clearance
Mucociliary
escalator
Complexity of Lung Clearance
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Pressurized Metered Dose Inhalers
bull Brief description HFA propellants device
valve actuator
bull Limitations Efficiency formulation design
space stability dose coordination
bull Advantages Portability pt acceptance
bull Is it practical to use this device
ndash Perhaps more evidence required to
determine platform applicability
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Nebulizers
bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip
bull Limitations Efficiency stability (prior amp during neb) dose times
bull Advantages Aqueous formulations
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Dry Powder Inhalers
bull Brief description Diverse devices passive active particle engineering
bull Limitations Formulationexcipient design window patient driven performance efficiency
bull Advantages Dose no coordination stability
bull Is it practical to use this device
ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary
ndash Newer devices achieve higher efficiencies less pt dependence
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Peptideprotein Device Reference clinical trial number
Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]
Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization
NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]
IgG1 Nebulization DPI [23] and [41][42] [43] and [44]
BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II
IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II
rh-IL-4 receptor AERx [47]
Bikunin (Aerolyticreg) Nebulization Aerovance Phase II
Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]
Interferon-alpha Nebulizer AERx [50] and [51][52]
Interferon-beta i-neb AAD NCT01126177 Synairgen phase II
Interferon-gamma i-neb AAD [53]
Interferon-omega Respimatreg [54]
Interleukin-2 Jet nebulizer [55] and [56]
Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]
Catalase [59]
Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]
Mn-Superoxide dismutase Respimatreg [54]
Calcitonin DPI [61]
Parathyroid hormone it [62]
Human growth hormone DPI [63]
Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34
Insulin-like growth factor-I Nebulizer [66]
GLP-1 it [67]
rhG-CSF Nebulizer [68]
Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Are there ways of overcoming these
cellular and extracellular barriers
bull Epithelia ndash some evidence
bull Mucus ndash only a few technologies
bull Alveolar Macrophages ndash only a few
technologies
bull Pulmonary surfactant ndash some evidence
bull Enzymatic barrier ndash some evidence
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Formulation approaches Surfactants
bull May increase the absorption of biologics through several mechanisms
bull alteration of mucus layer
bull protection against the enzymatic degradation
bull dissociation of proteins into oligomers or monomers
bull increase paracellular transport due to openings of tight junction
bull formation of micelles which facilitate protein transcellular transport
bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]
bull surfactant lauryl ether (rG-CSF) [99]
bull Span 85 for the administration of insulin [100 101]
97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43
98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71
99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6
100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73
102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Formulation approaches
bull Liposomes bull Protection from enzymatic deg enhance
absorption via surfactant recycling some peptides
hindered
bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin
bull Polymers bull Chitosan amp derivatives polyoxyethylene
Cryan AAPSJ 2005
Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14
Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44
Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats
J Pharm Sci 2008 97(12) p 5176-85
Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control
Release 2012 157(3) p 383-90
Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Formulation approaches Fusion Proteins
bull Receptor mediated transport across the
lung epithelium was successfully achieved
by fusing different proteins with the Fc
domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc
bull bioavailability retention of biological activity after
lung absorption and increased half-life
Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Formulation approaches Protease inhibitors
bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders
bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane
Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Formulation approaches Mucus
bull Most work focused on improving nanoparticle
transport
bull PEG coatings specific density mw (Hanes
JHU Kala Pharma)
bull Mucolytics in formulations
Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Formulation approaches Macrophages
bull Using particle shape and size
ndash Low density porous particles (Edwards et al 1997)
ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug
delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release
2007)
ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC
(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm
Sci 99 2343ndash2356 doi 101002jps22003)
ndash PEGylation (Patton et al Pulmonary administration of chemically modified
insulin US 6838076 B2)
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Future Prospects
bull Appears ~ 50 product pipelines are biologics
bull Appears ~ 50 FDA submissions are biologics
bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics
bull Renewed interest in gene therapy new gene editing technologies
bull siRNA amp miRNA
bull Its probably a great time to be working in inhaled biologics
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
Acknowledgements
bull Javier Morales Jason McConville AAPS
bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga
Ashkan Yazdi
The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults
for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at
Austin in accordance with its policy on objectivity in research
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