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Patricia KP BurnellInhalation Product Development
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• Inhaled products: types, development• The critical parameters• In-vitro testing• Ex-vivo testing
���� GlaxoSmithKline
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Product Development: drug ���� medicine
What dose?
Lung site to target?
Particles? Drops? Safe
ty a
nd E
ffica
cy
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‘Safe’ dose
���� GlaxoSmithKline
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FTIM Is the drug safe?
Proof of concept
Does the drug workas intended in (a few)patients?
Phase III Does the medicinework as intended withmany patients?
ClinicalPharmaceutical
Estimate formulation anddelivery device
Optimise formulation andchose inhaler
Consistency of manufactureStabilityRegistration of product
Phase IV Life-cyclemanagement
Line extensions
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• Rescue therapy : Bronchodilators– β2 adrenergic (e.g. salbutamol (albuterol),
salmeterol, formoterol, terbutaline)– M3 anticholinergics (e.g. ipratropium, tiotropium)
• Prophylaxis– inhaled corticosteroids (ICS, e.g. fluticasone,
beclomethasone, dexamethasone, budesonide)– NSAIDs (cromoglycates, xanthines)
���� GlaxoSmithKline
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���� GlaxoSmithKline
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-5
0
5
10
15
20
25
0 10 20 30 40Dose (µµµµg)
∆∆ ∆∆ FE
V 1 (%
)
Placebo 1.5 um 2.8 um 5 um
Zanen et al., Int J Pharmaceut 107 (1994) 211-17
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0
200
400
600
800
1000
1200
0 30 60 90 120 150 Time (mins)
FEF
25-7
5 (m
ls) I
mpr
ovem
ent
6.0 um
3.0 um
1.5 um
Placebo
10 20 40 100 Cumulative Dose (ug)
Brompton Study: Improvement in FEF vs. particlesize
Inhalation of monosizedalbuterol (salbutamol)sulphate.
Screening FEV1 with 200µg albuterol MDI was978 mls
FEF25-75= Forced ExpiratoryFlowrate between 25 - 75%lung deflation
���� GlaxoSmithKline
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00.10.20.30.40.50.60.70.80.9
1
Trachea Bronchi Bronchioles Alveoli
Rece
ptor
Rel
ativ
e de
nsit
y
Carstairs et al, Am Rev Respir Dis 132: 541-7 (1985); Mak & Barnes, Am Rev Respir Dis 141:1559-1568(1990); Jeffrey, p 80-108 in Asthma and Rhinitis, Blackwell Scientific (1995)
Airway smoothmuscle
M3 receptors
ββββ2 receptors
���� GlaxoSmithKline
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Distribution of inflammation in the airwaysIn
flam
mat
ory
inde
xIn
flam
mat
ory
inde
x(a
ctiv
ated
(act
ivat
ed e
osin
ophi
ls e
osin
ophi
ls/m
m)
/mm
)
00
1010
2020
3030
4040
5050
6060
7070
Large airwaysLarge airways Central airwaysCentral airways Small airwaysSmall airwaysHamid et al 1997
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Comparison of morning PEFR after treatment withfluticasone 250 µµµµg from Diskus and budesonide400 µµµµg from Turbuhaler
200
210
220
230
240
250
260
270
280
Baseline Week 20
FP 250µg bd (n=166)BUD 400µg bd (n=167)
am P
EFR
(L/m
in)
ns
P=0.002
(Ferguson et al, J Pediatr 1999)
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0.0
10.0
20.0
30.0
40.0
50.0
60.0
0 2 4 6 8 10
Particle size (µµµµm)
% o
f cha
ract
eris
ed d
ose
FPBud
NOT ALL DEVICES DELIVER THE SAME DOSE SIZE DISTRIBUTION
���� GlaxoSmithKline
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• Pressurised (propellant based) metered doseinhalers
• Dry powder inhalers• Liquid inhalers
���� GlaxoSmithKline
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Inhaled air entry
Metering valve
Mouthpiece
Formulation
CrimpGasket
Valve stem
Atomising nozzle
Actuator body
Aluminiumcan
Headspace
Propellant = Built in energy source���� GlaxoSmithKline
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Unit dose(Spinhaler, Rotahaler)
Energy assist
Reservoir Multi unit dose
Turbuhaler, UltrahalerDiskhaler
Diskus
Dryhaler
Inhale Device
���� GlaxoSmithKline
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���� GlaxoSmithKline
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Lactose + Salmeterol xinafoate= Serevent50 µ µ µ µg
Fluticasone propionate = Flixotide/Flovent50, 100, 250 and 500 µµµµg
Salbutamol sulphate= Ventolin200 µµµµg
Salmeterol xinafoate + Fluticasone propionate = Seretide50 µ µ µ µg 100, 250 and 500 µµµµg
12.5 or 25 mg
���� GlaxoSmithKline
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• Nebulizers (Sidestream, Ventstream, Pari, Halolite)– Dosing over minutes (5 to 15 mins)– Soft flume of fine droplets– High capability for targeting lung regions– Aqueous stability issues
• Respimat (Boehringer Ingelheim)– Soft flume of fine droplets– High capability for targeting lung regions
Air compressors, piezoelectric nozzles andothers provide the energy
���� GlaxoSmithKline
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• Dosing constraints• Physiochemical stability of drug substance• Commercial strategy
Particle size characteristics of the emitted dosefrom each type of inhaler may be vastly different
���� GlaxoSmithKline
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• Inertial impaction• Turbulent effects• Sedimentation• Diffusion• Electrostatic forces (?)
���� GlaxoSmithKline
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Big particle,high inertia
Small particle,low inertia
Stk= d2ρV/(9 ηL)where ρ = density of particleV= velocityη= air viscosityD= characteristic dimension
Impaction =f (d2.Q)where d= particle diameterand Q is flowrate
���� GlaxoSmithKline
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LIPS
Turbulence deposition ∝ d2, v
Turbulence depends on Re and StwhereRe, Reynold’s Number = ρv/µ andSt, Strouhal Number = τv/D
ρ = density of airµ = dynamic viscosity τ = time scale for unsteady flowsv = velocityD= characteristic dimension
���� GlaxoSmithKline
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���� GlaxoSmithKline
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Sedimentation velocity= d2ρg/18η
µm Vts (cms-1) T (s)
1 3.5e-03 57
3 2.9e-02 7
5 7.8e-02 3
8 2.0e-01 1
T = time take to settle 2 mm
Breath-hold during inhalation
���� GlaxoSmithKline
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Alveoli
Diffusion for particles < 0.5 µmBrownian motion, concentration gradient
���� GlaxoSmithKline
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Space charge forcesparticles of same polarityrepel each other
+++
++ +
As charged particles approachwalls, equal and opposite imagecharges are induced, resulting inenhanced deposition
+ +
+
+
+
+ -
--
-
���� GlaxoSmithKline
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For inhaled bronchodilators and corticosteroids
���� GlaxoSmithKline
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• Pharmaceutical development• Regulatory submissions• Benchmarking
���� GlaxoSmithKline
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Patient:•Age•Ability to use inhaler•Disease
Inhaler:•Formulation
Lung dose
Nominal dose > emitted dose
Regional lung dose
Blood levels
Safety Efficacy
���� GlaxoSmithKline
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In-vitro Ex-vivo In-vivo
• Content uniformity• Particle size
distribution• Degradation
products• Potency
• Pharmacokinetics• Pharmacodynamics
• Lung dose• Particle size
How does the emitted dose affect the lung dose andsubsequent clinical response?
���� GlaxoSmithKline
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Emitted dose
How much leaves the inhaler
Particle sizeof emitted
doseRegional lung deposition
Uni
form
ity
Lung dose
Dose to the target organ
���� GlaxoSmithKline
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• Pumps to ‘inhale’ dose• Standard flowrates (or pharmacopoeial methods)• Standard instruments• Determination of emitted dose by chemical assay• Determination of particle size distribution by
cascade impaction and chemical assay.
���� GlaxoSmithKline
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Pump
Filter
Inhaler
Replace filter witha cascade impactor to measure particle size distribution
time
Flowrate
���� GlaxoSmithKline
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AndersenCascade Impactor
Multi StageLiquid Impinger
Marple-MillerImpactor
Slide: Courtesy B Olsson, AstraZeneca
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Andersen Cascade ImpactorThroat
Preseparator
Baseplate
Collectionstage
Jet(s)
01234567Filter
Stages
Stk= d2ρV/(9 ηL)
Air
Jet
Collection plate
���� GlaxoSmithKline
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Andersen Cascade Impactor
Cutoffs shown correspond to 28 L/min.Adjusted for other flow rates.
Andersen samplers simulatedeposition in the humanrespiratory tract
Throat
Preseparator
Baseplate
Collectionstage
Jet(s)
01234567Filter
Stages
���� GlaxoSmithKline
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In-vivo• γ scintigraphy, PET• Gives estimation of regional
deposition• PET enables tracking of
both deposition anddisposition of label
• Labelling may affect particlesize distribution comparedto standard product.
Ex-vivo• Recording of patients’
inhalation (and doseactuation) profiles
• Use of breathing simulatorsto assess dose in-vitro
• Product used is thestandard product
• Assessment of particle sizeis realistic of patient use
• ‘Finger print’ of the product• Relatively cheap���� GlaxoSmithKline
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Pd time
Pressure
0 t
Electronic Lung
Q
���� GlaxoSmithKline
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The Electronic LungTM
Throat
Inhaler
Sample chamber(11 litres)
Cascade Impactorrun at 28 l/min
Piston
time
Pressuredrop
pressure feedback
Particle Cloud Detector
Filter
Pump
���� GlaxoSmithKline
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0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8 9 10
Dev
ice
Pres
sure
Dro
p (k
Pa)
0
10
20
30
40
50
60
70
80
90
Flow
rate
(L/m
in)
Pressure drop
Flowrate
Time (s) Time (s)
0.2
0.4
0.6
0.8
1.0
1.2
1.4
10
0
0 1 2 3 4 5 6 7 8 9
Dev
ice
Pres
sure
Dro
p (k
Pa)
0
5
10
15
20
25
30
35
40
45
Flow
rate
(L/m
in)
Pressure drop
Flowrate
Good inhalation Poor inhalation
Peak ≈≈≈≈ 7.5 kPa (95 L/min)
Peak ≈≈≈≈ 1.3 kPa (40 L/min)
���� GlaxoSmithKline
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TM TM µµµµ
0
20
40
60
80
100
120
0 50 100 150Peak inspiratory flowrate
mg
of d
rug
Total Emitted Dose of Inhaledß - Agonist (µg)Fine Particle Mass of Inhaledß - Agonist (µg)Total Emitted Dose of InhaledCorticosteroid (µg)Fine Particle Mass of InhaledCorticosteroid (µg)
Study DEV40026: GSK data on fileSeretide and Diskus are registered trademarks of GlaxoSmithKline
���� GlaxoSmithKline
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0
20
40
60
80
100
120
140
160
0 50 100 150
Peak inspiratory flowrate (L/min)
µµ µµg o
f dru
g
Total Emitted Dose of Inhaled Corticosteroid (µg)Fine Particle Mass of Inhaled Corticosteroid (µg)
Peak inspiratory flowrate (L/min)
0
1
2
3
4
5
6
7
0 20 40 60 80 100 120
µµ µµg o
f dru
gTotal Emitted Dose of Inhaled ß - Agonist (µg)
Fine Particle Mass of Inhaled ß - Agonist (µg)
Study DEV40026: GSK data on file
���� GlaxoSmithKline
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• Consortium (GSK, AstraZeneca and AventisPharma)
• Magnetic Resonance Imaging (D McRobbie,Charing Cross Hospital)
• 4 way randomised crossover study (n= 20) usingtidal breathing.
• Data-set has been reduced to 11 variables• Testing has been carried out (and on-going) to
determine filtration efficiencies• Intent is to develop an ‘average’, ‘large’ and ‘small’
throat���� GlaxoSmithKline
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a b
c d
���� GlaxoSmithKline
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���� GlaxoSmithKline
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a c
Device Diameter Ratio Area Ratioa 2.5 4.9c 1.4 1.5
MRI Scans Mouth vol Total vola 34252.9 53622.6c 22552.4 40798.2
1.8 3.2
1.5 1.3
���� GlaxoSmithKline
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a b
Device Diameter Ratio Resistivity Ratioa 2.5 0.0044b 2.5 0.0489MRI Scan Mouth vol Total vola 34252.9 53622.6b 32052.7 51558.3
1.0 0.1
1.07 1.04
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In-vitro throat is not too different from twointra-subject anatomical models
(Data: GlaxoSmithKline)
0.0
20.0
40.0
60.0
80.0
100.0
0.0 2.0 4.0 6.0 8.0 10.0 12.0
Particle diameter ( µµµµ m)
Cum
ulat
ive
per
cent
und
ersi
ze (%
)
GSK
Narrow mouth
Normal mouth
���� GlaxoSmithKline
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Data: AstraZenecaFlowrate= 30 L/min
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0
5
10
15
20
25
Swift cadaver Narrow Normal
Dos
e ex
cas
t (%
of L
C)
Data: AstraZeneca
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(VentolinTM AccuhalerTM, n=6, 4 kPa, 76 L/min)
0
5
10
15
20
25
30Pe
rcen
tage
of T
otal
Dos
e
Normal Narrow
Data: Aventis Pharma
Ventolin and Accuhaler are both trademarks of GlaxoSmithKline
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• In-vitro tests: standardised conditions to give anindication of emitted dose and its attributes, usedfor QA.
• In-vivo tests: Human conditions to determineclinical safety and efficacy
• Ex-vivo tests: potential to link the above
���� GlaxoSmithKline
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• In-vitro tests fulfil the requirements for regulatorypurposes to demonstrate uniformity of the product.
• In-vivo tests fulfil the requirements to demonstratesafety and efficacy of the formulation and deliverydevice
• Ex-vivo tests are novel, may yet be proven to linkthe two but are primarily aimed in understandingthe effect of the molecule/formulation/deliverysystem on the patient.
���� GlaxoSmithKline