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Selecting the Right Enabling Technology for Poorly Soluble Compounds
Irena McGuffyManager, R&D Formulations
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NCE Outlook For The Future –Lots of Potential for Poor Bioavailability
BCS Class I
~5%
BCS Class III
~5%
BCS Class II
~70%
BCS Class IV
~20%
Solubility
Low
High
High
LowPermeability
New Chemical Entities
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Optiform™ Technologies
• High-throughput platform for salt, crystal-form, and cocrystal screening
• Developed and refined over the past ten years within GlaxoSmithKline
• Applied to more than 500 compounds, spanning from early stage lead compounds through launched products
• Team of scientists with diverse backgrounds
— Analytical Chemistry
— Synthetic Chemistry
— Physical Chemistry
— Materials Science
— Crystal Engineering
— Pharmaceutical Sciences
— Automation and Software Development
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Hot Melt Extrusion (HME) - Introduction
HME is used in Pharma to develop Solid Dispersion dosage forms that enhance bioavailability of poorly soluble drugs.
HME is a fast-growing technology, due to recent commercialization of Solid Dispersion HME products
Reasons for HME success:
• Well-understood technology outside of Pharma
• Continuous processing allows good process control & scalability
• Solvent-free (unlike competing Solid Dispersion approaches)
• Extrudate is versatile in its end use, including potential incorporation in controlled release delivery formulations
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Solid Dispersion Products – Melt Approach Common
Product Company Matrix Excipient
Afeditab (nifedipine) Elan Poloxamer/PVP
HPMC
Cesamet (nabilone) Valeant PVP
Rezulin (troglitazone)* Pfizer PVP
PEG
Gris-Peg (griseofulvin) Pedinol PEG
Various
HPMC
Various
PEG-glyceride
PVP/PVA
HPMC
HPMC
Certican (everolimus) Novartis
Fenoglide (fenofibrate) LifeCycle Ph.
Ibuprofen Soliqs
Intelence (etravirine) Tibotec
Isoptin SRE-240 (verapamil) Soliqs
Norvir (ritonavir) Abbott
Kaletra (lopinavir/ritonavir) Abbott-Soliqs
LCP-Tacro (tacrolimus) LifeCycle Ph.
Sporanox (itraconazole) Janssen
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Hot Melt Extrusion – The Basics
• Twin-screw extruders with varying screw design / rotation achieve intimate mixing of drug and excipient
• Shear forces and heat drive melting of excipient, dissolution of API
• Cooled mixture is a Solid Dispersion preferably containing amorphous (non-crystalline) drug
• Process opportunities— Liquid drugs
— Potent drugs— Labile drugs (solvent or moisture sensitive)— Generation of “emulsifying systems”
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OSDrC® OPTIDOSETM Technology: Flexibility to Improve Your Treatments
• OSDrC® OPTIDOSETM Technology
— The broadest range: controlled release, combination products (tablet-within-a-tablet and pellets-within-a-tablet) and direct compression orally disintegrating tablets
— Optimized dosing, therapeutic, and plasma release profiles to meet patient needs in a high quality, one step manufacturing process.
• Broad Range of Tablet Options:
— Pulsatile Release Tablets
— Bi-Layer Tablets
— Combination Products (multiple API in single tablets)
— Dividable Tablets
— IR/ER Combination Tablets
— Direct Compression Orally Disintegrating Tablets (ODT)
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OSDrC® OPTIDOSETM makes it possible to control API release by altering the thickness of the outer coating.
Advantages over film-coated tablets include:
OSDrC® Tablets
• Simplified manufacturingprocess
• No solvents required
• Simplified process control
Controlled Release Based on Thickness of Outer Coating
24July 2011 OSDrC® OPTIDOSETM Technology
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• With conventional technology, enteric tablets could not be divided
OSDrC® Tablets
Target drug release profiles can be maintained, whether thetablets are divided or not
Dividable Core Tablets
26July 2011 OSDrC® OPTIDOSETM Technology
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OSDrC® TabletsReplacing Capsules with Tablets
Capsule Issues
• Cannot be divided
• Difficult to swallow
• Difficult to prevent tampering
July 2011 30OSDrC® OPTIDOSETM Technology
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• Tests have obtained same release characteristics ascapsules
Possible to encase pellets as a replacement for capsules
OSDrC® TabletsReplacing Capsules with Tablets
31July 2011 OSDrC® OPTIDOSETM Technology
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OSDrC® Tablets
Accurate placement of multiple cores makes it possible to manufacture pulsatile release formulations
Pulsatile Release Tablets
33July 2011 OSDrC® OPTIDOSETM Technology
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Nanoparticulate Oral Drug Delivery
Neat API Size-Reduced High-Energy Solid
Liquid API
Disintegrants, Surfactants
Micronized Amorphous,
Solid Dispersion
Softgels, SEDDS, liq.fill caps, etc.
Stability
DissolutionNanosized
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Spraying
• 4 commercial products: Tricor®, Triglide®, Emend®, Rapamune®
• Processed into variety of dosage forms (capsules, tablets) using established technologies
• High excipient:API ratio
• Redispersant excipients required
Freeze Drying
• No commercial products
• Requires specialized equipment
• Low excipient:API ratio
• Highly porous structure favorable for redispersing nano-particles
Nanoparticulate Oral Drug Delivery
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Patient Preferred Zydis® Fast-Dissolve Helps Improve Therapeutic Profile and Patient Adherence
• Zydis® Fast-Dissolve is a unique, freeze-dried oral solid dosage:
— Disperses instantly in the mouth - usually in about 3 seconds
— Taken without water, meeting the needs of patients who cannot or will not swallow oral medications
• Zydis® Fast-Dissolve provides valuable product differentiation for Branded OTC and Rx products: — Fastest dispersion dosage form on the market today combines with an
elegant and smooth mouth-feel to create product and brand loyalty for OTC products
— Immediate dispersion of API in the oral cavity supports buccal delivery for an improved therapeutic profile
— Shown to help drive market share and brand growth gains— Improved compliance in multiple therapeutic areas
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Zydis® Nanoparticulate Formulation Development Goals
1. Nanoparticle stabilization during wet milling AND freeze drying
2. Use of low concentrations of stabilizers with little to no adverse taste
3. Rapid dispersion of nanoparticle solid dosage form
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NAPROXEN Neat API Post milling 24hr hold
Gelatin #1
Gelatin #2
22 micron 164 nm 166 nm
22 micron 177 nm 175 nm
d50 Particle Size measured using Malvern Mastersizer
INDOMETHACIN Neat API Post milling 24hr hold
Gelatin #1
Gelatin #2
37 micron 151 nm 145 nm
37 micron 159 nm 150 nm
Wet Milling with Gelatin as stabilizer
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API concentration 15%w/w
Gelatin concentration 5%w/w
Optional excipients e.g. bulking agent, sweetener, flavor
Dose into blister Freeze
Freeze Dry
pores
ice matrix
Nano-susp.
Nanostabilization in Freeze-Dried Process
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NAPROXEN Neat API Post milling Freeze-Dried
Gelatin #1
Gelatin #2
22 micron 164 nm 167 nm
22 micron 177 nm 21 micron
INDOMETHACIN Neat API Post milling Freeze-Dried
Gelatin #1
Gelatin #2
37 micron 151 nm 142 nm
37 micron 159 nm 30 micron
In-process Particle Size During Milling & Freeze Drying
Similar results for phenacetin and fenofibrate
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0
100
200
300
400
500
600
0 1 2 3 6Time (months)
Part
icle
Siz
e (n
m)
D50 - 25°C D50 - 40°C/75% RHD90 - 25°C D90 - 40°C/75% RH
Nanoparticle Stability in Freeze-Dried Tablets
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Properties of Zydis® NanoparticulateFormulation
Drug Disintegration Time
Naproxen 2 seconds
8 seconds
2 seconds
Fenofibrate (48mg) 4 seconds
5 seconds
Indomethacin
Phenacetin
Fenofibrate (148mg)
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Fenofibrate 48 mg Dissolution in 0.4%SLS - With Pre-filter
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25 30Time (minutes)
Per
cent
Rel
ease
Tricor ZydisNano
In-Vitro Dissolution of Zydis® NanoparticulateFormulation
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Animals – 10Kg Beagle Dogs (n=6), fasted.
Dose – 48mg fenofibrate (human dose)
Test Articles:#1 Nanoparticulate API in tablet
#2 Micron-sized API In tablet
0500
10001500
200025003000
35004000
45005000
0 2 4 6 8
Time (hours)
Plas
ma
conc
(ng/
mL) Zydis-Nano
Zydis As-is
In-Vivo PK of Zydis® Nanoparticulate Formulation
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Softgel Technology
Good NCE Candidates• Poorly water soluble• Poorly permeable• Highly potent, low dose• Oxygen sensitive• Light sensitive• Liquid or low melting pointAdvantages of the Dosage Form• Proven technology• Robust dosage form (no brittleness or leaking)
• Appropriate for low to high viscosity formulations (up to ~15,000 cps)• Fill formulation temperatures up to ~40°C for gelatin-based softgels
and up to ~70°C for Vegicaps® Capsules• Minimal to no scale-up issues
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Colors,
Opacifiers,
Flavors
Composition of a Softgel Capsule
Lipophilic,Hydrophilic,
or Mixed Vehicle
Solution, Suspensionor highly viscous formula of Drug
GELATIN +
Plasticizerwater
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Polyethylene glycolsurfactants
Hydrophilic”water-loving"
Partial glyceridesSurfactantsFatty acids
Microemulsion"self-emulsifing systems"
OilsFatty acidsGlycerides
Partial glycerides
Lipophilic"oil-loving"
Solution, suspensionor semi-solid
The fill material can be a…
Softgel Fills
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Solubility Screening
• Solubility prediction
• Visual and quantitative solubility determination
• Use of robotics
Identification of SMEDDS/SNEDDS regions
• Pseudo-Ternary Phase Diagrams
SMEDDS Droplet Size Assessment
• Photon Correlation Spectroscopy @37°C
Digestibility
• In vitro lipolysis
Key Elements of a Softgel Formulation Development Program
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Dispersion Properties • 0.01N HCl• Neutral buffered solution
Challenge Studies • Temperature
— Cycling studies— Holding studies
• Water • Plasticizer• Characterization of precipitate
Compatibility Studies
• API:excipient mixes @ 40°C/75%RH, 50°C/Dry, 60°C/Dry
• Fill stability
Key Elements of a Fill Formulation Development Program
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Formulation of Lipid-based Fills…The Choice of Excipients Can Impact Performance
Nature of Lipid
• Lipids that can dissolve the drug
• Lipids (or their digestion products) have good solvent capacity to maintain drug solubility through the G.I.T.
Type of Surfactant
• Surfactants that can dissolve the drug
• Surfactants that maximize dispersion of the lipid phase
• Surfactants that can impact digestion negatively or positively
• Susceptibility of surfactant to digestion and its impact on solubilization capacity of formulations
Relative Proportion of Lipid to Surfactant
• Solubilization capacity of formulations before and after digestion
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Addressing Formulation Challenges Beyond Solubility Improvement
• Lipid-based formulations affect membrane permeability
— Passive transport through enterocytes
— Passive transport around enterocytes (tight junctions)
• Lipid-based formulations interact with intestinal-based drug transporter and metabolic processes
— P-gp efflux
— CYP3A4 metabolism
• Lipid-based formulations influence absorption pathways
— Lymphatic transport
Softgels for Permeation Enhancement
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Plasma Concentration Versus Time Curves for 3 Formulations of Cinnarizine in the Dog (n=6)
Time (hours)
Plas
ma
Cin
nariz
ine
(ng/
ml) 150
00 2 4 6 8 10 12 14 16 18
100
50
20 22 24
Formulations:Softgel: LCT Lipolysing AUC(0-24hr) 665 ng.h/mlSoftgel: Non-Lipolysing AUC(0-24hr) 451 ng.h/mlTablet: AUC(0-24hr) 406 ng.h/ml
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LBDS for Solubility and Permeability EnhancementExample: Amprenavir With Vitamin E TPGS
Ref: L.Yu, et al., Pharm. Res., 16: 1812 (1999)
Amprenavir absorption flux as a function of Vitamin E-TPGS concentration.
Amprenavir solubility as a function of Vitamin E-TPGS concentration in pH 7 phosphate buffer, ionic strength 0.15M.
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Softgels for Altering the Route of Absorption
Lipid in SMEDDSLymphatic transport
Plasma availability
Total bioavailability
% of total bioavailability due
to lymphatic transport
MLM 17.9±1.3 56.9±5.5 74.9±6.0 24.4±1.9
LML 27.4±1.3 37.2±6.2 64.6±7.1 43.3±3.1
Halofantrine bioavailability (mean % dose ± s.e., n=4-5) in lymph-cannulated canines after oral administration of SMEDDS formulation containing structured triglycerides
SMEDDS Formulation (%w/w)Halofantrine 5%Triglyceride 29%Maisine-35-1 29%Cremophor EL 20%Ethanol 7%
TriglycerideMLM (C8:0-C18:2-C8:0)LML (C18:2-C8:0-C18:2)
Ref: R.Holm, et al., Eur. J. Pharm. Sci., 20: 91 (2003)
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• Post-gastric (targeted) drug delivery
• Protection of acid-labile drugs from gastric fluids
• Reduced local gastric side effects
• Potential for enhanced drug absorption— Rapid release of fill contents at targeted site of delivery following
dissolution of film coat— High local concentrations of API and permeation enhancers
Film-coated Softgels for Targeted Delivery
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Film-coated Softgels for Targeted Delivery
USP <701>
T=0 T=3 mon T=6 mon T=9 mon T=12 mon
SGF, n=6
No evidence of disintegration
No evidence of disintegration
No evidence of disintegration
No evidence of disintegration
No evidence of disintegration
SIF, n=6
26 – 28 22 – 26 25 – 30 25 – 29 23 – 25
In-vitro Disintegration(min)
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Softgels for Targeted Delivery of Large Molecules
BCS Class III NCE
– MW > 2,500 Da
– Over 10 ionic groups
– Poorly permeable
– Freely soluble
Drug is not subject to enzymatic degradation
SC injection show complete absorption
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36Catalent Pharma Solutions data
EC softgel passing the pylorus to deliver proper absorption (78 % bioavailability)
time
Softgels for Targeted Delivery of Large Molecules
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Vegicaps® Capsules –The Only True Non-gelatin Softgel Option
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Non-gelatin based shell using plant-derived polysaccharides
Supports encapsulation of liquid fills, including lipid-based and hydrophilic formulations
Vegicaps® capsules expand the capabilities of softgel technology by enabling:
Vegicaps® Technology: Expands the Range of Fill Formulations Encapsulated into Softgels
• High melting point and sealing temperature of semi-solid fills for modified release (up to 70°C), improved stability, and conversion from hard-shell capsules
• Fill formulations prone to cross-linking hard or soft gelatin-derived capsules
• Compatibility with high pH fill formulations, and a broader range of fill excipients
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Differences in the properties of the Vegicaps® shell expands the capabilities of softgel technology
• Self-emulsifying formulations can be formulated with higher concentrations of “low” m.w. ingredients
• Co-solvents (propylene glycol)
• Solubilizers
• Penetration enhancers (Na caprate, lauric acid and its salts)
• Example: Octanoic acid (caprylic acid, C8)
Vegicaps® Technology: Expands the Range of Fill Formulations Encapsulated into Softgels
Softgels filled with ‘neat’caprylic acid
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