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The world leader in serving science
Rational Selection of Excipients For Improving The Bioavailability of Poorly Soluble Drugs: A Case Study
Sanjay Konagurthu, PhDSenior Director, Global Science and Technologies
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Today’s Environment: Increasing Complexity, Increasing Risks
70 – 90%
Solubility and bioavailability
challenges
30%
Phase I
14%
Phase II
8 – 9%
Phase III / NDA
Source: http://www.fdareview.org/03_drug_development.php
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A Better Approach Exists to Being ‘Phase Ready’
Traditional Approach Quadrant 2®
Duration to get to Phase 1 CTM (14 to 19 months) Duration to get to Phase 1 CTM (8 to 9 months)
Phase ready Phase ready
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Novel Quadrant 2® Program Solves This Dilemma
API chemical structure
Physicochemical properties
Business andclinical objectives
Technology selection
Patheon’s exclusivecomputational modeling
Technology selection
Excipient selection
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Quadrant 2® Technology Selection Process
API chemical structureSize reduction
Dispersion – Spray drying
Amorphous
Dispersion - HME
Dispersion – Coated beads
Lipids
Complexes
Patheon’s exclusivecomputational modeling
API chemical structure
Physicochemical properties
Business andclinical objectives
Patheon’s exclusivecomputational modeling
Excipient selection
Technology selection
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Quadrant 2® Technology Selection Process
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Quadrant 2® Excipient Selection Process
API chemical structure
Physicochemical properties
Business andclinical objectives
Technology selection
Excipient selectionExcipient selection
Patheon’s exclusivecomputational modeling
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Quadrant 2® Excipient Selection Process: Amorphous Dispersion Example
Computer simulation ofdrug and excipient
Solid state
• Hydroxypropyl methylcellulose (HPMC)• Hydroxypropyl cellulose (HPC)• Carboxymethyl ethylcellulose (CMEC)• Cellulose acetate phthalate (CAP)• Hydroxypropyl methylcellulose phthalate (HPMCP)• Hydroxypropyl methylcellulose acetate succinate
(HPMCAS)
Cellulosic Polymers• Poly(butyl methacrylate, (2-dimethylaminoethyl)
methacrylate, methyl methacrylate) (Eudragit E)• Poly(methacrylic acid, methyl methacrylate)
(Eudragit L100)• Poly(methacrylic acid, ethyl acrylate (Eudragit
L100-55)• Poly(methacrylic acid, methyl methacrylate)
(Eudragit S100)
Polymethacrylate Polymers
• Surfactants• Plasticizers• Permeation enhancers
Additives
• Polyvinyl pyrrolidone (PVP)• Polyvinyl alcohol (PVA)• Polyvinylcaprolactam-polyvinyl acetate-PEG
graft copolymer (Soluplus®)• Polyvinyl acetate phthalate (PVAP)• Polyvinylpyrrolidone-polyvinyl acetate
(PVP-VA) copolymer
Polyvinyl Polymers
API chemical structure
Physicochemical properties
Business andclinical objectives
Technology selection
Patheon’s exclusivecomputational modeling
Excipient selection
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Drug molecule – Run models & identify descriptors
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Polymer Selection – Identify complementary descriptors
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Molecular Dynamics Simulations
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Dipyridamole loading in HPMCAS-M (Spray-dried Amorphous Dispersions)
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Selection of Excipients for Lipid-based Formulations - Example
• Predicted lipid-excipient solubility provides a guideline for the feasibility of a lipid-based formulation (e.g. soft-gel, LFHS).
Indomethacin
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Accuracy
Quadrant 2® Technology And Excipient Selection: Proven Accuracy
Calcitriol (Rocaltrol) – LipidsItraconazole (Sporanox) – Coated
Beads and (Onmel) - HME
Technology Selection
Excipient Selection
90%
80%
Validated with over 150 drug products
Posaconazole (Noxafil) – HME
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Getting Started Is Quick And Easy
SME consultation
Business and clinical
objectives
SME review
Comprehensive report with path
forward
2 weeks
Patheon’s exclusivecomputational modeling
API chemical structure
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PK results
Quadrant 2® Is Part of Overall Approach to Accelerate the Timeline to Clinic
Computational modeling(2 weeks)
Preclinical development(6 to 8 weeks)
Early clinical studies(4 to 6 months)
SME consultand feasibility
proposalFeasibility studies and PK supplies First in human development and manufacturing
Product life cycle
Formulation services
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Patheon Has the Capabilities to Address the Needs of Your Molecule
Addressing the overwhelming majority of solubility challenges
Amorphous DispersionsSoftgels
Liquid Hard Shell
SprayDrying
Hot Melt Extrusion
CoatedBeads
Size Reduction
Lipids
Complexes
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Quadrant 2® is Part of Integrated Process to Get Your Molecule to Clinic, Fast
Work smarter and faster, not harder
Exclusive computational model
Validated and highly accurate
Scientifically-based recommendations
Expert consultation
Broad formulation capabilities
Quick to clinic Global networkProven record of
approval
150+2 weeks
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10 Centers of Excellence, One Global Network
Whitby,Canada
Center of Excellence for Scale Up
Toronto,Canada
Center of Excellence for Highly PotentProducts
Cincinnati, OHUSA
Center of Excellence for Controlled Release & Controlled Substances
Bend, ORUSA
Center of Excellence for Solubility
Highpoint, NCUSA
Center of Excellence for SoftgelsEnhancement
Greenville, NCUSA
Center of Excellence for Sterile and Oral Solid Dose Development
Bourgoin,France
Center of Excellence for Mid & Late stage OSD Development
Ferentino,Italy
Center of Excellence for Sterile liquid and lyophilized product development
Tilburg, Netherlands
Center of Excellence for Softgels &Solubility Enhancement
Milton Park,UK
Center of Excellence for Early Development and Solubility Enhancement
75+ Markets
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Case Study – Client X
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In-Silico Selection of Polymers for Compound X
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ASD formulations – Compound X:Polymer
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Spray drying Amorphous Solid Dispersion Formulations
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Compound X : PVAP in vivo data (dogs)
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Compound X Spray Drying Scale-up
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Design of Experiments (DOE) around Spray-drying Process
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Dosage Form Design Space – Choice of Tableting Excipients
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Formulation and Process Considerations for a Tablet
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Excipient Selection for a Tablet – Mechanical Properties
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Tabletability – Different Excipients
Presster: Dwell time 27 mSec (+0.5% Mg Stearate)Tye, Sun, Amidon, J.Pharm.Sci. 94(3), 465-72 (2005)
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Compaction Simulation to Guide Excipient Selection
Heckel Analysis
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Compound X - Dosage Form Development and Scale-up
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200-250 mgA Tablet Formulation Compound X
Parameter Value
Tooling 3750'' x 7480''Weight (mg) 1031
Weight (%RSD) 1.9Thickness
(mm)7.94
Hardness (kP) 19.1Friability (%wt ) 0.11Disintegration
Time (min)~2.0
Material Trade Name Percentage
SDI 40% X: HPMCAS‐L 50%
Mannitol Parteck M 100 28.50%
MCC Avicel PH101 13.50%
Croscarmellose Sodium Ac‐Di‐Sol 6%
Silicone Dioxide Cabo‐Sil M5P 1%
Magnesium Stearate (I.G.) Mg Stearate 0.50%
Magnesium Stearate (E.G.) Mg Stearate 0.50%
40% Cmpd X:HPMCAS‐L Tablet Formulation
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Phase 1 PK Study – Improved Bioavailability
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Summary
• Quadrant 2® provides a streamlined approach for technology and excipient selection.
• Rational strategy for excipient selection Improved solubility/bioavailability.
• Formulation strategy for dosage forms based on excipient mechanical properties.
• Scale-up and process development is critical to a program’s success.
• Reduced experimentation saves time/costs to FIH clinical trials.
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Thank You