an innovative approach to solubility enhancement …...an innovative approach to solubility...
TRANSCRIPT
The world leader in serving science
An Innovative Approach to Solubility Enhancement – Quadrant 2®
Jason M Vaughn, PhD
Senior Director
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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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Bioavailability: A Multi-Factorial Perspective
Bioavailability
Delivery Tools
• Solid dispersions
• Lipids (SEDD)
• Solubility enhancers
• (complexation, solutions)
• Excipients
• Nanoparticles / Micronization
• Particle engineering
API + Formulation
• API Solubility
• Particle size
• Crystal form
• Salt form
• Crystallinity
• GI activity
• Passive transport
• (trans/para cellular)
• Efflux substrates
• CYP substrates
Kinetics in GI
• Dispersion
• Dissolution
• Passive transport
• Active transport
• Efflux
• Metabolism
• Excretion
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• Multi-factorial challenges
• No one solution works for all molecules
• Need to consider integrated solutions
• Solid-state properties
• Biopharmaceutics
• Physiological factors
• Formulation design and delivery system
• Time/cost sensitive
Bioavailability Enhancement
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Solubilization• Solubility enhancers
• Complexation
• Lipids
• Surfactants
• Microenvironment
• Amorphous API
Solid Dispersion • Spray drying
• Hot melt extrusion
• Hot melt granulation
• Fluidbed layering
• Spinning disc
• Spray congealing
Size Reduction• Micronization
• High energy milling
• SEDD
• Microemulsions
Bioavailability Improvement Techniques
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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 and
clinical objectives
Technology selection
Patheon’s exclusive
computational modeling
Technology selection
Excipient selection
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Quadrant 2® Technology Selection Process
API chemical structure
Size reduction
Dispersion – Spray drying
Amorphous
Dispersion - HME
Dispersion – Coated beads
Lipids
Complexes
Patheon’s exclusive
computational modeling
API chemical structure
Physicochemical
properties
Business and
clinical objectivesPatheon’s exclusive
computational modeling
Excipient selection
Technology selection
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Quadrant 2® Technology Selection Process
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• Chemical structure • Melting Point
• Molecular Weight
• LogP or calculated ALogP
• Known or Calculated pKa
• Known or Calculated solubility
Inputs into Quadrant 2
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Technology Assessment is Dose Dependent
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Quadrant 2® Excipient Selection Process
API chemical structure
Physicochemical
properties
Business and
clinical objectives
Technology selection
Excipient selectionExcipient selection
Patheon’s exclusive
computational modeling
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Quadrant 2® Excipient Selection Process: Amorphous Dispersion Example
Computer simulation of
drug 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 and
clinical objectives
Technology selection
Patheon’s exclusive
computational 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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Example Drug Loading Assessment for Various Excipients in ASD
Polymer Predicted Maximum
Drug Loading (%)
Recommended Maximum
Drug Loading Range (%)
HPMC 36 35%-50%
PVP VA 64 40 35%-50%
Soluplus 49 40%-60%
HPMCAS-M 40 35%-50%
HPMCP-HP55 39 35%-50%
Eudragit L100-55 39 35%-50%
It should be noted that the predicted maximum drug loadings are based partially on
when the potential for drug-drug nucleation is observed.
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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 exclusive
computational 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 consult
and feasibility
proposal
Feasibility studies and animal PK
suppliesFirst 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
Spray
Drying
Hot Melt
Extrusion
Coated
Beads
Size
Reduction
Lipids
Complexes
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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 - Dosage Form Development and Scale-up
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Phase 1 PK Study – Improved Bioavailability
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Summary