Model-based Technology Selection for Bioavailability Enhancement CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017
Biopharmaceutical Classification System Approximately 80% of drugs in the pharmaceutical compounds pipeline exhibit low solubility and fall into the Biopharmaceutics Classification System (BCS) Class II or IV with the majority of these compounds being Class II (poor solubility, high permeability). 2008;7:255 270 CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 2
Important Properties to Define Problem Statement Dose / Dosage Format Solubility Lipophilic/ Hydrophobic / Ionic Structure/ MW Pharmacokinetics / Pharmacodynamics Pre-systemic metabolism CYP3A4 P-gp Efflux Bi-layer Permeability Polar Surface Area CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 3
Problem Statement Definition Guides Technology Choice Goal is to efficiently arrive at product development with certainty of approach SDD LIPIDIC NXSTAL Product Concept HME Technology/Formulation Molecule Problem Statement Prediction Product Development In vitro, in silico, & in vivo testing CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 4
Many Enabling Technologies Are Available Solid-State Alteration: Form, Particle Size Polymorphs New crystal compound Solid dispersions SDD, HME Cocrystals Lyophiles Salts Drug/polymer nanoparticles Nanocrystals (200 to 800 nm) Nanocrystals (<50 nm) Solvation, Complexation Cosolvents Surfactants Cyclodextrins Lipids: Oils SEDDS/SMEDDS Solid lipid pellets CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 H.D. Williams et al. Strategies to Address Low Solubility in Discovery and Development, Pharmacol Rev, 65(2013)315-499 CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 5
Conceptual Guidance Map for Technology Selection Based on Molecular Properties and Dose H.D. Williams et al. Strategies to Address Low Solubility in Discovery and Development, Pharmacol. Rev., 65(2013), 315-499 CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 6
Proposed Lipid/Amorphous Dispersion (ASD) Technology Guide Bioavailability Attribute Lipid ASD Comments Increase & Sustain Solubility X XX Reduce Efflux XX X Induce Fed State Promote Lymphatic Absorption Reduce Luminal Metabolism Decrease Hepatic Metabolism XX XX XX Reduce Food Effect X X X X X Primary ASD Performance Differentiator ASD Fasted Absorption Lipids Fed State Selected Other Attributes Lipid ASD Comments Tablet (Bias, capitalization) Patient Perception Commercial Precedence XX XX Dose per volume X XX IP Combine w/ Modified Release X X X XX 70% of oral DF are tablets ASDs Kinetic Lipids Thermodynamic Coatings, Osmotics, Matrix Critical Lipid Differentiators Critical ASD Differentiators CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 7
In Vitro Dissolution Testing is a Critical Tool for Assessing Oral Drug Product Bioperformance? source: M. Blewett CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017
Amorphous Enhancement & Polymer Sustainment Amorphous solubility defines solubility advantage for ASDs Polymer sustainment identifies excipient interactions & lead crystallization inhibitors CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 9
Membrane Test Compares ability of formulations to enhance free drug concentration at membrane surface Able to properly account for micelle, colloid, and particle contribution to boundary layer diffusion and dissolution rate Stewart et al. Mol. Pharmaceutics 2017, 14, 2032-2046 CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 10
Digestion Test Digestion tests are used to identify those formulations at low risk of showing drug precipitation in the intestine Provides a performance-based means to select lead formulations Measure digestion by titration Dosing units Sample and measure drug fate by HPLC Overhead stirrer ph probe Oil A q Pelle t Reaction vessel CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 11
Gastric Stomach Duodenum Transfer Test Investigate interplay of gastric environment and precipitation with continual drug transfer UV Detection Example Precipitation of a Weak Base with and without Polymer CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 12
In Vitro Testing is Based on the Formulation Approach and Risk Assessment Example of Using a Risk-Based Approach to In Vitro Testing (Compound X SDD) Preliminary Assessment Problem Statements ASD Screening Refined Problem Statements LogP Tm, Tg, Tm/Tg pka Aq. Sol Amorphous. Solubility Organic solubility Dose Gastric ph effect? MAD calculation Gastric ph Dependent Dissolution Low Solvent Solubility Crystallization-Storage Chemical Degradation-Processing Chemical Degradation-Storage 3-5 small scale SDDs mfr d SEM, PXRD DSC vs.rh Purity/assay UV transfer disso, multiple gastric ph Gastric ph Dependent Dissolution Low Solvent Solubility Crystallization-Storage Chemical Degradation-Processing Chemical Degradation-Storage Precipitation Stomach (high ph) Precipitation Intestine Good formulation approach identified before investing lots of Time and Money here Detailed Assessment of Performance, Stability, and Manufacturability CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 13
14 Case Studies CPHI DAVID K. LYON, PH.D. October 25, 2017
Celecoxib Physicochemical Properties SDD NSAID Lipid Properties MW 381 LogP 4 T m 163 C T g 60 C T m /T g (K/K) 1.3 pk a (Acidic) 11 Aqueous Solubility (µg/ml) 0.01N HCl ph 2 ~10 PBS ph 6.5 ~10 FaSSIF ~50 PK Dose (mg) 400 Permeability, P app High Efflux No Pre-systemic metabolism No CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017
In Vitro and Clinical Performance of 50% Celecoxib: HPMCAS-L SDDs Formulation: Evaluated multiple formulation options varying polymer and process (HME) 50% HPMCAS-L selected as lead due to dissolution rate Species are colloidal, dissolved, and micellar drug Performance: Supersaturation sustains through 50 minutes in µdisso test (worst case) Supersaturation ratio is measured at approximately 10x vs crystalline. Colloidal drug present appears larger Clinical data shows rank order increase but not IVIVC In Vitro Dissolution Clinical PK Data CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017
Lipid Formulation Provides Limited BA Enhancement Lipid Formulation Celebrex CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 N. Subramanian et al. Biol. Pharm. Bull. 27 (12) 1993-1999 (2004) CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 17
Increased Bioavailability and Rapid Onset using Amorphous Nanoparticles 1:1 Celecoxib : Ethyl Cellulose NP in Casein HPMCAS based SDD Commercial Capsule Morgen, M.M., et al., Pharm. Res., 29:2(2012) 427-440 CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 18
Technology Feasibility Program for Compound A SDD Lipid Physiochemical Properties MW ~500 LogP 5 T m T g ~150 C ~30 C T m /T g (K/K) ~1.4 pk a (Basic) ~5 Aqueous Solubility (µg/ml) 0.01N HCl ph 2 ~20 PBS ph 6.5 <1 FaSSIF ~20 FeSSIF ~150 PK Dose (mg) ~ 400 Bioavailability (fasted) 10% Food Effect Up to 10x CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017
Summary of SDD Performance in Feasibility Formulation: Evaluated 7 SDDs. 25 50A% using 3 grades HPMCAS, PVPVA and HPMC 25-50A% HPMCAS-L selected as lead Aggressive loading compromised with dose & pill burden Performance: Supersaturation sustains through 30 minutes in GB-IB dissolution test Supersaturation ratio is measured at approximately 20x vs. crystalline Particle size and active loading affect dissolution rate CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 20
Follow-up Dissolution Testing Suggests Rapid Precipitation with Slow Crystal Growth UV method developed to independently track concentration of dissolved drug and nanocrystalline drug Independent light microscopy confirms rapid formation of small drug crystals CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017 21
Summary Lipid Performance in Feasibility Digestion of lead formulations under simulated fasted state conditions: No evidence of precipitation before start of digestion Two lead formulations identified that effectively inhibit crystallization Supersaturation ratio is approximately 20x relative to crystalline in FaSSIF CPHI DAVID K. LYON, PH.D. October 25, 2017 22
Technology Comparison of Compound A at 250 mg Dose (Canine, N=6) Key findings: LFHC and LMP technologies give the highest BA increase (~10 x relative to commercial product), reducing the food-effect to ~1.6x at the 250 mg dose High exposure in the fasted state when using LFHC or LMP suggests strong possibility of a significant dose reduction Variability was lowest for LMP technology Commercial Product Fasted SDD Fasted (2x 125mg tablets) T6-LFHC Fasted (3x 83.3mg capsules) Commercial Product Fed LMP Fasted (4x 62.5mg capsules) CPHI DAVID K. LYON, PH.D. October 25, 2017 23
Summary Thoughts Formulation selection can be challenging for certain compounds in silico tools, in vitro tools, and historical experience can be used to focus on technologies and formulations with highest possibility of success Developing an in vivo predictive dissolution test requires understanding rate limiting step(s) to absorption Developing in vitro and in silico tools to directly compare critical performance attributes of different enabling technologies will enable more certainty in selection of the approach Building historical data set with multiple technologies will lead to improved technology selection based on: Product concept Physicochemical properties in vitro tools CPHI DAVID K. LYON, PH.D. October 25, 2017 24
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