Slide 1: Formulation Selection and in-vitro Screening for Oral Bioavailability Enhancement
Formulation Selection and in-vitro Screening for Oral Bioavailability Enhancement David K. Lyon, PhD Sr. Fellow, Global R&D ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019
Slide 2: Talk Outline
Talk Outline Low Oral Bioavailability Case Study #1 Case Study #2 Case Study #3 Summary and The available solutions Grease ball compounds Brick dust compounds Highly Loaded Take Away Points The new issue – which (abiraterone acetate) (itraconazole) Dosage Forms technology is best for my (posaconazol
Slide 3: Changing Landscape in Pharmaceutical Development
Changing Landscape in Pharmaceutical Development… Smaller companies Accelerated timelines driving innovation to market More complex, Shift to Uncertain in- highly potent specialized, market demand molecules enhanced drugs ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019 3
Slide 4: Small Pharma Companies are Driving Drug Innovation
Small Pharma Companies are Driving Drug Innovation Pipeline source: Citeline 11/2018; Special designations – total count of all regions by Biomedtracker 11/2018 ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019 4
Slide 5: Small Innovators are Increasingly Commercializing their Drug Products
Small Innovators are Increasingly Commercializing their Drug Products … vs. selling to or partnering with big pharma ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019 5/8
Slide 6: Outsourcing Trends Have Accelerated Accordingly
Outsourcing Trends Have Accelerated Accordingly Drivers of CDMO Outsourcing Growth • Small cos. tend to use partnering business models for development and manufacturing • Candidate molecules and target product profiles are more complex and can required more specialized enabling technologies to advan
Slide 7: Time is critical, time is money
Time is critical, time is money… Single service provider can provide for … • One point of contact • One service agreement • Coordinated problem-solving • Coordinated phase-appropriate approach • Ease of technology transfer • Ease of meeting timeline commitments ©Lonza Pharma & Biotech | AAPS Present
Slide 8: Lonza's global development & manufacturing network
Lonza’s global development & manufacturing network Europe • Edinburgh, UK APAC North America • Ploermel, France • Bend, OR • Mollinazzo, • Nansha, China • Quakertown, Switzerland PA • Visp, Switzerland • Tampa, FL 3 Regions 8 Sites • Full Chemistry (API) Capability drug substance intermediates and A
Slide 9: The Ongoing Issue
The Ongoing Issue Low solubility continues to plague development pipelines BCS Class I, 10% BCS Class IV, 25% Reference: BCS Class III, Drug-Like Property Concepts in Pharmaceutical Design, Di, Li; Kerns, BCS Class II, 15% 50% Edward H.; Carter, Guy T. In Current Pharmaceutical Design, Volume 15, Nu
Slide 10: Putting Low Drug Solubility in Context
Putting Low Drug Solubility in Context Venus de Milo Itraconazole (Marble, 100 B.C.) (PWSD) Solubility in water: Solubility in water: 14 µg/ml ~14 000 x ~1 - 4 ng/ml more water soluble than ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019 10
Slide 11: Putting Low Drug Solubility in Context
Putting Low Drug Solubility in Context Primary obstacles to low solubility Solid-state Solvation “Brick dust” “Greaseball” compounds compounds • Very strong crystalline lattice energy (1) is limiting to • Very low affinity for water (3) is limiting to solubility solubility • Address by changing the
Slide 12: Bioavailability Enhancement Platforms
Bioavailability Enhancement Platforms Formulators have access to a number of enabling technologies Enhanced Formulations Products • Applicable to broad compound space. Complementary • Preferred industry solutions, with proven ability to solve solubility related problems • Significant commercial prec
Slide 13: Marketed Amorphous Solid Dispersions Products
Marketed Amorphous Solid Dispersions Products Dr. Shaukat Ali 2012 Dr. Karl Kolter Lonza Pharma, Biotech and Nutrition | Webinar | October 23, 2019
Slide 14: Which Technology To Select for Which Compound?
Which Technology To Select for Which Compound? Why it is an important question…. Matching your compound with the wrong technology Exploring all possible technologies in parallel Challenging development Complex development Increase development time and costs Higher resource requirement (API, costs) H
Slide 15: Which Technology Should I Select for Which Compound?
Which Technology Should I Select for Which Compound? The issue faced by formulators • What technology is best for my compound? • How to approach? o Trial and error o Physical-Chemical-Biological Property Review o Decision trees – Fridgeirsdottir GA et al., Journal of Pharmaceutical Sciences 2016, 10
Slide 16: Technology Mapping and Compound Qualification
Technology Mapping and Compound Qualification Science-based approaches to selecting a technology for your compound Guidance Maps Compound and product qualification Log P/Log D Tm / Tg ratio Solubilities Polar surface area Dose pKa Effect of food Intestinal Metabolic permeability pathway P-gp Bioavai
Slide 17: In Vitro Dissolution Testing is a Critical Tool for Assessing Oral Drug Product Bioperformance
In Vitro Dissolution Testing is a Critical Tool for Assessing Oral Drug Product Bioperformance ? source: M. Blewett ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019 17
Slide 18: In vitro Performance Characterization Should be in vivo Relevant (ASDs)
In vitro Tools In vitro Performance Characterization Should be in vivo Relevant (ASDs) Amorphous Solubility Dissolution Flux Stomach → Duodenum • Amorphous “solubility” • Precipitation risk • Polymer selection • Drug/polymer interaction • Amorphous “solubility” • Dissolution rate • Clean measurement
Slide 19: Digestion Test (LBF)
In vitro Tools Digestion Test (LBF) 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 Dosing units Sample and measure drug Example Digestion Data by titra
Slide 20: In Vitro Performance Tests
In vitro Tools In Vitro Performance Tests In vitro performance tests for LBFs & SDDs • In vitro performance tools are essential and should be used during formulation development o Identify key obstacles to API solubilization o Screen-out poorly performing / variable formulations o Reduce risk of pro
Slide 21: Case Study 1: Abiraterone Acetate
Case Study 1: Abiraterone Acetate ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019
Slide 22: Compound & Product Analysis
CASE STUDY #1 Compound & Product Analysis Abiraterone acetate Compound property Value Log P 5.12 Aqueous solubility 1 µg/ml Tm 147-148°C Abiraterone acetate pKa 5.2 (base) Permeability Low, non P-gp substrate BCS Class Class IV at current dose Product feature Zytiga® (Janssen) Yonsa® (Churchill) Use
Slide 23: Enabling Technology Head-to-Head Comparison
CASE STUDY #1 Enabling Technology Head-to-Head Comparison Development strategy In vivo validation Define formulation design criteria Parallel formulation development • Maximize solubilized/supersaturated Lipid-based formulation Spray-dried dispersion drug at pH 6.5 • Physically stable • Max 4 dosage
Slide 24: LBF and SDD Development Snapshot
CASE STUDY #1 LBF and SDD Development Snapshot Abiraterone acetate Lipid-based formulation Spray-dried dispersion Dispersion testing Digestion testing Initial LBF concept formulations designed with aid of compound SDDs tested in gastric intestinal buffer stress test qualification and Lipidex® syst
Slide 25: In Vivo Head-to-Head Technology Comparison
CASE STUDY #1 In Vivo Head-to-Head Technology Comparison Abiraterone absorption from SDDs and LBFs in dogs LBF Underlying mechanisms: 2000.0 5000 Plasma abiraterone (μg/ml) • Ongoing solubilization required to 3750 offset low permeability AUC(0-24h) 1500.0 Zytiga® SDD 2500 • Drug has very high solub
Slide 26: LBF Optimization & Food-Effect Elimination
CASE STUDY #1 LBF Optimization & Food-Effect Elimination Can a LBF eliminate the abiraterone acetate food-effect? In vitro performance strategy Target Product Profile • Use existing in vitro and in vivo data as performance benchmark • >4-fold increase in exposure for significant dose reduction • Foc
Slide 27: Eliminating the food effect
CASE STUDY #1 Eliminating the food effect Lipid-based formulation offers a significant advantage • In vivo performance of Zytiga® tablets (250 mg) vs. optimized lipid-based formulation (50 mg) in beagle dogs (n=6): • 10-fold food-effect ✓ Matched Zytiga® fasted state exposure at 1/5th dose • Low and
Slide 28: Case Study 2: Itraconazole
Case Study 2: Itraconazole ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019
Slide 29: Compound & Product Analysis
CASE STUDY #2 Compound & Product Analysis Itraconazole Compound property Value Log P 5.7 Aqueous solubility 1-4 ng/ml in PBS Tm and Tg 167°C & 59°C pKa 3.7 (base) Permeability 3.29 ± 0.85 x 10-6 cm = Good permeability BCS Class Class II at current dose Itraconazole Product feature Sporanox® (Janssen
Slide 30: In Vivo Head-to-Head Technology Comparison
CASE STUDY #2 In Vivo Head-to-Head Technology Comparison Itraconazole absorption from solid dispersions and LBFs in rats 500.0 8000 AUC0-24h 6000 Underlying mechanisms: Plasma itraconazole (ng/ml) 400.0 4000 2000 • ITZ affinity for lipids / lipid 300.0 Sporanox® 0 colloids (3) is too little to off-
Slide 31: Hydrophilic SDD has the highest flux in vitro
CASE STUDY #2 Hydrophilic SDD has the highest flux in vitro Membrane Permeability Test No. Formulation Dispersion polymer Flux (µg/min/cm2) Colloid (µg/ml) 1 25% ITZ/75% HPMCAS SDD AFFINISOL 716HP 1.18 602 2 25% ITZ/75% HPMCAS SDD AFFINISOL 126HP 0.85 150 3 Sporanox® spray layered dispersion HPMC 0.
Slide 32: Optimizing Itraconazole Absorption from SDDs and LBFs
CASE STUDY #2 Optimizing Itraconazole Absorption from SDDs and LBFs Sprague-Dawley rats Greaseball N=4, ± SD, 20 mg/kg 1250.0 Sprague-Dawley rats Plasma itraconazole (ng/ml) N=6, ± SD LBF using ITZ 50 mg/kg 1000.0 lipophilic salt form 750.0 Salt formation 500.0 Sporanox® 250.0 LBF suspension Brick d
Slide 33: Case Study 3: High Loaded ASD Dosage Forms
Case Study 3: High Loaded ASD Dosage Forms ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019
Slide 34: High Loaded Dosage Forms (HLDF) Initiative
CASE STUDY #3 High Loaded Dosage Forms (HLDF) Initiative Strategies are needed to reduce pill burden of ASD drug products > 50% FDA-approved ASD drug products Large tablets are often needed for ASD drug products have doses > 100 mg 6 Number of approved ASD drug products 5 4 3 Capsules Tablets 2 1 0
Slide 35: High Loaded Dosage Forms (HLDF)
CASE STUDY #3 High Loaded Dosage Forms (HLDF) Novel architecture can allow us to access a new formulation space High loaded SDD in high Concentration Tg dispersion polymer sustaining polymer (e.g. Eudragit L100) (e.g. HPMCAS-H) HLDF Granulate (or add extra-granularly) Benchmark approach dispersion p
Slide 36: Comparison of PMMAMA and HPMCAS
CASE STUDY #3 Comparison of PMMAMA and HPMCAS Enteric Polymers with different properties and applications Eudragit L100 HPMCAS H OR CH2 OR O H H O OR H H OR H H H O O H Structure CH 2OR R= -H H -CH2 CHCH3 OR n -CH 3 -COCH 3 OCOCH 3 -COCH 2CH 2CO2 H -CH2 CHCH3 -CH 2CH(OH)CH 3 OCOCH2 CH 2 CO2 H Affini
Slide 37: Demonstrate HLDF in vivo – Posaconazole study in dogs
CASE STUDY #3 Demonstrate HLDF in vivo – Posaconazole study in dogs Beagle dogs (n=6), pentagastrin pre-treatment, crossover design, 100 mg dose Posaconazole (BCS 2 weak base) ≥ > > > 400 mg HLDF 250 mg HLDF Benchmark 250 mg neg. con. Xtal (more H) (less H) (1:1 H:drug) (no H) (1.5:1 H:drug) (0.5:1
Slide 38: High Loaded Dosage Forms (HLDF) Initiative
CASE STUDY #3 High Loaded Dosage Forms (HLDF) Initiative Demonstrated in vivo performance in fasted beagle dogs (n=6) using posaconazole model drug 400 mg 250 mg 400 mg 250 mg HLDF Crystalline HLDF HLDF benchmark negative suspension (more H) (less H) control (no H) 4000 3500 3000 400 mg HLDF tablet
Slide 39: Take Away Points
Take Away Points ©Lonza Pharma & Biotech | AAPS Presentation | November 4, 2019
Slide 40: Improving Oral Drug Bioavailability
Improving Oral Drug Bioavailability Which Technology To Select For Which Compound? • Oral bioavailability challenged molecules continue to be present in pharma & biotech pipelines • A significant number of these assets are in small company pipelines which often lack the resources to progress them •
Slide 41: Acknowledgements
Acknowledgements Lonza Pharma & Biotech colleagues • Dr. Hywel Williams • Dr. Hassan Benameur • Dr. Ed Jule • Dr. David Vodak • Dr. Michael Morgen • Dr. Deanna Muddie • Mr. Aaron Stewart • Dr. Michael Grass Collaborators (MDS) at Monash University • Prof. Colin Pouton • Dr. David Chalmers For more i