Improving Oral Bioavailability by Solid Dispersions: An OSPHENA (Ospemifene) Case Study Zhengming (Jimmy) Chen, Ph.D., Shionogi Inc. zhengming.chen@shionogi.com
Shionogi Global Business Locations London / Est. 2012 - Clinical Development - Sales Shionogi & Co., Ltd. Shionogi Limited Beijing Shionogi Beijing / Est.2013 - Promotion of R&D collaboration C&O Hong Kong Est. 1995 / Acq. 2011 - R&D - Manufacturing - Marketing - Sales Taiwan Shionogi Taipei / Est. 1963 - Import - Clinical Development - Sales Shionogi Inc. Florham Park, NJ Est. 2001 - Clinical Development - Marketing - Sales Shionogi Singapore Est. 2013 2
Strategic Products and Sales Breakdown Crestor Sales Breakdown FY2014 GI 1% Hormone Diagnostics 1% preparations 2% Others 3% Cymbalta Oncology 3% Respiratory, Allergy, Dermatology 14% CV 34% Irbetan Anti-infective 20% CNS & Pain 23% 3
Ospemifene Solid Dispersions Ospemifene Solubility Limitations Ospemifene is almost insoluble in water and buffers ph 1.2 to 8.0 (less than 0.0003 mg/ml) New Ospemifene Opportunity Potential to develop a formulation with: Significant increase in Ospemifene solubility Potential increase in bioavailability Potential opportunity to reduce the dose and cost of goods Additional marketing opportunities (product improvement, combination products, etc.) 4
Physicochemical Properties of Ospemifene Attribute Ospemifene Molecular formula C 24 H 23 ClO 2 Molecular weight 378.9 Ionization Hydroxyl compound, non-ionizable in physiological ph pka NA Log P 5.77 API form Free form API Description White to almost white crystalline powder API Polymorphism One polymorph Melting range ( C) 114-127 C Solubility Insoluble in water and buffers ph 1.2 to 8.0 (<0.0003 mg/ml) Dose 60 mg orally as free base BCS Classification 2 (high permeability and low solubility) Oral bioavailability Readily absorbed food effect taken with food Stability Stable at 15-25 C; not light sensitive 5
Solid Dispersions Trap molecule in amorphous state Disperse in a hydrophilic polymer matrix Inhibit crystallization Increase solubility Prepare by spray drying or melt extrusion 6
Development of Solid Dispersion Formulations Screening by solvent casting, 19 formulations Solubility, microscopy Feasibility of spray drying and melt extrusion, 5 formulations Lead formulations, 4 formulations Solubility, dissolution, microscopy, X-ray powder diffraction, long term stability 7
Solvent Casting Dissolve drug and polymer in a common solvent Cast film in petri dish Removal of solvent by evaporation Pulverize films into powder OSP/ PVP OSP/ Co-povidone OSP/ HPMC OSP/ HPMCAS OSP/ PVP OSP/ Co-povidone OSP/ HPMC OSP/ HPMCAS 8
Solid Dispersions of Ospemifene Solid dispersion Polymer/surfactant Drug/excipient ratio Preparation Hydrophilic polymer OSP/Co-povidone Co-povidone 1:4 Solvent casting, spray drying, melt extrusion OSP/HPC Hydroxypropylcellulose 1:4 Solvent casting OSP/HPMC Hypromellose 1:4 Solvent casting OSP/PVP Povidone 1:4 Solvent casting Enteric coating polymer OSP/Eudragit L100-55 Methaacrylic acid copolymer 1:4 Solvent casting OSP/HP55 Hypromellose phthalate 1:4 Solvent casting, spray drying, melt extrusion OSP/HPMCAS Hypromellose succinate acetate Surfactant 1:4 Solvent casting, spray drying OSP/Poloxamer Poloxamer 1:4 Solvent casting OSP/Soluplus Soluplus 1:4 Solvent casting 9
Solid Dispersions of Ospemifene Solid dispersion Polymer/surfactant Drug/excipient ratio Preparation Tertiary OSP/PVP/Span 20 Povidone, Span 20 1:3.4:0.6 Solvent casting OSP/PVP/Span 80 Povodone, Span 80 1:3.4:0.6 Solvent casting, spray drying, melt extrusion OSP/PVP/Tween 80 Povodone, Tween 80 1:3.4:0.6 Solvent casting OSP/PVP/Poloxamer Povodone, Poloxamer 1:3.4:0.6 Solvent casting OSP/PVP/AOT Povodone, sodium docusate 1:3.4:0.6 Solvent casting OSP/co-povidone/Span 20 OSP/co-povidone/Span 80 OSP/co-povidone/Tween 80 OSP/copovidone/Poloxamer OSP/co-povidone/AOT Co-povidone, Span 20 1:3.4:0.6 Solvent casting Co-povidone, Span 80 1:3.4:0.6 Solvent casting Co-povidone, Tween 80 1:3.4:0.6 Solvent casting Co-povidone, Poloxamer 1:3.4:0.6/1:2:2 Solvent casting, Spray drying, melt extrusion Co-povidone, sodium docusate 1:3.4:0.6 Solvent casting 10
Spray Drying Buchi B-290 Inlet temp: 50-80 C Aspirator: 70-100% Pump speed: 10-30% Solid content: 5% in ethanol or ethanol/water (8:2) OSP/HP55 11
Melt Extrusion Thermo Haake Minilab Temp: 120-180 C Motor speed: 100-200 rev/min Extruded solids pulverized OSP/co-povidone OSP/HP55 OSP/co-povidone/poloxamer OSP/Povidone/Span 80 12
Solubility Enhancement at ph 6.8 Formulation Increase of solubility OSP/Co-povidone/Poloxamer 1007 OSP/HPMCAS 776 OSP/Co-povidone/Tween80 460 OSP/HP55 450 OSP/Soluplus 367 OSP/Poloxamer 353 OSP/PVP/Span80 260 OSP/PVP/Span20 130 OSP/PVP/Tween80 100 OSP/Eudrgit L100 83 OSP/PVP/AOT 83 OSP/Co-povidone/AOT 73 OSP/Co-povidone 70 OSP/HPMC 53 OSP/Co-povidone/Span20 53 OSP/PVP/Poloxamer 40 OSP/HPC 23 OSP/Co-povidone/Span80 23 OSP/PVP 2 Shake flask, 23 C, 3 hr equilibrium solubility 13
Microdissolution of Ospemifene/HPMCAS ph 6.8 phosphate buffer@23 C Dissolution done in non-sink condition: API solubility less than 0.03 g/ml in ph 6.8 buffer Average of amount of Ospemifene dissolved within 3 hr for physical mixture: 0.16 g/ml Concentration decrease for solid dispersion due to significant supersaturation Peak solubility: 149 g/ml, 900 times more than physical mixture, 4900 times more than API 14
Microdissolution of Ospemifene/Copovidone ph 6.8 phosphate buffer@23 C Dissolution done in non-sink condition: API solubility less than 0.03 g/ml in ph 6.8 buffer Average of amount of Ospemifene dissolved within 3 hr for physical mixture: 0.05 g/ml Peak solubility: 18.2 g/ml, 360 times more than physical mixture, 600 times more than API 15
Microdissolution of Ospemifene/Co-povidone /Poloxamer in Simulated Intestine Fluid FeSSIF = 0.025 mg/ml FaSSIF = 0.01 mg/ml SDD FeSSIF=0.15 mg/ml SDD FaSSIF=0.03 mg/ml Spray dried formulation performed better than HME 16
Chemical Stability (7M & 2Y) Spray dried Ospemifene (OSP) formulations Peak No. Fresh sample 7 month old sample kept at RT, closed Name RT (min) RRT OSP- OSP- OSP-PVPVA64- OSP- OSP-PVPVA64- HP55 PVPVA64 Poloxamer OSP-HP55 PVPVA64 Poloxamer % Area % Area % Area % Area % Area % Area 1 Peak 1 3.559 0.39 DBNQ DBNQ DBNQ DBNQ DBNQ 2 Peak 2 3.601 0.40 3 Peak 3 4.532 0.50 DBNQ DBNQ DBNQ 4 Peak 4 4.720 0.52 DBNQ DBNQ DBNQ 5 Peak 5 5.072 0.56 DBNQ DBNQ 6 Peak 6 5.973 0.66 0.2 7 Peak 7 7.087 0.78 DBNQ 8 Peak 8 7.700 0.85 DBNQ 9 Peak 9 9.100 1.00 10 Peak 10 10.145 1.11 0.1 0.1 0.11 0.06 0.07 DBNQ 11 Peak 11 10.590 1.16 DBNQ 0.08 DBNQ 0.08 0.22 12 Peak 12 11.081 1.22 DBNQ DBNQ DBNQ 0.17 13 Peak 13 11.100 1.22 Total of Impurity (%) 0.30 0.18 0.11 0.23 0.15 0.22 Assay (%) 99.63 99.66 99.83 99.76 99.74 99.73 DBNQ: Detactable But Not Quantitated (if < 0.05%) Excellent chemical stability for the spray dried formulations of OSP/HP55, OSP/copovidone, OSP/co-povidone/poloxamer 17
Physical Stability Initial XRPD of OSP/Co-povidone XRPD of OSP/Co-povidone/Poloxamer 7 mon Initial 7 mon Initial 7 mon XRPD of OSP/HP55 Excellent physical stability for the spray dried formulations of OSP/HP55, OSP/co-povidone, OSP/co-povidone/poloxamer, no crystallization detected 18
Formulations for PK Studies Formulation Ospemifene/Copovidone, 1:4 Ospemifene/Copovidone/poloxamer, 1:2:2 Solubility enhancement @ph 6.8 Chemical stability 70x Stable for 7 month at 23 C 1007x Stable for 7 month at 23 C Ospemifene/HP55 450x Stable for 7 month at 23 C Physical stability Stable for 7 month at 23 C Stable for 7 month at 23 C Stable for 7 month at 23 C Spray dried materials 25 gram 25 gram 25 gram Ospemifene/HPMCAS 776x NA NA 25 gram 19
Initial Rat PK Samples/Groups A-F Animal group A B C D E F Animal Condition Fasted Fed Fasted Fasted Fasted Fasted Formulation Description Pure Ospemifene API in Size 9 gelatin capsule Pure Ospemifene API in Size 9 gelatin capsule Ospemifene spray-dried with PVPVA 64 (batch # ASD-N-017-15), Size 9 gelatin capsule Ospemifene spray-dried with HPMCAS LF (batch # ASD-N-017-16), Size 9 gelatin capsule Ospemifene spray-dried with HP-55 (batch # ASD-N-017-17), Size 9 gelatin capsule Ospemifene spray-dried with PVPVA 64, Poloxamer 407 (1:1) (batch # ASD- N-017-18), Size 9 gelatin capsule Average capsule fill weight (mg) * 6 mg/kg to the rats (average weight = 0.25 kg) Amount API dosed (mg)/animal MPK 1.5 1.5 6 1.5 1.5 6 7.5 1.5 6 7.6 1.5 6 7.5 1.5 6 7.5 1.5 6 20
Initial Results: Plasma concentration (ng/ml) Solid Dispersion Formulations 70 60 50 40 30 20 Mean time-plasma concentration profiles of ospemifene in rats following a single oral administration (6 mg/kg) Group A: Pure API, Fasted Group B: Pure API, Fed Group C: API Solid Dispersion1, Fasted Group D: API Solid Dispersion2, Fasted Group E: API Solid Dispersion3, Fasted Group F: API Solid Dispersion4, Fasted Cmax (ng/ml) AUCinf (hr*ng/ml) Group A 39.2 ± 16.1 429 ± 130 Group B 38.8 ± 16.3 345 ± 191 Group C 31.5 ± 18.3 167 ± 21 Group D 40.9 ± 22.8 156 Group E 23.6 ± 11.4 260 ± 157 Group F 33.2 ± 20.9 181 ± 86 Data are expressed as the mean ± SD of 3 rats. 10 0-1 4 9 14 19 24 Time (hr) We found out that the rat PK results are problematic due to small stomach fluid volumes in rats 21
Plasma concentration (ng/ml) Additional Rat PK: SD vs Pure API @ 30mpk 800.00 700.00 600.00 500.00 400.00 Group C Group E Group F Ospemifene Formulation AUC(INF) (ng/ml*h) C - Amorphous dispersion 2086 E - Pure API suspension (fasted) 742 F - Pure API suspension (fed) 912 300.00 C/E = 2086/742 = 2.81 200.00 100.00 0.00 0.0 5.0 10.0 15.0 20.0 25.0 30.0 Time (hrs) The AUC (from zero to infinity) represents the total drug exposure over time. 22
Dog PK (100mg/dog, Fasted) Solid dispersion was twice in fasted API, and equivalent to Fed API: API capsule API capsule Solid dispersion capsule Condition Fed Fasted Fasted mean SD mean SD mean SD Cmax 2843.3 823.1 1333.3 339.8 2470.0 303.5 AUCinf 14419.4 6050.1 7292.4 4344.7 15345.8 5905.7 Oral Bioavailability Improvement: 15345.8/7292.4 = 2.1 23
Key Findings 1 Solid dispersions of Ospemifene with hydrophilic polymers, enteric coating polymers and surfactants prepared by solvent casting, spray drying, and melt extrusion show solubility enhancement ranged from 2 to 1000 fold in ph 6.8 The solid dispersion with HPMCAS and HP55 has ph dependent solubility, with solubility enhancement of 776 and 450 fold in ph 6.8, respectively The solid dispersion with HPMCAS showed a time dependent solubility change in a microdissolution study in ph 6.8 due to the significant supersaturation, with a peak solubility: 149 µg/ml, 900 times more than physical mixture, 4900 times more than API The presence of poloxamer in the co-povidone formulation resulted in solubility enhancement of 1000 fold 24
Key Findings 2 1. The Initial rat PK studies revealed issues with wettability of dispersions upon administration of capsules containing Ospemifene spray-dried amorphous dispersions. 2. Good suspension vehicles for solid dispersions are difficult to find for multiple SD formulations 3. Solid dispersion formulation C (Ospemifene with PVPVA 64-Poloxamer P407) is 2.81 & 2.1 folds better than pure API fasted E with respect to AUC in both rat and dog PK studies respectively. 25
Acknowledgement Many thanks for my colleagues for their contributions to this project: Sean Chen Keven Halloran Jim Huang Kaoru Tominaga Beverly Langevin Jamie Boulet Lining Cai Kan He Naomi Tamura 26