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

Shionogi & Co., Ltd.

Taipei / Est. 1963

- Import

- Clinical Development

- Sales

Florham Park, NJ

Est. 2001

- Clinical Development

- Marketing

- Sales

Hong Kong

Est. 1995 / Acq. 2011

- R&D

- Manufacturing

- Marketing

- Sales

London / Est. 2012

- Clinical Development

- Sales

Taiwan ShionogiShionogi Inc.

C&O

Beijing ShionogiBeijing / Est.2013

- Promotion of R&D

collaboration

Est. 2013

Shionogi Singapore

Shionogi Limited

2

Strategic Products and Sales Breakdown

CNS & Pain

23%

Respiratory, Allergy,

Dermatology

14%

Oncology 3%

GI 1% Hormone

preparations 2% Others 3%

Anti-infective

20%

Diagnostics 1%

CV 34%

Sales Breakdown FY2014

Irbetan

Crestor

Cymbalta

3

4

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

5

Attribute Ospemifene

Molecular formula C24H23ClO2

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 polymorphMelting range (◦C) 114-127C

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 15-25C; not light sensitive

Solid Dispersions

6

• Trap molecule in amorphous state

• Disperse in a hydrophilic polymer matrix

• Inhibit crystallization

• Increase solubility

• Prepare by spray drying or melt extrusion

Development of Solid Dispersion Formulations

7

Screening by solvent casting,

19 formulations

Feasibility of spray drying and melt extrusion,

5 formulations

Lead formulations,

4 formulations

Solubility, microscopy

Solubility, dissolution,

microscopy, X-ray powder

diffraction, long term stability

Solvent Casting

8

OSP/

PVP

OSP/

Co-povidone

OSP/

HPMC

OSP/

HPMCAS

OSP/

PVP

OSP/

Co-povidoneOSP/

HPMC

OSP/

HPMCAS

➢ Dissolve drug and polymer in a common

solvent

➢ Cast film in petri dish

➢ Removal of solvent by evaporation

➢ Pulverize films into powder

Solid Dispersions of Ospemifene

9

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

1:4 Solvent casting, spray drying

Surfactant

OSP/Poloxamer Poloxamer 1:4 Solvent casting

OSP/Soluplus Soluplus 1:4 Solvent casting

Solid Dispersions of Ospemifene

10

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

Co-povidone, Span 20 1:3.4:0.6 Solvent casting

OSP/co-povidone/Span

80

Co-povidone, Span 80 1:3.4:0.6 Solvent casting

OSP/co-povidone/Tween

80

Co-povidone, Tween 80 1:3.4:0.6 Solvent casting

OSP/co-

povidone/Poloxamer

Co-povidone, Poloxamer 1:3.4:0.6/1:2:2 Solvent casting, Spray drying, melt

extrusion

OSP/co-povidone/AOT Co-povidone, sodium

docusate

1:3.4:0.6 Solvent casting

Spray Drying

• Buchi B-290

• Inlet temp: 50-80C

• Aspirator: 70-100%

• Pump speed: 10-30%

• Solid content: 5% in ethanol or ethanol/water (8:2)

11

OSP/HP55

Melt Extrusion

• Thermo Haake Minilab

• Temp: 120-180C

• Motor speed: 100-200 rev/min

• Extruded solids pulverized

12

OSP/co-povidone

OSP/HP55

OSP/co-povidone/poloxamer

OSP/Povidone/Span 80

Solubility Enhancement at pH 6.8

13

Formulation Increase of solubilityOSP/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, 23C, 3 hr

equilibrium solubility

Microdissolution of Ospemifene/HPMCAS

• 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

pH 6.8 phosphate buffer@23C

Microdissolution of Ospemifene/Co-povidone

• 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

pH 6.8 phosphate buffer@23C

16

➢ Spray dried formulation performed better than HME

FeSSIF = 0.025 mg/mL

FaSSIF = 0.01 mg/mL

SDD FeSSIF=0.15 mg/mL

SDD FaSSIF=0.03 mg/mL

Microdissolution of Ospemifene/Co-povidone/Poloxamer in Simulated Intestine Fluid

17

Chemical Stability (7M & 2Y)

Name RT (min) RRT

Spray dried Ospemifene (OSP) formulations

Peak No. Fresh sample 7 month old sample kept at RT, closed

OSP-

HP55

OSP-

PVPVA64

OSP-PVPVA64-

Poloxamer OSP-HP55

OSP-

PVPVA64

OSP-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/co-

povidone, OSP/co-povidone/poloxamer

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Physical Stability

XRPD of OSP/Co-povidone XRPD of OSP/Co-povidone/Poloxamer

XRPD of OSP/HP55

Initial

7 monInitial

7 mon

Initial

7 mon

❖ Excellent physical stability for

the spray dried formulations of

OSP/HP55, OSP/co-povidone,

OSP/co-povidone/poloxamer,

no crystallization detected

19

Formulations for PK Studies

Formulation Solubility

enhancement

@pH 6.8

Chemical

stability

Physical

stability

Spray dried

materials

Ospemifene/Co-

povidone, 1:4

70x Stable for 7

month at

23C

Stable for 7

month at

23C

25 gram

Ospemifene/Co-

povidone/poloxamer,

1:2:2

1007x Stable for 7

month at

23C

Stable for 7

month at

23C

25 gram

Ospemifene/HP55 450x Stable for 7

month at

23C

Stable for 7

month at

23C

25 gram

Ospemifene/HPMCAS 776x NA NA 25 gram

Initial Rat PK Samples/Groups A-F

20

Animal

group

Animal

ConditionFormulation Description

Average

capsule fill

weight (mg)

Amount API

dosed

(mg)/animal

MPK

A FastedPure Ospemifene API

in Size 9 gelatin capsule1.5 1.5 6

B FedPure Ospemifene API

in Size 9 gelatin capsule1.5 1.5 6

C Fasted

Ospemifene spray-dried with PVPVA 64

(batch # ASD-N-017-15),

Size 9 gelatin capsule

7.5 1.5 6

D Fasted

Ospemifene spray-dried with HPMCAS

LF (batch # ASD-N-017-16), Size 9

gelatin capsule

7.6 1.5 6

E Fasted

Ospemifene spray-dried with HP-55

(batch # ASD-N-017-17),

Size 9 gelatin capsule

7.5 1.5 6

F Fasted

Ospemifene spray-dried with PVPVA

64, Poloxamer 407 (1:1) (batch # ASD-

N-017-18), Size 9 gelatin capsule

7.5 1.5 6

* 6 mg/kg to the rats (average weight = 0.25 kg)

Initial Results: Solid Dispersion Formulations

0

10

20

30

40

50

60

70

-1 4 9 14 19 24

Pla

sm

a c

on

cen

trati

on

(n

g/m

L)

Time (hr)

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

• We found out that the rat PK results are problematic due to small stomach fluid volumes in rats

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.

AUCinf (hr*ng/mL)Cmax (ng/mL)

21

Additional Rat PK: SD vs Pure API @ 30mpk

22

0.00

100.00

200.00

300.00

400.00

500.00

600.00

700.00

800.00

0.0 5.0 10.0 15.0 20.0 25.0 30.0

Pla

sma

con

cen

trat

ion

(n

g/m

l)

Time (hrs)

Group C

Group E

Group F

Ospemifene FormulationAUC(INF)

(ng/mL*h)

C - Amorphous dispersion 2086

E - Pure API suspension (fasted) 742

F - Pure API suspension (fed) 912

C/E = 2086/742 = 2.81The AUC (from

zero to infinity)

represents the

total drug

exposure over

time.

Dog PK (100mg/dog, Fasted)

➢Solid dispersion was twice in fasted API, and equivalent

to Fed API:

23

API capsule API capsuleSolid 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

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

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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

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