© Oroxcell 2009

Pharmaceutical Sciences

© Oroxcell 2009 2

Table of contents

Pharmaceutical Sciences

1. Molecular diagnosis & analytical chemistry• Physicochemical evaluation• Method validation and ICH stability

2. Molecular Pharmaceutics• Early formulation• Drug rescue: Formulation Search Engine

3. Innovative Formulation• Lipid-based formulations: SEDDS/SMEDDS,

liposomes…• Functionalised Polymers• Cyclodextrin complexes …

4. Equipment & Technologies• Physico-chemistry and analytical chemistry• Formulation characterisation

3© Oroxcell 2009

Molecular Diagnosis & Analytical Chemistry

Physicochemical Evaluation

Drug design orientation

• pKa: Potentiometric titration, UV scans using Sirius technology

• logP and logD: Sirius technology or innovative liquid-liquid micropartitiontechnique** Demare S, Slater B, Lacombe G, Breuzin D, Dini C (2007) Accurate automated logPo/wmeasurement by gradient-flow liquid-liquid partition chromatography. Part 1. Neutralcompounds. J. Chromatogr. A. 1175(1):16-23.

• HSA binding: Affinity chromatography using a Human Serum Albumin column

• Solubility & Stability– In buffers– In ingredients– In human gastrointestinal fluids from healthy volunteers

4© Oroxcell 2009

Molecular Diagnosis & Analytical Chemistry

Physicochemical Evaluation

Correlation of determined parameters and literature values

logP(oxl) = 0.97*logP(lit) + 0.01

R2 = 0.954

logD7.4(oxl) = 0.95*logD7.4(lit) + 0.15

R2 = 0.942

0

1

2

3

4

5

0 1 2 3 4 5

Literature logP or logD pH 7.4

logP

or l

ogD

pH

7.4

(Oro

xcel

l)

logPlogD7.4

y = 0.92x - 0.86R2 = 0.9628

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Literature PPB%

Expe

rimen

tal P

PB%

(Oro

xcel

l)

logP and logD pH 7.4 values determined by micropartitionchromatography vs. literature values

HSA Percentage Protein Binding (PPB) determined by affinitychromatography vs. literature values

5© Oroxcell 2009

Molecular Diagnosis & Analytical Chemistry

Method validation and ICH stability

For API and Drug Product

• Research:– Pre-stability and forced degradation– HPLC-UV and HPLC-UV-MS method development

• GPL compliance:– HPLC-UV method validation– HPLC-UV impurity profile– ICH stability in climatic chambers– Reporting

• Empower data acquisition and treatment softwareLink to ICH website

Early Formulation

Optimal formulation for animal dosing

• Solutions, suspensions, emulsions …

• Preliminary stability testing

• Preliminary tolerability tests– Absence of critical adverse effects– Absence of biased pharmacological effects

• Database– Formulation composition– Volume of administration tolerated in animals

© Oroxcell 2009 6

Molecular Pharmaceutics

7© Oroxcell 2009

Molecular Pharmaceutics

Drug rescue: Formulation Search Engine

Formulation for an improved bioavailability

• Attractive approach combining molecular diagnosis and molecularpharmaceutics

• Application to pharmaceuticals and cosmetic agents

• Optimized probability of success for poorly soluble and effluxed drugs

• Requires only a gram-scale amount of active ingredient

• Reduced turn-around-time

• Oral and topical formulations

• GRAS ingredients

8© Oroxcell 2009

Molecular Pharmaceutics

Drug rescue: Formulation Search Engine

Chronology of events

1Molecular diagnosisIdentification of key parameters for drug formulation strategy:pKa, lipophilicity, solubility, absorption, metabolism…

2Molecular pharmaceuticsFormulation screening and ranking using in vitro cell models:Feasibility study, solublity, stability, absorption using Caco-2 cells….

3Proof of concept in animalsSelection of the most promising formulations before scale-upDetermination of PK parameters following administration

9© Oroxcell 2009

Molecular Pharmaceutics

Drug rescue: the example of HMR1297

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1 2 3 4 5 6

Hours

Radio

activ

ity m

g eq/L

PEG300/Water (30/70)

Before FSE

Poor plasmatic PK profile in ratsfollowing oral gavage

Rat:fa ~ < 1%

PoorSolubility

PoorPermeability

Degradationin the GI tract

Dog:fa ~ < 1%

F.S.E P-gp EffluxMechanism

fa: orally absorbed fraction

Monkey:fa ~ < 1%

Potential market:0 $

1 - Molecular diagnosis

Patent - WO 2006/018501

10© Oroxcell 2009

Molecular Pharmaceutics

Drug rescue: the example of HMR12972 - Molecular pharmaceutics

Rat:fa ~ 100%

Potential market:1 bn $

EnhancedPermeability

LimitedDegradation

in the GI tract

Monkey:fa ~ 100%

Dog:fa ~ 100 %

F1 & F2

EnhancedSolubility

P-gp EffluxInhibition

Improved plasmatic PK profile in ratsfollowing oral gavage

fa: orally absorbed fraction

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1 2 3 4 5 6

Hours

Radio

activ

ity m

g eq/L

PEG300/Water (30/70)Cyclodextrins/Water (50/50)F1F2

Patent - WO 2006/018501

3 - Proof of concept in animals

11© Oroxcell 2009

Molecular Pharmaceutics

Pharmaceutical optimisationof successful PK studyformulations

Mini-ternary diagrams for optimal self-emulsifying systems selection

Optimal composition area selectionaccording to:- Formulation appearance- Droplet size distribution- Droplet size populations- Drug stability and formulation stability

Mini-ternary diagram

12© Oroxcell 2009

Innovative Formulations

Lipid-based formulations: SEDDS/SMEDDS

Self-Emulsifying and Self-Microemulsifying Drug Delivery Systems

• Form emulsions and microemulsions once diluted with water• Used to improve solubility and enhance oral absorption• Successful approach for more than 10 chemical drugs• Database containing 200 lipid-based formulations• Suitable for pharmacological and toxicological studies and clinical use

Microemulsions and emulsions

13© Oroxcell 2009

Innovative Formulations

Functionalised polymers for encapsulationPharmaceutical applications

• To improve solubility for optimal oral or topical absorption• To improve stability and protect compounds against degradation• To design pH-dependant sustained release formulation• To modulate rheology of topical application• To protect the stomach against cytotoxic compounds

Cosmetic applications• To improve solubility for topical applications: fragrance, active ingredients, dyes• To improve stability• To improve formulation characteristics

Environmental applications• Heavy metals encapsulation in water• Toxic water soluble component elimination• Lipophilic compound elimination

Some examples• Dissolution of heavy metals, dyes, oils, terpens, aspirin

14© Oroxcell 2009

Innovative Formulations

1) Basic solution2) Drug (D)

D

D

D

D

D

D

1000 nm100 nm

1) pH<2

WaterDrug

Aqueous solution of drug withcontrolled viscosity (syrup)

2) pH>5

Functionalised polymers

Encapsulation main principle

15© Oroxcell 2009

Innovative Formulations

Cylodextrin Complexes

Cyclic glucose oligosaccharides

• Drugs are encapsulated in the hydrophobic core• Encapsulated drugs are more soluble in water• Used to enhance oral bioavailability• Used to mask undesired flavours

Main core of α-cyclodextrin

Crystal structure of rotaxane (blue)with a cyclodextrin (green)

16© Oroxcell 2009

Equipment & Technologies

Physicochemistry and analytical chemistryGlpKa-DPAS

• pKa measurement• Sirius Analytical

DSC (Differential Scanning Calorimetry)• Melting point measurement• Polymorphism study• TA Instruments

5 HPLC-UV and 1 UPLC-UV systems• Drug characterisation and quantification• Waters

1 LC-UV-MS• Drug impurity profile analysis• Agilent-Micromass

HPLC-UV laboratory

GlpKa-DPAS

LC-UV-MS system

17© Oroxcell 2009

Equipment & Technologies

Formulation characterisation

Nanosizer and Coulter Sizer 3• Droplet or solid particle size measurement• Malvern – Beckman

Optical microscope• Particle shape studies• Leica – Olympus

Dissolution bath• Dissolution profiling• Distek – Sotax

3 climatic chambers and 4 ovens• API and drug product forced degradation studies• ICH stability• Memmert

Coulter Sizer 3

Optical Microscope

Dissolution bath

Oroxcell SASParc Biocitech102, avenue Gaston RousselF-93 230 Romainville

Tel: 00 33 (0) 1 41 83 72 20Fax: 00 33 (0) 1 41 83 72 27E-mail: contact@oroxcell.com

www.oroxcell.com

© Oroxcell 2009 18