Bioavailability enhancement of poorly water soluble

drugs

Seoul – September 2012

Which functionality ? which product ? which process ?

Sustained Release

Excipients • Compritol 888 ATO• Precirol ATO 5• Gelucire 39/01 - 43/01

Process • Compression • Capsule filling • Melt granulation & pelletization • Spray cooling / Prilling

Final dosage forms • Tablet • Capsule • Granule/Pellet (Sachet / Capsule)

Excipients • Gelucire 44/14• Gelucire 50/13• Labrasol• Labrafils• See list of excipient for

SEDDS or SMEDDS

Process • Capsule filling • Adsorption / Compression• Melt granulation &

pelletization

Final dosage forms • Capsule• Tablet • Granule/Pellet (Sachet /

Capsule)

BioavailabilityEnhancement

Oral applications

Higher molecular weight than before

High particle size : > 10 microns

High static charges aggregate

Low polarity

Poor dissolution

Poor absorption

Factors responsible for poor bioavailability

Oral bioavailability /Drug Development Strategy

o Conventional formulations not appropriate

o Solubility - major problem to be addressed

o Formulation should improve : Solubilization of Drug in the GI Medium Drug absorption process

Lipid based formulationClassification

o Oily formulations

o Self-emulsifying formulations

Lipid based formulationClassification

o Oily formulations

o Self-emulsifying formulations

Oily formulation

o Dissolution of an active substance in a lipid based vehicle (vegetable oils, fatty acids, glycerides)

o This formulation is going to be digested in vivo and the API will be included into the mixed micelles.

Product Chemical Description Fatty acid

chain length

Maisine 35-1 Glycerol monolinoleate EP LCGlyceryl monolinoleate NF

Peceol Glycerol monooleate (type 40) EP LCGlyceryl monooleate (type 40) NF

Labrafac Lipophile Triglycerides medium-chain EP MCWL1349 Medium-chain triglycerides NF

Simple oil formulations list of some excipients

Lipid based formulation Classification

o Oily formulations

o Self-emulsifying formulations

Self-emulsifying formulation

o Formulation which does not contain water, composed of a lipophilic phase, surfactants and a drug

o Spontaneous formation of an o/w emulsion or a microemulsion (or nanoemulsion) once in contact with the GI medium

SELF

o Two types

SEDDS (Self Emulsifying Drug Delivery Systems) = active + surfactant = active + surfactant + lipidic phase

SMEDDS®*(Self Micro-Emulsifying Drug Delivery Systems)

= active + surfactant + cosurfactant (+cosolvent) + lipidic phase

* Patented by Gattefossé, EPB 0670715, JP 2877725, US 6 054136

Self-emulsifying systems

mono- & diesters of PEGSurfactants,

monoglyceridesco-

Surfactants,

Lipidic Phase,

di- & triglycerides

Labrasol® is a liquid and defined mixture containing :

Water Phase

Lipophilic Phase

Surfactants

Co-Surfactants

How to build a SELF ?

o Formulation steps

Selection of excipients • = screening test with binary mixture • = drug solubility / affinity

Design the phase diagrams

In-vitro characterization • = Dispersion testing • = Dissolution test USP method

List of excipients (1/2)

List of excipients (2/2)

R1

R2

R3

Guidelines: Design of phase diagrams

Limit of emulsificationMax quantity of lipid suchthat complete emulsificationoccurs on dispersion(~700 mg in 900 ml @ 37O)

Gelucire 44/14: MCT: Water

Note that more Peceol than MCT can be incorporated – reflecting increased amphiphilicity ofthe MG vs TG

Gelucire 44/14: LCM: Water

Note further that even more efficient emulsification occurs on incorporation of Capryol (HLB 6), rather than Peceol ((HLB 3.3)or MCT

Gelucire 44/14: MCM: Water

Case study: Comparison of Microemulsion versus

Emulsion

o Case of Cyclosporin A, of Sandoz Pharma*:

Emulsion: Sandimmune ®

Microemulsion: Neoral ®

o* (Meinzer A. et al. (1995). Microemulsion - a suitable galenical approach for the absorption enhancement of low soluble compounds? Bulletin Technique Gattefossé, 88, 21-26.)

Case study: Microemulsion versus standard emulsion

Particle size distribution determined by means of dynamic laser light scattering (PCS)

Sandimmune® in solution Classic Emulsion

Neoral® in solution Microemulsion

Case study: Microemulsion versus standard emulsion

Interindividual comparison of Cyclosporine concentration-time profiles following single oral administration.

Sandimmune®

300mg

Neoral®

180mg

Case study: Microemulsion versus standard emulsion

Geometric mean whole-blood Cyclosporine concentration-time profiles following single oral administrations under fasting conditions () and with a fat-rich meal() to 24 healthy male volunteers.

Sandimmune®

300mg

Neoral®

180mg

Microemulsion – reduced particle sizing advantages

o Increase of the « pseudo solubility » of the active substanceso Bioavailability improvement o Rapid onset of actiono Reduction of the intersubject variabilityo Reduction of the food effect

Market Case studies

Neoral – Cyclosporine (softgel)

Norvir – Ritonavir (softgel)

Fortorase – Saquinavir (softgel)

Agenerase – Amprenavir (softgel)

Solufen – Ibuprofen (Hard Gelatin capsule)

Lipirex – Fenofibrate (Hard Gelatin capsule)

In conclusion

Gattefossé excipients are lipid based ingredients - derivated from

vegetable origin

are functional - they provide solutions for formulation challenges

cover a wide range of applications – from SR to Bioavailability enhancement