Bioavailability enhancement of poorly water soluble drugs

Seoul September 2012

Oral applications
Which functionality ? which product ? which process ?
Sustained Release
Excipients Compritol 888 ATO
BioavailabilityEnhancement

Precirol ATO 5 Gelucire 39/01 - 43/01

Excipients Gelucire 44/14

Process Compression

Gelucire 50/13 Labrasol Labrafils See list of excipient for SEDDS or SMEDDS

Capsule filling Melt granulation & pelletization Spray cooling / Prilling

Process Capsule filling

Final dosage forms

Adsorption / Compression Melt granulation & pelletization

Tablet Capsule Granule/Pellet (Sachet / Capsule)

Final dosage forms Capsule

Tablet Granule/Pellet (Sachet / Capsule)

Factors responsible for poor bioavailability

Higher molecular weight than before

High particle size : > 10 microns High static charges aggregate

Low polarity
Poor dissolution

Poor absorption

Oral bioavailability / Drug Development Strategy

Conventional formulations not appropriate Solubility - major problem to be addressed Formulation should improve :

o
o o

Solubilization of Drug in the GI Medium Drug absorption process

Lipid based formulation Classification

o

Oily formulations

Self-emulsifying formulations

Lipid based formulation Classification

o

Oily formulations

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.

Simple oil formulations list of some excipients

Product Chemical Description Fatty acid chain length Maisine 35-1 Peceol Labrafac Lipophile WL1349
Glycerol monolinoleate EP Glyceryl monolinoleate NF Glycerol monooleate (type 40) EP Glyceryl monooleate (type 40) NF

LC LC

Triglycerides medium-chain EP Medium-chain triglycerides NF

MC

Lipid based formulation Classification

o

Oily formulations

Self-emulsifying formulations

Self-emulsifying formulation
o

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

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 Gattefoss, EPB 0670715, JP 2877725, US 6 054136

Self-emulsifying systems
Labrasol is a liquid and defined mixture containing : Surfactants, mono- & diesters of PEG co-Surfactants, monoglycerides

Lipidic Phase,
di- & triglycerides

Surfactan ts

Lipophilic Phase

Water Phase
CoSurfactants

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)

Guidelines: Design of phase diagrams

R1

R2

R3

Gelucire 44/14: MCT: Water

Limit of emulsification Max quantity of lipid such that complete emulsification occurs on dispersion (~700 mg in 900 ml @ 37O)

Gelucire 44/14: LCM: Water

Note that more Peceol than MCT can be incorporated reflecting increased amphiphilicity of the MG vs TG

Gelucire 44/14: MCM: Water

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

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 Gattefoss, 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

Increase of the pseudo solubility of the active substances
o

o
o o

Bioavailability improvement
Rapid onset of action Reduction of the intersubject variability

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

Gattefoss 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