Microemulsion- A suitable Galenical approach for the absorption enhancement of low soluble

compounds

B.T. Gattefosse No. 88, p. 21-26, 1995

A new microemulsion formulation of Cyclosporine

Objective: Cyclosporine A (CsA) absorption enhancement using ME formulation. CsA: immunosuppressive agent. Used for patient after organ transplantation. Used also in the treatment of autoimmune disorders.

Among the CsA available dosage forms:Injections: have severe side effects.The oral route is good alternative (emulsion and microemulsion);

CsA classical Sandimmune® emulsion: In the aqueous G.I.T, it forms crude emulsion good oral bioavailability, but with many disadvantages.

CsA Sandimmune® Neoral ® microemulsion:In the aqueous G.I.T, it forms microemulsion, with many advantages.

Why CsA needs absorption enhancement?large polypeptide, Mwt=1202 dalton, highly lipophilic, water solubility<0.002%.

What are the disadvantages of CsA classical Sandimmune® (capsule) macroemulsion dosage form?

1. Bile salt emulsification>digestion by pancreatic juice> CsA absorption,

2. CsA distributed into 3 phases:>ppted. Ca soap (small amount of CsA) >undigested lipid (large amount of CsA)>mixed micellar (small amount of CsA)(see figure)3. Narrow absorption widow > more reduction in

Sandimmune® bioavailability. (See figure)4. Inter and intra individual variations (digestion

dependant, pH, food, physiological factors).

Median absorption of Cs after intradoudenal administration of Sandimmune® pre-digested phases to bile duct cannulated rats (n=6).

Median relative bioavailability of 150 mg Cs after administration by intubation to different sites of the G.I.T in healthy volunteers (n=10).

Requirements of the ideal CsA formula:Fast release (use of the entire window),mimicking the mixed micellar phase,Stable, not affected by physiological conditions

>>> microemulsion pre-concentrate with the right type and level of excipients was developed (Sandimmune® Neoral ® ).

Composition of Neoral ® SMEDDS formulation:

Composition of formulation

Neoral ® SMEDDS

Oil: hydrolyzed corn oil,

Surfactant: polyoxy-hydrogenated castor oil

Solvent: glycerol, ethanol or PG

Drug content:10%

Tocopherol: as antioxidant

Neoral ® SMEDDS administered in soft or hard gelatin capsule, the digestive motility in the G.I.T provides the agitation necessary for self-emulsification. ME will form in situ with average droplet size as low as 30 nm.

Sandimmune® Neoral ®

Against

Sandimmune®

Formation of homogenous transparent ME, stable upon dilution with water (right).

Left: Cs suspension, mid: Sandimmune®

Production of constant, narrow range droplet size

Reduction of inter and intra individual variability.

Reduction of the food interaction. Fasting and fat-rich meal.

Reduction of the impact of bile on Cs absorption.

A: Sandimmune® Neoral ® , B: Sandimmune®

Improved bioavailability and dose linearity.