Microemulsion- A suitable Galenical approach for the absorption enhancement of low soluble compounds B.T. Gattefosse No. 88, p , 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.