Improvement of cyclosporine A bioavailability by incorporating ethyl docosahexaenoate in the microemulsion as an oil excipient.
The aims of this study were to determine the effect of ethyl docosahexaenoate (DHA-EE) on cyclosporine A (CsA) bioavailability, while also examining the effect of DHA-EE on CsA when DHA-EE was incorporated into a microemulsion formulation as an oil ingredient. The oral co-administration of DHA-EE and CsA increased the blood CsA concentration in a dose-dependent manner, and the AUC and C(max) both increased by about 2-fold with 100mg/kg DHA-EE. The microemulsion formulation of CsA consisted of Tween-20, ethanol, water, and DHA-EE (53.3/6.5/35.9/3.3 w/w%) (namely DHA-ME) was transparent and stable with an average particle size of 50 nm, which was similar to that of the control formulation incorporating vitamin E instead of DHA-EE (namely VE-ME). The permeabilities of CsA from DHA-ME, VE-ME and Neoral formulations across an artificial membrane were not significantly different. The C(max) and AUC(0-infinity) of CsA in rats administered DHA-ME significantly increased by approximately 2-fold in comparison to that of VE-ME. The relative oral bioavailability (F(r)) of DHA-ME in comparison to Neoral was determined to be 114%, while the F(r) of VE-ME was only 60%. It was, therefore, suggested that the use of DHA-EE as an oil excipient may be promising for the development of a microemulsion formulation of CsA with an improved oral bioavailability.
Hirunpanich
Vilasinee
V
Department of Clinical and Molecular Pharmacokinetics/Pharmacodynamics, Showa University, Tokyo 142-8555, Japan.
Sato
Hitoshi
H
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004281:Docosahexaenoic Acids / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D004655:Emulsions; D000431:Ethanol / Q000737:chemistry; D005079:Excipients / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008567:Membranes, Artificial; D008954:Models, Biological; D010316:Particle Size; D010539:Permeability; D011136:Polysorbates / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar
D004655:Emulsions; D005079:Excipients; D007166:Immunosuppressive Agents; D008567:Membranes, Artificial; D011136:Polysorbates; D004281:Docosahexaenoic Acids; D000431:Ethanol; C067518:4,7,10,13,16,19-docosahexaenoic acid ethyl ester; D016572:Cyclosporine