Bioavailability of cyclosporine in rats after intragastric administration: a comparative study of the L2-phase and two other lipid-based vehicles.
The purpose of this study was to evaluate formulations based on surface active dietary lipids only as oral vehicles for cyclosporine. The absolute bioavailability of cyclosporine from two new lipid vehicles was determined in rats after intragastric administration and compared to that of Sandimmun oral solution, which contains non-ionic surface active substances in addition to dietary lipids. In the new vehicles, cyclosporine was dissolved in two different mixtures of glycerides from long-chained fatty acids. One mixture forms an L2-phase, an oil with very low interfacial tension towards water, and was administered both as the oily L2-phase and as a predispersed emulsion formulation. The other mixture forms a liquid crystalline phase and was administered only as an aqueous dispersion. The mean bioavailability of cyclosporine from Sandimmun was 8% while it was 34% from the L2-phase, 38% from the predispersed L2-phase and 27% from the dispersed liquid crystalline phase. The coefficients of variation in area under the blood concentration curve after administration of the two formulations based on the L2-phase were quite low (31% for the L2-phase and 24% for the predispersed L2-phase) and comparable to that after intravenous administration (24%), while the dispersed liquid crystalline phase gave a higher variability (91%), comparable to that of Sandimmun oral solution (101%). The low variabilities found with the two L2-phase vehicles suggest that this formulation is "self-emulsifying' in the gastrointestinal tract. Since the L2-phase is based on dietary lipids only, it is expected to be well tolerated and could prove to be a good vehicle for long-term clinical use of oral cyclosporine.
Bojrup
M
M
Camurus AB, Ideon Research Park, Lund, Sweden.
Qi
Z
Z
Björkman
S
S
Ostraat
O
O
Landin
B
B
Ljusberg-Wahren
H
H
Ekberg
H
H
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002364:Caseins / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004655:Emulsions; D005989:Glycerides / Q000008:administration & dosage / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D014677:Pharmaceutical Vehicles; D010938:Plant Oils / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D012997:Solvents / Q000494:pharmacology; D013010:Sonication; D000074242:Sunflower Oil; D013500:Surface Tension / Q000187:drug effects; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013535:Suspensions
D002364:Caseins; D004655:Emulsions; D005989:Glycerides; D014677:Pharmaceutical Vehicles; D010938:Plant Oils; D012997:Solvents; D000074242:Sunflower Oil; D013501:Surface-Active Agents; D013535:Suspensions; D016572:Cyclosporine; C005953:monoolein