Stable bioavailability of cyclosporin A, regardless of food intake, from soft gelatin capsules containing a new self-nanoemulsifying formulation

Abstract

We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. The differences in bioavailability parameters (i.e., AUC(0-24h), AUC(0-infinity) and C(max)) between the treatments were within the range of 80-125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol.