Micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and controlled delivery of Cyclosporine A

The commercial formulation of Cyclosporine A (CsA) for intravenous administration contains Cremophor EL, a low molecular weight surfactant known to be toxic. In this study, micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) were investigated as alternative vehicles for the solubilization and delivery of CsA. PEO-b-PCL block copolymers having identical PEO chain lengths and PCL molecular weights of 5000, 13,000, or 24,000 g mol(-1) were synthesized and assembled into polymeric micelles using a co-solvent evaporation method. PEO-b-PCL micelles were then compared to Cremophor EL micelles for their functional properties in drug delivery including micellar size, thermodynamic stability, core viscosity, CsA encapsulation, and in vitro CsA release. Among different PCL block lengths, optimum solubilization was achieved by utilizing polymeric micelles having a PCL block of 13,000 g mol-1. CsA reached an aqueous solubility of 1.3 mg/mL in the presence of PEO-b-PCL micelles. This concentration is comparable to injectable CsA levels in its Cremophor EL formulation (0.5-2.5 mg/mL). In contrast to the Cremophor EL formulation, the in vitro rate of CsA release was significantly sustained by the polymeric micellar carrier. Within 12 h, only 5.8% of CsA was released from polymeric micelles while Cremophor EL micelles released 77% of their drug content. Accordingly, viscosity of the PEO-b-PCL micellar core was found to be significantly higher than Cremophor EL micelles. The results points to a potential for PEO-b-PCL micelles as nanoscopic drug carriers for efficient solubilization and controlled delivery of CsA. (c) 2005 Elsevier B.V. All rights reserved.