Novel cyclosporin A formulations using MPEG-hexyl-substituted polylactide micelles: a suitability study

The immunosuppressive agent Cyclosporin A (CsA) has very poor solubility in water and, in consequence, non-aqueous formulations have been developed for its intravenous administration to treat patients with transplant rejection. In this article, aqueous micelle solutions of novel amphiphilic copolymers based on methoxy-poly(ethylene glycol) (MPEG) and hexyl-substituted poly(lactides) (hexPLA) were studied for possible incorporation and formulation of CsA, and for their biocompatibility towards novel pharmaceutical applications. Above the critical micellar concentration (CMC), MPEG-hexPLA block-copolymers self-assemble into unimodal micelles with diameters of around 30 nm, either unloaded or drug-loaded. The best shelf-life stability of these formulations was observed when stored at 4°C with a drug loss inferior to 7% after 1 year. The polymer and micelle toxicities were evaluated in vitro for three different cell lines and in vivo using the chick embryo chorioallantoic membrane (CAM) model. The hemolytic property was assessed using human blood samples. As the studies revealed, MPEG-hexPLAs are non-toxic and do not show hemolysis; the same was found for the comparable MPEG-PLAs, both as unimers below their CMC and as polymeric micelles up to copolymer concentrations of 20 mg/mL. At this concentration, CsA was efficiently incorporated into MPEG-hexPLA micelles up to 6 mg/mL, which corresponds to a 500-fold increase of its water solubility. The current recommended clinical concentration administered per infusion (0.5-2.5 mg/mL) can be easily achieved and requires four times less copolymer than with the often-used Cremophor®EL surfactant. In this regard, MPEG-hexPLA micelle formulations can be an applicable formulation in transplant rejection treatments as an injectable CsA carrier system.