| Objective: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. To prepare Cyclosporin A-MPEG-hexyl-substituted polylactide micelles, analyzed the preparation technology, quality, character and optimize the best formula. Methods: MPEG-hexPLA and MPEG-PLA copolymers of5000g/mol were synthesized by ring opening polymerization (ROP). Preparation and size characterization of unloaded MPEG-(hex)PLA micelles and Incorporation of CsA into MPEG-hexPLA micelles. Detected In vitro toxicity by MTT and In vivo toxicity by the CAM model. Results Above the critical micellar concentration (CMC), MPEG-hexPLA block-copolymers selfassemble into unimodal micelles with diameters of around30nm, either unloaded or drug-loaded. The best shelf-life stability of these formulations was observed when stored at4℃with a drug loss inferior to7%after1year. 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. 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 of20mg/mL. At this concentration, CsA was efficiently incorporated into MPEG-hexPLA micelles up to6mg/mL, which corresponds to a500-fold increase of its water solubility. The current recommended clinical concentration administered per infusion (0.5-2.5mg/mL) can be easily achieved and requires four times less copolymer than with the often used Cremophor(?)EL surfactant. Conclusions:MPEG-hexPLA micelle formulations can be an applicable formulation in transplant rejection treatments as an injectable CsA carrier system. |
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