Polymeric nanomicelles for cyclosporine ocular delivery

Sara NICOLI, University of Parma

Cyclosporine A is a cyclic decapeptide with immunomodulatory and anti-inflammatory activity. Its has demonstrated good efficacy in the treatment of ocular diseases such as dry eye syndrome and uveitis. The drug is commonly formulated in oil-based or emulsion-based formulations, because of its high hydrophobic nature (logP=3) and poor aqueous solubility. The aim of the work was to prepare cyclosporine-loaded water-based vehicles for ocular delivery. As excipients, Pluronic F127 and TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) were selected.

Polymeric nanomicelles/nanosuspensions were prepared by dissolving Pluronic F127 and TPGS in water. An excess of drug was then added as ethanol solution. The formulation was stirred overnight to allow for ethanol evaporation, centrifuged, filtered (0.22 µm) and analysed by HPLC-UV to determine cyclosporine solubility. Different polymer concentrations (0.5-20 mM) and different TPGS: Pluronic ratios were evaluated. Cyclosporine accumulation into the cornea was studied using freshly explanted ocular bulbs: after 3h application, the cornea was dissected and extracted with CH3CN:CH3COOH 1% (87:13). The extracts were concentrated under N2 before analysis. Mucoadhesive properties of the formulations were also evaluated: 20 µl were applied to the cornea and, after 5 min of equilibration, simulated lacrimal fluid (SLF) was flushed on the tissue (rate 60 µl/min, syringe pump) and then collected at predetermined times for drug quantification.

Diluted blank micelles made of Pluronic F127 and TPGS (1:1) had a mean diameter of approx. 20 nm. In the presence of cyclosporine, the size increased to about 200 nm. The polymers were able to significantly improve cyclosporine solubility, which increased proportionally to polymer concentration; at 20 mM, 0.5% (w/v) drug concentration was obtained. Depending on the drug/polymer ratio, it was possible to prepare both micelles (transparent) or nanosuspensions (opalescent). Mucoadhesion experiments showed a higher cornea retention for nanosuspensions compared to micelles. Cornea accumulation data were 0.82±0.14 µg/cm2, 2.25±0.49 and 3.41±0.96 µg/cm2, for 5, 10 and 20 mM micelles, respectively.

The data collected suggest that micelles and nanosuspensions of Pluronic and TPGS can be a simple and valid alternative to current formulations for cyclosporine eye delivery.

 
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