Y-shaped methoxy poly (ethylene glycol)-block-poly (epsilon-caprolactone)-based micelles for skin delivery of ketoconazole: in vitro study and in vivo evaluation

- Ketoconazole-loaded micelles were prepared with high efficiency ((96.1 ± 0.76%) and ketoconazole' water-solubility enhancement. It showed comparable antifungal activity with free ketoconazole.
- Ex in vivo skin deposition of ketoconazole was obviously enhanced with less skin permeation by the drug-loaded micelles when compared with marketed ketoconazole cream.
- In vivo skin deposition and permeation study was firstly applied and its results confirmed that drug-loaded micelles improved ketoconazole's skin deposition and reduced its distribution in blood when compared with marketed keconazole cream from an in vivo perspective.

Ketoconazole is a hydrophobic broad-spectrum antifungal agent for skin infection therapy. In order to develop topical formulation of ketoconazole for improving its selective skin deposition and water-solubility, ketoconazole-loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(ɛ-caprolactone) micelles were prepared through thin-film hydration method with high entrapment efficiency (96.1 ± 0.76%) and small particle (about 58.66 nm). The drug-loaded micelles showed comparative in vitro antimicrobial activity with KET cream. In ex in vivo skin deposition and permeation study, ketoconazole-loaded micelles provided skin accumulation higher than marketed ketoconazole cream without obvious permeation in the whole period. Fluorescence microscopy study and histopathological study demonstrated the copolymeric micelles' penetrating into skin in depth due to its capability of weakening the barrier function of stratum corneum. In vivo skin deposition parameters further confirmed high skin deposition of drug-loaded micelles (AUC(0-t) = 396.16 μg·h/cm2) over marketed ketoconazole cream (AUC(0-t) = 250.03 μg·h/cm2). Meanwhile, in vivo pharmacokinetic parameters proved that ketoconazole-loaded micelles reduced ketoconazole's distribution in blood in comparison with the cream (AUC(0-t) = 93,028.00 μg·h/L vs AUC(0-t) = 151,714.00 μg·h/L), meaning lower possibility of its systemic unwanted effects in the skin fungal infection treatment. The results suggested that the copolymeric micelles can be adopted for specific delivering ketoconazole into skin for fungal infection cure.

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