Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

摘要

Cilostazol (CLZ), an anti-platelet agent, is primarily used following the onset of cerebral infarction. However, as CLZ is only marginally soluble in water, a strategy for patients with serious secondary conditions, such as impaired consciousness or aphagia, is required. In the present study, topical formulations containing CLZ nanocrystals (CLZ(nano)) were designed to enhance percutaneous absorption. In addition, the mechanism of penetration of CLZ(nano) through rat skin was investigated. A topical formulation containing CLZ nanoparticles (CLZ(nano) gel patch) was prepared using a combination of recrystallization and ball milling of an aqueous gel. The particle size of CLZ(nano) was 74.5 +/- 6.2 nm (mean +/- standard deviation). The concentration of permeated CLZ(nano) and penetration mechanism of the nanocrystals were measured in a percutaneous absorption experiment. The amount of penetrated CLZ, the penetration rate (J(c)), the penetration coefficient through the skin (K-p) and the skin/preparation partition coefficient (K-m) for the CLZ(nano) gel patch were all significantly higher than those of the CLZ powder (CLZ(micro)) gel patch, the CLZ(nano) ointment and the CLZ(micro) ointment. In in vitro percutaneous penetration experiments on the CLZ(nano) gel patches, there was a positive correlation between the number of CLZ(nano). Following the application of the CLZ(nano) gel patch on rat skin, 98% of penetrated CLZ was observed in nanoparticle form; for the CLZ(micro) gel patch, this figure was 9%. In addition, the CLZ concentrations in the plasma of rats administered the CLZ(nano) gel patches were significantly higher than those of rats administered the CLZ(nano) CP gel and PEG ointments. It was suggested that CLZnano (diameter 100 nm) were transferred through the intracellular spaces in the skin and then into peripheral blood vessels. To the best of our knowledge, this is the first report to elucidate the mechanism of the percutaneous penetration of nanocrystal medicines.