| Topical application of caffeine(CAF) could induce apoptosis in the epidermis of UVB-treated mice and subsuruently inhibite UVB-induced skin tumor. However, CAF represented highly hydrophilic property, resulting in restricted cutaneous permeation and poor skin retention caused by lipophilic barrier of the stratum corneum. Thus, the purpose of this study was to develop an optimal microemulsion(ME) formulation as topical vehicle to enhance skin retention of CAF and subsequently improve its therapeutic effect on UVB-induced skin carcinogenesis.In our study, oil phase was selected based on their solubility for CAF while surfactant and cosurfactant were screened according to oil-in-water ME region in pseudo-ternary phase diagram. The optimal pseudo-ternary phase diagram was developed composing of Labrafil M 1944 CS as oil phase, Cremophor EL as surfantant, tetraglycol as cosurfactant, and water. The mass ration of surfactant and cosurfactant was selected as 2:1.In the optimal pseudo-ternary phase diagram, four ME formulations(ME1-ME4) at water content of 50%,60%,70%,and 80%, respectively, were prepared along the water dilution line of oil to surfactant ration of 1:3(DL 1/3). These ME formulations were characterized in terms of appearance, morphology, droplet size and electric conductivity. In the results, the appearance of optimal ME4 formulation was clear and transparent by visual observation. The morphology of droplet was nearly spherical. The average droplet size of drug-loaded MEs ranged from 27.45 to 103.80 nm, which decreased as water in MEs decreased. The electric conductivity of MEs increased with the water content. Besides, the optimal ME4 formulation presented excellent centrifugal and long term stability.In vitro skin permeation study was carried out for ME optimization. The skin location amount of CAF from ME4 was signigicantly higher than control(P < 0.05). Thus ME4 was selected as the optimal ME formulation and composed of 5%(w/w) Labrafil M 1944 CS, 15%(w/w)Smix(2/1, Cremophor EL and tetraglycol) and 80%(w/w) aqueous phase. Visualizing distribution of rhodamine B within the skin layers further confirmed the skin targeting effect of hydrophilic substances from ME4 formulation.In pharmacokinetics study, the optimal ME4 resulted in higher percutaneous permeation efficiency with excellent in vitro-in vivo correlation(type A correlation). In pharmacodynamics studies, CAF-loaded ME4 was superior in terms of increasing apoptotic sunburn cells as compared with control(P < 0.05).In conclusion, the opimal ME4 might be a promising vehicle for the topical delivery of CAF to improve its skin retention and subsequently inhibit UVB-induced skin tumor. |
