Controlled transdermal delivery of beraprost, a prostaglandin I2analogue, by combined use of fatty acids and cyclodextrins

Saturated and unsaturated fatty acids enhanced the permeation of beraprost sodium, a chemically stable prostaglandin I2 analogue, from a silicone oil through the skin of hairless mice in vitro. The percutaneous permeation of beraprost showed a parabolic dependence on the lipophilicity of the saturated fatty acids, where capric acid was the most potent enhancer. Of the unsaturated fatty acids tested, oleic and linoleic acids showed greater enhancing effects on the percutaneous permeation of beraprost. When a pressure sensitive silicone adhesive tape containing beraprost sodium was applied onto the shaved skin of rats in vivo, oleic and capric acids enhanced the percutaneous absorption of beraprost, the former being more effective. In particular, the topical application of beraprost sodium with oleic acid significantly inhibited the progress of the laurate-induced peripheral vascular occlusive sequelae in the ear of rabbits. Spectroscopic studies indicated that cyclodextrin derivatives (CyDs) formed inclusion complexes with beraprost sodium with efficacy increasing in the order : sulfated β-CyD (S-β-CyD)hairless mouse skin was pretreated with oleic acid, the in vitro percutaneous permeation of beraprost from the silicone oil was sustained by the complexation with DM-β-and HP-β-CyDs, while S-β-CyD tended to increase the percutaneous permeation of the drug. Furthermore, HP-β-CyD eliminated undesirable properties of oleic acid in the silicone adhesive tape such as the reduction in the detachment force of the tape and the lability against oxidation. These results suggest that a combination of oleic acid with HP-β-CyD is particularly useful for controlling the transdermal delivery of beraprost from topical preparations intended for the systemic use.