MECHANISM FOR ENHANCEMENT EFFECT OF LIPID DISPERSE SYSTEM ON PERCUTANEOUS-ABSORPTION

To clarify the mechanism involved in the enhancement effect of lipid d isperse systems (LDS) on percutaneous absorption, the effect of the LD Ss of betahistine (BH), prepared using egg phosphatidylcholine (EPC, p hase transition temperture, tau(m), -15 to -17 degrees C) or hydrogena ted soybean phosphatidylcholine (HSPC, tau(m), 50 to 60 degrees C), ch olesterol, and dicetylphosphate, on the percutaneous absorption of BH, the amount of skin lipids (ceramides, triglycerides, and phospholipid s), the fluidity of skin lipids, and the partitioning of LDS-BH into t he skin layers were investigated using Wistar and hairless rats. Also examined was whether the LDS penetrated through the stratum corneum (S C) or follicles, using a fluorescent probe (Nile Red). The plasma conc entrations of BH were much higher and more sustained after application of a gel formulation containing EPC-LDS and D-limonene (prep. 2) than those after the non-LDS formulation containing D-limonene (prep. 1), whereas the plasma levels after application of a formulation containin g HSPC-LDS (prep. 5) were not largely increased compared with those af ter prep. 1. The content of ceramides (intercellular lipids) and trigl ycerides (sebaceous gland lipides) in the SC were dramatically decreas ed by the treatment with prep. 1 and prep. 2, with the more decreased levels of these lipids by the treatment with prep. 2. The phospholipid content of the SC was enhanced by 2-fold following the prep. 2 treatm ent, indicating the extensive incorporation of LDS lipids into the SC. The histochemical examination of the skin, following application of E PC-LDS with a fluorescent probe, indicated that the LDS lipids penetra ted rapidly through the SC and follicles into the viable skins. The fl uidity of the SC lipids was dramatically increased following the treat ment with the fluid EPC-LDS, whereas the fluidity was significantly de creased by the solid HSPC-LDS. The BH in each skin layer was also sign ificantly increased by the treatment with prep. 2. These results surel y demonstrated that the fluid LDS permeated rapidly into the SC and th e viable epidermis through the intercellular domains and the follicles in intact vesicles or lipid mixtures, thus ensuring the facilitated t ransport of LDS-drug through the skin.