Biol. Pharm. Bull. 28(9) 1689—1694 (2005)

drug administration. However, the barrier properties of the outermost layer, the stratum corneum, have limited the number of successful transdermal dosage forms developed thus far. One of the strategies for overcoming this problem is temporary local reduction of the barrier function of the stratum corneum with the aid of a percutaneous absorption enhancer. Sucrose fatty acid esters (sugar esters) are nonionic surfactants with sucrose as the polar head group and one or several fatty acid chains as the lipophilic moiety. Some of them are legally approved as food additives due to their high safety and are registered as pharmaceutical excipients in Japan, USA, Canada, Australia, and New Zeeland. Sugar esters have low irritancy to the skin and eyes. There have been several reports or patents about utilizing sugar esters as additives for drug formulations. Some sugar esters enhance gastrointestinal absorption of elastase and blactam antibiotics. The nasal mucosal absorption of peptides such as calcitonin, interferon, and a-human atrial natriuretic polypeptide are increased by sucrose laurate or sucrose stearate. Sucrose palmitate enhances the absorption of calcitonin from the oral mucosa and gingiva in rats. Ganem-Quintanar et al. examined the effect of sucrose stearate, oleate, palmitate, and laurate on the permeation of lidocaine hydrochloride through excised pig palate and cheek and reported that only sucrose laurate acted as an absorption enhancer. Some sugar esters act as percutaneous absorption enhancers. It has been reported that sucrose stearate and sucrose laurate increase percutaneous absorption of bromhexine in rats and oestradiol in rabbits, respectively. The percutaneous absorption of diltiazem and hydromorphone are also aided by some sugar esters. Nakada et al. examined the effect of more than 10 sugar esters with HLB ranging 2 to 16 on the absorption of calcitonin from oral mucosa in rats. An enhancing effect was found for sugar esters with HLB values ranging from 11 to 16. However, the effect of the length of the fatty acid chain and HLB of sugar esters on their activity as percutaneous absorption enhancers has not been reported. In the present study, we selected six sugar esters with HLB 5—16 and evaluated their effect on percutaneous drug permeation in in vitro experiments using excised hairless mouse skin. We employed lidocaine (LC, pKa 7.9) 15) and ketoprofen (KP, pKa 4.0) 16) as model basic and acidic drugs, respectively. The drugs were dissolved in buffer solutions with several pHs so that we could evaluate the effect of the sugar esters on the percutaneous permeation of ionized and unionized drug species. It has been reported that sugar esters form micelles in water and in an organic solvent. The micelles would affect the thermodynamic properties of a penetrant in a vehicle. To examine the effect of sugar esters on skin permeability and to minimize the effect on vehicle or interaction with drug in the vehicle, we employed the pretreatment technique. Excised hairless mouse skin was pretreated with sugar esters to allow them penetrate into the skin. Then an LC or KP solution with no sugar esters was applied to evaluate the drug permeation rate. In the next set of experiments, we applied drug solutions or suspensions containing selected sugar esters to the excised skin with no pretreatment to evaluate the effect of sugar esters formulated in a vehicle on skin permeability.