Transdermal therapeutic systems, intended to deliver a drug across skin for systemic activity, are receiving attention because these systems can (1) avoid hepatic first-pass metabolism, (2) maintain blood drug levels for an extended period of time by controlling the drug-release rate and (3) allow easy interruption of drug delivery.1,2) However, the stratum corneum is known to be a major barrier to drug permeation through the keratinized epithelium. Due to the poor skin permeation of drugs, transdermal administration is often limited.3) For enhancing drug delivery across the skin, the efficacy of penetration enhancers has been investigated.4) The penetration enhancers are generally classified as membraneacting types or co-solvent types. The membrane-acting types, such as fatty acid, 5-7) terpene [8][9][10] and surfactant, [11][12][13] achieve effects using small amounts by altering the condition of the lipid membrane constituting the stratum corneum. The co-solvent types, such as propylene glycol (PG), 10,14) polyethylene glycol 15) and ethanol, 8) achieve effects by improving the solubility of drugs or enhancing permeation of drugs through the skin.Propofol (PF), a lipophilic anesthetic, is widely used clinically as it (1) has a rapid onset and cessation of effects upon intravenous infusion, (2) accumulates little and induces a brief but profound anesthesia, (3) maintains a level in circulation similar to the levels achieved by inhalation anesthetics. The characteristics of PF, lipophilicity and low molecular weight (MWϭ178), is suited to the transdermal delivery. 16)Furthermore, as PF exists in the liquid state above 20°C, a high-concentration PF solution can be prepared. In the previous study, we confirmed that PF was absorbed through rat skin and induced a sedative effect in rats.17) By transdermal delivery of PF, the blood level of the drug can be maintained for an extended period of time. Hence, a possibility that PF can be developed as a transdermal dosage form of sedative or hypnotic is considered. In this study, the in vitro skin permeability and the in vivo absorbability of PF were investigated in rats using PF solutions containing various types of enhancers. Then, we estimated the effectiveness of enhancers on the transdermal delivery of PF. (Osaka, Japan) as the purest grade available. Macrogol 400 (MG) was of Japanese Pharmacopoeia (JP) grade. Sucrose fatty acid esters were obtained from MitsubishiKagaku Foods Corporation (Tokyo, Japan). We used four kinds of sucrose fatty acid esters (L595, L1695, O1570 and S1570). L, O and S indicate lauric acid, oleic acid and stearic acid, respectively. The hydrophilic lipophilic balance (HLB) values of L595, L1695, O1570 and S1570 were 5, 16, 15 and 15, respectively. All other chemicals were obtained commercially as the purest grade available. MATERIALS AND METHODS MaterialsAnimals Male Sprague-Dawley rats weighing approximately 200-220 g were purchased from Tokyo Laboratory Animals Science Co., Ltd. (Tokyo, Japan). The experimental protocol was approved by the...

Propofol (PF), a highly lipophilic anesthetic, has several desirable properties, such as the rapid onset and cessation of its effects upon intravenous infusion. In this study, the transdermal absorption of PF was investigated with the aim of the development of an alternative route of administration. PF solutions containing isopropyl myristate (IPM), ethanol or propylene glycol (PG) at various concentrations were prepared and applied to the abdominal skin of rats. Petrolatum and fatty alcohol propylene glycol (FAPG) ointments containing PF were also prepared and applied to the dorsal skin. Eyelid opening was measured and the ratio of the measured value to the initial value was calculated to evaluate the level of the pharmacological effect of the preparation. The PG solution containing 80% PF achieved higher plasma PF concentrations than the 100% PF solution. The PF-FAPG ointment produced a higher plasma PF concentration than the PF-petrolatum ointment. Furthermore, a drowsy state was confirmed after transdermal administration of 42% PF-FAPG ointment. These results indicate that the combination of PF and PG was appropriate for the transdermal absorption of PF, and PF was absorbed through the rat skin to an extent sufficient to cause a continuous sedative effect.