Ketotifen is one of the candidate drugs for developing a transdermal therapeutic system (TTS), because of its superior pharmacological action against asthma at low plasma concentrations.1) However, since the drug is present as cations at skin pH (pK a value of ketotifen is 8. 5 2) ), it exhibits low skin permeability. Therefore, application of a chemical or physical permeation enhancing system is necessary to develop its TTS potential. Thus the effects of chemical enhancers such as L-lactic acid-ethanol-isopropyl myristate have been examined. 1,3) Alkyl surfactants have been revealed to work as a chemical enhancer on skin permeation of various drugs.4,5) Among them, alkylammoniums such as n-dodecyltrimethylammonium are known to show marked enhancement effects on skin permeation of drugs such as methyl nicotinamide 6) and nonionized form of benzoic acid. 7) Chemical enhancers have been demonstrated to work after penetration into the stratum corneum by increasing either the partition of the drugs to the skin or their diffusion rates in the stratum corneum. 8) Since ketotifen is a cationic drug, electric interaction with enhancers may also affect their enhancement effects. Therefore, to clarify whether such an interaction is involved or not, in this study we examined the effects of alkyl surfactants with different electric charges. We examined the effects of anionic sodium dodecylsulfate (SDS), cationic n-dodecyltrimethylammonium bromide and non-ionic n-dodecyl-b-D-maltoside, all of which commonly have n-dodecyl group as their alkyl chains, on in vitro skin permeation of ketotifen. We compared the effects of these surfactants on ketotifen permeation with their effects on the anionic salicylate permeation. Furthermore, we examined the effects of these surfactants on the intradermal concentration of ketotifen.
ExperimentalMaterials Bromide salt of n-dodecyltrimethylammonium and 3-(lauryldimethylammonio)-1-propanesulfonate were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Ketotifen fumarate was from Sigma Chemical Co. (St. Louis, MO, U.S.A.). n-Dodecyl-b-D-maltoside was from Dojindo Laboratories (Kumamoto, Japan). Sodium dodecylsulfate (SDS) and all other reagents were purchased from Wako Pure Chemical Industries (Osaka, Japan).Skin Preparations Full thickness dorsal skin was excised from male guinea pigs and subcutaneous fat and other extraneous tissues were trimmed. Delipidized skin was prepared as described previously. 9) Stratum corneum lipids were extracted by incubating the excised skin with a chloroform-methanol mixture (2 : 1 vol) for 12 h and washing it extensively with phosphate buffered saline (PBS).
Measurement of in Vitro Skin PermeationIn vitro skin permeation of ketotifen was examined as described previously.10) The skin was mounted in a Franz cell with water jackets (37°C). The available diffusion area was about 0.64 cm 2 , and the lower cell volume was about 4.5 ml. The upper cells were filled with 1 ml saline either in the presence or absence of surfactants, and the receiver cel...
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