Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro. II: Drug, vehicle, and enhancer penetration kinetics.
The fluxes of representative hydrophilic (propranolol hydrochloride) and lipophilic (diazepam or indomethacin) drugs, administered as ethanolic solutions containing putative penetration enhancers (n-nonane, 1-nonanol, and 1-decanol), were measured across hairless mouse skin in vitro. Propranolol transport was augmented significantly by the presence of 4% (v/v) alkane or alkanol in the vehicle; diazepam and indomethacin, on the other hand, were enhanced only by n-nonane. Experiments with saturated solutions of the drugs as the donor phase revealed that the actions of the enhancers were taking place in the skin and were not a result of an alteration of solute thermodynamic activity in the vehicle. In separate runs, the impact of n-nonane and 1-nonanol on the percutaneous penetration of ethanol was determined. Temporal effects identical to those on the flux of propranolol were observed. A further measurement revealed that the penetration of 1-decanol, when administered as a 4% (v/v) solution in ethanol, followed a profile similar to that of the solvent (which, in turn, was comparable with that of the independently assessed propranolol hydrochloride). Thus, considerable linkage exists between the transport of a hydrophilic drug and the major vehicle component in the presence of n-nonane and 1-nonanol. The lipophilic drugs, conversely, were promoted only by n-nonane and only after most of the ethanol had been absorbed. The results show that an apparent synergy of transport between a putative enhancer and a cosolvent may not always lead to augmented drug flux. Study of the transport of all key formulation components is recommended, therefore, to optimize vehicles for transdermal drug delivery.
Hori
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Nitto Denko Corporation, Biological Research Laboratory, Osaka, Japan.
Maibach
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Guy
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D000473:Alkanes / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003975:Diazepam / Q000493:pharmacokinetics*; D004357:Drug Synergism; D000431:Ethanol / Q000493:pharmacokinetics / Q000494:pharmacology; D005233:Fatty Alcohols / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D014677:Pharmaceutical Vehicles / Q000493:pharmacokinetics / Q000494:pharmacology*; D011433:Propranolol / Q000493:pharmacokinetics*; D012869:Skin Absorption / Q000187:drug effects*; D014316:Tritium
D000473:Alkanes; D005233:Fatty Alcohols; D014677:Pharmaceutical Vehicles; D014316:Tritium; D000431:Ethanol; C029383:n-decyl alcohol; D011433:Propranolol; C014713:1-nonanol; D003975:Diazepam; C017573:nonane