Evaluation of in vitro percutaneous absorption of lorazepam and clonazepam from hydro-alcoholic gel formulations.
Clonazepam and lorazepam are two anxiolytics, antidepressant agents, having suitable features for transdermal delivery. The objectives of this study were to evaluate the in vitro percutaneous absorption of these drugs through excised human skin (stratum corneum and epidermis, SCE) and to determine their in vitro permeation behavior from a series of hydro-alcoholic gel formulations containing various enhancing agents. The best permeation profile was obtained for both drugs applying them together with Azone in combination with propylene glycol (PG): these enhancers were able to increase the clonazepam and lorazepam percutaneous fluxes at steady-state about threefold, compared to the free enhancer formulations (Control). To explain the mechanism of the used promoters, the benzodiazepine diffusion and partitioning coefficients from the gel containing the enhancers were calculated. The results indicated that the Azone in combination with PG could act by increasing the benzodiazepine diffusion coefficients, Transcutol increased only the SC/vehicle partition coefficients, limonene in combination with PG appeared to increase both partition and diffusion coefficients moderately, while PG did not increase both the parameters. Furthermore, to evaluate the potential application of tested benzodiazepine formulations containing Azone in combination with PG using the flux values from the in vitro experiments, the corresponding steady-state plasma concentrations (C(SS)) were calculated. The obtained calculated C(SS) values are within the lorazepam therapeutic range and suggest that transdermal delivery of this drug could be regarded as feasible.
Puglia
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Viale Andrea Doria no. 6, 95125, Catania, Italy. boninaf@mbox.unict.it
Bonina
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Trapani
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Franco
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Ricci
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D000328:Adult; D000438:Alcohols; D001381:Azepines; D002851:Chromatography, High Pressure Liquid; D002998:Clonazepam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053138:Cyclohexenes; D005260:Female; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005782:Gels; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D000077222:Limonene; D008140:Lorazepam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption; D013729:Terpenes; D014867:Water
D000438:Alcohols; D001381:Azepines; D053138:Cyclohexenes; D018757:GABA Modulators; D005782:Gels; D013729:Terpenes; D014867:Water; C035229:laurocapram; D002998:Clonazepam; D000077222:Limonene; D008140:Lorazepam