ABSTRACT
The aim was to evaluate the skin permeation and accumulation profiles of a highly lipophilic fatty ester using the combination of various permeation enhancing techniques to study the potential of highly lipophilic fatty esters as local topical agents. Permeation and accumulation profiles of ketorolac stearate (C18:0) were studied using solubility improved formulation, supersaturated solution of permeant in enhancer vehicle, lipophilic receptor solution, enhancer pretreatment, and the removal of stratum corneum and delipidization of skins. Impermeability and minimal skin accumulation of ketorolac stearate could delineate a preliminary possibility for designing safer topical agents without systemic absorption.
Subject(s)
Fatty Acids/pharmacokinetics , Ketorolac/pharmacokinetics , Skin Absorption/drug effects , Animals , Calibration , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Esters/chemistry , Esters/pharmacology , Fatty Acids/chemistry , In Vitro Techniques , Ketorolac/chemistry , Magnetic Resonance Spectroscopy , Mice , Mice, Hairless , Microscopy, Electron, Scanning , Molecular Weight , Skin/metabolism , SolubilityABSTRACT
The purpose of this study was to evaluate the physicochemical properties, skin permeation and accumulation profiles of model lipophilic ketorolac fatty ester (esters) prodrugs. Ketorolac linoleate (C18:2), oleate (C18:1) and stearate (C18:0) were evaluated for their solubility, capacity factor, enzymatic hydrolysis, chemical stability, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of supersaturated solution of permeants in the enhancer vehicle, lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc. Esters were highly lipophilic, chemically stable for the duration of observation, enzymatically unstable in hairless mouse skin/liver homogenates and plasma, and impermeable into the receptor solution. Absence of skin permeation, relative enzymatic stability during permeation and chemical stability of these esters could delineate preliminary possibilities for designing safer topical agents without systemic absorption.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Ketorolac/analogs & derivatives , Ketorolac/pharmacokinetics , Prodrugs/pharmacokinetics , Skin Absorption , Administration, Cutaneous , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Chromatography, High Pressure Liquid , Drug Stability , Esters/pharmacokinetics , Hydrogen-Ion Concentration , Hydrolysis , Ketorolac/chemical synthesis , Ketorolac/chemistry , Mice , Mice, Hairless , Molecular Structure , Molecular Weight , Permeability , Prodrugs/chemical synthesis , Prodrugs/chemistry , Solubility , Structure-Activity Relationship , TemperatureABSTRACT
PURPOSE: Classic penetration enhancement/retardation methods for improved dermal drug delivery primarily focus on co-applied chemicals aided alterations in skin accumulation/permeation profile, and in many cases, this has been achieved by compromising the systemic absorption/toxicities of penetrant/enhancer/retarder. In this study, higher dermal accumulation without systemic absorption of ketorolac and its fatty esters (esters) will be achieved by synthesizing lipophilic fatty ester soft prodrugs of ketorolac. METHODS: Ketorolac decenoate (C10:1), dodecenoate (C12:1) and palmitoleate (C16:1) were synthesized and evaluated for their lipophilicity, enzymatic hydrolysis, chemical stabilities, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc. RESULTS: Esters were highly lipophilic, chemically stable, enzymatically unstable in hairless mouse skin/liver homogenates and impermeable into the receptor solution. CONCLUSION: Higher dermal accumulation, absence of skin permeation, relative enzymatic stability in whole skins during permeation study and the pharmaceutical stability of esters could delineate a preliminary possibility for designing safer dermal agents with minimum potential for systemic absorption without the co-application of permeation enhancers or retarders.
