title: Transdermal delivery and accumulation of indomethacin in subcutaneous tissues in rats.
abstract: Oral non-steroidal anti-inflammatory drugs (NSAIDs) are effective pharmacotherapy for a wide variety of painful, inflammatory disorders. Development of an efficient means of topical administration of NSAIDs could increase local soft-tissue and joint concentrations while reducing systemic distribution of the drug, thereby reducing side-effects. With this in mind we studied the effects of a novel topical penetration enhancer for lipophilic compounds, a trans-phase delivery system (TPDS), a solution of benzyl alcohol, isopropanol and acetone, on the distribution of indomethacin in various tissues locally and remote from the site of application. We compared the TPDS with a 50:50 (v/v) mixture of propylene glycol and ethanol, a commonly used penetration enhancer, and with oral administration. We found that the TPDS was significantly superior to the other approaches at achieving high local-tissue concentrations in the vicinity of the site of application. In addition, comparison of these two carrier systems seems to clarify the different aqueous and hydrophobic pathways of drug penetration which emerge from various experimental findings and theoretical considerations. Our results suggest that this non-aqueous solvent system, and benzyl alcohol in particular, because of its unique physicochemical and solvating characteristics, might be able to deliver therapeutic levels of indomethacin to tissues close to the site of application in a safer and more effective manner than presently accepted forms of delivery.
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Medicine, University of Southern California, Los Angeles 90033, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Mikulak
authors.forename: C T
authors.initials: CT
authors.lastname: Vangsness
authors.forename: M E
authors.initials: ME
authors.lastname: Nimni
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019905:Benzyl Alcohol; D002250:Carbon Radioisotopes; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D007213:Indomethacin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D012869:Skin Absorption; D012996:Solutions; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002250:Carbon Radioisotopes; D014677:Pharmaceutical Vehicles; D012996:Solutions; D019905:Benzyl Alcohol; D007213:Indomethacin