UQ eSpace

Abstract

Transdermal delivery appears to be on the brink of rapid expansion for the administration of drugs with suitable physicochemical properties where current methods of administration are fraught with problems. Strategies of optimising drug delivery through this means have been the focus of much investigation in recent years. In this work, rapid and sensitive high-performance liquid chromatographic (HPLC) methods were developed for the determination of the non-steroidal anti-inflammatory drugs (NSAIDs) benzydamine, diclofenac and ketoprofen in rat plasma, skin, muscle and fat samples. Plasma and tissue protein were precipitated with methanol. Good recoveries were obtained for both plasma and tissues. Linearity of response was found to be good (r2 > 0.99) and consistently reproducible. The limits of quantitation of benzydamine, diclofenac and ketoprofen in plasma were 20, 3.2 and 1.5 ng on column respectively and 25, 3.2 and 4.2 ng respectively in 100 mg of tissue. The HPLC methods were applied for the determination of the pharmacokinetic parameters of these NSAIDs after topical application of commercially available formulations to male Wistar rats. The underlying tissue penetration of NSAIDs (benzydamine, diclofenac, ketoprofen, salicylate ester and salts) after topical application of their commercially available products was evaluated in a rat model. The results indicate that local direct tissue penetration of the drugs is dominant to the superficial muscle layer below the application sites. The NSAID concentrations in the deeper tissues approached concentrations observed in the contralateral tissues suggesting that drugs present in these tissues were due to the systemic blood supply. In vivo plasma and tissue concentration-time course profiles of salicylate showed a very rapid rise in the first 1h for the ester, methyl salicylate mirroring its effect on local blood flow. The in vitro delivery of the NSAIDs through full-thickness rat skin is not predictive of their in vivo penetration in the rat model. The ion pair concept was examined as an approach to optimise the topical delivery of salicylate. Although the ion pair formation between salicylate and primary amines had no effect on either the octanol/water partition coefficient or flux of salicylate through membranes, the tissue retention of salicylate was enhanced. The in vitro penetration of salicylate in the presence of primary amine counterions was not predictive of its in vivo transdermal delivery in rat model. A homologous series of tertiary amines imparted highly different hydrophobic properties to the ionisable salicylate upon ion pair formation and resulted in 1.3- to 4.8-fold enhancement of in vitro delivery through human epidermis. The results of the in vitro experiment show that salicylate flux through human epidermis may be related to the conductivity of the donor solution, lipophilicity of the ion pairs and molecular size of the counterions.