Transcutaneous delivery of anti-arthritic agents

Abstract

There is a substantial clinical need for improved therapeutic systems for the treatment of arthritis. This thesis concerns the development of a novel medication that is applied to the skin directly overlying the areas affected. The system comprises the co-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), plus a non-steroidal anti-inflammatory (NSAID) drug. The source of EPA and DHA is fish oil which contains high proportions of these compounds and, although still largely considered a 'neutraceutical', its therapeutic value is supported by an ever increasing body of evidence, both scientific and anecdotal. The NSAID examined was ketoprofen, a widely used drug, found in a number of topical preparations. Synergistic action involving the two substances would be expected to provide a multi-faceted attack on the aetiology of arthritis. Ketoprofen and EPA/DHA were successfully delivered across full-thickness porcine ear skin in-vitro, although the presence of thickening agent retarded permeation of the latter. The successful delivery of these compounds into the joint capsule of a porcine forelimb was also demonstrated in-vitro. A novel transcutaneous delivery model was developed and used to provide preliminary data for the uptake of EPA into an ex-vivo cartilage ex-plant post transcutaneous permeation. The last three chapters can be considered collectively as an investigation into the unexpected phenomenon of enhancement of EPA/DHA by ketoprofen and two main hypotheses were tested firstly, the formation of a Jt-jc ketoprofen / EPA complex - the existence of which was strongly supported by the NMR/molecular modelling work of Chapter 8 secondly, the ketoprofen inhibition of epidermal enzymes active upon EPA, discussed in Chapters 7 and 9. In summary, the development of a novel dual-action, transcutaneous anti-arthritic formulation is possible and has been supported by this work. Furthermore, a hitherto unknown topical delivery mechanism has been elucidated.EThOS - Electronic Theses Online ServiceGBUnited Kingdo