ROLE OF HEPARIN IN ENHANCING THE SKIN PENETRATION AND PAIN RELIEF FROM DICLOFENAC EPOLAMINE (DHEP) MEDICATED PLASTER
K.D.Rainsford 1, S.Rovati 2, A.Nencioni 3, C.Jones 4
1 Biomedical Research Centre, Sheffield Hallam University, Sheffield, S1 1WB, UK
2 R&D and Scientific Affairs, IBSA Institut Biochimique, Pambio-Noranco, Lugano, Switzerland, 
3 Pharmaceutical R&D, IBSA Institut Biochimique, Manno, Lugano, Switzerland
4 Scientific Advisor, IBSA Pharma Inc., Washington D.C., USA.

BACKGROUND & AIMS: Topical NSAIDs are effective in the treatment of musculo-skeletal inflammation/pain, while at the same time reducing the risk of systemic AEs. Among NSAIDs topical formulations, diclofenac epolamine (DHEP) medicated plaster was found amongst the most effective. Recently, the incorporation of heparin into the DHEP medicated plaster was developed with the aim to enhance diclofenac penetration to the site of inflammation. 
METHODS: (1) Heparin residual content in the medicated plaster was measured after 24-hour application in healthy volunteers participating in a PK (BA) study; (2) The release and permeation of DHEP from medicated plasters formulated with and without heparin were compared in a Franz cell diffusion system using different membranes. 
RESULTS:  (1) No pre-/post-application change in plaster heparin content was observed following 24-hour application in vivo, showing that heparin release from the plaster is negligible, if any, while at the same time DHEP content was substantially reduced; (2) Permeation profiles in Franz cells showed that both the amount and rate of DHEP release from heparin-containing plasters was significantly greater as compared to the reference formulation without heparin.
CONCLUSIONS: In vitro and in vivo data demonstrated that heparin is not released from the DHEP plaster formulation after topical application. This suggests that heparin works as permeability enhancer, increasing the release and skin penetration of diclofenac, thus providing an explanation for the significantly greater analgesic efficacy of the DHEP heparin plaster vs the DHEP plaster without heparin in clinical trials.