Rationale and evidence for the incorporation of heparin into the diclofenac epolamine medicated plaster

Abstract

The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains, and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP Plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient has been developed. Methods: We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions. Results: The data were consistent with the concept that heparin increased the clinical activity of the DHEP Plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP Plus medicated plaster. Efficacy studies showed that the DHEP Plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster. A c c e p t e d M a n u s c r i p t Conclusions: The benefit/risk assessment of DHEP Plus 180 mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.

The Efficacy of Topical Heparin Preparations for the Management of Pain and Superficial Vascular Disorders in Orthopaedic Surgery and Musculoskeletal Trauma

“…This different evolution can be explained by the depth and the magnitude of the injuries in Orthopedic and Traumatology clinic and by the fact that topical heparin induces mostly local superficial effects because topical heparin cannot follow diclofenac in systemic flow in clinically significant concentrations in order to induce intense and profound anti-inflammatory effect [4]. The present results are in line with previous reports showing that, even if it was demonstrated that topical heparin is not able to modify coagulation parameters [9,10], yet topical heparin demonstrated positive local microcirculation changes as increased capillary venous oxygen saturation, increased blood filing of microvessels, increased blood flow and velocity [11,12] and enhanced fibrinolytic effect [13]. The reported effects were more prominent when topical heparin was aided by dexpanthenol as penetration enhancer [12,14].…”