Hyaluronan as a drug delivery system for diclofenac: a hypothesis for mode of action.

Hyaluronan (HA) in combination with diclofenac is currently undergoing clinical trials as a topical preparation in the management of osteoarthritic pain, basal-cell carcinoma and actinic keratosis. These are clearly diverse pathologies, but in all cases substance P plays a central role either directly or through secondary mediators such as prostaglandin E2 and nitric oxide. A common mechanism for HA in combination with diclofenac in these conditions may be through ameliorating the direct and indirect effects of substance P. Additionally, HA appears to depot and hold diclofenac in the epidermis, thereby prolonging its pharmacokinetic half-life. In rabbits, stenosis following balloon angioplasty is prevented by a subcutaneous dose of HA, probably through blockade of cell-surface HA receptors (ICAM-1, CD44 & RHAMM). The physicochemical properties of HA, and the binding of HA to HA receptors, suggests that HA will have value as a novel drug delivery system.