Evaluation of topical formulations of selective cyclooxygenase 2 cox 2 inhibitiors for analgesic and antiinflammatory efficacy as well as plasma concentration profile

Abstract

Selective cyclo-oxygenase-2 (COX-2) inhibitors have been in use as analgesic and anti-inflammatory agents for over a decade. In addition they have been shown to have beneficial effect in cancer chemotherapy. However, COX-2 inhibition has been associated with an increased risk of cardiovascular as well as other adverse events in several clinical trials. Delivery of coxibs by topical route can be useful to avoid the adverse drug effects, without losing the beneficial effects of the coxibs. Topical formulations of Rofecoxib and Celecoxib were prepared, evaluated for its acceptability, efficacy and safety. These were tested for physical appearance, pH, spreadability, drug content uniformity and in vitro diffusion. Emulsion gel formulations were prepared containing 1-3% Rofecoxib or 3-5% Celecoxib (w/w) along with optimized amounts of Carbopol 940, Labrasol and Ethanol. Use of sub-micronised Rofecoxib/ Celecoxib in the above formulation (FG14/ FG30, respectively) resulted in improved in vivo efficacy. Selected formulations FGI4 and FG30 were evaluated in models of acute and chronic inflammation as well as hyperalgesia. Comparison of systemic exposure following topical as well as oral dosing by determining plasma concentrations of Rofecoxib/ Celecoxib in test animals, determination of skin irritation, gastic ulceration or other systemic adverse effect potential after chronic exposure and determining of ex-vivo COX-1 and COX-2 inhibition potential in rat blood were conducted to study the safety of topical gels. 1% (w/w) Rofecoxib gel, FG14 and Celecoxib gel containing 5% (w/w) of the drug, FG30, was significantly (p < 0.05) more effective in inhibiting inflammation and hyperalgesia associated with inflammation, compared to placebo gel, in acute and chronic model.