The Investigation Of Naproxen Gel-Microemulsion Transdermal Delivery System And Its Preliminary Pharmacodynamics Evaluation

Objective Poorly water-soluble naproxen was considered as a model drug in this paper. In order to avoid gastrointestinal irritation and reduce systemic toxicity reduced by conventional administration, naproxen transdermal drug delivery system was prepared. Due to the large drug consumption of naproxen, stable gel-microemulsion with high drug content was prepared, and its anti-inflammatory and analgesic effects were investigated.Method During the preformulation study, the analytical method of high performance liquid chromatogram (HPLC) for naproxen was established. The effect of formulation factors on in-vitro permeation performance of naproxen was evaluated by cumulative permeated amount, stable state permeation rate and permeation coefficient, which was conducted through Franz diffusion cell. Based on the solubility of naproxen, the oily phase, surfactant and cosurfactant composed of microemulsion were selected. The formulation of microemulsion was optimized through pseudo-ternary phase diagrams and transdermal permeation rate. Phase inversion temperature (PIT) method was used in naproxen microemulsion prepared to increase solubilizing content. Gel-microemulsion of naproxen was prepared by adding the gel-matrix (carbomer 980) directly into the optimization microemulsion, the best content of gel-matrix was selected according to the viscosity and percutaneous permeation parameter of gel-microemulsion. The stability of preparations both microemulsion and gel-microemulsion were studied by high temperature test, low temperature test, accelerated test and long-term test, through appearacarbomer 980nce observation, viscosity, pH and drug content measured. With diclofenacsodium-mayinglong (diclofenac sodium gel) as positive control, paw edema in rats were induced by carrageenin to observe the anti-inflammation effect of naproxen gel-microemulsion, while writhing test were adopted to study their analgesic effect. Finally, the influence of different dose of naproxen praeparatum to the skin irritation was studied by rabbit.Result The chromatographic condition of HPLC was estanblished.The column was an Kromasil C18 (4.6mm×250mm,5μm) with a mixture of Methanol-0.01mol·L-1 potassium dihydrogen phosphate (75:25) solution as the mobile phase, at a flow rate of 0.8mL·min-1. The column temperature was at 30℃.The detection wave-length was at 271nm.The sample size was 20 μL.Phosphate buffer of pH 7.4 was selected as receptor medium in transdermal permeation experiments. Selected menthene as oily phase, mixture of Tween 80 and Tween 20 (WT80:WT20=2:1) as surfactant, carbitol as cosurfactant, the optimum formulation of microemulsion vehicle was determined as 5% oily phase,17.5% surfactant mixture,17.5% cosurfactant and 60% water. The maxium drug content loaded in microemulsion prepared by PIT method was 4%, which was obviously larger than ordinary method (1.5%). The stable state permeation rate of optimized formulation of microemulsion through dialysis-membrane was 531.912μg·cm-2·h-1. The best content of carbomer 980 in gel-microemulsion was selected as 1.5%, of which the viscosity was 16.0 Pa·s, and Js was increased by 20% compared with the microemulsion with the same content of drug. high temperature test, low temperature test, accelerated test and long-term test showed the preparations both microemulsion and gel-microemulsion were stable. Local administration of both naproxen microemulsion and gel-microemulsion exhibited fine anti-inflammation and analgesic effect. Low, middle and high dose of both naproxen microemulsion and gel-microemulsion could dose-dependently inhibit reaction of writhing induced by acetic in mice. The results of anti-inflammation experiment demonstrated low, middle and high dose of both naproxen positive control gel and microemulsion could alleviate paw edema swell in rats induced by carrageenin in some degree, and the effect of middle and high dose was more effective. There had no evident difference in inhibition ratio for writhing induced by acetic between diclofenac sodium gel, naproxen microemulsion and gel-microemulsion. However, the effect of naproxen gel-microemulsion was longer and more stable in inhibiting paw edema swell in rats and elevating threshold of pain in mice than naproxen microemulsion and diclofenac sodium gel. It was shown in the skin irritation test that low, middle and high dose of naproxen praeparatum was no skin irritation to normal skin.Conclusion In this study, stable naproxen gel-microemusion with high drug content and good permeation performance was prepared, which had no skin irritation and exhibited better anti-inflammatory and analgesic effect, was expected to become a new promising vehicle for transdermal delivery of naproxen.