Two Transdermal Drug Delivery Formulations of Piroxicam

Piroxicam, a non-steroidal anti-inflammatory drug, mainly used for the treatment of rheumatic and rheumatoid arthritis, is a strong inhibitor of prostaglandin synthase. Piroxicam has the characteristics such as long half-life (50h), small dosage, no accumulation, exact effect and so on. Gastrointestinal side effects are the most common side effects of piroxicam by oral.It tends to cause gastrointestinal bleeding, ulcers and other adverse effects after long-term use of piroxicam orally. So, many researchers all over the word are focusing on the development of percutaneous formulations, such as emplastrum, ointments, liniment, gels, etc. In this study, we want to find the optimum percutaneous formulation of piroxicam through the research of piroxicam gels and microemulsion.In this study we first established an accurate, reliable in vitro analysis method and investigated the effect of various permeation enhancers on piroxicam percutaneous behavior. The experiment results showed that Azone, menthol and urea all can promote the penetration of piroxicam. Among these permeation enhancers, 1% Azone combined with 10% propylene glycol shows the best penetration enhancing effect, which can significantly increase the permeability of piroxicam (P <0.01)and its enhancement factor was 3.32 times.Previous studies showed that gels have the character such as strong adhesion, good skin absorption after topical administration. So, we started with preparation of piroxicam gel in this study. Based on the results of the permeation enhancers, we developed several piroxicam gels consists of different permeation enhancers and matrix, carbomer-940 and hydroxypropyl cellulose (HPC), for example. In vitro penetration enhancing effect research indicated that the optimal gel formulation of piroxicam was as following:hydroxypropyl cellulose (HPC) as a matrix, and 1% Azone combined with 10% propylene glycol as permeation enhancers. In order to further understand the permeability of piroxicam that we made by ourself, we compared it with domestic and original research product (Feldene Gel, Pfizer Limited) listed in the market.The results show that the permeability of piroxicam that we made is superior to domestic product but inferior to Feldene Gel.The advantages of microemulsion for the dermal delivery of drugs will be showed below:First,the concentration of drug in the skin is increased due to large amount of drug can be incorporated in the formulation. On the other hand,the increased thermodynamic activity of the drug may favor its partitioning into the skin. At the same time,the ingredients of mieroemulsion may reduce the diffusional barrier of the stratum corneum and inerease the permeation rate of drug via skin by acting as permeation enhancers. To further enhance the percutaneous permeability of piroxicam and improve the clinical efficacy, we prepared piroxicam microemulsion. The ability of Permeation in vitro and in vivo was evaluated.The basic components of microemulsion formulation were determined by investigating different oils, surfactants and cosurfactant.The pseudo-ternary phase diagram of microemulsion were made to determine the microemulsion area. And cumulative amount of piroxicam permeated through the rat skins per uint area at 12 hours were selected as the response variables to optimize the microemulsion formulation. The optimal formulation was:oil (Lauroglycol FCC) 10%, surfactant (Labrasol:Cremophor EL=1:1)26.6%,cosurfactant (Transcutol P) 13.3% and water 50%. The piroxicam microemulsion has some profiles:the average particle size was 19.4nm,100%, with homogeneous distribution; the viscosity was 0.079 Pa-s.We also compared the transdermal deliver kinetics of 0.5% piroxicam microemulsion and Feldene Gel by in vitro penetration test in rats. The results showed that the percutaneous penetration rate of piroxicam microemulsion was 1.66 times of Feldene Gel.In the last part of this study, we evaluated the pharmacokinetics and bioavailability of piroxicam microemulsion in rats in comparison with Feldene Gel. The pharmacokinetic parameters of piroxicam microemulsion were showed as following:t1/2 was 13.5hours, Tmax was 26hours, Cmax was (35.64±11.31)μg·mL-1, AUC0-t was(1511.78±388.38)μg·h·mL-1,relative bioavailability of piroxicam microemulsion was 185.63%.These figures suggested that piroxicam administration can increase its bioavailability in rats compared to Feldene Gel.