Design Of Meloxicam Transdermal Delivery System And Pharmacokinetic Evaluation

OBJECTIVES: Poorly water-soluble meloxicam （Mel） was considered as a model drug in this paper. In order to avoid gastrointestinal irritation and reduce systemic toxicity via oral administration, meloxicam gels and microemulsion transdermal system were prepared, respectively. The pharmacokinetics and topical tissues distribution of meloxicam gels in rats, beagle dogs and human were investigated. On one hand, the degree of meloxicam enriched in target tissues and the amount of meloxicam entered into the circulation of blood were investigated. On the other hand, the transdermal permeation mechanisms were studied in detail.METHODS: During the preformulation study, HPLC method was established for analysis of meloxicam in vitro. The solubility and oil/water partition coefficient of meloxicam were determined. The receptor medium was chosen to maintain the sink condition. Different permeation enhancers were investigated to screen the optimal permeation enhancers of meloxicam. From the result of preformulation, Carbopol 940 was decided to act as the gel base. The orthogonal experiment was applied to optimize the formulation of Mel gel by single factor experiments. The effects of various factors on the formation of microemulsion were investigated through pseudo-ternary phase diagrams and transdermal permeation rate of meloxicam. The optimal formulation was screened using the solubility of meloxicam in microemulsion and and transdermal permeation rate as index. The structures of microemulsion were presumed by electric conductance, viscosity, particle size as main evaluating indexes, and the correlation between the physicochemical properties and transdermal permeation rate of meloxicam microemulsion was evaluated.The acetic acid-induced body writhing test in mice, the dimethylbenxene-induced ear edema test in mice, the ovalbumin-induced rat hind paw edema and the cotton-induced granuloma test in rat were carried out to investigate the analgetic and anti-inflammatory effects of both meloxicam microemulsion and meloxicam gel with the votalin （diclofenac ointment） as positive control.High-performance liquid chromatography （HPLC） method and high-performance liquid chromatography-tandem mass spectrometric （LC/MS/MS） method were applied for the quantification of meloxicam in plasma, muscle and synovial fluid in rats, dogs and human after transdermal or oral administration of meloxicam in order to study the pharmacokinetic behavior and skin permeation mechanism.RESULTS: During the preformulation study, the solubility of meloxicam was pH-dependent and the solubility increased quickly when pH was higher than 7.4. The oil/water partition coefficient of meloxicam was 1.84±0.10 when distilled water was used as aqueous phase. 20% Ethanol- phosphate buffer （pH 7.4） was chosen as the receptor medium in transdermal permeation experiments and transcutol was chosen as penetration enhancer.The preparation of meloxicam gel was 1.0% Carbopol, 20% propylene glycol and 10% transcutol. The results of stability experiments showed that high temperature had great effect on the content of Meloxicam in gel, so gel should be enclosed and stored at common temperature.The final formulation of meloxicam microemulsion was obtained, consisting of 0.375% meloxicam, 5% IPM, 50% Tween 85/Ethanol （1:1） and water and the transdermal permeation rate was 5.40μg/cm²/h. The droplet size of microemulsion was 36.9 nm and phase transition temperature was 90℃. The morphology of microemulsion by transmission electron microscope was globe and regular. NMR indicated that hydroxy group of meloxicam was easy to bind with oxygen of polyoxyethylene of surfactant and form hydrogen bond.Local administration of either meloxicam gel or microemusion could inhibit both acute inflammation and the proliferation reaction in the late period of inflammation.After meloxicam was administered to rats at a dose of 7.5 mg/kg by intragastric and transdermal administration, respectively, the results showed that drug concentration in blood was very low after transdermal administration. AUC_0-t was 54.9μg·h/mL and 480.1μg·h/mL, respectively. Drug concentration in muscle was similar, and AUC_0-t （25.2μg·h/mL） in muscle after transdermal administration was a little higher than that of oral administration （17.2μg·h/mL）. It indicated that transdermal administration could produce low plasma concentration and relatively high concentration in target tissues, which reduced the system toxicant and side effects.After meloxicam was administered to dogs at a dose of 1.25 mg/kg and 0.31 mg/kg by transdermal and oral administration, the results showed that maximum concentration in plasma was 22±9 ng/mL and 780±136 ng/mL, AUC_0-t was 1.00±0.43μg·h/mL and 23.87±8.26μg·h/mL, respectively.The concentration ratio of synovial fluid to plasma （7.68） at 12 h after transdermal administration was much higher than that after oral administration （0.87）, which indicated that Meloxicam could concentrate in synovial fluid after transdermal administration. The drug concentration in synovial fluid from the treated side (C_max= 167.36±60.17) was higher than that (C_max= 20.60±12.34) from the untreated side, which indicated that the drug in the treated site was mainly reached by direct penetration into synovial fluid besides small amounts which was redistributied by systemic circulation, thereby transdermal penetration mechanism was illuminated.After meloxicam was administered to 10 health volunteers at a dose of 30 mg/kg and 7.5 mg/kg by transdermal and oral administration, respectively, the results showed AUC_0-t after transdermal administration was only 1.02% of that after oral administration, which indicated that the amount entered into systemic circulation was very small. Drug concentration in blood was very low after transdermal administration. The long half-life (t_1/2, 60.4 h) after transdermal administration was 2.16 times as long as that after oral administration （27.9 h）. This was because skin acted as a storeroom and drug penetrated slowly into target tissues. After meloxicam was administered to each patient at a dose of 7.5 mg and 15 mg/kg by oral and transdermal administration, respectively, the results showed the concentration ratio of synovial fluid to plasma at peak moment was 0.68 and 9.6, respectively, and drug could concentrate in synovial fluid by transdermal administration.CONCLUSION: In this study, meloxicam gel and meloxicam microemulsion of transdermal delivery were prepared. Fast, sensitive and robust HPLC and LC/MS/MS methods were developed, and successfully applied to the pharmacokinetic study of meloxicam after an oral or transdermal administration. The drug concentration of meloxicam in plasma, muscle and synovial fluid of rats, dogs and humans were investigated, the results showed that transdermal administration could produce low plasma concentration and high concentration in target tissues. Moreover, a transdermal permeation mechanisms of meloxicam after transdermal administration were proposed. It can be concluded that the drug in target tissue was mainly by direct penetration, while redistribution by systemic circulation was minor. Reliable scientific basis was provided for the new transdermal dosage form development and clinical application of meloxicam.