Study On Lornoxicam Hydrogel Patch

Lornoxicam (LNXC) is a new non-steroidal anti-inflammatory drug (NSAID).Different from other oxicams, it is rapidly absorbed by oral or intravenous administration, plasma biological half-life is short (3-5h), and no accumulation after multiple-dosage regimen in the therapeutic dosage range. The domestic injection and tablet have come into the market and been used in clinics already, but no report of transdermal drug delivery system (TDDS) in market. Like most of NSAIDs, application of lornoxicam is limited in the clinical treatment due to side effects, especially the high incidence of gastrointestinal dysfunction. In this research, based on the physicochemical properties and pharmacological characteristics of LNXC and the characteristics of transdermal patch, we wish to search for a better drug delivery system which can reduce adverse effects and improve patient compliance.LNXC hydrogel patch designed in the research belongs to the edge of adhesive type transdermal delivery system. The hydrophilic material has many advantages such as more medicines carried, better biocompatible, easy to soften the skin stratum corneum, good gas permeability and no skin irritation.while, the acrylate PSA has high adhesion. With the combination of characteristics of hydro gel and andacrylic resin, LNXC patch could be applied to the skin for a long time and maintain constant release rate, which make LNXC keep full effect in clinical treatment.In this study, optimal formulation was achieved by orthogonal experiment, and then LNXC hydrogel patch was prepared with the optimized prescription. Eventually, we evaluated its quality in vitro and researched its pharmacokinetics and pharmacodynamics. The entire study is divided into five parts: 1) Preformulation study of LNXC hydrogel patch; 2) Screening proper enhancers for transdermal delivery of LNXC; 3) Formulation study and process optimization; 4) Quality study including setting up of quality standards and quality control; 5) Pharmacokinetics research.Part One Preformulation study of LNXC hydrogel patchPenetration of drugs is mainly effected by skin physiology, physicochemical properties of drugs and delivery systems. According to the reports and experiment studies, physicochemical properties of LNXC such as the molecular weights, molecular structure, oil-water partition coefficient and degree of dissociation, and the clinical dosage and half-life are proved to suit for TDDS. To develop the TDDS of LNXC, the first step is to increase the water solubility because the drug is hardly dissolved in water. Therefore, solubility of LNXC in different solvents and different pH solutions was studied by UV method. Based on experimental results, the best solvent is chosen and pH8 phosphate buffer solution is selected as the receiving medium in vitro permeation study.Part Two Screening proper enhancers for transdermal delivery of LNXCHigh penetration rate is the presupposition of keeping the systemic or local effective blood concentration. Chemical enhancers are the most commonly used. In this paper, the enhancement of several common solvents and penetration enhancers for LNXC across full thickness mouse skin was studied and we especially focused on investigation of effect of joint enhancers with modified Franz diffusion cell. As a result, penetrable effect of oil-soluble enhancers was found to be better than the water-soluble enhancers. With propylene glycol as solvent, the enhancing effect was ranged in following order: 5% Azone> 3% Azone> 3% dodecanol > 5% dodecanol > 5% oleic acid> 5% IPM> 5% menthol> 3% menthol. Results of joint enhancers were as followed: penetration of dodecanol in combination with menthol was showed to be 3.65 times higher than menthol alone (P<0.01), lower than single dodecanol, but not significant (P>0.05). Penetration of Oleic acid, dodecanol and menthol mixed with Azone were higher than they used alone (P<0.05), but lower than the simple usage of Azone. Therefore, the penetration effect of joint enhancers was not the best. In the end, 1⁵% Azone with propylene glycol (PG) as solvent was preferred to be the penetration enhancers.The transdermal performance of LNXC by different species of animal skin showed that: in the same composition of penetration enhancers, permeability of LNXC by the mouse skin was better than rats', but the same kinds of enhancer performed similarly. This result also proved the reliability of selected penetration enhancers.Part Three Formulation study and process optimizationThe main content of this part include two aspects: 1) optimal formulation for the paste layer and preparation. Eudragit EPO was selected as adhesive matrix, triethyl citrate as plasticizer and succinic acid as crosslinking agent. The patch was prepared by a modification of organic solvent diffusion technique. Optimal formulation was achieved by orthogonal experimental on considering the factors of tack and cohesion.2) optimal formulation for the drug-containing matrix layer carefully, the top three factors affecting the drug penetration in vitro experiments were the drug content, penetration enhancers and content of blank gel.With the best optimized prescription,we definite LNXC patch formulation and preparation.Part Four Quality study including setting up of quality standards and quality controlA HPLC assay, which is rapid, accurate, reproducible and reliable, was established to measure the content of LNXC patch. The methodology for evaluating properties of LNXC patch in vitro was studied. The results showed that the content of the LNXC patches were stability, viscosity was moderate, the cumulated permeation amount of LNXC in 48h was up to 64.67% and the releasing rate was high (up to 80% in 2h) . The skin irritability study indicated that LNXC patch can be used safely.Part Five Research on the pharmacokinetics of LNXC hydrogel patchBased on the research in vitro, the pharmacokinetics of LNXC hydrogel patches was studied in this part. Method with specific, high sensitivity, wide linear range, precision, well recovery and plasma stability was established to determine the concentrations of LNXC in rat plasma by LC/MS/MS analysis, The analytical procedure was applied as a routine analysis of biological samples to support a pharmacokinetic study. Using the LNXC oral tablets as the reference, the relative bioavailability of LNXC in rats was performed. Pharmacokinetic parameters were evaluated according to the non-compartment model. The results showed that the concentration-time profiles of LNXC in blood followed an open single-compartment model with first order absorption in rats following a single oral dose administration of LNXC. Cmax were 4771.67±604.76ng.mL^-1, AUC (0-t) were 76013.817±2085.28ng·h·mL^-1. Compared with oral administration, the patch showed that MRT was increased, Cmax was reduced. AUC_0-∞ were 31828.33±15717.45,65814.17±56814.37,85439.95±24232.64ng·h·mL^-1, respectively; Cmax were 527.33±309.36ng·mL^-1, 1081.17±564.72ng·mL^-1 and 1863.47±304.53ng mL^-1, respectively. The value of AUC and Cmax were linear with the administered dose, respectively. The relative bioavailability is approximately 49.05±6.9%. The preliminary result of in vivo/in vitro correlation showed that: in vitro modelling of in vivo conditions might help provide a basd for predicting in vivo behaviour.In this paper, we successfully prepared LNXC hydrogel patch through the systematically selective prescription and process. Solvent dispersion method was used to solve the problem of the low loading drug amounts caused by poor solubility of LNXC. The optimized process was suitable for industrial production; and the established analysis method was accurate and reliable. LNXC Patch prepared in this study was stable and well permeable in vitro, sustained the blood concentration with minimal fluctuation and extended the dwell time in vivo.Formulations and technology of transdemal drug delivery system of lornoxicam have been applied for patents in China, the patent application number: CN201010204964.X.