Study On Ketoprofen Patch

Non-steroidal anti-inflammatory drugs （NSAIDs） are among the drugs most commonly used to reduce inflammation and pain. NSAIDs inhibit cyclooxygenase-2 at the inflammation focus, but, unfortunately, most of them also inhibit gastric mucous cyclooxygenase-1, which produces gastric damage. Ketoprofen, 2-[（2, 6-dichlorophenyl）amino] benzeneacetic acid is a non-selective cyclooxygenase-1/2 inhibitor when tested in vitro, but a slightly preferential cyclooxygenase-2 inhibitor when tested ex vivo. Although it is one of best-tolerated classical NSAIDs, gastropathy appears following chronic oral administration .Therefore, many improved method applied with a high degree of skin permeation could be useful in the treatment of not only locally inflamed skin tissues , but also inflammatory and painful states of supporting structures of the body—bones, ligaments, joints, tendons and muscles. It mainly inhibits the COX enzymes and the lipid oxygen, reversibly, thereby inhibiting the biosynthesis of prostaglandin and leukotriene. Clinical application meanly is for the treatment of arthritis, postoperative pain and chronic cancer pain, and so on. In order to avoid its adverse effect by oral administration and be administrated conveniently, the topical patch of indomethacin was formulated and studied.The physicochemical properties improvement of the drugs is a common approach to optimize their bioavailability and decrease their side effect. Complex formation is a used method for enhancing the solubility and dissolution rate of poor water soluble weak electrolyte drugs. Ketoprofen is an acidic compound （pKa3.80 at 25℃） with very low aqueous solubility （136mg/ml in water at 25℃） in the unionised form, which is unsuitable for TDDS. In this study, we synthesized a series of ionpairs of ketoprofen （KP） complexing with alkanolamines （ethanolamine, diethanolamine, triethanolamine, diethylamine, triethylamine, N-（2-hydroxyethyl） pyrrolidine） in order to increase the transdermal flux of KP.HPLC method was applied to determine the transdermal flux of ionpairs. Comparing with KP, the ionpairs have higher solubilities. In the study we evaluated the transdermal delivery potential of KP, and its alkanolmine ionpairs in vitro, the results indicated that the ionpairs of KP complex with diethylamine had the highest flux and solubilities in the six ionpairs. The effect of various classic of chemical enhancers were investigated for the transdermal delivery of the KP across rat skin in vitro, Azone and IPM in combination with oleum menthae showed highest flux. Therefore, the pertinent proportion of the mixture was applied as the enhancer. Differential scanning calorimetry was used to evaluate the compatibility between KP and MASCOS 10 （polyacrylic acid type） pressure sensitive adhesive. The experimental results showed that drug and excipients were stable and they were compatible with each other.The mono-factor method was adopted to optimize the patch formulation and the experiments investigating whether the preparation could be replicated were also performed. We have instituted quality standards including identification, related materials checking and content determination, and investigated the influences of temperature, light and humidity on the stability of the KP patches, the results indicated that the KP patches met all the standards in the CP 2005.A simple reversed-phase HPLC method has been developed for determination of KP in rat plasma, excised skin and muscles samples. As compared to oral administration without dose normalization, the C max values of transdermal administration were significantly decreased （1.02μg/ml for transdermal administration versus 37.17μg/ml for oral administration）. the [AUC] 0-48h values were significantly decreased （5.26μg·h/ml for transdermal administration versus 123.01μg·h/ml for oral administration）, On the contrary, the t max values evidently extended （8.00h for transdermal administration versus 0.17h for oral administration）, and the t_1/2 values increases as same（5.15h for transdermal administration versus 2.85h for oral administration）. The transdermal patches incorporating KP would provide a useful strategy for prevention and treatment of inflammation, suggesting that the possible side effects from KP may be attenuated due to the lowered peak concentrations, and pharmacological effects can be enhanced and extended.We performed the subsequent experiments including: blood concentration test, and local organizations, including the skin and meat accumulated concentration of the drug test, when the patches sold in Korea were chosen as control group. The concentration of skin and muscle samples applied the self-made patches after 24h showed 5.09, 14.29 times than Korea patches respectively. It showed that the Self-made patches can maintain a higher local drug concentration, and more conducive to the local treatment.