| Nimodipine is a potent dihydropyridine calcium antagonist with preferential effect on cerebral vessels, with both neurological and psychiatric pharmacological activity and can expand coronary artery with highly selectivity. Currently, the drug is the first choice for treatment of cerebrovascular disease, particularly with high clinical value on Alzheimer's disease. However,this drug has a poor oral bioavailability because of its high hepatic first pass effect,and it has a short elimination half-life,therefore,it is a potential candidate for transdermal studies. Nimodipine was made of hydrogel transdermal patch in this study. To evaluate the percutaneous permeability of nimodipine hydrogel transdermal patch, and compared pharmacokinetic parameters with that of oral administration and assess them reasonablly.Part one: Preparation of nimodipine hydrogel patch and its in vitro pereutaneous permeabilityTo prepare nimodipine hydrogel transdermal patch and investigate the effect of different factors on the percutaneous permeability of nimodipine.To evaluate the percutaneous permeability of nimodipine hydrogel transdermal patch in vitro. The nimodipine hydrogel transdermal patch was prepared with high polymer hydrophilic materials as matrix.The permeation flux of nimodipine was determined in vitro using Franz diffusion cell fitted with mouse skin.The content of nimodipine was measured by HPLC.The loading amounts, type of absorption promoting agents and their content were optimized. The best loading amount is 4mg/cm2. The penetration enhancers were found to increase the penetration of nimodipine and 5% oleic acid had the best penetration enhancing effect.The permeation of thiamazole hydrogel transdermal patch containing 5% oleic acid was in accordance with the zero-order kinetic.Nimodipine hydrogel transdermal patch presents high permeation rate of 28.10μg·cm-2·h-1 and cumulative permeation amount of 342.58μg·cm-2.Part two: The establishment of analytical method of nimodipine in biological matrixA reversed-phase high-performance liquid chromatographic(RP-HPLC) method has been developed for the determination of nimodipine in rat plasma. The sample pretreatment is liquid-liquid extraction for biological matrix. Separation was obtained on a Elite C18 column(150×4.6mm), using an excitation wavelength of 238nm. The isocratic mobile phase consisted of methanol-water (65:35, v/v) was run at a flow rate of 1.0 ml/min for biological matrix. The chromatographic system used provided good separation of the compound without interfering peaks from endogenous substance. The calibration curves were linear in each sample range with correlation coefficient above 0.99. respectively. The method has been successfully used to support the pharmacokinetics study of nimodipine. Following oral administration with different doses of nimodipine to SD rats (40mg/kg), the blood samples were collected at different time after dosing. All collected blood samples were centrifuged to obtain plasma and the concentrations of nimodipine in plasma were determined by HPLC method described as above, then calculated corresponding pharmacokinetic parameters based on the time process of blood drug concentration. The blood plasma Cot curve of nimodipine conformed to one compartment model of the first order absorption. The main pharmacokinetic parameters of nimodipine(40 mg·kg-1, 3, 5cm2) were T1/2(min):T1/2(min):81.16±17.25,192.90±12.85134,213.17±25.71;AUC(S0)(μg·ml-1·min):2764.76±131.29,12658.92±759.94,16434.81±434.73;AUCM(S1):318560.34±9853.16,5634548±585612.1,7828390±655744; MRT(min):115.00±8.38,445.10±23.55,476.32±26.71;VRT(min·min):8320.07±521.25,81250.13±8392.05,104365.77±16825.78. Drug absorption of two dose group nimodipine hydrogel paste relates to paste dose. With the contrast of oral nimodipine, its plasma conentration are much stabler and its bioavailabiliy are much higher. Part three: The pharmacokinetics study of nimodipine in rats...
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