| Objective: Mesylate doxazosin (DOX) is selective postsynapticα1-adrenergic receptors blockers, by blocking theα1-receptors to expand blood vessels, reduce vascular resistance, in order to decrease the blood pressure. DOX is suitable to primary mild and moderate hypertension and accompanied by hypertension patients with innocence prostatic hypertrophy. It also can well treat masculine hyperplasia of prostate. Now, most dosage forms are oral application preparations about DOX. These preparations need to take medicine everyday because the hypertension patients may lead to insetting disease even to threaten the life if stop taking medicine. So developing a prolonged action and delayed release preparation have large practical and academic meaning. This paper will combine DOX and microsphere administration in order to come true the purpose:safe, convenient utility.Methods : This experiment use the biodegradable polymers poly-L-lactide (PLA) as carry materials to prepare the microspheres by modified solvent evaporation method named organic-phase dispersing and solvent diffusion technique. First, the fundamental preparation condition such as formula factors and process factors were evaluated in the preliminary experiments and choose several significant factors to do the orthogonal design. Dependent variables or responses investigated in this study are loading efficiency, drug loading and mean diameter. Then we studied the methods which used to determine the drug loading and loading efficiency. We used methylene chloride to dissolve microspheres and then dissolve DOX by methanol. After filtered, the concentration of DOX was determined by HPLC system.We studied the content of accumulative release of microspheres on the basis of pretesting and scientific literatures and determined the concentration of DOX by the method of ultraviolet spectrophotometer. In this study, we investigated the influence for the content of accumulative release of microspheres in different medium, different pH conditions, different proportion organic solvent and different drug loading and then definite the release method taking burst effect and accumulative amount as evaluation indexes. We also initially studied the accelerate release and compared it with routine release about associatively. By stability experiments we studied the store conditions and stability.In this study, pharmacokinetics research was completed by rats hypodermic injection and the concentration of DOX in rats blood plasma was determined by HPLC system. We used model of in compartment to analyze the data. The pharmacokinetics parameters such as AUC0→t,AUMC,MRT was calculated by moment method according drug concentration time area under the curve.Results: The optimal formulation and process were defined through preliminary experiments and the orthogonal design. It was found that PLA concentration, theoretical drug loading, disperse speed,disperse medium concentration, the volume ratio between organic phase and disperse phase had much more influence on indexes of microspheres. The consequence of technology indicated DOX concentration and peak area had well linear correlation between 2.042μg/ml and 10.21μg/ml. The RSD of both within-day precision and between-day precision are less than 1.0%.The three results of recoveries are 100.12%,100.11% and 99.91%. The optimized microspheres were spherical and smooth. The average drug loading, encapsulation efficiency and mean diameter were 19.2%, 69.8%, 17μm.The content of DOX in release medium was determined by ultraviolet spectrophotometer. The linearity range was 1.674~8.37μg/ml.The RSD of precision was less than 2% and the results of recoveries were 101.36%,101.61%,101.42%. According the investigation about release conditions, we decided using the pH 7.4 PBS containing 30% EtOH as medium which including 0.2% Tween20 and 0.2%Tween80 as wetting agent and dispersant agent. The release temperature was 37℃and oscillation frequency was 100r/min. The burst release amount in 1 days was 6% and the release amount in 30 days was about 77%. The accelerate release temperature was 63℃and release time were 30 hours. In 30 hours, the accumulative release amount was about 74% and the release amount was great between 5~12 hours. The coefficient of correlation(R) between accelerate release and routine release was R=0.9727.The stability experiments indicted the microspheres would to be together and had no change in temperature of 40℃, so the microspheres couldn't be storaged in high temperature. In high humidity, the appearance,content and release have no marked change. According to the literature report, DOX need stored away from light, we also stored the microspheres away from light although the result of strong illumination experiment indicated the light had no influence on the quality.According to the SEM picture in different time of the accelerate release, the release is a combinative process of diffusion and degradation, but main dependent on the diffuse process.The content of DOX in rats blood plasma was determined by HPLC. The linearity range was 4~320ng/ml, R=0.9992. The sensitivity specificity and precision were consistent with request. The results of method recoveries were 95.81%,94.16%,97.99% and the results of method recoveries were 88.14%,84.58%,96.19%. Pharmacokinetics data were AUC0→∞=2852.19 (ng·ml)d,AUMC=44369.99,MRT=15.56d. DOX's release in rats blood plasma is stability, little burst release, well delayed release.Conclusions: Overall, the DOX microspheres in this study were smooth and spherical, and have good dispersibility and narrow size distribution and can be long term storaged in ordinary temperature. The release in vitro indicted the microspheres had well delayed release and consistent with Higuchi model. Experiments in rats indicated the DOX microspheres could prolong the residence time of drugin rats body and increased the bioavailability of DOX, so proved acandidate of new drug.
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