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无味盐酸苯环壬酯树脂复合物口腔崩解片的研究

发布时间:2018-10-25 16:33
【摘要】:盐酸苯环壬酯(Phencynonate hydrochloride)是中枢抗胆碱药,是新型抗晕动病药物。目前上市的制剂仅为普通片剂,为了提高患者的顺应性,本文以盐酸苯环壬酯为模型药物,以阳离子交换树脂Amberlite(?)*IRP88为载体制备了盐酸苯环壬酯树脂复合物口腔崩解片。 本文先对药物的溶解度、pKa, logP等理化性质进行了考察。药物分子结构中有碱性较强的胺基基团,适宜采用阳离子交换树脂Amberlite(?)IRP88制备药物树脂复合物。 为获得较高的药物利用率和适宜的载药量,对药液浓度、树脂用量、反应温度和溶液pH进行了考察,最终优化出制备条件为药物浓度C=1.0mg/mL,药物与Amberlite(?)IRP88用量比为1:2(wt/wt),反应温度为室温(25℃),介质为纯净水。通过X-射线粉末衍射(PXRD)和差示扫描量热法(DSC)分析表明,药物树脂复合物中药物是以离子键形式与树脂结合,而不是简单的物理吸附,吸附后药物的品型转变为无定形态。对影响药物树脂复合物体外释药的影响因素进行了研究,发现药物树脂复合物中药物的释放速率主要受H+强度、温度和介质中可交换离子的种类影响。介质中H+强度越高,药物释放速率越快:升高温度也可以提高释药速率;可交换离子的置换能力强弱顺序为H+Na+K+Ca2+,表明可交换离子的分子量越大,置换能力越弱。药物树脂复合物中药物的释放属于粒扩散机制。 采用直接压片法制备口腔崩解片,填充剂选择了药用新型辅料喷雾干燥甘露醇和甘露醇淀粉复合物,优化出两者最佳用量比例为1:1(mg/mg)。通过考察吸湿时间,体内外崩解时间对三种超级崩解剂羧甲基淀粉钠(CMS-Na)、交联聚维酮(PVPP)和交联羧甲基纤维素钠(CCMC-Na)进行筛选,得出含有20%PVPP的口腔崩解片吸湿时间和体内外崩解时间均是最短的,确定含有20%PVPP的处方为最终处方。 通过自制的药物树脂复合物口腔崩解片与上市品片在四种介质中的溶出度对比研究表明在pH1.0和pH4.5介质中白制品的释药速率显著快于上市品片,而在水中自制品基本无释放,在人工唾液中有根少量的释放。表明自制品在胃液环境中可以迅速释药而起效,在口腔中短时间内仅有微量释放而起到掩味作用。 采用志愿者单盲法评价药物树脂复合物口腔崩解片的口感,评价结果证明所制备的药物树脂复合物口腔崩解片,可以完全掩盖药物的苦味,而且无砂砾感。
[Abstract]:Phenyclic nonyl hydrochloride (Phencynonate hydrochloride) is a central anticholine drug and a new anti-motion sickness drug. In order to improve the compliance of patients, diphenyl nonyl hydrochloride was used as model drug and cation exchange resin Amberlite (?) * IRP88 as carrier to prepare oral disintegrating tablets of phenyclononyl hydrochloride resin complex. In this paper, the solubility, pKa, logP and other physicochemical properties of the drug were investigated. There are amino groups with strong alkalinity in the molecular structure of the drug, so it is suitable to use Amberlite (?) IRP88 as a cationic exchange resin to prepare the drug resin complex. In order to obtain higher drug utilization rate and suitable drug loading, the concentration of the solution, the amount of resin, the reaction temperature and the pH of the solution were investigated. The optimized preparation conditions were as follows: concentration of C _ (10) mg 路mL ~ (-1), dosage ratio of drug to Amberlite (?) IRP88 was 1:2 (wt/wt), reaction temperature was room temperature (25 鈩,

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