异丁立酮壳聚糖基聚电解质缓释片的研究

发布时间：2018-10-04 21:00

【摘要】：异丁立酮是一种本实验室自行合成,具有自主知识产权的新化合物。它是抗精神病药物帕潘立酮的前药。口服给药后,异丁立酮盐酸盐可以快速和完全地在体内代谢为帕潘立酮。壳聚糖(CS)是阳离子聚合物。CS已被确定为片剂的有用组分,其可以与阴离子产生聚电解质复合物(PEC)。根据以前的报道,基于PEC的基质片剂可能避免使用共价交联试剂,因为交联通过离子连接发生,并且还减少了基质的溶胀和侵蚀,因此延长了药物释放。通过该基质片可以使药物释放延长至24 h以上,对精神分裂症的治疗有明显的作用。本研究建立了异丁立酮盐酸盐的高效液相色谱体外分析方法,并通过准确度,精密度和专属性实验验证了方法可行性。对制备的异丁立酮长效缓释片剂进行了含量均匀度,稳定性,体外溶出等质量评价。根据体外释放行为,将阴离子的种类以及壳聚糖和阴离子的不同比例作为考察因素对片剂进行了处方筛选。最后以比格犬为动物模型,选择筛选后的最优处方进行了体内药代动力学分析。确定了血浆处理样品方法以及确定了检测条件。本实验最终选用壳聚糖作为阳离子,黄原胶作为阴离子,比例为1:1,采用湿法制粒直接压片法压片,每片含药量1.5 mg。药代动力学参数如下t1/2:8.14 h;Cmax273.84μg/L。本研究制备的片剂体外释放行为良好,能够达到释放24 h的实验目的。并且有良好的体内外相关性。体内药代动力学数据表明本研究制备的片剂具有较高的药时曲线下面积。通过本研究制得的片剂药物释放曲线更平滑,这对减少药物突释,延长药物释放时间,减少药物带来的毒副作用有着重要的意义。聚电解质聚合物PEC应用于制备片剂在本研究中展示了良好的特性。根据壳聚糖和阴离子可以在胃肠环境下自组装形成PEC膜的特性,我们可以通过简单的混合压片就可以制备出具备芯-壳结构的片剂来改善药物的释放,为以后需要制备突释小,释放行为均匀的缓释制剂提供了一个良好的参考和思路。
[Abstract]:Isobaridone is a new compound synthesized by our laboratory and has its own intellectual property rights. It is a prodrug for the antipsychotic Papanlitone. After oral administration, isobaridone hydrochloride can be quickly and completely metabolized in vivo as paparidone. Chitosan (CS) is a cationic polymer. CS has been identified as a useful component of tablets. It can produce polyelectrolyte complex (PEC). With anions. According to previous reports, PEC-based matrix tablets may avoid the use of covalent crosslinking reagents, because crosslinking occurs through ionic bonding and reduces swelling and erosion of the matrix, thus prolonging drug release. The drug release can be prolonged to more than 24 hours by the matrix tablet, which has obvious effect on the treatment of schizophrenia. In this study, a high performance liquid chromatography (HPLC) method for the determination of isobaridone hydrochloride in vitro was established, and the accuracy, precision and specificity of the method were verified by experiments. The content uniformity, stability and dissolution in vitro of the long-acting sustained-release isobaridone tablets were evaluated. According to the release behavior in vitro, the formulation of tablets was screened by the kinds of anions and the different ratios of chitosan and anions. Finally, the best prescription was selected and the pharmacokinetic analysis was carried out in vivo using Beagle dog as animal model. The method of plasma sample treatment and the detection conditions were determined. In this experiment, chitosan was used as cationic ion, xanthan gum as anion, the ratio was 1: 1, and the tablet was pressed directly by wet granulation, each tablet contained 1.5 mg.. The pharmacokinetic parameters are as follows: t 1 / 2: 8.14 h Cmax273.84 渭 g / L. The tablets prepared in this study have a good release behavior in vitro and can achieve the purpose of 24 h release. And there is good correlation in vivo and in vitro. The pharmacokinetic data in vivo showed that the tablets prepared in this study had a high area under the drug time curve. The drug release curve of tablets prepared in this study is smoother, which is of great significance for reducing the sudden release of drugs, prolonging the release time and reducing the side effects of drugs. Polyelectrolyte polymer PEC has shown good properties in the preparation of tablets. According to the characteristic that chitosan and anions can self-assemble to form PEC membrane in gastrointestinal environment, we can prepare tablets with core-shell structure to improve the release of drugs by simply mixing the tablets. The sustained release preparation with uniform release behavior provides a good reference and train of thought.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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