藻酸双酯钠缓释片的制备及体外释放特性考察

发布时间：2018-03-23 07:27

本文选题：藻酸双酯钠(PSS)　切入点：缓释片　出处：《中国海洋大学》2014年硕士论文　论文类型：学位论文

【摘要】：藻酸双酯钠(Propylene glycol alginate sodium sulfate, PSS)是中国自主研发的第一个海洋多糖药物,在临床上主要用于缺血性心脑血管疾病的治疗。但目前PSS的药物制剂仅仅有普通片剂及注射剂,且质量标准不够完善,尤其是其固体制剂缺少对溶出度的考察,不能满足日益增长的临床需求。同时,PSS普通片剂存在需多次给药,血药浓度波动较大,生物利用度低,患者顺应性差等问题,因此研究和开发PSS的缓释制剂等新剂型是临床上的迫切需要。本文以目前使用较为广泛的羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(CMC-Na)、十八醇作为骨架材料,分别采用湿法制粒和熔融制粒两种方法对PSS缓释片的制备工艺进行了研究；并对两种方法的片重差异,片剂硬度和工艺操作过程进行了比较,结果表明熔融制粒方法更适合于PSS缓释片的制备。根据PSS的结构和理化性质特点,本文分别采用高效凝胶渗透色谱(HPGPC)方法和柱前衍生高效液相色谱(PC-HPLC)法对PSS缓释片的含量和体外释放度测定进行了较为系统的研究。采用HPGPC法在多种凝胶色谱柱上未能将PSS与辅料完全分离,PSS与辅料色谱峰存在部分重叠；但将Shodex OHpak SB-806 HQ色谱柱与TSK gel G3000 PWXL色谱柱进行串联,可使PSS与各辅料的分离得到明显改善,而且采用峰高定量因可有效降低色谱峰少量重叠的影响,比采用峰面积定量具有更好的线性关系,该方法适合PSS缓释片的含量测定。采用PC-HPLC法将PSS缓释片进行降解和衍生后测定,各辅料不影响PSS的含量测定,在0.3～12 mg/mL浓度范围内与峰面积呈现良好的线性关系(R2=0.9983),精密度RSD为1.4%(n=5),重复性RSD为3.4%(n=5),具有专属性强,灵敏度高和重现性好的特点,适合PSS缓释片体外释放度的测定。通过单因素试验考察了HPMC、CMC-Na和十八醇用量对体外药物释放的影响,进一步运用正交设计法对处方进行了优化,并采用释药动力学模型对PSS缓释片的体外药物释放特性进行了拟合。结果表明,PSS缓释片的最适处方为HPMC、CMC-Na和十八醇的用量分别为片重的15%,10%和10%(W/W)。按最适处方制备的PSS缓释片在2、6、12 h内可分别释放药物30.3%,70.9%和95.5%,其药物释放行为符合一级方程,并以Fickian扩散和骨架溶蚀两种机制协同作用释放药物。本文对PSS缓释片的制备工艺、辅料对药物释放的影响和处方的优化进行了系统的研究,成功制备得到了药物释放行为符合一级方程的PSS缓释片；并建立了适用于PSS缓释片含量测定的高效凝胶渗透色谱法；建立了适用于PSS缓释片体外释放度测定的柱前衍生高效液相色谱方法。这些研究结果为PSS及其它海洋多糖药物缓释制剂的应用开发提供了基础和参考,在降低PSS临床应用中的不良反应,改善患者的顺应性方面具有重要的积极作用。
[Abstract]:Sodium alginate glycol alginate sodium sulfate (PSSs) is the first marine polysaccharide drug developed by China, which is mainly used in the treatment of ischemic cardio-cerebrovascular diseases. The quality standard is not perfect, especially its solid preparation is lack of the investigation of dissolution, and can not meet the increasing clinical demand. At the same time, the common tablets of PSS need to be given many times, the blood concentration fluctuates greatly, the bioavailability is low. Patients' compliance is poor, so it is an urgent need to study and develop new dosage forms of PSS, such as sustained-release formulations. In this paper, the widely used hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose sodium (CMC-Na), octadecanol (octadecanol) were used as skeleton materials. The preparation process of PSS sustained-release tablets was studied by wet granulation and melt granulation, and the weight difference, hardness and operation process of the two methods were compared. The results showed that the melt granulation method was more suitable for the preparation of PSS sustained-release tablets. The content and in vitro release of PSS sustained-release tablets were studied by high performance gel permeation chromatography (HPGPC) and precolumn derivatization high performance liquid chromatography (PC-HPLC), respectively. HPGPC method was used to determine the content and in vitro release rate of PSS sustained-release tablets on various gel chromatographic columns. The chromatographic peaks of PSS and excipients were partially overlapped; But when the Shodex OHpak SB-806 HQ column and the TSK gel G3000 PWXL column were connected in series, the separation of PSS and the excipients could be improved obviously, and the effect of a little overlap of the chromatographic peaks could be effectively reduced by using the quantitative factor of peak height. This method is suitable for the content determination of PSS sustained-release tablets. The PSS sustained-release tablets are degraded and derivatized by PC-HPLC method. The contents of PSS are not affected by the excipients. There is a good linear relationship between the peak area and the peak area in the concentration range of 0.3 ~ (12) mg/mL. The precision RSD is 1. 4% and the reproducible RSD is 3. 4%. It has the characteristics of high specificity, high sensitivity and good reproducibility. The effects of the dosage of HPMC, CMC-Na and octadecanol on drug release in vitro were investigated by single factor test, and the formulation was optimized by orthogonal design. The pharmacokinetic model was used to simulate the drug release characteristics of PSS sustained-release tablets in vitro. The results showed that the optimal formulation of PSS sustained-release tablets was that the dosage of HPMC- CMC-Na and octadecanol was 15g / 10% and 10g / W / WN of the tablet weight, respectively. Sustained release tablets could release 30. 30.9% and 95. 5% of the drugs within 12 h, respectively. The drug release behavior of the tablets was in accordance with the first order equation. In this paper, the preparation process of PSS sustained release tablets, the effect of excipients on drug release and the optimization of formulation were systematically studied. PSS sustained-release tablets with first-order equation were successfully prepared, and a high performance gel permeation chromatography was established for the determination of PSS sustained-release tablets. A precolumn derivatization high performance liquid chromatography (HPLC) method for the determination of in vitro release of PSS sustained-release tablets was established. These results provide a basis and reference for the application and development of PSS and other marine polysaccharide drug sustained-release preparations. It plays an important role in reducing adverse reactions in clinical application of PSS and improving compliance of patients.
【学位授予单位】：中国海洋大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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