一种注射型原位有机凝胶剂的性质和释药行为研究

发布时间：2018-06-25 10:11

本文选题：有机凝胶 + 长链脂肪酸　；参考：《吉林大学》2014年硕士论文

【摘要】：本研究针对上市长效制剂存在生产成本高，工艺复杂，制剂中溶剂的生物毒性等问题，设计开发一种生物相容性好、能平稳释药的小分子原位有机凝胶系统。选择药用的注射用大豆油作为凝胶基质，生物相容性辅料脂肪酸及脂肪酸酯作为凝胶因子，非典型性精神分裂症药物帕潘立酮为模型药物，研制能以液态注射，给药后立即转变为半固态药物贮库的注射型原位有机凝胶系统，并对其进行凝胶性质评价和释药行为研究。选择4种不同链长的商品化长链脂肪酸（肉豆蔻酸、棕榈酸、硬脂酸、花生酸），和2种硬脂酸酯（单硬脂酸甘油酯、三硬脂酸甘油酯）作为有机凝胶因子，进行凝胶因子的性质表征和成胶性研究。采用倒流法测定不同凝胶体系的凝胶化转变温度（Tsg）和凝胶化转变时间（tsg）；应用差示扫描量热法（DSC）对凝胶体系进行热分析；通过粘度测定来评价该凝胶体系的机械性能。结果表明，随着脂肪酸中烷烃链的增长，对注射用大豆油的胶凝能力增强。同时考察了不同凝胶因子添加量制备的凝胶剂的性质，其中分别以7.5%(w/v)硬脂酸和5.0%(w/v)花生酸制备的凝胶体系具有较适宜的凝胶化转变温度，较高的胶凝效率和一定的凝胶机械强度。而采用两种硬脂酸酯制备，不能得到均一的凝胶体系。显微镜观察有机凝胶剂具有紧密且均一的空间网状结构。凝胶初步稳定性实验表明此凝胶剂在常温、离心及反复升降温条件保持稳定。以优选的凝胶体系制备帕潘立酮载药有机凝胶，并进行体外释药研究。建立了帕潘立酮的体外定量方法，制备载药有机凝胶，测定凝胶化转变温度和时间，结果表明，，药物引入可以加快凝胶化转变速度，而不影响凝胶体系的凝胶化转变温度。对7.5%(w/v)硬脂酸和5.0%(w/v)花生酸制备的凝胶体系进行释药行为研究，考察体外释药行为的影响因素，结果表明，两种脂肪酸制备的凝胶体系对模型药物帕潘立酮均具有缓释效果，体外释药周期为1至3周；花生酸制备的凝胶体系对药物的缓释作用强于硬脂酸制备的凝胶体系。对帕潘立酮有机凝胶进行体内评价，考察凝胶剂的体内释药行为、形态变化和生物相容性。以大鼠为实验动物，于背部皮下注射优选帕潘立酮原位凝胶处方，考察凝胶剂的体内药代动力学行为。结果表明，凝胶剂在动物体内可以均匀释放1周，且无突释效应。采用Ritger-Peppas模型对体内释药曲线进行拟合，推断该制剂的释药机制为药物扩散和骨架溶蚀的共同作用。采用小动物活体成像系统观察给药后注射部位凝胶剂的变化，结果显示，于给药9天后，凝胶彻底消失，即释药结束后凝胶剂完全被体内摄取。用背部除毛的小鼠进行凝胶的组织刺激性实验，凝胶注射6天后，大鼠注射部位周围组织无明显炎症反应，证明凝胶剂具有良好的生物相容性。本研究开发的帕潘立酮原位有机凝胶长效注射剂制备工艺简单，生物相容性好，在体内可平稳释药一周，具备良好的实用价值和应用前景，也为长效缓释制剂的开发提供理论支持。
[Abstract]:In this study, we designed and developed a small molecular in situ organogels system with good biocompatibility and stable release, aiming at the problems of high production cost, complex process and the biological toxicity of solvent in the preparation of the long-acting preparation. For the gel factor, parpinone, an atypical schizophrenia drug, was used as a model drug to develop an injection in situ organogels system that could be injected into a liquid state by liquid injection into a semisolid drug store immediately after the drug was given, and the gel properties and drug release behavior were evaluated.
4 kinds of commercialized long chain fatty acids (myristic acid, palmitic acid, stearic acid, arachidic acid), and 2 kinds of stearate (glycerol monostearate, three stearic acid glyceride) were selected as organic gelatin factors to study the properties and gelation of gelation factors. The gel transition temperature of different gel systems was determined by reflux method. Tsg) and gelation time (TSG); thermal analysis of the gel system by differential scanning calorimetry (DSC); the mechanical properties of the gel system were evaluated by viscosity measurement. The results showed that the gelation capacity of soybean oil for injection was enhanced with the increase of alkane chain in fatty acids. The addition of different gel factors was also investigated. The gel properties of the gel prepared with 7.5% (w/v) stearic acid and 5% (w/v) arachidic acid have better gelation temperature, higher gelation efficiency and certain gel mechanical strength. The gel system can not be obtained by using two kinds of stearic esters. The microscope observation of organogels is tight. The gel initial stability test showed that the gel remained stable at room temperature, centrifugation and repeated heating and cooling conditions.
The Papin risperidone carrier organogels were prepared by the optimized gel system and the drug release in vitro was studied. The in vitro quantitative method of Papin risone was established to prepare the drug loaded organogels and to determine the gelation temperature and time. The results showed that the gelation speed of the gel could be accelerated by the introduction of the drug without affecting the gelation temperature of the gel system. The drug release behavior of 7.5% (w/v) stearic acid and 5% (w/v) arachidic acid was studied and the influencing factors of the release behavior in vitro were investigated. The results showed that the gel system prepared by two fatty acids had a sustained release effect on parpant model drug, and the release period was 1 to 3 weeks in vitro; the gel system prepared by arachidic acid The sustained release effect of the material is stronger than that of the stearic acid gel system.
The in vivo evaluation of Papin risperidone organogels was conducted in vivo to investigate the drug release behavior, morphological changes and biocompatibility of the gel in vivo. Taking the rat as the experimental animal, the prescription of Papin risone in situ gel was optimized by subcutaneous injection on the back, and the pharmacokinetic behavior of the gel in vivo was investigated. The results showed that the gel could release 1 evenly in the animal body. Ritger-Peppas model was used to fit the drug release curve in vivo. It was concluded that the release mechanism of the drug was the common effect of drug diffusion and skeleton dissolution. The gel agent of the injection site was observed by the living imaging system of small animals. The results showed that the gel disappeared completely after 9 days of administration, that is, the drug release knot. After 6 days of gel injection, there was no obvious inflammatory reaction in the tissue around the injection site of the rat, which proved that the gel had good biocompatibility.
The preparation of Papin risperidone in situ organogels has a simple preparation process, good biocompatibility, a stable release of drug in the body for a week, and has good practical value and application prospects. It also provides theoretical support for the development of long-acting sustained-release preparation.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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