热熔挤出技术制备酮咯酸氨丁三醇缓释植入剂

发布时间：2018-01-17 01:23

本文关键词：热熔挤出技术制备酮咯酸氨丁三醇缓释植入剂　出处：《广东药学院》2014年硕士论文　论文类型：学位论文

【摘要】：目的：建立实验室热熔挤出技术酮咯酸氨丁三醇缓释植入剂。采用热熔挤出技术制备酮咯酸氨丁三醇缓释植入剂并且对酮咯酸氨丁三醇植入剂的处方进行筛选和优化。建立酮咯酸氨丁三醇缓释植入剂高效液相色谱测定方法。研究观察酮咯酸氨丁三醇缓释植入剂的体内药物释放动力学。研发中度和高度镇痛并无成瘾性制剂，采用热熔挤出技术制备酮咯酸氨丁三醇缓释植入剂，希望填补和满足临床药物治疗的需要。方法：采用正交试验对植入剂的处方进行筛选和优化，主要考察三个因素：药物含量，泊洛沙姆与聚乳酸的投料比以及聚乳酸的分子量。考虑三个水平为：药物含量分别是20%，40%和90%；泊咯沙姆与聚乳酸的投料比为0:10,1:9以及2:8；聚乳酸的分子量为5万，16万和54万。采用L43的正交表进行试验设计。考察指标为外观，载药量和体外溶出度。进行了酮咯酸氨丁三醇缓释植入剂高效液相色谱测定方法学的验证。通过体内外释放度测定方法研究了酮咯酸氨丁三醇缓释植入剂在新西兰兔体内药物释放动力学特性。结果：发展了一种实验室的简易热熔挤出设备，可根据试验制剂的不同需要通过调整模具来改变制剂的规格，具有较高的灵活性。综合考察各种因素最后选定含药量为20%，聚乳酸的分子量为16万，聚乳酸和泊咯沙姆的投料比为9:1的植入剂处方。通过方法学验证，采用流动相为甲醇：水：三乙胺：冰醋酸=80:19.9:0.02:0.08，色谱柱： Kromasil C18柱（250A，，4.6mm），流速：1ml/min，检测波长319nm的色谱条件可作为酮咯酸氨丁三醇植入剂的兔体内药物测定方法。酮咯酸氨丁三醇的低中高日间精密度的相对标准偏差分别是8.16%，12.1%以及12.1%，分析方法的专属性符合要求。酮咯酸氨丁三醇的日间精密度分别为7.6%，7.1%以及3.8%，变异系数均少于15%。实验的低，中，高浓度的相对回收率分别是106.3%，113.7%和85.3%，均符合高浓度和中浓度的相对回收率应该在85%到115%范围以及低浓度靠近定量限80%到120%之间要求。室温下，样品在3个浓度相对应的RE%值分别为1.01%，0.96%，和1.00%,均符合稳定性要求。制备的酮咯酸氨丁三醇植入剂的释放时间能够延长到18天，制剂在第7天能够平稳释放，在新西兰兔体内的血药浓度能够达到0.3μg/ml。结论：初步探讨了热熔挤出技术制备酮咯酸氨丁三醇植入剂的方法，制备了试验的样品，考察了酮咯酸氨丁三醇植入剂的高效液相色谱法测定方法，进行了酮咯酸氨丁三醇植入剂的兔体内外释放动力学研究。这些实验工作说明，热熔挤出技术制备酮咯酸氨丁三醇植入剂是可行的，取得的数据为该产品的进一步研发提供了科学的依据。
[Abstract]:Objective:. A laboratory hot-melt extrusion technique was established for the preparation of ketoclalic acid aminobutanol sustained-release implants, and the formulation of ketoclalic acid aminobutanol implants was screened and optimized. A high performance liquid chromatography (HPLC) method was established for the determination of ketocloroic acid aminobutanol sustained-release implants. The pharmacokinetics of ketoclalic acid aminobutanol sustained-release implants in vivo was observed. Moderate and high analgesia was developed and no addictive preparations were developed. In order to fill in and meet the needs of clinical drug therapy, the sustained release implants of ketoclorobutanol were prepared by hot melt extrusion. Methods: orthogonal test was used to screen and optimize the prescription of the implant, and three main factors were investigated: drug content. The feed ratio of Poloxamer to polylactic acid and the molecular weight of polylactic acid were considered at three levels: the drug content was 20% and 90% respectively; The ratio of Poloxamer to polylactic acid was 0: 10: 1: 9 and 2: 8; The molecular weight of polylactic acid was 50,000 ~ 160,000 and 540,000. The orthogonal table of L43 was used to design the experiment. Drug loading and dissolution in vitro. The method for the determination of ketoralic acid aminobutanol sustained-release implants was validated by HPLC. In vivo and in vitro release assay was used to study the effect of ketocloroic acid aminobutanol sustained-release implants on neoxy. Pharmacokinetic characteristics of drug release in blue rabbits. Results: a simple hot-melt extrusion equipment in laboratory was developed, which can change the specification of the preparation by adjusting the mould according to the different needs of the test preparation. Comprehensive investigation of various factors finally selected the drug content is 20, the molecular weight of polylactic acid is 160,000. Polylactic acid and Poloxamer were used as implants with a ratio of 9: 1. The mobile phase consisted of methanol: water: triethylamine: glacial acetic acid 80: 19.9: 0.02: 0.08. Chromatographic column: Kromasil C18 column: 250Am / min, flow rate: 1 ml / min. The chromatographic conditions of detection wavelength at 319 nm can be used as a method for the determination of ketoclalic acid aminobutanol implants in rabbits. The relative standard deviations of low, medium and high inter-day precision of ketoclalate aminobutanol are 8.16%, respectively. In 12.1% and 12.1g, the specificity of the analytical method met the requirements. The interday precision of ketoclalic acid aminobutanol was 7.6% and 3.8%, respectively. The relative recoveries of low, medium and high concentrations were 106.3% and 85.3%, respectively. The relative recoveries of both high and medium concentrations should be in the range of 85% to 115% and the low concentrations should be in the range of 80% to 120% at room temperature. The RE% values of the samples at the three concentrations were 1. 01 and 0. 96, and 1.00% respectively. The release time of the ketocloroic acid aminobutanol implant was prolonged to 18 days, and the release time of the preparation was stable on the 7th day. In New Zealand rabbits, the concentration of the drug was 0.3 渭 g / ml. Conclusion: the method of preparing ketocloroic acid aminobutanol implant by hot melt extrusion was studied. The sample of the experiment was prepared and the HPLC method for the determination of ketoclalic acid aminobutanol implant was investigated. The release kinetics of ketoclalic acid aminobutanol implant was studied in vivo and in vitro. These experiments showed that it was feasible to prepare ketocloroic acid aminobutanol implant by hot melt extrusion. The obtained data provide a scientific basis for further research and development of the product.
【学位授予单位】：广东药学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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