【作者】 赵学刚；

【导师】 张兰桐；

【作者基本信息】 河北医科大学 ， 药物分析学， 2019， 硕士

【摘要】 目的:本课题研究氨酚羟考酮胶囊的制备工艺、氨酚羟考酮胶囊的质量控制方法及稳定性研究、氨酚羟考酮胶囊人体生物等效性试验,研究其人体相对生物利用度,评价人体生物等效性,为临床用药提供参考。方法:参考马林克罗制药有限公司生产的氨酚羟考酮胶囊（商品名:泰勒宁）处方,对使用的辅料进行原辅料相容性试验,使用与参比制剂处方中基本一致并且相容性良好的辅料进行处方筛选,考察对乙酰氨基酚的粉碎工艺及粒度,通过重量法测定处方中主要辅料玉米淀粉的含量,考察粘合剂的种类,润滑剂、助流剂、抗氧剂、表面活性剂的用量,确定优化处方和工艺,然后由小试、中试、大生产逐步放大批量,对自制制剂和参比制剂进行对比研究。参考国内外药典相关质量标准、ICH指导原则,建立本品对乙酰氨基酚、盐酸羟考酮有关物质检查方法,并对溶出度、含量测定、有关物质检查方法进行验证,同时对样品进行稳定性考察。建立LC-MS/MS法测定体内羟考酮、对乙酰氨基酚血药浓度检查方法,进行方法学验证。采用单中心、开放、随机、自身交叉对照,22例受试者分别服用自制的氨酚羟考酮胶囊与美国马林克罗制药公司生产的氨酚羟考酮胶囊（商品名:泰勒宁）,进行血药浓度测定,研究其人体相对生物利用度,考察两制剂的人体生物等效性。结果:原辅料相容性良好,采用优化工艺生产的氨酚羟考酮胶囊颗粒密度大,流动性好,装量差异小,崩解迅速,工艺重现性好。自制制剂和参比制剂有关物质杂质谱及含量基本一致,溶出行为基本一致,产品质量稳定、均一。建立了对乙酰氨基酚、盐酸羟考酮有关物质检查方法,有关物质检查、溶出度检查、含量测定方法专属性强,灵密度高,准确度、精密度、耐受性良好;影响因素试验、加速试验、长期稳定性考察,表明该工艺生产的产品稳定、均一、质量可控,为氨酚羟考酮胶囊质量控制和产品有效期的制定提供了依据。建立了LC-MS/MS内标法测定健康受试者血浆中羟考酮浓度方法,HPLC内标法测定健康受试者血浆中对乙酰氨基酚浓度方法,血浆中内源性物质及其它物质均不干扰样本峰和内标峰,专属性良好,灵敏度、准确度、批内和批间精密度均符合要求,该方法符合生物样本分析要求;经双向单侧t检验,羟考酮和对乙酰氨基酚的ln(AUC_0-16h)和ln(AUC_0-?)[1-2α]置信区间分别为92.3%¹06.4%、98.4%¹07.3%和92.4%¹06.3%、98.0%¹06.9%,在80%-125%范围内;羟考酮和对乙酰氨基酚的ln(C_max)[1-2α]置信区间分别为84.9%¹10%和87.8%¹10.7%,在80%¹25%范围内,说明两制剂具有生物等效性,自制制剂与参比制剂羟考酮和对乙酰氨基酚相对生物利用度F分别为（101.1±19.94）%和（103.5±11.94）%,符合生物利用度要求,两制剂具有生物等效性。结论:氨酚羟考酮胶囊制备工艺重现性好,生产的产品安全、有效、稳定、均一、质量可控,自制制剂和参比制剂体外质量基本一致,体内生物等效。更多还原

【Abstract】 Objective:The preparation technology,quality control and stability of oxycodone paracetamol capsules were studied in this paper.The bioequivalence test and relative bioavailability of human body were also studied to evaluate the bioequivalence of human body,so as to provide reference for clinical medication.Methods:Refer to the prescription of acetaminophen oxycodone capsule（trade name:taylox）produced by Mallinckrodt Pharmaceutical Co.,Ltd.,the compatibility test between API and excipients was carried out for the used excipients.Prescription screening was carried out with excipients with good compatibility used in the reference preparation.The crushing technology and particle size of acetaminophen were investigated.The content of maize starch was determined by gravimetric method.The types of adhesives,the dosage of lubricants,flow aids,antioxidants and surfactants were investigated.The prescription and process were finally determined.According to the small-scale test,pilot-scale test and production,the batches were gradually enlarged,and the self-made preparations and reference preparations were compared and studied.Referring to Pharmacopoeia and related quality standards,ICH guidelines,a method was established,by determinating paracetamol and oxycodone hydrochloride related substances in this product and the dissolution,content determination and related substance examination methods were verified.The stability of the samples was also investigated.The blood concentration of oxycodone and paracetamol in vivo was determined by LC-MS/MS,and the methodology was validated.By use of single-center,open,randomized and self-crossed control,22 subjects were given self-made oxycodone capsules and Taylor capsules（trade name:taylox）produced by Malinkro Pharmaceutical Company in the United States.The relative bioavailability and bioequivalence of the two preparations were studied.Results:The compatibility between APIs and excipients is good.The capsules produced by the optimized process have high particle density,good fluidity,small weight deviation;rapid disintegration and good reproducibility.The impurities and contents of related substances in self-made preparation and reference preparation are basically the same,the dissolution behavior is basically the same,and the product quality is stable and uniform.A method for the determination of paracetamol and oxycodone hydrochloride related substances was established.The methods for the examination of related substances,dissolution and content determination were specific,sensitive,accurate,precise and well tolerated.The test of influencing factors,accelerated test and long-term stability showed that the products produced by this process were stable,uniform and controllable in quality.These studies provide a basis for quality control and product validity of oxycodone acetaminophen capsules.Amethod for determination of oxycodone in plasma of healthy volunteers by LC-MS/MS internal standard was established.A method for determination of acetaminophen in plasma of healthy volunteers by HPLC internal standard method was established.Endogenous substances and other substances in plasma do not interfere with the sample peak and internal standard peak.The specificity is good.The sensitivity,accuracy,intra-batch and inter-batch precision meet the requirements.The method meets the requirements of biological sample analysis.The confidence intervals of Ln(AUC_0-16h)and LN(AUC_0-?)[1-2a]of oxycodone and acetaminophen were 92.3%-106.4%,98.4%-107.3%and92.4%-106.3%,98.0%-106.9%respectively,in the range of 80%-125%by two one-sided t-test The confidence intervals of ln(C_max)[1-2α]of oxycodone and acetaminophen were 84.9%-110%and 87.8%-110.7%,in the range of80%-125%.The results showed that the two preparationswere bioequivalent.The relative bioavailability F of oxycodone and paracetamol were（101.1±19.94）%and（103.5±11.94）%respectively,whichmetthe requirements of bioavailability.The two preparations were bioequivalent.Conclusion:The preparation process of oxycodone acetaminophen capsules has good reproducibility.The product is safe,effective,stable,uniform and controllable in quality.The self-made preparation is the same as reference preparation in both quality and bioequivalent更多还原