【作者】 刘洪英；

【导师】 郑小林； 皮喜田；

【作者基本信息】 重庆大学 ， 生物医学工程， 2010， 博士

【摘要】 在各种给药途径中,口服给药仍然占据着主导地位。人体胃肠道不同区段的解剖特征及生理环境各不相同,科学地研究药物在胃肠道各部位的吸收特性,获得药物吸收机制、明确吸收薄弱环节及影响生物利用度的关键因素,对于口服剂型研究具有重要的指导意义。遥控施药胶囊(Remote Controlled Capsule, RCC)是近年来获取胃肠道药物吸收特征的重要新技术之一,基于RCC的胃肠道局部药物吸收(Regional Drug Absorption,RDA)研究对于新药开发及药物传输技术均具有重要的指导意义,国内在该领域的研究尚处于空白。在国家863计划等项目支持下,本论文在胃肠道药物吸收模型、胃肠道遥控释药方法、定位跟踪技术、临床安全性增强等方面进行了深入研究,通过系列动物实验和志愿者实验,初步建立了基于RCC的胃肠道局部药物吸收特性检测方法,为我国新药及新剂型开发提供了一种创新技术。本论文的主要工作包括以下三部分:第一部分,基于RCC的药物胃肠道吸收模型研究。在药物胃肠道转运与吸收机理分析的基础上,提出了一种基于RDA的口服药物胃肠道吸收分析模型(In vivo Regional Drug Absorption, IVRDA),将药物的溶解度和渗透性作为胃肠道药物吸收的主要考虑因素,同时以动物实验数据、志愿者实验数据弥补体外模型数据的不足,并基于该模型提出了口服药物剂型与剂量优化设计的技术路线。第二部分,遥控施药胶囊系统关键技术研究。(1)研究了一种基于微推进器技术的新型释药方法,利用微推进器产生的推力进行药物释放,解决了传统利用弹簧驱动药物释放产生负压的缺点,基于微电子机械系统(Micro-Electro-Mechanical Systems,MEMS)工艺获得了尺寸为500μm×100μm×100μm的驱动器芯片,将微推进器的启动功率降低至200 mW以内。(2)开展了基于三维闪烁扫描的定位跟踪方法研究,利用ECT(Emission Computed Tomography,ECT)获取人体(或动物)腹部的正位和侧位图像,通过三维闪烁扫描定位算法获得RCC在体内的三维空间坐标。体外模拟实验表明该方法定位精度小于10 mm,初步志愿者实验表明,该方法能够获得RCC的体内三维轨迹,是一种具有潜力的智能胶囊胃肠道定位跟踪方法。(3)进行了基于胃肠道排空检测缓释胶囊的RCC临床安全性增强方法研究,设计了以固体烷烃混合物(CnH2n+2,n=16~35)为包衣的胃肠道排空检测缓释胶囊,48±6小时内在低速崩解的同时具有良好的形状保持度,可以有效地模拟RCC通过胃肠道的全过程,并成功用于临床实验前的志愿者筛选中。第三部分:基于RCC的胃肠道局部药物吸收特性实验研究。(1)开展了基于RCC的动物胃肠道局部药物吸收特性实验研究,以毕格犬为动物模型,盐酸二甲双胍为探测药物,获得了盐酸二甲双胍在毕格犬胃肠道不同部位的药代动力学参数。实验结果表明盐酸二甲双胍小肠段施药生物利用度最高,分别是胃部的1.33倍,结肠部的2.29倍。概括总结了基于RCC的动物胃肠道局部药物吸收研究标准操作流程。(2)基于RCC的志愿者局部药物吸收实验研究及方法验证。选取氨茶碱粉末作为模型药物,用课题组研制的RCC获得了氨茶碱粉末在志愿者小肠、结肠定位释放后的药代动力学特征,并与直接口服给药的药代动力学特征相比较,获得了氨茶碱于志愿者胃、小肠、结肠不同部位给药后的药代动力学特征差异,对本研究提出的IVRDA模型进行了验证,分析结果表明氨茶碱在结肠具有较好的吸收,可以开发为缓释制剂,模型验证结果和国外同类研究结果具有较好的一致性。本论文的创新点主要包括:(1)提出了一种基于RDA的口服药物胃肠道吸收分析模型(IVRDA模型),该模型以动物实验数据,志愿者实验数据弥补体外模型数据的不足,提高了模型的准确性,相关方法申请发明专利1项(200610095225.5)。(2)提出了一种基于微推进器技术的新型释药方法,首次将微推进器技术用于RCC,获得发明专利获权一项(ZL200610095354.4)。(3)提出了基于胃肠道排空检测缓释胶囊的RCC临床安全性增强方法,设计了以固体烷烃混合物为包衣的胃肠道排空检测缓释胶囊,志愿者实验表明该方法可以有效地模拟RCC通过胃肠道的全过程,获权两项发明专利(ZL200510057395.x;ZL2005100573964)。(4)在国内首次进行了基于RCC系统的志愿者胃肠道局部药物吸收特性研究,获得了氨茶碱在健康志愿者肠道各部位的吸收特性数据,并获得了胃肠道局部药物吸收特性检测方法标准流程,为我国新药研究提供了创新的方法和手段。论文在后续研究中,在基于微推进器技术的RCC方面应进一步减少功耗,并进一步提高系统的安全性,在三维闪烁扫描定位跟踪方法方面应研究ECT图像中标记点的计算机自动识别技术,构建数字化人体胃肠道模型以提高定位的准确性。由于本论文实验研究费用较贵,在经费限制下开展的实验例数有限,在后续研究中应增加实验数量以获得更多的数据,并将数据应用于新型口服制剂的研发之中。更多还原

【Abstract】 Oral drug delivery system is still in the leading position among all kinds of drug delivery systems. There are great differences in anatomical structures and physical environments in different parts of human gastrointestinal (GI) tract. So it is special meaningful for oral dosage form to study drug absorption characteristic in GI tract and acquire the mechanism of drug absorption, weak area of drug absorption, and main determining factors of bioavailability. Remote controlled capsule (RCC)is an important innovative technology to study drug absorption characteristic of human GI tract. In the development of new drug and new oral dosage form, it is meaningful to take regional drug absorption (RDA)studies based on RCC technology. This research, supported by the National High-tech Projects (863), has pioneered to study RDA technology. The key points of this research are as follows: GI tract drug absorption mechanism models, remote controlled capsule technology, smart capsule locating and mornitering technology, clinical security enhancement technology, animal experiments and clinical experiments. In this study, we initially established GI tract regional drug absorption characteristic detecting methods, which is a new technology for the new drug development in china.The main contents of work and research achievements of this study are as follow:Part I: Research on GI tract drug absorption mechanism models. In this part, the GI tract drug transit and absorption mechanism are carefully anayliszed. A new GI absorptiong mechanism model-in vivo regional drug absorption (IVRDA)model was presented based on RDA studies. In IVRDA model, solubility and penetrability are considered as the main determinating factors of GI drug absorption,at the same time, animal RDA datas and volunteer RDA datas are used together with in vitro experiment datas in the model. A technology routemap of development of innovate oral dosage form has been presented in this study.Part II: Research on the key technology of RCC system. (1) An innovative remote controlled drug release method is developed based on microthruster technology. A solid propellant microthruster is developed and incorporated for the first time in the actuation assembly of the proprietary RCC. It features gas production that generates the mechanical energy to empty the drug reservoir. The key component of the miniaturized thruster is a micro-electro-mechanical systems (MEMS)-based microigniter, 500 μm×100μm×100μm, where diazodinitrophenol (DDNP) as the detonating agent and black powder as the propellant are encapsulated. Experimental tests of ignition and combustion demonstrated that the power consumption is less of 200 mW. (3) This study proposed a method for clinical security enhancement of RCC based on GI tract transit simulating capsule, which is a sustained-release tablet to detect the empting and transiting process of the GI tract, and designed for the first time the tablets coated with solid alkane mixture (CnH2n+2, n=16~35), which maintain within 48±6 hours a good shape while slowly disintegrating. The entire process that RCC passes through the GI tract could be effectively simulated, the efficiency was proved by volunteer’s clinical trials.Part III: Experiments of GI tract regional drug absorption by the use of RCC. (1)RDA animal experiments. The pharmacokinetic parameters were acquired after the model drug(C4H11N5·HCl )was site-specific released in the different areas of the GI tract of beagles. Animal experiments showed that the bioavailability of C4H11N5·HCl is best when released in small intestine, which is 1.33 times than that in stomach and 2.29 times than that in colon. The standard operating procedure (SOP) of RDA study based on RCC was concluded in the dissertation. (2) RDA volunteers experiments. The pharmacokinetic parameters were acquired after the model drug (aminophylline) was site-specific released in the different areas of the GI tract of volunteers. The IVRDA model was tested by the use of pharmacokinetic parameters. The result showed that aminophylline was well absorpted in human colon and was suitable to be designed as sustained release formulations. The results calculated from the IVRDA model are coincident well with the other research results.The innovation points in this research are as follows: (1) A new GI absorptiong mechanism model-in vivo regional drug absorption (IVRDA)model are presented based on RDA studies. The accuracy of IVRDA model was improved by the use of animal RDA datas and volunteer RDA datas, an invention paten was applied (200610095225.5). (2) An innovative remote controlled drug release method is developed based on microthruster technology. A solid propellant microthruster is developed and incorporated for the first time in the actuation assembly of the proprietary RCC. An invention patent was authorized (ZL200610095354.4). (3) A method for clinical security enhancement of RCC based on GI tract transit simulating capsule. Two invention patents were authorized(ZL200510057395.x;ZL2005100573964).(4)RDA volunteers experiments was firstly conducted in China based on RCC. The pharmacokinetic parameters of aminophylline are acquired after the model drug was site-specific released in the different areas of the GI tract of volunteers. The standard operating procedure (SOP) of RDA study based on RCC is new method for the new drug development in China.In the sequential studies, the focal point of the research are as follow: the power consumption of the micro-thruster should be further decreased and the security of the RCC should be improved, the markers of the ECT images should be automatically recognized in 3DGS system, the digital GI tract model should be adopted to improve the the accuracy of 3DGS system. The cost of RDA experiments is expensive, so the amount of experiments is limited by the budget of the research. In the sequential studies, more experiment data should be acquired by more experiments.更多还原