Study On Regional Drug Absorption Of Gastrointestinal Tract Based On Remote Controlled Capsule

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.