| Chinese Medicine (TCM) is a precious heritage of China, which is a main preventative and therapeutic method of laboring people in thousands of years. TCM preparation (TCMP) is an important part of TCM, which is the sum of medicine experience of the laboring people in long time and has played a great role in the prosperity of Chinese nation, because of their precise composition, good curative effects and little side-effects. However, TCMP is faced with many problems today such as outdated dosage forms, backward techniques, lack of available quality estimation, which have hindered the development of TCM undertakings and movement toward the world. It is urgent to study TCMP by making full use of advanced science and techniques.Guanxindanshen(GXD) capsule has been listed in the first section of 2010's edition of "Pharmacopoeia of People's Republic of China" (2010PPRC), which is composed of "danshen" (Salviae Miltiorrhizae Radix et Rhizoma), "sanqi"(Notoginseng Radix et Rhizoma) and "jiangxiang you" (Dalbergiae Odoriferae Lignum oil). It has efficacy of activating blood, resolving stasis and regulating qi to relieve pain, and is primarily applied to the treatment of coronary artery disease, dyspnea and coronarism. The three extracts (Salvia total phenolic acids, Tanshinones and Notoginseng total saponins) also have been listed in the first section of 2010PPRC. In this thesis, GXD was selected as the model drug of GXD multiphase capsule (GXDMC) which was composed of " jiangxiang you" soft capsules, GXD immediate-release and sustained-release pellets, because of only three herbs in the recipe, more extensive basic researches and good curative effects.It is backward for the qualitative analytical methods of GXD in pharmacopoeia and could not precisely analyse the full contents of drugs. TLC methods were used to identify Salvianolic acid B, TashinoneⅡA, Ginsenoside Rg1 and Rb1, Nerolidol, and HPLC methods were used to determine Salvianolic acid B, TashinoneⅡA, Ginsenoside Rg1 and nerolidol. The HPLC method was built for the first time to dete'rmine the nerolidol in GXD capsule. Above mentioned analytical methods provided suitable means in future study of GXD multiphase capsule preparation.The initial technology could not remove large of impurities, a new one was studied in order to get rid of impurities. On the basic preparation of three extracts in 2010PPRC, Salvia total phenolic acids were prepared with water-decoction alcohol-precipitation extraction, and Tanshinones with alcohol-decoction water-precipitation extraction. The contents of Salvia-nolic acid B and TashinoneⅡA were all above 9.8%, separately in Salvia total phenolic acids and Tanshinones. Notoginseng total saponins were obtained with the methods of 70% alcohol-decoction and purified with macroporous resin adsorption separation, whose content was above 82%.The pharmacological effects of two technologies on T wave height, blood CK and LDH in myocardial ischemia rats were studied. The results showed that there was no significant difference on T wave height between original and new technologies (P>0.05). The compound extracts could evidently decrease both levels of CK and LDH as compared with control group (P<0.05), and there was significantly difference in decreasing the CK level as compared with original technology (P<0.05).The study on physicochemical properties of three extracts'powder showed that Salvia total phenolic acids and Notoginseng total saponins were hydrophilic, but Tanshinones were hydrophobic. The solubility of these extracts was good in 0.5%SDS, but the flowbility of them was poor all. Treatment with the light, temperature and moisture, the content of Salvianolic acid B, TashinoneⅡA and Ginsenoside Rg1, were kept unchanged. The active ingredient ratio in immediate-release and sustained-release parts was determined as 38.5:61.5 by pharmacokinetic parameters of TashinoneⅡA. Intestinal absorption experiments of rats in situ were used to study the absorption of Salvianolic acid B, TashinoneⅡA and Ginsenoside Rg1 in GXD. It was found that the absorption of Salvianolic acid B, TashinoneⅡA and Ginsenoside Rg1 complied with the first order kinetics by passive transport mechanism with and without ligation of rats'bile duct. There were no obvious differences among the absorptive rate constant of Salvianolic acid B, Tashinone IIA and Ginsenoside Rg1 in different parts of the rats'small intestine (P>0.05). According to the properties of GXD and characteristics of treatment disease, the GXDMC was designed as three delivery systems: " jiangxiang you" soft capsules, GXD immediate-release and sustained-release pellets. " jiang xiang you" soft capsules were prepared with gelatin and glycerol by dropping process. GXD immediate-release and sustained-release pellets were prepared by extrution-spheronization. GXD immediate-release pellets were prepared by selecting L-HPC as a disintegrating agent, MCC as a filler, and 1%HPMC (50% alcohol) as adhesion agent. The immediate-release pellets presented perfect sphericity and bulk density, and the accumulative release was above 95% in 15 minutes. GXD sustained-release pellets were prepared by extrution-spheronization using carbomer974P as a main matrix material, MCC as a filler. The effects of independent process parameters on yield, roundness and bulk density of pellets were studied by singer factor experiment. Central composite design was used to optimize the formula of sustained-release pellets. HPMC (6mPa·s) as a protective coating material and Acryl-EZE?93F as an enteric coating material were applied in an air suspension coating system to prepare the enteric coated GXD sustained-release matrix pellets. The dissolubility of the enteric coated pellets in 0.5%SDS (pH=1.0) was less than 5% within 2 hours. There were no obvious differences in the release characteristics between enteric coated and non-enteric coated sustained-release matrix pellets. It could satisfy request of enteric pharmaceutics.The materiomics release rates within 12h of the GXD sustained-release matrix pellets were determined by the paddle method with a rotate speed at 100 r·min-1, and the materiome was quantified by HPLC, UV-scan and Kalman filter methods. The results showed that the sustained-release time of the matrix pellets was above 10h in 0.5% SDS and the matrix pellets had good Higuchi release characteristics (R=0.9976). The numeric materiome release data were transformed into colors by Matlab7.0 to visualize the materiomic release profiles and synchronicity. |
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