Studies On Preparation Proceduce And Quality Of Fuzheng Xiaozheng Tablet

Fuzheng Xiaozheng (FZ) compound, based on clinical experience of Shen Shaogong (a distinguished veteran doctor of TCM) on curing abscess, scrofula and abdominal mass. FZ capsule was widely used as an adjuvant therapy medicine for cancer, especially for the patients with radiotherapy and chemotherapy. The therapeutic priciple of this compound was clearing away heat-toxins, and removing abdominal masses and benifiting Qi for eliminate pathogenic factors. Clinical researches demonstrate that FZ can significantly raise white blood cells, improve immune functions and the life quality of patients. But for FZ capsule, there’s no excipients in this clinical preparation, which can easily absorb moisture. And what’s more, as an preparation used in certain hospital, the process parameters was not very clearly too. In this thesis, systemly pharmacy researches of FZ were investigated to make sure the quality of this medicine.During the process studies, both of the chemical and pharmacodynamic indexes were selected to optimize its’extraction porsses. After comprehensive considered the extraction rate and the application compliance, tablet was chosen as the final dosage form.According to the hypothesis of "only the components which can be absorped into the blood might be the effective components" and the compound chemical ingredients^absorption component ingredients>efficacy ingredients, the quality standards of intermediates and final products were established by compared the components in blood and intestinal fluid (for the in vitro-everted intestinal sac model).In the extraction process of FZ tablet, firstly based on the characteristics of the active ingredients in each Chinese herbal medicines, extraction method was chosed through water extraction, ethanol extraction and comprehensive extraction, and then alcohol extraction method was selected since not only its’excellent effection on anticancer and elevate white blood cells, but the higher extraction yield of effective components. Secondly, orthogonal experimental design were used to optimize the process parameters, contents of total alkaloids (sum of berberine, palmatine, coptisine and epiberberine), scutellarin, total ginsenosides (total of ginsenoside Rg1, Re and Rb1), notoginsenoside R1 and extract yields were chosen as the quality control indexes. All these indexes were given different weight value according to its function in the formula. Orthogonal tests and comprehensive weight of multi-indexes were used to evaluate the extraction processes to determine the key technical parameters, such as the ethanol concentration and amount of extracting solvent, and times of extraction. And finally, each time of refluxing was investigated. The final optimized extraction technology was as follows:refluxing for 3 times with 6-fold 60%ethanol for 2h per time. The optimized extraction technology was varified both in laboratory and medium-scale manufactures to ensurethat the optimized process was stable.In the preparation process of FZ tablets, powdered sugar, microcrystalline cellulose, Polyvinylpyrrolidone K30, Crosslinking polyvingypyrrolidone, magnesium stearate and silica were selected as filler, adhesive, disintegrating agent and lubricant respectively. Central composite desigh-response surface methodology was used to optimize the dosage of powdered sugar, microcrystalline cellulose and Crosslinking polyvingypyrrolidone with disintegration time and dissolution as evaluation indexes. The results were analysised by SAS statistical software. The best formula was as follows:The main medicine 72.0%, powdered sugar 8.7%, microcrystalline cellulose 9.9%, crosslinking povidone 8.4%, magnesium stearate 0.5%, silica 0.5%. In addition, flowbility, compressed limit, hygroscopicity, critical relative humidity of granules were studied, and its’ standards were established.Thin film coating technology was used to enhance the stability of tablets. Two most commonly coating material were evaluated and the cellulose one was selected for its’ perfect moisture proofing effect and less effection on drug dissolution.Based on the hypothesis of only the components which can be absorped into blood components might be the effective components and the compound chemical ingredients?? absorption ingredients>efficacy ingredients. We tested the plasma after intragastric administration to rats.2.5 Times the amount of acetonitrile was added to depositing protein, and then detected by UPLC-MS. The chromatographic condition was gradient elution of methanol and 0.1% formic acid aqueous solution. The results showed that alkaloids and scutellarin were main components which can be absorped into blood, and both of them can be absorbed into blood within 2 hours.In vitro-everted intestinal sac model was used to investigate the intestinal absorption of the alkaloids with different concentration. The results showed that all characteristic of four active ingredients, berberine, palmatine, coptisine and epiberberine conformed to zero-order equation. The Ka of four ingredients at low dose has significant differences when compared with that of medium and high dose (P<0.05), but there was no obvious differences between medium and high dose (P>0.05). The absorption mechanization of four ingredients presented two absorption manners, they were positive diffusion and passive absorption. The absorption dosages in ileum is greater than that in jejunum.In order to control the qualities of the product, quality standards of FZ tablets and its’intermediates were established, which involves tablet’s appearance, friability, weight variation, disintegration time and dissolution rate. HPLC methods of determination of berberine, palmatine, coptisine, epiberberine, scutellarin, ginsenoside Rgi, Re,Rbl and notoginsenoside R1 was established, and also systematic methodology was inspected. Qualitative identification method of Rhizoma coptidis, Ginseng, Notoginseng and Euphorbiae were established using TLC.Accelerated test and long-term stability test was used to investigate the stability of the product. The results showed that examined indexes meet relevant provisions well, Fuzheng Xiaozheng tablet was stable.