Study On Preparation Process Of Matrine Gel-matrix Sustained Released Tablets

BackgroundAbout 2 billion people worldwide have been infected with the virus and about 350 million live with chronic infection. An estimated 600000 persons die each year due to the acute or chronic consequences of hepatitis B. About 25% of adults who become chronically infected during childhood later die from liver cancer or cirrhosis (scarring of the liver) caused by the chronic infection. The hepatitis B virus is 50 to 100 times more infectious than HIV. Hepatitis B virus is an important occupational hazard for health workers.As traditional Chinese medicines, Sophora Alopecuroides L. and Sophora Flavescens Ait have been used for the treatment of many diseases for thousands of years. Its alkaloid extract, marine, has long been extensively used in China. Oxymatrine(OM) is matrine synthesis, a monomer processed by oxidation, purification and extraction, and N-oxides of matrine.OM which possesses a special oxygen structure and whose molecular polarity is increased is more effect than Matrine.Hepatitis B is endemic in China and other parts of Asia. Most people in the region become infected with HBV during childhood. In these regions,8% to 10% of the adult population is chronically infected. Liver cancer caused by HBV is among the first three causes of death from cancer in men, and a major cause of cancer in women. High rates of chronic infections are also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and Indian sub-continent, an estimated 2% to 5% of the general population is chronically infected. Less than 1% of the population in Western Europe and North American is chronically infected.Matrine is a mixed alkaloid composed of noless than 98 percent of Oxymartine(OM) free of water and a very few quantity of Oxysophocarprine. The molecular formula of Oxymatrine is Ci5H24N2O2·H2O,and relative molecular mass is 282.38. Oxymatrine is white or almost white crystalline powder, odorless, bitter in taste. Easily dissolves in water, ethanol and chloroform. Dissolves in acetone. And slightly dissolve in ethylether.Basic pharmacological and clinical studies have shown that it has anti-cancer, anti-virus, anti-parasitic, anti-inflammatory, anti-arrhythmic and significantly increased the role of leukocyte and has broad prospects of development. From recent research, it is show that oxymatrine could eliminate or restrain the replication of viruses, regulation the immunity of people, strengthen the detoxication of liver. Also could promote the cell regeneration of liver, improve the liver function.Objects and significancesBecause of Poor fat-soluble character and the low bioavailability its utilization has been limited as the full play of clinical curative effect to a certain extent. The cost of the microsphere, micro-pellet, nano-preparation is very high, and it is hard to carry out from the industry. The gel Sustained Release Tablets technology in pharmacy is studied to improve the absorption of many Poor-water soluble drugs and their bioavailability remarkably, also these kinds of technology is easy and the cost of it is much cheaper. Under the guidance of theory of traditional Chinese medicine,system engineering and modern experiment design in the pharmacology, we choose marine with good function of anti-hepatitis virus as the model medicine to preparate the Matrine gel-matrix sustained-release tablets. And we study on the preparation, physics-chemistry characters, quality control, stability, pharmacokinetics and bioavailability of the Marine gel-matrix sustained-release tablets.Methods1.To prepare the Matrine gel-matrix sustained-release tablets which can sustained-release for 12h, several character of Matrine were examined before prescription. The basic physicalchemical properties of OM, drug release performance and drug content of tablets were determined by HPLC, which can satisfy and analytical requirement in this study correctly and conveniently. The solubilities of Matrine in solutions of different PH and in condition of different osmotic promoter's saturation solution were investigated.2. Matrine gel-matrix sustained-release tablets were designed and prepared according to addenda XIXD of CHP2005. Marine gel-matrix sustained-release tablets were compressed by wet granulation. The specifications and amount of HPMC and the type of filler as well as compression pressure was selected for the excellent drug release character and convenient process in this article. Because of they may effect the release of matrine gel-matrix sustained-release tablets. A similar factor (f2) was adopted for the similarity determine.3. In various external conditions, we investigate the primary stability of marine gel-matrix sustained-release tablets. Meanwhile, by means of HPLC to determine the content of marine and accomplishe the systematic methodology. Stability research include influence factors investigation and accelerated test. 4.The relative bioavailability and pharmacokinetics studies of OM were performed in six healthy beagle dogs, using marine capsules as the reference. The mothod of HPLC was established for determining OM and M, it's metabolite in dog plasma. The two preparations were bioequivalent according variance analysis for AUC0→β(OM) and AUC0→β(M).The release of OM from sustained released tablets in vitro correlated well with absorption fraction in vivo.Results and Discussion1. In this article the Oxymatrine analytical method in vitro was established by HPLC. OM in sustained-release gel-matrix tablets and the Oxymatrine release of sustained-release tablets was determined by HPLC. The detection wavelength was 220nm. Methodological study of the analysis showed that the method is viable, and have a good reproducibility and high accuracy. Matrine is soluble both in the water and the phosphate buffers at different pH condition. So control of the drug burst is the key designed to the sustained-release preparations. The results of Oil/water distribution coefficient showed that Matrine coefficient was small in the entire pH range of water. The description of release profiles suggested that among the different kinetics, the first-order became the most appropriate model to describe release kinetics.2. Prescription for the final choice was as followed:Matrine:HPMCK4M: HPMCK100M:MCC:lactose:Magnesium stearate= 30:30:20:13:6:1. When the Compression pressure was 50N, the products get better result. By analysis of release data from OM using different equations, OM released mainly by diffusion combineed with erosion from HPMC matrix.3. Results of the preliminary stability test showed that the marine gel-matrix sustained-release tablets are stable under light and high temperature. The content and release were not significantly changed. In high humidity condition of RH92.5%, the moisture situation is more serious up to as much as 25 percent. But in the humidity conditions of RH75%, the appearance, content and release had no significant change. According to the results of accelerated test after six months showed that gel-matrix sustained-release tablets can be stable for three years. But the goods should pay attention to moisture.4. The high-performance liquid chromatographic(HPLC) method has been developed for the determination of the sample. Separation was obtained on a Diamonsil C18 (250mm×46mm,5μm),using an excitation wavelength of 220nm.the isocratic mobile phase consisted of acetonitrile-water (15/85, V/V) was run at a flow rate of 1.0ml/min for different biological matrix. Column temperature was room temperature. The chromatographic system used provided good separation of the compound without interfering peaks from endogenous substance. The calibration curves were linear in eath sample range with correlation coefficient above 0.99.The pricsion of intra-day and inter-day were evaluation by analysis of variance with the result of 0.68-1.68% and0.49-1.48% respectively. The mothed has been successfully used to support the pharmacokinetics study.The relative bioavailability and pharmacokinetics studies of OM were performed in six healthy Beagle dogs, using marine commercial capsules as the reference. The pharmacokinetics parameters of OM in gel-matrix sustained-release tablets and commercial capsules analyzed by non-compartment model theory were Tmax 3.25±0.61 h,2.42±0.38 h; Cmax 4.76±0.60μg/mL,7.04±0.47μg/mL; AUC (0-t) 30.39±4.71μg·h/mL,28.64±4.46μg·h/mL. The relative bioavailability was 111.23%. The statistical analysis of the AUC0-∞(OM) and AUC0-∞(M) to evaluate the two formulations are bioequivalent. The pharmacokinetics parameters of M in gel-matrix sustained-release tablets and commercial capsules analyzed by non-compartment model theory were Tmax 6.17±2.04h,4.74±1.17 h; Cmax3.79±1.11μg/mL,5.35± 0.72μg/mL; AUC(0-t) 39.41±11.43μg·h/mL,42.74±4.81μg·h/mL. The relative bioavailability was 105.29% to the concentration of OM and M together,ConclusionThe results indicate that the preparation porcess as reasonable and practical, the standad is controllable, and the analysis technology are stable. the quality of the sample of teady on the whole as well.