| Objectives: Oral colon-specific drug delivery system (OCDDS) is a system through which the oral drug will not release in the upper gastrointestinal tract but disintegrate and release in the colon and play local or systemic treatment in the colon. Matrine displayed strong proliferation inhibitory effect against colon cancer SW1116 cells and colon adenocarcinoma SW620 cells. It can be used to prevent and treat colon carcinoma. Pectin is a kind of naturally polysaccharides. Pectin is intact in the upper gastrointestinal tract and degraded by colonic microflora. It is and can be used for microbially triggered colon-specific delivery system. The experiment made filmcoated matrine pellets with mixed-films of ethylcellulose and pectin. The coated pellet was expected to release most drug in the colon. It can increase the drug concentration of the colon and improve the efficacy.Methods: Pellet core containing matrine and microcrystalline cellulose were prepared by the process of extrusion–spheronization. The pellets were coated sequentially with(i)innermost sealing coat of OpadryⅡ,and(ii)outer coating layer of the mixture of pectin solution and Surelease?. Coating was performed using fluidized bed coater.The factors of prescription (dose of matrine and excerption of binder) were inspected which influenced formation and release of pellets. The orthogonal experiment was designed to screen technique in which the speed of extrusion, speed of spheronization and the time of spheronization were taken as three influential factors and three different levels were selected to part, each conformation of technique was selected refer to the orthogonal design table. Single-factor analysis was carried out to find out the main factors (the rat of pectin-Surelease? and the film thickness) affecting the drug release.Then orthogonal experiment design was carried out to find out the best prescription. The single factor experiment was designed to screen technique in the concentration of coating liquor, temperature of in air, pressure of spray and speed of transfuse.The dissolution test was established refer to the Basket Apparatus recorded in C.P. Initial studies were carried out in 750ml of 0.1mol·L-1P HCl for 2h. After this 250mL of 0.2 mol·L-1 trisodium phosphates was added to the dissolution media and the pH adjusted to 6.8. The study at a pH of 6.8 was continued for 3 h .Then the media was changed by pH 6.8PBS with 4% caecal content Bfor another 19h.According to the literature, HPLC method was established to determine the content and the release of matrine in the pellets.The stability of the pellets was investigated, which included stress testing and long-term testing. The appearance of pellets, release and drug content were major items investigated under the conditions of strong light, high temperature and high humidity.The mouse were administered orally coated and uncoated pellets via a polyethylene cannula, respectively, at a dosage of 50mg/kg. After then, the distribution of pellets in the gastrointestinal tract (GIT), the content of matrine in the upper GIT, and the drug concentrations in the plasma were investigated.Results: The dosage of matrine was 25% and the moistening agent was water. The optimization of technique was: speed of extrusion 30r/min, speed of spheronization 40r/min, the time of spheronization 4min. The antitack agent was aerosol. The material of sealing coat was 8% OpadryⅡsolution and the weight of coating was 3.0%. The optimization of the colonic coating prescription was 2% pectin solution:Surelease?=1:3(w:w) and the weight of coating was 190.0%. The optimization of technique were:temperature of in air 38~42℃,pressure of spray 0.05MPa,speed of transfuse 1.2ml/min.The results of the system serve experiment of the HPLC: the reserve time of matrine was about 8.4min, the recoveries were 99.09~100.3% and the precision<2.0%. Under the condition of 60℃the yellow color of the pellets was deeper. Under the condition of RH92.5%±5% for 10 days, the weight increasing ratio of pellets was more than 5% and there are tiny crazing on the coating. There was no significant difference in the physical appearance and content and percent of release of the pellets at the end of the strong light, high humidity (75%)and the long-term test.The uncoated pellets (controlled group) released most drug in the upper gastrointestinal tract(GIT). The coated pellets released little drug in the GIT and most in cecum and colon. The mean peak matrine concentrations in cecum, colon, cecal contents and colon contents, respectively, were 11.25±3.1μg/g, 9.818±2.1μg/g, 47.08±2.10μg/g and 36.10±8.0μg/g for matrine released from the uncoated pellets, and 156.8±27.6μg/g, 28.23±3.9μg/g, 485.1±61.3μg/g and 110.6±28.3μg/g for the administration of the coated pellets. In plasma, the observed mean CBmax from the coated pellets group (6.301±2.7μg/ml) was lower than that of the uncoated pellets group (15.84±1.6μg/ml). The observed mean TBmax of the coated pellets group (13h) was longer than that of the uncoated pellets group(2h).The AUC value was (85.14±6.02)μg·h/mL between the uncoated pellets and coated pellets (76.62±5.08)μg·h/mL respectively.
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