| The oral colon targeting drug delivery system is a new pattern drug delivery system which is specifically release in the colon. It received much concern and research because of it could increase colon local drug concentration, reduce medicine taking times, enhance the stability of drugs and reduce the adverse reactions and so on. According to the different drug release principles, OCTDDS can be divided into p H dependent type, time dependent type and enzyme dependent type,pressure control type and combined application type. In recent years,people paid more attention to the study of combined application of OCTDDS in order to achieve a better effect of colon specifically released.Sodium alginate, chitosan, pectin and other natural polysaccharides were not degraded in human gastric juice and intestinal fluid. But they could be degraded specifically by the enzymatic generated by the colon bacteria.So it could be used as a material of colon targeted drug delivery system.As a kind of clinical common inflammatory bowel disease,ulcerative colitis has been known and concerned by more and more people. It has been listed as one of refractory diseases in modern society by the World Health Organization because of its complex etiology, long course of disease, recurrence, complications, and the relatively high canceration rate. Due to the UC was mainly occurred in the colon and most probably occurred in sigmoid colon, the common oral preparation was difficult to intactly arrive at the lesion site. It was difficult to achieve therapeutic purposes when reached because the dose was depleted.Enemas and suppositories administration was always used as Chinesemedicine treatment for UC. If things continued in this way, most of the patients were not easy to accept and comply. To research an oral preparation which allowed the drug to be released slowly after reaching the colon is the purpose of this study. It achieves the goal of slowly releasing in the colon which can be used for the treatment of UC.It was a long history for Rhubarb to be used as herb, many of which have antibacterial and anti-inflammatory effect, can prevent the mucosal damage of gastrointestinal tract and protect the gastrointestinal tract.Several studies have shown that Rhubarb polysaccharide had obvious protective effect on stress gastric ulcer in rats, and it also had a good therapeutic effect on ulcerative colitis. It was reported that Rhubarb anthraquinone can repair intestinal mucosal injury by improving intestinal microcirculation, inhibiting inflammatory response and intestinal epithelial cells damage. Rhubarb was used as a model drug for the preparation of rhubarb colon-targeted pellets, which was used for evaluating the colon targeting property of the preparation via the study of release rate in vivo and in vitro and the intervention effect of UC model rats.1. To study the drug release influence factor and formulation optimization of rhubarb colon targeted pelletsThe pill-core was prepared by the dropping method, screening the suitable dropping distance, needles, stirring speed and excipients on the basis of pellets' size, shape and appearance; for researching the influencing factors of pellets preparetion technology and the release property, the concentration of alginate-pectin solution, chitosan solution and CaCl2 solution, the pH of chitosan-CaCl2 solution and the quantity of reagent were inspected with drug loading, envelop rate and the releasing rate as the indexes. Simultaneously, the pill-core fomulation was optimized by the orthogonal test. With release property as index, the coating weight was filtered. Finally, the rhubarb pellet that released atcolon was obtained.It was used the needle 7, dropping distance 8 cm, stirring speed 200r·min-1 and excipient 1:7(pectin:sodium alginate) to prepare the pill-core.Meanwhile, the 2% alginate-pectin solution, 0.7% chitosan solution, 1%CaCl2 solution, the pH 6.0 chitosan-CaCl2 solution and the 4:1 quantity of reagent(rheum:accessory) were chose as the optimal fomulation to prepare the pill-core. Then enteric coating weight to 30% and the enteric coated-pellet was got. In gastric juice after 2 h and in small intestinal juice after 3 h, the coated pellets were cumulated release to 2.01% and8.72% respectively, and were released to 92.58% in the colon fluid after 4h. The fomulation of colon-targeted pellet of rhubarb was definited, and the colon-targeted release was preliminary implemented.2. To study the distribution and drug release in gastrointestinal tract of rhubarb colon-targeted pellets in ratsThe rhubarb colon-specific pellets were administered by homemade rat mouth gag. The rats were respectively killed at different time points after administering, and the gastrointestinal tract were dissected. The appearance of pellets was observed and the sum of pellets were counted.The pellets distribution rates in the digestive tract in rats were calculated at different time point after administering. After the residue level of aloe-emodin, emodin and chrysophanol in pellets were respectively determined by HPLC, also the emodin in rats gastrointestinal tissue and content. The accumulative releasing was calculated and the drug concentration-time curve in the gastrointestinal tract was drawn, then the drug release property was evaluated.The pellets were transferred to colon completely, which had obvious late release effect. The colon distribution rate could reach the highest after 10~12 h, 52.7%. In 8 ~ 16 h, drugs haved a high concentration in the cecum and colon. Final release dosage percentage was 88.99%. Rhubarb colon-specific pellets possessed the characteristic of drug release incolon.3. Establishment of model of ulcerative colitis in rats and interventive effect of rhubarb colon-specific pelletsThe Oxazolone(OXZ) was used to build UC model in this paper.Wistar rats were randomly divided into intervention groups with rhubarb colon-targeted pellets(200 mg·kg-1, 140 mg·kg-1, 80 mg·kg-1), normal group and model group with 6 rats in each group and half male and half female. Intervention groups were given rhubarb colon-targeted pellets by gavage 3 days before modeling, and successive administration for 8 days.The fourth day after administration, intervention groups and model group were smeared on dorsal skin of rats with OXZ for 2 days and 2 days at interval. Except the rats in normal group, all rats were induced by OXZ enema on the eighth day. All rats were killed on the ninth day, then the colon tissues were harvested with laparotomy. The wet quality of colon tissues was weighed, and the colon injury were observed. The colon wet quality index were calculated and the colon lesions of rats were graded.The colon wet quality index(P<0.05) and the macroscopic colon lesions score(P<0.01) of the 140 mg·kg-1 group had significant difference with the model group. The colon tissue pathological damage of the UC rats can be obviously relieved with this dosage of rhubarb colon-targeted pellets. Rhubarb colon-targeted pellets have certain protective effect on UC rats. |
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