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In Vitro And In Vivo Evaluation Of 4-Aminosalicylic Acid-Glucoside And A Study Of Pharmacodynamics

Posted on:2016-02-04Degree:MasterType:Thesis
Country:ChinaCandidate:G L WuFull Text:PDF
GTID:2284330479992550Subject:Pharmaceutical
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Objective:To establish the content determination method of 4-aminosalicylic acid and 4-Acetamidosalicylic acid based on high-performance liquid chromatography(HPLC).To evaluate the 4-aminosalicylic acid-glucoside colon-targeted release property in vivo and in vitro by investigating its p H stability. At the same time, to study the treatment of UC in rats of the 4-ASA-Glu to provide an experimental basis for further research. Methods:The content determination method of 4-ASA and Ac-4-ASA was established by HPLC.The stability of 4-ASA-Glu was determined in different aqueous buffers(p H 1.2, 6.8 and 7.4) and the results showed that was stable over a period of 12 h.The colon-targeted characteristics of 4-ASA-Glu in vitro ware investigated. The 4-ASA-Glu(equivalent to 4-ASA 250 μg/m L) was incubated at 37℃ in diluted gastrointestinal contents from different parts of healthy and colitis rats, then samples were collected at different intervals and the concentration of released 4-ASA was determined by HPLC.Oral administration 4-ASA-Glu was investigated. At appropriate time intervals(0.5, 1, 2, 4, 6, 8 and 12 h), the contents of 4-ASA and Ac-4-ASA were detected from rat stomach, small intestine, cecum and colon segments contents and plasma samples by HPLC comprehensively.The model of UC in rats was set up by using TNBS. After given SASP, 4-ASA-Glu, 4-ASA and 5-ASA, the extent of colitis in rats of each group was significantly mitigated. Results:The linear range of 4-ASA in various gastrointestinal contents was 2.0-200.0 μg/m L, and the standard curves were all in good linearity(r>0.995).The intro-day and inter-day precision(RSD) were both less than 10 % respectively, the recovery of the method was in the range of(89.54 ± 0.60) % 97.02 ± 0.20 %. The linear range of Ac-4-ASA in various gastrointestinal contents was 2.0-200.0 μg/m L, and the standard curves were in good linearity(r>0.995). The recovery of the method was(88.43 ± 0.16) % 109.99 ± 2.49 %, and the precision, repeatability and stability met the requirements all.The stability of 4-ASA-Glu was determined in different aqueous buffers(p H 1.2, 6.8 and 7.4) and the results showed that was stable over a period of 12 h.The cumulative release rate of 4-ASA was lower than 8 % in the contents of stomach and small intestine of healthy and colitis rats in 12 h. The cumulative release rate of 4-ASA incubated on healthy contents of the caecum and colonic in 12 h was 69 % and 79 % respectively. Similarly, the amounts of 4-ASA released in caecum and colonic contents of colitis rats were 55 % and 74 % in 12 h respectively. 4-ASA-Glu can release a lot of parent drug 4-ASA in the caecum and colonic contents solution, that provide a basis for further study in vivo.The results showed that 4-ASA-Glu didn’t decompose substantially in rats’ stomach and small intestine and 4-ASA mainly distributed in rats’ caecum and colon within 12 h. The conclusion indicated that 4-ASA-Glu process target drug release characteristics in colon.The model of UC in rats was set up by using TNBS. After given SASP, 4-ASA-Glu, 4-ASA and 5-ASA, the extent of colitis in rats of each group was significantly mitigated. Compared with the model group, 4-ASA-Glu could significantly ameliorate DAI score and pathological change in colon caused by TNBS. It could also inhibit the activity of MPO and decrease colon index and gross score. Conclusions:4-ASA-Glu has colon delivery characteristics to play a role in the treatment of UC by releasing parent drug 4-ASA under the influence of cecum and colon contents solution.
Keywords/Search Tags:ulcerative colitis, 4-aminosalicylic acid, 4-aminosalicylic acid-glucosidase, oral colon delivery system, In vitro and in vivo evaluation, pharmacodynamics
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