| Objective: Indomethacin is one of the effective no-steroid antiinflammatories. It is used to treat rheumatism and atrophic arthritis in clinic. However, the clinical applications of Indomethacin in recent years shows that it can cause serious side-effects on gastrointestinal tract ,which limits its application. In order to eliminite bad effect of Indomethacin, Chitosan, Sodium Alginic Acid, Calcium chloride and Carbopol were adopted as additives to make bioadhesive gel beads.It had long effects on intestinal tract since it could adhere to mucosa. Method: Through the pre-experiment, the preliminary formula of gel beads were defined and the orthogonal experiment was adopted to select the ratio of additives. Meanwhile, scanning electron microscope and differential scanning calorimetry were used to study the appearance of gel beads , drug release and the gel beads formation mechanism. Rats were employed to verify bioadhesive behavior and pharmacokinetics of gel beads. At last,the correlation between in vitro and in vivo, quality determination and stability of gel beads were also studied.Preparation of gel beads: through pre-experiment the fomula were defined that possed the behavior of good adhesiveness and drug release. Based on the analysis of the factors which influenced the drug release behavior in phosphate buffer pH6.8, the orthogonal experiment design L9(34) was used to select the optimal fomula. In the course of that, the parameters of sustained-release model and adhesive retention rate were used to score every prescription. The scanning electron photomicrographs of surface and interior were taken before and after dissolution testing with paddle method for four hours.Through analysing the changes of gel beads before and after dissolution testing, the release mechanism of drug was studied. The content of Indomethacin in bioadhesive gel beads was determined by UV spectrophotography. Paddle method was employed in the experiment of dissolution and the concentration of Indomethacin was determined by UV spectrophotometer at 320nm so as to calculate accumulative release percentage.The chemical and physical stability of the optimal formula was investigated, including stress testing(high humidity testing, high temperature testing) and long-term testing.The small intestines of rats were used as organism tissue to test adhesive behavior of gel beads, including in vitro and in vivo.The studies of Patholog: the structure changes of rats intestinal villi after bioadhesion were observed by means of pathology methods in order to evaluate the property of gel beads. The formation mechanism of bioadhesive gel beads of Indomethacin was studied by means of differential scanning calorimetry. The informations taken from the diagrams showed that additives had reacted with each other.Bioavailability(1)High-performance Liquid Chromatogra- ph with Ultraviolet detector was adopted to determine the content of Indomethacin in plasma in which butyl ester of p-hydroxybenzoic acid was used as internal standard. The Liquid Chromatograph was equipped with a 256nm detector and a DIKMA? C18 column (4.6mm×250mm, 5 μm).Mobile phase was a suitable mixture of methylalcohol, water and phosphoric acid (75:25:0.025). The flow rate was about 1.0mL per minute and temperature was 25℃.(2)gel beads of Indomethacin and contrast drug were given to rats which had been divided into two groups in random. Sampling on suitable time and using HPLC to determine the concentration of Indomethacin in plasma. The pharmacokinetics parameters were fitted and calculated by sustain-release program.Result: The optimal formula was defined through the orthogonal experiment. The bioadhesive gel beads made from the optimal formula were white and smooth, with good fluidity, etc. The analysis of orthogonal results showed that the concentration of Chitosan had much more influence on drug release than any others. Crack on the surfaces of gel beads was observed after dissolution experiment in phosphate buffer pH6.8 for four hours, crystal of drug...
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