| Objectives:Indomethacin(IN) is one of the strongest cyclooxygenase(COX) inhibitors and it is main used for acute rheumatic and rheumatoid arthritis.In addition,IN has therapeutic effect to colon cancer to some extent.The bioavailability of common preparation of IN with a series of adverse reactions in gastrointestinal tract,liver or kidney is very low.This study is to prepare it through a series of messures for the sake of increasing the solubility, enhancing curative effect, at the same time its colon-specific formulation is profit for reducing adverse reactions.Methods:1 The preparation of IN colon-specific capsule:IN is a poorly water-solu- ble drug,it is suitable to make it into solid dispersion with DK as a type of carrier material.NC as the disintegrant,lactose as the filler,magnesium stearate as the lubricant to compress tablets.The diameter of the tablet is 3mm. The coating solution is made up of a certain amount of chitosan, triethyl citrate, talcum powder which are mixed with 5% acetic acid water solution.Using the coating solution to coat the tablets with a small bag roll type coating pot.Then test the various factors that influencing the drug releasing and select the best formulation based on the results of the orthogonal experimental design of three factors and three levels.2 The study of quality control about IN colon-specific capsule:In this section,HPLC method is established to determine the dissolution,content and content uniformity of IN capsules and the methodological study was carried out.IN capsules were prepared using the best prescription,and the stability of the preparation was measured by evaluating the appearance,dissolution and content.Stess testing and accelerated testing were carried out.3 HPLC method was established to determine IN in gastrointestinal tissues of Wistar rats.The tablets with no coating was taken as the reference preparation and the tablets coated as the experimental preparation.The concentration of IN in the gastrointestinal tissues at different point-in-time was detected both of the two preparations.Observed the appearance of the tablets fed and compared to evaluate the colon-specific effect of the preparation.4 HPLC method was established to determine IN in plasma of Beagle dogs.The IN ordinary capsules commercially available were taken as the reference preparation and self-made IN colon-target capsules as the the experimental preparation.Recorded the curves of the concentration of IN in plasma to time.Calculated the parameters of pharmacokinetics and the relative bioavailability.Results:1 Drug release rate as the index,the best formulation is carried out.The tablet’s best formulation:IN solid dispersion 5mg,lactose 7mg,NC 3mg,magnesium stearate 1%,the tablets’ hardness is 2kg and weight of one tablet is about 15 mg.The best constitution of the CS coating solution:The concentration is 2%,the amount of TM is 15%,talcum powder is 30%, coating weight is 5%.The best constitution of the outer coating solution: the concentration of Eudragit FS 30 D is 20%,the amount of TM is 5%,talcum powder is 40%,coating weight is 3%.2 Established a HPLC method of the determination of release rate of IN colon-target capsules.The detection wavelength was 320 nm with no interference of excipient.The IN study results showed that the linear relationship between the peak area and the concentration of IN was good in 3 release media.The study on stability,precision and recovery were all satisfactory.The method can be used for the determination of the drug release rate.Established a HPLC method for the determination of content and content uniformity of IN colon-target capsules.The detection wavelength was 320 nm with no interference of excipient.The results showed that within the concentration range of IN is between 0.2~50μg·m L-1,the linear relationship between the peak area and the concentration of IN was good.The regression equation was A=65151C+9771.7,the correlation coefficient γ=0.9998.Study on the sability,precision and recovery were all satisfactory.The method can used for the determination of content and content uniformity of IN colon-target capsules.4 The results of the stability of self-made preparation:Under the condition of wet RH 92.5%,high temperature of 60℃,strong light(4500Lx) and accelerated testing,there was no distinct change of the appearance,dissolution and content.The results showed that the capsules were stable to the mentioned conditions.5 Established a HPLC method for the determination of IN in the gastrointestinal tissues of Wistar rats.The detection wavelength was 228 nm with no interference of excipient.The IN study showed that within the concentration range of IN is between 0.2~10μg·m L-1,the linear relationship between the peak area and the concentration of IN was good.The regression equation was A=60681C+17576,the correlation coefficient γ=0.9994.Study on the accuracy,sability,precision and recovery were all satisfactory. The integrated tablets were found in the stomach and small intestine of rats in experimental group and no tablet in the control group which proved the effect of colon-target of the self-made preparation.6 Established a HPLC method for the determination of IN in the plasma of Beagle dogs.The detection wavelength was 228 nm with no interference of excipient.The IN study showed that within the concentration range of IN is between 0.08~8μg·m L-1,the linear relationship between the peak area and the concentration of IN was good.The regression equation was A=266793C+29584,the correlation coefficient r=0.9993.Study on the accuracy,sability,precision and recovery were all satisfactory. The Tmax of the reference preparation was 2.00 h and The Tmax of the self-made preparation was 16.25 h compared to the reference preparation was obviously delayed.The relative bioavailibility of the self-made preparation was 109.9%.It proved the effect of self-made IN colon-target capsules.Conclusions:The formulation and preparation process of IN colon-target capsules are simple with good reproducibility.The preparation with double layer of coat can protect the drug going through the stomach and small intestine with no release and when the drug arrived colon it wound release completely.Following this principle,the preparation will enhance the therapeutic effect towards the colon cancer.The method established of release and content determination can contribute to control the quality of the preparation.The in vivo evaluation in Wistar rats and Beagle dogs showed that the preparation had an accurate colon-target property. |
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