Study On Esomeprazole Sodium Enteric-coated Tablets

Esomeprazole sodium（Nexin）is the sodium salt of the L-isomer of omeprazole,the world’s first proton pump inhibitor,with a molecular weight of 367.41.The sulfoxide group in the esomeprazole structure gives it the characteristics of unstable properties,such as oxygenated easily,easily solved by tide and unstable in acidic conditions,so thatthe acidic compounds can quickly catalyze the degradation of esomeprazole sodium.Compared with omeprazole and other proton pump inhibitors,esomeprazole sodium can inhibit gastric acid secretion more persistently and effectively,so it is often used in the treatment of digestive system diseases.Because of the unstablel properties of acid,esomeprazole sodium is mainly in the form of injection on the market at present.Therefore,in order to investigate the stability of esomeprazole sodium,we optimized the preparation process of esomeprazole sodium enteric-coated tablets,and studied the absorption characteristics and pharmacokinetics of esomeprazole sodium enteric-coated tablets in rats.Firstly,the stability of esomeprazolesodium under the protection of different pH,solvent and protective agent was investigated.The results showed that esomeprazole sodium was more stable in organic solvent than in water.The protection of alkaline environment or protective agent can favor the stability of esomeprazolesodium.The choice of 0.3mg/ml sodium bicarbonate as alkaline protective agent was beneficial to the stability of Esomeprazole sodium within 4 h（degradation less than 4%）.Secondly,to investigate the release of esomeprazole sodium enteric-coated tablets,we established a high-efficiency and accurate in-vitro analytical method of HPLC.The method is high in specificity,and the linear relationship of esomeprazole sodium is good in the range of 1-100μg/ml（r=0.9993）.The results showed that the release curve of esomeiramine sodium enteric-coated tablets in acid and buffer is in accordance with the compendial standard.In this paper,the formulation of esomeprazole sodium was studied according to the stability of esomeprazole sodium,and the prescription of esomeprazole sodium tablet was screened out by changing the composition and dosage of adjunct on the basis of existing patent.Based on the experimental results of single factor investigation,the formulation of esomeprazole sodium enteric-coated tablets was further optimized by Central composite design-response surface method（CCD-RSM）.The optimal preparation of esomeprazole sodium enteric-coated tablets was determined as follows:the dosage of disintegrating agent was 8%-12%,isolation coating weight gains was 10%,and Intestinal coated weight gains was 19%-24%.The experimental results showed that the fitting equation had good predictability and was suitable for the preparation of esomeprazole sodium enteric-coated tablets.Next,we studied the intestinal absorption of esomeprazole sodium in rats.The results showed that the absorption rate constant of esomeprazole sodium in different parts of small intestine was obviously different,and duodenum>jejunum>ileum>colon,that is,duodenum was the best absorption site.After the addition of p-gp inhibitor verapamil,the absorption of esomeprazole sodium in the small intestine was significantly increased;that is to say taht esomeprazole sodium was the substrate of p-gp.After adding MRP2 inhibitor probenecid,the absorption parameters papp and ka of esomeprazole sodium were changed,but there was no statistical significance.It was speculated that esomeprazole sodium was not the substrate of MRP2.Finally,the pharmacokinetics of esomeprazole sodium enteric-coated tablets and normal tablets in rats was studied by orally administration.The plasma concentration was determined by HPLC and the pharmacokinetic parameters were calculated by DAS2.0 software.The results showed that,compared with normal tablets,the c_maxax and AUC of enteric-coated tablets were significantly increased,and the bioavailability of the drugs was significantly increased.