Preparation And Study Of Divided Dose Indapamide Sustained-release Tablet

Objectives: Sustained-release and controlled-release systems is quickly developing. The microencapsule tablet possess the common merit of sustained-release and controlled-release systems and the microcapsule. Indapamide was selected as the model drug for the study of the microencapsule table for oral adminisration. In our study, Indapamide was made into microencapsule table to increse the residence time in vivo and improve its absorption. The divided doses was the main characteristic of microencapsule table. At the same time it could increase the bioavailability obviously.Methods : On the basis of scientific literatures and pretesting, Indapamide microcapsule were prepared using gelatin-acacia,acacia-chitosan and alginate-chitosan as capsule wall material. Through the orthogonal experiment of four influencing factors and levels ,We analyzed the formula factors and the process factors, and selected the optimal formula. In the course of that, the envelopment ratio of microcapsules and drug release were selected as evaluation indexes.Study of the release behaviors: Using MCC as loading agent, we prepared Indapamide microencapsule tablet. The complete Indapamide microencapsule tablet , 1/2 tablet , 1/4 tablet , and Natrilix were investigated. The release medium was ethanol-water(5:895) with 75 r/min at the temperature of (37.0±0.5)℃, samples were obtained at set time and quantified at 242nm with UV spectrophotometer. The concentration of Indapamide was calculated by the standard curve, and then accumulative release percentages of sustained-released microcapsules were obtained.The chemical and physical stability of Indapamide microencapsule tablet was investigated under following circumstances: high humidity, high tempreture and strong light.Pharmacokinetics study in vivo: The Beagle dogs were selected as laboratory animals and divided into two groups. One group was given the Indapamide microencapsule tablet and the other was given Natrilix. Liquid chromatograph with ultraviolet detector was adopted in examining concentration of whole blood. A non-compartmental pharmacokinetic analysis was performed for each of the treatments and for each formulation. Then, we calculated the relative bioavailability of the Indapamide microencapsule tablet. The Loo-Reigelman equation was used to calculate the in vivo absorption percentage of the Indapamide microencapsule tablet, and then evaluate the correlation of the in vivo absorption and the in vitro release percentage.Results: Through the orthogonal experiment, the optimal formulation were defined. The microcapsules were prepared using alginate and chitosan as main materials.The conditions were that the ratio to and drug was 5:1,the concentration of materials was 2.5%, the temperature of stir was 40℃and the reaction time was 3h. The results showed that the envelopment ratiowas 95.3%,The release of drug in vitro could keep for 24h.The release profils in vitro were evaluated with"The similar factors". The similar factors were between 65 and 100. It found that The release of Indapamide microencapsule tablet and Natrilix in vitro were similar.Study of stability: The result proved that the character, content and release had not significant discrepancy at the condition of high humidity, high tempreture and strong light. Pharmacokinetics study in vivo of the Beagle dogs:Parameters were obtained from direct observation of the data include Cmax and Tmax . The area under the whole blood concentration–time curve (AUC) from the time of drug administration to the last blood sampling time (AUC0–t)was calculated according to the linear trapezoidal rule. The mean values of major pharmacokinetic parameters of Tmax ,Cmax, AUC0–∞, and MRT of Indapamide in Beagle dogs after oral administration for the Indapamide microencapsule tablet and Natrilix were (4.57±0.14)h and (4.42±0.20)h, (2.51±0.13)μg·ml-1 and (2.37±0.09)μg·ml-1, (53.96±4.99)μg·h-1·ml-1 and(42.45±0.99)μg·h-1·ml-1, (23.56±1.99)h and (42.45±0.99)h, respectively. There were significant differences between the two formulations. The relative bioavailability of the Indapamide microencapsule tablet was 125.4% by contrast Natrilix. It showed a good correlation between the in vitro release percentage and the in vivo absorption percentage. The correlation equation was: f=0.9437x+17.72, (r=0.9884)Conclusions: The results showed that the Indapamide microencapsule tablet could prolong the residence time of Indapamide in vivo. It could be good for sufficient absorption .There was also a good correlation between in vitro and in vivo. Accordingly the Indapamide microencapsule tablet could increase the bioavailability obviously.