Development Of Irbesartan Sustained Released Tablets

Irbesartan is an angiotensinâ…¡receptor antagonist. Irbesartan is a specific antagonism between angiotensinâ…¡and angiotensin-converting enzyme 1 receptor (AT1). The vasoconstriction and release of aldosterone can be inhibited, and blood pressure will be reduced. Irbesartan is mainly used to therapy hypertension clinically. A new indication that therapy the renal disease patients who also have hypertension andâ…¡type diabetes was approved by European Union. Irbesartan is the first antihypertensive drug approved by European Union which is used to prevent renal disease during early and late stage of diabetes. Compared to other drugs which are also angiotensin-converting enzyme 1 receptor antagonist, there is the greatest difference in pharmacokinetics parameter among them. Irbesartan has the highest bioavailability among them. Its blood pressure depression effect is steady, tolerance is good, and effect is more persistent. Its absorption is not influenced by food. Its plasma protein binding rate is the lowest. There is no relevant report about interaction with other drugs at present. The compliance of patients is good. Irbeasrtan is suited to patients who are not tolerant to angiotensin-converting enzyme inhibitor (ACEI). The incidence of severe cough is obviously lower than when used ACEI. According to all the above, irbesartan will become clinically promising antihypertensive agent and has excellent application prospect.Clinical research shows that 150mg irbesartan be taken orally once every day can therapy mild and moderate hypertension effectively. According to the clinical experiment CV131-030 which the Sanofi committed to USA FDA, it shows that the therapy effect of taking in twice was better than once when the daily dosage is both 150mg and the incidence of adverse reactions is lower. The optimal range of blood drug level is unexplained at present. Another research shows that only when the blood drug level is lower, there is positive dosage-reaction effect between blood drug level and lowering blood pressure effect to exist. So we want to develop irbesartan (150mg) 24h sustained release tablets. Compared to ordinary tablets, we want to attain following aims: release irbesartan slowly in order to avoid sudden increase of drug concentration and decrease the incidence of adverse reactions. Release irbesatan everlastingly in order to make the drug concentration in lower range, there will be sustained and stable lowering hypertension effect.In the thesis, we investigate the equilibrium solubility of irbesartan, the solubility curve in different pH solution is"U"shape. When pH is 4, the solubility is the minimum. Irbesatan is nearly insoluble in intestinal tract. To guarantee the release of irbesartan in later period, accordingly we divide the sustained release tablets into two parts. It is composed by sustained and quick release layers. In the sustained release layer, solid dispersions are prepared by the solvent method using PEG6000 as a hydrophilic carrier to improve the dissolution rate of irbesartan in the intestinal tract and increase the release rate in later period. Differential scanning calorimetry (DSC) was used to identify the existing state of irbesartan in the carrier. Results suggest that there were no chemical interactions between the drug and PEG6000, and the drug was simple eutectic mixture state in the carrier. The solid dispersion could significantly increase the dissolution rate of the drug. The results of stability test suggest that it was unstable to high temperature and high humidity but stable to highlight. It suggests to be kept in low temperate and dry container.Determination of content assay, related substance and in vitro release test methods were established. All methods have good linearity, sufficient recovery and reliable accuracy.Single factor investigation was used to optimize the best formulation. We investigated in vitro factors which influence on sustained tablets. We use several kinds of drug release model equation to fit for drug release curve and discuss the drug release mechanism. The results of these experiments show as following. The rotating speed of paddle had significant effect on the release of drug, release experiment should use paddle method with sagging basket. The release theory is primary corrosion and accessorial diffusion...