| Olmesartan medoxomil(OM)is an angiotensin ? receptor antagonist antihypertensive drug.It is absorbed and decomposed into olmesartan in the body to play a therapeutic role.It has many advantages such as minor side effects,stable drug effects,and good tolerance.It is currently the most widely studied antihypertensive drug.However,olmesartan medoxomil is a class II drug in the biopharmaceutics classification system(BCS),that is,it has good permeability but poor solubility,resulting in a low oral bioavailability of the drug,which limits its clinical application.Mechanochemical technology is applied by using ball milling equipment to convert its mechanical energy into chemical energy to activate the material,resulting in the change of the original crystal form,follow to a new phase formation.This technology is easy to operate,and the target product can be obtained in one step reaction.Furthermore,there is no organic solvent involved in the whole process,which is environmental friendly.It is often used in the preparation of solubilization systems for poorly soluble drug.This thesis applies mechanochemical technology to the study of the solubilization system of olmesartan medoxomil,aiming to increase its solubility and dissolution rate in water,and thereby increase its bioavailability.The main research contents are as follows:(1)Preparation of Olmesartan Medoxomil solid dispersion system by mechanical ball millingA solid dispersion system of olmesartan medoxomil was prepared by a rolling ball mill.Phase solubility analysis experiments show that the optimal molar ratio of olmesartan medoxomil to hydroxypropyl-?-cyclodextrin was 1: 1.Based on the effect of different solution p H on drug solubility,olmesartan medoxomil/hydroxypropyl-?-cyclodextrin/meglumineternary solid dispersion system was successfully prepared using meglumine as a p H regulator.Its solubility was 136.5times higher than that of the pure drug,the total dissolution release of the drug in 60 minutes increased from 26% to 94%;that was,the solubility and dissolution rate of olmesartan medoxomil solid dispersion was significantly improved.The physical characterization of the solid dispersion system by DSC,XRD,SEM etc.demonstrated that the crystalline structure of the drug was changed to an amorphous state.Membrane permeation test results showed that the penetration ability of drug in the olmesartan medoxomil/hydroxypropyl-?-cyclodextrin/meglumine ternary solid dispersion system is significantly higher than the original drug.The stability test results showed that the solubility and crystalline structure of the drug during the storage process had not changed.(2)Preparation of olmesartan medoxomil sustained-release complex system by mechanical ball millingThe olmesartan medoxomil/hydroxypropyl-?-cyclodextrin/hypromellose-E5sustained-release complex system was successfully prepared by using a rolling ball mill.The results of the solubility test and the dissolution test in vitro showed that the ball-milled complex could significantly improve the water solubility of the drug and hypromellose could effectively delay the dissolution release of the drug.The physical characterization results of DSC,XRD and SEM etc.showed that the drug was homogenously dispersed in the excipient molecular skeleton in an amorphous state.The stability test results exhibited that the system was highly hygroscopic and should be kept in dry condition and avoided from light.Pharmacokinetic studies in rats demonstrated that oral absorption bioavailability of olmesartan medoxomil in the ternary complex was significantly increased to 3.36 folds than the pure drug,and the release time of the maximum blood drug concentration in rats was prolonged from 2 h to 4 h,suggesting the prepared ternary complex system had a significant sustained release effect. |
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