Study On Preparation And Pharmacokinetics Of Atenolol Sustained Release Microcapsules

Hypertension has been recognized as "the most brutal killer"by the medical Expert athome and abroad. The death rate of hypertension is higher than any other disease.Hypertension has a serious impact on human health. Atenolol used for treatment ofhypertension, angina, early acute myocardial infarction and arrhythmia. Atenolol is better inβ1receptor blocker drugs and one of the widely used drugs.The dosage of atenolol ordinarytablets is2times a day, its plasma concentration have a large fluctuations.So It is necessary toinvent a sustained-release preparation which takes once a day. It helps to slow the bloodconcentration fluctuations and the incidence of adverse reactions. We prepare atenololsustained-release microcapsules with ethylcellulose as capsule material.Objectives: To study the analysis methods，preparation and pharmacokinetics.Methods: Analytical methods: to establish a method to determine the drug-loading rate of theatenolol sustained release microcapsules.Using the HPLC to establish a method for atenololsustained-release microcapsules to determine the drug content. By using UV to establish amethod to determine the cumulative release rate of microcapsules in water，0.1mol·L-1hydrochloric acid and the pH6.8phosphate buffer solution.Using the HPLC method toestablish the analysis method for atenolol in rats. Preparation: Using in-liquid drying methodto prepare atenolol sustained-release microcapsules. Studing the factors which influence drugrelease. Optimizing preparation by orthogonal experimental design.At the same time，validating the best technology of preparation and doing the quality evaluation.Pharmacokinetics:To randomly divide20healthy male rats into two groups.Administrating bysingle-dose. Before the Experiment, rats were fasted12h. Administrating atenololconventional tablets and sustained-release microcapsules respectively. Blooding0.5mL when0，0.5，1，2，3，4，6，8，10，12，16，24h. Treating blood samples properly and determinatingblood concentration, to study pharmacokinetics.Results: 1.Optimal conditions of preparation: The ratio of EC to drug is3.5:3，the amount ofemulsifying agent is0.5%，The optimum speed is320rpm.2. Microcapsules have a good morphological characteristics and uniform particle size. Thebulk density, angle of repose,drug loading rate and encapsulation efficiency ofmicrocapsules is0.4212g ml^-1,32.5°,35.91%,76.06%. The accumulated release rate of2,7,12and24h were29.00%,61.80%,84.11%and100.71%respectively. The drug releasefitted with the first-order equation.The equation is1n（1-Mt/M∞）=0.1404t，r=0.9906。3. Calculating pharmacokinetic parameters by compartment model.The T_max、C_max、AUC0-∞of the conventional tablet were （1.65±0.17h），（1.45±0.22）μg·mL^-1，（11.68±3.79）μg·h·mL^-1，The T_max、C_max、AUC0-∞of the sustained release microcapsules were（4.83±0.63） h，（0.63±0.25）μg·mL^-1，（10.89±6.29）μg·h·mL^-1。Calculating pharmacokinetic parameters bystatistical moment method, The T_max、C_max、AUC0-∞of the ordinary tablet were（1.65±0.24）h，（1.77±0.25）μg·mL^-1，（12.09±4.81）μg·h·mL^-1，The T_max、C_max、AUC0-∞ofthe sustained release microcapsules were（4.40±0.84）h，（0.80±0.23）μg·mL^-1，（12.40±6.48）μg·h·mL^-1。T-test was applied in the comparison of lnC_max、lnAUC0-t、lnAUC0-∞.The differences of T_maxwas analyzed with nonparametric test. results of the analysis of thecompartment model method and the statistical moment method show that the sustainedrelease microcapsules extended T_maxthan the conventional tablets, C_maxwas significantlyreduced. The difference was statistically significant （p <0.05）. AUC0-t、AUC0-∞was nosignificant difference （p>0.05）. Microcapsules relative bioavailability was （100.02±10.9）%.Wagner-nelson method was used to evaluate the in vivo-in vitro correlation. The regressionequation is F（t）=3.7515f（t）-58.197,（r=0.9792）.The statistical results showed that the invivo-in vitro correlation is significantly （p <0.05）.Conclusion: The analytical methods of atenolol is reasonable and reliable.The atenololsustained-release microcapsules have good quality, and the obvious characteristics of thesustained-release. It has stable plasma concentration, high bioavailability and good in vivo-invitro correlation.It have attained our expected aim. To provides a basis for further researchand development.