Study On Preparation And Pharmacokinetics Of Verapamil Hydrochloride Sustained-release Microspheres

Objectives To study the preparation，analysis methods and pharmacokinetics MethodsPreparation:Using spray drying method to prepare verapamil hydrochloride Sustained-releasemicrospheres. Through the orthogonal and single factor testing, the optimal formulation wasestablished, and doing the quality evaluation of sustained-release microspheres. Analyticalmethods: To determine the content of surstained-release of verapamil hydrochloridemicrospheres by the HPLC method and UV method. By using UV method to establish amethod to determine the cumulative release rate of microspheres in water，0.1mol·L^-1hydrochloric acid and the pH6.8phosphate buffer solution, with the method of similar factorf2, the similarity of the curve of different dissolution drugs is evaluated. Using the HPLCmethod to establish the analysis method for verapamil hydrochloride in rats.Pharmacokinetics: To randomly divide14healthy male rats into two groups，administratingby a single-dose of a single drug. Taking intragastric administration by verapamilhydrochloride tablets reference product and the homemade sustained release microspheres.Draw blood according to the planned time. Suitably handled the blood and assay it. Theplasma concentration result can be used for pharmacokinetics evaluation of the homemadesustained release microspheres.Results1. The drug loading rate，encapsulation efficiency，yield and bulk density of Verapamil hydrochloride sustained-release microspheres are25.10%、69.73%、29.37%、0.1549g·ml-1. The accumulated release rate of2、4、7、12and24h are44.39%、56.41%、70.08%、75.05%and79.36%respectively. The drug release fittedwith the Higuchi equation.The equation is Mt/M∞=0.175t1/2，r=0.9890，suggesting the invitro release of verapamil hydrochloride sustained-release microspheres being matrix erosioncontrolled mechanism.2. Calculating pharmacokinetic parameters by single-compartmentmodel.The T_max、C_max、AUC_0-∞of the ordinary tablets were （1.58±0.22）h，（0.97±0.11）μg·mL^-1，（6.40±1.92）μg·h·mL^-1，The T_max、C_max、AUC_0-∞of the sustained release microsphereswere（4.56±2.01）h，（0.42±0.14）μg·mL^-1，（7.01±3.24）μg·h·mL^-1。Calculating pharmacokinetic parameters by dual-chamber model method, The T_max、C_max、AUC_0-∞of the ordinary tabletswere （1.63±0.47）h，（1.01±0.20）μg·mL^-1，（6.27±2.40）μg·h·mL^-1，The T_max、C_max、AUC_0-∞of the sustained release microspheres were（4.68±1.81）h，（0.44±0.14）μg·mL^-1，（7.35±2.51）μg·h·mL^-1。T-test was applied in the comparison of lnC_max、lnAUC_0-t、lnAUC_0-∞.The Differences of T_maxwas analyzed with nonparametric test. results of the analysis ofthe single-compartment model method and the dual-chamber model method show that thesustained release microspheres extended T_maxthan the conventional tablets, C_maxwassignificantly reduced, The difference was statistically significant （p<0.05）. AUC_0-t、AUC_0-∞was no significant difference （p>0.05）. Microspheres relative bioavailability was（115.75±0.60）%. Wagner-nelson method was used to evaluate the in vivo-in vitro Correlation.The regression equation is F（t）=5.9303f（t）-196.55,（r=0.9764），The statistical results showedthat the in vivo-in vitro correlation is significantly （p<0.05）.Conclusion The analyticalmethods of Verapamil hydrochloride is reasonable and reliable.The verapamil hydrochloridesustained-release microspheres have the obvious characteristics of the sustained-release andstable plasma concentration in vitro；It is bioequivalent to the verapamil hydrochloride tabletsreference product in vivo. It have good in vivo-in vitro correlation. To provides a basis forfurther research and development.