Preparation And In Vitro-in Vivo Quality Evaluation Of Nicotinic Acid-simvastatin Double-layered Sustained Release Tablets

Objective: To prepare the compound NA-SVT double layered sustained release tabletsconsisting of NA sustained-release and simvastatin immediate release layers and also tofurther explore the main factors affecting in vitro release of NA and chemical stability of SVTin the preparation so as to develop a new blood-lipid lowering compound NA-SVTpreparation with better clinical efficacy, less toxcic and side effect, convenient use and cheapprice. Method: First，through the orthogonal and single factor testing, the optimal formulationof NA sustained release layer as well as SVT immediate release layer was established andthen three batches of NA-SVT double layered sustained-release tablets were prepared. Second,the main in vitro quality items of the NA-SVT double layered sustained-release tablets suchas the contents of NA and SVT, the release of NA, the dissolution of SVT were studied.Thirdly, the preliminary chemical stability of the NA-SVT double layered sustained-releasetablets was accomplished under high temperature, high humidity and strong illuminationconditions. Fourthly, the pharmacokinetics and bioavailability study of the compound NApreparation were completed in dogs in order to ascertain whether it was bioequivelent to themarketed NA sustained release tablets. Finally, the correlation between in vitro release and invivo absorption of NA in the sustained layer was studied. Results: Compared with themarketed NA sustained release tablets, the obtained similar factor （f₂） values for in vitrorelease of NA from three batches of the NA-SVT double layered sustained-release tabletswere all greater than75, indicating their in vitro release being very similar to that of themarketed NA reference preparation. The cumulative dissolution of SVT from the compoundNA preparation in30mins were found to be more than80%, conforming to the related specifications for the SVT tablets stated in2010edition of Chinese Pharmacopoeia.Meanwhile, the labeled contents of NA and SVT also complied with the related requirementsstated in the Chinese Pharmacopoeia. The in vitro release characteristic of NA from theNA-SVT double layered sustained-release tablets abided by Higuchi equation andRitger-Peppas equation, suggesting the in vitro release of NA being matrix erosion controlledmechanism. The chemical stability study proved the NA-SVT double layeredsustained-release tablets were not stable under high temperature, high humidity and strongillumination conditions. The main pharmacokinetic parameters of NA after orallyadminstrated500mg of the compound NA sustained release tablets and NA reference tabletsto dogs were as fol1ows: Cmaxwere （77.27±10.86） and （76.23±7.32）μg·mL^-1，t_maxwere（5.16±1.44）and（5.00±1.55）h；AUC0-∞wer（e416.64±60.52）and（377.53±50.70）μg·h·mL^-1,respectively. The relative bioavailability of the tested sustained preparation was（111.0±14.80）%and it had good in vitro-in vivo correlation. Conclusion: The in vitroquality items of the NA-SVT double layered sustained-release tablets conformed to therelevant quality standards. The compound NA preparation was bioequivalent to the NAreference product.