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In Silico Mechanistic Disposition And In Vivo Evaluation Of Zero-order Drug Release From A Novel Triple-layered Tablet Matrix
Published 2015 · Materials Science, Medicine
Objectives: The purpose of this study was to formulate novel triple-layered tablet (TLT) matrices employing modified polyamide 6,10 (mPA6,10) and salted-out poly(lactic-co-glycolic acid) (s-PLGA) in an attempt to achieve stratified zero-order drug release. Methods: mPA6,10 and s-PLGA were employed as the outer drug-carrier matrices, whereas poly(ethylene oxide) (PEO) was used as the middle-layer drug matrix. Diphenhydramine HCl, ranitidine HCl and promethazine were selected as model drugs to pre-optimize the TLT, whereas atenolol, acetylsalicylic acid and simvastatin were employed as a comparable fixed dose combination to test the TLT prototype in vitro and in vivo (Large White Pig model). A total of 17 formulations that varied in terms of polymer stoichiometry, salt addition and polymer–polymer ratios were generated using a Box-Behnken experimental design. Results: The in vitro drug release analysis revealed that release from the mPA6,10 layer was relatively linear with a burst release, which upon addition of sodium sulfate was reduced. Furthermore, formulations with higher quantities of mPA6,10 provided more controlled zero-order drug release and increased the matrix hardness. The addition of PEO to the s-PLGA layer significantly reduced the initial burst release that occurred when s-PLGA was used alone. Conclusions: The formulation with a lower s-PLGA:PEO ratio displayed superior zero-order release. Relatively, linear drug release was achieved from the middle-layer. The in vivo results proved the applicability of optimized TLT formulation in a therapeutic cardiovascular drug treatment regimen.