In silico mechanistic disposition and in vivo evaluation of zero-order drug release from a novel triple-layered tablet matrix

Abstract

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.

Keywords:

• cardiovascular therapeutic regimen
• in vivo drug release behavior
• Large White Pig Model
• modified polyamide 6,10
• stratified zero-order drug release
• triple-layered sold matrices

Declaration of interest

This work was funded by the National Research Foundation of South Africa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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