title: In silico mechanistic disposition and in vivo evaluation of zero-order drug release from a novel triple-layered tablet matrix.
abstract: OBJECTIVE
  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.
authors.affiliation: Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand , Johannesburg, 7 York Road, Parktown, 2193 , South Africa.
authors.forename: Kovanya
authors.initials: K
authors.lastname: Moodley
authors.forename: Yahya E
authors.initials: YE
authors.lastname: Choonara
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Lisa C
authors.initials: LC
authors.lastname: du Toit
authors.forename: Viness
authors.initials: V
authors.lastname: Pillay
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D065546:Drug Liberation; D019344:Lactic Acid / Q000737:chemistry; D009757:Nylons / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D009757:Nylons; D011108:Polymers; D013607:Tablets; C045688:nylon 6-10; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols
keywords: Large White Pig Model; cardiovascular therapeutic regimen; in vivo drug release behavior; modified polyamide 6,10; stratified zero-order drug release; triple-layered sold matrices