A polymeric triple-layered tablet for stratified zero-order drug release

摘要

Patient compliance is a major factor in achieving optimal therapeutic outcomes. Pill burden,uddue to multiple drug therapies, has a great detrimental impact on compliance of the patient.udDose-dependent side-effects, associated with peak-trough plasma fluctuations of drugs, alsoudhave a negative impact on patient compliance with drug therapy. It is under theseudcircumstances that zero-order drug release kinetics proves to be ideal. This is due to the lackudof peak-trough fluctuations that occur with zero-order drug release, thereby minimizing theudside-effects of drug therapy. Furthermore, a drug delivery system that may deliver more thanudone drug at a time may be beneficial to alleviate the pill burden associated with chronicuddiseases or specific health conditions. Novel drug delivery systems have been developedudthat offer zero-order or linear drug release. Amongst such systems are multilayered tablets.udHowever these systems generally offer the delivery of just one drug. The development of auddelivery system that is able to deliver up to three drugs in a zero-order manner may prove toudbe significantly beneficial to greatly increase patient compliance and in turn therapeuticudefficacy.udThe purpose of this study was to design a novel triple-layered tablet (TLT) matrix targeted atudachieving stratified zero-order drug release. The central factor for the establishment of theudTLT was the selection of ideal and novel polymers that are capable of acting as superior drugudrelease matrices. Modified polyamide 6,10 (PA6,10) and salted-out poly(lactic-co-glycolicudacid) (PLGA) were employed as the outer drug-carrier matrices whereas poly(ethyleneudoxide) (PEO) was used as the middle layer drug matrix. Specialized granulation techniquesudand direct compression were employed to prepare the TLT matrices. Diphenhydramine HCl,udranitidine HCl and promethazine were chosen as model drugs for the study due to theirudsimilar high aqueous solubilities (100mg/mL). Matrix hardness, gel strength, swelling/erosionudcharacteristics, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetryudand in vitro drug release analysis employing High Performance Liquid Chromatography wereudperformed on the TLT matrices in order to determine the physicomechanical andudphysicochemical nature of the TLT matrices. Computational molecular modeling (CMM) wasudemployed to characterize the formation and dissolution of the TLT matrices. A box-Behnkenudexperimental design was employed that resulted in the generation of 17 design formulationsudfor ultimate optimization. In vivo animal studies were performed in the Large White Pig modeludto assess drug release behavior of the TLT. Ultra Performance Liquid Chromatography wasudemployed for plasma sample analysis.udThe PA 6,10 layer provided relatively linear and controlled drug release patterns with anudundesirable burst release greater than 15%, which upon addition of sodium sulphate wasudgreatly reduced. The addition of PEO to the salted-out PLGA layer greatly reduced the initialudburst release that occurred when salted-out PLGA matrix was used alone. Desirable resultsudwere obtained from FTIR, hydration and swelling/erosion analysis. CMM elucidated theudpossible mechanism of zero-order release from respective layers. Upon completion of theudBox-Behnken design analysis, an optimized TLT formulation was established according toudthe formulation responses selected namely the rate constants and correlation coefficients.udThe TLT displayed desirable near linear release of all three drugs simultaneously over 24udhours, with approximately 10%, 50% and 90% of the drugs released in 1, 10 and 24 hours.udAn in vitro drug release comparison performed between the optimized TLT and theudcommercial tablets currently used, showed an unequivocal display of superiority of the TLT inudterms of linear drug release over commercial tablets. A cardiovascular related drug regimenud(Adco-simvastatin®, DISPRIN CV® and Tenormin 50®) was applied to the TLT to assess theudflexibility of incorporating a range of drugs. The TLT furthermore provided near linear toudlinear release of the therapeutic regimen over 24 hours and maintained superiority over theudcommercial tablets. Benchtop Magnetic Resonance Imaging, porosity analysis and ScanningudElectron Microscopy was utilized for further introspective characterization of the TLT. In vivoudanalysis demonstrated a definite control of drug release from the TLT as compared toudcommercial tablets which further confirmed the advantage of the TLT.