Design and Preparation of Zero-Order Prolonged Release Systems Based on Hydrophilic Polymers Obtained with a Non-Uniform Drug Distribution

Purpose The aim of the work was to evaluate the ability of NUDMAT, a novel non-uniform drug distribution matrix system, to reach a prolonged release with zero-order kinetics for drugs with different solubility. In particular, the study was focused on the preparation of NUDMAT systems by exploiting powder layering and using a high-viscosity hypromellose as the releasecontrolling agent. The performance of the different systems was studied employing Durbin-Watson statistic in order to assess the zero-order portions of the release profiles. Methods NUDMAT systems were prepared by layering onto inert cellulose cores (850μm diameter Cellets®, Pharmatrans, CH) 5 layers composed of different powder mixtures containing Acetaminophen (CFM, I), Lansoprazole (Aptalis, I) and Losartan Potassium (Aptalis, I) as a moderately, poorly and highly soluble model drug, respectively. Each layer was purposely designed to obtain a gradient distribution of the drug, with concentration decreasing in the outward direction. hypromellose (HPMC 2208, Methocel K15M, Colorcon, UK) was employed at 30% in each layer. The drug was progressively replaced by dibasic calcium phosphate dihydrate (Emcompress, JRS Pharma, D). The final diameter of the units was about 4mm. The powder layering process was carried out in rotary fluid bed equipment (GPCG 1.1, Glatt®, D) simultaneously spraying 5% w/w PVP (Kollidon 30, BASF, D) aqueous solution as a liquid binder. Release tests were performed in USP dissolution apparatus 1 (Mod.2100, Distek, USA; 100rpm, 37.0±0.5°C, n=6). Fluid samples were withdrawn automatically at fixed time points and the drugs were assayed spectrophotometrically. Results Following characterization of the powder mixtures and preliminary set-up of the operating conditions, the powder layering process turned out feasible in the preparation of the different NUDMAT systems with the three drugs considered. The final units were evaluated in terms of morphology, dimensions and in vitro release. Irrespective of the solubility characteristics of the drug incorporated, it was possible to obtain zero-order kinetics for >70% portions of the release curves. Conclusion The NUDMAT systems confirmed to be a versatile and robust tool for obtaining zero-order release of drugs with different solubility.