A novel approach for constant rate delivery of highly soluble bioactives from a simple monolithic system

A novel monolithic drug delivery system for highly water-soluble bioactive agents to follow pH-independent zero-order kinetics is described. The syste m utilizes a hydrophilic gel-based swellable polymeric material (polyethyle ne oxide), a model drug (metoprolol tartrate, 100% water soluble at 25 degr ees C) and different electrolytes, such as sodium carbonate and/or pentasod ium tripolyphosphate. Based on the induction of in situ intra-gel chemical reactions between different ionic species, drug and polymer, a heterogeneou s structure manifested as 'peripheral boundary stiffening,' is accomplished . The consequence of these interactions essentially include the development of gradient-controlled matrix swelling as elucidated through textural prof iling, which may contribute to inhibition of drug solubility and its outwar d diffusion. Analysis of textural profiles and photomicroscopy distinctly p rovides information on the disposition of peripheral boundary densification for the electrolyte-containing matrices. Electrolytic conductivity measure ments performed with the simultaneous analysis of matrix swelling showed th at sodium carbonate forms a highly reactive matrix within the first 3 h of medium penetration. On the other hand, larger molecules such as pentasodium tripolyphosphate maintain a constant conductivity level, which may be rela ted to its lower solubility and diffusion in comparison to sodium carbonate . Based on model fitting and statistical analysis, it is shown that drug re lease kinetics were adequately described by M-t/M-infinity = k(0)t, with ze ro-order release rate constant k(0) of 0.054 h(-1). This novel approach in formulation development could potentially be used for constant rate deliver y of highly soluble bioactive agents over an extended period for specific b iopharmaceutical needs. (C) 2000 Elsevier Science B.V. All rights reserved.