CROSS-LINKED HIGH AMYLOSE STARCH FOR CONTROLLED-RELEASE OF DRUGS - RECENT ADVANCES

Cross-linked high amylose starches have been developed as excipients f or the formulation of controlled-release solid dosage forms for the or al delivery of drugs. Advantages of this new class of excipients inclu de cost-effectiveness, readily accessible industrial manufacturing tec hnology, high active ingredient core loading and the possibility of ac hieving a quasi zero-order release for most drugs. In addition to the latter, other features distinguish cross-linked high amylose starches from other excipients used to prepare hydrophilic matrices. Among thes e are the absence of erosion, the limited swelling and the fact that i ncreasing cross-linking degrees results in increased water uptake rate , drug release rate and equilibrium swelling. Thus the goal of the pre sent study was to gain some insights into the mechanism of drug releas e control by matrices of cross-linked high amylose starch. Water trans port kinetics and dimensional changes were studied in matrices placed in water at 37 degrees C by an image analysis technique. The results s how that in the first 5 min, a gel layer is formed at the surface of t he tablet, after which the gel front seems to halt its progression tow ard the center of the tablet. Water continues to diffuse through the f ront and to invade the core. As a consequence, this latter swells, wit h a predominance for radial swelling. Equilibrium swelling is reached over 3 days, when the water concentration in the tablet becomes homoge neous and the whole tablet gelifies. Solid-state C-13-NMR were acquire d on cross-linked high amylose starch powders, tablets and hydrated ta blets with varying cross-linking degrees. They show a predominance of the V-type single helix arrangement of amylose in the dry state irresp ective of the cross-linking degree. Upon hydration, the homologues wit h a low cross-linking degrees show a transition from the V to the B-ty pe double helix arrangement. It is therefore hypothesized that the cap acity of amylose to undergo the V to B transition is an important fact or in controlling water transport and drug release rate. Finally appli cations to different drugs are reviewed briefly. They illustrate the v ersatility of this technology as generic versions of zero order OROS d rug (Efidac) and Fickian release conventional matrices (Voltaren SR) w ere developed and successfully tested in pilot clinical studies to be bioequivalent to the references. These studies further showed that cro ss-linked high amylose starch matrices have the lowest inter-subject v ariability among the systems tested and show a total absence of food e ffect. (C) 1998 Elsevier Science B.V.