title: Cross-linked high amylose starch for controlled release of drugs: recent advances.
abstract: Cross-linked high amylose starches have been developed as excipients for the formulation of controlled-release solid dosage forms for the oral delivery of drugs. Advantages of this new class of excipients include cost-effectiveness, readily accessible industrial manufacturing technology, high active ingredient core loading and the possibility of achieving 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 these are the absence of erosion, the limited swelling and the fact that increasing cross-linking degrees results in increased water uptake rate, drug release rate and equilibrium swelling. Thus the goal of the present study was to gain some insights into the mechanism of drug release control by matrices of cross-linked high amylose starch. Water transport kinetics and dimensional changes were studied in matrices placed in water at 37 degrees C by an image analysis technique. The results show that in the first 5 min, a gel layer is formed at the surface of the tablet, after which the gel front seems to halt its progression toward the center of the tablet. Water continues to diffuse through the front and to invade the core. As a consequence, this latter swells, with a predominance for radial swelling. Equilibrium swelling is reached over 3 days, when the water concentration in the tablet becomes homogeneous and the whole tablet gelifies. Solid-state 13C-NMR were acquired on cross-linked high amylose starch powders, tablets and hydrated tablets with varying cross-linking degrees. They show a predominance of the V-type single helix arrangement of amylose in the dry state irrespective of the cross-linking degree. Upon hydration, the homologues with a low cross-linking degrees show a transition from the V to the B-type double helix arrangement. It is therefore hypothesized that the capacity of amylose to undergo the V to B transition is an important factor in controlling water transport and drug release rate. Finally applications to different drugs are reviewed briefly. They illustrate the versatility of this technology as generic versions of zero order OROS drug (Efidac) and Fickian release conventional matrices (Voltaren SR) were developed and successfully tested in pilot clinical studies to be bioequivalent to the references. These studies further showed that cross-linked high amylose starch matrices have the lowest inter-subject variability among the systems tested and show a total absence of food effect.
authors.affiliation: Labopharm Inc., Laval, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Lenaerts
authors.forename: I
authors.initials: I
authors.lastname: Moussa
authors.forename: Y
authors.initials: Y
authors.lastname: Dumoulin
authors.forename: F
authors.initials: F
authors.lastname: Mebsout
authors.forename: F
authors.initials: F
authors.lastname: Chouinard
authors.forename: P
authors.initials: P
authors.lastname: Szabo
authors.forename: M A
authors.initials: MA
authors.lastname: Mateescu
authors.forename: L
authors.initials: L
authors.lastname: Cartilier
authors.forename: R
authors.initials: R
authors.lastname: Marchessault
mesh_terms: D000284:Administration, Oral; D000688:Amylose / Q000008:administration & dosage* / Q000737:chemistry; D003432:Cross-Linking Reagents; D004008:Diclofenac / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004337:Drug Carriers; D004809:Ephedrine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D012016:Reference Values
chemical_list: D003432:Cross-Linking Reagents; D004337:Drug Carriers; D004008:Diclofenac; D000688:Amylose; D004809:Ephedrine