Preparation and in vitro evaluation of chitosan matrices for colonic controlled drug delivery.
OBJECTIVE
The work was aimed at studying in vitro the release of 5-aminosalicylic acid (5-ASA) or diclofenac sodium (DS) from matrices based on chitosan (Ch) or Ch hydrochloride (Ch-HCl), destined to be introduced into enteric-coated capsules for controlled release to the colon.


METHODS
Matrices (diameter, 6 mm; weight, 50 mg) were prepared by compression of Ch or Ch-HCl microparticles mixed with 20 % 5-ASA or DS powder. Drug release from matrices to isotonic neutral buffers of different molarity was studied in vitro. In some cases, matrix incubation in rat cecal contents preceded the release test.


RESULTS
The matrices, especially the Ch-HCl-based ones, swelled in the dissolution medium without disintegrating. Drug release was diffusion-controlled and followed square-root-time kinetics. Release depended on the pH-dependent aqueous solubility of the drug. The internal pH of the swollen Ch-HCl-based matrix was acidic, so 5-ASA solubility and release were influenced by penetration of salts from the external buffer. In the Ch-HCl-based matrix DS was converted into the scarcely soluble diclofenac free acid, which prolonged the time for release of 50 % dose excessively (t50 =11.26 h). The enzymatic action of rat cecal microflora accelerated drug release from the Ch-HCl-based matrix. On the other hand, neither such a microflora nor the external medium hydrodynamics significantly affected drug release from the Ch-based matrix.


CONCLUSIONS
The Ch-based matrix was a reliable colonic controlled-release system for 5-ASA (t(50) =1.97 h) or DS (t(50) =3.58 h). For in vivo application, a number of matrices adequate to make up the therapeutic drug dose should be introduced into enteric-coated size 00 capsules.
Zambito
Ylenia
Y
Department of Bioorganic Chemistry and Biopharmaceutics, University of Pisa, Pisa, Italy.
Di Colo
Giacomo
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry*; D048271:Chitosan; D003106:Colon / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004008:Diclofenac / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D019804:Mesalamine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D002686:Chitin; D004008:Diclofenac; D019804:Mesalamine; D048271:Chitosan