title: A novel pH-sensitive hydrogel composed of N,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery.
abstract: A novel pH-sensitive hydrogel system composed of a water-soluble chitosan derivative (N,O-carboxymethyl chitosan, NOCC) and alginate blended with genipin was developed for controlling protein drug delivery. Genipin, a naturally occurring cross-linking agent, is significantly less cytotoxic than glutaraldehyde and may provide a less extent of cross-linking to form a semiinterpenetrating polymeric network (semi-IPN) within the developed hydrogel system. The drug-loading process used in the study was simple and mild. All procedures used were performed in aqueous medium at neutral environment. In the study, preparation of the NOCC/alginate-based hydrogels was reported. Swelling characteristics of these hydrogels as a function of pH values were investigated. Additionally, release profiles of a model protein drug (bovine serum albumin, BSA) from test hydrogels were studied in simulated gastric and intestinal media. The semi-IPN formation of the genipin-cross-linked NOCC/alginate hydrogel was confirmed by means of the scanning electron microscopy-energy dispersive X-ray spectrometer (SEM-EDS) and the ninhydrin assays. The percentage of decrease of free amino groups and cross-linking density for the NOCC/alginate hydrogel cross-linked with 0.75 mM genipin were 18% and 26 mol/m(3), respectively. At pH 1.2, the swelling ratio of the genipin-cross-linked NOCC/alginate hydrogel was limited (2.5) due to formation of hydrogen bonds between NOCC and alginate. At pH 7.4, the carboxylic acid groups on the genipin-cross-linked NOCC/alginate hydrogel became progressively ionized. In this case, the hydrogel swelled more significantly (6.5) due to a large swelling force created by the electrostatic repulsion between the ionized acid groups. The amount of BSA released at pH 1.2 was relatively low (20%), while that released at pH 7.4 increased significantly (80%). The results clearly suggested that the genipin-cross-linked NOCC/alginate hydrogel could be a suitable polymeric carrier for site-specific protein drug delivery in the intestine.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, 101 Section 2, Kung-Fu Road, Hsinchu 30013, Taiwan, ROC.
authors.forename: Sung-Ching
authors.initials: SC
authors.lastname: Chen
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Wu
authors.forename: Fwu-Long
authors.initials: FL
authors.lastname: Mi
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Lin
authors.forename: Lin-Chien
authors.initials: LC
authors.lastname: Yu
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D000464:Alginates / Q000737:chemistry*; D048271:Chitosan / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D020723:Glucuronic Acid / Q000737:chemistry*; D006603:Hexuronic Acids / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D057889:Iridoid Glycosides; D039823:Iridoids; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D011506:Proteins / Q000008:administration & dosage*; D011714:Pyrans / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors
chemical_list: D000464:Alginates; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006603:Hexuronic Acids; D020100:Hydrogels; D057889:Iridoid Glycosides; D039823:Iridoids; D011506:Proteins; D011714:Pyrans; C077199:O,N-carboxymethylchitosan; D012710:Serum Albumin, Bovine; D020723:Glucuronic Acid; D048271:Chitosan; C007834:genipin