A Novel PH-sensitive Hydrogel Based On Dual Crosslinked Alginate/N-α-glutaric Acid Chitosan For Oral Delivery Of Protein

Along with the recent advance of recombinant DNA techniques, a wide range of bioactive molecules like proteins, peptides, and enzymes are commercially available as drugs. Compared with the traditional drugs, these proteins and bioactive molecules will become the main means of drugs because of their low poisonous side-effects but high curative effects. Oral administration is considered as the most convenient and maximal acceptability way of protein drugs delivery, but due to the acidic denaturation and enzymatic degradation of these drugs in the upper part of the gastrointestinal tracts, so in far the protein drugs still have been administrated by injection. This way of administration of protein and peptide drugs is mainly confined by the low biological acceptability because that the half life of these drugs is so short that this process has to be repeated by hypodermic injections with high frequency, and this will bring patients great pain and liable to infection. In order to increase the curative effects of the protein drugs, lower the poisonous effects (mainly the antigenicity) and easy to administration, the study of the oral delivery of these protein drugs become the key research aspect in the area of drugs'control and release.In the study, chitosan was modified byα-Ketoglutaric acid to get N-α-glutaric acid chitosan (GAC) and GAC was dropped into the solution of alginate, then the homogeneous GAC and alginate solution added to calcium chloride solution, so the alginate and GAC were crosslinked by Ca²⁺ ion. After 30 min, these crosslinked beads were suspended in sodium sulfate solution for 30 min to form dual crosslinked hydrogel beads.The swelling behaviours of dual crosslinked gel beads in different pH environment were investigated in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF). The results indicated that the swelling ratios in the pH of 6.8 and 7.4 were six times and eleven times more than in the pH of 1.2, respectively. Bovine serum albumin (BSA), a model protein drug, was loaded in alginate/GAC gel beads and the loading efficiency was measured. The results were that the loading efficiency achieved 92% when the weight ratio of BSA and the whole beads above 20%. Meanwhile, the loading efficiency of BSA increased with the enhancement of the content of N-α-glutaric acid in the hydrogel beads.In addition, the sustained release profiles of BSA loaded gel beads were studied at different pH environment for simulating gastrointestinal condition. The amount of BSA released from the gel beads in SGF with pH 1.2 was relatively low (14%-18%), the cumulate release amount remained the same and achieved the balance; while in SIF and SCF with pH 6.8 and 7.4, along with the swelling of the hydrogel beads, the release ratio increased rapidly and almost 100% of BSA could be released within 3 h. The preliminary results clearly suggested that the dual crosslinked alginate/GAC gel beads may be a potential polymeric carrier for oral delivery of protein drugs.