Efficacy and mechanistic studies of chitosan as nasal absorption enhancer of peptide drugs : research report

Abstract

Objective. To evaluation the in vivo efficacy of chitosan as nasal absorption enhancers of peptides in rats and compare the results with that of hydroxypropyl- and dimethyl-Beta-cyclodextrins (HPBetaCD and DMBetaCD). Methods. Two types of chitosan. i.e., the free base (CSJ) and the glutamate salt form (CSG) were evaluated for their nasal absorption enhancing effect on salmon calcitonin (sCT) using an in vibo rat absorption technique. Solutions containing sCT and chitosan (0 to 1.25 % w/v) in isotonic phosphate buffers (pH 3.0 to 6.0) were nasally administered at the dose of 10 IU/kg. The plasma calcium lowering effect in each sCT-treated rat was determined by calculating the total percent decrease in plasma calcium (%D). Results. CSJ showed an increase in %D as the solution pH was decreased in accordance with the increased ionization and hydration of the free base chitosan at the more acidic pH. However, CSG showed an increase in %D with increasing pH, with maximum calcium lowereing effect observed at pH 6.0. At their optimal pH (4.0 for CSJ and 6.0 for CSG), the absorption enhancing effect of both chitosans was concentration dependent from 0.25 to 1.0 % w/v and leveled off at 1.25% w/v. Using specific RIA, the absolute bioavailability of plasma sCT was determined to be 2.45, 1.91, and 1.22 % for 1% CSJ, 5% DMBetaCD, and control group (intranasal sCt alone). Respectively. All the enhancers showed significant absorption enhancement with the highest effect observed with CSJ and DMBetaCD wheras the effect of HPBetaCD was the smallest. Also, the two chitosan did not possess any inhibitory effect on the in vitro activities of trypsin and leucine aminopeptidase, two major nasal proteolytic enzymes responsible for the degradation of sCT in the nasal cavity. Thus, the nasal absorption enhancement of chitosans may not involve protection of the peptide against proteolytic degradation in the nasal cavity. In conclusion, cationic polymer chitosans may have promising potential as an effective nasal absorption enhancer ofsCT.