POST-GRADUATE STUDENTS
The absorption enhancing property of chitosan and chitosan salts, has been well documented in the past few years. Very significant is their ability to increase the absorption of various peptide drugs in vitro and in vivo. The in vitro transport of the peptide 9-desglycinamide, 8-L-arginine vasopressin (DGAVP) across intestinal epithelial cells (Caco-2 cell monolayers) was increased significantly after administration with chitosan glutamate at pH 5.60. Similarly, the intraduodenal application of buserelin and chitosan hydrochloride in a gel formulation at pH 6.70 increased the absolute bioavailablilty of buserelin from 0.1 ± 0.1 % to 5.1 ± 1.5 % in experiments in rates while the nasal administration of insulin with chitosan glutamate at pH 4.40 resulted in a pronounced reduction of the blood glucose levels in rats and sheep. Increased peptide drug absorption could be attributed to the effect of chitosan on the integrity of the epithelial tights junctions. Chitosan opens the tight junctions to allow paracellular transport of large hydrophilic compounds. This interaction with the tight junctions is believed to be an interaction of the positively charged amino group on the C-2 position of chitosan, with the negatively charged sites on the cell surfaces and tight junctions. However, chitosan is a weak base and a certain amount of acid is required to transform the glucosamine units into the positively charged, water-soluble form. It has been shown that chitosan is ineffective as an absorption enhancer in neutral environments because it precipitates. Therefore, the use of chitosan in neutral and basic environments such as those found in the nasal and rectal cavities, and large intestine and colon, is limited. It has been shown recently that the partially quaternized derivative of chitosan, N-trimethyl chitosan chloride (TMC), was also able to increase the paracellular transport of several hydrophilic compounds and peptide drugs such as DGAVP (MW 1412), buserelin (MW 1300) and insulin (MW 5778) in Caco-2 cell monolayers. TMC has proven to be very soluble over a wide pH range (pH 1 – 9 ) up to 10 % w/v concentrations, even at degrees of quaternization as low as 10 %. Furthermore, it was found that the charge of TMC, as determined by its degree of quaternization, plays an important role in its ability to act as an absorption enhances, especially in neutral environments. Highly quaternized TMC (60 %) is able to increase the permeation of [14C]-mannitol across Caco-2 cell monolayers 31 – to 48-fold at 0.05 – 1,-.5 % w/v concentrations at pH of 7.40 whereby low quaternized TMS (12 %) and chitosan hydrochloride do not show any increases in the transport rate of this hydrophilic marker at pH 7.40. It was concluded that the charge density of highly quaternized TMC is sufficient for interaction with the negative charged sites on the cell membranes and tight junctions, while the charge density of sparingly quaternized TMC is still too low for an significant interactions. The aim of present investigation was to evaluate the effect of the degree of quaternization of TMC on its mucoadhesive characteristics, absorption enhancing properties (in vitro, in situ and in vivo) and toxicity profile in a neutral environment.
