Enhancement of paracellular drug transport across mucosal epithelia by N-trimethyl chitosan chloride

N-trimethyl chitosan chloride is a partially quaternized chitosan derivativ e with greatly enhanced water solubility especially at neutral and basic pH values. N-trimethyl chitosan chloride displayed potential as an absorption enhancer in previous experiments and, like chitosan, is able to open the t ight junctions of epithelial cells to allow the paracellular transport of l arge, hydrophilic compounds. The charge density of N-trimethyl chitosan chl oride, as determined by the degree of quaternization, is an important facto r that influences the absorption enhancement properties of this polymer. Th e effects of chitosan and N-trimethyl chitosan chloride, with varying degre es of quaternization (12-59%), on the transepithelial electrical resistance of Caco-2 monolayers and the in vitro and in vivo transport of the peptide drug, insulin, and the hydrophilic marker [C-14]-mannitol are discussed. A t a pH of 6.2, all the polymers (N-trimethyl chitosan chloride, chitosan hy drochloride, chitosan glutamate) are able to markedly reduce the transepith elial electrical resistance of Caco-2 cells. On the contrary, at a pH of 7. 4, only N-trimethyl chitosan chloride polymers with higher degrees of quate rnization (> 22%) are able to decrease the transepithelial electrical resis tance values significantly. In concordance with the transepithelial electri cal resistance results, N-trimethyl chitosan chloride polymers with higher degrees of quaternization (> 22%) were most effective as enhancers of the i n vivo absorption of [C-14]-mannitol administered intranasally at a pH of 7 .4 to rats. The results showed that N-trimethyl chitosan chloride acts as a novel absorption enhancer even at basic and neutral pH values where chitos an is ineffective as an absorption enhancer and that the degree of N-trimet hyl chitosan chloride quaternization is an important factor for determining the absorption-enhancing properties of this polymer especially in neutral and basic environments. It can be concluded that N-trimethyl chitosan chlor ine may contribute to the development of safe and effective drug delivery s ystems for the non-parenteral administration of large hydrophilic drugs suc h as peptides and proteins.