Synthesis, characterization and evaluation of thiolated quaternary ammonium-chitosan conjugates for enhanced intestinal drug permeation.
In a previous report quaternary ammonium-chitosan conjugates (N(+)-Chs) endowed with intestinal drug permeability-enhancing properties were described. They are characterized by short pendant chains of n adjacent diethyl-dimethylene-ammonium groups substituted onto the primary amino group of the chitosan (Ch) repeating units. In the present work two N(+)-Chs, one having DS (degree of substitution)=59.2+/-4.5%, n=1.7+/-0.1 (N(+)(60)-Ch), the other one having DS=40.6+/-1.3%, n=3.0+/-0.2 (N(+)(40)-Ch) were used to synthesize novel multifunctional non-cytotoxic Ch derivatives, each carrying thiol along with quaternary ammonium groups (N(+)-Ch-SH), with increased potential to enhance transepithelial drug transport. They have been obtained by transforming the residual free amino groups of N(+)(60)-Ch and N(+)(40)-Ch into 3-mercaptopropionamide moieties. The former yielded 4.5+/-0.7% thiol-bearing groups, the latter, 5.2+/-1.1% of such groups, on a Ch repeating unit basis. The multifunctional derivatives have improved the ability of the parent N(+)-Chs to enhance the permeability of the water-soluble macromolecular fluorescein isothiocyanate dextran, MW 4400 Da (FD4) and that of the lipophilic dexamethasone (DMS) across the excised rat intestinal mucosa and Caco-2 cell monolayer, respectively. The data from the present work altogether point to a synergism of quaternary ammonium and thiol groups to improve the intestinal drug absorption enhancing properties of the multifunctional Ch derivatives.
Zambito
Ylenia
Y
Department of Pharmaceutical Sciences, University of Pisa, 56126 Pisa, Italy.
Fogli
Stefano
S
Zaino
Chiara
C
Stefanelli
Fabio
F
Breschi
Maria C
MC
Di Colo
Giacomo
G
D000818:Animals; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism; D003907:Dexamethasone / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D000644:Quaternary Ammonium Compounds / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000644:Quaternary Ammonium Compounds; D013438:Sulfhydryl Compounds; D003907:Dexamethasone; D048271:Chitosan