title: Novel transmucosal absorption enhancers obtained by aminoalkylation of chitosan.
abstract: Literature data suggest that quaternized chitosans have a transmucosal drug absorption enhancing property depending on their MW, quaternization degree and other structural features. With the purpose of preparing novel effective promoters, a chitosan (Ch) from crab shell (ChC; viscometric MW, 800 kDa; deacetylation: 90%, IR; 84%, NMR) and one from shrimp shell (ChS; viscometric MW, 590 kDa; deacetylation: 90%, IR; 82%, NMR) were reacted with 2-diethylaminoethyl chloride (DEAE-Cl) and novel derivatives containing different percentages of pendant quaternary ammonium groups were obtained. NMR analysis, based on HSQC, COSY, TOCSY and ROESY maps, indicated that three partially substituted N,O-[N,N-diethylaminomethyl(diethyldimethylene ammonium)(n)]methyl chitosans, coded N(+)-ChS-2 (degree of substitution, DS=40%; n=1.6), N(+)-ChS-4 (DS=132%; n=2.5), and N(+)-ChC-4 (DS=85%; n=1.7) resulted from the reaction, depending on whether the DEAE-Cl/Ch repeating unit molar ratio, was 2:1 or 4:1. The effects of the derivatives on the permeability of rhodamine 123 (Rh-123), hydrophobic, marker of the transcellular absorption route, and of fluorescein sodium (NaFlu), polar, marker of the paracellular route, across excised porcine cheek epithelium were assessed, using Franz type diffusion cells. Rh-123 permeability was enhanced by N(+)-ChS-4 (enhancement ratio, ER=8.4) and by N(+)-ChC-4 (ER=3.9), whereas N(+)-ChS-2 was ineffective. NaFlu permeability was enhanced by N(+)-ChS-2 (ER=7.2), N(+)-ChS-4 (ER=7.4) and N(+)-ChC-4 (ER=6.6). In conclusion, the three derivatives, whichever their DS, promote paracellular transport, while transcellular transport is substantially accelerated only by the most substituted one.
authors.affiliation: Department of Bioorganic Chemistry & Biopharmaceutics, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Zambito
authors.forename: Gloria
authors.initials: G
authors.lastname: Uccello-Barretta
authors.forename: Chiara
authors.initials: C
authors.lastname: Zaino
authors.forename: Federica
authors.initials: F
authors.lastname: Balzano
authors.forename: Giacomo
authors.initials: G
authors.lastname: Di Colo
mesh_terms: D000042:Absorption; D000478:Alkylation; D000818:Animals; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D004983:Ethanolamines / Q000737:chemistry; D019793:Fluorescein / Q000378:metabolism; D015394:Molecular Structure; D009061:Mouth Mucosa / Q000378:metabolism*; D010539:Permeability; D013552:Swine
chemical_list: D004983:Ethanolamines; D048271:Chitosan; C007369:2-diethylaminoethanol; D019793:Fluorescein