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.
Novel transmucosal absorption enhancers obtained by aminoalkylation of chitosan
ZAMBITO, YLENIA;UCCELLO BARRETTA, GLORIA;BALZANO, FEDERICA;DI COLO, GIACOMO
2006-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
