Novel transmucosal absorption enhancers obtained by aminoalkylation of chitosan

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.