universidad de concepcion facultad de farmacia evaluacion de la ...

Universidad de Concepción
Magíster en Ciencias Farmacéuticas
SUMMARY
In the present work, we evaluated the effect of a semisynthetic derivative of
the cationic polymer Chitosan on intestinal permeability of Capreomycin sulfate, a
polypeptide antibiotic, using in vitro and in vivo models. N-trimethyl chitosan
chloride (TMC) is obtained by alkylation of the free amino groups with iodomethane
in basic conditions, and the obtained product is soluble in a wider pH range than
the original polymer. In order to improve it mucoadhesive and permeation
enhancer properties, we used a synthetic pathway that selectively alkylated the
amino groups and not the hydroxyl groups in carbons 3 and 6 which decreased the
potency of the polymer, leading to use higher quantities and limit its potential as a
functional excipient. This non methoxylated derivative of N-trimethyl chitosan
chloride reduced in a reversible way the transepithelial electrical resistance of
CaCo-2 monolayers at concentrations not higher than 0,003 % w/v, indicating that
the absence of steric hindrance from methoxyl groups improves the effect of TMC,
but at the expense of a narrow range of action and higher toxicity. The results of in
vitro permeation studies conducted in bicameral “Transwell ® ” systems suggest that
the permeability of Capreomycin sulfate is low, but it was not demonstrated if other
mechanisms like membrane transporters are involved. By using increasing
concentrations of TMC in the range of 0,001 to 0,003 % w/v, was observed a slight
increase in the transport of Capreomycin, but the differences between groups were
not statistically significant. In female Sprague-Dawley rats, using concentrations of
TMC equivalent to 0,005 and 0,01 % w/v, there was an erratic increase in plasma
concentrations that can be attributed to the low concentrations used and polymer
interactions with mucins in the intestinal lumen.
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