Chitosan as Absorption Enhancer of Hydrophilic Macromolecular Drugs

Illum and coworkers (1994) reported at first that chitosan is able to promote the transmucosal absorption of small polar molecules as well as peptide and protein drugs across nasal epithelia. Immediately afterward Artursson and collaborators (1994) reported that chitosan can increase the paracellular permeability of [14C]mannitol (a marker for paracellular routes) across Caco-2 intestinal epithelia.

Chitosan gels were first tested in vivo for their ability to increase the intestinal absorption by LueBen and coworkers in 1996c. The absorption enhancement of the peptide analog buserelin was studied after intraduodenal coadministration with chitosan (pH 6.7) in rats. Chitosan substantially increased the bioavailability of the peptide (5.1%) in comparison to control (no polymer) or Carbopol 934P containing formulations. Borchardt and his team (1996) investigated chitosan glutamate solutions at pH 7.4 for their effect in increasing the paracellular permeability of [14C]mannitol and fluorescently labeled dextran (MW 4,400 Da) in vitro in Caco-2 cells. No effect on the permeability of the monolayer could be observed, indicating that at neutral pH value chitosan is not effective as absorption enhancer. The pH dependency of chitosan's effect on epithelial permeability was further investigated by Kotze and coworkers (1998). Two chitosan salts (hydrochloride and glutamate) were evaluated for their ability to enhance the transport of [14C]mannitol across Caco-2 cell monolayers at two pH values, 6.2 and 7.4. At low pH both chitosans showed a pronounced effect on the permeability of the marker, leading to 25- (glutamate salt) and 36-fold (hydrochloride salt) enhancement. However, at pH 7.4 both chitosans failed to increase the permeability, due to their insolubility for use as absorption enhancer in more basic environment such as in the large intestine. These results made quite clear that chitosan (salts) cannot be used as absorption enhancers for in vivo studies when the drug should be released in the jejunum because of the insolubility and hence ineffectiveness at pH values higher than 6.5. N,N,N,-Trimethyl Chitosan Hydrochloride (TMC) Synthesis and Characterization of TMC

Sieval et al. (1998) and Kotze and collaborators (1998) based on the method of Domard et al. (1986) synthesized TMC. TMC is a partially quaternized derivative of chitosan, which is prepared by reductive methylation of chitosan with methyl iodide in a strong basic environment at an elevated temperature. The degree of quaternization can be altered by increasing the number of reaction steps by repeating them or by increasing the reaction time. TMC proved to be a derivative of chi-tosan with superior solubility and basicity, even at low degrees of quaternization, compared to chitosan salts. This quaternized chitosan shows much higher aqueous solubility than chitosan in a much broader pH and concentration range. The reason for this improved solubility is the substitution of the primary amine with methyl groups and the prevention of hydrogen bond formation between the amine and the hydroxylic groups of the chitosan backbone.

The absolute molecular weights, radius, and polydispersity of a range of TMC polymers with different degrees of quaternization (22.1, 36.3, 48.0, and 59.2%) were determined with size exclusion chromatography and multiangle laser light scattering (MALLS). The absolute molecular weight of the TMC polymers decreased with an increase in the degree of quaternization. The respective molecular weights measured for each of the polymers were 2.02 x 105,1.95 x 105, 1 .66 x 105, and 1.43 x 105 g/mole. It should be noted that the molecular weight of the polymer chain increases during the reductive methylation process due to the addition of the methyl groups to the amino group of the repeating monomer. However, a net decrease in the absolute molecular weight is observed due to degradation of the polymer chain caused by exposure to the specific reaction condition during the synthesis (Snyman et al., 2002). Polnok and coworkers (2004)

investigated the influence of the methylation process on the degree of quaterniza-tion on N -trimethyl chitosan chloride. 1H-Nuclear magnetic resonance spectra showed that the degree of quaternization was higher when using sodium hydroxide as base compared to dimethyl amino pyridine. The degrees of quaternization as well as O-methylation of TMC increased with the number of reaction steps.

The mucoadhesive properties of TMC with different degrees of quaternization, ranging between 22 and 49%, were investigated by the group of Snyman et al. (2002). TMC was found to have a lower intrinsic mucoadhesivity compared to the chitosan salts, chitosan hydrochloride and chitosan glutamate, but if compared to the reference polymer, pectin, TMC possesses superior mucoadhesive properties. The decrease in the mucoadhesion of TMC compared to the chitosan salts was explained by a change in the conformation of the TMC polymer due to interaction between the fixed positive charges on the quaternary amino group, which possibly also decreases the flexibility of the polymer backbone. The interpenetration into the mucus layer by the polymer is influenced by a decrease in flexibility resulting in a subsequent decrease in mucoadhesivity (Snyman et al., 2003).

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