Chiara Zaino

Improved synthesis of quaternary ammonium-chitosan conjugates (N+-Ch) for enhanced intestinal drug permeation

The pH-induced structural modifications of the reaction product between chitosan and 2-diethylaminoethyl chloride are studied with the purpose of testing and comparing the resulting chitosan derivatives on the basis of their intestinal drug permeability-enhancing properties. The reaction reproducibly yielded conjugates comprising short pendant chains of n adjacent diethyl-dimethylene-ammonium groups substituted onto the primary amino group of the chitosan repeating unit. The more significant derivatives, N(+)-Ch-7 (degree of substitution, DS=41%; n=3) and N(+)-Ch-8 (DS=59%; n=1.7) were prepared at pH 7 and 8, respectively. The apparent permeability (P(app)) of excised rat intestine was determined by means of Ussing type chambers. The hydrophilic fluorescein sodium (NaFlu) and fluorescein isothiocyanate dextran (MW 4400 Da) (FD-4), and the lipophilic rhodamine 123 (Rh-123), were applied in Ringer buffer to the apical side. Apical to basolateral transport was measured in the absence or presence of 0.5% (w/v) of the polymer under test. N(+)-Ch-7 and N(+)-Ch-8 were more effective P(app) enhancers than N-trimethyl-chitosan. Both N(+)-Ch-7 and N(+)-Ch-8 enhanced the P(app) of NaFlu (enhancement ratio, ER=1.84 and 1.33, respectively), while N(+)-Ch-8 was the more effective enhancer for FD-4 (ER=2.14). The P(app) of Rh-123 was significantly enhanced only by N(+)-Ch-7 (ER=1.37). Permeant-polymer binding counteracted the enhancement effect of polymer on transmembrane permeant flux. Contact with the chitosan conjugates did not impair the mucosal epithelium integrity.

Selected polysaccharides at comparison for their mucoadhesiveness and effect on precorneal residence of different drugs in the rabbit model.

Mucoadhesive polysaccharides may prolong the residence of ophthalmic drugs in precorneal area. In this article, the mucoadhesiveness of arabinogalactan, tamarind seed polysaccharide, hyaluronan, hydroxyethylcellulose is compared in vivo, by the polymer residence time in rabbit tear fluid, and in vitro, by the polymer-induced increase of viscosity of a mucin dispersion. Polymer residence is prolonged by increased viscosity but shortened by reflex tearing caused by excessive viscosity. Tamarind seed polysaccharide is the most effective in prolonging the residence of ketotifen and diclofenac in precorneal area; hence, it is the optimal eyedrop additive as it is mucoadhesive while not increasing viscosity excessively.

Synthesis, characterization and evaluation of thiolated quaternary ammonium-chitosan conjugates for enhanced intestinal drug permeation

In a previous report quaternary ammonium-chitosan conjugates (N(+)-Chs) endowed with intestinal drug permeability-enhancing properties were described. They are characterized by short pendant chains of n adjacent diethyl-dimethylene-ammonium groups substituted onto the primary amino group of the chitosan (Ch) repeating units. In the present work two N(+)-Chs, one having DS (degree of substitution)=59.2+/-4.5%, n=1.7+/-0.1 (N(+)(60)-Ch), the other one having DS=40.6+/-1.3%, n=3.0+/-0.2 (N(+)(40)-Ch) were used to synthesize novel multifunctional non-cytotoxic Ch derivatives, each carrying thiol along with quaternary ammonium groups (N(+)-Ch-SH), with increased potential to enhance transepithelial drug transport. They have been obtained by transforming the residual free amino groups of N(+)(60)-Ch and N(+)(40)-Ch into 3-mercaptopropionamide moieties. The former yielded 4.5+/-0.7% thiol-bearing groups, the latter, 5.2+/-1.1% of such groups, on a Ch repeating unit basis. The multifunctional derivatives have improved the ability of the parent N(+)-Chs to enhance the permeability of the water-soluble macromolecular fluorescein isothiocyanate dextran, MW 4400 Da (FD4) and that of the lipophilic dexamethasone (DMS) across the excised rat intestinal mucosa and Caco-2 cell monolayer, respectively. The data from the present work altogether point to a synergism of quaternary ammonium and thiol groups to improve the intestinal drug absorption enhancing properties of the multifunctional Ch derivatives.

Enhanced affinity of ketotifen toward tamarind seed polysaccharide in comparison with hydroxyethylcellulose and hyaluronic acid: A nuclear magnetic resonance investigation

Nuclear magnetic resonance (NMR) spectroscopy demonstrated that, in aqueous solution, ketotifen fumarate bound more strongly to tamarind seed polysaccharide (TSP) than to hydroxyethylcellulose or hyaluronic acid. Results were confirmed by dynamic dialysis technique.

A Novel Polyelectrolyte Complex (PEC) Hydrogel for Controlled Drug Delivery to the Distal Intestine

This work was aimed at preparing and evaluating a physically crosslinked hydrogel for the controlled release of diverse drugs to the distal intestine. A solution of fluorescein isothiocyanate dextran, MW 4400 Da (FD4), or a dispersion of micronized dexamethasone (DMS) was microencapsulated into a PEC hydrogel, composed of polycationic N-trimethyl chitosan (TMC) and polyanionic N-carboxymethyl chitosan (CMCh). A fine spray of a 1% CMCh solution containing 1% FD4 in solution or 0.1% DMS in dispersion was directed into a 2% TMC solution, then the resulting microcapsules (MCPS) were lyophilized. MCPS were analyzed by SEM and solid-state NMR. Drug release from MCPS was too fast, so these were compressed into matrices (weight 20 mg; diameter 6 mm; drug load 2.5%, with FD4, or 3.7%, with DMS) which were enteric coated. Drug release from matrices was studied simulating matrix transit across GI environments of different pHs, from stomach to proximal colon. The enteric film hindered release in stomach and proximal small intestine. After film dissolution at ileum pH, release occurred with a pattern described by the Peppas equation (n=0.6, with DMS; n=0.7, with FD4). As the pH changed from 7.4 to 6 (from ileum to ascending colon) MCPS were liberated from matrix surface. This phenomenon sustained the release rate. The present MCPS allow controlled doses of macromolecular or mi- croparticulate drugs being uniformly loaded into controlled-release matrices based on a physically crosslinked, biodegrad- able hydrogel.