Biomedical subjects

Ylenia Zambito

Publications and source records attributed to Ylenia Zambito.

8 recordsLinked to original sources

PubMed2006

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.

Absorption↗

PubMed2006

Nanoparticles based on N-trimethylchitosan: evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models.

Among the chitosan derivatives, trimethylchitosan (TMC) has been shown to have penetration enhancement properties also in intestinal environment. In addition, the use of nanoparticulate systems has the advantage of protecting peptidic drugs from intestinal degradations, due to internalisation behaviour. Therefore, the aim of this paper was to evaluate nanoparticulate systems based on TMC. In particular the mucoadhesive and absorption enhancement properties of nanoparticles based on TMC with different quaternization degree (QD) intended for the intestinal administration of macromolecules (peptides) have been evaluated. Comparison with chitosan (CS.HCl) nanoparticles was made. The nanoparticles were loaded with fluorescein isothiocyanate dextran (FD4, MW 4400 Da), used as the model macromolecule. The intestinal penetration enhancement properties of nanoparticles were investigated in an in vitro Caco-2 cell model and an ex vivo rat jejunum model. The mucoadhesion of the nanosystems was evaluated using excised rat jejunum. All of the nanoparticulate systems interacted with the Caco-2 cells decreasing the transepithelial electric resistance (TEER) and increasing Lucifer Yellow (LY) Papp (paracellular pathway marker). All the nanosystems improved FD4 Papp, with the exception of the nanoparticles based on TMC with the highest QD. In this case an entrapment of nanoparticles into Caco-2 cells was supposed. Analogous results were obtained using the excised rat jejunum model. The increase in QD of TMC was seen to favour the mucoadhesion, resulting in a prolonged residence time on intestinal mucosa. The nanoparticle penetration into excised rat jejunum tissue, observed by means of CLSM, suggested that the mucoadhesive properties delayed the absorption of nanoparticles, however they produced an increase in the contact time with intestinal epithelium, offering a better chance for internalisation. The improvement of mucoadhesion and of nanoparticle internalisation with respect to chitosan nanosystems makes the TMCs nanosystems suitable carriers for the intestinal absorption of peptides.

Adhesiveness↗

PubMed2006

Effects of N-trimethylchitosan on transcellular and paracellular transcorneal drug transport.

The effects of N-trimethylchitosan (TMC) on the transcorneal transport of dexamethasone, taken as a marker of the transcellular penetration route, and of tobramycin, a marker of the paracellular route, were studied by assessing the TMC effect on the intraocular pharmacokinetics of each marker. The drugs were topically applied via erodible inserts (weight, 20 mg; diameter, 6 mm; drug dose, 0.3 mg) based on poly(ethylene oxide), containing 10% w/w medicated TMC microspheres (diameter < 2.5 microm). Before application, drug release and insert erosion kinetics, and release mechanism were studied in vitro. With either drug, introduction of 10% TMC into insert did not substantially alter the release and erosion rates, hence this formulation was apt to isolate the transcorneal penetration enhancing effect of TMC. Ocular pharmacokinetics were determined in the rabbit model. TMC produced significant increases of dexamethasone Cmax (5.69 +/- 0.49 vs. 3.07 +/- 0.31 microg/ml) and AUC (619.3 +/- 32.5 vs. 380.5 +/- 32.0 microg min/ml) in the aqueous with respect to the reference TMC-free insert. On the other hand, TMC was unable to yield tobramycin concentrations in the aqueous exceeding the determination limit (0.5 microg/ml). In conclusion, TMC enhances transcorneal transport via the transcellular route, whereas it is unable to effectively open the tight junctions between corneal cells.

Absorption↗

PubMed2005

Buccal penetration enhancement properties of N-trimethyl chitosan: Influence of quaternization degree on absorption of a high molecular weight molecule.

The aim was to evaluate the influence of the degree of quaternization of N-trimethyl chitosans (TMCs) on the mucoadhesive and penetration enhancement properties towards buccal mucosa. Fluorescein isothiocyanate dextran (MW 4400 Da) (FD4) was used as model molecule. TMCs, obtained from chitosans of different MW (1460 and 580 kDa, respectively), were hydrated in distilled water and in pH 6.4 phosphate buffer (simulating the buccal fluid). The polymer solutions were subjected to mucoadhesion measurements towards bovine submaxillary mucin dispersion and porcine buccal mucosa and to FD4 permeation tests through porcine cheek epithelium. The trimethylation of chitosan allows maintenance or improvement of the mucoadhesive properties of the starting chitosans dependently on quaternization degree. In particular, the mucoadhesive properties increase on increasing degree of quaternization. The trimethylation does not produce any change in chitosan penetration enhancement properties when the medium is distilled water while if pH 6.4 buffer is used, the trimethylation produces an improvement in chitosan penetration enhancing effect. TMC derived from the lower MW chitosan and characterized by the highest degree of quaternization shows the best mucoadhesive and penetration enhancement properties and is the most promising TMC to improve the bioavailability of hydrophilic and large MW molecules (like peptides and proteins) when administered via buccal route.

Absorption↗

PubMed2005

A site-specific controlled-release system for metformin.

Oral absorption of the antihyperglycaemic agent metformin hydrochloride (MF-HCl) is confined to the upper part of the intestine, therefore rational controlled-release formulations of this drug should ensure a complete release during transit from stomach to jejunum. The aim of this study was the preparation of a system able to sustain release of high MF-HCl doses in compliance with the above requirement. Matrices (6 mm diameter; 50 mg weight) comprising varying drug-Precirol ATO 5 ratios were prepared by compression. The matrix containing 70% drug was coated on one face with Eudragit L100-55. Drug release to simulated gastric (SGF), jejunal (SJF) and ileal (SIF) fluids in sequence was studied using a modified USP rotating basket method. Release depended on drug load whereas it was independent of dissolution medium pH and hydrodynamics. Release kinetics were of radical t type and were determined by drug diffusion in aqueous pores created in the matrix by drug dissolution. An equation correlating rate-determining factors was developed, whereby the release pattern could be optimized. The half-coated matrix started release in SGF and completed it in SJF. The half-coated matrix, synchronizing drug release and matrix transit across the small intestine, may improve drug bioavailability and reduce side effects.

Biological Availability↗

PubMed2004

Effects of different N-trimethyl chitosans on in vitro/in vivo ofloxacin transcorneal permeation.

N-trimethyl chitosan (TMC) polymers differing in quaternization degree (QD) and molecular weight (MW) were prepared from two chitosans 90% deacetylated, one of higher MW (1460 kDa) (TMCH), the other of lower MW (580 kDa) (TMCL), by one (TMCH1, QD = 4%; TMCL1, QD = 3%), two (TMCH2, QD = 35%; TMCL2, QD = 46%), or three (TMCH3, QD = 90%; TMCL3, QD = 78%) reductive methylation steps. The derivatives were tested and compared for their ability to enhance the permeability of ofloxacin across rabbit corneal epithelium, reconstituted in vitro. TMC polymers of intermediate QD (TMCH2 and TMCL2), at the concentration of 0.001% w/v, produced significant permeability enhancements, independent of polymer MW. The enhancing effect did not increase when QD was increased (TMCH3 and TMCL3), while it was not significant with low QD values (TMCH1 and TMCL1). Such an effect was specific of chitosan derivatives, because fully quaternized DEAE-dextran (MeDD) was ineffective. The transcorneal permeability-enhancing property of TMCH2 and TMCL2, and the inefficacy of MeDD were confirmed by in vivo tests on rabbit eyes. However, unlike the in vitro experiments, the in vivo ones showed a stronger effect of the TMC having higher MW. TMCH2 produced antibiotic levels in the aqueous humor higher than the MIC(90%) for the more resistant ocular pathogens. These results point to this derivative as a potential ofloxacin absorption enhancer for the topical treatment of endophthalmitis.

Animals↗

PubMed2004

Methyl-DEAE-dextran: a candidate biomaterial.

The full quaternisation of DEAE-dextran was successfully attempted and an application of the quaternised product was suggested. Commercial DEAE-dextran was reacted with iodomethane at 60 degrees C in the presence of NaOH. The raw product was purified by dialysis, during which the iodide ion was replaced by chloride. N-methylation and O-methylation resulted from the reaction. A second methylation step produced no further changes in the molecule. Alkalimetry indicated the absence of amino groups in the methylated polymer molecule, thus testifying to a complete quaternisation. N-acetylcysteine (AcCy) was neutralised with the polymer in the hydroxide form, thus obtaining the methyl DEAE-dextran salt of AcCy (Me-DEAE-dextran/AcCy), whereby an ophthalmic formulation for the treatment of the dry eye syndrome was prepared. For comparison, the neutral AcCy salt of commercial DEAE-dextran (DEAE-dextran/AcCy) was prepared. The AcCy content in Me-DEAE-dextran/AcCy was higher than in DEAE-dextran/AcCy (23 vs 13%), while the viscosity of a solution containing the salt concentration corresponding to the therapeutic AcCy concentration (4%w/v) was lower with the former compared to the latter salt (20.5 vs 23.9 mPa s). Both solutions were ipotonic (245 mOsm/kg), whereas the commercial Tirocular is strongly hypertonic (900 mOsm/kg) and irritant.

Acetylcysteine↗

PubMedDate not supplied

Preparation and in vitro evaluation of chitosan matrices for colonic controlled drug delivery.

PURPOSE: The work was aimed at studying in vitro the release of 5-aminosalicylic acid (5-ASA) or diclofenac sodium (DS) from matrices based on chitosan (Ch) or Ch hydrochloride (Ch-HCl), destined to be introduced into enteric-coated capsules for controlled release to the colon. METHODS: Matrices (diameter, 6 mm; weight, 50 mg) were prepared by compression of Ch or Ch-HCl microparticles mixed with 20 % 5-ASA or DS powder. Drug release from matrices to isotonic neutral buffers of different molarity was studied in vitro. In some cases, matrix incubation in rat cecal contents preceded the release test. RESULTS: The matrices, especially the Ch-HCl-based ones, swelled in the dissolution medium without disintegrating. Drug release was diffusion-controlled and followed square-root-time kinetics. Release depended on the pH-dependent aqueous solubility of the drug. The internal pH of the swollen Ch-HCl-based matrix was acidic, so 5-ASA solubility and release were influenced by penetration of salts from the external buffer. In the Ch-HCl-based matrix DS was converted into the scarcely soluble diclofenac free acid, which prolonged the time for release of 50 % dose excessively (t50 =11.26 h). The enzymatic action of rat cecal microflora accelerated drug release from the Ch-HCl-based matrix. On the other hand, neither such a microflora nor the external medium hydrodynamics significantly affected drug release from the Ch-based matrix. CONCLUSIONS: The Ch-based matrix was a reliable colonic controlled-release system for 5-ASA (t(50) =1.97 h) or DS (t(50) =3.58 h). For in vivo application, a number of matrices adequate to make up the therapeutic drug dose should be introduced into enteric-coated size 00 capsules.

Animals↗