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PubMed2006

Mechanical properties and antibacterial efficacy of chitosan films.

Chitin, chitosan and quaternary chitosan films were prepared, and the mechanical properties and the antibacterial activities of chitosan and quaternary chitosan films were evaluated. The tensile strength of chitin films was 30-40% lower than that of chitosan films, but the crystallinity of the former was much higher than those of the latter. A detailed analysis of the crystallinity and orientation of crystallites of chitosan films revealed that the cast film prepared with acetic acid provided a little lower crystallinity than the others. The antibacterial activities of quaternary chitosan films against Staphylococcus aureus and Escherichia coil were stronger than those of chitosan films. The antibacterial activities of neutralized chitosan films may be slightly inferior to those of un-neutralized chitosan films. The improvement in the antibacterial activity of chitosan films against E. coli was slightly inferior to that against S. aureus. This phenomenon was particularly observed on the neutralized chitosan films. Though the antibacterial activity of chitosan was slightly inferior to that of the organic antibacterial compounds, we emphasize that chitosan would be a useful and suitable material with regard to its effect on the environmental ecosystem.

Acetic Acid↗
PubMed2005

Chitosan oligomers as potential and safe absorption enhancers for improving the pulmonary absorption of interferon-alpha in rats.

Effects of chitosan oligomers on pulmonary absorption of interferon-alpha (IFN) were examined by means of an in vivo pulmonary absorption experiment. Chitosan oligomers used in this study were chitosan dimer, tetramer, hexamer, and water-soluble (WS) chitosan. A significant increase in serum IFN concentrations was observed after intratracheal administration of IFN with these oligomers. Of these chitosan oligomers, 0.5% w/v chitosan hexamer appeared to be more effective in enhancing the pulmonary absorption of IFN than other oligomers at the same concentration, and the AUC value of IFN with chitosan hexamer increased 2.6-fold as compared with the control. On the other hand, chitosan polymers, which have relatively high molecular weights (22-96 kDa), were not effective in enhancing the pulmonary absorption of IFN due to their low solubility in water. Additionally, the effect of different concentrations (0.1%-1% w/v) of chitosan hexamer on the pulmonary absorption of IFN was studied. Of these different concentrations of chitosan hexamers, the highest AUC value of IFN was obtained in the presence of 0.5% w/v chitosan hexamer. Furthermore, chitosan oligomers did not cause any membrane damage to the rat pulmonary tissues, as determined by leakage of protein and lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid. Therefore, these findings indicated that the use of chitosan oligomers would be a promising approach for improving of the pulmonary absorption of biologically active peptides including IFN.

Absorption↗
PubMed2006

Antibacterial effects of chitosan solution against Legionella pneumophila, Escherichia coli, and Staphylococcus aureus.

Chitosan has been shown to have antibacterial activities on the growth of a wide variety of bacteria. Chitosan solution has been sold commercially for use as an antibacterial agent. Chitosan solution contains not only chitosan but also organic acids as solvents and desalted Japan Sea Proper Water (dJSPW). We aimed to clarify whether chitosan solution has antibacterial activity against bacteria invading bath water, and then to explore the causative factor among these ingredients. The antibacterial activity of full-strength chitosan solution and of 10(2)- and 10(4)-fold chitosan solution diluted with purified water was studied against Legionella pneumophila serogroups 1 (L. pneumophila SG1) and 6 (L. pneumophila SG6), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus) for 7 days at 37 degrees C. To clarify the causative factor in the antibacterial activity against E. coli, the antibacterial activities of the full-strength and diluted chitosan solutions for 24 h were examined. L. pneumophila SG1 and SG6, and E. coli could not survive in the chitosan solution or in the 10(2)-fold dilute solution for over a day at 37 degrees C. The cells of S. aureus were found to have decreased more than 2.46 log cfu/ml after 1 day of incubation, not only in the chitosan solutions, but also in phosphate buffer solution as a control. No inhibitory effect of dJSPW on the growth of the bacteria was observed. The antibacterial activity of the chitosan solution was lower compared with those of the organic acids solutions, and it increased with decreasing pH value. We observed the antibacterial activity of chitosan solution against L. pneumophila SG1 and SG6, and E. coli, suggesting it may be due to the decreased pH value derived from organic acids rather than from chitosan itself or dJSPW.

Acids↗
PubMed2000

Platelet derived growth factor releasing chitosan sponge for periodontal bone regeneration.

With an aim of improving bone regeneration, chitosan sponge containing platelet-derived growth factor-BB (PDGF-BB) were developed. For fabrication of chitosan sponge, chitosan solution was freeze-dried, crosslinked and freeze-dried again. PDGF-BB was incorporated into the chitosan sponge by soaking chitosan sponge into the PDGF-BB solution. Release kinetics of PDGF-BB, cell attachment, proliferation capacity and bony regenerative potentials of PDGF-BB-loaded chitosan sponge were investigated. Prepared chitosan sponge retained porous structure with 100 microm pore diameter that was suitable for cellular migration and growth. Release rate of PDGF-BB could be controlled by varying initial loading content of PDGF-BB to obtain optimal therapeutic efficacy. PDGF-BB-loaded chitosan sponge induced significantly high cell attachment and proliferation level, which indicated good cellular adaptability. PDGF-BB-loaded chitosan sponge demonstrated marked increase in new bone formation and rapid calcification. Degradation of the chitosan sponge was proceeded at defect site and subsequently replaced with new bone. Histomorphometric analysis confirmed that PDGF-BB-loaded chitosan sponge significantly induced new bone formation. These results suggested that chitosan sponge and PDGF-BB-loaded chitosan sponge may be beneficial to enhance periodontal bone regeneration.

Animals↗
PubMed2005

Antibacterial activity of N-alkylated disaccharide chitosan derivatives.

Antibacterial activity of the water-soluble N-alkylated disaccharide chitosan derivatives against Escherichia coli and Staphylococcus aureus was investigated. It was found that the antibacterial activity of chitosan derivatives was affected by the degree of substitution (DS) with disaccharide and the kind of disaccharide present in the molecule. Regardless the kind of disaccharide linked to the chitosan molecule, a DS of 30-40%, in general, exhibited the most pronounced antibacterial activity against both test organisms. E. coli and S. aureus were most susceptible to cellobiose chitosan derivative DS 30-40% and maltose chitosan derivative DS 30-40%, respectively, among the various chitosan derivatives examined. Although the disaccharide chitosan derivatives showed less antibacterial activity than the native chitosan at pH 6.0, the derivatives exhibited a higher activity than native chitosan at pH 7.0. Antibacterial activity of the chitosan derivatives (DS 30-40%) against E. coli increased as the pH increased from 5.0 and reached a maximum around the pH of 7.0-7.5. The effect of pH on the antibacterial activity of chitosan derivatives against S. aureus was not as pronounced as that observed with E. coli. Population reduction of E. coli or S. aureus in nutrient broth increased markedly upon increasing the concentration of chitosan derivatives from 0 to 500 ppm. No marked increase in population reduction was noted with further increase in the concentration of chitosan derivatives even up to 2000 ppm.

Alkylation↗
PubMedDate not supplied

PEI-g-chitosan, a novel gene delivery system with transfection efficiency comparable to polyethylenimine in vitro and after liver administration in vivo.

Polyethylenimine-graft-chitosan (PEI-g-chitosan) was synthesized by performing cationic polymerization of aziridine in the presence of water-soluble oligo-chitosan (M(n) = 3400). The absolute molecular weight and chemistry of the PEI-g-chitosan obtained were characterized using GPC, 13C and 1H NMR, respectively. The results indicated that all the amines of chitosan were grafted with oligo-PEI, and the average length of the oligo-PEI side chains was determined by the feed molar ratio of aziridne/amine in chitosan. PEI-g-chitosan of M(n) = 7400 with a polydispersity index (PDI) of 1.50, and PEI side chains of M(n) = 206 was prepared for gene delivery. Gel electrophoresis showed that DNA migration was retarded completely at a N/P ratio of 2.5/1, indicating good DNA condensation capability of PEI-g-chitosan. The sizes and the zeta-potentials of the complexes of PEI-g-chitosan/DNA were characterized. The cytotoxicity of PEI-g-chiotsan was evaluated, and the results reflected that PEI-g-chitosan had a lower cytotoxicity than PEI (25 K). Gene transfection efficiency of PEI-g-chitosan in HepG2, HeLa, and primary hepatocytes cells and after administration in the common bile duct of rat liver was determined. Remarkably, PEI-g-chitosan showed a higher transfection efficiency than that of PEI (25 K) both in vitro and in vivo. The systematic distribution and the distribution in liver of the gene expression of the complexes of PEI-chitosan/DNA were determined as well.

Animals↗
PubMed2004

Uptake and cytotoxicity of chitosan molecules and nanoparticles: effects of molecular weight and degree of deacetylation.

PURPOSE: To evaluate the effects of molecular weight (Mw) and degree of deacetylation (DD) on the cellular uptake and in vitro cytotoxicity of chitosan molecules and nanoparticles. METHODS: Chemical depolymerization and reacetylation produced chitosans of Mw 213,000 to 10,000 and DD 88-46%, respectively. Chitosan was labeled with FITC and transformed into nanoparticles by ionotropic gelation. Uptake of chitosan by confluent A549 cells was quantified by fluorometry, and in vitro cytotoxicity was evaluated by the MTT and neutral red uptakeassays. RESULTS: Nanoparticle uptake was a saturable event for all chitosan samples, with the binding affinity and uptake capacity decreasing with decreasing polymer Mw and DD. Uptake fell by 26% when Mw was decreased from 213,000 to 10,000, and by 41% when DD was lowered from 88% to 46%; the uptake data correlated with the zeta potential of the nanoparticles. Uptake of chitosan molecules did not exhibit saturation kinetics and was less dependent on Mw and DD. Postuptake quenching with trypan blue indicated that the cell-associated chitosan nanoparticles were internalized, but not the cell-associated chitosan molecules. Chitosan molecules and nanoparticles exhibited comparable cytotoxicity, yielding similar IC50 and IC20 values when evaluated against the A549 cells. Cytotoxicity of both chitosan entities was attenuated by decreasing polymer DD but was less affected by a lowering in Mw. CONCLUSIONS: Transforming chitosan into nanoparticles modified the mechanism of cellular uptake but did not change the cytotoxicity of the polymer toward A549 cells. Chitosan DD had a greater influence than Mw on the uptake and cytotoxicity of chitosan nanoparticles because of its effect on the zeta potential of the nanoparticles.

Acetylation↗
PubMed2002

Cholesterol-lowering properties and safety of chitosan.

Chitosan (CAS 9012-76-4) is derived by alkaline deacetylation from chitin, an abundant polymeric product of natural biosynthesis especially in crustaceans. It is available in a primary, unorganised structure, but also in a microcrystalline form. As a dietary supplement, chitosan has been claimed to control obesity and to lower serum cholesterol. A variety of chitosan products have been freely available worldwide in health stores and pharmacies. This review summarises the current knowledge about cholesterol-lowering and safety properties of chitosan and focuses its possible application for the treatment of hypercholesterolaemia. Chitosan behaves as a polycationic(+) cellulose-like fibrillar biopolymer that forms films with negatively charged surfaces. It is not specifically hydrolysed by digestive enzymes in man, but limited digestion of chitosan due to bacterial flora and to the unspecific enzymes might occur. Negatively charged molecules in stomach attach strongly to the positive charged tertiary amino group (-NH3+) of chitosan. Therefore, chitosan reduces fat absorption from gastrointestinal tract by binding with anionic carboxyl groups of fatty and bile acids, and it interferes with emulsification of neutral lipids (i.e., cholesterol, other sterols) by binding them with hydrophobic bonds. In short-term animal studies the safety of chitosan has been good. There are only few studies with chitosan in humans. In man, dietary chitosan has been reported to reduce serum total cholesterol levels by 5.8-42.6% and low-density lipoprotein levels by 15.1-35.1%. In short-term trials up to 12 weeks, no clinically significant symptoms have been observed with chitosan compared to placebo. Mild and transitory nausea and constipation have been reported in 2.6-5.4% of subjects. Although chitosan has been clinically well tolerated, it cannot be recommended to people allergic to crustaceans.

Animals↗
PubMed2005

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization.

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl(2) was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and approximately 100-400 microm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50-280%. CaCl(2) concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in approximately 30 min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1 h) values.

Alginates↗
PubMed2005

Preparation of cross-linked chitosan microspheres by spray drying: effect of cross-linking agent on the properties of spray dried microspheres.

Chitosan microspheres cross-linked with three different cross-linking agents viz, tripolyphosphate (TPP), formaldehyde (FA) and gluteraldehyde (GA) have been prepared by spray drying technique. The influence of these cross-linking agents on the properties of spray dried chitosan microspheres was extensively investigated. The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between 4.1-4.7 microm and 95.12-99.17%, respectively. Surface morphology, % erosion, % water uptake and drug release properties of the spray dried chitosan microspheres was remarkably influenced by the type (chemical or ionic) and extent (1 or 2% w/w) of cross-linking agents. Spray dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity, % water uptake, % erosion and drug release rate at both the cross-linking extent (1 and 2% w/w) when compared to those cross-linked with FA and GA. The sphericity and surface smoothness of the spray dried chitosan microspheres was lost when the cross-linking extent was increased from 1 to 2% w/w. Release rate of the drug from spray dried chitosan microspheres decreased when the cross-linking extent was increased from 1 to 2% w/w. The physical state of the drug in chitosan-TPP, chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffraction (XRD) study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP, chitosan-FA and chitosan-GA matrices followed Fick's law of diffusion.

Acetaminophen↗
PubMed2006

Effect of manufacturing parameters on the characteristics of vitamin C encapsulated tripolyphosphate-chitosan microspheres prepared by spray-drying.

To prepare the sustained release vitamin C carriers, vitamin C was successfully encapsulated in tripolyphosphate (TPP) cross-linked chitosan (TPP-chitosan) microspheres by the spray-drying method at different manufacturing conditions. Manufacturing parameters (inlet temperature, liquid flow rate, chitosan concentration and volume of 1% w/v TPP solution) had a significant influence on the characteristics of thus prepared microspheres. The optimum spray-drying conditions such as inlet temperature, liquid flow rate and compressed air flow rate for the encapsulation of vitamin C in TPP-chitosan microspheres was found to be 170 degrees C, 2 ml min(-1) and 101 min(-1), respectively. The size and yield of the TPP-chitosan microspheres ranged from 3.9-7.3 microm and 54.5-67.5%, respectively. The encapsulation efficiency of TPP-chitosan microspheres ranged from 45.72-68.7% and it decreased with the increasing volume of 1% w/v TPP solution. At the same cross-linking extent, the encapsulation efficiency of TPP-chitosan microspheres increased when the concentration of chitosan was increased from 0.5-1% w/v. Effect of volume of 1% w/v TPP solution on the surface morphology of chitosan microspheres was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These studies revealed that chitosan solution (250 ml) cross-linked with 15 ml 1% w/v TPP solution produced more porous microspheres than that cross-linked with 5 and 10 ml TPP solution. The release rate of vitamin C from TPP-chitosan microspheres decreased when the concentration of chitosan was increased from 0.5-1.0% w/v. Vitamin C release rate was also modulated by varying the volume of 1% w/v TPP solution. The release rate of vitamin C from TPP-chitosan microspheres decreased with increasing volume (5-15 ml) of 1% w/v TPP solution.

Ascorbic Acid↗
PubMed2007

Implantable biodegradable sponges: effect of interpolymer complex formation of chitosan with gelatin on the release behavior of tramadol hydrochloride.

The effect of interpolymer complex formation between positively charged chitosan and negatively charged gelatin (Type B) on the release behavior of tramadol hydrochloride from biodegradable chitosan-gelatin sponges was studied. Mixed sponges were prepared by freeze-drying the cross-linked homogenous stable foams produced from chitosan and gelatin solutions where gelatin acts as a foam builder. Generation of stable foams was optimized where concentration, pH of gelatin solution, temperature, speed and duration of whipping process, and, chitosan-gelatin ratio drastically affect the properties and the stability of the produced foams. The prepared sponges were evaluated for their morphology, drug content, and microstructure using scanning electron microscopy, mechanical properties, uptake capacity, drug release profile, and their pharmacodynamic activity in terms of the analgesic effect after implantation in Wistar rats. It was revealed that whipping 7% (w/w) gelatin solution, of pH 5.5, for 15 min at 25 degrees C with a stirring speed of 1000 rpm was the optimum conditions for stable gelatin foam generation. Moreover, homogenous, uniform chitosan-gelatin foam with small air bubbles were produced by mixing 2.5% w/w chitosan solution with 7% w/w gelatin solution in 1:5 ratio. Indeed, polyionic complexation between chitosan and gelatin overcame the drawbacks of chitosan sponge mechanical properties where, pliable, soft, and compressible sponge with high fluid uptake capacity was produced at 25 degrees C and 65% relative humidity without any added plasticizer. Drug release studies showed a successful retardation of the incorporated drug where the t50% values of the dissolution profiles were 0.55, 3.03, and 4.73 hr for cross-linked gelatin, un-cross-linked chitosan-gelatin, and cross-linked chitosan-gelatin sponges, respectively. All the release experiments followed Higuchi's diffusion mechanism over 12 hr. The achieved drug prolongation was a result of a combined effect of both cross-linking and polyelectrolyte complexation between chitosan and gelatin. The analgesic activity of the implanted tramadol hydrochloride mixed chitosan-gelatin sponge showed reasonable analgesic effect that was maintained for more than 8 hr. Therefore, the use of chitosan and gelatin together appears to allow the formulator to manipulate both the drug release profiles and the mechanical properties of the sponge that could be effectively implanted.

Analgesics, Opioid↗
PubMed2005

Effect of chitosan salts and molecular weight on a nanoparticulate carrier for therapeutic protein.

The objective of this study was to investigate the potential of chitosan salts as a carrier in the preparation of protein-loaded nanoparticles. Glutamic and aspartic acids were used to prepare chitosan salts of 35, 100, and 800 KDa. Nanoparticles of chitosan base, chitosan glutamate, and chitosan aspartate were produced by ionotropic gelation with sodium tripolyphosphate (TPP). Bovine serum albumin (BSA) was applied as a model protein at loading concentrations ranging from 0.2 to 2 mg/mL. The size of the nanoparticles, as measured by photon correlation spectroscopy, was in the range of 195 to 3450 nm, depending on type and molecular weight of chitosan. Nanoparticles prepared with higher molecular weight chitosan showed larger sizes. The encapsulation was controlled by the competition of BSA in forming ionic cross-linking with chitosan and by the entrapment of BSA during the gelation process. Higher BSA encapsulation efficiency (EE) was obtained for nanoparticles prepared with chitosan salts compared to those prepared with the base. The higher EE was a result of a higher degree of ionization, causing more active sites to interact with BSA. In addition, a higher and faster release of BSA from the nanoparticles into pH 7.4 buffer medium was observed for nanoparticles of the chitosan salts than was observed for nanoparticles of the chitosan base. The higher and faster release was attributed to higher EE and lower entrapment of BSA within the matrix of the nanoparticle during the gelation process. The influence of molecular weight on the property of nanoparticles exhibited different effects. The difference was a result of different organic acids used to prepare nanoparticles leading to the difference in polymer conformation and viscosity of organic acid solution. Therefore, this study showed that the characteristics of chitosan nanoparticles loaded with a protein drug could be readily modulated by changing the salt form or the molecular weight of the chitosan carrier.

Animals↗
PubMed2004

In vitro characterization and delivery of chitosan-DNA microparticles into mammalian cells.

PURPOSE: Chitosan has a high potential for transferring DNA molecules into mammalian cells because of its cationic properties. In the present study, we have investigated DNA encapsulation efficiency and loading capacity of chitosan microparticles prepared in different conditions, as well as in vitro DNA release from microparticles, and transfection of different cell lines with chitosan-DNA microparticles, which may be employed in future in vivo studies. METHODS: Plasmid DNAs were amplified in Escherichia coli DH5alpha and isolated by the alkali SDS-lysis method. Chitosan-DNA microparticles were prepared by the coacervation method by using different concentrations of chitosan and plasmid DNAs. In vitro release experiments were performed in PBS at 37 degrees C and DNA release was monitored spectrophotometrically. Transfection efficiency of chitosan-DNA microparticles into mammalian cells was determined by measuring the beta-galactosidase activity in cell lysates. RESULTS: DNA encapsulation efficiency and loading capacity of microparticles was altered depending on the chitosan and DNA concentrations. Approximately 75-85% of DNA was encapsulated into the chitosan-DNA microparticles. The average size of microparticles was found to be approximately 2 microm. In vitro studies revealed that the release of DNA from chitosan microparticles could be controlled by changing the formulation conditions. Although the transfection efficiency of chitosan-DNA microparticles was typically lower than that of DNA complexed with lipid-based reagents, in vitro transfection results indicated that HEK293 cells take up chitosan-DNA microparticles more efficiently compared to HeLa and mouse fibroblastic 3T3 cell lines. CONCLUSION: Chitosan microparticles provide a sustained release of plasmid DNA for a long period and they have a potential for DNA transfer into the mammalian cells. However, transfection efficiency of chitosan-DNA microparticles is low and dependent on the cell type.

Animals↗
PubMed1999

[Study on chitosan-Zn (II) complex by IR spectroscopy].

A series of chitosan-Zn (II) complexes were synthesized by reaction of chitosan and ZnSO4 in different ratios(chitosan : Zn (II) = 1 : 0.05-1 : 1) in dilute formic acid aqueous solution. The results showed that -NH2, -OH and -NHCO- of chitosan molecule were coordinated to Zn (II) based on the analyse of the IR spectra of chitosan, chitosan-H2SO4 and chitosan-ZnSO4. SO4(2-) of chitosan-ZnSO4 may be crosslinking of chitosan molecule, but Cl-, CH3COO- and NO3- were not crosslinked to chitosan molecule in the chitosan-ZnCl2, chitosan-Zn (CH3COO)2 and chitosan-Zn (NO3)2 complexes.

Chitosan↗
PubMed1989

Buoyant sustained release granules based on chitosan.

Attempts to develop sustained release intragastric 'floating' granules based on chitosan are described, using chitosan of different degrees of deacetylation (chitosan H and L), in granular form or in laminated preparations. The granules were made from chitosan H (chitosan H granules), from a 1:1 mixture of chitosan H and L (1:1 mixture granules), from a 1:2 mixture of chitosan H and L (1:2 mixture granules), or from chitosan L (chitosan L granules). They were prepared by a method involving deacidification, had internal cavities, were immediately buoyant in both acidic and neutral fluids, and gave sustained release of prednisolone (used as a model drug). The laminated preparations, composed of a chitosan granule layer and a chitosan L membrane, were also immediately buoyant in the same fluids, and also provided sustained release of the model drug. The release properties were controlled by regulating the chitosan L content of the granules, or the chitosan L membrane thickness of the laminate. In an absorption study using beagle dogs, sustained drug absorption from these preparations was obtained.

Animals↗
PubMed2005

Thiolated chitosan microparticles: a vehicle for nasal peptide drug delivery.

The goal of this study was to develop a microparticulate delivery system based on a thiolated chitosan conjugate for the nasal application of peptides. Insulin was used as model peptide. For thiolation of chitosan 2-iminothiolane was covalently linked to chitosan. The resulting chitosan-TBA (chitosan-4-thiobutylamidine) conjugate featured 304.89+/-63.45 micromol thiol groups per gram polymer. 6.5% of these thiol groups were oxidised. A mixture of the chitosan-TBA conjugate, insulin and the permeation mediator reduced glutathione were formulated to microparticles. Control microparticles comprised unmodified chitosan and insulin. As second control served mannitol-insulin microparticles. All microparticulate systems were prepared via the emulsification solvent evaporation technique. In 100 mM phosphate buffer pH 6.8 chitosan-TBA-insulin microparticles swelled 4.39+/-0.52-fold in size, whereas chitosan based microparticles did not swell at all. Chitosan-TBA microparticles showed a controlled release of fluorescein isothiocyanate (FITC)-labelled insulin over 6 h. Nasal administered chitosan-TBA-insulin microparticles led to an absolute bioavailability of 7.24+/-0.76% (means+/-S.D.; n=3) in conscious rats. In contrast, chitosan-insulin microparticles and mannitol-insulin microparticles exhibited an absolute bioavailability of 2.04+/-1.33% and 1.04+/-0.27%, respectively (means+/-S.D.; n=4). Because of these results microparticles comprising chitosan-TBA and reduced glutathione seem to represent a useful formulation for the nasal administration of peptides.

Administration, Intranasal↗
PubMed2003

Controlled release of fibroblast growth factors and heparin from photocrosslinked chitosan hydrogels and subsequent effect on in vivo vascularization.

Application of ultraviolet (UV) irradiation to a photocrosslinkable chitosan (Az-CH-LA) aqueous solution resulted within 10 s in an insoluble, flexible hydrogel. A low molecular weight acidic molecule like trypan blue and various high molecular weight molecules such as bovine serum albumin (BSA), heparin and protamine were all retained within the hydrogel, while a low molecular weight basic molecule like toluidine blue was rapidly released from the hydrogel. In the present work, we examined the retaining capability of the chitosan hydrogel for growth factors and controlled release of growth factors from the chitosan hydrogel in vitro and in vivo. Fibroblast growth factor-1 (FGF-1), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor(165) (VEGF(165)), heparin-binding epidermal growth factor (HB-EGF) in phosphate buffered saline (PBS) were mixed with Az-CH-LA aqueous solution to form growth factor-incorporated chitosan hydrogels. About 10-25% of the growth factor was released from a growth factor-incorporated chitosan hydrogel into PBS within the first day, after which no further substantial release took place. The growth factors interacted with Az-CH-LA molecules poly-ion complexation, and probably were unable to be released after the first day under the in vitro nondegradation conditions of the hydrogel. Although the FGF-1, FGF-2, and VEGF(165)-incorporated chitosan hydrogels on a culture plate significantly stimulated HUVEC growth, the stimulating activity of the growth factor-incorporated chitosan hydrogel was completely cancelled out by washing the hydrogel with PBS solution for 3 days or more. The stimulating activity on the HUVEC growth were however highly recovered by treating the washed growth factor-incorporated chitosan hydrogel during 7 days with chitinase and chitosanase to partly degrade the hydrogel, strongly suggesting that the growth factors within the hydrogel retained their biologically active forms. The chitosan hydrogel (100 microl) when implanted into the back of a mouse was biodegraded in about 10-14 days. When FGF-1- and FGF-2-incorporated chitosan hydrogels were subcutaneously implanted into the back of a mouse, significant neovascularization was induced near the implanted site of the FGF-1- and FGF-2-incorporated chitosan hydrogels. Furthermore, addition of heparin with either FGF-1 or FGF-2 into the hydrogel resulted in a significantly enhanced and prolonged vascularization effect. These results indicate that the controlled release of biologically active FGF-1 and FGF-2 with heparin is caused by biodegradation of the chitosan hydrogel, and subsequent induction of vascularization.

Animals↗