Chitosan and a modified chitosan as agents to improve performances of mucoadhesive vaginal gels

New mucoadhesive formulations were designed and studied in order to improve local vaginal therapy by increasing formulation retention prolonging thus drug-mucosa contact time. Some gels were prepared using hydroxyethylcellulose (HEC) alone or mixed with chitosan (CS) or its derivative 5-methyl-pyrrolidinone-chitosan (MPCS) and were loaded with the antibacterial metronidazole (MET) (0.75%). All formulations showed pseudoplastic flow and viscosity increase was observed proportionally to chitosan content (CS>MPCS). Prepared gels showed better extrusion properties (yield stress) than market formulation Zidoval. Mucoadhesion force studies permitted to point out that: (i) CS decreases mucoadhesion force; (ii) MPCS addition increases the mucoadhesion force at high percentage; (iii) all gels containing chitosan showed better mucoadhesive performances than Zidoval. Gels containing MPCS showed higher and faster drug release than those containing CS. All the preparations were able to release higher drug amounts if compared to market formulation. In conclusion MPCS improved gel characteristics in terms of mucoadhesion force, rheological behaviour and drug release pointing out that this modified chitosan is very suitable to obtain manageable and more acceptable vaginal formulation.     

Novel nanoparticles composed of chitosan and β-cyclodextrin derivatives as potential insoluble drug carrier

This research was aim to develop novel cyclodextrin/chitosan(CD/CS) nanocarriers for insoluble drug delivery through the mild ionic gelation method previously developed by our lab. A series of different bcyclodextrin(β-CD) derivatives were incorporated into CS nanoparticles including hydroxypropyl-bcyclodextrin(HP-β-CD), sulphobutylether-β-cyclodextrin(SB-β-CD), and 2,6-di-O-methy-β-cyclodextrin(DM-β-CD). Various process parameters for nanoparticle preparation and their effects on physicochemical properties of CD/CS nanoparticles were investigated, such as the type of CD derivatives,CD and CS concentrations, the mass ratio of CS to TPP(CS/TPP), and p H values. In the optimal condition,CD/CS nanoparticles were obtained in the size range of 215–276 nm and with the zeta potential from30.22 m V to 35.79 m V. Moreover, the stability study showed that the incorporation of CD rendered the CD/CS nanocarriers more stable than CS nanoparticles in PBS buffer at p H 6.8. For their easy preparation and adjustable parameters in nanoparticle formation as well as the diversified hydrophobic core of CD derivatives, the novel CD/CS nanoparticles developed herein might represent an interesting and versatile drug delivery platform for a variety of poorly water-soluble drugs with different physicochemical properties.     

壳聚糖纳米粒子荧光探针的制备和表征

通过低分子量的壳聚糖(LCS)聚阳离子与三聚磷酸钠(TPP)的静电作用制备纳米级壳聚糖微球,并利用壳聚糖链上丰富的氨基与荧光素异硫氰酸酯(FITC)反应从而制备纳米壳聚糖微球荧光探针(NFCS)。结果表明,当壳聚糖分子量为60000,LCS与TPP的质量比为6∶1时,可得到粒度均一的球形纳米粒子,平均粒径为40±3 nm。荧光倒置显微镜观察证实FITC结合到壳聚糖微球上。荧光光谱分析显示NFCS的最大激发波长、最大发射波长与游离态FITC无显著差异。光漂白实验证实NFCS的稳定性比游离态FITC有显著提高。     

Preparation and characterization of nanoparticles formed by chitosan-caseinate interactions

Intermacromolecular complexation between chitosan and sodium caseinate in aqueous solutions was studied as a function of pH (3–6.5), using absorbance measurements (at 600 nm), dynamic light scattering (DLS), and transmission electron microscopy (TEM). The chitosan–caseinate complexes formed were stable and soluble in the pH range 4.8–6.0. In this pH range, the biopolymers had opposite charges. At higher concentrations of chitosan (0.15 wt%), the soluble complexes associated to form larger particles. DLS data showed that, between pH 4.8 and 6.0, the particles formed by the complexation of chitosan and caseinate had sizes between 250 and 350 nm and these nanoparticles were visualized using negative staining TEM. Above pH 6.0, the nanoparticles associated to form larger particles, causing phase separation. Addition of NaCl increased the particle size. The pH dependence of the zeta potential of the mixture solutions was appreciably different from that of the pure protein and pure chitosan solutions.     

Preparation, characterization of hydrophilic and hydrophobic drug in combine loaded chitosan/cyclodextrin nanoparticles and in vitro release study

The compound nanoparticles of chitosan (CS) and cyclodextrin (CD) loading with hydrophilic and hydrophobic drug simultaneously were prepared via the cross-linking method. Methotrexate (MTX) and calcium folinate (CaF) were selected as the model drugs. The prepared nanoparticles were characterized by FT-IR spectroscopy to confirm the cross-linking reaction between CS and cross-linking agent. X-ray diffraction (XRD) was performed to reveal the form of the drug after encapsulation. The average size of nanoparticles ranged from 308.4 ± 15.22 to 369.3 ± 30.01 nm. The nanoparticles formed were spherical in shape with high zeta potentials (higher than +30mV). In vitro release studies in phosphate buffer saline (pH 7.4) showed an initial burst effect and followed by a slow drug release. Cumulative release data were fitted to an empirical equation to compute diffusional exponent (n), which indicated the non-Fickian trend for drug release.     

Preparation and properties of ionically cross‐linked chitosan nanoparticles

Chitosan nanoparticles were fabricated by a method of tripolyphosphate (TPP) cross‐linking. The influence of fabrication conditions on the physical properties and drug loading and release properties was investigated by transmission electron microscopy (TEM), dynamic light scattering (DLS), and UV–vis spectroscopy. The nanoparticles could be prepared only within a zone of appropriate chitosan and TPP concentrations. The particle size and surface zeta potential can be manipulated by variation of the fabrication conditions such as chitosan/TPP ratio and concentration, solution pH and salt addition. TEM observation revealed a core–shell structure for the as‐prepared nanoparticles, but a filled structure for the ciprofloxacin (CH) loaded particles. Results show that the chitosan nanoparticles were rather stable and no cytotoxicity of the chitosan nanoparticles was found in an in vitro cell culture experiment. Loading and release of CH can be modulated by the environmental factors such as solution pH and medium quality. Copyright © 2008 John Wiley & Sons, Ltd.     

Preparation and characterization of metronidazole‐loaded chitosan nanoparticles for drug delivery application

This study describes the preparation of mucoadhesive chitosan nanoparticles containing metronidazole (MZ) intended for colon‐specific delivery. The chitosan nanoparticles were prepared by the ionic gelation method and their in vitro properties were studied. The release profiles of MZ from the nanoparticles were determined by UV–Vis absorption measurement at λ_max 278 nm. Scanning electron microscopy was used for morphology observation. The nanoparticles exhibited mucoadhesive properties, which diminished with increasing drug content. The nanoparticles with a particle size range between 200 and 300 nm exhibited excellent mucoadhesive properties. The results show that the formulated nanoparticles have succeeded in controlling the release of MZ over a 12‐hr period. In conclusion, the release of MZ was found to be dependent upon the composition of the nanoparticles, the ratio of the components and possible particle size, as well as bioadhesive ability. Copyright © 2008 John Wiley & Sons, Ltd.     

Self-aggregated nanoparticles of cholesterol-modified glycol chitosan conjugate: Preparation, characterization, and preliminary assessment as a new drug delivery carrier

Cholesterol-modified glycol chitosan (CHGC) conjugate was synthesized and characterized by FTIR and ¹H NMR. The degree of substitution (DS) was 6.7 cholesterol groups per 100 sugar residues of glycol chitosan. CHGC formed self-aggregated nanoparticles with a roughly spherical shape and a mean diameter of 228 nm by probe sonication in aqueous medium. The physicochemical properties of the self-aggregated nanoparticles were studied using dynamic light scattering (DLS), transmission electron microscopy (TEM) and fluorescence spectroscopy. The critical aggregation concentration (CAC) of self-aggregated nanoparticles in aqueous solution was 0.1223 mg/mL. Indomethacin (IND), as a model drug, was physically entrapped into the CHGC nanoparticles by dialysis method. The characteristics of IND-loaded CHGC (IND-CHGC) nanoparticles was analyzed using DLS, TEM and high performance liquid chromatography (HPLC). The IND-CHGC nanoparticles were almost spherical in shape and their size increased from 275 to 384 nm with the IND-loading content increasing from 7.14% to 16.2%. The in vitro release behavior of IND from CHGC nanoparticles was studied by a dialysis method in phosphate buffered saline (PBS, pH 7.4). IND was released in a biphasic way. The initial rapid release in 2 h and slower release for up to 12 h were observed. The results indicated that CHGC nanoparticles had a potential as a drug delivery carrier.     

Nanoparticles from Chitosan

Novel biodegradable nanoparticles were synthesized by chemical modification of the chitosan linear chain. A natural dicarboxylic acid (malic acid) was used as a crosslinking agent for intramolecular covalent condensation reaction to obtain hydrophilic nanoparticles based on chitosan. A variety of methods including, solubility studies, laser light scattering (DLS), transmission electron microscopy (TEM) and nuclear magnetic resonance (NMR) was used to characterize the crosslinked macromolecules. The prepared biodegradable chitosan nanoparticles, soluble in aqueous media, might be useful for various biomedical applications, like injectable drug- or gene-delivery systems.     

Preparation and Characterization of a Novel Drug Delivery System: Biodegradable Nanoparticles in Thermosensitive Chitosan/Gelatin Blend Hydrogels

A novel injectable in situ gelling drug delivery system (DDS) consisting of biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanoparticles and thermosensitive chitosan/gelatin blend hydrogels was developed for prolonged and sustained controlled drug release. Four different HTCC nanoparticles, prepared based on ionic process of HTCC and oppositely charged molecules such as sodium tripolyphosphate, sodium alginate and carboxymethyl chitosan, were incorporated physically into thermosensitive chitosan/gelatin blend solutions to form the novel DDSs. Resulting DDSs interior morphology was evaluated by scanning electron microscopy. The effect of nanoparticles composition on both the gel process and the gel strength was investigated from which possible hydrogel formation mechanisms were inferred. Finally, bovine serum albumin (BSA), used as a model protein drug, was loaded into four different HTCC nanoparticles to examine and compare the effects of controlled release of these novel DDSs. The results showed that BSA could be sustained and released from these novel DDSs and the release rate was affected by the properties of nanoparticle: the slower BSA release rate was observed from DDS containing nanoparticles with a positive charge than with a negative charge. The described injectable drug delivery systems might have great potential application for local and sustained delivery of protein drugs.     

Synthesis of chitosan‐based thermo‐ and pH‐responsive porous nanoparticles by temperature‐dependent self‐assembly method and their application in drug release

In this research, thermo‐ and pH‐responsive chitosan‐based porous nanoparticles were prepared by the temperature‐dependent self assembly method. The chitosan‐graft‐poly(N‐isopropylacrylamide) (CS‐g‐PNIPAAm) copolymer solution was prepared through polymerization of N‐isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using cerium ammounium nitrate as the initiator. Then, CS‐g‐PNIPAAm solution was diluted by deionized water and heated to 40 °C for CS‐g‐PNIPAAm self‐assembly. After that, CS‐g‐PNIPAAm assembled to form micelles in which shell layer was CS. Crosslinking agent was used to reinforce the micelle structure to form nanoparticle. The molar ratio of CS/NIPAAm in the feed mixture was changed to investigate its effect on structure, morphology, thermal‐ and pH‐responsive properties of the nanoparticles. TEM images showed that a porous structure of nanoparticles was developed. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in‐vitro release experiment. These porous particles with environmentally sensitive properties are expected to be utilized in hydrophilic drug delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5126–5136, 2009     

Effects of surface modifications on the physicochemical properties of iron oxide nanoparticles and their performance as anticancer drug carriers

Surface of iron oxide nanoparticles were modified with citric acid (CA), chitosan (CS) and folic acid conjugated chitosan (FA-g-CS), respectively. Their physicochemical properties, doxorubicin loading capacity, drug release patterns and in vitro cytotoxicity were comparatively studied.     

Chitosan‐Capped Mesoporous Silica Nanoparticles as pH‐Responsive Nanocarriers for Controlled Drug Release

Herein, we present a straightforward synthesis of pH‐responsive chitosan‐capped mesoporous silica nanoparticles (MSNs). These MCM‐41‐type MSNs could be used as nanocapsules to accommodate guest molecules. Subsequently, (3‐glycidyloxypropyl)trimethoxysilane was grafted onto the surface of the MSNs, which served as a bridge to link between MSNs and chitosan, which is ubiquitous in nature and commercially available. Owing to the pH‐responsive and biocompatible features of chitosan, the loading and release of an anti‐cancer drug, doxorubicin hydrochloride, were carried out in vitro, in which the composite chitosan‐capped MSNs (CS‐MSNs) showed excellent environmental response. As the pH value of the media decreased, the degree of drug release correspondingly increased. Moreover, thanks to the perfect biocompatibility of chitosan, the CS‐MSNs exhibited lower cytotoxicity than that of the naked MSNs in an MTT assay. In addition, the in vitro kill potency against MCF‐7 breast‐cancer cells was enhanced over time, as well as with increasing concentration of the drug‐loaded CS‐MSNs. These results indicate that CS‐MSNs are promising candidates for pH‐responsive drug delivery in cancer therapy.     

Synthesis of poly(methyl methacrylate) core/chitosan-mixed-polyethyleneimine shell nanoparticles and their antibacterial property

The core–shell nanoparticles possessing poly(methyl methacrylate) (PMMA) core coated with chitosan (CS), polyethyleneimine (PEI), and chitosan-mixed-polyethyleneimine (CS/PEI) shells were synthesized in this work. The emulsifier-free emulsion polymerization triggered by a redox initiating system from t-butylhydroperoxide (TBHP) and amine groups on CS and/or PEI was used as a synthetic method. In the CS/PEI systems, the amount of CS was kept constant (0.5 g), while the amount of PEI was varied from 0.1 to 0.5 g. The surface and physico-chemical properties of prepared nanoparticles were then examined. FTIR spectra indicated the presence of grafted PMMA on CS and/or PEI, and the weight fraction of incorporated PEI in the CS/PEI nanoparticles. All nanoparticles were spherical in shape with uniform size distribution illustrated by scanning electron microscopy (SEM). The introduction of PEI to CS nanoparticles yielded the higher monomer conversion, grafting efficiency, and grafting percentage compared with the CS nanoparticles. The size of CS/PEI nanoparticles was smaller than the original CS and PEI nanoparticles, and tended to decrease with increasing amount of PEI introduced. The introduction of PEI also brought the higher colloidal stability to the nanoparticles as indicated by zeta-potential measurement and isoelectric point analysis. The nanoparticles exhibited a promising antibacterial activity against Staphylococcus aureus and Escherichia coli. The nanoparticle–bacteria interaction was studied via SEM. The results suggested that they would be useful as effective antibacterial agents.     

Physical and chemical characterization insulin-loaded chitosan-TPP nanoparticles

The purpose of this study was to develop and characterize insulin nanoparticles systems using chitosan. Insulin-loaded nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP). The interactions between insulin and chitosan were evaluated by differential scanning calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG), and Fourier-transform infrared (FTIR) spectroscopy. Besides, particle size distribution, polydispersity index (PDI), zeta potential, and association efficiency (AE%) of the nanoparticles were evaluated. In general, inert nanoparticles and insulin-loaded nanoparticles showed an average size of 260.56 nm (PDI 0.502) and 312.80 nm (PDI 0.481), respectively. Both nanoparticles showed positive charge, but after insulin incorporation the zeta potential was reduced, evidencing its incorporation. Nanoparticles obtained also showed AE% around 70%, measured by high-performance liquid chromatography (HPLC). The results of FTIR, DSC, and TG/DTG corroborated the data presented suggesting that insulin was successfully encapsulated. However, drug incorporation seems to be related not only to electrostatic interactions, but also to physical process and/or adsorption phenomena.     

Synthesis and characterization of stimuli‐responsive porous/hollow nanoparticles by self‐assembly of chitosan‐based graft copolymers and application in drug release

In this research, stimuli‐responsive porous/hollow nanoparticles were prepared by the self‐assembly method. First, chitosan‐graft‐poly(N‐isopropylacrylamide) (CS‐g‐PNIPAAm) copolymers were synthesized through polymerization of N‐isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using ceric ammounium nitrate as the initiator. Then, the CS‐g‐PNIPAAm copolymers were dissolved in the acetic acid aqueous solution and heated to 40 °C to induce their self‐assembly. After CS‐g‐PNIPAAm assembled to form micelles, a cross‐linking agent was used to reinforce the structure to form nanoparticles. The molecular weight of grafted PNIPAAm on CS chains was changed to investigate its effect on the structure, morphology, thermo‐, and pH‐responsive properties of the nanoparticles. TEM images showed that a porous or hollow structure in the interior of nanoparticles was developed, depending on the medium temperature. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing the pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in vitro release experiment. These porous/hollow particles with environmentally sensitive properties are expected to be used in hydrophilic drug delivery system. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2377–2387, 2010     

Development of Thiolated Chitosan Nanoparticles Based Mucoadhesive Vaginal Drug Delivery Systems

The aim of the present study was to evaluate the influence of the chitosan chain length on the drug loading and releasing in VFS (vaginal fluid simulant). Thiolated chitosan nanoparticles (TCS-NPs) were prepared using thioglycolic acid and 1-ethyl-3-3-(3-dimethylaminopropyl)carbodimide hydrochloride (EDC) and characterized with FTIR. The degree of thiol substitution was found out by Ellman’s method. TCS-NPs were developed using ionic cross-linking reaction with pentasodiumtripolyphosphate (TPP). Curcumin (CUR) loaded nanoparticles were obtained by encapsulation. DLS and SEM characterized these NPs with diameter between 200 ± 50 nm. Zeta potential of NPs was 11–38 mv. The maximal encapsulation efficiency was 86.26%. The in vitro drug release studies in VFA at pH 4.2 showed a sustained release profile over a period of 3 days.     

Influence of cetyltrimethylammonium bromide on physicochemical properties and microstructures of chitosan-TPP nanoparticles in aqueous solutions

The nanoparticles of chitosan (CS) were prepared using pentasodium triphosphate (TPP) as a crosslinking agent and the influences of cetyltrimethylammonium bromide (CTAB) on the physicochemical properties of the CS-TPP nanoparticles were first studied by laser light scattering, zeta potential, and transmission electron microscopy (TEM). The concentration played a significant role in controlling the particle size of CS and the overlap concentration c(*) was testified to be about 1.0 mg/mL. The combination of static light scattering (SLS) and dynamic light scattering (DLS) allowed us to obtain more information about the CS-TPP nanoparticles in the presence of surfactant molecules. The addition of CTAB could reduce the hydrodynamic diameter of nanoparticles effectively in the salt solutions and simultaneously increase the zeta potential of the nanoparticles. The effect of CTAB concentration on the size of CS-TPP nanoparticle was also examined. The critical micelle concentration (CMC) of CTAB was used to interpret the complicated complex formed by the polyelectrolyte and the surfactant. Finally, TEM was used to observe the CS-TPP nanoparticles, which were affected by CTAB, to verify the results obtained by light scattering.     

Synthesis and properties of chitosan‐based thermo‐ and pH‐responsive nanoparticles and application in drug release

In this research, thermo‐ and pH‐responsive nanoparticles with an average diameter of about 50–200 nm were synthesized via the surfactant‐free emulsion polymerization. The thermal/pH dual responsive properties of these nanoparticles were designed by the addition of a pH sensitive monomer, acrylic acid (AA), to be copolymerized with N‐isopropylacrylamide (NIPAAm) in a chitosan (CS) solution. The molar ratio of CS/AA/NIPAAm in the feed was changed to investigate its effect on structure, morphology, thermal‐ and pH‐responsive properties of the nanoparticles. It was found that CS‐PAA‐PNIPAAm nanoparticles could be well dispersed in the aqueous solution and carried positive charges on the surface. The addition of thermal‐sensitive NIPAAm monomer affected the polymerization mechanism and interactions between CS and AA. The particle size of the nanoparticles was found to be varied with the composition of NIPAAm monomer in the feed. The synthesized nanoparticles exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in vitro release experiment. The environmentally responsive nanoparticles are expected to be used in many fields such as drug delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2798–2810, 2009     

Radiation Synthesis of Superabsorbent Hydrogels Based on Chitosan and Acrylic Acid for Controlled Drug Release

Superabsorbent hydrogels based on the natural polymer chitosan and acrylic acid (CS/AAc) was prepared using ⁶⁰Co gamma radiation as a source of initiation and crosslinking. The factors, which affect the preparation of CS/AAc hydrogels such as irradiation dose, CS/AAc ratios, and acrylic acid monomer concentrations, to get the best optimum conditions, were investigated. The kinetic studies of the swelling of CS/AAc hydrogel showed that it follows a Fickian type of water diffusion. The Fickian constant value ‘n’ was more than 0.5 with a high swelling capacity of 300 g/g as superabsorbent hydrogel. In addition, the suitability of CS/AAc hydrogel as carrier material for the drug Chlortetracycline-HCl has been investigated by adsorption isotherm studies. The performance of drug release from hydrogel systems, influenced by acrylic acid ratio and the effect of pH of the medium was studied.