Thermosensitive hydrogels for nasal drug delivery: The formulation and characterisation of systems based on N-trimethyl chitosan chloride

Towards the development of a thermosensitive drug-delivery vehicle for nasal delivery, a systematic series of N-trimethyl chitosan chloride polymers, synthesised from chitosans of three different average molecular weights, have been co-formulated into a hydrogel with poly(ethylene glycol) and glycerophosphate. Rheological evaluations have shown that hydrogels derived from N-trimethyl chitosan with a low degree of quaternisation and high or medium average molecular weight exhibit relatively short sol-gel transition times at physiologically relevant temperatures. Also, the same hydrogels display good water-holding capacity and strong mucoadhesive potential, and their mixtures with mucus exhibit rheological synergy. An aqueous hydrogel formulation, derived from N-trimethyl chitosan of medium average molecular weight and low degree of quaternisation, appears particularly promising in that it exhibits most favourable rheological and mucoadhesive behaviour and a sol-gel transition that occurs at 32.5 °C within 7 min.     

Polyacrylamide-chitosan hydrogels: in vitro biocompatibility and sustained antibiotic release studies

Controlled drug delivery is gaining importance over the conventional methods of drug administration because of its inherent benefits. Self-regulated release from the delivery vehicle may enhance drug potency with a sustained action. The present study describes a novel hydrogel blend of polyacrylamide with chitosan for controlled delivery of antibiotics. Hydrogel was synthesized by cross-linking acrylamide-chitosan mixture (8:2 v/v) with N,N' methylene bisacrylamide. Hydrogel was characterized for surface morphology, hydrophilicity, pH-dependent swelling properties, cytotoxicity, and control release properties. Scanning electron microscopy (SEM) revealed the macroporous surface morphology of the matrix with average pore size at 104n plus/minus 7.61 mu. Hydrogel was found to be highly hydrophilic as assessed by octane contact angle (154.5 + 0.572) measurement. Hydrogel showed no cytotoxic effects on NIH3T3 and HeLa cells up to 40% of extract concentrations as determined by MTT and neutral red assay. This showed hydrogel biocompatibility and thus absence of deleterious effects of the hydrogel on cell viability and functionality. Hydrogels did not show any pH-dependent swelling profile, and they swelled considerably to achieve a swelling ratio of approximately 16.0 at the end of 24 hr. Amoxicillin was incorporated in the hydrogel matrix as a candidate antibiotic for release studies. In vitro release studies of amoxicillin revealed the sustained nature of delivery and matrix released 56.47 + 1.12% and 77.096 + 1.72% of amoxicillin at the end of 24 and 75 hr, respectively. Although in vivo studies are awaited, the present study provides enough documentation to consider polyacrylamidechiotsan hydrogel as a possible candidate for controlled delivery of antibiotics.     

Novel nanostructured supramolecular hydrogels for the topical delivery of anionic drugs

A bis-imidazolium-based amphiphilic molecule was used to form novel supramolecular gels in ethanol–water mixtures. The proportion of solvents, the concentration of gellant and the temperature are factors that strongly influence the gelling process. The physical gels that are formed comprise entangled fibers of around 100 nm in diameter, able to incorporate anionic drugs, whose morphology varies depending on the drug they incorporate. These hydrogels are soft and therefore optimum for skin application. They show good stability when compared to previously reported gels. Suitable drug release and skin permeation profiles were obtained, and, moreover, they seem to promote the retention of the drug inside the skin. Finally, effective in vivo anti-inflammatory activity was observed, especially with the indomethacin-incorporated gel, which indicates that these supramolecular hydrogels are a good option for the delivery of poor water soluble drugs for the treatment of acute inflammation or other skin diseases.     

Controlled local drug delivery strategies from chitosan hydrogels for wound healing

Introduction: The main target of tissue engineering is the preparation and application of adequate materials for the design and production of scaffolds, that possess properties promoting cell adhesion, proliferation and differentiation. The use of natural polysaccharides, such as chitosan, to prepare hydrogels for wound healing and controlled drug delivery is a research topic of wide and increasing interest.

Areas covered: This review presents the latest results and challenges in the preparation of chitosan and chitosan-based scaffold/hydrogel for wound healing applications. A detailed overview of their behavior in terms of controlled drug delivery, divided by drug categories, and efficacy was provided and critically discussed.

Expert opinion: The need to establish and exploit the advantages of natural biomaterials in combination with active compounds is playing a pivotal role in the regenerative medicine fields. The challenges posed by the many variables affecting tissue repair and regeneration need to be standardized and adhere to recognized guidelines to improve the quality of evidence in the wound healing process. Currently, different methodologies are followed to prepare innovative scaffold formulations and structures. Innovative technologies such as 3D printing or bio-electrospray are promising to create chitosan-based scaffolds with finely controlled structures with customizable shape porosity and thickness. Chitosan scaffolds could be designed in combination with a variety of polysaccharides or active compounds with selected and reproducible spacial distribution, providing active wound dressing with highly tunable controlled drug delivery.     

Nasal delivery of insulin using bioadhesive chitosan gels

Recently nasal delivery of insulin has gained considerable attention. Some limitations of this route include rapid mucociliary clearance of the drug from the site of deposition resulting in short time span available for absorption and low permeability of the nasal membrane for peptides. The objective of the present study was development of a chitosan bioadhesive gel for nasal delivery of insulin. A nasal perfusion test was used to study the toxicity of 4 absorption enhancers: saponin, sodium deoxycholate, ethylendiamine tetra-Acetic Acid (EDTA) and lecithin. The gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. Drug release was studied by a membraneless diffusion method and bioadhesion by a modified tensiometry test. The optimized gel was administered nasally in diabetic rats. The serum insulin levels were analyzed by an insulin enzyme immunoassay kit and serum glucose by glucose oxidase method kits. Formulations containing 2% of low molecular weight of chitosan with EDTA had higher release percentage and dissolution efficiency (DE)_2.5%, lower T_50% (Time required to release 50% of the drug), mean dissolution time, and bioadhesion than gels containing 4% of medium molecular weight of chitosan with lecithin. Insulin was released by a zero-order kinetic from the gels. The gel of 2% medium molecular weight of chitosan with EDTA caused increase in insulin absorption and reduction the glucose level by as much as 46% of the intravenous route. Considering our in vitro and in vivo studies, the proposed gel formulation could be a useful preparation for controlled delivery of insulin through the nasal route.     

Synthesis, characterization and evaluation of IPN hydrogels for antibiotic release

We prepared new ternary interpenetrating polymeric networks (IPN) systems containing chitosan, poly(N-vinylpyrrolidone) and poly(acrylamide) polymers. IPNs were synthesized by radical polymerization of acrylamide monomers in presence of glutaraldehyde (G) and N,N'-methylenebisacrylamide as crosslinkers and the other polymers. These IPNs were named as C-P-A. Glutaraldehyde were used in different concentration to control the network porous of IPNs. Spectroscopic and thermal analyses of these cylindrical shaped IPNs were made with fourier transform infrared spectroscopy analysis, thermogravimetric analysis, and thermomechanical analysis. Swelling studies of IPNs were carried out at pH 1.1 and pH 7.4 at 37°C. The swelling and diffusion parameters of IPNs in these solutions were calculated. Amoxicillin as a bioactive species was entrapped to the IPNs during synthesis. In vitro release kinetics of IPNs were investigated. The experimental data of swelling and release studies suggest clearly that the swelling and release process obeys second-order kinetics. The release of the entrapped bioactive species from IPNs depends on the degree of crosslinking of the polymer and pH of the medium at body temperature. We observed that amoxicillin release at pH 1.1 was higher than at pH 7.4. As a result, IPNs-based chitosan with different cross-linker concentration could be promising candidates for formulation in oral gastrointestinal delivery systems.     

Synthesis, characterization, and evaluation of phosphated cross-linked konjac glucomannan hydrogels for colon-targeted drug delivery

Hydrogel systems of konjac glucomannan (KGM) cross-linked with trisodium trimetaphosphate (STMP) were prepared for colon-targeting drug delivery. Swelling degrees of the hydrogels were measured in artificial gastrointestinal fluids and in sodium chloride solution with different concentrations to study their dependence on the cross-linking density and the ionic strength. The absorption of methylene blue was used to characterize the degree of the KGM cross-linking. In vitro release of model drug hydrocortisone was studied in presence and absence of β -mannanase. KGM cross-linked with STMP was able to retard the release of the poorly water-soluble drug and could be biodegraded enzymatically. Hydrocortisone release was cross-linking density dependent and controlled by degradation of the hydrogles.     

Targeted delivery of low molecular drugs using chitosan and its derivatives

Chitosan has prompted the continuous impetus for the development of safe and effective drug delivery systems because of its unique physicochemical and biological characteristics. The primary hydroxyl and amine groups located on the backbone of chitosan allow for chemical modification to control its physical properties. When the hydrophobic moiety is conjugated to a chitosan molecule, the resulting amphiphile may form self-assembled nanoparticles that can encapsulate a quantity of drugs and deliver them to a specific site of action. Chemical attachment of the drug to the chitosan throughout the functional linker may produce useful prodrugs, exhibiting the appropriate biological activity at the target site. Mucoadhesive and absorption enhancement properties of chitosan increase the in vivo residence time of the dosage form in the gastrointestinal tract and improve the bioavailability of various drugs. The main objective of this review is to provide an insight into various target-specific carriers, based on chitosan and its derivatives, towards low molecular weight drug delivery. The first part of the review is concerned with the organ-specific delivery of low molecular drugs using chitosan and its derivatives. The subsequent section considers the recent developments of drug delivery carriers for cancer therapy with special focus on various targeting strategies.     

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated.

Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics.

Results: The formulations showed rapid gelation (4–7 min) at 30–35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110–150 kDa led to generation of optimum spray with lower Dv₅₀, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions.

Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.     

Reacetylated chitosan microspheres for controlled delivery of anti-microbial agents to the gastric mucosa

The high aqueous solubility of chitosan restricts the utility of chitosan microspheres for gastric drug delivery. This paper describes the preparation of reacetylated chitosan microspheres with suitable properties for the controlled release of active anti-microbial agents, such as amoxycillin and metronidazole, in the gastric cavity. Two different microencapsulation approaches were developed and optimized in order to encapsulate hydrophilic (amoxycillin) and hydrophobic (metronidazole) compounds efficiently. The reacetylated chitosan microspheres exhibited a controlled water swelling capacity and gelified at acidic pH, resulting in prolonged release of the encapsulated antibiotics. The reacetylation time was found to be a key factor that affects not only drug release, but also encapsulation efficiency and anti-microbial activity of the encapsulated compound. The last two parameters were also dependent on drug solubility in the reacetylating agent. Using short reacetylation time periods, it was possible to efficiently control the release of both hydrophilic and lipophilic antibiotics while maintaining their activity against different bacteria. Consequently, reacetylated chitosan microspheres are promising vehicles for the controlled delivery of anti-microbial agents to the gastric cavity and, hence, for the eradication of Helicobacter pylori, a pathogen strongly associated with gastric ulcers and possibly gastric carcinoma.     

Sustained release of antineoplastic drugs from chitosan-reinforced alginate microparticle drug delivery systems

Alginate based microparticle drug delivery systems were prepared for the sustained release of antineoplastic drugs. Two drugs, 5-fluorouracil (5-FU) and tegafur, were encapsulated into the microparticles. The drug loaded microparticles were fabricated using a very convenient method under very mild conditions, i.e., directly shredding the drug loaded beads into microparticles in a commercial food processor. The mean sizes of the obtained microparticles were between 100 and 200 μm. To effectively sustain the drug release, alginate microparticles were reinforced by chitosan during gelation. The drug release from the chitosan-reinforced alginate microparticles was obviously slower than that from the unreinforced microparticles. The effect of the reinforcement conditions on the drug release property of the microparticles was studied, and the optimized concentration of chitosan solution for reinforcement was identified. The effects of drug feeding concentration and pH value of the release medium on the drug release were investigated.     

Nanoparticles for direct nose-to-brain delivery of drugs

This review aims to evaluate the evidence for the existence of a direct nose-to-brain delivery route for nanoparticles administered to the nasal cavity and transported via the olfactory epithelium and/or via the trigeminal nerves directly to the CNS. This is relevant in the field of drug delivery as well as for new developments in nanotechnology. Experiments in animal models have shown that nano-sized drug delivery systems can enhance nose-to-brain delivery of drugs compared to equivalent drug solutions formulations. Protection of the drug from degradation and/or efflux back into the nasal cavity may partly be the reason for this effect of nanoparticles. It is uncertain, however, whether drug from the nanoparticles is being released in the nasal cavity or the nanoparticles carrying the drug are transported via the olfactory system or the trigeminal nerves into the CNS where the drug is released. Furthermore, toxicity of nanoparticulate drug delivery systems in the nasal cavity and/or in the CNS has not been extensively studied and needs to be considered carefully.     

Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum

The aim of this study was to investigate the influence of pH, buffer species and ionic strength on the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets containing chitosan and xanthan gum prepared by a hot-melt extrusion process. Drug release from hot-melt extruded (HME) tablets containing either chitosan or xanthan gum was pH and buffer species dependent and the release mechanisms were controlled by the solubility and ionic properties of the polymers. All directly compressed (DC) tablets prepared in this study also exhibited pH and buffer species dependent release. In contrast, the HME tablets containing both chitosan and xanthan gum exhibited pH and buffer species independent sustained release. When placed in 0.1N HCl, the HME tablets formed a hydrogel that functioned to retard drug release in subsequent pH 6.8 and 7.4 phosphate buffers even when media contained high ionic strength, whereas tablets without chitosan did not form a hydrogel to retard drug release in 0.1N HCl. The HME tablets containing both chitosan and xanthan gum showed no significant change in drug release rate when stored at 40 °C for 1 month, 40 °C and 75% relative humidity (40 °C/75% RH) for 1 month, and 60 °C for 15 days.     

Tocol modified glycol chitosan for the oral delivery of poorly soluble drugs

The aim of this study was to develop tocol derivatives of chitosan able (i) to self-assemble in the gastrointestinal tract and (ii) to enhance the solubility of poorly soluble drugs. Among the derivatives synthesized, tocopherol succinate glycol chitosan (GC-TOS) conjugates spontaneously formed micelles in aqueous solution with a critical micelle concentration of 2 μg mL⁻¹. AFM and TEM analysis showed that spherical micelles were formed. The GC-TOS increased water solubility of 2 model class II drugs. GC-TOS loading efficiency was 2.4% (w/w) for ketoconazole and 0.14% (w/w) for itraconazole, respectively. GC-TOS was non-cytotoxic at concentrations up to 10 mg mL⁻¹. A 3.4-fold increase of the apparent permeation coefficient of ketoconazole across a Caco-2 cell monolayer was demonstrated. Tocol polymer conjugates may be promising vehicles for the oral delivery of poorly soluble drugs.     

The relation between swelling properties and cross-linking of hydrogels designed for colon-specific drug delivery

Copolymers of 2-hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA)-based hydrogels containing 5% and 10% of a cross-linking agent were studied as drug delivery systems. Terephthalic acid was covalently linked with HEMA, abbreviated as CA (cross-linking agent). Free radical cross-linking copolymerization of HEMA and methacrylic acid (MAA) in three different molar ratios, mixed with a particulate 3, 3-azobis (6-hydroxy benzoic acid) (ABHB) as an azo derivative of 5-aminosalicylic acid with the various ratios CA as cross-linking agent were carried out with using 2, 2, Azobisisobutyronitrile as initiator at the temperature range 60-70°C. The compositions of the cross-linked three-dimensional polymers were determined by FTIR spectroscopy. Glass transition temperature of the network polymers was determined calorimetrically. The hydrolysis of drug-polymer conjugates was carried out in cellophane membrane dialysis bags containing an aqueous buffer solution (pH 7.4 and pH 1) at 37°C. The drug-release profiles indicate that the amount of drug release depends on its degree of swelling and cross-linking.     

Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins

Chitosan/tripolyphosphate nanoparticles have already been demonstrated to promote peptide absorption through several mucosal surfaces. We have recently developed a new drug delivery system consisting of complexes formed between preformed chitosan/tripolyphosphate nanoparticles and phospholipids, named as lipid/chitosan nanoparticles (L/CS-NP) complexes. The aim of this work was to microencapsulate these protein-loaded L/CS-NP complexes by spray-drying, using mannitol as excipient to produce microspheres with adequate properties for pulmonary delivery. Results show that the obtained microspheres are spherical and present appropriate aerodynamic characteristics for lung delivery (aerodynamic diameters around 2–3 μm and low apparent tap density of 0.4–0.5 g/cm³). The physicochemical properties of the L/CS-NP complexes are affected by the phospholipids composition. Phospholipids provide a controlled release of the encapsulated protein (insulin), which was successfully associated to the system (68%). The complexes can be easily recovered from the mannitol microspheres upon incubation in aqueous medium, maintaining their morphology and physicochemical characteristics. Therefore, this work demonstrates that protein-loaded L/CS-NP complexes can be efficiently microencapsulated, resulting in microspheres with adequate properties to provide a deep inhalation pattern. Furthermore, they are expected to release their payload (the complexes and, consequently, the encapsulated macromolecule) after contacting with the lung aqueous environment.     

Superporous hydrogels based on blends of chitosan and polyvinyl alcohol as a carrier for enhanced gastric delivery of resveratrol

Resveratrol exhibits a number of pharmacological properties, notably antioxidant, anti-inflammatory and anti-cancer activities which are beneficial for the treatment of gastric diseases. However, the poor aqueous solubility and rapid metabolism are the important limitations in clinical uses. Superporous hydrogels (SPHs) based on chitosan/PVA blends were developed as a carrier for resveratrol solid dispersion (Res_SD) to increase the solubility and achieve sustained drug release in the stomach. The SPHs were prepared by gas forming method using glyoxal and sodium bicarbonate as cross-linking agent and gas generator, respectively. The solid dispersions of resveratrol with PVP-K30 were prepared by solvent evaporation and incorporated into the superporous hydrogels. All formulations showed rapid absorption of simulated gastric fluid and reached the equilibrium swollen state within a few minutes. The water absorption ratio and mechanical strength of SPHs were predominantly affected by the chitosan content, with maximum values at 1400 % and 375 g/cm², respectively.The Res_SD-loaded SPHs exhibited good floating properties and SEM micrographs revealed a highly interconnected pores structure with size around 150 μm. Resveratrol was efficiently entrapped within the SPHs at levels between 64 and 90 % w/w and efficient drug release was sustained over 12 h dependent on the concentration of chitosan and PVA. The Res_SD-loaded SPHs exhibited slightly less cytotoxic efffect towards AGS cells than pure resveratrol. Furthermore, the formulation showed similar anti-inflammatory activity against RAW 264.7 cells compared with indomethacin.     

Cyclodextrin controlled release of poorly water-soluble drugs from hydrogels

The effect of 2-hydroxypropyl-β-cyclodextrin and γ-cyclodextrin on the release of ibuprofen, ketoprofen and prednisolone was studied. Stability constants calculated for inclusion complexes show size dependence for complexes with both cyclodextrins. Hydrogels were prepared by ultraviolet irradiation and release of each model drug was studied. For drugs formulated using cyclodextrins an increase in the achievable concentration and in the release from hydrogels was obtained due to increased solubility, although the solubility of all γ-cyclodextrin complexes was limited. The Load also was increased by adjusting pH for the acidic drugs and this exceeds the increase obtained with γ-cyclodextrin addition.     

羧甲基壳聚糖温敏凝胶对小鼠L929细胞增殖的影响及其生物相容性研究

目的：自制羧甲基壳聚糖温敏凝胶,研究其对L929细胞增殖的影响并且通过动物实验探讨其组织相容性,为进一步的临床应用提供基础实验依据。方法：用羧甲基壳聚糖与甘油磷酸盐互配, 制备羧甲基壳聚糖温敏凝胶。采用MTT法测定不同浓度的凝胶浸提液对体外培养的L929细胞增殖的影响;将凝胶植入小鼠皮下,然后分别在3、7、14天处死,常规组织切片,HE染色观察凝胶周围组织的炎症反应。结果：培养24h后,各浓度浸提液组对L929细胞的增殖均有一定促进作用,在48h、72h、96h时,各实验组都较阴性及阳性对照组显示出较明显的促进细胞增殖作用,其中0.4倍浸提液组促增殖效果最明显（P＜0.05）;凝胶植入后前3d,实验组以急性炎症为主,随着时间的延长各实验组炎症细胞逐渐减少至消失,说明羧甲基温敏凝胶具有很好的组织相容性。结论：羧甲基壳聚糖温敏凝胶对L929细胞有明显的促进作用且具有良好的组织相容性,在牙周病治疗中具有潜在的应用价值。     

Synthesis and characterization of acrylic type hydrogels containing azo derivatives of 5-amino salicylic acid for colon-specific drug delivery

pH-sensitive hydrogels are suitable candidates for oral delivery of therapeutic peptides, proteins and drugs, due to their ability to respond to environmental pH changes. Terephthalic acid was covalently linked with 2-hydroxyethyl methacrylate (HEMA), abbreviated as cross-linking agent (CA). Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Free radical cross-linking copolymerization of polymerizable azo derivative of 5-ASA (APAS) and methacrylic acid (MAA) in two different molar ratios, with the various ratios CA as cross-linking agent were carried out with using 2, 2’-azobisisobutyronitrile (AIBN) as initiator at the temperature range 60–70 °C. The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. Glass transition temperature (Tg) of the network polymers was determined calorimetrically. The hydrolysis of drug-polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 7.4 and pH 1) at 37 °C. The effect of copolymer composition on the hydrolytic degradation was studied in simulated gastric fluid (SGF, pH 1) and simulated intestinal fluid (SIF, pH 7.4) at 37 °C. Monitoring of the hydrolysis process by HPLC and UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. The drug-release profiles indicate that amount drug release dependent on the content of MAA groups and crosslinking.