Interpenetrating Polymer Network Hydrogels of Chitosan: Applications in Controlling Drug Release
Chitosan is a natural polysaccharide obtained by alkaline deacetylation of chitin. It is cationic in ionic nature. Because of its biocompatibility and biodegradability, chitosan is employed as a drug carrier material in the development of various kinds of drug delivery. However, the extensive use of chitosan as a drug delivery carrier material is limited by its rapid dissolution in the acidic pH of the stomach, and this causes restrictions in controlling drug release from chitosan-based oral dosage forms. To overcome this limitation, modifications of chitosan to develop hydrogel systems are being investigated by researchers. Among these modified chitosan-based hydrogel systems, interpenetrated polymer network (IPN) hydrogels have enhanced mechanical properties at gastric pH, as well as improved control of drug release over a longer period. This chapter describes the preparations and properties, in terms of drug-releasing performance, of various chitosan-based IPN hydrogels for controlling drug release.
KeywordsChitosan Interpenetrating polymer network (IPN) Hydrogel Oral dosage forms Drug release
2 Production of Chitosan
3 Physiochemical Properties of Chitosan
3.1 Crystalline Structure of Chitosan
Chitosan is a heterogeneous polymer consisting of glucosamine (GlcN) and N-acetyl glucosamine (GlcNAc) units; its properties depend on the structure and composition. The crystalline structure of different chitin or chitosan samples is prepared by one of two different procedures: (a) partial deacetylation of chitin; or (b) partial reacetylation of fully deacetylated chitin. A less crystalline chitosan sample is produced by reacetylation of fully deacetylated chitosan rather than direct solid-state deacetylation of chitin. Production of less crystalline chitosan also depends on secondary treatment such as reprecipitation, drying, and freeze drying .
3.2 Degree of N-Acetylation of Chitosan
The ratio of GlcNAc to GlcN structural units is the important factor in the structure of chitosan and has a direct effect on the solubility of chitosan. In chitin, the acetylated unit prevalence is ≥90%, whereas chitosan is a fully or partially N-deacetylated derivative with a degree of acetylation of <30%. Assessment of the degree of deacetylation of chitin determines what deacetylation conditions are suitable to make quicker preparation of chitosan feasible . The quality of chitosan depends on the source of chitin and its process of isolation. The appearance of the polymer, the turbidity of the polymer solution, the degree of deacetylation, and the molecular weight are the main characteristics of chitosan polymer. Chitosan obtained from deacetylation of chitin becomes soluble in aqueous acidic solutions when the average degree of deacetylation is above 0.5, but not at an alkaline or physiological pH. The physical properties of chitosan in an aqueous solution of chitosan depend on the degree of deacetylation and the acetyl group distribution in the polymer chains. Acetyl group distribution in an uneven way will lower the solubility of chitosan. A problem with the solubility of chitosan always hinders its applicability domain . At the molecular level, modification of chitosan increases its solubility and stability, and thus it behaves as a versatile biopolymer. Chitosan hydrogel is one of its most important composites; it is composed of a crosslinked network of polymer chains with a high content of hydrophilic groups. Although it is superabsorbent of water, the chemical or physical bonds in between the polymeric chains make them water insoluble. Hydrogels are polymeric crosslinked network structures. The hydrogel structure is obtained with the presence of hydrophilic groups in a polymer network upon hydration in an aqueous environment. Hydrogels are broadly classified into two categories. Permanent/chemical gels are covalently crosslinked networks (replacing hydrogen bonds with stronger and stable covalent bonds), which establish an equilibrium swelling state based on the polymer–water interaction parameter and the crosslink density. In reversible/physical gels the networks are held together by molecular forces such as ionic, hydrogen bonding, or hydrophobic interactions . In physically crosslinked gels, dissolution is prevented by physical interactions between different polymer chains. All of these interactions are reversible and can be disrupted by changes in physical conditions or application of stress. Hydrogels are prepared by chemical or physical crosslinking processes. Methods for chemical crosslinking of hydrogels include (1) radical polymerization, (2) photopolymerization, (3) enzymatic reactions, and (4) covalent crosslinking via linkers. Physical crosslinking forms a nonpermanent network with physical interactions by hydrogen or electrostatic bonds, physical entanglements, and crystal formation. Physically crosslinked hydrogels are formed via ion interactions, graft copolymers, crystallization, and stereo complex formation .
4 Modifications of Chitosan
4.1 Hydrophobic Chitosan
Attachment of a hydrophobic moiety to the original structure of chitosan using covalent linkage is the process used to increase hydrophobicity. This hydrophobic interaction may enhance the stability of substituted chitosan by reducing the hydration of the matrix and also creates resistance to degradation by proteolytic enzymes. pH-sensitive chitosan can be produced by introduction of carboxylic acid groups into its structure. In an acidic environment the carboxylic groups exist in a nonionized form and therefore the chitosan polymer is poorly soluble in water, whereas in alkaline conditions the chitosan polymer is ionized and is considerably more hydrophilic. The hydrophobic excipient is expected to increase the mucoadhesivity through hydrophobic interactions. One of the approaches used to induce hydrophobic characteristics of chitosan is introduction of hydrophobic groups through addition of long-chain acyl chlorides and anhydrides into the chitosan structure.
4.2 Hydroxyalkyl Chitosans
Epoxidation of chitosan produces various derivatives of chitosan. N-hydroxyalkyl or O-hydroxyalkyl chitosans are widely applied in gene delivery .
4.3 Quaternized Chitosan
Quaternization or methylation of chitosan gives it enhanced solubility in neutral and alkaline environments of the intestine, which makes it more efficient than the parent chitosan for absorption across intestinal epithelial cells. Trimethylated chitosan (TMC) is prepared by reaction of chitosan with trimethyl iodide. TMC nanoconjugates with 35% quaternization contribute good penetration enhancement and mucoadhesive properties. N-hydroxypropyl trimethylammonium chitosan chloride (HTCC), which is obtained by reaction of chitosan with glycidyl trimethylammonium chloride, is preferred for oral insulin delivery.
4.4 Polyethylene Glycol–Grafted Chitosan Derivatives
The reaction between chitosan and polyethylene glycol (PEG), followed by reductive alkylation of an amino group of chitosan, helps to form grafted chitosan nanoconjugates. PEG with hydrophilic chitosan nanoparticles is used as an anionic drug carrier.
4.5 Thiolated Chitosan
To improve the permeation effect, thiolation of polymers confers the attribute of strong mucoadhesivity. Thiolation is done by derivatization of the primary amino groups of chitosan with thioglycolic acid, 2-iminothiolane, cysteine, and thiobutylamidine. Thiolated chitosan is also known for its in situ gelling features due to pH-dependent formation of intermolecular and intramolecular disulfide bonds. Chitosan–cysteine conjugates, chitosan-4-thio-butyl-amidine conjugates, and chitosan–thioglycolic acid conjugates are the three important types of chitosan conjugate. Trimethyl chitosan–cysteine conjugate (TMC-Cys) is used in vivo for oral delivery of docetaxel. Also, mono-N-carboxymethyl chitosan, N-sulfo-chitosan, and trimethylated chitosan are effective because of their mucoadhesive properties .
4.6 Chitosan and Sugar
To increase the water solubility of chitosan in a wide range of pH environments, sugar derivatives are synthesized, which are formed by amide linkage between chitosan and hydrophilic sugar moieties. Chitosan with monosaccharide and disaccharide composites occur via a chitosan N-alkylation process. Because of the cell and receptor specificity, a sugar chitosan composite is very useful for targeted drug delivery systems. Fucosylated chitosan and galactosylated chitosan are important for specific interaction with lectins and for targeting the delivery system to hepatocytes, respectively.
4.7 Chitosan and Methyl Acroloyl Glycine
A reaction between an amino group of chitosan and a carboxyl group of methyl acroloyl glycine (CS-MAG) produces a chitosan–methyl acroloyl conjugate. In comparison with crystalline chitosan, CS-MAG is an amorphous compound with lower intermolecular forces and thermal stability. The precursor can be materialized via a photopolymerization technique in the presence of a photoinitiator.
4.8 Chitosan and 4-Azido-benzoic Acid
4-Azido-benzoic acid (Az-CS), with two functional groups (azide and carboxylic acid), is one of the crosslinking agents and photoinitiators. Photosensitive chitosan derivatives are formed by a reaction between a carboxylic acid group of benzoic acid and an amino group of chitosan. After ultraviolet (UV) irradiation, the azide functional group is changed into nitrene, crosslinked to form a gel-like structure .
5 Various Chitosan-Based Interpenetrating Polymer Network Hydrogels
5.1 Semi-interpenetrating Polymer Network of Chlorpheniramine Maleate
A semi-IPN of chitosan–glutamic acid beads is formed by crosslinking between glutaraldehyde and chitosan. The formation of chitosan–glutamic acid beads can be done by one two processes: (1) beads are prepared with the same weight ratio but varying amounts of crosslinker; or (2) beads of different weight ratios are prepared with a fixed amount of crosslinker. The swelling profile of the beads and the release rate of chlorpheniramine maleate (CPM) in different pH solutions have been studied, and CPM shows a greater degree of swelling in a basic medium than in an acidic medium. The rate of swelling of the matrix and the release of drugs are dependent on the degree of crosslinking, the weight ratio of chitosan–glutamic acid, and the pH of the solution. With variations in the weight ratio of chitosan–glutamic acid, the concentration of glutaraldehyde, and drug loading, the desired release rates can be achieved, which also helps in optimizing the drug-entrapping capacity and sustained release for an extended period of time. The outcomes also suggest that chitosan–glutamic acid crosslinked beads are suitable for controlled release of drugs. A viscous solution of chitosan–glutamic acid is prepared in 2% acetic acid solution and extruded to an alkali–methanol solution, and the precipitated beads are crosslinked using a glutaraldehyde solution .
5.2 Clarithromycin Interpenetrating Polymer Network Hydrogel
Clarithromycin IPN hydrogel is formed by chemical crosslinking between chitosan, polyvinyl pyrrolidine, and polyacrylic acid. A formulation with a greater quantity of chitosan showed greater swelling and drug release due to the presence of an NH2 group, which ionizes at lower pH values. The results showed that IPN hydrogels exhibit greater swelling, mucoadhesion, and drug release at a lower pH value (pH 2), and are effective against Helicobacter pylori .
5.3 Metformin HCl Hydrogel
Hydrogels or polyelectrolyte systems are based on ionic crosslinking and are used as controlled-release dosage forms. These systems are based on the ability of their structure to entrap the drug within them. Metformin hydrochloride (MH) has been used as a model drug for this purpose. It is a highly water-soluble and low-permeability drug. Thus, development of a controllable dosage form system for controlled release of MH has been attempted. MH-loaded chitosan polyelectrolyte complex (PEC) hydrogel beads were prepared via ionotropic crosslinking with sodium tripolyphosphate (TPP). MH was dispersed in 1.5% glacial acetic acid and, with chitosan and polymers dispersed within it, was crosslinked with a 1% sodium tripolyphosphate solution adjusted to a pH of 6.0–6.4. The prepared beads were filtered and kept at 35 °C overnight to dry. The ratio of the polymer and drug combination was kept around 1:1. The particle shape, particle diameter, weight, percentage swelling, differential scanning calorimetry (DSC) findings, drug entrapment efficiency (DEE), and in vitro release were examined as physical and chemical characterization parameters of the resultant beads. The effects of incorporation of polymers such as sodium alginate, xanthan gum, hydroxypropyl methylcellulose, and hydroxyl ethylcellulose on the physicochemical properties of the beads were also studied. Spherical to oval beads with varying particle sizes, weights, DEEs, and sustained release profiles were obtained, depending on the polymer combination used. These beads were able to sustain the release of metformin HCl. In vitro dissolution studies were done to assess the release pattern of the drug from the beads over a 5- to 6-h period. The chitosan beads were subjected to stability studies for 1 month. The stability results for the chitosan beads after 1 month were shown to be favorable with respect to providing a possible controlled-release dosage form with the beads .
5.4 Repaglinide Semi-interpenetrating Polymer Network Hydrogel
A pH-sensitive chitosan/polyvinyl pyrrolidone (PVP)–based controlled drug release system for repaglinide has been studied. These hydrogels were obtained by crosslinking chitosan and PVP with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN) and were characterized for their content uniformity, swelling index (SI), mucoadhesion, wettability, in vitro release, and release kinetics, which showed more than 95% loading of repaglinide and good swelling and mucoadhesion properties under acidic conditions. The swelling properties directly correlated with the protonation of a primary amino group on chitosan. In an acidic medium, chitosan was ionized, and mucoadhesion occurred between the positively charged chitosan and the negatively charged mucus. In physiological medium conditions, less matrix swelling was noticed. The in vitro release profile revealed that the formulation containing chitosan (2% w/v) and PVP (4% w/v) in the ratio of 14:6 w/w provided complete drug release after 12 h. This release profile showed that all of the formulations followed a non-Fickian diffusion mechanism. The surface morphology of the semi-IPN was examined before and after dissolution in simulated gastric fluid (pH 1.2), which revealed generation of an open channel–like structure in the hydrogel after dissolution. The results also suggested that semi-IPNs of chitosan/PVP are good candidates for delivery of repaglinide in acidic environments .
5.5 Intelligent Semi-interpenetrating Polymer Network Chitosan–Polyethylene Glycol–Poly(Acrylamide) Hydrogel for Closed-Loop Insulin Delivery and Kinetic Modeling
An intelligent closed-loop insulin delivery system was developed for implantation with glucose-responsive semi-IPN hydrogels, which were synthesized from free radical polymerization of chitosan (CS), acrylamide (AAm), and polyethylene glycol (PEG). Immobilized glucose oxidase (GOx) and catalase (CAT), along with insulin, were loaded into the hydrogels to make an intelligent drug carrier capable of playing the role of an artificial pancreas. The glucose-responsive hydrogel acted as a self-regulating insulin delivery system, and the rate of insulin release was associated with the blood glucose level. Cell culture tests with fibroblast cells were conducted to perform biocompatibility testing for the drug carrier systems. The effects of the incorporated PEG on the swelling ratio (SR), drug loading capacity (DLC), and drug entrapment efficiency (DEE) of the intelligent semi-IPN hydrogels were evaluated using high-performance liquid chromatography (HPLC) and UV–visible spectroscopy. Optimization of the hydrogel was also investigated using a full factorial design and by changing the amount of PEG .
5.6 Hybrid pH-Sensitive Hydrogels of Chitosan-co-acrylic Acid for Controlled Release of Verapamil
Crosslinked hydrogels based on chitosan (CS) and acrylic acid (AA) were prepared by free radical polymerization with feed compositions using N,N-methylene-bis-acrylamide (MBA) as a crosslinking agent, with benzoyl peroxide used as a catalyst. The formation of hydrogel was done by electrostatic interaction between cationic groups in CS and anionic groups in AA. The formulated hydrogels were used for dynamic and equilibrium swelling studies. The swelling properties, the effect of pH, polymeric and monomeric compositions, and the degree of crosslinking were investigated. Swelling studies were performed in USP phosphate buffer solutions with varying pH values of 1.2, 5.5, 6.5, and 7.5. The outcomes revealed that swelling was increased by an increase in the proportion of AA in the structure of the hydrogels in solutions with higher pH values. This was due to the presence of more carboxylic groups available for ionization. On the other hand, with an increase in the chitosan content, swelling increased in a solution of acidic pH, but this swelling was not significant, and it was due to ionization of amine groups present in the structure of the hydrogel. Swelling properties were decreased with an increase in the crosslinking ratio, owing to a tighter hydrogel structure. Porosity and the sol–gel fraction were also measured. With increases in CS and AA content, porosity and the gel fraction increased, whereas with an increase in MBA content, porosity decreased and the gel fraction increased. The Flory–Rehner theory was used to calculate the diffusion coefficient (D) and network parameters such as the average molecular weight between crosslinks (Mc), the polymer volume fraction in the swollen state (V2s), the number of repeating units between crosslinks (Mr), and the crosslinking density (q). Selected samples were loaded with a model drug, verapamil. The release of verapamil depended on the ratio of CS to AA, the degree of crosslinking, and the pH of the medium. The release mechanisms were studied by fitting of the experimental data to model equations and calculation of the corresponding parameters. The outcomes revealed that the kinetics of drug release from the hydrogels in both pH 1.2 and pH 7.5 buffer solutions mainly followed non-Fickian diffusion .
5.7 pH-Sensitive Interpenetrating Network Hydrogels Based on Chitosan Derivatives and Alginate for Oral Drug Delivery
Methoxy polyethylene glycol–grafted carboxymethyl chitosan (mPEG-g-CMC) and alginate hydrogels were constructed as an IPN. mPEG-g-CMC hydrogel and mPEG were physically mixed with CMC hydrogel. Bovine serum albumin (BSA) was used as a model for a protein drug, which was encapsulated in the hydrogel network, and the drug release properties were studied. The hydrogels prepared by these two methods maintained good pH sensitivity; the loading capacity of the mPEG-g-CMC/alginate hydrogel was enhanced in comparison with that of the hydrogel prepared by physical mixing of mPEG. The burst release of the protein was slightly decreased at pH 1.2, while the release at pH 7.4 was improved and behaved like site-specific protein drug delivery in the intestine [18, 19].
5.8 Chitosan/Alginate Crosslinked Hydrogels: Preparation, Characterization, and Application for Cell Growth Purposes
A hybrid polymer network of chitosan was prepared with an alginate crosslinker using covalent linkage between two macromolecules. Fourier transform infrared (FTIR) spectroscopy and DSC were used as tools to characterize the structural and thermal behavior of these hydrogels. Scanning electron microscopy (SEM) with an atomic force microscopy (AFM) attachment was used to investigate the morphological nature of the crosslinked material. A mixture of water and phosphate-buffered saline (PBS) solution was used to analyze the swelling properties of the gel. Hydrogel stability was provided by the presence of alginate in the chitosan/alginate hydrogel. In comparison with chitosan/alginate hydrogel prepared with 1 wt% DCC (N,N′-dicyclohexylcarbodiimide), the swelling of chitosan/alginate hydrogel prepared with 3 wt% DCC was limited. Hydrogels seeded with L929 mouse fibroblasts were used to measure the degree of cell proliferation. Chitosan/alginate hydrogels with 1 wt% DCC provided a better environment for cell attachment and cell proliferation. This study evaluated functional hydrogel formation by crosslinked chitosan and alginate as a novel biomaterial .
5.9 In Situ Formation of Chitosan–Gold Hybrid Hydrogel and Its Application for Drug Delivery
Chitosan and chloroauric acid in an aqueous medium were used to develop a novel chitosan–gold (CS–Au) hybrid hydrogel. Its physiochemical parameters – such as its UV absorption, structure, morphology, and swelling properties – were studied. The CS–Au hybrid hydrogel exhibited a marked water-absorbing property and was acclaimed as a drug delivery system for the anticancer drug doxorubicin (DOX) because of its high equilibrium water swelling property. The DLC and sustained drug release pattern correlated with the results of drug loading and release experiments. Moreover, DOX released from hydrogel, which itself had no cytotoxicity, showed biological activity similar to that of free DOX but with lower cytotoxicity due to its controllable release. These characteristics are ideal for a local drug delivery system, indicated that it has a promising potential future in the medical or pharmaceutical area [21, 22].
5.10 Hydrogels Made from Chitosan and Silver Nitrate
A gelation of chitosan solution with silver nitrate was developed to be an essential antibacterial agent. The critical concentration of chitosan (c*) was used as the rate-limiting step for continuous production of chitosan–silver hydrogel. At lower concentrations, the formation of nano- and microhydrogels was assessed. The swelling properties of hydrogels was assessed by sol–gel analysis. Also, the following tests were employed: (1) the hydrogels were tested mechanically; (2) the silver concentration was measured by inductively coupled plasma–optical emission spectroscopy (ICP-OES); (3) the morphology of the products was measured by SEM; and (4) the product formed at a low concentration of chitosan (c < c*) was observed by dynamic light scattering (DLS) and UV–visible spectrophotometry. The obtained product was effective against Escherichia coli and Bacillus subtilis although the chitosan used in it showed no such activity .
5.11 Interpenetrating Polymer Network Hydrogels of Chitosan and Poly(2-Hydroxyethyl Methacrylate) for Controlled Release of Quetiapine
Interpenetrating polymer networks of chitosan and 2-hydroxyethyl methacrylate (HEMA) have been produced. pH was used as a limiting parameter to study the swelling properties and chitosan content of the network. At approximately 98 °C and 155 °C, two transitions were shown, which corresponded to the networks of pHEMA and chitosan, respectively, as per the DSC studies, and demonstrated that the obtained materials were amorphous and interpenetrated. The viscoelastic behavior of the materials was studied by creep recovery and stress relaxation studies. Quetiapine was used as a model drug to study controlled-release behavior, and it was found that the process was controlled by diffusion and by relaxation of the polymer network. Lysozyme enzyme was used to quantify the degradation of materials under simulated physiological conditions. An increase in the chitosan content directly correlated with the degree of degradation [24, 25, 26].
5.12 Production of Chitosan-Based Hydrogels for Biomedical Applications
Chitosan-based hydrogel is produced by hydrophilic reactions of polar functionalities such as amino and OH groups. Chitosan hydrogels are capable of absorbing large quantities of water without changes in structural features. Using a variety of strategies based on ionic, polyelectrolyte, chemical modification, and interpenetrating network techniques, chitosan-based hydrogels have been designed and investigated to deliver therapeutics to the site of action in a controlled-release manner. Micro- and nanosized configurations of chitosan-based hydrogel have shown immense applications in biomedical areas such as drug delivery, wound healing, and tissue engineering .
5.13 Interpenetrating Polymer Network Hydrogel Microspheres for Oral Controlled-Release Applications
Sodium carboxymethyl cellulose (Na-CMC) and polyvinyl alcohol (PVA) interpenetrating polymer network hydrogel microspheres were prepared by a water-in-oil (w/o) emulsion crosslinking method for an oral controlled-release drug delivery system for the nonsteroidal anti-inflammatory drug diclofenac sodium (DS). The microspheres were prepared with variation in the ratios of Na-CMC to PVA with constant percentage drug loading and extent of crosslinking density at polymer weight. SEM was used to identify loose and rigid surfaces of microspheres. The structure of the IPN was justified by FTIR spectroscopy and x-ray diffraction (XRD) analysis. The dispersive nature of the encapsulated drug was estimated by DSC analysis. The in vitro drug release study was evaluated depending on the acid and alkaline media. All formulations exhibited satisfactory physicochemical and in vitro release characteristics. The release data indicated a non-Fickian diffusion mechanism of drug release from the formulations. Thus, the study revealed that DS-loaded IPN microspheres are suitable for oral controlled-release application .
5.14 Synthesis of a Novel Interpenetrating Polymer Network Hydrogel as a Drug Delivery System
Novel IPN hydrogels of chitosan with poly(acrylic acid) were developed for controlled release of an amphetamine drug by use of simultaneous polymerization/crosslinking of an acrylic acid monomer in the presence of chitosan and a crosslinker. Variation in the composition of the IPN was achieved by variation in the concentration of the crosslinker. The characterization of the IPN in terms of pH-sensitive behavior was calculated by equilibrium swelling studies, which revealed that the release of amphetamine was much higher at pH 7.4 than at pH 1.2, which indicated that the release system was controlled and could be used as a release system for intestine-specific drug delivery [29, 30].
5.15 Sterculia Gum–Based Hydrogels for Drug Delivery Applications
Sterculia gum is one of the medicinally important plant-derived water-soluble polysaccharides obtained from the exudate of the tree Sterculia urens (family: Sterculiaceae). It was identified as a promising biodegradable material in the development of various biomedical applications, including drug delivery applications and wound dressing applications. Sterculia gum has also been employed as an excipient in the design of various pharmaceutical applications. In recent years, several attempts at modification of sterculia gum have been undertaken to develop sterculia gum–based hydrogels for controlling the rate of hydration and swelling, and also for tailoring the release profile of various types of drug. In the development of these sterculia gum–based hydrogels, modifications of sterculia gum through polymer blending, crosslinking, IPN formation, polymer grafting, etc., were investigated for improved drug delivery applications. Most of these previously reported sterculia gum–based hydrogels have been found to be effective for gastroretentive deliveries as wound dressings for sustained release of various drugs. This chapter provides a comprehensive and useful discussion on previously investigated sterculia gum–based hydrogels for use in drug delivery applications, describing the source, composition, and properties of sterculia gum, and discussing the formulations of various sterculia gum–based hydrogel systems used in various types of drug delivery application [31, 32].
5.16 Chitosan/Gelatin Membranes Using Chitosan Hydrogel
As we know, chitin and chitosan are novel biomaterials. In this work a suspension of chitosan hydrogel was mixed with gelatin to develop novel chitosan/gelatin membranes, which were characterized by SEM, XRD, mechanical, swelling, and thermal studies. The XRD data revealed homogeneous and smooth morphology of the chitosan/gelatin membranes, as well as showing good compatibility and interaction between the chitosan and gelatin. In wet conditions with a chitosan to gelatin mixture ratio of 0.5, stress and elongation of the chitosan/gelatin membranes were revealed, along with good swelling, mechanical, and thermal properties. Cell adhesion studies were also carried out, using human MG-63 osteoblast–like cells to quantify cell adhesion, in which cells were incubated with chitosan/gelatin membranes for 24 h to confirm the cell adhesion. The prepared chitosan/gelatin membranes were biologically active and were suitable for cell adhesion, which was an important criterion for tissue engineering .
5.17 Chitosan/Polyacrylonitrile Semi-interpenetrating Polymer Network Hydrogel
In one study a chitosan/polyacrylonitrile semi-IPN hydrogel system was formed, based on various blends of chitosan/polyacrylonitrile polymer. Crosslinking of chitosan via glutaraldehyde vapors was utilized to develop a semi-IPN, and DSC, FTIR, and field emission (FE)-SEM were used as tools to reflect the microstructures of the hydrogels. DSC thermograms of the hydrogel blends showed a single Tg value (at 179–152 °C for Gel1–Gel4), which confirmed good miscibility between the two polymers. For a semi-IPN (Gel7) the Tg appeared at slightly lower temperature (128 °C) than previously, which also suggested reduced intermolecular interactions between the two polymers being observed because of crosslinking of the chitosan. The FTIR data revealed no change in the characteristic band positions of the two polymers for the hydrogel blends (Gel1–Gel4) and also a characteristic doublet at 1563 cm−1 and 1630 cm−1, which confirmed crosslinking of chitosan with glutaraldehyde to form a semi-IPN hydrogel (Gel7). The FE-SEM images showed a homogenous surface (with no phase separation) and cross-sectional morphologies for the blend hydrogels (Gel1–Gel4) and semi-IPN hydrogel (Gel7). The percentage swelling was suggested to decrease with a simultaneous increase in stability as the crosslinking time was increased. The semi-IPN hydrogel (Gel7) showed improved stability and fair swelling. The potential of the blend hydrogel (Gel1) and semi-IPN hydrogel (Gel7) as adsorbents was studied using rhodamine B dye as an indicator. A significant adsorption affinity for rhodamine B dye was shown in the case of the semi-IPN hydrogel (Gel7). The outcomes best fitted pseudo-second-order kinetics and a Langmuir isotherm. An intraparticle diffusion model was used to confirm diffusion as the only rate-limiting step .
5.18 Semi-interpenetrating Polymer Network Superabsorbent Chitosan–Starch Hydrogel
In this study, a semi-IPN superabsorbent chitosan–starch (ChS) hydrogel was used to efficiently remove Direct Red 80 (DR80) dye from the aqueous phase. The effects of the initial pH, ChS dose, initial dye concentration, temperature, and salts on the sorption of DR80 dye were evaluated. A maximum swelling capacity of 15 g/g was shown in the case of the ChS hydrogel. The sorption equilibrium data revealed good agreement with a Freundlich isotherm, which also best fitted a pseudo-second-order kinetic model. The maximum uptake capacity and mean sorption energy of the hydrogel (312.77 mg/g and E = 11.34–14.9 kJ/mol) revealed that the sorption nature of DR80 was mainly of a chemisorption type. The spontaneous endothermic data of the sorption process correlated with the temperature dependency data, which were also favorable at a higher temperature on the basis of the enthalpy value (H° = +83.68 kJ/mol). Intraparticle diffusion data according to the Boyd model were used as a limiting step for DR80 uptake and, finally, sorption/desorption studies were performed to investigate the reusability of the ChS hydrogel, which demonstrated significant sorption for four consecutive cycles .
5.19 Glucose-Sensitive Antibacterial Chitosan–Polyethylene Oxide Hydrogel
This works reflects the development of a novel glucose-sensitive chitosan–polyethylene oxide (CS/Polyethylene oxide = 1:0.5–1:2.5) hydrogel for controlled release of metronidazole (MNZ) by use of chemical crosslinking and immobilization of the glucose oxidase (GOx) process. FTIR spectroscopy, compressive mechanical testing, rheological analysis, cytotoxicity testing, and antibacterial testing against Porphyromonas gingivalis were used as characterization tools for the hydrogel. The CS-Polyethylene oxide composite hydrogel possessed more significant mechanical properties and biocompatibility than a single-component hydrogel, which might have been the result of physical crosslinking and formation of a semi-IPN. This novel hydrogel has a unique self-regulating ability to release MNZ, depending on the response to the environmental glucose stimulus. It mainly releases more drugs at a higher glucose concentration that can be correlated with its ability to inhibit P. gingivalis. This study produced the glucose-sensitive antibacterial hydrogel as a new therapeutic material for treatment or prevention of periodontitis in diabetic patients [36, 37, 38].
5.20 Granular Semi-interpenetrating Polymer Network Hydrogel Based on Chitosan and Gelatin for Fast and Efficient Adsorption of Cu2+ Ions
Estimated adsorption isotherm parameters for adsorption of Cu2+ ion onto hydrogels. (Reproduced from Wen et al. , copyright © 2013, with permission from Elsevier BV)
5.21 Semi-interpenetrating Polymer Network Hydrogel: Preparation, Swelling Properties, and Adsorption Studies of Co (II)
Comparison of Co (II) adsorption capacities of some adsorbents. (Reproduced from Xiaohong et al. , copyright © 2016, with permission from Elsevier BV)
Adsorption capacity (mg g−1)
Concentration of Co ions (mg L−1)
Acacia nilotica leaf carbon
Modified chelating fibers
Crosslinked magnetic CSIS
Crosslinked magnetic CSMO
Apricot stone activated carbon
184 (a), 332 (b)
250 (a), 400 (b)
5.22 Interpenetrating Polymer Network Hydrogel Membrane of Poly(N-Isopropylacrylamide)/Carboxymethyl Chitosan
A poly(N-isopropylacrylamide)/carboxymethyl chitosan ((PNIPAAm)/(CMCS)) interpenetrating hydrogel was prepared, and the effects of the feed ratio of components, swelling medium and irradiation dose on the swelling and deswelling properties of the hydrogel were studied in detail. The outcomes revealed that the introduction of CMCS did not shift the lower critical solution temperature (LCST) (at 32 °C), which was similar to that of pure PNIPAAm. At pH 2, the lowest swelling ratio was observed. The thermosensitivity and pH sensitivity of the IPN hydrogel depended on the irradiation dose; the swelling ratio was decreased with an increasing dose. The ratio of PNIPAAm:CMCS with 1:4 w/w hydrogel was not thermosensitive in distilled water, whereas a discontinuous volume phase transition occurred in pH 2 buffer and a continuous transition was observed in pH 8 buffer. Consequently, a combination of pH and temperature might be coupled to control the responsive behavior of these hydrogels .
5.23 Controlled Release of Tinidazole and Theophylline from Chitosan-Based Composite Hydrogels
Swelling diffusion and network parameters of hydrogels. (Reproduced from Himadri et al. , copyright © 2014, with permission from Elsevier)
kD/n/D × 105a
Mc × 10−6/ρc × 10−17/ς
5.24 Chitosan-Poly(N-Isopropylacrylamide) Full Interpenetrating Polymer Network Hydrogels
5.25 Dual Crosslinked Iminoboronate–Chitosan Hydrogels
5.26 Ring-Like Structured Chitosan–Metal Hydrogel
5.27 Carboxymethyl Chitosan/ZnO Nanocomposite Hydrogels
Carboxymethyl chitosan/ZnO nanocomposite hydrogels were successfully prepared via in situ formation of ZnO nanorods in a crosslinked carboxymethyl chitosan (CMCh) matrix by connection of the CMCh hydrogel matrix with zinc nitrate solution followed by oxidation of zinc ions in an alkaline media. FTIR spectroscopy, XRD, and SEM were used as tools to characterize the CMCh/ZnO hydrogels. SEM revealed data on the ZnO nanorods in the hydrogel matrix, with the size ranging from 190 nm to 600 nm. In different pH media, the swelling behavior of the prepared nanocomposite hydrogels was evaluated. The CMCh/ZnO nanocomposite hydrogel showed greater swelling properties in different pH solutions than the neat CMCh hydrogel. Furthermore, the antibacterial activity of the CMCh/ZnO hydrogel against E. coli and Staphylococcus aureus was studied. An excellent antibacterial effect revealed the importance of the development of CMCh/ZnO nanocomposite hydrogel [46, 47].
5.28 Thyroxine-Releasing Chitosan/Collagen–Based Smart Hydrogels
In one study, new porous thyroxine-containing proangiogenic hydrogels were developed via a freeze gelation protocol. FTIR spectroscopic analysis was used to investigate the chemical structure of the synthesized hydrogels. SEM was used to analyze the morphology and pore dimensions of the hydrogels. A 10-μg thyroxine-loaded hydrogel (TLH-10) showed a greater degree of swelling than a 1-μg thyroxine-loaded hydrogel (TLH-1) and a control. Three different media – PBS, lysozyme, and hydrogen peroxide – were used to study the degradation of hydrogels, and relatively higher degradation was seen in hydrogen peroxide. Chick chorioallantoic membrane was used to check the angiogenic potential of the synthesized materials. The TLH-1 hydrogel stimulated angiogenesis more than TLH-10, and blood vessels were attached and very much grown into the scaffold .
5.29 Mucoadhesive Chitosan Hydrogels for Rectal Drug Delivery
Mucoadhesive drug delivery systems are mainly stuck on mucosal tissues and prolong the local retention time of drugs. Mucoadhesive rectal formulations have been used to treat various diseases such as hypertension and colon cancer. Ulcerative colitis (UC) is an inflammatory bowel disorder, mainly characterized by chronic inflammation of the colonic mucosa. It is commonly treated with sulfasalazine (SSZ), which is easily metabolized by intestinal flora and is biotransformed into the therapeutic 5-aminosalicylic acid (5-ASA) and a toxic by-product, sulfapyridine (SP). SSZ is mainly administered by the oral or rectal routes. The rectal route avoids unintended absorption of the drug or its degradation products in the upper gastrointestinal tract, because of the limited retention time.
In one study, a mucoadhesive hydrogel of catechol-modified chitosan (cat-CS) crosslinked by genipin was prepared to improve the efficacy of rectal SSZ administration. A UC mouse model was used to evaluate the efficacy of hydrogel with SSZ. In comparison with oral SSZ treatment, rectal SSZ/cat-CS delivery was more effective, showed equivalent histological scores, and induced a lower plasma concentration of the potentially toxic SP by-product. These results showed that SSZ/cat-CS rectal hydrogels are more effective and safer formulations for UC treatment than oral SSZ [49, 50].
5.30 Chitosan–Doxycycline Hydrogel: A Matrix Metalloproteinase Inhibitor/Sclerosing Embolizing Agent
In one study, an injectable occlusive chitosan (CH) hydrogel containing doxycycline (DOX) was prepared as a sclerosant and matrix metalloproteinase (MMP) inhibitor. Several CH-DOX hydrogel formulations were evaluated for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. Hydrogel prepared with 0.075 M sodium bicarbonate and 0.08 M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel followed a two-stage pattern: a burst release was followed by a slow continuous release. The released DOX was biologically active and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success rates of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appeared to be a promising new multifunctional embolic agent for the treatment of endoleaks [51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64].
5.31 Chitosan Hydrogels Enriched with Polyphenols
A novel injectable hydrogel of chitosan, sodium beta-glycerophosphate (Na-β-GP), and alkaline phosphatase (ALP), enriched with the polyphenols phloroglucinol (PG) and gallic acid (GA), was prepared for bone regeneration and characterized physicochemically and biologically, mainly in terms of its gelation kinetics, mineralizability, antioxidant properties, antibacterial activity, cytocompatibility, and ability to support adhesion and growth of human osteoblast–like MG63 cells. Enrichment of chitosan hydrogels with PG and GA had no negative effects on gelation kinetics and mineralizability. PG and GA both enhanced the antioxidant activity of unmineralized hydrogels. Mineralization also reduced the antioxidant activity of hydrogels containing GA. Hydrogels containing GA and PG and without polyphenols reduced the colony-forming ability of E. coli after 1-h, 3-h, and 6-h incubation and slowed E. coli growth in liquid culture for 150 min. Hydrogels with GA were cytotoxic and supported cell growth more poorly than polyphenol-free hydrogels. No negative effects of PG on cell adhesion and growth were shown .
5.32 Improved Sustained Release of Antigen from Immunostimulatory DNA Hydrogel
A novel antigen delivery system was developed using immunostimulatory DNA hydrogel (sDNA hydrogel) containing unmethylated cytosine–phosphate–guanine (CpG) sequences, which effectively induced an antigen-specific immune response through stimulation of the innate immune system. Relatively rapid release of antigens from the sDNA hydrogel was the main limitation of its potential. For enhancement of sDNA hydrogel potency with an improved sustained release property, a biocompatible cationic polymer chitosan was selected, which electrostatically interacted with DNA to form sDNA hydrogel. In comparison with unmixed sDNA hydrogel, chitosan–sDNA hydrogel was more stable, bound more water, was able to release antigen ovalbumin (OVA) more slowly in vitro, and provided longer retention at the injection site after intradermal injection into mice. Induction of a higher level of OVA-specific immunoglobulin G (IgG) in serum was seen with OVA-loaded chitosan–sDNA hydrogel than with OVA-loaded sDNA hydrogel with no chitosan after intradermal immunization in mice. These results indicated that the chitosan–sDNA hydrogel was an improved sustained release formulation for efficient induction of antigen-specific immune responses .
5.33 Sterilization-Free Chitosan Hydrogels
In one study, chitosan hydrogels were fabricated using steam sterilization, which was a simple, rapid, and solvent-free process. The resultant hydrogels were directly applied in vitro, in vivo, and in clinical studies. Drug-laden hydrogels were fabricated by this process to exhibit nearly zero-order release for up to 7 days. Also, a double-layer hydrogel system was developed for programmed drug release. In this case, the inner layer–encapsulated drug was released after degradation of the drug-free outer layer. The dimension of the outer layer was regulated for the delayed release time of the hydrogels .
5.34 Novel Thermosensitive Hydrogel Based on Chitosan/Hydroxypropyl Methylcellulose/Glycerol
In this work a novel thermosensitive hydrogel was prepared in physiological conditions, using chitosan together with hydroxypropyl methylcellulose and glycerol. The hydroxypropyl methylcellulose was used to facilitate the thermogelation process via a large proportion of hydrophobic interactions. In a heavy concentration of glycerol, the polymer water sheath was destroyed, which promoted formation of hydrophobic regions and lowered the phase transition temperature. The thermosensitive hydrogels showed a gelation time within 15 min at 37 °C at a near-physiological pH ranging from 6.8 to 6.9. FTIR, XRD, SEM, and rheological, mechanical, and contact angle studies were used to characterize the prepared hydrogels. The degradability, cytotoxicity, and protein release behaviors of the hydrogels were also investigated, indicating that the thermosensitive hydrogel possessed good fluidity, thermosensitivity, and biodegradability, with low cytotoxicity and controlled-release behavior, with great potential for use in biomedical applications .
5.35 Synthesis and Characterization of Chitosan Hydrogels
Novel chitosan hydrogels were prepared via crosslinking with dicarboxylic acids such as succinic, glutaric, and adipic acid, with the main intention being to compare the effect of the chain length on the behavior of the material. The swelling properties were studied at different pH values and temperatures, used as regulating parameters to evaluate the swelling properties of the hydrogels. The mechanical properties of these hydrogels were evaluated by creep recovery and stress relaxation studies, and the chitosan/succinic acid hydrogels exhibited completely viscous behavior. DSC and TGA were used to quantify the thermal behavior of the hydrogels, which revealed that the materials obtained were completely amorphous. Acetaminophen (paracetamol) was used as a positive control for the release kinetics studies. Finally, it was determined that the release process was controlled by the diffusion process .
5.36 Zinc–Pectinate–Sterculia Gum Interpenetrating Polymer Network Beads Encapsulating Ziprasidone HCl
Experimental plan of 32 full factorial design (with coded values in parentheses) with observed response values and various physical characteristics. (Reproduced from Bera et al. , copyright © 2015, with permission from Elsevier Ltd.)
Factors with normalized levels
Floating lag time (min)a
LM pectin (mg, X1)
SG (mg, X2)
93.62 ± 0.12
56.63 ± 1.23
2.24 ± 0.13
0.608 ± 0.18
1.33 ± 0.17
86.37 ± 0.25
58.57 ± 0.94
1.74 ± 1.56
0.651 ± 0.12
2.66 ± 0.31
80.03 ± 1.23
60.32 ± 1.97
1.23 ± 0.56
0.670 ± 0.17
4.62 ± 0.24
83.01 ± 0.89
59.64 ± 1.78
1.93 ± 0.54
0.658 ± 0.09
3.67 ± 0.33
74.47 ± 1.56
64.20 ± 1.18
1.53 ± 0.13
0.723 ± 0.05
6.35 ± 0.18
70.45 ± 1.78
66.80 ± 3.32
1.17 ± 0.15
0.856 ± 0.02
5.65 ± 0.22
71.91 ± 1.37
64.72 ± 0.29
1.80 ± 0.09
0.756 ± 0.16
7.41 ± 0.46
63.36 ± 0.47
69.67 ± 0.34
1.45 ± 0.74
0.739 ± 0.13
7.01 ± 0.50
61.48 ± 1.36
70.52 ± 1.85
1.12 ± 0.61
0.911 ± 0.19
8.66 ± 0.67
87.98 ± 1.15
58.81 ± 1.50
2.17 ± 0.13
0.612 ± 0.14
1.43 ± 0.27
88.79 ± 0.91
57.95 − 1.46
5.37 Chitosan-Based Nanoparticles for Oral Drug Delivery
Formulation chart for preparation of different alprazolam-loaded nanoparticles and their drug entrapment efficiency (DEE) values. (Reproduced from Jana et al. , copyright © 2013, with permission from Elsevier Ltd.)
Egg albumin (mg)
PEG 400 (mL)
Heating time (min)
DEE (%) (mean ± SD; n = 3)
90.48 ± 4.78
86.90 ± 3.43
83.22 ± 3.06
92.62 ± 4.08
83.58 ± 3.28
99.37 ± 4.86
68.12 ± 1.27
80.14 ± 2.64
84.70 ± 3.42
5.38 Novel Alginate Hydrogel Core–Shell Systems Ranitidine HCl and Aceclofenac Combination Therapy
Different formulations of aceclofenac-loaded alginate microspheres coated with Eudragit L-100, with drug entrapment efficiency (DEE) values and particle sizes. (Reproduced from Jana et al. , copyright © 2015, with permission from Elsevier BV)
Sodium alginate (%)
Coating solution (mL)
Coated microspheres containing aceclofenac
Particle size (μm)a
64.67 ± 2.41
677.18 ± 27.05
68.03 ± 2.16
666.03 ± 21.44
57.65 ± 1.18
567.82 ± 20.12
64.92 ± 2.49
672.93 ± 21.18
65.83 ± 2.02
652.04 ± 20.42
56.06 ± 1.12
551.29 ± 25.92
58.28 ± 1.42
567.04 ± 21.55
This chapter has provided a brief overview of the field of chitosan-based hydrogels, modified or functionalized biopolymer hydrogels, and composite materials that have been used for controlled-release drug delivery. Despite their limitations, chitosan hydrogels have been extensively used in controlled drug delivery systems for various active pharmaceutical ingredients targeting site-specific activities. Natural hydrogels are in demand in biomedical science especially for developing drug formulations for targeted and slow release, tissue regeneration, and molecular engineering.
7 Future Scope
Natural polymers have been the prime choice of scientists across the world because of their biodegradable and biocompatible nature, along with their extensive applications in the fields of controlled drug delivery. Full and semi-interpenetrating polymer networks of chitosan hydrogels with silver nitrate, thyroxine, and doxycycline as active pharmaceutical ingredients (APIs) have immune stimulatory, antibacterial, antifungal, and matrix metalloproteinase inhibitory properties, as well as many other properties. The future scope of this field will include investigation of natural polymers with their own activity profiles that can synergize the activity of APIs.
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