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Interpenetrating Polymer Network Hydrogels of Chitosan: Applications in Controlling Drug Release

  • Dilipkumar PalEmail author
  • Amit Kumar Nayak
  • Supriyo Saha
Living reference work entry
Part of the Polymers and Polymeric Composites: A Reference Series book series (POPOC)

Abstract

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.

Keywords

Chitosan Interpenetrating polymer network (IPN) Hydrogel Oral dosage forms Drug release 

1 Introduction

Chitin was first discovered in 1811 by Henry Braconnot, during studies conducted on mushrooms. The word “chitin” is derived from a Greek word meaning “tunic.” A linear aminopolysaccharide of glucosamine and N-acetylglucosamine units, which was named “chitosan” (pronounced “kite-o-san”) by Hoppe-Seiler, is obtained by alkaline deacetylation of chitin extracted from the exoskeleton of crustaceans, such as shrimps and crabs, and the cell walls of some fungi [1]. Chitosan was initially used as a hemostatic agent and then as a water purification agent and supplement for weight loss. Chitosan have various advantages for use in applications, as it has a defined chemical structure, which can be chemically and enzymatically modified for physical and biological functionality, and it is biodegradable and biocompatible?. The structure of chitosan is shown in Fig. 1.
Fig. 1

Structure of chitosan

2 Production of Chitosan

The raw materials for chitosan are abundantly available as the shells of crab, shrimp, and prawn. Through treatment with sodium hydroxide or digestion in the presence of proteolytic enzymes such as papain, proteins are removed from the ground shells. Calcium carbonate and calcium phosphate are extracted out with hydrochloric acid treatment [2]. Melanin and carotenoids are washed out by treatment with 0.02% potassium permanganate at 60 °C. Conversion of chitin to chitosan is achieved by hydrolysis of acetamide groups of chitin. Thermal treatment of chitin with a strong aqueous alkali such as sodium hydroxide or potassium hydroxide (40–50% at 100 °C) to remove some or all of the acetyl groups from the polymer produces partially deacetylated chitin, regarded as chitosan. Also, a deacetylation reaction is carried out in the presence of thiophenol as a scavenger of oxygen or under an N2 atmosphere to prevent chain degradation, which invariably occurs because of a peeling reaction under strong alkaline conditions [3]. The scheme for the production of chitosan is shown in Fig. 2.
Fig. 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 [4].

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 [5]. 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 [6]. 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 [7]. 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 [8].

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 [9].

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 [10].

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 [11].

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 [12].

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 [13].

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 [14].

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 [15].

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 [16].

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 [17].

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 [20].

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 [23].

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 [27].

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 [28].

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 [33].

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 [34].

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 [35].

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

In situ novel granular semi-IPN hydrogels were prepared in an aqueous solution by free radical grafting and crosslinking using chitosan (CTS), acrylic acid (AA), gelatin (GE), and MBA. FTIR spectra and elemental analysis were used as tools to confirm the grafting of AA monomers onto a CTS backbone, and the GE macromolecular chains were interpenetrated through the chitosan-g-poly(acrylic acid) (CTS-g-PAA) network. As per the SEM observations, the hydrogels were granular in nature and composed of numerous microspheres. The gel strength, adsorption, reuse, and recovery properties of the hydrogels for Cu2+ ions were thoroughly investigated. The outcomes indicated that the hydrogel with 2 wt% GE had the highest adsorption capacity of 261.08 mg/g, with a recovery ratio of 95.2%. Incorporation of 10 wt% GE enhanced the storage modulus by 103.4% (ω = 100 rad/s) and 115.1% (ω = 0.1 rad/s) and the adsorption rate by 5.67%. The adsorption capacity of the hydrogel was still as high as 153.9 mg/g after five cycles of adsorption–desorption, which correlated with the ion exchange and complexation interactions between the functional groups (-COO and -NH2) of the hydrogels and the Cu2+ ions being the predominant adsorption mechanisms [39]. Figure 3 shows the structural formation of the granular CTS-g-PAA/GE semi-IPN hydrogel. Figure 4 shows SEM images of the semi-IPN hydrogel. Table 1 lists the adsorption isotherm parameters for the adsorption of Cu2+ ions onto the hydrogels.
Fig. 3

Granular chitosan-g-poly(acrylic acid)/gelatin (CTS-g-PAA/GE) semi-interpenetrating polymer network hydrogel. (Reproduced from Wen et al. [39], copyright © 2013, with permission from Elsevier BV)

Fig. 4

Formed semi-interpenetrating polymer network (IPN) hydrogel before dewatering (a), after dewatering by methanol (b), and after drying (c). Scanning electron micrographs of semi-IPN10 hydrogel at magnifications of ×2000 (d) and ×5000 (e). (Reproduced from Wen et al. [39], copyright © 2013, with permission from Elsevier BV)

Table 1

Estimated adsorption isotherm parameters for adsorption of Cu2+ ion onto hydrogels. (Reproduced from Wen et al. [39], copyright © 2013, with permission from Elsevier BV)

Sample

Langmuir equation

Freundlich equation

qm

b

R2

K

n

R2

CTS-g-PAA

300.31

0.0356

0.9998

52.36

3.7543

0.9195

Semi-IPN2

305.82

0.0486

0.9999

61.65

4.0514

0.9259

Semi-IPN10

294.13

0.0271

0.9997

48.19

3.6784

0.9275

Semi-IPN20

277.04

0.0244

0.9996

43.36

3.6129

0.9246

CTS-g-PAA chitosan-g-poly(acrylic acid), IPN interpenetrating polymer network

5.21 Semi-interpenetrating Polymer Network Hydrogel: Preparation, Swelling Properties, and Adsorption Studies of Co (II)

Superadsorbent semi-IPN hydrogels of polyvinyl alcohol/poly(acrylic acid-co-acrylic amide) (PVA-P(AA-co-AM)) were developed via a free radical polymerization method under ultrasound-assisted conditions. The reaction conditions were optimized by L16(45) orthogonal experiments, and the formation of hydrogels was characterized by FTIR, SEM, and thermogravimetric analysis (TGA) studies. In various pH and saline solutions, the swelling properties of hydrogels were observed. The pH of the solution showed an obvious influence on the swelling characteristics of the hydrogel, and the salt resistance was greater in low valency of the salt solution relative to high valency. Also, the swelling behavior was evaluated in an aqueous solution, which revealed that the swelling process maintained the Schott model and non-Fickian diffusion properties. The optimum adsorption of cobalt (II) ions from aqueous solutions was observed at a pH value close to 4, and adsorption kinetics and adsorption isotherms for cobalt (II) were maintained with the pseudo-second-order model and the Freundlich model, respectively. Finally, it was concluded that the adsorption behavior was spontaneous and endothermic [40]. Figure 5 shows SEM images of P(AA-co-AM) and sodium lignosulfonate–grafted poly(acrylic acid-co-acryl amide)-17 (SL-P(AA-co-AM)-17). Table 2 compares the Co (II) adsorption capacities of some adsorbents.
Fig. 5

Scanning electron microscopy images showing different magnifications of poly(acrylic acid-co-acrylic amide) (P(AA-co-AM)) (a) and sodium lignosulfonate–grafted poly(acrylic acid-co-acryl amide)-17 (SL-P(AA-co-AM)-17) (b). (Reproduced from Xiaohong et al. [40], copyright © 2016, with permission from Elsevier BV)

Table 2

Comparison of Co (II) adsorption capacities of some adsorbents. (Reproduced from Xiaohong et al. [40], copyright © 2016, with permission from Elsevier BV)

Adsorbent

Adsorption capacity (mg g−1)

Concentration of Co ions (mg L−1)

Acacia nilotica leaf carbon

12.8

50

Modified chelating fibers

72.88

350

Crosslinked magnetic CSIS

53.51

350

Crosslinked magnetic CSMO

60.15

350

Nanostructured goethite

86.6

500

γ-MnO2 nanostructure

90.91

500

Apricot stone activated carbon

16.3

80

Nano-NaX geolite

125.3

400

Chitosan–montmorillonite

150

270

PVA-P (AA-co-AM)

184 (a), 332 (b)

250 (a), 400 (b)

CSIS chitosan–isatin Schiff’s base resin, CSMO chitosan–diacetylmonoxime Schiff’s base resin, PVA-P(AA-co-AM) polyvinyl alcohol/poly(acrylic acid-co-acrylic amide)

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 [41].

5.23 Controlled Release of Tinidazole and Theophylline from Chitosan-Based Composite Hydrogels

Free radical crosslink copolymerization of acrylic acid (AA) and N-methylene-bis-acrylamide (MBA) in the presence of chitosan (CS) was used to synthesize various composite hydrogels. During polymerization, CS was incorporated in situ in the crosslinked polyacrylic acid gel to obtain composite hydrogels. FTIR, 13C nuclear magnetic resonance (NMR), differential thermal analysis (DTA), TGA, XRD, swelling and diffusion characteristics, and network parameters were used to identify the structure and properties of the hydrogels. Tinidazole and theophylline were used as model drugs with these hydrogels to evaluate loading and in vitro release behaviors. The drug release behavior from the gels was strongly influenced by the wt% of CS and MBA and the pH of the medium. The release rate of these two drugs was much faster at pH 7.6 than at pH 1.5 [42]. Scheme 1 represents the formation of the composite hydrogel. Table 3 lists the swelling diffusion and network parameters of the hydrogels.
Scheme 1

Formation of composite hydrogel. (Reproduced from Himadri et al. [42], copyright © 2014, with permission from Elsevier)

Table 3

Swelling diffusion and network parameters of hydrogels. (Reproduced from Himadri et al. [42], copyright © 2014, with permission from Elsevier)

Polymer

ks2/r0a

ESRexpt/ESRcal (g/g)

r2/X2/F

kD/n/D × 105a

r2/X2/F

Mc × 10−6c × 10−17

MBA 1

0.001931/0.0323

13.06/14.84

0.96/0.0.449/910

0.018/0.57/2.5

0.963/0.0008/3363

21/0.53/916

MBA 2

0.0022/0.019

8.39/8.911

0.993/0.294/1365

0.041/0.39/1.81

0.990/0.0011/1920

3.3/4.14/812

MBA 3

0.009101/0.0705

6.32/5.46

0.937/0.169/1238

0.143/0.27/4.58

0.987/0.0009/5882

7.46/3.52/416

I 1.0

0.0025/0.0174

7.073/8.190

0.996/0.063/1885

0.038/0.42/3.32

0.951/0.0018/474

3.1/10.81/341

I 0.75

0.0023/0.028

11.3/12.56

0.986/0.610/280

0.043/0.38/2.23

0.998/0.0013/1779

3.2/5.52/417

I 0.5

0.0022/0.019

8.39/8.911

0.993/0.294/1365

0.041/0.39/1.81

0.990/0.0011/1920

3.3/4.14/812

I 0.25

0.0048/0.038

7.252/7.87

0.953/0.038/3029

0.148/0.28/1.84

0.9675/0.002/379

3.73/2.7/1261

CS 0.50

0.001790/0.029

13.157/14.47

0.992/0.132/4906

0.018/0.56/3.50

0.995/0.0014/5398

3.78/2.1/846

CS 1.0

0.001398/0.0295

16.32/19.74

0.996/0.306/3723

0.011/0.63/4.53

0.998/0.0042/1979

6.2/1.62/854

CS 2.0

0.001013/0.013

7.18/8.94

0.972/0.12/1423

0.012/0.62/1.18

0.908/0.0036/1746

1.38/2.4/421

AA 15

0.0020/0.0382

6.112/7.765

0.952/0.21/406

0.023/0.53/5.6

0.955/0.013/108

6.23/1.62/378

AA 20

0.0013/0.0201

7.433/8.16

0.986/0.80/423

0.013/0.63/7.91

0.988/0.002/829

10/0.8/817

AA 25

0.0022/0.019

8.39/8.911

0.993/0.294/1365

0.041/0.39/1.81

0.990/0.0011/1920

3.3/4.14/812

AA acrylic acid, CS chitosan, MBA N-methylene-bis-acrylamide

aks2 (g gel/g water min), r0 (g water/g gel min), kD, n, D (cm2/s)

5.24 Chitosan-Poly(N-Isopropylacrylamide) Full Interpenetrating Polymer Network Hydrogels

Chemical amalgamation of a methylene bis-acrylamide (MBAM) crosslinked poly(N-isopropylacrylamide (PNIPAM) network with a formaldehyde (HCHO) crosslinked CS network was used to develop full IPN chitosan/poly(N-isopropylacrylamide) (CS/PNIPAM) hydrogels. The extractability of PNIPAM within the gel, the phase transition behavior, the swelling dynamics in the aqueous phase, and the swelling behavior in ethanol/water mixtures were evaluated, and the microstructure was quite different from those of the semi-IPN CS/PNIPAM hydrogels, in which PNIPAM was simply embedded. Like the semi-IPN CS/PNIPAM hydrogels, however, the newly formed gel was temperature sensitive; it was transparent below 30 °C and opaque above that temperature. It was expected that the new smart hydrogels may find uses in separation science and also in the design and preparation of new soft machines [43]. Figure 6 shows general surface views of various xerogels. Figure 7 shows plots of the swelling ratio against the swelling time for the two CS/PNIPAM gels at two different temperatures.
Fig. 6

General surface view of various xerogels. (a) Chitosan (CS). (b) Semi-interpenetrating polymer network (IPN) CS/poly(N-isopropylacrylamide) (PNIPAM). (c) Full IPN CS/PNIPAM. (Reproduced from Mingzhen et al. [43], copyright © 2001, with permission from Elsevier BV)

Fig. 7

Plots of the swelling ratio against the swelling time for two chitosan/poly(N-isopropylacrylamide) (CS/PNIPAM) gels at two different temperatures. (Reproduced from Mingzhen et al. [43], copyright © 2001, with permission from Elsevier BV)

5.25 Dual Crosslinked Iminoboronate–Chitosan Hydrogels

Chitosan-based hydrogels have been extensively studied in biomedical, industrial, and environmental applications, but their biomedical use has been limited by the toxicity of different organic crosslinkers. To overcome this limitation, a new strategy to produce supramolecular chitosan hydrogels has been devised using low molecular weight compounds, which are able to form covalent linkages and H-bonds to give dual crosslinking hydrogels. To fulfill this purpose, 2-formyl phenylboronic acid was used, which incorporates imine stabilization via iminoboronate formation and has potential antifungal activity due to the presence of boric acid residue. Chemophysical crosslinking using a dual iminoboronate–chitosan network was used to form hydrogels, as indicated by FTIR and NMR spectroscopy. Further, XRD studies also demonstrated three-dimensional nanostructuring of the iminoboronate network with consequences for the micrometer-scale morphology and improvement of mechanical properties, evaluated by SEM and rheological investigation. The hydrogels showed strong inhibitory activity against Candida planktonic yeasts and biofilms, showing promise as a treatment for recurrent vulvovaginitis infections [44]. Scheme 2 shows the obtaining of the hydrogels and the model compound. Figure 8a shows representative XRD of the iminoboronate–chitosan xerogels and the chitosan reference. Figure 8b shows a schematic representation of an iminoboronate–chitosan cluster.
Scheme 2

Obtaining of the hydrogels and the model compound. (Reproduced from Daniela et al. [44], copyright © 2016, with permission from Elsevier Ltd.)

Fig. 8

(a) Representative x-ray diffraction of iminoboronate–chitosan xerogels and chitosan reference. (b) Schematic representation of an iminoboronate–chitosan cluster. (Reproduced from Daniela et al. [44], copyright © 2016, with permission from Elsevier Ltd.)

5.26 Ring-Like Structured Chitosan–Metal Hydrogel

To improve the adsorbent ability and facilitate the solid/liquid separation of chitosan, its structure was molded into several shapes. A ring-like structure of chitosan had a relatively large surface area and high chemical accessibility; the characteristics of its plate-like counterparts have not yet been reported. In this work, a novel concept was fabricated to form a highly efficient ring-like chitosan hydrogel structure via a sulfate ionic crosslinking method, and its mass production and formation mechanism were fully proposed. A ring-like chitosan–Fe(III) hydrogel exhibited outstanding adsorbent properties with an AR73 removal rate of 98.53% and a Cr(VI) removal rate of 90.53%. The adsorption of AR73 fitted well with the pseudo-second-order model and Langmuir isotherm model, which indicated that the chitosan–Fe(III) hydrogel ring structure possessed a considerable adsorption capacity of 205.2 mg/g. Also, the chitosan–Fe(III) hydrogel ring could efficiently adsorb both AR73 and Cr(VI) simultaneously (96.9% and 85.9%, respectively). Overall, this study revealed a facile method to prepare ring-like structures of chitosan–metal hydrogel, which could be mass-produced as multifunctional materials for practical applications [45]. Scheme 3 shows a schematic illustration of the transition of chitosan hydrogel in the deposition process. Figure 9 shows chitosan hydrogels with the addition of different kinds of metal salt.
Scheme 3

Schematic illustration of the transition of chitosan hydrogel in the deposition process. (Reproduced from Hao et al. [45], copyright © 2016, with permission from Elsevier Inc.)

Fig. 9

Chitosan hydrogel with addition of different kinds of metal salt. a1 FeCl3, a2 Fe(NO3)3, and a3 Fe2(SO4)3 at a low concentration. b1 FeCl3, b2 Fe(NO3)3, and b3 Fe2(SO4)3 at a high concentration. c1 NaCl, c2 NaNO3, and c3 Na2SO4 at a low concentration. d1 NaCl, d2 NaNO3, and d3 Na2SO4 at a high concentration. (Reproduced from Hao et al. [45], copyright © 2016, with permission from Elsevier Inc.)

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 [48].

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 [65].

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 [66].

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 [67].

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 [68].

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 [69].

5.36 Zinc–Pectinate–Sterculia Gum Interpenetrating Polymer Network Beads Encapsulating Ziprasidone HCl

In one study, ziprasidone was delivered via crosslinked low-methoxyl (LM) pectinate–sterculia gum (SG) IPN intragastric beads, which were created by simultaneous ionotropic gelation with zinc acetate and covalent crosslinking with glutaraldehyde. The effects of the pectin and SG content on the DEE and cumulative drug release after 8 h (Q8) were studied to optimize the beads, using a 32 factorial design. The optimized beads encapsulating ziprasidone HCl (F-O) displayed DEE values of 87.98 ± 1.15% and a Q8 of 58.81 ± 1.50%, with excellent buoyancy (floating lag time <2 min, buoyancy at 8 h >63%) and an optimum mucoadhesive effect with goat gastric mucosa. The drug release behavior was maintained by Higuchi kinetics with an anomalous transport mechanism. Analytical tools such as SEM, FTIR, DSC, and P-XRD were used to characterize the Zn–pectinate–SG IPN beads [70]. Figure 10 shows response surface three-dimensional (3D) plots and contour plots illustrating the effects of the LM pectin and SG amounts on DEE and on Q8(%). Figure 11 shows SEM images of Zn–pectinate–SG IPN beads (F-O) showing a rough surface at low magnification (×75) and the presence of pores and channels at high magnification (×900). Table 4 shows the experimental plan of the 32 full factorial design (with coded values in parentheses), with observed response values and various physical characteristics.
Fig. 10

Response surface three-dimensional (3D) plots (a) and contour plots (b) illustrating the effects of low-methoxyl (LM) pectin and sterculia gum (SG) amounts on the drug entrapment efficiency (DEE) percentage. Response surface 3D plots (c) and contour plots (d) demonstrating the effects of LM pectin and SG amounts on the cumulative drug release percentage after 8 h (Q8(%)). (Reproduced from Bera et al. [70], copyright © 2015, with permission from Elsevier Ltd.)

Fig. 11

Scanning electron microscopy images of Zn–pectinate–sterculia gum (SG) interpenetrating polymer network beads (F-O) showing a rough surface at low magnification (×75) (a) and the presence of pores and channels at high magnification (×900) (b). (Reproduced from Bera et al. [70], copyright © 2015, with permission from Elsevier Ltd.)

Table 4

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. [70], copyright © 2015, with permission from Elsevier Ltd.)

Formulation code

Factors with normalized levels

Responses

Diameter (mm)a

Density (gm/cm3)a

Floating lag time (min)a

LM pectin (mg, X1)

SG (mg, X2)

DEE (%)a

Q8 (%)a

F-1

750.00 (+1)

300.00 (+1)

93.62 ± 0.12

56.63 ± 1.23

2.24 ± 0.13

0.608 ± 0.18

1.33 ± 0.17

F-2

750.00 (+1)

250.00 (0)

86.37 ± 0.25

58.57 ± 0.94

1.74 ± 1.56

0.651 ± 0.12

2.66 ± 0.31

F-3

750.00 (+1)

200.00 (−1)

80.03 ± 1.23

60.32 ± 1.97

1.23 ± 0.56

0.670 ± 0.17

4.62 ± 0.24

F-4

675.00 (0)

300.00 (+1)

83.01 ± 0.89

59.64 ± 1.78

1.93 ± 0.54

0.658 ± 0.09

3.67 ± 0.33

F-5

675.00 (0)

250.00 (0)

74.47 ± 1.56

64.20 ± 1.18

1.53 ± 0.13

0.723 ± 0.05

6.35 ± 0.18

F-6

675.00 (0)

200.00 (−1)

70.45 ± 1.78

66.80 ± 3.32

1.17 ± 0.15

0.856 ± 0.02

5.65 ± 0.22

F-7

600.00 (−1)

300.00 (+1)

71.91 ± 1.37

64.72 ± 0.29

1.80 ± 0.09

0.756 ± 0.16

7.41 ± 0.46

F-8

600.00 (−1)

250.00 (0)

63.36 ± 0.47

69.67 ± 0.34

1.45 ± 0.74

0.739 ± 0.13

7.01 ± 0.50

F-9

600.00 (−1)

200.00 (−1)

61.48 ± 1.36

70.52 ± 1.85

1.12 ± 0.61

0.911 ± 0.19

8.66 ± 0.67

Experimental values

F-O

729.50

289.09

87.98 ± 1.15

58.81 ± 1.50

2.17 ± 0.13

0.612 ± 0.14

1.43 ± 0.27

Predicted values

% errorb

88.79 ± 0.91

57.95 − 1.46

 

DEE drug entrapment efficiency, F formulation code, LM low-methoxyl, Q8 cumulative drug release after 8 h, SG sterculia gum

aMean ± standard deviation; n = 3

bError (%) = [(predicted value − actual value)/predicted value] × 100

5.37 Chitosan-Based Nanoparticles for Oral Drug Delivery

Cationic chitosan and anionic egg albumin with PEG 400 were used with an interpolymeric complexation technique to develop novel nanoparticles for oral delivery of alprazolam, using a heat coagulation method at pH 5.4 and 80 °C. Nine different formulations were prepared with variable concentrations of chitosan, PEG 400, and heating times. The DEE of these nanoparticles was within the range of 68.12 ± 1.27 to 99.37 ± 4.86%. FTIR, DSC, powder XRD (P-XRD), and FE-SEM analytical techniques were used to characterize the nanoparticles. The average particle diameter, polydispersity index, and zeta potential of these nanoparticles were found to be 259.60 nm, 0.501, and −9.00 mV, respectively. The in vitro drug release profile of alprazolam-loaded nanoparticles showed a sustained drug release pattern over a period of 24 h. These newly developed chitosan–egg albumin–PEG nanoparticles were found to be a promising vehicle for sustained release delivery of lipophilic drugs [71]. Figure 12 shows an FE-SEM image of alprazolam-loaded chitosan–egg albumin–PEG nanoparticles (formulation 6 (F-6)) at ×65,000 magnification. Table 5 shows a formulation chart for the preparation of different alprazolam-loaded nanoparticles and their DEE values.
Fig. 12

Field emission scanning electron microscopy image of alprazolam-loaded chitosan–egg albumin–polyethylene glycol nanoparticles (formulation 6 (F-6)) at ×65,000 magnification. (Reproduced from Jana et al. [71], copyright © 2013, with permission from Elsevier Ltd.)

Table 5

Formulation chart for preparation of different alprazolam-loaded nanoparticles and their drug entrapment efficiency (DEE) values. (Reproduced from Jana et al. [71], copyright © 2013, with permission from Elsevier Ltd.)

Formulation code

Alprazolam (mg)

Egg albumin (mg)

Chitosan (mg)

PEG 400 (mL)

Heating time (min)

DEE (%) (mean ± SD; n = 3)

F-1

100

80

80

1.5

30

90.48 ± 4.78

F-2

100

80

80

0.5

10

86.90 ± 3.43

F-3

100

80

20

1.5

10

83.22 ± 3.06

F-4

100

80

20

0.5

30

92.62 ± 4.08

F-5

100

80

20

1.5

30

83.58 ± 3.28

F-6

100

80

80

0.5

30

99.37 ± 4.86

F-7

100

80

80

1.5

10

68.12 ± 1.27

F-8

100

80

20

0.5

10

80.14 ± 2.64

F-9

100

80

80

30

84.70 ± 3.42

F formulation, PEG polyethylene glycol, SD standard deviation

5.38 Novel Alginate Hydrogel Core–Shell Systems Ranitidine HCl and Aceclofenac Combination Therapy

A ranitidine HCl and aceclofenac composite hydrogel system was developed on the basis of a core–shell approach. Eudragit L-100 was used to coat aceclofenac-loaded alginate microspheres and freeze–thaw crosslinked chitosan–PVA gels containing ranitidine HCl utilized as the shell-forming material. The drug encapsulation efficiency of the Eudragit L-100 coated alginate microspheres was 56.06 ± 1.12% to 68.03 ± 2.16% with average particle sizes of 551.29 ± 25.92 μm to 677.18 ± 27.05 μm. In the chitosan–PVA gels the viscosity ranged between 505.74 ± 1.04 cps and 582.41 ± 2.09 cps. FTIR, SEM, and polarized microscopy analytical techniques were used to characterize the formulated hydrogels. The release of ranitidine HCl was comparatively higher in an acidic medium (pH 1.2) than in an alkaline medium (pH 7.4). In an alkaline medium (pH 7.4), release of aceclofenac was maintained at a slow rate and continued for up to 3.5 h. The release of ranitidine HCl in both media was assumed to follow a super case-II transport mechanism with predominance of a non-Fickian (anomalous) diffusion mechanism in the release of aceclofenac. So, these composite hydrogels were found to be highly suitable for simultaneous delivery of aceclofenac and ranitidine HCl with very minimal chances of excessive gastric acid secretion through suitable ranitidine HCl release in the gastric region [72]. Figure 13 shows SEM images of uncoated aceclofenac-loaded alginate microspheres and aceclofenac-loaded alginate microspheres coated with Eudragit L-100, and a cross-sectional view of aceclofenac-loaded alginate microspheres coated with Eudragit L-100. Table 6 lists the different formulations of aceclofenac-loaded alginate microspheres coated with Eudragit L-100, with DEE values and particle sizes.
Fig. 13

Scanning electron microscopy images of uncoated aceclofenac-loaded alginate microspheres (a and b), aceclofenac-loaded alginate microspheres coated with Eudragit L-100 (c), and a cross-sectional view of aceclofenac-loaded alginate microspheres coated with Eudragit L-100 (d). (Reproduced from Jana et al. [72], copyright © 2015, with permission from Elsevier BV)

Table 6

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. [72], copyright © 2015, with permission from Elsevier BV)

Formulation code

Sodium alginate (%)

Coating solution (mL)

Coated microspheres containing aceclofenac

DEE (%)a

Particle size (μm)a

F-1

3

10

64.67 ± 2.41

677.18 ± 27.05

F-2

3

5

68.03 ± 2.16

666.03 ± 21.44

F-3

2

10

57.65 ± 1.18

567.82 ± 20.12

F-4

3

10

64.92 ± 2.49

672.93 ± 21.18

F-5

3

5

65.83 ± 2.02

652.04 ± 20.42

F-6

2

5

56.06 ± 1.12

551.29 ± 25.92

F-7

2

10

58.28 ± 1.42

567.04 ± 21.55

F formulation

aMean ± standard deviation, n = 3

6 Conclusion

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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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Dilipkumar Pal
    • 1
    Email author
  • Amit Kumar Nayak
    • 2
  • Supriyo Saha
    • 3
  1. 1.Department of Pharmaceutical SciencesGuru Ghasidas Vishwavidyalaya (A Central University)BilaspurIndia
  2. 2.Department of PharmaceuticsSeemanta Institute of Pharmaceutical SciencesMayurbhanjIndia
  3. 3.Department of Pharmaceutical SciencesSardar Bhagwan Singh PG Institute of Biomedical Sciences and ResearchDehradunIndia

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