**3.3 Chitosan-based clay-containing material applications in drug delivery systems**

For controlled drug release systems, some carrier materials such as natural or synthetic polymers, metals, ceramics, oils, antibodies, magnetic components, and carbon are used in the world today. The most widely used of these materials are polymers, and some of these studies are in the stage of animal trials. Biocompatibility and biodegradability properties are sought in polymers used in drug delivery systems. Biodegradable polymers are polymers that can be enzymatically, microbiologically, or hydrolytically degraded in a physiological environment. The degradation products of biodegradable polymers must also be nontoxic. Biopolymers, modified natural polymers, and synthetic polymers are frequently used in the preparation of drug delivery systems. Along with this polymer, chemicals such as calcium hydroxyapatite, clay, organic-containing clay derivatives, magnetite and maghemite nanoparticles (for magnetic control), and graphene oxide are also used. In the following paragraphs, these subjects will be explained and studies on chitosan will be emphasized.

In recent years, studies have been carried out on the preparation and application of biodegradable polymer nanocomposites as controlled drug delivery systems [38–40]. Clay types such as montmorillonite (MMT), halloysite, organoclay, etc. are used in the preparation of these nanocomposites. MMT is a widely used material for controlled drug release as it retains the drug, thanks to its high cation exchange capacity. Clay minerals are natural cation exchangers and bind to the drug in solution by electrostatic attraction. Depending on the cation exchange capacity of the clay, cationic of the drug, release medium, and pH decide the release kinetics of the drug. It is possible to have different interactions such as hydrophobic, hydrogen bonding, ligand exchange, and water bridge, independent of electrostatic forces. These properties of clay encourage the use of clay for sustainable drug release [43]. However, the ability of clay particles to adsorb negative charged or neutral drugs is low. This limits the applications of negatively charged or neutral drugs. When preparing drug delivery systems, this disadvantage of clay should be taken into account [43].

Yuan et al. observed that the swelling rates of chitosan-clay biocomposites that they synthesized for drug release were lower than clay alone and chitosan alone. However, they stated that the drug release from the chitosan-clay biocomposite was more than that of clay and less than chitosan. They stated that with the addition of clay to chitosan, the interaction between the negatively charged groups in the clay and the positively charged NH3 + groups in the chitosan creates strong crosslinks. They stated that this situation affects the swelling behavior of the composite and, therefore, affects the diffusion of the drug in the structure [43]. Hua et al. studied the release of the drug ofloxacin from chitosan-MMT and chitosan-only hydrogel. They prepared different ratios of drug and clay with the same amount of chitosan, and they observed that the hydrogel containing the highest clay had the highest drug retention efficiency. With its high surface area, MMT adsorbed the drug not only on the inner and outer surfaces but also between the clay layers. With the addition of MMT, the drug release decreased and the dispersion viscosity of the drug increased. In the swelling test, the least swelling value was observed in chitosan, and the maximum swelling value was observed in the hydrogel with the highest MMT content. The amount and rate of drug release decreased as the amount of MMT increased. In the XRD analysis, the presence of the drug was observed in the medicated composite and chitosan, while the drug was lost in the hydrogel with high clay content. This indicates that drug molecules are lost at the polymeric level or get into the clay layers [44]. Cheikh et al. synthesized nanocomposite by intercalation method using chitosan and purified beidellite. In this study, they selected diclofenac sodium as a model drug and examined its release. According to the results of the analysis, the drug was both distributed between the layers of the clay and detected on the surface of the nanocomposite. They reported that with the nanocomposites they obtained, they reached 60% cumulative

#### *Chitosan-Based Nanocomposites for Biological Applications DOI: http://dx.doi.org/10.5772/intechopen.106379*

drug release in 8 hours at pH 6.8 [45]. In another study, Sharma et al. synthesized silymarin-loaded chitosan-MMT microbeads by ionotropic gelation method for the potential treatment of gastric ulcer [46]. Depan et al. grafted lactic acid onto chitosan and obtained the chitosan-g-lactic acid/Na+ MMT bionanocomposite. They characterized the structure of the composite by FTIR, XRD, SEM, and [1]H-NMR, and thought that this bionanocomposite could be used in controlled drug release and tissue engineering. For this purpose, they used the synthesized bionanocomposite for the transport of the drug sodium ibuprofen [47]. Sahoo et al. synthesized Chitosan/ polycaprolactone/Cloisite30B bionanocomposites using an 80:20 ratio of chitosan: polycaprolactone and Cloisite30B (organoMMT) at 1, 2.5 and 5% by mass and characterized their structures by FT-IR, XRD, and SEM. They reported that the synthesized biocomposite could be used in the controlled release of the drug doxycycline [48]. Parida et al. synthesized the Chitosan/Polyvinyl Alcohol/Cloisite30B bionanocomposite using Cloisite30B at different rates and reported that the composite could be used in controlled drug release [49]. In another study, Nanda et al. synthesized (by solvent removal method) Chitosan/Polylactic Acid/Cloisite30B bionanocomposites using different ratios of chitosan, polylactic acid, and Cloisite30B and characterized their structures with FT-IR, SEM, and XRD. They stated that the drug release properties of these biocomposites, which they used in the controlled release of paclitaxel anticancer drugs, were sensitive to pH and the amount of drug loaded [50]. Cojocariu et al. synthesized the Chitosan/Cloisite15A (organoMMT) bionanocomposite using different amounts of clay. They stated that the bionanocomposite has an intercalated structure by XRD and SEM analysis. They reported that the bionanocomposite containing 9% by mass of Cloisite15A delayed the controlled drug release [51].

It is known that hydrogels as new drug delivery systems have been used extensively in controlled drug release in recent years. Hydrogels provide control of drug release by showing swelling-shrinking behavior at different rates in different environments (temperature, pH, humidity, electric current, magnetic field, light, etc.) according to the cross-linker ratios in their content. Similarly, in nanoparticle synthesis, hydrogels are used for controlled size adjustment and stabilization of the produced nanometal particles [52]. Wang et al. synthesized a series of polymeric materials containing different amounts of attapulgite clay from the material they prepared with pH-sensitive chitosan, acrylic acid, attapulgite, and sodium alginate. Diclofenac sodium active drug substance was used to examine the controlled drug loading and release kinetics of the prepared materials. They reported that the material released 100% drug in basic medium and 3.76% in acidic medium [53]. Dinu et al. prepared chitosan/clinoptilolite biocomposite cryogels containing clinoptilolite clay in different proportions and investigated their drug release properties. SEM photographs revealed that the pores became smaller and the pore walls thickened as the clay content in the biocomposite increased. They reported that the swelling behavior of the cryogels they obtained and the drug release properties showed parallelism [54]. Luo and Mills used halloysite clay to strengthen chitosan hydrogels and prepared a biocompatible and biodegradable drug delivery system. They loaded gentamicin on both halloysite clay and chitosanhalloysite hydrogel. They observed that drug-loaded chitosan-halloysite hydrogels released drugs more slowly than drug-loaded halloysite hydrogels. They stated that as the rate of chitosan increased, long and effective drug release occurred over time [55]. Hua et al. synthesized chitosan/ofloxacin/MMT nanocomposite hydrogels using ofloxacin, a synthetic antibiotic, using sodium tripolyphosphate as the anionic cross-linker. In the drug delivery system, while the chitosan beads deteriorated within 3 hours at pH=1.2, it was determined as a result of the analysis that the synthesized

nanocomposite hydrogel degraded in 12 hours [55]. Ma et al. synthesized pH and temperature-sensitive carboxymethyl chitosan-g-poly(N, N-dimethyl acrylamide) polymers. They used vitamin B2 as a model drug and aimed to achieve intestinaltargeted controlled release of the developed drug-loaded hydrogels. Hydrogel beads were prepared by Ca2+ ionic crosslinking in an acidic solution and a double crosslinked network structure was obtained. The morphological features of the obtained products were also characterized. It was determined that the synthesized hydrogels performed an effective controlled release under gastrointestinal system conditions [56]. Aycan and Alemdar used hydroxyapatite-natural bone powder to increase the thermal and mechanical strength of chitosan hydrogels. They investigated the controlled and effective release of the drug under different physical conditions of the stomach and intestinal environment by loading the active ingredient of amoxicillin, which is used in the treatment of gastric ulcers, into hydrogels [57]. Yücel et al. prepared chitosan nanoparticles with quercetin, which is one of the polyphenolic compounds with antioxidant properties, and conducted in vitro and release studies. They observed that the quercetin release of nanoparticles could be sustained for 24 hours [58]. İnal investigated the release of indomethacin drug by synthesizing chitosan/κ-carrageenan/ chitosan trilayer microspheres. Controlled release studies were performed in pH 1.2 and 7.4 buffers and characterized by FTIR, SEM, and DSC. The drug entrapment efficiency of microspheres and the equilibrium swelling degree were determined by the particle size and controlled release data. He stated that the newly obtained system is a suitable controlled release system for drugs that cause stomach irritation [4]. Ulu A. synthesized allantoin-loaded chitosan nanoparticles and investigated the effect of chitosan molecular weights (low, medium, and high) on drug release. He proved that allantoin-loaded nanoparticles are affected by the molecular weight of chitosan by morphology, size, zeta potential, and loading efficiency methods. From the in vitro release results, it was observed that nanoparticles synthesized with chitosan with the lowest molecular weight were more effective in drug release [59].

Hospital infections significantly affect the success of implant materials placed in the body. Önder S. conducted a controlled release study of gentamicin, an antibiotic type, on a chitosan/titanium system that can be used to prevent infections. He first immobilized the antibiotic-laden chitosan onto titanium surfaces, and then exposed it to drying conditions (air and freeze-drying). It was observed that the release of antibiotics was higher on the freeze-drying surfaces. From the cell proliferation tests, it was observed that bone cells proliferated more in the chitosan/titanium system compared to the flat chitosan-coated surfaces [60]. In order to prevent infections related to implants and increase tissue interaction, studies are also carried out on the functionalization of implant surfaces and their drug release. Erşan and Önder S., in another of their studies, synthesized and characterized chitosan microspheres that can be used as bone filling material and drug delivery system, and determined the performance of microspheres in vitro. Microspheres were produced by the emulsion cross-linking method and used antibiotic ciprofloxacin as a drug. They tested the bioactivity of the microspheres in artificial body fluid and found that chitosan microspheres from the bioactivity tests had the potential to increase osteointegration. They stated that these spheres could be used as a filling material that can release biomolecules locally in bone tissue damage and can be used in surface modification of implant materials [38].

In drug delivery systems, functionalized, superparamagnetic magnetite (Fe3O4), and maghemite (ɣ-Fe2O3) nanoparticles enable the drug to reach the desired target cells with the effect of an externally applied magnetic field. Thus, the side effects

#### *Chitosan-Based Nanocomposites for Biological Applications DOI: http://dx.doi.org/10.5772/intechopen.106379*

of the drug are minimized. The surfaces of these nanoparticles, which are used as carrier systems, are usually functionalized with drugs, proteins, and genetic materials; and with these particles, the therapeutic agent is released at the targeted site [61]. Magnetite and maghemite nanoparticles are of great importance for biomedical applications because they are biocompatible and show low levels of toxicity [62]. Most of the applications in this field are biological investigations used to the orientation of the nanoparticle with the help of an externally applied magnetic field. Such materials, prepared by embedding ferromagnetic particles into the gel, are placed inside the body, the magnetic field is activated by a device used to provide a magnetic field, and the drug in the gel begins to be released [63]. Mahdavinia et al. synthesized magnetic and pH-sensitive hydrogel spheres obtained from carrageenan and carboxymethyl chitosan for a drug delivery system. Magnetic Fe3O4 nanoparticles were added to the biopolymer mixture by in situ polymerization method. The structural properties of the hydrogel spheres were characterized by TEM, SEM, XRD, and VSM techniques. The pH-dependent swelling behavior of hydrogels was investigated in various buffer solutions, and the swelling capacity of magnetic hydrogels was affected by the incorporation of magnetite nanoparticles into the carrageenan/chitosan complexes. The water absorption capacity of hydrogels decreased with increasing magnetite content. In the study, methotrexate, an anticancer drug was loaded into hydrogels as a model drug, and its release profiles were investigated at pH 7.4 and 5.3. Methotrexate encapsulation efficiency increased with increasing magnetite and chitosan content [64]. Long et al. synthesized chitosan/carrageenan/Fe3O4 nanoparticles, adsorbed bovine serum albumin into them, and studied the release behavior of protein from the nanoparticles [65]. Wang et al. prepared magnetic chitosan-5-fluorouracil nanoparticles for the target drug delivery system. The results showed that the loading capacity was 13.4%, and the percentage of release in phosphate buffer solution (pH=7.2) was 68% at 30 hours [66].
