Hydrogels are polymeric networks with three-dimensional configuration capable of imbibing large amounts of water or biological fluids. Owing to their ability to retain a significant amount of water, hydrogels mimic the natural structure of the body’s cellular makeup, which renders them important for an array of biomedical applications including tissue engineering, artificial organ and contact lens designing and most importantly in drug delivery. A truly amazing class of hydrogels that has found profound interests as drug delivery systems is the class of smart/ intelligent hydrogels. These hydrogels are endowed with the unique property to exhibit unusual volume changes in response to environmental stimuli. Efforts have focused mostly on designing hydrogel systems that make use of changes in response to pH and temperature. Despite numerous advantages, hydrogels are also associated with some inherent pharmacological limitations. The poor mechanical strength of many hydrogels results in their premature disintegration. The high water content and porous nature of the hydrogels often result in a relative rapid release of drug thereby reducing the therapeutic value.
The present study aims at addressing the above problems by incorporating preformed drug-cyclodextrin inclusion complexes (ICs) into the hydrogel matrix. Cyclodextrins are of interest in this context given their amphiphilic nature; a hydrophilic exterior and a hydrophobic pocket. The hydrophilic exterior can be useful for effective partitioning into the hydrogel matrix and maintaining the bulk hydrophilicity and swelling state of the hydrogel and the hydrophobic interior can facilitate the entrapment and controlled release of hydrophobic drugs and therapeutics. Of the parent α−, β− and −cyclodextrins, β−cyclodextrin (CD) is widely employed for pharmaceutical purposes in comparison to the other two. The scope of the present study particularly emphasizes the role of CD in controlled drug delivery from hydrogels.
Chapter 1 introduces the concept of hydrogels and their numerous applications in various fields. The utility of hydrogels as target-specific drug delivery agents has been discussed at length. The importance of cyclodextrins as drug delivery agents is hereby introduced. The different strategies of integrating hydrogels and cyclodextrins to achieve improved physico-chemical properties have also been discussed. The objective of the present thesis work is also given.
Chapter 2 provides information on the materials used and the methodologies employed for the studies.
Chapter 3 demonstrates the applicability of poly(vinyl alcohol) (PVA) hydrogels containing drug−CD ICs as controlled drug delivery systems. Different compositions of pure PVA hydrogels and CD−incorporated PVA hydrogels were synthesized with varying amount of the cross-linker glutaraldehyde (GA) by the solution casting technique. Hydrogels containing the free drug and ICs were also prepared and explored for their drug releasing properties. In this study, salicylic acid (SA) and ibuprofen (IBF) were chosen as the drugs of interest. The solid ICs of the drug in CD were prepared by the co-precipitation method. The swelling evaluation of the hydrogels indicated the decreased swelling with increasing GA content for both PVA and PVA-CD hydrogels. The role of CD, the effect of nature of drug and degree of cross-linking on the drug release process has also been investigated. The probable mechanism of drug release has also been addressed by fitting the release data to various mathematical equations. Controlled release of drug was achieved from the hydrogels containing the ICs. The effect of degree of cross-linking on the release pattern is strikingly different from hydrogels containing free drug and that with the ICs. The role of CD in the drug release process is not only because of its inclusion ability but also its effect on the polymer relaxation. GA, apart from cross-linking PVA, probably interacts with the hydroxyl groups of CDs thereby influencing the matrix structure. The nature of drug in terms of its binding efficacy with CD plays an important role. Thus the drug release is accomplished as a combination of the effects of drug diffusion, the polymer relaxation, the binding affinity of the drugs with CD and the effect of CD on the macromolecular relaxation. The cytotoxicity assay performed on the hydrogels by MTT colorimetric technique suggested a high compatibility of these hydrogels with the living tissues. Hence the strategy of incorporating pre-formed ICs into PVA hydrogels to achieve controlled delivery of drugs works quite well.
Chapter 4 presents the design of pH-responsive smart hydrogels based on chitosan (CS) and poly(acrylic acid) (PAA) for controlled drug delivery. This chapter consists of two parts; Part I: To explore the potential of GA cross-linked CS−PVA hydrogels towards the controlled delivery of non-steroidal anti-inflammatory drugs (NSAIDs), Naproxen (NX) and Diclofenac sodium (DS), to the intestine and Part II: To inspect the utility of PAA hydrogel microspheres towards controlled delivery of Dexamethasone (DX) and investigate the influence of method of preparation of IC on the drug release phenomenon from the microspheres.
Part I: pH-Sensitive CS−PVA hydrogels with varying amounts of PVA and cross-linked with GA were synthesized and explored for the delivery of NX and DS. The preformed solid NX−CD and DS−CD inclusion complexes were added directly into the CS−PVA hydrogels. With increased amount of PVA in CS−PVA hydrogels, the degree of swelling decreased due to increased hydrogel density. All the synthesized hydrogels exhibited maximum swelling at neutral pH. The presence of CD did not have any drastic effect on the swellability of the hydrogels. The antimicrobial property of CS was not compromised in the presence of PVA and/or CD in the hydrogels. The drug release from the IPN hydrogels was much prolonged as compared to pure CS hydrogels. The hydrogels containing the ICs released the drug considerably slower than those containing the free drug. With increasing PVA content, the rate of drug release was found to decrease. The in vitro drug release of hydrogels in simulated gastric fluid (SGF) showed negligible release of drug over a period of 2 h while it increased significantly in the simulated intestinal fluid (SIF). This release profile is suitable for the oral delivery of the drug. The pH-specific release of NX and DS from these hydrogels can be utilised for intestine−targeted delivery. The cytotoxic assay ensured them to be non-toxic and biocompatible and suggested their potential as controlled and intestine-specific drug delivery agents. Thus, it can be proposed that the deleterious effects of NSAIDs on the epithelium of the gastrointestinal tract (GIT) could be minimized by using the IC loaded hydrogels as drug delivery system (DDS) given that they provide a controlled release resulting in a reduced concentration of free NSAIDs.
Part II: In view of the importance of microspheres in drug delivery, PVA−PAA microspheres have been synthesized and examined for the controlled delivery of the common anti-inflammatory and immunosuppressant drug DX to the intestine. To regulate the release rate of DX, preformed solid ICs of DX with CD was added to the hydrogel microspheres. In order to study the influence of the method of preparation of IC on the release behaviour, the IC was prepared by two different methods: the co-precipitation (CP) and freeze-drying (FD). The GA cross-linked PVA−PAA hydrogel microspheres containing free drug, the physical mixture and the ICs were synthesized to investigate their drug release behaviour. The swelling characteristics of the microspheres indicated higher swelling in neutral pH than in acidic pH. The microspheres exhibited negligible drug release in pH 1.2 whereas significant release in pH 7.4. Slowest release was observed from the microspheres which contained the FD inclusion product. The drug release in SGF and SIF revealed approximately 5% of DX release during the initial 2 h in SGF and increasing significantly upon transferring to SIF. Thus the synthesized microspheres could be effectively employed for the controlled delivery of DX and their pH sensitivity could be exploited for the delivery to the intestine. Moreover, the compatibility of the synthesized microspheres with the living tissues further validates them as promising drug delivery systems.
Chapter 5 deals with regulating the delivery of the anticancer drug 5-Fluorouracil (5FU) from temperature-sensitive interpenetrating polymer network (IPN) hydrogels of guar gum (GG) and Poly (N−isopropylacrylamide) (PNIPAAm). In lieu of utilization of natural polysaccharides in drug delivery systems, GG is of particular interest because of its susceptibility to microbial degradation in the large intestine. The IPN hydrogels were synthesized using a non-toxic cross-linker, tetraethyl orthosilicate (TEOS). 5FU−CD solid ICs, prepared by freeze-drying method, were directly added to the hydrogel matrix. Incorporation of GG did not disturb the arrangement of PNIPAAm chains and the lower critical solution temperature (LCST) remained invariant. The hydrogels exhibited temperature-responsive swelling characteristics. The hydrogels also exhibited temperature dependence in their drug releasing characteristics. At higher temperature (above LCST) the release rate was considerably slower than that at lower temperature (below LCST). Presence of IC in the hydrogel matrix is capable of significantly controlling the drug release rate despite the fact that the matrix is undergoing a drastic morphological change above its LCST. The presence of CD in the hydrogels as ICs was vital in influencing the polymer relaxation and retarding the drug release rate from the hydrogels containing the ICs. The cytotoxicity assay performed on rat fibroblasts certified these hydrogels to be safe, nontoxic and biocompatible with living tissues thereby validating their potential as controlled drug delivery systems.
Chapter 6 focuses on the evaluation and comparison of the efficacy of GG-PAA-CD hydrogels with CD as a part of their network structure, and GG-PAA hydrogel containing the preformed DX-CD IC, for the controlled delivery of DX. IPN hydrogels composed of GG and PAA have been developed by using TEOS as cross-linker by varying the ratio of GG and PAA. The corresponding GG−PAA−CD hydrogels with CD as a part of the network structure were also synthesized. The swelling characteristics revealed maximum swelling at neutral pH. Controlled release of drug was obtained from CD-incorporated hydrogels as opposed to the fast release from the hydrogels without CD. Upon comparison it was found that the hydrogels containing preformed ICs performed better in terms of controlled release characteristics than the hydrogels containing CD as a part of their network structure. The cytotoxicity study revealed the biocompatible and nontoxic nature of these hydrogels validating them as promising drug delivery systems.
Chapter 7 provides the summary of the important findings of the work and also suggests the scope for future work
