STUDIES ON CHITOSAN BASED CONTROLLED DRUG RELEASE FORMULATIONS

Abstract

Polymers play an important role in the formulation of drug products. Polymer based excipents have often been used in formulations for a variety of reasons, including taste masking, protection, and stabilization of drugs etc. A new dimension for the use of polymeric materials as drug delivery devices is the incorporation of biodegradability into the system. A number of degradable polymers are potentially useful for this purpose, including a variety of synthetic and natural substances. Many attempts have been made to develop functional microcapsules in which permeability is controlled by temperature, pH, light, electric fields etc. One of the methods to obtain such microspheres is to first produce a kind of premicrosphere and then to coat or graft them with environment-sensitive materials. Chitin is the most abundant natural amino polysaccharide and estimated to be produced annually almost as much as cellulose. Chitin is a high molecular weight linear polymer of Nacetyl- D-glucosamine (7vr-acetyl-2-amino-2-deoxy-D-glucopyranose) units linked by (3-D (1—> 4) bonds. Chitosan is the jV-deacetylated derivative of chitin, though this Ndeacetylation is almost never complete. It has become of great interest not only as an underutilized resource, but also as a new functional material of high potential in various fields and recent progress in chitin chemistry is quite noteworthy. Chitosan is non-toxic and easily bioabsorbable, and has been explored for the release of several drugs. The use of chitosan in the development of oral sustained release preparations was indicated based on the intragastric floating tablets. Chitosan with its antacid and antiulcer characteristics may prevent or weaken drug irritation in the stomach. The thesis work carried out on chitosan controlled drug release formulations is well organized in five chapters as follows: First and foremost chapter is General introduction, comprising economic aspects and properties of chitosan viz., degree of 7V-acetylation, molecular weight and solvent and solution properties. An overview on controlled drug release formulations with an emphasis on chitosan systems is presented as Chapter 2. Chapter 3 of the thesis deals with the material characterization and investigations on chitosan bead formation. The %iV-deacetylation and viscosity average molecular weight of chitosan used were determined using some standard reported methods. Pure chitosan beads, chitosan beads with spacer groups (viz., glycine and poly(ethylene glycol) are prepared by adopting simple coacervation technique. Thyamine hydrochloride (Thy-HCl) is used as a model drug in these studies. The swelling behavior of the beads at different pH has been studied. The beads are accurately weighed [Wo] and immersed in solutions of pH 2.0 and 7.4. At predetermined time intervals, the swollen beads are weighed [Wt] after the beads are wiped with soft paper tissue. The degree of swelling for each sample at time t was calculated using the expression [Wt-Wo)/Wo]. The swelling of the beads follow the order Chitosan (C)>Chitosan-PEG (CP)>Chitosan-Glycine (CG). The lower swelling of the beads CP and CG when compared to the pure chitosan beads is due to the intermolecular hydrogen bond formation between hydroxyl groups of chitosan and the amino groups of glycine; hydroxyl groups of the respective compounds (CP). On the other hand, PEG is used as a plasticizer, which enhances water diffusivity and thus possess greater swelling ability when compared to CG beads. The amount of drug incorporated in the beads is determined by drug assay. The release experiments were performed in a glass apparatus in solutions of pH 2.0 and 7.4 at 37 °C. The release rate depends upon the swelling of the beads and followed the same trend (C>CP>CG). The release rates of Thy-HCl from the beads loaded with higher amounts of the drug for various time intervals at pH 2.0 and 7.4 are also observed. The release pattern of the drugs is similar for all the three concentrations of the drugs studied. These results obtained from the above investigations suggest the possibility of modifying the formulations to obtain desired controlled drug release. Crosslinking a polymer matrix generally leads to a reduction in permeability to solutes. The main objective of crosslinking is therefore to reduce the degree of equilibrium swelling achieved by the network under experimental conditions. Chapters 4 and 5 of the thesis therefore, describe the preparation techniques of crosslinked chitosan beads with spacer groups. Chapter 4 of the thesis highlights the preparation, characterization and drug release behavior of the semi-interpenetrating polymer network beads of chitosan-glycine crosslinked with different concentrations of glutaraldehyde. IR studies revealed the imine reaction (C=N) between the amino groups from chitosan and aldehydic groups in glutaraldehyde, and on reducing the crosslink concentration, the peak corresponding to imine bonds proportionally broadened. On the other hand, the amphoteric behavior of glycine leads to interact with chitosan through intermolecular physical crosslinks. The swelling response of the glutaraldehyde crosslinked chitosan beads in solutions of pH 2.0 and 7.4 at 37 °C is studied. The degree of swelling is very high in solution of pH 2.0 to that of pH 7.4, due to inherent hydrophobicity of the chitosan beads dominating at high pH value, which prevents faster swelling in neutral and alkaline media and as expected, the swelling is lower for highly iii crosslinked beads. Moreover, the solubility and degradation of the beads depends on the degree of crosslinking. The beads without glycine have the maximum solubility and the beads with glycine, due to the formation of physical intermolecular crosslinks are less soluble in comparison of the pure chitosan beads. Addition of the crosslinker greatly influences the solubility behavior. Whereas, the beads when placed in HC1 solution (pH 2.0), began to disintegrate very slowly from 8th day onwards. Complete degradation resulted in 17 days for C and CG and 5 months in case of crosslinked beads, whereas the beads found to maintain their shape and physical integrity at pH 7.4 for the studied period. Complete degradation of the polymer into water-soluble molecules or monomers appears to be a very slow process and could not be followed till the end. From the SEM studies it appears that the crosslinked beads are spherical in shape and the size varies from 1270-1800 u,m. From the morphology, rough and folded surface of the beads is evident and on decreasing the concentration, a decrease in the complexity of the surface folding is observed. Electron micrographs are scanned after allowing the beads to swell, in this case pores and cracks appeared on the surface of the beads and from the morphology it is evident that complex folded structure collapsed after attaining equilibrium swelling at pH 2.0. Recording the IR and UV spectra of the beads at equilibrium in swelling solutions of pH 2.0 and 7.4 at 37 °C monitored structural changes of the beads. Chlorphenramine maleate (CPM) is used as a model drug for the release studies. Encapsulation efficiency and drug loading capacity of the beads are evaluated by entrapping different amounts of drug. The drug encapsulation is affected by the drug concentration, lower the concentration, higher the encapsulation efficiency. However, increasing the initial drug concentration enhanced the drug loading. The release profile of drug (different concentrations) from crosslinked chitosan-glycine beads at various time intervals in solutions IV of pH 2.0 and 7.4 at 37 °C is studied. There is a burst release initially for the first hour in both the media followed by an almost constant release of the drug from the matrix for a period of 48 h. The amount and percentage of drug release were much higher in acidic solution than in basic solution, because the release rate depend on swelling of the beads. The release pattern of the drug is similar for all concentrations of the drug studied. However, it is found that the percent of drug released from chitosan beads stabilized, as the drug released is proportional to the concentrations of the drug. The last and final, Chapter 5 of the thesis describes the preparation and characterization of crosslinked chitosan-PEG semi-interpenetrating polymer network beads. Biocompafibility of poly(ethylene glycol) make it the polymer of choice for numerous biomedical applications. Here PEG an attractive biomaterial widely used in medical and pharmaceutical areas is employed as a spacer group to affect the properties of the beads and their swelling behavior. In this polymer system, a complexation through co-operative hydrogen bonding takes place as evident from IR studies. The rapid swelling of the beads with PEG as a spacer group unlike chitosan-glycine beads is due to water diffusivity property of PEG. From the swelling studies, it is clear that the character of the swelling curve changes more significantly over time at pH 2.0 than at pH 7.4. Moreover, the swelling can reach a stable equilibrium much more rapidly at pH 7.4 than at pH 2.0. It is also observed that swelling curves do not change greatly with time at pH 7.4, while at pH 2.0, the swelling degree of the beads begins to decline after the beads were swollen for some time, which may indicate the dissolution tendency of the beads exceeds the swelling degree. This may be due to the cleavage of imine bond in the beads due to protonation. Just like the CG system, the solubility and degradation behavior of CP system depends on the degree of crosslinking. Beads when placed in HC1 solution (pH 2.0) began to disintegrate very slowly from 8th day onwards, but CP beads were swollen about 15-20 times the original size and appeared to be gelled. The disintegration process was observed for 17 days in case of C into fine particles, whereas, 4 months in case of crosslinked chitosan beads. From the SEM studies, it appears that the crosslinked CP beads have rough and dense surfaces. The beads are almost spherical in shape and the size (1444-2008 urn) is found to be slightly more than that of the CG beads (1270-1800 |im). A decrease in the size of the beads (1312-1625 urn) after swelling is observed. From the morphological studies, it is evident that the complex folded structures collapsed with large voids after attaining equilibrium swelling at pH 2.0. Similar to the CG beads, the structural changes, entrapment efficiency, and drug loading capacity of the CP beads are studied. The interesting water diffusivity property of PEG made the difference in the properties of the beads, unlike CG beads. Isoniazid is used as a model drug. The release profile of drug from crosslinked CP beads at various time intervals in solutions of pH 2.0 and 7.4 at 37 °C is studied. The release pattern for all the concentrations of the drugs studied is similar to that of CG, but the amounts/percentage release are slightly higher, because of the water diffusivity property of PEG. The results demonstrate that with chitosan-glycine/PEG release systems, in vitro, a near zero order release of drugs is observed. It appears that the mechanism of drug release is due to diffusion through the swollen beads in the HC1.