טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentNeufeld Lena
SubjectBiopolymer-Clay Hydrogels as Control Drug Delivery
Systems
DepartmentDepartment of Chemical Engineering
Supervisor Professor Havazelet Bianco-Peled
Full Thesis textFull thesis text - English Version


Abstract


Inflammatory bowel diseases (IBD) are idiopathic diseases, apparently with a spontaneous origin, which include Crohn's disease and Ulcerative Colitis. These are chronic disorders of the gastrointestinal tract with a combined prevalence of about 150-200 cases per 100,000 in western countries. Mesalamine is a drug used extensively for long-term maintenance therapy in patients with mild to moderate IBD. Mesalamine may additionally provide protection against the development of colorectal cancer. Numerous in vitro studies found that the beneficial effects of mesalamine are related to its anti-inflammatory and anti-oxidant properties within the inflamed gut. One of the major drawbacks of mesalamine is fast absorbance in the upper gastrointestinal tract leading to a relatively small amount reaching the colon. Additionally, this treatment has gastrointestinal, haematological and general side effects.

This thesis describes two new designs for nanocomposite hydrogels for the delivery of mesalamine. The first is based on chemical cross-linked chitosan, and the second on a physically cross-linked, thermoreversible pectin-chitosan hydrogels . To enhance drug loading in chitosan, the mineral montmorillonite was incorporated into the matrix. The exfoliated silica montmorillonite nanosheets form interactions with both chitosan and mesalamine, thus affecting the hydrogel’s drug release mechanism and swelling properties.

The impact of montmorillonite and glutaraldehyde concentrations on the chemical cross-linked hydrogels properties was investigated. In vitro drug-release studies detected slower release at short times when montmorillonite was combined. This study is the first to evaluate the influence of pH during mixing and mixing duration on drug release rates. It was shown that lowering the pH during mixing delayed the release since the positively charged drug was better introduced between the montmorillonite layers, as confirmed by Differential Scanning Calorimetry (DSC) and Fourier Transform Infra-red spectroscopy (FTIR) analysis. All hydrogels showed prolonged sustained release of mesalamine over 24 h in simulated colonic fluid (pH 7.4). When modelled, the mesalamine release profile suggests a complex release mechanism, involving adsorption of the drug from the montmorillonite and diffusion out of the hydrogel. The results imply that chitosan-montmorillonite hydrogels can serve as potential drug carriers for controlled-release applications.

The thermoreversible physical pectin-chitosan hydrogels studied in the thesis is made from chitosan and pectin, a non-toxic, biocompatible and biodegradable natural polysaccharides. Sustained release over a period of 24 h in physiological conditions was observed for mesalamine as well as for two other model hydrophobic drugs, curcumin and progesterone. FTIR and DSC experiments were used to characterize the  interactions between the investigated drugs and the polyelectrolytes (chitosan and pectin). It was suggested that these interactions contribute to the prolonged release of the drugs. The release patterns exhibited different profiles depending on the released drug, montmorillonite concentration, total polymer concentration and the relative amount of pectin (r ratio).

The design of biomedical hydrogels that are both biodegradable and offer sustained release could open the door to a new generation of cross-linked functional hydrogels.