טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentKeren Shabtay
SubjectControlled Release of Hydrophobic Drugs from Nanocarriers
Embedded in Hydrogels
DepartmentDepartment of Nanoscience and Nanotechnology
Supervisor Full Professor Bianco-Peled Havazelet
Full Thesis textFull thesis text - English Version


Abstract

Over 40% of the drugs developed in the past two decades are extremely hydrophobic and their low solubility in water might lead to undesired pharmacokinetics properties. Incorporating a hydrophobic drug in o/w microemulsions (ME), thermodynamically stable dispersions of nanometric oil droplets in water, can enhance its solubility in water and improve its ability to act as a pharmaceutical agent. However, the low viscosity of ME prevents them from acting as efficient sustained drug delivery systems; to overcome this drawback a composite hydrogel, containing a ME embedded within a hydrogel, was designed.

The hydrogel studied in the thesis is made from chitosan, a non-toxic, biocompatible and biodegradable natural polysaccharide. This polymer can undergo crosslinking with genipin, a natural molecule, thus creating a three dimensional hydrogel. During the first phase of the research we encountered difficulties in obtaining chitosan hydrogels with reproducible properties. Therefore we aimed at investigating the reaction mechanism and its relation to the properties of hydrogels created from polymer solutions in pH values within the chitosan’s solubility range. This thesis shows that the reaction between chitosan and genipin is very slow, sometimes requiring more than four days to complete. Further, we discovered that altering the pH within the small range of 4.00 to 5.50 dramatically affects the reaction, leading to hydrogels differing both in appearance and in properties. Increasing the pH by 1.5 units led to an almost fourfold decrease in the gelation time and more than tenfold equilibrium swelling.  The strong dependence on the pH is associated with the inability of protonated amine groups to react with the genipin molecules. These findings provide an important and crucial insight towards the understanding of the impact of small changes under acidic pH conditions when designing and creating chitosan hydrogels crosslinked with the natural crosslinker genipin.

Once the knowledge regarding the network formation was established, we chose to proceed with the creation of composite chitosan hydrogels produced in distinct conditions leading to different crosslinking densities. We selected two formulations with identical chitosan and genipin concentrations, one was crosslinked at pH=4.0 and the other at pH 5.5.  The different crosslinking densities of the gels led to different release profiles, with the denser gel exhibiting a burst effect in water while the other a prolonged release of 48 hours. The intriguing phenomenon of the elongated release period from the less dense network was attributed to the formation of intermolecular interactions between the ME droplets and the polymeric network which was verified using FTIR experiments The release was investigated in physiological conditions as well; it exhibited a different profile due to the charges on the polymer backbone and led to a release of 24 hours. The chitosan composite hydrogels displayed a prolonged release period and are sustainable in physiological conditions.