טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentDavidovich-Pinhas Maya
SubjectAcrylated Polymers: A New concept in the Design of
Mucoadhesion Drug Delivery Systems
DepartmentDepartment of Chemical Engineering
Supervisor Professor Havazelet Bianco-Peled
Full Thesis textFull thesis text - English Version


Abstract

Transmucosal delivery of therapeutic agents is a non-invasive approach that utilizes human entry paths such as the nasal, buccal, and vaginal routs having mucus covered surface. Mucoadhesive polymers have the ability to adhere to those surfaces and by that promote drug release, targeting and absorption. Combining mucoadhesion ability with other advantages of polymeric drug carriers such as controlled drug release, protection, reduction of drug toxicity, improvement of drug solubility and bioavailability, allows design of powerful drug delivery systems.

This study was motivated by the need to develop new covalently associate mucoadhesive polymers that can interact non-specifically with mucin glycoproteins. Anovel approach for adhering polymers to the mucosa surface was developed. It utilizes a Michael type addition reaction where an acrylate end group on a polymer and the sulfide end group of the mucin type glycoprotein are associated. A proof of concept was provided using polyehtylene glycol di-acrylate (PEG-DA) whose its ability to create interactions with mucin type glycoproteins was verified using nuclear magnetic resonance (NMR and rheology experiments. Adhesion to fresh mucosa surface and  drug release ability in vitro were demonstrated. This approach was further developed by synthesizing new polymer based on alginate backbone carrying acrylated polyethylenglycol, alginate-PEGAc. The alginate swelling ability, which affects both adhesion strength and drug release, was characterized. Alginate-PEGAc was synthesized, verified using NMR, and lack of cytotoxicity was confirmed. Its ability to act as a sustained release mucoadhesive vehicle was demonstrated using tensile and in vitro release measurements. A significant increase of one order of magnitude in adhesion strength compare to alginate and a thiomer was demonstrated. Finally, in depth characterization of the thermal, structural and mechanical properties of alginate-PEGAc was performed. Thermal analysis detected one dehydration step followed by two distinct decomposition steps. SAXS patterns of alginate, thiolated alginate and alginate-PEGAc solution and calcium gel were well fitted to the “broken rod linked with flexible chains” model suggesting that they share a similar nanostructure. However, the scattering intensities increased in the order alginate>alg-thiol>alginate-PEGAc. Rheology measurements detected increase in the gelation kinetics and gel strength in the order alginate>alginate-thiol>alginate-PEGAc. These observations were attributed to the grafted side groups that interfere the gelation process. The effect of alginate-PEGAc gelation method (physical or chemical) was also studied. Radiation with UV of Ca cross-linked gels did not cause a significant change to the network structure and strength. Furtheremore, alginate-PEGAc could not be cross-linked only by UV radiation.