טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentEshel-Green Tal
SubjectChallenges in Mucoadhesion Characterization of Nanometric
Systems
DepartmentDepartment of Nanoscience and Nanotechnology
Supervisor Professor Havazelet Bianco-Peled
Full Thesis textFull thesis text - English Version


Abstract

Mucoadhesion is an important phenomenon when delivering dosage forms to mucous covered body organs. The adhesion of the drug delivery vehicle to the mucous membrane prolongs the resistance time of the drug carrier and provides better absorption of the drug at the target site.

This research thesis is constructed of two projects involving efforts to improve techniques for characterization of nanometric mucoadhesive formulations.

In the first project, for the first time to our knowledge, blockcopolymer micelles having acrylated end groups were fabricated for the development of a mucoadhesive drug loaded vehicle. The hydrodynamic redius of Pluronic? F127, modified with acrylate end groups (F127DA), was found to be similar to that of the unmodified Pluronic? F127 (F127) at 4.3.8 nm. Indomethacin was incorporated into the micelles and in vitro drug release assay demonstrated that the micelles sustained the release of the drug in comparison with free drug in solution (61% at 5 h vs. 75%). For mucoadhesion evaluation, viscosity profiling was performed demonstrating that elevated viscosity was achieved for acrylated micelles with mucin compared to mixtures of non-acrylated micelles with mucin. The mucoadhesivity of the acrylated micelles was further characterized using Nuclear magnetic resonance (NMR); data affirmed that Michael type addition reaction occurred between acrylates on the micelles corona and thiols present in the mucin. Small angle x-ray scattering (SAXS) data showed a modification in the scattering of F127DA micelles with the addition of pig gastric mucin attributed to mucin-polymer interactions.  Cryo-transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS) data detected an increase in the aggregates’ size for acrylated micelles, indicating enhanced mucoadhesion. Thus, acrylated F127DA micelles were found to be mucoadhesive, and a suitable candidate for micellar drug delivery to mucosal surfaces.

In the second project, the mucoadhesion of dissolved nanometric chains of alginate-thiol, a second generation mucoadhesive polymer, was evaluated. The evaluation was performed against porcine small intestine, and novel mucosa mimetic hydrogels.

Utilization of animal parts in ex-vivo mucoadhesion assays is a common approach however it presents many difficulties due to animal rights issues and variance between animals. Two PEGDA (poly(ethylene glycol) diacrylate) based hydrogels were examined to serve as tissue mimetics for mucoadhesion evaluation. One hydrogel, termed PEGDA-QT, was composed of pentaerythritol tetrakis (3-mercaptopropionate) and PEGDA, containing free thiol groups mimicking those found in natural mucosa. The other hydrogel was formed by ultraviolet curing of PEGDA and mimicked the mechanical property of mucosa, but not its chemical constitute. When ranking first generation mucoadhesive polymers using a tensile assay, both hydrogels showed good agreement with the ranking achieved for porcine small intestine. However, only PEGDA-QT and porcine small intestine shared a similar displacement curve. The same ranking for PEGDA-QT and porcine small intestine was also observed when comparing thiolated alginate to native alginate when using a tensile assay as well as a flow through method. Our findings suggest that PEGDA-QT could serve as a replacement for porcine small intestine, in both mucoadhesion evaluations using a tensile machine and the flow-through method for first and second-generation mucoadhesive polymers.