|M.Sc Student||Shitrit Yulia|
|Subject||Acrylated Chitosan for Mucoadhesive Drug Delivery Systems|
|Department||Department of Chemical Engineering||Supervisor||Professor Havazelet Bianco-Peled|
|Full Thesis text|
Over the last three decades, mucoadhesive drug delivery systems have gained interest due to their potential to optimize non-invasive delivery of therapeutic agents through the nasal, buccal, rectal and vaginal routs. This method of delivery utilizes vehicles capable of attaching to mucosal surfaces hence providing prolong residence time of drugs at the site of application. Although the combination of mucoadhesive properties with other advantages of polymeric drug carriers opened the way for the design of powerful non-invasive drug delivery vehicles, commercial products are scarce. Previous work conducted in our group suggested a novel mucoadhesive system based on polymers carrying acrylate side group which able to react with thiol groups present on mucin glycoprotein backbone via Michael type addition reaction and form stable covalent linkages. In the present study we expanded the knowledge on acrylate-based mucoadhesion polymers by creating an additional polymer and investigating its interactions with mucous. This new polymer is synthesized from chitosan (CS), a natural polysaccharide, conjugated to poly ethylene glycol diacrylate (PEGDA). The primary amino group on the CS backbone acts as a nucleophile and attacks one double bond on the PEGDA via Michael type reaction. The final product, termed chitosan-PEGAc, contains vinyl end group free for further interaction with mucous. For the synthesis we used PEGDA with molecular weight of 10 kDa which lead to acrylated chitosan with long grafted PEG chains (chitosan-PEGAc(10)) and PEGDA with molecular weight of 0.7 kDa which lead to acrylated chitosan with short grafted PEG chains (chitosan-PEGAc(0.7)). The synthesized product was verified by Fourier transform infrared spectroscopy (FTIR) and characterized using Nuclear magnetic resonance (NMR) that suggested higher PEGDA grafting density for chitosan-PEGAc(0.7) compare to chitosan-PEGAc(10). The acrylation percentage was calculated using a new approach developed by us, based on reaction of ninhydrin with primary amino group of chitosan, and supports the qualitative NMR findings. The adhesive properties were studied in semi-hydrated environment by tensile tests involving detachment of polymer tablets from fresh intestine sample and of polymer films from surfaces coated with mucin dispersion and in hydrated environment using the rotating cylinder method. Chitosan-PEGAc(10) presented improvement in mucoadhesive properties compared to chitosan. On the molecular level, rheology and NMR measurements of polymer/mucin mixtures provided additional evidences for strong interaction between Chitosan-PEGAc(10) and mucin glycoproteins. The mucoadhesion properties of chitosan-PEGAc(0.7) were not improved compare to chitosan, despite the high acrylation degree.
The release patterns of a hydrophilic model drug, Mesalamine, from polymeric compressed tablets were also examined. The release time from chitosan-PEGAc(0.7) and from chitosan-PEGAc(10) are considerably short compared to chitosan tablets. The swelling in equilibrium of chitosan-PEGAc(10) is significantly higher than the swelling of chitosan and chitosan-PEGAc(0.7).
The results presented in this thesis demonstrate enhanced mucoadhesion properties of the novel polymer with respect to natural and thiol-modified polymers. Based on our findings we believe that modified chitosan with PEG-acrylate represent a useful polymeric carrier matrix for delivery systems, which could provide a prolonged residence time of the drug on the mucosa.