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Date of Award


Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)


Pharmaceutical and Chemical Sciences

First Advisor

Xiaoling Li

First Committee Member

Donald Floriddia

Second Committee Member

Arthur Harrelson

Third Committee Member

Patrick Jones

Fourth Committee Member

D.Q. Wang


A novel mucoadhesive poly[acrylic acid-co-poly(ethylene glycol) monomethylether monomethacrylate-co-2-(N, N-Dimethylamino)ethyl methacrylate], [poly(AA-PEGMM-DMEMA)], was designed and synthesized based on a hypothesis that interactions between the negative charged surface of the buccal mucosa and the positive charged constituent in bioadhesive would increase the mucoadhesion. Introducing the cationic monomer DMEMA to poly(AA-PEGMM) increased the Lewis acid-base interaction between the polymer and the buccal mucosa, which led to a thermodynamic favorable mucoadhesion process. The polymer containing 1% DMEMA yielded the highest force of mucoadhesion among the polymers studied. The ATR-FTIR study revealed that intrapolymer interactions between the carboxyl groups in AA and the amino groups in DMEMA and interactions between polymer and buccal surface played important roles in the mucoadhesion of poly(AA-PEGMM-DMEMA). The optimal mucoadhesion can be achieved by balancing these two interactions. The thermodynamic analysis revealed the contributions of Lifshitz-van der Waals interaction and Lewis acid-base interaction, such as the interactions between the hydroxyl groups and the ester groups, to the mucoadhesion. A general trend of mucoadhesion of the polymer can be predicted from the total free energy of adhesion (Δ G TOT ) at different hydration levels. A mathematical model was established to quantitatively describe the contributions of the three stages that involved in the process of adhesion to the force of mucoadhesion by the surface free energy, the total free energy of adhesion, and the hydration of the polymer. Zalcitabine (ddC) was selected as the model drug in the drug loading, in vitro release and permeation studies. Changing the pH of the swelling medium can greatly affect the swelling of the polymer. The drug loading increased 3.6 times when the pH of the loading solution was changed from 2.2 to 8. The process of the swelling and drug release followed Fickian diffusion mechanism. Compared to the permeation of ddC through the polymer, the permeation of ddC through the buccal mucosa was the rate-limiting barrier to the transbuccal delivery of ddC. ddC permeated through buccal mucosa by passive diffusion over the range of concentrations examined. The total permeability of ddC through the buccal mucosa was contributed by the permeation of ionized and unionized species of ddC. A bilayer diffusion model was established to describe the relations among the permeability of the epithelium, the connective tissue and the full-thickness buccal mucosa. The histological study revealed that the basal lamina within the epithelium of buccal mucosa acted as the major barrier to the permeation of ddC. The permeation of ddC through the buccal mucosa can be effectively enhanced by co-administrating a penetration enhancer sodium glycodeoxycholate (GDC). GDC enhanced the buccal permeability of ddC up to 32 times. A zero-order delivery of the currently approved dosage of ddC can be achieved by a poly(AA-PEGMM-DMEMA) transbuccal drug delivery device with GDC as the penetration enhancer. The transbuccal delivery is a potential route for the administration of ddC.




0599969571 , 9780599969575

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