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.

Thesis (M.Sc.), Memorial University of Newfoundland, School of Pharmacy, / Typescript. Bibliography: p. 141-166.

Lors d’infections vaginales, divers pathogènes se développent au détriment de la flore locale. L’utilisation de lactobacilles en traitement prophylactique et/ou curatif pourrait pallier ce problème. Le but de ce travail de thèse a été de développer des microparticules mucoadhésives à base de pectine et d’acide hyaluronique (HA) pour la libération intravaginale de probiotiques. Quatre souches probiotiques ont été associées à des prébiotiques afin d’obtenir un effet symbiotique. Les microparticules ont été formulées par émulsification-gélification ionique. Dans un premier temps, l’étude de l’influence de différents paramètres de procédé et de formulation a permis de définir les conditions opératoires pour l’obtention de microparticules d'environ 140 µm de diamètre encapsulant des probiotiques viables. Puis, les propriétés mucoadhésives des microparticules ont été évaluées in-vitro et ex-vivo par des mesures rhéologiques en mode dynamique et par des tests d’indentation. La présence d’HA entraine une augmentation importante du pouvoir bioadhésif des particules. Enfin, ces microparticules ont été incorporées dans des comprimés par un procédé de granulation humide. L’encapsulation des bactéries permet leur protection lors du procédé de compression. De plus, contrairement aux formes classiques d'administration des probiotiques, les microparticules permettent d'obtenir un profil de libération prolongée des bactéries sur environ 10h contre 1h dans le cas d’un comprimé comportant des probiotiques non encapsulés. Un début de prolifération bactérienne s’opère entre 16 et 24 heures. Le comprimé ainsi développé est tout-à-fait adapté à une application vaginale / More than 300 millions of women around the world have urinary or vaginal infections, including yeast vaginitis and bacterial vaginosis. Vaginal use of probiotics offers a potential alternative approach to health restoration and maintenance of the vaginal microflora. Moreover, prebiotics may be combined with probiotics to obtain a symbiotic effect. The aim of this work was to develop pro- and pre-biotics-loaded bioadhesive microparticles by using pectin and hyaluronic acid (HA). Four probiotic strains classically used in vaginal applications and one prebiotic have been selected. Microparticles were produced by emulsification/gelation method using calcium as cross-linking agent. The study of process and formulation parameters allowed obtaining microparticles with a mean diameter of 140 µm which encapsulated between 1010 to 1011 cfu/g of microparticles. Their mucoadhesive properties have been proved both by rheological and indentation measurements in in-vitro and ex-vivo conditions. Moreover, results have shown that HA addition in pectin solutions enhanced the bioadhesive properties of the gel-based microparticles. Afterwards, microparticles have been incorporated inside tablet by wet granulation. Microencapsulation of probiotics allowed protecting them during the compression process. The kinetic release of probiotics studies in in-vitro conditions exhibited a sustained release profile for 10 hours against 1h for unencapsulated probiotics. A beginning of probiotic strain proliferation was observed between 16 to 24 hours. The developed tablet is well-suited to vaginal application

Since their accidental introduction into the Great Lakes in mid- to late-1980s, the freshwater zebra mussels, Dreissena polymorpha, have colonized most lakes and waterways across eastern North America. Their rapid spread is partly attributed to their ability to tenaciously attach to hard substrates via an adhesive apparatus called the byssus, resulting in serious environmental and economic impacts. A detailed ultrastructural study of the bysuss revealed a 10 nm adhesive layer at the attachment interface. Distributions of the main adhesive amino acid, 3,4-dihydroxyphenylalanine (DOPA), and its oxidizing (cross-linking) enzyme, catechol oxidase, were determined histochemically. It was found that, upon aging, DOPA levels remained high in the portion of the byssus closest to the interface, consistent with an adhesive role. In contrast, reduced levels of DOPA corresponded well with high levels of catechol oxidase in the load-bearing component of the byssus, presumably forming cross-links and increasing the cohesive strength.

Since their accidental introduction into the Great Lakes in mid- to late-1980s, the freshwater zebra mussels, Dreissena polymorpha, have colonized most lakes and waterways across eastern North America. Their rapid spread is partly attributed to their ability to tenaciously attach to hard substrates via an adhesive apparatus called the byssus, resulting in serious environmental and economic impacts. A detailed ultrastructural study of the bysuss revealed a 10 nm adhesive layer at the attachment interface. Distributions of the main adhesive amino acid, 3,4-dihydroxyphenylalanine (DOPA), and its oxidizing (cross-linking) enzyme, catechol oxidase, were determined histochemically. It was found that, upon aging, DOPA levels remained high in the portion of the byssus closest to the interface, consistent with an adhesive role. In contrast, reduced levels of DOPA corresponded well with high levels of catechol oxidase in the load-bearing component of the byssus, presumably forming cross-links and increasing the cohesive strength.