Liposomes have the ability to carry and deliver both hydrophilic and hydrophobic drugs and to protect them when injected into the circulatory system. They thus provide an attractive vehicle for drug delivery. However, problems of rapid clearance and inability to target liposomes to specific cells and tissues remain unresolved. Rapid clearance has been attributed to adsorption of opsonins, and one approach to reduce such adsorption is to create sterically stabilized liposomes by modifying the surface with polyethylene glycol (PEG) or dextran. To deliver their drug "payload" liposomes must interact with the membranes of target cells. Interactions with cellular components of the vascular walls have been observed for various sulfated polysaccharides such as heparin and functionalised dextrans. Based on the above considerations, the purpose of this work was to investigate the ability of various polymeric modifiers on liposomes to reduce protein adsorption and promote incorporation into target cells. Liposomes of composition PC/PEI cholesterol (70/10/20 mol %) were surface modified with PEG, dextran, heparin, and functionalised dextran. Protein adsorption was studied from solutions of IgG in buffer and from plasma. Adsorption from buffer was measured by radio labelling methods. For the plasma work, a total protein assay was used to determine the amount of protein adsorbed to the liposome surface, while gel electrophoresis and immunoblotting methods were used to examine the profiles of protein binding. Liposome incorporation into vascular smooth muscle and endothelial cells was evaluated using fluorescent labelling and radio labelling techniques. The IgG adsorption studies showed reduced adsorption on all polymer-modified liposomes. Plasma adsorption data showed that adsorbed protein layer compositions on the different liposome types were similar, but different from that of the plasma itself, showing that the plasma was fractionated on the liposome surfaces. Cell interaction studies showed that liposomes modified with dextran and sulfated dextran were incorporated into both cell types. The unmodified, PEG-and heparin-modified liposomes were not incorporated to any significant extent. / Thesis / Master of Engineering (ME)

A unique dosage form which uses a hydrophilic polymer was developed to provide for a predicable release of several drugs. This drug release could be optimized for controlled release using erosion. It can also be designed to release drug utilizing electrochemical processes. The accuracy of drug delivery in terms of dose and timing is of utmost importance for the patient’s health status and compliance. A well-designed drug delivery technology offers many advantages to the patient. These advantages include: reduction in dose frequency, reduction of drug side effects, reduced unwanted fluctuations in circulating drug levels, and a more uniform effect of the drug over time. The practice of drug delivery has been dramatically developed in the last decade including electronic controlled release innovative dosage forms. In this study the iontophoretic flux of ibuprofen was investigated using side- by-side diffusion cells. Iontophoresis is the process where electric current is applied to enhance transportation of drugs across the skin. The pH change was found to be an important factor in increasing the diffusion of the drug. The principle of using electric current as a driving force to control the drug release was initially demonstrated on an initial setup. Subsequently, a calcium binding polymer was the hydrogel used as a matrix to develop a new electric oral dosage form. The calcium binding polymer is produced in different forms. The production process of these forms suffers several limitations. In order to apply electric current in a practical way to the calcium binding polymer matrix a novel method was developed. The novel method also allowed for addressing the limitations related to the production process of the conventional dosage form made with this polymer. More uniform gel tablets in shape and size were produced. Different formulations were developed. Ibuprofen was the model drug initially used to investigate the factors that affected the release profiles of these tablets. A two-level, three-factor statistical design of experiments (DOE) was performed to evaluate the effect of those factors on certain responses. These responses included the release rate, time needed to release 80% of the model drug, and lag-time. A new formulation with certain adjuvants was developed. This formulation had the ability to release different kinds of drugs in a uniform release rate. A fail-safe tablet that can only release less than 20% of the drug in 24 hours was developed. The drug release was initiated only when the electric current was applied. This new electric dosage form was aimed to overcome the disadvantages related to conventional dosage forms such as the inability to supply drugs on demand. / Pharmaceutical Sciences

Ce travail est consacré à l’exploitation de la stéréocomplexation issue du mélange d’oligolactate de chiralité opposée (OLLA et ODLA) afin de construire des films multicouches à travers la technique de dépôt en couche par couche (LbL). Dans la littérature, cette interaction basée sur un phénomène de co-cristallisation, a été utilisée pour préparer des assemblages supramoléculaires (micelles, gels) en milieu solvant, à travers notamment la synthèse de copolymères greffés ou séquencés contenant des segments d’OLA. Dans ce contexte, des copolymères greffés constitués de chaîne principale hydrophile (guar ou alcool polyvinylique (PVOH)) porteur de segments d’OLA optiquement purs et de chiralité opposée (guar-g-OLA ou PVOH-g-OLA) ont été synthétisés. Ces dérivés ont été obtenus par un couplage de type « Grafting onto » basé sur une réaction d’estérification entre i) le polymère hydrophile et ii) des oligolactates L ou D, de masse contrôlée et porteurs de fonctions acide carboxylique en extrémité. Dans le cas des copolymères à base de guar, la synthèse s’est avérée laborieuse et n’a permis que d’obtenir des copolymères dont le pourcentage massique en OLA varie de 2 à 18 %. Concernant les copolymères à base de PVOH et à travers la variation des paramètres expérimentaux, des copolymères optiquement purs présentant des degrés de substitution (DS) en OLA variés (de 2 à 8 %), soit un pourcentage massique en OLA variant de 40 à 80 %, ont été obtenus. L’aptitude de ces derniers copolymères énantiomère à stéréocomplexer en masse et milieu solvant (DMSO) a été étudiée en détail par des techniques expérimentales complémentaires telles que la DSC, la DRX, la RMN 1H et la FTIR. Il s’avère que le greffage covalent des OLA sur la chaîne de PVOH ne limite en rien la stéréocomplexation. De plus, en milieu solvant, la cinétique de stéréocomplexation s’avère très rapide, ce qui est un pré-requis essentiel pour élaborer des films multicouches par la technique dite du LbL. Des analyses en AFM, de mouillabilité et de spectroscopie FTIR en mode ATR ont montré la faisabilité de construire des films multicouches LbL par stéréocomplexation. De plus, l’influence du degré de substitution de ces copolymères ainsi que l’impact du procédé de dépôt (« dip-coating » versus « spin-coating » de solutions de copolymères énantiomère seuls, ou de solutions de complexes préalablement formés) ont été étudiés. / This work is devoted to the exploitation of the mixture of stéréocomplexation oligolactate of opposite chirality (OLLA and ODLA) to construct multilayer films through deposition technique layer by layer (LbL). In the literature, this interaction based on the phenomenon of co-crystallization, was used to prepare supramolecular assemblies (micelles, gels) in a solvent medium, in particular through the synthesis of graft or block copolymers containing segments OLA. In this context, graft copolymers of hydrophilic main chain (guar or polyvinyl alcohol (PVOH)) bearing optically pure OLA segments of opposite chirality (guar-g-OLA or PVOH-g-OLA) were synthesized. These derivatives were obtained by a coupling type "grafting onto" based on an esterification reaction between i) the hydrophilic polymer and ii) oligolactates L- or D- with controlled mass and bearing carboxylic acid functions in end. In the case of guar-based copolymers, the synthesis has proved laborious and has allowed to obtain copolymers which the percentage by mass OLA varies from 2 to 18%. Regarding copolymers based PVOH and through the variation of experimental parameters, optically pure copolymers having different degrees of substitution (DS) of OLA (2 to 8%), a percentage by mass OLA ranging from 40 to 80 %, were obtained. The ability of these latter copolymers enantiomer to stereocomplexation in mass and in solvents (DMSO) was studied in detail by complementary experimental techniques such as DSC, XRD, 1 H NMR and FTIR. It turns out that the covalent grafting of OLA on the PVOH chain does not limit the stéréocomplexation. Moreover, in a solvent medium, the stéréocomplexation kinetics is very fast, which is an essential prerequisite for the development of multilayer films by the LbL technique called. Analyzes AFM, wettability and FTIR spectroscopy in ATR mode showed the feasibility of building LbL multilayer films by stéréocomplexation. In addition, the influence of degree of substitution of these copolymers as well as the impact of the deposition process ("dip coating" versus "spin coating" of copolymer solutions enantiomer alone, or complex solutions previously formed) have been studied.