| Summary: | This thesis is primarily concerned with understanding how the rate and extent of membrane permeation of a drug is affected by switching the donor delivery vehicle for different permeants and membranes. The project is funded by an industrial Collaborative Awards in Science and Engineering (CASE) award with an additional sponsorship by GlaxoSmithKline (GSK). The interest of GSK in this research is in the understanding of how the various types of topical formulation available, such as solutions, ointments, dispersions and emulsions, influence the characteristics of drug transport across a membrane. The rate and extent of membrane permeation from various types of topical formulation is experimentally investigated through the use of a developed automated method which is shown to be accurate and highly reproducible. The developed method incorporates stirred donor and re-circulating receiver compartments and continuous monitoring of the permeant concentration in the receiver phase. In a theoretical model based on rate-limiting membrane diffusion, an explicit set of equations are derived showing how the permeation extent and rate depend mainly on the membrane-donor and membrane-receiver partition coefficients of the permeant. The permeation of drug molecules from simple, single phase donor solutions are first investigated. The experimental permeation results for systems containing all possible combinations of hydrophilic or hydrophobic donor solvent, permeant and polymer membrane are measured using the developed method and are then compared to the calculated theoretical results. A quantitative comparison of model and experimental results from the widely-differing permeation systems successfully enables the systematic elucidation of all possible donor solvent effects in membrane permeation. For the experimental conditions used here, most of the permeation systems are in agreement with the model, demonstrating that the model assumptions are valid. In these cases, the dominant donor solvent effects arise from changes in the relative affinities of the permeant for the donor and receiver solvents and the membrane and are quantitatively predicted using the separately measured partition coefficients. It is also shown how additional donor solvent effects can arise when switching the donor solvent causes one or more of the model assumptions to be invalid. These effects include a change in rate-limiting step, permeant solution non-ideality and others. The development of a new type of formulation is investigated whereby the preparation of waterless, particle-stabilised emulsions is reported upon. The prepared emulsions incorporate a non-aqueous polar liquid phase, an immiscible oil phase and are stabilised by solid nanoparticles. Variation of the incorporated oil, polar liquid and particle hydrophobicity allow for the preparation of stable emulsions containing a wide range of liquids of both oil-in-polar liquid and polar liquid-in-oil emulsion types. The prepared formulations show great potential as vehicles for use in drug delivery in the pharmaceutical industry. These waterless emulsions provide several advantages such as high emulsion stability, aesthetic textures for topical application, aesthetic appearances (including the preparation of transparent emulsions through matching of the refractive index of the liquid phases) and the capability of containing very high hydrophobic drug concentrations dissolved within due to the absence of an aqueous liquid phase. The permeation of a drug molecule from more complex multiphase donor formulations, such as particle dispersions and particle stabilised emulsions, is also investigated. The delivery of a permeant across a synthetic membrane from both conventional oil-water and the developed waterless emulsions is discussed. The same experimental technique as that used to investigate the membrane permeation from single phase donor solutions is employed and a comparison of the experimental results to those calculated using the derived theoretical model is given. The theoretical model is adapted to account for the additional partioning of the permeant between the multiple phases present in these more complex donor formulations, but maintains the same set of underlying assumptions and fundamental principles of diffusion. The model successfully accounts for the experimental observations and reveals information regarding the mechanism of drug delivery from particle-stabilised emulsions. It is conclusively illustrated that permeant delivery from particle-stabilised emulsions occurs via partitioning of the drug between the dispersed and continuous emulsion phases prior to partitioning to the membrane exclusively from the emulsion continuous phase (i.e. dispersed emulsion droplet adhesion onto the surface of the membrane does not occur). Through analysis of the derived theoretical model, the extent and rate of membrane permeation of a permeant are correctly predicted to be independent of the emulsion type (i.e. oil-in-water or water-in-oil) and emulsion dispersed volume fraction for a given emulsion composition.
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