Morris, Rita Mary; (1998) Mechanisms of formation of multilamellar liposomes produced by the hydration of phospholipid films. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this thesis was to investigate the mechanisms by which liposomes are produced via the hydration of phospholipid films, with a view to gaining a greater understanding of the formation of multilamellar vesicles (MLVs) and the entrapment of water soluble drugs. The formation of liposomes from egg phosphatidylcholine and dipalmitoylphosphatidycholine (DPPC) films was examined using differential interference contrast microscopy and Environmental Scanning Electron Microscopy (ESEM). On addition of water to the films, tubular structures were observed which formed 'buds' with continuing hydration. ESEM studies indicated that a slower hydration induced by lowering the atmospheric pressure did not produce the tubular structures, but buds were seen to form directly from the film. A single agitation step was shown not to be sufficient to frilly break down the tubular and other structures to MLVs, but annealing followed by a second agitation step produced a more homogeneous vesicular population. The thermal characteristics of the various stages of MLV production were measured using differential scanning calorimetry, with thermal events indicative of the different stages being noted. The factors affecting the size and size distribution of multilamellar liposomes were investigated using univariate and multivariate factorial design. The factors investigated were the concentration of the phospholipid in organic solution, vacuum applied, amount of water added, duration of agitation stages before and after annealing, and the duration of annealing. The results indicated that the post-annealing agitation, phospholipid concentration, pre-annealing agitation, hydration time and water added to the film are all significant in affecting both the mean size and size distribution of MLVs. To investigate at which stage optimum aqueous drug entrapment occurs, a mainly aqueous marker, carboxyfluorescein (CF), was added at different stages of MLV production and the percentage of marker entrapped measured using fluorescence spectrometry. It was shown that adding the CF as an aliquot immediately prior to the first agitation step resulted in the greatest encapsulation.

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