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Title: Comparison and evaluation of different methods for the preparation of dried liposomes and nanoparticles as stable drug delivery vehicles
Author: Chen, Kun-Hung
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Abstract:
In this thesis, the effect of formulation on liposomes prepared by spray-drying, freeze- drying and spray-freeze-drying has been investigated. In related work the effect of freeze- drying on the transfection efficiency of a peptide/pDNA complex following freeze-drying- rehydration was also achieved. The effect of disaccharide and anti-adherent concentration on the stability of spray- dried liposomes was investigated. The optimum formulations contained a combination of 10% sucrose or 15% trehalose together with 0.5% (w/w) leucine. However, a marked increase in size of the rehydrated liposomes was obtained with further addition of 1% (w/w) leucine. Liposomes prepared by both the ethanol injection and proliposome method retained similar characteristics. Liposome powder containing 15% trehalose/0.5% leucine displayed the best aerodynamic characteristics probably because of the higher Tg value for trehalose. Next liposomes were prepared by the alcohol-based proliposome method to investigate the effects of sucrose or trehalose concentration on stability to freeze-drying. Tg' values of these dispersions were much lower than the Tg' of the pure sugar solutions leading to product collapse, while drug leakage and increased liposome size was seen for those formulated with 10% trehalose. Inclusion of an ethanol expulsion step increased Tg' and enabled preservation of structural stability and drug encapsulation following freeze-drying- rehydration. A spray-freeze-drying study demonstrated that inclusion of 30% (w/w) sucrose or trehalose prevented drug leakage but could not prevent size increase. The powders obtained exhibited a more compact structure with particle sizes of around 10 urn instead of the typical porous structure seen for spray freeze-dried powders. Addition of 5% PVP into liposome suspensions containing 10% disaccharide demonstrated some Iyoprotective effect in terms of entrapment efficiency was not as protective as the formulation containing 30% trehalose. An attempt to develop spray-dried polymer-coated liposomes suitable for nasal delivery was made. A combination of 10% (w/w) trehalose dihydrate and 0.2% (w/w) L-Leucine could effectively protect liposomes constituted of soya lecithin, DMPG and cholesterol against spray-drying damage albeit with a slight liposomal size increase. The addition of polymer coatings reduced the protective effect of sugars to a differing extent, while the size of chitosan- and TMC-coated liposomes was substantially greater than those with alginate coating. TMC-coated liposomes retained the highest BSA encapsulation and also still exhibited the ability to penetrate bovine nasal mucosa. The mucoadhesive strength of the powders was TMC-coated ~ chitosan-coated > alginate-coated liposome ~ uncoated liposomes. The peptide:pDNA (RALA-pEGFP-N1) complexes at various N/P ratios were freeze-dried. The N/P ratio of 1:10 exhibited the highest transfection efficiency, that was unexpectedly slightly increased after freeze-drying. Surprisingly, it was found that transfection efficiency of pEGFP-N1 complexed with RALA tended to gradually decrease with increasing concentration of trehalose and could unexpectedly be slightly improved by freeze-drying. CD spectra demonstrated that the a-helix structure of RALA became predominant upon association with pDNA and was not affected by trehalose. However, as added amount of trehalose at 50:1 or over 600:1 (w/w) of Iyoprotectant to pDNA, the secondary structure conversion of a-helix to partly random coil of RALA in the peptide/pDNA complexes was observed following freeze-drying although this was not correlated with transfection efficiency.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.579687  DOI: Not available
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