HIV continues to be a global healthcare challenge, with estimates suggesting there are currently 35.5 million infected people globally. To date, there have been an estimated 36 million HIV/AIDS related deaths worldwide. The story is changing however, with the advent of Highly Active Antiretroviral Therapies (HAART), allowing patients to live to normal life expectancies and with increasingly better quality of life. This, coupled with the fact that there has been a 40-fold increase in the number of people with access to antiretroviral therapy, has led to a 29% reduction in AIDS related deaths since 2005. Despite this encouraging data, there are still numerous limitations of antiviral therapy, including poor bioavailability, poor patient adherence, and emerging resistance. It is hoped that nanomedicine may offer a route to alleviating some of these issues by achieving an equal therapeutic concentration of drug but with a lower dose. The aims of this thesis were to develop a novel nanoemulsion based formulation of EFV and LPV and to assess the suitability of this formulation as dosage form. Nanoemulsions can be stabilised by surfactants, but often this can have unwanted safety profiles. Stabilisation can also be achieved using amphiphillic polymers that can be synthesised using biocompatible monomers like ethylene glycol. Chapter 2 demonstrates the synthesis of Ethylene Glycol based polymers using both conventional free radical and Atom Transfer Radical Polymerisation techniques. Nanoemulsions have previously been shown in the literature to increase the bioavailability of poorly water-soluble drugs, Chapter 3 shows the development and optimisation of an Oil-in-Water nanoemulsions. The data showed that nanoemulsions synthesised with volatile cosolvents were able to achieve sub 300 nm diameters and have good long-term stability. Increasing the accumulation and permeation of a poorly water-soluble compound should lead to improvements in bioavailability. Chapter 4 shows that the optimal nanoemulsion had comparable accumulation to aqueous solutions and superior apparent permeability cross Caco-2 cell monolayers. The antiviral activity was equipotent to the aqueous solution, as shown in Chapter 5. This confirms that nanoemulsion did not prevent the API from reaching its sight of action. Finally, all new formulations have the potential for detrimental side effects and immunological responses. It is therefore necessary to conduct pre clinical studies to predict such occurrences. Chapter 6 details the lack of immunological response seen in nanoemulsions, but highlights potential interactions with coagulation. In conclusion, this study has found that polymer stabilised oil-in-water nanoemulsions based on Castor oil have promising safety and pharmacological profiles. Further in vivo and studies are now warranted in order to further predict the suitability of nanoemulsions in man.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:666732 |
| Date | January 2015 |
| Creators | Hobson, James |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/2009461/ |
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