Ahmed, Abeer Mohamed; (2011) Development of a stable and safe amphotericin B-polymer complex for the treatment of leishmaniasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There continues to be a need for an affordable and stable formulation of amphotericin B (AmB) to treat visceral leishmaniasis which is prevalent in resource limited regions of the world. A new formulation must also be as safe and effective as current formulations. AmB is a poorly soluble polyene antibiotic that is toxic. Although the deoxycholate formulation of AmB (Fungizone®) is used in the treatment of visceral leishmaniasis, the liposomal formulation of AmB (AmBisome®) is a more effective formulation. AmBisome® is a safe medicine, but is limited by its high cost and the need for a cold chain. The research described in this thesis is focused on the development of a stable, nontoxic and non-covalently associated polymer complex of AmB. A water-soluble polymer was utilised to solubilise the AmB with the aim to minimise the toxicity of AmB. Since a polymer is used rather than lipids, such a formulation has the potential to be more stable and cost effective. Three polymers were investigated: poly(methacrylic acid), poly(vinyl vinylpyrrolindone-co methacrylic acid) and poly(glutamic acid) (PGA). The main focus was the development of an AmB-PGA complex. PGA is a biocompatible and biodegradable polymer that has been administered in humans and shown to be safe. Water soluble non-covalent complexes with AmB loadings in the range of 20.0-50.0% were prepared and characterised. The AmB-PGA complex displayed lower toxicity compared to Fungizone® towards human mammalian cells (red blood cells, KB and THP-1 cells). The AmB-PGA complex can be reproducibly prepared and is stable. The aggregation of AmB within the complex appears to be very similar to that for AmB in AmBisome®. The AmB-PGA complex is as active in vitro against intracellular Leishmania donovani amastigotes as Fungizone® and the complex is as active as AmBisome® in the established BALB/c mice model of acute visceral leishmaniasis. The AmB-PGA complex has the potential to be developed into a safe, stable, lipid free and cost effective formulation of AmB for the treatment of visceral leishmaniasis.

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