Investigation of supersaturated and solubilising preparations of poorly water-soluble photosensitisers intended for antimicrobial photodynamic therapy: Natural deep eutectic solvents and solid dispersions
AbstractAntimicrobial resistance is a global concern that threatens our ability to treat common infectious diseases. Measures to reduce the spread of antimicrobial resistance are valuable, but new antimicrobial treatments are also required to slow the current rise in antimicrobial resistance. One potential treatment modality is antimicrobial photodynamic therapy (aPDT), which combines a photosensitiser (PS), visible light and oxygen to produce cytotoxic species such as reactive oxygen species. The aim of the present thesis was to investigate two formulation strategies – natural deep eutectic solvents (NADES) and solid dispersions – of three poorly water-soluble PSs, and evaluate their potential in antimicrobial treatment based on in vitro phototoxicity studies in bacteria. Curcumin and two porphyrins were selected as model PSs. The PS-NADES (i.e. PS dissolved in NADES) and the solid dispersions of curcumin (containing a cyclodextrin and one/two polymer(s)) were diluted/dissolved in aqueous solvents to produce supersaturated solutions of the PSs. The physical stability of these aqueous preparations was highly variable, ranging from peak PS concentrations in a supersaturated state which lasted for <1 h to >7 d. A PS intended for aPDT should remain solubilised in a monomeric form for a certain amount of time to allow interactions with the target bacteria, followed by the time required for production of toxic photoproducts by the photoactivated PS. The rapid precipitation of curcumin in diluted NADES (>82% reduction in curcumin concentration within 1 h) was considered inconvenient in bacterial phototoxicity studies, yet this preparation appeared equally (or more) phototoxic as the curcumin solid dispersions in vitro. The porphyrins were equally or more phototoxic to the bacteria investigated when dissolved in NADES (diluted 1:200-1:400 than supersaturated solutions of the porphyrins in buffer. The increase in phototoxicity of the porphyrins was ascribed protonation (i.e. their obtaining a positive charge) in the acid-containing NADES, their supersaturated state in the diluted NADES, and/or an additional weakening effect of the NADES on the bacteria. An antibacterial effect of certain NADES without PSs was observed. NADES may be valuable solvents for various PSs intended for aPDT, as they may contribute an antibacterial effect as well as increase the (photo-) toxic potential of the dissolved PS. NADES as formulation strategy was considered intriguing for further studies in the field of aPDT, although the formulation must be tailored to each PS. The findings in this thesis offer a decent platform for the continued investigation of NADES as solvents for PSs (or drugs) intended for antimicrobial treatment.
List of papers
|I. Wikene KO, Hegge AB, Bruzell E, Tønnesen HH, 2015. Formulation and characterization of lyophilized curcumin solid dispersions for antimicrobial photodynamic therapy (aPDT): studies on curcumin and curcuminoids LII. Drug Development and Industrial Pharmacy 41 (6): 969-977. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.3109/03639045.2014.919315|
|II. Wikene KO, Bruzell E, Tønnesen HH, 2015. Improved antibacterial phototoxicity of a neutral porphyrin in natural deep eutectic solvents. Journal of Photochemistry and Photobiology B: Biology 148: 188-196. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.jphotobiol.2015.04.022|
|III. Wikene KO, Bruzell E, Tønnesen HH, 2015. Characterization and antimicrobial phototoxicity of curcumin dissolved in natural deep eutectic solvents. European Journal of Pharmaceutical Sciences 80: 26-32. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.ejps.2015.09.013|
|IV. Wikene KO, Rukke HV, Bruzell E, Tønnesen HH, 2016. Physicochemical characterisation and antimicrobial phototoxicity of an anionic porphyrin in natural deep eutectic solvents. European Journal of Pharmaceutics and Biopharmaceutics 105: 75-84. The paper is not available in DUO due to publisher restrictions. The published version is available at:: https://doi.org/10.1016/j.ejpb.2016.06.001|
|V. Wikene KO, Rukke HV, Bruzell E, Tønnesen HH, 2017. Investigation of the antimicrobial effect of natural deep eutectic solvents (NADES) as solvents in antimicrobial photodynamic therapy. Journal of Photochemistry & Photobiology, B: Biology 171 (2017) 27–33. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.jphotobiol.2017.04.030|