A presentation will be given on antimicrobial photodynamic therapy of oral infections in relation to the importance of drug formulation. The investigations to be presented are results of long-term cooperation between NIOM and the School of Pharmacy, University of Oslo.
Pharmaceutical formulation as a measure to improve antimicrobial phototoxicity
To increase the selection of suitable photosensitisers for use with antimicrobial treatment we have aimed to improve their phototoxic effect by optimized pharmaceutical formulations. Photosensitisers such as curcumin, lumichrome and/or certain porphyrins may exhibit low aqueous solubility, formation of non-reactive aggregates («stacking»), low selectivity towards bacteria and less effect on Gram-negative bacteria than Gram-positive in general. Physiochemical and photostability investigations were performed with a number of different pharmaceutical formulation strategies, such as nanocarriers (cyclodextrins, polymeric micelles), stabilised supersaturated solutions, solid foams, lyophilised powders and natural deep eutectic solvents (NADES; optically transparent liquids consisting of primary metabolites in a specific molar ratio). The formulations with the most optimal physiochemical properties containing the above-mentioned photosensitisers were further investigated in in vitro phototoxicity studies on planktonic Gram-positive and Gram-negative bacteria. Larger bacterial reductions were observed after exposure to supersaturated or Pluronic® solutions of curcumin than lumichrome. Rather, the latter photosensitiser was most efficient when formulated with cyclodextrins. Dissolved solid dispersions stabilised the supersaturated state of curcumin to a larger extent than did diluted NADES. However, aggregation and precipitation of curcumin were observed using either formulation principle, and in situ dilution may be required. The poorly water-soluble porphyrins meso-tetra(p-hydroxyphenyl)porphine (THPP) and meso-tetra(p-carboxyphenyl)porphine (TCPP) were highly soluble in several NADES despite the fact that the NADES were more polar than water. Exposure to 1 nM THPP in diluted NADES combined with less than 30 J/cm2 of blue light reduced bacterial survival, however, susceptibility was species dependent. The reduction in % colony forming units per ml of E. coli was about 60-fold higher when THPP was dissolved in NADES compared to in phosphate buffer. Furthermore, NADES without THPP and light also exerted a toxic effect on E. coli. Further studies are aimed at general toxicity evaluations of NADES and dose-response effects of light, photosensitiser and NADES (i.e. dilutions) followed by in vivo experiments. The formulation chosen for a specific photosensitiser must be tailor-made to achieve optimal phototoxic efficiency and physiochemical properties.
Ellen M. Bruzell1, Kristine O. Wikene2, Håkon Valen Rukke1, Hanne Hjorth Tønnesen2
1Nordic Institute of Dental Materials (NIOM), Oslo, Norway; 2 School of Pharmacy, University of Oslo, Oslo, Norway