Thermo-Responsive Microemulsions Containing Deep Eutectic-Based Antibiotic Formulations for Improved Treatment of Resistant Bacterial Ocular Infections

abstract

The rise of antibiotic resistant strains, as methicillin-resistant Staphylococcus aureus (MRSA), challenges the current treatment of infections. In the case of ocular infections, antibiotic eye drops are commonly prescribed. However, their efficacy is usually compromised by the low viscosity of these formulations and the eye drainage. To overcome these drawbacks, deep eutectic solvent (DES)-based microemulsions with thermo-responsive character, that increase their viscosity upon contact with the eye have been developed. Using betaine-based DES aqueous solutions, it is possible to increase up to 140-fold the water solubility of the antibiotic chloramphenicol, typically used in ocular infections. The DES solutions containing the antibiotic are applied as water phases in water-in-oil-in-water (w/o/w) microemulsions, being stable up to 3 months. Furthermore, a sustained-release and a higher permeation of the antibiotic through the cornea than that of commercialized eye drops is achieved, while presenting comparable cytotoxicity profiles (cell viabilities > 88%). Higher antimicrobial activity and faster action of the antibiotic in case of infection with MRSA is observed compared to the commercialized formulations (7 log(10) of inactivation in 48 h vs 72 h). Overall, these microemulsions comprising DES are a promising strategy to achieve higher antibiotic effectiveness in the treatment of resistant bacterial infections.

keywords

BETA-CYCLODEXTRIN; DRUG SOLUBILITY; CHLORAMPHENICOL; DELIVERY; SOLVENT; SYSTEMS; PERMEABILITY; MUCOADHESIVE; PERMEATION; STABILITY

subject category

Pharmacology & Pharmacy

authors

Pedro, SN; Gomes, ATPC; Vilela, C; Vitorino, C; Fernandes, R; Almeida, A; Amaral, MH; Freire, MG; Silvestre, AJD; Freire, CSR

Groups

G4 - Renewable Materials and Circular Economy
G5 - Biomimetic, Biological and Living Materials

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

acknowledgements

This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020, and LA/P/0006/2020, financed by national funds through the FCT/MEC (PIDDAC) and CESAM, UIDP/50017/2020, UIDB/50017/2020, and LA/P/0094/2020, financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. R.F. acknowledges FCT and Strategic Projects UIDB/04539/2020 and UIDP/04539/2020 (CIBB), and COMPETE-FEDER (POCI-01-0145-FEDER-007440); Centro 2020 Regional Operational Program: BRAINHEALTH 2020 (CENTRO-01-0145-FEDER-000008). CQC is supported by FCT through the project UID/QUI/00313/2020. FCT is also acknowledged for the doctoral grant (SFRH/BD/132584/2017) to S.N.P. and the research contracts under Scientific Employment Stimulus to C.V. (CEECIND/00263/2018 and 2021.01571.CEECIND) and C.S.R.F. (CEECIND/00464/2017). The authors would like to thank the Beira Litoral slaughterhouse (Aveiro, Portugal) for supplying the corneal tissue used in this research.