Abstract
Ceftazidime (CZ) and vancomycin (VA) are two antibiotics used to treat bacterial keratitis. Due to their physical incompatibility (formation of a precipitate), it is not currently possible to associate both molecules in a single container for ophthalmic administration. We firstly characterized the incompatibility then investigated if 2-hydroxypropyl-beta (HPβCD) and 2-hydroxypropyl-gamma cyclodextrins (HPγCD) could prevent this incompatibility. The impact of pH on the precipitation phenomena was investigated by analysing the supernatant solution of the mixture using high performance liquid chromatography. A characterization of the inclusion of CZ with HPγCD using 1H nuclear magnetic resonance (NMR), and VA with HPβCD using 1H-NMR and a solubility diagram was performed. A design of experiment was built to determine the optimal conditions to obtain a formulation that had the lowest turbidity and particle count. Our results showed that VA and CZ form an equimolar precipitate below pH 7.3. The best formulation obtained underwent an in-vitro evaluation of its antibacterial activity. The impact of HPCDs on incompatibility has been demonstrated through the inclusion of antibiotics and especially VA. The formulation has been shown to be able to inhibit the incompatibility for pH higher than 7.3 and to possess unaltered antibacterial activity.
Highlights
Infectious keratitis is a severe sight-threatening ocular infection with increasing prevalence worldwide, ranging from 2.5 to 799 cases per 100,000 population/year [1], despite it probably being under reported
We aimed to develop a formulation enabling a physically compatible mix of CZ and VA, each at a concentration of 25 mg mL−1 by using HPCD, in order to obtain an ophthalmic solution that can be used treat bacterial keratitis (BK)
After having characterized the inclusion of the antibiotics in HPCDs, we evaluated the impact of the concentration of HPβCD on the solubility profile of a 50 mg mL−1 VA
Summary
Infectious keratitis is a severe sight-threatening ocular infection with increasing prevalence worldwide, ranging from 2.5 to 799 cases per 100,000 population/year [1], despite it probably being under reported It is one of the most important causes of corneal opacifications, which is the second most common cause of blindness after cataracts, reportedly causing up to 5% of all blindness cases [2]. Identifying the causal pathogen to be able treat it with the appropriate antibiotic takes laboratory time that the patient often does not have, which is why an empiric treatment of antibiotic eye drops covering the spectra of the most common bacteria is recommended [7,8,9] Those eye drops are given to the hospitalized patient every 5 to 10 min the first hour, every hour (day and night) for 48 h before being reduced to hourly (daytime only) for several days. Due to its high molecular weight, it cannot penetrate the pores of the outer membrane of
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