Physicochemical and microbiological stability study of vancomycin 25 mg/ml eye drops stored at 2-8°C in low density polyethylene (LDPE) containers

Clement GIRARDETa, Mai Huong LE NGUYENa, Lydie LETHIERb, Samuel LIMATa,c, Christine FAGNONI-LEGATa, Yves GUILLAUMEa,b a Department of pharmacy, Besançon University Hospital, 3 Boulevard Alexandre Fleming, 25000 Besançon, France
b Department of analytical and physical chemistry, EA 481 “Integrative and Clinical Neuroscience”, Faculty of medical sciences, Bourgogne Franche-Comté University, 25030 Besançon Cedex, France.
c Bourgogne Franche-Comté University, INSERM, EFS BFC, UMR 1098, 25000 Besançon, France

Vancomycin eye drops are frequently used for bacterial keratitis while this molecule is commercially unavailable in a suitable formulation for ophthalmic administration. Therefore, the hospital pharmacy was commissioned to produce preparations of fortified vancomycin eye drops available in case of urgent prescriptions. Stability studies on this drug often lack some parameters and storage conditions of vancomycin 25 mg/ml solution.

The aim of the study was to determine the physicochemical and microbiological stability of vancomycin 25mg/ml eye drops stored in low density polyethylene (LDPE) bottles under refrigeration conditions (2-8°C).

Material and Method
Multiple batches of vancomycin 25 mg/ml eye drops were aseptically prepared in a laminar-airflow cabinet by diluting an injectable commercialized product of vancomycin in powder with NaCl 0.9%. The solution was then injected through a 0.22 µm filter before bottling to minimize the risk of contamination. One of batches prepared was analyzed immediately and the rest were stored at 2-8°C for 31 days under two conditions: “open” and “close”. The “open” bottles were opened and dropped one drop daily to model patients’ use, the “close” ones remained closed until their analysis day. Samples were examined by organoleptic analysis (clarity, color, odor and visible particles), pH and osmolarity measures, microbiological analysis and vancomycin dosage using high-performance liquid chromatography. We tested two bottle types immediately after preparation, on the 21st day and the 31st day after preparation. “Open” samples were more controlled on the 3rd, the 7th, the 14th, the 17th, the 24th and the 28th days after preparation. Stability was defined as the absence of particles and color variation, insignificant changes in pH and in osmolarity, the sterility and a remaining vancomycin concentration at least 90% of the initial concentration.

All samples remained clear, colorless and odorless with no precipitation or visible particles throughout the study. The pH and the osmolarity of all batches have insignificantly changed during storage in both “open” samples and “close” samples with a maximum deviation of 3% in pH (initial pH equal to 3,5) and 4% in osmolarity (initial osmolarity equal to 293 mosmol/l). All incubated samples found no sign of bacterial growth. The vancomycin concentration varied by no more than 3% of the initial concentration during the storage at 2-8°C whatever the opening state of the bottles, and no breakdown product was detected.

Discussion and Conclusion
A range of studies has described a worse stability of vancomycin solution at room temperature1 , this is the reason why we did not design our study at this storage condition. To conclude, vancomycin 25mg/ml eye drops were stable for a month under refrigeration storage and could be used within 31 days after opening without exceeding the BBD.

1 Curti C, Lamy E, Primas N, Fersing C, Jean C, Bertault-Peres P, et al. Stability studies of five anti-infectious eye drops under exhaustive storage conditions. Pharm. 1 déc 2017;72(12):741‑6.

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