Stability of frozen 1% voriconazole eye-drops in both glass and innovative containers

Marine Roche1,2, MSc, PharmD ; Damien Lannoy1,2, Ph.D., PharmD ; Florence Bourdon1, Ph.D., PharmD ; Cécile Danel2, Ph.D. ; Pierre Labalette3, Ph.D., MD ; Christophe Berneron1, PharmD ; Nicolas Simon1,2, Ph.D. PharmD ; Pascal Odou1,2, Ph.D., PharmD.
1 CHU Lille, Institut de Pharmacie, F-59000 Lille, France
2 Univ. Lille, EA 7365—GRITA—Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000 Lille, France
3 CHU Lille, Service d’ophtalmologie, F-5900 Lille, France


Purpose
To assess the physico-chemical stability of Voriconazole Eye-Drops (VED), when stored frozen and refrigerated once thawed, in 3 containers: Amber glass with a Low-Density PolyEthylene (LDPE) eyedropper, and two types of LDPE bottles: one classical and one with an innovative insert that maintains sterility after opening (Novelia® from Nemera).

Methods
Three batches of 1% VED (10 mL) were aseptically compounded from marketed injectable voriconazole (Vfend®) diluted in sterile water for injection. VEDs were stored for three months at -20°C in amber glass (n=32), classical LDPE (n=32) or innovative LDPE (n=31) bottles. Two stability-indicating methods (HPLC-UV-DAD as well as chiral chromatography) were developed. Stability study was conducted according to GERPAC-SFPC guidelines. At each study time, the following parameters were controlled: visual aspect, voriconazole concentration, pH and osmolality. In addition, non-visible particle count, sterility and absence of racemisation (impurity D – (2S,3R)-voriconazole) were assessed at the beginning and end of the study.
Results are expressed as mean ± standard deviation. Statistical analyses were performed using non parametric tests (α < 5%) in order to compare containers.

Results
When stored frozen, concentration was between 95.2±1.4% and 103.6±1.3% of initial concentration (C0) with no difference between the three containers (p=0.564; non-significant); Fifteen days after thawing, concentration was between 97.1±1.6% and 98.6±0.8% of Co with no difference between containers (p=0.278 and 0.368 for VED thawed at room temperature and at 2-8°C respectively, non-significant). pH remained stable between each time. Osmolality was slightly higher in glass (533.17 ± 8.93 mOsm/Kg) than in plastic containers (522.17±3.31 (classical LDPE); 517.5±12.42 mOsm/Kg (innovative LDPE)) (p=0.022). Sterility was preserved. Degradation product areas increased slightly but remained below the limit of quantification. Impurity D was never detected.

Conclusion
We have demonstrated that the ability of the innovative container Novelia® to maintain VED physicochemical and microbiological stability is no different from amber glass and classical LDPE containers. Real life studies are required to find out if there is a potential difference between Novelia® and other containers in terms of sterility preservation.

Keywords: Voriconazole, Ophthalmic solutions, Drug stability, Drug chirality, Container

List of Abbreviations:
High Performance Liquid Chromatography (HPLC)
Low Density PolyEthylene (LDPE)
Voriconazole Eye Drops (VED)

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