Comparative evaluation of lyophilized voriconazole formulations marketed in European Union

Adem Şahin; Göksu Yağ Çilingiroğlu; Tuğçe Çatak; Sakine Ulusoy; Ülküye Dudu Gül; Sena Özlem Gündoğdu

Comparative evaluation of lyophilized voriconazole formulations marketed in European Union

Abstract

Voriconazole is an antifungal derived from the structure of fluconazole and is designed to increase the efficacy and spectrum of action of fluconazole. In addition to the original formulation of the lyophilized product, there are several approved formulations in Europe. The aim of this study is to compare three lyophilized formulations of voriconazole in terms of manufacturing problems, stability and cost. For this purpose, three approved formulations were prepared. Briefly, sulfobutyl ether β-cyclodextrin (SBE-β-CD) was used to prepare the reference product formulation. The second formulation was prepared using arginine (Arg) and hydroxypropyl beta-cyclodextrin (HP-β-CD) as excipients. And the last formulation was prepared using sodium chloride (NaCl) and HP-β-CD as excipients. The prepared formulations were lyophilized. After lyophilization, the structure of the cake, assay, in vitro antifungal activity and stability of the formulations were evaluated. It was found that the formulation containing HP-β-CD and Arg should be freeze-dried at a lower primary drying temperature compared to the other formulations. The assays and in vitro antifungal activities of the formulations were found to be similar. The accelerated stability results showed that the impurity increase of the finished products in the Vor-SBE-β-CD and Vor-HP-β-CD-NaCl formulations was similar to that of the reference product. The impurity increase was slower in the Vor-HP-β-CD arginine formulation than in the others. The cost of Vor-SBE-β-CD was also higher than the others. Despite the advantages of SBE-β-CD, such as providing the same formula as the original product, HP-β-CD and NaCl/Arg-containing formulations can provide the targeted chemical quality at low cost.

Keywords

References

[1] Saravolatz, LD, Johnson LB, and Kauffman CA. Voriconazole: A New Triazole Antifungal Agent. Clinical Infectious Diseases. 2003; 36(5): 630-637. [CrossRef]
[2] Greer ND. Voriconazole: the newest triazole antifungal agent. Proceedings (Baylor University. Medical Center). 2003; 16(2): 241-248. [CrossRef]
[3] EMA, European Medicines Agency. Vfend. https://www.ema.europa.eu/en/medicines/human/EPAR/vfend (accessed March 15, 2022).
[4] EMA, European Medicines Agency. Vfend: EPAR - All Authorised presentations. https://www.ema.europa.eu/en/documents/all-authorised-presentations/vfend-epar-all-authorised-presentations_en.pdf (accessed March 15, 2022).
[5] Harding VD. Pharmaceutical formulations containing voriconazole. Patent Number: EP1001813B1. 1997.
[6] EMC, Electronic Medicines Compendium. Voriconazole Accordpharma 200mg Powder for Solution for Infusion-Accord-UK Ltd. https://www.medicines.org.uk/emc/product/2355/smpc (accessed March 15, 2022).
[7] Beena Uchil JH. Voriconazole Formulations. Patent Number: US20140275122A1. 2013.
[8] EMC, Electronic Medicines Compendium. Voriconazole 200mg powder for solution for infusion-Aspire Pharma Ltd. https://www.medicines.org.uk/emc/product/12389/smpc (accessed March 15, 2022).

[9] EMC, Electronic Medicines Compendium. VFEND 200 mg powder for solution for infusion. https://www.medicines.org.uk/emc/product/7976 (accessed March 15, 2022).
[10] Davis ME and Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nature Reviews Drug Discovery. 2004; 3(12): 1023-1035. [CrossRef]
[11] Jacob S and Nair AB. Cyclodextrin complexes: Perspective from drug delivery and formulation. Drug Development Research. 2018; 79(5): 201-217. [CrossRef]
[12] EMA, European Medicines Agency. Cyclodextrins used as excipients. https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-cyclodextrins-used-excipients-medicinal-products-human-use_en.pdf (accessed March 15, 2022).
[13] Australian Public Assessment Report for Voriconazole. https://www.tga.gov.au/sites/default/files/auspar-voriconazole-170629.pdf (accessed March 15, 2022).
[14] EMA, European Medicines Agency. VFEND Scientific Discussion. https://www.ema.europa.eu/en/documents/scientific-discussion/vfend-epar-scientific-discussion_en.pdf accessed March 15, 2022).
[15] Adams AIH, Gosmann G, Schneider PH, Bergold AM. LC Stability Studies of Voriconazole and Structural Elucidation of Its Major Degradation Product. Chromatographia. 2009; 69: 115-122. [CrossRef]
[16] Jameel F, Alexeenko A, Bhambhani A, Sacha G, Zhu T, Tchessalov S, Kumar L, Sharma P, Moussa E, Iyer L, Fang R, Srinivasan J, Tharp T, Azzarella J, Kazarin P, Jalal M. Recommended Best Practices for Lyophilization Validation—2021 Part I: Process Design and Modeling. AAPS PharmSciTech. 2021; 22(7): 221. [CrossRef]
[17] Colomer MP, Perez SL. Stable compositions of voriconazole. Patent Number: EP2409699B1. 2010.
[18] Patel SM, Nail SL, Pikal MJ, Geidobler R, Winter G, Hawe A, Davagnino J, Gupta SR. Lyophilized Drug Product Cake Appearance: What Is Acceptable? J Pharm Sci. 2017; 106(7): 1706-1721. [CrossRef]
[19] CLSI, The Clinical and Laboratory Standards Institute. Antifungal susceptibility testing of filamentous fungi, in Antimicrobial Susceptibility Testing Protocols. 2007; 209-241.

Details

Primary Language

English

Subjects

Pharmacology and Pharmaceutical Sciences (Other)

Journal Section

Research Article

Authors

Adem Şahin ^*
0000-0002-3996-2931
Türkiye

Göksu Yağ Çilingiroğlu This is me
0000-0002-3344-7920
Türkiye

Tuğçe Çatak This is me
0000-0002-2648-2066
Türkiye

Sakine Ulusoy This is me
0000-0001-9044-9079
Türkiye

Ülküye Dudu Gül
0000-0001-6443-1633
Türkiye

Sena Özlem Gündoğdu This is me
0000-0001-8509-7371
Türkiye

Publication Date

June 28, 2025

Submission Date

August 4, 2022

Acceptance Date

October 12, 2022

Published in Issue

Year 2023 Volume: 27 Number: 1

IZ

https://izlik.org/JA74GW25UX

Cite

RIS / Bibtex

APA

Şahin, A., Yağ Çilingiroğlu, G., Çatak, T., Ulusoy, S., Gül, Ü. D., & Gündoğdu, S. Ö. (2025). Comparative evaluation of lyophilized voriconazole formulations marketed in European Union. Journal of Research in Pharmacy, 27(1), 120-129. https://izlik.org/JA74GW25UX

AMA

1.Şahin A, Yağ Çilingiroğlu G, Çatak T, Ulusoy S, Gül ÜD, Gündoğdu SÖ. Comparative evaluation of lyophilized voriconazole formulations marketed in European Union. J. Res. Pharm. 2025;27(1):120-129. https://izlik.org/JA74GW25UX

Chicago

Şahin, Adem, Göksu Yağ Çilingiroğlu, Tuğçe Çatak, Sakine Ulusoy, Ülküye Dudu Gül, and Sena Özlem Gündoğdu. 2025. “Comparative Evaluation of Lyophilized Voriconazole Formulations Marketed in European Union”. Journal of Research in Pharmacy 27 (1): 120-29. https://izlik.org/JA74GW25UX.

EndNote

Şahin A, Yağ Çilingiroğlu G, Çatak T, Ulusoy S, Gül ÜD, Gündoğdu SÖ (June 1, 2025) Comparative evaluation of lyophilized voriconazole formulations marketed in European Union. Journal of Research in Pharmacy 27 1 120–129.

IEEE

[1]A. Şahin, G. Yağ Çilingiroğlu, T. Çatak, S. Ulusoy, Ü. D. Gül, and S. Ö. Gündoğdu, “Comparative evaluation of lyophilized voriconazole formulations marketed in European Union”, J. Res. Pharm., vol. 27, no. 1, pp. 120–129, June 2025, [Online]. Available: https://izlik.org/JA74GW25UX

ISNAD

Şahin, Adem - Yağ Çilingiroğlu, Göksu - Çatak, Tuğçe - Ulusoy, Sakine - Gül, Ülküye Dudu - Gündoğdu, Sena Özlem. “Comparative Evaluation of Lyophilized Voriconazole Formulations Marketed in European Union”. Journal of Research in Pharmacy 27/1 (June 1, 2025): 120-129. https://izlik.org/JA74GW25UX.

JAMA

1.Şahin A, Yağ Çilingiroğlu G, Çatak T, Ulusoy S, Gül ÜD, Gündoğdu SÖ. Comparative evaluation of lyophilized voriconazole formulations marketed in European Union. J. Res. Pharm. 2025;27:120–129.

MLA

Şahin, Adem, et al. “Comparative Evaluation of Lyophilized Voriconazole Formulations Marketed in European Union”. Journal of Research in Pharmacy, vol. 27, no. 1, June 2025, pp. 120-9, https://izlik.org/JA74GW25UX.

Vancouver

1.Adem Şahin, Göksu Yağ Çilingiroğlu, Tuğçe Çatak, Sakine Ulusoy, Ülküye Dudu Gül, Sena Özlem Gündoğdu. Comparative evaluation of lyophilized voriconazole formulations marketed in European Union. J. Res. Pharm. [Internet]. 2025 Jun. 1;27(1):120-9. Available from: https://izlik.org/JA74GW25UX