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Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

Authors :
Elisa Toropainen
Sara J. Fraser-Miller
Dunja Novakovic
Eva M. Del Amo
Kati-Sisko Vellonen
Marika Ruponen
Tapani Viitala
Ossi Korhonen
Seppo Auriola
Laura Hellinen
Mika Reinisalo
Unni Tengvall
Stephanie Choi
Mohammad Absar
Clare Strachan
Arto Urtti
Source :
Pharmaceutics, Vol 13, Iss 4, p 452 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d50) categories of the experimental suspensions were 0.37–1.33 and 3.12–3.50 µm and their viscosity levels were 1.3, 7.0, and 15 mPa·s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4–4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions.

Details

Language :
English
ISSN :
19994923
Volume :
13
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.2af1e0b88b534519bb185694d6e37fe4
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics13040452