Differentiating Between Perfluorohexyloctane Ophthalmic Solution and Water-Free Cyclosporine Ophthalmic Solution 0.1% for Dry Eye Disease: A Review of Preclinical and Clinical Characteristics

Abstract

Perfluorohexyloctane ophthalmic solution (Miebo) and water-free cyclosporine ophthalmic solution 0.1% (Vevye) are recently approved treatments for dry eye disease (DED). Perfluorohexyloctane (PFHO) uses a novel approach to treat evaporative DED, whereas water-free cyclosporine (CsA 0.1%) is formulated to increase ocular delivery of its active ingredient to improve tear production. The two medications utilize the distinctive properties of two different semifluorinated alkanes (SFAs) to elicit their therapeutic effects. PFHO consists of 100% active ingredient and forms a monolayer on the surface of the tear film to inhibit evaporation. CsA 0.1% utilizes a vehicle consisting of perfluorobutylpentane (PFBP) and ethanol to facilitate delivery of cyclosporine to ocular tissues. The structure of these SFAs determines their differing behaviors and functions. The longer chain length of PFHO results in a slower evaporation rate and facilitates formation of a stable monolayer on the ocular surface. In vitro, PFHO demonstrated a substantially lower evaporation rate versus PFBP or human meibum, as well as a significantly longer ocular surface residence time. Ex vivo, PFHO demonstrated a longer ocular surface residence time than PFBP. The shorter chain length of PFBP enables it to better solubilize cyclosporine and improve drug delivery to ocular tissues. Although both of these ophthalmic drops utilize SFAs, their differences-in physicochemical properties and the mechanisms by which they are understood to intervene in the DED cycle-are important considerations in treatment selection for patients with DED.

Keywords: Anti-evaporative; Cyclosporine; Dry eye; Immunomodulator; Perfluorobutylpentane; Perfluorohexyloctane; Semifluorinated alkane.

Fig. 1

Molecular structures of a perfluorohexyloctane (PFHO) and b perfluorobutylpentane (PFBP). Reproduced from Tsagogiorgas C, Otto M. Semifluorinated alkanes as new drug carriers—an overview of potential medical and clinical applications. Pharmaceutics. 2023;15:1211. https://doi.org/10.3390/pharmaceutics15041211 [13], under Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)

Fig. 2

Preclinical evaluations of perfluorohexyloctane (PFHO) and perfluorobutylpentane (PFBP). a In vitro percent evaporation rates over time. Evaporation rates were evaluated gravimetrically, adding 500 μL SFA to a preweighed tissue culture dish, and incubated at 35 ± 3 °C; the dish was then weighed again at each timepoint. b Ex vivo precorneal residence time measured by fluorescence intensity (0.05% w/v of fluorescent dye) of PFHO and PFBP vs. cyclosporine ophthalmic emulsion 0.05% and cyclosporine ophthalmic emulsion 0.1%. Fresh porcine corneas were incubated in a tissue culture dish at 35 ± 3 °C with a corneal sleeve placed on top. A peristaltic pump continuously perfused HBSS at a flow rate of 5.7 μL/min in and out of the dish, and 10 μL of each test formulation—each containing 0.05% w/v of fluorescent dye—was added. Fluorescence was then measured at each timepoint: every 30 s for the first 30 min, then every 2 min for up to 60 min. Note: The clinical significance of these data has not been established. Abbreviations: HBSS Hank’s balanced salt solution, PFBP perfluorobutylpentane, PFHO perfluorohexyloctane, SFA semifluorinated alkane, w/v weight per volume. Figures reprinted with permission from Agarwal P, et al. Int J Pharm. 2018;538(1–2):119–129 [10]

Fig. 3

Corneal penetration at 4 h of CsA solubilized in PFHO (0.05%) or PFBP (0.05% or 0.1%) from the test formulations (n = 3 for each). Amount of CsA (ng) per gram of corneal tissue following a 50-μL dose of test solution. Error bars represent the SEM. Note: PFHO (0.1%) was not included in the analysis as a result of difficulty solubilizing CsA 0.1%. There was no statistical analysis provided for the comparison of PFHO (0.05%) vs. PFBP (0.1%). The clinical significance of these data has not been established. Abbreviations: AUC_(0–4h) area under the curve from 0 to 4 h, CsA cyclosporine, PFBP perfluorobutylpentane, PFHO perfluorohexyloctane, SEM standard error of the mean. Figure created with data from Agarwal P, et al. Int J Pharm. 2018;538(1–2):119–129 [10]