THE DEVELOPMENT OF NEW therapeutic approaches is always exciting, particularly when the disease being treated is chronic, and frequently intractable, in response to standard therapies. Unfortunately, dry eye is such a disease, but new topical medications using semifluorinated alkane (SFA)-based compounds are promising, as they offer many unique properties of value to the ocular surface.

SFAs have been used in vitreoretinal surgery for many years but are only recently being used topically. They are inert, amphiphilic (constructed of both hydrophilic and hydrophobic elements, making them dissolvable in both polar and nonpolar solvents), and possess a very low surface tension (Tsagogiorgas and Otto, 2023; Delicado-Miralles et al, 2021). Importantly, SFAs are nonaqueous (zero water content). This prohibits microbial growth, so there is no need for additional preservatives and eliminates the need for oils or surfactants, which can irritate the ocular surface (Sheppard et al, 2021).

Perfluorohexyloctane (F₆H₈) works to increase tear breakup time (TBUT) and lipid layer thickness, forming a protective layer over the ocular surface that decreases tear evaporation (Delicado-Miralles et al, 2021). In clinical trials, F₆H₈ provided significant improvements in dry eye signs and symptoms compared to saline controls and was well tolerated without notable side effects (Tauber et al, 2023; Sheppard et al, 2023).

Reducing tear evaporation promotes homeostasis of the ocular surface by improving tear stability, decreasing osmolarity and inflammation, and preventing long-term tissue damage (Rolando and Merayo-Lloves, 2022). In Figures 1 and 2, the noninvasive tear breakup time of the patient’s right eye improved by more than five seconds after instillation of F₆H₈. 

Another potentially beneficial mechanism of action provided by SFAs may be thermal in nature. After instillation of F₆H₈, a drop in corneal surface temperature was noted; this temperature reduction was sufficient to activate corneal thermoreceptors (thereby triggering helpful reflex lacrimation and blinking) but not enough to cause ocular discomfort (Delicado-Miralles et al, 2021).

Perfluorobutylpentane (F₄H₅) is very similar to F₆H₈, but when used to dissolve the normally hydrophobic drug cyclosporine into solution form it has been shown in clinical trials to significantly improve signs and symptoms of dry eye compared to the vehicle (F₄H₅) alone (Sheppard et al, 2021). It also demonstrated an earlier onset of action compared to other cyclosporine formulations (improvement in signs as early as week two, with statistically significant improvements by week four), and was well tolerated (Akpek et al, 2023).

Both of these SFAs have been shown to improve the bioavailability of cyclosporine by increasing corneal penetration and prolonging precorneal presence in the tear film when compared to other formulations (Agarwal et al, 2018). With a dual mechanism of action (targeting both tear evaporation and inflammation), this combination may offer enhanced therapeutic value to the dry eye patient.

Both F₆H₈ and F₄H₅ are now U.S. Food and Drug Administration approved and commercially available. If they continue to provide relief to dry eye patients, it is likely that more ophthalmic medications will someday utilize these unique SFA compounds.

REFERENCES

1. Tsagogiorgas C, Otto M. Semifluorinated Alkanes as New Drug Carriers-An Overview of Potential Medical and Clinical Applications. Pharmaceutics. 2023 Apr 11;15:1211.

2. Delicado-Miralles M, Velasco E, Díaz-Tahoces A, Gallar J, Acosta MC, Aracil-Marco A. Deciphering the Action of Perfluorohexyloctane Eye Drops to Reduce Ocular Discomfort and Pain. Front Med (Lausanne). 2021 Oct 26;8:709712.

3. Sheppard JD, Wirta DL, McLaurin E, et al. A Water-free 0.1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 ESSENCE Study. Cornea. 2021 Oct 1;40:1290-1297. 

4. Tauber J, Berdy GJ, Wirta DL, Krösser S, Vittitow JL; GOBI Study Group. NOV03 for Dry Eye Disease Associated with Meibomian Gland Dysfunction: Results of the Ra ndomized Phase 3 GOBI Study. Ophthalmology. 2023 May;130:516-524.

5. Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL; MOJAVE Study Group. NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: The Randomized Phase 3 MOJAVE Study. Am J Ophthalmol. 2023 Aug;252:265-274. 

6. Rolando M, Merayo-Lloves J. Management Strategies for Evaporative Dry Eye Disease and Future Perspective. Curr Eye Res. 2022 Jun;47:813-823.

7. Akpek EK, Wirta DL, Downing JE, et al. Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease: The ESSENCE-2 Randomized Clinical Trial. JAMA Ophthalmol. 2023 May 1;141:459-466.

8. Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs. Int J Pharm. 2018 Mar 1;538:119-129.