Compositions and methods for ocular application

Abstract

The present application provides compositions and methods for reducing tear evaporation and for treatment of dry eye diseases. In one example, a composition is provided comprising a semi-fluorinated alkane compound such as, e.g., perfluorohexyloctane; and an additive selected from paraffin, medium chain triglycerides, propylene glycol diacetate, and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca. Eye drops comprising the compositions are also provided. Methods of using the compositions are also provided and include methods for reducing one or more symptoms of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, and methods for reducing or modifying tear evaporation rate, increasing tear retention time, protecting tear film, preventing tear evaporation, producing a soothing effect, or improving tear quality in an eye of a subject.

Description

[0001] Attorney Docket No. 43081-0039W01

[0002] COMPOSITIONS AND METHODS FOR OCULAR APPLICATION

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Application No. 63 / 681,379, filed on August 9, 2024, and U.S. Application No. 63 / 752,188, filed on January 31, 2025, the contents of which are hereby incorporated by reference.

[0005] TECHNICAL FIELD

[0006] This disclosure relates to topical ophthalmological compositions for reducing tear evaporation and for treatment of dry eye diseases and symptoms, and methods for making and using the compositions.

[0007] BACKGROUND

[0008] Millions of people worldwide suffer from discomfort or symptoms related to dry eye and dry eye related diseases. Dry eye disease (DED) is characterized by an abnormal tear film, a reduction of fluid on the ocular surface and / or an osmolarity imbalance in the normal tear film. All of these can cause increased water evaporation from the ocular surface. Dry eye disease includes dry eye syndrome and keratoconjunctivitis sicca, and dry eye related diseases can include other ocular diseases such as meibomian gland disfunction. Symptoms of dry eye and related diseases can include burning, eye dryness, pain in the eyes, and decline of visual performance can occur and cause discomfort to the patient. These symptoms are not exclusive to the described ocular diseases. They can also be experienced by individuals without a diagnosed ocular disease, and by individuals with other ocular diseases, including as side effects of other treatments. There are limited treatments available for these symptoms, or for dry eye disease and other related ocular diseases. Thus, there is a need for a widely available and effective treatment to help relieve these debilitating symptoms.

[0009] SUMMARY

[0010] This disclosure relates to compositions for topical ophthalmological compositions, comprising a semi-fluorinated alkane compound (SFA), and an additive Attorney Docket No. 43081-0039W01 selected from paraffin, medium chain triglycerides (MCT), and propylene glycol diacetate (PGD), and methods for making and using the compositions, such as methods for treating or slowing the progression of, or reducing one or more symptoms of, an ocular condition in a subject such as, e.g., dry eye disease or for reducing tear evaporation from an eye. This disclosure is based in part on a surprising realization that the compositions described herein can provide superior tear retention time, prevention of tear evaporation, and protection of tear film as compared to other available compositions.

[0011] Semi-fluorinated alkane compounds have previously been described, e.g., as potential useful carriers for ophthalmic active pharmaceutical compounds useful in treating ophthalmic disorders. For example, U.S. Pat. No. 8,614,178 describes a composition having a macrolide immunosuppressant useful in the prevention or therapy of keratoconjunctivitis sicca as active pharmaceutical ingredient, dissolved into a solution containing a semifluorinated alkane as liquid vehicle. Semifluorinated alkanes have also been described in U.S. Pat. No. 12,005,033 on their own, without any pharmaceutically active drug substance, as a treatment for keratoconjunctivitis sicca. Indeed, Vittitow et. al describe the apparent ability of the semi-fluorinated alkane, perfluorohexyloctane, marketed as MEIBO™, a single-component treatment for dry eye disease, to inhibit water evaporation.

[0012] This disclosure is based, at least in part, on a surprising realization that compositions comprising a semi-fluorinated alkane (SFA) in combination with certain additives described herein, such as paraffin, medium chain triglycerides (MCT), and propylene glycol diacetate (PGD) or combinations thereof, can provide even greater reduction of tear evaporation as compared to an SFA compound alone. These compositions can thus be useful, with or without an active pharmaceutical agent, to treat dry eye diseases or improve one or more symptoms thereof. The compositions can also be useful for modifying, reducing, or preventing tear evaporation and increasing comfort in the eye of subject, whether or not the subject has an ocular disease or condition.

[0013] This disclosure provides compositions comprising a semi-fluorinated alkane (SFA) compound and an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof, and methods for making and using the compositions. The compositions described herein can provide Attorney Docket No. 43081-0039W01 improved tear evaporation rates, reduced tear evaporation rates, or treatment of one or more symptoms of dry eye diseases. The compositions can be free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.

[0014] In one aspect, described herein is a method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or combinations thereof in a subject in need thereof, the method comprising administering to the subject the topical ophthalmological composition comprising: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.

[0015] In another aspect, provided herein is a method for reducing or modifying tear evaporation rate, increasing tear retention time, protecting tear film, preventing tear evaporation, producing a soothing effect, or improving tear quality in an eye of a subject, comprising administering to the subject the topical ophthalmological composition comprising: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye Attorney Docket No. 43081-0039W01 disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.

[0016] In these and other instances, the methods and topical ophthalmological compositions can optionally have the following features. The topical ophthalmological compositions can consist essentially of the semifluorinated alkane compound and the additive or consist essentially of the semifluorinated alkane compound, the additive, and an API selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, a muscarinic receptor agonist, a muscarinic receptor antagonist, a muscarinic cholinergic receptor agonist, or combinations thereof. The compositions can be non-aqueous. The semi-fluorinated alkane compound can be present in a concentration of from about 50% to about 99.9% (w / w) in the topical ophthalmological composition. The additive can be present in a concentration of from about 0.1% to about 50% (w / w). The additive can be present in a concentration of from about 1% to about 30% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 70% to about 99% (w / w). The semifluorinated alkane compound can be perfluorohexyloctane (F6H8). The additive can be PGD. The additive can be paraffin. The paraffin can be liquid paraffin. The paraffin can be light liquid paraffin. The additive can be MCT. The MCT can be a triglyceride of fatty acids and the fatty acids can comprise hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations of two or more thereof. The MCT can be a triglyceride of fatty acids and the fatty acids can consist essentially of hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations thereof. The topical ophthalmological composition can be in the form of a solution, a suspension, or an emulsion. The ophthalmological composition can be in the form of a solution and the additive can comprise from about 0.1% to about 2.9% (w / w) MCT. The ophthalmological composition can be in the form of an emulsion and the additive can comprise from about 3% to about 50% (w / w) MCT. The topical ophthalmological composition can be a nanoemulsion. The additive can comprise from about 10% to about 50% (w / w) MCT. The nano-emulsion can have a droplet particle size D90 of less than about 100 nm, less than about 50 nm, less than about 20 nm, less than or equal to about 10 nm, or has a droplet particle size D90 of from about 5 nm to about 20 nm. Attorney Docket No. 43081-0039W01

[0017] In these and other instances, the methods and topical ophthalmological compositions can optionally have the following features. The additive can be present in a concentration of about 1% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 99% (w / w), the additive is present in a concentration of about 2% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 98% (w / w), the additive is present in a concentration of about 3% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 97% (w / w), the additive is present in a concentration of about 4% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 96% (w / w), the additive is present in a concentration of about 5% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 95% (w / w), wherein the additive is present in a concentration of about 10% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 90% (w / w), wherein the additive is present in a concentration of about 15% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 85% (w / w), wherein the additive is present in a concentration of about 20% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 80% (w / w), wherein the additive is present in a concentration of about 25% (w / w) and the semifluorinated alkane compound is present in a concentration of about 75% (w / w), or wherein the additive is present in a concentration of about 30% (w / w) and the semifluorinated alkane compound is present in a concentration of about 70% (w / w).

[0018] In these and other instances, the methods and topical ophthalmological compositions can optionally have the following features. The additive can be MCT, the MCT can be present in an amount of from about 3% to about 30% (w / w), and the SFA can be present in an amount of from about 70% to about 97% (w / w). The additive can be PGD, the PGD can be present in an amount of from about 3% to about 10% (w / w), and the SFA can be present in an amount of from about 90% to about 97% (w / w). The additive can be paraffin, the paraffin can be present in an amount of from about 1% to about 20% (w / w), and the SFA can be present in an amount of from about 80% to about 99%. The subject can be a human. The topical ophthalmological composition can be free from perfluorobutylheptane (F4H5).

[0019] In another aspect, provided herein are eye drops consisting essentially of: Attorney Docket No. 43081-0039W01 a semi fluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof, or a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof; and an API selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, or combinations thereof.

[0020] In these and other instances, the eye drops can optionally have the following features. The eye drops can be non-aqueous. The semi-fluorinated alkane compound can be present in a concentration of from about 50% to about 99.9% (w / w) in the topical ophthalmological composition. The additive can be present in a concentration of from about 0.1% to about 50% (w / w). The additive can be present in a concentration of from about 1% to about 30% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 70% to about 99% (w / w). The semifluorinated alkane compound can be perfluorohexyloctane (F6H8). The additive can be PGD. The additive can be paraffin. The paraffin can be liquid paraffin. The paraffin can be light liquid paraffin. The additive can be MCT. The MCT can be a triglyceride of fatty acids and the fatty acids comprise hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations of two or more thereof. The MCT can be a triglyceride of fatty acids and the fatty acids consist essentially of hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations thereof.

[0021] In these and other instances, the eye drops can optionally have the following features. The eye drops can be in the form of a solution, a suspension, or an emulsion. Attorney Docket No. 43081-0039W01

[0022] The eye drops can be in the form of a solution and the additive can comprise from about 0.1% to about 2.9% (w / w) MCT. The eye drops can be in the form of an emulsion and the additive can comprise from about 3% to about 50% (w / w) MCT. The eye drops can be in the form of a nanoemulsion. The additive can comprise from about 10% to about 50% (w / w) MCT. The nano-emulsion can have a droplet particle size D90 of less than about 100 nm, less than about 50 nm, less than about 20 nm, less than or equal to about 10 nm, or has a droplet particle size D90 of from about 5 nm to about 20 nm.

[0023] In these and other instances, the eye drops can optionally have the following features. The additive can be present in a concentration of about 1% (w / w) and the semifluorinated alkane compound is present in a concentration of about 99% (w / w), the additive is present in a concentration of about 2% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 98% (w / w), the additive is present in a concentration of about 3% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 97% (w / w), the additive is present in a concentration of about 4% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 96% (w / w), the additive is present in a concentration of about 5% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 95% (w / w), wherein the additive is present in a concentration of about 10% (w / w) and the semifluorinated alkane compound is present in a concentration of about 90% (w / w), wherein the additive is present in a concentration of about 15% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 85% (w / w), wherein the additive is present in a concentration of about 20% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 80% (w / w), wherein the additive is present in a concentration of about 25% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 75% (w / w), or wherein the additive is present in a concentration of about 30% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 70% (w / w).

[0024] In these and other instances, the eye drops can optionally have the following features. The additive can be MCT, the MCT can be present in an amount of from about 3% to about 30% (w / w), and the SFA can be present in an amount of from about 70% to about 97% (w / w). The additive can be PGD, the PGD can be present in an amount of Attorney Docket No. 43081-0039W01 from about 3% to about 10% (w / w), and the SFA can be present in an amount of from about 90% to about 97% (w / w). The additive can be paraffin, the paraffin can be present in an amount of from about 1% to about 20% (w / w), and the SFA can be present in an amount of from about 80% to about 99%. The eye drops can be free from perfluorobutylheptane (F4H5).

[0025] In these and other instances, the methods and topical ophthalmological compositions can optionally have the following features. The composition can further comprise an API. The API can be selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, a muscarinic receptor agonist, a muscarinic receptor antagonist, a muscarinic cholinergic receptor agonist, or combinations thereof. The TRPM8 agonist can be selected from menthol (5-Methyl-2-(propan-2-yl)cyclohexan-l- ol), AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methyl ethyl) cyclohexanecarboxamide), derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof. The API can be present in a concentration of from about 0.0001% to 0.1% (w / w). The API can be selected from aceclidine and atropine, or derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof. The API can be present in a concentration of from about 0.01% to 0.1% (w / w).

[0026] In these and other instances, the eye drops described herein can optionally have the following features. The API can be a TRPM8 agonist selected from menthol (5- Methyl-2-(propan-2-y l)cy clohexan- 1 -ol), AR- 15512 (( 1 R, 2 S, 5R)-N-(4-m ethoxy phenyl)- 5-methyl-2-(l -methylethyl) cyclohexanecarboxamide), derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof. In some instances, the API can be present in an amount of from about 0.0001% to 0.1%. In some instances, the API can be present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5%, from about 0.1% to about 1% (w / w), 0.0001% to about 0.1% (w / w), from about 0.005% to about 1.5% (w / w), from about 0.01% to about 1.5% (w / w), from about 0.05% to about 1.5% (w / w), from about 0.005% to about 1% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.1% (w / w), from about 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), or from about 0.01% to about 0.5% (w / w)0.0001% to Attorney Docket No. 43081-0039W01 about 0.1% (w / w), 0.001% to about 0.01 % (w / w), about 0.001% to about 1% (w / w), about 0.003% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.02% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.5% (w / w), about 1.0% (w / w), or about 1.5% (w / w). In some instances, the API can be menthol, and the menthol can be present in a concentration of from about 0.01% to about 1.5% (w / w). In some instances, the API can be AR-15512 and the AR-15512 is present in a concentration of from about 0.0001% to about 0.01% (w / w).

[0027] In some embodiments, the compositions and methods provided herein can provide several advantages. First, in some instances, the compositions provided herein can provide protection of tear fdm and improved tear quality. This can, in some instances, improve visual function, reduce symptoms such as irritation, redness, itchiness, and ocular fatigue, or improve the function and healing of various parts of an eye.

[0028] Second, in some instances, the compositions and methods provided herein can provide a decrease in evaporation rate of water or tears from an eye of a subject. This can lead to increased tear retention time and prevention of tear evaporation. These benefits can, in some instances, reduce actual dryness of an eye, or reduce the sensation of dryness and associated symptoms in an eye.

[0029] Third, in some instances, the compositions and methods provided herein can provide a soothing or comforting effect to an eye of a subject, whether or not an ocular disease is present.

[0030] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1A is a graph showing the linear regression curve of the PBS group according to Example 1.

[0033] FIG. IB is a graph showing the linear regression curve of the F6H8 group according to Example 1 .

[0034] FIG. 1C is a graph showing the linear regression curve of the 90%F6H8-

[0035] 10%MCT group according to Example 1. Attorney Docket No. 43081-0039W01

[0036] FIG. 2 is a graph showing the comparative evaporation rate of certain test articles according to Example 1.

[0037] DETAILED DESCRIPTION

[0038] Provided herein are compositions for treating dry eye and related diseases, and for reducing or modifying tear evaporation rate, increasing tear retention time. The compositions can, in some instances comprise a semifluorinated alkane and an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof. Also provided herein are methods for making and using the compositions, such as for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or combinations thereof in a subject in need thereof, and for reducing or modifying tear evaporation rate, increasing tear retention time, protecting tear film, preventing tear evaporation, producing a soothing effect, or improving tear quality in an eye of a subject.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0040] As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

[0041] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the eye tissue with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the eye tissue in need of treatment, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the ocular tissue. Attorney Docket No. 43081-0039W01

[0042] As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. In some embodiment, a human subject may be of any age, for example, from 0 to 100 years old. As used herein, “pediatric subject” and “child” are used interchangeably and refer to subjects from 0 to 18 years old, for example, 1, 2, 5, 10, 12, or 14 years old.

[0043] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

[0044] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.c., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0045] In some instances of the compositions described herein, the composition is nonaqueous. In some instances of the compositions described herein, the composition is a solution, a suspension, an emulsion, or an oil-in-oil emulsion.

[0046] The compositions described herein can include a semifluorinated alkane (SFA). A semifluorinated alkane is an amphiphilic liquid with two mutually immiscible moieties (hydrocarbon segment and perfluorinated segment) bound covalently. In some instances, the semifluorinated alkane can be a partially fluorinated alkane compound having a formula CF3(CF2)m(CH2)nCH.3. In some instances, m is an integer from 1 to 10, and n is an integer from 1 to 10. For example, m is can be 1, 2, 3, 4, 5, or 6. In another example, n can be 1, 2, 3, 4, 5, or 6. Suitable examples of semifluorinated alkane compounds include perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyl decane (F6H10). In some instances, the SFA is perfluorohexyloctane (F6H8).

[0047] The structure of F6H8 is shown below: Attorney Docket No. 43081-0039W01

[0048] F6H8 (CF3(CF 2)5(CH2)7CH3)

[0049] In some instances, the SFA can be present in the compositions in an amount of from about 50% to about 99% (w / w), from about 60% to about 99% (w / w), from about 65%> to about 99% (w / w), from about 70%> to about 99% (w / w), from about 75%o to about 99%o (w / w), from about 80% to about 99%o (w / w), from about 85%) to about 99% (w / w), from about 90%> to about 99% (w / w), from about 95%> to about 99% (w / w), from about 50%o to about 90% (w / w), from about 60%> to about 90% (w / w), from about 70% to about 90%o (w / w), about 99% (w / w), about 98%> (w / w), about 97%> (w / w), about 96%o (w / w), about 95% (w / w), about 94%> (w / w), about 93%o (w / w), about 92%> (w / w), about 91% (w / w), about 90% (w / w), about 89% (w / w), about 88% (w / w), about 87%> (w / w), about 86%o (w / w), about 85%> (w / w), about 80%> (w / w), about 75%> (w / w), about 70%> (w / w), about 65% (w / w), about 60% (w / w), about 55%o (w / w), or about 50% (w / w).

[0050] The compositions described herein can include an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof.

[0051] In some instances, the additive can be present in an amount of from about 1% to about 50%o (w / w), from about 1% to about 45%> (w / w), from about 1% to about 4O%o (w / w), from about 1% to about 35% (w / w), 1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1%> to about 20% (w / w), from about 1% to about 15% (w / w), from about 1% to about 10%> (w / w), from about 5%o to about 20%o (w / w), from about 5% to about 15% (w / w), from about 10% to about 15% (w / w), from about 10% to about 20%o (w / w), from about 10%> to about 30%> (w / w), about 30%> (w / w), about 25% (w / w), about 20% (w / w), about 15%> (w / w), about 10%o (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w). Attorney Docket No. 43081-0039W01

[0052] In some instances the compositions described herein can include paraffin. In some instances the paraffin can be liquid paraffin. In some instances, the paraffin can be light liquid paraffin.

[0053] In some instances the compositions described herein can include propylene glycol diacetate (PGD), also known as 1,2-Diacetoxypropane.

[0054] In some instances, the compositions described herein can include medium chain triglycerides (MCT). Medium-chain triglycerides (MCTs) are triglycerides of fatty acids. The fatty acids have an aliphatic chain of 6-12 carbon atoms, and can be, for example, hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid. The MCTs can be a single triglyceride or a mixture of triglycerides. Representative chemical structures of the MCTs are shown below.

[0055] In some instances, the fatty acids in the MCT can comprise hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations of two or more thereof. In some instances, the fatty acids in the MCT consist essentially of hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations thereof.

[0056] In some instances, the MCT can be present in the compositions in an amount of from about 1% to about 50% (w / w), from about 1% to about 45% (w / w), from about 1% to about 40% (w / w), from about 1% to about 35%> (w / w), 1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1% to about 20% (w / w), from about 1% to about 15% (w / w), from about 1% to about 10% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 10% to about 15% (w / w), from about 10% to about 20% (w / w), from about 10% to about 30% (w / w), about 30% (w / w), about 25% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% Attorney Docket No. 43081-0039W01

[0057] (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w). In some instances, the MCT can be present in the compositions in an amount of from about 5% to about 20% (w / w) MCT.

[0058] The compositions of the present application can include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration include ocular, topical ocular, ocular injection, and the like. In some embodiments, the topical composition is an ophthalmic composition, e.g., for intraocular administration. Suitable examples of ophthalmic compositions include eye drops, emulsions, nanoemulsions, and oils. Any one of these ophthalmic compositions can be administered directly to the cornea or surface of the eye, using, for example, a plastic or latex applicator (e.g., a single-use applicator), an eye dropper, a glass pipette, or a rubber bulb.

[0059] In some instances, the composition has a pH of about 6 to about 8.

[0060] In some instances, the compositions (e.g., topical ophthalmic compositions) of the present application can provide reduced rate of water or tear evaporation e.g., as determined by an assay known in the art or described in the working examples herein. In some instances, the water or tear evaporation rate is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, slower than the rate exhibited by a semi-fluorinated alkane alone.

[0061] In some instances, the compositions are prepared by uniformly and intimately bringing into association the SFA and the additive as disclosed herein.

[0062] In some instances, the compositions can be in the form of an organic composition without aqueous components.

[0063] In some instances, the compositions can be in the form of a solution or suspension. In some instances, the compositions can be in the form of an emulsion. In some instances, the compositions can be in the form of a nano / emulsion. In some instances, the nano-emulsions can be oil-in-oil emulsions. In some instances, the nanoemulsions can have a droplet size D90 of less than 100 nm.

[0064] “Droplet size” of an emulsion refers to the peak droplet size or the mean droplet size, of the dispersed phase. “Droplet size D90” refers to the case that 90% of the particles have a size smaller than the indicated size. Droplet size can be measured by Attorney Docket No. 43081-0039W01 methods known in the art, e.g., by light scattering after dilution in water using a High- Performance Particle Sizer.

[0065] In some instances, the nano-emulsions can have a droplet size D90 of less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, or less than about 50 nm, or from about 1 to 20 nm, from about 1 to 10 nm, from about 1 to 5 nm, or from about 2 to 3 nm.

[0066] In some instances, the methods for making the nano emulsions can comprise combining an additive with a semi-fluorinated alkane compound to form a mixture, wherein said mixture comprises from about 1% to about 50% (w / w) said additive and from about 50% to about 99% (w / w) of said semi-fluorinated alkane compound; and emulsifying said mixture and reducing droplet particle size D90 within said mixture to less than 100 nm by physical agitation selected from high speed stirring, vortexing, sonicating, heating and stirring, or homogenizing the mixture until the droplet size reaches droplet particle size D90 of less than 100 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, or less than about 50 nm, or from about 1 to 20 nm, from about 1 to 10 nm, from about 1 to 5 nm, or from about 2 to 3 nm. In some instances, the methods for making the nano emulsions can comprise uniformly and intimately bringing into association the additive and SFA as disclosed herein, and emulsifying said mixture and reducing droplet particle size D90 within said mixture to less than 100 nm by physical agitation as described herein.

[0067] In some instances, the methods can further comprise measuring the droplet particle size of the mixture during or following said physical agitation.

[0068] This disclosure also includes pharmaceutical kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the Attorney Docket No. 43081-0039W01 components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein.

[0069] In some embodiments, a kit can comprise a dispensing device preloaded with a composition as described herein.

[0070] Also provided herein are methods for treating ocular diseases or conditions using the compositions described herein. In some instances, the ocular diseases or conditions can be related to dry eye.

[0071] Exemplary, nonlimiting dry eye diseases or related conditions that can be treated with the compositions, described herein include dry eye syndrome, dysfunctional tear syndrome, keratoconjunctivitis sicca, Sjogren syndrome, lacrimal gland insufficiency, meibomian gland disease, dry eye disease (DED), including, aqueous deficient DED and evaporative DED, as well as other related ocular diseases.

[0072] Also provided herein are methods of improving tear quality, reducing, or modifying tear evaporation rate, increasing tear retention time, protecting tear film, preventing tear evaporation, producing a soothing effect, or otherwise relieving ocular symptoms that occur in a subject, with or without a diagnosed ocular disease or condition.

[0073] In some instances, the methods can include a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject comprising administering the topical ophthalmological compositions described herein to the eye of a subject. Administering can in some instances include contacting the eye with the composition.

[0074] In some instances, the compositions can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, two times daily, three times daily, or four times daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month), or sporadically, e.g., on an as / needed basis. In some instances, the compositions can be administered once every about 2 to about 8 hours. In some instances, the compositions can be administered three times a day. In some instances, the compositions can be administered once a day. Attorney Docket No. 43081-0039W01

[0075] In some instances of the compositions and methods described herein, the compositions described herein can include an active pharmaceutical ingredient (API) compound. APIs, their analogs, their salts, and their free base forms (where applicable) are included within the scope of the present invention. Such solvates include for example hydrates, alcoholates (e.g., ethanol solvate), and the like. APIs can exist in different polymorphic forms. Such forms are intended to be included within the scope of the present disclosure.

[0076] Exemplary, non-limiting APIs useful in the compositions described herein can include antibiotics, topical transient receptor potential melastatin 8 (TRPM8) agonists, macrolide immunosuppressants useful in the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or other compounds useful in the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca. Many such compounds are active in targeting tear production problems in a subject suffering from the above noted diseases. Without being bound by theory, since the compositions described herein, comprising an SFA and an additive described herein reduce tear evaporation rates, adding active compounds that target tear production can allow for a two / pronged approach to treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca, or related diseases or symptoms.

[0077] Additional exemplary non-limiting APIs useful in the compositions described herein can include a muscarinic receptor agonist, a muscarinic receptor antagonist, or a muscarinic cholinergic receptor agonist.

[0078] In some instances, the API can be a muscarinic receptor agonist. Exemplary nonlimiting muscarinic receptor agonists can include acetylcholine, arecoline, oxotremorine, muscarine, carbachol, nebracetam, bethanechol, pilocarpine, and desmethylclozapine, or a pharmaceutically acceptable salt thereof.

[0079] In some instances, the compositions herein can comprise a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient. Muscarinic cholinergic receptor agonists can, in some instances, cause pupil contraction to alter the focusing depth of field of an eye. In some instances, this can temporarily relieve symptoms of certain eye diseases or conditions such as presbyopia. In Attorney Docket No. 43081-0039W01 some instances, through the muscarinic cholinergic receptors, the agonists can lower intraocular pressure (IOP). This mechanism can, in some instances, be used to treat glaucoma alongside dry eye diseases. In some instances, the muscarinic cholinergic receptor agonist can be selected from the group consisting of aceclidine, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline, and aprolidine, or combinations thereof.

[0080] In some instances, the muscarinic cholinergic receptor agonist can be present in an amount of from about 0.1% to about 5% (w / w), from about 0.1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.1% to about 0.5% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.7% (w / w), from about 0.1% to about 2% (w / w), from about 0.3% to about 2% (w / w), from about 0.5% to about 2% (w / w), from about 0.7% to about 2% (w / w), from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), or about 2% (w / w).

[0081] In some instances, the muscarinic cholinergic receptor agonist can be aceclidine. In some instances, the aceclidine can be in salt form, such as, for example aceclidine sulfate. In some instances, the aceclidine can be in salt form, such as, for example aceclidine hydrochloride. In some instances, the aceclidine can be in free base form. In some instances, the aceclidine can be present in an amount of from about 0.01% to about 10% (w / w), from about 0.01% to about 9% (w / w), from about 0.01% to about 8% (w / w), from about 0.01% to about 7% (w / w), from about 0.01% to about 6% (w / w), from about Attorney Docket No. 43081-0039W01

[0082] 0.01% to about 5% (w / w), from about 0.01% to about 4% (w / w), from about 0.01% to about 3% (w / w), from about 0.01% to about 2% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.9% (w / w), from about 0.01% to about 0.8% (w / w), from about 0.01% to about 0.7% (w / w), from about 0.01% to about 0.6% (w / w), from about 0.01% to about 0.5% (w / w), from about 0.01% to about 0.4% (w / w), from about 0.01% to about 0.3% (w / w), from about 0.01% to about 0.2% (w / w), from about 0.01% to about 0.1% (w / w), from about 1% to about 10% (w / w), from about 1% to about 9% (w / w), from about 1% to about 8% (w / w), from about 1% to about 7% (w / w), from about 1% to about 6% (w / w), from about 1% to about 5% (w / w), from about 1% to about 4% (w / w), from about 1% to about 3% (w / w), from about 1% to about 2% (w / w), from about 0.01% to about 1%, 0.01% to about 0.95% (w / w), 0.01% to about .9% (w / w), 0.01% to about 0.85% (w / w), 0.01% to about 0.8% (w / w), 0.01% to about 0.75% (w / w), 0.01% to about 0.7% (w / w), 0.01% to about 0.65% (w / w), 0.01% to about 0.6% (w / w), 0.01% to about 0.55% (w / w), 0.01% to about 0.5% (w / w), 0.01% to about 0.45% (w / w), 0.01% to about 0.4% (w / w), 0.01% to about 0.35% (w / w), 0.01% to about 0.3% (w / w), 0.01% to about 0.25% (w / w), 0.01% to about 0.2% (w / w), 0.01% to about 0.15% (w / w), 0.01% to about 0.1% (w / w), 0.01% to about 0.09% (w / w), 0.01% to about 0.08% (w / w), 0.01% to about 0.07% (w / w), 0.01% to about 0.06% (w / w), 0.01% to about 0.05% (w / w), 0.01% to about 0.04% (w / w), 0.01% to about 0.03% (w / w), 0.01% to about 0.02% (w / w), from about 0.1% to about 5% (w / w), from about 0.1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0. 1% to about 0.5% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.7% (w / w), from about 0.1% to about 2% (w / w), from about 0.3% to about 2% (w / w), from about 0.5% to about 2% (w / w), from about 0.7% to about 2% (w / w), from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from Attorney Docket No. 43081-0039W01 about 1 .3% to about 1 .5% (w / w), from about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), or about 2% (w / w). In some instances, the aceclidine can be present in an amount of from about 0.01% to about 10% (w / w).

[0083] In some instances, the API can be a muscarinic receptor antagonist. Exemplary non-limiting muscarinic receptor antagonists can include atropine, hyoscyamine, scopolamine, diphenhydramine, dimenhydrinate, dicycloverine, tolterodine, oxybutynin, ipratropium, pirenzepine, telenzepine, tripitramine, gallamine, methoctramine, darifenacin, tiotropium, chlorpromazine, and haloperidol, a free base form, or a pharmaceutically acceptable salt thereof.

[0084] In some instances, the API can be atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0085] In some instances, the API can be in a salt form. In some instances, the API can be in a free base form. In some instances, the API can be in a free acid form.

[0086] In some instances, the API can be present in the compositions described herein in an amount of from about 0.0001% to about 5% (w / w), from about 0.01% to about 5% (w / w) , from about 0.1% to about 5% (w / w) , from about 0.2% to about 5% (w / w) , from about 0.5% to about 5% (w / w) , from about 1% to about 5% (w / w) , from about 2% to about 5% (w / w) , from about 3% to about 5% (w / w) , from about 4% to about 5% (w / w) , from about 0.001% to about 2% (w / w) , from about 0.001% to about 1% (w / w) , from about 0.001% to about 0.9% (w / w) , from about 0.001% to about 0.8% (w / w) , from about 0.001% to about 0.7% (w / w) , from about 0.001% to about 0.6% (w / w) , from about 0.001% to about 0.5% (w / w) , from about 0.001% to about 0.4% (w / w) , from about 0.001% to about 0.3% (w / w) , from about 0.001% to about 0.2% (w / w) , from about 0.001% to about 0.1% (w / w), about 0.0001% to about 0.9% (w / w) , from about 0.0001% to about 0.8% (w / w) , from about 0.0001% to about 0.7% (w / w) , from about 0.0001% to about 0.6% (w / w) , from about 0.0001% to about 0.5% (w / w) , from about 0.0001% to about 0.4% (w / w) , from about 0.0001% to about 0.3% (w / w) , from about 0.0001% to about 0.2% (w / w) , from about 0.0001% to about 0.1% (w / w), from about Attorney Docket No. 43081-0039W01

[0087] 0.01% to about 2% (w / w) , from about 0.01% to about 1% (w / w) , from about 0.01% to about 0.9% (w / w) , from about 0.01% to about 0.8% (w / w) , from about 0.01% to about 0.7% (w / w) , from about 0.01% to about 0.6% (w / w) , from about 0.01% to about 0.5% (w / w) , from about 0.01% to about 0.4% (w / w) , from about 0.01% to about 0.3% (w / w) , from about 0.01% to about 0.2% (w / w) , from about 0.01% to about 0.1% (w / w), from about 0.001% to about 2% (w / w) , from about 0.001% to about 1% (w / w) , from about 0.1% to about 0.9% (w / w) , from about 0.1% to about 0.8% (w / w) , from about 0.1% to about 0.7% (w / w) , from about 0.1% to about 0.6% (w / w) , from about 0.1% to about 0.5% (w / w) , from about 0.1% to about 0.4% (w / w) , from about 0.1% to about 0.3% (w / w), and from about 0.1% to about 0.2% (w / w). In some instances, the API can be present in the compositions or nano-emulsions described herein in an amount of about 0.02% (w / w). In some instances, the API can be present in the compositions or nanoemulsions described herein in an amount of about 0.04% (w / w). In some instances, the API can be present in the compositions or nano-emulsions described herein in an amount of about 0.05% (w / w). In some instances, the API can be present in the compositions or nano-emulsions described herein in an amount of about 1% (w / w). In some instances, the API can be present in an amount of from about 0.0001% to 0.1%. In some instances, the API can be present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5%, from about 0.1% to about 1% (w / w), 0.0001% to about 0.1% (w / w), from about 0.005% to about 1.5% (w / w), from about 0.01% to about 1.5% (w / w), from about 0.05% to about 1.5% (w / w), from about 0.005% to about 1% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.1% (w / w), from about 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), or from about 0.01% to about 0.5% (w / w)0.0001% to about 0.1% (w / w), 0.001% to about 0.01% (w / w), about 0.001% to about 1% (w / w), about 0.003% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.02% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.5% (w / w), about 1.0% (w / w), or about 1.5% (w / w). In some instances, the API can be menthol, and the menthol can be present in a concentration of from about 0.01% to about 1.5% (w / w). In some instances, the API can be AR-15512 and the AR-15512 is present in a concentration of from about 0.0001% to about 0.01% (w / w). Attorney Docket No. 43081-0039W01

[0088] In some instances, provided herein are compositions comprising a therapeutically effective amount of a TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide)), or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof as an active pharmaceutical ingredient; a semifluorinated alkane compound; and an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof. The compositions can, in some instances, be topical ophthalmological compositions.

[0089] TRPM8 agonists, such as AR-15512 and menthol, can act as potent and selective agonists of the TRPM8 (transient receptor potential melastatin 8) cold thermoreceptor. TRPM8 is a calcium-permeable ion channel, serves as a detector of cold in humans, and is involved in the regulation of blink rate and tear production. Stimulation of this receptor can lead to restoration of tear film volume and a reduction of ocular discomfort in patients suffering from dry eye symptoms or dry eye syndrome.

[0090] Non-limiting exemplary TRPM8 agonists include menthol (e.g., 5-Methyl-2- (propan-2-yl)cyclohexan-l-ol); AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl- 2-(l -methylethyl) cyclohexanecarboxamide); eucalyptol (l,3,3-Trimethyl-2- oxabicyclo[2.2.2]octane); Cryosim-3 or IVW-1001 (diisopropyl(nonyl)phosphine oxide); Icilin (3-(2-Hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(lH)-one); Dendreon D3263 (3-(2-aminoethyl)-l-((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l- carbonyl)-5-methoxy-l,3-dihydro-2H-benzo[d]imidazol-2-one hydrochloride); Borneol (rel -(1 R ,2 S ,4 R )-l,7,7-Trimethylbicyclo[2.2.1]heptan-2-ol); WS-5 (ethyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carbonyl)carbamate), structure shown below:

[0091] CPS369 (ethyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carbonyl)alaninate), structure shown below: Attorney Docket No. 43081-0039W01

[0092] CPS368 (methyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carbonyl)alaninate;

[0093] CPS 125 ((lR,2S,5R)-2-isopropyl-5-methyl-N-(4-(N-(pyrimidin-2- yl)sulfamoyl)phenyl)cyclohexane-l -carboxamide), structure shown below:

[0094] Frescolat ML ((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-hydroxypropanoate), structure shown below:

[0095] Frescolat MGA (((5S,6S,9R)-6-isopropyl-9-methyl-l,4-dioxaspiro[4.5]decan-2- yl)methanol), structure shown below: Attorney Docket No. 43081-0039W01

[0096] WS-3 (N-ethyl-2-isopropyl-5-methylcyclohexane-l -carboxamide), structure shown below: WS-23 (3-isopropyl-N,2,4-trimethylpentanamide), structure shown below:

[0097] Rotundifolone ((1 S,6S)-6-methyl-3-(propan-2-ylidene)-7-oxabicyclo[4.1 ,0]heptan-2- one), structure shown below:

[0098] Cubebol ((3S,3aR,3bR,4S,7R,7aR)-4-isopropyl-3,7-dimethyloctahydro-lH- cyclopenta[l,3]cyclopropa[l,2]benzen-3-ol), structure shown below: -isopropyl-3-methyl-2-methylenecyclohexan-l-ol, structure shown below: Attorney Docket No. 43081-0039W01

[0099] 4-(3, 5-dimethoxyphenyl)-l -((lR,2S,5R)-2-isopropyl-5-methylcy cl ohexyl)-lH- 1 ,2,3- tri azole, structure shown below: (lR,2S,5R)-N-((S)-2-(2-aminoacetamido)-2-phenylethyl)-2-isopropyl-5- methylcyclohexane-1 -carboxamide, structure shown below:

[0100] (R)-2-((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carboxamido)-l -phenylethyl glycinate, structure shown below:

[0101] (lR,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-2-isopropyl-5- methylcyclohexane-l-carboxamide, structure shown below:

[0102] (lR,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-l -carboxamide, structure shown below: Attorney Docket No. 43081-0039W01 pyl-5-methylcyclohexyl)oxy)propane-l,2-diol, structure shown

[0103] 4-((lS,2R)-2-(4-allyl-2,6-dimethoxyphenoxy)-l-ethoxypropyl)-2-methoxyphenol, structure shown below:

[0104] 4-((lS,2S)-2-(4-allyl-2,6-dimethoxyphenoxy)-l-ethoxypropyl)-2-methoxyphenol, structure shown below: 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-l-(((lS,2R,5S)-2-isopropyl-5- methylcyclohexyl)oxy)propyl)-2-methoxyphenol, structure shown below: Attorney Docket No. 43081-0039W01 di-sec-butyl(pentyl)phosphine oxide, structure shown below: ethyl 5-oxo- 1,2, 3, 4, 4a, 10b, 1 l,12a-octahydrospiro[naphtho[l,2-c]chromene-12,2'-

[0105] [l,3]dithiolane]-4b(5H)-carboxylate, structure shown below: 10b-((2-mercaptoethyl)thio)-l,3,4,10b-tetrahydro-6H-spiro[pyrido[2,l-a]isoindole-2,2'-

[0106] [l,3]dithian]-6-one, structure shown below:

[0107] (S)-4-cyclohexyl-4,5-dimethyl-2-(2-oxo-2-phenylethyl)-2,4-dihydro-3H-pyrazol-3-one, structure shown below: Attorney Docket No. 43081-0039W01

[0108] 5-((l S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-l,5- dimethylimidazolidine-2, 4-dione, structure shown below: (S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-phenylethyl)propanamide, structure shown below:

[0109] N-(lH-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, structure shown below: Attorney Docket No. 43081-0039W01

[0110] 2-((2,3-dihydro-lH-inden-5-yl)oxy)-N-(lH-pyrazol-3-yl)-N-(thiophen-2- ylmethyl)acetamide, structure shown below:

[0111] (E)-N-(lH-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-3-(p-tolyl)acrylamide, structure shown below:

[0112] (S)-2-(cyclohexanecarbonyl)-l,2,3,6,7, 1 lb-hexahydro-4H-pyrazino[2, l-a]isoquinolin-4- one aka Praziquantel, structure shown below: Attorney Docket No. 43081-0039W01

[0113] Tacrolimus ((-)-(3 S,4R,5 S,8R,9E, 12 S, 14 S, 15R, 16 S, 18R,26aS)-8-allyl-

[0114] 5,6,8,l l,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-{(E)-2-

[0115] [(lR,3R,4R)-4-hydroxy-3-methylcyclohexyl]-l-methylvinyl }-14,16-dimethoxy-

[0116] 4,10,12,18-tetram ethyl- 15,19-epoxy-3H-pyrido[2, 1 -c] [1 ,4]oxaazacyclotricosane- l,7,20,21(4H,23H)-tetrone), structure shown below:

[0117] CPS- 113 ((lR,2S,5R)-N-(4-fluorophenyl)-2-isopropyl-5-methylcyclohexane-l- carboxamide), structure shown below:

[0118] 6-(3-chlorophenyl)-3-(2-hydroxyphenyl)-3,4-dihydropyrimidin-2(lH)-one, structure shown below: Attorney Docket No. 43081-0039W01 ethyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l -carbonyl)glycinate, structure shown below:

[0119] (lR,2S,5R)-N-(l-(2-aminoethyl)-3-phenyl-lH-pyrazol-5-yl)-2-isopropyl-5- methylcy cl ohexane-1 -carboxamide, structure shown below: minoethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane- shown below: and derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof. The compositions described herein can also include combinations of two or more TRPM8 agonists.

[0120] TRPM8 agonists such as menthol or AR-15512, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can, in some instances, aid in treatment of dry eye syndrome, or keratoconjunctivitis sicca. In some instances, TRPM8 agonists (e.g., menthol or AR- 15512) or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can slow the progression of, treat, or reduce or relieve symptoms of certain ocular diseases or conditions, such as dry Attorney Docket No. 43081-0039W01 eye syndrome or keratoconjunctivitis sicca, dry eye disease, inflammatory dry eye, redness, or meibomian gland disfunction.

[0121] In some instances, the TRPM8 agonists (e.g., menthol or AR-15512) or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.001% to about 0.01% (w / w), from about 0.001% to about 0.009% (w / w), from about 0.001% to about 0.008% (w / w), from about 0.001% to about 0.007% (w / w), from about 0.001% to about 0.006% (w / w), from about 0.001% to about 0.005% (w / w), from about 0.001% to about 0.004% (w / w), from about 0.001% to about 0.003% (w / w), from about 0.001% to about 0.002% (w / w), from about 0.0001% to about 0.001% (w / w), from about 0.0001% to about 0.0009% (w / w), from about 0.0001% to about 0.0008% (w / w), from about 0.0001% to about 0.0007% (w / w), from about 0.0001% to about 0.0006% (w / w), from about 0.0001% to about 0.0005% (w / w), from about 0.0001% to about 0.0004% (w / w), from about 0.0001% to about 0.0003% (w / w), from about 0.0001% to about 0.0002% (w / w), from about 0.15% to about 0.5% (w / w), from about 0.15% to about 0.45% (w / w), from about 0.15% to about 0.4% (w / w), from about 0.15% to about 0.35% (w / w), from about 0.15% to about 0.3% (w / w), from about 0.15% to about 0.25% (w / w), from about 0.15% to about 0.2% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.5% (w / w), from about 0.1% to about 0.45% (w / w), from about 0.1% to about 0.4% (w / w), from about 0.1% to about 0.35% (w / w), from about 0.1% to about 0.3% (w / w), from about 0.1% to about 0.25% (w / w), from about 0.1% to about 0.2% (w / w), from about 0.15% to about 0.5% (w / w), from about 0.15% to about 0.45% (w / w), from about 0.15% to about 0.4% (w / w), from about 0.15% to about 0.35% (w / w), from about 0.15% to about 0.3% (w / w), from about 0.15% to about 0.25% (w / w), from about 0.15% to about 0.2% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.7% (w / w), from about 0.1% to about 2% (w / w), from about 0.3% to about 2% (w / w), from about 0.5% to about 2% (w / w), from about 0.7% to about 2% (w / w), from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to Attorney Docket No. 43081-0039W01 about 2% (w / w), from about 1 .7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 0.001%(w / w), about 0.002% (w / w), about 0.003%(w / w), about 0.004% (w / w), about 0.005%(w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.0017% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.002% (w / w), about 0.0021% (w / w), about 0.0022% (w / w), about 0.0023% (w / w), about 0.0024% (w / w), about 0.0025% (w / w), about 0.0026% (w / w), about 0.0027% (w / w), about 0.0028% (w / w), about 0.0029% (w / w), about 0.0030% (w / w), about 0.0031% (w / w), about 0.0032% (w / w), about 0.0033% (w / w), about 0.0034% (w / w), about 0.0035% (w / w), about 0.0036% (w / w), about 0.0037% (w / w), about 0.0038% (w / w), about 0.0039% (w / w), about 0.0001% (w / w), about 0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w), or about 0.0009% (w / w).

[0122] In some instances, the compositions provided herein can include an API that is a macrolide immunosuppressants useful in the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca. In some instances, the macrolide immunosuppressant can be cyclosporine.

[0123] In some instances, provided herein are compositions comprising a therapeutically effective amount of cyclosporine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof as an active pharmaceutical ingredient; a semi-fluorinated alkane compound; and an additive selected Attorney Docket No. 43081-0039W01 from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof. The compositions can, in some instances, be topical ophthalmological compositions.

[0124] Cyclosporine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can, in some instances, aid in treatment of dry eye syndrome, or keratoconjunctivitis sicca. In some instances, cyclosporine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can slow the progression of, treat, or reduce or relieve symptoms of certain ocular diseases or conditions, such as dry eye syndrome or keratoconjunctivitis sicca, dry eye disease, inflammatory dry eye, redness, or meibomian gland disfunction.

[0125] In some instances, the cyclosporine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.001% to about 0.01% (w / w), from about 0.001% to about 0.009% (w / w), from about 0.001% to about 0.008%

[0126] (w / w), from about 0.001% to about 0.007% (w / w), from about 0.001% to about 0.006%

[0127] (w / w), from about 0.001% to about 0.005% (w / w), from about 0.001% to about 0.004%

[0128] (w / w), from about 0.001% to about 0.003% (w / w), from about 0.001% to about 0.002%

[0129] (w / w), from about 0.0001% to about 0.001% (w / w), from about 0.0001% to about 0.0009% (w / w), from about 0.0001% to about 0.0008% (w / w), from about 0.0001% to about 0.0007% (w / w), from about 0.0001% to about 0.0006% (w / w), from about 0.0001% to about 0.0005% (w / w), from about 0.0001% to about 0.0004% (w / w), from about 0.0001% to about 0.0003% (w / w), from about 0.0001% to about 0.0002% (w / w), from about 0.15% to about 0.5% (w / w), from about 0.15% to about 0.45% (w / w), from about 0.15% to about 0.4% (w / w), from about 0.15% to about 0.35% (w / w), from about 0.15% to about 0.3% (w / w), from about 0.15% to about 0.25% (w / w), from about 0.15% to about 0.2% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.5% (w / w), from about 0.1% to about 0.45% (w / w), from about 0.1% to about 0.4% (w / w), from about 0.1% to about 0.35% (w / w), Attorney Docket No. 43081-0039W01 from about 0.1% to about 0.3% (w / w), from about 0.1% to about 0.25% (w / w), from about 0.1% to about 0.2% (w / w), from about 0.15% to about 0.5% (w / w), from about 0.15% to about 0.45% (w / w), from about 0.15% to about 0.4% (w / w), from about 0.15% to about 0.35% (w / w), from about 0.15% to about 0.3% (w / w), from about 0.15% to about 0.25% (w / w), from about 0.15% to about 0.2% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.7% (w / w), from about 0.1% to about 2% (w / w), from about 0.3% to about 2% (w / w), from about 0.5% to about 2% (w / w), from about 0.7% to about 2% (w / w), from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 0.001%(w / w), about 0.002% (w / w), about 0.003%(w / w), about 0.004% (w / w), about 0.005%(w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.0017% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.002% (w / w), about 0.0021% (w / w), about 0.0022% (w / w), about 0.0023% (w / w), about 0.0024% (w / w), about 0.0025% (w / w), about 0.0026% (w / w), about 0.0027% (w / w), about 0.0028% (w / w), about 0.0029% (w / w), about 0.0030% (w / w), about 0.0031% (w / w), about 0.0032% (w / w), about 0.0033% (w / w), about 0.0034% (w / w), about 0.0035% (w / w), about 0.0036% (w / w), about 0.0037% (w / w), about 0.0038% (w / w), about 0.0039% (w / w), about 0.0001% (w / w), about 0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% Attorney Docket No. 43081-0039W01

[0130] (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w), or about 0.0009% (w / w).

[0131] The compositions disclosed herein may, in some instances, also comprise one or more additional therapeutic agents, excipients, or diluents including, but not limited to, absorbents, anti-irritants, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, prescription drugs, surfactants / detergent cleansing agents, penetration enhancers, viscosity enhancers, and thickeners.

[0132] The invention will be further described in the following examples, which do not limit the scope of the invention.

[0133] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0134] EXAMPLES

[0135] Example 1: Evaporation Studies of F6H8 and F4H5 with various additives

[0136] The ability of F6H8 and F4H5, each in combination with various additives, to prevent water evaporation, was tested according to the in vitro assay for modeling tear evaporation published in Vittitow J, Kissing R, DeCory H, Borchman D. In vitro inhibition of evaporation with perfluorohexyloctane, an eye drop for dry eye disease. Curr Ther Res Clin Exp. 2023 ;98: 100704.

[0137] Method:

[0138] An incubator was prepared with 25°C / 40%RH and an open container with 8 mm height. 1 mL PBS was added to the container followed by 0.1 ml of testing article (TA). The total weight was measured at t=0 and again every 10 minutes for a total of 100 minutes in the incubator. The weight loss per minute was calculated to determine the water evaporation rate.

[0139] Results: Attorney Docket No. 43081-0039W01

[0140] Table 1 below shows the evaporation rate and number of trials for each testing article. Linear regression curves are shown in FIG 1 A for PBS, FIG IB for F6H8, and FIG 1C for 10%MCT-90%F6H8. The results for TA 100% F6H8 confirm the published Vittitow et. al study and show that the evaporation rate with F6H8 was about 33% that of the PBS control, a highly significant difference. Surprisingly, it was found that some of the additives substantially enhance the protective effects of the SFA, F6H8. For example, addition of MCT to F6H8 cuts evaporation further by another 50% (see FIG 1C). The addition of PGD (propylene glycol diacetate, or 1,2-Diacetoxypropane) and paraffin each also surprisingly substantially enhanced the protective effects of F6H8. Other additives did not have significant effects or performed slightly worse than the PBS control. Surprisingly, F4H5, another SFA which was expected to have a similar effect as F6H8, appeared to cause an increase in evaporation. However, this increase occurred quickly, within the first 10 minutes, after which the rate of evaporation was like that of the PBS control.

[0141] Table 1: Evaporation Rate for F6H8 and F4H5 with various additives Attorney Docket No. 43081-0039W01

[0142] Example 2: Evaporation Rate for various SFAs with various additives

[0143] The ability of various SFAs, each in combination with various additives, to prevent water evaporation, is tested according to the methods described in Example 1.

[0144] OTHER EMBODIMENTS

[0145] It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0146] EXEMPLARY EMBODIMENTS

[0147] Embodiment 1. A method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or combinations thereof in a subject in need thereof, the method comprising administering to the subject the topical ophthalmological composition comprising: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and Attorney Docket No. 43081-0039W01 an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.

[0148] Embodiment 2. A method for reducing or modifying tear evaporation rate, increasing tear retention time, protecting tear film, preventing tear evaporation, producing a soothing effect, or improving tear quality in an eye of a subject, comprising administering to the subject the topical ophthalmological composition comprising: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.

[0149] Embodiment 3. The method of any one of embodiments 1-2 or 50, wherein the topical ophthalmological composition consists essentially of the semifluorinated alkane compound and the additive or consists essentially of the semifluorinated alkane compound, the additive, and an API selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, a muscarinic receptor agonist, a muscarinic receptor antagonist, a muscarinic cholinergic receptor agonist, or combinations thereof.

[0150] Embodiment 4. The method of any one of embodiments 1-3, 50, or 53, wherein the topical ophthalmological composition is non-aqueous. Attorney Docket No. 43081-0039W01

[0151] Embodiment 5. The method of any one of embodiments 1-4, 50, or 53, wherein the semi-fluorinated alkane compound is present in a concentration of from about 50% to about 99.9% (w / w) in the topical ophthalmological composition.

[0152] Embodiment 6. The method of any one of embodiments 1-5, 50, or 53, wherein the additive is present in a concentration of from about 0.1% to about 50% (w / w).

[0153] Embodiment 7. The method of any one of embodiments 1-6, 50, or 53, wherein the additive is present in a concentration of from about 1% to about 30% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 70% to about 99% (w / w).

[0154] Embodiment 8. The method of any one of embodiments 1-7, 50, or 53, wherein the semifluorinated alkane compound is perfluorohexyloctane (F6H8).

[0155] Embodiment 9. The method of any one of embodiments 1-8, 50, or 53, wherein the additive is PGD.

[0156] Embodiment 10. The method of any one of embodiments 1-8, 50, or 53, wherein the additive is paraffin.

[0157] Embodiment 11. The method of embodiment 10, wherein the paraffin is liquid paraffin.

[0158] Embodiment 12. The method of any one of embodiments 1-8, 50, or 53, wherein the additive is MCT.

[0159] Embodiment 13. The method of embodiment 12, wherein the MCT is a triglyceride of fatty acids and the fatty acids comprise hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations of two or more thereof. Attorney Docket No. 43081-0039W01

[0160] Embodiment 14. The method of any one of embodiments 12-13 wherein the MCT is a triglyceride of fatty acids and the fatty acids consist essentially of hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations thereof.

[0161] Embodiment 15. The method of any one of embodiments 1-14, 50, 53, or 59, wherein the topical ophthalmological composition is in the form of a solution, a suspension, or an emulsion.

[0162] Embodiment 16. The method of any one of embodiments 1-15, 50 53, or 59, wherein the ophthalmological composition is in the form of a solution and wherein the additive comprises from about 0.1% to about 2.9% (w / w) MCT.

[0163] Embodiment 17. The method of any one of embodiments 1-15, 50, 53, or 59, wherein the ophthalmological composition is in the form of an emulsion and wherein the additive comprises from about 3% to about 50% (w / w) MCT.

[0164] Embodiment 18. The method of any one of embodiments 1-15, 17, 50, 53, or 59, wherein the topical ophthalmological composition is a nanoemulsion.

[0165] Embodiment 19. The method of embodiment 18, wherein the additive comprises from about 10% to about 50% (w / w) MCT.

[0166] Embodiment 20. The method of any one of embodiments 18 or 19, wherein the nano-emulsion has a droplet particle size D90 of less than about 100 nm, less than about 50 nm, less than about 20 nm, less than or equal to about 10 nm, or has a droplet particle size D90 of from about 5 nm to about 20 nm.

[0167] Embodiment 21. The method of any one of embodiments 1-15, 50, 53, or 59, wherein, in the topical ophthalmological composition, the additive is present in a concentration of about 1% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 99% (w / w), the additive is present in a concentration of about Attorney Docket No. 43081-0039W01

[0168] 2% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 98% (w / w), the additive is present in a concentration of about 3% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 97% (w / w), the additive is present in a concentration of about 4% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 96% (w / w), the additive is present in a concentration of about 5% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 95% (w / w), wherein the additive is present in a concentration of about 10% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 90% (w / w), wherein the additive is present in a concentration of about 15% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 85% (w / w), wherein the additive is present in a concentration of about 20% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 80% (w / w), wherein the additive is present in a concentration of about 25% (w / w) and the semifluorinated alkane compound is present in a concentration of about 75% (w / w), or wherein the additive is present in a concentration of about 30% (w / w) and the semifluorinated alkane compound is present in a concentration of about 70% (w / w).

[0169] Embodiment 22. The method of embodiment 21, wherein the additive is MCT, the MCT is present in an amount of from about 3% to about 30% (w / w), and the SFA is present in an amount of from about 70% to about 97% (w / w).

[0170] Embodiment 23. The method of embodiment 21, wherein the additive is PGD, the PGD is present in an amount of from about 3% to about 10% (w / w), and the SFA is present in an amount of from about 90% to about 97% (w / w).

[0171] Embodiment 24. The method of embodiment 21, wherein the additive is paraffin, Attorney Docket No. 43081-0039W01 the paraffin is present in an amount of from about 1% to about 20% (w / w), and the SFA is present in an amount of from about 80% to about 99%.

[0172] Embodiment 25. The method of any one of embodiments 1-24, 50, 53, or 59, wherein the subject is a human.

[0173] Embodiment 26. The method of any one of embodiments 1-25, 50, 53, or 59, wherein the topical ophthalmological composition is free from perfluorobutylheptane (F4H5).

[0174] Embodiment 27. Eye drops consisting essentially of: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluoroh exyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof; or a semi fluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof; and an API selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, or combinations thereof.

[0175] Embodiment 28. The eye drops of embodiment 27 or 57, wherein the eye drops are non-aqueous. Attorney Docket No. 43081-0039W01

[0176] Embodiment 29. The eye drops of any one of embodiments 27-28, or 57, wherein the semi-fluorinated alkane compound is present in a concentration of from about 50% to about 99.9% (w / w) in the topical ophthalmological composition.

[0177] Embodiment 30. The eye drops of any one of embodiments 27-29, or 57, wherein the additive is present in a concentration of from about 0.1% to about 50% (w / w).

[0178] Embodiment 31. The eye drops of any one of embodiments 27-30, or 57, wherein the additive is present in a concentration of from about 1% to about 30% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 70% to about 99% (w / w).

[0179] Embodiment 32. The eye drops of any one of embodiments 27-31, or 57, wherein the semifluorinated alkane compound is perfluorohexyloctane (F6H8).

[0180] Embodiment 33. The eye drops of any one of embodiments 27-32, or 57, wherein the additive is PGD.

[0181] Embodiment 34. The eye drops of any one of embodiments 27-32, or 57, wherein the additive is paraffin.

[0182] Embodiment 35. The eye drops of embodiment 34, wherein the paraffin is liquid paraffin.

[0183] Embodiment 36. The eye drops of any one of embodiments 27-32, or 57, wherein the additive is MCT.

[0184] Embodiment 37. The eye drops of embodiment 36, wherein the MCT is a triglyceride of fatty acids and the fatty acids comprise hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations of two or more thereof. Attorney Docket No. 43081-0039W01

[0185] Embodiment 38. The eye drops of any one of embodiments 36-37 wherein the MCT is a triglyceride of fatty acids and the fatty acids consist essentially of hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations thereof.

[0186] Embodiment 39. The eye drops of any one of embodiments 27-38, 57, or 60, wherein the eye drops are in the form of a solution, a suspension, or an emulsion.

[0187] Embodiment 40. The eye drops of any one of embodiments 27-39, 57, or 60, wherein the eye drops are in the form of a solution and wherein the additive comprises from about 0.1% to about 2.9% (w / w) MCT.

[0188] Embodiment 41. The eye drops of any one of embodiments 27-40, 57, or 60, wherein the eye drops are in the form of an emulsion and wherein the additive comprises from about 3% to about 50% (w / w) MCT.

[0189] Embodiment 42. The eye drops of any one of embodiments 27-39, 41, 57, or 60, wherein the eye drops are in the form of a nanoemulsion.

[0190] Embodiment 43. The eye drops of embodiment 42, wherein the additive comprises from about 10% to about 50% (w / w) MCT.

[0191] Embodiment 44. The eye drops of any one of embodiments 42 or 43, wherein the nano-emulsion has a droplet particle size D90 of less than about 100 nm, less than about 50 nm, less than about 20 nm, less than or equal to about 10 nm, or has a droplet particle size D90 of from about 5 nm to about 20 nm.

[0192] Embodiment 45. The eye drops of any one of embodiments 27-39, 57, or 60, wherein the additive is present in a concentration of about 1% (w / w) and the semifluorinated alkane compound is present in a concentration of about 99% (w / w), the additive is present in a concentration of about 2% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 98% (w / w), the additive is present in a Attorney Docket No. 43081-0039W01 concentration of about 3% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 97% (w / w), the additive is present in a concentration of about 4% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 96% (w / w), the additive is present in a concentration of about 5% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 95% (w / w), wherein the additive is present in a concentration of about 10% (w / w) and the semifluorinated alkane compound is present in a concentration of about 90% (w / w), wherein the additive is present in a concentration of about 15% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 85% (w / w), wherein the additive is present in a concentration of about 20% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 80% (w / w), wherein the additive is present in a concentration of about 25% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 75% (w / w), or wherein the additive is present in a concentration of about 30% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 70% (w / w).

[0193] Embodiment 46. The eye drops of embodiment 45, wherein the additive is MCT, the MCT is present in an amount of from about 3% to about 30% (w / w), and the SFA is present in an amount of from about 70% to about 97% (w / w).

[0194] Embodiment 47. The eye drops of embodiment 45, wherein the additive is PGD, the PGD is present in an amount of from about 3% to about 10% (w / w), and the SFA is present in an amount of from about 90% to about 97% (w / w).

[0195] Embodiment 48. The eye drops of embodiment 45, wherein the additive is paraffin, Attorney Docket No. 43081-0039W01 the paraffin is present in an amount of from about 1% to about 20% (w / w), and the SFA is present in an amount of from about 80% to about 99%.

[0196] Embodiment 49. The eye drops of any one of embodiments 27-48, 57, or 60, wherein the eye drops are free from perfluorobutylheptane (F4H5).

[0197] Embodiment 50. A method for enhancing the effect of F6H8 on reducing tear evaporation rate or for improving the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or combinations thereof in a subject in need thereof with F6H8 comprising: mixing F6H8 with an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof to generate a combined composition comprising F6H8 and the additive; and optionally administering the combined composition to an eye of the subject.

[0198] Embodiment 51. The method of any one of embodiments 1-2, 4-26, or 59, wherein the composition further comprises an API.

[0199] Embodiment 52. The method of embodiment 51, wherein the API is selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, a muscarinic receptor agonist, a muscarinic receptor antagonist, a muscarinic cholinergic receptor agonist, or combinations thereof.

[0200] Embodiment 53. The method of any one of embodiments 3 or 52, wherein the TRPM8 agonist is selected from menthol (5-Methyl-2-(propan-2-yl)cyclohexan-l-ol), AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide), derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof. Attorney Docket No. 43081-0039W01

[0201] Embodiment 54. The method of any one of embodiments 3-26, 51-53, and 59, wherein the API is present in a concentration of from about 0.0001% to about 5% (w / w), from about 0. 1% to about 2% (w / w), from about 0.1% to about 1.5%, from about 0.1% to about 1% (w / w), 0.0001% to about 0.1% (w / w), from about 0.005% to about 1.5% (w / w), from about 0.01% to about 1.5% (w / w), from about 0.05% to about 1.5% (w / w), from about 0.005% to about 1% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.1% (w / w), from about 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), or from about 0.01% to about 0.5% (w / w)0.0001% to about 0.1% (w / w), 0.001% to about 0.01% (w / w), about 0.001% to about 1% (w / w), about 0.003% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.02% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.5% (w / w), about 1.0% (w / w), or about 1.5% (w / w).

[0202] Embodiment 55. The method of any one of embodiments 3 or 52, wherein the API is selected from aceclidine and atropine, or derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof.

[0203] Embodiment 56. The method of any one of embodiments 51-52 or 55, wherein the API is present in a concentration of from about 0.01% to 0.1% (w / w).

[0204] Embodiment 57. The eyedrops of any one of embodiments 27-49 or 60, wherein the API is a TRPM8 agonist selected from menthol (5-Methyl-2-(propan-2- yl)cyclohexan-l-ol), AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l- methylethyl) cyclohexanecarboxamide), derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof.

[0205] Embodiment 58. The eyedrops of any one of embodiments 27-49 or 60, wherein the API is present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5%, from about 0.1% to about 1% (w / w), 0.0001% to about 0.1% (w / w), from about 0.005% to about 1.5% (w / w), from about 0.01% to about 1.5% (w / w), from about 0.05% to about 1.5% (w / w), from about 0.005% to about 1% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to Attorney Docket No. 43081-0039W01 about 0.1% (w / w), from about 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), or from about 0.01% to about 0.5% (w / w)0.0001% to about 0.1% (w / w), 0.001% to about 0.01% (w / w), about 0.001% to about 1% (w / w), about 0.003% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.02% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.5% (w / w), about 1.0% (w / w), or about 1.5% (w / w).

[0206] Embodiment 59. The method of embodiment 10, wherein the liquid paraffin is light liquid paraffin.

[0207] Embodiment 60. The eye drops of embodiment 34, wherein the liquid paraffin is light liquid paraffin.

[0208] Embodiment 61. The method of embodiment 54, wherein the menthol is present in a concentration of from about 0.01% to about 1.5% (w / w).

[0209] Embodiment 62. The method of embodiment 54, wherein the AR-15512 is present in a concentration of from about 0.0001% to about 0.01% (w / w).

[0210] Embodiment 63. The eye drops of embodiment 58, wherein the menthol is present in a concentration of from about 0.01% to about 1.5% (w / w).

[0211] Embodiment 64. The eye drops of embodiment 58, wherein the AR-15512 is present in a concentration of from about 0.0001% to about 0.01% (w / w).

[0212] REFERENCES

[0213] Vittitow J, Kissing R, DeCory H, Borchman D. In vitro inhibition of evaporation with perfluorohexyloctane, an eye drop for dry eye disease. Curr Ther Res Clin Exp. 2023;98: 100704.

Claims

Attorney Docket No. 43081-0039W01WHAT IS CLAIMED IS:

1. A method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or combinations thereof in a subject in need thereof, the method comprising administering to the subject a topical ophthalmological composition comprising: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), propylene glycol diacetate (PGD), and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.

2. A method for reducing or modifying tear evaporation rate, increasing tear retention time, protecting tear fdm, preventing tear evaporation, producing a soothing effect, or improving tear quality in an eye of a subject, comprising administering to the subject a topical ophthalmological composition comprising: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof, wherein the topical ophthalmological composition is free from any other active pharmaceutical compound useful for the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, or keratoconjunctivitis sicca.Attorney Docket No. 43081-0039W013. The method of claim 1 or 2, wherein the topical ophthalmological composition consists essentially of the semifluorinated alkane compound and the additive or consists essentially of the semifluorinated alkane compound, the additive, and an API selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, a muscarinic receptor agonist, a muscarinic receptor antagonist, a muscarinic cholinergic receptor agonist, or combinations thereof.

4. The method of claim 3, wherein the TRPM8 agonist is selected from menthol (5- Methyl-2-(propan-2-yl)cyclohexan-l-ol), AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)- 5-methyl-2-(l -methylethyl) cyclohexanecarboxamide), derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof.

5. The method of claim 3, wherein the API is selected from aceclidine and atropine, or derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof.

6. The method of any one of claims 3-5, wherein the API is present in a concentration of from about 0.01% to 0.1% (w / w). the API is present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5%, from about 0.1% to about 1% (w / w), 0.0001% to about 0.1% (w / w), from about 0.005% to about 1.5% (w / w), from about 0.01% to about 1.5% (w / w), from about 0.05% to about 1.5% (w / w), from about 0.005% to about 1% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.1% (w / w), from about 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), or from about 0.01% to about 0.5% (w / w)0.0001% to about 0.1% (w / w), 0.001% to about 0.01% (w / w), about 0.001% to about 1% (w / w), about 0.003% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.02% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.5% (w / w), about 1.0% (w / w), or about 1.5% (w / w).Attorney Docket No. 43081-0039W017. The method of any one of claims 1-6, wherein the topical ophthalmological composition is non-aqueous.

8. The method of any one of claims 1-7, wherein the additive is present in a concentration of from about 1% to about 30% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 70% to about 99% (w / w).

9. The method of any one of claims 1-8, wherein, in the topical ophthalmological composition, the additive is present in a concentration of about 1% (w / w) and the semifluorinated alkane compound is present in a concentration of about 99% (w / w), the additive is present in a concentration of about 2% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 98% (w / w), the additive is present in a concentration of about 3% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 97% (w / w), the additive is present in a concentration of about 4% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 96% (w / w), the additive is present in a concentration of about 5% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 95% (w / w), wherein the additive is present in a concentration of about 10% (w / w) and the semifluorinated alkane compound is present in a concentration of about 90% (w / w), wherein the additive is present in a concentration of about 15% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 85% (w / w), wherein the additive is present in a concentration of about 20% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 80% (w / w), wherein the additive is present in a concentration of about 25% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 75% (w / w), or wherein the additive is present in a concentration of about 30% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 70% (w / w).

10. The method of any one of claims 1-9, wherein the topical ophthalmological composition is free from perfluorobutylheptane (F4H5).Attorney Docket No. 43081-0039W0111 . Eye drops consisting essentially of: a semifluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; and an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof; or a semi fluorinated alkane compound selected from perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10) and combinations thereof; an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof; and an API selected from a TRPM8 agonist, an antibiotic, a macrolide immunosuppressant, or combinations thereof.

12. The eye drops of claim 11, wherein the eye drops are non-aqueous.

13. The eye drops of any one of claims 11-12, wherein the additive is present in a concentration of from about 1% to about 30% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 70% to about 99% (w / w).

14. The eye drops of any one of claims 11-13, wherein the additive is present in a concentration of about 1% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 99% (w / w), the additive is present in a concentration of about 2% (w / w) and the semi -fluorinated alkane compound is present in a concentration of about 98% (w / w), the additive is present in a concentration of about 3% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 97% (w / w), the additive is present in a concentration of about 4% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 96% (w / w), the additive is present in aAttorney Docket No. 43081-0039W01 concentration of about 5% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 95% (w / w), wherein the additive is present in a concentration of about 10% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 90% (w / w), wherein the additive is present in a concentration of about 15% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 85% (w / w), wherein the additive is present in a concentration of about 20% (w / w) and the semi-fluorinated alkane compound is present in a concentration of about 80% (w / w), wherein the additive is present in a concentration of about 25% (w / w) and the semifluorinated alkane compound is present in a concentration of about 75% (w / w), or wherein the additive is present in a concentration of about 30% (w / w) and the semifluorinated alkane compound is present in a concentration of about 70% (w / w).

15. The eye drops of any one of claims 11-14, wherein the eye drops are free from perfluorobutylheptane (F4H5).

16. The eye drops of any one of claims 11-15, wherein the TRPM8 agonist is selected from menthol (5-Methyl-2-(propan-2-yl)cyclohexan-l-ol), AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide), derivatives, analogues, racemic mixtures, or diastereomers or enantiomers thereof, or combinations thereof.

17. The eye drops of any one of claims 11-16, wherein the API is present in a concentration of from about 0.01% to 0.1% (w / w). the API is present in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5%, from about 0.1% to about 1% (w / w), 0.0001% to about 0.1% (w / w), from about 0.005% to about 1.5% (w / w), from about 0.01% to about 1.5% (w / w), from about 0.05% to about 1.5% (w / w), from about 0.005% to about 1% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.1% (w / w), from about 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), or from about 0.01% to about 0.5% (w / w)0.0001% to about 0.1% (w / w), 0.001% to about 0.01% (w / w), about 0.001% to about 1% (w / w), about 0.003% (w / w), about 0.005% (w / w), about 0.01% (w / w), aboutAttorney Docket No. 43081-0039W010.02% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.5% (w / w), about 1 .0% (w / w), or about 1.5% (w / w).

18. A method for enhancing the effect of F6H8 on reducing tear evaporation rate or for improving the treatment of dry eye disease, dry eye syndrome, meibomian gland disfunction, keratoconjunctivitis sicca, or combinations thereof in a subject in need thereof with F6H8 comprising: mixing F6H8 with an additive selected from paraffin, medium chain triglycerides (MCT), PGD, and combinations thereof to generate a combined composition comprising F6H8 and the additive; and optionally administering the combined composition to an eye of the subject.

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