Transient receptor potential melastatin 8 agonist-containing ocular conditions and uses thereof

Abstract

The present application provides compositions and methods for treating ocular conditions (e.g., dry eye syndrome, dry eye disease, keratoconjunctivitis sicca, inflammatory dry eye, redness, or meibomian gland dysfunction). The compositions can comprise a transient receptor potential melastatin 8 (TRPM8) agonist (e.g., menthol or AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl) cyclohexanecarboxamide)) and a semi-fluorinated alkane compound; or can comprise a TRPM8 agonist (e.g., menthol AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl) cyclohexanecarboxamide)), a semi-fluorinated alkane compound. The compositions can confer chemical stability of the TRPM8 agonist.

Description

[0001] TRANSIENT RECEPTOR POTENTIAL MELASTATIN 8 AGONIST-CONTAINING OCULAR CONDITIONS AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Application No. 63 / 667,888, filed on July 5, 2024, and U.S. Application No. 63 / 752,122, filed on January 31, 2025, the contents of which are hereby incorporated by reference.

[0004] TECHNICAL FIELD

[0005] This disclosure relates to pharmaceutical compositions comprising a transient receptor potential melastatin 8 (TRPM8) agonist (e.g., menthol or AR-15512 ((1R,2S,5R)-N- (4-methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide)) and a semifluorinated alkane compound. This disclosure also relates to methods of treatment of an ocular condition (e.g., dry eye syndrome, dry eye disease, keratoconjunctivitis sicca, inflammatory dry eye, redness, or meibomian gland dysfunction) using the compositions.

[0006] BACKGROUND

[0007] Various attempts have been made to formulate active pharmaceutical ingredients compounds (APIs) for ocular delivery, e.g., for treating and preventing conditions in the eye or improving symptoms thereof. However, challenges with delivery formulations can limit the usability of the APIs, their activity and shelf life, and can in some instances result in systemic side effects. In common practice, APIs for ophthalmological are often formulated in aqueous formulations, however, many APIs can degrade in aqueous formulations. Sometimes adjustments to pH can slow the degradation of APIs in aqueous formulations, but such pH adjustments can result in ocular irritation and discomfort for the user. There remains a need for improved compositions for ophthalmological delivery of APIs.

[0008] SUMMARY

[0009] This disclosure relates to compositions and methods for treating an ocular condition. The compositions can comprise a TRPM8 agonist (e.g., menthol or AR-15512 ((1R,2S,5R)- N-(4-methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide)) and a semifluorinated alkane compound. In some instances, the compositions can further comprise an organic cosolvent. This disclosure is based, at least in part, on a realization that certain compositions comprising semi -fluorinated alkane compounds can provide improved stability and / or solubility of TRPM8 agonists (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) for ophthalmological formulations. This disclosure is also based, at least in part, on a realization that TRPM8 agonists (e.g., menthol or AR-15512) surprisingly dissolves at therapeutically effective amounts in 100% of a semi-fluorinated alkane compound. Such properties can, for example, reduce the need for formulation complexity, reduce costs, reduce chances of irritation with additives, and potentially increase comfort. In some instances, the formulations disclosed herein can be used with minimal or no irritation in the eye of a subject.

[0010] Various compounds such as AR-15512 have been investigated for treatment of ocular conditions (e.g., dry eye syndrome), but these compounds can have problems with stability in traditional aqueous ophthalmological formulations. For example, compounds can break down rapidly in traditional aqueous formulations. Many attempts to improve stability of compounds in pharmaceutical formulations can lead to eye irritation because of the compounds used to stabilize the active pharmaceutical ingredient. There remains a need for improved treatments for ocular conditions, including compositions that retain stability while also providing minimal or no irritation to the eye.

[0011] This disclosure provides compositions comprising a TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) and a semi-fluorinated alkane compound, as well as methods for treating an ocular condition with the compositions disclosed herein. The compositions described herein provide improved stability and / or solubility of the TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) without a negative effect on eye irritation. The compositions described herein can provide reduced need for formulation complexity, reduced costs, reduced chances of irritation with additives, and potentially increase comfort. In some instances, the formulations also provide the ability to use higher concentrations of the TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2- (1 -methylethyl) cyclohexanecarboxamide)) in the compositions.

[0012] In one aspect, described herein is a topical ophthalmological composition 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)) as an active pharmaceutical ingredient; and a semifluorinated alkane compound.

[0013] The composition can optionally include one or more of the following features. The semi -fluorinated alkane compound can be present as a liquid vehicle. The TRPM8 agonist can be AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide). The TRPM8 agonist can be menthol. The semifluorinated alkane can be a compound of formula RFRH or of formula RFRHRF, wherein RF is a perfluorinated hydrocarbon with 15 or less carbon atoms, and wherein RH is a nonfluorinated hydrocarbon with 15 or less carbon atoms. The semifluorinated alkane can be selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10). The semifluorinated alkane can be F6H8 (perfluorohexyloctane). The semifluorinated alkane can be perfluorobutylpentane (F4H5).

[0014] The composition can optionally further comprise one or more organic cosolvents. The organic cosolvent can be selected from the group consisting of liquid paraffin, vitamin E acetate, D-a-tocopherol, oleic acid, ethyl oleate and combinations thereof. The liquid paraffin can be light liquid paraffin.

[0015] In these and other instances, the composition can include the following optional features. The concentration of the organic cosolvent in the composition can be less than or equal to about 50% (w / w). The concentration of organic cosolvent in the composition can be from about 0.01% to 15% (w / w) or about 0.01% to 10% (w / w). The organic cosolvent can be present in a concentration of from about 0.01 % (w / w) to about 50% (w / w) and the semifluorinated alkane compound is present in a concentration of from about 50% to about 100%.

[0016] The TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)- 5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) can be present in a concentration of from about 0.0001% to about 0.1% (w / w), 0.001% to about 0.01% (w / w), or about 0.003% (w / w). The TRPM8 agonist can be AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl- 2-(l -methylethyl) cyclohexanecarboxamide). The TRPM agonist can be menthol. The menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide) can be in a free base form or a salt form. The menthol or AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide) can be in free base form and the concentration of the menthol or AR-15512 can be from about 0.0001% (w / w) to about 0.1% (w / w), from about 0.001% to about 0.01% (w / w), or about 0.003% (w / w). The topical ophthalmological composition can be a non-aqueous solution, a suspension, or an emulsion. The TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) in the topical ophthalmological composition can be chemically stable at room temperature for at least 0.5 year, for at least 1 year, or for at least 2 years. The topical ophthalmological composition can cause minimal or no irritation in a mammalian eye.

[0017] In another aspect, provided herein are eye drops comprising any one of the topical ophthalmological compositions described herein.

[0018] In another aspect, provided herein are methods for treating ocular conditions in a subject in need thereof, comprising administering any one of the topical ophthalmological compositions described herein. In such methods, the topical ophthalmological composition can optionally cause minimal or no irritation in the eye of the subject.

[0019] In another aspect, provided herein is a topical ophthalmological composition comprising: a therapeutically effective amount of AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide); and a semifluorinated alkane compound as liquid vehicle. The composition can optionally include one or more of the following features. The AR-15512 can be in free base form and can be present in a concentration of from about 0.0001% to about 0.1% (w / w), from about 0.001% to about 0.01% (w / w), or about 0.003% (w / w).

[0020] In another aspect, provided herein is a topical ophthalmological composition comprising: a therapeutically effective amount of menthol; and a semi -fluorinated alkane compound as liquid vehicle. The composition can optionally include one or more of the following features. The menthol can be present in a concentration of from about 0.0001% to about 0.1% (w / w), from about 0.001% to about 0.01% (w / w), or about 0.003% (w / w).

[0021] In another aspect, a topical ophthalmological composition is provided, comprising: a therapeutically effective amount of menthol; and a semi-fluorinated alkane compound. In some instances, the semi-fluorinated alkane compound can be present as a liquid vehicle. The composition can optionally include one or more of the following features. The composition can optionally include one or more of the following features. The menthol can be present in a concentration of from about 0.0001% to about 5% (w / w), from about 0.001% to about 1% (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 0.05% 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). The semifluorinated alkane can be selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyl decane (F6H10).

[0022] In another aspect, provided herein is a method of reducing the cooling effect of a transient receptor potential melastatin 8 (TRPM8) agonist on a subject or a tissue of a subject, comprising contacting the subject or the tissue of the subject with a composition comprising the TRPM8 agonist; and a semifluorinated alkane compound, wherein the subject experiences no cooling effect or lesser cooling effect upon contact with the composition as compared to a comparative cooling effect experienced upon contact with a comparative composition comprising a similar amount of the TRPM8 agonist alone or in combination with an aqueous vehicle.

[0023] In these and other instances, the method can optionally include one or more of the following features. The TRPM8 agonist can be menthol. The menthol can be present in a concentration of from about from about 0.001% to about 1% (w / w). The semifluorinated alkane can be selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10).

[0024] In some instances, the compositions and methods provided herein can provide several advantages. This disclosure is based on the discovery that the TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) can be dissolved in a semi -fluorinated alkane compound at sufficient concentration to have biological efficacy. Such formulations can be made into useful products for medical use and regulatory approval. These formulations can be nonirritating in the eye when dosed at a concentration higher than what is needed for some indications.

[0025] This disclosure is also based on the surprising discovery that the compositions and methods described herein can reduce the cooling effect of a TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)). Some individuals find the typical cooling effect of TRPM8 agonists uncomfortable or unpleasant. This can, in some instances, particularly be the case in ocular delivery of TRPM8 agonists. However, the compositions described herein can surprisingly reduce that cooling sensation of the TRPM8 agonists, thus resulting in greater comfort and desirability of the compositions for beneficial ocular use, such as for stimulating tear production or treating dry eye symptoms or symptoms of meibomian gland dysfunction.

[0026] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 is an exploded, schematic cross-sectional view of an exemplary embodiment of a dispenser as described herein.

[0029] DETAILED DESCRIPTION

[0030] 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- (1 -methylethyl) cyclohexanecarboxamide)) as an active pharmaceutical ingredient; and a semifluorinated alkane compound (e.g., F6H8 (perfluorohexyloctane) or F4H5 (perfluorobutylpentane)). The semifluorinated alkane compound can, in some embodiments be the liquid vehicle of the composition. In some embodiments, the composition can further comprise an organic cosolvent. The compositions can provide stable formulations for TRPM8 agonists.

[0031] 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.

[0032] As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.e., 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 (z.e., reversing the pathology and / or symptomatology).

[0037] In some instances, provided herein are compositions comprising a therapeutically effective amount of a TRPM8 agonist (e.g., menthol and AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide)) as an active pharmaceutical ingredient; and a semifluorinated alkane compound. The compositions can, in some instances, be topical ophthalmological compositions.

[0038] An exemplary TRPM8 agonist is AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5- methyl-2-(l -methylethyl) cyclohexanecarboxamide), or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof. Another exemplary TRPM8 agonist is menthol (e.g., 5-Methyl-2-(propan-2-yl)cyclohexan-l-ol), or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof. Other non-limiting exemplary TRPM8 agonists include 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:

[0039] CPS369 (ethyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carbonyl)alaninate), structure shown below:

[0040] CPS368 (methyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carbonyl)alaninate;

[0041] CPS 125 ((lR,2S,5R)-2-isopropyl-5-methyl-N-(4-(N-(pyrimidin-2- yl)sulfamoyl)phenyl)cyclohexane-l -carboxamide), structure shown below:

[0042] Frescolat ML ((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-hydroxypropanoate), structure shown below: a

[0043] Frescolat MGA (((5S,6S,9R)-6-isopropyl-9-methyl-l,4-dioxaspiro[4.5]decan-2-yl)methanol), structure shown below:

[0044] WS-3 (N-ethyl-2-isopropyl-5-methylcyclohexane-l -carboxamide), structure shown below: WS-23 (3-isopropyl-N,2,4-trimethylpentanamide), structure shown below:

[0045] Rotundifolone ((1 S,6S)-6-methyl-3-(propan-2-ylidene)-7-oxabicyclo[4.1 ,0]heptan-2-one), structure shown below:

[0046] 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:

[0047] (lS,3R,6S)-6-isopropyl-3-methyl-2-methylenecyclohexan-l-ol, structure shown below:

[0048] 4-(3,5-dimethoxyphenyl)-l-((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl)-lH- 1,2, 3-tri azole, structure shown below:

[0049] (lR,2S,5R)-N-((S)-2-(2-aminoacetamido)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane- 1 -carboxamide, structure shown below:

[0050] (R)-2-((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carboxamido)-l-phenylethyl glycinate, structure shown below: (lR,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-2-isopropyl-5- methylcyclohexane-1 -carboxamide, structure shown below: (lR,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-l-carboxamide, structure shown below:

[0051] 3-(((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)propane-l,2-diol, structure shown below:

[0052] 4-((lS,2R)-2-(4-allyl-2,6-dimethoxyphenoxy)-l-ethoxypropyl)-2-methoxyphenol, structure shown below:

[0053] 4-((lS,2S)-2-(4-allyl-2,6-dimethoxyphenoxy)-l-ethoxypropyl)-2-methoxyphenol, structure shown below:

[0054] 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-l-(((lS,2R,5S)-2-isopropyl-5- methylcyclohexyl)oxy)propyl)-2-methoxyphenol, structure shown below: di-sec-butyl(pentyl)phosphine oxide, structure shown below: ethyl 5-oxo-l,2,3,4,4a,10b,l l,12a-octahydrospiro[naphtho[l,2-c]chromene-12,2'-

[0055] [l,3]dithiolane]-4b(5H)-carboxylate, structure shown below:

[0056] 10b-((2-mercaptoethyl)thio)-l,3,4,10b-tetrahydro-6H-spiro[pyrido[2,l-a]isoindole-2,2'- [l,3]dithian]-6-one, structure shown below: (S)-4-cyclohexyl-4,5-dimethyl-2-(2-oxo-2-phenylethyl)-2,4-dihydro-3H-pyrazol-3-one, structure shown below:

[0057] 5-(cyclohex-l-en-l-yl)-l,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-

[0058] 2,4,6(lH,3H,5H)-trione, structure shown below:

[0059] 5 -(( 1 S,2R,4R)-bicy clo[2.2.1 ]heptan-2-yl)-3 -(2-(3 -hy droxyphenyl)-2-oxoethyl)- 1,5- dimethylimidazolidine-2, 4-dione, structure shown below:

[0060] N-(lH-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, structure shown below:

[0061] 2-((2,3-dihydro-lH-inden-5-yl)oxy)-N-(lH-pyrazol-3-yl)-N-(thiophen-2- ylmethyl)acetamide, structure shown below:

[0062] (E)-N-(lH-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-3-(p-tolyl)acrylamide, structure shown below:

[0063] (S)-2-(cyclohexanecarbonyl)-l,2,3,6,7, 1 lb-hexahydro-4H-pyrazino[2, l-a]isoquinolin-4-one aka Praziquantel, structure shown below:

[0064] Tacrolimus ((-)-(3 S,4R,5 S,8R,9E, 12S, 14S, 15R, 16S, 18R,26aS)-8-allyl-

[0065] 5,6,8,ll,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-{(E)-2-

[0066] [(1R, 3R,4R)-4-hydroxy-3-methylcy cl ohexyl]-l-methylvinyl}-14,16-dimethoxy-4, 10,12,18- tetramethyl- 15, 19-epoxy-3H-pyrido[2, 1 -c] [1 ,4]oxaazacyclotricosane- 1,7,20,21 (4H,23H)- tetrone), structure shown below: CPS-113 ((lR,2S,5R)-N-(4-fluorophenyl)-2-isopropyl-5-methylcyclohexane-l- carboxamide), structure shown below:

[0067] 6-(3 -chlorophenyl)-3 -(2-hy droxyphenyl)-3 ,4-dihy dropyrimidin-2( 1 H)-one, structure shown below: ethyl ((lR,2S,5R)-2-isopropyl-5-methylcyclohexane-l-carbonyl)glycinate, structure shown below: (lR,2S,5R)-N-(l-(2-aminoethyl)-3-phenyl-lH-pyrazol-5-yl)-2-isopropyl-5- methylcyclohexane-1 -carboxamide, structure shown below:

[0068] (lR,2S,5R)-N-((S)-2-(2-aminoethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-l- carb oxami de, structure 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.

[0069] In some instances, provided herein are compositions comprising a therapeutically effective amount of a TRPM8 agonist (e.g., menthol and AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide)), or combinations thereof, or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof as an active pharmaceutical ingredient; and a semi-fluorinated alkane compound. The compositions can, in some instances, be topical ophthalmological compositions.

[0070] TRPM8 agonists, such as AR-15512 and menthol, can act as potent and selective agonists of the TRPM8 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.

[0071] TRPM8 agonists (e.g., menthol and AR-15512), or combinations thereof, or a derivative, analogue, 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 and AR-15512), or combinations thereof, or a derivative, analogue, 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 dysfunction.

[0072] In some instances, the TRPM8 agonists (e.g., menthol and AR-15512), or combinations thereof, or a derivative, analogue, 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 0.0001% 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 0.05% to about 1% (w / w), from about 0.005% to about 0.5% (w / w), from about 0.01% to about 0.5% (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 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). In some instances, the TRPM8 agonists (e.g., menthol and AR-15512), or combinations thereof, or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of from about 0.0001% to about 0.1% (w / w). In some instances, the TRPM8 agonists (e.g., menthol and AR-15512), or combinations thereof, or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of from about 0.001% to about 0.01% (w / w). In some instances, the TRPM8 agonists (e.g., menthol and AR-15512), or combinations thereof, or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of about 0.003% (w / w).

[0073] In some instances, the compositions described herein include enantiomers or diastereomers of the TRPM8 agonists. For example, nonlimiting exemplary enantiomers or diastereomers of AR-15512 include (lS,2R,5S)-N-(4-methoxyphenyl)-5-methyl-2-(l- methylethyl)cyclohexanecarboxamide or (1 S,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l - methylethyl)cyclohexanecarboxamide. In some instances, the compositions described herein include derivatives of the TRPM8 agonists (e.g., menthol and AR-15512).

[0074] In some instances, the compositions comprise a semifluorinated alkane compound. The semifluorinated alkane compound can act, in some instances, as a liquid vehicle. A semifluorinated alkane (SFA) compound is an amphiphilic liquid with two mutually immiscible moieties (hydrocarbon segment and perfluorinated segment) bound covalently. The semi -fluorinated alkane compound can, in some instances, have a formula of RFRH or a formula of RFRHRF; RF is a perfluorinated hydrocarbon with 1 to 15 carbon atoms, and wherein RH is a non-fluorinated hydrocarbon with 1 to 15 carbon atoms.

[0075] Examples of semifluorinated alkanes that can be useful in the compositions described herein include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10); preferably, perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6), and perfluorohexyl octane (F6H8). In some instances, the semifluorinated alkane is perfluorohexyloctane (F6H8). In some instances, the semifluorinated alkane is perfluorobutylpentane (F4H5).

[0076] The structure of F6H8 is shown below.

[0077] F6H8 (CF3(CF2)5(CH2)7CH3)

[0078] In some instances, the semifluorinated alkane can be present in an amount of from about 0% to about 99.9% (w / w), from about 0.1% to about 99.9% (w / w), from about 0.1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 10% to about 99.9% (w / w), from about 20% to about 99.9% (w / w), from about 30% to about 99.9% (w / w), from about 40% to about 99.9% (w / w), from about 50% to about 99.9% (w / w), from about 60% to about 99.9% (w / w), from about 65% to about 99.9% (w / w), from about 70% to about 99.9% (w / w), from about 75% to about 99.9% (w / w), from about 80% to about 99.9% (w / w), from about 85% to about 99.9% (w / w), from about 90% to about 99.9% (w / w), from about 95% to about 99.9% (w / w), from about 98% to about 99.9% (w / w), from about 20% to about 80% (w / w), from about 20% to about 70% (w / w), from about 20% to about 60% (w / w), from about 20% to about 50% (w / w), from about 20% to about 40 % (w / w), from about 20% to about 30% (w / w), from about 30% to about 80% (w / w), from about 40% to about 80% (w / w), from about 50% to about 80% (w / w), from about 60% to about 80% (w / w), from about 70% to about 80% (w / w), about 99.9% (w / w), about 99% (w / w), about 98% (w / w), about 97% (w / w), about 96% (w / w), about 95% (w / w), about 94% (w / w), about

[0079] 93% (w / w), about 92% (w / w), about 91% (w / w), about 90% (w / w), about 85% (w / w), about

[0080] 80% (w / w), about 75% (w / w), about 70% (w / w), about 65% (w / w), about 60% (w / w), about

[0081] 55% (w / w), about 50% (w / w), about 45% (w / w), about 40% (w / w), about 35% (w / w), about

[0082] 30% (w / w), about 25% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about

[0083] 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), about 1% (w / w), about 0.5% (w / w), or about 0.1% (w / w).

[0084] In some instances, the semifluorinated alkane is F6H8 (perfluorohexyloctane). In some instances, the semifluorinated alkane is perfluorobutylpentane (F4H5).

[0085] In some instances, the compositions can further comprise one or more organic cosolvents. The cosolvent can, in some instances, work to further improve solubility of the TRPM8 agonists. The organic cosolvent can, in some instances, be selected from the group consisting of liquid paraffin, vitamin E acetate, D-a-tocopherol, oleic acid, ethyl oleate and combinations thereof.

[0086] In some instances, the organic co-solvent can be present in an amount of from about 0.001% to about 50% (w / w), from about 0.05% to about 50%, from about 0.01% to about 50% (w / w), from about 0.01% to about 45% (w / w), from about 0.01% to about 40% (w / w), from about 0.01% to about 35% (w / w), from about 0.01% to about 30% (w / w), from about 0.01% to about 25% (w / w), from about 0.01% to about 20% (w / w), from about 0.01% to about 15% (w / w), or from about 0.01% to about 10% (w / w).

[0087] The compositions described herein can include paraffin. In some instances, the paraffin can be liquid paraffin. In some instances, the liquid paraffin can be light liquid paraffin.

[0088] In some instances, the paraffin can be present 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), from about 20% 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% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w).

[0089] In some instances, the compositions can comprise a combination of one or more organic cosolvents as described herein and one or more SFAs as described herein. In some instances, the cosolvent can be present in an amount of about 0.001% (w / w) and the SFA can be present in an amount of about 99.999% (w / w); the cosolvent can be present in an amount of about 0.01% (w / w) and the SFA can be present in an amount of about 99.99% (w / w); the cosolvent can be present in an amount of about 0.1% (w / w) and the SFA can be present in an amount of about 99.9 % (w / w); the cosolvent can be present in an amount of about 1% (w / w) and the SFA can be present in an amount of about 99% (w / w); the cosolvent can be present in an amount of about 2% (w / w) and the SFA can be present in an amount of about 98% (w / w); the cosolvent can be present in an amount of about 5% (w / w) and the SFA can be present in an amount of about 95% (w / w); the cosolvent can be present in an amount of about 7% (w / w) and the SFA can be present in an amount of about 93% (w / w); the cosolvent can be present in an amount of about 10% (w / w) and the SFA can be present in an amount of about 90% (w / w); the cosolvent can be present in an amount of about 13% (w / w) and the SFA can be present in an amount of about 87% (w / w); the cosolvent can be present in an amount of about 15% (w / w) and the SFA can be present in an amount of about 85% (w / w); the cosolvent can be present in an amount of about 17% (w / w) and the SFA can be present in an amount of about 83% (w / w); the cosolvent can be present in an amount of about 20% (w / w) and the SFA can be present in an amount of about 80% (w / w); the cosolvent can be present in an amount of about 23% (w / w) and the SFA can be present in an amount of about 77% (w / w); the cosolvent can be present in an amount of about 25% (w / w) and the SFA can be present in an amount of about 75% (w / w); the cosolvent can be present in an amount of about 27% (w / w) and the SFA can be present in an amount of about 73% (w / w); the cosolvent can be present in an amount of about 30% (w / w) and the SFA can be present in an amount of about 70% (w / w); the cosolvent can be present in an amount of about 33% (w / w) and the SFA can be present in an amount of about 67% (w / w); the cosolvent can be present in an amount of about 35% (w / w) and the SFA can be present in an amount of about 65% (w / w); the cosolvent can be present in an amount of about 37% (w / w) and the SFA can be present in an amount of about 63% (w / w); the cosolvent can be present in an amount of about 40% (w / w) and the SFA can be present in an amount of about 60% (w / w); the cosolvent can be present in an amount of about 43% (w / w) and the SFA can be present in an amount of about 57% (w / w); the cosolvent can be present in an amount of about 45% (w / w) and the SFA can be present in an amount of about 55% (w / w); the cosolvent can be present in an amount of about 47% (w / w) and the SFA can be present in an amount of about 53% (w / w); the cosolvent can be present in an amount of about 50% (w / w) and the SFA can be present in an amount of about 50% (w / w).

[0090] In some instances, SFA can be the only vehicle and the SFA can be present in an amount of about 98% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 98.5% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 98.6% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 98.7% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 98.8% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 98.9% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.0% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.1% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.2% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.3% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.4% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.5% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.6% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.7% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.8% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 99.9% (w / w); SFA can be the only vehicle and the SFA can be present in an amount of about 100% (w / w).

[0091] In some instances, the concentration of the organic cosolvent in the composition is less than or equal to about 50% (w / w). In some instances, the concentration of organic cosolvent in the composition is from about 0.01% to 10% (w / w).

[0092] The pharmaceutical compositions may also comprise one or more additional therapeutic agents, excipients, or diluents including, but not limited to, absorbents, antiirritants, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, prescription drugs, surfactants / detergent cleansing agents, penetration enhancers, viscosity enhancers, and thickeners.

[0093] The pharmaceutical compositions of the present application can include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration include topical, ocular, topical ocular, injection, and the like.

[0094] Compositions and formulations described herein can be conveniently presented in a unit dosage form or a multi-dosage form. In some instances, compositions and formulations described herein can be conveniently presented in a dosage form (unit or multiple) that can be used with or in an automated dosing apparatus or regimen.

[0095] In some instances, the topical compositions of the present disclosure can be prepared and used in the form of a non-aqueous solution, a suspension, or an emulsion. In some instances, the topical compositions can be in an emulsion form. In some instances, the topical compositions can be in an organic solution. In some instances, the compositions can be in the form of an organic composition without aqueous components.

[0096] In some instances, the topical composition is an ophthalmic composition, e.g., for intraocular administration. Suitable examples of topical ophthalmological compositions described herein are a non-aqueous solution, a suspension, or an emulsion.

[0097] In some instances, the compositions described herein can be stable compositions. The compositions can provide chemical stability of the TRPM8 agonists (e.g., menthol or AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) in the composition for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, or more, at room temperature.

[0098] In some instances, the compositions described herein can be non-irritating. The compositions described herein can, in some instances, cause minimal or no irritation in a mammalian eye.

[0099] Any one of these ophthalmic compositions can be administered directly to 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.

[0100] Also provided herein are dispensers comprising the compositions described herein. In one example of FIG. 1, an example dispenser 10 contains a liquid 14 of the compositions or nano-emulsions. Applicant surprisingly discovered that the compositions described herein are less stable in low density polyethylene (LDPE) and in polypropylene (PP) than in other materials such as glass or polyethylene terephthalate (PET). Without being bound by theory it is believed that LDPE and PET material absorb one or more components of the compositions or nano-emulsions described herein, thereby reducing the content of the active pharmaceutical ingredient (API) over time.

[0101] The dispenser 10 includes a container portion 18 having an interior wall 22 defining an interior volume 26 and adapted to contact and store a liquid 14 within at least a portion of the interior volume 26; a dispensing portion 30 adapted to dispense one or more drops of a liquid 14 out of the container portion 18; and, contained within the interior volume 26, a liquid 14 comprising compositions or nano-emulsion as described herein, or a composition comprising about 0.001% to about 5% (w / w) API; and from about 50% to about 99% (w / w) of a semi -fluorinated alkane compound.

[0102] In some instances, the interior wall 22 of the dispenser 10 comprises less than about 10%, less than about 5%, or less than about 1% of one or more of low density polyethylene (LDPE) or polypropylene (PP). In some instances, the interior wall 22 does not comprise low density polyethylene (LDPE) or polypropylene (PP). In some instances, the interior wall 22 comprises glass or polyethylene terephthalate. In some instances, the interior wall 22 consists essentially of glass or polyethylene terephthalate (PET).

[0103] In some instances, the concentration of the API in the compositions or nanoemulsions of the liquid 14 remains more than 90% of the initial API concentration after storage in the dispenser 10 for a period of 6 months. In some instances, the concentration of the API in the compositions or nano-emulsions of the liquid 14 remains more than 90% of the initial API concentration after storage in the dispenser 10 for a period of 12 months.

[0104] In some instances, the container portion 18 and the dispensing portion 30 can each, independently, comprise or consist of the same material or different materials. In some instances, the container portion 18 and the dispensing portion 30 can each, independently, consist essentially of glass or polyethylene terephthalate (PET). In some instances, the dispensing portion 30 can comprise low density polyethylene (LDPE) or polypropylene (PP), particularly where the compositions or nano-emulsions of the liquid 14 do not typically come into contact with the dispensing portion 30 during normal storage of the compositions or nano-emulsions of the liquid 14, but come into contact with the dispensing portion 30 briefly during dispensation, such as when a drop is passing through the dispensing portion 30 from the container portion 18 during administration to an eye of a subject. Without being bound by theory, it is believed such limited contact of the compositions or nano-emulsions of the liquid 14 with LDPE or PET will have little or no effect on the compositions or nano-emulsions of the liquid 14.

[0105] In some instances, the dispenser 10 is adapted to dispense drops each independently having a volume of from about 5 pl to about 40 pl.

[0106] The compositions and nano-emulsions described herein can be conveniently presented in a unit dosage form or a multi -dosage form (e.g., the dispenser 10). In some embodiments, compositions and formulations described herein can be conveniently presented in a dosage form (unit or multiple) that can be used with or in an automated dosing apparatus or regimen.

[0107] In some instances, the dispenser 10 may optionally have a cap 34 that is removable from the container portion 18. For example, the cap 34 can cover the dispensing portion 30 during storage.

[0108] 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 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.

[0109] In some instances, a kit can comprise a dispensing device preloaded with a composition as described herein.

[0110] Also provided herein are methods for treating ocular diseases or conditions using the compositions, and methods described herein.

[0111] In some instances, the ocular condition is selected from dry eye syndrome, dry eye disease, keratoconjunctivitis sicca, inflammatory dry eye, redness, and meibomian gland dysfunction.

[0112] Also provided herein are methods of delivering TRPM8 agonists (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)) to an eye of a subject comprising administering to the eye of the subject a topical ophthalmological composition described herein.

[0113] In some instances, methods are providing for administering, to the eye of a subject, an effective amount of a TRPM8 agonist (e.g., menthol or AR-15512 ((lR,2S,5R)-N-(4- methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide)). In some instances, the compositions described herein can be in the form of an eye drop. In some instances, the methods can further comprise applying the eye drop to an eye of the subject.

[0114] Also provided herein are methods for reducing the cooling effect of a transient receptor potential melastatin 8 (TRPM8) agonists. TRPM8 agonists, such as AR-15512 and menthol, can act as potent and selective agonists of the TRPM8 cold thermoreceptor. In some instances, this means that a subject coming into contact with such TRPM8 agonists may feel a cold or cooling sensation. While this sensation can be beneficial in some cases, such as taste or mouth feel, some individuals may find the sensation unpleasant or uncomfortable. This discomfort or unpleasant feeling can occur, for example, in instances of ocular, nasal, mucosal, or skin application of TRPM8 agonist containing compositions. This disclosure is, at least in part, based on the surprising discovery that the compositions and methods described herein can reduce the cooling effect of a TRPM8 agonist (e.g., menthol or AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide)). The compositions described herein can surprisingly reduce that cooling sensation of the TRPM8 agonists, thus resulting in greater comfort and desirability of the compositions for beneficial uses, such as those described herein.

[0115] In some instances, methods are provided herein for reducing the cooling effect of a transient receptor potential melastatin 8 (TRPM8) agonists on a subject or a tissue of a subject, comprising contacting the subject or the tissue of the subject with a composition comprising the TRPM8 agonist; and a semifluorinated alkane compound, wherein the subject experiences no cooling effect or lesser cooling effect upon contact with the composition as compared to a comparative cooling effect experienced upon contact with a comparative composition comprising a similar amount of the TRPM8 agonist alone or in combination with an aqueous vehicle. In some instances, the TRPM8 agonist is menthol. In some instances, menthol is present in a concentration of from about from about 0.001% to about 1% (w / w).

[0116] The invention will be further described in the following examples, which do not limit the scope of the invention.

[0117] 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.

[0118] EXAMPLES

[0119] Example 1: Solubility of Acoltremon (AR-15512) in Exemplary Formulations

[0120] 1.2 Chromatographic conditions

[0121] Chromatographic column: Shimadau Shim-pack GIST C18 5um, 4.6 mm (ID) x 250 mm (L),

[0122] 5 pm

[0123] Mobile phase A: 0.05%(v / v)TFA / water

[0124] Mobile phase B: 0.05%(v / v)TFA / acetonitrile

[0125] Flow rate: 1.0 mL / min Wavelength : 214 nm

[0126] Injection volume: 10 pL Column temperature : 45 °C

[0127] Time (min) %Mobile Phase A %Mobile Phase B

[0128] Table 1

[0129] 1.3 Results

[0130] Table 2. Acoltremon (AR-15512) Saturated solubility (mg / g) Example 2: Solubility of Menthol in Various Solvents

[0131] 2.1 Chromatographic Condition

[0132] 2.2 Experimental Procedure

[0133] An appropriate amount of menthol was added to F4H5, F6H8 or PBS. The compositions were sonicated and vortexed. The mixture was filtered through a 0.22-micron membrane, diluted, and injected into GC for content analysis.

[0134] 2.3 Results

[0135] Results are shown in Table 3 below.

[0136] Example 3: Schirmer Test Results

[0137] Standard Schirmer Tests were conducted on various exemplary compositions of the invention, as well as on commercially available compositions as a comparative. A Schirmer Test is a standard assay in dry eye diagnosis and research (Amano et al., Clin Ophthalmol , 2017 Sep 14: 11 : 1677-1682, doi: 10.2147 / OPTH.S148167).

[0138] 3.1 Schirmer Test Results for Rohto All-In-One Solution (Commercially Available Comparative)

[0139] 3.1.1 Experimental Procedure, Schirmer Test Rohto All-In-One A standard Schirmer Test was conducted using Rohto All-In-One (a commercially available aqueous eye drop solution containing hypromellose, tetrahydozoline HCL, zinc sulfate, boric acid, edetate disodium, menthol, polysorbate 80, purified water, sodium borate) to determine the efficacy of the available treatment and any related symptoms felt by volunteer subjects thereafter.

[0140] During the first visit, the subjects were tested twice (approximately 30 minutes apart). The right eye was treated with Rohto All-in-one and the left eye was treated with lubricant (artificial tears) as control during all tests. The distance results of the Schirmer Test for the comparative commercially available Rohto All-In-One are recorded below in Table 4. The second visit was 12 days after the first visit and followed the same procedure.

[0141] After each test, volunteer subjects were asked about symptoms they felt while receiving treatment, specifically if any irritation or cooling was endured. Their responses were shown in Table 4 below. 3.1.2 Results, Schirmer Test Rohto All-In-One

[0142] Table 4 shows the results of the Schirmer Tests using Rohto All-In-One as well the symptoms felt by volunteer subjects.

[0143]

[0144]

[0145] 3.2 Schirmer Test Results for Various Concentrations of Menthol in SFA

[0146] 3.2.1 Experimental Procedure, Schirmer Test Menthol in SFA

[0147] A standard Schirmer Test was conducted using different concentrations of Menthol in F6H8, as well as F6H8 by itself, to determine the efficacy of exemplary compositions and any related symptoms felt by volunteer subjects thereafter.

[0148] One volunteer subject (Subject X) was tested using F6H8 as a control in the left eye and different concentrations of menthol in F6H8 in the right eye. During each visit, two Schirmer tests were conducted, approximately 10 minutes apart. The distance results are recorded below in Table 5.1. The volunteer subject was also asked about any irritation or cooling symptoms during or after treatment.

[0149] Volunteer Subject A was tested again along with Volunteer Subject B with no control in the left eye and different concentrations of F6H8. The same procedures were used for this testing. 3.2.2 Results, Schirmer Test Menthol in SFA

[0150] Tables 5.1 and 5.2 show the results of Schirmer Tests conducted for various exemplary compositions using different concentrations of menthol in F6H8, as well as F6H8 itself.

[0151]

[0152] OTHER EMBODIMENTS

[0153] 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.

[0154] Exemplary Embodiments

[0155] Embodiment 1. A topical ophthalmological composition comprising: a therapeutically effective amount of a transient receptor potential melastatin 8 (TRPM8) agonist as an active pharmaceutical ingredient (API); and a semifluorinated alkane compound.

[0156] Embodiment 2. The topical ophthalmological composition of embodiment 1, wherein the semifluorinated alkane compound is present as a liquid vehicle.

[0157] Embodiment 3. The topical ophthalmological composition of any one of embodiment 1 or embodiment 2, wherein the TRPM8 agonist is selected from menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide) or a derivative, or diastereomer or enantiomer thereof, or combinations thereof.

[0158] Embodiment 4. The topical ophthalmological composition of any one of embodiments 1 to 3, wherein the semifluorinated alkane is a compound of formula RFRH or of formula RFRHRF, wherein RF is a perfluorinated hydrocarbon with 15 or less carbon atoms, and wherein RH is a nonfluorinated hydrocarbon with 15 or less carbon atoms.

[0159] Embodiment 5. The topical ophthalmological composition of any one of embodiments 1 to 4, wherein the semifluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10).

[0160] Embodiment 6. The topical ophthalmological composition of embodiment 5, wherein the semifluorinated alkane is F6H8 (perfluorohexyloctane).

[0161] Embodiment 7. The topical ophthalmological composition of embodiment 5, wherein the semifluorinated alkane is perfluorobutylpentane (F4H5).

[0162] Embodiment 8. The topical ophthalmological composition of any one of embodiments 1 to 7, further comprising one or more organic cosolvents. Embodiment 9. The topical ophthalmological composition of embodiment 8, wherein the organic cosolvent is selected from the group consisting of liquid paraffin, vitamin E acetate, D-a-tocopherol, oleic acid, ethyl oleate and combinations thereof.

[0163] Embodiment 10. The topical ophthalmological composition of any one of embodiments 8, 9, or 43, wherein the concentration of the organic cosolvent in the composition is less than or equal to about 50% (w / w).

[0164] Embodiment 11. The topical ophthalmological composition of any one of embodiments 8, 9, or 43, wherein the concentration of organic cosolvent in the composition is from about 0.001% to about 50% (w / w), optionally from about 0.01% to about 10% (w / w).

[0165] Embodiment 12. The topical ophthalmological composition of any one of embodiments 8, 9, or 43 wherein the organic cosolvent is present in a concentration of from about 0.001 % (w / w) to about 50% (w / w) and the semi-fluorinated alkane compound is present in a concentration of from about 50% to about 99.999%.

[0166] Embodiment 13. The topical ophthalmological composition of any one of embodiments 1 to 12, or 43, wherein the TRPM8 agonist is present in a concentration of from about 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 0.05% 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), or about 0.1% (w / w), optionally wherein the TRPM8 agonist is selected from menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide).

[0167] Embodiment 14. The topical ophthalmological composition of any one of embodiments 1 to 13, or 43, wherein the TRPM8 agonist is selected from menthol or AR- 15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cy cl ohexanecarb oxami de) .

[0168] Embodiment 15. The topical ophthalmological composition of any one of embodiments 1 to 14, or 43, wherein the topical ophthalmological composition is a nonaqueous solution, a non-aqueous suspension, or a non-aqueous emulsion.

[0169] Embodiment 16. The topical ophthalmological composition of any one of embodiments 1 to 15, or 43, wherein the TRPM8 agonist in the topical ophthalmological composition is chemically stable at room temperature for at least 0.5 year, for at least 1 year, or for at least 2 years.

[0170] Embodiment 17. A topical ophthalmological composition comprising: a therapeutically effective amount of AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)- 5-methyl-2-(l -methylethyl) cyclohexanecarboxamide); and a semi -fluorinated alkane compound as liquid vehicle.

[0171] Embodiment 18. The topical ophthalmological composition of embodiment 17, wherein the AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide) is present in a concentration of from about 0.0001% to about 0.1% (w / w), from about 0.001% to about 0.1% (w / w), or about 0.003% (w / w).

[0172] Embodiment 19. Eye drops comprising the topical ophthalmological composition of any one of embodiments 1 to 18, or 35 to 43.

[0173] Embodiment 20. The topical ophthalmological composition of any one of embodiments 1 to 18 or the eye drops of embodiment 19, wherein the topical ophthalmological composition causes minimal or no irritation in a mammalian eye.

[0174] Embodiment 21. A dispenser comprising: a container portion comprising an interior wall defining an interior volume and adapted to contact and store a liquid within at least a portion of the interior volume; a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion; and any one of the compositions of embodiments 1-18 and 20 or the eye drops of embodiment 19 or 20 contained within the interior volume.

[0175] Embodiment 22. The dispenser of embodiment 21, wherein the interior wall comprises less than about 10% of one or more of low density polyethylene (LDPE) or polypropylene (PP).

[0176] Embodiment 23. The dispenser of 21 or 22, wherein the interior wall does not comprise low density polyethylene (LDPE) or polypropylene (PP).

[0177] Embodiment 24. The dispenser of any one of embodiments 21-23, wherein the interior wall comprises glass or polyethylene terephthalate.

[0178] Embodiment 25. The dispenser of any one of embodiments 21-24, wherein the interior wall consists essentially of glass or polyethylene terephthalate (PET).

[0179] Embodiment 26. The dispenser of any one of embodiments 21-25, wherein the concentration of the API remains more than 90% of the initial API concentration after storage in the dispenser for a period of at least 6 months, or wherein the concentration of the API remains more than 90% of the initial API concentration after storage in the dispenser for a period of at least 12 months or wherein the concentration of the API remains more than 90% of the initial API concentration after storage in the dispenser for at least a period of 24 months.

[0180] Embodiment 27. The dispenser of any one of embodiments 21-26, wherein the container portion and the dispensing portion each, independently, consist essentially of glass or polyethylene terephthalate (PET).

[0181] Embodiment 28. The dispenser of any one of embodiments 21-27, wherein the volume of the one or more drops each independently is from about 5 pl to about 40 pl.

[0182] Embodiment 29. A method for treating an ocular condition in a subject in need thereof, the method comprising administering the topical ophthalmological composition of any one of embodiments 1 to 18 and 20 or the eye drops of embodiment 19 or 20 to an eye of the subject.

[0183] Embodiment 30. The method of embodiment 29, wherein the ocular condition is dry eye syndrome, dry eye disease, keratoconjunctivitis sicca, inflammatory dry eye, redness, or meibomian gland dysfunction.

[0184] Embodiment 31. A method for delivering a TRPM8 agonist to an eye of a subject, the method comprising administering to the eye of the subject the topical ophthalmological composition of any one of embodiments 1 to 18 and 20 or the eye drops of embodiment 19 or 20 to an eye of the subj ect.

[0185] Embodiment 32. A method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, meibomian gland disfunction, or inflammatory dry eye in a subject in need thereof, the method comprising administering to the subject the topical ophthalmological composition of any one of embodiments 1 to 18 and 20 or the eye drops of embodiment 19 or 20 to an eye of the subject.

[0186] Embodiment 33. The method of any one of embodiments 29 to 32, wherein the topical ophthalmological composition causes minimal or no irritation in the eye of the subject.

[0187] Embodiment 34. The method of any one of embodiments 29 to 33, wherein the subject is a human.

[0188] Embodiment 35. A topical ophthalmological composition comprising: a therapeutically effective amount of menthol; and a semi -fluorinated alkane compound.

[0189] Embodiment 36. The topical ophthalmological composition of embodiment 35, wherein the menthol is present in a concentration of from about 0.0001% to about 5% (w / w), from about 0.001% to about 1% (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 0.05% 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).

[0190] Embodiment 37. The topical ophthalmological composition of embodiment 35, wherein the menthol is present in a concentration of from about 0.1% to about 1% (w / w).

[0191] Embodiment 38. The topical ophthalmological composition of embodiment 35, wherein the menthol is present in a concentration of from about 0.1% to about 1% (w / w).

[0192] Embodiment 39. The topical ophthalmological composition of embodiment 35, wherein the menthol is present in a concentration of from about 0.01% to about 1.5% (w / w).

[0193] Embodiment 40. The topical ophthalmological composition of any one of embodiments 35 to 39, wherein the semifluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10).

[0194] Embodiment 41. The topical ophthalmological composition of embodiment 40, wherein the semifluorinated alkane is F6H8 (perfluorohexyloctane).

[0195] Embodiment 42. The topical ophthalmological composition of embodiment 40, wherein the semifluorinated alkane is perfluorobutylpentane (F4H5).

[0196] Embodiment 43. The topical ophthalmological composition of embodiment 9, wherein the liquid paraffin is light liquid paraffin.

[0197] Embodiment 44. A method of reducing the cooling effect of a transient receptor potential melastatin 8 (TRPM8) agonist on a subject or a tissue of a subject, comprising contacting the subject or the tissue of the subject with a composition comprising the TRPM8 agonist; and a semifluorinated alkane compound, wherein the subject experiences no cooling effect or lesser cooling effect upon contact with the composition as compared to a comparative cooling effect experienced upon contact with a comparative composition comprising a similar amount of the TRPM8 agonist alone or in combination with an aqueous vehicle.

[0198] Embodiment 45. The method of embodiment 44, wherein the TRPM8 agonist is menthol.

[0199] Embodiment 46. The method of any one of embodiments 44 to 45, wherein the menthol is present in a concentration of from about from about 0.001% to about 1% (w / w).

[0200] Embodiment 47. The method of any one of embodiments 44 to 46, wherein the semifluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10).

[0201] Embodiment 48. The method of embodiment 47, wherein the semifluorinated alkane is F6H8 (perfluorohexyloctane).

[0202] Embodiment 49. The method of embodiment 47, wherein the semifluorinated alkane is perfluorobutylpentane (F4H5).

Claims

WHAT IS CLAIMED IS:

1. A topical ophthalmological composition comprising: a therapeutically effective amount of a transient receptor potential melastatin 8 (TRPM8) agonist as an active pharmaceutical ingredient (API); and a semifluorinated alkane compound.

2. The topical ophthalmological composition of claim 1, wherein the TRPM8 agonist is selected from menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l- methylethyl) cyclohexanecarboxamide) or a derivative, or diastereomer or enantiomer thereof, or combinations thereof.

3. The topical ophthalmological composition of any one of claims 1 to 2, wherein the semifluorinated alkane compound is a compound of formula RFRH or of formula RFRHRF, wherein RF is a perfluorinated hydrocarbon with 15 or less carbon atoms, and wherein RH is a nonfluorinated hydrocarbon with 15 or less carbon atoms.

4. The topical ophthalmological composition of any one of claims 1 to 3, wherein the semifluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10).

5. The topical ophthalmological composition of claim 4, wherein the semifluorinated alkane is F6H8 (perfluorohexyloctane).

6. The topical ophthalmological composition of claim 4, wherein the semifluorinated alkane is perfluorobutylpentane (F4H5).

7. The topical ophthalmological composition of any one of claims 1 to 6, further comprising one or more organic cosolvents.

8. The topical ophthalmological composition of claim 7, wherein the organic cosolvent is selected from the group consisting of liquid paraffin, vitamin E acetate, D-a- tocopherol, oleic acid, ethyl oleate and combinations thereof.

9. The topical ophthalmological composition of any one of claims 7 to 8, wherein a concentration of the organic cosolvent in the composition is less than or equal to about 50% (w / w).

10. The topical ophthalmological composition of any one of claims 7 to 8, wherein a concentration of the organic cosolvent in the composition is from about 0.001% to about 50% (w / w), optionally from about 0.01% to about 10% (w / w).

11. The topical ophthalmological composition of any one of claims 7 to 8 wherein the organic cosolvent is present in a concentration of from about 0.001 % (w / w) to about 50% (w / w) and the semifluorinated alkane compound is present in a concentration of from about 50% to about 99.999%.

12. The topical ophthalmological composition of any one of claims 1 to 11, wherein the TRPM8 agonist is present in a concentration of from about 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 0.05% 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), or about 0.1% (w / w), optionally wherein the TRPM8 agonist is selected from menthol or AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl- 2-(l -methylethyl) cyclohexanecarboxamide).

13. The topical ophthalmological composition of any one of claims 1 to 12, wherein the topical ophthalmological composition is a non-aqueous solution, a non-aqueous suspension, or a non-aqueous emulsion.

14. A topical ophthalmological composition comprising: a therapeutically effective amount of AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide); and a semi -fluorinated alkane compound.

15. A topical ophthalmological composition comprising: a therapeutically effective amount of menthol; and a semi -fluorinated alkane compound.

16. The topical ophthalmological composition of claim 15, wherein the menthol is present in a concentration of from about 0.0001% to about 5% (w / w), from about 0.001% to about 1% (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 0.05% 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).

17. Eye drops comprising the topical ophthalmological composition of any one of claims 1 to 16.

18. A method for treating an ocular condition in a subject in need thereof, the method comprising administering the topical ophthalmological composition of any one of claims 1 to 16 or the eye drops of claim 17 to an eye of the subject.

19. The method of claim 18, wherein the ocular condition is dry eye syndrome, dry eye disease, keratoconjunctivitis sicca, inflammatory dry eye, redness, or meibomian gland dysfunction.

20. A method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, meibomian gland disfunction, or inflammatory dry eye in a subject in need thereof, the method comprising administering to the subject the topical ophthalmological composition of any one of claims 1 to 16 or the eye drops of claim 17 to an eye of the subject.

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