Pharmaceutical ophthalmic compositions and uses thereof

Abstract

Provided herein are pharmaceutical ophthalmic compositions comprising (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (WS-12) for effectively treating dry eye in a subject in need thereof, effectively reducing dry eye in a subject in need thereof, effectively reducing the likelihood of dry eye in a subject in need thereof, or treating, preventing or ameliorating the signs or symptoms of dry eye in a subject in need thereof.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 290,781, filed December 17, 2021, the entire contents of which are incorporated by reference herein.

[0002] Field The present disclosure generally relates to pharmaceutical ophthalmic compositions of (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (WS-12) and uses thereof. The structure of WS-12 is shown below: [ka] [Background technology]

[0003] background Moisture retention of the ocular surface and other exposed mucous membranes is maintained by a continuous aqueous fluid secretion produced by exocrine glands. Disturbances in this process result in ocular, oral, and vaginal dryness syndromes with high prevalence, especially among the elderly (Moss, SE, et al. 2008. Optom. Vis. Sci. 85:668-674; Barker, KE & Savage, NW 2005. Aust. Dent. J. 50:220-223; Leiblum, SR, et al. 2009. J. Sex Med 6:2425-2433). Tear flow that occurs in the absence of stimulation by emotional or exogenous stimuli is referred to as "basal" tear secretion. In the eye, basal tear flow is adjusted to variations in environmental conditions and blinking rate (Dartt, DA 2009, Prog. Retin. Eye Res. 28:155-177). Tear production is also significantly increased upon ocular surface stimulation (Acosta, MC et al. 2004. Invest Ophthalmol. Vis. Sci. 45:2333-2336). Stimuli are detected by mechano-nociceptor and polymodal nociceptor trigeminal nerve endings that are sensitive to pain (Belmonte, C., et al. 2004. Exp. Eye Res. 78:513-525) and injurious mechanical forces, noxious heat and irritant chemicals that cause stimulation-induced tear production. However, the neural structures responsible for sensing ocular surface dryness to regulate basal tear production rate remain to be defined.

[0004] Dry eye (also known as xerophthalmia) is a disease characterized by persistent dryness of the conjunctiva and opacity of the cornea. As used herein, dry eye also encompasses the disorder known as meibomian gland dysfunction, or MGD.

[0005] More than 30 million people in the United States alone suffer from dry eye, but less than 10% are actually treated.In addition, the prevalence of dry eye continues to rise as a result of the aging of the population and the more frequent use of contact lenses, computers, smartphones and tablets.Dry eye represents one of the most common diseases or disorders that patients seek appointments with ophthalmologists or optometrists, and the majority of these patients are not considered to receive drug intervention or punctal plugs (Stonecipher et al., Therapeutics and Clinical Risk Management 2013, 9:409-415).

[0006] Many causes can lead to dry eye, which is more common in the elderly. Among the diseases or disorders that cause or are associated with dry eye are: reduced function, inflammation or blockage of the meibomian glands, vitamin A deficiency, Sjogren's syndrome, rheumatoid arthritis and other rheumatic diseases, chemical burns or burns, or drugs (e.g., atenolol, chlorpheniramine, hydrochlorothiazide, isotretinoin, ketorolac, ketotifen, levocabastine, levofloxacin, oxybutynin, or tolterodine).

[0007] Treatments for dry eye include the use of corticosteroids, which can be effective in the early stages of the disease, vitamin A supplements, and pilocarpine, a drug that increases tear production. Preparations such as artificial tears, solutions of hydroxypropyl methylcellulose (hypromellose) and carbomer gel, are used to reduce dryness when applied to the conjunctiva. However, these treatments have clear limitations with respect to their respective effectiveness and toxicity.

[0008] Therefore, there is a need to provide a pharmaceutical ophthalmic composition that treats or reduces the signs or symptoms of a disease or disorder involving tear production in a subject.There is also a need to provide such a pharmaceutical ophthalmic composition, in which the stability of the pharmacoactive ingredients contained in such a pharmaceutical ophthalmic composition is maintained to maximize the pharmaceutical activity of the pharmaceutical ophthalmic composition in each dose administered.There is also a need for a pharmaceutical ophthalmic composition that treats or reduces the possibility of dry eye, and its signs or symptoms in a subject, that does not contain preservatives that may have adverse effects on the subject. WO 2012 / 032209 describes WS-12, an agonist of TRPM8 calcium channel, useful in treating xerophthalmia or dry eye. It is important to maintain the stability of WS-12 aqueous ophthalmic compositions to maximize the pharmaceutical activity of WS-12 in each dose administered. Thus, there is a need for pharmaceutical ophthalmic compositions that contain WS-12 in a container that can maintain the stability of WS-12 with respect to exposure to high temperature, humidity, and light (and especially ultraviolet light), among other types of external influences. The citation of any reference herein should not be construed as an admission that such reference is available as prior art to the present disclosure. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2012 / 032209 [Non-patent literature]

[0010] [Non-Patent Document 1] Moss, SE, et al. 2008. Optom. Vis. Sci. 85:668-674 [Non-Patent Document 2] Barker, KE & Savage, NW 2005. Aust. Dent. J. 50:220-223 [Non-Patent Document 3] Leiblum, SR, et al. 2009. J. Sex Med 6:2425-2433 [Non-Patent Document 4] Dartt, DA 2009, Prog. Retin. Eye Res. 28:155-177 [Non-Patent Document 5] Acosta, MC et al. 2004. Invest Ophthalmol. Vis. Sci. 45:2333-2336 [Non-Patent Document 6] Belmonte, C., et al. 2004. Exp. Eye Res. 78:513-525 Summary of the Invention [Means for solving the problem]

[0011] Abstract Provided herein are new and useful pharmaceutical ophthalmic compositions for (a) treating or reducing the likelihood of an ocular disease or disorder involving tear production (e.g., dry eye) in a subject; (b) treating or reducing the signs or symptoms of such ocular diseases or disorders, or (c) a combination of (a) and (b). Methods for treating an ocular disease or disorder involving tear production in a subject and / or treating or reducing the signs or symptoms of such ocular diseases or disorders are also provided.

[0012] Broadly, the disclosure extends to a pharmaceutical ophthalmic composition comprising from about 0.0005% w / v to about 0.01% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (WS-12) or a pharma- ceutically acceptable salt thereof, from about 0.1% w / v to about 5% w / v of a solubilizing agent, from about 0.1% w / v to about 0.5% w / v of a viscosity modifying agent, from about 0.3% w / v to about 1% w / v of a buffer, and from about 0.1% w / v to about 1.0% w / v of a tonicity agent.

[0013] The pH of the pharmaceutical ophthalmic composition of the present disclosure may range from about pH 5.0 to about 8.5. More specifically, the pH of the pharmaceutical ophthalmic composition of the present disclosure may range from about pH 6.7 to about 7.3. In certain embodiments, the pH of the pharmaceutical ophthalmic composition of the present disclosure is about 7. The pharmaceutical ophthalmic composition of the present disclosure may further include a pH adjuster to obtain a desired pH. Many pH adjusters are applied, including the pH adjuster in the pharmaceutical ophthalmic composition of the present disclosure. A specific example of a pH adjuster applied in the pharmaceutical ophthalmic composition of the present disclosure is sodium hydroxide (e.g., 1N sodium hydroxide). A sufficient amount of 1N sodium hydroxide is added to adjust the pH to about 7.

[0014] Further, the stabilizing agents applied in the pharmaceutical ophthalmic compositions of the present disclosure include polyethylene glycol (PEG) 400, castor oil, polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyl 35 castor oil (KOLLIPHOR® EL), and refined polyoxyl 35 castor oil (KOLLIPHOR® ELP), and any combination thereof. In certain embodiments, the solubilizing agent is polyoxyl 35 castor oil (KOLLIPHOR® EL).

[0015] According to the FAO / WHO Joint Expert Committee on Food Additives (JECFA), WS-12 is insoluble in water and only slightly soluble in avocado oil or ethanol. Unexpectedly, certain excipients, including polyvinylpyrrolidone (PVP), propylene glycol, and ethylene oxide-formaldehyde-paraoctylphenol copolymer (Tyloxapol), did not satisfactorily solubilize the active agent WS-12, whereas others, including polyethylene glycol (PEG) 400, castor oil, polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyl 35 castor oil (KOLLIPHOR® EL or KOLLIPHOR® ELP), did satisfactorily solubilize the active agent WS-12. In some embodiments, the compositions provided herein comprise about 1.5 to about 5 w / v% polyethylene glycol 400. In some embodiments, the compositions provided herein comprise about 1 w / v% castor oil. In some embodiments, the compositions provided herein comprise about 0.1 to about 4 w / v% polyoxyethylene (20) sorbitan monooleate. In some embodiments, the compositions provided herein comprise about 1 to about 5 w / v% polyoxyl 35 castor oil.

[0016] In addition, various viscosity modifiers can be easily used in the pharmaceutical ophthalmic compositions of the present disclosure (e.g., cellulose derivatives, clays, aluminum or magnesium silicates, natural gums, synthetic polymers; colloidal silicon dioxide, silicates, and any combination thereof, to name just a few). Specific examples of cellulose derivatives applied in the pharmaceutical ophthalmic compositions of the present disclosure include, but are certainly not limited to, methylcellulose, microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Similarly, some clays can also be used (e.g., hectorite, bentonite, aluminum and / or magnesium silicates, and kaolin). Natural gums applied in the pharmaceutical ophthalmic compositions of the present disclosure include acacia, guar gum, tragacanth, xanthan gum, alginate, carrageenan, locust bean gum, or any combination thereof. In a specific embodiment of the pharmaceutical ophthalmic compositions of the present disclosure, the viscosity modifier is hydroxypropylmethylcellulose (hypromellose).

[0017] Further, in the pharmaceutical ophthalmic composition of the present disclosure, a particular tonicity agent applied is sodium chloride.

[0018] Many buffer solutions are applied in the pharmaceutical ophthalmic composition of the present disclosure.Examples include, but are certainly not limited to, phosphate buffer, citrate buffer, TRIS base, TRIS HCl, PBS, HEPES, MES, PIPES, and TES.Other buffer solutions include boric acid.In some embodiments, the buffer solution comprises phosphate.

[0019] The pharmaceutical ophthalmic compositions of the present disclosure further comprise purified water.

[0020] Similarly, specific examples of pharmaceutical ophthalmic compositions of the present disclosure include: (a) about 0.003% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; (b) about 0.14% w / v hypromellose; (c) about 3.0% w / v polyoxyl 35 castor oil; (d) about 0.78% w / v phosphate buffer (e.g., sodium phosphate buffer, e.g., sodium phosphate monobasic or sodium dihydrogen phosphate dihydrate) (e) about 0.55% w / v NaCl; (f) a sufficient amount of NaOH (e.g., 1 N NaOH) to provide a pharmaceutical ophthalmic composition with a pH of about 7; and (g) Purified water.

[0021] Another example of a pharmaceutical ophthalmic composition of the present disclosure includes: (a) 0.003±15% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; (b) 0.14±15% w / v hypromellose; (c) 3.0±15% w / v polyoxyl 35 castor oil; (d) 0.78±15% w / v phosphate buffer (e.g., sodium phosphate buffer, e.g., sodium phosphate monobasic or sodium dihydrogen phosphate dihydrate) (e) 0.55±15% w / v NaCl; (f) a sufficient amount of NaOH (e.g., 1 N NaOH) to provide a pharmaceutical ophthalmic composition with a pH of about 7; and (g) Purified water.

[0022] Another example of a pharmaceutical ophthalmic composition of the present disclosure includes: (a) 0.003±10% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; (b) 0.14±10% w / v hypromellose; (c) 3.0±10% w / v polyoxyl 35 castor oil; (d) 0.78±10% w / v phosphate buffer (e.g., sodium phosphate buffer, e.g., sodium phosphate monobasic or sodium dihydrogen phosphate dihydrate) (e) 0.55±10% w / v NaCl; (f) a sufficient amount of NaOH (e.g., 1 N NaOH) to provide a pharmaceutical ophthalmic composition with a pH of about 7; and (g) Purified water.

[0023] Yet another example of a pharmaceutical ophthalmic composition of the present disclosure includes: (a) about 0.0014% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; (b) about 0.14% w / v hypromellose; (c) about 3.0% w / v polyoxyl 35 castor oil; (d) about 0.78% w / v phosphate buffer (e.g., sodium phosphate buffer, e.g., sodium phosphate monobasic or sodium dihydrogen phosphate dihydrate) (e) about 0.55% w / v NaCl; (f) a sufficient amount of NaOH (e.g., 1 N NaOH) to provide a pharmaceutical ophthalmic composition with a pH of about 7; and (g) Purified water.

[0024] Another example of a pharmaceutical ophthalmic composition of the present disclosure includes: (a) about 0.0014±15% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; (b) about 0.14±15% w / v hypromellose; (c) about 3.0±15% w / v polyoxyl 35 castor oil; (d) about 0.78±15% w / v phosphate buffer (e.g., sodium phosphate buffer, e.g., sodium phosphate monobasic or sodium dihydrogen phosphate dihydrate) (e) about 0.55±15% w / v NaCl; (f) a sufficient amount of NaOH (e.g., 1 N NaOH) to provide a pharmaceutical ophthalmic composition with a pH of about 7; and (g) Purified water.

[0025] Another example of a pharmaceutical ophthalmic composition of the present disclosure includes: (a) about 0.0014±10% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; (b) about 0.14±10% w / v hypromellose; (c) about 3.0±10% w / v polyoxyl 35 castor oil; (d) about 0.78±10% w / v phosphate buffer (e.g., sodium phosphate buffer, e.g., sodium phosphate monobasic or sodium dihydrogen phosphate dihydrate) (e) about 0.55±10% w / v NaCl; (f) a sufficient amount of NaOH (e.g., 1 N NaOH) to provide a pharmaceutical ophthalmic composition with a pH of about 7; and (g) Purified water.

[0026] Additionally, the present disclosure further extends to various methods for treating various ocular diseases or disorders, and / or signs or symptoms associated with such diseases or disorders, with the pharmaceutical ophthalmic compositions disclosed herein.

[0027] In particular, the present disclosure extends to a method for treating and / or reducing the signs or symptoms of an ocular disease or disorder involving tear production, said method comprising administering a therapeutically effective amount of a pharmaceutical ophthalmic composition of the present disclosure, hi a specific embodiment, the ocular disease or disorder is dry eye.

[0028] The present disclosure further extends to a method for treating or reducing ocular irritation involving tear production in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical ophthalmic composition of the present disclosure.

[0029] Also provided is a method for treating or reducing the signs or symptoms of ocular diseases or disorders in a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical ophthalmic composition of the present disclosure.Therefore, the method of the present disclosure is easily applied in treating or reducing the signs or symptoms of ocular diseases or disorders (e.g., dry eye).Examples of such symptoms of dry eye that can be easily treated or reduced with a therapeutically effective amount of the pharmaceutical ophthalmic composition of the present disclosure include a reduction in visual analog scale (VAS) symptom scores (ocular discomfort score [ODS], ocular dryness score or ocular pain score) or a reduction in the scores obtained from the "Symptom Assessment In Dry Eye" questionnaire, which is disclosed and verified in Schaumberg et al., "Global Dry Eye Symptom Index", The Ocular Surface, 5(1):50-57(2007), and is designed to quantify the frequency and severity of symptoms of dry eye syndrome based on visual analog scale (SANDE questionnaire), ocular dryness, and ocular pain or irritation, to name just a few. Similarly, symptoms of dry eye that can be treated or reduced with the pharmaceutical ophthalmic compositions of the present disclosure include, but are not limited to, Schirmer score (unanesthetized and anesthetized), ocular surface staining, conjunctival redness, tear film breakup time, and tear production. The Schirmer test (first disclosed by Otto Schirmer in 1903) is designed to test whether a subject's eye produces enough tear fluid to keep the eye hydrated (Schirmer O, Studien zur Physiologie und Pathologie der Tranenabsonderung und Tranenbfuhr (Arch. Klin. Opthalmol. 56:197-291 (1903)). Thus, this test is relevant to determine whether the subject produces a sufficient amount of tear fluid to lubricate the eye. Ocular staining is also used as a sign of dry eye disease or disorder. In ocular surface staining, a dye is placed on the surface of the eye to reveal abnormalities on the surface of the eye.Once the dye is placed in the eye, the staining pattern observed using the dye is usually recorded through imaging.The imaged staining pattern can then be used to diagnose the presence and severity of dry eye.Many dyes are applied in eye surface staining, including but not limited to rose bengal, lissamine green, and fluorescein, to name just a few.

[0030] These and other aspects of the present disclosure will be better understood with reference to the following drawings and detailed description. [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 is a bar graph showing the reported change in ocular discomfort (ODS-VAS) in subjects administered a therapeutically effective amount of a pharmaceutical ophthalmic composition of the present disclosure (*=p<0.05).

[0032] [Diagram 2] FIG. 2 is a bar graph showing the change in SANDE score observed in subjects administered the pharmaceutical ophthalmic compositions of the present disclosure.

[0033] [Diagram 3] FIG. 3 is a bar graph showing the change in Dry Eye Disease Symptom VAS Score Ocular Dryness (EDS-VAS) observed in subjects administered a pharmaceutical ophthalmic composition of the present disclosure compared to the ocular dryness observed prior to such administration.

[0034] [Figure 4] FIG. 4 is a bar graph comparing the change in Schirmer scores in anesthetized subjects observed between the scores obtained at the baseline visit and the scores obtained from subjects with treatment with either a 0.0014% w / v or a 0.003% w / v WS-12 pharmaceutical ophthalmic composition as disclosed herein on days 28 and 84 of the clinical trial described herein.

[0035] [Diagram 5] FIG. 5 is a bar graph comparing the change in Schirmer scores in non-anesthetized subjects observed between the scores obtained at the baseline visit and the scores obtained from subjects with treatment with either a 0.0014% w / v or a 0.003% w / v WS-12 pharmaceutical ophthalmic composition as disclosed herein on days 1 and 14 of the study described herein.

[0036] [Figure 6] FIG. 6 is a bar graph tracking conjunctival redness in subjects in a clinical trial administered 0.0014% w / v WS-12 and 0.003% w / v WS-12 pharmaceutical ophthalmic compositions of the present disclosure.

[0037] [Figure 7] FIG. 7 is a bar graph of subjects who underwent ocular surface staining on days 14, 28, and 84 of the trial.

[0038] [Figure 8] 8 shows WS-12 content over time in blow-fill-sealed containers containing Formulation 1 after two-stage storage conditions including a first storage temperature followed by a second storage temperature. Examples correspond to 1, 2, 3, 4, 7, 8, 9, or 10 days of storage at 40° C. followed by up to about 150 days of storage at 25° C. Control samples were stored at 25° C. without the first storage at 40° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Detailed Description The present disclosure is based in part on the discovery that, surprisingly and unexpectedly, WS-12 can be sufficiently solubilized in the pharmaceutical ophthalmic composition of the present disclosure, so that upon delivery to a subject, WS-12 is readily bioavailable.Furthermore, the pharmaceutical ophthalmic composition of the present disclosure does not require a preservative, such as benzalkonium chloride.The pharmaceutical ophthalmic composition of the present disclosure can be provided as an aqueous solution.

[0040] Accordingly, the present disclosure provides a pharmaceutical ophthalmic composition comprising from about 0.0005% w / v to about 0.01% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (WS-12) or a pharma- ceutically acceptable salt thereof, from about 0.1% w / v to about 5% w / v of a solubilizing agent, from about 0.1% w / v to about 0.5% w / v of a viscosity modifier, from about 0.3% w / v to about 1% w / v of a buffer, and from about 0.1% w / v to about 1.0% w / v of a tonicity agent.

[0041] In some embodiments, the pharmaceutical ophthalmic composition comprises: (a) Approximately 0.0005% w / v, 0.00076% w / v, 0.0008% w / v, 0.001% w / v, 0.0014% w / v, 0.0015% w / v, 0.001519% w / v, 0.002% w / v, 0.003% w / v, 0.003039% w / v, 0.004% w / v, 0.005% w / v, 0.006% w / v, 0.006078% w / v, 0.007% w / v, 0.008% w / v, 0.009% w / v, or 0.009116% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (WS-12) or a pharma- ceutically acceptable salt thereof; (b) about 0.1% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.5% w / v, 1% w / v, 1.5% w / v, 2% w / v, 2.0% w / v, 2.00% w / v, 3% w / v, 3.0% w / v, 3.00% w / v, 4% w / v, 4.0% w / v, 4.00% w / v, 5% w / v, 5.0% w / v, or 5.00% w / v of a solubilizing agent (e.g., polyethylene glycol (PEG) 400, castor oil, polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyl 35 castor oil (KOLLIPHOR® EL or KOLLIPHOR® ELP)). (c) about 0.1% w / v, 0.14% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.45% w / v, or 0.5% w / v of a viscosity modifying agent (e.g., hypromellose); (d) about 0.3% w / v, 0.31% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.78% w / v, 0.8% w / v, 0.9% w / v, 1% w / v, or 1.0% w / v of a buffer (e.g., monosodium phosphate); and (e) a tonicity agent (e.g., sodium chloride) at about 0.1% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.49% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v, 0.7% w / v, 0.71% w / v, 0.8% w / v, or 0.9% w / v; Includes.

[0042] Further, for example, WS-12 in compositions comprising WS-12 has been found to undergo adsorption to the polyolefin material in which it is contained. Such adsorption properties (e.g., adsorption, absorption, or both) cause uncertainty regarding the long-term concentration stability of WS-12 stored in such materials. A process has been discovered for stabilizing a WS-12-containing composition disposed within a polymeric (e.g., plastic, e.g., polyolefin) container. The process involves exposing the WS-12 composition in the container to a temperature greater than about 20-25° C. (e.g., at about 40° C.) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, up to about 2 weeks, which process has been found to reduce WS-12 concentration fluctuations when subsequently stored at 20-25° C. for about 7, 14, 90, 140, 150, 160, 180, 365, or more days. For example, such WS-12 concentration variation is limited to a loss of about 6% w / v or less of WS-12 during storage (e.g., at ambient temperatures of about 20-25° C. or lower) following the heat treatment process. One advantage of such a process is that the compositions provided herein may be stored at ambient temperatures without the need for refrigerated storage. The benefits of such storage conditions are readily apparent, including ease of storage and transportation, particularly to residences or geographic locations where electricity or refrigeration are either unreliable or unavailable.

[0043] Accordingly, also provided herein is a process for preparing an article of manufacture, wherein the article comprises a composition provided herein in a polymeric container, wherein the process includes maintaining the article at a first temperature of about 35-45° C. (e.g., about 40° C.). The article can be subsequently stored, e.g., without refrigeration, at ambient temperature or at a lower second temperature (e.g., at about 20-25° C. or lower). Thus, the WS-12 composition in the article (e.g., a WS-12 aqueous composition in fluid contact with the polymeric container) has a WS-12 concentration variation of less than about 6% w / v during storage at the second temperature. In some embodiments, the concentration variation of WS-12 is less than about 5% w / v, less than about 4% w / v, less than about 3% w / v, or less than about 2% w / v. It is understood that % w / v herein may correspond to % as determined by liquid chromatography (LC; e.g., high performance LC (HPLC)). In some embodiments, storage of the article at the second temperature comprises at least about 7, 14, 90, 140, 150, 160, 180, 365, or more days, e.g., at least about 1, 2, 4, 12, 20, 30, 52, or more weeks, e.g., at least about 1, 3, 6, 9, or 12 months, e.g., at least about half a year, a year, or more years.

[0044] The present disclosure also extends to methods of treating or reducing tear production-related ocular irritation in a subject in need thereof, treating or reducing at least one sign or symptom of an ocular disease or disorder involving tear production.

[0045] 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 this disclosure belongs. However, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure.

[0046] All numerous designations, e.g., volume, mass, etc., are approximations which are varied (+) or (-) by increments of 1.0 or 0.1, where appropriate. It is to be understood, although not always expressly stated, that all numerical designations are preceded by the term "about."

[0047] Numerical terms and phrases are used throughout this specification and claims and are defined below.

[0048] "About" and "approximately" are used interchangeably and mean plus or minus a percentage (e.g., ±5%) of the number, parameter, or characteristic so modified, as understood by one of ordinary skill in the art as appropriate for the scientific context in which the term is utilized.

[0049] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0050] As used herein, the terms "comprising," "including," and "comprises" are intended to mean that the compositions, preparations, and methods disclosed herein include the recited elements, but do not exclude others.

[0051] As used herein, the phrase "pH modifier" refers to an excipient used in a pharmaceutical composition that, due to its cationic or anionic properties, serves to control and maintain the pharmaceutical composition at a desired pH.

[0052] As used herein, the phrase "ocular disease or disorder" refers to a disease or disorder of the eye as described above.

[0053] As used herein, a "sign" of a disease or disorder is objective evidence of the disease that can be observed or measured.

[0054] As used herein, a "symptom" of a disease or disorder is a subjective experience of an underlying health problem that cannot be observed by a clinician or others other than the individual experiencing the symptom.

[0055] The term "therapeutically effective amount" as used herein refers to the amount of agent required to treat, ameliorate, or prevent the targeted disease or disorder, or to show a detectable therapeutic or preventive effect on the targeted disease or disorder, or on the signs or symptoms associated with the targeted disease or disorder. In general, the therapeutically effective amount can be initially estimated either in cell culture assays or in animal models (e.g., in non-human primates, mice, rabbits, dogs, or pigs). The animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. For pharmaceutical ophthalmic compositions of the present disclosure, therapeutically effective doses or amounts can be initially estimated using a variety of techniques well known in the art. Initial doses used in animal testing can be based on effective concentrations established in cell culture assays. Suitable dosage ranges for human subjects can be determined, for example, using data obtained from animal testing, cell culture assays, and human clinical trials.

[0056] composition The pharmaceutical ophthalmic composition of the present disclosure can be formulated in various dosage forms according to known methods, for example, as described in the Japanese Pharmacopoeia, 17th Edition, General Rules for Preparations, etc. Examples of dosage forms include injections, eye drops, eye ointments, ear drops, topical liquids, sprays, ointments, gels, and syrups. From the viewpoint of advantageously utilizing the pharmacological action of WS-12, the above dosage form is preferably a dosage form for ophthalmic diseases, specifically, eye drops or eye ointments, and particularly preferably, eye drops. Thus, in some embodiments, the pharmaceutical ophthalmic composition of the present disclosure can be administered locally to the eye of a subject.

[0057] Optionally, the pharmaceutical ophthalmic compositions of the present disclosure may contain one or more additional active pharmaceutical ingredients depending on the ocular disease or disorder for which the pharmaceutical ophthalmic composition is to be used to treat or reduce the signs or symptoms of a disease or disorder involving tear production in a subject. Examples include, but are not limited to: alpha 1 receptor blockers (including bunazosin or a salt or solvate thereof (e.g., bunazosin hydrochloride)); alpha 2 receptor agonists (including brimonidine or a salt or solvate thereof (e.g., brimonidine tartrate), and apraclonidine or a salt or solvate thereof); beta-blockers (including carteolol or a salt or solvate thereof (e.g., carteolol hydrochloride), nipradilol or a salt or solvate thereof, timolol or a salt or solvate thereof (e.g., timolol maleate), betaxolol or a salt or solvate thereof (e.g., betaxolol hydrochloride), levobunolol or a salt or solvate thereof (e.g., levobunolol hydrochloride), befunolol or a salt or solvate thereof, atenolol or a salt or solvate thereof, and metipranolol or a salt or solvate thereof); carbon dioxide acid dehydratase inhibitors (including dorzolamide or a salt or solvate thereof (e.g., dorzolamide hydrochloride), brinzolamide or a salt or solvate thereof, acetazolamide or a salt or solvate thereof, dichlorphenamide or a salt or solvate thereof, and methazolamide or a salt or solvate thereof); prostaglandins (including analogs and derivatives thereof (e.g., prostaglandin F2α derivatives) including isopropyl unoprostone or a solvate thereof, tafluprost or a solvate thereof, travoprost or a solvate thereof, bimatoprost or a solvate thereof, latanoprost or a solvate thereof, cloprostenol or a solvate thereof, and fluprostenol or a solvate thereof); ρ kinase inhibitors (including netarsudil, ripasudil or a salt or solvate thereof, Y-39983, and H-1129);Sympathomimetics (including dipivefrin or a salt or solvate thereof (e.g., dipivefrin hydrochloride), and epinephrine or a salt or solvate thereof (e.g., epinephrine, epinephrine borate, or epinephrine hydrochloride); parasympathomimetics (including distigmine bromide or a salt or solvate thereof, pilocarpine or a salt or solvate thereof (e.g., pilocarpine, pilocarpine hydrochloride, or pilocarpine nitrate, and carbachol or a salt or solvate thereof); calcium antagonists (including lomerizine or a salt or solvate thereof (e.g., lomerizine hydrochloride)); and cholinesterase inhibitors (including demecarium or a salt or solvate thereof, echothiophate or a salt or solvate thereof, and physostigmine or a salt or solvate thereof). These APIs may be mixed with WS-12 in the pharmaceutical ophthalmic compositions of the present disclosure either singly or in combinations of two or more.

[0058] As explained above, many solubilizers are applied to the pharmaceutical ophthalmic compositions of the present disclosure. As used herein, the term "solubilizer" in relation to pharmaceutical compositions refers to an excipient that increases the solubility of the active pharmaceutical ingredient (API) in water. WS-12, which is the API in the pharmaceutical ophthalmic compositions of the present disclosure, is insoluble in water. Therefore, a solubilizer may be added to the pharmaceutical ophthalmic compositions of the present disclosure to increase its solubility in water and, consequently, to ensure that its bioavailability is therapeutically effective upon delivery. Examples of solubilizers applied to the pharmaceutical ophthalmic compositions of the present disclosure include polyethylene glycol (PEG) 400, castor oil, polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyl 35 castor oil (KOLLIPHOR® EL or KOLLIPHOR® ELP), and any combination thereof. In certain embodiments, the solubilizer is polyoxyl 35 castor oil.

[0059] Micelles or micelles (plural micelles or micelles, respectively) are aggregates of surfactant molecules dispersed in a liquid that form a colloidal suspension. A typical micelle in water forms aggregates with the hydrophilic "head" regions in contact with the surrounding solvent, and segregates the hydrophobic single tail region in the center of the micelle. Without being bound by theory, it is believed that this phase is caused by the packing behavior of single-tail lipids in the bilayer. The formation of micelles is brought about by the difficulty of filling the entire internal volume of the bilayer (e.g., in liposomes) while accommodating the area per head group imposed on the molecule by wetting of the lipid head groups. This type of micelle is known as a normal phase micelle (oil-in-water micelle). Reverse micelles have the head groups in the center with the tails extended outwards (water-in-oil micelle). Micelles are approximately spherical in shape. Other phases are also possible, including ellipsoids, cylinders, and bilayer-like shapes. The shape and size of micelles are a function of the molecular geometry of the surfactant molecule and the solution conditions (e.g., surfactant concentration, temperature, pH, and ionic strength). The process of forming micelles is known as micellization and forms part of the phase behavior of many lipids according to their polymorphism. When surfactants are present above their critical micelle concentration (CMC), they can act as emulsifiers, allowing compounds that are normally insoluble (in the solvent used) to dissolve. This occurs because insoluble species that are themselves solubilized in the bulk solvent can be incorporated into the core of the micelle due to favorable interactions of the head group with the solvent species.

[0060] Thus, in some embodiments, the solubilizer has a CMC of less than about 0.1% w / w at 37° C. In some embodiments, the solubilizer that is polyoxyl 35 castor oil has a CMC of about 0.02% w / w at 37° C. In some embodiments, upon heating the undiluted solubilizer, the last solid component of polyoxyl 35 castor oil melts at about 26° C. to produce a clear oily liquid. In some embodiments, the solubilizer is present at or above its CMC value. In some embodiments, the compositions herein include at least a portion of WS-12 encapsulated within the micelles of the solubilizer. In some embodiments, more than 50%, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or more, or essentially all, of the WS-12 present in the composition is encapsulated within the micelles of the solubilizer. In some embodiments, the micelles have an average diameter of about 2 to about 20 nm. In some embodiments, the micelles have an average diameter of about 4 to about 10 nm. In some embodiments, the micelles have an average diameter of about 5 nm ± 2 nm. In some embodiments, the micelles have an average diameter of 5 nm ± 0.5 nm. Thus, in some embodiments, WS-12 is trapped within micelles having an average diameter of about 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, or 20 ± 0.5 nm. In some embodiments, the micelles are unilamellar. In some embodiments, the micelles are spherical (e.g., when the surfactant is present at or above its CMC). In some embodiments, the surfactant forms cylindrical micelles or other aggregated phases (e.g., hexagonal, cubic, or lamellar phases) when the surfactant is present at higher concentrations above the CMC of the surfactant. In some embodiments, the surfactant forms multilamellar liposomes.In some embodiments, the WS-12 in the compositions provided herein has a concentration of up to about 200 μM.

[0061] Furthermore, many viscosity modifiers are easily applied to the pharmaceutical ophthalmic compositions of the present disclosure. As used herein, the phrase "viscosity modifier" in relation to pharmaceutical compositions refers to excipients intended to change the consistency or texture of the pharmaceutical composition. These include thickeners, gelling agents, and stiffening agents that are used to transform liquids into gels, pastes, or powders to assist formulators in creating the ideal product for end users. They can also modify the consistency of liquids. Viscosity modifiers applied in the pharmaceutical ophthalmic composition of the present disclosure include cellulose derivatives (e.g., methylcellulose, microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or any combination thereof); clays (e.g., hectorite, bentonite, aluminum and / or magnesium silicate, kaolin, or any combination thereof); natural gums (e.g., acacia, guar gum, tragacanth, xanthan gum, alginate, carrageenan, locust bean gum, or any combination thereof); synthetic polymers; colloidal silicon dioxide; or any combination thereof. In certain embodiments of the pharmaceutical ophthalmic composition of the present disclosure, the viscosity modifier is hydroxypropylmethylcellulose.

[0062] As described herein, the pharmaceutical ophthalmic composition of the present disclosure includes a tonicity agent. The term "tonicity" refers to the effective osmotic pressure gradient; the water potential of two solutions separated by a semipermeable cell membrane. It depends on the relative concentration of selective membrane-permeable solutes across the cell membrane, which determines the direction and extent of osmotic flux. Therefore, to prevent the osmotic shock of the pharmaceutical ophthalmic composition of the present disclosure to target cells, a tonicity agent (e.g., dextrose, glycerin, mannitol, potassium chloride, sodium chloride, or any combination thereof) is included. In a particular example, the tonicity agent is sodium chloride.

[0063] The pH of the pharmaceutical ophthalmic compositions of the present disclosure ranges from about 5.0 to about 8.5, and more particularly, from about 6.7 to about 7.3. In certain embodiments, the pharmaceutical ophthalmic compositions of the present disclosure have a pH of about 7. A pH adjuster is readily applied to the pharmaceutical ophthalmic compositions of the present disclosure to provide the composition with a desired pH. Examples of pH adjusters applied herein include, but are certainly not limited to, soda ash, sodium hydroxide, sodium silicate, sodium phosphate, lime, sulfuric acid, and hydrofluoric acid, to name just a few. In certain pharmaceutical ophthalmic compositions of the present disclosure, the pH adjuster used is 1N sodium hydroxide, and the desired pH is about 7.

[0064] The pharmaceutical ophthalmic compositions of the present disclosure further comprise a buffer (e.g., phosphate buffer, citrate buffer, TRIS base, TRIS HCl, PBS, HEPES, MES, PIPES, or TES, to name just a few). Phosphate buffer is a particular buffer applied to the pharmaceutical ophthalmic compositions disclosed herein.

[0065] Specific examples of pharmaceutical ophthalmic compositions of the present disclosure are shown in Table 1 below. [Table 1] 1 1N solution (if necessary).

[0066] method As explained above, the present disclosure extends to various methods for treating, reducing, ameliorating, reducing the likelihood of, preventing an ocular disease or disorder, a sign or symptom of such a disease or disorder, or a combination thereof in a subject in need thereof. In certain embodiments, the disease or disorder involves tear production (e.g., dry eye (xerophthalmia), keratoconjunctivitis sicca, or Sjogren's syndrome). Thus, the present disclosure extends to a method for treating or reducing the likelihood of dry eye in a subject, comprising administering a therapeutically effective amount of a pharmaceutical ophthalmic composition of the present disclosure.

[0067] Applicable ocular diseases or disorders that the pharmaceutical ocular composition or method of the present disclosure can be used to treat, improve or prevent are not limited. Specific diseases or disorders that can be prevented or treated with the pharmaceutical ocular composition or method of the present disclosure include, but are certainly not limited to, dry eye or Sjogren's syndrome. The term "dry eye" is understood according to the recently reviewed definition of dry eye provided by TFOS DEWS II. Dry eye disease (DED), also referred to as "dry eye syndrome" or "keratoconjunctivitis sicca", is a multifactorial disease of the ocular surface that is characterized by loss of tear film homeostasis and is accompanied by ocular symptoms such as tear film instability and hyperosmolarity, ocular surface inflammation and damage, and sensory nervous system abnormalities play a pathogenetic role (Craig et al., The Ocular Surface 2017, 15, 276-283). Dry eye occurs when the eye either does not produce enough tears or tears evaporate too quickly. A number of causes can result in dry eye. It is more common in elderly people.The causes of dry eye include, but are not limited to, MGD and other ocular inflammatory processes, vitamin A deficiency, Sjogren's syndrome, rheumatoid arthritis and other rheumatic diseases and disorders, chemical burns or burns, drugs (e.g., atenolol, chlorpheniramine, diuretics, hydrochlorothiazide, isotretinoin, ketorolac, ketotifen, levocabastine, levofloxacin, oxybutynin, and tolterodine).Sjogren's syndrome is an immune disorder characterized by dry mouth and / or dry eye.

[0068] Optionally, the pharmaceutical ophthalmic compositions of the present disclosure may be stored in a package that blocks the transmission of light, and in particular light having wavelengths ranging from about 1 nm to about 340 m (e.g., ultraviolet light). Such a package may be included as a primary package (e.g., a container that is opaque or transparent with respect to visible light). Optionally, the package of the pharmaceutical ophthalmic composition of the present disclosure, and at least one of the primary package or secondary package, may include at least one material that blocks the transmission of ultraviolet light. Examples of such packages and UV light blocking materials applied to such packages are disclosed in PCT Application Publication WO / 2021 / 195256, which is incorporated herein by reference in its entirety. In some embodiments, the pharmaceutical ophthalmic compositions provided herein may be prepared or placed in a container for storage at ambient or elevated temperatures. Any discoloration of the composition that may occur may be reduced when stored in a polyolefin plastic container as compared to a polyvinyl chloride plastic container. Without wishing to be bound by theory, the containers applied herein may reduce the exposure of the contents of the container to electromagnetic radiation, whether it be visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) radiation (e.g., having a wavelength of about 190-320 nm (UV B radiation) or about 320-380 nm (UV A radiation)). Some containers also include a second component that has the ability to reduce the exposure of the contents of the container to infrared radiation, or has such an ability. The containers that may be used include those made of polyolefins (e.g., polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container. The container may further be placed inside a second container, such as a container of paper, cardboard, paperboard, metal film, or foil, or combinations thereof, to further reduce the exposure of the contents of the container to UV light, visible light, or infrared radiation.Compounds and compositions that benefit from reduced discoloration, decomposition, or both during storage include pharmaceutical ophthalmic compositions provided herein. Pharmaceutical ophthalmic compositions provided herein may require storage lasting up to or longer than 3 months; in some cases, up to or longer than 1 year. The container can be in any form suitable for containing the contents; for example, bag, bottle, or box.

[0069] As described herein, the aqueous ophthalmic compositions or methods of the present disclosure specifically include WS-12, which modulates, and is in particular an agonist of, the Transient Receptor Potential cation channel subfamily M member 8, or TRPM8 receptor, a protein that in humans is encoded by the TRPM8 gene (Clapham DE, et al. 2005. Pharmacological Reviews 57 (4): 427-50). Upon activation, TRPM8 is a stimulator of the ophthalmic membrane, which is a membrane-associated protein (Mg) that regulates the ophthalmic membrane and regulates the ophthalmic membrane. + ) and calcium ions (Ca 2+ ) into the cell, thus causing depolarization of the cell and resulting in a change in membrane potential. The TRPM8 protein is expressed in sensory neurons and is activated by low temperature (below approximately 26°C), by chemicals, and by electrical potentials. TRPM8 is also expressed in the prostate, lung, and bladder.

[0070] The human TRPM8 gene is located in the 2p37.1 region of chromosome 2; it encodes a 1104 amino acid protein (NP-076985.4) that is encoded by the sequence of nucleotides NM-024080.4. The TRPM8 gene has six transmembrane segments, the C-terminus and N-terminus of which are on the cytoplasmic side. The four subunits tetramerize to form an active channel.

[0071] The TRPM8 receptor is involved in the control of tear production, and its activation using its agonists results in increased tear production. Specifically, the cold thermoreceptor that innervates the mammalian cornea retains a tonic trigger activity at normal corneal temperatures and is remarkably sensitive to small temperature fluctuations at the surface of the eye (e.g., those resulting from the interval between blinks and evaporation of the precorneal tear film during exposure to a dry environment). This remarkable cold sensitivity is the result of high expression of the TRPM8 channel, which crucially determines the increased frequency of spontaneous basal activity and elicitation of responses to cold. Furthermore, ablation of the TRPM8 channel with genetic techniques halves tear secretion in mice. Partial silencing by corneal heating also reduces tear secretion in humans.

[0072] In view of the above, TRPM8 is a molecular target for moisture detection in cool thermoreceptor nerve fibers that innervate the exposed ocular surface in terrestrial animals.

[0073] In some embodiments, provided herein is a method of treating and / or reducing a symptom of an ocular disease or condition involving tear production, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a molecule that specifically binds to a TRPM8 (transient receptor potential cation channel subfamily M member 8) receptor; wherein binding of said molecule to said TRPM8 receptor modulates activity of said TRPM8 channel; wherein binding of the molecule to the TRPM8 receptor increases or decreases tear secretion caused by an ocular disease or condition; wherein the concentration of said molecule required to bind to and modulate TRPM8 receptors in a tissue is not sufficient to be toxic to a subject in need thereof; wherein the molecule is WS-12 or a salt thereof.

[0074] The term "treating" or "treatment" refers to both therapeutic and prophylactic treatment or preventative measures, where the objective is to prevent or stop (reduce) unwanted physiological changes or disorders (e.g., dry eyes, vagina, or mouth). For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction in the extent of disease, stabilization of pathological conditions (specifically, not worsening), slowing or halting disease progression, improvement or alleviation and remission (both partial and complete) of both detectable and undetectable pathological conditions. Subjects in need of treatment include subjects already suffering from the disease or disorder, and subjects susceptible to the disease or disorder, or subjects in whom the disease or disorder is to be prevented.

[0075] A "method of treatment" is defined as the administration of a pharmaceutical composition containing a TRPM8 agonist (eg, WS-12) to a subject in need of this treatment.

[0076] In the present disclosure, "TRPM8 receptor agonist" is defined as any molecule that can specifically bind to the TRPM8 receptor and, upon binding, can cause an increase in the activity of the TRPM8 channel, i.e., increase the flow of sodium and calcium through the channel, causing cell depolarization. These agonists increase the stimulation of tear secretion by cold-sensitive fibers. There are a wide variety of tests available for detecting the activity of TRPM8 receptor agonists, such as whole-cell patch clamp electrophysiology tests (see Example 1), calcium microscopy (Bodding et al., 2007, Cell Calcium, 42, 618-628) and fluorometric imaging plate reader assays (Behrendt et al., 2004. J. Pharmacol. 141, 737-745), among others, which are mentioned in the examples of the present disclosure. As explained above, WS-12 is a TRPM8 receptor agonist and produces a cold sensation (via the TRPM8 receptor), which can reduce discomfort and pain.

[0077] In some embodiments, pharmaceutical ophthalmic compositions of the present disclosure include those listed in Table 2. [Table 2]

[0078] The present disclosure may be better understood by reference to the following non-limiting examples, which are provided as illustrative of the present disclosure. The following examples are presented in order to more fully illustrate preferred embodiments of the present disclosure. However, they should not be construed in any way as limiting the broad scope of the present disclosure. EXAMPLES

[0079] Working Example Preparation of the formulations of the present disclosure In some embodiments, the pharmaceutical ophthalmic composition of the present disclosure includes, among other ingredients, WS-12 and a solubilizer, in particular polyoxyl 35 castor oil (KOLLIPHOR EL). Polyoxyl 35 castor oil is a polyethoxylated form of castor oil formed from the reaction between castor oil and ethylene oxide. It is a non-ionic surfactant that is miscible with water. In some embodiments, the pharmaceutical ophthalmic composition of the present disclosure further includes hypromellose (METHOCEL F4M), which increases the viscosity of the composition. Additionally, the pharmaceutical ophthalmic composition of the present disclosure is buffered to have a desired pH. In some embodiments, the desired pH is about 7, and the buffer used is a phosphate buffer. Sodium chloride may also be included to make the pharmaceutical ophthalmic composition of the present disclosure isotonic.

[0080] As explained above, WS-12 is insoluble in water. Nevertheless, it was necessary to identify an excipient that would provide WS-12 with a solubility of about 200 μM (0.0058%) in an aqueous medium compatible with administration (e.g., topical administration) to humans (e.g., the human eye). Several solubilizers were evaluated, including PEG 400 (polyethylene glycol 400), KOLLIDON 30 (polyvinylpyrrolidone), propylene glycol, TWEEN® 80 (polyoxyethylene (20) sorbitan monooleate), KOLLIPHOR® EL or KOLLIPHOR® ELP (polyoxyl 35 castor oil), and tyloxapol (ethylene oxide-formaldehyde-p-octylphenol copolymer). It was determined that TWEEN® 80 significantly increased WS-12 solubility. However, the concentration of TWEEN® 80 required to provide this enhancement was higher than the highest level of TWEEN® 80 previously used in any conventional commercial ophthalmic product (i.e., 4%), as shown in the FDA Inactive Ingredient Database. The excipients, KOLLIDON® 30 (polyvinylpyrrolidone), propylene glycol, and tyloxapol (ethylene oxide-formaldehyde-p-octylphenol copolymer), were found to be unable to solubilize WS-12 to the desired level of 200 μM. A KOLLIPHOR® EL concentration of ≧3% w / v successfully dissolved WS-12 at a level of 200 μM. Polyoxyl 35 castor oil is used in commercial ophthalmic products at a concentration of about 5% (FDA Inactive Ingredient Database). Thus, in certain embodiments, the pharmaceutical ophthalmic compositions provided herein contain about 3% KOLLIPHOR® EL w / v as a solubilizing agent.The solubility was determined by adding an excess of WS-12 to the composition, stirring at the temperatures set forth in Table 3 (about 2° C. to about 8° C., and about 17° C.) to allow the WS-12 to reach equilibrium solubility, filtering the mixture to remove undissolved WS-12, and determining the amount of WS-12 dissolved in the composition by HPLC. [Table 3]

[0081] pH and osmolality are important properties of pharmaceutical ophthalmic compositions for topical ophthalmic route of topical administration to the eye. A pH of about 7 was selected to be close to the pH of human tears for physiological comfort. Phosphate buffer was used to maintain a pH of 7. For comfort during administration, NaCl was added to make certain formulations isotonic with an osmolality similar to human tears (about 300 mOsm / kg).

[0082] As described herein, the pharmaceutical ophthalmic composition of the present disclosure further comprises a viscosity modifying agent.In some embodiments, the pharmaceutical ophthalmic composition provided herein is more viscous than water and has a viscosity of more than 1.0 cP.Thus, the pharmaceutical ophthalmic composition of the present disclosure can have a viscosity of about 2 cP, about 3 cP, or about 4 cP, or even greater.In some embodiments, the pharmaceutical ophthalmic composition of the present disclosure has a viscosity of less than about 5 cP or less than about 4 cP, for example, about 3 cP.

[0083] Physicochemical and biological properties of the pharmaceutical ophthalmic compositions of the present disclosure Solubility: The concentrations of WS-12 in the studies described below (0.0014% and 0.003% w / v) are below the saturation limit of WS-12. Therefore, precipitation is not a concern.

[0084] Particulate Matter: Particulate matter is controlled as part of the drug product specification and control is consistent with compendial methods.

[0085] Osmolality: The pharmaceutical ophthalmic compositions of the present disclosure may have an osmolality ranging from about 270 to about 340 mOsm / kg. In certain embodiments, the osmolality is about 300 mOsm / kg. Sodium chloride is used as an osmolality adjusting agent.

[0086] test Study Background: The study disclosed herein tests the effectiveness of the disclosed pharmaceutical ophthalmic compositions comprising the TRPM8 agonist WS-12 to treat, ameliorate, or prevent dry eye and signs or symptoms associated therewith.

[0087] TRPM8 (Transient Receptor Potential Melastatin) receptors are cool thermoreceptors that play an important role in tear film homeostasis (Eguchi et al., Biomed. Res. Int. 2017; Craig et al., The Ocular Surface 2017, 15, 276-283). These receptors are located on the eyelids and cornea and detect the decrease in corneal temperature associated with tear evaporation at the ocular surface.

[0088] A large-scale (n=369), multi-center, vehicle-controlled, double-blind, randomized Phase 2b study was conducted to evaluate the safety and efficacy of two pharmaceutical ophthalmic compositions of the present disclosure, one with a WS-12 concentration of 0.0014% w / v and the other with a WS-12 concentration of 0.003% w / v. Criteria for inclusion of subjects in the trial: Male or female, aged 30 years or older at the time of the screening visit; b. Have a history of dry eye disease within the past 6 months; c. Used and / or desired to use artificial tears for dry eye disease within 2 months prior to the screening visit. d. Having symptoms of dry eye disease based on the Ocular Discomfort Score (ODS)-VAS and the Global SANDE questionnaire at both the Screening and Baseline visits, e. Schirmer test score under anesthesia ≥ 2 and < 10 mm / 5 min at both the Screening and Baseline visits; f. A total corneal fluorescein staining score of ≥ 2 and ≤ 15 based on the revised NEI grading scheme (0-20) (with no areas scoring > 3 at the screening visit); g. BCVA of 20 / 200 (0.70 logMar) or better in both eyes at both the Screening and Baseline visits; h. Good general and ocular health as determined by the Investigator using medical history, eye examination, blood chemistry and hematology, urine analysis and vital signs at the Screening Visit; i. be competent to sign the informed consent, including compliance with the Informed Consent Form (ICF) and the requirements and limitations listed in this protocol; j. Able and willing to comply with the instructions of the study, as assessed by the investigator, and likely to complete all required study visits.

[0089] Thus, in some embodiments of the methods provided herein, the subject includes one or more of the inclusion criteria identified above.

[0090] Criteria for exclusion of subjects from the trial: History or presence of any ocular disease or disorder (other than DED) in either eye that, in the opinion of the investigator, may interfere with the interpretation of the trial results or the safety of the subject. a. History of eye surgery within 1 year prior to the screening visit. b. Presence of punctal or intracanalicular plugs in either eyelid within 1 year prior to the Screening Visit, or anticipated plug insertion or occlusion at any time during the study. c. Wearing contact lenses in either eye within 7 days prior to the screening visit or planning to wear them during the study. d. Regular use of lid hygiene within 14 days prior to the screening visit or any plan to use it during the study. e. Use of any ocular topical medication for DED, ocular corticosteroids or NSAIDs, glaucoma medications, eye whitening, topical antibiotics, topical antihistamines, mast cell stabilizers, or other OTC or dietary supplements except artificial tears within 30 days prior to the screening visit or planned use during the study. f. Systemic corticosteroid use initiated <90 days prior to the Baseline visit or change in dose during the study. Non-ophthalmic topical corticosteroids (including nasal inhalers) are permitted. g. Known allergy or hypersensitivity to an investigational intervention or investigational diagnostic. h. A positive pregnancy test at the Screening or Baseline visit, currently breastfeeding or planning to become pregnant during the study. Women of childbearing potential who are not using a medically acceptable form of contraception. i. The subject has a condition or situation that, in the opinion of the Investigator, may place the subject at significant risk or may confound the results of the trial.

[0091] Thus, in some embodiments of the methods provided herein, the subject does not have one or more of the above-identified exclusion criteria.

[0092] Subject Disposition: A total of 369 subjects were selected and randomized, the majority of whom (>94% in the active treatment group) completed the study by Day 84. [Table 4]

[0093] Adverse events leading to discontinuation included: (a) Burning sensation at the application site (2 patients receiving WS-12 0.0014% w / v formulation and 1 patient receiving WS-12 0.003% w / v formulation); (b) stinging pain at the application site (one patient who received the WS-12 0.003% w / v formulation); (c) eyelid edema (one patient who received WS-12 0.0014% w / v formulation); (d) epithelial defect (1 in vehicle); and (e) Respiratory failure (1 in vehicle). [Table 5]

[0094] Clinical Trial Description: The clinical trial conducted on the pharmaceutical ophthalmic composition of the present disclosure was a multicenter, vehicle-controlled, double-blind, randomized clinical trial. All subjects enrolled suffered from dry eye disease. The trial consisted of a screening visit and a baseline visit to determine eligibility, followed by efficacy evaluations at Day 14 (Visit 3), Day 28 (Visit 4), and Day 84 (Visit 5 / End of Study). Safety was assessed at all study visits. All subjects underwent Controlled Adverse Environment (CAE) endpoints at Screening, Baseline, Day 28, and Day 84 visits. Only subjects who were eligible based on the inclusion / exclusion criteria were enrolled and randomized in a 1:1:1 ratio within each site to receive one drop of placebo (e.g., formulation 1 without WS-12), WS-12 0.0014% or WS-12 0.003% twice daily in both eyes for 84 days. The objective of the study was to evaluate the safety, tolerability and efficacy of the topical pharmaceutical ophthalmic composition of the present disclosure compared to vehicle administered twice daily in subjects with dry eye disease. The timeline of the study is shown in Table 6 below. [Table 6]

[0095] Effect of the pharmaceutical ophthalmic composition of the present disclosure on symptoms of dry eye disease: Table 7 below shows the effect of administering a pharmaceutical ophthalmic composition to subjects according to the description of the clinical trial discussed above on the following symptoms associated with dry eye disease: (a) Ocular discomfort score (ODS-VAS); (b) SANDE score; (c) Eye dryness (EDS-VAS). [Table 7]

[0096] The results of the clinical trials clearly demonstrated improvement in symptoms in dry eye disease following administration of a therapeutically effective amount of the pharmaceutical ophthalmic composition of the present disclosure.

[0097] Figure 1 clearly shows that on day 84 of treatment, subjects reported a change in ocular discomfort of -20.6 for the 0.003% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure compared to that reported at their respective baseline visit, and a decrease of -13.36 for the vehicle BID reported during the same period. It should be noted that a decrease in score represents an improvement, e.g., a reduction in symptoms.

[0098] FIG. 2 clearly shows that subjects administered 0.003% w / v or 0.0014% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure for 84 days showed a reduction in Global SANDE scores of 17.2 and 12.9, respectively, as compared to scores obtained from the subjects at a baseline visit occurring naturally before the pharmaceutical ophthalmic composition of the present disclosure was administered to said subjects.

[0099] Figure 3 is a bar graph showing the change in Eye Dryness Symptom VAS score (EDS-VAS) observed in subjects administered a pharmaceutical ophthalmic composition of the present disclosure compared to the ocular dryness observed prior to such administration. Figure 3 clearly shows that subject-reported ocular dryness following administration of the 0.003% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure was reduced by 17.1 compared to the ocular dryness reported by said subjects at their respective baseline visits, whereas subjects receiving only the vehicle reported only a 10.8 reduction in ocular dryness over the same period.

[0100] Effect of the Pharmaceutical Ophthalmic Compositions of the Present Disclosure on Symptoms of Dry Eye Disease: As explained above, the symptoms of dry eye disease evaluated in the clinical trials disclosed herein were: (a) Schirmer score (unanesthetized); (b) conjunctival redness; and (c) Whole eye surface staining. [Table 8]

[0101] Schirmer Score without Anesthesia: The data in Figure 4 clearly shows that treatment with either 0.0014% w / v or 0.003% w / v WS-12 pharmaceutical ophthalmic composition as disclosed herein resulted in an increase in Schirmer score. This means that the subjects' tear production was increased relative to the score of subjects who received vehicle only. Figure 5 further confirms this observation. Figure 5 clearly shows that a statistically significant number of subjects who received the pharmaceutical ophthalmic composition achieved the endpoint of a ≧10 mm increase in Schirmer score compared to subjects who received vehicle only.

[0102] Conjunctival redness: It is well established that people suffering from dry eye disease can suffer from conjunctival redness. Conjunctival redness was graded according to the following scale (half-maximum (0.5) unit increments may be used): None 0=Normal, no vasodilation; Trace 1=Trace ciliary or conjunctival vasodilation; Mild 2=Broad ciliary vasodilation; Moderate 3=Broad ciliary vasodilation and slight horizontal conjunctival vasodilation; Severe 4=Broad ciliary. Measurements were taken at the baseline visit and on days 14, 28, and 84 of the study. Figure 6 clearly shows that subjects administered the 0.003% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure clearly showed a reduction in conjunctival redness compared to subjects administered vehicle only.

[0103] Ocular surface staining: Ocular surface staining is a method for observing ocular surface damage.The data shown in Figure 7 clearly shows that administering the pharmaceutical ocular composition of the present disclosure to subjects causes a decrease in ocular surface damage, while subjects in the above clinical trial who only receive vehicle show little or no improvement in the actual worsening of surface damage.

[0104] Overall safety of the pharmaceutical ophthalmic composition of the present disclosure: Overall, the pharmaceutical ophthalmic composition of the present disclosure was well tolerated. There were no serious treatment-emergent adverse events (TEAEs) considered to be related to the pharmaceutical ophthalmic composition of the present disclosure. Furthermore, most TEAEs rarely led to discontinuation of the study, and the majority were ocular in nature. Table 9 provides an overall safety summary. [Table 9]

[0105] Ocular Treatment Emergent Adverse Events: As explained above, the majority of TEAEs were ocular in nature. Table 10 provides a breakdown of the types of ocular TEAEs observed and their respective frequencies. [Table 10-1] [Table 10-2]

[0106] Non-ocular treatment-emergent adverse events: As explained above, the majority of TEAEs were eye-related. However, some were not eye-related. Non-ocular treatment-emergent TEAEs are listed in Table 11, as well as their respective incidences. The percentage of non-ocular treatment-emergent adverse events across all groups was similar, with no notable findings. Additionally, no systemic adverse events were considered to be possibly or possibly related to the pharmaceutical ophthalmic composition of the present disclosure. [Table 11]

[0107] Summary: In this trial, 369 dry eye subjects were randomized to one of three treatments: (a) 0.0014% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure (Formulation 2); (b) a 0.003% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure (Formulation 1); and (c) Vehicle (formulation 1 or 2 without WS-12).

[0108] The data obtained clearly shows that statistically significant efficacy was demonstrated for the pharmaceutical ophthalmic compositions of the present disclosure, and in particular the 0.003% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure, across a number of pre-specified symptom and sign endpoints. Symptoms of dry eye disease or disorder for which statistically significant efficacy was clearly demonstrated include: (a) Eye discomfort; (b) SANDE; and (c) Dry eyes.

[0109] Indications of dry eye disease or disorders where statistically significant efficacy has been demonstrated include: (a) Tear production; (b) conjunctival redness; and (c) Ocular surface staining.

[0110] It was further observed that the efficacy of the pharmaceutical ophthalmic composition of the present disclosure was observed within 14 days of the initiation of the trial, with continued improvement in dry eye symptoms and signs evident over the three month duration of the trial. Efficacy in signs was evident as early as after the first dose (day 1). Efficacy in signs and symptoms was observed on day 14.

[0111] Furthermore, data from the clinical trial clearly demonstrated that the pharmaceutical ophthalmic composition of the present disclosure was safe and well tolerated, with the majority (approximately 95%) of all ocular adverse events being rated as mild, and less than 2% of subjects administered the 0.003% w / v WS-12 pharmaceutical ophthalmic composition of the present disclosure discontinued participation in the clinical trial due to adverse events. Furthermore, no systemic or serious adverse events were attributable to the pharmaceutical ophthalmic composition of the present disclosure.

[0112] Storage of the Pharmaceutical Ophthalmic Compositions of the Present Disclosure The pharmaceutical ophthalmic compositions of the present disclosure may be stored in unit dose or multi-dose containers made of polymers, including one or more polyolefins. In some embodiments, the multi-dose containers include those with designs useful for multi-dose preservative-free (MDPF) applications. WS-12 is a chemically stable molecule that is generally not susceptible to degradation by typical drug stressors (e.g., acid, base, peroxide, heat, light). WS-12 is physically unstable in the ophthalmic compositions of the present disclosure because it interacts with the polyolefin container in which it is held. The adsorption process reduces the effective concentration of WS-12 in the eye drops.

[0113] It was discovered that there is an inverse relationship between the crystallinity of the polyolefin and the amount of WS-12 absorbed into the polyolefin when the pharmaceutical composition is stored in contact with the polyolefin at elevated temperatures (e.g., 40°C). Crystallinity was measured by determining the melting temperature of the polyolefin by DSC. Higher melting temperatures indicate greater crystallinity. Table 12 shows that polyolefins with high melting points (e.g., HDPE and PP) produced the lowest percent loss in WS-12, while polyolefins with low melting points (e.g., LDPE 5) showed the greatest loss of WS-12. [Table 12]

[0114] LDPE 1, LDPE 2, LDPE 3, LDPE 4, and LDPE 5 in Table 12 correspond to LDPE from different suppliers. The melting point values ​​of the polyolefins were experimentally determined by differential scanning calorimetry (DSC). The density of the polyolefins was as provided by the manufacturer's product data sheet.

[0115] Unit dose containers for ophthalmic compositions can be produced using form-fill-synthesis (BFS) technology, which involves continuous operations of forming the container, filling the product, and sealing. The unit dose containers are small and typically flexible to allow the patient to easily squeeze out the eye drops. Low density polyethylene (LDPE) is a polyolefin commonly used in BFS because containers made from it are generally easy to bend by hand. The adsorption of WS-12 by LDPE has been found to be temperature dependent, with higher temperatures resulting in greater loss of WS-12 from solution and onto or into the container material by adsorption, absorption, or both. For this reason, LDPE BFS containers holding the ophthalmic compositions must be stored at 5° C. to minimize loss of WS-12 from solution into the container.

[0116] The "curing" technique, or process, described herein takes advantage of the temperature dependence of WS-12 absorption into LDPE to produce a product that is stable when stored at 25° C. In some embodiments, the curing technique comprises: (a) producing a BFS container filled with a pharmaceutical ophthalmic composition provided herein; (b) storing the filled BFS container at a first temperature (e.g., 40° C.) to drive WS-12 into the LDPE container in order to saturate the container walls with WS-12; and (c) subsequently storing the BFS container at a second temperature (e.g., 25° C.) where further loss of WS-12 to the container walls occurs due to the saturation process.

[0117] FIG. 8 shows the trend of WS-12 content in BFS units produced and cured at 40° C. for 1, 2, 3, 4, 7, 8, 9, and 10 days, followed by long-term storage at 25° C. The loss of WS-12 in the cured units is compared to units that did not undergo curing (i.e., they were stored only at 25° C. (99A Long-Term 25° C. trace)). The first data point of each line represents the content of WS-12 in the BFS article after the curing period (e.g., first temperature of storage). The amount of WS-12 lost to the LDPE increased as the duration of curing at 40° C. increased from 1 to 10 days. Subsequent storage of the cured units at 25° C. resulted in a slower rate of loss of WS-12 (e.g., adsorption) to the LDPE when compared to the uncured units. After a 10 day curing period at 40°C (filled circles), the WS-12 content in BFS units stored at 25°C remained constant over the 140 day period.

[0118] Without being bound by theory, the curing technique may be to saturate the walls of the BFS container with WS-12 so that no further loss occurs during long-term storage at 25° C. The amount of WS-12 lost to the walls of the container during the curing period may be compensated for by adding an excess of WS-12 to the ophthalmic composition such that the concentration of WS-12 after the curing period is 100% of the label claim. This strategy increases the feasibility of a physically stable pharmaceutical composition of WS-12 in a compressible LDPE BFS container that can be stored at room temperature. This strategy may be applied to any type of LDPE, regardless of the source of the LDPE.

[0119] Although storage under refrigerated conditions (e.g., at or below about 4° C.) can slow down the adsorption properties of the polyolefin containers, such storage conditions are not feasible under all conditions inhabited by individuals in need of the usefulness of the compositions provided herein. Thus, the compositions and processes provided herein address the need for shelf-stable storage of such useful compositions.

[0120] The present disclosure should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the present disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. approximately 0.003% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

2. approximately 0.0014% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

3. approximately 0.003% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7.0; Purified water, qss to approximately 1.0 mL; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

4. approximately 0.0014% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7.0; Purified water, qss to approximately 1.0 mL; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

5. The pharmaceutical ophthalmic composition of claim 1, wherein the pharmaceutical ophthalmic composition is in a polyolefin container.

6. The pharmaceutical ophthalmic composition of claim 2, wherein the pharmaceutical ophthalmic composition is in a polyolefin container.

7. The pharmaceutical ophthalmic composition of claim 3, wherein the pharmaceutical ophthalmic composition is in a polyolefin container.

8. The pharmaceutical ophthalmic composition of claim 4, wherein the pharmaceutical ophthalmic composition is in a polyolefin container.

9. 9. The pharmaceutical ophthalmic composition of one of claims 1 to 8 for use in a method for treating or reducing the likelihood of dry eye in a subject in need thereof.

10. 9. The pharmaceutical ophthalmic composition of one of claims 1 to 8 for use in a method for treating or reducing the signs or symptoms of an ophthalmic disease or disorder involving tear production in a subject in need thereof.

11. 9. The pharmaceutical ophthalmic composition of claim 1 for use in a method for treating or reducing tear production-related ocular irritation in a subject in need thereof.

12. 1. A pharmaceutical ophthalmic composition for use in a method of treating dry eye in a subject in need thereof, said pharmaceutical ophthalmic composition comprising: approximately 0.003% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

13. 1. A pharmaceutical ophthalmic composition for use in a method of treating or reducing the likelihood of dry eye in a subject in need thereof, said pharmaceutical ophthalmic composition comprising: approximately 0.0014% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

14. A pharmaceutical ophthalmic composition for use in a method of reducing the likelihood of dry eye in a subject in need thereof, said pharmaceutical ophthalmic composition comprising: approximately 0.003% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

15. A pharmaceutical ophthalmic composition for use in a method of reducing the likelihood of dry eye in a subject in need thereof, said pharmaceutical ophthalmic composition comprising: approximately 0.0014% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

16. 1. A pharmaceutical ophthalmic composition for use in a method of reducing a sign or symptom of dry eye in a subject in need thereof, said pharmaceutical ophthalmic composition comprising: approximately 0.003% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

17. 1. A method of reducing a sign or symptom of dry eye in a subject in need thereof, comprising: approximately 0.0014% w / v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide; about 0.14% w / v hypromellose; Approximately 3.0% w / v Polyoxyl 35 Castor Oil; about 0.78% w / v sodium dihydrogen phosphate dihydrate buffer; Approximately 0.55% w / v NaCl; NaOH (e.g., 1 N NaOH) in an amount sufficient to provide a pharmaceutical ophthalmic composition having a pH of about 7; Purified water; and Viscosity less than 5 centipoise 1. A pharmaceutical ophthalmic composition comprising:

18. The pharmaceutical ophthalmic composition for use according to one of claims 12 to 17, wherein the pharmaceutical ophthalmic composition is formulated for topical administration to the subject.

Images