Pharmaceutical compositions containing nabilone for the treatment of ophthalmic conditions

Abstract

The present disclosure provides compositions comprising at least one compound of Formula (I), suitable for application to the ocular surface. The present disclosure also provides methods of making compositions comprising at least one compound of Formula (I). The present disclosure further provides methods of using compositions comprising at least one compound of Formula (I) to reduce intraocular pressure, provide neuroprotection, and / or treat ocular conditions such as glaucoma.

Description

[Technical Field]

[0001] The present disclosure provides compositions comprising at least one compound of Formula (I), suitable for application to the ocular surface. The present disclosure also provides methods of making compositions comprising at least one compound of Formula (I). The present disclosure further provides methods of using compositions comprising at least one compound of Formula (I) to reduce intraocular pressure, provide neuroprotection, and / or treat ocular conditions such as glaucoma. [Background technology]

[0002] The prevalence of neuropathological eye conditions is a significant public health issue. For example, glaucoma is one of the leading causes of blindness worldwide. In the United States alone, it is estimated that over 3 million individuals live with the disease. Glaucoma refers to a group of eye conditions that cause damage to the retina and optic nerve of the eye. Abnormally high intraocular pressure (IOP) causes damage to the optic nerve, which ultimately leads to optic nerve degeneration and retinopathy, resulting in vision loss and blindness.

[0003] In recent years, several lipophilic (and poorly water-soluble) drugs have become available for treating glaucoma and other ocular conditions. For example, compounds isolated from the cannabis plant, such as tetrahydrocannabinol (THC), and other modulators of cannabinoid receptors CB1 and CB2, have been shown to reduce IOP and possess neuroprotective and anti-inflammatory properties in the eye, making them useful for treating various ocular diseases (see Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Patent Document 1, Patent Document 2, Patent Document 3, and Non-Patent Document 4). However, these and other lipophilic drugs present formulation challenges to scientists because their low aqueous solubility prevents the preparation of eye drop solutions with sufficient drug concentrations to be delivered for clinical efficacy and safety. Most traditional lipophilic dosage forms for ocular application (e.g., oil solutions, lotions, and gels) are uncomfortable for patients and do not provide sufficient local drug concentrations in the eye. Therefore, low-viscosity polar and semi-polar formulations presented as eye drops are generally preferred.

[0004] For some lipophilic drugs, emulsions can offer significant advantages, including increased solubility of the active ingredient, prolonged topical activity, and improved ocular bioavailability. However, the design of biologically compatible, stable, and sterilizable emulsion formulations remains a challenge.

[0005] Thus, there is a continuing need for new or improved ophthalmic drug delivery systems that are stable, well tolerated, have enhanced activity, and have other advantageous characteristics. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2016 / 0184259 [Patent Document 2] U.S. Patent No. 9,265,724 [Patent Document 3] U.S. Patent No. 11,786,463 [Non-patent literature]

[0007] [Non-Patent Document 1] J.Pharm.Sci.,2012,101(2):616-626 [Non-patent document 2] Ophthalmic.Res.,1992,24:142-149 [Non-patent document 3] International J.Pharm.,2010,393:238-243 [Non-patent document 4] Br.J.Ophthalmol.,2004,88:708-713 Summary of the Invention

[0008] The present invention provides a composition suitable for application to the ocular surface, comprising: at least one compound of formula (I);

[0009] [ka]

[0010] wherein R1 and R2 together form =O, or R1 is -OH and R2 is -H. Oil and A surfactant, water, The present invention relates to a composition comprising a continuous phase comprising water and a dispersed phase comprising a plurality of nano-sized particles of at least one compound of formula (I), oil droplets, or a combination thereof, wherein at least about 60% of the at least one compound of formula (I) is in the dispersed phase.

[0011] In some embodiments, the composition is a dispersion, a suspension, an emulsion, or any combination thereof. In some embodiments, the compound of formula (I) is

[0012] [ka]

[0013] is selected from the group consisting of: In some embodiments, the compound of formula (I) is

[0014] [ka]

[0015] is. In some embodiments, the compound of formula (I) is

[0016] [ka]

[0017] is. In some embodiments, the compound of formula (I) is

[0018] [ka]

[0019] It is a racemic mixture of In some embodiments, the compound of formula (I) is

[0020] [ka]

[0021] is. In some embodiments, at least about 90% by weight of the compound in the composition is present after the composition is stored under conditions selected from the group consisting of at least 2 years at about 5°C and at least 1 month at about 25°C.

[0022] In some embodiments, the oil and water are present in the composition in a ratio (w / w) of about 1:1 to about 1:1000. In some embodiments, the composition is a suspension or emulsion.

[0023] In some embodiments, the composition is a microemulsion or nanodispersion. In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of less than about 500 nm, e.g., less than 500 nm, hi some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of less than about 350 nm.

[0024] In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm.

[0025] In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 350 nm. In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of about 100 nm to about 200 nm.

[0026] In some embodiments, the composition comprises about 0.005% to about 0.5% by weight of a compound of formula (I). In some embodiments, the oil is selected from the group consisting of sesame oil, safflower oil, linseed oil, castor oil, medium chain diglyceride ester oil, medium chain triglyceride ester oil, soybean oil, olive oil, cottonseed oil, peanut oil, mineral oil, and combinations thereof.

[0027] In some embodiments, the oil is sesame oil, safflower oil, castor oil, or linseed oil. In some embodiments, the oil is safflower oil.

[0028] In some embodiments, the oil is mineral oil. In some embodiments, the oil is castor oil. In some embodiments, the composition comprises from about 1.5% to about 25.0% oil by weight.

[0029] In some embodiments, the surfactant is selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyethylene (20) sorbitan monolaurate (TWEEN® 20), 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane (tyloxapol), sorbitan monooleate (Span® 80), polyoxyethylated 12-hydroxystearic acid (KOLLIPHER™ HS15), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polysorbate 80, and combinations thereof.

[0030] In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate (TWEEN® 80). In some embodiments, the composition comprises about 0.5% to about 5% by weight of a surfactant.

[0031] In some embodiments, the composition further comprises a co-solvent. In some embodiments, the composition further comprises a co-solvent, wherein the co-solvent is glycerin.

[0032] In some embodiments, the composition comprises about 1% to about 10% by weight of a co-solvent. In some embodiments, the composition further comprises at least one pH adjusting agent. In some embodiments, the composition further comprises at least one pH adjuster, wherein the at least one pH adjuster is sodium hydroxide or hydrochloric acid.

[0033] In some embodiments, the composition further comprises at least one pH adjuster, wherein the at least one pH adjuster is sodium hydroxide and hydrochloric acid. In some embodiments, the composition has a pH of about 6.5 to about 7.5.

[0034] In some embodiments, the composition further comprises a stabilizer. In some embodiments, the composition further comprises a stabilizer, wherein the stabilizer is an antioxidant.

[0035] In some embodiments, the composition further comprises a stabilizer, wherein the stabilizer is an antioxidant selected from the group consisting of α-tocopherol acetate, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), monothioglycerol, bisulfite, and combinations thereof.

[0036] In some embodiments, the composition further comprises a stabilizer, wherein the stabilizer is an antioxidant, wherein the antioxidant is selected from the group consisting of BHT, BHA, and combinations thereof. In some embodiments, the composition has an osmolality of about 250 mOsm / L to about 330 mOsm / L.

[0037] In some embodiments, the composition is adapted to be permeable through the patient's cornea and to provide a therapeutically effective concentration of at least one compound of Formula (I). In some embodiments, the composition comprises: about 0.005% to about 0.5% by weight of a compound of formula (I); about 5% to about 25% by weight of an oil selected from the group consisting of sesame oil, castor oil, mineral oil, and combinations thereof; about 1.5% to about 2.5% by weight of polyoxyethylene (20) sorbitan monooleate (TWEEN® 80); about 0.01% by weight to about 1.25% by weight of BHT; about 0.01% to about 1.25% by weight of BHA; about 2.5% by weight of glycerin; and water.

[0038] The present invention also discloses a method for treating or preventing an ocular condition in a subject identified as in need of such treatment, comprising administering to at least one eye of the subject in need thereof a therapeutically effective amount of a composition disclosed herein.

[0039] In some embodiments, the composition is administered once daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered topically.

[0040] In some embodiments, the composition is administered topically as drops, a liquid wash, a gel, an ointment, a spray, or a combination thereof. In some embodiments, the composition is applied to the ocular surface in one or more drops.

[0041] In some embodiments, the ocular condition is selected from the group consisting of glaucoma, age-related macular degeneration (AMD), ophthalmitis, and conjunctivitis. In some embodiments, the ocular condition is glaucoma.

[0042] In some embodiments, the method reduces intraocular pressure (IOP) for a period of at least about 1 hour after administering the composition to the eye. In some embodiments, the method reduces intraocular pressure (IOP) for a period of at least about 4 hours after administering the composition to the eye.

[0043] The present invention also provides a method for preparing the compositions disclosed herein, comprising: combining the compound with an oil to form an oil phase; combining a surfactant and water to form an aqueous phase; combining an oil phase and an aqueous phase to form a premix; homogenizing the premix to form a homogenized premix; and microfluidizing the homogenized premix to provide the composition.

[0044] In some embodiments, the oil phase is prepared at a temperature of about 50°C to about 100°C. In some embodiments, the aqueous phase is prepared at a temperature of about 50°C to about 100°C. In some embodiments, the premix is ​​homogenized at a speed of about 5000 rpm to about 15000 rpm.

[0045] In some embodiments, the premix is ​​homogenized for about 2 minutes to about 20 minutes. In some embodiments, the homogenized premix is ​​microfluidized at a temperature of about 15°C to about 50°C and subsequently cooled to a temperature of about 15°C to about 30°C using cold water circulating in the jacket of the mixing vessel.

[0046] In some embodiments, the premix is ​​microfluidized at a pressure of about 69 MPa to about 138 MPa (about 10,000 PSI to about 20,000 PSI). In some embodiments, the method of preparing further comprises adjusting the pH of the homogenized premix to about 6.5 to about 7.5.

[0047] In some embodiments, the oil droplets comprise at least one compound of formula (I) dissolved in oil. [Brief explanation of the drawings]

[0048] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate the invention and, together with the description, further serve to explain the principles of the invention and to enable one skilled in the art to make and use the invention.

[0049] The present invention is now described with reference to the accompanying drawings, where like reference numbers indicate identical or functionally similar elements. [Figure 1] 1 is a graph comparing nabilone solubility in oils ("supernatants") applicable to topical ophthalmic formulations. "Bulk Form I" is commercially available nabilone (Purysis LLC, Athens, GA). "NF Crystals" is "Bulk Form I" nanosized to a median mass diameter (MMD) particle size of less than 500. [Figure 2] FIG. 1 is a graph showing the average droplet size (Z Avg) and polydispersity index (PDI) of samples described in Example 1 of Nabilone nanoemulsion (0.01 wt %) collected at 12 minute increments (cycles 1-5) during high shear homogenization using a suitable homogenizer such as a MICROFLUIDIZER® (Microfluidics, Westwood, MA). [Figure 3] 1 is a graph showing the size distribution by intensity of samples described in Example 1 of Nabilone nanoemulsion (0.01 wt %) collected at specific times during microfluidization (cycle 3). [Figure 4] 1 is a graph showing the size distribution by intensity of samples described in Example 1 of Nabilone nanoemulsion (0.01 wt %) collected at specific times (cycle 5) during microfluidization. [Figure 5] 1 is a graph showing the size distribution by time of samples described in Example 1 of Nabilone nanoemulsion (0.01 wt%) collected at various times (cycles 1-5) during microfluidization. A D(10) value means that 10% of the particles in the composition are smaller than the indicated size. A D(50) value means that 50% of the particles in the composition are smaller than the indicated size. A D(90) value means that 90% of the particles in the composition are smaller than the indicated size. A D(99) value means that 99% of the particles in the composition are smaller than the indicated size. [Figure 6]1 is a graph showing the average droplet size (Z Avg) and polydispersity index (PDI) of samples described in Example 3 of Nabilone nanoemulsion (0.05 wt%) collected at 12 minute increments (cycles 1-5) during microfluidization. [Figure 7] 1 is a graph showing the size distribution by intensity of samples described in Example 3 of Nabilone nanoemulsion (0.05% by weight) collected at specific times during microfluidization (cycle 3). [Figure 8] 1 is a graph showing the size distribution by intensity of samples described in Example 3 of Nabilone nanoemulsion (0.05 wt %) collected at specific times (cycle 5) during microfluidization. [Figure 9] 1 is a graph showing the size distribution over time of samples described in Example 3 of Nabilone nanoemulsion (0.05 wt %) collected at various times (cycles 1-5) during microfluidization. [Figure 10] 1 is a graph comparing the measured intraocular pressure (IOP) in the eyes of untreated control mice and in the eyes of mice treated with the Nabilone composition (0.01% by weight) described in Example 1 over a 48-hour period following dosing. [Figure 11] 1 is a graph comparing the measured intraocular pressure (IOP) in the eyes of untreated control mice and in the eyes of mice treated with the Nabilone composition (0.05% by weight) described in Example 3 over a 48-hour period following dosing. [Figure 12] 1 is a graph comparing the measured intraocular pressure (IOP) in untreated control mouse eyes and in mouse eyes treated with a timolol composition (0.5% by weight) over a 48-hour period following dosing. [Figure 13] 1 is a graph comparing the measured intraocular pressure (IOP) in the eyes of untreated control mice and in the eyes of mice treated with the control composition (vehicle of nabilone nanoemulsion (0.05% by weight)) described in Example 4 over a 48-hour period after dosing. [Figure 14]1 is a graph comparing the measured intraocular pressure (IOP) in untreated mouse eyes and in mouse eyes treated with nabilone nanoemulsion (0.025% by weight) over a 48-hour period following dosing. [Figure 15] 1 is a graph comparing intraocular pressure (IOP) in untreated mouse eyes and in mouse eyes treated with nabilone nanoemulsion (0.075% by weight) over a 48-hour period following dosing. [Figure 16] 1 is a composite graph showing intraocular pressure (IOP) in untreated mouse eyes ("nabilone untreated naive" 0.01%, 0.025%, 0.05%, and 0.075% by weight) and in eyes of mice treated with nabilone nanoemulsion (0.01%, 0.025%, 0.05%, and 0.075% by weight), matching placebo ("nabilone naive timolol" 0.5% by weight), and timolol (0.5% by weight). [Figure 17] FIG. 1 is a graph showing the dose response of nabilone nanoemulsion (“Nab” 0.01%, 0.025%, 0.05%, and 0.075% by weight) as a percentage of intraocular pressure (IOP) reduction 6 hours after dosing compared to placebo vehicle (“Vehicle”) and timolol (0.5% by weight). [Figure 18] FIG. 1 is a graph showing the dose response of nabilone nanoemulsion (“Nab” 0.01%, 0.025%, 0.05%, and 0.075% by weight) as a percentage of intraocular pressure (IOP) reduction 24 hours after dosing compared to placebo vehicle (“Vehicle”) and timolol (0.5% by weight). DETAILED DESCRIPTION OF THE INVENTION

[0050] As used above and throughout the description, the following terms, unless otherwise indicated, shall be understood to have the following meanings: Unless otherwise indicated, the terms "a," "an," and "the," and similar references, when used in the context of describing particular embodiments of this application (particularly in the context of the claims), can be construed to encompass both the singular and the plural. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein.

[0051] Whenever an embodiment is described herein using the word "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0052] The term "about" encompasses the range of experimental error that occurs in any measurement. Throughout this specification and claims, the term "about" used in connection with numerical values ​​indicates an interval of accuracy known and acceptable to those skilled in the art. Generally, such an interval of accuracy is ±10%. Thus, "about 10" means 9 to 11. All numbers herein indicating quantities, ratios of materials, physical properties of materials, and / or uses should be understood as modified by the word "about" unless expressly indicated otherwise.

[0053] As used herein, "weight percent" or "wt%" or "% by weight" refers to the weight percentage of a component compared to the total weight of the composition. For example, the weight percentage of Nabilone refers to the weight percentage of active Nabilone in the composition.

[0054] As used herein, the phrase "mass median diameter" refers to the particle size where 50% of the particle mass (e.g., oil droplets, solid particles) is contained in smaller particles and 50% is contained in larger particles. The phrase mass median diameter can be abbreviated as MMD.

[0055] Nabilone, sold under the trade name CESAMET™ as a polymorphic crystalline powder in capsules for oral administration, is a synthetic cannabinoid. Nabilone is a 1:1 racemic mixture of the 6aR,10aR ((6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6,6a,7,8,10,10a-hexahydro-9H-benzo[c]chromen-9-one) and 6aS,10aS ((6aS,10aS)-1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6,6a,7,8,10,10a-hexahydro-9H-benzo[c]chromen-9-one) enantiomers.

[0056] In the summary of approval criteria for NDA 18-677, approved on December 26, 1985, oral doses of CESAMET™ were tested for the treatment of glaucoma. The study included 17 patients. During the study, 5% of the 17 patients reported experiencing 78.9% of adverse events, with five serious adverse events reported. All but one of the 5% of patients experienced an adverse event after a single dose. Notable adverse events of note were a significant drop in blood pressure (hypotension) experienced by the patient, and one patient became nauseous and fainted after a single dose. Due to the prevalence of adverse events, the study was discontinued.

[0057] Nabilone is difficult to dissolve in most solvents, making it very difficult to prepare liquid compositions containing nabilone. Table 1 lists solvents in which nabilone is readily soluble. These solvents are not suitable for use in human pharmaceutical formulations. Nabilone is insoluble in water at any pH based on the USP classification of solubility: readily soluble is >100 mg / mL, soluble is 33-100 mg / mL, poorly soluble is 10-33 mg / mL, slightly soluble is 1-10 mg / mL, very slightly soluble is 0.1-1 mg / mL, and virtually insoluble is <0.1 mg / mL.

[0058] [Table 1]

[0059] Also, it is difficult to solubilize nabilone in pharmaceutically acceptable oils, even at high temperatures. As shown in Table 2, even after heating to 90°C, only a very small amount of nabilone dissolves in refined sesame oil, with most of the nabilone settling to the bottom.

[0060] [Table 2]

[0061] Nabilone solubility in other oils applicable to topical ophthalmic formulations is summarized in Figure 1 , where “bulk form I” is a typical lot of nabilone (Purisys LLC, Athens, GA) and “NF crystals” are nanosized from bulk form I.

[0062] As described herein, the disclosed compositions are suitable for topical administration of at least one compound of Formula (I) to the ocular surface. The compositions are stable, well-tolerated, and capable of delivering a therapeutically effective amount of at least one compound of Formula (I) to a target site, including on the surface of the eye and / or within the eye. Surprisingly, the compositions are physically, chemically, and / or microbiologically stable and exhibit effective and long-lasting intraocular pressure (IOP) reduction effects.

[0063] The present invention provides a composition suitable for application to the ocular surface, comprising: at least one compound of formula (I);

[0064] [ka]

[0065] wherein R1 and R2 together form =O, or R1 is -OH and R2 is -H. Oil and A surfactant, water, The composition comprises a continuous phase comprising water and a dispersed phase comprising a plurality of nano-sized particles of at least one compound of formula (I), oil droplets, or a combination thereof, wherein at least about 60% of the at least one compound of formula (I) is in the dispersed phase.

[0066] The present invention also provides a composition suitable for application to the ocular surface, comprising: at least one compound of formula (I);

[0067] [ka]

[0068] wherein R1 and R2 together form =O, or R1 is -OH and R2 is -H. Oil and A surfactant, optionally a co-solvent; Optionally, a pH adjuster; optionally a buffer; optionally a stabilizer; water, The composition comprises a continuous phase comprising water and a dispersed phase comprising a plurality of nano-sized particles of at least one compound of formula (I), oil droplets, or a combination thereof, wherein at least about 60% of the at least one compound of formula (I) is in the dispersed phase.

[0069] Compounds of formula (I) In some embodiments, in at least one compound of Formula (I), R 1 and R 2 together form ═O.

[0070] In some embodiments, in at least one compound of Formula (I), R 1 is —OH and R 2 is —H. In some embodiments, at least one compound of formula (I) is

[0071] [ka]

[0072] and combinations thereof. In some embodiments, at least one compound of formula (I) is

[0073] [ka]

[0074] is. In some embodiments, at least one compound of formula (I) is

[0075] [ka]

[0076] is. In some embodiments, at least one compound of formula (I) is nabilone. In some embodiments, the compound of formula (I) is

[0077] [ka]

[0078] It is a racemic mixture of The racemic mixture of Compound 1 and Compound 2 is commonly known as Nabilone. In some embodiments, the compound is a metabolite of Nabilone, which can exist in four isomeric forms as shown in Scheme 1 below.

[0079] Scheme 1.

[0080] [ka]

[0081] 6aR,9S,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-1,9-diol

[0082] [ka]

[0083] (6aR,9R,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-1,9-diol

[0084] [ka]

[0085] (6aS,9S,10aS)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-1,9-diol

[0086] [ka]

[0087] (6aR,10aR)-1-Hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6,6a,7,8,10,10a-hexahydro-9H-benzo[c]chromen-9-one In some embodiments, at least one compound of formula (I) is

[0088] [ka]

[0089] is. Compounds 3 and 5 are metabolites of nabilone. In some embodiments, the amount of at least one compound of Formula (I) present in the composition is from about 0.005% to about 0.5% by weight, from about 0.005% to about 0.1% by weight, from about 0.005% to about 0.05% by weight, from about 0.005% to about 0.015% by weight, from about 0.005% (w / w) to about 0.01% (w / w), from about 0.01% to about 0.5% by weight, or from about 0. 0.1% by weight to about 0.1% by weight, about 0.01% by weight to about 0.05% by weight, about 0.01% by weight to about 0.015% by weight, about 0.015% by weight to about 0.5% by weight, about 0.015% by weight to about 0.1% by weight, about 0.015% by weight to about 0.05% by weight, about 0.05% by weight to about 0.5% by weight, about 0.05% by weight to about 0.1% by weight, or about 0.1% by weight to about 0.5% by weight.

[0090] In some embodiments, at least one compound of Formula (I) is present in the composition at about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight.

[0091] In some embodiments, the at least one compound of Formula (I) is present in the composition at about 0.005% by weight. In some embodiments, the at least one compound of Formula (I) is present in the composition at about 0.015% by weight.

[0092] In some embodiments, the at least one compound of Formula (I) is present in the composition at about 0.05% by weight. In some embodiments, the at least one compound of Formula (I) is present in the composition at about 0.075% by weight.

[0093] In some embodiments, the at least one compound of Formula (I) is present in the composition at about 0.5% by weight. In some embodiments, at least one compound of Formula (I) is in the dispersed phase of the composition and water is in the continuous phase of the composition.

[0094] In some embodiments, the at least one compound of Formula (I) in the dispersed phase is present as a plurality of nano-sized particles or is dissolved in oil droplets. In some embodiments, the at least one compound of Formula (I) in the dispersed phase is present as a plurality of nano-sized particles, dissolved in oil droplets.

[0095] In some embodiments, at least about 50%, about 60%, about 70%, about 80%, or about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm.

[0096] In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm. In some embodiments, at least about 80% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm. In some embodiments, at least about 70% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm. In some embodiments, at least about 60% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm. In some embodiments, at least about 50% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm.

[0097] In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 350 nm. In some embodiments, at least about 80% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 350 nm. In some embodiments, at least about 70% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 350 nm. In some embodiments, at least about 60% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 350 nm. In some embodiments, at least about 50% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 350 nm.

[0098] In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 200 nm. In some embodiments, at least about 80% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 200 nm. In some embodiments, at least about 70% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 200 nm. In some embodiments, at least about 60% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 200 nm. In some embodiments, at least about 50% of the at least one compound of Formula (I) in the composition has a mass median diameter of less than about 200 nm.

[0099] In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 80% of the at least one compound of Formula (I) in the composition has a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 70% of the at least one compound of Formula (I) in the composition has a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 60% of the at least one compound of Formula (I) in the composition has a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 50% of the at least one compound of Formula (I) in the composition has a mass median diameter of about 100 nm to about 200 nm.

[0100] In some embodiments, the mass median diameter of at least one compound of Formula (I) in the composition ranges from about 1 nm to about 500 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, about 1 nm to about 100 nm, about 1 nm to about 50 nm, about 50 nm to about 500 nm, about 50 nm to about 300 nm, about 50 nm to about 200 nm, about 50 nm to about 100 nm, about 100 nm to about 500 nm, about 100 nm to about 300 nm, about 100 nm to about 200 nm, about 200 nm to about 500 nm, about 200 nm to about 300 nm, or about 300 nm to about 500 nm.

[0101] oil As used herein, the term "oil" refers to any non-polar chemical that is in liquid form at ambient temperature and atmospheric pressure and is both hydrophobic and lipophilic.

[0102] In some embodiments, the oil in the composition is of animal or plant origin, hi some embodiments, the oil in the composition is of synthetic origin. In some embodiments, the oil in the composition is a vegetable oil.

[0103] In some embodiments, the oil in the composition is sesame oil, safflower oil, linseed oil, castor oil, medium chain diglyceride ester oil, medium chain triglyceride ester oil, soybean oil, olive oil, cottonseed oil, peanut oil, mineral oil, or a combination thereof.

[0104] In some embodiments, the oil in the composition is a pharmaceutically acceptable oil. In some embodiments, the oil in the composition is sesame oil, safflower oil, castor oil, or a combination thereof.

[0105] In some embodiments, the oil in the composition is sesame oil. In some embodiments, the oil in the composition is safflower oil. In some embodiments, the oil in the composition is mineral oil.

[0106] In some embodiments, the oil in the composition is castor oil. In some embodiments, the oil in the composition is MIGLYOL812N. In some embodiments, the oil is present in the composition at about 1.5% to about 25% by weight.

[0107] In some embodiments, the amount of oil present in the composition is about 1.5% to about 25% by weight, about 1.5% to about 20% by weight, about 1.5% to about 15% by weight, about 1.5% to about 10% by weight, about 1.5% to about 5% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, or about 20% to about 25% by weight.

[0108] In some embodiments, the oil is present in the composition at about 1.5%, about 5%, about 10%, about 15%, about 20%, or about 25% by weight. In some embodiments, the oil is in the dispersed phase of the composition and the water is in the continuous phase of the composition, hi some embodiments, the oil in the dispersed phase is present as a plurality of nano-sized particles or droplets of oil.

[0109] In some embodiments, at least about 50%, about 60%, about 70%, about 80%, or about 90% of the oil droplets in the composition have a mass median diameter of less than about 500 nm. In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of less than about 500 nm. In some embodiments, at least about 80% of the oil droplets in the composition have a mass median diameter of less than about 500 nm. In some embodiments, at least about 70% of the oil droplets in the composition have a mass median diameter of less than about 500 nm. In some embodiments, at least about 60% of the oil droplets in the composition have a mass median diameter of less than about 500 nm. In some embodiments, at least about 50% of the oil droplets in the composition have a mass median diameter of less than about 500 nm.

[0110] In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 80% of the oil droplets in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 70% of the oil droplets in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 60% of the oil droplets in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 50% of the oil droplets in the composition have a mass median diameter of less than about 350 nm.

[0111] In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 80% of the oil droplets in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 70% of the oil droplets in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 60% of the oil droplets in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 50% of the oil droplets in the composition have a mass median diameter of less than about 200 nm.

[0112] In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 80% of the oil droplets in the composition have a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 70% of the oil droplets in the composition have a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 60% of the oil droplets in the composition have a mass median diameter of about 100 nm to about 200 nm. In some embodiments, at least about 50% of the oil droplets in the composition have a mass median diameter of about 100 nm to about 200 nm.

[0113] In some embodiments, the mass median diameter of the oil droplets in the composition ranges from about 1 nm to about 500 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, about 1 nm to about 100 nm, about 1 nm to about 50 nm, about 50 nm to about 500 nm, about 50 nm to about 300 nm, about 50 nm to about 200 nm, about 50 nm to about 100 nm, about 100 nm to about 500 nm, about 100 nm to about 300 nm, about 100 nm to about 200 nm, about 200 nm to about 500 nm, about 200 nm to about 300 nm, or about 300 nm to about 500 nm.

[0114] surfactants In some embodiments, the surfactant in the composition is a nonionic, anionic, cationic, amphoteric, or zwitterionic surfactant.

[0115] In some embodiments, the surfactant can be polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyethylene (20) sorbitan monolaurate (TWEEN® 20), 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane (tyloxapol), sorbitan monooleate (Span® 80), polyoxyethylated 12-hydroxystearic acid (KOLLIPHER™ HS15), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polysorbate 80, or a combination thereof.

[0116] In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate (TWEEN® 80) or tyloxapol. In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate (TWEEN® 80).

[0117] In some embodiments, the surfactant is polyoxyl 40 stearate, polysorbate 80, or polyoxyl 35 castor oil. In some embodiments, the amount of surfactant present in the composition is about 0.5% to about 5% by weight, about 0.5% to about 2.5% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 1% by weight, about 1% to about 5% by weight, about 1% to about 2.5% by weight, about 1% to about 2% by weight, about 1.5% to about 5% by weight, about 1.5% to about 2% by weight, or about 2% to about 5% by weight.

[0118] In some embodiments, the surfactant is present in the composition at about 0.5%, about 1%, about 1.5%, about 2.5%, or about 5% by weight. water In some embodiments, the oil is in the dispersed phase and the water is in the continuous phase.

[0119] In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:5 to about 1:1000, or from about 1:20 to about 1:100. In some embodiments, the oil to water ratio (w / w) in the composition is about 1:10, about 1:30, about 1:50, about 1:70, or about 1:100.

[0120] In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:1 to about 1:1000. In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:10 to about 1:1000. In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:1 to about 1:100. In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:1 to about 1:50. In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:4 to about 1:100. In some embodiments, the oil to water ratio (w / w) in the composition ranges from about 1:10 to about 1:20.

[0121] dispersion liquid In some embodiments, the composition is in the form of a dispersion. A dispersion is a system in which one substance is dispersed within another substance. In some embodiments, a dispersion is a heterogeneous system in which the dispersed phase, typically a discontinuous liquid such as some type of particle or oil droplets, is physically distinguishable from the medium in which it is dispersed. In some embodiments, the dispersion is a suspension, an emulsion, or a combination thereof. In some embodiments, the dispersion is a suspension. In some embodiments, the dispersion is an emulsion.

[0122] suspension In some embodiments, the composition is in the form of a suspension. As used herein, the term "suspension" refers to a dispersion of solid material (dispersed phase) in a liquid (continuous phase), regardless of the particle size of the solid material. However, the particle size of the solid material can affect the physicochemical behavior of the suspension. For this reason, a distinction is made between colloidal dispersions and coarse dispersions, with colloidal dispersions having particle sizes ranging up to about 1 micron and coarse dispersions having larger particles. Pharmaceutical suspensions straddle the boundary between colloidal and coarse dispersions, with solid particles generally ranging from 0.1 to 10 micrometers. Suspensions are not optically transparent and will appear cloudy unless the particle size falls within the colloidal range.

[0123] emulsion In some embodiments, the composition is in the form of an emulsion. As used herein, the term "emulsion" refers to a colloidal dispersion of two or more liquid immiscible phases (or substantially immiscible phases) in the form of droplets. One of the liquid phases is usually a dispersed phase, and the other is a continuous phase, with the dispersed phase being dispersed throughout the continuous phase as multiple droplets. Based on the size of the droplets, the emulsion may be in the form of a colloidal dispersion, a microemulsion, or a nanoemulsion. An emulsion is an oil-in-water (o / w) emulsion when the continuous phase is an aqueous solution, or a water-in-oil (w / o) emulsion when the continuous phase is an oil. Other examples of emulsions include oil-in-water (o / w / o) emulsions, which contain droplets of oil contained within aqueous droplets dispersed in a continuous oil phase.

[0124] In some embodiments, the composition is in the form of a microemulsion. -6 ) droplet size. In some embodiments, the composition is in the form of a nanoemulsion. Nanoemulsions are particles with a size of nanometers (10 -9 ) droplet size.

[0125] In some embodiments, at least about 60% of the at least one compound of Formula (I) is present in the dispersed phase. In some embodiments, at least about 70% of the at least one compound of Formula (I) is in the dispersed phase. In some embodiments, at least about 80% of the at least one compound of Formula (I) is in the dispersed phase. In some embodiments, at least about 90% of the at least one compound of Formula (I) is in the dispersed phase. In some embodiments, at least about 95% of the at least one compound of Formula (I) is in the dispersed phase.

[0126] In some embodiments, about 60% to about 95% of the at least one compound of Formula (I) is in the dispersed phase. In some embodiments, the percentage of the at least one compound of Formula (I) in the dispersed phase is about 60% to about 95%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 95%, about 70% to about 90%, about 70% to about 80%, about 80% to about 95%, about 80% to about 90%, or about 90% to about 95%.

[0127] Other ingredients In some embodiments, the composition further comprises at least one co-solvent, hi some embodiments, the at least one co-solvent is glycerin, propylene glycol, polyethylene alcohol, ethanol, propylene glycol esters, polyethylene glycol esters, or combinations thereof.

[0128] In some embodiments, the co-solvent is glycerin. In some embodiments, the amount of at least one co-solvent present in the composition is about 1% to about 10% by weight, about 1% to about 5% by weight, about 1% to about 2.5% by weight, about 1% to about 2% by weight, about 1% to about 1.5% by weight, about 1.5% to about 10% by weight, about 1.5% to about 5% by weight, about 1.5% to about 2.5% by weight, about 1.5% to about 2% by weight, about 2% to about 10% by weight, about 2% to about 5% by weight, about 2% to about 2.5% by weight, or about 2.5% to about 5% by weight.

[0129] In some embodiments, the co-solvent is present in the composition at about 1 wt %, about 1.5 wt %, about 2 wt %, about 2.5 wt %, about 5 wt %, or about 10 wt %. In some embodiments, glycerin is present in the composition at about 2.5% by weight.

[0130] In some embodiments, the co-solvent is a humectant (ie, retains moisture). In some embodiments, the composition further comprises at least one stabilizer, hi some embodiments, the stabilizer is an antioxidant.

[0131] In some embodiments, the composition further comprises at least one antioxidant. As used herein, the term "antioxidant" refers to an agent used to inhibit oxidation and thus prevent the deterioration of a preparation due to oxidation caused by the presence of oxygen free radicals or free metals in the composition. In some embodiments, the at least one antioxidant is α-tocopherol acetate, butylated hydroxyanisole (BHA), vitamin E, fumaric acid, ascorbyl palmitate, butylated hydroxytoluene (BHT), monothioglycerol, propyl gallate, sulfur dioxide, sodium thiosulfate, sodium sulfite, ascorbic acid, erythorbic acid, bisulfite, potassium metabisulfite, malic acid, sodium metabisulfite, sodium formaldehyde sulfoxylate, or a combination thereof.

[0132] In some embodiments, the at least one antioxidant used in the composition is BHA, BHT, or a combination thereof. In some embodiments, the concentration of the antioxidant in the composition is from about 0.001% to about 0.5% by weight, from about 0.001% to about 0.1% by weight, from about 0.001% to about 0.05% by weight, from about 0.001% to about 0.01% by weight, from about 0.001% to about 0.005% by weight, from about 0.005% to about 0.5% by weight, from about 0.005% to about 0.1% by weight %, about 0.005% to about 0.05% by weight, about 0.005% to about 0.01% by weight, about 0.01% to about 0.5% by weight, about 0.01% to about 0.1% by weight, about 0.01% to about 0.05% by weight, about 0.05% to about 0.5% by weight, about 0.05% to about 0.1% by weight, about 0.1% to about 0.5% by weight, about 0.005% to about 0.01% by weight, about 0.01% to about 0.5% by weight, about 0.01% to about 0.1% by weight, about 0.01% to about 0.05% by weight, about 0.05% to about 0.5% by weight, about 0.05% to about 0.1% by weight, or about 0.1% to about 0.5% by weight.

[0133] In some embodiments, the concentration of the antioxidant in the composition is about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight. In some embodiments, the composition comprises about 0.03% by weight of an antioxidant (e.g., BHT and / or BHA). In some embodiments, the composition comprises about 0.03% by weight of BHT and about 0.03% by weight of BHA.

[0134] In some embodiments, the composition further comprises at least one pH adjuster, hi some embodiments, the at least one pH adjuster is lactic acid, citric acid, phosphoric acid, acetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, or a combination thereof.

[0135] In some embodiments, the pH adjuster is sodium hydroxide or hydrochloric acid. In some embodiments, the pH adjuster is sodium hydroxide. In some embodiments, the pH adjuster is hydrochloric acid. In some embodiments, the pH adjuster is sodium hydroxide and hydrochloric acid.

[0136] In some embodiments, the pH adjusting agent is present in an amount sufficient to provide a near-neutral pH level. In some embodiments, the pH adjusting agent is present in an amount sufficient to provide a pH of about 6.5 to about 7.5. In some embodiments, the pH adjusting agent is present in an amount sufficient to provide a pH of about 6.8 to about 7.2.

[0137] In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the buffering agent is sodium diphosphate dibasic heptahydrate (NaH2PO4·7H2O), sodium phosphate monobasic dihydrate (NaH2PO4·2H2O), or a combination thereof. In some embodiments, the buffering agent is sodium diphosphate dibasic heptahydrate. In some embodiments, the buffering agent is sodium phosphate monobasic dihydrate. In some embodiments, the buffering agent is a combination of sodium diphosphate dibasic heptahydrate and sodium phosphate monobasic dihydrate.

[0138] In some embodiments, the composition further comprises at least one other active pharmaceutical ingredient. In some embodiments, the at least one other active pharmaceutical ingredient is suitable for ophthalmic use. In some embodiments, the at least one other active pharmaceutical ingredient is timolol or latanoprost.

[0139] It is believed that the particular combination of ingredients and process steps described herein impart unexpected physical, chemical, and / or microbiological stability to the compositions of the present invention. A "physically stable" composition is one that, under appropriate storage conditions, does not exhibit visible phase separation between oil and aqueous phase components, e.g., for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.

[0140] In some embodiments, the composition remains stable after storage for at least two years at a temperature of about 5° C., such that there is no visible phase separation between the oil and aqueous phase components after such storage. In some embodiments, the composition remains stable after storage for at least one month at a temperature of about 25° C., such that there is no visible phase separation between the oil and aqueous phase components after such storage.

[0141] A "chemically stable" composition is one in which the concentration of the active pharmaceutical ingredient (e.g., at least one compound of Formula (I)) does not change by more than about 20% for at least about two weeks or about one month under appropriate storage conditions.

[0142] In some embodiments, the concentration of at least one compound of Formula (I) does not change by more than about 5%, about 10%, about 15%, or about 20% under appropriate storage conditions for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.

[0143] In some embodiments, at least about 90% by weight of the initial compound of Formula (I) in the composition remains in undecomposed form after storage for at least 2 years at a temperature of about 5° C. In some embodiments, at least about 90% by weight of the initial compound of Formula (I) in the composition remains in undecomposed form after storage for at least 2 months at a temperature of about 25° C. In some embodiments, at least about 90% by weight of the compound of Formula (I) in the composition remains in undecomposed form after storage for at least 1 month under controlled temperature conditions of about 20° C. to about 25° C.

[0144] In some embodiments, at least about 95% by weight of the initial compound of Formula (I) in the composition remains in undecomposed form after storage for at least 2 years at a temperature of about 5° C. In some embodiments, at least about 95% by weight of the initial compound of Formula (I) in the composition remains in undecomposed form after storage for at least 2 months at a temperature of about 25° C.

[0145] In some embodiments, the composition does not require the use of conventional preservatives and / or excipients with antimicrobial properties to maintain the microbiological stability of the composition. In some embodiments, the composition is substantially free of preservatives. In some embodiments, the composition is substantially free of benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, EDTA, and sorbic acid.

[0146] In addition to the advantageous physical, chemical, and microbiological stability provided by the composition, it has also been surprisingly discovered that the composition is highly suitable for topical administration to the eye of animals (e.g., humans). The composition has been well tolerated in animal studies, and no irritating effects have been detected upon topical application.

[0147] The present invention, in some embodiments, comprises: at least one compound of formula (I); Oil and A surfactant, water, Further provided is a composition wherein the dispersed phase is a plurality of nano-sized particles of at least one compound of formula (I), oil droplets, or a combination thereof, wherein at least about 60% of the at least one compound of formula (I) is in the dispersed phase, and water forms the continuous phase, and wherein the osmolality of the composition is substantially similar to the osmolality of human tear fluid.

[0148] As used herein, the term "osmolality" refers to the concentration of osmotically active solutes in a solution. In some embodiments, the composition exhibits an osmolality substantially similar to that of human tear fluid. In some embodiments, the osmolality of the composition is about 300 mOsm / L to about 340 mOsm / L.

[0149] In some embodiments, compositions are characterized by their osmotic pressure.The term "osmotic pressure" refers to the concentration of osmotically active solute per kg of solvent.Physiologically acceptable osmotic pressure is the osmotic pressure that conforms to the normal function of living organisms.Therefore, for the purpose of the present invention, the osmotic pressure of the composition is substantially similar to the osmotic pressure of human tear fluid.

[0150] In some embodiments, the composition has an osmolality of about 250 mOsm / kg to about 330 mOsm / kg, 250 mOsm / kg to about 300 mOsm / kg, 250 mOsm / kg to about 275 mOsm / kg, 275 mOsm / kg to about 330 mOsm / kg, 270 mOsm / kg to about 300 mOsm / kg, or 300 mOsm / kg to about 330 mOsm / kg.

[0151] In some embodiments, the osmolality of the composition is from about 290 mOsm / kg to about 315 mOsm / kg. The present disclosure provides, in some embodiments, at least one compound of formula (I); Sesame oil and a surfactant selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyethylene (20) sorbitan monolaurate (TWEEN® 20), 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane (tyloxapol), sorbitan monooleate (Span® 80), polyoxyethylated 12-hydroxystearic acid (KOLLIPHER™ HS15), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polysorbate 80, and combinations thereof; and water, Further provided is a composition, wherein the composition comprises a continuous phase comprising water and a dispersed phase comprising a plurality of nano-sized particles of at least one compound of Formula (I), oil droplets, or a combination thereof, wherein at least about 60% of the at least one compound of Formula (I) is in the dispersed phase.

[0152] The present disclosure also provides about 0.005% to about 0.5% by weight of a compound of formula (I); about 5% to about 25% by weight of an oil selected from the group consisting of sesame oil, mineral oil, and castor oil; about 1.5% to about 2.5% by weight of polyoxyethylene (20) sorbitan monooleate (TWEEN® 80); about 0.01% by weight to about 1.25% by weight of BHT; about 0.01% to about 1.25% by weight of BHA; about 2.5% by weight of glycerin; and water.

[0153] The present disclosure also provides methods of making the compositions of the present invention. In some embodiments, the compositions comprise: combining a compound of formula (I) with an oil to form an oil phase; combining a surfactant with water to form an aqueous phase; combining an oil phase and an aqueous phase to form a premix; homogenizing the premix to form a homogenized premix; and The composition is prepared by microfluidizing a homogenized premix to provide the composition.

[0154] In some embodiments, the premix is ​​homogenized at a speed of about 5000 rpm for about 2 minutes. In some embodiments, homogenization of the premix is ​​carried out at a speed of about 5000 rpm for about 20 mm.

[0155] In some embodiments, the oil to water ratio (w / w) in the premix ranges from about 1:10 to about 1:1000 or from about 1:20 to about 1:100. In some embodiments, the amount of oil in the premix is ​​from about 1.5% to about 5.0% by weight.

[0156] After the homogenization step, an additional (e.g., second) portion of water can be added to form a diluted or bulk sample. The bulk sample can be filtered through a membrane to obtain a composition having oil droplets of a desired size. Suitable membranes include, for example, polymeric membranes having a maximum pore size of about 200 nm to about 500 nm (or about 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, or about 450 nm). In some embodiments, the membrane comprises a polymeric material selected from polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE), and poly(ether sulfone) (PES).

[0157] particle size Laser diffraction was used to measure and determine the particle size distribution of the disclosed compositions, where particles refer to solid particles, liquid particles (e.g., particles dissolved in oil droplets), or a combination thereof. While other methods exist for determining particle size distribution, samples are analyzed by laser diffraction to determine whether they meet particle size requirements. In the example, collected samples were tested using the Malvern Masterizer 3000 method with parameters obtained from a Malvern ZetaSizer (Malvern Instruments, Malvern, UK). The particle size of the sample was analyzed by laser diffraction. Laser diffraction calculates particle size distribution by measuring the angular variation in the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam, while small particles scatter light at large angles. The angular scattering intensity data is analyzed to calculate the size of the particles responsible for forming the scattering pattern using the Mie theory of light scattering. Particle size is reported as volume-equivalent spherical diameter.

[0158] Particle size distribution can be expressed by four values: "D" represents the percentage of particles in the composition that are smaller than the indicated size. Rather than measuring particles one by one, analyzers used in laser diffraction to determine particle size use light at different angles and then capture the diffraction pattern from an image sensor. Then, by performing addition, subtraction, and cross-analysis calculations, the instrument determines the statistical ratio of particle sizes. The instrument also uses software to calculate the mass median diameter. The mass median diameter (MMD) is the particle size where half of the particle mass is contained in smaller particles and half is contained in larger particles. Therefore, the MMD is half of the total particle mass.

[0159] A D10 or D(10) value means that 10% of the particles in the composition are smaller than the indicated size. A D50 or D(50) value means that 50% of the particles in the composition are smaller than the indicated size. D50 is the median particle size distribution where 50% of the particles are smaller than this size and 50% of the particles are larger than this size. A D90 or D(90) value means that 90% of the particles in the composition are smaller than the indicated size. A D99 or D(99) value means that 99% of the particles in the composition are smaller than the indicated size.

[0160] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter (MMD) such that 50% of the dispersed droplet mass is qualitatively less than about 500 nm. In some embodiments, at least about 80% of the particles in the composition have a mass median diameter less than about 500 nm. In some embodiments, at least about 70% of the particles in the composition have a mass median diameter less than about 500 nm. In some embodiments, at least about 60% of the particles in the composition have a mass median diameter less than about 500 nm. In some embodiments, at least about 50% of the particles in the composition have a mass median diameter less than about 500 nm.

[0161] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 80% of the particles in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 70% of the particles in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 60% of the particles in the composition have a mass median diameter of less than about 350 nm. In some embodiments, at least about 50% of the particles in the composition have a mass median diameter of less than about 350 nm.

[0162] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 80% of the particles in the composition have a mass median diameter of less than about 500 nm. In some embodiments, at least about 70% of the particles in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 60% of the particles in the composition have a mass median diameter of less than about 200 nm. In some embodiments, at least about 50% of the particles in the composition have a mass median diameter of less than about 200 nm.

[0163] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter of less than about 100 nm. In some embodiments, at least about 80% of the particles in the composition have a mass median diameter of less than about 100 nm. In some embodiments, at least about 70% of the particles in the composition have a mass median diameter of less than about 100 nm. In some embodiments, at least about 60% of the particles in the composition have a mass median diameter of less than about 100 nm. In some embodiments, at least about 50% of the particles in the composition have a mass median diameter of less than about 100 nm.

[0164] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter of about 100 nm to about 500 nm, about 100 nm to about 350 nm, about 100 nm to about 200 nm, about 200 nm to about 500 nm, about 200 nm to about 350 nm, or about 350 nm to about 500 nm. In some embodiments, at least about 90% of the particles in the composition have a mass median diameter of about 100 nm to about 200 nm.

[0165] Methods of treatment or prevention The present invention also provides methods for treating or preventing a subject in need of neuroprotection. In some embodiments, the subject is a human patient in need of neuroprotection. Neuroprotection refers to the preservation of neural tissue (such as the retinal nerve or optic nerve) and / or the regeneration of ocular nerves, and can typically be measured by a reduction in neuronal death and / or degeneration associated with a neuropathological condition (e.g., neurological injury or disease). Neuropathic conditions can include diseases and / or disorders such as blinding eye diseases, including macular degeneration, retinitis pigmentosa, and glaucoma. Neuropathic conditions, such as neuropathic pain, can also be treated.

[0166] The term "subject," as used herein, refers to a mammal, e.g., a human, a domestic animal, e.g., a feline or canine subject, a farm animal (e.g., a bovine, equine, caprine, ovine, and porcine subject), a wild animal, or a research animal (e.g., a mouse, rat, rabbit, goat, sheep, pig, dog, cat, or bird, e.g., a chicken, turkey, and songbird). In some embodiments, the subject is a human subject.

[0167] The present invention also provides methods for treating an ocular condition in a subject by administering a therapeutically effective amount of a composition of the present invention to the eye of the subject. In some embodiments, the ocular condition is glaucoma, age-related macular degeneration (AMD), ophthalmitis, or conjunctivitis. In some embodiments, the ocular condition is glaucoma.

[0168] In some embodiments, the ocular condition is a disease of the immune system (e.g., an inflammatory disease). In some embodiments, the ocular condition is a disease of the immune system, such as dry eye disease, posterior uveitis, retinitis, uveoretinitis, proliferative vitreoretinopathy, anterior uveitis, episcleritis, scleritis, ocular neuropathic pain, or ocular inflammation caused by a non-infectious condition. In some embodiments, ocular neuropathic pain can result from dry eye, trauma, corneal abrasion, corneal burn, corneal transplant, autoimmune disease, or allergens.

[0169] In some embodiments, the composition provides a reduction in intraocular pressure (IOP). In some embodiments, the composition provides a reduction in intraocular pressure for a period of at least about 1 hour after administration of the composition to the subject's eye. In some embodiments, the composition provides a reduction in intraocular pressure for a period of at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours after administration of the composition to the subject's eye. In some embodiments, the composition provides a reduction in intraocular pressure for a period of at least about 8 hours, at least about 12 hours, or at least about 24 hours after administration of the composition to the subject's eye. In some embodiments, the composition increases aqueous humor outflow in the subject's eye.

[0170] As used herein, "topical administration" refers to localized administration to the surface of a tissue, such as to the eye, particularly any external surface of the eye normally accessible between the eyelids. In some embodiments, the composition is topically administered as drops, a liquid wash, a gel, an ointment, a spray, or a combination thereof. In some embodiments, the composition is in the form of an eye drop solution. For example, the composition can be provided in a hard and / or squeeze bottle with a fitting cap configured to serve as a dropper.

[0171] In some embodiments, the composition is administered topically as drops. In some embodiments, the composition is applied to the ocular surface in one or more drops. In some embodiments, 1-10 drops, 1-5 drops, 1-2 drops, 2-10 drops, 2-5 drops, or 5-10 drops of the composition are administered per day.

[0172] Local administration can further be achieved by injecting the composition via a device such as a pump-catheter system, a continuous or selective release device, a contact lens, or a combination thereof. The composition can also be administered in an injectable form, for example, such that the composition is injected behind the eye and / or where administration includes intravitreal injection.

[0173] In some embodiments, the composition is administered once daily. In some embodiments, the composition is administered twice daily. In some embodiments, administration occurs twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, eight times daily, nine times daily, or ten times daily. In some embodiments, administration occurs continuously via a release device.

[0174] Also provided herein are kits for treating or preventing an ocular condition in a subject. In some embodiments, the ocular condition is glaucoma. The kits may include any of the compositions described herein. The kits may include a therapeutically effective amount of a composition of the present invention and may further include instructions for administering the composition to a patient with an ocular condition (such as neuropathic pain, glaucoma, age-related macular degeneration (AMD), ophthalmia, or conjunctivitis). The instructions may include publications, diagrams, or any other medium of expression that can be used to communicate the usefulness of the composition and its administration. The instructions for the kit may be attached to a container containing the composition of the present invention or may otherwise be provided together with the container containing the composition. Alternatively, the instructions may be provided separately, for example, by electronic transmission, e.g., by computer, email, or download from a website. The kit may further include at least one additional agent, such as an additional pharmaceutical agent useful for treating or preventing an ocular condition. [Example]

[0175] Having now generally described the invention, it will be understood by reference to the following examples, which are provided herein for purposes of illustration only and are not intended to be limiting, unless specifically stated.

[0176] Example 1: Preparation of a 1000G batch of Nabilone nanoemulsion 0.01% (w / w) Using the ingredients shown in Table 3, 1000 grams of 0.01% w / w Nabilone nanoemulsion was prepared using the following method: A 200 mL beaker was obtained and labeled "oil phase." The tare weight of the beaker was obtained. 20.02 g of sesame oil was dispensed into the "oil phase" beaker, and the oil phase was heated to 75.0±5°C. 0.1005 g of Nabilone was weighed and dissolved in the sesame oil and heated to 75.0±5°C with magnetic stirring at 500 rpm. Visual inspection confirmed that the Nabilone was dissolved in the oil. A 1500 mL beaker was obtained and labeled "aqueous phase." 20.03 g of TWEEN® 80 and 25.05 g of glycerin were added to the aqueous phase beaker. 934.91 g of purified water was added and mixed with magnetic stirring. The aqueous phase was heated to 75.0 ± 5°C with magnetic stirring at 500 rpm. The "oil phase" was gradually added to the "aqueous phase" beaker and mixed for 5 minutes at a stirring speed of 1000 rpm. The mixture was homogenized at 10,000 rpm for 5 minutes using a homogenizer (IKA T-18 Digital ULTRA-TURRAX™, IKA Works, Inc., Wilmington, North Carolina) to form a premix. The post-homogenization yield was calculated. A MICROFLUIDIZER® (Microfluidics M-110P, Microfluidics, Westwood, Massachusetts) was heated to a target temperature of 25°C (± 2°C). The premix was added to the microfluidizer and treated at 103 MPa (15,000 PSI). The first three strokes were discarded as waste. After processing the premix for 12 minutes, the product was collected in an intermediate container. From the intermediate vessel, a 12.5 g sample (cycle 1) was collected for particle size evaluation. The microfluidizer reservoir was drained, and after two processing strokes, the contents of the intermediate vessel were returned to the reservoir and the process repeated. After 12 minutes of processing, the product was collected in the intermediate vessel. From the intermediate vessel, a 12.5 g sample (cycle 2) was collected for particle size evaluation. This process was repeated for three more cycles (cycles 3, 4, and 5), with a 12.5 g sample collected for particle size evaluation after each microfluidization cycle. After the fifth cycle, the product was collected and weighed.The pH of the emulsion was checked and adjusted to 7.02 using 1N NaOH followed by 1N HCl with mixing.

[0177] A particle size analyzer (Masterizer 3000 (Malvern Panalytical, Malvern, UK) was used for particle size distribution analysis. The particle size results obtained from the samples are shown in Figures 2 to 8.

[0178] [Table 3]

[0179] Example 2: Preparation of a 1000G placebo batch for comparison with Nabilone nanoemulsion 0.01% (w / w) The method of Example 1 was used to prepare a placebo batch of nabilone nanoemulsion 0.01% (w / w) using the ingredients shown in Table 4 (absent nabilone).

[0180] [Table 4]

[0181] Example 3: Preparation of a 1000G batch of Nabilone nanoemulsion 0.05% (w / w) Table 5 shows the composition of the 0.05% w / w nabilone nanoemulsion prepared using the method of Example 1.

[0182] [Table 5]

[0183] Example 4: Preparation of a 1000G placebo batch for comparison with Nabilone nanoemulsion 0.05% (w / w) A placebo formulation of 0.05% (w / w) nabilone nanoemulsion was prepared using the materials and method of Example 1. The composition of this batch is summarized in Table 6 (nabilone absent).

[0184] [Table 6]

[0185] Example 5: Preparation of a 1000G batch of Nabilone nanoemulsion 0.075% (w / w) Using the method of Example 1 and the materials shown in Table 7, a 1000 gram batch of 0.075% w / w Nabilone nanoemulsion was prepared.

[0186] [Table 7]

[0187] Example 6: Preparation of a 1000G batch of Nabilone nanoemulsion 0.025% (w / w) Using the method of Example 1 and the materials shown in Table 8, a 1000 gram batch of 0.025% w / w Nabilone nanoemulsion was prepared.

[0188] [Table 8]

[0189] Example 7: Preparation of Nabilone nanoemulsion 0.075% (w / w) with antioxidants A 0.075% w / w nabilone nanoemulsion was prepared using the materials in Table 9 and the method of Example 1 with the addition of antioxidants. Antioxidants and co-solvents can be added to the pharmaceutical composition to maintain shelf-life stability. A co-solvent (glycerin) was added to the aqueous phase as described in Example 1, and the antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were added to the oil phase, followed by nabilone. The composition was shown to be stable for at least six months at refrigerated (5°C) and room temperature (25°C) conditions by assay, impurities, particle size distribution, and pH.

[0190] [Table 9]

[0191] Example 8: Preparation of a placebo batch of nabilone nanoemulsion 0.075% (w / w) A placebo batch of Nabilone nanoemulsion 0.075% was prepared according to the method of Example 1 using the materials in Table 10.

[0192] [Table 10]

[0193] Example 9: Composition of Nabilone 0.025% (w / w) in Castor Oil Formulation A 0.025% w / w nabilone nanoemulsion was prepared using the ingredients in Tables 13-15 based on the method of Example 1, substituting castor oil for sesame oil and polysorbate 80, polyoxyl 35 castor oil, or polyoxyl 40 stearate for TWEEN® 80. The buffering agents sodium phosphate dibasic heptahydrate and sodium phosphate monobasic dihydrate were added to the aqueous phase.

[0194] [Table 11]

[0195] [Table 12]

[0196] [Table 13]

[0197] Example 10: Composition of Nabilone 0.025% (w / w) in a mineral oil formulation A 0.025% w / w nabilone nanoemulsion was prepared using the ingredients in Tables 14-16 based on the method of Example 1, substituting mineral oil for sesame oil and polysorbate 80, polyoxyl 35 castor oil, or polyoxyl 40 stearate for TWEEN® 80. The buffering agents sodium phosphate dibasic heptahydrate and sodium phosphate monobasic dihydrate were added to the aqueous phase.

[0198] [Table 14]

[0199] [Table 15]

[0200] [Table 16]

[0201] Example 11: Mouse test for IOP-lowering effect animal Male C57BL / 6J mice (Jackson Laboratories, Bar Harbor, ME, 8 months of age) were maintained under a 12-hour light / 12-hour dark regime (lights on at 0600) and fed a standard chow diet. All experimental procedures were performed in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the University of North Texas Health Science Center Institutional Animal Care and Use Committee Regulations and Guidelines.

[0202] Ophthalmic preparations Nabilone nanoemulsions (0.01, 0.025, 0.05, and 0.075 wt %) were prepared as described in Examples 1, 3, 5, and 6. Control placebo nanoemulsions (for comparison with 0.01, 0.025, 0.05, and 0.075 wt % Nabilone nanoemulsions) were prepared as described in Examples 2, 4, and 8. Timolol maleate (0.5 wt %) was purchased from Sandoz Inc., Princeton, NJ (a Novartis Division) (manufactured for Sandoz Inc. by Alcon Laboratories Inc., Fort Worth, TX).

[0203] IOP measurement IOP was measured in behaviorally trained, conscious animals using a TONOLAB® rebound tonometer (Colonial Medical Supply, Franconia, NH) according to the procedure described in Wang et al., Invest Ophthalmol Vis. Sci., 2005, 46:4617-4621. The indicated formulation was administered topically to the left eye of each animal. The contralateral eye was not treated.

[0204] Animals were divided into four groups (identified below). Baseline IOP was measured in both eyes at -1 hour before drug treatment, and direct ophthalmoscopy was performed. One 5 μL drop was then topically instilled into the left eye of each mouse. The contralateral (right) eye was untreated.

[0205] IOP in both eyes was measured again at 2, 4, 6, 24, 30, and 48 hours after dosing. In addition to IOP measurements, animals were evaluated by direct ophthalmoscopy for possible ocular and gross systemic adverse effects.

[0206] Group 1: Nabilone (0.01% by weight) Group 2: Nabilone (0.05% by weight) Group 3: Nabilone control (0.05% by weight) Group 4: Timolol (0.5% by weight) The results are shown in Figures 9-13 and show a comparison of the IOP effects of Nabilone compositions (0.01% and 0.05% by weight), a Nabilone control composition (0.05% by weight), and timolol. The compositions were administered once between 9 and 10 AM (time 0), immediately after the baseline IOP measurement. Data are presented as the mean ± SEM (standard error of the mean).

[0207] Formulation efficacy was also tested with 0.025 and 0.075 wt% nabilone nanoemulsions as follows: Group 1: Nabilone (0.025% by weight) Group 2: Nabilone (0.075% by weight) Group 3: Nabilone control (0.075% by weight) Group 4: Timolol (0.5% by weight) The results are shown in Figures 14 and 15. The combined dose responses of 0.01, 0.025, 0.05, and 0.075 wt% Nabilone nanoemulsion are shown in Figures 16, 17, and 18.

[0208] All tested Nabilone compositions (containing 0.01, 0.025, 0.05, and 0.075% by weight of Nabilone API) provided significant intraocular pressure (IOP) reduction. No tachyphylaxis or adverse effects were observed over a 48-hour period.

[0209] Compared with the contralateral untreated eye, eyes treated with the placebo vehicle did not experience a reduction in IOP. Nabilone formulations (0.01, 0.025, 0.05, and 0.075% by weight) produced a dose-dependent response in the treated eye. Nabilone formulations (0.05% and 0.075%) produced IOP reductions comparable to timolol (0.5%) early after dosing. Nabilone formulations (0.05% and 0.075%) maintained IOP reductions up to 24 hours after dosing, whereas the IOP reductions produced by the other formulations were diminished.

[0210] It should be understood that the "Detailed Description" section, in addition to the "Summary" and "Abstract" sections, are intended to be used to interpret the claims. The "Summary" and "Abstract" sections may set forth one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors, and in no way limit the scope of the invention and the appended claims.

[0211] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0212] All publications, patents, and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. 1. A composition suitable for application to the ocular surface, comprising: at least one compound of formula (I); 【Chemistry 1】 (In the formula, R １ and R ２ are taken together to form =O or R １ is —OH, and R ２ is -H) Oil and A surfactant, water, The composition comprises a continuous phase comprising water and a dispersed phase comprising a plurality of nano-sized particles of at least one compound of formula (I), droplets of said oil, or a combination thereof, wherein at least about 60% of said at least one compound of formula (I) is in said dispersed phase.

2. The composition of claim 1 , wherein the composition is in the form of a dispersion, a suspension, an emulsion, or any combination thereof.

3. The compound of formula (I) 【Chemistry 2】 10. The composition of claim 1, selected from the group consisting of:

4. The compound of formula (I) 【Transformation 3】 The composition according to claim 1 or 2,

5. The compound of formula (I) 【Chemistry 4】 The composition according to claim 1 or 2,

6. The compound of formula (I) 【Transformation 5】 3. The composition of claim 1, wherein the compound is a racemic mixture of

7. The compound of formula (I) 【Transformation 6】 The composition according to claim 1 or 2,

8. 8. The composition of any one of claims 1 to 7, wherein at least about 90% by weight of the initial compound in the composition is present after the composition is stored under conditions selected from the group consisting of at least 2 years at about 5°C and at least 1 month at about 25°C.

9. 9. The composition of any one of claims 1 to 8, wherein the oil and water are present in the composition in a ratio (w / w) of about 1:1 to about 1:1000.

10. The composition according to any one of claims 1 to 9, wherein the composition is in the form of a suspension or emulsion.

11. The composition according to any one of claims 1 to 10, wherein the composition is in the form of a microemulsion or nanodispersion.

12. 12. The composition of any one of claims 1 to 11, wherein at least about 90% of the droplets of the oil in the composition have a mass median diameter of less than about 500 nm.

13. 12. The composition of any one of claims 1 to 11, wherein at least about 90% of the droplets of the oil in the composition have a mass median diameter of less than about 350 nm.

14. 12. The composition of any one of claims 1 to 11, wherein at least about 90% of the droplets of the oil in the composition have a mass median diameter of from about 100 nm to about 200 nm.

15. 15. The composition of any one of claims 1 to 14, wherein at least about 90% of the at least one compound of formula (I) in the composition has a mass median diameter of less than about 500 nm.

16. 15. The composition of any one of claims 1 to 14, wherein at least about 90% of the at least one compound of formula (I) in the composition has a mass median diameter of less than about 350 nm.

17. 15. The composition of any one of claims 1 to 14, wherein at least about 90% of the at least one compound of formula (I) in the composition has a mass median diameter of less than about 100 nm to about 200 nm.

18. The composition of any one of claims 1 to 17, wherein the composition comprises from about 0.005% to about 0.5% by weight of the compound of formula (I).

19. 19. The composition of any one of claims 1 to 18, wherein the oil is selected from the group consisting of sesame oil, safflower oil, linseed oil, castor oil, medium chain diglyceride ester oil, medium chain triglyceride ester oil, soybean oil, olive oil, cottonseed oil, peanut oil, mineral oil, and combinations thereof.

20. The composition of any one of claims 1 to 19, wherein the oil is sesame oil, safflower oil, castor oil, or linseed oil.

21. The composition according to any one of claims 1 to 20, wherein the oil is safflower oil.

22. The composition of any one of claims 1 to 19, wherein the oil is a mineral oil.

23. The composition of any one of claims 1 to 20, wherein the oil is castor oil.

24. The composition of any one of claims 1 to 23, wherein the composition comprises from about 1.5% to about 25.0% by weight of oil.

25. 25. The composition of any one of claims 1 to 24, wherein the surfactant is selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (TWEEN® 80), polyoxyethylene (20) sorbitan monolaurate (TWEEN® 20), 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane (tyloxapol), sorbitan monooleate (Span® 80), polyoxyethylated 12-hydroxystearic acid (KOLLIPHER™ HS 15), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polysorbate 80, and combinations thereof.

26. 26. The composition of any one of claims 1 to 25, wherein the surfactant is polyoxyethylene (20) sorbitan monooleate (TWEEN® 80).

27. The composition of any one of claims 1 to 26, wherein the composition comprises from about 0.5% to about 5% by weight of a surfactant.

28. The composition of any one of claims 1 to 27, further comprising a co-solvent.

29. 29. The composition of claim 28, wherein the co-solvent is glycerin.

30. 30. The composition of claim 28 or 29, wherein the composition comprises from about 1% to about 10% by weight of a co-solvent.

31. The composition of any one of claims 1 to 30, further comprising at least one pH adjuster.

32. 32. The composition of claim 31, wherein the at least one pH adjuster is sodium hydroxide or hydrochloric acid.

33. 32. The composition of claim 31, wherein the at least one pH adjuster is sodium hydroxide and hydrochloric acid.

34. The composition of any one of claims 1 to 33, wherein the composition has a pH of about 6.5 to about 7.

5.

35. The composition of any one of claims 1 to 34, further comprising a stabilizer.

36. 36. The composition of claim 35, wherein the stabilizer is an antioxidant.

37. 37. The composition of claim 36, wherein the antioxidant is selected from the group consisting of α-tocopherol acetate, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), monothioglycerol, bisulfite, and combinations thereof.

38. 38. The composition of claim 36 or 37, wherein the antioxidant is selected from the group consisting of BHT, BHA, and combinations thereof.

39. 39. The composition of any one of claims 1 to 38, wherein the composition has an osmolality of about 250 mOsm / L to about 330 mOsm / L.

40. 40. The composition of any one of claims 1 to 39, wherein the composition is adapted to be permeable through the cornea of ​​a patient and to provide a therapeutically effective concentration of the at least one compound of formula (I).

41. The composition comprises: about 0.005% to about 0.5% by weight of the compound of formula (I); about 5% to about 25% by weight of an oil selected from the group consisting of sesame oil, castor oil, mineral oil, and combinations thereof; about 1.5% to about 2.5% by weight of polyoxyethylene (20) sorbitan monooleate (TWEEN® 80); about 0.01% to about 1.25% by weight of BHT; about 0.01% to about 1.25% by weight of BHA; About 2.5% by weight of glycerin; and water. The composition of any one of claims 1 to 40.

42. 42. A method of treating or preventing an ocular condition in a subject identified as in need of such treatment, comprising administering to at least one eye of the subject in need thereof a therapeutically effective amount of the composition of any one of claims 1 to 41.

43. 43. The method of claim 42, wherein the composition is administered once daily.

44. 43. The method of claim 42, wherein the composition is administered twice daily.

45. The method of any one of claims 42 to 44, wherein the composition is administered topically.

46. 46. ​​The method of any one of claims 42 to 45, wherein the composition is administered topically as drops, a liquid wash, a gel, an ointment, a spray, or a combination thereof.

47. 47. The method of any one of claims 42 to 46, wherein the composition is applied to the ocular surface in one or more drops.

48. 48. The method of any one of claims 42 to 47, wherein the ocular condition is selected from the group consisting of glaucoma, age-related macular degeneration (AMD), ophthalmitis, and conjunctivitis.

49. 49. The method of any one of claims 42 to 48, wherein the eye condition is glaucoma.

50. 50. The method of any one of claims 42-49, wherein the method reduces intraocular pressure (IOP) for a period of at least about 1 hour after administering the composition to the eye.

51. 51. The method of any one of claims 42-50, wherein the method reduces intraocular pressure (IOP) for a period of at least about 4 hours after administering the composition to the eye.

52. A method for preparing a composition according to any one of claims 1 to 41, comprising the steps of: combining said compound with said oil to form an oil phase; combining the surfactant with water to form an aqueous phase; combining the oil phase and the aqueous phase to form a premix; homogenizing the premix to form a homogenized premix; microfluidizing said homogenized premix to provide said composition.

53. 53. The method of claim 52, wherein the oil phase is prepared at a temperature of about 50°C to about 100°C.

54. 54. The method of claim 52 or 53, wherein the aqueous phase is prepared at a temperature of from about 50°C to about 100°C.

55. 55. The method of any one of claims 52 to 54, wherein the premix is ​​homogenized at a speed of about 5,000 rpm to about 15,000 rpm.

56. 56. The method of any one of claims 52 to 55, wherein the premix is ​​homogenized for about 2 minutes to about 20 minutes.

57. 57. The method of any one of claims 52 to 56, wherein the homogenized premix is ​​microfluidized at a temperature of about 15°C to about 50°C and subsequently cooled to a temperature of about 15°C to about 30°C using cold water circulating in the jacket of a mixing vessel.

58. 58. The method of any one of claims 52-57, wherein the premix is ​​microfluidized at a pressure of about 69 MPa to about 138 MPa (about 10,000 PSI to about 20,000 PSI).

59. 59. The method of any one of claims 52-58, further comprising adjusting the pH of the homogenized premix to about 6.5 to about 7.

5.

60. 10. The composition of claim 1, wherein the droplets of the oil comprise at least one compound of formula (I) dissolved in the oil.

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