Pharmaceutical compositions comprising cannabinolone for treatment of ophthalmic conditions

Abstract

The present disclosure provides a composition comprising at least one compound of formula (I), which composition is suitable for application to an ocular surface. The present disclosure also provides a method of preparing a composition comprising at least one compound of formula (I). The present disclosure also provides methods of providing intraocular pressure reduction, neuroprotection, and / or treatment of ophthalmic disorders such as glaucoma using compositions comprising at least one compound of Formula (I).

Description

Technical Field

[0001] The present disclosure provides a composition comprising at least one compound of formula (I) suitable for application to an ocular surface. The present disclosure also provides a method for preparing a composition comprising at least one compound of formula (I). The present disclosure also provides a method for using a composition comprising at least one compound of formula (I) to provide intraocular pressure reduction, neuroprotection, and / or treatment of ophthalmic conditions such as glaucoma. Background Art

[0002] The prevalence of neuropathological ophthalmic conditions is an important public health issue. For example, glaucoma is one of the leading causes of blindness worldwide. In the United States alone, it is estimated that more than 3 million people suffer from the disease. Glaucoma refers to a group of eye conditions that damage the retina and optic nerve of the eye. Abnormally high intraocular pressure (IOP) causes optic nerve damage, 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 the treatment of glaucoma and other ophthalmic conditions. For example, isolated compounds from the cannabis plant, such as tetrahydrocannabinol (THC), and other modulators of the cannabinoid receptors CB1 and CB2, have been shown to lower IOP and have neuroprotective and anti-inflammatory properties in the eye and are therefore useful for the treatment of a variety of ophthalmic diseases (J. Pharm. Sci., 2012, 101(2):616-626; Ophthalmic. Res., 1992, 24:142-149; International J. Pharm., 2010, 393:238-243; U.S. Patent Publication No. 2016 / 0184259; U.S. Patent No. 9,265,724; U.S. Patent No. 11,786,463; and Br. J. Ophthalmol., 2004, 88:708-713). However, these and other lipophilic drugs present formulation challenges to scientists because the low water solubility of the drugs hinders the preparation of eye drop solutions with sufficient drug concentration to achieve 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 concentration to the eye. Therefore, low-viscosity polar and semi-polar formulations are generally preferred as eye drops.

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

[0005] Therefore, there is a continuing need for new or improved ophthalmic drug delivery systems that are stable, well tolerated, have enhanced activity, and possess other advantageous characteristics. Summary of the Invention

[0006] The present invention relates to a composition suitable for application to the surface of the eye, the composition comprising:

[0007] At least one compound of formula (I)

[0008]

[0009] wherein R1 and R2 together form =0, or R1 is -OH and R2 is -H;

[0010] Oil;

[0011] surfactants; and

[0012] water,

[0013] The composition comprises a continuous phase comprising water; and a dispersed phase comprising a plurality of nanosized particles, oil droplets, or a combination thereof of at least one compound of Formula (I), and wherein at least about 60% of the at least one compound of Formula (I) is in the dispersed phase.

[0014] In some embodiments, the composition is a dispersion; a suspension; an emulsion; or any combination thereof.

[0015] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0016]

[0017]

[0018] In some embodiments, the compound of formula (I) is

[0019]

[0020] In some embodiments, the compound of formula (I) is

[0021]

[0022] In some embodiments, the compound of formula (I) is

[0023] A racemic mixture of.

[0024] In some embodiments, the compound of formula (I) is

[0025]

[0026] In some embodiments, at least about 90% by weight of the compound is present in the composition after storage under conditions selected from the group consisting of: at least two years at about 5°C; and at least one month at about 25°C.

[0027] 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.

[0028] In some embodiments, the composition is a suspension or emulsion.

[0029] In some embodiments, the composition is a microemulsion or nanodispersion.

[0030] 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, such as less than 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 350 nm.

[0031] In some embodiments, at least about 90% of the oil droplets in the composition have a mass median diameter between about 100 nm and about 200 nm.

[0032] 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.

[0033] 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.

[0034] In some embodiments, at least about 90% of the at least one compound of Formula (I) in the composition has a mass median diameter between about 100 nm and about 200 nm.

[0035] In some embodiments, the composition comprises from about 0.005% to about 0.5% by weight of the compound of Formula (I).

[0036] In some embodiments, the oil is selected from the group consisting of sesame oil, safflower oil, linseed oil, castor oil, medium chain diglyceride oils, medium chain triglyceride oils, soybean oil, olive oil, cottonseed oil, peanut oil, mineral oil, and combinations thereof.

[0037] In some embodiments, the oil is sesame oil, safflower oil, castor oil, or linseed oil.

[0038] In some embodiments, the oil is safflower oil.

[0039] In some embodiments, the oil is mineral oil.

[0040] In some embodiments, the oil is castor oil.

[0041] In some embodiments, the composition comprises from about 1.5% to about 25.0% oil by weight.

[0042] In some embodiments, the surfactant is selected from the group consisting of: polyoxyethylene (20) sorbitan monooleate ( 80); Polyoxyethylene (20) sorbitan monolaurate ( 20); 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and ethylene oxide (tyloxapol); sorbitan monooleate (Span 80); polyoxyethylated 12-hydroxystearic acid ( HS15); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; polyoxyl 40 stearate; polysorbate 80; and combinations thereof.

[0043] In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate ( 80).

[0044] In some embodiments, the composition comprises from about 0.5% to about 5% by weight of a surfactant.

[0045] In some embodiments, the composition further comprises a co-solvent.

[0046] In some embodiments, the composition further comprises a co-solvent, wherein the co-solvent is glycerol.

[0047] In some embodiments, the composition comprises from about 1 wt % to about 10 wt % of a co-solvent.

[0048] In some embodiments, the composition further comprises at least one pH adjuster.

[0049] 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.

[0050] 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.

[0051] In some embodiments, the composition has a pH of about 6.5 to about 7.5.

[0052] In some embodiments, the composition further comprises a stabilizer.

[0053] In some embodiments, the composition further comprises a stabilizer, wherein the stabilizer is an antioxidant.

[0054] In some embodiments, the composition further comprises a stabilizer, wherein the stabilizer is an antioxidant selected from the group consisting of alpha-tocopheryl acetate, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), monothioglycerol, bisulfite, and combinations thereof.

[0055] In some embodiments, the composition further comprises a stabilizer, wherein the stabilizer is an antioxidant, and wherein the antioxidant is selected from the group consisting of BHT, BHA, and combinations thereof.

[0056] In some embodiments, the composition has an osmolarity of about 250 mOsm / L to about 330 mOsm / L.

[0057] In some embodiments, the composition is adapted to penetrate the cornea of ​​a patient to provide a therapeutically effective concentration of at least one compound of Formula (I).

[0058] In some embodiments, the composition comprises

[0059] from about 0.005% to about 0.5% by weight of a compound of formula (I);

[0060] 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;

[0061] About 1.5% to about 2.5% by weight of polyoxyethylene (20) sorbitan monooleate ( 80);

[0062] from about 0.01 wt % to about 1.25 wt % BHT;

[0063] from about 0.01 wt % to about 1.25 wt % BHA;

[0064] about 2.5% by weight glycerol; and

[0065] water.

[0066] Also disclosed herein is a method of treating or preventing an ophthalmic condition in a subject identified as in need of such treatment, the method comprising administering to at least one eye of the subject in need thereof a therapeutically effective amount of a composition disclosed herein.

[0067] In some embodiments, the composition is administered once daily.

[0068] In some embodiments, the composition is administered twice daily.

[0069] In some embodiments, the composition is administered topically.

[0070] In some embodiments, the composition is administered topically as liquid drops, liquid lotion, gel, ointment, spray, or a combination thereof.

[0071] In some embodiments, the composition is applied to the ocular surface as one or more drops.

[0072] In some embodiments, the ophthalmic condition is selected from the group consisting of glaucoma, age-related macular degeneration (AMD), ophthalmitis, and conjunctivitis.

[0073] In some embodiments, the ophthalmic condition is glaucoma.

[0074] 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.

[0075] 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.

[0076] The present invention also discloses a method for preparing the composition disclosed herein, comprising:

[0077] mixing the compound and oil to form an oil phase;

[0078] mixing the surfactant and water to form an aqueous phase;

[0079] combining the oil phase and the water phase to form a premix;

[0080] homogenizing the premix to form a homogenized premix; and

[0081] The homogenized premix is ​​microfluidized to provide a composition.

[0082] In some embodiments, the oil phase is prepared at a temperature of about 50°C to about 100°C.

[0083] In some embodiments, the aqueous phase is prepared at a temperature of about 50°C to about 100°C.

[0084] In some embodiments, the premix is ​​homogenized at a speed of about 5000 rpm to about 15000 rpm.

[0085] In some embodiments, the premix is ​​homogenized for about 2 minutes to about 20 minutes.

[0086] In some embodiments, the homogenized premix is ​​microfluidized at a temperature of about 15°C to about 50°C; and subsequently cooled at a temperature of about 15°C to about 30°C using cooling water circulating in the jacket of the mixing vessel.

[0087] In some embodiments, the premix is ​​microfluidized at a pressure of about 10,000 PSI to about 20,000 PSI.

[0088] In some embodiments, the preparation method further comprises adjusting the pH of the homogenized premix to about 6.5 to about 7.5.

[0089] In some embodiments, the oil droplets comprise at least one compound of Formula (I) dissolved in the oil. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The accompanying drawings, which are incorporated herein and constitute a part of the specification, illustrate the present invention and, together with the description, further serve to explain the principles of the invention and enable those skilled in the relevant art to make and use the invention.

[0091] The present invention will now be described with reference to the accompanying drawings, in which like reference numbers indicate identical or functionally similar elements.

[0092] Figure 1 is a graph comparing the solubility of nabilone in oils ("supernatant") suitable for topical ophthalmic formulations. "Bulk Form I" is commercially available nabilone (Purysis LLC, Athens, GA). "NF Crystals" is "Bulk Form I" that has been nanosized to a particle size of less than 500 median mass diameter (MMD).

[0093] Figure 2 is shown in Figure 1. Graph of 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 with ELISA® Microfluidics, Westwood, MA.

[0094] Figure 3 is a graph showing the size distribution by intensity of a sample described in Example 1 of nabilone nanoemulsion (0.01 wt %) collected at a specific time period (cycle 3) during microfluidization.

[0095] Figure 4 is a graph showing the size distribution by intensity for a sample described in Example 1 of nabilone nanoemulsion (0.01 wt %) collected at a specific time period (cycle 5) during microfluidization.

[0096] Figure 5is a graph showing the size distribution by time period for samples described in Example 1 of nabilone nanoemulsion (0.01 wt %) collected at various time periods (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. And a D(99) value means that 99% of the particles in the composition are smaller than the indicated size.

[0097] Figure 6 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 approximately 12 minute increments (cycles 1-5) during microfluidization.

[0098] Figure 7 is a graph showing the size distribution by intensity for a sample described in Example 3 of nabilone nanoemulsion (0.05 wt %) collected at a specific time period (cycle 3) during microfluidization.

[0099] Figure 8 is a graph showing the size distribution by intensity for a sample described in Example 3 of nabilone nanoemulsion (0.05 wt %) collected at a specific time period (cycle 5) during microfluidization.

[0100] Figure 9 is a graph showing the size distribution by time period of samples described in Example 3 of nabilone nanoemulsion (0.05 wt %) collected at various time periods (cycles 1-5) during microfluidization.

[0101] Figure 10 is a graph comparing intraocular pressure (IOP) measured in the eyes of untreated control mice and in the eyes of mice treated with the nabilone composition described in Example 1 (0.01 wt %) for 48 hours after dosing.

[0102] Figure 11 is a graph comparing intraocular pressure (IOP) measured in the eyes of untreated control mice and in the eyes of mice treated with the nabilone composition described in Example 3 (0.05 wt %) for 48 hours after dosing.

[0103] Figure 12 is a graph comparing intraocular pressure (IOP) measured in eyes of untreated control mice and in eyes of mice treated with a timolol composition (0.5 wt %) for 48 hours after administration.

[0104] Figure 13is a graph comparing intraocular pressure (IOP) measured in the eyes of untreated control mice and in the eyes of mice treated with the control composition described in Example 4 (nabilone nanoemulsion (0.05 wt %) in vehicle) for 48 hours after administration.

[0105] Figure 14 is a graph comparing intraocular pressure (IOP) measured in untreated mouse eyes and in mouse eyes treated with nabilone nanoemulsion (0.025 wt %) for 48 hours after dosing.

[0106] Figure 15 is a graph comparing intraocular pressure (IOP) in untreated mouse eyes and in mouse eyes treated with nabilone nanoemulsion (0.075 wt %) for 48 hours after dosing.

[0107] Figure 16 is a composite graph showing the intraocular pressure in untreated mouse eyes ("naive group for nabilone untreated" 0.01%, 0.025%, 0.05% and 0.075% (by weight)) and in mouse eyes treated with nabilone nanoemulsions (0.01%, 0.025%, 0.05% and 0.075% (by weight)), with corresponding placebo ("naive group for timolol untreated" 0.5% by weight) and with timolol (0.5% by weight).

[0108] Figure 17 is a graph showing the dose response of nabilone nanoemulsions ("Nab" 0.01%, 0.025%, 0.05% and 0.075% by weight) compared to placebo vehicle ("Vehicle") and timolol (0.5% by weight) expressed as the percent reduction in intraocular pressure (IOP) 6 hours after dosing.

[0109] Figure 18 is a graph showing the dose response of nabilone nanoemulsions ("Nab" 0.01%, 0.025%, 0.05% and 0.075% by weight) compared to placebo vehicle ("Vehicle") and timolol (0.5% by weight) expressed as the percent reduction in intraocular pressure (IOP) 24 hours after dosing. DETAILED DESCRIPTION

[0110] As used above and throughout the specification, the following terms shall be understood to have the following meanings unless otherwise indicated.

[0111] Unless otherwise indicated, the terms "a," "an," "the," and similar references used in the context of describing particular aspects of the application (especially in the context of the claims) may be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein.

[0112] It should be understood that wherever herein any aspect described with the language "comprising," other similar aspects described with the language "consisting of" or "consisting essentially of" are also provided.

[0113] The term "about" encompasses the range of experimental error that occurs in any measurement. The term "about" used in conjunction with numerical values ​​throughout the specification and claims indicates an accuracy interval familiar and acceptable to those skilled in the art. Generally speaking, this accuracy interval is ±10%. Thus, "about ten" means 9 to 11. Unless otherwise expressly indicated, all numbers in this specification indicating amounts of materials, ratios, physical properties of materials, and / or uses should be understood to be modified by the word "about."

[0114] As used herein, "weight percent" or "wt%" or "wt%" refers to the weight percent of an ingredient compared to the total weight of the composition. For example, the weight percent of nabilone refers to the weight percent of active nabilone in the composition.

[0115] As used herein, the phrase "mass median diameter" refers to the particle size at which 50% of the mass of a particle (eg, oil droplets, solid particles) is contained in smaller particles and 50% is contained in larger particles. The phrase mass median diameter may be abbreviated as MMD.

[0116] Nabilone is a synthetic cannabinoid that is marketed under the trade name Nabilone is sold as a polymorphic crystalline powder in capsules for oral administration. Nabilone is a 1:1 racemic mixture of the optical isomers 6aR,10aR ((6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octyl)-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-octyl)-6,6a,7,8,10,10a-hexahydro-9H-benzo[c]chromen-9-one).

[0117] In the summary of the basis for approval of NDA 18-677, approved on December 26, 1985, the The study included 17 patients. During the study, 5% of the 17 patients reported experiencing adverse events (78.9%), of which five serious adverse events were reported. All but one of the 5% of patients experienced adverse events after a single dose. Notable adverse events were significant drops in blood pressure (hypotension) experienced by patients, with one patient experiencing nausea and syncope after a single dose. Due to the prevalence of adverse events, the study was discontinued.

[0118] Nabilone is difficult to dissolve in most solvents, making the preparation of liquid compositions containing it very challenging. Table 1 includes solvents in which nabilone is readily soluble. These solvents are not suitable for human pharmaceutical formulations. Based on the USP solubility classification, nabilone is insoluble in water at all pH values: readily soluble at >100 mg / mL; soluble at 33 mg / mL to 100 mg / mL; slightly soluble at 10 mg / mL to 33 mg / mL; slightly soluble at 1 mg / mL to 10 mg / mL; very slightly soluble at 0.1 mg / mL to 1 mg / mL; and practically insoluble at <0.1 mg / mL.

[0119] Table 1. Solubility of Nabilone in Common Solvents

[0120]

[0121]

[0122] Even at elevated temperatures, dissolving nabilone in pharmaceutically acceptable oils is challenging. As shown in Table 2, even after heating to 90°C, only a very small amount of nabilone dissolved in refined sesame oil, with the majority of nabilone settling to the bottom.

[0123] Table 2. Solubility of Nabilone in Sesame Oil

[0124]

[0125] The solubility of nabilone in other oils suitable for topical ophthalmic formulations is summarized in Figure 1 , where “bulk Form I” is a typical batch of nabilone (Purisys LLC, Athens, GA) and “NF crystals” are nanosized from bulk Form I.

[0126] As described herein, the disclosed compositions are suitable for topical administration of at least one compound of formula (I) to the surface of the eye. 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 sites 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 persistent intraocular pressure (IOP) lowering effects.

[0127] The present invention provides a composition suitable for application to the surface of the eye, the composition comprising:

[0128] At least one compound of formula (I)

[0129]

[0130] wherein R1 and R2 together form =0, or R1 is -OH and R2 is -H;

[0131] Oil;

[0132] surfactants; and

[0133] water,

[0134] The composition comprises a continuous phase comprising water; and a dispersed phase comprising a plurality of nanosized particles, oil droplets, or a combination thereof of at least one compound of Formula (I), and wherein at least about 60% of the at least one compound of Formula (I) is in the dispersed phase.

[0135] The present invention also provides a composition suitable for application to the surface of the eye, the composition comprising:

[0136] At least one compound of formula (I)

[0137]

[0138] wherein R1 and R2 together form =0, or R1 is -OH and R2 is -H;

[0139] Oil;

[0140] surfactants;

[0141] Optionally, a co-solvent;

[0142] Optionally, a pH adjuster;

[0143] Optionally, a buffer;

[0144] Optionally, a stabilizer; and

[0145] water,

[0146] The composition comprises a continuous phase comprising water; and a dispersed phase comprising a plurality of nanosized particles, oil droplets, or a combination thereof of at least one compound of Formula (I), and wherein at least about 60% of the at least one compound of Formula (I) is in the dispersed phase.

[0147] Compounds of formula (I)

[0148] In some embodiments, in at least one compound of Formula (I), R1 and R2 are taken together to form =0.

[0149] In some embodiments, in at least one compound of Formula (I), R1 is -OH and R2 is -H.

[0150] In some embodiments, at least one compound of Formula (I) is selected from the group consisting of:

[0151] and their combinations.

[0152] In some embodiments, at least one compound of Formula (I) is:

[0153] In some embodiments, at least one compound of Formula (I) is:

[0154] In some embodiments, at least one compound of formula (I) is nabilone. In some embodiments, the compound of formula (I) is

[0155] A racemic mixture of.

[0156] The racemic mixture of Compound 1 and Compound 2 is commonly referred to as nabilone.

[0157] In some embodiments, the compound is a metabolite of nabilone. As shown in Scheme 1 below, metabolites of nabilone can exist in four isomeric forms.

[0158] Solution 1.

[0159]

[0160] (6aR,9S,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[3-(2-methyloctan-2-yl)-1,2-dimethyl-2 ...6a,7,8,9,10

[0161] [c]chromene-1,9-diol

[0162]

[0163] (6aR,9R,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[3-(2-methyloctan-2-yl)-1,2-dimethyl-2 ...6a,7,8,9,10

[0164] [c]chromene-1,9-diol

[0165]

[0166] (6aS,9S,10aS)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[3-(2-methyloctan-2-yl)-1,2-dimethyl-2-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[3-(2-methyloc

[0167] [c]chromene-1,9-diol

[0168]

[0169] (6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6,6a,7,8,10,10a-hexahydro-9H-

[0170] Benzo[c]chromen-9-one

[0171] In some embodiments, at least one compound of Formula (I) is:

[0172]

[0173] Compounds 3 and 5 are metabolites of nabilone.

[0174] 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, from about 0.01% to about 0.15% by weight, % to about 0.1 wt %, about 0.01 wt % to about 0.05 wt %, about 0.01 wt % to about 0.015 wt %, about 0.015 wt % to about 0.5 wt %, about 0.015 wt % to about 0.1 wt %, about 0.015 wt % to about 0.05 wt %, about 0.05 wt % to about 0.5 wt %, about 0.05 wt % to about 0.1 wt %, or about 0.1 wt % to about 0.5 wt %.

[0175] 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.

[0176] In some embodiments, at least one compound of Formula (I) is present in the composition at about 0.005% by weight.

[0177] In some embodiments, at least one compound of Formula (I) is present in the composition at about 0.015% by weight.

[0178] In some embodiments, at least one compound of Formula (I) is present in the composition at about 0.05% by weight.

[0179] In some embodiments, at least one compound of Formula (I) is present in the composition at about 0.075% by weight.

[0180] In some embodiments, at least one compound of Formula (I) is present in the composition at about 0.5% by weight.

[0181] 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.

[0182] In some embodiments, the at least one compound of Formula (I) in the dispersed phase is present as a plurality of nanometer-sized particles or dissolved in oil droplets.

[0183] In some embodiments, the at least one compound of Formula (I) in the dispersed phase exists as a plurality of nanometer-sized particles and is dissolved in the oil droplets.

[0184] In some embodiments, at least about 50%, about 60%, about 70%, about 80%, or about 90% of at least one compound of Formula (I) in the composition has a mass median diameter of less than about 500 nm.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] Oil

[0191] As used herein, the term "oil" refers to any non-polar chemical substance that is in liquid form at ambient temperature and atmospheric pressure and that is both hydrophobic and lipophilic.

[0192] In some embodiments, the oil in the composition is of animal or plant origin. In some embodiments, the oil in the composition is of synthetic origin.

[0193] In some embodiments, the oil in the composition is a vegetable oil.

[0194] In some embodiments, the oil in the composition is sesame oil, safflower oil, linseed oil, castor oil, medium chain diglyceride oil, medium chain triglyceride oil, soybean oil, olive oil, cottonseed oil, peanut oil, mineral oil, or a combination thereof.

[0195] In some embodiments, the oil in the composition is a pharmaceutically acceptable oil.

[0196] In some embodiments, the oil in the composition is sesame oil, safflower oil, castor oil, or a combination thereof.

[0197] In some embodiments, the oil in the composition is sesame oil.

[0198] In some embodiments, the oil in the composition is safflower oil.

[0199] In some embodiments, the oil in the composition is mineral oil.

[0200] In some embodiments, the oil in the composition is castor oil.

[0201] In some embodiments, the oil in the composition is MIGLYOL 812N.

[0202] In some embodiments, the oil is present in the composition at about 1.5% to about 25% by weight.

[0203] In some embodiments, the amount of oil present in the composition is from about 1.5% to about 25% by weight, from about 1.5% to about 20% by weight, from about 1.5% to about 15% by weight, from about 1.5% to about 10% by weight, from about 1.5% to about 5% by weight, from about 5% to about 25% by weight, from about 5% to about 20% by weight, from about 5% to about 15% by weight, from about 5% to about 10% by weight, from about 10% to about 25% by weight, from about 10% to about 20% by weight, from about 15% to about 25% by weight, from about 15% to about 20% by weight, or from about 20% to about 25% by weight.

[0204] 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.

[0205] In some embodiments, the oil is in the dispersed phase of the composition and the water is in the continuous phase of the composition. In some embodiments, the oil in the dispersed phase exists as a plurality of nanometer-sized particles or oil droplets.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] surfactants

[0213] In some embodiments, the surfactant in the composition is a nonionic surfactant, anionic surfactant, cationic surfactant, amphoteric surfactant, or zwitterionic surfactant.

[0214] In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate ( 80); Polyoxyethylene (20) sorbitan monolaurate ( 20); 4-(1,1,3,3-tetramethylbutyl)phenol, polymer with formaldehyde and ethylene oxide (tyloxapol); sorbitan monooleate ( 80); Polyoxyethylated 12-hydroxystearic acid ( HS15); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; polyoxyl 40 stearate; polysorbate 80; or a combination thereof.

[0215] In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate ( 80) or tyloxapol.

[0216] In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate ( 80).

[0217] In some embodiments, the surfactant is polyoxyl 40 stearate, polysorbate 80, or polyoxyl 35 castor oil.

[0218] In some embodiments, the amount of surfactant present in the composition is from about 0.5% to about 5% by weight, from about 0.5% to about 2.5% by weight, from about 0.5% to about 1.5% by weight, from about 0.5% to about 1% by weight, from about 1% to about 5% by weight, from about 1% to about 2.5% by weight, from about 1% to about 2% by weight, from about 1.5% to about 5% by weight, from about 1.5% to about 2% by weight, or from about 2% to about 5% by weight.

[0219] 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.

[0220] water

[0221] In some embodiments, oil is in the dispersed phase and water is in the continuous phase.

[0222] In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:5 to about 1:1000 or about 1:20 to about 1:100. In some embodiments, the ratio of oil to water (w / w) in the composition is about 1:10, about 1:30, about 1:50, about 1:70, or about 1:100.

[0223] In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:1 to about 1:1000. In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:10 to about 1:1000. In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:1 to about 1:100. In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:1 to about 1:100. In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:1 to about 1:50. In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:4 to about 1:100. In some embodiments, the ratio of oil to water (w / w) in the composition is in the range of about 1:10 to about 1:20.

[0224] dispersion

[0225] In some embodiments, the composition is in the form of a dispersion. A dispersion is a system in which one substance is dispersed in another substance. In some embodiments, a dispersion is a heterogeneous system in which the dispersed phase (usually a certain type of particles or discontinuous liquid, such as 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.

[0226] suspension

[0227] In some embodiments, the composition is in the form of a suspension.

[0228] As used herein, the term "suspension" refers to a dispersion of a solid material (dispersed phase) in a liquid (continuous phase) without reference to the particle size of the solid material. However, the particle size of the solid material can affect the physicochemical behavior of the suspension. Therefore, there is a distinction between colloidal dispersions and coarse dispersions, wherein colloidal dispersions have a particle size range of up to about 1 micron, while coarse dispersions have larger particles. Pharmaceutical suspensions fall on the borderline between colloidal dispersions and coarse dispersions, wherein the solid particles are typically in the range of 0.1 micron to 10 microns. Suspensions are not optically transparent, and they will appear turbid unless the size of the particles falls within the colloid range.

[0229] Lotion

[0230] In some embodiments, the composition is in the form of an emulsion.

[0231] 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 typically the dispersed phase, and the other liquid phase is the continuous phase, wherein the dispersed phase is dispersed in the continuous phase as a plurality of droplets. Based on the size of the droplets, the emulsion can be in the form of a colloidal dispersion, a microemulsion, or a nanoemulsion. If the continuous phase is an aqueous solution, the emulsion is an oil-in-water (o / w) emulsion, or if the continuous phase is an oil, the emulsion is a water-in-oil (w / o) type. Other examples of emulsions include oil-in-water-in-oil (o / w / o) emulsions, which comprise oil droplets contained in aqueous droplets dispersed in a continuous oil phase.

[0232] In some embodiments, the composition is in the form of a microemulsion. A microemulsion has a droplet size in microns (10 -6 ).

[0233] In some embodiments, the composition is in the form of a nanoemulsion. A nanoemulsion has a droplet size in nanometers (10 -9 ).

[0234] 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.

[0235] In some embodiments, between about 60% and about 95% of the compound of at least one formula (I) is in the dispersed phase. In some embodiments, the percentage of at least one compound of formula (I) in the dispersed phase is between about 60% and about 95%, about 60% and about 90%, about 60% and about 80%, about 60% and about 70%, about 70% and about 95%, about 70% and about 90%, about 70% and about 80%, about 80% and about 95%, about 80% and about 90%, or about 90% and about 95%.

[0236] Other components

[0237] In some embodiments, the composition may further comprise at least one co-solvent. In some embodiments, the at least one co-solvent is glycerol, propylene glycol, polyethylene glycol, ethanol, a propylene glycol ester, a polyethylene glycol ester, or a combination thereof.

[0238] In some embodiments, the co-solvent is glycerol.

[0239] In some embodiments, the at least one co-solvent is present in the composition in an amount from about 1% to about 10% by weight, from about 1% to about 5% by weight, from about 1% to about 2.5% by weight, from about 1% to about 2% by weight, from about 1% to about 1.5% by weight, from about 1.5% to about 10% by weight, from about 1.5% to about 5% by weight, from about 1.5% to about 2.5% by weight, from about 1.5% to about 2% by weight, from about 2% to about 10% by weight, from about 2% to about 5% by weight, from about 2% to about 2.5% by weight, or from about 2.5% to about 5% by weight.

[0240] 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%.

[0241] In some embodiments, glycerin is present in the composition at about 2.5% by weight.

[0242] In some embodiments, the co-solvent is a humectant (ie, retains moisture).

[0243] In some embodiments, the composition further comprises at least one stabilizer. In some embodiments, the stabilizer is an antioxidant.

[0244] In some embodiments, the composition may further comprise at least one antioxidant. As used herein, the term "antioxidant" refers to an agent that inhibits oxidation and is therefore used to prevent the formulation from oxidative deterioration due to the presence of oxygen free radicals or free metals in the composition. In some embodiments, at least one antioxidant is alpha-tocopheryl acetate, butylated hydroxyanisole (BHA), vitamin E, fumaric acid, ascorbyl palmitate, butylated hydroxytoluene (BHT), monothioglycerol, propyl gallate, sulfur dioxide, sodium thiosulfate, sodium sulfite, ascorbic acid, isoascorbic acid, bisulfite, potassium metabisulfite, malic acid, sodium metabisulfite, sodium formaldehyde sulfoxylate, or a combination thereof.

[0245] In some embodiments, the at least one antioxidant used in the composition is BHA, BHT, or a combination thereof.

[0246] In some embodiments, the concentration of the antioxidant in the composition ranges from about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.5%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, or about 0.1% to about 0.5%.

[0247] In some embodiments, the concentration of the antioxidant in the composition is about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, 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.

[0248] In some embodiments, the composition further comprises at least one pH adjusting agent. In some embodiments, the at least one pH adjusting agent is lactic acid, citric acid, phosphoric acid, acetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, or a combination thereof.

[0249] In some embodiments, the pH adjusting agent is sodium hydroxide or hydrochloric acid. In some embodiments, the pH adjusting agent is sodium hydroxide. In some embodiments, the pH adjusting agent is hydrochloric acid. In some embodiments, the pH adjusting agent is sodium hydroxide and hydrochloric acid.

[0250] In some embodiments, the pH adjusting agent is present in an amount sufficient to provide a pH level of about neutral. 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.

[0251] In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the buffering agent is sodium phosphate dibasic heptahydrate (NaH2PO4·7H2O), sodium phosphate monobasic dihydrate (NaH2PO4·2H2O), or a combination thereof. In some embodiments, the buffering agent is sodium phosphate dibasic heptahydrate. In some embodiments, the buffering agent is sodium phosphate monobasic dihydrate. In some embodiments, the buffering agent is a combination of sodium phosphate dibasic heptahydrate and sodium phosphate monobasic dihydrate.

[0252] 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.

[0253] It is believed that the specific combination of components and process steps described herein imparts unexpected physical, chemical and / or microbiological stability to the compositions of the present invention.

[0254] "Physically stable" compositions are those in which there is no visible phase separation between the oil and water phase components, e.g., under appropriate storage conditions, e.g., for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.

[0255] In some embodiments, the composition remains stable after storage for at least two years at a temperature of about 5°C, such that no visible phase separation between the oil phase component and the water phase component exists 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 no visible phase separation between the oil phase component and the water phase component exists after such storage.

[0256] A "chemically stable" composition is one in which the concentration of the active pharmaceutical ingredient (eg, at least one compound of Formula (I)) does not vary by more than about 20% over at least about two weeks or about one month under appropriate storage conditions.

[0257] In some embodiments, under appropriate storage conditions, the concentration of at least one compound of Formula (I) does not vary by more than about 5%, about 10%, about 15%, or about 20% over at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.

[0258] In some embodiments, at least about 90% by weight of the original compound of formula (I) in the composition remains in undegraded form after storage for at least two years at a temperature of about 5° C. In some embodiments, at least about 90% by weight of the original compound of formula (I) in the composition remains in undegraded form after storage for at least two months at a temperature of about 25° C. In some embodiments, at least about 90% by weight of the original compound of formula (I) in the composition remains in undegraded form after storage for at least one month under controlled temperature conditions of about 20° C. to about 25° C.

[0259] In some embodiments, at least about 95% by weight of the original compound of formula (I) in the composition remains in undegraded form after storage for at least two years at a temperature of about 5° C. In some embodiments, at least about 95% by weight of the original compound of formula (I) in the composition remains in undegraded form after storage for at least two months at a temperature of about 25° C.

[0260] In some embodiments, the compositions do not require the use of conventional preservatives and / or excipients with antimicrobial properties to maintain the microbial stability of the composition. In some embodiments, the compositions are substantially free of preservatives. In some embodiments, the compositions are substantially free of benzalkonium chloride; thimerosal; chlorobutanol; methylparaben; propylparaben; phenylethyl alcohol; EDTA; and sorbic acid.

[0261] In addition to the advantageous physical, chemical and microbiological stability provided by the composition, it was surprisingly found that the composition is very suitable for topical application to the eyes of animals (e.g., humans). The composition was well tolerated in animal studies and no irritation was detected when topically applied.

[0262] In some embodiments, the present invention also provides a composition comprising:

[0263] at least one compound of formula (I);

[0264] Oil;

[0265] surfactants;

[0266] and water,

[0267] wherein the dispersed phase is a plurality of nanosized particles, oil droplets, or combinations thereof of at least one compound of Formula (I), 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 osmolarity of the composition is substantially similar to the osmolarity of human tears.

[0268] As used herein, the term "osmolarity" refers to the concentration of osmotically active solutes in a solution. In some embodiments, the composition exhibits an osmolarity substantially similar to the osmolarity of human tears. In some embodiments, the composition has an osmolarity of about 300 mOsm / L to about 340 mOsm / L.

[0269] In some embodiments, a composition is characterized by its osmolality. The term "osmolality" refers to the concentration of osmotically active solutes per kg of solvent. A physiologically acceptable osmolality is an osmolality that is consistent with the normal function of a living organism. Thus, for the purposes of the present invention, the osmolality of a composition is substantially similar to the osmolality of human tears.

[0270] In some embodiments, the composition has an osmolality of about 250 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 250 mOsm / kg to about 330 mOsm / kg, about 250 mOsm / kg to about 300 mOsm / kg, about 250 mOsm / kg to about 275 mOsm / kg, about 275 mOsm / kg to about 330 mOsm / kg, about 270 mOsm / kg to about 300 mOsm / kg, or about 300 mOsm / kg to about 330 mOsm / kg.

[0271] In some embodiments, the composition has an osmolality of about 290 mOsm / kg to about 315 mOsm / kg.

[0272] In some embodiments, the present disclosure also provides a composition comprising:

[0273] at least one compound of formula (I);

[0274] sesame oil;

[0275] Surfactant selected from the group consisting of: polyoxyethylene (20) sorbitan monooleate ( 80); Polyoxyethylene (20) sorbitan monolaurate ( 20); 4-(1,1,3,3-tetramethylbutyl)phenol, polymer with formaldehyde and ethylene oxide (tyloxapol); sorbitan monooleate ( 80); Polyoxyethylated 12-hydroxystearic acid ( HS15); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; polyoxyl 40 stearate; polysorbate 80; and combinations thereof;

[0276] and water,

[0277] wherein the composition comprises a continuous phase comprising water; and a dispersed phase comprising a plurality of nanosized particles, oil droplets, or a combination thereof of at least one compound of formula (I); and wherein at least about 60% of the at least one compound of formula (I) is in the dispersed phase.

[0278] The present disclosure also provides a composition comprising:

[0279] from about 0.005% to about 0.5% by weight of a compound of formula (I);

[0280] from about 5% to about 25% by weight of an oil selected from the group consisting of sesame oil, mineral oil, and castor oil;

[0281] About 1.5% to about 2.5% by weight of polyoxyethylene (20) sorbitan monooleate ( 80);

[0282] from about 0.01 wt % to about 1.25 wt % BHT;

[0283] from about 0.01 wt % to about 1.25 wt % BHA;

[0284] about 2.5% by weight glycerol; and

[0285] water.

[0286] The present disclosure also provides a method for preparing the composition of the present invention. In some embodiments, the composition is prepared by:

[0287] mixing a compound of formula (I) and oil to form an oil phase;

[0288] mixing the surfactant and water to form an aqueous phase;

[0289] combining the oil phase and the water phase to form a premix;

[0290] homogenizing the premix to form a homogenized premix; and

[0291] The homogenized premix is ​​microfluidized to provide a composition.

[0292] In some embodiments, homogenization of the premix is ​​performed at a speed of about 5000 rpm for about 2 minutes.

[0293] In some embodiments, homogenization of the premix is ​​performed at a speed of about 5000 rpm for about 20 mm.

[0294] In some embodiments, the ratio of oil to water (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 wt% to about 5.0 wt%.

[0295] In some embodiments, the film comprises a polymeric material selected from the group consisting of polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE) and poly(ether sulfone) (PES).

[0296] granularity

[0297] Laser diffraction is used to measure and determine the particle size distribution of the disclosed compositions, where particles refer to solid particles, liquid particles (such as particles dissolved in oil droplets), or a combination thereof. There are other methods for determining particle size distribution, but in order to determine whether a sample meets the particle size requirement limits, the sample is analyzed by laser diffraction. In the examples, the Malvern Masterizer 3000 method is used to test the collected samples using parameters obtained from a Malvern ZetaSizer (Malvern Instruments, Malvern, United Kingdom). The particle size of the sample is analyzed by laser diffraction. Laser diffraction calculates the particle size distribution by measuring the angular change in the intensity of light scattered when a laser beam passes through a dispersed particle sample. Large particles scatter light at a small angle relative to the laser beam, while small particles scatter light at a large angle. Using the Mie theory of light scattering, the angular scattering intensity data is analyzed to calculate the size of the particles responsible for generating the scattering pattern. Particle size is reported as volume equivalent spherical diameter.

[0298] Particle size distribution can be expressed using four values. "D" represents the percentage of particles in the composition that are smaller than the indicated size. The analyzer used with laser diffraction to determine particle size does not measure particles one by one, but uses light with different angles and then retrieves the diffraction pattern from the image sensor. The instrument then determines the statistical proportion of particle sizes by performing addition, subtraction, and cross-analysis calculations. The instrument also uses software to calculate the mass median diameter. The mass median diameter (MMD) is the particle size at which 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.

[0299] 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. And a D99 or D(99) value means that 99% of the particles in the composition are smaller than the indicated size.

[0300] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter (MMD), wherein 50% of the mass of the dispersed droplets are qualitatively less than about 500 nm in size. 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] In some embodiments, at least about 90% of the particles in the composition have a mass median diameter between about 100 nm and about 500 nm, about 100 nm and about 350 nm, about 100 nm and about 200 nm, about 200 nm and about 500 nm, about 200 nm and about 350 nm, or about 350 nm and about 500 nm. In some embodiments, at least about 90% of the particles in the composition have a mass median diameter between about 100 nm and about 200 nm.

[0305] Methods of treatment or prevention

[0306] The present invention also provides a method 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 protection of neural tissue (such as retinal nerve or optic nerve) and / or the regeneration of the ocular nerve, and can generally be measured by the reduction of the death and / or degeneration of neurons related to neuropathological conditions (for example, nerve damage or disease). Neurological conditions may include diseases and / or obstacles such as blinding eye diseases, including macular degeneration, retinitis pigmentosa and glaucoma. Neurological conditions, such as neuropathic pain, can also be treated.

[0307] As used herein, the term "subject" refers to a mammal, such as a human, domestic animal, such as a feline or canine subject, farm animal (e.g., bovine, equine, caprine, ovine, and porcine subjects), wild animal, or research animal (e.g., mouse, rat, rabbit, goat, sheep, pig, dog, cat, or avian species, such as chicken, turkey, and songbird). In some embodiments, the subject is a human subject.

[0308] The present invention also provides a method for treating an ophthalmic condition in a subject by administering a therapeutically effective amount of a composition of the present invention to the subject's eye. In some embodiments, the ophthalmic condition is glaucoma, age-related macular degeneration (AMD), ophthalmitis, or conjunctivitis. In some embodiments, the ophthalmic condition is glaucoma.

[0309] In some embodiments, the ophthalmic condition is an immune system disease (e.g., an inflammatory disease). In some embodiments, the ophthalmic condition is an immune system disease such as dry eye, 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 be caused by dry eye, trauma, corneal abrasions, corneal burns, corneal transplants, autoimmune diseases, or allergens.

[0310] In some embodiments, the composition provides a reduction in intraocular pressure (IOP). In some embodiments, after the composition is applied to the eyes of the experimenter, the composition provides a reduction in intraocular pressure that continues for a period of at least about 1 hour. In some embodiments, after the composition is applied to the eyes of the experimenter, the composition provides a reduction in intraocular pressure that continues 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. In some embodiments, after the composition is applied to the eyes of the experimenter, the composition provides a reduction in intraocular pressure that continues for a period of at least about 8 hours, at least about 12 hours, or at least about 24 hours. In some embodiments, the composition increases the aqueous humor outflow of the experimenter's eyes.

[0311] As used herein, "topical administration" refers to local application to a tissue surface. For example, to the eye, particularly any external aspect of the eye that is normally accessible between the eyelids. In some embodiments, the composition is topically administered as liquid drops, liquid lotions, gels, ointments, sprays, or combinations thereof. In some embodiments, the composition is in the form of an eye drop solution. For example, the composition can be present in a rigid and / or squeeze-type bottle equipped with an adaptable cap configured to act as a dropper.

[0312] In some embodiments, the composition is administered topically as liquid drops. In some embodiments, the composition is applied to the ocular surface as one or more drops. In some embodiments, between 1 and 10 drops, between 1 and 5 drops, between 1 and 2 drops, between 2 and 10 drops, between 2 and 5 drops, or between 5 and 10 drops of the composition are administered daily.

[0313] Topical administration can also be performed by infusing 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 into the back of the eye and / or where administration involves intravitreal injection.

[0314] In some embodiments, the composition is administered once a day. In some embodiments, the composition is administered twice a day. In some embodiments, administration is performed 2 times a day, 3 times a day, 4 times a day, 5 times a day, 6 times a day, 7 times a day, 8 times a day, 9 times a day, or 10 times a day. In some embodiments, administration is performed continuously via a release device.

[0315] Also provided herein is a kit for treating or preventing an ophthalmic condition of a subject. In some embodiments, the ophthalmic condition is glaucoma. The kit may include any composition as described herein. The kit may include a therapeutically effective amount of the composition of the present invention, and may also include explanatory materials for applying the composition to a patient suffering from an ophthalmic condition (such as neuropathic pain, glaucoma, age-related macular degeneration (AMD), ophthalmitis or conjunctivitis). The explanatory materials may include publications, diagrams or any other expression media, which may be used to convey the usefulness of the composition and its application. The explanatory materials of the kit may be attached to a container containing the composition of the present invention, or may otherwise be provided together with a container containing the composition. Alternatively, the explanatory materials may be provided separately, for example, by electronic transmission, for example, by a computer, such as by email, or downloaded from a website. The kit may also include at least one additional agent, for example, such as an additional agent that may be used to treat or prevent an ophthalmic condition.

[0316] Example

[0317] Having now generally described the invention, the invention 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 otherwise specified.

[0318] Example 1: Preparation of 1000G batch of nabilone nanoemulsion 0.01% (w / w)

[0319] Using the materials shown in Table 3, 1000 grams of a 0.01% w / w nabilone nanoemulsion was prepared using the following method: Obtain a 200 mL beaker and label it "Oil Phase". Obtain the tare weight of the beaker. Dispense 20.02 g of sesame oil into the "Oil Phase" beaker and heat the oil phase to 75.0 ± 5°C. Weigh 0.1005 g of nabilone and dissolve it in the sesame oil and heat it at 75.0 ± 5°C with magnetic stirring at 500 rpm. Visually confirm that nabilone is dissolved in the oil. Obtain a 1500 mL beaker and label it "Water Phase". Add 20.03 g of sesame oil to the water phase beaker. 80 and 25.05 g glycerol. Add 934.91 g purified water and mix under magnetic stirring. Heat the aqueous phase at 75.0 ± 5 ° C under magnetic stirring at 500 rpm. Gradually add the "oil phase" to the "water phase" beaker and mix at a stirring rate of 1000 rpm for 5 minutes. Use a homogenizer (IKA T-18 Digital ULTRA- IKA Works, Inc., Wilmington, NC) The mixture was homogenized at 10,000 rpm for 5 minutes to form a premix. The yield after homogenization was calculated. (Microfluidics M-110P, Microfluidics, Westwood, MA) is heated to a target temperature of 25°C (± 2°C). The premix is ​​added to the microfluidizer and processed at 15,000PSI. The first three processing cycles are discarded as waste. After processing the premix for 12 minutes, the product is collected in an intermediate container. A 12.5g sample (cycle 1) is collected from the intermediate container for particle size assessment. After the reservoir of the microfluidizer is emptied and processed for two processing cycles, the contents of the intermediate container are transferred back to the reservoir and the process is repeated. After processing for 12 minutes, the product is collected in an intermediate container. A 12.5g sample (cycle 2) is collected from the intermediate container for particle size assessment. The process is repeated for three more cycles (cycles 3, 4 and 5), wherein a 12.5g sample is collected after each microfluidization cycle for particle size assessment. After the fifth cycle, the product is collected and the weight is measured. The pH of the emulsion was checked and adjusted to 7.02 with 1 N NaOH and then 1 N HCl with mixing.

[0320] Particle size distribution analysis was performed using a particle size analyzer (Masterizer 3000 (Malvern Panalytical, Malvern, United Kingdom)). The particle size results obtained from the samples are shown in Figures 2 to 8 middle.

[0321] Table 3. Composition of Nabilone Nanoemulsion 0.01% (w / w)

[0322]

[0323] Example 2: Preparation of a 1000G Placebo Batch for Comparison with Nabilone Nanoemulsion 0.01% (w / w)

[0324] A placebo batch of nabilone nanoemulsion 0.01% (w / w) was prepared using the method of Example 1 using the materials shown in Table 4 (where nabilone was not present).

[0325] Table 4. Placebo batches of nabilone nanoemulsion 0.01% (w / w)

[0326]

[0327] Example 3: Preparation of 1000G batch of nabilone nanoemulsion 0.05% (w / w)

[0328] Table 5 shows the composition of 0.05% w / w nabilone nanoemulsion prepared using the method of Example 1.

[0329] Table 5. Composition of Nabilone Nanoemulsion 0.05% (w / w)

[0330]

[0331] Example 4: Preparation of a 1000G Placebo Batch for Comparison with Nabilone Nanoemulsion 0.05% (w / w)

[0332] A placebo formulation of 0.05% (w / w) nabilone nanoemulsion was prepared using the materials described in Example 1. The composition of this batch is summarized in Table 6 (without nabilone).

[0333] Table 6. Placebo batches of nabilone nanoemulsion 0.05% (w / w)

[0334]

[0335] Example 5: Preparation of 1000G batch of nabilone nanoemulsion 0.075% (w / w)

[0336] A 1000 gram batch of 0.075% w / w nabilone nanoemulsion was prepared using the method of Example 1 and the materials shown in Table 7.

[0337] Table 7. Composition of Nabilone Nanoemulsion 0.075% (w / w)

[0338]

[0339] Example 6: Preparation of 1000G batch of nabilone nanoemulsion 0.025% (w / w)

[0340] A 1000 gram batch of 0.025% w / w nabilone nanoemulsion was prepared using the method of Example 1 and the materials shown in Table 8.

[0341] Table 8. Composition of Nabilone Nanoemulsion 0.025% (w / w)

[0342]

[0343]

[0344] Example 7: Preparation of 0.075% (w / w) Nabilone Nanoemulsion with Antioxidant

[0345] Based on the method of Example 1, a 0.075% w / w nabilone nanoemulsion was prepared using the materials in Table 9, with the addition of an antioxidant. Antioxidants and cosolvents can be added to the pharmaceutical composition to maintain shelf-life stability. The cosolvent (glycerol) 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 prior to the addition of nabilone. The composition was shown to be stable in terms of assay, impurities, particle size distribution, and pH for at least six months under refrigerated (5°C) and room temperature (25°C) conditions.

[0346] Table 9. Composition of 0.075% (w / w) Nabilone Nanoemulsion and Antioxidants

[0347]

[0348] Example 8: Preparation of a Placebo Batch of Nabilone Nanoemulsion 0.075% (w / w)

[0349] Based on the method of Example 1, a placebo batch of nabilone nanoemulsion 0.075% was prepared using the materials in Table 10.

[0350] Table 10. Placebo batches of Nabilone nanoemulsion 0.075% (w / w)

[0351]

[0352]

[0353] Example 9: Composition of Nabilone 0.025% (w / w) in Castor Oil Formulation

[0354] Based on the method of Example 1, 0.025% w / w nabilone nanoemulsions were prepared using the materials in Tables 13 to 15, with castor oil replacing sesame oil, and polysorbate 80, polyoxyl 35 castor oil, or polyoxyl 40 stearate replacing 80. Add the buffers disodium hydrogen phosphate heptahydrate and sodium dihydrogen phosphate dihydrate to the aqueous phase.

[0355] Table 11: Composition of Nabilone Nanoemulsion 0.025% (w / w) with Castor Oil and Polysorbate 80

[0356]

[0357] Table 12: Composition of Nabilone Nanoemulsion 0.025% (w / w) with Castor Oil and Polyoxyl 40 Stearate

[0358]

[0359]

[0360] Table 13: Composition of 0.025% (w / w) Nabilone Nanoemulsion with Castor Oil and Polyoxyl 35 Castor Oil

[0361]

[0362] Example 10: Composition of Nabilone 0.025% (w / w) in Mineral Oil Formulation

[0363] Based on the method of Example 1, 0.025% w / w nabilone nanoemulsions were prepared using the materials in Tables 14 to 16, with mineral oil replacing sesame oil and polysorbate 80, polyoxyl 35 castor oil, or polyoxyl 40 stearate replacing 80. Add the buffers disodium hydrogen phosphate heptahydrate and sodium dihydrogen phosphate dihydrate to the aqueous phase.

[0364] Table 14: Composition of Nabilone Nanoemulsion 0.025% (w / w) with Mineral Oil and Polysorbate 80

[0365]

[0366]

[0367] Table 15: Composition of Nabilone Nanoemulsion 0.025% (w / w) with Mineral Oil and Polyoxyl 35 Castor Oil

[0368]

[0369] Table 16: Composition of Nabilone Nanoemulsion 0.025% (w / w) with Mineral Oil and Polyoxyl 35 Castor Oil

[0370]

[0371] Example 11: IOP-lowering effect in mice

[0372] animal

[0373] Male C57BL / 6J mice (Jackson Laboratories, Bar Harbor, ME; 8 months old) were maintained under 12-hour light / 12-hour dark conditions (light on at 0600 hours) 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 regulations and guidelines of the Institutional Animal Care and Use Committee of the University of North Texas Health Science Center.

[0374] Ophthalmic preparations

[0375] Nabilone nanoemulsions (0.01 wt%, 0.025 wt%, 0.05 wt%, and 0.075 wt%) were prepared as described in Examples 1, 3, 5, and 6. Control placebo nanoemulsions (for comparison with 0.01 wt%, 0.025 wt%, 0.05 wt%, 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).

[0376] IOP measurement

[0377] According to the procedure described in Wang et al., Invest Ophthalmol Vis. Sci., 2005, 46: 4617-4621, the IOP was determined in behaviorally trained, conscious animals using a rebound tonometer (Colonial Medical Supply, Franconia, NH). The indicated formulations were topically applied to the left eye of each animal. The contralateral eye was not treated.

[0378] Animals were divided into four groups (as designated below). Baseline IOP was measured in both eyes at -1 hour before drug treatment and direct ophthalmoscopy was performed. Next, a single 5 μL drop was topically instilled into the left eye of each mouse. The contralateral (right) eye was not treated.

[0379] IOP was measured again in both eyes at 2 hours, 4 hours, 6 hours, 24 hours, 30 hours and 48 hours after dosing.In addition to IOP measurements, animals were evaluated for possible ocular and general systemic adverse effects by direct ophthalmoscopy.

[0380] Group 1: Nabilone (0.01 wt%)

[0381] Group 2: Nabilone (0.05 wt%)

[0382] Group 3: Control against Nabilone (0.05 wt%)

[0383] Group 4: Timolol (0.5 wt%)

[0384] The results are presented in Figures 9-13 , which shows a comparison of the IOP effects of nabilone compositions (0.01 wt% and 0.05 wt%), a control composition of nabilone (0.05 wt%), and timolol. The compositions were administered once at 9-10 AM (time 0) immediately after baseline IOP measurement. Data are shown as mean ± SEM (standard error of the mean).

[0385] The formulation effects of 0.025 wt% and 0.075 wt% nabilone nanoemulsions were also studied as follows:

[0386] Group 1: Nabilone (0.025 wt%)

[0387] Group 2: Nabilone (0.075 wt%)

[0388] Group 3: Control against Nabilone (0.075 wt%)

[0389] Group 4: Timolol (0.5 wt%)

[0390] The results are presented in Figure 14 and Figure 15 The combined dose responses of 0.01 wt%, 0.025 wt%, 0.05 wt% and 0.075 wt% nabilone nanoemulsions are shown in FIG. Figure 16 、 Figure 17 and Figure 18 middle.

[0391] All nabilone compositions tested (containing 0.01%, 0.025%, 0.05%, and 0.075% by weight of nabilone API) produced significant reductions in intraocular pressure (IOP). No tachyphylaxis or adverse effects were observed over the 48-hour period.

[0392] Eyes treated with the placebo vehicle did not reduce IOP compared to the contralateral untreated eye. Nabilone formulations (0.01%, 0.025%, 0.05%, and 0.075%) provided IOP reduction in treated eyes with a dose-dependent response. Nabilone formulations (0.05% and 0.075%) provided IOP reduction comparable to timolol (0.5%) within the early hours of dosing. Nabilone formulations (0.05% and 0.075%) maintained IOP reduction for up to 24 hours after dosing, while IOP reduction with the other formulations was attenuated.

[0393] It should be understood that the Detailed Description section is intended to be used to interpret the claims, in addition to the Summary section and the Abstract section. The Summary and Abstract sections may set forth one or more, but not all, exemplary embodiments of the present invention as contemplated by the inventors and are therefore not intended to limit the present invention and the appended claims in any way.

[0394] 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.

[0395] All publications, patents, and patent applications mentioned in this specification are herein 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. A composition suitable for application to the surface of the eye, comprising: At least one compound of formula (I) wherein R1 and R2 together form =0, or R1 is -OH and R2 is -H; Oil; surfactants; and water, wherein the composition comprises a continuous phase comprising water; and a dispersed phase comprising a plurality of nanosized particles, oil droplets, or a combination thereof of at least one compound of formula (I); and wherein at least about 60% of the at least one compound of formula (I) is in the dispersed phase.

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

3. The composition according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:

4. The composition according to any one of claims 1 to 2, wherein the compound of formula (I) is 5. The composition according to any one of claims 1 to 2, wherein the compound of formula (I) is 6. The composition according to any one of claims 1 to 2, wherein the compound of formula (I) is A racemic mixture of.

7. The composition according to any one of claims 1 to 2, wherein the compound of formula (I) is 8. The composition of any one of claims 1 to 7, wherein at least about 90% by weight of the starting compound is present in the composition after storage of the composition under conditions selected from the group consisting of: at least two years at about 5°C; and at least one month at about 25°C.

9. The composition of any one of claims 1 to 8, wherein the oil and the 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 an emulsion.

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

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

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

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

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. 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. 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. 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 oils, medium chain triglyceride oils, 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 of 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 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 oil.

25. The composition according to any one of claims 1 to 24, wherein the surfactant is selected from the group consisting of: polyoxyethylene (20) sorbitan monooleate ( 80); Polyoxyethylene (20) sorbitan monolaurate ( 20); 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and ethylene oxide (tyloxapol); sorbitan monooleate (Span 80); polyoxyethylated 12-hydroxystearic acid ( HS15); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; polyoxyl 40 stearate; polysorbate 80; and combinations thereof.

26. The composition according to any one of claims 1 to 25, wherein the surfactant is polyoxyethylene (20) sorbitan monooleate ( 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. The composition of claim 28, wherein the co-solvent is glycerol.

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

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

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

33. The composition of claim 31 , wherein the at least one pH adjusting agent 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. The composition of claim 35, wherein the stabilizer is an antioxidant.

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

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

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

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

41. The composition of any one of claims 1 to 40, wherein the composition comprises: from about 0.005% to about 0.5% by weight of the compound of formula (I); from 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 ( 80); from about 0.01 wt % to about 1.25 wt % BHT; from about 0.01 wt % to about 1.25 wt % BHA; about 2.5% by weight glycerol; and water.

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

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

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

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

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

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

50. The method of any one of claims 42 to 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. The method of any one of claims 42 to 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 of preparing a composition according to any one of claims 1 to 41, comprising: mixing the compound and the oil to form an oil phase; mixing the surfactant and water to form an aqueous phase; combining the oil phase and the water phase to form a premix; homogenizing the premix to form a homogenized premix; as well as The homogenized premix is ​​microfluidized to provide the composition.

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

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

55. The method of any one of claims 52 to 54, wherein the premix is ​​homogenized at a speed of about 5000 rpm to about 15000 rpm.

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. 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 at a temperature of about 15°C to about 30°C using cooling water circulating in the jacket of the mixing vessel.

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

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

5.

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

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