Compositions and methods for treating ocular diseases

Abstract

To provide a composition for improving stability of a tear film of dry eye.SOLUTION: The ophthalmic composition free from a steroidal androgen comprises a β - cyclodextrin derivative, sodium chloride, a buffer and water, wherein the β - cyclodextrin derivative is selected from the group consisting of (2-hydroxypropyl) - β - cyclodextrin, methyl - β - cyclodextrin and heptakis (2, 6-di-O-methyl) - β - cyclodextrin, and the buffer is selected from the group consisting of monosodium phosphate monohydrate, citric acid and sodium citrate.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This invention claims priority to U.S. Provisional Application No. 62 / 869,133, filed July 1, 2019, and U.S. Provisional Application No. 62 / 903,898, filed September 22, 2019, both of which are incorporated by reference for all purposes as if fully set forth herein.

[0002] The present invention relates to compositions and methods for treating meibomian gland dysfunction (MGD), blepharitis, dry eye disease, and related ophthalmic indications in affected eyes. The present invention also relates to compositions for use as artificial tears or ocular lubricants. [Background technology]

[0003] Meibomian glands are a type of sebaceous gland located in the tarsal plate of the upper and lower eyelids. These glands are responsible for producing meibum, an oily substance that prevents the evaporation of the tear film and keeps the closed eyelids airtight. There are approximately 50 meibomian glands in the upper eyelid and 25 in the lower eyelid. Meibomian glands are distinguished by grape-like clusters of acini at the junction between the eyelid mucosa and skin. They empty their lipid contents (meibum) at this junction to coat the ocular surface through holocrine secretion. The glands are anchored by cells that produce polar and nonpolar lipids, which are stored in lysosomes and then fuse into larger storage granules. As these cells continue to expand with lipids, they eventually undergo apoptosis and rupture, releasing meibum into the meibomian gland orifices, where it spills onto the ocular surface. Meibum is fluid at ocular surface temperature and is distributed over the ocular surface as a thin, smooth layer over the aqueous layer. This lipid layer prevents evaporation of the aqueous layer. Alterations in meibum composition, properties, and levels can have significant effects on the health of the eyelid margin and ocular surface. Meibomian gland dysfunction is fairly common in the general population, and its incidence is increased in contact lens wearers, estimated to be as high as 39%.

[0004] Secretions from the meibomian glands form the lipid layer of tears, composed of polar and nonpolar lipids. The lipid composition of meibum can influence tear parameters, such as the initial formation of a composite monolayer with polar and nonpolar phases, sufficient fluidity at body temperature, and the ability to compress and expand during blinking. These properties are crucial for effectively structuring polar lipids and achieving fluidity (a molten physical state) at normal body temperature. Any changes in the degree of fatty acid saturation can lead to tear instability.

[0005] Although patients with MGD typically have normal production of aqueous tears by the lacrimal glands, they may experience atrophy of the meibomian glands, often accompanied by metaplasia of the ductal epithelium of these glands. Anterior erosions of the mucocutaneous junction are also frequently observed, as are infections of the eyelids and conjunctiva, irregular eyelid margins, changes in the corneal epithelium, and corneal neovascularization. In some cases, abnormal overproduction of meibum can cause similar problems.

[0006] Because the meibomian glands lining the eyelids produce lipids that promote tear stability and reduce tear film evaporation, meibomian gland dysfunction can lead to lipid deficiencies that destabilize the tear film, causing reduced tear breakup time and evaporative dry eye.

[0007] MGD is also characterized by an increase in the melting point of lipids, causing lipid solidification and inhibition of meibomian gland secretion. This can lead to cysts, infections, and a decrease in the lipid content of tears. MGD is also characterized by excessive, abnormally cloudy secretions, which block the meibomian gland orifices. This is followed by meibomian gland duct metaplasia (abnormal hyperkeratosis). The obstruction and resistance to flow result in inflammation and neovascularization (redness) of the tissues around the orifices. Inflammatory mediators accumulate in the tear film, causing damage to the ocular surface. The sequelae of all these events is inflammatory scarring of the ducts, leading to duct narrowing. The lacrimal glands initially swell and eventually atrophy.

[0008] Common complaints of patients with MGD include blurred or filmy vision, light sensitivity, photophobia, ocular burning or foreign body sensation, excessive tearing, contact lens intolerance, and pain.

[0009] Photosensitivity is the intolerance to light, including sunlight, fluorescent light, and incandescent light. Photosensitivity is a symptom of MGD and is associated with other conditions, including corneal abrasion, uveitis, meningitis, retinal detachment, contact lens irritation, sunburn, and refractive surgery.

[0010] Blurred vision is a lack of sharpness of vision and can result from abnormalities such as myopia, hyperopia, presbyopia, and astigmatism. It is also associated with MGD and other ocular surface conditions.

[0011] Currently, various lipid-based artificial tears or lubricants are used to relieve the symptoms of MGD. Physical treatments, such as good hygiene, heat, and massage, are also often used. However, these treatments do not cure the disease. Effective and safe treatments for MGD are needed.

[0012] Blepharitis and dry eye disease frequently occur in patients with MGD as a direct or indirect consequence of the disease. These conditions share many of the symptoms described above and are considered to be related manifestations of MGD. Both of these conditions are multifactorial and highly complex. A brief description of these conditions follows.

[0013] Blepharitis is inflammation of the eyelids, usually affecting both eyes along the eyelid margins. It can develop in the later stages of MGD or independently. In MGD, blockage and congestion of the meibomian glands leads to posterior blepharitis. This is commonly associated with acne rosacea and is suspected to have a hormonal etiology. Anterior blepharitis is caused by bacterial infection and can be treated with antibiotics. Both anterior and posterior blepharitis can be caused by Demodex mites. The exact pathophysiology of blepharitis is multifactorial and remains unclear. Patients with blepharitis often experience symptoms associated with MGD and dry eye disease, such as itchy, burning, and crusting eyelids. They may also experience tearing, blurred vision, and a foreign body sensation.

[0014] Dry eye disease (DED) is a condition in which the eyes lack sufficient tear fluid to lubricate and nourish them. Tears are necessary to maintain the health of the anterior surface of the eye and provide clear vision. Dry eye is a common and often chronic problem. Global prevalence is estimated at 5% to 34%. Insufficient tear volume or tear quality is the cause of DED. Tear production can decrease with age, as well as with various diseases and as a side effect of certain medications. Environmental conditions, such as wind and dry weather, can also increase tear evaporation and therefore decrease tear production. Symptoms of dry eye disease can manifest when normal tear production is reduced or when abnormalities in meibum lipids cause rapid tear evaporation from the eye. DED primarily caused by reduced tear production is defined as aqueous-deficient DED. DED caused by increased tear evaporation is defined as evaporative DED. While the latter accounts for the majority of cases, many patients experience mixed causes. Summary of the Invention [Problem to be solved by the invention]

[0015] Most current treatments for DED aim to attenuate the immune response. The present invention focuses on improving tear film stability to attack one of the early pathological events of the disease. [Means for solving the problem]

[0016] In one embodiment, a method for treating an ocular disease in an affected eye comprises administering to the affected eye of a subject in need of such treatment a steroidal androgen-free composition containing a therapeutically effective amount of a β-cyclodextrin derivative, wherein the β-cyclodextrin derivative is the active pharmaceutical ingredient for treating the ocular disease, and the β-cyclodextrin derivative is the only active pharmaceutical ingredient for treating the ocular disease.

[0017] In another embodiment, the eye disease is one selected from the group consisting of meibomian gland dysfunction, blepharitis, and dry eye disease.

[0018] In another embodiment, the steroidal androgen-free composition is administered topically to the affected eye or to the skin surrounding the affected eye.

[0019] In another embodiment, the β-cyclodextrin derivative is (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, or 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin. Phosphorus, 6-monodeoxy-6-monobromo-β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo) -β-cyclodextrin, heptakis(6-deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino) )propyl-β-cyclodextrin, heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoaminota-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,Heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-amino)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof.

[0020] In another embodiment, the β-cyclodextrin derivative is present in the composition at a concentration of 0.1 to 30% w / w, 0.5 to 25% w / w, 1 to 20% w / w, 5 to 15% w / w, 8 to 12% w / w, about 10 w / w or 10 w / w.

[0021] In another embodiment, the steroidal androgen-free composition does not include androgens with steroidal chemical structures, testosterone, or precursors of testosterone.

[0022] In another embodiment, the method further comprises maintaining the effect of treating meibomian gland dysfunction for a period of time following administration.

[0023] In another embodiment, the period of time after administration is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0024] In another embodiment, the method further comprises dissolving lipid crystals deposited at the orifices of the meibomian glands of the affected eye and increasing tear film stability.

[0025] In another embodiment, the method further comprises one of the following steps: reducing foreign body sensation in the affected eye, hyperemia or redness in the affected eye and eyelid margin, obstruction of the meibomian gland orifice in the affected eye, inflammation of ocular tissue, corneal staining in the affected eye, burning sensation in the affected eye, photophobia, blurred vision, pain in the affected eye, or itching in the affected eye, increasing tear breakup time (TBUT), improving astigmatism, decreasing the phase transition temperature of meibum, improving clinical signs and symptoms of meibomian gland dysfunction (MGD), and combinations thereof. The ocular tissue is selected from the group consisting of meibomian glands, ducts, orifices, eyelids, cornea, and conjunctiva.

[0026] In another embodiment, the steroidal androgen-free composition comprises a β-cyclodextrin derivative as the only active pharmaceutical ingredient. The steroidal androgen-free composition is an ophthalmic composition.

[0027] In another embodiment, the steroidal androgen-free composition consists essentially of a β-cyclodextrin derivative and one or more ingredients selected from the group consisting of hydroxypropyl guar, xantham gum, trehalose, sodium chloride, castor oil, Cremophor ELP, polysorbate 80, HPMC2910, edetate disodium, glycerin, a buffer, and water.

[0028] In another embodiment, the buffering agent is selected from the group consisting of monobasic sodium phosphate monohydrate, citric acid, and sodium citrate.

[0029] In another embodiment, the β-cyclodextrin derivative is present in the steroidal androgen-free composition in a concentration of 0.1% w / w to 30% w / w.

[0030] In another embodiment, in the steroidal androgen-free composition, the β-cyclodextrin derivative is selected from the group described above.

[0031] In another embodiment, the steroidal androgen-free composition is a solution, suspension, emulsion, gel, ointment, or cream.

[0032] In another embodiment, the steroidal androgen-free composition is an artificial tear or a lubricant.

[0033] In another embodiment, the steroidal androgen-free composition consists of a β-cyclodextrin derivative, sodium chloride, a buffer, and water.

[0034] In another embodiment, in the steroidal androgen-free composition, the β-cyclodextrin derivative is selected from the group described above.

[0035] In another embodiment, the buffering agent is selected from the group consisting of monobasic sodium phosphate monohydrate, citric acid, and sodium citrate.

[0036] In another embodiment, the steroidal androgen-free composition comprises 5% to 20% of the β-cyclodextrin derivative, 0.20% to 0.80% sodium chloride, 0.10% to 0.30% monosodium phosphate monohydrate, and water.

[0037] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0038] The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention. [The present invention 1001] 1. A method for treating an ocular disease in an affected eye of a subject in need of such treatment, comprising administering to the affected eye a therapeutically effective amount of a β-cyclodextrin derivative, the composition being free of steroidal androgens; the β-cyclodextrin derivative is a pharmaceutically active ingredient for treating the eye disease, The method, wherein the β-cyclodextrin derivative is the sole pharmaceutically active ingredient for treating the ocular disease. [The present invention 1002] 1001. The method of claim 1001, wherein said eye disease is one selected from the group consisting of meibomian gland dysfunction, blepharitis, and dry eye disease. [The present invention 1003] 1003. The method of claim 1001 or 1002, wherein said steroidal androgen-free composition is administered topically to said affected eye or topically to the skin surrounding said affected eye. [The present invention 1004] The β-cyclodextrin derivatives include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-6-monobromo -β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6- Deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis Heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-amino)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof. [The present invention 1005] 1006. The method of any of claims 1001 to 1004, wherein the β-cyclodextrin derivative is present in the composition at a concentration of 0.1 w / w to 30% w / w, 0.5 w / w to 25% w / w, 1 w / w to 20% w / w, 5 w / w to 15% w / w, 8 w / w to 12% w / w, about 10 w / w or 10 w / w. [The present invention 1006] 1006. The method of any of claims 1001 to 1005, wherein said steroidal androgen-free composition does not include androgens having a steroidal chemical structure, testosterone, or precursors of testosterone. [The present invention 1007] The method of the present invention 1001 further comprising a step of maintaining the effect of treating meibomian gland dysfunction for a certain period of time after administration. [The present invention 1008] 1007. The method of claim 1007, wherein the period of time after administration is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. [The present invention 1009] dissolving lipid crystals deposited at the orifices of the meibomian glands of the affected eye; and 1001. The method of claim 1001, further comprising the step of increasing tear film stability. [The present invention 1010] reducing foreign body sensation in the affected eye, hyperemia or redness of the affected eye and eyelid margin, obstruction of the meibomian gland orifices in the affected eye, inflammation of ocular tissue, corneal staining in the affected eye, burning sensation in the affected eye, photophobia, blurred vision, pain in the affected eye, or itching in the affected eye; Increasing the tear film breakup time (TBUT); Steps to improve astigmatism: reducing the phase transition temperature of meibum; improving the clinical signs and symptoms of meibomian gland dysfunction (MGD), and combinations thereof; 1001. The method of claim 1001, wherein said ocular tissue is selected from the group consisting of meibomian glands, ducts, orifices, eyelids, cornea, and conjunctiva. [The present invention 1011] A steroidal androgen-free composition comprising a β-cyclodextrin derivative as an active pharmaceutical ingredient, wherein the steroidal androgen-free composition is an ophthalmic composition. [The present invention 1012] The steroidal androgen-free composition of the present invention, wherein the steroidal androgen-free composition consists essentially of a β-cyclodextrin derivative and one or more ingredients selected from the group consisting of hydroxypropyl guar, xantham gum, trehalose, sodium chloride, castor oil, Cremophor ELP, polysorbate 80, HPMC2910, edetate disodium, glycerin, a buffer, and water. [The present invention 1013] 1012. The method of claim 1012, wherein said buffering agent is selected from the group consisting of monosodium phosphate monohydrate, citric acid, and sodium citrate. [The present invention 1014] 1014. The steroidal androgen-free composition of any of claims 1011 to 1013, wherein the β-cyclodextrin derivative is present in the steroidal androgen-free composition at a concentration of 0.1% w / w to 30% w / w. [The present invention 1015] The β-cyclodextrin derivatives include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-6-monobromo -β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6- Deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis Heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,The steroidal androgen-free composition of any of claims 1011 to 1014, wherein the steroidal androgen-free composition is selected from the group consisting of (3-di-O-methyl-6-deoxy-6-amino)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof. [The present invention 1016] 1016. The steroidal androgen-free composition of any of claims 1011 to 1015, wherein said steroidal androgen-free composition is a solution, suspension, emulsion, gel, ointment, or cream. [The present invention 1017] 1016. The steroidal androgen-free composition of any of claims 1011 to 1015, wherein said steroidal androgen-free composition is an artificial tear or a lubricant. [The present invention 1018] A steroidal androgen-free composition comprising a β-cyclodextrin derivative, sodium chloride, a buffer, and water. [The present invention 1019] The β-cyclodextrin derivatives include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-6-monobromo -β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6- Deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis Heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,The steroidal androgen-free composition of the present invention is selected from the group consisting of (3-di-O-methyl-6-deoxy-6-amino)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof. [The present invention 1020] The steroidal androgen-free composition of the present invention, wherein the buffering agent is selected from the group consisting of monosodium phosphate monohydrate, citric acid, and sodium citrate. [The present invention 1021] The steroidal androgen-free composition of the present invention 1018, wherein the steroidal androgen-free composition is composed of 5% to 20% of the β-cyclodextrin derivative, 0.20% to 0.80% of sodium chloride, 0.10 to 0.30% of monosodium phosphate monohydrate, and water. [Brief explanation of the drawings]

[0039] [Figure 1] FIG. 1 shows the effect of 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) on photosensitivity and blurred vision over 24 weeks in a Phase 2 clinical trial. [Figure 2] Figure 1 shows the effect of 2-HP-β-CD on photosensitivity and blurred vision over 12 months in a Phase 2 clinical trial. [Figure 3] This figure shows the overall mean score of patients with diseased eyes in a phase 2 clinical trial who received topical eye drops of a 2-hydropropyl-β-cyclodextrin formulation at a concentration of 10% (w / w) three times a day for four weeks and were followed up for five months. [Figure 4] 1 shows the mean ocular symptom scores of patients in a phase 2 clinical trial. [Figure 5] The mean visual function scores in the phase 2 clinical trial are shown. [Figure 6] The mean impact scores on patients' quality of life in the Phase 2 clinical trial are shown. [Figure 7] 1 shows ocular symptom scores at each scheduled visit for pterygium patients with and without dry eye in a Phase 2 clinical trial. [Figure 8] 1 shows the mean change from baseline in ocular symptom scores at each scheduled visit for pterygium patients with and without dry eye in a Phase 2 clinical trial. [Figure 9] 1 shows ocular symptom scores at each scheduled visit for pterygium patients with dry eye in a Phase 2 clinical trial. [Figure 10] 1 shows the mean change from baseline in ocular symptom scores at each scheduled visit for pterygium patients with dry eye in a Phase 2 clinical trial. DETAILED DESCRIPTION OF THE INVENTION

[0040] Detailed Description of the Illustrated Embodiments Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings.

[0041] The present invention provides compositions and methods for treating meibomian gland dysfunction (MGD), blepharitis, and dry eye disease. Without being bound by theory, the methods utilize two important properties of cyclodextrin derivatives: 1) their ability to sequester and dissolve cholesterol, and 2) their ability to inhibit immune activity, such as macrophage activation. The first ability is to remove excess lipids deposited near the orifices of the meibomian glands, promoting lipid mobility and altering the composition of meibum to increase its fluidity at ambient temperatures on the ocular surface. The second ability is to attenuate abnormal immune activity present in the eyes of MGD patients. These patients have elevated cytokines and immune cell activity, including macrophages and T cells. Unlike current treatments for MGD, the present invention has the potential to modify the disease in addition to improving symptoms, such as light sensitivity and blurred vision.

[0042] Cyclodextrins belong to the cyclic oligosaccharide family and are composed of a macrocyclic ring of glucose subunits linked by α-1,4-glycosidic bonds. Cyclodextrins can contain six to eight glucose monomers in a ring, forming a cone-shaped molecule. Naturally occurring cyclodextrins include α-, β-, and γ-cyclodextrins, which contain six, seven, and eight glucose units, respectively. The number of glucose units is important for the biological and non-biological activities associated with these molecules. This application discloses an unexpected finding regarding cholesterol binding capacity in relation to the number of glucose units. The inventors have discovered that β-cyclodextrin, which contains seven glucose units, but not α- or γ-cyclodextrins, which contain six or eight glucose units, can bind significantly more cholesterol.

[0043] Natural cyclodextrin can be chemically modified by the addition of other groups, such as hydroxypropyl or methyl groups, to produce "cyclodextrin derivatives." Cyclodextrin derivatives have different physical and chemical properties and may behave differently when interacting with other molecules. This has led to the unexpected finding that the modification groups on cyclodextrin derivatives determine their ability to dissolve cholesterol in water. Methyl derivatives of β-cyclodextrin have the highest ability to dissolve cholesterol in water, followed by hydroxypropyl derivatives. As discussed below, the ranking of various cyclodextrin derivatives supports the application of compositions and methods.

[0044] The present disclosure is based on the unexpected finding by the present inventors that only certain derivatives of β-cyclodextrin have significant ability to sequester and solubilize cholesterol. Another unexpected finding is that certain modifications of β-cyclodextrin are more effective than others at sequestering cholesterol. These unexpected findings form the basis of the present disclosure, in which selected derivatives of selected cyclodextrins are used in compositions and methods for treating MGD, blepharitis, and dry eye disease. Specifically, the β-cyclodextrin derivatives used herein include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin. Heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monobromo-α-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl) -β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6-deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin Chlodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3- di-O-acetyl-6-sulfo)β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-amino)β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)β-cyclodextrin, or a combination thereof.

[0045] U.S. Patent Application No. 9,937,188 (Allergan, Inc.) discloses the use of formulations containing testosterone or related androgens for the treatment of keratoconjunctivitis sicca and meibomian gland disease. In this patent, cyclodextrin acts as a solubilizer for the active ingredient, testosterone, and is disclosed as one of the inactive excipients, which also include castor oil, C10-30 alkyl acrylate crosspolymer, and polyoxyl 40 stearate. The method of the present invention is fundamentally different in two respects: 1) specific derivatives of cyclodextrin, rather than cyclodextrin in general, are disclosed in the compositions and methods herein; 2) the disclosed compounds are used as active ingredients for the treatment of MGD and related disorders, and are not used as inactive excipients in formulations such as those disclosed in U.S. Patent Application No. 9,937,188. Importantly, the disclosed method does not use steroidal androgens, as disclosed in U.S. Patent Application No. 9,937,188. This important distinction avoids many of the potential steroid-related side effects, such as virilization in women and prostate stimulation in men. Androgens control the development, differentiation, and function of male reproductive and accessory tissues. Testosterone regulates the expression of thousands of genes in ocular tissues. While such gene regulation in the meibomian gland produces beneficial effects as disclosed in U.S. Patent Application No. 9937188, altering the expression of so many genes increases the potential for side effects. ANDROGEL contains 1% testosterone as its active ingredient and is approved for topical use as replacement therapy for disorders associated with a deficiency or absence of endogenous testosterone in men. ANDROGEL's product insert indicates a potential risk of worsening benign prostatic hyperplasia (BPH) and prostate cancer in patients with BPH. Inadvertent exposure of ANDROGEL 1% to women and children should be avoided. Secondary exposure to testosterone may cause signs of virilization, and ANDROGEL 1% should be discontinued until the cause of virilization is identified.Other side effects observed in clinical trials of ANDROGEL 1% include azoospermia, edema with or without congestive heart failure, and sleep apnea. Patients treated with ANDROGEL 1% should have serum testosterone, prostate-specific antigen, hemoglobin, hematocrit, liver function tests, and lipid levels monitored regularly. This application excludes the use of testosterone, and cyclodextrin is used as the sole active ingredient, avoiding the side effects associated with testosterone.

[0046] As used herein, an "ophthalmic composition" is useful for placement on the surface of a human or animal eye. Such compositions are preferably administered to a patient's eye in the form of a fluid. By administering the composition as a fluid, administration can be performed without forming an incision in the eye. As used herein, a "transdermal composition" delivers a therapeutically effective amount of an active ingredient to the entire skin of a patient. The transdermal composition typically includes a carrier (such as a liquid, gel, or solid matrix, or a pressure-sensitive adhesive) into which the active ingredient to be delivered is incorporated.

[0047] As used herein, "active pharmaceutical ingredient" refers to a therapeutic agent or substance used to treat a medical ophthalmic disease or ophthalmic condition and / or otherwise beneficially affect a patient's eye, and "sole active pharmaceutical ingredient" refers to the one and only therapeutic agent or substance used to treat a medical ophthalmic disease or ophthalmic condition and / or otherwise beneficially affect a patient's eye.

[0048] The β-cyclodextrin derivative described herein is the sole pharmaceutically active ingredient of the ophthalmic composition. The ophthalmic composition does not contain any other pharmaceutically active ingredients for treating ocular diseases. Specifically, the ophthalmic composition does not contain androgens with steroidal chemical structures, testosterone, or testosterone precursors. The ophthalmic composition may contain one or more inactive ingredients selected from the group consisting of hydroxypropyl guar, xantham gum, trehalose, sodium chloride, castor oil, Cremophor ELP, polysorbate 80, HPMC2910, edetate disodium, glycerin, and a buffering agent. The ophthalmic composition may be an aqueous formulation.

[0049] As used herein, the term "therapeutically effective amount" is intended to mean a non-toxic but sufficient concentration or amount of a β-cyclodextrin derivative, more specifically, a β-cyclodextrin derivative selected from the group described above, to provide the desired therapeutic effect. The effective amount will vary from subject to subject, depending on the individual's age, general condition, cyclic polysaccharide, etc. Thus, it is not always possible to precisely specify an effective concentration or amount. However, an appropriate effective amount in each individual case can be determined by one of ordinary skill in the art using routine experimentation. Furthermore, the exact effective amount of the β-cyclodextrin derivative incorporated into the compositions or dosage forms of the present invention is not critical, so long as the concentration is within a range sufficient to easily apply a solution or formulation to deliver an amount of the β-cyclodextrin derivative-containing compound within the therapeutically effective range.

[0050] 2-Hydroxypropyl-β-cyclodextrin (2-HP-β-CD) (CAS number: 128446-35-5) is a modified cyclodextrin derivative and has the following formula I. 2,6-Di-O-methyl-β-cyclodextrin (also known as heptakis(2,6-di-O-methyl)-β-cyclodextrin, CAS number 51166-71-3) is a modified cyclodextrin derivative and has the following formula II. [ka]

[0051] In a clinical trial investigating the treatment of pterygium, the unexpected finding was that the vehicle (2-HP-β-CD formulation I) reduced symptoms of foreign body sensation, pain, redness, and especially light sensitivity and blurred vision in pterygium patients. Pterygium is a common eye disorder that causes several eye symptoms commonly seen in MGD. It is also commonly seen in diseases such as blepharitis and dry eye. Meibomian gland dysfunction is common in pterygium. In this clinical trial, patients were given a questionnaire to assess several common eye symptoms, including inflammation, foreign body sensation, pain, light sensitivity, and blurred vision. Results showed that ocular symptom scores, including irritation, foreign body sensation, pain, light sensitivity, and blurred vision, significantly decreased during cyclodextrin treatment compared to pretreatment baseline. In particular, light sensitivity and blurred vision significantly improved during treatment with the vehicle compared to pretreatment baseline. Even more surprisingly, these symptom-relieving effects were maintained for as long as 5 months after administration of the vehicle, the main component of which was 10% 2-HP-β-CD (w / w).

[0052] Compositions and methods for treating ocular conditions are disclosed. The methods involve administering to a patient in need thereof an appropriate ophthalmic formulation containing 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The disclosed methods are used to achieve sustained improvement in the overall symptoms associated with MGD, blepharitis, and dry eye disease. [Example]

[0053] The present invention is further described in the following representative examples, which do not limit the scope of the invention as claimed.

[0054] Example 1: 2-HP-β-CD Formulation I The formulation of this example contains 5% to 20% (preferably 10%) 2-HP-β-CD (w / w), 0.10 to 0.30% (preferably 0.16%) monosodium phosphate monohydrate (w / w), 0.20 to 0.80% (preferably 0.52%) sodium chloride (w / w), and water. The formulation has a pH of 4 to 9 (preferably 7.4).

[0055] Example 2: Application of 2-HP-β-CD Formulation I A phase 2a, multicenter, randomized, vehicle-controlled, dose-escalation study was conducted to evaluate the safety, efficacy, and pharmacokinetics of nintedanib ophthalmic solution (2-HP-β-CD formulation I) in patients with primary or recurrent pterygium.

[0056] In this multicenter, randomized, double-blind, vehicle-controlled, parallel study, vehicle and 0.2% nintedanib were administered as repeated eye drops three times daily (TID) for 28 days with a 5-month follow-up period.

[0057] result: In clinical trials, pterygium patients were asked 15 questions regarding ocular signs, symptoms, and quality of life. Surprisingly, 2-HP-β-CD Formulation I produced unexpected improvements in light sensitivity and blurred vision. As shown in Table 1, these two symptoms were statistically improved at weeks 2 and 4 of treatment. The trend toward improvement continued even after treatment was discontinued at weeks 8, 16, and 24. The results are shown in Figure 1. No statistically significant effects were observed in the other questions.

[0058] [Table 1]

[0059] Example 3: 2-HP-β-CD Formulation II The formulation in this example contains 0.1-0.5% castor oil (w / w), 0.1-1.0% polysorbate 80, super refined (w / w), 0.1-1.0% Cremophor ELP (w / w), 5-20% 2-HP-β-CD (w / w), 0.010-0.30% citric acid (w / w), 0.030-0.060% sodium citrate (w / w), 0.01-1.0% HPMC2910 (w / w), 0.01-0.5% edetate disodium (w / w), and water. The pH of the formulation is 4.0-9.0. Glycerin is used to adjust the osmolality of the solution to 280-300 mOsm / kg.

[0060] Example 4: Application of 2-HP-β-CD Formulation II A phase 3, multicenter, randomized, vehicle-controlled, dose-escalation study was conducted to evaluate the safety, efficacy, and pharmacokinetics of nintedanib ophthalmic solution (2-HP-β-CD formulation II) in patients with primary or recurrent pterygium.

[0061] The treatment period in the Phase 3 trial was longer than that in the Phase 2a trial. The results are shown in Figure 2.

[0062] Example 5: Application of 2-HP-β-CD Formulation I

[0063] A Phase 2a, multicenter, randomized, vehicle-controlled, dose-escalation study was conducted to evaluate the safety, efficacy, and pharmacokinetics of nintedanib ophthalmic solution in patients with primary or recurrent pterygium. This multicenter, randomized, double-blind, vehicle-controlled, parallel study included repeated instillation of vehicle and 0.2% nintedanib three times daily (TID) for 28 days, with a 5-month follow-up period. The 2-HP-β-CD formulation described in Example 1 was used as the vehicle.

[0064] Patients with pterygium often have atrophy of the meibomian glands and present with the clinical signs and symptoms of MGD, including eye pain, itching, foreign body sensation, redness, light sensitivity, and blue vision. In a phase II clinical trial, pterygium patients were asked 15 questions regarding ocular symptoms, vision-related function, and quality of life via the Pterygium Symptoms and Quality of Life (PSLQ) questionnaire.

[0065] result: PSLQ analysis was performed on the four mean category scores: overall, ocular symptoms, vision-related function, and quality of life impact. The results of the analysis are summarized in Tables 2–5. Significant improvements in PSLQ scores were observed in the 2-HP-β-CD group compared with baseline. Statistically significant changes (improvements) from baseline were detected in the PSLQ overall score and ocular symptoms score at weeks 2, 4, and 8, the quality of life impact score at week 2, and the vision-related function score at weeks 4 and 8 in the 2-HP-β-CD group.

[0066] Surprisingly, improvements in ocular symptoms and vision-related function were observed not only during weeks 2 and 4 of the 2-HP-β-CD treatment period, but also continued through week 8 after the 2-HP-β-CD treatment period had ended.

[0067] [Table 2]

[0068] [Table 3]

[0069] [Table 4]

[0070] [Table 5]

[0071] Additionally, an analysis was conducted to examine the potential therapeutic effect of 10% 2-hydroxypropyl β-cyclodextrin in patients with symptoms such as ocular pain, itching, foreign body sensation, redness, light sensitivity, and blurred vision, which are frequently observed in patients with MGD. These symptom scores were assessed by patients as part of the PSLQ questionnaire.

[0072] 1) Patients with dry eye vs. those without dry eye, combining nintedanib and vehicle treatment groups (based on patient history) Results: Dry Eye Patients vs. Non-Dry Eye Patients for Ocular Symptom Score as Part of the PSLQ: Figure 7 shows the mean PSLQ ocular symptom score at each scheduled visit for pterygium patients with and without dry eye, and Figure 8 shows the mean change from baseline in ocular symptom score at each scheduled visit for pterygium patients with and without dry eye.

[0073] Pterygium patients with dry eye were compared with those without dry eye. For this comparison, all pterygium patients with dry eye in the drug and vehicle groups were combined, as were pterygium patients without dry eye. The number of data points for each group was 17 for dry eye and 18 for no dry eye. Results showed statistically significant differences between the dry eye and no dry eye groups at weeks 2 (p=0.042) and 4 (p=0.025). The mean difference in ocular symptom relief on the PSLQ was 0.50 at week 2 and 0.61 at week 4. Pterygium patients with dry eye had higher baseline scores and greater reductions in ocular symptom scores from baseline during treatment compared with pterygium patients without dry eye.

[0074] 2) Nintedanib versus vehicle for patients with dry eye (based on patient history). Results: Nintedanib vs. vehicle in dry eye patients with regard to ocular symptom scores as part of the PSLQ: Figure 9 shows the mean PSLQ ocular symptom scores at each scheduled visit for pterygium patients with dry eye, and Figure 10 shows the mean change from baseline in ocular symptom scores at each scheduled visit for pterygium patients with dry eye.

[0075] Drug- and vehicle-treated patients with dry eye pterygium responded similarly to the PSLQ ocular symptoms. Changes from baseline in the PSLQ ocular symptoms were similar throughout the treatment period, with no statistically significant differences observed at any time point.

[0076] Conclusion: Evidence supports that 10% 2-hydroxypropyl-β-cyclodextrin affected PSLQ responses in pterygium patients with and without dry eye. The magnitude of the reduction in PSLQ ocular symptom scores was statistically significantly greater in pterygium patients with dry eye than in pterygium patients without dry eye.

[0077] On the other hand, when comparing patients with dry eye pterygium treated with nintedanib 0.2% or vehicle, there was no statistically significant difference between the two treatment groups, indicating that nintedanib 0.2% was not the primary cause of the decrease in PSLQ scores in patients with dry eye pterygium, while 10% 2-hydroxypropyl-β-cyclodextrin was the primary cause of the decrease in PSLQ scores in patients with dry eye pterygium.

[0078] Example 6: Cholesterol solubility in cyclodextrins The solubility of cholesterol in the presence of cyclodextrin (CD) has been measured and reported (Nishijo, J., Moriyama, S., and Shiota S., Chem. Pharm. Bull., 51(11)1253-1257, 2003). Cholesterol Solubility in the Presence of CD: A 20-ml L-shaped test tube was filled with an appropriate concentration of CD solution and an excess aliquot of cholesterol (7.0 ml) and sealed. The tubes were incubated at 10, 25, 37, and 45°C with shaking for 1 week until solubility equilibrium was reached. The solution was then filtered through a membrane, and 3.0 ml of color reagent was added to 0.1 ml of the filtrate. The reaction mixture was then heated at 37°C for 5 minutes, and the absorbance at 600 nm was measured using a pre-prepared calibration curve. The stability of the cholesterol-CD complex was measured at 25°C using a Shimadzu RF-503A fluorescence spectrophotometer. Table 6 shows the increase in absorbance due to cholesterol solubilized by CD in aqueous solution at 37°C.

[0079] [Table 6]

[0080] As shown in Table 6, the absorbance was zero in the presence of α-CD, β-CD, and γ-CD, suggesting that these CDs do not form soluble complexes with cholesterol in aqueous solution. While only a slight increase in absorbance was observed in the presence of HP-β-CD, a significant increase in absorbance was observed in the presence of DOM-β-CD. These results suggest that DOM-β-CD has a strong ability to form soluble complexes with cholesterol in aqueous solution, whereas HP-β-CD has a weak ability. Although soluble complex formation between α-CD, β-CD, and γ-CD and cholesterol was not detected, insoluble complex formation may occur.

[0081] Example 7: Safety of 10% HP-β-CD (vehicle in Phase 2 clinical trials) This example demonstrates the safety of HP-β-CD in humans. The data are from the second stage of a Phase 2 clinical trial in pterygium patients who received topical 10% HP-β-CD as a vehicle for the test article. Patients were treated for 4 weeks with three doses per day and followed for an additional 20 weeks after treatment stopped. The safety evaluation also included a 20-week treatment-free period. The example shows results for the vehicle and not for the test article unrelated to this invention.

[0082] All safety analyses were performed on the safety population. Adverse events were coded using MedDRA nomenclature. The number and percentage of patients reporting adverse events were tabulated based on preferred term and / or system organ class. Tabulations were generated for all adverse events, regardless of causality, as well as treatment-related adverse events.

[0083] The mean duration of exposure to study treatment was 28 days, with 96% of patients having at least 28 days of treatment (Table 7). [Table 7]

[0084] Adverse events

[0085] A summary of adverse events is shown in Table 8. Ocular treatment-emergent adverse events (TEAEs) of any causality were reported in 16.0% (4 / 25) of the study eyes of patients in the vehicle group. There were no study discontinuations due to adverse events. No deaths or serious adverse events attributable to the drug were reported.

[0086] [Table 8]

[0087] In summary, in the phase 2 pterygium clinical trial using 10% HP-β-CD as a vehicle, only one treatment-related TEAE was reported, demonstrating an excellent safety profile.

[0088] Example 8: Screening of various cyclodextrins (CDs) and CD derivatives for their ability to dissolve cholesterol in water

[0089] the purpose: To measure the level of cholesterol that can be dissolved in water when ten types of CDs and their derivatives are added at three concentrations.

[0090] method: The CDs tested were α-cyclodextrin (ACD), β-cyclodextrin (BCD), γ-cyclodextrin (GCD), 2-hydroxypropyl-α-cyclodextrin (HP-ACD), 2-hydroxypropyl-β-cyclodextrin (HP-BCD), 2-hydroxypropyl-γ-cyclodextrin (HP-GCD), random methyl-β-cyclodextrin (M-BCD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-BCD), 6-O-α-maltosyl-β-cyclodextrin (6-AM-BCD), and sulfobutylated β-cyclodextrin (SBE-BCD).

[0091] All CD solutions were prepared at a starting 20% ​​(w / v) solution by precisely adding approximately 800 mg of CD to 4 milliliters of water, and for each sample preparation experiment, 1% and 10% were diluted to 2 mL from this 20% solution.

[0092] Cholesterol was added precisely to all aqueous CD solutions at approximately 40 mg / mL, or approximately 80 mg per 2 mL. This amount of cholesterol was sufficient to completely saturate the CD solution with a white precipitate, a floating substance, or both. All samples were conditioned at ambient temperature by shaking on a rotator for 5 days.

[0093] After equilibration at ambient temperature for 5 days with shaking, the clear or translucent fraction was filtered through a 0.2 μm filter. 50 μL of the filtrate was diluted with 450 μL of methanol (10×) and subjected to HPLC analysis. The mobile phase was acetonitrile:water (70:30), the flow rate was 0.5 ml / min, and detection was by UV at 210 nm on a NOVAPAK phenyl column (7.6 cm × 3.9 mm I.D.).

[0094] The results are summarized in Table 9.

[0095] [Table 9]

[0096] All natural, unmodified CDs had no or very low (below the method sensitivity) ability to solubilize cholesterol in water. The HP derivatives showed unexpectedly large differences among α-, β-, and γ-CD. HP-ACD had no detectable cholesterol-solubilizing activity, and HP-GCD had very low levels. In contrast, HP-BCD had substantial cholesterol-solubilizing activity.

[0097] Further studies focused on the BCD type and other derivatives of this type of CD. The results were unexpected: cholesterol-dissolving ability was ranked in the following order: methyl > hydroxypropyl > sulfobutyl > unmodified (no activity). Among the methylated BDs, M-BCD and DM-BCD were equally effective, while 6-Am-BCD was approximately half as effective. For CDs that showed cholesterol-dissolving activity, the activity was proportional to the CD concentration.

[0098] Summary of unexpected findings:

[0099] 1) Natural α-, β-, and γ-CD had no or very low ability to dissolve cholesterol in water.

[0100] 2) Among the CD derivatives, only the β-CD derivative showed substantial ability to dissolve cholesterol in water.

[0101] 3) For β-CD derivatives, the order of potency was methyl->hydroxypropyl->sulfobutyl-.

[0102] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

1. 1. A method for treating an ocular disease in an affected eye, comprising administering to the affected eye of a subject in need of such treatment a therapeutically effective amount of a steroidal androgen-free composition comprising a β-cyclodextrin derivative; the β-cyclodextrin derivative is a pharmaceutically active ingredient for treating the eye disease; The method, wherein the β-cyclodextrin derivative is the sole pharmaceutically active ingredient for treating the ocular disease.

2. 10. The method of claim 1, wherein the eye disease is one selected from the group consisting of meibomian gland dysfunction, blepharitis, and dry eye disease.

3. 3. The method of claim 1 or 2, wherein the steroidal androgen-free composition is administered topically to the affected eye or to the skin surrounding the affected eye.

4. The β-cyclodextrin derivatives include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-6-monobromo -β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6- (6-deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl β-cyclodextrin, succinyl β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl β-cyclodextrin, heptakis Heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,The method according to any one of claims 1 to 3, wherein the cyclodextrin is selected from the group consisting of heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof.

5. 5. The method of any one of claims 1 to 4, wherein the β-cyclodextrin derivative is present in the composition at a concentration of 0.1 to 30% w / w, 0.5 to 25% w / w, 1 to 20% w / w, 5 to 15% w / w, 8 to 12% w / w, about 10 w / w or 10 w / w.

6. 6. The method of claim 1, wherein the steroidal androgen-free composition does not contain androgens having a steroidal chemical structure, testosterone, or precursors of testosterone.

7. 10. The method of claim 1, further comprising the step of maintaining the effect of treating meibomian gland dysfunction for a period of time after administration.

8. 8. The method of claim 7, wherein the period of time after administration is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

9. dissolving lipid crystals deposited at the orifices of the meibomian glands of the affected eye; and The method of claim 1 , further comprising increasing tear film stability.

10. reducing foreign body sensation in the affected eye, hyperemia or redness of the affected eye and eyelid margin, obstruction of the meibomian gland orifices in the affected eye, inflammation of ocular tissue, corneal staining in the affected eye, burning sensation in the affected eye, photophobia, blurred vision, pain in the affected eye, or itching in the affected eye; Increasing tear film breakup time (TBUT); Steps to improve astigmatism: reducing the phase transition temperature of meibum; improving the clinical signs and symptoms of meibomian gland dysfunction (MGD); and combinations thereof; 10. The method of claim 1, wherein the ocular tissue is selected from the group consisting of a meibomian gland, a duct, an orifice, an eyelid, a cornea, and a conjunctiva.

11. A steroidal androgen-free composition comprising a β-cyclodextrin derivative as an active pharmaceutical ingredient, wherein the steroidal androgen-free composition is an ophthalmic composition.

12. 12. The steroidal androgen-free composition of claim 11, wherein the steroidal androgen-free composition consists essentially of a β-cyclodextrin derivative and one or more ingredients selected from the group consisting of hydroxypropyl guar, xantham gum, trehalose, sodium chloride, castor oil, Cremophor ELP, polysorbate 80, HPMC 2910, edetate disodium, glycerin, a buffer, and water.

13. 13. The method of claim 12, wherein the buffering agent is selected from the group consisting of monosodium phosphate monohydrate, citric acid, and sodium citrate.

14. 14. The steroidal androgen-free composition of any one of claims 11 to 13, wherein the β-cyclodextrin derivative is present in the steroidal androgen-free composition in a concentration of 0.1% w / w to 30% w / w.

15. The β-cyclodextrin derivatives include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-6-monobromo -β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6- (6-deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis Heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,The steroidal androgen-free composition according to any one of claims 11 to 14, wherein the steroidal androgen-free composition is selected from the group consisting of heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof.

16. 16. The steroidal androgen-free composition of any one of claims 11 to 15, wherein the steroidal androgen-free composition is a solution, suspension, emulsion, gel, ointment, or cream.

17. 16. The steroidal androgen-free composition of any one of claims 11 to 15, wherein the steroidal androgen-free composition is an artificial tear or a lubricant.

18. A steroidal androgen-free composition comprising a β-cyclodextrin derivative, sodium chloride, a buffer, and water.

19. The β-cyclodextrin derivatives include (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin, 6-monodeoxy-6-monoazido-β-cyclodextrin, 6-monodeoxy-6-monoiodo-β-cyclodextrin, 6-monodeoxy-6-monothio-β-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-β-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-β-cyclodextrin, and 6-monodeoxy-6-monobromo -β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-chloro)-β-cyclodextrin, heptakis(6-deoxy-6-bromo)-β-cyclodextrin, heptakis(6-deoxy-6-iodo)-β-cyclodextrin, heptakis(6- (6-deoxy-6-thio)-β-cyclodextrin, sulfobutylated β-cyclodextrin, acetyl β-cyclodextrin, carboxymethyl-β-cyclodextrin, succinyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin, sulfobutylated β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, heptakis(6-deoxy-6-amino)-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis Heptakis(2,3-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-β-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin, heptakis(6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin, heptakis(2,19. The steroidal androgen-free composition of claim 18, wherein the steroidal androgen-free composition is selected from the group consisting of heptakis(2,3-di-O-methyl-6-deoxy-6-amino)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-β-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-β-cyclodextrin, and combinations thereof.

20. 19. The steroidal androgen-free composition of claim 18, wherein the buffering agent is selected from the group consisting of monosodium phosphate monohydrate, citric acid, and sodium citrate.

21. 19. The steroidal androgen-free composition of claim 18, wherein the steroidal androgen-free composition is comprised of 5% to 20% of the β-cyclodextrin derivative, 0.20% to 0.80% sodium chloride, 0.10% to 0.30% monosodium phosphate monohydrate, and water.

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