Use method and pharmaceutical composition of selective SYK inhibitor

Abstract

Provided herein are methods of treating allergic and / or inflammatory diseases or conditions of the eye using Syk inhibitors (e.g., selective Syk inhibitor Compound 1 or a pharmaceutically acceptable salt thereof). Also provided are pharmaceutical compositions, in particular eye drop ophthalmic compositions, comprising Compound 1 or a pharmaceutically acceptable salt thereof, useful in the methods.

Description

[0001] This application is a divisional application of the invention patent application which entered the Chinese national phase on September 8, 2020, with application number 201980017916.9, application date on March 8, 2019, and invention name “Methods of use and pharmaceutical compositions of selective SYK inhibitors”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Nos. 62 / 641,094, filed March 9, 2018, and 62 / 663,999, filed April 27, 2018, which are hereby incorporated by reference in their entireties. Technical Field

[0004] The present disclosure relates to methods of treating ophthalmic diseases, such as allergic conjunctivitis and ocular inflammatory diseases, and pharmaceutical compositions for use therein. Background Art

[0005] Millions of Americans suffer from eye allergies. Most approved treatments for eye allergies are antihistamines, mast cell stabilizers, or both, which primarily work to reduce the signs and / or symptoms of an early allergic reaction. Traditional mast cell stabilizers have limited efficacy. Medications with antihistamine activity can work more intensely during the acute phase of an allergic reaction but generally relieve itching more than redness or swelling. While effective, antihistamines and antihistamine / mast cell stabilizers do not completely reduce signs and symptoms, and most patients are not completely satisfied with their relief. Steroids can also be used in more severe cases, but they are generally given in an acute setting with limited efficacy, require prolonged administration, and can cause side effects when administered chronically as topical eye drops. New treatments are needed that are faster-acting, longer-lasting, better at treating signs and symptoms, and safer with repeated dosing. There is also evidence that many patients with ocular allergies exhibit a persistent late-stage inflammatory response, necessitating the need for anti-allergy medications that are effective not only for the treatment of acute allergic reactions but also for the more complex chronic inflammatory environment caused by overlapping and ongoing allergen exposure. Existing treatments on the market are inadequate to address persistent or ongoing allergic reactions or the inflammatory component of such reactions.

[0006] Dry eye is a relatively common condition characterized by an inadequate tear film protecting the cornea. Traditionally, treatments for dry eye include eyelid hygiene, topical antibiotics (erythromycin or bacitracin ointment), oral tetracyclines (tetracycline, doxycycline, or minocycline), anti-inflammatory compounds (cyclosporine), and corticosteroids. These treatments are often time-consuming, frustrating, and often ineffective or inconsistent. Dry eye affects tens of millions of people worldwide, with an estimated nearly 5 million Americans aged 50 and older suffering from the condition. Of these, 3 million are women and 1.5 million are men. Dry eyes are common in older adults, but can occur at any age. Dry eye can also be caused by environmental factors and prolonged visual tasks. Dry eye is a potentially disabling condition that adversely impacts vision-related quality of life. Current treatment options are limited and expensive. Despite its high prevalence, dry eye remains a treatment challenge. Therefore, new therapies for dry eye remain unmet need.

[0007] Dry eye, also known as keratoconjunctivitis sicca (KCS), can be a temporary or chronic condition. Severe dry eye is a debilitating disease that affects millions of people worldwide and can be disabling for some. Millions of these people suffer from the most severe form. The disease often causes severe eye discomfort, leading to a dramatic change in quality of life, poor ocular surface health, significantly reduced visual acuity, and a threat to vision. Patients with severe dry eye develop sensitivity to light and wind, preventing them from spending significant time outdoors, and are often unable to read or drive due to discomfort.

[0008] In addition to allergies, there is a need for new anti-inflammatory agents for the treatment of ocular diseases and conditions. Current therapies such as steroids have well-known ocular side effects when administered repeatedly over prolonged periods of time (e.g., more than a few weeks). Therefore, there is a need for treatments that are equally or more effective and / or safer than existing anti-inflammatory drugs. Summary of the Invention

[0009] Provided herein are methods of treating ophthalmic allergic diseases, dry eye, and / or inflammatory diseases using Syk inhibitors. In some embodiments, a method of treating an ophthalmic disease is provided, comprising topically administering a therapeutically effective amount of a Syk inhibitor to the eye of a patient in need thereof.

[0010] In some embodiments, a method of treating an ophthalmic disease using 2-((1R,2S)-2-aminocyclohexylamino)-4-(3-(pyrimidin-2-yl)phenylamino)pyrimidine-5-carboxamide, a specific Syk inhibitor, or a salt thereof is provided.

[0011] The structural formula of 2-((1R,2S)-2-aminocyclohexylamino)-4-(3-(pyrimidin-2-yl)phenylamino)pyrimidine-5-carboxamide (also referred to herein as Compound 1) is as follows:

[0012] It is described in US Patent No. 8,318,755, which is incorporated herein by reference in its entirety.

[0013] In some embodiments, provided herein is a method for treating an ophthalmic disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the ophthalmic disease or condition is allergic and / or inflammatory, including one or more of the following: allergic conjunctivitis (also known as ocular allergy or eye allergy, including acute allergic conjunctivitis, chronic allergic conjunctivitis, transient allergic conjunctivitis, persistent allergic conjunctivitis, seasonal allergic conjunctivitis, or perennial allergic conjunctivitis), rhinoconjunctivitis, dry eye, keratoconjunctivitis, ocular inflammation, ocular surface or eyelid inflammation (e.g., dry eye, blepharitis, pterygium, peripheral corneal infiltrates, post-keratoplasty, blepharitis, episcleritis, scleritis, keratitis, fungal keratitis, blepharodermatitis, bacterial and viral conjunctivitis, atopic keratoconjunctivitis (AKC), neurotrophic keratitis, GVHD graft-versus-host disease), other ocular surface inflammation, irritation and / or congestion, and / or eyelid inflammation. Anterior chamber disease (e.g., anterior uveitis, postoperative inflammation, iritis), vernal keratoconjunctivitis (VKC), giant papillary conjunctivitis (GPC), neurotrophic keratitis, GVHD graft-host disease, traumatic and postoperative iritis, uveitis, palpebral maculopathy, pterygium, contact lens-induced dry eye, other steroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye, posterior uveitis, retinal diseases (e.g., macular edema with cystic macular edema), diabetic macular edema, branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), eye redness, eye swelling / chemosis, eyelid swelling, eyelid congestion, and itchy eyes, steroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye, and eye diseases requiring the use of corticosteroids. In some embodiments, the ophthalmic disease or condition is acute or chronic allergic conjunctivitis, which can be seasonal, perennial, transient, or persistent allergic conjunctivitis.

[0015] In some embodiments, the method treats anterior segment inflammatory diseases. In some embodiments, the method treats ocular surface inflammatory diseases, such as dry eye, blepharitis, pterygium, peripheral corneal infiltration, post-keratoplasty period, blepharophimosis, scleritis, scleritis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, fungal keratitis (through TLR signal transduction), bacterial or viral conjunctivitis (treatment of the inflammatory part, not necessarily as an anti-infective agent), steroid-responsive inflammation of the palpebral conjunctiva and bulbar conjunctiva of the eyeball, cornea and anterior segment of the eye, and other eye diseases requiring the use of corticosteroids. In some embodiments, the method treats anterior chamber inflammatory diseases, such as anterior uveitis, postoperative inflammation or traumatic and postoperative iritis.

[0016] In some embodiments, the method treats one or more signs / symptoms of allergic conjunctivitis, including redness, itching, eyelid swelling, conjunctival swelling, discomfort, increased tear production, sensitivity to light, keratitis, corneal staining, conjunctival staining, or markers of ocular inflammation, etc. In some embodiments, the method treats one or more signs and / or symptoms of dry eye, including discomfort, dryness, grittiness, dryness, burning, keratitis, conjunctival redness, conjunctival staining, corneal staining, decreased tear production, decreased tear breakup time, decreased quality of life, and decreased visual function.

[0017] In some embodiments, the method treats dry eye.

[0018] In some embodiments, provided herein is a method of treating an ophthalmic disease or condition comprising topically administering to a patient in need thereof about 0.001 mg to about 1 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once a day, twice a day, three times a day, or four times a day. In some embodiments, the method comprises administering about 0.001 mg to about 1 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to each eye of the patient.

[0019] In some embodiments, provided are pharmaceutical compositions suitable for treating ophthalmic diseases or conditions, particularly ophthalmic compositions in the form of eye drops, comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.

[0020] In some embodiments, provided herein are eye drop ophthalmic compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, a buffer, a tension modifier, and a vehicle (e.g., water). In some embodiments, the eye drop ophthalmic composition further comprises a preservative. In some embodiments, the eye drop ophthalmic composition further comprises a demulcent, a surfactant, or a polymer system.

[0021] The eye drop ophthalmic composition described herein contains Compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 0.001% to about 10%; about 0.01% to about 10%; about 0.05% to about 10%; about 0.1% to about 10%; about 0.2% to about 7%; about 0.3% to about 5%; about 0.4% to about 2%; or about 0.5% to about 1% w / w. In some embodiments, the eye drop ophthalmic composition contains about 0.5% to about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the eye drop ophthalmic composition contains about 0.5% or about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the eye drop ophthalmic composition contains Compound 1 HCl salt.

[0022] In some embodiments, the tension regulator is one or more of glycerol (also known as glycerol), NaCl, and KCl. In some embodiments, the eye drop ophthalmic composition comprises about 0.1% to about 5% w / w of tension regulator. In some embodiments, the eye drop ophthalmic composition comprises about 0.2% to about 2% w / w of tension regulator. In some embodiments, the eye drop ophthalmic composition comprises about 0.5% to about 1.5% w / w of tension regulator. In some embodiments, the eye drop ophthalmic composition comprises about 0.5% w / w of tension regulator. In some embodiments, the eye drop ophthalmic composition comprises about 1.5% w / w of tension regulator. In some embodiments, the eye drop ophthalmic composition comprises about 1% to about 2% w / w of glycerol. In some embodiments, the eye drop ophthalmic composition comprises about 1.5% w / w of glycerol.

[0023] In some embodiments, the eye drop ophthalmic composition comprises about 0.005% to about 0.02% w / w of a preservative. In some embodiments, the eye drop ophthalmic composition comprises about 0.01% w / w of a preservative. In some embodiments, the preservative is benzalkonium chloride. In some embodiments, the eye drop ophthalmic composition comprises about 0.005% to about 0.02% w / w of benzalkonium chloride. In some embodiments, the eye drop ophthalmic composition comprises about 0.01% w / w of benzalkonium chloride. In some embodiments, the eye drop ophthalmic composition does not comprise a preservative.

[0024] In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is about 5 mM to about 20 mM phosphate buffer. In some embodiments, the buffer is about 10 mM phosphate buffer.

[0025] In some embodiments, the vehicle comprises water and the eye drop ophthalmic composition is an aqueous ophthalmic composition.

[0026] In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.1% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer in water, and having a pH of about 5.5 to 7.5.

[0027] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer formulated with water and having a pH of about 5.5 to 7.5.

[0028] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a buffer formulated with water, and having a pH of about 5.5 to 7.5.

[0029] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a buffer formulated with water, and having a pH of about 6.

[0030] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a buffer formulated with water, and having a pH of about 6.

[0031] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a phosphate buffer formulated with water, and having a pH of about 5.5 to 7.5.

[0032] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0033] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0034] In some embodiments, an aqueous ophthalmic composition is provided comprising about 1% w / w Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0035] In some embodiments, the aqueous ophthalmic composition is free of stabilizers.

[0036] In some embodiments, the aqueous ophthalmic composition further comprises a stabilizer.

[0037] Also provided herein are methods of using and making the compositions described herein.

[0038] These and other embodiments are described in greater detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Shown are the changes in mean hyperemia scores before and after conjunctival allergen challenge in the mouse experiment described in Example 6.

[0041] Figure 2A Baseline imaging of the conjunctiva using in vivo confocal microscopy to assess microvasculature and score inflammation as described in Example 7 on a scale from 0 (no leukocytes) to 4 (visible cellular inflammation) is shown. Figure 2B Shown is an image of the conjunctiva after allergen challenge 8 hours after treatment. Figure 1 and 2, from left to right: vehicle (N=3), (N=8), Composition B, 1% of Compound 1 (N=7) and Composition A, 0.5% of Compound 1 (N=5). Detailed description

[0043] definition

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art. As used herein, unless otherwise indicated, the following terms have the following meanings. Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the compositions and methods described herein. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references cited herein are incorporated by reference in their entirety.

[0045] The headings used in this application are for reference purposes only and do not limit the disclosure in any way.

[0046] The term "comprise" and its variations, such as "comprising," are to be interpreted in an open, inclusive sense, i.e., "including, but not limited to." When used to define compositions and methods, "consisting essentially of" or its grammatical variations shall mean the exclusion of other elements that are of any material significance to the compositions and methods for their intended use, but shall not exclude elements that do not materially affect the characteristics of the compositions or methods. "Consisting of" or its grammatical variations shall mean the exclusion of elements not specifically recited. Embodiments defined by each of these transition terms are within the scope of this disclosure. For example, when a composition is described as comprising ingredients A, B, and C, a composition consisting essentially of A, B, and C and a composition consisting of A, B, and C are independently within the scope of this disclosure.

[0047] It is noted here that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "pharmaceutically acceptable vehicle" includes reference to both one and more than one pharmaceutically acceptable vehicle.

[0048] The term "about" refers to within ±20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.05% of a given value or range. In one embodiment, about means ±5% of a given value or range. In another embodiment, "about" means ±4% of a given value or range. In another embodiment, "about" means ±3% of a given value or range. In another embodiment, "about" means ±2% of a given value or range. In another embodiment, "about" means ±1% of a given value or range. In another embodiment, "about" means ±0.5% of a given value or range. In another embodiment, "about" means ±0.05% of a given value or range. The term "about x" includes the values ​​"x" and "x".

[0049] The term "administering" refers to the introduction of a pharmaceutical agent into a patient. A therapeutic amount may be administered, which may be determined by an attending physician or the like. When used in conjunction with a compound or composition, the related terms and phrases "administering" and "administering" (and grammatical equivalents) refer to both direct administration (which may be administered to a patient by a medical professional or by the patient through self-administration) and / or indirect administration (which may be the act of prescribing a drug). Administration requires the delivery of the drug to the patient.

[0050] The terms "dose" and "dosage" refer to the total amount of active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) administered to a patient in a single dose. The terms "dose" and "dosage" are used interchangeably herein.

[0051] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or pharmaceutical agent that, when administered to a patient suffering from a condition or disease, will have the intended therapeutic effect (e.g., alleviate or cure the disease, relieve, alleviate, lessen, or eliminate one or more symptoms or manifestations of the patient's condition or disease). The therapeutic effect does not necessarily occur with a single administration, but can occur after a series of doses administered over a period of time (e.g., one day, two days, three days, four days, five days, one week, two weeks, three weeks, one month, etc., or as needed and appropriate).

[0052] The term "pharmaceutically acceptable" means generally safe and non-toxic for administration in vivo, preferably to humans.

[0053] The term "patient" refers to a mammal, such as a human, cow, rat, mouse, dog, cat, monkey, ape, goat, sheep, cattle, horse, or deer. As described herein, the patient can be human. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or adolescent.

[0054] "Treatment" is defined as the action of an agent on a disease, condition, or disorder to reduce or ameliorate the deleterious or any other undesirable effects of the disease, condition, or disorder and / or its symptoms. As used herein, treatment encompasses the treatment of human patients and includes: (a) reducing the risk of the disease or disorder developing in a patient determined to be susceptible to the disease or disorder but not yet diagnosed as having the disease or disorder, (b) hindering the development of the disease or disorder, and / or (c) relieving the disease or disorder, i.e., causing regression of the disease or disorder and / or relieving one or more symptoms of the disease or disorder. For the treatment of an ophthalmic disease or disorder, beneficial or desired clinical results include, but are not limited to, reducing or eliminating allergic reactions and / or inflammation, reducing or eliminating one or more symptoms of the ophthalmic disease, such as reducing or eliminating itchy eyes, and / or reducing or eliminating conjunctival redness, reducing ocular discomfort, reducing corneal or conjunctival pigmentation, etc., including any other symptom or combination of symptoms provided herein.

[0055] As used herein, "% w / w" refers to the weight of a component based on the total weight of the composition in which it is contained. For example, if component 1 is present in an amount of 50 mg in a 100 mg composition, then component 1 is present in an amount of 50% w / w. It should be understood that, unless otherwise expressly stated, "% w / w" refers to the percentage of an agent or excipient relative to the total weight of a composition described herein. Unless expressly stated, weight percentages described herein do not include the weight of the container.

[0056] Treatment

[0057] Provided herein are methods for treating ophthalmic diseases using Syk inhibitors. In some embodiments, provided herein is a method for treating an ophthalmic disease or condition, comprising topically administering a therapeutically effective amount of a Syk inhibitor to the eye of a patient in need thereof. In some embodiments, provided herein are uses of Syk inhibitors in the treatment of ophthalmic diseases or conditions. In some embodiments, provided herein are uses of Syk inhibitors in the preparation of a medicament for treating an ophthalmic disease or condition.

[0058] In some embodiments, the Syk inhibitor is administered once, twice, three times, or four times daily in the form of an ophthalmic composition. In some embodiments, the Syk inhibitor can be administered via a sustained-release drug delivery mechanism. In some embodiments, the method comprises topically administering to the eye of a patient in need thereof about 0.001 mg to about 10 mg of the Syk inhibitor once, twice, or three times daily. In some embodiments, the method comprises administering to a patient in need thereof about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg, or any range (inclusive) between any two values, of a Syk inhibitor once daily, twice daily, or three times daily. In some embodiments, the method comprises topically administering one or two drops of an ophthalmic composition comprising a Syk inhibitor to an eye of a patient in need thereof once daily, twice daily, three times daily, or four times daily.

[0059] In some embodiments, provided herein is a method for treating an ophthalmic disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the treatment of an ophthalmic disease or condition. In some embodiments, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of an ophthalmic disease or condition.

[0061] The chemical name of compound 1 is: 2-((1R,2S)-2-aminocyclohexylamino)-4-(3-(pyrimidin-2-yl)phenylamino)pyrimidine-5-carboxamide, and the structural formula is:

[0062]

[0063] It is described in US Patent No. 8,318,755, which is incorporated herein by reference in its entirety.

[0064] Compound 1 or a pharmaceutically acceptable salt thereof is also referred to herein as an active ingredient or API. Pharmaceutically acceptable salts of Compound 1 include acid addition salts whose counterions are non-toxic to patients at pharmaceutical doses of the salt, such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, fluorescein, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate , methanesulfonate, 2-naphthalenesulfonic acid, nicotinate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, undecanoate, hydrohalide (such as hydrochloride and hydrobromide), sulfate, phosphate, nitrate, amidosulfate, malonate, salicylate, methylenebis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluene tartrate, ethanesulfonate, cyclohexylaminosulfonate, quinate, etc. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is one or more of the formate, oxalate, maleate, citrate, phosphate or hydrochloride of Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is one or more of the formate, maleate, citrate, phosphate or hydrochloride of Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is the hydrochloride of Compound 1, also known as the HCl salt of Compound 1 or Compound 1 hydrochloride. In some embodiments, the ophthalmic composition (eg, an aqueous ophthalmic composition) comprises a cation of Compound 1 and an anion of an acid described herein.

[0065] In some embodiments, the ophthalmic disease or condition is allergic and / or inflammatory, including one or more of the following diseases: allergic conjunctivitis (also known as ocular allergy or eye allergy, including acute allergic conjunctivitis, chronic allergic conjunctivitis, transient allergic conjunctivitis, persistent allergic conjunctivitis, seasonal allergic conjunctivitis, or perennial allergic conjunctivitis), rhinoconjunctivitis, dry eye, keratoconjunctivitis, ocular inflammation, ocular surface or eyelid inflammation (e.g., dry eye, blepharitis, pterygium, peripheral corneal infiltrates, post-keratoplasty, blepharophimosis, episcleritis, scleritis, keratitis, fungal keratitis, eyelid dermatitis, bacterial and viral conjunctivitis, atopic keratoconjunctivitis (AKC), neurotrophic In some embodiments, the ophthalmic disease or condition is acute or chronic allergic conjunctivitis, which may be seasonal, perennial, transient or persistent allergic conjunctivitis.

[0066] In some embodiments, the ophthalmic disease or condition is one or more of the following: allergic conjunctivitis (e.g., acute allergic conjunctivitis, chronic allergic conjunctivitis, transient allergic conjunctivitis, persistent allergic conjunctivitis, seasonal allergic conjunctivitis, or perennial allergic conjunctivitis), rhinoconjunctivitis, dry eye, keratoconjunctivitis, blepharitis, eyelid dermatitis, blepharoconjunctivitis, viral conjunctivitis, bacterial conjunctivitis, other infections caused by viruses, bacteria, or fungi, eye inflammation, irritation, and / or congestion, inflammation of the ocular surface, eyelid, or anterior or posterior chamber of the eye, atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VK), C), neurotrophic keratitis, GVHD graft-host disease, traumatic and postoperative iritis, iritis, episcleritis, keratitis, uveitis, palpebral fissure maculopathy, pterygium, contact lens-induced dry eye, posterior uveitis, retinal diseases (such as macular edema with cystic macular edema), diabetic macular edema, branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), redness of the eye, swollen eyelids, eyelid congestion, swollen and itchy eyes, steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye, and eye diseases requiring the use of corticosteroids. In some embodiments, the ophthalmic disease or condition is acute or chronic allergic conjunctivitis, which can be seasonal, perennial, transient, or persistent.

[0067] In some embodiments, the ophthalmic disease or condition is an anterior segment inflammatory disease. In some embodiments, the ophthalmic disease or condition is an ocular surface inflammatory disease, such as dry eye, blepharitis, pterygium, peripheral corneal infiltration, post-keratoplasty period, blepharophimosis, scleral epidermitis, iritis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, fungal keratitis (through TLR signal transduction), bacterial or viral conjunctivitis (treatment of the inflammatory part, not necessarily as an anti-infective agent), steroid-responsive inflammation of the palpebral and bulbar conjunctiva of the eyeball, cornea and anterior segment, and an eye disease requiring the use of corticosteroids. In some embodiments, the ophthalmic disease or condition is an anterior chamber inflammatory disease, such as anterior uveitis, postoperative inflammation, or traumatic or postoperative iritis.

[0068] In some embodiments, the method treats symptoms of an ophthalmic disease or condition including redness, inflammation, irritation, eyelid swelling, eyelid congestion, chemosis (conjunctival swelling), increased tear production, itching, burning, foreign body sensation and / or other discomfort, dryness, grittiness, burning, keratitis, conjunctival redness, conjunctival staining, corneal staining, decreased tearing, decreased tear breakup time, decreased quality of life, decreased visual function, or a combination thereof. Symptoms of dry eye include, but are not limited to, stinging or burning of the eye; a grittiness or gritty sensation, as if there is a foreign body in the eye; excessive tearing after a very severe dry eye episode; a fine discharge from the eye; eye pain and redness; episodes of blurred vision; heavy eyelids; inability to cry during emotional stress; contact lens discomfort; decreased tolerance for reading, working on a computer, or any activity requiring sustained visual attention; and eye fatigue.

[0069] In some embodiments, the method treats symptoms of acute or chronic allergic conjunctivitis, including itching, redness (e.g., conjunctival redness, scleral redness, and ciliary body redness), inflammation, eyelid swelling, chemosis, increased tear production, and photosensitivity.

[0070] In some embodiments, the method further treats one or more other allergy symptoms, including nasal allergy symptoms, such as nasal congestion, rhinorrhea, and nasal itching, ear or throat itching, and allergic headaches.

[0071] In some embodiments, the method treats symptoms of dry eye, including stinging and / or burning sensations, grittiness, episodes of excessive tearing, fine discharge, pain, redness, blurred vision, double eyelids, inability to cry, discomfort (e.g., when wearing contact lenses), decreased tolerance for visual attention, and eye fatigue.

[0072] In some embodiments, allergic conjunctivitis is caused by perennial allergens (e.g., cat dander, dog dander, dust mites, and / or cockroaches) and / or seasonal allergens (e.g., tree, grass, and / or ragweed pollen) or pollutants. In some embodiments, dry eye is caused by environmental factors, nutrition, inflammatory diseases, systemic diseases, hydration levels, genetic factors, neurotrophic disorders or diseases, neurological conditions, or other dysfunction of the tear film (tear production, mucus production, lipid production) or other ocular surface disorders.

[0073] In some embodiments, the ophthalmic disease or condition is allergic and / or inflammatory, including signs and / or symptoms of one or more of the following diseases: allergic conjunctivitis (including acute allergic conjunctivitis, chronic allergic conjunctivitis, seasonal allergic conjunctivitis, or perennial allergic conjunctivitis), rhinoconjunctivitis, dry eyes, keratoconjunctivitis, blepharitis, eyelid dermatitis, blepharoconjunctivitis, pterygium, post-operative corneal transplantation, blepharitis, epiiritis, iritis, keratitis, peripheral corneal infiltrates, fungal keratitis, bacterial and viral conjunctivitis, post-operative inflammation, ocular inflammation, inflammation of the ocular surface, eyelid, or anterior or posterior chamber, atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), giant papillary conjunctivitis (GPC), neurotrophic keratitis, GVHD graft-host disease, traumatic or postoperative iritis, uveitis, palpebral maculopathy, pterygium, contact lens-induced dry eye, other ocular surface inflammation, irritation, and / or congestion, posterior uveitis, retinal diseases, diabetic macular edema, branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), eye redness, eyelid swelling, eyelid congestion, eye swelling, and itchy eyes, steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye, and eye diseases requiring corticosteroids.

[0074] In some embodiments, the ophthalmic disease or condition is one or more of dry eye, blepharitis, pterygium, peripheral corneal infiltrate, post-keratoplasty period, blepharophimosis, epi-iritis / iritis, atopic keratoconjunctivitis, fungal keratitis, allergy, AKC, VKC, GPC, bacterial or viral conjunctivitis, anterior uveitis, traumatic or post-operative iritis, eyelid swelling, eye redness, irritation, ocular surface inflammation, or post-operative inflammation.

[0075] In some embodiments, one or more of eye redness, inflammation, swelling, discomfort, increased tearing and itching, keratitis, corneal staining, conjunctival staining, or markers of inflammation are reduced or eliminated.

[0076] In some embodiments, the ophthalmic disease is one or more of dry eye, allergic conjunctivitis, keratoconjunctivitis (sicca), keratitis, blepharitis, pterygium, peripheral corneal infiltrates, post-keratoplasty period, blepharitis, epiiritis / iritis, atopic keratoconjunctivitis, fungal keratitis, bacterial and viral conjunctivitis, anterior uveitis or post-operative inflammation and signs and / or symptoms thereof.

[0077] In addition, the FDA-accepted allergy clinical model, conjunctival allergen challenge (CAC), may become a standard for screening and developing new products. CAC can be used to screen new anti-inflammatory drugs to identify potential uses in conditions and diseases other than those specifically targeted for allergy. CAC can be used for dose ranging, proof of concept, and identification of specific anti-inflammatory effects.

[0078] Compound 1 or its pharmaceutically acceptable salt can be applied in a suitable composition, for example, in the form of a solution, suspension, emulsion, ointment, gel, spray, depot or sustained-release implant or depot, and can be applied topically as eye drops or intraocular injections, implants or inserts, or systemically. When applied topically, Compound 1 or its pharmaceutically acceptable salt can be applied to one or both eyes. It can be applied to the naked eye, eyes with contact lenses, or within or on contact lenses or contact lens packaging solutions. Compound 1 or its pharmaceutically acceptable salt can be applied once a day, twice a day, three times a day, four times a day, or more times at appropriate intervals throughout the day, or as needed. In some embodiments, Compound 1 or its pharmaceutically acceptable salt is administered once a day. In some embodiments, Compound 1 or its pharmaceutically acceptable salt is administered twice a day. In some embodiments, Compound 1 is administered in the form of an ophthalmic composition comprising Compound 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles include carriers, diluents, or excipients suitable for ophthalmic use. For example, generally, acceptable vehicles themselves do not produce undesirable irritation and do not induce the secretion of tears that entrain the active ingredient. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in a composition described herein.

[0079] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof can be administered via a sustained-release drug delivery system that releases Compound 1 over time. For example, a sustained-release drug delivery system can deliver about 0.001 mg to about 10 mg of Compound 1 to the eye of a patient in need thereof. In some embodiments, the method comprises administering to an eye of the patient about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg of Compound 1, or any range (including endpoints) between any two values. The sustained-release drug delivery system can deliver Compound 1 over a period of about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 1 day, about 1 week, about 1 month, or about 1 year. In some embodiments, Compound 1 can be administered over a period of time determined by a medical practitioner.

[0080] In some embodiments, the method further comprises administering another agent, such as an antihistamine, a vasoconstrictor, an antibiotic, an anti-inflammatory, an immunosuppressant, an agent for relieving dry eye or discomfort or signs, an anti-vascular agent, an anti-fibrotic agent, an anti-angiogenic agent, a wound healing agent, etc., either in a fixed combination or in the form of concomitant or adjunctive administration.

[0081] Pharmaceutical composition

[0082] Also provided herein are pharmaceutical compositions suitable for treating ophthalmic diseases or conditions (such as those described herein), particularly eye drop ophthalmic compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable liquid vehicle. The eye drop liquid vehicle can be aqueous or non-aqueous in nature. In some embodiments, the vehicle comprises water, and the eye drop ophthalmic composition is an aqueous ophthalmic composition.

[0083] In some embodiments, the compositions provided herein are stable clear liquids suitable for use as eye drops with a minimal number of excipients that deliver an effective amount of the active ingredient with minimal or no side effects or discomfort to the eye.

[0084] In some embodiments, the ophthalmic composition (e.g., an aqueous ophthalmic composition) comprises a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is one or more of a formate, an oxalate, a maleate, a citrate, a phosphate, or a hydrochloride. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Compound 1 HCl salt.

[0085] In some embodiments, the ophthalmic composition (e.g., an aqueous ophthalmic composition) comprises Compound 1 and / or a cation of Compound 1, and an anion of an acid. In some embodiments, the anion of the acid is a formate anion, an oxalate anion, a maleate anion, a citrate anion, a phosphate anion, or a chloride anion (Cl - )

[0086] In some embodiments, an eye drop ophthalmic composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, a liquid vehicle, and an excipient is provided, which may include a buffer, a tonicity adjuster, a stabilizer, a solubilizer, a preservative, a surfactant, a demulcent, a viscosity increasing agent, a chelating agent, an antioxidant, and a penetration enhancer.

[0087] In some embodiments, provided are aqueous ophthalmic compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, water, and excipients, which may include one or more of a buffer, a tonicity adjuster, a stabilizer, a preservative, a surfactant, a demulcent, a viscosity enhancer, a chelating agent, an antioxidant, and a penetration enhancer.

[0088] In some embodiments, an aqueous ophthalmic composition is provided, the method comprising mixing Compound 1 or a pharmaceutically acceptable salt thereof, water, and an excipient, wherein the excipient may comprise one or more of a buffer, a tonicity adjuster, a stabilizer, a preservative, a surfactant, a demulcent, a viscosity enhancer, a chelating agent, an antioxidant, and a penetration enhancer. In some embodiments, the method further comprises adjusting the pH of the composition.

[0089] In some embodiments, the aqueous ophthalmic composition is a clear solution. In other embodiments, the ophthalmic composition can be a non-aqueous liquid.

[0090] In some embodiments, the buffer is selected from a borate buffer, a phosphate buffer, a carbonate buffer, and an acetate buffer, or a combination thereof.

[0091] In some embodiments, the tonicity adjusting agent is one or more of glycerol (also known as glycerol), sodium chloride (NaCl), potassium chloride (KCl), dextrose, sucrose, mannitol, sorbitol, polyethylene glycol (PEG), PEG 3350, magnesium citrate, lactulose, and a colloid osmotic agent (e.g., pentavalent starch, hemistarch, gelatin polypeptide, dextran, albumin, alginate, and crystalline cellulose derivatives), or a combination thereof. In some embodiments, the tonicity adjusting agent is one or more of glycerol, NaCl, and KCl.

[0092] In some embodiments, the preservative is selected from chlorobutanol, sodium dehydroacetate, benzalkonium chloride (BAC), cetylpyridinium chloride, phenylethyl alcohol, parabens (e.g., methyl, ethyl, propyl, or butyl), benzethonium chloride, sodium perborate, sepazonium, iodine, polyquaternium salts (polyquad), sodium chlorite, and hypochlorous acid, or a combination thereof. In some embodiments, the preservative is benzalkonium chloride.

[0093] In some embodiments, the viscosity increasing agent is selected from methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, carboxymethylcellulose, chondroitin sulfate, salts thereof, or combinations thereof.

[0094] Examples of chelating agents include sodium edetate and citric acid.

[0095] Examples of stabilizers include sodium edetate, sodium bisulfite, and stabilizers as defined in U.S. Patent Application Publication No. 2007 / 0265234, herein incorporated by reference in its entirety.

[0096] In some embodiments, the stabilizer is one or more of a polysorbate (e.g., polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80), PEG-35 castor oil (e.g., PEG-30 castor oil, PEG-33 castor oil, PEG-35 castor oil, PEG-36 castor oil, or PEG-40 castor oil), and polyvinylpyrrolidone (also known as povidone or PVP, e.g., PVP K20, PVP K25, PVP K29 / 32, PVP K32, PVP K35, and PVP K40).

[0097] Examples of solubilizers include, but are not limited to, polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate, and semifluorinated alkanes.

[0098] In some embodiments, the ophthalmic composition (eg, an aqueous ophthalmic composition) does not comprise a stabilizer or solubilizer.

[0099] It is expected that the eye drops can be 25 μL (microliters) to 50 μL. In some embodiments, the eye drops are administered to the patient at 1 to 2 drops per eye. As a non-limiting example, a single drop of a 5 to 10 mg / mL composition of compound 1 may contain 0.125 mg to 0.5 mg of compound 1. Thus, in a non-limiting example, the patient receives up to 2 drops (1 mg total) per eye (2 mg total for both eyes) twice a day, thus administering a total of 4 mg to the patient per day.

[0100] The ophthalmic compositions described herein (e.g., aqueous ophthalmic compositions) can comprise or deliver to the eye Compound 1, or a pharmaceutically acceptable salt thereof, in an amount (% w / w) of about 0.001% to about 10%; about 0.01% to about 10%; about 0.05% to about 10%; about 0.1% to about 1%; about 0.1% to about 2%; about 0.1% to about 5%; about 0.1% to about 10%; about 0.2% to about 7%; about 0.3% to about 5%; about 0.4% to about 2%; or about 0.5% to about 1% w / w. In some embodiments, the ophthalmic composition (e.g., aqueous ophthalmic composition) comprises Compound 1, or a pharmaceutically acceptable salt thereof, in an amount (% w / w) of about 0.001% to about 7%; about 0.001% to about 5%; about 0.001% to about 2%; or about 0.001% to about 1% w / w. In some embodiments, the ophthalmic composition (e.g., an aqueous ophthalmic composition) comprises Compound 1 or a pharmaceutically acceptable salt thereof in an amount (% w / w) of about 0.01% to about 7%; about 0.01% to about 5%; about 0.01% to about 2%; or about 0.01% to about 1% w / w. For example, the ophthalmic composition (e.g., an aqueous ophthalmic composition) may comprise (% w / w) about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about

[0101] 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about

[0102] 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about

[0103] 2.7%, about 2.8%, about 2.9% or about 3% w / w or any range between any two numbers (including endpoints) of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the ophthalmic composition (e.g., an aqueous ophthalmic composition) comprises about 0.5% to about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the ophthalmic composition (e.g., an aqueous ophthalmic composition) comprises about 0.5% or about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 5.5 to about 8. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 6 to about 7.5. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 6.5 to about 7.3. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 6.8 to about 7.2. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is about 7. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 5.5 to about 7. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 5.7 to about 6.5. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 5.9 to about 6.3. In some embodiments, the pH of the ophthalmic composition (e.g., an aqueous ophthalmic composition) is from about 6 to about 6.2. In some embodiments, the pH of the ophthalmic composition (eg, an aqueous ophthalmic composition) is about 6.

[0105] In some embodiments, the pH of the composition is adjusted by one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, citric acid, phosphoric acid, acetic acid, and hydrochloric acid.

[0106] In some embodiments, the aqueous ophthalmic composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, a buffer for adjusting the pH of the composition, and water. In some embodiments, the buffer is selected from borate buffers, phosphate buffers, citrate buffers, carbonate buffers, and acetate buffers. In some embodiments, the concentration of the buffer in the ophthalmic composition is from about 1 mM to about 150 mM or higher, depending on the specific buffer selected. In some embodiments, the concentration of the buffer is less than 100 mM, for example, from about 1 mM to about 25 mM, or from about 1 mM to about 20 mM.

[0107] In some embodiments, the buffer is a citrate buffer or a phosphate buffer. In some embodiments, the buffer is about 5 mM to about 20 mM citrate buffer. In some embodiments, the buffer is about 5 mM to about 20 mM phosphate buffer. In some embodiments, the buffer is about 10 mM citrate buffer. In some embodiments, the buffer is about 10 mM phosphate buffer.

[0108] In some embodiments, the aqueous ophthalmic composition has an osmotic pressure of about 200 to about 350 mOsm / kg. In some embodiments, the aqueous ophthalmic composition has an osmotic pressure of about 230 to about 310 mOsm / kg.

[0109] In some embodiments, the aqueous ophthalmic composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, a tonicity adjusting agent for adjusting the osmotic pressure of the composition, and water.

[0110] In some embodiments, the aqueous ophthalmic composition comprises about 0.1% to about 5% w / w of a tonicity adjusting agent. In some embodiments, the aqueous ophthalmic composition comprises about 0.2% to about 2% w / w of a tonicity adjusting agent. In some embodiments, the aqueous ophthalmic composition comprises about 0.5% to about 1.5% w / w of a tonicity adjusting agent. In some embodiments, the aqueous ophthalmic composition comprises about 0.5% w / w of a tonicity adjusting agent. In some embodiments, the aqueous ophthalmic composition comprises about 1.5% w / w of a tonicity adjusting agent. In some embodiments, the aqueous ophthalmic composition comprises about 0.2% to about 1% w / w of NaCl. In some embodiments, the aqueous ophthalmic composition comprises about 0.5% w / w of NaCl. In some embodiments, the aqueous ophthalmic composition comprises about 1% to about 2% w / w of glycerin. In some embodiments, the aqueous ophthalmic composition comprises about 1.5% w / w of glycerin.

[0111] In some embodiments, the aqueous ophthalmic composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, a buffer, a tonicity adjuster, and water.

[0112] In some embodiments, the aqueous ophthalmic composition further comprises a preservative to prevent decomposition or microbial growth.

[0113] In some embodiments, the aqueous ophthalmic composition comprises about 0.005% to about 0.02% w / w preservative. In some embodiments, the aqueous ophthalmic composition comprises about 0.01% w / w preservative.

[0114] In some embodiments, the aqueous ophthalmic composition comprises about 0.005% to about 0.02% w / w benzalkonium chloride. In some embodiments, the aqueous ophthalmic composition comprises about 0.01% w / w benzalkonium chloride.

[0115] In some embodiments, the aqueous ophthalmic composition further comprises a stabilizer to prevent physical changes, such as precipitation.

[0116] In some embodiments, the aqueous ophthalmic composition comprises from about 0% to about 5% w / w of a stabilizer. In some embodiments, the aqueous ophthalmic composition comprises from about 1% to about 3% w / w of a stabilizer. In some embodiments, the aqueous ophthalmic composition comprises about 2% w / w of a stabilizer.

[0117] In some embodiments, the stabilizer is polysorbate 80 (PS80, trade name Montanox TM 80. TW 80 and 80), PEG-35 castor oil (also known as polyoxyethylene 35 hydrogenated castor oil, polyoxyl-35 castor oil, macrogolglycerol ricinoleate, trade name EL, ELP and EL) and povidone K29 / 32 (PVP K29 / 32, trade name Plasdone TM In some embodiments, the aqueous ophthalmic composition comprises about 0% to about 5% w / w polysorbate 80, PEG-35 castor oil, or PVP K29 / 32.

[0118] In some embodiments, the aqueous ophthalmic composition comprises about 1% to about 3% w / w polysorbate 80, PEG-35 castor oil, or PVP K29 / 32. In some embodiments, the aqueous ophthalmic composition comprises about 2% w / w polysorbate 80, PEG-35 castor oil, or PVP K29 / 32.

[0119] In some embodiments, the aqueous ophthalmic composition does not comprise a stabilizer, yet is surprisingly stable.

[0120] In some embodiments, the aqueous ophthalmic composition comprises a solubilizer. Examples of solubilizers include, but are not limited to, polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate. In some embodiments, the aqueous ophthalmic composition does not comprise a solubilizer.

[0121] In some embodiments, the aqueous ophthalmic composition comprises a viscosity increasing agent.

[0122] In some embodiments, the aqueous ophthalmic composition comprises a chelating agent. In some embodiments, the chelating agent is sodium edetate or citric acid.

[0123] In some embodiments, an ophthalmic composition is provided comprising about 0.1% w / w to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, a tonicity adjuster, a buffer, and water.

[0124] In some embodiments, an ophthalmic composition is provided comprising about 0.5% w / w to about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, a tonicity adjuster, a buffer, and water.

[0125] In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.001% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water, and having a pH of about 5.5 to 7.5.

[0126] In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.01% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water, and having a pH of about 5.5 to 7.5.

[0127] In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.1% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water, and having a pH of about 5.5 to 7.5.

[0128] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.001% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water and having a pH of about 5.5 to 7.5.

[0129] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.01% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water and having a pH of about 5.5 to 7.5.

[0130] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water and having a pH of about 5.5 to 7.5.

[0131] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w glycerin, about 0.005% and about 0.02% w / w benzalkonium chloride, and a buffer formulated with water and having a pH of about 5.5 to 7.5.

[0132] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1% to about 2% w / w of glycerol, about 0.005% and about 0.02% w / w of benzalkonium chloride, and a buffer formulated with water and having a pH of about 6.

[0133] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, about 0.005% and about 0.02% w / w of benzalkonium chloride, and a buffer formulated with water and having a pH of about 6.

[0134] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 HCl salt, about 1% to about 2% w / w glycerin, about 0.005% and about 0.02% w / w benzalkonium chloride, and a phosphate buffer formulated with water and having a pH of about 5.5 to 7.5.

[0135] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0136] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0137] In some embodiments, an aqueous ophthalmic composition is provided comprising about 1% w / w Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0138] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% of Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w polysorbate 80, and about 10 mM citrate buffer formulated with water and having a pH of about 6.

[0139] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, about 2% w / w of PEG-35 castor oil, and about 10 mM citrate buffer formulated with water and having a pH of about 6.

[0140] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% of Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w polysorbate 80, and about 10 mM phosphate buffer formulated with water and having a pH of about 6.

[0141] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, about 2% w / w of PEG-35 castor oil, and about 10 mM phosphate buffer formulated with water and having a pH of about 6.

[0142] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w PVP K29 / 32, and about 10 mM phosphate buffer formulated with water and having a pH of about 6.

[0143] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.001% to about 2% w / w of Compound 1 and / or its cation, Cl - , about 1% to about 2% w / w tonicity adjusting agent, about 0.005% and about 0.02% w / w preservative, a buffer and water, and having a pH of about 5.5 to 7.5.

[0144] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.01% to about 2% w / w of Compound 1 and / or its cation, Cl - , about 1% to about 2% w / w tonicity adjusting agent, about 0.005% and about 0.02% w / w preservative, a buffer and water, and having a pH of about 5.5 to 7.5.

[0145] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 and / or its cation, Cl - , about 1% to about 2% w / w tonicity adjusting agent, about 0.005% and about 0.02% w / w preservative, a buffer and water, and having a pH of about 5.5 to 7.5.

[0146] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 and / or its cation, Cl - , about 1% to about 2% w / w glycerin, about 0.005% and about 0.02% w / w benzalkonium chloride, a buffer, and water, and having a pH of about 5.5 to 7.5.

[0147] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 and / or its cation, Cl - , about 1% to about 2% w / w glycerin, about 0.005% and about 0.02% w / w benzalkonium chloride, a buffer, and water, and having a pH of about 6.

[0148] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 2% w / w of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.005% and about 0.02% w / w benzalkonium chloride, a buffer, and water, and having a pH of about 6.

[0149] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 and / or its cation, Cl - , about 1% to about 2% w / w glycerol, about 0.005% and about 0.02% w / w benzalkonium chloride, a phosphate buffer, and water, and having a pH of about 5.5 to 7.5.

[0150] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 and / or its cation, Cl -, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 10 mM phosphate buffer and water, and has a pH of about 6.

[0151] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 10 mM phosphate buffer and water, and has a pH of about 6.

[0152] In some embodiments, an aqueous ophthalmic composition is provided comprising about 1% w / w of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 10 mM phosphate buffer and water, and has a pH of about 6.

[0153] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w to about 1% of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w polysorbate 80, about 10 mM citrate buffer and water, and having a pH of about 6.

[0154] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w to about 1% of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w PEG-35 castor oil, about 10 mM citrate buffer and water, and having a pH of about 6.

[0155] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w to about 1% of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w polysorbate 80, about 10 mM phosphate buffer and water, and has a pH of about 6.

[0156] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% to about 1% w / w of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w PEG-35 castor oil, about 10 mM phosphate buffer and water, and having a pH of about 6.

[0157] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w of Compound 1 and / or its cation, Cl - , about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w PVP K29 / 32, about 10 mM phosphate buffer and water, and having a pH of about 6.

[0158] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w to about 1% of Compound 1 and / or its cation, Cl - , about 0.5% w / w NaCl, about 0.01% w / w benzalkonium chloride, about 2% w / w PVPK29 / 32, about 10 mM phosphate buffer and water, and having a pH of about 6.

[0159] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.5% w / w to about 1% of Compound 1 and / or its cation, Cl - , about 0.5% w / w NaCl, about 0.01% w / w benzalkonium chloride, about 2% w / w PVPK29 / 32, about 10 mM phosphate buffer and water, and having a pH of about 6.

[0160] In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.01% to about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, about 1% to about 2% w / w of a tonicity adjuster, about 0.005% and about 0.02% w / w of a preservative, and a buffer formulated with water, and having a pH of about 5.5 to about 7.5.

[0161] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.01% to about 5% w / w of Compound 1 HCl salt, about 1% to about 2% w / w glycerin, about 0.005% and about 0.02% w / w benzalkonium chloride, and a buffer formulated with water and having a pH of about 5.5 to about 7.5.

[0162] In some embodiments, an aqueous ophthalmic composition is provided comprising about 0.1% to about 5% w / w of Compound 1 HCl salt, about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, and about 10 mM phosphate buffer in water, and having a pH of about 6.

[0163] In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.01% to about 5% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, and about 10 mM phosphate buffer in water, and having a pH of about 6. In some embodiments, an aqueous ophthalmic composition is provided, comprising about 0.01% to about 5% w / w of Compound 1 HCl salt, about 1.5% w / w of glycerol, and about 10 mM phosphate buffer in water, and having a pH of about 6, wherein the aqueous ophthalmic composition is free of a preservative.

[0164] In some embodiments, an aqueous ophthalmic composition is provided, which is prepared by the following method, comprising mixing about 0.001% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof with about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer prepared with water. In some embodiments, the method further comprises adjusting the pH to about 5.5 to 7.5.

[0165] In some embodiments, an aqueous ophthalmic composition is provided, which is prepared by the following method, comprising mixing about 0.01% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof with about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer prepared with water. In some embodiments, the method further comprises adjusting the pH to about 5.5 to 7.5.

[0166] In some embodiments, an aqueous ophthalmic composition is provided, which is prepared by the following method, comprising mixing about 0.1% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof with about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer prepared with water. In some embodiments, the method further comprises adjusting the pH to about 5.5 to 7.5.

[0167] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.001% to about 2% w / w of Compound 1 HCl salt with about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer in water. In some embodiments, the process further comprises adjusting the pH to about 5.5 to 7.5.

[0168] In some embodiments, an aqueous ophthalmic composition is provided, which is prepared by the following method, comprising mixing about 0.01% to about 2% w / w of Compound 1 HCl salt with about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer prepared with water. In some embodiments, the method further comprises adjusting the pH to about 5.5 to 7.5.

[0169] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.1% to about 2% w / w of Compound 1 HCl salt with about 1% to about 2% w / w of a tonicity adjuster, about 0.005% to about 0.02% w / w of a preservative, and a buffer in water. In some embodiments, the process further comprises adjusting the pH to about 5.5 to 7.5.

[0170] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.1% to about 2% w / w of Compound 1 HCl salt with about 1% to about 2% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a buffer prepared with water. In some embodiments, the process further comprises adjusting the pH to about 5.5 to 7.5.

[0171] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.1% to about 2% w / w of Compound 1 HCl salt with about 1% to about 2% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a buffer prepared with water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0172] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.1% to about 2% w / w of Compound 1 HCl salt with about 1.5% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a buffer prepared with water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0173] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.5% to about 1% w / w of Compound 1 HCl salt with about 1% to about 2% w / w of glycerol, about 0.005% to about 0.02% w / w of benzalkonium chloride, and a phosphate buffer prepared with water. In some embodiments, the process further comprises adjusting the pH to about 5.5 to 7.5.

[0174] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.5% to about 1% w / w of Compound 1 HCl salt with about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, and 10 mM phosphate buffer in water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0175] In some embodiments, an aqueous ophthalmic composition is provided, prepared by the following method, comprising mixing about 0.5% w / w of Compound 1 HCl salt with about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, and 10 mM phosphate buffer prepared in water. In some embodiments, the method further comprises adjusting the pH to about 6.

[0176] In some embodiments, an aqueous ophthalmic composition is provided, prepared by the following method, comprising mixing about 1% w / w of Compound 1 HCl salt with about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, and 10 mM phosphate buffer prepared in water. In some embodiments, the method further comprises adjusting the pH to about 6.

[0177] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.5% w / w to about 1% of Compound 1 HCl salt with about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w polysorbate 80, and 10 mM citrate buffer in water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0178] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.5% w / w to about 1% of Compound 1 HCl salt with about 1.5% w / w glycerin, about 0.01% w / w benzalkonium chloride, about 2% w / w PEG-35 castor oil, and 10 mM citrate buffer in water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0179] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.5% w / w to about 1% of Compound 1 HCl salt with about 1.5% w / w glycerol, about 0.01% w / w benzalkonium chloride, about 2% w / w polysorbate 80, and 10 mM phosphate buffer in water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0180] In some embodiments, an aqueous ophthalmic composition is provided, prepared by a process comprising mixing about 0.5% w / w to about 1% of Compound 1 HCl salt with about 1.5% w / w glycerin, about 0.01% w / w benzalkonium chloride, about 2% w / w PEG-35 castor oil, and 10 mM phosphate buffer in water. In some embodiments, the process further comprises adjusting the pH to about 6.

[0181] In some embodiments, an aqueous ophthalmic composition is provided, prepared by the following method, comprising mixing about 0.5% w / w of Compound 1 HCl salt with about 1.5% w / w of glycerol, about 0.01% w / w of benzalkonium chloride, about 2% w / w of PVP K29 / 32, and 10 mM phosphate buffer in water. In some embodiments, the method further comprises adjusting the pH to about 6.

[0182] The compositions described herein can be contained in a container of an appropriate size (e.g., at most about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 1 mL, about 2.5 mL, about 5 mL, 7.5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, or about 40 mL). In some embodiments, the container is suitable for applying eye drops.

[0183] In some embodiments, the container is of a suitable size to accommodate 1 to 2 unit doses. In some embodiments, the container is sealed. In some embodiments, the container provides an antiseptic seal. In some embodiments, the container includes a puncture seal. In some embodiments, the container includes a blow-fill-seal type closure.

[0184] In some embodiments, the aqueous ophthalmic compositions of the present disclosure can be prepared by mixing appropriate amounts of Compound 1 or a pharmaceutically acceptable salt thereof, a tonicity adjuster, a preservative, and optionally a stabilizer in an aqueous buffer described herein to form a clear solution.

[0185] In some embodiments, a method for treating an ophthalmic disease as described herein is provided, comprising administering a therapeutically effective amount of an aqueous ophthalmic composition as described herein to the eye of a patient in need thereof. A single administration or unit dose of an aqueous ophthalmic composition as described herein refers to administering the composition to one or both eyes, and each administration may include one, two, three, four, five, six, seven, eight or more drops of the composition. The composition may be administered once a day, twice a day, three times a day, four times a day, or more at appropriate intervals throughout the day or as needed. In some embodiments, the composition may be administered via a sustained-release delivery system.

[0186] In some embodiments, the therapeutically effective amount of the aqueous ophthalmic composition comprises about 0.001 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, about 0.15 mg to about 8 mg, about 0.25 mg to about 5 mg, or about 1 mg to about 5 mg, about 0.2 mg to about 1 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof, applied to one eye in need of treatment. In some embodiments, the therapeutically effective amount of the aqueous ophthalmic composition is about 0.01 mL to about 0.5 mL. In some embodiments, the therapeutically effective amount of the aqueous ophthalmic composition is about 0.005 mL, about 0.01 mL, about 0.025 mL, about 0.03 mL, about 0.035 mL, about 0.04 mL, about 0.05 mL, about 0.07 mL, about 0.1 mL, about 0.15 mL, about 0.2 mL, about 0.25 mL, about 0.3 mL, about 0.35 mL, about 0.4 mL, about 0.45 mL, about 0.5 mL, or any range (including endpoints) between any two values, applied to one eye in need of treatment. In some embodiments, the therapeutically effective amount of the aqueous ophthalmic composition is one to ten drops applied to one or both eyes. In some embodiments, the therapeutically effective amount of the aqueous ophthalmic composition is one, two, three, four, five, six, seven, eight, nine, or ten drops applied to one eye, or any range (including endpoints) between any two values. In some embodiments, the aqueous ophthalmic composition is administered once a day, twice a day, three times a day, four times a day, or more times a day at appropriate intervals throughout the day, or as needed.

[0187] In some embodiments, provided herein are the purposes of pharmaceutical compositions as herein described in the treatment of ophthalmic diseases as herein described. In some embodiments, the aqueous ophthalmic composition is applied to an eye with a dosage of about 0.005mL to about 0.5mL. In some embodiments, the aqueous ophthalmic composition is applied to an eye with a dosage of about 0.01mL, about 0.025mL, about 0.03mL, about 0.035mL, about 0.04mL, about 0.045mL, about 0.05mL, 0.07mL, about 0.1mL, about 0.15mL, about 0.2mL, about 0.25mL, about 0.3mL, about 0.35mL, about 0.4mL, about 0.45mL or about 0.5mL or any range (including endpoints) between any two values. In some embodiments, one to ten drops of the aqueous ophthalmic composition are applied to an eye. In some embodiments, one, two, three, four, five, six, seven, eight, nine, or ten drops of the aqueous ophthalmic composition, or any range between any two values ​​(including the endpoints), are applied to one or both eyes. In some embodiments, the aqueous ophthalmic composition is applied once a day, twice a day, three times a day, four times a day, or more times at appropriate intervals throughout the day, or as needed.

[0188] In some embodiments, a kit is provided comprising an ophthalmic composition as described herein contained in a container prepared from a pharmaceutically acceptable packaging material. Pharmaceutically acceptable packaging materials include, but are not limited to, low-density polyethylene ("LDPE"), high-density polyethylene ("HDPE"), polypropylene, polystyrene, polycarbonate, polyesters (e.g., polyethylene terephthalate and polyethylene naphthalate), nylon, polyvinyl chloride, polyvinylidene chloride, polytetrafluoroethylene, and other materials known to those of ordinary skill in the art. In some embodiments, the container is a flexible bottle made from LDPE or HDPE. In some embodiments, the container comprises an ophthalmic composition of about 0.01mL to about 50mL, for example, about 0.05mL, about 0.1mL, about 0.2mL, about 0.3mL, about 0.4mL, about 0.5mL, about 1mL, about 2mL, about 2.5mL, about 3mL, about 4mL, about 5mL, about 7.5mL, about 10mL, about 15mL, about 20mL, about 25mL, about 30mL, about 35mL, about 40mL, about 45mL or about 50mL or any range (including endpoints) between any two values ​​of the ophthalmic composition. In certain embodiments, the container holds multiple dosages. In some embodiments, the container comprises a single unit dose or a daily dose. In certain embodiments, the container is sealed. Special multi-dose preservative-free containers can also be used, for example, containers with a filter, a sophisticated or a dual-chamber container. Example

[0189] Example 1. Preparation of aqueous ophthalmic composition

[0190] Generally, the aqueous ophthalmic compositions described herein are prepared by dissolving the excipients in a desired volume of water in a suitable container and then adding the active ingredient. Thereafter, the pH is adjusted to the desired value and more water is added to the desired final volume. The concentrations or amounts listed in the following examples may vary by ±10%, ±5%, or ±1% of the stated values.

[0191] Example 2. Solubility study

[0192] Solubility studies were performed where the HCl salt or free base was added at a concentration of 10 mg / mL (1%) to the following formulation buffer: pH 6, 10 mM citrate buffer, 1% PEG400, 1% glycerol, 0.3% NaCl, 0.05% PS80.

[0193] Increase the pH of soluble samples to better understand their properties. Visually inspect the sample for clarity or turbidity. HCl salts are soluble even at pH 6 but form a precipitate as the pH increases from 6. The free base is insoluble.

[0194] The free base was insoluble in various solubilizing agents. The only sample with a solubility of 1-10 mg / mL was a combination of 3% glycerol, 5% PEG 400, 5% PEG-35 castor oil, 15% polysorbate 60, 4% polysorbate 80, 2% PVP K29 / 32, and 10% propylene glycol. 5% PEG 400 produced a clear solution with pH adjustment / buffering, but the pH was 3. 10% propylene glycol produced a clear solution with pH adjustment / buffering at pH 6.1, but the buffer concentration was approximately 20 mM phosphate for 1 mg / mL Compound 1 and estimated to be approximately 200 mM for 10 mg / mL Compound 1.

[0195] Table 2-1: Free alkali dissolution results

[0196]

[0197] *Add 1 M citric acid to PEG 400, adding 300 μL to dissolve the API; final pH is 3.0.

[0198] **Add 1M sodium dihydrogen phosphate to propylene glycol and dissolve the API after adding 500 μL; final pH is 6.1

[0199] The formulations in Table 2-2 were prepared and inspected for appearance. Formulations that produced clear solutions were stored at ambient temperature (15°C to 25°C). After 8 weeks, those formulations that remained clear were analyzed by a qualified HPLC method. For formulations that were clear at T0 and remained clear after 8 weeks of storage, their initial (T0) and 8-week (T8W) pH and osmolality were recorded (see Tables 2-3 and 2-4).

[0200] All solutions containing NaCl as a tonicity modifier (Formulations 2-4, 2-5, 2-6, 2-10, 2-11, and 2-12) failed to form clear solutions initially or remained clear after 8 weeks. In addition, the formulation containing citrate buffer and PVP K29 / 32 (Formulation 2-3) produced a turbid suspension. Most solutions containing glycerol were clear within 8 weeks.

[0201] Table 2-2. Preparations

[0202]

[0203] Table 2-3: Appearance, pH and osmotic pressure results (T0)

[0204]

[0205]

[0206] Table 2-4: Appearance, pH and osmotic pressure results (T8W)

[0207]

[0208] As shown in Table 2-4, after 8 weeks, formulations 2-1, 2-2, 2-7, 2-8, and 2-9 remained clear. The impurities and mass balance of those formulations were tested by HPLC analysis. Formulation 7 had two impurity peaks that were considered significant compared to the other formulations.

[0209] Example 3. In vivo compatibility study

[0210] An in vivo study was conducted to test the tolerability of the four formulations in Table 3-1 in rabbits. In this study, each group consisted of 3 rabbits (2 males, 1 female) that received one formulation. The rabbits were dosed 4 times a day for 7 consecutive days (2 hours between doses). The dose consisted of applying 50 μL of the appropriate formulation (topical eye drops) to the right eye of the rabbit; the left eye served as a contralateral control and did not receive treatment. Before treatment, the eyes of each rabbit were graded for irritation symptoms using the Draize scoring method, and again once a day after the last daily dose. A score of 0 indicates no irritation, while a score of 1, 2, 3, or 4 indicates that irritation was observed. The higher the value, the more severe the irritation observed.

[0211] Each formulation and category had a maximum of 21 observations (3 rabbits x 7 days). The tolerability scores are listed in Table 3-2. Of the four formulations, solutions with either citric acid buffer or phosphate buffer and PEG-35 castor oil (Formulations 3-2 and 3-3) were the best tolerated.

[0212] Table 3-1: Preparations used in tolerance studies

[0213]

[0214] Table 3-2: Irritation scores in tolerance studies

[0215]

[0216]

[0217] Example 4. Stability

[0218] Solutions were prepared with different levels of PEG-35 castor oil (2%, 1% and 0%) (Table 4-1) and stored at 25° C. for long-term storage and 40° C. for accelerated storage. After one month, all samples were analyzed by a qualified HPLC method.

[0219] Table 4-1: Effect of stabilizers on study preparations

[0220] preparation API buffer preservative Tonicity regulators stabilizer 4-1 0.5% HCl salt 10 mM phosphate, pH 6 0.1% BAC 1.5% glycerol 2% PEG-35 castor oil 4-2 0.5% HCl salt 10 mM phosphate, pH 6 0.1% BAC 1.5% glycerol 1% PEG-35 castor oil 4-3 0.5% HCl salt 10 mM phosphate, pH 6 0.1% BAC 1.5% glycerol 0% PEG-35 castor oil

[0221] Table 4-2: Summary of impurity results – 1 month

[0222]

[0223] Formulations with increasing API concentrations and decreasing preservative concentrations were found to be stable for at least 6 months at 25°C.

[0224]

[0225]

[0226] Example 5. Toxicity studies in dogs and rabbits

[0227] Toxicity studies were conducted in dogs and rabbits with the following two formulations.

[0228]

[0229] Study 1: Each formulation was administered to seven dogs of each sex, with four dogs of each sex used for toxicity assessment and three dogs of each sex used as recovery animals to assess the reversibility of potential treatment-related effects. Each dog received four 50 μL doses of the designated formulation daily for 28 days (recovering dogs were untreated for an additional 14 days). No deaths or clinical signs of toxicity related to treatment were observed during the study.

[0230] Study 2: Each formulation was administered to 11 rabbits of each sex. The rabbits were divided, with 5 rabbits of each sex used for core toxicity, 3 rabbits of each sex for toxicokinetics assessment, and 3 rabbits of each sex used as recovery animals to assess the reversibility of potential treatment-related effects. Each rabbit received 4 doses of 50 μL of Compound 1 ophthalmic solution daily for 28 days (recovering rabbits were not treated for an additional 14 days). No deaths or clinical signs of toxicity related to treatment were observed during the study.

[0231] Example 6. Study of Compound 1 in a mouse model of allergic conjunctivitis

[0232] In a mouse model of the disease, compound 1 showed efficacy in alleviating allergic conjunctivitis.

[0233] Mice were sensitized with subcutaneous injections of short ragweed allergen (days 1 and 11) and subjected to conjunctival allergen challenge (CAC) with short ragweed allergen on day 18. After challenge, mice were randomly divided into treatment groups (n=8) and administered topical test compounds: vehicle, 0.1% Compound 1, 1% Compound 1, 1% prednisolone, or normal saline (BSS) twice daily for 2 days, then three times daily for 4 days during the allergen challenge period. Challenges were performed twice daily from day 21 to day 24. Responses to allergen challenge were assessed after challenges 1, 4, 6, and 8.

[0234] like Figure 1 As shown, on the 4th of the 4 test days, Compound 1 (1%) significantly reduced the mean change in congestion (before and after CAC) compared to saline. On the 2nd of the 4 test days, Compound 1 (0.1%) significantly reduced the mean change in congestion compared to saline. The positive control, prednisolone (1.0%), also caused a significant reduction in the mean change in congestion on the 2nd of the 4 test days. On the 3rd of the 4 test days, a statistically significant reduction in the overall mean congestion was observed with 1% Compound 1. No significant changes in ocular discharge, eyelid swelling, or strabismus were observed.

[0235] Example 7. Clinical efficacy and safety of compound 1 in the treatment of acute and chronic allergic conjunctivitis

[0236] In a study utilizing the conjunctival allergen challenge (CAC) clinical model, eligible patients with acute or chronic allergic conjunctivitis were randomized to receive one of the five interventions listed below, each administered at a dose of 1 drop for six doses. The CAC model is a standardized clinical method for evaluating the allergic and anti-inflammatory activity of new drugs. It has been accepted by the FDA for clinical development of new therapies and has been used to develop 19 drugs currently on the market. In the CAC model, a dose of allergen is administered to the patient's eye in a controlled manner in an office setting to induce a controlled allergic reaction. Drugs are administered at predetermined time points, and signs and symptoms are collected at predetermined time points to evaluate efficacy.

[0237]

[0238] Composition A: 0.5% w / w Compound 1 HCl salt, 1.5% w / w glycerol, 0.01% w / w BAC, 10 mM phosphate buffer, pH 6.0.

[0239] Composition B: 1.0% w / w Compound 1 HCl salt, 1.5% w / w glycerol, 0.01% w / w BAC, 10 mM phosphate buffer, pH 6.0.

[0240] ·Placebo: 0.01% w / w BAC, 1.5% w / w glycerol, pH 6.0.

[0241] After undergoing screening and baseline CAC, patients were randomly assigned in a blinded manner to receive study treatment 8 hours before or 15 minutes after CAC at Visit 4b and Visit 5. Patients then continued to take the drug BID and underwent a series of repeated CAC challenges 6 and 8 hours after the drug dose.

[0242] Outcome indicators:

[0243] Itchy eyes [Timeframe: 5, 7, and 10 minutes after allergen administration (CAC)]

[0244] The subjects rated eye itching using a 0-4 scale (0 = none to 4 = severe). The mean of the eye itching scores of both eyes was analyzed.

[0245] Conjunctival redness [Time frame: 7, 15, and 20 minutes after allergen administration CAC]

[0246] The investigators assessed conjunctival redness using a 0-4 scale (0 = none to 4 = severe). The mean of the conjunctival redness scores for both eyes was analyzed.

[0247] Additional variables assessing efficacy include eyelid swelling, conjunctival edema, tearing, nasal symptoms, and exploratory assessment of biomarkers and exploratory imaging of inflammation by in vivo confocal microscopy to indicate biological activity.

[0248] result:

[0249] In this study, compound 1 showed clear and consistent biological effects at both concentrations.

[0250] When administered 8 hours before challenge, both Compositions A and B showed a significant improvement over vehicle and Statistically superior clinically relevant therapeutic effect on eye redness and conjunctival swelling (chemosis). In addition, both Compositions A and B showed efficacy in preventing ciliary body and scleral redness when administered 8 hours before CAC. The differences (ciliary body erythema and scleral erythema) were statistically significant.

[0251] Table 7-1 shows the results of the experiment using the composition A, B or Conjunctival injection scores in treated subjects compared to vehicle, as assessed by the Investigator at Visit 4b (allergen challenge given 8 hours after the first dose) and Visit 5a (allergen challenge given 15 minutes after the second dose). and / Pred All patients in the group were given

[0252] A larger negative number indicates greater efficacy (i.e., a larger difference between drug and placebo). Surprisingly, at Visit 4b, which measures efficacy (duration of action) 8 hours after dosing, Compositions A and B outperformed the standard allergy therapy. is the leading drug currently on the market and was included as the active comparator. Also surprising was that the data showed that Compound 1 worked better 8 hours after dosing than 15 minutes after dosing (Visit 5a).

[0253] Table 7-1. Conjunctival redness

[0254]

[0255]

[0256] In Tables 7-1 to 7-11, a: statistically different from the vehicle; b: statistically superior to

[0257] Tables 7-2 to 7-11 show the results of the studies on the effects of Composition A, B, or Effects compared to vehicle on ciliary body redness, scleral redness, conjunctival edema, eyelid swelling, tearing, rhinorrhea, nasal itching, ear itching or throat itching, nasal congestion and eye itching.

[0258] Table 7-2. Ciliary body redness

[0259]

[0260] Table 7-3. Scleral redness

[0261]

[0262] Table 7-4. Conjunctival edema

[0263]

[0264] Table 7-5. Eyelid swelling

[0265]

[0266] Table 7-6. Tears

[0267]

[0268] Table 7-7. Rhinorrhea

[0269]

[0270] Table 7-8. Nasal Itch

[0271]

[0272] Table 7-9. Itchy ears or throat

[0273]

[0274] Table 7-10. Nasal congestion

[0275]

[0276] Table 7-11. Itchy eyes

[0277]

[0278] Conjunctivae were imaged using in vivo confocal microscopy to assess microvasculature and inflammation was scored on a scale of 0 (absence of leukocytes) to 4 (visible inflammation of cells). Figure 2A and 2B Scores at baseline (no treatment) and after CAC 8 hours after treatment are shown separately. Figure 2BThe effect of the Compound 1 formulation on objective imaging of reduced inflammation compared to placebo is shown. In the bar graph, the bars represent from left to right: Placebo, Patanol, Composition B, Composition A.

[0279] This is the first time that a specific Syk inhibitor has been clinically evaluated in the eye in this way. In fact, past attempts to formulate soluble and stable formulations of Syk-specific inhibitors and to demonstrate efficacy in relevant models have failed. Given the recognized mechanism of action of Syk kinase in mast cell degranulation, and the central role of mast cells in allergic reactions, clinical data support the surprising efficacy of compound 1 in reducing vasodilation (redness) and reducing inflammation. This effect is strong, as can be seen, for example, from reduced conjunctival edema (inflammation of conjunctival tissue) and objectively from the lower leukocyte inflammation scores shown by confocal imaging. In particular, compound 1 reduced redness to a greater extent 8 hours after administration compared to 15 minutes after administration. This is in contrast to current standard drugs such as antihistamines / mast cell stabilizers (such as Compound 1, which served as the active comparator in this trial and has been a market-leading treatment for ocular allergies for approximately two decades, exhibits a higher level of efficacy with an onset of action of 15 minutes compared to a duration of action of 8 hours in this study. This clinical data supports the potent effect of Compound 1 in reducing congestion and inflammation in the eye. The described composition is expected to surprisingly provide improved comfort, safety, efficacy, solubility, and stability.

[0280] Compositions A and B were safe and well tolerated. No treatment-related serious adverse events occurred, and all treatment-related adverse events in the Compound 1 group were rated as mild. The reduced comfort score for the Compound 1 composition was in the comfort section on the scale and within the historical average for currently marketed products.

Claims

1. An ophthalmic composition consisting of 0.5% w / w to 1.0% w / w of the HCl salt of compound 1 of the formula below, 1.5% w / w of glycerol, 0.01% w / w of benzalkonium chloride, and 10 mM of a phosphate buffer in water, and having a pH of 6:

2. The ophthalmic composition of claim 1, wherein the composition is stable for 6 months or longer.

3. Use of the ophthalmic composition according to claim 1 in the preparation of a medicament for treating allergic conjunctivitis.

4. The use according to claim 3, wherein the allergic conjunctivitis is chronic allergic conjunctivitis.

5. The use according to claim 3, wherein the allergic conjunctivitis is acute allergic conjunctivitis.

6. The use according to claim 3, wherein one or more of eye redness, inflammation, swelling, discomfort, increased tear secretion and eye itching, keratitis, corneal pigmentation, conjunctival pigmentation or inflammatory markers are reduced or eliminated.

7. Use of the HCl salt of Compound 1 of the following formula in the preparation of a medicament for treating allergic conjunctivitis, the medicament consisting of 0.5% w / w to 1.0% w / w of the HCl salt of Compound 1, 1.5% w / w of glycerol, 0.01% w / w of benzalkonium chloride, and 10 mM of a phosphate buffer prepared with water, and having a pH of 6:

8. The use according to claim 7, wherein the HCl salt of Compound 1 is administered to the eye in an amount of 0.01 mg to 1 mg.

9. The use according to claim 7, wherein the HCl salt of Compound 1 is administered once a day.

10. The use according to claim 7, wherein the HCl salt of Compound 1 is administered twice a day.

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