Compounds and their salts and polymorphs for the treatment of disorders - Patents.com

Abstract

Disclosed herein are salts of the compound of formula (I) and polymorphs thereof, methods of making same, and methods of their use in treating ocular diseases and disorders, particularly ocular diseases and disorders associated with inflammation and / or vascular proliferation in a subject. The methods include administering a therapeutically effective amount of a salt of the compound of formula (I) and polymorphic forms thereof to a subject in need thereof.

Description

[Technical field]

[0001] background Field of Disclosure This application relates to the fields of medicinal chemistry, formulation science, and medicine.In particular, this application relates to salt forms of the compound of formula (I), its polymorphs, and the methods of making and using such salt forms and polymorphs for treating ocular diseases and disorders, particularly ocular diseases and disorders associated with inflammation and / or vascular proliferation.This disclosure also relates to the use of the salt forms described herein for treating diseases or disorders associated with fibrosis. [Background technology]

[0002] 2. Description of Related Art Eye diseases with inflammation and / or vascular proliferation usually, but not always, involve the anterior and posterior eye.For example, eye disorders with the etiology of inflammation and / or vascular proliferation can be corneal edema, anterior and posterior uveitis, pterygium, corneal disease caused by infection with microbes or microorganisms, such as bacteria, viruses, fungi, amoebas and parasites, dry eye, conjunctivitis, allergy and laser-induced exudation, non-age-related macular degeneration, macular edema, diabetic retinopathy (DR), age-related macular degeneration (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3), von Hippel-Lindau disease of the eye characterized by the proliferation of small blood vessels in the retina, and proliferative vitreoretinopathy (PVR).

[0003] DR, one of the above eye diseases, is a common complication of diabetes and remains one of the major causes of vision loss. See Non-Patent Document 4; Non-Patent Document 5. Vision loss in DR develops due to slow and progressive changes to the retinal microvasculature (pericytes and endothelial cells), leading to breakdown of the blood-retinal barrier, pathological neovascularization and scarring. Based on the degree of vascular abnormality, DR can be broadly categorized into non-proliferative DR (NPDR) and proliferative DR (PDR). See Non-Patent Document 6. In the case of NPDR, hyperglycemia induces thickening of the capillary basement membrane, apoptosis or "drop-out" of pericytes, microaneurysms and vascular leakage. Obstruction of retinal capillaries causes localized hypoxia, which increases the production of angiogenic growth factors. In some microvessels, endothelial cells become apoptotic, resulting in acellular capillaries (lacking both pericytes and endothelial cells), capillary occlusion and compartments of retinal nonperfusion. Adherent leukocytes may also contribute to the pathology by causing retinal capillary occlusion. See Non-Patent Document 7. Multiple hemorrhages, soft white spots, cotton wool spots, intraretinal microvascular abnormalities, and venous beading and loops develop. Increased compartments of tissue nonperfusion stimulate the production of angiogenic factors that lead to the proliferation of blood vessels, which is a hallmark feature of PDR. Retinal neovascularization may be accompanied by fibrosis resulting in fibrovascular ridges that extend into the vitreous cavity or onto the surface of the retina. Contraction of the fibrovascular ridges causes retinal detachment and reduced vision and blindness. See Non-Patent Document 8.

[0004] The pathogenesis of DR is not fully understood. However, metabolic and biochemical changes, such as increased flux of glucose through the polyol pathway, activation of protein kinase C, oxidative damage and increased formation of advanced glycation end products, are contributing factors in the development of DR. See Non-Patent Document 4. Accumulating evidence indicates that vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis in DR (see Non-Patent Document 9), and intercellular adhesion molecule-1 (ICAM-1)-mediated leukocytosis results in secondary endothelial damage. See Non-Patent Document 10; Non-Patent Document 11. Recently, DR has been classified as a chronic inflammatory disease. It has also been recognized that anti-inflammatory therapy prevents the classic histopathological features of DR: the formation of acellular capillaries, the development of retinal hemorrhages, the progression of microaneurysms, and the loss of pericytes. See Non-Patent Document 12; Non-Patent Document 13. In line with this concept, studies have demonstrated that anti-inflammatory therapy prevents the classic histopathological features of DR: the formation of acellular capillaries, the development of retinal hemorrhages, the progression of microaneurysms, and the loss of pericytes. See Non-Patent Document 12; Non-Patent Document 13.

[0005] Currently, DR is treated by laser photocoagulation, which is a procedure that destroys neovascular and surrounding hypoxic tissue. See 14. Laser photocoagulation is beneficial, but can destroy healthy retina, and the disease continues despite intensive treatment. Therefore, less invasive therapies are being investigated, with a particular focus on inhibition of damaging molecules such as VEGF and ICAM-1. See 15; 9; 11. In addition to eye diseases associated with inflammation and / or vascular proliferation, such as diabetic retinopathy, there remains a need for additional therapies to treat corneal edema, anterior and posterior uveitis, pterygium, corneal diseases caused by infection with microorganisms or microorganisms, such as bacteria, viruses, fungi, amoebas and parasites, dry eye, conjunctivitis, allergies and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration, and von Hippel-Lindau disease of the eye. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 4,522,811 [Patent Document 2] U.S. Patent No. 6,596,298 [Patent Document 3] U.S. Patent No. 7,067,116 [Patent Document 4] U.S. Patent No. 7,182,964 [Patent Document 5] U.S. Patent No. 7,241,411 [Patent Document 6] U.S. Patent No. 4,328,245 [Patent Document 7] U.S. Patent No. 4,409,239 [Patent Document 8] U.S. Patent No. 4,410,545 [Patent Document 9] U.S. Reissue Patent No. 28,819 [Patent Document 10] U.S. Patent No. 4,358,603 [Patent Document 11] U.S. Patent No. 3,710,795 [Non-Patent Document]

[0007] [Non-Patent Document 1] Kim et al. 2001 [Non-Patent Document 2] A.M. Joussen et al. 2004 [Non-Patent Document 3] S.C. Pflugfelder 2004 [Non-Patent Document 4] Cheung et al. 2005 [Non-Patent Document 5] Santos et al. 2005 [Non-Patent Document 6] Klein et al. 2004 [Non-Patent Document 7] Joussen, et al. 2004 [Non-Patent Document 8] Watkins 2003 [Non-Patent Document 9] Sarlos, et al. 2003 [Non-Patent Document 10] Joussen, et al. 2002 [Non-Patent Document 11] Khalfaoui et al. 2009 [Non-Patent Document 12] Adamis 2002 [Non-Patent Document 13] Joussen, Poulaki et al. 2002 [Non-Patent Document 14] Aiello 2003 [Non-Patent Document 15] Arita, et al. [Non-Patent Document 16] Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, Pa. 1995 [Non-Patent Document 17] Ansel,Introduction to Pharmaceutical Dosage Forms,4th Edition(1985),126 [Non-Patent Document 18] Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th edition (1975) Summary of the Invention

[0008] In one aspect, the application is directed to pharma- ceutically acceptable salts of the compounds of formula (I), including crystalline forms thereof.

[0009] [ka]

[0010] In some embodiments of this aspect of the disclosure, the pharma- ceutically acceptable salt of the compound of formula (I) may be a sodium salt, a potassium salt, a zinc salt, a magnesium salt, or a calcium salt of the compound of formula (I).

[0011] In some embodiments of the first aspect of the disclosure, the pharma- ceutically acceptable salt of the compound of formula (I) may be a choline salt, an L-lysine salt, a tert-butylamine salt, a diethanolamine salt, or a meglumine salt of the compound of formula (I).

[0012] In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) may be a crystalline form of the L-lysine salt of the compound of formula (I), which may exhibit an X-ray powder diffraction pattern having at least three characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ (±0.2 degrees 2θ).

[0013] In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) may be a crystalline form of the L-lysine salt of the compound of formula (I), which may exhibit an X-ray powder diffraction pattern having at least four characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ (±0.2 degrees 2θ).

[0014] In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) may be a crystalline form of the L-lysine salt of the compound of formula (I), which may exhibit an X-ray powder diffraction pattern having at least five characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ (±0.2 degrees 2θ).

[0015] In some embodiments, a crystalline form of the L-lysine salt of the compound of formula (I) may exhibit the X-ray powder diffraction pattern depicted in FIG.

[0016] In some embodiments of this aspect of the disclosure, the crystalline form of the L-lysine salt of the compound of Formula (I) exhibits a melting point of about 197-203°C.

[0017] In some embodiments of this aspect of the disclosure, the pharma- ceutically acceptable salt of the compound of Formula (I) may be a crystalline form of the tert-butylamine salt of the compound of Formula (I), which may exhibit an X-ray powder diffraction pattern having at least three characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ (±0.2 degrees 2θ).

[0018] In some embodiments of the first aspect of the disclosure, the pharma- ceutically acceptable salt of the compound of Formula (I) may be a crystalline form of the tert-butylamine salt of the compound of Formula (I), which may exhibit an X-ray powder diffraction pattern having at least four characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ (±0.2 degrees 2θ).

[0019] In some embodiments of the first aspect of the disclosure, the pharma- ceutically acceptable salt of the compound of Formula (I) may be a crystalline form of the tert-butylamine salt of the compound of Formula (I), which may exhibit an X-ray powder diffraction pattern having at least five characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ (±0.2 degrees 2θ).

[0020] In some embodiments, a crystalline form of the tert-butylamine salt of the compound of Formula (I) may exhibit the X-ray powder diffraction pattern depicted in FIG.

[0021] In some embodiments, the crystalline form of the tert-butylamine salt of the compound of Formula (I) exhibits a melting point of about 196-224°C.

[0022] In some embodiments, any one of the pharma- ceutically acceptable salts of the compound of formula (I) listed above and its crystalline forms and a pharma- ceutically acceptable excipient.

[0023] In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is the L-lysine salt of the compound of formula (I). In other embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is the tert-butylamine salt of the compound of formula (I).

[0024] In some embodiments of this aspect of the disclosure, disclosed herein are methods of treating an ophthalmic disease, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound of Formula (I) and crystalline forms thereof.

[0025] In some embodiments, disclosed herein are methods for treating chronic myocardial infarction, comprising administering to a subject a therapeutically effective amount of a pharma- ceutical acceptable salt of a compound of formula (I) as disclosed herein, and a crystalline form thereof. The method of treating an eye disease comprises administering to the patient a therapeutically effective amount of a vitreous retinopathy inhibitor, a vitreous retinopathy inhibitor, or a vitreous retinopathy inhibitor. It may be proliferative vitreoretinopathy corneal edema, anterior and posterior uveitis, pterygium, corneal disease, dry eye, conjunctivitis, allergic and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration, or von Hippel-Lindau disease of the eye.

[0026] In some embodiments, disclosed herein is a method of reducing at least one of the level of ICAM-1 mRNA in the retina of a subject; the level of VEGF mRNA in the retina of a subject; and the number of white blood cells in the retina of a subject, comprising administering to the subject a therapeutically effective amount of any one of the salts of the compound of Formula (I) disclosed herein and crystalline forms thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable salt of the compound of Formula (I) disclosed herein and crystalline forms thereof.

[0027] In some embodiments, disclosed herein is a method for treating the disease or condition associated with fibrosis, including but not limited to selected from fibrotic skin disorders, such as keloids, hypertrophic scars and scleroderma; pulmonary diseases, such as pulmonary fibrosis; heart diseases, such as heart failure caused by ischemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; and kidney diseases, such as glomerulonephritis and diabetic nephropathy and progressive kidney disease caused by liver cirrhosis, comprising administering to a subject a therapeutically effective amount of the pharmacologic acceptable salt of the compound of formula (I) disclosed herein and its crystalline form.In some embodiments, the disease or condition is diabetic heart disease or diabetic kidney disease.In some embodiments, the disease or condition is diabetic cardiomyopathy. In some embodiments, kidney disease may include progressive glomerular kidney disease, including, without limitation, diabetic nephropathy (e.g., that which is a consequence of type I or type II diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis), or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephropathy).

[0028] In some embodiments of the second aspect of the present disclosure, any one of the methods listed above, wherein a pharma- ceutically acceptable salt of the compound of formula (I) and its crystalline forms disclosed herein is orally administered.

[0029] In some embodiments of the second aspect of the present disclosure, any one of the methods listed above, wherein a pharma- ceutically acceptable salt of the compound of formula (I) and its crystalline forms disclosed herein, or a composition comprising same, is administered to the eye.

[0030] In some embodiments, a method for treating an eye disease comprising administering to a subject a therapeutically effective amount of any one of the L-lysine salt of the compound of formula (I) and its crystalline forms and / or the tert-butylamine salt of the compound of formula (I) and its crystalline forms; or a combination thereof.

[0031] In some embodiments of the second aspect of the present disclosure, there is a method of treating an ocular disease comprising administering to a subject a therapeutically effective amount of any one of the L-lysine salt of the compound of formula (I) and polymorphs thereof and the tert-butylamine salt of the compound of formula (I) and polymorphs thereof, wherein the ocular disease may be diabetic retinopathy, proliferative vitreoretinopathy corneal edema, anterior and posterior uveitis, pterygium, corneal disease, dry eye, conjunctivitis, allergy and laser induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration or von Hippel-Lindau disease of the eye.

[0032] In some embodiments, disclosed herein is a method of reducing at least one of the level of ICAM-1 mRNA in the retina of a subject; the level of VEGF mRNA in the retina of a subject; and the number of white blood cells in the retina of a subject, comprising administering to a subject a therapeutically effective amount of any one of the L-lysine salts of the compound of Formula (I) and its crystalline forms; or a therapeutically effective amount of any one of the tert-butylamine salts of the compound of Formula (I) and its crystalline forms.

[0033] In some embodiments, disclosed herein is a method for treating a disease or condition associated with fibrosis, comprising administering to a subject a therapeutically effective amount of any one of the L-lysine salts of the compound of formula (I) and its crystalline forms; or a therapeutically effective amount of any one of the tert-butylamine salts of the compound of formula (I) and its crystalline forms. In some embodiments, the fibrotic disease or disorder may be, for example, a fibrotic skin disorder selected from keloids, hypertrophic scars, and scleroderma. In some embodiments, the disease or disorder associated with fibrosis may be pulmonary fibrosis. In some embodiments, the disease or disorder associated with fibrosis may be heart disease. In some embodiments, the heart disease may be heart failure due to ischemic heart disease, valvular heart disease, and hypertensive heart disease, diabetic cardiomyopathy, and hypertension. In some embodiments, the disease or disorder associated with fibrosis may be heart disease. In some embodiments, the kidney disease may be progressive kidney disease due to glomerulonephritis and diabetic nephropathy and cirrhosis of the liver. In some embodiments, the kidney disease may be progressive glomerular kidney disease, diabetic nephropathy, primary glomerulonephritis or secondary glomerulonephritis. In some embodiments, the primary glomerulonephritis may be membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis or membranous focal segmental glomerulosclerosis. In some embodiments, the secondary glomerulonephritis may be diabetic nephropathy or ischemic nephropathy. In some embodiments, the kidney disease may include progressive kidney disease of predominant tubulointerstitial origin. In some specific embodiments, the kidney disease may be chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis or reflux nephropathy.

[0034] In some embodiments, pharma- ceutically acceptable salts of the compounds of formula (I) and their crystalline forms may be administered orally.

[0035] In other embodiments, pharma- ceutically acceptable salts of the compounds of formula (I) and their crystalline forms may be administered to the eye. [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 depicts an example of an X-ray powder diffraction pattern of a crystalline form of the L-lysine salt of the compound of formula (I). [Diagram 2] FIG. 2 depicts an example of a differential thermal analysis and thermogravimetric analysis overlay for a crystalline form of the L-lysine salt of the compound of formula (I). [Diagram 3] FIG. 3 depicts an example of an X-ray powder diffraction pattern of crystalline Form I of the tert-butylamine salt of compound of formula (I). [Figure 4] FIG. 4 depicts an example of a differential thermal analysis and thermogravimetric analysis overlay for crystalline Form I of the tert-butylamine salt of compound of formula (I). [Diagram 5] FIG. 5 depicts an example of dynamic vapor sorption results for a crystalline form of the L-lysine salt of the compound of formula (I). [Figure 6] FIG. 6 depicts an example of dynamic vapor sorption results for a crystalline form of the tert-butylamine salt of the compound of formula (I). [Figure 7] FIG. 7 depicts an example of an X-ray powder diffraction pattern of crystalline Form II of the tert-butylamine salt of compound of formula (I). [Figure 8] FIG. 8 depicts an example of an X-ray powder diffraction pattern of crystalline Form III of the tert-butylamine salt of compound of formula (I). [Figure 9] FIG. 9 depicts an example of differential scanning calorimetry (DSC) data for crystalline Form III of the tert-butylamine salt of compound of formula (I). [Figure 10] FIG. 10 depicts an example of an X-ray powder diffraction pattern of crystalline Form IV of the tert-butylamine salt of compound of formula (I). [Figure 11] FIG. 11 depicts an example of differential scanning calorimetry (DSC) data for crystalline Form IV of the tert-butylamine salt of the compound of formula (I). [Figure 12]FIG. 12 depicts an example of the dissolution profile of a crystalline form of the L-lysine salt of the compound of formula (I) and a crystalline form of the tert-butylamine salt of the compound of formula (I) in Fasted Stated Simulated Intestinal Fluid (FaSSIF) medium. [Figure 13] FIG. 13 depicts an example of the dissolution profile of a crystalline form of the L-lysine salt of the compound of formula (I) and a crystalline form of the tert-butylamine salt of the compound of formula (I) in phosphate buffered saline (PBS) medium. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] definition In this specification, a number of terms are used that are well known to those of skill in the art. Nonetheless, for purposes of clarity, a number of terms are defined.

[0038] The term "pharmaceutical acceptable salts" as used herein refers to salts that retain the desired biological activity of the compound of formula (I). Suitable pharmaceutical acceptable salts of the compound of formula (I) and its polymorphs include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc, and organic salts made from organic bases such as choline, diethanolamine, or morpholine. Other examples of organic salts are ammonium salts, such as tert-butylamine and diethanolamine; quaternary salts, such as tetramethylammonium salts and choline salts; amino acid addition salts, such as salts with glycine, arginine, and L-lysine. Additional information regarding pharmaceutical acceptable salts can be found in Non-Patent Document 16. In the case of agents that are solid, it will be understood by those skilled in the art that the disclosed compounds of formula (I), agents, and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of this disclosure and the specified formula.

[0039] The terms "treating," "treat," or "treatment," as used herein, generally refer to the amelioration or elimination of the described condition after it has been established. The term "prevention," as used herein, generally refers to treatment to prevent the onset of the described condition or processes that may lead to the condition ("primary" prevention), or to prevent the recurrence of symptoms of the condition.

[0040] The term "subject," as used herein, generally refers to any warm-blooded animal, such as, but not limited to, a mouse, a guinea pig, a dog, a horse, or a human. In a preferred embodiment, the subject is a human.

[0041] The term "therapeutically effective amount" or "effective amount" as used herein is an amount sufficient to produce beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of a disease state.

[0042] The term "pharmaceutical acceptable," as used herein, generally refers to a substance or composition that is chemically and / or toxicologically compatible with the other ingredients comprising the formulation, and / or the subject being treated.

[0043] The term "suitable solvent" as used herein generally refers to a mixture of solvents, in addition to a single solvent. The solvent may be selected from, for example, aprotic polar solvents such as DMF, DMA, DMSO, dimethylpropylene urea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, THF, 1,4-dioxane, methyl t-butyl ether, dimethoxymethane, and ethylene glycol dimethyl ether; alcohol solvents such as MeOH, EtOH, and isopropanol; and halogen-containing solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane, as appropriate for a given reaction step. The mixture of solvents may also include a biphasic mixture.

[0044] General overview Disclosed herein are pharma- ceutically acceptable salts and crystalline forms of the compound of formula (I), which is shown below:

[0045] [ka]

[0046] Some embodiments include salts of the compound of formula (I) and crystalline forms thereof, acceptable salts may be, but are not limited to, sodium salts, potassium salts, zinc salts, magnesium salts, calcium salts, choline salts, L-lysine salts, tert-butylamine salts, and diethanolamine salts.

[0047] Other salt forms of formula (I) include the L-lysine salts and crystalline forms thereof and the tert-butylamine salts and crystalline forms thereof described herein.

[0048] The present application also relates to methods of using various salts of the compound of formula (I) and polymorphs thereof for treating diseases and disorders, particularly by administering to a patient a composition comprising a therapeutically effective amount of one or more salt forms of the compound of formula (I) and one or more pharma- ceutical acceptable excipients.

[0049] The present application also relates to methods of crystallizing various salt forms of the compound of formula (I) and its crystalline forms. The salt forms advantageously exhibit improved solubility, bioavailability, stability, processability and ease of production. As a result, the salt forms of the compound of formula (I) and its crystalline forms provide long-term stability, low water vapor adsorption and desorption, and superior solubility properties compared to the free acid form of the compound of formula (I).

[0050] Salts of the Compound of Formula (I) and Crystalline Forms of the Salts Disclosed herein are salts and crystalline forms of the compound of formula (I).

[0051] Some embodiments include salts of the compounds of formula (I) and polymorphs thereof, acceptable salts may be, but are not limited to, sodium, potassium, zinc, magnesium, or calcium salts.

[0052] Some embodiments include the sodium salt of the compound of formula (I) and crystalline forms thereof.

[0053] Some embodiments include the potassium salt of the compound of formula (I) and its crystalline forms.

[0054] Some embodiments include the zinc salt of the compound of formula (I) and crystalline forms thereof.

[0055] Some embodiments include the magnesium salt of the compound of formula (I) and crystalline forms thereof.

[0056] Some embodiments include the calcium salt of the compound of formula (I) and its crystalline forms.

[0057] Some embodiments include salts of the compounds of formula (I), and acceptable salts may be, but are not limited to, a choline salt, an L-lysine salt, a tert-butylamine salt, or a diethanolamine salt.

[0058] Some embodiments include the choline salt of the compound of formula (I) and crystalline forms thereof.

[0059] Some embodiments include the L-lysine salt of the compound of formula (I) and crystalline forms thereof.

[0060] Some embodiments include the tert-butylamine salt of the compound of formula (I) and its crystalline forms.

[0061] Some embodiments include the diethanolamine salt of the compound of formula (I) and crystalline forms thereof.

[0062] Crystalline forms of the compound of formula (I) Disclosed herein are salts and crystalline forms of the compound of formula (I). Unless otherwise stated, the X-ray powder diffraction data provided herein was determined using a Cu Kα radiation source.

[0063] In some embodiments, the crystalline form of the salt of the compound of formula (I) may be solvated. In some embodiments, the crystalline form of the salt of the compound of formula (I) may be a hydrate. In some embodiments, the crystalline form of the salt of the compound of formula (I) may be non-solvated.

[0064] Crystalline Form of the L-Lysine Salt of the Compound of Formula (I) ("Crystalline Salt A") Some embodiments include a non-solvated L-lysine salt form of the compound of formula (I), optionally referred to herein as crystalline Salt A. While the precise conditions for forming crystalline Salt A may be determined empirically, the exemplary methods disclosed herein have been found to be suitable in practice for forming crystalline Salt A.

[0065] Crystalline Salt A is characterized using various techniques, which are described in more detail in the Experimental Methods section herein. Figure 1 depicts an example of an X-ray powder diffraction (XRPD) pattern for crystalline Salt A. As shown in Figure 1, crystalline Salt A obtainable by the method disclosed herein has approximately 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.00, 25.00, 26.00, 27.00, 28.00, 29.00, 30.00, 31.00, 32.00, 33.00, 34.00, 35.00, 36.00, 37.00, 38.00, 39.00, 40.00, 41.00, 42.00, 43.00, 44.00, 45.00, 46.00, 47.00, 48.00, 49.00, 50.00, 51.00, 52.00, 53.00, 54.00, 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 70.00, 72.00, 74.00, 76.00, 78.00, 79.00, 80.00 Thus, in some embodiments, the crystalline form of the compound of Formula (I) has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 characteristic peaks) selected from about 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, and 26.00 degrees 2θ. In some embodiments, the crystalline form of the compound of Formula (I) has at least three characteristic peaks selected from about 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ.

[0066] As will be understood by those skilled in the art, due to experimental variations when X-ray diffraction patterns are measured on different instruments, peak positions are considered to be equal when the 2-theta (2θ) values ​​match within a certain degree of variation. For example, the United States Pharmacopeia states that identity is confirmed when the angular settings of the 10 most intense diffraction peaks match those of a reference material within ±0.2 degrees, and the relative intensities of the peaks do not vary by more than 20%. Thus, in some embodiments, the peak positions described herein include a variation within ±0.5 degrees 2θ. In other embodiments, the peak positions described herein include a variation within ±0.2 degrees 2θ. As disclosed herein, the term "about" is defined as ±0.5 degrees 2θ when referring to 2θ values.

[0067] Figure 2 depicts an example of a differential thermal analysis (DTA) and thermogravimetric analysis (TG) overlay for crystalline Salt A. In one case, crystalline Salt A exhibited a weight loss of 2.3% when run from 25°C to 300°C. The DTA analysis indicates a melting range of approximately 197-203°C for crystalline Salt A.

[0068] FIG. 5 depicts an example of dynamic vapor sorption (DVS) analysis for crystalline salt A, showing a mass gain of 4.2 wt % (1.3 equivalents of water) at 90% relative humidity (RH).

[0069] Crystalline Salt A may therefore be characterized as being stable over a wide range of humidities. Crystalline Salt A also exhibits good crystallinity, has a relatively high melting point (about 200° C.), and does not show any evidence of hydrate formation.

[0070] Crystalline Form of the tert-Butylamine Salt of the Compound of Formula (I) ("Crystalline Salt B") Some embodiments include a non-solvated tert-butylamine salt of the compound of formula (I), which is referred to herein as crystalline Salt B. The precise conditions for forming crystalline Salt B may be determined empirically, and it is only possible to provide a number of methods that have been found to be suitable in practice.

[0071] Crystalline Salt B was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 3 depicts an example of an X-ray powder diffraction (XRPD) pattern for the salt structure of Form I of crystalline Salt B. Crystalline Salt B obtainable by the methods disclosed herein exhibits prominent peaks at about 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ. Thus, in some embodiments, the crystalline form of the compound of formula (I) has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 characteristic peaks) selected from about 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ. The crystalline form of the compound has at least three characteristic peaks selected from about 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ.

[0072] Figure 4 depicts an example of a differential thermal analysis (DTA) and thermogravimetric analysis (TG) overlay for Form I of crystalline Salt B. In one case, crystalline Salt B did not exhibit significant mass loss until after the onset of thermal decomposition. DTA analysis indicates a melting point range of about 196-224 °C for crystalline Salt B.

[0073] FIG. 6 depicts an example of dynamic vapor sorption (DVS) analysis for Form I of crystalline salt B, showing negligible water uptake at 90% RH.

[0074] Form I of Crystalline Salt B may therefore be characterized as non-hygroscopic and stable over a wide range of humidities. Crystalline Salt B also exhibits good crystallinity, has a relatively high melting point (about 210° C.), and does not show any evidence of hydrate formation.

[0075] Methods for Producing Crystalline Forms of Formula (I) Salt forms of the compound of formula (I), including for example the L-lysine salt form, may be prepared by the procedure outlined below. The compound of formula (I) is dissolved in a minimum amount of a solvent selected from 2-propanol, acetonitrile, ethanol, ethyl acetate, methanol and isopropyl acetate. L-lysine (1.05 equivalents) is then added and the sample temperature is cycled between ambient and elevated temperatures, for example 40°C, in fixed time cycles, for example 4 hour cycles, for an extended duration, for example 72 hours. After such time, an anti-solvent selected from the list of heptane or toluene is added to the mixture and the sample is stored at 2-8°C to promote precipitation. The L-lysine salt of the compound of formula (I) may be isolated as a crystalline material via centrifugal filtration, particularly from a solvent mixture consisting of methanol / toluene. If no crystalline material is obtained, the solvent is allowed to evaporate under ambient conditions. At this point, the salt form of the compound of formula (I), such as the L-lysine salt form, can be obtained as a crystalline material, particularly from solvent mixtures consisting of 2-propanol / heptane, acetonitrile / toluene, and ethanol / heptane. The solid observed was dried under vacuum at elevated temperatures, such as 40° C., for extended periods of time, such as 6 hours.

[0076] Alternative salt forms of the compound of formula (I), including, for example, the tert-butylamine salt of the compound of formula (I), may be prepared by the procedure outlined below. The compound of formula (I) is dissolved in a minimum amount of a solvent selected from 2-propanol, acetonitrile, ethanol, ethyl acetate, methanol and isopropyl acetate. tert-butylamine is then added and the sample temperature is cycled between ambient and elevated temperatures, for example 40°C, in fixed time cycles, for example 4 hour cycles, for an extended duration, for example 72 hours. After such time, the salt form of the compound of formula (I), for example the tert-butylamine salt form, may be obtained as a crystalline material by filtration, especially when using a solvent selected from the list of 2-propanol, acetonitrile, ethyl acetate and isopropyl acetate. If no crystalline material is obtained, an anti-solvent selected from the list of heptane or toluene is added to the mixture and the solvent is allowed to evaporate under ambient conditions. After this time, the tert-butylamine salt of the compound of formula (I) may be obtained as a crystalline material. The observed solid is dried under vacuum for an extended duration, e.g., 6 hours, at elevated temperature, e.g., 40° C. Other crystalline forms of the tert-butylamine salt of the compound of formula (I), e.g., Form II, Form III, and Form IV, may be prepared by using 1,1,1,3,3,3-hexafluoroisopropanol (HFIPA) as a solvent.

[0077] Non-limiting examples of preparing various crystalline forms of the salt of the compound of formula (I) are provided in the Examples.

[0078] Formulation of pharmaceutical compositions The salts of the compound of formula (I) and its crystalline forms (e.g., crystalline salt A, crystalline salt B disclosed herein) can be provided in combination with other therapeutic agents or in pharmaceutical compositions. The pharmaceutical compositions provided herein contain a therapeutically effective amount of the salt forms of the compound of formula (I) and its crystalline forms.

[0079] The compositions provided herein may comprise one or more salt forms and crystalline forms of the compound of formula (I) provided herein, either alone or in combination or in admixture.The compositions are formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release preparations or elixirs in sterile solutions or suspensions for oral administration or parenteral administration, as well as transdermal patch preparations and dry powder inhalants.Typically, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Non-Patent Document 17).

[0080] In some embodiments, the composition comprising the salt of the compound of formula (I) and its crystalline form may comprise one or more salts of the compound of formula (I) and its crystalline form. In some embodiments, the total amount of the salt of the compound of formula (I) and its crystalline form in the composition may comprise at least about 50% by weight of the salt form of the compound of formula (I). In some embodiments, the total amount of the salt of the compound of formula (I) and its crystalline form in the composition may comprise at least about 80% by weight of the salt form of the compound of formula (I). In some embodiments, the total amount of the salt of the compound of formula (I) and its crystalline form in the composition may comprise at least about 95%, 96%, 97%, 98%, or 99% by weight of the salt form of the compound of formula (I).

[0081] In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 50% by weight of crystalline salt A. In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 80% by weight of crystalline salt A. In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 95% by weight of crystalline salt A. In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 96%, 97%, 98%, or 99% by weight of crystalline salt A.

[0082] In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 50% by weight of crystalline salt B. In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 80% by weight of crystalline salt B. In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 95% by weight of crystalline salt B. In some embodiments, the total amount of the salt of the compound of Formula (I) in the composition may comprise at least about 96%, 97%, 98%, or 99% by weight of crystalline salt B.

[0083] In some embodiments, the composition comprises crystalline salt A. For example, the total amount of the salt of the compound of formula (I) and its polymorphs in the composition may comprise at least about 20%; at least about 50%; at least about 90%; at least about 95%; or at least about 99% crystalline salt A. Similarly, the composition may also comprise, for example, crystalline salt B. The total amount of the salt of the compound of formula (I) and its polymorphs in the composition may comprise at least about 20%; at least about 50%; at least about 90%; at least about 95%; or at least about 96%, 97%, 98%, or 99% crystalline salt B.

[0084] In certain embodiments, pharmaceutical compositions containing one or more salts and polymorphs thereof provided herein are prepared by using known techniques including, but not limited to, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0085] In the composition, an effective concentration of one or more salts of the compound of formula (I) and crystalline forms thereof described herein are mixed with a suitable pharmaceutical carrier or vehicle. The concentration of the compound in the composition is effective for delivery of an amount that, upon administration, treats, prevents, or ameliorates one or more symptoms of fibrotic diseases or disorders, including those described herein.

[0086] Typically, the composition is formulated for single dosage administration.To formulate the composition, the weight ratio of the salt and its crystalline form are dissolved, suspended, dispersed or otherwise mixed in the selected medium at effective concentration so that the condition to be treated is alleviated or ameliorated.The pharmaceutical carrier or medium suitable for administration of the compound provided herein includes any carrier that is known to those skilled in the art to be suitable for a particular mode of administration.

[0087] Additionally, the salts and polymorphs thereof can be formulated as the sole pharma- ceutical active ingredient in the composition or can be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, can also be suitable as pharma- ceutical acceptable carriers. They can be prepared according to methods known to those skilled in the art. For example, liposomal formulations can be prepared as described in U.S. Pat. No. 5,399,133. Briefly, liposomes, such as multilamellar vesicles (MLVs), can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0088] One or more salts and crystalline forms thereof provided herein are included in a pharma- ceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without undesirable side effects in the treated subject.

[0089] The concentration of one or more salts and crystalline forms thereof provided herein in pharmaceutical composition depends on the absorption, inactivation and excretion rate of compound, the physicochemical characteristics of compound, dosage schedule and the amount administered as well as other factors known to those skilled in the art.For example, the amount delivered is sufficient to ameliorate one or more of the symptoms of fibrotic disease or disorder, including those described herein.

[0090] Effective amounts of the salts or crystalline forms thereof provided herein can be determined by one of ordinary skill in the art and include exemplary dosages of about 0.05-100 mg of active compound per kg of body weight per day for mammals, which may be administered in a single dose or in the form of individual divided doses, for example, 1-4 times per day. It will be understood that the specific dose level and frequency of dosing for any particular subject can vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, the rate of excretion, drug combination, and the severity of the particular condition. In some embodiments, the daily dosage of the salts of the compounds of formula (I) and crystalline forms thereof provided herein can vary over a wide range, from about 0.01 mg or 0.01 mg to about 1000 mg or 1000 mg per adult human per day. For example, the dosage may be 100 mg or 1000 mg per day. The dosage may range from about 0.1 mg or 0.1 mg to about 200 mg or 200 mg per kilogram of body weight per day. In some embodiments, the dosage may range from 0.2 mg to 20 mg per day. In some embodiments, the dosage may range from 0.5 mg to 10 mg per day. Small doses (0.01 to 1 mg / kg per day) may be administered initially, followed by increasing the dose to about 1000 mg / kg per day. If the response in the subject is insufficient at such doses, even higher doses (or higher doses effective by different, more localized delivery routes) may be used to the extent that patient tolerance allows. More preferred dosages are in the range of 0.1 to 300 mg per kilogram of body weight per day, more preferably 0.1 to 100 mg per kilogram of body weight per day. The suitable dose may be administered in multiple subdoses per day. In some embodiments, the daily dosage is 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, g, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, 9.75 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg.For oral administration, the compositions may be provided in unit dosage form, e.g., tablet or capsule or liquid form, containing from about 0.01 mg or 0.01 mg to about 1000 mg or 1000 mg, e.g., 0.01, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 400, 500, 750, 800, 850, 900, 950, and 1000 milligrams of active ingredient for symptomatic adjustment of dosage to the subject to be treated. In some embodiments, the compositions may be provided in unit dosage form, e.g., tablet or capsule or liquid form, containing from about 0.01 μg or 0.01 μg to about 1000 μg or 1000 μg of active ingredient for symptomatic adjustment of dosage to the subject being treated, e.g., 0.01, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, and 1000 micrograms.

[0091] Pharmaceutical compositions comprising one or more salts and crystalline forms thereof provided herein can be administered at once or divided into a number of smaller doses administered at intervals.It is understood that the precise dosage and duration of treatment are functions of the disease being treated and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data.It should be noted that concentration and dosage values ​​can also vary with the severity of the condition to be alleviated.It should be further understood that for any particular subject, specific dosage regimen should be adjusted over time according to individual need and the professional judgment of the person who administers or supervises the administration of the composition, and that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the salts and polymorphs thereof, compositions, methods and other subject matter provided herein.

[0092] As such, effective concentrations or amounts of one or more of the salts and crystalline forms described herein may be administered as suitable pharmaceutical carriers for systemic, topical or local administration to form pharmaceutical compositions. The one or more salts and their crystalline forms provided herein are contained in an amount effective for ameliorating one or more symptoms of disease or disorder described herein, or for treating or preventing said disease or disorder.The concentration of one or more salts and their crystalline forms in the composition depends on the absorption, inactivation, excretion rate, dosage schedule, amount administered, specific formulation of active compound, as well as other factors known to those skilled in the art.

[0093] The composition is intended to be administered by a suitable route, including oral administration in the form of liquid formulations, including capsules, tablets, granules, powders, or syrups; parenteral administration, for example, subcutaneous, intravenous, intramuscular, using intersternal injection or infusion techniques (as a sterile injectable aqueous (aq.) or non-aqueous solution or suspension); intranasal administration, for example, by inhalation spray; topical administration, for example, in the form of creams or ointments; intrarectal administration, for example, in the form of suppositories; by liposomes; and topical administration. The composition can be in liquid, semi-liquid, or solid form, and is formulated in a manner suitable for each route of administration. In certain embodiments, administration of the formulation includes parenteral and oral modes of administration. In one embodiment, the composition is administered orally. In another embodiment, the composition is administered directly to the eye via injection.

[0094] In certain embodiments, the pharmaceutical compositions provided herein that include one or more salts and crystalline forms thereof are solid (e.g., powder, tablet, and / or capsule).In certain such embodiments, the solid pharmaceutical compositions that include one or more salts and polymorphs thereof provided herein are prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, gums, lubricants, binders, and disintegrants.

[0095] In certain embodiments, the pharmaceutical composition provided herein, comprising one or more salts and crystalline forms thereof, is liquid or semi-liquid.In certain such embodiments, the liquid pharmaceutical composition comprising one or more salts of the compound of formula (I) can be prepared by dissolving the salts of the compound of formula (I) in a suitable solvent or mixture of solvents, including but not limited to water, methanol, ethanol, n-propanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, acetone, dimethylsulfoxide, chloroform, and isopropyl myristate.In other such embodiments, the one or more salts of the compound of formula (I) and crystalline forms thereof can be formulated as a suspension in a liquid dispersion medium comprising one or more liquids.

[0096] In certain embodiments, the pharmaceutical composition comprising one or more salts and crystalline forms thereof provided herein comprises a delivery system.Examples of delivery systems include, but are not limited to, liposomes and emulsions.Certain delivery systems are useful for preparing certain pharmaceutical compositions, including those that comprise hydrophobic compounds.In certain embodiments, certain organic solvents, such as dimethylsulfoxide, are used.

[0097] In certain embodiments, pharmaceutical compositions comprising one or more salts and crystalline forms thereof (active ingredients) provided herein contain one or more tissue-specific delivery molecules designed to deliver the pharmaceutical composition to a specific tissue or cell type. For example, in certain embodiments, the pharmaceutical composition contains liposomes coated with tissue-specific antibodies.

[0098] In certain embodiments, pharmaceutical compositions comprising one or more salts and crystalline forms thereof provided herein include a co-solvent system. Certain such co-solvent systems include, for example, benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and a water-soluble glycerol-containing ... In certain embodiments, such cosolvent systems are used for hydrophobic compounds. A non-limiting example of such a cosolvent system is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™, and 65% w / v of polyethylene glycol 300 in absolute ethanol. The proportions of such cosolvent systems can be varied considerably without significantly altering the solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components can be varied. For example, other surfactants can be used in place of Polysorbate 80™; the proportion size of the polyethylene glycol can be varied; other biocompatible polymers, such as polyvinylpyrrolidone, can replace the polyethylene glycol; and other sugars or polysaccharides can be substituted for dextrose.

[0099] In certain embodiments, the solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can contain any of the following components: sterile diluents, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol and methylparaben; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates, and phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or single or multiple dose vials made of glass, plastic, or other suitable materials.

[0100] When salt and its crystalline form show poor solubility, methods of solubilizing compound can be used.Such methods are known to those skilled in the art and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as polyoxyethylene derivatives of sorbitan monolaurate, such as TWEEN® or polysorbate surfactants, or dissolving in aqueous sodium bicarbonate.Derivatives of compound, such as prodrugs of compound, can also be used in the formulation of effective pharmaceutical compositions.

[0101] In certain embodiments, the pharmaceutical composition comprising one or more salts or crystalline forms thereof provided herein comprises sustained release system.A non-limiting example of such sustained release system is a semipermeable matrix of solid hydrophobic polymer.In certain embodiments, sustained release system can release compound over a period of hours, days, weeks or months, depending on their chemical nature.

[0102] In certain embodiments, the mixture resulting from mixing or adding the salts described herein and their crystalline forms can be a solution, suspension or emulsion.The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the salts described herein in the selected carrier or vehicle.The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder or condition being treated, and can be empirically determined.

[0103] The pharmaceutical compositions are provided in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions, containing a suitable amount of the salts and polymorphs thereof or pharma- ceutically acceptable derivatives thereof, for administration to humans and animals. Pharmaceutically active compounds and their derivatives are typically formulated and administered in unit dosage forms.

[0104] The compositions may contain, in addition to one or more salts and crystalline forms thereof provided herein, other ingredients, including, but not limited to, diluents, such as lactose, sugars, and the like. cellulose, dicalcium phosphate, or carboxymethylcellulose; lubricants such as magnesium stearate, calcium stearate, and talc; and binders such as starch, natural gums such as gum acacia, gelatin, glucose, molasses, polyvinylpyrrolidone, cellulose and its derivatives, povidone, crospovidone, and other such binders known to those skilled in the art. Liquid pharma-ceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the salts described herein or their crystalline forms and optional pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, glycol, and ethanol, thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, or solubilizers, or pH buffering agents, such as sodium acetate or citrate, or cyclodextrin derivatives, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Non-Patent Document 18. The composition or formulation to be administered will, in any event, contain a quantity of active compound sufficient to alleviate the symptoms of the subject being treated.

[0105] Dosage forms or compositions may be prepared containing one or more salts and crystalline forms thereof provided herein in the range of 0.005%-100%, with the remainder consisting of non-toxic carriers. For oral administration, pharma- ceutically acceptable non-toxic compositions are formed by the incorporation of any of the commonly used excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained release formulations, including, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and others. Methods for the preparation of these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100%, in one embodiment 0.1-85%, and in another embodiment 75-95% of the active ingredient. In some embodiments, the composition comprises 1-10% active ingredient. In some embodiments, the composition comprises 10-25% active ingredient. In some embodiments, the composition comprises 15-35% active ingredient. In some embodiments, the composition comprises 40-60% active ingredient. In some embodiments, the composition comprises 50-75% active ingredient.In some embodiments, the active ingredient is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% , 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0106] In certain embodiments, the salt and its crystalline form can be administered in a suitable form for immediate release or sustained release.Immediate release or sustained release can be achieved by using suitable pharmaceutical compositions or, particularly in the case of sustained release, devices such as subcutaneous implants or osmotic pumps.Exemplary compositions for external administration include mineral oil (e.g., PLASTIBASE®) gelled with an external carrier such as polyethylene.

[0107] In certain embodiments, pharmaceutical salt and its crystalline form comprise one or more salts and its polymorphs provided herein in therapeutically effective amount.In certain embodiments, therapeutically effective amount is sufficient to prevent, reduce or ameliorate the symptoms of disease or prolong the life of the subject being treated.The determination of therapeutically effective amount is well within the capabilities of those skilled in the art.

[0108] In addition to one or more salts and crystalline forms thereof provided herein, the composition can contain other active compounds to obtain desired combination of properties.The salts and crystalline forms thereof provided herein can also be advantageously administered for therapeutic or prophylactic purposes with another pharmacological agent known in the art to be valuable in treating one or more of the diseases, disorders, or medical conditions mentioned herein above, such as, but not limited to, those described herein, eye diseases, or fibrotic diseases or disorders associated with inflammation and / or vascular proliferation.It should be understood that such combination therapy constitutes a further aspect of the compositions and treatment methods provided herein.

[0109] In certain embodiments, pharmaceutical compositions comprising one or more salts and crystalline forms thereof provided herein are useful for treating conditions or disorders in mammals, particularly human subjects. Suitable routes of administration include, but are not limited to, oral, rectal, mucosal, intestinal, enteral, topical, suppository, via inhalation, intrathecal, intracerebroventricular, intraperitoneal, intranasal, intraocular, and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical compositions are administered to achieve local exposure rather than systemic exposure. For example, pharmaceutical compositions can be directly injected into the desired compartment of effect (e.g., eye or corneal compartment). In certain embodiments, pharmaceutical compositions are administered locally, dosage regimens are adjusted to achieve the desired local concentration of the salts provided herein or crystalline forms thereof.

[0110] In certain embodiments, pharmaceutical compositions comprising one or more salts and crystalline forms thereof provided herein are administered in dosage unit form (e.g., tablet, capsule, pill, injection, bolus).

[0111] In certain embodiments, the pharmaceutical composition is administered once a day, twice a day, three times a day, or four or more times a day, as needed. It will be appreciated by those skilled in the art that the particular dose, frequency, and duration of administration will depend on numerous factors, including, without limitation, the desired biological activity, the condition of the subject, and tolerability of the pharmaceutical composition.

[0112] In certain embodiments, the pharmaceutical compositions provided herein are administered for a period of continuous treatment. For example, the pharmaceutical compositions provided herein can be administered for a period of days, weeks, months, or years.

[0113] The dosage, the interval between doses, and the duration of treatment may be adjusted to achieve the desired effect. In certain embodiments, the dosage and the interval between doses are adjusted to maintain a desired concentration of the compound in the subject. For example, in certain embodiments, the dosage and the interval between doses are adjusted to provide a plasma concentration of the salt provided herein or a crystalline form thereof in an amount sufficient to achieve the desired effect. In certain such embodiments, the plasma concentration is maintained above the minimum effective concentration (MEC). In certain embodiments, the pharmaceutical compositions provided herein are administered using a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, 30-90% of the time, or 50-90% of the time.

[0114] Compositions for oral administration In certain embodiments, oral pharmaceutical dosage forms are either solid, gel or liquid.Solid dosage forms are tablets, capsules, granules, and bulk powders.Oral tablet types include compressed, chewable lozenges and tablets that can be enteric coated, sugar coated or film coated.Capsules can be hard or soft gelatin capsules, and granules and powders can be provided in non-foaming or foaming form with the combination of other ingredients known to those skilled in the art.

[0115] In certain embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges and other solid dosage forms can contain any of the following ingredients, or compounds of a similar nature: binders; diluents; disintegrants; lubricants; glidants; sweeteners; and flavoring agents.

[0116] In certain embodiments, the pharmaceutical composition for oral administration is a push-fit capsule made of gelatin. Certain such push-fit capsules contain one or more compounds provided herein in admixture with one or more fillers, such as lactose, binders, such as starch, and / or lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In certain embodiments, the pharmaceutical composition for oral administration is a soft sealed capsule made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds provided are dissolved or suspended in suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers can be added.

[0117] In certain embodiments, pharmaceutical composition is prepared for buccal administration.Certain such pharmaceutical composition is tablet or lozenge formulated in conventional manner.In some embodiments, composition is made with degradable film, such as pullulan, or formulated as degradable film as described in the art (see, for example, U.S. Patent No. 5,399,621; U.S. Patent No. 5,399,621; U.S. Patent No. 5,399,633; and U.S. Patent No. 5,433,666).

[0118] Examples of binders for use in the compositions provided herein include microcrystalline cellulose, gum tragacanth, glucose solution, gum arabic, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Lubricants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, sodium alginate, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate. Sweeteners include sucrose, lactose, mannitol, xylitol and artificial sweeteners, for example, saccharin. Flavoring agents include natural flavors extracted from plants, e.g., fruits, and synthetic blends of compounds that produce a pleasant sensation, e.g., but are not limited to, peppermint and methyl salicylate, and include spray-dried natural and artificial flavors. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include glyceryl stearate, glyceryl stearate, cellulose acetate phthalate, and cellulose acetate phthalate. Examples of suitable adhesives include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[0119] When oral administration is desired, the compound can be provided in a composition that protects the compound from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.The composition can also be formulated in combination with an antacid or other such ingredient.

[0120] When the dosage unit form is a capsule, it can contain liquid carriers, such as fatty oils, in addition to the above-mentioned types of materials.In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as sugar and other enteric coatings.The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles or chewing gums.Syrups can contain, in addition to the active compounds, sucrose as a sweetener and certain preservatives, dyes and colorings and flavorings.

[0121] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers (gastric acid suppressants), and diuretics.

[0122] The pharma- ceutically acceptable carriers included in the tablet are binders, lubricants, diluents, disintegrants, colorants, flavoring agents, and wetting agents. Enteric-coated tablets resist the action of stomach acid due to the enteric coating, and dissolve or disintegrate in the neutral or alkaline intestines. Sugar-coated tablets are compressed tablets coated with different layers of pharma- ceutical acceptable materials. Film-coated tablets are compressed tablets that are coated with polymers or other suitable coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharma- ceutical acceptable materials previously described. Coloring agents can also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar-coated, multiple compressed, and chewable tablets. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0123] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and foamable preparations reconstituted from foaming granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0124] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents, and preservatives. Suspensions use pharma-ceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-foaming granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[0125] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives are glycerin, methyl and propyl paraben, benzoic acid d), sodium benzoate, and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, gum arabic, gum tragacanth, xanthan gum, propylene glycol alginate, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include xanthan gum, sodium carboxymethylcellulose, pectin, tragacanth, Veegum®, and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[0126] For solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils or triglycerides, can be encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patent No. 5,399,623; U.S. Patent No. 5,433,363; and U.S. Patent No. 5,433,363. For liquid dosage forms, the solution, for example in polyethylene glycol, can be diluted with a sufficient quantity of a pharma- ceutical acceptable liquid carrier, for example water, to be easily measured for administration.

[0127] Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the salts provided herein or crystalline forms thereof in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those described in U.S. Patent No. 5,393,311 and U.S. Patent No. 5,433,633. Briefly, such formulations include those that contain a compound provided herein, a dialkylated mono or polyalkylene glycol, including, but not limited to, 1,2-dimethoxy-methane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0128] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetal that is pharmaceutically acceptable.The alcohol used in these formulations is any pharmaceutically acceptable water-miscible solvent that has one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.Acetals include, but are not limited to, the di(lower alkyl) acetal of lower alkyl aldehyde, such as acetaldehyde diethyl acetal.

[0129] In all embodiments, the tablet and capsule formulations may be coated as known by those skilled in the art to modify or sustain the dissolution of the salts described herein or their crystalline forms, for example, they may be coated with conventional enterically digestible coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

[0130] Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. High molecular weight excipients such as cellulose and microcrystalline cellulose (AVICEL®) or polyethylene glycol (PEG); excipients to aid mucoadhesion such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and / or maleic anhydride copolymers (e.g., GANTREZ®); and agents for controlling release such as polyacrylic acid copolymers (e.g., CARBOPOL® 934) may also be included in such formulations. Lubricants, glidants, flavors, colors, and stabilizers may also be added for ease of fabrication and use.

[0131] In certain such embodiments, pharmaceutical compositions for oral administration are formulated by combining one or more salts and crystalline forms thereof provided herein with one or more pharma- ceutically acceptable carriers. Certain such carriers allow the compounds provided herein to be formulated into dosage forms for oral ingestion by subjects, such as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions. In certain embodiments, pharmaceutical compositions for oral use are obtained by mixing one or more salts and crystalline forms thereof provided herein with one or more solid excipients. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). In certain embodiments, such mixtures are optionally milled and auxiliary agents are optionally added. In certain embodiments, the pharmaceutical composition is formulated to obtain tablets or dragee cores, hi certain embodiments, disintegrating agents are added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0132] In certain embodiments, dragee cores are provided with coatings.In certain such embodiments, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.Dyes or pigments can be added to tablets or dragee coatings.

[0133] In certain embodiments, the daily dosage regimen for a subject comprises an oral dose of 0.1 μg to 2000 mg of the salt provided herein or a crystalline form thereof. In certain embodiments, the daily dosage regimen for a subject comprises an oral dose of 1 μg to 500 mg of the salt provided herein or a crystalline form thereof. In certain embodiments, the daily dosage regimen for a subject comprises an oral dose of 10 μg to 100 mg of the salt provided herein or a crystalline form thereof. In certain embodiments, the daily dosage regimen for a subject comprises an oral dose of the salt provided herein or a crystalline form thereof selected from among 0.01, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 400, 500, 750, 800, 850, 900, 950, and 1000 milligrams. In certain embodiments, the daily dosage regimen is administered as a single daily dose. In certain embodiments, the daily dosage regimen is administered as a single daily dose. In embodiments, the daily dosage regimen is administered as two, three, four, or more than four doses.

[0134] Injectables, Solutions and Emulsions In certain embodiments, pharmaceutical compositions are prepared for transmucosal administration. In certain such embodiments, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0135] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, mannitol, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution or ethanol. Additionally, if desired, the administered pharmaceutical composition can also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizing agents, solubility enhancing agents, and other such agents, such as mono- or diglycerides, fatty acids such as oleic acid, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a delayed-release or sustained-release system, such that a constant level of dosage is maintained (see, for example, US Pat. No. 5,399,333), is also contemplated herein.Briefly, the salts or crystalline forms thereof provided herein are provided with an outer polymeric membrane that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol ternary copolymers, and the like. The salt or crystalline form thereof is dispersed in a solid inner matrix surrounded by an ethylene / vinyloxy-ethanol copolymer, such as polymethyl-methacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene-terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethyl-siloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate. The salt or crystalline form thereof diffuses through the outer polymer membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the activity of the compound and the needs of the subject, as well as its specific nature.

[0136] Parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, subcutaneous tablets, sterile dry soluble products ready to be combined with a solvent just before use, such as lyophilized powders, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just before use, and sterile emulsions. The solutions can be either aqueous or non-aqueous.

[0137] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), as well as solutions containing viscosity enhancing and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0138] Pharmaceutically acceptable carriers used in parenteral preparations can be aqueous media, non-aqueous media, These include antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharma- ceutically acceptable substances.

[0139] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multi-dose containers, and include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxy-propyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). Sequestering or chelating agents for metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0140] The concentration of the pharma- ceutical active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the subject or animal, as is known in the art.

[0141] Unit dosage parenteral preparations are packaged in an ampoule, vial or syringe with a needle.As known and practiced in the art, all preparations for parenteral administration must be sterile.

[0142] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[0143] Injectables are designed for local and systemic administration. Typically, therapeutically effective dosages are formulated to contain at least about 0.1% w / w to about 90% w / w or higher, and in some embodiments, higher than 1% w / w, of the active compound with respect to the tissue being treated. The active ingredient can be administered once or divided into multiple smaller doses that are administered at intervals of time. The precise dosage and duration of treatment is a function of the tissue being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​may also vary with the age of the individual being treated. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the formulation, and that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the formulations provided herein.

[0144] The salts and their crystalline forms can be formulated in any suitable medium or form. For example, they can be micronized or in other suitable form, and / or can be derivatized to produce a more soluble active product or to produce a prodrug or for other purposes. The form of the resulting mixture can vary depending, for example, on the intended mode of administration and the salts and their polymorphs in the selected carrier or medium. The effective concentration will depend upon numerous factors, including solubility in the body. The effective concentration will be sufficient for ameliorating the symptoms of the condition and may be empirically determined.

[0145] In certain embodiments, pharmaceutical compositions are prepared for administration by injection, and the pharmaceutical compositions include a carrier and are formulated in an aqueous solution, such as water or a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients (e.g., ingredients that aid solubility or serve as preservatives) are included. In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers and / or suspending agents. Certain pharmaceutical compositions for injection are presented in unit dosage form, for example, in ampoules or multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles and may include formulatory agents, such as suspending, stabilizing and / or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions also can contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0146] In certain embodiments, provided pharmaceutical compositions are administered by continuous intravenous infusion, hi certain such embodiments, between 0.01 μg and 500 mg of the composition are administered per day.

[0147] freeze-dried powder Also of interest herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0148] Sterile lyophilized powders are prepared by dissolving the salts provided herein or crystalline forms thereof in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agents. The solvent may also contain a buffer, typically at approximately neutral pH, such as citrate, sodium or potassium phosphate or other such buffers known to those of skill in the art. Subsequent sterile filtration of the solution under standard conditions known to those of skill in the art, followed by lyophilization, provides the desired formulation. Generally, the resulting solution is apportioned into vials for lyophilization. In some embodiments, each vial contains a single dosage of 10 μg to 1000 mg. In another embodiment, each vial contains a single dosage of 100 μg to 500 mg. In another embodiment, each vial contains a single dosage of 0.1 mg to 50 mg. In another embodiment, each vial contains a single dosage of 0.5 mg to 20 mg. In another embodiment, each vial contains a single dosage of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In another embodiment, each vial contains multiple dosages of a salt of a compound described herein or a crystalline form thereof. The lyophilized powder can be stored under appropriate conditions, for example, at about 4° C. to room temperature.

[0149] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, approximately 1 mg to 50 mg is added to 1 mL of sterile water or other suitable In some embodiments, 5 mg to 35 mg is added per mL of sterile water or other suitable carrier. In other embodiments, 10 mg to 30 mg of lyophilized powder is added per mL of sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amounts can be empirically determined.

[0150] Methods of treatment using salts of the compound of formula (I), its crystalline forms and compositions thereof Also provided herein is the method of using the salt provided herein and its crystalline form and composition.Method includes treating, preventing or ameliorating one or more of the diseases, disorders or medical conditions mentioned herein above, such as, but not limited to, eye diseases associated with inflammation and / or vascular proliferation, or fibrotic diseases and disorders, including those described herein.In certain embodiments, provided herein is the method of treating a subject by administering the salt provided herein and its polymorphs.In certain embodiments, a subject is treated prophylactically to reduce or prevent the occurrence of a condition.

[0151] The administration of the salt of the compound of formula (I) and its crystalline form or any composition containing it to a subject can be by any of the approved modes for enteral administration, such as oral or rectal administration, or parenteral administration, such as subcutaneous, intramuscular, intravenous and intradermal routes.Injection can be via bolus, or constant or intermittent infusion.The active compound is typically included in a pharmaceutically acceptable carrier, excipient and / or diluent in an amount sufficient to deliver a therapeutically effective dose to a patient.

[0152] The salt of the compound of formula (I) and its crystalline form may be formulated into a composition for administration to a subject in need thereof. For example, in one embodiment, one or more salts of the compound of formula (I) and its crystalline form may be combined with one or more excipients in a solid formulation for administration to a subject in need thereof. In other embodiments, one or more salts of the compound of formula (I) and its crystalline form may be formulated into a liquid composition for administration to a subject in need thereof. In some such embodiments, one or more salts of the compound of formula (I) and its crystalline form may be dissolved in one or more liquid solvents to form a solution for administration to a subject in need thereof. In other such embodiments, one or more salts of the compound of formula (I) and its crystalline form may be dispersed in one or more liquids to form a suspension for administration to a subject in need thereof.

[0153] Compositions provided herein can be used in the treatment of various conditions.For example, the composition comprising one or more salts of compound of formula (I) and its crystalline form can be used to treat eye disease or disorder, including but not limited to diabetic retinopathy, corneal edema, anterior and posterior uveitis, pterygium, corneal disease, dry eye, conjunctivitis, allergy and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration and / or von Hippel-Lindau disease of eye.

[0154] In another embodiment, compositions comprising one or more salts of the compound of formula (I) and crystalline forms thereof may be used to treat conditions including, but not limited to, corneal diseases that may be caused by infection with a small organism or microorganism. The small organism or microorganism may be selected from any of the group including bacteria, viruses, fungi, amoebas, and parasites.

[0155] In another embodiment, compositions comprising one or more salts of the compound of formula (I) and crystalline forms thereof may be used to treat conditions including, but not limited to, ocular diseases associated with inflammatory and / or vascular proliferative diseases.

[0156] In another embodiment, compositions comprising one or more salts of the compound of formula (I) and crystalline forms thereof may be used to reduce at least one of, but not limited to, the level of ICAM-1 mRNA in a subject's retina; the level of VEGF mRNA in a subject's retina; and the number of white blood cells in a subject's retina.

[0157] In another embodiment, the composition comprising one or more salts of the compound of formula (I) and its crystalline form can be used to treat the disease or condition associated with fibrosis.Such disease may include, for example, fibrotic skin disorders, such as keloids, hypertrophic scars and scleroderma; lung diseases, such as pulmonary fibrosis; heart diseases, such as heart failure caused by ischemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; and kidney diseases, such as glomerulonephritis and diabetic nephropathy and progressive kidney disease caused by liver cirrhosis.In a preferred embodiment, the disease or condition is diabetic heart disease or diabetic kidney disease.In a further preferred embodiment, the disease or condition is diabetic cardiomyopathy. In some embodiments, the kidney disease may include, but is not limited to, progressive glomerular kidney disease, including diabetic nephropathy (e.g., those resulting from type I or type II diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis) or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephropathy). In some embodiments, the kidney disease may include progressive kidney disease of predominant tubulointerstitial origin. In some embodiments, the kidney disease may include, for example, chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0158] In another embodiment, a kit for treating an eye disease associated with inflammation and / or vascular proliferation comprising at least one salt of a compound of formula (I) and a crystalline form thereof; and instructions for administering same to a subject to treat the eye disease.

[0159] In another embodiment, a kit for treating a disease or condition associated with fibrosis comprising at least one salt of a compound of formula (I) and a crystalline form thereof; and instructions for administering same to a subject to treat a disease or condition associated with fibrosis.

[0160] In certain embodiments, provided is a method of treating a subject by administering a composition comprising at least one salt of a compound of formula (I) or a crystalline form thereof.

[0161] In certain embodiments, provided are methods of treating a subject by administering a composition comprising a salt of the compound of Formula (I) and polymorphs thereof by reducing at least one of: the level of ICAM-1 mRNA in the subject's retina; the level of VEGF mRNA in the subject's retina; and the number of white blood cells in the subject's retina.

[0162] Methods of using crystalline forms of the compound of formula (I) and compositions thereof In certain embodiments, one or more salts of the compound of formula (I) and its crystalline form provided herein can be administered in combination with one or more other therapeutic agents.In certain embodiments, such one or more other therapeutic agents are designed to treat the same disease or condition as one or more compounds or pharmaceutical compositions provided herein.In certain embodiments, such one or more other therapeutic agents are designed to treat a disease or condition different from one or more compounds or compositions provided herein.In certain embodiments, such one or more other therapeutic agents are designed to treat the undesirable effects of one or more compounds or compositions provided herein.In certain embodiments, one or more compounds or compositions provided herein are administered in combination with another therapeutic agent to treat the undesirable effects of the other therapeutic agent.

[0163] In using the salts of the compound of formula (I) and their crystalline forms, they can be administered in any form or mode that makes the compound bioavailable.Those skilled in the art of preparation of formulations can easily select the appropriate form and mode of administration depending on the specific characteristics of the selected compound, the condition to be treated, the stage of the condition to be treated and other relevant circumstances.For further information, see Non-Patent Document 16.

[0164] The salts of the compound of formula (I) and its crystalline forms may be administered alone or in the form of a pharmaceutical composition in combination with pharma- ceutically acceptable carriers, diluents, adjuvants and / or excipients.

[0165] However, the salt of the compound of formula (I) and its crystalline form are typically used in the form of pharmaceutical compositions that are formulated according to the desired mode of administration.The suitable compositions for use in the method of the present disclosure may be prepared according to methods and procedures known to those skilled in the art, and may therefore comprise pharmaceutically acceptable carriers, excipients, diluents and / or adjuvants.Therefore, in a further embodiment, the present disclosure provides pharmaceutical compositions that comprise the salt of the compound of formula (I) and its crystalline form and pharmaceutically acceptable carriers, diluents, adjuvants or excipients.

[0166] In certain embodiments, the compound or composition provided herein and one or more other therapeutic agents are administered simultaneously.In some embodiments, the compound or composition provided herein and one or more other therapeutic agents are administered at different times.In certain embodiments, the compound or composition provided herein and one or more other therapeutic agents are prepared together in a single preparation.In certain embodiments, the compound or composition provided herein and one or more other therapeutic agents are prepared separately.

[0167] In another embodiment, a pharmaceutical pack or kit includes one or more containers filled with one or more of the components of the pharmaceutical composition. In such a pack or kit, a container with a unit dosage of the agent can be found. The kit can include a composition (including a lyophilized composition) that includes the active agent as a concentrate that can be further diluted prior to use, or they can be provided at the concentration of use, in which case a vial may contain one or more dosages. Conveniently, in the kit, a single dosage can be provided in a sterile vial, so that the physician can directly use the vial, which has the desired amount and concentration of the agent. Various documents can be associated with such containers, such as instructions for use, or notices in the form prescribed by government agencies regulating the production, use, or sale of pharmaceutical or biological products, reflecting the approval by the agency of the production, use, or sale for human administration.

[0168] The salt and crystalline form described herein may be used or administered in combination with one or more additional drugs for the treatment of the disorders / diseases described.The components may be administered in the same formulation or in separate formulations or compositions.When administered in separate formulations or compositions, the salt and crystalline form of the present disclosure or the formulation or composition containing it may be administered sequentially or simultaneously with other drugs.

[0169] In addition to being able to be administered in combination with one or more additional drugs, the salt of the compound of formula (I) and its crystalline form may be used in combination therapy. When this is done, the compounds are typically administered in combination with each other. Therefore, one or more of the salts of the compound of formula (I) of the present disclosure and its crystalline form may be administered simultaneously (as a combined preparation) or sequentially to achieve the desired effect. Each of the compounds of formula (I) This is particularly desirable when the therapeutic profiles of the salt and its crystalline form are different such that the combined effect of the two drugs provides an improved therapeutic outcome.Administration may be systemic, regional or local.

[0170] The disclosed pharmaceutical compositions of salts of the compound of formula (I) and its crystalline form may be administered by standard routes.Generally, the compositions may be administered parenterally (e.g., intravenously, intraspinal, subcutaneously or intramuscularly), orally or topically.The specific route of administration used in any given situation depends on a number of factors, including the nature of the condition being treated, the severity and extent of the condition, the required dosage of the specific compound being delivered, and the potential side effects of the compound.

[0171] Pharmaceutical compositions of the disclosed salts of the compound of formula (I) and its crystalline forms for parenteral injection include pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use.

[0172] In using the salts of the compound of formula (I) and their crystalline forms, one skilled in the art may prepare pharma- ceutically acceptable excipient compositions with the aid of the method described in J. Med. Soc. 1999, 133:1311-1325.

[0173] The topical composition of the present disclosure comprises an active ingredient together with one or more acceptable carriers, and optionally any other therapeutic ingredients.Compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the area where treatment is required, such as liniments, lotions, creams, powders, patches, sprays, inhalants, ointments or pastes, and drops suitable for administration to the eyes, ears or nose.The active ingredient is mixed under sterile conditions with a pharma-ceutically acceptable carrier and any necessary preservatives, buffers, or propellants that may be required.

[0174] Droplets according to the present disclosure may comprise a sterile aqueous or oily solution or suspension. These may be prepared by dissolving the active ingredient in an aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative, optionally including a surfactant. The resulting solution may then be clarified by filtration, transferred to a suitable container and sterilized. Sterilization may be achieved by autoclaving or maintaining at 90-100°C for half an hour, or by filtration followed by transfer to a container by a sterilization technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, diluted alcohol and propylene glycol.

[0175] Lotions according to the present disclosure include those suitable for application to the skin or eyes. Eye lotions may include a sterile aqueous solution, optionally containing a bactericide, and may be prepared by a method similar to that described above for the preparation of drops. Lotions or liniments for application to the skin may also include an agent for promoting drying and cooling the skin, such as alcohol or acetone, and / or a moisturizer, such as glycerol, or an oil, such as castor oil or peanut oil.

[0176] Creams, ointments or pastes according to the present disclosure are semi-solid preparations of active ingredients for external application.They may be made by mixing the active ingredients in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with a greasy or non-greasy base.The base may be a hydrocarbon, such as hard, soft or liquid paraffin, glycerol, beeswax, metal soap; mucilage; oils of natural origin, such as almond, corn, peanut, castor or olive oil; alcohol, For example, it may contain wool fat or a derivative thereof, or a fatty acid, such as stearic acid or oleic acid, together with propylene glycol or macrogol.

[0177] The compositions may incorporate any suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

[0178] The amount of compound administered is preferably to treat and reduce or alleviate the condition.Therapeutically effective amount can be easily determined by the attending physician by using conventional techniques and observing the results obtained under similar circumstances.In determining the therapeutically effective amount, many factors are taken into account, including but not limited to the species of animal, its size, age and general health condition, the specific condition involved, the severity of the condition, the patient's response to treatment, the specific compound administered, the mode of administration, the bioavailability of the administered preparation, the selected dosage regime, the use of other pharmaceuticals and other relevant circumstances.

[0179] Those skilled in the art can determine by routine experimentation the effective, non-toxic amount of compound required to treat applicable diseases and conditions. In general, typical and effective dosages are expected to be in the range of about 0.01 to about 1000 mg per kilogram of body weight per day, typically about 0.1 to about 100 mg per kilogram of body weight per day, more typically about 1 to about 10 mg per kilogram of body weight per day, and even about 5 mg per kilogram of body weight per day. Small doses (0.01 to 1 mg / kg per day) may be administered initially, followed by increasing the dose to about 1000 mg / kg per day. If the response in the subject is insufficient at such doses, higher doses (or higher effective doses via different, more localized delivery routes) may be used to the extent that patient tolerance allows. A more preferred dosage is within the range of 0.1 to 300 mg per kilogram of body weight per day, more preferably 0.1 to 100 mg per kilogram of body weight per day. A suitable dose may be administered in multiple subdoses per day.

[0180] Typically, in therapeutic applications, treatment is for the duration of the disease state.

[0181] Furthermore, it will be apparent to one skilled in the art that the optimal amount and interval of individual dosing, e.g., the number of doses of a composition given per day for a defined number of days, will be determined by the nature and extent of the disease state being treated, the form, route and site of administration, and the nature of the particular individual being treated.

[0182] The following numbered embodiments are disclosed herein:

[0183] Embodiment 1: Formula (I):

[0184] [ka]

[0185] A crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I).

[0186] Embodiment 2: The crystalline form of embodiment 1, wherein the pharma- ceutically acceptable salt is selected from the group consisting of sodium salts, potassium salts, zinc salts, magnesium salts, and calcium salts.

[0187] Embodiment 3: The crystalline form of embodiment 1, wherein the pharma- ceutically acceptable salt is selected from the group consisting of a choline salt, an L-lysine salt, a tert-butylamine salt, and a diethanolamine salt.

[0188] Embodiment 4: The crystalline form of embodiment 3, wherein the pharma- ceutically acceptable salt is an L-lysine salt.

[0189] Embodiment 5: The crystalline form of embodiment 4, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least three characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ (±0.2 degrees 2θ).

[0190] Embodiment 6: The crystalline form of embodiment 4, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least four characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ (±0.2 degrees 2θ).

[0191] Embodiment 7: The crystalline form of embodiment 4, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least five characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, 26.00 degrees 2θ (±0.2 degrees 2θ).

[0192] Embodiment 8: The crystalline form of embodiment 4, exhibiting the X-ray powder diffraction pattern depicted in FIG.

[0193] Embodiment 9: The crystalline form of any one of embodiments 4, 5, 6, 7, and 8, having a melting point of about 197-203° C.

[0194] Embodiment 10: The crystalline form of embodiment 3, wherein the pharma- ceutically acceptable salt is a tert-butylamine salt.

[0195] Embodiment 11: The crystalline form of embodiment 10, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least three characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ (±0.2 degrees 2θ).

[0196] Embodiment 12: The crystalline form of embodiment 10, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least four characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ (±0.2 degrees 2θ).

[0197] Embodiment 13: The crystalline form of embodiment 10, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least five characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, 26.12 degrees 2θ (±0.2 degrees 2θ).

[0198] Embodiment 14: The crystalline form of embodiment 10, exhibiting an X-ray powder diffraction pattern depicted in FIG.

[0199] Embodiment 15: The crystalline form of any one of embodiments 10, 11, 12, 13, or 14, having a melting point of about 196-224° C.

[0200] Embodiment 16: A pharmaceutical composition comprising the crystalline form of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, and a pharma- ceutical acceptable excipient.

[0201] Embodiment 17: Formula (I):

[0202] [ka]

[0203] L-lysine salt of the compound.

[0204] Embodiment 18: Formula (I):

[0205] [ka]

[0206] The tert-butylamine salt of the compound.

[0207] Embodiment 19: A method of treating an eye disease comprising administering to a subject a therapeutically effective amount of a crystalline form of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0208] Embodiment 20: The method of embodiment 19, wherein the eye disease is selected from the group including diabetic retinopathy, proliferative vitreoretinopathy corneal edema, anterior and posterior uveitis, pterygium, corneal diseases, dry eye, conjunctivitis, allergic and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration and von Hippel-Lindau disease of the eye.

[0209] Embodiment 21: A method of reducing at least one of the following in a subject: the level of ICAM-1 mRNA in the retina of the subject; the level of VEGF mRNA in the retina of the subject; and the number of white blood cells in the retina of the subject, comprising administering to the subject a therapeutically effective amount of a crystalline form of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, or the pharmaceutical composition of embodiment 16.

[0210] Embodiment 22: A method of treating a disease or condition associated with fibrosis, comprising administering to a subject a therapeutically effective amount of a crystalline form of any one of embodiments 1 to 16.

[0211] Embodiment 23: The method of embodiment 22, wherein the disease or disorder associated with fibrosis is selected from the group consisting of fibrotic skin disorders, lung diseases, cardiac diseases, and kidney diseases.

[0212] Embodiment 24: The method of embodiment 23, wherein the fibrotic skin disorder is selected from the group consisting of keloids, hypertrophic scars and scleroderma.

[0213] Embodiment 25: The method of embodiment 23, wherein the pulmonary disease is pulmonary fibrosis.

[0214] Embodiment 26: The method of embodiment 23, wherein the heart disease is selected from the group consisting of heart failure due to ischemic heart disease, diabetic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, and hypertension.

[0215] Embodiment 27: The method of embodiment 23, wherein the kidney disease is selected from the group consisting of progressive glomerular kidney disease and diabetic kidney disease.

[0216] Embodiment 28: The method of embodiment 27, wherein the progressive kidney disease is primary glomerulonephritis or secondary glomerulonephritis.

[0217] Embodiment 29: The primary glomerulonephritis is selected from the group consisting of membranous nephropathy, focal segmental glomerulosclerosis, membranous 29. The method of embodiment 28, wherein the patient is selected from the group consisting of proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, and membranous focal segmental glomerulosclerosis.

[0218] Embodiment 30: The method of embodiment 28, wherein the secondary glomerulonephritis is diabetic nephropathy or ischemic nephropathy.

[0219] Embodiment 31: The method of embodiment 23, wherein the kidney disease is a progressive kidney disease predominantly of tubulointerstitial origin.

[0220] Embodiment 32: The method of embodiment 31, wherein the kidney disease is interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0221] Embodiment 33: The method of any one of embodiments 19, 20, and 21, wherein the crystalline form or composition is administered orally.

[0222] Embodiment 34: The method of any one of embodiments 19, 20, and 21, wherein the crystalline form or composition is administered to the eye.

[0223] Embodiment 35: A method of treating an eye disease, comprising administering to a subject a therapeutically effective amount of a compound of any one of embodiments 17 and 18.

[0224] Embodiment 36: The method of embodiment 35, wherein the eye disease is selected from the group including diabetic retinopathy, proliferative vitreoretinopathy corneal edema, anterior and posterior uveitis, pterygium, corneal diseases, dry eye, conjunctivitis, allergy and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration and von Hippel-Lindau disease of the eye.

[0225] Embodiment 37: A method of reducing at least one of: the level of ICAM-1 mRNA in the retina of the subject; the level of VEGF mRNA in the retina of the subject; and the number of white blood cells in the retina of the subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 17 and 18.

[0226] Embodiment 38: A method of treating a disease or condition associated with fibrosis, comprising administering to a subject a therapeutically effective amount of a compound of embodiment 17 or 18.

[0227] Embodiment 39: The method of embodiment 38, wherein the disease or disorder associated with fibrosis is selected from the group consisting of fibrotic skin disorders, lung diseases, cardiac diseases, and kidney diseases.

[0228] Embodiment 40: The method of embodiment 39, wherein the fibrotic skin disorder is selected from the group consisting of keloids, hypertrophic scars and scleroderma.

[0229] Embodiment 41: The method of embodiment 39, wherein the pulmonary disease is pulmonary fibrosis.

[0230] Embodiment 42: The method of embodiment 39, wherein the heart disease is selected from the group consisting of heart failure due to ischemic heart disease, diabetic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, and hypertension.

[0231] Embodiment 43: The method of embodiment 39, wherein the kidney disease is selected from the group consisting of progressive glomerular kidney disease and diabetic kidney disease.

[0232] Embodiment 44: The progressive glomerular kidney disease is primary glomerulonephritis or secondary glomerulonephritis. 43. The method of embodiment 42, wherein

[0233] Embodiment 45: The method of embodiment 44, wherein the primary glomerulonephritis is selected from the group consisting of membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, and membranous focal segmental glomerulosclerosis.

[0234] Embodiment 46: The method of embodiment 44, wherein the secondary glomerulonephritis is diabetic nephropathy or ischemic nephropathy.

[0235] Embodiment 47: The method of embodiment 39, wherein the kidney disease is a progressive kidney disease predominantly of tubulointerstitial origin.

[0236] Embodiment 48: The method of embodiment 47, wherein the kidney disease is interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0237] Embodiment 49: The method of any one of embodiments 35-48, wherein the crystalline form or composition is administered orally.

[0238] Embodiment 50: The method of any one of embodiments 35-48, wherein the crystalline form or composition is administered to the eye. EXAMPLES

[0239] Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0240] X-ray powder diffraction (XRPD) XRPD analysis was performed on a PANalytical X'pert pro with a PIXcel detector (128 channels) and samples were scanned from 3 to 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a multi-well plate with a Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and run in transmission mode (step size 0.0130° 2θ, step time 18.87 s) using a generator setting of 40 kV / 40 mA with Cu K radiation (α 1 λ=1.54060 Å;α 2 = 1.54443 Å;β = 1.39225 Å;α 1 :α 2 Ratio = 0.5) was used for analysis. Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0241] Alternatively, samples were analyzed on a Rigaku MiniFlex 600 with a D / tex detector. Optics were equipped with 5° Soller slits in both the incident and diffracted beams with 1.25° DS, 8 mm SS, and 0.15 micron Ni Kβ filters. Scans were acquired from 3 to 40° 2θ with 0.02° / step at 10° 2θ / min for powders or 3° 2θ / min for drop cast films. Thermogravimetric Analysis (TG)

[0242] Approximately 5-10 mg of material was added to a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto - Simultaneous DSC and held at room temperature. The sample was then heated at a rate of 10 °C / min from 30 °C to 400 °C while the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas at 200 cm 3 A flow rate of 1 / min was used.

[0243] Differential thermal analysis (DTA) Approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and held at room temperature. The sample was then heated at a rate of 10°C / min from 20°C to 300°C while the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas at 300 cm 3 A flow rate of 1 / min was used.

[0244] Dynamic Vapor Sorption (DVS) Approximately 10-20 mg of sample was placed in a mesh vapor sorption balance pan and loaded onto a DVS Intrinsic Dynamic Vapor Sorption Balance by Surface Measurement Systems. The sample was subjected to a ramping profile of 40-90% relative humidity (RH) in 10% increments, with the sample held at each step until a stable weight was achieved at 25°C (dm / dt 0.004%, minimum step length 30 min, maximum step length 500 min). After completion of the sorption cycle, the sample was dried to 0% RH using the same procedure and then returned to 40% RH for a second sorption cycle. Two cycles were performed. The weight change during the sorption / desorption cycle was plotted to determine the hygroscopicity of the sample. XRPD analysis was then performed on any solids that were retained.

[0245] Approximate solubility measurement All samples were prepared at 20 mg / mL. The initial pH of each sample was recorded and adjusted as required using 0.1 M NaOH and 0.1 M HCl. Samples were stirred at 37° C. for 3 hours. Samples were collected and the pH was recorded and adjusted if required. Samples were filtered via centrifugation and the filtered mother liquor was analyzed by HPLC.

[0246] The HPLC conditions were as follows: Column: Waters Sunfire® C18, 150×4.6 mm 3.5 μm; Column temperature: 25° C.; Autosampler temperature: Ambient; UV wavelength: 220 nm; Injection volume: 10 μL; Flow rate: 1.0 mL / min; Mobile phase A: H 2Mobile phase A: 0.05% TFA in CAN; mobile phase B: 0.05% TFA in CAN.

[0247] The HPLC gradient program was as follows:

[0248] [Table 1]

[0249] dissolution research Approximately 175 mg of each batch was weighed and compressed in a 13 mm Wood die for 3 minutes at approximately 3000 lbs of force using a mini hydraulic press to create disks for intrinsic dissolution evaluation. The surface of each disk was carefully inspected to ensure it was uniform, smooth, and free of loose powder.

[0250] Dissolution experiments were performed by mounting the Wood die containing the disks onto a matching shaft on an Erweka DT6 dissolution apparatus. The disks were lowered into the media (500 mL, 37° C.) and immediately spun at 100 rpm. Duplicate samples of media (0.2 mL) were removed prior to immersion of the disks and at 2, 5, 10, 15, 20, 25, 30, 60, and 90 minutes after the experiment had begun. Sampling was discontinued when substantial dissolution was visible or the disks disintegrated in the media.

[0251] At the end of each experiment, the disks were removed from the medium and examined to ensure that the surface of the disk remained uniform, and the extent of dissolution was qualitatively assessed over the course of the experiment. Medium samples were centrifuged (10,000 rpm x 3 min) and a small aliquot (50 μL) was removed and diluted 5-fold with 50% aqueous acetonitrile prior to HPLC analysis.

[0252] Example 1 Preparation of a crystalline form of the L-lysine salt of the compound of formula (I) ("Crystalline Salt A") The compound of formula (I) was dissolved in a minimum amount of methanol. L-Lysine (1.05 equivalents) was then added and the sample temperature was cycled between ambient and 40°C in 4 hour cycles for approximately 72 hours. After this time, a single anti-solvent, toluene, was added to the mixture and the sample was stored at 2-8°C to promote precipitation. Other solvent / anti-solvent systems were used, including (i) 2-propanol / heptane, (ii) acetonitrile / toluene, and (iii) ethanol / heptane. The L-Lysine salt of the compound of formula (I) was isolated as a crystalline material via centrifugal filtration. If no crystalline material was obtained, the solvent was allowed to evaporate under ambient conditions. Formula (I) The L-lysine salt of compound (I) was obtained as a crystalline material. The solid observed was dried under vacuum at 40° C. for approximately 6 hours.

[0253] Example 2 Preparation of a Crystalline Form of the tert-Butylamine Salt of Compound of Formula (I) ("Crystalline Salt B") The compound of formula (I) was dissolved in a minimum amount of a single solvent selected from 2-propanol, acetonitrile, ethyl acetate, and isopropyl acetate. tert-butylamine (1.05 equivalents) was then added and the sample temperature was cycled between ambient temperature and 40°C for 4 hours over a period of about 72 hours. After this time, the tert-butylamine salt of the compound of formula (I) was obtained as a crystalline material by filtration. If no crystalline material was obtained, a single anti-solvent selected from heptane and toluene was added to the mixture and the solvent was allowed to evaporate under ambient conditions. After this time, the tert-butylamine salt of the compound of formula (I) was obtained as a crystalline material. The observed solid was dried under vacuum at 40°C for about 6 hours.

[0254] Example 2 Further preparation of crystalline form I of the tert-butylamine salt of the compound of formula (I) The compound of formula (I) (0.83 mmol) was dissolved in 7 mL of ethyl acetate at 40° C. with stirring. tert-butylamine (0.87 mmol) was added to the solution of the compound of formula (I), resulting in immediate precipitation of the tert-butylamine salt. The mixture was annealed for 72 hours by temperature cycling between 25° C. and 40° C. Vacuum filtration of the solid followed by vacuum drying at 40° C. afforded a crystalline white powder identified as tert-butylamine salt Form I.

[0255] Example 3 Seeded recrystallization preparation of Form I of the tert-butylamine salt of compound of formula (I) Crystalline salt B (12.72 wt%) in 80 / 20 methanol / ethyl acetate was prepared at 20° C. The temperature was then increased to 60° C. at 1° C. / min and held for 1 hour. The mixture was then cooled to 50° C. at 0.3° C. / min and held at that temperature for 75 minutes. The mixture was seeded with 2 wt% Form I seeds and then cooled to 10° C. at 0.08° C. / min and held for 1 hour. Ethyl acetate was then added over a 2 hour period until the methanol to ethyl acetate ratio reached 20 / 80. The temperature was held at 10° C. for an additional 2 hours. The solid was then collected by filtration.

[0256] Example 4 Seeded reactive recrystallization preparation of Form I of the tert-butylamine salt of compound of formula (I) A compound of formula (I) (12.8 wt%) in 80 / 20 methanol / ethyl acetate was prepared at 20° C. to form a crystallization mixture. The temperature was then ramped to 50° C. at 1° C. / min and held for 75 minutes. 1.5-1.6 molar equivalents of tert-butylamine were then added to the mixture to achieve a pH of 7.8-8.2. The mixture was then ramped to 60° C. at 1° C. / min and held for 1 hour. The mixture was cooled to 50° C. at 0.3° C. / min and held at that temperature for 75 minutes. The mixture was seeded with 2 wt% Form I seeds and then cooled to 10° C. at 0.08° C. / min and held for 1 hour. Ethyl acetate was then added over a period of 2 hours until the ratio of methanol to ethyl acetate reached 20 / 80. The temperature was held at 10° C. for an additional 2 hours. The solid was then collected by filtration.

[0257] Example 5 Preparation of Form II of the tert-butylamine salt of compound of formula (I) The tert-butylamine salt of the compound of formula (I) was dissolved in 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIPA) and allowed to evaporate slowly at ambient temperature to produce the tert-butylamine salt Form II.

[0258] Example 6 Preparation of Crystalline Form III of the tert-butylamine salt of the compound of formula (I) Crystalline Form II of the tert-butylamine salt of compound of formula (I) was heated at 77° C.-90° C. and then further dried under vacuum at 40° C. overnight to obtain Form III of the tert-butylamine salt.

[0259] Example 7 Preparation of Crystalline Form IV of the tert-butylamine salt of the compound of formula (I) Crystalline Form IV of the tert-butylamine salt of compound of formula (I) was prepared according to the method of Example 5. Further slow evaporation afforded Form IV.

[0260] Example 8 Dissolution profiles of crystalline salt A and crystalline salt B The dissolution profiles of Crystalline Salt A and Crystalline Salt B were compared to the free acid of the compound of formula (I).

[0261] In FaSSIF medium (FIG. 12), both Crystalline Salt A and Crystalline Salt B demonstrated superior dissolution profiles compared to the solubility of the free acid of the compound of formula (I).

[0262] In PBS medium (Figure 13), crystalline Salt A demonstrated a superior dissolution profile compared to that of the free acid of the compound of formula (I), and crystalline Salt B demonstrated a comparable, if not better, dissolution profile compared to that of the free acid of the compound of formula (I).

[0263] Example 9 Characterization of crystal samples The crystalline solid form was characterized by XRPD, thermogravimetric analysis (TG), and DTA.

[0264] The XRPD pattern of crystalline Salt A (Figure 1) indicates high crystallinity. A melting temperature range of approximately 197-203 °C was observed using differential thermal analysis (Figure 2). Crystalline Salt A showed a mass gain of 4.2 wt% (1.3 equivalents of water) at 90% RH by dynamic vapor sorption / desorption analysis (Figure 5).

[0265] The XRPD pattern of crystalline Salt B Form I (Figure 3) shows high crystallinity. A melting temperature range of approximately 196-224 °C was observed using differential thermal analysis (Figure 4). Crystalline Salt B was non-hygroscopic by dynamic vapor sorption / desorption analysis (Figure 6).

[0266] The XRPD pattern of crystalline Salt B Form II (Figure 7) shows a high degree of crystallinity.

[0267] The XRPD pattern of crystalline Salt B Form III (Figure 8) shows high crystallinity. The DSC data (Figure 9) shows the loss of HFIPA around 80-90°C, followed by two endotherms at 155-165°C, and finally a large melting endotherm at approximately 200°C, consistent with Form I.

[0268] The XRPD pattern of crystalline salt B Form IV (Figure 10) shows high crystallinity. The DSC data (Figure 11) shows that Form IV loses HFIPA and converts to Form III upon vacuum drying at 40°C. This event at 80-100°C is followed by two endotherms at 155-165°C and finally a large melting endotherm at approximately 200°C, consistent with Form I.

[0269] Example 10 X-ray powder diffraction (XRPD) measurement of crystalline salt A XRPD measurements were performed on crystalline Salt A of compound of formula (I). The peaks observed are shown in Table 1. Prominent peaks are listed in Table 2. Note that the preferred orientation state in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material.

[0270] The range of data collected may have been instrument dependent. Under most circumstances, relying on a discrete number of XRPD peaks in the range from 0° 2θ to approximately 30° 2θ is sufficient for the purposes of identifying polymorphic forms. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ based on the instrument used to collect the data and / or the inherent peak resolution. Peak positions along the x-axis (° 2θ) in both figures and tables were determined using proprietary software and rounded to one or two significant numbers after the decimal point based on the criteria above. Peak position variations are given within ±0.2° 2θ. For the purposes of listing d-spacing, the wavelength used to calculate d-spacing was 1.54252 Å (0.5:0.5, CuKα 1 : CuKα 2 ) was.

[0271] [Table 2]

[0272] [Table 3]

[0273] Table 2 shows the XRPD data identified as "prominent peaks" as the term is used herein. The prominent peaks are a subset of the entire observed peak list. The prominent peaks are selected from the observed peaks by identifying low angle peaks that have strong intensity, preferably non-overlapping.

[0274] [Table 4]

[0275] Example 11 X-ray powder diffraction (XRPD) measurements of crystalline salt B form I XRPD measurements were performed on Form I of the crystalline salt B of the compound of formula (I). The peaks observed are shown in Table 3. Prominent peaks are listed in Table 4. Note that the preferred orientation state in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material.

[0276] The range of data collected may have been instrument dependent. Under most circumstances, relying on the selection of a discrete number of XRPDs within the range of 0° 2θ to approximately 30° 2θ is sufficient for the purposes of identifying polymorphic forms. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ based on the instrument used to collect the data and / or the inherent peak resolution. Peak positions along the x-axis (° 2θ) in both figures and tables were determined using proprietary software and rounded to one or two significant numbers after the decimal point based on the criteria above. Peak position variance is given within ±0.2° 2θ. For the listing of d-spacing, the wavelengths used to calculate d-spacing were Cu-Kα 1 and Cu-Kα 2 The wavelength weighted average was 1.54252 Å.

[0277] [Table 5]

[0278] [Table 6]

[0279] Table 4 provides the XRPD data identified as "prominent peaks". Prominent Peaks is a subset of the entire observed peak list. Prominent peaks are selected from the observed peaks by identifying low angle peaks that have strong intensity, preferably non-overlapping.

[0280] [Table 7]

[0281] Example 12 X-ray powder diffraction (XRPD) measurements of crystalline salt B form II XRPD measurements were performed on Form II of the crystalline salt B of the compound of formula (I). The peaks observed are shown in Table 5. Prominent peaks are listed in Table 6. Note that the preferred orientation state in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material.

[0282] The range of data collected may have been instrument dependent. Under most circumstances, relying on the selection of a discrete number of XRPDs within the range of 0° 2θ to approximately 30° 2θ is sufficient for the purposes of identifying polymorphic forms. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ based on the instrument used to collect the data and / or the inherent peak resolution. Peak positions along the x-axis (° 2θ) in both figures and tables were determined using proprietary software and rounded to one or two significant numbers after the decimal point based on the criteria above. Peak position variance is given within ±0.2° 2θ. For the listing of d-spacing, the wavelengths used to calculate d-spacing were Cu-Kα 1 and Cu-Kα 2 The wavelength weighted average was 1.54252 Å.

[0283] [Table 8]

[0284] Table 6 provides the XRPD data identified as "prominent peaks". Prominent Peaks is a subset of the entire observed peak list. Prominent peaks are selected from the observed peaks by identifying low angle peaks that have strong intensity, preferably non-overlapping.

[0285] [Table 9]

[0286] Example 13 X-ray powder diffraction (XRPD) measurements of crystalline salt B form III XRPD measurements were performed on Form III of the crystalline salt B of the compound of formula (I). The peaks observed are shown in Table 7. Prominent peaks are listed in Table 8. It should be noted that the preferred orientation state in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material.

[0287] The range of data collected may have been instrument dependent. Under most circumstances, relying on the selection of a discrete number of XRPDs within the range of 0° 2θ to about 30° 2θ is sufficient for the purposes of identifying polymorphic forms. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ based on the instrument used to collect the data and / or the inherent peak resolution. Peak locations (° 2θ) along the x-axis in both figures and tables were determined using proprietary software and were adjusted according to the above criteria. The data are rounded to one or two significant numbers after the decimal point based on the d-spacing. Peak position variations are given within ±0.2° 2θ. For the listing of d-spacing, the wavelengths used to calculate d-spacing are Cu-Kα 1 and Cu-Kα 2 The wavelength weighted average was 1.54252 Å.

[0288] [Table 10]

[0289] Table 8 provides XRPD data identified as "prominent peaks". Prominent peaks are a subset of the entire observed peak list. Prominent peaks are selected from the observed peaks by identifying low angle peaks that have strong intensity, preferably non-overlapping.

[0290] [Table 11]

[0291] Example 14 X-ray powder diffraction (XRPD) measurements of crystalline salt B form IV XRPD measurements were performed on Form IV of the crystalline salt B of compound of formula (I). The peaks observed are shown in Table 9. Prominent peaks are listed in Table 10. Note that the preferred orientation state in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material.

[0292] The range of data collected may have been instrument dependent. Under most circumstances, relying on the selection of a discrete number of XRPDs within the range of 0° 2θ to about 30° 2θ is sufficient for the purposes of identifying polymorphic forms. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ based on the instrument used to collect the data and / or the inherent peak resolution. Along the x-axis in both figures and tables, The positions of the peaks (° 2θ) were determined using proprietary software and rounded to one or two significant numbers after the decimal point based on the criteria above. The variation in peak positions is given within ±0.2° 2θ. For the listing of d-spacing, the wavelengths used to calculate d-spacing are Cu-Kα 1 and Cu-Kα 2 The wavelength weighted average was 1.54252 Å.

[0293] [Table 12]

[0294] Table 10 provides the XRPD data identified as "prominent peaks." The observed peak list is a subset of the entire observed peak list. Prominent peaks are selected from the observed peaks by identifying low angle peaks that have strong intensity and are preferably non-overlapping.

[0295] [Table 13]

[0296] Example 15 X-ray powder diffraction (XRPD) measurements of alternative crystalline salts An XRPD measurement is performed on the crystalline salt form of the compound of formula (I). It is noted that although peaks are observed, none of the peaks are known to be representative or characteristic of this material, as the preferred orientation state in this sample is unknown.

[0297] The range of data collected may have been instrument dependent. Under most circumstances, relying on a discrete number of XRPD peaks in the range from 0° 2θ to approximately 30° 2θ is sufficient for the purposes of identifying polymorphic forms. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ based on the instrument used to collect the data and / or the inherent peak resolution. Peak positions along the x-axis (° 2θ) in both figures and tables were determined using proprietary software and rounded to one or two significant numbers after the decimal point based on the criteria above. Peak position variability is given within ±0.2° 2θ. For the listing of d-spacing, the wavelengths used to calculate d-spacing were Cu-Kα 1 and Cu-Kα 2 The wavelength weighted average was 1.54252 Å.

[0298] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather are intended to cover all modifications and alternatives falling within the true scope and spirit of the present application.

Claims

1. Formula (I): 【Chemistry 1】 A crystalline pharma- ceutically acceptable salt of the compound of formula (I).

2. 2. The crystal of claim 1, wherein the pharma- ceutically acceptable salt is selected from the group consisting of sodium salts, potassium salts, zinc salts, magnesium salts, and calcium salts.

3. 2. The crystal of claim 1, wherein the pharma- ceutically acceptable salt is selected from the group consisting of a choline salt, an L-lysine salt, a tert-butylamine salt, and a diethanolamine salt.

4. The crystal according to claim 3, wherein the pharma- ceutically acceptable salt is an L-lysine salt.

5. 5. The crystal of claim 4, wherein the crystal exhibits an X-ray powder diffraction pattern having at least three characteristic peaks selected from the group consisting of peaks at 4.23, 7.92, 10.59, 14.44, 15.25, 15.50, 19.32, 19.87, 21.30, 23.41, 23.94, 24.42, 25.30, 25.81, and 26.00 degrees 2θ (±0.2 degrees 2θ).

6. The crystal described in claim 4 or 5, having a melting point of 197 to 203°C.

7. The crystal according to claim 3 , wherein the pharma- ceutically acceptable salt is a tert-butylamine salt.

8. 8. The crystal of claim 7, wherein the crystal exhibits an X-ray powder diffraction pattern having at least three characteristic peaks selected from the group consisting of peaks at 13.59, 13.75, 17.93, 18.36, 18.44, 19.39, 20.26, 20.77, 21.22, 21.78, 21.84, 22.82, 23.34, 23.91, and 26.12 degrees 2θ (±0.2 degrees 2θ).

9. The crystal described in claim 7 or 8, having a melting point of 196 to 224°C.

10. A pharmaceutical composition comprising the crystal of any one of claims 1 to 9 and a pharma- ceutically acceptable excipient.

11. The pharmaceutical composition of claim 10 for treating an eye disease.

12. 12. The pharmaceutical composition of claim 11, wherein the ocular disease is selected from the group consisting of diabetic retinopathy, proliferative vitreoretinopathy corneal edema, anterior and posterior uveitis, pterygium, corneal diseases, dry eye, conjunctivitis, allergic and laser induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration and von Hippel-Lindau disease of the eye.

13. A pharmaceutical composition for treating a disease or condition associated with fibrosis, comprising a crystal described in any one of claims 1 to 9 and a pharma- ceutically acceptable excipient.

14. 14. The pharmaceutical composition of claim 13, wherein the disease or condition associated with fibrosis is selected from the group consisting of fibrotic skin disorders, lung diseases, cardiac diseases, and kidney diseases.

15. 15. The pharmaceutical composition of claim 14, wherein the fibrotic skin disorder is selected from the group consisting of keloids, hypertrophic scars and scleroderma.

16. The pharmaceutical composition of claim 14, wherein the pulmonary disease is pulmonary fibrosis.

17. 15. The pharmaceutical composition of claim 14, wherein the cardiac disease is selected from the group consisting of heart failure due to ischemic cardiac disease, diabetic cardiac disease, valvular cardiac disease, hypertensive cardiac disease, diabetic cardiomyopathy, and hypertension.

18. 15. The pharmaceutical composition of claim 14, wherein the kidney disease is selected from the group consisting of progressive glomerular kidney disease, diabetic kidney disease, and progressive kidney disease of predominantly tubulointerstitial origin.

19. The pharmaceutical composition according to any one of claims 11 to 18, wherein the pharmaceutical composition is administered orally.

20. The pharmaceutical composition according to any one of claims 11 to 18, wherein the pharmaceutical composition is administered to the eye.

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