Compositions comprising PGI2-receptor agonists and processes for preparation thereof

Abstract

To provide a method for the treatment of a prostacyclin (PGI2) receptor mediated disorder.SOLUTION: A pharmaceutical composition for use in a method for the treatment of a prostacyclin (PGI2) receptor mediated disorder comprises 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) and a compound selected from pharmaceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1. The composition has a specific emission rate as measured under specific conditions.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] In some embodiments, the present invention relates to methods of using and compositions comprising a prostacyclin (PGI2) receptor agonist selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), its pharma- ceutically acceptable salts, solvates, and hydrates. The compositions of the invention may be used to treat, for example, pulmonary hypertension (PAH); idiopathic PAH; familial PAH; PAH associated with collagen vascular disease, congenital heart disease, portal hypertension, HIV infection, drug or toxin ingestion, hereditary hemorrhagic telangiectasia, splenectomy, pulmonary veno-occlusive disease (PVOD), or pulmonary capillary hemangiomatosis (PCH); PAH with severe venous or capillary complications; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina, stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; individuals who have undergone angioplasty or coronary artery bypass surgery. They are useful in treating blood clot formation in the body or in individuals with atrial fibrillation; atherothrombosis; asthma or symptoms thereof; diabetes-related disorders such as diabetic peripheral neuropathy, diabetic nephropathy, or diabetic retinopathy; glaucoma or other eye diseases associated with abnormal intraocular pressure; hypertension; inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis; Crohn's disease; transplant rejection; multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative colitis; atherosclerosis; acne; type I diabetes; type II diabetes; sepsis; and chronic obstructive pulmonary disease (COPD). [Background technology]

[0002] PGI2 is a lipid molecule derived from arachidonic acid via cyclooxygenase pathway.PGI2 is a potent vasodilator, antiproliferative, antithrombotic, and antiplatelet agent that mediates its effect as an agonist of G protein-linked receptor (PGI2 receptor; for example, human PGI2 receptor, GenBank® Accession No. NP_000951, and its alleles).It is known that the binding of PGI2 (or other such agonist) to PGI2 receptor leads to the binding with G protein and increases the intracellular cAMP level (see, for example, Zhang et al, Arch.Biochem.Biophys, 2006, 454:80-88).

[0003] PAH is a life-threatening disease characterized by progressive pulmonary vasculopathy leading to right ventricular hypertrophy. Left untreated, right heart failure occurs. Prostacyclin, which has vasodilatory and antiproliferative effects on pulmonary vasculature, has been shown to be lower in patients with PAH compared to normal controls. Exogenous administration of prostacyclin or analogs of prostacyclin (i.e., agonists of the PGI2-receptor) has become an important strategy in the treatment of PAH. (e.g., Tuder et al,Am.J.Respir.Crit.Care.Med,1999,159:1925-1932;Humbert et al,J.Am.Coll.Cardiol,2004,43:13S-24S;Rosenzweig,Expert Opin.Emerging Drugs,2006,11:609-619;McLaughlin et al. (See al,Circulation,2006,114:1417-1431;Rosenkranz,Clin.Res.Cardiol,2007,96:527-541;Driscoll et al,Expert Opin.Pharmacother,2008,9:.2 65-81).

[0004] Treprostinil and iloprost are FDA-approved analogs of prostacyclin that are not orally active like prostacyclin. Beraprost is an orally active analog of prostacyclin approved for the treatment of PAH in Japan, but has failed to be registered for the treatment of PAH in Europe and the United States. Of the three FDA-approved medications, prostacyclin has been best studied in PAH patients. The estimated annual cost of treating PAH with these agents ranges from $25,000 to $200,000, depending on the dosage. Currently, many experts consider intravenous prostacyclin to be the most reliable agent for the management of the sickest PAH patients. Due to the short half-life of prostacyclin, intravenous treatment is complicated by the need for continuous infusion. If the infusion is abruptly interrupted, the patient is placed at risk of potentially fatal rebound pulmonary hypertension, and at considerable risk of catheter-related complications, including sepsis (see, e.g., Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619; Naeije et al, Expert Opin. Pharmacother, 2007, 8:2247-2265; Strauss et al, Clin. Chest. Med, 2007, 28:127-142; Driscoll et al, Expert Opin. Pharmacother, 2008, 9:65-81).

[0005] Orally effective non-prostanoid PGI2-receptor agonists that provide similar clinical benefits to currently available PGI2-receptor agonists may improve the standard of care for PAH. The compositions of the present invention include a PGI2-receptor agonist, Compound 1, a novel non-prostanoid oral drug candidate discovered by Arena Pharmaceuticals, Inc., and are intended for the treatment of PAH. Compound 1 is disclosed in PCT Publication No. WO2009 / 117095, which is incorporated herein by reference in its entirety. Various synthetic routes to Compound 1, its related salts, prodrugs, crystalline forms, and intermediates are reported in PCT Publication No. WO2011 / 037613, which is incorporated herein by reference in its entirety. 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (compound 1) is disclosed in WO2009 / 117095, which is incorporated herein by reference in its entirety.

[0006] Compound 1 has the potential to improve the treatment of PAH by providing patients with an oral, once-daily option that targets the PGI2-receptor. In light of the potential of Compound 1, side effects associated with this class of compound may be observed in patients. Examples of such side effects include nausea and headache.

[0007] Compound 1 has a long plasma half-life (~24 hours). Unlike many active compounds, sustained release formulations of compound 1 are not required to achieve once-daily dosing. However, side effects (such as nausea and headache) are associated with the class of compounds that target the IP receptor, and compound 1 is a particularly potent IP receptor agonist. There is evidence of a dose-response relationship for some of the drugs that target the prostacyclin receptor. However, the association between drug plasma levels and hemodynamic parameters is unknown. Understanding the association between plasma levels and clinical response may help define therapeutic dosage levels. Therefore, it is desirable to develop new pharmaceutical compositions that balance once-daily dosing and improved pharmacokinetics by modifying the release of compound 1, and to develop treatment regimens with compound 1 that constitute plasma levels, in order to optimize the treatment of patients with life-threatening disorders. Summary of the Invention

[0008] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0009] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is one or more of the following release rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium.

[0010] In some embodiments, the diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of an aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and a pH of 6.3-7.3 at a temperature of 37° C.±0.5° C.

[0011] In some embodiments, the diffusion rate is measured in 400-600 mL of an aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M, at a temperature of 37° C.±0.5° C. and a pH of 6.3-7.3, using a USP Apparatus 2 (paddle) at 40-60 rpm.

[0012] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0013] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is the following release rate (a): (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0014] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0015] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is the following release rate (b): (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0016] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0017] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is the following release rate (c): (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0018] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0019] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rate (a) and (b), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; and (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0020] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0021] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rate (a) and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0022] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0023] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rate (b) and (c), wherein: (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0024] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0025] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0026] In some embodiments, provided herein are compositions having a weight percent emission rate of a compound disclosed herein in an aqueous medium, where the emission rate is measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of an aqueous medium containing sodium phosphate at a concentration of 0.05 M and at a temperature of 37° C.±0.5° C. and a pH of 6.8.

[0027] In some embodiments, provided herein are compositions having a weight percent emission rate of a compound disclosed herein in an aqueous medium, where the emission rate is measured in 500 mL of an aqueous medium containing sodium phosphate at a concentration of 0.05 M, at a temperature of 37° C.±0.5° C. and a pH of 6.8, at 50 rpm, using a USP apparatus 2 (paddle).

[0028] In some embodiments, provided herein are compositions disclosed herein, the compositions are tablets. In some embodiments, provided herein are compositions disclosed herein, the compositions are in tablets produced using a wet granulation process.

[0029] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the excipient is present in an amount equal to about 40% to about 60% by weight.

[0030] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., and the excipient is present in an amount equal to about 40% to about 60% by weight.

[0031] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and the second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C.

[0032] In some embodiments, provided herein is a process for preparing a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1 as disclosed herein, the process comprising mixing the compound, ethanol, a first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and a second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C. to form the composition.

[0033] In some embodiments, provided herein are pharmaceutical compositions comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid.

[0034] In some embodiments, provided herein is a pharmaceutical composition prepared by a process comprising curing a mixture comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, a first excipient, and a second excipient, to form the composition, wherein the first excipient comprises a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the second excipient comprises an ester of a polyalcohol and a fatty acid.

[0035] In some embodiments, provided herein is a process for preparing a pharmaceutical composition, the process comprising: and (c) a copolymer comprising a polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and a copolymer comprising a first excipient and a second excipient, the first excipient comprising a copolymer comprising: (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid, to form a composition.

[0036] In some embodiments, the present specification provides a method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising administering to the individual a dosage of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, sufficient to achieve a plasma concentration of Compound 1 of at least about 2.5 ng / mL in the individual.

[0037] In some embodiments, provided herein is a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering to the individual Compound 1 at a dosage sufficient to achieve a plasma concentration of Compound 1 of at least about 2.5 ng / mL in the individual.

[0038] In some embodiments, the present specification provides a method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising administering to the individual a dosage of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, sufficient to achieve a plasma concentration of Compound 1 of at least about 5 ng / mL in the individual.

[0039] In some embodiments, provided herein are methods for treating pulmonary arterial hypertension (PAH) in an individual, the methods comprising administering to the individual Compound 1 at a dosage sufficient to achieve a plasma concentration of Compound 1 of at least about 5 ng / mL in the individual.

[0040] In some embodiments, provided herein is a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering a dosage of Compound 1 to the individual, determining the plasma level of Compound 1 in the individual, and increasing the dosage of Compound 1 if the individual does not have at least a threshold plasma level.

[0041] In some embodiments, the present specification provides a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering a dosage of Compound 1 to the individual, determining a plasma level of Compound 1 in the individual, and discontinuing administration of Compound 1 to the individual if the individual does not have at least a threshold plasma level.

[0042] In some embodiments, the present specification provides a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering a dosage of Compound 1 to the individual, determining a plasma level of Compound 1 in the individual, and continuing administration of Compound 1 to the individual if the individual has at least a threshold plasma level, or discontinuing administration of Compound 1 to the individual if the individual does not have at least a threshold plasma level.

[0043] In some embodiments, the present specification provides a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering a maximum tolerated dose of Compound 1 to the individual, determining a plasma level of Compound 1 in the individual, and discontinuing administration of Compound 1 to the individual if the individual does not have at least a threshold plasma level at the maximum tolerated dose.

[0044] In some embodiments, the present specification provides a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering a maximum tolerated dose of Compound 1 to the individual, determining a plasma level of Compound 1 in the individual, and continuing to administer Compound 1 to the individual if the individual has at least a threshold plasma level at the maximum tolerated dose, or discontinuing administration of Compound 1 to the individual if the individual does not have at least a threshold plasma level at the maximum tolerated dose.

[0045] In some embodiments, provided herein is a method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering a dosage of Compound 1 to the individual, determining the plasma level of Compound 1 in the individual, and increasing the dosage of Compound 1 to the individual until a threshold plasma level is reached.

[0046] In some embodiments, provided herein is a method for selecting a dose of Compound 1 for an individual with pulmonary arterial hypertension (PAH), the method comprising determining the plasma level of Compound 1 in the individual, and increasing the dose of Compound 1 to the individual until a threshold plasma level is reached.

[0047] In some embodiments, provided herein is a method for selecting a dose of Compound 1 for an individual with pulmonary arterial hypertension (PAH), the method comprising determining a plasma level of Compound 1 in the individual, and maintaining a dose of Compound 1 to the individual if a threshold plasma level is reached.

[0048] In some embodiments, provided herein is a method for selecting a dose of Compound 1 for an individual with pulmonary arterial hypertension (PAH), the method comprising determining a plasma level of Compound 1 in the individual, and reducing the dose of Compound 1 to the individual if a threshold plasma level is exceeded.

[0049] In some embodiments, the plasma concentration of Compound 1 is at least or at least about 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5.6, 5.7, 5.75, 5.8, 5.9, 6.0, 6.1, 6.2, 6.25, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.5, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 5, 6.6, 6.7, 6.75, 6.8, 6.9, 7.0, 7.1, 7.2, 7.25, 7.3, 7.4, 7.5, 7.6, 7.7, 7.75, 7.8, 7.9, 8.0, 8.1, 8.2, 8.25, 8.3, 8.4, 8.5, 8.6, 8.7, 8.75, 8.8, 8.9, 9.0, 9.1, 9.2, 9.25, 9.3, 9.4, 9.5, 9.6, 9.7, 9.75, 9.8, 9.9, or 10 ng / mL.

[0050] In some embodiments, the plasma concentration of Compound 1 is about 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, or 5.0 ng / mL.

[0051] In some embodiments, the threshold plasma level of Compound 1 is about 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, 2, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4, 4 .1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5, 5.1, 5.2, 5.25, 5.3, 5.4, 5.5, 5.6, 5.7, 5.75, 5.8, 5.9, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, and 10 ng / ml.

[0052] In some embodiments, the therapeutically effective amount of Compound 1 is about 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, Selected from 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, and 1.5 mg.

[0053] In some embodiments, the therapeutically effective amount of Compound 1 is a starting dosage selected from about 0.01, 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.075, 0.08, 0.09, and 0.1 mg per day.

[0054] In some embodiments, the therapeutically effective amount of Compound 1 is a maximum tolerated dose selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45, and 1.5 mg.

[0055] In some embodiments, the therapeutically effective amount of Compound 1 is a maximum dosage selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45, and 1.5 mg.

[0056] In some embodiments, the therapeutically effective amount of Compound 1 is a maximum tolerated dose selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45, and 1.5 mg.

[0057] In some embodiments, the therapeutically effective amount of Compound 1 is about 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 7 The maintenance doses are 35mg, 0.4mg, 0.45mg, 0.5mg, 0.55mg, 0.6mg, 0.65mg, 0.7mg, 0.75mg, 0.8mg, 0.85mg, 0.9mg, 0.95mg, 1.0mg, 1.05mg, 1.1mg, 1.15mg, 1.2mg, 1.25mg, 1.3mg, 1.35mg, 1.4mg, 1.45mg, and 1.5mg.

[0058] In some embodiments, the threshold plasma level is a peak plasma level.

[0059] In some embodiments, the threshold plasma level is a trough plasma level.

[0060] In some embodiments, the threshold plasma levels are a peak plasma level and a trough plasma level.

[0061] In some embodiments, the threshold plasma level is about, at least, or at least about 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5.6, 5.7, 5.75, 5.8, 5.9, 6.0, 6.1, 6.2, 6.25, 6.3, 6.4, 6.5, 6.6, 6.7, 6.75, 6.8, peak plasma levels of 6.9, 7.0, 7.1, 7.2, 7.25, 7.3, 7.4, 7.5, 7.6, 7.7, 7.75, 7.8, 7.9, 8.0, 8.1, 8.2, 8.25, 8.3, 8.4, 8.5, 8.6, 8.7, 8.75, 8.8, 8.9, 9.0, 9.1, 9.2, 9.25, 9.3, 9.4, 9.5, 9.6, 9.7, 9.75, 9.8, 9.9, or 10 ng / mL, and ,2.25,2.3,2.4,2.5,2.6,2.7,2.75,2.8,2.9,3.0,3.1,3.2,3.25,3.3,3.4,3.5,3.6,3.7,3.75,3.8,3.9,4.0,4.1,4.2,4.25,4.3,4.4,4.5,4.6,4.7,4.75,4.8,4.9,5.0,5.1,5.2,5.25,5.3,5.4,5.5,5.6,5.7,5.75,5.8,5.9,6.0,6.1,6.2,6.25, and trough plasma levels of 6.3, 6.4, 6.5, 6.6, 6.7, 6.75, 6.8, 6.9, 7.0, 7.1, 7.2, 7.25, 7.3, 7.4, 7.5, 7.6, 7.7, 7.75, 7.8, 7.9, 8.0, 8.1, 8.2, 8.25, 8.3, 8.4, 8.5, 8.6, 8.7, 8.75, 8.8, 8.9, 9.0, 9.1, 9.2, 9.25, 9.3, 9.4, 9.5, 9.6, 9.7, 9.75, 9.8, 9.9, or 10 ng / mL.

[0062] In some embodiments, the threshold plasma level is a peak plasma level of about, or at least about, 2.5 ng / mL and a trough plasma level of about, or at least about, 2.5 ng / mL.

[0063] In some embodiments, the threshold plasma level is a peak plasma level of about, or at least about, 5 ng / mL and a trough plasma level of about, or at least about, 2.5 ng / mL.

[0064] In some embodiments, the threshold plasma levels are a peak plasma level of about 5 ng / mL and a trough plasma level of about 2.5 ng / mL.

[0065] In some embodiments, Compound 1 is in a pharmaceutical composition having a dissipation rate weight of the compound in an aqueous medium of one or more of (a), (b), and (c), where (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in the aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in the aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in the aqueous medium, the dissipation rate being measured in a USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of an aqueous medium having a pH of 6.3-7.3 at a temperature of 37° C.±0.5° C., containing sodium phosphate at a concentration of 0.04-0.06 M.

[0066] In some embodiments, Compound 1 is in a pharmaceutical composition having a dissipation rate weight of the compound in an aqueous medium of one or more of (a), (b), and (c), where (a) about 40% by weight or less of the compound is released in the aqueous medium over the first 2 hours; (b) about 40% by weight to about 60% by weight of the compound is released in the aqueous medium over the first 5 hours; and / or (c) about 80% by weight or less of the compound is released in the aqueous medium over the first 14 hours, the dissipation rate being measured in a USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of an aqueous medium having a pH of 6.3-7.3 at a temperature of 37° C.±0.5° C., containing sodium phosphate at a concentration of 0.04-0.06 M.

[0067] In some embodiments, the pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0068] In some embodiments, the pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising a release modifier having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the second excipient comprising a release modifier having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0069] In some embodiments, the pharmaceutical composition has a release rate selected from: (a); (b); (c); (a) and (b); (a) and (c); (b) and (c); (a), (b), and (c).

[0070] In some embodiments, the first excipient is present in an amount equal to about 5% to about 45% by weight and the second excipient is present in an amount equal to about 5% to about 45% by weight.

[0071] In some embodiments, the first excipient is present in an amount equal to about 5% to about 45% by weight and the second excipient is present in an amount equal to about 5% to about 45% by weight.

[0072] In some embodiments, the first excipient is present in an amount equal to about 10% to about 40% by weight and the second excipient is present in an amount equal to about 10% to about 40% by weight.

[0073] In some embodiments, the first excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight and the second excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight.

[0074] In some embodiments, said first excipient is present in an amount equal to about 25% by weight and said second excipient is present in an amount equal to about 25% by weight.

[0075] In some embodiments, the emission rate is the emission rate measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 and at a temperature of 37° C.±0.5° C.

[0076] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0077] In some embodiments, the emission rate is the emission rate measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C. using USP Apparatus 2 (paddle) at 50 rpm.

[0078] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0079] In some embodiments, the pharmaceutical composition is a tablet comprising a core and a coating.

[0080] In some embodiments, the core comprises hydroxypropyl methylcellulose.

[0081] In some embodiments, the coating does not include hydroxypropyl methylcellulose.

[0082] In some embodiments, the therapeutically effective amount of compound 1 is selected from about 0.01% to about 1% by weight of the composition; about 0.01% to about 0.6% by weight of the composition; about 0.02% to about 0.3% by weight of the composition; about 0.03% to about 0.2% by weight of the composition; about 0.04% to about 0.12% by weight of the composition; about 0.04% to about 0.1% by weight of the composition; about 0.04% to about 0.1% by weight of the composition; about 0.05% to about 0.08% by weight of the composition; about 0.06% by weight of the composition; or about 0.01 mg to about 1 mg.

[0083] In some embodiments, the therapeutically effective amount of Compound 1 is suitable for once-daily administration to an individual.

[0084] In some embodiments, the pharmaceutical composition comprises about 0.05% by weight of Compound 1, about 25% by weight of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25% by weight of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0085] In some embodiments, the pharmaceutical composition comprises about 0.05 mg of Compound 1; about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C.; and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0086] In some embodiments, the pharmaceutical composition comprises about 0.01 mg to about 0.8 mg of compound 1, about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0087] In some embodiments, the pharmaceutical composition comprises about 0.01 mg to about 0.8 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0088] In some embodiments, the pharmaceutical composition comprises about 0.01 mg to about 0.8 mg of Compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., about 25 mg of Methocel™ K4M Premium CR, and about 25 mg of Methocel™ K100 Premium LVCR.

[0089] In some embodiments, the pharmaceutical composition is storage stable.

[0090] In some embodiments, the pharmaceutical composition is a tablet.

[0091] In some embodiments, the tablets contain 0.05 mg, 0.25 mg, or 0.4 mg of Compound 1.

[0092] In some embodiments, the pharmaceutical composition is a capsule.

[0093] In some embodiments, the release rate of Compound 1 after storage of the pharmaceutical composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the release rate of the compound before storage at a given dissolution time point of 2 hours or more, wherein the release rates after storage and before storage are each measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at 37° C.±0.5° C., said aqueous medium comprising sodium phosphate at a concentration of 0.05 M.

[0094] In some embodiments, the pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising a copolymer comprising: (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid.

[0095] In some embodiments, the first excipient comprises poloxamer 188.

[0096] In some embodiments, the second excipient comprises glycerol monostearate and has a monoester content of at least about 90%.

[0097] In some embodiments, the second excipient comprises glycerol monostearate and has a monoester content of at least about 95%.

[0098] In some embodiments, the pharmaceutical composition is a setting composition.

[0099] In some embodiments, the weight ratio of the first excipient to the second excipient is selected from the following: about 70:30 to about 10:90, about 50:50 to about 30:70, about 70:30, about 50:50, about 40:60, and about 30:70.

[0100] In some embodiments, the emission rate is the emission rate measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C. using USP Apparatus 2 (paddle) at 50 rpm.

[0101] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0102] In some embodiments, the compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) and pharma- ceutically acceptable salts, solvates, and hydrates thereof is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

[0103] In some embodiments, the compound is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

[0104] In some embodiments, the pharmaceutical composition exhibits peaks in a PXRD spectrum having the following 2θ values: 19.7°, 20.2°, 20.7°, 22.6°, 23.1°, and 23.7°.

[0105] In some embodiments, the present specification provides a method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising administering to the individual a starting dose of Compound 1, the starting dose being equivalent to 0.05 mg of Compound 1 per day for about one week, and, if the individual tolerates the starting dose, administering an increased dose in an amount equivalent to 0.05 mg more than the starting dose for about one week, and further increasing the dose if the individual tolerates the increased dose.

[0106] Some embodiments further include administering increased doses for about one week, followed by repeated cycles of increasing doses, as long as the patient tolerates further increased doses, until the optimal dose is administered.

[0107] In some embodiments, provided herein are methods for treating pulmonary arterial hypertension (PAH) in an individual, the methods including administering to the individual a starting dose of Compound 1, the starting dose being equivalent to 0.05 mg of Compound 1 per day for about one week, and, if the individual tolerates the starting dose, administering an increased dose in an amount equivalent to 0.05 mg more than the starting dose for about one week, and further increasing the dose if the individual tolerates the increased dose.

[0108] Some embodiments further include administering increased doses for about one week, followed by repeated cycles of increasing doses, as long as the patient tolerates further increased doses, until the optimal dose is administered.

[0109] In some embodiments, Compound 1 is titrated for about 9 weeks, or for at least about 9 weeks.

[0110] In some embodiments, Compound 1 is titrated for about 16 weeks, or for at least about 16 weeks. [Brief description of the drawings]

[0111] [Figure 1] 1 shows the release profile of Compound 1 in an immediate release formulation. [Diagram 2] 1 shows a flowchart of an example process for manufacturing a modified release pharmaceutical composition containing Compound 1 ("API" in the flowchart). [Diagram 3] 1 shows the dissolution profiles for capsules containing Compound 1 with various Gelucire® 50 / 13 to Kolliphor® RH40 ratios. The profile of an immediate release (IR) composition (leftmost plot) is also shown for comparison. [Figure 4]1 shows the dissolution profile for capsules containing Compound 1 using Gelucire® 50 / 13 and Kolliphor® RH40 in a 75:25 ratio at various storage times. [Figure 5A] Figure 1 shows the dissolution profile for a 0.04 mg capsule of Compound 1 in Gelucire® 50 / 13: (i) Initial (time = 0). [Figure 5B] Figure 2 shows the dissolution profile for a 0.04 mg capsule of Compound 1 in Gelucire® 50 / 13. (ii) After 18 hours of curing at 40°C. [Figure 5C] Figure 2 shows the dissolution profile for a 0.04 mg capsule of Compound 1 in Gelucire® 50 / 13. (iii) After storage for 2 weeks at 40°C and 75% RH. [Figure 6] Dissolution profiles for capsules containing Compound 1 in 50:50 Poloxamer 188:food grade GMS are shown: (i) uncured (T=0), (ii) after 18 hours of curing at 50° C., (iii) after 1 week of curing and storage at 40° C. and 75% RH, (iv) after 2 weeks of curing and storage at 40° C. and 75% RH, and (v) after 4 weeks of curing and storage at 40° C. and 75% RH. [Figure 7A] FIG. 1 shows a comparison of powder X-ray diffraction (PXRD) spectra of capsules containing poloxamer 188 and food grade GMS in a 50:50 weight ratio (i) before and (ii) after curing for 18 hours at 50° C. The solid line is for 50:50 poloxamer-GMS, 0.04 mg of Compound 1 at 18 hours, 50° C. The dashed line is for 50:50 poloxamer-GMS, 0.04 mg of Compound 1 at T=0. [Figure 7B]Shown are powder X-ray diffraction spectra of capsules containing poloxamer 188 and research grade GMS in a 50:50 weight ratio (i) before and (ii) after curing at 50° C. for 18 hours. Shown are powder X-ray diffraction spectra of capsules containing poloxamer 188 and research grade GMS in a 50:50 weight ratio (i) before and (ii) after curing at 50° C. for 18 hours. Additionally, (iii) the PXRD spectrum of a capsule containing poloxamer 188 and food grade GMS in a 50:50 weight ratio after curing at 50° C. for 18 hours is shown for comparison. [Figure 7C] Three powder X-ray diffraction spectra are shown for capsules containing poloxamer 188 and research grade GMS in a 50:50 weight ratio: (i) before curing ("uncured"), (ii) after partial curing at 47.5°C for 10 hours ("partially cured"), and (iii) after curing at 50°C for 18 hours ("fully cured"). [Figure 8] 1 shows the release profile of a pharmaceutical composition containing poloxamer 188 and food grade GMS in a weight ratio of 70:30, and 0.5 mg of Compound 1. [Figure 9] 1 shows the release profile of a pharmaceutical composition containing poloxamer 188 and food grade GMS in a 50:50 weight ratio, and 0.5 mg of Compound 1. [Figure 10] 1 shows the release profile of a pharmaceutical composition containing poloxamer 188 and food grade GMS in a weight ratio of 30:70, and 0.5 mg of Compound 1. [Figure 11A] The release profiles of the following compositions are shown: (A) an immediate release composition comprising 0.03 mg of Compound 1; (B) a composition comprising poloxamer 188 and food grade GMS in a 50:50 weight ratio and 0.03 mg of Compound 1; (C) a composition comprising poloxamer 188 and food grade GMS in a 40:60 weight ratio and 0.03 mg of Compound 1; (D) a composition comprising poloxamer 188 and food grade GMS in a 30:70 weight ratio and 0.03 mg of Compound 1. [Figure 11B] 1 shows the release profile for a composition containing poloxamer 188 and food grade GMS in a 30:70 weight ratio, and 0.12 mg of Compound 1. [Figure 12] 1 shows dissolution profiles for tablets containing Compound 1 (0.05 mg), Methocel K4M Premium CR (25 mg), and Methocel 100 Premium LVCR (25 mg). Each plot point represents an average value; (a) diamonds: initial dissolution profile; (b) squares: profile after storage at 40° C. and 75% RH for 6 months. [Figure 13] 1 shows dissolution profiles for tablets containing Compound 1 (0.5 mg), Methocel K4M Premium CR (25 mg), and Methocel 100 Premium LVCR (25 mg). Each plot point represents an average value; (a) diamonds: initial dissolution profile; (b) squares: profile after storage at 40° C. and 75% RH for 6 months. [Figure 14] Dissolution profiles are shown for: (a) (diamonds) tablets containing Compound 1 (0.05 mg), Methocel K4M Premium CR (25 mg), and Methocel 100 Premium LVCR (25 mg); (b) (squares) tablets containing Compound 1 (0.5 mg), Methocel K4M Premium CR (25 mg), and Methocel 100 Premium LVCR (25 mg); and (c) (triangles) capsules containing Compound 1 (0.03 mg), poloxamer 188, and food grade GMS in a 30:70 ratio. Each plot point represents the average value. All three dissolution profiles were determined after storage at 40° C. and 75% RH for 6 months. Profiles (a) and (b) were determined using USP1 (basket) at 100 rpm. Profile (c) was determined using USP2 (paddle) at 50 rpm. [Figure 15] 1 shows the mean plasma concentrations of Compound 1 measured pre-dose and 4 hours post-dose in the clinical trial described in Example 8. [Figure 16] 1 shows a scatter plot of Cmax and last Compound 1 dose level in patients as described in Example 8. [Figure 17] 1 shows the change in PVR as a function of plasma levels of Compound 1 as described in Example 8. [Figure 18] 1 shows the change in 6MWD as a function of plasma levels of Compound 1 as described in Example 8. [Figure 19] 1 shows the change in BNP as a function of plasma levels of Compound 1 as described in Example 8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0112] Compound 1 is a potent IP receptor agonist. Due to the low doses of Compound 1 required for therapeutic purposes, solid oral dosage forms (such as tablets) would require extensive formulation development to achieve content uniformity. Thus, liquid-filled hard capsules were developed along with immediate release formulations for the initial clinical studies with Compound 1. However, immediate release capsule formulations have a high C max and peak-to-trough fluctuations, which may affect tolerability and patient compliance. To alleviate these concerns, the dosage for the immediate-release capsule formulation was reduced to twice daily administration.

[0113] Modified release capsule formulations were developed for subsequent clinical studies to achieve a once-daily dose while addressing the shortcomings of immediate release formulations. These modified release capsule formulations demonstrated the desired combination of properties, balancing once-daily dosing with stable release properties and improved pharmacokinetics. Modified release tablet formulations were also developed to achieve content uniformity and further improve stability and manufacturing process. Such modified release formulations of Compound 1 are described herein. Herein, the efficacy of Compound 1 correlates better with peak and trough plasma levels than with dosing.

[0114] definition For clarity and consistency, the following definitions are used throughout this patent document.

[0115] The term "agonist" as used herein refers to a moiety that can interact with and activate a G protein-coupled receptor, such as PGI2, thereby initiating the physiological or pharmacological response characteristic of the receptor.For example, agonist can activate the intracellular response when binding to the receptor, or enhance GTP binding to the membrane.

[0116] The term "in need of treatment" and the term "in need of" when referring to treatment are used interchangeably and refer to the judgment by a caregiver (e.g., in the case of humans, a physician, nurse, nurse practitioner, etc.; in the case of animals, including non-human mammals, a veterinarian) that an individual or animal needs or would benefit from treatment. This judgment is within the area of ​​the caregiver's expertise, but is made based on a variety of factors, including knowledge that the individual or animal is ill or will become ill as a result of a disease, illness, or disorder treatable by the compounds of the invention. Thus, the compounds of the invention can be used in prophylactic or preventative methods, or the compounds of the invention can be used to alleviate, inhibit, or ameliorate a disease, illness, or disorder.

[0117] The term "individual" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0118] The term "modulate" or "modulating" refers to an increase or decrease in the amount, quality, response, or effect of a particular activity, function, or molecule.

[0119] The term "composition" refers to compounds, including but not limited to salts, solvates, and hydrates of a compound of the present invention in combination with at least one additional component.

[0120] The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, such as a compound as described herein, including but not limited to salts, solvates, and hydrates of the compounds of the present invention, whereby the composition is applicable for studies pursuing a particular efficacious outcome in a mammal (such as but not limited to a human). Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0121] The term "hydroxypropyl methylcellulose", which may also be referred to as "hypromellose", refers to the propylene glycol ether of methylcellulose. Hydroxypropyl methylcellulose is available in different viscosities. For example, the hydroxypropyl methylcellulose may be hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C. For example, the hydroxypropyl methylcellulose may be Methocel K4M Premium CR. For example, the hydroxypropyl methylcellulose may be hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C. For example, the hydroxypropyl methylcellulose may be Methocel K100 Premium LVCR.

[0122] The term "a copolymer comprising: (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain attached to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain attached to the poly(propylene oxide) chain" refers to a poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) block copolymer.

[0123] The term "polyoxyethylene fats" as used herein refers to a class of excipients that includes or consists essentially of a single compound or mixture of compounds resulting from the reaction of various amounts of ethylene oxide with one or more glycerides derived from one or more hydroxyl-substituted fatty acids. An example of a hydroxyl-substituted fatty acid is ricinoleic acid. An example of a glyceride derived from one or more hydroxyl-substituted fatty acids is castor oil. An example of a polyoxyethylene fat is Kolliphor® RH40 (formerly known as Cremophor® RH40) (BASF, Mount Olive, NJ).

[0124] The term "stearoyl polyoxylglycerides" refers to mixtures of mono-, di-, and triesters of glycerol and mono- and diesters of polyethylene glycol having a nominal average relative molecular weight of 300 to 4000. Examples of stearoyl polyoxylglycerides include stearoyl polyoxyl-32 glycerides such as Gelucire® 50 / 13 (Gattefosse, France) and Acconon® C-50 (ABITEC, USA).

[0125] The term "poloxamer" as used herein refers to an excipient that comprises a copolymer comprising: (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain attached to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain attached to the poly(propylene oxide) chain. In some embodiments, the copolymer has an average molecular weight of about 17,500 or less, such as an average molecular weight of about 7,680 to about 9,510. In some embodiments, the excipient consists essentially of the copolymer. In some embodiments, the excipient is a copolymer.

[0126] In some embodiments, the copolymer is represented by the following chemical structure:

[0127] [ka] wherein the copolymer value for variable a at each occurrence is independently 1 to about 141, such as about 64 to about 141, about 80 to about 101, or 1 to about 101; and the copolymer value for variable b is 1 to about 56, such as about 27 to about 56, about 37 to about 44. Poloxamers are known or can be prepared by methods in the art. Many poloxamers are commercially available. Representative examples of poloxamers include, but are not limited to, poloxamer 124 (Pluronic® L44NF), poloxamer 188 (Pluronic® F68NF), poloxamer 237 (Pluronic® F87NF), poloxamer 338 (Pluronic® F108NF), poloxamer 407 (Pluronic® F127NF), and the like.

[0128] In some embodiments, the copolymer values ​​for variables a and b are as follows:

[0129] [Table 1]

[0130] The term "glycerol monostearate," as used herein, also known as "glycerol monostearate" or "GMS," refers to an excipient that contains the monoester of glycerol and stearic acid.

[0131] The term "monoester content", also referred to as "monoglyceride content", is the amount of monoester of glycerol and stearic acid in an excipient as a molar percentage relative to the sum of the amounts of monoester, diester of glycerol and stearic acid, triester of glycerol and stearic acid, and glycerol in the excipient. Various forms of glycerol monostearate (GMS) are commercially available. "Laboratory grade" GMS has a lower monoester content than "NF" grade GMS. NF grade GMS has a lower monoester content than "food grade" GMS. In some embodiments, the compositions of the present invention include food grade GMS. As used herein, "food grade" GMS has a monoester content of at least about 95%. Representative examples of commercially available GMS include, but are not limited to, Myverol™ 18-04K, Myverol™ 18-06K, Myverol™ 18-06PK, Myverol™ 18-04K, and the like.

[0132] The term "hardened composition" as used herein refers to a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, and a first excipient and a second excipient that are hardened together.

[0133] The term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician, or caregiver, or individual, which includes one or more of the following: (1) Prevention of disease, e.g., prevention of a disease, illness, or disorder in an individual who is susceptible to the disease, illness, or disorder but who has not yet experienced or exhibited any symptom or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, illness, or disorder (i.e., preventing further progression of the symptoms and / or symptoms) in an individual experiencing or exhibiting the symptoms or symptoms of the disease, illness, or disorder; and (3) Remission of a disease, e.g., remission of a disease, illness, or disorder (i.e., reversal of symptoms and / or symptomology) in an individual experiencing or exhibiting symptoms or symptomology of the disease, illness, or disorder.

[0134] The term "an amount equivalent to" followed by a recitation of an amount of Compound 1 (e.g., 0.01 mg of Compound 1) refers to an amount of a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof equivalent to the recited amount of Compound 1.

[0135] The term "wt %," when referring to the amount of a component present in a composition, such as Compound 1 or an excipient, refers to the amount of that composition as a % by weight of the composition.

[0136] The term "dissipation rate", also referred to herein as "dissolution rate", in relation to a compound, refers to the percentage amount of said compound released in an aqueous medium over a particular period of time. For example, the recitation "a dissipation rate per weight of compound in an aqueous medium that is dissipation rate (a), where (a) about 15% to about 35% by weight of compound is released over the first 2 hours" means that the weight % of compound released over the first 2 hours is about 15% to about 35% by weight of the starting amount of compound. The term "release profile", also referred to herein as "dissolution profile", in relation to a compound, refers to a plot showing the percentage amount of said compound released over time in an aqueous medium. The aqueous medium may be an aqueous medium as described herein.

[0137] Composition and Manufacturing Process In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0138] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is one or more of the following release rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium.

[0139] In some embodiments, the diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of an aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and a pH of 6.3-7.3 at a temperature of 37° C.±0.5° C.

[0140] In some embodiments, the diffusion rate is measured in 400-600 mL of an aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M, at a temperature of 37° C.±0.5° C. and a pH of 6.3-7.3, using a USP Apparatus 2 (paddle) at 40-60 rpm.

[0141] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0142] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is the following release rate (a): (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0143] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0144] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is the following release rate (b): (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0145] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0146] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is the following release rate (c): (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0147] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0148] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rate (a) and (b), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; and (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0149] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0150] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rate (a) and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0151] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0152] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rate (b) and (c), wherein: (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0153] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0154] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is release rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0155] In some embodiments, provided herein are compositions having a weight percent emission rate of a compound disclosed herein in an aqueous medium, where the emission rate is measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of an aqueous medium containing sodium phosphate at a concentration of 0.05 M and at a temperature of 37° C.±0.5° C. and a pH of 6.8.

[0156] In some embodiments, provided herein are compositions having a weight percent emission rate of a compound disclosed herein in an aqueous medium, where the emission rate is measured in 500 mL of an aqueous medium containing sodium phosphate at a concentration of 0.05 M, at a temperature of 37° C.±0.5° C. and a pH of 6.8, at 50 rpm, using a USP apparatus 2 (paddle).

[0157] In some embodiments provided herein is a composition disclosed herein, wherein the composition is a tablet.

[0158] In some embodiments provided herein, a composition disclosed herein is a capsule.

[0159] In some embodiments, provided herein are compositions having one or more of the emission rates (a), (b), and (c) as disclosed herein, the compositions being selected from the group consisting of (1) ethers of cellulose, such as hydroxypropyl methylcellulose, (2) esters of cellulose, (3) cellulose acetate, (4) ethyl cellulose, (5) polyvinyl acetate, (6) neutral copolymers based on ethyl acrylate and methyl methacrylate, (7) copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, (8) pH-insensitive ammonio methacrylate copolymers, and (9) cellulose esters. The composition further comprises one or more excipients selected from the group consisting of polymers, (9) polyethylene oxide, (10) polyvinylpyrrolidone, (11) naturally occurring polysaccharides such as xanthan gum and locust bean gum, (12) polyethylene glycol, (13) polypropylene glycol, (14) castor oil, (15) triacetin, (16) tributyl citrate, (17) triethyl citrate, (18) acetyl tri-n-butyl citrate, (19) diethyl phthalate, (20) dibutyl sebacate, (21) acetylated mono- and diglycerides, and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11) and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (12) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (13) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (14) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (2), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (3), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (4), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (3), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (4), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (6), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (2), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (4), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (14), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (4), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (14), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (6), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (12), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (8), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (12), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (12), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (13), (14), and mixtures thereof.

[0160] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C.

[0161] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the excipient is present in an amount equal to about 40% to about 60% by weight. In some embodiments, the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the excipient is present in an amount equal to about 45% to about 55% by weight. In some embodiments, the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., the excipient being present in an amount equal to about 50% by weight.

[0162] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0163] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the excipient is present in an amount equal to about 40% to about 60% by weight. In some embodiments, the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the excipient is present in an amount equal to about 45% to about 55% by weight. In some embodiments, the composition comprises an excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., the excipient being present in an amount equal to about 50% by weight.

[0164] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and the second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C.

[0165] In some embodiments, provided herein is a process for preparing a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1 as disclosed herein, the process comprising mixing the compound, ethanol, a first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and a second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C.

[0166] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has a dissipation rate per weight of compound in an aqueous medium as dissipation rate (a), where: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0167] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has a dissipation rate per weight of compound in an aqueous medium as dissipation rate (b), wherein: (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0168] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has a dissipation rate per weight of compound in an aqueous medium as dissipation rate (c), where: (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0169] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has a diffusion rate per weight of the compound in an aqueous medium as diffusion rates (a) and (b), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; and (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0170] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has a diffusion rate per weight of the compound in the aqueous medium as diffusion rates (a) and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0171] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has a diffusion rate per weight of the compound in the aqueous medium as diffusion rates (b) and (c), wherein: (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0172] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about a 2% amount in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about a 2% amount in water at 20° C.; The composition has emission rates (a), (b), and (c) per weight of compound in an aqueous medium, where: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0173] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the first excipient is present in an amount equal to about 5% to about 45% by weight, and the second excipient is present in an amount equal to about 5% to about 45% by weight. In some embodiments, the first excipient is present in an amount equal to about 10% to about 40% by weight and the second excipient is present in an amount equal to about 10% to about 40% by weight. In some embodiments, the first excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight and the second excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight. In some embodiments, the first excipient is present in an amount equal to about 25% by weight and the second excipient is present in an amount equal to about 25% by weight.

[0174] In some embodiments, provided herein are compositions having a weight percent release rate of a compound disclosed herein in an aqueous medium, the release rate being measured in a USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C. In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05 M.

[0175] In some embodiments, provided herein is a composition disclosed herein, the composition being a tablet. In some embodiments, the tablet comprises a core and a coating. In some embodiments, the core is selected from the group consisting of (1) ethers of cellulose, such as hydroxypropylmethylcellulose, (2) esters of cellulose, (3) cellulose acetate, (4) ethylcellulose, (5) polyvinyl acetate, (6) neutral copolymers based on ethyl acrylate and methyl methacrylate, (7) copolymers of acrylates and methacrylates with quaternary ammonium groups, (8) pH-insensitive ammonio methacrylate copolymers, (9) polyethylene oxide, (10) polyvinylpyrrolidone, (11) polyvinylpyrrolidone, (12) polyvinylpyrrolidone, (13) polyvinylpyrrolidone, (14) polyvinylpyrrolidone, (15) polyvinylpyrrolidone, (16) polyvinylpyrrolidone, (17) polyvinylpyrrolidone, (18) polyvinylpyrrolidone, (19) polyvinylpyrrolidone, (20) polyvinylpyrrolidone, (21) polyvinylpyrrolidone, (22) polyvinylpyrrolidone, (23) polyvinylpyrrolidone, (24) polyvinylpyrrolidone, (25) polyvinylpyrrolidone, (26) polyvinylpyrrolidone, (27) polyvinylpyrrolidone, (28) polyvinylpyrrolidone, (29) polyvinylpyrrolidone, (30) polyvinylpyrrolidone, (31) polyvinylpyrrolidone, (32) polyvinylpyrrolidone, (33) polyvinylpyrrolidone, (34) polyvinylpyrrolidone, (35) polyvinylpyrrolidone, (36) polyvinylpyrrolidone, (3 In some embodiments, the core comprises one or more excipients selected from the group consisting of glyceryl acrylate, glyceryl acrylate, glyceryl acrylate, glyceryl acrylate (10) glyceryl acrylate (11) naturally occurring polysaccharides such as xanthan gum and locust bean gum, (12) polyethylene glycol, (13) polypropylene glycol, (14) castor oil, (15) triacetin, (16) tributyl citrate, (17) triethyl citrate, (18) acetyl tri-n-butyl citrate, (19) diethyl phthalate, (20) dibutyl sebacate, (21) acetylated mono- and diglycerides, and mixtures thereof. In some embodiments, the core comprises hydroxypropyl methylcellulose. In some embodiments, the coating does not comprise hydroxypropyl methylcellulose.In some embodiments, the coating is selected from the group consisting of (1) ethers of cellulose, such as hydroxypropylmethylcellulose, (2) esters of cellulose, (3) cellulose acetate, (4) ethylcellulose, (5) polyvinyl acetate, (6) neutral copolymers based on ethyl acrylate and methyl methacrylate, (7) copolymers of acrylates and methacrylates with quaternary ammonium groups, (8) pH-insensitive ammonio methacrylate copolymers, (9) polyethylene oxide, (10) polyvinylpyrrolidone, and (11) polyvinylpyrrolidone. The composition does not contain one or more excipients selected from the group consisting of lolidone, (11) naturally occurring polysaccharides such as xanthan gum and locust bean gum, (12) polyethylene glycol, (13) polypropylene glycol, (14) castor oil, (15) triacetin, (16) tributyl citrate, (17) triethyl citrate, (18) acetyl tri-n-butyl citrate, (19) diethyl phthalate, (20) dibutyl sebacate, (21) acetylated mono- and diglycerides, and mixtures thereof. In some embodiments, provided herein are tablets having one or more of the emission rates (a), (b), and (c) as disclosed herein, the tablets being made from any of the following: (1) ethers of cellulose, such as hydroxypropyl methylcellulose; (2) esters of cellulose; (3) cellulose acetate; (4) ethyl cellulose; (5) polyvinyl acetate; (6) neutral copolymers based on ethyl acrylate and methyl methacrylate; (7) copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups; (8) pH-insensitive ammonio methacrylate copolymers; (10) polyvinylpyrrolidone, (11) naturally occurring polysaccharides such as xanthan gum and locust bean gum, (12) polyethylene glycol, (13) polypropylene glycol, (14) castor oil, (15) triacetin, (16) tributyl citrate, (17) triethyl citrate, (18) acetyl tri-n-butyl citrate, (19) diethyl phthalate, (20) dibutyl sebacate, (21) acetylated mono- and diglycerides, and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (1) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (12) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (13) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (14) and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (2), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (3), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (4), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (8), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (1), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (1), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (3), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (4), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (2), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (4), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (3), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (3), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (5), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (4), (13), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (4), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (6), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (5), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (7), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (6), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (8), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (7), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (9), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (10), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (8), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (10), and mixtures thereof.In some embodiments, the excipient is selected from the group consisting of (9), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (9), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (11), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (10), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11), (12), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (11), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (12), (13), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (12), (14), and mixtures thereof. In some embodiments, the excipient is selected from the group consisting of (13), (14), and mixtures thereof. In some embodiments, the core comprises hydroxypropyl methylcellulose and the coating does not comprise hydroxypropyl methylcellulose.In some embodiments, the core comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present at about 2% in water at 20° C., the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present at about 2% in water at 20° C., and the coating does not comprise hydroxypropyl methylcellulose.

[0176] In some embodiments, the tablet has a circular cross-section with a diameter of about 1 / 4 to about 1 / 3 inch. In some embodiments, the tablet has a circular cross-section with a diameter of about 1 / 4 inch. In some embodiments, the tablet has a circular cross-section with a diameter of about 1 / 3 inch.

[0177] In some embodiments, the tablet has a circular cross-section with a diameter of about 6.35 mm to about 8.46 mm. In some embodiments, the tablet has a circular cross-section with a diameter of about 6.35 mm. In some embodiments, the tablet has a circular cross-section with a diameter of about 8.46 mm.

[0178] In some embodiments, the oral form has content uniformity (e.g., with respect to Compound 1). In some embodiments, the content uniformity is as measured by the Content Uniformity test method in the International Pharmacopoeia (IP), British Pharmacopoeia (BP), United States Pharmacopoeia (USP), or European Pharmacopoeia (Ph.Eur.), each of which is incorporated herein by reference. In some embodiments, the oral form has a relative standard deviation of content that is less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%. In some embodiments, the oral form does not have a value that is outside of a range of content, e.g., 75-125%, 80-125%, 85-120%, 85-115%, 90-120%, 90-110%, or 95-105%. In some embodiments, the oral form has a content of about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% or more, hi some embodiments, the oral form has a content of about 100.5%, 101%, 102%, 103%, 104%, 105%, 110%, 115%, 120%, or 125% or less.

[0179] In some embodiments, the tablet has a hardness of about 5 kp to about 9 kp. In some embodiments, the tablet has a hardness of about 6 kp to about 8 kp. In some embodiments, the tablet has a hardness of about 7 kp.

[0180] In some embodiments, the tablet has a core weight of about 95 mg to about 105 mg. In some embodiments, the tablet has a core weight of about 97.5 mg to about 102.5 mg. In some embodiments, the tablet has a core weight of about 99 mg to about 101 mg. In some embodiments, the tablet has a core weight of about 100 mg.

[0181] In some embodiments, the tablets have a coating weight of about 3 mg to about 5 mg. In some embodiments, the tablets have a core weight of about 3.5 mg to about 4.5 mg. In some embodiments, the tablets have a core weight of about 4 mg.

[0182] In some embodiments, the tablet has a total weight of about 98 mg to about 110 mg. In some embodiments, the tablet has a total weight of about 101 mg to about 107 mg. In some embodiments, the tablet has a total weight of about 104 mg.

[0183] In some embodiments, the therapeutically effective amount of Compound 1 in the composition is about 0.01% to about 1% by weight, such as about 0.01% to about 0.6% by weight, about 0.02% to about 0.3% by weight, about 0.03% to about 0.2% by weight, about 0.04% to about 0.12% by weight, about 0.04% to about 0.1% by weight, about 0.05% to about 0.08% by weight, about 0.06% by weight, etc. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.025%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.03% by weight. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.04%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.05% by weight. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.06% by weight. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.1%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.2%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.25%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.3% by weight. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.35%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.4%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.5% by weight. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.6%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.7%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.75%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.8%. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.9%. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.0%.

[0184] In some embodiments, the therapeutically effective amount of Compound 1 in the composition is about 0.01 mg to about 1.5 mg, e.g., about 0.01 to about 1.45 mg, about 0.01 to about 1.2 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.8 mg, about 0.01 mg to about 0.6 mg, about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, about 0.06 mg, etc.

[0185] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein a therapeutically effective amount of Compound 1 is selected from about 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day.

[0186] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein a therapeutically effective amount of Compound 1 is selected from 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day.

[0187] In some embodiments, the therapeutically effective amount of Compound 1 is about 0.018 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.025 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.01 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.02 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.025 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.03 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.04 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.05 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.06 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.065 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.07 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.075 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.08 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.09 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.1 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.12 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.15 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.16 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.2 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.25 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.3 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.35 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.4 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.45 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.5 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.55 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.6 mg.In some embodiments, the therapeutically effective amount of Compound 1 is about 0.65 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.7 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.75 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.8 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.85 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.9 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 0.95 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.0 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.1 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.2 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.25 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.3 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.35 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.4 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.45 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 1.5 mg.

[0188] In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose.

[0189] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein the therapeutically effective amount of compound 1 is a starting dosage amount selected from 0.01, 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.075, 0.08, 0.09, or 0.1 mg per day. In some embodiments, the therapeutically effective amount of compound 1 is a starting dosage amount and is about 0.01 mg. In some embodiments, the therapeutically effective amount of compound 1 is a starting dosage amount and is about 0.02 mg. In some embodiments, the therapeutically effective amount of compound 1 is a starting dosage amount and is about 0.025 mg. In some embodiments, the therapeutically effective amount of compound 1 is a starting dosage amount and is about 0.03 mg. In some embodiments, the therapeutically effective amount of compound 1 is a starting dosage amount and is about 0.04 mg. In some embodiments, the therapeutically effective amount of compound 1 is a starting dosage amount and is about 0.05 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose and is about 0.06 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose and is about 0.07 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose and is about 0.075 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose and is about 0.08 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose and is about 0.09 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the starting dose and is about 0.1 mg.

[0190] In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated dose.

[0191] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein the therapeutically effective amount of compound 1 is the highest tolerated dose selected from 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day. In some embodiments, the therapeutically effective amount of compound 1 is the highest tolerated dose and is about 0.4 mg. In some embodiments, the therapeutically effective amount of compound 1 is the highest tolerated dose and is about 0.45 mg. In some embodiments, the therapeutically effective amount of compound 1 is the highest tolerated dose and is about 0.5 mg. In some embodiments, the therapeutically effective amount of compound 1 is the highest tolerated dose and is about 0.55 mg. In some embodiments, the therapeutically effective amount of compound 1 is the highest tolerated dose and is about 0.6 mg. In some embodiments, the therapeutically effective amount of compound 1 is the highest tolerated dose and is about 0.65 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 0.7 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 0.75 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 0.8 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 0.85 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 0.9 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 0.95 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the highest tolerated dose and is about 1.0 mg.

[0192] In some embodiments, the therapeutically effective amount of Compound 1 is a maximum dose.

[0193] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein the therapeutically effective amount of compound 1 is a maximum dose selected from 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day. In some embodiments, the therapeutically effective amount of compound 1 is a maximum dose and is about 0.4 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum dose and is about 0.45 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum dose and is about 0.5 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum dose and is about 0.55 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum dose and is about 0.6 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum dose and is about 0.65 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 0.7 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 0.75 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 0.8 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 0.85 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 0.9 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 0.95 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum dose and is about 1.0 mg.

[0194] In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated dose.

[0195] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein the therapeutically effective amount of compound 1 is a maximum tolerated amount selected from 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day. In some embodiments, the therapeutically effective amount of compound 1 is a maximum tolerated amount and is about 0.4 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum tolerated amount and is about 0.45 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum tolerated amount and is about 0.5 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum tolerated amount and is about 0.55 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum tolerated amount and is about 0.6 mg. In some embodiments, the therapeutically effective amount of compound 1 is a maximum tolerated amount and is about 0.65 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 0.7 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 0.75 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 0.8 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 0.85 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 0.9 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 0.95 mg. In some embodiments, the therapeutically effective amount of Compound 1 is the maximum tolerated amount and is about 1.0 mg.

[0196] In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose.

[0197] In some embodiments, provided herein is a pharmaceutical composition according to any of the embodiments described herein, wherein the therapeutically effective amount of Compound 1 is a maintenance dose selected from 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.01 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.02 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.025 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.03 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.04 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.05 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.06 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.065 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.07 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.075 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.08 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.09 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.1 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.12 mg.In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.15 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.16 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.2 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.25 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.3 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.35 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.4 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.45 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.5 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.55 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.6 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.65 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.7 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.75 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.8 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.85 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.9 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 0.95 mg. In some embodiments, the therapeutically effective amount of Compound 1 is a maintenance dose and is about 1.0 mg.

[0198] In some embodiments, the starting dose is for a patient. In some embodiments, the starting dose is for a patient population. In some embodiments, the highest tolerated dose is for a patient. In some embodiments, the highest tolerated dose is for a patient population. In some embodiments, the maximum dose is for a patient. In some embodiments, the maximum dose is for a patient population. In some embodiments, the maximum tolerated dose is for a patient. In some embodiments, the maximum tolerated dose is for a patient population. In some embodiments, the maintenance dose is for a patient. In some embodiments, the maintenance dose is for a patient population.

[0199] In some embodiments, the starting dose of Compound 1 is selected from about 0.01, 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.075, 0.08, 0.09, or 0.1 mg once a day. In some embodiments, the starting dose of Compound 1 is 0.01 mg once a day. In some embodiments, the starting dose of Compound 1 is 0.02 mg once a day. In some embodiments, the starting dose of Compound 1 is 0.05 mg once a day. In some embodiments, the starting dose of Compound 1 is 0.06 mg once a day.

[0200] In some embodiments, the dosage of Compound 1 is escalated at weekly intervals from 0.05 mg once daily up to a maximum tolerated dose of 0.8 mg once daily.

[0201] In some embodiments, the dose of Compound 1 is escalated at weekly intervals. In some embodiments, the dose of Compound 1 is escalated at monthly intervals.

[0202] In some embodiments, the dosage of Compound 1 is increased by an amount selected from about 0.02 mg, 0.05 mg, 0.75 mg, and 0.1 mg once daily.

[0203] In some embodiments, the dosage of Compound 1 is increased at weekly intervals by an amount selected from about 0.02 mg, 0.05 mg, 0.75 mg, and 0.1 mg once daily.

[0204] In some embodiments, the maximum tolerated dose of Compound 1 is selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.6 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.75 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.8 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.4-1.0 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.6-1.0 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.6-0.8 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.65-1.0 mg once per day. In some embodiments, the maximum tolerated dose of compound 1 is 0.65-0.8 mg once per day. In some embodiments, the maximum tolerated dose of compound 1 is greater than 0.4 mg once per day. In some embodiments, the maximum tolerated dose of compound 1 is greater than 0.6 mg once per day. In some embodiments, the maximum tolerated dose of compound 1 is greater than 0.8 mg once per day. In some embodiments, the maximum tolerated dose of compound 1 is greater than 1.0 mg once per day.

[0205] In some embodiments, the maximum dose of Compound 1 is selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.6 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.75 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.8 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.4 to 1.0 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.6 to 1.0 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.6 to 0.8 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.65 to 1.0 mg once per day. In some embodiments, the maximum dose of Compound 1 is 0.65-0.8 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 0.4 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 0.6 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 0.8 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 1.0 mg once per day.

[0206] In some embodiments, the maximum tolerated dose of compound 1 is selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.6 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.75 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.8 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.75 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.8 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.4 to 1.0 mg once a day. In some embodiments, the maximum tolerated dose of compound 1 is 0.6 to 1.0 mg once a day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.6-0.8 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.65-1.0 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is 0.65-0.8 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is greater than 0.4 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is greater than 0.6 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is greater than 0.8 mg once per day. In some embodiments, the maximum tolerated dose of Compound 1 is greater than 1.0 mg once per day.

[0207] In some embodiments, the maximum dosage of compound 1 in the dosage form is selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg. In some embodiments, the maximum dosage of compound 1 in the dosage form is 0.6 mg. In some embodiments, the maximum dosage of compound 1 in the dosage form is 0.75 mg. In some embodiments, the maximum dosage of compound 1 in the dosage form is 0.8 mg. In some embodiments, the maximum dosage of compound 1 is 0.4 to 1.0 mg once a day. In some embodiments, the maximum dosage of compound 1 is 0.6 to 1.0 mg once a day. In some embodiments, the maximum dosage of compound 1 is 0.6 to 0.8 mg once a day. In some embodiments, the maximum dosage of compound 1 is 0.65 to 1.0 mg once a day. In some embodiments, the maximum dose of Compound 1 is 0.65-0.8 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 0.4 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 0.6 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 0.8 mg once per day. In some embodiments, the maximum dose of Compound 1 is greater than 1.0 mg once per day.

[0208] In some embodiments, the maintenance dose of Compound 1 is selected from about 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, and 1.0 mg per day. In some embodiments, the maintenance dose of Compound 1 is 0.4 to 1.0 mg once a day. In some embodiments, the maintenance dose of Compound 1 is 0.6-1.0 mg once a day. In some embodiments, the maintenance dose of Compound 1 is 0.6-0.8 mg once a day. In some embodiments, the maintenance dose of Compound 1 is 0.65-1.0 mg once a day. In some embodiments, the maintenance dose of Compound 1 is 0.65-0.8 mg once a day. In some embodiments, the maintenance dose of Compound 1 is determined by tolerability. In some embodiments, the maintenance dose of Compound 1 is greater than 0.4 mg once a day. In some embodiments, the maintenance dose of Compound 1 is greater than 0.6 mg once a day. In some embodiments, the maintenance dose of Compound 1 is greater than 0.8 mg once a day. In some embodiments, the maintenance dose of Compound 1 is greater than 1.0 mg once a day.

[0209] In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of about 2 ng / mL. In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of about 2.5 ng / mL. Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of about 2.75 ng / mL.

[0210] In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of about 3 ng / mL. In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of at least about 3 ng / mL, such as about 3.1 ng / mL, about 3.2 ng / mL, about 3.3 ng / mL, about 3.4 ng / mL, about 3.5 ng / mL, about 3.6 ng / mL, about 3.7 ng / mL, about 3.8 ng / mL, or about 3.9 ng / mL.

[0211] In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of about 4 ng / mL. In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of at least about 4 ng / mL, such as about 4.1 ng / mL, about 4.2 ng / mL, about 4.3 ng / mL, about 4.4 ng / mL, about 4.5 ng / mL, about 4.6 ng / mL, about 4.7 ng / mL, about 4.8 ng / mL, or about 4.9 ng / mL.

[0212] In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of about 5 ng / mL. In some embodiments, Compound 1 is administered in an amount sufficient to achieve a plasma concentration of Compound 1 in the patient of at least about 5 ng / mL, such as about 5.1 ng / mL, about 5.2 ng / mL, about 5.3 ng / mL, about 5.4 ng / mL, about 5.5 ng / mL, about 5.6 ng / mL, about 5.7 ng / mL, about 5.8 ng / mL, or about 5.9 ng / mL.

[0213] In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 3 ng / mL to about 5 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 3.5 ng / mL to about 5 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 4 ng / mL to about 5 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 4.5 ng / mL to about 5 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 3 ng / mL to about 4.5 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 3 ng / mL to about 4 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 3 ng / mL to about 4 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 of about 3 ng / mL to about 3.5 ng / mL in the patient. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 in the patient of about 3.5 ng / mL to about 5.0 ng / mL. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 in the patient of about 3.5 ng / mL to about 4.5 ng / mL. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 in the patient of about 3.5 ng / mL to about 4.0 ng / mL.

[0214] In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 in the patient that is equal to or greater than the binding affinity concentration. In some embodiments, compound 1 is administered in an amount sufficient to achieve a plasma concentration of compound 1 in the patient that is equal to or greater than 3.4 nM.

[0215] In some embodiments, the dose of Compound 1 administered to an individual is selected based on the correlation with the individual's plasma level. In some embodiments, the dose of Compound 1 administered to an individual is an amount that corresponds to at least a threshold plasma level in the individual. In some embodiments, Compound 1 is administered in an amount that reaches at least a threshold plasma level in the individual. In some embodiments, Compound 1 is titrated to the individual until at least a threshold plasma level is achieved in the individual.

[0216] In some embodiments, Compound 1 is titrated to the individual for at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks.

[0217] In some embodiments, administration of Compound 1 is continued when the individual achieves at least a threshold plasma level of Compound 1 at the starting dose. In some embodiments, administration of Compound 1 is continued when the individual achieves at least a threshold plasma level of Compound 1 at the highest tolerated dose. In some embodiments, administration of Compound 1 is continued when the individual achieves at least a threshold plasma level of Compound 1 at the highest dose. In some embodiments, administration of Compound 1 is continued when the individual achieves at least a threshold plasma level of Compound 1 at the highest tolerated dose. In some embodiments, administration of Compound 1 is continued when the individual achieves at least a threshold plasma level of Compound 1 at the maintenance dose.

[0218] In some embodiments, administration of Compound 1 is discontinued if the individual does not achieve at least a threshold plasma level of Compound 1 at the starting dose. In some embodiments, administration of Compound 1 is discontinued if the individual does not achieve at least a threshold plasma level of Compound 1 at the highest tolerated dose. In some embodiments, administration of Compound 1 is discontinued if the individual does not achieve at least a threshold plasma level of Compound 1 at the highest dose. In some embodiments, administration of Compound 1 is discontinued if the individual does not achieve at least a threshold plasma level of Compound 1 at the highest tolerated dose. In some embodiments, administration of Compound 1 is discontinued if the individual does not achieve at least a threshold plasma level of Compound 1 at the maintenance dose.

[0219] In some embodiments, the threshold plasma concentration in an individual is about 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, 2, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4 , 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5, 5.1, 5.2, 5.25, 5.3, 5.4, 5.5, 5.6, 5.7, 5.75, 5.8, 5.9, 6, 6.6.25, 5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, or 10 ng / ml.

[0220] Those skilled in the art will recognize that the term "plasma concentration" is a type of "plasma level."

[0221] In some embodiments, in patients receiving an intolerable dose of Compound 1, the dose of Compound 1 is reduced to a previously tolerated dose. In some embodiments, the previously tolerated dose is the maximum tolerated dose for the patient.

[0222] In some embodiments, the amount of Compound 1 is adjusted to account for differences in bioequivalence between the immediate release form and the sustained release form. For example, in some embodiments, 0.8 mg of Compound 1 in sustained release form is provided to be equivalent to two 0.3 mg of immediate release form of Compound 1, where the sustained release form has less than 100% bioequivalence with the immediate release form.

[0223] In some embodiments, provided herein are pharmaceutical compositions comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid.

[0224] In some embodiments, provided herein is a pharmaceutical composition prepared by a process comprising curing a mixture comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, a first excipient, and a second excipient, to form the composition, wherein the first excipient comprises a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the second excipient comprises an ester of a polyalcohol and a fatty acid.

[0225] In some embodiments, provided herein is a process for preparing a pharmaceutical composition, the process comprising: and (c) a copolymer comprising a polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and a copolymer comprising a first excipient and a second excipient, the first excipient comprising a copolymer comprising: (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid, to form a composition.

[0226] In some embodiments of the compositions provided herein, the dissipation rate is one or more of dissipation rates (a), (b), and / or (c) disclosed herein.

[0227] In some embodiments, the emission rate is the emission rate measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 and at a temperature of 37° C.±0.5° C.

[0228] In some embodiments, the emission rate is the emission rate measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium containing sodium phosphate at a concentration of 0.05 M at a temperature of 37° C.±0.5° C.

[0229] USP Apparatus 1 (BASKETS) is described, for example, in the United States Pharmacopeial Convention, February 1, 2012, Chapter 711 ("Dissolution"), which is incorporated herein by reference in its entirety. See http: / / www.usp.org / sites / default / files / usp_pdf / EN / USPNF / revisions / m99470-gc_711.pdf. The USP Apparatus 1 (BASKETS) assembly consists of: a vessel, which may be coated and made of glass or other inert transparent material; a motor; a metallic drive shaft; and a cylindrical basket. The material must not adsorb, react with, or interfere with the analyte being tested. The vessel is partially immersed in a suitable water bath of any convenient size or is heated by a suitable device such as a heating jacket. The water bath or heating device allows the temperature in the vessel to be maintained at 37±0.5° during testing and the bath flow to be kept in constant smooth operation. None of the parts of the assembly, including the environment in which it is placed, contributes significant movement, agitation, or vibration beyond that due to the smoothly rotating stirring element. A device that allows observation of the specimen and the stirring element during testing is preferred. The vessel is cylindrical with a hemispherical bottom and one of the following dimensions and capacities: for a nominal capacity of 1 L, the height is 160 mm to 210 mm and its internal diameter is 98 mm to 106 mm; for a nominal capacity of 2 L, the height is 280 mm to 300 mm and its internal diameter is 98 mm to 106 mm; and for a nominal capacity of 4 L, the height is 280 mm to 300 mm and its internal diameter is 145 mm to 155 mm. Its sides are flanged at the top. A fitted cover may be used to retard deposition. If a cover is used, an opening sufficient to allow for immediate insertion of a thermometer and collection of the specimen is provided. The shaft is positioned so that its axis is no more than 2 mm from the vertical axis of the vessel at any point and rotates smoothly and without significant vibrations that may affect the results. The vertical centre line of the blade passes through the axis of the shaft so that the base of the blade is level with the base of the shaft.A distance of 25±2mm between the base of the blade and the bottom of the container interior is maintained during the test. The blade and shaft, which may be metallic or suitably inert, comprise a single entity. A suitable two-part separable design may be used, provided that the assembly remains tightly engaged during the test.

[0230] A speed adjusting device is used that allows the shaft rotation speed to be selected and maintained at a specified speed within ±4%. The shaft and basket components of the stirring element are made of stainless steel, type 316, or other inert material. A gold-coated basket with a thickness of approximately 0.0001 in. (2.5 μm) may be used. The dosing unit is placed in the drying basket at the beginning of each test. The distance between the bottom of the inside of the container and the bottom of the basket is maintained at 25 ± 2 mm during the test.

[0231] The USP Apparatus 2 (Paddle Apparatus) is described, for example, in the United States Pharmacopeial Convention, February 1, 2012, Chapter 711 ("Dissolution"), which is incorporated herein by reference in its entirety. See http: / / www.usp.org / sites / default / files / usp_pdf / EN / USPNF / revisions / m99470-gc_711.pdf. The assembly of Apparatus 1 is used, except that a paddle formed of a blade and a shaft is used as the stirring element. The shaft is positioned so that its axis is no more than 2 mm from the vertical axis of the vessel at any point and rotates smoothly and without significant vibrations that may affect the results. The vertical centerline of the blade passes through the axis of the shaft so that the bottom of the blade is horizontal with the bottom of the shaft. A distance of 25±2 mm between the bottom of the blade and the bottom of the inside of the vessel is maintained during the test. The blade and shaft, which may be metallic or suitably inert, comprise a single entity. Any suitable two-part separable design may be used, provided that the assembly remains tightly engaged during testing. The paddle blades and shaft may be coated with a coating to render them inert. The dosing unit may be submerged to the bottom of the container before blade rotation begins. A small loose piece of non-reactive material, such as a wire helix of no more than a few turns, may be attached to the dosing unit, which will float. Other effective sinker devices may be used.

[0232] When water or a specified percentage of broth at a pH below 6.8 is specified as the broth, the same broth may be used with the addition of purified pepsin to produce not more than 750,000 units of activity per 1000 mL. In media at pH 6.8 or above, pancreatin may be added to produce not more than 1750 USP units of protease activity per 1000 mL.

[0233] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0234] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is one or more of the following release rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0235] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0236] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is one or more of the following release rates (a), (b), and (c), wherein: (a) about 40% by weight or less of the compound is released over the first 2 hours in an aqueous medium; (b) about 40% to about 60% by weight of the compound is released over the first 5 hours in an aqueous medium; and / or (c) about 80% or less by weight of the compound is released over the first 14 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0237] In some embodiments, the composition has a dissipation rate (a). In some embodiments, the composition has a dissipation rate (b). In some embodiments, the composition has a dissipation rate (c). In some embodiments, the composition has dissipation rates (a) and (b). In some embodiments, the composition has dissipation rates (a) and (c). In some embodiments, the composition has dissipation rates (b) and (c). In some embodiments, the composition has dissipation rates (a), (b), and (c).

[0238] In some embodiments, the emission rate is the emission rate measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 and at a temperature of 37° C.±0.5° C.

[0239] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0240] In some embodiments, the diffusion rate is measured in USP Apparatus 2 (paddle) at 50 rpm in 500 mL of an aqueous medium having a pH of 6.8 and a temperature of 37° C.±0.5° C., wherein the aqueous medium contains sodium phosphate at a concentration of 0.05 M.

[0241] In some embodiments, the composition is a tablet.

[0242] In some embodiments, the composition is a capsule.

[0243] In some embodiments, the pharmaceutical composition is a tablet.

[0244] In some embodiments, the pharmaceutical composition is a capsule.

[0245] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and the second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C.

[0246] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises a release modifier having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and the second excipient comprises a release modifier having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C.

[0247] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.; The composition has a dissipation rate per weight of the compound in an aqueous medium as one or more of dissipation rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0248] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises a release modifier having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and the second excipient comprises a release modifier having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C.; The composition has a dissipation rate per weight of the compound in an aqueous medium as one or more of dissipation rates (a), (b), and (c), wherein: (a) about 40% by weight or less of the compound is released over the first 2 hours in an aqueous medium; (b) about 40% to about 60% by weight of the compound is released over the first 5 hours in an aqueous medium; and / or (c) about 80% or less by weight of the compound is released over the first 14 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0249] In some embodiments, the composition has a dissipation rate (a). In some embodiments, the composition has a dissipation rate (b). In some embodiments, the composition has a dissipation rate (c). In some embodiments, the composition has dissipation rates (a) and (b). In some embodiments, the composition has dissipation rates (a) and (c). In some embodiments, the composition has dissipation rates (b) and (c). In some embodiments, the composition has dissipation rates (a), (b), and (c).

[0250] In some embodiments, the composition is a tablet.

[0251] In some embodiments, the pharmaceutical composition is a tablet.

[0252] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the first excipient is present in an amount equal to about 5% to about 45% by weight, and the second excipient is present in an amount equal to about 5% to about 45% by weight.

[0253] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, wherein the first excipient comprises a release modifier having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and the second excipient comprises a release modifier having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., wherein the first excipient is present in an amount equal to about 5% to about 45% by weight, and the second excipient is present in an amount equal to about 5% to about 45% by weight.

[0254] In some embodiments, the first excipient is present in an amount equal to about 10% to about 40% by weight and the second excipient is present in an amount equal to about 10% to about 40% by weight.

[0255] In some embodiments, the first excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight and the second excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight.

[0256] In some embodiments, said first excipient is present in an amount equal to about 25% by weight and said second excipient is present in an amount equal to about 25% by weight.

[0257] In some embodiments, the composition has a dissipation rate per weight of compound in an aqueous medium as one or more of dissipation rates (a), (b), and (c), where: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This diffusion rate is measured in USP Apparatus 1 (basket) at 80-120 rpm in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M and at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3.

[0258] In some embodiments, the emission rate is the emission rate measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 and at a temperature of 37° C.±0.5° C.

[0259] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0260] In some embodiments, the emission rate is the emission rate measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C. using USP Apparatus 2 (paddle) at 50 rpm.

[0261] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0262] In some embodiments, the composition is a tablet.

[0263] In some embodiments, the pharmaceutical composition is a tablet.

[0264] In some embodiments, the tablet comprises a core and a coating.

[0265] In some embodiments, the core comprises hydroxypropyl methylcellulose.

[0266] In some embodiments, the coating does not include hydroxypropyl methylcellulose.

[0267] In some embodiments, the core comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present at about 2% in water at 20° C., the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present at about 2% in water at 20° C., and the coating does not comprise hydroxypropyl methylcellulose.

[0268] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.01% to about 1% by weight of the composition.

[0269] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.01% to about 0.6% by weight of the composition.

[0270] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.02% to about 0.3% by weight of the composition.

[0271] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.03% to about 0.2% by weight of the composition.

[0272] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.04% to about 0.12% by weight of the composition.

[0273] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.04% to about 0.1% by weight of the composition.

[0274] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.04% to about 0.1% by weight of the composition.

[0275] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.05% to about 0.08% by weight of the composition.

[0276] In some embodiments, the therapeutically effective amount of Compound 1 is about 0.06% by weight of the composition.

[0277] In some embodiments, the therapeutically effective amount of Compound 1 is from about 0.01 mg to about 1 mg.

[0278] In some embodiments, the compound is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

[0279] In some embodiments, the therapeutically effective amount of Compound 1 is suitable for once-daily administration to a subject.

[0280] In some embodiments, the therapeutically effective amount of Compound 1 is suitable for once-daily administration to a subject.

[0281] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0282] [ka] wherein the composition comprises about 0.05% by weight of Compound 1, about 25% by weight of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25% by weight of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0283] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0284] [ka] wherein the composition comprises about 0.05 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0285] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0286] [ka] Here, the composition contains about 0.01 mg to about 0.8 mg of compound 1, about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0287] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0288] [ka] Here, the composition contains about 0.01 mg to about 0.6 mg of compound 1, about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0289] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0290] [ka] Here, the composition contains about 0.01 mg to about 0.8 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0291] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0292] [ka] Here, the composition contains about 0.01 mg to about 0.6 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0293] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0294] [ka] Here, the composition comprises about 0.01 mg to about 0.8 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C, about 25 mg of Methocel (trademark) K4M Premium CR, and about 25 mg of Methocel (trademark) K100 Premium LVCR.

[0295] In some embodiments, provided herein is a pharmaceutical composition comprising 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0296] [ka] Here, the composition comprises about 0.01 mg to about 0.6 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C, about 25 mg of Methocel (trademark) K4M Premium CR, and about 25 mg of Methocel (trademark) K100 Premium LVCR.

[0297] In some embodiments, provided herein is a process for preparing a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, the process comprising mixing the compound with a first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., a second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C., and optionally additional pharma- ceutically acceptable excipients to form the pharmaceutical composition.

[0298] In some embodiments, provided herein is a process for preparing a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, the process comprising mixing the compound with a first excipient comprising a release modifier having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., a second excipient comprising a release modifier having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C., and optionally additional pharma- ceutically acceptable excipients to form the pharmaceutical composition.

[0299] In some embodiments, provided herein is a process for preparing a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, the process comprising mixing the compound, ethanol, a first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in about 2% amount in water at 20° C., and a second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in about 2% amount in water at 20° C. to form the composition.

[0300] In some embodiments, the pharmaceutical composition is a tablet.

[0301] In some embodiments, a pharmaceutical composition is provided herein, wherein the composition is storage stable.

[0302] In some embodiments, the storage-stable composition is a pharmaceutical composition, and the pharmaceutical composition is a tablet.

[0303] In some embodiments, the shelf-stable composition is a pharmaceutical composition, and the pharmaceutical composition is a capsule.

[0304] In some embodiments, the storage-stable composition is a pharmaceutical composition, wherein the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, each of the release rates after storage and before storage being measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of an aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., wherein the aqueous medium comprises sodium phosphate at a concentration of 0.05 M.

[0305] In some embodiments, provided herein are pharmaceutical compositions comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, wherein the composition comprises a first excipient and a second excipient, the first excipient comprising a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid.

[0306] In some embodiments, the pharmaceutical composition is a composition.

[0307] In some embodiments, the first excipient comprises poloxamer 188.

[0308] In some embodiments, the second excipient comprises glycerol monostearate and has a monoester content of at least about 90%.

[0309] In some embodiments, the second excipient comprises glycerol monostearate and has a monoester content of at least about 95%.

[0310] In some embodiments, the composition is a curable composition.

[0311] In some embodiments, provided herein is a pharmaceutical composition prepared by a process comprising curing a mixture comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, a first excipient, and a second excipient, to form the composition, wherein the first excipient comprises a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the second excipient comprises an ester of a polyalcohol and a fatty acid.

[0312] In some embodiments, the first excipient comprises poloxamer 188 and the second excipient comprises glycerol monostearate and has a monoester content of at least about 90%.

[0313] In some embodiments, the first excipient comprises poloxamer 188 and the second excipient comprises glycerol monostearate and has a monoester content of at least about 95%.

[0314] In some embodiments, curing of the mixture is carried out at a temperature of about 45°C to about 55°C.

[0315] In some embodiments, curing of the mixture is carried out at a temperature of about 50° C. to about 50° C. for about 12 hours to about 36 hours.

[0316] In some embodiments, the weight ratio of the first excipient to the second excipient is from about 70:30 to about 10:90.

[0317] In some embodiments, the weight ratio of the first excipient to the second excipient is from about 50:50 to about 30:70.

[0318] In some embodiments, the weight ratio of the first excipient to the second excipient is about 70:30.

[0319] In some embodiments, the weight ratio of the first excipient to the second excipient is about 50:50.

[0320] In some embodiments, the weight ratio of the first excipient to the second excipient is about 40:60.

[0321] In some embodiments, the weight ratio of the first excipient to the second excipient is about 30:70.

[0322] In some embodiments, the composition has a dissipation rate per weight of compound in an aqueous medium as one or more of dissipation rates (a), (b), and (c), where: (a) about 15% to about 35% of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% of the compound is released over the first 8 hours in aqueous medium.

[0323] In some embodiments, the composition has a dissipation rate (a).

[0324] In some embodiments, the composition has a dissipation rate (b).

[0325] In some embodiments, the composition has a dissipation rate (c).

[0326] In some embodiments, the composition has emission rates (a) and (b).

[0327] In some embodiments, the composition has emission rates (a) and (c).

[0328] In some embodiments, the composition has emission rates (b) and (c).

[0329] In some embodiments, the composition has dissipation rates (a), (b), and (c).

[0330] In some embodiments, the composition is a capsule.

[0331] In some embodiments, the emission rate is the emission rate measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C. using USP Apparatus 2 (paddle) at 50 rpm.

[0332] In some embodiments, the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

[0333] In some embodiments, the compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) and pharma- ceutically acceptable salts, solvates, and hydrates thereof is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

[0334] In some embodiments, the composition exhibits peaks in a PXRD spectrum having the following 2θ values: 19.7°, 20.2°, 20.7°, 22.6°, 23.1°, and 23.7°.

[0335] In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, having the structure:

[0336] [ka] and a compound selected from pharma- ceutical acceptable salts, solvates, and hydrates thereof in an amount equal to a therapeutically effective amount of Compound 1, the composition having a release rate per weight of the compound in an aqueous medium that is one or more of the following release rates (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; This release rate is measured in 400-600 mL of aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M, at a temperature of 37°C ± 0.5°C and a pH of 6.3-7.3, in a USP Apparatus 1 (basket) at 80-120 rpm. The pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid.

[0337] In some embodiments of the pharmaceutical compositions disclosed herein, the first excipient comprises poloxamer 188.

[0338] In some embodiments of the pharmaceutical compositions disclosed herein, the second excipient comprises glycerol monostearate and has a monoester content of at least about 50%. In some embodiments, the second excipient comprises glycerol monostearate and has a monoester content of at least about 60%, such as at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, etc.

[0339] In some embodiments of the pharmaceutical compositions disclosed herein, the weight ratio of the first excipient to the second excipient is about 30:70.

[0340] In some embodiments of the pharmaceutical compositions disclosed herein, the first excipient comprises poloxamer 188 and the second excipient comprises glycerol monostearate and has a monoester content of at least about 90%, wherein the weight ratio of the first excipient to the second excipient is about 30:70.

[0341] In some embodiments of the pharmaceutical compositions disclosed herein, the first excipient comprises poloxamer 188 and the second excipient comprises glycerol monostearate and has a monoester content of at least about 95%, wherein the weight ratio of the first excipient to the second excipient is about 30:70.

[0342] In some embodiments, the pharmaceutical composition is in a dosage form comprised of a size 4 gelatin capsule, such as a white opaque hard capsule. In some embodiments, the pharmaceutical composition is in a dosage form comprised of a size 2 gelatin capsule, such as a white opaque hard capsule. In some embodiments, the pharmaceutical composition is in a dosage form comprised of a size 4 HPMC capsule. In some embodiments, the pharmaceutical composition is in a dosage form comprised of a size 2 HPMC capsule.

[0343] In some embodiments of the pharmaceutical compositions disclosed herein, the compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

[0344] In some embodiments of the pharmaceutical compositions disclosed herein, the compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, is a pharma- ceutically acceptable salt of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

[0345] In some embodiments, the therapeutically effective amount of Compound 1 is suitable for once-daily administration to a subject, such as a patient.

[0346] In some embodiments, the therapeutically effective amount of Compound 1 is suitable for twice daily administration to a subject, such as a patient.

[0347] In some embodiments, the pharmaceutical composition contains a release modifier. In some embodiments, the release modifier is hydroxypropyl methylcellulose. For example, in some embodiments, the release modifier is hydroxypropyl methylcellulose K4M CR and / or hydroxypropyl methylcellulose K100 LVCR. In some embodiments, the release modifier is a resin. For example, in some embodiments, the release modifier is an ethylene oxide resin (such as Polyox® resin). In some embodiments, the release modifier is another excipient known in the pharmaceutical art for modifying the release of an active agent.

[0348] In some embodiments, the pharmaceutical composition includes a filler. For example, in some embodiments, the pharmaceutical composition includes microcrystalline cellulose. In some embodiments, the filler is another excipient known in the pharmaceutical art. In some embodiments, the pharmaceutical composition includes a lubricant. For example, in some embodiments, the pharmaceutical composition includes silicon dioxide. In some embodiments, the lubricant is another excipient known in the pharmaceutical art. In some embodiments, the pharmaceutical composition includes a lubricant. For example, in some embodiments, the pharmaceutical composition includes magnesium stearate. In some embodiments, the lubricant is another excipient known in the pharmaceutical art. In some embodiments, the pharmaceutical composition includes a film coating. For example, in some embodiments, the pharmaceutical composition includes Opadry®. In some embodiments, the film coating is another excipient known in the pharmaceutical art.

[0349] In some embodiments, the pharmaceutical composition is in the form of granules, spheroids, or pellets, for example in a capsule or other suitable dosage form. In some embodiments, the pharmaceutical composition is in the form of a capsule, such as a hard capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet.

[0350] In addition to the above ingredients, the pharmaceutical compositions may further contain appropriate amounts of other substances, such as stabilizers, excipients, lubricants, binders, granulation aids, colorants, flavorings, and glidants conventionally used in the pharmaceutical art.

[0351] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, a hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and a hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C., the composition comprising about 0.01% to about 1% Compound 1 by weight of the composition, such as about 0.02% to about 0.5%, about 0.03% to about 0.4%, about 0.05% to about 0.2%, about 0.03%, about 0.5%, about 0.1%, 0.2%, or 0.5% Compound 1 by weight of the composition.

[0352] In some embodiments, the pharmaceutical composition comprises about 0.03% by weight of Compound 1, about 5% to about 45% by weight of a hydroxypropyl methylcellulose (first excipient) having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 5% to about 45% by weight of a hydroxypropyl methylcellulose (second excipient) having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C. In some embodiments, the composition comprises about 0.03% by weight of Compound 1, about 10% to about 40% by weight of the first excipient, and about 10% to about 40% by weight of the second excipient. In some embodiments, the composition comprises about 0.03% by weight of Compound 1, about 12.5% ​​to about 37.5% by weight of a first excipient, and about 12.5% ​​to about 37.5% by weight of a second excipient. In some embodiments, the composition comprises about 0.03% by weight of Compound 1, about 25% by weight of a hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 25% by weight of a hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0353] In some embodiments, the pharmaceutical composition comprises about 0.05% by weight of Compound 1, about 5% to about 45% by weight of a hydroxypropyl methylcellulose (first excipient) having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 5% to about 45% by weight of a hydroxypropyl methylcellulose (second excipient) having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C. In some embodiments, the composition comprises about 0.05% by weight of Compound 1, about 10% to about 40% by weight of the first excipient, and about 10% to about 40% by weight of the second excipient. In some embodiments, the composition comprises about 0.05% by weight of Compound 1, about 12.5% ​​to about 37.5% by weight of a first excipient, and about 12.5% ​​to about 37.5% by weight of a second excipient. In some embodiments, the composition comprises about 0.05% by weight of Compound 1, about 25% by weight of a hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 25% by weight of a hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0354] In some embodiments, the pharmaceutical composition comprises about 0.1% by weight of Compound 1, about 5% to about 45% by weight of a hydroxypropyl methylcellulose (first excipient) having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 5% to about 45% by weight of a hydroxypropyl methylcellulose (second excipient) having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C. In some embodiments, the composition comprises about 0.1% by weight of Compound 1, about 10% to about 40% by weight of the first excipient, and about 10% to about 40% by weight of the second excipient. In some embodiments, the composition comprises about 0.1% by weight of Compound 1, about 12.5% ​​to about 37.5% by weight of a first excipient, and about 12.5% ​​to about 37.5% by weight of a second excipient. In some embodiments, the composition comprises about 0.1% by weight of Compound 1, about 25% by weight of a hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 25% by weight of a hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0355] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0356] In some embodiments, the pharmaceutical compositions herein comprise about 0.05 mg of Compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0357] In some embodiments, the pharmaceutical compositions herein comprise about 0.1 mg of Compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0358] In some embodiments, the pharmaceutical compositions herein comprise an amount of Compound 1 equivalent to about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, about 0.06 mg, or a mixture of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 350 mg, about 400 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 35 ...40 and about 5 mg to about 45 mg, such as about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg, of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

[0359] In some embodiments, the pharmaceutical compositions herein comprise about 0.01 mg to about 0.6 mg of Compound 1, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, about 0.06 mg, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20° C., and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20° C.

[0360] In some embodiments, the pharmaceutical compositions herein comprise from about 0.01 mg to about 0.6 mg, such as from about 0.02 to about 0.3 mg, from about 0.03 to about 0.2 mg, from about 0.04 to about 0.12 mg, from about 0.04 to about 0.1 mg, from about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 25 mg of Methocel™ K4M Premium CR, and about 25 mg of Methocel™ K100 Premium LVCR.

[0361] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and food grade glycerol monostearate, the compositions comprising about 0.0066% to about 0.666% of Compound 1 by weight of the composition.

[0362] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and food grade glycerol monostearate, the compositions comprising about 0.0066% to about 0.4% of Compound 1 by weight of the composition.

[0363] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and food grade glycerol monostearate, the compositions comprising about 0.0133% to about 0.2% of Compound 1 by weight of the composition.

[0364] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and food grade glycerol monostearate, the compositions comprising about 0.02% to about 0.133% of Compound 1 by weight of the composition.

[0365] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and food grade glycerol monostearate, the compositions comprising about 0.0266% to about 0.066% of Compound 1 by weight of the composition.

[0366] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and food grade glycerol monostearate, the compositions comprising about 0.0333% to about 0.066% of Compound 1 by weight of the composition.

[0367] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, Poloxamer 188, and food grade glycerol monostearate, the composition comprising about 0.04% of Compound 1 by weight of the composition.

[0368] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the compositions comprise about 0.0066% to about 0.666% of Compound 1 by weight of the composition.

[0369] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the compositions comprise about 0.0066% to about 0.4% of Compound 1 by weight of the composition.

[0370] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the compositions comprise about 0.0133% to about 0.2% of Compound 1 by weight of the composition.

[0371] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the compositions comprise about 0.02% to about 0.133% of Compound 1 by weight of the composition.

[0372] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the compositions comprise about 0.0266% to about 0.066% of Compound 1 by weight of the composition.

[0373] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the compositions comprise about 0.0333% to about 0.066% of Compound 1 by weight of the composition.

[0374] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 90%, wherein the composition comprises about 0.04% of Compound 1 by weight of the composition.

[0375] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the compositions comprise about 0.0066% to about 0.666% of Compound 1 by weight of the composition.

[0376] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the compositions comprise about 0.0066% to about 0.4% of Compound 1 by weight of the composition.

[0377] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the compositions comprise about 0.0133% to about 0.2% of Compound 1 by weight of the composition.

[0378] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the compositions comprise about 0.02% to about 0.133% of Compound 1 by weight of the composition.

[0379] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the compositions comprise about 0.0266% to about 0.066% of Compound 1 by weight of the composition.

[0380] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the compositions comprise about 0.0333% to about 0.066% of Compound 1 by weight of the composition.

[0381] In some embodiments, the pharmaceutical compositions herein comprise Compound 1, poloxamer 188, and glycerol monostearate having a monoester content of at least about 95%, wherein the composition comprises about 0.04% of Compound 1 by weight of the composition.

[0382] In some embodiments, the pharmaceutical compositions herein comprise an amount of Compound 1 equivalent to about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, about 0.06 mg, about 45 mg to about 135 mg, such as about 45 mg, about 60 mg, about 75 mg, about 90 mg, about 105 mg, about 120 mg, or about 135 mg of food grade GMS, and about 105 mg to about 15 mg, such as about 105 mg, about 90 mg, about 75 mg, about 60 mg, about 45 mg, about 30 mg, or about 15 mg of Poloxamer 188. In some embodiments, the compositions herein comprise about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.12 mg, about 0.2 mg, about 0.3 mg, about 0.5 mg, or about 0.6 mg of Compound 1; about 45 mg to about 135 mg, such as about 60 mg, about 75 mg, about 90 mg, about 105 mg, about 120 mg, or about 135 mg of food grade GMS; and about 105 mg to about 15 mg, such as about 105 mg, about 90 mg, about 75 mg, about 60 mg, about 45 mg, about 30 mg, or about 15 mg of Poloxamer 188.

[0383] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of food grade glycerol monostearate.

[0384] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 45 mg of Poloxamer 188, and about 105 mg of food grade glycerol monostearate.

[0385] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 105 mg of Poloxamer 188, and about 45 mg of food grade glycerol monostearate.

[0386] In some embodiments, the pharmaceutical compositions herein comprise from about 0.01 mg to about 0.6 mg, such as from about 0.02 to about 0.3 mg, from about 0.03 to about 0.2 mg, from about 0.04 to about 0.12 mg, from about 0.04 to about 0.1 mg, from about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 90%.

[0387] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 90%.

[0388] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 90%.

[0389] In some embodiments, the pharmaceutical compositions herein comprise from about 0.01 mg to about 0.6 mg, such as from about 0.02 to about 0.3 mg, from about 0.03 to about 0.2 mg, from about 0.04 to about 0.12 mg, from about 0.04 to about 0.1 mg, from about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 95%.

[0390] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 95%.

[0391] In some embodiments, the pharmaceutical compositions herein comprise about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 95%.

[0392] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 75 mg of Poloxamer 188, and about 75 mg of Myverol™ 18-04 K.

[0393] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 45 mg of Poloxamer 188, and about 105 mg of Myverol™ 18-04 K.

[0394] In some embodiments, the pharmaceutical compositions herein contain about 0.01 mg to about 0.6 mg, such as about 0.02 to about 0.3 mg, about 0.03 to about 0.2 mg, about 0.04 to about 0.12 mg, about 0.04 to about 0.1 mg, about 0.05 to about 0.08 mg, or about 0.06 mg, of Compound 1, about 105 mg of Poloxamer 188, and about 45 mg of Myverol™ 18-04 K.

[0395] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of food grade glycerol monostearate.

[0396] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of food grade glycerol monostearate.

[0397] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of food grade glycerol monostearate.

[0398] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 90%.

[0399] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 90%.

[0400] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 90%.

[0401] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 95%.

[0402] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 95%.

[0403] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 95%.

[0404] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 75 mg of Poloxamer 188, and about 75 mg of Myverol™ 18-04K.

[0405] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 45 mg of Poloxamer 188, and about 105 mg of Myverol™ 18-04K.

[0406] In some embodiments, the pharmaceutical compositions herein comprise about 0.03 mg of Compound 1, about 105 mg of Poloxamer 188, and about 45 mg of Myverol™ 18-04K.

[0407] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of food grade glycerol monostearate.

[0408] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of food grade glycerol monostearate.

[0409] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of food grade glycerol monostearate.

[0410] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 90%.

[0411] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 90%.

[0412] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 90%.

[0413] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 95%.

[0414] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 95%.

[0415] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 95%.

[0416] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 75 mg of Poloxamer 188, and about 75 mg of Myverol™ 18-04K.

[0417] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of Myverol™ 18-04K.

[0418] In some embodiments, the pharmaceutical compositions herein comprise about 0.5 mg of Compound 1, about 105 mg of Poloxamer 188, and about 45 mg of Myverol™ 18-04K.

[0419] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of food grade glycerol monostearate.

[0420] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of food grade glycerol monostearate.

[0421] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of food grade glycerol monostearate.

[0422] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 90%.

[0423] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 90%.

[0424] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 90%.

[0425] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 75 mg of poloxamer 188, and about 75 mg of glycerol monostearate having a monoester content of at least about 95%.

[0426] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 45 mg of poloxamer 188, and about 105 mg of glycerol monostearate having a monoester content of at least about 95%.

[0427] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 105 mg of poloxamer 188, and about 45 mg of glycerol monostearate having a monoester content of at least about 95%.

[0428] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 75 mg of Poloxamer 188, and about 75 mg of Myverol™ 18-04K.

[0429] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 45 mg of Poloxamer 188, and about 105 mg of Myverol™ 18-04K.

[0430] In some embodiments, the pharmaceutical compositions herein comprise about 0.12 mg of Compound 1, about 105 mg of Poloxamer 188, and about 45 mg of Myverol™ 18-04K.

[0431] In any of the embodiments in which the composition comprises a glycerol monostearate having a monoester content of at least about 95%, the glycerol monostearate may have a monoester content of at least about 96%, such as at least about 97%, at least about 98%, at least about 99%, etc.

[0432] In some embodiments, provided herein is a pharmaceutical composition having a dissipation rate per weight of a compound in an aqueous medium that is one or more of dissipation rates (a), (b), and / or (c) disclosed herein, the composition comprising a first excipient and a second excipient, wherein said first excipient comprises hydroxypropyl methylcellulose having a viscosity of about 2300 mPA sec to about 3800 mPA sec when present in an amount of about 2% in water at 20° C., and said second excipient comprises hydroxypropyl methylcellulose having a viscosity of about 75 mPA sec to about 120 mPA sec when present in an amount of about 2% in water at 20° C., the weight ratio of first excipient to second excipient is about 50:50, and said dissipation rate is the dissipation rate measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at a temperature of 37° C.±0.5° C. at a pH of about 6.8, and wherein said aqueous medium comprises sodium phosphate at a concentration of 0.05 M.

[0433] In some embodiments, provided herein is a pharmaceutical composition having a dissipation rate per weight of a compound in an aqueous medium that is one or more of dissipation rates (a), (b), and / or (c) disclosed herein, the composition comprising a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA sec to about 3800 mPA sec when present in an amount of about 2% in water at 20° C., and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA sec to about 3800 mPA sec when present in an amount of about 2% in water at 20° C. hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water, a first excipient is present in an amount equal to about 25% by weight, and a second excipient is present in an amount equal to about 25% by weight, said diffusion rate being measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of an aqueous medium having a pH of about 6.8 at a temperature of 37° C.±0.5° C., and said aqueous medium comprising sodium phosphate at a concentration of 0.05 M.

[0434] In some embodiments, provided herein is a pharmaceutical composition having a dissolution rate per weight of a compound in an aqueous medium that is one or more of dissolution rates (a), (b), and / or (c) disclosed herein, the composition comprising a first excipient and a second excipient, the first excipient comprising poloxamer 188, the second excipient comprising glycerol monostearate and having a monoester content of at least about 95%, the weight ratio of the first excipient to the second excipient being about 30:70, the dissolution rate being measured in a USP apparatus 2 (paddle) at 50 rpm in 500 mL of an aqueous medium having a pH of about 6.8 at a temperature of 37° C.±0.5° C. In some embodiments, the aqueous medium is an aqueous medium comprising sodium phosphate at a concentration of 0.05 M.

[0435] In some embodiments, the present invention relates to a process for the preparation of a pharmaceutical composition comprising Compound 1. The process in one embodiment includes mixing a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, with a first excipient disclosed herein, a second excipient disclosed herein, and optionally additional pharma- ceutically acceptable excipients to form a pharmaceutical composition.

[0436] In some embodiments, the pharmaceutical compositions herein are in the form of a capsule. In some embodiments, the pharmaceutical compositions herein are in the form of a tablet.

[0437] In some embodiments of the pharmaceutical compositions and / or processes disclosed herein, a mixture comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, a first excipient disclosed herein, and a second excipient disclosed herein may be formed in any order. For example, in some embodiments, forming a mixture of the compound and the two excipients may include mixing the two excipients to form an initial mixture. Mixing the two excipients may include melting the two excipients together. The initial mixture may be subsequently mixed with the compound to form a mixture of the compound and the two excipients.

[0438] In some embodiments, provided herein is a pharmaceutical composition prepared by a process comprising curing a mixture comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, a first excipient, and a second excipient, to form the composition, wherein the first excipient comprises a copolymer comprising (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the second excipient comprises an ester of a polyalcohol and a fatty acid.

[0439] In some embodiments, provided herein is a process for preparing a pharmaceutical composition, the process comprising: and (c) a copolymer comprising a polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and a copolymer comprising a first excipient and a second excipient, the first excipient comprising a copolymer comprising: (a) a first polyoxyethylene chain; (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain; and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain; and the second excipient comprising an ester of a polyalcohol and a fatty acid, to form a composition.

[0440] In some embodiments of the pharmaceutical compositions and / or processes disclosed herein, the step of curing the mixture is carried out at a temperature of about 40°C to about 70°C, such as about 45°C to about 70°C, about 45°C to about 65°C, about 45°C to about 60°C, about 45°C to about 55°C, about 50°C to about 55°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, or about 55°C. The temperature at which the mixture is cured is also referred to as the curing temperature. The time for curing the mixture at the curing temperature is also referred to as the curing time. In some embodiments, the mixture is cured for about 10 hours to about 1 week. In some embodiments, the mixture is cured for about 10 hours to about 48 hours, such as about 12 hours to about 36 hours, about 16 hours to about 24 hours, about 18 hours, etc. In some embodiments, the mixture is cured at a temperature of about 40° C. to about 70° C., such as about 50° C. to about 60° C., such as about 50° C. to about 55° C., for about 10 hours to about 48 hours, such as about 12 hours to about 36 hours, about 16 hours to about 24 hours, about 18 hours, etc. In some embodiments, the mixture is cured at a temperature of about 50° C. for about 18 hours. In some embodiments, the mixture is cured at a temperature of about 55° C. for about 36 hours.

[0441] In some embodiments, the mixture is cured at a temperature of 50°C to 60°C, such as about 50°C or about 55°C, for about 10 hours to about 48 hours, such as about 12 hours to about 36 hours, about 16 hours to about 24 hours, about 18 hours, etc. In some embodiments, the mixture is cured at a temperature of about 50°C for about 18 hours. In some embodiments, the mixture is cured at a temperature of about 55°C for about 36 hours. In some embodiments of the pharmaceutical composition disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C to about 70°C. In some embodiments of the pharmaceutical composition disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C to about 65°C. In some embodiments of the pharmaceutical composition disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C to about 70°C. In some embodiments of the pharmaceutical compositions disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C to about 70°C. In some embodiments of the pharmaceutical compositions disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C to about 70°C. In some embodiments of the pharmaceutical compositions disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C to about 70°C. In some embodiments of the pharmaceutical compositions disclosed herein, at least one of the first excipient and the second excipient has a melting point of about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, about 55°C, about 56°C, about 57°C, about 58°C, about 59°C, or about 60°C. In some embodiments, each of the first excipient and the second excipient independently has a melting point that is about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, or about 55°C.

[0442] In some embodiments of the pharmaceutical composition disclosed herein, the composition is a hardened composition. In some embodiments, the hardened composition is a composition in which a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) and its pharma- ceutically acceptable salts, solvates, and hydrates, a first excipient, and a second excipient are hardened together at a hardening temperature disclosed herein. In some embodiments, the hardened composition is prepared by a process comprising hardening a mixture disclosed herein.

[0443] In some embodiments, the curing of the mixture results in a change in the powder X-ray diffraction (PXRD) spectrum. In some embodiments, the pharmaceutical composition comprises a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and its pharma- ceutically acceptable salts, solvates, and hydrates, poloxamer 188, and glycerol monostearate, and the composition exhibits peaks in the PXRD spectrum with the following 2θ values: 19.7°, 20.2°, 20.7°, 21.6°, 22.6°, 23.1°, and 23.7°. In some embodiments, the composition exhibits peaks in the PXRD spectrum with the following 2θ values: 19.7°, 20.2°, 20.7°, 22.6°, 23.1°, and 23.7°. Each of the PXRD peak values ​​reported above may vary by ±0.2 2θ. In some embodiments of compositions having peaks in a PXRD spectrum disclosed herein, the composition comprises a glycerol monostearate having a monoester content of at least about 90%, such as at least about 95%. In some embodiments of compositions having peaks in a PXRD spectrum disclosed herein, the composition comprises poloxamer 188 and a glycerol monostearate having a monoester content of at least about 90%, such as at least about 95%, in a weight ratio of poloxamer 188:glycerol monostearate of about 70:30 to 10:90, such as 60:40 to about 20:80, about 50:50 to about 30:70, about 50:50, about 40:60, about 30:70.

[0444] In some embodiments, the first excipient is a copolymer comprising (a) a first polyoxyethylene chain, (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain, and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the first excipient consists essentially of the copolymer.

[0445] In some embodiments, the first excipient comprises poloxamer 188, or the first excipient consists essentially of poloxamer 188.

[0446] In some embodiments, the first excipient comprises a copolymer as defined herein, and the first excipient is a copolymer.

[0447] In some embodiments, the first excipient comprises poloxamer 188, or the first excipient is poloxamer 188.

[0448] In some embodiments, the second excipient comprises glycerol monostearate, the second excipient consists essentially of glycerol monostearate, e.g., in some embodiments where the second excipient comprises glycerol monostearate and has a monoester content of at least about 50%, the second excipient consists essentially of glycerol monostearate and has a monoester content of at least about 50%. For example, in some embodiments where the second excipient comprises glycerol monostearate and has a monoester content of at least about 60%, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, etc., the second excipient consists essentially of glycerol monostearate and has a monoester content of at least about 60%, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, etc.

[0449] In some embodiments, the second excipient comprises glycerol monostearate, the second excipient is glycerol monostearate. For example, in some embodiments, where the second excipient comprises glycerol monostearate and has a monoester content of at least about 50%, the second excipient is glycerol monostearate having a monoester content of at least about 50%. For example, in some embodiments where the second excipient comprises glycerol monostearate and has a monoester content of at least about 60%, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, etc., the second excipient is a glycerol monostearate with a monoester content of at least about 60%, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, etc.

[0450] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, a first excipient, and a second excipient, wherein the first excipient comprises a copolymer comprising (a) a first polyoxyethylene chain, (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain, and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the second excipient comprises an ester of a polyalcohol and a fatty acid to form the composition.

[0451] In some embodiments, the present invention relates to a storage-stable pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, as disclosed herein. As used herein, "storage-stable" means that the dissipation rate of the compound is substantially the same after storage of the composition at 40°C and 75% RH. In some embodiments of the storage-stable composition, the dissipation rate of the compound is substantially the same after storage at 40°C and 75% RH for at least about one month. In some embodiments of the storage-stable composition, the dissipation rate of the compound is substantially the same after storage at 40°C and 75% RH for at least about six months. In some embodiments of the storage-stable composition, the dissipation rate of the compound is substantially the same after storage at 25°C and 60% RH for at least about two years.

[0452] In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point, where the release rates before and after storage are each measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound release rate before storage at any given dissolution time point for 2 hours or more, the release rates after storage and before storage are each measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 10% of the compound release rate before storage at any dissolution time point for 2 hours or more, the release rates after storage and before storage are each measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound emission rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point, where the emission rates before and after storage are each measured in a USP Apparatus 2 (paddle) at 50 rpm in 500 mL of an aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., where the aqueous medium contains sodium phosphate at a concentration of 0.05 M.In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, the release rates after storage and before storage are each measured with USP Apparatus 2 (paddle) at 50 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 1 month does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, the release rates after storage and before storage are each measured with USP Apparatus 2 (paddle) at 50 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M.

[0453] In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point, where the release rates before and after storage are each measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, the release rates after storage and before storage are each measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, the release rates after storage and before storage are each measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound emission rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point, where the emission rates before and after storage are each measured in a USP Apparatus 2 (paddle) at 50 rpm in 500 mL of an aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., where the aqueous medium contains sodium phosphate at a concentration of 0.05 M.In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, the release rates after storage and before storage are each measured with USP Apparatus 2 (paddle) at 50 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound release rate after storage of the composition at 40° C. and 75% RH for at least about 6 months does not vary by more than about 20% of the compound release rate before storage at a given dissolution time point of 2 hours or more, the release rates after storage and before storage are each measured with USP Apparatus 2 (paddle) at 50 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M.

[0454] In some embodiments, the compound emission rate after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point. In some embodiments, the compound emission rate after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point, where the emission rates before and after storage are each measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound emission rate after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point of 2 hours or more, the emission rates after storage and before storage are each measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound emission rate after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point of 2 hours or more, the emission rates after storage and before storage are each measured by USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the emission rate of the compound after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the emission rate of the compound before storage at a given dissolution time point, where the emission rates before and after storage are each measured in a USP Apparatus 2 (paddle) at 50 rpm in 500 mL of an aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., where the aqueous medium contains sodium phosphate at a concentration of 0.05 M.In some embodiments, the compound emission rate after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point of 2 hours or more, the emission rates after storage and before storage are each measured with USP Apparatus 2 (paddle) at 50 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M. In some embodiments, the compound emission rate after storage of the composition at 25° C. and 60 RH for at least about 2 years does not vary by more than about 20% of the compound emission rate before storage at a given dissolution time point of 2 hours or more, the emission rates after storage and before storage are each measured with USP Apparatus 2 (paddle) at 50 rpm in 500 mL of aqueous medium at pH 6.8 at a temperature of 37° C.±0.5° C., the aqueous medium containing sodium phosphate at a concentration of 0.05 M.

[0455] In some embodiments, the dissipation rates disclosed herein are dissipation rates determined by HPLC.

[0456] In some embodiments, provided herein is a composition that is any of the tablet formulations disclosed herein, such as the tablet formulations disclosed in Table 4.

[0457] In some embodiments, provided herein are esters of Compound 1. In some embodiments, provided herein are 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, ethanol ester. In some embodiments, provided herein are 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, ethylene glycol ester. In some embodiments, provided herein are 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, glycerol ester. In some embodiments, provided herein are 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, polyethylene glycol ester. In some embodiments, provided herein is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, propylene glycol ester.

[0458] An example of a manufacturing process suitable for the pharmaceutical compositions disclosed herein is shown in FIG.

[0459] The compound or composition provided herein can be formulated into pharmaceutical composition using techniques well known to those skilled in the art.Other suitable pharmaceutically acceptable carriers than those mentioned herein are known in the art.See, for example, Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0460] Certain compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic acid form. Methods for preparing optically active forms from optically active starting materials are known in the art and include, for example, by resolution of racemic mixtures or stereoselective synthesis.

[0461] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. One method includes fractional crystallization (e.g., diastereomeric salt resolution) using a "chiral resolving acid" that is an optically active, salt-forming organic acid. Suitable resolving agents for fractional crystallization are, for example, optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms (e.g., S and R forms, or diastereomerically pure forms) of β-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0462] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Appropriate elution solvent compositions can be determined by one skilled in the art.

[0463] The compounds described herein may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0464] The compounds described herein may also include tautomers, such as keto-enol tautomers, which may be in equilibrium or sterically locked into a certain form by appropriate substitution.

[0465] It is appreciated that certain features disclosed herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0466] Instructions and procedures The compositions disclosed herein are useful for treating diseases and disorders related to the regulation of PGI2 receptor activity and for improving their symptoms. Accordingly, some embodiments of the present invention relate to a method for regulating the activity of PGI2 receptor by contacting the PGI2 receptor with a composition according to any of the embodiments described herein.

[0467] In some embodiments, provided herein is a method of stimulating the PGI2 receptor by contacting the PGI2 receptor with a composition according to any of the embodiments described herein.

[0468] In some embodiments, provided herein is a method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0469] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in a method of treating a human or animal via therapy.

[0470] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in a method of modulating PGI2 receptor activity.

[0471] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in a method of stimulating the PGI2 receptor.

[0472] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating a PGI2 receptor-mediated disorder.

[0473] The compositions disclosed herein are useful for treating and ameliorating symptoms of other diseases and disorders associated with modulation of PGI2 receptor activity, including, but not limited to, the following:

[0474] 1. Pulmonary Arterial Hypertension (PAH) Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, remodeling of the pulmonary vascular wall, and thrombosis contribute to the increased pulmonary vascular resistance in PAH (Humbert et al, J. Am. Coll. Cardiol, 2004, 43:13S-24S).

[0475] The pharmaceutical composition of the present invention disclosed herein is useful for treating pulmonary hypertension (PAH) and its symptoms. PAH is understood to include the following forms of pulmonary hypertension as described in the World Health Organization (WHO) 2003 clinical classification of pulmonary hypertension: idiopathic PAH (IPAH); familial PAH (FPAH); other disease-associated PAH (APAH), such as collagen vascular disease-associated PAH, congenital left-to-right shunt-associated PAH, portal hypertension-associated PAH, HIV infection-associated PAH, drug- or toxin-associated PAH, or other-associated PAH; and significant venous or capillary complications-associated PAH.

[0476] Idiopathic PAH refers to PAH with an unknown cause.

[0477] Familial PAH refers to PAH with suspected or proven genetic transmission.

[0478] Collagen vascular disease-associated PAH is understood to include scleroderma-associated PAH, CREST syndrome (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia)-associated PAH, systemic lupus erythematosus (SLE)-associated PAH, rheumatoid arthritis-associated PAH, Takayasu's arteritis-associated PAH, polymyositis-associated PAH, and dermatomyositis-associated PAH.

[0479] Congenital left-to-right shunt-associated PAH is understood to include atrial septal defect (ASD)-associated PAH, ventricular septal defect (VSD)-associated PAH, and patent ductus arteriosus-associated PAH.

[0480] Drug- or toxin-associated PAHs are understood to include PAHs associated with the ingestion of aminorex, PAHs associated with the ingestion of fenfluramine compounds (e.g., PAHs associated with the ingestion of fenfluramine or PAHs associated with the ingestion of dexfenfluramine), PAHs associated with the ingestion of certain toxic oils (e.g., PAHs associated with the ingestion of rapeseed oil), PAHs associated with the ingestion of pyrrolizidine alkaloids (e.g., PAHs associated with the ingestion of bush tea), and PAHs associated with the ingestion of monocrotaline.

[0481] Other associated PAH is understood to include thyroid disorder-associated PAH, glycogen storage disease-associated PAH, Gaucher disease-associated PAH, hereditary hemorrhagic telangiectasia-associated PAH, hemochromatosis-associated PAH, myeloproliferative disorder-associated PAH, and splenectomy-associated PAH.

[0482] PAH associated with significant venous or capillary complications is understood to include pulmonary veno-occlusive disease (PVOD)-associated PAH, and pulmonary capillary hemangiomatosis (PCH)-associated PAH.

[0483] (See, for example, Simonneau et al, J. Am. Coll. Cardiol, 2004, 43:5S-12S; McGoon et al, Chest, 2004, 126:14S-34S; Rabinovitch, Annu. Rev. Pathol. Mech. Dis, 2007, 2:369-399; McLaughlin et al, Circulation, 2006, 114:1417-1431; Strauss et al, Clin. Chest. Med, 2007, 28:127-142; Taichman et al, Clin. Chest. Med, 2007, 28:1-22).

[0484] Evidence supporting the association of scleroderma with PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Badesch et al. (Badesch et al, Ann. Intern. Med, 2000, 132:425-434). Evidence supporting the association of collagen vascular disease mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjogren's syndrome, and CREST syndrome with PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Humbert et al. (Eur. Respir. J, 1999, 13:1351-1356). Evidence supporting the association of CREST syndrome with PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Miwa et al. (Int. Heart J, 2007, 48:417-422). Evidence supporting the association between SLE and PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Robbins et al. (Chest, 2000, 117:14-18). Evidence supporting the association between HIV infection and PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Aguilar et al. (Am. J. Respir. Crit. Care Med, 2000, 162:1846-1850). Evidence supporting the association between congenital heart disease (including ASD, VSD, and patent ductus arteriosus) and PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Rosenzweig et al. (Circulation, 1999, 99:1858-1865). Evidence supporting the association of fenfluramine, dexfenfluramine, anorectic agents, and PAH is provided by Archer et al. (Am. J. Respir. Crit. Care Med, 1998, 158:1061-1067). Evidence supporting the association of hereditary hemorrhagic telangiectasia with PAH is provided by McGoon et al. (Chest, 2004, 126:14-34).Evidence supporting the association between splenectomy and PAH is provided by Hoeper et al. (Ann. Intern. Med, 1999, 130:506-509). Evidence supporting the association between portal hypertension and PAH and the beneficial effect of PGI2 receptor agonists on PAH is provided by Hoeper et al. (Eur. Respir. J, 2005, 25:502-508).

[0485] Symptoms of PAH include dyspnea, angina, loss of consciousness, and edema (McLaughlin et al, Circulation, 2006, 114:1417-1431). The pharmaceutical compositions of the invention disclosed herein are useful for treating the symptoms of PAH.

[0486] In some embodiments, provided herein is a method for treating pulmonary hypertension (PAH) in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0487] In some embodiments, provided herein is a method for treating idiopathic PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0488] In some embodiments, provided herein is a method for treating familial PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0489] In some embodiments, provided herein is a method for treating collagen vascular disease-associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0490] In some embodiments, provided herein is a method for treating PAH associated with a collagen vascular disease selected from scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0491] In some embodiments, a method is provided for treating congenital heart disease associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0492] In some embodiments, provided herein is a method for treating PAH associated with a congenital heart disease selected from an atrial septal defect (ASD), a ventricular septal defect (VSD), and a patent ductus arteriosus in an individual, the method comprising administering to an individual in need thereof a composition according to any of the embodiments described herein.

[0493] In some embodiments, provided herein is a method for treating portal hypertension-associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0494] In some embodiments, provided herein is a method for treating PAH associated with HIV infection in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0495] In some embodiments, provided herein is a method for treating PAH associated with ingestion of a drug or toxin in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0496] In some embodiments, provided herein is a method for treating hereditary hemorrhagic telangiectasia associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0497] In some embodiments, provided herein is a method for treating splenectomy-associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0498] In some embodiments, provided herein is a method for treating PAH associated with venous or capillary complications in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0499] In some embodiments, provided herein is a method for treating pulmonary veno-occlusive disease (PVOD) associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0500] In some embodiments, provided herein is a method for treating pulmonary capillary hemangiomatosis (PCH)-associated PAH in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0501] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH.

[0502] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating idiopathic PAH.

[0503] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating familial PAH.

[0504] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating collagen vascular disease-associated PAH.

[0505] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in the treatment of PAH associated with a collagen vascular disease selected from scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis.

[0506] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating congenital heart disease associated PAH.

[0507] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH associated with congenital heart disease selected from atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus.

[0508] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating portal hypertension-associated PAH.

[0509] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH associated with HIV infection.

[0510] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH associated with ingestion of a drug or toxin.

[0511] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating hereditary hemorrhagic telangiectasia associated PAH.

[0512] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH associated with splenectomy.

[0513] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH associated with significant venous or capillary complications.

[0514] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating PAH associated with pulmonary veno-occlusive disease (PVOD).

[0515] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating pulmonary capillary hemangiomatosis (PCH)-associated PAH.

[0516] 2. Antiplatelet therapy (diseases related to platelet aggregation) Antiplatelet agents (antiplatelets) are prescribed for a variety of conditions, such as coronary artery disease, where they are used to help prevent myocardial infarction or stroke in patients at risk of developing obstructive blood clots (e.g., coronary artery thrombosis).

[0517] In a myocardial infarction ("MI" or "heart attack"), the heart muscle does not receive enough oxygen-rich blood as a result of a blockage in the coronary blood vessels. When taken during or shortly after (preferably within 30 minutes) an attack, antiplatelets may reduce damage to the heart.

[0518] A transient ischemic attack ("TIA" or "mini stroke") is a brief interruption in the flow of oxygen to the brain due to reduced blood flow through an artery, usually due to a blockage by a blood clot. Antiplatelet drugs have been shown to be effective in preventing TIAs.

[0519] Angina is a brief, often recurrent chest pain, pressure, or discomfort caused by inadequate flow of oxygen-rich blood to part of the heart (ischemia). In patients with angina, antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.

[0520] A stroke is an event in which the brain does not receive enough oxygen-rich blood, usually due to blockage of a blood vessel in the brain by a blood clot. In high-risk patients, regular intake of antiplatelets has been shown to prevent the formation of blood clots that cause a first or second stroke.

[0521] Angioplasty is a catheter-based technique used to open arteries blocked by blood clots. Depending on whether stenting is performed immediately after this procedure to keep the artery open, antiplatelets can reduce the risk of forming additional blood clots after the procedure.

[0522] Coronary artery bypass surgery is a surgical procedure in which an artery or vein is taken from anywhere in the body and grafted onto a blocked coronary artery, rerouting blood around the blockage through the newly attached blood vessel. After surgery, antiplatelets can reduce the risk of a second blood clot.

[0523] Atrial fibrillation is the most common type of persistent irregular heart rhythm (arrhythmia). Atrial fibrillation affects approximately 2 million Americans annually. In atrial fibrillation, the atria (the upper chambers of the heart) rapidly fire electrical signals that cause it to vibrate instead of contracting normally. As a result, the heart beats abnormally fast and highly irregular. When given after a symptom of atrial fibrillation, antiplatelets can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism).

[0524] There is evidence that PGI2 receptor agonists are potential antiplatelet therapies because they inhibit platelet aggregation (see, e.g., Moncada et al, Lancet, 1977, 1:18-20). Genetic deficiency of the PGI2 receptor in mice has been shown to increase the propensity for thrombosis (Murata et al, Nature, 1997, 388:678-682).

[0525] PGI2 receptor agonists can be used, for example, to treat claudication or peripheral vascular disease, as well as cardiovascular complications, arterial thrombosis, atherosclerosis, serotonin-induced vasoconstriction, ischemia-reperfusion injury, and arterial restenosis after angioplasty or stent placement. (For example, Fetalvero et al,Prostaglandins Other Lipid Mediat,2007,82:109-118;Arehart et al,Curr.Med.Chem,2007,14:2161-2169;Davi et al,N.Engl.J.Med,2007,357:2482-2494;Fetalvero et al. al,Am.J.Physiol.Heart.Circ.Physiol,2006,290:H1337-H1346;Murata et al,Nature,1997,388:678-682;Wang et al,Proc.Natl.Acad.Sci.USA,2006,103:14507-14512;Xiao et al al,Circulation,2001,104:2210-2215;McCormick et al,Biochem.Soc.Trans,2007,35:910-911;Arehart et al,Circ.Res,2008,Mar 6 Epub ahead of print).

[0526] PGI2 receptor agonists can also be used alone or in combination with thrombolytic therapy, such as human tissue plasminogen activator (t-PA), to provide cardioprotection following myocardial dysfunction after MI or ischemia, including the resulting complications, or protection from ischemic trauma during percutaneous coronary intervention.PGI2 receptor agonists can also be used in antiplatelet therapy, such as in combination with α-tocopherol (vitamin E), echistatin (disintegrin), or heparin in hypercoagulant conditions (see, for example, Chan, J.Nutr, 1998, 128:1593-1596; Mardla et al, Platelets, 2004, 15:319-324; Bernabei et al, Ann.Thorac.Surg, 1995, 59:149-153; Gainza et al, J.Nephrol, 2006, 19:648-655).

[0527] The PGI2 receptor agonist disclosed herein provides beneficial improvements in microcirculation to patients who need antiplatelet therapy, for example, but not limited to, by antagonizing the vasoconstrictive product of aggregating platelets.Thus, in some embodiments, the present invention provides a method for reducing platelet aggregation in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (compound 1) as disclosed herein, and its pharmaceutical acceptable salts, solvates, and hydrates. In a further embodiment, the present invention provides a method of treating coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, or any of the foregoing conditions, in a patient in need of such treatment, comprising administering to the patient a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), as disclosed herein, and pharma- ceutical acceptable salts, solvates, and hydrates thereof.

[0528] In a further embodiment, the present invention provides a method for reducing the risk of thrombus formation in a patient who has undergone angioplasty or coronary artery bypass surgery or who suffers from atrial fibrillation, the method comprising the step of administering to the patient when such risk is present a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutical acceptable salts, solvates, and hydrates thereof, as disclosed herein.

[0529] In some embodiments, provided herein is a method for the treatment of platelet aggregation in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0530] In some embodiments, provided herein is a method for the treatment of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, or atrial fibrillation in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0531] In some embodiments, provided herein is a method for reducing the risk of thrombus formation in an individual who has undergone angioplasty or coronary artery bypass surgery, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0532] In some embodiments, provided herein is a method for reducing the risk of thrombus formation in an individual suffering from atrial fibrillation, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0533] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating platelet aggregation.

[0534] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, or atrial fibrillation.

[0535] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in a method for treating clot formation in an individual who has undergone angioplasty or coronary artery bypass surgery.

[0536] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in a method for treating clot formation in an individual with atrial fibrillation.

[0537] 3. Atherosclerosis Atherosclerosis is a complex disease characterized by inflammation, lipid accumulation, cell death, and fibrosis. Atherosclerosis is the leading cause of death in many countries, including the United States. Atherosclerosis, as the term is used herein, is understood to include damage to large or medium-sized arteries, which results in the progressive accumulation of smooth muscle cells in the intima and lipids.

[0538] It has been shown that agonists of the PGI2 receptor may provide prevention of atherosclerosis, such as atherothrombosis (Arehart et al, Curr. Med. Chem, 2007, 14:2161-2169; Stitham et al, Prostaglandins Other Lipid Mediat, 2007, 82:95-108; Fries et al, Hematology Am. Soc. Hematol. Educ. Program, 2005, :445-451; Egan et al, Science, 2004, 306:1954-1957; Kobayashi et al, J. Clin. Invest, 2004, 114:784-794; Arehart et al, Circ. Res, 2008, Mar 6 Epub ahead of print).

[0539] It has been shown that defective PGI2 receptor signaling occurs to accelerate atherothrombosis in humans, and that agonists of the PGI2 receptor may provide prevention of atherothrombosis in humans (Arehart et al, Circ. Res, 2008, Mar 6 Epub ahead of print).

[0540] The pharmaceutical compositions of the present invention disclosed herein are useful for treating atherosclerosis and treating the symptoms thereof. Thus, in some embodiments, the present invention provides a method for treating atherosclerosis in a patient in need of treatment, comprising administering to the patient a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) as disclosed herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof. In a further embodiment, a method for treating atherosclerosis in a patient in need of treatment is provided, comprising administering to the patient a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) as disclosed herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof.

[0541] In some embodiments, provided herein is a method for the treatment of atherosclerosis in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0542] In some embodiments, provided herein is a method for the treatment of atherothrombosis in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0543] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating atherosclerosis.

[0544] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating atherothrombosis.

[0545] 4. Asthma Asthma is a lymphocyte-mediated inflammatory airway disorder characterized by airway eosinophilia, increased mucus production by goblet cells, and remodeling of airway wall architecture. The prevalence of asthma has increased dramatically worldwide in recent decades. In mice, genetic deletion of the PGI2 receptor has been shown to increase allergic airway inflammation (Takahashi et al, Br J Pharmacol, 2002, 137:315-322). Agonists of the PGI2 receptor have been shown to be able to suppress not only the progression of asthma when given during the sensitization phase, but also cardinal features of experimental asthma when given during the challenge phase (Idzko et al, J. Clin. Invest, 2007, 117:464-472; Nagao et al, Am. J. Respir. Cell, 2003, 3:865-878), at least in part by significantly interfering with the function of antigen-presenting dendritic cells in the airways (Idzko et al, J. Clin. Invest, 2007, 117:464-472; Zhou et al, J. Immunol, 2007, 178:702-710; Jaffar et al, J. Immunol, 2007, 179:6193-6203; Jozefowski et al, Int. Immunopharmacol, 2003, 3:865-878). Mol. Biol, 2003, 29:314-320). These cells are important for both the early and maintenance phases of allergic asthma, because the deterioration of airway dendritic cells during the second challenge in sensitized mice eliminates all characteristic features of asthma, an effect that can be completely restored by adoptive transfer of wild-type dendritic cells (van Rijt et al, J. Exp. Med, 2005, 201:981-991). It has further been shown that agonists of the PGI2 receptor can inhibit inflammatory cytokine secretion by human alveolar macrophages (Raychaudhuri et al, J. Biol. Chem, 2002, 277:33344-33348). The pharmaceutical compositions of the present invention disclosed herein are useful for treating asthma, and treating its symptoms.Thus, in some embodiments, the present invention provides a method for treating asthma in a patient in need of treatment, the method comprising administering to the patient a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), as disclosed herein, and pharma- ceutically acceptable salts, solvates, and hydrates thereof. In a further embodiment, a method for treating asthma symptoms in a patient in need of treatment is provided, the method comprising administering to the patient a pharmaceutical composition comprising a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), as disclosed herein, and pharma-ceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, a method is provided herein for the treatment of asthma in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0546] In some embodiments, provided herein is a method for treating asthma symptoms in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0547] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating asthma.

[0548] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating a symptom of asthma.

[0549] 5. Diabetes-related conditions Although hyperglycemia is a major factor in the pathogenesis of diabetic complications such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR), increased vasoconstriction and platelet aggregation in diabetic patients also contribute to disease progression (Cameron et al, Naunyn Schmiedebergs Arch.Pharmacol,2003,367:607-614). Agonists of the PGI2 receptor promote vasodilation and inhibit platelet aggregation. Improvement of capillary blood flow can benefit diabetic complications (Cameron,Diabetologia,2001,44:1973-1988).

[0550] It has been shown that PGI2 receptor agonists can prevent and reverse motor and sensory peripheral nerve conduction abnormalities in streptozotocin-diabetic rats (Cotter et al, Naunyn Schmiedebergs Arch. Pharmacol, 1993, 347:534-540). Further evidence demonstrating the beneficial effects of PGI2 receptor agonists in the treatment of diabetic peripheral neuropathy is provided by Hotta et al. (Diabetes, 1996, 45:361-366), Ueno et al. (Jpn. J. Pharmacol, 1996, 70:177-182), Ueno et al. (Life Sci, 1996, 59:PL105-PL110), Hotta et al. (Prostaglandins, 1995, 49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okuda et al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB J, 2003, 17:779-781). Evidence supporting the beneficial effect of PGI2 receptor agonists in the treatment of diabetic nephropathy is provided by Owada et al. (Nephron, 2002, 92: 788-796) and Yamashita et al. (Diabetes Res. Clin. Pract, 2002, 57: 149-161). Evidence supporting the beneficial effect of PGI2 receptor agonists in the treatment of diabetic retinopathy is provided by Yamagishi et al. (Mol. Med, 2002, 8: 546-550), Burnette et al. (Exp. Eye Res, 2006, 83: 1359-1365), and Hotta et al. (Diabetes, 1996, 45: 361-366).It has been shown that PGI2 receptor agonists can reduce increased tumor necrosis factor-α (TNF-α) levels in diabetic patients, suggesting that PGI2 receptor agonists may contribute to preventing the progression of diabetic complications (Fujiwara et al, Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394).

[0551] In some embodiments, provided herein is a method for treating a diabetes-related disorder in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0552] In some embodiments, provided herein is a method for treating diabetic peripheral neuropathy in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0553] In some embodiments, provided herein is a method for the treatment of diabetic nephropathy in an individual, the method comprising administering to an individual in need thereof a composition according to any of the embodiments described herein.

[0554] In some embodiments, provided herein is a method for the treatment of diabetic retinopathy in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0555] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating a diabetic-related disorder.

[0556] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating diabetic peripheral neuropathy.

[0557] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating diabetic nephropathy.

[0558] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating diabetic retinopathy.

[0559] 6. Glaucoma Evidence that topical administration of PGI2 receptor agonists results in a reduction in intraocular pressure (IOP) in rabbits and dogs, with consequent beneficial effects in the treatment of glaucoma, has been provided by Hoyng et al. (Hoyng et al, Invest. Ophthalmol. Vis. Sci, 1987, 28:470-476).

[0560] In some embodiments, provided herein is a method for the treatment of glaucoma or other ocular diseases associated with abnormal intraocular pressure in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0561] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating glaucoma or other ocular diseases associated with abnormal intraocular pressure.

[0562] 7. Hypertension Agonists of PGI2 receptors have been shown to have activity for regulating vascular tone, vasodilation, and improving pulmonary hypertension (see, for example, Strauss et al, Clin Chest Med, 2007, 28:127-142; Driscoll et al, Expert Opin. Pharmacother, 2008, 9:65-81). Evidence that demonstrates the beneficial effect of agonists of PGI2 receptors on the treatment of hypertension is provided by Yamada et al. (Peptides, 2008, 29:412-418). Evidence that agonists of PGI2 receptors can prevent cerebral ischemia is provided by Dogan et al. (Gen. Pharmacol, 1996, 27:1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab, 2006, 26:491-501).

[0563] In some embodiments, provided herein is a method for treating hypertension in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0564] In some embodiments, provided herein is a method for the treatment of hypertension with the intent of preventing cerebral ischemia in an individual, the method comprising administering to the individual a composition according to any of the embodiments described herein.

[0565] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in treating hypertension.

[0566] In some embodiments, provided herein is a composition according to any of the embodiments described herein for use in the treatment of hypertension for the prevention of cerebral ischemia.

[0567] 8. Anti-inflammatory treatment Anti-inflammatory drugs are prescribed for a variety of illnesses. For example, in inflammatory diseases, anti-inflammatory drugs are used to reduce it by interfering with the underlying cause. There is evidence that PGI2 receptor agonists inhibit inflammation and are therefore a potential treatment for anti-inflammatory therapy. It has been shown that agonists of the PGI2 receptor can inhibit the production of proinflammatory cytokines and chemokines (interleukin 12 (IL-12), tumor necrosis factor-α (TNF-α), IL-1α, IL-6, macrophage inflammatory protein-1α (MIP-1α), and monocyte chemotactic protein-1 (MCP-1)) and the T cell stimulatory function of dendritic cells (Jozefowski et al, Int. Immunopharmacol, 2003, 865-878; Zhou et al, J. Immunol, 2007, 178:702-710; Nagao et al, Am. J. Respir. Cell Mol. Biol, 2003, 29:314-320; Idzko et al, J. Clin. Invest, 2007, 117:464-472). Agonists of the PGI2 receptor have been shown to be able to inhibit proinflammatory cytokine (TNF-α, IL-1β, IL-6, granulocyte-macrophage stimulating factor (GM-CSF)) production by macrophages (Raychaudhuri et al, J. Biol. Chem, 2002, 277:33344-33348; Czeslick et al, Eur. J. Clin. Invest, 2003, 33:1013-1017; Di Renzo et al, Prostaglandin Leukot. Essent. Fatty Acids, 2005, 73:405-410; Shinomiya et al, Biochem. Pharmacol, 2001, 61:1153-1160). Agonists of the PGI2 receptor have been shown to be able to stimulate anti-inflammatory cytokine (IL-10) production by dendritic cells (Jozefowski et al, Int. Immunopharmacol, 2003, 865-878; Zhou et al, J. Immunol, 2007, 178:702-710).It has been shown that agonists of the PGI2 receptor can stimulate anti-inflammatory cytokine (IL-10) production by macrophages (Shinomiya et al, Biochem. Pharmacol, 2001, 61:1153-1160). It has been shown that agonists of the PGI2 receptor can inhibit chemokine (CCL17)-induced chemotaxis of leukocytes (CD4+Th2 T cells) (Jaffar et al, J. Immunol, 2007, 179:6193-6203). Agonists of the PGI2 receptor have been shown to be able to prevent atherosclerosis, including atherothrombosis (Arehart et al, Curr. Med. Chem, 2007, 14:2161-2169; Stitham et al, Prostaglandins Other Lipid Mediat, 2007, 82:95-108; Fries et al, Hematology Am. Soc. Hematol. Educ. Program, 2005, :445-451; Egan et al, Science, 2004, 306:1954-1957; Kobayashi et al, J. Clin. Invest, 2004, 114:784-794; Arehart et al, Circ. Res, 2008, Mar 6 Epub ahead of print). It has been shown that PGI2 receptor agonists can relieve asthma (Idzko et al, J. Clin. Invest, 2007, 117:464-472; Jaffar et al, J. Immunol, 2007, 179:6193-6203; Nagao et al, Am. J. Respir. Cell. Mol. Biol, 2003, 29:314-320). It has been shown that PGI2 receptor agonists can reduce the production of TNF-α in type 2 diabetes patients (Fujiwara et al, Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394; Goya et al, Metabolism, 2003, 52:192-198). It has been shown that agonists of the PGI2 receptor can inhibit ischemia-reperfusion injury (Xiao et al, Circulation, 2001, 104:2210-2215).Agonists of the PGI2 receptor have been shown to inhibit restenosis (Cheng et al, Science, 2002, 296:539-541). Agonists of the PGI2 receptor have been shown to attenuate pulmonary vascular injury and shock in a rat model of septic shock (Harada et al, Shock, 2008, Feb 21 Epub ahead of print). Agonists of the PGI2 receptor have been shown to reduce blood levels of TNF-α in vivo in patients with rheumatoid arthritis, which has been shown to be associated with improvements in the clinical course of the disease (Gao et al, Rheumatol. Int, 2002, 22:45-51; Boehme et al, Rheumatol. Int, 2006, 26:340-347).

[0568] The pharmaceutical compositions of the invention disclosed herein provide a beneficial reduction in inflammation. The pharmaceutical compositions of the invention disclosed herein provide a beneficial reduction in harmful inflammatory responses associated with inflammatory diseases. Thus, in some embodiments, the invention provides a method for reducing inflammation in a patient in need thereof, comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the invention provides a method for reducing the production of IL-12, TNF-α, IL-1α, IL-1β, IL-6, MIP-1α, or MCP-1 in a patient in need thereof, comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the invention provides a method for reducing the production of TNF-α in a patient in need thereof, comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the invention provides a method for increasing the production of IL-10 in a patient in need thereof, comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the invention provides a method for reducing harmful inflammatory responses associated with inflammatory diseases in a patient in need thereof, comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the present invention provides a method for treating an inflammatory disease or a symptom thereof in a patient in need of treatment, the method comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the present invention provides a method for treating an inflammatory disease or a symptom thereof in a patient in need of treatment, the method comprising administering to the patient a pharmaceutical composition disclosed herein. In some embodiments, the present invention provides a method for treating an inflammatory disease or a symptom thereof in a patient in need of treatment, the method comprising administering to the patient a pharmaceutical composition disclosed herein, the inflammatory disease being selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, diabetes (including type 1 and type 2 diabetes), sepsis, chronic obstructive pulmonary disease (COPD), and asthma.

[0569] In some embodiments, provided herein is a method for treating inflammation in an individual, the method comprising administering to the individual a composition according to any of the emb...

Claims

1. A method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising administering to the individual a dosage of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, sufficient to achieve a plasma concentration of Compound 1 of at least about 2.5 ng / mL in the individual.

2. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering to the individual a dose of Compound 1 sufficient to achieve a plasma concentration of Compound 1 of at least about 2.5 ng / mL in the individual.

3. A method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising administering to the individual a dosage of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, sufficient to achieve a plasma concentration of Compound 1 of at least about 5 ng / mL in the individual.

4. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising administering to the individual a dose of Compound 1 sufficient to achieve a plasma concentration of Compound 1 of at least about 5 ng / mL in the individual.

5. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering a dose of Compound 1 to the individual and determining the plasma level of Compound 1 in the individual; and increasing the dosage of Compound 1 if the individual does not have at least the threshold plasma level.

6. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering a dose of Compound 1 to said individual; determining the plasma level of Compound 1 in the individual; and discontinuing administration of Compound 1 to the individual if the individual does not have at least the threshold plasma level.

7. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering a dose of Compound 1 to said individual; determining the plasma level of Compound 1 in the individual; continuing to administer Compound 1 to the individual if the individual has at least the threshold plasma level; or and discontinuing administration of Compound 1 to the individual if the individual does not have at least the threshold plasma level.

8. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering to said individual a maximum tolerated dose of Compound 1; determining the plasma level of Compound 1 in the individual; and discontinuing administration of Compound 1 to the individual if the individual does not have at least the threshold plasma level at the maximum tolerated dose.

9. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering to said individual a maximum tolerated dose of Compound 1; determining the plasma level of Compound 1 in the individual; continuing administration of Compound 1 to the individual if the individual has at least the threshold plasma level at the maximum tolerated dose; or and discontinuing administration of Compound 1 to the individual if the individual does not have at least the threshold plasma level at the maximum tolerated dose.

10. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering a dose of Compound 1 to said individual; determining the plasma level of Compound 1 in the individual; and increasing the dosage of Compound 1 to the individual until a threshold plasma level is reached.

11. 1. A method for selecting a dosage of Compound 1 for an individual with pulmonary arterial hypertension (PAH), the method comprising: determining the plasma level of Compound 1 in the individual; and increasing the dosage of Compound 1 to the individual until a threshold plasma level is reached.

12. 1. A method for selecting a dosage of Compound 1 for an individual with pulmonary arterial hypertension (PAH), the method comprising: determining the plasma level of Compound 1 in the individual; and maintaining the dosage of Compound 1 to the individual when the threshold plasma level is reached.

13. 1. A method for selecting a dosage of Compound 1 for an individual with pulmonary arterial hypertension (PAH), the method comprising: determining the plasma level of Compound 1 in the individual; and decreasing the dosage of Compound 1 to the individual if the threshold plasma level is exceeded.

14. or wherein the plasma concentration of compound 1 is at least about 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5.0, 5.1, 5.2, 5.25, 5.3, 5.4, 5.5, 5.6, 5.7, 5.75, 5.8, 5.9, 6.0, 6.1, 6.2, 6.25, 6.3, 6.4, 6.5, 14. The method of any one of claims 1 to 13, wherein the concentration of the antibody is 6.6, 6.7, 6.75, 6.8, 6.9, 7.0, 7.1, 7.2, 7.25, 7.3, 7.4, 7.5, 7.6, 7.7, 7.75, 7.8, 7.9, 8.0, 8.1, 8.2, 8.25, 8.3, 8.4, 8.5, 8.6, 8.7, 8.75, 8.8, 8.9, 9.0, 9.1, 9.2, 9.25, 9.3, 9.4, 9.5, 9.6, 9.7, 9.75, 9.8, 9.9, or 10 ng / mL.

15. 15. The method of any one of claims 1 to 14, wherein the plasma concentration of Compound 1 is about 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, or 5.0 ng / mL.

16. 2.6, 2.7, 2.75, 2.8, 2.9, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.1, 4.2, 4.25, 4.3, 16. The method of any one of claims 1 to 15, wherein the concentration is selected from 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5, 5.1, 5.2, 5.25, 5.3, 5.4, 5.5, 5.6, 5.7, 5.75, 5.8, 5.9, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, and 10 ng / ml.

17. The therapeutically effective amount of Compound 1 is about 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg 17. The method of any one of claims 1 to 16, wherein the effective dose of the compound is 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, and 1.5 mg.

18. 18. The method of any one of claims 1 to 17, wherein the therapeutically effective amount of Compound 1 is a starting dosage amount selected from about 0.01, 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.075, 0.08, 0.09, and 0.1 mg per day.

19. 19. The method of any one of claims 1 to 18, wherein the therapeutically effective amount of Compound 1 is a maximum tolerated dose selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, and 1.5 mg per day.

20. 20. The method of any one of claims 1 to 19, wherein the therapeutically effective amount of Compound 1 is a maximum dosage selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, and 1.5 mg per day.

21. 21. The method of any one of claims 1 to 20, wherein the therapeutically effective amount of Compound 1 is a maximum tolerated dose selected from about 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, and 1.5 mg per day.

22. The therapeutically effective amount of Compound 1 is about 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.065 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.16 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 22. The method of any one of claims 1 to 21, wherein the maintenance dose is selected from 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, and 1.5 mg.

23. 23. The method of any one of claims 1 to 22, wherein the threshold plasma level is a peak plasma level.

24. 24. The method of any one of claims 1 to 23, wherein the threshold plasma level is a trough plasma level.

25. 25. The method of any one of claims 1 to 24, wherein the threshold plasma levels are a peak plasma level and a trough plasma level.

26. The threshold plasma level is about, at least, or at least about 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5.0, 5.1, 5.2, 5.25, 5.3, 5.4, 5.5, 5.6, 5.7, 5.75, 5.8, 5.9, 6.0, 6.1, 6.2, 6.25, 6.3, 6. 4, 6.5, 6.6, 6.7, 6.75, 6.8, 6.9, 7.0, 7.1, 7.2, 7.25, 7.3, 7.4, 7.5, 7.6, 7.7, 7.75, 7.8, 7.9, 8.0, 8.1, 8.2, 8.25, 8.3, 8.4, 8.5, 8.6, 8.7, 8.75, 8.8, 8.9, 9.0, 9.1, 9.2, 9.25, 9.3, 9.4, 9.5, 9.6, 9.7, 9.75, 9.8, 9.9, or 10 ng / mL peak plasma levels, and About, at least, or at least about 2.0, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5.0, 5.1, 5.2, 5.25, 5.3, 5.4, 5.5, 5.6, 5.7, 5.75, 5.8, 5.9, 6.0, 6.1, 6.2, 6.

26. The method of any one of claims 1 to 25, wherein the trough plasma level is 25, 6.3, 6.4, 6.5, 6.6, 6.7, 6.75, 6.8, 6.9, 7.0, 7.1, 7.2, 7.25, 7.3, 7.4, 7.5, 7.6, 7.7, 7.75, 7.8, 7.9, 8.0, 8.1, 8.2, 8.25, 8.3, 8.4, 8.5, 8.6, 8.7, 8.75, 8.8, 8.9, 9.0, 9.1, 9.2, 9.25, 9.3, 9.4, 9.5, 9.6, 9.7, 9.75, 9.8, 9.9, or 10 ng / mL.

27. The threshold plasma level is a peak plasma level of about, or at least about, 2.5 ng / mL; and 27. The method of any one of claims 1 to 26, wherein the trough plasma level is about, or at least about, 2.5 ng / mL.

28. The threshold plasma level is a peak plasma level of about, or at least about, 5 ng / mL; and 28. The method of any one of claims 1 to 27, wherein the trough plasma level is about, or at least about, 2.5 ng / mL.

29. The threshold plasma level is Peak plasma levels of about 5 ng / mL, and 29. The method of any one of claims 1 to 28, wherein the trough plasma level is about 2.5 ng / mL.

30. Compound 1 is in a pharmaceutical composition having a compound release rate weight in an aqueous medium of one or more of (a), (b), and (c), wherein: (a) about 15% to about 35% by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 24% to about 59% by weight of the compound is released over the first 4 hours in an aqueous medium; and / or (c) about 43% to about 96% by weight of the compound is released over the first 8 hours in an aqueous medium; 30. The method according to any one of claims 1 to 29, wherein the diffusion rate is measured in 400-600 mL of an aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M, at a temperature of 37°C ± 0.5°C and at a pH of 6.3-7.3 in a USP Apparatus 1 (basket) at 80-120 rpm.

31. Compound 1 is in a pharmaceutical composition having a compound release rate weight in an aqueous medium of one or more of (a), (b), and (c), wherein: (a) about 40% or less by weight of the compound is released over the first 2 hours in an aqueous medium; (b) about 40% to about 60% by weight of the compound is released over the first 5 hours in an aqueous medium; and / or (c) about 80% or less by weight of the compound is released over the first 14 hours in an aqueous medium; 31. The method according to any one of claims 1 to 30, wherein the diffusion rate is measured in 400-600 mL of an aqueous medium containing sodium phosphate at a concentration of 0.04-0.06 M, at a temperature of 37°C ± 0.5°C and at a pH of 6.3-7.3 in a USP Apparatus 1 (basket) at 80-120 rpm.

32. 32. The method of any one of claims 1 to 31, wherein the pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and the second excipient comprising hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

33. 33. The method of any one of claims 1 to 32, wherein the pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising a release modifier having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and the second excipient comprising a release modifier having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

34. The pharmaceutical composition comprises: (a); (b); (c); (a) and (b); (a) and (c); (b) and (c); (a), (b), and (c) 34. The method of any one of claims 1 to 33, having a diffusion rate selected from:

35. 35. The method of any one of claims 1 to 34, wherein the first excipient is present in an amount equal to about 5% to about 45% by weight and the second excipient is present in an amount equal to about 5% to about 45% by weight.

36. 36. The method of any one of claims 1 to 35, wherein the first excipient is present in an amount equal to about 5% to about 45% by weight and the second excipient is present in an amount equal to about 5% to about 45% by weight.

37. 37. The method of any one of claims 1 to 36, wherein the first excipient is present in an amount equal to about 10% to about 40% by weight and the second excipient is present in an amount equal to about 10% to about 40% by weight.

38. 38. The method of any one of claims 1 to 37, wherein the first excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight and the second excipient is present in an amount equal to about 12.5% ​​to about 37.5% by weight.

39. 39. The method of any one of claims 1 to 38, wherein the first excipient is present in an amount equal to about 25% by weight and the second excipient is present in an amount equal to about 25% by weight.

40. 40. The method of any one of claims 1 to 39, wherein the diffusion rate is measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37°C ± 0.5°C, at 100 rpm in USP Apparatus 1 (basket).

41. 41. The method of any one of claims 1 to 40, wherein the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

42. 42. The method of any one of claims 1 to 41, wherein the emission rate is measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37°C ± 0.5°C, at 50 rpm with USP Apparatus 2 (paddle).

43. 43. The method of any one of claims 1 to 42, wherein the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

44. 44. The method of any one of claims 1 to 43, wherein the pharmaceutical composition is a tablet comprising a core and a coating.

45. 45. The method of any one of claims 1 to 44, wherein the core comprises hydroxypropyl methylcellulose.

46. 46. ​​The method of any one of claims 1 to 45, wherein the coating does not include hydroxypropyl methylcellulose.

47. The therapeutically effective amount of Compound 1 is From about 0.01% to about 1%, by weight of the composition; From about 0.01% to about 0.6% by weight of the composition; From about 0.02% to about 0.3% by weight of the composition; From about 0.03% to about 0.2% by weight of the composition; From about 0.04% to about 0.12% by weight of the composition; From about 0.04% to about 0.1% by weight of the composition; From about 0.04% to about 0.1% by weight of the composition; From about 0.05% to about 0.08% by weight of the composition; About 0.06% by weight of the composition; About 0.01 mg to about 1 mg 47. The method of any one of claims 1 to 46, wherein the method is selected from the group consisting of

48. 48. The method of any one of claims 1 to 47, wherein the therapeutically effective amount of Compound 1 is suitable for once-daily administration to an individual.

49. The method of any one of claims 1 to 48, wherein the pharmaceutical composition comprises about 0.05% by weight of compound 1, about 25% by weight of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25% by weight of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

50. 50. The method of any one of claims 1 to 49, wherein the pharmaceutical composition comprises about 0.05 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

51. 51. The method of any one of claims 1 to 50, wherein the pharmaceutical composition comprises about 0.01 mg to 0.8 mg of compound 1, about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 5 mg to about 45 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

52. 52. The method of any one of claims 1 to 51, wherein the pharmaceutical composition comprises about 0.01 mg to 0.8 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, and about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C.

53. 53. The method of any one of claims 1 to 52, wherein the pharmaceutical composition comprises about 0.01 mg to 0.8 mg of compound 1, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 2300 mPA seconds to about 3800 mPA seconds when present in an amount of about 2% in water at 20°C, about 25 mg of hydroxypropyl methylcellulose having a viscosity of about 75 mPA seconds to about 120 mPA seconds when present in an amount of about 2% in water at 20°C, about 25 mg of Methocel™ K4M Premium CR, and about 25 mg of Methocel™ K100 Premium LVCR.

54. 54. The method of any one of claims 1 to 53, wherein the pharmaceutical composition is storage stable.

55. 55. The method of any one of claims 1 to 54, wherein the pharmaceutical composition is a tablet.

56. 56. The method of any one of claims 1 to 55, wherein the tablet contains 0.05 mg, 0.25 mg, or 0.4 mg of compound 1.

57. 57. The method of any one of claims 1 to 56, wherein the pharmaceutical composition is a capsule.

58. 58. The method of any one of claims 1 to 57, wherein the emission rate of Compound 1 after storage of the pharmaceutical composition at 40°C and 75% RH for at least about 1 month does not vary by more than about 20% of the emission rate of the compound before storage at a given dissolution time point of 2 hours or more, wherein the emission rates after storage and before storage are each measured in USP Apparatus 1 (basket) at 100 rpm in 500 mL of aqueous medium at 37°C ± 0.5°C and pH 6.8, wherein the aqueous medium comprises sodium phosphate at a concentration of 0.05 M.

59. 59. The method of any one of claims 1 to 58, wherein the pharmaceutical composition comprises a first excipient and a second excipient, the first excipient comprising a copolymer comprising (a) a first polyoxyethylene chain, (b) a poly(propylene oxide) chain conjugated to the first polyoxyethylene chain, and (c) a second polyoxyethylene chain conjugated to the poly(propylene oxide) chain, and the second excipient comprises an ester of a polyalcohol and a fatty acid.

60. 60. The method of any one of claims 1 to 59, wherein one of the excipients is poloxamer 188.

61. 61. The method of any one of claims 1 to 60, wherein the second excipient comprises glycerol monostearate and has a monoester content of at least about 90%.

62. 62. The method of any one of claims 1 to 61, wherein the second excipient comprises glycerol monostearate and has a monoester content of at least about 95%.

63. 63. The method of any one of claims 1 to 62, wherein the pharmaceutical composition is a setting composition.

64. The weight ratio of the first excipient to the second excipient is About 70:30 to about 10:90, About 50:50 to about 30:70, About 70:30, about 50:50, Approximately 40:60, and Approximately 30:70 64. The method of any one of claims 1 to 63, selected from:

65. 65. The method of any one of claims 1 to 64, wherein the emission rate is the emission rate measured in 500 mL of aqueous medium at pH 6.8 at a temperature of 37°C ± 0.5°C, at 50 rpm with USP Apparatus 2 (paddle).

66. 66. The method of any one of claims 1 to 65, wherein the aqueous medium comprises sodium phosphate at a concentration of 0.05M.

67. 67. The method of any one of claims 1 to 66, wherein the compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharma- ceutically acceptable salts, solvates, and hydrates thereof, is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

68. 68. The method of any one of claims 1 to 67, wherein the compound is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1).

69. 69. The method of any one of claims 1 to 68, wherein the pharmaceutical composition exhibits peaks in a PXRD spectrum having the following 2θ values: 19.7°, 20.2°, 20.7°, 22.6°, 23.1°, and 23.7°.

70. 1. A method for treating a PGI2 receptor-mediated disorder in an individual, the method comprising: administering to the individual a starting dose of Compound 1, the starting dose being equivalent to 0.05 mg of Compound 1 per day for about one week; administering an increased dose equivalent to 0.05 mg more than the starting dose for about one week if the individual tolerates the starting dose, and further increasing the dose if the individual tolerates the increased dose.

71. 71. The method of any one of claims 1 to 70, further comprising administering increased doses for about one week, followed by repeating the cycle of increasing doses, as long as the patient tolerates further increased doses, until the optimal dose is administered.

72. 1. A method for treating pulmonary arterial hypertension (PAH) in an individual, the method comprising: administering to the individual a starting dose of Compound 1, the starting dose being equivalent to 0.05 mg of Compound 1 per day for about one week; administering an increased dose equivalent to 0.05 mg more than the starting dose for about one week if the individual tolerates the starting dose, and further increasing the dose if the individual tolerates the increased dose.

73. 73. The method of any one of claims 1 to 72, further comprising administering increased doses for about one week, followed by repeating the cycle of increasing doses, as long as the patient tolerates further increased doses, until the optimal dose is administered.

74. 74. The method of any one of claims 1 to 73, wherein compound 1 is titrated for at least about 9 weeks.

75. 74. The method of any one of claims 1 to 73, wherein compound 1 is titrated for at least about 16 weeks.

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