Glucocorticoid receptor modulator formulations

Abstract

The present invention provides formulations of (R)-(1-(4-fluorophenyl)-6-((4-trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, and methods for making and using same.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 378,578, filed October 6, 2022, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which exhibits both circadian rhythmic changes and elevations in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid that acts by binding to the intracellular glucocorticoid receptor (GR). The mineralocorticoid receptor (MR), also known as type I glucocorticoid receptor (GR I), binds cortisol and can be activated by aldosterone in humans. Compositions containing modulators of either or both GR and MR can be used to treat various diseases and disorders. In humans, GR can exist in two forms: the 777-amino acid ligand-binding GR-alpha and the GR-beta isoform, which lacks the 50 carboxy-terminal residues. Because these residues comprise the ligand-binding domain, GR-beta is unable to bind natural ligands and is constitutively localized in the nucleus.

[0003] The biological effects of cortisol, including those caused by hypercortisolism, can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of drugs can inhibit the physiological effects of GR-agonist binding. These antagonists include compounds that bind to GR, thereby inhibiting the ability of agonists to effectively bind to and / or activate GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, with a dissociation constant (Kd) of 10 -9 M (Cadepond (1997) Annu. Rev. Med. 48:129).

[0004] In addition to cortisol, the biological effects of other steroids can be modulated at the GR level using receptor modulators, such as agonists, partial agonists, and antagonists. When administered to a subject in need thereof, steroids may not only provide the intended therapeutic effect, but may also have negative side effects.

[0005] Amyotrophic lateral sclerosis (ALS) is a rare and devastating disease with no adequate treatment options. It is characterized by progressive degeneration of motor neurons in both the brain and spinal cord, resulting in progressive muscle weakness, devastating disability, and death, typically within 3–5 years of symptom onset. Only a small percentage of patients survive beyond 10 years. Fifty percent of patients die within 30 months of symptom onset, and approximately 20% survive 5–10 years after onset. (Riva N, Agosta F, Lunetts C, Filippi M, Quattrini A. 2016. Recent advances in amyotrophic lateral sclerosis. J. Neurol. 263:1241–1254) Respiratory failure is the most common cause of death in patients with ALS (Riva et al. 2016, Turner MR, Hardman O, Benatar M, Brooks BR, Chio A, de Carvalho M, et al. 2013. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 12:310-322). Familial ALS accounts for 10% of cases, and sporadic ALS accounts for the remaining 90% of cases (Van Damme P, Robberecht W, Van Den Bosch L. 2017. Modeling amyotrophic lateral sclerosis: progress and possibilities. Dis. Model. Mech. 10:537-549).

[0006] The compounds of U.S. Patent No. 8,859,774 have shown utility for treating this condition. New forms of these compositions are needed. Surprisingly, the present invention meets these and other needs. Summary of the Invention

[0007] In one embodiment, the present invention provides Compound I, (R)-(1-(4-fluorophenyl)-6-((4-trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, in an amount of 1 to 25% (w / w); [ka] A composition is provided that includes a co-solvent in an amount of 1-25% (w / w) and a surfactant in an amount of 50-90% (w / w).

[0008] In another embodiment, the present invention provides a unit dosage form for oral administration consisting essentially of a capsule containing a composition of the present invention.

[0009] In another embodiment, the present invention provides a method for treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention, thereby treating the disorder or condition.

[0010] In another embodiment, the present invention provides a method for treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention, thereby treating the disorder or condition.

[0011] In another embodiment, the present invention provides a method of treating amyotrophic lateral sclerosis (ALS), comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating ALS.

[0012] In another embodiment, the present invention provides a method of treating Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating Alzheimer's disease.

[0013] In another embodiment, the present invention provides a method of treating Huntington's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating Huntington's disease. DETAILED DESCRIPTION OF THE INVENTION

[0014] I. Overview Disclosed herein are formulations of Compound I, (R)-(1-(4-fluorophenyl)-6-((4-trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, including co-solvents and surfactants. [ka]

[0015] II. Definition "About" refers to ±5% of the specified value unless otherwise indicated.

[0016] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0017] "Co-solvent" refers to an ingredient in a composition that improves the solubility and miscibility of other ingredients in the composition.

[0018] "Surfactant" refers to any agent that alters the surface properties between two liquids or between a liquid and a solid. Surfactants useful in the present invention include, but are not limited to, nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants, ampholytic surfactants, or salts thereof. The hydrophilic / lipophilic balance (HLB) of a surfactant describes the surfactant's affinity for water or oil (1 to 20, with 1 being lipophilic and 20 being hydrophilic). The HLB of a mixture of two surfactants is equal to the weight fraction of surfactant A times its HLB value plus the weight fraction of surfactant B times its HLB value (weighted average). Anionic surfactants useful in the present invention include, but are not limited to, soaps containing sodium, potassium, and ammonium salts of aliphatic carboxylic acids, typically alkali soaps of fatty acids such as sodium stearate. Additional anionic surfactants include organic amine soaps, such as organic amine salts of aliphatic carboxylic acids, typically fatty acids such as triethanolamine stearate. Cationic surfactants useful in the present invention include, but are not limited to, amine salts such as octadecylammonium chloride and quaternary ammonium compounds such as benzalkonium chloride.Nonionic surfactants useful in the present invention include, but are not limited to, polyoxyethylene castor oil derivatives, polysorbates, sorbitan esters, polyoxyethylene alkyl ethers, poloxamers, and vitamin E derivatives.Those skilled in the art will understand that other surfactants are useful in the present invention.

[0019] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and its absorption by the subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, oils, fatty acid esters, cosolvents, surfactants, cosurfactants, and antioxidants. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0020] "Treate," "treating," and "treatment" refer to any indication of successful treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter, for example, remission; remission; reducing symptoms or making the patient more tolerant of the injury, pathology, or condition; slowing the rate of degeneration or decline; reducing the debilitating end point of degeneration; or improving the patient's physical or mental health. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0021] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, intrathecal administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject.

[0022] "Patient" or "subject" refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, bovines, deer, horses, and other non-mammalian animals. In some embodiments, the patient is a human.

[0023] A "therapeutically effective amount" refers to that amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Fridrun and Jones, Pharmaceutical Capsules, (2004); Lieberman, Pharmaceutical Dosage Forms (Disperse Systems vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 2000). th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0024] "Glucocorticoid receptor" ("GR") refers to one of a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also called the cortisol receptor. This term includes GR, recombinant GR, and mutant GR isoforms.

[0025] The cortisol receptor is a glucocorticoid receptor (GR), particularly type II GR, that specifically binds cortisol and / or cortisol analogues such as dexamethasone (see, for example, Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0026] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (GR I), which is activated by aldosterone in humans.

[0027] "Glucocorticoid receptor modulator" (GRM) refers to any compound that modulates any biological response associated with the binding of a glucocorticoid receptor to an agonist. As used herein, with respect to GRM, the glucocorticoid receptor may be GR, or both. For example, GRMs acting as agonists, such as dexamethasone, increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human liver hepatocellular carcinoma cell line; ECACC, UK). GRMs acting as antagonists, such as mifepristone, inhibit the agonist-induced increase in tyrosine aminotransferase (TAT) activity in HepG2 cells. TAT activity can be measured as outlined in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0028] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits any biological response associated with the binding of a glucocorticoid receptor to an agonist. As used herein, with respect to GRA, the glucocorticoid receptor may be GR, or both. Thus, GR antagonists can be identified by measuring a compound's ability to inhibit the effects of dexamethasone. TAT activity can be measured as outlined in the article by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Inhibitors have an IC of less than 10 micromolar. 50 (half maximal inhibitory concentration).

[0029] "Modulate" and "modulating" are used according to their plain and ordinary meaning and refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, when used in reference to the effect of a modulator on a target protein, modulating means altering by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

[0030] "Modulator" refers to a composition that increases or decreases the level of a target molecule, or the function of a target molecule, or the physical state of the molecule's target.

[0031] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist at a receptor molecule or inhibiting the signal produced by the receptor-agonist. A receptor antagonist inhibits or suppresses an agonist-mediated response, such as gene expression.

[0032] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. An antagonist can inhibit expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or less compared to a control in the absence of the antagonist. In some embodiments, inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more over expression or activity in the absence of the antagonist.

[0033] "Inhibit," "inhibit," and "inhibitor" refer to a compound that inhibits a particular action or function or a method of inhibiting the same.

[0034] "Disorder" or "condition" refers to a state or condition of a patient or subject that can be treated with a glucocorticoid receptor modulator of the present invention.

[0035] "Amyotrophic lateral sclerosis," "ALS," and "Lou Gehrig's disease" refer to a group of neurodegenerative disorders characterized by the loss of motor neurons in the anterior horns of the spinal cord and the cortical neurons that provide their afferent input. ALS can initially affect either upper or lower motor neurons, but over time, regardless of the primary lesion area, the disease has a symmetric, generalized nature (Mitsumoto, H. et al., Amyotrophic Lateral Sclerosis, In Contemporary Neurology Series 49, Philadelphia, FA Davis Company (1998)). Both sporadic and familial forms of ALS occur, with familial ALS, usually autosomal dominant, accounting for approximately 10% of ALS cases (Dion PA et al., Nat. Rev. Genet. 10:769-782 (2009)). Symptoms of ALS typically appear earlier in familial cases, but the clinical course of the familial and sporadic forms is similar. Several types of genetic mutations have been identified as the cause of familial ALS, and approximately 20% of familial cases are caused by inherited mutations in Cu / Zn superoxide dismutase (SOD1), a protein that protects motor neurons from free radical damage (Rosen DR et al., Nature, 362:59-62 (1993)).

[0036] Unlike some forms of familial ALS, the specific etiology of sporadic ALS remains elusive, with different hypotheses proposed, including glutamate-mediated excitability, mitochondrial dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation (Dib M, Drugs, 63:289-310 (2003); Strong MJ, Pharmacology & Therapeutics, 98:379-414 (2003); Bruijn LI et al., Annu. Rev. Neurosci, 27:723-749 (2004); Dibernardo AB et al., Biochimica et Biophysica Acta, 1762:1139-1149 (2006)).

[0037] When used in connection with a group of substituents or a "substituent group" herein, "a," "an," or "a(n)" means at least one. For example, when a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl, where each alkyl and / or aryl is optionally different. In another example, when a compound is substituted with "a" substituents, the compound is substituted with at least one substituent, where each substituent is optionally different.

[0038] III. Composition The present invention provides pharmaceutically acceptable compositions of (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (Compound I; see Example 1 of U.S. Pat. No. 8,859,774 ), which offer surprisingly improved solubility and stability of the compositions. Compound I is substantially insoluble in water and difficult to solubilize in most dosage forms that would be suitable for pharmaceutical use, and conventional methods have proven unsuccessful in providing pharmaceutically acceptable compositions of this compound. Even when small amounts of Compound I can be solubilized, compositions prepared by conventional methods have proven unstable when Compound I comes out of solution, undergoes rapid degradation, or is found to be incompatible with pharmaceutically acceptable capsules. Surprisingly, the compositions disclosed herein overcome previous problems of solubility and bioavailability and provide pharmaceutically acceptable compositions with enhanced solubility and bioavailability that are suitable for use in treating conditions and disorders amenable to treatment by administration of Compound I.

[0039] The compositions of the present invention are Type IV compositions according to the Lipid Formulation Classification System (LFCS). The LFCS identifies the characteristics of lipid systems (CW Outon, Eur. J. Pharm. Sci., 11(Suppl. 2) (2000), pp. S93-S98). As classified by the LFCS, Type I formulations are oils that require digestion, Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS), and Type III systems are SEDDSs or self-microemulsifying drug delivery systems (SMEDDS) or self-nanoemulsifying drug delivery systems (SNEDDS) that contain some water-soluble surfactants and / or cosolvents (Type IIIA) or a larger proportion of water-soluble components (Type IIIB). Type IV systems represent formulations that contain primarily hydrophilic surfactants and cosolvents that disperse and dissolve in aqueous media to provide a solution. Further description of the lipid formulation classification system can be found in FABAD J. Pharm. Sci., pages 55-64, 2013.

[0040] The present invention provides compositions of (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (Compound I; CORT113176; Dazcorilant; see Example 1 of U.S. Pat. No. 8,859,774). In some embodiments, the present invention provides compositions of Compound I having the following structure: [ka] and a pharmaceutically acceptable excipient.

[0041] In some embodiments, the present invention provides a method for treating a pulmonary arthritis with a 1-25% (w / w) amount of Compound I, (R)-(1-(4-fluorophenyl)-6-((4-trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone; [ka] A composition is provided that includes a co-solvent in an amount of 1-25% (w / w) and a surfactant in an amount of 50-90% (w / w).

[0042] Compound I Compound I can be present in the compositions of the present invention in any suitable relative amount. For example, Compound I can be present in the compositions of the present invention in an amount of 1-50% (w / w), or 1-25%, or 5-40%, or 10-30%, or 10-25%, or 13-22%, or 10-20%, or 15-20%, or 13-17%, or 14-16%, or 18-22%, or 18-20%, or 18-22%, or 19-21% (w / w). Representative amounts of Compound I in the compositions of the present invention include, but are not limited to, about 10% (w / w), or about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or about 25% (w / w). Other amounts of Compound I useful in the compositions of the present invention include about 18.0% (w / w), or about 18.1, 18.2, 18.25, 18.3, 18.4, 18.5, 18.6, 18.7, 18.75, 18.8, 18.9, or about 19.0% (w / w).

[0043] In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 1-25% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 10-25% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 15-20% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 13-22% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 15-20% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 18-20% (w / w).

[0044] In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of about 15% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of about 18.75% (w / w). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of about 20% (w / w).

[0045] Compound I can be present in the compositions of the present invention in any suitable absolute amount. For example, Compound I can be present in the compositions of the present invention in an amount of 1 to 500 mg, or 10 to 400 mg, or 20 to 300 mg, or 30 to 200 mg, or 40 to 100 mg, or 50 to 100 mg, or 55 to 90 mg, or 60 to 90 mg, or 55 to 85 mg, or 70 to 80 mg, or 72 to 78 mg, or 74 to 76 mg. Representative amounts of Compound I in the compositions of the present invention include, but are not limited to, about 10 mg, or 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg. Other representative amounts of Compound I in the compositions of the present invention include, but are not limited to, about 55 mg, or 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or about 85 mg. Other representative amounts of Compound I in the compositions of the present invention include, but are not limited to, about 50 mg, 75 mg, 100 mg, or about 150 mg.

[0046] In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 50-150 mg. In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 50-100 mg. In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 55-85 mg. In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 55-65 mg. In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 70-80 mg. In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 75-85 mg.

[0047] In some embodiments, the compositions of the present invention comprise a composition in which Compound I is present in an amount of about 60 mg. In some embodiments, the compositions of the present invention comprise a composition in which Compound I is present in an amount of about 75 mg. In some embodiments, the compositions of the present invention comprise a composition in which Compound I is present in an amount of about 80 mg.

[0048] In some embodiments, the compositions of the present invention include a composition in which Compound I is present in an amount of about 50 mg. In some embodiments, the compositions of the present invention include a composition in which Compound I is present in an amount of about 75 mg. In some embodiments, the compositions of the present invention include a composition in which Compound I is present in an amount of about 100 mg. In some embodiments, the compositions of the present invention include a composition in which Compound I is present in an amount of about 125 mg. In some embodiments, the compositions of the present invention include a composition in which Compound I is present in an amount of about 150 mg.

[0049] Co-solvent The cosolvent of the composition of the present invention can include any suitable cosolvent.For example, the cosolvent in the composition of the present invention can include, but is not limited to, polyethylene glycol (PEG), ethanol, propylene glycol, glycerol, diethylene glycol monoethyl ether, glycofurol, triacetin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, propylene glycol ester, or a combination thereof.

[0050] In some embodiments, the compositions of the present invention include compositions in which the co-solvent comprises polyethylene glycol (PEG), ethanol, propylene glycol, glycerol, diethylene glycol monoethyl ether, glycofurol, triacetin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, propylene glycol esters, or combinations thereof. In some embodiments, the compositions of the present invention include compositions in which the co-solvent comprises polyethylene glycol (PEG).

[0051] When the cosolvent of the present compositions is polyethylene glycol (PEG), the PEG can have any suitable molecular weight that is liquid or semi-solid at room temperature. For example, the PEG cosolvent in the present compositions can have a molecular weight of 100-5000 daltons, or 100-2500 daltons, or 100-1000 daltons, or 100-750 daltons, or 200-600 daltons, or 300-500 daltons. Representative molecular weights of PEG cosolvents in the present compositions include, but are not limited to, about 220 daltons, or 260, 310, 350, 400, 440, 480, 530, 570, 620, or about 660 daltons. In some embodiments, the present compositions include compositions in which the cosolvent comprises polyethylene glycol (PEG 400) having a molecular weight of about 400 daltons.

[0052] The cosolvent may be present in the compositions of the present invention in any suitable amount. For example, the cosolvent may be present in the compositions of the present invention in an amount of 1-90% (w / w), or 5-25% (w / w), or 2-20%, or 3-15%, or 4-10%, or 5-8%, or 6-7% (w / w). Representative amounts of the cosolvent in the compositions of the present invention include, but are not limited to, about 1% (w / w), or 2, 3, 4, 5, 6, 7, 8, 9, or about 10% (w / w). Other representative amounts of the cosolvent in the compositions of the present invention include, but are not limited to, about 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, or about 6.9% (w / w).

[0053] In some embodiments, the compositions of the present invention include compositions in which the co-solvent is present in an amount of 1-25% (w / w). In some embodiments, the compositions of the present invention include compositions in which the co-solvent comprises PEG 400 in an amount of 5-8% (w / w). In some embodiments, the compositions of the present invention include compositions in which the co-solvent comprises PEG 400 in an amount of 6-7% (w / w). In some embodiments, the compositions of the present invention include compositions in which the co-solvent comprises PEG 400 in an amount of 6.5% (w / w).

[0054] The cosolvent can be present in the compositions of the present invention in any suitable absolute amount. For example, the cosolvent can be present in the compositions of the present invention in an amount of 1-100 mg, or 5-50 mg, or 10-40 mg, or 15-35 mg, or 20-30 mg, or 22-28 mg, or 24-28 mg, or 25-27 mg. Representative amounts of cosolvent in the compositions of the present invention include, but are not limited to, about 15 mg, or 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or about 35 mg.

[0055] In some embodiments, the compositions of the present invention include compositions in which the co-solvent is present in an amount of 20-30 mg, hi some embodiments, the compositions of the present invention include compositions in which the co-solvent is present in an amount of about 26 mg.

[0056] surfactants The surfactant of the composition of the present invention can comprise any suitable surfactant.The surfactant of the composition of the present invention is generally a hydrophilic nonionic surfactant, and generally has an HLB value of greater than 10 or greater than 12.Other nonionic surfactants useful in the composition of the present invention have an HLB value of greater than 4. For example, surfactants that may be used in the compositions of the present invention include vitamin E polyethylene glycol succinate (vitamin E TPGS), sorbitan monooleate, sorbitan monolaurate, polysorbate 80, polysorbate 20, Solutol HS 15, poloxamer 407 or poloxamer 168, Labrafil® M-1944CS, Labrafil M-2125CS, Labrasol® (Gattefosse, Saint-Priest, Lyon, France), Softigen® 767 (IOI Oleo GmbH, Germany), Gelucires (including Gelucire 44 / 14, 48 / 16, and 50 / 13), Kolliphor RH40, Kolliphor® EL (also known as Cremophor), Kolliphor P188, Kolliphor® HS 15, Kolliphor® RH40, macrogol glycerol hydroxystearate (available from SIGMA-Aldrich, St. Louis, MO, USA), or combinations thereof.

[0057] In some embodiments, the compositions of the present invention include compositions where the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS), polysorbate, Solutol HS 15, poloxamer 407, Labrafil® M-1944CS, Labrafil M-2125CS, Labrasol®, Softigen® 767, Gelucire, Kolliphor, or a combination thereof. In some embodiments, the compositions of the present invention include compositions where the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS). In some embodiments, the compositions of the present invention include compositions where the surfactant comprises PEG 400 and vitamin E TPGS.

[0058] The surfactant may be present in the compositions of the present invention in any suitable amount. For example, the surfactant may be present in the compositions of the present invention in an amount of 10-95% (w / w), or 25-95% (w / w), or 50-95% (w / w), or 50-90% (w / w), or 60-90% (w / w), or 65-85% (w / w), or 70-80% (w / w), or 72-78% (w / w), or 72-76% (w / w), or 74-76% (w / w), or 76-80% (w / w). Representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 50% (w / w), or 55, 60, 65, 70, 75, 80, 85, 90, or about 95% (w / w). Other representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 71, or 72, 73, 74, 75, 76, 77, 78, or about 79% (w / w).Other representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 73.1% (w / w), or 73.2, 73.25, 73.3, 73.4, 73.5, 73.6, 73.7, 73.75, 73.8, 73.9, 74.0, 74.1, 74.2, 72.25, 74.3, 74.4, 74.5, 74.6, 74.7, 74.75, 74.8, or about 74.9% (w / w). Other representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 78.1% (w / w), or 78.2, 78.25, 78.3, 78.4, 78.5, 78.6, 78.7, 78.75, 78.8, or about 78.9% (w / w).

[0059] In some embodiments, the compositions of the present invention include compositions in which the surfactant is present in an amount of 10-90% (w / w). In some embodiments, the compositions of the present invention include compositions in which the surfactant is present in an amount of 50-90% (w / w). In some embodiments, the compositions of the present invention include compositions in which the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 70-80% (w / w). In some embodiments, the compositions of the present invention include compositions in which the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 72-78% (w / w). In some embodiments, the compositions of the present invention include compositions in which the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 74-76% (w / w).

[0060] In some embodiments, the compositions of the present invention include compositions in which the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of about 73.5% (w / w). In some embodiments, the compositions of the present invention include compositions in which the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of about 74.75% (w / w). In some embodiments, the compositions of the present invention include compositions in which the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of about 78.5% (w / w).

[0061] The surfactant may be present in the compositions of the present invention in any suitable absolute amount. For example, the surfactant may be present in the compositions of the present invention in an amount of 100-1000 mg, 100-500 mg, 150-450 mg, 200-400 mg, 250-350 mg, or 275-325 mg. Representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, or about 350 mg. Other representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 291 mg, or 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, or about 319 mg.

[0062] In some embodiments, the compositions of the present invention include a composition in which the surfactant is present in an amount of 275-325 mg. In some embodiments, the compositions of the present invention include a composition in which the surfactant is present in an amount of about 294 mg. In some embodiments, the compositions of the present invention include a composition in which the surfactant is present in an amount of about 299 mg. In some embodiments, the compositions of the present invention include a composition in which the surfactant is present in an amount of about 314 mg.

[0063] combination In some embodiments, the compositions of the present invention comprise a composition comprising Compound I, PEG400, and Vitamin E TPGS. In some embodiments, the compositions of the present invention consist essentially of a composition comprising Compound I, PEG400, and Vitamin E TPGS. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I, PEG400, and Vitamin E TPGS.

[0064] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 18.75% (w / w), PEG 400 in an amount of about 6.5% (w / w), and Vitamin E TPGS in an amount of about 74.75% (w / w). In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 75 mg, PEG 400 in an amount of about 26 mg, and Vitamin E TPGS in an amount of about 299 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 75 mg, PEG 400 in an amount of 26 mg, and Vitamin E TPGS in an amount of 299 mg.

[0065] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 50 mg, PEG 400 in an amount of about 17 mg, and Vitamin E TPGS in an amount of about 200 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 50 mg, PEG 400 in an amount of 17 mg, and Vitamin E TPGS in an amount of 200 mg.

[0066] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 75 mg, PEG 400 in an amount of about 26 mg, and Vitamin E TPGS in an amount of about 299 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 75 mg, PEG 400 in an amount of 26 mg, and Vitamin E TPGS in an amount of 299 mg.

[0067] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 100 mg, PEG 400 in an amount of about 35 mg, and Vitamin E TPGS in an amount of about 399 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 100 mg, PEG 400 in an amount of 35 mg, and Vitamin E TPGS in an amount of 399 mg.

[0068] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 125 mg, PEG 400 in an amount of about 43 mg, and Vitamin E TPGS in an amount of about 498 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 125 mg, PEG 400 in an amount of 43 mg, and Vitamin E TPGS in an amount of 498 mg.

[0069] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 150 mg, PEG 400 in an amount of about 52 mg, and Vitamin E TPGS in an amount of about 598 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 150 mg, PEG 400 in an amount of 52 mg, and Vitamin E TPGS in an amount of 598 mg.

[0070] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 15% (w / w), PEG 400 in an amount of about 6.5% (w / w), and Vitamin E TPGS in an amount of about 78.5% (w / w). In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 60 mg, PEG 400 in an amount of about 26 mg, and Vitamin E TPGS in an amount of about 314 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of about 60 mg, PEG 400 in an amount of about 26 mg, and Vitamin E TPGS in an amount of about 314 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 60 mg, PEG 400 in an amount of 26 mg, and Vitamin E TPGS in an amount of 314 mg.

[0071] In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 20.0% (w / w), PEG 400 in an amount of about 6.5% (w / w), and Vitamin E TPGS in an amount of about 73.5% (w / w). In some embodiments, the compositions of the present invention comprise a composition comprising Compound I in an amount of about 80 mg, PEG 400 in an amount of about 26 mg, and Vitamin E TPGS in an amount of about 294 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of about 80 mg, PEG 400 in an amount of about 26 mg, and Vitamin E TPGS in an amount of about 294 mg. In some embodiments, the compositions of the present invention comprise a composition consisting of Compound I in an amount of 80 mg, PEG 400 in an amount of 26 mg, and Vitamin E TPGS in an amount of 294 mg.

[0072] The compositions of the present invention can be prepared and administered in a wide variety of oral dosage forms, including, but not limited to, liquid-filled capsules or solution products for oral or enteral administration. Other oral preparations include tablets, pills, powders, dragees, capsules, slurries, suspensions, and the like, suitable for ingestion by a patient. Accordingly, the present invention also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and / or excipients and either a compound or a pharmaceutically acceptable salt of a compound.

[0073] For preparing compositions from Compound I, pharmaceutically acceptable carriers can be either solid, semi-solid, or liquid. A solid carrier can also be one or more substances that can act as solubilizers, emulsifiers, dispersants, antioxidants, or encapsulating materials. Details regarding formulation and administration techniques are well-documented in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0074] In addition, the carriers or excipients used in the pharmaceutical compositions of the present invention are commercially available. By way of further example, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Md. (2000), and H.C. Cansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Md. (1999).

[0075] Pharmaceutical preparations can be prepared in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, i.e., a package containing discrete amounts of preparation, such as capsules or solutions packaged in bottles, vials or blister packs.

[0076] The compositions of the present invention may be in unit dosage form. The unit dosage of the compositions of the present invention may be any suitable amount. For example, the compositions of the present invention may be in a unit dosage form of 100-1000 mg, 200-750 mg, 250-750 mg, 300-500 mg, 350-450 mg, or 375-425 mg. Representative unit dosage amounts of the compositions of the present invention include, but are not limited to, 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or approximately 750 mg. In some embodiments, the compositions of the present invention comprise a 400 mg unit dosage form of the composition. In some embodiments, the compositions of the present invention comprise a 267 mg unit dosage form of the composition. In some embodiments, the compositions of the present invention comprise a 533 mg unit dosage form of the composition. In some embodiments, the compositions of the present invention comprise a 667 mg unit dosage form of the composition. In some embodiments, the compositions of the present invention comprise an 800 mg unit dosage form of the composition.

[0077] Dosing regimens also take into account pharmacokinetic parameters well known in the art, i.e., absorption, bioavailability, metabolism, clearance rate, etc. (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; latest edition of Remington's (cited above)). The current state of the art allows the clinician to determine the dosing regimen for the individual patient, the GR and / or MR modulator, and the disease or condition being treated.

[0078] Single or multiple administrations of the composition can be administered depending on the dosage and frequency required and tolerated by the patient. The compound should provide a sufficient amount of the active agent to effectively treat the disease state. Thus, in some embodiments, pharmaceutical formulations for oral administration of the compound have a daily dose of about 0.5 to about 30 mg per kilogram of body weight per day. In some embodiments, the dosage may be about 1 mg to about 20 mg per kg of body weight per patient per day. Actual methods for preparing parenterally administrable formulations are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, "Receptor-Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0079] In some embodiments, the pharmaceutical formulation for oral administration of the compound has a daily dose of about 50 mg to about 300 mg of Compound I. In some embodiments, the daily dose of Compound I is about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 300 mg. In some embodiments, the daily dose of Compound I is provided in a single unit dosage form. In some embodiments, the daily dose of Compound I is provided in two, three, or four unit dosage forms, each containing 50 mg, 75 mg, 100 mg, or 150 mg of Compound I. In some embodiments, the daily dose of Compound I is provided in two, three, or four unit dosage forms, each containing 50 mg, 75 mg, or 100 mg of Compound I. In some embodiments, the daily dose is 75 mg of Compound I, provided in one unit dosage form containing 75 mg of Compound I. In some embodiments, the daily dose is 100 mg of Compound I, provided in one unit dosage form containing 100 mg of Compound I. In some embodiments, the daily dose is 100 mg of Compound I provided as two unit dosage forms each containing 50 mg of Compound I. In some embodiments, the daily dose is 150 mg of Compound I provided as one unit dosage form containing 150 mg of Compound I. In some embodiments, the daily dose is 150 mg of Compound I provided as two unit dosage forms each containing 75 mg of Compound I. In some embodiments, the daily dose is 150 mg of Compound I provided as three unit dosage forms each containing 50 mg of Compound I. In some embodiments, the daily dose is 300 mg of Compound I provided as two unit dosage forms each containing 150 mg of Compound I. In some embodiments, the daily dose is 300 mg of Compound I provided as three unit dosage forms each containing 100 mg of Compound I. In some embodiments, the daily dose is 300 mg of Compound I provided as four unit dosage forms each containing 75 mg of Compound I.

[0080] Compound I described herein can be used in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or in combination with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agent.

[0081] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or adjuncts may be linked or conjugated to each other.

[0082] After the compositions of the invention have been formulated in one or more acceptable carriers, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of Compound I, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

[0083] In some embodiments, the present invention provides a unit dosage form for oral administration consisting essentially of a capsule containing a composition of the present invention. The capsule can be any suitable type of capsule. For example, the capsule can be a softgel capsule or a hardgel capsule. In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form in which the capsule is a softgel capsule or a hardgel capsule. In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form in which the capsule is a softgel capsule. In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form in which the capsule is a hardgel capsule.

[0084] In some embodiments, the unit dosage form for oral administration of the present invention consists essentially of a softgel capsule containing a composition consisting of Compound I in an amount of 75 mg, polyethylene glycol having a molecular weight of about 400 daltons (PEG 400) in an amount of 26 mg, and vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 299 mg.

[0085] In some embodiments, the unit dosage form for oral administration of the present invention consists essentially of a hard gel capsule containing a composition consisting of Compound I in an amount of 75 mg, polyethylene glycol having a molecular weight of about 400 daltons (PEG 400) in an amount of 26 mg, and vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 299 mg.

[0086] In some embodiments, the unit dosage form for oral administration of the present invention consists essentially of a hard gel capsule containing a composition consisting of Compound I in an amount of 50 mg, polyethylene glycol having a molecular weight of about 400 daltons (PEG 400) in an amount of 17 mg, and vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 199 mg.

[0087] In some embodiments, the unit dosage form for oral administration of the present invention consists essentially of a hard gel capsule containing a composition consisting of Compound I in an amount of 100 mg, polyethylene glycol having a molecular weight of about 400 daltons (PEG 400) in an amount of 35 mg, and vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 399 mg.

[0088] In some embodiments, the unit dosage form for oral administration of the present invention consists essentially of a hard gel capsule containing a composition consisting of Compound I in an amount of 150 mg, polyethylene glycol having a molecular weight of about 400 daltons (PEG 400) in an amount of 52 mg, and vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 598 mg.

[0089] IV. Methods and Uses In some embodiments, the present invention provides methods for treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention, thereby treating the disorder or condition.

[0090] In some embodiments, the present invention provides a method of treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention, thereby treating the disorder or condition.

[0091] In some embodiments, the present invention provides methods for modulating glucocorticoid receptor activity using the technology described herein. In some embodiments, the method includes contacting a GR with an effective amount of a composition of the present invention or Compound I and detecting a change in GR activity.

[0092] In some embodiments, the present invention provides methods for modulating glucocorticoid receptor activity using the technology described herein. In some embodiments, the method includes contacting the GR or both with an effective amount of a composition of the present invention or Compound I, and detecting a change in GR activity, MR activity, or both.

[0093] In some embodiments, the glucocorticoid receptor modulator is an antagonist of GR activity or MR activity, or both GR and MR activity (also referred to herein as a "glucocorticoid receptor antagonist"). As used herein, a glucocorticoid receptor antagonist refers to any composition or compound that partially or completely inhibits (antagonizes) the binding of a glucocorticoid receptor agonist (e.g., cortisol, aldosterone, and synthetic or natural cortisol or aldosterone analogs) to GR, thereby inhibiting any biological response associated with the binding of GR to the agonist.

[0094] In some embodiments, the glucocorticoid receptor modulator is a specific glucocorticoid receptor antagonist. As used herein, a specific glucocorticoid receptor antagonist refers to a composition or compound that preferentially binds to GR rather than another nuclear receptor (NR), thereby inhibiting any biological response associated with the binding of GR to an agonist. In some embodiments, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the androgen receptor (AR), estrogen receptor (ER), or progesterone receptor (PR). In some embodiments, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the progesterone receptor (PR). In some embodiments, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the androgen receptor (AR). In some embodiments, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the estrogen receptor (ER).

[0095] In some embodiments, a specific glucocorticoid receptor antagonist binds to GR with an association constant (Kd) that is at least 10-fold lower than the association constant (Kd) of AR or PR. In some embodiments, a specific glucocorticoid receptor antagonist binds to GR with a Kd that is at least 100-fold lower than the association constant (Kd) of AR or PR. In some embodiments, a specific glucocorticoid receptor antagonist binds to GR with a Kd that is at least 1000-fold lower than the association constant (Kd) of AR, PR, or ER.

[0096] In some embodiments, the present invention provides a method of treating amyotrophic lateral sclerosis (ALS), comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating ALS.

[0097] Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) is a progressive neuromuscular condition characterized by weakness, muscle wasting, fasciculations, and increased reflexes. Approximately 30,000 Americans currently suffer from the disease. The annual incidence rate is 1-2 per 100,000. The disease is most commonly diagnosed in middle age and affects men more than women. ALS is characterized by adult-onset, idiopathic, progressive degeneration of spinal cord anterior horn cells and upper and lower motor neurons, resulting in progressive muscle weakness, wasting, and fasciculations. Atrophy of spinal cord anterior horn cells and replacement of large motor neurons by fibrous astrocytes (gliosis) stiffens the affected anterior and lateral columns of the spinal cord, hence the term "lateral sclerosis." Typical signs and symptoms of ALS include muscle weakness, muscle wasting (atrophy), muscle fasciculations, muscle spasms, slowed movements, poor balance, coordination, changes in voice quality, dysarthria, difficulty swallowing, incomplete eye closure, excessive salivation, emotional dysregulation, and premature death.

[0098] Up to 10% of ALS cases are familial and are usually autosomal dominant. Several causative genes are known, of which mutant superoxide dismutase 1 (SOD) and mutant C9orf72 (i.e., a G4C2 hexanucleotide repeat in the C9orf72 gene) are the most frequently observed in familial ALS (fALS) and sporadic ALS (sALS). Several other genes are known to cause classical ALS, but they account for a lower percentage of cases than mutant SOD1. These genes include mutant FUS (fused to sarcoma), mutant TARDBP genes that result in modification of TAR DNA-binding protein 43 (TDP-43), and optinourin.

[0099] Clinical symptoms vary depending on the area of ​​the nervous system damaged and the progression of pathological changes. The classic symptom of ALS is insidious, progressive, asymmetric muscle weakness and atrophy, accompanied by neurological signs, particularly fasciculations and hyperreflexia. Patients usually present with dexterity or gait problems resulting from muscle weakness. Difficulty speaking or swallowing is an early symptom in the bulbar form of the disease. Over a period of months or years, patients with ALS develop severe, progressive muscle weakness and other symptoms caused by loss of both upper and lower motor neuron function. Sphincter control, sensory function, intellectual ability, and skin integrity are preserved. Patients become completely incapacitated and often require ventilatory support and gastrostomy. Death usually occurs within five years of diagnosis and is due to respiratory failure or cachexia. The diagnosis of ALS is clinical, based on characteristic signs of progressive weakness, atrophy, fasciculations, and hyperreflexia affecting several areas of the body. Early differential diagnosis may include musculoskeletal, neurological, or systemic conditions. The etiology of the disease is unknown. Current management involves aggressive and individualized relief of symptoms and complications.

[0100] Examples of disorders or conditions suitable for use in the present invention include, but are not limited to, neurodegeneration, Alzheimer's disease, Huntington's disease, Parkinson's disease, cognitive enhancement, mild cognitive impairment, psychosis, or dementia. In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating Alzheimer's disease. In some embodiments, the present invention provides a method of treating Huntington's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating Huntington's disease.

[0101] V. Working Example Example 1. Preparation of Compound I Compound I can be prepared as described in Example 1, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, of U.S. Pat. No. 8,859,774, which is incorporated herein in its entirety for all purposes. [ka]

[0102] Example 2. Preparation of a Type IV formulation of Compound I in softgel capsules A Type IV formulation in a softgel capsule was prepared according to the following method.

[0103] Step 1: Vitamin E TPGS was preheated to a temperature of 65°C in a suitable oven until melted, and 74.75g was dispensed into a suitable mixing container. While maintaining the temperature at 40°C and stirring, polyethylene glycol (6.5g) and Compound I (18.75g) were added to the container and the contents mixed until a visually homogeneous solution was formed. The resulting solution (fill matrix) was then degassed, subjected to a nitrogen blanket, and stored at 45-55°C until packaging. Step 2: A gel mass was prepared using gelatin, purified water, and a sorbitol specialty glycerin blend. The gel mass was then color transformed by adding titanium dioxide and red iron oxide. Step 3: The fill matrix was encapsulated into softgel capsules. Step 4: The capsules were dried and hardened in a tumble dryer and drying chamber. Step 5: The bulk capsules are bulk packaged in polyethylene-lined corrugated shipping cartons. Step 6: The capsules were filled into their final packaging configuration, such as bottles or blisters. [Table 1] [Table 2] [Table 3]

[0104] Example 3. Preparation of a Type IV formulation of Compound I in 150 mg strength hard gel capsules A Type IV formulation in a hard gel capsule was prepared according to the following method. Step 1: Vitamin E TPGS was preheated to a temperature of 65°C in a suitable oven until melted, and 448.5 g was dispensed into a suitable mixing container. While maintaining the temperature at 45-55°C and stirring, polyethylene glycol (39.0 g) and Compound I (112.5 g) were added to the container, and the contents were mixed until a visually homogeneous solution was formed. The resulting solution (filled matrix) was then stored at 45-55°C until encapsulation. Step 2: The melt-fill matrix (800 mg) was encapsulated into size 00el hard gelatin capsules. Step 3: The capsules were banded using a 25% w / w gelatin solution. The capsules were then kept on a drying rack on the capsule banding machine until they were dried and sealed. Step 4: The capsules were filled into their final packaging configuration, such as bottles or blisters. [Table 4]

[0105] Example 4. Stability Study of Compound I Form III and Form IV Loading Matrices Type IV fill matrices were prepared as described above using 18.75% w / w Compound I fill matrix as shown in Table 1, and tested under various accelerated stability conditions and compared to Type III fill matrices. For water-spiked samples of Type IV formulations, 5 g of water was stirred into the solution. The solutions were then filled into vials while still molten and stored in the vials for stability testing.

[0106] Samples of Type III formulations were prepared according to known methods using the w / w percentages in Table 5. For example, Kolliphor ELP and Masester E8120 were preheated to a temperature of 65°C in a suitable oven until melted. Caproyl 90 (32.24g), Masester E8120 (24.83g), and Kolliphor ELP (24.18g) were added to a suitable mixing vessel and stirred until homogeneous while maintaining a temperature of 40°C. Compound I (18.75g) was added and mixed until dissolved, forming a completely homogeneous solution. For samples containing antioxidants, the required amount of antioxidant (0.167g dl-alpha tocopherol or 0.02g BHT) was added, and the levels of Caproyl 90, Masester E8120, and Kolliphor ELP were proportionally reduced to compensate for the antioxidants present. The solution was stirred until all ingredients were dissolved and the solution was homogeneous. For the water-added samples, 5 g of water was stirred into the solution. [Table 5]

[0107] The stability of Type IV capsule fill matrix samples was evaluated as solutions in closed glass screw-cap vials stored under accelerated conditions and compared to alternative Type III formulations with or without antioxidants. For example, 2 g amounts of each solution type were filled into 4 mL amber glass vials, the headspace was purged with nitrogen, and the vials were capped. Samples were placed in stability chambers at 30°C / 65% RH and 40°C / 75% RH. Impurity assays and levels were evaluated over periods of up to 12 weeks using suitable HPLC methods.

[0108] For antioxidants in Type III formulations, typical usage levels of either 0.02% w / w butylated hydroxytoluene (BHT) or 0.16% w / w vitamin E (dl-alpha tocopherol) were added along with additional samples without evaluating the antioxidant. 5% water (wet samples) was added to some vials to promote degradation, as it is known that moisture can migrate from the capsule shell into the fill matrix during manufacturing or storage. Samples without added water (dry samples) were also evaluated. For Type IV formulations, no antioxidants were added, but both wet and dry samples were evaluated. Samples were stored at 40°C / 75% RH and 30°C / 65% RH for up to 12 weeks, and assay and total impurity determinations were performed. Results are shown in Tables 6, 7, 8, and 9. [Table 6] [Table 7] [Table 8] [Table 9]

[0109] Example 5. Stability Study of Compound I Formulation IV in 150 mg Strength Hard Gel Capsules Stability data was obtained for 150 mg strength hard gel capsules prepared according to the method of Example 3. Clear 7 mL glass vials with polypropylene screw caps containing the hard gel capsules of Example 3 were stored under ambient conditions (15-25°C in the dark). Assays and levels of two major impurities (COR176-6 and CORT125863) were determined after 12 and 24 months. [ka] [Table 10]

[0110] Example 6. Preparation of a Type IV formulation of Compound I in 75 mg strength hard gel capsules A Type IV formulation in a 75 mg strength hard gel capsule was prepared according to the following method. Step 1: Vitamin E TPGS was preheated to a temperature of 60-65°C in a suitable oven until melted, and 1943.5 g was dispensed into a suitable mixing vessel. While maintaining the temperature at 40-50°C and stirring, polyethylene glycol (169.0 g) and Compound I (487.5 g) were added to the vessel, and the contents were mixed until a visually homogeneous solution was formed. The resulting solution (fill matrix) was then stored at 45-55°C until encapsulation. Step 2: The melt-fill matrix (400 mg) was encapsulated into size 0 hard gelatin capsules. Step 3: The capsules were banded using a gelatin solution, then dried and sealed. Step 4: The capsules are filled into their final packaging configuration in bottles. Alternative packaging such as blisters is considered. [Table 11]

[0111] Example 7. Stability Study of Compound I Formulation IV in 75 mg Strength Hard Gel Capsules A 60 ml HPDE bottle containing 30 hard gel capsules of Example 5 was stored under ICH stability conditions. Assay and levels of two major impurities (COR176-6 and CORT125863) were determined for up to 3 months. [Table 12] [Table 13]

[0112] Example 8. Preparation of a Type IV formulation of Compound I in 75 mg strength softgel capsules A Type IV formulation in a softgel capsule was prepared according to the following method and in accordance with Table 1. Step 1: Vitamin E TPGS was preheated to a temperature of 65°C in a suitable oven until melted, and 747.5g was dispensed into a suitable mixing vessel. While maintaining the temperature at 40°C and stirring, polyethylene glycol (65.0g) and Compound I (187.5g) were added to the vessel, and the contents were mixed until a visually homogeneous solution was formed. The resulting solution (fill matrix) was then degassed, subjected to a nitrogen blanket, and stored at 40-45°C until packaging. Step 2: A gel mass was prepared using gelatin, purified water, and a sorbitol specialty glycerin blend. The gel mass was then color transformed by adding titanium dioxide and red iron oxide. Step 3: The fill matrix (400 mg) was encapsulated into softgel capsules. Step 4: The capsules were dried and hardened in a tumble dryer and drying chamber. Step 5: The bulk capsules were packaged in polyethylene-lined corrugated shipping cartons. Step 6: The capsules were filled into their final packaging configuration in bottles or blisters.

[0113] Example 9. Stability of Compound I Formulation IV in 75 mg Strength Softgel Capsules Blisters containing 75 mg strength softgel capsules provided in Example 8 were stored under ICH conditions. Assay and levels of two major impurities (COR176-6 and CORT125863) were determined at 25° C. and 60% relative humidity (RH) for up to 22 months, as shown in Table 14, and at 40° C. and 75% RH for up to 6 months, as shown in Table 15. [Table 14] [Table 15]

[0114] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference mentioned herein, including all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications, is hereby incorporated by reference in its entirety to the extent not inconsistent with this description. In the event of a conflict between this application and the references provided herein, this application shall control.

Claims

1. 1. A composition comprising: Compound I, (R)-(1-(4-fluorophenyl)-6-((4-trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, in an amount of 1 to 25% (w / w); [[Chemical Formula 1]] a co-solvent in an amount of 1-25% (w / w); and a surfactant in an amount of 50-90% (w / w).

2. 2. The composition of claim 1, wherein Compound I is present in an amount of 15-20% (w / w).

3. 3. The composition of claim 1, wherein compound I is present in an amount of 18 to 20% (w / w).

4. The composition of any one of claims 1 to 3, wherein Compound I is present in an amount of about 18.75% (w / w).

5. 5. The composition of any one of claims 1 to 4, wherein Compound I is present in an amount of 50 to 150 mg.

6. The composition of any one of claims 1 to 5, wherein Compound I is present in an amount of about 75 mg.

7. The composition of any one of claims 1 to 5, wherein Compound I is present in an amount of about 150 mg.

8. 8. The composition of any one of claims 1 to 7, wherein the co-solvent comprises polyethylene glycol (PEG), ethanol, propylene glycol, glycerol, diethylene glycol monoethyl ether, glycofurol, triacetin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, propylene glycol esters, or a combination thereof.

9. The composition of any one of claims 1 to 8, wherein the co-solvent comprises polyethylene glycol (PEG).

10. The composition of any one of claims 1 to 9, wherein the co-solvent comprises polyethylene glycol having a molecular weight of about 400 Daltons (PEG 400).

11. The composition of any one of claims 1 to 10, wherein the co-solvent comprises PEG 400 in an amount of 5 to 8% (w / w).

12. The composition of any one of claims 1 to 11, wherein the co-solvent comprises PEG 400 in an amount of 6-7% (w / w).

13. The composition of any one of claims 1 to 12, wherein the co-solvent comprises PEG 400 in an amount of about 6.5% (w / w).

14. 14. The composition of any one of claims 1 to 13, wherein the surfactant comprises Vitamin E polyethylene glycol succinate (Vitamin E TPGS), sorbitan monooleate, polysorbate, Solutol HS 15, Poloxamer 407, Labrafil® M-1944CS, Labrafil® M-2125CS, Labrasol®, Softigen® 767, Gelucire, Kolliphor, or a combination thereof.

15. The composition of any preceding claim, wherein the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS).

16. 16. A composition according to any preceding claim, wherein the surfactant comprises Vitamin E polyethylene glycol succinate (Vitamin E TPGS) in an amount of 70-80% (w / w).

17. 17. A composition according to any preceding claim, wherein the surfactant comprises Vitamin E polyethylene glycol succinate (Vitamin E TPGS) in an amount of 74-76% (w / w).

18. 18. The composition of any one of claims 1 to 17, wherein the surfactant comprises Vitamin E polyethylene glycol succinate (Vitamin E TPGS) in an amount of about 74.75% (w / w).

19. Compound I in an amount of about 18.75% (w / w); PEG 400 in an amount of about 6.5% (w / w); and Vitamin E TPGS in an amount of about 74.75% (w / w).

20. Compound I in an amount of about 75 mg; PEG 400 in an amount of about 26 mg; and Vitamin E TPGS in an amount of about 299 mg.

21. Compound I in an amount of 75 mg; PEG 400 in an amount of 26 mg; and Vitamin E TPGS in an amount of 299 mg.

22. Compound I in an amount of about 50 mg; PEG 400 in an amount of about 17 mg; and Vitamin E TPGS in an amount of about 199 mg.

23. Compound I in an amount of about 100 mg; PEG 400 in an amount of about 35 mg; and Vitamin E TPGS in an amount of about 399 mg.

24. Compound I in an amount of about 150 mg; PEG 400 in an amount of about 52 mg; and Vitamin E TPGS in an amount of about 598 mg.

25. Compound I in an amount of about 15% (w / w); PEG 400 in an amount of about 6.5% (w / w); and Vitamin E TPGS in an amount of about 78.5% (w / w).

26. Compound I in an amount of about 60 mg; PEG 400 in an amount of about 26 mg; and Vitamin E TPGS in an amount of about 314 mg.

27. Compound I in an amount of about 20.0% (w / w); PEG 400 in an amount of about 6.5% (w / w); and Vitamin E TPGS in an amount of about 73.5% (w / w).

28. Compound I in an amount of about 80 mg; PEG 400 in an amount of about 26 mg; and Vitamin E TPGS in an amount of about 294 mg.

29. 29. The composition of any one of claims 1 to 21 or 25 to 28 in a 400 mg unit dosage form.

30. 30. A unit dosage form for oral administration consisting essentially of a capsule containing the composition of any one of claims 1 to 29.

31. 31. The unit dosage form of claim 30, wherein the capsule is a soft gel capsule or a hard gel capsule.

32. Compound I in an amount of 75 mg; polyethylene glycol (PEG 400) having a molecular weight of about 400 daltons in an amount of 26 mg; 32. The unit dosage form of claim 30 or 31, consisting essentially of a softgel capsule containing the composition consisting of vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 299 mg.

33. 31. The unit dosage form of claim 30, wherein the capsule is a hard gel capsule.

34. Compound I in an amount of 75 mg; polyethylene glycol (PEG 400) having a molecular weight of about 400 daltons in an amount of 26 mg; 34. The unit dosage form of claim 30 or 33, consisting essentially of a hard gel capsule containing the composition consisting of vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 299 mg.

35. Compound I in an amount of 50 mg; polyethylene glycol (PEG 400) having a molecular weight of about 400 daltons in an amount of 17 mg; 34. The unit dosage form of claim 30 or 33, consisting essentially of a hard gel capsule containing the composition consisting of vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 199 mg.

36. Compound I in an amount of 100 mg; polyethylene glycol (PEG 400) having a molecular weight of about 400 daltons in an amount of 35 mg; 34. The unit dosage form of claim 30 or 33, consisting essentially of a hard gel capsule containing the composition consisting of vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 399 mg.

37. Compound I in an amount of 150 mg; polyethylene glycol (PEG 400) having a molecular weight of about 400 daltons in an amount of 52 mg; 34. The unit dosage form of claim 30 or 33, consisting essentially of a hard gel capsule containing the composition consisting of vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 598 mg.

38. 38. A method of treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of any one of claims 1 to 29, or a unit dosage form of any one of claims 30 to 37, thereby treating said disorder or condition.

39. 38. A method of treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of any one of claims 1 to 29, or a unit dosage form of any one of claims 30 to 37, thereby treating said disorder or condition.

40. 38. A method of treating amyotrophic lateral sclerosis (ALS), comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 1-29, or the unit dosage form of any one of claims 30-37, thereby treating ALS.

41. 38. A method of treating Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 1 to 29, or the unit dosage form of any one of claims 30 to 37, thereby treating Alzheimer's disease.

42. 38. A method of treating Huntington's disease, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 1 to 29, or the unit dosage form of any one of claims 30 to 37, thereby treating Huntington's disease.

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