Formulations of glucocorticoid receptor modulators

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 of making and using the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 378,578, filed on October 6, 2022, which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] In most species, including humans, the physiological glucocorticoid is Cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (adrenocorticotropic hormone), which shows circadian changes and increases in response to stress and food. Cortisol levels respond to many physical and physiological stresses, including trauma, surgery, exercise, anxiety and depression within minutes. Cortisol is a steroid and exerts its effects by binding to intracellular glucocorticoid receptors (GR). Mineralocorticoid receptors (MR), also known as type I glucocorticoid receptors (GR I), bind to Cortisol and may also be activated by aldosterone in the human body. Compositions comprising one or both of the modulators of GR and MR can be used to treat a variety of diseases and conditions. In humans, GR exists in two forms: a 777 amino acid ligand-binding GR-α; and a GR-β isoform with 50 carboxyl-terminal residues missing. Because these residues contain ligand-binding domains, GR-β cannot bind to natural ligands and is constitutively located in the nucleus.

[0004] The biological effects of Cortisol, including those caused by hypercortisolemia, can be regulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of agents are capable of inhibiting the physiological effects of GR-agonist binding. These antagonists include compositions that inhibit the ability of agonists to effectively bind to and / or activate GR by binding to GR. It has been found that one such known GR antagonist, mifepristone, is an effective anti-glucocorticoid agent in humans (Bertagna (1984) Journal of Clinical Endocrinology and Metabolism (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).

[0005] 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 a steroid is administered to a subject in need, it can provide both the intended therapeutic effect and negative side effects.

[0006] Amyotrophic lateral sclerosis (ALS) is a rare and devastating disease with insufficient treatment options. It is characterized by progressive degeneration of motor neurons in the brain and spinal cord, leading to progressive muscle weakness, permanent disability and death usually within 3-5 years from the onset of symptoms. Only a small number of patients survive more than 10 years. 50% of patients die within 30 months of symptom onset; approximately 20% of patients survive 5-10 years after onset (Riva N, Agosta F, Lunetts C, Filippi M, Quattrini A. 2016. Recent advances in amyotrophic lateralsclerosis. J. Neurol. 263: 1241–1254). Respiratory failure is the most common cause of death in ALS patients (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. Modelling amyotrophic lateral sclerosis: progression and possibilities. Dis. Model. Mech. 10:537–549).

[0007] The compounds of U.S. Pat. No. 8,859,774 have been shown to be useful in treating this condition. What is needed are new forms of these compositions. Surprisingly, the present invention meets these and other needs. Summary of the invention

[0008] In one embodiment, the present invention provides a composition comprising:

[0009] 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:

[0010]

[0011] in an amount of 1 to 25% (w / w); a co-solvent in an amount of 1 to 25% (w / w); and a surfactant in an amount of 50 to 90% (w / w).

[0012] 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.

[0013] In another embodiment, the invention provides a method of treating a condition or disorder by modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the invention, thereby treating the condition or disorder.

[0014] In another embodiment, the invention provides a method of treating a condition or disorder by antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the invention, thereby treating the condition or disorder.

[0015] 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.

[0016] In another embodiment, the present invention provides a method for 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.

[0017] 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

[0018] I. Summary

[0019] Disclosed herein is a formulation 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:

[0020]

[0021] With co-solvents and surfactants.

[0022] II. Definitions

[0023] "About" means plus or minus 5% of the specified value unless otherwise indicated.

[0024] As used herein, "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of 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 recipients thereof.

[0025] "Co-solvent" refers to a component in a composition that improves the solubility and miscibility of other components in the composition.

[0026] "Surfactant" refers to any agent that changes the surface properties between two liquids or between a liquid and a solid. Surfactants that can be used in the present invention include, but are not limited to, nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants, amphoteric surfactants, or salts thereof. The hydrophilic / lipophilic balance (HLB) of a surfactant describes the affinity of a surfactant to water or oil (1-20, 1 being lipophilic and 20 being hydrophilic). The HLB of a blend of two surfactants is equal to the weight fraction of surfactant A multiplied by its HLB value plus the weight fraction of surfactant B multiplied by its HLB value (weighted average). Anionic surfactants that can be used in the present invention include, but are not limited to, soaps, including alkaline soaps, such as sodium salts, potassium salts, and ammonium salts of aliphatic carboxylic acids (usually fatty acids), such as sodium stearate. Additional anionic surfactants include organic amine soaps, such as organic amine salts of aliphatic carboxylic acids (usually fatty acids), such as triethanolamine stearate. Cationic surfactants that can be used in the present invention include, but are not limited to, amine salts such as octadecyl ammonium 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 appreciate that other surfactants may be used in the present invention.

[0027] "Pharmaceutically acceptable excipient" refers to a substance that helps to administer the active agent to a subject and allows the subject to absorb the active agent. Pharmaceutical excipients that can be used 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 can be used in the present invention.

[0028] "Treat," "treating," and "treatment" refer to any sign of successful treatment or improvement of an injury, pathology, or condition, including any objective or subjective parameter, such as relief; remission; reduction of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; reducing frailty at the degenerative endpoint; improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of physical examinations, neuropsychiatric examinations, and / or psychiatric evaluations.

[0029] "Administering" refers to oral administration, administration by 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.

[0030] "Patient" or "subject" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other non-mammalian animals. In some embodiments, the patient is a human.

[0031] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition that can be used to treat or improve an identified disease or condition, or can be used to show a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment, and can be determined by those skilled in the art using known techniques (see, e.g., Fridrun and Jones, Pharmaceutical Capsules, (2004), Lieberman, Pharmaceutical Dosage Forms (Disperse Systems Vol. 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, 20th edition, 2003, Gennaro ed., Lippincott, Williams & Wilkins).

[0032] "Glucocorticoid receptor" ("GR") refers to one of a family of intracellular receptors that specifically bind to Cortisol and / or Cortisol analogs (such as dexamethasone) (see, e.g., Turner and Muller, J. Mol. Endocrinol. Oct. 1, 2005 35 283-292). Glucocorticoid receptor is also known as Cortisol receptor. The term encompasses isoforms of GR, recombinant GR, and mutant GR.

[0033] The Cortisol receptor is a glucocorticoid receptor (GR), in particular a type II GR, that specifically binds Cortisol and / or a Cortisol analog (such as dexamethasone) (see, for example, Turner and Muller, J. Mol. Endocrinol. Oct 1, 2005 35 283-292).

[0034] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (GRI), which is activated by aldosterone in humans.

[0035] "Glucocorticoid receptor modulator" (GRM) refers to any compound that regulates the biological response associated with the combination of glucocorticoid receptor and agonist. As used herein, with respect to GRM, glucocorticoid receptor can be GR or both. For example, GRM acting as an agonist such as dexamethasone increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (hepatocellular carcinoma cell line of human liver; ECACC, UK). GRM acting as an antagonist such as mifepristone inhibits the increase in agonist-induced tyrosine aminotransferase (TAT) activity in HepG2 cells. TAT activity can be measured by literature A.Ali et al., J.Med.Chem., 2004, 47, 2441-2452.

[0036] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits a 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. Therefore, GR antagonists may be identified by measuring the ability of a compound to inhibit the effects of dexamethasone. TAT activity may be measured by the literature A.Ali et al., J.Med.Chem., 2004, 47, 2441-2452. Inhibitors are IC 50 Compounds with a half maximal inhibitory concentration (50%) of less than 10 micromolar.

[0037] "Modulate" and "modulating" are used in their ordinary sense to refer to the act of changing or causing a change in one or more properties. "Modulate" refers to the process of changing or altering one or more characteristics. For example, when applied to the effect of a modulator on a target protein, modulating refers to changing by increasing or decreasing a characteristic or function of the target molecule or the amount of the target molecule.

[0038] "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 a molecular target.

[0039] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist to a receptor molecule or inhibiting the signal produced by a receptor agonist. Receptor antagonists inhibit or reduce agonist-mediated responses, such as gene expression.

[0040] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. The 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, the inhibition is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more of the expression or activity in the absence of the antagonist.

[0041] "Inhibition," "inhibit" and "inhibitor" refer to a compound or method that prevents a specific effect or function.

[0042] "Condition" or "disorder" refers to a state of being or health condition in a patient or subject that can be treated with the glucocorticoid receptor modulators of the invention.

[0043] "Amyotrophic lateral sclerosis," "ALS," and "Lou Gehrig's disease" refer to a group of neurodegenerative diseases characterized by the loss of motor neurons in the ventral horn of the spinal cord and cortical neurons that provide afferent input. ALS can initially affect primarily upper or lower motor neurons, but regardless of where the primary area of ​​lesion is, over time the disease acquires symmetrical systemicity (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 together with familial ALS, which is usually autosomal dominant and accounts for approximately 10% of ALS (Dion PA et al., Nat. Rev. Genet. 10:769-782 (2009)). ALS symptoms usually appear earlier in familial cases, but the clinical course of familial and sporadic forms is similar. Several types of gene mutations have been identified as causes of the development of familial ALS, with approximately 20% of familial cases caused by inherited mutations in the protein Cu / Zn superoxide dismutase (SOD1) that protects motor neurons from free radical damage (Rosen DR et al., Nature, 362:59-62 (1993)).

[0044] Unlike some forms of familial ALS, the specific cause of sporadic ALS remains elusive, with different hypotheses proposed, including glutamate-mediated excitotoxicity, impaired mitochondrial function, 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)).

[0045] "One", "an" or "an" when used herein to refer to a group of substituents or "substituent groups" means at least one. For example, where a compound is substituted with "one" alkyl or aryl group, the compound is optionally substituted with at least one alkyl and / or at least one aryl group, wherein each alkyl and / or aryl group is optionally different. In another example, where a compound is substituted with "one" substituent group, the compound is substituted with at least one substituent group, wherein each substituent group is optionally different.

[0046] III. Composition

[0047] 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. Patent 8,859,774) which surprisingly provide improved solubility and stability of the compositions. Compound I is virtually insoluble in water and is difficult to dissolve in most dosage forms suitable for pharmaceutical use; conventional methods have proven unsuccessful in providing pharmaceutically acceptable compositions of this compound. Compositions prepared by conventional methods, even if capable of dissolving small amounts of Compound I, have proven to be unstable, Compound I precipitates out of solution, or Compound I is found to rapidly degrade therein, or Compound I is incompatible with pharmaceutically acceptable capsules. Surprisingly, the compositions disclosed herein overcome previous solubility and bioavailability problems and provide pharmaceutically acceptable compositions with enhanced solubility and bioavailability useful for treating disorders and conditions amenable to treatment by administration of Compound I.

[0048] According to lipid preparation classification system (LFCS), composition of the present invention is IV type composition.LFCS identifies the feature of lipid system (CW Puton, Eur.J.Pharm.Sci., 11 (supplement 2) (2000), pp. S93-S98). As classified in LFCS, I type preparation is the oil that needs digestion, II type preparation is the self-emulsifying drug delivery system (SEDDS) that is insoluble in water, III type system is SEDDS or self-microemulsifying drug delivery system (SMEDDS) or self-nanoemulsifying drug delivery system (SNEDDS), it contains some water-soluble surfactants and / or cosolvents (IIIA types) or water-soluble components (IIIB types) of larger proportion.IV type system represents mainly containing dispersion and being dissolved in aqueous medium to provide the hydrophilic surfactant and the preparation of cosolvent of solution.Further description of lipid preparation classification system can also be in FABAD J.Pharm.Sci., pp. 55-64, 2013.

[0049] The present invention provides a composition 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; dazucorilant; see Example 1 of U.S. Patent 8,859,774). In some embodiments, the present invention provides a composition comprising Compound I having the following structure:

[0050]

[0051] and a pharmaceutically acceptable excipient.

[0052] In some embodiments, the present invention provides 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:

[0053]

[0054] in an amount of 1 to 25% (w / w); a co-solvent in an amount of 1 to 25% (w / w); and a surfactant in an amount of 50 to 90% (w / w).

[0055] Compound I

[0056] Compound I can be present in any suitable relative amount in the composition of the present invention. For example, Compound I can be present in an amount of 1% to 50% (weight / weight), or 1% to 25%, or 5% to 40%, or 10% to 30%, or 10% to 25%, or 13% to 22%, or 10% to 20%, or 15% to 20%, or 13% to 17%, or 14% to 16%, or 18% to 22%, or 18% to 20%, or 18% to 22%, or 19% to 21% (weight / weight) in the composition of the present invention. Representative amounts of Compound I in the composition of the present invention include, but are not limited to, about 10% (weight / weight), or about 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or about 25% (weight / weight). Other amounts of Compound I that can be used in the compositions of the 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).

[0057] In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 1% to 25% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 10% to 25% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 15% to 20% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 13% to 22% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 15% to 20% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which Compound I is present in an amount of 18% to 20% (weight / weight).

[0058] In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 15% (w / w). In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 18.75% (w / w). In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 20% (w / w).

[0059] Compound I can be present in the composition of the present invention in any suitable absolute amount. For example, Compound I can be present in the composition of the present invention in an amount of 1mg to 500mg, or 10mg to 400mg, or 20mg to 300mg, or 30mg to 200mg, or 40mg to 100mg, or 50mg to 100mg, or 55mg to 90mg, or 60mg to 90mg, or 55mg to 85mg, or 70mg to 80mg, or 72mg to 78mg, or 74mg to 76mg. The representative amount of Compound I in the composition of the present invention includes but is not limited to about 10mg, or 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg or about 100mg. Other representative amounts of Compound I in the compositions of the present invention include, but are not limited to, about 55 mg, or 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, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg 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.

[0060] In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of 50 mg to 150 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of 50 mg to 100 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of 55 mg to 85 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of 55 mg to 65 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of 70 mg to 80 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of 75 mg to 85 mg.

[0061] In some embodiments, the compositions of the present invention include compositions wherein Compound 1 is present in an amount of about 60 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound 1 is present in an amount of about 75 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound 1 is present in an amount of about 80 mg.

[0062] In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 50 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 75 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 100 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 125 mg. In some embodiments, the compositions of the present invention include compositions wherein Compound I is present in an amount of about 150 mg.

[0063] Co-solvent

[0064] 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, glycerine, diethylene glycol monoethyl ether, tetrahydrofuran polyglycol ether, triacetin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, propylene glycol ester or their combination.

[0065] In some embodiments, the compositions of the present invention include compositions wherein the cosolvent includes 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. In some embodiments, the compositions of the present invention include compositions wherein the cosolvent includes polyethylene glycol (PEG).

[0066] When the cosolvent of the composition of the present invention is polyethylene glycol (PEG), PEG can have any suitable molecular weight, which is liquid or semisolid at room temperature.For example, the PEG cosolvent in the composition of the present invention can have 100 daltons to 5000 daltons, or 100 daltons to 2500 daltons, or 100 daltons to 1000 daltons, or 100 daltons to 750 daltons, or 200 daltons to 600 daltons, or 300 daltons to 500 daltons of molecular weight.The representative molecular weight of PEG cosolvent in the composition of the present invention includes but is not limited to about 220 daltons, or 260 daltons, 310 daltons, 350 daltons, 400 daltons, 440 daltons, 480 daltons, 530 daltons, 570 daltons, 620 daltons or about 660 daltons.In some embodiments, the composition of the present invention includes the composition wherein the cosolvent includes the polyethylene glycol (PEG400) with a molecular weight of about 400 daltons.

[0067] Cosolvents can be present in the compositions of the present invention in any suitable amount. For example, cosolvents can be present in the compositions of the present invention in an amount of 1% to 90% (weight / weight), or 5% to 25% (weight / weight), or 2% to 20%, or 3% to 15%, or 4% to 10%, or 5% to 8%, or 6% to 7% (weight / weight). Representative amounts of cosolvents in the compositions of the present invention include, but are not limited to, about 1% (weight / weight), or 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or about 10% (weight / weight). Other representative amounts of cosolvents 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% (weight / weight).

[0068] In some embodiments, the compositions of the present invention include compositions in which the cosolvent is present in an amount of 1% to 25% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the cosolvent includes PEG400 in an amount of 5% to 8% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the cosolvent includes PEG400 in an amount of 6% to 7% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the cosolvent includes PEG400 in an amount of about 6.5% (weight / weight).

[0069] Cosolvent can be present in the composition of the present invention with any suitable absolute amount.For example, cosolvent can be present in the composition of the present invention with 1mg to 100mg, or 5mg to 50mg, or 10mg to 40mg, or 15mg to 35mg, or 20mg to 30mg, or 22mg to 28mg, or 24mg to 28mg, or 25mg to 27mg. The representative amount of cosolvent in the composition of the present invention includes but is not limited to about 15mg, or 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg or about 35mg.

[0070] In some embodiments, the compositions of the present invention include compositions wherein the co-solvent is present in an amount of 20 mg to 30 mg. In some embodiments, the compositions of the present invention include compositions wherein the co-solvent is present in an amount of about 26 mg.

[0071] Surfactants

[0072] The surfactant of the composition of the present invention may include any suitable surfactant. The surfactant of the composition of the present invention is generally a hydrophilic nonionic surfactant and generally has an HLB value greater than 10 or greater than 12. Other nonionic surfactants that can be used in the composition of the present invention have an HLB value greater than 4. For example, the surfactant of the composition of the present invention includes, but is not limited to, vitamin E polyethylene glycol succinate (vitamin E TPGS), sorbitan monooleate, sorbitan monolaurate, polysorbate 80, polysorbate 20, Solutol HS15, poloxamer 407 or poloxamer 168, M-1944CS, Labrafil M-2125CS, (Gattefosse,Saint-Priest,Lyon,France)、 767 (IOIOleo GmbH, Germany), Gelucires (including Gelucire 44 / 14,48 / 16and 50 / 13), Kolliphor RH40, EL (also known as cremophor), Kolliphor P188, HS15, RH40 (hydroxystearate macrogol glyceride) (available from SIGMA-Aldrich, St. Louis, MO, USA), or a combination thereof.

[0073] In some embodiments, the compositions of the present invention include wherein the surfactant includes vitamin E polyethylene glycol succinate (vitamin E TPGS), polysorbate, Solutol HS15, poloxamer 407, M-1944CS, Labrafil M-2125CS, In some embodiments, the compositions of the present invention include compositions wherein the surfactant includes vitamin E polyethylene glycol succinate (vitamin E TPGS). In some embodiments, the compositions of the present invention include compositions comprising PEG400 and vitamin E TPGS.

[0074] Surfactant can be present in the composition of the present invention with any suitable amount.For example, surfactant can be present in the composition of the present invention with 10% to 95% (weight / weight), or 25% to 95% (weight / weight), or 50% to 95% (weight / weight), or 50% to 90% (weight / weight), or 60% to 90% (weight / weight), or 65% to 85% (weight / weight), or 70% to 80% (weight / weight), or 72% to 78% (weight / weight), or 72% to 76% (weight / weight), or 74% to 76% (weight / weight), or 76% to 80% (weight / weight) amount. The representative amount of surfactant in the composition of the present invention includes but is not limited to about 50% (weight / weight), or 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or about 95% (weight / weight). 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% (weight / weight). Other representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 73.1% (weight / weight), 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% (weight / weight). 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).

[0075] In some embodiments, the compositions of the present invention include compositions in which the surfactant is present in an amount of 10% to 90% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the surfactant is present in an amount of 50% to 90% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the surfactant includes vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 70%-80% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the surfactant includes vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 72%-78% (weight / weight). In some embodiments, the compositions of the present invention include compositions in which the surfactant includes vitamin E polyethylene glycol succinate (vitamin E TPGS) in an amount of 74%-76% (weight / weight).

[0076] In some embodiments, the compositions of the present invention include compositions wherein the surfactant includes 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 wherein the surfactant includes 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 wherein the surfactant includes vitamin E polyethylene glycol succinate (Vitamin E TPGS) in an amount of about 78.5% (w / w).

[0077] Surfactant can be present in the composition of the present invention with any suitable absolute amount.For example, surfactant can be present in the composition of the present invention with 100mg to 1000mg, or 100mg to 500mg, or 150mg to 450mg, or 200mg to 400mg, or 250mg to 350mg, or 275mg to 325mg amount.Representative amount of surfactant in the composition of the present invention includes but is not limited to about 250mg, or 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345 or about 350mg. Other representative amounts of surfactant in the compositions of the present invention include, but are not limited to, about 291 mg, or 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg or about 319 mg.

[0078] In some embodiments, the composition of the present invention includes a composition in which a surfactant is present in an amount of 275mg to 325mg. In some embodiments, the composition of the present invention includes a composition in which a surfactant is present in an amount of about 294mg. In some embodiments, the composition of the present invention includes a composition in which a surfactant is present in an amount of about 299mg. In some embodiments, the composition of the present invention includes a composition in which a surfactant is present in an amount of about 314mg.

[0079] combination

[0080] In some embodiments, the compositions of the present invention include compositions comprising Compound I, PEG400, and Vitamin E TPGS. In some embodiments, the compositions of the present invention consist essentially of compositions comprising Compound I, PEG400, and Vitamin E TPGS. In some embodiments, the compositions of the present invention include compositions consisting of Compound I, PEG400, and Vitamin E TPGS.

[0081] In some embodiments, the compositions of the present invention include compositions comprising: Compound I in an amount of about 18.75% (w / w); PEG400 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 include compositions comprising: Compound I in an amount of about 75 mg; PEG400 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 include compositions consisting of: Compound I in an amount of 75 mg; PEG400 in an amount of 26 mg; and Vitamin E TPGS in an amount of 299 mg.

[0082] In some embodiments, the compositions of the invention include compositions comprising: Compound I in an amount of about 50 mg; PEG400 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 invention include compositions consisting of: Compound I in an amount of 50 mg; PEG400 in an amount of 17 mg; and Vitamin E TPGS in an amount of 200 mg.

[0083] In some embodiments, the compositions of the invention include compositions comprising: Compound I in an amount of about 75 mg; PEG400 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 invention include compositions consisting of: Compound I in an amount of 75 mg; PEG400 in an amount of 26 mg; and Vitamin E TPGS in an amount of 299 mg.

[0084] In some embodiments, the compositions of the present invention include compositions comprising: Compound I in an amount of about 100 mg; PEG400 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 include compositions consisting of: Compound I in an amount of 100 mg; PEG400 in an amount of 35 mg; and Vitamin E TPGS in an amount of 399 mg.

[0085] In some embodiments, the compositions of the present invention include compositions comprising: Compound I in an amount of about 125 mg; PEG400 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 include compositions consisting of: Compound I in an amount of 125 mg; PEG400 in an amount of 43 mg; and Vitamin E TPGS in an amount of 498 mg.

[0086] In some embodiments, the compositions of the present invention include compositions comprising: Compound I in an amount of about 150 mg; PEG400 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 include compositions consisting of: Compound I in an amount of 150 mg; PEG400 in an amount of 52 mg; and Vitamin E TPGS in an amount of 598 mg.

[0087] In some embodiments, the compositions of the present invention include compositions comprising: Compound I in an amount of about 15% (w / w); PEG400 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 include compositions comprising: Compound I in an amount of about 60 mg; PEG400 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 include compositions consisting of: Compound I in an amount of about 60 mg; PEG400 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 include compositions consisting of: Compound I in an amount of 60 mg; PEG400 in an amount of about 26 mg; and Vitamin E TPGS in an amount of about 314 mg.

[0088] In some embodiments, the compositions of the present invention include compositions comprising: Compound I in an amount of about 20.0% (w / w); PEG400 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 include compositions comprising: Compound I in an amount of about 80 mg; PEG400 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 include compositions consisting of: Compound I in an amount of about 80 mg; PEG400 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 include compositions consisting of: Compound I in an amount of 80 mg; PEG400 in an amount of about 26 mg; and Vitamin E TPGS in an amount of about 294 mg.

[0089] The compositions of the present invention can be prepared and administered in a variety of oral dosage forms (including but not limited to liquid-filled capsules or solution products for oral or enteral administration). Other oral formulations include tablets, pills, powders, dragees, capsules, slurries, suspensions, etc. suitable for patient intake. Therefore, the present invention also provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and / or excipients and a compound or a pharmaceutically acceptable salt of the compound.

[0090] For preparing compositions from Compound I, pharmaceutically acceptable carriers can be solid, semisolid or liquid. A solid carrier can be one or more substances that can also act as a solubilizer, emulsifier, dispersant, antioxidant or encapsulating material. Technical details regarding formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0091] In addition, the carrier or excipient used in the pharmaceutical composition of the present invention is commercially available. As a further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott Williams & White, Baltimore, Md. (2000); and HC Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition, Lippincott Williams & White, Baltimore, Md. (1999).

[0092] Pharmaceutical preparations can be prepared in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged capsules or solutions in bottles, vials, or blister packs.

[0093] The composition of the present invention can be a unit dosage form. The unit dosage form of the composition of the present invention can be any suitable amount. For example, the composition of the present invention can be a unit dosage form of 100mg to 1000mg, or 200mg to 750mg, or 250mg to 750mg, or 300mg to 500mg, or 350mg to 450mg, or 375mg to 425mg. The representative unit dosage form amount of the composition of the present invention includes but is not limited to 100mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg or about 750mg. In some embodiments, the composition of the present invention includes a composition of a unit dosage form of 400mg. In some embodiments, the composition of the present invention includes a composition of a unit dosage form of 267mg. In some embodiments, the composition of the present invention includes a composition of a unit dosage form of 533mg. In some embodiments, the composition of the present invention includes a composition of a unit dosage form of 667mg. In some embodiments, the compositions of the present invention include 800 mg of the composition in unit dosage form.

[0094] The dosage regimen also takes into account pharmacokinetic parameters well known in the art, i.e., rate of absorption, bioavailability, metabolism, clearance, 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, supra). The prior art allows the clinician to determine the dosage regimen for each individual patient, GR and / or MR modulator, and disease or condition being treated.

[0095] Single or multiple administrations of the composition can be administered according to the dosage and frequency required and tolerated by the patient. The compound should provide a sufficient amount of active agent to effectively treat the disease state. Therefore, in some embodiments, the daily amount of the pharmaceutical preparation for oral administration of the compound is between about 0.5 mg to about 30 mg per kilogram of body weight per day. In some embodiments, the dosage can be about 1 mg to about 20 mg per kg of body weight per patient per day. The actual method for preparing a preparation that can be administered parenterally will be known or understood by those skilled in the art, and is described in more detail in publications such as Remington's (see above). See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal et al., eds., De Gruyter, New York (1987).

[0096] In some embodiments, the daily amount of the pharmaceutical formulation for oral administration of the compound is between about 50 mg and about 300 mg of Compound I. In some embodiments, the daily amount 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 amount of Compound I is provided in a single unit dosage form. In some embodiments, the daily amount 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 amount 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 amount is 75 mg of Compound I, provided as one unit dosage form containing 75 mg of Compound I. In some embodiments, the daily amount is 100 mg of Compound I, provided as one unit dosage form containing 100 mg of Compound I. In some embodiments, the daily amount is 100 mg of Compound I, provided as two unit dosage forms each containing 50 mg of Compound I. In some embodiments, the daily amount is 150 mg of Compound I, provided as one unit dosage form containing 150 mg of Compound I. In some embodiments, the daily amount is 150 mg of Compound I, provided as two unit dosage forms each containing 75 mg of Compound I. In some embodiments, the daily amount is 150 mg of Compound I, provided as three unit dosage forms each containing 50 mg of Compound I. In some embodiments, the daily amount is 300 mg of Compound I, provided as two unit dosage forms each containing 150 mg of Compound I. In some embodiments, the daily amount is 300 mg of Compound I, provided as three unit dosage forms each containing 100 mg of Compound I. In some embodiments, the daily amount is 300 mg of Compound I, provided as four unit dosage forms each containing 75 mg of Compound I.

[0097] The compounds described herein may be used in combination with other agents known to be useful in modulating the glucocorticoid receptor, or with adjunctive agents that may not be ineffective alone but may aid in the efficacy of the active agent.

[0098] In some embodiments, co-administration includes administration of one activating agent and administration of a second activating agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours. Co-administration includes simultaneous, approximately simultaneous (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other) or sequential administration of two activating agents in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., a single pharmaceutical composition comprising two activating agents is prepared. In some embodiments, an activating agent can be formulated separately. In some embodiments, an activating agent and / or an adjuvant can be connected or conjugated to each other.

[0099] After the composition of the present invention has been formulated in one or more acceptable carriers, the composition can be placed in an appropriate container and labeled for use in treating a designated condition. For the administration of Compound I, such a label will include, for example, instructions for the amount, frequency, and method of administration.

[0100] 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 soft gelatin capsule or a hard gelatin 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 soft gelatin capsule or a hard gelatin 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 soft gelatin 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 hard gelatin capsule.

[0101] In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form consisting essentially of a soft gelatin capsule, which contains a composition consisting of: Compound I in an amount of 75 mg; polyethylene glycol having a molecular weight of about 400 Daltons (PEG400), in an amount of 26 mg; and vitamin E polyethylene glycol succinate (vitamin E TPGS), in an amount of 299 mg.

[0102] In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form consisting essentially of a hard gelatin capsule, which contains a composition consisting of: Compound I in an amount of 75 mg; polyethylene glycol having a molecular weight of about 400 Daltons (PEG400), in an amount of 26 mg; and vitamin E polyethylene glycol succinate (vitamin E TPGS), in an amount of 299 mg.

[0103] In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form consisting essentially of a hard gelatin capsule containing a composition consisting of: Compound I in an amount of 50 mg; polyethylene glycol having a molecular weight of about 400 Daltons (PEG400), in an amount of 17 mg; and vitamin E polyethylene glycol succinate (vitamin E TPGS), in an amount of 199 mg.

[0104] In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form consisting essentially of a hard gelatin capsule, which contains a composition consisting of: Compound I in an amount of 100 mg; polyethylene glycol having a molecular weight of about 400 Daltons (PEG400), in an amount of 35 mg; and vitamin E polyethylene glycol succinate (vitamin E TPGS), in an amount of 399 mg.

[0105] In some embodiments, the unit dosage form for oral administration of the present invention is a unit dosage form consisting essentially of a hard gelatin capsule, which contains a composition consisting of: Compound I in an amount of 150 mg; polyethylene glycol having a molecular weight of about 400 Daltons (PEG400), in an amount of 52 mg; and vitamin E polyethylene glycol succinate (vitamin E TPGS), in an amount of 598 mg.

[0106] IV. How to use

[0107] In some embodiments, the present invention provides a method of treating a condition or disorder by modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention, thereby treating the condition or disorder.

[0108] In some embodiments, the present invention provides a method of treating a condition or disorder by antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention, thereby treating the condition or disorder.

[0109] In some embodiments, the invention provides methods for modulating glucocorticoid receptor activity using the technology described herein. In some embodiments, the method comprises contacting GR with an effective amount of a composition of the invention or Compound I, and detecting changes in GR activity.

[0110] In some embodiments, the invention provides methods for modulating glucocorticoid receptor activity using the technology described herein. In some embodiments, the method comprises contacting GR or both with an effective amount of a composition of the invention or Compound I, and detecting changes in GR activity, MR activity, or both.

[0111] 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 the GR, thereby inhibiting any biological response associated with the binding of the GR to the agonist.

[0112] 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 inhibits any biological response associated with the combination of GR and an agonist by binding to GR in preference to binding to another nuclear receptor (NR). In some embodiments, the binding of a specific glucocorticoid receptor antagonist to GR is preferred to binding to androgen receptor (AR), estrogen receptor (ER) or progesterone receptor (PR). In some exemplary embodiments, the binding of a specific glucocorticoid receptor antagonist to GR is preferred to binding to progesterone receptor (PR). In some embodiments, the binding of a specific glucocorticoid antagonist to GR is preferred to binding to androgen receptor (AR). In some embodiments, the binding of a specific glucocorticoid antagonist to GR is preferred to binding to androgen receptor (AR). In some embodiments, the binding of a specific glucocorticoid antagonist to GR is preferred to binding to estrogen receptor (ER).

[0113] In some embodiments, the association constant (Kd) of a specific glucocorticoid receptor antagonist binding to GR is at least 10 times smaller than the Kd for binding to AR or PR. In some embodiments, the association constant (Kd) of a specific glucocorticoid receptor antagonist binding to GR is at least 100 times smaller than the Kd for binding to AR or PR. In some embodiments, the association constant (Kd) of a specific glucocorticoid receptor antagonist binding to GR is at least 1000 times smaller than the Kd for binding to AR, PR or ER.

[0114] In some embodiments, the present invention provides a method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating ALS.

[0115] Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is a progressive neuromuscular disorder characterized by weakness, muscle atrophy, fasciculations, and increased reflexes. Currently, approximately 30,000 Americans suffer from the disease. The annual incidence is one to two cases per 100,000 people. The disease is most often diagnosed in middle-aged people, and more men than women. ALS is characterized by adult-onset, idiopathic, progressive degeneration of the anterior horn cells and upper and lower motor neurons of the spinal cord, resulting in progressive muscle weakness, atrophy, and fasciculations. Atrophy of the anterior horn cells of the spinal cord and replacement of large motor neurons by fibrillar astrocytes (gliosis) lead to stiffening of the affected anterior and lateral columns of the spinal cord, hence the name "lateral sclerosis." Typical signs and symptoms of ALS include muscle weakness, muscle atrophy (atrophy), muscle fasciculations, muscle cramps, slow movement, poor balance, incoordination, changes in voice quality, dysarthria, dysphagia, incomplete eye closure, drooling, pseudobulbar reactions, and premature death.

[0116] Up to 10% of ALS is familial, usually autosomal dominant. Several causative genes are known, and of these, mutant superoxide dismutase 1 (SOD) and mutant C9orf72 (i.e., a G4C2 hexanucleotide repeat in the C9orf72 gene) are most common in familial ALS (fALS) and sporadic ALS (sALS). Several other genes are known to be causes of classic ALS, although these genes account for a lower proportion of cases than mutant SOD1; these genes include mutant FUS (fused in sarcomas), mutant TARDBP genes that lead to modifications of TAR DNA binding protein 43 (TDP-43), and the optic neuropathy-inducing protein gene (optineurin).

[0117] Clinical manifestations vary depending on the area of ​​the nervous system that is damaged and the progression of pathological changes. The typical manifestation of ALS is insidious, progressive, asymmetric muscle weakness and atrophy, accompanied by neurological signs, especially fasciculations and hyperreflexia. It usually presents as flexibility or gait problems caused by muscle weakness. Difficulty speaking or swallowing are the initial symptoms of the bulbar form of the disease. Over a period of months or years, ALS patients develop severe progressive muscle weakness and other symptoms caused by loss of upper and lower motor neuron function. Sphincter control, sensory function, intelligence, and skin integrity are preserved. Patients become completely disabled and often require ventilatory support and gastrostomy. Death usually occurs within five years of diagnosis and is attributed 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 can include musculoskeletal, neurological, or systemic conditions. The cause of this disease is unknown. Current management includes active, personalized relief of symptoms and complications.

[0118] Examples of conditions or disorders suitable for use of 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.

[0119] V. Examples

[0120] Example 1. Preparation of Compound I

[0121] Compound I can be prepared as described in U.S. Pat. No. 8,859,774 (incorporated herein in its entirety for all purposes)

[0122] 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:

[0123]

[0124] Example 2. Preparation of Type IV Formulation of Compound I in Soft Gelatin Capsules

[0125] The IV formulation in soft gelatin capsules was prepared according to the following method:

[0126] Step 1: Preheat Vitamin E TPGS to a temperature of 65°C until melted in a suitable oven and dispense 74.75 g into a suitable mixing container. While maintaining the temperature at 40°C and stirring, polyethylene glycol (6.5 g) and compound I (18.75 g) are added to the container and the contents are mixed until a visually uniform solution is formed. The resulting solution (filling matrix) is then degassed, covered with nitrogen, stored until encapsulation, and stored at 45°C-55°C until encapsulation.

[0127] Step 2: Prepare a gel mass using a blend of gelatin, purified water and sorbitol-specific glycerin. The color of the gel mass is then transformed by adding titanium dioxide and red iron oxide.

[0128] Step 3: Encapsulate the fill matrix into soft gelatin capsules.

[0129] Step 4: Drying and hardening of capsules in drum dryer and drying chamber.

[0130] Step 5: Pack the capsules in batches in polyethylene lined corrugated shipping boxes.

[0131] Step 6: Packing the capsules into their final packaging form, such as bottles or blisters.

[0132] Table 1. Formulation IV of Compound I in soft gelatin capsules (75 mg concentration)

[0133]

[0134]

[0135] Table 2. Type IV formulation of compound I (filling matrix 60 mg concentration)

[0136]

[0137] Table 3. Type IV formulation of compound I (filling matrix 80 mg concentration)

[0138]

[0139] Example 3. Preparation of Type IV Formulation of Compound I in Hard Gelatin Capsules (150 mg Concentration) The IV formulation in hard gelatin capsules was prepared according to the following method:

[0140] Step 1: Preheat Vitamin E TPGS to a temperature of 65°C until melted in a suitable oven and dispense 448.5 g into a suitable mixing container. While maintaining the temperature at 45°C-55°C and stirring, add polyethylene glycol (39.0 g) and Compound I (112.5 g) to the container and mix the contents until a visually uniform solution is formed. The resulting solution (filling matrix) is then stored at 45°C-55°C until encapsulation.

[0141] Step 2: The melted fill matrix (800 mg) was encapsulated into size 00el hard gelatin capsules.

[0142] Step 3: Encapsulate the capsules using a 25% w / w gelatin solution. The capsules are then placed on a drying rack on the capsule encapsulation equipment until dry and sealed.

[0143] Step 4: Packing the capsules into their final packaging form, such as bottles or blisters.

[0144] Table 4. Formulation IV of Compound I, fill matrix and hard gelatin capsule (150 mg concentration)

[0145]

[0146] 1 Applied as a 25% gelatin solution. Water is removed during drying.

[0147] Example 4. Stability test of type III and type IV filling matrices of compound I

[0148] Using the 18.75% weight / weight Compound I fill matrix shown in Table 1, the IV fill matrix was prepared as described above and tested under various accelerated stability conditions and compared with the III fill matrix. For samples of the IV formulation spiked with water, 5 g of water was stirred into the solution. The solution, still in a molten state, was then filled into vials and stored for in-vial stability testing.

[0149] Using the weight / weight percentages in Table 5, samples of Type III formulations are prepared according to known methods. For example, Kolliphor ELP and Masester E8120 are preheated to a temperature of 65° C. in a suitable oven until melted. Caproyl 90 (32.24 g), Masester E8120 (24.83 g), and Kolliphor ELP (24.18 g) are added to a suitable mixing container and stirred until uniform while maintaining a temperature of 40° C. Compound I (18.75 g) is added and mixed until dissolved and a completely uniform solution is formed. For samples containing antioxidants, the desired amount of antioxidant (0.167 g dl-α tocopherol or 0.02 g BHT) is added, and the levels of Caproyl 90, Masester E8120, and Kolliphor ELP are reduced in proportion to compensate for the presence of antioxidants. The solution is stirred until all substances are dissolved and the solution is uniform. For samples mixed with water, 5 g of water is stirred into the solution.

[0150] Table 5. Type III Filling Matrix Formulations

[0151]

[0152]

[0153] The stability of Type IV capsule fill matrix samples as solutions stored in sealed glass screw-cap vials under accelerated conditions was evaluated and compared to alternative Type III formulations with or without antioxidants. For example, 2 g quantities of each solution type were filled into 4 mL amber glass vials, the headspace was nitrogen purged and the vials were capped. The samples were placed in stability chambers at 30°C / 65% RH and 40°C / 75% RH. Assay and impurity levels were evaluated over a period of up to 12 weeks using an appropriate HPLC method.

[0154] For antioxidants in type III formulations, typical use levels are 0.02% weight / weight butylated hydroxytoluene (BHT) or 0.16% weight / weight vitamin E (dl-alpha tocopherol) added with additional samples without evaluating antioxidants. Some vials are mixed with 5% water (wet samples) to promote degradation, because it is known that moisture will migrate from the capsule shell to the filling matrix during manufacturing or storage. Unwatered samples (dry samples) were also evaluated. For type IV formulations, no antioxidants were added, but both wet and dry samples were evaluated. The samples were stored at 40°C / 75%RH and 30°C / 65%RH for up to twelve weeks, and the content and total impurities were determined. The results are shown in Tables 6, 7, 8 and 9.

[0155] Table 6. Content data of capsule filling matrix stored at 30°C / 60%RH

[0156]

[0157] NA - Not Evaluated

[0158] Table 7. Content data of capsule filling matrix stored at 40°C / 75%RH

[0159]

[0160] NA - Not Evaluated

[0161] Table 8. Impurity data of capsule fill matrix stored at 30°C / 65%RH

[0162]

[0163] NA = Not Evaluated

[0164] Table 9. Impurity data of capsule filling matrix stored at 40°C / 75%RH

[0165]

[0166] NA = Not Evaluated

[0167] Example 5. Stability test of IV formulation of compound I (150 mg concentration) in hard gelatin capsules

[0168] Stability data were obtained for hard gelatin capsules at a concentration of 150 mg prepared according to the method of Example 3. Clear 7 mL glass vials with polypropylene screw caps containing the hard gelatin capsules of Example 3 were stored under ambient conditions (15-25° C. in the dark). The assay and the levels of two key impurities (COR176-6 and CORT125863) were determined after 12 and 24 months.

[0169]

[0170] Table 10. Stability data of Formulation IV of Compound I (150 mg) in hard gelatin capsules (glass vial)

[0171]

[0172]

[0173] No chromatographic response factors were applied to impurities.

[0174] Example 6. Preparation of Type IV Formulation of Compound I in Hard Gelatin Capsules (75 mg Concentration) The IV formulation in a 75 mg strength hard gelatin capsule is prepared according to the following method:

[0175] Step 1: Preheat Vitamin E TPGS to a temperature of 60°C-65°C until melted in a suitable oven and dispense 1943.5 g into a suitable mixing container. While maintaining the temperature at 40°C-50°C and stirring, add polyethylene glycol (169.0 g) and Compound I (487.5 g) to the container and mix the contents until a visually uniform solution is formed. The resulting solution (filling matrix) is then stored at 45°C-55°C until encapsulation.

[0176] Step 2: The melted fill matrix (400 mg) was encapsulated into size 0 hard gelatin capsules.

[0177] Step 3: The capsules are coated with gelatin solution, then dried and sealed.

[0178] Step 4: Pack the capsules into their final packaging form in bottles. Consider alternative packaging such as blisters.

[0179] Table 11. Formulation IV of Compound I in hard gelatin capsules (75 mg concentration)

[0180]

[0181] 1 Applied as an aqueous solution containing 21.43% w / w gelatin, 1.17% w / w polysorbate 80 and 0.87% w / w FD&C blue dye. Water is removed during drying.

[0182] Example 7. Stability test of type IV formulation (75 mg concentration) of compound I in hard gelatin capsules

[0183] 60 ml HPDE bottles containing 30 hard gelatin capsules of Example 5 were stored under ICH stability conditions. The assay and the levels of two key impurities (COR176-6 and CORT125863) were determined for up to 3 months.

[0184] Table 12. Room temperature storage (25°C / 60% RH) of Type IV formulation of Compound I (75 mg concentration) in hard gelatin capsules (HDPE bottles)

[0185]

[0186] A chromatographic relative response factor (RRF) of 2.72 was applied to the COR176-6 impurity, while an RRF of 1.30 was applied to CORT125863.

[0187] Table 13. Accelerated Temperature Storage (40°C / 75%RH) of Formulation IV of Compound I (75 mg concentration) in Hard Gelatin Capsules (HDPE Bottles)

[0188]

[0189] A chromatographic relative response factor (RRF) of 2.72 was applied to the COR176-6 impurity, while an RRF of 1.30 was applied to CORT125863.

[0190] Example 8. Preparation of Type IV Formulation of Compound I in Soft Gelatin Capsules (75 mg Concentration) The IV formulation in soft gelatin capsules was prepared according to the following method and in accordance with Table 1:

[0191] Step 1: Preheat Vitamin E TPGS to a temperature of 65°C until melted in a suitable oven and dispense 747.5 g into a suitable mixing container. While maintaining the temperature at 40°C and stirring, polyethylene glycol (65.0 g) and compound I (187.5 g) are added to the container and the contents are mixed until a visually uniform solution is formed. The resulting solution (filling matrix) is then degassed, blanketed with nitrogen, and stored at 40°C-45°C until encapsulation.

[0192] Step 2: Prepare a gel mass using a blend of gelatin, purified water and sorbitol-specific glycerin. The color of the gel mass is then transformed by adding titanium dioxide and red iron oxide.

[0193] Step 3: Encapsulate the fill matrix (400 mg) into soft gelatin capsules.

[0194] Step 4: Drying and hardening of capsules in drum dryer and drying chamber.

[0195] Step 5: Pack the batches of capsules in polyethylene lined corrugated shipping boxes.

[0196] Step 6: Packing the capsules into their final packaging form in bottles or blisters.

[0197] Example 9. Stability of Formulation IV of Compound I (75 mg concentration) in Soft Gelatin Capsules

[0198] Blisters containing 75 mg strength soft gelatin capsules as provided in Example 8 were stored under ICH conditions. The assay and levels of two key 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.

[0199] Table 14. Soft gelatin capsules (75 mg) in blisters stored at room temperature (25°C / 60% RH)

[0200]

[0201] Chromatographic relative response factors have been applied to COR176-6 (2.72) and CORT125863 (1.30).

[0202] Table 15. Soft gelatin capsules in blisters (75 mg concentration) at accelerated temperature storage (40°C / 75% RH)

[0203]

[0204] Chromatographic relative response factors have been applied to COR176-6 (2.72) and CORT125863 (1.30).

[0205] Although the foregoing invention has been described in detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be made within the scope of the appended claims. In addition, each reference, including all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification, are incorporated herein by reference in their entirety to the extent that they are not inconsistent with this specification. In the event of a conflict between the present application and the references provided herein, the present application shall prevail.

Claims

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: Amounts of 1% to 25% (weight / weight); a co-solvent in an amount of 1% to 25% (w / w); and Surfactant, in an amount of 50% to 90% (w / w).

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

3. A composition as claimed in claim 1 or 2, 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. The composition of any one of claims 1 to 4, wherein Compound I is present in an amount of 50 mg to 150 mg.

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

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

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 (PEG400) having a molecular weight of about 400 Daltons.

11. The composition of any one of claims 1 to 10, wherein the co-solvent comprises PEG400 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 PEG400 in an amount of 6% to 7% (w / w).

13. The composition of any one of claims 1 to 12, wherein the co-solvent comprises PEG400 in an amount of about 6.5% (w / w).

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 HS15, poloxamer 407, M-1944CS, M-2125CS, 767. Gelucire, Kolliphor, or a combination thereof.

15. The composition of any one of claims 1 to 14, wherein the surfactant comprises vitamin E polyethylene glycol succinate (vitamin E TPGS).

16. The composition of any one of claims 1 to 15, wherein the surfactant comprises vitamin E polyethylene glycol succinate (Vitamin E TPGS) in an amount of 70% to 80% (w / w).

17. The composition of any one of claims 1 to 16, wherein the surfactant comprises vitamin E polyethylene glycol succinate (Vitamin E TPGS) in an amount of 74% to 76% (w / w).

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. The composition of any one of claims 1 to 18, comprising: Compound I, in an amount of about 18.75% (w / w); PEG400 in an amount of about 6.5% (w / w); and Vitamin E TPGS, in an amount of about 74.75% (w / w).

20. The composition of any one of claims 1 to 19, comprising: Compound I, in an amount of about 75 mg; PEG400 in an amount of about 26 mg; and Vitamin E TPGS, amount is about 299 mg.

21. A composition as described in any one of claims 1 to 20, consisting of: Compound I, in an amount of 75 mg; PEG400, amount: 26 mg; and Vitamin E TPGS, quantity is 299mg.

22. The composition of any one of claims 1 to 19, comprising: Compound I, in an amount of about 50 mg; PEG400 in an amount of about 17 mg; and Vitamin E TPGS, amount is about 199 mg.

23. A composition as claimed in any one of claims 1 to 19, comprising: Compound I, in an amount of about 100 mg; PEG400 in an amount of about 35 mg; and Vitamin E TPGS, amount is about 399 mg.

24. A composition as claimed in any one of claims 1 to 19, comprising: Compound I, in an amount of about 150 mg; PEG400 in an amount of about 52 mg; and Vitamin E TPGS, amount is about 598 mg.

25. The composition of any one of claims 1 to 18, comprising: Compound I, in an amount of about 15% (w / w); PEG400 in an amount of about 6.5% (w / w); and Vitamin E TPGS, in an amount of about 78.5% (w / w).

26. The composition of any one of claims 1 to 25, comprising: Compound I, in an amount of about 60 mg; PEG400 in an amount of about 26 mg; and Vitamin E TPGS, amount is about 314 mg.

27. A composition as claimed in any one of claims 1 to 18, comprising: Compound I, in an amount of about 20.0% (w / w); PEG400 in an amount of about 6.5% (w / w); and Vitamin E TPGS, in an amount of about 73.5% (w / w).

28. A composition as claimed in any one of claims 1 to 27, comprising: Compound I, in an amount of about 80 mg; PEG400 in an amount of about 26 mg; and Vitamin E TPGS, amount is about 294 mg.

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

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

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

32. The unit dosage form of claim 30 or 31 consisting essentially of a soft gelatin capsule containing a composition consisting of: Compound I, in an amount of 75 mg; Polyethylene glycol (PEG400) having a molecular weight of about 400 Daltons, in an amount of 26 mg; and Vitamin E polyethylene glycol succinate (Vitamin E TPGS), amount is 299 mg.

33. The unit dosage form of claim 30, wherein said capsule is a hard gelatin capsule.

34. The unit dosage form of claim 30 or 33 consisting essentially of a hard gelatin capsule containing a composition consisting of: Compound I, in an amount of 75 mg; Polyethylene glycol (PEG400) having a molecular weight of about 400 Daltons, in an amount of 26 mg; and Vitamin E polyethylene glycol succinate (Vitamin E TPGS), amount is 299 mg.

35. The unit dosage form of claim 30 or 33 consisting essentially of a hard gelatin capsule containing a composition consisting of: Compound I, in an amount of 50 mg; Polyethylene glycol (PEG400) having a molecular weight of about 400 Daltons, in an amount of 17 mg; and Vitamin E polyethylene glycol succinate (Vitamin E TPGS), amount 199 mg.

36. The unit dosage form of claim 30 or 33 consisting essentially of a hard gelatin capsule containing a composition consisting of: Compound I, in an amount of 100 mg; Polyethylene glycol (PEG400) having a molecular weight of about 400 Daltons, in an amount of 35 mg; and Vitamin E polyethylene glycol succinate (Vitamin E TPGS), amount 399 mg.

37. The unit dosage form of claim 30 or 33 consisting essentially of a hard gelatin capsule containing a composition consisting of: Compound I, in an amount of 150 mg; Polyethylene glycol (PEG400) having a molecular weight of about 400 Daltons, in an amount of 52 mg; and Vitamin E polyethylene glycol succinate (Vitamin E TPGS), amount is 598 mg.

38. 1 kinds of methods for treating a condition or illness by regulating the glucocorticoid receptor, said method comprising administering a therapeutically effective amount of a composition as described in any one of claims 1 to 29 or a unit dosage form as described in any one of claims 30 to 37 to a subject who needs such treatment, thereby treating said condition or illness.

39. 1 kinds of methods for treating a condition or illness by antagonizing glucocorticoid receptor, said method comprising administering a therapeutically effective amount of a composition as described in any one of claims 1 to 29 or a unit dosage form as described in any one of claims 30 to 37 to a subject who needs such treatment, thereby treating said condition or illness.

40. A method of treating amyotrophic lateral sclerosis (ALS), the method 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 ALS.

41. A method of treating Alzheimer's disease, the method 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. A method of treating Huntington's disease, the method 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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