Corticotropin-releasing factor receptor antagonists

Abstract

To provide novel pharmaceutical compositions for treatment of congenital adrenal hyperplasia (CAH).SOLUTION: The present invention provides pharmaceutical compositions comprising 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 545,393, filed August 14, 2017, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Corticotropin-releasing factor (CRF), a 41-amino acid peptide, is the primary physiological peptide regulating the secretion of proopiomelanocortin (POMC)-derived peptides from the anterior pituitary gland. In addition to its endocrine role in the pituitary gland, immunohistochemical localization of CRF has revealed that this hormone is widely distributed throughout the central nervous system outside the hypothalamus and exerts a wide range of autonomic, electrophysiological, and behavioral effects, consistent with its role as a neurotransmitter or neuromodulator in the brain. CRF also plays an important role in coordinating immune system responses to physiological, psychological, and immunological stressors. Summary of the Invention

[0003] The present invention provides novel pharmaceutical compositions comprising 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using such pharmaceutical compositions for the treatment of congenital adrenal hyperplasia (CAH).

[0004] In one aspect, the present disclosure provides a compound 1, [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0005] In one embodiment, the pharmaceutical composition comprises about 1 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 5 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 10 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 10 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 10 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0006] In one embodiment, the pharmaceutical composition comprises about 50 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 150 mg to about 250 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0007] In one embodiment, the pharmaceutical composition comprises about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 250 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 150 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 50 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 30 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0008] In one embodiment, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is in the form of microparticles. In one embodiment, the average size of the microparticles is about 1 μm to about 20 μm. In one embodiment, the average size of the microparticles is about 5 μm to about 15 μm. In one embodiment, the average size of the microparticles is less than about 10 μm.

[0009] In one embodiment, the capsule is a hard gelatin capsule. In one embodiment, the capsule is a soft gelatin capsule. In one embodiment, the capsule is formed using a material selected from the group consisting of natural gelatin, synthetic gelatin, pectin, casein, collagen, proteins, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, and any combination thereof.

[0010] In one embodiment, the pharmaceutical composition contains no additional excipients. In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0011] In one aspect, the present disclosure provides a compound 1, [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0012] In one embodiment, the pharmaceutical composition comprises about 1 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 5 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 10 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 10 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 10 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0013] In one embodiment, the pharmaceutical composition comprises about 50 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 150 mg to about 250 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0014] In one embodiment, the pharmaceutical composition comprises about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 250 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 150 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 50 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition comprises about 30 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0015] In one embodiment, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is in the form of microparticles. In one embodiment, the average size of the microparticles is about 1 μm to about 20 μm. In one embodiment, the average size of the microparticles is about 5 μm to about 15 μm. In one embodiment, the average size of the microparticles is less than about 10 μm.

[0016] In one embodiment, the tablet is made by compression, molding, or extrusion. In one embodiment, the tablet is made by hot melt extrusion. In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0017] In one embodiment, the pharmaceutical composition is stable at 25° C. for at least 1 month. In one embodiment, the pharmaceutical composition is stable at 25° C. for at least 3 months. In one embodiment, the pharmaceutical composition is stable at 25° C. for at least 6 months. In one embodiment, the pharmaceutical composition is stable at 25° C. for at least 9 months. In one embodiment, the pharmaceutical composition is stable at 25° C. for at least 12 months.

[0018] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0019] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0020] [Figure 1] FIG. 1 shows Compound 1 in CAH patients after 14 days of once-daily dosing at each dose level.

[0021] [Figure 2] FIG. 2 shows the attenuation of ACTH in different subjects by administration of Compound 1.

[0022] [Figure 3] FIG. 3 shows the reduction in 17-OHP by administration of Compound 1.

[0023] [Figure 4] FIG. 4 shows the reduction in androstenedione with compound administration.

[0024] [Figure 5] FIG. 5 shows the percentage release of manufactured formulations A-1, A-2, and A-3 under the conditions of a medium containing 0.1 N HCl + 1.0% SDS, 50 rpm, 900 mL, and using USP-II (paddle).

[0025] [Figure 6] FIG. 6 shows the release rates of manufactured formulations B-1, B-2, and B-3 under the conditions of a medium containing 0.1 N HCl + 1.0% SDS, 50 rpm, 900 mL, and using USP-II (paddle).

[0026] [Figure 7] FIG. 7 shows the release rates of manufactured formulations C-1, C-2, and C-3 under the conditions of a medium containing 0.1N HCl + 1.0% SDS, 50 rpm, 900 mL, and using USP-II (paddle). DETAILED DESCRIPTION OF THE INVENTION

[0027] CRF has been associated with psychiatric and neurological disorders, including depression and anxiety, as well as Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy, migraine, alcohol abuse, substance abuse, abuse-related withdrawal, obesity, metabolic syndrome, congenital adrenal hyperplasia (CAH), Cushing's disease, hypertension, stroke, irritable bowel syndrome, stress-induced gastric ulcers, premenstrual syndrome, psychosexual dysfunction, preterm labor, inflammatory diseases, allergies, multiple sclerosis, visceral pain, sleep disorders, pituitary or ectopic pituitary tumors, chronic fatigue syndrome, and fibromyalgia.

[0028] The CRF receptor subtypes CRF1 and CRF2 have been identified, but their heterogeneous distribution in the brain suggests their potential for diverse functions. For example, CRF1 receptors, which are widely distributed in the brain, are strongly associated with emotionality associated with exposure to environmental stressors. Importantly, CRF1 receptors appear to mediate and select for anxiety-provoking behaviors, whereas CRF2 receptors do not. Their more discrete distribution in the septal hypothalamus and availability of alternative endogenous ligands suggest a distinct functional role for CRF2 receptors. For example, a novel CRF family neuropeptide with preferential affinity for CRF2 receptors compared with CRF1 receptors has been reported to suppress appetite without exhibiting the behavioral activation profile observed with selective CRF1 receptor agonism. In other cases, CRF2 receptor agonism produces effects similar to those reported for CRF1 antagonists and CRF1 gene deletion. For example, while CRF2 agonists have been proposed as anti-obesity drugs, CRF1 antagonists may also be important treatments for obesity.

[0029] Treatment of CAH, from diagnosis in infancy through adulthood, is based on normalizing hormone and steroid levels using a variety of medications. Glucocorticoids, the current standard of care for CAH, are used to both correct the deficiency of endogenous cortisol and reduce the elevated levels of ACTH from the pituitary gland, which increases androgen production. Unlike treatment for Addison's disease (adrenal insufficiency), in which cortisol replacement is sufficient, treatment for CAH also requires reducing ACTH production to regulate subsequent androgen excess. Thus, the goals of glucocorticoid therapy include preventing virilization and menstrual disorders in women through cortisol replacement and ACTH suppression. In patients with salt-wasting CAH, mineralocorticoid replacement is required to achieve normal plasma renin activity to maintain steady-state blood pressure, electrolyte balance, and volume status.

[0030] A glucocorticoid treatment program is necessary to support normal physiological function and also ensure that sufficient cortisol is available during events that may elicit a strong stress response (e.g., intercurrent illness, exercise, hypotension). Careful monitoring is also required to avoid the development of Addison's syndrome due to inadequate treatment. While excessive mineralocorticoid treatment can cause hypertension, inadequate treatment can result in hypotension, salt wasting, fatigue, and increased glucocorticoid requirements. Typical laboratory tests used to monitor treatment efficacy include measurement of plasma 17-OHP levels, androstenedione levels, testosterone levels, renin activity, and electrolytes.

[0031] Adult patients with CAH have increased prevalence of cardiovascular risk factors, including obesity, hypertension, and insulin resistance. A large cohort study of pediatric and adult patients with CAH (n = 244) found that patients prescribed various glucocorticoid treatment regimens frequently developed hormonal dysregulation and the adverse events described above. Treatment of CAH involves attempts to normalize cortisol deficiency with glucocorticoids (usually hydrocortisone in children, but often more potent agents with narrow therapeutic indices, such as dexamethasone in adults), and, if necessary, with mineralocorticoids (usually fludrocortisone) in cases of salt-wasting CAH. However, the glucocorticoid doses required to achieve adequate suppression of androgen excess are typically much higher than the usual physiologic doses used for cortisol replacement alone in patients with Addison's disease. This increased exposure to glucocorticoids may lead to increased cardiovascular risk factors, impaired glucose tolerance, and bone mineral loss in patients with CAH.

[0032] CRF is thought to be the primary physiological regulator of basal and stress-induced release of adrenocorticotropic hormone ("ACTH"), β-endorphin, and other proopiomelanocortin ("POMC")-derived peptides from the anterior pituitary gland. CRF secretion triggers the release of ACTH from corticotrophs in the anterior pituitary gland via binding to the CRF1 receptor, a member of the class B family of G protein-coupled receptors.

[0033] Given the physiological importance of CRF1, the development of biologically active small molecules that have significant CRF receptor binding activity and can antagonize the CRF1 receptor remains desirable and is the subject of ongoing research and development for the treatment of anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, and substance abuse.

[0034] The pituitary hormone ACTH, under the control of corticotropin-releasing factor (CRF) secreted from the hypothalamus, stimulates cholesterol uptake, drives pregnenolone synthesis, and initiates steroidogenesis in the adrenal gland. The adrenal cortex is composed of three regions, each producing a different class of hormone, but much of this hormone production is driven by ACTH, which mobilizes cholesterol through this pathway. Deficiency of these enzymes as a result of mutation or deletion increases the concentration of their substrates. In CAH, the most common condition, caused by mutation or deletion in the 21-hydroxylase gene (CYP21 A2), potent androgens are produced by the adrenal gland through the accumulation of their steroid precursors, progesterone and 17-hydroxyprogesterone (17-OHP). In these cases, plasma concentrations of 17-OHP can reach 10 to 1,000 times normal levels. This increase results in excessive production of androgens, particularly androstenedione, testosterone, and dihydroxytestosterone, leading to virilization in women. Furthermore, the deficiency of 21-hydroxylase in CAH results in insufficient biosynthesis of glucocorticoids and mineralocorticoids, particularly cortisol and aldosterone. Cortisol is an essential negative feedback regulator of CRF secretion in the hypothalamus and ACTH release in the pituitary. Insufficient glucocorticoid synthesis and release removes inhibitions on the hypothalamus and pituitary, resulting in increased ACTH levels. This excess ACTH stimulation leads to hypertrophy of the zona fasciculata and zona reticularis, resulting in adrenal hyperplasia.

[0035] In one embodiment, a CRF receptor antagonist useful in the treatment of CAH is 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine.

[0036] Specific Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein. Certain preferred methods, devices, and materials are described below.

[0037] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, a reference to an "excipient" refers to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

[0038] The use of the term "about" implies that the value contains the standard level of error for the device or method being employed to determine the value.

[0039] The use of the term "or" in the claims is intended to mean "and / or" unless expressly indicated to refer to only alternatives or unless the alternatives are mutually exclusive, although the present disclosure supports the definition of referring to only alternatives and "and / or."

[0040] The terms "comprise," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," is open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also encompasses other unlisted steps.

[0041] "Administering," when used in connection with a therapeutic agent, means administering the therapeutic agent systemically or locally into or onto a target tissue, or administering a therapeutic agent to a patient to allow the therapeutic agent to have a positive effect on the target tissue. "Administering" a pharmaceutical composition may be accomplished by injection, topical administration, oral administration, alone or in combination with other known techniques, or by other methods.

[0042] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0043] The term "pharmaceutical composition" refers to a composition containing at least one active ingredient, such as Compound 1, and thus suitable for testing a particular efficacy outcome in a mammal (e.g., without limitation, a human). Those skilled in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired efficacy outcome based on the needs of the artisan.

[0044] The term "supraphysiological" amount refers to elevated hormone levels compared to the average values found in healthy individuals.

[0045] The term "physiological amount" refers to the average hormone level found in healthy individuals.

[0046] A "therapeutically effective amount" or "effective amount," as used herein, refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, said response including one or more of the following: (1) disease prevention, e.g., prevention of a disease, disorder, or disorder in an individual who may be predisposed to the disease, disorder, or disorder but who has not yet experienced or exhibited the symptoms or symptomology of the disease; (2) disease suppression, e.g., suppression of a disease, disorder, or disorder (i.e., prevention of further occurrence of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, disorder, or disorder; and (3) disease amelioration, e.g., amelioration of a disease, disorder, or disorder (i.e., reversal of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, disorder, or disorder.

[0047] The terms "treat," "treated," "treatment," or "treating," as used herein, refer to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, aimed at preventing or delaying (reducing) an undesirable physiological condition, disorder, or disease, or achieving a beneficial or desired clinical result. For purposes herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent of the abnormality, disorder, or disease; stabilization (i.e., not worsening) of the abnormality, disorder, or disease state; delay in the onset or progression of the abnormality, disorder, or disease; improvement in the abnormality, disorder, or disease state; and remission (which may be partial or complete), which may be detectable or undetectable, or which may result in enhancement or amelioration of the abnormality, disorder, or disease. Treatment includes eliciting a clinically meaningful response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Prophylactic benefit of treatment includes preventing the abnormality, slowing the progression of the abnormality, stabilizing the abnormality, or reducing the likelihood of the abnormality occurring. As used herein, "treat," "treated," "treatment," or "treating" also includes prevention in some embodiments.

[0048] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will immediately occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0049] compound Disclosed herein is 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine (or 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine), its pharmaceutically acceptable salts, and / or solvates thereof. [ka] In some embodiments, 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine is referred to as Compound 1. In some embodiments, 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine is referred to as Compound 1.

[0050] Pharmaceutical Composition Poorly soluble drugs can be difficult to formulate using techniques such as high shear wet granulation. Optimal delivery of poorly soluble drugs may require complex techniques such as solid solution amorphous dispersions (e.g., hot melt extrusion or spray drying), nanoformulations, or lipid-based formulations. Hydrophobic drug substances may be considered poorly soluble according to USP standards and are known to be difficult to granulate with water and other excipients, as most excipients for immediate release formulations can be water-soluble or water-swellable.

[0051] The production of mini-tablets for high-dose, poorly soluble drug substances may require high concentrations of the drug substance. However, as the drug concentration increases beyond a certain value, granule formation becomes more difficult, and at certain drug doses, granule formation may become impossible.

[0052] In one embodiment, the pharmaceutical compositions described herein may be pharmaceutical compositions for the pediatric population. Therefore, it may be necessary to keep the pharmaceutical composition as small as possible to facilitate pill swallowing and promote patient compliance. In some embodiments, the tablet weight is less than 400 mg. In some embodiments, the tablet weight is less than 300 mg. In some embodiments with a 200 mg dose strength, the amount of drug in the tablet is greater than 50%. In some embodiments with a 200 mg dose strength, the amount of drug in the tablet is greater than 66%. In some embodiments with a 200 mg dose strength, the amount of drug is maximized.

[0053] Disclosed herein are pharmaceutical compositions comprising Compound 1, its pharmaceutically acceptable salts, and / or solvates thereof.

[0054] Dosage form In some embodiments, the pharmaceutical compositions described herein are provided in unit dosage form. As used herein, a "unit dosage form" refers to a composition containing an amount of Compound 1 suitable for administration to an animal subject, preferably a mammalian subject, in a single dose in accordance with good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is to be administered once per day or once per treatment course. Such dosage forms are contemplated to be administered once, twice, three times, or more times per day, and may be administered as an infusion over a period of time (e.g., over about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be given more than once during the course of treatment, although a single dose is not specifically excluded.

[0055] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose, as well as the appropriate duration and frequency of administration, will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Typically, an appropriate dose and treatment regimen provides a sufficient amount of the composition to achieve a therapeutic and / or prophylactic effect, for example, an increased frequency of complete or partial remission, or an improved clinical outcome such as an increased disease-free interval and / or overall survival, or a reduced severity of symptoms. The optimal dose is usually determined using experimental models and / or clinical trials. The optimal dose is determined based on the patient's size, weight, or blood volume.

[0056] In some embodiments, the pharmaceutical compositions described herein are formulated as oral dosage forms. Suitable oral dosage forms include, for example, tablets, pills, sachets, and capsules. In some embodiments, the pharmaceutical compositions further comprise one or more pharmaceutically acceptable excipients. For a list of pharmaceutically acceptable excipients, see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 2001). st See Ed. Mack Pub. Co., Easton, PA (2005).

[0057] Capsules In some embodiments, the pharmaceutical composition is formulated as a capsule. In some embodiments, the pharmaceutical composition is formulated as a hard gel capsule. In some embodiments, the pharmaceutical composition is formulated as a soft gel capsule.

[0058] In some embodiments, the capsule is formed using the following materials, including, but not limited to, natural gelatin, synthetic gelatin, pectin, casein, collagen, proteins, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, or any combination thereof. In some embodiments, the capsule is formed using preservatives, colorants, opacifiers, flavorings, sweeteners, sugars, gastroresistant substances, or any combination thereof. In some embodiments, the capsule is coated. In some embodiments, the coating covering the capsule includes, but is not limited to, an immediate-release coating, a protective coating, an enteric or delayed-release coating, a sustained-release coating, a barrier coating, a seal coating, or a combination thereof. In some embodiments, the capsule herein is a hard capsule or a soft capsule. In some embodiments, the capsule is a seamless capsule. In some embodiments, the capsule is broken, allowing the particulate matter to be sprinkled on soft food and swallowed without chewing. In some embodiments, the capsules vary in shape and size. Examples of capsule shapes include, but are not limited to, round, oval, cylindrical, oblong, twist-off, and irregular shapes. The size of the capsule may vary based on the volume of the particulate material. In some embodiments, the size of the capsule is adjusted based on the volume of the particulate material and powder. Hard or soft gelatin capsules may be conventionally manufactured as single-body units containing the standard capsule shapes listed above. Single-body soft gelatin capsules may typically be provided in shapes such as oval, oblong, and the like, in sizes ranging from 3 to 22 microns (1 micron equals 0.0616 mL).The gelatin capsules may be manufactured conventionally, for example, as two-piece hard gelatin capsules that may or may not be sealed, and are typically of standard shape, and come in a variety of standard sizes conventionally designated (000), (00), (0), (1), (2), (3), (4), and (5), with the highest number corresponding to the smallest size. In some embodiments, the pharmaceutical compositions (e.g., capsules) described herein are swallowed whole.

[0059] In some embodiments, the capsule comprises one or more pharmaceutically acceptable excipients, hi some embodiments, the capsule does not comprise any additional excipients.

[0060] In some embodiments, capsules are developed, manufactured, and marketed for insoluble drug substances. In some embodiments, a drug substance is insoluble if its solubility in water is less than 0.002 mg / mL. In some embodiments, the capsules have a maximum dosage strength of 200 mg. In some embodiments, the drug substance in the capsules is released immediately into the dissolution medium using USP Apparatus I. In some embodiments, the drug substance in the capsules is released immediately into the dissolution medium using USP Apparatus II.

[0061] tablet Insoluble drugs can be difficult to formulate using standard techniques such as high-shear wet granulation. Optimal delivery of insoluble drugs may require complex techniques such as solid solution amorphous dispersions (hot-melt extrusion or spray drying), nanoformulations, or lipid-based formulations. Hydrophobic drug substances may be considered insoluble according to USP standards and are known to be difficult to granulate with water and other excipients. This is likely because most known excipients for immediate-release formulations are water-soluble or water-swellable. Making tablets of insoluble, high-dose drug substances can require high concentrations of the drug substance. However, as drug concentration increases beyond a certain value, granule formation can become increasingly difficult. Furthermore, at certain drug doses, granule formation may be impossible.

[0062] In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0063] In some embodiments, the tablet is prepared by compression, molding, or extrusion, optionally with one or more pharmaceutically acceptable excipients. In some embodiments, compressed tablets are prepared by free-flowing compression of Compound 1, optionally with pharmaceutically acceptable excipients. In some embodiments, molded tablets are prepared by molding a mixture of Compound 1 powder moistened with an inert liquid diluent. In some embodiments, the tablet is prepared by hot-melt extrusion. In some embodiments, extruded tablets are prepared by forcing a mixture containing Compound 1 through an orifice or die under controlled conditions. In some embodiments, the tablet is coated or scored. In some embodiments, the tablet is formulated for delayed or controlled release of Compound 1. In some embodiments, the tablet is developed, manufactured, or marketed for an insoluble drug substance. In some embodiments, the drug substance is insoluble if its solubility in water is less than 0.002 mg / mL. In some embodiments, the tablet has a dose strength of up to 200 mg. In some embodiments, the drug substance in the tablet is released immediately into the dissolution medium using USP Apparatus I. In some embodiments, the drug substance in the tablet is released immediately into the dissolution medium using USP Apparatus II.

[0064] In some embodiments, the tablet size is less than about 1000 mg, less than about 800 mg, less than about 600 mg, less than about 400 mg, or less than about 200 mg. In some embodiments, the tablet has a dose strength of greater than about 50 mg, greater than about 100 mg, greater than about 150 mg, greater than about 200 mg, or greater than about 250 mg. In some embodiments, the tablet size is less than about 1000 mg and the dose strength is greater than about 50 mg. In some embodiments, the tablet size is less than 800 mg and the dose strength is greater than about 100 mg. In some embodiments, the tablet size is less than 600 mg and the dose strength is greater than about 150 mg. In some embodiments, the tablet size is less than 400 mg and the dose strength is greater than about 200 mg. In some embodiments, the tablet size is less than 400 mg and the dose strength is 200 mg. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents. In some embodiments, more than about 40% of the tablet dissolves in conventional solvents. In some embodiments, more than about 50% of the tablet dissolves in conventional solvents. In some embodiments, more than about 60% of the tablet dissolves in conventional solvents. In some embodiments, more than about 70% of the tablet dissolves in conventional solvents. In some embodiments, more than about 80% of the tablet dissolves in conventional solvents. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents in less than 24 hours. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents in less than 12 hours. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents in less than 6 hours. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents in less than 3 hours. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents in less than 2 hours. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 40% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 50% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 60% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 70% of the tablet dissolves in conventional solvents in less than 60 minutes.In some embodiments, more than about 80% of the tablet dissolves in conventional solvents in less than 60 minutes, hi some embodiments, more than 70% of the tablet dissolves in conventional solvents in 60 minutes.

[0065] In some embodiments, the tablets are manufactured on a commercial scale.

[0066] In some embodiments, the tablet comprises one or more pharmaceutically acceptable excipients.

[0067] In some embodiments, the tablet is coated with a coating material, e.g., a sealant. In some embodiments, the coating material is water-soluble. In some embodiments, the coating material includes a polymer, a plasticizer, a pigment, or any combination thereof. In some embodiments, the coating material is in the form of a film coating, such as a gloss film, a pH-independent film coating, an aqueous film coating, a dry powder film coating (e.g., a fully dry powder film coating), or any combination thereof. In some embodiments, the coating material is highly adhesive. In some embodiments, the coating material provides a low level of water permeability. In some embodiments, the coating material provides oxygen barrier protection. In some embodiments, the coating material allows for rapid disintegration for rapid release of Compound 1. In some embodiments, the coating material is colored, clear, or white. In some embodiments, the coating is an enteric coating. Exemplary coating materials include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, cellulose acetate trimellitate, sodium alginate, zein, and any combination thereof.

[0068] Pharmaceutically acceptable excipients In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient. In some embodiments, the composition does not include a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient," as used herein, refers to one or more compatible solid or encapsulating substances suitable for administration to a mammal. The term "compatible," as used herein, means that the components of the composition are miscible with the subject compound and with each other under normal use conditions without interactions that would significantly reduce the pharmaceutical efficacy of the composition. In some embodiments, the pharmaceutically acceptable excipient has sufficiently high purity and sufficiently low toxicity to be suitable for administration, preferably to an animal to be treated, preferably to a mammal to be treated.

[0069] Some examples of substances that can be used as pharmaceutically acceptable excipients include: Amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is L-arginine. · Monosaccharides such as glucose (grape sugar), arabinose, mannitol, fructose (levulose), and galactose. Cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose. · Solid lubricants such as talc, stearic acid, magnesium stearate, and sodium stearyl fumarate. · Polymers such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol. · Emulsifiers such as polysorbates. Wetting agents such as sodium lauryl sulfate, Tween®, Span, alkyl sulfates, and alkyl ethoxylate sulfates. · Cationic surfactants such as cetrimide, benzalkonium chloride, and cetylpyridinium chloride. ·Diluents such as calcium carbonate, microcrystalline cellulose, calcium phosphate, starch, pregelatinized starch, sodium carbonate, mannitol, and lactose. · Binders such as starch (corn starch and potato starch), gelatin, sucrose, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC). · Disintegrating agents such as starch and alginic acid. · Superdisintegrants such as Ac-Di-Sol, croscarmellose sodium, sodium starch glycolate, and crospovidone. · Glidants such as silicon dioxide. · Coloring agents such as FD&C dyes. · Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors. Preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, parabens, and sodium benzoate. · Tonicity agents such as sodium chloride, potassium chloride, mannitol, and glycerin. · Antioxidants such as sodium bisulfite, acetone-sodium bisulfite, formaldehyde-sodium sulfoxylate, thiourea, and EDTA. · pH adjusters such as NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. Cryoprotectants such as sodium phosphate, potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates (e.g., glucose, mannitol, and dextran). Surfactants such as sodium lauryl sulfate. Cationic surfactants such as cetrimide (including tetradecyltrimethylammonium bromide, including dodecyl and hexadecyl compounds), benzalkonium chloride, and cetylpyridinium chloride. Some examples of anionic surfactants include alkyl sulfates, alkyl ethoxylate sulfates, soaps, carboxylate ions, sulfate ions, and sulfonate ions. Some examples of nonionic surfactants include polyoxyethylene derivatives, polyoxypropylene derivatives, polyol derivatives, polyol esters, polyoxyethylene esters, poloxamers, glycols, glycerol esters, sorbitan derivatives, polyethylene glycols (such as PEG-40, PEG-50, and PEG-55), and fatty alcohol esters. Carbohydrates, modified carbohydrates, lactose (including a-lactose monohydrate, spray-dried lactose, and anhydrous lactose), starch, pregelatinized starch, sucrose, mannitol, sorbitol, and organic substances such as cellulose (including powdered cellulose and microcrystalline cellulose). Inorganic substances such as calcium phosphate (including anhydrous dibasic calcium phosphate, calcium hydrogen phosphate, and tribasic calcium phosphate). Co-processed diluents. Compression aid. ·Anti-tacking agents such as silicon dioxide and talc.

[0070] content In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 50 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 40 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 30 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 20 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 10 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 5 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 5 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0071] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 1 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 5 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 10 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0072] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 20 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0073] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 30 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0074] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 40 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0075] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises about 50 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0076] In some embodiments, the pharmaceutical composition comprises about 100 mg to about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg to about 250 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0077] In some embodiments, the pharmaceutical composition comprises about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 90 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 80 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 40 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 30 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 20 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0078] particle size In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises Compound 1, or a pharmaceutically acceptable salt or solvate thereof, in the form of microparticles. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 100 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 50 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 30 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 20 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 5 μm to about 15 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 10 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 3 μm to about 10 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 4 μm to about 9 μm.

[0079] In some embodiments, the microparticles of Compound 1 have an average size of less than about 100 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 80 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 60 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 50 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 40 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 30 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 20 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 10 μm.

[0080] Pharmacokinetics In some embodiments, Compound 1 inhibits T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T maxIn some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max It is formulated as a capsule or tablet so that the duration of action is about 3 to about 5 hours.

[0081] In some embodiments, Compound 1 inhibits T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max In some embodiments, Compound 1 is formulated as a capsule or tablet to provide a T max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max It is formulated as a capsule or tablet so that the onset of action is approximately 1 hour.

[0082] stability The pharmaceutical compositions described herein are stable under various storage conditions, including refrigerated, ambient, and accelerated conditions. Stable, as used herein, refers to a pharmaceutical composition that contains at least about 95% of the initial content of Compound 1 and contains less than about 5% (w / w) of impurities or related substances overall at the end of a given storage period. The percentage of impurities is calculated based on the content of the impurities relative to the content of Compound 1. Stability is assessed by HPLC or any other known testing method. In some embodiments, a stable pharmaceutical composition contains about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2.5% (w / w), about 2% (w / w), about 1.5% (w / w), about 1% (w / w), or about 0.5% (w / w) of impurities or related substances overall. In other embodiments, a stable pharmaceutical composition contains about 5% (w / w) of impurities or related substances overall. In yet another embodiment, the stable pharmaceutical composition contains about 4% (w / w) total impurities or related substances. In yet another embodiment, the stable pharmaceutical composition contains about 3% (w / w) total impurities or related substances. In yet another embodiment, the stable pharmaceutical composition contains about 2% (w / w) total impurities or related substances. In yet another embodiment, the stable pharmaceutical composition contains about 1% (w / w) total impurities or related substances.

[0083] Under refrigerated conditions, the pharmaceutical compositions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the refrigerated conditions are 5±5°C. In some embodiments, the refrigerated conditions are about 0°C, about 0.1°C, about 0.2°C, about 0.3°C, about 0.4°C, about 0.5°C, about 0.6°C, about 0.7°C, about 0.8°C, about 0.9°C, about 1°C, about 1.1°C, about 1.2°C, about 1.3°C, about 1.4°C, about 1.5°C, about 1.6°C, about 1.7°C, about 1.8°C, about 1.9°C, about 2°C, about 2.1°C, about 2.2°C, about 2.3°C, about 2.4°C, about 2.5°C, about 2.6°C, about 2.7°C, about 2.8°C, about 2.9°C, about 3.0°C, about 3.1°C, about 3.2°C, about 3.3°C, about 3.4°C, about 3.5°C, about 3.6°C, about 3.7°C, about 3.8°C, about 3.9°C, about 4.0°C, about 4.1°C, about 4.2°C, about 4.3°C, about 4.4°C, about 4.5°C, about 4.6°C, about 4.7°C, about 4.8°C, about 4.9 .3°C, about 2.4°C, about 2.5°C, about 2.6°C, about 2.7°C, about 2.8°C, about 2.9°C, about 3°C, about 3.1°C, about 3.2°C, about 3.3°C, about 3.4°C, about 3.5°C, about 3.6°C, about 3.7°C, about 3.8°C, about 3.9°C, about 4°C, about 4.1°C, about 4.2°C, about 4.3°C, about 4.4°C, about 4.5°C, about 4.6°C, about 4.7°C, about 4.8°C, about 4. .9℃, about 5℃, about 5.1℃, about 5.2℃, about 5.3℃, about 5.4℃, about 5.5℃, about 5.6℃, about 5.7℃, about 5.8℃, about 5.9℃, about 6℃, about 6.1℃, about 6.2℃, about 6.3℃, about 6.4℃, about 6.5℃, about 6.6℃, about 6.7℃, about 6.8℃, about 6.9℃, about 7℃, about 7.1℃, about 7.2℃, about 7.3℃, about 7.4℃, about 7.5 9°C, about 9.1°C, about 9.2°C, about 9.3°C, about 9.4°C, about 9.5°C, about 9.6°C, about 9.7°C, about 9.8°C, about 9.9°C, or about 10°C. Under accelerated conditions, the pharmaceutical compositions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months.Accelerated conditions for the pharmaceutical compositions described herein include temperatures at or above ambient temperature levels (e.g., 25±5°C). In some cases, the accelerated conditions are about 40±2°C. In some cases, the accelerated conditions are about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C. Accelerated conditions for the pharmaceutical compositions described herein also include RH at or above ambient humidity levels (55±10% relative humidity (RH)). In other cases, the accelerated conditions are about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In other cases, the accelerated conditions are about 40°C or 60°C at ambient humidity. In yet other cases, the accelerated conditions are about 40±2°C at a humidity of 75±5% RH.

[0084] In some embodiments, the pharmaceutical composition is stable at about 5±5°C to about 25±5°C for at least 12 months. In one embodiment, the pharmaceutical composition is stable at about 5±5°C for at least 12 months. In one embodiment, the pharmaceutical composition is stable at about 25±5°C for at least 12 months. In one embodiment, the pharmaceutical composition is stable at about 5±5°C for at least 24 months. In one embodiment, the pharmaceutical composition is stable at about 25±5°C for at least 24 months.

[0085] Usage Disclosed herein are methods for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the CAH is classical CAH. In some embodiments, the CAH is non-classical CAH. In some embodiments, the methods described herein result in a decrease in hormone levels. Such hormones include deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, aldosterone, pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone (17-OHP), dehydroepiandrosterone, androstenediol, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, estriol, and adrenocorticotropic hormone (ACTH). In some embodiments, the methods described herein result in a decrease in 17α-hydroxyprogesterone (17-OHP). In some embodiments, the methods described herein result in a decrease in adrenocorticotropic hormone (ACTH), also known as corticotropin.

[0086] Also provided herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising: (i) measuring hormone levels in a subject in need of said treatment; (ii) Compound 1, [ka] or a pharmaceutically acceptable salt or solvate thereof, and (iii) repeating steps (i) and (ii) until the hormone levels reach a predetermined range, followed by maintenance therapy with daily administration of Compound 1; A method is disclosed that includes:

[0087] In some embodiments, the hormone is 17α-hydroxyprogesterone (17-OHP), adrenocorticotropic hormone (ACTH), testosterone, or androstenedione.

[0088] In some embodiments, the hormone is 17-OHP and the predetermined range is about 200 ng / dL to about 400 ng / dL, hi some embodiments, the hormone is 17-OHP and the predetermined range is less than about 400 ng / dL, less than about 350 ng / dL, less than about 300 ng / dL, less than about 250 ng / dL, or less than about 200 ng / dL.

[0089] In some embodiments, the hormone is ACTH and the predetermined range is less than about 100 pg / mL, hi some embodiments, the hormone is ACTH and the predetermined range is less than about 100 pg / mL, less than about 90 pg / mL, or less than about 80 pg / mL.

[0090] In some embodiments, the hormone is testosterone and the predetermined range is about 14 ng / dL to about 76 ng / dL, hi some embodiments, the hormone is testosterone and the predetermined range is less than about 76 ng / dL, less than about 70 ng / dL, less than about 65 ng / dL, less than about 60 ng / dL, less than about 55 ng / dL, less than about 50 ng / dL, less than about 45 ng / dL, less than about 40 ng / dL, less than about 35 ng / dL, less than about 30 ng / dL, less than about 25 ng / dL, less than about 20 ng / dL, or less than about 15 ng / dL.

[0091] In some embodiments, the hormone is androstenedione and the predetermined range in men is about 30 ng / dL to about 200 ng / dL, hi some embodiments, the hormone is androstenedione and the predetermined range in men is less than about 200 ng / dL, less than about 150 ng / dL, less than about 100 ng / dL, less than about 50 ng / dL, or less than about 30 ng / dL.

[0092] In some embodiments, the hormone is androstenedione and the predetermined range in women is about 40 ng / dL to about 150 ng / dL, hi some embodiments, the hormone is androstenedione and the predetermined range in women is less than about 150 ng / dL, less than about 100 ng / dL, less than about 50 ng / dL, or less than about 40 ng / dL.

[0093] In some embodiments, the methods described herein comprise administering the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once a month, twice a month, three times a month, once a week, twice a week, three times a week, every other day, once a day, twice a day, three times a day, or four times a day. In some embodiments, the methods described herein administer Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once a day. In some embodiments, the methods described herein administer Compound 1, or a pharmaceutically acceptable salt or solvate thereof, twice a day.

[0094] In some embodiments, the methods described herein involve administering about 1 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, per day. In some embodiments, about 100 mg to about 1600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, per day. In some embodiments, about 200 mg to about 1600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, per day. In some embodiments, about 200 mg to about 1200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, per day. In some embodiments, about 200 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, per day. In some embodiments, about 200 mg to about 800 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, per day. In some embodiments, about 100 mg to about 800 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 800 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 100 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 300 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 100 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered daily, and in some embodiments, about 300 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered daily.

[0095] In some embodiments, less than about 2000 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1800 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1000 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 800 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 600 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 500 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 400 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 300 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 200 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered per day.

[0096] In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein and the subject is in a fed state. In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein and the subject is in a fasted state.

[0097] In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein at bedtime.

[0098] In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein up to about 4 hours before bedtime. In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein up to about 3 hours before bedtime. In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein up to about 2 hours before bedtime. In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein up to about 1 hour before bedtime. In some embodiments, the methods described herein comprise administering a pharmaceutical composition described herein up to about 30 minutes before bedtime.

[0099] In some embodiments, the methods described herein comprise the administration of a pharmaceutical composition described herein during the night.

[0100] In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 11 PM. In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 10 PM. In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 9 PM. In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 8 PM.

[0101] In some embodiments, the methods described herein involve administering a pharmaceutical composition described herein at or before the expected time of diurnal release of adrenocorticotropic hormone (ACTH). In some embodiments, the methods described herein involve administering a pharmaceutical composition described herein about 3 to 4 hours before the expected time of diurnal release of adrenocorticotropic hormone (ACTH).

[0102] Combination therapy Disclosed herein are methods for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, the methods comprising administering a combination of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and a glucocorticoid. In some embodiments, the amount of glucocorticoid administered is reduced compared to a method that does not include administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0103] In some embodiments, the methods described herein reduce the dosage of glucocorticoids from supraphysiological amounts to physiological amounts.

[0104] In some embodiments, the methods described herein reduce a condition associated with high-dose glucocorticoid therapy, in some embodiments, the condition associated with high-dose glucocorticoid therapy is obesity, insulin resistance, metabolic disorder, hypertension, cardiovascular disease, or osteoporosis.

[0105] In some embodiments, the dosage of the glucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 80%, or about 90% when compared to a method that does not include administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dosage of the glucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% when compared to a method that does not include administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments, the dose of glucocorticoid is reduced by about 1% to about 90%, about 1% to about 60%, about 1% to about 30%, about 1% to about 10%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 15% to about 25%, about 20% to about 30%, about 5% to about 25%, about 20% to about 50%, about 30% to about 60%, or about 40% to about 70% when compared to a method that does not include administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0107] In some embodiments, the glucocorticoid is administered at a dose of about 0.1 mg / day to about 25 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 20 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 15 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 12 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 11 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 10 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 9 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 8 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 7 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 6 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 5 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 4 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 3 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 2 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 3 mg / day to about 13 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 5 mg / day to about 11 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 8 mg / day to about 11 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 9 mg / day to about 12 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 9 mg / day to about 10 mg / day, hi some embodiments, the glucocorticoid is administered at a dose of about 5 mg / day to about 10 mg / day.

[0108] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered simultaneously. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered in a single pharmaceutical composition. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered in separate pharmaceutical compositions.

[0109] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 24 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 8 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 6 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 4 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 2 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 1 hour. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 30 minutes, hi some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 10 minutes.

[0110] In some embodiments, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone, hi some embodiments, the glucocorticoid is hydrocortisone.

[0111] In some embodiments, the glucocorticoid is hydrocortisone and is administered at a dose less than the recommended dose of 15-25 mg / day.

[0112] In some embodiments, the glucocorticoid is prednisone and is administered at a dose less than the recommended dose of 5-7.5 mg / day.

[0113] In some embodiments, the glucocorticoid is prednisolone and is administered at a dose less than the recommended dose of 4-6 mg / day.

[0114] In some embodiments, the glucocorticoid is dexamethasone and is administered at a dose less than the recommended dose of 0.25-0.5 mg / day.

[0115] Disclosed herein are methods for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, the methods comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with a glucocorticoid and, optionally, a mineralocorticoid. In some embodiments, the mineralocorticoid is fludrocortisone, and the dose is less than the recommended dose of 0.05-0.2 mg / day. [Example]

[0116] The following examples further illustrate the present invention, but should not be construed as limiting the scope of the present invention in any way. In particular, the processing conditions are merely exemplary and can be easily modified by those skilled in the art.

[0117] All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended solely to facilitate understanding of the present invention and does not limit the scope of the present invention unless specifically stated in the claims. Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.

[0118] Example 1: Pharmaceutical Composition The pharmaceutical composition is prepared as a size 1 white hard gelatin capsule containing 200 mg of Compound 1 micronized to an average size of 10 μm or less. The pharmaceutical composition does not contain any additional excipients.

[0119] Example 2: Stability of pharmaceutical compositions Stability Data Overview A summary of the stability testing of the pharmaceutical compositions is shown in Table 1. The pharmaceutical compositions were prepared by filling pure Compound 1 without any added excipients into size 0 capsules in three strengths (1 mg, 5 mg, and 50 mg), which were blister-packaged in polyvinyl chloride (PVC) film.

[0120] No significant trends were observed among the three lots for any of the attributes evaluated through stability studies under long-term accelerated conditions. [Table 1]

[0121] Stability Testing Protocol Stability testing protocols for various pharmaceutical compositions are listed in Tables 2, 3, and 4. [Table 2] [Table 3] [Table 4]

[0122] These supporting data indicate that the pharmaceutical composition is stable for a minimum of six months (until the end of the study). No adverse trends were identified under long-term or accelerated conditions. Quantitative results were consistent throughout the study, and no new related species were observed during the stability study. Reported stability results for lots stored in the blister pack configuration are considered supportive of the updated packaging configuration of a 30 mL HDPE bottle, induction seal, and child-resistant cap. Both configurations are excipient-free and protected from light.

[0123] Example 3: Phase 1 Clinical Trial Compound 1 was investigated in two Phase 1 studies in healthy adult volunteers.

[0124] Study 1 was a first-in-human study in which single ascending doses of Compound 1 were administered orally to healthy adult subjects to evaluate its safety, tolerability, and PK. Safety and tolerability were assessed across a wide range of single oral doses, and dose escalation proceeded after review of safety data from the previous dose. Data from this study were used to guide dose selection for Study 2.

[0125] Study 2, a two-part, multiple-dose study, determined the safety and tolerability of repeated daily doses of Compound 1 and examined its effects on biomarkers relevant to the treatment of alcohol dependence. Part B examined the interaction of Compound 1 with midazolam (a substrate of cytochrome P450 3A4 [CYP3A4]) to determine whether Compound 1 significantly inhibits the metabolism of drugs metabolized by CYP3A4.

[0126] In the first study, Compound 1 was administered as a single oral dose of 2, 10, 50, 150, 400, or 800 mg to healthy adult subjects in the fed state and as a single oral dose of 150 mg to healthy adult subjects in the fasted state. In the fed state, absorption occurred somewhat slower, with C peaks occurring 4 to 6 hours after administration. max We've reached our peak.

[0127] Table 5 summarizes the PK parameters at each dose level. When Compound 1 was administered under fed conditions, the time to reach the maximum plasma concentration (T max ) median time occurred between 4 and 6 hours. When 150 mg of Compound 1 was administered in the fasting state, T max The median half-life (t) after a single oral dose was 10.05 hours, ranging from 6 to 12 hours, suggesting that delayed absorption may occur under fasting conditions. 1 / 2 ) (fed and fasted states) was 31 to 44 hours, ranging from 11 to 101 hours. The apparent volume of distribution (V z / F) was large and varied considerably, with the greatest variability seen at the top two dose levels, 400 mg and 800 mg. [Table 5]

[0128] As part of this single-dose escalation study, the effect of food on PK was investigated, examining exposure to the 150 mg dose level of Compound 1 in both fed and fasted states. A total of six subjects received 150 mg of Compound 1 in each of these two dose groups. Of these six subjects, four subjects received the same dose of Compound 1 in both fed and fasted states. Administration of Compound 1 in the fasted state resulted in a significantly flatter mean concentration-time profile (i.e., significantly less absorption) when compared to the mean profile at the same dose obtained within 5 minutes after a standardized breakfast. Fed State, AUC for 150 mg Dose 0-∞ and C maxThe mean values of α, β, and β were approximately 3-fold and 11-fold greater than those in the fasted state, respectively. Table 6 summarizes the PK parameters at the 150 mg dose level under both fed and fasted conditions. [Table 6]

[0129] Dose proportionality of Compound 1 at doses of 50 to 800 mg administered under fed conditions was evaluated using the PK parameter AUC 0-∞ and C max The results of this analysis showed that with each doubling of the dose, the AUC 0-∞ It was suggested that the increase in C was predicted to be more than 1.74 times greater than predicted based on dose proportionality. max Although the dose-proportionality of AUC appeared to be exceeded, the 90% confidence interval was only partially within the 0.8-1.25 range, making it impossible to determine by formal testing. 0-∞ or C max No conclusions could be drawn from this.

[0130] PK was also evaluated in Study 2, a multiple-ascending dose study. In Part A of the study, subjects were divided into three cohorts and received 50 mg, 150 mg, or 200 mg of Compound 1 or placebo for 14 consecutive days (at least six subjects in each cohort received Compound 1 and two subjects received placebo). Compound 1 plasma concentrations reached near steady-state values two weeks after dosing, with accumulation ratios ranging from 2.51 to 3.65. In Part B, the interaction of Compound 1 with midazolam (a CYP3 A4 substrate) was examined to determine whether this compound significantly inhibits the metabolism of drugs metabolized by CYP3 A4. Serial blood samples were collected to determine plasma concentrations of the study drug after a single dose of Compound 1 and at steady state. All doses were administered under fed conditions. Assessment of diurnal cortisol levels was performed both before and during the dosing period, as well as under glucose clamp conditions.

[0131] Overall, the concentration-time profile of Compound 1 showed moderately slow absorption, with C values reaching C values at a median of 5 hours after oral administration. max Consistent with the single-dose study (Study 1) described above, concentrations appeared to decline biexponentially, characterized by a rapid decline during the first 24 hours. After 2 weeks of multiple daily dosing, the t 1 / 2 That is, the accumulation ratio of Compound 1 was 2.51 to 3.65 (see Table 7). max appeared consistent across doses. Overall, half-life, weight-normalized CL / F, and V / F were consistent between 150 mg and 200 mg; however, values for the latter two parameters nearly doubled at the 50 mg dose level. Variability (CV%) in apparent clearance and volume of distribution was large but not reduced by weight normalization. [Table 7]

[0132] Table 8 shows the AUC 0-24 and Cmax The results of the dose proportionality evaluation are shown in Table 1. 0-24 and C max The adjusted means of the slopes on days 1 and 14 were all greater than 1, which indicates that the AUC 0-24 and C max This shows that the increase in the value of is slightly more than proportional. [Table 8]

[0133] safety Two Phase 1 studies (Study 1 and Study 2) evaluated the safety of Compound 1 in healthy adult volunteers. Both studies assessed adverse events (AEs), clinical laboratory tests, vital signs (supine blood pressure and pulse rate), and electrocardiograms (ECGs). Overall, Compound 1 was well tolerated in Study 1. Compound 1 was generally well tolerated in the healthy subject population studied at multiple doses up to 200 mg.

[0134] The first study examined effects on biomarkers relevant to the treatment of alcohol dependence. Compound 1 was compared against placebo using five clusters of the ARCI-49 (Addiction Research Center Inventory Questionnaire): the Morphine-Benzedrine Group Scale, which measures euphoria; the Acid-Diethylamide Group Scale, which assesses dysphoria and physical changes; the Pentobarbital-Chlorpromazine-Alcohol Group Scale, which measures sedation; the Benzedrine Group (BG), which measures intellectual efficiency and energy; and the Amphetamine Group Scale, which measures the effects of d-amphetamine. No systematic patterns or dose-responses were identified in the changes from baseline or differences above placebo within each cluster.

[0135] In summary, single oral doses up to 800 mg and multiple doses up to 200 mg of Compound 1 were well tolerated in healthy male and female subjects.

[0136] Example 4: Phase 2 Multiple Ascending Dose Clinical Trial Cohort A of the Phase 2 study will involve a 6-week, multiple-ascending dose study of Compound 1 for the treatment of adult patients with classic CAH. After screening, eligible patients will be enrolled in a 6-week treatment period followed by a 4-week washout / safety follow-up period.

[0137] This cohort will consist of approximately nine patients, who will receive Compound 1 daily for up to six weeks. Compound 1 will be administered as an oral daily dose. Patients will be titrated with Compound 1 at two-week intervals through three ascending dose strengths. Patients will undergo overnight PK / PD assessments at baseline, including a pre-dose overnight PK / PD assessment and, after administration of the first dose, a post-dose overnight PK / PD assessment. At the end of each two-week dosing period, patients will return for one overnight steady-state PK / PD assessment. Outpatient follow-up visits will occur 30 days after the last dose. After completion of the first cohort (Cohort A), the study will progress to a multiple ascending dose (MAD) design with up to three consecutive cohorts (Cohort B, Cohort C, and Cohort D) to further evaluate the safety, PK, and PD of various SPR001 dosing regimens and identify optimal dosing. Each cohort will undergo a 2-week run-in period, a 2-week treatment period, and a 30-day washout and safety follow-up period. The run-in period will be conducted at screening, during which subjects will complete a paper diary of each dose of glucocorticoid medication taken, the time of each meal, and daily bedtime and wake-up times to ensure compliance with the background glucocorticoid regimen and the stability of the subject's daily routine.

[0138] Patients in Cohort B will receive 200 mg of study drug twice daily, once in the morning and once in the evening, with meals or a consistent light snack. For Cohorts C and D, dose level, frequency, and timing will be determined based on interim data from the previous cohort. However, the dose level for each successive cohort will be limited to twice the daily dose level of the previous cohort. Study design Type of study: interventional study ·Main purpose: treatment Phase of study: Phase 2 Intervention trial model: sequential allocation Cohort count: Maximum 4 Shielding: No shielding Allocation: Non-randomized - Enrollment: Maximum of 27 people (estimated) [Table 9] Evaluation items Primary endpoint: 1. Evaluating the safety of Compound 1 in subjects with CAH. 2. Evaluate the safety of Compound 1 in subjects with classic CAH, as measured by percent and absolute change in 17-OHP compared to baseline. Secondary endpoints: 3. Identify the dose of Compound 1 that produces pharmacodynamic changes in plasma concentrations of ACTH, androstenedione, and testosterone, as measured by absolute and percent changes from baseline due to treatment. 4. Confirmation of the pharmacokinetics of Compound 1 in subjects with CAH 5. Exploring possible relationships between pharmacology and pharmacokinetics Examination 7. To explore the dose of Compound 1 that induces changes in urinary pharmacodynamic biomarkers, as measured by absolute and percent change from baseline due to treatment. Eligibility Minimum age: 18 years old Maximum age: Gender: Both men and women Gender consideration: None No healthy volunteers included Criteria: Inclusion on the boundary standard: Selection criteria: Male and female patients aged 18 years and older. The diagnosis of classic CAH due to 21-hydroxylase deficiency has been documented. - Elevated 17-OHP at screening · Stable glucocorticoid replacement therapy for at least 30 days Exclusion criteria: · Clinically significant unstable medical condition, illness, or chronic disease Clinically significant psychiatric disorder Clinically significant abnormalities in laboratory findings or laboratory evaluations History of bilateral adrenalectomy or hypopituitarism Pregnant or childcare women Use of any other investigational drug within 30 days Inability to understand and comply with study procedures, inability to understand the risks, and / or unwillingness to provide written informed consent result: This Phase 2 study showed that Compound 1 was generally well tolerated. In this study, a range of safe doses was established after exploring a wide dose range (a five-fold range) (see Figure 1).

[0139] Regarding patient-level response to Compound 1, 80% demonstrated a decrease in ACTH (see Figure 2). A decrease in ACTH typically indicates target engagement and functional CRF1 receptor antagonism. 80% of patient subjects demonstrated a decrease in ACTH. 70% of subjects demonstrated a decrease in ACTH of greater than 25%. 40% of subjects were in the normal range after treatment.

[0140] Based on standard endpoint criteria, a decrease in 17-OHP indicates disease "control." This allows for steroid tapering. 80% of subjects demonstrated a decrease in 17-OHP (see Figure 3). 50% of subjects demonstrated a greater than 25% decrease in 17-OHP. 50% of subjects were within the reference range (1200 ng / dL) after treatment. Compound 1 attenuated the morning increase in A4, indicating that Compound 1 can control excess androgen production and its associated symptoms (see Figure 4). 100% of subjects demonstrated a decrease in androstenedione (at various doses). 60% of subjects demonstrated a greater than 25% decrease in androstenedione. 50% of subjects were within the normal reference range after treatment.

[0141] Example 5: Formulation Development The objectives of this study were: (1) to evaluate various formulations to obtain 200 mg immediate-release core tablets of Compound 1; (2) to evaluate the dissolution characteristics of Compound 1 tablets in wet granulation and in granulation with Gelucire 48 / 16 and / or Vitamin E TPGS; and (3) to evaluate the dissolution of tablets / capsules in various biorelevant media and sink conditions to compare the dissolution of the API within the capsules.

[0142] Experimental results Compound 1 tablets were formulated in two steps.

[0143] In the first manufacturing phase, two immediate-release test formulations were produced. In the first trial, Compound 1 was granulated using Gelucire (10%) and included a filler and disintegrant. No surfactant was used in this formulation. The granules were finally blended and compressed to a tablet weight of 500 mg. No problems were observed during granulation or compression. In the second trial, a wet granulation method using HPC as a binder was performed and included a filler and disintegrant. Sodium lauryl sulfate was used as a surfactant at a concentration of 1%. When the granules were softer than in the first trial, poor flow was observed in the final blend. Increasing the filler in the extragranular portion improved flow and weight variability during compression. These tablets were compressed to a tablet weight of 600 mg. The dissolution of the first and second trial batches was investigated in different biorelevant media: SGF (simulated gastric fluid), SIF (simulated intestinal fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid).

[0144] In a second manufacturing phase, two additional formulations were produced containing 8% Gelucire and Vitamin E TPGS and a higher concentration of sodium lauryl sulfate. The surfactant percentage was increased to 7%. These tablets were compressed to a tablet weight of 570 mg. No issues were observed during manufacturing. Further development involved a higher concentration of Gelucire (25%). Due to the high concentration of Gelucire in the formulations, the granules could not be compressed, so they were manually filed into size 0 capsules.

[0145] Further development of the wet granulation process was recommended due to poor flow and suboptimal granule size. Granules from the wet granulation formulation also showed variability in weight upon compression.

[0146] Release in SIF and FaSSIF was very slow, ranging from 0.5% to 3% at 60 minutes for Gelucire and HPC formulations. Release in SGF and FeSSIF was higher, ranging from 11% to 16% at 60 minutes. The higher release in SGF and FeSSIF is likely due to the presence of surfactants in the media. However, lipid excipients and high concentrations of surfactants did not improve dissolution in biorelevant media. At 60 minutes, release was less than 2% in SIF and FeSSIF, approximately 15% in SGF, and 10% in FeSSIF. Higher concentrations of Gelucire in capsule formulations did not improve dissolution. Comparison of API dissolution in capsules and various formulations did not reveal any improvement in dissolution. Animal pK studies were also performed using the wet granulation and Gelucire formulations. These dissolution and pK studies indicate that current formulation approaches may not be suitable for improving the bioavailability or minimizing the food effect of Compound 1. In Study 2 / 3, different formulation approaches for Compound 1 were recommended.

[0147] Example 6: Preliminary tablet formulation The objective of this routine experiment was to develop, manufacture, and commercialize a miniature tablet or capsule for an insoluble (less than 0.002 mg / mL solubility in water and at all physiological pH values ranging from 1.2 to 7.5) drug substance in dosage strengths up to 200 mg. The tablets should be released immediately into the dissolution medium using USP Apparatus I or II. success criteria 1: Tablet size less than 400 mg at 200 mg dosage strength 2: Over 70% dissolves in conventional solvents in 60 minutes.

[0148] Normal manufacturing procedure The relevant excipients were hand sieved and dry blended. A binder solution was added and the mixture was subjected to wet granulation. The granules were milled and dried. The resulting granules were dry milled and added to other relevant common granules and excipients. The mixture was then compressed into tablets to achieve the desired tablet weight.

[0149] A granulation was developed that minimized the amount and number of excipients. The granulation consisted of at least 90% Compound 1, surfactants and binders, and optionally, a superdisintegrant. After successful granulation, other excipients were added to enable compression. These excipients included compression aids, lubricants, anti-sticking agents, and superdisintegrants.

[0150] Two blends were granulated: one containing 95% Compound 1, 1% sodium lauryl sulfate, and 4% HPC-EXF; the other containing 91% Compound 1, 1% sodium lauryl sulfate (a surfactant and wetting agent), 6% PVP (a water-soluble binder), and 2% Ac-Di-Sol (a water-swellable superdisintegrant).

[0151] Granulations composed of HPC-EXF (binder) were further blended with SiO2 (flow aid and anti-sticking agent), Ac-Di-Sol (water-swellable disintegrant), and magnesium stearate (lubricant). Various levels of MCC were added to the tablets (0, 10, and 20% levels). All three formulations (90%, 81%, and 71% DL) rapidly dissolved, with no significant changes in the stability phase under open dish conditions. Granulations containing PVP as a binder were repeated three times. The first granulation consisted of 93% Compound 1, 6% PVP, and 1% SLS. This formulation had poor manufacturing characteristics (granule flow), but tablet dissolution was acceptable. No further stability testing was performed.

[0152] The second granulation (same as the first) had acceptable manufacturing characteristics (good flow and compaction), but dissolution was somewhat slower and there was a significant change in stability duration under very stressful conditions.

[0153] The third granulation consisted of 91% Compound 1, 6% PVP, 1% SLS, and 2% Ac-Di-Sol as an intragranular superdisintegrant. This granulation was further blended with SiO2 (a flow aid and anti-sticking agent), Ac-Di-Sol (a water-swellable disintegrant), and magnesium stearate (a lubricant). Various levels of MCC were added to the tablets (0, 10, and 20%). All three formulations (86%, 77%, and 68% DL) were rapidly dissolved.

[0154] This demonstrated successful tableting of Compound 1 with aqueous solubility below 0.002 mg / mL, maintaining greater than 50% drug loading, and acceptable dissolution in conventional solvents (1% SLS and USP Apparatus II). The tablets were manufactured using conventional high-shear wet granulation techniques. [Table 10]

[0155] Example 7: Tablet Formulation A Three formulations were prepared by wet granulation using the common granules and PVP K30 as a binder (see Table 11), with MCC PH102 as the diluent and drug loadings of 95%, 85%, and 75%, respectively. [Table 11]

[0156] Compound 1, povidone, and sodium lauryl sulfate were mixed to obtain a dry mixture. Water was added to the dry mixture, and wet granulation was carried out at an impeller speed of approximately 550-560 rpm. The wet granules were then sieved and dried. The dried granules were then dry-sieved and then compressed into tablets.

[0157] In process control testing, each tablet performed well. The dissolution results for A-1 and A-3 showed similar curves, while A-2 was slightly slower than the other two in the first few points (see Table 12 and Figure 5). [Table 12]

[0158] Example 8: Tablet Formulation B Three formulations were prepared by wet granulation using the common granules and PVP K30 as a binder (see Table 13), with drug loadings of 95%, 85%, and 75%, respectively, using MCC PH102 as a diluent. [Table 13]

[0159] Compound 1, povidone, and sodium lauryl sulfate were mixed to obtain a dry mixture. Water was added to the dry mixture, and wet granulation was carried out at an impeller speed of approximately 600-610 rpm. The wet granules were then sieved and dried. The dried granules were then dry-sieved and then compressed into tablets.

[0160] The dissolution results indicate that the slower dissolution than the previously mentioned tablets may be caused by more granules and higher hardness (see Table 14 and Figure 6). [Table 14]

[0161] Example 9: Tablet Formulation C Three formulations were prepared by wet granulation using a common granule, PVP K30 as a binder, and 2% intragranular croscarmellose sodium (see Table 15). [Table 15]

[0162] Compound 1, povidone, croscarmellose sodium, and sodium lauryl sulfate were mixed to obtain a dry mixture. Water was added to the dry mixture, and wet granulation was carried out at an impeller speed of approximately 600-610 rpm. The wet granules were then sieved and dried. The dried granules were then dry-sieved and compressed into tablets.

[0163] The dissolution results indicated that the faster dissolution than the other tablets may be due to the additional amount of croscarmellose sodium (see Table 16 and Figure 7). [Table 16]

[0164] Example 10: Tablet Formulation D Two formulations were prepared using wet granulation (see Table 17). [Table 17]

[0165] Compound 1, povidone, croscarmellose sodium, and sodium lauryl sulfate were mixed to obtain a dry mixture. Water was added to the dry mixture, and wet granulation was carried out at an impeller speed of approximately 600-610 rpm. The wet granules were then sieved and dried. The dried granules were then dry-sieved and compressed into tablets.

[0166] The release characteristics of formulations D-1 and D2 were similar to the above formulations and did not change significantly (see Table 18). [Table 18]

[0167] Both formulations had faster release properties in SGF medium (see Table 19). [Table 19]

[0168] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will immediately occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A pharmaceutical composition for use in a subject in need of treatment for congenital adrenal hyperplasia (CAH), said pharmaceutical composition comprising: CRF １ an antagonist or a pharmaceutically acceptable salt thereof, The CRF １ The antagonist is 【Chemical 1】 and The pharmaceutical composition contains about 200 mg to about 800 mg of the CRF １ Contains antagonists, The pharmaceutical composition is in an oral dosage form.

2. 10. The pharmaceutical composition of claim 1, wherein the oral dosage form is a tablet.

3. 10. The pharmaceutical composition of claim 1, wherein the oral dosage form is a capsule.

4. The CRF １ The pharmaceutical composition according to any one of claims 1 to 3, wherein the dose of the antagonist is about 800 mg.

5. The CRF １ The pharmaceutical composition according to any one of claims 1 to 3, wherein the dose of the antagonist is about 600 mg.

6. The CRF １ The pharmaceutical composition according to any one of claims 1 to 3, wherein the dose of the antagonist is about 400 mg.

7. The CRF １ The pharmaceutical composition according to any one of claims 1 to 3, wherein the dose of the antagonist is about 200 mg.

8. The pharmaceutical composition of any one of claims 1 to 3, further comprising a binder.

9. 9. The pharmaceutical composition of claim 8, wherein the binder comprises hydroxypropyl cellulose.

10. The pharmaceutical composition according to any one of claims 1 to 5, further comprising a surfactant.

11. 11. The pharmaceutical composition of claim 10, wherein the surfactant comprises sodium lauryl sulfate.

12. The pharmaceutical composition according to any one of claims 1 to 7, further comprising a disintegrant.

13. 13. The pharmaceutical composition of claim 12, wherein the disintegrant comprises croscarmellose sodium.

14. The pharmaceutical composition according to any one of claims 1 to 9, further comprising a glidant.

15. The pharmaceutical composition according to any one of claims 1 to 10, further comprising a lubricant.

16. The pharmaceutical composition according to any one of claims 1 to 11, further comprising a diluent.

17. 17. The pharmaceutical composition of claim 16, wherein the diluent comprises microcrystalline cellulose.

18. The pharmaceutical composition according to any one of claims 1 to 13, characterized in that the pharmaceutical composition reduces androstenedione (A4) levels from baseline.

19. The pharmaceutical composition of any one of claims 1 to 14, wherein the subject is in a fed state.

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