Pharmaceutical formulations containing relacorilant, heteroaryl-ketone fused azadecahydronaphthalene compounds

Abstract

Disclosed herein are new formulations containing relacorilant ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone) that are suitable for administration, including oral administration, to patients with conditions that can be susceptible to treatment by glucocorticoid receptor modulators (GRMs). Single unit dosage forms include soft gel capsules containing these formulations. Such soft gel capsules can contain, for example, relacorilant formulations containing 25 milligrams (mg), 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or other amounts of relacorilant. These new formulations and single unit dosage forms can be used to treat diseases and conditions including Cushing's syndrome, Cushing's disease, and other conditions.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980084873.6, filed on December 18, 2019, entitled "Pharmaceutical Formulation Containing a Z-decahydronaphthalene Compound Fused with Rellacoran and Heteroaryl-Ketone".

[0002] Cross-references to related applications

[0003] This application claims priority and benefit to U.S. Application Serial No. 62 / 781,983, filed December 19, 2018, the entire contents of which are hereby incorporated by reference. Background Technology

[0004] Many heteroaryl-ketone-fused azadecahydronaphthalene compounds bind to glucocorticoid receptors (GR) and thus can possess therapeutic activity. Such compounds and their activities are disclosed, for example, in U.S. Patent Nos. 8,859,774; 9,273,047; 9,707,223; 9,943,505; and 9,956,216. Pharmaceutical formulations containing heteroaryl-ketone-fused azadecahydronaphthalene compounds can be used to administer those compounds to humans or animals for therapeutic purposes.

[0005] Glucocorticoid receptors (GRs) play a vital role in normal physiology, and disruption or alteration of GR function is associated with numerous diseases and conditions. The most important GR ligand in humans is cortisol. Cortisol binds to GR to activate it. Compounds that bind to GR and affect its activity are called glucocorticoid receptor modulators (GRMs). For example, GRMs that reduce GR activity by interfering with GR or competing with ligands that bind to GR are called GR antagonists (GRAs). Diseases and conditions associated with abnormal GR activation include Cushing's syndrome (usually caused by excessive cortisol), Addison's disease (usually caused by insufficient cortisol levels), and others. Therapeutic uses of GRM compounds, whether as a single agent or in combination with other agents, include the treatment of endocrine disorders including Cushing's syndrome and Cushing's disease, cancer, immune system disorders, cardiovascular diseases including hypertension, diabetes, hyperglycemia, liver disease, bone diseases, obesity, antipsychotic drug-induced weight gain, mental illnesses, addictive behaviors and conditions, and other diseases and conditions.

[0006] However, many GRM compounds are difficult to formulate into compositions suitable for administration to individuals who require the compound. Many such compounds are only slightly soluble in water, may be incompatible with other components commonly used in pharmaceutical compositions, or may have other properties that make it difficult to prepare therapeutic formulations. Many GRM compounds are unstable, degrading over time or becoming unstable upon exposure to light or heat. These characteristics of one heteroaryl-ketone-fused azeolide compound may differ from those of another heteroaryl-ketone-fused azeolide compound, making formulations suitable for one heteroaryl-ketone-fused azeolide compound potentially unsuitable for different heteroaryl-ketone-fused azeolide compounds.

[0007] For example, many heteroaryl-ketone-fused azadecahydronaphthalene compounds are poorly soluble in water and may have poor bioavailability in some formulations. Poor solubility or bioavailability necessitates the administration of large volumes of solution, large pellets or tablets, or large quantities of pills or tablets, to provide sufficient active compound for effective treatment. Furthermore, some heteroaryl-ketone-fused azadecahydronaphthalene compounds and formulations containing these compounds may interact with or be incompatible with capsule materials. Such interactions, incompatibilities, and instabilities can lead to the degradation of heteroaryl-fused azadecahydronaphthalene compounds, reducing their bioavailability or their efficacy for therapeutic purposes. For these and other reasons, pharmaceutical formulations in pellets, tablets, injectable solutions, and other pharmaceutical preparations are generally unsuitable for therapeutic use.

[0008] Therefore, there is a need for improved formulations of azidehydronaphthalene compounds containing heteroaryl-ketone fused compounds with improved stability and / or bioavailability. Summary of the Invention

[0009] The applicant hereby discloses a formulation comprising a heteroaryl-ketone fused azidehydronaphthalene (HKFA) compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone (Example 18 of US 8,859,774), also known as “Relacorilant” and “CORT125134”, having the following structure:

[0010]

[0011] In embodiments, the formulations disclosed herein are suitable for pharmaceutical use and have improved stability and / or bioavailability compared to existing or alternative formulations. In embodiments, the formulation may comprise relakolan and pharmaceutically acceptable excipients. In embodiments, the formulation contains relakolan and pharmaceutically acceptable excipients and is suitable for use in pharmaceutical compositions for oral administration of relakolan to human patients to treat a disease or condition or for oral administration of relakolan to animals for veterinary therapeutic purposes.

[0012] In the embodiments, the pharmaceutical formulation is suitable for administering an effective amount of rengamol, for example, a unit-dose formulation containing about 1 mg to about 1000 mg of rengamol or about 1 mg to about 500 mg of rengamol. In the embodiments, a unit-dose formulation contains 10 mg, or 20 mg, or 25 mg, or 50 mg, or 100 mg, or 200 mg, or 300 mg, or 400 mg, or 500 mg of rengamol. In the embodiments, the pharmaceutical formulation is suitable for administering an effective amount of rengamol, for example, a daily dose of rengamol from about 1 mg / kg / day to 100 mg / kg / day, or a daily dose of rengamol from about 1 mg / kg / day to 20 mg / kg / day.

[0013] In one embodiment, a pharmaceutical preparation containing renalacyclolin is suitable for administration when encapsulated in a gelatin capsule. In another embodiment, a pharmaceutical preparation containing renalacyclolin is suitable for administration when encapsulated in a soft gelatin (“soft gel”) capsule.

[0014] Formulations containing ryracolan may contain, for example, about 5% to about 35% ryracolan, about 45% to about 75% surfactant, about 5% to about 35% solubilizer, and may contain an antioxidant. In one embodiment, formulations containing ryracolan may contain, for example, about 10% to about 30% ryracolan, about 50% to about 70% surfactant, about 10% to about 30% solubilizer, and may contain an antioxidant. In another embodiment, formulations containing ryracolan may contain, for example, about 12% to about 28% ryracolan, about 52% to about 68% surfactant, about 12% to about 28% solubilizer, and may contain an antioxidant. In a further embodiment, the formulation may have the following composition: about 15% to 25% ryracolan, about 55% to 65% surfactant, and about 15% to 25% solubilizer, optionally containing an antioxidant. In other embodiments, the formulation may have the following composition: about 20% ryracolan, about 60% surfactant, about 20% solubilizer, and about 0.02% antioxidant. In a specific embodiment, the formulation may have the following composition: about 20% ryracolan, about 60% polyoxyglyceride, about 20% propylene glycol compound, and about 0.02% antioxidant. In a further specific embodiment, the formulation may have the following composition: about 20% ryracolan, about 60% lauryl polyoxy-32 glyceride, about 20% propylene glycol monocaprylate, and about 0.02% antioxidant (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), tocopherol, gallate, or other antioxidants).

[0015] In an embodiment, the capsule containing the formulation containing ryracoran can be a soft gel capsule. The soft gel capsule for containing the formulation containing ryracoran can be made of about 50% to about 75% gelatin and about 25% to about 50% plasticizer (e.g., a sorbitol / glycerol blend), wherein purified water and / or colorant are included as needed; and can be made of about 58% to about 68% gelatin and about 30% to about 42% plasticizer, or about 60% to about 70% gelatin and about 30% to about 40% plasticizer, or about 63% to about 65% gelatin and about 35% to about 37% plasticizer, or about 64% gelatin and about 36% plasticizer, wherein purified water and / or colorant are included as needed. In the implementation scheme, a batch of materials for preparing soft gel capsules for containing formulations containing ryracolan can be made, for example, 195.05 g of gelatin and 111.46 g of a sorbitol / glycerol blend, wherein purified water and / or coloring agents are included as needed.

[0016] In a further exemplary embodiment, the applicant discloses a soft gel capsule containing ryracolan; the soft gel capsule containing ryracolan can be any soft gel capsule containing any ryracolan formulation disclosed herein. In embodiments, the soft gel capsule containing the ryracolan formulation can be made of about 63% to about 65% gelatin and about 35% to about 37% plasticizer, or about 64% gelatin and about 36% plasticizer, wherein purified water and / or colorant are included as desired. The plasticizer can be, for example, a sorbitol / glycerol blend. The ryracolan contained in the soft gel capsule can be any formulation described herein. In embodiments, the soft gel capsule containing ryracolan contains about 15% to about 25% ryracolan, about 50% to about 70% surfactant, about 15% to about 25% solubilizer of the ryracolan formulation, and may contain an antioxidant. In the implementation scheme, the soft gel capsule containing ryracolan comprises a ryracolan formulation containing about 20% ryracolan, about 60% surfactant, about 20% solubilizer, and may also contain an antioxidant.

[0017] In embodiments, the formulations disclosed herein are suitable for treating conditions characterized by cortisol overdose. In embodiments, the formulations disclosed herein are suitable for treating Cushing's syndrome, including Cushing's disease. In embodiments, the formulations disclosed herein are suitable for treating other conditions. In embodiments of such treatments, the pharmaceutical composition comprising renalacrilan can be administered alone or in combination with other treatments for such diseases and conditions.

[0018] Many HKFA compounds are poorly soluble, difficult to formulate with pharmaceutically acceptable excipients, and unstable in many formulations (i.e., degrade in unacceptable amounts over time). The applicant hereby discloses novel formulations and pharmaceutical compositions containing relakolan that exhibit improved stability compared to alternative formulations and compositions suitable for individual human administration. It is believed that the novel formulations disclosed herein allow for the safe and effective administration of relakolan to patients suffering from diseases and conditions readily treatable by GRMs (e.g., relakolan). Compared to alternative formulations and compositions, the disclosed formulations offer advantages including improved stability and compatibility with capsules suitable for oral administration, providing an improved relakolan formulation and treatment using such an improved relakolan-containing formulation.

[0019] Brief description of the attached figures

[0020] Figure 1 The plasma concentrations of relakolan in healthy, fasting human individuals at various time points following ingestion of 150 mg relakolan (provided in soft gel capsules containing the formulation listed in Table III) are shown. At its peak, Cp was approximately 3 hours after administration. maxThe concentration was approximately 200 ng / mL (hollow circle; this composition was tested on 8 individuals; the individuals were fasting when they were orally administered the renalaculan preparation).

[0021] Figure 2 An idealized side view of a container used for an in vitro digestion assay of a formulation is illustrated. The container holds the active pharmaceutical ingredient and can be dispensed into three stages.

[0022] Figure 3 Showing according to Figure 2 The results of the in vitro digestion assay showed that up to about 15% of the Table I formulation was partitioned into the aqueous phase in the early stages of the in vitro assay, and about 10% was partitioned into the aqueous phase at time zero of the assay. Detailed description

[0023] Many fused azeolide compounds are difficult to formulate, and many are unstable over time in formulations suitable for oral administration. Therefore, developing stable and bioavailable formulations containing fused azeolide compounds is a significant challenge that must be overcome to provide improved fused azeolide formulations suitable for human administration. A preferred embodiment requires the development of stable and bioavailable formulations containing fused azeolide compounds suitable for oral administration to human patients.

[0024] The applicant has surprisingly developed several formulations that allow the incorporation of the heteroaryl-ketone-fused azidehydronaphthalene (HKFA) compound “Relakolan” into pharmaceutical compositions suitable for oral administration to patients. Relakolan is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone and has the following structure:

[0025]

[0026] Compared to other, existing, or alternative formulations containing renalakolan, these formulations offer improved stability and enhanced compatibility with capsules.

[0027] This document discloses novel formulations and pharmaceutical compositions containing relacoran. In embodiments, the formulations may comprise relacoran and pharmaceutically acceptable excipients, such as solubilizers, surfactants, antioxidants, fillers, or one or more other excipients. In embodiments, solubilizers such as glycerides (including glyceryl caprylate, polyethylene glycerol, or polypropylene glycerol) (commercially available as, for example, Capmul ECM (glyceryl decanoate)) and surfactants such as polyethoxylated castor oil or other oils (commercially available as, for example, Kolliphor EL) provide superior pharmaceutical formulations compared to existing or alternative formulations. In embodiments, such formulations containing HKFA compounds may also comprise antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), gallate esters such as propyl gallate, tocopherols such as α-tocopherol, or other antioxidants.

[0028] In the embodiments, the applicant discloses gelatin (“soft gel”) capsule formulations suitable for encapsulating formulations containing relacoran. Soft gel capsules for containing relacoran formulations can be made from about 50% to about 75% gelatin and about 25% to about 50% plasticizer, wherein purified water and / or colorant are included as needed; and can be made from about 60% to about 70% gelatin and about 30% to about 40% plasticizer, or about 63% to about 66% gelatin and about 34% to about 37% plasticizer, wherein purified water and / or colorant are included as needed. In the embodiments, a batch of materials for preparing soft gel capsules for containing relacoran formulations can be made from, for example, 195.05 g of gelatin and 111.46 g of a sorbitol / glycerol blend plasticizer. In the embodiments, the gelatin capsules may contain purified water as needed, and may also contain colorant as needed.

[0029] In the implementation plan, the applicant discloses formulations containing rilatin, including but not limited to the following formulations (“%” are considered as weight percentages herein):

[0030] A formulation comprising about 10% to about 30% of ryracolan, about 50% to about 70% of a surfactant, about 10% to about 30% of a solubilizer, and optionally comprising an antioxidant;

[0031] A formulation comprising about 15% to about 25% of ryracolan, about 55% to about 65% of a surfactant, about 15% to about 25% of a solubilizer, and optionally comprising an antioxidant;

[0032] A formulation comprising about 18% to 22% ryracolan, about 56% to 64% surfactant and about 18% to 22% solubilizer, optionally comprising an antioxidant;

[0033] A formulation comprising about 20% ryracolan, about 60% surfactant, about 20% solubilizer, and about 0.1 to about 0.5% antioxidant;

[0034] A formulation comprising about 20% ryracoran, about 60% polyoxyglyceride compound, about 20% propylene glycol compound, and about 0.02% BHT or BHA; and

[0035] A formulation comprising about 20% ryracolan, about 60% lauroyl polyoxy-32 glyceryl ester, about 20% propylene glycol monocaprylate, and about 0.02% BHT or BHA.

[0036] In the implementation details, the applicant discloses formulations containing rilatin, including but not limited to the following formulations, which are provided below in amounts contained in a single capsule (e.g., a soft gel capsule):

[0037] A formulation comprising 25 mg of ryracolan, 74.975 mg of lauroyl polyoxy-32 glyceryl ester, 25 mg of propylene glycol monocaprylate, type I, and 0.025 mg of butylated hydroxytoluene (BHT).

[0038] A formulation comprising 50 mg of ryracolan, 149.95 mg of lauroyl polyoxy-32 glyceryl ester, 50 mg of propylene glycol monocaprylate, type I, and 0.05 mg of butylated hydroxytoluene (BHT);

[0039] A formulation comprising 100 mg of ryracolan, 299.9 mg of lauroyl polyoxy-32 glyceryl ester, 100 mg of propylene glycol monocaprylate, type I, and 0.1 mg of butylated hydroxytoluene (BHT);

[0040] A formulation comprising 200 mg of ryracolan, 599.8 mg of lauroyl polyoxy-32 glyceryl ester, 200 mg of propylene glycol monocaprylate, type I, and 0.2 mg of butylated hydroxytoluene (BHT);

[0041] A formulation comprising 300 mg of ryracolan, 899.7 mg of lauroyl polyoxy-32 glyceryl ester, 300 mg of propylene glycol monocaprylate, type I, and 0.3 mg of butylated hydroxytoluene (BHT);

[0042] A formulation comprising 400 mg of ryracolan, 1199.6 mg of lauroyl polyoxy-32 glyceryl ester, 400 mg of propylene glycol monocaprylate, type I, and 0.4 mg of butylated hydroxytoluene (BHT);

[0043] A formulation comprising 500 mg of ryracolan, 1499.5 mg of lauroyl polyoxy-32 glyceryl ester, 500 mg of propylene glycol monocaprylate, type I, and 0.5 mg of butylated hydroxytoluene (BHT);

[0044] A formulation comprising 750 mg ryracolan, 2249.25 mg lauroyl polyoxy-32 glyceryl ester, 750 mg propylene glycol monocaprylate, type I, and 0.75 mg butylated hydroxytoluene (BHT);

[0045] A formulation comprising 1000 mg relactone, 2999 mg lauroyl polyoxy-32 glyceryl ester, 1000 mg propylene glycol monocaprylate, type I, and 1 mg butylated hydroxytoluene (BHT); and other formulations in the same proportions. To determine the amounts of other formulations containing different amounts of relactone X in the same proportions, the ratio of X to 100 mg relactone must be determined, and the amount of each component in the aforementioned formulation containing 100 mg relactone is multiplied by this ratio. For example, when other formulations contain 800 mg relactone, the 800 mg relactone: 100 mg relactone ratio is 8, and the amount of each component in the formulation containing 100 mg relactone will be multiplied by 8.

[0046] In the implementation plan, the applicant discloses in this document single-unit dosage forms containing rilatolalan, including but not limited to the following single-unit dosage forms:

[0047] A single unit dosage form comprising capsules containing a homogeneous mixture of about 10 mg to about 70 mg of renalacrilan and pharmaceutically acceptable excipients, wherein the homogeneous mixture is a formulation as disclosed herein, including, for example, the formulations disclosed above; and

[0048] A single unit dosage form consisting of capsules containing a homogeneous mixture of about 20 mg to about 50 mg of renalacolan and pharmaceutically acceptable excipients, wherein the homogeneous mixture is a formulation as disclosed herein, including, for example, the formulations disclosed above.

[0049] A single unit dosage form comprising capsules containing a homogeneous mixture of about 50 mg to about 200 mg of ryracolan and pharmaceutically acceptable excipients, wherein the homogeneous mixture is a formulation as disclosed herein, including, for example, the formulations disclosed above.

[0050] A single unit dosage form comprising capsules containing a homogeneous mixture of about 100 mg to about 400 mg of ryracolan and pharmaceutically acceptable excipients, wherein the homogeneous mixture is a formulation as disclosed herein, including, for example, the formulations disclosed above.

[0051] A single unit dosage form consisting of capsules containing a homogeneous mixture of about 200 mg to about 500 mg of ryracolan and pharmaceutically acceptable excipients, wherein the homogeneous mixture is a formulation as disclosed herein, including, for example, the formulations disclosed above.

[0052] In embodiments, the contents of a single unit dosage form (including those disclosed above) as disclosed herein weigh from about 300 mg to about 600 mg. In embodiments, the contents of a single unit dosage form (including those disclosed above) as disclosed herein have a total weight of about 300 mg; or about 400 mg; or about 500 mg; or about 600 mg; or about 700 mg; or about 800 mg; or about 900 mg; or about 1 gram (g); or about 1.5 g; or about 2 g. In embodiments, the single unit dosage form is encapsulated in a soft gel capsule. In other embodiments, the single unit dosage form is encapsulated in a hard-shell capsule, which may have a size selected from, for example, size 5, size 4, size 3, size 2, size 1, size 0, size 00, and size 000.

[0053] Relacoxetine binds to the glucocorticoid receptor (GR) and is a GR modulator (GRM). Relacoxetine GR modulation involves antagonizing the binding of other ligands, such as cortisol, to GR; therefore, relacoxetine is a GR antagonist (GRA). Because relacoxetine binds well to GR but poorly to only the progesterone receptor (PR) and other steroid hormone receptors, relacoxetine can be termed a selective GR modulator (SGRM). The novel pharmaceutical compositions disclosed herein are useful, for example, by providing pharmaceutical compositions for modulating GR without significantly affecting PR.

[0054] In the implementation scheme, as one of their functions, formulations containing relakolan can reduce the harmful effects of excessive cortisol levels in individuals to whom they have been administered. In the implementation scheme, as one of their functions, formulations containing relakolan can effectively treat the condition in individuals to whom they have been administered. In the implementation scheme, as one of their functions, formulations containing relakolan can effectively enhance the therapeutic effect of co-administered drugs or therapies in individuals to whom they have been administered, wherein the administration of the co-administered drugs or therapies may be close in time to the administration of the relakolan-containing formulation, or the co-administered drugs or therapies may be administered some time before, simultaneously with, or after the administration of the relakolan-containing formulation.

[0055] In the implementation plan, the applicant discloses methods for treating conditions that are readily treatable with renalacrim, including but not limited to the following methods:

[0056] A method for treating conditions readily treatable with renalacrilan includes administering renalacrilan in a single unit dosage form, wherein the single unit dosage form contains a homogeneous mixture of the renalacrilan and a pharmaceutical excipient, and wherein the homogeneous mixture is a formulation as disclosed herein. In embodiments of the method disclosed herein, the single unit dosage form comprises a capsule containing about 10 mg to about 500 mg of renalacrilan.

[0057] In embodiments of the methods disclosed herein, a single unit dosage form comprises a capsule containing a homogeneous mixture of about 5 mg to about 500 mg of relactin. In embodiments of the methods disclosed herein, a single unit dosage form comprises a capsule containing a homogeneous mixture of about 10 mg to about 250 mg of relactin. In embodiments of the methods disclosed herein, a single unit dosage form comprises a capsule containing a homogeneous mixture of about 20 mg to about 150 mg of relactin.

[0058] In one embodiment, the pharmaceutical composition containing renalafenamide is formulated for oral administration. In another embodiment, oral administration includes sublingual administration. In yet another embodiment, the HKFA compound is formulated for suppository administration and may be administered rectally or vaginally.

[0059] B. Definition

[0060] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology.

[0061] As used herein, the term "compound" is used to refer to a molecular moiety having a distinctive, identifiable chemical structure. A compound can exist as a free substance, in which it does not associate with other molecules. A compound can also exist as part of a larger aggregate, in which it associates with other molecules but retains its chemical properties. A solvate in which a compound associates with a solvent molecule is an example of this form of association. A hydrate is a solvate in which the solvent of association is water. The expression "compound" refers to the molecular moiety itself (having the stated structure), whether it exists in a free or associated form.

[0062] "Patient," "individual," and "individual in need" refer to people who have or are suspected of having a disease or condition that can be treated with therapeutic drugs.

[0063] As used herein, the terms “administer,” “administering,” or “administered” refer to the provision of a compound or composition (such as those described herein) to an individual or patient.

[0064] As used herein, the term "administration" refers to the delivery of a drug or other therapeutic agent into the body of an individual who requires treatment with that drug or therapeutic agent, thereby effectively achieving a therapeutic effect. Administration can be carried out via any suitable route of administration, including, for example, oral administration; intravenous administration; subcutaneous administration; parenteral administration; intra-arterial administration; nasal administration; topical administration; and other routes of administration.

[0065] "Treatment," "treating," and "treatment" refer to the provision of a drug or other therapeutic agent to a patient. Such treatment aims to, and usually results in, a reduction, improvement, lessening, or elimination of symptoms of the disease or condition to be treated. Such treatment aims to, and usually results in, indications of success in the treatment or improvement of a pathology or condition. Indicators of success include, for example, any objective or subjective parameter, such as relief; remission; reduction of symptoms or making the pathology or condition more tolerable to the patient; slowing the rate of deterioration or decline; making the endpoint of degeneration less severe; or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters; including physical examination results; histopathological examination results (e.g., analysis of biopsy tissue); laboratory analysis of urine, saliva, tissue samples, serum, plasma, or blood; or imaging.

[0066] As used herein, the term “Cushing’s syndrome” refers to a range of symptoms caused by excess cortisol (excess cortisol is called “hypercortisolism”). “Cushing’s disease” refers to pituitary-dependent Cushing’s syndrome, such as excess cortisol caused by pituitary abnormalities (usually pituitary tumors). Symptoms associated with and indicative of Cushing’s syndrome include, for example, elevated blood pressure (hypertension), elevated blood sugar (hyperglycemia), weight gain (usually in the midsection and on the face causing the characteristic “moon face”), immunosuppression, thin skin, acne, depression, hirsutism, and other symptoms. Excess cortisol leading to Cushing’s syndrome may be due to exogenous cortisol (or cortisol analogs, such as prednisone, cortisone, dexamethasone, or other cortisol analogs or cortisol mimics); it may be due to a pituitary tumor; it may be due to an adrenal tumor or other adrenal disease; it may be due to a tumor not located in or near the pituitary or adrenal glands; or it may be due to another cause. In some cases, patients with Cushing's syndrome may refuse surgery, or surgery may fail to cure the disease or relieve symptoms; GRMs, such as rilatone, are often used to treat such patients.

[0067] Conditions associated with Cushing's syndrome may include, but are not limited to, conditions associated with endogenous Cushing's syndrome; hyperglycemia secondary to Cushing's syndrome; Cushing's syndrome associated with or causing type 2 diabetes or glucose intolerance; and hyperglycemia secondary to or causing Cushing's syndrome.

[0068] The term "glucocorticoid" or "glucocorticoid hormone" (both abbreviated as GC) refers to steroid hormones or synthetic analogs that bind to glucocorticoid receptors. Glucocorticoids are typically characterized by having 21 carbon atoms, an α,β-unsaturated ketone in ring A, and an α-keto alcohol group linked to ring D. These groups exhibit varying degrees of oxidation or hydroxylation at C-11, C-17, and C-19; see Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," in Biochemistry, Daisy et al. (eds.), 1989, pg. 567.

[0069] As used herein, the term “glucocorticoid receptor” (“GR”) refers to a family of intracellular receptors that specifically bind to cortisol and / or cortisol analogs. Glucocorticoid receptors are also known as cortisol receptors. The term includes isotypes of GR, recombinant GR, and mutant GR. “Glucocorticoid receptor” (“GR”) refers to type II GR that specifically binds to cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35283-292).

[0070] As used herein, the terms "effective amount," "effective quantity," "therapeutic amount," and "therapeutic effective amount" refer to the amount of one or more pharmacological agents that effectively treat, eliminate, or alleviate at least one symptom of the treated disease. In some cases, "effective amount," "effective quantity," "therapeutic amount," and "therapeutic effective amount" may refer to the amount of a functional agent or pharmaceutical composition used to demonstrate a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art.

[0071] As used herein, the term “consistently made of” in connection with a list of ingredients in a formulation refers to the ingredients, wherein the formulation may also include any unlisted ingredients that do not substantially affect the efficacy of the formulation.

[0072] As used herein, the terms “excipient,” “pharmaceuticalally acceptable excipient,” and “pharmaceuticalally acceptable carrier” are used interchangeably to refer to any compound or material contained in a formulation or pharmaceutical composition other than the active ingredient (or multiple active ingredients, wherein more than one compound may have the desired pharmaceutical activity). Excipients may function as, for example, solvents, solubilizers or solubilizers; emulsifiers; expanders; stabilizers; diluents; surfactants; preservatives; colorants; flavoring agents; fillers; lubricants; or other agents that may perform other functions. Non-limiting examples of excipients include water, sodium chloride (NaCl), physiological saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and colorants. As used herein, these terms are intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, and absorption delay agents that are compatible with drug administration. Those skilled in the art will recognize that other pharmaceutical excipients may be used in this invention, and their uses are well known in the art. Any such pharmaceutically acceptable excipient is contemplated for use in the formulations disclosed herein, unless the excipient is incompatible with the active compound. It should be understood that supplementary active compounds may also be incorporated into the composition. It should be understood that pharmaceutically acceptable excipients are non-toxic. Further information regarding suitable pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0073] As used herein, “active pharmaceutical ingredient,” “API,” and variations thereof refer to compounds in a formulation or pharmaceutical composition that have therapeutic activity when administered to a patient. Although other ingredients may also have beneficial effects, the formulation or pharmaceutical composition is designed and has been developed to deliver the API in order to provide the therapeutic benefits of the API to the patient to whom it is administered, and any beneficial effects of other ingredients are incidental.

[0074] As used herein, the terms “formulation,” “pharmaceutical formulation,” “composition,” “pharmaceutical composition,” etc., are interchangeable and refer to a composition suitable for administration to a patient to treat a medical condition or improve the symptoms of a medical condition. Pharmaceutical formulations disclosed herein comprise an active ingredient (e.g., renalacyclolin) and an inert ingredient (e.g., a pharmaceutically acceptable excipient). In embodiments, the pharmaceutical formulation comprises one or more active ingredients and one or more pharmaceutically acceptable excipients. The pharmaceutical formulation is suitable for administration to a patient; in embodiments, the pharmaceutical formulation is suitable for oral administration to a patient.

[0075] As used herein, the terms "percentage" and "%" refer to a percentage obtained by comparing a first value with a second value and multiplying the resulting decimal part by 100. As used herein, the first value can be the weight of an ingredient in a formulation containing multiple components, and the second value can be the weight of all components (i.e., the total weight of the formulation). Therefore, for example, when the weight of the dose of relakolan in a pharmaceutical formulation containing relakolan is 100 mg, and the total weight of all components in the formulation is 400 mg, then relakolan accounts for 25% of the formulation.

[0076] As used herein, the terms “percentage by weight,” “% by weight,” “(% w / w),” etc., refer to the percentage of a component of a composition relative to the total weight of a composition containing at least two components.

[0077] As used herein, the phrase “about x% to about y%” (where x and y can be any numbers) is included in the inbound usage, such that the range includes the stated numerical values ​​as well as all values ​​between these minimum and maximum values.

[0078] As used herein, the phrases “unit dosage form” and “single unit dosage form” refer to a formulation contained in pills, capsules, and other closed containers suitable for administration to a patient. The dose (i.e., the amount of API) in a unit dosage form is fixed and allows for standardized dosing without requiring the patient or healthcare practitioner to measure the API or the formulation. The dose administered to a patient can be increased by administering multiple pills, capsules, etc. In some cases, fractional dosing can be administered, for example, by cutting a pill into two or more pieces.

[0079] In the implementation scheme, the formulations containing renalacyclolan disclosed herein are suitable for oral administration.

[0080] Pharmaceutical formulations may be contained in capsules for administering a pharmaceutical ingredient, such as renalacyclolin, to a patient for therapeutic purposes. In an embodiment, such capsules are suitable for administering a pharmaceutical ingredient, such as renalacyclolin, to a patient in a unit dose.

[0081] preparation

[0082] Heteroaryl-ketone fused azidehydronaphthalene (HKFA) compounds can be used in formulations as disclosed herein, including formulations suitable for oral administration (see, for example, U.S. Patent No. 8,859,774, the entire contents of which are incorporated herein by reference). Relakolan is an exemplary HKFA compound, and formulations of relakolan in a form suitable for oral administration to patients are useful. Relakolan is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone (Example 18 of US 8,859,774), also known as “CORT125134”, and has the following structure:

[0083]

[0084] A formulation suitable for administration to a patient, and in an embodiment, a formulation suitable for oral administration to a patient may contain about 1% to about 50% by weight of renalakolan; in an embodiment, such a formulation may contain about 5% to about 35% by weight of renalakolan; in an embodiment, such a formulation may contain about 10% to about 30% by weight of renalakolan; in an embodiment, such a formulation may contain about 15% to about 25% by weight of renalakolan; in a further embodiment, such a formulation may contain about 17% to about 23% by weight of renalakolan; in a further embodiment, such a formulation may contain about 19% to about 21% by weight of renalakolan; and in an embodiment, such a formulation may contain about 20% by weight of renalakolan.

[0085] Therefore, the applicant discloses herein that compositions containing renalacrilan can be used to treat patients with conditions that are readily treatable with renalacrilan, and can be used to treat patients requiring such treatment. Conditions readily treatable with renalacrilan may include, but are not limited to, any conditions, symptoms, and diseases disclosed herein (e.g., see above), including, for example, Cushing's syndrome, Cushing's disease, diabetes, hyperglycemia, and other conditions.

[0086] For the preparation of pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable excipients may be solid or liquid. Formulations may include those incorporated into or contained in tablets, pills, capsules, pouches, or suppositories. Excipients may be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials, as disclosed herein (e.g., above). Technical details regarding formulation and administration are described in detail in scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pa. ("Remington's").

[0087] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth gum; low-melting-point wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol; starches derived from corn, wheat, rice, potatoes, or other plants; cellulose, such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; and gums, including gum arabic and tragacanth gum; and proteins including, but not limited to, gelatin and collagen. If desired, disintegrants or solubilizers, such as croscarmellose, agar, alginate, or salts thereof, such as sodium alginate, may be added.

[0088] The formulations disclosed herein may include excipients and other components known in the art as suitable for administration to humans in pharmaceutical compositions. Such excipients and components include, but are not limited to, surfactants, solubilizers, antioxidants, fillers, and other components. For example, suitable commercially available excipients and components include, but are not limited to, Capmul ECM (glyceryl decanoate); Kolliphor EL (polyethoxylated castor oil); Kolliphor EM; Gelucire 44 / 14 (lauroyl polyoxy-32 glyceryl ester); Capryol PGMC (propylene glycol monocaprylate); polysorbate 20; polysorbate 80; sorbitol / glycerol blends (e.g., "50 / 50 Blend Sorbitol Special" commercially available from SPIPharma, Septemes, FR). TM "); corn oil; lauroglycol 90 (propylene glycol monolaurate 90); butylated hydroxytoluene (BHT); butylated hydroxyanisole (BHA); tert-butylhydroquinone (TBHQ); propyl gallate; α-tocopherol (vitamin E); myristic acid; etc.

[0089] surface activator

[0090] As used herein, the term "surfactant" refers to (but is not limited to) polysorbate (polyoxyethylene dehydrated sorbitol monolaurate) surfactants and detergents (e.g., 20. 80, etc.; may include polyoxyglycerol esters, such as lauryl polyoxyglycerol ester and other polyoxyglycerol esters, and may include ionic surfactants and nonionic surfactants.

[0091] Formulations suitable for administration to patients (including oral administration) and containing relakolan may contain surfactants, including nonionic surfactants, in proportions of about 10% to about 90% by weight; in embodiments, such formulations and compositions containing relakolan may contain surfactants, including nonionic surfactants, in proportions of about 15% to about 80% by weight; in embodiments, such formulations and compositions containing relakolan may contain surfactants, including nonionic surfactants, in proportions of about 20% to about 75% by weight; and in embodiments, such formulations and compositions containing relakolan may contain surfactants, including nonionic surfactants, in proportions of about 25% to about 70% by weight. In embodiments, such formulations and compositions containing relakolan may not contain nonionic surfactants. In embodiments, such formulations and compositions containing relakolan may not contain surfactants.

[0092] Surfactants, including nonionic surfactants, are used as excipients. Surfactant excipients suitable for use in the formulations disclosed herein may include nonionic surfactants, including sorbitol surfactants, such as sorbitol monooleate; polysorbates (available in various strengths, including, for example, polysorbate 20, polysorbate 80, also known as…) 20 and 80 (as described above); and other nonionic surfactants, including, for example, those containing... or (For example, EL, EL, RH40 The surfactants sold (RH 60, etc.), d-α-tocopherol, Solutol HS15, poloxamer 407, etc. M-1944CS(Gattefosse), Labrafil M-2125CS(Gattefosse), (Gattefosse, Saint-Priest, Lyon, France), 767) and other surfactants known in the art.

[0093] For example, polysorbate (polyoxyethylene dehydrated sorbitan monolaurate) surfactants and detergents (e.g., 20. Nonionic detergents and surfactants (such as "20" and "80", where the numbers "20" and "80" indicate the number of repeating polyethylene glycol units in the polymer) are used as excipients in formulations and, in addition to their role as surfactants, also contribute to the emulsification and / or dissolution of active compounds. Such nonionic detergents and surfactants are available, for example, from SIGMA-Aldrich, St. Louis, MO, USA.

[0094] In implementation methods, formulations containing ryracoran, as disclosed herein, may include Gelucire as a surfactant (e.g., 44 / 14, from Gattefosse, Saint-Priest, Lyon, France).

[0095] In implementation schemes, formulations containing ryrakolan, as disclosed herein, may include "Kolliphor" as a surfactant. EL (also known as cremophor; see above) is polyethoxylated castor oil used as a nonionic oil-in-water emulsifier. Kolliphor P188 is poloxamer. HS15 (polyethylene glycol (15)-hydroxystearate) is a solubilizer / emulsifier. RH40 is poly(ethylene glycol) glycerol hydroxystearate. These materials were obtained from SIGMA-Aldrich, St. Louis, MO, USA.

[0096] Solubilizer

[0097] Formulations suitable for administration to patients (including oral administration) and containing relacoran may comprise solvents, solubilizers, or solubilizers, or multiple solvents, solubilizers, or solubilizers, in proportions from about 2% by weight to about 90% by weight; in embodiments, such formulations and compositions containing relacoran may comprise solvents, solubilizers, or solubilizers, or multiple solvents, solubilizers, or solubilizers, in proportions from about 3% by weight to about 80% by weight; or, in embodiments, in proportions from about 5% by weight to about 70% by weight; or, in embodiments, in proportions from about 8% by weight to about 60% by weight; or, in further embodiments, in proportions from about 10% by weight to about 50% by weight. In embodiments, such formulations and compositions containing relacoran may not contain a solvent.

[0098] As used herein, the term "solvent" refers to, but is not limited to, a solubilizer, such as polyethylene glycol (PEG), ethanol, propylene glycol, glycerol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, other water-soluble organic solvents, and other solubilizers known in the art. In embodiments, the solubilizer may be, for example, propylene glycol or propylene glycol esters, such as propylene glycol octanoate (e.g., propylene glycol monooctanoate).

[0099] Many forms of polyethylene glycol and its derivatives can be used as solubilizers and in other ways in the formulations disclosed herein. For example, PEG can have an average molecular weight of 300 kD or 400 kD (e.g., polyethylene glycol 300, polyethylene glycol 400); it can be used in the form of succinates as polyethylene glycol (PEG) succinates (e.g., polyethylene glycol 1000 succinate) and as mono- and di-fatty acid esters of PEG (e.g., PEG300, 400, and 1750 mono- and di-fatty acid esters); and in other forms. Polyethylene glycols with a wide range of molecular weights (e.g., PEG300 with an average molecular weight of about 300 g / mol and PEG400 with an average molecular weight of about 400 g / mol) are available, for example, from SIGMA-Aldrich, St. Louis, MO, USA.

[0100] Solvents, solubilizers, and solubilizers used as excipients in formulations disclosed herein may also include ethanol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, and other water-soluble organic solvents. In embodiments, formulations containing HKFA as disclosed herein may contain diethylene glycol monoethyl ether (as named herein). (sold under the names dioxitol and others); For example HP, derived from Gattefosse, Saint-Priest, Lyon, France.

[0101] Other excipients

[0102] The excipients used in the formulations disclosed herein may include lipids and phospholipids, including naturally occurring lipid compositions such as castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil. Excipients used in the formulations disclosed herein may also include phospholipids such as phosphatidylcholine, distearylphosphatidylglycerol, L-α-dimyristoylphosphatidylcholine, L-α-dimyristoylphosphatidylglycerol, and other phospholipids. Lipids and phospholipids can be used as, for example, emulsifiers, extenders, fillers, lubricants, and for other purposes.

[0103] In embodiments, formulations containing GRM, as disclosed herein, may comprise triglycerides, including medium-chain triglycerides. Medium-chain triglycerides are triglycerides with a fatty acid chain length of about 6 to about 12 carbon atoms. Triglycerides may include, for example, 1,2,3-triacetoxypropane (also known as triacetin or triacetic acid glyceride). Triacetin is available, for example, from SIGMA-Aldrich, St. Louis, MO, USA. Triglyceride excipients such as triacetin can be used as, for example, solvents, plasticizers, and wetting agents.

[0104] The excipients used in the formulations disclosed herein may include various cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, etc. Cyclodextrins can be used as, for example, emulsifiers, solubilizers, and for other purposes.

[0105] Preparations containing Rillacoran

[0106] In implementation schemes, formulations containing ryracoran, as disclosed herein, may comprise propylene glycol monocaprylate (e.g., from Gattefosse, Saint-Priest, Lyon, France, using Capryol). TM 90 sales). In embodiments, formulations containing ryracorin as disclosed herein may comprise capryloyl hexanoyl polyoxyglyceride, for example (Sold by Gattefosse, Saint-Priest, Lyon, France; see above).

[0107] In embodiments, formulations suitable for administration to patients (including oral administration) and containing relacoran may contain polyethylene glycol (PEG) in proportions of about 5% to about 50% by weight; in embodiments, such formulations and compositions containing GRM may contain PEG in proportions of about 10% to about 40% by weight; in embodiments, such formulations and compositions containing relacoran may contain PEG in proportions of about 15% to about 30% by weight.

[0108] In the implementation scheme, formulations suitable for administration to patients (including oral administration) and containing renalacyclolan may contain polysorbate (e.g., 5% to 75% by weight) in proportions of about 5% to about 75% by weight. 20 or 80); In an embodiment, such a formulation and composition containing ryracoran may contain about 20% to about 60% polysorbate by weight. In an embodiment, such a formulation and composition containing ryracoran may not contain polysorbate.

[0109] The excipients used in formulations disclosed herein may comprise organic materials (which may be liquid or semi-solid at room temperature), such as beeswax, tocopherols (e.g., α-tocopherol (also known as vitamin E or vitamin E)), oleic acid, gum arabic, lanolin, starch, syrup, honey, and medium-chain monoglycerides and diglycerides. Such organic materials may be used as, for example, extenders, fillers, lubricants, and for other purposes.

[0110] In embodiments, formulations containing ryracorin as disclosed herein may comprise vitamin E (e.g., α-tocopherol and other tocopherols, including, for example, α-tocopherol polyethylene glycol succinate (vitamin E TPGS)). Vitamin E, including vitamin E TPGS, may be obtained, for example, from SIGMA-Aldrich, St. Louis, MO, USA. Vitamin E may be used, for example, as a solubilizer; as an emulsifier; and as an antioxidant.

[0111] Other excipients and materials that can be used in formulations and in the preparation of pharmaceutical products for administration (including those for oral administration) include sterile water for rinsing; ethanol; gelatin (e.g., edible gelatin with a gel strength measured in "Bloom," such as gelatin 220 Bloom); and coating agents such as hydroxypropyl methylcellulose (HPMC, "hydroxypropyl methylcellulose," for example...). 603 and 615) and polyvinyl alcohol coating materials; and other materials.

[0112] Exemplary formulation

[0113] Many GRMs, including many HKFA GRMs, are difficult to formulate into pharmaceutically acceptable formulations. Problems include poor solubility in water; poor solubility in solvents suitable for pharmaceutical formulations; poor stability; photosensitivity; precipitation in physiological environments; low bioavailability; incompatibility with pharmaceutically acceptable capsules and coatings; and other difficulties. Poor stability is a particular problem when developing formulations suitable for administration to patients in clinical practice.

[0114] The applicant discloses formulations herein that are believed to overcome these obstacles. Some embodiments of suitable formulations are given in the examples and are also described more generally herein. For example, a formulation suitable for oral administration to humans and containing relakolan may contain, for example, about 15% to about 25% relakolan, about 50% to about 70% surfactant, about 15% to about 25% solubilizer, and may contain a small but effective amount of antioxidant (e.g., less than about 0.1%), where % represents % w / w. In another example, a formulation suitable for oral administration to humans and containing relakolan may contain, for example, about 20% relakolan, about 60% surfactant, about 20% solubilizer, and may optionally contain a small but effective amount of antioxidant (e.g., less than about 0.1%), where % represents % w / w.

[0115] In embodiments of such formulations, the surfactant may be a glyceryl ester, such as a polyoxyglyceryl ester, for example, lauroyl polyoxy-32 glyceryl ester. In embodiments, the surfactant may be a polysorbate, such as TWEEN 20 or TWEEN 80. It should be understood that other suitable surfactants are known to those skilled in the art and may be used in conjunction with or in place of polysorbate. It should be understood that other suitable surfactants are known to those skilled in the art.

[0116] In embodiments of such formulations, the solubilizer may include glycerol or polyethylene glycol or polypropylene glycol. In embodiments of such formulations, the surfactant may be propylene glycol, such as propylene glycol monocaprylate, such as propylene glycol monocaprylate type I. In embodiments of such formulations, the surfactant may be glyceryl decanoate. In other embodiments of such formulations and pharmaceutical compositions (but not limited to), the solubilizer may be one or more oils, such as corn oil, castor oil, and other oils; may be one or more of polyethylene glycol (PEG), ethanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide; and may include combinations thereof. It should be understood that other suitable solubilizers are known to those skilled in the art and may be used in conjunction with or in place of the solubilizers described herein.

[0117] In the implementation scheme, an antioxidant is included in the formulation containing ryracoran suitable for administration to humans. The antioxidant may be, for example, BHT, BHA, TBHQ, α-tocopherol (vitamin E), gallate esters (e.g., propyl gallate) or other antioxidants, and may include combinations thereof.

[0118] For example, an embodiment of a formulation containing ryracolan suitable for administration to humans may include one or more of the following commercially available ingredients: Capmul MCM; Kolliphor EL; Kolliphor ELP; Gelucire 44 / 14; Capryol PGMC; polysorbate 80; propyl gallate; BHT; BHA; α-tocopherol; myristic acid; etc.

[0119] In this embodiment, a unit dose of renlakolan is contained in a capsule, such as a soft gel capsule or a hard-shell capsule. The formulation may be encapsulated in a gelatin capsule; for example, in a preferred embodiment, the capsule may be a soft gel capsule. Soft gel capsules are typically prepared to a size suitable for containing their contents. The size of the capsule is typically designed to contain one milligram or a few milligrams up to several hundred milligrams of the active pharmaceutical ingredient (API), such as renlakolan. In the implementation scheme, the amount of rilacin contained in the soft gel capsule may be about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 170 mg, about 175 mg, about 180 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg or more. Hard-shell capsules can be selected in sizes suitable for containing the required formulation, and can be, for example, size 5 capsules, size 4 capsules; size 3 capsules; size 2 capsules; size 1 capsules; size 0 capsules; size 00 capsules; and other sizes of capsules.

[0120] Dosage

[0121] In some embodiments, the formulation is suitable for administering an effective amount of relakolan, for example, in the form of a unit-dose formulation containing about 1 mg to about 500 mg of relakolan. In some embodiments, the unit-dose relakolan formulation is suitable for oral administration. In some embodiments, the unit-dose relakolan formulation may contain up to about 750 mg of relakolan. In some embodiments, the unit dose of relakolan is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 750 mg. In some embodiments, the formulation containing relakolan is suitable for daily administration, twice-daily administration, or three times-daily administration. In the implementation scheme, the formulation containing rilatolalan is suitable for administration every other day, or every three days, or every four days, or every five days, or every six days, or once a week. In the implementation scheme, the formulation containing rilatolalan is suitable for administration for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weeks.

[0122] In the embodiments, the pharmaceutical formulation is suitable for administering an effective amount of renalacrim, for example, from about 1 mg / kg / day to 100 mg / kg / day, preferably a daily dose of about 1 mg / kg / day to about 20 mg / kg / day. In some embodiments, the daily dose of renalacrim is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg / day. In the embodiments, renalacrim is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weeks.

[0123] In some embodiments, a pharmaceutical formulation containing relacolin is suitable for administration when encapsulated in a gelatin capsule. In other embodiments, a pharmaceutical formulation containing relacolin is suitable for administration when encapsulated in a soft gelatin (“soft gel”) capsule. In some embodiments, such a soft gel capsule comprises about 50% to about 75% gelatin and about 25% to about 50% a sorbitol / glycerol blend, and may also contain purified water and / or a coloring agent. In some embodiments, a unit dose of the relacolin formulation is contained in a soft gel capsule. Exemplary soft gel capsules may consist of the following components:

[0124] gelatin 195.05 purified water According to the needs of gel formulation Sorbitol / glycerol blend 111.46 Colorant As needed

[0125] The sorbitol / glycerol blend contains a 50:50 blend of sorbitol and glycerol.

[0126] In the implementation scheme, a pharmaceutical formulation containing rilacin is suitable for administration with another pharmaceutical formulation, such as with pills, tablets, oral solutions, injectables, or other formulations containing another active ingredient.

[0127] The formulations and methods disclosed herein can be used to treat patients with any condition that is readily treatable with GRM, as described above.

[0128] In one embodiment, the pharmaceutical composition comprising relacoran is formulated for oral administration. In another embodiment, oral administration includes sublingual administration. In yet another embodiment, relacoran is formulated for administration in suppository form and may be administered rectally or vaginally.

[0129] Methods for treating diseases, including but not limited to, Cushing's syndrome, by administering GRM in such pharmaceutical compositions are also provided. In one embodiment, the pharmaceutical composition disclosed herein is administered to a patient suffering from a disease or condition that is readily treatable by GRM; in another embodiment, administration includes oral administration.

[0130] Pharmaceutical formulations containing renalacyclolin are preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing an appropriate amount of renalacyclolin. The unit dosage form may be, for example, a pill or capsule comprising or containing renalacyclolin.

[0131] In one embodiment, a unit dosage form contains about 0.1 mg of renquercetin to about 750 mg of renquercetin; in a further embodiment, a unit dosage form contains about 1 mg of renquercetin to about 600 mg of renquercetin; in a further embodiment, a unit dosage form contains about 5 mg of renquercetin to about 500 mg of renquercetin; in a further embodiment, a unit dosage form contains about 10 mg of renquercetin to about 400 mg of renquercetin; in a further embodiment, a unit dosage form contains about 15 mg of renquercetin to about 350 mg of renquercetin; in a further embodiment, a unit dosage form contains about 20 mg of renquercetin to about 300 mg of renquercetin; in a further embodiment, a unit dosage form contains about 25 mg of renquercetin to about 250 mg of renquercetin.

[0132] In specific embodiments, a unit dosage form may contain about 5 mg to about 200 mg of relakolan. In further embodiments, a unit dosage form may contain about 10 mg to about 150 mg of relakolan. In other embodiments, a unit dosage form may contain about 15 mg to about 100 mg of relakolan. In still further embodiments, a unit dosage form may contain about 20 mg to about 80 mg of relakolan. In some embodiments, a unit dosage form may contain about 25 mg to about 75 mg of relakolan. In other embodiments, a unit dosage form may contain about 30 mg to about 60 mg of relakolan.

[0133] In specific implementation schemes, the unit dosage form may contain approximately 10 mg of rennet; or approximately 25 mg of rennet; or approximately 40 mg of rennet; or approximately 50 mg of rennet; or approximately 75 mg of rennet; or approximately 100 mg of rennet; or approximately 125 mg of rennet; or approximately 150 mg of rennet; or approximately 200 mg of rennet; or approximately 250 mg of rennet. Or approximately 300 mg of ralicolan; or approximately 350 mg of ralicolan; or approximately 400 mg of ralicolan; or approximately 450 mg of ralicolan; or approximately 500 mg of ralicolan; or approximately 550 mg of ralicolan; or approximately 600 mg of ralicolan; or approximately 650 mg of ralicolan; or approximately 700 mg of ralicolan; or approximately 750 mg of ralicolan; or approximately 800 mg of ralicolan.

[0134] A unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, and powder in vials or ampoules. Furthermore, a unit dosage form can be the capsule, tablet, sachets, or lozenge itself, or it can be any of these dosage forms in appropriate quantities in package form.

[0135] A single-unit dosage form containing rilacoxan can be administered once daily, or two, three, or more times daily to provide the preferred daily dose level. Multiple units of a single-unit dosage form containing rilacoxan can be administered simultaneously or on the same day to achieve the required daily dose (amount of rilacoxan).

[0136] The composition may also contain other compatible therapeutic agents. The compounds described herein may be used in combination with each other, or in combination with adjuvants that may not be effective on their own but may contribute to the efficacy of the active agent.

[0137] use

[0138] In some embodiments, relakolan is suitable for treating diseases characterized by cortisol overdose. For example, in embodiments, pharmaceutical preparations containing relakolan are suitable for treating Cushing's syndrome, including Cushing's disease and other diseases and conditions. Such treatment can be administered alone or in combination with other treatments for such diseases and conditions.

[0139] Pharmaceutical formulations containing renalacyclolin and the methods of administration of pharmaceutical formulations containing renalacyclolin disclosed herein may be used to treat patients with any condition that is readily treatable with GRM. Conditions readily treatable with GRM may include, but are not limited to, conditions such as obesity, diabetes, hyperglycemia, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease, cognitive impairment, Cushing's syndrome, Addison's disease, osteoporosis, asthenia, muscular atrophy, inflammatory diseases, osteoarthritis, rheumatoid arthritis, asthma and rhinitis, adrenal-related disorders, viral infections, immunodeficiency, immune modulation, and autoimmune diseases. Sexual disorders, allergic reactions, wound healing, compulsive behaviors, multidrug resistance, addiction, psychosis, anorexia, cachexia, post-traumatic stress disorder, postoperative fractures, medical catabolism, major psychotic depression, mild cognitive impairment, psychosis, dementia, stress disorder, antipsychotic drug-induced weight gain, delirium, cognitive impairment in patients with depression, cognitive decline in individuals with Down syndrome, psychosis associated with interferon-alpha therapy, chronic pain, pain associated with gastroesophageal reflux disease, postpartum psychosis, postpartum depression, neurological disorders in premature infants, and migraines. In some embodiments, the condition or symptom may be major psychotic depression, stress disorder, or antipsychotic drug-induced weight gain. In embodiments, the condition or symptom may be selected from obesity, diabetes, hyperglycemia, hypertension, depression, anxiety, and Cushing's syndrome. In embodiments, the condition or symptom may be Cushing's syndrome, and in certain embodiments may be Cushing's disease, and may include hyperglycemia secondary to Cushing's syndrome.

[0140] Other conditions that can be treated with the formulations disclosed herein include alcohol dependence, symptoms of alcohol withdrawal, and cognitive deficits associated with excessive alcohol consumption. The formulations disclosed herein can also be used to treat cancers such as bone cancer, breast cancer, prostate cancer, ovarian cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer, and other cancers, including but not limited to leukemia, lymphoma, and neuroblastoma. Example

[0141] The following examples are provided by way of illustrative purposes of implementations of the methods disclosed herein, and are intended to illustrate, but not limit, formulations containing renalacolan of this disclosure.

[0142] In the following embodiments, the excipients include: glycerides, such as lauroyl polyoxyglycerides, such as lauroyl polyoxy-32 glycerides and diglycerides; propylene glycol, such as propylene glycol monocaprylate; sorbitol; glycerol; and blends comprising sorbitol and glycerol; and may include colorants and antioxidants, such as butylated hydroxytoluene (BHT). Purified water may also be used if necessary.

[0143] In a further embodiment, the formulation may contain surfactants, including but not limited to polysorbate (polyoxyethylene dehydrated sorbitan monolaurate) surfactants and detergents (e.g. 20. 80, etc.); lipids, such as corn oil, castor oil, cottonseed oil, olive oil, peanut oil and other oils, including medium-chain triglycerides of hydrogenated vegetable oils, coconut oil and palm seed oil and other oils suitable for use in pharmaceutical compositions for human administration; solubilizers (including solvents and solubility enhancers), such as polyethylene glycol (PEG), ethanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide and other water-soluble organic solvents, but not limited thereto; and antioxidants, such as BHT, butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), vitamin E (α-tocopherol), etc., but not limited thereto.

[0144] In the following embodiments, the gel capsules used are soft gel capsules and contain gelatin, sorbitol, and glycerin. Additionally, the soft gel capsules typically also contain purified water (as required for gel preparation) and a colorant (if desired). An exemplary gel capsule shell comprises 195.05 g of gelatin; and 111.46 g of a sorbitol-glycerin blend containing equal amounts of sorbitol and glycerin, and a smaller amount of D-glucol. The sorbitol-glycerin blend can be used as "Sorbitol Special". TM "Obtained from SPIPharma (Septemes, FR)."

[0145] As mentioned above, many GRMs, including many HKFA GRMs such as renala, have poor solubility in pharmaceutically acceptable compositions and solvents; furthermore, pharmaceutical formulations of many such GRMs (including many such HKFA GRMs) typically offer only poor bioavailability. In addition, many GRMs, including many HKFA GRMs, are difficult to formulate to provide acceptable stability. Many GRMs, such as renala, are unstable over time in some formulations, particularly in alkaline (low pH) formulations, or when exposed to light, or under other storage conditions. Due to the requirements for solubilization and the solvents required for such solubilization, many GRMs, including many HKFA GRMs, are difficult to formulate to provide acceptable biocompatibility in pharmaceutical formulations (e.g., providing formulations that do not include or include only minimal amounts of excipients that may have unpleasant, adverse, or toxic effects on the individual to whom the formulation is administered).

[0146] The following examples discuss several exemplary formulations containing relakolan prepared as discussed herein. All formulations discussed herein are believed to provide a useful amount of solubilization of the active ingredient and provide sufficient formulation stability, including sufficient stability of the active ingredient, to be suitable for administration to human individuals. Suitable stability includes the ability of the formulation to maintain an effective amount of relakolan over a period of time (within months, or potentially even years of storage). In particular, all formulations discussed herein are believed to provide a useful amount of solubilization of relakolan and provide sufficient formulation stability, including sufficient stability of relakolan, to be suitable for administration to human individuals. Furthermore, the formulations disclosed herein are believed to provide improved bioavailability of relakolan compared to existing or alternative formulations. The relakolan-containing formulations disclosed herein are further believed to provide improved biocompatibility compared to existing or alternative formulations. The formulations disclosed herein are suitable for administration to human individuals and are believed to be suitable for treating human individuals suffering from conditions that can be readily treated with HKFA compounds such as relakolan. The formulation disclosed herein is considered to provide an improved pharmaceutical formulation that addresses problems of poor solubility, poor bioavailability, poor biocompatibility, or poor stability previously encountered in existing or alternative formulations of renalacolan administered to human individuals.

[0147] The following embodiments are provided by way of example only and not by way of limitation. Those skilled in the art will readily recognize that many non-critical parameters can be changed or modified to produce substantially similar results.

[0148] Example 1 "Clinical Formulation"

[0149] Rellakolan was found to be stable in acidic aqueous solutions; however, it was found to degrade over time in neutral solutions at elevated temperatures, and that it was sensitive to alkaline conditions. The stability of rellakolan and its compatibility with various excipients were tested, and suitable excipients were identified. An initial formulation containing polyethoxylated castor oil (Kolliphor EL, derived from BASF, Florham Park, New Jersey) and a mixture of monoacylglycerols (Capmul MCM, medium-chain monoacylglycerols, primarily caprylic and capric acids, fatty acids derived from ABITEC Corporation, Columbus, Ohio) showed significant decomposition (i.e., instability) after two weeks of stability testing at 40°C and 75% relative humidity, and at 60°C. Other formulations containing propylene glycol monocaprylate (Capryol PGMC, derived from Gattefosse USA, New Jersey) and stearoyl polyoxy-32 glyceryl ester (Gelucire 50 / 13, derived from Gattefosse USA, New Jersey) did not provide the required solubility. Stearoyl polyoxy-32 glyceryl ester (Gelucire 44 / 14, derived from Gattefosse USA, New Jersey) was then used instead of stearoyl polyoxy-32 glyceryl ester. As described below, the formulations in Table III surprisingly provided improved stability for relacolan formulations intended for human patient administration, including oral administration.

[0150] Several test formulations were prepared and subjected to stability and other tests. The composition of these test formulations is given in Table I, where “API” represents ryracolan; “MDC” represents medium-chain monoglycerides (mainly caprylic and capric acids); “PEC” represents polyethoxylated castor oil; “LPG” represents lauroyl polyoxy-32 glycerol; “PGM” represents propylene glycol monocaprylate; “BHT” represents butylated hydroxytoluene; “BHA” represents butylated hydroxyanisole; “GLT” represents propyl gallate; “MYR” represents myristic acid; and “AT” represents α-tocopherol.

[0151] Table I Test Formulations

[0152] A 20API, 40MDC, 40PEC 7.0 B 20API, 39.96MDC, 40PEC, 0.04BHT C 20API, 39.91MDC, 40PEC, 0.04BHT, 0.04BHA D 20API, 39.76MDC, 40PEC, 0.04BHT, 0.2GLT 7.0 E 20API, 39.8MDC, 40PEC, 0.2AT F 20API, 39.26MDC, 40PEC, 0.04BHT, 0.2GLT, 0.5MYR G 20API, 59.98LPG, 20PGM, 0.02BHT 4.0

[0153] The stability of relakolan in several test formulations was examined at 50°C for two weeks. The degree of degradation observed with the preferred formulation (Formulation G in Table I above) indicates good compatibility with these reagents during manufacturing and long-term storage. The amounts of relakolan and relakolan-derived impurities were measured by high-performance liquid chromatography (HPLC). After two weeks of storage at 50°C, the amount of relakolan in Formulation G did not decrease significantly. Compared with other formulations, Formulation G showed the highest percentage of relakolan, the lowest amount of impurities, and the smallest increase in impurities after two weeks of storage at 50°C.

[0154] The stability of ryracoran in a range of possible excipients (including the formulations in Table I) was also examined at 40°C and 75% RH and at 60°C for two weeks. The main degradation pathway was the aromatic decarbonylation reaction of ryracoran with propylene glycol monooctanoate and lauroyl polyoxy-32 glycerol excipients. Ryracoran showed good stability with both excipients. In the formulations in Table I, ryracoran exhibited good stability at 40°C / 75% RH. At 60°C, degradation in lauroyl polyoxy-32 glycerol was more significant than in propylene glycol monooctanoate; however, the degree of degradation observed indicates good compatibility with these reagents during manufacturing and long-term storage. These results are shown in Table II (purity is shown as a percentage of (ryracoran at the end of the test period) to (ryracoran plus the total amount of ryracoran-derived impurities)).

[0155] Table II. Compatibility of Rillacoran with Excipients

[0156]

[0157] As a result of this test, the final improved formulation was determined.

[0158] Table III below provides improved formulations suitable for incorporating relakolan into soft gel capsules with improved dissolution and stability. These formulations may be used to provide, for example, 100 mg of relakolan per capsule (which may be suitable for administration, for example, to patients with Cushing's syndrome or Cushing's disease). The formulations may also be used to provide 150 mg of relakolan per capsule, or other amounts of relakolan, along with other ingredients at appropriately scaled percentages (maintaining the same relative proportions of all ingredients).

[0159] The formulations listed in Table III include the following components (percentages are by weight):

[0160] Table III "Clinical Formulations"

[0161]

[0162]

[0163] Relakolan (API) dissolves well in this formulation and is stable in it. The formulation is a semi-solid. This formulation provides suitable bioavailability for clinical application, such as… Figure 1 The illustrative pharmacokinetic curves are shown. Eight fasting human volunteers were administered 150 mg of renalacullan from the formulation in Table III, and plasma levels of renalacullan were measured over time after administration. The mean (with standard deviation) for the eight individuals is shown. The peak plasma concentration measured in these individuals was approximately 175 ng / mL.

[0164] The stability of the formulation was tested. Stability testing included testing some formulations for up to one year. The applicant has determined that ryracoran is sensitive to both humidity and light. Furthermore, the applicant has determined that ryracoran is more stable in formulations with neutral or acidic pH, and significantly less stable over time in formulations with alkaline pH (e.g., particularly at pH values ​​greater than 8).

[0165] In vitro models were also used to simulate the digestive effects of the formulation (see Williams HD et al., J. PharmSci. 101:3360-3380 (2012)). An illustrative diagram of the in vitro model is shown below. Figure 2 The results of this test are considered to indicate the bioavailability of the drug when administered in vivo. The in vitro digestion model comprises three phases in a single container: i) a flaky precipitate containing the precipitated drug and insoluble fatty acid soaps (e.g., calcium); ii) an aqueous phase containing the drug dissolved in micelles and vesicle structures, comprising bile salts (BS, e.g., sodium taurodeoxycholate used by Williams et al.) and phospholipids (PL) and exogenous lipid digestion products (e.g., fatty acids (FA), monoglycerides (MG), and diglycerides (DG)); and iii) an undispersed oil phase, typically containing the drug, residual triglycerides (TG), and some diglycerides (DG). The experimental configuration used when performing the in vitro digestion model is shown in [reference needed]. Figure 2 middle, Figure 2 An idealized side view of a container used for an in vitro digestion assay of a formulation is illustrated. The container contains the active pharmaceutical ingredient, which can be dispensed into three phases. The amount of API found in each of the three phases provides a measure of the API's expected behavior in vivo and allows for comparison of the expected bioavailability produced by the formulations being compared. For example, the amount of API found in the aqueous phase provides an estimate of the amount (or proportion) of API that will be found in an individual's plasma after administration of the API in that formulation.

[0166] Figure 3 The results of in vitro digestion tests for the formulations in Table III are shown. Figure 3The data provided exemplify the performance of the formulation in Table III over time in an in vitro digestion model. Approximately 10-15% of rilatocana was partitioned into the aqueous phase early in the testing period, and this percentage then decreased over time. These results further demonstrate a correlation between the in vitro digestion model and the human PK curves of the formulation (see [link to relevant documentation]). Figure 1 ).

[0167] The Table III formulation was also administered to monkeys for in vivo testing (100 mg API, rilacoxetine). These results showed considerable plasma exposure (AUC) in monkeys. inf These results are shown in Table IV.

[0168] Table IV 100mg Dosage

[0169] <![CDATA[C max (ng / mL)]]> 1266 <![CDATA[AUC inf .]]> 11653 <![CDATA[AUC 0-24 ]]> 10347

[0170] In the implementation details, those skilled in the art will understand that modifications to these formulations may include: using purified, commercially available excipients (e.g., purified Kolliphor ELP significantly reduces impurities compared to unlabeled Kolliphor products); and a lower pH (e.g., pH less than pH 8, and preferably about pH 7 or lower) may contribute to further reduction of impurities. It is believed that reduced impurities improve the stability and other performance parameters of the formulation.

[0171] Other formulations containing ryracolan have been prepared, some prior to the preparation of Table III, and some after their testing in an attempt to improve upon the Table III formulations. For example, the initial formulation containing a mixture of polyethoxylated castor oil and monoglycerides (medium-chain monoglycerides, primarily caprylic and capric acids, fatty acids) exhibited significant decomposition (i.e., instability) when stability was tested for two weeks at 40°C and 75% relative humidity. Attempts to improve the Table III formulation (a formulation containing 20% ​​ryracolan, 40% polyoxylated castor oil surfactant, and 40% glyceryl caprylate solubilizer, where percentages are by weight) were found to be unstable (impurities increased by 4.5% over one month at 40°C and 75% relative humidity) and were deemed unsuitable for clinical use, at least for this reason. Therefore, the Table III formulation was found to be unexpectedly stable while providing adequate bioavailability, contrary to all the other tested formulations. Thus, the Table III formulation offers a surprising and unexpected advantage over the other formulations.

[0172] Example 2. A formulation with a certain range of relakolan dosage.

[0173] Relakolan formulations containing multiple amounts of relakolan can be provided. For example, single unit dosage forms containing 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, and 500 mg of relakolan can be prepared according to the methods provided herein. This embodiment provides instructions for preparing relakolan formulations for use in preparing single unit dosage forms containing a range of relakolan amounts. The single unit dosage form may be a soft gel capsule containing these formulations.

[0174] Table V. Relacolan formulation (regarding several dosages)

[0175]

[0176] Soft gel capsules may be filled with the formulations described in Table V above to provide a single unit dosage form containing the desired amount of ryracoran. Soft gel capsules containing the ryracoran formulations described in Table V may be made from about 50% to about 75% gelatin and about 25% to about 50% sorbitol / glycerol blend (by weight), wherein purified water and / or coloring agents are included as desired. In some embodiments, soft gel capsules containing these ryracoran formulations may be made from about 60% to about 70% gelatin and about 30% to about 40% plasticizer, or about 63% to about 66% gelatin and about 34% to about 37% plasticizer, wherein purified water and / or coloring agents are included as desired. In a specific implementation, the soft gel capsules containing these rilac preparations may be made from a blend of 64% gelatin and 36% sorbitol / glycerol (by weight), or a blend of 63.64% gelatin and 36.36% sorbitol / glycerol (by weight), these percentages excluding the weight of any purified water and / or coloring agents that may be included as desired.

[0177] All patents, patent publications, publications, and patent applications referenced in this specification are incorporated herein by reference in their entirety, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Furthermore, although the invention has been described in detail by way of exemplary illustration and examples for purposes of clarity, it will be readily apparent to those skilled in the art, based on the teachings of the invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A formulation for oral administration of rilacone ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone), rilacone having the following structure: ； The formulation comprises: Approximately 20% of the Rillakoran; Approximately 60% lauroyl polyoxyglyceride, and Approximately 20% propylene glycol monooctanoate, The percentages are weight percentages, and the formulation is a soft gel capsule.

2. The formulation of claim 1, further comprising an antioxidant.

3. The formulation of claim 2, wherein the formulation comprises about 0.02% antioxidant.

4. The formulation of claim 2 or 3, wherein the antioxidant is butylated hydroxytoluene (BHT).

5. A unit dose of renalacyclocarb for oral administration, comprising a soft gel capsule containing a renalacyclocarb formulation comprising 20% ​​renalacyclocarb, 59.98% lauroyl polyoxyglyceride, 20% propylene glycol monooctanoate and 0.02% butylated hydroxytoluene (BHT), wherein the percentages are by weight.

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