Immediate release formulations of TYK2 inhibitors

Abstract

Described herein are immediate release oral tablet compositions for the treatment of TYK2 mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 583,934, filed September 20, 2023, the contents of which are incorporated herein by reference in their entirety.

[0003] background

[0004] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins (including TYK2) are essential for cytokine signaling. TYK2 binds to the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as restriction factors)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncosin M, ciliary neurotrophic factor, myocardial trophic factor 1, myocardial trophic factor-like cytokines, and LIF). Subsequently, activated TYK2 continues to phosphorylate other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0005] IL-23-induced TYK2 activation is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. TYK2 knockout or inhibition by tyrphostin significantly reduced IL-23 and IL-22-induced dermatitis.

[0006] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell proliferation (GCH) and excessive mucus secretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6.

[0007] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduced Tyk2 activity decreases the production of Th1 / Th17-related cytokines, matrix metalloproteinases, and other key inflammatory markers.

[0008] Compared to controls, TYK2 knockout mice exhibited complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and showed no CD4 T cell infiltration in the spinal cord, indicating that TYK2 is crucial for pathogenic CD4-mediated disease development in MS. This confirms earlier studies that correlated increased TYK2 expression with MS susceptibility. The loss of TYK2 function through mutation leads to reduced neuronal demyelination and increased myelin regeneration, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating diseases.

[0009] TYK2 is the only signaling messenger shared by IL-12 and IL-23. TYK2 knockout reduces methylated BSA-induced paw pad thickening, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0010] Studies on the co-linkage and association between various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disease) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and a reduced incidence of SLE in families with affected members. Genome-wide association studies between individuals with SLE and those without the disease have revealed a highly significant association between the TYK2 locus and SLE.

[0011] TYK2 has been shown to play a crucial role in maintaining tumor surveillance, and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with effective suppression of natural killer (NK) cells and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be well-suited for treating autoimmune diseases or transplant rejection. While other members of the JAK family, such as JAK3, have similar roles in the immune system, TYK2 has been shown to be a superior target due to its involvement in fewer and more tightly coupled signaling pathways, resulting in fewer off-target effects.

[0012] Studies of T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via TYK2 signaling mediated by STAT1, maintaining cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduces cell growth. TYK2-specific activating mutations that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, kinase function of TYK2 has also been identified as necessary for increased cancer cell survival because the TYK2 enzyme possesses kinase-death mutations (M978Y or M978F) in addition to the activating mutation (E957D) that leads to transformation failure.

[0013] Therefore, selective inhibition of TYK2 has been shown to be a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as those in 70% of adult T-cell leukemia cases. TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death induced by amyloid-β (Aβ) peptide. Reduced TYK2 phosphorylation of STAT3 following Aβ administration leads to reduced neuronal cell death, and increased STAT3 phosphorylation has been observed in the post-mortem brains of Alzheimer's patients. Inhibition of the JAK-STAT signaling pathway has also been associated with the reversal of hair loss associated with hair growth and alopecia areata.

[0014] Therefore, there is a need for compositions that inhibit the activity of TYK2 to treat one or more of the conditions described herein without the side effects associated with JAK2 inhibition. Summary of the Invention

[0015] This document partially describes immediate-release oral tablet compositions for the treatment of TYK2-mediated diseases. For example, this document discloses immediate-release oral tablet compositions comprising: about 20 mg, about 40 mg, or about 60 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3The composition comprises pyridin-2-yl)cyclopropanecarboxamide, wherein the 20 mg, 40 mg, or 60 mg is based on the free base content of the compound; and wherein the compound is present in salt form; and pharmaceutically acceptable excipients; wherein the composition has a dissolution rate of greater than 85% within 20 minutes as measured by the USP Device II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate), and 0.25% sodium lauryl sulfate at 37°C.

[0016] In some implementation schemes, the compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridinylcyclopropanecarboxamide exists in the form of a hydrochloride salt. For example, this document discloses an immediately-release, fixed-dose oral tablet composition comprising: an in-particle component containing 20 mg, 40 mg, or 60 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 The compound comprises: pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg is based on the free base content of the compound; a diluent; about 3 to about 7 wt% disintegrant; and a flow aid and / or lubricant; and an extra-particle component comprising: about 1 to 3 wt% disintegrant; and a flow aid and / or lubricant; wherein each weight percentage is based on the total weight of the intra-particle component and the extra-particle component.

[0017] For example, this document discloses an immediately-release oral tablet composition comprising: an intragranular component containing: about 20 mg to about 60 mg of... N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3The compound comprises: pyridin-2-yl)cyclopropaneformamide hydrochloride; wherein the 20 mg to 60 mg is based on the free base content of the compound; microcrystalline cellulose; mannitol; crospovidone; colloidal silica; sodium stearoyl fumarate; optionally copovidone and optionally succinic acid; and an extraparticle component comprising crospovidone, colloidal silica and sodium stearoyl fumarate.

[0018] Additionally, this document discloses an immediately-release oral tablet composition comprising: an in-particle component comprising about 20 mg to about 60 mg of the compound; wherein the 20 mg to 60 mg is based on the amount of free base of the compound; about 33 wt% to about 35 wt% of microcrystalline cellulose; about 33 wt% to about 35 wt% of mannitol; about 4 wt% to about 6 wt% of crospovidone; about 0.5 wt% to about 1.5 wt% of colloidal silica; and about 0.5 wt% to about 1.5 wt% of sodium stearoyl fumarate; and an out-of-particle component comprising about 1.0 wt% of crospovidone, about 0.5 wt% of colloidal silica, and about 1.5 wt% of sodium stearoyl fumarate; wherein each weight percentage is based on the total weight of the in-particle component and the out-of-particle component.

[0019] Brief description of the attached diagram

[0020] Figure 1 The dissolution rates of tablets A20, B20, and C20 under non-sedimentation dissolution conditions in a pH 4 buffer medium were described.

[0021] Figure 2 Dissolution and stability studies of tablet B20 were described after storage for up to 3 months, up to 6 months, or up to 9 months under various temperature and humidity conditions.

[0022] Figure 3 Dissolution and stability studies of tablet C20 were described after storage for up to 3 months or up to 6 months under various temperature and humidity conditions.

[0023] Detailed Explanation

[0024] The features and other details of this disclosure will now be described in more detail. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are listed herein. These definitions should be read in light of the remainder of this disclosure and as will be understood by those skilled in the art. 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.

[0025] definition

[0026] Unless the context clearly indicates otherwise, the singular forms “an,” “a,” and “the” as used herein and in the appended claims include plural references. Thus, for example, a reference to “pharmaceutical” includes a variety of such pharmaceuticals and their equivalents known to those skilled in the art. When a scope is used herein, it is intended to include all combinations and sub-combinations of the scope and particular embodiments. Unless otherwise indicated or inferred, when referring to a number or numerical range, the term “about” means that the mentioned number or numerical range is an approximation within experimental variability (or within statistical experimental error), and therefore in some cases, the number or numerical range will vary between 1% and 15% of the stated number or numerical range, for example, a variation of ±10% from the nominal value. When the term “about” is used before a quantifiable value, this disclosure also includes the specific quantifiable value itself, unless otherwise specifically stated. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude the following: in some other embodiments, for example, any embodiment of a substance composition, composition, method or process described herein is “composed of the described features” or “consistently composed of the described features”.

[0027] As used herein, the terms “treatment,” “prevention,” “improvement,” and “inhibition,” and words derived therefrom, do not necessarily imply 100% or complete treatment, prevention, improvement, or inhibition. Rather, varying degrees of treatment, prevention, improvement, and inhibition exist, and those skilled in the art will recognize such degrees as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount and level of treatment, prevention, improvement, or inhibition of a disease in mammals. For example, a disease, including its symptoms or condition, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, treatment, prevention, improvement, or inhibition provided by the methods disclosed herein may include treating, preventing, improving, or inhibiting one or more conditions or symptoms of a disease (e.g., cancer or an inflammatory disease). Additionally, for the purposes of this document, “treatment,” “prevention,” “improvement,” or “inhibition” encompasses delaying the onset of a disease or its symptoms or condition.

[0028] As used herein, the term "effective amount" or "therapeutic effective amount" means that administering a sufficient amount of the compound or composition disclosed herein (e.g., an oral tablet composition) will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated (e.g., cancer or an inflammatory disease). In some embodiments, the result is a reduction and / or relief of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compounds disclosed herein required to clinically significantly reduce the symptoms of the disease. In some embodiments, techniques such as dose escalation studies are used to determine the appropriate "effective" amount for any individual case.

[0029] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other undesirable reactions when administered to animals or humans when appropriate. For human use, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0030] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refer to any and all solvents, dispersion media, coatings, isotonics, and absorption delay agents compatible with drug administration. The use of such media and agents in the active pharmaceutical ingredient is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic efficacy.

[0031] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, formulated together with one or more pharmaceutically acceptable excipients.

[0032] As used herein, the term "pharmaceutically acceptable salt" or "salt" refers to a salt of a basic group that may be present in the compound used in the composition. In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. The basic compounds included in the compositions of the present invention are capable of forming a variety of salts with a variety of inorganic and organic acids.

[0033] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucose, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptates, glycerophosphates, glycolic acid salts, hemisulfates, heptanoates, hexyn-1,6-dicitates, hydroxybenzoates, and γ-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, iodide, isobutyrate, lactate, maleate, malonate, methane sulfonate, mandelate metaphosphate, methane sulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propane sulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluene sulfonate, undecanoate, and xylene sulfonate.

[0034] Furthermore, the compounds described herein can be prepared by reacting their free base form with a pharmaceutically acceptable inorganic or organic acid to form a pharmaceutically acceptable salt form. This pharmaceutically acceptable inorganic or organic acid includes, but is not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, and trifluoroacetic acid. Citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, aryl sulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid.

[0035] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition refers to any disease or other harmful condition in which TYK2 or its mutants are known to play a role. Therefore, another embodiment involves treating or reducing the severity of one or more diseases in which TYK2 or its mutants are known to play a role. Such TYK2-mediated diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases.

[0036] Composition

[0037] This document discloses, for example, an immediately-release oral tablet composition comprising:

[0038] Compounds of approximately 20 mg, approximately 40 mg, or approximately 60 mg N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropane formamide, wherein the 20 mg, 40 mg or 60 mg is based on the free base content of the compound; and wherein the compound exists in the form of a salt; and

[0039] Pharmaceutically acceptable excipients; wherein the composition exhibits a dissolution rate greater than 85% within 20 minutes when measured by the USP Device II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate) and 0.25% sodium lauryl sulfate at 37°C.

[0040] In other embodiments, the disclosed immediate-release oral tablet composition comprises, for example:

[0041] The granule contains approximately 20 mg, 40 mg, or 60 mg of compounds. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide, wherein the 20 mg, 40 mg or 60 mg is based on the free base content of the compound; and wherein the compound is present in salt form; and one or more pharmaceutically acceptable excipients; and

[0042] Extragranular components, which contain one or more pharmaceutically acceptable excipients.

[0043] In some implementation schemes, the compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridinylcyclopropanecarboxamide is present in the form of hydrochloride. For example, in some embodiments, the disclosed immediate-release oral tablet composition comprises, for example:

[0044] Intragranular components, which include:

[0045] Compounds of approximately 20 mg, approximately 40 mg, or approximately 60 mg N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg, 40 mg or 60 mg is based on the free base content of the compound;

[0046] Diluent;

[0047] Approximately 3 to 7% by weight of disintegrant; and

[0048] Flow aids and / or lubricants; and

[0049] Extraparticle components, which include:

[0050] Approximately 1 to 3% by weight of disintegrant; and

[0051] Flow aids and / or lubricants;

[0052] The weight percentages are based on the total weight of the internal and external components of the particle.

[0053] In some embodiments, the immediate-release oral tablet composition of this disclosure comprises, for example, about 20 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 320 mg is pyridin-2-yl)cyclopropanecarboxamide hydrochloride; wherein the 20 mg is based on the free base content of the compound. In other embodiments, the immediately-release oral tablet composition of this disclosure comprises, for example, about 40 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropaneformamide hydrochloride; wherein the 40 mg is based on the free base content of the compound.

[0054] This document also discloses, for example, an immediately-release, fixed-dose oral tablet composition comprising:

[0055] Intragranular components, which include:

[0056] 20 mg of compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 20 mg of pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the amount is based on the free base content of the compound;

[0057] Diluent;

[0058] Approximately 3 to 7% by weight of disintegrant; and

[0059] Flow aids and / or lubricants; and

[0060] Extraparticle components, which include:

[0061] Approximately 1 to 3% by weight of disintegrant; and

[0062] Flow aids and / or lubricants;

[0063] The weight percentages are based on the total weight of the internal and external components of the particle.

[0064] This article further discloses an immediate-release fixed-dose oral tablet composition comprising:

[0065] Intragranular components, which include:

[0066] 40 mg of compound N -(4-((2-methoxy-3-(1-(methyl- d3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 40 mg is based on the free base content of the compound;

[0067] Diluent;

[0068] Approximately 3 to 7% by weight of disintegrant; and

[0069] Flow aids and / or lubricants; and

[0070] Extraparticle components, which include:

[0071] Approximately 1 to 3% by weight of disintegrant; and

[0072] Flow aids and / or lubricants;

[0073] The weight percentages are based on the total weight of the internal and external components of the particle.

[0074] Additionally, this document discloses, for example, an immediate-release fixed-dose oral tablet composition comprising:

[0075] Intragranular components, which include:

[0076] 60 mg of compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropaneformamide hydrochloride, wherein the 60 mg is based on the free base content of the compound;

[0077] Diluent;

[0078] Approximately 3 to 7% by weight of disintegrant; and

[0079] Flow aids and / or lubricants; and

[0080] Extraparticle components, which include:

[0081] Approximately 1 to 3% by weight of disintegrant; and

[0082] Flow aids and / or lubricants;

[0083] The weight percentages are based on the total weight of the internal and external components of the particle.

[0084] This article also discloses an immediately-release oral tablet composition comprising:

[0085] Intragranular components, which include:

[0086] From about 10% to about 26% by weight N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridinylcyclopropanecarboxamide hydrochloride;

[0087] Diluent;

[0088] Approximately 3 to 7% by weight of disintegrant; and

[0089] Flow aids and / or lubricants; and

[0090] Extraparticle components, which include:

[0091] Approximately 1 to 3% by weight of disintegrant; and

[0092] Flow aids and / or lubricants;

[0093] The weight percentages are based on the total weight of the internal and external components of the particle.

[0094] In some embodiments, the in-particle component of the immediately-release oral tablet compositions covered herein comprises, for example, about 20% to about 24% by weight of a compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 32-pyridinylcyclopropanecarboxamide hydrochloride; wherein the weight percentage is based on the total weight of the in-particle and out-of-particle components. For example, in some embodiments, the in-particle component comprises, for example, about 10% to about 26% by weight, about 10% to about 24% by weight, about 12% to about 26% by weight, about 12% to about 24% by weight, about 16% to about 24% by weight, about 18% to about 24% by weight, about 18% to about 26% by weight, about 20% to about 26% by weight, about 22% to about 26% by weight, about 20% to about 24% by weight, about 20% to about 22% by weight, about 21% to about 22% by weight, about 18% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, or about 26% by weight of a compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropaneformamide hydrochloride; wherein the weight percentage is based on the total weight of the in-particle and out-of-particle components.

[0095] In other embodiments, the disintegrant in the intragranule component of the immediately-release oral tablet compositions covered herein comprises, for example, crospovidone. For example, in some embodiments, the intragranule component comprises about 4% to about 10% by weight, about 5% to about 10% by weight, about 2% to about 8% by weight, about 3% to about 7% by weight, about 4% to about 6% by weight, about 3% to about 5% by weight, about 4% to about 5% by weight, about 2% by weight, about 5% by weight, about 6% by weight, about 7% by weight, or about 8% by weight, wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component. For example, in some embodiments, the intragranule component comprises about 4% to about 6% by weight of crospovidone, wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component. In some embodiments, the intragranule component comprises about 5% by weight of crospovidone, wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component.

[0096] In some embodiments, the flow aid in the intraparticle component of the immediately-release oral tablet compositions covered herein comprises, for example, colloidal silica. For example, in some embodiments, the intraparticle component comprises about 0.5 wt% to about 2.0 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 1.0 wt%, about 1.0 wt% to about 1.5 wt%, about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, or about 2.0 wt% of colloidal silica, wherein the weight percentages are based on the total weight of the intraparticle component and the extraparticle component. For example, in some embodiments, the intraparticle component comprises, for example, about 1.0 wt% of colloidal silica, wherein the weight percentages are based on the total weight of the intraparticle component and the extraparticle component.

[0097] In some embodiments, the lubricant included in the in-particle component of the immediately-release oral tablet compositions covered herein comprises, for example, sodium stearoyl fumarate. For example, in some embodiments, the in-particle component comprises about 0.5 wt% to about 2.0 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 1.0 wt%, about 1.0 wt% to about 1.5 wt%, about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, or about 2.0 wt% of sodium stearoyl fumarate, wherein the weight percentages are based on the total weight of the in-particle component and the out-of-particle component. For example, in some embodiments, the in-particle component comprises, for example, about 1.0 wt% of sodium stearoyl fumarate, wherein the weight percentages are based on the total weight of the in-particle component and the out-of-particle component.

[0098] In some embodiments, the diluent in the intragranule component of the immediately-release oral tablet compositions covered herein comprises, for example, microcrystalline cellulose and mannitol. For example, in some embodiments, the intragranule component comprises, for example, about 10% to about 24% by weight, about 12% to about 26% by weight, about 12% to about 24% by weight, about 16% to about 24% by weight, about 18% to about 24% by weight, about 18% to about 26% by weight, about 20% to about 26% by weight, about 22% to about 26% by weight, about 20% to about 24% by weight, about 20% to about 22% by weight, about 21% to about 22% by weight, about 18% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, or about 26% by weight; wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component. In other embodiments, for example, the intragranule component comprises about 20% to about 23% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component. In yet another embodiment, the intragranule component comprises about 21% to about 22% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component. For example, in some embodiments, the intragranule component comprises about 22% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component.

[0099] In some embodiments, the diluent in the extragranule component of the immediately-release oral tablet compositions covered herein comprises, for example, microcrystalline cellulose and mannitol. For example, in some embodiments, the extragranule component comprises, for example, about 10% to about 24% by weight, about 12% to about 26% by weight, about 12% to about 24% by weight, about 16% to about 24% by weight, about 18% to about 24% by weight, about 18% to about 26% by weight, about 20% to about 26% by weight, about 22% to about 26% by weight, about 20% to about 24% by weight, about 20% to about 22% by weight, about 21% to about 22% by weight, about 18% by weight, about 20% by weight, about 21% by weight, 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, or about 26% by weight; wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component. In other embodiments, for example, the extragranular component comprises about 20% to about 23% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranular and extragranular components. In yet another embodiment, the extragranular component comprises about 21% to about 22% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranular and extragranular components. For example, in some embodiments, the extragranular component comprises about 22% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranular and extragranular components.

[0100] In another embodiment, the intragranule component of the disclosed immediately-release oral tablet composition comprises, for example, about 32% to about 36% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component. In other embodiments, the intragranule component comprises about 33% to about 35% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component. In some embodiments, the intragranule component comprises, for example, about 34% by weight of microcrystalline cellulose, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component.

[0101] In some embodiments, the intragranule component of the immediately-release oral tablet compositions covered herein comprises, for example, about 10% to about 24% by weight, about 12% to about 26% by weight, about 12% to about 24% by weight, about 16% to about 24% by weight, about 18% to about 24% by weight, about 18% to about 26% by weight, about 20% to about 26% by weight, about 22% to about 26% by weight, about 20% to about 24% by weight, about 20% to about 22% by weight, about 21% to about 22% by weight, about 18% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, or about 26% by weight; wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component. In other embodiments, for example, the intragranule component comprises about 20% to about 23% by weight of mannitol, wherein the weight percentages are based on the total weight of the intragranule component and the extragranule component. In another embodiment, the intraparticle component comprises about 21% to about 22% by weight of mannitol, wherein the weight percentage is based on the total weight of the intraparticle component and the extraparticle component. For example, in some embodiments, the intraparticle component comprises about 22% by weight of mannitol, wherein the weight percentage is based on the total weight of the intraparticle component and the extraparticle component.

[0102] In another embodiment, the intragranule component of the disclosed immediately-release oral tablet composition comprises, for example, from about 32% to about 36% by weight of mannitol, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component. In other embodiments, the intragranule component comprises, for example, from about 33% to about 35% by weight of mannitol, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component. In some embodiments, the intragranule component comprises, for example, about 34% by weight of mannitol, wherein the weight percentage is based on the total weight of the intragranule component and the extragranule component.

[0103] In other embodiments, for example, the in-particle component of the disclosed immediately-release oral tablet composition further comprises, for example, copovidone. In some embodiments, the in-particle component further comprises about 10% to about 20% by weight, about 12% to about 18% by weight, about 13% to about 17% by weight, about 14% to about 16% by weight, about 15% to about 20% by weight, about 15% to about 18% by weight, about 15% to about 16% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, or about 18% by weight; wherein the weight percentages are based on the total weight of the in-particle component and the out-of-particle component. In another embodiment, the in-particle component further comprises, for example, about 14% to about 16% by weight of copovidone, wherein the weight percentages are based on the total weight of the in-particle component and the out-of-particle component. In some embodiments, for example, the in-particle component further comprises about 15% by weight of copovidone, wherein the weight percentages are based on the total weight of the in-particle component and the out-of-particle component.

[0104] In other embodiments, for example, the intragranular component of the disclosed immediate-release oral tablet composition further comprises, for example, succinic acid. In some embodiments, the intragranular component of the disclosed immediate-release oral tablet composition further comprises, for example, about 5% to about 15% by weight, about 7% to about 13% by weight, about 9% to about 11% by weight, about 5% to about 10% by weight, about 7% to about 10% by weight, about 8% to about 10% by weight, about 9% to about 12% by weight, about 9% to about 10% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight, wherein the weight percentages are based on the total weight of the intragranular and extragranular components. In some embodiments, the intragranular component of the disclosed immediate-release oral tablet composition further comprises, for example, about 8% to about 12% by weight, wherein the weight percentages are based on the total weight of the intragranular and extragranular components. In other embodiments, the intraparticle component further comprises, for example, about 9% to about 11% by weight of succinic acid, wherein the weight percentage is based on the total weight of the intraparticle component and the extraparticle component. In some embodiments, the intraparticle component further comprises, for example, about 10% by weight of succinic acid, wherein the weight percentage is based on the total weight of the intraparticle component and the extraparticle component.

[0105] In some embodiments, the extraparticle component of the immediately-release oral tablet compositions covered herein comprises, for example, crospovidone. For example, in some embodiments, the extraparticle component comprises about 0.5 wt% to about 2.0 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 1.0 wt%, about 1.0 wt% to about 1.5 wt%, about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, or about 2.0 wt% of crospovidone, wherein the weight percentages are based on the total weight of the intraparticle and extraparticle components. For example, in some embodiments, the extraparticle component comprises, for example, about 1.0 wt% of crospovidone, wherein the weight percentages are based on the total weight of the intraparticle and extraparticle components.

[0106] In some embodiments, the extraparticle component of the immediately-release oral tablet compositions covered herein comprises, for example, colloidal silica. For example, in some embodiments, the extraparticle component comprises about 0.5 wt% to about 2.0 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 1.0 wt%, about 1.0 wt% to about 1.5 wt%, about 0.25 wt% to about 1.0 wt%, about 0.25 wt% to about 0.75 wt%, about 0.25 wt% to about 0.5 wt%, about 0.25 wt%, about 0.5 wt%, about 0.75 wt%, about 1.0 wt%, about 1.5 wt%, or about 2.0 wt% of colloidal silica, wherein the weight percentages are based on the total weight of the intraparticle and extraparticle components. For example, in some embodiments, the extraparticle component comprises, for example, about 0.5 wt% of colloidal silica, wherein the weight percentages are based on the total weight of the intraparticle and extraparticle components.

[0107] In some embodiments, the extragranule component of the immediately-release oral tablet compositions covered herein comprises, for example, sodium stearoyl fumarate. For example, in some embodiments, the extragranule component comprises about 0.5 wt% to about 2.0 wt%, about 0.5 wt% to about 1.5 wt%, about 1.0 wt% to about 1.5 wt%, about 1.0 wt% to about 2.0 wt%, about 1.25 wt% to about 1.75 wt%, about 1.25 wt% to about 1.5 wt%, about 1.0 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2.0 wt% of sodium stearoyl fumarate, wherein the weight percentages are based on the total weight of the intragranule and extragranule components. For example, in some embodiments, the extragranule component comprises, for example, about 1.5 wt% of sodium stearoyl fumarate, wherein the weight percentages are based on the total weight of the intragranule and extragranule components.

[0108] For example, in some embodiments, the extragranular components of the immediately-release oral tablet compositions covered herein comprise crospovidone, colloidal silica, and sodium stearoyl fumarate. In some embodiments, for example, the extragranular components of the immediately-release oral tablet compositions covered herein comprise, for example, about 1.0% by weight of crospovidone, about 0.5% by weight of colloidal silica, and about 1.5% by weight of sodium stearoyl fumarate.

[0109] In other embodiments, the disclosed immediate-release oral tablet composition further comprises a film coating. In other embodiments, the disclosed immediate-release oral tablet composition further comprises, for example, a titanium dioxide-free film coating. In some embodiments, the film coating comprises, for example, calcium carbonate.

[0110] This document further discloses, for example, an immediately-release oral tablet composition comprising:

[0111] Intragranular components, which include:

[0112] Compounds of approximately 20 mg to approximately 60 mg N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg to 60 mg is based on the free base content of the compound;

[0113] Diluent;

[0114] Approximately 3 to 7% by weight of disintegrant; and

[0115] Flow aids and / or lubricants; and

[0116] Extraparticle components, which include:

[0117] Approximately 1 to 3% by weight of disintegrant; and

[0118] Flow aids and / or lubricants;

[0119] The weight percentages are based on the total weight of the internal and external components of the particle.

[0120] In some embodiments, the immediate-release oral tablet compositions covered herein comprise, for example:

[0121] The intragranular components comprise approximately 20 mg to approximately 60 mg of compounds. N -(4-((2-methoxy-3-(1-(methyl-d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg to 60 mg is based on the free base content of the compound; microcrystalline cellulose; mannitol; crospovidone; colloidal silica; sodium stearoyl fumarate; optional copovidone and optional succinic acid; and

[0122] The extraparticle components include cross-linked polyvinylpyrrolidone, colloidal silica, and sodium stearoyl fumarate.

[0123] In other embodiments, the immediate-release oral tablet compositions covered herein comprise, for example:

[0124] The intraparticle components contain approximately 20 mg to approximately 60 mg of compounds. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 The compound comprises pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg to 60 mg is based on the amount of free base of the compound; about 33 wt% to about 35 wt% microcrystalline cellulose; about 33 wt% to about 35 wt% mannitol; about 4 wt% to about 6 wt% crospovidone; about 0.5 wt% to about 1.5 wt% colloidal silica; and about 0.5 wt% to about 1.5 wt% sodium stearoyl fumarate; and

[0125] The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate;

[0126] The weight percentages are based on the total weight of the internal and external components of the particle.

[0127] In other embodiments, the immediate-release oral tablet compositions covered herein comprise, for example:

[0128] The intraparticle components contain approximately 20 mg to approximately 60 mg of compounds. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d 3 The compound comprises: pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg to 60 mg is based on the amount of free base of the compound; about 21 wt% to about 22 wt% microcrystalline cellulose; about 21 wt% to about 22 wt% mannitol; about 4 wt% to about 6 wt% crospovidone; about 0.5 wt% to about 1.5 wt% colloidal silica; about 0.5 wt% to about 1.5 wt% sodium stearoyl fumarate; about 14 to about 16 wt% copovidone; and about 9 to about 11 wt% succinic acid; and

[0129] The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate;

[0130] The weight percentages are based on the total weight of the internal and external components of the particle.

[0131] In some embodiments, the immediate-release oral tablet composition of this disclosure comprises, for example, about 20 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 20 mg is pyridin-2-yl)cyclopropanecarboxamide hydrochloride; wherein the 20 mg is based on the free base content of the compound. In other embodiments, the immediately-release oral tablet composition of this disclosure comprises, for example, about 40 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide hydrochloride; wherein the 40 mg is based on the free base content of the compound. In other embodiments, the immediately-release oral tablet composition of this disclosure comprises, for example, about 60 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride; wherein the 60 mg is based on the free base content of the compound. In other embodiments, the immediately-release oral tablet composition of this disclosure comprises, for example, about 20 mg to about 60 mg of the compound. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropanecarboxamide hydrochloride; wherein the 20 mg to 60 mg is based on the free base content of the compound.

[0132] This article further discloses an immediately-release oral tablet composition comprising:

[0133] The component within the particles comprises approximately 21% to approximately 22% by weight of N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 Pyridin-2-yl)cyclopropanecarboxamide hydrochloride; about 33% to about 35% by weight of microcrystalline cellulose; about 33% to about 35% by weight of mannitol; about 4% to about 6% by weight of crospovidone; about 0.5% to about 1.5% by weight of colloidal silica; and about 0.5% to about 1.5% by weight of sodium stearoyl fumarate; and

[0134] The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate;

[0135] The weight percentages are based on the total weight of the internal and external components of the particle.

[0136] Additionally, this document discloses an immediate-release oral tablet composition comprising:

[0137] The intraparticle components contain approximately 22% by weight of N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3Pyridin-2-yl)cyclopropanecarboxamide hydrochloride; about 34 wt% microcrystalline cellulose; about 34 wt% mannitol; about 5.0 wt% crospovidone; about 1.0 wt% colloidal silica; and about 1.0 wt% sodium stearoyl fumarate; and

[0138] The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate;

[0139] The weight percentages are based on the total weight of the internal and external components of the particle.

[0140] This article also discloses an immediately-release oral tablet composition comprising:

[0141] The component within the particles comprises approximately 21% to approximately 22% by weight of N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 Pyridin-2-yl)cyclopropanecarboxamide hydrochloride; about 21% to about 22% by weight of microcrystalline cellulose; about 21% to about 22% by weight of mannitol; about 4% to about 6% by weight of crospovidone; about 0.5% to about 1.5% by weight of colloidal silica; about 0.5% to about 1.5% by weight of sodium stearoyl fumarate; about 14% to about 16% by weight of copovidone; and about 9% to about 11% by weight of succinic acid; and

[0142] The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate;

[0143] The weight percentages are based on the total weight of the internal and external components of the particle.

[0144] This article further discloses an immediately-release oral tablet composition comprising:

[0145] The intraparticle components contain approximately 22% by weight of N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3Pyridin-2-yl)cyclopropanecarboxamide hydrochloride; about 22 wt% microcrystalline cellulose; about 22 wt% mannitol; about 5.0 wt% crospovidone; about 1.0 wt% colloidal silica; about 1.0 wt% sodium stearoyl fumarate; about 15.0 wt% copovidone; and about 10.0 wt% succinic acid; and

[0146] The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate;

[0147] The weight percentages are based on the total weight of the internal and external components of the particle.

[0148] In some embodiments, the immediately-release oral tablet compositions disclosed herein are substantially stable after storage, for example, for one month, or up to three months, or up to six months, or up to nine months, at 25°C and 60% relative humidity, at 30°C and 75% relative humidity, or at 40°C and 75% relative humidity. In other embodiments, the immediately-release oral tablet compositions disclosed herein exhibit a dissolution rate greater than 85% within 20 minutes when measured by the USP Device II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate), and 0.25% sodium lauryl sulfate at 37°C.

[0149] In some embodiments, the disclosed immediate-release oral tablet composition comprises about 20 mg to about 24 mg of N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 pyridin-2-yl)cyclopropanecarboxamide hydrochloride. In other embodiments, the disclosed immediate-release oral tablets contain about 42 mg to about 46 mg of [the product / formula / container name - missing from original text]. N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 pyridin-2-yl)cyclopropanecarboxamide hydrochloride. In other embodiments, the disclosed immediate-release oral tablets contain about 62 mg to about 66 mg of [the product / formula / container name - missing from original text]. N -(4-((2-methoxy-3-(1-(methyl- d 3)-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridinylcyclopropanecarboxamide hydrochloride.

[0150] Pharmaceutical Composition

[0151] In some embodiments, the compounds provided herein are substantially pure because they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated, for example, in one or more steps of the synthetic method.

[0152] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and suitable 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. Generally, an appropriate dose and treatment regimen provides an amount of the composition sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free survival and / or overall survival, or reduced symptom severity). Optimal doses are typically determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0153] For example, in some embodiments, the disclosed compound or composition (e.g., an oral tablet composition) may be administered to a patient once daily. In other embodiments, the disclosed compound or composition (e.g., an oral tablet composition) may be administered to a patient twice daily.

[0154] Suitable dosages and dosage regimens are determined using conventional range-finding techniques known to those skilled in the art. Generally, the initial treatment dose is small, less than the optimal dose of the compounds disclosed herein. Subsequently, the dose is increased in small increments until the optimal effect is achieved in such cases. In some embodiments, the method of the invention involves administering about 0.1 µg to about 50 mg of at least one compound described herein per kilogram of subject body weight. For a 70 kg patient, a more commonly used dose is about 10 µg to about 200 mg of the compounds disclosed herein, depending on the subject's physiological response.

[0155] For example only, the dosage of the compounds described herein for treating diseases as described herein is about 0.001 to about 1 mg / kg of the subject's body weight per day, such as about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg / kg of body weight per day. In some embodiments, the compound described herein is used in the described method at a dose of about 1 to about 1000 mg / kg of the body weight of the subject being treated, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg daily, wherein the amount of the fixed dose is equivalent to N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 The amount of free base of pyridin-2-yl)cyclopropaneformamide.

[0156] Furthermore, by way of example only, the dosage of this compound used in methods of treating diseases as described herein may be a fixed dose, such as a fixed dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, or 80 mg, wherein the amount of the fixed dose is equivalent to N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 The amount of free base of pyridin-2-yl)cyclopropaneformamide.

[0157] Treatment

[0158] The methods described herein are used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase is TYK2.

[0159] This article provides a method for treating a disease or disorder, wherein the disease or disorder is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplant-related disease, the method comprising administering an effective amount of the composition described herein (e.g., an immediately released oral tablet composition) to a patient in need.

[0160] In some implementations, the disease or disorder is an autoimmune disease. In some implementations, the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0161] In some implementations, the disease or disorder is an inflammatory disease. In some implementations, inflammatory diseases include rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0162] In some implementations, the disease or disorder is a proliferative disorder. In some implementations, the proliferative disorder is cancer. In some implementations, the proliferative disorder is a hematologic cancer. In some implementations, the proliferative disorder is leukemia. In some implementations, the leukemia is T-cell leukemia. In some implementations, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some implementations, the proliferative disorder is polycythemia vera, myelofibrosis, primary proliferative disorder, or thrombocythemia.

[0163] In some implementations, the disease or disorder is an endocrine disorder. In some implementations, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0164] In some implementations, the disease or disorder is a neurological disease. In some implementations, the neurological disease is Alzheimer's disease.

[0165] In some embodiments, the proliferative disease is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0166] In some implementations, the disease or obstacle is related to the transplant. In some implementations, the transplant-related disease or obstacle is transplant rejection or graft-versus-host disease.

[0167] In some embodiments, the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disease or disorder is associated with type I interferon signaling. In some embodiments, the disease or disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disease or disorder is associated with IL-23 signaling.

[0168] This article provides methods for treating inflammatory or allergic skin conditions such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic skin conditions.

[0169] This article provides methods for treating other diseases or conditions, such as those with inflammatory components, such as eye diseases and conditions, such as ocular allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving or having autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and Steven-Johnson syndrome. Irritable bowel syndrome (IBS), idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerulonephropathy, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (pre- and post-), ​​Sjogren's syndrome, dry keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change nephropathy, chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, catabolic disorders, obesity, embryonic growth restriction, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, pigmentary disorders, Paget's disease, pancreatitis, and hereditary periodic fever. Syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, allergic reaction, sinusitis, ocular allergy, silica-induced disease, COPD (reduced damage, tracheal inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease. Diseases, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epididymitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura. (purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0170] In some implementations, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryptothermal protein-associated periodic syndrome (CAPS), or osteoarthritis.

[0171] In some implementations, the inflammatory disease is a Th1 or Th17-mediated disease. In some implementations, the Th17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0172] In some implementations, the inflammatory disease is Sjögren's syndrome, allergic diseases, osteoarthritis, eye conditions (such as ocular allergies, conjunctivitis, dry keratoconjunctivitis, vernal conjunctivitis) or diseases affecting the nose (such as allergic rhinitis).

[0173] It should be understood that dosing regimens for treating, preventing, or improving conditions for which remission is sought are adjusted based on a variety of factors, such as the subject's disease, disorder, or condition; the subject's age, weight, sex, diet, and medical status. Therefore, in some cases, the actual dosing regimen used may vary, and in some implementations, may differ from the dosing regimen described herein.

[0174] The compounds and compositions described herein are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing compounds varies. Thus, in one embodiment, the compositions described herein are used as a preventative agent and are continuously administered to a subject predisposed to developing a condition or disease to prevent its occurrence. In another embodiment, the composition is administered to the subject during symptom onset or as soon as possible after symptom onset. In a particular embodiment, the compositions described herein are administered as soon as possible after the onset of a disease or condition is detected or suspected, and treatment is continued for the duration required for the disease. In some embodiments, the duration of treatment varies and is adjusted to suit the specific needs of each subject. For example, in a particular embodiment, the compounds described herein or preparations containing such compounds are administered for at least 2 weeks, about 1 month, or about 5 years.

[0175] Example

[0176] The following examples are provided for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0177] N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridinylcyclopropanecarboxamide hydrochloride (compound A) can be prepared according to the synthetic procedure described in WO 2020 / 086616, the entire contents of which are incorporated herein by reference. Compound A is, for example, a regulator of tyrosine kinase 2 (TYK2), such as an inhibitor of TYK2, and its free base form is shown below:

[0178] .

[0179] Example 1: Composition

[0180] According to Table 1, an immediate-release oral tablet composition (tablet A10) containing 10 mg of the free base of compound A and an immediate-release oral tablet composition (tablet A20) containing 20 mg of the free base of compound A were prepared.

[0181] Table 1.

[0182]

[0183] a This is equivalent to 10 mg or 20 mg of free base of compound A.

[0184] b Purified water is a processing aid that is removed as part of the film coating process.

[0185] Immediately released oral tablet compositions containing 20 mg of the free base of compound A (tablet B20), 40 mg of the free base of compound A (tablet B40), 20 mg of the free base of compound A (tablet C20), and 40 mg of the free base of compound A (tablet C40) were prepared according to Table 2.

[0186] Table 2.

[0187]

[0188] a This is equivalent to 20 mg of free base of compound A.

[0189] b This is equivalent to 40 mg of free base of compound A.

[0190] Further immediate-release oral tablet compositions of this disclosure are prepared according to Table 3.

[0191] Table 3.

[0192]

[0193] Example 2: Preparation method

[0194] For example, tablets B20, B40, C20, and C40 are manufactured via a dry granulation, tableting, and coating process described below. This common blending method is used to prepare, for example, 20 mg and 40 mg tablets, and can also be used to prepare, for example, 60 mg tablets or other strengths of tablets by scaling up the components accordingly.

[0195] 1. Intraparticle blending

[0196] a. Microcrystalline cellulose (MCC), compound A hydrochloride, mannitol, colloidal silica, crospovidone, succinic acid (for immediate release C tablets), and copovidone (for immediate release C tablets) are premixed in a blender.

[0197] b. Pass the mixture through Comil to de-clump the mixture.

[0198] c. In the main blending step, the de-agglomerated powder is mixed in the blender.

[0199] d. Lubricate the mixture with sieved sodium stearoyl fumarate (SSF).

[0200] 2. Dry granulation is carried out using a roller compactor and a built-in mill.

[0201] 3. Blending of extra-particle components

[0202] a. Mix the granules with cross-linked polyvinyl chloride that has been manually sieved outside the granules and colloidal silica that has been manually sieved.

[0203] b. The mixture is then lubricated with SSF that has been manually sieved.

[0204] 4. Compress the final blend from step 3 into 20 mg or 40 mg tablets. Smaller or larger tablets (e.g., 60 mg, 30 mg) can be prepared by appropriately adjusting the proportions of the components.

[0205] 5. The tablets are coated with a thin film using Opadry coating in a pan coating machine.

[0206] 6. The tablets are then packaged in high-density polyethylene (HDPE) bottles containing a desiccant and sealed with a child-proof cap.

[0207] Example 3: Biorelated Dissolution Study

[0208] In dissolution tests, tablets were compared to examine differences in maximum dissolution, supersaturation, and persistence in buffer media. The tests were conducted as a single-stage dissolution test under sediment-free conditions at pH 4.0, in which 20 mg tablets (e.g., tablet A20, tablet B20, or tablet C20) and 250 mL of simulated gastric fluid were mixed in a 1L Type II dissolution apparatus at 100 RPM stirring speed and 37°C. Samples were analyzed using a fiber optic probe.

[0209] The results are shown in Figure 1 In the middle. For example Figure 1 As shown, tablets B20 and C20 exhibited a significant improvement in non-precipitation dissolution at pH 4 compared to tablet A20.

[0210] Example 4: Stability and dissolution studies

[0211] Samples of tablets B20 and C20 were stored in 30 mL HDPE bottles with polypropylene caps, each containing 1 g of silica gel desiccant. Samples were stored for one month, up to three months, up to six months, and up to nine months at 25°C and 60% RH, 30°C and 75% RH, or 40°C and 75% RH, respectively. The samples were then subjected to a dissolution method (USP apparatus II (paddle), 75 rpm, 900 mL pH 4.5 (50 mM acetate) and 0.25% SLS, 37°C). Specific test parameters are shown in Table 4, and results are presented in [Table data missing]. Figure 2 and Figure 3 middle. Figure 2 The study described the dissolution and stability of tablet B20 after storage for up to 3 months, 6 months, or 9 months under different temperature and humidity conditions. Figure 3 The dissolution and stability of tablet C20 were studied after storage for up to 3 months or up to 6 months under different temperature and humidity conditions.

[0212] Table 4.

[0213]

[0214] Example 5: Pharmacokinetic Study

[0215] Studies were conducted to investigate the relative bioavailability of compound A in single oral doses in different compositions. Treatment A (2 × 20 mg tablet A20), treatment B (2 × 20 mg tablet B20), treatment C (2 × 20 mg tablet C20), or treatment E (40 mg liquid formulation) were administered to healthy human subjects (n=24), and their pharmacokinetic parameters were measured. The results are shown in Table 5. As shown in Table 5, absorption was rapid and T0 was high between tablet formulations. maxQuite similar. T for all tablet formulations. 1 / 2 The absorption time was approximately 8 hours. Treatments B and C showed absorption rates comparable to treatment A (C... max ) and bioavailability (AUC).

[0216] Table 5.

[0217]

[0218] By incorporating via reference

[0219] All publications and patents mentioned herein, including those listed below, are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In the event of any conflict, this application (including any definitions herein) shall prevail.

[0220] Equivalent schemes and scope

[0221] In the claims, unless otherwise indicated or apparent from the context, articles such as “a,” “an,” and “the” may refer to one or more. Unless otherwise indicated or apparent from the context, a claim or description including “or” among one or more members of a group is deemed satisfied if one, more than one, or all of the members of a group are present in, used in, or otherwise associated with a given product or method. The invention includes embodiments in which exactly one member of a group is present in, used in, or otherwise associated with a given product or method. The invention also includes embodiments in which more than one or all of the members of a group are present in, used in, or otherwise associated with a given product or method.

[0222] Furthermore, this invention covers all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, any claim dependent on another claim may be modified to include any limitations present in any other claim dependent on the same basic claim. When elements are presented in list form, such as in Markush groups, each subgroup of the elements is also disclosed, and any element may be removed from the group. It should be understood that, generally, when referred to as comprising a particular element and / or feature in an aspect of the invention, certain embodiments of the invention or an aspect thereof consist of or are substantially composed of such elements and / or features. For the sake of brevity, these embodiments are not specifically described herein. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. When a range is given, endpoints are included. Furthermore, unless otherwise stated or clearly understood from the context and by one of ordinary skill in the art, values ​​expressed as ranges in different embodiments of the invention may assume any particular value or subrange within the range, up to one-tenth of the lower limit unit of the range, unless the context expressly specifies otherwise.

[0223] This application references various granted patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any specific embodiments of the invention falling within the scope of the prior art may be expressly excluded from any one or more claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly stated herein. Any specific embodiment of the invention may be excluded from any claim for any reason, whether or not the reason relates to the existence of the prior art.

[0224] Those skilled in the art should recognize or be able to determine equivalent solutions to the specific embodiments described herein through routine experiments. The scope of the embodiments described herein is not intended to be limited to the foregoing description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. An immediately-release oral tablet composition comprising: Compounds of approximately 20 mg, approximately 40 mg, or approximately 60 mg N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropaneformamide, wherein the 20 mg, 40 mg, or 60 mg is based on the free base content of the compound; and wherein the compound is present in salt form; and Pharmaceutically acceptable excipients; wherein the composition has a dissolution rate of greater than 85% within 20 minutes when measured by USP Device II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate) and 0.25% sodium lauryl sulfate at 37°C.

2. The immediate-release oral tablet composition of claim 1, comprising: The granular component comprises about 20 mg, about 40 mg, or about 60 mg of the compound, wherein the 20 mg, 40 mg, or 60 mg is based on the free base content of the compound; and wherein the compound is present in salt form; and one or more pharmaceutically acceptable excipients; and Extragranular components, which contain one or more pharmaceutically acceptable excipients.

3. The immediate-release oral tablet composition of claim 1 or 2, wherein the compound is present in the form of a hydrochloride salt.

4. The immediate-release oral tablet composition according to any one of claims 1 to 3, comprising: Intraparticle components, which include: Compounds of approximately 20 mg, approximately 40 mg, or approximately 60 mg N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg, 40 mg or 60 mg is based on the free base content of the compound; Diluent; Approximately 3 to 7% by weight of disintegrant; and Flow aids and / or lubricants; and Extraparticle components, which include: Approximately 1 to 3% by weight of disintegrant; and Flow aids and / or lubricants; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

5. The immediate-release oral tablet composition according to any one of claims 1 to 4, having 20 mg of the compound.

6. The immediate-release oral tablet composition according to any one of claims 1 to 4, having 40 mg of the compound.

7. An immediate-release, fixed-dose oral tablet composition comprising: Intraparticle components, which include: 20 mg of compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridin-2-yl)cyclopropanecarboxamide hydrochloride, wherein the 20 mg is based on the free base content of the compound; Diluent; Approximately 3 to 7% by weight of disintegrant; and Flow aids and / or lubricants; and Extraparticle components, which include: Approximately 1 to 3% by weight of disintegrant; and Flow aids and / or lubricants; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

8. An immediate-release fixed-dose oral tablet composition comprising: Intraparticle components, which include: 40 mg of compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropaneformamide hydrochloride, wherein the 40 mg is based on the free base content of the compound; Diluent; Approximately 3 to 7% by weight of disintegrant; and Flow aids and / or lubricants; and Extraparticle components, which include: Approximately 1 to 3% by weight of disintegrant; and Flow aids and / or lubricants; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

9. An immediate-release, fixed-dose oral tablet composition comprising: Intragranular components, which include: 60 mg of compound N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 )pyridin-2-yl)cyclopropaneformamide hydrochloride, wherein the 60 mg is based on the free base content of the compound; Diluent; Approximately 3 to 7% by weight of disintegrant; and Flow aids and / or lubricants; and Extraparticle components, which include: Approximately 1 to 3% by weight of disintegrant; and Flow aids and / or lubricants; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

10. An immediately-release oral tablet composition comprising: Intraparticle components, which include: From about 10% to about 26% by weight N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridinylcyclopropanecarboxamide hydrochloride; Diluent; Approximately 3 to 7% by weight of disintegrant; and Flow aids and / or lubricants; and Extraparticle components, which include: Approximately 1 to 3% by weight of disintegrant; and Flow aids and / or lubricants; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

11. The immediate-release oral tablet composition of claim 10, wherein the in-particle component comprises about 20% to about 24% by weight of the compound.

12. The immediate-release oral tablet composition of any one of claims 6 to 11, wherein the disintegrant in the intragranular component comprises crospovidone.

13. The immediate-release oral tablet composition of any one of claims 6 to 12, wherein the in-particle component comprises about 4% to about 6% by weight of crospovidone.

14. The immediate-release oral tablet composition of any one of claims 6 to 13, wherein the flow aid in the intraparticle component comprises colloidal silica.

15. The immediate-release oral tablet composition of any one of claims 6 to 14, wherein the in-particle component comprises about 0.5% to about 1.5% by weight of colloidal silica.

16. The immediate-release oral tablet composition of any one of claims 6 to 15, wherein the lubricant in the intragranular component comprises sodium stearoyl fumarate.

17. The immediate-release oral tablet composition of any one of claims 6 to 16, wherein the in-particle component comprises about 0.5% to about 1.5% by weight of sodium stearoyl fumarate.

18. The immediate-release oral tablet composition of any one of claims 6 to 17, wherein the diluent in the intragranular component comprises microcrystalline cellulose and mannitol.

19. The immediate-release oral tablet composition of any one of claims 6 to 18, wherein the in-particle component comprises about 20% to about 36% by weight of microcrystalline cellulose and about 20% to about 36% by weight of mannitol.

20. The immediate-release oral tablet composition of any one of claims 6 to 19, wherein the intragranular component further comprises copovidone and succinic acid.

21. The immediate-release oral tablet composition of any one of claims 6 to 20, wherein the in-particle component further comprises about 13% to about 17% by weight of copovidone and about 8% to about 12% by weight of succinic acid.

22. The immediate-release oral tablet composition of any one of claims 6 to 21, wherein the extragranular component comprises crospovidone, colloidal silica, and sodium stearoyl fumarate.

23. The immediate-release oral tablet composition of any one of claims 6 to 22, wherein the extragranular component comprises about 1.0 wt% crospovidone, about 0.5 wt% colloidal silica and about 1.5 wt% sodium stearoyl fumarate.

24. An immediately-release oral tablet composition comprising: Intraparticle components, which include: Compounds of approximately 20 mg to approximately 60 mg N -(4-((2-methoxy-3-(1-(methyl- d 3 )-1 H -1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3- d 3 2-pyridin-2-yl)cyclopropaneformamide hydrochloride, wherein the 20 mg to 60 mg is based on the free base content of the compound; Diluent; Approximately 3 to 7% by weight of disintegrant; and Flow aids and / or lubricants; and Extraparticle components, which include: Approximately 1 to 3% by weight of disintegrant; and Flow aids and / or lubricants; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

25. The immediate-release oral tablet composition of claim 24, comprising: The granule component comprises: about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base content of the compound; microcrystalline cellulose; mannitol; crospovidone; colloidal silica; sodium stearoyl fumarate; optional copovidone and optional succinic acid; and The extraparticle components include cross-linked polyvinylpyrrolidone, colloidal silica, and sodium stearoyl fumarate.

26. The immediate-release oral tablet composition of claim 24, comprising: The granular component comprises about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base content of the compound; about 33 wt% to about 35 wt% of microcrystalline cellulose; about 33 wt% to about 35 wt% of mannitol; about 4 wt% to about 6 wt% of crospovidone; about 0.5 wt% to about 1.5 wt% of colloidal silica; and about 0.5 wt% to about 1.5 wt% of sodium stearoyl fumarate; and The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

27. The immediate-release oral tablet composition of claim 24, comprising: The granular component comprises about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base content of the compound; about 21 wt% to about 22 wt% of microcrystalline cellulose; about 21 wt% to about 22 wt% of mannitol; about 4 wt% to about 6 wt% of crospovidone; about 0.5 wt% to about 1.5 wt% of colloidal silica; about 0.5 wt% to about 1.5 wt% of sodium stearoyl fumarate; about 14 to about 16 wt% of copovidone; and about 9 to about 11 wt% of succinic acid; and The particulate components include approximately 1.0% by weight of crospovidone, approximately 0.5% by weight of colloidal silica and approximately 1.5% by weight of sodium stearoyl fumarate; The weight percentages are based on the total weight of the intraparticle components and the extraparticle components.

28. The immediate-release oral tablet composition of any one of claims 24 to 27, comprising about 20 mg of the compound, wherein the 20 mg is based on the amount of free base of the compound.

29. The immediate-release oral tablet composition of any one of claims 24 to 27, comprising about 40 mg of the compound, wherein the 40 mg is based on the free base content of the compound.

30. The immediate-release oral tablet composition of any one of claims 24 to 27, comprising about 60 mg of the compound, wherein the 60 mg is based on the amount of free base of the compound.

31. The immediate-release oral tablet composition of any one of claims 1 to 30, wherein the composition is substantially stable after storage for one month or three months at 25°C and 60% relative humidity, at 30°C and 75% relative humidity, or at 40°C and 75% relative humidity.

Images