Oral dosage form of TRβ agonist VK2809 for the treatment of liver disorders and method for preparing same - Patents.com

Abstract

The present disclosure is directed to an oral dosage form of TRβ agonist VK2809 and a method for preparing the same. The present disclosure provides an oral dosage form of VK2809 with improved stability and dissolution properties that allow storage under standard conditions by using spray drying with one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), copovidone, poloxamer 407, hypromellose acetate succinate (HPMCAS), polyacrylates, and combinations thereof.

Description

[Technical field]

[0001] The compositions and methods of the present disclosure relate broadly to the field of oral dosage forms of thyroid hormone receptor-β (TRβ) agonists for the treatment of liver disorders, fibrotic diseases and inflammation. [Background technology]

[0002] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland in response to various stimuli (e.g., thyrotropin-releasing hormone (TRH) from the hypothalamus). Thyroid hormones are iodized O-aryltyrosine analogs that are excreted into the circulation primarily as 3,3',5,5'-tetraiodothyronine (T4). T4 is rapidly deiodized in local tissues by thyroxine 5'-deiodinase to 3,3',5'-triiodothyronine (T3), the most potent TH. T3 is metabolized to inactive metabolites via various pathways, including those involving deiodination, glucuronidation, sulfation, deamination, and decarboxylation. The majority of circulating T4 and T3 are eliminated through the liver.

[0003] The biological activity of THs is largely mediated by the thyroid hormone receptor (TR). TRs belong to the nuclear receptor superfamily and, together with their common partner, the retinoid X receptor, form heterodimers that act as ligand-inducible transcription factors. Like other nuclear receptors, TRs have ligand-binding and DNA-binding domains and regulate gene expression by ligand-dependent interactions with DNA response elements (thyroid response elements, TREs). Currently, the literature indicates that TRs are encoded by two separate genes (TRα and TRβ) and that multiple isoforms are produced through alternative splicing (Williams, Mol. Cell. Biol. 20(22):8329-42 (2000); Nagaya et al., Biochem. Biophys. Res. Commun. 226(2):426-30 (1996)). The major isoforms identified to date are TRα-1, TRα-2, TRβ-1 and TRβ-2. TRα-1 is expressed ubiquitously in rats, with highest expression in skeletal muscle and brown fat. TRβ-1 is also expressed ubiquitously, with highest expression in liver, brain, and kidney. TRβ-2 is expressed in specific regions of the anterior pituitary gland and hypothalamus, as well as in the developing brain and inner ear. In rat and mouse liver, TRβ-1 is the predominant isoform (80%). The TR isoforms found in humans and rats are highly homologous to each other in their amino acid sequences, suggesting that each serves specialized functions.

[0004] THs affect the growth, metabolism and physiology of almost all organs. THs lower serum cholesterol and triglycerides. However, side effects of TH action include cardiac arrhythmias, bone loss, irritability and anxiety.

[0005] TRβ agonists can be useful as therapeutic agents for pathologies such as hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), and various fibrotic diseases and disorders.However, some TRβ agonists may be poorly soluble and / or have undesirable stability profiles.The low aqueous solubility and poor stability of such compounds may require special storage conditions for the compounds, and may present challenges in preparing formulations that achieve appropriate exposure to subjects and do not degrade when stored under standard conditions.

[0006] Thus, there is a need to provide drug formulations that provide suitable exposure to a subject for drugs that have poor aqueous solubility. Further, there is a need for drug formulations that have improved stability such that the drug does not degrade under ambient conditions and room temperature storage can be utilized. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 7,829,552 [Patent Document 2] WO 87 / 05297, Johnston et al., published September 11, 1987 [Non-patent literature]

[0008] [Non-Patent Document 1] Williams, Mol. Cell. Biol. 20(22):8329–42 (2000) [Non-Patent Document 2] Nagaya et al., Biochem. Biophys. Res. Commun. 226(2):426-30 (1996) [Non-Patent Document 3] Xu, J. Med. Chem., 2016, 59, 6553~6579 [Non-Patent Document 4] Stewart et al., Mol. Pharmaceutics, 2017, 12, 2437~2449 Summary of the Invention

[0009] In a first aspect of the present disclosure, the present specification provides a compound having the following structure:

[0010] [ka]

[0011] The present invention provides an oral dosage form comprising: (A) a composition comprising one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), copovidone, poloxamer 407, hypromellose acetate succinate (HPMCAS), polyacrylates, and combinations thereof; and (B) one or more ductile fillers, brittle fillers, disintegrants, glidants, lubricants, or combinations thereof. In some embodiments, the polymer can be polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA).

[0012] In some embodiments of the first aspect, Compound 1 and one or more polymers can be combined to form a spray-dried dispersion. In other embodiments, Compound 1 and one or more polymers can be combined to form a hot melt extrudate.

[0013] In some embodiments of the first aspect, the weight ratio of compound 1 to one or more polymers in the composition can be 1:10 to 10:1. In other embodiments, the weight ratio of compound 1 to one or more polymers in the composition can be 1:1 to 1:4. In some particular embodiments, the weight ratio of compound 1 to one or more polymers in the composition can be 1:3.

[0014] In some embodiments of the first aspect, the composition may comprise 5% to 25% by weight of the dosage form, while in other embodiments, the composition may comprise 10% to 15% by weight of the dosage form.

[0015] In some embodiments of the first aspect, the ductile filler is selected from microcrystalline cellulose and silicified microcrystalline cellulose. In some particular embodiments, the ductile filler is microcrystalline cellulose.

[0016] In some embodiments of the first aspect, the microcrystalline cellulose may comprise 40% to 60% by weight of the dosage form. In other embodiments, the microcrystalline cellulose may comprise 45% to 55% by weight of the dosage form. In some embodiments, the microcrystalline cellulose may comprise 50% by weight of the dosage form.

[0017] In some embodiments of the first aspect, the brittle filler can include lactose monohydrate, spray-dried lactose, anhydrous lactose, lactose monohydrate, anhydrous lactose, mannitol, and combinations thereof. In some embodiments, the brittle filler can include lactose monohydrate, anhydrous lactose, or mannitol.

[0018] In some embodiments of the first aspect, the brittle filler may comprise 10% to 40% by weight of the dosage form. In other embodiments, the brittle filler may comprise 20% to 30% by weight of the dosage form. In some embodiments, the brittle filler may comprise 25% by weight of the dosage form.

[0019] In some embodiments of the first aspect, the disintegrant may be selected from carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, starch, pregelatinized starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone crospovidone, hydroxypropyl cellulose, magnesium aluminometasilicate, and polacrilin potassium. In some embodiments, the disintegrant may be croscarmellose sodium or crospovidone.

[0020] In some embodiments of the first aspect, the disintegrant may comprise 5% to 15% by weight of the dosage form, hi other embodiments, the disintegrant may comprise 10% by weight of the dosage form.

[0021] In some embodiments of the first aspect, the lubricant may be selected from the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate, and magnesium stearate. In some particular embodiments, the lubricant may be magnesium stearate.

[0022] In some embodiments of the first aspect, the lubricant may comprise 0.1% to 3% by weight of the dosage form. In other embodiments, the lubricant may comprise 0.1% to 1% by weight of the dosage form. In some embodiments, the lubricant may comprise 5% by weight of the dosage form.

[0023] In some embodiments of the first aspect, the glidant can be silicon dioxide, starch, or talc. In some particular embodiments, the glidant can be silicon dioxide.

[0024] In some embodiments of the first aspect, the glidant comprises 0.1% to 3% by weight of the dosage form. In other embodiments, the glidant may comprise 0.1% to 1% by weight of the dosage form. In some embodiments, the glidant may comprise 5% by weight of the dosage form.

[0025] In some embodiments of the first aspect, the oral dosage forms described herein can include (a) an intragranular portion comprising: (i) Compound 1 or a pharma- ceutically acceptable salt thereof, and one or more polymers; (ii) a ductile filler; (iii) a brittle filler; (iv) a disintegrant; (v) a glidant; and (vi) a lubricant; and (b) an extragranular portion comprising: (i) a disintegrant; and (ii) a lubricant.

[0026] In some embodiments of the first aspect, the dosage form can be characterized as having 90%-100% of the original amount of Compound 1 after one month of storage at 50° C. and ambient relative humidity (RH). In other embodiments, the dosage form can be characterized as having 95%-100% of the original amount of Compound 1 after one month of storage at 50° C. and ambient relative humidity (RH). In yet other embodiments, the dosage form can be characterized as having 90%-100% of the original amount of Compound 1 after two months of storage at 50° C. and ambient relative humidity (RH). In other embodiments, the dosage form can be characterized as having 95%-100% of the original amount of Compound 1 after two months of storage at 50° C. and ambient relative humidity (RH).

[0027] In a second aspect of the disclosure, there is provided herein a method of preparing an oral dosage form as described herein, comprising the steps of: (a) preparing a pregranulation preblend comprising: (i) a composition comprising Compound 1 and one or more polymers; (ii) a ductile filler; (iii) a brittle filler; (iv) a disintegrant; and (v) a glidant; (b) blending the preblend composition; (c) further adding a lubricant to the pregranulation preblend; (d) slugging the pregranulation preblend; and (e) granulating the pregranulation preblend to form a granular material.

[0028] In some embodiments, the method may further comprise the steps of: (f) adding a disintegrant to the granular material; (g) further blending the granular material; (h) further adding a lubricant to the granular material and the blend to form a final blend; and (i) compressing the final blend into a dosage form.

[0029] In a third aspect of the present disclosure, there is provided herein a method of preventing, treating or ameliorating one or more fatty liver diseases in a subject in need thereof, comprising administering to said subject in need thereof an oral dosage form as described herein.

[0030] In some embodiments, the fatty liver disease may be selected from the group consisting of steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

[0031] In some embodiments, the method can include administration of a second agent, hi some embodiments, the second agents can be administered sequentially or simultaneously.

[0032] In some embodiments, the method may prevent, treat, or ameliorate fibrosis, fibrotic conditions, or fibrotic symptoms. In some embodiments, the method may reduce the amount of extracellular matrix protein present in one or more tissues of the subject. In some embodiments, the method may reduce the amount of collagen present in one or more tissues of the subject. In some embodiments, the method may reduce the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject. [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 shows relative scattering absorbance versus measured concentration of Compound 1 from stock solutions into biorelevant media at 37° C. [Diagram 2]FIG. 1 shows the dissolution of Compound 1 spray-dried dispersion in 0.5% simulated intestinal fluid in PBS buffer (pH 6.5) after exposure to 0.01 N HCl for 30 min, as measured by UV-Vis probe. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present disclosure provides oral administration formulations of Compound 1.

[0035] [ka]

[0036] Compound 1 is a low solubility lipophilic prodrug compound in development for the treatment of chronic liver disease, including non-alcoholic fatty liver disease (NAFLD). Compound 1 can be prepared according to known methods, including those described in U.S. Patent No. 7,829,552, the entirety of which is incorporated herein by reference. Current clinical dosage forms are encapsulated PEG-based formulations that achieve adequate exposure, but require cold chain storage due to chemical stability challenges. Provided herein is an immediate release tablet formulation that includes a solid amorphous spray-dried dispersion (SDD) of Compound 1 that has improved stability so that room temperature storage can be utilized, and that matches or exceeds the exposure achieved by current formulations.

[0037] definition The term "mammal" is used in its ordinary biological sense, and thus specifically includes humans and non-human mammals such as dogs, cats, horses, donkeys, mules, cows, domestic buffalo, camels, llamas, alpacas, bison, yaks, goats, sheep, pigs, elk, deer, domestic antelope, as well as non-human primates and many other species.

[0038] "Subject," as used herein, means a human or a non-human mammal, including, but not limited to, a dog, cat, horse, donkey, mule, cow, domestic buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer, domestic antelope, or non-human primate, selected for treatment or therapy.

[0039] "Subject suspected of suffering from" refers to a subject exhibiting one or more clinical indicators of a disease or condition. In certain embodiments, the disease or condition is one or more fibrosis, fibrotic conditions, or fibrotic symptoms. In certain embodiments, the disease or condition is scleroderma. In certain embodiments, the disease or condition is non-alcoholic steatohepatitis (NASH). In certain embodiments, the disease or condition is cirrhosis. In certain embodiments, the disease or condition is non-alcoholic fatty liver disease (NAFLD). In certain embodiments, the disease or condition is idiopathic pulmonary fibrosis. In certain embodiments, the disease or condition is atherosclerosis. In certain embodiments, the disease or condition is hepatitis, alcoholic fatty liver disease, asthma, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, scleroderma, pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis; interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration. fibrosis, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, surgical complications, fibrotic chronic transplant vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal stenosis, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components.

[0040] As used herein, "fibrosis" refers to the abnormal deposition of extracellular matrix proteins. Such proteins include, but are not limited to, collagen, elastin, fibronectin, laminin, keratin, keratin sulfate, fibrin, perlecan, agrin, or aggrecan. As used herein, "collagen" refers to any one of the collagen subtypes, including, but not limited to, types I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, or XVIII. Exemplary collagen types and subtypes include types I, Ia, II, III, IV, and V, among others. As used herein, fibrosis can occur alone or as a symptom or sequela of another pathology. As used herein, fibrosis may be due to a genetic condition, a genetic predisposition, an environmental insult, an injury, injury healing, an autoimmune condition, or a chronic inflammation, a chronic inflammatory condition, or another condition that causes abnormal or excessive deposition of extracellular matrix components. Fibrosis as referred to herein may be assessed by assaying or determining the presence or level of one or more biomarkers. Biomarkers of the presence of fibrosis include, but are not limited to, expression of Col1a1, Col3a1, ACTA2, ENPP2, and / or LGALS1 genes, or any combination or product thereof. Diagnosis or assessment of fibrosis may further be performed by determining the presence or level of type I collagen and / or hydroxyproline, or any combination or product thereof. Diagnosis or assessment of fibrosis may also be performed by histological, histochemical, or immunohistochemical analysis of one or more samples from a subject.

[0041] "Glycogen storage disease" refers to any one or more of a group of disorders generally characterized by impairment in the synthesis, transport, or utilization of glycogen due to the loss of a necessary enzymatic activity. Glycogen storage diseases are generally classified into types according to their symptoms and etiology. Known types include GSD type 0 (aglycogenesis, glycogen synthase deficiency); GSD type 1 (von Gierke disease, glucose-6-phosphatase translocase / transporter deficiency, GSD I); GSD type 2 (Pompe disease, α-1-4-glucosidase deficiency, GSD II); GSD type 3 (Cohri disease, Forbes disease, limit dextrinosis, debranching enzyme disease; amylo-1-6-glucosidase deficiency due to loss of glucosidase and / or transferase activity, GSD III); GSD type 4 (Anderson disease, glycogen phosphorylase deficiency, branching enzyme deficiency, amylopectinosis, glycogen branching enzyme deficiency; amylo-1,4→1,6 transglucosidase deficiency, GSD IV); GSD type 5 (McArdle disease, glycogen phosphorylase (muscle type) deficiency, GSD GSD type V); GSD 6 (Herth's disease; glycogen phosphorylase E (liver type) deficiency, GSD VI); GSD 7 (Tarui's disease; phosphofructokinase deficiency, GSD VII); GSD types 8, 9 (GSD with phosphorylase activation system deficiency; phosphorylase kinase (liver or muscle isoform) deficiency, GSD VIII and GSD IX); GSD 10 (cyclic AMP-dependent kinase deficiency, GSD X); GSD 11 (Fanconi-Bickel syndrome; glucose transporter type 2 (GLUT2) deficiency, GSD XI); and GSD 12 (aldolase A deficiency, GSD XII). Subtypes of glycogen storage diseases are also known, in particular GSD 1a, which is caused by a mutation in the gene for glucose-6-phosphatase (G6PC) and causes, among other symptoms, excessive accumulation of glycogen and lipids in liver tissue, hepatomegaly, hepatic adenoma, and hepatocellular carcinoma. Symptoms of glycogen storage diseases can include elevated or decreased blood glucose, insulin insensitivity, muscle disorders, and hepatic symptoms such as steatosis, hyperlipidemia, hypercholesterolemia, cardiac hypertrophy, hepatomegaly, fibrosis, cirrhosis, hepatocellular adenoma, and hepatocellular carcinoma.Symptoms can also include insulin insensitivity, elevated or reduced blood glucose, renal dysfunction, and / or fibrosis.

[0042] As used herein, "inflammatory disease" refers to a disease or disorder characterized by inflammation. Exemplary inflammatory diseases include acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis of the liver, colitis, congestive heart failure, conjunctivitis, cyclosporine, and pulmonary tuberculosis. Phosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammation cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, nonalcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, abdominal Inflammation includes, but is not limited to, omentitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein inflammation, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendonitis, tendinosis, tendonitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, bladder trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis. Inflammation as referred to herein can be assessed by assaying or determining the presence or level of one or more biomarkers.Biomarkers of the presence of inflammation include, but are not limited to, expression of the TNF, CARD15, IL4R, IL23R, CTLA4, ANXA1, ANXA2, LGALS3, and / or PTPN22 genes, or any combination or product thereof.

[0043] The term "atherosclerosis" refers to a condition characterized by irregular distribution of lipid deposits in the intima of large and medium-sized arteries, which induce fibrosis and calcification. Atherosclerosis increases the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions.

[0044] "Subject in need thereof" means a subject identified as in need of treatment or therapy.

[0045] A therapeutic effect relieves to some extent one or more of the symptoms of a disease or disorder, including curing the disease or disorder. "Cure" means that the symptoms of an active disease are eliminated. However, even after a cure is achieved, certain long-term or permanent effects of the disease (such as extensive tissue damage) may exist.

[0046] "Treat", "treatment", or "treating" as used herein refers to administering a pharmaceutical composition for prophylaxis and / or therapy. The term "prophylactic treatment" refers to treating a patient who does not already suffer from the disease or disorder in question, but who is susceptible to or otherwise at risk for a particular disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder. The term "therapeutic treatment" refers to administering a treatment to a patient who already suffers from a disease or disorder.

[0047] "Preventing" or "prevention" refers to delaying or forestalling the onset, occurrence or progression of a condition or disease for a period of time, including weeks, months, or years.

[0048] "Amelioration" refers to a decrease in the severity of at least one indicator of a condition or disease. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of an indicator may be determined by subjective or objective measures known to those skilled in the art.

[0049] "Modulation" refers to a perturbation of function or activity. In certain embodiments, modulation refers to an increase in gene expression. In certain embodiments, modulation refers to a decrease in gene expression. In certain embodiments, modulation refers to an increase or decrease in the total serum level of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the free serum level of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the total serum level of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in the free serum level of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in the total bioavailability of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the total bioavailability of a specific non-protein factor.

[0050] "Administering" means providing an agent or composition to a subject, and includes, but is not limited to, administration by a medical professional and self-administration.

[0051] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof. Agents include, but are not limited to, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0052] "Drug" means a substance that produces a therapeutic effect when administered to a subject.

[0053] "Pharmaceutical composition" refers to a mixture of substances, including a pharmaceutical agent, suitable for administration to an individual. For example, a pharmaceutical composition can include a modified oligonucleotide and a sterile aqueous solution.

[0054] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the associated compound and are not biologically or otherwise undesirable. In many cases, the compounds herein are capable of forming acid and / or base salts due to the presence of phenolic and / or phosphonate groups or groups similar thereto. Those skilled in the art will recognize that the protonation state of any or all of these compounds may vary depending on the pH and ionicity of the surrounding solution, and thus, the present disclosure contemplates multiple charge states of each compound. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety.

[0055] Pharmaceutical Compositions The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating the conditions described herein. In some embodiments, pharmaceutical compositions comprising Compound 1 can be formulated for oral administration. In some particular embodiments, pharmaceutical compositions comprising Compound 1 can be formulated as tablets. Some embodiments of the pharmaceutical compositions described herein include (a) a safe and therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof; and (b) a pharma-ceutically acceptable carrier, diluent, excipient, or combination thereof.

[0056] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition that contains an amount of compound that is suitable for administration to a subject in a single dose according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of treatment. A unit dosage form can include a single daily dose, or a fractional dose, where several unit dosage forms are administered over the course of a day to complete a daily dose. According to the present disclosure, a unit dosage form can be given more or less frequently than once per day, and can be administered more than once in a course of treatment.

[0057] The actual unit dose of Compound 1 described herein will depend on the particular compound and the condition being treated. In some embodiments, the dose can be from about 0.01 mg / kg body weight to about 120 mg or more / kg body weight, from about 0.05 mg / kg body weight to about 70 mg / kg body weight, from about 0.1 mg / kg body weight to about 50 mg / kg body weight, from about 1.0 mg / kg body weight to about 10 mg / kg body weight, from about 5.0 mg / kg body weight to about 10 mg / kg body weight, or from about 10.0 mg / kg body weight to about 20.0 mg / kg body weight. In some embodiments, the dosage can be less than 100 mg / kg body weight, 90 mg / kg body weight, 80 mg / kg body weight, 70 mg / kg body weight, 60 mg / kg body weight, 50 mg / kg body weight, 40 mg / kg body weight, 30 mg / kg body weight, 25 mg / kg body weight, 20 mg / kg body weight, 10 mg / kg body weight, 7.5 mg / kg body weight, 6 mg / kg body weight, 5 mg / kg body weight, 4 mg / kg body weight, 3 mg / kg body weight, 2.5 mg / kg body weight, 1 mg / kg body weight, 0.5 mg / kg body weight, 0.1 mg / kg body weight, 0.05 mg / kg body weight, or 0.005 mg / kg body weight. In some embodiments, the actual unit dosage is 0.05, 0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0, or 25.0 mg / kg body weight. Therefore, when administered to a 70 kg human, the dose range is about 0.1 mg to 70 mg, about 1 mg to about 50 mg, about 0.5 mg to about 10 mg, about 1 mg to about 10 mg, about 2.5 mg to about 30 mg, about 35 mg or less to about 700 mg or more, about 7 mg to about 600 mg, about 10 mg to about 500 mg, about 20 mg to about 300 mg, or about 200 mg to about 2000 mg. In some embodiments, the actual unit dose is 0.1 mg. In some embodiments, the actual unit dose is 0.5 mg. In some embodiments, the actual unit dose is 1 mg. In some embodiments, the actual unit dose is 1.5 mg. In some embodiments, the actual unit dose is 2 mg. In some embodiments, the actual unit dose is 2.5 mg. In some embodiments, the actual unit dose is 3 mg. In some embodiments, the actual unit dose is 3.5 mg. In some embodiments, the actual unit dose is 4 mg.In some embodiments, the actual unit dose is 4.5 mg. In some embodiments, the actual unit dose is 5 mg. In some embodiments, the actual unit dose is 10 mg. In some embodiments, the actual unit dose is 20 mg. In some embodiments, the actual unit dose is 25 mg. In some embodiments, the actual unit dose is 250 mg or less. In some embodiments, the actual unit dose is 100 mg or less. In some embodiments, the actual unit dose is 70 mg or less.

[0058] In some embodiments, Compound 1 is administered in an amount of about 1-50 mg / m 2 of body surface area. 2In some embodiments, compound 1 is administered at a dose ranging from about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 13.75, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 22.5, 1 to 25, 1 to 27.5, 1 to 30, 1.5 to 2, 1.5 to 3, 1.5 to 4, 1.5 to 5, 1.5 to 6, 1.5 to 7, 1.5 to 8, 1.5 to 9, 1.5 to 10, 1.5 to 11, 1.5 to 12, 1.5 to 13, 1.5 to 13.75, 1.5 to 14, 1.5 to 15, 1.5 ~16, 1.5~17, 1.5~18, 1.5~19, 1.5~20, 1.5~22.5, 1.5~25, 1.5~27.5, 1.5~30, 2.5~2, 2.5~3, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~8, 2.5~9, 2.5~10, 2.5~11, 2.5~12, 2.5~13, 2.5~13.75, 2.5~14, 2.5~15, 2.5~16, 2.5~17, 2.5~18, 2.5~19, 2.5~20, 2.5~22.5, 2.5~25, 2.5~27.5, 2.5~30, 2.5~7.5, 3~4 , 3~5, 3~6, ​​3~7, 3~8, 3~9, 3~10, 3~11, 3~12, 3~13, 3~13.75, 3~14, 3~15, 3~16, 3~17, 3~18, 3~19, 3~20, 3~22.5, 3~25, 3~27.5, 3~30, 3.5~6.5, 3.5~13.75, 3.5~15, 2.5~17.5, 4~5, 4~6, 4~7, 4~8, 4~9, 4~10, 4~11, 4~12, 4~13, 4~13.75, 4~14, 4~15, 4~16, 4~17, 4~18, 4~19, 4~20, 4~22.5, 4~25, 4~27. 5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27.5, 6-30, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-13.75, 7~14, 7~15, 7~16, 7~17, 7~18, 7~19, 7~20, 7~22.5, 7~25, 7~27.5, 7~30, 7.5~12.5, 7.5~13.5, 7.5~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~13.75, 8~14, 8~ 15, 8~16, 8~17, 8~18, 8~19, 8~20, 8~22.5, 8~25, 8~27.5, 8~30, 9~10, 9~11, 9~12, 9~13, 9~13.75, 9~14, 9~15, 9~16, 9~17, 9~18, 9~19, 9~20, 9~22.5, 9~25 , 9~27.5, 9~30, 10~11, 10~12, 10~13, 10~13.75, 10~14, 10~15, 10~16, 10~17, 10~18, 10~19, 10~20, 10~22.5, 10~25, 10~27.5, 10~30, 11.5~15.5, 12.5~1 4.5, 7.5-22.5, 8.5-32.5, 9.5-15.5, 15.5-24.5, 5-35, 17.5-22.5, 22.5-32.5, 25-35, 25.5-24.5, 27.5-32.5, 2-20, 2.5-22.5, or 9.5-21.5 mg / m2 of body surface area. 2 In some embodiments, Compound 1 is administered at a dose ranging from about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5 , 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area 2In some embodiments, Compound 1 is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5 , 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area 2 In some embodiments, Compound 1 is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 , 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29 .5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50mg / 1m of body surface area 2 It is administered in doses of over 100 mg / kg.

[0059] In some embodiments, a dose of the compound is about 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.5 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 20 mg, 0.5 mg to 10 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 20 mg, 1 mg to 10 mg, 2.5 mg to 50 mg, 2.5 mg to 20 mg, 2.5 mg to 10 mg, or about 2.5 mg to 5 mg. In some embodiments, the TR-β agonist compound dose is about 5 mg to 300 mg, 5 mg to 200 mg, 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, or about 40 mg to 60 mg. In some embodiments, the amount of Compound 1 administered is about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the amount of Compound 1 administered is about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5 mg to 40 mg, 5 mg to 42 mg, 5 mg to 44 mg, 5 mg to 46 mg, 5 mg to 48 mg, 5 mg to 50 mg, 5 mg to 52 mg, 5mg~54mg, 5mg~56mg, 5mg~58mg, 5mg~60mg, 7mg~7.7mg, 7mg~9mg, 7mg~10mg, 7mg~12mg, 7mg~14mg, 7mg~15mg, 7mg~16mg, 7mg~18mg, 7mg~20mg, 7mg~22mg, 7mg~24mg, 7mg~26mg, 7mg~28mg, 7mg~30mg, 7mg~32mg, 7mg~34mg, 7mg~36mg, 7mg~38mg, 7mg~40mg, 7mg~42mg, 7mg~44mg, 7mg~46mg, 7mg~48mg, 7mg~50mg,7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg, 30mg~36mg, 30mg~38mg, 30mg~40mg, 30mg~42mg, 30mg~44mg, 30mg~46mg, 30mg~48mg, 30mg~50mg, 30mg~52mg, 30mg~54mg, 30mg~56mg, 30mg~58mg, 30mg~60mg, 33mg~34mg, 33mg~36mg, 33mg~38mg, 33mg~40mg, 33mg~42mg, 33mg~44mg, 3 3mg~46mg, 33mg~48mg, 33mg~50mg, 33mg~52mg, 33mg~54mg, 33mg~56mg, 33mg~58mg, 33mg~60mg, 36mg~38mg, 36mg~40mg, 3 6mg~42mg, 36mg~44mg, 36mg~46mg, 36mg~48mg, 36mg~50mg, 36mg~52mg, 36mg~54mg, 36mg~56mg, 36mg~58mg, 36mg~60mg, 40 mg~42mg, 40mg~44mg, 40mg~46mg, 40mg~48mg, 40mg~50mg, 40mg~52mg, 40mg~54mg, 40mg~56mg, 40mg~58mg, 40mg~60mg, 43 mg~46mg, 43mg~48mg, 43mg~50mg, 43mg~52mg, 43mg~54mg, 43mg~56mg, 43mg~58mg, 42mg~60mg, 45mg~48mg, 45mg~50mg, 45m g to 52 mg, 45 mg to 54 mg, 45 mg to 56 mg, 45 mg to 58 mg, 45 mg to 60 mg, 48 mg to 50 mg, 48 mg to 52 mg, 48 mg to 54 mg, 48 mg to 56 mg, 48 mg to 58 mg, 48 mg to 60 mg, 50 mg to 52 mg, 50 mg to 54 mg, 50 mg to 56 mg, 50 mg to 58 mg, 50 mg to 60 mg, 52 mg to 54 mg, 52 mg to 56 mg, 52 mg to 58 mg, or 52 mg to 60 mg. In some embodiments, the Compound 1 dose is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or more than about 200 mg.about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or less than about 200 mg. In some embodiments, the Compound 1 dose is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0060] Tablet formulation Compound 1 can be combined with one or more polymers and then another formulation to form a desired dosage form. In some embodiments, compound 1 is in the form of a spray-dried dispersion (SDD). In other embodiments, compound 1 is in the form of a hot melt extrudate. In some embodiments, the dosage form is an oral dosage form. In some specific embodiments, the oral dosage form is a tablet. In other embodiments, the oral dosage form is a capsule.

[0061] In some embodiments, the polymer for preparing the spray-dried dispersion containing Compound 1 can be selected from one or more of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), copovidone, poloxamer 407, hypromellose acetate succinate (HPMCAS), Eudragit®, and polyacrylate. In some embodiments, the polymer can be PVP. In some embodiments, the polymer can be PVP-VA. In other embodiments, the polymer can be HPMCAS. In yet other embodiments, the polymer can be HPMC. In some embodiments, the polymer can be Eudragit®. In some embodiments, the polymer for preparing the spray-dried dispersion of Compound 1 can be a combination of PVP-VA and poloxamer 407.

[0062] A spray-dried dispersion of Compound 1 and one or more polymers can be prepared by combining Compound 1 and the polymer in a suitable solvent and then spraying the feed into a hot drying medium to remove the solvent. The preparation of a spray-dried dispersion (SDD) of Compound 1 and one or more polymers can increase the aqueous solubility (and therefore bioavailability) of Compound 1 and can increase the stability of Compound 1 so that it can be stored under standard conditions.

[0063] In some embodiments, the mass ratio of compound 1 to polymer in the SDD is about 1:10 to about 10:1. For example, in some embodiments, the mass ratio of compound 1 to polymer in the SDD is about 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, or 5:1. In some embodiments, the mass ratio of compound 1 to polymer in the SDD can be in the range of about 1:1 to 5:1, 1.5:1 to 5:1, 2:1 to 4:1, 2.5:1 to 3.5:1, or 3:1 to 5:1. In some embodiments, the mass ratio of compound 1 to polymer in the SDD can be in the range of about 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, or 1:2 to 1:4. In some embodiments, the mass ratio of compound 1 to polymer in the SDD can be about 1:3.

[0064] Compound 1 can be formulated into a tablet for oral administration to a subject in need thereof. In some embodiments, compound 1 in the tablet can be present at about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% by weight of the tablet, or within a range defined by any two of the above amounts. For example, in some embodiments, compound 1 in the tablet can be present at about 5% to 25%, 10% to 20%, 5% to 15%, or 10% to 15% by weight.

[0065] The tablet formulation of Compound 1 described herein can further include a ductile filler. In some embodiments, the ductile filler in the tablet can be present at about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% by weight of the tablet, or within a range defined by any two of the above amounts. For example, in some embodiments, the ductile filler in the tablet can be present at about 30% to 70%, 40% to 60%, 45% to 55%, or 50% to 55% by weight. In some embodiments, the ductile filler can be microcrystalline cellulose. In other embodiments, the ductile filler can include silicified microcrystalline cellulose.

[0066] The tablet formulation of Compound 1 described herein can further include a brittle filler. In some embodiments, the brittle filler in the tablet can be present at about 10%, 15%, 20%, 25%, 30%, 35%, or 40% by weight of the tablet, or within a range defined by any two of the above amounts. For example, in some embodiments, the brittle filler in the tablet can be present at about 10% to 40%, 10% to 30%, 15% to 30%, or 20% to 30% by weight. In some embodiments, the brittle filler can be lactose monohydrate, spray-dried lactose, anhydrous lactose, lactose monohydrate, anhydrous lactose, mannitol, or a combination thereof. In some specific embodiments, the brittle filler can be lactose monohydrate. In other specific embodiments, the brittle filler can be mannitol. In yet other specific embodiments, the brittle filler can be anhydrous lactose.

[0067] The tablet formulation of Compound 1 described herein can further include a disintegrant. In some embodiments, the disintegrant in the tablet can be present at about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of the tablet, or within a range defined by any two of the above amounts. For example, in some embodiments, the disintegrant in the tablet can be present at about 5% to 20%, 5% to 15%, 10% to 15%, or 10% to 20% by weight. In some embodiments, the disintegrant can be carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, starch, pregelatinized starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone crospovidone, hydroxypropyl cellulose, magnesium aluminometasilicate, polacrilin potassium, or any combination thereof. In some specific embodiments, the disintegrant can be croscarmellose sodium. In other embodiments, the disintegrant can be crospovidone.

[0068] The tablet formulation of Compound 1 described herein can further include a glidant. In some embodiments, the glidant in the tablet can be present at about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% by weight of the tablet, or within a range defined by any two of the above amounts. For example, in some embodiments, the glidant in the tablet can be present at about 0.1% to 2.0%, 0.3% to 2.0%, 0.1% to 1.0%, or 0.5% to 1.0% by weight. In some embodiments, the glidant can be silicon dioxide, starch, talc, or any combination thereof. In some particular embodiments, the glidant can be silicon dioxide.

[0069] The tablet formulation of Compound 1 described herein can further include a lubricant. In some embodiments, the lubricant in the tablet can be present at about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% by weight of the tablet, or within a range defined by any two of the above amounts. For example, in some embodiments, the lubricant in the tablet can be present at about 0.1% to 2.0%, 0.3% to 2.0%, 0.1% to 1.0%, or 0.5% to 1.0% by weight. In some embodiments, the lubricant can be stearic acid, talc, glyceryl behenate, sodium stearyl fumarate, magnesium stearate, or any combination thereof, hi some particular embodiments, the lubricant can be magnesium stearate.

[0070] The tablet formulation of Compound 1 described herein can include an intragranular component and an extragranular component. For example, in some embodiments, the tablet formulation can include an intragranular component comprising Compound 1 and one or more polymers; a ductile filler; a brittle filler; a disintegrant; a glidant; and a lubricant; and an extragranular component comprising a disintegrant and a lubricant. In some embodiments, the disintegrant in the intragranular component can be the same as the disintegrant in the extragranular component. In some embodiments, the disintegrant in the intragranular component can be different from the disintegrant in the extragranular component. In some embodiments, the lubricant in the intragranular component can be the same as the lubricant in the extragranular component. In other embodiments, the lubricant in the intragranular component can be different from the lubricant in the extragranular component.

[0071] In some embodiments, tablet formulations comprising Compound 1 described herein contain one or more polymers at about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%, or within a range bounded by any two of the above amounts. For example, in some embodiments, the one or more polymers in the tablet can be present at about 5% to 25%, 10% to 20%, 5% to 15%, or 10% to 15% by weight.

[0072] Unlike current clinical formulations of Compound 1, tablet formulations comprising Compound 1 described herein are stable under standard storage conditions. For example, tablet formulations described herein exhibit minimal degradation as measured by HPLC when stored in high density polyethylene bottles at 40° C. or 50° C. and ambient relative humidity (RH) for 1, 2, and 3 months. In some embodiments, the amount of Compound 1 in the tablet formulation can account for 95%, 96%, 97%, 98%, 99% or more by weight of the original amount of Compound 1 in the formulation when stored in a closed bottle at 40° C. and ambient RH for 1 month. In some embodiments, the amount of Compound 1 in the tablet formulation can account for 95%, 96%, 97%, 98%, 99% or more by weight of the original amount of Compound 1 in the formulation when stored in a closed bottle at 50° C. and ambient RH for 1 month. In some embodiments, the amount of compound 1 in the tablet formulation can represent 95%, 96%, 97%, 98%, 99% or more by weight of the original amount of compound 1 in the formulation after storage in a closed bottle at 40° C. and ambient RH for 2 months. In some embodiments, the amount of compound 1 in the tablet formulation can represent 95%, 96%, 97%, 98%, 99% or more by weight of the original amount of compound 1 in the formulation after storage in a closed bottle at 50° C. and ambient RH for 2 months. In some embodiments, the amount of compound 1 in the tablet formulation can represent 95%, 96%, 97%, 98%, 99% or more by weight of the original amount of compound 1 in the formulation after storage in a closed bottle at 40° C. and ambient RH for 3 months. In some embodiments, the amount of Compound 1 in a tablet formulation can comprise 95%, 96%, 97%, 98%, 99% or more by weight of the original amount of Compound 1 in the formulation after storage in a closed bottle at 50° C. and ambient RH for 3 months.

[0073] Second drug The dosage forms of Compound 1 disclosed herein may be administered in combination with one or more second agents. In some embodiments, the dosage forms of Compound 1 disclosed herein may be administered in combination with one second agent. In some embodiments, the compound may be administered in combination with two second agents. In some embodiments, the compound may be administered in combination with three or more second agents.

[0074] In some embodiments, the dosage forms of Compound 1 presented herein can be co-administered with one or more second agents. In other embodiments, the dosage forms of Compound 1 of the present disclosure can be administered sequentially with one or more second agents. In some embodiments, Compound 1 and the second agent are included together in the dosage forms described herein.

[0075] In one aspect, the dosage forms of Compound 1 presented herein can be administered in combination with a peroxisome proliferator-activated receptor (PPAR) modulator. A PPAR modulator is a pharmaceutical compound that can be used, for example, to lower triglyceride levels and blood glucose levels in a subject. PPAR modulators can be classified as PPARα modulators, PPARγ modulators, or PPARδ agonists. In some embodiments, the PPAR modulator is

[0076] [ka]

[0077] In some embodiments, the PPAR modulator may be:

[0078] [ka]

[0079] In some embodiments, the PPAR modulator may be:

[0080] [ka]

[0081] In some embodiments, the PPAR modulator may be:

[0082] [ka]

[0083] In some embodiments, the PPAR modulator can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0084] In some embodiments, the dosage forms of Compound 1 presented herein may be administered in combination with a fibric acid derivative. Fibric acid derivatives are a group of lipid-lowering drugs that have the ability to lower the lipid profile of a subject. In some embodiments, the fibric acid derivative may be fenofibrate. In some embodiments, the fibric acid derivative may be gemfibrozil. In some embodiments, the fibric acid derivative may be fenofibric acid. In some embodiments, the fibric acid derivative may be clofibrate. In some embodiments, the fibric acid derivative may be any pharma- ceutically acceptable salt or prodrug of the above.

[0085] In some embodiments, the dosage forms of Compound 1 presented herein may be administered in combination with a bile acid receptor modulator. Bile acid receptors include, but are not limited to, FXR (farnesoid X receptor) and TGR5. In some embodiments, the bile acid receptor modulator is

[0086] [ka]

[0087] In some embodiments, the bile acid receptor modulator can be:

[0088] [ka]

[0089] In some embodiments, the bile acid receptor modulator can be:

[0090] [ka]

[0091] In some embodiments, the bile acid receptor modulator can be:

[0092] [ka]

[0093] (tropifexol). In some embodiments, the bile acid modulator can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0094] In some embodiments, the dosage forms of Compound 1 provided herein may be administered in combination with a bile acid receptor modulator. In some embodiments, the bile acid receptor modulator may be selected from the group consisting of FXR agonists, FXR antagonists, TGR agonists, and FXR / TGR dual agonists. In some embodiments, the bile acid receptor modulator is

[0095] [ka]

[0096] (wherein n is 2 or 3);

[0097] [ka]

[0098] (wherein R is H or F),

[0099] [ka]

[0100] [ka]

[0101] [ka]

[0102] [ka]

[0103] where R is H or benzyl,

[0104] [ka]

[0105] [ka]

[0106] where R is H or methyl;

[0107] [ka]

[0108] [ka]

[0109] where R is H or methyl;

[0110] [ka]

[0111] (wherein Y is F or Cl),

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] where X is H or OMe;

[0117] [ka]

[0118] [ka]

[0119] where R is H or ethyl;

[0120] [ka]

[0121] (wherein R is H or OH),

[0122] [ka]

[0123] or a pharma- ceutically acceptable salt of any of the above, the entirety of which is incorporated herein by reference.

[0124] In some embodiments, the dosage forms of Compound 1 presented herein may be administered in combination with an anti-inflammatory compound. In some embodiments, the anti-inflammatory compound is

[0125] [ka]

[0126] In some embodiments, the anti-inflammatory compound can be:

[0127] [ka]

[0128] In some embodiments, the anti-inflammatory compound can be a polyclonal or monoclonal anti-LPS immunoglobulin. In some embodiments, the anti-LPS immunoglobulin can be IMM-124E. In some embodiments, the anti-inflammatory compound can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0129] In some embodiments, the second agent can be an anti-fibrotic compound. In some embodiments, the anti-fibrotic compound is

[0130] [ka]

[0131] In some embodiments, the anti-fibrotic compound can be:

[0132] [ka]

[0133] In some embodiments, the anti-fibrotic compound can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0134] In some embodiments, the dosage forms of Compound 1 presented herein may be administered in combination with a GLP-1 agonist. GLP-1 is a pharmaceutical compound that can be used, for example, to treat type 2 diabetes in a subject. In some embodiments, the GLP-1 agonist can be dulaglutide. In some embodiments, the GLP-1 agonist can be exenatide. In some embodiments, the GLP-1 agonist can be liraglutide. In some embodiments, the GLP-1 agonist can be albiglutide. In some embodiments, the GLP-1 agonist can be lixisenatide. In some embodiments, the GLP-1 agonist can be semaglutide. In some embodiments, the GLP-1 agonist can be insulin glargine. In some embodiments, the GLP-1 agonist can be

[0135] [ka]

[0136] (PF06882961). In some embodiments, the GLP-1 agonist can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0137] In some embodiments, the dosage forms of Compound 1 presented herein may be administered in combination with a GLP-1 metabolic modulator. In some embodiments, the metabolic modulator may be a thyroid hormone receptor agonist. In other embodiments, the metabolic modulator may be a selective androgen receptor modulator. In some embodiments, the metabolic modulator may be a mitochondrial membrane transport protein modulator. In other embodiments, the metabolic modulator may be a selective estrogen receptor modulator. In some embodiments, the metabolic modulator may be a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In some embodiments, the metabolic modulator may be a dipeptidyl peptidase 4 (DPP-4) inhibitor. In some embodiments, the metabolic modulator may be an inhibitor of sodium glucose cotransporter 1 and / or 2 (SGLT1, SGLT2, or a dual SGLT1 / SGLT2 inhibitor). In some embodiments, the metabolic modulator can be recombinant fibroblast growth factor 19 (FGF19) or a modified analog, or recombinant fibroblast growth factor 21 (FGF21) or a PEGylated variant thereof. In some embodiments, the metabolic modulator can be

[0138] [ka]

[0139] In some embodiments, the metabolic modulator can be

[0140] [ka]

[0141] In some embodiments, the metabolic modulator can be

[0142] [ka]

[0143] In some embodiments, the metabolic modulator may be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0144] In some embodiments, the dosage forms of Compound 1 presented herein may be administered in combination with a fish oil derivative. Fish oil contains ω-3-fatty acids, which are polyunsaturated fatty acids (PUFAs) characterized by a double bond that is three atoms away from the terminal methyl group. They are widely distributed in nature and play an important role in the human diet and human physiology, especially in relation to lipid metabolism. In some embodiments, the fish oil derivative can be an ω-3-fatty acid alkyl ester. For example, the fish oil derivative can be an ω-3-fatty acid methyl ester, ethyl ester, n-propyl ester, or isopropyl ester. In some embodiments, the fish oil derivative can be an ω-3-fatty acid triglyceride. In some embodiments, the fish oil derivative can be ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate. In some embodiments, the fish oil derivative can be ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate. In some embodiments, the fish oil derivative can be ethyl (7Z,10Z,13Z,16Z,19Z)-docosapentaenoate. In some embodiments, the fish oil derivative can be ethyl hexadecatrienoate. In some embodiments, the fish oil derivative can be alpha-linolenic acid ethyl ester. In some embodiments, the fish oil derivative can be ethyl (6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoate. In some embodiments, the fish oil derivative can be ethyl eicosatrienoate. In some embodiments, the fish oil derivative can be ethyl eicosatetraenoate. In some embodiments, the fish oil derivative can be ethyl heneicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl eicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl heneicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl tetracosapentaenoate. In some embodiments, the fish oil derivative can be herring acid ethyl ester.In some embodiments, the fish oil derivative can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0145] Method of administration In some embodiments, the composition may be administered once, twice, three times, or four times per day. In other embodiments, the composition may be administered once, twice, or three times per week. In other embodiments, the composition is administered every other day, every third day, or every third day. In other embodiments, the composition is administered every other week, every two weeks, or every third week. In other embodiments, the composition is administered once or twice per month.

[0146] In some embodiments, the initial loading dose is administered more than the subsequent doses (maintenance doses). The dosage form or mode of administration of the maintenance dose may be different from that used for the loading dose. In any of the embodiments disclosed herein, the maintenance dose may include administration of the unit dosage form at any administration schedule contemplated herein, including but not limited to once a month or more than once a month, once every two weeks or more than once a week, once a week or more than once a week, once a day or more than once a day. It is contemplated within the present disclosure that a drug holiday may be incorporated into the administration period of the maintenance dose. Such a drug holiday may occur immediately after administration of the loading dose or at any time during the administration period of the maintenance dose. In some embodiments, the loading dose is 300 mg or less, 250 mg or less, 200 mg or less, 150 mg or less, 100 mg or less, 50 mg or less, 25 mg or less, 20 mg or less, 15 mg or less, 10 mg or less, or 5 mg or less. In some embodiments, the loading dose is 300mg, 250mg, 200mg, 150mg, 100mg, 50mg, 25mg, 20mg, 15mg, 10mg, 5mg, or 2mg. In some embodiments, the maintenance dose is 300mg or less; 200mg or less, 100mg or less, 50mg or less, 25mg or less, 20mg or less, 15mg or less, 10mg or less, 5mg or less, 2.5mg or less, or 1mg or less. In some embodiments, the maintenance dose is 300mg, 250mg, 200mg, 100mg, 50mg, 25mg, 20mg, 15mg, 10mg, 5mg, 2.5mg, or 1mg.

[0147] Treatment Some embodiments of the disclosed methods and compositions are directed to a method for preventing, treating, or ameliorating one or more fatty liver diseases in a subject, comprising administering to a subject in need thereof an effective amount of compound 1 as described herein in combination with one or more second agents. In some embodiments, the fatty liver disease can be steatosis. In other embodiments, the fatty liver disease can be non-alcoholic fatty liver disease. In some embodiments, the fatty liver disease can be non-alcoholic steatohepatitis (NASH). In some embodiments, the subject can have two or more of the fatty liver diseases listed above.

[0148] Some embodiments of the methods and compositions of the present disclosure relate to a method of reducing or preventing deposition of an extracellular matrix protein, comprising administering to a subject in need thereof an effective amount of a compound 1 as described herein in combination with one or more second agents as described herein. In some embodiments, the deposition of an extracellular matrix protein can comprise abnormal or excessive deposition of the protein. In some embodiments, the extracellular matrix protein can comprise one or more of collagen, keratin, elastin, or fibrin. In some embodiments, the extracellular matrix protein can comprise collagen. In some embodiments, the extracellular matrix protein can comprise type I collagen. In some embodiments, the extracellular matrix protein can comprise type Ia collagen. In some embodiments, the extracellular matrix protein can comprise type III collagen. Some embodiments of the compositions and methods of the present disclosure relate to a method of treating fibrosis or a symptom or sequelae thereof, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0149] In some embodiments, the compounds and compositions comprising compound 1 described herein and / or one or more second agents described herein can be used to treat a variety of conditions resulting from fibrosis or inflammation, particularly conditions associated with abnormal collagen deposition. Examples of conditions include glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), nonalcoholic steatohepatitis (NASH), liver cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, muscle fibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, liver and gallbladder cirrhosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse ... Fibrosis, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, surgical complications, fibrotic chronic transplant vasculopathy and / or chronic rejection of transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal strictures, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components such as collagen.

[0150] In some embodiments, the disclosed methods include methods of treating, ameliorating, or preventing a fibrotic condition. In some embodiments, the fibrotic condition may be associated with another condition. In some embodiments, the fibrotic condition or primary condition may further include chronic inflammation of an organ, tissue, spatial region, or fluid-connected area of ​​the subject's body. In some embodiments, the inflammation may include activation of one or more TGF-β-dependent signaling pathways. In some embodiments, the TGF-β-dependent signaling pathways may include one or more elements responsive to T3 or T4. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of one or more of collagen, keratin, or elastin. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type I collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type Ia collagen. In some embodiments, the fibrotic condition can involve abnormal or excessive deposition of type III collagen.In some embodiments, the fibrotic condition is Glycogen Storage Disease Type III (GSD III), Glycogen Storage Disease Type VI (GSD VI), Glycogen Storage Disease Type IX (GSD IX), nonalcoholic steatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis , endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, complications of surgery, fibrotic chronic transplant vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal strictures, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, and progressive massive fibrosis. In some embodiments, the fibrotic condition can include one or more of GSD III, GSD IX, non-alcoholic steatohepatitis, cirrhosis of the liver and / or pancreas, scleroderma, idiopathic pulmonary fibrosis, psoriasis, non-alcoholic fatty liver disease, Dupuytren's disease, and / or any combination thereof.

[0151] According to the methods and compositions disclosed herein, the fibrotic pathology or pathology with sequelae of fibrosis may further include chronic inflammation. According to the methods and compositions disclosed herein, the fibrotic pathology or pathology with sequelae of fibrosis may further include activation of one or more TGF-β-dependent signaling pathways. According to the methods and compositions disclosed herein, the fibrotic pathology or pathology with sequelae of fibrosis may further include activation and / or suppression of one or more thyroid receptor β (TRβ)-dependent signaling pathways. According to the methods and compositions disclosed herein, the fibrotic pathology or pathology with sequelae of fibrosis may further include involvement of signaling pathways responsive to triiodothyronine (T3), thyroxine (T4), any combination thereof, or mimetics thereof. According to the methods and compositions disclosed herein, the fibrotic condition or condition having sequelae of fibrosis can further include involvement of a receptor responsive to T3, T4, any combination thereof, or a mimetic thereof. In some embodiments according to the methods and compositions disclosed herein, the fibrotic condition or condition having sequelae of fibrosis can include involvement of TRβ.

[0152] In some embodiments, the compositions and methods described herein provide compositions and methods for the treatment, amelioration, prevention, or cure of collagen deposition. In some embodiments, the collagen deposition includes abnormal or excessive deposition of collagen. In some embodiments, the collagen deposition can include abnormal or excessive deposition of type I collagen. In some embodiments, the collagen deposition can include abnormal or excessive deposition of type Ia collagen. In some embodiments, the collagen deposition can include abnormal or excessive deposition of type III collagen. According to the methods and compositions disclosed herein, the collagen deposition can further include the involvement of a receptor responsive to T3, T4, any combination thereof, or a mimic thereof. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition can include the involvement of TRβ. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition can be prevented, ameliorated, or cured by administration of one or more TRβ agonists.

[0153] In some embodiments, administration of a dosage form of Compound 1 described herein reduces expression of Colal, Col3al, α-SMA, and / or Galectin 1 genes, or any combination or product thereof, in a subject to which the combination is administered. In some embodiments, administration of a dosage form of Compound 1 described herein reduces the degree of fibrosis observable by histology, histochemistry, immunohistochemistry, etc., and / or reduces the amount, accumulation, or distribution of type 1 collagen and / or hydroxyproline, or any combination thereof, in a subject to which the combination is administered. In some embodiments, administration of a dosage form of Compound 1 described herein as disclosed herein reduces total serum lipids, total serum cholesterol, total serum triglycerides, total liver lipids, total liver cholesterol, total liver triglycerides, or any combination thereof. EXAMPLES

[0154] The compositions and methods described herein are further illustrated by the following non-limiting examples.

[0155] Example 1 Preparation of spray-dried dispersion of Compound 1 The following formulations were prepared and spray dried to form amorphous spray dried dispersions (SDD) for subsequent testing: (a) 25 / 75 (w / w) Compound 1 / hydroxypropyl methylcellulose acetate succinate type M (HPMCAS-M); (b) 25 / 75 (w / w) Compound 1 / hydroxypropyl methylcellulose acetate succinate type L (HPMCAS-L); (c) 25 / 75 (w / w) Compound 1 / polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA64); (d) 25 / 75 (w / w) Compound 1 / Eudragit® L100; and (e) (w / w) Compound 1 / HPMC E3.

[0156] These SDD intermediate formulations were spray dried in a Bend Lab Dryer (BLD-35) with a drying gas flow rate capacity of 35 kg / hr. The BLD-35 is a custom-built spray dryer that accommodates batch sizes from 0.5 to <1 kg for early feasibility, pharmacokinetic, and toxicology supplies. The BLD-35 uses a pressure swirl nozzle to atomize the spray-dried solution into small droplets that are then dried with a heated nitrogen stream and collected using a cyclone. The manufacturing conditions are listed in Table 1. All five SDDs were successfully manufactured with high yields. A small amount of insoluble particles were observed in the acetone solution, but they did not affect the process and are therefore believed to be impurities or other non-Compound 1 materials. The spray-dried dispersions showed typical SDD morphology with no evidence of crystallinity.

[0157] [Table 1]

[0158] Example 2 Water solubility of compound 1 The equilibrium solubility of crystalline Compound 1 in 0.01 N HCl and PBS buffer (pH 6.5) at 37° C. was assessed by measuring the dissolved concentration of Compound 1 in a saturated solution in each medium, respectively. The experimental solubility values ​​listed in Table 2 were obtained by measuring the supernatant concentration after centrifugation at 386,000×g.

[0159] [Table 2]

[0160] Amorphous solubility of compound 1 was determined by slow addition of the API from an organic stock solution to the aqueous medium of interest. Upon reaching amorphous solubility, a drug-concentrated phase forms and is measured by detection by UV / visible light scattering and / or dynamic light scattering (DLS).

[0161] The solubility of amorphous compound 1 in PBS (pH 6.5) alone and in PBS (pH 6.5) containing 0.5% simulated intestinal fluid (SIF) was evaluated. Figure 1 shows the measured concentration and light scattering of compound 1 from a stock solution in methanol over time. The onset of scattering in SIF-containing media occurred for compound 1 from 180-210 μg / mL onwards. In PBS alone, compound 1 precipitated as soon as the stock solution was introduced into the media, and therefore no estimate of amorphous solubility was obtained. This is consistent with earlier solubility studies, where crystalline solubility in PBS was very low in the absence of bile salts.

[0162] Example 3 Solubility of spray-dried dispersions of compound 1 SDD was evaluated in a non-sink dissolution test designed to monitor dissolution rate and inhibition of crystallization during transfer from simulated gastric to simulated intestinal media. In the gastric to intestinal buffer (G-IB) transfer dissolution test, pH 2 ("gastric"; "G") medium was added to each sample at a target dose concentration of 1000 μg compound / mL. After 30 minutes of exposure to gastric media, concentrated simulated intestinal buffer was added to reach a final composition of 0.5% SIF in PBS (pH 6.5) at half the dose concentration (500 μg compound / mL). This dose concentration was chosen to be twice the estimated amorphous solubility in an attempt to simultaneously discriminate based on dissolution rate and persistence of supersaturation. Concentration was monitored by in situ UV fiber optic probe (stirring speed: 100 revolutions per minute) and evaluation by microcentrifuge (15,800×g) or ultracentrifuge (300,000×g). The precipitate (insoluble drug) and total soluble drug were separated by microcentrifugation. The total soluble drug consists of three soluble species: free soluble drug ("free drug"), drug associated with bile salt micelles ("micelle-bound drug"), and drug in small aggregates of approximately 50-300 nm in size ("colloidal drug"). The ultracentrifuge further separates the colloidal drug, and the supernatant contains only free and micelle-bound drug. These three species have different activities in vivo and can be used to help differentiate formulations. The free drug is the smallest species and the only one that is believed to partition directly to the cell membrane of the epithelium. The micelle-bound drug can cross the unstirred mucus boundary layer and deliver the free drug when a concentration gradient is created by the absorption of the free soluble drug. Finally, drug-polymer colloids are a source of fast-dissolving drugs and, in some cases, can penetrate the unstirred mucus boundary layer (Stewart et al., Mol. Pharmaceutics, 2017, 12, 2437-2449).

[0163] The results of the G-IB dissolution test are shown in Figure 2 and Table 3. All SDD formulations containing enteric polymers reached amorphous solubility in intestinal buffer within 10 minutes. These dispersions appeared to form colloids in IB, with the 25 / 75 Compound 1 / HPMCAS-L SDD allowing the highest concentration. The in situ measurements of the Eudragit-containing SDD did not match the concentrations measured after centrifugation. A closer look at the raw data from the UV probe revealed a spectral shift in this sample that led to erroneous measurements. The exact reason for this shift is currently unknown. It may be due to detector saturation resulting from undissolved solids or specific interactions between the drug and polymer in solution. All SDDs showed significantly improved dissolution compared to crystalline Compound 1.

[0164] [Table 3]

[0165] Example 4 Release stability of spray-dried dispersions of compound 1 Compound 1 SDD was aged in the open at 40° C. / 75% relative humidity (RH) for 2 weeks to provide an initial assessment of Compound 1 SDD chemical stability. Stability samples were tested using HPLC using the method in Table 4.

[0166] [Table 4]

[0167] Stability samples were tested for assay and related substances. The results of the analysis are listed in Table 5. Possible degradation from processing was observed in all SDD formulations with total impurities increasing from 0.65% (HPMCAS-M SDD) to 1.42% (HPMCAS-L SDD). This was mainly due to API processing related impurities.

[0168] [Table 5]

[0169] The PVP-VA containing dispersion showed the best chemical stability at 40° C. and 75% RH. The neutral PVP-VA polymer appears to be the least reactive with compound 1. The Eudragit and HPMC containing dispersions had the worst chemical stability at 40° C. and 75% RH. This is mostly due to the growth of hydrolysis products of compound 1 in the Eudragit containing SDD and the growth of unknown decomposition products in the HPMC containing SDD. In the HPMCAS-M and HPMCAS-L containing SDD, similar growth of all impurities was observed after 2 weeks in open conditions at 40° C. and 75% relative humidity.

[0170] Example 5 Closed stability packaging study of Compound 1 spray-dried dispersions Due to extensive decomposition observed after 2 weeks in open conditions at 40° C. / 75% RH, a closed condition stability study with desiccant was initiated for Compound 1 SDD. Samples were stored in 4 mL scintillation vials and evaluated for stability at 2 weeks, 6 weeks, and 3 months when sealed in 60 cc HDPE bottles with heat-induced sealing and 0.5 g desiccant.

[0171] The chemical stability of Compound 1 SDD after 2 weeks under closed conditions was evaluated by HPLC using the method described in Table 4 herein. The PVP-VA-containing SDD showed the best chemical stability after 2 weeks under closed conditions, with little to no degradation. Of the SDDs containing enteric (acidic) polymers, the HPMCAS-M-based SDD provided the best chemical stability profile. All SDDs containing cellulosic polymers show the same growth of impurities after 2 weeks under 40 / 75 closed conditions. Upon closer inspection, this impurity is present in the incoming API at levels that are below the threshold used for integration. The HPMC-containing dispersions showed the worst chemical stability under closed conditions. The Eudragit-containing dispersions posed a moderate risk to chemical stability at 40 / 75 closed conditions, with a slight increase in Compound 1 hydrolysis products and unknown impurities after 2 weeks. Further evidence was observed that unknown degradation products may form during manufacturing and co-elute with known synthetic impurities. The closed state stability degradation data at 2 weeks is listed in Table 6, and the closed state stability degradation data at 6 weeks is listed in Table 7. Additionally, no changes were observed in the particle morphology and crystallinity of SDD after 6 weeks at 40°C / 75% RH.

[0172] [Table 6]

[0173] [Table 7]

[0174] Example 6 Closure stability packaging study of PVP-VA SDD of compound 1 The chemical stability of the PVP-VA containing SDD of Compound 1 under closed conditions was evaluated by HPLC using the method described in Table 4 herein. The 25 / 75 (w / w) Compound 1 PVP-VA SDD showed minimal degradation after 3 months of storage under closed conditions. The 25 / 70 / 5 (w / w / w) Compound 1 / PVP-VA / Poloxamer 407 SDD also showed good chemical stability upon analysis at 6 weeks. The stability data for the PVP-VA containing SDD of Compound 1 are listed in Table 8.

[0175] [Table 8]

[0176] Example 7 Tablet formulation of compound 1 Tablets were prepared by combining all intragranular materials except lubricant (i.e., active intermediates, ductile fillers, brittle fillers, disintegrants, and glidants) and blending the materials in a 16 quart V-shell blender at a speed of 16 revolutions per minute (rpm) for 60 revolutions to form a preblend. The preblend was then de-lumped by blending with a 032R screen in a Quadro Comil model U5 using a round mill impeller at a speed of 1500±100 rpm. The de-lumped materials were then returned to the 16 quart V-shell blender and blended for 180 revolutions at 16 rpm to form a pre-granulation main blend. The pre-granulation blend prepared according to this example had high bulk and tap density and a relatively low Carr index, indicating that the pre-granulation blend should have acceptable flow properties for roller compaction. The pre-granulation blend was also found to exhibit high compressibility, tabletability, and compactibility.

[0177] The intragranular lubricant was added to the pre-granulation primary blend and mixed by hand for approximately 15-30 seconds, then passed through a #20 mesh screen back into the blender and mixed at 16 rpm for 48 revolutions to form the primary lubricant pre-granulation blend. The primary lubricant pre-granulation blend was roller compacted using a Gerties Mini-Pactor using the settings in Table 9 to form the intragranular blend.

[0178] [Table 9]

[0179] The extragranular disintegrant was added to the intragranular blend and blended in an 8 quart V-shell blender for 180 revolutions at 18 rpm to form the extragranular main blend. The extragranular lubricant was passed through a #20 mesh screen and added to the extragranular main blend and blended for 48 revolutions at 18 rpm to form the extragranular lubricant blend. The extragranular blend prepared according to this example has high bulk and tap density and a relatively low Carr index, indicating that the pre-granulation blend should have acceptable flow properties for roller compaction.

[0180] The extragranular lubricant blend was then compressed on a Korsch XL100 tablet press (9 / 32 inch SRC tooling, Sotax ST50 tablet hardness tester) to form tablets with a target weight of 150 mg. The tablet press was adjusted as necessary to achieve the target tablet weight and hardness. The tablets were then de-dusted with a vibrator and / or vacuum de-duster. The compression parameters are described below.

[0181] [Table 10]

[0182] Two rounds of formulation and manufacturing were performed. The first round, "Round A," focused on identifying formulations for use with the Compound 1 / PVP-VA64 25 / 75 (w / w) spray dried dispersion. Selected brittle fillers and disintegrants were varied to evaluate the disintegration time and stability performance of the formulations. In "Round B" of the formulation, lactose monohydrate was replaced with anhydrous lactose to evaluate whether different forms of lactose would result in different stability outcomes within the tablets. Tablets A1, A2, A3, and B1 were determined to have acceptable friability and dissolution. The formulations are summarized in Table 10. Formulations C1 and C2 are separate manufacturing batches and have the same composition as formulation A1.

[0183] [Table 11]

[0184] Tablets A1, A2, A3, and B1 were evaluated in a USP II sink dissolution test with 1% by weight sodium lauryl sulfate (SLS) at 50° C. All tablets showed adequate average release of the formulations, with formulations A1, A2, and B1 having greater than 80% release after 10 minutes.

[0185] Example 8 Stability of tablet formulations Tablet formulations were subjected to stability studies. Tablets were packaged in heat sealed HDPE bottles with minimal head space and stored in temperature controlled stability chambers at 50°C, 40°C, 25°C, and 5°C. Humidity in the chambers was controlled to be or could be ambient humidity. For each specific formulation, the conditions are listed in Table 11 below.

[0186] An overall comparison of the tablet formulations showed that Formulation A1 showed the least change in total impurities between t=0 and 1 month under all conditions, suggesting that it is the most chemically stable.

[0187] [Table 12A]

[0188] [Table 12B]

[0189] [Table 12C]

[0190] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity.

[0191] In general, it is understood by those skilled in the art that the terms used herein, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "including, but not limited to," etc.). It is further understood by those skilled in the art that if a particular number of introduced claim recitations is intended, such intention will be clearly set forth in the claim, and that in the absence of such a setting, no such intention exists. For example, as an aid to understanding, the following appended claims include the use of the introductory phrases "at least one" and "one or more" to introduce the claim recitations. However, the use of such phrases should not be construed as indicating that the introduction of a claim recitation with the indefinite article "a" or "an" limits any particular claim that includes such introduced claim recitation to embodiments that include only one such recitation, even when the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"). The same applies to the use of definite articles used to introduce claim recitations. Moreover, even when a specific number of introduced claim recitations is explicitly recited, those skilled in the art will recognize that such recitation should be construed to mean at least the recited number (e.g., the recitation "two recitations" without other modifiers simply means at least two recitations, or more than two recitations).Furthermore, when a term similar to "at least one of A, B, and C, etc." is used, such a structure is generally intended in the sense that one of ordinary skill in the art would understand the term (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B and C together, etc.). When a term similar to "at least one of A, B, or C, etc." is used, such a structure is generally intended in the sense that one of ordinary skill in the art would understand the term (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B and C together, etc.). It will further be appreciated by those skilled in the art that virtually any disjunctive word and / or phrase, whether in the specification, claims, or drawings, presenting two or more alternative terms, should be understood to contemplate the possibility of including one of the terms, either the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0192] Additionally, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also described thereby with respect to any individual members of the Markush group or subgroups of members thereof.

[0193] As will be understood by those skilled in the art, for all purposes, including in terms of providing a written description, all ranges disclosed herein encompass all possible subranges and combinations of subranges. Any range described is fully described and can be readily recognized as being capable of breaking down the same range into at least equal divisions, thirds, fourths, fifths, tenths, etc. As a non-limiting example, each of the ranges discussed herein can be readily broken down into a lower third, a middle third, and an upper third, etc. As will also be understood by those skilled in the art, all language such as "up to," "at least," "greater than," "less than," etc., refers to a range that includes the recited number and can then be broken down into the subranges discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1-5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0194] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those of skill in the art. The various aspects and embodiments disclosed herein are intended to be illustrative and not limiting, with the true scope and spirit being indicated by the following claims.

Claims

1. (A) Compound 1 having the following structure or a pharmaceutically acceptable salt thereof; 【Chemistry 1】 one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), copovidone, poloxamer 407, hypromellose acetate succinate (HPMCAS), polyacrylates, and combinations thereof; a composition comprising (B) one or more ductile fillers, brittle fillers, disintegrants, glidants, lubricants, or combinations thereof 1. An oral dosage form comprising:

2. 10. The oral dosage form of claim 1, wherein the polymer is polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA).

3. 10. The oral dosage form of claim 1, wherein Compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers are combined to form a spray-dried dispersion.

4. 10. The oral dosage form of claim 1, wherein Compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers are combined to form a hot melt extrudate.

5. 2. The oral dosage form of claim 1, wherein the weight ratio of Compound 1 or a pharmaceutically acceptable salt thereof to the one or more polymers in the composition is 1:1 to 1:

4.

6. 6. The oral dosage form of claim 5, wherein the weight ratio of Compound 1 or a pharmaceutically acceptable salt thereof to the one or more polymers in the composition is 1:

3.

7. 10. The oral dosage form of claim 1, wherein the composition comprises 5% to 25% by weight of the oral dosage form.

8. 10. The oral dosage form of claim 1, wherein the ductile filler is selected from microcrystalline cellulose and silicified microcrystalline cellulose.

9. 9. The oral dosage form of claim 8, wherein the ductile filler is microcrystalline cellulose.

10. 10. The oral dosage form of claim 9, wherein the microcrystalline cellulose comprises 40% to 60% by weight of the oral dosage form.

11. 11. The oral dosage form of claim 10, wherein the microcrystalline cellulose comprises 50% by weight of the oral dosage form.

12. 10. The oral dosage form of claim 1, wherein the brittle filler comprises lactose monohydrate, spray-dried lactose, anhydrous lactose, lactose monohydrate, anhydrous lactose, or mannitol, or a combination thereof.

13. 10. The oral dosage form of claim 1, wherein the brittle filler comprises 10% to 40% by weight of the oral dosage form.

14. 14. The oral dosage form of claim 13, wherein the brittle filler comprises 25% by weight of the oral dosage form.

15. 2. The oral dosage form of claim 1, wherein the disintegrant is selected from carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, starch, pregelatinized starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone crospovidone, hydroxypropyl cellulose, magnesium aluminum metasilicate, and polacrilin potassium.

16. 10. The oral dosage form of claim 1, wherein the disintegrant comprises 5% to 15% by weight of the oral dosage form.

17. 17. The oral dosage form of claim 16, wherein the disintegrant comprises 10% by weight of the oral dosage form.

18. 10. The oral dosage form of claim 1, wherein the lubricant is selected from the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate, and magnesium stearate.

19. 19. The oral dosage form of claim 18, wherein the lubricant is magnesium stearate.

20. 10. The oral dosage form of claim 1, wherein the lubricant comprises 0.1% to 1% by weight of the oral dosage form.

21. 10. The oral dosage form of claim 1, wherein the glidant is silicon dioxide, starch, or talc.

22. 10. The oral dosage form of claim 1, wherein the glidant comprises 0.1% to 1% by weight of the oral dosage form.

23. (a) an intragranular portion comprising: (i) a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers; (ii) a ductile filler; (iii) a brittle filler; (iv) a disintegrant; (v) a glidant; and (vi) a lubricant; and (b) an extragranular portion comprising: (i) a disintegrant; and (ii) a lubricant.

10. The oral dosage form of claim 1, comprising:

24. 10. The oral dosage form of claim 1, wherein the dosage form has 90% to 100% of the original amount of Compound 1 or a pharmaceutically acceptable salt thereof after storage at 50°C and ambient relative humidity (RH) for 1 month.

25. 25. The oral dosage form of claim 24, wherein the dosage form has 90% to 100% of the original amount of Compound 1 or a pharmaceutically acceptable salt thereof after storage at 50°C and ambient relative humidity (RH) for 2 months.

26. 24. A method for preparing the oral dosage form of claim 23, comprising: (a) preparing a pre-granulation preblend comprising: (i) a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers; (ii) a ductile filler; (iii) a brittle filler; (iv) a disintegrant; and (v) a glidant; (b) blending the pre-granulation preblend; (c) adding a lubricant to the pre-granulation preblend; (d) slugging the pre-granulation preblend; and (e) Granulating the pre-granulation preblend to form intragranular portions A method comprising:

27. An oral dosage form according to any one of claims 1 to 25 for use in the prevention, treatment, or amelioration of one or more fatty liver diseases in a subject.

28. The oral dosage form of claim 27, wherein the one or more fatty liver diseases are selected from the group consisting of steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

29. The oral dosage form of claim 27, wherein the oral dosage form is for administration with a second drug.

30. 30. The oral dosage form of claim 29, wherein the second agent is for sequential or simultaneous administration.

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