Oral dosage forms for the treatment of liver disorders and methods for preparing same - Patents.com

Abstract

The present disclosure is directed to oral dosage forms of TRβ agonists and methods for preparing same. The present disclosure provides oral dosage forms of TRβ agonists with improved stability characteristics that allow for storage under standard conditions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 426,161, filed November 17, 2022, entitled "Oral Dosage Forms for the Treatment of Liver Damage and Methods for Preparing the Same," the disclosure of which is incorporated herein by reference in its entirety.

[0002] 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 damage, fibrotic disease, and inflammation. [Background technology]

[0003] Thyroid hormones (THs) 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 iodinated O-aryltyrosine analogs excreted into the circulation primarily as 3,3',5,5'-tetraiodothyronine (T4). T4 is rapidly deiodinated 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, and decarboxylation. The majority of circulating T4 and T3 are lost through the liver.

[0004] The biological activity of THs is largely mediated by thyroid hormone receptors (TRs). 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 possess ligand-binding and DNA-binding domains and regulate gene expression through ligand-dependent interactions with DNA response elements (thyroid response elements, TREs). Current literature indicates that TRs are encoded by two distinct genes (TRα and TRβ), with multiple isoforms 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 ubiquitously expressed in rats, with highest expression in skeletal muscle and brown fat. TRβ-1 is also ubiquitously expressed, with highest expression in the 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 in their amino acid sequences, suggesting that each fulfills specialized functions.

[0005] THs affect the growth, metabolism, and physiological function of nearly every organ. THs lower serum cholesterol and triglycerides. However, side effects of TH action include cardiac arrhythmias, bone loss, irritability, and anxiety.

[0006] TRβ agonists can be useful as therapeutic agents for conditions 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 adequate exposure to subjects and do not decompose when stored under standard conditions. [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 Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, there is a need to provide drug formulations that provide suitable exposure to a subject for drugs with poor aqueous solubility. Additionally, there is a need for drug formulations that have improved stability so that the drug does not degrade under ambient conditions and room temperature storage can be utilized. [Means for solving the problem]

[0010] A first aspect of the present disclosure relates to a compound 1 having the following structure or a pharmaceutically acceptable salt thereof: [ka] Polyethylene glycol, caprylic triglyceride, capric triglyceride, caprylic acid diglyceride, capric diglyceride, caprylic acid monoglyceride, capric acid monoglyceride, polyethylene glycol, sorbitan monooleate, oleic acid, polyethoxylated castor oil, lauroyl polyoxyl-32 glyceride, sorbitan monooleate, phosphatidylcholine, glyceryl stearate, oleaic acid and one or more liquid excipients selected from the group consisting of glycerol monocaprylate, glycerol monolaurate, ascorbyl palmitate, lecithin, sorbitan monolaurate, tocophersolan, ethanol, propylene glycol monocaprylate, linoleic acid monoglyceride, oleic acid monoglyceride, linoleic acid diglyceride, oleic acid diglyceride, linoleic acid triglyceride, oleic acid triglyceride, glycerol monocaprylocaprate, and combinations thereof.

[0011] In some embodiments of the first aspect, the composition further comprises an antioxidant. In some embodiments, the antioxidant is butylated hydroxytoluene.

[0012] In some embodiments of the first aspect, the oral dosage forms described herein are in the form of gelatin-based capsules.

[0013] In some embodiments of the first aspect, Compound 1 is present in the composition at a concentration of from 0.1 mg to 100 mg per mL of excipient.

[0014] In some embodiments of the first aspect, the excipient comprises Maisine® CC (glycerol / glyceryl monolinoleate). In some embodiments, the excipient comprises 20% to 60% by weight of Maisine® CC.

[0015] In some embodiments of the first aspect, the oral dosage forms described herein can be characterized as having 95% to 100% of the original amount of Compound 1 after one month of storage at 25°C and 60% relative humidity (RH). In other embodiments, the oral dosage forms described herein can be characterized as having 98% to 100% of the original amount of Compound 1 after one month of storage at 25°C and 60% relative humidity (RH). In some embodiments, the oral dosage forms described herein can be characterized as having 95% to 100% of the original amount of Compound 1 after two months of storage at 25°C and 60% relative humidity (RH). In other embodiments, the oral dosage forms described herein can be characterized as having 98% to 100% of the original amount of Compound 1 after two months of storage at 25°C and 60% relative humidity (RH).

[0016] A second aspect of the present disclosure relates to 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.

[0017] In some embodiments of the second aspect, the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

[0018] In some embodiments of the second aspect, the method includes administering a second agent. In some embodiments, the second agents may be administered sequentially or simultaneously.

[0019] In some embodiments of the second aspect, the method may prevent, treat, or ameliorate fibrosis, a fibrotic condition, or a fibrotic symptom. 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. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure provides an oral dosage formulation of Compound 1. [ka] Compound 1 is a low-solubility lipophilic prodrug compound in development for the treatment of chronic liver diseases, including nonalcoholic 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 a softgel formulation (i.e., a formulation in a gelatin-based shell) for oral administration that is sufficiently effective for oral administration to subjects and sufficiently stable for storage under standard conditions.

[0021] 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.

[0022] "Subject," as used herein, means a human or 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.

[0023] "Subject suspected of suffering from" means 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, muscle fibrosis, pancreatic fibrosis, myelofibrosis, 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 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 scars, 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.

[0024] 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, injury, injury healing, an autoimmune condition, or chronic inflammation, a chronic inflammatory condition, or another condition that causes abnormal or excessive deposition of extracellular matrix components. Fibrosis 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 fibrosis include, but are not limited to, expression of the Col1a1, Col3a1, ACTA2, ENPP2, and / or LGALS1 genes, or any combination or product thereof. Fibrosis can be further diagnosed or assessed by determining the presence or level of type I collagen and / or hydroxyproline, or any combination or product thereof. Fibrosis can also be diagnosed or assessed by histological, histochemical, or immunohistochemical analysis of one or more samples from a subject.

[0025] "Glycogen storage disease" refers to any one or more of a group of disorders generally characterized by impairment in glycogen synthesis, transport, or utilization due to loss of necessary enzymatic activity. Glycogen storage diseases are generally classified into types according to their symptoms and etiology. Known types of GSD 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 (Cori 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); and GSD type 5 (McArdle disease, glycogen phosphorylase (muscle type) deficiency, GSD GSD type V); GSD type 6 (Haas disease; glycogen phosphorylase E (liver type) deficiency, GSD VI); GSD type 7 (Tarui disease; phosphofructokinase deficiency, GSD VII); GSD types 8 and 9 (GSD with phosphorylase activation system deficiency; phosphorylase kinase (liver or muscle isoform) deficiency, GSD VIII and GSD IX); GSD type 10 (cyclic AMP-dependent kinase deficiency, GSD X); GSD type 11 (Fanconi-Bickel syndrome; glucose transporter type 2 (GLUT2) deficiency, GSD XI); and GSD type 12 (aldolase A deficiency, GSD XII). Subtypes of glycogen storage diseases are also known, particularly GSD 1a, which is caused by mutations in the glucose-6-phosphatase (G6PC) gene and leads to excessive accumulation of glycogen and lipids in liver tissue, hepatomegaly, hepatic adenoma, and hepatocellular carcinoma, among other symptoms. Symptoms of glycogen storage disease can include elevated or decreased blood glucose, insulin insensitivity, muscle disorders, and liver symptoms such as steatosis, hyperlipidemia, hypercholesterolemia, cardiac hypertrophy, hepatomegaly, fibrosis, cirrhosis, hepatocellular adenoma, and hepatocellular carcinoma.Symptoms may also include insulin insensitivity, elevated or depressed blood glucose, renal dysfunction, and / or fibrosis.

[0026] 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, cyclosporin, and cyclosporin. Phosphamide-induced cystitis, cystic fibrosis, cystitis, colds, 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, infections, 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, non-alcoholic 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, peritonitis, 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, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, bladder trigonitis, tuberculosis, tumor, urethritis, uritis, uveitis, vaginitis, vasculitis and vulvitis.Inflammation referred to herein can be evaluated 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.

[0027] The term "atherosclerosis" refers to a condition characterized by irregularly distributed 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.

[0028] "Subject in need thereof" means a subject identified as in need of treatment or therapy.

[0029] A therapeutic effect relieves to some extent one or more symptoms of a disease or disorder, and includes curing the disease or disorder. "Cure" means that 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.

[0030] "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 have the disease or disorder in question, but who is susceptible to or otherwise at risk for the particular disease or disorder, whereby the treatment reduces the likelihood of the patient developing the disease or disorder. The term "therapeutic treatment" refers to administering a treatment to a patient who already has the disease or disorder.

[0031] "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.

[0032] "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.

[0033] "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.

[0034] "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.

[0035] 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. They can be natural products, synthetic compounds, or chemical compounds, or a combination of two or more substances.

[0036] "Drug" means a substance that produces a therapeutic effect when administered to a subject.

[0037] "Pharmaceutical composition" means 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.

[0038] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the associated compound and is 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; therefore, 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 using 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 (incorporated herein by reference in its entirety).

[0039] Pharmaceutical Composition The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating the conditions described herein. In some embodiments, a pharmaceutical composition comprising Compound 1 can be formulated for oral administration. In certain embodiments, a pharmaceutical composition comprising Compound 1 can be formulated as a tablet. In other certain embodiments, a pharmaceutical composition comprising Compound 1 can be formulated as a gelcap. Some embodiments of the pharmaceutical compositions described herein comprise (a) a safe and therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0040] The compositions described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" refers to a composition containing an amount of compound that is suitable for administration to a subject in a single dose according to good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of treatment. A unit dosage form can contain 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.

[0041] 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 about 0.01 mg / kg body weight to about 120 mg or more / kg body weight, about 0.05 mg / kg body weight or less to about 70 mg / kg body weight, about 0.1 mg / kg body weight to about 50 mg / kg body weight, about 1.0 mg / kg body weight to about 10 mg / kg body weight, about 5.0 mg / kg body weight to about 10 mg / kg body weight, or 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 dose 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.

[0042] In some embodiments, Compound 1 is administered in an amount of about 1-50 mg / m 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 to 22.5, 8.5 to 32.5, 9.5 to 15.5, 15.5 to 24.5, 5 to 35, 17.5 to 22.5, 22.5 to 32.5, 25 to 35, 25.5 to 24.5, 27.5 to 32.5, 2 to 20, 2.5 to 22.5, or 9.5 to 21.5 mg / m 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 exceeding 100 mg / kg.

[0043] In some embodiments, one 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 52mg, 45mg to 54mg, 45mg to 56mg, 45mg to 58mg, 45mg to 60mg, 48mg to 50mg, 48mg to 52mg, 48mg to 54mg, 48mg to 56mg, 48mg to 58mg, 48mg to 60mg, 50mg to 52mg, 50mg to 54mg, 50mg to 56mg, 50mg to 58mg, 50mg to 60mg, 52mg to 54mg, 52mg to 56mg, 52mg to 58mg, or 52mg to 60mg. 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.The amount is less than 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 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.

[0044] Soft gel formulation Compound 1 can be formulated as a liquid fill composition for oral administration to a subject in need thereof. In some embodiments, Compound 1 can be formulated into a softgel for oral administration to a subject in need thereof. Softgels for oral administration include liquid fills and capsules. In some embodiments, Compound 1 can be formulated into a liquid fill with one or more excipients.

[0045] In some embodiments, the liquid fills described herein can be used to fill hard gelatin or HPMC capsules. In some embodiments, the liquid fills described herein can be used to fill starch-based polyvinyl alcohol thermoplastic capsules. In some embodiments, the liquid fills can be used to fill any suitable capsule known in the art.

[0046] In some embodiments, a particular excipient can comprise 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight of the liquid fill. In some embodiments, a particular excipient can comprise 5% to 10% by weight of the liquid fill. In some embodiments, a particular excipient can comprise 10-20% by weight, 20-30% by weight, 30-40% by weight, 40-50% by weight, 50-60% by weight, 60-70% by weight, 70-80% by weight, 90-99% by weight, 10-30% by weight, 20-40% by weight, 30-50% by weight, 40-60% by weight, 50-70% by weight, 60-80% by weight, 70-90% by weight, or 80-99% by weight of the liquid fill. In some embodiments, the liquid fill includes one excipient. In other embodiments, the liquid fill includes two excipients. In yet other embodiments, the liquid fill includes three excipients. In yet other embodiments, the liquid fill includes four or more excipients.

[0047] In some embodiments described herein, the excipient may be selected from Maisine® CC, Crodamol™ GTCC, Crodamol™ GMCC, Capmul PG-8, Labrasol® ALF, Capryol™ 90, Caproyl™ PGMC, Kolliphor® EL, Kolliphor® RH 40, Tween® 80, Miglyol 812N, Span 80, Span 20, Vitamin E TPGS, Gelucire 44 / 14, oleic acid, Phosphal 53 MCT, Capmul MCM, Labrafac Lipophyle WL 1349, polyethylene glycols such as PEG-400, and combinations thereof. Excipients are often known by their trade names, descriptions of which are provided herein.

[0048] Table 1A

[0049] Table 1B

[0050] In some embodiments, the excipient can include Maisine®. In certain embodiments, the excipient can be Maisine® CC. In other embodiments, the excipient can be a combination of Maisine® CC and one additional excipient. In yet other embodiments, the excipient can be a combination of Maisine® CC and two or more additional excipients. In some embodiments, the excipient can include Maisine® and Capmul PG-8. In other embodiments, the excipient can include Crodamol™ GTCC, Maisine® CC, and Caproyl™ PGMC. In yet other embodiments, the excipient can include Crodamol™ GTCC and Labrasol® ALF 60%. In some additional embodiments, the excipient can include Crodamol™ GTCC, Labrasol® ALF, and Maisine CC. In other embodiments, the excipient can include Maisine® CC and Caproyl™ PGMC. In yet other embodiments, the excipients can include Labrasol® ALF and Capryol PGMC. In some embodiments, the excipients can include Labrasol® and Koliphor® EL. In other embodiments, the excipients can include Labrasol® ALF, Koliphor® EL, and Tween® 80. In still other embodiments, the excipients can include Koliphor® EL and Tween 80®. In some embodiments, the excipients can include Labrasol® ALF, Capryol™ PGMC, and PEG-400. In other embodiments, the excipients can include Labrasol.

[0051] In some embodiments, the excipient comprises 20% to 60% by weight of the liquid fill. In some embodiments, the excipient comprises 25% to 65% by weight of Maisine® CC by weight of the liquid fill. In some embodiments, the excipient comprises 20% to 70% by weight of Maisine® CC by weight of the liquid fill. In some embodiments, the excipient comprises 20% to 80% by weight of Maisine® CC by weight of the liquid fill. In some embodiments, the excipient comprises 10% to 90% by weight of Maisine® CC by weight of the liquid fill. In some embodiments, the excipient comprises 10% to 95% by weight of Maisine® CC by weight of the liquid fill. In some embodiments, the excipient comprises 5% to 100% by weight of Maisine® CC by weight of the liquid fill.

[0052] In some embodiments, Maisine® CC comprises about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, Maisine® CC comprises about 90% to about 100% of the liquid fill present in the softgel dosage form. In some embodiments, Maisine® CC comprises about 90% to about 100% of the liquid fill present in the softgel dosage form. In some embodiments, Maisine® CC accounts for about 95% to about 100% of the liquid fill present in the softgel dosage form. In some embodiments, Maisine® CC accounts for about 96% to about 100% of the liquid fill present in the softgel dosage form. In some embodiments, Maisine® CC accounts for about 97% to about 100% of the liquid fill present in the softgel dosage form. In some embodiments, Maisine® CC accounts for about 98% to about 100% of the liquid fill present in the softgel dosage form. In some embodiments, Maisine® CC accounts for about 99% to about 100% of the liquid fill present in the softgel dosage form.

[0053] In some embodiments, Crodamol GMCC comprises about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, Crodamol GMCC comprises about 20% to about 50% of the liquid fill present in the softgel dosage form. In some embodiments, Crodamol GMCC comprises about 25% to about 40% of the liquid fill present in the softgel dosage form.

[0054] In some embodiments, Caproyl PGMC comprises about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, Caproyl PGMC comprises about 20% to about 70% of the liquid fill present in the softgel dosage form. In some embodiments, Caproyl PGMC comprises about 30% to about 60% of the liquid fill present in the softgel dosage form. In some embodiments, Caproyl PGMC comprises about 30% to about 50% of the liquid fill present in the softgel dosage form.

[0055] In some embodiments, Labrasol comprises about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, Labrasol comprises about 20% to about 70% of the liquid fill present in the softgel dosage form. In some embodiments, Labrasol comprises about 30% to about 60% of the liquid fill present in the softgel dosage form. In some embodiments, Labrasol comprises about 30% to about 50% of the liquid fill present in the softgel dosage form.

[0056] In some embodiments, Kolliphor EL comprises about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, Kolliphor EL comprises about 20% to about 70% of the liquid fill present in the softgel dosage form. In some embodiments, Kolliphor EL comprises about 30% to about 60% of the liquid fill present in the softgel dosage form. In some embodiments, Kolliphor EL comprises about 30% to about 50% of the liquid fill present in the softgel dosage form.

[0057] In some embodiments, Tween 80 comprises about 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, Tween 80 comprises about 20% to about 40% of the liquid fill present in the softgel dosage form. In some embodiments, Tween 80 comprises about 25% to about 35% of the liquid fill present in the softgel dosage form.

[0058] In some embodiments, PEG 400 comprises at least about 5%, 10%, 15%, 20%, 25%, or 30% by weight of the liquid fill present in the softgel dosage form, or within a range defined by the values ​​above. In some embodiments, PEG 400 comprises about 5% to about 30% of the liquid fill present in the softgel dosage form. In some embodiments, PEG 400 comprises about 10% to about 30% of the liquid fill present in the softgel dosage form. In some embodiments, PEG 400 comprises about 10% to about 20% of the liquid fill present in the softgel dosage form.

[0059] In some embodiments, the liquid fill can include one excipient, hi certain embodiments, the excipient can be Maisine.

[0060] In some embodiments, the liquid fill can include two excipients. In some embodiments, the excipients can be Crodamol GMCC and Labrasol ALF. In certain embodiments, Crodamol GMCC and Labrasol ALF can be present in a 40:60 weight ratio. In other embodiments, the excipients can be Labrasol ALF and Kolliphor EL. In certain embodiments, Labrasol ALF and Kolliphor EL can be present in a 50:50 weight ratio. In certain embodiments, Labrasol ALF and Kolliphor EL can be present in a 30:70 weight ratio. In some embodiments, the excipients can be Maisine and Caproyl PGMC. In certain embodiments, Maisine and Caproyl PGMC can be present in a 60:40 weight ratio. In certain embodiments, Maisine and Caproyl PGMC can be present in a 40:60 weight ratio.

[0061] In some embodiments, the liquid fill can include three excipients. In some embodiments, the excipients can be Crodamol GMCC, Maisine CC, and Caproyl PGMC. In certain embodiments, Crodamol GMCC, Maisine CC, and Caproyl PGMC can be present in a mass ratio of 30:30:40. In certain embodiments, Crodamol GMCC, Maisine CC, and Caproyl PGMC can be present in a mass ratio of 20:40:40. In some embodiments, the excipients can be Crodamol GMCC, Labrasol ALF, and Maisine CC. In certain embodiments, Crodamol GMCC, Labrasol ALF, and Maisine CC can be present in a mass ratio of 25:35:40. In certain embodiments, Crodamol GMCC, Labrasol ALF, and Maisine CC can be present in a mass ratio of 30:40:30.

[0062] In some embodiments, Compound 1 can be present in the liquid fill of a softgel dosage form at about 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%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% by weight of the liquid fill, or within a range defined by any two of the foregoing amounts.

[0063] In some embodiments, Compound 1 may be present in the liquid fill of the softgel dosage form at about 0.001 mg / mg of liquid fill, 0.005 mg / mg of liquid fill, 0.01 mg / mg of liquid fill, 0.02 mg / mg of liquid fill, 0.03 mg / mg of liquid fill, 0.04 mg / mg of liquid fill, 0.05 mg / mg of liquid fill, 0.06 mg / mg of liquid fill, 0.07 mg / mg of liquid fill, 0.08 mg / mg of liquid fill, 0.09 mg / mg of liquid fill, 0.10 mg / mg of liquid fill, 0.11 mg / mg of liquid fill, 0.12 mg / mg of liquid fill, 0.13 mg / mg of liquid fill, 0.14 mg / mg of liquid fill, or 0.15 mg / mg of liquid fill by mass of the liquid fill, or within a range defined by any two of the foregoing amounts. For example, Compound 1 can be present in the liquid fill in an amount of 0.001 mg to 0.01 mg per 1 mg of liquid fill, 0.01 mg to 0.10 mg per 1 mg of liquid fill, 0.01 mg to 0.05 mg per 1 mg of liquid fill, 0.02 mg to 0.05 mg per 1 mg of liquid fill, 0.02 mg to 0.06 mg per 1 mg of liquid fill, 0.01 mg to 0.03 mg per 1 mg of liquid fill, 0.02 mg to 0.03 mg per 1 mg of liquid fill, 0.04 mg to 0.06 mg per 1 mg of liquid fill, or 0.05 mg to 0.06 mg per 1 mg of liquid fill.

[0064] In some embodiments, the softgel formulations described herein can further comprise an antioxidant. In some embodiments, the antioxidant can be vitamin E, ascorbic acid, sodium ascorbate, erythorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone, cresol, p-cresol, or any combination thereof. In certain embodiments, the antioxidant is butylated hydroxytoluene.

[0065] In some embodiments, an antioxidant may be present in the liquid formulation present in a softgel dosage form 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 liquid formulation, or within a range bounded by any two of the foregoing amounts.

[0066] Second drug The dosage forms of Compound 1 disclosed herein may be administered in combination with one or more second drugs. In some embodiments, the dosage forms of Compound 1 disclosed herein may be administered in combination with one second drug. In some embodiments, the compound may be administered in combination with two second drugs. In some embodiments, the compound may be administered in combination with three or more second drugs.

[0067] In some embodiments, the dosage forms of Compound 1 provided herein can be co-administered with one or more second agents. In other embodiments, the dosage forms of Compound 1 disclosed herein 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.

[0068] In one aspect, the dosage form of Compound 1 provided herein can be administered in combination with a peroxisome proliferator-activated receptor (PPAR) modulator. PPAR modulators are pharmaceutical compounds 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 [ka] In some embodiments, the PPAR modulator may be: [ka] In some embodiments, the PPAR modulator may be: [ka] In some embodiments, the PPAR modulator may be: [ka] In some embodiments, the PPAR modulator can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0069] 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 capable of lowering a subject's lipid profile. 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 pharmaceutically acceptable salt or prodrug of the above.

[0070] 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 [ka] In some embodiments, the bile acid receptor modulator may be: [ka] In some embodiments, the bile acid receptor modulator may be: [ka] In some embodiments, the bile acid receptor modulator may be: [ka] (tropifexor). In some embodiments, the bile acid modulator can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0071] 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 an FXR agonist, an FXR antagonist, a TGR agonist, and an FXR / TGR dual agonist. In some embodiments, the bile acid receptor modulator is [ka] (wherein n is 2 or 3), [ka] (wherein R is H or F), [ka] [ka] [ka] [ka] where R is H or benzyl, [ka] [ka] where R is H or methyl, [ka] [ka] where R is H or methyl, [ka] wherein Y is F or Cl; [ka] [ka] [ka] [ka] [ka] (wherein X is H or OMe), [ka] [ka] where R is H or ethyl, [ka] (wherein R is H or OH), [ka] or a pharmaceutically acceptable salt of any of the foregoing, the entirety of which is incorporated herein by reference.

[0072] In some embodiments, the dosage forms of Compound 1 presented herein can be administered in combination with an anti-inflammatory compound. In some embodiments, the anti-inflammatory compound is [ka] In some embodiments, the anti-inflammatory compound can be: [ka] 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 pharmaceutically acceptable salt or prodrug of any of the above.

[0073] In some embodiments, the second agent can be an anti-fibrotic compound. In some embodiments, the anti-fibrotic compound is [ka] In some embodiments, the anti-fibrotic compound can be: [ka] In some embodiments, the anti-fibrotic compound can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0074] In some embodiments, the dosage forms of Compound 1 presented herein can 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 [ka] (PF06882961). In some embodiments, the GLP-1 agonist can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0075] 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. [ka] In some embodiments, the metabolic modulator may be: [ka] In some embodiments, the metabolic modulator may be: [ka] In some embodiments, the metabolic modulator can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0076] In some embodiments, the dosage forms of Compound 1 presented herein can 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 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, particularly 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 herinic acid ethyl ester.In some embodiments, the fish oil derivative can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0077] Administration method 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 three weeks. In other embodiments, the composition is administered once or twice per month.

[0078] In some embodiments, an initial loading dose is administered that is greater than 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 comprise administration of a unit dosage form at any administration schedule contemplated herein, including, but not limited to, once a month or multiple times per month, once every two weeks or multiple times per two weeks, once a week or multiple times per week, or once a day or multiple times per 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 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 50 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, or 2 mg. In some embodiments, the maintenance dose is 300 mg or less; 200 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, 5 mg or less, 2.5 mg or less, or 1 mg or less. In some embodiments, the maintenance dose is 300 mg, 250 mg, 200 mg, 100 mg, 50 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 2.5 mg, or 1 mg.

[0079] Treatment method Some embodiments of the methods and compositions of the present disclosure relate 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 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 above fatty liver diseases.

[0080] Some embodiments of the methods and compositions of the present disclosure relate to a method of reducing or preventing deposition of extracellular matrix proteins, comprising administering to a subject in need thereof an effective amount of a compound 1 described herein in combination with one or more second agents described herein. In some embodiments, the deposition of extracellular matrix proteins can comprise abnormal or excessive deposition of the proteins. In some embodiments, the extracellular matrix proteins can comprise one or more of collagen, keratin, elastin, or fibrin. In some embodiments, the extracellular matrix proteins can comprise collagen. In some embodiments, the extracellular matrix proteins can comprise type I collagen. In some embodiments, the extracellular matrix proteins can comprise type Ia collagen. In some embodiments, the extracellular matrix proteins 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 sequela thereof, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0081] In some embodiments, compositions comprising a compound and 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. Exemplary 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), cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, muscle fibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, and diffuse interstitial fibrosis. 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 These include 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 scarring, 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 that result in excessive deposition of extracellular matrix components such as collagen.

[0082] In some embodiments, the methods of the present disclosure include methods for treating, ameliorating, or preventing a fibrotic condition. In some embodiments, the fibrotic condition can be associated with another condition. In some embodiments, the fibrotic condition or primary condition can further include chronic inflammation of an organ, tissue, spatial region, or fluid-connected area of ​​a subject's body. In some embodiments, the inflammation can include activation of one or more TGF-β-dependent signaling pathways. In some embodiments, the TGF-β-dependent signaling pathway can include one or more elements responsive to T3 or T4. In some embodiments, the fibrotic condition can include abnormal or excessive deposition of one or more of collagen, keratin, or elastin. In some embodiments, the fibrotic condition can include abnormal or excessive deposition of collagen. In some embodiments, the fibrotic condition can include abnormal or excessive deposition of type I collagen. In some embodiments, the fibrotic condition can include abnormal or excessive deposition of type Ia collagen. In some embodiments, the fibrotic condition can include 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), or glycogen storage disease type IV (GSD IV). IX), non-alcoholic 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 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 scarring, 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.

[0083] According to the methods and compositions disclosed herein, a condition resulting from a fibrotic or fibrotic sequelae may further include chronic inflammation. According to the methods and compositions disclosed herein, a condition resulting from a fibrotic or fibrotic sequelae may further include activation of one or more TGF-β-dependent signaling pathways. According to the methods and compositions disclosed herein, a condition resulting from a fibrotic or fibrotic sequelae 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, a condition resulting from a fibrotic or fibrotic sequelae may further include the 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 with 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 with sequelae of fibrosis can include involvement of TRβ.

[0084] In some embodiments, the compositions and methods described herein provide compositions and methods for treating, ameliorating, preventing, or curing collagen deposition. In some embodiments, the collagen deposition includes abnormal or excessive collagen deposition. 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 receptors responsive to T3, T4, any combination thereof, or mimetics 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.

[0085] In some embodiments, administration of a dosage form of Compound 1 described herein reduces expression of Cola1, Col3a1, 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. [Example]

[0086] The compositions and methods described herein are further illustrated by the following non-limiting examples.

[0087] Example 1 Preparation of Liquid Fill Composition To determine the suitability of each system, various liquid fill compositions of Compound 1 were prepared. The concentration of Compound 1 was 50 mg per gram of liquid fill. The various compositions prepared are shown in Table 1 below.

[0088] [Table 2]

[0089] Example 2 Hydrolytic stability data for compound 1 in liquid excipients To assess excipient compatibility, a placebo mix was first prepared for each formulation. Once excipient compatibility was confirmed, a 50 mg / g Compound 1 formulation mix was prepared and 5% (w / w) water was added to assess the effect that moisture migration during encapsulation might have on hydrolysis impurities. Samples with added water were stored at 40°C. Hydrolytic stability data are listed in Table 2 below. It was determined that the use of Kolliphor EL increased the formation of impurities resulting from the hydrolysis of Compound 1.

[0090] [Table 3A]

[0091] [Table 3B]

[0092] Example 3 Preparation of softgel (formulation A) Fill material preparation: Compound 1 5 mg softgel fill material was prepared in a Becomix 2.5 L (MV27) equipped with a homogenizer and agitator blade. Potency adjustments were made based on Compound 1 potency to compensate for the mass of glyceryl monolinoleate NF (Maisine® CC). The BHT concentration remained constant (0.2% of total fill mass). The active mixture was prepared by mixing Maisine® CC, Compound 1, and butylated hydroxytoluene (BHT) at 20°C to 30°C for at least 2.5 hours until Compound 1 and BHT were dissolved. The product temperature was maintained between 20°C and 30°C during mixing and degassing by adjusting the mixing vessel in cooling mode. The mix was degassed for 20 minutes, poured into a clean, dry stainless steel container, and blanketed with nitrogen.

[0093] Gel mass preparation: One 200 kg gel melt of OET-004037 (L2DDXHBHM Gelatin Clear) composed of Gelatin Type 195 Acid-Treated Bone, NF, Sorbitol Special Glycerin Blend, and USP, EP Purified Water was prepared by gel preparation personnel. The color of the gel melt was converted to OET-005037@920P milky white by adding titanium dioxide and purified water for use in encapsulating Compound 1 5 mg softgels.

[0094] Encapsulation: A four-oval die set and a standard drug pump were used for encapsulation. Immediately after encapsulation (filling and sealing), the fresh softgels were moved along a conveyor into a tumble dryer basket. The softgels were allowed to dry sufficiently to withstand spreading into shallow trays for tunnel drying without significant sticking or distortion. Formulation A had the composition shown below in Table 3.

[0095] [Table 4]

[0096] Example 4 Preparation of 10 mg softgels Preparation of 10 mg softgels: Compound 1 10 mg softgel fill material was prepared according to the method described in Example 3 above. Various softgel formulations are described below in Table 4. Formulations A through E demonstrated significantly improved hydrolytic stability of Compound 1 compared to the current formulation, which contains 86% polyethylene 6000, 10% polyethylene 1000, 1% Kolliphor P188, and 0.15% citric acid.

[0097] [Table 5]

[0098] Example 5 Preparation of additional 10 mg softgels Fill material preparation: Compound 1 10 mg softgel fill material was prepared in a Becomix 2.5 L (MV27) equipped with a homogenizer and agitator blade. A potency adjustment was made based on Compound 1 potency to compensate for the mass of Miglyol 812N. The active mixture was prepared by mixing Miglyol 812N, Crodamol GMCC (pre-melted at 40°C), Span 80, Vitamin E TPGS, and Compound 1 at 20°C-30°C until Compound 1 was dissolved. The product temperature was maintained between 20°C-30°C during mixing and degassing by adjusting the mixing vessel in cooling mode. The mix was degassed for 20 minutes, poured into a clean, dry stainless steel container, and blanketed with nitrogen.

[0099] Gel mass preparation: One 200 kg gel melt of OET-004037 (L2DDXHBHM Gelatin Clear) composed of Gelatin Type 195 Acid-Treated Bone, NF, Sorbitol Special Glycerin Blend, and USP, EP Purified Water was prepared by gel preparation personnel. The color of the gel melt was converted to OET-005037@920P milky white by adding titanium dioxide and purified water for use in encapsulating Compound 1 10 mg softgels.

[0100] Encapsulation: A four oval die set and a standard drug pump were used for encapsulation. Immediately after encapsulation (filling and sealing), the fresh softgels were moved along a conveyor into a tumble dryer basket. The softgels were allowed to dry sufficiently to withstand spreading into shallow trays for tunnel drying without significant sticking or distortion. Formulation G had the composition shown below in Table 5.

[0101] [Table 6]

[0102] Example 6 Softgel Storage Stability The softgels were packaged in 40 white round high-density polyethylene 40cc bottles with white plastic child-resistant caps and heat-induction sealed with foil, polyethylene terephthalate film, and 0.035-inch white backed pulp paperboard with heat seal, and stability was studied under ICH conditions of 5°C / ambient humidity and 25°C / 60% RH. Additionally, formulation stability studies were conducted at accelerated conditions of 40°C / 75% RH. Impurity levels were measured by HPLC. Stability results are listed below in Table 6.

[0103] [Table 7]

[0104] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled 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. Compound 1 having the following structure or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 Polyethylene glycol, caprylic triglyceride, capric triglyceride, caprylic acid diglyceride, capric diglyceride, caprylic acid monoglyceride, capric monoglyceride, polyethylene glycol sorbitan monooleate, oleic acid, polyethoxylated castor oil, lauroyl polyoxyl-32 glyceride, sorbitan monooleate, phosphatidylcholine, glyceryl stearate, oleaic acid, ascorbyl palmitate, lecithin, sorbitan monolaurate, tocophersolan, ethanol, propylene glycol monocaprylate, linoleic acid monoglyceride, oleic acid monoglyceride, linoleic acid diglyceride, Maisine® one or more excipients selected from the group consisting of CC (glycerol / glyceryl monolinoleate), oleic acid diglyceride, linoleic acid triglyceride, oleic acid triglyceride, glycerol monocaprylocaprate, and combinations thereof; 1. An oral dosage form comprising:

2. 10. The oral dosage form of claim 1, wherein Compound 1 and one or more excipients are present in a liquid fill within an outer capsule.

3. 3. The oral dosage form of claim 2, wherein the outer capsule is a gelatin-based capsule.

4. 4. The oral dosage form of claim 2 or 3, wherein the dosage form further comprises an antioxidant.

5. 5. The oral dosage form of claim 4, wherein the antioxidant is butylated hydroxytoluene.

6. 6. The oral dosage form of any one of claims 2 to 5, wherein Compound 1 is present in the composition at a concentration of 0.1 mg to 100 mg per gram of liquid fill.

7. 7. The oral dosage form of claim 6, wherein Compound 1 is present in the liquid fill at a concentration of 5 mg to 25 mg per gram of liquid fill.

8. 8. The oral dosage form of claim 7, wherein Compound 1 is present in the liquid fill at a concentration of about 20 mg per gram of liquid fill.

9. 9. The oral dosage form of claim 2, wherein the excipient comprises Maisine® CC (glycerol / glyceryl monolinoleate).

10. 10. The oral dosage form of claim 9, wherein Maisine® CC comprises 90% to 99% by weight of the liquid fill.

11. 11. The oral dosage form of claim 10, wherein Maisine® CC comprises 93% to 96% by weight of the liquid fill.

12. 12. The oral dosage form of claim 11, wherein Maisine® CC comprises 95% by weight of the liquid fill.

13. 10. The oral dosage form of claim 9, wherein the excipient comprises 20% to 60% Maisine® CC by weight of the liquid fill.

14. 14. The oral dosage form of claim 2, wherein the liquid fill comprises Crodamol, Capryol PGMC, Labrasol ALF, or a combination thereof.

15. 15. The oral dosage form of any one of claims 1 to 14, characterized in that the dosage form has 95% to 100% of the original amount of Compound 1 after 1 month of storage at 25°C and 60% relative humidity (RH).

16. 16. The oral dosage form of claim 15, wherein the dosage form has 98% to 100% of the original amount of Compound 1 after storage for 1 month at 25°C and 60% relative humidity (RH).

17. 16. The oral dosage form of claim 15, wherein the dosage form has 95% to 100% of the original amount of Compound 1 after 2 months of storage at 25°C and 60% relative humidity (RH).

18. 16. The oral dosage form of claim 15, wherein the dosage form has 98% to 100% of the original amount of Compound 1 after 2 months of storage at 25°C and 60% relative humidity (RH).

19. 20. 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 of any one of claims 1 to 18.

20. 20. The method of claim 19, wherein the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

21. 21. The method of claim 19 or 20, comprising administration of a second agent.

22. 22. The method of claim 21, wherein the second agent is administered sequentially or simultaneously.

23. 23. The method of any one of claims 19 to 22, wherein the method prevents, treats, or ameliorates fibrosis, a fibrotic condition, or a fibrotic symptom.

24. 24. The method of any one of claims 19 to 23, wherein the method reduces the amount of extracellular matrix protein present in one or more tissues of the subject.

25. 25. The method of any one of claims 19 to 24, wherein the method reduces the amount of collagen present in one or more tissues of the subject.

26. 26. The method of claim 25, wherein the method reduces the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

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