Oral dosage form for treating liver diseases and preparation method thereof

Abstract

The present disclosure relates to oral dosage forms of TRbeta agonists and methods of making the same. The present disclosure provides oral dosage forms of TRbeta agonists having improved stability properties that allow storage under conventional conditions.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 426,161, filed on November 17, 2022, entitled "ORAL DOSAGE FORMS FOR THE TREATMENT OF LIVER DISORDERS AND METHODS OF PREPARING THE SAME", the disclosure of which is incorporated herein by reference in its entirety. Technical field

[0003] The compositions and methods of the present disclosure generally relate to the field of oral dosage forms of thyroid hormone receptor - β (TRβ) agonists for the treatment of liver diseases, fibrotic diseases, and inflammation. Background art

[0004] Thyroid hormones (THs) are synthesized in the thyroid gland in response to thyroid - stimulating hormone (TSH), which is secreted by the pituitary gland in response to various stimuli (such as thyrotropin - releasing hormone (TRH) from the hypothalamus). Thyroid hormones are iodinated O - aryl tyrosine analogues and are mainly secreted into the bloodstream as 3,3′,5,5′ - tetraiodothyronine (T4). T4 is rapidly deiodinated to 3,3′,5′ - triiodothyronine (T3) by thyroid hormone 5′ - deiodinase in local tissues, and T3 is the most potent TH. T3 is metabolized to inactive metabolites via multiple pathways, including deiodination, glucuronidation, sulfation, deamination, and decarboxylation, etc. Most of the circulating T4 and T3 are eliminated by the liver.

[0005] The biological activity of TH is mainly mediated by the thyroid hormone receptor (TR). TR belongs to the nuclear receptor superfamily and forms a heterodimer with its regular partner, the retinoic X receptor, and serves as a ligand-induced transcription factor. Like other nuclear receptors, TR has a ligand-binding domain and a DNA-binding domain and regulates gene expression through ligand-dependent interactions with DNA response elements (thyroid response elements, TREs). Currently, the literature shows that TR is encoded by two different genes (TRα and TRβ), and these two genes produce multiple isoforms 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 main isoforms that have been discovered so far are TRα-1, TRα-2, TRβ-1, and TRβ-2. TRα-1 is ubiquitously expressed in rats, with the highest expression levels in skeletal muscle and brown adipose tissue. TRβ-1 is also ubiquitously expressed, with the highest expression levels in the liver, brain, and kidney. TRβ-2 is expressed in the anterior pituitary, specific regions of the hypothalamus, and the developing brain and inner ear. In the liver of rats and mice, TRβ-1 is the predominant isoform (80%). The TR isoforms found in humans and rats are highly homologous in terms of their amino acid sequences, indicating that each plays a specialized function.

[0006] TH affects growth, metabolism, and the physiological functions of almost all organs. TH reduces serum cholesterol and triglycerides. However, the side effects of TH action include arrhythmia, osteoporosis, tension, and anxiety.

[0007] TRβ agonists can be used as therapeutic agents for conditions such as hepatitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and various fibrotic diseases and disorders. However, some TRβ agonists may have poor water solubility and / or undesirable stability characteristics. Such compounds with low water solubility and poor stability may require special compound storage conditions and may pose challenges in preparing formulations that provide adequate exposure for an individual and do not degrade when stored under conventional conditions.

[0008] Accordingly, there is a need to provide pharmaceutical formulations that provide appropriate exposure of drugs with poor water solubility to an individual. In addition, there is a need for pharmaceutical formulations with improved stability such that the drug does not degrade under environmental conditions and can be used for storage at room temperature. SUMMARY OF THE INVENTION

[0009] A first aspect of the present disclosure relates to an oral dosage form comprising a composition, the composition comprising: Compound 1 having the following structure:

[0010]

[0011] or a pharmaceutically acceptable salt thereof; and one or more liquid excipients selected from polyethylene glycol, glyceryl trioctanoate, glyceryl tridecanoate, diglyceryl dioctanoate, diglyceryl didecanoate, glyceryl monocaprylate, glyceryl monocaprate, polysorbate 80, oleic acid, polyethoxylated castor oil, lauroyl polyoxyglycerides - 32, sorbitan monooleate, phosphatidylcholine, glyceryl stearate, oleic acid, ascorbyl palmitate, lecithin, sorbitan monolaurate, tocophersolan, ethanol, propylene glycol monocaprylate, glyceryl mono - linoleate, glyceryl monooleate, dilinoleoyl glycerol, dioleoyl glycerol, trilinoleoyl glycerol, trioleoyl glycerol, caprylic / capric glycerides and combinations thereof.

[0012] In some embodiments of the first aspect, the composition further comprises an antioxidant. In some embodiments, the antioxidant is butylated hydroxytoluene.

[0013] In some embodiments of the first aspect, the oral dosage form described herein is in the form of a gelatin - based capsule.

[0014] In some embodiments of the first aspect, Compound 1 is present in the composition at a concentration of 0.1 mg to 100 mg per mL of excipient.

[0015] In some embodiments of the first aspect, the excipient comprises CC (glycerol / glyceryl mono - linoleate). In some embodiments, the excipient contains 20 wt% to 60 wt% of CC.

[0016] In some embodiments of the first aspect, the oral dosage form described herein may be characterized by having 95% to 100% of the original amount of Compound 1 after storage at 25 °C and 60% relative humidity (RH) for 1 month. In other embodiments, the oral dosage form described herein may be characterized by having 98% to 100% of the original amount of Compound 1 after storage at 25 °C and 60% relative humidity (RH) for 1 month. In some embodiments, the oral dosage form described herein may be characterized by having 95% to 100% of the original amount of Compound 1 after storage at 25 °C and 60% relative humidity (RH) for 2 months. In other embodiments, the oral dosage form described herein may be characterized by having 98% to 100% of the original amount of Compound 1 after storage at 25 °C and 60% relative humidity (RH) for 1 month.

[0017] The second aspect of the present disclosure relates to a method for preventing, treating, or ameliorating one or more fatty liver diseases in an individual in need thereof, the method comprising administering to the individual in need thereof, the method comprising administering an oral dosage form as described herein.

[0018] In some embodiments of the second aspect, the fatty liver disease is selected from steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

[0019] In some embodiments of the second aspect, wherein the method comprises administering a second agent. In some embodiments, the second agent can be administered sequentially or simultaneously.

[0020] In some embodiments of the second aspect, the method can result in preventing, treating, or ameliorating fibrosis, fibrotic conditions, or fibrotic symptoms. In some embodiments, the method can result in a decrease in the amount of extracellular matrix proteins present in one or more tissues of the individual. In some embodiments, the method can result in a decrease in the amount of collagen present in one or more tissues of the individual. In some embodiments, the method can result in a decrease in the amount of type I, type Ia, or type III collagen present in one or more tissues of the individual. Detailed Description

[0021] The present disclosure provides an oral dosage form formulation of Compound 1:

[0022]

[0023] Compound 1 is a low solubility lipophilic prodrug compound that is being developed for the treatment of chronic liver diseases including non-alcoholic fatty liver (NAFLD). Compound 1 can be prepared according to known methods, which include those described in U.S. Patent No. 7,829,552, which is incorporated herein by reference in its entirety. The current clinical dosage form is an encapsulated PEG-based formulation that provides sufficient exposure but requires cold chain storage due to chemical stability challenges. Provided herein is a soft gel formulation (i.e., a formulation with a gelatin-based shell) for oral administration, which is sufficiently effective for oral administration to an individual and is sufficiently stable for storage under conventional conditions.

[0024] Definition

[0025] The term "mammal" is used in its usual biological sense. Thus, it specifically includes humans and non-human mammals such as dogs, cats, horses, donkeys, mules, cows, domestic water buffalo, camels, llamas, alpacas, bison, yaks, goats, sheep, pigs, elk, deer, domestic antelopes, and non-human primates, as well as many other species.

[0026] As used herein, "subject" means a human or non-human mammal, including but not limited to a dog, cat, horse, donkey, mule, cow, domestic water buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer, domestic antelope, or non-human primate selected for treatment or therapy.

[0027] "Subject suspected of having... " means a subject that exhibits one or more clinical indicators of a disease or condition. In certain embodiments, the disease or condition is one or more fibromas, fibrotic disorders 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, cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, liver and gallbladder sclerosis, splenic fibrosis, scleroderma, pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis; interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonia, hypersensitivity pneumonia, non-specific interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac 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 allograft vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, joint fibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibrotic proliferative lesions of the oral cavity, fibrotic intestinal strictures, Crohn's disease, glial scar formation, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis caused by radiation exposure, fibrosis caused by rupture of breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or its symptoms or sequelae, or other diseases or conditions that result in excessive deposition of extracellular matrix components.

[0028] 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, basement membrane proteoglycan, syndecan, or aggrecan. As used herein, "collagen" refers to any of the subtypes of collagen, 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, in particular, types I, Ia, II, III, IV, and V. Fibrosis as used herein can occur spontaneously or as a symptom or sequela of another disorder. Fibrosis as used herein can be caused by a genetic disorder, genetic susceptibility, environmental damage, injury, wound healing, an autoimmune disease, chronic inflammation, a chronic inflammatory disease, or another condition that results in abnormal or excessive deposition of extracellular matrix components. Fibrosis as referred to herein can be evaluated by detecting or determining the presence or level of one or more biomarkers. Biomarkers for the presence of fibrosis include, but are not limited to, the expression of the Col1a1, Col3a1, ACTA2, ENPP2, and / or LGALS1 genes or any combination or product thereof. The diagnosis or assessment of fibrosis can also be performed by determining the presence or level of type I collagen and / or hydroxyproline or any combination or product thereof. The diagnosis or assessment of fibrosis can also be achieved by histological, histochemical, or immunohistochemical analysis of one or more samples from an individual.

[0029] "Glycogen storage disease" means any one or more of a group of diseases characterized by a dysfunction in the synthesis, transport, or utilization of glycogen, which dysfunction is usually due to the loss of activity of an essential enzyme. Glycogen storage diseases are usually classified by type according to their symptoms and causes. Known types include GSD type 0 (aglycogenosis, 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, debrancher disease; amyloglucosidase 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; starch-1,4 to 1,6 transglucosidase deficiency, GSD IV); GSD type 5 (McArdle disease; glycogen phosphorylase (muscle type) deficiency, GSD V); GSD type 6 (Hers disease; glycogen phosphorylase E (liver type) deficiency, GSD VI); GSD type 7 (Tarui 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 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 a mutation in the glucose-6-phosphatase (G6PC) gene and, among other symptoms, results in the excessive accumulation of glycogen and lipids in liver tissue, hepatomegaly, hepatic adenomas, and hepatocellular carcinoma. The symptoms of glycogen storage diseases can include elevated or decreased blood glucose, insulin insensitivity, myopathy, and hepatic symptoms (such as steatosis, hyperlipidemia, hypercholesterolemia, cardiomegaly, hepatomegaly, fibrosis, cirrhosis, hepatic adenomas, and hepatocellular carcinoma). Symptoms can also include insulin insensitivity, elevated or decreased blood glucose, renal dysfunction, and / or fibrosis.

[0030] As used herein, "inflammatory disease" refers to a disease or disorder characterized by inflammation. Exemplary inflammatory diseases include, but are not limited to: 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 diseases, balanitis, blepharitis, bronchitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcers, digestive system diseases, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infections, inflammatory bowel disease, inflammatory myocardial 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 fatty liver disease, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammation, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein inflammation, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stricture, stomatitis, stroke, surgical complications, synovitis, tendinitis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumors, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis.Inflammation as referred to herein can be evaluated by detecting or determining the presence or level of one or more biomarkers. Biomarkers for the presence of inflammation include, but are not limited to, the expression of TNF, CARD15, IL4R, IL23R, CTLA4, ANXA1, ANXA2, LGALS3, and / or PTPN22 genes or any combination or product thereof.

[0031] The term "atherosclerosis" refers to a condition characterized by irregularly distributed lipid deposits in the intima of medium and large arteries, where these deposits trigger fibrosis and calcification. Atherosclerosis increases the risk of angina, stroke, heart attack, or other cardiac or cardiovascular diseases.

[0032] "An individual in need" means an individual determined to be in need of therapy or treatment.

[0033] Treatment efficacy alleviates one or more symptoms of a disease or disorder to some extent and includes curing the disease or condition. "Cure" means that the symptoms of the active disease are eliminated. However, even after a cure is achieved, some long-term or permanent effects of the disease may still be present (e.g., extensive tissue damage).

[0034] As used herein, "treat", "treatment", or "treating" refers to the administration of a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating an individual who has not yet exhibited the symptoms of a disease or disorder but is susceptible to or at risk of 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 treating an individual who already has a disease or disorder.

[0035] "Preventing" or "prevention" means delaying or stopping the occurrence, development, or progression of a particular condition or disease over a period of time, including weeks, months, or years.

[0036] "Improve" means reducing the severity of at least one indicator of a condition or disease. In some embodiments, improvement includes delaying or slowing the progression of one or more indicators of the condition or disease. The severity of the indicator can be determined by subjective or objective measurements known to those of skill in the art.

[0037] "Modulation" means perturbation of a function or activity. In certain embodiments, modulation means an increase in gene expression. In certain embodiments, modulation means a decrease in gene expression. In certain embodiments, modulation means an increase or decrease in the total serum level of a specific protein. In certain embodiments, modulation means an increase or decrease in the free serum level of a specific protein. In certain embodiments, modulation means an increase or decrease in the total serum level of a specific non-protein factor. In certain embodiments, modulation means an increase or decrease in the free serum level of a specific non-protein factor. In certain embodiments, modulation means an increase or decrease in the total bioavailability of a specific protein. In certain embodiments, modulation means an increase or decrease in the total bioavailability of a specific non-protein factor.

[0038] "Administer" means to provide an agent or composition to an individual and includes, but is not limited to, administration by a professional medical staff and self-administration.

[0039] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof. It includes, but is not limited to, proteins, polypeptides, peptides or mimetics, organic small 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.

[0040] "Agent" means a substance that provides a therapeutic effect when administered to an individual.

[0041] "Pharmaceutical composition" means a mixture of substances suitable for administration to an individual, said mixture containing an agent. For example, a pharmaceutical composition can contain a modified oligonucleotide and a sterile aqueous solution.

[0042] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound associated therewith and are not undesirable in a biological or other respect. In many cases, due to the presence of phenolic and / or phosphonate groups or similar groups, the compounds of the present invention are capable of forming acid salts and / or base salts. Those of ordinary skill in the art will recognize that the protonation state of any or all of these compounds may vary with the pH and ionic characteristics of the surrounding solution, and thus the present disclosure contemplates multiple charge states for each compound. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which the 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 bases and organic bases. Inorganic bases from which the salts can be derived include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts are particularly preferred. Organic bases from which the salts can be derived include, for example, primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, for example, 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).

[0043] Drug ingredient

[0044] The useful compounds described above can be formulated into pharmaceutical compositions for treating the conditions described herein. In some embodiments, a pharmaceutical composition comprising Compound 1 can be formulated for oral administration. In some specific embodiments, a pharmaceutical composition comprising Compound 1 can be formulated into tablets. In other specific embodiments, a pharmaceutical composition comprising Compound 1 can be formulated into Gelcaps. Some embodiments of the pharmaceutical compositions described herein include: (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 a combination thereof.

[0045] The compositions described herein are preferably provided in unit dosage forms. As used herein, a "unit dosage form" is a composition that contains an amount of a compound suitable for administration as a single dose to an individual in accordance with good medical practice. However, the preparation of a single dosage form or unit dosage form does not mean administration once a day or once per course of treatment. The unit dosage form may include a once-daily dose or divided sub-doses, where multiple unit dosage forms need to be administered within a day in order to complete the daily dose. According to the present disclosure, the unit dosage form may be administered more or less than once a day, and may be administered more than once during a course of treatment.

[0046] The actual unit dose of Compound 1 described herein depends on the specific compound and the condition to be treated. In some embodiments, the dose can be from about 0.01 mg / kg body weight to about 120 mg / kg body weight or more, from about 0.05 mg / kg body weight or less 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 dose 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. Thus, for a person weighing 70 kilograms, the dose range is from about 0.1 mg to 70 mg, from about 1 mg to about 50 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 10 mg, from about 2.5 mg to about 30 mg, from about 35 mg or less to about 700 mg or more, from about 7 mg to about 600 mg, from about 10 mg to about 500 mg or from about 20 mg to about 300 mg or from 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 certain 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.

[0047] In some embodiments, Compound 1 may be administered at about 1 - 50 mg / m 2Dose administration based on body surface area. In some embodiments, Compound 1 is administered at about 1 - 2, 1 - 3, 1 - 4, 1 - 5, 1 - 6, 1 - 7, 1 - 8, 1 - 9, 1 - 10, 1 - 11, 1 - 12, 1 - 13, 1 - 13.75, 1 - 14, 1 - 15, 1 - 16, 1 - 17, 1 - 18, 1 - 19, 1 - 20, 1 - 22.5, 1 - 25, 1 - 27.5, 1 - 30, 1.5 - 2, 1.5 - 3, 1.5 - 4, 1.5 - 5, 1.5 - 6, 1.5 - 7, 1.5 - 8, 1.5 - 9, 1.5 - 10, 1.5 - 11, 1.5 - 12, 1.5 - 13, 1.5 - 13.75, 1.5 - 14, 1.5 - 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 - 14.5, 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 / m. 2 Dose administration based on body surface area. In some embodiments, Compound 1 is administered at 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 mg / m 2Dose administration based on body surface area. In some embodiments, Compound 1 is administered at less than 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 / m 2 Dose administration based on body surface area. In some embodiments, Compound 1 is administered at greater than 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 / m 2 Dose administration based on body surface area.

[0048] In some embodiments, the dose of Compound 1 is about 0.1 mg - 100 mg, 0.1 mg - 50 mg, 0.1 mg - 20 mg, 0.1 mg - 10 mg, 0.5 mg - 100 mg, 0.5 mg - 50 mg, 0.5 mg - 20 mg, 0.5 mg - 10 mg, 1 mg - 100 mg, 1 mg - 50 mg, 1 mg - 20 mg, 1 mg - 10 mg, 2.5 mg - 50 mg, 2.5 mg - 20 mg, 2.5 mg - 10 mg, or about 2.5 mg - 5 mg. In some embodiments, the dose of the TR-β agonist compound is about 5 mg - 300 mg, 5 mg - 200 mg, 7.5 mg - 200 mg, 10 mg - 100 mg, 15 mg - 100 mg, 20 mg - 100 mg, 30 mg - 100 mg, 40 mg - 100 mg, 10 mg - 80 mg, 15 mg - 80 mg, 20 mg - 80 mg, 30 mg - 80 mg, 40 mg - 80 mg, 10 mg - 60 mg, 15 mg - 60 mg, 20 mg - 60 mg, 30 mg - 60 mg, or about 40 mg - 60 mg. In some embodiments, the amount of Compound 1 administered is about 20 mg - 60 mg, 27 mg - 60 mg, 20 mg - 45 mg, or 27 mg - 45 mg. In some embodiments, the amount of Compound 1 administered is about 5 mg - 7.5 mg, 5 mg - 9 mg, 5 mg - 10 mg, 5 mg - 12 mg, 5 mg - 14 mg, 5 mg - 15 mg, 5 mg - 16 mg, 5 mg - 18 mg, 5 mg - 20 mg, 5 mg - 22 mg, 5 mg - 24 mg, 5 mg - 26 mg, 5 mg - 28 mg, 5 mg - 30 mg, 5 mg - 32 mg, 5 mg - 34 mg, 5 mg - 36 mg, 5 mg - 38 mg, 5 mg - 40 mg, 5 mg - 42 mg, 5 mg - 44 mg, 5 mg - 46 mg, 5 mg - 48 mg, 5 mg - 50 mg, 5 mg - 52 mg, 5 mg - 54 mg, 5 mg - 56 mg, 5 mg - 58 mg, 5 mg - 60 mg, 7 mg - 7.7 mg, 7 mg - 9 mg, 7 mg - 10 mg, 7 mg - 12 mg, 7 mg - 14 mg, 7 mg - 15 mg, 7 mg - 16 mg, 7 mg - 18 mg, 7 mg - 20 mg, 7 mg - 22 mg, 7 mg - 24 mg, 7 mg - 26 mg, 7 mg - 28 mg, 7 mg - 30 mg, 7 mg - 32 mg, 7 mg - 34 mg, 7 mg - 36 mg, 7 mg - 38 mg, 7 mg - 40 mg, 7 mg - 42 mg, 7 mg - 44 mg, 7 mg - 46 mg, 7 mg - 48 mg, 7 mg - 50 mg, 7 mg - 52 mg, 7 mg - 54 mg, 7 mg - 56 mg, 7 mg - 58 mg,7 mg - 60 mg, 9 mg - 10 mg, 9 mg - 12 mg, 9 mg - 14 mg, 9 mg - 15 mg, 9 mg - 16 mg, 9 mg - 18 mg, 9 mg - 20 mg, 9 mg - 22 mg, 9 mg - 24 mg, 9 mg - 26 mg, 9 mg - 28 mg, 9 mg - 30 mg, 9 mg - 32 mg, 9 mg - 34 mg, 9 mg - 36 mg, 9 mg - 38 mg, 9 mg - 40 mg, 9 mg - 42 mg, 9 mg - 44 mg, 9 mg - 46 mg, 9 mg - 48 mg, 9 mg - 50 mg, 9 mg - 52 mg, 9 mg - 54 mg, 9 mg - 56 mg, 9 mg - 58 mg, 9 mg - 60 mg, 10 mg - 12 mg, 10 mg - 14 mg, 10 mg - 15 mg, 10 mg - 16 mg, 10 mg - 18 mg, 10 mg - 20 mg, 10 mg - 22 mg, 10 mg - 24 mg, 10 mg - 26 mg, 10 mg - 28 mg, 10 mg - 30 mg, 10 mg - 32 mg, 10 mg - 34 mg, 10 mg - 36 mg, 10 mg - 38 mg, 10 mg - 40 mg, 10 mg - 42 mg, 10 mg - 44 mg, 10 mg - 46 mg, 10 mg - 48 mg, 10 mg - 50 mg, 10 mg - 52 mg, 10 mg - 54 mg, 10 mg - 56 mg, 10 mg - 58 mg, 10 mg - 60 mg, 12 mg - 14 mg, 12 mg - 15 mg, 12 mg - 16 mg, 12 mg - 18 mg, 12 mg - 20 mg, 12 mg - 22 mg, 12 mg - 24 mg, 12 mg - 26 mg, 12 mg - 28 mg, 12 mg - 30 mg, 12 mg - 32 mg, 12 mg - 34 mg, 12 mg - 36 mg, 12 mg - 38 mg, 12 mg - 40 mg, 12 mg - 42 mg, 12 mg - 44 mg, 12 mg - 46 mg, 12 mg - 48 mg, 12 mg - 50 mg, 12 mg - 52 mg, 12 mg - 54 mg, 12 mg - 56 mg, 12 mg - 58 mg, 12 mg - 60 mg, 15 mg - 16 mg, 15 mg - 18 mg, 15 mg - 20 mg, 15 mg - 22 mg, 15 mg - 24 mg, 15 mg - 26 mg, 15 mg - 28 mg,15 mg - 30 mg, 15 mg - 32 mg, 15 mg - 34 mg, 15 mg - 36 mg, 15 mg - 38 mg, 15 mg - 40 mg, 15 mg - 42 mg, 15 mg - 44 mg, 15 mg - 46 mg, 15 mg - 48 mg, 15 mg - 50 mg, 15 mg - 52 mg, 15 mg - 54 mg, 15 mg - 56 mg, 15 mg - 58 mg, 15 mg - 60 mg, 17 mg - 18 mg, 17 mg - 20 mg, 17 mg - 22 mg, 17 mg - 24 mg, 17 mg - 26 mg, 17 mg - 28 mg, 17 mg - 30 mg, 17 mg - 32 mg, 17 mg - 34 mg, 17 mg - 36 mg, 17 mg - 38 mg, 17 mg - 40 mg, 17 mg - 42 mg, 17 mg - 44 mg, 17 mg - 46 mg, 17 mg - 48 mg, 17 mg - 50 mg, 17 mg - 52 mg, 17 mg - 54 mg, 17 mg - 56 mg, 17 mg - 58 mg, 17 mg - 60 mg, 20 mg - 22 mg, 20 mg - 24 mg, 20 mg - 26 mg, 20 mg - 28 mg, 20 mg - 30 mg, 20 mg - 32 mg, 20 mg - 34 mg, 20 mg - 36 mg, 20 mg - 38 mg, 20 mg - 40 mg, 20 mg - 42 mg, 20 mg - 44 mg, 20 mg - 46 mg, 20 mg - 48 mg, 20 mg - 50 mg, 20 mg - 52 mg, 20 mg - 54 mg, 20 mg - 56 mg, 20 mg - 58 mg, 20 mg - 60 mg, 22 mg - 24 mg, 22 mg - 26 mg, 22 mg - 28 mg, 22 mg - 30 mg, 22 mg - 32 mg, 22 mg - 34 mg, 22 mg - 36 mg, 22 mg - 38 mg, 22 mg - 40 mg, 22 mg - 42 mg, 22 mg - 44 mg, 22 mg - 46 mg, 22 mg - 48 mg, 22 mg - 50 mg, 22 mg - 52 mg, 22 mg - 54 mg, 22 mg - 56 mg, 22 mg - 58 mg, 22 mg - 60 mg, 25 mg - 26 mg, 25 mg - 28 mg, 25 mg - 30 mg, 25 mg - 32 mg, 25 mg - 34 mg, 25 mg - 36 mg, 25 mg - 38 mg, 25 mg - 40 mg, 25 mg - 42 mg, 25 mg - 44 mg, 25 mg - 46 mg, 25 mg - 48 mg,25 mg - 50 mg, 25 mg - 52 mg, 25 mg - 54 mg, 25 mg - 56 mg, 25 mg - 58 mg, 25 mg - 60 mg, 27 mg - 28 mg, 27 mg - 30 mg, 27 mg - 32 mg, 27 mg - 34 mg, 27 mg - 36 mg, 27 mg - 38 mg, 27 mg - 40 mg, 27 mg - 42 mg, 27 mg - 44 mg, 27 mg - 46 mg, 27 mg - 48 mg, 27 mg - 50 mg, 27 mg - 52 mg, 27 mg - 54 mg, 27 mg - 56 mg, 27 mg - 58 mg, 27 mg - 60 mg, 30 mg - 32 mg, 30 mg - 34 mg, 30 mg - 36 mg, 30 mg - 38 mg, 30 mg - 40 mg, 30 mg - 42 mg, 30 mg - 44 mg, 30 mg - 46 mg, 30 mg - 48 mg, 30 mg - 50 mg, 30 mg - 52 mg, 30 mg - 54 mg, 30 mg - 56 mg, 30 mg - 58 mg, 30 mg - 60 mg, 33 mg - 34 mg, 33 mg - 36 mg, 33 mg - 38 mg, 33 mg - 40 mg, 33 mg - 42 mg, 33 mg - 44 mg, 33 mg - 46 mg, 33 mg - 48 mg, 33 mg - 50 mg, 33 mg - 52 mg, 33 mg - 54 mg, 33 mg - 56 mg, 33 mg - 58 mg, 33 mg - 60 mg, 36 mg - 38 mg, 36 mg - 40 mg, 36 mg - 42 mg, 36 mg - 44 mg, 36 mg - 46 mg, 36 mg - 48 mg, 36 mg - 50 mg, 36 mg - 52 mg, 36 mg - 54 mg, 36 mg - 56 mg, 36 mg - 58 mg, 36 mg - 60 mg, 40 mg - 42 mg, 40 mg - 44 mg, 40 mg - 46 mg, 40 mg - 48 mg, 40 mg - 50 mg, 40 mg - 52 mg, 40 mg - 54 mg, 40 mg - 56 mg, 40 mg - 58 mg, 40 mg - 60 mg, 43 mg - 46 mg, 43 mg - 48 mg, 43 mg - 50 mg, 43 mg - 52 mg, 43 mg - 54 mg, 43 mg - 56 mg, 43 mg - 58 mg, 42 mg - 60 mg, 45 mg - 48 mg, 45 mg - 50 mg, 45 mg - 52 mg, 45 mg - 54 mg, 45 mg - 56 mg, 45 mg - 58 mg, 45 mg - 60 mg, 48 mg - 50 mg, 48 mg - 52 mg, 48 mg - 54 mg, 48 mg - 56 mg, 48 mg - 58 mg, 48 mg - 60 mg, 50 mg - 52 mg, 50 mg - 54 mg, 50 mg - 56 mg, 50 mg - 58 mg, 50 mg - 60 mg52 mg - 54 mg, 52 mg - 56 mg, 52 mg - 58 mg, or 52 mg - 60 mg. In some embodiments, the dose of Compound 1 is greater than 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 about 200 mg. In some embodiments, the dose of Compound 1 is less than 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 about 200 mg. In some embodiments, the dose of Compound 1 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.

[0049] Soft gel preparation

[0050] Compound 1 can be formulated into a liquid-filled composition for oral administration to an individual in need. In some embodiments, Compound 1 can be formulated into a soft gel for oral administration to an individual in need. Soft gels for oral administration include a liquid fill and a capsule. In some embodiments, Compound 1 can be formulated into the liquid fill with one or more excipients.

[0051] 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 fill can be used to fill any suitable capsule known in the art.

[0052] In some embodiments, a particular excipient may be 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 may be 5%-10% (by weight) of the liquid fill. In some embodiments, a particular excipient may be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 90-99%, 10-30%, 20%-40%, 30-50%, 40-60%, 50-70%, 60-80%, 70-90% or 80-99% (by weight) of the liquid fill. In some embodiments, the liquid fill comprises one excipient. In other embodiments, the liquid fill comprises two excipients. In still other embodiments, the liquid fill comprises three excipients. In yet other embodiments, the liquid fill comprises four or more excipients.

[0053] In some embodiments provided herein, the excipient may be selected from CC, Crodamol TM GTCC, Crodamol TM GMCC, Capmul PG-8, ALF, Capryol TM 90, Caproyl TM PGMC, EL, RH 40, 80, Miglyol 812N, Span 80, Span 20, Vitamin E TPGS, Gelucire44 / 14, oleic acid, Phosphal 53MCT, Capmul MCM, LabrafacLipophyle WL 1349, polyethylene glycol (e.g., PEG-400) and combinations thereof. Excipients are generally known by their trade names, the descriptions of which are provided herein.

[0054]

[0055]

[0056] In some embodiments, the excipient may comprise In some specific embodiments, the excipient may be CC. In other embodiments, the excipient may be A combination of CC and an additional excipient. In still other embodiments, the excipient can be A combination of CC and two or more additional excipients. In some embodiments, the excipient may include and Capmul PG-8. In other embodiments, the excipient may include Crodamol TM GTCC, CC and Caproyl TM PGMC. In still other embodiments, the excipient may include Crodamol TM GTCC and ALF60%. In some additional embodiments, the excipient may include Crodamol TM GTCC, ALF and Maisine CC. In other embodiments, the excipient may include CC and Caproyl TM PGMC. In still other embodiments, the excipient may include ALF and Capryol PGMC. In some embodiments, the excipient may include and EL. In other embodiments, the excipient may include ALF, EL and 80. In still other embodiments, the excipient may include EL and Tween In some embodiments, the excipient may include ALF, Capryol TM PGMC and PEG-400. In other embodiments, the excipient may include Labrasol.

[0057] In some embodiments, the excipient accounts for 20% to 60% (by weight) of the liquid filling. In some embodiments, the excipient includes 20% to 70% (by weight) of CC in the liquid filling. In some embodiments, the excipient includes 20% to 80% (by weight) of CC in the liquid filling. In some embodiments, the excipient includes 10% to 90% (by weight) of CC in the liquid filling. In some embodiments, the excipient includes 10% to 95% (by weight) of CC in the liquid filling. In some embodiments, the excipient includes 5% to 100% (by weight) of CC.

[0058] In some embodiments, 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 filling present in the soft gel dosage form, or within the range defined by the above values. In some embodiments, CC comprises about 90% to about 100% of the liquid filling present in the soft gel dosage form. In some embodiments, CC comprises about 90% to about 100% of the liquid filling present in the soft gel dosage form. In some embodiments, CC comprises about 95% to about 100% of the liquid filling present in the soft gel dosage form. In some embodiments, CC comprises about 96% to about 100% of the liquid filling present in the soft gel dosage form. In some embodiments, CC comprises about 97% to about 100% of the liquid filling present in the soft gel dosage form. In some embodiments, CC comprises about 98% to about 100% of the liquid filling present in the soft gel dosage form. In some embodiments, CC comprises about 99% to about 100% of the liquid filling present in the soft gel dosage form.

[0059] In some embodiments, Crodamol GMCC comprises about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% (by weight) of the liquid filling present in the soft gel dosage form, or within the range defined by the above values. In some embodiments, Crodamol GMCC comprises about 20% to about 50% of the liquid filling present in the soft gel dosage form. In some embodiments, Crodamol GMCC comprises about 25% to about 40% of the liquid filling present in the soft gel dosage form.

[0060] In some embodiments, CaproylPGMC comprises about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% (by weight) of the liquid filling present in the soft gel dosage form, or within the range defined by the above values. In some embodiments, Caproyl PGMC comprises about 20% to about 70% of the liquid filling present in the soft gel dosage form. In some embodiments, CaproylPGMC comprises about 30% to about 60% of the liquid filling present in the soft gel dosage form. In some embodiments, Caproyl PGMC comprises about 30% to about 50% of the liquid filling present in the soft gel dosage form.

[0061] In some embodiments, Labrasol comprises about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% (by weight) of the liquid filling present in the soft gel dosage form, or is within the range defined by the above values. In some embodiments, Labrasol comprises from about 20% to about 70% of the liquid filling present in the soft gel dosage form. In some embodiments, Labrasol comprises from about 30% to about 60% of the liquid filling present in the soft gel dosage form. In some embodiments, Labrasol comprises from about 30% to about 50% of the liquid filling present in the soft gel dosage form.

[0062] 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 filling present in the soft gel dosage form, or is within the range defined by the above values. In some embodiments, Kolliphor EL comprises from about 20% to about 70% of the liquid filling present in the soft gel dosage form. In some embodiments, Kolliphor EL comprises from about 30% to about 60% of the liquid filling present in the soft gel dosage form. In some embodiments, Kolliphor EL comprises from about 30% to about 50% of the liquid filling present in the soft gel dosage form.

[0063] In some embodiments, Tween 80 comprises about 20%, 25%, 30%, 35%, 40%, 45%, or 50% (by weight) of the liquid filling present in the soft gel dosage form, or is within the range defined by the above values. In some embodiments, Tween 80 comprises from about 20% to about 40% of the liquid filling present in the soft gel dosage form. In some embodiments, Tween 80 comprises from about 25% to about 35% of the liquid filling present in the soft gel dosage form.

[0064] In some embodiments, PEG 400 comprises at least about 5%, 10%, 15%, 20%, 25%, or 30% (by weight) of the liquid filling present in the soft gel dosage form, or is within the range defined by the above values. In some embodiments, PEG 400 comprises from about 5% to about 30% of the liquid filling present in the soft gel dosage form. In some embodiments, PEG 400 comprises from about 10% to about 30% of the liquid filling present in the soft gel dosage form. In some embodiments, PEG 400 comprises from about 10% to about 20% of the liquid filling present in the soft gel dosage form.

[0065] In some embodiments, the liquid filling may include an excipient. In some specific embodiments, the excipient may be Maisine.

[0066] In some embodiments, the liquid filling may include two excipients. In some embodiments, the excipients may be Crodamol GMCC and Labrasol ALF. In some embodiments, Crodamol GMCC and Labrasol ALF may be present in a weight ratio of 40:60. In other embodiments, the excipients may be Labrasol ALF and Kolliphor EL. In some embodiments, Labrasol ALF and Kolliphor EL may be present in a weight ratio of 50:50. In certain other embodiments, Labrasol ALF and Kolliphor EL may be present in a weight ratio of 30:70. In some embodiments, the excipients may be Maisine and Caproyl PGMC. In certain embodiments, Maisine and Caproyl PGMC may be present in a weight ratio of 60:40. In certain other embodiments, Maisine and Caproyl PGMC may be present in a weight ratio of 40:60.

[0067] In some embodiments, the liquid filling may include three excipients. In some embodiments, the excipients may be Crodamol GMCC, Maisine CC and Caproyl PGMC. In some embodiments, the weight ratio of Crodamol GMCC, Maisine CC and Caproyl PGMC is 30:30:40. In some embodiments, the weight ratio of Crodamol GMCC, Maisine CC and Caproyl PGMC is 20:40:40. In some embodiments, the excipients may be Crodamol GMCC, Labrasol ALF and Maisine CC. In some embodiments, the weight ratio of Crodamol GMCC, Labrasol ALF and Maisine CC is 25:35:40. In some embodiments, the weight ratio of Crodamol GMCC, Labrasol ALF and Maisine CC is 30:40:30.

[0068] In some embodiments, Compound 1 may be present in the liquid filling 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 filling or within a range defined by any two of the foregoing amounts.

[0069] In some embodiments, Compound 1 may be present in the liquid filling of the soft gel formulation at about 0.001 mg / mg liquid filling, 0.005 mg / mg liquid filling, 0.01 mg / mg liquid filling, 0.02 mg / mg liquid filling, 0.03 mg / mg liquid filling, 0.04 mg / mg liquid filling, 0.05 mg / mg liquid filling, 0.06 mg / mg liquid filling, 0.07 mg / mg liquid filling, 0.08 mg / mg liquid filling, 0.09 mg / mg liquid filling, 0.10 mg / mg liquid filling, 0.11 mg / mg liquid filling, 0.12 mg / mg liquid filling, 0.13 mg / mg liquid filling, 0.14 mg / mg liquid filling, or 0.15 mg / mg liquid filling (by weight), or within a range defined by any two of the foregoing amounts. For example, Compound 1 may be present in the liquid filling in an amount of 0.001 mg to 0.01 mg / mg liquid filling, 0.01 mg to 0.10 mg / mg liquid filling, 0.01 mg to 0.05 mg / mg liquid filling, 0.02 mg to 0.05 mg / mg liquid filling, 0.02 mg to 0.06 mg / mg liquid filling, 0.01 mg to 0.03 mg / mg liquid filling, 0.02 mg to 0.03 mg / mg liquid filling, 0.04 mg to 0.06 mg / mg liquid filling, 0.05 mg to 0.06 mg / mg liquid filling.

[0070] In some embodiments, the soft gel formulations described herein may further comprise an antioxidant. In some embodiments, the antioxidant may 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 some specific embodiments, the antioxidant is butylated hydroxytoluene.

[0071] In some embodiments, the antioxidant may be present in the liquid formulation in the soft gel 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), or within the range defined by any two of the above amounts.

[0072] Second medicament

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

[0074] In some embodiments, the dosage form of Compound 1 proposed herein can be administered simultaneously with one or more second agents. In other embodiments, the dosage form 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 form described herein.

[0075] In one aspect, the dosage form of Compound 1 proposed 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 reduce the triglyceride level and blood glucose level of an individual. PPAR modulators can be classified as PPARα modulators, PPARγ modulators, or PPARδ agonists. In some embodiments, the PPAR modulator can be In some embodiments, the PPAR modulator can be In some embodiments, the PPAR modulator can be In some embodiments, the PPAR modulator can be In some embodiments, the PPAR modulator can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0076] In some embodiments, the dosage form of Compound 1 proposed herein can be administered in combination with a fibrate derivative. Fibrate derivatives are a class of lipid-lowering drugs that have the effect of reducing an individual's blood lipids. In some embodiments, the fibrate derivative can be fenofibrate. In some embodiments, the fibrate derivative can be gemfibrozil. In some embodiments, the fibrate derivative can be fenofibric acid. In some embodiments, the fibrate derivative can be clofibrate. In some embodiments, the fibrate derivative can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0077] In some embodiments, the dosage form of Compound 1 proposed herein can 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 can be In some embodiments, the bile acid receptor modulator can be In some embodiments, the bile acid receptor modulator can be In some embodiments, the bile acid receptor modulator can be (tropifexor). In some embodiments, the bile acid receptor modulator can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0078] In some embodiments, the dosage form of Compound 1 proposed herein can be administered in combination with a bile acid receptor modulator. In some embodiments, the bile acid receptor modulator can be selected from FXR agonists, FXR antagonists, TGR agonists, and dual FXR / TGR agonists. In some embodiments, the bile acid receptor modulator can be selected from the compounds disclosed in Xu, J. Med. Chem. 2016, 59, 6553 - 6579, which is incorporated herein by reference in its entirety, and the bile acid receptor modulator includes compounds selected from the following:

[0079]

[0080]

[0081] where n is 2 or 3

[0082]

[0083] where R is H or F

[0084]

[0085]

[0086]

[0087]

[0088] When R is H or benzyl

[0089]

[0090]

[0091] wherein R is H or methyl

[0092]

[0093]

[0094]

[0095] wherein R is H or methyl

[0096]

[0097] wherein Y is F or Cl

[0098]

[0099]

[0100]

[0101]

[0102]

[0103] wherein X is H or OMe

[0104]

[0105]

[0106] wherein R is H or ethyl wherein R is H or OH

[0107]

[0108]

[0109] or a pharmaceutically acceptable salt of any of the foregoing.

[0110] In some embodiments, the dosage form of Compound 1 presented herein can be administered in combination with an anti-inflammatory compound. In some embodiments, the anti-inflammatory compound can be In some embodiments, the anti-inflammatory compound can be 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 foregoing.

[0111] In some embodiments, the second agent can be an anti-fibrotic compound. In some embodiments, the anti-fibrotic compound can be

[0112] In some embodiments, the anti-fibrotic compound can be In some embodiments, the anti-fibrotic compound can be a pharmaceutically acceptable salt or prodrug of any of the foregoing.

[0113] In some embodiments, the dosage form 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 to treat type 2 diabetes in an individual. 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 lysine. 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 is In some embodiments, the GLP-1 agonist can be a pharmaceutically acceptable salt or prodrug of any of the above.

[0114] In some embodiments, the dosage form of Compound 1 proposed herein can be administered in combination with a GLP-1 metabolism regulator. In some embodiments, the metabolism regulator can be a thyroid hormone receptor agonist. In other embodiments, the metabolism regulator can be a selective androgen receptor modulator. In some embodiments, the metabolism regulator can be a mitochondrial membrane transporter regulator. In other embodiments, the metabolism regulator can be a selective estrogen receptor modulator. In some embodiments, the metabolism regulator can be an inhibitor of stearoyl-CoA desaturase 1 (SCD1). In some embodiments, the metabolism regulator can be an inhibitor of dipeptidyl peptidase 4 (DPP-4). In some embodiments, the metabolism regulator can be an inhibitor of sodium-glucose cotransporter 1 and / or 2 (SGLT1, SGLT2 or dual SGLT1 / SGLT2 inhibitor). In some embodiments, the metabolism regulator can be recombinant fibroblast growth factor 19 (FGF19) or an engineered analog, or recombinant fibroblast growth factor 21 (FGF21) or its pegylated variant. In some embodiments, the metabolism regulator can be...

[0115]

[0116] In some embodiments, the metabolism regulator can be In some embodiments, the metabolism regulator can be In some embodiments, the metabolism regulator can be a pharmaceutically acceptable salt or prodrug of any of the foregoing.

[0117] In some embodiments, the dosage form of Compound 1 described herein can be administered in combination with fish oil derivatives. Fish oil contains ω-3-fatty acids, which are polyunsaturated fatty acids (PUFAs) characterized by having double bonds three atoms away from the terminal methyl group. They are widely distributed in nature and play important roles in human diet and human physiology, especially in lipid metabolism. In some embodiments, the fish oil derivative can be an alkyl ester of ω-3-fatty acid. For example, the fish oil derivative can be methyl ester, ethyl ester, n-propyl ester, or isopropyl ester of ω-3-fatty acid. In some embodiments, the fish oil derivative can be a triglyceride of ω-3-fatty acid. In some embodiments, the fish oil derivative can be ethyl (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate. 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 ethyl α-linolenate. 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 eicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl docosapentaenoate. In some embodiments, the fish oil derivative can be ethyl eicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl tetracosapentaenoate. In some embodiments, the fish oil derivative can be ethyl nisinic acid. In some embodiments, the fish oil derivative can be a pharmaceutically acceptable salt or prodrug of any of the foregoing.

[0118] Administration method

[0119] In some embodiments, the composition can be administered once, twice, three times, or four times a day. In other embodiments, the composition can be administered once, twice, or three times a week. In other embodiments, the composition can be administered once every other day, every three days, or every four days. In other embodiments, the composition can be administered once every other week, every three weeks, or every four weeks. In other embodiments, the composition can be administered once or twice a month.

[0120] In some embodiments, an initial loading dose is administered, which is higher than subsequent doses (maintenance doses). The dosage form or mode of administration of the maintenance dose may be different from the dosage form or mode of administration used for the loading dose. In any of the embodiments disclosed herein, the maintenance dose may include administering unit dosage forms according to any dosing schedule contemplated herein, the dosing schedule including, but not limited to, once a month or multiple times a month, once every two weeks or multiple times every two weeks, once a week or multiple times a week, once a day or multiple times a day. Incorporating a dosing holiday into the dosing period of the maintenance dose is contemplated in the present disclosure. Such a dosing holiday may occur immediately after administering the loading dose or at any time during the administration 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, 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 certain 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.

[0121] Treatment method

[0122] Some embodiments of the methods and compositions according to the present disclosure relate to methods of preventing, treating or ameliorating one or more fatty liver diseases in an individual, the method comprising co-administering an effective amount of Compound 1 described herein with one or more second agents to an individual in need thereof. In some embodiments, the fatty liver disease may be steatosis. In other embodiments, the fatty liver disease may be non-alcoholic fatty liver. In some embodiments, the fatty liver disease may be non-alcoholic steatohepatitis (NASH). In some embodiments, the individual may have two or more of the above fatty liver diseases.

[0123] Some embodiments of the methods and compositions according to the present disclosure relate to methods of reducing or preventing the deposition of extracellular matrix proteins, the methods comprising administering to a subject in need thereof an effective amount of Compound 1 described herein in combination with one or more second agents described herein. In some embodiments, the deposition of extracellular matrix proteins may include abnormal or excessive deposition of the proteins. In some embodiments, the extracellular matrix proteins may include one or more of collagen, keratin, elastin, or fibrin. In some embodiments, the extracellular matrix proteins may include collagen. In some embodiments, the extracellular matrix proteins may include type I collagen. In some embodiments, the extracellular matrix proteins may include type Ia collagen. In some embodiments, the extracellular matrix proteins may include type III collagen. Some embodiments of the compositions and methods according to the present disclosure relate to methods of treating fibrosis or its symptoms or sequelae, the methods comprising administering to a subject in need thereof an effective amount of the compounds described herein.

[0124] In some embodiments, the compounds described herein and compositions comprising Compound 1 and / or one or more of the second agents described herein can be used to treat various conditions caused by fibrosis or inflammation, particularly including conditions associated with abnormal collagen deposition. Exemplary conditions include glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSDVI), glycogen storage disease type IX (GSD IX), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, cirrhosis and cholecystosclerosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonia, hypersensitivity pneumonia, non-specific interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid, hypertrophic scar, nephrogenic systemic fibrosis, injection fibrosis, surgical complications, fibrotic chronic graft vasculopathy and / or chronic rejection of transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, joint fibrosis, Dupuytren's contracture, dermatomyositis-polymyositis, mixed connective tissue disease, fibrotic proliferative lesions of the oral cavity, fibrotic intestinal stricture, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis resulting from radiation exposure, fibrosis resulting from rupture of breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting from excessive deposition of extracellular matrix components such as collagen.

[0125] In some embodiments, the methods of the present disclosure include methods of treating, ameliorating, or preventing fibrotic conditions. In some embodiments, the fibrotic condition may be secondary to another condition. In some embodiments, the fibrotic condition or the primary condition may further include chronic inflammation in an organ, tissue, spatial region, or fluid connection region within an individual. 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 pathway 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 may include abnormal or excessive deposition of type III collagen. In some embodiments, the fibrotic condition may include glycogen storage disease type III (GSDIII), glycogen storage disease type VI (GSDVI), glycogen storage disease type IX (GSD IX), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, cardiac fibrosis, fibrosis associated with organ transplantation, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, cirrhosis and cholecystosclerosis, splenic fibrosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonia, hypersensitivity pneumonitis, non-specific interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid, hypertrophic scar, nephrogenic systemic fibrosis, injection fibrosis, surgical complications, fibrotic chronic allograft vasculopathy and / or chronic rejection of a transplanted organ, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, joint fibrosis, Dupuytren's contracture, dermatomyositis-polymyositis, mixed connective tissue disease, oral fibroproliferative lesion, fibrotic intestinal stricture, Crohn's disease, glial scar, meningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis resulting from radiation exposure, fibrosis resulting from rupture of breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or one or more of the foregoing.In certain embodiments, the fibrotic condition may include one or more of GSDIII, GSDIX, non-alcoholic steatohepatitis, cirrhosis, and / or pancreatic cancer, scleroderma, idiopathic pulmonary fibrosis, psoriasis, alcoholic fatty liver, Dupuytren's disease, and / or any combination thereof.

[0126] As the methods and compositions disclosed herein, fibrotic conditions or conditions having fibrosis as a sequela may also include chronic inflammation. As the methods and compositions disclosed herein, fibrotic conditions or conditions having fibrosis as a sequela may also include activation of one or more TGF-β-dependent signaling pathways. According to the methods and compositions disclosed herein, fibrotic conditions or conditions having fibrosis as a sequela may also include activation and / or inhibition of one or more thyroid receptor β (TRβ)-dependent signaling pathways. According to the methods and compositions disclosed herein, fibrotic conditions or conditions having fibrosis as a sequela may also include involvement of signaling pathways responsive to triiodothyronine (T3), thyroxine (T4), any combination thereof, or their mimetics. According to the methods and compositions disclosed herein, fibrotic conditions or conditions having fibrosis as a sequela may also include involvement of receptors responsive to T3, T4, any combination thereof, or their mimetics. In some embodiments, according to the methods and combinations disclosed herein, fibrotic conditions or conditions having fibrosis as a sequela may include involvement of TRβ.

[0127] 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 deposition of collagen. In some embodiments, the collagen deposition may include abnormal or excessive deposition of type I collagen. In some embodiments, the collagen deposition may include abnormal or excessive deposition of type Ia collagen. In some embodiments, the collagen deposition may include abnormal or excessive deposition of type III collagen. According to the methods and compositions disclosed herein, the collagen deposition may also include involvement of receptors responsive to T3, T4, any combination thereof, or their mimetics. In some embodiments of the methods and combinations disclosed herein, the collagen deposition may include involvement of TRβ. In some embodiments of the methods and compositions disclosed herein, the collagen deposition may be prevented, ameliorated, or cured by administering one or more agonists of TRβ.

[0128] In some embodiments, administration of Compound 1 described herein results in decreased expression of the Cola1, Col3a1, αSMA, and / or Galectin1 genes or any combination thereof, or their products, in an individual to whom the composition is administered. In some embodiments, administration of a dosage form of Compound 1 described herein results in a reduced degree of fibrosis as observed by histology, histochemistry, immunohistochemistry, etc., and / or a decrease in the amount, accumulation, or distribution of type I collagen and / or hydroxyproline, or any combination thereof, in an individual to whom the composition is administered. In some embodiments, administration of a dosage form of Compound 1 described herein in the manner disclosed herein results in a decrease in total serum lipids, total serum cholesterol, total serum triglycerides, total liver lipids, total liver cholesterol, total liver triglycerides, or any combination thereof.

[0129] Examples

[0130] The compositions and methods described herein are further illustrated by the following non-limiting examples.

[0131] Example 1: Preparation of liquid-filled composition

[0132] To determine the suitability of each system, liquid-filled compositions of Compound 1 were prepared. The concentration of Compound 1 was 50 mg per gram of liquid fill.

[0133] Table 1: Initial liquid-filled preparation of Compound 1

[0134]

[0135] Example 2: Hydrolysis stability data of Compound 1 in liquid excipient

[0136] To evaluate the compatibility of the excipients, placebo mixtures were first prepared for each formulation. After confirming the compatibility of the excipients, a 50 mg / g formulation mixture of Compound 1 was prepared and 5% w / w water was added thereto in order to evaluate the effect of water migration during encapsulation on hydrolysis impurities. The water-added samples were stored at a temperature of 40 °C. Hydrolysis stability data are provided in Table 2 below. The results showed that the use of Kolliphor EL led to an increase in the formation of impurities due to the hydrolysis of Compound 1.

[0137] Table 2: Hydrolysis stability of Compound 1 preparation

[0138]

[0139]

[0140] Example 3: Preparation of soft gel (Preparation A)

[0141] Filling material preparation: 5 mg of the filling material of Compound 1 in soft gel was prepared in a Becomix 2.5L (MV27) equipped with a homogenizer and a stirring blade. Potency adjustment was carried out based on the potency of Compound 1, and compensation was made for the weight of glyceryl mono-linoleate NF( CC). The concentration of BHT was kept constant (0.2% of the total weight of the filling). CC, Compound 1, and butylated hydroxytoluene (BHT) were mixed at 20 °C - 30 °C for at least 2.5 hours until Compound 1 and BHT were dissolved to prepare the active mixture. During mixing and degassing, the product temperature was maintained at 20 °C - 30 °C by adjusting the cooling mode of the mixing container. The mixture was degassed for 20 minutes, poured into a clean and dry stainless-steel container, and isolated with nitrogen.

[0142] Gel preparation : A 200 kg of OET-004037 (L2DDXHBHM gelatin clear) gel melt was prepared by a gel preparer, and the gel melt was composed of Type 195 acid bone gelatin, NF, sorbitol special glycerol blend, and purified water USP, EP. By adding titanium dioxide and purified water, the color of the gel melt was converted to OET-005037@920P opaque white for encapsulating Compound 1 (5 mg soft gel).

[0143] Encapsulation : Encapsulation was carried out using a No. 4 oval mold and a standard medicine pump. After encapsulation (filling and sealing), the fresh soft gels were immediately transferred to a drum drying basket through a conveyor belt. The well-dried soft gels could be spread on a shallow tray for tunnel drying without significant sticking or deformation. Formulation A had the composition shown in Table 3 below.

[0144] Table 3: 5mg soft gel Preparation A

[0145]

[0146] Example 4: Preparation of 10mg soft gel

[0147] Preparation of 10mg soft gel: The filling material of Compound 1 (10 mg soft gel) was prepared according to the method in Example 3 above. Various soft gels were prepared as provided in Table 4 below. Compared with the existing formulation containing 86% polyethylene 6000, 10% polyethylene 1000, 1% Kolliphor P188, and 0.15% citric acid, Formulations A - E showed significantly improved hydrolysis stability of Compound 1.

[0148] Table 4: 10mg soft gel preparation

[0149]

[0150] Example 5: Preparation of additional 10mg soft gel

[0151] Filling material preparation : The filling material for Compound 1 (10 mg soft gel) was prepared in a Becomix 2.5L (MV27) equipped with a homogenizer and stirring blades. Potency adjustment was performed based on the potency of Compound 1, and the weight of Miglyol 812N was compensated. 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. During mixing and degassing, the product temperature was maintained at 20°C - 30°C by adjusting the cooling mode of the mixing container. The mixture was degassed for 20 minutes, poured into a clean and dry stainless-steel container, and isolated with nitrogen.

[0152] Gel preparation : Prepared by Gel The preparer prepared 200 kg of the melt of OET-004037 (L2DDXHBHM gelatin clear), and the Coag Gel melt was composed of type 195 acid bone gelatin, NF, sorbitol special glycerol blend, and purified water USP, EP. By adding titanium dioxide and purified water, the Gel color of the melt was converted to OET-005037@920P opaque white for encapsulating Compound 1 (10 mg soft gel). Gel

[0153] Encapsulation : Encapsulation was performed using a No. 4 oval mold and a standard medicine pump. After encapsulation (filling and sealing), the fresh soft gels were immediately transferred to a drum drying basket via a conveyor belt. The well-dried soft gels could be spread on a shallow tray for tunnel drying without significant sticking or deformation. Preparation G has the composition shown in Table 5 below.

[0154] Table 5: 10mg soft gel Preparation G

[0155]

[0156] Example 6: Storage stability of soft gel

[0157] ​The soft gel is packaged in a 40-cc white round high-density polyethylene bottle containing 40 units, with a white plastic child-resistant cap and heat-sealed with a 0.035" white inner liner board (with aluminum foil, polyethylene terephthalate film, and heat seal). Stability is measured under the ICH conditions of 5°C / ambient humidity and 25°C / 60% relative humidity. In addition, the stability study of the formulation is conducted under accelerated conditions of 40°C / 75% relative humidity. The impurity levels are measured by HPLC. The stability results are provided in Table 6 below.

[0158] Table 6: Long-term stability of soft gel

[0159]

[0160] NT = Not Tested

[0161] Although 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 for illustrative purposes only and are not intended to be limiting, and the true scope and spirit are indicated by the appended claims.

Claims

1. An oral dosage form comprising Compound 1 having the following structure: or a pharmaceutically acceptable salt thereof; and One or more excipients selected from the group consisting of polyethylene glycol, glyceryl tricaprylate, glyceryl tricaprate, glyceryl dicaprylate, glyceryl dicaprate, glyceryl monocaprylate, glyceryl monocaprate, polysorbate 80, oleic acid, polyethoxylated castor oil, lauroyl polyoxyglycerides - 32, sorbitan monooleate, phosphatidylcholine, glyceryl stearate, oleic acid, ascorbyl palmitate, lecithin, sorbitan monolaurate, tocopherol, ethanol, propylene glycol monocaprylate, glyceryl mono - linoleate, glyceryl monooleate, diglyceryl linoleate, CC (glycerol / glyceryl monolinoelate), diglyceryl oleate, triglycerin linoleate, triglycerin oleate, caprylic - capric acid glyceryl monoester and combinations thereof.

2. The oral dosage form according to claim 1, wherein Compound 1 and the one or more excipients are in the liquid filling within an outer capsule.

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

4. The oral dosage form according to any one of claims 2 and 3, wherein the dosage form further comprises an antioxidant.

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

6. The oral dosage form according to 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 the liquid filling.

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

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

9. The oral dosage form according to any one of claims 2 to 8, wherein the excipient comprises CC (glycerol / glycerol monolinoeate).

10. The oral dosage form according to claim 9, wherein CC accounts for 90% to 99% by weight of the liquid filling.

11. The oral dosage form according to claim 10, wherein CC accounts for 93% to 96% by weight of the liquid filling.

12. The oral dosage form according to claim 11, wherein CC accounts for 95% by weight of the liquid filling.

13. The oral dosage form according to claim 9, wherein the excipient comprises 20% to 60% by weight of the liquid filling of CC.

14. The oral dosage form according to any one of claims 2 to 13, wherein the liquid filling comprises Crodamol, Capryol PGMC, Labrasol ALF, or a combination thereof.

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

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

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

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

19. A method for preventing, treating, or improving one or more fatty liver diseases in an individual in need thereof, the method comprising administering to the individual in need thereof an oral dosage form according to any one of claims 1 to 18.

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

21. The method according to claim 19 or 20, wherein the method comprises administering a second agent.

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

23. The method according to any one of claims 19 to 22, wherein the method results in the prevention, treatment, or improvement of fibrosis, fibrotic conditions, or fibrotic symptoms.

24. The method according to any one of claims 19 to 23, wherein the method results in a decrease in the amount of extracellular matrix proteins present in one or more tissues of the individual.

25. The method according to any one of claims 19 to 24, wherein the method results in a decrease in the amount of collagen present in one or more tissues of the individual.

26. The method according to claim 25, wherein the method results in a decrease in the amount of type I, type Ia or type III collagen present in one or more tissues of the individual.

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