Cyclic phosphonate compositions and methods for their preparation

Abstract

A pharmaceutical composition comprising: Compounds of formula (I) [Formula 1] JPEG2025508852000011.jpg54170 and polymeric materials, wherein said compound of formula (I) maintains a supersaturated concentration in said pharmaceutical composition and is suitable for storage at room temperature.

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to Chinese application CN202210172544.0, filed on February 24, 2022. The entirety of the aforementioned application is incorporated herein by reference.

[0002] [Field of the Invention] FIELD OF THE DISCLOSURE This application relates generally to the field of pharmaceutical formulations, and in particular to suitable cyclic phosphonate pharmaceutical compositions and methods for their preparation.

[0003] [background] The cyclic phosphonate compound represented by formula (I) (molecular formula: CHClOP, molecular weight: 514.98, CAS number: 852948-13-1) is a novel oral thyroid hormone beta receptor agonist (THR-β agonist) that is expected to be used for fatty liver disease.

[0004] [ka]

[0005] Chinese Patent Application 202010105909.9 discloses a solubilized composition of the compound shown in formula (I) and a preparation method thereof. The semi-solid capsules prepared by this technique need to be stored at a temperature lower than room temperature (below 15°C), which makes storage and transportation inconvenient. Chinese Patent Application 202010227177.0 discloses another composition of the compound shown in formula (I) and a preparation method thereof. The pharmaceutical preparation prepared by this technique can be stably stored at room temperature (below 30°C), but there is also a problem that the maintenance time of the supersaturated concentration is short. From the results of Table 7 of Example 2 in the patent, it can be revealed that the solubility of each preparation in Examples G1 to L1 at 360 minutes is only 38.9% to 76.3% of the maximum value, and some drugs are rapidly precipitated from the supersaturated aqueous solution.

[0006] Dissolution of a drug is a prerequisite for oral absorption to exert a therapeutic effect in the body. After oral administration, a drug usually remains in the mouth and esophagus for less than 1 minute, in the stomach for 0.5-2 hours, in the small intestine for 6-8 hours, in the large intestine for 10-20 hours, and throughout the entire digestive tract for more than 24 hours. Therefore, maintaining a stable supersaturated concentration for a longer period of time through preparation techniques is helpful in achieving solubilization and synergistic effects.

[0007] [overview] One aspect of the present application relates to a pharmaceutical composition comprising, in parts by weight: (1) A compound of formula (I)

[0008] [ka] (2) Polymeric materials from parts 9 to 45; wherein the compound of formula (I) maintains a supersaturated concentration in the pharmaceutical composition and is suitable for storage at room temperature. In some embodiments, the pharmaceutical composition is in the form of an amorphous solid dispersion prepared by hot melt extrusion, wherein the pharmaceutical composition spontaneously forms nanomicelles, wherein the compound of formula (I) is stably distributed in the hydrophobic interior of the nanomicelles or in the hydrophobic interior of the membrane of the nanomicelles due to the water-insolubility and high lipid solubility of the compound of formula (I), thus maintaining a stable supersaturated concentration in the pharmaceutical composition.

[0009] In some embodiments, the compound of formula (I) is formulated in a stabilized formulation that can be stored at stable supersaturated concentrations at room temperature for at least 3 months, 4 months, 5 months, or 6 months.

[0010] In some embodiments, the pharmaceutical composition comprises, in parts by weight, 1 part of a compound of formula (I) and 9-15, 9-20, 9-25, 9-30, 9-35, 9-40, 15-20, 15-25, 15-30, 15-35, 15-40, 15-45, 20-25, 20-30, 20-35, 20-40, 20-45, 25-30, 25-35, 25-40, 25-45, 30-35, 30-40, 35-45, 35-40, 35-45, or 40-45 parts of polymeric material.

[0011] In some embodiments, the polymeric material comprises one or more polymers selected from the group consisting of polyvinyl lactam polymers, cellulosic polymers, polyacrylics, polyethylene glycols, polyoxyethylenes, and polyvinyl alcohols.

[0012] In some embodiments, the polymeric material comprises one or more polyvinyl lactam polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone (PVP / VA), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®). In some embodiments, the polymeric material comprises polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the polymeric material consists of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0013] In some embodiments, the polymeric material comprises one or more cellulosic polymers selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl hydroxyethyl cellulose (MHEC), hydroxypropyl methylcellulose succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMCP), and cellulose acetate phthalate (CAP).

[0014] In some embodiments, the polymeric material comprises one or more polyacrylic resins selected from the group consisting of methacrylic acid copolymers, methacrylic acid-ethyl acrylate copolymers, aminomethacrylic acid copolymers, and methacrylate copolymers.

[0015] In some embodiments, the pharmaceutical composition further comprises one or more non-polymeric materials, hi some embodiments, the pharmaceutical composition further comprises one or more non-polymeric materials selected from the group consisting of pharma- ceutically acceptable pharmaceutical excipients, non-volatile weak acids, neutral or weakly acidic inorganic substances, and pharma- ceutically acceptable excipients having a melting point below 80° C.

[0016] In some embodiments, the pharmaceutical composition may comprise a lipid material, such as triethyl citrate, acetylated triethyl citrate, propylene glycol biskwai esters, medium chain triglycerides, monoglycerides, monooleate, diethylene glycol monoethyl ether, hydrogenated castor oil, myristyl alcohol, hexadecanol, stearyl alcohol, palmitic acid, palmitoyl alcohol, 2,6-di-tert-butyl-p-cresol, vitamin E, poloxamer 188, poloxamer 407, polyethylene glycol 15-hydroxystearate (Kolliphor® HS 15), sodium dodecyl sulfate, propylene glycol monooleate ... cutanoate, polyethylene glycol oleate (Labrafac™ lipophilic WL1349), propylene glycol monolaurate, lauric acid polyglycerol ester (Gelucire® 44 / 14), stearic acid polyglycerol ester (Gelucire® 50 / 13), caprylic acid polyglycerol ester (Labrasol®), sorbitan fatty acid ester polyoxyethylene ether (Tween), sorbitan fatty acid ester (Span), and Vitamin E polyglycol succinate®.

[0017] In some embodiments, the pharmaceutical composition is free of other non-polymeric materials. In some embodiments, the compound of formula (I) is prepared by spray drying, solvent evaporation, or hot melt extrusion. In some embodiments, the compound of formula (I) is prepared by spray drying, or hot melt extrusion. In some embodiments, the compound of formula (I) is prepared by hot melt extrusion.

[0018] In some embodiments, the compound of formula (I) is present in the pharmaceutical compositions of the present application in a crystalline form, an amorphous form, or a partially crystalline / partially amorphous form. In some embodiments, the amorphous form of the compound of formula (I) is present in the pharmaceutical composition of the present application in an amount of 50% by weight or greater of the total amount of the compound of formula (I).

[0019] In some embodiments, the amorphous form of the compound of formula (I) is present in the pharmaceutical composition of the present application in an amount of 80% by weight or greater of the total amount of the compound of formula (I). In some embodiments, the amorphous form of the compound of formula (I) is present in the pharmaceutical composition of the present application in an amount of 90% by weight or greater of the total amount of the compound of formula (I).

[0020] In some embodiments, the pharmaceutical compositions of the present application further comprise one or more pharma- ceutically acceptable excipients, such as diluents, adhesives, disintegrants, lubricants, and the like.

[0021] In some embodiments, the pharmaceutical composition of the present application is in the form of particles or powder. In some embodiments, the pharmaceutical composition of the present application is processed into a capsule or tablet, or formulated into particles or granules and packaged in a bag, or processed into a suspension.

[0022] Another aspect of the present application relates to a process or method for preparing the pharmaceutical composition of the present application. In some embodiments, the process or method comprises extruding a mixture comprising, by weight, (1) 1 part of a compound of formula (I), and (2) 9 to 45 parts of a polymeric material by hot melt extrusion to form an extrudate, wherein the compound of formula (I) maintains a supersaturated concentration in the extrudate at room temperature.

[0023] In some embodiments, the compound of formula (I) maintains a supersaturated concentration in the extrusion product for at least 3 months, 4 months, 5 months, or 6 months at room temperature. In some embodiments, the extrusion product is ground or chopped into particles or powder. In some embodiments, the particles or powder are packaged in a capsule or sachet or compressed into a tablet. In some embodiments, the particles or powder are packaged in a hydroxypropyl methylcellulose capsule.

[0024] In certain embodiments, the pharmaceutical compositions of the present application are formulated into a fixed dose tablet or capsule containing 1-15 mg of the compound of formula (I). In certain embodiments, the fixed dose tablet or capsule contains 2.5 mg or 5 mg of the compound of formula (I).

[0025] One aspect of the present application is a method of treating a disease in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition described herein. In certain embodiments, the disease is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). [Brief description of the drawings]

[0026] [Figure 1] 1 shows dissolution curves (n=6) for formulation samples of compositions A1 to C1 of Example 1. [Diagram 2] 1 shows dissolution curves (n=6) for samples formulated according to composition a2 of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present disclosure will now be described in detail and with reference to exemplary embodiments, but the disclosure is not limited to the specific embodiments illustrated in the drawings and the appended claims.

[0028] [Detailed Description] Reference will now be made in detail to certain aspects and exemplary embodiments of the present application, examples of which are shown in the accompanying structures and drawings. Aspects of the present application are described in conjunction with exemplary embodiments, including methods, materials, and examples, and the description is non-limiting, and the scope of the present application is intended to encompass all equivalents, alternatives, and modifications commonly known or incorporated herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present application belongs. Those skilled in the art will recognize many techniques and materials similar or equivalent to those described herein, which can be used to implement aspects and embodiments of the present application. The described aspects and embodiments in the present application are not limited to the described methods and materials.

[0029] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0030] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such ranges are expressed, other embodiments include from one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each range are significant both in relation to the other endpoint and independently of the other endpoint. Additionally, it is understood that a number of values ​​are disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, when the value "10" is disclosed, "about 10" is also disclosed. Additionally, when a value is disclosed, it is understood that "less than or equal to that value," "more than or equal to that value," and possible ranges between the values ​​are also disclosed, as would be properly understood by a skilled artisan. For example, when the value "10" is disclosed, "less than or equal to 10" and "more than or equal to 10" are also disclosed.

[0031] I. Definition "Administration" means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administration by a medical professional and self-administration.

[0032] Administration of the compounds disclosed herein or pharma- ceutically acceptable salts thereof, or the additional therapeutic agents disclosed herein, can be via any of the accepted modes of administration for agents that serve similar utility, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, intravaginal, rectal, or ocular. Oral and parenteral administration are routine in the treatment of the indications that are the subject of the preferred embodiments.

[0033] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, and intracranial administration.

[0034] "In combination" or "combination" refers to a compound of formula (I) and at least one additional therapeutic agent that are substantially effective in the body at the same time. Both can be administered at substantially the same time, or both can be administered at different times but have an effect on the body at the same time. For example, "in combination" includes administering a compound of formula (I) before administering at least one additional therapeutic agent, and then administering at least one additional therapeutic agent while the function of the compound of formula (I) is substantially present in the body. Furthermore, "in combination" includes administering at least one additional therapeutic agent before administering a compound of formula (I), and then administering a compound of formula (I) while the function of the at least one additional therapeutic agent is substantially present in the body. When a pharmaceutical composition is described as comprising a compound of formula (I) in combination with at least one additional therapeutic agent, the term refers to both agents being present in the composition at the same time. The terms "concomitant" and "combination" may further relate to the advantageous use of compounds of formula (I) with at least one additional therapeutic agent in the absence of concomitant treatment of a liver disease, such as NAFLD or NASH.

[0035] "Active pharmaceutical ingredient" means the substance in a pharmaceutical composition that provides a desired therapeutic effect. The term "pharmaceutical acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the mammal being treated with the formulation.

[0036] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes any solvent, diluent, emulsifier, binder, buffer, dispersion medium, coating agent, antibacterial and antifungal agent, isotonic and absorption delaying agent, and the like, or any other compound known by a person skilled in the art to be useful in the preparation of pharmaceutical preparations. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition. In addition, various adjuvants as are commonly used in the art may be included. These and other such compounds are described in the literature, for example, in the Merck Index, Merck & Company, Rahway, NJ. Discussions regarding the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press.

[0037] "Unit dosage form" refers to a composition that contains an amount of compound suitable for single administration to a subject according to good medical practice.However, as described further below, the preparation of a single or unit dosage form does not mean that the dosage form is administered once a day or once per treatment course.

[0038] A "loading dose" refers to an initial administration of a compound in an amount that is higher than subsequent doses. "Maintenance administration" refers to a subsequent administration following a loading dose, which is administered later than the loading dose. Those skilled in the art will recognize that the dosage form or method of administration of the maintenance administration may be different from that used for the loading dose. In any of the embodiments disclosed herein, the maintenance administration may include administration of a unit dosage form at any administration schedule contemplated herein, including, but not limited to, once a month or multiple times a month, biweekly or multiple times every two weeks, once a week or multiple times a week, daily or multiple times a day. It is contemplated within the present disclosure that the administration period of the maintenance administration may incorporate a dosing rest period. The dosing rest period may occur immediately after administration of the loading dose or at any time during the administration period of the maintenance dose. As used herein, the administration period of the maintenance administration may be referred to as the "maintenance phase" of the treatment period.

[0039] The phrase "administration method" refers to the means by which a compound is administered to a subject. Thus, the phrase encompasses the dosage form (e.g., tablet, powder, solution, suspension, emulsion, aerosol, etc.) and the mechanism by which the dosage form is applied to a subject (e.g., by oral administration or injection, etc.). "Administration method" may further encompass the dose, dosage amount, and administration schedule by which the compound is administered to a subject. The phrase "treatment period" refers to the period beginning with administration of the first dosage and ending with administration of the last dosage, the length of which is determined by one skilled in the art of treating a particular disease.

[0040] The phrase "dose rest period" refers to a period of 24 hours or more during which no dosage is administered to a subject or a period of 24 hours or more during which a subject is administered a reduced dosage. "Fatty liver disease" and liver disorders include primary fatty liver disease, steatosis or nonalcoholic fatty liver (NAFL), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). Fatty liver disease is a condition in which large vacuoles of triglyceride fat accumulate in liver cells, typically by a process of steatosis (i.e., abnormal retention of lipids within the cells). The accumulation of fat may also be accompanied by progressive inflammation of the liver (hepatitis), called steatohepatitis. Given the contribution of alcohol, fatty liver disease may be called alcoholic steatosis or nonalcoholic fatty liver disease (NAFLD).

[0041] "Nonalcoholic fatty liver disease (NAFLD)" is a general term for a group of liver diseases that affect people who drink little or no alcohol. As the name suggests, the main feature of NAFLD is the accumulation of too much fat in liver cells. NAFLD is becoming increasingly common around the world, especially in Western countries. In the United States, it is the most common form of chronic liver disease, affecting about a quarter of the population. Some people with NAFLD also develop "nonalcoholic steatohepatitis (NASH)," a progressive form of fatty liver disease characterized by inflammation of the liver that can progress to advanced scarring (cirrhosis) and liver failure. This damage is similar to the damage caused by heavy alcohol consumption.

[0042] As used herein, "subject" 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 a non-human primate selected for treatment or therapy.

[0043] By "suspected subject" is meant a subject who exhibits one or more clinical indicators of a disease or condition. By "subject in need thereof" is meant a subject identified as in need of therapy or treatment.

[0044] II. Pharmaceutical Compositions One aspect of the present application is a method for the preparation of a compound of formula (I)

[0045] [ka] and 3 parts by weight to 90 parts by weight of a polymeric material; wherein the compound of formula (I) is present in the pharmaceutical composition at a supersaturated concentration. The pharmaceutical composition is stable at room temperature for extended periods of time.

[0046] In some embodiments, the pharmaceutical composition is in the form of an amorphous solid dispersion prepared by hot melt extrusion, wherein the pharmaceutical composition spontaneously forms nanomicelles, wherein the compound of formula (I) distributes into the hydrophobic compartment of the nanomicelles due to the water-insolubility and high lipid solubility of the compound of formula (I), thus maintaining a stable supersaturated concentration in the pharmaceutical composition.

[0047] In some embodiments, the compound of formula (I) is formulated in a stabilized formulation that allows the compound of formula (I) to be stored at a stable supersaturated concentration at room temperature for at least 3 months, 4 months, 5 months, or 6 months.

[0048] In some embodiments, the pharmaceutical composition comprises, in parts by weight, 1 part of a compound of formula (I) and 9-15, 9-20, 9-25, 9-30, 9-35, 9-40, 15-20, 15-25, 15-30, 15-35, 15-40, 15-45, 20-25, 20-30, 20-35, 20-40, 20-45, 25-30, 25-35, 25-40, 25-45, 30-35, 30-40, 35-45, 35-40, 35-45, or 40-45 parts of polymeric material.

[0049] In some embodiments, the polymeric material comprises one or more polymers selected from the group consisting of polyvinyl lactam polymers, cellulosic polymers, polyacrylics, polyethylene glycols, polyoxyethylenes, and polyvinyl alcohols.

[0050] In some embodiments, the polymeric material comprises one or more polyvinyl lactam polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone (PVP / VA), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®). In some embodiments, the polymeric material comprises polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the polymeric material consists of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0051] In some embodiments, the polymeric material comprises one or more cellulosic polymers selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl hydroxyethyl cellulose (MHEC), hydroxypropyl methylcellulose succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMCP), and cellulose acetate phthalate (CAP).

[0052] In some embodiments, the polymeric material comprises one or more polyacrylic resins selected from the group consisting of methacrylic acid copolymers, methacrylic acid-ethyl acrylate copolymers, aminomethacrylic acid copolymers, and methacrylate copolymers.

[0053] In some embodiments, the pharmaceutical composition further comprises one or more non-polymeric materials, hi some embodiments, the pharmaceutical composition further comprises one or more non-polymeric materials selected from the group consisting of pharma- ceutically acceptable pharmaceutical excipients, non-volatile weak acids, neutral or weakly acidic inorganic substances, and pharma- ceutically acceptable excipients having a melting point below 80° C.

[0054] In some embodiments, the pharmaceutical composition may comprise a lipid material, such as triethyl citrate, acetylated triethyl citrate, propylene glycol biskwai esters, medium chain triglycerides, monoglycerides, monooleate, diethylene glycol monoethyl ether, hydrogenated castor oil, myristyl alcohol, hexadecanol, stearyl alcohol, palmitic acid, palmitoyl alcohol, 2,6-di-tert-butyl-p-cresol, vitamin E, poloxamer 188, poloxamer 407, polyethylene glycol 15-hydroxystearate (Kolliphor® HS 15), sodium dodecyl sulfate, propylene glycol monooleate ... cutanoate, polyethylene glycol oleate (Labrafac™ lipophilic WL1349), propylene glycol monolaurate, lauric acid polyglycerol ester (Gelucire® 44 / 14), stearic acid polyglycerol ester (Gelucire® 50 / 13), caprylic acid polyglycerol ester (Labrasol®), sorbitan fatty acid ester polyoxyethylene ether (Tween), sorbitan fatty acid ester (Span), and Vitamin E polyglycol succinate®.

[0055] In some embodiments, the pharmaceutical composition comprises 1 part by weight of a compound of formula (I) and 17-27, 19-25, 21-23 parts by weight of a polymeric material, in some embodiments, the polymeric material comprises a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0056] In some embodiments, the pharmaceutical composition comprises 1 part by weight of a compound of formula (I) and 28-38, 30-36, 32-34 parts by weight of a polymeric material. In some embodiments, the polymeric material comprises polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the pharmaceutical composition further comprises 0.2-5 parts of triethyl citrate. In some embodiments, the pharmaceutical composition further comprises 1 part of triethyl citrate.

[0057] In some embodiments, the pharmaceutical composition is free of other non-polymeric materials. In some embodiments, the compound of formula (I) is prepared by spray drying, solvent evaporation, or hot melt extrusion. In some embodiments, the compound of formula (I) is prepared by spray drying, or hot melt extrusion. In some embodiments, the compound of formula (I) is prepared by hot melt extrusion.

[0058] In some embodiments, the compound of formula (I) is present in the pharmaceutical compositions of the present application in a crystalline form, an amorphous form, or a partially crystalline / partially amorphous form. In some embodiments, the amorphous form of the compound of formula (I) is present in the pharmaceutical composition of the present application in an amount of 50% by weight or greater of the total amount of the compound of formula (I).

[0059] In some embodiments, the amorphous form of the compound of formula (I) is present in the pharmaceutical composition of the present application in an amount of 80% by weight or greater of the total amount of the compound of formula (I). In some embodiments, the amorphous form of the compound of formula (I) is present in the pharmaceutical composition of the present application in an amount of 90% by weight or greater of the total amount of the compound of formula (I).

[0060] In some embodiments, the pharmaceutical compositions of the present application further comprise one or more pharma- ceutically acceptable excipients, such as diluents, adhesives, disintegrants, lubricants, and the like.

[0061] Exemplary substances which can function as pharma- ceutically acceptable excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents; stabilizers; antioxidants; preservatives, pyrogen-free water, isotonic saline; and phosphate buffer solutions.

[0062] 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 a single administration to a subject in accordance with good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of treatment. A unit dosage form may include a single daily dose, or a fractional sub-dose, where multiple unit dosage forms would be administered during a day to complete a daily dose. In accordance with the present disclosure, a unit dosage form may be administered more or less than once per day, and may be administered multiple times during a treatment period. The dosage forms may be administered in any manner consistent with their formulation, including orally, parenterally, or as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours).

[0063] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, tablet crushed, enteric coated, sugar coated, film coated, or compressed multiple times, and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, and contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0064] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also include one or more components, such as the sweeteners, flavorings, and colorings disclosed above.

[0065] The compositions may be coated by conventional methods, typically with a pH or time dependent coating, so that the active agent is released in the gastrointestinal tract near the desired site of topical application, or at various times to prolong the desired effect. The dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes, and shellac.

[0066] In some embodiments, the pharmaceutical compositions of the present application may optionally contain one or more other active agents. In some embodiments, the pharmaceutical composition of the present application is in the form of particles or powder. In some embodiments, the pharmaceutical composition of the present application is processed into a capsule or tablet, or formulated into particles or granules and packaged in a bag, or processed into a suspension.

[0067] III.Preparation method Another aspect of the present application relates to a process or method for preparing the pharmaceutical composition of the present application. In some embodiments, the process or method comprises the steps of spray drying, solvent evaporation, or hot melt extrusion, extruding a pre-extrusion mixture comprising, by weight, (1) 1 part of a compound of formula (I), and (2) 3 to 90 parts of a polymeric material by hot melt extrusion to form an extrusion product, wherein the compound of formula (I) maintains a supersaturated concentration in the extrusion product at room temperature.

[0068] In some embodiments, the process or method includes extruding a pre-extrusion mixture comprising, by weight, (1) 1 part of a compound of formula (I), and (2) 3 to 90 parts of a polymeric material by hot melt extrusion to form an extrusion product, wherein the compound of formula (I) maintains a supersaturated concentration in the extrusion product at room temperature. In some embodiments, the extrusion step is performed at an extrusion temperature of 80°C to 140°C or 90°C to 130°C.

[0069] In some embodiments, the pre-extrusion mixture comprises, in parts by weight, 1 part of a compound of formula (I) and 9-15, 9-20, 9-25, 9-30, 9-35, 9-40, 9-45, 15-20, 15-25, 15-30, 15-35, 15-40, 15-45, 20-25, 20-30, 20-35, 20-40, 20-45, 25-30, 25-35, 25-40, 25-45, 30-35, 30-40, 35-45, 35-40, 35-45, or 40-45 parts of a polymeric material.

[0070] In some embodiments, the polymeric material comprises one or more polymers selected from the group consisting of polyvinyl lactam polymers, cellulosic polymers, polyacrylics, polyethylene glycols, polyoxyethylenes, and polyvinyl alcohols.

[0071] In some embodiments, the polymeric material comprises one or more polyvinyl lactam polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone (PVP / VA), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®). In some embodiments, the polymeric material comprises polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the polymeric material consists of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0072] In some embodiments, the polymeric material comprises one or more cellulosic polymers selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl hydroxyethyl cellulose (MHEC), hydroxypropyl methylcellulose succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMCP), and cellulose acetate phthalate (CAP).

[0073] In some embodiments, the polymeric material comprises one or more polyacrylic resins selected from the group consisting of methacrylic acid copolymers, methacrylic acid-ethyl acrylate copolymers, aminomethacrylic acid copolymers, and methacrylate copolymers.

[0074] In some embodiments, the pre-extrusion mixture further comprises one or more non-polymeric materials, hi some embodiments, the pre-extrusion mixture further comprises one or more non-polymeric materials selected from the group consisting of pharma- ceutically acceptable pharmaceutical excipients, non-volatile weak acids, neutral or weakly acidic inorganic substances, and pharma- ceutically acceptable excipients having a melting point below 80° C.

[0075] In some embodiments, the pre-extrusion mixture may contain a lipid material, such as triethyl citrate, acetylated triethyl citrate, propylene glycol biskwai esters, medium chain triglycerides, monoglycerides, monooleate, diethylene glycol monoethyl ether, hydrogenated castor oil, myristyl alcohol, hexadecanol, stearyl alcohol, palmitic acid, palmitoyl alcohol, 2,6-di-tert-butyl-p-cresol, vitamin E, poloxamer 188, poloxamer 407, polyethylene glycol 15-hydroxystearate (Kolliphor® HS 15), sodium dodecyl sulfate, propylene glycol mono and one or more pharma- ceutically acceptable excipients having a melting point of less than 80° C. selected from the group consisting of polyglycerol esters of lauric acid (Gelucire® 44 / 14), polyglycerol esters of stearic acid (Gelucire® 50 / 13), polyglycerol esters of caprylic acid (Labrasol®), sorbitan fatty acid ester polyoxyethylene ethers (Tween), sorbitan fatty acid esters (Span), and Vitamin E polyglycol succinate®.

[0076] In some embodiments, the pre-extrusion mixture comprises 1 part by weight of a compound of formula (I) and 17-27, 19-25, 21-23 parts by weight of a polymeric material. In some embodiments, the polymeric material comprises a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0077] In some embodiments, the pre-extrusion mixture comprises 1 part by weight of a compound of formula (I) and 28-38, 30-36, 32-34 parts by weight of a polymeric material. In some embodiments, the polymeric material comprises a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the pre-extrusion mixture further comprises 0.2-5 parts of triethyl citrate. In some embodiments, the pharmaceutical composition further comprises 1 part of triethyl citrate.

[0078] In some embodiments, the pre-extrusion mixture does not include other non-polymeric materials. In some embodiments, the compound of formula (I) maintains a supersaturated concentration in the extrusion product for at least 3 months, 4 months, 5 months, or 6 months at room temperature.

[0079] In some embodiments, the extrusion product is ground or chopped into particles or powder. In some embodiments, the particles or powder are packaged in a capsule or sachet or compressed into a tablet. In some embodiments, the particles or powder are packaged in a hydroxypropyl methylcellulose capsule.

[0080] The advantage of the methods and formulations disclosed herein is that the prepared pharmaceutical composition can prolong the time of maintaining the supersaturated concentration of the compound of formula (I) by forming nanomicelles, thus providing a more stable dissolution of the active ingredient in the pharmaceutical composition.

[0081] IV. Treatment method Another aspect of the present application provides a method of lowering low density lipoprotein and triglyceride levels, reducing lipotoxicity, improving liver function, and reducing liver fat using the pharmaceutical composition of the present application, the method comprising administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of the present application.

[0082] Another aspect of the present application relates to a method of treating or ameliorating symptoms of non-alcoholic steatohepatitis (NASH), comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition of the present application.

[0083] In some embodiments, the subject has fatty liver disease, or a fibrotic and / or inflammatory disease affecting the liver. In some embodiments, the subject has secondary fatty liver disease, such as alcoholic liver disease (ALD), fatty liver associated with chronic hepatitis infection, total parenteral nutrition (TPN), Reye's syndrome, and the like, as well as gastrointestinal disorders, such as intestinal bacterial overgrowth (IBO), gastroparesis, irritable bowel (IBS) disorders, and the like.

[0084] In certain preferred embodiments, the disease to be treated using the compositions described herein is liver fibrosis, such as fatty liver, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), and hepatocellular carcinoma (HCC).

[0085] In some embodiments, the subject to be treated has NAFLD. In some embodiments, the subject has diabetes. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject is type 1 diabetes. In certain embodiments, the subject with NAFLD has type 2 diabetes mellitus (T2DM). In other embodiments, the subject with NAFLD has metabolic syndrome (MS).

[0086] In some embodiments, the subject has a metabolic disease or disorder.Exemplary metabolic diseases or disorders for treatment with the compositions of the present application include diabetes, metabolic syndrome, obesity, hyperlipidemia, hypercholesterolemia, arteriosclerosis, hypertension, NASH, NAFL, NAFLD, hepatic steatosis, and any combination thereof.

[0087] In some embodiments, the subject has metabolic syndrome (MS). In some embodiments, the subject has one or more of these diseases or disorders. In some embodiments, the subject is at risk of developing one or more of these diseases.

[0088] In some embodiments, the subject has insulin resistance, elevated blood glucose concentrations, high blood pressure, elevated cholesterol levels, elevated triglyceride levels, or is obese.

[0089] In some embodiments, the subject has polycystic ovary syndrome. In some embodiments, the patient being treated is at risk of developing liver fibrosis or cirrhosis.

[0090] In some embodiments, the fibrosis comprises non-cirrhotic liver fibrosis. In some embodiments, the liver fibrosis is advanced. In some embodiments, the disease affects tissues selected from the group consisting of liver, kidney, skin, epidermis, endothelium, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testes, penis, ovaries, adrenal glands, arteries, veins, colon, intestine (such as the small intestine), biliary tract, soft tissue (such as the mediastinum or retroperitoneum), bone marrow, joints, and stomach fibrosis, particularly liver, gut, lung, heart, kidney, muscle, skin, soft tissue, bone marrow, intestinal, eye, and joint fibrosis.

[0091] In some embodiments, the disease is a metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, infectious pathogen-induced liver disease, inflammatory liver disease, immune system dysfunction-mediated liver disease, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathy, such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel disease, clopidogrelosis, and the like. ulcerative colitis, keloids, old myocardial infarction, scleroderma / systemic sclerosis, inflammatory diseases, neurodegenerative diseases, cancer, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, meningiomas associated with neurofibromatosis, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative / myelodysplastic disorders, mastocytosis, dermatofibrosarcoma, solid tumors, such as breast, lung, thyroid, or colorectal cancer, prostate cancer, liver fibrosis or cirrhosis of any cause, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis Cirrhosis, drug-induced liver fibrosis or cirrhosis, infectious pathogen-induced liver fibrosis or cirrhosis, parasitic infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV infection-induced liver fibrosis or cirrhosis, HCV infection-induced liver fibrosis or cirrhosis, HIV infection-induced liver fibrosis or cirrhosis, HCV and HIV dual infection-induced liver fibrosis or cirrhosis, radiotherapy or chemotherapy-induced fibrosis or cirrhosis, biliary fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, intestinal fibrosis of any etiology fibrosis, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestinal (e.g. small intestine) fibrosis, colonic fibrosis, gastric fibrosis, skin fibrosis, epidermal fibrosis, endothelial fibrosis, skin fibrosis due to scleroderma / systemic sclerosis, pulmonary fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway disease such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, renal fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue (e.g. mediastinal or retroperitoneal) fibrosis, bone marrow fibrosis, arthrofibrosis, tendon fibrosis, cartilage fibrosis, pancreatic fibrosis, uterine fibrosis, nervous system fibrosis, testicular fibrosis,ovarian fibrosis, adrenal fibrosis, arterial fibrosis, venous fibrosis, ocular fibrosis, endocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal workers' pneumoconiosis), proliferative fibrosis, neoplastic fibrosis, peri-implant fibrosis and asbestosis, arthrofibrosis, adhesive capsulitis.

[0092] In some embodiments, the disease is metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, infectious pathogen-induced liver disease, inflammatory liver disease, immune system dysfunction-mediated liver disease, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathy, e.g., primary cirrhosis, Primary cholangitis (PSC), primary biliary cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, colorectal cancer, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or is liver cirrhosis, infectious pathogen-induced liver fibrosis or cirrhosis, parasitic infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV infection-induced liver fibrosis or cirrhosis, HCV infection-induced liver fibrosis or cirrhosis, HIV infection-induced liver fibrosis or cirrhosis, HCV and HIV co-infection-induced liver fibrosis or cirrhosis, radiotherapy- or chemotherapy-induced fibrosis or liver cirrhosis, biliary fibrosis, liver fibrosis or liver cirrhosis due to any chronic cholestatic disease, intestinal fibrosis of any etiology, Crohn's disease induced fibrosis, ulcerative colitis induced fibrosis, intestinal (e.g. small intestine) fibrosis, colonic fibrosis, gastric fibrosis, pulmonary fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway diseases such as COPD, asthma, emphysema, smoker's lung, tuberculosis, etc., pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF).

[0093] The methods described herein may be used in any of a variety of forms suitable for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. Those skilled in the art will understand that oral and nasal compositions include compositions administered by inhalation and prepared using available methods. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Any pharmaceutically active material may be included, and any pharmaceutically active material does not substantially interfere with the activity of the compound. The amount of carrier used in combination with the compound is sufficient to provide the actual amount of the material for administration per unit dose of the compound. Techniques and compositions for preparing dosage forms useful in the methods described herein are described, for example, in Modern Pharmaceutics, 4th ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al, Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th ed. (2004).

[0094] In some embodiments, the method further comprises administering to the subject an effective amount of an additional therapeutic agent. In various embodiments, the additional therapeutic agent is selected from the group consisting of one or more of a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, an antidiabetic agent, an antifibrotic compound, an antioxidant, an anti-inflammatory compound, a lipid-lowering agent, a fish oil derivative, an analogue thereof, a pegylated variant thereof, or any combination of the foregoing.

[0095] In other embodiments, the additional therapeutic agent is selected from the group consisting of one or more of a fibrate, a bile acid receptor modulator, an anti-inflammatory compound, an anti-fibrotic compound, a GLP-1 (glucagon-like peptide-1) agonist, a metabolic regulator, a fish oil derivative, a diacylglycerol acyltransferase (DGAT) inhibitor, or any combination of the foregoing.

[0096] In another embodiment, the additional therapeutic agent is an agent that increases insulin secretion. In another example, the additional therapeutic agent is an agent that increases the sensitivity of a target cell, tissue, or organ to insulin. In another example, at least one additional therapeutic agent is an agent that lowers blood glucose levels.

[0097] In another embodiment, the at least one additional therapeutic agent is insulin or an insulin analog. In a further embodiment, the insulin or insulin analog is selected from Humulin R, insulin lispro (Humalog), insulin aspart (Novolog), insulin glulisine (Apidra), prompt insulin zinc (Semilente), insulin glargine (Lantus), insulin detemir (Levemir), isophane insulin, insulin zinc (Lente), long-acting insulin zinc (Ultralente), insulin degludec, Exubera, and Afrezza.

[0098] In other embodiments, the additional therapeutic agent is an inhibitor of ATP-sensitive K+ channels in pancreatic beta cells. In further embodiments, the at least one additional therapeutic agent is a sulfonylurea. In further embodiments, the sulfonylurea is selected from the group consisting of tolbutamide (Orinase®), acetohexamide (Dymelor), tolazamide (Tolinase®), chlorpropamide (Diabinese®), carbutamide (Glucidoral®), metahexamide, glipizide (Glucotrol®), glyburide or glibenclamide (Micronase®), glycopyramide, gliquidone (Glurenorm), gliclazide (Uni Diamicron), glibornuride, glisoxepide, glimepiride (Amaryl®), and JB253 (Broichhagen et al., Nature 2003, 144:1311-1325). Comm. 5, Article No. 5116 (2014)). In another further embodiment, the at least one additional therapeutic agent is selected from meglitinide, repaglinide (Prandin®), nateglinide (Starlix®), mitiglinide, and linoglilide.

[0099] In other embodiments, the additional therapeutic agent is an agonist of FFA1 / GPR40 (free fatty acid receptor 1). In further embodiments, the FFA1 / GPR40 agonist is fasiglifam.

[0100] In another embodiment, the additional therapeutic agent is an incretin mimetic. In a further embodiment, the incretin mimetic is glucagon-like peptide-1 (GLP-1) or an agonist of its GLP-1 receptor. In a further embodiment, the GLP-1 receptor agonist is selected from exenatide / exendin-4, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, BRX-0585 (Pfizer / Biorexis), and CJC-1 134-PC (exendin-4 conjugated to human albumin). In another further embodiment, the incretin mimetic is gastric inhibitory peptide (GIP) or a GIP analog.

[0101] In other embodiments, the additional therapeutic agent is an inhibitor of dipeptidyl peptidase-4 (DPP-4, also known in the art as DPP-IV). In further examples, the DPP-4 inhibitor is selected from vildagliptin (Galvus®), sitagliptin (Januvia®), saxagliptin (Onglyza®), linagliptin (Tradjenta®), alogliptin, septagliptin, anagliptin, gemigliptin, teneligliptin, carmegliptin, gosogliptin, dutogliptin, berberine, and lupeol.

[0102] In other embodiments, the additional therapeutic agent is a human peroxisome proliferator-activated receptor (PPAR) gamma agonist. In further embodiments, the PPAR gamma agonist is selected from a thiazolidinedione and a glitazone, such as rosiglitazone, troglitazone, pioglitazone, englitazone, balaglitazone, rivoglitazone, ciglitazone, lobeglitazone, and netoglitazone.

[0103] In other embodiments, the additional therapeutic agent is a biguanide. In further embodiments, the biguanide is selected from metformin, buformin, and phenformin.

[0104] In other embodiments, the additional therapeutic agent is a bile acid adsorbent, hi further examples, the bile acid adsorbent is selected from an anion exchange resin, a quaternary amine (e.g., cholestyramine or colestipol), and an ileal bile acid transporter inhibitor.

[0105] In other embodiments, the additional therapeutic agent is an agent that enhances glucose metabolism (e.g., glucose phosphorylation). In one embodiment, at least one additional therapeutic agent is a glucokinase activator. In a further embodiment, the glucokinase activator is a compound described in WO2000 / 058293.

[0106] In another embodiment, the additional therapeutic agent is an agent that inhibits renal reabsorption of glucose. In one embodiment, the at least one additional therapeutic agent is an SGLT-2 inhibitor. In a further embodiment, the SGLT-2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, remogliflozin, sergliflozin, tofogliflozin, ipragliflozin, and ertugliflozin.

[0107] In another embodiment, the additional therapeutic agent is an agent that reduces glucose absorption in the intestine. In one embodiment, the at least one additional therapeutic agent is an alpha-glucosidase inhibitor. In a further embodiment, the alpha-glucosidase inhibitor is selected from miglitol (Glyset®), acarbose (Precose®), and voglibose.

[0108] In other embodiments, the additional therapeutic agent is an agent that slows gastric emptying and / or suppresses glucagon. In one embodiment, the at least one additional therapeutic agent is amylin or an amylin analog. In a further embodiment, the amylin analog is pramlintide.

[0109] In other embodiments, the additional therapeutic agent is a microsomal triglyceride transfer protein (MTP) inhibitor, hi further embodiments, the MTP inhibitor is selected from midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, and fluparoxan.

[0110] In other embodiments, the additional therapeutic agent is selected from bromocriptine, benfluorex, and tolrestat. In other embodiments, the additional therapeutic agent is a bile acid FXR agonist, including obeticholic acid (OCA) and INT-767. Non-bile acid FXR agonists include cilobexol (GS-9674), tropifexol (LJN-452), nidufexol (LMB763), and EDP-305. Additional FXR agonists include analogs, pegylated variants, and combinations of the aforementioned FXR agonists.

[0111] In other embodiments, the additional therapeutic agent is a PPAR agonist, including but not limited to GW9578, GW7647, GW590735, and GFT505. PPAR agonists include PPAR-alpha (PPAR-α) agonists, PPAR-gamma (PPAR-γ) agonists, PPAR-epsilon (PPAR-δ) agonists, dual PPAR-α / γ agonists, dual PPAR-α / δ agonists, and pan-PPAR agonists that target all three PPAR isozymes (i.e., α / β / γ). Exemplary PPAR-α agonists include bezafibrate, fenofibrate, pemafibrate, gemfibrozil, clofibrate, and omega-3 polyunsaturated fatty acids (Ω-PUFAs), such as Omacor. PPAR-gamma agonists include, but are not limited to, pioglitazone, lobeglitazone, rosiglitazone, INT131, MSDC-0602K, and GW501516. Exemplary PPAR-delta agonists are seradelpar, GW501516, an exemplary dual PPAR alpha / gamma agonist is saroglitazar, an exemplary dual PPAR-alpha / delta agonist is elafibranor, and exemplary pan-PPAR agonists include lanifibranor, netoglitazone, GW677964, DRL-605, and GW25019. Additional PPAR agonists include analogs, pegylated variants, and combinations of the aforementioned PPAR agonists.

[0112] In other embodiments, the additional therapeutic agent is a fibrate, including, but not limited to, fenofibrate, fenofibric acid, gemfibrozil, clofibrate, pemafibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, ABT-335, etofibrate, pirifibrate, beclofibrate, analogs thereof, pegylated variants thereof, and combinations thereof.

[0113] In other embodiments, the additional therapeutic agent is a GLP-1 (glucagon-like peptide-1) agonist, including, but not limited to, dulaglutide, exenatide, liraglutide, albiglutide, lixisenatide, semaglutide, insulin glargine, artificial analogs thereof, pegylated variants thereof, and combinations thereof.

[0114] In other embodiments, the additional therapeutic agent is a metabolic modulator, including, but not limited to, thyroid hormone receptor agonists, selective androgen receptor modulators, mitochondrial membrane transport protein modulators, selective estrogen receptor modulators, stearoyl-CoA desaturase 1 (SCD1) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, inhibitors of sodium glucose cotransporter 1 and / or 2 (SGLT1, SGLT2, or dual SGLT1 / SGLT2 inhibitors), recombinant fibroblast growth factor 19 (FGF19), recombinant fibroblast growth factor 21 (FGF21), artificial analogs thereof, pegylated variants thereof, and combinations thereof.

[0115] In other embodiments, the additional therapeutic agent is a fish oil derivative and an omega-3 fatty acid ethyl ester, such as ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate, ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate, ethyl (72,10Z,13Z,16Z,19Z)-docosapentaenoate, ethyl hexadecatrienoate, alpha -Omega-3-fatty acid alkyl esters including, but not limited to, linolenic acid ethyl ester, ethyl (6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoate, ethyl eicosatrienoate, ethyl eicosatetraenoate, ethyl heneicosapentaenoate, ethyl eicosapentaenoate, ethyl heneicosapentaenoate, ethyl tetracosapentaenoate, and herbicidal ethyl ester. In another embodiment, the fish oil derivative is an omega-3 fatty acid triglyceride.

[0116] In other embodiments, the additional therapeutic agent is a diacylglycerol acyltransferase (DGAT) inhibitor, including but not limited to, compounds disclosed in US Pat. No. 8,962,618.

[0117] In other embodiments, the additional therapeutic agent is an antidiabetic agent, including, but not limited to, dulaglutide, semaglutide, exenatide, liraglutide, albiglutide, lixisenatide, semaglutide, insulin glargine, incretin hormone agonists including glucagon-like peptide 1 receptor agonists (GLP-1RA), including glucagon (GCG) and its agonists, and glucose-dependent insulinotropic polypeptide (GIP) agonists; dipeptidyl peptidase 4 (DPP4) inhibitors including sitagliptin and vildagliptin; inhibitors of sodium glucose cotransporter 1 and / or 2 (SGLT1, SGLT2, and dual SGLT1 / SGLT2 inhibitors); oral insulin, and dual or triple agonists thereof. SGLT2 inhibitors include dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, luseogliflozin, licogliflozin (LIK066; dual SGLT1 / 2). An exemplary GLP-1 / GCG receptor dual agonist is cotadutide (MEDI0382). An exemplary GLP-1 / GIP receptor dual agonist includes CT868 and trizepatide (LY3298176). An exemplary GLP-1 / GCG / GIP triple agonist is HM15211. An exemplary dual GLP-1 / FGF21 agonist is YH25724. Additional antidiabetic drugs include metformin, pioglitazone, and rosiglitazone, as well as analogs, pegylated variants, and combinations of the aforementioned antidiabetic drugs.

[0118] In some embodiments, the additional therapeutic agent is a CCR2 and / or CCR5 antagonist, such as cenicriviroc (a dual CCR2 / CCR5 antagonist); an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, such as selonsertib; angiotensin receptor blockers (ARBs), such as losartan; transforming growth factor beta (TGF-β) inhibitors, such as galunisertib; fibroblast growth factor 19 (FGF19) and FGF19 analogs, such as NGM282; FGF21 and FGF21 analogs, such as pegbelfermin (BMS-986036), PF-05231023, AKR-001, and BI O89-100, etc.; agonist anti-FGFR1c / KLB antibodies, such as NGM313 (MK-3655) and BFKB8488A, etc.; Takeda G protein-coupled receptor 5 (TGR5) activators, such as INT-777, etc.; RDX8940; galectin 3 antagonists, such as Verapectin (GR-MD-02), and GB1211, etc.; Hsp47 antagonists, such as ND-LO2-s0201 siRNA, etc.; anti-lysyl oxidase-like 2 (LOXL-2) mAbs, such as simtuzumab, etc.; IL-11 inhibitors, as well as their analogs, pegylated variants, and combinations thereof.

[0119] In other embodiments, the additional therapeutic agent is a receptor tyrosine kinase inhibitor (RTKI), such as nintedanib and sorafenib; angiotensin II (AT1) receptor blockers, connective tissue growth factor (CTGF) inhibitors, or activators of the latent TGF.beta complex, such as, for example, MMP2, MMP9, THBS1, or cell surface integrins, TGF-β receptor type I (TGFBRI) or type II (TGFBRII), and their ligands, such as TGF-β, activin, inhibin, nodal, anti-Mullerian hormonal inhibitors, and / or activators of the latent TGF.beta complex, such as, for example, MMP2, MMP9, THBS1, or cell surface integrins, TGF-β receptor type I (TGFBRI) or type II (TGFBRII), and their ligands, such as, for example, ... anti-Mullerian hormonal inhibitors, and / or activators of the latent TGF.beta complex, such as, for example, MMP2, MMP9, THBS1, anti-Mullerian hormonal inhibitors, and / or activators of the latent TGF.beta. complex, such as, for example, MMP2, MMP9, THBS1, anti-Mullerian hormonal Antifibrotic compounds that may interfere with TGF.beta and BMP activation pathways, including mons, GDFs, and BMPs; auxiliary coreceptors (also known as type III receptors); components of SMAD-dependent canonical pathways, including regulatory or inhibitory SMAD proteins; members of SMAD-independent or non-canonical pathways, including various branches of MAPK signaling, TAK1, Rho-like GTPase signaling pathways, phosphatidylinositol-3 kinase / AKT pathways, and TGF-β-induced epithelial-mesenchymal transition (EMT) steps; Hh ligases. canonical and non-canonical hedgehog signaling pathways, including those affected by TGF-β signaling; canonical and non-canonical wingless (wnt) and notch signaling pathway inhibitor members, including those affected by TGF-β signaling; pirfenidone; nintedanib; collagenases, such as Clostridium histolyticum collagenase; steroids (such as corticosteroids, such as prednisone); BMP9 and / or BMP10 antagonists; immunosuppressants and / or anti-inflammatory agents, such as gamma interferon. , cyclophosphamide, azathioprine, methotrexate, penicillamine, cyclosporine, colchicine, antithymocyte globulin, mycophenolate mofetil, and hydroxychloroquine; calcium channel blockers (e.g., nifedipine); para-aminobenzoic acid (PABA); dimethyl sulfoxide; pan-caspase inhibitors; TGF-β signaling modifiers, such as relaxin, SMAD7, HGF, and BMP7, as well as TGF-β1, TGF-βRI, TGF-βRII, EGR-1, and CTGF inhibitors;Cytokines and cytokine receptor antagonists (IL-1β, IL-5 inhibitors of IL-6, IL-13, IL-21, IL-4R, IL-13Rα1, GM-CSF, TNFα, oncostatin M, WISP-1, and PDGF), cytokines and chemokines, such as IFN-γ, IFN-α / β, IL-12, IL-10, HGF, CXCL10, and CXCL11; chemokine antagonists, including inhibitors of CXCL1, CXCL2, CXCL12, CCL2, CCL3, CCL6, CCL17, and CCL18; chemokine receptor agonists, including inhibitors of CCR2, CCR3, CCR5, CCR7, CXCR2, and CXCR4; TLR antagonists, including inhibitors of TLR3, TLR4, and TLR9; angiogenesis antagonists, such as VEGF-specific antibodies and adenosine deaminase replacement therapy; beta-blockade anti-fibrotic agents selected from the group consisting of antihypertensive agents, including inhibitors of ANGII, angiotensin converting enzyme (ACE), and aldosterone; vasoactive agents, such as ET-1 receptor antagonists and bocetan; inhibitors of enzymes that synthesize and process collagen, including inhibitors of prolyl hydroxylases; B-cell antagonists, such as rituximab; integrin / adhesion molecule antagonists that inhibit α1β1 and αvβ6 integrins, and inhibitors of integrin linked kinases; antibodies and small molecule inhibitors against ICAM-1 or VCAM-1; pro-apoptotic agents that target myofibroblasts; MMP inhibitors against MMP2, MMP9, or MMP12; antibodies and small molecule inhibitors against TIMP-1;

[0120] In other embodiments, the additional therapeutic agent is an antioxidant, including, but not limited to, vitamin E, glutathione (GSH), L-glutamyl-L-cysteinyl-glycine, ursodeoxycholic acid (UDCA), resveratrol, silymarin, metadoxine, and analogs, pegylated variants, and combinations thereof.

[0121] In other embodiments, the additional therapeutic agent is an anti-inflammatory compound, such as a phosphodiesterase (PDE) inhibitor and / or a tumor necrosis factor alpha (TNF-α) inhibitor, such as pentoxifylline (PTX); L-carnitine; selonsertib; tipelukast; vitamin D3; G protein-coupled receptor 84 (GRP84); ursodeoxycholic acid (UDCA); vascular adhesion protein-1 (VAP-1) / semicarbazide-sensitive amine oxidase (SSAO) inhibitor, such as BI1467335 (PXS-4728A), LJP-1586, and LJP-1207; caspase inhibitors, such as emricasan and GS-9450; Toll-like receptor (TLR)-4 antagonists, such as JKB-121; nucleotide binding and oligomerization domains. (NOD)-like receptor (NLR) inhibitors, such as NLR family pyrin domain containing 3 (NLRP3) inhibitors, MCC950, and the like; JAK / STAT inhibitors; glucocorticoids, NSAIDs, cyclophosphamide, nitrosoureas, folic acid analogs, purine analogs, pyrimidine analogs, methotrexate, azathioprine, mercaptopurine, cyclosporine, myriocin, tacrolimus, sirolimus, mycophenolic acid derivatives, fingolimod, and other sphingosine-1-phosphate receptor modulators, monoclonal and / or polyclonal antibodies against targets such as proinflammatory cytokines and proinflammatory cytokine receptors, T cell receptors, and integrins, analogs thereof; pegylated variants thereof, and combinations thereof.

[0122] In other embodiments, the additional therapeutic agent is a lipid lowering agent, such as ezetimibe; HMG-CoA reductase inhibitors (statins), including lipophilic statins, such as, for example, atorvastatin, simvastatin, lovastatin, and fluvastatin, and hydrophilic statins, such as, for example, rosuvastatin, pravastatin, and pitavastatin; stearoyl-CoA desaturase 1 (SCD-1) inhibitors, such as, for example, the compounds of Formula I; acetyl-CoA carboxylase ( Examples of suitable anti-inflammatory drugs include, but are not limited to, ACE inhibitors, such as GS-0976, PF-05221304, PF-05175157, NDI-010976, filsocostat, ND-630, ND-654, and the like; diacylglycerol O-acyltransferase-2 (DGAT-2) inhibitors, such as PF-06865571 and IONIS-DGAT2rx, and the like; fatty acid synthase (FAS) inhibitors, such as TVB-2640 and FT-4101, and the like.

[0123] In other embodiments, the additional therapeutic agent is a fish oil derivative, such as, for example, ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate, ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate, ethyl (72,10Z,13Z,16Z,19Z)-docosapentaenoate, ethyl hexadecatrienoate, ethyl alpha-linolenate ... In another embodiment, the fish oil derivative is an omega-3 fatty acid triglyceride, including, but not limited to, omega-3 fatty acid alkyl esters, including ethyl (6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoate, ethyl eicosatrienoate, ethyl eicosatetraenoate, ethyl heneicosapentaenoate, ethyl eicosapentaenoate, ethyl heneicosapentaenoate, ethyl tetracosapentaenoate, and herbicidal ethyl ester.

[0124] In other embodiments, the additional therapeutic agent is aramchol (3-arachidylamide-7a,12a-dihydroxy-5-cholan-24-oic acid), which is a bile acid / fatty acid complex containing an arachidic acid moiety and a cholic acid moiety. Aramchol is described in U.S. Patent Nos. 6,384,024, 6,395,722, 6,589,946, 7,501,403, 8,110,564, and 8,975,246, which are incorporated herein by reference.

[0125] In other embodiments, the additional therapeutic agent is a VDR agonist selected from the group consisting of calciferol, alphacalcidol, 1,25-dihydroxyvitamin D3, vitamin D2, vitamin D3, calcitriol, vitamin D4, vitamin D5, dihydrotachysterol, calcipotriol, tacalcitol 1,24-dihydroxyvitamin D3, and paricalcitol.

[0126] In other embodiments, the additional therapeutic agent is an acetyl CoA carboxylase inhibitor; an adenosine A3 receptor agonist; an aldosterone agonist and a mineralocorticoid agonist; and an AMP-activated protein kinase stimulator; an amylin receptor agonist and a calcitonin receptor agonist; angiopoietin-related protein 3 inhibitor; an anti-LPS antibody; an apical sodium co-dependent bile acid transporter inhibitor; betaine anhydrous or RM-003; a bioactive lipid; a cannabinoid CB1 receptor antagonist; a dual cannabinoid CB1 receptor antagonist; receptor / iNOS inhibitors;caspase inhibitors;cathepsin inhibitors;CCR antagonists;CCR3 chemokine modulators and eotaxin 2 ligand inhibitors;diacylglycerol-O-acyltransferase (DGAT) inhibitors;dipeptidyl peptidase IV (DPP4) inhibitors;insulin ligands and insulin receptor agonists;insulin sensitizers and MCH receptor 1 antagonists;NOX (NADPH oxidase) inhibitors, e.g. dual NOX 1 and 4 inhibitors;extracellular matrix protein modulators;stearodes fibroblast growth factor 19 (FGF-19) receptor ligands, such as recombinant fibroblast growth factor 19 (FGF-19) protein, or functionally modified variants of the FGF-19 protein; fibroblast growth factor 21 (FGF-21) receptor ligands, such as fibroblast growth factor 21 (FGF-21) protein, or functionally modified variants of the FGF-21 protein; farnesoid X receptor (FXR) agonists ;galectin 3 inhibitors;glucagon-like peptide-1 (GLP-1) analogs, and GLP-1 receptor agonists;G protein-coupled receptor (GPCR) modulators;G protein-coupled receptor 84 antagonists, connective tissue growth factor ligand inhibitors, and free fatty acid receptor 1 agonists;hedgehog cell signaling pathway inhibitors;integrin inhibitors;ketohexokinase inhibitors;leukotriene (LTy) phosphodiesterase (PDEy lipoxygenase (LO) inhibitors;lysyl oxidase homolog 2 inhibitors (LOXL2 inhibitors);macrolides;Methyl-CpG-binding protein 2 regulators and transglutaminase inhibitors; miRNA antagonists; mitochondrial carrier family inhibitors and mitochondrial phosphate carrier protein inhibitors; monoclonal antibodies; myeloperoxidase inhibitors; mTOR regulators; NAD-dependent deacetylase sirtuin stimulators; PDE5 inhibitors; nicotinic acid receptor (GPR109) agonists; nuclear receptor ligands; P2Y13 protein agonists; phenylalanine hydroxylase stimulators; protease-activated receptor (PAR)-2 antagonists agonists;protein kinase modulators;Rho-associated protein kinase 2 (ROCK2) inhibitors;sodium-glucose transport (SGLT) 1 inhibitors;sodium-glucose transport (SGLT) 2 inhibitors;stearoyl-CoA desaturase-1 inhibitors;signal-regulating kinase 1 (ASK1) inhibitors;thyroid receptor beta (THRβ) agonists;Toll-like receptor 2 (TLR-2) antagonists;Toll-like receptor 4 (TLR-4) antagonists;type I natural killer T cell inhibitors;tyrosine kinase receptor (RTK) modulators;uric acid aniline ion exchanger 1 inhibitors and xanthine oxidase inhibitors; vascular adhesion protein-1 (VAP-1) inhibitors; acetyl-CoA carboxylase inhibitors; anti-LPS antibodies; apical sodium co-dependent bile acid transporter inhibitors; bioactive lipids; cannabinoid CB1 receptor antagonists; dual cannabinoid CB1 receptor / iNOS inhibitors; caspase inhibitors; cathepsin inhibitors; CCR antagonists; diacylglycerol-O-acyltransferase (DGAT) inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors; NOX (NADPH oxidase) inhibitors sidase inhibitors, e.g. dual NOX1 and 4 inhibitors;extracellular matrix protein modulators;stearoyl-CoA desaturase-1 inhibitors / fatty acid bile acid conjugates (FABAC);glucagon-like peptide-1 (GLP-1) analogs;G protein-coupled receptor (GPCR) modulators;integrin inhibitors;leukotriene (LT) / phosphodiesterase (PDE) / lipoxygenase (LO) inhibitors;macrolides;miRNA antagonists;monoclonal antibodies;mTOR modulators;nuclear receptor ligands;P2Y13 protein agonists;Fibroblast growth factor 19 (FGF-19) receptor ligand, e.g., recombinant fibroblast growth factor 19 (FGF-19) protein or a functionally modified variant of the FGF-19 protein; Fibroblast growth factor 21 (FGF-21) receptor ligand, e.g., fibroblast growth factor 21 (FGF-21) protein or a functionally modified variant of the FGF-21 protein;

[0127] Other active agents for use in combination with the compounds of formula I of the present application include antibiotics, such as rifaximin, norfloccin, and augmentin; mitochondrial-derived peptides, such as MOTS-c and CB4211; growth differentiation factor (GDF15) antagonists, such as NGM395, NN-9215, and (LA-GDF15); mineralocorticoid receptor antagonists, such as spironolactone, eplerenone, and aparalenone (MT-3995); adipokines, such as for example, leptin, adipoleptin, metreleptin, and osmotin; ileal bile acid transporter (IBAT) / apical sodium-dependent bile acid transporter (ASBT) inhibitors, for example, A4250 and vorixibat; thyroid hormone receptor beta (THRβ) agonists, for example, resmetirom (MGL-3196); TNF-α inhibitors, for example, infliximab, and thalidomide; IL-1 receptor antagonists, for example, anakinra; probiotics, for example, VSL#3 and Lactobacillus rhamnosus GG, etc.; mitochondrial membrane transport protein modulators; androgen receptor modulators; estrogen receptor modulators; bicyclol; docosahexanoic acid (DHA); cysteamine tartrate (CB); PXL065 (DRX-065); orlistat; IL-22; G-CSF; Imm-124E; pirfenidone, nintedanib, and / or fibroblast growth factor receptor antagonists, and / or collagenases, such as collagenase analogs from Clostridium histolyticum; pegylated variants thereof; and combinations thereof.

[0128] Dosing regimen When administered in combination with an additional therapeutic agent, the pharmaceutical composition of the present application and the additional therapeutic agent may be administered simultaneously or sequentially.

[0129] In some embodiments, a dose is administered every other day during the treatment period. In other embodiments, a dose is administered twice every three days during the treatment period. In yet other embodiments, a dose is administered twice every four days during the treatment period.

[0130] In some embodiments, a dose is administered for one day followed by a two day dosing rest. In some embodiments, a dose is administered for one day followed by a two day dosing rest. In some embodiments, a dose is administered for one day followed by a three day dosing rest. In some embodiments, a dose is administered for one day followed by a four day dosing rest. In some embodiments, a dose is administered for one day followed by a five day dosing rest. In some embodiments, a dose is administered for one day followed by a six day dosing rest. In some embodiments, a dose is administered for one day followed by a seven day dosing rest. In some embodiments, a dose is administered for one day followed by a eight day dosing rest. In some embodiments, a dose is administered for one day followed by a nine day dosing rest. In some embodiments, a dose is administered for one day followed by a ten day dosing rest. In some embodiments, a dose is administered for one day followed by a eleven day dosing rest. In some embodiments, a dose is administered for one day followed by a twelve day dosing rest. In some embodiments, dosing is administered for one day followed by 13 days of dosing rest, hi some embodiments, dosing is administered for one day followed by 14 days of dosing rest.

[0131] In some embodiments, a dose is administered daily for two days followed by one day of dosing rest. In some embodiments, a dose is administered daily for two days followed by two days of dosing rest. In some embodiments, a dose is administered daily for two days followed by three days of dosing rest. In some embodiments, a dose is administered daily for two days followed by four days of dosing rest. In some embodiments, a dose is administered daily for two days followed by five days of dosing rest. In some embodiments, a dose is administered daily for two days followed by six days of dosing rest. In some embodiments, a dose is administered daily for two days followed by seven days of dosing rest. In some embodiments, a dose is administered daily for two days followed by eight days of dosing rest. In some embodiments, a dose is administered daily for two days followed by nine days of dosing rest. In some embodiments, a dose is administered daily for two days followed by ten days of dosing rest. In some embodiments, a dose is administered daily for two days followed by eleven days of dosing rest. In some embodiments, a dose is administered daily for two days followed by twelve days of dosing rest. In some embodiments, dosing is done daily for two days followed by 13 days of dosing rest, hi some embodiments, dosing is done daily for two days followed by 14 days of dosing rest.

[0132] In some embodiments, the dose is administered daily for three days followed by one day of dosing rest. In some embodiments, the dose is administered daily for three days followed by two days of dosing rest. In some embodiments, the dose is administered daily for three days followed by three days of dosing rest. In some embodiments, the dose is administered daily for three days followed by four days of dosing rest. In some embodiments, the dose is administered daily for three days followed by five days of dosing rest. In some embodiments, the dose is administered daily for three days followed by six days of dosing rest. In some embodiments, the dose is administered daily for three days followed by seven days of dosing rest. In some embodiments, the dose is administered daily for three days followed by eight days of dosing rest. In some embodiments, the dose is administered daily for three days followed by nine days of dosing rest. In some embodiments, the dose is administered daily for three days followed by ten days of dosing rest. In some embodiments, the dose is administered daily for three days followed by eleven days of dosing rest. In some embodiments, the dose is administered daily for three days followed by twelve days of dosing rest. In some embodiments, dosing is administered daily for 3 days followed by 13 days of dosing rest, hi some embodiments, dosing is administered daily for 3 days followed by 14 days of dosing rest.

[0133] In some embodiments, a dose is administered daily for 4 days followed by a 1 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 2 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 3 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 4 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 5 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 6 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 7 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 8 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 9 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 10 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 11 day dosing rest. In some embodiments, a dose is administered daily for 4 days followed by a 12 day dosing rest. In some embodiments, dosing is administered daily for 4 days followed by 13 days of dosing rest, hi some embodiments, dosing is administered daily for 4 days followed by 14 days of dosing rest.

[0134] In some embodiments, the dose is administered daily for 5 days followed by a 1 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 2 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 3 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 4 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 5 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 6 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 7 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 8 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 9 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 10 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 11 day dosing rest. In some embodiments, the dose is administered daily for 5 days followed by a 12 day dosing rest. In some embodiments, dosing is administered daily for 5 days followed by 13 days of dosing rest, hi some embodiments, dosing is administered daily for 5 days followed by 14 days of dosing rest.

[0135] In some embodiments, a dose is administered daily for six days, followed by one day of dosing rest. In some embodiments, a dose is administered daily for six days, followed by two days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by three days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by four days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by five days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by six days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by seven days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by eight days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by nine days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by ten days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by eleven days of dosing rest. In some embodiments, a dose is administered daily for six days, followed by twelve days of dosing rest. In some embodiments, dosing is administered daily for 6 days followed by 13 days of dosing rest, hi some embodiments, dosing is administered daily for 6 days followed by 14 days of dosing rest.

[0136] In some embodiments, a dose is administered daily for 7 days followed by a 1 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 2 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 3 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 4 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 5 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 6 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 7 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 8 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 9 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 10 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 11 day dosing rest. In some embodiments, a dose is administered daily for 7 days followed by a 12 day dosing rest. In some embodiments, dosing is done daily for 7 days followed by 13 days of dosing rest, hi some embodiments, dosing is done daily for 7 days followed by 14 days of dosing rest.

[0137] In some embodiments, a dose is administered daily for 8 days followed by a 1 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 2 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 3 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 4 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 5 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 6 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 7 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 8 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 9 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 10 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 11 day dosing rest. In some embodiments, a dose is administered daily for 8 days followed by a 12 day dosing rest. In some embodiments, dosing is administered daily for 8 days followed by 13 days of dosing rest, hi some embodiments, dosing is administered daily for 8 days followed by 14 days of dosing rest.

[0138] In some embodiments, a dose is administered daily for 9 days followed by a 1 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 2 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 3 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 4 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 5 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 6 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 7 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 8 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 9 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 10 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 11 day dosing rest. In some embodiments, a dose is administered daily for 9 days followed by a 12 day dosing rest. In some embodiments, dosing is administered daily for 9 days followed by 13 days of dosing rest, hi some embodiments, dosing is administered daily for 9 days followed by 14 days of dosing rest.

[0139] In some embodiments, the dose is administered daily for 10 days followed by a 1 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 2 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 3 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 4 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 5 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 6 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 7 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 8 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 9 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 10 day dosing rest. In some embodiments, the dose is administered daily for 10 days followed by a 11 day dosing rest. In some embodiments, dosing is done daily for 10 days followed by a 12 day rest period. In some embodiments, dosing is done daily for 10 days followed by a 13 day rest period. In some embodiments, dosing is done daily for 10 days followed by a 14 day rest period.

[0140] In some embodiments, the dose is administered daily for 11 days, followed by a 1 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 2 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 3 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 4 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 5 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 6 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 7 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by an 8 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 9 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by a 10 day dosing rest. In some embodiments, the dose is administered daily for 11 days, followed by an 11 day dosing rest. In some embodiments, dosing is done daily for 11 days followed by a 12 day dosing rest period. In some embodiments, dosing is done daily for 11 days followed by a 13 day dosing rest period. In some embodiments, dosing is done daily for 11 days followed by a 14 day dosing rest period.

[0141] In some embodiments, the dose is administered daily for 12 days followed by a 1 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 2 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 3 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 4 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 5 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 6 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 7 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 8 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 9 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by a 10 day dosing rest. In some embodiments, the dose is administered daily for 12 days followed by an 11 day dosing rest. In some embodiments, dosing is done daily for 12 days followed by a 12 day rest period. In some embodiments, dosing is done daily for 12 days followed by a 13 day rest period. In some embodiments, dosing is done daily for 12 days followed by a 14 day rest period.

[0142] In some embodiments, the dose is administered daily for 13 days, followed by a 1-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 2-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 3-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 4-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 5-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 6-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 7-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by an 8-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 9-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by a 10-day dosing rest. In some embodiments, the dose is administered daily for 13 days, followed by an 11-day dosing rest. In some embodiments, dosing is administered daily for 13 days followed by a 12 day dosing rest period. In some embodiments, dosing is administered daily for 13 days followed by a 13 day dosing rest period. In some embodiments, dosing is administered daily for 13 days followed by a 14 day dosing rest period.

[0143] In some embodiments, the dose is administered daily for 14 days followed by a 1 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 2 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 3 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 4 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 5 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 6 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 7 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 8 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 9 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by a 10 day dosing rest. In some embodiments, the dose is administered daily for 14 days followed by an 11 day dosing rest. In some embodiments, dosing is administered daily for 14 days followed by a 12 day dosing rest period. In some embodiments, dosing is administered daily for 14 days followed by a 13 day dosing rest period. In some embodiments, dosing is administered daily for 14 days followed by a 14 day dosing rest period.

[0144] In some embodiments, the dose is administered daily for 30 days, followed by a 30 day rest period. In some embodiments, the dose is administered daily for 30 days, followed by a 25-30 day rest period. In some embodiments, the dose is administered daily for 30 days, followed by a 20-25 day rest period. In some embodiments, the dose is administered daily for 30 days, followed by a 15-20 day rest period. In some embodiments, the dose is administered daily for 30 days, followed by a 10-15 day rest period. In some embodiments, the dose is administered daily for 30 days, followed by a 5-10 day rest period. In some embodiments, the dose is administered daily for 30 days, followed by a 1-5 day rest period.

[0145] In some embodiments, the dose is administered daily for 25-30 days, followed by a 30 day rest period. In some embodiments, the dose is administered daily for 25-30 days, followed by a 25-30 day rest period. In some embodiments, the dose is administered daily for 25-30 days, followed by a 20-25 day rest period. In some embodiments, the dose is administered daily for 25-30 days, followed by a 15-20 day rest period. In some embodiments, the dose is administered daily for 25-30 days, followed by a 10-15 day rest period. In some embodiments, the dose is administered daily for 25-30 days, followed by a 5-10 day rest period. In some embodiments, the dose is administered daily for 25-30 days, followed by a 1-5 day rest period.

[0146] In some embodiments, the dose is administered daily for 20-25 days, followed by a 30 day rest period. In some embodiments, the dose is administered daily for 20-25 days, followed by a 25-30 day rest period. In some embodiments, the dose is administered daily for 20-25 days, followed by a 20-25 day rest period. In some embodiments, the dose is administered daily for 20-25 days, followed by a 15-20 day rest period. In some embodiments, the dose is administered daily for 20-25 days, followed by a 10-15 day rest period. In some embodiments, the dose is administered daily for 20-25 days, followed by a 5-10 day rest period. In some embodiments, the dose is administered daily for 20-25 days, followed by a 1-5 day rest period.

[0147] In some embodiments, the dose is administered daily for 15-20 days, followed by a 30 day rest period. In some embodiments, the dose is administered daily for 15-20 days, followed by a 25-30 day rest period. In some embodiments, the dose is administered daily for 15-20 days, followed by a 20-25 day rest period. In some embodiments, the dose is administered daily for 15-20 days, followed by a 15-20 day rest period. In some embodiments, the dose is administered daily for 15-20 days, followed by a 10-15 day rest period. In some embodiments, the dose is administered daily for 15-20 days, followed by a 5-10 day rest period. In some embodiments, the dose is administered daily for 15-20 days, followed by a 1-5 day rest period.

[0148] In any of the foregoing embodiments, the daily dose may be administered in a single or daily dose, or in two or more divided doses administered multiple times per day. For example, the compounds described herein may be administered once per day, twice per day, three times per day, or four times per day.

[0149] In some embodiments, the subject's thyroid hormone levels, T3, T4 or TSH levels are monitored, and the daily dose can be discontinued or reduced on any day that the T3, T4 or TSH levels are below a predetermined threshold. If the T3, T4 or TSH levels rise above a predetermined threshold during the cessation of administration, the normal daily dose can be continued.

[0150] Dosage The unit dosage forms may comprise a single daily dose, or divided subdoses, whereby multiple unit dosage forms are administered during the course of a day to complete the daily dose. In accordance with the present disclosure, the unit dosage forms may be administered more or less than once per day, and may be administered multiple times during the treatment period. Such dosage forms may be administered in any manner consistent with their formulation, including orally, parenterally, or as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours). While single doses are specifically contemplated, compositions administered according to the methods described herein may also be administered as a continuous infusion or via an implantable infusion pump.

[0151] In one embodiment, the compound of formula I and at least one additional therapeutic agent (e.g., an additional therapeutic agent described herein) are administered at substantially the same dosage as that administered in each monotherapy. In one embodiment, the compound of formula I is administered at a dosage less than its monotherapy dosage (e.g., less than 90%, less than 80%, less than 70%, less than 60%>, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%). In one embodiment, at least one additional therapeutic agent (e.g., an additional therapeutic agent described herein) is administered at a dosage less than its monotherapy dosage (e.g., less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%). In one embodiment, both the first compound and at least one additional therapeutic agent (e.g., an additional therapeutic agent described herein) are administered at dosages that are less than their respective monotherapy dosages (e.g., less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%).

[0152] The actual unit dosage of the active compounds described herein depends on the particular compound and the condition being treated. In some embodiments, the dosage may be from about 0.01 mg / kg to about 120 mg / kg or more of body weight, from about 0.05 mg / kg or less to about 70 mg / kg of body weight, from about 0.1 mg / kg to about 50 mg / kg of body weight, from about 1.0 mg / kg to about 10 mg / kg of body weight, from about 5.0 mg / kg to about 10 mg / kg of body weight, or from about 10.0 mg / kg to about 20.0 mg / kg of body weight.

[0153] In some embodiments, dosage may be less than 100 mg / kg, less than 90 mg / kg, less than 80 mg / kg, less than 70 mg / kg, less than 60 mg / kg, less than 50 mg / kg, less than 40 mg / kg, less than 30 mg / kg, less than 25 mg / kg, less than 20 mg / kg, less than 10 mg / kg, less than 7.5 mg / kg, less than 6 mg / kg, less than 5 mg / kg, less than 4 mg / kg, less than 3 mg / kg, less than 2.5 mg / kg, less than 1 mg / kg, less than 0.5 mg / kg, less than 0.1 mg / kg, less than 0.05 mg / kg, or less than 0.005 mg / kg per kg of body weight. In some embodiments, the actual unit dosage is 0.05 mg / kg, 0.07 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, 5.0 mg / kg, 10.0 mg / kg, or 25.0 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be 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.

[0154] 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 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. In some embodiments, the actual unit dose is 5 mg.

[0155] In some embodiments, the method of administration includes administering a loading dose followed by a 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, or 100 mg or less. In some embodiments, the maintenance dose is 300 mg or less, 200 mg or less, 100 mg or less, 50 mg or less, 40 mg or less, 25 mg or less, 10 mg or less, 5 mg or less, or 1 mg or less.

[0156] In some embodiments, the loading dose is administered over a one day period. In some embodiments, the loading dose is administered over a two day period. In some embodiments, the loading dose is administered over a three day period. In some embodiments, the loading dose is administered over a four day period. In some embodiments, the loading dose is administered over a five, six or seven day period. In some embodiments, the loading dose is administered over a period of eight to fourteen days or less. In some embodiments, the loading dose is administered over a fourteen day period.

[0157] Administration of the active agents described herein may be accomplished by adjusting the dosing schedule so that the subject undergoes a partial or complete reduction in regular dosing for a period of time, after which dosing is resumed.

[0158] In some embodiments, doses are administered daily for 1 to 30 days, followed by a dosing rest period of 1 to 30 days. In some embodiments, no dose is administered during the dosing holiday period.

[0159] In further embodiments, the compound of formula I and its metabolites are allowed to be completely cleared from the subject's body prior to administration of the next dose. In some other embodiments, a lower than normal daily dose is administered during the dosing holiday.

[0160] In some embodiments, the maximum serum concentration of the compound of formula I during the dosing schedule is less than 120 ng / ml, less than 100 ng / ml, less than 90 ng / ml, less than 80 ng / ml, less than 70 ng / ml, less than 60 ng / ml, or less than 50 ng / ml.

[0161] In some embodiments, the minimum serum concentration during the dosing schedule is less than 10 ng / ml, less than 1 ng / ml, less than 0.1 ng / ml, less than 0.01 ng / ml, or less than 0.001 ng / ml.

[0162] In some embodiments, the maximum serum concentration of the compound of formula I during the initial (loading) phase of administration is less than 500 ng / ml, less than 400 ng / ml, less than 300 ng / ml, less than 200 ng / ml, less than 150 ng / ml, less than 120 ng / ml, less than 100 ng / ml, less than 90 ng / ml, less than 80 ng / ml, less than 70 ng / ml, less than 60 ng / ml, or less than 50 ng / ml.

[0163] In some such embodiments, the maximum serum concentration during the initial phase of administration is 5 ng / ml to 250 ng / ml. In some embodiments, the maximum serum concentration of the compound of Formula I during the subsequent (maintenance) phase of administration is less than 350 ng / ml, less than 200 ng / ml, less than 120 ng / ml, less than 100 ng / ml, less than 90 ng / ml, less than 80 ng / ml, less than 70 ng / ml, less than 60 ng / ml, or less than 50 ng / ml, less than 40 ng / ml, less than 35 ng / ml, or less than 10 ng / ml.

[0164] Those skilled in the art will easily recognize the methods that exist in the art for monitoring the serum concentration of drugs and how to adjust the dosage of the compounds disclosed herein to achieve desired serum concentration.In some embodiments, the weekly dose administered is 600mg or less.In some embodiments, the weekly dose administered is 500mg or less, 400mg or less, 300mg or less, 200mg or less, 100mg or less, 50mg or less, 40mg or less, 25mg or less, 10mg or less, or 5mg or less, or within the range defined by any two of the above.

[0165] In accordance with the present disclosure, the administration schedule may be modified to achieve the desired therapeutic effect. In particular, the described administration schedule modifications may be repeated throughout the course of treatment.

[0166] For example, in certain embodiments, the first dose may be higher, lower, or the same as the doses subsequent to the first dose. Additionally, a loading dose may precede the disclosed dosing regimen, and a dosing holiday period may or may not follow administration of the loading dose.

[0167] The present application is further illustrated by the following examples, which should not be construed as limiting. All references, patents, published patent application contents, and figures and tables cited throughout this application are hereby incorporated by reference.

[0168] [Example] Example 1 Composition of the formulation:

[0169] [Table 1]

[0170] Preparation process: 1. Pretreatment of API and excipients: API and excipients used in formulation research are ground, sieved and dried by the methods of conventional preparation technology to prevent caking during storage and reduce the moisture content of hygroscopic excipients so as to meet the standards for further preparation; 2. Ingredients: API and excipients for hot melt extrusion are weighed according to the formulation proportion and preparation scale; 3. Blending: uniformly blending API and excipients with the finished ingredients by the method of conventional preparation technology; 4. Hot melt extrusion method: set extrusion temperature in different areas of the extruder; after preheating to the set temperature, keep the temperature for 15-30 minutes, add uniformly mixed API and excipients by the way of manual feeding or by using loss-in-weight loss feeder, and extrude at the set extrusion speed; by adjusting the temperature of different areas of the extruder barrel, screw rotation speed, and feeding speed, control the temperature of the extrusion die between 90℃ and 130℃, keep the screw torque in a stable range, and make the extruded material transparent; adjust the extrusion speed and feeding speed, and control the residence time of the material in the barrel of the hot melt extruder within 30 minutes; 5. Grinding of the extrudate: grinding the cooled extrudate by methods of conventional preparation technology; 6. Overall mixing: Add other excipients according to the prescription ratio, and mix the above materials by the mixing method of conventional preparation technology; 7. Preparation: Compress formulations A1 and C1 into capsule-type tablets. Fill the entire mixture of formulation B1 into Vcaps Plus® (size 3) hydroxypropyl methylcellulose capsules; 8. Packaging: Put the tablets of formula A1 and B1 and the capsules of formula B1 into HDPE bottles and seal them with aluminum film; 9. Storage: Packaged tablets or capsules of a compound of formula (I) are stored at room temperature (below 30° C.).

[0171] Comparative Example 1 Composition of the formulation

[0172] [Table 2]

[0173] Preparation process: 1. Pretreatment of API and excipients: API and excipients used in formulation research are ground, sieved and dried by the methods of conventional preparation technology to prevent caking during storage and reduce the moisture content of hygroscopic excipients so as to meet the standards for further preparation; 2. Ingredients: API and excipients for hot melt extrusion are weighed according to the formulation proportion and preparation scale; 3. Blending: uniformly blending API and excipients with the finished ingredients by the method of conventional preparation technology; 4. Hot melt extrusion method: set extrusion temperature in different areas of the extruder; after preheating to the set temperature, keep the temperature for 15-30 minutes, add uniformly mixed API and excipients by the way of manual feeding or by using loss-in-weight feeder, and extrude at the set extrusion speed; by adjusting the temperature of different areas of the extruder barrel, screw rotation speed, and feeding speed, control the temperature of the extrusion die between 100℃ and 130℃, keep the screw torque in a stable range, and make the extruded material transparent; adjust the extrusion speed and feeding speed, and control the residence time of the material in the barrel of the hot melt extruder within 30 minutes; 5. Grinding of the extrudate: grinding the cooled extrudate by methods of conventional preparation technology; 6. Overall mixing: Add other excipients according to the prescription ratio, and mix the above materials by the mixing method of conventional preparation technology; 7. Preparation: Compress the formulation b2 into capsule-shaped tablets; 8. Packaging: The tablets of formula b2 are put into HDPE bottles and sealed with aluminum film; 9. Storage: Packaged tablets or capsules of a compound of formula (I) are stored at room temperature (below 30° C.).

[0174] Effect Example 1 In this example, the rationale for the selection of the proportions and preparation steps of the compositions of the present invention is illustrated by a 24 hour elevated pH dissolution study design.

[0175] Granules obtained by hot melt extrusion according to formulations A1 to C1 in Example 1 and granules obtained by hot melt extrusion according to formulation a2 in Comparative Example 1 are taken, and the pH transition and supersaturation maintenance time in simulated human digestive fluid are investigated.

[0176] The dissolution conditions were as follows: first, 750mL of degassed hydrochloric acid solution at pH 2.0 at 37°C±0.5°C was used as the dissolution medium, then, dissolution was performed by paddle method with stirring at 50 rpm for 2 hours, then, 250mL of degassed phosphate buffer solution at pH 6.8 was added, then, dissolution was performed by paddle method with stirring at 50 rpm for 22 hours (USP apparatus II). Granules were weighed directly and accurately, then, poured, and samples were taken at 30, 60, 90, 120, 180, 240, 360, 480, 720, 960, 1200, and 1440 minutes after pouring, then, the filtrate was taken, and diluted with 75% acetonitrile water solution in equal proportions, and the concentration of the compound represented by formula (I) was measured by HPLC.

[0177] HPLC measurement conditions: Octadecylsilane-bonded silica gel was selected as the packing material (Welch Ultimate® XB-C18 4.6 * 150 mm, 5 μm, or equivalent column), 0.05% trifluoroacetic acid aqueous solution-acetonitrile (30:70) was used as the mobile phase, the flow rate was 1.0 ml / min, the column temperature was 30° C., and the detection wavelength was 230 nm. The reference solution and the test solution (in the reference solution and the test solution, the injection volume of 2 mg formulation is 40 μl, and the injection volume of 5 mg and 10 mg formulation is 20 μl) are accurately measured and injected into the liquid chromatograph respectively, the chromatograms are recorded, and the solubility is calculated according to the peak area according to the external standard method.

[0178] result: I. As shown in Table 3 and Figure 1, the compound represented by formula (I) in the extrudate prepared according to the proportions in Example 1 of the present invention can achieve stable supersaturated dissolution within 24 hours, and the solubility at the end of 24 hours is 88.8%-100.0% of the solubility at the highest point.

[0179] II. As shown in Table 4 and Figure 2, the compound of formula (I) in Comparative Example 1 had obvious supersaturated precipitation during dissolution, and the dissolution rate at the end of 24 hours was only 28.3% compared with the dissolution rate at the highest point.

[0180] III. The calculated areas under the dissolution curve were 171.2% (83104.5 / 48549.0*100%), 170.2% (82648.5 / 48549.0*100%), and 211.0% (102456.0 / 48556.0%) of Comparative Example 1, respectively.

[0181] Conclusion: The dissolution comparison results of Example 1 and Comparative Example 1 show that the technical scheme described in Example 1 has a special advantage in maintaining a stable supersaturated concentration of the compound represented by formula (I) for a long time.

[0182] [Table 3]

[0183] [Table 4]

[0184] Effect Example 2 The concentration of the micellar system consisting of the compound of formula (I) and the carrier excipient in the 900mL dissolution cup is too low to be measured by the laser particle size method. The micellar sizes that can be formed in Example 1 and Comparative Example 1 were compared by the following improved method.

[0185] The extrusion powders of Example 1 and Comparative Example 1 containing 5 mg of the compound shown in formula (I) were placed in a 100 mL volumetric flask, and then pH 6.0 phosphate buffer with a concentration of 50 mM was added at 37.0°C ± 0.5°C to volumetric capacity, and the mixture was shaken in a water bath at 37.0°C ± 0.5°C for 15 minutes to completely dissolve and disperse. The samples were measured by a NICOMPTM380ZLS laser particle size analyzerTM. The particle size distribution of the micelles was calculated using the intensity of the Gaussian distribution, and the results are shown in Table 5.

[0186] The particle size measurement results showed that the nanomicelles prepared by the scheme of Example 1 had smaller particle sizes and more concentrated particle distribution compared to the micelles prepared by the scheme of Comparative Example 1, suggesting that the nanomicelles prepared by the scheme of Example 1 have excellent stability.

[0187] [Table 5]

Claims

1. 1. A pharmaceutical composition comprising, in parts by weight: (1) A compound of formula (I) 【Chemical 1】 (2) 9 parts to 45 parts of polymeric material wherein the compound of formula (I) maintains a supersaturated concentration in the pharmaceutical composition, and is suitable for storage at room temperature.

2. 10. The pharmaceutical composition of claim 1, wherein the polymeric material comprises one or more polymers selected from the group consisting of polyvinyl lactam polymers, cellulose derivative polymers, polyacrylic resins, polyethylene glycols, polyoxyethylenes, and polyvinyl alcohols.

3. 3. The pharmaceutical composition of claim 1 or claim 2, wherein the polymeric material comprises one or more polyvinyl lactam polymers selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone (PVP / VA), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

4. 10. The pharmaceutical composition of claim 1, wherein the polymeric material comprises polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

5. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises nanomicelles.

6. 6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of an amorphous solid dispersion prepared by hot-melt extrusion.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition is formulated into a fixed dose tablet or capsule containing 1 mg to 15 mg of the compound of formula (I).

8. 8. The pharmaceutical composition of claim 7, wherein the fixed dose tablet or capsule contains 2.5 mg or 5 mg of the compound of formula (I).

9. 9. The pharmaceutical composition of claim 1, further comprising one or more non-polymeric materials selected from the group consisting of pharmaceutically acceptable pharmaceutical excipients, non-volatile weak acids, neutral or weakly acidic inorganic substances, and pharmaceutically acceptable excipients having a melting point below 80°C.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the compound of formula (I) is present in the pharmaceutical composition in crystalline, amorphous, or partially crystalline / partially amorphous form.

11. 11. The pharmaceutical composition of claim 10, wherein the amorphous form of the compound of formula (I) is present in the pharmaceutical composition in an amount of 50% by weight or greater of the total amount of the compound of formula (I).

12. 11. The pharmaceutical composition of claim 10, wherein the amorphous form of the compound of formula (I) is present in the pharmaceutical composition in an amount of 80% by weight or greater of the total amount of the compound of formula (I).

13. 11. The pharmaceutical composition of claim 10, wherein the amorphous form of the compound of formula (I) is present in the pharmaceutical composition in an amount of 90% by weight or greater of the total amount of the compound of formula (I).

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the composition is formulated in a sustained release or delayed release formulation.

15. Use of a pharmaceutical composition according to any one of claims 1 to 14 in the manufacture of a medicament for treating a disease in a patient.

16. 16. The use of claim 15, wherein the disease is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

17. 1. A method for preparing a pharmaceutical composition comprising the steps of: extruding a pre-extrusion mixture comprising, by weight, (1) 1 part of a compound of formula (I), and (2) 9 to 45 parts of a polymeric material by a hot melt extrusion process to form an extrudate; and cutting or grinding the extruded product into granules or powder; wherein the compound of formula (I) maintains a supersaturated concentration in the extrudate at room temperature.

18. 18. The method of claim 17, further comprising compressing the granules or powder into a fixed dose tablet.

19. 18. The method of claim 17, wherein the extrusion step is carried out at an extrusion temperature of 90°C to 130°C.

20. 20. The method of any one of claims 17 to 19, wherein the polymeric material comprises polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

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