Solid dosage form of elafibranol

Abstract

The present invention relates to formulations of elafibranol or pharmaceutically acceptable salts or esters thereof and their use. In particular, the present invention relates to oral dosage forms comprising at least elafibranol or pharmaceutically acceptable salts or esters thereof, fillers, disintegrants and binders.

Description

[Technical Field]

[0001] This invention relates to a formulation of elafibranol and its use. [Background technology]

[0002] Elafibranol is a molecule first published in international publication 2004 / 005233. As a dual PPARα / δ agonist, elafibranol shows promise in treating a variety of conditions. Initially, elafibranol was described as effective in treating many metabolic disorders, and since then, during Phase 2 clinical trials, its efficacy in treating cholestatic disorders, particularly present-day biliary cholangitis (PBC), has been discovered. Elafibranol was evaluated in Phase 3 clinical trials for the treatment of PBC (ClinicalTrials.gov Identifier: NCT0452665). Treatment with elafibranol resulted in significant improvement in the relevant chemical indicators of cholestatic disorder compared to placebo (N Engl J Med. 2023 Nov 13. doi: 10.1056 / NEJMoa2306185). In light of these positive results, a marketing authorization application was recently approved by the EMA (European Medicines Agency) and the FDA (Food and Drug Administration). As a result, elafibranol has the potential to become the first second-line treatment for PBC, and further improvements to the formulation are expected to yield benefits. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2004 / 005233 [Non-patent literature]

[0004] [Non-Patent Document 1] N Engl J Med. 2023 Nov 13. doi: 10.1056 / NEJMoa2306185 [Overview of the project] [Means for solving the problem]

[0005] The present invention relates to novel compositions of elafibranol or its pharmaceutically acceptable salts or esters.

[0006] In a first aspect, the present disclosure relates to an oral solid dosage form comprising elafibranol in particulate form or a pharmaceutically acceptable salt or ester of elafibranol. In a particular embodiment, the elafibranol in particulate form or a pharmaceutically acceptable salt or ester thereof comprises at least 90% particles with a diameter of 15 μm or less. In another particular embodiment, the elafibranol in particulate form or a pharmaceutically acceptable salt or ester thereof comprises at least 50% particles with a diameter of 5 μm or less. In yet another embodiment, the elafibranol in particulate form or a pharmaceutically acceptable salt or ester thereof comprises It contains at least 90% of particles with a diameter of 15 μm or less, and Contains at least 50% particles with a diameter of 5 μm or less.

[0007] In the second aspect, this disclosure is i) Elafibranol or its pharmaceutically acceptable salts or esters, ii) Fillers, iii) Disintegrants, and iv) Binder The present invention provides an oral solid dosage form containing [the specified ingredient].

[0008] In certain embodiments, the oral solid dosage form is i) Elafibranol or its pharmaceutically acceptable salts or esters, ii) A filler selected from the group consisting of mannitol, microcrystalline cellulose, and lactose monohydrate. iii) A disintegrant selected from the group consisting of crospovidone and croscarmethylose sodium, and iv) A binder selected from the group consisting of hydroxypropylcellulose, copovidone, povidone, and hydroxypropylmethylcellulose. including.

[0009] In certain embodiments, elafibranor or a pharmaceutically acceptable salt or ester thereof is in particulate form, e.g., the particulate form disclosed herein. <0​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​(b) an outer phase comprising a disintegrant, a glidant and a lubricant Includes.

[0016] In certain embodiments, the oral solid dosage form contains magnesium stearate as a lubricant.

[0017] In another specific embodiment, the oral solid dosage form contains anhydrous colloidal silica as a fluidizing agent.

[0018] In another specific embodiment, the oral solid dosage form is a coated tablet.

[0019] In another specific embodiment, the tablet contains granules as the internal phase.

[0020] In certain embodiments, the internal phase of the tablet is i) Elafibranol or its pharmaceutically acceptable salts or esters, ii) Microcrystalline cellulose, iii) Croscarmellose sodium, and iv) Povidone Includes.

[0021] In yet another specific embodiment, the internal phase of the tablet is i) Elafibranol in particulate form or a pharmaceutically acceptable salt or ester thereof, ii) Microcrystalline cellulose, iii) Croscarmellose sodium, and iv) Povidone Includes.

[0022] In another specific embodiment, the dosage form according to the present invention contains at least 20%, preferably at least 35%, of elafibranol. In yet another specific embodiment, the dosage form contains 20 to 60% by mass of elafibranol or a pharmaceutically acceptable salt or ester thereof. In yet another embodiment, the dosage form contains 35 to 40% by mass of elafibranol or a pharmaceutically acceptable salt or ester thereof. In yet another embodiment, the dosage form contains 35 to 180 mg (preferably 40 to 120 mg) of elafibranol or a pharmaceutically acceptable salt or ester thereof.

[0023] In further embodiments, the dosage form contains 40 mg of elafibranol or a pharmaceutically acceptable salt or ester thereof. In another specific embodiment, the dosage form contains 80 mg of elafibranol or a pharmaceutically acceptable salt or ester thereof. In further embodiments, the dosage form contains 120 mg of elafibranol or a pharmaceutically acceptable salt or ester thereof. In another specific embodiment, the dosage form contains 180 mg of elafibranol or a pharmaceutically acceptable salt or ester thereof.

[0024] According to a specific embodiment, when tested using a paddle device at 75 rpm, 37°C ± 0.5°C, and with 1000 mL of water containing SDS at concentrations of 0.6% for 40 mg, 0.8% for 80 mg, and 1% for 120 mg, in accordance with European Pharmacopeia 5.0, paragraph 2.9.3, at which point at which the SDS is released from the oral solid dosage form within 15 minutes.

[0025] According to another specific embodiment, when tested using a paddle device at 75 rpm, 37°C ± 0.5°C, and with 1000 mL of water containing SDS at concentrations of 0.6% for 40 mg, 0.8% for 80 mg, and 1% for 120 mg, in accordance with European Pharmacopeia 5.0, paragraph 2.9.3, at which point at which the SDS is released from the oral solid dosage form within 30 minutes.

[0026] This disclosure also relates to dosage forms of the disclosure for use in methods of treating diseases in subjects who benefit from the activation of PPARs (peroxisome proliferator-activated receptors).

[0027] This disclosure further relates to a method for treating diseases in subjects who benefit from activation of PPARs (peroxisome proliferator-activated receptors) by administering the oral solid dosage form of this disclosure to subjects who require it.

[0028] This disclosure further relates to the use of the oral solid dosage forms of this disclosure for the manufacture of pharmaceuticals that treat diseases in subjects who benefit from the activation of PPARs (peroxisome proliferator-activated receptors).

[0029] In certain embodiments, the disease is selected from the group consisting of PBC, PSC (present-day sclerosing cholangitis), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, hepatic fibrosis, and cirrhosis. In preferred examples, the disease is PBC or PSC, more preferably PBC.

[0030] Another aspect of the present disclosure relates to a method for treating PBC in a patient in need thereof by administering an oral solid dosage form of the present disclosure, wherein the dosage form is a dose unit, and the dose unit, preferably a tablet, contains at least 35% elafibranol, and the method is such that at least 75% of the dosage unit dissolves within 15 minutes when tested with a paddle device at 75 rpm, 37°C ± 0.5°C, and with SDS in 1000 mL of water, where the SDS is 0.6% for a 40 mg dose, 0.8% for an 80 mg dose, and 1% for a 120 mg dose, respectively, according to European Pharmacopeia 5.0, paragraph 2.9.3.

[0031] The disclosure further relates to an oral solid dosage form of the disclosure for use in a method of treating PBC, wherein the dosage form is a dose unit, and the dose unit, preferably a tablet, contains at least 35% elafibranol, and the dosage form is such that at least 75% of the dosage unit dissolves within 15 minutes when tested with a paddle device at 75 rpm, 37°C ± 0.5°C, and with SDS in 1000 mL of water, where the SDS is 0.6% for a 40 mg dose, 0.8% for an 80 mg dose, and 1% for a 120 mg dose, respectively, according to European Pharmacopeia 5.0, paragraph 2.9.3.

[0032] The Disclosure further relates to the use of the oral solid dosage form of the Disclosure in the manufacture of a pharmaceutical product for the treatment of PBC, wherein the dosage form is a dose unit, and the dose unit, preferably a tablet, contains at least 35% elafibranol, and the use is such that at least 75% of the dosage form unit dissolves within 15 minutes when tested with a paddle device at 75 rpm, 37°C ± 0.5°C, and with SDS in 1000 mL of water, where the SDS is 0.6% for a 40 mg dose, 0.8% for an 80 mg dose, and 1% for a 120 mg dose, respectively.

[0033] A further aspect of the present disclosure is a method for treating cholestasis or liver disease such as PBC, PSC, NAFLD, NASH, cirrhosis, hepatitis C infection, alcoholic liver disease, progressive fibrosis, or hepatic fibrosis in a patient in need, by administering a composition comprising elafibranol or a pharmaceutically acceptable salt or ester thereof, wherein elafibranol or a pharmaceutically acceptable salt or ester thereof is in particulate form. In one embodiment, 90% of the particles are 15 μm or less in diameter. In a further embodiment, 50% of the particles are 5 μm or less in diameter. In yet another embodiment, 90% of the particles are 15 μm or less in diameter and 50% of the particles are 5 μm or less in diameter.

[0034] This disclosure further relates to compositions comprising elafibranol or a pharmaceutically acceptable salt or ester thereof for use in methods of treating cholestasis or liver diseases such as PBC, PSC, NAFLD, NASH, cirrhosis, hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, or hepatic fibrosis, wherein elafibranol or a pharmaceutically acceptable salt or ester thereof is in particulate form. In one embodiment, 90% of the particles have a diameter of 15 μm or less. In a further embodiment, 50% of the particles have a diameter of 5 μm or less. In yet another embodiment, 90% of the particles have a diameter of 15 μm or less, and 50% of the particles have a diameter of 5 μm or less.

[0035] This disclosure further relates to the use of compositions comprising elafibranol or a pharmaceutically acceptable salt or ester thereof for the manufacture of pharmaceuticals for treating cholestasis or liver diseases such as PBC, PSC, NAFLD, NASH, cirrhosis, hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, or hepatic fibrosis, wherein elafibranol or a pharmaceutically acceptable salt or ester thereof is in particulate form. In one embodiment, 90% of the particles have a diameter of 15 μm or less. In a further embodiment, 50% of the particles have a diameter of 5 μm or less. In yet another embodiment, 90% of the particles have a diameter of 15 μm or less, and 50% of the particles have a diameter of 5 μm or less. [Brief explanation of the drawing]

[0036] [Figure 1] This table shows the dissolution and release rate and stability of tablets of Formulation 1 containing jet-pulverized elafibranol 80 mg. [Figure 2] This table shows the dissolution rate and stability of tablets of Formulation 2 containing jet-pulverized elafibranol 120 mg. [Figure 3] This table shows the dissolution rate and stability of tablets of Formulation 4 containing jet-pulverized elafibranol 80 mg. [Figure 4] This table shows the dissolution and release rate and stability of tablets of Formulation 3 containing 120 mg of jet-pulverized elafibranol. [Figure 5] This graph shows the absolute change in alkaline phosphatase (ALP) from baseline over 12 weeks in a group of patients treated with the oral solid dosage form (dosage forms 3 and 4) according to the present invention, which contains either elafibranol 80 mg or 120 mg. [Figure 6] This graph shows the mean relative change in ALP from baseline over 12 weeks in a group of patients treated with the oral solid dosage forms (formulations 3 and 4) according to the present invention, which contain elafibranol 80 mg or 120 mg. [Figure 7] This table shows the decrease in ALP levels analyzed using Fisher's exact test with a modified intention to treat (mITT) set in subjects treated with the oral solid dosage forms (formulations 3 and 4) according to the present invention, which contain 80 mg or 120 mg of elafibranol. Abbreviations: ALP: alkaline phosphatase; EOT = end of treatment. [Figure 8] This table (mITT set) shows the absolute and relative changes from baseline in γ-glutamyl transpeptidase. Abbreviations: CI = Confidence Interval, EOT = End of Treatment, GGT = γ-glutamyl transpeptidase, SD = Standard Deviation. [Figure 9]This graph shows the mean relative change in gamma-glutamyl transpeptidase (GGT) levels from baseline to week 12 for each treatment group (mITT set). [Figure 10] This graph shows the median relative change from baseline in the pruritic visual analog score over 12 weeks (mITT set). [Modes for carrying out the invention]

[0037] Typically, powders are tableted by direct compression or by manufacturing granules and then tableting them. However, tableting by direct compression and granulation is greatly affected by the physical properties of the drug, often resulting in large variations in weight during tableting and poor content uniformity, which in turn leads to poor manufacturability when considering productivity. Furthermore, these methods may result in pharmaceuticals with low solubility. This disclosure provides an oral solid dosage form of ellafibranol or a pharmaceutically acceptable salt or ester thereof that does not have these problems.

[0038] Unless otherwise defined herein, all technical and scientific terms used herein shall have meanings that are generally understood by those skilled in the art to which this disclosure pertains.

[0039] All percentages and ratios used herein are in terms of weight, unless otherwise defined.

[0040] The term "filler" as used herein refers to an agent that increases the volume of a very small amount of active ingredient. Fillers include, for example, mannitol, microcrystalline cellulose, lactose (e.g., lactose monohydrate), and mixtures thereof.

[0041] The term "binder" as used herein refers to an agent or mixture of agents that increases the viscosity of a liquid, thereby keeping the active ingredient suspended and enabling precise administration. Binders include, but are not limited to, povidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and mixtures thereof.

[0042] The term "disintegrant" as used herein refers to an agent that facilitates the disintegration of an oral solid dosage form. Exemplary fluidizing agents include crospovidone, croscarmellose sodium, and mixtures thereof.

[0043] The term “glidant” as used herein refers to an agent added to improve the fluidity of a powder. Exemplary glidants include silica, preferably colloidal silica, and more preferably anhydrous colloidal silica.

[0044] The term "lubricant" as used herein refers to a substance that helps reduce friction between contacting surfaces. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oils, and glycerine fumarate, and / or combinations thereof. In certain embodiments, the lubricant is magnesium stearate.

[0045] The term "organ" refers to a differentiated structure in an organism that consists of cells and tissues and performs a specific function (e.g., heart, lungs, kidneys, liver). This term also includes parts of the body that perform a function or cooperate in an activity (e.g., the eyes and related structures that make up the visual organs). Furthermore, the term "organ" also includes substructures composed of differentiated cells and tissues that have the potential to develop into a complete structure (e.g., the lobes or parts thereof of the liver).

[0046] "Elafibranol" refers to 2-[2,6-dimethyl-4-[(E)3-(4-methylsulfanylphenyl)-3-oxopropa-1-enyl]phenoxy]-2-methylpropanoic acid, a compound formerly known as GFT505. In the context of this disclosure, the term "elafibranol" refers to all forms of elafibranol, e.g., amorphous, crystalline, and substantially pure.

[0047] References in this disclosure regarding the dosage, amount, or percentage of elafibranol are based on the free base equivalent of elafibranol. For example, 35 mg of elafibranol refers to 35 mg of elafibranol in its free base form, or an equivalent amount of a salt or ester of elafibranol.

[0048] As used herein, "elafibranol composition" or "pharmaceutical composition" refers to an oral solid dosage form according to the present invention, i.e., elafibranol or a pharmaceutically acceptable salt or ester of elafibranol, in particular elafibranol or a pharmaceutically acceptable salt of elafibranol, more specifically an oral solid dosage form containing elafibranol.

[0049] The articles "a" and "an" are used in this disclosure to refer to one or more (i.e., at least one) of the articles' subjective objects. For example, "an element" means one or more elements.

[0050] In this disclosure, unless otherwise specified, the terms "and / or" are used to mean either "and" or "or".

[0051] In this specification, the term "purity" refers to the chemical analysis value of the obtained compound, for example, by HPLC. The purity of ellafibranol can be calculated from the peak surface area. In one embodiment, the purity takes into account organic impurities in the sample. In one embodiment, the purity of ellafibranol is at least 98%, preferably at least 99%, of the peak surface area.

[0052] "Treatment" includes any effect that results in improvement, reduction, reduction, adjustment, or elimination of symptoms, disease, or disorder.

[0053] "Treatment" or "treatment" of a disease state includes inhibiting the disease state, i.e., stopping the progression of the disease state or its clinical symptoms, or alleviating the disease state, i.e., causing a temporary or permanent regression of the disease state or its clinical symptoms.

[0054] The term “regmen” refers to a protocol relating to the dosage and / or timing of administration of one or more therapeutic agents (e.g., the oral solid dosage forms of elafibranole described herein, or other active agents such as UDCA) for the treatment of diseases, disorders, or symptoms described herein. A regimen may include active administration periods and rest periods known in the art. An active administration period includes administration over a specified time course, including, for example, the number and timing of administrations of the oral solid dosage forms described herein. Some regimens may include one or more rest periods in which the compound is not actively administered.

[0055] "Preventing" a disease state includes preventing the development of clinical symptoms of a disease state in individuals who are exposed to or susceptible to a disease state but have not yet experienced or shown symptoms of the disease state.

[0056] In this specification, the terms “inhibition” or “suppression,” when applied to a disease or symptom, mean a detectable positive effect on the progression or onset of the disease or symptom. Such positive effects include delaying or preventing the onset of at least one symptom or sign of the disease or symptom, alleviating or restoring a symptom or sign, and delaying or preventing further worsening of a symptom or sign.

[0057] "Symptoms" refers to all diseases, disorders, symptoms, and signs.

[0058] In this specification, the term “effective dose” means the amount of elafibranol or a pharmaceutically acceptable salt or ester of elafibranol that, when administered in an appropriate dose, produces an acute or chronic therapeutic effect. The effect includes, to the extent detectable, prevention, modification, suppression, or recovery of symptoms, signs, or underlying conditions of a disease / condition and associated complications.

[0059] For any compound, the therapeutically effective dose can first be estimated using either a cell culture assay or an animal model (usually rats, mice, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine effective doses and routes of administration in humans. Therapeutic / preventive effects and toxicity are determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED50 (the dose that produces a therapeutic effect in 50% of the population) and LD50 (the dose that is lethal in 50% of the population). The ratio of the dose to toxicity and therapeutic effect is the therapeutic index, which can be expressed as the LD50 / ED50 ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred.

[0060] A toxicology program conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines demonstrates that elafibranol is non-transmissible or mutatoxic. Based on the results of acute toxicity tests, no signs of toxicity were detected in rats and mice up to a single oral dose of 1000 mg / kg, leading to the conclusion that elafibranol is extremely safe.

[0061] The dosage and method of administration are adjusted to ensure sufficient levels of the active agent or to maintain the desired effect. Factors to be considered include the severity of the disease state, the subject's overall health status, age, weight, sex, diet, timing and frequency of administration, concomitant drug use, sensitivity to response, and tolerance / responsiveness to treatment.

[0062] The term “administration” refers to the act of delivering the oral solid dosage forms described herein to a subject by oral administration. This term may also refer to the frequency with which the oral solid dosage forms described herein are provided to a patient (e.g., daily, weekly, monthly, etc.). Administration is generally performed after the onset of a disease, disorder, or symptom, or the onset of such symptoms, but in some cases it may be performed before the onset of a disease, disorder, or symptom (e.g., administration to a patient predisposed to such a disease, disorder, or symptom).

[0063] The oral solid dosage forms of the present invention may be administered to a patient alone or in combination with other agents. Combination administration is intended to include simultaneous or sequential administration of the oral solid dosage forms individually or in combination (with one or more compounds or agents). Accordingly, the oral solid dosage forms may also be combined with other active substances as desired. Such other active substances include substances useful for reducing the metabolic degradation of ellafibranol or its pharmaceutically acceptable salts or esters, and activators known to be useful in the treatment of diseases, such as UDCA (ursodeoxycholic acid) or obeticholic acid. Alternatively, the oral solid dosage forms described herein may be used in combination with adjuvants that are not effective alone but can contribute to or enhance the efficacy of the activator.

[0064] The timing of concomitant administration depends in part on the combination and composition being administered, and may include administration concurrently with, before, or after the administration of one or more additional therapies.

[0065] As used herein, “pharmacological effect” includes an effect that occurs on a subject to achieve the intended therapeutic objective. In one embodiment, a pharmacological effect means that the principal symptom of the subject to treatment is prevented, mitigated, or reduced. For example, a pharmacological effect is an effect that results in the prevention, mitigation, or reduction of the principal symptom of the subject to treatment. In another embodiment, a pharmacological effect means that the impairment or symptoms of the principal symptom of the subject to treatment are prevented, mitigated, or reduced. For example, a pharmacological effect is an effect that results in the prevention or reduction of the principal symptom of the subject to treatment.

[0066] In this specification, “dosage unit formulation” or “dosage unit” refers to a physically distinct unit suitable as a unit dose to a target for treatment, each unit containing a predetermined amount of active reagent calculated to produce the desired therapeutic effect. The specifications of the dosage unit formulation in this disclosure are determined and directly depend on the inherent properties of the active reagent, the specific therapeutic effect to be achieved, and the inherent limitations of the technique for compounding such active reagents for the treatment of an individual.

[0067] The unit dosage form can take any of the various forms, including, for example, capsules or tablets. The amount of elafibranol (e.g., elafibranol or its pharmaceutically acceptable salts or esters) in the unit dosage form is the effective dose and varies depending on the specific treatment in question. Those skilled in the art will understand that the dosage should be appropriately adjusted according to the patient's age and symptoms.

[0068] The term "immediate release" is defined as the release of elafibranol from the dosage form within a relatively short time, generally within about 30 minutes, and especially within about 15 minutes.

[0069] "Subject" or "patient" includes mammals, such as humans, companion animals (e.g., dogs, cats, and birds), livestock (e.g., cattle, sheep, pigs, horses, and chickens), and laboratory animals (e.g., rats, mice, guinea pigs, and birds). In one embodiment, the subject or patient is human. Patients as described herein include patients having the diseases or conditions described herein. Patients may be described or referred to by the condition being treated. For example, a patient suffering from PBC is referred to herein as a PBC patient. Patients as described herein may have pre-existing conditions (e.g., conditions present at the time of the first dose other than the disease or condition being treated by the oral dosage form described herein). In one example, the patient is an elderly or pregnant patient. In another example, the patient is a pediatric patient.

[0070] As used herein, the term “pharmaceutically acceptable” means, within the bounds of sound medical judgment, a compound, raw material, composition, filler, binder, fluidizer, disintegrant and / or dosage form suitable for use in contact with human and animal tissues in a reasonable benefit-to-risk ratio without causing excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0071] "Pharmacologically acceptable excipients" means excipients that are generally safe, non-toxic, and not biologically or otherwise undesirable, and are useful for preparing pharmaceutical compositions, and include excipients acceptable for veterinary and human medical uses. As used herein and in claims, "pharmaceutically acceptable excipients" includes one or more such excipients.

[0072] The pharmaceutical compositions of this disclosure are formulated to be compatible with their intended route of administration, namely the oral route in this disclosure.

[0073] As used herein, “control” means a baseline level determined for each patient, a quantity or level considered normal by those skilled in the art, or any level or measurement taken by the biomaker described herein from a patient or population of patients at any point in time for a particular condition.

[0074] As used herein, “cholestasis” or “cholestasis disorder” refers to a disease or condition in which bile excretion from the liver is impaired or inhibited, and which may occur in the liver or bile ducts. Intrahepatic cholestasis and extrabile cholestasis are the two types of cholestasis. Intrahepatic cholestasis (occurring within the liver) is most commonly seen in primary biliary cholangitis, primary biliary cirrhosis, primary sclerosing cholangitis, sepsis (systemic infection), acute alcoholic hepatitis, drug toxicity, and malignant tumors. Extrahepatic cholestasis (occurring outside the liver) can be caused by bile duct tumors, strictures, cysts, diverticula, stone formation in the common bile duct, pancreatitis, pancreatic tumors or pseudocysts, and compression by masses or tumors of neighboring organs. The clinical symptoms and signs of cholestasis include itching, fatigue, jaundice of the skin or eyes, indigestion of certain foods, nausea, vomiting, pale stools, dark urine, and pain in the upper right abdomen. Patients with cholestasis can be diagnosed and clinically monitored based on a series of standard clinical tests, including the measurement of serum levels of alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), 5' nucleotidase, bilirubin, bile acids, and cholesterol. Generally, a patient is diagnosed with cholestasis if all three diagnostic markers—alkaline phosphatase, GGT, and 5' nucleotidase—are considered abnormally high. Normal serum levels of these markers may vary slightly depending on the laboratory and procedure, according to the testing protocol. Therefore, based on the specific laboratory and procedure, a physician can determine what constitutes an abnormally high blood concentration of each marker. For example, patients suffering from cholestasis typically have blood alkaline phosphatase levels of approximately 125 IU / L or higher, GGT levels of approximately 65 IU / L or higher, and 5' nucleotidase levels of approximately 17 NIL or higher. Because serum marker levels are prone to fluctuation, cholestasis may be diagnosed based on abnormal values ​​of these three markers, in addition to the presence of at least one of the aforementioned symptoms, such as pruritus (itching).

[0075] Fibrosis refers to a condition involving the development of excessive fibrous connective tissue, such as scar tissue, in a tissue or organ. Such scar tissue formation can occur in response to infection, inflammation, or organ damage caused by disease, external factors, or chemical toxicity. Fibrosis can occur in a variety of tissues and organs, including the liver, kidneys, intestines, lungs, and heart.

[0076] In this disclosure, “particle size reduction” is performed with the aim of improving the dissolution rate and bioavailability of a drug by increasing the surface area (specific surface area, or “SSA”) of the drug, by crushing solid particles with mechanical force such as impact, shear, or friction to reduce the particle size. Known particle size reduction methods include, but are not limited to, high-speed rotary impact mills (hammer mills and impact mills) that reduce particle size by the impact force of a hammer or pin rotating at high speed in a chamber, carrier mills (ball mills or vibratory mills) that reduce the particle size of a powder by impact or frictional force in a rotating cylinder in which the powder and magnetic balls are arranged, and fluid energy mills (jet mills) that reduce particle size by injecting compressed air and raw material particles from a nozzle and causing particles accelerated by the jet of compressed air to collide with swirling particles in a chamber. In one embodiment, the particle size of ellafibranol is reduced using a jet mill.

[0077] As defined herein, “micronization” means reducing the particle size of the active ingredient in this disclosure, ellafibranol, or a pharmaceutically acceptable salt or ester thereof, to less than approximately 15 μm. In some examples, ellafibranol has a particle size distribution of D90 15 μm or less and D50 5 μm or less.

[0078] The oral solid dosage forms of the present disclosure, comprising elafibranol or a pharmaceutically acceptable salt or ester thereof in the form of particles, have improved solubility and dissolution.

[0079] The pharmaceutical composition contains the entire active ingredient, and when the pharmaceutical composition contains a capsule shell, a carrier, an excipient, a diluent, a disintegrant, a lubricant, and a binder, the measurement is performed with these components.

[0080] The present disclosure also relates to an isotopically labeled elafibranor or a pharmaceutically acceptable salt or ester thereof, which are identical to those described in the present disclosure and the following formulas, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into elafibranor or a pharmaceutically acceptable salt or ester thereof are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 14 C, and 18 F. Elafibranor or a pharmaceutically acceptable salt or ester thereof containing the aforementioned isotopes and / or other isotopes of other atoms is within the scope of the present disclosure. Isotopically labeled elafibranor or a pharmaceutically acceptable salt or ester thereof, such as 3 H, 14 C incorporated with a radioactive isotope, is useful for drug and / or substrate tissue distribution assays. Due to ease of preparation and ease of detection, tritium isotopes, namely 3 H, and carbon-14 isotopes, namely 14 C, are particularly preferred. Furthermore, deuterium, namely 2Substitution with heavier isotopes, such as 1H, may be preferable in some situations, as it can lead to certain therapeutic benefits due to improved metabolic stability, such as an extended half-life in vivo or a reduction in the required dose. Isotope-labeled ellafibranols or their pharmaceutically acceptable salts or esters can generally be prepared by performing the procedures disclosed in the examples of this disclosure, by substituting readily available isotope-labeled reagents with unisotopically labeled reagents. In one embodiment, ellafibranols or their pharmaceutically acceptable salts or esters are unisotopically labeled. In one embodiment, deuterated ellafibranols are useful in bioanalytical assays. In other embodiments, ellafibranols or their pharmaceutically acceptable salts or esters are radiolabeled.

[0081] In one embodiment, the pharmaceutical composition may further comprise a coating composition comprising a sugar-based coating agent, a water-soluble film coating agent, an enteric coating agent, and a delayed-release coating agent, or any combination thereof. Such coating agents may be useful, for example, to protect ellafibranol from light. In other embodiments, the coating agent may be any coating agent known in the art. Examples of coating agents include sucrose, alone or in combination with agents such as talc, calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, and pullulan or any combination thereof; cellulose derivatives, e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethylcellulose; synthetic polymers, e.g., polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, and polyvinylpyrrolidone; polysaccharides, e.g., pullulan; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; carboxymethylethylcellulose; cellulose acetate phthalate; acrylic acid derivatives, e.g., methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; natural substances, e.g., shellac; titanium dioxide; polyvinyl alcohol, polyethylene glycol; talc; lecithin; and / or combinations thereof. In one embodiment, the coating agent is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, polyethylene glycol, and lecithin, or a combination thereof. In particular, the coating agent is Opadry® II (e.g., Opadry® II green, white, yellow, orange, etc.).

[0082] In specific embodiments, the pharmaceutical composition further comprises a colorant (also called a dye). Depending on the circumstances, the colorant may be added to the coating. Preferably, the coating agent is not white. More preferably, the coating agent is yellow, orange, green, or blue.

[0083] In particular, this pharmaceutical composition further comprises a coloring agent selected from the group consisting of synthetic food coloring agents and natural coloring agents. The coloring agent may be a synthetic coloring agent, for example, Brilliant Blue FCF (E133), Indigotine (E132), First Green FCF (E143), Erythrosine (E127), Alura Red AC (E129), Tartrazine (E102), and Sunset Yellow FCF (E110).

[0084] The coloring agent may be aluminum lake. The term "aluminum lake" refers to the pigment produced by the reaction of aluminum hydroxide with a food coloring agent.

[0085] In a preferred embodiment of the present invention, the colorant is Sunset Yellow FCF Aluminum Lake.

[0086] Preferably, the pharmaceutical composition comprising elafibranol or a pharmaceutically acceptable salt or ester thereof is in the form of solid particles.

[0087] The proportions of the active ingredient (i.e., elafibranol or its pharmaceutically acceptable salts or esters) and various excipients of the oral solid dosage forms of this disclosure can vary. For example, the oral solid dosage form may contain the active ingredient in amounts such as 35 mg to 180 mg, 40 mg to 120 mg, etc., per oral solid dosage form. Furthermore, the oral solid dosage form may contain microcrystalline cellulose as a filler in amounts of 20 to 55% by mass, particularly 40 to 49% by mass, or 43 to 48% by mass. Furthermore, the composition may contain povidone as a binder in amounts of 2 to 6% by mass, or 4 to 5% by mass. Furthermore, the composition may contain croscarmellose sodium as a disintegrant in amounts of 1 to 10% by mass, particularly 3.5 to 6.5% by mass. Furthermore, the composition may contain colloidal silica as a fluidizer in amounts of 0.01 to 0.2% by mass. Furthermore, the composition may contain magnesium stearate as a lubricant in amounts of 0.5 to 1.5% by mass.

[0088] In preferred embodiments, the oral solid dosage form of the present disclosure is a tablet containing elafibranol or a pharmaceutically acceptable salt or ester thereof.

[0089] In certain embodiments, this specification discloses tablets comprising: (a)(i) Elafibranol or its pharmaceutically acceptable salts or esters, (ii) Fillers, (iii) Disintegrants, and (iv) Binder The internal phase, including, (b) An outer phase comprising a disintegrant, a fluidizing agent, and a lubricant.

[0090] In certain embodiments, when tested using a paddle device at 75 rpm, 37°C ± 0.5°C, and with SDS in 1000 mL of water, where the SDS content is 0.6% for 40 mg, 0.8% for 80 mg, and 1% for 120 mg, according to European Pharmacopeia 5.0, paragraph 2.9.3, at least 90%, preferably elafibranol or its pharmaceutically acceptable salt or ester, is released from the tablet within 30 minutes.

[0091] In certain embodiments, when tested using a paddle device at 75 rpm, 37°C ± 0.5°C, and with SDS in 1000 mL of water, where the SDS content is 0.6% for 40 mg, 0.8% for 80 mg, and 1% for 120 mg, according to European Pharmacopeia 5.0, paragraph 2.9.3, at which point at which the tablets are released from the tablets within 15 minutes.

[0092] In yet another specific embodiment, the tablets disclosed herein include: (a)(i) Elafibranol or any pharmaceutically acceptable salt or ester thereof; (ii) A filler selected from the group consisting of mannitol, microcrystalline cellulose, and lactose; (iii) A disintegrant selected from the group consisting of crospovidone and croscarmellose sodium; and (iv) A binder selected from the group consisting of HPC, copovidone, povidone, and hydroxypropyl methylcellulose. The internal phase, including, (b) An outer phase comprising a disintegrant selected from the group consisting of crospovidone and croscarmellose sodium, colloidal silica as a fluidizer, and magnesium stearate as a lubricant.

[0093] In further embodiments, the tablet includes: (a)(i) Elafibranol or any pharmaceutically acceptable salt or ester thereof; (ii) Microcrystalline cellulose; (iii) Croscarmellose sodium; and (iv) Povidone, The internal phase, including, (b) An outer phase comprising croscarmellose sodium, colloidal silica, and magnesium stearate.

[0094] In another specific embodiment, the tablets disclosed herein include, with respect to the total weight of the tablets: (a)(i) 20-60% by mass of elafibranol or a pharmaceutically acceptable salt or ester thereof; (ii) 20-55% by mass of microcrystalline cellulose; (iii) 0.8 to 6% by mass of croscarmellose sodium; and (iv) 2-6 mass% povidone, The internal phase, including, (a) 0.2-4% by mass of croscarmellose sodium; 0.1 to 4% by mass of colloidal silica; and 0.1-2% by mass of magnesium stearate; The Minister of Foreign Affairs, including the Minister of Foreign Affairs.

[0095] In yet another embodiment, the tablet further comprises an external coating (also called a film coating). In a further embodiment, the tablet comprises 2 to 10% by mass of the external coating relative to the total weight of the tablet. Useful coating agents are listed above. In a particular embodiment, the coating comprises a polyvinyl alcohol such as Opadry® II. In a specific embodiment, the external coating comprises a colorant (also called a dye). Preferably, the colorant is not white. More preferably, the colorant is yellow, orange, green, or blue. The colorant may be a synthetic colorant, for example, Brilliant Blue FCF (E133), Indigotine (E132), First Green FCF (E143), Erythrosine (E127), Alura Red AC (E129), Tartrazine (E102), and Sunset Yellow FCF (E110). The colorant may be an aluminum lake. The term “aluminum lake” refers to a pigment produced by the reaction of aluminum hydroxide with a food colorant.

[0096] In a preferred embodiment of the present invention, the external coating includes a colorant which is Sunset Yellow FCF Aluminum Lake.

[0097] In certain embodiments, the tablets of the present disclosure contain elafibranol in particulate form or a pharmaceutically acceptable salt or ester thereof. In other embodiments, the elafibranol in particulate form or a pharmaceutically acceptable salt or ester thereof contains at least 90% of particles with a diameter of 15 μm or less, and / or at least 50% of particles with a diameter of 5 μm or less.

[0098] In a preferred embodiment, the tablet contains elafibranol. In another embodiment, the tablet contains 35 mg to 180 mg of elafibranol, particularly 40 to 120 mg of elafibranol. In a more specific embodiment, the tablet contains 40 mg of elafibranol. In yet another specific embodiment, the tablet contains 120 mg of elafibranol. In a more specific embodiment, the tablet contains 180 mg of elafibranol.

[0099] In one embodiment, the oral solid dosage form useful for the therapeutic method described herein is the composition described in Example 3.

[0100] In another embodiment, the present disclosure provides a method for preparing an oral solid dosage form comprising a therapeutically effective amount of elafibranol or a pharmaceutically acceptable salt or ester thereof in the form of particles, the method comprising: i) micronizing elafibranol or a pharmaceutically acceptable salt or ester thereof to such an extent that at least 90% of the particles have a diameter of less than 15 μm and / or at least 50% of the particles have a diameter of less than 5 μm; and ii) combining the micronized particles with at least one pharmaceutically acceptable excipient. In one embodiment, micronization is performed using a jet mill.

[0101] Tablets can be manufactured through a manufacturing process that includes wet granulation, preferably wet granulation by roller compression, followed by tablet compression and, if necessary, coating. In particular, tablets can be manufactured through a manufacturing process that includes wet granulation by roller compression, followed by tablet compression and coating. The processes used in the manufacture of tablets may include pre-mixing, wet granulation, final mixing, compression, and coating.

[0102] In short, wet granulation can be carried out as follows: Elafibranol or its pharmaceutically acceptable salt or ester (e.g., its particulate form), filler, binder, and disintegrant are weighed and mixed, and then a wet solution is added. The wet granules are then sieved through a rotary screen into an air-fluidized tank. The residual moisture content can be measured at this stage before the drying process. The wet granules can be fluidized by the incoming air and dried. The drying process can then be stopped when the residual moisture content of the dried granules is less than 10% by mass of the total granules, preferably less than 5% by mass. The dried granules can also be sieved directly, and residual moisture analysis can be performed as needed.

[0103] The disintegrant, fluidizer, and lubricant may be mixed with the dried and calibrated granules prepared above.

[0104] Using a rotary tablet press, the final mixture can be compressed to produce tablets. By adjusting the compression parameters, tablets of the desired weight, hardness, thickness, and abrasion resistance can be manufactured. Variations in tablet weight can also be reduced by adjusting the speed of the tablet press and the feeder.

[0105] In one embodiment, the oral dosage form of the ellafibranol composition comprises a film coating comprising one or more excipients selected from polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), talc, and iron oxide. The film coating preferably further comprises a colorant (also called a dye). Preferably, the colorant is not white. More preferably, the colorant is yellow, orange, green, or blue. The colorant may be a synthetic colorant, for example, comprising Brilliant Blue FCF (E133), Indigotine (E132), First Green FCF (E143), Erythrosine (E127), Alura Red AC (E129), Tartrazine (E102), and Sunset Yellow FCF (E110). The colorant may be an aluminum lake. The term "aluminum lake" refers to a pigment produced by the reaction of aluminum hydroxide with a food colorant.

[0106] In a preferred embodiment of the present invention, the film coating comprises a colorant which is Sunset Yellow FCF Aluminum Lake. In a preferred embodiment of the present invention, the oral dosage form of the ellafibranol composition comprises a film coating which comprises one or more excipients selected from polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), talc, iron oxide, and Sunset Yellow FCF Aluminum Lake.

[0107] In one embodiment, water and a coating agent (e.g., Opadry® II White, Opadry® II Green, Opadry® II Yellow, or Opadry® II Orange, preferably Opadry® II Green, Opadry® II Yellow, or Opadry® II Orange) can be mixed for film coating. Core tablets can then be coated with this mixture and tested for weight uniformity, average mass, thickness, dissolution, disintegration time, and appearance.

[0108] In another aspect, the present disclosure provides oral solid dosage forms disclosed herein for use in the treatment or prevention of a disease or condition.

[0109] In another aspect, the Disclosure provides a method for treating or preventing a disease or condition, comprising administering an effective amount of the oral solid dosage form of the Disclosure to a patient in need thereof.

[0110] In another aspect, the present disclosure provides the use of the oral solid dosage forms disclosed herein for the manufacture of a pharmaceutical product for the treatment or prevention of a disease or condition.

[0111] It will be understood that the actual amount of elafibranol administered will be determined by considering relevant circumstances, including the symptoms being treated, the chosen route of administration, the form of elafibranol administered, the individual patient's age, weight, response, and the severity of the patient's symptoms. Therefore, the above-mentioned dosage range is not intended to limit the scope of this disclosure in any way. In some cases, a dosage below the lower limit of the above range may be more than sufficient, and in some cases, a higher dosage may be adopted without causing adverse side effects. In one embodiment, these higher dosages may be divided into several smaller doses initially for administration throughout the day.

[0112] Examples of diseases or symptoms include, but are not limited to, cholestatic diseases, fibrosis, and liver diseases. In particular, diseases or symptoms may be selected from the group consisting of cholestatic diseases and hepatic fibrosis. In certain embodiments, diseases or symptoms may be selected from the group consisting of PBC, PSC, NAFLD, NASH, hepatitis C infection, alcoholic liver disease, liver damage due to progressive hepatic fibrosis, hepatic fibrosis, or cirrhosis.

[0113] In one embodiment, the disease or symptom is PBC. PBC is a chronic disease in which the bile ducts of the liver are gradually destroyed. As a result, bile accumulates in the liver, leading to tissue damage and scarring or fibrosis, and eventually cirrhosis. PBC may be advanced-stage PBC. "Advanced-stage PBC" refers to PBC characterized by one or more of the following: baseline total bilirubin level > upper limit of the normal range (ULN); baseline total ALP level > 5 times ULN; baseline transient elastography (TE) level > 10.7 kPa; cirrhosis based on initial or baseline biopsy results, or a patient with an Ishak score of 6 (cirrhosis) or Ludwig / Scheuer PBC stage 4; or a history of ascites, cirrhosis, jaundice, portal hypertension, portal hypertensive gastropathy, or esophageal varices.

[0114] In one embodiment, the disease or condition is PSC. PSC is a rare disease affecting the bile ducts. In PSC, the bile ducts become scarred. The bile ducts gradually narrow, causing bile to reflux into the liver and damage it.

[0115] NAFLD is a condition characterized by the accumulation of fat in the liver (known as fatty infiltration). NAFLD is one of the most common causes of chronic liver disease and encompasses a range of symptoms associated with fat deposition in hepatocytes. These range from simple fatty liver to NASH, advanced fibrosis, and cirrhosis. The disease is almost always asymptomatic and is often discovered incidentally due to elevated liver enzyme levels. NAFLD is strongly associated with obesity and insulin resistance and is now widely recognized as a hepatic component of metabolic syndrome.

[0116] NASH is a condition characterized by inflammation of the liver and the accumulation of fat and fibrous (scar) tissue. Blood liver enzyme levels can be higher than the mild elevation seen in non-alcoholic fatty liver disease (NAFL). Similar symptoms occur in people who abuse alcohol, but NASH occurs in people who drink little to no alcohol. NASH affects 2-5% of Americans and is most common in people with one or more of the following conditions: obesity, diabetes, hyperlipidemia, insulin resistance, use of certain medications, or exposure to toxins. NASH is becoming increasingly common worldwide as a cause of chronic liver disease and is associated with increased liver-related mortality and hepatocellular carcinoma, even in the absence of cirrhosis. 15-20% of NASH patients progress to cirrhosis, and it is now one of the primary indications for liver transplantation in the United States.

[0117] Furthermore, the method provided herein is a method for treating cholestatic diseases (such as PBC or PSC), NAFLD, NASH, hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, hepatic fibrosis, or cirrhosis in patients in need, by administering an effective amount of the above oral dosage form.

[0118] In certain embodiments, the method is a method for treating PBC by administering an effective amount of the above oral dosage form. In one embodiment, the method is a method for treating PBC by administering the above oral dosage form.

[0119] In yet another embodiment, the method is a method of treating PSC by administering an effective amount of the above oral dosage form. In one embodiment, the method is a method of treating PSC by administering the above oral dosage form.

[0120] In another embodiment, the method is a method for treating NAFLD by administering an effective amount of the above oral dosage form. In one embodiment, the method is a method for treating NAFLD by administering the above oral dosage form.

[0121] In another embodiment, the method is a method for treating NASH by administering an effective amount of the above oral dosage form. In one embodiment, the method is a method for treating NASH by administering the above oral dosage form. Patients with NASH may be high-risk NASH patients. A "high-risk NASH patient" refers to a patient who has one or more of the following characteristics: NAS > 4; baseline fibrosis stage 2 or 3; or baseline fibrosis stage 1 with a comorbidity (type 2 diabetes, BMI > 30 kg / m2, or ALT > 60 U / T).

[0122] In yet another embodiment, the method is a method for treating fibrosis by administering an effective amount of the above oral dosage form. In one embodiment, the fibrosis is selected from the group consisting of hepatic fibrosis, renal fibrosis, and intestinal fibrosis. In a further embodiment, the fibrosis is hepatic fibrosis, such as progressive hepatic fibrosis. In one embodiment, the method is a method for treating fibrosis by administering the above oral dosage form. In another embodiment, the disclosure provides a method for inhibiting or restoring fibrosis, particularly hepatic fibrosis, comprising administering a therapeutically effective amount of the oral dosage form of the disclosure to a subject in need thereof. In one embodiment, the subject has hepatic fibrosis and does not have a cholestatic disease. In another embodiment, the subject has hepatic fibrosis and a cholestatic disease.

[0123] In one embodiment, the subjects have hepatic fibrosis associated with diseases selected from the group consisting of hepatitis B; hepatitis C; parasitic liver disease; post-transplant bacterial, viral and fungal infections; alcoholic liver disease; NAFLD; NASH; liver disease induced by methotrexate, isoniazid, oxyphenistatin, methyltopa, chlorpromazine, tolbutamide, or amiodarone; autoimmune hepatitis; sarcoidosis; Wilson's disease; hemochromatosis; Gaucher disease; glycogen storage disorders of type IV, VI, IX, or X; alpha-1-antitrypsin (α1-antitrypsin) deficiency; Zellweger disease; tyrosine-induced dysplasia; fructose-induced dysplasia; galactose-induced dysplasia; vascular disorders associated with Budd-Chiari syndrome, venous occlusion, or portal vein thrombosis; and congenital hepatic fibrosis.

[0124] In another embodiment, the subjects have intestinal fibrosis associated with a disease selected from the group consisting of Crohn's disease, ulcerative colitis, post-radiotherapy colitis, and microscopic colitis.

[0125] In another embodiment, the subject has renal fibrosis associated with a disease selected from the group consisting of diabetic nephropathy, hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.

[0126] In yet another embodiment, the method is a method for treating liver cirrhosis by administering an effective amount of the above oral dosage form. In one embodiment, the method is a method for treating liver cirrhosis by administering the above oral dosage form.

[0127] In one embodiment, the disease or condition is hyperlipidemia. In one embodiment, the oral dosage form of the Disclosure is useful for the treatment or prevention of NAFLD or NASH associated with hyperlipidemia. In one embodiment, the composition of the Disclosure is useful for the treatment or prevention of NASH associated with hyperlipidemia.

[0128] In another embodiment, the disease or symptom is a cardiovascular disease. In another embodiment, the cardiovascular disease is arteriosclerosis, hypercholesterolemia, or hypertriglyceridemia.

[0129] In another embodiment, the oral dosage forms of the present disclosure are also useful for reducing liver enzymes. In one embodiment, the subjects who need to reduce liver enzymes do not have a cholestatic disease. In another embodiment, the subjects who need to reduce liver enzymes have a cholestatic disease. In one embodiment, the liver enzymes are alkaline phosphatase, γ-glutamyl transpeptidase (GGT), and / or 5' nucleotides.

[0130] In some cases, the methods using the oral dosage forms of the present invention as described herein may also include assessment, monitoring, measurement, or detection of liver function. Assessment, monitoring, measurement, or detection of liver function may be performed in any treatment course as described herein. Liver function can be determined, for example, by assessing, monitoring, measuring, or detecting the levels of one or more liver biomarkers compared to a control. In some cases, the control is a baseline taken from the patient before the start of treatment. In other cases, the control is a pre-established baseline considered to be within the normal range. The measured or detected values ​​of liver function biomarkers and controls may be expressed as a comparison to the upper limit of normal (ULN).

[0131] Liver biomarkers can be used to evaluate and quantify the efficacy of the course of treatment with the oral dosage forms described herein. In other cases, liver biomarkers described herein can be used to evaluate and quantify liver function in the course of treatment with the ellafibranol compositions described herein. Liver biomarkers can also be used to predict whether a patient or patient population is sensitive to treatment with the ellafibranol compositions described herein. In one embodiment, the liver biomarker used includes evaluating, monitoring, measuring, or detecting the amount or level of aspartate transaminase (AST), alanine transaminase (ALP), alkaline phosphatase (ALP), bilirubin, glycine-conjugated ellafibranol, taurine-conjugated ellafibranol, bile acids, bile acid glycine conjugates, or bile acid taurine conjugates. For example, the liver biomarker to be evaluated, monitored, measured, or detected may be ALP.

[0132] Treatment using the oral dosage forms described herein can reduce the levels of ALP and / or bilirubin in the subjects requiring it.

[0133] In particular, treatment using the oral dosage forms described herein can reduce the bilirubin levels of the target individual, preferably within the normal range.

[0134] In particular, treatment using the oral dosage forms described herein can reduce and / or normalize ALP levels in subjects requiring such treatment.

[0135] The decrease in ALP levels can be expressed as a percentage change relative to ULN. For example, treatment with the oral dosage forms described herein can reduce the ALP levels of patients described herein to approximately 5 times, 4 times, 3 times, 2 times, 1.7 times, 1.5 times, 1.25 times, or below ULN.

[0136] Treatment using the oral dosage forms described herein can normalize ALP levels in subjects requiring such treatment.

[0137] Normalization of ALP levels is defined as an ALP level less than 1.0 × ULN.

[0138] In another embodiment, one or more biomarkers can be used to stratify a patient population that is receiving or scheduled to receive treatment with the oral dosage forms described herein. For example, patients with PBC can be stratified for the risk of hepatocellular carcinoma (HCC).

[0139] Furthermore, this specification also provides a method for reducing or eliminating failure of liver transplant rejection by administering an effective amount of the oral dosage form described above. In some cases, administration of the oral dosage form described herein lowers ALP and / or bilirubin levels. In one embodiment, administration of the oral dosage form described herein lowers ALP and bilirubin levels, thereby reducing transplant complications or rejection. In another embodiment, administration of an effective amount of the oral dosage form described herein improves the post-transplant survival rate of liver transplant patients.

[0140] Another aspect of this disclosure is a method for treating solid tumor cancer by administering an effective amount of an oral dosage form described herein. In one embodiment, the method is a method for treating solid tumor cancer by administering an oral dosage form described herein. In another embodiment, such a method includes the treatment of hepatocellular carcinoma (HCC), colorectal cancer, gastric cancer, liver cancer, breast cancer, kidney cancer, or pancreatic cancer by administering an oral dosage form described herein. In one embodiment, it is a method for treating HCC by administering an effective amount of an oral dosage form described herein. In one embodiment, it is a method for treating colorectal cancer by administering an effective amount of an oral dosage form described herein. In another embodiment, it is a method for treating gastric cancer by administering an effective amount of an oral dosage form described herein. In another embodiment, it is a method for treating liver cancer by administering an effective amount of an oral dosage form described herein. In yet another embodiment, it is a method for treating kidney cancer by administering an effective amount of an oral dosage form described herein. In yet another embodiment, it is a method for treating pancreatic cancer by administering an effective amount of an oral dosage form described herein. The cancer treatment described herein is understood to also be carried out by administering an effective amount of the oral dosage form described herein in combination with one or more anticancer agents.

[0141] In one embodiment, the subject suffers from a cholestatic disorder associated with a disease or condition selected from the group consisting of, for example, primary liver cancer or biliary tract cancer, metastatic cancer, sepsis, chronic central venous nutrition, cystic fibrosis, and granulomatous liver disease.

[0142] In one embodiment, cholestatic disorder is defined as abnormally elevated serum levels of alkaline phosphatase, γ-glutamyl transpeptidase (GGT), and / or 5' nucleotidase. In another embodiment, cholestatic disorder is further defined as presenting with at least one clinical symptom. In one embodiment, the symptom is pruritus (itching). In another embodiment, cholestatic disorder is selected from the group consisting of primary biliary cholangitis (PBC), primary biliary cirrhosis, primary sclerosing cholangitis (PSC), biliary atresia, drug-induced cholestasis, cholestasis, pregnancy-related intracholestasis, progressive familial intrahepatic cholestasis (PFIC), infectious cholangitis, cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, asymptomatic cholangiopancreatosis, and central venous nutrition-associated cholestasis. In a preferred embodiment, cholestatic disorder is PBC or PSC.

[0143] In another embodiment, the Disclosure also provides methods for treating or preventing all forms of symptoms associated with elevated lipid levels. In one embodiment, the symptoms are hyperlipidemia associated with symptoms selected from: refractory primary biliary cholangitis; primary biliary cholangitis, primary sclerosing cholangitis, and non-alcoholic steatohepatitis with elevated liver function test values ​​and hyperlipidemia; refractory primary biliary cirrhosis; primary biliary cirrhosis, primary sclerosing cholangitis, and non-alcoholic steatohepatitis with elevated liver function test values ​​and hyperlipidemia; and hepatitis B, hepatitis C, or chronic liver disease associated with alcohol consumption. In another embodiment, the Disclosure provides methods for treating or preventing hyperlipidemia that is primary hyperlipidemia with or without a genetic component, or hyperlipidemia associated with coronary artery disease, cerebrovascular disease, peripheral vascular disease, aortic aneurysm, or carotid atherosclerosis.

[0144] In one aspect, the disclosure provides a method for treating or preventing primary sclerosing cholangitis and chronic hepatitis caused by hepatitis B, hepatitis C, or alcohol. In one aspect, the disclosure provides a method for treating or preventing other arterial diseases associated with hyperlipidemia. In one aspect, the disclosure provides a method for treating or preventing hypertriglyceridemia.

[0145] One of the advantages of the oral solid dosage forms of the present disclosure is a reduction in the incidence and / or severity of pruritus in subjects treated with the oral solid dosage forms according to the methods of the present disclosure. In one embodiment, the incidence of pruritus in subjects treated with the compositions of the present disclosure is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0146] The oral dosage forms of elafibranol described herein may be administered according to a dosage plan. A dosage plan refers to the continuous and intermittent administration of the oral dosage forms described herein in one or more amounts as described herein. Therefore, in certain cases, a dosage plan may include the continuous administration of the oral dosage forms described herein over any number of days, weeks, months, or years as described herein. In other cases, a dosage plan may include intermittent administration of the oral dosage forms described herein, for example, administration of the composition for a period followed by a rest or drug-free period during which the oral solid dosage form is not administered.

[0147] The administration schedules for the oral solid dosage forms described herein include, for example, daily (QD), every other day (Q2D), once weekly (QW), twice weekly (BID), three times weekly (TIW), once monthly (QM), or twice monthly (Q2M). In one embodiment, the oral dosage forms described herein are administered in QD doses. Therefore, an effective amount of the ellafibranol composition described herein can be administered in QD doses to treat the diseases or symptoms described herein.

[0148] In another embodiment, the oral dosage form described herein is administered in Q2D doses. An effective dose of the oral dosage form described herein may be administered in Q2D doses to treat the disease or symptoms described herein. In another embodiment, the oral dosage form described herein is administered in QW doses. An effective dose of the oral dosage form described herein may be administered in QW doses to treat the disease or symptoms described herein.

[0149] In another embodiment, the oral dosage forms described herein are administered by BID. An effective dose of the oral dosage forms described herein may be administered by BID to treat the disease or condition described herein.

[0150] In another embodiment, the oral dosage forms described herein are administered by TIW (Time-Induced Wet) dose. An effective dose of the oral dosage forms described herein may be administered by TIW to treat the disease or condition described herein.

[0151] In another embodiment, the oral dosage forms described herein are administered by QM. An effective dose of the oral dosage forms described herein may be administered by QM to treat the disease or condition described herein.

[0152] In another embodiment, the oral dosage forms described herein are administered in Q2M. An effective dose of the oral dosage forms described herein may be administered in Q2M to treat the disease or condition described herein.

[0153] The oral dosage forms described herein may be administered for any number of days, weeks, months, or years, as long as the dose is effective for the patient and the patient can tolerate that dose (e.g., the adjusted or readjusted dose described herein). In some cases, the oral dosage forms described herein may be administered to the patient described herein until effectiveness is lost or until unacceptable toxicity or undesirable side effects occur. The daily dose of the oral dosage forms described herein may depend on the patient's tolerance to the dose, composition, or frequency of administration.

[0154] The dosage of the oral dosage forms described herein can be determined based on the patient's medical history.

[0155] Furthermore, this specification provides a method for treating PBC by administering an effective dose of the oral dosage form described herein to a patient in need, wherein the effective dose is either 80 mg or 120 mg.

[0156] Furthermore, this specification provides methods for treating diseases or symptoms described herein, the treatments further comprising the administration of one or more active agents. For example, UDCA is commonly administered in the treatment of PBC, but the majority of patients administered UDCA alone either have an insufficient response to the treatment or no response at all. In such cases, a new or additional agent is needed for the treatment of PBC. The oral dosage forms described herein can be administered in combination with UDCA as described herein (for example, according to one or more of the above-mentioned dosing regimens). In some cases, UDCA is administered at a dose of approximately 10-15 mg / kg / day. In other cases, UDCA is administered at a dose of approximately 300, 600, 900, or 1200 mg / day. Administration of UDCA may include a rest or drug-free period of 1, 2, 3, or 4 weeks. For example, the oral dosage forms described herein are administered in combination with UDCA as described herein, and UDCA is administered at the dose specified above or according to the package insert. The term "package insert" refers to the instructions typically included on the market packaging of a drug approved by the FDA or a similar regulatory body outside the United States, including, for example, information regarding the drug's use, dosage, administration method, contraindications, and / or warnings regarding its use.

[0157] In other examples, other active agents include peroxisome proliferator-activated receptor alpha (PPARα) agonists, peroxisome proliferator-activated receptor delta (PPARδ) agonists, dual PPARα / δ agonists, dual PPARα / γ agonists, or pan-PPAR agonists, HMG-CoA reductase inhibitors, GLP1 agonists, insulin, insulin mimetic drugs, metformin, GTP4 agonists, HST2 inhibitors, DPP-IV inhibitors, SGLT2 inhibitors, or hydroxysteroid dehydrogenase (HSD) inhibitors (e.g., 11β-HSD1 inhibitors, ASK1 inhibitors, ACC1 inhibitors, NOX1 and / or NOX4 inhibitors), or inhibitors or antagonists of one or more chemokine receptors, such as CCR2 and CCR5.

[0158] If the oral dosage form described herein is useful for the treatment of cancer described herein, the composition may be administered in combination with one or more anticancer agents.

[0159] This disclosure is further illustrated by the following embodiments. It should be understood that these embodiments are provided to illustrate specific embodiments and are not intended to limit the scope of this disclosure. [Examples]

[0160] Example 1: Particle size analysis It has been found that aggregate particle size plays a major role in variations in the solubility, mixing uniformity, and content uniformity of tablet formulations. To obtain an appropriate particle size distribution, the grinding of elafibranol was studied. In the fine grinding process, powder particles are accelerated using an air jet in a tornado-shaped flow path within the fine grinding chamber of the grinder. As the particles move through the circular flow path, they collide, reducing their particle size. Due to centrifugal force, larger particles are pushed out of the chamber, while smaller particles concentrate in the center of the grinder, and are sent to the outlet when they reach the appropriate particle size.

[0161] The elafibranolic atomization process was carried out using the following jet mill apparatus: Micronister Alpine 200 Aeroplex, under ambient temperature and humidity conditions.

[0162] The feeder delivers the dosage to the micronizer via two screws. This system ensures a uniform flow rate. At the tip of the micronizer, a disposable sleeve is used to separate air and particulate matter.

[0163] The atomized elafibranol powder is then collected in a polyethylene bag, and its weight at the end of the atomization process is recorded.

[0164] The criteria obtained are as follows: Acceptance criteria: D50% ≤ 5 μm and D90% ≤ 15 μm

[0165] The obtained D50% and D90% values, as well as the calculated [mean + standard deviation], are summarized in Table 1 below. [Table 1]

[0166] Example 2: Improvement of the manufacturing process for elafibranol tablets. 1. Preparation of a wetting solution Purified water is weighed manually into stainless steel containers.

[0167] 2. Granulation 2.1 Wet granulation Elafibranol, microcrystalline cellulose, povidone, and croscarmellose sodium were weighed and added directly to the bowl of the mixer. A wetting solution was gradually added while mixing the raw materials to obtain homogeneous wet granules.

[0168] 2.2 Wet Calibration The wet granules were sieved directly into an air-fluidized bed tank through a rotary screen equipped with a sieving machine.

[0169] 2.3 Drying The tank containing the sieved wet granules was placed in an air-fluidized bed dryer. The wet granules were fluidized by the air and then dried.

[0170] 2.4 Sieving The dried granules were sieved through a rotary screen equipped with a sieving machine and then directly into stainless steel containers for mixing.

[0171] 3.Final mixing Croscarmellose sodium, anhydrous colloidal silica, and magnesium stearate were weighed and added to a stainless steel container containing dried and calibrated granules.

[0172] The mixture was then blended in a bottle blender.

[0173] 4.Tablet compression Using a rotary tablet press, the final mixtures of elafibranol 180 mg, 120 mg, 80 mg, and 40 mg tablets were compressed to theoretical masses of 450 mg, 300.0 mg, 200.0 mg, and 100.0 mg, respectively. The same procedure was used to compress the elafibranol 40 mg and 120 mg tablets (see Table 4 below for quantities and masses).

[0174] 5. Film coating 5.1 Preparation of film coating solution Cold water was weighed and placed in a container, and OpaDry® II was added little by little while stirring until a homogeneous mixture was obtained.

[0175] 5.2 Coating Using an automated coating system, core tablets were coated with the following amounts: 180 mg elafibranol coated tablets with a theoretical mass of 471.0 mg, 120 mg elafibranol coated tablets with a theoretical mass of 314.0 mg, 80 mg elafibranol coated tablets with a theoretical mass of 220 mg (see Table 2) or 209.3 mg (see Table 3), and 40 mg elafibranol coated tablets with a theoretical mass of 104.7 mg.

[0176] Example 3: Tablet formulation [Table 2]

[0177] The amounts of each active ingredient and excipient in Formulation 1 were increased by 1.5 times to obtain Formulation 2, which contains 120 mg of elafibranol.

[0178] [Table 3]

[0179] [Table 4]

[0180] Example 4: Dissolution test of elafibranol tablets Before tableting, elafibranol was jet-milled as described above to reduce the particle size of the raw material. Jet milling (i.e., micronization) resulted in a raw material with smaller, more uniform particle size and an increased surface area, leading to faster drug release from tablets containing jet-milled elafibranol.

[0181] 80 mg and 120 mg elafibranol tablets (formulations 1 and 2 of Example 3) were observed, and drug release was evaluated.

[0182] In tests, coated tablets containing elafibranol released at least 75% of the drug within 15 minutes under the conditions of a solid dosage form dissolution test using a paddle device, according to European Pharmacopeia 2.9.3.

[0183] The dissolution method is described in European Pharmacopeia 5.0, paragraph 2.9.3 and US Pharmacopeia. <711> Using the paddle apparatus (apparatus 2) described in the general chapter, elution solutions were prepared by dissolving 1000 mL of 1.0% and 0.8% sodium lauryl sulfate (SLS) in purified water into elafibranol 120 mg and 80 mg coated tablets, respectively, with a paddle speed of 75 rpm. The conditions were developed by varying the SLS concentration to obtain the precipitation state of the elution solution. The specified conditions made it possible to distinguish formulations tested during formulation and process development in terms of their dissolution profiles. The assay was performed in accordance with European Pharmacopeia 2.2.29 and US Pharmacopeia. <621> The assay was performed by liquid chromatography as described in the general chapter, and the assay was based on reversed-phase isocratic HPLC with UV detection at 357 nm.

[0184] The dissolution and release rates of tablets containing jet-milled elafibranol are shown in Figure 1 (80 mg - Formulation 1) and Figure 2 (120 mg - Formulation 2).

[0185] Example 5: Active ingredient content and uniformity test of elafibranol tablets Identification and assay of ellafibrano Analytical methods for identification and assay are based on European Pharmacopeia 2.2.29 and US Pharmacopeia. <621> Liquid chromatography as described in the general chapter was used; this analytical method is based on reversed-phase gradient HPLC with 350 nm UV detection and PDA detection (wavelengths of 200-500 nm) for identification. This method used a Phenomenex, Synergi Polar-RP column (particle size 4 μm, 150 × 4.6 mm) equilibrated at 25°C, with a two-component mobile phase of methanol (with 0.01% trifluoroacetic acid) and water (with 0.05% trifluoroacetic acid). The tablets were placed in water, ellafibranol was extracted with methanol, and the extracted material was injected into the HPLC column for analysis. Elafibranol was quantified using an external standard.

[0186] Identification was performed by retention time (HPLC-UV) and UV spectroscopy (HPLC-PDA) of the active ingredient.

[0187] ·Content uniformity Content uniformity is based on European Pharmacopeia 2.9.40 and US Pharmacopeia. <905> The procedure was carried out according to the method described, and the HPLC chromatography conditions were the same as those used in the assay.

[0188] The results are shown in Figure 1 (80 mg - Formulation 1) and Figure 2 (120 mg - Formulation 2).

[0189] Example 7: Stability test of elafibranol tablets 80 mg and 120 mg The stability of the 80 mg and 120 mg tablets (Formulation 1 and Formulation 2) was tested in stability tests.

[0190] Stability testing was conducted at 25°C and 60% relative humidity (RH) for a maximum of 36 months. During the test period, average mass, mass uniformity, decay time, elution rate, and the content of ellafibranol and degradation products were measured periodically.

[0191] The prescription results for 80 mg and 120 mg tablets are shown in Figure 1 (80 mg - Formulation 1) and Figure 2 (120 mg - Formulation 2).

[0192] Example 8: Drugs used in clinical trials The stability of the 80 mg and 120 mg tablets (Formulation 4 and Formulation 3) was tested in stability tests for clinical lots.

[0193] Stability tests were conducted for 60 months at 25°C and 60% relative humidity (RH) for an 80 mg dose, and for 48 months at 30°C and 75% relative humidity (RH) for a 120 mg dose.

[0194] During the test period, the average mass, mass uniformity, decay time, elution time, and the content of ellafibranol and degradation products were measured periodically.

[0195] The prescription results for 80 mg and 120 mg tablets are shown in Figure 3 (80 mg - Formulation 4) and Figure 4 (120 mg - Formulation 3).

[0196] Elafibranol was supplied as 80 mg or 120 mg white to off-white round coated tablets (different sizes) without printed markings. Elafibranol 120 mg and 80 mg tablets contained elafibranol (active ingredient) and excipients (microcrystalline cellulose, povidone, croscarmellose, anhydrous colloidal silica, magnesium stearate, and Opadry® II White).

[0197] Two placebo tablets (each the same size as the corresponding active tablet) corresponding to either an 80 mg or 120 mg elafibranol tablet were provided as unprinted, unmarked, white to off-white, round coated tablets. The placebo tablets contained the same excipients as the active tablet, plus lactose monohydrate (used in place of the active ingredient, elafibranol).

[0198] The beneficial effects of elafibranol on liver function related to PBC were consistently observed in all Phase 2a clinical trials involving subjects treated with 80 mg / day of elafibranol for 1–3 months, and in Phase 2b clinical trials involving subjects treated with 80 mg / day and 120 mg / day of elafibranol for 12 months.

[0199] Example 9: Phase 2 Clinical Trial This example describes a double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of once-daily (qd) elafibranol 80 mg and 120 mg compared to placebo in a PBC population.

[0200] This study included a screening visit followed by a 12-week double-blind treatment period. Patients participated in the study visit at the time of randomization and at weeks 2, 4, 8, and 12 of the treatment period.

[0201] Elafibranol was administered once daily at a dose of 80 mg or 120 mg for 12 weeks in the tablet dosage forms of the present invention (Formulations 4 and 3), in an orally disintegrating manner. The 120 mg and 80 mg elafibranol tablets contain elafibranol (active ingredient) and excipients (microcrystalline cellulose, povidone, croscarmellose, anhydrous colloidal silica, magnesium stearate, and Opadry® II White). The white tablets were provided to participants in aluminum blister packs.

[0202] The primary objective is to compare the effects of daily oral administration of elafibranol 80 mg and 120 mg on changes in serum alkaline phosphatase (ALP) in patients with inadequate responses to PBC and ursodeoxycholic acid (UDCA) with those of placebo.

[0203] ALP level The primary endpoint of this study is to evaluate the effect of elafibranol 80 mg or 120 mg in terms of the relative change from baseline in serum ALP levels compared to placebo.

[0204] The absolute change in serum ALP levels from baseline was measured up to weeks 2, 4, 8, and 12.

[0205] In this study, all subjects had baseline ALP > 1.67 × ULN (104 U / L in women), with mean baseline ALP levels ranging from 2.5 to 3.4 × ULN. Baseline GGT levels were also elevated in all treatment groups, ranging from 4.5 to 7.8 ULN (36 U / L in women). Mean alkaline phosphatase and GGT levels were slightly lower in the elafibranol 120 mg treatment group and slightly higher in the elafibranol 80 mg treatment group compared to the placebo group.

[0206] In the primary efficacy analysis conducted using ANCOVA based on non-parametric randomization with baseline ALP as a covariate, each dose showed a statistically significant therapeutic effect compared to placebo (p<0.001). The estimated therapeutic effect was -52.0% (95% CI [-62.5;-41.5]) in the elafibranol 80 mg treatment group and -43.9% (95% CI [-55.7;-32.1]) in the elafibranol 120 mg treatment group.

[0207] The mean relative change (%) from baseline to the endpoint in serum ALP was -48.3% in the elafibranol 80 mg treatment group, -40.6% in the elafibranol 120 mg treatment group, and 3.2% in the placebo group.

[0208] The primary efficacy support analysis, performed using ANCOVA with baseline ALP as a covariate, was consistent with the primary efficacy analysis. The estimated therapeutic effect was -51.4% (95% CI [-63.3;-39.5]) in the elafibranol 80 mg treatment group and -43.9% (95% CI [-55.8;-31.9]) in the elafibranol 120 mg treatment group.

[0209] The mean ALP levels (95% CI) from baseline to week 12 are shown in Figure 5 for each treatment group. Both the elafibranol 80 mg and 120 mg treatment groups showed a decrease in ALP levels throughout the 12-week study.

[0210] The mean (95% CI) relative change (%) of ALP from baseline to week 12 is shown in Figure 6 for each treatment group. The mean relative change (%) from baseline shows a decrease in ALP levels in the elafibranol 80 mg and 120 mg treatment groups, starting at week 2 and continuing until week 12.

[0211] Analyzed on the mITT set using Fishers exact test, the response rate to treatment, defined as a reduction of at least 10%, 20%, and 40% of ALP from baseline to the endpoint, showed a statistically significantly higher proportion of responders in all three response categories at the endpoint compared to placebo in both the elafibranol 80 mg and 120 mg treatment groups (p<0.001) (Figure 7).

[0212] Responses based on Paris I, Paris II, Toronto I, and Toronto II risk scores The proportion of patients meeting the PBC response criteria was calculated by applying the disease prognosis risk criteria of Paris I, Toronto I, Toronto II, Toronto III, Toronto IV, Mayo II, and Barcelona. The Paris I risk score was defined as ALP ≤ 3 × ULN and AST ≤ 2 × ULN, and bilirubin was within the normal range.

[0213] The response rates to treatment from baseline to the endpoint, as defined by the Paris I risk score, were 80.0%, 78.6%, and 53.3% in the elafibranol 80 mg group, the elafibranol 120 mg group, and the placebo group, respectively.

[0214] Paris II risk scores were defined as ALP ≤ 1.5 × ULN and AST ≤ 1.5 × ULN, and bilirubin was defined as being within the normal range. The response rates from baseline to the endpoint, as defined by the Paris II risk score, were 53.3%, 50.0%, and 0% in the elafibranol 80 mg group, elafibranol 120 mg group, and placebo group, respectively. The proportion of responders was significantly higher in both elafibranol treatment groups compared to placebo (p=0.002 and p=0.002, GENFIT, GFT505B-216-1 Clinical Study Report: Final v1.0, 14 June 2019, p. 94 of 1663, elafibranol 80 mg vs. placebo and elafibranol 120 mg vs. placebo, respectively).

[0215] The Toronto I risk score was defined as ALP ≤ 1.67 × ULN. The response rates from baseline to the endpoint, as defined by the Toronto I risk score, were 66.7%, 78.6%, and 6.7% in the elafibranol 80 mg group, the elafibranol 120 mg group, and the placebo group, respectively. The proportion of responders was significantly higher in both elafibranol treatment groups compared to placebo (p=0.002 and p<0.001 for elafibranol 80 mg vs placebo and elafibranol 120 mg vs placebo, respectively).

[0216] The Toronto II risk score was defined as ALP ≤ 1.75 × ULN. The response rates from baseline to the endpoint, as defined by the Toronto II risk score, were 66.7%, 78.6%, and 6.7% in the elafibranol 80 mg group, elafibranol 120 mg group, and placebo group, respectively. The proportion of responders was significantly higher in both elafibranol treatment groups compared to placebo (p=0.002 and p<0.001 for elafibranol 80 mg vs. placebo and elafibranol 120 mg vs. placebo, respectively).

[0217] GGTF The absolute and relative changes in GGT from baseline to endpoint are shown in Figure 8 for the mITT set.

[0218] The mean relative change (%) of GGT from baseline to endpoint was -37.1% in the elafibranol 80 mg treatment group, -40.0% in the elafibranol 120 mg treatment group, and 0.2% in the placebo group.

[0219] In the mITT set, an analysis using ANCOVA based on non-parametric randomization with baseline GGT as a covariate showed that each dose had a statistically significant therapeutic effect compared to placebo (p ≤ 0.002).

[0220] The estimated therapeutic effect was -38.6% (95% CI [-56.8;-20.4]) in the elafibranol 80 mg treatment group and -39.9% (95% CI [-58.1;-21.6]) in the elafibranol 120 mg treatment group.

[0221] Figure 9 shows the mean relative mean percentage (%) of GGT from baseline to week 12 in the mITT set for each treatment group. The mean relative mean percentage (%) from baseline shows a measurable decrease in GGT levels as early as week 2 in the elafibranol 80 mg and 120 mg treatment groups.

[0222] Changes in itching Given that pruritus is a significant adverse event in patients with PBC, pruritus was also assessed. More specifically, this involved changes in pruritus from baseline (through the 5D-ICT scale, which measures the severity, duration, direction [improvement or worsening], impairment [impact on daily life], and distribution of itching) and the Visual Analog Scale (VAS) for pruritus.

[0223] The 5D-ict scale is a highly reliable, multidimensional measure of pruritus validated to detect changes over time in patients with chronic pruritus. (Elman S, et al., The 5-Ditch scale: a new measure of pruritus. Br J Dermatol. 2010;162(3):587-593.). The Visual Analogue System (VAS) is a highly reliable and validated method for assessing pruritus. (Reich A, et al., Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol. 2012;92(5):497-501.).

[0224] The pruritus score and absolute change from baseline are provided for each domain of the 5D-ict scale (duration, severity, direction, impairment, and distribution), as well as for each subject and each visit's VAS. Baseline and endpoint values ​​are flagged in this list, and the total score for each visit is also summarized in this list.

[0225] We evaluated the summary of pruritus score values, the absolute change in pruritus score values, and the relative change in pruritus score values ​​using the 5D-ICT scale (duration, severity, direction, impairment, and distribution) and VAS. The median relative mean of the pruritus VAS from baseline to the endpoint was -23.7%, -49.5%, and -7.1% in the elafibranol 80 mg treatment group, the elafibranol 120 mg treatment group, and the placebo treatment group, respectively.

[0226] The median relative percentage change (%) in pruritus VAS from baseline to week 12 is shown in Figure 10 for each treatment group. In both the elafibranol 80 mg and elafibranol 120 mg treatment groups, the median VAS score decreased as early as week 2.

[0227] Example 10: Phase 3 Clinical Trial This example describes a double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of elafibranol 80 mg once daily (qd) compared to placebo in a PBC population.

[0228] This study included a screening visit followed by a 52-week double-blind treatment period. Patients participated in the study visit at randomization and at weeks 4, 13, 26, and 39 of the treatment period.

[0229] Elafibranol was administered once daily at a dose of 80 mg for 52 weeks in the tablet dosage form of the present invention (Formulation 4), in an orally controlled manner. The 80 mg elafibranol tablet contains elafibranol (active ingredient) and excipients (microcrystalline cellulose, povidone, croscarmellose, anhydrous colloidal silica, magnesium stearate, and Opadry® II White). The white tablets were provided to participants in aluminum blister packs.

[0230] The primary objective was to compare the effects of daily oral administration of elafibranol 80 mg on changes related to biochemical indicators of cholestasis or pruritus in patients with PBC (pulmonary cholestasis) with inadequate response to or intolerance of ursodeoxycholic acid (UDCA) compared to placebo.

[0231] Biochemical responses (the primary endpoint) were observed in 51% of patients (55 out of 108) who received elafibranol and 4% (2 out of 53) who received placebo, with a difference of 47 percent points (95% confidence interval [CI], 32-57; P<0.001). Alkaline phosphatase levels normalized in 15% of patients in the elafibranol group at week 52, while none in the placebo group normalized (difference, 15 percent points; 95% CI, 6-23; p=0.002). Among patients with moderate to severe pruritus (44 patients in the elafibranol group and 22 patients in the placebo group), the least squares mean change in WI-NRS from baseline over 52 weeks did not differ significantly between groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99~0.42; P=0.20).

[0232] Example 11: Photostability stress study Two lots of 80 mg elafibranol tablets (formulation 4 from Example 3) were observed to evaluate their photostability. - Tablets containing Opadry® Orange (=Opadry® Orange Coated Tablets=LOT M0002) - Tablets containing Opadry® White (= Opadry® White coated tablets = LOT M0002)

[0233] Following exposure to ultraviolet light in accordance with the ICH guidelines for photostability testing (ICH Guidelines "Stability Testing: Photostability Testing of New Drug Substances and Products Q1"), uncoated tablets M0002 and M0003 were subjected to three tests. - Drawing test: Observation of some color changes before and after exposure to ultraviolet light; - Elafibranol content test: Measurement of elafibranol content before and after exposure to ultraviolet light; and - Impurity testing: Measurement of impurities in tablets before and after exposure to ultraviolet light.

[0234] Opadry® coating composition Opadry (Registered Trademark) White = Opadry (Registered Trademark) II Complete Coating System 85F18422 White = Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol / Macrogol, and Talc.

[0235] Opadry (Registered Trademark) Orange = Opadry (Registered Trademark) II Complete Coating System 85F53893 Orange = Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol / Macrogol, Talc, and FD&C Yellow #6 / Sunset Yellow FCF Aluminum Lake.

[0236] List of Raw Materials

[0237]

Table 5

[0238] Results Description Results: LOT M0002 (Opadry (Registered Trademark) Orange Coating): No difference is seen between stressed and non-stressed samples. No difference in appearance or color is observed.

[0239] LOT M0003 (Opadry (Registered Trademark) White Coating): Significant deterioration of the original color is observed. The stressed sample (exposed to ultraviolet light) changes from white to a light pink color.

[0240] Erafibranol Content Results: Table 5 shows that both the stressed samples of batches M0002 and M0003 fully meet the specification criteria of the test "GFT505 Content". A slight decrease in the GFT505 content of M0003 can be mentioned.

[0241]

Table 6

[0242] Impurity Test Table 6 shows that the stress samples from batch M0002 fully meet the specifications for impurity testing. All impurities are detected below the limit of quantification (LOQ) and the limit of removal (LOR).

[0243] Table 6 also shows the presence of unknown impurities RRT 1.28, RRT 1.32, and RRT 1.68 in batch M0003 after UV exposure. This significant increase in unknown impurities exceeds the specification limits.

[0244] [Table 7]

[0245] conclusion Tablet M0002 fully meets the specifications for the photostability test. No issues were found with the Opadry® orange coating. On the other hand, after the photostability test, tablet M0003 showed a significant increase in unknown impurities and exhibited a pale pink color. In conclusion, a coloring agent is necessary to achieve photostability for the tablets.

Claims

1. i) Elafibranol or its pharmaceutically acceptable salts or esters; ii) A filler selected from the group consisting of mannitol, microcrystalline cellulose, and lactose monohydrate; iii) A disintegrant selected from the group consisting of crospovidone and croscarmethylose sodium; iv) A binder selected from the group consisting of hydroxypropylcellulose, copovidone, povidone, and hydroxypropylmethylcellulose. An oral solid dosage form containing [the specified ingredient].

2. The oral solid dosage form according to claim 1, wherein elafibranol or a pharmaceutically acceptable salt or ester thereof is micronized.

3. The oral solid dosage form according to claim 1 or 2, wherein elafibranol or a pharmaceutically acceptable salt or ester thereof is in the form of particles, and at least 90% of the particles have a diameter of 15 μm or less.

4. An oral solid dosage form according to any one of claims 1 to 3, wherein at least 50% of the particles have a diameter of 5 μm or less.

5. An oral solid dosage form according to any one of claims 1 to 4, wherein the dosage form contains 20 to 60% by mass of elafibranol or a pharmaceutically acceptable salt or ester thereof.

6. An oral solid dosage form according to any one of claims 1 to 5, wherein the dosage form contains 35 to 40% by mass of elafibranol or a pharmaceutically acceptable salt or ester thereof.

7. An oral solid dosage form according to any one of claims 1 to 6, wherein the dosage form contains 35 to 180 mg of elafibranol or a pharmaceutically acceptable salt or ester thereof.

8. An oral solid dosage form according to any one of claims 1 to 7, wherein the dosage form contains 40 to 120 mg of elafibranol or a pharmaceutically acceptable salt or ester thereof.

9. The oral solid dosage form according to any one of claims 1 to 8, wherein the dosage form is a tablet.

10. The aforementioned dosage form, which is a tablet, is given in relation to the total weight of the tablet: (a)(i) 30-60% by mass of elafibranol or a pharmaceutically acceptable salt or ester thereof; (ii) 20–55% by mass of microcrystalline cellulose; (iii) 0.8 to 6% by mass of croscarmellose sodium; and (iv) 2-6% by mass of povidone, The internal phase, including, (b) 0.2–4% by mass of croscarmellose sodium; 0.1 to 0.4 mass% colloidal silica; and 0.1–2% by mass of magnesium stearate; External Minister An oral solid dosage form according to any one of claims 1 to 9, comprising:

11. The oral solid dosage form according to claim 9 or 10, wherein the tablets are obtained by performing the steps of wet granulation, followed by tablet compression and, if necessary, coating.

12. The oral solid dosage form according to any one of claims 9 to 11, wherein the dosage form includes an external coating.

13. The oral solid dosage form according to claim 12, wherein the external coating contains a coloring agent.

14. An oral solid dosage form according to any one of claims 1 to 13, for use in patients who require it for the treatment or prevention of liver damage due to present-day biliary cholangitis (PBC), present-day sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis C infection, alcoholic liver disease, hepatic fibrosis, cirrhosis, or progressive fibrosis.

15. The oral solid dosage form according to claim 14, wherein the composition is administered orally once a day.

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