pharmaceutical

Abstract

To provide an agent useful for treating high HDL-cholesterolemia.SOLUTION: The present invention provides an agent for preventing and / or treating high HDL-cholesterolemia, containing pemafibrate or a salt thereof or their solvates.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a medicine containing pemafibrate or a salt thereof, or a solvate thereof. [Background technology]

[0002] High-density lipoprotein (HDL) is known to inhibit arteriosclerosis by transporting cholesterol accumulated in peripheral tissues, such as the vascular endothelium, to the liver. High levels of HDL cholesterol (HDL-C) in the blood are generally considered beneficial. It has been reported that individuals with low levels of HDL cholesterol in the blood are at higher risk of developing cardiovascular disease. A U-shaped relationship has been observed between HDL cholesterol levels in the blood and the onset of cardiovascular disease, and individuals with significantly elevated serum HDL cholesterol (also referred to as HDL-C levels) have been shown to be at higher risk of developing cardiovascular disease (Non-Patent Documents 1 and 2). Furthermore, it has recently been revealed that elevated HDL-C levels are also a risk factor for age-related macular degeneration (Non-Patent Document 3). Therefore, although treatment for elevated HDL-C levels is necessary, no established treatment has yet been established.

[0003] Cholesteryl ester transfer protein (CETP) is known as a protein that regulates the amount of HDL cholesterol in the blood. This protein is synthesized in the liver and small intestine and present in serum. It regulates the quantity and quality of HDL cholesterol and LDL cholesterol by transferring HDL cholesterol to very-low-density lipoprotein (VLDL) cholesterol and low-density lipoprotein (LDL) cholesterol. It is known that a CETP gene deficiency causes lipoprotein metabolic abnormalities due to a lack of CETP in the blood, resulting in a significant increase in HDL cholesterol. CETP deficiency has been cited as one of the causes of hyper-HDL cholesterol (Non-Patent Document 4).

[0004] Pemafibrate (chemical name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) or its salts or solvates thereof is a compound with PPARα activity, and PPARα activators are known to have the effect of lowering blood triglycerides and increasing HDL cholesterol (Patent Document 1). However, there have been no reports on the effect of this compound on hyper HDL-cholesterolemia. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2005 / 023777 Pamphlet [Non-patent literature]

[0006] [Non-Patent Document 1] Christian M. Madsen et al. European Heart Journal (2017) 38,2478-2486 [Non-patent document 2] Agerholm-Larsen B et al. Circulation 2000;101:1907-1912 [Non-patent document 3] Fan Q et al. Int J Epidemiol. 2017 46, (6) 1891-1902 [Non-patent document 4] Yamashita S et al. Curr Opin Lipidol. 2016 Oct;27(5):459-72 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a pharmaceutical agent effective in treating hyper HDL-cholesterolemia. [Means for solving the problem]

[0008] In order to achieve the above object, the present inventors have conducted extensive research and have unexpectedly found that (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid (hereinafter also referred to as "pemafibrate") significantly reduces HDL-C levels in patients with hyper HDL-C and is effective in treating hyper HDL-C, thereby completing the present invention.

[0009] That is, the present invention provides a preventive and / or therapeutic agent for hyper HDL-cholesterolemia and diseases caused thereby, which contains pemafibrate or a salt thereof, or a solvate thereof. [Brief explanation of the drawings]

[0010] [Figure 1] This shows the change in HDL-C levels when pemafibrate was administered at a dose of 0.4 mg per day in two divided doses for 52 consecutive weeks to patients with high HDL-C due to CETP deficiency. DETAILED DESCRIPTION OF THE INVENTION

[0011] Pemafibrate (compound name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) used in the present invention is represented by the following formula (1):

[0012] [ka]

[0013] It is a compound represented by the chemical structural formula: Furthermore, the medicine used in the present invention is a medicine containing pemafibrate or a salt thereof, or a solvate thereof.

[0014] In one embodiment of the present invention, a salt or solvate of pemafibrate can be used. The salt of pemafibrate is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; amine salts such as ammonium salt, trialkylamine salt and pyridinium salt; mineral acid salts such as hydrochloride and sulfate; and organic acid salts such as acetate. Furthermore, the solvate of pemafibrate is not particularly limited as long as it is a pharmaceutically acceptable solvate, and examples thereof include hydrates. Furthermore, a solvate of a salt of pemafibrate may also be used. In the present invention, it is particularly preferred to use pemafibrate.

[0015] Pemafibrate or a salt thereof or a solvate thereof can be produced, for example, according to the method described in International Publication No. 2005 / 023777.

[0016] In one embodiment of the present invention, serum HDL cholesterol levels can be lowered and hyperHDL-cholesterolemia can be prevented and / or treated by administering a pharmaceutical containing a therapeutically effective amount of pemafibrate or a salt thereof, or a solvate thereof to a patient with abnormally high HDL-C levels.

[0017] In another embodiment of the present invention, diseases caused by elevated HDL-C levels, such as coronary artery disease and age-related macular degeneration, can be prevented and / or treated by administering to a patient a medicament containing a therapeutically effective amount of pemafibrate or a salt thereof, or a solvate thereof.

[0018] In another embodiment of the present invention, CETP deficiency and diseases associated with CETP deficiency can be prevented and / or treated by administering to a patient with CETP deficiency a pharmaceutical containing a therapeutically effective amount of pemafibrate or a salt thereof, or a solvate thereof. Diseases associated with CETP deficiency include, but are not limited to, hyper-HDLemia and diseases caused by hyper-HDLemia (coronary artery disease, age-related macular degeneration, etc.).

[0019] In another embodiment of the present invention, pemafibrate or a salt thereof, or a solvate thereof can be used as an HDL cholesterol-lowering agent for lowering serum HDL cholesterol levels. The HDL cholesterol-lowering agent of the present invention can be used, for example, for the prevention and / or treatment of hyper-HDL-cholesterolemia, and for the prevention and / or treatment of diseases caused by hyper-HDL-cholesterolemia.

[0020] As used herein, "hyper HDL-cholesterolemia" refers to a disease in which the amount of HDL cholesterol in the blood is abnormally high. Causes of hyper HDL-cholesterolemia include primary and secondary causes, such as CETP deficiency and familial hyperalphalipoproteinemia, and secondary causes include heavy alcohol consumption, primary biliary cholangitis, obstructive pulmonary disease, and administration of insulin preparations.

[0021] As used herein, "coronary artery disease" refers to a disease caused by abnormalities in the coronary arteries or occlusion of the coronary arteries, such as angina pectoris and myocardial infarction, and includes, but is not limited to, exertional angina, resting angina, organic angina, vasospastic angina, stable angina, unstable angina, acute myocardial infarction, subacute myocardial infarction, and old myocardial infarction.

[0022] As used herein, "age-related macular degeneration" refers to a disease in which the macula in the retina of the eye degenerates with age. Age-related macular degeneration is classified into "exudative" and "dry" types depending on the cause. In the "exudative type," abnormal choroidal neovascularization occurs from the choroid and spreads to the retinal surface. The new blood vessels are fragile, which can lead to bleeding and accumulation of exudate, causing macular dysfunction, deviation, and decreased vision. Ultimately, irreversible degeneration of the macula occurs, resulting in significant visual impairment. In the "atrophic type," the macula degenerates with age, and depending on the extent of the degeneration, rapid visual impairment can occur. Another characteristic of the atrophic type is that no choroidal neovascularization is observed.

[0023] As an embodiment of the present invention, the following [1] to [9] can be mentioned. [1] A method for increasing HDL-C containing pemafibrate or its salt or a solvate thereof Preventive and / or therapeutic drugs for diabetes. [2] A preventive and / or therapeutic agent for diseases caused by high HDL-C levels, comprising pemafibrate, a salt thereof, or a solvate thereof. [3] The preventive and / or therapeutic drug according to [2], wherein the disease caused by high HDL-cholesterolemia is one or more diseases selected from the group consisting of coronary artery disease and age-related macular degeneration. [4] The preventive and / or therapeutic agent according to any one of [1] to [3], wherein the hyper HDL-cholesterolemia is hyper HDL-cholesterolemia associated with CETP deficiency. [5] A drug for preventing and / or treating CETP deficiency, containing pemafibrate or a salt thereof, or a solvate thereof. [6] An HDL cholesterol lowering agent containing pemafibrate, a salt thereof, or a solvate thereof. [7] The HDL cholesterol-lowering agent according to [6], which is for the prevention and / or treatment of hyper HDL-cholesterolemia. [8] The HDL cholesterol-lowering agent according to [6], which is for the prevention and / or treatment of diseases caused by high HDL-cholesterol levels. [9] The pharmaceutical agent according to any one of [1] to [8], which is for use in patients with a serum HDL cholesterol level of 100 mg / dL or higher.

[0024] Furthermore, the following [A1] to [A9] can be mentioned as one embodiment of the present invention. [A1] A method for preventing and / or treating hyper HDL-cholesterolemia, comprising administering pemafibrate, a salt thereof, or a solvate thereof to a subject. [A2] A method for preventing and / or treating a disease caused by elevated HDL-C levels, comprising administering pemafibrate, a salt thereof, or a solvate thereof to a subject. [A3] The preventive and / or therapeutic method according to [A2], wherein the disease caused by high HDL-cholesterolemia is one or more diseases selected from the group consisting of coronary artery disease and age-related macular degeneration. [A4] The preventive and / or therapeutic method according to any one of [A1] to [A3], wherein the elevated HDL-cholesterolemia is elevated HDL-cholesterolemia associated with CETP deficiency. [A5] A method for preventing and / or treating CETP deficiency, comprising administering pemafibrate, a salt thereof, or a solvate thereof to a subject. [A6] A method for lowering serum HDL cholesterol levels in a subject, comprising administering pemafibrate, a salt thereof, or a solvate thereof to the subject. [A7] A method for lowering serum HDL cholesterol levels according to [A6], which is used for the prevention and / or treatment of hyper HDL-cholesterolemia. [A8] A method for lowering serum HDL cholesterol levels according to [A6], which is used for the prevention and / or treatment of diseases caused by high HDL-cholesterol levels. [A9] The method according to any one of [A1] to [A8], wherein the subject's serum HDL cholesterol level is 100 mg / dL or higher.

[0025] Furthermore, the following [B1] to [B9] can be mentioned as one embodiment of the present invention. [B1] Pemafibrate or a salt thereof, or a solvate thereof for use in the prevention and / or treatment of hyper HDL-cholesterolemia. [B2] Pemafibrate or a salt thereof, or a solvate thereof for use in the prevention and / or treatment of diseases caused by elevated HDL-C levels. [B3] Pemafibrate or a salt thereof, or a solvate thereof according to [B2], wherein the disease caused by high HDL-C levels is one or more diseases selected from the group consisting of coronary artery disease and age-related macular degeneration. [B4] Pemafibrate or a salt thereof, or a solvate thereof according to any one of [B1] to [B3], wherein the hyper HDL-cholesterolemia is hyper HDL-cholesterolemia associated with CETP deficiency. [B5] Pemafibrate or a salt thereof, or a solvate thereof for use in the prevention and / or treatment of CETP deficiency. [B6] Pemafibrate, a salt thereof, or a solvate thereof for lowering serum HDL cholesterol levels. [B7] Pemafibrate or a salt thereof, or a solvate thereof according to [B6], which is used for the prevention and / or treatment of hyper HDL-cholesterolemia. [B8] Pemafibrate or a salt thereof, or a solvate thereof according to [B6], for use in the prevention and / or treatment of diseases caused by elevated HDL-cholesterolemia. [B9] Pemafibrate or a salt thereof, or a solvate thereof according to any one of [B1] to [B8], which is used in a subject whose serum HDL cholesterol level is 100 mg / dL or higher.

[0026] Furthermore, the following [C1] to [C9] can be mentioned as one embodiment of the present invention. [C1] Use of pemafibrate, a salt thereof, or a solvate thereof for the manufacture of a pharmaceutical for the prevention and / or treatment of hyper HDL-cholesterolemia. [C2] Use of pemafibrate, a salt thereof, or a solvate thereof for the manufacture of a pharmaceutical for the prevention and / or treatment of a disease caused by hyper HDL-cholesterolemia. [C3] The use described in [C2], wherein the disease caused by high HDL-C levels is one or more diseases selected from the group consisting of coronary artery disease and age-related macular degeneration. [C4] The use according to any one of [C1] to [C3], wherein the hyper HDL-cholesterolemia is hyper HDL-cholesterolemia associated with CETP deficiency. [C5] Use of pemafibrate, a salt thereof, or a solvate thereof for the manufacture of a medicament for the prevention and / or treatment of CETP deficiency. [C6] Use of pemafibrate, a salt thereof, or a solvate thereof for the manufacture of a pharmaceutical for lowering serum HDL cholesterol levels. [C7] The use according to [C6], wherein the pharmaceutical is used for the prevention and / or treatment of hyper HDL-cholesterolemia. [C8] The use according to [C6], wherein the pharmaceutical is used for the prevention and / or treatment of a disease caused by high HDL-cholesterolemia. [C9] The pharmaceutical agent according to any one of [C1] to [C8], which is intended to be administered to a subject whose serum HDL cholesterol level is 100 mg / dL or higher.

[0027] Pemafibrate or a salt thereof, or a solvate thereof used in carrying out the present invention can be prepared into a pharmaceutical composition (preparation) by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, but are not limited to, excipients, binders, fillers, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, diluents, and the like.

[0028] The pharmaceutical compositions containing pemafibrate or a salt thereof, or a solvate thereof used in the practice of the present invention can be formulated using pharmaceutically acceptable carriers into dosage forms such as tablets, capsules, granules, powders, lotions, ointments, injections, suppositories, eye drops, etc. These preparations can be produced by known methods.

[0029] Pemafibrate, its salts, or solvates thereof used in the practice of the present invention can be administered orally or parenterally, with oral administration being preferred. The therapeutically effective dose and frequency of administration of pemafibrate, its salts, or solvates thereof vary depending on the patient's weight, age, sex, symptoms, etc., but can be appropriately determined by those skilled in the art. For example, for a typical adult, pemafibrate can be administered at 0.05 to 0.8 mg per day in 1 to 3 divided doses, preferably 0.2 to 0.4 mg per day in 1 to 2 divided doses, and more preferably 0.1 to 0.8 mg per day in 1 or 2 divided doses.

[0030] The present invention will be further described below with reference to examples, but the present invention is not limited to these examples. [Example]

[0031] Example 1. Examination of changes in blood parameters after administration of pemafibrate to patients with high HDL-C due to CETP deficiency Adult patients with CETP deficiency and serum HDL cholesterol levels of 200 mg / dL or higher were orally administered pemafibrate at a dose of 0.4 mg per day in two divided doses for 52 weeks. Blood samples were taken from the patients before and every four weeks thereafter to measure lipid parameters. The lipid parameters measured from the blood samples are shown in Figure 1.

[0032] As can be seen from Figure 1, pemafibrate significantly reduced the patient's high serum HDL cholesterol level, improving the patient's condition. [Industrial Applicability]

[0033] According to the present invention, pemafibrate reduces HDL-C levels in patients with hyper HDL-C and is useful as a therapeutic agent for hyper HDL-C.

Claims

1. A preventive and / or therapeutic drug for hyper-HDL-Cemia containing pemafibrate or a salt thereof, or a solvate thereof, characterized in that 0.1 to 0.8 mg of pemafibrate or a salt thereof, or a solvate thereof is orally administered once or twice daily to an adult patient with hyper-HDL-Cemia whose serum HDL cholesterol level is 100 mg / dL or higher.

2. A method for treating hyper-HDL-C in adult patients with serum HDL cholesterol levels of 200 mg / dL or more, comprising orally administering 0.1 to 0.8 mg of pemafibrate or a salt thereof or a solvate thereof in one or two divided doses per day. and a drug for preventing and / or treating hyper-HDL-cholesterolemia, comprising a salt thereof or a solvate thereof.

3. A preventive and / or therapeutic drug for hyper-HDL-Cemia containing pemafibrate or a salt thereof, or a solvate thereof, characterized in that 0.1 to 0.8 mg of pemafibrate or a salt thereof, or a solvate thereof is orally administered once or twice daily to an adult patient with CETP deficiency and hyper-HDL-Cemia whose serum HDL cholesterol level is 200 mg / dL or more.

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