WO2015030033A1 - 脂質異常症治療剤 - Google Patents
脂質異常症治療剤 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention aims to prevent and / or treat lipemia conditions such as atherosclerosis and hypercholesterolemia, for example, (R) -2- [3-[[N- ( The present invention relates to a composition containing benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid and ⁇ -3 fatty acid or an ester derivative thereof, and a combination thereof.
- Dyslipidemia especially hypercholesterolemia, has already become a disease area with a high level of medical satisfaction due to the appearance of statins.
- statins the results of many large-scale clinical trials have revealed that lowering LDL cholesterol in blood leads to prevention of coronary artery disease (the lower lower the better), and stricter lipid control is required.
- PPAR is one of the receptors belonging to the nuclear receptor family. This receptor is known to have three subtypes ( ⁇ , ⁇ , ⁇ ) (Non-patent Document 2). Among these, PPAR ⁇ is mainly expressed in the liver, and when PPAR ⁇ is activated, production of apo C-III is suppressed, and then lipoprotein lipase (LPL) is activated, resulting in fat Disassembled. As PPAR ⁇ agonists, unsaturated fatty acids, fibrates such as fenofibrate, bezafibrate, gemfibrozil and the like are known (Non-patent Document 3). In recent years, compounds having a PPAR ⁇ activation action more selectively and selectively than conventional fibrate drugs have been reported (Patent Documents 1 to 10).
- ⁇ -3 fatty acids represented by icosapentaic acid (EPA) and docosahexaenoic acid (DHA) are long-chain essential fatty acids mainly contained in fish fats.
- This fatty acid reduces blood triglycerides by suppressing absorption of triglycerides from the intestinal tract, suppressing biosynthesis in the liver, and enhancing plasma lipoprotein lipase activity (Non-patent Documents 4 and 5), inhibiting liver cholesterol synthesis, cholesterol It has been reported that blood total cholesterol is reduced by promoting biliary excretion (Non-patent Document 6).
- Non-patent Document 8 the total cholesterol values reported in these two are data showing an increase in the combination group, and LDL cholesterol lowering action cannot be confirmed.
- Patent Document 11 the disclosed data is dosing data for one patient with acute pancreatitis in the background, and there is no comparison with the effects of fenofibrate or omega-3 fatty acids alone. In addition, LDL cholesterol lowering action has not been confirmed.
- An object of the present invention is to provide a combination pharmaceutical composition and a medicament for preventing and / or treating dyslipidemic conditions such as atherosclerosis, hypercholesterolemia, hyper-LDL cholesterolemia, hypertriglyceridemia. To provide a combination.
- Patent Document 1 a dyslipidemia that has a selective PPAR ⁇ activation action and is not accompanied by weight gain or obesity in mammals including humans. It is disclosed that it is useful as a preventive and / or therapeutic agent for arteriosclerosis, diabetes, diabetic complications (diabetic nephropathy, etc.), inflammation, heart disease, etc., (R) -2- [3- [[N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid (Example 85 of Patent Document 1) or a salt thereof and ⁇ -3 fatty acid
- the present invention was completed by finding the fact that a combination with a certain EPA exerts a strong blood LDL cholesterol lowering effect.
- the present invention a) (R) -2- [3-[[N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid (hereinafter referred to as Compound A) Or a salt thereof or a solvate thereof, and b) omega-3 fatty acids or ester derivatives thereof,
- the present invention provides a pharmaceutical composition for preventing and / or treating dyslipidemia.
- a pharmaceutical composition for preventing and / or treating hyper-LDL cholesterolemia comprising:
- a pharmaceutical composition comprising Compound A, a salt thereof, or a solvate thereof, and an omega-3 fatty acid or an ester derivative thereof in a patient with dyslipidemia or a patient who is likely to have dyslipidemia.
- EPA icosapentaic acid
- the ester derivative of ⁇ -3 fatty acid is ethyl icosapentate.
- the drug and pharmaceutical composition of the present invention have an excellent blood LDL cholesterol lowering action, and are useful for the prevention and / or treatment of dyslipidemia, particularly hyper LDL-C blood.
- FIG. 1 is a graph showing plasma VLDL-C upon administration of Compound A (0.1 mg / kg) or EPA (3000 mg / kg) alone and in combination.
- FIG. 2 is a diagram showing triglyceride (TG) upon administration of Compound A or EPA alone and in combination.
- FIG. 3 is a graph showing plasma LDL-C upon administration of Compound A or EPA alone and in combination.
- (R) -2- [3-[[N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid (compound A) used in the present invention is for example, it can be produced according to the method described in WO2005 / 023777 pamphlet or the like. Moreover, it can also formulate according to the method as described in literature.
- salts and solvates can be produced by conventional methods.
- the salt of compound A is not particularly limited as long as it is pharmaceutically acceptable; for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt Organic base salts such as trialkylamine salts; mineral acid salts such as hydrochlorides and sulfates; organic acid salts such as acetates.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt
- ammonium salt Organic base salts such as trialkylamine salts
- mineral acid salts such as hydrochlorides and sulfates
- organic acid salts such as acetates.
- solvate of Compound A or a salt thereof examples include hydrates, alcohol solvates (for example, ethanol solvates) and the like.
- ⁇ -3 fatty acids in the present invention include icosapentoic acid (EPA) and docosahexaenoic acid (DHA).
- EPA icosapentoic acid
- DHA docosahexaenoic acid
- Eicosapentic acid refers to All-cis-5,8,11,14,17-icosapentic acid, which is easily obtained by hydrolyzing natural glycerin esters obtained from fish fats and others to remove the glycerin moiety It is also possible to use a commercially available product. Examples of commercial products containing EPA include EPA preparation Epadale and omacor (EPA / DHA / vitamin E preparation). Moreover, the said icosapentoic acid may form the salt with sodium and potassium, for example.
- ester derivatives of omega-3 fatty acids include glycerin esters and C 1-4 alkyl esters.
- the C 1-4 alkyl ester include methyl ester, ethyl ester, propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, t-butyl ester, etc., preferably methyl ester, ethyl ester, propyl An ester, particularly preferably an ethyl ester.
- glycerin ester can be easily extracted from natural resources as natural glycerin ester.
- the lower alkyl ester can be easily produced by dehydrating and condensing an aliphatic lower alcohol with ⁇ -3 fatty acid.
- the purity of the ⁇ -3 fatty acid or its ester derivative is not particularly limited, but a high purity is preferable from the viewpoint that a small dose is required.
- the agent of the present invention is useful for the prevention and / or treatment of dyslipidemia such as hypercholesterolemia and hyper LDL-C blood.
- dyslipidemia refers to the total triglyceride (TG) level, total cholesterol (TC) level, VLDL cholesterol (VLDL-C) level, LDL cholesterol (LDL-C) level, or HDL cholesterol (HDL- C)
- TC total cholesterol
- VLDL-C VLDL cholesterol
- LDL-C LDL cholesterol
- HDL- C HDL cholesterol
- a disease requiring a decrease in LDL cholesterol (LDL-C) and / or triglyceride (TG) is that the amount of LDL-C and / or TG in blood is higher than the normal value. Refers to cases.
- Compound A of the present invention or a salt thereof, or a solvate thereof alone or in combination with other pharmaceutically acceptable carriers, is used for tablets, capsules, granules, powders, lotions, ointments, injections. Or a dosage form such as a suppository. These preparations can be produced by known methods.
- solubilizing agents such as tragacanth gum, gum arabic, sucrose fatty acid ester, lecithin, olive oil, soybean oil, PEG400; excipients such as starch, mannitol, lactose; methylcellulose, carboxymethylcellulose Precise combination of binders such as sodium and hydroxypropylcellulose; disintegrants such as crystalline cellulose and carboxymethylcellulose calcium; lubricants such as talc and magnesium stearate, fluidity improvers such as light anhydrous silicic acid, etc. Can be manufactured.
- the pharmaceutical composition of the present invention is used in combination with a) Compound A, or a salt thereof or a solvate thereof, and b) an omega-3 fatty acid or an ester derivative thereof, in addition to the action of each drug.
- a) Compound A, or a salt thereof or a solvate thereof Used as a form that can prevent and / or treat dyslipidemia such as hypercholesterolemia and hyper-LDL-C blood using the synergistic blood HDL-C elevating action of both drugs
- dyslipidemia such as hypercholesterolemia and hyper-LDL-C blood using the synergistic blood HDL-C elevating action of both drugs
- Compound A, or a salt thereof, or a solvate thereof, and omega-3 fatty acid or an ester derivative thereof may be administered simultaneously, or may be administered separately at intervals.
- Compound A or a salt thereof or a solvate thereof and ⁇ -3 fatty acid or an ester derivative thereof may be formulated into a single formulation, or both drugs may be formulated separately and used as a kit. That is, the pharmaceutical composition of the present invention comprises at least one of a drug comprising at least one selected from Compound A, a salt thereof, or a solvate thereof as an active ingredient, and an omega-3 fatty acid or an ester derivative thereof. It may be a kit comprising a combination of drugs containing one kind.
- the compounding ratio of Compound A, or a salt thereof, or a solvate thereof, and ⁇ -3 fatty acid or an ester derivative thereof is the effective dose of each active ingredient.
- the range can be appropriately selected, but in general, the mass ratio is preferably in the range of 1:10 to 1: 100000, and more preferably in the range of 1: 2000 to 1: 30000.
- the mass ratio is preferably 1: 2000 to 1: 30000 from the viewpoint of obtaining a particularly excellent synergistic effect.
- the dosage forms of both drugs may be the same or different.
- count of administration of each component may differ.
- the compound A of the present invention, or a salt thereof, or a solvate thereof is administered by oral administration or parenteral administration.
- the dosage of the pharmaceutical agent of the present invention varies depending on the weight, age, sex, symptoms, etc. of the patient, but in the case of a normal adult, (R) -2- [3-[[N- (benzoxazol-2-yl)- N-1- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid is preferably administered in an amount of 0.001 to 100 mg, preferably 0.1 to 0.4 mg per day, in 1 to 3 divided doses.
- the omega-3 fatty acid or its ester derivative is preferably administered in an amount of 100 to 10,000 mg, preferably 1800 to 2700 mg as EPA, 1 to 3 times a day.
- TG was measured by an automatic analyzer using a measuring reagent Qualgent TG (Sekisui Medical Co., Ltd.).
- the synergistic effect was determined by the bulge formula (there is a synergistic effect if the relative value in the group used in combination is smaller than the product of the relative value of single agent A and the relative value of single agent B).
- Control Group 2 Compound A 0.1 mg / kg
- Group 3 EPA 200mg / kg
- Group 4 Compound A 0.1 mg / kg and EPA 200 mg / kg 3.
- Statistical analysis and data processing method The results are shown as mean ⁇ standard deviation.
- Example 2 Combined effect of Compound A and EPA on LDL-C in Wister rats
- Control Group 2 Compound A 0.1 mg / kg
- Group 3 EPA 200mg / kg
- Group 4 Compound A 0.1 mg / kg and EPA 200 mg / kg
- Group 5 EPA 3000mg / kg
- Group 6 Compound A 0.1 mg / kg and EPA 3000 mg / kg 3.
- Statistical analysis and data processing method The results are shown as mean ⁇ standard deviation. Comparison between the control group and the drug administration group was performed by Dunnett's multiple comparison test, and a risk rate of less than 5% was determined to be significant. 4). Results The results of measuring LDL-C after administration of each drug are shown in FIG. In addition, Table 3 shows the relative values of each group of LDL-C.
- the drug and pharmaceutical composition of the present invention have excellent blood VLDL-C lowering action and blood LDL-C lowering action, and dyslipidemia, particularly high LDL cholesterolemia, low HDL-C blood Since it is useful for the prevention and / or treatment of TG blood, it has industrial applicability.
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Abstract
Description
a)(R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸(以下、化合物Aと称する場合がある。)、若しくはその塩又はこれらの溶媒和物、及び、
b)ω-3脂肪酸又はそのエステル誘導体、
を含有してなる脂質異常症の予防及び/又は治療用医薬組成物を提供するものである。
a)(R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、若しくはその塩又はこれらの溶媒和物、及び、
b)ω-3脂肪酸又はそのエステル誘導体、
を含有してなる、高LDLコレステロール血症の予防及び/又は治療用医薬組成物を提供するものである。
(1)(R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、若しくはその塩又はこれらの溶媒和物、及びω-3脂肪酸又はそのエステル誘導体を含有してなる、脂質異常症の予防及び/又は治療用医薬組成物。
(2)ω-3脂肪酸がイコサペント酸(EPA)である、前記(1)に記載の医薬組成物。
(3)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(1)に記載の医薬組成物。
(4)脂質異常症が、高LDLコレステロール(LDL-C)血症及び/又は高トリグリセライド(TG)血症である、前記(1)~(3)のいずれかに記載の医薬組成物。
(5)化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(1)~(4)のいずれかに記載の医薬組成物。
(6)化合物A、若しくはその塩又はこれらの溶媒和物、及びω-3脂肪酸又はそのエステル誘導体を含有してなる、LDLコレステロール(LDL-C)及び/又はトリグリセライド(TG)を低下させるための医薬組成物。
(7)ω-3脂肪酸がイコサペント酸(EPA)である、前記(6)に記載の医薬組成物。
(8)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(7)に記載の医薬組成物。
(9)LDLコレステロール(LDL-C)の低下を必要とする疾患が、高LDLコレステロール(LDL-C)血症である、前記(6)~(8)のいずれかに記載の医薬組成物。
(10)トリグリセライド(TG)の低下を必要とする疾患が、高トリグリセライド(TG)血症である、前記(6)~(8)のいずれかに記載の医薬組成物。
(11)化合物A、若しくはその塩又はこれらの溶媒和物若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(6)~(10)のいずれかに記載の医薬組成物。
(13)ω-3脂肪酸がイコサペント酸(EPA)である、前記(12)に記載の方法。
(14)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(12)に記載の方法。
(15)脂質異常症が、高LDLコレステロール(LDL-C)血症及び/又は高トリグリセライド(TG)血症である、前記(12)~(14)のいずれかに記載の方法。
(16)医薬組成物における化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(12)~(15)のいずれかに記載の患者の脂質異常症を予防及び/又は治療する方法。
(17)LDLコレステロール(LDL-C)及び/又はトリグリセライド(TG)の低下を必要とする患者に、化合物A、若しくはその塩又はこれらの溶媒和物、及びω-3脂肪酸又はそのエステル誘導体を含有してなる医薬組成物の有効量を投与することからなる、患者のLDLコレステロール(LDL-C)及び/又はトリグリセライド(TG)を低下させる方法。
(18)ω-3脂肪酸がイコサペント酸(EPA)である、前記(17)に記載の方法。
(19)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(17)に記載の方法。
(20)LDLコレステロール(LDL-C)の低下を必要とする疾患が、高LDLコレステロール(LDL-C)血症である、前記(17)~(19)のいずれかに記載の方法。
(21)トリグリセライド(TG)の低下を必要とする疾患が、高トリグリセライド(TG)血症である、前記(17)~(19)のいずれかに記載の方法。
(22)医薬組成物における化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(17)~(21)のいずれかに記載の方法。
(24)ω-3脂肪酸がイコサペント酸(EPA)である、前記(23)に記載の化合物若しくはその塩又はこれらの溶媒和物。
(25)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(23)に記載の化合物若しくはその塩又はこれらの溶媒和物。
(26)脂質異常症が、高LDLコレステロール(LDL-C)血症及び/又は高トリグリセライド(TG)血症である、前記(23)~(25)のいずれかに記載の化合物若しくはその塩又はこれらの溶媒和物。
(27)医薬組成物における化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(23)~(26)のいずれかに記載の化合物若しくはその塩又はこれらの溶媒和物。
(28)ω-3脂肪酸又はそのエステル誘導体と組み合わせてLDLコレステロール(LDL-C)及び/又はトリグリセライド(TG)を低下させるための医薬組成物として使用するための、化合物A、若しくはその塩又はこれらの溶媒和物。
(29)ω-3脂肪酸がイコサペント酸(EPA)である、前記(28)に記載の化合物若しくはその塩又はこれらの溶媒和物。
(30)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(28)に記載の化合物若しくはその塩又はこれらの溶媒和物。
(31)LDLコレステロール(LDL-C)の低下を必要とする疾患が、高LDLコレステロール(LDL-C)血症である、前記(28)~(30)のいずれかに記載の化合物若しくはその塩又はこれらの溶媒和物。
(32)トリグリセライド(TG)の低下を必要とする疾患が、高トリグリセライド(TG)血症である、前記(28)~(30)のいずれかに記載の化合物若しくはその塩又はこれらの溶媒和物。
(33)医薬組成物における化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(28)~(32)のいずれかに記載の化合物若しくはその塩又はこれらの溶媒和物。
(35)ω-3脂肪酸がイコサペント酸(EPA)である、前記(34)に記載の使用。
(36)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(34)に記載の使用。
(37)脂質異常症が、高LDLコレステロール(LDL-C)血症及び/又は高トリグリセライド(TG)血症である、前記(34)~(36)のいずれかに記載の使用。
(38)医薬組成物における化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(34)~(37)のいずれかに記載の使用。
(39)ω-3脂肪酸又はそのエステル誘導体と組み合わせてLDLコレステロール(LDL-C)及び/又はトリグリセライド(TG)を低下させるための医薬組成物を製造するための、化合物A、若しくはその塩又はこれらの溶媒和物の使用。
(40)ω-3脂肪酸がイコサペント酸(EPA)である、前記(39)に記載の使用。
(41)ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、前記(39)に記載の使用。
(42)LDLコレステロール(LDL-C)の低下を必要とする疾患が、高LDLコレステロール(LDL-C)血症である、前記(39)~(41)のいずれかに記載の使用。
(43)トリグリセライド(TG)の低下を必要とする疾患が、高トリグリセライド(TG)血症である、前記(39)~(41)のいずれかに記載の使用。
(44)医薬組成物における化合物A、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である、前記(39)~(43)のいずれかに記載の使用。
実施例1 ラットのVLDL-C及びTGに対する化合物AとEPAの併用効果
1.方法
Wisterラット(7週齢、雄、日本チャールスリバー(株))を実験に使用した。飽食下に頸静脈より採血し、血漿中TG、TC及び体重をもとに4群(N=8)に群分けした。翌日から、溶媒(0.5% メチルセルロース水溶液:MC)、(R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸(化合物A)及び/又はEPAを1日1回経口投与した。最終投与日の午後に、4時間絶食条件下でペントバルビタール麻酔下に採血し、血漿中のVLDL-CをUsuiらの方法(Usui S et al. Clin Chem. 46, 63-72, 2000.)により高速液体クロマトグラフィーを用いて測定した。また、TGは自動分析装置により、測定試薬クオリジェントTG(積水メディカル(株))を用いて測定した。相乗効果は、バルジの式(単剤Aの相対値と単剤Bの相対値との積よりも併用した群における相対値が小であれば相乗効果あり)により判定した。
2.群構成
第1群:Control
第2群:化合物A 0.1mg/kg
第3群:EPA 200mg/kg
第4群:化合物A 0.1mg/kgとEPA 200mg/kg
3.統計解析及びデータ処理法
結果は、平均値±標準偏差で示した。対照群と薬物投与群との比較はDunnettの多重比較検定で行い、危険率5%未満を有意差ありと判定した。
4.結果
VLDL-Cを測定した結果を図1に示す。また、VLDL-Cの各群の相対値を表1に示す。化合物Aの単独投与ではVLDL-Cに対する低下傾向が認められ、EPAの単独投与ではVLDL-Cに対して明らかな影響は認められなかったが、化合物A 0.1mg/kgとEPA 200mg/kgとの併用投与群では、有意(**:p<0.01、対コントロール)でかつ相乗的(Control群に対する、単剤A投与群の相対値と単剤B投与群の相対値との積(0.68×0.92=0.63)より併用した群における相対値(0.49)が小である)なVLDL-Cの低下が認められた(図1、表1)。
TGを測定した結果を図2に示す。また、TGの各群の相対値を表2に示す。化合物Aの単独投与ではTGに対する低下傾向が認められ、EPAの単独投与ではTGに対して明らかな影響は認められなかったが、化合物A 0.1mg/kgとEPA 200mg/kgとの併用投与群では、有意(*:p<0.05、対コントロール)でかつ相乗的(Control群に対する、単剤A投与群の相対値と単剤B投与群の相対値との積(0.82×1.10=0.90)より併用した群における相対値(0.676)が小である)なTGの低下が認められた(図2、表2)。これらの成績は、単剤では薬物治療に抵抗性を示す患者においても、本発明の薬剤及び医薬組成物が脂質異常改善作用を発揮することを示唆する。
1.方法
Wisterラット(7週齢、雄、日本チャールスリバー(株))を実験に使用した。飽食下に頸静脈より採血し、血漿中TG、TC及び体重をもとに6群(N=8)に群分けした。翌日から、溶媒(0.5% メチルセルロース水溶液:MC)、(R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸(化合物A)及び/又はEPAを1日1回経口投与した。最終投与日の午後に、4時間絶食条件下でペントバルビタール麻酔下に採血し、血漿中のLDL-CをUsuiらの方法(Usui S et al. Clin Chem. 46, 63-72, 2000.)により高速液体クロマトグラフィーを用いて測定した。相乗効果は、バルジの式(単剤Aの相対値と単剤Bの相対値との積よりも併用した群における相対値が小であれば相乗効果あり)により判定した。
2.群構成
第1群:Control
第2群:化合物A 0.1mg/kg
第3群:EPA 200mg/kg
第4群:化合物A 0.1mg/kgとEPA 200mg/kg
第5群:EPA 3000mg/kg
第6群:化合物A 0.1mg/kgとEPA 3000mg/kg
3.統計解析及びデータ処理法
結果は、平均値±標準偏差で示した。対照群と薬物投与群との比較はDunnettの多重比較検定で行い、危険率5%未満を有意差ありと判定した。
4.結果
各薬剤を投与した後のLDL-Cを測定した結果を図3に示す。また、LDL-Cの各群の相対値を表3に示す。化合物Aの単独投与ではLDL-Cに対する明らかな影響は認められず、EPAの単独投与ではLDL-Cに対して有意(*:p<0.05、対コントロール)ではあるが軽度の低下作用を認めた。ところが、驚くべきことに、化合物A 0.1mg/kgとEPA 200mg/kgとの併用投与群及び化合物A 0.1mg/kgとEPA 3000mg/kgとの併用投与群では、有意(***:p<0.001、対コントロール)でかつ相乗的(Control群に対する、単剤A 0.1mg/kg投与群の相対値と単剤EPA 200mg/kg投与群の相対値との積(1.02×0.84=0.86)より併用した群における相対値(0.73)が小である、及び単剤A 0.1mg/kg投与群の相対値と単剤EPA 3000mg/kg投与群の相対値との積(1.02×0.85=0.87)より併用した群における相対値(0.56)が小である)なLDL-Cの低下が認められた。この成績は、単剤では薬物治療に対する効果が弱い患者においても、本発明の薬剤及び医薬組成物が脂質異常改善作用を発揮することを示唆する。
Claims (11)
- (R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、若しくはその塩又はこれらの溶媒和物、及びω-3脂肪酸又はそのエステル誘導体を含有してなる脂質異常症の予防及び/又は治療用医薬組成物。
- ω-3脂肪酸がイコサペント酸である、請求項1に記載の医薬組成物。
- ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、請求項1に記載の医薬組成物。
- 脂質異常症が、高LDLコレステロール血症及び/又は高トリグリセライド血症である、請求項1~3のいずれかに記載の医薬組成物。
- (R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である請求項1~4のいずれかに記載の医薬組成物。
- (R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、若しくはその塩又はこれらの溶媒和物、及びω-3脂肪酸又はそのエステル誘導体を含有してなるLDLコレステロール及び/又はトリグリセライドを低下させるための医薬組成物。
- ω-3脂肪酸がイコサペント酸である、請求項6に記載の医薬組成物。
- ω-3脂肪酸のエステル誘導体がイコサペント酸エチルである、請求項6に記載の医薬組成物。
- LDL-Cの低下を必要とする疾患が、高LDLコレステロール血症である、請求項6~8のいずれかに記載の医薬組成物。
- トリグリセライドの低下を必要とする疾患が、高トリグリセライド血症である、請求項6~8のいずれかに記載の医薬組成物。
- (R)-2-[3-[[N-(ベンズオキサゾール-2-イル)-N-3-(4-メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、若しくはその塩又はこれらの溶媒和物とω-3脂肪酸又はそのエステル誘導体の質量比が、1:2000~1:30000である請求項6~10のいずれかに記載の医薬組成物。
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Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003043997A1 (en) | 2001-11-15 | 2003-05-30 | Eli Lilly And Company | Peroxisome proliferator activated receptor alpha agonists |
WO2004103997A1 (en) | 2003-05-21 | 2004-12-02 | Pfizer Products Inc. | TETRAHYDROISOQUINOLINE DERIVATIVES AS PPAR-α ACTIVATORS |
WO2005009942A1 (ja) | 2003-07-28 | 2005-02-03 | Kyorin Pharmaceutical Co., Ltd. | 光学活性置換フェニルプロピオン酸誘導体 |
WO2005023777A1 (ja) | 2003-09-03 | 2005-03-17 | Kowa Co., Ltd. | Ppar活性化化合物及びこれを含有する医薬組成物 |
WO2005097784A1 (de) | 2004-04-07 | 2005-10-20 | Bayer Healthcare Ag | Phenylthioessigsäure-derivate und ihre verwendung |
WO2006033891A2 (en) | 2004-09-16 | 2006-03-30 | Merck & Co., Inc. | Compounds for the treatment of dyslipidemia and other lipid disorders |
WO2006049232A1 (ja) | 2004-11-04 | 2006-05-11 | Mitsubishi Pharma Corporation | チアゾール環を含むカルボン酸誘導体およびその医薬用途 |
WO2006062932A2 (en) * | 2004-12-06 | 2006-06-15 | Reliant Pharmaceuticals, Inc. | Treatment with omega-3 fatty acids and ppar agonist and/or antagonist and a combination product thereof |
WO2008006043A2 (en) | 2006-07-07 | 2008-01-10 | Bristol-Myers Squibb Company | 1,3-oxazole derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents |
WO2008120472A1 (ja) * | 2007-03-29 | 2008-10-09 | Kowa Company, Ltd. | 高脂血症の予防及び/又は治療剤 |
WO2009047240A1 (en) | 2007-10-09 | 2009-04-16 | Smithkline Beecham Corporation | Indole derivatives useful as ppar activators |
WO2009080248A1 (de) | 2007-12-20 | 2009-07-02 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 2-phenylpyrimidin-5-carbonsäuren und ihre verwendung |
US20100081694A1 (en) * | 2008-09-30 | 2010-04-01 | Epax As | Composition comprising at least one ppar agonist and a lipid component |
-
2014
- 2014-08-27 KR KR1020237011090A patent/KR20230050472A/ko not_active Application Discontinuation
- 2014-08-27 MY MYPI2016700544A patent/MY182468A/en unknown
- 2014-08-27 EP EP14841322.2A patent/EP3040071A4/en not_active Ceased
- 2014-08-27 WO PCT/JP2014/072380 patent/WO2015030033A1/ja active Application Filing
- 2014-08-27 AU AU2014312931A patent/AU2014312931B2/en active Active
- 2014-08-27 EP EP21192564.9A patent/EP3939586A1/en active Pending
- 2014-08-27 CN CN201480033806.9A patent/CN105307653B/zh active Active
- 2014-08-27 KR KR1020157035948A patent/KR20160045042A/ko active Application Filing
- 2014-08-27 CN CN201910559476.1A patent/CN110327331B/zh active Active
- 2014-08-27 TW TW103129484A patent/TWI718089B/zh not_active IP Right Cessation
- 2014-08-27 CA CA2919817A patent/CA2919817C/en active Active
- 2014-08-27 US US14/913,064 patent/US20160206598A1/en not_active Abandoned
- 2014-08-27 KR KR1020217026669A patent/KR20210107168A/ko not_active IP Right Cessation
- 2014-08-27 JP JP2015534249A patent/JPWO2015030033A1/ja active Pending
- 2014-08-27 MX MX2016002370A patent/MX2016002370A/es unknown
-
2016
- 2016-02-14 IL IL244106A patent/IL244106B/en active IP Right Grant
- 2016-02-19 ZA ZA2016/01152A patent/ZA201601152B/en unknown
- 2016-07-05 HK HK16107763.2A patent/HK1219662A1/zh unknown
-
2018
- 2018-09-21 JP JP2018176777A patent/JP6650006B2/ja active Active
- 2018-10-03 US US16/150,514 patent/US20190030005A1/en active Pending
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003043997A1 (en) | 2001-11-15 | 2003-05-30 | Eli Lilly And Company | Peroxisome proliferator activated receptor alpha agonists |
WO2004103997A1 (en) | 2003-05-21 | 2004-12-02 | Pfizer Products Inc. | TETRAHYDROISOQUINOLINE DERIVATIVES AS PPAR-α ACTIVATORS |
WO2005009942A1 (ja) | 2003-07-28 | 2005-02-03 | Kyorin Pharmaceutical Co., Ltd. | 光学活性置換フェニルプロピオン酸誘導体 |
WO2005023777A1 (ja) | 2003-09-03 | 2005-03-17 | Kowa Co., Ltd. | Ppar活性化化合物及びこれを含有する医薬組成物 |
WO2005097784A1 (de) | 2004-04-07 | 2005-10-20 | Bayer Healthcare Ag | Phenylthioessigsäure-derivate und ihre verwendung |
WO2006033891A2 (en) | 2004-09-16 | 2006-03-30 | Merck & Co., Inc. | Compounds for the treatment of dyslipidemia and other lipid disorders |
WO2006049232A1 (ja) | 2004-11-04 | 2006-05-11 | Mitsubishi Pharma Corporation | チアゾール環を含むカルボン酸誘導体およびその医薬用途 |
WO2006062932A2 (en) * | 2004-12-06 | 2006-06-15 | Reliant Pharmaceuticals, Inc. | Treatment with omega-3 fatty acids and ppar agonist and/or antagonist and a combination product thereof |
JP2008524120A (ja) | 2004-12-06 | 2008-07-10 | レリアント ファーマスーティカルズ インコーポレイテッド | オメガ−3脂肪酸類及びpparアゴニスト及び/又はアンタゴニスト並びにその併用製品を用いた治療 |
WO2008006043A2 (en) | 2006-07-07 | 2008-01-10 | Bristol-Myers Squibb Company | 1,3-oxazole derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents |
WO2008120472A1 (ja) * | 2007-03-29 | 2008-10-09 | Kowa Company, Ltd. | 高脂血症の予防及び/又は治療剤 |
WO2009047240A1 (en) | 2007-10-09 | 2009-04-16 | Smithkline Beecham Corporation | Indole derivatives useful as ppar activators |
WO2009080248A1 (de) | 2007-12-20 | 2009-07-02 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 2-phenylpyrimidin-5-carbonsäuren und ihre verwendung |
US20100081694A1 (en) * | 2008-09-30 | 2010-04-01 | Epax As | Composition comprising at least one ppar agonist and a lipid component |
Non-Patent Citations (12)
Title |
---|
"Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases", 2012, JAPAN ATHEROSCLEROSIS SOCIETY |
ATHEROSCLEROSIS, vol. 18, no. 5, 1990, pages 536 |
EUR. J. PHARMACOL., vol. 231, 1993, pages 121 - 127 |
EUR. J. PHARMACOL., vol. 235, 1993, pages 221 - 227 |
FOLIA PHARMACOL. JPN., vol. 129, 2007, pages 267 - 270 |
J. ATHEROSCLER. THROMB., vol. 16, no. 3, 2009, pages 283 - 291 |
J. ATHEROSCLER. THROMB., vol. 16, no. 5, 2009, pages 674 - 683 |
J. LIPID RESEARCH, vol. 37, 1996, pages 907 - 925 |
See also references of EP3040071A4 |
TRENDS IN ENDOCRINOLOGY AND METABOLISM, vol. 15, no. 7, 2004, pages 324 - 330 |
USUI S ET AL., CLIN. CHEM., vol. 46, 2000, pages 63 - 72 |
YUKIYOSHI YAMAZAKI ET AL.: "S13-5 Kokassei katsu Kosentakuteki PPAR a Agonist no Sosei", ABSTRACTS OF 131TH ANNUAL MEETING OF PHARMACEUTICAL SOCIETY OF JAPAN, vol. 1, 2011, pages 160, XP008182820 * |
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CN110327331B (zh) | 2022-04-26 |
IL244106B (en) | 2020-11-30 |
KR20230050472A (ko) | 2023-04-14 |
EP3040071A4 (en) | 2017-04-12 |
JP2018197273A (ja) | 2018-12-13 |
CN105307653B (zh) | 2019-07-26 |
ZA201601152B (en) | 2018-05-30 |
CA2919817C (en) | 2021-05-25 |
JP6650006B2 (ja) | 2020-02-19 |
MY182468A (en) | 2021-01-25 |
TW201542205A (zh) | 2015-11-16 |
AU2014312931A1 (en) | 2016-02-18 |
MX2016002370A (es) | 2016-05-31 |
TWI718089B (zh) | 2021-02-11 |
IL244106A0 (en) | 2016-04-21 |
AU2014312931B2 (en) | 2019-09-19 |
CN110327331A (zh) | 2019-10-15 |
EP3040071A1 (en) | 2016-07-06 |
JPWO2015030033A1 (ja) | 2017-03-02 |
US20160206598A1 (en) | 2016-07-21 |
KR20160045042A (ko) | 2016-04-26 |
HK1219662A1 (zh) | 2017-04-13 |
EP3939586A1 (en) | 2022-01-19 |
CA2919817A1 (en) | 2015-03-05 |
CN105307653A (zh) | 2016-02-03 |
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