WO1994010125A1 - Derives de la glycerine et leur utilisation - Google Patents

Derives de la glycerine et leur utilisation Download PDF

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Publication number
WO1994010125A1
WO1994010125A1 PCT/EP1993/002917 EP9302917W WO9410125A1 WO 1994010125 A1 WO1994010125 A1 WO 1994010125A1 EP 9302917 W EP9302917 W EP 9302917W WO 9410125 A1 WO9410125 A1 WO 9410125A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
acid
acyl group
residue
Prior art date
Application number
PCT/EP1993/002917
Other languages
English (en)
Inventor
Shizuo Nagahama
Keiko Ochiai
Setsuya Ohba
Takako Tomita
Toshio Wakabayashi
Original Assignee
Sandoz Ltd.
Sandoz-Patent-Gmbh
Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP31025392A external-priority patent/JPH06192177A/ja
Priority claimed from JP20418293A external-priority patent/JPH0776519A/ja
Application filed by Sandoz Ltd., Sandoz-Patent-Gmbh, Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Sandoz Ltd.
Publication of WO1994010125A1 publication Critical patent/WO1994010125A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds

Definitions

  • the present invention relates to glycerin derivatives, in particular to triglycerides, and pharmaceutical and nutrition uses thereof.
  • EPA eicosapentaenoic
  • DHA docosahexaenoic acid
  • GLA ⁇ - linolenic acid
  • glycerides of unsaturated fatty acids have been proposed for use in medicine or nutrition: for prevention and treatment of gallstones (Japanese patent application J6 0169-148A - Nippon Oils & Fats KK) ; for antithrombotic and hypolipaemic uses (European Patent Application EP 0298293 - Fresnius AG) ; to improve peripheral blood circulation (European Patent Application EP 0304603), and for prevention of thromboses (Japanese patent application J6 0132-916A - Nisshin Oil Mills KK) .
  • a fat clysis preparation containing purified soybean oil is commercially available as Soyacal (GB 2050799 - Green Cross Corporation) .
  • Eicosapentaenoic acid EPA
  • DHA docosahexaenoic acid
  • Linoleic acid is an unsaturated fatty acid component of plant oils such as soybean oil and sunflower oil
  • GLA ⁇ -linolenic acid
  • plant oils are also composed of complex mixtures of numerous fatty acid triglycerides.
  • the above plant oils contains neither EPA nor DHA. Consequently single compound triglyceride products containing EPA and/or DHA in combination with LLA and/or GLA are not natural components of plant oils, or fish oils nor can they be separated or purified therefrom.
  • Purified soybean oil is composed of triglycerides containing fatty acids which have up to 18 carbon atoms.
  • human cells contain lipid derived from unsaturated fatty acids having at least 20 carbon atoms such as EPA and DHA, particularly DHA.
  • EPA and DHA unsaturated fatty acids having at least 20 carbon atoms
  • DHA particularly DHA
  • the unsaturated fatty acid triglycerides which have been used to date in medicines and foods have comprised complex mixtures of many different triglyceride compounds. It is believed that single, chemically defined triglyceride compounds will provide improved medicinal and food products.
  • the objects of the present invention include the provision of novel triglyceride derivatives, and platelet aggregation inhibitor, fat clysis and anti-hypertriglyceridemic preparations containing the derivatives: Accordingly the present invention provides a compound of formula
  • R x and R 2 are acyl groups derived from different unsaturated fatty acids, both R 1 groups being identical, one acyl group of and R 2 is an acyl group derived from EPA or DHA, and the other acyl group is an acyl group derived from LLA, GLA, EPA or DHA.
  • the invention includes a compound of formula I in pure form.
  • a compound of formula I "in pure form” comprises at least 90%, preferably at least 95%, especially about 96-99%, by weight of a single compound of formula I.
  • Such a compound in pure form typically contains less than 10%, advantageously less than 5%, by weight in total of other compounds of formula I.
  • the compounds of formula I may be chemically synthesized; for instance in a first embodiment, as described below.
  • glycerol is allowed to react with LLA, GLA, EPA or DHA to obtain the corresponding 1,3-diacylglyceride.
  • the amount of unsaturated fatty acid used per mole of glycerol is preferably 1.9 to 2.2 mol.
  • the reaction temperature is preferably between -30°C and -10°C.
  • the solvent is selected preferably from pyridine, tetrahydrofuran, methylene chloride and mixtures of these.
  • the condensation agent used for the condensation reaction is preferably N,N'-dicyclohexylcarbodiimide.
  • a second step the above 1,3-diacylglyceride is reacted with an unsaturated fatty acid to provide a 1,2,3,-triacylglyceride of formula (I) .
  • the unsaturated fatty acid used in the second step is different from that used in the first step and is EPA or DHA, when LLA or GLA is used in the first step; EPA LLA or GLA, when DHA is used in the first step; or DHA LLA or GLA when EPA is used in the first step.
  • N,N'- dicyclohexylcarbodiimide is used as the condensation agent in the second step.
  • the amount of unsaturated fatty acid used per mole of the 1,3-diacylglyceride is preferably 0.95 to 1.1 mol.
  • the reaction temperature is preferably room temperature, and the reaction solvent is selected from methylene chloride, ethyl acetate and tetrahydrofuran.
  • the 2-monoacylglyceride may be prepared in a first step and this intermediate then reacted to provide the triglyceride of formula I.
  • Dimethylaminopyridine is preferably used as a reaction catalyst in both the first and second steps.
  • the invention includes a process for the production of a compound of formula I which comprises appropriately acylating a compound of formula la
  • Ra ⁇ is R ⁇ or hydrogen, both Ra x groups are identical and Ra 2 is R 2 or hydrogen, provided that one of Ra x and Ra 2 is other than hydrogen.
  • the compound of formula I may be prepared using dihydroxyacetone (HOCH 2 COCH 2 OH) as starting material, comprising 1) a first step in which the dihydroxyacetone is reacted with LLA, GLA, EPA or DHA to obtain the corresponding 1,3-diacyl-2-propanone; 2) a second step in which the 2-propanone is reduced to give the corresponding 1,3- diacylglyceride; and 3) a third step in which the 1,3- diacylglyceride is reacted with an unsaturated fatty acid to provide a 1,2,3-triacylglyceride of formula I, as described above for the second step of the first embodiment.
  • dihydroxyacetone HOCH 2 COCH 2 OH
  • the invention includes a process for the production of a compound of formula I, which comprises the step of reducing a 1,3-diacyl-2-propanone of formula lb
  • R__ is as defined above, to obtain the corresponding 1,3- diacylglyceride.
  • the compounds of formula I have pharmacological activity and are therefore useful as pharmaceuticals.
  • the compounds show platelet aggregation inhibition activity; for instance when tested in an assay as described in Example 11.
  • the compounds are, therefore, useful for the therapy or prevention of diseases caused by platelet aggregation such as thrombotic inflammation and arterial sclerosis.
  • the compounds may also be used in a well-balanced nutrient clysis.
  • Example 8 has anti-hypertriglyceridemic activity; for instance when tested in an assay as described in Example 12.
  • Compounds having such anti- hypertriglyceridemic activity are useful for the therapeutic treatment or prevention of diseases caused by hypertriglyceridemia, such as cardiac infarction or ateriosclerosis.
  • the invention also includes the use of a compound of formula I, e.g. in pure form, as a pharmaceutical or nutrient.
  • the invention includes a pharmaceutical or nutrient, e.g. fat clysis, composition comprising an effective amount of a compound of formula I, e.g. in pure form.
  • a pharmaceutical or nutrient e.g. fat clysis
  • compositions typically comprise the compound of formula I together with a pharmaceutically- or nutritionally-acceptable diluent, excipient or vehicle.
  • the compositions may be for oral or parenteral, including injectable, administration.
  • the dose at which the compound is administered to adults, both for inhibition of patelet aggregation and anti-trihypertriglyceridemic uses, may be in the range from 100 mg to 5 g/day, preferably from 200 mg to 2 g/day. It can be administered once a day or by dividing a dose into two or three doses a day as required. It is preferably orally administered or intravenously injected.
  • the compound of the present invention may be prepared in capsule, tablet or granular form by mixing it with a preparation vehicle or excipient according to a usual method. Further, the compound of the present invention can be included with cyclodextrin to stabilize it.
  • the triglyceride derivative of the present invention can be prepared as an emulsion by dispersing the triglyceride derivative, normally at a concentration in the range from about 10 to about 20% (w/v) , with distilled water for injection, purified yolk lecithin and glycerin and emulsifying the resultant dispersion under pressure.
  • purified soybean oil may be mixed with the triglyceride derivative. In this case, the mixing ratio of the purified soybean oil is preferably in the range of 0 to 97 w/v%.
  • the fat clysis preparation of the present invention can be prepared by the same method as that used for preparing the above emulsion for intravenous injection.
  • the fat clysis preparation according to the invention can be used not only as a clysis preparation for the therapy of thrombotic inflammation and arterial sclerosis, but .also as a well-balanced nutrient clysis.
  • the dose at which the emulsion may be injected into adults is usually in the range from 1 ml to about 500 ml per day.
  • compounds II, V, VII and X are preferred for use in fat clysis preparations.
  • Example 1 Compound of formula I wherein x is linoleyl residue and R is docosahexanoyl residue
  • Example 2 Compound of formula I wherein R, is linolevl residue and R, is eicosapentaenovl residue
  • Eicosapentaenoic acid is allowed to condensation-react with 1,3- dilinoleylglyceride as obtained in Example 1(1) in the same manner as in Example 1(2) to give 1,3-di-9,12-octadienoyl-2- 5,8,11,14,17-eicosapentaenoylglyceride.
  • This product has the following physicochemical charcteristics.
  • reaction mixture is filtered, and the filtrate evaporated to dryness under reduced pressure.
  • residue is then subjected to silica gel chromatography, and 701 mg of 1,3-di ⁇ -linolenoylglyceride is obtained from a methylene chloride-acetone 1% elution fraction.
  • This product has the following physicochemical characteristics.
  • Example 5 Compound of formula I wherein R t is docosahexaenoyl residue and R protest is ⁇ -linolen ⁇ l residue
  • 1,3-Didocosahexaenoylglyceride as obtained in Example 4(1) is allowed to condensation-react with ⁇ -linolenic acid in the same manner as in Example 1(2) to give l,3-di-4,7,10,13,16,19- docosahexaenoyl-2-6, 9, 12-octadecatrienoylglyceride.
  • Thisproduct has the following physicochemical characteristics.
  • Example 6 Compound of formula I wherein R, is docosahexaenoyl residue and R is eicosapentaenoyl residue
  • 1,3-Didocosahexaenoylglyceride is allowed to condensation-react with eicosapentaenoic acid in the same manner as in Example 4(2) to give 1,3-di-4,7, 10, 13, 16,19-docosahexaenoyl-2-5,8, 11, 14, 17- eicosapentaenoylglyceride.
  • This product has the following physicochemical characteristics: 94/10125 neat IRv (cm "1 ) : 3015, 1745 purity >94% Max
  • Example 7 Compound of formula I wherein R t is eicosapentaenoyl residue and R 2 is linoleyl residue
  • Example 8 Compound of formula I wherein R. is eicosapentaenoyl residue and R. is ⁇ -linolen ⁇ l residue
  • 1,3-Dieicosapentaenoylglyceride as obtained in Example 7(1) is allowed to react with ⁇ -linolenic acid in the same manner as in Example 1(1) to obtain 1,3-dieicosapentaenoyl-2-6, 9, 12- octadecatrienoylglyceride.
  • This product has the following physicochemical characteristics.
  • Example 9 Compound of formula I wherein R, is eicosapentaenoyl residue and C is dPCQsa exaenQyl residue
  • 1,3-Dieicosapentaenoylglyceride as obtained in Example 7(1) is allowed to react with docosahexaenoic acid in the same manner as in Example 1(2) to obtain l,3-dieicosapentaenoyl-2- 4,7,10,13,16,19-docosahexaenoylglyceride.
  • This product has the following physicochemical characteristics.
  • Example 11 Activity as inhibitors of platelet aggregation.
  • Capsules each containing 200 mg of the compound of formula VI or the compound of formula IX are formed at room temperature using a rotary encapsulating machine.
  • a gelatin capsule-forming recipe is used employing as the coating substrate 2.2 kg of gelatin, 0.66 kg of glycerin, 4.4 g of methylparaben, 1.1 g of propylparaben, 1.1 g of Yellow No. 5 and 1.8 kg of purified water.
  • mice Male ICR mice (aged 5 weeks) are used for an acute toxicity test by oral administration.
  • the compounds of the present invention, II, V, VII and IX have LD 50 values of 5 g/kg or more, and thus have high safety.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé de la formule (I). Dans cette formule, R1 et R2 sont des groupes acyle dérivés de différents acides gras insaturés, les deux groupes R1 étant identiques, un des groupes acyle R1 ou R2 étant un groupe acyle dérivé de l'acide eicosapentanoïque ou de l'acide docosahexanoïque et l'autre groupe acyle étant un groupe acyle dérivé de l'acide linoléique, de l'acide η-linoléique, de l'acide eicosapentanoïque ou de l'acide docosahexanoïque. Ce composé est de préférence sous une forme pure contenant au moins 90 % du composé. Il a des propriétés d'inhibition de l'agrégation plaquettaire, et il peut être utilisé d'une manière avantageuse en médecine non seulement pour le traitement ou la prévention d'inflammations thrombotiques et de l'artériosclérose induite par une agrégation plaquettaire, mais encore comme clystère alimentaire équilibré. Egalement, certains composés de la formule (I), en particulier le composé dans lequel R1 est un reste eicosapentanoyle et R2 est un reste η-linolénoyle, ont une activité antihypertriglycéridémie et ils sont utiles pour le traitement ou la prévention de maladies provoquées par l'hypertriglycéridémie, comme par exemple les infarctus du myocarde ou l'artériosclérose.
PCT/EP1993/002917 1992-10-27 1993-10-21 Derives de la glycerine et leur utilisation WO1994010125A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP4/288684 1992-10-27
JP28868492 1992-10-27
JP31025392A JPH06192177A (ja) 1992-10-27 1992-11-19 グリセリン誘導体並びにこれを含有する血小板凝集抑制剤および脂肪輸液剤
JP4/310253 1992-11-19
JP17675093 1993-07-16
JP5/176750 1993-07-16
JP5/204182 1993-08-18
JP20418293A JPH0776519A (ja) 1993-07-16 1993-08-18 抗高トリグリセリド血症剤

Publications (1)

Publication Number Publication Date
WO1994010125A1 true WO1994010125A1 (fr) 1994-05-11

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611569A2 (fr) * 1993-01-27 1994-08-24 Scotia Holdings Plc Triglycérides
US9629820B2 (en) 2012-12-24 2017-04-25 Qualitas Health, Ltd. Eicosapentaenoic acid (EPA) formulations
US10123986B2 (en) 2012-12-24 2018-11-13 Qualitas Health, Ltd. Eicosapentaenoic acid (EPA) formulations
US11007173B2 (en) 2009-09-23 2021-05-18 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
US11033523B2 (en) 2009-04-29 2021-06-15 Amarin Pharmaceuticals Ireland Limited Pharmaceutical compositions comprising EPA and a cardiovascular agent and methods of using the same
US11103477B2 (en) 2009-04-29 2021-08-31 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US11116742B2 (en) 2018-09-24 2021-09-14 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US11141399B2 (en) 2012-12-31 2021-10-12 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
US11179362B2 (en) 2012-11-06 2021-11-23 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US11185525B2 (en) 2013-02-06 2021-11-30 Amarin Pharmaceuticals Ireland Limited Methods of reducing apolipoprotein C-III
US11285127B2 (en) 2013-10-10 2022-03-29 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US11291643B2 (en) 2011-11-07 2022-04-05 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
US11439618B2 (en) 2009-06-15 2022-09-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
US11446269B2 (en) 2014-06-16 2022-09-20 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids
US11547710B2 (en) 2013-03-15 2023-01-10 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin
US11712428B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11712429B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11986452B2 (en) 2021-04-21 2024-05-21 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of heart failure

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60132916A (ja) * 1983-12-21 1985-07-16 Nisshin Oil Mills Ltd:The 血栓症予防食品または医薬品
EP0271909A2 (fr) * 1986-12-17 1988-06-22 Green Cross Corporation Composition à base de triglycérides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60132916A (ja) * 1983-12-21 1985-07-16 Nisshin Oil Mills Ltd:The 血栓症予防食品または医薬品
EP0271909A2 (fr) * 1986-12-17 1988-06-22 Green Cross Corporation Composition à base de triglycérides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"CHEMICAL ABSTRACTS SERVICE.REGISTRY HANDBOOK.NUMBER SECTION.1988 SUPPLEMENT", 1988, AMERICAN CHEMICAL SOCIETY, COLUMBUS,OHIO,US *
PATENT ABSTRACTS OF JAPAN vol. 009, no. 281 (C - 314) 14 November 1985 (1985-11-14) *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611569A2 (fr) * 1993-01-27 1994-08-24 Scotia Holdings Plc Triglycérides
EP0611569A3 (fr) * 1993-01-27 1997-07-30 Scotia Holdings Plc Triglycérides.
US5670540A (en) * 1993-01-27 1997-09-23 Scotia Holdings Plc Triglycerides of fatty acids
US5866703A (en) * 1993-01-27 1999-02-02 Scotia Holdings Plc Triglycerides
US11690820B2 (en) 2009-04-29 2023-07-04 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
US11033523B2 (en) 2009-04-29 2021-06-15 Amarin Pharmaceuticals Ireland Limited Pharmaceutical compositions comprising EPA and a cardiovascular agent and methods of using the same
US11103477B2 (en) 2009-04-29 2021-08-31 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US11213504B2 (en) 2009-04-29 2022-01-04 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US11147787B2 (en) 2009-04-29 2021-10-19 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US11154526B2 (en) 2009-04-29 2021-10-26 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
US11400069B2 (en) 2009-04-29 2022-08-02 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
US11464757B2 (en) 2009-06-15 2022-10-11 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
US11439618B2 (en) 2009-06-15 2022-09-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
US11007173B2 (en) 2009-09-23 2021-05-18 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
US11712429B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11712428B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11291643B2 (en) 2011-11-07 2022-04-05 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
US11179362B2 (en) 2012-11-06 2021-11-23 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US10123986B2 (en) 2012-12-24 2018-11-13 Qualitas Health, Ltd. Eicosapentaenoic acid (EPA) formulations
US10039734B2 (en) 2012-12-24 2018-08-07 Qualitas Health, Ltd. Eicosapentaenoic acid (EPA) formulations
US9629820B2 (en) 2012-12-24 2017-04-25 Qualitas Health, Ltd. Eicosapentaenoic acid (EPA) formulations
US11141399B2 (en) 2012-12-31 2021-10-12 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
US11185525B2 (en) 2013-02-06 2021-11-30 Amarin Pharmaceuticals Ireland Limited Methods of reducing apolipoprotein C-III
US11547710B2 (en) 2013-03-15 2023-01-10 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin
US11285127B2 (en) 2013-10-10 2022-03-29 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US11446269B2 (en) 2014-06-16 2022-09-20 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids
US11369582B2 (en) 2018-09-24 2022-06-28 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US11298333B1 (en) 2018-09-24 2022-04-12 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US11116743B2 (en) 2018-09-24 2021-09-14 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US11116742B2 (en) 2018-09-24 2021-09-14 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US11717504B2 (en) 2018-09-24 2023-08-08 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US11986452B2 (en) 2021-04-21 2024-05-21 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of heart failure

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