巴西专利BR112012006692B1 PHARMACEUTICAL COMPOSITION UNDERSTANDING A HYDROXY DERIVATIVE OF ATORVASTATIN AND AN OIL UNDERSTANDI

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专利摘要:
pharmaceutical composition comprising omega-3 fatty acid and a hydroxy derivative of a statin and methods of using them in various embodiments, the present invention provides compositions and methods for treating and / or preventing a disease related to cardiovascular disease in an individual in need for it.
公开号:BR112012006692B1
申请号:R112012006692-7
申请日:2010-09-23
公开日:2021-04-13
发明作者:Jonathan Rowe
申请人:Amarin Corporation Plc；
IPC主号:

专利说明:

Fundamentals of the Invention
[001] Cardiovascular disease is a leading cause of death in the United States and most European countries. It is estimated that more than 70 million people in the United States alone suffer from cardiovascular disease or disorder, including, but not limited to, high blood pressure, cardio-coronary disease, dyslipidemia, congestive heart failure and stroke. There is a need for better treatments for cardiovascular diseases, illnesses and related disorders. Summary of the Invention
[002] In various embodiments, the present invention provides pharmaceutical compositions and methods of using such compositions to treat and / or prevent cardiovascular-related diseases. In one embodiment, a pharmaceutical composition comprising a statin or a derivative of a statin, for example, a hydroxy derivative of a statin, or a pharmaceutically acceptable salt thereof and an Omega-3 fatty acid is provided. The term “statin hydroxy derivative” here refers to a compound of statin origin (ie, a known class of HMG-CoA reductase inhibitors), which has at least one hydroxy substituent group. In one embodiment, a hydroxyl group is attached to a phenyl ring of the parent statin.
[003] In another embodiment, a pharmaceutical composition comprising a hydroxy derivative of a statin or a pharmaceutically acceptable salt thereof, and an oil comprising an Omega-3 fatty acid is provided. In a related embodiment, the oil is composed of at least 95% by weight of eicosapentaenoic acid or its derivatives, for example, eicosapentaenoate acetate.
[004] In various embodiments, the hydroxy derivative of a statin is selected from a hydroxy derivative of atorvastatin, mevastatin, pitavastatin, pravasta- tine, rosuvastatin, fluvastatin, simvastatin, lovastatin, cerivastatin and their pharmaceutically acceptable salts.
[005] In other embodiments, the hydroxy derivative of a statin is selected from ortho or hydroxy-atorvastatin, calcium p-hydroxy atorvastatin, disodium atorvastatin p-hydroxy, calcium o-hydroxy atorvastatin, atorvastatin o-hydroxy , p-hydroxy atorvastatin, p-hydroxy atorvastatin calcium, p-hydroxy atorvastatin disodium, o-hydroxy atorvastatin calcium, o-hydroxy atorvastatin lactone d5, 2-hydroxy disodium sodium atorvastatin, 2-hydroxy atorvastatin bisodium, p -atorvastatin lactone hydroxy, calcium d5 p-hydroxy atorvastatin, lactone p-hydroxy atorvastatin d5, and bisodic 4-hydroxy atorvastatin.
[006] In still other embodiments, the oil comprises one or more of: (a) about 0.2% to about 0.5% by weight of ethyl octadecatetraenoate, (b) about 0.05% to about 0.20% o, by weight of ethyl nonaecapentaenoate, (c) from about 0.2% to about 3% by weight of ethyl arachidonate, (d) about 0.3% to about 0.5% in weight of ethyl eicosatetraenoate, (e) about 0.8% to about 0.25% by weight of ethyl heneicosapentaenoate, (f) from about 0.02% to about 0.1% by weight of ethyl 17E- icosapentaenoate, (g) from about 0.02% to about 0.1%> by weight of 5-ethyl icosapentanoate, (h) from about 0.01%) to about 0.15% by weight of ethyl 5E, 8E-icosapentaenoate, (i) from about 0.01% to about 0.15%), by weight, of ethyl 8E, 1-1E icosapentaenoate, (j) from about 0.01% to about 0 , 15% by weight of ethyl 5E, 14E-icosapentaenoate, (k) from about 0.01%> to about 0.15% by weight of ethyl 5E, 8E, HE, 17E-icosapentaenoate, (l) no amount or substantially no amount of ethyl ics ahexaenoate, (m) no amount or substantially no amount of ethyl 11Z eicosenoate, (n) no amount or substantially no amount of ethyl docosahexaenoic acid, and / or (o) from about 0.02% to about 0, 1% ethyl nonadecapentaenoate.
[007] In yet another embodiment, the invention provides a method of treating a related cardiovascular disease, in an individual in need, comprising administering to the individual a composition as described herein. In one embodiment, the related cardiovascular disease is atherosclerosis.
[008] These and other embodiments of the present invention will be described in more detail below. Brief Description of Drawings
[009] Figure 1 shows the effects of EPA, DHA and EPA / DHA, in combination with atorvastatin, atorvastatin o-hydroxy metabolite, simvastatin or rosovasastatine, on the lipid peroxidation of the membrane.
[0010] Figure 2 shows the effects of EPA in combination with atorvastatin, o-hydroxy metabolite atorvastatin, simvastatin or rosuvastatin, on the lipid peroxidation of the membrane.
[0011] Figure 3 shows the effects of DHA in combination with atorvastatin, o-hydroxy metabolite atorvastatin, simvastatin or rosuvastatin, on the lipid peroxidation of the membrane.
[0012] Figure 4 shows the effects of EPA / DHA in combination with atorvastatin, o-hydroxy metabolite atorvastatin, simvastatin or rosuvastatin, on the lipid peroxidation of the membrane.
[0013] Figure 5 shows the effects of atorvastatin, atorvastatin o-hydroxy metabolite, simvastatin or rosuvastatin, in combination with EPA, DHA or EPA / DHA on the lipid peroxidation of the membrane.
[0014] Figure 6 shows the effects of atorvastatin, in combination with EPA, DHA or EPA / DHA, on the lipid peroxidation of the membrane.
[0015] Figure 7 shows the effects of the o-hydroxy metabolite atorvastatin in combination with EPA, DHA or EPA / DHA, on the lipid peroxidation of the membrane.
[0016] Figure 8 shows the effects of simvastatin, in combination with EPA, DHA or EPA / DHA, on the lipid peroxidation of the membrane.
[0017] Figure 9 shows the effects of rosuvastatin in combination with EPA, DHA and EPA / DHA, on the lipid peroxidation of the membrane. Detailed Description of the Invention
[0018] Although the present invention is capable of being materialized in several forms, the description presented below of the various modalities is made with the purpose that the present disclosure is considered as an example of the invention, and is not intended to limit the invention to specific modalities illustrated. Titles are provided for convenience only and are not to be considered to limit the invention in any way. The modalities illustrated under any title can be combined with the modalities illustrated under any other title.
[0019] The use of numerical values in the various quantitative values specified in the present application, unless expressly stated otherwise, are demonstrated as approximations as if the minimum and maximum values within the indicated intervals were both preceded by the term "about". In addition, the disclosure of the ranges is intended to be a continuous range including any and all values between the minimum and maximum values mentioned, as well as any relationships (and ranges of any such relationships) that can be formed by dividing a mentioned numerical value. in any other revealed numeric value. Therefore, the one usually versed in the technique will appreciate that many such relationships, ranges and range ratios can be unequivocally derived from the numerical values presented here and in all cases, such proportions, ranges and range ratios represent the various modalities of the present invention.
[0020] In one embodiment, the invention provides a pharmaceutical composition comprising a statin or a hydroxy derivative of a statin or a pharmaceutically acceptable salt thereof and an oil comprising an Omega-3 fatty acid. Hydroxy derivative of a statin
[0021] In one embodiment, the hydroxy derivative of a statin comprises hydroxy-atorvastatin of the following structure:

[0022] In another embodiment, the hydroxy derivative of a statin comprises hydroxy-fluvastatin with the following structure:
or a pharmaceutically acceptable salt thereof.
[0023] In another embodiment, the hydroxy derivative of a statin comprises hydroxy-lovastatin, for example, of the following structure:

(3-hydroxy-lovastatin) or its pharmaceutically acceptable salt of either
[0024] In another embodiment, the hydroxy derivative of a statin comprises hydroxy-simvastatin, for example, of the following structure:
or a pharmaceutically acceptable salt of any of the above.
[0025] In another embodiment, the hydroxy derivative of a statin comprises hydroxy-cerivastatin, for example, of the following structure:
or a pharmaceutically acceptable salt thereof.
[0026] In another embodiment, the hydroxy derivative of a statin comprises hydroxy-pitavastatin, for example, of the following structure:
or a pharmaceutically acceptable salt thereof.
[0027] In other embodiments, the hydroxy derivative of a statin is selected from ortho or para-hydroxy atorvastatin and its salts, for example, p-hydroxy atorvastatin calcium, p-hydroxy atorvastatin disodium, o-hydroxy atorvastatin- calcium trine, atorvastatin lactone o-hydroxy, calcium d5 atorvastatin o-hydroxy, d5 disodium o-hydroxy-atorvastatin, lactone d5 o-hydroxy atorvastatin, lactone atorvastatin 2-hydroxy, lactone p-hydroxy atorvastatin, p -calcium atorvastatin d5 hydroxide, p-hydroxy atorvastatin lactone d5, and 4-hydroxy atorvastatin disodium. In other embodiments, the statin comprises atorvastatin, simvastatin or rosuvastatin.
[0028] In various embodiments, a composition of the present invention comprises a statin, hydroxy derivative of a statin or a pharmaceutically acceptable salt in an amount of about 0.01 mg to about 500 mg, from about 0.1 mg to about 250 mg, or about 1 mg to about 100 mg, for example, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.
[0029] In various embodiments, the compositions of the present invention comprise an oil. In one embodiment, the oil comprises a fatty acid, for example, an omega-3 fatty acid. In another embodiment, omega-3 fatty acid comprises eicosapentaenoic acid or a pharmaceutically acceptable ester, conjugate, derivative or salt, or mixtures of any of the foregoing, collectively referred to herein as "EPA". The term "pharmaceutically acceptable" used herein means that the substance in question does not produce unacceptable toxicity to the individual or the interaction with the other components of the composition.
[0030] In another embodiment, the oil is composed of at least about 95% by weight of EPA. In one embodiment, EPA comprises all cis of 5, 8,11,14,17-pentaenoic acid. In another embodiment, EPA is composed of an ester of eicosapentaenoic acid. In another embodiment, EPA is composed of a C1-C5 alkyl ester of eicosapentaenoic acid. In another embodiment, EPA is composed of eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In yet another embodiment, EPA is composed of all 5, 8, 11,14,17-pentaenoic acid ethyl ester cis.
[0031] In another embodiment, EPA is in the form of ethyl-EPA, lithium EPA, EPA mono-, di- or triglyceride or any other pharmaceutically acceptable ester or salt of EPA, or EPA-free acid form. EPA can be in the form of a 2-substituted derivative or another derivative, which slows down its oxidation rate, but otherwise does not alter its biological action in any substantial way.
[0032] In another embodiment, the oil comprises docosahexaenoic acid (DHA) or a derivative thereof, for example, ethyl-DHA. In another embodiment, the oil is composed of at least about 95% by weight of DHA or a derivative thereof, for example, E-DHA.
[0033] In yet another embodiment, the oil contains no more than about 10%, no more than about 9%, and no more than about 8%, no more than about 7%, and no more than about 6% and no more than about 5%, and no more than about 4% and no more than about 3%, no more than about 2%, and no more than about 1%, or not more than about 0.5% by weight, of DHA or a derivative thereof, such as ethyl-DHA, if any. In another embodiment, a composition of the invention contains substantially no docosahexaenoic acid or a derivative thereof. In yet another embodiment, a composition useful in the present invention does not contain any docosahexaenoic acid or a derivative thereof.
[0034] In one embodiment, the oil comprises ethyl eicosapentaenoate and ethyl docosahexaenoic acid in a molar ratio of about 1: 1 to about 1.5: 1, from about 1.1: 1 to about 1.4: 1 , for example, about 1.3: 1.
[0035] In another modality, the oil contains less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4% , less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.25%, by weight, of any fatty acid other than EPA. Illustrative examples of a "fatty acid other than EPA" include linoleic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA), eicosatrienoic acid (ETA) ) and / or docosapentaenoic acid (DPA). In another embodiment, an oil useful in a composition of the present invention contains from about 0.1% to about 4%, from about 0.5% to about 3%, or about 1% to about 2%, in weight, of total fatty acids, other than ethyl-EPA and / or ethyl-DHA.
[0036] In another embodiment, an oil useful in the compositions of the present invention has one or more of the following characteristics: (a) ethyl ester of eicosapentaenoic acid represents at least about 96%, at least about 97%, or at least less than 98%, by weight, of all fatty acids present, (b) the oil contains no more than> about 4%, and no more than about 3%, or no more than about 2% by weight of total fatty acids other than the ethyl ester of eicosapentaenoic acid, (c) the oil contains no more than about 0.6%, no more than about 0.5%, or no more than about 0.4% of any individual fatty acid other than the ethyl ester of eicosapentaenoic acid, (d) the oil has a refractive index (20 ° C) of about 1 to about 2, from about 1.2 to about from 1.8 or about 1.4 to about 1.5, (e), the composition has a density (20 ° C) of about 0.8 to about 1.0, of about 0.85 at about 0.95 or about 0.9 to about 0.92, (e) the oil does not o contains no more than about 20 ppm, no more than about 15 ppm, or no more than about 10 ppm heavy metals, (f) the oil contains no more than ppm up to about 5, no more than than about 4 ppm, no more than about 3 ppm, or no more than about 2 ppm arsenic, and / or (g), the oil has a peroxide value of no more than about 5 meq / kg, no more than about 4 meq / kg, no more than about 3 meq / kg, or no more than about 2 meq / kg.
[0037] In one embodiment, the oil is composed of at least about 95% by weight of ethyl eicosapentaenoate (EPA-E), from about 0.2% to about 0.3% by weight of ethyl octadecatetraenoate (ODTA- E), from about 0.05% to about 0.20% by weight of ethyl nonaecapentaenoate (NDPA-E), from about 0.2% to about 0.4% by weight of ethyl arachidonate (AA- E), from about 0.3% to about 0.5% by weight of ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.15% heneicosapentaenoate acetate (HPA-E) .
[0038] In another embodiment, the oil is composed of at least about 96% by weight of ethyl eicosapentaenoate, from about 0.22% to about 0.28% by weight of ethyl octadecatetraenoate, from about 0.075% to about 0.15% by weight of ethyl nonaecapentaenoate, from about 0.25% to about 0.35% by weight of ethyl arachidohydrate, from about 0.3% to about 0.4% in weight of ethyl eicosatetraenoate (ETA-E), and about 0.075% to about 0.15% heneicosapentaenoate acetate (HPA-E).
[0039] In other embodiments, the oil comprises one or more of: (a) about 0.2% to about 0.5% by weight of ethyl octadecatetraenoate, (b) about 0.05% to about> 0.20% by weight of ethyl nonaecapentaenoate, (c) about 0.2% to about 3% by weight of ethyl arachidonate, (d) about 0.3% to about 0.5% by weight of ethyl eicosatetraenoate, (e) about 0.8% to about 0.25% by weight of ethylene heicosapentaenoate, (f) from about 0.02% to about 0.1% by weight of ethyl 17E-icosapentaenoate , (g) from about 0.02% to about 0.1% by weight of 5-ethyl icosapentanoate, (h) from about 0.01% to about 0.15% by weight of 5E ethyl , 8E icosapentaenoate, (i) about 0.01% to about 0.15%, by weight, of ethyl 8E, 1-lE icosapentaenoate, (j) about 0.01% to about 0 , 15% by weight of ethyl 5E, 14E-icosapentaenoate, (k) about 0.01% to about 0.15% by weight of ethyl 5E, 8E, HE, 17E-icosapentaenoate, (1) no amount or substantially no amount of ethyl icosahexaenoa therefore, (m) no amount or substantially no amount of ethyl 11Z-eicosenoate, (n) no amount or substantially no amount of docosahexaenoic acid ethyl, and / or (o) from about 0.02% to about 0.1% ethyl nonadecapentaenoate. In other embodiments, the oil is composed of one or more, two or more, any three or more, any four or more, five or more of any, any six or more, any seven or more, any eight or more, nine or any plus, any ten or more, any 11 or more, any 12 or more, any 13 or more, any 14 or more or all 15 of: (a) - (o) immediately above.
[0040] In another embodiment, the oil is composed of at least about 95% by weight of ethyl eicosapentaeoate, and about 0.2% to about 3.5% by weight of ethyl arachidonate.
[0041] In another embodiment, EPA is present in a composition of the present invention in an amount of about 50 mg to about 5000 mg, from about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg , about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1200 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1,675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1,875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, c about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.
[0042] In another embodiment, the composition of the present invention is present in a capsule, for example, a capsule comprising gelatin. In yet another embodiment, at least about 100 mg to about 2 g of such a composition is present in each capsule. Therapeutic Methods
[0043] In one embodiment, the invention provides a method for the treatment and / or prevention of a related cardiovascular disease, comprising administering a composition or compositions, as disclosed herein, to an individual in need thereof. In another embodiment, the invention provides a method for the treatment and / or prevention of related cardiovascular diseases, comprising co-administering to a subject in need of him a first pharmaceutical composition comprising a hydroxy derivative of a statin and a second pharmaceutical composition comprising as an oil established here. The terms "co-administration" and "co-administration" here include the administration of two or more compositions, as part of a coordinated dosing regimen if the compositions are administered sequentially, substantially simultaneously or individually.
[0044] The term "cardiovascular-related disease" here refers to any disease or disorder of the heart or blood vessels (ie, arteries and veins), or any symptom thereof. Non-limiting examples of related diseases include hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia, heart disease, vascular disease, atherosclerosis, stroke, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.
[0045] The term "treatment" with respect to a particular disease or disorder includes, but is not limited to, inhibiting the disease or disorder, for example, stopping the development of the disease or disorder; alleviate the disease or disorder, for example, cause regression of the disease or disorder, or the alleviation of a condition caused by or resulting from the disease or disorder, for example, alleviate, prevent or treat the symptoms of the disease or disorder. The term “prevention”, in relation to a given disease or disorder means: preventing the onset of the development of the disease, if nothing happened, preventing the disease or disorder from occurring in an individual who may be predisposed to the disorder or disease, but has not hitherto diagnosed as having the disease or disorder, and / or preventing the further development of the disease or disorder, if it is already present.
[0046] In one embodiment, the present invention provides a method of blood lipid therapy which comprises administering to an individual or group of individuals in need thereof, a composition or pharmaceutical compositions as described herein. In another modality, the individual or group of individuals has hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and / or very high triglycerides.
[0047] In another modality, the individual or group of individuals to be treated has a baseline level of triglycerides (average or median baseline level of triglycerides in the case of a group of individuals), fed or fasting, of about 200 mg / dL to about 500 mg / dL. In another embodiment, the individual or group of individuals has a baseline level of LDL-C (mean or median baseline level of LDL-C), regardless of statin therapy, from about 40 mg / dL to about 100 mg / dL.
[0048] In another embodiment, the individual or group of individuals to be treated according to the methods of the invention has a body mass index (BMI or BMI) of no more than about 45 kg / m2.
[0049] In one embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits an absolute baseline plasma level in fasting total free fatty acid (or the mean thereof) not greater than about 300 nmol / ml, not more than about 250 nmol / ml, not more than about 200 nmol / ml, not more than about 150 nmol / ml, not more than about 100 nmol / ml, or not more than about 50 nmol / ml.
[0050] In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits an absolute baseline plasma level in fasting free EPA (or mean, in the case of an individual group) no higher than about 0.70 nmol / ml, not more than about 0.65 nmol / ml, not more than about 0.60 nmol / ml, not more than about 0.55 nmol / ml, not more than about 0.50 nmol / mL, no more than about 0.45 nmol / mL, or no greater than about 0.40 nmol / mL. In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits a fasting basal plasma level (or average thereof) of free EPA, expressed as a percentage of total free fatty acids , of no more than about 3%, no more than about 2.5%, no more than about 2%, no more than about 1.5%, no more than about 1% , no more than about 0.75%, no more than about 0.5%, no more than about 0.25%, no more than about 0.2% or no more than about 0.15%. In such an embodiment, plasma levels of free EPA and / or levels of total fatty acids are determined prior to the initiation of therapy.
[0051] In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits an absolute baseline plasma level in free (or average) free EPA fasting up to about 1 nmol / mL, not more than about 0.75 nmol / ml, not more than about 0.50 nmol / ml, not more than about 0.4 nmol / ml, not more than about 0.35 nmol / ml, or not greater than about 0.30 nmol / mL.
[0052] In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits a basic level of plasma, serum or red blood cell membranes in the blood no higher than about 150 μg / mL, not more than about 125 μg / mL, not more than about 100 μg / mL, not more than about 95 μg / mL, not more than about 75 μg / mL, not more than about 60 μg / mL, not greater than about 50 μg / mL, not greater than about 40 μg / mL, not greater than about 30 μg / mL, or not greater than about 25 μg / mL.
[0053] In another embodiment, the methods of the present invention comprise a step of measuring the basal lipid profile of the individual (or mean of the group of individuals) before initiating therapy. In another embodiment, the methods of the present invention comprise the step of identifying an individual or group of individuals with one or more of the following procedures: baseline non-HDL-C value (or average value) of about 200 mg / dL up to about 400 mg / dL, for example, at least about 210 mg / dL, at least about 220 mg / dL, at least about 230 mg / dL, at least about 240 mg / dL, at least about 250 mg / dL, at least about 260 mg / dL, at least about 270 mg / dL, at least about 280 mg / dL, at least about 290 mg / dL, or at least about 300 mg / dL; baseline total cholesterol (or mean value) from about 250 mg / dL to about 400 mg / dL, for example, at least about 260 mg / dL, at least about 270 mg / dL, at least about 280 mg / dL, or at least about 290 mg / dL; baseline vLDL-C value (or mean value) of about 140 mg / dL to about 200 mg / dL, for example, at least about 150 mg / dL, at least about 160 mg / dL, at least about 170 mg / dL, at least about 180 mg / dL, or at least about 190 mg / dL; baseline HDL-C value (or mean value) of about 10 to about 100 mg / dL, for example, no more than about 90 mg / dL, no more than about 80 mg / dL, no more than about 70 mg / dL, no more than about 60 mg / dL, no more than about 60 mg / dL, no more than about 50 mg / dL, no more than about 40 mg / dL , no more than about 35 mg / dL, no more than about 30 mg / dL, no more than about 25 mg / dL, no more than about 20 mg / dL, or no more than about 15 mg / dL, and / or baseline LDL-C (or average value) from about 30 to about 300 mg / dL, for example, not less than about 40 mg / dL, not less than about 50 mg / dL, not less than about 60 mg / dL, not less than about 70 mg / dL, not less than about 90 mg / dL or not less than about 90 mg / dL.
[0054] In a related embodiment, when treating according to the present invention, for example, for a period of about 1 to 200 weeks, from about 1 to about 80 weeks, from about 1 to about 50 weeks, from about 1 to about 40 weeks, from about 1 to about 20 weeks, from about 1 to about 15 weeks, from about 1 to about 12 weeks, from about 1 to about 10 weeks, from about 1 to about 5 weeks, from about 1 to about 2 weeks or about 1 week, the individual or group of individuals exhibits one or more of the following results: a) Reduction of triglyceride levels in relation to at baseline or placebo control; b) reduction of apo B levels in relation to baseline or placebo control; c) increase in HDL-C compared to baseline or placebo control; d) no increase in LDL-C compared to baseline or placebo control; e) reduction in LDL-C levels compared to baseline or placebo control; f) reduction in non-HDL-C levels compared to baseline or placebo control; g) reduction in vLDL levels in relation to baseline or placebo control; h) increase in apo A-I levels compared to baseline or placebo control; i) increase in the apo A-I / apo B ratio compared to baseline or placebo control; j) reduction of lipoprotein levels in relation to baseline or placebo control; k) reduction in the number of LDL particles in relation to baseline or placebo control; l) reduction in LDL size compared to baseline or placebo control; m) reduction in the remaining level of cholesterol particles in relation to the baseline level or placebo control; n) reduction in the levels of oxidized LDL in relation to the baseline level or placebo control; o) reduced fasting plasma glucose (FPG) compared to baseline or placebo control; p) reduction in hemoglobin Alc (HbAlc) in relation to baseline or placebo control; q) reduction of insulin resistance in the homeostasis model compared to baseline or placebo control r) reduction of phospholipase A2 associated with lipoprotein compared to baseline or placebo control; s) reduction in molecule-1 of intracellular adhesion compared to baseline or placebo control; t) reduction of interleukin-2 compared to baseline or placebo control; u) reduction in plasminogen activating inhibitor-1 compared to baseline or placebo control; v) reduction in the high sensitivity of C-reactive protein compared to baseline or placebo control; w) increase in EPA in serum phospholipids compared to baseline or placebo control; x) increase in EPA in the blood cell membrane compared to baseline or placebo control, and / or y) decrease or increase in one or more of phospholipids and / or red blood cells in the docosahexaenoic acid (DHA) content ), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic acid (PA), stearidonic acid (SA) or oleic acid (OA) in relation to the baseline level or placebo control.
[0055] In one embodiment, the methods of the present invention comprise measuring the baseline levels of one or more markers set forth in (a) - (y) above, prior to administration to the individual or group of individuals. In another embodiment, the methods comprise administering to the individual a composition as described herein, after determining the baseline levels of one or more markers shown in (a) - (y), then taking additional measurements of said one or more markers.
[0056] In another embodiment, when treating with a composition of the present invention, for example, over a period of about 1 to about 200 weeks, from about 1 to about 100 weeks, from about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the individual or group of individuals displays any 2 or more than, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any d and 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more of, any 24 or more of, or the total of 25 results (a ) - (y) described above.
[0057] In another embodiment, when treating with a composition of the present invention, the individual or group of individuals exhibits one or more of the following results: a) a reduction in the level of triglycerides of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45 %, at least about 50%, at least about 55%, or at least about 75% (actual% change or average% change) from baseline or placebo control; b) an increase of less than 30%, an increase of less than 20%, an increase of less than 10%, an increase of less than 5% or no increase in non-HDL-C levels or a reduction in non-HDL-C levels of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (change actual% or average% change) from baseline or placebo control; c) increase in HDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30 %, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual% change or average% change ) compared to the baseline or placebo control; d) an increase of less than 30%, an increase of less than 20%, an increase of less than 10%, an increase of less than 5% or no increase in LDL-C or a reduction in LDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40 %, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (actual% change or average% change) in relation to the level baseline or placebo control; e) reduction in Apo B levels, of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30 %, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual% change or% change mean) in relation to the baseline level or placebo control; f) reduction in vLDL levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) from baseline or placebo control; g) increase in apo AI levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) from baseline or placebo control; h) increase of the apo AI B / apo ratio of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) in relation to at baseline or placebo control; i) reduction in lipoprotein levels (a) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) in relation to baseline level or placebo control; j) reduction in the average number of LDL particles by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about. 50%, or at least about 100% (% of actual change or average change%) in relation to the baseline level or placebo control; k) increase in the average LDL particle size of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) in relation to the level baseline or placebo control; l) reduction in the remaining level of cholesterol particles of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) in relation to at baseline or placebo control; m) reduction in oxidized LDL levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) from baseline or placebo control; n) reduction in plasma fasting glucose (FPG) levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least at least about 30%, at least about 35% o, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change ) in relation to the baseline level or placebo control; o) reduction in hemoglobin Alc (HbAlc) of at least about 5%, at least about 10%, at least about 15%, at least about 20% o, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% (actual% change or average% change) from baseline or placebo control; p) reduction of the insulin resistance index in the homeostasis model by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (real% change or average% change) in relation to the baseline level or placebo control; q) reduction of phospholipase A2 associated with lipoprotein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30 %, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) from baseline or placebo control; r) reduction in intracellular adhesion molecule-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) in relation to baseline level or placebo control; s) reduction of interleukin-2 by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) from baseline or placebo control; t) reduction in plasminogen activator inhibitor-1 of at least about 5%, at least about 10%, at least about 15%>, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change) in relation to at baseline or placebo control; u) reduction in high sensitivity of C-reactive protein (hsCRP) of at least about 5%, at least about> 10%, at least about 15%, at least about 20%, at least about 25% at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or average% change ) in relation to the baseline level or placebo control; v) increase in EPA in serum phospholipids of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%, at least about 200% or at least about 400% ( real% change or average% change) from baseline or placebo control; w) increase of EPA in serum phospholipids and / or in red cell membranes of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25 %, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%, at least about 200%, or at least about 400% (actual% change or average% change) from baseline or placebo control; x) reduction or increase in one or more of phospholipids and / or red blood cells with a content of DHA, DPA, AA, PA, SA or AO of at least about 5%, at least 55% or at least about 75% (change actual% or average% change) from baseline or placebo control, and / or y) reduction in total cholesterol levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50 %, at least about 55% or at least about 75% (actual% change or average% change) from baseline.
[0058] In one embodiment, the methods of the present invention comprise measuring the baseline levels of one or more markers defined in (a) - (y) prior to administration to the individual or group of individuals. In another embodiment, the methods comprise administering to a subject a composition as described here, after the baseline levels of one or more markers defined in (a) - (y) are determined, and then taking a second measurement of one or more markers as measured at baseline levels for comparison.
[0059] In another embodiment, when treating with a composition of the present invention, for example, over a period of about 1 to about 200 weeks, from about 1 to about 100 weeks, from about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the individual or group of individuals displays any 2 or more than, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any d and 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more of, any 24 or more of, or the total of 25 results (a ) - (y) described above.
[0060] The parameters (a) - (y) can be measured according to any clinically acceptable methodology. For example, triglycerides, total cholesterol, HDL-C and fasting blood sugar can be sampled from the serum and analyzed using standard photometric techniques. VLDL-TG, LDL-C and VLDL-C can be calculated or determined using fractionation of serum lipoprotein through preparative ultra-centrifugation and subsequent quantitative analysis by refractometry or by analytical methodology by ultracentrifuge. Apo A-I, Apo B and hsCRP can be determined from the serum using standard nephelometric techniques. Lipoprotein (a) can be determined from serum using standard turbidimetric immunoassay techniques. The number of LDL particles and the particle size can be determined using nuclear magnetic resonance (NMR) spectrometry. Remnantslipoproteins and LDL-phospholipase A2 can be determined from plasma or serum EDTA and serum, respectively, using enzymatic immunostaining techniques. Oxidized LDL, levels of intracellular adhesion of molecule-1 and interleukin-2 can be determined from the serum using standard enzyme immunoassay techniques. These techniques are described in detail in the standard literature; for example, Tietz Fundamentals of Clinical Chemistry, 6th ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.
[0061] In one embodiment, the individual or group of individuals fasts for up to 12 hours before the blood sample is taken, for example, about 10 hours.
[0062] In another embodiment, the present invention provides a method of treating or preventing primary hypercholesterolemia and / or mixed dyslipidemia (Fredrickson Types Ila and IIb) in an individual with that need, including administering compositions to one or more individuals, as revealed here. In a related embodiment, the present invention provides a method of reducing triglyceride levels in an individual or individuals, when treatment with a statin or niacin controlled release monotherapy is considered inadequate (Frederickson's type IV hyperlipidemia).
[0063] In another embodiment, the present invention provides a method of treating or preventing the risk of non-fatal recurrent myocardial infarction in a patient with a history of myocardial infarction, which comprises administering to the individual one or more compositions as disclosed herein.
[0064] In another embodiment, the present invention provides a method of treating, delaying the progression of, or promoting regression of atherosclerotic disease in an individual in need, including administration to an individual in need of one or more compositions as disclosed herein.
[0065] In another embodiment, the present invention provides a method of inhibiting the oxidation of lipoproteins in an individual in need thereof, including administering to an individual in need thereof one or more compositions as disclosed herein.
[0066] In another embodiment, the present invention provides a method of scavenging free radicals in an individual in need of it, comprising administering to an individual in need of one or more compositions, as disclosed herein.
[0067] In another embodiment, the present invention provides a method for inhibiting the chelation of metal ions from lipoproteins in an individual in need thereof, comprising administering to an individual in need of one or more compositions, as disclosed herein.
[0068] In another embodiment, the present invention provides a method of treating or preventing very high serum triglyceride levels (e.g., hyperlipidemia types IV and V) in an individual in need, including administration to one individual of one or more compositions, as disclosed herein.
[0069] In one embodiment, the composition of the present invention is administered to an individual in an amount sufficient to provide a daily dose of ethyl eicosapentaenoate from about 1 mg to about 10,000 mg, 25 about 5000 mg, from about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 8 50 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.
[0070] In another embodiment, the composition of the present invention is administered to an individual in an amount sufficient to provide a daily dose of hydroxy-derived from a statin of about 0.01 mg to about 500 mg, of about 0, 1 mg to about 250 mg, or about 1 mg to about 100 mg, for example, from about 1 mg to about 5 mg, about 10 mg, about 15 mg, about 20 mg , about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 70 mg about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.
[0071] In another embodiment, any of the methods described here are used to treat an individual or individuals who consume a traditional Western diet. In one embodiment, the methods of the present invention include a step of identifying an individual as a consumer of a Western diet or a consumer of a prudent diet and then treating the individual, if the individual is considered a consumer of a Western diet. The term “western diet” generally refers to a typical diet that consists of a total percentage of calories from about 45% to about 50% of carbohydrates, from about 35% to about 40% of fat and about 10 % up to about 15% protein. A Western diet can alternatively or additionally be characterized by a relatively high intake of red and processed meats, sweets, refined grains, and desserts, for example, more than 50%, more than 60% or more, or 70% of total calories from these sources.
[0072] In another embodiment, any of the methods described here are used to treat an individual or individuals who consume less than (real or average) about 150 g, less than about 125 g, less than about 100 g , less than about 75 g, less than about 50 g, less than about 45 g, less than about 40 g, less than about 35 g, less than about 30 g, less than about 25 g, less about 20 g or less than about 15 g of fish per day.
[0073] In another embodiment, any of the methods described here are used to treat an individual or individuals who consume less than (real or average) about 10 g, less than about 9 g, less than about 8 g , less than about 7 g, less than about 6 g, less than about 5 g, less than about 4 g, less than about 3 g, less than about 2 g per day of omega-3 fatty acids from dietary sources.
[0074] In another embodiment, any of the methods described here are used to treat an individual or individuals who consume less than (real or average) about 2.5 g, less than about 2 g, less than about 1.5 g, less than about 1 g, less than about 0.5 g, less than about 0.25 g, or less than about 0.2 g per day of EPA and DHA or derived from any one of the dietary sources.
[0075] In one embodiment, a composition as described herein, is administered to an individual once or twice a day. In another embodiment, from 1, 2, 3 or 4 capsules, each containing about 500 mg to about 1 g of a composition as described herein, are administered to an individual per day. In another embodiment, 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the individual in the morning, for example, between about 5:00 am and about 11:00 am, and 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject, in the evening, for example, between about 17:00 h and about 23:00 h.
[0076] In another embodiment, compositions useful according to the methods of the invention are administrable orally. The terms, “administrable orally” or “oral administration” include any form of delivery of a therapeutic agent or a composition thereof to an individual in which the agent or composition is placed in the individual's mouth, the agent or composition is or not ingested. Thus, "oral administration" includes buccal and sublingual, as well as esophageal administration. In one embodiment, the composition is present in a capsule, for example, a soft gelatin capsule.
[0077] A composition for use according to the invention can be formulated as one or more dosage units. The terms "unit dose" and "unit dose" herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. These dosage units can be administered from one to a plurality (for example, 1 to about 10, 1-8, 1-6, 1-4 or 1-2) times a day, or as many times as necessary to obtain a therapeutic response.
[0078] In another embodiment, the invention provides the use of any composition described herein for the treatment of moderate to severe hypertriglyceridemia in an individual with that need, comprising: providing an individual who has a fasting baseline triglyceride level of about 500 mg / dL to about 1500 mg / dL and administer to the subject a pharmaceutical composition as described herein. In one embodiment, the composition comprises from about 1 g to about 4 g of ethyl ester of eicosapentaenoic acid, wherein the composition substantially does not contain docosahexaenoic acid. EXAMPLES Example 1
[0079] An experiment was carried out to test EPA, DHA, EPA + DHA with and without certain statins and a statin derivative (eg atorvastatin, rosuvastatin, simvastatin and hydroxy-atorvastatin), in membrane models enriched with PUFAs and cholesterol at levels that reproduce disease or conditions of high cardiovascular risk (ie, hypercholesterimia).
[0080] EPA and DHA were tested individually, at a fixed concentration of 10.0 μM or in combination at 5.65 μM and 4.35 μM (EPA and DHA, respectively), which is a molar ratio of 1.3: 1. Separate and combined effects of these agents on the formation of lipid peroxide (LOOH) were examined in cholesterol-phospholipid (C / P) molar ratios of 0.5: 1, 1.0: 1 and 1.5: 1. The levels of lipid hydroperoxides were measured by EPA, DPH and EPA / DPH on the cholesterol enriched membrane prepared in the absence and presence of a statin.
[0081] 1,2-Dilinoleoyl-3-sn-phosphatidylcholine (DLPC) was obtained from Avanti Polar Lipids (Alabaster, AL) and stored in chloroform (25 mg / mL) at -80 ° C until use. The cholesterol obtained is stored in chloroform (10 mg / ml) at -20 ° C. Iodide-CHOD color reagent (stock) was prepared according to a modified procedure by El-Saadani et al. (El-Saadani M, Esterbauer H, El-Sayed M, Goher M, Nassar AY, Jurgens G. A spectrophotometric assay for lipid peroxides in serum lipoproteins using commercially available reagents J Lipid Res 1989; 30: 627-30) consisted of 0.2 M K2HPO4, 0.12 M KI, 0.15 mM NaN3, 10 μM ammonium molybdate, and 0.1 g / L benzalkonium chloride. Before experimental use, the CHOD reagent was activated by adding 24 μM ethylene diaminetetraacetic acid (EDTA), 20 μM butylated hydroxytoluene (BHT), and 0.2% Triton X-100. The statin was prepared in ethanol just before use and added together with the component lipids containing fixed amounts of EPA, DPH or EPA / DPH at equivalent levels. The compounds and lipids were added in combination during the preparation of the membrane sample to ensure complete incorporation of the lipid bilayers.
[0082] Membrane samples consisting of DLPC ± cholesterol, with cholesterol-phospholipid (C / P) molar relations in the range 0.5 to 1.5, were prepared as follows. The lipid compounds (in chloroform) were transferred to test tubes 13 x 100 mm and dried under a steady stream of nitrogen gas with a swirling mixture. The lipid was dried in conjunction with EPA, DPH or EPA / DPH prepared in the absence or presence of a statin at equimolar levels.
[0083] The residual solvent was removed by drying for a minimum of 3 h in vacuo. After dehydration, each membrane sample was resuspended in diffraction buffer (0.5 mM HEPES, 154 mM NaCl, pH 7.3) to obtain a final phospholipid concentration of 1.0 mg / mL. Multilamellar vesicles (MLV) were formed by swirling the mixture for 3 minutes at room temperature. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965; 13: 238-52. Immediately after the initial MLV preparation, aliquots of each membrane sample will be taken for baseline peroxidation analyzes (0 h).
[0084] All lipid membrane samples were subjected to auto-oxidation as a function of time, by incubation at 37 ° C in a water bath by uncovered shaking. Small aliquots of each sample were removed at 24-hour intervals and combined with 1.0 mL of CHOD-iodide active color reagent. To ensure spectrophotometric readings of the absorbance in the ideal range, sample volumes taken to measure the formation of lipid peroxide were adjusted to an extent of peroxidation and a range between 100 and 10 μL. The test samples were immediately covered with aluminum foil and incubated at room temperature for more than 4 h, in the absence of light. Absorbances were measured against a CHOD blank at 365 nm using a Beckman DU-640 spectrophotometer.
[0085] The colorimetric CHOD assay is based on the oxidation of iodide (r) by lipid hydroperoxides (LOOH) and is carried out according to the following reaction scheme:

[0086] The amount of triiodide anion (I3-) released in this reaction is directly proportional to the amount of lipid hydroperoxides present in the membrane sample. The molar absorptivity value (ε) of I3- is 2.46 x 104 M-1cm-1 at 365 nm.
[0087] As shown in Figure 1, EPA, DHA and EPA / DHA plus hydroxy-atorvastatin exhibited significantly lower lipid hydroperoxide formation compared to the control.
[0088] As shown in Figure 2, EPA plus hydroxy-atorvastatin exhibited significantly lower lipid hydroperoxide formation compared to EPA + atorvastatin, EPA + simvastatin or EPA + rosuvastatin.
[0089] As shown in Figure 3, DHA plus hydroxy-atorvastatin exhibited significantly lower lipid hydroperoxide formation compared to DHA + atorvastatin, DHA + simvastatin or DHA + rosuvastatin.
[0090] As shown in Figure 4, EPA / DHA plus hydroxy-atorvastatin exhibited significantly lower lipid hydroperoxide formation compared to EPA / DHA + atorvastatin, EPA / DHA + simvastatin or EPA / DHA + rosuvastatin.
[0091] As shown in Figure 5, EPA, DHA and EPA / DHA plus hydroxy-atorvastatin or rosuvastatin exhibited significantly lower lipid hydroperoxide formation compared to the control.

权利要求:
Claims (7)
[0001]
1. Pharmaceutical composition CHARACTERIZED by the fact that it comprises: (a) a hydroxy derivative of atorvastatin or a pharmaceutically acceptable salt thereof and (b) an oil comprising 95% by weight of ethyl eicosapentaenoate or 95% by weight of ethyl docosahexaenoate, wherein the atorvastatin hydroxy derivative or a pharmaceutically acceptable salt thereof is selected from atorvastatin o-hydroxy, atorvastatin p-hydroxy, calcium atorvastatin p-hydroxy, disodium atorvastatin p-hydroxy, atorvastatin o-hydroxy of calcium, lactone atorvastatin o-hydroxy, calcium d5 atorvastatin o-hydroxy, d5 disodium atorvastatin o-hydroxy, lactone atorvastatin o-hydroxy d5, bisodium atorvastatin 2-hydroxy, atorvastatin p-hydroxy de lactone, calcium d5 atorvastatin p-hydroxy, lactone atorvastatin p-hydroxy d5 and bisodium sodium atorvastatin 4-hydroxy.
[0002]
2. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that the oil comprises 95% by weight of ethyl eicosapentaenoate.
[0003]
3. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that the oil comprises 95% by weight of ethyl docosahexaenoate.
[0004]
4. Pharmaceutical composition, according to claim 2, CHARACTERIZED by the fact that the oil comprises ethyl eicosapentaenoate and ethyl docosahexaenoate.
[0005]
5. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that the atorvastatin hydroxy derivative is selected from ortho or for atorvastatin hydroxy and pharmaceutically acceptable salts thereof.
[0006]
6. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that it also comprises tocopherol in an amount of 0.1% to 0.3% by weight.
[0007]
7. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that 0.5 g to 2 g of said pharmaceutical composition is present in a capsule.

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同族专利:

公开号 | 公开日

AU2016269422A1|2016-12-22|

AU2010298222B2|2017-01-05|

SG10201405994UA|2014-10-30|

RU2758369C2|2021-10-28|

AU2010298222A1|2012-04-19|

NZ599061A|2014-05-30|

KR101798670B1|2017-11-16|

US20150265574A1|2015-09-24|

ES2554657T3|2015-12-22|

BR112012006692B8|2021-05-25|

US20200093790A1|2020-03-26|

CA2775339C|2017-03-28|

WO2011038122A1|2011-03-31|

KR20120083408A|2012-07-25|

AU2016269422B2|2018-07-26|

EP2480248B1|2015-09-02|

BR112012006692A2|2017-02-21|

MX2012003555A|2012-07-03|

BR122019016628B8|2021-07-27|

ZA201202263B|2013-06-26|

RU2012116079A|2013-10-27|

CA2775339A1|2011-03-31|

US10493058B2|2019-12-03|

EP2480248A4|2013-05-15|

US20110071176A1|2011-03-24|

RU2017112737A3|2020-06-25|

IN2012DN03314A|2015-10-23|

US11007173B2|2021-05-18|

BR122019016628B1|2021-02-23|

EP2480248A1|2012-08-01|

RU2017112737A|2019-01-25|

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