compositions and their uses to treat and / or prevent cardiovascular disease

专利摘要:
COMPOSITIONS AND METHODS TO TREAT AND / OR PREVENT CARDIOVASCULAR DISEASE. In various embodiments, the present invention provides pharmaceutical compositions that comprise fatty acid methods for treating individuals using them.
公开号:BR112012022336A2
申请号:R112012022336-4
申请日:2011-03-04
公开日:2020-07-21
发明作者:Jonathan Rowe
申请人:Amarin Pharma, Inc.；
IPC主号:

专利说明:

: "COMPOSITIONS AND THEIR USES TO TREAT AND / OR PREVENT CARDIOVASCULAR DISEASE". BACKGROUND OF THE INVENTION - Cardiovascular disease is one of the main causes of death in the United States in most European countries. It is estimated that more than 70 million people alone. The United States suffers from cardiovascular disease or disorder, including, but not limited to, high blood pressure, coronary heart disease, dyslipidemia, congestive heart failure and stroke, and there is a need for better treatments for cardiovascular diseases and disorders.
SUMMARY In various embodiments, the present invention provides pharmaceutical compositions and methods of using these compositions to increase EPA levels in plasma, serum and / or red blood cells (RBC), and / or to treat or prevent cardiovascular disease.
In one embodiment, the invention provides a pharmaceutical composition comprising, consisting of or consisting essentially of at least 95% by weight of ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5 % by weight of ethyl octadechatrateate (ODTA-E), about 0.05% to about 0.25% by weight of ethyl nonaecapentaenoenate (NDPA-E), about 0.2% to about from 0.45% by weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% of heneicosapentaenoate acetate (HPA-E). In another embodiment, the composition is present in a coated capsule. In another embodiment, the composition contains substantially no or no amount of docasaxenoic acid (DHA) or a derivative thereof, such as ethyl-DHA (DHA-E), for example, no more than about 0.06% to about 0.05%, or about 0.04% by weight.
In another embodiment, the invention provides a method for increasing levels of EPA in serum, plasma and / or red blood cells (RBC) comprising administering a composition as described herein to an individual in need of an increase in EPA levels in serum, plasma and / or RBC. In a related modality. 30 da, the individual has an EPA level in the baseline plasma, serum and / or RBC less than about 50 ng / g by administering the composition to the individual for a period of at least about 6 weeks, the individual presents, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 350% or at least 400% increase (change in baseline EPA level divided by EPA level) in plasma, serum and / or RBC EPA levels compared to baseline. In a related embodiment, the individual has a baseline plasma EPA, serum and / or RBC level not greater than about 50 µg / g. In another modality, the individual is
'equipped with an amount of said composition effective to achieve such increases in EPA levels. In another modality, the individual is equipped with about 2 g to about-. about 4 g per day of said composition. In another embodiment, the invention provides a method of treating cardiovascular disease in an individual in need thereof, comprising administering a composition as described herein for the individual. In a related modality, the individual has a baseline EPA level of plasma, serum and / or RBC not greater than about 50 ug / g by administering the composition to the individual for a period of at least about 6 weeks, the individual exhibits at least about 100% at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350% or at least about 400% increase in plasma, serum and / or RBC levels of EPA compared to baseline. In a related modality, the individual has a baseline plasma, serum and / or RBC EPA level not greater than about 50 µg / g. In another embodiment, the individual is equipped with about 2 g to about 4 g per day of said composition. These and other embodiments of the present invention will be described in greater detail below. Figure 1 shows blood EPA levels after several administrations of EPA. Figure 2 shows an increase in EPA over the baseline after several administrations of EPA.
DETAILED DESCRIPTION While the present invention is capable of being incorporated in several forms, the following description of various modalities is made with the understanding that the present description is to be considered as an example of the invention, and is not intended - to limit the invention to the specific modalities illustrated. Titles are provided for convenience only and are not to be constructed to limit the invention in any way. The modalities illustrated under any heading can be combined with modalities illustrated under any other heading. The use of numerical values in the various quantitative values specified in this application, unless expressly stated otherwise, are demonstrated as approximations as if the minimum and maximum values within the indicated ranges were both preceded by the word "about". In addition, the description of intervals is intended to be a continuous interval, including all values between the minimum and maximum values recited, as well as any intervals that can be formed by such values. Also stated here are any and all reasons (and the ranges of any such reasons) that can be formed by dividing a numerical value described into any other numerical value described. Therefore, the person skilled in the art will appreciate that
'many such ratios, ranges and range of ratios can be unequivocally from the numerical values presented in this document and in all cases, such reasons, ranges, and ranges of ratios represent various modalities of the present in- convention.
In one embodiment, the invention provides pharmaceutical compositions comprising eicosapentaenoic acid or a derivative thereof. In one embodiment, these compositions comprise eicosapentaenoic acid, or a pharmaceutically acceptable ester, conjugated, derivative or salt thereof, or mixtures of any of the above, collectively referred to herein as "EPA". The term "pharmaceutically acceptable" in the present context means that the substance in question does not produce unacceptable toxicity to the individual or the interaction with the other components of the composition.
In one embodiment, EPA comprises all cis-eicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, EPA is composed of an eicosapentaenoic acid ester. In another embodiment, EPA is composed of a C1- C5 alkyl ester of eicosa- —pentaenoic acid. In another embodiment, EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In another embodiment, EPA comprises all cis-eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.
In another embodiment, EPA is in the form of ethyl-EPA, lithium EPA, mono-, di- or tri-glyceride EPA or any other EPA ester or salt, or in the form of EPA-free acid. EPA may also be in the form of a 2-substituted derivative or another derivative, which slows down its oxidation rate, but does not otherwise alter its biological action in a substantial way.
In another embodiment, the composition is present in a dosage unit (for example, a capsule), in an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg about 1000 mg, for example, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 ma, '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 - 30 of 450 mg, about 450 mg, about 500 mg, about 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 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 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 2300 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.
In another embodiment, a composition useful according to the invention 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%, 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 docosahexaenoic acid (DHA) or a derivative thereof, such as ethyl-DHA, if any. In another embodiment, a composition of the invention contains substantially no DHA or eti-DHA. In yet another embodiment, a composition useful in the present invention does not contain DHA or a derivative thereof, such as DHA-E.
In another embodiment, EPA comprises at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% in weight of all fatty acids present in a composition according to the invention.
In another embodiment, a composition useful according to the invention 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 the total composition, or by weight of the total fatty acid content, of any fatty acid or a derivative of it that is not 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, a composition useful according to the invention contains about 0.1% to about 4%, about 0.5% to about 3%, or about 1% to about 2% by weight of the total fatty acids other than EPA and / or DHA.
In another embodiment, a composition according to the invention has one or more of the following characteristics: (a) eicosapentaenoic ethyl ester acid represents at least about 96%, at least about 97%, or at least about 98% in weight, of all fatty acids present in the composition, (b) the composition contains no more than about 4% and no more than about 3%, or no more than about 2% by weight, of the fatty acids totals other than eicosapentaenoic ethyl ester acid, (c) the composition - contains no more than about 0.6%, no more than about 0.5%, or no more than about 0.4% of any acid individual fat other than eicosapentaenoic ethyl ester acid, (d) the composition has a refractive index (20ºC) of about 1 to about 2, about 1.2 to about 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, about 0.85 to about 0.95 or about 0 , 9 to about 0.92, (e) the composition does not contain more than about 20 ppm, not more than - about 15 ppm, or no more than about 10 ppm heavy metals, (f) the composition contains no more than about 5 ppm, no more than about 4 ppm, no more than about 3 ppm, or no more than about 2 ppm arsenic, and / or (g) the composition has a peroxide value of no more than about 5 meq / kg, unless more than about 4 meq / Kkg, no more than about 3 meq / Kkg, or no more than about 2 meq / Kkg.
In another embodiment, the invention provides a composition comprising, consisting essentially of, or consisting of at least 95%, 96%, 97% by weight or eicosapentaenoate acetate, from about 0.2% to about 0.5 % by weight of ethyl octadecatetraeneate, from about 0.05% to about 0.25% by weight of ethyl nonaecapentaenoate, about 0.2% to about 0.45% by weight of ethyl arachidonate, about 0.3% to about 0.5% by weight of ethyl eicosatetraenoate, and about 0.05% to about 0.32% of heneicosapentaenoate acetate. Optionally, the composition does not contain more than about 0.06%, about 0.05%, or about 0.04% by weight or DHA derived therefrom such as eti-DHA. In one embodiment, the composition contains substantially no or no amount of DHA or derivative thereof, such as ethyl-DHA. The composition also - optionally comprises one or more antioxidants (for example, tocopherol) or other impurities, in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example, about 0.2% by weight of tocopherol. In another embodiment, about 500 mg to about 1 g of the composition is supplied in a capsule.
In another embodiment, the invention provides a composition comprising, consisting of or consisting essentially of, at least 96% by weight ethyl eicosapentaenoate, about 0.22% to about 0.4% by weight ethyl octadecatetraenoate, about 0.075% to about 0.20% by weight of ethyl nonaecapentaenoate, about 0.25% to about 0.40% by weight of ethyl arachidonate, about 0.3% to about 0.4 % by weight ei- — ethyl katetraenoate and about 0.075% to about 0.25% henicosapentaenoate acetate. Optionally, the composition does not contain more than about 0.06%, about 0.05% or about 0.04% by weight or DHA derived therefrom such as eti-DHA. In a
Accordingly, the composition contains substantially no or no amount of DHA or derivative thereof, such as ethyl-DHA. The composition also optionally comprises one or more antioxidants (for example, tocopherol) or other impurities, in an amount of not more than about 0.5% or not more than 0.05%. In another mode, the composition comprises about 0.05% to about 0.4%, for example, about 0.2% by weight of tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the previous composition in a capsule shell. In another embodiment, the invention provides a composition comprising, consisting of, or consisting essentially of at least 96%, 97% or 98% by weight of eicosapentaenoate acetate, from about 0.25% to about 0.38% by weight ethyl octadecatetrahydrate, about 0.10% to about 0.15% by weight ethyl nonaecapentaenoate, about 0.25% to about 0.35% by weight ethyl arachidonate, about 0.31% to about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20% heneicosapentaenoate acetate. Optionally, the composition does not contain more than about 0.06%, about 0.05%, or about 0.04%, by weight, or DHA derived from the same as ethyl-DHA. In one embodiment, the composition contains substantially none or no amount of DHA or derivative thereof, such as ethyl-DHA. The composition also optionally comprises one or more antioxidants (for example, tocopherol) or other trans-impurities, in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example, about 0.2% by weight of tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the above composition in a capsule shell.
In another embodiment, the invention provides a method of increasing the levels of EPA in serum, plasma and / or red blood cells (RBC), comprising administering a composition as described herein to an individual in need of such treatment.
. In one embodiment, after oral administration of a composition as defined herein to an individual, for a period of at least about 5, about 10, about 15, about 20, about 25, about 30, about 35 , about 40, about 42, about 45 or about 50 days, the individual exhibits at least about 2 times, at least about 3 times, at least about 3.5 times, at least about 3 , 75 times or at least one change of 4 times (final absolute level of EPA divided by baseline EPA level) in serum, plasma and / or EPA RBC. In one embodiment, the method comprises a step of identifying a patient in need of an increase in EPA in serum, plasma and / or red blood cells (RBC) before said step of administration. In a related mode, the individual has a baseline EPA level in plasma, serum and / or
BR RBC not greater than about 50 ug / g. In another embodiment, the individual is provided with about 2 g to about 4 g per day of said composition. In another embodiment, after administration of the composition to the individual as described above, the individual experiences a decrease in the levels of DHA, AA and / or DGLA in plasma, serum and / or RBC. In another way, after the administration of the composition to the individual as described above, the individual - presents an increase in the levels of DPA of the plasma, serum and / or RBC. In yet another mode, after administration of the composition to the individual as described above, plasma DHA, serum and / or RBC levels decrease by at least 16%, plasma DGLA, serum and / or RBC levels decrease by at least 31%, plasma AA, serum and / or RBC levels decrease by at least 20% and / or plasma, serum and / or RBC levels increase by more than 130%. In another embodiment, the invention provides a method of increasing levels of EPA in serum, plasma and / or red blood cells (RBC), comprising administering a composition as described herein to an individual in need of increasing serum EPA levels. , plasma and / or RBC. In a related embodiment, by administering the composition to the individual, for a period of at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 42, about 45, or about 50 days, the individual exhibits at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350% or at least about 400% increase (change in EPA level from baseline divided by baseline EPA level) in plasma, serum and / or RBC EPA levels in relation to the baseline. In a related modality, the individual has a baseline EPA level in plasma, serum and / or RBC not greater than about 50 µg / g. In another modality, the individual is provided with about 2g of about 4g of each composition. In another embodiment, after administration of the composition to the individual as described above, the individual exhibits a decrease in the levels of DHA, AA and / or DGLA in plasma, serum and / or RBC. In another embodiment, after administering the composition to the individual as described above, the individual exhibits an increase in the levels of plasma, serum and / or RBC DPA. In yet another modality, after administering the composition to the individual described above, plasma DHA, serum and / or RBC levels decrease by at least 16%, plasma DGLA, serum and / or RBC decrease by at least 31%, plasma AA, serum and / or RBC levels decrease by at least 20%, and / or plasma, serum and / or RBC DPA levels increase by more than 130%.
In a related embodiment, by oral administration of about 2 to about 4 g per day of a composition as defined herein for an individual, for a period of at least about 5, about 10, about 15, about 20, about 25, about
. of about 30, about 35, about 40, about 45 or about 50 days, the individual exhibits at least about an increase of 10 µg / g, at least about an increase of 15 µg / g, by: at least about 20 ug / g increase, at least about 25 ug / g increase, - at least about 30 ug / g increase, at least about 35 ug / 9g increase, at least about an increase of 40 ug / g, at least about an increase of 45 ug / 9,] by at least about an increase of 50 ug / g, at least about an increase of 75 Vg / g, at least about of an increase of 100 µg / 9g, or at least about an increase of 150 µg / g in serum, plasma and / or red blood cell EPA compared to the baseline. In another modality, after the administration of the composition described above to the individual, the individual has a decrease in the DHA, AA and / or DGLA levels of plasma, serum and / or RBC. In another embodiment, after administration of the composition described above to the individual, the individual has an increase in the levels of plasma, serum and / or RBC DPA. In yet another embodiment, after administration of the composition described above to the individual, plasma DHA, serum and / or RBC levels decrease by at least 16%, plasma DGLA, serum and / or RBC levels decrease by at least 31%, the levels of AA in plasma, serum and / or RBC decrease by at least 20%, and / or the levels of DPA in the plasma, serum and / or RBC increase by more than 130%.
In another embodiment, the subject has not had an Omega-3 fatty acid therapy or supplement for at least 2 weeks, 3 weeks, 4 weeks, 6 weeks or 12 weeks before starting treatment, as described herein.
In one embodiment, the invention provides a method for the treatment and / or prevention of related cardiovascular diseases, comprising administering to an individual in need of such treatment or preventing a composition as defined herein. The term "related cardiovascular disease" here refers to any disease or disorder of the heart or blood vessels (i.e., arteries and veins), or any symptom thereof. Non-limiting examples of related cardiovascular diseases and disorders include hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia, heart disease. coronary disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.
- 30 The term "treatment" with respect to a particular disease or disorder, includes, but is not limited to, inhibition of the disease or disorder, for example, stopping the development of the disease or disorder; alleviate the disease or disorder, for example, cause the disease or disorder to regress, or alleviate 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 disease development, if none has occurred preventing the disease or disorder from occurring in an individual who may be predisposed to the disease or disorder,
: but that has not yet been diagnosed as having the disorder or disease, and / or preventing the further disease / disorder from developing if already present. In one embodiment, the present invention provides a method of lipid - blood therapy which comprises administering to an individual or group of individuals in need of a pharmaceutical composition as described herein. In another fashion, the individual or group of individuals has hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and / or very high triglycerides.
In another modality, the individual or group of individuals to be treated has a baseline triglyceride level (mean or median baseline triglyceride level, in the case of a group of individuals), fed or fasted, of about 200 mg / dl and about 500 mg / dl. In another modality, the individual or group of individuals has a baseline LDL-C level (mean or median baseline LDL-C level), despite statin therapy of around 40 mg / dl to about 100 mg / dl.
In one embodiment, the individual or group of individuals to be treated in accordance with the methods of the present invention is on concomitant statin therapy, for example, atorvastatin, rosuvastatin or simvastatin therapy (with or without ezetimibe). In another modality, the individual is on stable concomitant statin therapy at the time of the start of ultrapure EPA therapy.
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 BM! Average) of no more than about 45 kg / m 2.
In another embodiment, the invention provides a method of maintaining LDL control in a patient who is on stable statin therapy and requires triglyceride reduction therapy, the method comprising identifying an individual who is being treated with statin stable and requires triglyceride reduction therapy, administration to an individual of a pharmaceutically acceptable composition comprising from about 1 g to about 4 g of EPA per day (e.g., ultrapure E-EPA), in which after administration. traction of the composition to the individual, the individual has a clinically significant reduction in fasting triglycerides compared to the control. In the present context, the term "clinically significant reduction in fasting triglycerides" means a reduction in triglycerides in an amount that corresponds to a reduction in the risk of an adverse cardiovascular event. Typically, each 10 mg / d decline! triglycerides results in less than 1.6% risk of death, myocardial infarction and recurrent acute coronary syndrome. See, for example Miller et al, “impact of trilglyceride level beyond low-density lip- —proteincholesterol after acute coronary syndrome in the PROVE IT-TIMI 22”, JACC Vol. 51, No. 7 (2008), incorporated herein by reference . Therefore, in one embodiment, a "clinically significant reduction in fasting triglycerides" means a reduction of 10 mg / dl. At the
. In this context, the term "maintaining control of LDL" means any clinically significant change in adverse LDL levels during therapy. In one embodiment, the invention provides a method for reducing triglycerides in - an individual on stable statin therapy having baseline fasting triglycerides of about 200 mg / dlacercade 500 mg / dl, the method comprising administering to the individual a pharmaceutical composition comprising about 1 g to about 4 g of EPA (for example, ultrapure EPA), where after administration of the composition to the individual per day, for a period of about 12 weeks, the individual presents at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least at least 65%, at least 70% or at least 75% lower fasting triglycerides than a control subject maintained on stable statin therapy without concurrent ultrapure EPA for a period of about 12 weeks, in which the control subject also also has basal fasting triglycerides of about 200 mg / dl ac about 500 mg / dl. The term "stable statin therapy" used here means that the individual, group of subjects, control subject or group of control subjects in question has been taking a stable daily dose of a statin (for example, atorvastatin, rosuvastatin or simvastati - na) for at least 4 weeks before baseline fasting triglyceride measurements (the "grace period"). For example, an individual or control subject over stable statin therapy would receive a constant dose per day (that is, the same dose each day) with statin for at least 4 weeks immediately before baseline fasting triglyceride measurement. . In one embodiment, the LDL-C of the control individual or individual is maintained between about 40 mg / dl to about 100 mg / dl, during the qualification period. The subject and the control subject are then continued on their steady state dose — for the 12-week post-baseline period.
In one embodiment, the statin is administered to the subject and the control subject in an amount of about 1 mg to about 500 mg, about 5 mg to about 200 mg, or about 10 mg to about 100 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 ma, - 30 about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 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 —mqg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In another modality, the individual (and, optionally, the control individual) has a baseline LDL-C level, despite therapy with
: in the stable, from about 40 mg / dl to about 100 mg / dl. In another modality, the individual and / or control individual has a body mass index (BMI, or BMI) of no more than. that about 45 kg / m .
- In another embodiment, the invention provides a method for reducing triglycerides in the group of subjects being treated with a stable statin having an average baseline fasting triglycerides of about 200 mg / dl to about 500 mg / dl, the method comprising adding administration to members of the group of individuals of a pharmaceutical composition comprising about 1 g to about 4 g of ultrapure EPA per day, in which after administration of the composition to members of the group of individuals per day, for a period of - around 12 weeks, the group of individuals exhibits at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least at least 50%, at least 55%), at least 60%, at least 65%, at least 70%, at least 75% of lower fasting triglycerides than a group of control subjects maintained on statin therapy stable without concomitant ultrapure EPA, for a period of about 12 weeks, Control individuals also have an average baseline fasting triglyceride of about 200 mg / dl and about 500 mg / dl. In a related modality, stable statin therapy will be sufficient such that the group of individuals has an average LDL-C level of about at least about 40 mg / dl, and no more than about 100 mg / dl for the four weeks immediately before - measurement of basal fasting triglycerides.
In another embodiment, the invention provides a method for reducing triglycerides in the group of subjects being treated with a stable statin and having an average fasting average triglyceride level of about 200 mg / dl and about 500 mg / dl, the method comprising administration to members of the group of individuals of a pharmaceutical composition - comprising about 1 g to about 4 g of ultrapure EPA, in which after administration of the composition to members of the group of individuals per day, for a period of about 12 weeks, the group of individuals exhibits (a) at least 10%, at least 15%,. at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, - at least 70%, at least 75% lower fasting triglycerides compared to a group of control subjects maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks, and (b) there was no increase in average LDL-C levels compared to baseline, where the control subject also has an average baseline fasting triglyceride of about 200 mg / dl and about 500 mg / dl.
In another embodiment, the invention provides a method for reducing triglycerides in subjects being treated with a stable statin and having an average baseline fasting triglyceride level of about 200 mg / dl to about 500 mg / dl, the method comprising
: giving the individual the administration of a pharmaceutical composition that comprises about 1 g to about 4 g of ultrapure EPA, in which after the daily administration of the composition. the individual, over a period of about 12 weeks, the group of individuals exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% at least 40%, at least 45%, at least 50%, at least '55%, at least 60%, at least 65%, at least 70% or at least 75% lower fasting triglycerides compared to one control subject maintained on stable statin therapy without concomitant ultrapure EPA for a period of about 12 weeks, and (b) no increase in serum LDL-C compared to baseline, in which the Baseline control also has fasting triglycerides from about 200 mg / dl to about 500 mg / dl.
In another embodiment, the invention provides a method for reducing triglycerides in the individual group being treated with a stable statin and having an average baseline fasting triglyceride level of about 200 mg / dl to about 500 mg / dl, the method comprising administering to members of the group of individuals a pharmaceutical composition comprising about 1 g to about 4 g of ultrapure EPA, wherein after administration of the composition to members of the individual group per day for a period of about 12 weeks , the group of individuals exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower average fasting triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or average in the plasma of at least at least 50% lower or in LDL-C serum compared to the levels of a group of control subjects maintained on stable statin therapy without concurrent ultrapure EPA, for a period of about 12 weeks, in which the control subject it also has an average basal fasting triglyceride of about 200 mg / dl to about 500 mg / dl.
- In another embodiment, the invention provides a method for reducing triglycerides in the group of subjects being treated with a stable statin and having a medium triglyceride level - - 30 - basal fasting ratios from about 200 mg / dl to about 500 mg / dl, the method comprising administering to members of the group of individuals a pharmaceutical composition comprising about 1 g to about 4 g of ultrapure EPA, in which after the daily administration of the composition to members of the individual group, over a period of about 12 weeks, the group of individuals exhibits (a) at least 10%, at least 15%, at least - 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% of lower average triglycerides and (b) at least 5% , fur
: at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50% lower LDL-C , in plasma or serum compared to a group of control subjects maintained on stable statin therapy without concurrent ultrapure EPA, for a period of about 12 weeks, in which the control subject group also had fasting triglycerides - baseline from about 200 mg / dl to about 500 mg / dl.
In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits a baseline absolute plasma level of fasting total free fatty acid (or the mean thereof) not exceeding about 300 nmoi / ml, not more than about 250 nmol / ml, not more than about 200 nmol / ml, not more than about 150 not nmol / ml, more than about 100 nmol / ml, or not more than about 50 nmol / ml.
In another embodiment, the individual or patient group to be treated according to the methods of the present invention exhibits an absolute baseline fasting level of free EPA plasma (or average in the case of a group of individual) not greater than about 0, 70 nmol / ml, - not more than about 0.65 nmol / ml, not more than about 0.680 nmol / ml, not more than about 0.55 nmol / ml, not more than about 0.50 nmol / ml, not more than about 0.45 nmol / ml, or not more 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 baseline fasting plasma level (or average thereof) of free EPA, expressed as a percentage of the total fatty acids of free acid, no more than about 3%, no more than about 2.5%, no more than about 2%, and 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 a modality, plasma-free EPA and / or total levels — fatty acids are determined before therapy begins.
In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits an absolute baseline level of plasma fasting. Free EPA (or average of these) not more than 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 more than about 0.30 nmol / ml.
In another embodiment, the individual or group of individuals to be treated according to the methods of the present invention exhibits a baseline fasting EPA level of plasma, serum or red blood cell membrane not greater than about 150 µg / ml, no more than about 125 ug / ml, not more than about 100 ug / ml, not more than about 95 ug / ml, not more than about 75 pg / ml, not more than about 60 ug / ml, not greater than about 50 pg / ml, not more than about 40 pg / ml, not more than about 30 ug / ml, or not more than about 25 pg / ml.
: 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. start 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: baseline non-HDL-C value from about 200 mg / dl to about 400 mg / dl 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 cholesterol value! total - 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 from 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 HDHD-C from about 10 to about 100 mg / dl, for example, not more than about 90 mg / dl , not more than about 80 mg / dl, and not more than about 70 mg / dl, and not more than about 60 mg / dl, and not more than about 60 mg / dl, and not more than about 50 mg / dl, not more than about 40 mg / dl, not more than about 35 mg / dl, and not more than about 30 mg / dl, not more than about 25 mg / dl, and not more than about 20 mg / dl, or not more than about 15 mg / dl, and / or the baseline C-LDL value of about 30 to about 300 mg / dl, for example, not less than about 40 mg / dl, and not less than about 50 mg / dl, and not less than about 60 mg / dl, and not less than about 70 mg / dl, and not less than about 90 mg / dl or not less q about 90 mg / dl.
In a related embodiment, after treatment in accordance with the present invention, for example, over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, 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. 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 - mana, the individual or the group of individuals exhibits one or more of the following results: (a) reduced triglyceride levels compared to the baseline; (b) reduced apo B levels compared to the baseline; (c) increased HDL-C levels compared to the baseline; (d) no increase in LDL-C compared to the baseline; (e) a reduction in LDL-C levels compared to the baseline; (f) a reduction in non-HDL-C levels compared to the baseline; (g) a reduction in VLDL levels compared to the baseline;
. (h) an increase in apo A-l levels | compared to the baseline; (i) an increase in the apo A- | / apo B compared to the baseline; '(]) a reduction of lipoprotein A by levels compared to the baseline; - (Kk) a reduction in the number of LDL particles compared to the baseline; (1) a reduction in LDL size compared to the baseline; (m) a reduction in the remaining cholesterol particles compared to the baseline; (n) a reduction in the levels of oxidized LDL compared to the baseline; (o) a reduction in fasting plasma glucose (FPG) relative to the baseline; (p) a reduction in hemoglobin Ar (HbAr) compared to the baseline; (q) a reduction in insulin resistance model of homeostasis compared to baseline; (r) a reduction in the associated phospholipase A2 lipoprotein compared to the baseline; (s) a reduction in intracellular adhesion molecule-1 compared to baseline; (t) a reduction in interleukin-2 compared to the baseline; (u) a reduction in plasminogen activating inhibitor-1 compared to the baseline; (v) a reduction in the high sensitivity of C-reactive protein (hsCRP) compared to the baseline; (w) an increase in the EPA of plasma or serum phospholipids compared to the baseline; (x) an increase in the EPA of the red blood cell membrane compared to the baseline; and / or; (y) a reduction or increase in one or more phospholipids in plasma, serum and / or red blood cell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic acid (PA), stearidonic acid (SA) or. oleic acid (OA) compared to the baseline. In one embodiment, the methods of the present invention comprise measuring the baseline levels of one or more markers defined in (a) to (y) above, before being administered to the individual or group of individuals. In another embodiment, the methods comprise administering a composition as described herein to the individual, after the baseline levels of one or more markers defined in (a) to (y) have been determined, and subsequently perform an additional measurement of said one or more markers.
In another embodiment, through treatment with a composition of the present invention, for example, over a period of about 1 to about 200 weeks,
about 1 to about 100 weeks, 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 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 two or more, any of 3 or 'more than, any of 4 or more, any of 5 or more of, any 6 or more of, any 7 or more of, any of 8 or more of, any of 9 or more of, any 10 or more of, any of 11 or more of, any of 12 or more of, any of 13 or more of, any of 14 or more of, any of 15 or more of, any of 16 or more than, any of 17 or —more than, any of 18 or more of, any of 19 or more of, any of 20 or more of, any of 21 or more of, any of 22 or more of, any of 23 or more than, any of 24 or more of, or all 25 of results (a) to (y) described immediately above.
In another embodiment, by treatment 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 median% change) in relation to the baseline; (b) an increase of less than 30%, less than 20% increase, less than 10% increase, less than 5% increase or no increase in non-HDL-C or a decrease in HDL-C levels in 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% (% actual change or median% change) - in relation to the baseline; (c) an increase in HDL-C 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 median% change) compared to the baseline; (d) an increase of less than 30%, less than 20% increase, less than 10% increase, less than 5% increase or no increase in LDL-C or a reduction in LDL-C 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% of
. change or median% of change) in relation to the baseline;
- (e) a decrease 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% of change or median% of change) in relation to the baseline;
(f) a 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 median% change ) in relation to the baseline;
(g9) an increase in apo Al 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 median% change) compared to the baseline;
(h) an increase in apo Al / apo B 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 median% of change) in relation to the baseline;
(i) a 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
'at least about 45%, at least about 50%, or at least about 100% (% of actual change or median% of change) in relation to the baseline;
- 30 (1) a reduction in the average number of LDL 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% (% real change or median% of change) in relation to the baseline;
(k) an 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% (% of actual change or median% of change) in relation to the baseline; : (1) a reduction in the remaining cholesterol of the particle type 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% (% change real or median% of change) in relation to the baseline; (m) a reduction in oxidized LDL 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% (% of actual change or median% of change) in relation to the baseline; (n) a reduction in fasting plasma glucose (FPG) 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% (% of actual change or median% of change) in relation to the baseline; (o) a reduction in hemoglobin Alc (HbAlc) 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%, or at least about 50% (% of actual change or median% of change) from the baseline; bp) a reduction in insulin resistance of the model homeostasis index 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%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual% change or median% of change) compared to the 'baseline; (q) a reduction in phospholipase A2-associated lipoprotein of at least about - 30 - 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 median% of change) compared to the baseline; (7) a reduction in molecule-1 of intracellular adhesion 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 median% change) compared to the baseline; (s) a reduction in interleukin-2 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 - less than 45%, at least about 50% or at least about 100% (actual% change or median% change ) compared to the baseline;
(t) a reduction in plasminogen activating 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 median% change) compared to the baseline;
(u) a reduction in the high sensitivity of C-reactive protein (hnsCRP) 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 median% change) compared to the baseline;
(v) an increase in plasma EPA, serum phospholipids or RBC 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 median% change) in relation to the baseline;
(w) an increase in plasma EPA, serum phospholipid and / or RBC membrane 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 at least about 40%, at least about 45%, at least about 50%, at least. at least about 100%, at least about 200% or at least about 400% (% of actual change or median% of change) compared to the baseline; - 30 (x) a reduction or increase in one or more of plasma DHA, DPA, AA, PA and / or OA, serum phospholipids and / or RBC, 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 at least about 50%, at least about 55% or at least about —75% (actual% change or median% change) compared to the baseline and / or;
(y) a 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 median% change) compared to the baseline.
In one embodiment, the methods of the present invention comprise measuring the baseline levels of one or more markers defined in (a) to (y) before they are administered to the individual or group of individuals. In another embodiment, the methods comprise administering a composition as described here to the individual, after the baseline levels of one or more markers defined in (a) to (y) are determined, and then take a second measurement of one or more markers as a baseline measure for comparison.
In another embodiment, by treatment with a composition of the present invention, for example, over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, 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 | at about 2 weeks or about 1 week, the individual or group of individuals displays any two or more, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or —More than, any 8 or more of, any 9 or more of, 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 18 or more of, any 19 or more of, any 20 or more of, any 21 or more, any 22 or more, any 23 or more of, any 24 or more than, or all 26 or more of the results (a) to (y) described immediately above.
Parameters (a) - (y) can be measured according to any clinically acceptable methodology. For example, triglycerides, cholesterol! total, HDL-C and fasting blood sugar can be serum samples and analyzed using standard photometry techniques. VLDL-TG, LDL-C and VLDL-C can be calculated or determined using fractionation of lipoproteins in serum by preparative ultracentrifugation and subsequent quantitative analysis by refractometry or by ultracentrifugal analytical methodology. Apo Al, Apo B and hsCRP can be determined from the standard using serum nephelometry techniques. Lipoprotein (a) can be determined from serum using standard turbidimetric immunoassay techniques. Number of LDL particles and particle size can - be determined using nuclear magnetic resonance (NMR) spectrometry. The remaining lipoproteins and LDL-phospholipase A2 can be determined from plasma or serum and serum EDTA, respectively, using enzyme immunostaining techniques.
: stop. The levels of interleukin-2 and oxidized LDL intercellular adhesion molecule-1 can be determined from serum using standard enzyme immunoassay techniques. These techniques are described in detail in standard textbooks, for example, Tietz - Fundamentals of Clinical Chemistry, 6th ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company. 'In one mode, individuals fast for up to 12 hours before collecting the blood sample, for example, about 10 hours. In another embodiment, the present invention provides a method of treating or preventing primary hypercholesterolemia and / or mixed dyslipidemia (Fredrickson Types lla and lb) in a patient in need thereof, comprising administering to the patient one or more compositions, such as described here. In a related embodiment, the present invention provides a method of reducing triglyceride levels in an individual or individuals to treatment with a statin, niacin or prolonged-release monotherapy is considered inadequate (Frederickson type IV hyperlipidemia).
In another embodiment, the present invention provides a method of treating or preventing the risk of recurrent non-fatal myocardial infarction in a patient with a history of myocardial infarction, which comprises administering to the patient one or more compositions, as described here.
In another embodiment, the present invention provides a method for delaying the progression of, or promoting regression of, atherosclerotic disease in a patient in need of it, comprising administration to an individual with a need for one or more of the compositions as described herein.
In another embodiment, the present invention provides a method of treating or preventing very high levels of serum triglycerides (eg, types IV and V, of hyperli- epidemic), in a patient in need, including administration to the patient of one or more compositions, as described herein.
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 eicosapentaenoic acid from about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about - 30 — from 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 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about —S550 mg, about 575 mg, about 600 mg, about 625 mg, about 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 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. 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.
In another embodiment, any of the methods described here is 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 to be a consumer of the Western diet. The term "Western diet" here generally refers to a typical diet that consists of, as a percentage of total calories, about 45% to about 50% carbohydrates, about 35% to about 40% fat and about 10% to about 15% protein. The Western diet may 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%, or more than 60% or more than 70% of the total calories from these sources.
In another embodiment, any of the methods described here are used in the treatment. of 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 9, less - 30 - about 50 g, less about 45 g, less than about 40 g, less than about 35 g, less than about 30 g, less than about 25 g, less than about 20 g or less than about 15 g of fish per day. In another embodiment, any of the methods described here is used to treat an individual or individuals who consume less than (real or average) about 109 g, less than about 9 g, less than about 8 g, less about 7 9, 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 3 from dietary sources.
: In another modality, any of the methods described here is used to treat an individual or individuals who consume less than (real or average) about 2.59, - 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 (together) from from dietary sources.
In one embodiment, a composition as described herein, is administered to an individual once or twice a day. In another embodiment, 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 overnight, for example, between about 17:00 and about 11:00.
In one embodiment, an individual being treated according to the methods of the present invention is not on fibrate or nitrate therapy.
In another embodiment, compositions useful according to the methods of the invention are orally administrable. The terms "orally administrable" or "oral administration" here 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, —whether the agent or composition is ingested. Thus, "oral administration" includes oral and sublingual as well as esophageal administration. In one embodiment, the composition is present in a capsule, for example, a soft gelatin capsule.
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 one by one. plurality (for example, 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) times a day, or as many times as necessary to obtain a therapeutic response.
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 this need, comprising: providing an individual who has a baseline fasting triglyceride level of about 500 mg / dl at about 1500 mg / dl and administer to the individual a pharmaceutical composition as described herein. In one embodiment, the composition comprises about | g to about 4 g of ethyl ester of eicosapentaenoic acid, wherein the composition contains substantially no docosahexaenoic acid.
In another modality, the individual to be treated has diabetes.
EXAMPLES The following examples are for illustrative purposes only and should not be construed as limiting. - Example 1 A single, double-blind, randomized, parallel group center, study ranging from placebo-controlled dose of E-EPA in individuals with age-associated disability (AAMI) was performed. The primary objective was to examine the effect of eti-EPA versus placebo on cognitive performance in individuals with AAMI as measured by the power of attention tasks in a computerized trial mass over a 6-week period. The secondary objectives were: (1) to examine the effect of E-EPA versus placebo for 6 weeks in the following tests on the computerized cognitive battery: continuity of attention tasks, quality of working memory tasks, quality of episodic memory tasks ; speed of attention tasks; (2) to assess the safety and tolerability of E-EPA versus placebo from routine clinical laboratory testing, adverse events (AE) and vital signs monitoring, and (3) assess the potential dose-effect relationship of E- EPA on cognitive terminals by measuring essential fatty acids in plasma and red blood cell membranes. 94 subjects were randomized.
The work plan was to register 96 individuals who would be randomly assigned to one of four possible treatment groups for 6 weeks, in a balanced block design (24 individuals per group), as follows:
1. 1g of eti-EPA daily
2. 2g of eti-EPA daily
3.4 g of eti-EPA daily
4. Placebo (paraffin oil) daily Ethyl-EPA was supplied as gelatin capsules of 500 mg providing ethyl-EPA of>. 96% purity, 0.25% to 0.38% by weight ethyl octadecatetraenoate, 0.075% to 0.15% by weight ethyl nonaecapentaenoate, 0.25% and 0.35% by weight ethyl arachidonate , - 30 0.3% ab04% by weight of ethyl eicosatetraenoate (ETA-E), from 0.075% to 0.15% of ethylene-sapentaenoate and 0.2% of dlI-tocopherol as an antioxidant. Corresponding placebo capsules contained 467 g of liquid paraffin and 0.2% di-tocopherol. The placebo group was subsequently randomized, so that an equal number of individuals (8) were assigned 1 g, 2 g and 4 g of placebo. The Study Drug was taken twice daily (BID), - as a divided dose (for example, for the 1 g dose, 500 mg was administered in the morning and an additional 500 mg was given in the evening) with a light meal or meal.
The study consisted of a screening visit, a training visit and four visits
study sites. At the screening visit, individuals' eligibility was determined through | of cognitive tests (paired verbal subscale of associated learning [PAL], vocabulary sub-test, Clinical Questionnaire on Access to Memory [MAC-Q], mini mental status assessment [MEEM] and MINI [mini neuropsychiatric international interview , sections 1 and —2 of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) in addition to dysthymia]), hematology, clinical chemistry and 12-lead electrocardiogram (ECG). On the training visit, subjects were shown how to use the computerized CDR system. The individuals took the study drug for 6 weeks and on days 0, 14, 28 and 42, the individuals were subjected to a battery of CDR cognitive tests.
Inclusion criteria
1. Written informed consent.
2. Men and women volunteers between 50 and 70 years old.
3. Self-report of complaints of memory loss reflected in everyday problems such as difficulty in remembering the names of people after the introduction, lost objects, - difficulty in remembering various items for purchase or various tasks to be performed, problems of remembering phone numbers or postal codes and difficulty recalling information quickly or following distraction as determined by a score of 25 or more on the MAC-OQ questionnaire. The onset of memory loss was to be described as gradual, with no sudden worsening in recent months.
4. The possession of subjective and objective cognitive dysfunction, with a score of at least one standard deviation (SD) below the average for the age-matched elderly population as determined by the total count between 13 and 20 from the PAL subset of Escal- Memory of Wechsler.
5. Evidence of adequate intellectual function, as determined by a scale score of at least 9 (gross score of at least 32) on the Wechsler Intelligence Scale (WAIS) Vocabulary subtest.
6. Absence of dementia, as determined by a score of 24 or more. in the MMSE.
7. Non-smokers or ex-smokers for> 3 months.
8. Was able to travel to the center and judged by the Investigator to be likely to be able to continue to travel for the duration of the study and compliance with the logistical aspects of the study.
9. Body mass index (BMI) <29.5 kg / m Exclusion Criteria
1. Unlikely or unable to meet drug research dosage requirements.
2. Diagnosis of major depressive disorder, Alzheimer's or vascular dementia,
. as defined according to the MINI / DSM-IV (TR) Proofreading criteria. | 3. Past or current history of a neurological or psychiatric disorder that could. have affected cognitive function. - 4. Past or current history of inflammatory gastrointestinal disease, such as Crohn's disease or ulcerative colitis. - 5. Constipation that required active treatment.
6. Current or previous history of cancer, excluding the diagnosis of basal cell carcinoma.
7. Any history or evidence of clinically significant cardiac abnormality — as measured by the 12-lead ECG.
8. Any other medical condition or intercurrent illness not properly controlled, which, in the investigator's opinion, may have put the individual at risk by participating in the study or may have influenced the results of the study or affected the individual's ability to participate in the study.
9. Clinically significant abnormal screening laboratory results (hematology, biochemistry) on screening or vital signs that are outside the normal range for this population, which, in the opinion of the investigator, affected the individual's suitability for the study.
10. Any changes to the medication prescribed for a medical condition within 4 weeks of the baseline visit.
11. Omega-3 supplementation within 4 weeks after baseline visit or during the study treatment period.
12. Currently taking anticoagulants or daily aspirin dose> 325 mg.
13. Cold flu or cough remedies containing opiates or antihistamines, within 2 weeks of the baseline visit or during the treatment period — for 6 weeks.
14. Known allergy to any study drug ingredient or placebo.
Any individual could withdraw from the study at any time, his or her legal guardian's request, or at the discretion of the investigator, if the individuals continued inclusion was not in their best interest, or in case of severe AE or unexpected - 30 da Every reasonable effort has been made to document the outcome of the matter and the reasons for the withdrawal. Any ongoing EA was followed up until the event was resolved, stabilized or otherwise explained. The individuals who were removed were not replaced. Individuals were assigned unique identification numbers according to a randomization list generated by predetermined Catalent Pharma Solutions and used in the packaging of medicines.
The study drug was administered orally BID as a divided dose with food, for 6 weeks. Patients were randomized to 1 out of six treatment groups
possible measures (Table 1). Table 1. Treatment Groups: “Gwpo .— Doseigg Pharmaceuticals - Dosage form (capsuleem all gem) The Gmwpo Pharmaceutical dose = Gem formulation (gel capsule) Active 1 1 Ethyl-EPA 1 x 500 mg BID Active 2 2 Eti-EPA 2x500 mg BID Active 3 4 Eti-EPA 4 x 500 mg BID Placebo 1 1 Paraffin oil 1x 500 mg BID Placebo2 2 Paraffin oil 2x500 mg BID Placebo 3 4 Paraffin oil 4 x 500 mg BID “BID = twice daily , etirEPA = ethi-eicosapentaeenoic acid | The study drug was dispensed on visits 3, 4 and 5, the maximum period between Visit3 and each subsequent visit was: * Visit 3 to Visit 4 (2 weeks + 2 days of visit 3).
* Visit 3 to Visit 5 (4 weeks + 2 days of visit 3).
* Visit 3 to Visit 6 (6 weeks + 2 days of visit 3).
All treatment packages were identical in appearance, in order to keep the individual and investigator blind during the study. The staff of the organization of the clinical investigation / researcher, sponsor and the individuals remained blind throughout this study. The investigator was allowed to undo the blindness of individual individuals if it was considered clinically imperative. The process for breaking blindness is described below.
Omega-3 supplements had to be stopped at least four weeks before the initial visit (visit 3). Cough and flu drugs that contain opiates or antihistamines had to be stopped 2 weeks before the baseline visit (Visit 3) and were not allowed for the duration of the study.
- The existing medication must have been stable for 4 weeks before the baseline visit (Visit 3), and the maintenance dose for the duration of the study. When a dose change was absolutely necessary, it was recorded in the electronic case report (eCRF) format.
Individuals who required anticoagulant medication during the study were removed. Psychological or therapeutic counseling was not authorized for the duration of the study, as it may have interfered with the results of the study. Unused study drug was returned to the study site. Individuals who used less than 80% of the prescribed dose were considered non-compliant.
In the cognitive tests of screening and aptitude for the study, the use of
using Verbal Paired Associates 1 (Wechsler Memory Scale), WAIS Vocabulary subtest, MAC-Q, MMSE and MINI (DSM-IV Sections 1 and 2 plus Dysthymia). . A selection of tasks from the computerized cognitive CDR assessment system was administered (Appendix 8 of the protocol) at Visit 2 (training visit), Visit —3 (baseline), Visit 4 (Day 14), Visit 5 ( day 28) and Visit 6 (day 42). Parallel forms of - tests were presented in each test session. All tasks were controlled by computer, the information presented on high resolution monitors, and the responses recorded using a response model containing two buttons of one marked "no" and the other "yes". Five composite CDR scores were used as variables for primary / secondary results. The task titles were:. Word Presentation. Numeric Working Memory. Immediate Word Reminder 15. Delayed Word Reminder. Image Presentation. Word recognition. Simple Reaction Time. Image recognition 20. Digital Surveillance. Visual Bond-Lader. Choice Reaction Time. Analog Scales of Mood and Surveillance. Spatial Working Memory 25. Designing, using the Computer mouse To ensure the coherence of the approach, complete training on the cognitive tests and battery of CDR tests was given to study the local team and de - study individuals. The results of each variable were automatically recorded using the machine interface developed by CDR.
. 30 An AE was defined as any medical occurrence temporarily associated with the use of a medication or not considered related to the medicinal product.
The investigator was responsible for detecting and documenting adverse events. At each visit, the individual was asked about AEs through non-main questions. AEs were registered from the moment an individual gave an informed consent in writing and considered eligible to participate until the end of the treatment period. Ongoing AEs at the end of the treatment period were followed up
until resolution or return to baseline or normal value or, if the event was con- considered related to the study drug. , A serious adverse event (AGE) was defined as any AE at any dose. that: * resulted in death; - * it was life-threatening; * required hospitalization or the extension of the existing hospitalization; * + resulted in deficiency or disability, or * resulted in a congenital anomaly / birth defect.
Other events were considered EAGs if they compromised the individual or medical requirement or surgical intervention to prevent one of the results listed above.
Regardless of the above criteria, any EA that the sponsor or investigator considered to be serious should have been immediately reported as an EAG.
Any death or EAG experienced by the individual while receiving or within 30 days of the last dose of the experimental drug must be reported immediately (within 24 hours of learning the event) to pharmacovigilance.
All EAs (including EAGs) must be accurately recorded on the individual's eCRF adverse effects page, from the first administration of the experimental drug up to 30 days after the last dose.
The blood samples for the laboratory evaluations of hematology (a 5 ml blood sample) and clinical chemistry (a 10 ml blood sample) listed in Table 2, were collected at the screening visit (Visit 1). The samples were processed and analyzed by Simbec Laboratories Ltd.
Table 2. Laboratory Evaluations: Pharmacodynamics: Measurements of essential fatty acids (EFA)
Blood samples (10 ml) were collected at Visit 1 (screening) and at visits i 4,5 and 6. The analysis was performed by MSR Lipid Analysis, Scottish Plant Research Institute, Dundee, UK. The screening sample acted as a basis for EFA measurements. "Lipid was extracted from plasma, serum and RBC suspensions and converted to fatty acid methyl esters that were analyzed by gas chromatography to 'obtain fatty acid profiles such as fatty acid micrograms per gram of sample (UFA / g) and percentage of normalized area The computerized CDR system has been used to measure the effects of drugs on cognitive function in a variety of clinical trials. Efficacy was assessed using a battery of cognition tests designed by CDR Safety data was analyzed by Quanticate.
Populations analyzed included: * intention to treat population (ITT): All randomized individuals with at least one post-baseline visit were included in this population, regardless of the treatment actually received.
* By Population Protocol (PP): All randomized individuals who completed the study, excluding a significant deviated protocol, were defined as the PP Security population. A PP Effectiveness population was based on the individuals who completed the efficacy. The interception of PP safety and efficacy populations defined the PP Study Population.
* Safety Population: All randomized individuals who received at least one dose of study medication.
Summary statistics were provided for the ITT and PP study populations separately for all composite classifications, main and supporting variables. Statistical synthesis was performed for both unadjusted and difference from the baseline data (ie, the difference from the time corresponding to the pre-dose assessments on Day 0). Summary statistics were calculated by treatment day, and time point. The summary statistics comprised n, mean, median, error, SD, standard. mean (SEM), minimum and maximum values. Difference from baseline data for each important variable was assessed by - 30 a covariance analysis (ANCOVA) using SASO version PROC MIXED 8.2.
The fixed effects for treatment, day, hour, point, treatment per day, treatment per point of time, treatment per day per point in time have been put together. The individual within the treatment was fitted as a repeated effect using the repeated instruction. The composite symmetry covariance structure was used. The pre-dose assessments corresponding to the time of individuals on Day O were used as a covariate in the analysis. The mean of the least squares (mean LS) was calculated for treatment per day, treatment per time point and treatment per day per time point interaction. This formal analysis was conducted for the ITT and PP study populations separately.
Security assessments were based on the security population. Safety and tolerability were assessed in terms of adverse events, vital signs, 12-lead ECG, clinical laboratory data, clinical history, and study drug compliance. Safety and tolerability data were presented by the treatment group. All safety data were listed individually by individual.
Plasma EFA and RBC data were collected at baseline, days 14, 28 and 42 and summarized per visit for each treatment group. Baseline change and percentage change from baseline has also been summarized. The ANCOVA comparison of groups —detailedethyl-EPA and ethyl-EPA versus placebo was performed.
The sample size calculation was based on attention span. Ispronicline (50 mg), a partial neuronal nicotinic acetylcholine receptor agonist, in subjects with AAMI on day 21 of repeated doses in a previous study demonstrated a 61 ms benefit (mean 50 mg = -32.54, SD = 61 , 22; placebo mean = 28.25, SD = 49.64) for attention. Using an SD set, a sample size of 15 individuals per treatment arm was considered sufficient to detect a difference of 61 ms, with a power of 80% and a significance level of 5% (without adjustment for multiple tests). As there was no previous experience with the compound or mechanism of action with these cognitive measures, a sample size of 24 individuals per treatment arm was chosen - enough to allow for initial surveys.
There were no changes in the conduct of the study. The following changes were made to the planned analyzes: The equation for calculating the memory speed was changed to SPEEDMEM (memory speed) = SPMRT (spatial working memory speed) + NVMRT (numerical working speed) + DRECRT (speed word recognition) + DPICRT (image recognition speed).
* The pre-dose assessments corresponding to the individual's time on day O were used as a covariate in the analysis.
. * Day O has been removed from the Day values in the ANCOVA variable value list.
Covariable = Baseline has been changed to covariate = pre-dose assessments .- 30 corresponding to the time on Day O of the ANCOVA variable value list.
* Day by point in time has been added to the list of effects of the model in SASQ code for the ANCOVA model.
* The F test table and the treatment effects table have been added to the list of ANCOVA summary tables.
* ANCOVA summary tables were renumbered following ANCOVA's gross output.
* Figures were included for treatment, treatment per day, treatment by point in time, treatment by effects day by point in time for mean LS of ANCOVA.
* Figures were added for differences from mean ANCOVA LS to placebo (95% confidence interval [CI]).
* The post-hoc analysis was performed which compared the individual placebo groups (1 g2ge4gde paraffin paraffin) with the corresponding dose of ethiH-EPA, rather than to a pooled placebo group.
Ninety-one individuals completed the study, three individuals discontinued; 2 subjects in the 2 g ethyl-EPA treatment group (1 subject due to an EAG considered unrelated to the study drug and 1 due to a protocol violation and 1 subject from the 2 g placebo group due to an EA.
For the sake of attention, there was no statistically significant effect of the treatment, nor any treatment per day, treatment by point in time or treatment per day by point in time interactions. There was no difference in the mean LS between the active treatment and the placebo, at any point in time. For the choice reaction period - there were statistically significant benefits for ethyl-EPA of 1 g and 2 g on day 28, and some trends for the benefit of ethyl-EPA of 1 g and 4 g on day 42, against placebo, but without a treatment-related pattern were observed.
Continuity of care did not show a difference between placebo and ethyl-EPA, except for an overall decrease in ethyl-EPA of 2 g, which was only visible in the ITT population.
The subtasks of detected digital surveillance goals showed isolated decreases for active versus placebo treatment, but there was no obvious pattern related to treatment.
Quality of Working Memory was the only result that showed a statistically significant treatment compound by the interaction of the day in the F ratio. However, - there was only one statistically significant decrease for eti-EPA of 19 and 2g versus placebo on the days 14 and 28, and these were more likely to be due to chance and unrelated to treatment.
Quality of episodic secondary memory showed a statistically significant decrease for eti-EPA versus placebo at various points in time. However, - 30 seems unlikely to be an effect of active treatment as the unadjusted data showed pre-existing differences between treatment groups that were most notable on day O in the first evaluation session. In the difference from baseline data that was calculated before the ANCOVA analysis, these differences were no longer evident. This suggests that the ANCOVA model mounted a strong negative correlation with the baseline values. This is often the case when the variability within individuals overlaps the variability between individuals.
The speed of memory and the spatial subtasks and numerical speeds of working memory and the speed of word and image recognition showed no differences in performance, in the F ratio statistics, between eti-EPA and placebo. For readiness self-assessment, there was no apparent difference in classifications between ethyl-EPA and placebo. There were isolated falls in the classification for active versus placebo treatment that were not likely to be related compound.
'Self-assessment contentment showed a statistically significant decrease in the classification for eti-EPA of 2 g on day 28. However, these individual reductions were not statistically significant. It is unlikely that this was a treatment-related effect, as it was restricted to a single day and no other - dose showed a similar pattern on any other day. For self-assessment without calm, there was no difference in the classification between active treatment and placebo. When the results of each dose of eti-EPA and its corresponding placebo were compared (post-hoc), it was found that the 4 g eti-EPA improved the reaction time of individuals in attention tasks (attention power , simple reaction time and choice reaction time). This was seen most clearly for the reaction choice time, in which a pattern of gradual improvement during the evaluation day for 4 g was observed. It is possible that a long period of administration would clarify the effects of ethyl-EPA on these parameters. The value of EPA (shown in Table 3), DPAN-3 and the EPA / AA ratio (data not shown) of the erythrocyte plasma increased substantially from baseline to Day 42 for AMR- treatment groups. 101 1, 2, and 4g. AA, DHA and DGLA values decreased substantially from baseline (data not shown). Table 3. Mean (SD) of EPA Change (Plasma and RBC ug / g9)) from the baseline. La uu for 1g 2g and 1g (Ne7) | 2g (N = S) | of (N = 23) (N = 24) (N = 24) (N = 8) 483 line 44.9 49.1 47.5 | 42.1 42.5 base 63103) (25.01) (017.23) (26.41) (16.18) | 186) Day 14 | 612 207.7 | 16024.69 | 12 | 219 (26.61) (42.25) (57.05) (19.82) 132.91) (36.03) (46.23) (38.68) (15.46) (13.64) (14.03) Day 42 62.0 133.4 204.6 11.9 04 | 44 39.43) 43.34) (80.69) (26.34) 2118) (23.32) 198 line 18.9 19.8 DA 19.3 172 base (10.85) 8.91) 5.28) 5.77) 16.58) (4.94); 123 26.9 39.5 0.5 DO (7A7) Í 26 Day 14 3 | Es | 0356 | 633) Day 28 14.5 32.9 502 | 15416) | 0.0 (7.06 | 0.6 (10.47) 0011) (15.82) | (4.42) Year date | give | cos6m | (550) (6.97)
As can be seen in Table 3, the 2 g dose of AMR101 per day, plasma EPA levels increased by 297% after 42 days, and at the AMR101 dose of 4 g per day, plasma EPA levels increased by 417% compared to the baseline.
Grimsgaard et al. previously published an article describing serum phospholipid levels at baseline and after 7 weeks of supplementation with 4 g per day of 90% ethyl-DHA, 4 g per day of 95% ethyl-EPA with some DHA present, or corn oil.
I am. J.
Clin.
Nutr. 1997; 66: 649-59 (1997). The complete profile of other fatty acids and the ingredients present in these compositions is unknown.
After supplementation, over a 7-week period, subjects showed only a 297% increase in NOEPA in serum phospholipid compared to the 417% increase shown above with a composition of the invention.
A comparison of other changes in plasma / serum fatty acids is shown in Table 4. Table 4. Percentage change in fatty acids from baseline after 4 q dose administration
In addition, in the Japanese eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS), Yokoyama et al. reported that they followed more than 18,000 patients randomized to receive a 1800 mg composition of EPA (Epadel) with statins, or with statins only after 5 years of follow-up.
Lancet 2007; 369: 1090-1098. After 5 years of treatment, subjects showed an increase in plasma EPA of only 70% (from baseline 93 mg / L to 169 mg / L). Figures 1 and 2 show a comparison of the change in plasma / serum EPA levels observed with the AMR101 treatment in the present study compared to that observed with different EPA compositions in the JELIS study and by Grimsgaard.
As “* 25 will be noted, at -2g per day, AMRI01 achieved a much greater increase in plasma EPA compared to baseline (- 4 times) after just 6 weeks than in the JELIS 'study observed (<2 times) at after 5 years of treatment.
In addition, at 4 g per dose per day, AMR101 treatment for 6 weeks achieved much higher plasma EPA levels (> 250 ug / g) than reported by Grimsgaard after 7 weeks of treatment (87.66 ug / serum). In general, the 4 g dose per day of AMR101 resulted in a more than 5-fold increase over baseline plasma EPA while the 4 g dose per day of the Grimsgaard composition resulted in less than one 3-fold increase in serum EPA.
These results were unexpected.
Example 2
A placebo-controlled, double-blind, randomized, multi-center examination was performed in North America to determine whether 1 gram twice a day of EPA 'for 6 months improves motor performance in Huntington's patients. Post-hoc analysis - was performed to assess the effect of EPA on non-fasting triglycerides.
R 5 The study of the effects of ethyl-EPA on the progression of Huntington's disease enrolled in the study with 41 locations in Canada and the United States. Based on the results of the previous study, the inclusion criteria in the study were designed to enrich the participation of individuals with Huntington's disease, with a CAG repetition below 45, without the need for genetic tests to reveal the length of expansions of research participants or researchers. To participate in the study, individuals had to have the clinical characteristics of HD and either a confirmed family history or a known CAG expansion. Eligibility criteria included a minimum age of 35, a total functional capacity of at least 7, minimal dystonia (not exceeding 2 in the UHDRS in both trunk or extremities), minimal bradykinesia (not exceeding 2 UHDRS by bradykinesia) , the use of adequate birth control, the ability to take oral medications and, at will and the ability to comply with study requirements. Subjects were not eligible to participate if, within 60 days of the initial visit, they had used Omega-3 fatty acid supplements, tetrabenazine or reserpine, high or variable doses of oral antipsychotic medications (eg, -haloperidol), steroids except preparations for topical use, supplements of high doses of selenium, lithium, high doses of benzodiazepines, anticoagulation medication (eg coumarin), high doses (greater than 325 mg per day) of aspirin, unstable if receptor antagonists NMD A (eg, memantine), unstable doses of antiepileptic medications, or whether they had participated in other investigative studies of the drug. The use of deposit neuroleptics was also excluded within 6 months of the initial visit, a history of tardive dyskinesia, unstable medical or psychiatric illness, major depression (defined as a score greater than 20 in the Depression Inventory of. Beck | !), suicidal ideation, clinically significant substance abuse within 12 months: from the initial visit, women who were pregnant or nursing, known allergy to - 30 ethyl EPA or placebo, or previous participation in an EPA research study.
This was a randomized, double-blind, placebo-controlled study of parallel groups of EPA (1 gram twice / day). The Ethics Committee at each participating location approved the research plan and consent documents. Eligible study participants provided written consent. At the baseline visit, participants were randomly assigned according to a balanced block of computer-generated randomization plan that was stratified by location generated by the University of Rochester's Biostatistics Center. Subjects were randomly assigned in a 1: 1 ratio to receive the active drug (n = 158), in the form of two 500 mg capsules of AMR101 orally or placebo (n = 154), in the form of two capsules of 500 mg containing light paraffin oil and 0.2% DL-alpha-tocopherol, twice daily orally, for 6 months. After 6 months, all TREND-HD participants were treated: 5 —comAMRIO1 for 6 months in an open label form. Only data from the first 6 months were used to assess the effects of AMR101 on lipids.
The study outcome was the change in the absence of fasting triacylglycerol (TG) in those AMR101 compared to those who received placebo.
Safety was assessed at all study visits, including the evaluation and assessment of adverse events and serious adverse events and review of clinical analysis tests (blood count, serum biochemistry and pregnancy urine tests). The safety of the research participants was monitored blindly by a medical monitor from the sponsor and the Huntington Study Group. In addition, an independent safety monitoring committee that had access to safety data assessment treatment work throughout the study to determine whether modifications were necessary to carry out the trial.
Changes in lipid levels were compared using a covariance analysis (ANCOVA) with the treatment group as a factor of interest, location as a stratification factor, and baseline value as a covariant. All subjects who received study medication were included in the safety analysis. For each type of adverse event, treatment groups were compared for the occurrence of at least one event using Fisher's exact test. Continuous safety measures, such as laboratory test results and vital signs, were analyzed using methods similar to those described above for the primary response variable (ANCOVA).
—Corrections for multiple comparisons were not made in the assessment of safety data.
One hundred and forty-five subjects in AMR101 (92% of those assigned) and 141 of those who received placebo (92% of those assigned) had cell EPA content: red blood determined at baseline and month 6. The content of blood cells - 30 red blood at the 20:05 n3 baseline (EPA) increased significantly after 6 months in patients on AMR101 (from an average of 0.52% to 3.07%), but decreased on placebo group (from an average of 0.61% to 0.55%); p <0.0001). After 6 months, subjects who took AMR101 had a 26 mg / dl drop in TGs from a base of 171 compared to a reduction of 11 mg / dl from a base of 187 mg / dl in those who received placebo, p = 0.007. Cholesterol! total was reduced significantly more in people who took AMR101 (9.5 mg / dL) from a 204 mg / dL baseline than in those who took placebo (2.5 mg / dL) from a baseline of 208 mg / dL, p = 0.009. Lipid and motor score data are presented in Tables 5 and 6, respectively. i Table 5. Engine Scoring Results. All participants of Participants with CAG <CO and the sense | Es Total engine score 4 scale | thyl- Placebo | Ethyl Value- | Placebo | Unified disease assessment value | EPA P EPA Pp eee e ie At baseline [average (SD)] 25.2 [239 (8.1) | 016 24.9 23.4 0.18 ss to DS [5 | Variation in the total score 0.2 1.0 0.20 0.3 0.70 4 to 6 month engine (average) and qe je e | and | Variation in the total score 2.0 0.02 1.2 1.6 0.004 engine from 4 to 12 months (mean) e e je je qe je Table 6. Results of lipid parameters. Baseline triglycerides (mean | 171 + 108 187 + 139 0.27 steel 2) ONLY IF Total baseline cholesterol (mean | 204 + 41.4 208 + 40.6 0.42 paeiso Se SA SS SAS 1 SA Triglyceride variation after 6 months | -25.8 + 89.1 | -11.1+ 105.2 | 0.007
EEE TA Cholesterol variation! total after 6 months | -9.5 + 28.6 -2.5 + 24.7 0.009 qimeanesaeso the ESS [9%] Variation of triglycerides after 12 months | -17.7 + 86.7 | -40.0 + 126.0 intimate o [E Total cholesterol variation after 12 months | -5.6 + 25.5 -6.9 + 34.5 0.95 Qineta paso The SAS (SS 10 Compared to these data for AMR101, Grimsgaard reported a decrease (from baseline) of only 12% in serum triglycerides in the EPA group after 7 In addition, the addition of the EPA Epadel composition to the statin therapy in the JELIS study resulted in only a 9% decrease in triglycerides after 5 years of treatment. and compare the contents of Epadel capsules with AMR101 capsules Six capsules of each composition were selected for analysis by gas chromatography Averages of six capsules for each of the two compounds
positions are shown in Table 7. Table 7. Measured and identified components of AMR101 and Epadel.
Component 1 [AE 3 | os | [HPRAE o nos ND =% by weight less than 0.05% Example 4 A multiple dose pharmacokinetic study, phase |, in healthy male volunteers was performed at a single center.
Twenty-four individuals were divided into two treatment groups of 12 individuals each. (Groups A and B) The two groups received the same total daily dose of AMR101, but the dosing regimens were different.
All subjects received a single oral dose of 2 g AMR101 on Day 1. Treatment group A received 28 continuous doses once a day of 2 g AMR101. Treatment group B received 27 continuous two daily doses of 1 g of AMR101 and made a single 2 g of AMR101 on day 30. Levels of EPA and other essential fatty acids were determined in plasma and red blood cells .
Blood samples for pharmacokinetic analysis were performed at the following points in time for treatment groups A and B: Days 1 and 30: pre-dose, 1, 2, 3, 4, 5, 6, 8, 20, 12, 24, 36 and 48 hours post-dose; Days 9, 16, 23: pre-morning dose; Days 37, 44, 58: post last dose.
A first interim report presents the following pharmacokinetic results for Treatment of Group B:. Plasma - Day 1 (Pre-dose, 1, 2, 3, 4, 5, 6, 8, 20, 12, 24, 36 and 48 hours after the dose); Red cell - Day 1 (pre-dose and 36 hours), day 30 (1 h after dose), day 37, Day 44, Day 58. Using a corrected value obtained by subtracting the pre-administration concentration from of the concentrations of each sample, a single oral dose of 2 g of AMR101 resulted in a rapid increase in lipids in the plasma EPA.
Maximum values were observed for 5 hours after administration, with EPA levels remaining above the baseline, 48 hours after administration.
The elimination half-life of EPA from clear plasma was 87 + 65 hours (baseline not subtracted) and 42 + 31h (baseline subtracted). A summary of the pharmacokinetic data is presented in the
Table 8. Table 8. Non-compartmental analysis - Arithmetic Mean and SD. Ú Average Terminal | Clearance | VoDna | VoDno | Concen | Tmax S Half-time oral Phase termi- traction state (h) life residence (h) final ready | maximum drug to mg mg / ml)
0.202 Baseline | 42.2 63.6 127 58.8 62.8 55.5 4.64 subtracted In the oral administration of population protocol AMR101 resulted in increasing levels of EPA RBC from an average value of 190.4 mg / g before dosing on Day 1 to 40.3 mg / hour after last dose on Day 30.

权利要求:
Claims (20)
[1]
1. Composition CHARACTERIZED for comprising ethyl eicosapentaenoate for use in increasing plasma and / or serum EPA in an individual having base triglycerides from 200 mg / dl to 500 mg / dL, and under stable statin therapy, where the composition - 5 comprises at least 96% by weight of ethyl eicosapentaenoate; from 0.2% to 0.5% by weight of ethyl octadecatetraenoate; from 0.05% to 0.25% by weight of ethyl nonadecapentaenoate; from 0.2% to 0.45% by weight of ethyl arachidonate; from 0.3% to 0.5% by weight of ethyl eicosatetraenoate; from 0.05% to 0.32% of ethyl heneicosapentaenoate; and not more than 0.05% ethyl-DHA, if applicable, and where the treatment involves administering to the individual the composition daily in an amount sufficient to increase the plasma and / or serum EPA levels in the at least 200% compared to the baseline.
[2]
2. Composition CHARACTERIZED for comprising ethyl eicosapentaenoate to increase plasma and / or serum EPA by at least 200% compared to baseline in an individual having very high serum triglyceride levels, where the composition comprises at least 96 % by weight of ethyl eicosapentaenoate; from 0.2% to 0.5% by weight of ethyl octadecatetraenoate; from 0.05% to 0.25% by weight of ethyl novecapentaenoate; from 0.2% to 0.45% by weight of ethyl arachidonate; from 0.3% to 0.5% by weight of ethyl eicosatetraenoate; from 0.05% to 0.32% of ethylene hyeosapentaenoate, and no more than 0.05% of ethyl-DHA, if applicable.
[3]
3. Use of ethyl eicosapentaenoate CHARACTERIZED for being in the manufacture of a drug to increase the plasma and / or serum EPA by at least 200% compared to the baseline in an individual having 200 mg / base triglycerides dL at 500 mg / dL, and under stable statin therapy, where the composition comprises at least 96% by weight of ethyl eicosapentaenoate; from 0.2% to 0.5% by weight of ethyl octadecatetrahydrate; from 0.05% to 0.25% by weight of ethyl nonadecapentaenoate; from 0.2% to 0.45% by weight of ethyl arachidonate; from 0.3% to 0.5% by weight of ethyl eicosatetraenoate; from 0.05% to 0.32% of ethyl heneicosapentaenoate; and no more than 0.05% ethyl- - DHA, if applicable.
[4]
4. Use of ethyl eicosapentaenoate CHARACTERIZED because it is in the manufacture of a drug to increase the plasma and / or serum EPA by at least 200% compared to the baseline in an individual having very high triglyceride levels, on - that the medicinal product comprises at least 96% by weight of ethyl eicosapentaenoate; from 0.2% to 0.5% by weight of ethyl octadecatetraenoate; from 0.05% to 0.25% by weight of ethyl nonadapapenoenoate; from 0.2% to 0.45% by weight of ethyl arachidonate; from 0.3% to 0.5% by weight of ethyl eicosatetraenoate; from 0.05% to 0.32% of ethyl heneicosapentaenoate; and no more than 0.05% ethyl-DHA, if applicable.
[5]
5. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that after administration of 2 g of the composition to the individual, daily, for a period of at least 6 weeks, the individual displays | at least 200% increase in plasma and / or serum EPA compared to the baseline line.
[6]
6. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that after administration of 4 g of the composition to the individual, daily, for a period of at least 6 weeks, the individual exhibits at least 300% increase in plasma and / or serum EPA compared to baseline
[7]
7. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that the composition is administered in an amount sufficient to increase plasma EPA levels and / or serum, in an individual, at least 300% compared to the baseline.
[8]
8. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that the composition is administered in an amount sufficient to increase plasma EPA levels and / or serum, in an individual, at least 400% compared to the baseline.
[9]
9. Composition or use, according to claim 8, CHARACTERIZED by the fact that the composition is administered to the individual daily for a period of at least 6 weeks.
[10]
10. Composition or use according to any one of claims 5, 6 or 9, CHARACTERIZED by the fact that the individual has a baseline plasma and / or serum EPA level not exceeding 50 pg / ml.
[11]
11. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that after administration of 4 g of the composition to the individual, daily, for a period of at least 6 weeks, the individual exhibits at least 400% increase in plasma and / or serum EPA compared to baseline.
[12]
: 30 12. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that after the daily administration of the composition to the individual, the individual presents an increase in serum and / or plasma DPA levels and a decrease in serum and / or plasma AA, DHA, and / or DGLA levels.
[13]
13. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED by the fact that after administration, daily, of the composition to the individual, for a period of at least 6 weeks , the individual experiences an increase in serum and / or plasma DPA levels and a decrease in AA, DHA,
and / or serum and / or plasma DGLA compared to baseline.
[14]
14. Composition, according to claim 1 or 2, or use, according to claim 7 or 3, CHARACTERIZED by the fact that after administration, daily, of the composition to the individual, for a period of at least 6 weeks, the individual has a decrease in serum and / or plasma DHA levels of at least 16% compared to the baseline; a decrease in DGLA levels in serum and / or plasma of at least 31% compared to baseline; a decrease in serum and / or plasma AA levels of at least 20% compared to the baseline; and / or an increase in DPA levels in serum and / or plasma of at least 130% compared to baseline.
[15]
15. Composition according to claim 1 or 2, or use according to claim 3 or 4, CHARACTERIZED in that the composition comprises at least 96% by weight of ethyl eicosapentaenoate; from 0.22% to 0.4% by weight of ethyl octadecatetra-enoate; from 0.075% to 0.20% by weight of ethyl nonadecapentaenoate; from 0.25% to 0.40% by weight of ethyl arachidonate; from 0.3% to 0.4% by weight of ethyl eicosatetraenoate; and 0.075% to 0.25% ethyl heneicosapentaenoate.
[16]
16. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED in that the composition comprises at least 98%, by weight, of ethyl eicosapentaenoate; from 0.25% to 0.38% by weight of ethyl octadechatrateate; from 0.10% to 0.15% by weight of ethyl nonadecapentaenoate; from 0.25% to 0.35% by weight of ethyl arachidonate; from 0.31% to 0.38% by weight of ethyl eicosatetraenoate; and 0.08% to 0.20% ethyl heneicosapentaenoate.
[17]
17. Composition according to claim 1 or 2, or use according to claim 3 or 4, CHARACTERIZED by the fact that the composition still comprises toco-ferol in an amount of 0.1% to 0.3% by weight .
[18]
18. Composition, according to claim 1 or 2, or use, according to claim 3 or 4, CHARACTERIZED in that the composition is present in a coated capsule.
[19]
19. Composition, according to claim 1 or 2, or use, according to - claim 3 or 4, CHARACTERIZED by the fact that the LDL-C level in the individual is reduced by “30 by at least 5% compared to the base.
[20]
20. Use of ethyl eicosapentaenoate CHARACTERIZED because it is in the manufacture of a medication to maintain LDL control and clinically significantly reduce fasting triglycerides in an individual who is under stable statin therapy and requires triglyceride reduction therapy compared to control, where the medicine com-preprehends ultra-pure 1ga4gEEPA.
. 1, 300 * 8 250 2 z À â 200 â = nn H PS E Baseline Ê 1 TO 3 20 DO FA 2 Sos E JA o na: Z is FA mA AMRI691 - 6 weeks JELIS 5 years GRIMSGARRD 7 weeks Fig. 1
2.56
Ê: es â ã * RSS Y ã & Pe 28 Ss Pe E
It's AMBI0NT = 6 weeks. JELISSanos - GRIMSGARRD 7 weeks Fig. 2

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法律状态:
2020-08-04| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-09-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-12-08| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-12-15| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A01N 37/00 , A61K 31/20 Ipc: A61K 31/232 (2006.01), A61K 31/20 (2006.01), A61K |

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2020-12-29| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-04-27| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-08-17| B09B| Patent application refused [chapter 9.2 patent gazette]|

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2021-10-26| B12B| Appeal against refusal [chapter 12.2 patent gazette]|

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2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US31044310P| true| 2010-03-04|2010-03-04|

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US61/310,443|2010-03-04|

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PCT/US2011/027218|WO2011109724A1|2010-03-04|2011-03-04|Compositions and methods for treating and/or preventing cardiovascular disease|

---