(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0021504 A1
`Yokoyama et al.
`(43) Pub. Date:
`Jan. 25, 2007
`
`US 20070021504A1
`
`(54)
`
`(75)
`
`COMPOSITION AND/OR METHOD FOR
`PREVENTING ONSET AND/OR
`RECURRENCE OF CARDOVASCULAR
`EVENTS
`
`(73) Assignee: MOCHIDA PHARMACEUTICAL
`CO., LTD., Tokyo (JP)
`(21) Appl. No.:
`11/481,956
`
`Inventors: Mitsuhiro Yokoyama, Hyogo (JP);
`Hideki Origasa, Toyama (JP);
`Masunori Matsuzaki, Yamaguchi (JP);
`Yuji Matsuzawa, Hyogo (JP); Yasushi
`Saito, Chiba (JP); Yuichi Ishikawa,
`Hyogo (JP); Shinichi Oikawa, Tokyo
`(JP); Jun Sasaki, Fukuoka (JP);
`Hitoshi Hishida, Aichi (JP); Hiroshige
`takura, Tokyo (JP); Toru Kita, Kyoto
`(JP); Akira Kitabatake, Nara (JP);
`Noriaki Nakaya, Tokyo (JP); Toshiie
`Sakata, Fukuoka (JP); Kazuyuki
`Shimada, Tochigi (JP); Kunio Shirato,
`Miyagi (JP)
`Correspondence Address:
`BRCH STEWART KOLASCH & BRCH
`PO BOX 747
`FALLS CHURCH, VA 22040-0747 (US)
`
`(22) Filed:
`(30)
`
`Jul. 7, 2006
`Foreign Application Priority Data
`
`Jul. 8, 2005 (JP)...................................... 2005-200503
`
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`A6II 3L/23
`(52) U.S. Cl. .............................................................. 514/552
`
`(57)
`
`ABSTRACT
`
`Provided are composition and/or methods useful in prevent
`ing onset and/or recurrence of cardiovascular events, espe
`cially in patients who have escaped the unstable period after
`cardiovascular angioplasty or in hyperlipidemia patients
`who have been treated with HMG-CoA RI.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1044, p. 1 of 9
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`US 2007/0021504 A1
`
`Jan. 25, 2007
`
`COMPOSITION AND/OR METHOD FOR
`PREVENTING ONSET AND/OR RECURRENCE OF
`CARDOVASCULAR EVENTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`0001. This application claims the benefit of priority to
`Japan Patent Application No. 2005-200503, filed on Jul. 8,
`2005, which is incorporated herein by reference.
`
`TECHNICAL FIELD
`0002 This invention relates to compositions and/or
`methods for preventing onset and/or recurrence of cardio
`vascular events which contain at least ethyl icosapentate
`(hereinafter abbreviated as EPA-E).
`
`BACKGROUND ART
`0003 Westernization of diet has resulted in the increase
`of patients Suffering from lifestyle-related diseases such as
`diabetes, hyperlipidemia, and hypertension. Some of these
`diseases finally lead to arteriosclerotic diseases such as
`myocardial infarction, angina pectoris, and cerebral infarc
`tion and sometimes results in death. As treatment of arte
`riosclerotic diseases, for example, drugs or Surgical methods
`Such as vascular angioplasty are generally utilized.
`0004 For prevention of arteriosclerotic diseases or
`improvement of quality of life, it is important to reduce risk
`factors such as hyperlipidemia, diabetes, hypertension, and
`Smoking habit. In the major epidemiological Survey where
`incidence rates of hyperlipidemia and coronary artery dis
`ease were examined, positive correlation was found between
`serum total cholesterol (hereinafter abbreviated as T-Cho)
`concentration or serum triglyceride (hereinafter abbreviated
`as TG) concentration and the onset of the coronary artery
`disease. More specifically, even stronger positive correlation
`was found for the serum low density lipoprotein cholesterol
`(hereinafter abbreviated as LDL-Cho) concentration, while
`negative correlation was found for the serum high density
`lipoprotein cholesterol (hereinafter abbreviated as HDL
`Cho) concentration.
`0005 Pharmacotherapy of hyperlipidemia has become
`relatively easy, and Suppression of onset of coronary artery
`diseases by a strong therapy of hyperlipidemia using 3-hy
`droxy-3-methylglutaryl coenzyme A reductase inhibitor
`(hereinafter abbreviated as HMG-CoARI) has been proved
`in a large scale clinical trial. For example, when male
`hyperlipidemia patients with no history of myocardial inf
`arction were orally administered with pravastatin sodium for
`an average period of 4.9 years, serum T-Cho concentration
`decreased by 20%, serum LDL-Cho concentration decreased
`by 26%, serum HDL-Cho concentration increased by 5%,
`and serum TG decreased by 12%, and as a consequence, the
`total incidence rate of nonfatal myocardial infarction and
`cardiovascular death decreased by 31% (The New England
`Journal of the Medicine, 1995, vol. 333, pp. 1301-1307).
`When patients with history of angina pectoris or myocardial
`infarction were orally administered with simvastatin for an
`average period of 5.4 years, serum T-Cho concentration
`decreased by 25%, and serum LDL-Cho concentration
`decreased by 35%, serum HDL-Cho concentration increased
`by 8%, and serum TG decreased by 10%, and as a conse
`quence, the incidence rate of major cardiovascular events
`
`decreased by 34% (The Lancet, 1994, vol. 344, the issue of
`pp. 1383-1389). The decrease in the incidence rate of the
`cardiovascular events was also approximately 20 to 30% in
`other large scale clinical trials using HMG-CoA RI
`(Archives of Internal Medicine, 1999, vol. 159, No. 1, pp.
`1793-1802). These results may not be sufficient for clinical
`practice.
`0006.
`It has been reported that when a capsule that
`includes a (0-3 polyunsaturated fatty acid composition con
`taining EPA-E and ethyl docosahexaenoate (hereinafter
`abbreviated as DHA-E) in a total amount of 850 to 882 mg
`was orally administered to patients within three months from
`the onset of acute myocardial infarction every day for 3.5
`years, the combined incidence rate of cardiovascular death,
`nonfatal myocardial infarction, and nonfatal cerebral infarc
`tion decreased by 20%, and that, while cardiovascular death
`decreased by 30%, no significant effect was observed on
`nonfatal cardiovascular events (The Lancet, Vol. 354, Aug.
`7, 1999, pp. 447-455). It was also reported that their death
`rate decreased when 1 g of essential fatty acids containing
`EPA-E and DHA-E in a total amount of 85% was admin
`istered to patients with history of myocardial infarction
`every day for 3.5 years (WO00/48592 (JP 2002-537252A)).
`It is also disclosed that the use of EPA or DHA in combi
`nation with a cholesterol synthesis inhibitor represses car
`diovascular events (U.S. Pat. No. 6,159,993).
`0007 High purity EPA-E is commercially available in the
`trade names of Epadel and Epadel S (manufactured by
`Mochida Pharmaceutical Co., Ltd.) as the therapeutic drug
`for hyperlipidemia. It has been reported that when such high
`purity EPA-E is orally administered at 600 mg per admin
`istration and three times a day immediately after meal (when
`serum TG is abnormal, the dose can be increased to the level
`of 900 mg per administration and three times a day), serum
`T-Cho concentration and serum TG can be reduced by 3 to
`6% and by 14 to 20%, respectively (Drug Interview Form
`“EPA preparation, Epadel capsule 300', revised in July,
`2002; January, 2003; pp. 21-22.), and that, based on such
`action, such high purity EPA-E is expected to exert effects
`on cardiovascular events of hyperlipidemia patients (Ameri
`can Heart Journal, 2003, vol. 146, No. 4, pp. 613-620.).
`0008. On the other hand, as an option for treatment of
`Ischemic heart disease, a Surgical treatment, cardiovascular
`angioplasty Such as PTCA, and coronary Stent implantation
`has been widely carried out mainly for serious patients, but
`cardiovascular events are easy to occur after the angioplasty.
`For example, the cardiovascular event after PTCA is due to
`resetenosis at the PTCA site, which generally means pro
`gression of stenosis in more than 50% of the region
`expanded by PTCA, or generation of new lesion in many
`cases. The resetenosis rate is approximately 30-40% and the
`resetenosis is usually observed at or within six months. The
`resetenosis rate can be reduced by using stent but it is not
`always reliable (T. Yamaguchi & M. Kitahara, Kon-nichi no
`tiryoushishin, published by IGAKUSHOIN, pp. 237, 2003).
`0009. As medical treatment with drugs after cardiovas
`cular angioplasty, anti-platelet agents are often used. For
`example, combination of aspirin and Ticlopidine (Clopi
`dogrel) is administered as a matter of course when a stent is
`inserted. For prevention of stent thrombi, combination of
`aspirin and ciloStaZol is administered (T. Yamaguchi & M.
`Kitahara, Kon-nichi no tiryoushishin, published by
`
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`IGAKUSHOIN, pp. 245-246, 2003). In particular, care after
`the Surgery is considered important.
`0010 Although fish oil or omega-3 fatty acids have been
`administered to the patients with resetenosis in the unstable
`period after cardiovascular angioplasty, there are controver
`sial reports regarding their efficacy, while there is a view that
`they have to start to be administered before the cardiovas
`cular angioplasty (J Am Coll Cardiol. 2005 May
`17:45(10): 1723-8: Am Heart J. 2002 June; 143(6):E5; JAm
`Coll Cardiol. 1999 May: 33(6):1619-26: Am J Cardiol
`77.31-36 (1996))
`0011
`Although it was reported that two-year administra
`tion of HMG-CoA RI, plavastatin, after PTCA had reduced
`the resetenosis rate and thus been effective for repression of
`the cardiovascular events (Am J Cardiol. 2000 Oct. 1;
`86(7):742-6) as well as that three- to four-year administra
`tion of fluvastatin from immediately after Percutaneous
`Coronary Artery intervention repressed the onset of the the
`cardiovascular events (JAMA. 2002 Jun. 26: 287(24):3215
`22), an improved treatment is expected which enable more
`repression of the cardiovascular events.
`
`SUMMARY OF THE INVENTION
`0012. In view of the situation that death from the cardio
`vascular diseases is still a major cause of death, and it is a
`serious problem that many cardiovascular events are still
`impossible to prevent by the HMG-CoA RI therapy, an
`object of the present invention is to provide a composition
`and/or method for preventing onset and/or recurrence of the
`cardiovascular events.
`0013 In order to solve the problems described above, the
`inventors of the present invention made an extensive study
`and found that EPA-E has an effect of preventing onset
`and/or recurrence of the cardiovascular events, and in par
`ticular, an effect of preventing onset and/or recurrence of the
`cardiovascular events in patients who have escaped the
`unstable period after cardiovascular angioplasty. The present
`invention has been thus completed on the basis of such
`findings. Accordingly, the present invention is directed to:
`(1) composition for preventing onset and/or recurrence of
`cardiovascular events comprising at least EPA-E as its
`effective component; specifically,
`0014 (2) composition for preventing onset and/or recur
`rence of cardiovascular events in a hyperlipidemia patient to
`whom HMG-CoA RI treatment has been carried out, com
`prising administrating to the patient the composition con
`taining ethyl icosapentate as its effective component;
`00.15
`(3) method for preventing onset and/or recurrence
`of cardiovascular events in a patient who has history of acute
`myocardial infarction, comprising administrating to the
`patient the composition containing ethyl icosapentate as its
`effective component;
`0016 (4) method for preventing onset and/or recurrence
`of cardiovascular events in a patient who has escaped the
`unstable period after cardiovascular angioplasty, comprising
`administrating to the patient the composition containing
`ethyl icosapentate as its effective component;
`(5) method according to (4), in which the composition starts
`to be administered after the patient has escaped the unstable
`period;
`
`0017 (6) method for preventing onset and/or recurrence
`of cardiovascular events in a patient beyond six months after
`the cardiovascular angioplasty, comprising administrating to
`the patient the composition containing ethyl icosapentate as
`its effective component;
`(7) method according to any of (4) to (6), in which the
`administration of the composition is started beyond six
`months after the cardiovascular angioplasty and is continued
`at least for two years;
`0018 (8) method according to any of (4) to (7), in which
`the cardiovascular angioplasty is selected from a group
`consisting of percutaneous transluminal coronary angio
`plasty (PTCA), percutaneous transluminal coronary reca
`nalization (PTCR), directional coronary atherectomy
`(DCA), coronary stent implantation (coronary artery stent
`ing), and coronary artery bypass grafting (AC bypass graft
`ing);
`(9) method according to any of (1) to (8), in which the
`patient suffers from hyperlipidemia;
`(10) method according to any of (1) to (9), in which the
`proportion of the ethyl icosapentate in the total content of
`fatty acids and derivatives thereof is 96.5% by weight or
`more;
`(11) method according to any of (1) to (10), in which the
`ethyl icosapentate is orally administered at an amount of 0.3
`g/day to 6.0 g/day immediately after meals;
`(12) method according to any of (1) to (11), in which the
`composition is used in combination with an inhibitor for
`3-hydroxy-3-methylglutaryl coenzyme A reductase;
`(13) method according to (12), in which the inhibitor is
`pravastatin or simvastatin; and
`(14) method according to any of (1) to (13), further com
`prising DHA-E.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENT
`0019. Next, the present invention is described in detail.
`0020. A first embodiment of the present invention is a
`composition and/or a method for preventing onset and/or
`recurrence of the cardiovascular events which contains
`EPA-E as its effective component.
`0021 Although any composition for prevention of any
`onset and/or recurrence of cardiovascular events at least
`containing EPA-E as its effective component is within the
`Scope of this invention, preferred examples include compo
`sitions for prevention of cardiovascular death, fatal myocar
`dial infarction, Sudden cardiac death, nonfatal myocardial
`infarction, cardiovascular angioplasty, new onset of rest
`angina and effort angina, and destabilization of angina
`pectoris. The subject of the administration of the composi
`tion includes all humans requiring prevention of onset of
`cardiovascular events, and preferred examples include
`hyperlipidemia patients. While EPA-E content in the total
`fatty acid and dosage of administration are not particularly
`limited as long as intended effects of the present invention
`are attained, high purity EPA-E is preferred; for example, the
`composition having a proportion of the EPA-E of preferably
`40% by weight or more, more preferably 90% by weight or
`more, and still more preferably 96.5% by weight or more in
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`total of the fatty acids and their derivatives. The daily
`amount in terms of EPA-E is typically 0.3 to 6.0 g/day,
`preferably 0.9 to 3.6 g/day, and still more preferably 1.8 to
`2.7 g/day.
`0022. Other preferable fatty acid contained is any
`omega-3 unsaturated fatty acid, especially DHA-E. The ratio
`of EPA-E/DHA-E in the composition, the content of EPA-E
`and DHA-E in the total fatty acids and administration
`amount of EPA-E and DHA-E are not limited but the ratio
`is preferably 0.8 or more, more preferably 1.0 or more, still
`more preferably 1.2 or more. The composition is preferably
`highly purified; for example, the proportion of EPA-E+
`DHA-E in the fatty acids and their derivatives is preferably
`40% by weight or more, more preferably 80% by weight or
`more, and still more preferably 90% or more. The daily
`amount in terms of EPA-E+DHA-E is typically 0.3 to 10.0
`g/day, preferably 0.5 to 6.0 g/day, and still more preferably
`1.0 to 4.0 g/day. The low content of other long chain
`saturated fatty acids is preferred, and among the long chain
`unsaturated fatty acids, the content of (D-6 fatty acids, and in
`particular, the content of arachidonic acid is preferably as
`low as less than 2% by weight, and more preferably less than
`1% by weight.
`0023. A second embodiment of the present invention is a
`composition and/or a method for preventing onset and/or
`recurrence of cardiovascular events of hyperlipidemia
`patients who is undergoing HMG-CoA RI therapy, which
`contains at least EPA-E as its effective component. While
`HMG-CoA RI includes all inhibitors of 3-hydroxy-3-meth
`ylglutaryl coenzyme A reductase, a pharmaceutically admin
`istrable inhibitor is preferably used, which is preferably
`pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin,
`atorvastatin, pitavastatin, rosuvastatin, and salts and deriva
`tives thereof, and more preferably, pravastatin, lovastatin,
`simvastatin, fluvastatin, atorvastatin, pitavastatin, or rosuv
`astatin, and most preferably, pravastatin or simvastatin.
`0024 All pharmaceutically administrable salts can be
`used, and preferred are sodium and potassium salts such as
`pravastatin Sodium, fluvastatin Sodium, cerivastatin Sodium,
`atorvastatin calcium, pitavastatin calcium, and rosuvastatin
`calcium. In the present invention, “pravastatin', for
`example, also includes the pravastatin in the form of a salt
`unless otherwise noted.
`0.025 A third embodiment of the present invention is a
`composition and/or a method for preventing onset and/or
`recurrence of cardiovascular events in patients who have
`history of acute myocardial infarction, which contains at
`least EPA-E as its effective component.
`0026.
`In the second and third embodiments of the present
`invention, preferred embodiments of the type of the cardio
`vascular events, proportion of the EPA-E in the total fatty
`acid, daily amount, and proportion of other long chain fatty
`acids are the same as those of the first embodiment of the
`present invention as described above.
`0027 A fourth embodiment of the present invention is a
`composition and/or a method for preventing onset and/or
`recurrence of cardiovascular events in patients who have
`escaped the unstable period after cardiovascular angioplasty,
`which contains at least EPA-E as its effective component.
`The patients who underwent cardiovascular angioplasty
`have a high possibility to show the symptoms due to the
`
`cardiovascular angioplasty itself within about six months
`and a higher possibility within about three months, after the
`cardiovascular angioplasty. This period is referred to as the
`unstable period in this specification. Therefore, a fourth
`embodiment of the present invention is preferably a com
`position for preventing onset and/or recurrence of cardio
`vascular events in patients beyond six months after the
`cardiovascular angioplasty. Thus the cardiovascular events
`Such as resetenosis during the unstable period, which are
`caused by the cardiovascular angioplasty itself, are excluded
`from the scope of this invention. The type of the cardiovas
`cular angioplasty is not particularly limited, and examples
`include percutaneous transluminal coronary angioplasty
`(hereinafter abbreviated as PTCA), percutaneous translumi
`nal coronary recanalization (hereinafter abbreviated as
`PTCR), directional coronary atherectomy (hereinafter
`abbreviated as DCA), coronary stent implantation (coronary
`artery stenting), and coronary artery bypass grafting (here
`inafter abbreviated as AC bypass grafting).
`0028. A fifth embodiment of the present invention is a
`composition and/or a method for preventing onset and/or
`recurrence of cardiovascular events in patients who have
`escaped the unstable period after cardiovascular angioplasty,
`which contains at least EPA-E as its effective component,
`and preferably a composition for preventing onset and/or
`recurrence of cardiovascular events in patients beyond six
`months after the cardiovascular angioplasty.
`0029. The composition according to the fourth and fifth
`embodiments is administered to the patients who have
`escaped the unstable period after cardiovascular angioplasty
`and preferably to the patients beyond six months after the
`cardiovascular angioplasty.
`0030 The cardiovascular events that occur after the
`unstable period are thought to generate by a mechanism
`which is different from that of the cardiovascular events such
`as resetenosis during the unstable period, which are caused
`by the cardiovascular angioplasty itself. The rate of the
`cardiovascular events that occur after the unstable period is
`relatively high. The composition according to the fourth and
`fifth embodiments is administered after the unstable period,
`specifically beyond after cardiovascular angioplasty. The
`composition is preferable to be administered continuously
`for a long time, specifically for two years or more, more
`preferably for three years and a half or more, still more
`preferably for five years or more and thus is effective for
`preventing onset and/or recurrence of cardiovascular events
`which occur after the unstable period.
`0031 While EPA-E content in the total fatty acid and
`dosage of the compositions according to the fourth and fifth
`embodiments of the present invention are not particularly
`limited as long as the composition contains EPA-E as its
`effective component and intended effects of the present
`invention are attained, high purity EPA-E is preferably used;
`for example, the composition having a proportion of the
`EPA-E of preferably 40% by weight or more, more prefer
`ably 90% by weight or more, and still more preferably
`96.5% by weight or more in total of the fatty acids and their
`derivatives. The daily amount in terms of EPA-E is typically
`0.3 to 6 g/day, preferably 0.9 to 3.6 g/day, and still more
`preferably 1.8 to 2.7 g/day.
`0032. Other preferable fatty acid contained is any
`omega-3 unsaturatedfatty acid, especially DHA-E. The ratio
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`of EPA-E/DHA-E in the composition, the content of EPA-E
`and DHA-E in the total fatty acids and administration
`amount of EPA-E and DHA-E are not limited but the ratio
`is preferably 0.8 or more, more preferably 1.0 or more, still
`more preferably 1.2 or more. The composition is preferably
`highly purified; for example, the proportion of EPA-E+
`DHA-E in the fatty acids and their derivatives is preferably
`40% by weight or more, more preferably 80% by weight or
`more, and still more preferably 90% or more. The daily
`amount in terms of EPA-E+DHA-E is typically 0.3 to 10.0
`g/day, preferably 0.5 to 6.0 g/day, and still more preferably
`1.0 to 4.0 g/day. The low content of other long chain
`saturated fatty acids is preferred, and among the long chain
`unsaturated fatty acids, the content of (D-6 fatty acids, and in
`particular, the content of arachidonic acid is preferably as
`low as less than 2% by weight, and more preferably less than
`1% by weight.
`0033. The compositions according to the first to fifth
`embodiments of the present invention have the effect of
`preventing onset and/or recurrence of cardiovascular events
`when orally administered to a normal person, a person
`Suffering from hyperlipidemia, diabetes or hypertension
`with the risk of cardiovascular events, or a patient to whom
`HMG-CoA RI treatment has been carried out, although
`those whom the compositions are administered are not
`limited thereto. The composition of the present invention
`also has a combined effect when used with HMG-CoA RI,
`and accordingly, onset and/or recurrence of the cardiovas
`cular events can be even more effectively prevented by using
`in combination with the HMG-CoA RI.
`0034. The compositions of the present invention contain
`a smaller amount of impurities such as Saturated fatty acids
`and arachidonic acid, which are unfavorable for cardiovas
`cular events, than fish oil or fish oil concentrate, and
`intended effects can be attained without causing problems
`like overnutrition or excessive intake of vitamin A. In
`addition, since the effective form of the present composition
`is an ester, which is more stable to oxidation than that in fish
`oil in which its effective form is a triglyceride, a sufficiently
`stable composition can be produced by adding a conven
`tional antioxidant. Thus the use of the EPA-E has enabled
`production of a composition for preventing onset and/or
`recurrence of cardiovascular events which can be used in
`clinical practice.
`0035) In the present invention, the term "icosapentaenoic
`acid designates all-cis-5,8,11,14, 17-icosapentaenoic acid.
`0036). In the present invention, the term “cardiovascular
`events' is used to generally refer to pathological changes of
`cardiovascular system, and includes cardiovascular death
`(fatal myocardial infarction and Sudden cardiac death), non
`fatal myocardial infarction, cardiovascular angioplasty
`(PTCA, PTCR, DCA, coronary stent implantation (coronary
`artery stenting), and AC bypass grafting), new onset of rest
`angina or effort angina, and destabilization of angina pec
`toris (hospitalization, and PTCA, PTCR, DCA, coronary
`stent implantation (coronary artery stenting), AC bypass
`grafting, or other cardiovascular angioplasty).
`0037. In the present invention, the term “hyperlipidemia
`patient designates the patient experiencing increase in
`serum T-Cho concentration, increase in serum LDL-Cho
`concentration, decrease in serum HDL-Cho concentration,
`or increase in serum TG. In the narrow sense, the term
`
`"hyperlipidemia patient' designates, a patient who suffers
`from any one of hypercholesterolemia (with the serum
`T-Cho concentration of about 220 mg/dl or higher, and in the
`narrower sense, with the serum T-Cho concentration of 250
`mg/dl or higher), hyper-LDL cholesterolemia (with the
`serum LDL-Cho concentration of 140 mg/dl or higher),
`hypo-HDL cholesterolemia (with the serum HDL-Cho con
`centration of less than 40 mg/dl) and hypertriglyceridemia
`(with the serum TG of 150 mg/dl or higher).
`0038. In the present invention, the term “use in combi
`nation with HMG-CoARI” includes both the embodiment in
`which the composition containing EPA-E as its effective
`component and the HMG-CoA RI are simultaneously
`administered and the embodiment in which both agents are
`separately administered. When these agents are simulta
`neously administered, they may be formulated either as a
`combination drug, or separate drugs. When these agents are
`separately administered, the composition containing EPA-E
`as its effective component may be administered either before
`or after the HMG-CoA RI. The administration amount and
`ratio of the the composition containing EPA-E as its effec
`tive component and the HMG-CoA RI may be adequately
`selected. Preferable examples of use of HMG-CoA RI which
`is administered in combination is the similar to those shown
`in the second embodiment as example.
`0039 The compositions and/or methods according to the
`first to fifth embodiments of the present invention has the
`action of preventing onset and/or recurrence of the cardio
`vascular events by sole administration of the composition,
`and in particular, the present composition is expected to
`exert an effect of preventing onset and/or recurrence of the
`cardiovascular events which cannot be prevented by admin
`istration of the HMG-CoA RI. In addition, EPA-E has not
`only the action of reducing the serum T-Cho concentration
`and the serum TG, but also the action of Suppressing platelet
`aggregation based on inhibition of arachidonic acid cascade,
`which is a pharmacological action different from the HMG
`CoA RI. Therefore, the stronger action of preventing onset
`and/or recurrence of the cardiovascular events of the present
`composition can be exerted by using in combination with the
`HMG-CoA RI.
`0040. The compositions according to the first to fifth
`embodiments of the present invention can pharmaceutically
`accepted carriers as well as its effective component. Since
`EPA-E and DHA-E are highly unsaturated, inclusion of an
`effective amount of an antioxidant Such as butylated
`hydroxytoluene, butylated hydroxyanisole, propyl gallate,
`gallic acid, and pharmaceutically acceptable quinone, and
`C-tocopherol is preferable.
`0041. The preparation may be orally administered to the
`patients in the dosage form of tablet, capsule, microcapsule,
`granules, fine granules, powder, oral liquid preparation,
`syrup, or jelly. Preferably, the preparation is filled in a
`capsule Such as Soft capsule or microcapsule and is orally
`administered.
`0042. It is to be noted that high purity EPA-E soft capsule
`(EpadelTM and Epadel STM) are commercially available in
`Japan as safe therapeutic agents for arteriosclerosis obliter
`ans and hyperlipidemia with reduced side effects, and the
`proportion of EPA-E in the total fatty acid is at least 96.5%
`by weight. Further, soft capsule (OmacorTM. Ross products)
`containing about 46% by weight of EPA-E and about 38%
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1044, p. 5 of 9
`
`

`

`US 2007/0021504 A1
`
`Jan. 25, 2007
`
`by weight of DHA-E is commercially available in the U.S.
`and other countries as a therapeutic agent for hypertriglyc
`eridemia. These drugs may be purchased for use in the
`present invention.
`0043. The amount and period for administration of the
`composition for preventing onset and/or recurrence of the
`cardiovascular events of the present invention should be
`sufficient for the expression of the intended action and may
`be adequately adjusted depending on the dosage form,
`administration route, frequency, severity of the symptoms,
`body weight, age, and the like. When orally administered,
`the composition may be administered at an amount of 0.3 to
`6 g/day, preferably 0.9 to 3.6 g/day, and more preferably 1.8
`to 2.7 g/day in terms of EPA-E, and while the composition
`is typically administered in 3 doses, the total amount may
`optionally be administered in a single dose or in a few doses.
`The composition is preferably administered during or after
`the meal, and more preferably, immediately (within 30
`minutes) after the meal. When such an amount of the
`composition is orally administered, the administration
`period is typically at least one year, preferably at least two
`years, more preferably at least three years and a half, and
`further more preferably at least five years. The administra
`tion is preferably continued as long as there is a considerable
`risk of onset and/or recurrence of the cardiovascular events.
`If necessary, drug holidays of about one day to three months,
`and preferably about one week to one month may be given.
`0044) The HMG-CoARI that is used in combination with
`the composition according to the first to fifth embodiments
`of the present invention is preferably used according to the
`recommended administration procedure and the drug type,
`and the dosage form, administration method, frequency per
`day may be adequately adjusted depending on severity of the
`symptoms, body weight, sex, age, and the like. When orally
`administered, the HMG-CoA RI is typically administered 1
`or two times per day at 0.05 to 200 mg/day, and preferably
`0.1 to 100 mg/day, and the total amount may optionally be
`administered in a few doses. The amount may be reduced
`according to the administration amount of EPA-E.
`0045. It is to be noted that pravastatin sodium (Mevalo
`tinTM tablets and fine granules, Sankyo Co., Ltd.), simvas
`tatin (LipovasTM tablets, Banyu Pharmaceutical Co., Ltd.),
`fluvastatin sodium (LocholTM tablets, Novartis Pharma K.K.
`and Tanabe Seiyaku Co., Ltd.), atorvastatin calcium hydrate
`(LipitorTM tablets, Astellas Pharma Inc. and Pfizer), pitav
`astatin calcium (LivaloTM tablets, Kowa Company, Ltd. and
`Sankyo Co., Ltd., and rosuvastatin calcium (CrestorTM tab
`lets, AstraZeneca K.K. and Shionogi & Co., Ltd.) are
`commercially available in Japan as drugs for treating hyper
`lipidemia, and lovastatin (MevacorTM tablets, Merck) is
`commercially available in the U.S. as a drug for treating
`hyperlipidemia. These drugs may be purchased and used
`according to the directions recommended by the manufac
`turer. Optionally, at least two of these drugs can be combined
`and used together.
`0046) The preferable daily amount are, for example, 5-60
`mg or preferably 10-20 mg for pravastatin sodium, 2.5-60
`mg or preferably 5-20 mg for simvastatin, 10-180 mg or
`preferably 20-60 mg for fluvastatin sodium, 5-120 mg or
`preferably 10-40 mg foratorvastatin calcium hydrate, 0.5-12
`mg or preferably 1-4 mg for pitavastatin calcium, 1.25-60
`mg or preferably 2.5-20 mg for rosuvastatin calcium, 5-160
`
`mg or preferably 10-80 mg for lovastatin, and 0.075-0.9 mg
`or preferably 0.15-0.3 mg for cervastatin but not limited to
`them.
`0047 The compound of the first to