Cardiac Dysfunction-ameliorating Agent Or Cardiac Function-maintaining Agent Patent Application (2025)

U.S. patent application number 12/282448 was filed with the patent office on 2009-10-01 for cardiac dysfunction-ameliorating agent or cardiac function-maintaining agent. This patent application is currently assigned to KANEKA CORPORATION. Invention is credited to Kenji Fujii, Kazunori Hosoe, Hideyuki Kishida, Hiroshi Kubo.

CARDIAC DYSFUNCTION-AMELIORATING AGENT OR CARDIACFUNCTION-MAINTAINING AGENT

Abstract

An object of the present invention is to provide a highly safeoral composition superior in a cardiac dysfunction-ameliorating orcardiac function-maintaining action. The present inventors haveconducted intensive studies in an attempt to solve theaforementioned problems and found that use of, particularly,reduced coenzyme Q10 from among highly safe coenzyme Q affords acomposition useful for amelioration of cardiac dysfunction andmaintenance of cardiac function. Accordingly, the present inventionprovides a cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent containing reduced coenzyme Q as anactive ingredient, and a pharmaceutical product, a food, an animaldrug, a feed and the like, which contain the agent.

 SUGHRUE MION, PLLC 2100 PENNSYLVANIA AVENUE, N.W., SUITE 800 WASHINGTON DC 20037 US

Foreign Application Data

Claims

1. A cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent comprising a reduced coenzyme Qrepresented by the following formula (1): ##STR00004## wherein n isan integer of 1-12, as an active ingredient.

2. The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of claim 1, wherein the reduced coenzymeQ is a reduced coenzyme Q 10 wherein n is 10.

3. The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of claim 1, further comprising apharmaceutical agent for treating a cardiac disease.

4. The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of claim 3, wherein the pharmaceuticalagent for treating a cardiac disease is one or more kinds ofpharmaceutical agents selected from the group consisting of acardiotonic agent, an antiarrhythmic agent, a vasodilator, anantihypertensive agent, an antiplatelet agent and a diuretic.

5. A pharmaceutical product or quasi-drug comprising the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of claim 1.

6. A food comprising the cardiac dysfunction-ameliorating agent orcardiac function-maintaining agent of claim 1.

7. The food of claim 6, which is a food with health claims.

8. The food with health claims of claim 7, which is a food forspecified health uses.

9. A veterinary pharmaceutical product comprising the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of claim 1.

10. A veterinary feed for ameliorating or preventing cardiacdysfunction, comprising the cardiac dysfunction-ameliorating agentor cardiac function-maintaining agent of claim 1.

11. A method of controlling cardiac function, comprisingadministering a cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent comprising a reduced coenzyme Qrepresented by the following formula (1): ##STR00005## wherein n isan integer of 1-12, as an active ingredient, to a subject ofadministration.

12. The method of claim 11, wherein the subject of administrationis a healthy human or healthy animal having a potential risk ofcardiac dysfunction.

13. The method of claim 11, wherein the subject of administrationis suffering from cardiac dysfunction and under a treatmentthereof, and the method further comprises administering the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent as an aid for the treatment.

14. Use of a reduced coenzyme Q represented by the followingformula (1): ##STR00006## wherein n is an integer of 1-12, for theproduction of a cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent.

15. A commercial package comprising the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of claim 1, and a written matter stating that the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent can or should be used for controlling cardiac function.

Description

TECHNICAL FIELD

[0001] The present invention relates to a cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent comprising reduced coenzyme Q as an active ingredient.

BACKGROUND ART

[0002] Cardiac disease is one of the important causes of death forJapanese people, of which angina pectoris, myocardial infarctionand cardiac failure are highly important as the pathologypotentially directly causing death. "Easily-fatigued", "shortbreath", "episode of chest pain", "palpitation", "dizziness, faint"and the like are symptoms frequently associated with cardiacdiseases. For example, "episode of chest pain" is a symptom mostlyrelated to angina pectoris-myocardial infarction, and"easily-fatigued", "short breath" and "palpitation" are symptomsmostly related to cardiac failure. Angina pectoris is a state inwhich arteriosclerosis is formed in the coronary of the heart, thearteriosclerosis causes stenosis which prevents sufficient supplyof blood to the cardiac muscle, and the cardiac muscle runs shortof oxygen and produces a chest pain. Myocardial infarction refersto the pathology where the coronary is completely obstructed andblood supply is completely prevented, thus causing a partial deathof the heart. Cardiac failure refers to the pathology where thehematological supply is insufficient for the systemic demand, sincethe pumping function of the heart became lower. Cardiac failure isthe pathology that commonly occurs at late stages of any cardiacdiseases, which shows characteristic symptoms of short breath,generalized fatigability, palpitation, swelling of lower leg andthe like.

[0003] Angina pectoris, myocardial infarction and cardiac failureare treated by a drug therapy, a catheter treatment, a surgicaltreatment and the like. Particularly, in cardiac diseases, a drugtherapy is highly important among the treatments. Therefore, manydrugs are currently used for the treatment of cardiac diseases.Nevertheless, cardiac disease is the second major cause of deathnext to cancer for Japanese people, and the number thereof keepsrising due to the westernized eating habits and lifestyle. In thecircumstances, there is a demand for the development of apharmaceutical product or functional food showing an amelioratingor prophylactic action on cardiac dysfunction, which is safe andcan be continuously ingested every day.

[0004] Such reports relating to a composition having a cardiacdysfunction-ameliorating or cardiac function-maintaining actionconcern a composition or food and drink containing, as an activeingredient, arachidonic acid or a compound containing arachidonicacid as a constituent fatty acid (patent reference 1), acomposition containing pycnogenol (patent reference 2) and thelike.

[0005] Coenzyme Q is an essential component widely distributed inliving organisms from bacterium to mammal, and is known to be anelectron transport system constituent component of mitochondria inthe cells of a living body. Coenzyme Q functions as a transportcomponent in the electron transport system by repeating oxidizationand reduction in mitochondria, and is one of the coenzymesnecessary for producing ATP (adenosine triphosphate), which is anintracorporeal energy source. In human, coenzyme Q10 in which theside chain of coenzyme Q has 10 repeat structures is the maincomponent, and aids the life activity of cells and tissues. InJapan, oxidized coenzyme Q10 is used as a drug for congestive heartfailure, and in Europe and the United States, oxidized coenzyme Q10is widely used as a health food. There are reports on theeffectiveness for cardiac diseases other than cardiac failure, suchas angina pectoris (non-patent reference 1), myocardial infarction(non-patent reference 2) and the like, as well as hypertension(non-patent reference 3).

[0006] An important characteristic of coenzyme Q10 is its highsafety. It has been reported that consecutive administration of1200 mg/kg/day for 52 weeks in a chronic toxicity test of oxidizedcoenzyme Q10 in rats did not show a toxic influence (non-patentreference 4). For human (body weight 50 kg), 1200 mg/kg/daycorresponds to 60 g/day. In view of the fact that the usual dosageof oxidized coenzyme Q10 used as a health food in Europe and theUnited States is 100-300 mg/day, coenzyme Q10 is an extremelyhighly safe supplement material.

[0007] It is known that generally about 40-90% of coenzyme Q in theliving organisms is in a reduced form. It has also been reportedthat a pharmaceutical composition containing reduced coenzyme Q issuperior in oral absorbability (patent reference 3). However,reduced coenzyme Q is difficult to handle since it is easilyoxidized by oxygen in the air, and the oxidized coenzyme Q isgenerally conventionally commercially available and is used as apharmaceutical agent orfood because once ingested, oxidizedcoenzyme Q is converted to reduced coenzyme Q in the body. Asmentioned above, the action of oxidized coenzyme Q on the cardiacfunction has already been confirmed and oxidized coenzyme Q hasbeen put to practical use. Due to the aforementioned circumstances,however, application of reduced coenzyme Q itself to a cardiacfunction associated disease has not been tried. For example, thereare reports on the methods for the treatment and/or prophylaxis ofblood vessel diseases characterized by a shortage of nitric oxide(NO), comprising combining a therapeutic agent for angina pectorisand an antioxidant, which include a case reciting oxidized coenzymeQ and reduced coenzyme Q as simple examples of the antioxidant(patent reference 4), and a report on a composition that enhancescell energy metabolism by combining oxidized coenzyme Q10 orreduced coenzyme Q10 with two or more kinds of cytochromes a, b, cand the like (patent reference 5). Nevertheless, the action ofreduced coenzyme Q itself on the cardiac function has not beenconfirmed.

[0008] patent reference 1: JP-A-2005-132758

[0009] patent reference 2: JP-A-2005-239581

[0010] patent reference 3: JP-A-10-109933

[0011] patent reference 4: National Publication of InternationalPatent Application No. 2003-514020

[0012] patent reference 5: National Publication of InternationalPatent Application No. 2004-518712

[0013] non-patent reference 1: Am J Cardiol 1985; 56(4):247-51.

[0014] non-patent reference 2: Mol Cell Biochem 2003; 246(1-2):75-82.

[0015] non-patent reference 3: Biofactors 2003; 18(1-4):91-100.

[0016] non-patent reference 4: J Agric Food Chem 1999; 47:3756-3763.

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Invention

[0017] An object of the present invention is to provide a highlysafe composition superior in a cardiac dysfunction-ameliorating orcardiac function-maintaining action.

Means of Solving the Problems

[0018] The present inventors have conducted intensive studies in anattempt to solve the aforementioned problems and found that use of,particularly, reduced coenzyme Q10 from among highly safe coenzymeQ is effective for the amelioration of cardiac dysfunction andmaintenance of cardiac function. Accordingly, the present inventionis as follows.

[0019] [1] A cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent comprising reduced coenzyme Qrepresented by the following formula (1):

##STR00001##

wherein n is an integer of 1-12, as an active ingredient.

[0020] [2] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of [1], wherein the reduced coenzyme Qis a reduced coenzyme Q10 wherein n is 10.

[0021] [3] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of [1] or [2], further comprising apharmaceutical agent for treating a cardiac disease.

[0022] [4] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of [3], wherein the pharmaceutical agentfor treating a cardiac disease is one or more kinds ofpharmaceutical agents selected from the group consisting of acardiotonic agent, an antiarrhythmic agent, a vasodilator, anantihypertensive agent, an antiplatelet agent and a diuretic.

[0023] [5] A pharmaceutical product or quasi-drug, comprising thecardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of any of [1] to [4].

[0024] [6] A food comprising the cardiac dysfunction-amelioratingagent or cardiac function-maintaining agent of any of [1] to[4].

[0025] [7] The food of [6], which is a food with health claims.

[0026] [8] The food with health claims of [7], which is a food forspecified health uses.

[0027] [9] An animal drug comprising the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of any of [1] to [4].

[0028] [10] A feed for ameliorating or preventing cardiacdysfunction, comprising the cardiac dysfunction-ameliorating agentor cardiac function-maintaining agent of any of [1] to [4].

[0029] [11] A method of controlling cardiac function, comprisingadministering a cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent comprising a reduced coenzyme Qrepresented by the following formula (1):

##STR00002##

wherein n is an integer of 1-12, as an active ingredient, to asubject of administration.

[0030] [12] The method of [11], wherein the aforementioned subjectof administration is a healthy human or healthy animal having apotential risk of cardiac dysfunction.

[0031] [13] The method of [11], wherein the aforementioned subjectof administration is suffering from cardiac dysfunction and under atreatment thereof, and the method further comprises administeringthe aforementioned cardiac dysfunction-ameliorating agent orcardiac function-maintaining agent as an aid of the treatment.

[0032] [14] Use of a reduced coenzyme Q represented by thefollowing formula (1):

##STR00003##

wherein n is an integer of 1-12, for the production of a cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent.

[0033] [15] A commercial package comprising the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of any of [1] to [4], and a written matter stating that thecardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent can or should be used for controllingcardiac function.

EFFECT OF THE INVENTION

[0034] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention comprisingreduced coenzyme Q10 as an active ingredient provides superioreffects of ameliorated condition of cardiac dysfunction andmaintenance of cardiac function. In addition, the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of the present invention causes no side effects and is highlysafe. Thus, a composition comprising the agent can be ingesteddaily and continuously not only as a pharmaceutical product butalso as a quasi-drug, a food or a food with health claims.

BEST MODE FOR CARRYING OUT THE INVENTION

[0035] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention comprisesreduced coenzyme Q as an active ingredient. In the presentinvention, the cardiac dysfunction means a disease state where theheart function is impaired or does not work properly, such asangina pectoris, myocardial infarction, cardiac failure, cardiacmuscle disease, valvular disease, arrhythmia and the like, and apre-disease state associated with the risk thereof. The cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of the present invention has an action of ameliorating thecondition of the cardiac dysfunction, or an action of preventingthe condition, namely, an action of controlling cardiacfunction.

[0036] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention containsreduced coenzyme Q as an essential active ingredient. However,reduced coenzyme Q can be used alone, or coenzyme Q in a mixed formof reduced coenzyme Q and oxidized coenzyme Q can also be used.When coenzyme Q in a mixed form of reduced coenzyme Q and oxidizedcoenzyme Q is to be used, the proportion of reduced coenzyme Qrelative to the total coenzyme Q is preferably not less than 20 wt%, more preferably not less than 40 wt %, further preferably notless than 50 wt %, still more preferably not less than 60 wt %,particularly preferably not less than 80 wt %, most preferably notless than 96 wt %, relative to the total amount of coenzyme Q(i.e., total amount of reduced coenzyme Q and oxidized coenzyme Q).While the upper limit of the proportion of reduced coenzyme Qrelative to the total coenzyme Q is not particularly limited, it isgenerally not more than 99.9 wt %, preferably not more than 99.5 wt%. Use of reduced coenzyme Q alone (i.e., 100 wt % reduced type) isadmissible.

[0037] The proportion of oxidized coenzyme Q and reduced coenzyme Qin coenzyme Q can be generally determined by a method includingquantifying oxidized coenzyme Q and reduced coenzyme Q in a sampleby an HPLC system using a UV detector and calculating theproportion based on the obtained amount ratio, or a methodincluding calculating the proportion of oxidized coenzyme Q andreduced coenzyme Q from peak areas obtained by a system combiningHPLC with an electrochemical detector. A system incorporating anelectrochemical detector is highly useful for measuring the ratioof reduced type present in a trace amount in a living organism orsample, since it can specifically measure an oxidized or reducedsubstance and has high sensitivity. The present invention measuredby incorporating an electrochemical detector manufactured byShiseido Co., Ltd. into HPLC analysis apparatus manufactured bySHIMADZU Corporation under the conditions of the followingHPLC.

[0038] column: YMC-Pack (ODS-A303), detection wavelength: 275nm,

[0039] mobile phase: methanol (88%)+hexane (12%), flow rate: 1ml/min.

[0040] The method of obtaining reduced coenzyme Q to be used in thepresent invention is not particularly limited and, for example, amethod including obtaining coenzyme Q containing oxidized coenzymeQ as a main component by a conventionally known method such assynthesis, fermentation, extraction from naturally occurringsubstances and the like, and concentrating reduced coenzyme Qfraction in an outflow fluid by chromatography, and the like can beemployed. In this case, where necessary, a general reducing agentsuch as sodium borohydride, sodium dithonite (sodium hydrosulfite),ascorbic acid and the like is added to the above-mentioned coenzymeQ, oxidized coenzyme Q contained in the above-mentioned coenzyme Qis reduced according to a conventional method to give reducedcoenzyme Q, and the reduced coenzyme Q is concentrated bychromatography. In addition, reduced coenzyme Q can also beobtained by a method including reacting an existing high-puritycoenzyme Q (oxidized coenzyme Q) with the above-mentioned reducingagent. Alternatively, fungus etc. containing reduced coenzyme Q canalso be used. Furthermore, it is possible to reduce oxidizedcoenzyme Q into reduced coenzyme Q in a preparation by producingthe preparation using oxidized coenzyme Q together with a substancehaving reducing ability such as vitamins and the like.

[0041] Preferred as reduced coenzyme Q to be used in the presentinvention is reduced coenzyme Q10 having 10 repeat structures inthe side chain (the above-mentioned formula (1) wherein n is10).

[0042] The cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention can alsocontain, besides reduced coenzyme Q, a known pharmaceutical agentfor treating cardiac diseases. Such pharmaceutical agent fortreating cardiac diseases is not particularly limited, andcardiotonic agent, antiarrhythmic agent, vasodilator,antihypertensive agent, antiplatelet agent, diuretic and the like,which are generally employed, can be used preferably.

[0043] Specific examples of such pharmaceutical agent for treatingcardiac diseases include digitoxin, digoxin, methyldigoxin,lanatoside C, proscillaridin, deslanoside, dopamine, doputamin,docarpamine, denopamine, aminophylline, amrinone, olprinone,milrinone, vesnarinone, pimobendan, bucladesine sodium,ubidecarenone, quinidine, procainamide, ajmaline, disopyramide,cibenzoline, lidocain, phenytoin, mexiletine, aprindine,flecainide, propafenone, pilsicainide, sotalol, amyl nitrite,nitroglycerol, isosorbide, diltiazem, nicardipine, nifedipine,verapamil, dilazep, dipyridamole, etafenone, trimetazidine,trapidil, nicorandil or a salt thereof and the like. While theproportion of reduced coenzyme Q and the above-mentionedpharmaceutical agent for treating cardiac diseases is notparticularly limited, it is within the range of 100:1-1:100,preferably 10:1-1:10, by weight ratio.

[0044] In addition, the cardiac dysfunction-ameliorating agent orcardiac function-maintaining agent of the present invention can beused as it is, or in the form of a composition containing the same,which is used as a pharmaceutical product, a quasi-drug, a food, Ananimal drug, a feed and the like aiming at ameliorating cardiacdysfunction or maintaining cardiac function. In this case, theabove-mentioned composition can contain various additives which areacceptable medically or under food hygiene law and the like. Suchadditives are not particularly limited and, for example, fats andoils, excipient, disintegrant, lubricant, binder, coating agent,colorant, anticoagulant, absorption promoter, solubilizing agents,stabilizer, health food material, dietary supplement material(supplement material) and the like can be mentioned.

[0045] The above-mentioned fats and oils are not particularlylimited and edible fats and oils can be used. For example, plantoils such as corn oil, rape seed oil, soybean oil, sesame oil,olive oil, safflower oil, cottonseed oil, sunflower oil, rice branoil, Japanese basil oil, perilla oil, flaxseed oil, tuberose oil,cacao butter, peanuts oil, palm oil, palm kernel oil and the like,animal oils such as fish oil, beef fat, lard, milk fat, egg-yolkoil and the like, synthetic oils such as medium-chain triglycerideand the like, fats and oils resulting from partitioning,hydrogenation, transesterification and the like of the above oilsas starting materials, or a mixed oil thereof and the like can bementioned.

[0046] The above-mentioned excipient is not particularly limitedand, for example, sucrose, lactose, glucose, cornstarch, mannitol,crystalline cellulose, calcium phosphate, calcium sulfate and thelike can be mentioned.

[0047] The above-mentioned disintegrant is not particularly limitedand, for example, starch, agar, calcium citrate, calcium carbonate,sodium hydrogen carbonate, dextrin, crystalline cellulose,carboxymethylcellulose, tragacanth and the like can bementioned.

[0048] The above-mentioned lubricant is not particularly limitedand, for example, talc, magnesium stearate, polyethylene glycol,silica, hydrogenated vegetable oil and the like can bementioned.

[0049] The above-mentioned binder is not particularly limited and,for example, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, tragacanth, shellac, gelatin, gumarabic, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid,polymethacrylic acid, sorbitol and the like can be mentioned.

[0050] The above-mentioned coating agent is not particularlylimited, and gum arabic, opadry, asiatica, caster wax, carboxyvinylpolymer, carmellose, hydrated silicon dioxide, magnesium silicate,vinyl acetate resin, stearic acid, cetanol,hydroxypropylmethylcellulose and the like can be mentioned.

[0051] The above-mentioned colorant is not particularly limitedand, for example, those permitted for addition to pharmaceuticalproducts and food, and the like can be used.

[0052] The above-mentioned anticoagulant is not particularlylimited and, for example, stearic acid, talc, light anhydroussilicic acid, hydrated silicon dioxide and the like can bementioned.

[0053] The above-mentioned absorption promoter is not particularlylimited and, for example, higher alcohols, higher fatty acids,surfactants such as glycerolfatty acid ester and the like can bementioned.

[0054] The above-mentioned solubilizing agent is not particularlylimited and, for example, organic acids such as fumaric acid,succinic acid, malic acid and the like can be mentioned.

[0055] The above-mentioned stabilizer is not particularly limitedand, for example, benzoic acid, sodium benzoate, ethylparahydroxybenzoate and the like can be mentioned.

[0056] The above-mentioned health food material is not particularlylimited and, for example, kanpo medicines (e.g., ireito, unkeito,unsei'in, ogi-kentyuto, oren-gedokuto, orento, kakkonto,kami-kihito, kami-syoyosan, kanbaku-daisoto, kikyoto, kihito,kyumi-binroto, keigai-rengyoto, keisi-ka-syakuyaku-daioto,keihi-ka-syakuyakuto, keihi-ka-ryukotu-boreito, keisito,keisi-ninzinto, keisi-bukuryogan, keihito, kososan, gokoto,gosyakusan, gosha-jinkigan, gorinsan, saikanto,saiko-ka-ryukotu-boreito, saiko-keisi-kankyoto, saiko-keisito,saiko-seikanto, saibokuto, saireito, sansoninto, ziin-kokato,sigyakusan, sikunsito, simotuto, sya-kanzoto, syakuyakukanzoto,zyuzen-taihoto, zyumi-haidokuto, syoken-tyuto, syosaikoto,syoseiryuto, syohusan, sin'i-seihaito, sinpito, sinbuto,seizyo-bohuto, seisyo-ekkito, seisin-rensiin, seihaito,sokei-kakketuto, daio-kanzoto, daio-botanpito, daikentyuto,daisaikoto, daisaikoto-kyo-daio, daijyokito, daibohuto,jidaboku-ippo, tyoi-zyokito, tyotosan, tyoyoto, tyoreito,tyoreito-go-simotuto, tudosan, tokaku-zyokito, toki-insi,toki-kentyuto, toki-syakuyakusan, tokito, nitinto, nyosinsan,ninzinto, ninzin-yoeito, hainosankyuto, bakumondoto, hatimi-ziogan,hange-kobokuto, hange-syasinto, byakko-ka-ninzinto, bukuryoin,bukuryoin-go-hange-kobokuto, heiisan, boi-ogito, bohu-tusyosan,hotyu-ekkito, maoto, mao-busi-saisinto, makyo-kansekito,masiningan, mokuboito, yokukansan, yokukansan-ka-tinpi-hange,rikkunsito, rikkosan, ryutan-syakanto, ryokankyo-mi-singeninto,rokumi-ziogan and the like), tea leaves (e.g., green tea, unmilledrice tea, powdered tea, green tea of middle grade, toasted tea,roasted tea, jasmine tea, oolong tea, hongcha, heicha, huacha,jincha, baicha and the like), herbs (e.g., Italian parsley,elecampane, olive, oregano, cardoon, chamomile, curry plant,catnip, caraway, Christmas rose, crimson clover, cornflower, commonmallow, salad burnet, santolina, cinnamon, jasmine, stevia, sage,European linden, scented geranium, St. John's wort, soapwort,Solomon's-seal, thyme, tansy, chervil, chive, nasturtium, jujube,basil, honeysuckle, hyssop, flax, fennel, foxglove, blackhollyhock, French marigold, betony, heliotrope, bergamot, hempagrimony, rue, pot marigold, borage, white horehound, myrtle,mullein, marjoram, mint, yarrow, lavender, lady's bedstraw, lemongrass, lemon verbena, lemon balm, rose, rosemary, rocket, wildstrawberry, wild pansy, forget-me-not and the like), pycnogenol,flavangenol, propolis, ginkgo leaf, royal jelly, carnitine,mushrooms, aojiru (green-leaved-vegetable juice) and extractthereof and the like can be mentioned.

[0057] The above-mentioned nutritional supplementary food materialis not particularly limited and amino acids, metal ions, proteins,saccharides, fatty acids, yeast extract, vegetable extract, fishmeat extract, fruit, fruit extract and the like can bementioned.

[0058] In addition, the cardiac dysfunction-ameliorating agent orcardiac function-maintaining agent of the present invention, or acomposition containing the same can also contain other antioxidantsubstances, antioxidant enzyme, vitamins and the like. Theantioxidant substance is not particularly limited and, for example,citric acid and derivatives thereof, vitamin C and derivativesthereof, lycopene, vitamin A, carotenoids, vitamin B andderivatives thereof, flavonoids, polyphenols, glutathione,selenium, sodium thiosulfate, vitamin E and derivatives thereof,pyrroloquinoline quinone and derivatives thereof and the like canbe mentioned. The antioxidant enzyme is not particularly limitedand, for example, superoxide dismutase (SOD), glutathioneperoxidase, glutathione-S-transferase, glutathione reductase,catalases, ascorbic acid peroxidase and the like can be mentioned.The above-mentioned vitamins are not particularly limited and, forexample, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E,vitamin K or derivatives thereof and the like can be mentioned.

[0059] In the cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention, and apharmaceutical product, a quasi-drug, a food, an animal drug and afeed, which contain the agent, the content, dosage form,preservation method and preservation form of reduced coenzyme Q arenot limited, and can be appropriately determined according to theuse thereof and product concept thereof. For example, in thecardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention, and theabove-mentioned composition containing the same, the content ofreduced coenzyme Q is preferably 0.01-99 wt %, more preferably0.1-50 wt %, relative to the whole preparation or composition.

[0060] The administration form and dosage form of the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of the present invention, and a composition containing thesame may be any form of liquid or solid, and various administrationmethods such as oral, injection, nasal, instillation, suppository,food containing reduced coenzyme Q, and the like can be employed.While oral administration is generally considered to be mosteffective from the aspects of dose and the like, when oraladministration is difficult, the cardiac dysfunction-amelioratingagent or cardiac function-maintaining agent of the presentinvention and a composition containing the same can be administeredby a route other than oral administration without any problem. Forexample, suppository, skin external preparation and the like maybe, nonlimitatively, employed for patients or the elderly havingdifficulty in ingesting nutrients orally.

[0061] Examples of the form for preparing a composition containingthe cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention as apharmaceutical product or a quasi-drug include oral preparations(syrup, capsule, granule, pill, powder, tablet, drink), injection,infusion, nasal drop, eye drop, suppository and spray, as well asadministration from the skin by ointment or an adhesivepreparation.

[0062] The form of food containing the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of the present invention is not particularly limited and, forexample, general food forms such as edible fat and oil composition,cooking oil, spray oil, butter, margarine, shortening, whippingcream, concentrated milk, whiteners, dressings, pickle liquids,breads, cakes, pies, cookies, Japanese confectionaries, snacks,fried snacks, chocolates and chocolate confectioneries, riceconfectioneries, roux, sauce, basting, toppings, ice creams,noodles, bread mix, fried food, processed meat products, fish pasteproducts, frozen food such as frozen entrees, frozen meat andfrozen vegetables, rice, jam, cheese, cheese food, cheese-likefood, chewing gums, candies, fermented milk, canned food, drinksand the like, as well as supplement forms such as capsule, tabletand the like, food with health claims such as food for specifiedhealth uses, food with nutrient function claims and the like,health food, dietary supplement can be prepared. In the case of theabove-mentioned food with health claims and supplement, a label canbe placed thereon to indicate its use for amelioration of cardiacdysfunction or maintenance of cardiac function.

[0063] Furthermore, for animal purposes, the agent can beingested/administered in a form such as an animal drug, a feed andthe like.

[0064] The dosage in the amount of reduced coenzyme Q of thecardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention and theabove-mentioned composition containing the same is preferably30-1200 mg for a day for an adult. It is more preferably 50-800 mg,and most preferably 100-300 mg. For children other than adults andanimals, the above-mentioned preferable dosage can be calculatedbased on the body weight.

[0065] However, the dosage varies depending on the above-mentionedpreferable dose and dosage form of the preparation, and highlyabsorbable preparation can achieve the desired object with a lowdosage.

[0066] The above-mentioned dose per day can be ingested at one timeor in several times. One dose of the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of the present invention and a composition containing thesame can be packed as a single unit. For example, in the case of apharmaceutical product, food with health claims and supplement, apacking form wherein the ingestion per 1 dose is a unit, and in thecase of a drink, a packing form wherein the drink is packed in abottle and the like for complete ingestion at one time, and thelike can be mentioned.

[0067] As mentioned above, the cardiac dysfunction-amelioratingagent or cardiac function-maintaining agent containing reducedcoenzyme Q as an active ingredient can control cardiac function byadministration to a subject. The control of cardiac function inthis case includes not only ameliorating or treating cardiacdysfunction by ingestion of the cardiac dysfunction-amelioratingagent or cardiac function-maintaining agent of the presentinvention and a composition containing the same as a pharmaceuticalproduct, but also maintaining cardiac function or preventingcardiac dysfunction by daily ingestion thereof as food. Forexample, the method of controlling cardiac function of the presentinvention also includes ingestion (administration) of the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent of the present invention to a healthy human or healthy animalwith a normal cardiac function at present but having a potentialrisk of cardiac dysfunction, thereby to maintain cardiac functionand prevent the condition of cardiac dysfunction, and administeringthe cardiac dysfunction-ameliorating agent or cardiacfunction-maintaining agent of the present invention to a patient oranimal patient under the condition of cardiac dysfunction or undermedication with other drugs and other treatments, as a support ofthe treatment. In other words, the method of controlling cardiacfunction of the present invention also includes concurrentingestion of a known pharmaceutical agent for treating cardiacdiseases as mentioned above and the cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent containing reduced coenzyme Q as an active ingredient.

[0068] Furthermore, the present invention also provides acommercial package containing the above-mentioned cardiacdysfunction-ameliorating agent or cardiac function-maintainingagent and a written matter (for example, instruction etc.) relatingthereto, which describes that the cardiac dysfunction-amelioratingagent or cardiac function-maintaining agent can or should be usedfor controlling cardiac function.

EXAMPLES

[0069] The present invention is explained in more detail in thefollowing by referring to Examples, which are not to be construedas limitative. The purity of reduced coenzyme Q10 and oxidizedcoenzyme Q10, and the ratio (weight ratio) of reduced coenzymeQ10/oxidized coenzyme Q10 was calculated by the above-mentionedHPLC analysis.

Production Example 1

Production of Reduced Coenzyme Q10

[0070] Oxidized coenzyme Q10 (100 g, purity 99.4%) and L-ascorbicacid (60 g) were added to ethanol (1000 g), and the mixture wasstirred at 78.degree. C. to perform a reduction reaction. After 30hr, the reaction mixture was cooled to 50.degree. C., and ethanol(330 g) and water (70 g) were added thereto while maintaining thesame temperature. The ethanol solution (containing 100 g of reducedcoenzyme Q10) was cooled to 2.degree. C. at a cooling rate of10.degree. C./hr with stirring to give white slurry.

[0071] The obtained slurry was filtered under reduced pressure, andthe wet crystals were washed with cold ethanol, cold water and coldethanol in this order (the temperature of the cold solvent used forwashing was 2.degree. C.). Furthermore, the wet crystals were driedunder reduced pressure (20-40.degree. C., 1-30 mmHg) to give whitedry crystals (97 g, reduced coenzyme Q10/oxidized coenzymeQ10=99/1). All operations except drying under reduced pressure wereperformed under a nitrogen atmosphere.

Production Example 2

Production of Reduced Coenzyme Q10

[0072] Oxidized coenzyme Q10 (100 g) was dissolved in heptane (100g, 25.degree. C.). An aqueous solution of sodium hyposulfite (100g, purity not less than 75%) in water (1000 ml) was gradually addedas a reducing agent with stirring, and the reduction reaction wasperformed at 25.degree. C., pH 4-6. After 2 hr, the aqueous phasewas removed from the reaction mixture, and the heptane phase waswashed 6 times with deaerated saturated brine (1000 g). All theabove operations were performed under a nitrogen atmosphere. Theheptane phase was subjected to solvent substitution under reducedpressure to give 7% (w/w) ethanol solution of reduced coenzyme Q10at 50.degree. C. (containing 100 g of reduced coenzyme Q10). Water(50 g) was added to the ethanol solution, and cooled to 2.degree.C. at a cooling rate of 10.degree. C./hr with stirring toprecipitate crystals. All operations were performed under anitrogen atmosphere. The obtained slurry was filtered under reducedpressure, and wet crystals were washed with cold ethanol, coldwater and cold ethanol in this order (the temperature of the coldsolvent to be used for washing was 2.degree. C.). Furthermore, thewet crystals were dried under reduced pressure (20-40.degree. C.,1-30 mmHg) to give white dry crystals (97 g, reduced coenzymeQ10/oxidized coenzyme Q10=99/1).

Example 1

Effect on Cardiac Disease

<Experiment System>

[0073] Male SD rats (9-week-old, Japan SLC Inc.) were divided intofour groups. Each rat was anesthetized with pentobarbital sodium(35-45 mg/kg, i.p.), and fixed at the dorsal position. A trachealtube was orally inserted into the airway, artificial respirationwas performed by an artificial respirator for small animals, andthe medial wall of the thorax was opened to expose the heart. Inthree groups, the left anterior descending artery (LAD) wasobstructed for 30 min with a surgical needle with a thread. At thistime, an electrocardiogram was measured via an amplifier forelectrocardiogram, and the presence or absence of occlusion wasconfirmed based on the changes in the ST electrical potential andcardiac muscle color. An ischemia-reperfusion model was prepared byreperfusing the blood flow after 30 min from the occlusion.Thereafter, in all groups, the thorax was closed, sutured, anddisinfected with a veterinary Isodine solution.

[0074] The following samples were administered to each group for 1week before the above-mentioned operation and 4 weeks after theoperation (total 5 weeks).

1 (Sham Group: N=3)

[0075] Group for which open chest surgery alone was performedwithout occlusion treatment, and corn oil was orally administeredat 5 ml/kg per day

2 (Control Group: N=8)

[0076] Group for which occlusion treatment was performed, and cornoil was orally administered at 5 ml/kg per day

3 (Oxidized Coenzyme Q10 group: N=7)

[0077] Group for which occlusion treatment was performed, andoxidized coenzyme Q10 dissolved in corn oil was orally administeredat a dosage of 30 mg/kg per day based on the amount of oxidizedcoenzyme Q10

4 (Reduced Coenzyme Q10 Group: N=8)

[0078] Group for which occlusion treatment was performed, andoxidized coenzyme Q10 (containing 1 wt % of oxidized coenzyme Q10)dissolved in corn oil was orally administered at a dosage of 30mg/kg per day based on the amount of reduced coenzyme Q10

<Cardiac Function Evaluation>

[0079] After measuring the body weight on the next day of the finaladministration, the rats were fixed at the dorsal position underpentobarbital sodium (25-35 mg/kg, i.p.) anesthesia, and a mirrorcatheter was inserted into the right carotid artery. Afterconfirmation of the stable condition, the left ventricle internalpressure wave pattern was led to a biological electric amplifier toenlarge same, and the left ventricular end-diastolic pressure(LVEDP) was measured.

<Anatomy>

[0080] After cardiac function evaluation, the animals wereeuthanized by dislocation of cervical spine under anesthesia, andthe heart was removed. The right atrium weight, left atrium weight,right ventricle weight, left ventricle weight and overall weight ofthe heart (weight of both atria+weight of both ventricles) weremeasured. For evaluation, the body weight ratio of the right atriumweight, the body weight ratio of the left atrium weight, the bodyweight ratio of the right ventricle weight and the body weightratio of the left ventricle weight were calculated.

[0081] Table 1 shows the results of cardiac function evaluation(left ventricle diastolic pressure), and Table 2 shows the resultsof heart weight (body weight ratio).

TABLE-US-00001 TABLE 1 (cardiac function) mean .+-. standard errorleft ventricle end-diastolic pressure (mmHg) 1. sham group 4.1 .+-.0.3** 2. control group 7.7 .+-. 0.5 3. oxidized coenzyme Q10 group8.3 .+-. 0.7 4. reduced coenzyme Q10 group 5.7 .+-. 0.4* (*p <0.05, **p < 0.01 t-test vs. control group)

TABLE-US-00002 TABLE 2 (body weight ratio of heart weight) averageright left right left atrium atrium ventricle ventricle 1. shamgroup 0.110 0.068 0.454 1.714 2. control group 0.187 0.100 0.5461.906 3. oxidized coenzyme 0.135 0.081 0.498 1.823 Q10 group 4.reduced coenzyme 0.146 0.089 0.508 1.879 Q10 group

[0082] From the results of Table 1, the ischemia reperfusion model(control group) showed increased ventricular end-diastolic pressureas compared to the sham group, since cardiac function decreased tocause accumulation of blood. In contrast, it has been clarifiedthat the group administered with reduced coenzyme Q10 showedsignificant suppression of elevation of the end-diastolic pressure,thus ameliorating the cardiac function. Administration of oxidizedcoenzyme Q10 did not provide an ameliorating effect.

[0083] From the results of Table 2, the ischemia reperfusion model(control group) showed decreased cardiac function as compared tothe sham group, causing congested blood circulation leading toedema, which increased the heart weight. In contrast, it has beenclarified that the oxidized coenzyme Q10 group and the groupadministered with reduced coenzyme Q10 showed a suppressed increasein the heart weight in all parts, and edema was ameliorated.

[0084] From the above-mentioned results, oxidized coenzyme Q10 andreduced coenzyme Q10 were common in that they both have anameliorating effect on edema caused by cardiac ischemia. However,reduced coenzyme Q10 clearly showed an ameliorating effect ondecreased cardiac function, for which oxidized coenzyme Q10 failedto show effect. Hence, reduced coenzyme Q10 is considered to have astronger cardiac function ameliorating effect than oxidizedcoenzyme Q10, or effective for broader pathology relating tocardiac function.

Example 2

Absorbability Evaluation

[0085] Example 1 revealed that reduced coenzyme Q10 has a strongercardiac function-ameliorating effect than oxidized coenzyme Q10. Onthe other hand, it has been disclosed that oral absorbability ofcoenzyme Q10 can be enhanced by the co-presence of reduced coenzymeQ10, as compared to oxidized coenzyme Q10 alone, and that theutilization of reduced coenzyme Q10 is extremely effective forincreasing oral absorbability in various uses (JP-A-10-109933).Thus, whether or not the difference in the effect in Example 1 iscaused by the difference in the transferability of coenzyme Q10into the heart was examined.

<Experiment System>

[0086] Male SD rats (5-week-old, Japan SLC Inc.) were each orallyadministered with soybean oil (control group), oxidized coenzymeQ10 (100 mg/kg) dissolved in soybean oil (oxidized coenzyme Q10group) and reduced coenzyme Q10 (containing 1 wt % of oxidizedcoenzyme Q10; 100 mg/kg) dissolved in soybean oil (reduced coenzymeQ10 group) once a day for 4 consecutive weeks (each group N=3).After completion of the administration, blood samples were takenand the heart was removed, and the total amount of coenzyme Q10(total amount of oxidized coenzyme Q10 and reduced coenzyme Q10) inplasma and heart was quantified by HPLC according to a conventionalmethod.

[0087] The results are shown in Table 3.

TABLE-US-00003 TABLE 3 (concentration average: .mu.g/ml) plasmaheart control group 0.02 9.59 oxidized coenzyme Q10 group 0.35 9.69reduced coenzyme Q10 group 0.39* 9.33 (*p < 0.05 t-testcomparison with oxidized coenzyme Q10 group)

[0088] As shown in Table 3, the concentration of coenzyme Q10 inplasma was higher in the reduced coenzyme Q10 administration groupthan in the oxidized coenzyme Q10 administration group, asconventionally reported. However, the coenzyme Q10 concentration inthe heart was not different in any administration group. Therefromthe difference in the cardiac function-ameliorating effect betweenreduced coenzyme Q10 and oxidized coenzyme Q10 cannot be explainedonly by the difference in the concentration in plasma. Hence, themore superior cardiac function-ameliorating effect of reducedcoenzyme Q10 is an unexpected result.

Formulation Example 1

Powder

[0089] Reduced coenzyme Q10 (containing 1 wt % of oxidized coenzymeQ10) was dissolved in propanol, and adsorbed to microcrystallinecellulose and dried under reduced pressure.

[0090] This was mixed with cornstarch under a nitrogen stream togive a powder.

TABLE-US-00004 reduced coenzyme Q10 9.9 parts by weight oxidizedcoenzyme Q10 0.1 part by weight microcrystalline cellulose 40 partsby weight cornstarch 55 parts by weight.

Formulation Example 2

Capsule

[0091] In the same manner as in Formulation Example 1, a powderwith the following formulation was prepared, and filled in agelatin capsule according to a conventional method. The capsulethus filled was sealed, packed under a nitrogen atmosphere, andrefrigerated for preservation.

TABLE-US-00005 reduced coenzyme Q10 19.8 parts by weight oxidizedcoenzyme Q10 0.2 part by weight microcrystalline cellulose 40 partsby weight cornstarch 20 parts by weight lactose 65 parts by weightmagnesium stearate 3 parts by weight polyvinylpyrrolidone 2 partsby weight.

Formulation Example 3

Soft Capsule

[0092] Corn oil was heated to 50.degree. C., and reduced coenzymeQ10 (containing about 1 wt % of oxidized coenzyme Q10) melted atthe same temperature was added and dissolved therein. This wasprepared into a soft-capsule according to a conventionalmethod.

TABLE-US-00006 reduced coenzyme Q10 49.5 parts by weight oxidizedcoenzyme Q10 0.5 part by weight corn oil 350 parts by weight.

Formulation Example 4

Tablet

[0093] Reduced coenzyme Q10 (containing about 1 wt % of oxidizedcoenzyme Q10) was dissolved in propanol, adsorbed tomicrocrystalline cellulose and dried under reduced pressure. Thiswas mixed with cornstarch, lactose, carboxymethylcellulose andmagnesium stearate under a nitrogen atmosphere. Then, an aqueoussolution of polyvinylpyrrolidone was added as a binder and themixture was granulated according to a conventional method. This wasmixed with talc as a lubricant and the mixture was compressed togive a tablet. The tablet was packed under a nitrogen atmosphereand refrigerated for preservation.

TABLE-US-00007 reduced coenzyme Q10 19.8 parts by weight oxidizedcoenzyme Q10 0.2 part by weight cornstarch 25 parts by weightlactose 15 parts by weight calcium carboxymethylcellulose 10 partsby weight microcrystalline cellulose 40 parts by weightpolyvinylpyrrolidone 5 parts by weight magnesium stearate 3 partsby weight talc 10 parts by weight

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