WO2008050483A1 - Cardiovascular preparation - Google Patents

Abstract

Disclosed is a novel cardiovascular preparation. The cardiovascular preparation comprises a combination of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone.

Description

 Specification

 Cardiovascular drugs

 Technical field

 [0001] The present invention relates to a cardiovascular drug. More specifically, the present invention relates to a cardiovascular drug having an excellent action for preventing and / or improving myocardial ischemia.

 Background art

 [0002] A normal heart rhythmically repeats contraction and relaxation, and pumps blood continuously throughout the body. This is a result of the regularity of excitatory contraction by intracellular Ca ion inflow and outflow. However, it has been clarified that when this excitatory contraction is broken, contraction and diastolic failure occur (Non-patent Document 1). Ischemic heart disease is common to two pathologies of diastolic and systolic dysfunction. It is said that it is important to dilate coronary vessels as quickly as possible during an ischemic heart disease attack and promote adequate blood flow improvement. This is because the longer the myocardial ischemia time, the more irreversible the impairment of cardiac function and coronary vascular function. For this purpose, drugs such as nitroglycerin that promote coronary vasodilation during ischemic attacks are administered, but these drugs are often insufficient or ineffective, and in such cases Coronary revascularization (PTCA) and coronary bypass surgery (peripheral artery or vein transplantation) are also performed.

 [0003] Adenosine 5'-triphosphate (hereinafter sometimes abbreviated as ATP) is a substance that is widely involved in metabolism of carbohydrates, fats, or proteins as a phosphate donor. The energy generated by this is the driving force for energy-requiring reactions in living bodies.

[0004] Drugs containing ATP include improvement of sequelae of head trauma, heart failure, stabilization of regulatory function in regulatory eye strain, chronic gastritis with decreased gastrointestinal function, Meniere's disease and dizziness based on inner ear disorders Efficacy against is recognized. As a pharmacological action of ATP, it is recognized that coronary blood vessels and peripheral blood vessels are dilated in the heart to increase coronary blood flow and cardiac output (Non-patent Document 2). Also, the crown movement It has been reported that the blood flow in the collateral circulation path of the Inu myocardial infarction model with ligated veins is prevented to prevent the deterioration of the pathological condition (Non-patent Document 3). Furthermore, it is known that combined administration by injection of ATP and magnesium chloride is effective for ischemic myocardium and can be used as a therapeutic agent for angina pectoris and myocardial infarction (Non-patent Document 4).

[0005] Tubidecarenone is also called Coenzyme Q ₁₀ (CoQ ₁₀ ) and the like and is used in medicine as a metabolic cardiotonic agent due to its special physiological action. Myocardial protective effect derived from the antioxidant effect of ubidecarenone, prevention of carcinogenesis, anti-aging effect, blood LD L oxidation suppression, suppression of blood pressure rise, improvement of oxygen utilization efficiency in ischemic myocardium, myocardial mitochondria ATP synthesis activation and cardiac function improvement have been reported. The action is taken up by mitochondria in the myocardial cells in the myocardium and acts directly on the ischemic myocardium, improving myocardial energy metabolism in hypoxia and improving oxygen utilization efficiency. It is considered. Furthermore, it has been recognized that the decrease in cardiac function is suppressed in a myocardial infarction model, and the long-term survival rate is improved with respect to the life prognosis after myocardial infarction (Non-patent Document 5).

 [0006] However, in any of the above-described known techniques, adenosine 5'-triphosphate or a physiologically acceptable salt thereof is combined with ubide force renon to prevent and / or improve myocardial ischemia. There is no suggestion or teaching that a synergistic effect is exerted.

 Non-Patent Document 1: F o I i c a .P har mm a c o I .J pn 2004 1 23 23-93

 Non-Patent Document 2: Japanese Pharmaceutical Collection 25th edition, pages 69_70

 Non-Patent Document 3: Basics and Clinical Practice of ATP 1 964 Volume 2 Page 1 37

 Non-Patent Document 4: Chiba Medical Journal 1 985 61 Vol. 3 No. 1 99-209 Non-Patent Document 5: Japanese Pharmaceutical Collection 25th Edition 2357-2358

 Disclosure of the invention

 Problems to be solved by the invention

 [0007] An object of the present invention is to provide a new circulatory organ drug.

Means for solving the problem [0008] As a result of intensive studies to solve the above problems, the present inventors surprisingly use adenosine 5'-triphosphate or a physiologically acceptable salt thereof in combination with ubidecarenone. As a result, it was found that the prophylactic and / or ameliorating action of the myocardial ischemic state was recognized, and that the combined effect was synergistic compared to the case where they were used alone, and the present invention was completed. did.

 That is, the present invention provides a cardiovascular drug comprising adenosine 5′-triphosphate or a physiologically acceptable salt thereof in combination with ubide force renon.

 [0010] The present invention also provides use of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubide force renon for the manufacture of a drug for cardiovascular organs.

 [001 1] The present invention also relates to a method for preventing diseases of the circulatory organ, comprising administering an effective amount of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. / Or provide treatment.

 The invention's effect

 [0012] The cardiovascular drug of the present invention is a highly effective prevention and / or myocardial ischemic state due to a synergistic effect of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubide force Lennon. It has an improving effect and can be suitably used as a circulatory organ drug. In addition, by preventing and / or improving the ischemic state of the myocardium, it is particularly useful as a preventive and / or therapeutic agent for ischemic heart disease, and also for the prevention and / or treatment of diseases selected from the group consisting of angina pectoris and myocardial infarction. Alternatively, it can be suitably used as a therapeutic agent. Furthermore, palpitations and / or shortness of breath that appear as symptoms in the ischemic state of the myocardium can be eliminated based on the prevention and / or improvement action of the ischemic state of the myocardium.

 Brief Description of Drawings

 [0013] [FIG. 1] FIG. 1 is a diagram showing ST segment values in ATP 30 mg / kg, ubidecarenone 1 mg / kg, and a combination administration group thereof.

BEST MODE FOR CARRYING OUT THE INVENTION [0014] The cardiovascular drug of the present invention is a combination of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. That is, the circulatory organ drug of the present invention administers adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone simultaneously or at different times.

 [0015] The cardiovascular drug of the present invention is a combination of a unit dosage form preparation containing adenosine 5'-triphosphate or a physiologically acceptable salt thereof and a unit dosage form preparation containing ubide force renone. Provided as (kit) or as a pharmaceutical composition (combination agent) in unit dosage form containing adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone together . More preferably, it is provided as a pharmaceutical composition comprising adenosine 5′-triphosphate or a physiologically acceptable salt thereof together with ubidecarenone.

 [0016] Adenosine 5'-triphosphate or a physiologically acceptable salt thereof used in the circulatory organ drug of the present invention is a known substance and can be easily obtained by those skilled in the art. The type of physiologically acceptable salt of adenosine 5'-triphosphate is not particularly limited, but examples thereof include alkali metal salts such as sodium salt and force salt; alkalis such as magnesium salt and calcium salt. Examples include earth metal salts. Of these, adenosine 5′-disodium triphosphate is particularly preferred from the viewpoint of preventing and / or improving the ischemic state of the myocardium. Formulations containing adenosine 5'-triphosphate or its physiologically acceptable salts are already marketed as oral dosage forms or injections, and adenosine 5'-triphosphate or physiologically acceptable When the pharmaceutical of the present invention is provided using a preparation containing the salt alone, a commercially available preparation of adenosine 5′-triphosphate or a salt thereof may be used. For example, “Adefos” (Kowa Co., Ltd.) is commercially available.

[0017] The ubide force lenone used in the circulatory organ drug of the present invention is a known substance and can be easily obtained by those skilled in the art. Preparations containing ubide force Lenone have already been marketed as oral dosage forms. When the circulatory organ drug of the present invention is provided using a preparation containing ubide force Lenone alone, Formulation May be used. For example, “Nyquinone Tablets” (Eisai Co., Ltd.) is commercially available.

 [0018] The cardiovascular drug in the present invention is preferably used for preventing and / or improving a state in which the function of the heart is not complete (heart failure). More preferably, it is selected from the group consisting of angina pectoris and myocardial infarction as an agent for preventing and / or treating ischemic heart disease by preventing and / or improving the ischemic state of the myocardium. It is used as a prophylactic and / or therapeutic agent for diseases. The circulatory organ drug of the present invention can also be used for the purpose of eliminating symptoms such as palpitation and / or shortness of breath.

 [0019] The combination ratio (combination ratio) of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone in the cardiovascular drug of the present invention is not particularly limited, and is specifically described in Examples below. Those skilled in the art can appropriately select the test method. In the present invention, from the viewpoint of the synergistic effect of preventing and / or improving the myocardial ischemic state, ubide force Lennon is used with respect to 1 part by mass of adenosine 5′-triphosphate or a physiologically acceptable salt thereof. Is preferably used in the range of 0.0001 to 1000 parts by mass, more preferably in the range of 0.001 to 100 parts by mass, and particularly preferably in the range of 0.01 to 10 parts by mass.

 [0020] In addition to adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone, the cardiovascular drug of the present invention has an effect of preventing and / or improving myocardial ischemia. For the purpose of enhancement, vitamin E or a derivative thereof may be further added. Such vitamin E or its derivatives include succinic acid d_a-tocopherol, succinic acid dI-a-tocopherol, succinic acid dI-a-tocopherol calcium, acetic acid d-a-tocopherol, acetic acid dI-a ― 卜 KOFUE GUJI SOLE, d_HII 卜 KOFUE GUJI ONE OLE, dl _HIICHI In the present invention, d-histcopherol acetate is particularly preferred from the viewpoint of synergistic effect of preventing and / or improving myocardial ischemia.

[0021] Although the combination ratio (combination ratio) of vitamin E or a derivative thereof that can be optionally blended with the cardiovascular drug of the present invention is not limited at all, the ischemic state of the myocardium From the viewpoint of the synergistic effect of the prevention and / or amelioration action of, for example, adenosine 5′-triphosphate or a physiologically acceptable salt thereof, 1 part by mass of vitamin E or its derivative About 1 to 100 parts by mass, preferably about 0.1 1 to 10 parts by mass, particularly preferably about 0.03 to 3 parts by mass.

 [0022] The dosage form of the cardiovascular drug of the present invention may be either oral administration or parenteral administration. An oral dosage form is preferred.

 Also suitable for oral administration is a solid, semi-solid, or adenosine 5'-triphosphate or physiologically acceptable salt thereof and ubide force Lenone in one unit dosage form, or More preferably, it is provided as a liquid pharmaceutical composition.

 [0023] In providing the circulatory organ drug of the present invention as a medicine suitable for oral administration or a medicine suitable for parenteral administration, the dosage form is not particularly limited. For example, solid pharmaceutical compositions such as powders, granules, tablets, wearable tablets, film-coated tablets, dragees, soft capsules, hard capsules; liquid pharmaceutical compositions such as drinks; jelly agents, etc. Any of the semi-solid pharmaceutical compositions may be used. In the present invention, a solid pharmaceutical composition is particularly preferred.

[0024] In providing the medicine for cardiovascular system of the present invention as a pharmaceutical composition comprising adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubide force renone together, the pharmaceutical composition The amount of each component is not particularly limited, and is determined according to the form of the pharmaceutical composition, taking into account the combination ratio as described above as appropriate. For example, when providing as a solid pharmaceutical composition, 10 to 30 O mg of adenosine 5′-triphosphate or a physiologically acceptable salt thereof per unit of pharmaceutical composition, 1 to 10 O mg can be added. In addition, in addition to adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubide force Lennon, vitamin E or its derivative is added, for example, vitamin E or its derivative per dosage unit. About 3 to 300 mg can be blended. [0025] The drug for cardiovascular organs of the present invention includes adenosine 5'-triphosphate or a physiologically acceptable salt thereof, ubidecarenone, and components other than vitamin E or a derivative thereof for the purpose of formulation. It can mix | blend suitably according to it. Examples of such components include vitamins, vitamin-like substances, minerals, caffeine drugs, amino acids, crude drugs, and drugs for liver damage.

 [0026] Vitamins include thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl sulfate ester, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, sicothiamine, bisibutiamine, bisbenchamine, full Thiamine, prosultiamine, benfotiamine, flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, hydroxocobalamin Ascorbic acid, calcium ascorbate, sodium ascorbate, nicotinic acid, nicotinic acid amide, pante , Calcium pantothenate, sodium pantothenate, panthetin, biotin, folic acid, retinoic acetate, retinoic palmitate, vitamin A oil, liver oil, strong liver oil, ergocalciferol, cholecalciferol, etc. It is done.

 [0027] Examples of vitamin-like substances include inositol, inositol hexanicotinate, orotic acid, choline orotate, gamma mono oryzanol, thioctic acid, octanoic acid amide, carnitine chloride, choline bitartrate, rutin and the like. The

[0028] As minerals, calcium citrate, calcium glycephosphate, sodium gluconate, magnesium carbonate, sodium gluconate, calcium carbonate, calcium gluconate, precipitated calcium carbonate, calcium lactate, anhydrous calcium hydrogen phosphate, phosphorus Calcium hydrogen hydride, ammonium iron citrate, ferrous fumarate, iron sulfate, sodium chondroitin sulfate, etc. [0029] Examples of caffeine drugs include caffeine, anhydrous caffeine, sodium caffeine benzoate, aminophylline, diprofylline, proxyphylline and the like.

 [0030] Examples of amino acids include L-aspartic acid, L-aspartic acid potassium,

 L-aspartate sodium, L-aspartate magnesium, salt-cysteine cysteine, L-cysteine, Laminoacetic acid, L-isoleucine, arginine hydrochloride, lysine hydrochloride, L-glutamic acid, L-sodium glutamate, L-threonine, L —Palin, L-histidine hydrochloride, L-leucine, DL-methionine, L-phenylalanine, L-tributophane and the like.

 [0031] Herbal medicines include Akiyo, Azanyak, Ikarisou Extract, Ikarisou Dry Extract, Oren, Kashu, Gajutsu, Shinto, Kanzo, Kikuyo, Kiyoukatsu, Kiyonin, Kokushi, Keihi, Gou, Pepper, Kohaku, and Fifty Frost , Psycho, Psycho, Saffron, Sangaku, Ji, Shakanzo, Peonies, Jiakow, Jinko, Shinju, Senso, Animal Bile (Yutan, Beef Bile Extract), Seiha Hawthorn, Senkiyu, Souju, Daiso, Soya Yellow Roll, Taiji , Agar powder, tenma, touki, carrot, park mondo, hange, hampi, beak cucumber, bukkuriyo, pohfu, homika extract, porei, maou, machinin, ryuuno, lyon, antelope kaku, rojiyo And the like.

 [0032] Drugs for liver damage include ursodesoxycholic acid, dehydrocholic acid, glucuronolactone, glucuconic acid, glucuconic acid amide, glycyrrhizic acid, sodium glycyrrhizinate, diisopropylamine dichloroacetate, Examples include methylmethionine sulfone chloride, liver hydrolyzate, and yolk lecithin.

[0033] The cardiovascular drug of the present invention can be appropriately prepared by a technique commonly used in the art. In this case, if necessary, one or more kinds of additive for pharmaceuticals usually used in the art may be used. Examples of pharmaceutical additives include excipients, binders, disintegrants, lubricants, coloring agents, and corrigents. However, it is not limited to these.

 [0034] Examples of excipients include lactose, starches, crystalline cellulose, sucrose, mannitol, and light anhydrous key acid. Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, alpha starch, polyvinylpyrrolidone, polyvinyl alcohol, or pullulan. Examples of the disintegrant include carmellose, carmello-carcinum, croscarmellose sodium, crospovidone, corn starch, or low-substituted hydroxypropylcellulose. Examples of the lubricant include magnesium stearate and talc. Examples of the colorant include tar pigment and iron sesquioxide. Examples of the corrigent include stevia, aspartame, 1-menthol, d-porneol, and fragrances.

 [0035] The dose of the circulatory organ drug of the present invention is not particularly limited, and can be appropriately selected according to various conditions such as the form of the medicine, the degree of the symptom to be applied, or the age of the patient. In normal cases, adenosine 5'-triphosphate or its salt should be administered to adults at about 3 to 3 OO Omg / day, especially about 10 to 1 OO Omg / day, and about 30 to 30 Omg / day. That's fine. Depending on the dose, the dose of ubide force renon can be determined by the above-mentioned ratio, but the dose of vitamin E or its derivative can be determined. For example, ubidecarenone is about 1 to 10 O Omg / day, especially 3 About 300 mg / day, more preferably about 10 to 10 Omg / day, vitamin E or a derivative thereof about 1 to 100 Omg / day, especially about 3 to 300 mg / day, further 1 About 0 to 10 Omg / day may be administered.

[0036] The method for administering the cardiovascular drug of the present invention is not particularly limited, and adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubide force renone are administered simultaneously or at different times. be able to. When adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubide force lenone are administered at different times, the blood concentration of the active ingredient administered previously exhibits the effect of the present invention. It is desirable to administer the other active ingredient within a time period that does not drop below the concentration. In the present invention As a method for administering a cardiovascular drug in this case, adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubide force lenone are used from the viewpoint of preventing and / or improving myocardial ischemia. It is preferable to administer simultaneously.

[0037] The circulatory organ drug of the present invention has an excellent prevention and / or improvement action against the ischemic state of the myocardium, and is based on the action of preventing and / or improving the ischemic state of the myocardium. In addition, palpitations and / or shortness of breath that appear as symptoms in the ischemic state of the myocardium can be resolved.

 Example

 [0038] The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples.

[0039] Test Example 1 Evaluation test for prevention and / or improvement of myocardial ischemia

 <Test method>

 Myocardial ischemia is reflected in changes in the ST segment or T wave of the electrocardiogram. Intravenous administration of vasopressin to rats has been reported to cause persistent ST segment depression on the electrocardiogram due to myocardial ischemia (S. Satoh, eta I, Life Science 72 (1): 1 03-1 1 2, 2002). ST segment values were calculated according to the test methods described in the literature, and the effect of preventing and / or improving myocardial ischemia was examined based on whether or not the decrease in ST segment values was suppressed by drug administration. .

[0040] The test drug or control drug is orally administered to 7 to 8 male Donryu rats (10 weeks old, Nippon Selichi Co., Ltd.) in each of the test drug administration group and the control drug administration group. 15 minutes later, pentobarbital (50 mg / kg, Nacalai Tesque) Vasopressin under anesthesia ([A rg ⁸ ]-VASO PRES SIN, manufactured by SI GMA) 0.5 IU / ml L / kg administered intravenously did. Two days later, an electrocardiogram was measured under anesthesia with pentobarbital (50 mg / kg), and the ST segment value was calculated. Furthermore, a value obtained by subtracting the average ST segment value of the control drug administration group (0.5% methylcellulose administration group) from the ST segment value of each test drug administration group was evaluated as the “ST segment depression suppression amount”. [0041] As the test drug, adenosine 5'-disodium triphosphate (manufactured by CA LBI OCH EM, hereinafter abbreviated as "ATP" in the examples) 3 Omg / kg, ubidecarenone (Co., Ltd.) 1% / kg, and a combination of ATP 30 mg / kg and ubidecarenone 1 mg / kg (hereinafter abbreviated as “AT P + ubidecarenone” in the Examples), 0.5% The test was suspended or dissolved in methylcellulose. As a control drug, 0.5% methylcellulose (hereinafter abbreviated as “MC” in the examples) was used.

 [0042] <Test results>

 The test results are shown in Table 1 and Fig. 1.

[0043] [Table 1]

 * * P 0. 0 1 vs. 0.5% MC (Tu k e y Ty e multiple comparison)

N = 7 ~ 8

[0044] In comparison with the control drug-administered group administered with 0. 5% MC, almost no suppression of ST segment depression was observed in the ATP single-administration group and the ubide force Lenone single-administration group (ST segment). (34.7 de I ta; UV, 19.6 delta; UV only). In the circulatory organ administration group (ATP + ubidecarenone) of the present invention, significant suppression of ST segment depression was observed (56.5 de I ta V as ST segment depression suppression amount). There was a significant difference in segmental values in comparison with the control drug-administered group that received MC. Therefore, the combination of ATP and ubidecarenone has a synergistic effect on the prevention and / or amelioration of myocardial ischemia. It was concluded that From the above results, the circulatory organ drug of the present invention is effective for the prevention and / or synergistic prevention of myocardial ischemia by the combination of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. It was also found that it has an improving effect.

Production example 1

 Daily dose

Adenosine triphosphate ninatrium 1 20. 0 mg ubide force Lenone 30. 0 mg acetic acid d_one Tokov: L mouth 1 10.0 mg nicotinic acid amide 20. 0 mg riboflavin 6.0 mg

D—Manny I 325. 8 mg Crystalline cellulose 1 44. 0 mg Carmellose calcium 36. 0 mg Hydroxypropyl cellulose 21.0 mg Magnesium sulphate 7.2 mg

 720 g adenosine triphosphate ninatrium, 80 g ubide force Lennon

, Acetic acid d—Hiichi Tokoff: 60 g of L mouthpiece, 20 g of dicotinic acid 1, 20 g of poflavine, D_manni! 1 954.8 g, crystalline cellulose

864 g, Carmello monocalcium 21 6 g, Hydroxypropyl cellulose 1 26 g are put into a high-speed stirring granulator (Bowrec: FM-VG-25 type) and mixed, and then 700 g of ethanol is added and kneaded. Furthermore, crushing and granulation was performed using a granulator (Sekai Okada: N D — 1 OS type). The granulated product was dried using a fluid bed dryer (Freund Sangyo: NF LO-5 type) and then sized using a granulator (Okada Seie: ND-10S type). This granulated product (4276.8 g) and magnesium stearate (43.2 g) were put into a blender (Asahi Kogyo B2 / 09 model), mixed, and then tableted with a 7 mm diameter and 1 Omm radius of curvature. Machine (field iron Where: HT—AP 18 SS type) 1 tablet 1 20 mg tablet was obtained.

Production example 2

 Daily dose

Adenosine triphosphate ninatrium 1 20. 0 mg ubide force renon 30.0 mg wild boar I 45.0 mg nicotinic acid 30.0 mg diprofylline 30. 0 mg caffeine 1 5. 0 mg dehydrocholic acid 30.0 mg nitric acid Thiamine 1 5.0 mg Riboflavin 6.0 mg

D-mannil I 231.2 mg crystalline cellulose 1 56.0 mg carmellose 40.0 mg hydroxypropylcellulose 24.0 mg magnesium sulphate 7.8 ms

 Adenosine triphosphate disodium 720 g, ubide force renon 1 80 g

, Inositol 270 g, Nicotinic acid 1 80 g, Diprofylline 1 8

O g, caffeine 9 O g, dehydrocholic acid 1 80 g, thiamine nitrate 9 O g, riboflavin 36 g, D-mannitol 1 387.2 g, crystalline cellulose 936 g, carmellose 240 g, hydroxypropyl cellulose "I 44 g was put into a high-speed agitation granulator (Bowrec: FM-VG-25 type) and mixed, then 750 g of ethanol was added and kneaded, and further a granulator (Sei Okada: N D_ 1 OS The granulated product was dried using a fluidized bed dryer (Freund Sangyo: NF LO-5 type), and then a granulator (Sekai Okada: ND-10S type). This sized product 4633. 2 g, stearin 46.8 g of magnesium oxide was put into a blender (Asahi Kogyo B2 / 09 type), mixed, and then a tableting machine with a 7mm diameter and 1 Omm radius of curvature (Hatetsu Station: HT-AP 1 tablet with 1 8 SS type 1 30 mg tablets were obtained.

Production Example 3

 Daily dose

Ninatrimu adenosine triphosphate 1 20. Omg ubide force renon 30. Omg aminoethylsulfonic acid 1 50. Omg thiamine hydrochloride 6. Omg ascorbic acid 1 5. Omg rutin 30. Omg methionine 30. Omg

D—Manny I 1 7 1. 2 mg Crystalline cellulose 1 56. Omg Carmellose 40. Omg Hydroxypropylcellulose 24. Omg Magnesium swellate 7.8 ms

Adenosine triphosphate disodium 720 g, ubidecarenone 1 80 g, aminoethylsulfonic acid 900 g, thiamine hydrochloride 36 g, ascorbic acid 90 g, rutin 1 80 g, methionine 1 80 g, D-manni! 2 0 g, crystalline cellulose 936 g, carmellose 240 g, hydroxypropyl cellulose 144 g were put into a high-speed agitation granulator (Bowrec: FM-VG-25 type 25), mixed, and then ethanol 780 g And kneaded and granulated using a granulator (Okada Seie: N D_ 1 OS type). This granulated product was dried using a fluid bed dryer (Freund Sangyo: NF LO-5 type) and then sized using a granulator (Sei Okada: N D_ 1 OS type). Mixer of this sized product 4 633.2 g and magnesium stearate 46.8 g (Asahi Industries : B 2/1 09 model) and after mixing, 1 tablet 1 with a tableting machine (Hatetsu Works: HT--AP 1 8 SS model) with a 7 mm diameter and 10 mm radius of curvature 30 mg tablets were obtained.

Production Example 4

 Daily dose

Adenosine triphosphate Ninatrium 1 20 • 0 mg tubide force Lenon 30 • 0 mg Senso 5 • 0 mg Jacow 1 4 • 0 mg Gour 3 • 0 mg Carrot 25 • 0 mg Anemone powder 6 • 0 mg Shinju 7 • 5 mg Ryuno 2 • Fu mg Animal Bile 8 • 0 mg Sodium Chondroitin Sulfate 200 • 0 mg Erythritol I 8 1 • 8 mg Crystalline Cellulose 225 • 0 mg Croscalme Snatrium 27 • 0 mg Hydroxypropyl Cellulose 36 • 0 mg Stearic Acid Magnesium 9 0 mg

Adenosine triphosphate disodium 600 g, Ubidecarenone 1 50 g, Senso 25 g, Jiakou 70 g, Gor 15 g, Carrot 1 25 g, Anemone powder 30 g, Shinju 37.5 g, Ryuno 13.5 g, Animal bile 40 g, chondroitin sodium sulfate 1 000 g, erythrocytes! 909 g, crystalline cellulose 1 1 25 g, croscarmellose sodium 1 35 g, hydroxypropylcellulose 1 80 g Stirrable granulator (Bowrec: FM-VG-25 type), mix, add 700 g of ethanol, knead, and use granulator (Okada Seie: ND-10S type) And crushed and granulated. This granulated product was dried using a fluid bed dryer (Freund Sangyo: NF LO _5 type) and then sized using a granulator (Okada Seie: ND-10S type). This granulated product 4455 g and magnesium stearate 45 g are put into a mixing machine (Asahi Kogyo B2 / 09 type) and mixed, and then a tableting machine with a 7.5mm diameter and a curvature radius of 14mm is attached. (Hatabe Works: HT-AP 1 8 SS type) 1 tablet 1 50 mg tablet was obtained.

Production Example 5

 Daily dose

Adenosine triphosphate ninatrium 1 20.0 mg ubide force renone 30.0 mg sodium riboflavin phosphate 10.0 mg pyridoxine hydrochloride 50.0 mg calcium pantothenate 20.0 mg sodium glutamate 40.0 mg proxyphylline 50. 0 mg Ursodeoxycholic acid 1 0.0 mg Lactose 1 20.0 mg Crystalline cellulose 90.0 mg Carmellose calcium 30.0 mg Hydroxypropylcellulose 24.0 mg Magnesium stearate 6.0 mg

Adenosine triphosphate disodium 840 g, ubidecarenone 210 g, sodium lipoflavin phosphate 70 g, pyridoxine hydrochloride 350 g, pantothenate calcium 140 g, sodium glutamate 280 g, proxyphyrin 350 g, ursodeoxycoic acid 70 g, lactose 8 4 O g, crystalline cellulose 630 g, carmello monocalcium 210 o g, hydroxypropyl cellulose 1 68 g are put into a high-speed agitation granulator (Baurec: FM-VG-25 type) and mixed, and then 700 g of ethanol is added. In addition, kneading and further granulating using a granulator (Okada Seie: N D — 1 OS type). The granulated product was dried using a fluid bed dryer (Freund Sangyo: NF LO-5 type) and then sized using a granulator (Sei Okada: N D_ 1 OS type). This granulated product (41 58 g) and magnesium stearate (42 g) were put into a blender (Asahi Kogyo: B2 / 09 model) and mixed, and then a tableting machine equipped with a punch with a diameter of 8 mm and a radius of curvature of 14 mm ( 1 tablet of 20 Omg was obtained with Hata Iron Works: HT-AP 1 8 SS type.

Claims

The scope of the claims  [I] Adenosine 5'—a cardiovascular drug comprising a combination of triphosphate or a physiologically acceptable salt thereof and ubide force renon.  [2] The cardiovascular drug according to claim 1, further comprising vitamin E or a derivative thereof.  [3] The circulatory organ drug according to claim 1 or 2, which is a prophylactic and / or therapeutic agent for ischemic heart disease.  [4] The circulatory organ drug according to claim 1 or 2, which is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of angina pectoris and myocardial infarction. [5] The circulatory organ drug according to any one of claims 1 to 4, which resolves palpitation and / or shortness of breath. [6] The present invention is used for prevention and / or amelioration of an ischemic state of the myocardium. The circulatory organ drug according to any of 5 to 5. [7] The cardiovascular drug according to any one of claims 1 to 6, which is for oral administration. [8] Use of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone for the manufacture of a cardiovascular drug. [9] The use according to claim 8, which further uses vitamin E or a derivative thereof.  [10] The use according to claim 8 or 9, wherein the cardiovascular drug is a prophylactic and / or therapeutic agent for ischemic heart disease.  [I I] The use according to claim 8 or 9, wherein the cardiovascular drug is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of angina pectoris and myocardial infarction.  [12] The cardiovascular drug is one that resolves palpitation and / or shortness of breath. ~ 1 Use according to any one of 1. [13] The use according to any one of claims 8 to 12, wherein the cardiovascular drug is used for prevention and / or improvement of an ischemic state of the myocardium. [14] The use according to any one of claims 8 to 13, wherein the cardiovascular drug is for oral administration. [15] A method for preventing and / or treating a cardiovascular disease, comprising administering an effective amount of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubide force lenone.  [16] The prophylactic and / or therapeutic method according to claim 15, further comprising administering an effective amount of vitamin E or a derivative thereof. [17] The prophylactic and / or therapeutic method according to claim 15 or 16, wherein the circulatory organ disease is ischemic heart disease. 18. The prophylactic and / or therapeutic method according to claim 15 or 16, wherein the circulatory organ disease is a disease selected from the group consisting of angina pectoris and myocardial infarction. [19] The prophylaxis and / or treatment method according to claim 15 or 16, wherein the palpitations and / or shortness of breath are resolved. [20] The present invention is used for prevention and / or improvement of an ischemic state of the myocardium. 5. Prevention method and / or treatment method according to 5 or 16. [21] The prophylactic method and / or therapeutic method according to claim 15 or 16, wherein the administration form is oral administration.