JPWO2008050483A1 - Cardiovascular drugs - Google Patents

Abstract

The present invention relates to a cardiovascular drug comprising a combination of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. According to the present invention, a new cardiovascular drug is provided.

Description

  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.

  A normal heart rhythmically repeats contraction and relaxation, and pumps blood continuously throughout the body. This is a result of regularly performing excitation-contraction coupling by intracellular Ca ion inflow / outflow. However, it has been clarified that contraction failure and diastolic failure occur when this excitation-contraction link fails (Non-patent Document 1). Ischemic heart disease is common to two pathologies of diastolic and systolic failure. It is said that it is important to dilate coronary vessels as soon as possible during an ischemic heart disease attack and promote sufficient blood flow improvement. This is because the longer the myocardial ischemia time, the more irreversible the cardiac function and coronary vascular function are. For this purpose, drugs such as nitroglycerin that promote coronary vasodilatation during ischemic attacks have been administered, but these drugs are often ineffective or ineffective, and in such cases Coronary vessel reconstruction (PTCA) and coronary artery bypass surgery (transplantation of peripheral arteries or veins) are also being performed.

  Adenosine 5′-triphosphate (hereinafter sometimes abbreviated as ATP) is a substance widely involved in metabolism of carbohydrates, fats, proteins, etc. as a phosphate donor, and the energy generated by the hydrolysis reaction of ATP is It is a driving force for energy demand reaction in living body.

  Drugs containing ATP are effective for the 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 It has been. 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). In addition, it has been reported that the blood flow in the collateral circulation path of a canine myocardial infarction pathological model in which coronary arteries are ligated 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).

Ubidecarenone is also called coenzyme Q ₁₀ (CoQ ₁₀ ) and the like, and is used in pharmaceuticals as a metabolic cardiotonic agent and the like due to its specific physiological action. Myocardial protective effect derived from the antioxidant effect of ubidecarenone, prevention of carcinogenesis, anti-aging effect, suppression of blood LDL oxidation, suppression of blood pressure increase, improvement of oxygen utilization efficiency in ischemic myocardium, activation of myocardial mitochondrial ATP synthesis, Improvements in cardiac function have been reported. It is thought that the action is taken up by mitochondria in the myocardial cells in the myocardium and directly acts on the ischemic myocardium to improve myocardial energy metabolism in hypoxia and improve oxygen utilization efficiency. Yes. Furthermore, it has been recognized that a decrease in cardiac function is suppressed in a myocardial infarction model, and a long-term survival rate is improved with respect to life prognosis after myocardial infarction (Non-patent Document 5).

However, in any of the above-mentioned known techniques, a synergistic effect on the prevention and / or amelioration of the myocardial ischemic state is achieved by combining adenosine 5′-triphosphate or a physiologically acceptable salt thereof with ubidecarenone. It is not suggested or taught.
Folica. Pharmacol. Jpn 2004, 123, 87-93 Japan Pharmaceutical Collection 25th edition, pages 69-70 ATP Basics and Clinic 1964 Volume 2 Page 137 Chiba Medical Journal, Vol. 61, No. 3, pp. 199-209, 1985 Japanese Pharmaceutical Collection 25th edition 2357-2358

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

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly become prominent by using adenosine 5′-triphosphate or a physiologically acceptable salt thereof together with ubidecarenone. It was found that the action of preventing and / or improving the ischemic state of the myocardium was observed, and the combined effect thereof was synergistic compared to the case where they were used alone, thereby completing the present invention.

  That is, the present invention provides a cardiovascular drug comprising a combination of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone.

  The present invention also provides the use of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone for the manufacture of a cardiovascular drug.

  The present invention also provides a method for preventing and / or treating cardiovascular disease, comprising administering an effective amount of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. It is to provide.

  The cardiovascular drug of the present invention has an extremely excellent myocardial ischemic prevention and / or amelioration action by a synergistic effect of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. And can be suitably used as a circulatory organ drug. Further, by the action of preventing and / or improving the ischemic state of the myocardium, as a preventive and / or therapeutic agent for ischemic heart disease in particular, the prevention and / or treatment of diseases selected from the group consisting of angina pectoris and myocardial infarction. Or it can use suitably 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 action of preventing and / or improving the ischemic state of the myocardium.

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

  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.

  The cardiovascular drug of the present invention is provided as a combination (kit) of a unit dosage form preparation containing adenosine 5′-triphosphate or a physiologically acceptable salt thereof and a unit dosage form preparation containing ubidecarenone. Or provided as a pharmaceutical composition (compound) in unit dosage form comprising 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.

  Adenosine 5'-triphosphate or a physiologically acceptable salt thereof used for the cardiovascular drug of the present invention is a known substance and can be easily obtained by those skilled in the art. The kind of physiologically acceptable salt of adenosine 5′-triphosphate is not particularly limited, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt. It is done. Of these, adenosine 5'-triphosphate disodium is particularly preferable from the viewpoint of preventing and / or improving myocardial ischemia. Preparations containing adenosine 5'-triphosphate or physiologically acceptable salts thereof 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 a 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.

  Ubidecarenone 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. A preparation containing ubidecarenone has already been marketed as an oral dosage form, and when the circulatory organ drug of the present invention is provided using a preparation containing ubidecarenone alone, a commercially available preparation of ubidecarenone may be used. . For example, “Neuquinone Tablet” (Eisai Co., Ltd.) is commercially available.

  The cardiovascular drug in the present invention is preferably used for preventing and / or improving a state in which the heart does not function perfectly (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. Used as a preventive 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.

  The combination ratio (formulation ratio) of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone in the circulatory organ drug of the present invention is not particularly limited, and is specifically shown in Examples below. Those skilled in the art can appropriately select the test method and the like. In the present invention, from the viewpoint of synergistic effect of preventing and / or improving the myocardial ischemic state, ubidecarenone is added to 1 part by mass of adenosine 5′-triphosphate or a physiologically acceptable salt thereof. It is preferable to use 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.

  In addition to adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone, the cardiovascular drug of the present invention has the purpose of preventing and / or improving the myocardial ischemic state. Further, vitamin E or a derivative thereof may be blended. Such vitamin E or derivatives thereof include d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, Examples thereof include d-α-tocopherol and dl-α-tocopherol. In the present invention, d-α-tocopherol acetate is particularly preferred from the viewpoint of synergistic effect of preventing and / or improving myocardial ischemia.

  The combination ratio (mixing ratio) of vitamin E or a derivative thereof that can be optionally blended with the circulatory organ drug of the present invention is not limited at all, but the synergistic effect of preventing and / or improving myocardial ischemia From the viewpoint of, for example, vitamin E or a derivative thereof is about 0.001 to 100 parts by mass, preferably 0.01 to 10 parts per 1 part by mass of adenosine 5′-triphosphate or physiologically acceptable salt thereof. It can be used in the range of about part by mass, particularly preferably about 0.03 to 3 parts by mass.

The administration form of the cardiovascular drug of the present invention may be either oral administration or parenteral administration. An oral dosage form is preferred.
Also, a cardiovascular drug suitable for oral administration is a solid, semi-solid, or liquid form comprising adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone in one unit dosage form. More preferably, it is provided as a pharmaceutical composition.

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

  In providing the cardiovascular drug of the present invention as a pharmaceutical composition comprising adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone together, the amount of each component in the pharmaceutical composition Is not particularly limited, and is determined according to the form of the pharmaceutical composition in consideration of the combination ratio described above as appropriate. For example, when providing as a solid pharmaceutical composition, about 10 to 300 mg of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and about 1 to 100 mg of ubidecarenone are mixed per dosage unit of the pharmaceutical composition. be able to. In addition, in addition to adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone, when vitamin E or a derivative thereof is further blended, for example, vitamin E or a derivative thereof is 3 to 3 per dosage unit. About 300 mg can be blended.

  In the circulatory organ drug of the present invention, adenosine 5′-triphosphate or a physiologically acceptable salt thereof, ubidecarenone, and ingredients other than vitamin E or a derivative thereof are appropriately blended according to the blending purpose. be able to. Examples of such components include vitamins, vitamin-like substances, minerals, caffeine drugs, amino acids, crude drugs, and drugs for liver damage.

  Vitamins include thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl sulfate ester, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisibthiamine, bisbenchamine, fullsultiamine, prosulsulfate. Thiamine, benfotiamine, flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, hydroxocobalamin, mecobalamin, ascorbic acid, calcium ascorbate Sodium ascorbate, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, Sodium Toten acid, pantethine, biotin, folic acid, retinol acetate, retinol palmitate, vitamin A oil, cod liver oil, strong liver oil, ergocalciferol, cholecalciferol, and the like.

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

  Minerals include calcium citrate, calcium glycerophosphate, sodium gluconate, magnesium carbonate, sodium gluconate, calcium carbonate, calcium gluconate, precipitated calcium carbonate, calcium lactate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, iron citrate Examples include ammonium, ferrous fumarate, iron sulfate, sodium chondroitin sulfate, and the like.

  Examples of caffeine drugs include caffeine, anhydrous caffeine, sodium benzoate caffeine, aminophylline, diprofylline, proxyphylline and the like.

  As amino acids, L-aspartic acid, potassium L-aspartate, sodium L-aspartate, magnesium L-aspartate, cysteine cysteine hydrochloride, L-cysteine, aminoacetic acid, L-isoleucine, arginine hydrochloride, lysine hydrochloride, L -Glutamic acid, sodium L-glutamate, L-threonine, L-valine, L-histidine hydrochloride, L-leucine, DL-methionine, L-phenylalanine, L-tryptophan and the like.

  Herbal medicines include Achillea, Acacia yak, Ikarisou extract, Ikarisou dried extract, Auren, Kashu, Gakutsu, Kamisu, Kanzo, Kyoko, Kyokatsu, Kyonin, Kokushi, Keihi, Gooh, Pepper, Kohaku, End of frost, Psycho, Psycho, Saffron, Sanyaku, Giant, Shakaku, Peonies, Musk, Jinko, Shinju, Senso, Animal gall ingredients (Yutan, Beef bile extract), Hawthorn, Senkyu, Suzutsu, Daiou, Soybean yellow roll, Taiso, Clove, Agaric powder, Tenma, Toki, Carrot, Bakumondo, Hange, Hampi, Sandalwood, Bukuryu, Bowfu, Homika extract, Boray, Maoh, Machinin, Ryuno, Lyon, Anemone, and Rokujo.

  Drugs for liver damage include ursodeoxycholic acid, dehydrocholic acid, glucuronolactone, glucuronic acid, glucuronic acid amide, glycyrrhizic acid, sodium glycyrrhizinate, dichloroacetic acid diisopropylamine, methylmethionine sulfonium chloride, liver hydrolyzate, York lecithin and the like.

  The cardiovascular drug of the present invention can be appropriately prepared by a technique commonly used in the art. In this case, you may use 1 type (s) or 2 or more types of the additives for a formulation normally used in this industry as needed. Examples of the additive for formulation include, but are not limited to, excipients, binders, disintegrants, lubricants, coloring agents, and corrigents.

  Examples of the excipient include lactose, starches, crystalline cellulose, sucrose, mannitol, and light anhydrous silicic acid. Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, or pullulan. Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, crospovidone, corn starch, and low-substituted hydroxypropylcellulose. Examples of the lubricant include magnesium stearate or talc. Examples of the colorant include tar pigments and iron sesquioxide. Examples of the corrigent include stevia, aspartame, l-menthol, d-borneol, and fragrance.

  The dosage 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 pharmaceutical form, the degree of symptoms to be applied, or the age of the patient. Usually, adenosine 5'-triphosphate or a salt thereof may be administered to an adult at about 3 to 3000 mg / day, particularly about 10 to 1000 mg / day, and further about 30 to 300 mg / day. Depending on the dose, the dose of ubidecarenone and the dose of vitamin E or a derivative thereof can be determined according to the above-mentioned ratio. For example, ubidecarenone is about 1 to 1000 mg / day, particularly about 3 to 300 mg / day, About 10 to 100 mg / day may be administered, and vitamin E or a derivative thereof is about 1 to 1000 mg / day, particularly about 3 to 300 mg / day, and further about 10 to 100 mg / day may be administered.

  The administration method for the cardiovascular drug of the present invention is not particularly limited, and adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone can be administered simultaneously or at different times. When adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone are administered at different times, the blood concentration of the previously administered active ingredient is lower than the concentration at which the effect of the present invention is exerted. It is desirable to administer the other active ingredient within a time period that does not decrease to the minimum. As a method for administering the cardiovascular drug in the present invention, adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone are used from the viewpoint of preventing and / or improving the ischemic state of the myocardium. It is preferable to administer simultaneously.

  The circulatory organ drug of the present invention has an excellent preventive and / or ameliorating action on the ischemic state of the myocardium. Palpitations and / or shortness of breath that appear as symptoms in the blood state can be resolved.

  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.

Test Example 1 Evaluation Test for Prevention and / or Improvement of Myocardial Ischemia <Test Method>
The ischemic state of the myocardium 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 sustained ST segment depression on the electrocardiogram due to myocardial ischemia (S. Satoh, et al, Life Science 72 (1): 103-112, 2002). The ST segment value was calculated according to the test method described in this document, and the effect of preventing and / or improving myocardial ischemia was examined depending on whether or not the decrease in ST segment value was suppressed by drug administration.

The test drug or control drug was orally administered to 7 to 8 male Donryu rats (10 weeks old, Nippon SLC Co., Ltd.) for each test drug administration group and control drug administration group. Under anesthesia with barbital (50 mg / kg, Nacalai Tesque), vasopressin ([Arg ⁸ ] -VASOPRESSIN, manufactured by SIGMA) 0.5 IU / mL / kg was intravenously administered. Two days later, an electrocardiogram was measured under anesthesia with pentobarbital (50 mg / kg), and an ST segment value was calculated. Furthermore, the value obtained by subtracting the average value of the ST segment values 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 drop suppression amount”.

  As test drugs, adenosine 5′-triphosphate disodium (CALBIOCHEM, hereinafter abbreviated as “ATP” in the Examples) 30 mg / kg, ubidecarenone (manufactured by Kaneka Corporation) 1 mg / kg, and A combination of 30 mg / kg of ATP and 1 mg / kg of ubidecarenone (hereinafter abbreviated as “ATP + ubidecalenone” in the Examples) was used, and these were suspended or dissolved in 0.5% methylcellulose and used for the test. As a control drug, 0.5% methylcellulose (hereinafter abbreviated as “MC” in the Examples) was used.

<Test results>
The test results are shown in Table 1 and FIG.

  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 ubidecarenone single-administration group. 0.7 delta μV, only 19.6 delta μV). However, in the administration group (ATP + ubidecalenone) of the cardiovascular drug of the present invention, significant suppression of ST segment depression was observed (55.6 delta μV as the ST segment depression suppression amount), and MC was administered at the ST segment value. A significant difference was observed in comparison with the control drug administration group. From this, it was concluded that the combination of ATP and ubidecarenone has a synergistic effect on the prevention and / or improvement of the myocardial ischemia. From the above results, the circulatory organ drug of the present invention can prevent and / or improve synergistic myocardial ischemia by the combined use of adenosine 5′-triphosphate or a physiologically acceptable salt thereof and ubidecarenone. It became clear that it had an effect | action.

Production Example 1
Daily dose of adenosine triphosphate disodium 120.0mg
Ubidecarenone 30.0mg
D-α-Tocopherol acetate 10.0 mg
Nicotinamide 20.0mg
Riboflavin 6.0mg
D-mannitol 325.8 mg
Crystalline cellulose 144.0mg
Carmellose calcium 36.0mg
Hydroxypropylcellulose 21.0mg
Magnesium stearate 7.2mg
Total 720.0mg

  Adenosine triphosphate disodium 720 g, ubidecarenone 180 g, acetic acid d-α-tocopherol 60 g, nicotinamide 120 g, riboflavin 36 g, D-mannitol 1954.8 g, crystalline cellulose 864 g, carmellose calcium 216 g, hydroxypropyl cellulose 126 g After putting into a granulator (Paurec: FM-VG-25 type) and mixing, 700 g of ethanol was added and kneaded, and further granulated using a granulator (Okada Seiko: ND-10S type). The granulated product was dried using a fluid bed dryer (Freund Sangyo: NFLO-5 type) and then sized using a granulator (Okada Seiko: ND-10S type). This sized powder 4276.8 g and magnesium stearate 43.2 g were put into a mixer (Asahi Kogyo Co., Ltd .: B2 / 109 type) and mixed, and then a tableting machine equipped with a punch having a diameter of 7 mm and a radius of curvature of 10 mm (Hatateko) Place: HT-AP18SS type), 1 tablet of 120 mg was obtained.

Production Example 2
Daily dose of adenosine triphosphate disodium 120.0mg
Ubidecarenone 30.0mg
Inositol 45.0mg
Nicotinic acid 30.0mg
Diprofylline 30.0mg
Caffeine 15.0mg
Dehydrocholic acid 30.0mg
Thiamine nitrate 15.0mg
Riboflavin 6.0mg
D-mannitol 231.2mg
Crystalline cellulose 156.0mg
Carmellose 40.0mg
Hydroxypropylcellulose 24.0mg
Magnesium stearate 7.8mg
Total 780.0mg

  Adenosine triphosphate disodium 720 g, ubidecarenone 180 g, inositol 270 g, nicotinic acid 180 g, diprofylline 180 g, caffeine 90 g, dehydrocholic acid 180 g, thiamine nitrate 90 g, riboflavin 36 g, D-mannitol 1387.2 g, crystalline cellulose 936 g, carmellose 936 g Then, 144 g of hydroxypropylcellulose was put into a high-speed agitation granulator (Paurek: FM-VG-25 type), mixed, kneaded with 750 g of ethanol, and further granulated (Okada Seiko: ND-10S type). Was crushed and granulated. The granulated product was dried using a fluid bed dryer (Freund Sangyo: NFLO-5 type) and then sized using a granulator (Okada Seiko: ND-10S type). This sized product 4633.2 g and magnesium stearate 46.8 g were put into a mixer (Asahi Kogyo Co., Ltd .: B2 / 109 type) and mixed, and then a tableting machine (Hatetsu Kokko Co., Ltd.) equipped with a 7 mm diameter and 10 mm curvature radius Place: HT-AP18SS type), 1 tablet of 130 mg was obtained.

Production Example 3
Daily dose of adenosine triphosphate disodium 120.0mg
Ubidecarenone 30.0mg
Aminoethylsulfonic acid 150.0mg
Thiamine hydrochloride 6.0mg
Ascorbic acid 15.0mg
Rutin 30.0mg
Methionine 30.0mg
D-mannitol 171.2mg
Crystalline cellulose 156.0mg
Carmellose 40.0mg
Hydroxypropylcellulose 24.0mg
Magnesium stearate 7.8mg
Total 780.0mg

  Adenosine triphosphate disodium 720 g, ubidecarenone 180 g, aminoethylsulfonic acid 900 g, thiamine hydrochloride 36 g, ascorbic acid 90 g, rutin 180 g, methionine 180 g, D-mannitol 1027.2 g, crystalline cellulose 936 g, carmellose 240 g, hydroxypropyl cellulose 144 g Add to 780 g of ethanol and knead after mixing with high-speed agitation granulator (Paurek: FM-VG-25 type), and knead and granulate using a granulator (Okada Seiko: ND-10S type). did. The granulated product was dried using a fluid bed dryer (Freund Sangyo: NFLO-5 type) and then sized using a granulator (Okada Seiko: ND-10S type). This sized product 4633.2 g and magnesium stearate 46.8 g were put into a mixer (Asahi Kogyo Co., Ltd .: B2 / 109 type) and mixed, and then a tableting machine (Hatetsu Kokko Co., Ltd.) equipped with a 7 mm diameter and 10 mm curvature radius Place: HT-AP18SS type), 1 tablet of 130 mg was obtained.

Production Example 4
Daily dose of adenosine triphosphate disodium 120.0mg
Ubidecarenone 30.0mg
Senso 5.0mg
Musk 14.0mg
Goo 3.0mg
Carrot 25.0mg
Anemone powder 6.0mg
Shinju 7.5mg
Ryunow 2.7mg
Animal bile 8.0mg
Chondroitin sodium sulfate 200.0mg
Erythritol 181.8mg
Crystalline cellulose 225.0mg
Croscarmellose sodium 27.0mg
Hydroxypropylcellulose 36.0mg
Magnesium stearate 9.0mg
Total 900.0mg

  Adenosine triphosphate disodium 600 g, ubidecalenone 150 g, senso 25 g, musk 70 g, carrot 15 g, carrot 125 g, antelope powder 30 g, Shinju 37.5 g, rhododendron 13.5 g, animal bile 40 g, chondroitin sulfate 1000 g, erythritol 909 g 1125 g of cellulose, 135 g of croscarmellose sodium, and 180 g of hydroxypropyl cellulose were put into a high-speed stirring granulator (Paurek: FM-VG-25 type), mixed, kneaded with 700 g of ethanol, and further granulated ( Okada Seiko: ND-10S type). The granulated product was dried using a fluid bed dryer (Freund Sangyo: NFLO-5 type) and then sized using a granulator (Okada Seiko: ND-10S type). This granulated product 4455g and magnesium stearate 45g were put into a blender (Asahi Kogyo Co., Ltd .: B2 / 109 type) and mixed, and then a tableting machine (Yata Iron Works: fitted with a punch with a diameter of 7.5 mm and a curvature radius of 14 mm) HT-AP18SS type), 1 tablet of 150 mg was obtained.

Production Example 5
Daily dose of adenosine triphosphate disodium 120.0mg
Ubidecarenone 30.0mg
Riboflavin sodium phosphate 10.0mg
Pyridoxine hydrochloride 50.0mg
Calcium pantothenate 20.0mg
Sodium glutamate 40.0mg
Proxyphyrin 50.0mg
Ursodeoxycholic acid 10.0mg
Lactose 120.0mg
Crystalline cellulose 90.0mg
Carmellose calcium 30.0mg
Hydroxypropylcellulose 24.0mg
Magnesium stearate 6.0mg
Total 600.0mg

  Adenosine triphosphate disodium 840 g, ubidecalenone 210 g, riboflavin sodium phosphate 70 g, pyridoxine hydrochloride 350 g, pantothenate calcium 140 g, sodium glutamate 280 g, proxyphylline 350 g, ursodeoxycholic acid 70 g, lactose 840 g, crystalline cellulose 630 g, carmellose calcium 210 g and 168 g of hydroxypropylcellulose were put into a high-speed agitation granulator (Paurek: FM-VG-25 type), mixed, kneaded with 700 g of ethanol, and further granulated (Okada Seiko: ND-10S type). ) For pulverization and granulation. The granulated product was dried using a fluid bed dryer (Freund Sangyo: NFLO-5 type) and then sized using a granulator (Okada Seiko: ND-10S type). 4158 g of this sized product and 42 g of magnesium stearate were introduced into a blender (Asahi Kogyo: B2 / 109 type) and mixed, and then a tableting machine equipped with a punch having a diameter of 8 mm and a radius of curvature of 14 mm (Hatetsu Works: HT- AP18SS type), 1 tablet 200 mg was obtained.

Claims (21)

  A circulatory organ drug comprising adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone.   Furthermore, the medicine for circulatory organs of Claim 1 formed by combining vitamin E or its derivative (s).   The circulatory organ drug according to claim 1 or 2, which is a prophylactic and / or therapeutic agent for ischemic heart disease.   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.   The circulatory organ drug according to any one of claims 1 to 4, which eliminates palpitation and / or shortness of breath.   The circulatory organ drug according to any one of claims 1 to 5, which is used for prevention and / or improvement of an ischemic state of the myocardium.   The circulatory organ drug according to any one of claims 1 to 6, which is for oral administration.   Use of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone for the manufacture of a cardiovascular drug.   The use according to claim 8, which further uses vitamin E or a derivative thereof.   The use according to claim 8 or 9, wherein the cardiovascular drug is a prophylactic and / or therapeutic agent for ischemic heart disease.   The use according to claim 8 or 9, wherein the cardiovascular drug is a preventive and / or therapeutic agent for a disease selected from the group consisting of angina pectoris and myocardial infarction.   The use according to any one of claims 8 to 11, wherein the circulatory organ drug resolves palpitations and / or shortness of breath.   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.   The use according to any one of claims 8 to 13, wherein the cardiovascular drug is for oral administration.   A method for preventing and / or treating a circulatory organ disease, comprising administering an effective amount of adenosine 5'-triphosphate or a physiologically acceptable salt thereof and ubidecarenone.   The method according to claim 15, further comprising administering an effective amount of vitamin E or a derivative thereof.   The prophylactic and / or therapeutic method according to claim 15 or 16, wherein the circulatory organ disease is ischemic heart disease.   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.   The prophylaxis and / or treatment method according to claim 15 or 16, which eliminates palpitation and / or shortness of breath.   The prevention method and / or treatment method according to claim 15 or 16, which is used for prevention and / or improvement of an ischemic state of the myocardium.   The prophylactic method and / or therapeutic method according to claim 15 or 16, wherein the administration form is oral administration.

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