Vasodilator composition, vasodilator composition kit, pharmaceutical composition for diseases caused by vascular stenosis or obstructive disorder, and pharmaceutical composition kit for diseases caused by vascular stenosis or obstructive disorder

Abstract

Provided is a vasodilator composition that enables adjustment of the dose of NO.　The composition according to the present invention contains microbubbles wherein the microbubbles contain nitrogen monoxide as a gas component.

Description

[Technical Field]

[0001] The present invention relates to a vasodilator composition, a vasodilator composition kit, a pharmaceutical composition for treating diseases caused by vascular stenosis or occlusive disorders, and a pharmaceutical composition kit for treating diseases caused by vascular stenosis or occlusive disorders. [Background technology]

[0002] Nitric oxide (NO), a gas, is commonly used as a medicine. Specifically, patients with pulmonary hypertension or other conditions are inhaled to induce pulmonary vasodilation by taking NO from the lungs into the blood vessels, thereby treating the condition (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Air Water Inc., Mallinckrodt Manufacturing LLC, and Sumitomo Seika Chemicals Co., Ltd., "Pulmonary Vasodilator (Inhalation Gas) iFlo (Registered Trademark) Inhalation 800 ppm," October 2017 Summary of the Invention [Problem to be solved by the invention]

[0004] However, NO reacts easily with oxygen, and when it does, it is converted into nitrogen dioxide (NO2). Furthermore, NO2 is known to be the most toxic of all nitrogen oxides, causing damage to the respiratory system, including the lungs. Therefore, if the NO concentration is increased during inhalation in an attempt to increase the concentration of NO administered to a patient, high concentrations of NO2 are generated during inhalation, potentially causing respiratory damage. Therefore, controlling the dosage of NO presents a problem.

[0005] Therefore, an object of the present invention is to provide a vasodilator composition that allows the dosage of NO to be adjusted. [Means for solving the problem]

[0006] In order to achieve the above object, the vasodilator composition of the present invention (hereinafter also referred to as "composition") contains microbubbles, The microbubbles contain nitric oxide as a gas component.

[0007] The vasodilator composition kit of the present invention (hereinafter also referred to as "composition kit") contains a vasodilator composition and other ingredients, The vasodilator composition and the other components are arranged separately, The vasodilator composition is the vasodilator composition of the present invention.

[0008] The pharmaceutical composition (hereinafter also referred to as "pharmaceutical composition") of the present invention for diseases caused by vascular stenosis or occlusive disorders (hereinafter also referred to as "vasostenosis") contains the vasodilator composition of the present invention.

[0009] The pharmaceutical kit of the present invention for diseases caused by vascular stenosis or occlusive disorder (hereinafter also referred to as "pharmaceutical kit") includes the vasodilator composition kit of the present invention. [Effects of the Invention]

[0010] According to the present invention, the dose of NO can be adjusted. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a cross-sectional view showing an example of a multi-chamber container containing the composition of the present invention and other components. [Figure 2] FIG. 2 is a schematic diagram showing a microbubble production device in Example 1. [Figure 3A] FIG. 3A is a graph showing the relative intracellular Ca 2+ concentration in Example 1. [Figure 3B] FIG. 3B is a graph showing the relative intracellular Ca 2+ concentration in Example 1. [Figure 3C] FIG. 3C is a graph showing the relative intracellular Ca 2+ concentration in Example 1. [Figure 3D] FIG. 3D is a graph showing the relative intracellular Ca 2+ concentration in Example 1. [Figure 4] FIG. 4 is a graph showing the change in blood pressure over time in Example 2. [Figure 5] FIG. 5 is a graph showing an electrocardiogram in Example 3. [Figure 6] FIG. 6 is a graph showing the results of blood pressure and electrocardiogram in Example 3. [Figure 7] FIG. 7 is a graph showing coronary artery perfusion in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0012] <Vasodilator composition> The vasodilator composition of the present invention contains microbubbles, and the microbubbles contain nitric oxide as a gas component. The composition of the present invention is characterized by containing the microbubbles, and other configurations and conditions are not particularly limited. Since the composition of the present invention contains NO as microbubbles, it can be directly administered to the body of a recipient, for example, by intravenous administration. Therefore, the composition of the present invention can increase or decrease the dose to the recipient by increasing or decreasing the amount of the composition administered to the recipient. Therefore, the composition of the present invention can adjust the dose of NO, and, for example, it can also adjust the degree of vasodilation. Furthermore, since the composition of the present invention can be directly administered to the body of a recipient, it can be administered locally, for example, as by inhalation, or systemically.

[0013] In the present invention, "vasodilation" refers to the expansion of the inner diameter of a blood vessel caused by the relaxation of vascular endothelial cells. The blood vessel may be, for example, either an artery or a vein, but is preferably an artery. The "vasodilation" may be evaluated directly, for example, by measuring the inner diameter of the blood vessel, or indirectly by measuring another indicator. The direct evaluation can be performed, for example, by measuring the inner diameter of the subject's blood vessel using an ultrasound diagnostic device. Examples of the subject's blood vessel include blood vessels surrounding the administration site of the composition of the present invention, coronary arteries of the heart, and pulmonary arteries. It is also known that vasodilation in a subject decreases blood pressure. Therefore, the indirect evaluation can be performed, for example, by measuring the blood pressure of the subject using blood pressure as the other indicator. The blood pressure is, for example, mean blood pressure. In the present invention, vasodilation can be evaluated, for example, when the inner diameter of the blood vessel of a subject administered with the composition of the present invention is significantly expanded compared to the inner diameter of a subject not administered with the composition of the present invention or to a subject administered with a composition having the same composition except that the microbubbles do not contain NO.

[0014] In the present invention, "microbubbles" refers to a closed, minute space made of gas surrounded by something other than gas, and can also be referred to as, for example, fine bubbles. Examples of the microbubbles include fine bubbles. The fine bubbles generally refer to microbubbles having a diameter of less than 100 μm. The bubble diameter refers to the equivalent sphere diameter of the bubbles. The bubble diameter may be the average diameter (arithmetic mean diameter) of microbubbles obtained by the measurement method described below. The fine bubbles (FB) may be microbubbles or ultrafine bubbles (UFB). The microbubbles generally refer to microbubbles having a diameter of 1 μm or more and less than 100 μm. The ultrafine bubbles generally refer to microbubbles having a diameter of less than 1 μm.

[0015] The microbubbles are dispersed in a medium. The microbubbles are dispersed throughout or partially within the medium. In the latter case, the microbubbles can be said to be localized in a portion of the medium. The medium can be, for example, a liquid or a solid. The liquid can be, for example, an aqueous solvent containing water, an oily solvent, or a mixture thereof. The liquid can also include a sol. The solid can be, for example, a solidified version of the liquid. The solid can also include a gel. The liquid can be, for example, physiological saline; a buffer solution such as a phosphate buffer; an infusion solution such as an extracellular fluid or an intracellular fluid; water such as distilled water or pure water; a cell culture medium such as DMEM or RPMI1640; an organ preservation solution; or the like. The solid can be, for example, a solidified version of the liquid.

[0016] The microbubbles may contain only NO as a gas (gas component), or may contain other gases. The NO can be, for example, the active ingredient in the microbubbles. Examples of the other gases include biological gases such as carbon monoxide (CO), hydrogen sulfide (HS), and hydrogen (H); rare gases such as helium (He), argon (Ar), krypton (Kr), and xenon (Xe); carbon dioxide (CO), nitrous oxide (NO), carbon dioxide (CO), nitrogen (N), methane (CH), ethane (CHCH), propane (CHCHCH), fluoromethane (CHF), difluoromethane (CHF), carbon tetrafluoride (CF), ethylene oxide (CHO), and air. In the present invention, "biogas" refers to a gas containing carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (HS), or hydrogen (H), or a mixed gas containing two or more of these. In the presence of oxygen or ozone, nitric oxide reacts with the oxygen or ozone to form nitrogen dioxide (NO). Nitrogen dioxide is known to be toxic. Therefore, it is preferable that the microbubbles are substantially free of oxygen or ozone. "Substantially free" means, for example, that the concentration of oxygen or ozone in the sample is below the detection limit of a gas chromatograph. When the microbubbles contain two or more gas components, it is preferable that the gas components other than NO are gas components that do not react with NO, such as the rare gases or nitrogen. The microbubbles do not, for example, consist of only air. In the present invention, the "air" refers, for example, to the air (atmosphere) used in producing the microbubbles. When the gas in the microbubbles is a medical gas grade gas, it is preferably a gas derived from a medical gas.

[0017] The density of the microbubbles means the number of microbubbles relative to the volume of the medium. The "density" can also be referred to as the number concentration. The lower limit of the density of the microbubbles is, for example, 5×10 5 pieces / ml, 1×10 6 pieces / ml, 5×10 6 pieces / ml, 1×10 7 pieces / ml, 5×107 pieces / ml, 1×10 8 pieces / ml, 5×10 8 pieces / ml, 1×10 9 cells / ml, preferably 1 x 10 6 pieces / ml, 5×10 6 pieces / ml, 1×10 7 pieces / ml, 5×10 7 pieces / ml, 1×10 8 pieces / ml, 5×10 8 The upper limit of the density of the microbubbles is, for example, 1.5 × 10 9 pieces / ml, 2×10 9 pieces / ml, 3×10 9 pieces / ml, 5×10 9 pieces / ml, 7×10 9 pieces / ml, 9×10 9 pieces / ml, 1×10 10 pieces / ml, 5×10 10 pieces / ml, 1×10 11 pieces / ml, 5×10 11 pieces / ml, 1×10 12 pieces / ml, 5×10 12 The density range of the microbubbles is, for example, 5×10 5 pieces / ml~5×10 12 pieces / ml, 5×10 5 pieces / ml~1×10 12 pieces / ml, 5×10 5 pieces / ml~5×10 11 pieces / ml, 5×10 5 pieces / ml~1×10 11 pieces / ml, 5×10 5 pieces / ml~5×10 10 pieces / ml, 5×10 5 pieces / ml~1×10 10 pieces / ml, 1×10 6 pieces / ml~9×10 9 pieces / ml, 5×10 6 pieces / ml~9×10 9 pieces / ml, 1×10 7 pieces / ml~7×10 9 pieces / ml, 5×10 7 pieces / ml~7×10 9 pieces / ml, 1×10 8 pieces / ml~5×109 pieces / ml, 5×10 8 pieces / ml~5×10 9 pieces / ml, 1×10 9 pieces / ml~3×10 9 pieces / ml, 5×10 8 pieces / ml~2×10 9 pieces / ml, 5×10 8 pieces / ml~1.5×10 9 pieces / ml.

[0018] The density, bubble diameter, and average diameter (hereinafter also referred to as "characteristics") of the microbubbles can be measured appropriately depending on the medium in which the microbubbles are dispersed. When the microbubbles are dispersed in a liquid medium, the microbubble characteristics can be calculated by analyzing the bubbles in the composition of the present invention using particle trajectory analysis. The particle trajectory analysis can be performed, for example, using a NanoSight (registered trademark) NS300 (manufactured by Malvern Instrument) in accordance with Example 1 described below. The microbubble characteristics may also be calculated using an analysis method other than particle trajectory analysis. In this case, the microbubble characteristics obtained by the other analysis method satisfy the above-mentioned examples when converted to the calculated values ​​obtained by the particle trajectory analysis. When the microbubbles are dispersed in a solid medium, the microbubble characteristics can be calculated based on the characteristics of the microbubbles in the liquid before solidification of the medium and the characteristics of the microbubbles in the liquid obtained by dissolving the solid medium.

[0019] The proportion of NO in the gas is, for example, more than 0% and 100% or less, 10 to 100%, 20 to 100%, 30 to 100%, 40 to 100%, 50 to 100%, 60 to 100%, 70 to 100%, 80 to 100%, 90 to 100%, 95 to 100%, 96 to 100%, 97 to 100%, 98 to 100%, 99 to 100%, and preferably 90 to 100%.

[0020] The composition of the present invention can be produced, for example, by a method for producing microbubbles such as fine bubbles using any gas. Therefore, the method for producing the composition of the present invention includes, for example, a bubble production step in which microbubbles are produced using a gas containing NO and a medium. Specifically, when the composition of the present invention is a liquid, the liquid composition can be produced using, for example, a gas containing NO, the medium, and a microbubble production device using a swirl flow method, an ejector method, a Venturi method, a static mixer method, a micropore method, a pressure dissolution method, or an ultrasonic cavitation method. Furthermore, when the composition of the present invention is a solid, the solid composition can be produced by solidifying the liquid composition using a known method. When the solid is a gel, the gel composition can be produced, for example, by mixing the liquid composition with a gelling agent. At the start of the bubble production step, the NO-containing gas is in a gaseous, liquid, or solid state. The NO-containing gas may contain multiple types of gases. In this case, each gas may be supplied separately to the bubble-producing process, or all or part of the NO-containing gas may be supplied simultaneously to the bubble-producing process. As a specific example, when the gases are NO and CO, NO and CO may be introduced simultaneously or separately.

[0021] The composition of the present invention may be, for example, in vivo You can also use in In vitro The composition of the present invention can be used, for example, as a research reagent or as a pharmaceutical. In the latter case, the composition of the present invention can also be referred to as a pharmaceutical or pharmaceutical composition for diseases caused by vasoconstriction.

[0022] There are no particular limitations on the subjects to which the composition of the present invention is administered. in vivo When the composition of the present invention is used in a pharmaceutical composition for a human being, the subject of administration can be, for example, a human or a non-human animal other than a human. Examples of the non-human animal include mammals such as mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys, and guinea pigs, as well as birds and fish. in In vitro When used in the above, the administration target can be, for example, a cell, a tissue, an organ, etc., and examples of the cells can be, for example, a cell collected from a living body, a cultured cell, etc., and examples of the tissue or organ can be, for example, a tissue (biological tissue) or an organ collected from a living body, etc. Examples of the cells can be, for example, a vascular endothelial cell, a vascular smooth muscle cell, etc.

[0023] The conditions for use (administration conditions) of the composition of the present invention are not particularly limited, and the administration form, administration time, dosage, etc. can be appropriately determined depending on the type of subject to be administered, etc.

[0024] The dosage of the composition of the present invention is not particularly limited. in vivo When used in the above range, the density of the microbubbles can be appropriately determined depending on, for example, the type, symptoms, age, and administration method of the subject. 8 pieces / ml~5×10 12 When a composition of the present invention is administered to a human at a dose of 1 / ml, the total daily dose of NO is, for example, 0.1 to 10 ml / kg body weight. The composition of the present invention is administered, for example, 1 to 5 times, 1 to 3 times, or preferably once per day. When administered intravenously to an adult human, the daily dose of NO is, for example, 2.5 mg, and the daily dose is, for example, once per day. The content of the compound in the composition is not particularly limited and can be appropriately determined, for example, depending on the daily dose described above. The composition of the present invention may be administered, for example, continuously or discontinuously. The discontinuous administration can also be referred to as intermittent administration. The composition of the present invention may be administered, for example, at predetermined intervals. The predetermined intervals may be approximately equal or equal, or may be unequal. The predetermined intervals may be, for example, every 8 to 12 hours or every day.

[0025] The administration form of the composition of the present invention is not particularly limited. in vivoWhen the compound is administered intravenously, it may be administered orally or parenterally. Examples of parenteral administration include intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, nasal administration, pulmonary administration, intraperitoneal administration, and topical administration.

[0026] The dosage form of the composition of the present invention is not particularly limited and can be appropriately determined depending on, for example, the administration form. Examples of the dosage form include liquid and solid forms. Specific examples of the dosage form include oral preparations such as modified-release preparations (enteric preparations, sustained-release preparations, etc.), capsules, oral liquids (elixirs, suspensions, emulsions, perfumes, lemonades, etc.), syrups (syrup preparations, etc.), granules (effervescent granules, fine granules, etc.), powders, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving agents, coated tablets, etc.), pills, and oral jellies; oral preparations such as oral tablets (gums, sublingual tablets, troches, drops, buccal tablets, adhesive tablets, etc.), oral sprays, oral semisolid preparations, and mouthwashes; injections (implanted injections, sustained-release injections, infusions (infusion preparations, etc.), freeze-dried injections, powder injections, pre-filled syringes, nasal preparations such as nasal drops (nasal liquid preparations, nasal powder preparations, etc.); rectal preparations such as suppositories, rectal semisolid preparations, and enemas; vaginal preparations such as vaginal suppositories and vaginal tablets; skin preparations such as topical liquid preparations (spirits, liniments, lotions, etc.), creams, gels, topical solid preparations (topical powder preparations, etc.), sprays (topical aerosols, pump sprays, etc.), patches (tapes, poultices, etc.), and ointments. When the composition of the present invention is administered orally, the dosage form may be, for example, a tablet, a coated tablet, a pill, fine granules, granules, powder, capsule, liquid, syrup, emulsion, suspension, etc. When the composition of the present invention is administered parenterally, the dosage form may be, for example, an injection preparation, an intravenous drip preparation, etc. When the composition of the present invention is administered transdermally, the dosage form may be, for example, a patch, an ointment, an ointment, a cream, a lotion, or other topical agent.

[0027] The composition of the present invention may contain, for example, additives as needed. When the composition of the present invention is used as a medicine or pharmaceutical composition, the additive preferably comprises a pharmaceutically acceptable additive or a pharmaceutically acceptable carrier. The additive is not particularly limited, and examples thereof include osmotic pressure regulators such as salts, base materials, excipients, colorants, lubricants, binders, disintegrants, stabilizers, coating agents, preservatives, pH adjusters, flavoring agents such as fragrances, etc. In the present invention, the amount of the additive is not particularly limited as long as it does not interfere with the function of NO.

[0028] Examples of the excipient include sugar derivatives such as lactose, lactose hydrate, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, and dextrin; cellulose derivatives such as crystalline cellulose; organic excipients such as gum arabic, dextran, and pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Examples of the colorant include yellow ferric oxide. Examples of the lubricant include metal stearates such as stearic acid, calcium stearate, and magnesium stearate; talc; polyethylene glycol; silica; and hydrogenated vegetable oil. Examples of the flavoring agent include flavorings such as cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, and cinnamon powder, as well as sweeteners and acidulants. Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, etc. Examples of the disintegrant include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starches and chemically modified celluloses such as carboxymethyl starch, carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, and sodium starch glycolate; examples of the stabilizer include parahydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; sorbic acid; and examples of the coating agent include hypromellose, macrogols such as Macrogol 6000, talc, titanium oxide, etc.

[0029] The composition of the present invention can, for example, dilate the blood vessels of a subject to which it is administered, and therefore can be suitably used, for example, as a therapeutic agent for diseases caused by vasoconstriction.

[0030] <Vasodilator Composition Kit> As described above, the vasodilator composition kit of the present invention comprises a vasodilator composition and other ingredients, the vasodilator composition and the other ingredients being arranged separately, and the vasodilator composition is the vasodilator composition of the present invention. The composition kit of the present invention is characterized by comprising the vasodilator composition, which is the vasodilator composition of the present invention, and other configurations and conditions are not particularly limited. According to the composition kit of the present invention, the dosage of NO can be adjusted by adjusting the dosage of the composition. The description of the composition of the present invention can be used for the composition kit of the present invention.

[0031] The other components are not particularly limited and can be appropriately determined depending on the contents of the composition and the purpose of administration to the subject, and examples thereof include additives, drugs, nutrients, etc. Examples of the drugs include antibiotics, etc. When the osmotic pressure of the composition is not adjusted, the other components preferably include an osmotic pressure adjuster (substance). Examples of the osmotic pressure adjuster include sugars such as glucose; salts (electrolytes) such as sodium chloride, calcium chloride, calcium chloride, sodium bicarbonate, and magnesium chloride; amino acids; proteins, etc. Examples of the nutrients include sugars such as glucose, vitamins, etc. The other components may be solid or liquid. In the former case, the other components are preferably disposed in an undissolved state in a solvent or the like and are preferably configured to be dissolved, for example, when mixed with the composition. In the latter case, the other components are preferably dissolved, for example, in a solvent.

[0032] In the composition kit of the present invention, the composition and the other components are arranged separately, i.e., the composition and the other components are arranged in an unmixed state or in a state where they are not in contact with each other. Specifically, the composition and the other components are arranged in different locations in a container that contains them.

[0033] In the composition kit of the present invention, the composition and the other components are preferably contained in a container. In this case, the container has a first chamber containing the composition and a second chamber containing the other components. In the container, the first chamber and the second chamber may each be configured independently, i.e., as separate containers, or may be integrated, i.e., as a single container. When the first chamber and the second chamber are configured as a single container, the container preferably has a separation section that can separate the first chamber and the second chamber. When the container has a separation section, the first chamber and the second chamber are arranged, for example, via the separation section. When the composition and the other components are mixed and administered to a recipient, the separation section is preferably configured to allow communication between the first chamber and the second chamber.

[0034] The container having the first and second chambers can be, for example, a medical multi-chamber container. Examples of the multi-chamber container include a plastic double bag in which multiple chambers are formed by providing the separating section inside a plastic bag (e.g., JP 2016-190646 A, JP 2016-131577 A, etc.), a dissolution kit in which a container containing other components and a container containing a dissolution solution (corresponding to the composition) are integrated so as to be able to communicate with each other (e.g., WO 96 / 25136 A, etc.), and a double-chamber pre-filled syringe (e.g., JP 2012-245086 A, etc.).

[0035] An example of the multi-chamber container containing the composition and the other components in the composition kit of the present invention will be described with reference to FIG. 1. FIG. 1 is a cross-sectional view showing an example of the composition kit of the present invention. As shown in FIG. 1, the composition kit includes a container 10, a composition 11, and other components 21. The container 10 includes a first chamber 1 containing the composition 11, a second chamber 2 containing the other components 21, and a separating section 3 that separates the first chamber 1 from the second chamber 2 and allows communication between the first chamber 1 and the second chamber 2. The container 10 further includes a hanging section 5 from which the container 10 can be hung.

[0036] As shown in FIG. 1, container 10 is formed from sheets 13 and 14 and a discharge section (discharge port) 22. As shown in FIG. 1, sheets 13 and 14 are welded to sheet 13 at the upper end thereof to form upper end 12 of first chamber 1, and are connected to discharge section 22 at the lower end sides of sheets 13 and 14. Sheets 13 and 14 are also welded to each other at their centers to form isolation section 3. The weld of isolation section 3 is peelable, and by applying pressure to first chamber 1, the weld of sheets 13 and 14 in isolation section 3 is released, allowing first chamber 1 and second chamber 2 to communicate with each other. In container 10, first chamber 1 is the space from upper end 12 of sheets 13 and 14 to isolation section 3. In container 10, second chamber 2 is the space from isolation section 3 to discharge section 22 of sheets 13 and 14.

[0037] Plastic sheets can be used for sheets 13 and 14. The plastic sheet is preferably composed of multiple layers, for example, including an inner layer, an outer layer, and an intermediate layer. Thermoplastic resins such as thermoplastic olefin resins, thermoplastic propylene resins, and thermoplastic polyethylene resins can be used for the inner layer and the outer layer. By using such thermoplastic resins, the outer peripheries of first chamber 1 and second chamber 2, upper end 12, and separator 3 can be easily formed by stacking sheets 13 and 14 facing each other and heat sealing them, thereby producing container 10. The intermediate layer is preferably made of, for example, a highly flexible resin, and a thermoplastic olefin resin composition can be used as a specific example.

[0038] The volumes and shapes of the first chamber 1 and the second chamber 2 are not particularly limited and can be set appropriately depending on, for example, the amounts of the composition and other components to be administered.

[0039] The composition kit of the present invention can, for example, dilate the blood vessels of a subject to be administered, and therefore can be suitably used, for example, as a therapeutic agent for a disease caused by vasoconstriction.

[0040] <Pharmaceutical Composition> The pharmaceutical composition of the present invention for diseases caused by vascular stenosis or occlusive disorders comprises the vasodilator composition of the present invention. The pharmaceutical composition of the present invention is characterized by comprising the composition of the present invention, and other configurations and conditions are not particularly limited. The pharmaceutical composition of the present invention makes it possible to adjust the dosage of NO by adjusting the dosage of the composition. The pharmaceutical composition of the present invention is capable of dilating stenotic blood vessels, making it possible to treat diseases caused by vascular stenosis or occlusive disorders. The explanations of the composition and composition kit of the present invention can be used for the pharmaceutical composition of the present invention.

[0041] In the present invention, the "vascular stenosis or obstructive disorder" means, for example, an increase in vascular resistance or poor blood circulation that causes blood flow disorder.

[0042] Examples of diseases caused by vascular stenosis include angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, acute heart failure, etc. The pharmaceutical composition of the present invention can also be used to treat an attack of angina pectoris (anginal attack).

[0043] In the present invention, "treatment" may mean any of treating, preventing, ameliorating, alleviating, remission, inhibiting the progression of symptoms, and / or halting the progression of symptoms of a disease. Therefore, the pharmaceutical composition of the present invention can also be referred to as, for example, a therapeutic agent, preventive agent, ameliorating agent, alleviating agent, remission agent, progression-inhibiting agent, and / or progression-halting agent for a disease.

[0044] The pharmaceutical composition of the present invention may be used as a pharmaceutical composition for diseases other than those caused by vasoconstriction.

[0045] <Medicine kit> The pharmaceutical kit of the present invention for diseases caused by vascular stenosis or occlusive disorders (hereinafter also referred to as "pharmaceutical kit") includes the vasodilator composition kit of the present invention. The pharmaceutical kit of the present invention is characterized by including the composition kit of the present invention, and other configurations and conditions are not particularly limited. According to the pharmaceutical kit of the present invention, the dosage of NO can be adjusted by adjusting the dosage of the composition. According to the pharmaceutical kit of the present invention, stenotic blood vessels can be dilated, and therefore diseases caused by vascular stenosis or occlusive disorders can be treated. The pharmaceutical kit of the present invention can be applied to the explanations of the composition, composition kit, and pharmaceutical composition of the present invention.

[0046] The pharmaceutical kit of the present invention may be used as a pharmaceutical kit for diseases other than those caused by vascular stenosis or occlusive disorders.

[0047] <Treatment method> The method of the present invention for treating a disease caused by vascular stenosis or occlusive disorder (hereinafter also referred to as "treatment method") comprises an administration step of administering the vasodilator composition of the present invention to a patient. The treatment method of the present invention is characterized by administering the composition of the present invention, and other steps and conditions are not particularly limited. According to the treatment method of the present invention, the dose of NO can be adjusted by adjusting the dose of the composition. According to the treatment method of the present invention, stenotic blood vessels can be dilated, and therefore diseases caused by vascular stenosis or occlusive disorder can be treated. The treatment method of the present invention can be applied to the explanations of the composition, composition kit, pharmaceutical composition, and pharmaceutical kit of the present invention.

[0048] The therapeutic method of the present invention can also be referred to as a treatment carried out on patients with diseases caused by, for example, vascular stenosis or occlusive disorders. Therefore, the therapeutic method of the present invention can also be referred to as a treatment method for diseases caused by, for example, vascular stenosis or occlusive disorders.

[0049] The therapeutic method of the present invention may use the pharmaceutical composition as the composition. Furthermore, the therapeutic method of the present invention may use a composition kit or a pharmaceutical kit (hereinafter, collectively referred to as a "kit") as the composition.

[0050] When the treatment method of the present invention uses the kit, the composition and the other components may be administered simultaneously or separately in the administration step. When the composition and the other components are administered simultaneously, the treatment method of the present invention preferably includes a mixing step of mixing the composition and the other components in the kit prior to the administration step. In this case, the resulting mixture is administered to a patient in the administration step.

[0051] The administration conditions in the administration step can be as described above. [Example]

[0052] Next, examples of the present invention will be described, but the present invention is not limited to the following examples.

[0053] [Example 1] It was confirmed that the composition of the present invention reduces calcium ion concentration in cardiac myoblasts.

[0054] Vasodilation by NO occurs because NO reduces the calcium ion concentration in vascular smooth muscle cells, thereby inhibiting the contraction of vascular endothelial cells. Therefore, the composition of the present invention can reduce intracellular calcium ions (Ca 2+ It was confirmed that the composition of the present invention has a vasodilatory effect by examining whether a decrease in the concentration of vasopressin was observed.

[0055] (1) Preparation of the composition The composition of the present invention was produced using a microbubble-producing apparatus 100 shown in FIG. 2. As shown in FIG. 2, the production apparatus 100 has syringes 32 and 33 arranged on two sides of a three-way stopcock 31. In the production apparatus 100, the syringes 32 and 33 are connected via the three-way stopcock 31. First, the syringe 32 was disconnected from the three-way stopcock 31, and 20 ml of Earle's balanced salt solution (EBSS) was introduced into it. The EBSS had a composition of 26 mmol / L NaHCO3, 1 mmol / L NaH2PO4, 5.4 mmol / L KCl, 116 mmol / L NaCl, 5.5 mmol / L glucose, and 2 mmol / L CaCl2, with a pH of 7.4. Next, the syringe 32 was reconnected to the three-way stopcock 31, and the gas inside the three-way stopcock 31 was removed. After the removal, syringe 33 was disconnected from three-way stopcock 31, and 20 ml of medical nitric oxide (manufactured by Taiyo Nippon Sanso Corporation, NO concentration: 99.0 (v / v)% or higher) was introduced into syringe 33. Then, syringe 33 was reconnected to three-way stopcock 31. After the connection, the plungers of syringes 32 and 33 were continuously piston-moved within the outer barrels for 10 minutes to produce microbubbles containing NO as a gas component, thereby producing a composition of the present invention (composition of Example 1-1). A composition (composition of Example 1-2) was produced in the same manner, except that the EBSS was previously degassed with argon (Ar degassing) to remove dissolved air from the EBSS.

[0056] (2) Composition characteristics The compositions obtained in Example 1(1) and those diluted 10-fold or 100-fold were allowed to stand for about 1 hour, and then the physical properties of the compositions were measured using a NanoSight (registered trademark) NS300 (manufactured by Malvern Instrument) with default parameters. The measurements were carried out at 25°C. As a result, the average diameter and density of microbubbles in the compositions were as follows: (Composition of Example 1-1 (NO UFB)) Undiluted (x1): Average diameter: 116.1±39.8 nm, density: 3.52×109 ±1.12×10 8 pcs / ml; 10-fold dilution (x10): Average diameter: 116.1±39.8 nm, density: 1.06×10 9 ±2.97×10 7 pcs / ml; 100-fold dilution (x100): Average diameter: 113.4±39.2 nm, density: 1.51×10 8 ±6.57×10 6 pcs / ml; (Composition of Example 1-2 (Ar-substituted, Ar NO UFB)) Undiluted (x1): Average diameter: 137.0±48.2 nm, density: 2.89×10 9 ±4.10×10 7 pcs / ml; 10-fold dilution (x10): Average diameter: 126.3±49.5 nm, density: 7.81×10 8 ±1.38×10 7 pcs / ml; 100-fold dilution (x100): Average diameter: 116.4±43.0 nm, density: 1.13×10 8 ±3.29×10 6 pieces / ml

[0057] (3) Measurement of calcium ion concentration Rat cardiac myoblasts (H9C2) were used to measure changes in calcium ion concentration. The H9C2 cell culture medium consisted of DMEM (Dulbecco's Modified Eagle Medium: DMEM ((+) 4.5 g / L D-glucose, (+) 110 mg / L pyruvate, (-) L-glutamine (Gibco)), 10% fetal bovine serum (FBS, BioWest), 100 mg / L pyruvate (Sigma), 10 mL / L L-glutamine (200 mmol / L 100×L L-glutamine, (Gibco)), 100 U / mL penicillin (Fujifilm Wako Pure Chemical Industries, Ltd.), and 100 μg / mL streptomycin (Fujifilm Wako Pure Chemical Industries, Ltd.). H9C2 cells were pre-cultured in a 96-well plate at 3.0 × 10 3 The cells were seeded at 100 μl per well and cultured until confluent. 2+ The concentration was measured using [Ca 2+ ] The fluorescent probe used for measurement was Fura 2-AM (Mw: 1001.85, Dojindo Chemical Industries, Cat. No.: F015).

[0058] First, a 1 mmol / L Fura2-AM DMSO solution was added to EBSS to a concentration of 5 μmol / L, and then Pluronic® F-127 was added to a concentration of 0.01 (w / v)%, followed by ultrasonic dissolution to prepare a loading buffer. Next, the medium for the H9C2 cells was removed, and an equal volume of loading buffer was added. The cells were incubated at 37°C for 20 minutes to allow Fura2-AM to be incorporated into the H9C2 cells. After the incubation, the cells were washed four times with EBSS. 100 μL of each composition was added and exposed to the cells. The changes in fluorescence intensity were measured over time to determine the intracellular Ca concentration. 2+ The change in the relative concentration was observed. In the measurement, the excitation light was 340 nm or 380 nm, and the measurement wavelength of the obtained fluorescence was 510 nm. 2+The relative concentration was calculated as the ratio of the fluorescence intensity at 510 nm (340 nm) at 340 nm to the fluorescence intensity at 510 nm (380 nm) at 380 nm (340 nm / 380 nm). Control 1 (untreated) was measured in the same manner except that it was untreated. Control 2 (Air UFB) was measured in the same manner except that a composition prepared using air instead of NO was used. Control 3 (Nifedipine) was measured in the same manner except that a 10 μmol / L nifedipine solution was used instead of the composition. Control 4 (NO dissolved) was measured in the same manner except that NO-dissolved EBSS was used instead of the composition. These results are shown in Figures 3A-D.

[0059] Figure 3A-D shows the intracellular Ca 2+ 3A shows the results of the composition of Example 1-1 (×1) and Controls 1 to 4, FIG. 3B shows the results of the composition of Example 1-1 (×1) without dilution with Ar-degassed EBSS and Controls 1 to 5, FIG. 3C shows the results of the dilution series of the composition of Example 1-1 and Control 1, and FIG. 3D shows the results of the dilution series of the composition of Example 1-2 and Control 1. In FIGS. 3A to 3D, the horizontal axis shows the elapsed time after treatment with each composition, and the vertical axis shows the intracellular Ca 2+ The relative concentration values ​​are shown.

[0060] As shown in Figures 3A and 3B, in Controls 1 to 4, intracellular Ca 2+ In contrast, in the undiluted (×1) compositions of Example 1-1 and Example 1-2, the intracellular Ca concentration was almost unchanged or slightly decreased. 2+ The concentration of the serotonin-containing compound significantly decreased. Furthermore, the composition of the present invention exerted a stronger effect on intracellular Ca2+ levels than the NO-dissolved solution. 2+ It was found that it has the effect of reducing concentration.

[0061] Next, as shown in Figures 3C and 3D, in the compositions of Examples 1-1 and 1-2, which were undiluted (x1), diluted 10-fold (x10), and diluted 100-fold (x100), intracellular Ca increased in a microbubble density (concentration)-dependent manner.2+ Furthermore, when the results of the compositions of Example 1-1 and Example 1-2 were compared, there was a significant difference in the intracellular Ca concentration between the two. 2+ No significant difference in the degree of concentration decrease was observed, indicating that the NO in the composition of the present invention was hardly oxidized in the composition. These results demonstrate that the degree of action of the composition of the present invention can be adjusted by adjusting the density and dosage of the microbubbles, and that the NO in the microbubbles is stable.

[0062] These findings suggest that the composition of the present invention reduces calcium ion concentration in cardiac myoblasts and has a vasodilatory function.

[0063] [Example 2] It was confirmed that the composition of the present invention exhibits a vasodilatory effect.

[0064] A probe for detecting arterial pressure was inserted into the femoral artery of an anesthetized inbred Lewis rat (male, 10 weeks old) or dog (male Beagle, 1 year old). Then, the composition of Example 1-1 (x1) was administered via the femoral vein at 1 ml / kg body weight. After administration, the blood pressure of the rats and dogs was measured over time. The results are shown in Figure 4.

[0065] Figure 4 is a graph showing changes in blood pressure over time. In Figure 4, (A) shows the results for rats, and (B) shows the results for dogs. In Figure 4, the horizontal axis shows the time after administration of the composition, and the vertical axis shows blood pressure. As shown in Figures 4(A) and (B), blood pressure decreased rapidly after administration of the composition of Example 1-1, and the decrease in blood pressure continued for approximately 45 minutes after administration.

[0066] From the above, it was found that the composition of the present invention exhibits a vasodilatory effect.

[0067] [Example 3] It was confirmed that the composition of the present invention can suppress angina pectoris.

[0068] Donryu rats, in which angina attacks can be induced by administration of vasopressin (VP), were used as angina model rats. First, an electrocardiogram was attached to the Donryu rats, and a probe for detecting arterial pressure was inserted into the femoral artery to measure the electrocardiogram and blood pressure over time. Next, 1 ml / kg body weight of physiological saline was administered to the Donryu rats via the femoral vein. Five minutes after administration, vasopressin was administered via the femoral vein to induce an angina attack. After confirming the end of the angina attack via electrocardiogram, 1 ml / kg body weight (×1) of the composition of Example 1-1 was administered to the Donryu rats via the femoral vein. Five minutes after administration, vasopressin was administered via the femoral vein to induce an angina attack. These results are shown in Figures 5 and 6.

[0069] FIG. 5 is a graph showing electrocardiograms. In FIG. 5, (A) shows the results for Donryu rats administered with physiological saline, and (B) shows the results for Donryu rats administered with the composition of Example 1-1. In addition, in FIG. 5, the left graph shows the electrocardiogram of a normal rat, and the right graph shows the electrocardiogram of a rat when an angina attack was induced with vasopressin. As shown in FIG. 5(A), when physiological saline was administered, ST depression characteristic of an angina attack was observed upon administration of vasopressin. In contrast, as shown in FIG. 5(B), when the composition of Example 1-1 was administered, ST depression characteristic of an angina attack was not observed, and angina attacks were suppressed.

[0070] Next, Figure 6 is a graph showing the results of blood pressure and electrocardiogram. In Figure 6, (A) shows the blood pressure results, and (B) shows the electrocardiogram S wave results. In Figure 6(A), the horizontal axis shows the time after administration of physiological saline or the composition of Example 1-1, and the vertical axis shows the mean blood pressure. In Figure 6(B), the horizontal axis shows the time after administration of physiological saline or the composition of Example 1-1, and the vertical axis shows the electrocardiogram. As shown in Figure 6(A), blood pressure decreased after administration of the composition of Example 1-1, indicating vasodilation. Furthermore, after vasopressin administration, there was no difference between the group administered with physiological saline and the group administered with the composition of Example 1-1. On the other hand, as shown in Figure 6(B), after vasopressin administration, S waves were significantly reduced in the group administered with physiological saline, whereas the reduction in S waves was suppressed in the group administered with the composition of Example 1-1, indicating that angina attacks were suppressed.

[0071] From the above, it was found that the composition of the present invention can suppress angina pectoris.

[0072] [Example 4] It was confirmed that the composition of the present invention exhibits a vasodilatory effect.

[0073] The heart was removed from the Donryu rat of Example 3. It was then placed in a Langendorff perfusion apparatus and placed in an extracorporeal circulation environment. Under this condition, 1 ml of the undiluted (×1) composition of Example 1-1 was administered to the circulating fluid, and the coronary artery perfusion rate was measured every minute for 5 minutes. A control was also measured in the same manner, except that physiological saline was administered instead of the composition of Example 1-1. These results are shown in Figure 7.

[0074] Figure 7 is a graph showing coronary artery perfusion. In Figure 7, the horizontal axis represents the time after administration of physiological saline or the composition of Example 1-1, and the vertical axis represents coronary artery perfusion. As shown in Figure 7, the group administered with the composition of Example 1-1 (NO UFB) showed an increased coronary artery perfusion compared to the group administered with physiological saline (Control). This is presumably because the NO in the composition of Example 1-1 dilated the coronary arteries, allowing a greater amount of fluid to flow.

[0075] From the above results, it was found that the composition of the present invention exhibits a vasodilatory effect.

[0076] Although the present invention has been described above with reference to the embodiments and examples, the present invention is not limited to the above-described embodiments and examples. Various modifications that can be understood by those skilled in the art can be made to the configuration and details of the present invention within the scope of the present invention.

[0077] This application claims priority based on Japanese Patent Application No. 2020-021195, filed on February 12, 2020, the disclosure of which is incorporated herein in its entirety.

[0078] <Additional Notes> Some or all of the above-described embodiments and examples can be described as, but are not limited to, the following supplementary notes. (Appendix 1) Contains microbubbles, A vasodilator composition, wherein the microbubbles contain nitric oxide as a gas component. (Appendix 2) The density of the microbubbles is 5×10 5 ~5×10 12 10. The vasodilator composition of claim 1, wherein the vasodilator composition is 0.1 mg / ml. (Appendix 3) 3. The vasodilator composition according to claim 1, wherein the proportion of nitric oxide in the gaseous components is 80% or more. (Appendix 4) 4. A vasodilator composition according to any one of claims 1 to 3, wherein the gaseous component is substantially free of oxygen. (Appendix 5) Further, the medium includes 5. A vasodilator composition according to any one of claims 1 to 4, wherein the medium is at least one of a liquid and a solid. (Appendix 6) a vasodilator composition and other ingredients, The vasodilator composition and the other components are arranged separately, A vasodilator composition kit, wherein the vasodilator composition is a vasodilator composition described in any one of Appendices 1 to 5. (Appendix 7) Further comprising a container, The container has a first chamber, a second chamber, and a separator; The vasodilator composition is contained in the first chamber; The other ingredients are contained in the second chamber, 7. The vasodilator composition kit according to claim 6, wherein the isolation section isolates the first chamber from the second chamber and allows communication between the first chamber and the second chamber. (Appendix 8) 8. The vasodilator composition kit according to claim 6 or 7, wherein the other components include an osmotic agent. (Appendix 9) A pharmaceutical composition for a disease caused by vascular stenosis or occlusive disorder, comprising a vasodilator composition described in any one of Appendixes 1 to 5. (Appendix 10) The pharmaceutical composition according to claim 9, wherein the disease caused by vascular stenosis or occlusive disorder is at least one disease selected from the group consisting of angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, and acute heart failure. (Appendix 11) the disease caused by vascular stenosis or occlusive disorder is angina pectoris; 11. The pharmaceutical composition according to claim 9 or 10, which is a pharmaceutical composition used for preventing, suppressing, reducing, ameliorating, alleviating, or remission of angina attacks. (Appendix 12) 12. A pharmaceutical composition according to any one of Appendices 9 to 11, for intravenous administration. (Appendix 13) A pharmaceutical kit for treating diseases caused by vascular stenosis or occlusive disorders, comprising a vasodilator composition kit according to any one of claims 6 to 8. (Appendix 14) The pharmaceutical kit according to claim 13, wherein the disease caused by vascular stenosis or occlusive disorder is at least one disease selected from the group consisting of angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, and acute heart failure. (Appendix 15) the disease caused by vascular stenosis or occlusive disorder is angina pectoris; 15. The pharmaceutical kit according to claim 13 or 14, which is a pharmaceutical kit for use in preventing, suppressing, reducing, ameliorating, alleviating, or remission of angina attacks. (Appendix 16) 16. A pharmaceutical kit according to any one of Appendices 13 to 15, for intravenous administration. (Appendix 17) A method for treating a disease caused by vascular stenosis or occlusive disorder, comprising administering to a patient a vasodilator composition described in any one of Appendices 1 to 5. (Appendix 18) A vasodilator composition kit according to any one of claims 6 to 8, comprising: a mixing step of mixing the vasodilator composition with other components; and administering the resulting mixture to a patient. (Appendix 19) The method of claim 17 or 18, wherein the disease caused by vascular stenosis or occlusive disorder is at least one disease selected from the group consisting of angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, and acute heart failure. (Appendix 20) the disease caused by vascular stenosis or occlusive disorder is angina pectoris; 20. The method of claim 18 or 19, wherein the administration of the vasodilator composition or mixture prevents, inhibits, reduces, improves, alleviates, or relieves angina attacks. (Appendix 21) 21. The method of any one of claims 17 to 20, wherein the vasodilator composition or mixture is administered intravenously. (Appendix 22) A vasodilator composition for use in vasodilatation, the vasodilator composition comprises microbubbles; A vasodilator composition, wherein the microbubbles contain nitric oxide as a gas component. (Appendix 23) A vasodilator composition for use in treating a disease caused by vascular stenosis or occlusive disorder, the vasodilator composition comprises microbubbles; A vasodilator composition, wherein the microbubbles contain nitric oxide as a gas component. (Appendix 24) The vasodilator composition according to claim 23, wherein the disease caused by vascular stenosis or obstructive disorder is at least one disease selected from the group consisting of angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, and acute heart failure. (Appendix 25) the disease caused by vascular stenosis or occlusive disorder is angina pectoris; 25. A vasodilator composition according to claim 23 or 24, which is a vasodilator composition used for preventing, suppressing, reducing, ameliorating, alleviating, or remission of angina attacks. (Appendix 26) A vasodilator composition according to any one of claims 23 to 25, for intravenous administration. [Industrial Applicability]

[0079] As described above, the present invention allows for the adjustment of the dose of NO. Furthermore, since the composition of the present invention allows for the adjustment of the dose of NO, it is also possible to adjust, for example, the degree of vasodilation. Furthermore, since the composition of the present invention can be administered directly into the body of a recipient, it can be administered locally, as in the case of administration by inhalation, or systemically. Therefore, the present invention can be suitably used, for example, in the treatment of diseases caused by vasoconstriction, and is extremely useful in the medical and pharmaceutical fields. [Explanation of symbols]

[0080] 1 Room 1 10 containers 11 Composition 12 Upper end 13, 14 sheets 2 Room 2 21 Other ingredients 22 Discharge section 3 Isolation section 5 Hanging section

Claims

1. containing microbubbles and an aqueous solvent, The microbubbles contain nitric oxide as a gas component, the microbubbles are surrounded by the aqueous solvent; A vasodilator composition, wherein the microbubbles have a bubble diameter of less than 100 μm.

2. The density of the microbubbles is 5×10 ５ ~5 x 10 １２ The vasodilator composition of claim 1, wherein the concentration is 1 / ml.

3. 3. The vasodilator composition according to claim 1, wherein the proportion of nitric oxide in the gaseous components is 80% or more.

4. The vasodilator composition of claim 1 , wherein the gaseous component is substantially free of oxygen.

5. a vasodilator composition and other ingredients, The vasodilator composition and the other components are arranged separately, A vasodilator composition kit, wherein the vasodilator composition is a vasodilator composition described in any one of claims 1 to 4.

6. Further comprising a container, The container has a first chamber, a second chamber, and an isolation portion; The vasodilator composition is contained in the first chamber; The other ingredients are contained in the second chamber, The vasodilator composition kit according to claim 5 , wherein the isolation section isolates the first chamber from the second chamber and allows the first chamber to communicate with the second chamber.

7. The vasodilator composition kit according to claim 5 or 6, wherein the other components include an osmotic agent.

8. A pharmaceutical composition for treating a disease caused by vascular stenosis or occlusive disorder, comprising the vasodilator composition according to any one of claims 1 to 4.

9. 9. The pharmaceutical composition according to claim 8, wherein the disease caused by vascular stenosis or occlusive disorder is at least one disease selected from the group consisting of angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, and acute heart failure.

10. the disease caused by vascular stenosis or occlusive disorder is angina pectoris; 10. The pharmaceutical composition according to claim 8 or 9, which is used for preventing, suppressing, reducing, ameliorating, alleviating, or remission of angina attacks.

11. A pharmaceutical composition according to any one of claims 8 to 10, for intravenous administration.

12. A pharmaceutical kit for treating a disease caused by vascular stenosis or occlusive disorder, comprising the vasodilator composition kit according to any one of claims 5 to 7.

13. The pharmaceutical kit according to claim 12, wherein the disease caused by vascular stenosis or occlusive disorder is at least one disease selected from the group consisting of angina pectoris, myocardial infarction, cerebral infarction, transient ischemic attack, pulmonary hypertension, and acute heart failure.

14. the disease caused by vascular stenosis or occlusive disorder is angina pectoris; The pharmaceutical kit according to claim 12 or 13, which is used for preventing, suppressing, reducing, ameliorating, alleviating, or remission of angina attacks.

15. A pharmaceutical kit according to any one of claims 12 to 14, for intravenous administration.

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