Vasodilator composition and kit thereof, and pharmaceutical composition and kit using the same

Abstract

A vasodilator composition capable of regulating the administration amount of NO is provided. The composition of the present invention comprises microbubbles containing nitric oxide 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 obstructive disorders, and a pharmaceutical composition kit for treating diseases caused by vascular stenosis or obstructive disorders. Background Art

[0002] Nitric oxide (NO) as a gas is also generally used as a drug. Specifically, a treatment is performed by having a patient with pulmonary hypertension or the like inhale NO, and taking NO from the lungs into the blood vessels to induce pulmonary vascular dilation (Non-Patent Document 1).

[0003] Prior art literature

[0004] Non-patent literature

[0005] Non-Patent Literature 1: AIR WATER INC., Mallinckrodt Manufacturing LLC, and Sumitomo Seika Co., Ltd., “Pulmonary vasodilator (inhalation gas) iFlo (registered trademark) for inhalation 800 ppm,” October 2017 Summary of the invention

[0006] Problem that the invention aims to solve

[0007] However, NO easily reacts with oxygen, and when it reacts with oxygen, it is converted into nitrogen dioxide (NO2). In addition, it is known that NO2 has the highest toxicity among nitrogen oxides, causing obstruction of respiratory organs such as the lungs. Therefore, if an attempt is made to increase the concentration of NO administered to a patient in order to increase the NO concentration when inhaled into the lungs, a high concentration of NO2 is generated when inhaled, which may cause respiratory obstruction. Therefore, NO has the problem of being difficult to control the dosage.

[0008] Therefore, an object of the present invention is to provide a vasodilator composition capable of regulating the administered amount of NO.

[0009] Solutions for solving problems

[0010] In order to achieve the aforementioned object, the vasodilator composition of the present invention (hereinafter also referred to as "composition") comprises microbubbles,

[0011] The aforementioned fine bubbles contain nitric oxide as a gas component.

[0012] The vasodilator composition kit of the present invention (hereinafter also referred to as "composition kit") comprises a vasodilator composition and other components.

[0013] The aforementioned vasodilator composition and the aforementioned other components are configured in an isolated manner,

[0014] The aforementioned vasodilator composition is the aforementioned vasodilator composition of the present invention.

[0015] The pharmaceutical composition (hereinafter also referred to as "pharmaceutical composition") of the present invention for treating diseases caused by vascular stenosis or obstructive disorders (hereinafter collectively referred to as "vascular stenosis") comprises the aforementioned vasodilator composition of the present invention.

[0016] The pharmaceutical kit for treating a disease caused by vascular stenosis or obstructive disorder (hereinafter also referred to as "pharmaceutical kit") of the present invention comprises the aforementioned vasodilator composition kit of the present invention.

[0017] Effects of the Invention

[0018] According to the present invention, the administration amount of NO can be adjusted. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a cross-sectional view showing an example of a multi-chamber container containing the composition of the present invention and other components.

[0020] Figure 2 This is a schematic diagram showing a device for producing fine bubbles in Example 1.

[0021] Figure 3A is a graph showing the intracellular Ca in Example 1. 2+ A graph showing the relative concentrations.

[0022] Figure 3B is a graph showing the intracellular Ca in Example 1. 2+ A graph showing the relative concentrations.

[0023] Figure 3C is a graph showing the intracellular Ca in Example 1. 2+ A graph showing the relative concentrations.

[0024] Figure 3D is a graph showing the intracellular Ca in Example 1. 2+ A graph showing the relative concentrations.

[0025] Figure 4 This is a graph showing changes in blood pressure over time in Example 2.

[0026] Figure 5 : is a figure which shows the electrocardiogram in Example 3.

[0027] Figure 6 Graphs showing the results of blood pressure and electrocardiogram in Example 3.

[0028] Figure 7 Graph showing the coronary artery perfusion in Example 4. DETAILED DESCRIPTION

[0029] <Vasodilator composition>

[0030] 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 in that it contains the microbubbles, and other configurations and conditions are not particularly limited. The composition of the present invention contains NO as microbubbles, so it can be directly administered to the body of the administration subject by, for example, intravenous administration. Therefore, according to the composition of the present invention, by increasing or decreasing the amount of the composition administered to the administration subject, the administration amount to the administration subject can be increased or decreased. Therefore, according to the composition of the present invention, the administration amount of NO can be adjusted, for example, the degree of vascular dilation can also be adjusted. In addition, the composition of the present invention can be directly administered to the body of the administration subject, for example, it can be locally administered as in the case of administration based on inhalation, and it can also be systemically administered.

[0031] 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 aforementioned blood vessel may be, for example, any of an artery and a vein, but is preferably an artery. The aforementioned "vasodilation" may be evaluated directly by measuring the inner diameter of the blood vessel, for example, or may be evaluated indirectly by measuring other indicators. The aforementioned direct evaluation may be evaluated, for example, by measuring the inner diameter of the blood vessel of the object using an ultrasonic diagnostic device or the like. Examples of the aforementioned object's blood vessels include blood vessels around the administration site of the composition of the present invention, coronary arteries of the heart, pulmonary arteries, and the like. In addition, it is known that if blood vessels in the administration object expand, blood pressure decreases. Therefore, the aforementioned indirect evaluation may be evaluated, for example, by setting the aforementioned other indicators as blood pressure and measuring the blood pressure of the aforementioned administration object. The aforementioned blood pressure is, for example, the average blood pressure. In addition, in the present invention, for example, when the inner diameter of the blood vessels of the administration object administered with the composition of the object is significantly expanded compared with the inner diameter of the blood vessels of the administration object not administered with the composition of the present invention, or the administration object administered with the same composition except that the microbubbles do not contain NO, the occurrence of vasodilation can be evaluated.

[0032] In the present invention, "microbubbles" refer to closed microscopic spaces formed by gas and surrounded by substances other than gas, and may also be referred to as microbubbles. Examples of the aforementioned microbubbles include fine bubbles. The aforementioned small bubbles generally refer to microbubbles having a bubble diameter of less than 100 μm. The aforementioned bubble diameter refers to the equivalent spherical diameter of the bubble. The aforementioned bubble diameter may be the average diameter (arithmetic mean diameter) of the microbubbles obtained using the measurement method described later. The aforementioned small bubbles (fine buble: FB) may be microbubbles (Micro bubbles) or ultrafine bubbles (ultra finebuble: UFB). The aforementioned microbubbles generally refer to microbubbles having a bubble diameter of more than 1 μm and less than 100 μm. The aforementioned ultrafine bubbles generally refer to microbubbles having a bubble diameter of less than 1 μm.

[0033] The aforementioned microbubbles exist in the form of being dispersed in the medium. The aforementioned microbubbles exist in the form of being dispersed in the whole or part of the aforementioned medium. In the latter case, it can also be said that the aforementioned microbubbles exist locally in a part of the aforementioned medium. The aforementioned medium may be, for example, a liquid or a solid. The aforementioned liquid may be, for example, an aqueous solvent including water, an oily solvent or a mixed solvent thereof. In addition, the aforementioned liquid includes a sol. The aforementioned solid may be, for example, a solid obtained by solidifying the aforementioned liquid. In addition, the aforementioned solid includes a gel. The aforementioned liquid may be, for example, physiological saline; buffer solutions such as phosphate buffer; infusion solutions such as extracellular fluid and intracellular fluid; water such as distilled water and pure water; cell culture solutions such as DMEM and RPMI1640; organ preservation solution; etc. The aforementioned solid may be, for example, a solidified product of the aforementioned liquid.

[0034] The aforementioned microbubbles may contain only NO as a gas (gas component), or may contain other gases. The aforementioned NO may also be referred to as an effective component in the aforementioned microbubbles. The aforementioned other gases may include, for example, biogas such as carbon monoxide (CO), hydrogen sulfide (H2S), and hydrogen (H2); rare gases such as helium (He), argon (Ar), krypton (Kr), and xenon (Xe); carbon dioxide (CO2), nitrous oxide (N2O), carbon dioxide (CO2), nitrogen (N2), methane (CH4), ethane (CH3CH3), propane (CH3CH2CH3), fluoromethane (CH3F), difluoromethane (CH2F2), carbon tetrafluoride (CF4), ethylene oxide (C2H4O), air, etc. In the present invention, "biogas" refers to a gas including carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (H2S), or hydrogen (H2), or a mixed gas containing two or more of these. Nitric oxide reacts with oxygen or ozone in the presence of oxygen or ozone to become nitrogen dioxide (NO2). In addition, nitrogen dioxide is known to show toxicity. Therefore, the aforementioned microbubbles, for example, preferably do not substantially contain oxygen or ozone. The aforementioned substantially does not contain, for example, means that the concentration of oxygen or ozone in the sample is a concentration below the detection limit in the gas chromatograph. When the aforementioned microbubbles contain two or more gas components, the gas components other than NO are preferably gas components that do not react with NO, such as the aforementioned rare gases, nitrogen, etc. The aforementioned microbubbles do not include, for example, the case where the gas is only air. In the present invention, the aforementioned "air" refers to, for example, the air (atmosphere) used when making the aforementioned microbubbles. When there is a gas of medical gas grade, the gas in the aforementioned microbubbles is preferably a gas derived from medical gas.

[0035] The density of the microbubbles refers to the number of microbubbles relative to the volume of the medium. The “density” may also be referred to as the number concentration. The lower limit of the density of the microbubbles is, for example, 5×10 5 / ml, 1×10 6 / ml, 5×10 6 / ml, 1×10 7 / ml, 5×10 7 / ml, 1×10 8 / ml, 5×10 8 / ml, 1×10 9 / ml, preferably 1×10 6 / ml, 5×10 6 / ml, 1×10 7 / ml, 5×10 7 / ml, 1×10 8 / ml, 5×10 8The upper limit of the density of the microbubbles is, for example, 1.5×10 9 / ml, 2×10 9 / ml, 3×10 9 / ml, 5×10 9 / ml, 7×10 9 / ml, 9×10 9 / ml, 1×10 10 / ml, 5×10 10 / ml, 1×10 11 / ml, 5×10 11 / ml, 1×10 12 / ml, 5×10 12 The density of the microbubbles is, for example, in the range of 5×10 5 / ml~5×10 12 / ml, 5×10 5 / ml~1×10 12 / ml, 5×10 5 / ml~5×10 11 / ml, 5×10 5 / ml~1×10 11 / ml, 5×10 5 / ml~5×10 10 / ml, 5×10 5 / ml~1×10 10 / ml, 1×10 6 / ml~9×10 9 / ml, 5×10 6 / ml~9×10 9 / ml, 1×10 7 / ml~7×10 9 / ml, 5×10 7 / ml~7×10 9 / ml, 1×10 8 / ml~5×10 9 / ml, 5×10 8 / ml~5×10 9 / ml, 1×10 9 / ml~3×10 9 / ml, 5×10 8 / ml~2×10 9 / ml, 5×10 8 / ml~1.5×10 9 Pieces / ml.

[0036] The density, bubble diameter and average diameter (hereinafter also referred to as "characteristics") of the aforementioned microbubbles can be appropriately measured according to the medium in which the aforementioned microbubbles are dispersed. When the aforementioned microbubbles are dispersed in a liquid medium, the characteristics of the aforementioned microbubbles can be calculated by analyzing the bubbles in the composition of the present invention using a particle trajectory analysis method. The aforementioned particle trajectory analysis method can be implemented, for example, according to Example 1 described later, using NanoSight (registered trademark) NS300 (manufactured by Malvern Instrument Co., Ltd.). The characteristics of the aforementioned microbubbles can also be calculated using other analytical methods other than the particle trajectory analysis method. In this case, the characteristics of the microbubbles obtained in other analytical methods satisfy the aforementioned example when converted into calculated values ​​obtained using the aforementioned particle trajectory analysis method. When the aforementioned microbubbles are dispersed in a solid medium, the characteristics of the aforementioned microbubbles can be calculated based on the characteristics of the microbubbles in the liquid before the solidification of the aforementioned medium, and the characteristics of the microbubbles in the liquid obtained by dissolving the solid medium.

[0037] The proportion of NO in the aforementioned gas is, for example, more than 0% and less than 100%, 10-100%, 20-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 95-100%, 96-100%, 97-100%, 98-100%, 99-100%, and preferably 90-100%.

[0038] The composition of the present invention can be manufactured, for example, by a method for manufacturing microbubbles such as small bubbles using any gas. Therefore, the method for manufacturing the composition of the present invention, for example, includes a bubble manufacturing process for manufacturing microbubbles using a gas and a medium containing NO. As a specific example, when the composition of the present invention is a liquid, the composition of the aforementioned liquid can be manufactured, for example, using a gas containing NO, the aforementioned medium and a swirl method, an ejector method (ejector), a Venturi method (Venturi), a static mixer method (static mixer), a microporous method, a pressurized dissolution method or an ultrasonic cavitation method. In addition, when the composition of the present invention is a solid, the composition of the aforementioned solid can be manufactured by solidifying the composition of the aforementioned liquid using a known method. In the case where the aforementioned solid is a gel, the composition of the gel can be manufactured, for example, by mixing the composition of the aforementioned liquid with a gelling agent. At the beginning of the aforementioned bubble manufacturing process, the state of the aforementioned gas containing NO is gas, liquid, or solid. The aforementioned gas containing NO can contain multiple gases. In this case, each gas can be supplied to the aforementioned bubble manufacturing process separately, and all or part of the aforementioned gas containing NO can also be supplied to the aforementioned bubble manufacturing process simultaneously. As a specific example, when the aforementioned gases are NO and CO, NO and CO may be introduced simultaneously or separately.

[0039] The compositions of the present invention can be used, for example, in vivo ( in vivo Use, can also be in vitro ( in vitro The composition of the present invention can be used as a research reagent or a drug. In the latter case, the composition of the present invention can also be called a drug or a pharmaceutical composition for a disease caused by vascular stenosis.

[0040] There is no particular limitation on the subject to which the composition of the present invention may be administered. in vivo When the composition of the present invention is used, the aforementioned administration object may include, for example, humans or non-human animals other than humans. Examples of the aforementioned non-human animals include mammals such as mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys, guinea pigs, birds, fish, etc. in vitro When the composition of the present invention is used, the administration object may include, for example, cells, tissues, organs, etc., the cells may include, for example, cells collected from a living body, cultured cells, etc., and the tissues or organs may include, for example, tissues (living tissues) or organs collected from a living body, etc. Examples of the cells include vascular endothelial cells, vascular smooth muscle cells, etc.

[0041] The use conditions (administration conditions) of the composition of the present invention are not particularly limited, and for example, the administration form, administration period, administration amount, etc. can be appropriately set according to the type of the administration target, etc.

[0042] The dosage of the composition of the present invention is not particularly limited. in vivo When the composition of the present invention is used, the density of the microbubbles can be appropriately determined according to the type, symptoms, age, and administration method of the subject. 8 / ml~5×10 12 When a composition of 100 mg / ml is administered to a human, the total amount of NO administered per day is, for example, 0.1 to 10 ml / kg body weight. The number of times the composition of the present invention is administered per day is, for example, 1 to 5 times, 1 to 3 times, and preferably once. In addition, when intravenously administered to an adult, the amount of NO administered per day is, for example, 2.5 mg, and the number of times per day is, for example, once. There is no particular limitation on the content of the compound in the aforementioned composition, and for example, it can be appropriately set according to the aforementioned daily administration amount. The composition of the present invention can be administered continuously or non-continuously. The aforementioned non-continuous administration can also be referred to as intermittent administration, for example. The composition of the present invention can be administered, for example, at specified intervals. The aforementioned specified intervals can be approximately equal intervals or equal intervals, or can be unequal intervals. The aforementioned specified intervals can include, for example, 8 to 12 hour intervals, 1 day intervals, etc.

[0043] There is no particular limitation on the form of administration of the composition of the present invention. in vivo When administering the composition of the present invention, it can be administered orally or parenterally. Examples of the parenterally administered method include intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, nasal administration, transpulmonary administration, intraperitoneal administration, and topical administration.

[0044] The dosage form of the composition of the present invention is not particularly limited, and can be appropriately determined according to the aforementioned administration form, for example. The aforementioned dosage form can be, for example, liquid or solid. As a specific example, the aforementioned dosage form can include release-regulated preparations (enteric preparations, sustained-release preparations, etc.), capsules, oral liquid preparations (elixirs, suspensions, emulsions, aromatic waters, lemonades, etc.), syrups (syrup preparations, etc.), granules (foaming granules, fine particles, etc.), powders, tablets (orally disintegrating tablets, chewable tablets, foaming tablets, dispersible tablets, dissolving agents, covered tablets, etc.), pills, oral gel preparations and other oral preparations; oral tablets (gels, sublingual preparations, lozenges, drops, buccal tablets, adhesive tablets, etc.), oral sprays, oral semisolid preparations, mouthwashes and other oral application preparations; injections (embedded injections, continuous injections, infusions (drip preparations, etc.), freeze-dried injections, powder injections, prefilled injections Preparations for injection such as oral administration (such as oral inhalation devices, cartridges, etc.); preparations for dialysis such as dialysis preparations (preparations for peritoneal dialysis, preparations for hemodialysis); preparations for bronchial and pulmonary application such as inhalation agents (inhalation aerosols, inhalation liquid preparations, inhalation powders, etc.); preparations for eye administration such as eye ointments and eye drops; preparations for ear administration such as ear drops; preparations for nasal application such as nasal drops (nasal liquid preparations, nasal powders, etc.); preparations for rectal application such as suppositories, rectal semisolid preparations, and enema; preparations for vaginal application such as vaginal suppositories and vaginal tablets; liquid preparations for external use (alcohol preparations, liniments, emulsions, etc.), creams, gels, solid preparations for external use (external powders, etc.), sprays (external aerosols, foaming pumps, etc.), patches (tapes, poultices, etc.), ointments, etc., etc. When the composition of the present invention is administered orally, the dosage form may include, for example, tablets, coated tablets, pills, fine granules, granules, powders, capsules, liquid preparations, syrups, emulsions, suspensions, etc. When the composition of the present invention is administered parenterally, the dosage form may include, for example, preparations for injection, preparations for drip administration, etc. When the composition of the present invention is administered percutaneously, the dosage form may include, for example, external medicines such as patches, coatings, ointments, creams, and lotions.

[0045] The composition of the present invention may include additives as needed, and when the composition of the present invention is used as a medicine or a pharmaceutical composition, the additives preferably include pharmaceutically acceptable additives or pharmaceutically acceptable carriers. The additives are not particularly limited, and for example, osmotic pressure regulators such as salts, base materials, excipients, colorants, lubricants, binders, disintegrants, stabilizers, coating agents, preservatives, pH adjusters, flavoring agents such as spices, etc. can be listed. In the present invention, the amount of the additives is not particularly limited as long as it does not hinder the function of NO.

[0046] Examples of the aforementioned excipients include sugar derivatives such as lactose, lactose hydrate, white sugar, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate, and magnesium aluminum; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and inorganic excipients such as sulfates such as calcium sulfate. Examples of the aforementioned colorants include yellow iron oxide, etc. Examples of the aforementioned lubricants include metal stearates such as stearic acid, calcium stearate, and magnesium stearate; talc; polyethylene glycol; silicon dioxide; hydrogenated vegetable oil, etc. Examples of the aforementioned flavoring and smelling agents include spices such as cocoa powder, menthol, incense powder, peppermint oil, borneol, and cinnamon powder, sweeteners, and acidulants. Examples of the aforementioned binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, etc. Examples of the aforementioned disintegrant include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starches and chemically modified celluloses such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate. Examples of the aforementioned stabilizer include parabens such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; sorbic acid, etc. Examples of the aforementioned coating agent include polyethylene glycols such as hypromellose and polyethylene glycol 6000, talc, titanium oxide, etc.

[0047] The composition of the present invention can, for example, dilate blood vessels of a subject to which it is administered. Therefore, the composition of the present invention can be suitably used as a therapeutic agent for diseases caused by vascular stenosis, for example.

[0048] <Vasodilator composition kit>

[0049] As described above, the vasodilator composition kit of the present invention comprises a vasodilator composition and other components, wherein the vasodilator composition and the other components are arranged in isolation, and the vasodilator composition is the vasodilator composition of the present invention. The composition kit of the present invention is characterized in that it comprises 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 referred to in the above.

[0050] The aforementioned other ingredients are not particularly limited and can be appropriately determined according to the content of the aforementioned composition and the purpose of administration to the subject. For example, the aforementioned additives, drugs, nutrients, etc. can be listed. Examples of the aforementioned drugs include antibiotics, etc. In the case where the osmotic pressure of the aforementioned composition is not adjusted, it is preferred that the aforementioned other ingredients contain an osmotic pressure regulator (substance). Examples of the aforementioned osmotic pressure regulating substances include sugars such as glucose; salts (electrolytes) such as sodium chloride, calcium chloride, calcium chloride, sodium bicarbonate, magnesium chloride, etc.; amino acids; proteins, etc. Examples of the aforementioned nutrients include sugars such as glucose, vitamins, etc. The aforementioned other ingredients may be solid or liquid. In the former case, the aforementioned other ingredients are configured in a state where they are not dissolved in a solvent, etc., for example, preferably configured to be dissolved when mixed with the aforementioned composition. In the latter case, the aforementioned other ingredients are preferably dissolved in a solvent, for example.

[0051] In the composition kit of the present invention, the composition and the other components are arranged in isolation, that is, the composition and the other components are arranged in an unmixed or non-contacted state. Specifically, the composition and the other components are arranged in different locations in the container containing them.

[0052] In the composition kit of the present invention, the aforementioned composition and the aforementioned other components are preferably contained in a container. In this case, the aforementioned container, for example, comprises a first chamber for containing the aforementioned composition and a second chamber for containing the aforementioned other components. In the aforementioned container, the aforementioned first chamber and the aforementioned second chamber may be each independently constituted, that is, constituted as independent containers, or may be integrally constituted, that is, constituted as one container. When the aforementioned first chamber and the aforementioned second chamber are constituted as one container, the aforementioned container preferably comprises a separation portion capable of isolating the aforementioned first chamber from the aforementioned second chamber. When the aforementioned container comprises a separation portion, the aforementioned first chamber and the aforementioned second chamber are, for example, arranged across the aforementioned separation portion. It is preferably constituted in the following manner: when the aforementioned composition and the aforementioned other components are mixed and administered to the subject of administration, the aforementioned separation portion can connect the aforementioned first chamber and the aforementioned second chamber.

[0053] The container having the first chamber and the second chamber may be, for example, a multi-chamber container for medical use. The multi-chamber container may be, for example, a plastic double-chamber bag in which a plurality of chambers are formed by providing the partition in a plastic bag (e.g., Japanese Patent Application Publication No. 2016-190646, Japanese Patent Application Publication No. 2016-131577, etc.), a dissolving solution kit in which a container containing other components and a container containing a dissolving solution (corresponding to the composition) are connected and integrated (e.g., International Publication No. 96 / 25136, etc.), a double-chamber prefilled syringe (e.g., Japanese Patent Application Publication No. 2012-245086, etc.), etc.

[0054] use Figure 1An example of the multi-chamber container containing the composition and the other components in the composition kit of the present invention will be described. Figure 1 : is a cross-sectional view showing an example of the composition kit of the present invention. Figure 1 As shown, the composition kit comprises a container 10, a composition 11, and other components 21. The container 10 comprises: a first chamber 1 storing the composition 11; a second chamber 2 storing other components 21; and a partition 3 that isolates the first chamber 1 from the second chamber 2 and enables communication between the first chamber 1 and the second chamber 2. The container 10 further comprises a hanging portion 5 on which the container 10 can be hung.

[0055] like Figure 1 As shown, the container 10 is formed by the sheet 13 and the sheet 14, and the discharge portion (discharge port) 22. Figure 1 As shown, the sheets 13 and 14 are welded to the sheet 13 at the upper end of the sheet 14, thereby forming the upper end 12 of the first chamber 1, and the lower end sides of the sheets 13 and 14 are connected to the discharge portion 22. In addition, the sheets 13 and 14 are welded at their central portions to form the partition 3. The weld of the partition 3 can be peeled off, and by applying pressure to the first chamber 1, the weld of the sheets 13 and 14 in the partition 3 is released, so that the first chamber 1 and the second chamber 2 are connected. In the container 10, the first chamber 1 is a space from the upper end 12 of the sheets 13 and 14 to the partition 3. In addition, in the container 10, the second chamber 2 is a space from the partition 3 of the sheets 13 and 14 to the discharge portion 22.

[0056] Plastic sheets can be used as the sheets 13 and 14. The aforementioned plastic sheet is preferably composed of multiple layers, for example, it has an inner surface layer, an outer surface layer, and an intermediate layer. As the aforementioned inner surface layer and the aforementioned outer surface layer, for example, thermoplastic resins such as thermoplastic olefin resins, thermoplastic propylene resins, and thermoplastic polyethylene resins can be used. By using such thermoplastic resins, the sheets 13 and 14 are stacked in a manner relative to each other and heat-sealed, thereby easily forming the outer periphery of the first chamber 1 and the second chamber 2, the upper end portion 12, and the isolation portion 3, and the container 10 can be manufactured. The aforementioned intermediate layer is preferably a resin with high flexibility, and as a specific example, a thermoplastic olefin resin composition can be used.

[0057] The volumes and shapes of the first chamber 1 and the second chamber 2 are not particularly limited and can be appropriately set according to, for example, the dosages of the aforementioned composition and other components.

[0058] The composition kit of the present invention can, for example, dilate blood vessels of a subject to which the composition kit is administered. Therefore, the composition kit of the present invention can be suitably used as a therapeutic drug for diseases caused by vascular stenosis, for example.

[0059] <Drug Composition>

[0060] The pharmaceutical composition for diseases caused by vascular stenosis or obstructive disorders of the present invention comprises the aforementioned vasodilator composition of the present invention. The pharmaceutical composition of the present invention is characterized by comprising the aforementioned composition of the present invention, and other constitutions and conditions are not particularly limited. According to the pharmaceutical composition of the present invention, the dosage of NO can be adjusted by adjusting the dosage of the aforementioned composition. According to the pharmaceutical composition of the present invention, since it can dilate narrowed blood vessels, it can treat diseases caused by vascular stenosis or obstructive disorders. The pharmaceutical composition of the present invention can refer to the description of the aforementioned composition and composition kit of the present invention.

[0061] In the present invention, the aforementioned "vascular stenosis or obstructive disorder" refers to, for example, an increase in vascular resistance or poor blood circulation that causes blood flow disorder.

[0062] 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 (angina attack).

[0063] In the present invention, "treatment" can be used in any meaning of the treatment, prevention, improvement, alleviation, mitigation, inhibition of symptom progression, and / or cessation of symptom progression of a disease. Therefore, the pharmaceutical composition of the present invention can also be referred to as a therapeutic drug, a preventive drug, an improving drug, a mitigating drug, a palliative drug, a progression inhibitor, and / or a progression stopper for a disease.

[0064] The pharmaceutical composition of the present invention can also be used as a pharmaceutical composition for diseases other than diseases caused by vascular stenosis.

[0065] <Drug kit>

[0066] The pharmaceutical kit for treating diseases caused by vascular stenosis or obstructive disorders of the present invention (hereinafter also referred to as "pharmaceutical kit") comprises the aforementioned vasodilator composition kit of the present invention. The pharmaceutical kit of the present invention is characterized by comprising the aforementioned 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 aforementioned composition. According to the pharmaceutical kit of the present invention, since it can dilate narrowed blood vessels, it can treat diseases caused by vascular stenosis or obstructive disorders. The pharmaceutical kit of the present invention can refer to the description of the aforementioned composition, composition kit, and pharmaceutical composition of the present invention.

[0067] The pharmaceutical kit of the present invention can also be used as a pharmaceutical kit for diseases other than diseases caused by vascular stenosis or obstructive disorders.

[0068] <Treatment Method>

[0069] The method for treating a disease caused by vascular stenosis or obstructive disorder of the present invention (hereinafter also referred to as "the method for treating") comprises a step of administering the aforementioned vasodilator composition of the present invention to a patient. The method for treating the present invention is characterized by administering the aforementioned composition of the present invention, and other steps and conditions are not particularly limited. According to the method for treating the present invention, the dosage of NO can be adjusted by adjusting the dosage of the aforementioned composition. According to the method for treating the present invention, since the narrowed blood vessels can be dilated, the disease caused by vascular stenosis or obstructive disorder can be treated. The method for treating the present invention can refer to the description of the aforementioned composition, composition kit, pharmaceutical composition, and pharmaceutical kit of the present invention.

[0070] The therapeutic method of the present invention can also be referred to as a treatment for a patient suffering from a disease caused by vascular stenosis or obstructive disorder. Therefore, the therapeutic method of the present invention can also be referred to as a treatment method for a disease caused by vascular stenosis or obstructive disorder.

[0071] The therapeutic method of the present invention may also use the aforementioned pharmaceutical composition as the aforementioned composition. In addition, the therapeutic method of the present invention may also use a composition kit or a pharmaceutical kit (hereinafter collectively referred to as a "kit") as the aforementioned composition.

[0072] When the treatment method of the present invention uses the aforementioned kit, in the aforementioned administration step, the aforementioned composition and the aforementioned other components may be administered simultaneously or separately. When the aforementioned composition and the aforementioned other components are administered simultaneously, the treatment method of the present invention preferably includes a mixing step of mixing the aforementioned composition and the aforementioned other components in the aforementioned kit before the aforementioned administration step. In this case, in the aforementioned administration step, the obtained mixture is administered to the patient.

[0073] The conditions for administering in the administering step can refer to the above-mentioned description.

[0074] Example

[0075] Next, examples of the present invention will be described. However, the present invention is not limited to the following examples.

[0076] [Example 1]

[0077] It was confirmed that the composition of the present invention reduces the calcium ion concentration in cardiac myoblasts.

[0078] NO-based vasodilation is caused by NO lowering the calcium ion concentration in vascular smooth muscle cells, thereby inhibiting the contraction of vascular endothelial cells. 2+) concentration was reduced, thereby confirming that the composition of the present invention has a vasodilation function.

[0079] (1) Preparation of composition

[0080] The composition of the present invention is used Figure 2 The microbubbles are manufactured by the manufacturing device 100 shown in FIG. Figure 2 As shown, in the manufacturing device 100, syringes 32 and 33 are arranged on both sides of the three-way stopcock 31. In the manufacturing device 100, the syringes 32 and 33 are connected through the three-way stopcock 31. First, the syringe 32 is released from the three-way stopcock 31, and 20 ml of Earle's balanced salt solution (EBSS) is introduced into it. The composition of EBSS is 26mmol / l NaHCO3, 1mmol / l NaH2PO4, 5.4mmol / l KCl, 116mmol / l NaCl, 5.5mmol / l glucose, and 2mmol / l CaCl2, pH 7.4. Then, the syringe 32 is connected to the three-way stopcock 31 again, and the gas in the three-way stopcock 31 is removed. After the above removal, the syringe 33 is released from the three-way stopcock 31, and 20 ml of medical nitric oxide (manufactured by TAIYO NIPPON SANSO CORPORATION, NO concentration: 99.0 (v / v)% or more) is introduced into it. Then, the syringe 33 was connected to the three-way stopcock 31 again. After the above connection, the plungers of the syringes 32 and 33 were continuously piston-moved in the outer cylinder for 10 minutes to produce microbubbles containing NO as a gas component, thereby producing the composition of the present invention (the composition of Example 1-1). In addition, for EBSS, the dissolved air in the EBSS was removed by degassing with argon gas (Ar degassing) in advance, and the composition (the composition of Example 1-2) was produced in the same manner.

[0081] (2) Characteristics of the composition

[0082] The composition obtained by (1) of Example 1 and the composition diluted 10 times or 100 times were left to stand for about 1 hour, and then the physical properties of the composition were measured using NanoSight (registered trademark) NS300 (manufactured by Malvern Instrument) using default parameters. It should be noted that the above measurement was performed at 25°C. As a result, the average diameter of the microbubbles in the above composition and the density of the microbubbles are as follows.

[0083] (Composition of Example 1-1 (NO UFB))

[0084] No dilution (×1):

[0085] Average diameter: 116.1±39.8nm, density: 3.52×10 9 ±1.12×10 8 Pieces / ml;

[0086] 10-fold dilution (×10):

[0087] Average diameter: 116.1±39.8nm, density: 1.06×10 9 ±2.97×10 7 Pieces / ml;

[0088] 100-fold dilution (×100):

[0089] Average diameter: 113.4±39.2nm, density: 1.51×10 8 ±6.57×10 6 Pieces / ml;

[0090] (Composition of Example 1-2 (Ar substitution, Ar NO UFB))

[0091] No dilution (×1):

[0092] Average diameter: 137.0±48.2nm, density: 2.89×10 9 ±4.10×10 7 Pieces / ml;

[0093] 10-fold dilution (×10):

[0094] Average diameter: 126.3±49.5nm, density: 7.81×10 8 ±1.38×10 7 Pieces / ml;

[0095] 100-fold dilution (×100):

[0096] Average diameter: 116.4±43.0nm, density: 1.13×10 8 ±3.29×10 6 Pieces / ml

[0097] (3) Determination of calcium ion concentration

[0098] The change in calcium ion concentration was measured using rat cardiac myogenic cells (H9C2). The culture medium of H9C2 cells was 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-glutamine, (Gibco)), 100 U / ml penicillin (FUJIFILM Wako Pure Chemical Corporation), 100 μg / ml streptomycin (FUJIFILM Wako Pure Chemical Corporation). H9C2 cells were pre-incubated at 3.0×10 3 Cells / 100 μl / well were seeded in 96-well plates and cultured until confluence was achieved. 2+ The concentration was determined using [Ca 2+ ]Fura 2-AM (Mw.: 1001.85, Dojin Chemical Co., Ltd., Cat. No.: F015) was used as the fluorescent probe for measurement.

[0099] First, a 1 mmol / l Fura 2-AM DMSO solution was added to EBSS to make 5 μmol / l, and then Pluronic (registered trademark) F-127 was added to make 0.01 (w / v)%, and ultrasonic dissolution was performed to prepare a loading buffer. Next, after removing the culture medium of H9C2 cells, an equal amount of loading buffer was added, and incubated at 37°C for 20 minutes, thereby allowing Fura2-AM to enter the H9C2 cells. After the above incubation, the cells were washed 4 times with EBSS. In addition, 100 μl of each composition was added, and after exposure, the fluorescence intensity change was measured over time to observe the intracellular Ca 2+ The excitation light in the above measurement is 340nm or 380nm, and the measurement wavelength of the obtained fluorescence is 510nm. 2+The relative value of the concentration was calculated as the ratio (340nm / 380nm) of the fluorescence intensity at 510nm at 340nm (340nm) to the fluorescence intensity at 510nm at 380nm (380nm). Control 1 (untreated) was performed in the same manner except that no treatment was performed. Control 2 (air UFB) was performed in the same manner except that a composition prepared by using air instead of NO was used. Control 3 (nifedipine) was performed in the same manner except that a 10μmol / l nifedipine solution was used instead of the aforementioned composition. Control 4 (dissolved NO) was measured in the same manner except that EBSS in which NO was dissolved was used instead of the aforementioned composition. These results are shown in Figure 3A ~D.

[0100] Figure 3A ~D is the intracellular Ca 2+ A graph showing the relative concentrations. Figure 3A The results of the composition of Example 1-1 and controls 1 to 4 are shown (×1). Figure 3B The results of the composition of Example 1-1 without dilution (×1) and Controls 1 to 5 using Ar-degassed EBSS are shown. Figure 3C The dilution series of the composition of Example 1-1 and the results of Control 1 are shown, Figure 3D The results of a dilution series of the compositions of Examples 1-2 and Control 1 are shown. Figure 3A In Figures 1 to 4, the horizontal axis represents the time after treatment with each composition, and the vertical axis represents the intracellular Ca 2+ Relative value of concentration.

[0101] like Figure 3A and Figure 3B As shown, in controls 1 to 4, intracellular Ca 2+ The concentration was almost unchanged or slightly decreased. In contrast, in the compositions of Example 1-1 and Example 1-2 without dilution (×1), the intracellular Ca 2+ In addition, it can be seen that the composition of the present invention has a stronger intracellular Ca 2+ The concentration reduction effect.

[0102] Then, if Figure 3C and Figure 3D As shown, intracellular Ca was observed in the compositions of Example 1-1 and Example 1-2 without dilution (×1), 10-fold dilution (×10), and 100-fold dilution (×100). 2+ The concentration decreased depending on the density (concentration) of the microbubbles. In addition, when comparing the results of the compositions of Example 1-1 and Example 1-2, the intracellular Ca 2+No significant difference was observed in the degree of reduction in concentration, indicating that the NO in the composition of the present invention was hardly oxidized in the composition. From these results, it can be seen that by adjusting the density and dosage of the microbubbles in the composition of the present invention, the degree of action can be adjusted and the NO in the microbubbles can be stabilized.

[0103] The above results suggest that the composition of the present invention reduces the calcium ion concentration in cardiac myocytes and has a vasodilation function.

[0104] [Example 2]

[0105] It was confirmed that the composition of the present invention exhibits a vasodilating effect.

[0106] A probe for detecting arterial pressure was inserted into the femoral artery of anesthetized inbred Lewis rats (♂, 10 weeks old) or dogs (Beagle, ♂, 1 year old). Then, the composition of Example 1-1 described above (×1) was administered from the femoral vein in an amount of 1 ml / kg body weight. Then, the blood pressure of the rats and dogs was measured over time after the administration. These results are shown in Figure 4 .

[0107] Figure 4 It is a graph showing changes in blood pressure over menstruation. Figure 4 In the figures, (A) shows the results for rats, and (B) shows the results for dogs. Figure 4 In the figure, the horizontal axis represents the time after administration of the aforementioned composition, and the vertical axis represents blood pressure. Figure 4 As shown in (A) and (B), blood pressure rapidly decreased after administration of the composition of Example 1-1, and the decrease in blood pressure continued until about 45 minutes after administration.

[0108] The above results show that the composition of the present invention exhibits a vasodilatory effect.

[0109] [Example 3]

[0110] It was confirmed that the composition of the present invention can suppress angina pectoris.

[0111] As angina pectoris model rats, Donryu rats, in which angina attacks can be induced by administering vasopressin (VP), were used. First, an electrocardiograph was installed on the Donryu rats, and a probe for detecting arterial pressure was inserted into the femoral artery, and the electrocardiogram and blood pressure were measured over time. Next, 1 ml / kg body weight of normal saline was administered to the Donryu rats through the femoral vein. Five minutes after the administration, vasopressin was administered through the femoral vein to induce an angina attack. After the end of the angina attack was confirmed on the electrocardiogram, 1 ml / kg body weight (×1) of the composition of Example 1-1 was administered to the Donryu rats through the femoral vein. Five minutes after the administration, vasopressin was administered through the femoral vein to induce an angina attack. These results are shown in Figure 5 and 6 .

[0112] Figure 5 It is a diagram showing an electrocardiogram. Figure 5 In the figures, (A) shows the results of Donryu rats administered with physiological saline, and (B) shows the results of Donryu rats administered with the composition of Example 1-1. Figure 5 In the figure, the left figure shows the electrocardiogram of a normal rat, and the right figure shows the electrocardiogram of a rat when angina pectoris was induced by administration of vasopressin. Figure 5 As shown in (A), when saline was administered, a characteristic decrease in ST was observed when vasopressin was administered. Figure 5 As shown in (B), when the composition of Example 1-1 was administered, the ST decrease characteristic of angina pectoris attack was not observed, and the angina pectoris attack was suppressed.

[0113] then, Figure 6 It is a graph showing the results of blood pressure and electrocardiogram. Figure 6 In the figure, (A) shows the result of blood pressure, and (B) shows the result of S wave of electrocardiogram. Figure 6 In (A), the horizontal axis represents the time after administration of physiological saline or the composition of Example 1-1, and the vertical axis represents the mean blood pressure. Figure 6 In (B), the horizontal axis represents the time after administration of physiological saline or the composition of Example 1-1, and the vertical axis represents the electrocardiogram. Figure 6 As shown in (A), it can be seen that after administration of the composition of Example 1-1, blood pressure was lowered and blood vessels were dilated. In addition, after administration of vasopressin, 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, Figure 6 As shown in (B), it was found that after administration of vasopressin, the S wave was significantly decreased in the group administered with physiological saline, whereas the decrease of the S wave was suppressed in the group administered with the composition of Example 1-1, thereby suppressing the onset of angina pectoris.

[0114] The above results show that the composition of the present invention can suppress angina pectoris.

[0115] [Example 4]

[0116] It was confirmed that the composition of the present invention exhibits a vasodilating effect.

[0117] The heart was removed from the Donryu rat of the aforementioned Example 3. Then, it was placed in a Langendorff perfusion apparatus and placed in an extracorporeal circulation environment. In this state, the coronary artery perfusion volume when 1 ml of the undiluted (×1) composition of Example 1-1 was applied to the circulating fluid was measured every 1 minute and the measurement was continued for 5 minutes. In addition, in the control, physiological saline was administered instead of the composition of the aforementioned Example 1-1, and the measurement was performed in the same manner. These results are shown in Figure 7 .

[0118] Figure 7 It is a graph showing coronary artery perfusion. Figure 7 In the figure, the horizontal axis represents the time after administration of physiological saline or the composition of Example 1-1, and the vertical axis represents the coronary artery perfusion. Figure 7 As shown, the coronary artery perfusion volume increased in the group administered with the composition of Example 1-1 (NO UFB) compared with the group administered with physiological saline (control). This is presumably because NO in the composition of Example 1-1 dilates the coronary artery and enables a larger amount of fluid to flow.

[0119] The above results show that the composition of the present invention exhibits a vasodilatory effect.

[0120] The present invention has been described above with reference to the embodiments and examples, but the present invention is not limited to the above-described embodiments and examples. The configuration and details of the present invention can be modified in various ways that can be understood by those skilled in the art within the scope of the present invention.

[0121] This application claims the benefit of priority based on Japanese patent application No. 2020-021195, filed on February 12, 2020, the disclosure of which is incorporated herein in its entirety.

[0122] <Appendix>

[0123] A part or all of the above-mentioned embodiments and examples are described as in the following appendix, but are not limited to the following contents.

[0124] (Appendix 1)

[0125] A vasodilator composition comprising microbubbles,

[0126] The aforementioned fine bubbles contain nitric oxide as a gas component.

[0127] (Appendix 2)

[0128] The vasodilator composition according to Appendix 1, wherein the density of the microbubbles is 5×10 5 ~5×10 12 Pieces / ml.

[0129] (Appendix 3)

[0130] The vasodilator composition according to Appendix 1 or 2, wherein the ratio of the nitric oxide in the gas component is 80% or more.

[0131] (Appendix 4)

[0132] The vasodilator composition according to any one of Appendixes 1 to 3, wherein the gas component does not substantially contain oxygen.

[0133] (Appendix 5)

[0134] The vasodilator composition according to any one of Appendixes 1 to 4, further comprising a medium, wherein the medium is at least one of a liquid and a solid.

[0135] (Appendix 6)

[0136] A vasodilator composition kit, comprising a vasodilator composition and other components,

[0137] The aforementioned vasodilator composition and the aforementioned other components are configured in an isolated manner,

[0138] The aforementioned vasodilator composition is the vasodilator composition described in any one of Appendixes 1 to 5.

[0139] (Appendix 7)

[0140] The vasodilator composition kit according to Appendix 6, further comprising a container,

[0141] The container comprises a first chamber, a second chamber, and a separation portion.

[0142] The vasodilator composition is contained in the first chamber.

[0143] The aforementioned other components are stored in the aforementioned second chamber,

[0144] The isolation portion isolates the first chamber from the second chamber and enables the first chamber to communicate with the second chamber.

[0145] (Appendix 8)

[0146] The vasodilator composition kit according to Appendix 6 or 7, wherein the other components include an osmotic pressure regulating substance.

[0147] (Appendix 9)

[0148] A pharmaceutical composition for treating a disease caused by vascular stenosis or obstructive disorder, comprising the vasodilator composition described in any one of Appendixes 1 to 5.

[0149] (Appendix 10)

[0150] The pharmaceutical composition according to Appendix 9, 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.

[0151] (Appendix 11)

[0152] The pharmaceutical composition according to Appendix 9 or 10, wherein the disease caused by vascular stenosis or obstructive disorder is angina pectoris,

[0153] The pharmaceutical composition is a pharmaceutical composition for preventing, inhibiting, reducing, improving, alleviating or relieving angina attacks.

[0154] (Appendix 12)

[0155] The pharmaceutical composition according to any one of Appendices 9 to 11, which is for intravenous administration.

[0156] (Appendix 13)

[0157] A pharmaceutical kit for treating diseases caused by vascular stenosis or obstructive disorders, comprising the vasodilator composition kit described in any one of Appendixes 6 to 8.

[0158] (Appendix 14)

[0159] The drug kit according to Appendix 13, 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.

[0160] (Appendix 15)

[0161] The pharmaceutical kit according to Appendix 13 or 14, wherein the disease caused by vascular stenosis or obstructive disorder is angina pectoris,

[0162] The drug kit is a drug kit for preventing, inhibiting, reducing, improving, alleviating, or relieving angina attacks.

[0163] (Appendix 16)

[0164] The pharmaceutical kit according to any one of Appendices 13 to 15, which is for intravenous administration.

[0165] (Appendix 17)

[0166] A method for treating a disease caused by vascular stenosis or obstructive disorder, comprising: administering the vasodilator composition described in any one of Appendixes 1 to 5 to a patient.

[0167] (Appendix 18)

[0168] A method for treating a disease caused by vascular stenosis or obstructive disorder, comprising the following steps:

[0169] In the vasodilator composition kit described in any one of Appendices 6 to 8, a mixing step of mixing the vasodilator composition and other ingredients;

[0170] The step of administering the obtained mixture to a patient.

[0171] (Appendix 19)

[0172] The treatment method according to Appendix 17 or 18, 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.

[0173] (Appendix 20)

[0174] The method of treatment according to Appendix 18 or 19, wherein the disease caused by vascular stenosis or obstructive disorder is angina pectoris,

[0175] By administering the aforementioned vasodilator composition or mixture, angina attacks can be prevented, inhibited, reduced, improved, alleviated, or relieved.

[0176] (Appendix 21)

[0177] The method of any one of Appendixes 17 to 20, wherein the vasodilator composition or mixture is administered intravenously.

[0178] (Appendix 22)

[0179] A vasodilator composition, which is a vasodilator composition for vasodilation,

[0180] The aforementioned vasodilator composition contains microbubbles,

[0181] The aforementioned fine bubbles contain nitric oxide as a gas component.

[0182] (Appendix 23)

[0183] A vasodilator composition, which is a vasodilator composition for treating diseases caused by vascular stenosis or obstructive disorders,

[0184] The aforementioned vasodilator composition contains microbubbles,

[0185] The aforementioned fine bubbles contain nitric oxide as a gas component.

[0186] (Appendix 24)

[0187] The vasodilator composition according to Appendix 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.

[0188] (Appendix 25)

[0189] The vasodilator composition according to Appendix 23 or 24, wherein the disease caused by vascular stenosis or obstructive disorder is angina pectoris,

[0190] The vasodilator composition is a vasodilator composition for preventing, inhibiting, reducing, improving, alleviating, or relieving angina attacks.

[0191] (Appendix 26)

[0192] A vasodilator composition according to any one of Appendixes 23 to 25, for intravenous administration.

[0193] Industrial Applicability

[0194] As described above, according to the present invention, the amount of NO administered can be adjusted. In addition, according to the composition of the present invention, the amount of NO administered can be adjusted, for example, the degree of vasodilation can also be adjusted. In addition, the composition of the present invention can be directly administered into the body of the subject to be administered, so for example, local administration can be performed in the same manner as administration by inhalation, and systemic administration can also be performed. Therefore, the present invention can be suitably used, for example, to treat diseases caused by vascular stenosis, and is extremely useful in the medical field, the pharmaceutical field, etc.

[0195] Description of Reference Numerals

[0196] 1 Room 1

[0197] 10 Container

[0198] 11 Composition

[0199] 12 Upper end

[0200] 13, 14 Sheet

[0201] 2 Room 2

[0202] 21 Other ingredients

[0203] 22 Discharge section

[0204] 3 Isolation

[0205] 5. Hanging part

Claims

1. A vasodilator composition for vasodilation, the vasodilator composition comprising microbubbles and a medium, The microbubbles contain nitric oxide as a gas component, The gas component is in direct contact with the medium, In the gas component, the proportion of nitric oxide is more than 80%, The gas composition contains substantially no oxygen, The density of the microbubbles is 1×10 8 ~5×10 12 Pieces / ml, The diameter of the microbubbles is less than 1 μm. The medium is a liquid, and the liquid is at least one selected from sol, physiological saline, buffer, infusion solution and water.

2. A vasodilator composition kit for vasodilation, the vasodilator composition kit comprising a vasodilator composition and other ingredients, The vasodilator composition and the other components are configured in an isolated manner, The vasodilator composition is the vasodilator composition according to claim 1.

3. The vasodilator composition kit according to claim 2, further comprising a container, The container has a first chamber, a second chamber, and a separation portion. The vasodilator composition is contained in the first chamber, The other components are stored in the second chamber, The isolation portion isolates the first chamber from the second chamber and enables communication between the first chamber and the second chamber.

4. The vasodilator composition kit according to claim 2 or 3, wherein: The other ingredients include an osmotic pressure regulating substance.

5. A pharmaceutical composition for diseases caused by vascular stenosis or obstructive disorders, comprising the vasodilator composition according to claim 1.

6. The pharmaceutical composition according to claim 5, 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.

7. The pharmaceutical composition according to claim 5 or 6, wherein The disease caused by vascular stenosis or obstructive disorder is angina pectoris, The pharmaceutical composition is a pharmaceutical composition for preventing or inhibiting angina attacks.

8. The pharmaceutical composition according to claim 5 or 6, which is for intravenous administration.

9. A pharmaceutical kit for treating a disease caused by vascular stenosis or obstructive disorder, comprising the vasodilator composition kit according to any one of claims 2 to 4.

10. The pharmaceutical kit according to claim 9, 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.

11. The pharmaceutical kit according to claim 9 or 10, wherein: The disease caused by vascular stenosis or obstructive disorder is angina pectoris, The drug kit is a drug kit for preventing or inhibiting angina attacks.

12. The pharmaceutical kit according to claim 9 or 10, which is for intravenous administration.

13. Use of the composition of claim 1 in the manufacture of a pharmaceutical composition for treating diseases caused by vascular stenosis or obstructive disorders.

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