External carbon dioxide agent

Abstract

To provide a nonaqueous carbon dioxide external preparation in single dosage form.SOLUTION: An external preparation comprises a paste base, carbonate, an acid and / or a substance which produces an acid by hydrolysis, and alcohol. By applying the external preparation to the skin, it is possible to readily achieve the unique effects of carbon dioxide. This renders the preparation beneficial.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a non-aqueous carbon dioxide external preparation that can be used by simply applying it to the skin or by additionally supplying water thereto.

Background Art

[0002] As carbon dioxide external preparations, there are compositions for preparing carbon dioxide external preparations comprising a combination of a water-containing viscous composition containing an acid or a carbonate and granules containing an acid or a carbonate, wherein the water-containing viscous compositions or the water-containing viscous composition and the granules are mixed to cause the acid and the carbonate to react to generate carbon dioxide (see Patent Documents 1 to 5); a material for preparing a carbon dioxide external preparation comprising a main agent in which a viscous substance containing at least an acid and water is impregnated in a stretchable polymer three-dimensional network structure and brought into contact with the skin during use, and a reactant containing at least a carbonate that generates carbon dioxide when brought into contact with the main agent during use, and generating carbon dioxide by the reaction of the main agent and the reactant (see Patent Document 6); a carbon dioxide-supplying skin cosmetic containing (A) a non-aqueous liquid composition containing a carbonate or a bicarbonate and (B) an acidic non-aqueous liquid composition, wherein the composition (A) and the composition (B) are mixed during use and further water is supplied thereto to generate carbon dioxide (see Patent Document 7); a foaming external preparation having (A) an acidic non-aqueous liquid composition and (B) a water-containing liquid composition containing a basic composition, and using the mixture of the (A) acidic non-aqueous liquid composition and the (B) water-containing liquid composition (see Patent Document 8); a gel-like substance or a two-component type foaming skin cosmetic having a viscosity of 4000 mPa·s or more at 20°C and being substantially non-aqueous (see Patent Document 9), etc. are disclosed.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

[0004] In a carbon dioxide topical preparation consisting of two or more ingredients, including an aqueous viscous composition, the aqueous viscous composition can contain only either an acid or a carbonate, and the majority of its weight is water, making it difficult to reduce the weight of the carbon dioxide topical preparation. Furthermore, topical carbon dioxide preparations consisting of two or more agents require all the necessary preparations to be mixed at the time of use to generate carbon dioxide, and then the resulting topical carbon dioxide preparation must be applied to the desired area, which is time-consuming. The foaming skin cosmetic preparation disclosed in Patent Document 9 is substantially non-aqueous and therefore lightweight, but two-component carbon dioxide topical preparations are specifically disclosed in Examples 1 to 10. Furthermore, although single-component skin cosmetic preparations are disclosed in Examples 11 and 12, both have problems with the physical properties of the gel, and in fact, it was not possible to obtain a gel-type skin cosmetic preparation whose physical properties could be evaluated (see Test Example 2 below). Therefore, there has been a demand for a single-component external carbon dioxide preparation that can provide sufficient and sustained carbon dioxide effects by simply supplying water and is easy to use. [Means for solving the problem]

[0005] The inventor of the present invention has found that a paste-like carbon dioxide external preparation composed of a paste base (hereinafter also simply referred to as "base"), alcohol, carbonate, acid and / or a substance that generates an acid by hydrolysis (hereinafter also referred to as "acid substitute") can obtain sufficient and continuous effects specific to carbon dioxide, such as vasodilatory effects, simply by applying it to the skin or by further supplying water, and thus completed the present invention.

Effects of the Invention

[0006] The carbon dioxide external preparation of the present invention has adhesiveness, so it can be applied to the skin, cloth, etc. By simply applying it to the skin or by further additionally supplying water, vasodilatory effects, muscle strength enhancing effects, fatigue recovery promoting effects, antitumor effects by cancer cell-specific apoptosis inducing effects, fracture healing promoting effects, wound healing promoting effects, lipid metabolism promoting effects, beauty effects, effects of improving pigmentation, and other effects specific to carbon dioxide can be obtained. It is convenient to carry and easy to use. In addition, since the carbon dioxide external preparation of the present invention can provide a previously known carbon dioxide gas pack agent by adding an appropriate amount of water and dissolving it in a container, it can also be used for the above purposes.

Modes for Carrying Out the Invention

[0007] In the carbon dioxide external preparation of the present invention, the paste base, alcohol, carbonate, acid and / or a substance that generates an acid by hydrolysis form a paste, and the carbon dioxide generation reaction does not occur until water is supplied, and they coexist stably. The carbon dioxide external preparation of the present invention is basically non-aqueous, but a small amount of water content is acceptable. The upper limit of the allowable water content of alcohol varies depending on the blending raw materials, but is approximately 2%. For the total amount of the carbon dioxide external preparation, the upper limit of the allowable water content is approximately 1.8%. The paste referred to in the present invention means a fluid that can be thinly spread and has a viscosity and adhesiveness such that it does not drip when applied to the skin, cloth, etc. The paste base referred to in the present invention means a substance that imparts viscosity to alcohol, and as the paste base, a carboxyvinyl polymer is preferred. In the present invention, an alkyl-modified carboxyvinyl polymer is regarded as equivalent to a carboxyvinyl polymer and can be used instead of the carboxyvinyl polymer or together with the carboxyvinyl polymer. In the present invention, bicarbonate is regarded as equivalent to carbonate and can be used instead of carbonate or together with carbonate.

[0008] When water is supplied to the carbon dioxide external preparation of the present invention, carbonate, an acid, and / or a substance that generates an acid by hydrolysis dissolve and react to generate carbon dioxide. When the carbon dioxide external preparation of the present invention contains an appropriate amount of moisture in the skin, just by applying it to the skin, mainly alcohol in the external preparation absorbs the moisture of the skin, and by this moisture, carbonate in the external preparation, and an acid and / or a substance that generates an acid by hydrolysis dissolve and react to generate carbon dioxide. At this time, the generated carbon dioxide is immediately absorbed by the skin and acts with almost no formation of bubbles. When the moisture of the skin is low or when it is desired to increase the amount of generated carbon dioxide, it is advisable to moisten the skin of the target site in advance. The method of moistening is not particularly limited, and the target site may be immersed in water, covered with a wet towel, etc., exposed to steam, or covered with a polymer film. Alternatively, after applying the carbon dioxide external preparation of the present invention to the target site, water may be sprayed on the surface of the external preparation, steam may be applied, or a wet towel may be covered to supply water. Alternatively, the skin may be steamed by covering it with a polymer film. Of course, these methods may be appropriately combined.

[0009] As the paste base used in the present invention, a carboxyvinyl polymer is preferred, and as the carboxyvinyl polymer, it can be used without particular limitation as long as it is soluble in alcohol and water. In the following description of the paste base, a carboxyvinyl polymer is used as a specific example, but the paste base of the carbon dioxide external preparation of the present invention can be used without particular limitation as long as it imparts viscosity to alcohol. In the carbon dioxide external preparation of the present invention, the blending amount of the carboxyvinyl polymer may be any amount as long as it forms a paste having a viscosity and adhesiveness that can be applied to the skin, cloth, etc. A suitable blending amount of the carboxyvinyl polymer is generally 0.1 to 40% by mass based on the total amount of the solid raw materials of the carbon dioxide external preparation of the present invention.

[0010] The carbon dioxide external preparation of the present invention may further contain a thickener. Here, the thickener is a thickener different from the carboxyvinyl polymer (hereinafter also referred to as "additional thickener"), and by this, the relative blending amount of the carboxyvinyl polymer is reduced, and the stringing phenomenon peculiar to the carboxyvinyl polymer is suppressed. Further, when an additional thickener having a slower dissolution or swelling rate in water than the carboxyvinyl polymer is used, the water absorption rate of the carbon dioxide external preparation becomes slower, and the dissolution rate of the carbonate and the acid and / or the substance that generates an acid by hydrolysis also becomes slower. Therefore, the generation rate of carbon dioxide is suppressed, and the generation of carbon dioxide becomes continuous, which is preferable. As the additional thickener, one or more selected from the group consisting of natural polymers, semi-synthetic polymers, synthetic polymers, and inorganic substances can be used. Examples of natural polymers include plant-based polymers such as gum arabic, carrageenan, galactan, agar, quince seed, guar gum, tamarind gum, tragacanth gum, pectin, mannan, locust bean gum, rice starch, wheat flour starch, corn starch, potato starch, etc.; microbial-based polymers such as curdlan, xanthan gum, succinoglucan, dextran, hyaluronic acid, pullulan, etc.; and protein-based polymers such as albumin, casein, collagen, gelatin, fibroin, etc.

[0011] Examples of semi-synthetic polymers include cellulose-based polymers such as ethyl cellulose, carboxymethyl cellulose and its salts, carboxymethyl ethyl cellulose and its salts, carboxymethyl starch and its salts, croscarmellose and its salts, crystalline cellulose, cellulose acetate, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, powdered cellulose, methyl cellulose, and methylhydroxypropyl cellulose; starch-based polymers such as pregelatinized starch, partially pregelatinized starch, carboxymethyl starch, dextrin, and methyl starch; alginic acid-based polymers such as alginic acid, sodium alginate, and propylene glycol alginate; and other polysaccharide-based polymers such as sodium chondroitin sulfate and sodium hyaluronate.

[0012] Examples of synthetic polymers include sodium polyacrylate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, polyvinylpyrrolidone, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl methacrylate copolymer, ethyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymer, and dimethylaminoethyl methacrylate-methyl methacrylate copolymer. Examples of inorganic substances include hydrous silicon dioxide, light anhydrous silicic acid, colloidal alumina, bentonite, laponite, and hectorite. Preferred thickeners other than carboxyvinyl polymers include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, sodium polyacrylate, carrageenan, hydroxyethyl cellulose, xanthan gum, and gellan gum. The amount of the additional thickener to be added is about 0.1 to 50 times, preferably about 5 to 20 times, the mass of the carboxyvinyl polymer.

[0013] The alcohol used in the carbon dioxide topical agent of the present invention is not particularly limited as long as it is liquid at room temperature and can be used in topical agents, and examples thereof include monohydric alcohols such as methanol, ethanol, n-propanol, and isopropanol; and polyhydric alcohols such as isopentyldiol, ethylene glycol, diethylene glycol, glycerin, diglycerin, 1,3-butylene glycol, 1,2-pentanediol, propanediol, propylene glycol, dipropylene glycol, hexylene glycol, and polyethylene glycol, and one or more of these can be used. Among these, polyhydric alcohols are preferred. The amount of alcohol to be added may be any amount that allows the topical carbon dioxide agent of the present invention to have a viscosity and adhesive strength that allows it to be applied to skin, cloth, etc., and that allows the alcohol-insoluble solid ingredients to form a paste with a viscosity that does not cause precipitation. The preferred amount of alcohol to be added is approximately 80 to 400% by mass of the total amount of the solid ingredients of the topical carbon dioxide agent of the present invention. In the carbon dioxide topical agent of the present invention, even if some of the alcohol-insoluble solid raw material precipitates, the topical agent can be stirred at the time of use to disperse the precipitate throughout.

[0014] In addition, the alcohol-insoluble solid raw material preferably has as small a particle size as possible and has the same or similar specific gravity so as to be less likely to precipitate in the carbon dioxide topical agent of the present invention. Alcohol is hygroscopic, and if its water content is above a certain level, carbon dioxide may be generated during the production of the carbon dioxide topical agent of the present invention.To prevent this, it is preferable to dry the alcohol before use.As a drying method, a known drying method suitable for the type of alcohol can be used, such as using a desiccant such as molecular sieve, calcium oxide, magnesium oxide, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulfate, silica, or zeolite.

[0015] A desiccant can be further added to the topical carbon dioxide agent of the present invention. Because alcohol is hygroscopic, the carbonate and acid and / or substances that generate acid by hydrolysis contained in the topical carbon dioxide agent of the present invention may dissolve in the water absorbed by the alcohol in the topical carbon dioxide agent, which may generate carbon dioxide before use. Therefore, by adding a desiccant, the carbon dioxide generating reaction can be prevented from occurring until water is supplied to the topical carbon dioxide agent. As the desiccant, any known desiccant that can be used for drying depending on the type of alcohol can be used. Examples include calcium oxide, magnesium oxide, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulfate, silica, zeolite, etc., and one or more of these can be used. Furthermore, anhydrous carbonates, acids and / or anhydrous substances that generate acids by hydrolysis can also be used as desiccants. Of course, these can also be used in combination with the above-mentioned desiccants.

[0016] The carbonate used in the carbon dioxide topical agent of the present invention is not particularly limited as long as it reacts with an acid to generate carbon dioxide, and examples thereof include ammonium carbonate, ammonium bicarbonate, potassium carbonate, potassium bicarbonate, potassium sesquicarbonate, sodium carbonate, sodium bicarbonate, sodium sesquicarbonate, magnesium carbonate, magnesium bicarbonate, calcium bicarbonate, and calcium carbonate, and one or more of these may be used. The preferred blending amount of carbonate is approximately 1 to 60 mass % relative to the total amount of the solid raw materials of the carbon dioxide external preparation of the present invention. To slow the rate of reaction with the acid, the carbonate may be formulated as slow-release granules or the like using conventional pharmaceutical means.

[0017] The acid used in the carbon dioxide topical agent of the present invention is not particularly limited as long as it reacts with carbonate to generate carbon dioxide, and one or more acids selected from the group consisting of organic acids or inorganic acids can be used. Examples of organic acids include dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, phthalic acid, isophthalic acid, and terephthalic acid; acidic amino acids such as glutamic acid and aspartic acid; and hydroxy acids such as glycolic acid, malic acid, tartaric acid, itatartaric acid, citric acid, isocitric acid, hydroxyacrylic acid, α-hydroxybutyric acid, glyceric acid, tartronic acid, salicylic acid, gallic acid, lactic acid, tropic acid, ascorbic acid, and gluconic acid. One or more of these may be used. Examples of inorganic acids include phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium sulfite, potassium sulfite, sodium pyrosulfite, potassium pyrosulfite, sodium acid hexametaphosphate, potassium acid hexametaphosphate, sodium acid pyrophosphate, potassium acid pyrophosphate, and sulfamic acid, and one or more of these may be used. The amount of acid to be added is an amount that can neutralize a portion, preferably all, of the carbonate in the carbon dioxide topical agent of the present invention. In order to slow down the reaction rate with the carbonate, in the case of a solid acid, it may be in the form of slow-release granules or the like using a conventional pharmaceutical means.

[0018] Substances that generate acid upon hydrolysis and are used in the topical carbon dioxide agent of the present invention include lactones such as glucono-delta-lactone and pantolactone, cyclic dimers of organic acids such as D,L- or L-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) and D,L- or L-glycolide, and acid anhydrides such as phthalic anhydride, maleic anhydride, and succinic anhydride, and one or more of these may be used. Since substances that generate acid by hydrolysis generate a small amount of acid at the beginning of dissolving in water, the amount of carbon dioxide generated at the beginning of supplying water to the carbon dioxide topical agent of the present invention may be smaller than when using an acid.By using this in combination with an acid, the amount of carbon dioxide generated can be made to be a certain level or more from the beginning of supplying water to the carbon dioxide topical agent of the present invention, and the generation of carbon dioxide can be sustained. The compounding quantity of the substance that generates an acid by hydrolysis is an amount that can neutralize a part, preferably all, of the carbonate used in the external preparation for carbon dioxide of the present invention. In order to suppress the reaction rate with the carbonate, the substance that generates an acid by hydrolysis may be sustained-release granules or the like using ordinary pharmaceutical means.

[0019] In the external preparation for carbon dioxide of the present invention, a water-soluble excipient can be further added. In the present invention, carbon dioxide is generated by the reaction of an acid and a carbonate, and water is required for this reaction. When the external preparation for carbon dioxide of the present invention contains a water-soluble excipient, the amount of water absorbed by the external preparation increases, the generation reaction of carbon dioxide is likely to occur, and the amount of carbon dioxide generated also increases. As the water-soluble excipient, those having solubility defined as "easily soluble" or "extremely easily soluble" described in the 15th revised Japanese Pharmacopoeia are preferable. Specifically, monosaccharides such as arabinose, galactose, glucose, xylose, sorbose, fructose, mannose, ribose, rhamnose, disaccharides such as sucrose, cellobiose, trehalose, maltose, lactulose, lactose, sugar alcohols such as arabitol, erythritol, xylitol, sorbitol, maltitol, mannitol, etc. can be mentioned, and one or more of these are used.

[0020] In the external preparation for carbon dioxide of the present invention, a heating agent can be further added. In the present invention, carbon dioxide is generated by the reaction of a carbonate and an acid in the presence of water, but this reaction is an endothermic reaction. When the amount of water is large, the temperature of the external preparation for carbon dioxide becomes low, and when applied to the skin, it may lower the skin temperature and prevent the blood flow increasing action by transdermal absorption of carbon dioxide. The heating agent can improve this problem. The exothermic agent can be, for example, calcium chloride, which generates heat of hydration when dissolved in water. The amount of exothermic agent to be added can be easily determined based on the amount of water used in the topical carbon dioxide agent of the present invention, the amount of heat generated per mass of the exothermic agent, and the desired water temperature. That is, if 5 g of water is added to the topical carbon dioxide agent of the present invention and the desired water temperature is to be raised by 5 degrees, then, in theory, 123 mg of calcium chloride should be added to the topical carbon dioxide agent. The amount of exothermic agent to be added can be freely selected, but a range of 5 to 30% by mass based on the total solid content of the topical carbon dioxide agent is preferred.

[0021] When the topical carbon dioxide agent of the present invention is dissolved or swollen with an appropriate amount of water, it generates carbon dioxide and becomes a viscous topical carbon dioxide agent. Adding a large amount of water is undesirable because it results in a viscous aqueous solution with low viscosity, which increases the dissipation of carbon dioxide. The mixing ratio of the topical carbon dioxide agent of the present invention to water is generally 0.1 to 40 parts by weight, preferably 0.5 to 10 parts by weight, per 1 part by weight of the topical carbon dioxide agent.

[0022] If the topical carbon dioxide agent of the present invention is applied directly to a moist wound surface, water is supplied to the topical agent from exudates on the wound surface, eliminating the need for additional water supply. Similarly, for organs and tissues with high water content, such as the oral cavity and large intestine, the topical carbon dioxide agent of the present invention can be applied directly, eliminating the need for additional water supply. Of course, even in this type of application, the amount of carbon dioxide generated can be increased by additionally supplying water. A preferred embodiment of the topical carbon dioxide preparation of the present invention comprises a carboxyvinyl polymer paste base to which malic acid and / or tartaric acid and sodium dihydrogen phosphate are added as acids, one or more dihydric or trihydric alcohols selected from 1,3-butylene glycol, propylene glycol, and glycerin as alcohols, one or more thickeners selected from hydroxypropyl cellulose, hydroxypropylmethylcellulose, carrageenan, sodium alginate, and sodium carboxymethylcellulose, and optionally sodium sulfate as a desiccant. The carbon dioxide external preparation of the present invention can be applied to a carrier and used as a sheet agent. When the carrier has water retention, it is preferable to add water to the carrier because the amount of carbon dioxide generated increases compared to simply attaching the sheet agent to the target site. Examples of the water-retaining carrier include woven fabric, non-woven fabric, sponge, etc., and one or more of these are used.

[0023] By injecting the carbon dioxide external preparation of the present invention into the large intestine, it absorbs the moisture in the large intestine and generates carbon dioxide, so it is possible to treat and prevent hemorrhoids, and also to treat constipation caused by a decrease in the defecation reflex function.

Examples

[0024] Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[0025] Examples 1 to 74 As shown in Tables 1-6, a carbon dioxide external preparation was prepared by a conventional method using a carbonate, an acid and / or a substance that generates an acid by hydrolysis (an acid or its substitute), an alcohol, a carboxyvinyl polymer (a base), and optionally a thickener different from the carboxyvinyl polymer (an additional thickener), a water-soluble excipient, and a desiccant. The numbers in the table indicate the parts by mass of each raw material. Unless otherwise specified, the alcohol was used as it was, such as a reagent. The amount of alcohol used after drying is indicated in italics. The drying of 1,3-butylene glycol and propylene glycol was carried out by adding anhydrous sodium sulfate to 1,3-butylene glycol or propylene glycol contained in a covered container such as a transparent or semi-transparent plastic bottle and stirring. Anhydrous sodium sulfate absorbs the moisture of the polyhydric alcohol and solidifies at the bottom of the container, but anhydrous sodium sulfate was added until the added anhydrous sodium sulfate did not solidify and remained in granular form and precipitated. Then, the lid of the container was tightened and left overnight, and the next day, it was confirmed that the sodium sulfate at the bottom of the container remained in fine granular form before use. The drying of glycerin was carried out by adding silicon dioxide, which was about 5% of the mass of glycerin, to the glycerin in a container with a lid, such as a transparent or translucent plastic bottle, using silicon dioxide instead of anhydrous sodium sulfate, and then shaking the container. After that, the lid of the container was tightened and left overnight, and it was used after the next day. Ethanol used was absolute ethanol.

[0026] [Table 1]

[0027] [Table 2]

[0028] [Table 3]

[0029] [Table 4]

[0030] [Table 5]

[0031] [Table 6]

[0032] Test Example 1 Physical Property Evaluation 1) Viscosity Thirty minutes after the preparation of the external carbon dioxide agent of the present invention in a glass beaker, when the glass beaker was tilted, if the external carbon dioxide agent immediately flowed out, it was evaluated as ×; if it flowed down slowly like honey, it was evaluated as △; if it did not flow down within 30 seconds even when the glass beaker was tilted, it was evaluated as ○. 2) Storage Stability In some of the examples, approximately 1 g of the topical carbon dioxide agent of the present invention was placed in an aluminum pouch measuring 115 mm × 90 mm, and after removing as much air as possible, the pouch was heat-sealed and stored at 40° C. After 4 weeks, the storage stability was evaluated by visual inspection, with pouches that expanded being rated as × and those that did not expand being rated as ○. The evaluation results are shown in Tables 8 and 9. All of the carbon dioxide external preparations of the present invention exhibited desirable viscosity and good storage stability.

[0033] Test Example 2 Comparison with Prior Art According to Example 11 of Patent Document 9, foaming skin cosmetics were prepared in a 50 ml glass beaker using 1.5 g of sodium bicarbonate, 50 mg of phenoxyethanol, 1.5 g of anhydrous citric acid, 100 mg of hydroxypropyl methylcellulose, and 6.85 g of 1,3-butylene glycol. A total of three preparations were performed using different production lots of hydroxypropyl methylcellulose. However, the viscosity of the resulting foaming skin cosmetics was insufficient, and solid ingredients settled to the bottom of the beaker. A 62-year-old man applied 1.5 g of the resulting foaming skin cosmetics to the back of his left hand in an attempt to evaluate them as shower cosmetics. However, all foaming skin cosmetics immediately dripped, making evaluation difficult. Test Example 3 Vasodilatory effect 1) Intensity and duration of redness The main basis for the effectiveness of topical carbon dioxide agents is the vasodilatory effect caused by the transdermal absorption of carbon dioxide (Tanaka Masaya, Carbon Dioxide Transdermal Absorption Agent "Eco Two Gel," Monthly Bioindustry, October 2006, pp. 74-83, CMC Publishing). Therefore, since the strength of the vasodilatory effect is proportional to the intensity of redness of the skin in the same subject, the degree of redness of the Example and the carbon dioxide gas pack Eco Two Gel BC (manufactured by CosmePro Co., Ltd.) was visually compared and evaluated.

[0034] [Table 7] Specifically, 0.2 g of the topical carbon dioxide agent of the present invention was applied to a 4 cm square area on the back of the left hand, and a 4 cm square piece of cotton soaked in approximately 2 g of purified water was immediately placed on top of it.The degree of redness and persistence of the redness of the skin under the topical agent were visually evaluated by one tester (a 62-year-old man) according to the following criteria.As a control, a topical carbon dioxide agent was prepared using the carbon dioxide gas pack Eco2 Gel BC (manufactured by CosmePro Co., Ltd.), and 1 g of this was applied to a 4 cm square area on the back of the right hand. 2)pH measurement It is known that the lower the pH of water, the greater the proportion of carbon dioxide present in molecular form (undissociated carbon dioxide), and the greater the amount absorbed percutaneously (see the aforementioned Monthly Bioindustry). Therefore, two minutes after application, the pH was measured by placing a pH test paper on the cotton pad to which the topical carbon dioxide agent of the present invention had been applied. The evaluation results, along with the physical property evaluation results, are shown in Tables 8 and 9. The external carbon dioxide preparation of the present invention generally exhibited a pH value in the acidic range, and the intensity and duration of reddening also showed favorable results.

[0035] [Table 8]

[0036] [Table 9]

[0037] Test Example 4 (Muscle Fatigue Recovery Test) It is known that transdermal absorption of carbon dioxide has muscle training effects and promotes recovery from muscle fatigue ( Journal of the Japanese Orthopaedic Association, 88:34-39, 2014). In Test Example 4, we investigated whether the topical carbon dioxide preparation of the present invention can restore grip strength caused by muscle fatigue. The test was conducted by an orthopedic specialist at an orthopedic clinic. Six male subjects were first tested for grip strength in both hands using a digital grip strength meter. Generally, grip strength is easier in the dominant hand. Therefore, to more accurately measure the effects of the topical carbon dioxide agent of the present invention, the agent was administered to the non-dominant hand. 1g of the external carbon dioxide agent of Example 65 was applied to the entire forearm of the non-dominant hand, and after resting for 10 minutes, the grip strength of both hands was measured.Since muscle fatigue occurs during the first grip strength measurement, if the grip strength is measured again 10 minutes after the measurement, the grip strength will usually decrease.If the external carbon dioxide agent of the present invention can recover muscle fatigue or increase muscle strength, it is expected that the grip strength of the non-dominant hand that has used the external carbon dioxide agent of the present invention will decrease less or increase more than the grip strength of the dominant hand that has not used the external carbon dioxide agent of the present invention. For example, if the grip strength of the dominant hand decreases by 1 kg due to muscle fatigue, the increase or decrease is -1 kg. If the increase or decrease in the grip strength of the non-dominant hand using the external carbon dioxide agent of the present invention is +1 kg, assuming that the muscle strength recovery ability of the left and right hands of each subject is approximately the same, the external carbon dioxide agent of the present invention will change the grip strength increase or decrease of -1 kg to +1 kg in the same subject, so the muscle fatigue recovery degree can be estimated to be +2 kg. Therefore, the recovered grip strength in this test is defined as follows:

number

[0038] [Table 10]

[0039] Test Example 5 (Joint Contracture Improvement Test) This test was conducted by a physical therapist. The subject was a 78-year-old woman with spastic muscles in the lower leg due to hemiplegia after stroke. No improvement in symptoms was observed with normal rehabilitation, and she had severe contracture and gait disturbance. When 1 g of the carbon dioxide external preparation of Example 61 was applied to the lower leg, the dorsiflexion angle of the ankle joint improved by 5 to 10 degrees approximately 10 minutes later, and walking became easier. Thus, the effect of improving joint contracture by the carbon dioxide external preparation of the present invention was clarified.

[0040] Test Example 6 (Pain Reduction Test) This test was conducted by a physical therapist. The subject was a 58-year-old woman with De Quervain's syndrome for whom the oral anti-inflammatory drug loxoprofen sodium was ineffective for pain. There was pain in the tendons of the extensor pollicis brevis and abductor pollicis longus on the radial side of the wrist joint. When 0.5 g of the carbon dioxide external preparation of Example 64 was applied to the target site, the pain almost disappeared approximately 10 minutes later. Thus, the pain reduction effect by the carbon dioxide external preparation of the present invention was clarified.

[0041] Test Example 7 (Pain Reduction Test) This test was conducted by a physical therapist. The subject was a 16-year-old male baseball pitcher who had pain during pitching in the area of the latissimus dorsi at the lower angle of the right scapula and for whom diclofenac sodium ointment was ineffective for pain. When 0.3 g of the carbon dioxide external preparation of Example 64 was applied to the target site, the pain almost disappeared approximately 10 minutes later, and pitching could be performed at full strength. Thus, the pain reduction effect by the carbon dioxide external preparation of the present invention was clarified. As is clear from the above, it is obvious that the carbon dioxide external preparation of the present invention can obtain an excellent carbon dioxide external preparation with a large percutaneous absorption amount of carbon dioxide and a continuous generation of carbon dioxide by simply applying it to the skin or further supplying water.

[0042] Test Example 8 (Ganglion Treatment Test) This test was conducted by an athletic trainer. The subject was a male gymnast in his 20s who had a ganglion on the front of his right ankle, approximately 1 cm in diameter and 4 mm in height. When 0.1 g of the topical carbon dioxide preparation of Example 73 was applied to the ganglion and surrounding skin once daily for one week, the ganglion completely disappeared, demonstrating the therapeutic effect of the topical carbon dioxide preparation of the present invention on ganglion cysts.

[0043] Test example 9 (test to improve rheumatoid pain and knee stiffness) The subject was a woman in her 80s whose rheumatoid arthritis-related knee stiffness and pain had not improved with oral anti-inflammatory drugs such as loxoprofen sodium. When 0.1 g of the topical carbon dioxide preparation of Example 73 was applied to the skin of the knee once a day, after 2-3 days she no longer woke up in the middle of the night due to knee pain and found walking easier, demonstrating the effectiveness of the topical carbon dioxide preparation of the present invention in improving rheumatoid pain and knee stiffness.

[0044] Test Example 10 (Pigmentation Improvement Test) The subject was a woman in her 40s who had undergone pubic hair removal at a medical institution and had brown pigmentation in the bald area. When 0.1 g of the topical carbon dioxide preparation of Example 72 was applied once a day to the pigmented area, the pigmentation disappeared after one week, a time when the anti-inflammatory drugs and other medications taken by the subject usually do not have any effect. This clearly demonstrated the pigmentation-improving effect of the topical carbon dioxide preparation of the present invention. [Industrial Applicability]

[0045] The topical carbon dioxide agent of the present invention is useful because it is composed of a paste base, alcohol, carbonate, acid, and / or a substance that generates acid upon hydrolysis, and can provide the effects unique to carbon dioxide simply by applying it to the skin, or by further adding water.

Claims

【Claim 1】 A non-aqueous paste-like external agent for carbon dioxide, comprising: a) a paste base, b) an alcohol, c) a carbonate and / or a hydrogen carbonate, and d) an acid and / or a substance that generates an acid upon hydrolysis, wherein, as a), 0.1-10% by mass of a carboxyvinyl polymer and / or an alkyl-modified carboxyvinyl polymer; as b), 40-95% by mass of one or more alcohols selected from the group consisting of 1,3-butylene glycol, propylene glycol, glycerin, and polyethylene glycol that is liquid at room temperature; as c), 1-20% by mass of a carbonate and / or a hydrogen carbonate; and as d), 0.1-20% by mass of an acid and / or a substance that generates an acid upon hydrolysis; wherein, as d), sodium dihydrogen phosphate is selected, An external agent for carbon dioxide for use by applying the agent directly to the skin without additionally supplying water to the skin, whether before or after application.

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