Carbon dioxide external preparation

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 topical preparation that can be used simply by applying it to the skin or by additionally supplying water. [Background technology]

[0002] As topical carbon dioxide agents, compositions for preparing topical carbon dioxide agents are available, which are composed of a combination of an aqueous viscous composition containing an acid or a carbonate and granules containing an acid or a carbonate, and which generate carbon dioxide by mixing the aqueous viscous compositions together or the aqueous viscous composition with the granules, causing the acid and the carbonate to react with each other (see Patent Documents 1 to 5); and materials for preparing topical carbon dioxide agents, which are composed of an elastic polymer three-dimensional network structure impregnated with a viscous substance containing at least an acid and water, and which are made of a base agent that comes into contact with the skin during use, and a reacting agent containing at least a carbonate that generates carbon dioxide upon contact with the base agent during use, and generate carbon dioxide by the reaction between the base agent and the reacting agent (see Patent Document 6). ); a carbon dioxide-supplying skin cosmetic which contains (A) a non-aqueous liquid composition containing a carbonate or bicarbonate and (B) an acidic non-aqueous liquid composition, and which, when used, mixes the compositions (A) and (B) and then supplies water to generate carbon dioxide (see Patent Document 7); a foaming topical preparation which contains (A) an acidic non-aqueous liquid composition and (B) an aqueous liquid composition containing a basic composition, and which is used by mixing the (A) acidic non-aqueous liquid composition with the (B) aqueous liquid composition (see Patent Document 8); and a gel-like or two-component foaming skin cosmetic which has a viscosity of 4000 mPa·s or more at 20°C and is substantially non-aqueous (see Patent Document 9). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2000-319187 [Patent Document 2] International Publication No. 2002 / 80941 [Patent Document 3] International Publication No. 2006 / 80398 [Patent Document 4] International Publication No. 2003 / 57228 [Patent Document 5] International Publication No. 2005 / 16290 [Patent Document 6] International Publication No. 2004 / 4745 [Patent Document 7] Japanese Patent Publication No. 2005-89357 [Patent Document 8] Japanese Patent Publication No. 2015-180610 [Patent Document 9] Japanese Patent Publication No. 2005-194233 Summary of the Invention [Problem to be solved by the invention]

[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 present inventors have discovered that a paste-like topical carbon dioxide preparation, which consists essentially of a paste base (hereinafter simply referred to as "base"), alcohol, carbonate, acid, and / or a substance that generates acid upon hydrolysis (hereinafter also referred to as "acid substitute"), can sufficiently and sustainably achieve the vasodilatory effects unique to carbon dioxide simply by applying it to the skin, or by further adding water, and have completed the present invention. [Effects of the Invention]

[0006] The topical carbon dioxide agent of the present invention is adhesive and can be applied to the skin, cloth, etc., and by simply applying it to the skin, or by additionally supplying water, it can provide the effects unique to carbon dioxide, such as vasodilatory effects, muscle strengthening effects, promoting fatigue recovery, antitumor effects through the induction of cancer cell-specific apoptosis, promoting fracture healing, promoting wound healing, promoting lipid metabolism, beautifying the skin, and improving pigmentation, and is convenient to carry and use. Furthermore, the carbon dioxide topical agent of the present invention can be used for the above-mentioned purpose by adding an appropriate amount of water to dissolve it in a container to provide a conventional carbon dioxide gas pack. DETAILED DESCRIPTION OF THE INVENTION

[0007] The topical carbon dioxide agent of the present invention is a paste containing a paste base, alcohol, carbonate, acid, and / or a substance that generates acid upon hydrolysis, which coexist stably without causing a carbon dioxide generating reaction until water is added. The topical carbon dioxide preparation of the present invention is basically non-aqueous, but it may contain a small amount of water. The upper limit of the water content of the alcohol is approximately 2%, depending on the ingredients. The upper limit of the water content of the total volume of the topical carbon dioxide preparation is approximately 1.8%. The paste referred to in the present invention refers to a fluid substance that can be spread thinly and has a viscosity and adhesive strength that prevents it from dripping when applied to the skin, cloth, etc. The paste base in this invention refers to a substance that imparts viscosity to alcohol, and a carboxyvinyl polymer is preferred as the paste base. In this invention, alkyl-modified carboxyvinyl polymers are considered equivalent to carboxyvinyl polymers and can be used instead of or together with carboxyvinyl polymers. For purposes of this invention, bicarbonates are considered equivalent to carbonates and can be used in place of or in conjunction with carbonates.

[0008] When water is supplied to the carbon dioxide external preparation of the present invention, the carbonate and the acid and / or the substance that generates acid upon hydrolysis dissolve and react to generate carbon dioxide. When the skin is adequately moist, the topical carbon dioxide agent of the present invention can be applied to the skin. The moisture in the agent, primarily the alcohol, absorbs the moisture. The moisture dissolves and reacts with the carbonate salt in the agent and the acid and / or substances that generate acid upon hydrolysis, generating carbon dioxide. The generated carbon dioxide is immediately absorbed by the skin without forming bubbles, achieving its intended effect. When skin moisture is low or when increased carbon dioxide generation is desired, it is advisable to moisten the skin at the target site beforehand. Moisturizing methods are not particularly limited, and include immersing the target site in water, covering it with a wet towel, exposing it to steam, or covering it with a polymer film. Alternatively, after applying the topical carbon dioxide agent of the present invention to the target site, moisture can be supplied by pouring water, exposing it to steam, or covering it with a wet towel. Alternatively, the skin can be steamed by covering it with a polymer film. Of course, these methods can also be combined as appropriate.

[0009] Carboxyvinyl polymer is suitable as the paste base used in the present invention, and any carboxyvinyl polymer can be used without particular limitation as long as it is soluble in alcohol and water. In the following explanation of the paste base, carboxyvinyl polymer is used as a specific example, but the paste base of the carbon dioxide topical agent of the present invention can be used without particular limitation as long as it imparts viscosity to alcohol. The amount of carboxyvinyl polymer in the topical carbon dioxide agent of the present invention may be any amount that results in a paste-like substance with a viscosity and adhesive strength that allows application to skin, cloth, etc. The preferred amount of carboxyvinyl polymer is approximately 0.1 to 40% by mass of the total amount of solid raw materials in the topical carbon dioxide agent of the present invention.

[0010] The topical carbon dioxide preparation of the present invention may further contain a thickener. Here, the thickener is a thickener other than the carboxyvinyl polymer (hereinafter also referred to as "additional thickener"), which reduces the relative amount of carboxyvinyl polymer blended and suppresses the stringiness characteristic of carboxyvinyl polymer. Furthermore, the use of an additional thickener that dissolves or swells in water more slowly than the carboxyvinyl polymer slows the water absorption rate of the topical carbon dioxide preparation and also slows the dissolution rate of carbonates and acids and / or substances that generate acids by hydrolysis, thereby suppressing the rate of carbon dioxide generation and ensuring sustained carbon dioxide generation, 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, and potato starch; microbial polymers such as curdlan, xanthan gum, succinoglucan, dextran, hyaluronic acid, and pullulan; and protein-based polymers such as albumin, casein, collagen, gelatin, and fibroin.

[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 addition, even if some of the alcohol-insoluble solid raw material precipitates in the carbon dioxide topical agent of the present invention, 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 amount of the substance that generates an acid upon hydrolysis is an amount that can neutralize a portion, preferably all, of the carbonate used in the carbon dioxide topical agent of the present invention. To slow the rate of reaction with carbonate, the substance that generates acid upon hydrolysis may be formulated into slow-release granules or the like using conventional pharmaceutical means.

[0019] The topical carbon dioxide preparation of the present invention can further contain a water-soluble excipient. In the present invention, carbon dioxide is generated by the reaction of an acid with a carbonate, and this reaction requires water. If the topical carbon dioxide preparation of the present invention contains a water-soluble excipient, the amount of water absorbed by the topical carbon dioxide preparation increases, making it easier for the carbon dioxide generating reaction to occur and increasing the amount of carbon dioxide generated. The water-soluble excipient is preferably one having a solubility defined as "easily soluble" or "extremely soluble" as described in the 15th edition of the Japanese Pharmacopoeia. Specific examples include monosaccharides such as arabinose, galactose, glucose, xylose, sorbose, fructose, mannose, ribose, and rhamnose, disaccharides such as sucrose, cellobiose, trehalose, maltose, lactulose, and lactose, and sugar alcohols such as arabitol, erythritol, xylitol, sorbitol, maltitol, and mannitol. One or more of these may be used.

[0020] The topical carbon dioxide preparation of the present invention can further contain a heat-generating agent. In the present invention, carbon dioxide is generated by the reaction of carbonate with acid in the presence of water. This reaction is endothermic, and if the amount of water is large, the temperature of the topical carbon dioxide preparation will be low, which may lower the skin temperature when applied to the skin and hinder the blood flow-increasing effect caused by the transdermal absorption of carbon dioxide. The heat-generating agent can alleviate 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 topical carbon dioxide agent of the present invention can be applied to a carrier and used as a sheet. If the carrier has water retention properties, impregnating the carrier with water is preferable because it increases the amount of carbon dioxide generated compared to simply applying the sheet to the target area. Examples of the water-retentive support include woven fabric, nonwoven fabric, and sponge, and one or more of these may be used.

[0023] When injected into the large intestine, the carbon dioxide topical agent of the present invention absorbs water in the large intestine and generates carbon dioxide, making it possible to treat and prevent hemorrhoids and also to treat constipation caused by a decrease in defecation reflex function. [Example]

[0024] The present invention will now be described in detail 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, topical carbon dioxide preparations were prepared using carbonate, acid and / or substances that generate acid upon hydrolysis (acid or substitutes), alcohol, carboxyvinyl polymer (base), and, if necessary, a thickener other than carboxyvinyl polymer (additional thickener), water-soluble excipient, and desiccant in a conventional manner. The numbers in the tables indicate the parts by weight of each ingredient. Unless otherwise specified, the alcohol was used 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 in a lidded container such as a transparent or translucent plastic bottle and stirring. Anhydrous sodium sulfate absorbs the moisture from the polyhydric alcohol and solidifies at the bottom of the container, but the added anhydrous sodium sulfate did not solidify and remained as granules until it precipitated. The container was then closed and left overnight. The next day, it was confirmed that the sodium sulfate at the bottom of the container remained as fine granules before use. Glycerin was dried using silicon dioxide instead of anhydrous sodium sulfate by adding silicon dioxide in an amount of about 5% of the mass of glycerin to glycerin contained in a lidded container such as a transparent or translucent plastic bottle, and then shaking the container.The container was then closed and left overnight, and used the next day or later. Absolute ethanol was used.

[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 preparing the topical carbon dioxide agent of the present invention in a glass beaker, the glass beaker was tilted. If the topical carbon dioxide agent immediately flowed out, it was evaluated as X; if it flowed out slowly like honey, it was evaluated as △; if it did not flow out within 30 seconds of tilting the glass beaker, 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 hemiplegia due to a stroke who had spastic muscles in her lower leg. Conventional rehabilitation did not improve her symptoms, and she had severe contracture and difficulty walking. When 1 g of the topical carbon dioxide preparation of Example 61 was applied to her lower leg, approximately 10 minutes later, the ankle dorsiflexion angle improved by 5 to 10 degrees, making walking easier. This clearly demonstrated the effect of the topical carbon dioxide preparation of the present invention in improving joint contracture.

[0040] Test Example 6 (Pain Relief Test) This study 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 in alleviating her pain. She experienced pain in the tendons of the extensor pollicis brevis and abductor pollicis longus on the flexible side of the wrist. When 0.5 g of the topical carbon dioxide preparation of Example 64 was applied to the target area, the pain almost disappeared after approximately 10 minutes, demonstrating the pain-reducing effect of the topical carbon dioxide preparation of the present invention.

[0041] Test Example 7 (Pain Relief Test) This test was conducted by a physical therapist. The subject was a 16-year-old male baseball pitcher who experienced pain in the area of ​​the latissimus dorsi muscle at the right inferior angle of the scapula when pitching, and diclofenac sodium ointment had not been effective in alleviating the pain. When 0.3 g of the topical carbon dioxide preparation of Example 64 was applied to the target area, the pain nearly disappeared after approximately 10 minutes, and the subject was able to pitch with full force, demonstrating the pain-reducing effect of the topical carbon dioxide preparation of the present invention. As is clear from the above, it is clear that the topical carbon dioxide agent of the present invention can be obtained as an excellent topical carbon dioxide agent that has a large amount of transdermal absorption of carbon dioxide and sustained carbon dioxide generation, simply by applying it to the skin or by 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] An invention as described in either the claims or the specification.