Tranexamic acid-containing preparations

Abstract

PROBLEM TO BE SOLVED: To solve a problem of a pharmaceutical preparation in which tranexamic acids is blended that when the preparation is attached near a mouth of a container housing the preparation, a phenomenon that moisture vaporizes with lapse of time to precipitate hard crystal occurs, fastening of a cap becomes poor, or crystal enters the pharmaceutical preparation use feeling is impaired.SOLUTION: The above-described problem is solved when 2 or more types of water-soluble polymers selected from carboxyvinyl polymer, xanthan gum, and alginate are blended into a pharmaceutical preparation blended with tranexamic acids. Furthermore, the above-described problem is solved when glycerol is blended by 2 to 10 wt.% of the pharmaceutical preparation, and a pharmaceutical preparation with excellent use feeling can be obtained.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a preparation containing tranexamic acids. [Background technology]

[0002] Tranexamic acid or its derivatives or salts (tranexamic acids) are known to have the effect of suppressing rough skin and pigmentation, and are often used as ingredients in topical skin preparations such as cosmetics. However, tranexamic acid is highly crystalline, and when a cosmetic or other preparation adheres to the mouth of a container, the water evaporates over time, causing hard crystals to precipitate. This causes problems such as the cap not fitting tightly or the crystals getting mixed into the preparation, impairing its usability. To address this issue, various methods have been attempted. For example, efforts have been made to solve the above problem by incorporating specific surfactants (Patent Documents 1 to 3), silica-coated zinc oxide (Patent Document 4), polyhydroxy acid (Patent Document 5), or inositol and polyhydric alcohol (Patent Document 6) into the formulation together with tranexamic acid to suppress crystal precipitation, or by devising the shape of the container for storing the formulation containing tranexamic acid. Furthermore, although precipitation can be suppressed by increasing the amount of polyhydric alcohol such as glycerin, this makes the product unsuitable for use from an organoleptic standpoint. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2005-68076 [Patent Document 2] Japanese Patent Application Laid-Open No. 2011-84551 [Patent Document 3] Japanese Patent Application Laid-Open No. 2011-195460 [Patent Document 4] Japanese Patent Application Laid-Open No. 2012-201660 [Patent Document 5] Japanese Patent Application Laid-Open No. 2013-121955 [Patent Document 6] Japanese Patent Application Laid-Open No. 2016-121092 DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0004] Although tranexamic acid-containing formulations are effective, they have problems with sensory limitations and the suppression of crystallization. Furthermore, there is a need for a formulation that does not cause crystal precipitation over a long period of time, has no sensory limitations, and can be applied to a wide variety of formulations. [Means for solving the problem]

[0005] As a result of extensive research, the present inventors have found that by blending two or more water-soluble polymers selected from carboxyvinyl polymer, xanthan gum, and alginate, it is possible to suppress the precipitation of tranexamic acids while still providing a good feel when used, and have thus completed the present invention.

[0006] Tranexamic acid refers to trans-4-aminomethylcyclohexane-1-carboxylic acid. The derivatives of tranexamic acid are not particularly limited, but include esters and amides. Examples of tranexamic acid esters include tranexamic acid lauryl ester, tranexamic acid hexadecyl ester, and tranexamic acid cetyl ester, and examples of tranexamic acid amides include tranexamic acid methylamide. Examples of salts of tranexamic acid or its derivatives include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, zinc salt, iron salt, ammonium salt, salts with basic amino acids such as arginine, histidine, lysine, ornithine, and salts with amines such as monoethanolamine, diethanolamine, triethanolamine, etc. Of these, sodium salt, potassium salt, triethanolamine salt, and arginine salt are preferred when the formulation is used as an external preparation for skin. There are no particular restrictions on the amount of tranexamic acid or its derivatives or salts thereof to be added, but crystal precipitation becomes a problem mainly when the amount is 0.5% by weight or more.

[0007] The carboxyvinyl polymer is an acidic polymer mainly composed of acrylic acid polymer, and commercially available products can be used, such as Hiviswako 103, 104, and 105 (manufactured by Wako Pure Chemical Industries, Ltd.) and the Carbopol series (manufactured by BFGoodrich). Xanthan gum is a polysaccharide obtained by fermentation of the fungus Xanthomonas campestris, and is used as a water-soluble thickener, gelling agent, emulsifier, dispersion / suspension stabilizer, etc. Specific examples include Kelzan and Keltrol (both manufactured by Kelco, USA), Roadpol (manufactured by Rhone-Poulenc Japan Co., Ltd.), Echogum (manufactured by Dainippon Pharmaceutical Co., Ltd.), and San-Ace (manufactured by San-Ei Gen FFI, Inc.). Alginic acid is a linear acidic sugar composed of mannuronic acid and guluronic acid, which are linked by 1,4 bonds. It is a block copolymer consisting of randomly bonded homopolymer fractions of mannuronic acid, homopolymer fractions of guluronic acid, and fractions in which mannuronic acid and guluronic acid are randomly arranged. It is extracted from brown algae, such as kelp and wakame seaweed. There are various water-soluble salts, but sodium salts are commonly used due to their high solubility in water.

[0008] The amount of carboxyvinyl polymer to be added varies depending on the type of tranexamic acid or carboxyvinyl polymer, the type and amount of other ingredients, and the pH, but the effect of suppressing crystal precipitation is exhibited when the amount is 0.01% by weight or more, preferably 0.03% by weight or more, and more preferably 0.05% by weight or more. The amount of xanthan gum or alginate to be added varies depending on the type of tranexamic acid, xanthan gum, or alginate, and the types and amounts of other ingredients added, but the effect of suppressing crystal precipitation is exerted when added at 0.005% by weight or more, preferably 0.01% by weight or more. The upper limit of the amount of carboxyvinyl polymer, xanthan gum, and alginate to be added varies greatly depending on the type of these polymers and the amount of other water-soluble polymers to be added. However, for carboxyvinyl polymer, the amount is preferably 0.5% by weight or less, and for xanthan gum and alginate, the combined amount of xanthan gum and alginate is preferably 2.0% by weight or less. If the upper limit is exceeded, the feel during use will be poor, and the expected quality may not be achieved depending on the application of the formulation. Although there is no problem with blending water-soluble polymers other than carboxyvinyl polymer, xanthan gum, and alginate, suppressing the precipitation of tranexamic acids crystals using water-soluble polymers other than carboxyvinyl polymer, xanthan gum, and alginate requires a much larger blending amount than a combination of two or more of carboxyvinyl polymer, xanthan gum, and alginate, which results in a poor feel when used and makes the product unsuitable for use. Furthermore, as a result of the inventor's investigations, it was found that a combination of a carboxyvinyl polymer and xanthan gum, and a combination of a carboxyvinyl polymer and alginate were particularly effective in the present invention. Furthermore, the viscosity of these water-soluble polymers has little effect on the precipitation of tranexamic acids crystals, but the amount of water-soluble polymer that is added has a proportional effect, so the grade of these water-soluble polymers is selected depending on the purpose.

[0009] While other ingredients may be selected arbitrarily, the inclusion of a polyhydric alcohol is useful for suppressing crystal precipitation. Glycerin is particularly effective, and although the amount varies greatly depending on the type and amount of other polyhydric alcohols, tranexamic acids, carboxyvinyl polymers, xanthan gum, alginates, and other ingredients, it has been found that adding 2 to 10% by weight, and more preferably 5 to 10% by weight, of glycerin significantly suppresses the precipitation of tranexamic acid crystals. However, if the amount exceeds 10% by weight, the feel of use deteriorates and the expected quality may not be achieved depending on the application of the formulation. Of course, polyhydric alcohols other than glycerin can also be added. Examples include polyhydric alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, and higher polyethylene glycols; propylene glycol, dipropylene glycol, and higher polypropylene glycols; butylene glycols such as 1,3-butylene glycol and 1,4-butylene glycol; diglycerin and higher polyglycerins; sugar alcohols such as sorbitol, mannitol, xylitol, and maltitol; ethylene oxide (hereinafter abbreviated as EO) and propylene oxide (hereinafter abbreviated as PO) adducts of glycerins; EO and PO adducts of sugar alcohols; monosaccharides such as galactose, glucose, and fructose and their EO and PO adducts; and polysaccharides such as maltose and lactose and their EO and PO adducts.

[0010] The above raw materials are mixed with oils, surfactants, water-soluble ingredients, chemicals, etc. as needed to prepare the product. Other examples of ingredients that can be blended include natural animal and vegetable oils and fats such as olive oil, mink oil, castor oil, palm oil, beef tallow, evening primrose oil, coconut oil, castor oil, cacao oil, macadamia nut oil, etc.; waxes such as jojoba oil, beeswax, lanolin, carnauba wax, candelilla wax, etc.; higher alcohols such as lauryl alcohol, stearyl alcohol, cetyl alcohol, oleyl alcohol, etc.; higher fatty acids such as lauric acid, palmitic acid, stearic acid, oleic acid, behenic acid, lanolin fatty acid, etc.; higher aliphatic hydrocarbons such as liquid paraffin, solid paraffin, etc. fin, squalane, petrolatum, ceresin, microcrystalline wax, etc.; synthetic ester oils such as butyl stearate, hexyl laurate, diisopropyl adipate, diisopropyl sebacate, octyldodecyl myristate, isopropyl myristate, isopropyl palmitate, isopropyl myristate, cetyl isooctanoate, neopentyl glycol dicaprate; oil-soluble active ingredients such as vitamin E, carrot oil; water-soluble ingredients such as purified water, ion-exchanged water, natural water, water-soluble polymers such as alkylated carboxyvinyl polyacrylate Polymers, sodium polyacrylate, carboxymethylcellulose, sodium hyaluronate, sodium alginate; surfactants: anionic surfactants (alkyl carboxylates, alkyl sulfonates, alkyl sulfates, alkyl phosphates), cationic surfactants (alkylamines, alkyl quaternary ammonium salts), amphoteric surfactants: carboxylic acid amphoteric surfactants (amino, betaine), sulfate ester amphoteric surfactants, sulfonic acid amphoteric surfactants, phosphate ester amphoteric surfactants, nonionic surfactants (ether-type nonionic surfactants, ether-ester-type nonionic surfactants, ester-type nonionic surfactants, block polymer-type nonionic surfactants, nitrogen-containing nonionic surfactants), other surfactants (natural surfactants, protein hydrolyzed derivatives, polymeric surfactants, surfactants containing titanium and silicon, fluorocarbon surfactants); drugs such as conchiolin hydrolyzate, vitamin C, allantoin, placenta extract, elastin, arbutin, collagen, triclosan, trichlorocarbamate, dipotassium glycyrrhizinate, methylparaben, butylparaben;Examples of powders include talc, sericite, mica, kaolin, silica, calcium carbonate, methylsiloxane network polymer, acrylic resin spheres, nylon fibers, zinc oxide, iron oxide, zirconium oxide, ultramarine, and Prussian blue. The above ingredients are selected into the required dosage form such as liquid or cream to prepare the formulation. [Example]

[0011] Next, the present invention will be described in detail with reference to examples and comparative examples. [Table 1]

[0012] [Table 2]

[0013] [Table 3]

[0014] [Table 4]

[0015] The notes are as follows: Note 1) Wako Pure Chemical Industries, Ltd. Product name: Hivis Wako 105 Note 2) Lubrizol Advanced Materials, Inc., product name: Pemulen TR-1 Note 3) Lubrizol Advanced Materials, Inc. Product name: Carbopol ETD2020 Note 4) Kikkoman Biochemifa Corporation, product name: Duck Algin NSPHR The crystal precipitation state in the table was judged as follows: 0.1 g was dropped onto a mini Petri dish, and after storing it in a 40°C thermostatic chamber for 24 hours, the result was visually confirmed. 5 = No visible crystals. 4 = Trace amounts of crystals visible to the naked eye. 3 = A small amount of crystals visible to the naked eye. 2 = A certain amount of crystals can be visually observed. 1 = A large amount of crystals can be visually confirmed.

[0016] As described above, it was found that the precipitation of tranexamic acid crystals is suppressed when a formulation containing tranexamic acid or its derivatives or salts is combined with two or more water-soluble polymers selected from carboxyvinyl polymer, xanthan gum, and alginate. Furthermore, it was found that by blending 2 to 10% by weight of glycerin, the precipitation of tranexamic acids crystals was further suppressed and a preparation with a good feel when used could be obtained.

Claims

[Claim 1] A preparation containing 2% by weight of tranexamic acid, which contains only two water-soluble polymers, namely, 0.01 to 0.5% by weight of a carboxyvinyl polymer and 0.01 to 0.5% by weight of xanthan gum, and further contains 0.01 to 0.1% by weight of a polyhydric alcohol containing glycerin and potassium hydroxide, the amount of glycerin being 5 to 10% by weight (excluding 5% by weight) of the preparation, and the combined use of the carboxyvinyl polymer and the xanthan gum inhibits crystallization of tranexamic acid. (However, the following exceptions apply: １） A cosmetic or topical skin preparation containing the following components (A) and (B): (A) Tranexamic acid or a derivative thereof or a salt thereof (B) Phytic acid or its salt ）。

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