Pharmaceutical preparation containing tranexamic acids

Abstract

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 formulation containing tranexamic acids.

Background Art

[0002] Tranexamic acid, its derivatives, or its salts (tranexamic acids) are known to have the effect of suppressing skin roughness and pigmentation, and are often used as components to be incorporated into topical skin preparations such as cosmetics. However, tranexamic acid is highly crystalline, and when the preparation such as cosmetics adheres to the vicinity of the mouth of the container storing this, over time, as moisture evaporates, a phenomenon occurs where hard crystals precipitate, causing problems such as poor cap tightening or the crystals mixing into the preparation and impairing the usability. Various methods have been tried as countermeasures for this. For example, by incorporating a specific surfactant (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) together with tranexamic acid into the preparation, crystal precipitation is suppressed, or the shape of the container for storing the preparation containing tranexamic acid is devised, and thus the above problems have been attempted to be solved. Also, if the blending amount of polyhydric alcohol such as glycerin is increased, precipitation can be suppressed, but it is unacceptable in terms of functionality for use.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Disclosure of the Invention

Problems to be Solved by the Invention

[0004] Although the tranexamic acid-containing preparation is an effective preparation, there are problems in terms of sensory limitations and crystal suppression. Furthermore, crystal precipitation does not occur for a long time, and a preparation that is applicable to a wide variety of preparations without sensory limitations has been desired.

Means for Solving the Problems

[0005] As a result of intensive studies, the present inventors have found that by blending two or more water-soluble polymers selected from carboxyvinyl polymer, xanthan gum, and alginate, crystal precipitation of tranexamic acid can be suppressed in a state with good usability, and the present invention has been completed.

[0006] Tranexamic acid refers to trans-4-aminomethylcyclohexane-1-carboxylic acid. The derivatives of tranexamic acid are not particularly limited, and examples include ester forms and amide forms. Examples of the ester of tranexamic acid include lauryl tranexamate, cetyl tranexamate, and hexadecyl tranexamate, and examples of the amide form of tranexamic acid include methylamide of tranexamic acid. In addition, the 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, and ornithine; salts with amines such as monoethanolamine, diethanolamine, and triethanolamine. Among these, sodium salt, potassium salt, triethanolamine salt, and arginine salt are preferable when formulating as a skin external preparation. The compounding amount of tranexamic acid, its derivatives or salts thereof is not particularly limited, but crystal precipitation becomes a problem mainly when it is 0.5% by weight or more.

[0007] Carboxyvinyl polymer is an acidic polymer mainly composed of acrylic acid polymers, and commercially available products can be used. Specifically, for example, Hibiswako 103, 104, 105 (manufactured by Wako Pure Chemical Industries, Ltd.), Carbopol series (manufactured by BFGoodrich), etc. can be mentioned. Xanthan gum is a polysaccharide obtained by the fermentation action of Xanthomonas campestris bacteria, and is used as a water-soluble thickening agent, gelling agent, emulsifying agent, dispersion / suspension stabilizer, etc. Specifically, Kelzan, Kelcrol (both manufactured by Kelco, USA), Lodopole (manufactured by Rhône-Poulenc Japan Co., Ltd.), Echo Gum (manufactured by Dainippon Pharmaceutical Co., Ltd.), Sun Ace (manufactured by San-Ei Gen F.F.I., Inc.), etc. are available. Alginic acid is a linear acidic saccharide composed of mannuronic acid and guluronic acid and formed by 1,4-linkage, and is a block copolymer in which a homopolymer fraction of mannuronic acid, a homopolymer fraction of guluronic acid, and a fraction in which mannuronic acid and guluronic acid are randomly arranged are arbitrarily combined, and is extracted from brown algae typified by kombu and wakame. There are various water-soluble salts, but sodium salts are widely used because of their high solubility in water.

[0008] The compounding amount of carboxyvinyl polymer varies depending on the types of tranexamic acids, carboxyvinyl polymer, the types and amounts of other compounding components, and pH, but an effect of suppressing crystal precipitation is exhibited when 0.01% by weight or more, preferably 0.03% by weight or more, more preferably 0.05% by weight or more is compounded. The compounding amounts of xanthan gum and alginate vary depending on the types of tranexamic acids, xanthan gum and alginate, and the types and amounts of other compounding components, but an effect of suppressing crystal precipitation is exhibited when 0.005% by weight or more, preferably 0.01% by weight or more is compounded. The upper limits of the compounding amounts of carboxyvinyl polymer, xanthan gum, and alginate vary greatly depending on the types of these and the compounding amounts of other water-soluble polymers, etc. In the case of carboxyvinyl polymer, it is 0.5% by weight or less. For xanthan gum and alginate, the total amount of xanthan gum and alginate is preferably 2.0% by weight or less. If the upper limit is exceeded, the usability deteriorates, and the expected quality cannot be obtained depending on the use of the preparation. There is no problem with the compounding of water-soluble polymers other than carboxyvinyl polymer, xanthan gum, and alginate. However, in order to suppress the precipitation of tranexamic acid crystals by water-soluble polymers other than carboxyvinyl polymer, xanthan gum, and alginate, a much larger compounding amount is required compared to a combination of two or more of carboxyvinyl polymer, xanthan gum, and alginate, resulting in poor usability and being unacceptable for use. Furthermore, as a result of the inventors' studies, the combination of carboxyvinyl polymer and xanthan gum, and the combination of carboxyvinyl polymer and alginate were particularly effective in the present invention. Also, the viscosity of these water-soluble polymers has little effect on the precipitation of tranexamic acid crystals, and the compounding amount of the water-soluble polymer affects it proportionally. Therefore, the grade of these water-soluble polymers is selected according to the purpose.

[0009] Other raw materials to be compounded in the preparation can be arbitrarily selected, but compounding a polyhydric alcohol is useful for suppressing crystal precipitation. In particular, glycerin is effective, and it varies greatly depending on the types and amounts of other polyhydric alcohols, tranexamic acids, carboxyvinyl polymer, xanthan gum, alginate, and other compounding components. However, it has been found that when 2 to 10% by weight, more preferably 5 to 10% by weight of glycerin is compounded, the precipitation of tranexamic acid crystals can be significantly suppressed. However, if it exceeds 10% by weight, the usability deteriorates, and the expected quality cannot be obtained depending on the use of the preparation. Of course, polyhydric alcohols other than glycerin can also be compounded. Examples include ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycols with more repeating units, propylene glycol, dipropylene glycol, polypropylene glycols with more repeating units, butylene glycols such as 1,3 - butylene glycol and 1,4 - butylene glycol, diglycerin, polyglycerins with more repeating units, 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, polysaccharides such as maltose and lactose and their EO and PO adducts, and other polyhydric alcohols.

[0010] Together with the above raw materials, an oil agent, surfactant, water - soluble component, drug, etc. are blended as necessary to prepare the product. Examples of other raw materials to 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, cocoa butter, 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, 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 components such as purified water, ion-exchanged water, natural water, water-soluble polymers such as alkylated carboxyvinyl polymer, sodium polyacrylate, carboxymethyl cellulose, sodium hyaluronate, sodium alginate; surfactants anionic surfactants (alkyl carboxylates, alkyl sulfonates, alkyl sulfate esters, alkyl phosphate esters), cationic surfactants (alkyl amine salts, alkyl quaternary ammonium salts), amphoteric surfactants: carboxylic acid type amphoteric surfactants (amino type, betaine type), sulfate ester type amphoteric surfactants, sulfonate type amphoteric surfactants, phosphate ester type amphoteric surfactants, nonionic surfactants (ether type nonionic surfactants, ether ester type nonionic surfactants, ester type nonionic surfactants, block polymer type nonionic surfactants, nitrogen-containing type nonionic surfactants), other surfactants (natural surfactants, derivatives of protein hydrolysates, polymer surfactants, surfactants containing titanium and silicon, fluorocarbon surfactants); drugs such as conchiolin hydrolyzate, vitamin C, allantoin, placenta extract, elastin, arbutin, collagen, triclosan, trichlorocarban, dipotassium glycyrrhizinate, methyl paraben, butyl paraben;Powders, for example, talc, sericite, mica, kaolin, silica, calcium carbonate, methylsiloxane network polymer, acrylic resin spheres, nylon fibers, zinc oxide, iron oxide, zirconium oxide, ultramarine, cobalt blue, etc. can be mentioned.; Select the above raw materials in a necessary dosage form such as liquid or cream form, and prepare a preparation.

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] Note: It is as follows. Note 1) Manufactured by Wako Pure Chemical Industries, Ltd., product name Hibisuwako 105 Note 2) Manufactured by Lubrizol Advanced Materials, product name Pemulen TR-1 Note 3) Manufactured by Lubrizol Advanced Materials, product name Carbopol ETD 2020 Note 4) Manufactured by Kikkoman Biochemifa, product name Duckargine NSPHR The precipitation state of the crystals in the table was determined as follows. 0.1 g was dropped into a minishale, stored in a constant temperature bath at 40 °C for 24 hours, and visually confirmed. 5 = No crystals can be visually confirmed. 4 = A trace amount of crystals can be visually confirmed. 3 = A small amount of crystals can be visually confirmed. 2 = A certain amount of crystals can be visually confirmed. 1 = A large amount of crystals can be visually confirmed.

[0016] As described above, it was found that when two or more water-soluble polymers selected from carboxyvinyl polymer, xanthan gum, and alginate are blended in a preparation containing tranexamic acid, its derivative, or its salt, precipitation of tranexamic acid crystals is suppressed. Furthermore, it was found that by blending 2 to 10% by weight of glycerin, precipitation of tranexamic acid crystals is further suppressed, and a preparation with good usability can be obtained.

Claims

1. A tranexamic acid formulation containing two or more water-soluble polymers selected from carboxyvinyl polymer, xanthan gum, and alginate.

2. The tranexamic acid formulation according to Claim 1, containing two water-soluble polymers of carboxyvinyl polymer and xanthan gum.

3. The tranexamic acid formulation according to any one of Claims 1 to 3, further containing a polyhydric alcohol containing glycerin.

4. The tranexamic acid formulation according to Claim 4, wherein the blending amount of glycerin is 2 to 10% by weight of the formulation.

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