JP7731064B2 - Tranexamic acid-containing preparations - Google Patents

Description

The present invention relates to a formulation containing tranexamic acids.

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 to be incorporated into 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 moisture evaporates over time, causing the precipitation of hard crystals. This causes problems such as the cap not fitting tightly or the crystals being mixed into the preparation, impairing the feel when used.
To address this issue, various methods have been attempted, including, for example, suppressing crystal precipitation 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, and 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.

Japanese Patent Application Laid-Open No. 2005-68076 JP 2011-84551 A JP 2011-195460 A Japanese Patent Application Laid-Open No. 2012-201660 JP 2013-121955 A JP 2016-121092 A

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 precipitate crystals over long periods of time, has no sensory limitations, and can be used in a wide variety of formulations.

After extensive research, the inventors discovered 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 pleasant feel during use, and thus completed the present invention.

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 preparation is used as an external preparation for skin.
There is no particular limitation 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.

The carboxyvinyl polymer is an acidic polymer mainly composed of an 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 BF Goodrich).
Xanthan gum is a polysaccharide obtained by fermentation of Xanthomonas campestris bacteria, 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 Co., Ltd.).
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 a random combination of a homopolymer fraction of mannuronic acid, a homopolymer fraction of guluronic acid, and a randomly arranged fraction of mannuronic acid and guluronic acid. 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.

The amount of carboxyvinyl polymer to be added varies depending on the type of tranexamic acid or carboxyvinyl polymer, the types and amounts 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 the amount added is 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, in the case of carboxyvinyl polymer, the amount is preferably 0.5% by weight or less, and in the case of 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 obtained depending on the application of the formulation.
Although there is no problem with blending water-soluble polymers other than carboxyvinyl polymers, xanthan gum, and alginates, suppressing the precipitation of tranexamic acids crystals using water-soluble polymers other than carboxyvinyl polymers, xanthan gum, and alginates requires a significantly larger blending amount than a combination of two or more of carboxyvinyl polymers, xanthan gum, and alginates, which results in a poor feel during use 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.

While other ingredients may be selected arbitrarily for incorporation into the formulation, the incorporation 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 incorporation of 2 to 10 wt. %, more preferably 5 to 10 wt. %, of glycerin significantly suppresses crystal precipitation of tranexamic acids. However, if the amount exceeds 10 wt. %, 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 EO and PO adducts thereof, and polysaccharides such as maltose and lactose and EO and PO adducts thereof.

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, squalane, petrolatum, ceresin, microcrystalline cellulose, etc. Listarin 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 polymer, sodium polyacrylate, carboxymethylcellulose, sodium hyaluronate, sodium alginate surfactants: anionic surfactants (alkyl carboxylates, alkyl sulfonates, alkyl sulfate ester salts, alkyl phosphate ester salts), cationic surfactants (alkylamine salts, alkyl quaternary ammonium salts), amphoteric surfactants: carboxylic acid type amphoteric surfactants (amino type, betaine type), sulfate ester type amphoteric surfactants, sulfonic acid 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), etc. Other surfactants (natural surfactants, protein hydrolysate derivatives, polymer surfactants, surfactants containing titanium and silicon, fluorocarbon surfactants); drugs such as conchiolin hydrolysate, vitamin C, allantoin, placenta extract, elastin, arbutin, collagen, triclosan, trichlorocarban, dipotassium glycyrrhizinate, methylparaben, butylparaben; powders such as talc, sericite, mica, kaolin, silica, calcium carbonate, methylsiloxane network polymer, acrylic resin spheres, nylon fiber, 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.

Next, the present invention will be described in detail with reference to examples and comparative examples.

The notes are as follows:
Note 1) Wako Pure Chemical Industries, Ltd. Product name: Hivis Wako 105
Note 2) Product name: Pemulen TR-1, manufactured by Lubrizol Advanced Materials
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 thermostatic chamber at 40° C. 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 can be seen with the naked eye.
2 = A certain amount of crystals can be visually confirmed.
1 = A large amount of crystals can be visually confirmed.

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 thereof 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 good usability was obtained.

Claims (1)

A formulation containing 2% by weight of tranexamic acid (excluding the following), 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 formulation, and the combined use of the carboxyvinyl polymer and the xanthan gum inhibits crystallization of tranexamic acid .
1)
A cosmetic or topical skin preparation containing the following components (A) and (B):
(A) tranexamic acid or its derivative or salt thereof (B) phytic acid or its salt).