External composition

Abstract

To provide compositions for external use with improved stability of a heparinoid, and to provide compositions for external use with improved formulation stability.SOLUTION: We have found that by compounding a heparinoid and tranexamic acid, the stability of the heparinoid in the composition for external use can be improved and the decomposition of the components over time can be suppressed. We have also found that additionally compounding placenta extract suppresses precipitation. That is, the present invention is a composition for external use characterized by containing (a) a heparinoid and (b) tranexamic acid or a salt thereof. Further, it is preferable to contain (c) placenta extract.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a topical composition containing a heparinoid and tranexamic acid. [Background technology]

[0002] Heparinoids are a type of acidic mucopolysaccharides, and are incorporated into external preparations such as medicines and quasi-drugs because of their wide range of effects, including moisturizing and anti-inflammatory effects on the skin, promoting blood flow, and treating and preventing scars and keloids. Various studies have been conducted to improve the effects of heparinoids, and it is known that by combining heparinoids with betaines, for example, the heparinoids' effect of enhancing keratin moisture retention and the moisturizing effect of betaines act synergistically, resulting in a remarkable improvement and prevention effect on rough skin (Patent Document 1).

[0003] While the usefulness of heparinoids on the skin has been demonstrated, it has become clear that aqueous solutions and ointments containing heparinoids decompose over time and have low stability. Conventionally, methods of blending polydextrose, mannitol, chondroitin sulfate, etc. with heparinoids have been reported as formulation techniques for improving the stability of heparinoids (Patent Document 2).

[0004] Tranexamic acid has hemostatic, anti-inflammatory and whitening effects, and is used as an ingredient in medicines and cosmetics. It is widely used as such (Patent Document 3).

[0005] Placental extract is an extract extracted from the placenta of mammals such as pigs, cows, horses, humans, or sheep. Placental tissue of mammals is rich in amino acids, active peptides, vitamins, minerals, sugars, enzymes, nucleic acids, etc., which are nutrients essential for fetal growth, and the extract extracted from the placenta of the mammals is called placental extract. The placental extract has effects such as cell proliferation, improvement of immunity, improvement of blood pressure, antioxidant effect, anti-inflammatory effect, analgesic effect, and blood coagulation inhibition effect, and is used as a raw material for cosmetics such as whitening cosmetics, dietary supplements such as fatigue recovery drinks, and pharmaceuticals such as anti-aging drugs (Patent Document 4). Adriza (registered trademark) Active Lotion was released in May 2019 as a cosmetic product containing heparinoids and placenta extract. However, no topical compositions containing heparinoids and tranexamic acid are known, and there have been no reports on the effects on stability of the inclusion of these ingredients. Furthermore, no topical compositions containing placenta extract are known, and there have been no reports on the effects on stability. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2000-143486 A [Patent Document 2] Japanese Patent Application Publication No. 2-282331 [Patent Document 3] JP 2009-234957 A [Patent Document 4] JP 2011-160742 A Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a composition for external use which contains a heparinoid with excellent stability, and also to provide a composition for external use which has excellent formulation stability. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems, and have found that by combining a heparinoid with tranexamic acid, the stability of the heparinoid in the external composition can be improved and the decomposition of the components over time can be suppressed.Furthermore, by further combining placental extract, precipitation over time can be suppressed, and thus the present invention has been completed.

[0009] That is, the present invention provides: (1) A composition for external use, comprising (a) a heparinoid and (b) tranexamic acid or a salt thereof, (2) (a) the composition for external use according to (1), wherein the content of the heparinoid is 0.01 to 5 w / w%; (3) (b) The composition for external use according to (1) or (2), wherein the content of tranexamic acid or a salt thereof is 0.1 to 10 w / w%. (4) The composition for external use according to any one of (1) to (3), wherein the content of (b) tranexamic acid or a salt thereof is 0.2 parts by mass or more per 1 part by mass of (a) the heparinoid. (5) A composition for external use, comprising (a) a heparinoid, (b) tranexamic acid or a salt thereof, and (c) a placenta extract. (6) (c) The composition for external use according to (5), wherein the content of the placenta extract is 0.01 to 5 w / w%. (7) The composition for external use according to (5) or (6), wherein the content of (c) placenta extract is 0.2 parts by mass or more per part by mass of (a) heparinoid. (8) The composition for external use according to any one of (5) to (7), wherein the content of (c) placenta extract is 0.05 parts by mass or more per 1 part by mass of (b) tranexamic acid. (9) The composition for external use according to any one of (1) to (8), which is a cosmetic, a quasi-drug, or a pharmaceutical. Effect of the Invention

[0010] The present invention provides a composition for external use that contains a heparinoid and tranexamic acid and has excellent stability of the heparinoid. In addition, by further incorporating placental extract, it is possible to provide a composition for external use that has excellent stability of the formulation with suppressed precipitation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The components used in the topical composition of the present invention may be of the same quality as those normally used in pharmaceuticals, quasi-drugs, or cosmetics.

[0012] The content of the heparinoid in the composition for external use of the present invention is preferably 0.01 to 5 w / w%, more preferably 0.1 to 0.5 w / w%.

[0013] The tranexamic acid in the composition for external use of the present invention may be used as a salt thereof. The salt is not particularly limited as long as it is pharmacologically (pharmaceutical) or physiologically acceptable as an external agent. Examples of the salt of tranexamic acid 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, lysine, histidine, ornithine; and salts with amines such as monoethanolamine, diethanolamine, and triethanolamine. The salt of tranexamic acid may be used alone or in combination of two or more. In order to further enhance the effects of the present invention, the content of tranexamic acid in the topical preparation of this embodiment is, for example, based on the total amount of the topical preparation, usually 0.1 to 10% by weight, preferably 0.1 to 5.0% by weight, and more preferably 0.2 parts by weight or more, per part by weight of the heparinoid, and more preferably 0.2 to 20 parts by weight. If the content of tranexamic acid is within the above range, in addition to the effects of the present invention, the effects of tranexamic acid, such as whitening, anti-inflammation, and improvement of rough skin, can be obtained.

[0014] The origin of the placenta extract in the composition for external use of the present invention may be, for example, human, cow, pig, horse, sheep, etc., but is preferably pig. In addition, a commercially available product (e.g., Biocatalyzer Placenta APF (SW) (M-PE-APF)) may be used as a placenta extract. The content of the placenta extract of the present invention in the composition for external use of the present invention is preferably 0.01 to 5 w / w%, more preferably 0.1 to 0.5 w / w%. In addition, it is preferably 0.2 parts by mass or more per part by mass of heparinoid, more preferably in the range of 0.2 to 20 parts by mass. In addition, it is preferably 0.05 parts by mass or more per part by mass of tranexamic acid, more preferably in the range of 0.05 to 1 part by mass.

[0015] The composition for external use of the present invention preferably contains water. The content of water in the composition for external use of the present invention is preferably 1 to 99.9 w / w%, more preferably 50 to 98.8 w / w%, and even more preferably 60.0 to 98.0 w / w%.

[0016] In addition to the above-mentioned components, the topical composition of the present invention may contain various components used in ordinary cosmetics, quasi-drugs, pharmaceuticals, etc., as appropriate, within the scope of not impairing the effects of the present invention.For example, pH adjusters (potassium hydroxide, sodium hydroxide, citric acid, sodium citrate, etc.), fragrances, refreshing agents (menthol, peppermint oil, camphor, etc.), anti-inflammatory agents (salicylic acid, glycyrrhetinic acid, allantoin, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), disinfectants (chlorhexidine gluconate, isopropylmethylphenol, etc.), preservatives (parabens (methylparaben, butylparaben, propylparaben, etc.), benzoic acid or its salts, phenoxyethanol, etc.), moisturizers (heartbeatin, nicotinic acid, benzoic acid, benzoylparaben ... uronic acid or its salt, chondroitin sulfate, polyhydric alcohol (glycerin, diglycerin, 1,3-butylene glycol, propylene glycol, 1,2-pentanediol, etc.), amino acids (L-serine, L-proline, L-hydroxyproline, glycine, etc.), lipidure, sorbitol, maltitol, etc.), thickeners (polyvinylpyrrolidone, sodium alginate, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), various plants and animals (courgette, Phellodendron bark, etc.) Extracts of vitamins (retinol palmitate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, riboflavin, nicotinamide, etc.), antioxidants (dibutylhydroxytoluene, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), dissolution aids (various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), oil-based gelling agents (inulin stearate, dextrin palmitate, etc.), metabolic activators, adhesives, antihistamines Examples of suitable anesthetics include anesthetics (chlorpheniramine maleate, etc.), local anesthetics (procaine, tetracaine, bupivacaine, mepipacaine, chloroprocaine, proparacaine, meprylcaine or salts thereof, orthocaine, oxethazaine, oxypolyethyleneoxydecane, Scopolia extract, percaminpase, tesitdesitin, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (γ-oryzanol, nonylic acid vanillylamide, nicotinic acid benzyl ester, capsaicin, chili pepper extract, etc.), and mucopolysaccharides (glucosamine, etc.). These ingredients may be used alone or in combination of two or more. The amount of these ingredients added is not particularly limited and can be appropriately determined while taking into consideration the feeling of use, etc. When a pharmacological ingredient is contained, the content may be appropriately determined depending on the type of pharmacological ingredient used, the expected effect, etc.

[0017] The composition for external use of the present invention can be used for applications such as cosmetics, quasi-drugs, and pharmaceuticals.

[0018] The form of the topical composition of the present invention is not particularly limited as long as it is a formulation that can be applied to the skin.Specific formulations include lotions, creams, milky lotions, gels, packs, etc.The topical composition of the present invention may be a W / O or O / W type emulsion formulation.

[0019] The topical composition of the present invention can be prepared by a conventional method depending on the dosage form. EXAMPLES

[0020] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0021] (Analysis of heparinoids) The heparinoid in the topical composition containing the heparinoid can be analyzed by preparing a sample by diluting with an appropriate solvent and subjecting the sample to liquid chromatography under the following conditions, for example. The test conditions may be appropriately adjusted depending on the equipment, materials, reagents, etc. used, after checking the reproducibility of the system and the peak area. <Liquid chromatography test conditions> Detector: Ultraviolet absorption photometer (measurement wavelength 202 nm) Guard column: 2mm x 50mm USP L61packing column Column: 2mm x 250mm USP L61packing column Column temperature: 40℃ Flow rate: 0.22mL / min Mobile phase A: Dissolve 0.8 g of sodium dihydrogen phosphate in 2000 mL of water and add phosphoric acid to adjust to pH 3.0. Mobile phase B: Dissolve 0.8 g of sodium dihydrogen phosphate and 280 g of sodium perchlorate monohydrate in 2000 mL of water and add phosphoric acid to adjust to pH 3.0. Mobile phase delivery: Linear concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1 do.

[0022] [Table 1]

[0023] (Method of preparing a composition for external use) According to the formulation shown in Table 2 below, a heparinoid, tranexamic acid, and placenta extract were uniformly mixed with purified water to obtain external compositions of Examples 1 to 7 and Comparative Examples 1 and 2.

[0024] (Stability evaluation of heparinoids) Each of the compositions for external use in Examples 1 to 7 and Comparative Examples 1 and 2 was filled into a 30 mL screw tube and stored at 65°C for 2 weeks. After storage, each liquid was thoroughly mixed and then tested. Each liquid was diluted to an appropriate concentration with ultrapure water by the same procedure immediately after preparation and after storage, and tested by liquid chromatography under the above conditions. Each peak area was measured, and the remaining rate of heparinoids was calculated using the following formula 1.

[0025] <Expression 1> Residual rate (%) = peak area after storage / peak area immediately after preparation × 100

[0026] [Table 2]

[0027] As is clear from the results in Table 2, when the heparinoid was used alone (Comparative Examples 1 and 2), a decrease in the components in the heparinoid was observed after storage, but when tranexamic acid was added, the stability of the heparinoid was improved (Examples 1 to 7).

[0028] (Stability evaluation of formulations) 100 mL of each of the compositions for external use of Examples 1, 2, and 8 to 14 was filled into a 200 mL glass container and stored at room temperature for 3 weeks. The appearance (precipitation) after storage was visually evaluated. The results are shown in Table 3.

[0029] [Table 3]

[0030] In Examples 1, 9, 11, and 13, although the stability of the heparinoid contained in the topical composition was not affected, precipitation was confirmed in the preparation. On the other hand, by blending placenta extract with a topical composition containing a heparinoid and tranexamic acid, precipitation was suppressed (Examples 2, 8, 10, 12, and 14). By suppressing precipitation, the deterioration of the preparation quality due to changes in appearance and usability was suppressed.

[0031] From the above, it was found that by further adding placenta extract to a topical composition containing a heparinoid and tranexamic acid, the stability of the components in the heparinoid was improved and precipitation was suppressed. (Prescription example)

[0032] [Table 4] [Industrial Applicability]

[0033] The present invention makes it possible to provide a topical composition having improved stability of a heparinoid, and further, to provide a topical composition having improved formulation stability by inhibiting precipitation.

Claims

1. A composition for external use comprising (a) a heparinoid, (b) tranexamic acid or a salt thereof, and (c) a placenta extract.

2. (c) The composition for external use according to claim 1, wherein the content of placenta extract is 0.01 to 5 w / w%.

3. (c) The content of placenta extract is 0.2 parts by mass per 1 part by mass of (a) heparinoid. The composition for external use according to claim 1 or 2, wherein the amount of the composition is 1 to 2 parts by mass or more.

4. The composition for external use according to any one of claims 1 to 3, wherein the content of (c) placenta extract is 0.05 parts by mass or more per 1 part by mass of (b) tranexamic acid.

5. The composition for external use according to any one of claims 1 to 4, which is a cosmetic, a quasi-drug, or a pharmaceutical.

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