JP7637342B2 - External Composition - Google Patents

Description

The present invention relates to a topical composition containing a heparinoid and tranexamic acid.

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

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. Previously, methods of blending heparinoids with polydextrose, mannitol, chondroitin sulfate, etc. have been reported as formulation techniques for improving the stability of heparinoids (Patent Document 2).

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

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 the effects of cell proliferation, improving immunity, improving 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).
Adriace (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 no reports have been published on the effect on stability of the inclusion of these ingredients. Furthermore, no topical compositions containing placenta extract are known, and no reports have been published on the effect on stability.

JP 2000-143486 A Japanese Patent Application Publication No. 2-282331 JP 2009-234957 A JP 2011-160742 A

The object of the present invention is to provide a topical composition having excellent stability of heparinoids. It is also to provide a topical composition having excellent formulation stability.

As a result of intensive research conducted by the inventors to solve the above problems, they discovered that by combining a heparinoid with tranexamic acid, the stability of the heparinoid in the topical composition is improved and the decomposition of the components over time can be suppressed. They also discovered that adding placenta extract further suppresses precipitation over time, which led to the completion of the present invention.

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 1 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.

The present invention makes it possible to provide a topical composition that contains a heparinoid and tranexamic acid and has excellent stability of the heparinoid. Furthermore, by further incorporating placenta extract, it is possible to provide a topical composition that has excellent stability and suppresses precipitation.

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

The content of the heparinoid in the topical composition of the present invention is preferably 0.01 to 5 w/w%, and more preferably 0.1 to 0.5 w/w%.

The tranexamic acid in the composition for external use of the present invention may be used as its salt. 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.
From the viewpoint of further enhancing the effect 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, and preferably 0.1 to 5.0% by weight, of tranexamic acid or its total content. Also, it is preferably 0.2 parts by weight or more, and more preferably in the range of 0.2 to 20 parts by weight, per part by weight of the heparinoid. If the content of tranexamic acid or its total content is within the above range, in addition to the effect of the present invention, the effects of tranexamic acid such as whitening, anti-inflammation, and improvement of rough skin can be obtained.

The placenta extract in the topical composition of the present invention may originate from, for example, human, bovine, porcine, equine, or ovine sources, with porcine being preferred. Commercially available placenta extracts (e.g., Biocatalyzer Placenta APF (SW) (M-PE-APF)) may also be used. The content of the placenta extract of the present invention in the topical composition of the present invention is preferably 0.01 to 5 w/w%, more preferably 0.1 to 0.5 w/w%. It is also preferred that the content is 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. It is also preferred that the content is 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.

The topical composition of the present invention preferably contains water. The content of water in the topical composition 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%.

In addition to the above-mentioned components, the composition for external use 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.), bactericides (chlorhexidine gluconate, isopropylmethylphenol, etc.), preservatives (parabens (methylparaben, butylparaben, propylparaben, etc.), benzoic acid or its salts, phenoxyethanol, etc.), moisturizers (heart rate inhibitors, benzoic acid derivatives, etc.), and the like. uronic acid or its salt, chondroitin sulfate, polyhydric alcohols (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 animals and plants (courgettes, Phellodendron bark, etc.), Extracts of (seaweed, peonies, licorice, rosemary, sage, etc.), vitamins (retinol palmitate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, riboflavin, nicotinamide, etc.), antioxidants (dibutylhydroxytoluene, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizing agents (various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), oily 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 protective agents (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.

The topical composition of the present invention can be used for applications such as cosmetics, quasi-drugs, and pharmaceuticals.

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, and packs. The topical composition of the present invention may be a W/O or O/W type emulsion formulation.

The topical composition of the present invention can be manufactured by conventional methods depending on the dosage form.

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

(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: 2 mm x 50 mm USP L61 packing column Column: 2 mm x 250 mm USP L61 packing column Column temperature: 40°C
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 the pH to 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 the pH to 3.0.
Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 to perform linear concentration gradient control.

(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.

(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 formulation was thoroughly mixed and then tested. Each liquid formulation immediately after preparation and after storage was diluted to an appropriate concentration with ultrapure water by the same procedure and tested by liquid chromatography under the above conditions. Each peak area was measured, and the remaining rate of heparinoid was calculated using the following formula 1.

<Formula 1>
Residual rate (%) = peak area after storage/peak area immediately after preparation × 100

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 improved (Examples 1 to 7).

(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.

In Examples 1, 9, 11, and 13, although there was no effect on the stability of the heparinoid contained in the topical composition, precipitation was confirmed in the formulation. 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, deterioration of the formulation quality associated with changes in appearance and usability was suppressed.

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)

The present invention makes it possible to provide a topical composition in which the stability of the heparinoid is improved. Furthermore, it makes it possible to provide a topical composition in which the formulation stability is improved by inhibiting precipitation.

Claims (5)

A composition for external use comprising (a) a heparinoid, (b) tranexamic acid or a salt thereof, and (c) a placenta extract. (c) The composition for external use according to claim 1 , wherein the content of placenta extract is 0.01 to 5 w/w%. 3. The composition for external use according to claim 1 or 2 , wherein the content of (c) placenta extract is 0.2 parts by mass or more per 1 part by mass of (a) heparinoid. 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. The composition for external use according to any one of claims 1 to 4 , which is a cosmetic, a quasi-drug, or a pharmaceutical.