Liquid composition

Abstract

To provide a liquid composition enabling suppression of time-dependent degradation of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide.SOLUTION: A liquid composition is adopted in which the ethanol content and pH have a specific relationship.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a liquid composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide. [Background technology]

[0002] Hair color is due to melanin produced by melanocytes, and graying is a phenomenon caused by a decrease in the number of melanocytes in the hair follicle and the melanin content (Non-Patent Document 1). It has been reported that N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide, an agonist of a type of melanocyte-stimulating hormone (α-MSH), can protect the function of melanocytes, promote hair pigmentation, and reduce graying (Non-Patent Document 2).

[0003] To date, hair treatment compositions and scalp and / or hair compositions containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide have been developed (Patent Documents 1 and 2). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Tobin, DJ et al. (2011) Pigment Cell Melanoma Res. 24(1), 75-88 [Non-patent document 2] S. Almeida Scalvino et al. (2018) International Journal of Cosmetic Science. 40, 516-524 [Patent documents]

[0005] [Patent Document 1] Patent No. 6556392 [Patent Document 2] Japanese Patent Publication No. 2022-192020 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors produced a liquid composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide and made the surprising discovery that the content of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide decreases over time due to decomposition.

[0007] Therefore, an object of the present invention is to provide a liquid composition in which the decomposition of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide over time is inhibited. [Means for solving the problem]

[0008] As a result of extensive research to solve the above problems, it was found that N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide is stable in a liquid composition that satisfies the conditions expressed by a linear equation with pH and ethanol content as two variables.

[0009] That is, the present invention relates to, but is not limited to, the following: [1] N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by weight or more of ethanol. A liquid composition containing ethanol and having a pH of less than 10, The condition of the following formula (1) is satisfied, Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). The composition does not contain acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysineamide or a pharmaceutically acceptable salt thereof. [2] The liquid composition according to [1], which contains a Lewis acid having a pKa of 7.0 or less. [3] The liquid composition according to [2], wherein the Lewis acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, acetic acid, tartaric acid, maleic acid, malic acid, gluconic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and isostearic acid. [4] The liquid composition according to any one of [1] to [3], which contains a polyhydric alcohol. [5] The liquid composition according to any one of [1] to [4], which contains a Lewis base having a pKa of 6.0 or more. [6] A method for producing a liquid composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, comprising: The liquid composition contains N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by mass or more of ethanol, has a pH of less than 10, and satisfies the condition of the following formula (1): Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). and mixing the ingredients so that the liquid composition does not contain acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysineamide or a pharmaceutically acceptable salt thereof. [7] A method for improving the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof in a liquid composition, comprising: The method includes a step of mixing raw materials so that the liquid composition contains N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by mass or more of ethanol, has a pH of less than 10, and satisfies the condition of the following formula (1): Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). [Effects of the Invention]

[0010] According to the present invention, it is possible to provide a liquid composition in which the decrease in N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide over time is suppressed. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a graph in which the compositions in Table 1 are plotted, with the vertical axis representing ethanol content (%) and the horizontal axis representing pH. DETAILED DESCRIPTION OF THE INVENTION

[0012] The liquid compositions of the present invention and related methods are described below. (liquid composition) The liquid composition of the present invention comprises, in addition to N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, 5 It contains at least 100% by weight of ethanol and water as the primary liquid medium.

[0013] The water content in the liquid composition is not limited, but is typically 20% by mass or more, 25% by mass or more, 30% by mass or more, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more. The water content in the liquid composition of the present invention is adjusted appropriately so as to adjust the contents of other components, and therefore the upper limit of the water content is not limited. However, typical examples of the upper limit of the water content are 94% by mass or 85% by mass of the liquid composition. Therefore, typical examples of the water content are 20 to 94% by mass, 25 to 94% by mass, 30 to 94% by mass, 40 to 94% by mass, 50 to 94% by mass, 60 to 94% by mass, 70 to 94% by mass, or 80 to 94% by mass.

[0014] The liquid composition may be in the form of a solution or a suspension.

[0015] (N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide) N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide in the present invention is a synthetic tetrapeptide consisting of palmitic acid, arginine, histidine, phenylalanine, and tryptophan. It has CAS number 827029-84-5 and is also known as Grayverse, Greyverse, or palmitoyl tetrapeptide-20. N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide can be produced by standard peptide synthesis methods. It can also be purchased from a reagent or raw material manufacturer. It is available, for example, from Lucas Meyer Cosmetics.

[0016] The content of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide in the liquid composition of the present invention is not particularly limited, but is preferably 0.00000001 to 0.1 mass%, more preferably 0.0000001 to 0.01 mass%, and even more preferably 0.00001 to 0.003 mass%.

[0017] (ethanol content and pH) The liquid composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide of the present invention contains 5% by mass or more of ethanol, has a pH of less than 10, and satisfies the condition of the following formula (1). Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). When the liquid composition of the present invention satisfies this condition, the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide in the liquid composition is increased.

[0018] The ethanol content of the liquid composition of the present invention is 5% or more. In the present invention, the higher the ethanol content, the better the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide. The ethanol content in the composition is preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 25% by mass or more, more preferably 30% by mass or more, more preferably 35% by mass or more, and more preferably 40% by mass or more. From the viewpoint of skin irritation, it is preferably 60% by mass or less or 70% by mass or less. Therefore, examples of preferred ethanol contents are 5 to 70 mass%, 15 to 70 mass%, 20 to 70 mass%, 25 to 70 mass%, 30 to 70 mass%, 35 to 70 mass%, 40 to 70 mass%, 5 to 60 mass%, 15 to 60 mass%, 20 to 60 mass%, 25 to 60 mass%, 30 to 60 mass%, 35 to 60 mass%, and 40 to 60 mass%. % by volume.

[0019] The ethanol content can be adjusted by adjusting the amount of ethanol or raw materials containing ethanol used in the production of the liquid composition. The ethanol content in the liquid composition of the present invention may be measured by any known measurement method such as gas chromatography. Examples of gas chromatography conditions for measuring the ethanol content are shown below.

[0020] Internal standard: acetonitrile Injection volume: 1μL Injection method: Split (1:10) Detector: Flame ionization detector (FID) Column: DB-WAX (Agilent J&W) 0.53 mm diameter x 30 m, 1 μm Column temperature: Initial temperature 50℃ (5 min) Temperature rise: 50℃ / min Final temperature: 220℃ (15min) Inlet temperature: 230℃ Detector temperature: 230℃ Carrier gas: Helium Furthermore, as long as the liquid composition of the present invention satisfies the condition of formula (1), the pH of the composition is not limited, but preferably the pH of the composition is less than 10. In the present invention, the lower the pH, the better the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide. Therefore, the pH of the liquid composition of the present invention is preferably less than 10, more preferably 8 or less, more preferably 7.5 or less, more preferably 7 or less, more preferably 6.5 or less, more preferably 6 or less, and more preferably 5.4 or less. From the viewpoints of usability and skin irritation, a pH of 4.5 or more is preferable. Therefore, examples of preferred pH values ​​are 4.5 or more and less than 10, 4.5 to 8, 4.5 to 7.5, 4.5 to 7, 4.5 to 6.5, 4.5 to 6, and 4.5 to 5.4.

[0021] To adjust the pH of the liquid composition of the present invention, an acid, including a Lewis acid, which will be described later, and / or a base, including a Lewis base, which will be described later, can be used. The pH of the liquid composition of the present invention may be measured by any known method. Typically, the measurement is carried out at a liquid temperature of about 25°C.

[0022] (Lewis acid) The liquid composition of the present invention may contain a Lewis acid having a pKa of 7.0 or less. Examples of Lewis acids having a pKa of 7.0 or less include hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, acetic acid, tartaric acid, maleic acid, malic acid, gluconic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and isostearic acid. These acids may be used alone or in combination. The content of the Lewis acid in the liquid composition of the present invention is not particularly limited, but is preferably 0.000001 to 10% by mass, more preferably 0.00001 to 3% by mass, and even more preferably 0.0001 to 1% by mass.

[0023] (Lewis base) The liquid composition of the present invention may contain a Lewis base having a pKa of 6.0 or higher, if necessary. By adding a Lewis base having a pKa of 6.0 or higher, the pH of the liquid composition can be maintained at a specific value. Examples of Lewis bases having a pKa of 6.0 or higher include sodium hydroxide, potassium hydroxide, trometamol, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Examples of Lewis bases include amines, or sodium salts of Lewis acids, such as sodium citrate, potassium salts of Lewis acids, etc. The content of the Lewis base in the liquid composition of the present invention is not particularly limited, but is, for example, preferably 0.000001 to 10% by mass, more preferably 0.00001 to 3% by mass, and even more preferably 0.0001 to 1% by mass.

[0024] (Polyhydric alcohol) The liquid composition of the present invention can contain a polyhydric alcohol. Examples of polyhydric alcohols include glycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, and polyethylene glycol. These may be used alone or in combination of two or more. The content of the polyhydric alcohol in the liquid composition of the present invention is preferably 1 to 30% by mass, more preferably 2 to 15% by mass, and even more preferably 5 to 12% by mass.

[0025] (Other ingredients) The liquid composition of the present invention can be blended with various active ingredients or additives that can be contained in cosmetics, quasi-drugs, pharmaceuticals, reagents, etc., within the scope that does not impair the effects of the present invention.

[0026] On the other hand, the liquid composition of the present invention does not contain acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysineamide or a pharmaceutically acceptable salt thereof. Note that acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysineamide is a synthetic tetrapeptide consisting of acetic acid, lysine, glycine, histidine, and lysine, and is a compound also known as acetyl tetrapeptide-3 (CAS number 827306-88-7).

[0027] (applicable) The liquid composition of the present invention can be used for pharmaceuticals, quasi-drugs, cosmetics, reagents, etc. The preferred administration form is external application to the skin, including the scalp, and / or hair. Examples of dosage forms include lotions, liquids, gels, and sprays.

[0028] (method) The liquid composition of the present invention can be produced by a known method. During production, various active ingredients or additives that can be contained in cosmetics, quasi-drugs, pharmaceuticals, reagents, etc. can be blended within a range that does not impair the effects of the present invention.

[0029] In another aspect, the present invention is a method for preparing a liquid composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, the method comprising: The liquid composition contains N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by weight or more of ethanol, has a pH of less than 10, and satisfies the condition of the following formula (1): Equation (1) Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). The method includes a step of mixing the raw materials so as to satisfy the above.

[0030] Preferably, in this method, the raw materials are mixed so that the liquid composition does not contain acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysineamide or a pharmaceutically acceptable salt thereof. As is clear from the above description of the liquid composition, the raw materials used in the production of the liquid composition are N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, ethanol, water, etc. The method for adjusting the ethanol content and pH in the liquid composition is described in the section on the liquid composition. This is self-evident from the above description. The preferred ranges of the content and pH are as described above for the liquid composition. Specific examples and amounts of other components to be added are also as described above for the liquid composition.

[0031] The production method of the present invention can improve the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof in a liquid composition. Therefore, in another aspect, the production method is a method for improving the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof in a liquid composition.

[0032] (Numerical range) For clarity, numerical ranges expressed herein by lower and upper limits include the endpoints of the lower and upper limits.

[0033] EXAMPLES The present invention will be explained in more detail below with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited to these Examples in any way. [Example]

[0034] (Examples 1 to 32, Comparative Examples 1 to 22, Controls 1 to 5) Tables 1A to 1E show the formulations of Examples 1 to 32, Comparative Examples 1 to 22, and Controls 1 to 5. For convenience, in Tables 1A to 1E, N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide is referred to as the "peptide compound." Liquid compositions having the formulations shown in Tables 1A-1B were prepared as follows. N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide, glycerin, and ethanol in the amounts shown in Tables 1A-1B, along with an appropriate amount of sodium citrate, were added to a total volume of 100 g with purified water, and the mixture was stirred and dissolved to obtain a composition. An appropriate amount of citric acid was then added to adjust the pH to the desired level. Liquid compositions having the formulations shown in Tables 1C-1D were prepared in the same manner as the liquid compositions shown in Tables 1A-1B, except that sodium citrate and citric acid were replaced with sodium hydroxide and phosphoric acid or lactic acid. Liquid compositions having the formulations shown in Table 1E were prepared in the same manner as the liquid compositions shown in Tables 1A-1B, except that sodium citrate and citric acid were replaced with sodium hydroxide and citric acid or lactic acid, and 1,3-butylene glycol was added.

[0035] (Stability test) The liquid compositions of Examples 1 to 32, Comparative Examples 1 to 22, and Controls 1 to 5 were stored at 65°C for 7 days, and then the content of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide was measured by high performance liquid chromatography. The improvement rate of each liquid composition compared to the control was calculated using the following formula (2). The controls used for the calculation were liquid compositions selected from Controls 1 to 5, which had the same composition except for the ethanol content and pH. The content of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide in each control was 80% or less compared to that immediately after preparation.

[0036] Formula (2) ([amount of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide decomposition in the control]-[amount of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide decomposition in Examples 1 to 32 and Comparative Examples 1 to 22])*100 / [amount of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide decomposition in the control] Points with an improvement rate of 30% or more are indicated by a circle, and points with an improvement rate of less than 30% are indicated by an x.

[0037] As is clear from Table 1, N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide was more stable at lower pH levels and at higher amounts of ethanol.

[0038] [Table 1A] [Table 1B] [Table 1C] [Table 1D] [Table 1E]

[0039] As is clear from FIG. 1, the Examples, in which N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide is a stable liquid composition, and the Comparative Examples, in which N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide is an unstable test liquid, can be separated by a linear line shown in the following formula (1), in which pH and ethanol content are the two variables.

[0040] Equation (1): Ethanol content (%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). Table 2 below shows the value of 22×[pH]−[ethanol content (%)] for each example, comparative example, and control.

[0041] [Table 2]

[0042] As is clear from Table 2, the liquid compositions of Examples 1 to 32 conformed to the formula 22×[pH]-[ethanol content (%)]≦120, and the liquid compositions of Comparative Examples 1 to 22 conformed to the formula 22×[pH]-[ethanol content (%)]>120.

[0043] The composition of the production example described in paragraph 0040 of Patent Document 2 (JP 2022-192020 A), which is a prior art, has an ethanol content of 15% by mass and a pH of 6.5, and does not satisfy the condition of formula (1). The correlation coefficients of the hydroxyl groups in the hydroxyl groups were in the range of 120 to 120°C and belonged to the area below the straight line in Figure 1.

[0044] The present invention makes it possible to provide an N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide-containing composition that can suppress decomposition over time in a composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide. [Industrial Applicability]

[0045] The present invention facilitates the storage of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide-containing liquid compositions under good conditions, and is therefore useful in industries belonging to technical fields such as cosmetics, quasi-drugs, pharmaceuticals, and reagents.

Claims

1. A liquid composition comprising N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by weight or more of ethanol, and having a pH of less than 10, The condition of the following formula (1) is satisfied: Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). The composition does not contain acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysine amide or a pharmaceutically acceptable salt thereof.

2. 10. The liquid composition of claim 1, comprising a Lewis acid having a pKa of 7.0 or less.

3. 3. The liquid composition according to claim 2, wherein the Lewis acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, acetic acid, tartaric acid, maleic acid, malic acid, gluconic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and isostearic acid.

4. The liquid composition according to any one of claims 1 to 3, which contains a polyhydric alcohol.

5. The liquid composition according to any one of claims 1 to 3, comprising a Lewis base having a pKa of 6.0 or more.

6. 1. A method for preparing a liquid composition containing N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, comprising: The liquid composition contains N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by mass or more of ethanol, has a pH of less than 10, and satisfies the condition of the following formula (1): Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition). and mixing the ingredients so that the liquid composition does not contain acetyl-L-lysyl-L-glycyl-L-histidyl-L-lysineamide or a pharmaceutically acceptable salt thereof.

7. 1. A method for improving the stability of N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof in a liquid composition, comprising: The method includes a step of mixing raw materials so that the liquid composition contains N-palmitoyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof, water, and 5% by mass or more of ethanol, has a pH of less than 10, and satisfies the condition of the following formula (1): Equation (1): Ethanol content (mass%)≧22×[pH]−120 (wherein [pH] is the pH of the liquid composition).

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