Transdermal absorption enhancer

Abstract

To provide a percutaneous absorption promoter that can promote the percutaneous absorption of a hydrophilic agent.SOLUTION: An agent for promoting the percutaneous absorption of a hydrophilic agent is used that contains α-hydroxy acid as an active ingredient.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a transdermal absorption enhancer.

Background Art

[0002] Hydrophilic drugs such as glycylglycine having a pore shrinking effect and tranexamic acid having anti-inflammatory and whitening effects are highly hydrophilic and tend to crystallize. In order to improve the skin effect of hydrophilic drugs, it is required to further enhance the penetration effect of hydrophilic drugs into the skin.

[0003] So far, a transdermal absorption promoting topical skin composition prepared by blending a mixture of 1,2-alkanediols having 4 to 8 carbon atoms with a water-soluble topical skin drug ingredient (see Patent Document 1), a transdermal absorption enhancer of isobutyl resorcinol in a topical skin agent composed of a water-soluble non-volatile liquid substance having a solubility parameter of 16 or more (see Patent Document 2), a transdermal absorption enhancer containing difructose anhydride as an active ingredient (see Patent Document 3), and a transdermal absorption enhancer or a transdermal absorption control agent composed of a hydrophilic polyglycerol-modified silicone (see Patent Document 4), etc. A variety of compositions and agents for promoting transdermal absorption are known, but further improvement is required particularly from the viewpoint of promoting the transdermal absorption of hydrophilic drugs.

[0004] Also, it is known that by combining a specific organic acid, a specific surfactant, and a specific anti-skin roughness component, it is possible to effectively suppress the regeneration of horny plugs without causing skin roughness (see Patent Document 5), but it is not known at all that α-hydroxy acid can promote the transdermal absorption of hydrophilic drugs.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

[0006] The inventors have surprisingly discovered that α-hydroxy acids can promote the transdermal absorption of hydrophilic drugs. This invention is based on these findings.

[0007] The present invention provides the following: (1) A transdermal absorption enhancer for hydrophilic drugs, containing an α-hydroxy acid as an active ingredient. (2) The transdermal absorption enhancer according to (1), wherein the hydrophilic agent is a hydrophilic agent whose logP value, which represents the water / octanol partition coefficient, is 2.0 or less. (3) The transdermal absorption enhancer according to (1) or (2), wherein the hydrophilic agent comprises one or more selected from the group consisting of glycylglycine, tranexamic acid, and nicotinamide. (4) The transdermal absorption enhancer according to any one of (1) to (3), wherein the hydrophilic agent contains glycylglycine and tranexamic acid. (5) The transdermal absorption enhancer according to any one of (1) to (4), wherein the α-hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, and citric acid. (6) The transdermal absorption enhancer according to (5), wherein the amount of glycolic acid added is 0.1 to 2% by mass relative to the total amount of the transdermal absorption enhancer. (7) The transdermal absorption enhancer according to (5) or (6), wherein the amount of lactic acid added is 0.1 to 3% by mass relative to the total amount of the transdermal absorption enhancer. (8) The transdermal absorption enhancer according to any one of (5) to (7), wherein the amount of citric acid added is 0.1 to 4% by mass relative to the total amount of the transdermal absorption enhancer. (9) The transdermal absorption enhancer according to any one of (1) to (8), wherein the amount of the hydrophilic agent is 1 to 6% by mass relative to the total amount of the transdermal absorption enhancer. (10) The mass ratio of the hydrophilic agent to the α-hydroxy acid (amount of hydrophilic agent in the transdermal absorption enhancer: amount of α-hydroxy acid in the transdermal absorption enhancer) is 1:4 to 3:7, and The hydrophilic agent is glycylglycine or tranexamic acid. A transdermal absorption enhancer as described in any of (1) to (9). (11) A transdermal absorption enhancer as described in any of (1) to (10), wherein the pH is 5 or less. (12) A composition for promoting the transdermal absorption of hydrophilic drugs, containing an α-hydroxy acid as an active ingredient. (13) The composition described in (12), which is a composition for external use on the skin.

[0008] The present invention offers the advantage of being able to promote the transdermal absorption of hydrophilic drugs such as glycylglycine and tranexamic acid by using the transdermal absorption enhancer. [Brief explanation of the drawing]

[0009] [Figure 1] This shows the cumulative amount of glycylglycine absorbed over time (nmol / cm2) in the transdermal absorption confirmation test of Test Example 1. [Figure 2] This shows the cumulative amount of tranexamic acid absorbed over time (nmol / cm2) in the transdermal absorption confirmation test of Test Example 1.

[0010] The present invention provides a transdermal absorption enhancer for hydrophilic drugs containing an α-hydroxy acid as an active ingredient. Specific description of the invention

[0011] <α-hydroxy acid> The transdermal absorption promoter of the present invention contains α-hydroxy acid as an active ingredient. α-Hydroxy acid has conventionally been used as a buffering agent or neutralizing agent in cosmetics and detergents, and has also been incorporated into various cosmetics for the purpose of softening the cutin or activating cells. The α-hydroxy acid incorporated into the cosmetics of the present invention is not particularly limited, and examples thereof include glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, glyceric acid, pyruvic acid, mandelic acid, etc. It may be used alone or in combination of two or more. Among these, it is preferably at least one selected from the group consisting of glycolic acid, lactic acid, and citric acid, and more preferably used in combination of glycolic acid, lactic acid, and citric acid.

[0012] The amount of α-hydroxy acid used in the transdermal absorption promoter of the present invention is not particularly limited, but is preferably 1.5 to 5% by mass, more preferably 2 to 4% by mass, based on the total amount of the transdermal absorption promoter.

[0013] When the α-hydroxy acid used in the transdermal absorption promoter of the present invention contains glycolic acid, the amount of glycolic acid is not particularly limited, but is preferably 0.1 to 2% by mass, more preferably 0.3 to 1.5% by mass, based on the total amount of the transdermal absorption promoter.

[0014] When the α-hydroxy acid used in the transdermal absorption promoter of the present invention contains lactic acid, the amount of lactic acid is not particularly limited, but is preferably 0.1 to 3% by mass, more preferably 0.5 to 1.5% by mass, based on the total amount of the transdermal absorption promoter.

[0015] When the α-hydroxy acid used in the transdermal absorption promoter of the present invention contains citric acid, the amount of citric acid is not particularly limited, but is preferably 0.1 to 4% by mass, more preferably 1 to 2% by mass, based on the total amount of the transdermal absorption promoter.

[0016] <Hydrophilic agent> The present invention is a transdermal absorption enhancer for hydrophilic drugs containing an α-hydroxy acid as an active ingredient.Drugs whose transdermal absorption is promoted by containing α-hydroxy acids as active ingredients are not particularly limited as long as they are hydrophilic, but are preferably hydrophilic drugs with a logP value of 2.0 or less, which represents the water / octanol partition coefficient, and more preferably arbutin (LogP=-0.6), L-ascorbic acid (LogP=-1.6), hydroquinone (LogP=-0.6), glutathione (LogP=-4.5), pantothenic acid (LogP=-1.1), tranexamic acid (LogP=-2), kojic acid (LogP=-0.9), and L-cysteine. Calcium (LogP=-2.5), ellagic acid (LogP=1.1), resorcinol (LogP=0.8), rutin (LogP=-1.3), tryptophan (LogP=-1.1), histidine (LogP=-3.2), glycylglycine (logP=-2.3), flavonoids such as quercetin (LogP=1.5) and quercitrin (LogP=0.9), catechin (LogP=0.4), gallic acid (LogP=0.7), kinetin (LogP=1), alpha-lipoic acid (LogP=1.7), erythorbic acid (LogP=-1.6), thiotaurine (LogP=-0.1), Urea (LogP=-1.4), Nicotine (LogP=1.2), Nicotinic acid (LogP=0.4), Nicotinamide (logP=-0.4), Hydroxyproline (LogP=-3.3), Serine (LogP=-3.1), Glutamic acid (LogP=-3.7), Arginine (LogP=-4.2), Alanine (LogP=-3), Minoxidil (LogP=1.2), D-Glucosamine (LogP=-2.8), N-Acetyl-D-Glucosamine (LogP=-1.7), Hyaluronic acid (LogP=-7.4), A hydrophilic agent comprising one or more selected from the group consisting of raffinose (LogP=-5.8), azelaic acid (LogP=1.6), γ-aminobutyric acid (LogP=-3.2), allantoin (LogP=-2.2), L-carnitine (LogP=-0.2), and biotin (LogP=0.3), more preferably a hydrophilic agent comprising one or more selected from the group consisting of glycylglycine, tranexamic acid, and nicotinamide, and even more preferably a hydrophilic agent containing glycylglycine and tranexamic acid.Here, the logP value is a coefficient representing polarity based on the ease of distribution of a substance between water and octanol as defined in Chemical Reviews vol71(6),525(1971) and the like.

[0017] The blending amount of the hydrophilic drug whose transdermal absorption is promoted by the transdermal absorption promoter of the present invention is not particularly limited, but is preferably 1 to 6% by mass, more preferably 1 to 3% by mass, based on the total amount of the transdermal absorption promoter.

[0018] In the transdermal absorption promoter of the present invention, the mass ratio of the hydrophilic drug to α-hydroxy acid (the blending amount of the hydrophilic drug in the transdermal absorption promoter: the blending amount of α-hydroxy acid in the transdermal absorption promoter) is not particularly limited, but is preferably 1:1 to 1:4, more preferably 1:1.2 to 1:3.5.

[0019] According to a preferred embodiment of the transdermal absorption promoter of the present invention, there is provided a transdermal absorption promoter of a hydrophilic drug containing α-hydroxy acid as an active ingredient, wherein the mass ratio of the hydrophilic drug to the α-hydroxy acid (the blending amount of the hydrophilic drug in the transdermal absorption promoter: the blending amount of α-hydroxy acid in the transdermal absorption promoter) is 1:1 to 1:4, and the hydrophilic drug is glycylglycine or tranexamic acid.

[0020] [[ID=~16]]The pH of the transdermal absorption promoter of the present invention is not particularly limited, but is preferably 5 or less. The pH of the transdermal absorption promoter of the present invention can be measured, for example, using a pH meter or the like.

[0021] In the transdermal absorption promoter of the present invention, it is preferable to contain succinic acid. The blending amount of succinic acid is not particularly limited, but is preferably 0.1 to 6% by mass, more preferably 0.1 to 1% by mass, based on the total amount of the transdermal absorption promoter.

[0022] In addition to the components mentioned above, the transdermal absorption enhancer of the present invention may contain, as needed, powder components, oily components, UV absorbers, various aqueous solvents, metal ion chelating agents, monosaccharides, oligosaccharides, amino acids, organic amines, polymer emulsions, alcohols, pH adjusters, dispersants, antioxidants, fragrances, preservatives, stabilizers, and the like.

[0023] According to another aspect of the present invention, a composition for promoting the transdermal absorption of a hydrophilic agent containing an α-hydroxy acid as an active ingredient is provided. The transdermal absorption promoting composition is preferably a composition for topical application to the skin.

[0024] The transdermal absorption enhancer, transdermal absorption enhancing composition, and topical skin composition of the present invention described above can be widely applied to cosmetics, pharmaceuticals, and quasi-drugs. For example, applicable products include foundations, makeup bases, serums, lotions, creams, lipsticks, eyeshadows, eyeliners, mascaras, sprays, mousses, and dermatological ointments.

[0025] <Methods to promote transdermal absorption> Another aspect of the present invention provides a method for promoting the transdermal absorption of a hydrophilic agent, comprising administering an α-hydroxy acid to a target. Another preferred aspect of the present invention provides a method for promoting the transdermal absorption of a hydrophilic agent (excluding medical procedures on humans), comprising administering an α-hydroxy acid to a target. Here, "medical procedures on humans" means acts such as administering a drug to a human being with the need for a prescription from a doctor or the like. The target to which the α-hydroxy acid and hydrophilic agent are administered may be a human or an animal other than a human, but it is preferable that it be a human. Examples of animals other than humans include livestock such as horses and cattle, pets such as dogs and cats, and ornamental animals kept in zoos, etc.

[0026] According to another aspect of the present invention, the use of α-hydroxy acids is provided for the production of a transdermal absorption enhancer (or transdermal absorption enhancer) for hydrophilic agents.

[0027] According to another aspect of the present invention, the use of α-hydroxy acids is provided for promoting the transdermal absorption of hydrophilic agents. [Examples]

[0028] The present invention will be specifically described based on the following examples, but the present invention is not limited to these examples. Unless otherwise specified, the content is expressed in mass percent.

[0029] Test Example 1: Transdermal Absorption Confirmation Test The transdermal absorption of the formulations in Examples 1-3 and Comparative Examples 1-4 (see Table 1) was confirmed in vitro using Franz cells. The results of the transdermal absorption are shown in Figures 1 and 2.

[0030] The transdermal absorption of glycylglycine and tranexamic acid from the compositions prepared below was confirmed by measuring them over time using Franz cells in an infinitely closed system.

[0031] More specifically, a stirring bar was placed in a static Franz cell (vertical glass diffusion cell, 10 mm aperture diameter, 4.0 mL receiver capacity <Permegia>), and 4 mL of PBS manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. was injected. A Strat-M™ membrane (Merck) was placed between the Franz cell and a ground-seal glass donor and secured with a clip. To create an infinitely closed system, the test sample (composition) was placed on the glass donor, and Parafilm was used to prevent changes due to sample evaporation.

[0032] The constant temperature bath was set to 37°C, and the constant temperature bath and the Franz cells were connected in series with silicone tubing to maintain a constant temperature in the reservoir solution. Each Franz cell was placed in a stirrer, stirring was started, and the test began. At regular intervals from the start of stirring (1 hour, 2 hours, 3 hours, 6 hours, 9 hours, and 24 hours), 0.5 mL of the reservoir solution was taken, and the glycylglycine content and tranexamic acid content in the reservoir solution were quantified by LC / MS, and the cumulative permeation amount of glycylglycine (nmol / cm³) was determined. 2(See Figure 1) and cumulative permeation of tranexamic acid (nmol / cm³) 2 (See Figure 2) was calculated.

[0033] Analysis conditions Glycylglycine LC / MS_ MRM 130.90 > 73.9 negative (Shimadzu MS8050) was quantified and detected. Tranexamic acid LC / MS_SIM m / z 158_positive (Shimadzu MS8050) was quantified and detected.

[0034] Regarding Figure 1, which shows the cumulative permeation amount of glycylglycine, multiple comparisons were performed using the Tukey-Kramer method between Example 3 and Comparative Example 2, between Example 3 and Comparative Example 1, and between Example 3 and Example 1. In all cases, p<0.05 was obtained, indicating a statistically significant difference.

[0035] Regarding Figure 2, which shows the cumulative permeation of tranexamic acid, multiple comparisons were performed using the Tukey-Kramer method between Example 3 and Comparative Example 4, between Example 3 and Example 2, and between Example 3 and Comparative Example 3. The results showed p<0.05, indicating a statistically significant difference.

[0036] Water-soluble active ingredients used in cosmetics and quasi-drugs include whitening agents, anti-aging agents, and antioxidants. Examples include agents, moisturizers, hair growth products, cell activators, vitamins, and amino acids. Specifically These include arbutin (LogP=-0.6), L-ascorbic acid (LogP=-1.6), Hydroquinone (LogP=-0.6), glutathione (LogP=-4.5), pantothenic acid (LogP=-1.1), tranexamic acid (LogP=-2), kojic acid (LogP=-0.9), L-cysteine ​​(LogP=-2.5), ellagic acid (LogP=1.1), resorcinol (LogP=0.8), rutin (LogP=-1.3), tryptophan (LogP=-1.1), Flavonoids such as stidine (LogP=-3.2), glycylglycine (logP=-2.3), quercetin (LogP=1.5), and quercitrin (LogP=0.9), catechin (LogP=0.4), gallic acid (LogP=0.7), kinetin (LogP=1), alpha-lipoic acid (LogP=1.7), erythorbic acid (LogP=-1.6), and thiotaurine (LogP=-0. 1) Urea (LogP=-1.4), Nicotine (LogP=1.2), Nicotinic acid (LogP=0.4), Nicotinamide (logP=-0.4), Hydroxyproline (LogP=-3.3), Serine (LogP=-3.1), Glutamic acid (LogP=-3.7), Arginine (LogP=-4.2), Alanine (LogP=-3), Minoxidil (LogP=1.2), D- Examples include lucosamine (LogP=-2.8), N-acetyl-D-glucosamine (LogP=-1.7), hyaluronic acid (LogP=-7.4), raffinose (LogP=-5.8), azelaic acid (LogP=1.6), γ-aminobutyric acid (LogP=-3.2), allantoin (LogP=-2.2), L-carnitine (LogP=-0.2), and biotin (LogP=0.3).

[0037] [Table 1]

Claims

1. A transdermal absorption enhancer for hydrophilic agents, It contains α-hydroxy acid as an active ingredient, The α-hydroxy acid is glycolic acid, lactic acid, and citric acid. A transdermal absorption enhancer for hydrophilic agents, wherein the hydrophilic agent comprises one or more selected from the group consisting of glycylglycine, tranexamic acid, and nicotinamide.

2. The transdermal absorption enhancer according to claim 1, wherein the hydrophilic agent contains glycylglycine and tranexamic acid.

3. The transdermal absorption enhancer according to claim 1 or 2, wherein the amount of glycolic acid blended is 0.1 to 2% by mass relative to the total amount of the transdermal absorption enhancer.

4. The transdermal absorption enhancer according to any one of claims 1 to 3, wherein the amount of lactic acid added is 0.1 to 3% by mass relative to the total amount of the transdermal absorption enhancer.

5. The transdermal absorption enhancer according to any one of claims 1 to 4, wherein the amount of citric acid added is 0.1 to 4% by mass relative to the total amount of the transdermal absorption enhancer.

6. A transdermal absorption enhancer according to any one of claims 1 to 5, wherein the pH is 5 or less.

7. The transdermal absorption enhancer according to any one of claims 1 to 6, further comprising succinic acid.

8. It contains α-hydroxy acid as an active ingredient, It further contains a hydrophilic agent, The α-hydroxy acid is glycolic acid, lactic acid, and citric acid. A composition for promoting the transdermal absorption of a hydrophilic agent, wherein the hydrophilic agent comprises one or more selected from the group consisting of glycylglycine, tranexamic acid, and nicotinamide.

9. The transdermal absorption-promoting composition according to claim 8, wherein the amount of the hydrophilic agent is 1 to 6% by mass relative to the total amount of the transdermal absorption-promoting composition.

10. The mass ratio of the hydrophilic agent to the α-hydroxy acid (amount of hydrophilic agent in the transdermal absorption-enhancing composition: amount of α-hydroxy acid in the transdermal absorption-enhancing composition) is 1:1 to 1:4, and The transdermal absorption-promoting composition according to claim 8 or 9, wherein the hydrophilic agent is glycylglycine or tranexamic acid.

11. A transdermal absorption promoting composition according to any one of claims 8 to 10, further comprising succinic acid.

12. A composition for external use on the skin, according to any one of claims 8 to 11.

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