Efficient transdermal absorption enhancer for tranexamic acid and derivatives thereof and preparation method of efficient transdermal absorption enhancer

Abstract

The invention discloses an efficient transdermal absorption enhancer for tranexamic acid and derivatives thereof and a preparation method of the efficient transdermal absorption enhancer. The invention relates to an efficient transdermal absorption enhancer for tranexamic acid and derivatives thereof, which comprises bis-diethoxy diethylene glycol cyclohexane 1, 4-dicarboxylate and hydroxyethyl piperazine ethanesulfonic acid. Furthermore, the efficient transdermal absorption enhancer for the tranexamic acid and the derivatives of the tranexamic acid further comprises isosorbide dimethyl ether and / or hydrogenated lecithin. In research, the inventor finds that bis-diethoxy diethylene glycol cyclohexane 1, 4-dicarboxylate and hydroxyethyl piperazine ethanesulfonic acid are combined to serve as a transdermal absorption enhancer of tranexamic acid and derivatives thereof, and the transdermal absorption of tranexamic acid and derivatives thereof can be synergistically improved, so that the transdermal absorption of tranexamic acid and derivatives thereof is enhanced, and the transdermal absorption of tranexamic acid and derivatives thereof is enhanced. The transdermal patch has a very excellent transdermal absorption effect on tranexamic acid and derivatives thereof; therefore, the efficient transdermal absorption enhancer disclosed by the invention has important significance in improving the efficacy of tranexamic acid products.

Description

Technical Field

[0001] The invention relates to the field of transdermal technology, and in particular to a high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives and a preparation method thereof. Background Art

[0002] Tranexamic acid, also known as tranexamic acid, is a highly effective antioxidant and hemostatic drug. In recent years, it has been widely used in the cosmetics industry for its whitening, spot-lightening and anti-inflammatory effects. However, due to the natural barrier properties of the skin, tranexamic acid and its derivatives are difficult to effectively penetrate the epidermis, affecting the effective performance of its active ingredients. Therefore, the development of an effective penetration-enhancing technology is of great significance for improving the efficacy of tranexamic acid products. Summary of the invention

[0003] In order to overcome at least one technical problem existing in the prior art, the present invention provides a high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives and a preparation method thereof.

[0004] The present invention firstly provides a highly effective transdermal absorption enhancer for tranexamic acid and its derivatives, which comprises bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethane sulfonic acid.

[0005] The inventors found in their research that the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethanesulfonic acid as a transdermal absorption enhancer for tranexamic acid and its derivatives can synergistically improve the transdermal absorption of tranexamic acid and its derivatives, and its transdermal absorption effect on tranexamic acid and its derivatives is much higher than that of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate or hydroxyethylpiperazineethanesulfonic acid alone; it has a very excellent transdermal absorption effect on tranexamic acid and its derivatives.

[0006] Preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate to hydroxyethylpiperazineethane sulfonic acid is 1-3:1-2.

[0007] Most preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate to hydroxyethylpiperazineethane sulfonic acid is 3:2.

[0008] Preferably, the highly efficient transdermal absorption enhancer for tranexamic acid and its derivatives further comprises isosorbide dimethyl ether and / or hydrogenated lecithin.

[0009] The inventors found in further research that further adding isosorbide dimethyl ether or hydrogenated lecithin to the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid can further improve the transdermal absorption of tranexamic acid and its derivatives.

[0010] Preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethane sulfonic acid and isosorbide anhydride in the high-efficiency transdermal absorption enhancer is 1-3:1-2:0.2-1.

[0011] Most preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethane sulfonic acid and isosorbide anhydride in the high-efficiency transdermal absorption enhancer is 3:2:1.

[0012] Preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethane sulfonic acid and hydrogenated lecithin in the high-efficiency transdermal absorption enhancer is 1-3:1-2:0.2-1.

[0013] Most preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethane sulfonic acid and hydrogenated lecithin in the high-efficiency transdermal absorption enhancer is 3:2:1.

[0014] Preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethane sulfonic acid, isosorbide dimethyl ether and hydrogenated lecithin in the high-efficiency transdermal absorption enhancer is 1-3:1-2:0.2-1:0.2-1.

[0015] Most preferably, the mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethanesulfonic acid, isosorbide dimethyl ether and hydrogenated lecithin in the high-efficiency transdermal absorption enhancer is 3:2:0.5:0.5.

[0016] The inventors found in further research that, in the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid, further adding a single isosorbide anhydride dimethyl ether or a single hydrogenated lecithin can further improve the transdermal absorption of tranexamic acid and its derivatives, but the improvement is not large; however, in the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid, further adding isosorbide anhydride dimethyl ether and hydrogenated lecithin at the same time can further significantly improve the transdermal absorption of tranexamic acid and its derivatives; the degree of improvement in the transdermal absorption of tranexamic acid and its derivatives is significantly higher than that of adding only a single isosorbide anhydride dimethyl ether or a single hydrogenated lecithin.

[0017] Preferably, the derivative is hexadecyl tranexamic acid ester.

[0018] The present invention also provides a method for preparing the above-mentioned high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives, comprising the following steps: The highly effective transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by uniformly mixing bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethane sulfonic acid; or, The highly effective transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by uniformly mixing bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid with isosorbide anhydride dimethyl ether and / or hydrogenated lecithin.

[0019] Beneficial effects: The present invention provides a new high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives. The inventors found in their research that the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethanesulfonic acid as a transdermal absorption enhancer for tranexamic acid and its derivatives can synergistically improve the transdermal absorption of tranexamic acid and its derivatives, and has a very excellent transdermal absorption effect on tranexamic acid and its derivatives; therefore, the use of the high-efficiency transdermal absorption enhancer of the present invention is of great significance for improving the efficacy of tranexamic acid products. DETAILED DESCRIPTION

[0020] The following is a clear and complete description of the technical solutions in the embodiments of the present invention in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] Example 1 Preparation of a highly effective transdermal absorption enhancer for tranexamic acid and its derivatives The highly efficient transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by combining bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethane sulfonic acid in a mass ratio of 3:2.

[0022] Example 2 Preparation of a highly effective transdermal absorption enhancer for tranexamic acid and its derivatives The highly efficient transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by combining bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazine ethane sulfonic acid and isosorbide anhydride in a mass ratio of 3:2:1.

[0023] Example 3 Preparation of a highly effective transdermal absorption enhancer for tranexamic acid and its derivatives The highly effective transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by combining bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethane sulfonic acid and hydrogenated lecithin in a mass ratio of 3:2:1.

[0024] Example 4 Preparation of a highly effective transdermal absorption enhancer for tranexamic acid and its derivatives The highly efficient transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by combining bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazine ethane sulfonic acid, isosorbide dimethyl ether and hydrogenated lecithin in a mass ratio of 3:2:0.5:0.5.

[0025] Experimental example: Transdermal absorption experiment of tranexamic acid and its derivatives (1) Take a three-dimensional sample of the back skin of a one-month-old suckling pig and rinse it with PBS buffer (0.01 M); (2) Fixing the pig skin between the receiving chamber and the supply chamber of a diffusion cell (Franz cell), wherein the dermis layer side of the pig skin faces the receiving chamber, and the stratum corneum layer side of the pig skin faces the supply chamber; (3) After the pig skin is tightened and fixed, add 7.0 mL of receiving solution (0.01 M PBS buffer) into the receiving chamber, exhaust the air, and make the dermis layer of the skin in close contact with the receiving solution; (4) In the supply chamber, add the sample solution to the surface of the pig skin and spread it evenly. Perform 3 replicates and parallels for each sample. (5) Turn on the electromagnetic stirrer in the receiving chamber and stir in a water bath at 31-33°C (make sure there are no bubbles in the water bath) at a stirring speed of 300 rpm; (6) After 6 hours, skin samples were collected, PBS buffer (0.01 M) was added to wash the skin and dried, then the skin was cut with a blade and fixed with 4% paraformaldehyde solution for 24 hours. Skin sections were obtained after freezing; (7) The skin sections were observed and photographed using a fluorescence microscope to calculate the optical density value. The larger the optical density value, the better the skin penetration effect. The average optical density values ​​of each group are shown in Table 1.

[0026] The preparation method of the test sample solution of the experimental group is: the transdermal absorption enhancer, tranexamic acid (or its derivatives) and deionized water are uniformly mixed in a weight ratio of 1:9:90 to obtain the test sample solution.

[0027] The transdermal absorption enhancer in the test sample solutions 1 to 4 is the high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives prepared in Examples 1 to 4; the transdermal absorption enhancer in the test sample solutions 5 and 6 is single bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate or single hydroxyethylpiperazineethane sulfonic acid.

[0028] The preparation method of the control group test sample solution is: tranexamic acid (or its derivatives) and deionized water are uniformly mixed in a weight ratio of 9:91 to obtain the control group test sample solution.

[0029] Table 1. Skin penetration effect test results

[0030] It can be seen from the experimental results in Table 1 that the average optical density value of tranexamic acid and its derivative hexadecyl tranexamic acid in experimental group 1 is much higher than that in the control group; this shows that the high-efficiency transdermal absorption enhancer prepared by combining bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethane sulfonic acid in the present invention has a very excellent transdermal absorption effect on tranexamic acid and its derivatives.

[0031] It can be seen from the experimental results in Table 1 that the average optical density value of tranexamic acid and its derivative hexadecyl tranexamic acid ester in experimental group 1 is also much higher than that in experimental groups 5 and 6; this shows that the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethanesulfonic acid as a transdermal absorption enhancer for tranexamic acid and its derivatives can synergistically improve the transdermal absorption of tranexamic acid and its derivatives, and its transdermal absorption effect on tranexamic acid and its derivatives is much higher than that of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate or hydroxyethylpiperazineethanesulfonic acid alone.

[0032] It can be seen from the experimental results in Table 1 that the average optical density values ​​of tranexamic acid and its derivative hexadecyl tranexamic acid ester in experimental groups 2 and 3 are also higher than those in experimental group 1; this shows that further adding isosorbide dimethyl ether or hydrogenated lecithin to the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid can further improve the transdermal absorption of tranexamic acid and its derivatives.

[0033] It can be seen from the experimental results in Table 1 that the average optical density value of tranexamic acid and its derivative hexadecyl tranexamic acid in experimental group 4 is also significantly higher than that in experimental group 1, and is also significantly higher than that in experimental groups 2 and 3; this shows that: in the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid, further adding a single isosorbide anhydride dimethyl ether or a single hydrogenated lecithin can further improve the transdermal absorption of tranexamic acid and its derivatives, but the improvement is not large; however, in the combination of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid, further adding isosorbide anhydride dimethyl ether and hydrogenated lecithin at the same time can further significantly improve the transdermal absorption of tranexamic acid and its derivatives; the degree of improvement in the transdermal absorption of tranexamic acid and its derivatives is significantly higher than that of adding only a single isosorbide anhydride dimethyl ether or a single hydrogenated lecithin.

[0034] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0035] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A highly effective transdermal absorption enhancer for tranexamic acid and its derivatives, comprising bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazineethane sulfonic acid, characterized in that: Also included are dimethyl isosorbide and hydrogenated lecithin; The mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazineethanesulfonic acid, isosorbide dimethyl ether and hydrogenated lecithin in the high-efficiency transdermal absorption enhancer is 1-3:1-2:0.2-1:0.2-1.

2. The high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives according to claim 1, characterized in that: The mass ratio of bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate, hydroxyethylpiperazine ethane sulfonic acid, isosorbide dimethyl ether and hydrogenated lecithin in the high-efficiency transdermal absorption enhancer is 3:2:0.5:0.

5.

3. The high-efficiency transdermal absorption enhancer for tranexamic acid and its derivatives according to claim 1, characterized in that: The derivative is hexadecyl tranexamic acid.

4. The method for preparing a highly effective transdermal absorption enhancer for tranexamic acid and its derivatives according to any one of claims 1 to 3, characterized in that: The following steps are included: The highly effective transdermal absorption enhancer for tranexamic acid and its derivatives is obtained by uniformly mixing bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate and hydroxyethylpiperazine ethane sulfonic acid with isosorbide dimethyl ether and hydrogenated lecithin.

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