JP2010229100A - External preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation for the skin which includes tranexamic acid dissolved stably in high concentration, exhibits high penetration of tranexamic acid into the stratum corneum even with a practically small amount of application, although externally applied tranexamic acid normally penetrates little into the stratum corneum and has lasting penetration of tranexamic acid into the stratum corneum by controlling the re-crystalization of tranexamic acid on the surface of the skin after application. <P>SOLUTION: The external preparation for the skin is of an emulsion type and includes an aqueous phase containing tranexamic acid or its salt, an oil phase and a surfactant. The oil phase contains a higher fatty acid. The surfactant used is one kind or not less than two kinds selected from among phosphate-based anionic surfactants and/or nonionic surfactants having an HLB of 6.0-18.0. The tranexamic acid or its salt is dissolved in the aqueous phase having an adjusted pH of 4.0-6.0 in an amount of 5.0-12.0 mass% to the total amount of the external preparation for the skin. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an external preparation for skin intended to improve skin symptoms by external application of tranexamic acid, which is difficult to permeate the stratum corneum, which is a substance permeation barrier due to its high water solubility. In particular, the present invention relates to an emulsified skin external preparation capable of obtaining sufficient stratum corneum permeability and long-lasting permeation even with a small amount of formulation applied to be practically applied.

  Stain is one of the skin problems that many women currently have, and various cosmetics and quasi-drugs are applied and used to improve it. However, in the past, they did not lead to treatment, and it was difficult to obtain an effect with an external preparation especially for symptoms that are said to develop in connection with female hormones such as melasma.

  In recent years, the effectiveness against melasma has been found and approved in oral pharmaceutical preparations containing tranexamic acid, which was an ethical pharmaceutical ingredient, as an active ingredient. Since tranexamic acid is a highly water-soluble drug listed in the Japanese Pharmacopoeia (see Non-Patent Document 1), when applied to the skin, it is difficult to penetrate the stratum corneum, which is a large barrier for substance penetration. It is difficult to penetrate inside.

  In general, in the skin permeation process of drugs from topical skin preparations, it is necessary to increase the thermodynamic activity of drugs on the skin after application and to increase the drug solubility in the skin barrier mainly composed of the stratum corneum. If these are not achieved, the permeation rate will not increase. In tranexamic acid, when the concentration of tranexamic acid in the preparation is less than 5% by mass, a sufficient amount of stratum corneum permeation cannot be obtained. Due to the high recrystallization property on the skin surface after application, sufficient solubility in the stratum corneum is not obtained, and the stratum corneum permeability as expected cannot be obtained only by increasing the concentration in the preparation. It was. Tranexamic acid is a highly water-soluble drug. However, according to Non-Patent Document 1, the upper limit of solubility in water is about 16% at maximum, so that high concentration of tranexamic acid can be stabilized in the preparation. This is partly because it is difficult to dissolve it. For this reason, tranexamic acid with low permeability to the stratum corneum and high recrystallization on the skin surface after application had sufficient stratum corneum permeability and a function to maintain it. No external preparation for skin was obtained.

  In many known technical literatures, a topical skin preparation containing tranexamic acid is shown, and in some cases, it is shown as a technique for improving skin symptoms. I can't find anything that clearly states the study. Prior art document information for the present invention is as follows.

  Japanese Patent No. 2906269 (Patent Document 1) describes an external preparation for skin intended to prevent coloring of tranexamic acid by combining sodium bisulfite with tranexamic acid, and Japanese Patent Application Laid-Open No. 3-279314. (Patent Document 2) describes an external preparation for skin intended to prevent the rancidity and odor of oil by combining and blending tranexamic acid with oil having an iodine value of 50 or more, and JP-A-3-279316. (Patent Document 3) describes an external preparation for skin intended to prevent coloring of tranexamic acid by blending a specific phosphate with tranexamic acid. And these patent documents 1-3 describe that 0.1-30 mass% of tranexamic acids can be mix | blended. However, Patent Documents 1 to 3 do not investigate the incorporation of a high concentration of tranexamic acid without crystallization, increase the skin permeability, and maintain the permeability. Not. The solubility of tranexamic acid in water is 16%, as described above. Even in Examples of Patent Documents 1 to 3, the amount of tranexamic acid (salt) is 1.0% by mass in most cases, and other than that, 0.1% by mass, 2.0% by mass, 6.0% by mass 15.0 mass% is disclosed for each one example. However, when the present inventors prepared a 15% tranexamic acid-containing lotion shown in Example 15 of Patent Document 2, it was formulated in a state where tranexamic acid crystals were dispersed. That is, when a high concentration of tranexamic acid shown in Patent Document 2 is formulated, a preparation in which crystals are dispersed is formed, and when used, a rough feeling is felt and the feeling of use is greatly impaired. In addition, as a result of testing for skin permeability, the permeation rate was very low (see “Comparative Example 1” in the Examples section below). That is, it was confirmed that the skin permeability of crystallized tranexamic acid does not increase even when the concentration of tranexamic acid is increased.

  Japanese Patent Application Laid-Open No. 7-215839 (Patent Document 4) describes an external preparation for skin containing erythritol, tranexamic acid and skin-covering components (fatty acids and the like), and the preferred blending amount of tranexamic acid is 0.1-15. It is described that it is mass%. As will be described later, the present inventors have found that it is impossible to blend at a high concentration without adjusting the pH of the aqueous phase in which tranexamic acid is dissolved low. However, there is no description or suggestion about the pH of the aqueous phase in Patent Document 4, and it is clear that the formulation example of high concentration of tranexamic acid in Examples described in Patent Document 4 is a system in which undissolved crystals are dispersed. . Therefore, it can be easily inferred that even when the preparation disclosed in Patent Document 4 is transdermally administered, tranexamic acid, which is a water-soluble drug, has a very low stratum corneum permeability.

  Japanese Patent Application Laid-Open No. 2001-97815 (Patent Document 5) describes a water-in-oil emulsified composition that enhances the penetration ability of amino acids into the skin, and describes the blending of fatty acids typified by isostearic acid. However, there is no illustration of tranexamic acid as a specific example of an amino acid, and it is described in one line that tranexamic acid can be blended as an optional additive component ([0022]). Since there is no description of skin permeation data regarding tranexamic acid in Patent Document 5 and the pH of the aqueous phase is not adjusted, it is clear that sufficient skin permeability of tranexamic acid cannot be expected.

  Japanese Patent Application Laid-Open No. 2002-128646 (Patent Document 6) describes a skin external preparation for sunscreen containing a whitening agent (such as tranexamic acid) and a fatty acid (salt), and the blending amount of the whitening agent (such as tranexamic acid) 0.001 to 10% by mass is described. However, Patent Document 6 does not describe pH adjustment of the aqueous phase. When only tranexamic acid is dissolved in an aqueous phase that has not been adjusted for pH, the pH of the aqueous phase does not become 6 or less, so it is clear that crystals are precipitated when the content is 5% by mass or more. Therefore, as a matter of course, improvement in keratin permeability cannot be expected.

  Japanese Patent Application Laid-Open No. 2003-160465 (Patent Document 7) describes a pretreatment agent for promoting percutaneous absorption in which a water-soluble drug (tranexamic acid or the like) and a fatty acid (salt) having 8 to 24 carbon atoms are blended. . Although the formulation example which mix | blended tranexamic acid as the whitening agent in this patent document 7 is shown by Example 9, the compounding quantity is only 1.0 mass%. Since Patent Document 7 is a pretreatment agent before drug administration and describes that pH 7 to 10 is preferable ([0010]), the approach is completely different from the present invention.

  JP-A-2003-160468 (Patent Document 8) describes a cleaning composition containing a whitening agent (such as tranexamic acid) and a fatty acid (salt) having 8 to 24 carbon atoms. Although the formulation example which mix | blended tranexamic acid as the whitening agent in this patent document 8 is shown by Example 4, the compounding quantity is only 1.0 mass%. Since the cleaning composition of Patent Document 8 is described as having a pH of 7 to 10 ([0018]), the present invention and the approach are completely different.

  Japanese Patent Application Laid-Open No. 2004-161623 (Patent Document 9) describes an aqueous stick-shaped anti-acne composition containing a protease inhibitor (such as tranexamic acid) and a higher fatty acid salt, and the protease inhibitor (such as tranexamic acid). ) Is described as 0.01 to 10% by mass. However, the patent document 9 does not describe a specific formulation example in which tranexamic acid is blended, and does not describe or suggest the relationship between pH adjustment and the amount of tranexamic acid blended.

  Japanese Patent Application Laid-Open No. 2004-307353 (Patent Document 10) describes an oil-in-water emulsion composition containing a nonionic surfactant of HLB 7 to 9 and a salt-type drug component (such as tranexamic acid salt). It is described that the preferable compounding amount of the type drug component is 0.1 to 30% by mass. However, there is no description about the blending of fatty acid in Patent Document 9, and it can be easily analogized that high keratin permeability cannot be obtained even when tranexamic acid is blended. There is no specific formulation example in which the tranexamic acid is blended in the document. The object of the invention described in the document is emulsion stability and usability (skin spreading, stickiness, freshness, penetrating feeling), and the above-mentioned "penetrating feeling" is only by sensory evaluation, and the skin of the drug Neither the improvement of the permeability to the skin, the maintenance of the permeability, etc. nor the objective evaluation examination has been performed, and the object is different from the present invention for these purposes.

  Japanese Patent Application Laid-Open No. 2005-255667 (Patent Document 11) contains 0.01 to 2% by mass of an oil component containing 34% by mass or more of isostearic acid in the total oil content, a specific hydrophilic surfactant and a lipophilic surfactant. Liquid cosmetics to be contained are described, and tranexamic acid (salt) is described as an optional additive ([0026]). There is no description of high concentration formulation of tranexamic acid in this document, and only a formulation example containing 1.0% by mass of tranexamic acid is shown in Example 18.

  Japanese Patent Application Laid-Open No. 2006-282632 (Patent Document 12) describes a solid water-in-oil emulsified cosmetic containing a whitening component (tranexamic acid or the like), and contains 0.01 to 20% by weight of the whitening component. However, there is no description about pH adjustment of the aqueous phase. Further, this document does not describe a specific formulation example containing tranexamic acid.

  Japanese Patent Application Laid-Open No. 2006-312603 (Patent Document 13) discloses a sheet-like skin in which a base material on a sheet is impregnated with an oil-in-water emulsion composition containing a water-soluble drug (such as tranexamic acid) and a hydrophilic nonionic surfactant. An external preparation is described. However, since the external preparation for skin of this document does not adjust the pH to the acidic side, it can be inferred that high concentration of tranexamic acid does not dissolve stably. In fact, in the examples of this document, the amount of tranexamic acid is only 2.0% by mass.

  Japanese Unexamined Patent Application Publication No. 2007-161612 (Patent Document 14) describes an external preparation for skin containing a branched fatty acid (such as isostearic acid) and tranexamic acid, but the preferred amount of tranexamic acid is 0.001 to 0. .1% by mass and low blending. With such a low blending, the expected stratum corneum permeability cannot be obtained.

Japanese Patent No. 2906269 JP-A-3-279314 JP-A-3-279316 Japanese Patent Laid-Open No. 7-215839 JP 2001-97815 A JP 2002-128646 A JP 2003-160465 A JP 2003-160468 A JP 2004-161623 A JP 2004-307353 A JP 2005-255667 A JP 2006-282632 A JP 2006-312603 A JP2007-161612A

“Fifteenth revision Japanese Pharmacopoeia Manual for Pharmaceuticals”, C-2743-2749, Yodogawa Shoten, July 2006

  Tranexamic acid is a white crystal or crystalline powder, and as mentioned above, it is difficult to dissolve it in a high concentration, and it is difficult to formulate it into a preparation. There was a problem that the crystal was recrystallized and the feeling of use such as a rough feeling deteriorated. In addition, due to this recrystallization property, there is a problem that the skin permeability does not increase even when a high concentration is added to a general external preparation.

  The invention aims to solve these conventional problems, and tranexamic acid with low stratum corneum permeability in external application has high stratum corneum permeability of tranexamic acid even at a practically small coating amount, An object of the present invention is to provide an external preparation for skin that stably dissolves high-concentration tranexamic acid excellent in the durability of stratum corneum permeation by suppressing recrystallization of tranexamic acid on the skin surface after application.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have an amino group and a carboxyl group in the molecular structure in the aqueous phase (components excluding the oil phase and surfactant) when preparing an emulsion type preparation. When dissolving tranexamic acid, which is an amphoteric ion, the pH of the aqueous phase is adjusted to 4.0 to 6.0, and the solubility of tranexamic acid is significantly improved by dissolving in the aqueous phase under such conditions. I found out. As a result, it was confirmed that tranexamic acid can be dissolved at a high concentration in the emulsified preparation, and that the stratum corneum permeability of tranexamic acid is greatly increased by containing higher fatty acids that are electrostatically paired. . Furthermore, by incorporating a specific anionic surfactant and / or a nonionic surfactant of HLB 6.0 to 18.0, it was possible to prepare an emulsified skin external preparation excellent in stability. As a result, the present inventors have found that the recrystallization of tranexamic acid on the skin surface after application can be suppressed even at a practical application amount, and that high stratum corneum permeability of tranexamic acid can be maintained, and the present invention is completed. It came.

  That is, the present invention is an emulsified skin external preparation containing an aqueous phase containing tranexamic acid or a salt thereof, an oil phase, and a surfactant, which contains a higher fatty acid in the oil phase and phosphoric acid as a surfactant. One type or two or more types selected from ester-based anionic surfactants and / or nonionic surfactants having an HLB of 6.0 to 18.0 are used, and the tranexamic acid or a salt thereof has a pH. The above-mentioned emulsified skin external preparation, characterized by being dissolved in a blending ratio of 5.0 to 12.0 mass% with respect to the total amount of the external preparation for skin in an aqueous phase adjusted to 4.0 to 6.0. provide.

  The present invention also provides the above-mentioned emulsified skin external preparation, wherein the higher fatty acid is one or more selected from stearic acid, isostearic acid, and oleic acid.

  In the present invention, the phosphate anionic surfactant is one or more selected from polyoxyethylene cetyl ether phosphate, polyoxyethylene lauryl ether phosphate, or salts thereof. The emulsified external skin preparation is provided.

  In the present invention, the nonionic surfactant having an HLB of 6.0 to 18.0 is polyoxyethylene hydrogenated castor oil, glycerin polyoxyethylene monostearate, sorbitan polyoxyethylene monostearate, polyoxyethylene monoester. One or two selected from sorbitan oleate, polyethylene glycol monostearate, polyethylene glycol monooleate, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether The emulsified skin external preparation described above is provided.

  The present invention also provides the above-mentioned emulsified skin external preparation, which is a preparation for treating spots (liver spots).

  Moreover, this invention adds tranexamic acid or its salt to an aqueous phase so that it may become a mixture ratio of 5.0-12.0 mass% with respect to the skin external preparation whole quantity, Then, pH of this aqueous phase is set to 4.0-. By adjusting to 6.0, tranexamic acid or a salt thereof is dissolved in the aqueous phase, and then the aqueous phase having a pH of 4.0 to 6.0 and the oil phase in which the tranexamic acid or the salt is dissolved are dissolved in a phosphate ester system. An anionic surfactant and / or a nonionic surfactant having an HLB of 6.0 to 18.0 is emulsified to provide a method for producing the emulsified skin external preparation.

  According to the present invention, a preparation in which tranexamic acid is stably dissolved at a high concentration can be obtained, and by maintaining the high stratum corneum permeability of tranexamic acid after open application, a sufficient amount of tranexamic acid can be obtained even in external application. An emulsified external skin preparation that can be supplied to the affected area is obtained.

It is a graph which shows the permeation | transmission rate of tranexamic acid in an Example. It is the microscope picture (drawing substitute photograph) which observed the state (state of the formulation which remain | survives on the skin) of the horny layer side of the skin collect | recovered after completion | finish of the in vitro skin permeability test after applying the formulation of Example 3. . It is the microscope picture (drawing substitute photograph) which observed the state (state of the formulation which remain | survives on the skin) of the horny layer side of the skin collect | recovered after completion | finish of the in vitro skin permeability test after applying the formulation of the comparative example 2. . It is the microscope picture (drawing substitute photograph) which observed the state (state of the formulation which remain | survives on the skin) of the horny layer side of the skin collect | recovered after completion | finish of the in vitro skin permeability test after applying the formulation of the comparative example 4. . It is a graph which shows the relationship between the time after administration and the plasma tranexamic acid density | concentration in the in-vivo single-dose transdermal absorption test of the formulation of Example 3 and the comparative example 3. FIG.

  Hereinafter, the present invention will be described in detail. In the following, “POE” means polyoxyethylene.

  The emulsified skin external preparation according to the present invention contains an aqueous phase containing tranexamic acid or a salt thereof as an active ingredient, an oil phase, and a surfactant.

Tranexamic acid (C ₈ H ₁₅ NO ₂ ) is blended in a free form and a salt form. Although it does not specifically limit as a salt, For example, in addition to alkali metal salts or alkaline-earth metal salts, such as sodium salt, potassium salt, and calcium salt, salts, such as ammonium salt, amine salt (triethanolamine salt etc.), and amino acid salt, are included. Can be mentioned.

In the present invention, the tranexamic acid or a salt thereof is contained in an aqueous phase whose pH is adjusted to 4.0 to 6.0, preferably 5.0 to 5.5. By setting the pH of the aqueous phase in the above range, the solubility of tranexamic acid in water is significantly improved. Therefore, tranexamic acid (salt) in the external preparation for skin can be blended at a high concentration in the state of being dissolved in the aqueous phase in the external preparation for skin, and after application to the skin, recrystallization of tranexamic acid (salt) Can be prevented. For this reason, the stratum corneum permeability of tranexamic acid (salt) can be enhanced, and the maintenance of stratum corneum permeation is also improved by preventing recrystallization on the skin after application. In addition, after application, there is no rough feeling due to recrystallization, and the usability is excellent.
Here, “the pH of the aqueous phase is 4.0 to 6.0” means an aqueous component (for example, purified water, tranexamic acid or the like) excluding the oil phase-containing component and the surfactant in the emulsion external preparation of the present invention. The pH of the phase (= water phase) containing a salt, an organic acid, an inorganic acid, an inorganic salt, a polyhydric alcohol, etc.) is 4.0 to 6.0.

  An organic acid is preferably used to adjust the pH of the aqueous phase to 4.0 to 6.0. The organic acid is not particularly limited as long as it is usually used for pharmaceuticals and external preparations, and examples thereof include malic acid, citric acid, lactic acid, gluconic acid, tartaric acid, etc., among them, the viewpoint of maintaining pH. Therefore, malic acid, citric acid, and tartaric acid are particularly preferable. One or more organic acids can be used. In order to adjust the pH of the aqueous phase to 4.0 to 6.0, not only an organic acid but also an inorganic acid (such as phosphoric acid) may be used.

  The amount of the organic acid is not particularly limited as long as the pH of the aqueous phase can generally be adjusted to 4.0 to 6.0, but is generally 0.5 in the total amount of the emulsified skin external preparation of the present invention. It is preferable to blend about ~ 2.0% by mass. If the pH of the aqueous phase is less than 4.0, it is not preferable in terms of safety to the skin in the application of the preparation. On the other hand, if the pH of the aqueous phase exceeds 6.0, high concentration of tranexamic acid may be stably dissolved. Can not.

  The blending amount of traxamic acid or a salt thereof in the emulsified skin external preparation of the present invention is 5.0 to 12.0% by mass, preferably 7.0 to 10.0% by mass. If it is less than 5.0% by mass, clear stratum corneum permeability and its persistence cannot be obtained, while if it exceeds 12.0% by mass, it is difficult to dissolve in the preparation or it is difficult to re-apply on the skin surface after application. Crystallization is unfavorable because it causes discomfort and irritation in the act of applying to the skin, and high stratum corneum permeability cannot be expected.

  In the present invention, a higher fatty acid is contained in the oil phase. The higher fatty acids are not particularly limited as long as they are usually used for pharmaceuticals and external preparations, and those having about 12 to 24 carbon atoms are used. Specifically, for example, stearic acid, isostearic acid, Examples include oleic acid, capric acid, myristic acid and the like. By blending these higher fatty acids, it is possible to adjust the feeling of use during coating, among which stearic acid, isostearic acid and oleic acid are preferred.

  As for the compounding quantity of a higher fatty acid, 1.0-6.0 mass% is preferable in the whole quantity of this invention emulsification type skin external preparation. If it is less than 1.0% by mass, it is difficult to obtain a high stratum corneum permeability of tranexamic acid. On the other hand, if it exceeds 6.0% by mass, it is not preferable from the viewpoint of safety to the skin.

  The emulsified skin external preparation of the present invention further contains a phosphate ester anionic surfactant and / or a nonionic surfactant having an HLB of 6.0 to 18.0. By containing these surfactants, it is possible to obtain an emulsified composition that more stably maintains high stratum corneum permeability. Even if these are used respectively or both are used simultaneously, the high stratum corneum permeability is not impaired. Also, by properly using them, either an oil-in-water type or a water-in-oil type can be used.

  As the phosphate ester type anionic surfactant, polyoxyalkylene phosphate salt is preferably used in the present invention. Specifically, POE cetyl ether phosphoric acid or a salt thereof, POE lauryl ether phosphoric acid or a salt thereof are preferably used. In addition, the suitable addition mole number of polyalkylene is 2-10, More preferably, it is 4-8. Although it does not specifically limit as a salt, For example, in addition to alkali metal salts or alkaline-earth metal salts, such as sodium salt, potassium salt, and calcium salt, salts, such as ammonium salt, amine salt (triethanolamine salt, etc.), and amino acid salt, are included. Can be mentioned. By containing a phosphate ester-based anionic surfactant, a water-in-oil emulsion type skin external preparation can be obtained, and the tranexamic acid stratum corneum permeability can be increased and the stability of the preparation can be improved. . When a phosphate ester-based anionic surfactant is blended, the blending amount is preferably 0.5 to 5.0% by mass in the total amount of the external preparation for skin in order to sufficiently exhibit the above effects.

  Nonionic surfactants having an HLB of 6.0 to 18.0 include POE hydrogenated castor oil, glycerin POE monostearate, sorbitan POE monostearate, sorbitan POE monooleate, polyethylene glycol monostearate, monoolein Acid polyethylene glycol, POE cetyl ether, POE stearyl ether, POE oleyl ether, POE behenyl ether and the like are preferably used. By blending a nonionic surfactant having an HLB of 6.0 to 14.0, a desired emulsified skin external preparation can be prepared. When mix | blending these nonionic surfactants, the compounding quantity has preferable 0.5-5.0 mass% in this invention external preparation for skin. If the blending amount is too small, the stratum corneum permeability may not be maintained at a high level. On the other hand, if the blending amount is too large, problems may occur in the feeling of use and stability at the time of application.

  The skin external preparation of the present invention can adopt any emulsification type, water-in-oil type or oil-in-water type, by appropriately selecting blending components and the like. In order to obtain a water-in-oil emulsion type, a nonionic surfactant is not added (= only a phosphate anionic surfactant is added), or an HLB of 6.0 or more and 14.0 or less. The case where a nonionic surfactant is preferably blended in an amount of 5.0% by mass or less is exemplified. On the other hand, in order to obtain an oil-in-water emulsion type, for example, when a nonionic surfactant having an HLB greater than 14.0 and 18.0 or less is preferably blended in an amount of 0.5 to 5.0% by mass, etc. Is mentioned.

  In the present invention, a higher alkyl sulfate ester salt may be further blended from the viewpoint of further improving the stability of the preparation and the stratum corneum permeability of tranexamic acid. Examples of the higher alkyl sulfate ester salt include sodium lauryl sulfate, potassium lauryl sulfate, sodium cetyl sulfate, and potassium cetyl sulfate. In the present invention, sodium cetyl sulfate is particularly preferable. When the higher alkyl sulfate salt is blended, the blending amount is 0.01 to 0.2% by mass. If the blending amount is too small, the formulation cannot be stabilized and the stratum corneum permeability can not be further increased. Moreover, when there are too many compounding quantities, it is unpreferable at the surface of the safety | security with respect to skin.

  In the emulsified skin external preparation of the present invention, optional addition components that can be usually added to the skin external preparation other than the above-mentioned components can be appropriately blended as necessary within the range not impairing the effects of the present invention. Examples of these components include hydrocarbons (such as petroleum jelly, liquid paraffin, and squalane), fatty acid esters (such as isopropyl myristate, diethyl sebacate), higher alcohols, surfactants, silicone oil, organic solvents (ethanol, carbonic acid, etc.) Propylene, benzyl alcohol, etc.), powders (synthetic magnesium silicate, dextrin palmitate, etc.), water-soluble polymers (carboxyvinyl polymer, hydroxypropyl cellulose, xanthan gum, sodium hyaluronate, etc.), polyhydric alcohol (glycerin) 1,3-butylene glycol, etc.). Moreover, antioxidants, chelating agents, inorganic salts, preservatives and the like can be blended as necessary.

  The method for producing an emulsified skin external preparation according to the present invention includes, for example, adding tranexamic acid or a salt thereof to the aqueous phase so as to have a blending ratio of 5.0 to 12.0 mass% with respect to the total amount of the external preparation for skin. By adjusting the pH of the aqueous phase to 4.0 to 6.0, tranexamic acid or a salt thereof is dissolved in the aqueous phase, and then water having a pH of 4.0 to 6.0 in which the tranexamic acid or a salt thereof is dissolved is dissolved. A preferred example is a method of emulsifying a phase and an oil phase with a phosphate ester anionic surfactant and / or a nonionic surfactant having an HLB of 6.0 to 18.0. Mechanical treatment is preferred for emulsification. Moreover, you may perform some heating for uniformity according to the component to be used.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to a following example. In addition, all compounding quantities are shown by the mass%.

[Examples 1 to 13, Comparative Examples 1 to 4]
An external preparation for skin having the following composition was prepared.

(Example 1: Water-in-oil emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 5.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Sodium hydroxide 0.4
Purified water 70.1
Squalane 5.0
Isostearic acid 4.0
POE (5) cetyl ether phosphoric acid 4.0
The pH of the aqueous phase of Example 1 was 5.1.

(Example 2: Water-in-oil emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 7.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Sodium hydroxide 0.15
Purified water 68.35
Squalane 5.0
Isostearic acid 4.0
POE (5) cetyl ether phosphoric acid 4.0
The pH of the aqueous phase of Example 2 was 5.1.

(Example 3: Water-in-oil emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 65.5
Squalane 5.0
Isostearic acid 4.0
POE (5) cetyl ether phosphoric acid 4.0
The pH of the aqueous phase of Example 3 was 5.1.

(Example 4: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (20) hydrogenated castor oil (HLB = 10.5) 2.0
The pH of the aqueous phase of Example 4 was 5.1.

(Example 5: Water-in-oil emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (10) cetyl ether (HLB = 13.5) 2.0
The pH of the aqueous phase of Example 5 was 5.1.

(Example 6: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (6) sorbitan monostearate (HLB = 9.5) 2.0
The pH of the aqueous phase of Example 6 was 5.1.

(Example 7: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (10) behenyl ether (HLB = 10.0) 2.0
The pH of the aqueous phase of Example 7 was 5.1.

(Example 8: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 65.5
Squalane 5.0
Isostearic acid 4.0
POE (5) cetyl ether phosphate 2.0
POE (10) cetyl ether (HLB = 13.5) 2.0
The pH of the aqueous phase of Example 8 was 5.1.

(Example 9: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.4
Squalane 5.0
Isostearic acid 4.0
POE (10) cetyl ether (HLB = 13.5) 2.0
Sodium cetyl sulfate 0.1
The pH of the aqueous phase of Example 9 was 5.1.

(Example 10: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 65.4
Squalane 5.0
Isostearic acid 4.0
POE (10) cetyl ether (HLB = 13.5) 2.0
Sodium cetyl sulfate 0.1
POE (5) cetyl ether phosphate 2.0
The pH of the aqueous phase of Example 10 was 5.1.

(Example 11: Oil-in-water emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (20) cetyl ether (HLB = 17.0) 2.0
The pH of the aqueous phase of Example 11 was 5.1.

(Example 12: Oil-in-water emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
Citric acid 1.0
L-tartaric acid 0.5
1,3-butylene glycol 5.0
Purified water 58.9
Behenyl alcohol 3.0
Stearyl alcohol 1.2
Isostearic acid 4.0
White petrolatum 4.0
Light liquid paraffin 4.0
Methylpolysiloxane 2.0
Isopropyl myristate 4.0
Ethylparaben 0.2
POE (20) behenyl ether (HLB = 16.5) 0.7
Glycerol monostearate 1.5
The pH of the aqueous phase of Example 12 was 5.5.

(Example 13: Oil-in-water emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
Citric acid 1.0
L-tartaric acid 0.5
1,3-butylene glycol 5.0
Purified water 58.9
Behenyl alcohol 3.0
Stearyl alcohol 1.2
Stearic acid 4.0
White petrolatum 4.0
Light liquid paraffin 4.0
Methylpolysiloxane 2.0
Isopropyl myristate 4.0
Ethylparaben 0.2
POE (20) behenyl ether (HLB = 16.5) 0.7
Glycerol monostearate 1.5
The pH of the aqueous phase of Example 13 was 5.5.

(Comparative example 1: lotion)
(Mixed component) (mass%)
Tranexamic acid 15.0
Glycerin 2.0
1,3-butylene glycol 2.0
Carboxyvinyl polymer 0.2
Purified water 62.18
Ethanol 15.0
Purified lecithin 0.02
Oleyl alcohol 0.5
POE (60) hydrogenated castor oil (HLB = 14.0) 3.0
Methylparaben 0.1
The aqueous phase of Comparative Example 1 had a pH of 7.4 and was a preparation in which crystals of tranexamic acid were dispersed.

(Comparative Example 2: Water-in-oil emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
Sorbitan trioleate (HLB = 4.3) 2.0
The pH of the aqueous phase of Comparative Example 2 was 5.1.

(Comparative Example 3: Oil-in-water emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
Glycerin 3.0
1,3-butylene glycol 5.0
Polyethylene glycol 1500 2.5
Xanthan gum 0.02
Citric acid 0.02
Sodium citrate 0.08
Purified water 52.33
Behenyl alcohol 3.0
Stearyl alcohol 1.8
White petrolatum 4.0
Microcrystalline wax 1.0
Jojoba oil 3.0
Squalane 4.0
Methylpolysiloxane 2.0
Tetra-2-ethylhexanoic acid pentaerythritol 4.0
Methylparaben 0.25
POE (60) glyceryl isostearate (HLB = 16.0) 2.3
Glycerol monostearate 1.7
The aqueous phase of Comparative Example 3 had a pH of 7.2 and was a preparation in which crystals of tranexamic acid were dispersed.

(Comparative Example 4: Oil-in-water emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
Citric acid 0.5
L-tartaric acid 1.0
1,3-butylene glycol 10.0
Purified water 57.8
Behenyl alcohol 3.3
Stearyl alcohol 0.9
White petrolatum 4.0
Light liquid paraffin 4.0
Methylpolysiloxane 2.0
Isopropyl myristate 4.0
Ethylparaben 0.2
POE (20) behenyl ether (HLB = 16.5) 0.7
POE (50) hydrogenated castor oil (HLB = 13.5) 0.1
Glycerol monostearate 1.5
The pH of the aqueous phase of Comparative Example 4 was 5.5.

[Solubility of tranexamic acid in topical skin preparation]
In all the external preparations for skin of Examples 1 to 13, tranexamic acid was dissolved. Further, Comparative Examples 2 and 4 were dissolved in the same manner as in Examples, but Comparative Examples 1 and 3 were preparations in which crystals of tranexamic acid were dispersed, and a foreign body feeling was felt when applied.

[In vitro skin permeability test]
As an index for evaluating the stratum corneum permeability of tranexamic acid, skin permeability tests using lab skins were conducted on Examples 1 to 13 and Comparative Examples 1 to 4. The method is as follows.
(Method)
A lab skin [hairless mouse (HR-1), Hoshino Test Animal Breeding Co., Ltd.] is placed on a ² -chamber Franz diffusion cell (effective transmission area 3.14 cm ² , receiver side volume 17 mL) with the stratum corneum on top It was attached to become. The test preparation is uniformly applied to the donor side (corner layer side) so as to be 5 mg / cm ^2, and a phosphate buffer solution of pH 7.4 is used as the receiver side (dermis side) solution. The skin surface temperature was kept at 30 ° C. by perfusing 37 ° C. water. The donor side was placed in an unoccluded state, and 1 mL was sampled at 2, 4, 6, 8, 10, 24 hours while stirring the receiver solution with a magnetic stirrer. For the sampled solution, the concentration of tranexamic acid in the receiver solution is measured using high performance liquid chromatography, the cumulative amount of tranexamic acid permeated is calculated from the obtained quantitative value, and per unit area of tranexamic acid from the relationship with time. The steady state permeation rate was calculated.
(result)
FIG. 1 shows the permeation rates obtained for the transdermally absorbable preparations of Examples 1 to 13 and Comparative Examples 1 to 4 (n = 3, mean ± SD). FIG. 1 shows that the skin permeation rate per unit area of tranexamic acid from the skin external preparations of Examples 1 to 13 according to the present invention is high.

  As is clear from the comparison between Example 8 and Example 9 in FIG. 1, in Example 8, the phosphate ester anionic surfactant in the formulation of Example 9 was changed to sodium cetyl sulfate. It was confirmed that the permeation rate was slightly increased. Further, in contrast to Example 9 and Example 5, the addition of sodium cetyl sulfate to the formulation of Example 5 further improved the solubility of tranexamic acid in the formulation, resulting in a decrease in thermodynamic activity. Although it seems that the obtained permeation | transmission rate fell, it turns out that the permeation | transmission rate from the formulation of this invention is high with respect to a comparative example clearly.

[Recrystallization on the skin after open application]
As an index of evaluation of recrystallization property on the skin when tranexamic acid was opened, in vitro skin permeability was measured for Example 3 and Comparative Examples 2 and 4 in which tranexamic acid was dissolved in the preparation. The state of the preparation remaining on the stratum corneum side of the skin collected after the test was observed with a microscope. The method is as follows.
(Method)
After completion of the in vitro skin permeability test, the skin was carefully removed from the cell, and a cellophane tape was applied to the surface of the stratum corneum and peeled off. The peeled tape was affixed to a slide glass, and the recrystallization property of tranexamic acid in the preparation remaining on the skin surface was observed with a microscope (Olympus AX80 type).
(result)
2, 3 and 4 show micrographs of Example 3, Comparative Example 2 and Comparative Example 4, respectively. Compared with the state of Example 3, it can be seen that in Comparative Examples 2 and 4, large crystals of tranexamic acid were precipitated even though tranexamic acid was dissolved in the preparation.

[Trends in plasma concentration of tranexamic acid in a single-dose transdermal absorption test in vivo]
As an index for evaluating the stratum corneum permeability of tranexamic acid, the skin external preparations of Example 3 and Comparative Example 3 were subjected to an in vivo single-dose transdermal absorption test. The method is as follows.
(Method)
100 mg of the test preparation was uniformly applied to a 4 × 5 cm back part of a 6-week-old male rat (HWY system, Nippon SLC Co., Ltd.), and the test was performed in an unoccluded state. At 2, 4, 6, 8, 24, and 48 hours after the start of the test, 200 μL of blood was collected from the subclavian vein, and 50 μL of plasma was used for quantification. Quantification was performed by LC / MS / MS, and the plasma concentration transition of tranexamic acid was obtained.
(result)
FIG. 5 shows changes in plasma concentration of tranexamic acid obtained for the external preparation for skin of Example 3 and Comparative Example 3 (n = 4, mean ± SD). FIG. 5 shows that the stratum corneum permeability of tranexamic acid from the skin external preparation of Example 3 according to the present invention is high, and the high permeability was maintained for a long time.

  Further formulation examples are shown below.

(Example 14: Water-in-oil type emulsified skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 68.0
Squalane 5.0
Isostearic acid 4.0
POE (10) lauryl ether phosphate 1.5

(Example 15: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (7) oleyl ether (HLB = 10.5) 2.0

(Example 16: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
Polyethylene glycol monostearate (10EO) (HLB = 11.0) 2.0

(Example 17: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
L-tartaric acid 0.5
Citric acid 1.0
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Oleic acid 2.0
POE (5) cetyl ether phosphoric acid 4.0

(Example 18: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 12.0
DL-malic acid 0.5
L-tartaric acid 1.0
Citric acid 0.5
1,3-butylene glycol 3.0
Purified water 70.0
Squalane 5.0
Isostearic acid 4.0
POE (5) cetyl ether phosphoric acid 4.0

(Example 19: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (5) glyceryl monostearate (HLB = 9.5) 2.0

(Example 20: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (15) glyceryl monostearate (HLB = 13.5) 2.0

(Example 21: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (6) sorbitan monooleate (HLB = 10.0) 2.0

(Example 22: Oil-in-water type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 12.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 51.8
Behenyl alcohol 3.0
Stearyl alcohol 1.0
White petrolatum 4.0
Light liquid paraffin 2.0
Methylpolysiloxane 2.0
Isopropyl myristate 4.0
Ethylparaben 0.2
Isostearic acid 4.0
POE (20) sorbitan monooleate (HLB = 15.0) 3.0
Glycerol monostearate 1.5

(Example 23: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 65.5
Liquid paraffin 4.0
Isopropyl myristate 1.0
Isostearic acid 4.0
POE (5) cetyl ether phosphate 2.0
Polyethylene glycol monooleate (6EO) (HLB = 8.5) 2.0

(Example 24: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 65.5
Liquid paraffin 4.0
Isopropyl myristate 1.0
Isostearic acid 4.0
POE (5) cetyl ether phosphate 2.0
Polyethylene glycol monooleate (10EO) (HLB = 11.0) 2.0

(Example 25: Water-in-oil type skin external preparation)
(Mixed component) (mass%)
Tranexamic acid 10.0
DL-malic acid 1.0
L-tartaric acid 0.5
Glycerin 5.0
1,3-butylene glycol 5.0
Purified water 67.5
Squalane 5.0
Isostearic acid 4.0
POE (8) stearyl ether (HLB = 10.0) 2.0

  According to the present invention, an emulsified skin external preparation in which a high concentration of tranexamic acid is stably dissolved can be obtained, and high stratum corneum permeability after open application of tranexamic acid, which is originally low in stratum corneum permeability, can be maintained. In particular, an excellent external preparation for skin for treating skin diseases such as spots (liver spots) is provided.

Claims (6)

  An emulsified skin external preparation containing an aqueous phase containing tranexamic acid or a salt thereof, an oil phase, and a surfactant, which contains a higher fatty acid in the oil phase, and a phosphate anionic interface as a surfactant One or more active agents and / or nonionic surfactants having an HLB of 6.0 to 18.0 are used, and the tranexamic acid or a salt thereof has a pH of 4.0 to 4.0. The emulsified skin external preparation described above, which is dissolved in a water phase adjusted to 6.0 at a blending ratio of 5.0 to 12.0 mass% with respect to the total amount of the external preparation for skin.   The emulsified skin external preparation according to claim 1, wherein the higher fatty acid is one or more selected from stearic acid, isostearic acid, and oleic acid.   The phosphoric acid ester-based anionic surfactant is one or more selected from polyoxyethylene cetyl ether phosphate, polyoxyethylene lauryl ether phosphate, and salts thereof. The emulsification type skin external preparation as described.   Nonionic surfactants having an HLB of 6.0-18.0 are polyoxyethylene hydrogenated castor oil, glycerin polyoxyethylene monostearate, sorbitan polyoxyethylene monostearate, sorbitan polyoxyethylene monooleate, mono One or more selected from polyethylene glycol stearate, polyethylene glycol monooleate, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether, Item 4. The emulsified external skin preparation according to any one of Items 1 to 3.   The emulsified skin external preparation according to any one of claims 1 to 4, which is a preparation for treating spots (liver spots).   After adding tranexamic acid or a salt thereof to the aqueous phase so that the blending ratio is 5.0 to 12.0% by mass with respect to the total amount of the external preparation for skin, the pH of the aqueous phase is adjusted to 4.0 to 6.0. Then, tranexamic acid or a salt thereof is dissolved in the aqueous phase, and then the aqueous phase and the oil phase having a pH of 4 to 6 in which the tranexamic acid or a salt thereof is dissolved are converted to a phosphate anionic surfactant and / or HLB. The manufacturing method of the emulsification type | formula external preparation in any one of Claims 1-5 which consists of emulsifying with the nonionic surfactant of 6.0-18.0.