WO2018062958A1 - Composition comprising benzoic acid amide compound and solubilizing agent - Google Patents

Abstract

The present specification relates to a skin external composition comprising: a solute which is a benzoic acid amide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and at least one first solubilizing agent selected from among diethylene glycol monoethyl ether, methyl gluceth, glycerol ether, polyethylene glycol, and a polyethylene glycol/propylene glycol copolymer, and provides a skin external composition with improved solubility and feeling of use.

Description

A composition comprising a benzoic acid amide compound and a dissolution aid

The present specification relates to a benzoic acid compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solute that is a solvate thereof; And a solubilizing agent; the composition for external application of the skin, wherein the composition relates to a composition, wherein solubility is improved.

Melanin protects skin organs under the dermis by blocking UV rays in the epidermal layer and protects the skin by absorbing free radicals. In addition, melanin is a major factor in determining the color of the skin, and when present in excess, it is also a cause of skin pigmentation such as spots, freckles and spots. Melanin is made from melanocytes present in the basal layer of the skin, and it is known that the production is promoted by stimulation such as ultraviolet rays or inflammation. Therefore, the production of melanin may be reduced by reducing external stimuli and blocking signal transduction, or inhibiting the synthesis or activity of melanin-producing enzyme tyrosinase. Currently, kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butylresosocinol, resveratrol, ceramide, sphingosine-1-phosphate, sphingosylphosphorylcholine, etc. promote the degradation or control glycosylation of tyrosinase. It is known to regulate melanin production. However, they were not highly utilized due to unsatisfactory whitening effects, low stability, and skin irritation. Recently, benzoic acid amides having excellent whitening effects and low side effects have been studied.

 It has been predicted that it will have a skin whitening effect from the white and traditional hands of people making hanji as a raw material for making traditional Korean paper. Scientific research has confirmed that kazinol, which is an excellent whitening ingredient, is contained in the roots of the mulberry tree, and the "doughwood extract" is a functional cosmetic raw material and has been announced in the KFDA. In this study, we analyzed the structure of Kazinols, the whitening effect ingredients in the mulberry tree, through the molecular modeling technique. In particular, in the case of Kazinol F, despite the excellent whitening effect, it is difficult to use as a single component since it is present in a small amount in the mulberry and is easily decomposed by temperature.

Dihydroxybenzyl Adamantnyldimethoxybenzamide is a newly designed structure considering the efficacy, stability, and ease of manufacture through QSAR and 3D-QSAR among 100 derivatives prepared by simulating the structure of Kazinol F, a trace component of the young mulberry. One compound. The compound inhibits melanin synthesis by reducing MITF expression leading to cAMP-PKA-CREB signal and, consequently, by inhibiting the activity of tyrosinase, TRP-1, and TRP-2, the major proteins associated with melanin synthesis regulated by MITF. The mechanism of the new whitening effect was elucidated and confirmed through cell and artificial skin.

However, no studies have been made to improve the solubility of the composition comprising the benzoic acid amide material, and the researchers of the present invention have led to the present invention by studying a composition having improved solubility of the benzoic acid amide material.

In view of the above problems, the inventors of the present invention have led to the present invention by studying a composition comprising a dissolution aid for improving the solubility of the composition comprising a benzoic acid amide compound.

One aspect of the present invention is to provide a composition that improves the solubility of the benzoic acid amide compound while not adversely affecting the usability.

One aspect of the present invention is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And

A composition for external application for skin, including diethylene glycol monoethyl ether, methylgluses, glyceryl ether, polyethylene glycol, and a first dissolution aid comprising at least one of polyethylene glycol and polypropylene glycol copolymers. Provides:

[Formula 1]

In Chemical Formula 1

R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy,

R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₅ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₅ haloalkyl,

n is an integer selected from 1 to 5.

In one aspect of the invention, R ₁ , R ₃ and R ₄ in Formula 1 are hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ halo Independently selected from the group consisting of alkoxy,

R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₃ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₃ haloalkyl,

n may be a compound having an integer selected from 1 to 3, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

In one aspect of the invention, the solute is

5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2-hydroxy-4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide,

5-adamantan-1-yl-2,4-dihydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

5-adamantan-1-yl-2-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- [2- (4-hydroxyphenyl) -ethyl] -2,4-dimethoxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide,

3-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -4-hydroxy-benzoic acid amide,

3-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -4-methoxy-benzoic acid amide,

3-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4-hydroxy-benzoic acid amide,

3-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

3-adamantan-1-yl-4-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

3-adamantan-1-yl-N- [2- (4-hydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

3-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -4-hydroxy-benzoic acid amide,

3-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,5-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (3,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acidamide and

5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, a compound thereof, an isomer thereof, and a pharmaceutically acceptable compound thereof Possible salts, hydrates thereof or solvates thereof.

In one aspect of the invention, the solute may be 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acidamide.

In one aspect of the invention, methylgluses is methyl Gluceth 10 or methyl Gluceth 20, glyceryl ether is Glycereth-26 or glycerol Glycereth-12, polyethylene glycol is Fiji-8 (PEG-8) or Fiji-6 (PEG-6), and polyethylene glycol / polypropylene glycol copolymer Easy / Fiji-17 / 6 copolymer (PEG / PPG-17 / 6 copolymer).

In one aspect of the invention, the solute and the first dissolution aid may be a weight ratio of 1: 0.1 to 9900.

In one aspect of the invention, the solute and the first dissolution aid may be a weight ratio of 1: 50 to 700.

In one aspect of the invention, the first dissolution aid may be included in 0.1 to 99.99% by weight based on the total weight of the composition.

In one aspect of the invention, the solute may be included from 0.01% to 20% by weight relative to the total weight of the composition.

In one aspect of the invention, the composition is a second dissolution aid that is a cyclodextrin; Xanthan gum, Hydroxypropyl Methylcellulose, Sodium Polyacrylate, Sodium magnesium silicate, Hydroxyethylacrylate / Sodium acryloyldimethyl taurate Polymer (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), Polyacrylate-13 / Polyisobutin / Polysorbate-20, Fiji-240 / H-Didia copolymer bis-decyl Tetrases-20 ether (PEG-240 / HDI Copolymer Bis-Decyltetraceth-20 Ether) and magnesium aluminum silicate (Magnesium Aluminum Silicate) is one or more selected from the group consisting of a third dissolution aid; further comprises at least one selected from the group consisting of The external preparation composition may be used.

In one aspect of the invention, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclo At least one of dextrins.

In one aspect of the invention, the composition further comprises a second dissolution aid, the second dissolution aid may be included 0.1 to 98% by weight relative to the total weight of the composition.

In one aspect of the invention, the composition further comprises a second dissolution aid, the weight ratio of the solute, the first dissolution aid and the second dissolution aid may be a weight ratio of 1: 50 to 500: 1 to 20.

In one aspect of the invention, the composition further comprises a third dissolution aid, the third dissolution aid may be included 0.1 to 98% by weight relative to the total weight of the composition.

In one aspect of the invention, the composition further comprises a second dissolution aid and a third dissolution aid, wherein the weight ratio of the solute, the first dissolution aid, the second dissolution aid and the third dissolution aid is 1: 10 to 200: It may be a weight ratio of 1 to 20: 1 to 20.

In another aspect of the present invention, the topical skin composition may be a composition for skin whitening.

In another aspect of the invention, the external composition for skin may be a pharmaceutical or cosmetic composition.

The composition according to an aspect of the present invention is excellent in solubility of the solute benzoic acid amide compound, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof or solvate thereof.

The composition according to an aspect of the present invention does not precipitate the benzoic acid amide compound that is a solute.

When applying the composition according to an aspect of the present invention on the skin is excellent solubility and excellent use.

1 is a photograph of Examples 1, 4, 6, 7 and 8 of the present invention.

Figure 2 is a photograph confirming the dissolution state of Example 8 and Comparative Example 3 of the present invention by an optical microscope and a general microscope.

Figure 3 is a photograph when the residual amount of water is added after dissolving 0.1% by weight of DBAB in 3% by weight of the dissolution aids of Examples 2 to 8 in the present invention.

FIG. 4 is a photograph of the appearance of the composition when the dissolution aid of Example 7 is 30% by weight, 40% by weight and 50% by weight when DBAB is 0.1% by weight and the balance is water in Experimental Example 4 of the present invention.

FIG. 5 is a photograph of the appearance of the composition when the dissolution aid of the Example and the dissolution aid of the comparative example are used when DBAB 0.1 wt% and the balance is water in Experimental Example 4 of the present invention.

Figure 6 is a photograph comparing the solubility in Experimental Example 5 of the present invention when using the second dissolution aid in addition to the first dissolution aid cyclodextrin.

Figure 7 confirms the solubility of the present invention Example 9 and Comparative Example 6 by polarization micrographs.

8 and 9 are photographs comparing the solubility in Experimental Example 6 of the present invention when the first dissolution aid (dissolution aid of Example 7), the second dissolution aid (cyclodextrin), and the third dissolving agent (HPMC) were used together. to be. The weight percentages of the first, second and third solubilizers were shown in sequence.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And

A composition for external application for skin, including diethylene glycol monoethyl ether, methylgluses, glyceryl ether, polyethylene glycol, and a first dissolution aid comprising at least one of polyethylene glycol and polypropylene glycol copolymers. Provides:

[Formula 1]

In Chemical Formula 1

R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy,

R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₅ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₅ haloalkyl,

n is an integer selected from 1 to 5.

In one aspect of the invention, R ₁ , R ₃ and R ₄ in Formula 1 are hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ halo Independently selected from the group consisting of alkoxy,

R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₃ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₃ haloalkyl,

n may be a compound having an integer selected from 1 to 3, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

In one aspect of the invention, the solute is

5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2-hydroxy-4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide,

5-adamantan-1-yl-2,4-dihydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

5-adamantan-1-yl-2-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- [2- (4-hydroxyphenyl) -ethyl] -2,4-dimethoxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide,

3-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -4-hydroxy-benzoic acid amide,

3-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -4-methoxy-benzoic acid amide,

3-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4-hydroxy-benzoic acid amide,

3-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

3-adamantan-1-yl-4-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

3-adamantan-1-yl-N- [2- (4-hydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

3-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -4-hydroxy-benzoic acid amide,

3-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -4-methoxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (2,5-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

5-adamantan-1-yl-N- (3,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acidamide and

5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, a compound thereof, an isomer thereof, and a pharmaceutically acceptable compound thereof Possible salts, hydrates thereof or solvates thereof.

In one aspect of the invention, the solute may be 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acidamide.

In one aspect of the invention, the composition may comprise a water-soluble polar solvent as a solvent. Specifically, the composition may use water as a solvent.

In one aspect of the invention, methylgluses is methyl Gluceth 10 or methyl Gluceth 20, glyceryl ether is Glycereth-26 or glycerol Glycereth-12, polyethylene glycol is Fiji-8 (PEG-8) or Fiji-6 (PEG-6), and polyethylene glycol / polypropylene glycol copolymer Easy / Fiji-17 / 6 copolymer (PEG / PPG-17 / 6 copolymer).

In one aspect of the invention, the solute and the first dissolution aid may be a weight ratio of 1: 0.1 to 9900. In one embodiment, the solute and the first dissolution aid are 1: 0.5 or more, 1: 1 or more, 1: 1.5 or more, 1: 2.0 or more, 1: 5 or more, 1:10 or more, 1:30 or more, 1: 50 or more, 1:80 or more, 1: 100 or more, 1: 200 or more, 1: 500 or more, 1: 800 or more, 1: 1000 or more, 1: 1 500 or more, 1: 2000 or more, 1: 3000 or more or 1: It can be 5000 or more. Also, 1: 9900 or less, 1: 9800 or less, 1: 9500 or less, 1: 9000 or less, 1: 8000 or less, 1: 7500 or less, 1: 7000 or less, 1: 5000 or less, 1: 3000 or less, 1: 1000 Or less, 1: 700 or less, 1: 500 or less, 1: 450 or less, 1: 350 or less, 1: 250 or less, 1: 200 or less, 1: 150 or less, 1: 100 or less, 1:80 or less, 1:50 Or less than 1:40, less than or equal to 1:30, less than or equal to 1:20, less than or equal to 1:10, or less than or equal to 1: 5. Preferably, the solute and the first dissolution aid may be in a weight ratio of 1:50 to 700.

In one aspect of the invention, the first dissolution aid may be included in 0.1 to 99.99% by weight based on the total weight of the composition. In one embodiment, the first dissolution aid is 0.1% by weight, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight or more based on the total weight of the composition , At least 6 wt%, at least 10 wt%, at least 20 wt%, at least 30 wt%, or at least 35 wt%. In addition, the first dissolution aid may be up to 99 wt%, up to 95 wt%, up to 90 wt%, up to 85 wt%, up to 80 wt%, up to 60 wt%, up to 50 wt%, up to 45 wt%, 40 wt% Up to 35 wt%, up to 30 wt%, up to 25 wt%, up to 20 wt%, up to 15 wt%, up to 14 wt%, up to 13 wt%, up to 12 wt%, up to 11 wt% or up to 5 wt% It may be:

In one aspect of the invention, the solute may be included from 0.01% to 20% by weight relative to the total weight of the composition. The solutes of the present invention may be 0.01% to 20% by weight, specifically 0.1% to 10% by weight, more specifically 0.5% to 5% by weight, based on the total weight of the composition. When included in the above range is not only suitable for showing the intended effect of the present invention, it can satisfy both the stability and safety of the composition, it may be appropriate to include in the above range in terms of cost-effectiveness. Specifically, when less than 0.01% by weight, sufficient skin whitening effect may not be obtained, and when it exceeds 20% by weight, it may not be preferable because of low cost-effectiveness.

In one aspect of the invention, the composition is a second dissolution aid that is a cyclodextrin; Xanthan gum, Hydroxypropyl Methylcellulose, Sodium Polyacrylate, Sodium magnesium silicate, Hydroxyethylacrylate / Sodium acryloyldimethyl taurate Polymer (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), Polyacrylate-13 / Polyisobutin / Polysorbate-20, Fiji-240 / H-Didia copolymer bis-decyl Tetrases-20 ether (PEG-240 / HDI Copolymer Bis-Decyltetraceth-20 Ether) and magnesium aluminum silicate (Magnesium Aluminum Silicate) is one or more selected from the group consisting of a third dissolution aid; further comprises at least one selected from the group consisting of The external preparation composition may be used.

In one aspect of the invention, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclo At least one of dextrins.

In one aspect of the invention, the composition further comprises a second dissolution aid, the second dissolution aid may be included 0.1 to 98% by weight relative to the total weight of the composition. In one embodiment, the second dissolution aid is at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt%, based on the total weight of the composition. , At least 6 wt%, at least 10 wt%, at least 20 wt%, at least 30 wt%, or at least 35 wt%. In addition, the second dissolution aid may be 98% by weight, 95% by weight, 90% by weight, 85% by weight, 80% by weight, 60% by weight, 50% by weight, 45% by weight, 40% by weight. Up to 35 wt%, up to 30 wt%, up to 25 wt%, up to 20 wt%, up to 15 wt%, up to 14 wt%, up to 13 wt%, up to 12 wt%, up to 11 wt% or up to 5 wt% It may be:

In one aspect of the invention, the composition further comprises a second dissolution aid, the weight ratio of the solute, the first dissolution aid and the second dissolution aid may be a weight ratio of 1: 50 to 500: 1 to 20. In one embodiment, the weight ratio of the solute, the first dissolution aid and the second dissolution aid may be a weight ratio of 1:80 to 400: 3 to 15. In addition, the weight ratio may be 1:90 to 300: 4 to 10, the weight ratio of 1:95 to 200: 5 to 10, or the weight ratio of 1:98 to 150: 5 to 7.

In one aspect of the invention, the composition further comprises a third dissolution aid, the third dissolution aid may be included 0.1 to 98% by weight relative to the total weight of the composition. In one embodiment, the third dissolution aid is 0.1% by weight, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight or more based on the total weight of the composition , At least 6 wt%, at least 10 wt%, at least 20 wt%, at least 30 wt%, or at least 35 wt%. In addition, the third dissolution aid is 98% by weight, 95% by weight, 90% by weight, 85% by weight, 80% by weight, 60% by weight, 50% by weight, 45% by weight, 40% by weight. Up to 35 wt%, up to 30 wt%, up to 25 wt%, up to 20 wt%, up to 15 wt%, up to 14 wt%, up to 13 wt%, up to 12 wt%, up to 11 wt% or up to 5 wt% It may be: In one embodiment, the weight ratio of the solute, the first dissolution aid and the third dissolution aid may be in a weight ratio of 1: 100 to 600: 1 to 10. In addition, the weight ratio may be 1: 200 to 500: 3 to 10 or the weight ratio of 1: 300 to 450: 5 to 10.

In one aspect of the invention, the composition further comprises a second dissolution aid and a third dissolution aid, wherein the weight ratio of the solute, the first dissolution aid, the second dissolution aid and the third dissolution aid is 1: 10 to 200: It may be a weight ratio of 1 to 20: 1 to 20. In one embodiment, the weight ratio is 1:15 or more: 2 or more: 2 or more, 1:20 or more: 3 or more: 3 or more, 1:50 or more: 4 or more: 4 or more, 1:70 or more: 5 or more: 5 Or 1:90 or greater: 6 or greater: 6 or greater. The weight ratio is 1: 150 or less: 15 or less: 15 or less, 1: 140 or less: 13 or less: 13 or less, 1: 130 or less: 11 or less: 11 or less, 1: 110 or less: 10 or less: 10 or less, 1 : 105 or less: 8 or less: 8 or less: 1:90 or less: 7 or less: 7 or less

In another aspect of the present invention, the topical skin composition may be a composition for skin whitening. The external preparation composition for the skin may exhibit an excellent skin whitening effect, and specifically may improve or prevent blemishes, freckles, moles, and skin pigmentation.

In another aspect of the invention, the external composition for skin may be a pharmaceutical or cosmetic composition.

In one aspect of the invention, the composition may be a cosmetic composition. Cosmetic compositions herein can be prepared in any formulation commonly prepared in the art, including, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto.

In one aspect of the invention the composition may be a pharmaceutical composition. The pharmaceutical composition may exhibit an excellent skin whitening effect, and specifically may improve or treat blemishes, freckles, moles, and skin pigmentation. Pharmaceutical compositions according to one aspect of the invention may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like. Formulations for parenteral administration may be, but are not limited to, solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or sprays. The formulations can be readily prepared according to conventional methods in the art and include surfactants, excipients, hydrating agents, emulsifiers, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, preservatives or Other commercially available auxiliaries can be used as appropriate.

The active ingredient of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, sex, weight, pathology and severity of the subject to be administered, the route of administration or the judgment of the prescriber. Dosage determination based on these factors is within the level of one skilled in the art and its daily dosage may be, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / kg. May be, but is not limited to.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

Experimental Example  1. 5- Adamantane -1-yl-N- (2,4- Dihydroxybenzyl ) -2,4- Dimethoxy - Solubility of Soluble Aids in Benzoic Acid Amides  compare

5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acidamide for each of the following Table 1 (test group) and Table 2 (control) components Solubility in (hereinafter referred to as DBAB) was measured.

DBAB is mixed at 37 ° C. for 24 hours at an excess ratio of 10 or more components belonging to the test group and the control group, followed by centrifugation at 13000 rpm for 5 minutes using a centrifuge (Hanil Science micro 12), and the supernatant is analyzed by HPCL.

Experimental results were as shown in Table 1 and Table 2.

	Ingredients	Solubility, mg / mL
Test group	diethylene glycol monoethyl ether	178.82 ± 0.77
	Methyl Gluceth-10	143.72
	Methyl Gluceth-20	126.32
	Glycereth-26	110.60
	PEG / PPG-17 / 6 COPOLYMER	81.26
	PEG 6	61.71 ± 0.17
	PEG 8	75.13 ± 0.19

	Ingredients	Solubility, mg / mL
	Control	1,2-propandiol	4.4 ± 0.02
		1,3-PROPANEDIOL	5.92
		PEG / PPG / Polybutylene Glycol-8 / 5/3 Glycerin	42.99
		Dipropylene glycol	11.54
		Glycerol	0.9 ± 0.01
		Poloxamer 124	24.59 ± 0.1
		Triglycerides, Medium chain	6.96 ± 0.02
		Triacetin	9.84 ± 0.04
		1,3-BG	9.34 ± 0.37
		Ethanol	9.58 ± 0.64
		Octyldodecanol	2.11 ± 0.01
		Oleyl alcohol	4.14 ± 0.01
		Isopropyl Myristate	0.89 ± 0.02
		Oleic acid	0.01 ± 0.00
		Coco caprylocaprate	0.52 ± 0.00
		Polysorbate 20	30.76 ± 0.48
		Polysorbate 60	30.9 ± 0.03
		Polysorbate 80	11.05 ± 18.65
		Propylene glycol monolaurate	5.44 ± 0.03
		Caprylocaproyl polyoxyl-8 glycerides	40.86 ± 0.16
Oleoyl polyoxyl-6 glycerides		5.29 ± 0.01

Diethylene glycol monoethyl ether, a dissolution aid as shown in Table 1, Methyl Gluceth 10, Methyl Gluceth 20, Glycereth-26, blood Easy / Fiji-17 / 6 copolymer (PEG / PPG-17 / 6 copolymer), Fiji-6 (PEG-6) and Fiji-8 (PEG-8) are 5-adamantane-1-yl It was found that the solubility in -N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide (DBAB) was excellent at 60 mg / mL or more.

Example  1 to 8 and Comparative example  1 to 5

It is a composition containing each of the first dissolution aid of Table 1 of Experimental Example 1 and 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide Examples 1-8 were prepared.

As in Examples 1 to 8 below, the weight ratio of DBAB: first soluble aid was mixed in a ratio of 1:10 and mixed while warming up to 50 degrees Celsius or less. After warming for at least 10 minutes, stored at 25 ° C to 30 ° C for 7 days, and then confirmed precipitation.

Example 1: A weight ratio of DBAB to diethylene glycol monoethyl ether was mixed at 1:10.

Example 2: A weight ratio of DBAB to Methyl Gluceth-10 E10KC (Korea KCI) was mixed at a ratio of 1:10.

Example 3: A weight ratio of DBAB to Methyl Gluceth-10 E10KCH (Korea KCI) was mixed at 1:10.

Example 4: A weight ratio of DBAB to Methyl Gluceth-20 was mixed at 1:10.

Example 5: The weight ratio of DBAB to Glycereth-12 was mixed at 1:10.

Example 6: The weight ratio of DBAB to Glycereth-26 was mixed at 1:10.

Example 7: The weight ratio of DBAB to PEG / PPG-17 / 6 COPOLYMER was mixed at 1:10.

Example 8: The weight ratio of DBAB to PEG 8 was mixed at 1:10.

Experimental results were as shown in FIG. The components of the above example were dissolved transparently and remained transparent even after 7 days, but in Example 8 of PEG-8, which had low solubility among the example components, it was confirmed that some precipitated after 7 days.

Dipropylene Glycol (Comparative Example 1), PEG.PPG.POLYBUTYLENE GLYCOL-8.5.3 GLYCERIN (Comparative Example 2), 1,3-PROPANEDIOL (Comparative Example 3), PEG 32 (Comparative Example 4), PEG 75 (Comparative Example 5 ) Was mixed with the DBAB in the same manner as used in the above example, so that it did not transparently dissolve or precipitated more than PEG 8, indicating poor solubility.

Experimental Example  2. Example  8 and Comparative example  Check the dissolution of 3 (optical method)

The difference was confirmed by observing the polarization microscope of Example 8 and Comparative Example 3. Experimental results were as shown in FIG. It can be seen that the presence or absence of precipitation in the polarizing microscope.

Experimental Example  3. First  Identify the effects of reducing the proportion of dissolution aids

In Example 2, the area | region which melt | dissolved transparently was confirmed, reducing the ratio of each dissolution aid. It was confirmed that the weight ratio of the dissolution aid: DBAB of Example 4 was transparently dissolved until 7.9: 1, and Example 7 was transparently dissolved up to 7.5: 1 and Example 5, 6 was 7: 1. In particular, when the solubility of Examples 4 and 5 was compared, it was expected that Example 5 would be better, so that Glycereth-3, Glycereth-7, Glycereth-8 and the like having lower molecular weight than Example 5 would be better. .

Experimental Example  4. When water is added First  Check the effectiveness of the dissolution aid

After dissolving 0.1 wt% of DBAB in 3 wt% of the dissolution aid of Examples 2 to 8, it was confirmed that the DBAB precipitated as shown in FIG. 3.

In particular, when the solubility was measured, Example 8, which had the poorest solubility among the examples, showed the most precipitate in FIG. 3, and Example 2 (Methyl Gluceth-10) was more effective than Example 4 (Methyl Gluceth-20). Solubility was better because there was less precipitation at the top. Therefore, Methyl Gluceth-5, which has a lower molecular weight than Methyl Gluceth-10, is expected to have better solubility.

When using only Example 7, it was confirmed that when dissolved in the 50% by weight DBAB 0.1% by weight, the remaining amount of water was transparent (Fig. 4), 30% by weight, 40% by weight was confirmed to be opaque dissolved. However, when the water is fixed at 50% and the remainder is filled with Comparative Example 3, it was confirmed that the transparent solution was dissolved even at a lower weight% (FIG. 5). In FIG. 5, when 35 wt% of Example 7 was used and 15 wt% of Comparative Example 3 was used, and the remainder was prepared with water, it was confirmed that the dissolution aid was opaque.

Experimental Example  5. First  Hydroxyl as a dissolution aid propyl  beta cyclodextrin  Check the effect when adding (hereinafter, CD)

In Experimental Example 4, Example 7 was able to dissolve 0.1 wt% of DBAB transparently using at least 35 wt% (when using Comparative Example 3) using 50 wt%. However, when using 0.5% by weight of the CD was confirmed that the transparent dissolving in 20% by weight of the dissolution aid of Example 7. Experimental results were as shown in FIG.

When water was fixed at 50% by weight and 0.5% by weight of CD was used, it precipitated when using only 10% of Example 7 (first left), but was transparently dissolved when using 20% by weight. When 1.0 wt% of CD was used, only 10 wt% of the dissolution aid Example 7 was found to be transparently dissolved (FIG. 6).

Experimental Example  6. First  Hydroxyl as a dissolution aid propyl  Effect of methyl cellulose (HPMC) and CD in combination

When adding 0.5% by weight of HPMC to 0.1% by weight of DBAB, the dissolution aid of Example 7 was found to be transparently dissolved at least 45% by weight.

When the DBAB used in 0.1% by weight of 0.6% by weight CD 30% by weight of the component of Example 7 and the rest was filled with water it was confirmed that the transparent dissolution.

When using HPMC 0.5% by weight, CD 0.6% by weight in DBAB 0.1% by weight, 5% by weight of the components used in Example 7 and the rest was filled with water it was confirmed that the transparent dissolved.

When using 30% by weight of Example 7 components in 0.1% by weight of DBAB, it was confirmed that only 2% by weight of HPMC should be dissolved transparently.

DBAB 0.1% by weight CD 2% by weight 5% by weight of the component of Example 4 When 5% by weight of the component of Example 6 is used it was confirmed that the transparent dissolution in 0.2% by weight of xanthan gum.

Therefore, their content was confirmed to have a complementary effect that can lower the other components when increasing the content of the component to increase the dissolving power.

When 0.3% by weight of CDAB and 1% by weight of HPMC were used in 0.1% by weight of DBAB, 30% by weight of the dissolution aid of Example 7 was confirmed to be transparently dissolved.

When 0.3% by weight of CD and 0.5% by weight of HPMC were used in 0.1% by weight of DBAB, it was confirmed that the dissolution aids of Example 7 were opaquely dissolved using 15, 16, 20, and 25% by weight.

In addition, when 0.3% by weight of CDAB and 1% by weight of HPMC were used in 0.1% by weight of DBAB, it was confirmed that the dissolution aid of Example 7 was opaquely dissolved even when 5 and 20% by weight were used.

In addition, when 0.3% by weight of CDAB and 2% by weight of HPMC were used in 0.1% by weight of DBAB, it was confirmed that the dissolution aid of Example 7 was opaquely dissolved even by using 20% by weight.

When using 0.3% by weight of CD and 0.4% by weight of HPMC in 0.1% by weight of DBAB, 20% by weight of the dissolution aid of Example 7 was confirmed to be transparently dissolved.

When using 0.7% by weight of CD and 0.1% by weight of HPMC in DBAB 0.1% by weight, 5% by weight of the dissolution aid of Example 7 was confirmed to be transparently dissolved.

When 0.7% by weight of CD and 1% by weight of HPMC were used in 0.1% by weight of DBAB, it was confirmed that the dissolution aids of Example 7 were opaquely dissolved even when 1, 3, 4, and 5% by weight were used.

When using 0.9% by weight of CD in 0.1% by weight of DBAB, only 5 and 10% by weight of the components of Example 7 were used and it was confirmed to be transparently dissolved.

When using 1% by weight of CDAB, 0.1% by weight of HPMC in 0.1% by weight of DBAB, 5% by weight of the dissolution aid of Example 7 was confirmed to be transparently dissolved.

Experimental Example  7. Third Melting Aid  medium HPMC  Confirm other dissolution aids

When 0.5% by weight of CD was dissolved in 15% by weight of the dissolution aid, and 1% by weight of Cellulose gum was dissolved in transparent water. When hydroxyethylcellulose was substituted by 1% by weight instead of cellulose gum, it could be confirmed that it was opaque.

CD 0.6% by weight, Example 8 Dissolving aid 5% by weight of the dissolving aid Examples and Comparative Examples were filled with 0.5% by weight and the rest was filled with water to determine whether to dissolve transparently or opaque to determine the dissolution aid.

Sodium hyaluronate, Cellulose Gum, XANTHAN GUM, Sodium Polyacrylate, SODIUM MAGNESIUM SILICATE, Hydroxyethyl acrylate.sodium acryloyldimethyl taurate copolymer Bis-Decyltetraceth-20 Ether, Polyvinyl Alcohol (2 product reviews PVA 205, PVA 217), Magnesium Aluminum Silicate, HPMC (brand name methocel, pharmacoat 630, pharmacoat 615, pharmacoat 645, metolose SM-4)

Sodium hyaluronate, cellulose gum, Polyvinyl Alcohol, bentonite, POLOXAMER 407, Hydroxypropyl Starch Phosphate, and SODIUM MAGNESIUM SILICATE were precipitated and the rest was not precipitated.

Thus, examples of XANTHAN GUM, Sodium Polyacrylate, SODIUM MAGNESIUM SILICATE, hydroxyethyl acrylate. Aluminum Silicate, HPMC. However, when mixed with other dissolution aids such as PEG-8, CD, etc., it was confirmed that even if the dissolution aid was low solubility was precipitated under the experimental conditions can have the effect.

Experimental Example  8. Check the stabilization effect in the formulation

In Table 3, vegetable squalane, caprylic / capric triglyceride, arachidyl alcohol / behenyl alcohol / arachidyl glucoside, and liquid paraffin were weighed in one beaker at a time and warmed to 70 degrees Celsius, and the remaining ingredients were added to other beakers. It was prepared by heating to 70 degrees Celsius and mixing and cooling for 5 minutes at 3000 rpm using a homomixer (Japan Primix Co., homomixer Mark 2 model).

Preparation of Example 9 and Comparative Example 6 prepared in the same manner as in Experimental Example 2 DBAB precipitation was confirmed by a polarizing microscope. (Figure 7)

	Example 9	Comparative Example 6
DBAB	0.1 wt%	0.1 wt%
Methyl Gluceth-20	10.0 wt%	-
HPMC	1.0% of U%	-
CD	0.6 wt%	-
Vegetable squalane	2.6 wt%	2.6 wt%
Caprylic / Capric Triglycerides	3.0 wt%	3.0 wt%
Arachidyl Alcohol and Behenyl Alcohol and Arachidyl Glucoside	1.5 wt%	1.5 wt%
CETEARYL ALCOHOL	0.5 wt%	0.5 wt%
glycerin	3.0 wt%	3.0 wt%
Butylene glycol	3.0 wt%	3.0 wt%
Liquid paraffin	7.0 wt%	7.0 wt%
Beta Glucan	7.0 wt%	7.0 wt%
Carbomer	0.1 wt%	0.1 wt%
Triethanolamine	0.1 wt%	0.1 wt%
Purified water	Remaining amount	Remaining amount

Experimental Example  9. Example  9 and Comparative example  6 of Feeling  Measure

The usability of the contents produced in Experimental Example 8 was measured. Moisturizing, stickiness, and softness after use were measured on a nine-point scale by subjective scoring of the evaluator, and the feeling of use when the content of methyl glutes-20 was increased in Example 9 was also confirmed. At this time, the content of more than 20% by weight was confirmed to increase the negative feeling factor such as stickiness, stuffiness.

Hereinafter, an example of the formulation of the composition according to the present invention will be described, but this is not intended to limit the present invention, but only to explain in detail.

Formulation Example 1 Flexible Lotion

To a flexible lotion was prepared in a conventional manner according to the composition shown in Table 4.

ingredient	Content (weight%)
DBAB	0.1 wt%
Methyl Gluceth-20	10.0 wt%
HPMC	1.0 wt%
CD	0.6 wt%
PEG-30 hydrogenated caster oil	1.2 wt%
ethanol	5.0 wt%
Butylene glycol	2.0 wt%
Propylene glycol	2.0 wt%
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 2 Nutritional Lotion (Milk Lotion)

To the nutritional lotion was prepared in a conventional manner according to the composition shown in Table 5.

ingredient	Content (weight%)
DBAB	0.1 wt%
Methyl Gluceth-20	10.0 wt%
HPMC	1.0 wt%
CD	0.6 wt%
PEG-30 hydrogenated caster oil	2.0 wt%
glycerin	3.0 wt%
Butylene glycol	3.0 wt%
Propylene glycol	3.0 wt%
Carboxy Vinyl Polymer	0.1 wt%
Beeswax	4.0 wt%
Caprylic / Capric Triglycerides	5.0 wt%
Squalane	5.0 wt%
Liquid paraffin	0.5 wt%
Cetearyl Alcohol	1.0 wt%
Triethanolamine	0.2 wt%
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

 Formulation Example 3 Nutrition Cream

To the nutrition cream was prepared in a conventional manner according to the composition shown in Table 6.

ingredient	Content (% by weight)
DBAB	0.1 wt%
Methyl Gluceth-20	10.0 wt%
HPMC	1.0 wt%
CD	0.6 wt%
PEG-30 hydrogenated caster oil	3.0 wt%
glycerin	3.0 wt%
Butylene glycol	3.0 wt%
Liquid paraffin	7.0 wt%
Beta Glucan	7.0 wt%
Carbomer	0.1 wt%
Caprylic / Capric Triglycerides	3.0 wt%
Squalane	5.0 wt%
Cetearyl Glucoside	1.5 wt%
Sorbitan stearate	0.4 wt%
Triethanolamine	0.1 wt%
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

 Formulation Example 4 Massage Cream

To prepare a massage cream in a conventional manner according to the composition described in Table 7.

ingredient	Content (% by weight)
DBAB	0.1 wt%
Methyl Gluceth-20	10.0 wt%
HPMC	1.0 wt%
CD	0.6 wt%
PEG-30 hydrogenated caster oil	4.0 wt%
Vitamin E Acetate	5.0 wt%
glycerin	8.0 wt%
Butylene glycol	4.0 wt%
Liquid paraffin	45.0 wt%
Beta Glucan	7.0 wt%
Carbomer	0.1 wt%
Caprylic / Capric Triglycerides	3.0 wt%
Beeswax	4.0 wt%
Cetearyl Glucoside	1.5 wt%
Sesqui oleic acid sorbitan	0.9 wt%
Vaseline	3.0 wt%
paraffin	1.5 wt%
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

 [Formulation Example 5] Pack

To prepare a pack in a conventional manner according to the composition described in Table 8.

ingredient	Content (% by weight)
DBAB	0.1 wt%
Methyl Gluceth-20	10.0 wt%
HPMC	1.0 wt%
CD	0.6 wt%
PEG-30 hydrogenated caster oil	4.0 wt%
Vitamin E Acetate	8.0 wt%
glycerin	4.0 wt%
Polyvinyl alcohol	15.0 wt%
Hyaluronic acid extract	5.0 wt%
Beta Glucan	7.0 wt%
Allantoin	0.1 wt%
Nonyl Phenyl Ether	0.4 wt%
Polysorbate 60	1.2 wt%
ethanol	6.0 wt%
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 6 Ointment

Ointments are prepared in a conventional manner according to the compositions set forth in Table 9 below.

ingredient	Content (% by weight)
DBAB	0.1 wt%
Methyl Gluceth-20	10.0 wt%
HPMC	1.0 wt%
CD	0.6 wt%
PEG-30 hydrogenated caster oil	3.0 wt%
Vitamin E Acetate	4.0 wt%
Butylene glycol	4.0 wt%
Liquid paraffin	15.0 wt%
Beta Glucan	7.0 wt%
Carbomer	0.1 wt%
Caprylic / Capric Triglycerides	3.0 wt%
Squalane	1.0 wt%
Cetearyl Glucoside	1.5 wt%
Sorbitan stearate	0.4 wt%
Cetearyl Alcohol	1.0 wt%
Beeswax	4.0 wt%
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Claims (17)

1. A solute that is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; And

   A composition for external application for skin, including diethylene glycol monoethyl ether, methylgluses, glyceryl ether, polyethylene glycol, and a first dissolution aid comprising at least one of polyethylene glycol and polypropylene glycol copolymers. :

   [Formula 1]

   

   In Chemical Formula 1

   R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy,

   R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₅ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₅ haloalkyl,

   n is an integer selected from 1 to 5.
2. The method of claim 1,

   R ₁ , R ₃ and R ₄ of Formula 1 are each independently hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ haloalkoxy Selected,

   R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₃ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₃ haloalkyl,

   n is a compound having an integer selected from 1 to 3, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
3. The method of claim 2,

   Said solute

   5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2,4-dihydroxy-benzoic acid amide,

   5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2-hydroxy-4-methoxy-benzoic acid amide,

   5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

   5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide,

   5-adamantan-1-yl-2,4-dihydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

   5-adamantan-1-yl-2-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

   5-adamantan-1-yl-N- [2- (4-hydroxyphenyl) -ethyl] -2,4-dimethoxy-benzoic acid amide,

   5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

   5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide,

   5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide,

   3-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -4-hydroxy-benzoic acid amide,

   3-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -4-methoxy-benzoic acid amide,

   3-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4-hydroxy-benzoic acid amide,

   3-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

   3-adamantan-1-yl-4-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

   3-adamantan-1-yl-N- [2- (4-hydroxyphenyl) -ethyl] -4-methoxy-benzoic acid amide,

   3-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -4-hydroxy-benzoic acid amide,

   3-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -4-methoxy-benzoic acid amide,

   5-adamantan-1-yl-N- (2,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acid amide,

   5-adamantan-1-yl-N- (2,5-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,

   5-adamantan-1-yl-N- (3,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acidamide and

   5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, a compound thereof, an isomer thereof, and a pharmaceutically acceptable compound thereof The external preparation composition for skin, which is a possible salt, a hydrate thereof, or a solvate thereof.
4. The method of claim 3, wherein

   The solute is 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide.
5. The method of claim 1,

   Methylgluses is Methyl Gluceth 10 or Methyl Gluceth 20,

   Glyceryl ether is Glycereth-26 or Glycereth-12,

   Polyethylene glycol is Fiji-8 (PEG-8) or Fiji-6 (PEG-6),

   The polyethylene glycol / polypropylene glycol copolymer is a skin external preparation composition which is a sebum / fiji-17 / 6 copolymer (PEG / PPG-17 / 6 copolymer).
6. The method of claim 1,

   The solute and the first dissolution aid are in a weight ratio of 1: 0.1 to 9900, the external composition for skin.
7. The method of claim 1,

   The first dissolution aid is 0.1 to 99.99% by weight relative to the total weight of the composition, the external composition for skin.
8. The method of claim 1,

   The solute is contained in 0.01 to 20% by weight based on the total weight of the composition, the external composition for skin.
9. The method of claim 1,

   The composition is

   A second dissolution aid that is cyclodextrin; And

   Xanthan gum, Hydroxypropyl Methylcellulose, Sodium Polyacrylate, Sodium magnesium silicate, Hydroxyethylacrylate / Sodium acryloyldimethyl taurate copolymer (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), Polyacrylate-13 / Polyisobutin / Polysorbate-20, Fiji-240 / H-Didia copolymer bis-decyltetra It further comprises at least one selected from the group consisting of: at least one third melting aid selected from the group consisting of cess-20 ether (PEG-240 / HDI Copolymer Bis-Decyltetraceth-20 Ether) and magnesium aluminum silicate (Magnesium Aluminum Silicate) Skin external preparation composition.
10. The method of claim 9,

    The cyclodextrin is any one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin. External preparation composition.
11. The method of claim 9,

    The composition further comprises a second dissolution aid,

    The second dissolution aid is 0.1 to 98% by weight relative to the total weight of the composition, the external composition for skin.
12. The method of claim 9,

    The composition further comprises a second dissolution aid,

    The weight ratio of the solute, the first dissolution aid and the second dissolution aid is 1: 50 to 500: 1 to 20, the skin external composition.
13. The method of claim 9,

    The composition further comprises a third dissolution aid,

    The third dissolution aid is 0.1 to 98% by weight relative to the total weight of the composition, the external composition for skin.
14. The method of claim 9,

    The composition further comprises a third dissolution aid,

    The weight ratio of the solute, the first dissolution aid and the third dissolution aid is a weight ratio of 1: 100 to 600: 1 to 10, the external composition for skin
15. The method of claim 9,

    The composition further comprises a second dissolution aid and a third dissolution aid,

    The weight ratio of the solute, the first dissolution aid, the second dissolution aid and the third dissolution aid is 1: 10 to 200: 1 to 20: 1 to 20, the skin external composition.
16. The method according to any one of claims 1 to 15,

    The external preparation composition for skin whitening composition.
17. The method according to any one of claims 1 to 15,

    The skin external preparation composition is a pharmaceutical or cosmetic composition.

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