WO2020091311A1 - Composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

The present disclosure relates to a skin composition for external use 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; a first solubilizer which is a glycyrrhizic acid derivative; and a second solubilizer which is a glycerylether or a polyethyleneglycol/polypropyleneglycol copolymer, and provides a skin composition for external use having improved solubility.

Description

Composition comprising benzoic acid amide compound and dissolution aid

This application claims priority to Korean Patent Application No. 10-2018-0132134 filed on October 31, 2018 and all profits arising therefrom, the contents of which are incorporated herein by reference in their entirety.

The present specification is a benzoic acid amide compound, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof; And a composition for external application for skin comprising a solubilizing agent, the composition relates to a composition characterized in that the solubility is improved.

Melanin protects the skin organs under the dermis by blocking ultraviolet rays in the epidermal layer and protects the skin by absorbing bio-free radicals. In addition, melanin is a major factor in determining the color of skin, and if it is 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 base layer of the skin, and is known to promote production by irritation such as ultraviolet rays or inflammation. Therefore, it is possible to reduce external stimulation, block signal transmission, or reduce the production of melanin by inhibiting or inhibiting the synthesis or synthesis of tyrosinase, a melanin-producing enzyme. Currently, kojic acid, hydroquinone, arbutin, azelaic acid, aloesine, 4-butylresorcinol, resveratrol, ceramide, sphingosine-1-phosphoric acid, sphingosylphosphorylcholine, etc. can promote the degradation of tyrosinase or regulate glycosylation. It is known that it can regulate melanin production. However, they were not highly utilized due to unsatisfactory whitening effect, low stability, and skin irritation. Recently, a benzoic acid amide substance having excellent whitening effect and low side effects has been studied.

The mulberry tree has traditionally been predicted to have a skin whitening effect from the fact that the hand of a person making Korean paper has been white and used as a raw material for producing Korean paper. Therefore, scientific research has confirmed that kazinol, an ingredient with excellent whitening effect, is found in the roots of mulberry tree, and "dakberry extract" is a functional cosmetic ingredient that has been announced by the Ministry of Food and Drug Safety. Thus, the structure of Kazinols, which are the whitening effect components in mulberry tree, was analyzed through molecular modeling techniques to analyze the functional groups showing the whitening effect of Kazinols. In particular, in the case of Kazinol F, despite the excellent whitening effect, it is present in a trace amount in mulberry tree and has a structure that is easily decomposed by temperature, making it difficult to use as a single component.

Dihydroxybenzyl Adamantnyldimethoxybenzamide is a new structure design that considers the structure, the active relationship (QSAR) and 3D-QSAR, among the 100 types of derivatives that mimic the structure of Kazinol F, a trace component of mulberry tree, and considers efficacy, stability, and ease of manufacture. It is one compound. This compound reduces the expression of MITF linked to the cAMP-PKA-CREB signal and consequently inhibits the activity of the major proteins tyrosinase, TRP-1, and TRP-2 in relation to melanin synthesis regulated by MITF, thereby inhibiting melanin synthesis. The mechanism of the new whitening effect was identified and confirmed through cells and artificial skin.

However, there has been no research to improve the solubility of the composition containing the benzoic acid amide material, and the researchers of the present invention have come to the present invention by studying the composition with improved solubility of the benzoic acid amide material.

[Advanced technical literature]

[Patent Document]

(Patent Document 1) Korean Registered Patent No. 10-1604053

(Patent Document 2) U.S. Patent No. 8697151

(Patent Document 3) U.S. Patent No. 9216145

(Patent Document 4) Japanese Patent Publication No. 2011-528708

(Patent Document 5) Japanese Patent Publication No. 2015-0120716

(Patent Document 6) Korean Registered Patent No. 10-1502533

[Non-patent literature]

(Non-Patent Document 1) Adamantyl N-benzylbenzamide: New series of depigmentation agents with tyrosinase inhibitory activity, Bioorg. Med. Chem. Lett., 2012, 22 (5), 2110-2113

(Non-Patent Document 2) Whitening effect of Adamantyl Benzamide derivative. Journal of the Korean Cosmetic Society. 2013 Vol. 39, No. 2, pp. 127-132.

(Non-Patent Document 3) 3D-QSAR study of adamantyl N-benzylbenzamides as melanogenesis inhibitors. Bioorg. Med. Chem. Lett., 2014, 24, 667-673.

(Non-patent document 4) A novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP-PKA-CREB-activated microphthalmia-associated transcription factor and tyrosinase expression. Experimental Dermatology, 2013, 22, 748-774.

In view of the above problems, the inventors of the present invention came to the present invention by studying a composition containing a solubilizing agent for improving the solubility of a composition containing a benzoic acid amide compound.

One aspect of the present invention is to provide a stable composition while improving the solubility of the benzoic acid amide compound.

One aspect of the present invention, a compound of Formula 1, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof;

Glycyrrhizic Acid derivative first solubilizer; And

Provided is a composition for external application for skin comprising a second solubilizing agent which is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer:

[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.

The composition according to an aspect of the present invention is excellent in solubility of the solute benzoic acid amide compound, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof. The composition according to an aspect of the present invention does not precipitate a solute benzoic acid amide compound, has excellent solubility, and has excellent stability.

1 is a photograph of Example 1 of the present invention.

2 is a photograph of Comparative Example 1 of the present invention.

3 is a photograph of Example 2 of the present invention.

4 is a photograph of Examples 3 to 5 of the present invention (DG in FIG. 4 corresponds to Example 3, GA corresponds to Example 4, and MAG corresponds to Example 5).

Hereinafter, the present invention will be described in detail.

One aspect of the present invention, a compound of Formula 1, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof;

Glycyrrhizic Acid derivative first solubilizer; And

Provided is a composition for external application for skin comprising a second solubilizing agent which is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer:

[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 of Formula 1 are each 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 an integer selected from 1 to 3, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates 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 acid amide and

Compound selected from the group consisting of 5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, isomers thereof, and pharmaceutically acceptable 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 solute may be included in an amount of 0.01 to 20% by weight relative to the total weight of the composition. In one aspect of the present invention, the solute may be at least 0.01% by weight, at least 0.02% by weight, at least 0.1% by weight, at least 0.5% by weight, at least 1% by weight, at least 5% by weight, or at least 10% by weight based on the total weight of the composition, , 20 wt% or less, 15 wt% or less, 10 wt% or less, or 5 wt% or less. Specifically, it may be 0.02 to 10% by weight, and more specifically, 0.02 to 5% by weight. When included in the above range, it is not only suitable to exhibit the intended effect of the present invention, but also satisfies both the stability and safety of the composition, and it may be appropriate to include the above range in terms of cost effectiveness. Specifically, if it is less than 0.01% by weight, a sufficient skin whitening effect cannot be obtained, and if it exceeds 20% by weight, the cost-effectiveness may be low, which may be undesirable.

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

In one aspect of the present invention, the first solubilizing agent may be a glycyrrhizic acid derivative, and the glycyrrhizic acid derivative may be dipotassium glycyrrhizate, glycyrrhizic acid, or glycyrrhize Hydrolyzed Glycyrrhizinate, Methyl Glycyrrhizate, Tripotassium Glycyrrhizate, Trisodium Glycyrrhizate, Glycirizine Acid Methyl Ester ) And monoammonium Glycyrrhizate, and specifically, Dipotassium Glycyrrhizate, Glycyrrhizic Acid and Monoammonium Glycyrrhizate. Glycyrrhizate) may be one or more selected from the group consisting of.

In one aspect of the invention, the solute and the first solubilizing agent may be a weight ratio of 1: 0.01 to 9990. In one embodiment, the solute and the first solubilizing agent are 1: 0.01 or more, 1: 0.05 or more, 1: 0.1 or more, 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: 1500 or more, 1: 2000 or more, 1: 3000 or more, or 1: 5000 or more. In addition, 1: 9990 or less, 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, 1:40 or less, 1:30 or less, 1:20 or less, 1:10 or less, or 1: 5 or less. Specifically, the solute and the first solubilizing agent may have a weight ratio of 1: 1 to 700.

In one aspect of the invention, the first dissolution aid may be included in an amount of 0.01 to 99% by weight relative to the total weight of the composition. In one embodiment, the first dissolution aid is 0.01 wt% or more, 0.05 wt% or more, 0.1 wt% or more, 0.2 wt% or more, 0.3 wt% or more, 0.4 wt% or more, 0.5 wt% or more based on the total weight of the composition , 0.6% or more, 0.7% or more, 0.8% or more, 0.9% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more , 10% or more, 20% or more, 30% or more, or 35% or more. In addition, the first dissolution aid is 99% by weight or less, 95% by weight or less, 90% by weight or less, 85% by weight or less, 80% or less, 60% or less, 50% or less, 45% or less, 40% or less Or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less Or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less Or less, 0.8% by weight or less, 0.7% by weight or less, or 0.6% by weight or less.

In one aspect of the present invention, the composition for external application for skin may include a second dissolution aid that is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer. Specifically, the first solubilizing agent, glycyrrhizic acid (Glycyrrhizic Acid) derivative may be contained in an amount of 0.01% by weight or more and 98% by weight or less, more specifically 0.01% by weight or more, 0.02% by weight or more, 0.04 Above wt%, above 0.06%, above 0.08%, above 0.1%, above 0.5%, above 1%, above 1.5%, above 2%, above 3%, above 4%, 5 It may be greater than or equal to 6% by weight, greater than or equal to 6%, greater than or equal to 20%, greater than or equal to 30%, or greater than or equal to 35% by weight, less than or equal to 98%, less than or equal to 95%, less than or equal to 90%, and less than or equal to 85% by weight , 80% or less, 60% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less , 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7 It may be less than or equal to 6% by weight, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%.

In one aspect of the invention, the second solubilizing agent is glycereth-26 (Glycereth-26), glycereth-12 (Glycereth-12) or sebum / fiji-17 / 6 copolymer (PEG / PPG-17) / 6 copolymer).

In one aspect of the present invention, the second dissolution aid may be included in an amount of 0.01 to 98% by weight based on the total weight of the composition. In one embodiment, the second dissolution aid is 0.01 wt% or more, 0.02 wt% or more, 0.04 wt% or more, 0.06 wt% or more, 0.08 wt% or more, 0.1 wt% or more, 0.2 wt% or more, based on the total weight of the composition , 0.3% or more, 0.4% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more , 8% or more, 9% or more, 10% or more, 20% or more, 30% or more, or 35% or more. In addition, the second dissolution aid is 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% Or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less Or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less , 0.8% by weight or less, 0.7% by weight or less, or 0.6% by weight or less.

In one aspect of the invention, the weight ratio of the solute, the first solubilizing agent and the second solubilizing agent may be a weight ratio of 1: 1 to 500: 1 to 20. In one embodiment, the weight ratio of the solute, the first solubilizer and the second solubilizer may be 1: 1 to 400: 1 to 15. In addition, it may be a weight ratio of 1: 1 to 300: 1 to 10, a weight ratio of 1: 1 to 200: 1 to 10, or a weight ratio of 1: 1 to 150: 1 to 7.

In one aspect of the present invention, the composition for external application for skin is cyclodextrin, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxy With ethyl acrylate / sodium acryloyldimethyl taurate copolymer and polyacrylate-13 / polyisobutene / polysorbate-20 It may further include a third or more dissolution aid selected from the group consisting of. Specifically, the first solubilizing agent, glycyrrhizic acid (Glycyrrhizic Acid) derivative may be contained in an amount of 0.01% by weight or more and 98% by weight or less based on the total weight of the composition, more specifically 0.01% by weight or more, 0.02% by weight or more, 0.04% or more, 0.06% or more, 0.08% or more, 0.1% or more, 0.5% or more, 1% or more, 1.5% or more, 2% or more, 3% or more, 4% or more, 5 wt% or more, 6 wt% or more, 10 wt% or more, 20 wt% or more, 30 wt% or more, or 35 wt% or more, 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% Or less, 80% or less, 60% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less Or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7 It may be less than or equal to 6% by weight, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%.

In one aspect of the present invention, the third dissolution aid is cyclodextrin, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose Hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer, polyacrylate-13 / polyisobutene / polysorbate-20 (Polyacrylate-13 / Polyisobutene / Polysorbate-20) , Sodium Magnesium Silicate, Bentonite, Poloxamer 407, Hydroxypropyl Starch Phosphate, PG-240 / H Copolymer Bis-decyltetrases-20 ether (PEG-240 / HDI Copolymer Bis-Decyltetraceth-20 Ether), Polyvinyl Alcohol, Magnesium Aluminum Silicate Silicate), polyvinylpirrolidone, acrylate / C10-30 alkyl acrylate crosspolymer (acrylic acid and alkyl methacrylate copolymer), adipic acid, neopentyl glycol crosspolymer, dimethicone, VP, VA Copolymer, amodimethicone, ammonium acryloyl dimethyltaurate / VP copolymer, carbomer, carrageenan, seratonia silicua gum, cyanopsis tetragonolova (Guar) gum, agar, potassium chloride and glucose, poly Quaternium-7, polyquaternium-10, polyquaternium-67, cetyl hydroxyethylcellulose, dihydro xanthan gum, dextrin myristate, gellan gum, glycerin, glyceryl acrylate, acrylic acid copolymer, hydrolyzed wheat Protein, PVP crosspolymer, isononanoyl diglycerin, dilinoleic acid copolymer, lauryl dimethicone, polyglycerin-3 copolymer, polymethylsilsquioxane, phenoxyethanol, chlorine Lephenesin, chlorphenesin, capryl glycol, mannan, olea europaea (olive) oil, butadiene, styrene copolymer, PEG-240 / HDI copolymer bis-decyltetrases-20 ether, polyacrylamide, C13- 14 isoparaffin, laureth-7, polyacrylate crosspolymer-8, polyacrylate-2 crosspolymer, polyurethane-10, PEG-12 dimethicone, polyurethane-14 AMP-acrylate copolymer, potassium alginate, PVP, sodium carboxymethyl starch, hydrogenated polydecene, PPG-5-laures-5, stearalkonium, hectorite, styrene, acrylate, ammonium methacrylate copolymer, tamarindose indica seed polysaccharide, VP, meta Krillamide, vinyl imidazole copolymer, palmet-25 acrylate copolymer, VA copolymer, butylene glycol, 1,2-hexanediol, caprylyl glycol, tropolone, mannan or Zea May ) It can be a starch, and cellulose gum; Xanthan gum; Sodium polyacrylate; Hydroxypropyl methyl cellulose; Hydroxyethyl acrylate / sodium acryloyl dimethyl taurate copolymer; Polyacrylate-13 / polyisobutyne / polysorbate-20; Sodium magnesium silicate; Bentonite; Poloxamer 407; Hydroxypropyl starch phosphate; PEG-240 / HD copolymer bis-decyltetrases-20 ether; Polyvinyl alcohol; Magnesium aluminum silicate; Polyvinylpyrrolidone; Acrylate / C10-30 alkyl acrylate crosspolymer (acrylic acid.alkyl methacrylate copolymer); Adipic acid / neopentyl glycol crosspolymer / dimethicone / VP / VA copolymer / amodimethicone; Ammonium acryloyldimethyltaurate-VP copolymer; Carbomer; Carrageenan / Ceratonia silicqua gum / Ciamopsis tetragonolova (Guar) gum / agar / potassium chloride and glucose; Polyquaternium-7; Polyquaternium-10; Polyquaternium-67; Cetyl hydroxyethyl cellulose; Dihydro xanthan gum; Dextrin myristate; Gellan gum; Glycerin / glyceryl acrylate / acrylic acid copolymer; Hydrolyzed wheat protein. PVP crosspolymer; Isononanoyl diglycerin; Dilinoleic acid copolymer; Lauryl dimethicone / polyglycerin-3 copolymer / polymethylsilsquioxane / phenoxyethanol / chlorphenesin / capryl glycol; Met; Olea Europaea (olive) oil, butadiene / styrene copolymer; Polyacrylamide / C13-14 isoparaffin / laures-7; Polyacrylate crosspolymer-8; Polyacrylate-2 crosspolymer; Polyurethane-10, PEG-12 dimethicone; Polyurethane-14 AMP-acrylate copolymer; Potassium alginate; PVP; Sodium carboxymethyl starch; Sodium polyacrylate / hydrogenated polydecene / PPG-5-laures-5; Stearalkonium; Hectorite; Styrene / acrylate / ammonium methacrylate copolymer; Tamarindue indica seed polysaccharides; VP / methacrylamide / vinyl imidazole copolymer; Acrylate / palmet-25 acrylate copolymers; Ethylene / VA copolymer, butylene glycol, 1,2-hexanediol, caprylyl glycol, Tropolone, or Zea May (corn) starch. Specifically, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate / sodium acryloyl dimethyltaurate co It may be a polymer (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer) or polyacrylate-13 / polyisobutene / polysorbate-20.

In one aspect of the invention, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ- It may be one or more selected from the group consisting of cyclodextrin.

In one aspect of the present invention, the third solubilizing agent may contain 0.1 to 98% by weight based on the total weight of the composition. In one embodiment, the third dissolution aid is 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more based on the total weight of the composition , 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 20% or more, 30% or more, or 35% or more. In addition, the third dissolution aid is 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% Or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less Or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, or 5% by weight or less.

In one aspect of the invention, the weight ratio of the solute, the first solubilizer, the second solubilizer and the third solubilizer may be 1: 1 to 200: 1 to 20: 1 to 20. In one embodiment, the weight ratio is 1: 1 or more: 2 or more: 2 or more, 1: 1 or more: 3 or more: 3 or more, 1: 1 or more: 4 or more: 4 or more, 1: 1 or more: 5 or more: 5 Or more or 1: 1 or more: 6 or more: 6 or more. In addition, 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 It may be: 105 or less: 8 or less: 8 or less or 1:90 or less: 7 or less: 7 or less.

In another aspect of the present invention, the composition for external application for skin may be a composition for skin whitening. The composition for external application for skin may exhibit excellent skin whitening effects, and may specifically improve or prevent blemishes, freckles, spots, and skin pigmentation.

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

In one aspect of the invention, the composition may be a cosmetic composition. The cosmetic composition of the present specification may be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleaning , May be formulated as an oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto.

In one aspect of the present invention, the composition may be a pharmaceutical composition. The pharmaceutical composition may exhibit excellent skin whitening effects, and may specifically improve or treat blemishes, freckles, spots, and skin pigmentation. The pharmaceutical composition according to one aspect of the present invention may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like. Formulations for parenteral administration may be solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or sprays, but are not limited thereto. The formulations can be readily prepared according to conventional methods in the art, surfactants, excipients, hydrating agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, preservatives or Other commercial adjuvants 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, gender, weight, pathology and severity of the subject to be administered, the route of administration or the judgment of the prescriber. Determination of the application amount based on these factors is within the level of those skilled in the art, the daily dose of which is, for example, 0.1 mg / kg / day to 100 mg / kg / day, more specifically 5 mg / kg / day to 50 mg / kg / Can be a day, but is not limited to this.

According to another aspect of the present invention, a compound of Formula 1, an isomer thereof, and a pharmaceutical thereof for an individual in need of prevention, improvement, or treatment of diseases related to skin whitening, such as blemishes, freckles, spots, and skin pigmentation A solute that is an acceptable salt, hydrate or solvate thereof; Glycyrrhizic Acid derivative first solubilizer; And glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer, a composition comprising a second solubilizing agent, a disease related to skin whitening, such as spots, freckles, spots, skin pigmentation, etc. It may be related to the prevention, improvement, or treatment of diseases. In one aspect of the present invention, administration of the method may be performed according to the administration method and administration dose described herein.

In another aspect, the present invention provides a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof for preparing a pharmaceutical composition for skin whitening; Glycyrrhizic Acid derivative first solubilizer; And a second dissolution aid that is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer.

In another aspect, the present invention is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof for preparing a cosmetic composition for skin whitening; Glycyrrhizic Acid derivative first solubilizer; And a second dissolution aid that is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer.

In another aspect, the present invention is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solute thereof; Glycyrrhizic Acid derivative first solubilizer; And a glyceryl ether or a second soluble adjuvant that is a polyethylene glycol / polypropylene glycol copolymer.

In another aspect, the present invention is a solute that is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof for skin whitening use; Glycyrrhizic Acid derivative first solubilizer; And it may be related to a composition comprising a; a second dissolution aid that is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer.

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

[Preparation Example] Preparation of a solubilizing aid to improve the solubility of 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide (hereinafter, DBAB)

To identify a solubilizing agent that enhances the solubility of DBAB, 5% by weight of Dipotassium Glycyrrhizate (hereinafter, purchased from DG, Maruzen Pharmaceuticals Co., Ltd.) as the first solubilizing agent, and Glycereth-26 as a second solubilizing agent Synthesis) After adding 10% by weight and 0.5% by weight of Xanthan gum (CP KELCO) as a third dissolution aid, fill the remaining content with water and use a homomixer (Japan Primix, homomixer Mark 2 model) at 3000 rpm for 10 minutes. It was made uniform by stirring. Then, 0.1% by weight of DBAB was added and stirred for 20 minutes with a homomixer to mix to prepare Example 1.

Additionally, the composition was prepared in the same manner as in Example 1, wherein the first solubilizer was 0.1% by weight of DG, and the second solubilizer was 40% by weight of PEG / PPG-17 / 6 copolymer (Konlub). The composition was prepared.

The composition was prepared in the same manner as in Example 1, but the type and content of the first solubilizer were as follows, and the second solubilizer was 40% by weight of the PEG / PPG-17 / 6 copolymer (Konlub), and the third solubilizer. The hydroxypropyl cyclodextrin (hereinafter, CD, purchased from Nihon Shokunin Kako (Japan)) 0.6 wt% to prepare the composition of Examples 3 to 5.

Example 3: DG 0.1 wt%

Example 4: Glycyrrhizic Acid (hereinafter, GA, purchased from Maruzen Pharmaceuticals Co., Ltd.) 0.1 wt%

Example 5: Monoammonium Glycyrrhizate (hereinafter, purchased from MAG, Maruzen Pharmaceuticals Co., Ltd.) 0.1 wt%

[Experimental Example 1] Solubility test of the dissolution aid including the first dissolution aid of Dipotassium Glycyrrhizate, the second dissolution aid of Glycereth-26, and the third dissolution aid of Xanthan gum

In order to confirm the solubilizer to enhance the solubility of DBAB, it was prepared in the same manner as in Example 1, wherein the first and second solubilizers and the third solubilizer were the same, and only the first solubilizer was DG 1 wt% Another Comparative Example 1 was prepared, and solubility of Example 1 and Comparative Example 1 was confirmed. As a result, Example 1 was transparently dissolved (FIG. 1), but Comparative Example 1 was found to have poor solubility because it was not transparently dissolved.

[Experimental Example 2] Solubility test of dissolution aids including the first dissolution aid of Dipotassium Glycyrrhizate and the second dissolution aid of PEG / PPG-17 / 6 copolymer

In order to confirm the solubilizer to enhance the solubility of DBAB, as a result of confirming the solubility of Example 2, 0.1% by weight of DG as the first solubilizer and 40% by weight of PEG / PPG-17 / 6 copolymer as the second solubilizer It was confirmed that Example 2 was dissolved transparently (Fig. 3).

This is prepared in the same manner as in Example 2, but does not contain the first solubilizer, Comparative Example 2, which contains the second solubilizer PEG / PPG-17 / 6 copolymer in 50% by weight, is transparently dissolved. As a dissolution aid for DBAB, DG was found to have a dissolution effect of 10% by weight of PEG / PPG-17 / 6 copolymer when mixed with PEG / PPG-17 / 6 copolymer. In addition, it was confirmed that the contents of the first and second dissolution aids of the present invention have a complementary effect to lower other components when the content of the component that increases the dissolving power is increased.

[Experimental Example 3] Solubility test of dissolution aids including a first dissolution aid of Dipotassium Glycyrrhizate, Glycyrrhizic Acid or Monoammonium Glycyrrhizate, a second dissolution aid of PEG / PPG-17 / 6 copolymer, and a third dissolution aid of cyclodextrin

To confirm the solubility aids that enhance the solubility of DBAB, as a result of confirming the solubility of Examples 3 to 5, respectively, the first solubility aid contains DG, GA or MAG 0.1 wt%, and the second solubility aid is PEG / It was confirmed that Examples 3 to 5 containing 15% by weight of PPG-17 / 6 copolymer and 0.6% by weight of CD as a third dissolution aid were transparently dissolved (FIG. 4).

Through this, it was found that the first dissolution aids DG, GA and MAG have similar solubility to DBAB. In addition, the content of the first to third dissolution aids of the present invention was confirmed to have a complementary effect to lower other components when increasing the content of the component that increases the dissolving power.

[Experimental Example 4] Check stability

As a result of confirming the stability of Examples 1 to 5, Examples 1 to 5 remained stable when stored in a constant temperature bath at 45 ° C. for 13 days.

Hereinafter, a formulation example of the composition according to the present invention will be described, but this is not intended to limit the present invention, but only to be specifically described.

[Formulation Example 1] Flexible lotion

According to the composition shown in Table 1, a flexible lotion was prepared by a conventional method.

ingredient	Content (% by weight)
DBAB	0.1 wt%
DG	5.0 wt%
Xanthan gum	0.5 wt%
Glycereth-26	10 wt%
PEG-30 hydrogenated castor oil	1.2 wt%
ethanol	5.0 wt%
Butylene Glycol	2.0 wt%
Propylene glycol	2.0 wt%
Preservatives, pigments, flavors	Proper
Purified water	Balance

[Formulation Example 2] Nutrition lotion (milk lotion)

Nutritional lotion was prepared in a conventional manner according to the composition shown in Table 2 below.

ingredient	Content (% by weight)
DBAB	0.1 wt%
DG	5.0 wt%
Xanthan gum	0.5 wt%
Glycereth-26	10 wt%
PEG-30 hydrogenated castor oil	2.0 wt%
glycerin	3.0 wt%
Butylene Glycol	3.0 wt%
Propylene glycol	3.0 wt%
Carboxyvinyl polymer	0.1 wt%
Wax	4.0 wt%
Caprylic / Capric Triglyceride	5.0 wt%
Squalane	5.0 wt%
Floating paraffin	0.5 wt%
Cetearyl alcohol	1.0 wt%
Triethanolamine	0.2 wt%
Preservatives, pigments, flavors	Proper
Purified water	Balance

[Formulation Example 3] Nutrition Cream

A nutritional cream was prepared in a conventional manner according to the composition shown in Table 3 below.

ingredient	Content (% by weight)
DBAB	0.1 wt%
DG	5.0 wt%
Xanthan gum	0.5 wt%
Glycereth-26	10 wt%
PEG-30 hydrogenated castor oil	3.0 wt%
glycerin	3.0 wt%
Butylene Glycol	3.0 wt%
Floating paraffin	7.0 wt%
Beta glucan	7.0 wt%
Carbomer	0.1 wt%
Caprylic / Capric Triglyceride	3.0 wt%
Squalane	5.0 wt%
Cetearyl Glucoside	1.5 wt%
Sorbitan stearate	0.4 wt%
Triethanolamine	0.1 wt%
Preservatives, pigments, flavors	Proper
Purified water	Balance

[Formulation Example 4] Massage Cream

Massage cream is prepared by a conventional method according to the composition shown in Table 4 below.

ingredient	Content (% by weight)
DBAB	0.1 wt%
DG	5.0 wt%
Xanthan gum	0.5 wt%
Glycereth-26	10 wt%
PEG-30 hydrogenated castor oil	4.0 wt%
Vitamin E acetate	5.0 wt%
glycerin	8.0 wt%
Butylene Glycol	4.0 wt%
Floating paraffin	45.0 wt%
Beta glucan	7.0 wt%
Carbomer	0.1 wt%
Caprylic / Capric Triglyceride	3.0 wt%
Wax	4.0 wt%
Cetearyl Glucoside	1.5 wt%
Sesqui oleic acid sorbitan	0.9 wt%
Vaseline	3.0 wt%
paraffin	1.5 wt%
Preservatives, pigments, flavors	Proper
Purified water	Balance

[Formulation Example 5] Pack

Packs are prepared by conventional methods according to the compositions listed in Table 5 below.

ingredient	Content (% by weight)
DBAB	0.1 wt%
DG	5.0 wt%
Xanthan gum	0.5 wt%
Glycereth-26	10 wt%
PEG-30 hydrogenated castor 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%
Preservatives, pigments, flavors	Proper
Purified water	Balance

[Formulation Example 6] Ointment

Ointments were prepared in a conventional manner according to the composition shown in Table 6 below.

ingredient	Content (% by weight)
DBAB	0.1 wt%
DG	5.0 wt%
Xanthan gum	0.5 wt%
Glycereth-26	10 wt%
PEG-30 hydrogenated castor oil	3.0 wt%
Vitamin E acetate	4.0 wt%
Butylene Glycol	4.0 wt%
Floating paraffin	15.0 wt%
Beta glucan	7.0 wt%
Carbomer	0.1 wt%
Caprylic / Capric Triglyceride	3.0 wt%
Squalane	1.0 wt%
Cetearyl Glucoside	1.5 wt%
Sorbitan stearate	0.4 wt%
Cetearyl alcohol	1.0 wt%
Wax	4.0 wt%
Preservatives, pigments, flavors	Proper
Purified water	Balance

Claims (18)

1. A compound of Formula 1, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof;

   Glycyrrhizic Acid derivative first solubilizer; And

   A composition for external application for skin comprising a second solubilizing agent which is a glyceryl ether or a polyethylene glycol / polypropylene glycol copolymer:

   [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. According to claim 1,

   R ₁ , R ₃ and R ₄ in Chemical Formula 1 are independently hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ haloalkoxy, respectively. Is 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 an integer selected from 1 to 3, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, the composition for external application for skin.
3. According to claim 2,

   The 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 acid amide and

   Compound selected from the group consisting of 5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, isomers thereof, and pharmaceutically acceptable A composition for external application for skin, which is a possible salt, a hydrate or a solvate thereof.
4. According to claim 3,

   The solute is 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide, a composition for external application for skin.
5. According to claim 1,

   The solute is contained in an amount of 0.01 to 20% by weight relative to the total weight of the composition, the composition for external application for skin.
6. According to claim 1,

   The solute and the first solubilizing agent is a weight ratio of 1: 0.01 to 9990, the composition for external application for skin.
7. According to claim 1,

   The first dissolution aid is 0.01 to 99% by weight relative to the total weight of the composition, the composition for external application for skin.
8. According to claim 1,

   The glycyrrhizic acid derivatives are Dipotassium Glycyrrhizate, Glycyrrhizic Acid, Hydrolyzed Glycyrrhizinate, Methyl Glycyrrhizinate, Methyl Glycyrrhizate, Tripotassium Glycylate (Tripotassium Glycyrrhizate), Trisodium Glycyrrhizate (Trisodium Glycyrrhizate), Glycyrrhizic Acid Methyl Ester (Glycyrrhizic Acid, Methyl Ester) And Monoammonium Glycyrrhizate (Monoammonium Glycyrrhizate) At least one selected from the group consisting of: external composition for skin.
9. According to claim 1,

   The glyceryl ether is glycereth-26 (Glycereth-26) or glycereth-12 (Glycereth-12), the composition for external application for skin.
10. According to claim 1,

    The polyethylene glycol / polypropylene glycol copolymer is a sebum / sebum -17/6 copolymer (PEG / PPG-17 / 6 copolymer), the composition for external application for skin.
11. According to claim 1,

    The second dissolution aid is 0.01 to 98% by weight relative to the total weight of the composition, the composition for external application for skin.
12. According to claim 1,

    The solute, the weight ratio of the first solubilizing agent and the second solubilizing agent is a weight ratio of 1: 1 to 500: 1 to 20, the composition for external application for skin.
13. According to claim 1,

    The composition for external application for skin is cyclodextrin, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate / sodium acryl One or more agents selected from the group consisting of hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer and polyacrylate-13 / polyisobutene / polysorbate-20. 3 The composition for external application for skin further comprising a solubilizing agent.
14. The method of claim 13,

    The cyclodextrin is at least one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin, Skin external composition.
15. The method of claim 13,

    The third dissolution aid is 0.1 to 98% by weight relative to the total weight of the composition, the composition for external application for skin.
16. The method of claim 13,

    The solute, the first solubilizer, the second solubilizer and the third solubilizer weight ratio is 1: 1 to 200: 1 to 20: 1 to 20 weight ratio, the composition for external application for skin.
17. The method according to any one of claims 1 to 16,

    The composition for external application for skin is a composition for skin whitening.
18. The method according to any one of claims 1 to 16,

    The composition for external application for skin is a pharmaceutical or cosmetic composition.

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