TWI814926B - A composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

The present specification relates to a composition for external application to a skin, 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 glyceryl ether or polyethylene glycol/polypropylene glycol copolymer, and provides a composition for external application to a skin with improved solubility.

Description

Composition containing benzamide compound and co-solvent

This application claims the priority rights of Korean Patent Application No. 10-2018-0132134 filed on October 31, 2018. The entire disclosure of this application is incorporated herein by reference.

This specification relates to a composition with improved solubility for external application to the skin, the composition comprising: as a benzamide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate thereof Solute of solvate; and co-solvent.

Melanin can block UV rays in the epidermis to protect the skin organs below the dermis, and scavenge free radicals to protect the skin. Likewise, melanin is the main determinant of skin color, so when there is too much melanin, it leads to pigmentation such as spots, freckles and dark spots. Melanin is produced on melanocytes present in the basal layer of the epidermis, and it is known that melanin production is promoted by stimulation such as UV or inflammation. Therefore, melanin production can be inhibited by reducing external stimuli, blocking signal transduction, or inhibiting the synthesis or activity of tyrosinase, which is the enzyme that produces melanin. So far, kojic acid, hydroquinone, arbutin, azelaic acid, aloin, 4-butylresorcinol, resveratrol, ceramide, and sphingosine-1-phosphate have been known , sphingosine phosphocholine and its analogs can regulate melanin production by promoting tyrosinase decomposition or regulating glycosylation. However, these substances are not widely used due to unsatisfactory skin whitening effects and stability as well as skin irritation. Recently, benzamide substances that have excellent whitening effects and have few side effects have been studied.

Broussonetia kazinoki Sieb. is a traditional raw material for making Korean paper. From ancient times, it was predicted that Broussonetia japonica would have a skin whitening effect because the hands of those who made Korean paper were white and beautiful. Scientific research has confirmed that Broussonetal tree is an excellent ingredient for whitening effect. It is contained in the roots of Broussonetia papyrifera, and Broussonetus bleudensis extract is also a substance declared as a functional cosmetic raw material by the Ministry of Food and Drug Safety. . Accordingly, the functional groups showing the whitening effect of mulberry tree, which is a component with a whitening effect present in mulberry tree, have been analyzed by molecular modeling of the structure of mulberry tree. . Specifically, in the case of Broussonetyl alcohol F, although it has an excellent whitening effect, since it exists in small amounts in Broussonetal tree and is easily decomposed by temperature, it is actually difficult to use it as a single component.

Dihydroxybenzyladamantyldimethoxybenzamide is a compound among more than 100 derivatives prepared by simulating the structure of the minor component of this tree mulberry tree, which is mulberry tree alcohol F. The structure is newly designed by taking into account efficacy, stability, ease of manufacturing, etc. through structure activity relationship (QSAR) and 3D-QSAR. The compound reduces the expression of MITF that generates the cAMP-PKA-CREB signal, thereby inhibiting the activities of tyrosinase, TRP-1, and TRP-2, which are involved in MITF The main protein related to the regulation of melanin synthesis. The mechanism of the novel whitening effect of inhibiting melanin synthesis has been identified and demonstrated with cells and artificial skin.

However, studies to improve the solubility of compositions containing benzamide substances were not performed, and the researchers of the present invention came to the present invention by studying compositions with improved solubility of benzamide substances. [citation list] [Patent Document] (Patent Document 1) Korean 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 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 (Whitening Effect of Adamantyl Benzamide Derivative) Journal of the society of cosmetic scientists of Korea. 2013, Volume 39, Issue 2, Issue 127- 132 pages. (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 inhibits melanin production by inhibiting the expression of cAMP-PKA-CREB-activated microphthalmia-related transcription factors and tyrosinase (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.

[Technical Issue]

In consideration of the above problems, the inventors of the present invention came to the present invention by studying a composition containing a cosolvent that improves the solubility of a composition containing a benzamide compound.

An aspect of the present invention is to provide a stable composition while improving the solubility of the benzamide compound. [Solution to the problem]

Aspects of the present invention are directed to providing a composition for external application to skin, the composition comprising: a solute that is a compound of Formula 1 below, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or Its solvate; a first co-solvent, the first co-solvent is a glycyrrhizic acid derivative; and a second co-solvent, the second co-solvent is glyceryl ether or polyethylene glycol/polypropylene glycol copolymer: [Formula 1] Wherein R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxyl, 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; and n is selected An integer from 1 to 5. [Advantageous effects of the present invention]

The composition according to one aspect of the present invention is excellent in the solubility of a solute, which is a benzamide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvent thereof chemical. The composition according to one aspect of the present invention does not precipitate the benzamide compound as a solute, and has excellent solubility and stability.

Hereinafter, the present invention is described in detail.

Aspects of the present invention are directed to providing a composition for external application to skin, the composition comprising: a solute that is a compound of Formula 1 below, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or Its solvate; a first co-solvent, the first co-solvent is a glycyrrhizic acid derivative; and a second co-solvent, the second co-solvent is glyceryl ether or polyethylene glycol/polypropylene glycol copolymer: [Formula 1] Wherein R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxyl, 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; and n is selected An integer from 1 to 5.

In one aspect of the invention, the composition can be a compound of formula 1, wherein R ₁ , R ₃ and R ₄ of formula 1 are each independently selected from the group consisting of: hydrogen, hydroxyl, C ₁ to C ₃ alkoxy radical, C ₃ to C ₆ cycloalkoxy group, aryloxy group and C ₁ to C ₃ haloalkoxy group; R ₂ is selected from the group consisting of: hydrogen, C ₁ to C ₃ alkyl group, C ₃ to C ₆ Cycloalkyl, aryl and C ₁ to C ₃ haloalkyl; and n is an integer selected from 1 to 3, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates, Among them, in formula 1,

In one aspect of the invention, the solute may be a compound selected from the group consisting of: 5-Adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2,4-dihydroxybenzamide; 5-Adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2-hydroxy-4-methoxy-benzamide; 5-Adamantan-1-yl-N-(3,4-dihydroxybenzyl)-2,4-dihydroxybenzamide; 5-Adamantan-1-yl-N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxy-benzamide; 5-Adamantan-1-yl-2,4-dihydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-benzamide; 5-adamantan-1-yl-2-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxy-benzamide; 5-Adamantan-1-yl-N-[2-(4-hydroxyphenyl)-ethyl]-2,4-dimethoxy-benzamide; 5-Adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dihydroxybenzamide; 5-Adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2-hydroxy-4-methoxy-benzamide; 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzamide; 3-Adamantan-1-yl-N-(3,4-dihydroxybenzyl)-4-hydroxy-benzamide; 3-Adamantan-1-yl-N-(3,4-dihydroxybenzyl)-4-methoxy-benzamide; 3-Adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-hydroxy-benzamide; 3-Adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-methoxy-benzamide; 3-Adamantan-1-yl-4-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-benzamide; 3-Adamantan-1-yl-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxy-benzamide; 3-Adamantan-1-yl-N-(2,4-dihydroxybenzyl)-4-hydroxy-benzamide; 3-Adamantan-1-yl-N-(2,4-dihydroxybenzyl)-4-methoxy-benzamide; 5-Adamantan-1-yl-N-(2,5-dimethoxybenzyl)-2,4-dihydroxybenzamide; 5-Adamantan-1-yl-N-(2,5-dihydroxybenzyl)-2,4-dihydroxybenzamide; 5-Adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide; and 5-Adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzamide, its isomers, and its pharmaceutically acceptable salts , its hydrate, or its solvate.

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

In one aspect of the invention, the solute may be included in an amount of 0.01 to 20% by weight based on the total weight of the composition. In one aspect of the invention, the solute may be present at 0.01 wt% or more, 0.02 wt% or more, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, based on the total weight of the composition. more, 5% by weight or more, or 10% by weight or more, and 20% by weight or less, 15% by weight or less, 10% by weight or less, or 5% by weight or less. be included. Specifically, the content of solute may be from 0.02 to 10% by weight, and more specifically from 0.02 to 5% by weight. Within the above range, the desired effects of the present invention can be fully achieved while satisfying both the stability and safety of the composition, and this range is appropriate in terms of cost effectiveness. Specifically, in cases where the solute is included in an amount less than 0.01% by weight, the skin whitening effect may be insufficient. Furthermore, in cases where solutes are included in amounts exceeding 20% by weight, cost effectiveness may be less, and thus may be undesirable.

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

In one aspect of the present invention, the first co-solvent can be a glycyrrhizic acid derivative, wherein the glycyrrhizic acid derivative can be one or more selected from the group consisting of: dipotassium glycyrrhizate, glycyrrhizic acid, hydrolyzed glycyrrhizic acid , methyl glycyrrhizate, tripotassium glycyrrhizinate, trisodium glycyrrhizinate, methyl glycyrrhizinate, and monoammonium glycyrrhizinate. Specifically, the glycyrrhizic acid derivative may be one or more selected from the group consisting of: dipotassium glycyrrhizinate, glycyrrhizic acid, and monoammonium glycyrrhizinate.

In one aspect of the present invention, the weight ratio of the solute and the first co-solvent can be from 1:0.01 to 1:9990. In one embodiment, the solute and the first co-solvent can be 1:0.01 or greater, 1:0.05 or greater, 1:0.1 or greater, 1:0.5 or greater, 1:1 or greater, 1 :1.5 or larger, 1:2.0 or larger, 1:5 or larger, 1:10 or larger, 1:30 or larger, 1:50 or larger, 1:80 or larger, 1: 100 or larger, 1:200 or larger, 1:500 or larger, 1:800 or larger, 1:1000 or larger, 1:1500 or larger, 1:2000 or larger, 1:3000 Or greater, or a weight ratio of 1:5000 or greater. In addition, the solute and the first co-solvent may be 1:9990 or less, 1:9900 or less, 1:9800 or less, 1:9500 or less, 1:9000 or less, 1:8000 or less. Small, 1:7500 or smaller, 1:7000 or smaller, 1:5000 or smaller, 1:3000 or smaller, 1:1000 or smaller, 1:700 or smaller, 1:500 or smaller , 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, A weight ratio of 1:50 or less, 1:40 less, 1:30 or less, 1:20 or less, 1:10 or less, or 1:5 or less. Specifically, the weight ratio of the solute and the first co-solvent can be from 1:1 to 1:700.

In one aspect of the invention, the first co-solvent may be included in an amount of 0.01 to 99% by weight based on the total weight of the composition. In one embodiment, the content of the first co-solvent may be 0.01% by weight or greater, 0.05% by weight or greater, 0.1% by weight or greater, 0.2% by weight or greater, 0.3% by weight or greater, 0.4 0.5% by weight or more, 0.6% by weight or more, 0.7% by weight or more, 0.8% by weight or more, 0.9% by weight or more, 1% by weight or more, 2% by weight % or greater, 3% by weight or greater, 4% by weight or greater, 5% by weight or greater, 6% by weight or greater, 10% by weight or greater, 20% by weight or greater, 30% by weight or greater, or 35% by weight or greater. In addition, the content of the first co-solvent may be 99 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less. Small, 50% by weight or less, 45% by weight or less, 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, 20% by weight or less , 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2% by weight or less, 1 0.9% by weight 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 composition for external application to the skin may include a second co-solvent that is a glyceryl ether or a polyethylene glycol/polypropylene glycol copolymer. Specifically, the glycyrrhizic acid derivative as the first co-solvent may be included 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, the content of the first co-solvent may be 0.01% by weight or greater, 0.02% by weight or greater, 0.04% by weight or greater, 0.06% by weight or greater, 0.08% by weight or greater, 0.1% by weight % or greater, 0.5% by weight or greater, 1% by weight or greater, 1.5% by weight or greater, 2% by weight or greater, 3% by weight or greater, 4% by weight or greater, 5% by weight or greater, 6% by weight or greater, 10% by weight or greater, 20% by weight or greater, 30% by weight or greater, or 35% by weight or greater, and 98% by weight or less, 95% by weight % or less, 90% by weight or less, 85% by weight or less, 80% by weight or less, 60% by weight or less, 50% by weight or less, 45% by weight or less, 40% by weight or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or Smaller, 12 wt% or less, 11 wt% or less, 10 wt% or less, 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less Small, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less.

In one aspect of the present invention, the second co-solvent may be glycerol polyether-26, glycerol polyether-12, or PEG/PPG-17/6 copolymer.

In one aspect of the invention, the second cosolvent 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 content of the second co-solvent may be 0.01% by weight or greater, 0.02% by weight or greater, 0.04% by weight or greater, 0.06% by weight or greater, 0.08% by weight or greater, 0.1 Weight % or greater, 0.2 weight % or greater, 0.3 weight % or greater, 0.4 weight % or greater, 0.5 weight % or greater, 1 weight % or greater, 2 weight % or greater, 3 weight % or greater, 4% by weight or greater, 5% by weight or greater, 6% by weight or greater, 7% by weight or greater, 8% by weight or greater, 9% by weight or greater, 10% by weight or greater, 20% by weight or greater, 30% by weight or greater, or 35% by weight or greater. In addition, the content of the second co-solvent may be 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less. Small, 50% by weight or less, 45% by weight or less, 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, 20% by weight or less , 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2% by weight or less, 1 0.9% by weight 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 co-solvent and the second co-solvent may be from 1:1 to 500:1 to 20. In one embodiment, the solute, the first co-solvent and the second co-solvent may be in a weight ratio of 1:1 to 400:1 to 15. In addition, the solute, the first co-solvent and the second co-solvent may be in a weight ratio of 1:1 to 300:1 to 10, in a weight ratio of 1:1 to 200:1 to 10, or in a weight ratio of 1:1 to 150:1 to 7 weight ratio.

In one aspect of the present invention, the composition for external application to the skin may further comprise at least one third co-solvent selected from the group consisting of: cyclodextrin, cellulose gum, sanxian gum, polyacrylic acid Sodium, Hydroxypropyl Methylcellulose, Hydroxyethyl Acrylate/Sodium Acrylyl Dimethyl Taurate Copolymer, and Polyacrylate-13/Polyisobutylene/Polysorbate-20. Specifically, the first co-solvent of glycyrrhizic acid may be included in an amount of 0.01% by weight or greater and 98% by weight or less based on the total weight of the composition. More specifically, the content of the first co-solvent may be 0.01% by weight or greater, 0.02% by weight or greater, 0.04% by weight or greater, 0.06% by weight or greater, 0.08% by weight or greater, 0.1% by weight % or greater, 0.5% by weight or greater, 1% by weight or greater, 1.5% by weight or greater, 2% by weight or greater, 3% by weight or greater, 4% by weight or greater, 5% by weight or greater, 6% by weight or greater, 10% by weight or greater, 20% by weight or greater, 30% by weight or greater, or 35% by weight or greater, and 98% by weight or less, 95% by weight % or less, 90% by weight or less, 85% by weight or less, 80% by weight or less, 60% by weight or less, 50% by weight or less, 45% by weight or less, 40% by weight or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or Smaller, 12 wt% or less, 11 wt% or less, 10 wt% or less, 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less Small, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less.

In one aspect of the present invention, the third co-solvent can be cyclodextrin, cellulose gum, sanxian gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/acrylamide dimethyl Sodium taurate copolymer, polyacrylate-13/polyisobutylene/polysorbate-20, sodium magnesium silicate, bentonite, poloxamer 407, hydroxypropyl starch phosphate, PEG-240/HDI copolymer Bis-decyltetradecanol-20 ether, polyvinyl alcohol, magnesium aluminum silicate, polyvinylpyrrolidone, acrylate/C10-30 alkyl acrylate crosspolymer (alkyl acrylate methacrylate copolymer), adipic acid, neopentyl glycol cross-linked polymer, dimethyl silicone oil, VP, VA copolymer, amine dimethyl silicone oil, acrylonitrile dimethyl ammonium taurate VP copolymer, carbomer, Procarine gum, carob bean gum, guar (guar) gum, agar, potassium chloride and glucose, polyquaternium-7, polyquaternium-10, polyquaternium-67, cetyl hydroxyl Ethyl cellulose, dihydrocannabinol, dextrin myristate, gellan gum, glycerin, glyceryl acrylate, acrylic acid copolymer, hydrolyzed wheat protein, PVP cross-linked polymer, isononyl diglycerol , bislinoleic acid copolymer, lauryl dimethyl silicone oil, polyglycerol-3 copolymer, polymethyl sesquioxane, phenoxyethanol, chlorophenesin, caprylyl glycol, mannan, oleocanthal (olivea) ) oil, butadiene, styrene copolymer, PEG-240/HDI copolymer bis-decyltetradecanol-20 ether, polyacrylamide, C13-14 isoparaffin, laureth-7 , polyacrylate crosspolymer-8, polyacrylate-2 crosspolymer, polyurethane-10, PEG-12 dimethicone, polyurethane-14 AMP-acrylate copolymer Material, potassium alginate, PVP, sodium carboxymethyl starch, hydrogenated polydecene, PPG-5-laureth-5, selatonium chloride, lithium bentonite, styrene, acrylate, ammonium methacrylate Copolymer, tamarind seed polysaccharide, VP, methacrylamide, vinylimidazole copolymer, palm leaf-25 acrylate copolymer, VA copolymer, butanediol, 1,2-hexanediol, octyldiol Alcohol, tropone, mannan, or maize (corn) starch, and cellulose gum; Sanxian gum; sodium polyacrylate; hydroxypropyl methylcellulose; hydroxyethyl acrylate/acrylamide dimethyl Sodium taurate copolymer; polyacrylate-13/polyisobutylene/polysorbate-20; sodium magnesium silicate; bentonite; poloxamer 407; hydroxypropyl starch phosphate; PEG-240/HDI copolymer Bis-decyltetradecanol-20 ether; polyvinyl alcohol; magnesium aluminum silicate; polyvinylpyrrolidone; acrylate/C10-30 alkyl acrylate crosspolymer (alkyl acrylate methacrylate copolymer); adipic acid/neopentyl glycol crosspolymer/dimethyl silicone oil/VP/VA copolymer/amine dimethyl silicone oil; acrylonitrile dimethyl ammonium taurate VP-copolymer; carbomer; Carrageenan/Carob gum/Guar (guar) gum/Agar/Potassium chloride and glucose; Polyquaternium-7; Polyquaternium-10; Polyquaternium-67; Cetyl Hydroxyethyl cellulose; dihydroglucan; dextrin myristate; gellan gum; glycerol/glyceryl acrylate/acrylic acid copolymer; hydrolyzed wheat protein, PVP cross-linked polymer; isononyl dimer Glycerin; bis-linoleic acid copolymer; lauryl dimethicone/polyglycerol-3 copolymer/polymethylsesesquioxane/phenoxyethanol/chlorophenanglyceryl ether/octanediol; mannan; Olea europaea ( Olive) oil; butadiene/styrene copolymer; polyacrylamide/C13-14 isoparaffin/laureth-7; polyacrylate crosspolymer-8; polyacrylate-2 crosspolymer Material; Polyurethane-10, PEG-12 dimethicone; Polyurethane-14 AMP-acrylate copolymer; Potassium alginate; PVP; Sodium carboxymethyl starch; Sodium polyacrylate/hydrogenated Polydecene/PPG-5-Laureth-5; Selatonium chloride; Lithium bentonite; Styrene/acrylate/ammonium methacrylate copolymer; Tamarind seed polysaccharide; VP/methacrylamide /vinylimidazole copolymer; acrylate/palm leaf-25 acrylate copolymer; ethylidene/VA copolymer, butylene glycol, 1,2-hexanediol, octanoyl glycol, topoxone, or corn (corn) starch. Specifically, the third co-solvent can be cellulose gum, Sanxian gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acrylate dimethyl taurate copolymer, or polyacrylate. Acrylate-13/Polyisobutylene/Polysorbate-20.

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

In one aspect of the invention, the third co-solvent may be included in an amount of 0.1 to 98% by weight based on the total weight of the composition. In one embodiment, the third co-solvent may be 0.1% by weight or greater, 0.5% by weight or greater, 1% by weight or greater, 2% by weight or greater, 3% by weight or greater, based on the total weight of the composition. Greater, 4% by weight or greater, 5% by weight or greater, 6% by weight or greater, 7% by weight or greater, 8% by weight or greater, 9% by weight or greater, 10% by weight or greater It is included in an amount of 20% by weight or greater, 30% by weight or greater, or 35% by weight or greater. In addition, the third co-solvent may be 98% by weight or less, 95% by weight or less, 90% by weight or less, 85% by weight or less, 80% by weight or less, 60% by weight or less, 50% by weight or less. % by weight or less, 45% by weight or less, 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, 20% by weight or less, 15% by weight % or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, 10% by weight or less, 9% by weight or less, 8% by weight or less, 7 wt% or less, 6 wt% or less, or 5 wt% or less.

In one aspect of the present invention, the solute, the first co-solvent, the second co-solvent, and the third co-solvent may be in a weight ratio of 1:1 to 200:1 to 20:1 to 20. In one embodiment, the weight ratio may be 1:1 or greater:2 or greater:2 or greater, 1:1 or greater:3 or greater:3 or greater, 1:1 or greater :4 or greater:4 or greater, 1:1 or greater:5 or greater:5 or greater, or 1:1 or greater:6 or greater:6 or greater. In addition, the weight ratio may be 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. Small: 11 or smaller, 1:110 or smaller: 10 or smaller, 1:105 or smaller: 8 or smaller, or 1:90 or smaller: 7 or smaller:7.

In another aspect of the invention, the composition for external application to the skin may be a skin whitening composition. The compositions applied externally to the skin can exhibit excellent skin whitening effects and, in particular, can improve or prevent spots, freckles, dark spots, and skin pigmentation.

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

In one aspect of the invention, the composition may be a cosmetic composition. Cosmetic compositions according to the present description may be prepared into any formulation commonly prepared in the relevant art. For example, they may be formulated as solutions, suspensions, emulsions, ointments, gels, emulsions, lotions, powders, soaps, cleansers containing surfactants, oils, foundation creams, foundation emulsions, foundations Waxes, and sprays, but are not limited to these.

In one aspect of the invention, the composition may be a pharmaceutical composition. The pharmaceutical composition can exhibit excellent skin whitening effects and, specifically, can improve or treat spots, freckles, dark spots, and skin pigmentation. Pharmaceutical compositions according to an aspect of the invention may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, and subcutaneously. Formulations for parenteral administration may be, but are not limited to, solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches, or sprays. The formulations may be readily prepared by methods commonly used in the relevant art. In addition, surfactants, excipients, hydrating agents, emulsification accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, flavors, stabilizers, preservatives, antibacterial agents and other conventional adjuvants may be appropriate. way to use.

The active ingredients of the pharmaceutical composition according to one aspect of the invention vary depending on the age, gender, weight, pathological condition and severity of the subject to be administered, the route of administration, or the discretion of the prescriber. Determination of dosages to be administered taking these factors into account is within the skill level of those skilled in the art. The daily dosage may be, for example, 0.1 mg/kg/day to 100 mg/kg/day, more specifically 5 mg/kg/day to 50 mg/kg/day, but is not limited thereto.

In another aspect, the present invention may relate to a method for preventing, ameliorating, or treating diseases related to skin whitening, such as spots, freckles, dark spots, or skin pigmentation, wherein the method includes providing a method for preventing, ameliorating, or treating diseases related to skin whitening. , or to treat diseases related to skin whitening, such as spots, freckles, dark spots, or skin pigmentation, a composition is administered to a subject, the composition comprising the compound of the above formula 1, its isomers, and its The solute of a pharmaceutically acceptable salt, its hydrate, or its solvate; as the first cosolvent for glycyrrhizic acid derivatives; and as the second cosolvent for glyceryl ether or polyethylene glycol/polypropylene glycol copolymer . In one aspect of the invention, the method of administration can be performed according to the administration methods and dosages described herein.

In another aspect, the present invention may relate to a solute that is a compound of Formula 1 above, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; as a third glycyrrhizic acid derivative A co-solvent; and the use as a second co-solvent of glyceryl ether or polyethylene glycol/polypropylene glycol copolymer for preparing skin whitening pharmaceutical compositions.

In another aspect, the present invention may relate to a solute that is a compound of Formula 1 above, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; as a third glycyrrhizic acid derivative A co-solvent; and the use as a second co-solvent of glyceryl ether or polyethylene glycol/polypropylene glycol copolymer for preparing skin whitening cosmetic compositions.

In another aspect, the present invention may relate to the use of a composition for skin whitening, the composition comprising a compound of Formula 1 above, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or The solute of its solvate; as the first cosolvent for glycyrrhizic acid derivatives; and as the second cosolvent for glyceryl ether or polyethylene glycol/polypropylene glycol copolymer.

In another aspect, the present invention may relate to a composition for skin whitening, the composition comprising a compound of Formula 1 above, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or The solute of its solvate; as the first cosolvent for glycyrrhizic acid derivatives; and as the second cosolvent for glyceryl ether or polyethylene glycol/polypropylene glycol copolymer.

In the following, the invention is described in more detail via examples. It will be obvious to those of ordinary skill in the relevant art that these embodiments are for illustrative purposes only and the scope of the present invention should not be construed as being limited by these embodiments. [Preparation Example] Preparation of enhanced dissolution of 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzamide (hereinafter referred to as DBAB) sexual co-solvent

In order to identify a cosolvent that enhances the solubility of DBAB, 5% by weight of dipotassium glycyrrhizinate (hereinafter referred to as DG, purchased from Maruzen Pharmaceuticals Co., Ltd.) was added as the first cosolvent, and 10% by weight of glycerol polyether -26 (Dongnam Chemical Co., Ltd.) as the second co-solvent, and 0.5% by weight of CP KELCO as the third co-solvent, and the remaining content is filled with water, and a homogeneous mixer (Japan Primix, Homogeneous mixer type 2) Stir the mixture thoroughly at 3000 rpm for 10 minutes to homogenize. Thereafter, 0.1 wt% of DBAB was added and a homomixer was used to stir and mix for 20 minutes to prepare Example 1.

In addition, the composition of Example 2 was prepared in the same manner as in Example 1 above, except that the first co-solvent was 0.1 wt% DG, and the second co-solvent was 40 wt% PEG/PPG-17/6 copolymer. Other than things (Konlub).

The compositions of Examples 3 to 5 are prepared in the same manner as in Example 1 above, in which the type and content of the first co-solvent are as follows, and the second co-solvent is 40% by weight of PEG/PPG-17/6 copolymer ( Konlub), and the third co-solvent is 0.6% by weight of hydroxypropylcyclodextrin (hereinafter referred to as CD, purchased from Nihon Shokunin Kako, Japan). Example 3: DG 0.1% by weight Example 4: Glycyrrhizic acid (hereinafter referred to as GA, purchased from Maruzen Pharmaceuticals Co., Ltd.) 0.1% by weight Example 5: Monoammonium glycyrrhizinate (hereinafter referred to as MAG, purchased from Maruzen Pharmaceuticals Co., Ltd.) 0.1% by weight [Experimental Example 1] Solubility experiment of a cosolvent containing the first cosolvent of dipotassium glycyrrhizinate, the second cosolvent of glyceryl polyether-26, and the third cosolvent of Sanxianjiao

In order to identify the co-solvent that enhances the solubility of DBAB, the same second co-solvent and third co-solvent as in Example 1 above were used to prepare Comparative Example 1 in the same manner as Example 1, except that the first The co-solvent DG is 1% by weight, and the solubility of Example 1 and Comparative Example 1 is identified. Therefore, Example 1 dissolved transparently (Figure 1), while Comparative Example 1 dissolved opaquely, thereby resulting in poor solubility. [Experimental Example 2] Solubility experiment of a cosolvent containing the first cosolvent of dipotassium glycyrrhizinate and the second cosolvent of PEG/PPG-17/6 copolymer

In order to identify co-solvents that enhance the solubility of DBAB, due to the identification of the solubility of Example 2 above, we identified 0.1 wt% DG as the first co-solvent and 40 wt% PEG/PPG-17/6 copolymer as the second co-solvent. Example 2 of the two co-solvents was dissolved transparently (Figure 3).

Comparative Example 2 was prepared in the same manner as Example 2 above, except that Comparative Example 2 did not contain the first co-solvent but contained 50% by weight of PEG/PPG-17/6 copolymer as the second co-solvent. Dissolve. Therefore, it was found that when mixed with PEG/PPG-17/6 copolymer, DG as a co-solvent for DBAB has as much dissolving effect as 10 wt% of PEG/PPG-17/6 copolymer. In addition, when the content of ingredients that increase solubility increases, the content of the first and second co-solvents of the present invention is identified as having a complementary effect that can reduce other ingredients. [Experimental Example 3] A cosolvent containing dipotassium glycyrrhizinate, glycyrrhizic acid or monoammonium glycyrrhizinate, a second cosolvent of PEG/PPG-17/6 copolymer, and a third cosolvent of cyclodextrin. Solvent solubility test

In order to identify the co-solvent that enhances the solubility of DBAB, due to the identification of the solubility of the above Examples 3 to 5, we identified 0.1% by weight of DG, GA or MAG as the first co-solvent and 15% by weight of PEG/PPG- Examples 3 to 5 with 17/6 copolymer as the second co-solvent and 0.6 wt% CD as the third co-solvent were dissolved transparently (Figure 4).

From this, it was found that DG, GA and MAG as first co-solvents have similar solubility for DBAB. In addition, when the content of ingredients that increase solubility increases, the content of the first to third co-solvents of the present invention is identified as having a complementary effect that can reduce other ingredients. [Experimental Example 4] Identification stability

Due to the identification of the stability of Examples 1 to 5 above, Examples 1 to 5 remained stable when stored in a 45°C thermostat for 13 days.

In the following, formulation examples of the composition according to the present invention are described in detail. However, the following formulation examples are for illustrative purposes only, and the scope of the invention is not limited thereto. [Preparation example 1] Skin softener

Skin softeners were prepared according to commonly used methods using the compositions described in Table 1 below. Table 1 Element Content(wt.%) DBAB 0.1% by weight DG 5.0% by weight Sanxianjiao 0.5% by weight Glyceryl polyether-26 10% by weight PEG-30 hydrogenated castor oil 1.2% by weight ethanol 5.0% by weight Butanediol 2.0% by weight propylene glycol 2.0% by weight Preservatives, coloring agents and flavoring agents Appropriate amount Purify water margin [Preparation example 2] Nutrient solution (milk body lotion)

The nutrient solution was prepared according to commonly used methods using the composition described in Table 2 below. Table 2 Element Content(wt.%) DBAB 0.1% by weight DG 5.0% by weight Sanxianjiao 0.5% by weight Glyceryl polyether-26 10% by weight PEG-30 hydrogenated castor oil 2.0% by weight glycerin 3.0% by weight Butanediol 3.0% by weight propylene glycol 3.0% by weight carboxylated vinyl polymer 0.1% by weight beeswax 4.0% by weight Caprylic/capric triglyceride 5.0% by weight Squalane 5.0% by weight liquid paraffin 0.5% by weight cetearyl alcohol 1.0% by weight Triethanolamine 0.2% by weight Preservatives, coloring agents and flavoring agents Appropriate amount Purify water margin [Preparation example 3] Nutrient cream

Nutritional cream is prepared according to commonly used methods using the composition described in Table 3 below. table 3 Element Content(wt.%) DBAB 0.1% by weight DG 5.0% by weight Sanxianjiao 0.5% by weight Glyceryl polyether-26 10% by weight PEG-30 hydrogenated castor oil 3.0% by weight glycerin 3.0% by weight Butanediol 3.0% by weight liquid paraffin 7.0% by weight beta-glucan 7.0% by weight carbomer 0.1% by weight Caprylic/capric triglyceride 3.0% by weight Squalane 5.0% by weight Cetearyl glycoside 1.5% by weight Sorbitol stearate 0.4% by weight Triethanolamine 0.1% by weight Preservatives, coloring agents and flavoring agents Appropriate amount Purify water margin [Preparation example 4] Massage cream

The massage cream was prepared according to commonly used methods using the composition described in Table 4 below. Table 4 Element Content(wt.%) DBAB 0.1% by weight DG 5.0% by weight Sanxianjiao 0.5% by weight Glyceryl polyether-26 10% by weight PEG-30 hydrogenated castor oil 4.0% by weight Vitamin E Acetate 5.0% by weight glycerin 8.0% by weight Butanediol 4.0% by weight liquid paraffin 45.0% by weight beta-glucan 7.0% by weight carbomer 0.1% by weight Caprylic/capric triglyceride 3.0% by weight beeswax 4.0% by weight Cetearyl glycoside 1.5% by weight Sorbitan sesquioleate 0.9% by weight Vaseline 3.0% by weight Paraffin 1.5% by weight Preservatives, coloring agents and flavoring agents Appropriate amount Purify water margin [Preparation Example 5] Packaging

The packages were prepared according to commonly used methods using the compositions described in Table 5 below. table 5 Element Content(wt.%) DBAB 0.1% by weight DG 5.0% by weight Sanxianjiao 0.5% by weight Glyceryl polyether-26 10% by weight PEG-30 hydrogenated castor oil 4.0% by weight Vitamin E Acetate 8.0% by weight glycerin 4.0% by weight polyvinyl alcohol 15.0% by weight Hyaluronic acid extract 5.0% by weight beta-glucan 7.0% by weight Allantoin 0.1% by weight Nonyl phenyl ether 0.4% by weight Polysorbate 60 1.2% by weight ethanol 6.0% by weight Preservatives, coloring agents and flavoring agents Appropriate amount Purify water margin [Preparation Example 6] Ointment

The ointment was prepared according to commonly used methods using the composition described in Table 6 below. Table 6 Element Content(wt.%) DBAB 0.1% by weight DG 5.0% by weight Sanxianjiao 0.5% by weight Glyceryl polyether-26 10% by weight PEG-30 hydrogenated castor oil 3.0% by weight Vitamin E Acetate 4.0% by weight Butanediol 4.0% by weight liquid paraffin 15.0% by weight beta-glucan 7.0% by weight carbomer 0.1% by weight Caprylic/capric triglyceride 3.0% by weight Squalane 1.0% by weight Cetearyl glycoside 1.5% by weight Sorbitol stearate 0.4% by weight cetearyl alcohol 1.0% by weight beeswax 4.0% by weight Preservatives, coloring agents and flavoring agents Appropriate amount Purify water margin

without

Figure 1 is a photograph of Embodiment 1 of the present invention.

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

Figure 3 is a photograph of Embodiment 2 of the present invention.

Figure 4 is a photograph of Embodiments 3 to 5 of the present invention (DG in Figure 4 corresponds to Embodiment 3, GA corresponds to Embodiment 4, and MAG corresponds to Embodiment 5).

Domestic storage information (please note in order of storage institution, date and number) without Overseas storage information (please note in order of storage country, institution, date, and number) without

Claims (13)

A composition for external application to the skin, the composition comprising: a solute, the solute being 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy - benzamide, its stereoisomer, its pharmaceutically acceptable salt, or its hydrate; a first co-solvent, the first co-solvent is a glycyrrhizic acid derivative; and a second co-solvent, the The second co-solvent is glyceryl ether or polyethylene glycol/polypropylene glycol copolymer, wherein the glycyrrhizic acid derivative is one or more selected from the following groups: dipotassium glycyrrhizinate, glycyrrhizic acid, and monoglycyrrhizic acid. Ammonium, and wherein the solute and the first co-solvent are in a weight ratio of 1:1 to 50. The composition for external application to skin as claimed in claim 1, wherein the solute is included in an amount of 0.01 to 20% by weight based on the total weight of the composition. The composition for external application to skin as claimed in claim 1, wherein the first co-solvent is included in an amount of 0.01 to 99% by weight based on the total weight of the composition. The composition for external application to skin as described in claim 1, wherein the glyceryl ether is glycerol polyether-26 or glycerol polyether-12. The composition for external application to skin as claimed in claim 1, wherein the polyethylene glycol/polypropylene glycol copolymer is a PEG/PPG-17/6 copolymer. The composition for external application to skin as claimed in claim 1, wherein the second co-solvent is included in an amount of 0.01 to 98% by weight based on the total weight of the composition. The composition for external application to skin as claimed in claim 1, wherein the solute, the first co-solvent and the second co-solvent are in a weight ratio of 1:1 to 50:1 to 20. The composition for external application to skin as described in claim 1, the composition further comprises at least one third co-solvent selected from the group consisting of: cyclodextrin, cellulose gum, and sanxian gum. , sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acrylate dimethyl taurate copolymer, and polyacrylate-13/polyisobutylene/polysorbate-20. The composition for external application to skin as described in claim 8, wherein the cyclodextrin is one or more selected from the group consisting of: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin Dextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin. The composition for external application to skin as claimed in claim 8, wherein the third co-solvent is included in an amount of 0.01 to 98% by weight based on the total weight of the composition. The composition for external application to skin as described in claim 8, wherein the solute, the first co-solvent, the second co-solvent, and the third co-solvent are 1:1 to 50:1 to 20: 1 to 20 weight ratio. The composition for external application to skin according to any one of claims 1 to 11, wherein the composition for external application to skin The finished product is a skin whitening composition. The composition for external application to the skin according to any one of claims 1 to 11, wherein the composition for external application to the skin is a pharmaceutical or cosmetic composition.