TWI872018B - Composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

The present disclosure relates to a composition for external application for skin which comprises 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 one or more selected from the group consisting of a polyethylene glycol/polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400; a second solubilizer which is cyclodextrin; and a third solubilizer which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, a hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer, and polyacrylate-13/polyisobutene/polysorbate-20 and has an improved solubility of the benzoic acid amide compound.

Description

Composition containing benzoic acid amide compound and solubilizer

The present invention relates to a composition for external use on the skin, which contains a solute and a solubilizer. The solute is a benzoic acid amide compound, its isomer, its pharmaceutically acceptable salt, its hydrate or its solvate; and the solubility of the benzoic acid amide compound is improved.

Melanin protects the skin organs under the dermis by blocking ultraviolet rays in the epidermis and by absorbing free radicals in the body. In addition, melanin is also a major factor in determining skin color, so when present in excess, it will cause skin pigmentation, such as melasma, freckles, and spots. Melanin is produced in melanocytes in the basal layer of the skin, and its production is known to be promoted by stimulation caused by ultraviolet rays or inflammation. Therefore, melanin production may be reduced by reducing external stimulation and blocking signal transmission or by inhibiting the synthesis or activity of tyrosinase (the enzyme that produces melanin). It is known that kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butylresorcinol, resveratrol, ceramide, sphingosine-1-phosphate, sphingosylphosphorylcholine, etc. can promote the decomposition of tyrosinase or control the production of melanin by regulating glycation. However, due to unsatisfactory whitening effect, low stability and skin irritation, these substances are usually not used. Recently, research has been conducted on benzoic acid amide, a substance with excellent whitening effect but few side effects.

Paper mulberry is traditionally a raw material for Korean paper and is expected to have skin whitening effects because the hands of people who made Korean paper in the past were white and soft. Scientific research has found that the roots of paper mulberry contain kazinols, which are ingredients with excellent whitening effects. "Paper mulberry extract" has also been announced by the Food and Drug Safety Department as a functional cosmetic raw material. The structure of kazinols, a component with whitening effects in paper mulberry, was analyzed by molecular simulation technology to identify the functional groups that can express the whitening effects of kazinols. In particular, arboric acid F has an excellent whitening effect but is difficult to be actually used as a single ingredient because it exists in trace amounts in arboric acid and is easily decomposed by temperature.

Dihydroxybenzyl adamantnyldimethoxybenzamide is a newly designed compound by preparing 100 derivatives by simulating the structure of the architrave F (a component present in trace amounts in architrave) and considering their efficacy, stability, ease of production, etc. through quantitative structure-activity relationship (QSAR) and 3D-QSAR. The compound reduces the expression of MITF associated with cAMP-PKA-CREB signaling, thereby inhibiting the activity of tyrosinase, TRP-1 and TRP-2 (which are the main proteins involved in the melanin synthesis process regulated by MITF). The mechanism of the novel whitening effect of inhibiting melanin synthesis has been studied and confirmed using cells and artificial skin.

However, there has been no research on improving the solubility of compositions containing benzoic acid amide substances. The inventors of the present invention studied compositions with improved solubility of benzoic acid amide substances, thereby completing the present invention. [Citation List] [Patent Literature] Korean Patent No. 10-1604053 U.S. Patent No. 8697151 U.S. Patent No. 9216145 Japanese Patent Application Publication No. 2011-528708 Japanese Patent Application Publication No. 2015-0120716 Korean Patent No. 10-1502533 [Non-patent Literature] Adamantyl N-benzylbenzamide: New series of depigmentation agents with tyrosinase inhibitory activity, Bioorg. Med. Chem. Lett., 2012, 22(5), 2110-2113 Whitening Effect of Adamantyl Benzamide Derivatives, Journal of the Korean Society of Cosmeticology, 2013 Vol. 39, No. 2, pp. 127-132 3D-QSAR study of adamantyl N-benzylbenzamides as melanogenesis inhibitors, Bioorg. Med. Chem. Lett., 2014, 24, 667-673 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 issues]

In view of the above problems, the inventors of the present invention studied a composition containing a solubilizer, which is used to improve the solubility of a composition containing a benzoic acid amide compound, thereby completing the present invention.

One aspect of the present invention provides a composition having a stable and improved solubility of a benzoic acid amide compound. [Solution to the problem]

One aspect of the present invention provides a composition for external use on the skin, comprising: a solute, which is a compound represented by Chemical Formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate or its solvate; a first solubilizer, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer, copolymer) and polyacrylate-13/polyisobutylene/polysorbate-20: [Chemical Formula 1] In the chemical formula 1, 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 halogen alkoxy, and 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 halogen alkyl, and n is an integer selected from 1 to 5. [Beneficial Effects of the Invention]

The composition of one aspect of the present invention has a benzoic acid amide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as a solute having excellent solubility. In the composition of one aspect of the present invention, the benzoic acid amide compound as a solute does not precipitate. The composition of one aspect of the present invention has excellent solubility and exhibits excellent stability.

The present invention will be described in detail below.

One aspect of the present invention provides a composition for external use on the skin, comprising: a solute, which is a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; a first solubilizer, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20: [Chemical Formula 1] In the chemical formula 1, 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 halogen alkoxy, and 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 halogen alkyl, and n is an integer selected from 1 to 5.

In one aspect of the present invention, the solute may be a compound represented by Chemical 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 ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ halogen 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 halogen alkyl, and n is selected from an integer of 1 to 3, isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof.

In one embodiment of the present 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-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-dihydroxybenzyl)-4-methoxy-benzoic acid amide phenyl)-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-4-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-benzoic acid amide; 3-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-4-methoxy-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 5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide, its isomers, its pharmaceutically acceptable salts, its hydrates or its solvates.

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

In one aspect of the present invention, the content of the solute may be from 0.01 to 20 wt % based on the total weight of the composition. The possible content of the solute of the present invention is 0.01 wt % or more, 0.02 wt % or more, 0.1 wt % or more, 0.5 wt % or more, 1 wt % or more, 5 wt % or more, or 10 wt % or more, and 20 wt % or less, 15 wt % or less, 10 wt % or less, or 5 wt % or less based on the total weight of the composition. The solute content may be from 0.02 to 10 wt %, more particularly from 0.02 to 5 wt %. When the content of the solute is within the above range, not only the expected effect of the present invention can be properly demonstrated, but also the stability and safety of the composition can be satisfied. From the perspective of cost-effectiveness, it may be appropriate to contain the solute within the above range. Specifically, when the solute content is less than 0.01 wt %, the skin whitening effect is insufficient, and because of low cost-effectiveness, it is not desirable that the solute content exceeds 20 wt %.

In one aspect of the present invention, the composition may contain a water-soluble polar solvent as a solvent. In particular, in the composition, water is used as a solvent.

In one aspect of the present invention, the first solubilizer may be one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400. In particular, the first solubilizer may include both polyethylene glycol/polypropylene glycol copolymer and propylene glycol and may contain polyethylene glycol-400. The polyethylene glycol/polypropylene glycol copolymer as the first solubilizer may be PEG/PPG-17/6 copolymer, and the propylene glycol as the first solubilizer may be 1,3-propylene glycol.

In one aspect of the present invention, the weight ratio between the solute and the first solubilizing agent may be 1:0.1 to 9900. In a specific embodiment, the weight ratio between the solute and the first solubilizing agent may be 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, the weight ratio between the solute and the first solubilizing agent may be 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. In particular, the weight ratio between the solute and the first solubilizer may be 1:50 to 700.

In one aspect of the present invention, the first solubilizing agent may be present in an amount of from 0.1 to 99 wt % based on the gross weight of the composition. In a specific embodiment, the first solubilizing agent may be present in an amount of from 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, 6 wt % or more, 10 wt % or more, 20 wt % or more, 30 wt % or more, or 35 wt % or more, based on the gross weight of the composition. In addition, the first solubilizing agent may be present in an amount of 99 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 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 less, 12 wt % or less, 11 wt % or less, or 5 wt % or less, based on the total weight of the composition.

In one aspect of the present invention, the third solubilizer may be one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20.

In one aspect of the present invention, the second solubilizing agent may be present in an amount of from 0.1 to 98 wt % based on the total weight of the composition. In a specific embodiment, the second solubilizing agent may be present in an amount of 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, 6 wt % or more, 10 wt % or more, 20 wt % or more, 30 wt % or more, or 35 wt % or more, based on the total weight of the composition. In addition, the second solubilizing agent may be present in an amount of 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 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 less, 12 wt % or less, 11 wt % or less, or 5 wt % or less, based on the total weight of the composition.

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

In one aspect of the present invention, the cyclodextrin used as the second solubilizing agent may be any one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin.

In one aspect of the present invention, the third solubilizing agent may be: cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyl dimethyl taurate copolymer, polyacrylate-13/polyisobutylene/polysorbate-20, sodium magnesium silicate, bentonite, poloxamer 407, hydroxypropyl starch phosphate, PEG-240/HDI copolymer bis-decyltetradecyl alcohol polyether (decyltetradecyl alcohol polyether) adeceth)-20 ether, polyvinyl alcohol, magnesium aluminum silicate, polyvinyl pyrrolidone, acrylates/C10-30 alkyl acrylate crosspolymer (acrylic acid/alkyl methacrylate copolymer), adipic acid, neopentyl glycol crosspolymer, dimethicone, VP, VA copolymer, amodimethicone, ammonium acryloyldimethyl taurate/VP copolymer, carbomer, carrageenan, carob gum (ceratonia siliqua gum), guar bean gum, agar, potassium chloride and glucose, polyquaternium-7, polyquaternium-10, polyquaternium-67, cetyl hydroxyethyl cellulose, dehydrogenated xanthan gum, dextrin myristate, gellan gum, glycerin, glyceryl acrylate, acrylic acid copolymer, hydrolyzed wheat protein, PVP crosslinked polymer, isononanoyl diglycerol, dimerized linoleic acid copolymer , lauryl dimethicone, polyglyceryl-3 copolymer, polymethylsilsesquioxane, phenoxyethanol, chlorphenesin, caprylyl glycol, polymannos, olea europaea (olive) oil, butadiene, styrene copolymer, PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, polyacrylamide, C13-14 Isoalkane, 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-laureth-5, stearalkonium hectorite, styrene, acrylates, ammonium methacrylate copolymer, Tamarindus Indica seed polysaccharides, VP, methacrylamide, vinyl imidazole copolymer, palmeth-25 acrylate copolymer, VA copolymer, butylene glycol, 1,2-hexanediol, caprylyl glycol, tropolone, polymannos, or Zea mays. May) (corn) starch; and may be: cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyl dimethyl taurate Copolymer, Polyacrylate-13/Polyisobutene/Polysorbate-20, Sodium Magnesium Silicate, Bentonite, Poloxamer 407, Hydroxypropyl Starch Phosphate, PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether, Polyvinyl Alcohol, Magnesium Aluminum Silicate, Polyvinyl Pyrrolidone, Acrylates/C10-30 Alkyl Acrylate Crosspolymer (Acrylic Acid/Alkyl Methacrylate Copolymer), Adipic Acid/Neopentyl Glycol Crosspolymer/Dimethicone/VP/VA Copolymer/Amodimethicone, Ammonium Acryloyldimethyl Taurate/VP Copolymer, Carbomer, Carrageenan/Carob Gum/Guar Gum/Agar/Potassium Chloride and Glucose, Polyquaternium-7, Polyquaternium-10, Polyquaternium-67, Cetyl Hydroxyethyl Cellulose, Dehydroxanthan Gum, Dextrin Myristate, Gellan Gum, Glycerin/Glyceryl Acrylate/Acrylic Acid Copolymer, Hydrolyzed Wheat Protein/PVP Crosslinked Polymer, Isononyl Diglycerol, Dimer Linoleic Acid Copolymer, Lauryl Dimethicone/Polyglyceryl-3 Copolymer/Poly Methylsilsesquioxane/phenoxyethanol/chlorphenesin/caprylyl glycol, polymannos, olea europaea (olive) oil, butadiene/styrene copolymer, polyacrylamide/C13-14 isoalkanes/laureth-7, polyacrylate crosspolymer-8, polyacrylate-2 crosspolymer, polyurethane-10, PEG-12 dimethicone, polyurethane-14 AMP-acrylates copolymer, potassium alginate, PVP, sodium carboxymethyl starch, sodium polyacrylate/hydrogenated polydecene/PPG-5-laureth-5, ammonium stearate, hydrophilic stone, styrene/acrylates/ammonium methacrylate copolymer, tamarind polysaccharides, VP/methacrylamide/vinyl imidazole copolymer, acrylates/palmeth-255 acrylates copolymer, ethylhexane/VA copolymer, butylene glycol, 1,2-hexanediol, caprylyl glycol, cycloheptatrienolone, or Zea May (corn) starch. In particular, the third solubilizer may be cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer or polyacrylate-13/polyisobutylene/polysorbate-20.

In one aspect of the present invention, the third solubilizing agent content may be from 0.1 to 98 wt % based on the gross weight of the composition. In a specific embodiment, the third solubilizing agent content may be 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, 6 wt % or more, 10 wt % or more, 20 wt % or more, 30 wt % or more, or 35 wt % or more based on the gross weight of the composition. In addition, the third solubilizing agent content 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, 50 wt % or less, 45 wt % or less, 40 wt % 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 less, 12 wt % or less, 11 wt % or less, or 5 wt % or less.

In one aspect of the present invention, the weight ratio between the solutes, the first solubilizer, the second solubilizer and the third solubilizer may be 1: 10 to 200: 1 to 20: 1 to 20. In a specific embodiment, the weight ratio may be 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 more, or 1: 90 or more: 6 or more: 6 or more. 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: 11 or less, 1: 110 or less: 10 or less: 10 or less, 1: 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 skin topical composition may be a skin whitening composition. The skin topical composition can exhibit excellent skin whitening effects, especially improving or preventing liver spots, freckles, spots and skin pigmentation.

In still another aspect of the present invention, the skin topical composition may be a pharmaceutical or cosmetic composition.

In one aspect of the present invention, the composition may be a cosmetic composition. The cosmetic composition of the present invention may be prepared in any formulation that is accustomed to being prepared in the art. The cosmetic composition may be prepared in the form of, for example, but not limited to, the following formulations: solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing oils, powder foundations, emulsion foundations, wax foundations, and sprays.

In one aspect of the present invention, the composition may be a pharmaceutical composition. The pharmaceutical composition can exhibit excellent skin whitening effects and can particularly improve or treat liver spots, freckles, spots and skin pigmentation. The pharmaceutical composition of one aspect of the present invention may be administered via the following methods: parenteral, rectal, topical, transdermal, intravenous, intramuscular, intraperitoneal, subcutaneous, etc. The preparation for parenteral administration may be a solution, suspension, emulsion, gel, injection (injections), drops (drops), suppositories (suppositories), patches (patches) or sprays (sprays), but is not limited thereto. Such preparations can be easily prepared by methods commonly used in the art, and surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, coloring agents, spices, stabilizers, antiseptics, preservatives or other common adjuvants may be used appropriately.

The dosage of the active ingredient of the pharmaceutical composition according to one aspect of the present invention may vary according to the age, sex, weight, pathological condition and severity of the individual to be administered, the route of administration or the judgment of the prescriber. Determining the dosage based on these factors is within the level of a person skilled in the art, and the daily dosage may be, for example, from 0.1 mg/kg/day to 100 mg/kg/day or more, particularly from 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, improving or treating skin whitening-related diseases, such as liver spots, freckles, spots and skin pigmentation, comprising administering the following to an individual in need of prevention, improvement or treatment of skin whitening-related diseases, such as liver spots, freckles, spots and skin pigmentation: a composition containing a solute, the solute being a compound represented by Chemical Formula 1, its isomers, its pharmaceutically acceptable salts, its aqueous solutions a first solubilizing agent, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizing agent, which is cyclodextrin; and a third solubilizing agent, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20. In one aspect of the present invention, the administration of the above method can be carried out according to the administration method and dosage described herein.

In yet another embodiment, the present invention may relate to the use of a solute in the manufacture of a skin whitening pharmaceutical composition, wherein the solute is a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; a first solubilizer, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20.

In yet another embodiment, the present invention may relate to the use of a solute for preparing a skin whitening cosmetic composition, wherein the solute is a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; a first solubilizer, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20.

In yet another aspect, the present invention may relate to the use of a composition containing a solute for skin whitening, wherein the solute is a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; a first solubilizer, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20.

In yet another aspect, the present invention may relate to a composition for skin whitening purposes containing a solute, wherein the solute is a compound represented by Chemical Formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate or its solvate; a first solubilizer, which is one or more selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20.

[Examples] The present invention will be described in more detail below with reference to examples. Those skilled in the art should understand that these examples are only used to illustrate the present invention, and the scope of the present invention should not be interpreted as being limited to these examples.

[ Embodiment 1 to 8] Preparation can enhance 5- Diamond -1- base -N-(2,4- Dihydroxybenzyl )-2,4- Dimethoxy - Benzoic acid amide ( Hereinafter referred to as DBAB) Solubility enhancer

In order to identify a solubilizer that can enhance the solubility of DBAB, 15 wt% PEG/PPG-17/6 copolymer (Konlub) and 20 wt% 1,3-propylene glycol (Fermandiol) as the first solubilizer, 0.5 wt% hydroxypropyl cyclodextrin (hereinafter referred to as CD, purchased from NIHON SHOKUHIN) as the second solubilizer, 1 wt% cellulose gel (CMC) as the third solubilizer and a balance of water were mixed together, and the mixture was stirred thoroughly at 3000 rpm for 10 minutes using a homogenizer (Japan PRIMIX Corporation, Homomixer Mark 2 model) until uniform. Then DBAB was added thereto, and the mixture was mixed for 20 minutes using a homogenizer to prepare the composition of Example 1.

The compositions of Examples 2 to 8 were prepared in the same manner as Example 1, except that the first solubilizer was 5 wt% PEG-400, the second solubilizer was 0.6 wt% CD, and the type and content of the third solubilizer were as follows. Example 2: 1 wt% of hydroxypropyl methylcellulose (hereinafter referred to as HPMC) (Pharmacoat 630 HPMC) Example 3: 0.5 wt% of sodium polyacrylate Example 4: 0.5 wt% of xanthan gum Example 5: 0.5 wt% of hydroxyethyl acrylate/sodium acryloyl dimethyl taurate copolymer Example 6: 0.5 wt% of polyacrylate-13/polyisobutylene/polysorbate-20 Example 7: 0.5 wt% of HPMC (Pharmacoat 630 HPMC) Example 8: 0.5 wt% of HPMC (Methocel E4M)

[ Experimental Examples 1] Use PEG/PPG-17/6 Copolymers and 1,3- Propylene glycol ( First solubilizer ) With cellulose glue ( The third solubilizer ) Solubility test of solubilizer

In order to identify a solubilizing agent that can improve the solubility of DBAB, the composition of Comparative Example 1 was prepared in the same manner as Example 1, except for the following conditions: the first solubilizing agent and the second solubilizing agent were the same as those used in Example 1, but the third solubilizing agent was changed to 1.0 wt% hydroxyethyl cellulose (Natrosol 250HR). The solubility of the compositions in Example 1 and Comparative Example 1 was tested. The results showed that DBAB transparently dissolved in the composition of Example 1 ( FIG. 1 ), but DBAB did not transparently dissolve in the composition of Comparative Example 1, and the solubility was poor.

[ Experimental Examples 2] Use PEG-400 Solubility test of the first solubilizer and various third solubilizers

In order to identify a solubilizing agent that can enhance the solubility of DBAB, the solubility of DBAB in the compositions of Examples 2 to 8 was tested.

First, it was confirmed that DBAB was transparently dissolved in the composition of Example 2 containing 5 wt % PEG-400 as a first solubilizer, 0.6 wt % CD as a second solubilizer, and 1 wt % HPMC as a third solubilizer.

In the case of Examples 3 to 8, the types and contents of the first solubilizer and the second solubilizer are the same as those of Example 2, but the content of the third solubilizer is 0.5 wt% (half of that of Example 2), which confirms that the solubility of DBAB in the composition of Example 3 (third solubilizer: sodium polyacrylate) is the highest, and DBAB is also transparently dissolved in the compositions of Examples 4 to 6 (the third solubilizer is respectively: xanthan gum (Example 4), hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer (Example 5), and polyacrylate-13/polyisobutylene/polysorbate-20 (Example 6)). In the case of Examples 7 and 8, in which HPMC as a third solubilizer was included but the content was different from that of Example 2 and was 0.5 wt %, it was confirmed that DBAB was transparently dissolved in the composition but the solubility was not as high as that of Examples 3 to 6 ( FIG. 1 ).

In addition, the composition was mixed with DBAB in the same manner as described in the examples and the DBAB solubility was tested. The types and contents of the first solubilizer and the second solubilizer in the composition were the same as those in Examples 3 to 8, and the content of the third solubilizer was 0.5 wt %, but the types of the third solubilizer were as follows: sodium magnesium silicate (Comparative Example 2), bentonite (Comparative Example 3), poloxamer 407 (Comparative Example 4), hydroxypropyl starch phosphate (Comparative Example 5), PEG-240/HDI copolymer bis-decyltetradecyl alcohol polyether-20 ether (Comparative Example 6), polyvinyl alcohol (Comparative Example 7), magnesium aluminum silicate (Comparative Example 8) and polyvinyl pyrrolidone (Comparative Example 9). The results showed that DBAB was not transparently dissolved or precipitated in the compositions of Comparative Examples 2 to 9, and had poor solubility.

[ Experimental Examples 3] Testing stability

The stability of the compositions of Examples 3 to 8 was tested. The results showed that the composition of Example 3 remained stable after being stored in a thermostat at 45° C. for 13 days.

[ Experimental Examples 4] According to the type and content of the first solubilizer, the second solubilizer and the third solubilizer DBAB Solubility

In order to detect the degree to which the first solubilizer, the second solubilizer, and the third solubilizer enhance the solubility of DBAB, a composition (Example 9) containing 5 wt% PEG/PPG-17/6 copolymer (Konlub) (first solubilizer), 0.6 wt% CD (second solubilizer), and 0.5 wt% HPMC (Pharmacoat 630 HPMC) (third solubilizer) was prepared in the same manner as in Example 1, and the DBAB solubility was detected. As a result, it was confirmed that DBAB was transparently dissolved in the composition.

[ Experimental Examples 5] According to the content of the third solubilizer DBAB Solubility

After adding 3.0 wt% sodium polyacrylate (third solubilizer) to 0.1 wt% DBAB, a balance amount of water was added to the mixture to prepare a composition (Example 10), and the DBAB solubility was tested. The results showed that DBAB particles were dissolved in the composition and were in an invisible colloid state (Figure 2).

The following is a description of the formulation examples of the composition of the present invention, but it is not intended to limit the present invention but only to illustrate the present invention.

[ Preparation Example 1] Moisturizing liquid The moisturizing liquid was prepared by a conventional method according to the composition shown in Table 1 below. [Table 1] Element Content (wt%) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 Hydrogenated Castor Oil 1.2 wt% Ethanol 5.0 wt% Butanediol 2.0 wt% Propylene glycol 2.0 wt% Preservatives, colorants, flavorings Moderate Purified water Balance

[ Preparation Example 2] Nourishing lotion ( emulsion ) Nourishing lotion was prepared by a conventional method according to the composition shown in Table 2 below. [Table 2] Element Content (wt%) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 Hydrogenated Castor Oil 2.0 wt% glycerin 3.0 wt% Butanediol 3.0 wt% Propylene glycol 3.0 wt% Carboxyvinyl polymer 0.1 wt% Beeswax 4.0 wt% Caprylic/capric triglyceride 5.0 wt% Squalane 5.0 wt% Liquid wax 0.5 wt% Cetearyl Alcohol 1.0 wt% Triethanolamine 0.2 wt% Preservatives, colorants, flavorings Moderate Purified water Balance

[ Preparation Example 3] Nourishing cream Nourishing cream was prepared according to the composition shown in Table 3 below by a conventional method. [Table 3] Element Content (wt%) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 Hydrogenated Castor Oil 3.0 wt% glycerin 3.0 wt% Butanediol 3.0 wt% Liquid wax 7.0 wt% β-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, colorants, flavorings Moderate Purified water Balance

[ Preparation Example 4] Massage Cream A massage cream was prepared by a conventional method according to the composition shown in Table 4 below. [Table 4] Element Content (wt%) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 Hydrogenated Castor Oil 4.0 wt% Vitamin E Acetate 5.0 wt% glycerin 8.0 wt% Butanediol 4.0 wt% Liquid wax 45.0 wt% β-Glucan 7.0 wt% Carbomer 0.1 wt% Caprylic/capric triglyceride 3.0 wt% Beeswax 4.0 wt% Cetearyl Glucoside 1.5 wt% Sorbitan sesquioleate 0.9 wt% Wax 3.0 wt% Wax 1.5 wt% Preservatives, colorants, flavorings Moderate Purified water Balance

[ Preparation Example 5] Facial mask A facial mask was prepared by a conventional method according to the composition shown in Table 5 below. [Table 5] Element Content (wt%) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 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% β-Glucan 7.0 wt% Allantoin 0.1 wt% Nonylphenyl ether 0.4 wt% Polysorbate 60 1.2 wt% Ethanol 6.0 wt% Preservatives, colorants, flavorings Moderate Purified water Balance

[ Preparation Example 6] Ointment An ointment was prepared by a conventional method according to the composition shown in Table 6 below. [Table 6] Element Content (wt%) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 Hydrogenated Castor Oil 3.0 wt% Vitamin E Acetate 4.0 wt% Butanediol 4.0 wt% Liquid wax 15.0 wt% β-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% Beeswax 4.0 wt% Preservatives, colorants, flavorings Moderate Purified water Balance

without

Figure 1 is a picture of embodiments 1, 3, 4, 7 and 8 of the present invention. Figure 2 is a picture showing the stability of embodiment 10 of the present invention.

Claims (11)

A composition for external use on skin comprises: a solute, which is 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide and its isomers, its pharmaceutically acceptable salts or hydrates thereof; a first solubilizer, which is one or more selected from the group consisting of 1,3-propylene glycol and polyethylene glycol-400; a second solubilizer, which is cyclodextrin; and a third solubilizer, which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutylene/polysorbate-20. For example, in the skin topical composition of item 1 of the patent application, the solute content is from 0.01 to 20 wt% based on the total weight of the composition. For example, in the skin topical composition of item 1 of the patent application, the weight ratio between the solute and the first solubilizer is 1:0.1 to 9900. For example, in the skin topical composition of item 1 of the patent application, the content of the first solubilizer is from 0.1 to 99 wt% based on the total weight of the composition. For example, in the skin topical composition of claim 1, the cyclodextrin is any one or more of the following: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin. For example, in the skin topical composition of item 1 of the patent application, the content of the second solubilizer is from 0.1 to 98 wt% of the total weight of the composition. For example, in the skin topical composition of item 1 of the patent application, the weight ratio of the solute, the first solubilizer and the second solubilizer is 1:50 to 500:1 to 20. For example, in the skin topical composition of item 1 of the patent application, the content of the third solubilizer is from 0.1 to 98 wt% of the total weight of the composition. For example, in the skin topical composition of item 1 of the patent application, the weight ratio of the solute, the first solubilizer, the second solubilizer and the third solubilizer is 1:10 to 200:1 to 20:1 to 20. For example, a composition for external use on the skin in any one of items 1 to 9 of the patent application scope, wherein the composition for external use on the skin is a skin whitening composition. For example, a composition for external use on the skin in any of items 1 to 9 of the patent application scope, wherein the composition for external use on the skin is a pharmaceutical or cosmetic composition.