WO2020153520A1 - Composition comprising benzoic acid amide compound and solubilizing agents - Google Patents

Abstract

The present specification relates to an external-use skin preparation composition comprising: a solute which is a benzoic acid amide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; a first solubilizing agent 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 solubilizing agent which is a cyclodextrin; and a third solubilizing agent which is one or more selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methyl cellulose, a hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer and polyacrylate-13/polyisobutene/polysorbate-20, and provides an external-use skin preparation composition having improved solubility.

Description

Composition comprising benzoic acid amide compound and dissolution aid

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 the 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 and block signal transmission, or to reduce the production of melanin by inhibiting or inhibiting the synthesis or activity of the melanin-producing enzyme tyrosinase. 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. Accordingly, scientific research has confirmed that kazinol, an ingredient with excellent whitening effect, is found in the roots of mulberry tree, and "Dak tree extract" is a functional cosmetic ingredient that is also 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 that show 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 kinds of derivatives prepared by simulating the structure of Kazinol F, a trace component of mulberry tree. It is one compound. This compound inhibits melanin synthesis by reducing the MITF expression linked to the cAMP-PKA-CREB signal and, as a result, inhibiting the activity of tyrosinase, TRP-1, and TRP-2, the major proteins in relation to the melanin synthesis regulated by MITF. 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]

Korean Registered Patent No. 10-1604053

U.S. Patent No. 8697151

U.S. Patent No. 9216145

Japanese Patent Publication No. 2011-528708

Japanese Patent Publication No. 2015-0120716

Korean Registered 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 Cosmetic Society. 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.

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 comprising 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; And

A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;

A second dissolution aid that is a cyclodextrin; And

Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethylacrylate/Sodium acryloyl dimethyltaurate copolymer (hydroxyethyl external preparation for skin comprising a third soluble adjuvant selected from the group consisting of acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 Provides the composition:

[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 one 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 Examples 1, 3, 4, 7 and 8 of the present invention.

2 is a photograph confirming the stability of Example 10 of the present invention.

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; And

A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;

A second dissolution aid that is a cyclodextrin; And

Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethylacrylate/Sodium acryloyl dimethyltaurate copolymer (hydroxyethyl external preparation for skin comprising a third soluble adjuvant selected from the group consisting of acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 Provides the composition:

[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. The solute of the present invention 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% by weight % Or less, 15% or less, 10% or less, or 5% 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 invention, the first dissolution aid may be at least one selected from the group consisting of polyethylene glycol / polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400. Specifically, the first dissolution aid may include both polyethylene glycol/polypropylene glycol copolymer and propylene glycol, and may include polyethylene glycol-400. The first dissolution aid polyethylene glycol / polypropylene glycol copolymer is PEG / PPG-17/6 copolymer (PEG/PPG-17/6 copolymer), propylene glycol is 1,3 -Propanediol (1,3-propanediol).

In one aspect of the invention, the solute and the first solubilizing agent may be a weight ratio of 1: 0.1 to 9900. In one embodiment, the solute and the first solubilizing agent are 1:0.5 or more, 1:1 or more, 1:1.5 or more, 1:2.0 or more, 1:5 or more, 1:10 or more, 1:30 or more, 1: 50 or more, 1:80 or more, 1:100 or more, 1:200 or more, 1:500 or more, 1:800 or more, 1:1000 or more, 1:1500 or more, 1:2000 or more, 1:3000 or more, or 1: It can be 5000 or more. In addition, 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 solubilizer may be in a weight ratio of 1:50 to 700.

In one aspect of the present invention, the first dissolution aid may be included in an amount of 0.1 to 99% by weight based on the total weight of the composition. In one embodiment, the first 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, 10% or more, 20% or more, 30% or more, or 35% or more. In addition, the first dissolution aid is 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% 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 or 5% or less It may be:

In one aspect of the invention, the third dissolution aid is cellulose gum (Cellulose gum), xanthan gum (Xanthan gum), sodium polyacrylate (Sodium Polyacrylate), hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxyethyl acrylic Group consisting of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer and polyacrylate-13/polyisobutene/polysorbate-20 It may be one or more selected from.

In one aspect of the present invention, the second dissolution aid 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 second 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, 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 or 5% or less It may be:

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

In one aspect of the invention, the second solubilizing agent, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxy Oxypropyl-γ-cyclodextrin.

In one aspect of the invention, the third dissolution aid is cellulose gum (Cellulose gum), xanthan gum (Xanthan gum), sodium polyacrylate (Sodium Polyacrylate), hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxyethyl acrylic Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, polyacrylate-13/polyisobutene/polysorbate-20, sodium magnesium 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, Polyvinylpirrolidone, Acrylate/C10-30 Alkyl Acrylate Crosspolymer ( Acrylic acid and alkyl methacrylate copolymer), adipic acid, neopentyl glycol crosspolymer, dimethicone, VP, VA copolymer, amodimethicone, ammonium acryloyldimethyltaurate/VP copolymer, carbomer, carrageenan , Seratonia silicqua gum, cyanopsis tetragonolova (Guar) gum, agar, potassium chloride and glucose, polyquaternium-7, polyquaternium-10, polyquaternium-67, cetyl hydroxyethylcellulose, di Hydroxanthan 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, 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, stearal Conium, hectorite, styrene, acrylate, ammonium methacrylate copolymer, tamarindise indica seed polysaccharide, VP, methacrylamide, vinyl imidazole copolymer, palmet-25 acrylate copolymer, VA copolymer, butylene Glycol, 1,2-hexanediol, caprylyl glycol, Tropolone, Mannan or Zea May (corn) starch, 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/H 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, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate co It may be a polymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) or polyacrylate-13/polyisobutene/polysorbate-20.

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, 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 or 5% or less It may be:

In one aspect of the present invention, the weight ratio of the solute, the first solubilizer, the second solubilizer and the third solubilizer may be 1: 10 to 200: 1 to 20: 1 to 20. In one embodiment, the weight ratio is 1:15 or more: 2 or more: 2 or more, 1:20 or more: 3 or more: 3 or more, 1:50 or more: 4 or more: 4 or more, 1:70 or more: 5 or more: 5 Or more or more than 1:90:6 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 dosage 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.

In another aspect, the present invention provides 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 spots, freckles, spots, and skin pigmentation A solute that is an acceptable salt, hydrate or solvate thereof; A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; A second dissolution aid that is a cyclodextrin; And cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( Composition comprising at least one third dissolution aid selected from the group consisting of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20. It may be related to a method for preventing, improving, or treating a disease related to skin whitening including administration of, for example, spots, freckles, spots, and skin pigmentation. 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; A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; A second dissolution aid that is a cyclodextrin; And cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and a third soluble adjuvant selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; It may be about

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; A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; A second dissolution aid that is a cyclodextrin; And cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and a third soluble adjuvant selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; It may be about

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; A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; A second dissolution aid that is a cyclodextrin; And cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and at least one third dissolution aid selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; The composition may relate to skin whitening use.

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; A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400; A second dissolution aid that is a cyclodextrin; And cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and at least one third dissolution aid selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; It may be related to the composition.

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.

[ Example 1 to 8] 5- Adamantane -1-yl-N-(2,4- Dihydroxybenzyl )-2,4- Dimethoxy -Benzoic acid amide (hereinafter, DBAB Preparation of dissolution aids to enhance the solubility of)

To identify a solubilizing agent that enhances the solubility of DBAB, 15% by weight of PEG/PPG-17/6 COPOLYMER (Konlub) and 20% by weight of 1,3-Propanediol (Fermandiol) as a first solubilizing agent, and a second solubilizing agent Hydroxypropyl cyclodextrin (hereinafter, CD, purchased from NIHON SHOKUHIN) 0.5% by weight and 1% by weight of Cellulose Gum (CMC) as a third solubilizing agent was added, and then the remaining content was filled with water to form a homomixer (Japan Primix, homomixer Mark 2 model) was uniformly stirred for 10 minutes at 3000 rpm. Then, DBAB was added and stirred for 20 minutes with a homomixer to mix to prepare Example 1.

The composition was prepared in the same manner as in Example 1, wherein the first dissolution aid was PEG-400 5% by weight, the second dissolution aid was 0.6% by weight of CD, and the type and content of the third dissolution aid was as follows. The compositions of Examples 2 to 8 were prepared.

Example 2: Hydroxypropyl methylcellulose (hereinafter referred to as HPMC) (Pharmacoat 630 HPMC) 1 wt%

Example 3: Sodium Polyacrylate 0.5% by weight

Example 4: Xanthan Gum 0.5 wt%

Example 5: Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer 0.5 wt%

Example 6: 0.5% by weight of Polyacrylate-13/Polyisobutene/Polysorbate-20

Example 7: HPMC (Pharmacoat 630 HPMC) 0.5% by weight

Example 8: HPMC (Methocel E4M) 0.5% by weight

[ Experimental Example 1] PEG/ PPG -17/6 COPOLYMER and 1,3- Propanediol 1st Solubilizer and Cellulose Gum Third Solubility test of solubilizers containing solubilizers

In order to confirm the solubilizing agent that enhances the solubility of DBAB, it was prepared in the same manner as in Example 1, but the first and second solubilizing agents were the same as in Example 1, and only the third solubilizing agent was hydroxyethylcellulose (Natrosol 250HR ) 1.0% by weight to prepare another Comparative Example 1, it was confirmed the solubility of Example 1 and Comparative Example 1. 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] PEG-400 1st Solubilizers and various types Third Solubility test of solubilizers containing solubilizers

To confirm the solubility aids that enhance the solubility of DBAB, the solubility of Examples 2 to 8 was confirmed.

First, it was confirmed that Example 2, comprising 5% by weight of PEG-400 as the first solubilizer and 0.6% by weight of CD as the second solubilizer, and 1% by weight of HPMC as the third solubilizer, was transparently dissolved.

In the case of Examples 3 to 8, wherein the types and contents of Example 2 and the first dissolution aid and the second dissolution aid are the same, but the content of the third dissolution aid is 0.5% by weight, which is half of Example 2, Example 3 (Third Solubilizer: Sodium Polyacrylate) has the best solubility, Examples 4 to 6 (Third Solubilizer is Xanthan Gum (Example 4), Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer (Example 5), Polyacrylate- 13/Polyisobutene/Polysorbate-20 (Example 6)) was also confirmed to be transparently dissolved. As the third solubilizing agent, HPMC containing HPMC, but unlike Example 2, the contents of Examples 7 and 8 having a content of 0.5% by weight were not excellent in solubility compared to Examples 3 to 6, but it was confirmed that DBAB was transparently dissolved (FIG. 1). ).

In addition, the types and contents of Examples 3 to 8 and the first dissolution aid and the second dissolution aid are the same, and the third dissolution aid contains 0.5% by weight, but the types of the third dissolution aid are respectively Sodium Magnesium Silicate (Compare Example 2), Bentonite (Comparative Example 3), Poloxamer 407 (Comparative Example 4), Hydroxypropyl Starch Phosphate (Comparative Example 5), PEG-240/HDI Copolymer Bis-Decyltetraceth-20 Ether (Comparative Example 6), Polyvinyl Alcohol (Comparative Example) Example 7), Magnesium Aluminum Silicate (Comparative Example 8), and the composition of Polyvinylpirrolidone (Comparative Example 9) was mixed with DBAB in the same manner as used in the above Examples to confirm the solubility. It was found that the precipitate had poor solubility.

[ Experimental Example 3] Check stability

As a result of confirming the stability of Examples 3 to 8, Example 3 was kept stable when stored in a constant temperature bath at 45° C. for 13 days.

[ Experimental Example 4] DBAB , 1st Solubilizer, 2nd Dissolution aids and Third Check the solubility according to the type and content of dissolution aid

To confirm the degree of enhancement of the solubility of DBAB according to the content of the first solubilizer, the second solubilizer and the third solubilizer, prepared in the same manner as in Example 1, but the first solubilizer was 5% by weight A composition comprising PEG/PPG-17/6 COPOLYMER (Konlub), 0.6% by weight of CD as a second solubilizer, and 0.5% by weight of HPMC (Pharmacoat 630 HPMC) as a third solubilizer (Example 9) As a result of preparing and confirming the solubility, it was confirmed that it dissolved transparently.

[ Experimental Example 5] DBAB , Third Solubility check according to the content of solubilizer

After adding 3.0% by weight of sodium polyacrylate as a third dissolution aid to 0.1% by weight of DBAB, the remaining content was filled with water to prepare a composition (Example 10), and the solubility was confirmed. It was confirmed that it was dissolved with a gel (Fig. 2).

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%
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%
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%
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%
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%
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%
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 in a conventional manner according to the composition shown in Table 4.

ingredient	Content (% by weight)
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%
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%
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%
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 are prepared in a conventional manner according to the composition shown in Table 6 below.

ingredient	Content (% by weight)
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%
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 (15)

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

   A first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;

   A second dissolution aid that is a cyclodextrin; And

   Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethylacrylate/Sodium acryloyldimethyltaurate copolymer (hydroxyethyl external preparation for skin comprising a third soluble adjuvant selected from the group consisting of acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 Composition:

   [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 of 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 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 polyethylene glycol / polypropylene glycol copolymer is PEG / PPG-17/6 copolymer (PEG/PPG-17/6 copolymer),

   The propylene glycol is 1,3-propanediol (1,3-propanediol), external composition for skin.
7. According to claim 1,

   The solute and the first solubilizing agent is a weight ratio of 1: 0.1 to 9900, the composition for external application for skin.
8. According to claim 1,

   The first dissolution aid is 0.1 to 99% by weight relative to the total weight of the composition, the composition for external application for skin.
9. According to claim 1,

   Cyclodextrin is at least one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin, skin Composition for external application.
10. According to claim 1,

    The second dissolution aid is 0.1 to 98% by weight relative to the total weight of the composition, the composition for external application for skin.
11. 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: 50 to 500: 1 to 20, the composition for external application for skin.
12. According to claim 1,

    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.
13. According to claim 1,

    The solute, the first solubilizer, the second solubilizer and the third solubilizer weight ratio is 1: 10 to 200: 1 to 20: 1 to 20 weight ratio, the composition for external application for skin.
14. The method according to any one of claims 1 to 13,

    The composition for external application for skin is a composition for skin whitening.
15. The method according to any one of claims 1 to 13,

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

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