KR102623441B1 - A composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

The present specification includes solutes that are benzoic acid amide compounds, isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof; A first solubilizing agent that is a glycyrrhizic acid derivative; The present invention relates to a composition for topical skin application comprising a second solubilizing agent that is glyceryl ether or polyethylene glycol/polypropylene glycol copolymer, and provides a composition for topical skin application with improved solubility.

Description

A composition comprising benzoic acid amide compound and solubilizer}

The present specification includes solutes that are benzoic acid amide compounds, isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof; and a solubility aid, wherein the composition relates to a composition characterized by improved solubility.

Melanin protects skin organs under the dermis by blocking ultraviolet rays in the epidermal layer and protects the skin by absorbing biological free radicals. Additionally, melanin is the main factor that determines skin color, so when it is present in excess, it is also the cause of skin pigmentation such as spots, freckles, and moles. Melanin is produced in melanocytes present in the basal layer of the skin, and its production is known to be promoted by stimuli such as ultraviolet rays or inflammation. Therefore, melanin production can be reduced by reducing external stimulation, blocking signal transmission, or inhibiting the synthesis or activity of tyrosinase, a melanin-producing enzyme. Currently, kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butylresorcinol, resveratrol, ceramide, sphingosine-1-phosphate, sphingosylphosphorylcholine, etc. promote the decomposition of tyrosinase or regulate glycation. It is known to be able to regulate melanin production. However, these have not been widely used due to unsatisfactory whitening effect, low stability, and skin irritation. Recently, benzoic acid amide substance with excellent whitening effect and few side effects has been studied.

Mulberry tree is a raw material used to traditionally manufacture Hanji, and has long been predicted to have a skin whitening effect because the hands of Hanji makers have been white and fair. Accordingly, scientific research has confirmed that mulberry roots contain kazinol, an ingredient with excellent whitening effects, and "mulberry extract" is also a substance notified by the Ministry of Food and Drug Safety as a functional cosmetic ingredient. Accordingly, the structure of Kazinol, a whitening effect component present in mulberry tree, was analyzed for functional groups that exhibit the whitening effect of Kazinol through molecular modeling techniques. In particular, in the case of Kazinol F, despite its excellent whitening effect, it exists in trace amounts in mulberry tree and has a structure that is easily decomposed by temperature, making it difficult to actually use it as a single ingredient.

Dihydroxybenzyl Adamantnyldimethoxybenzamide is one of over 100 derivatives manufactured by imitating the structure of Kazinol F, a trace component of paper mulberry, and its new structure was designed in consideration of efficacy, stability, and ease of manufacture through structure-activity relationship (QSAR) and 3D-QSAR. It is a compound. This compound reduces the expression of MITF, which is linked to the cAMP-PKA-CREB signal, and consequently inhibits the activity of tyrosinase, TRP-1, and TRP-2, which are key proteins related to melanin synthesis regulated by MITF, thereby inhibiting melanin synthesis. The mechanism of the new whitening effect was identified and confirmed using 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 studied a composition with improved solubility of the benzoic acid amide material and arrived at the present invention.

Korean Patent No. 10-1604053 US Patent No. 8697151 US Patent No. 9216145 Japanese Patent Publication No. 2011-528708 Japanese Patent Publication No. 2015-0120716 Korean Patent No. 10-1502533

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 derivative. Journal of the Korean Cosmetic Society. 2013 Volume 39, Number 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.

Focusing on the above problems, the inventors of the present invention studied a composition containing a solubility aid to improve the solubility of a composition containing a benzoic acid amide compound and arrived at the present invention.

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

One aspect of the present invention is a solute that is a compound of the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof;

A first solubilizing agent that is a glycyrrhizic acid derivative; and

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

[Formula 1]

In Formula 1 above,

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

Figure 1 is a photograph of Example 1 of the present invention.
Figure 2 is a photograph of Comparative Example 1 of the present invention.
Figure 3 is a photograph of Example 2 of the present invention.
Figure 4 is a photograph of Examples 3 to 5 of the present invention (DG in Figure 4 corresponds to Example 3, GA corresponds to Example 4, and MAG corresponds to Example 5).

Hereinafter, the present invention will be described in detail.

One aspect of the present invention is a solute that is a compound of the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof;

A first solubilizing agent that is a glycyrrhizic acid derivative; and

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

[Formula 1]

In Formula 1 above,

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 selected from hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ halo. independently selected from the group consisting of alkoxy,

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

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

In one aspect of the invention, the solute is

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

5-adamantane-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxy-benzoic acid amide and

Compounds selected from the group consisting of 5-adamantane-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide, isomers thereof, and pharmaceutically acceptable compounds thereof. It may be a possible salt, a hydrate thereof, or a solvate thereof.

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 solute may be included in an amount of 0.01% by weight to 20% by weight based on 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. % or less, 15 weight% or less, 10 weight% or less, or 5 weight% or less. Specifically, it may be 0.02 to 10% by weight, and more specifically, it may be 0.02 to 5% by weight. When included within the above range, it is not only appropriate to achieve the intended effect of the present invention, but also satisfies both stability and safety of the composition, and it may also be appropriate to include within the above range in terms of cost-effectiveness. Specifically, if it is less than 0.01% by weight, sufficient skin whitening effect cannot be obtained, and if it exceeds 20% by weight, it may be undesirable due to low cost-effectiveness.

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

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

In one aspect of the present invention, the solute and the first solubilizing agent may have a weight ratio of 1:0.01 to 9990. In one embodiment, the solute and the first solubilizing agent are 1:0.01 or more, 1:0.05 or more, 1:0.1 or more, 1:0.5 or more, 1:1 or more, 1:1.5 or more, 1:2.0 or more, 1: 5 or greater, 1:10 or greater, 1:30 or greater, 1:50 or greater, 1:80 or greater, 1:100 or greater, 1:200 or greater, 1:500 or greater, 1:800 or greater, 1:1000 or greater, 1: It may be 1500 or more, 1:2000 or more, 1:3000 or more, or 1:5000 or more. Also, 1:9990 or less, 1:9900 or less, 1:9800 or less, 1:9500 or less, 1:9000 or less, 1:8000 or less, 1:7500 or less, 1:7000 or less, 1:5000 or less, 1:3000 or less. Below, 1:1000 or below, 1:700 or below, 1:500 or below, 1:450 or below, 1:350 or below, 1:250 or below, 1:200 or below, 1:150 or below, 1:100 or below, 1:80 It may be 1:50 or less, 1:40 or less, 1:30 or less, 1:20 or less, 1:10 or less, or 1:5 or less. Specifically, the solute and the first solubilizing agent may have a weight ratio of 1:1 to 700.

In one aspect of the present invention, the first solubilizing agent 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 first solubilizing agent is present in an amount of 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, 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 more, 3% by weight or more, 4% by weight or more, 5% by weight or more, 6% by weight or more , it may be 10% by weight or more, 20% by weight or more, 30% by weight or more, or 35% by weight or more. In addition, the first solubilizing agent is present in an amount of 99% 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% 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% by weight or less, 0.9% by weight or less. It may be 0.8 weight% or less, 0.7 weight% or less, or 0.6 weight% or less.

In one aspect of the present invention, the composition for external application for skin may include a second solubilizing agent that is glyceryl ether or polyethylene glycol/polypropylene glycol copolymer. Specifically, the first solubilizing agent, a glycyrrhizic acid derivative, may be included in an amount of 0.01% by weight or more and 98% by weight or less, and more specifically, 0.01% by weight or more, 0.02% by weight or more, and 0.04% by weight or more. % by weight or more, 0.06% by weight or more, 0.08% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 1.5% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 5 It may be more than % by weight, more than 6% by weight, more than 10% by weight, more than 20% by weight, more than 30% by weight, or more than 35% by weight, and less than 98% by weight, less than 95% by weight, less than 90% by weight, less than 85% by weight. , 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% 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. , may be 4% by weight or less, 3% by weight or less, 2% by weight or less, or 1% by weight or less.

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

In one aspect of the present invention, the second solubilizing agent may be included in an amount of 0.01 to 98% by weight based on the total weight of the composition. In one embodiment, the second solubilizing agent is present in an amount of 0.01% by weight or more, 0.02% by weight or more, 0.04% by weight or more, 0.06% by weight or more, 0.08% by weight or more, 0.1% by weight or more, 0.2% by weight or more. , 0.3% by weight or more, 0.4% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 5% by weight or more, 6% by weight or more, 7% by weight or more , it may be 8% by weight or more, 9% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, or 35% by weight or more. In addition, the second dissolution aid is 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% 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. 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% by weight or less, 0.9% by weight or less , may be 0.8 wt% or less, 0.7 wt% or less, or 0.6 wt% or less.

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

In one aspect of the present invention, the composition for external application for skin includes cyclodextrin, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose. Ethyl acrylate/sodium acryloyldimethyl taurate copolymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and Polyacrylate-13/Polyisobutene/Polysorbate-20 It may further include one or more third solubilizing agents selected from the group consisting of Specifically, the first solubilizing agent, a glycyrrhizic acid derivative, may be included in an amount of 0.01% by weight or more and 98% by weight or less, and more specifically, 0.01% by weight or more, 0.02% by weight or more, and 0.04% by weight or more. % by weight or more, 0.06% by weight or more, 0.08% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 1.5% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 5 It may be more than % by weight, more than 6% by weight, more than 10% by weight, more than 20% by weight, more than 30% by weight, or more than 35% by weight, and less than 98% by weight, less than 95% by weight, less than 90% by weight, less than 85% by weight. , 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% 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. , may be 4% by weight or less, 3% by weight or less, 2% by weight or less, or 1% by weight or less.

In one aspect of the present invention, the third solubilizing agent is cyclodextrin, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, Polyacrylate-13/Polyisobutene/Polysorbate-20 , Sodium Magnesium Silicate, Bentonite, Poloxamer 407, Hydroxypropyl Starch Phosphate, PEG-240/HDI Copolymer Bis-decyltetraceth-20 Ether (PEG-240/HDI Copolymer Bis-Decyltetraceth-20 Ether), Polyvinyl Alcohol, Magnesium Aluminum Silicate, Polyvinylpirrolidone, 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, carbo Mer, carrageenan, Ceratonia siliqua gum, Siamopsis tetragonolova (Guar) gum, agar, potassium chloride and glucose, polyquaternium-7, polyquaternium-10, polyquaternium-67, cetyl hydroxyethyl. Cellulose, dihydroxanthan gum, dextrin myristate, gellan gum, glycerin, glyceryl acrylate, acrylic acid copolymer, hydrolyzed wheat protein.PVP crosspolymer, isononanoyl diglytherin, dilinoleic acid copolymer, lauryl. Dimethicone, polyglycerin-3 copolymer, polymethylsilsquioxane, phenoxyethanol, chlorphenesin, caprylic glycol, mannan, Olea Europaea (olive) oil, butadiene, styrene copolymer, PEG -240/HDI copolymer bis-decyltetraceth-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-laureth-5, stearalkonium, hectorite, Styrene, acrylate, ammonium methacrylate copolymer, Tamarindus indica seed polysaccharide, VP, methacrylamide, vinyl imodazole copolymer, palmet-25 acrylate copolymer, VA copolymer, butylene glycol, 1,2 -It may be hexanediol, caprylyl glycol, Tropolone, Mannan or Zea May (corn) starch, cellulose gum; xanthan gum; sodium polyacrylate; hydroxypropylmethylcellulose; Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer; polyacrylate-13/polyisobutin/polysorbate-20; sodium magnesium silicate; bentonite; poloxamer 407; Hydroxypropyl Starch Phosphate; PEG-240/HDI copolymer bis-decyltetraceth-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 siliqua gum/Siamopsis tetragonolova (Guar) gum/agar/potassium chloride and glucose; polyquaternium-7; polyquaternium-10; polyquaternium-67; cetyl hydroxyethylcellulose; dihydroxanthan gum; Dextrin myristate; gellan gum; Glycerin/glyceryl acrylate/acrylic acid copolymer; Hydrolyzed wheat protein.PVP crosspolymer; isononanoyl diglytherin; Dilinoleic acid copolymer; Lauryl dimethicone/polyglycerin-3 copolymer/polymethylsilsquioxane/phenoxyethanol/chlorphenesin/caprylic glycol; met; Olea europaea (olive) oil, butadiene/styrene copolymer; Polyacrylamide/C13-14isoparaffin/Laureth-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-laureth-5; stearalkonium; hectorite; styrene/acrylate/ammonium methacrylate copolymer; Tamarindus indica seed polysaccharide; VP/methacrylamide/vinyl imodazole copolymer; Acrylate/palmet-25 acrylate copolymer; It may be ethylene/VA copolymer, butylene glycol, 1,2-hexanediol, caprylyl glycol, Tropolone, or Zea May (corn) starch. Specifically, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyl taurate It may be a polymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) or Polyacrylate-13/Polyisobutene/Polysorbate-20.

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

In one aspect of the present invention, the third solubilizing agent 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 solubilizing agent is present in an amount of at least 0.1% by weight, at least 0.5% by weight, at least 1% by weight, at least 2% by weight, at least 3% by weight, at least 4% by weight, and at least 5% by weight, based on the total weight of the composition. , 6% by weight or more, 7% by weight or more, 8% by weight or more, 9% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, or 35% by weight or more. In addition, the third solubilizing agent is present in an amount of 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. 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. It may be 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less, or 5 wt% or less.

In one aspect of the present invention, the weight ratio of the solute, the first solubilizing agent, the second solubilizing agent, and the third solubilizing agent may be 1: 1 to 200: 1 to 20: 1 to 20. In one embodiment, the weight ratio is 1:1 or more:2 or more:2 or more, 1:1 or more:3 or more:3 or more, 1:1 or more:4 or more:4 or more, 1:1 or more:5 or more:5 It may be more than or 1:1 or more:6 or more:6 or more. In addition, the weight ratio is 1:150 or less:15 or less:15 or less, 1:140 or less:13 or less:13 or less, 1:130 or less:11 or less:11 or less, 1:110 or less:10 or less:10 or less, 1 :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 skin application can exhibit an excellent skin whitening effect, and can specifically improve or prevent blemishes, freckles, moles, and skin pigmentation.

In another aspect of the present invention, the external skin 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 specification can be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing agents. , oil, powder foundation, emulsion foundation, wax foundation, spray, etc., but is not limited thereto.

In one aspect of the present invention, the composition may be a pharmaceutical composition. The pharmaceutical composition can exhibit an excellent skin whitening effect and can specifically improve or treat blemishes, freckles, moles, 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, etc. Formulations for parenteral administration may be solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches, or sprays, but are not limited thereto. The formulation can be easily prepared according to conventional methods in the field, and contains surfactants, excipients, wetting agents, emulsification accelerators, suspending agents, salts or buffers for adjusting osmotic pressure, colorants, flavorings, stabilizers, preservatives, preservatives or Other commonly used supplements can be used appropriately.

The active ingredient of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, gender, weight, pathological condition and severity of the subject to be administered, route of administration, or the judgment of the prescriber. Determination of the application amount based on these factors is within the level of one 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. /It may be work, but is not limited to this.

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

[ Manufacturing example ] 5- Adamantane -1-day-N-(2,4- dihydroxybenzyl )-2,4- Dimethoxy -Benzoic acid amide (hereinafter, DBAB ) Manufacture of solubility aids that improve the solubility of

In order to identify a solubilizing agent that improves the solubility of DBAB, 5% by weight of Dipotassium Glycyrrhizate (hereinafter referred to as DG, purchased from Maruzen Pharmaceuticals Co., Ltd.) was used as the first solubilizing agent, and Glycereth-26 (Dongnam) was used as the second solubilizing agent. After adding 10% by weight of Xanthan gum (CP KELCO) as a third dissolution aid and 0.5% by weight of It was stirred to make it uniform. Afterwards, 0.1% by weight of DBAB was added and mixed by stirring with a homomixer for 20 minutes to prepare Example 1.

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

A composition was prepared in the same manner as in Example 1, except that the type and content of the first solubilizing agent were as follows, the second solubilizing agent was 40% by weight of PEG/PPG-17/6 copolymer (Konlub), and the third solubilizing agent was prepared the compositions of Examples 3 to 5 containing 0.6% by weight of hydroxypropyl cyclodextrin (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 Glycyrrhizate (hereinafter referred to as MAG, purchased from Maruzen Pharmaceuticals Co., Ltd.) 0.1% by weight

[ Experiment example One] Dipotassium Glycyrrhizate 1st Solubilizing agent, Glycereth -26 second solubilizing agent and of xanthan gum 3rd Solubility test of solubility aids including solubility aids

In order to identify a solubility aid that improves the solubility of DBAB, it was prepared in the same manner as in Example 1, except that the second and third solubilizers were the same as in Example 1, and only the first solubility agent contained 1% by weight of DG. Another Comparative Example 1 was prepared, and the solubility of Example 1 and Comparative Example 1 was confirmed. As a result, Example 1 was dissolved transparently (Figure 1), but Comparative Example 1 did not dissolve transparently, indicating that the solubility was poor.

[ Experiment example 2] Dipotassium Glycyrrhizate 1st Solubilizer, PEG/ PPG -17/6 copolymer 2nd Solubility test of solubility aids including solubility aids

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

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

[ Experiment example 3] Dipotassium Glycyrrhizate , Glycyrrhizic Acid or Monoammonium Glycyrrhizate 1st Solubilizer, PEG/ PPG -17/6 copolymer 2nd Solubilizers and of cyclodextrin 3rd Solubility test of solubility aids including solubility aids

In order to identify a solubility aid that improves the solubility of DBAB, the solubilities of Examples 3 to 5 were checked, and the results showed that each contained 0.1% by weight of DG, GA, or MAG as the first solubility aid, and PEG/MAG as the second solubility aid. It was confirmed that Examples 3 to 5 containing 15% by weight of PPG-17/6 copolymer and 0.6% by weight of CD as a third solubilizing agent were transparently dissolved (FIG. 4).

Through this, it was found that the first solubilizing agents, DG, GA, and MAG, had similar solubilities to DBAB. In addition, it was confirmed that the contents of the first to third solubility aids of the present invention have a complementary effect in that increasing the content of the component that increases solubility can lower other components.

[ Experiment example 4] Check stability

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

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

[ Formulation example 1] Soft lotion

Soft lotion was prepared in a conventional manner according to the composition shown in Table 1 below.

ingredient Content (% by weight) DBAB 0.1% by weight DG 5.0% by weight Xanthan gum 0.5% by weight Glycereth-26 10% by weight PEG-30 hydrogenated castor oil 1.2% by weight ethanol 5.0% by weight Butylene glycol 2.0% by weight propylene glycol 2.0% by weight Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[ Formulation example 2] Nutritional lotion ( milk Lotion)

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

ingredient Content (% by weight) DBAB 0.1% by weight DG 5.0% by weight Xanthan gum 0.5% by weight Glycereth-26 10% by weight PEG-30 hydrogenated castor oil 2.0% by weight glycerin 3.0% by weight Butylene glycol 3.0% by weight propylene glycol 3.0% by weight Carboxy 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, flavoring Appropriate amount Purified water remaining amount

[ Formulation example 3] Nutrition cream

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

ingredient Content (% by weight) DBAB 0.1% by weight DG 5.0% by weight Xanthan gum 0.5% by weight Glycereth-26 10% by weight PEG-30 hydrogenated castor oil 3.0% by weight glycerin 3.0% by weight Butylene glycol 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 Glucoside 1.5% by weight Sorbitan Stearate 0.4% by weight Triethanolamine 0.1% by weight Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[ Formulation example 4] Massage Cream

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

ingredient Content (% by weight) DBAB 0.1% by weight DG 5.0% by weight Xanthan gum 0.5% by weight Glycereth-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 Butylene glycol 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 Glucoside 1.5% by weight Sorbitan sesquioleate 0.9% by weight Vaseline 3.0% by weight paraffin 1.5% by weight Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[ Formulation example 5] Pack

The pack is manufactured by a conventional method according to the composition shown in Table 5 below.

ingredient Content (% by weight) DBAB 0.1% by weight DG 5.0% by weight Xanthan gum 0.5% by weight Glycereth-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, flavoring Appropriate amount Purified water remaining amount

[ Formulation example 6] Ointment

An ointment is prepared by a conventional method according to the composition shown in Table 6 below.

ingredient Content (% by weight) DBAB 0.1% by weight DG 5.0% by weight Xanthan gum 0.5% by weight Glycereth-26 10% by weight PEG-30 hydrogenated castor oil 3.0% by weight Vitamin E Acetate 4.0% by weight Butylene glycol 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 Glucoside 1.5% by weight Sorbitan Stearate 0.4% by weight cetearyl alcohol 1.0% by weight beeswax 4.0% by weight Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

Claims (18)

5-adamantane-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide, its isomer, pharmaceutically acceptable salt thereof, hydrate or solvate thereof phosphorus solute;
A first solubilizing agent that is a glycyrrhizic acid derivative; and
Contains a second solubilizing agent that is glyceryl ether or polyethylene glycol/polypropylene glycol copolymer,
The glycyrrhizic acid derivative is at least one selected from the group consisting of Dipotassium Glycyrrhizate, Glycyrrhizic Acid, and Monoammonium Glycyrrhizate,
The composition for external application for skin, wherein the solute and the first solubilizing agent are in a weight ratio of 1:1 to 50.
delete delete delete According to clause 1,
A composition for external application for skin, wherein the solute is contained in an amount of 0.01% by weight to 20% by weight based on the total weight of the composition.
delete According to clause 1,
A composition for external application for skin, wherein the first solubilizing agent is 0.01 to 99% by weight based on the total weight of the composition.
delete According to clause 1,
The glyceryl ether is Glycereth-26 or Glycereth-12, a composition for external application for skin.
According to clause 1,
The polyethylene glycol/polypropylene glycol copolymer is a PEG/PPG-17/6 copolymer (PEG/PPG-17/6 copolymer).
According to clause 1,
A composition for external application for skin, wherein the second solubilizing agent is 0.01 to 98% by weight based on the total weight of the composition.
According to clause 1,
The weight ratio of the solute, the first solubilizing agent, and the second solubilizing agent is 1:1 to 50:1 to 20.
According to clause 1,
The skin external composition includes cyclodextrin, cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, and hydroxyethyl acrylate/sodium acrylate. At least one agent selected from the group consisting of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer and Polyacrylate-13/Polyisobutene/Polysorbate-20. 3. A composition for external use on the skin, further comprising a solubilizing agent.
According to clause 13,
The cyclodextrin is any one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin, Composition for external application to the skin.
According to clause 13,
A composition for external application for skin, wherein the third solubilizing agent is 0.1 to 98% by weight based on the total weight of the composition.
According to clause 13,
The weight ratio of the solute, the first solubilizing agent, the second solubilizing agent, and the third solubilizing agent is 1: 1 to 50: 1 to 20: 1 to 20.
According to any one of claims 1, 5, 7 and 9 to 16,
The composition for external application for skin is a composition for skin whitening.
According to any one of claims 1, 5, 7 and 9 to 16,
The composition for external application to the skin is a cosmetic composition.