KR102506882B1 - A composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

In the present specification, 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 selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400; a second solubilizing agent which is a cyclodextrin; and cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer and polyacrylate-13/polyisobutin/polysorbate-20. It relates to a composition for external application for skin comprising at least one third solubilizing agent selected from the group consisting of, and provides a composition for external application for skin with improved solubility.

Description

A composition comprising a benzoic acid amide compound and a solubilizer

The present specification is a solute which is a benzoic acid amide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; And a composition for external application for skin comprising a solubilizing agent, wherein the composition has 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. In addition, since melanin is a major factor determining the color of the skin, it is also a cause of skin pigmentation such as melasma, freckles, and dots when present in excess. Melanin is produced in melanocytes present in the basal layer of the skin, and it is known that its production is promoted by stimuli such as ultraviolet rays or inflammation. Therefore, it is possible to reduce the production of melanin by reducing external stimuli, blocking signal transmission, or inhibiting the synthesis or activity of tyrosinase, a melanin-producing enzyme. Currently, kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butylesorcinol, resveratrol, ceramide, sphingosine-1-phosphate, and sphingosylphosphorylcholine promote the breakdown of tyrosinase or regulate glycosylation. It is known that it can regulate melanin production. However, their utilization was not high because of their unsatisfactory whitening effect, low stability, and skin irritation. Recently, benzoic acid amide materials with excellent whitening effect and few side effects have been studied.

Paper mulberry is traditionally a raw material for manufacturing Korean paper, and it has been predicted that it will have a skin whitening effect because the hands of people who make Korean paper have been white and tender. Accordingly, scientific research has confirmed that the mulberry root contains kazinol, a component with excellent whitening effect, and "mulberry extract" is also a substance notified by the Ministry of Food and Drug Safety as a raw material for functional cosmetics. Accordingly, functional groups representing the whitening effect of Kazinol were analyzed through molecular modeling techniques for the structure of Kazinol, which is a whitening effect component present in paper mulberry. In particular, in the case of Kazinol F, despite its excellent whitening effect, it is present in a small amount in mulberry trees and has a structure that is easily decomposed by temperature, making it difficult to use as a single component in practice.

Dihydroxybenzyl Adamantnyldimethoxybenzamide is a newly designed structure in consideration of efficacy, stability, and ease of manufacture through structural activity relationship (QSAR) and 3D-QSAR among 100 derivatives manufactured by mimicking the structure of Kazinol F, a trace component of paper mulberry. is a compound This compound reduces the expression of MITF linked to the cAMP-PKA-CREB signal and consequently inhibits the activity of tyrosinase, TRP-1 and TRP-2, which are major proteins in relation to the melanin synthesis regulated by MITF, thereby inhibiting melanin synthesis. The mechanism of the novel whitening effect was identified, and it was confirmed through cells and artificial skin.

However, there has been no study to improve the solubility of the composition containing the benzoic acid amide material, and the researchers of the present invention have studied a composition with improved solubility of the benzoic acid amide material to reach the present invention.

KR10-1604053 B1 US8697151 B2 US9216145 B2 JP2011-528708 A JP2015-0120716 A KR10-1502533 B1

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 studied a composition containing a solubilizing agent for improving the solubility of a composition containing a benzoic acid amide compound and came to the present invention.

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 is a solute which is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and

a first solubilizing agent selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400;

a second solubilizing agent which is a cyclodextrin; and

Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethyl Acrylate/Sodium Acryloyldimethyltaurate Copolymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 (Polyacrylate-13/Polyisobutene/Polysorbate-20). A composition is provided:

[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 a benzoic acid amide compound as a solute, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The composition according to one aspect of the present invention does not precipitate a solute, benzoic acid amide compound, has excellent solubility and 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 is a solute which is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and

a first solubilizing agent selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400;

a second solubilizing agent which is a cyclodextrin; and

Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethyl Acrylate/Sodium Acryloyldimethyltaurate Copolymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 (Polyacrylate-13/Polyisobutene/Polysorbate-20). A composition is provided:

[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 present invention, R ₁ , R ₃ and R ₄ in 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;

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

In one aspect of the present 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-adamantane-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

A compound selected from the group consisting of 5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide, an isomer thereof, and a pharmaceutically acceptable compound thereof possible salts thereof, hydrates thereof, or solvates 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% to 20% by weight based on the total weight of the composition. The solute of the present invention may be 0.01% by weight or more, 0.02% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 5% by weight or more, or 10% by weight or more based on the total weight of the composition. % 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, it may be 0.02 to 5% by weight. When included in the above range, it is suitable not only to exhibit the intended effect of the present invention, but also to satisfy both the stability and safety of the composition, and it may be appropriate to include it in the above range in terms of cost effectiveness. Specifically, when it is less than 0.01% by weight, sufficient skin whitening effect cannot be obtained, and when it exceeds 20% by weight, cost effectiveness is low, which may be undesirable.

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 at least one selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400. Specifically, the first solubilizing agent may include both polyethylene glycol/polypropylene glycol copolymer and propylene glycol, and may include polyethylene glycol-400. The polyethylene glycol/polypropylene glycol copolymer, which is the first solubilizing agent, is a PEG/PPG-17/6 copolymer, and propylene glycol is a 1,3 -It may be propanediol (1,3-propanediol).

In one aspect of the present invention, the solute and the first solubilizing agent may have 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. Also, 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 1:700 or less, 1:500 or less, 1:450 or less, 1:350 or less, 1:250 or less, 1:200 or less, 1:150 or less, 1:100 or less, 1:80 or less, 1:50 or less, 1:40 or less, 1:30 or less, 1:20 or less, 1:10 or less, or 1:5 or less. Specifically, the solute and the first solubilizing agent may have a weight ratio of 1:50 to 700.

In one aspect of the present invention, the first solubilizing agent 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 solubilizing aid is present in an amount of 0.1% 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, or 5% by weight or more based on the total weight of the composition. , 6 wt% or more, 10 wt% or more, 20 wt% or more, 30 wt% or more, or 35 wt% or more. In addition, the first solubilizing 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% 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% may be below.

In one aspect of the present invention, the third solubilizing agent is cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate A group consisting of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer and polyacrylate-13/polyisobutene/polysorbate-20 (Polyacrylate-13/Polyisobutene/Polysorbate-20) It may be one or more selected from.

In one aspect of the present invention, the second 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 second solubilizing aid is present in an amount of 0.1% 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, or 5% by weight or more based on the total weight of the composition. , 6 wt% or more, 10 wt% or more, 20 wt% or more, 30 wt% or more, or 35 wt% or more. In addition, the second solubilizing 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 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% may be below.

In one aspect of the present invention, the weight ratio of the solute, the first solubilizing agent and the second solubilizing agent may be 1:50 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 1:80 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 second solubilizing agent cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin It may be any one or more of hydroxypropyl-γ-cyclodextrins.

In one aspect of the present invention, the third solubilizing agent is cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, Polyacrylate-13/Polyisobutene/Polysorbate-20, Sodium Magnesium 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, 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 , Seratonia siliqua gum, Cyamopsis tetragonoloba (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-decyltetracese-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, Stearal Conium, Hectorite, Styrene, Acrylates, Ammonium Methacrylate Copolymer, Tamarindus Indica Seed Polysaccharide, VP, Methacrylamide, Vinyl Imodazole Copolymer, Palmet-25 Acrylate Copolymer, VA Copolymer, Butylene It may be glycol, 1,2-hexanediol, caprylyl glycol, Tropolone, Mannan or Zea May (corn) starch, cellulose gum; xanthan gum; sodium polyacrylate; hydroxypropylmethylcellulose; hydroxyethyl acrylate/sodium acryloyldimethyltaurate 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; Acrylates/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 Silicua Gum/Ciamopsis Tetragonoloba (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/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 copolymers; Tamarindus indica seed polysaccharide; VP/methacrylamide/vinyl imodazole copolymer; acrylate/palmet-25 acrylate copolymer; 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 acryloyldimethyltaurate co It may be a polymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) or polyacrylate-13/polyisobutene/polysorbate-20 (Polyacrylate-13/Polyisobutene/Polysorbate-20).

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 aid is 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, or 5 wt% or more based on the total weight of the composition. , 6% 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 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 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% may be below.

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: 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 1:90 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 application for skin may exhibit an excellent skin whitening effect, and specifically, it may improve or prevent melasma, freckles, moles, 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 present invention, the composition may be a cosmetic composition. The cosmetic composition of the present specification may be prepared in any formulation commonly prepared in the art, for example, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing , It 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 can exhibit an excellent skin whitening effect, and can specifically improve or treat melasma, freckles, dots, 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, or the like. 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 a conventional method in the art, and may include surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for adjusting osmotic pressure, coloring agents, spices, stabilizers, preservatives, preservatives, or Other commercially available adjuvants can be suitably used.

The active ingredient of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, sex, weight, pathological condition 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, and its daily administration dose 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, but is not limited to.

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 being limited by these examples.

[ Example 1 to 8] 5- Adamantane -1-day-N-(2,4- dihydroxybenzyl )-2,4- dimethoxy - Benzoic acid amide (hereinafter, DBAB ) Manufacture of solubility aids that enhance the solubility of

In order 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) were used as the first solubilizing agent, and the second solubilizing agent After adding 0.5% by weight of raw hydroxypropyl cyclodextrin (hereinafter CD, purchased from NIHON SHOKUHIN) and 1% by weight of Cellulose Gum (CMC) as a third solubilizing agent, the remaining content was filled with water and mixed with a homomixer (Primix, Japan). A homomixer Mark 2 model) was thoroughly stirred at 3000 rpm for 10 minutes to make it uniform. After that, DBAB was added and mixed by stirring with a homomixer for 20 minutes to prepare Example 1.

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

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

Example 3: Sodium Polyacrylate 0.5% by weight

Example 4: Xanthan Gum 0.5% by weight

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

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

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 No. 1 of solubility aids and cellulose gum (Cellulose Gum) 3rd Solubility test of dissolution aids including dissolution aids

In order to confirm a solubility adjuvant that enhances the solubility of DBAB, it is prepared in the same manner as in Example 1, but the first solubility adjuvant and the second solubility adjuvant are the same as in Example 1, and only the third solubility adjuvant is Hydroxyethylcellulose (Natrosol 250HR ) 1.0% by weight of Comparative Example 1 was prepared, and the solubility of Example 1 and Comparative Example 1 was confirmed. As a result, it was found that Example 1 was transparently dissolved (FIG. 1), but Comparative Example 1 was not transparently dissolved and thus had poor solubility.

[ Experimental example 2] of PEG-400 No. 1 Solubilizers and various types of 3rd Solubility test of dissolution aids including dissolution aids

In order to confirm a solubilizing agent that enhances the solubility of DBAB, the solubility of Examples 2 to 8 was confirmed.

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

In the case of Examples 3 to 8, in which the type and content of the first solubilizing agent and the second solubilizing agent are the same as those of Example 2, but the content of the third solubilizing agent is 0.5% by weight, which is half of Example 2, Example 3 (Third solubility aid: Sodium Polyacrylate) has the best solubility, and in Examples 4 to 6 (the third solubility aid 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. Examples 7 and 8 containing HPMC as the third solubilizing agent but containing 0.5% by weight, unlike Example 2, did not have excellent solubility compared to Examples 3 to 6, but it was confirmed that DBAB melted transparently (FIG. 1). ).

In addition, the type and content of the first solubilizing agent and the second solubilizing agent are the same as those of Examples 3 to 8, and the third solubilizing agent is included at 0.5% by weight, but the type of the third solubilizing agent is Sodium Magnesium Silicate (comparison). 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 6) Example 7), Magnesium Aluminum Silicate (Comparative Example 8), and Polyvinylpirrolidone (Comparative Example 9) were mixed with DBAB in the same way as in the above Example to confirm the solubility. As a result, Comparative Examples 2 to 9 did not melt transparently or It was found that it precipitated and the solubility was not good.

[ Experimental example 3] Check stability

As a result of confirming the stability of Examples 3 to 8, Example 3 remained stable when stored in a thermostat at 45 ° C for 13 days.

[ Experimental example 4] DBAB , No. 1 solubilizer, No. 2 Solubilizer and 3rd Solubility check according to type and content of solubilizing agent

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

[ Experimental example 5] DBAB , 3rd Solubility confirmation according to the content of the solubilizing agent

After adding 3.0% by weight of sodium polyacrylate as a third solubilizing agent to 0.1% by weight of DBAB, a composition (Example 10) was prepared by filling the remaining content with water, and as a result of checking the solubility, DBAB particles were not visible. It was confirmed that it was dissolved as a non-gel (Fig. 2).

Hereinafter, formulation examples 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 be specifically described.

[ formulation example 1] Soft lotion

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

ingredient Content (% by weight) DBAB 0.1% by weight PEG-400 5.0% by weight HPMC 1.0% by weight CD 0.6% 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, Colors, Flavors Appropriate amount Purified water balance

[ formulation example 2] Nutrition lotion ( milk Lotion)

Nutrition 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 PEG-400 5.0% by weight HPMC 1.0% by weight CD 0.6% 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 carboxyvinyl 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, Colors, Flavors Appropriate amount Purified water balance

[ formulation example 3] Nourishing Cream

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

ingredient Content (% by weight) DBAB 0.1% by weight PEG-400 5.0% by weight HPMC 1.0% by weight CD 0.6% 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, Colors, Flavors Appropriate amount Purified water balance

[ formulation example 4] Massage Cream

A massage cream was prepared in a conventional manner according to the composition shown in Table 4 below.

ingredient Content (% by weight) DBAB 0.1% by weight PEG-400 5.0% by weight HPMC 1.0% by weight CD 0.6% 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 Sesquioleate Sorbitan 0.9% by weight Vaseline 3.0% by weight paraffin 1.5% by weight Preservatives, Colors, Flavors Appropriate amount Purified water balance

[ formulation example 5] Pack

A pack was prepared by a conventional method according to the composition shown in Table 5 below.

ingredient Content (% by weight) DBAB 0.1% by weight PEG-400 5.0% by weight HPMC 1.0% by weight CD 0.6% 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, Colors, Flavors Appropriate amount Purified water balance

[ formulation example 6] Ointment

An ointment was prepared in a conventional manner according to the composition shown in Table 6 below.

ingredient Content (% by weight) DBAB 0.1% by weight PEG-400 5.0% by weight HPMC 1.0% by weight CD 0.6% 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, colors, flavors Appropriate amount Purified water balance

Claims (15)

As a composition for external application for skin, the composition for external application for skin
5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvent thereof solutes as cargo;
a first solubilizing agent selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400;
a second solubilizing agent which is a cyclodextrin; and
Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethyl Acrylate/Sodium Acryloyldimethyltaurate Copolymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 (Polyacrylate-13/Polyisobutene/Polysorbate-20).
The composition for external application for skin is a cosmetic composition for external application for skin.
delete delete delete According to claim 1,
The solute is contained in 0.01% to 20% by weight based on the total weight of the composition, the composition for external application for skin.
According to claim 1,
The polyethylene glycol/polypropylene glycol copolymer is a PEG/PPG-17/6 copolymer,
The propylene glycol is 1,3-propanediol, a composition for external application for skin.
According to claim 1,
The solute and the first solubilizing agent are 1: weight ratio of 0.1 to 9900, composition for external application for skin.
According to claim 1,
The first solubilizing agent is 0.1 to 99% by weight based on the total weight of the composition, the composition for external application for skin.
According to claim 1,
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 use.
According to claim 1,
The second solubilizing agent is 0.1 to 98% by weight based on the total weight of the composition, external composition for skin.
According to claim 1,
The weight ratio of the solute, the first solubilizing agent and the second solubilizing agent is 1: 50 to 500: a weight ratio of 1 to 20, composition for external application for skin.
According to claim 1,
The third solubilizing agent is 0.1 to 98% by weight based on the total weight of the composition, the composition for external application for skin.
According to claim 1,
The weight ratio of the solute, the first solubilizing agent, the second solubilizing agent and the third solubilizing agent is 1: 10 to 200: 1 to 20: a weight ratio of 1 to 20, composition for external application for skin.
The method of any one of claims 1 and 5 to 13,
The composition for external application for skin is a composition for skin whitening. delete

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