TWI737825B - Composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

The present disclosure relates to a composition for external application for skin containing 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 first solubilizer which is one or more of diethylene glycol monoethyl ether, methyl gluceth, glyceryl ether, polyethylene glycol, and polyethylene glycol/polypropylene glycol copolymer, and it provides a composition for external application for skin improved in solubility and feel of use.

Description

Composition containing benzoic acid amide compound and solubilizer

The present disclosure relates to a composition for external use on the skin, which includes a benzoic acid amide compound, an isomer of the compound, a pharmaceutically acceptable salt of the compound, and the compound The hydrate or the solvate of the compound; and a solubilizer, and the composition has improved solubility.

Melanin protects the skin organs under the dermis by blocking ultraviolet rays in the epidermis, and it protects the skin by absorbing free radicals in the body. In addition, melanin is the main factor determining skin color, and when it exists in excess, it will cause pigmentation such as melasma, freckle and facial moles. Melanin is caused by melanocytes in the basal layer of the skin, and the stimulation of ultraviolet light or inflammation can promote its production. Therefore, the production of melanin can be reduced by reducing external stimuli, as well as signal transmission blocking, synthesis inhibition or activity inhibition of the melanin-producing enzyme tyrosinase. Recently, kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butylresorcinol are known , Resveratrol, ceramide, sphingosine-1-phosphate, sphingosylphosphorylcholine, and the like Promote the decomposition of tyrosinase, or regulate glycation to regulate melanin production. However, they are not often used because they do not satisfy the whitening effect, low stability and skin irritation, and benzoic acid amide substances with excellent whitening effect and low side effects have recently been studied.

Paper mulberry is traditionally used as the original material for the production of hanji, and judging from the fact that the hanji maker has white and smooth hands, paper mulberry is expected to have a skin whitening effect. Scientific research has shown that kazinols (which is an ingredient with excellent whitening effect) is contained in the roots of Broussonetia papyrifera, and "Broussonetia papyrifera extract" is approved by the Ministry of Food and Drug Safety Drug Safety) is a substance labeled as a functional cosmetic raw material. The structure of Broussonetia papyrifera, which is a component that has a whitening effect and is present in Broussonetia papyrifera, has been analyzed by molecular modeling techniques, and it has been identified that Broussonetia papyrifera has a whitening effect. In particular, although Broussonetia papyrifera F has an excellent whitening effect, it is difficult to actually use Broussonetia papyrifera F as a separate component because it is present in a small amount in Broussonetia papyrifera and has a structure that is easily decomposed depending on temperature.

Dihydroxybenzyl adamantnyldimethoxybenzamide (Dihydroxybenzyl adamantnyldimethoxybenzamide) is a compound with a newly designed structure that takes into account the performance, stability, and production of more than 100 kinds of simulated berry F structure The resulting derivatives can be easily manufactured through quantitative structure-activity relationship (QSAR) models and 3D-QSAR. The new whitening effect mechanism of this compound has been confirmed. Among them, the compound reduces MITF performance, resulting in cAMP-PKA-CREB signal, and thus inhibits tyrosinase, TRP-1, and TRP-2 (the three are regulated by MITF) The activity of the main protein related to melanin production, the production of melanin is therefore suppressed, which has been confirmed by the use of cells and artificial skin.

However, research to improve the solubility of the composition containing the amide benzoate has not been conducted. The inventors of the present invention completed the present invention by studying compounds with improved solubility of the amide benzoate.

[technical problem]

In consideration of the above problems, the inventors of the present invention have studied a composition containing a solubilizer for improving the solubility of a composition containing a benzoic acid amide compound, thereby completing the present invention.

One aspect of the present invention provides a composition which has improved solubility of the amide benzoate compound and does not adversely affect the feeling in use.

[Question Answer]

在上式(1)中， R₁ 、R₃ 、及R₄ 各自獨立選自由氫(hydrogen)、羥基(hydroxy)、C₁ 至C₅ 烷氧基(C₁ to C₅ alkoxy)、C₃ 至C₆ 環烷氧基(C₃ to C₆ cycloalkoxy)、芳氧基(aryloxy)、以及C₁ 至C₅ 鹵烷氧基(C₁ to C₅ haloalkoxy)組成之族群， R₂ 選自由氫(hydrogen)、C₁ 至C₅ 烷基(C₁ to C₅ alkyl)、C₃ 至C₆ 環烷基(C₃ to C₆ cycloalkyl)、芳基(aryl)、以及C₁ 至C₅ 鹵烷基(C₁ to C₅ haloalkyl)組成之族群， 以及n為選自1至5的整數。One aspect of the present invention provides a composition for external skin application, comprising: a solute, which is a compound represented by the following formula 1, an isomer of the compound, a pharmaceutically acceptable salt of the compound, and the compound Hydrate or solvate of the compound; and a first solubilizer, which is diethylene glycol monoethyl ether, methyl gluceth, glyceryl ether One or more of ether), polyethylene glycol, and polyethylene glycol/polypropylene glycol copolymer: [Formula 1]

In the above formula _{(1), R 1, R} 3, and R ₄ are each independently selected from the group consisting of hydrogen (hydrogen), hydroxy (hydroxy), C ₁ to C ₅ alkoxy _{(C 1 to C 5 alkoxy)} , C 3 to C ₆ alkoxy, cycloalkyl _{(C 3 to C 6 cycloalkoxy)} , aryloxy group (aryloxy), and a C ₁ to C ₅ haloalkoxy (C ₁ to C ₅ haloalkoxy) the group consisting of, R ₂ selected from the group consisting of hydrogen (hydrogen), C ₁ to C ₅ alkyl (C ₁ to C ₅ alkyl), C ₃ to C ₆ cycloalkyl (C ₃ to C ₆ cycloalkyl), aryl (aryl), and C ₁ to C ₅ halo A group _{consisting of C 1} to C ₅ haloalkyl, and n is an integer selected from 1 to 5.

In one aspect of the present invention, the solute may be the compound represented by the above formula 1, an isomer of the compound, a pharmaceutically acceptable salt of the compound, a hydrate of the compound, or solvates of the compounds of wherein R _1, R _3, and R ₄ are each independently selected from the group consisting of hydrogen (hydrogen), hydroxy (hydroxy), C ₁ to C ₃ alkoxy _{(C 1 to C 3 alkoxy)} , C 3 to C ₆ cycloalkoxy (C ₃ to C ₆ cycloalkoxy), aryloxy (aryloxy), and C ₁ to C ₃ haloalkoxy (C ₁ to C ₃ haloalkoxy) group consisting of, wherein R _{2 is} selected from hydrogen (hydrogen), C ₁ to C ₃ alkyl (C ₁ to C ₃ alkyl), C ₃ to C ₆ cycloalkyl (C ₃ to C ₆ cycloalkyl), aryl (aryl), and C ₁ to C ₃ halo A group _{consisting of C 1} to C ₃ haloalkyl, and n is an integer selected from 1 to 3.

In one aspect of the present invention, the solute may be a compound selected from the following groups, including: 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]-2,4-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-[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)-2,4-dihydroxy-benzoic acid amide), 5-adamantan-1- 5-adamantan-1-yl-N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxy-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 -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-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-hydroxyphenyl)-ethyl]-2,4-dimethoxy-benzoic acid amide), 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl Yl)-2,4-dihydroxy-benzoic acid amide (5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dihydrox y-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-hydroxy-4-methoxy-benzoic acid amide), 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4 -Dimethoxy-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-hydroxy-benzoic acid amide), 3- Adamantan-1-yl-N-(3,4-dihydroxybenzyl)-4-methoxy-benzoic acid amide (3-adamantan-l-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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl) (Phenyl)-ethyl]-4-methoxy-benzoic acid amide (3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-methoxy-benzoic acid amide ), 3-adamantan-1-yl-4-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-benzoic acid amide (3-adamantan-1-yl-4-hydroxy-N -[2-(4-hydroxyphenyl)-ethyl]-benzoic acid amide), 3-adamantan-1-yl-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxy- 3-adamantan-l-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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-4-methoxy-benzoic acid amide (3-adamantan- 1-yl-N-(2,4-dihydroxybenzyl)-4-methoxy-benzoic acid amide), 5-adamantan-1-yl-N-(2,5-dimethoxybenzyl)-2,4- Dihydroxy-benzoic acid amide (5-adamantan-1-yl-N-(2,5-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-(2,5-dihydroxybenzyl)-2,4-dihydroxy-benzoic acid amide), 5-adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxy-benzoic acid amide (5-adamantan-1-yl-N-(3,5- dimethoxybenzyl)-2,4-dihydroxy-benzoic acid amide), and 5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide (5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide).

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

In one aspect of the present invention, the methyl gluceth may be methyl gluceth-10 or methyl gluceth-20. -20), the glycerol ether can be glycereth-26 or glycereth-12, the polyethylene glycol can be PEG-8 or PEG-6, and the polyethylene glycol/polypropylene glycol The copolymer can be PEG/PPG-17/6 copolymer.

In one aspect of the present invention, the weight ratio of the solute to the first solubilizer may be 1:0.1-9900.

In one aspect of the present invention, the weight ratio of the solute to the first solubilizer may be 1:50-700.

In one aspect of the present invention, based on the total weight of the composition, the content of the first solubilizer may be 0.1 wt% (weight percentage) to 99.99 wt%.

In one aspect of the present invention, based on the total weight of the composition, the content of the solute may be 0.01 wt% to 20 wt%.

In one aspect of the present invention, the composition may be a composition for external use on the skin, which further includes one or more selected from the following groups: a second solubilizer, which is cyclodextrin; and The third solubilizer, which is selected from xanthan gum, hydroxypropyl methylcellulose, sodium polyacrylate, sodium magnesium silicate, hydroxyethyl acrylate A hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, polyacrylate-13/polyisobutylene/polysorbate-20 (polyacrylate-13/polyisobutene/polysorbate-20) , PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, and one or more of the group consisting of magnesium aluminum silicate.

In one aspect of the present invention, the cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin Any one or more of dextrin or hydroxypropyl-γ-cyclodextrin.

In one aspect of the present invention, the composition may further include the second solubilizer, and based on the total weight of the composition, the content of the second solubilizer may be 0.1 wt% to 98 wt%.

In one aspect of the present invention, the composition may further include the second solubilizer, and the weight ratio of the solute, the first solubilizer and the second solubilizer may be 1:50-500:1-20 .

In one aspect of the present invention, the composition may include the third solubilizer, and based on the total weight of the composition, the content of the third solubilizer may be 0.1 wt% to 98 wt%.

In one aspect of the present invention, the composition further includes the second solubilizer and the third solubilizer, and the weight ratio of the solute, the first solubilizer, the second solubilizer, and the third solubilizer It can be 1: 10-200: 1-20: 1-20.

In another aspect of the present invention, the composition for external use on the skin may be a composition for whitening skin.

In another aspect of the present invention, the composition for external use on the skin may be a medicinal or cosmetic composition.

[Efficacy of invention]

The composition according to one aspect of the present invention has excellent solubility for a solute, the solute being a benzoic acid amide compound, the isomer of the compound, the pharmaceutically acceptable salt of the compound, and the hydration of the compound Or a solvate of the compound.

In the composition according to one aspect of the present invention, the solute that is the amide benzoate compound does not precipitate.

When applied to the skin, the composition according to one aspect of the present invention has excellent solubility and excellent feeling in use.

The present invention will be described in detail below.

在上式(1)中， R₁ 、R₃ 、及R₄ 各自獨立選自由氫(hydrogen)、羥基(hydroxy)、C₁ 至C₅ 烷氧基(C₁ to C₅ alkoxy)、C₃ 至C₆ 環烷氧基(C₃ to C₆ cycloalkoxy)、芳氧基(aryloxy)、以及C₁ 至C₅ 鹵烷氧基(C₁ to C₅ haloalkoxy)組成之族群， R₂ 選自由氫(hydrogen)、C₁ 至C₅ 烷基(C₁ to C₅ alkyl)、C₃ 至C₆ 環烷基(C₃ to C₆ cycloalkyl)、芳基(aryl)、以及C₁ 至C₅ 鹵烷基(C₁ to C₅ haloalkyl)組成之族群，以及 n為選自1至5的整數。One aspect of the present invention provides a composition for external skin application, comprising: a solute, which is a compound represented by the following formula 1, an isomer of the compound, a pharmaceutically acceptable salt of the compound, and the compound Hydrate or solvate of the compound; and a first solubilizer, which is diethylene glycol monoethyl ether, methyl gluceth, glyceryl ether One or more of ether), polyethylene glycol, and polyethylene glycol/polypropylene glycol copolymer: [Formula 1]

In the above formula _{(1), R 1, R} 3, and R ₄ are each independently selected from the group consisting of hydrogen (hydrogen), hydroxy (hydroxy), C ₁ to C ₅ alkoxy _{(C 1 to C 5 alkoxy)} , C 3 to C ₆ alkoxy, cycloalkyl _{(C 3 to C 6 cycloalkoxy)} , aryloxy group (aryloxy), and a C ₁ to C ₅ haloalkoxy (C ₁ to C ₅ haloalkoxy) the group consisting of, R ₂ selected from the group consisting of hydrogen (hydrogen), C ₁ to C ₅ alkyl (C ₁ to C ₅ alkyl), C ₃ to C ₆ cycloalkyl (C ₃ to C ₆ cycloalkyl), aryl (aryl), and C ₁ to C ₅ halo A group _{consisting of C 1} to C ₅ haloalkyl, and n is an integer selected from 1 to 5.

In one aspect of the present invention, the solute may be the compound represented by the above formula 1, an isomer of the compound, a pharmaceutically acceptable salt of the compound, a hydrate of the compound, or solvates of the compounds of wherein R _1, R _3, and R ₄ are each independently selected from the group consisting of hydrogen (hydrogen), hydroxy (hydroxy), C ₁ to C ₃ alkoxy _{(C 1 to C 3 alkoxy)} , C 3 to C ₆ cycloalkoxy (C ₃ to C ₆ cycloalkoxy), aryloxy (aryloxy), and C ₁ to C ₃ haloalkoxy (C ₁ to C ₃ haloalkoxy) group consisting of, wherein R _{2 is} selected from hydrogen (hydrogen), C ₁ to C ₃ alkyl (C ₁ to C ₃ alkyl), C ₃ to C ₆ cycloalkyl (C ₃ to C ₆ cycloalkyl), aryl (aryl), and C ₁ to C ₃ halo A group _{consisting of C 1} to C ₃ haloalkyl, and n is an integer selected from 1 to 3.

In one aspect of the present invention, the solute is a compound selected from the following groups, including: 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]-2,4-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-[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)-2,4-dihydroxy-benzoic acid amide), 5-adamantan-1-yl -N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxy-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- 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-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-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)-2,4-dihydroxybenzyl) -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-hydroxy-4-methoxy-benzoic acid amide), 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4- Dimethoxy-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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-(3,4-dihydroxybenzyl)-4-hydroxy-benzoic acid amide) Alk-1-yl-N-(3,4-dihydroxybenzyl)-4-methoxy-benzoic acid amide (3-adamantan-l-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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl) 3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-methoxy-benzoic acid amide) , 3-adamantan-1-yl-4-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-benzoic acid amide (3-adamantan-1-yl-4-hydroxy-N- [2-(4-hydroxyphenyl)-ethyl]-benzoic acid amide), 3-adamantan-1-yl-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxy-benzene 3-adamantan-l-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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-4-methoxy-benzoic acid amide (3-adamantan-1 -yl-N-(2,4-dihydroxybenzyl)-4-methoxy-benzoic acid amide), 5-adamantan-1-yl-N-(2,5-dimethoxybenzyl)-2,4-di 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-(2,5-dihydroxybenzyl)-2,4-dihydroxy-benzoic acid amide), 5 -Adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxy-benzoic acid amide (5-adamantan-1-yl-N-(3,5-dimethoxybenzyl) )-2,4-dihydroxy-benzoic acid amide), and 5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide ( 5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide), the isomer of the compound, the pharmaceutically acceptable salt of the compound, The hydrate of the compound or the solvate of the compound.

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

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

In one aspect of the present invention, the methyl gluceth is methyl gluceth-10 (Methyl Gluceth-10) or methyl gluceth-20 (Methyl Gluceth-10). -20), the glycerol ether is glycereth-26 (glycereth-26) or glycereth-12 (glycereth-12), the polyethylene glycol is PEG-8 or PEG-6, and the The copolymer of polyethylene glycol/polypropylene glycol is PEG/PPG-17/6 copolymer.

In one aspect of the present invention, the weight ratio of the solute and the first solubilizing agent may be 1: 0.1-9900. In one embodiment, the weight ratio of the solute and the first solubilizer may be 1:0.5 or more, 1:1 or more, 1:1.5 or more, 1:2.0 or more, 1:5 or more, 1:10 or more, 1. : 30 or more, 1:50 or more, 1:80 or more, 1: 100 or more, 1: 200 or more, 1: 500 or more, 1: 800 or more, 1: 1000 or more, 1: 1500 or more, 1: 2000 or more, 1 : 3000 or more, or 1: 5000 or more. In addition, the weight ratio of the solute and the first solubilizer may be 1: 9900 or less, 1: 9800 or less, 1: 9500 or less, 1: 9,000 or less, 1: 8,000 or less, 1: 7500 or less, 1: 7,000 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. The weight ratio of the solute and the first solubilizer may preferably be 1:50-700.

In one aspect of the present invention, based on the total weight of the composition, the content of the first solubilizer may be 0.1 wt% to 99.99 wt%. In one embodiment, based on the total weight of the composition, the content of the first solubilizer may be 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 10 wt% or more, 20 wt% or more, 30 wt% or more, or 35 wt% or more. In addition, the first solubilizing agent may be 99 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% or less. wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or Below 5 wt%.

In one aspect of the present invention, based on the total weight of the composition, the content of the solute may be 0.01 wt% to 20 wt%. Based on the total weight of the composition, the solute content of the present invention can be from 0.01 wt% to 20 wt%, specifically from 0.1 wt% to 10 wt%, and more specifically, from 0.5 wt% to 5 wt% %. When the solute content is in the above range, not only the intended effect of the present invention can be exhibited, but also the stability and safety of the composition can be satisfied, and the solute in the above range is also in a cost-effective point of view. Specifically, when the solute content is less than 0.01 wt%, sufficient skin whitening effect cannot be obtained, and the solute content is preferably not more than 20 wt% because of its low cost-effectiveness.

In one aspect of the present invention, the composition may be a composition for external use on the skin, and further includes one or more selected from the following groups: a second solubilizer, which is cyclodextrin; and a The third solubilizer, which is selected from xanthan gum, hydroxypropyl methylcellulose, sodium polyacrylate, sodium magnesium silicate, hydroxyethyl acrylate A hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, polyacrylate-13/polyisobutylene/polysorbate-20 (polyacrylate-13/polyisobutene/polysorbate-20) , PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, and one or more of the group consisting of magnesium aluminum silicate.

In one aspect of the present invention, the cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, Any one or more of hydroxypropyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin.

In one aspect of the present invention, the composition may further include the second solubilizer, and based on the total weight of the composition, the content of the second solubilizer may be 0.1 wt% to 98 wt%. In one embodiment, based on the total weight of the composition, the content of the second solubilizer may be 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 10 wt% or more, 20 wt% or more, 30 wt% or more, or 35 wt% or more. In addition, the second solubilizer may be 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% or less. wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or Below 5 wt%.

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

In one aspect of the present invention, the composition may further include the third solubilizer, and based on the total weight of the composition, the content of the third solubilizer may be 0.1 wt% to 98 wt%. In one embodiment, based on the total weight of the composition, the content of the third solubilizer may be 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 10 wt% or more, 20 wt% or more, 30 wt% or more, or 35 wt% or more. In addition, the third solubilizer may be 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% or less. wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or Below 5 wt%. In one embodiment, the weight ratio of the solute, the first solubilizer and the third solubilizer may be 1:100-600:1-10. In addition, the weight ratio may be 1: 200-500: 3-10 or 1: 300-450: 5-10.

In one aspect of the present invention, the composition further includes the second solubilizer and the third solubilizer, and the weight ratio of the solute, the first solubilizer, the second solubilizer, and the third solubilizer may be It is 1: 10-200: 1-20: 1-20. In an embodiment, the weight ratio may be 1:15 or more: 2 or more: 2 or more, 1:20 or more: 3 or more: 3 or more, 1:50 or more: 4 or more: 4 or more, 1:70 or more: 5 Above: 5 or above, or 1:90 or above: 6 or above: 6 or above. In addition, the weight ratio can be 1: 150 or less: 15 or less: 15 or less, 1: 140 or less: 13 or less: 13 or less, 1: 130 or less: 11 or less: 11 or less, 1: 110 or less: 10 or less: 10 or less, 1: 105 or less: 8 or less: 8 or less, or 1: 90 or less: 7 or less: 7 or less.

In one aspect of the present invention, the composition for external skin application may be a composition for skin whitening. The composition for external use on the skin can have an excellent skin whitening effect, and in particular, it can improve or prevent melasma, freckle, facial moles, and pigmentation.

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

In one aspect of the present invention, the composition may be a cosmetic composition. The cosmetic composition of the present invention can be conveniently manufactured in this field, and can be prepared into any preparation. For example, it can be formed into solution, suspension, emulsifier, paste, gel, cream, lotion, Powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, waxy foundation (wax foundation), spray (spray), etc., but the present invention is not limited thereto.

In one aspect of the present invention, the composition may be a pharmaceutical composition. The pharmaceutical composition can have an excellent skin whitening effect, and in particular, it can improve or treat melasma, freckle, facial moles, and pigmentation. According to one aspect of the present invention, the pharmaceutical composition can be parenterally, rectally, topically, transdermally, intravenously, intramuscularly, and intraperitoneally. (intraperitoneally), subcutaneously, etc. The preparation for parenteral administration may be a solution, suspension, buoyant, gel, injection, drop, suppository, patch, or spray, but the present invention does not Limited to this. These preparations can be easily produced by methods known in this field, such as surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, Salts or buffers to control osmotic pressure, coloring agents, perfumes, stabilizers, antiseptics, preservatives, or other conventional adjuvants (adjuvants) ) Can be used appropriately.

According to one aspect of the present invention, the active ingredient of the pharmaceutical composition changes depending on the age, sex, weight, pathological condition, the severity of the subject, the method of administration, or the judgment of the prescriber . Based on these factors, the dosage is within the level of a person with general knowledge in this field. The daily dosage can be, for example, from 0.1 mg/kg/day (mg/kg/day) to 100 mg/kg /day, and more specifically from 5 mg/kg/day to 50 mg/kg/day, but the present invention is not limited thereto.

[Example]

Hereinafter, the present invention will be described in more detail with reference to Examples. Those skilled in the art should understand that these examples are for illustrative purposes only, and the scope of the present invention is not construed as being limited by these examples.

Experimental example 1 . 5- Adamantane -1- base -N-(2,4- Dihydroxybenzyl )-2,4- Dimethoxy - Comparison of the solubility of benzoic acid amides in solubilizers.

Measure 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide (hereinafter referred to as DBAB) in Table 1 (test group) and Table 2 (Control group) shows the solubility of each component.

The components of the test group and the control group were mixed with DBAB at an excess ratio of 10 or more, at 37°C for 24 hours, by using a centrifuge (Micro 12, manufactured by HANIL SCIENCE CO., LTD.) Manufacturing) The mixture was centrifuged at 13,000 rpm for 5 minutes, and the supernatant was analyzed by HPLC.

The experimental results are presented in Tables 1 and 2 below.

[Table 1]

[Table 2]

As shown in Table 1, it can be found that 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide (DBAB) is effective in the second solubilizer Ethylene glycol monoethyl ether, methylglucitol-10, methylglucitol-20, glycerol-26, PEG/PPG-17/6 copolymer, PEG-6 and PEG-8 The solubility is as good as above 60 mg/mL.

Examples 1-8 and Comparative Examples 1-5

Contains the respective first solubilizers in Table 1 of Experimental Example 1 and 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid Amine compositions were prepared as Examples 1-8.

As in Examples 1 to 8 below, DBAB and the respective first solubilizer are mixed at a weight ratio of DBAB: solubilizer of 1:10 when heated to below 50°C. After heating and mixing for more than 10 minutes, the mixture was stored at a room temperature of 25°C-30°C for 7 days, and it was confirmed whether there was any precipitate.

Example 1: DBAB and diethylene glycol monoethyl ether were mixed in a weight ratio of 1:10 DBAB: diethylene glycol monoethyl ether.

Example 2: DBAB and Methylglucitol-10 E10KC (KCI, South Korea) were mixed in a weight ratio of 1:10 DBAB: Methylglucitol-10 E10KC.

Example 3: DBAB and Methylglucitol-10 E10KCH (KCI, South Korea) were mixed in a weight ratio of 1:10 DBAB: Methylglucitol-10 E10KCH.

Example 4: DBAB and methylglucitol-20 were mixed in a weight ratio of 1:10 DBAB: methylglucitol-20.

Example 5: DBAB and methyl glucitol-12 were mixed in a weight ratio of 1:10 DBAB: methyl glucitol-12.

Example 6: DBAB and glycerol polyether-26 were mixed in a weight ratio of 1:10 DBAB: glycerol polyether-26.

Example 7: DBAB and PEG/PPG-17/6 copolymer were mixed in a weight ratio of 1:10 DBAB: PEG/PPG-17/6 copolymer.

Example 8: DBAB and PEG 8 were mixed in a weight ratio of DBAB:PEG 8 of 1:10.

The results of the experiment are shown in Figure 1. It can be confirmed that the components of the example can completely dissolve DBAB and the solution remains clear after 7 days, but the DBAB in example 8 partially precipitated after 7 days. Among them, PEG-8 is shown to be useful for the example. The ingredients have low solubility.

When the experiment was carried out in the same way as the above example, DBAB and dipropylene glycol (comparative example 1), PEG.PPG. polybutylene glycol-8.5.3 glycerol (comparative example 2), 1,3-propanediol (comparative When Example 3), PEG 32 (Comparative Example 4) and PEG 75 (Comparative Example 5) are mixed, it can be found that the solubility of DBAB in these solubilizers is poor, as DBAB is not completely dissolved or compared with the case of using PEG 8. Precipitate more volume.

Experimental example 2 . Confirm instance 8 And comparative example 3 Dissolved state ( Optical method ) .

The difference between Example 8 and Comparative Example 3 was confirmed by observation with a polarized light microscope. The experimental results are presented in Figure 2. The presence or absence of precipitation can be confirmed by using a polarizing microscope.

Experimental example 3 . Confirm the effect when the ratio of the first solubilizer is reduced

In Examples 2 to 7, the range in which DBAB can be completely dissolved was determined by reducing the ratio of each solubilizer. It can be confirmed that DBAB can be completely dissolved until the solubilizer of Example 4: The weight ratio of DBAB is 7.9:1, the weight ratio of the solubilizer up to Example 7: DBAB is 7.5:1, and the solubilizer of Example 5 and 6: The weight ratio of DBAB is 7:1. Specifically, when the solubility of DBAB of Example 4 and Example 5 are compared with each other, the solubility of DBAB of Example 5 is better. Therefore, it can be expected that the solubility of DBAB is in glycerol polyether-3, glycerol polyether-7, and glycerol polyether. -8 is better when the solubilizer has a lower molecular weight than that of Example 5.

Experimental example 4 . Confirm the effect of the first solubilizer when adding water.

It can be confirmed that the DBAB shown in FIG. 3 is precipitated, when 0.1 wt% of DBAB is dissolved in 3 wt% of the solubilizer of Examples 2 to 8, and water is added as a remainder.

Specifically, when the solubility of DBAB is measured as shown in FIG. 3, it can be observed that Example 8 has the largest amount of precipitation, which has low solubility of DBAB in all the examples. The solubility of DBAB in Example 2 (methylglucitol-10) is better than that in Example 4 (methylglucitol-20), because the upper precipitation part phase in Example 2 It is smaller than Example 4. Therefore, it can be expected that when a substance having a lower molecular weight, such as methylglucitol-5, is used, better DBAB solubility than methylglucitol-10 can be obtained.

In the case of using only the solubilizer of Example 7, it can be confirmed that when the solubilizer is 50 wt%, the DBAB is 0.1 wt%, and the remainder is water (Figure 4), DBAB can be completely dissolved. When the solubilizer is 30 wt% and 40 wt%, DBAB cannot be completely dissolved. However, it is certain that even when the solubilizer of Example 7 is used in a lower weight ratio, the water is fixed at 50%, and the remainder is the solubilizer of Comparative Example 3 (Figure 5), DBAB still Can be completely dissolved. It can be confirmed from Figure 5 that when the solubilizer used in Example 7 is 35wt% and the solubilizer used in Comparative Example 3 is 15 wt%, and the remaining material is water, DBAB can be completely dissolved, but the solution increases in other In the case of solvents, it is not completely dissolved.

Experimental example 5 . Confirm when adding hydroxypropyl β Cyclodextrin (Hydroxyl Propyl Beta Cyclodextrin , Hereinafter referred to as CD) Efficacy when entering the first solubilizer.

In Experimental Example 4, the amount of the solubilizer in Example 7 was at least 35 wt% (when Comparative Example 3 was used) to 50 wt% to completely dissolve 0.1 wt% of DBAB. However, it can be confirmed that when the amount of CD used is 0.5 wt%, even if the amount of solubilizer used in Example 7 is 20 wt%, DBAB can be completely dissolved. The experimental results are presented in Figure 6.

In one case, the amount of water is fixed at 50 wt%, and the amount of CD is 0.5 wt%. When the amount of solubilizer in Example 7 is only 10 wt%, DBAB will precipitate out (leftmost), but when Example 7 is increased When the amount of solvent used is 20 wt%, DBAB is completely dissolved. It can be confirmed that when the amount of CD used is 1.0 wt%, when the amount of solubilizer in Example 7 is only 10 wt%, DBAB will be completely dissolved (Figure 6).

Experimental example 6 . Confirmed when hydroxypropyl methylcellulose (Hydroxyl Propyl Methyl Cellulose , Hereinafter referred to as HPMC) and CD Efficacy when used together with the first solubilizer.

It can be confirmed that when 0.5 wt% of HPMC is added to 0.1 wt% of DBAB, when the solubilizer added in Example 7 is 45 wt% or more, DBAB can be completely dissolved.

It can be confirmed that when 0.6 wt% CD is used for 0.1 wt% DBAB, when the amount of solubilizer used in Example 7 is 30 wt% and the remainder is water, DBAB can be completely dissolved.

It can be confirmed that when 0.5 wt% HPMC and 0.6 wt% CD are used for 0.1 wt% DBAB, when the component usage amount of Example 7 is 5 wt% and the rest is water, DBAB can be completely dissolved.

It can be confirmed that in the case of using 30 wt% of the ingredients of Example 7 for 0.1 wt% of DBAB, when the amount of HPMC used is 2 wt%, DBAB can be completely dissolved.

It can be confirmed that when 2 wt% CD, 5 wt% of Example 4 ingredients, and 5 wt% of Example 6 ingredients are used for 0.1 wt% DBAB, when the usage amount of xanthan gum is 0.2 wt% , DBAB can be completely dissolved.

Therefore, it can be confirmed that these ingredients have complementary effects. When the content of the ingredients that can increase the solubility of DBAB increases, the content of other ingredients can be reduced.

It can be confirmed that when 0.3 wt% CD and 1 wt% HPMC are used for 0.1 wt% DBAB, when the usage amount of the solubilizer in Example 7 is 30 wt%, DBAB can be completely dissolved.

It can be confirmed that when 0.3 wt% CD and 0.5 wt% HPMC are used for 0.1 wt% DBAB, even when the amount of solubilizer used in Example 7 is 15 wt%, 16 wt%, 20 wt%, and 25 wt% At this time, DBAB cannot be completely dissolved.

In addition, it can be confirmed that when 0.3 wt% CD and 1 wt% HPMC are used for 0.1 wt% DBAB, even when the use amount of the solubilizer in Example 7 is 5 wt% and 20 wt%, DBAB cannot completely Dissolve.

In addition, it can be confirmed that when 0.3 wt% CD and 2 wt% HPMC are used for 0.1 wt% DBAB, even when the usage amount of the solubilizer in Example 7 is 20 wt%, DBAB cannot be completely dissolved.

It can be confirmed that when 0.3 wt% CD and 0.4 wt% HPMC are used for 0.1 wt% DBAB, when the usage amount of the solubilizer in Example 7 is 20 wt%, DBAB can be completely dissolved.

It can be confirmed that when 0.7 wt% CD and 0.1 wt% HPMC are used for 0.1 wt% DBAB, when the usage amount of the solubilizer in Example 7 is 5 wt%, DBAB can be completely dissolved.

It can be confirmed that when 0.7 wt% CD and 1 wt% HPMC are used for 0.1 wt% DBAB, immediately when the amount of solubilizer used in Example 7 is 1 wt%, 3 wt%, 4 wt%, and 5 wt% At this time, DBAB cannot be completely dissolved.

It can be confirmed that when 0.9 wt% CD is used for 0.1 wt% DBAB, even when the usage amount of the solubilizer in Example 7 is 5 wt% and 10 wt%, DBAB can be completely dissolved.

It can be confirmed that when 1 wt% CD and 0.1 wt% HPMC are used for 0.1 wt% DBAB, when the usage amount of the solubilizer in Example 7 is 5 wt%, DBAB can be completely dissolved.

Experimental example 7 . In addition to the third solubilizer HPMC Identification of solubilizers other than

It can be confirmed that when the amount of solubilizer used in Example 7 is 15 wt% and the amount of cellulose gum is 1 wt%, 0.5 wt% of CD is added and the rest is water, DBAB can be completely dissolved. It can be confirmed that when 1wt% hydroxyethylcellulose is used instead of cellulose gum, DBAB is not completely precipitated.

By using 0.6 wt% of CD, 5 wt% of the solubilizer of Example 8, 0.5 wt% of the solubilizer of each example and the comparative example below 0.5 wt%, and water as the remaining material to select the solubilizer, as a judge whether the DBAB can be completely Dissolved or precipitated incompletely.

When sodium hyaluronate, cellulose gum, xanthan gum, sodium polyacrylate, sodium magnesium silicate, hydroxyethyl acrylate/ A hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, a mixture of polyacrylate-13, polyisobutene, and polysorbate 20) Bentonite, poloxamer 407, hydroxypropyl starch phosphate, PEG-240/HDI copolymer bis-decyltetradecyl alcohol polyether-20 , Polyvinyl alcohol (two product names are PVA 205 and PVA 217), magnesium aluminum silicate, HPMC (product name: methocel, pharmacoat 630, pharmacoat 615, pharmacoat 645, and metolose SM-4) are used for screening, when using sodium hyaluronate, cellulose gum, polyvinyl alcohol, bentonite, poloxamer 407, hydroxypropyl starch phosphate, magnesium silicate Precipitation occurs in the case of aluminum, and no precipitation occurs when the others are used.

Therefore, Sanxian gum, sodium acrylate, sodium magnesium silicate, hydroxyethyl acrylate/sodium acrylate dimethyl taurate copolymer, polyacrylate-13 and a mixture of polyisobutylene and polysorbate-20, PEG -240/HDI copolymer bis-decyltetradecyl alcohol polyether-20, magnesium aluminum silicate and HPMC can be used as example solubilizers. However, it has been confirmed that the efficacy of solubilizers can even be obtained from solubilizers that have low solubility (and therefore cause precipitation when used with other solubilizers such as PEG-8, CD, etc.).

Experimental example 8 . Confirm the stabilizing effect of the formulation.

As shown in Table 3 below, vegetable squalane, caprylic/capric triglyceride, arachidyl alcohol/behenyl alcohol/arachidyl glucoside (arachidyl alcohol/behenyl alcohol/arachidyl glucoside) and The liquid paraffin is weighed in a beaker once and heated to 70°C, and the other components are weighed in another beaker and heated to 70°C. Use an emulsifier (homomixer Mark 2 model PRIMIX company) to mix these together at 3000 rpm Continue to cool for 5 minutes to prepare the formulation.

The preparations of Example 9 and Comparative Example 6 thus produced were used to confirm the precipitation of DBAB, and a polarizing microscope was used by the same method as in Experimental Example 2 (FIG. 7 ). [table 3]

Experimental example 9 ：Measurement example 9 And comparative example 6 Sense of use

The feeling of use of the ingredients produced in Experimental Example 8 was measured. The subjective score of the evaluator is measured on a 9-point scale to provide a moisturizing feel such as moisture feel, stickiness, and flexible feel after use. Example 9 Methylglucitol The feeling of use with increased polyether-20 content was also evaluated. At this time, it can be confirmed that when the content of methylglucitol-20 is 20 wt% or more, negative factors such as stickiness and frustration in use increase.

Hereinafter, examples of preparations according to the present invention will be described, but they are not intended to limit the present invention, but are merely illustrative.

[Formulation example 1] Moisturizing emulsion

The moisturizing emulsion has the composition shown in Table 4 below and is prepared by a conventional method. [Table 4]

[Formulation example 2] Nourishing lotion (milky white lotion)

The nourishing emulsion has the composition shown in Table 5 below and is prepared by a conventional method. [table 5]

[Preparation example 3] Nourishing cream

The nourishing cream has the composition shown in Table 6 below and is prepared by a conventional method. [Table 6]

[Preparation example 4] Massage cream

The massage cream has the composition shown in Table 7 below and is prepared by a conventional method. [Table 7]

[Formulation example 5] Packaging

The package has the composition system shown in Table 8 below and is prepared by a known method. [Table 8]

[Preparation Example 6] Ointment

The ointment has the composition system shown in Table 9 below and is prepared by a known method [Table 9]

without

Figure 1 is a photograph of Examples 1, 4, 6, 7 and 8 of the present invention. 2a to 2d are photographs confirming the dissolution state of Example 8 and Comparative Example 3, taken through an optical microscope and a general display lens. The picture of Figure 3 shows that 0.1 wt% of DBAB was dissolved in 3 wt% of the solubilizers of Examples 2 to 8, and water was added as a remainder to the solution of Experimental Example 4 of the present invention. Figure 4 is a photograph of the appearance of the composition, where the DBAB is 0.1% by weight, the remainder is water, and the solubilizer of Example 7 in Experimental Example 4 of the present invention is 30% by weight, 40% by weight, and 50% by weight. Figures 5a and 5b are photos of the appearance of the composition, in which DBAB is 0.1% by weight, the remainder is water, and the solubilizer of the example and the solubilizer of the comparative example are used in Experimental Example 4 of the present invention. Fig. 6 is a photograph of comparison of solubility when cyclodextrin of the second solubilizer is added to the first solubilizer in Experimental Example 5 of the present invention. Figures 7a and 7b are photographs confirming the dissolution state of Example 9 and Comparative Example 6 of the present invention, taken through a polarizing microscope. Figures 8 and 9 are when the first solubilizer (the solubilizer of Example 7), the second solubilizer (cyclodextrin), and the third solubilizer (HPMC) are used together in Experimental Example 6 of the present invention Photo of solubility comparison. The weight ratios of the first, second, and third solubilizers are sequentially indicated.

Claims (16)

A composition for external skin application, comprising: a solute, which is a compound represented by the following formula 1, a pharmaceutically acceptable salt of the compound, or a hydrate of the compound; and a first solubilizer, which is two Diethylene glycol monoethyl ether, Methyl Gluceth, glyceryl ether, polyethylene glycol, and a combination of polyethylene glycol/polypropylene glycol One or more of polymers (polyethylene glycol/polypropylene glycol copolymer); wherein the methyl glucethether is methyl gluceth-10 or methyl gluceth-10 -20 (Methyl Gluceth-20), the glycerol ether is glycerol polyether-26 or glycerol polyether-12, the polyethylene glycol is PEG-8 or PEG-6, and the copolymer of polyethylene glycol/polypropylene glycol The polymer is PEG/PPG-17/6 copolymer:

In the above formula _{(1), R 1, R} 3, and R ₄ are each independently selected from the group consisting of hydrogen (hydrogen), hydroxy (hydroxy), C ₁ to C ₅ alkoxy _{(C 1 to C 5 alkoxy)} , C 3 to C ₆ alkoxy, cycloalkyl _{(C 3 to C 6 cycloalkoxy)} , aryloxy group (aryloxy), and a C ₁ to C ₅ haloalkoxy (C ₁ to C ₅ haloalkoxy) the group consisting of, R ₂ selected from the group consisting of hydrogen (hydrogen), C ₁ to C ₅ alkyl (C ₁ to C ₅ alkyl), C ₃ to C ₆ cycloalkyl (C ₃ to C ₆ cycloalkyl), aryl (aryl), and C ₁ to C ₅ halo A group _{consisting of C 1} to C ₅ haloalkyl, and n is an integer selected from 1 to 5. The composition for external use on the skin as described in item 1 of the scope of patent application, wherein R ₁ , R ₃ , and R ₄ are each independently selected from hydrogen, hydroxy, and C ₁ to C ₃ alkoxy (C _{1 to C 3 alkoxy), C} 3 to C ₆ cycloalkoxy _{(C 3 to C 6 cycloalkoxy)} , aryloxy group (aryloxy), and a C ₁ to C ₃ haloalkoxy (C ₁ to C ₃ haloalkoxy) The composition group, wherein R _{2 is} selected from hydrogen, C ₁ to C ₃ alkyl (C ₁ to C ₃ alkyl), C ₃ to C ₆ cycloalkyl (C ₃ to C ₆ cycloalkyl), aryl ( the group consisting of aryl), and a C ₁ to C ₃ haloalkyl _{(C 1 to C 3 haloalkyl)} , and n is an integer selected from 1-3. The composition for external use on the skin described in item 2 of the scope of the patent application, wherein the solute is a compound selected from the following groups, including: 5-adamantan-1-yl-N-[2-(3,4-二(Hydroxyphenyl)-ethyl]-2,4-dihydroxy-benzoic acid amide (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-[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)-2,4-dihydroxy-benzoic acid amide), 5-adamantan-1-yl-N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxy-benzoic acid amide (5-adamantan-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-2,4- 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-2-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxy-benzoic acid amide), 5-adamantan Alk-1-yl-N-[2-(4-hydroxyphenyl)-ethyl]-2,4-dimethoxy-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-benzene 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dihydroxy-benzoic acid amide), 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl) Hydroxybenzyl)-2-hydroxy-4-methoxy-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 (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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-(3,4-dihydroxybenzyl)-4-methoxy 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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-methoxy 3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-methoxy-benzoic acid amide), 3-adamantan-1-yl-4 -Hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-benzoic acid amide (3-adamantan-1-yl-4-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl] -benzoic acid amide), 3-adamantan-1-yl-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxy-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-hydroxy-benzoic acid amide), 3-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-4- 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-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-(2,5-dihydroxybenzyl) )-2,4-dihydroxy-benzoic acid amide), 5-adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxy-benzoic acid amide (5- adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxy-benzoic acid amide), and 5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy -5-methoxybenzyl)-benzoic acid amide (5-adamantan-1-yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)-benzoic acid amide). The composition for external skin application as described in item 3 of the scope of the patent application, wherein the solute is 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy -Benzoic acid amide (5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide). The composition for external use on the skin as described in item 1 of the scope of patent application, wherein the weight ratio of the solute to the first solubilizing agent is 1:0.1-9900. The composition for external use on the skin described in item 1 of the scope of the patent application, wherein based on the total weight of the composition, the composition includes 0.1 wt% to 99.99 wt% of the first solubilizer. The composition for external use on the skin as described in item 1 of the scope of patent application, wherein based on the total weight of the composition, the composition includes 0.01 wt% to 20 wt% of the solute. The composition for external use on the skin as described in claim 1, wherein the composition further includes one or more selected from the following groups: a second solubilizer, which is cyclodextrin; and a second solubilizer Three solubilizers, which are selected from xanthan gum, hydroxypropyl methylcellulose, sodium polyacrylate, sodium magnesium silicate, hydroxyethyl acrylate /Ahydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, polyacrylate-13/polyisobutylene/polysorbate-20 (polyacrylate-13/polyisobutene/polysorbate-20), PEG One or more of the group consisting of -240/HDI copolymer bis-decyltetradeceth-20 ether and magnesium aluminum silicate. The composition for external skin application as described in item 8 of the scope of patent application, wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, Any one or more of hydroxypropyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin. The composition for external skin application as described in item 8 of the scope of patent application, wherein the composition further comprises the second solubilizer, and based on the total weight of the composition, the content of the second solubilizer is 0.1wt% To 98wt%. The composition for external use on skin as described in claim 8, wherein the composition further comprises the second solubilizer, and the weight ratio of the solute, the first solubilizer and the second solubilizer is 1:50 -500: 1-20. The composition for external skin application as described in item 8 of the scope of patent application, wherein the composition further includes the third solubilizer, and based on the total weight of the composition, the content of the third solubilizer is 0.1wt% To 98wt%. The composition for external skin application as described in item 8 of the scope of patent application, wherein the composition further comprises the third solubilizer, and the weight ratio of the solute, the first solubilizer and the third solubilizer is 1:100 -600: 1-10. The composition for external use on the skin according to claim 8, wherein the composition further includes the second solubilizer and the third solubilizer, and the solute, the first solubilizer, the second solubilizer, and The weight ratio of the third solubilizer is 1:10-200:1-20:1-20. The composition for external use on the skin according to any one of the scope of the patent application from 1 to 14, wherein the composition for external use on the skin is a composition for whitening skin. The composition for external use on the skin according to any one of the scope of the patent application from 1 to 14, wherein the composition for external use on the skin is a medicinal or cosmetic composition.

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