KR20190063982A - A composition comprising benzoic acid amide compound and solubilizer - Google Patents

Abstract

The present invention provides a composition for external application to a skin, comprising: a solute which is a benzoic acid amide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; a first solubilizer which is at least one selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400; a second solubilizer which is cyclodextrin; and a third solubilizer which is at least one selected from the group consisting of cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer, and polyacrylate-13/polyisobutene/polysorbate-20. According to the present invention, the composition for external application to a skin has improved solubility.

Description

Benzoic acid amide compound and solubilizer. ≪ RTI ID = 0.0 > [0002] <

The present disclosure relates to a solvate which is a benzoic acid amide compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And a solubilizing adjuvant, wherein the composition has improved solubility.

Melanin protects the skin by blocking the ultraviolet rays from the epidermis layer, protecting the dermis organs below the skin, and absorbing free radicals. In addition, melanin is a major factor in determining the color of skin, and when it is present in excess, melanin is a cause of skin pigmentation such as spots, freckles, and spots. Melanin is produced in melanocytes in the basal layer of the skin, which is known to be stimulated by stimulation of ultraviolet light or inflammation. Therefore, it is possible to reduce the external stimulus, block the signal transmission, or inhibit the synthesis of melanin producing enzyme tyrosinase or inhibit the activity of melanin. At present, it is known that accelerating the degradation of tyrosinase or regulating glycosylation, such as kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butyl resorcinol, resveratrol, ceramide, sphingosine- It is known that melanin production can be regulated. However, they have not been utilized due to unsatisfactory whitening effect, low stability, and skin irritation. Recently, benzoic acid amide materials with excellent whitening effect and low side effects have been studied.

Mackerel has been traditionally used as a raw material for producing Korean paper, and it has been predicted that skin whitening effect will be obtained from the fact that the hands of the person making the Korean paper have been white. Scientific studies have shown that it contains kazinol, which is an ingredient that has excellent whitening effect on the root of mulberry leaves. "Mulberry extract" is a functional cosmetic raw material and is also a substance that is notified in the pharmaceuticals. The structure of Kazinol species, which is a whitening effect component present in mulberry tree, was analyzed by molecular modeling to identify the effect of whitening effect on Kazinol species. Especially, Kazinol F has a structure that is present in trace amount in mackerel and is easily decomposed by temperature in spite of its excellent whitening effect, so it is difficult to use it as a single component.

Dihydroxybenzyl Adamantnyldimethoxybenzamide has been newly designed with consideration of efficacy, stability and manufacturability through structural activity relation (QSAR) and 3D-QSAR among 100 kinds of derivatives prepared by simulating the structure of kazinol F, which is a trace component of mulberry. Lt; / RTI > This compound reduces the expression of MITF linked to the cAMP-PKA-CREB signal and consequently inhibits melanin synthesis by inhibiting the activity of the major proteins tyrosinase, TRP-1, and TRP-2 in relation to MITF-regulated melanin synthesis The mechanism of new whitening effect was identified, and it was confirmed through cell and artificial skin.

However, there has been no research to improve the solubility of the composition containing the benzoic acid amide material, and the inventors of the present invention have studied the composition having improved solubility of the benzoic acid amide substance, leading to the present invention.

KR10-1604053 B1 US8697151 B2 US9216145 B2 JP2011-528708A JP2015-0120716A 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 Society of Cosmeticology. 2013 Vol. 39, No. 2, pp. 127-132. 3D-QSAR study of adamantyl N-benzylbenzamides as melanogenesis inhibitors. Bioorg. Med. Chem. Lett., 2014, 24, 667-673. A novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP-PKA-CREB-activated microphthalmia-associated transcription factor and tyrosinase expression. Experimental Dermatology, 2013, 22, 748-774.

In view of the above problems, the inventors of the present invention studied a composition containing a solubilizing aid for solubility improvement of a composition containing a benzoic acid amide compound, leading 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.

An aspect of the present invention is a pharmaceutical composition comprising a compound of the following formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And

Polyethylene glycol / polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400;

A second dissolution aid, which is cyclodextrin; And

Cellulose gum, Xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer (hydroxyethyl acrylate) and a third dissolution assistant selected from the group consisting of polyacrylate-13 / polyacrylate / sodium acryloyldimethyl taurate copolymer and polyacrylate-13 / polyisobutene / polysorbate-20. A composition is provided:

[Chemical Formula 1]

In Formula 1,

R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy,

R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₅ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₅ haloalkyl,

n is an integer selected from 1 to 5;

The composition according to one aspect of the present invention is excellent in the solubility of the 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 benzoic acid amide compound as a solute, has excellent solubility, and has excellent stability.

1 is a photograph of Examples 1, 3, 4, 7 and 8 of the present invention.
2 is a photograph showing the stability of the tenth embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

An aspect of the present invention is a pharmaceutical composition comprising a compound of the following formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And

Polyethylene glycol / polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400;

A second dissolution aid, which is cyclodextrin; And

Cellulose gum, Xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer (hydroxyethyl acrylate) and a third dissolution assistant selected from the group consisting of polyacrylate-13 / polyacrylate / sodium acryloyldimethyl taurate copolymer and polyacrylate-13 / polyisobutene / polysorbate-20. A composition is provided:

[Chemical Formula 1]

In Formula 1,

R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy,

R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₅ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₅ haloalkyl,

n is an integer selected from 1 to 5;

In one aspect of the present invention, R ₁ , R ₃ and R ₄ of formula 1 are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ halo Lt; / RTI > is independently selected from the group consisting of < RTI ID =

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

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

In one aspect of the present invention,

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,

2,4-dihydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,

5-adamantan-l-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,

(2,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide, 5-adamantan-

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

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-l-yl-N- (2,4-dihydroxybenzyl) -4-methoxy- benzoic acid amide,

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

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

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

5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, its isomers and its pharmaceutically acceptable salts A salt thereof, a hydrate thereof or a solvate thereof.

In one aspect of the invention, the solute may be 5-adamantan-l-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 solutes of the present invention may be present in an amount of at least 0.01 wt%, at least 0.02 wt%, at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 5 wt%, or at least 10 wt% Or less, 15 wt% or less, 10 wt% or less, or 5 wt% or less. Specifically from 0.02 to 10% by weight, and more specifically from 0.02 to 5% by weight. When it is included in the above range, it is not only suitable for exhibiting the intended effect of the present invention but also can satisfy both the stability and safety of the composition and may be suitably included in the above range in terms of cost effectiveness. Concretely, when it is less than 0.01% by weight, sufficient skin whitening effect can not be obtained, and when it exceeds 20% by weight, it is not preferable because it is low in cost.

In one aspect of the invention, the composition may comprise 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 dissolution aid may be at least one selected from the group consisting of polyethylene glycol / polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400. Specifically, the first dissolution aid may include both polyethylene glycol / polypropylene glycol copolymer and propylene glycol, and may include polyethylene glycol-400. The polyethylene glycol / polypropylene glycol copolymer as the first dissolution aid is a PEG / PPG-17/6 copolymer, and propylene glycol is 1,3 Propanediol. ≪ / RTI >

In one aspect of the present invention, the solute and the first dissolution aid may be in a weight ratio of 1: 0.1 to 9900. In one embodiment, the solute and the first solubilizer are present in a ratio of 1: 0.5 or greater, 1: 1 or greater, 1: 1.5 or greater, 1: 2.0 or greater, 1: 5 or greater, 1: 10 or greater, 1 or more, 1: 80 or more, 1: 100 or more, 1: 200 or more, 1: 500 or more, 1: 800 or more, May be more than 5000. 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 1:40 or less, 1:30 or less, 1:20 or less, 1:10 or less, or 1: 5 or less. Specifically, the solute and the first solubilizer may be in a weight ratio of 1: 50 to 700.

In one aspect of the present invention, the first dissolution auxiliary agent may be contained in an amount of 0.1 to 99% by weight based on the total weight of the composition. In one embodiment, the first solubilizing adjuvant is present in an amount of at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt% , At least 6 wt%, at least 10 wt%, at least 20 wt%, at least 30 wt%, or at least 35 wt%. The first solubilizing agent may be present in an amount of 99 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or 5 wt% or less, ≪ / RTI >

In one aspect of the present invention, the third dissolution aid is selected from the group consisting of Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, (Hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer) and polyacrylate-13 / polyisobutene / polysorbate-20 (polyacrylate-13 / polyisobutene / polysorbate-20) . ≪ / RTI >

In one aspect of the present invention, the second dissolution aid may be included in an amount of 0.1 to 98% by weight based on the total weight of the composition. In one embodiment, the second solubilizing adjuvant is present in an amount of at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt% , At least 6 wt%, at least 10 wt%, at least 20 wt%, at least 30 wt%, or at least 35 wt%. The second solubilizing agent may be present in an amount of up to 98% by weight, up to 95% by weight, up to 90% by weight, up to 85% by weight, up to 80% by weight, up to 60% by weight, up to 50% 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or 5 wt% or less, ≪ / RTI >

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

In one aspect of the present invention, the second dissolution aid, cyclodextrin, is selected from the group consisting of? -Cyclodextrin,? -Cyclodextrin,? -Cyclodextrin, hydroxypropyl-? -Cyclodextrin, Hydroxypropyl- < RTI ID = 0.0 > y-cyclodextrin. ≪ / RTI >

In one aspect of the present invention, the third dissolution aid is selected from the group consisting of Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Sodium acryloyldimethyl taurate copolymer, polyacrylate-13 / polyisobutene / polysorbate-20, sodium acrylate / sodium acrylate / sodium acrylate / Sodium Magnesium Silicate, Bentonite, Poloxamer 407, Hydroxypropyl Starch Phosphate, Pigment-240 / HI Dia Copolymer Bis-Decyl Tetraseth-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, Chalcone, ammonium acryloyldimethyltaurate, VP copolymer, carbomer, carrageenan, ceratonia siliqua gum, cyanoboxystetra gonorrobar, agar, potassium chloride and glucose, polyquaternium-7, poly Polyvinylpyrrolidone, quaternium-10, polyquaternium-67, cetylhydroxyethylcellulose, dihydroxanthan gum, dextrin myristate, gellan gum, glycerin, glyceryl acrylate, acrylic acid copolymer, hydrolyzed wheat protein, PVP crosspolymer, Polyglycerin-3 copolymers, polymethylsuccioxane, phenoxyethanol, chlorphenesin (chlorphenesin), and the like. ), Capryl glycols, mannan, oleaguae oil, butadiene, styrene copolymers, PEG-240 / HDI copolymer bis-decyltetraseth-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 carboxy Methyl stearate, hydrogene polydecene, PPG-5-laureth-5, stearalkonium, hectorite, styrene, acrylate, ammonium methacrylate copolymer, tamarind deuce indica seed polysaccharide, VP, methacrylamide, vinyl But are not limited to, imidazole copolymers, palmet-25 acrylate copolymers, VA copolymers, butylene glycol, 1,2-hexanediol, caprylyl glycol, Tropolone, Mannan or Zea May ) It can be starch , Cellulose gum; Xanthan gum; Sodium polyacrylate; Hydroxypropylmethylcellulose; Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer; Polyacrylate-13 / polyisobutene / polysorbate-20; Sodium magnesium silicate; Bentonite; Poloxamer 407; Hydroxypropyl starch phosphate; ≪ tb > < SEP > 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 / serratonia germplasia gum / cyanobacter stitra gonorrobar / agar / potassium chloride and glucose; Polyquaternium-7; Polyquaternium-10; Polyquaternium-67; Cetylhydroxyethylcellulose; Dihydroxanthan gum; Dextrin myristate; Gellan gum; Glycerin / glyceryl acrylate / acrylic acid copolymer; Hydrolyzed wheat protein. PVP crosspolymer; Isononanoyl diglycerine; Dilinoleic acid copolymer; Lauryl dimethicone / polyglycerin-3 copolymer / polymethylsuccioxane / phenoxyethanol / chlorphenesin / caprylglycol; Met; Olea oil, olivary 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 copolymers; Potassium alginate; PVP; Sodium carboxymethyl starch; Sodium polyacrylate / hydrogene polydecene / PPG-5-laureth-5; Stearalkonium; Hectorite; Styrene / acrylate / ammonium methacrylate copolymers; Tamarin deuce Indica seed polysaccharide; VP / methacrylamide / vinyl imidazole copolymer; Acrylate / palmet-25 acrylate copolymer; Ethylene / VA copolymer, butylene glycol, 1,2-hexanediol, caprylyl glycol, Tropolone, or Zea May (maize) starch. Specific examples of the polymer include cellulose gum, xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate / sodium acryloyldimethyltaurate ko (Hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer) or polyacrylate-13 / polyisobutene / polysorbate-20.

In one aspect of the present invention, the third dissolution aid may be included in an amount of 0.1 to 98% by weight based on the total weight of the composition. In one embodiment, the third solubilizing aid is present in an amount of at least 0.1%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5% , At least 6 wt%, at least 10 wt%, at least 20 wt%, at least 30 wt%, or at least 35 wt%. The third solubilizing aid may be present in an amount of up to 98% by weight, up to 95% by weight, up to 90% by weight, up to 85% by weight, up to 80% by weight, up to 60% by weight, up to 50% 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or 5 wt% or less, ≪ / RTI >

In one aspect of the present invention, the weight ratio of the solute, the first dissolution aid, the second dissolution aid, and the third dissolution aid may be 1:10 to 200: 1 to 20: 1 to 20. In one embodiment, the weight ratio is 1:15 or higher: 2 or higher: 2 or higher, 1:20 or higher: 3 or higher: 3 or higher, 1:50 or higher: 4 or higher: 4 or higher, 1:70 or higher: 5 or higher: 5 Or more than 1:90: 6 or more: 6 or more. 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 : 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 improve or prevent spots, freckles, dots and skin pigmentation.

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

In one aspect of the invention, the composition may be a cosmetic composition. The cosmetic composition of the present invention may be prepared in any formulation conventionally produced in the art and may be in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant- , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto.

In one aspect of the invention, the composition may be a pharmaceutical composition. The pharmaceutical composition may exhibit an excellent skin whitening effect and specifically improve or treat spots, freckles, dots and skin pigmentation. The pharmaceutical composition according to one aspect of the present invention can be administered by parenteral, rectal, topical, transdermal, intravenous, intramuscular, intraperitoneal, subcutaneous, and the like. Formulations for parenteral administration may be, but are not limited to, solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or spray formers. The formulations may be readily prepared according to conventional methods in the art and may be prepared by conventional means including, but not limited to, surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, Other commonly used adjuvants may be used.

The effective ingredients 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, route of administration, or judgment of the prescriber. Determination of the amount of application based on these factors is within the level of ordinary skill in the art and its daily dose is, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / / Day, but is not limited thereto.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

[ Example  1-8] 5- Adamantan Yl-N- (2,4- Dihydroxybenzyl ) -2,4- Dimethoxy -Benzoic acid amide (hereinafter referred to as " DBAB ) ≪ / RTI >

15% by weight of PEG / PPG-17/6 COPOLYMER (Konlub) and 20% by weight of 1,3-Propanediol (Fermandiol) as the first dissolution aid were added to the second dissolution aid 0.5% by weight of hydroxypropylcyclodextrin (hereinafter, CD purchased from NIHON SHOKUHIN) and 1% by weight of Cellulose Gum (CMC) as a third dissolution aid were added, and the remaining contents were filled with water and homomixer homomixer Mark 2 model) at 3000 rpm for 10 minutes. DBAB was then added and mixed for 20 minutes with a homomixer to produce Example 1.

The composition was prepared in the same manner as in Example 1 except that the first dissolution aid was PEG-400 5 wt%, the second dissolution aid was CD 0.6 wt%, and the third dissolution aid was the following The compositions of Examples 2 to 8 were prepared.

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

Example 3: Sodium Polyacrylate 0.5 wt%

Example 4: Xanthan Gum 0.5 wt%

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

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

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

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

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

DBAB was prepared in the same manner as in Example 1 except that the first and second dissolution aids and second dissolution aids were the same and only the third dissolution aid was Hydroxyethylcellulose (Natrosol 250HR ) Was prepared in an amount of 1.0% by weight, and the solubilities of the above Example 1 and Comparative Example 1 were confirmed. As a result, Example 1 was dissolved in a transparent state (FIG. 1), but it was found that Comparative Example 1 was not transparently melted and its solubility was poor.

[ Experimental Example  2] PEG-400 1st  Dissolution aids and various types of Third  Solubility test of solubilizer containing solubilizer

The solubilities of the above Examples 2 to 8 were confirmed in order to confirm solubility enhancing agents for improving the solubility of DBAB.

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

In the case of Examples 3 to 8, in which the content of the third dissolution aid is 0.5% by weight, the content and the content of the first dissolution aid and the second dissolution aid are the same, (Example 4), Hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer (Example 5), Polyacrylate-sodium acrylate dimethacrylate copolymer (Example 5), and Comparative Examples 4 to 6 (the third dissolution assistant was Xanthan Gum 13 / Polyisobutene / Polysorbate-20 (Example 6)) was also confirmed to be dissolved transparently. Examples 7 and 8, which contain HPMC as the third solubilizing aid and have a content of 0.5 wt% different from Example 2, are not excellent in solubility as compared with Examples 3 to 6, but DBAB is transparently melted (see Fig. 1 ).

In addition, the types and contents of the first dissolution aid and the second dissolution aid were the same as those of Examples 3 to 8, and the third dissolution aid was 0.5 wt%, and the third dissolution aid was Sodium Magnesium Silicate 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 Example 7), Magnesium Aluminum Silicate (Comparative Example 8), and Polyvinylpyrrolidone (Comparative Example 9) were mixed with DBAB in the same manner as in the above examples to confirm solubility. As a result, all of Comparative Examples 2 to 9 did not melt And it was found that the solubility was not good.

[ Experimental Example  3] Confirm stability

As a result of confirming the stability of Examples 3 to 8, Example 3 was kept stably when stored for 13 days in a 45 ° C thermostat

[ Experimental Example  4] DBAB , 1st  Dissolution aids, Second  Dissolution aids and Third  Determination of solubility according to type and content of dissolution aid

To confirm the degree of enhancement of the solubility of DBAB according to the contents of the first dissolution aid, second dissolution aid, and third dissolution aid, the first dissolution aid was prepared in the same manner as in Example 1 except that 5 wt% (Example 9) so as to contain PEG / PPG-17/6 COPOLYMER (Konlub), 0.6 wt% CD as the second dissolution aid and 0.5 wt% HPMC (Pharmacoat 630 HPMC) as the third dissolution aid As a result of confirming the solubility, it was confirmed that it was dissolved in a transparent state.

[ Experimental Example  5] DBAB , Third  Determination of solubility according to the content of dissolution aid

The composition (Example 10) was prepared by adding 3.0% by weight of sodium polyacrylate as a third dissolution aid to 0.1% by weight of DBAB and filling the remaining contents with water. As a result of checking the solubility, (Fig. 2). ≪ tb > < TABLE >

Hereinafter, a formulation example of the composition according to the present invention will be described, but this is not intended to limit the present invention, but merely to illustrate it.

[ Formulation Example  1] Flexible lotion

Flexible lotion was prepared by a conventional method according to the composition shown in Table 1 below.

ingredient Content (% by weight) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 hydrogenated castor oil 1.2 wt% ethanol 5.0 wt% Butylene glycol 2.0 wt% Propylene glycol 2.0 wt% Preservative, coloring, fragrance Suitable amount Purified water Balance

[ Formulation Example  2] Nourishing lotion ( milk  Lotion)

Nutrition lotion was prepared according to a conventional method according to the composition shown in Table 2 below.

ingredient Content (% by weight) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 hydrogenated castor oil 2.0 wt% glycerin 3.0 wt% Butylene glycol 3.0 wt% Propylene glycol 3.0 wt% Carboxyvinyl polymer 0.1 wt% Wax 4.0 wt% Caprylic / capric triglyceride 5.0 wt% Squalane 5.0 wt% Liquid paraffin 0.5 wt% Cetearyl alcohol 1.0 wt% Triethanolamine 0.2 wt% Preservative, coloring, fragrance Suitable amount Purified water Balance

 [ Formulation Example  3] Nourishing cream

Nutrition creams were prepared according to the compositions shown in Table 3 below in a conventional manner.

ingredient Content (% by weight) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 hydrogenated castor oil 3.0 wt% glycerin 3.0 wt% Butylene glycol 3.0 wt% Liquid paraffin 7.0 wt% Beta Glucan 7.0 wt% Carbomer 0.1 wt% Caprylic / capric triglyceride 3.0 wt% Squalane 5.0 wt% Cetearyl glucoside 1.5 wt% Sorbitan stearate 0.4 wt% Triethanolamine 0.1 wt% Preservative, coloring, fragrance Suitable amount Purified water Balance

 [ Formulation Example  4] Massage cream

Massage creams are prepared in a conventional manner according to the composition shown in Table 4 below.

ingredient Content (% by weight) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 hydrogenated castor oil 4.0 wt% Vitamin E acetate 5.0 wt% glycerin 8.0 wt% Butylene glycol 4.0 wt% Liquid paraffin 45.0 wt% Beta Glucan 7.0 wt% Carbomer 0.1 wt% Caprylic / capric triglyceride 3.0 wt% Wax 4.0 wt% Cetearyl glucoside 1.5 wt% Sesquioleic acid sorbitan 0.9 wt% Vaseline 3.0 wt% paraffin 1.5 wt% Preservative, coloring, fragrance Suitable amount Purified water Balance

 [ Formulation Example  5] Pack

The pack is prepared in a conventional manner according to the composition shown in Table 5 below.

ingredient Content (% by weight) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 hydrogenated castor oil 4.0 wt% Vitamin E acetate 8.0 wt% glycerin 4.0 wt% Polyvinyl alcohol 15.0 wt% Hyaluronic acid extract 5.0 wt% Beta Glucan 7.0 wt% Allantoin 0.1 wt% Nonyl phenyl ether 0.4 wt% Polysorbate 60 1.2 wt% ethanol 6.0 wt% Preservative, coloring, fragrance Suitable amount Purified water Balance

[ Formulation Example  6] Ointment

Ointments were prepared in a conventional manner according to the composition shown in Table 6 below.

ingredient Content (% by weight) DBAB 0.1 wt% PEG-400 5.0 wt% HPMC 1.0 wt% CD 0.6 wt% PEG-30 hydrogenated castor oil 3.0 wt% Vitamin E acetate 4.0 wt% Butylene glycol 4.0 wt% Liquid paraffin 15.0 wt% Beta Glucan 7.0 wt% Carbomer 0.1 wt% Caprylic / capric triglyceride 3.0 wt% Squalane 1.0 wt% Cetearyl glucoside 1.5 wt% Sorbitan stearate 0.4 wt% Cetearyl alcohol 1.0 wt% Wax 4.0 wt% Preservative, coloring, fragrance Suitable amount Purified water Balance

Claims (15)

A solute which is a compound of the following formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
Polyethylene glycol / polypropylene glycol copolymer, propylene glycol, and polyethylene glycol-400;
A second dissolution aid, which is cyclodextrin; And
Cellulose gum, Xanthan gum, sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer (hydroxyethyl acrylate) and a third dissolution assistant selected from the group consisting of polyacrylate-13 / polyacrylate / sodium acryloyldimethyl taurate copolymer and polyacrylate-13 / polyisobutene / polysorbate-20. Composition:

[Chemical Formula 1]

In Formula 1,
R ₁ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy,
R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₅ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₅ haloalkyl,
n is an integer selected from 1 to 5;
The method according to claim 1,
Wherein R ₁ , R ₃ and R ₄ are independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₃ haloalkoxy, Selected,
R ₂ is selected from the group consisting of hydrogen, C ₁ to C ₃ alkyl, C ₃ to C ₆ cycloalkyl, aryl and C ₁ to C ₃ haloalkyl,
and n is an integer selected from 1 to 3, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
3. The method of claim 2,
The solute
5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2,4- dihydroxy- benzoic acid amide,
5-adamantan-1-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -2-hydroxy-4- methoxy- benzoic acid amide,
5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,
5-adamantan-1-yl-N- (3,4-dihydroxybenzyl) -2-hydroxy-4-methoxy- benzoic acid amide,
2,4-dihydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -benzoic acid amide,
5-adamantan-l-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,
(2,4-dihydroxybenzyl) -2-hydroxy-4-methoxy-benzoic acid amide, 5-adamantan-
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-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-l-yl-N- [2- (3,4-dihydroxyphenyl) -ethyl] -4- methoxy- benzoic acid amide,
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-l-yl-N- (2,4-dihydroxybenzyl) -4-methoxy- benzoic acid amide,
5-adamantan-1-yl-N- (2,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acid amide,
5-adamantan-1-yl-N- (2,5-dihydroxybenzyl) -2,4-dihydroxy-benzoic acid amide,
5-Adamantan-1-yl-N- (3,5-dimethoxybenzyl) -2,4-dihydroxy-benzoic acid amide and
5-adamantan-1-yl-2,4-dihydroxy-N- (3-hydroxy-5-methoxybenzyl) -benzoic acid amide, its isomers and its pharmaceutically acceptable salts A salt thereof, a hydrate thereof or a solvate thereof.
The method of claim 3,
Wherein the solute is 5-adamantan-1-yl-N- (2,4-dihydroxybenzyl) -2,4-dimethoxy-benzoic acid amide.
The method according to claim 1,
Wherein the solute is contained in an amount of 0.01 to 20% by weight based on the total weight of the composition.
The method according to claim 1,
The polyethylene glycol / polypropylene glycol copolymer is a Pigment / PPE-17/6 copolymer (PEG / PPG-17/6 copolymer)
Wherein the propylene glycol is 1,3-propanediol.
The method according to claim 1,
Wherein the solute and the first dissolution aid are in a weight ratio of 1: 0.1 to 9900.
The method according to claim 1,
Wherein the first dissolution auxiliary agent is 0.1 to 99% by weight based on the total weight of the composition.
The method according to claim 1,
Cyclodextrin is at least one of? -Cyclodextrin,? -Cyclodextrin,? -Cyclodextrin, hydroxypropyl-? -Cyclodextrin, hydroxypropyl-? -Cyclodextrin and hydroxypropyl-? -Cyclodextrin, ≪ / RTI >
The method according to claim 1,
Wherein the second dissolution auxiliary agent is 0.1 to 98% by weight based on the total weight of the composition.
The method according to claim 1,
Wherein the weight ratio of the solute, the first dissolution aid and the second dissolution aid is in a weight ratio of 1: 50 to 500: 1 to 20.
The method according to claim 1,
Wherein the third dissolution auxiliary agent is 0.1 to 98% by weight based on the total weight of the composition.
The method according to claim 1,
Wherein the weight ratio of the solute, the first dissolution aid, the second dissolution aid, and the third dissolution aid is a weight ratio of 1:10 to 200: 1 to 20: 1 to 20.
14. The method according to any one of claims 1 to 13,
The composition for external application for skin is a composition for whitening skin.
14. The method according to any one of claims 1 to 13,
The composition for external application for skin is a pharmaceutical or cosmetic composition.

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