WO2020153520A1 - Composition comprenant un composé de type amide d'acide benzoïque et des agents de solubilisation - Google Patents

Composition comprenant un composé de type amide d'acide benzoïque et des agents de solubilisation Download PDF

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Publication number
WO2020153520A1
WO2020153520A1 PCT/KR2019/001082 KR2019001082W WO2020153520A1 WO 2020153520 A1 WO2020153520 A1 WO 2020153520A1 KR 2019001082 W KR2019001082 W KR 2019001082W WO 2020153520 A1 WO2020153520 A1 WO 2020153520A1
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Prior art keywords
benzoic acid
acid amide
composition
adamantan
skin
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PCT/KR2019/001082
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English (en)
Korean (ko)
Inventor
이창근
박성일
안지혜
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(주)아모레퍼시픽
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Priority to CN201980016877.0A priority Critical patent/CN111867559A/zh
Priority to PCT/KR2019/001082 priority patent/WO2020153520A1/fr
Publication of WO2020153520A1 publication Critical patent/WO2020153520A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

  • the present specification is a benzoic acid amide compound, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof; And a composition for external application for skin comprising a solubilizing agent, the composition relates to a composition characterized in that the solubility is improved.
  • Melanin protects the skin organs under the dermis by blocking ultraviolet rays in the epidermal layer and protects the skin by absorbing bio-free radicals.
  • melanin is a major factor in determining the color of the skin, and if it is present in excess, it is also a cause of skin pigmentation such as spots, freckles, and spots.
  • Melanin is made from melanocytes present in the base layer of the skin, and is known to promote production by irritation such as ultraviolet rays or inflammation. Therefore, it is possible to reduce external stimulation and block signal transmission, or to reduce the production of melanin by inhibiting or inhibiting the synthesis or activity of the melanin-producing enzyme tyrosinase.
  • kojic acid, hydroquinone, arbutin, azelaic acid, aloesine, 4-butylresorcinol, resveratrol, ceramide, sphingosine-1-phosphoric acid, sphingosylphosphorylcholine, etc. can promote the degradation of tyrosinase or regulate glycosylation. It is known that it can regulate melanin production. However, they were not highly utilized due to unsatisfactory whitening effect, low stability, and skin irritation. Recently, a benzoic acid amide substance having excellent whitening effect and low side effects has been studied.
  • the mulberry tree has traditionally been predicted to have a skin whitening effect from the fact that the hand of a person making Korean paper has been white and used as a raw material for producing Korean paper. Accordingly, scientific research has confirmed that kazinol, an ingredient with excellent whitening effect, is found in the roots of mulberry tree, and "Dak tree extract" is a functional cosmetic ingredient that is also announced by the Ministry of Food and Drug Safety.
  • Kazinols which are the whitening effect components in mulberry tree, was analyzed through molecular modeling techniques to analyze the functional groups that show the whitening effect of Kazinols.
  • Kazinol F despite the excellent whitening effect, it is present in a trace amount in mulberry tree and has a structure that is easily decomposed by temperature, making it difficult to use as a single component.
  • Dihydroxybenzyl Adamantnyldimethoxybenzamide is a new structure design that considers the structure, the active relationship (QSAR) and 3D-QSAR, among the 100 kinds of derivatives prepared by simulating the structure of Kazinol F, a trace component of mulberry tree. It is one compound. This compound inhibits melanin synthesis by reducing the MITF expression linked to the cAMP-PKA-CREB signal and, as a result, inhibiting the activity of tyrosinase, TRP-1, and TRP-2, the major proteins in relation to the melanin synthesis regulated by MITF. The mechanism of the new whitening effect was identified and confirmed through cells and artificial skin.
  • a novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP-PKA-CREB-activated microphthalmia-associated transcription factor and tyrosinase expression.
  • the inventors of the present invention came to the present invention by studying a composition containing a solubilizing agent for improving the solubility of a composition comprising a benzoic acid amide compound.
  • One aspect of the present invention is to provide a stable composition while improving the solubility of the benzoic acid amide compound.
  • One aspect of the present invention a compound of Formula 1, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof;
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;
  • a second dissolution aid that is a cyclodextrin
  • Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethylacrylate/Sodium acryloyl dimethyltaurate copolymer (hydroxyethyl external preparation for skin comprising a third soluble adjuvant selected from the group consisting of acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 Provides the composition:
  • 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.
  • composition according to one aspect of the present invention is excellent in solubility of the solute benzoic acid amide compound, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof.
  • the composition according to an aspect of the present invention does not precipitate a solute benzoic acid amide compound, has excellent solubility, and has excellent stability.
  • Example 10 of the present invention is a photograph confirming the stability of Example 10 of the present invention.
  • One aspect of the present invention a compound of Formula 1, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof;
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;
  • a second dissolution aid that is a cyclodextrin
  • Cellulose gum, Xanthan gum, Sodium Polyacrylate, Hydroxypropyl Methylcellulose, Hydroxyethylacrylate/Sodium acryloyl dimethyltaurate copolymer (hydroxyethyl external preparation for skin comprising a third soluble adjuvant selected from the group consisting of acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20 Provides the composition:
  • 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.
  • R 1 , R 3 and R 4 of Formula 1 are each hydrogen, hydroxy, C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, aryloxy and C 1 to C 3 halo Independently selected from the group consisting of alkoxy,
  • R 2 is selected from the group consisting of hydrogen, C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, aryl and C 1 to C 3 haloalkyl,
  • n may be an integer selected from 1 to 3, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof.
  • the solute is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the solute may be 5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acidamide.
  • the solute may be included in an amount of 0.01 to 20% by weight relative to the total weight of the composition.
  • the solute of the present invention may be at least 0.01% by weight, at least 0.02% by weight, at least 0.1% by weight, at least 0.5% by weight, at least 1% by weight, at least 5% by weight, or at least 10% by weight, based on the total weight of the composition, 20% by weight % Or less, 15% or less, 10% or less, or 5% or less. Specifically, it may be 0.02 to 10% by weight, and more specifically, 0.02 to 5% by weight.
  • the composition may include a water-soluble polar solvent as a solvent.
  • the composition may use water as a solvent.
  • 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.
  • the first dissolution aid may include both polyethylene glycol/polypropylene glycol copolymer and propylene glycol, and may include polyethylene glycol-400.
  • the first dissolution aid polyethylene glycol / polypropylene glycol copolymer is PEG / PPG-17/6 copolymer (PEG/PPG-17/6 copolymer), propylene glycol is 1,3 -Propanediol (1,3-propanediol).
  • the solute and the first solubilizing agent may be a weight ratio of 1: 0.1 to 9900.
  • the solute and the first solubilizing agent are 1:0.5 or more, 1:1 or more, 1:1.5 or more, 1:2.0 or more, 1:5 or more, 1:10 or more, 1:30 or more, 1: 50 or more, 1:80 or more, 1:100 or more, 1:200 or more, 1:500 or more, 1:800 or more, 1:1000 or more, 1:1500 or more, 1:2000 or more, 1:3000 or more, or 1: It can be 5000 or more.
  • the solute and the first solubilizer may be in a weight ratio of 1:50 to 700.
  • the first dissolution aid may be included in an amount of 0.1 to 99% by weight based on the total weight of the composition.
  • the first dissolution aid is 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more based on the total weight of the composition , 6% or more, 10% or more, 20% or more, 30% or more, or 35% or more.
  • the first dissolution aid is 99 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% Or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less or 5% or less It may be:
  • the third dissolution aid is cellulose gum (Cellulose gum), xanthan gum (Xanthan gum), sodium polyacrylate (Sodium Polyacrylate), hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxyethyl acrylic Group consisting of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer and polyacrylate-13/polyisobutene/polysorbate-20 It may be one or more selected from.
  • 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.
  • the second dissolution aid is 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more based on the total weight of the composition , 6% or more, 10% or more, 20% or more, 30% or more, or 35% or more.
  • the second dissolution aid is 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% Or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less or 5% or less It may be:
  • the weight ratio of the solute, the first solubilizer and the second solubilizer may be 1: 50 to 500: 1 to 20. In one embodiment, the weight ratio of the solute, the first solubilizer and the second solubilizer may be 1: 80 to 400: 3 to 15. In addition, it may be a weight ratio of 1: 90 to 300: 4 to 10, a weight ratio of 1: 95 to 200: 5 to 10, or a weight ratio of 1: 98 to 150: 5 to 7.
  • the second solubilizing agent cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and hydroxy Oxypropyl- ⁇ -cyclodextrin.
  • the third dissolution aid is cellulose gum (Cellulose gum), xanthan gum (Xanthan gum), sodium polyacrylate (Sodium Polyacrylate), hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxyethyl acrylic Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, polyacrylate-13/polyisobutene/polysorbate-20, sodium magnesium Sodium Magnesium Silicate, Bentonite, Poloxamer 407, Hydroxypropyl Starch Phosphate, PG-240/H Copolymer Bis-decyltetrases-20 ether (PEG- 240/HDI Copolymer Bis-Decyltetraceth-20 Ether), Polyvinyl Alcohol, Magnesium Aluminum Silicate, Polyvinylpirrolidone, Acrylate/C10-30 Alkyl Acrylate Crosspolymer ( Acrylic acid and alky
  • PVP crosspolymer Isononanoyl diglycerin; Dilinoleic acid copolymer; Lauryl dimethicone/polyglycerin-3 copolymer/polymethylsilsquioxane/phenoxyethanol/chlorphenesin/capryl glycol; Met; Olea Europaea (olive) oil, butadiene/styrene copolymer; Polyacrylamide/C13-14 isoparaffin/laures-7; Polyacrylate crosspolymer-8; Polyacrylate-2 crosspolymer; Polyurethane-10, PEG-12 dimethicone; Polyurethane-14 AMP-acrylate copolymer; Potassium alginate; PVP; Sodium carboxymethyl starch; Sodium polyacrylate/hydrogenated polydecene/PPG-5-laures-5; Stearalkonium; Hectorite; Styrene/acrylate/ammonium methacrylate copolymer; Tamarindue indica seed polysaccharides
  • cellulose gum xanthan gum, sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate co It may be a polymer (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) or polyacrylate-13/polyisobutene/polysorbate-20.
  • the third solubilizing agent may contain 0.1 to 98% by weight based on the total weight of the composition.
  • the third dissolution aid is 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more based on the total weight of the composition , 6% or more, 10% or more, 20% or more, 30% or more, or 35% or more.
  • the third dissolution aid is 98 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 60 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% Or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less or 5% or less It may be:
  • the weight ratio of the solute, the first solubilizer, the second solubilizer and the third solubilizer may be 1: 10 to 200: 1 to 20: 1 to 20. In one embodiment, the weight ratio is 1:15 or more: 2 or more: 2 or more, 1:20 or more: 3 or more: 3 or more, 1:50 or more: 4 or more: 4 or more, 1:70 or more: 5 or more: 5 Or more or more than 1:90:6 or more:6 or more.
  • the weight ratio is 1:150 or less:15 or less:15 or less, 1:140 or less:13 or less: 13 or less, 1:130 or less:11 or less: 11 or less, 1:110 or less:10 or less: 10 or less, 1 It may be :105 or less:8 or less:8 or less or 1:90 or less:7 or less:7 or less.
  • the composition for external application for skin may be a composition for skin whitening.
  • the composition for external application for skin may exhibit excellent skin whitening effects, and may specifically improve or prevent blemishes, freckles, spots, and skin pigmentation.
  • the composition for external application for skin may be a pharmaceutical or cosmetic composition.
  • the composition may be a cosmetic composition.
  • the cosmetic composition of the present specification may be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleaning , May be formulated as an oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto.
  • the composition may be a pharmaceutical composition.
  • the pharmaceutical composition may exhibit excellent skin whitening effects, and may specifically improve or treat blemishes, freckles, spots, and skin pigmentation.
  • the pharmaceutical composition according to one aspect of the present invention may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like.
  • Formulations for parenteral administration may be solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or sprays, but are not limited thereto.
  • formulations can be readily prepared according to conventional methods in the art, surfactants, excipients, hydrating agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, preservatives or Other commercial adjuvants can be used as appropriate.
  • the active ingredient of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, gender, weight, pathology and severity of the subject to be administered, the route of administration or the judgment of the prescriber. Determination of the application amount based on these factors is within the level of those skilled in the art, the daily dosage of which is, for example, 0.1 mg/kg/day to 100 mg/kg/day, more specifically 5 mg/kg/day to 50 mg/kg /Can be a day, but is not limited to this.
  • the present invention provides a compound of Formula 1, an isomer thereof, and a pharmaceutical thereof for an individual in need of prevention, improvement, or treatment of diseases related to skin whitening, such as spots, freckles, spots, and skin pigmentation
  • a solute that is an acceptable salt, hydrate or solvate thereof
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400
  • a second dissolution aid that is a cyclodextrin
  • cellulose gum, xanthan gum sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer
  • Composition comprising at least one third dissolution aid selected from the group consisting of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and polyacrylate-13/polyisobutene/polysorbate-20.
  • It may be related to a method for preventing, improving, or treating a disease related to skin whitening including administration of, for example, spots, freckles, spots, and skin pigmentation.
  • administration of the method may be performed according to the administration method and administration dose described herein.
  • the present invention provides a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof for preparing a pharmaceutical composition for skin whitening;
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;
  • a second dissolution aid that is a cyclodextrin;
  • cellulose gum, xanthan gum sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and a third soluble adjuvant selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; It may be about
  • the present invention is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof for preparing a cosmetic composition for skin whitening;
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;
  • a second dissolution aid that is a cyclodextrin;
  • cellulose gum, xanthan gum sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and a third soluble adjuvant selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; It may be about
  • the present invention is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solute thereof;
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;
  • a second dissolution aid that is a cyclodextrin;
  • the composition may relate to skin whitening use.
  • the present invention is a solute that is a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof for skin whitening use;
  • a first dissolution aid selected from the group consisting of polyethylene glycol/polypropylene glycol copolymer, propylene glycol and polyethylene glycol-400;
  • a second dissolution aid that is a cyclodextrin;
  • cellulose gum, xanthan gum sodium polyacrylate, hydroxypropylmethylcellulose, hydroxyethylacrylate/sodium acryloyldimethyltaurate copolymer ( hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer) and at least one third dissolution aid selected from the group consisting of polyacrylate-13/polyisobutene/polysorbate-20; It may be related to the composition.
  • solubilizing agent that enhances the solubility of DBAB
  • CD Hydroxypropyl cyclodextrin
  • the composition was prepared in the same manner as in Example 1, wherein the first dissolution aid was PEG-400 5% by weight, the second dissolution aid was 0.6% by weight of CD, and the type and content of the third dissolution aid was as follows.
  • the compositions of Examples 2 to 8 were prepared.
  • Example 2 Hydroxypropyl methylcellulose (hereinafter referred to as HPMC) (Pharmacoat 630 HPMC) 1 wt%
  • Example 3 Sodium Polyacrylate 0.5% by weight
  • Example 4 Xanthan Gum 0.5 wt%
  • Example 5 Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer 0.5 wt%
  • Example 6 0.5% by weight of Polyacrylate-13/Polyisobutene/Polysorbate-20
  • Example 7 HPMC (Pharmacoat 630 HPMC) 0.5% by weight
  • Example 8 HPMC (Methocel E4M) 0.5% by weight
  • Example 1 In order to confirm the solubilizing agent that enhances the solubility of DBAB, it was prepared in the same manner as in Example 1, but the first and second solubilizing agents were the same as in Example 1, and only the third solubilizing agent was hydroxyethylcellulose (Natrosol 250HR ) 1.0% by weight to prepare another Comparative Example 1, it was confirmed the solubility of Example 1 and Comparative Example 1. As a result, Example 1 was transparently dissolved (FIG. 1), but Comparative Example 1 was found to have poor solubility because it was not transparently dissolved.
  • Example 2 comprising 5% by weight of PEG-400 as the first solubilizer and 0.6% by weight of CD as the second solubilizer, and 1% by weight of HPMC as the third solubilizer, was transparently dissolved.
  • Example 3 Third Solubilizer: Sodium Polyacrylate
  • Examples 4 to 6 Third Solubilizer is Xanthan Gum (Example 4)
  • Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer Example 5
  • Polyacrylate- 13/Polyisobutene/Polysorbate-20 Example 6)
  • HPMC containing HPMC but unlike Example 2, the contents of Examples 7 and 8 having a content of 0.5% by weight were not excellent in solubility compared to Examples 3 to 6, but it was confirmed that DBAB was transparently dissolved (FIG. 1). ).
  • Examples 3 to 8 and the first dissolution aid and the second dissolution aid are the same, and the third dissolution aid contains 0.5% by weight, but the types of the third dissolution aid are respectively Sodium Magnesium Silicate (Compare Example 2), Bentonite (Comparative Example 3), Poloxamer 407 (Comparative Example 4), Hydroxypropyl Starch Phosphate (Comparative Example 5), PEG-240/HDI Copolymer Bis-Decyltetraceth-20 Ether (Comparative Example 6), Polyvinyl Alcohol (Comparative Example) Example 7), Magnesium Aluminum Silicate (Comparative Example 8), and the composition of Polyvinylpirrolidone (Comparative Example 9) was mixed with DBAB in the same manner as used in the above Examples to confirm the solubility. It was found that the precipitate had poor solubility.
  • Example 3 was kept stable when stored in a constant temperature bath at 45° C. for 13 days.
  • the second solubilizer and the third solubilizer prepared in the same manner as in Example 1, but the first solubilizer was 5% by weight A composition comprising PEG/PPG-17/6 COPOLYMER (Konlub), 0.6% by weight of CD as a second solubilizer, and 0.5% by weight of HPMC (Pharmacoat 630 HPMC) as a third solubilizer (Example 9)
  • PEG/PPG-17/6 COPOLYMER Konlub
  • HPMC Pharmacoat 630 HPMC
  • Example 10 After adding 3.0% by weight of sodium polyacrylate as a third dissolution aid to 0.1% by weight of DBAB, the remaining content was filled with water to prepare a composition (Example 10), and the solubility was confirmed. It was confirmed that it was dissolved with a gel (Fig. 2).
  • a flexible lotion was prepared by a conventional method.
  • Nutritional lotion was prepared in a conventional manner according to the composition shown in Table 2 below.
  • a nutritional cream was prepared in a conventional manner according to the composition shown in Table 3 below.
  • Packs are prepared by conventional methods according to the compositions listed in Table 5 below.
  • Ointments are prepared in a conventional manner according to the composition shown in Table 6 below.

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Abstract

La présente invention concerne une composition de préparation cutanée à usage externe comprenant : un soluté qui est un composé de type amide d'acide benzoïque, un isomère correspondant, un sel pharmaceutiquement acceptable correspondant, un hydrate correspondant ou un solvate correspondant ; un premier agent de solubilisation qui est un ou plusieurs éléments choisis dans le groupe constitué par un copolymère de polyéthylèneglycol/polypropylèneglycol, le propylèneglycol et le polyéthylèneglycol-400 ; un deuxième agent de solubilisation qui est une cyclodextrine ; et un troisième agent de solubilisation qui est un ou plusieurs éléments choisis dans le groupe constitué par la gomme de cellulose, la gomme de xanthane, le polyacrylate de sodium, l'hydroxypropylméthylcellulose, un copolymère d'acrylate d'hydroxyéthyle/acryloyldiméthyltaurate de sodium et le polyacrylate-13/polyisobutène/polysorbate-20 et concerne une composition de préparation cutanée à usage externe présentant une solubilité améliorée.
PCT/KR2019/001082 2019-01-25 2019-01-25 Composition comprenant un composé de type amide d'acide benzoïque et des agents de solubilisation WO2020153520A1 (fr)

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CN201980016877.0A CN111867559A (zh) 2019-01-25 2019-01-25 含有苯甲酰胺化合物以及增溶剂的组合物
PCT/KR2019/001082 WO2020153520A1 (fr) 2019-01-25 2019-01-25 Composition comprenant un composé de type amide d'acide benzoïque et des agents de solubilisation

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KR100683876B1 (ko) * 1999-08-16 2007-02-15 쉐링 악티엔게젤샤프트 벤즈아미드 유도체를 유효 성분으로 포함하는 약제
KR20150032534A (ko) * 2012-05-22 2015-03-26 제넨테크, 인크. Ｎ-치환된 벤즈아미드 및 통증의 치료에서 이들의 용도
KR20180036598A (ko) * 2016-09-30 2018-04-09 (주)아모레퍼시픽 벤조산아마이드 화합물 및 용해보조제를 포함하는 조성물
KR20180111350A (ko) * 2017-03-31 2018-10-11 (주)아모레퍼시픽 벤조산아마이드 화합물 및 사이클로덱스트린 용해보조제를 포함하는 조성물

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KR100683876B1 (ko) * 1999-08-16 2007-02-15 쉐링 악티엔게젤샤프트 벤즈아미드 유도체를 유효 성분으로 포함하는 약제
KR20050056198A (ko) * 2002-08-12 2005-06-14 비르키르 스베인슨 건선 치료를 위한 ｃｇｒｐ 안타고니스트 화합물의 용도
KR20150032534A (ko) * 2012-05-22 2015-03-26 제넨테크, 인크. Ｎ-치환된 벤즈아미드 및 통증의 치료에서 이들의 용도
KR20180036598A (ko) * 2016-09-30 2018-04-09 (주)아모레퍼시픽 벤조산아마이드 화합물 및 용해보조제를 포함하는 조성물
KR20180111350A (ko) * 2017-03-31 2018-10-11 (주)아모레퍼시픽 벤조산아마이드 화합물 및 사이클로덱스트린 용해보조제를 포함하는 조성물

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