WO2016122172A1 - Composition pour favoriser la santé capillaire ou la pousse des cheveux, présentant une stabilité améliorée et contenant de la mélatonine - Google Patents

Composition pour favoriser la santé capillaire ou la pousse des cheveux, présentant une stabilité améliorée et contenant de la mélatonine Download PDF

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WO2016122172A1
WO2016122172A1 PCT/KR2016/000742 KR2016000742W WO2016122172A1 WO 2016122172 A1 WO2016122172 A1 WO 2016122172A1 KR 2016000742 W KR2016000742 W KR 2016000742W WO 2016122172 A1 WO2016122172 A1 WO 2016122172A1
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composition
hair growth
melatonin
hair
weight
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PCT/KR2016/000742
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English (en)
Korean (ko)
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이풍석
이동일
전예지
유영근
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현대약품 주식회사
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Priority to CN201680007880.2A priority Critical patent/CN107205908B/zh
Publication of WO2016122172A1 publication Critical patent/WO2016122172A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • 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
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • 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
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • 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
    • A61K8/67—Vitamins
    • A61K8/673—Vitamin B group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition for promoting hair growth, wool or hair growth which has dramatically improved stability, dosage compliance and therapeutic effect.
  • Human hair loss cycle is largely divided into anagen, catagen and telogen.
  • the growth phase is a time when hair growth grows rapidly due to vigorous cell division and cell division.
  • the lifespan of the growing season varies depending on the type of hair, but for hair it is about 3-6 years.
  • Growth hair accounts for 80-90% of the total hair, and hair loss is progressing in people who have short hair growth periods and long hair periods, resulting in a decrease in the proportion of growth hairs in the overall hair.
  • the degenerative phase is the end of the growth phase of the hair and the production of the hair gradually slows down, resulting in cell division and growth stopping.
  • the degenerative lifespan is about 1-1.5 months and about 1% of the hair belongs to this stage.
  • Resting phase is the final stage of growth when hair follicles and papillae are completely separated, causing hair follicles to atrophy and hair roots to rise upwards and hair fall out.
  • the rest period lasts 3-4 months and 4-14% of all hairs fall into this stage.
  • the activity of the nipple is active again, new nipples are created, and the hair in the resting period is pushed out of the scalp.
  • alopecia The main cause of alopecia is known to be related to male hormones and steroid hormones, and there are reports that stress is largely involved. Recently, it has been suggested that renal dysfunction is a direct cause of hair loss, Many are unknown about the cause or mechanism of occurrence.
  • Finasteride is a drug that inhibits the 5 ⁇ -reductase enzyme, which converts testosterone to dihydrotestosterone (DHT), and serves to grow soft hair into thick and long hair. It is effective in improving hair loss in the short term, but side effects such as erectile dysfunction, decreased sexual function, and breast enlargement in men have been reported.
  • Minoxidil is a drug that can be purchased without a doctor's prescription because of its safety and effectiveness. In December 1997, it was approved by the US FDA as the first anti-hair loss treatment. This drug has the effect of promoting hair growth by improving blood circulation and opening potassium channels, but it may cause local reactions such as itching and rashes, and tachycardia.
  • Melatonin is a hormone produced and secreted by the pineal gland of the brain and is made through tryptophan (serotonin).
  • Melatonin is an endocrine modulator that has the function of regulating hair growth, pigmentation or peeling, is capable of controlling the hair cycle, and promotes hair growth as a DNA repair derivative.
  • melatonin may be an alternative to minimize various side effects of existing hair loss treatments, but it is difficult to commercialize it in the form of external preparations due to its low light stability and relatively low solubility. Therefore, there is a need for the development of a pharmaceutical composition containing melatonin as a pharmacological component and having improved storage stability and excellent taking convenience while optimizing drug delivery efficiency and drug persistence.
  • the present inventors have made diligent research efforts to develop a composition for promoting hair growth, wool, or hair growth which has less side effects than conventional hair loss treatment agents and has excellent storage stability and administration convenience.
  • the inclusion of melatonin, dexpanthenol, biotin and nicotinic acid amide in certain amounts improves the light stability of pharmacological melatonin, improves the transparency of the formulation, and maximizes drug absorption, especially transdermal penetration.
  • the present invention has been completed by discovering that the stability of the formulation can be greatly improved by minimizing chemical and physical changes caused by ultraviolet rays during storage.
  • Another object of the present invention to provide a method for promoting hair growth, wool or hair growth.
  • the present invention provides a composition for promoting hair growth, wool or hair growth comprising melatonin, dexpanthenol, biotin and nicotinic acid amide as an active ingredient.
  • the present inventors have made diligent research efforts to develop a composition for promoting hair growth, wool, or hair growth which has less side effects than conventional hair loss treatment agents and has excellent storage stability and administration convenience.
  • the inclusion of melatonin, dexpanthenol, biotin and nicotinamide in a certain amount improves the light stability of the pharmacological melatonin, improves the transparency of the formulation, and improves the absorption of the drug, It has been found that the physical change can be minimized to significantly improve the stability of the formulation.
  • the antioxidant effect can be maximized to prevent inflammation and show anti-inflammatory effects.
  • promoting hair growth means promoting the production and growth of hair and ultimately increasing the proportion of growing hair in total hair. Therefore, the term means inhibiting hair loss caused by decreasing the specific gravity of growing hair, and therefore has the same meaning as “improve hair loss”, “hair loss prevention” and “hair loss treatment”.
  • melatonin used in the present invention is included in an amount of 0.001-1.0 wt% based on the total amount of the composition of the present invention. More specifically, it is included in 0.005-0.5% by weight, even more specifically, it is included in 0.01-0.3% by weight, and most specifically, it is included in 0.05-0.2% by weight.
  • dexpanthenol used in the present invention is included in an amount of 0.01-0.5% by weight based on the total amount of the composition of the present invention. More specifically, it is included at 0.02-0.4% by weight, even more specifically, it is included at 0.05-0.3% by weight, and most specifically, it is included at 0.1-0.2% by weight.
  • the biotin (biotin) used in the present invention is included in 0.001-0.05% by weight relative to the total amount of the composition of the present invention. More specifically, it is included in 0.002-0.04% by weight, even more specifically, it is included in 0.005-0.03% by weight, most specifically, it is included in 0.01-0.02% by weight.
  • nicotinamide used in the present invention is included at 0.006-0.3% by weight based on the total amount of the composition of the present invention. More specifically, it is included as 0.012-0.24% by weight, even more specifically, it is included as 0.03-0.18% by weight, and most specifically, it is included as 0.06-0.12% by weight.
  • the composition of the present invention further comprises a light stabilizer.
  • Photostabilization of the present invention includes, but is not limited to, the trapping of radicals, the decomposition of hydroperoxides, the trapping of heavy metals, and the stabilization by quenching of singlet oxygen, and possible physical and chemical changes due to exposure to visible and ultraviolet light. It includes any mechanism that blocks or mitigates.
  • the light stabilizers used in the present invention are, for example, triazole-based, benzophenone-based, hindered amine light stabilizer (HALS), hindered phenolic light stabilizer (Hindered Phenol Light Stabilizer), Al-Mg (aluminum Magnesium-based stabilizers, but is not limited thereto.
  • HALS hindered amine light stabilizer
  • Hindered Phenol Light Stabilizer hindered phenolic light stabilizer
  • Al-Mg aluminum Magnesium-based stabilizers, but is not limited thereto.
  • the light stabilizer used in the present invention is benzophenone. More specifically, the benzophenone is included in an amount of 0.008-0.5% by weight, more specifically 0.04-0.3% by weight, most specifically 0.08-0.2% by weight based on the total amount of the composition of the present invention. do.
  • the composition of the present invention further comprises a formulation stabilizer.
  • Formulation stabilizers are, for example, parahydroxybenzoic acid ester derivatives, pyrrolidinone derivatives, alcohols, phenol derivatives, thimerosal, acetic anhydride, sodium carboxylate, lauryl sulfate (lauryl sulfate), sulfide compounds, sulfites, ascorbic acid, retinol, recotinol, tocopherol, butyl hydroxy anisole, but are not limited thereto.
  • the agent stabilizer used in the present invention is methyl-2-pyrrolidinone. More specifically, the methyl-2-pyrrolidinone is included in the amount of 0.05-2.0% by weight, even more specifically 0.1-1.5% by weight, most specifically 0.5- 1.0 wt%.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the above-described active ingredient.
  • Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils, and the like. It doesn't happen.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, a kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
  • Suitable dosages of the pharmaceutical compositions of the present invention vary depending on factors such as the formulation method, mode of administration, age, weight, sex, pathological condition, food, time of administration, route of administration, rate of excretion, and response to response of the patient. Can be. Preferred dosages of the pharmaceutical compositions of the invention are in the range of 0.001-100 mg / kg on an adult basis.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered topically to the skin, subcutaneous infusion, transdermal administration, or the like.
  • the administration is preferably applied topically to the scalp or through transdermal administration.
  • compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container.
  • the formulation may be in the form of solutions, suspensions, syrups, emulsions or toners, lotions, creams and shampoos in oils or aqueous media, or in the form of extracts, powders, granules, tablets or capsules, It may further include.
  • the pharmaceutical composition of the present invention is an external skin composition.
  • the formulation of the external composition for skin is not particularly limited, but a powder, gel, ointment, cream, liquid or aerosol formulation is preferred.
  • the gel base material of the external skin preparation is carbomer, polyethylene glycol, polypropylene glycol, polyacrylic acid, carboxymethyl cellulose, hydroxymethyl cellulose. 1 selected from (Hydroxymethylcellulose), polyvinylpyrrolidone, gelatin, gelatin, alginate salt, chitin or chitosan derivatives, hyaluronic acid and collagen Species or two or more kinds may be used, but are not limited thereto.
  • composition of the present invention can be used as an external skin composition in the form of a topical application to the scalp.
  • the pharmaceutical composition of the present invention can be used for promoting hair growth, wool, or hair growth of all animals including humans, and the subject is not limited to humans.
  • the invention is a cosmetic composition.
  • Antioxidant composition of the present invention can be prepared in the form of hair growth, wool, or cosmetic composition for promoting hair growth.
  • the cosmetic composition of the present invention may be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, nourishing lotion, lotion, nourishing cream, massage cream, essence, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.
  • the carrier component is animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide. This can be used.
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.
  • solvents, solubilizers or emulsions are used as carrier components, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
  • liquid carrier diluents such as water, ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.
  • the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide.
  • Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
  • ingredients included in the cosmetic composition of the present invention include ingredients conventionally used in cosmetic compositions, and include, for example, conventional auxiliaries such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings. It may include.
  • the invention is a functional food composition.
  • Functional food compositions of the present invention include ingredients that are commonly added in the manufacture of food, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings.
  • ingredients that are commonly added in the manufacture of food, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings.
  • flavoring agents or natural carbohydrates may be included as additional ingredients in addition to the active ingredient.
  • natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); Disaccharides (eg maltose, sucrose, etc.); oligosaccharide; Polysaccharides (eg, dextrins, cyclodextrins, etc.); And sugar alcohols (eg, xylitol, sorbitol, erythritol, and the like).
  • flavoring agent natural flavoring agents (e.g., taumartin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.
  • natural flavoring agents e.g., taumartin, stevia extract, etc.
  • synthetic flavoring agents e.g., saccharin, aspartame, etc.
  • the present invention provides hair growth and wool comprising 0.001-1.0% by weight of melatonin, 0.01-0.5% by weight of dexpanthenol, 0.001-0.05% by weight of biotin and 0.006-0.3% by weight of nicotinic acid amide as active ingredients. Or it provides a pharmaceutical composition for promoting hair growth.
  • the present aspect of the hair growth, wool or hair growth promoting composition is another aspect of the hair growth, wool or hair growth promoting composition already described above to clearly limit the content of the active ingredient, the other aspect of the invention All the contents described in the detailed description are used, and overlapping contents will be omitted to avoid excessive complexity of the description.
  • the present invention provides a composition for preventing or treating hair loss comprising melatonin, dexpanthenol, biotin and nicotinamide as an active ingredient.
  • hair loss prevention means increasing the specific gravity of growth hair, thereby preventing hair loss caused by decreasing the specific gravity of the growth phase hair
  • hair loss treatment herein refers to the specific gravity of the growth phase hair described above.
  • Increasing means slowing the progression of hair loss, suppressing the symptoms of hair loss, and ultimately reducing the area of the scalp of the hair off state.
  • One aspect of the present invention uses the contents described for the composition for promoting hair growth, wool or hair growth, which is another aspect of the present invention described above, and overlapping contents will be omitted to avoid excessive complexity of the present specification.
  • Another aspect of the present invention is a pharmaceutical composition for preventing or treating hair loss comprising 0.001-1.0% by weight of melatonin, 0.01-0.5% by weight of dexpanthenol, 0.001-0.05% by weight of biotin and 0.006-0.3% by weight of nicotinic acid amide as active ingredients.
  • composition for preventing or treating hair loss is clearly defined in the content of the active ingredient in another aspect of the composition for preventing or treating hair loss described above, described in the detailed description of the invention with respect to the other aspect All contents are used, and overlapping contents will be omitted in order to avoid excessive complexity of the description of the present specification.
  • Another aspect of the present invention includes administering to a subject in need thereof a pharmaceutically effective amount of the composition for promoting hair growth, wool or hair growth comprising melatonin, dexpanthenol, biotin and nicotinamide as an active ingredient.
  • a pharmaceutically effective amount of the composition for promoting hair growth, wool or hair growth comprising melatonin, dexpanthenol, biotin and nicotinamide as an active ingredient.
  • the term "pharmaceutically effective amount” means an amount sufficient to promote hair growth, wool or hair growth of a subject using the above-described composition, and to achieve the effect of preventing, reducing or treating hair loss symptoms.
  • the term “subject” refers to any animal including a human, and is not particularly limited, and particularly refers to a hair, wool or an object in need of promoting hair growth. Since the method of the present invention relates to a method for administering the above-described hair growth, wool or hair growth promoting composition to a subject, the overlapping description is used, and the description is omitted to avoid excessive complexity of the description. .
  • Another aspect of the present invention comprises 0.001-1.0% by weight of melatonin, 0.01-0.5% by weight of dexpanthenol, 0.001-0.05% by weight of biotin and 0.006-0.3% by weight of nicotinic acid amide as active ingredients. It provides a method for promoting hair growth, wool or hair growth comprising administering a pharmaceutically effective amount of a to a subject in need thereof.
  • the method of the present invention relates to a method for administering the above-described hair growth, wool or hair growth promoting composition to a subject, and the specific content of the components of the hair growth, wool or hair growth promoting method described above in detail.
  • overlapping content is used, and the description is omitted to avoid excessive complexity of the description.
  • the present invention is hair growth, wool or hair growth promoting pharmaceutical composition, cosmetic composition or functional food composition comprising melatonin, dexpanthenol, biotin and nicotinamide as active ingredients, hair growth, wool or hair growth using the above-mentioned composition Provide a method of promotion.
  • composition of the present invention stabilizes the preparation and significantly inhibits scalp inflammation while improving the light stability of the pharmacologically active melatonin, thereby maximizing the hair growth or wool effect.
  • composition of the present invention can be usefully used as an effective hair regrowth, wool promoter, or prevention or treatment of hair loss at the same time increased light stability, preservation, ease of administration and therapeutic effect.
  • FIG. 1 shows the results of AREA OF HAIR RESTORATION 9 days after test substance treatment in dexamethasone induced alopecia C57BL / 6 mouse model.
  • the arrowed part of FIG. 1 shows the range analyzed using ImageJ software (NIH, Bethesda, MD) after photographing the application site with a digital camera.
  • Example 11 Comparative Example 1 Melatonin 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.01 0.2 - Dexpanthenol - 0.1 - - 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Biotin - - 0.01 - 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Nicotinic acid amide - - - 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 N-methyl-2-pyridyridone - - - - 0.5 One 0.5 0.5 0.5 0.5 0.5 - Benzophenone - - - - - - - 0.04 0.08 0.08 0.08 - Polyoxyl 40
  • Examples 1 to 5 are intended to establish a basic formulation formulation for establishing a formulation suitable for the efficacy, effect and properties of the composition of the present invention
  • Example 8 and Example 9 is the application of the composition to ensure the stability of the formulation from chemical and physical changes caused by ultraviolet light.
  • Free radicals are considered as a causative agent of aging (eg, hair loss, skin aging).
  • the antioxidant activity was measured by measuring the free radical scavenging activity according to the use of a light stabilizer.
  • a DPPH test group sample 0.1% by weight of melatonin, 0.01% by weight of biotin, 0.06% by weight of nicotinic acid amide and 0.1% by weight of dexpanthenol were stirred for 10 minutes until completely dissolved in ethanol. Then, a DPPH (1-diphenyl-2-picrylhydrazyl) solution was prepared with 80 ⁇ g / ml ethanol, and each fraction was dissolved in ethanol in 1 ml of the solution to a concentration of 2 mg / ml.
  • the color change of DPPH was then measured by absorbance at 517 nm at the wavelength of absorption using a UV spectrophotometer, and the inhibitory effect was calculated by calculating the magnitude of activity into the following equation:
  • Experimental results Melatonin, biotin, nicotinamide And dexpanthenol, the antioxidant effect was measured best, and when dexpanthenol, biotin, nicotinamide were used alone, the antioxidant effect was significantly higher than that containing all of melatonin, biotin, nicotinic acid amide, and dexpanthenol. The result is a decrease.
  • Table 3 The results are shown in Table 3.
  • a composition comprising melatonin, biotin, dexpanthenol and nicotinic acid amide as an active ingredient is prepared, and the effect of the composition of the active ingredient on the stability of melatonin Measured through stability test.
  • the photostability chamber was tested under VIS 40 klux conditions in accordance with Stability Testing: Photo stability Testing of New Drug Substances and Products (Q1b) of the International Conference on Harmonization (ICH) guidelines.
  • test group (Example 1-Example 5) was prepared according to the method of Table 2. And 50g each of the test group was filled in a pump-type transparent container (HDPE). The filled sample was placed in the irradiation direction in the light stability chamber and sampled by 2 mL at each time interval. When the sampling was completed, it was quantitatively analyzed by liquid chromatography (HPLC).
  • HPLC liquid chromatography
  • HPLC analysis conditions were the detector, ultraviolet ultraviolet photometer (wavelength 225 nm) column C18 (4.6 mm x 50 mm, 1.8 ⁇ m) or equivalent column, mobile phase 0.018 mol / L phosphate buffer (pH 3.0): acetonitrile ( 90: 10)
  • the flow rate was 1 mL / min
  • the injection amount was 50 ⁇ L
  • the temperature was 25 ° C.
  • the injection order was standard solution (3 times) and sample solution (2 times).
  • the stability of the formulation composition was higher in the melatonin, biotin, nicotinic acid amide and dexpanthenol group than in the melatonin alone group, and it was noted that mixing the biotin, nicotinic acid amide and dexpanthenol with the melatonin improved the content stability.
  • One effect was found. The results are shown in Table 4.
  • the phosphate buffer was prepared by dissolving 2.45 g of potassium dihydrogen phosphate in water to 1 L, and then adjusting the pH to 3.0 by adding 20% phosphoric acid.
  • each stabilizer (benzophenone, zinc oxide, ethylhexylsalicylate, titanium oxide) was added to 0.1% by weight of melatonin until it was completely dissolved in ethanol for 10 minutes. It was.
  • test group was filled in a pump-type transparent container (HDPE).
  • HDPE pump-type transparent container
  • HPLC analysis conditions were the detector was an ultraviolet absorbance spectrometer (wavelength 225 nm) column was C 18 (4.6 mm x 50 mm, 1.8 ⁇ m) or equivalent column, mobile phase 0.018 mol / L phosphate buffer (pH 3.0): acetonitrile ( 90: 10) The flow rate was 1 mL / min, the injection volume was 50 ⁇ L, the temperature was 25 ° C, and the injection order was standard solution (3 times) and sample solution (2 times).
  • the stabilizing activity was measured in the order of methyl-2-pyrrolidinone, ascorbic acid, tocopherol, butyl hydroxyanisole, and the most preferable bar stabilizer as the stabilizing activity of methyl-2-pyrrolidinone. It can be seen that methyl-2-pyrrolidinone can be used.
  • the photostabilization activity was measured in the order of benzophenone, zinc oxide, ethyl hexane salicylate, and titanium oxide.
  • the photostabilization activity of benzophenone was the best, and as a photostabilizer, benzophenone was most preferably used. there was.
  • the results are shown in Table 5 and Table 6.
  • the phosphate buffer solution was prepared by dissolving 2.45 g of potassium dihydrogen phosphate in water to 1 L, and then adjusting the pH to 3.0 by adding 20% phosphoric acid.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Melatonin Melatonin + Dexpanthenol Melatonin + Biotin Melatonin + Nicotinamide Melatonin + Biotin + Nicotinamide + Dexpanthenol 0 100.1 100.1 99.7 99.7 100.0 15 99.8 99.7 99.8 99.6 99.9 30 98.4 99.4 99.5 99.0 99.8 45 98.7 99.2 99.7 99.4 100.0 60 97.9 98.6 99.2 98.6 100.0 75 96.7 98.2 98.0 97.7 99.8 90 95.6 97.7 97.2 96.5 100.3 105 93.9 97.2 96.8 96.0 99.6 120 Not detected 93.7 92.4 90.7 99.3 (Unit: Melatonin Content (%))
  • benzophenone can be used as an excellent light stabilizer, but there are some known side effects such as disturbing the endocrine system, which may worsen allergic diseases.
  • Biotin, nicotinamide, and dexpanthenol combinations and methyl-2-pyrrolidinone to additionally include the group in melatonin, or to use methyl-2-pyrrolidinone, or to compensate for it while reducing the content of benzophenone It is possible to increase the light stability of melatonin in such a manner as to use.
  • the light stability of melatonin is significantly increased and further enhanced by additional inclusion of additional stabilizers or light stabilizers such as methyl-2-pyrrolidinone, benzophenone Stability can be secured.
  • the breeding box has a color-coded individual identification card, and the animal room use record sheet is attached at the entrance of the breeding room.
  • This test is set to a temperature of 23 ⁇ 3 °C, relative humidity of 55 ⁇ 15%, ventilation times of 10-20 times / hr, lighting time of 12 hours (lighting up from 8 am to 8 pm off) and illuminance of 150 to 300 Lux.
  • the study was conducted in Room 2 of the Rodent Breeding Area of the Korean Institute of Animal Science.
  • the environmental conditions such as temperature, humidity, ventilation frequency and illumination of the animal room were measured once a week. As a result of environmental measurement, no abnormality was observed that would adversely affect the test results.
  • Feed was supplied to Dream Feed of experimental animal feed produced by Cargill Agripurina Co., Ltd. and fed to the feeder freely.
  • the rug was used by receiving wooden rugs from Saron Bio.
  • mice with no skin scars and pink back skin were selected and randomly grouped. Each group was divided into excipient control group, positive control group (3% minoxidil administration group), HTB005 (1) ⁇ HTB005 (5) administration group to administer the test substance.
  • Clinical application was administered through the skin coating, and the test substance was administered once / day and 9 days from the 7th day after hair removal, and dexamethasone was administered once / day and 7 days from the 9th day after hair removal.
  • dexamethasone it was applied at 1 mL / head.
  • the spray was applied using a spray container (approximately 0.18 mL / 1 time) to spread the skin evenly over a section.
  • test substance and the positive control substance were applied using a spray container to spread a 1.5 cm ⁇ 1.5 cm size mold on the depilated skin and spread evenly in a predetermined section.
  • Body weight measurement It was measured on the day of hair removal, and once / week thereafter.
  • test substance application site was extracted and fixed in 10% neutral buffered formalin solution.
  • the tissues were prepared for histopathological examination, followed by H & E (Hematoxylin & Eosin) staining, hair follicle formation, and hair follicle growth rate. According to the hair growth effect evaluation was performed. The number of hair follicles and the growth period was evaluated by photographing using an optical microscope (Olympus BX53, Japan), and then randomly selecting 5 photos for each subject.
  • H & E Hematoxylin & Eosin
  • Minoxidil has been reported to be effective against androgenetic alopecia (Messenger AG et al, 2004) and was used as a positive control in this study.
  • the hair growth area of all the test substance-administered groups showed a tendency higher than that of the excipient control group at 7 days after the start of the test substance administration.
  • the hair growth area of the melatonin 0.01% and the melatonin 0.2% administration group tended to be higher than that of the excipient control group, and the hair growth area of the melatonin 0.01% and melatonin 0.2% administration groups was positive in the 12 and 16 days after the start of the administration of the test substance. The higher the tendency, the more likely that the test substance may help to promote hair growth.
  • the hair follicle ratio of the melatonin 0.01% and the melatonin 0.2% group tended to be higher than that of the positive control group.
  • the hair growth area of the 0.2% melatonin-treated group was higher than that of the excipient control group and the positive control group on all measurement days, and melatonin was observed.
  • the 0.01% administration group a higher tendency was observed in all measurement days except the 9th day compared to the excipient control group and the positive control group.
  • the number of hair follicles and growth rate of hair follicles of 0.01% melatonin and 0.2% melatonin administration group was higher than that of the excipient control group and the positive control group.
  • Rehair area unit % group 9th day G1 1.257 G2 22.33 G3 20 G5 10.1 G6 0.295 G7 37.2
  • Active hair follicles represent the proportion of individual hair follicles and hair converted to histopathologic findings in the hair growth test. Histopathological examination is divided into growth stage, resting stage and degenerative stage, and only the ratio of hair follicle growing stage is calculated. The growth stage, resting stage and degeneration stage were determined and determined by comprehensive consideration of the number of hair follicles, the size of hair follicles and the thickness and shape of hair. The calculation method is as follows:
  • Active hair follicle ratio number of animals in which the hair removal site is converted to growth / the total number of animals in each test group X 100.

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Abstract

La présente invention concerne une composition pharmaceutique pour favoriser la santé capillaire ou la pousse des cheveux, contenant de la mélatonine, du dexpanthénol, de la biotine et de nicotinamide en tant que principes actifs. La composition selon la présente invention maximise la croissance des cheveux ou les effets liés à la santé des cheveux, par la stabilisation d'une préparation, tout en améliorant la stabilité à la lumière de la mélatonine, qui est un principe pharmacologiquement actif, et en inhibant de façon significative l'inflammation du cuir chevelu. Par conséquent, la composition selon la présente invention peut être utile en tant que promoteur d'une pousse efficace des cheveux ou de la santé des cheveux ou en tant qu'agent pour la prévention ou le traitement de la chute des cheveux, ladite composition augmentant simultanément la stabilité à la lumière, la capacité de conservation, la commodité d'administration et les effets thérapeutiques.
PCT/KR2016/000742 2015-01-30 2016-01-22 Composition pour favoriser la santé capillaire ou la pousse des cheveux, présentant une stabilité améliorée et contenant de la mélatonine WO2016122172A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61212512A (ja) * 1985-03-19 1986-09-20 Shiseido Co Ltd 養毛料
JP2969179B2 (ja) * 1994-12-08 1999-11-02 クレット−ロッホ、ローレ、マリア 毛髪の成長，及び選択的には皮膚並びに爪の成長を促進し，抜け毛を防止又は抑制するための合成製剤
KR20050083836A (ko) * 2002-10-30 2005-08-26 아에스아테 아게 어플라이드 사이언스 앤드 테크놀로지 멜라토닌, 징코 빌로바, 및 비오틴을 포함하는 제제
KR20120051199A (ko) * 2010-11-12 2012-05-22 애경산업(주) 탈모방지 및 양모를 위한 모발 또는 두피 화장료 조성물
KR20140107010A (ko) * 2013-02-27 2014-09-04 케일럽 멀티랩 (주) 발모 촉진용 조성물

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1562585E (pt) * 2002-10-30 2011-02-23 Asat Ag Applied Science & Tech Unidades de dosagem diária de melatonina
DE102007039745A1 (de) * 2007-08-22 2009-02-26 Henkel Ag & Co. Kgaa Haarbehandlungsmittel mit Pflegestoff(en) und Melatonin/Agomelatin
DE102007039741A1 (de) * 2007-08-22 2009-02-26 Henkel Ag & Co. Kgaa Haarbehandlungsmittel mit Tensid(en) und Melatonin/Agomelatin
DE102007039743A1 (de) * 2007-08-22 2009-02-26 Henkel Ag & Co. Kgaa Haarbehandlungsmittel mit Alkohol(en) und Melatonin/Agomelatin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61212512A (ja) * 1985-03-19 1986-09-20 Shiseido Co Ltd 養毛料
JP2969179B2 (ja) * 1994-12-08 1999-11-02 クレット−ロッホ、ローレ、マリア 毛髪の成長，及び選択的には皮膚並びに爪の成長を促進し，抜け毛を防止又は抑制するための合成製剤
KR20050083836A (ko) * 2002-10-30 2005-08-26 아에스아테 아게 어플라이드 사이언스 앤드 테크놀로지 멜라토닌, 징코 빌로바, 및 비오틴을 포함하는 제제
KR20120051199A (ko) * 2010-11-12 2012-05-22 애경산업(주) 탈모방지 및 양모를 위한 모발 또는 두피 화장료 조성물
KR20140107010A (ko) * 2013-02-27 2014-09-04 케일럽 멀티랩 (주) 발모 촉진용 조성물

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