WO2016122172A1 - Composition for hair health or hair growth promotion, having improved stability and containing melatonin - Google Patents

Composition for hair health or hair growth promotion, having improved stability and containing melatonin Download PDF

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Publication number
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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Prior art keywords
composition
hair growth
melatonin
hair
weight
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PCT/KR2016/000742
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French (fr)
Korean (ko)
Inventor
이풍석
이동일
전예지
유영근
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현대약품 주식회사
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Priority to CN201680007880.2A priority Critical patent/CN107205908B/en
Publication of WO2016122172A1 publication Critical patent/WO2016122172A1/en

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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

The present invention relates to a pharmaceutical composition for a hair health or hair growth promotion, containing melatonin, dexpanthenol, biotin and nicotinamide as active ingredients. The composition of the present invention maximizes hair growth or hair health effects by stabilizing a preparation while improving the light stability of melatonin, which is a pharmacologically active ingredient, and significantly inhibiting scalp inflammation. Therefore, the composition of the present invention can be useful as an effective hair growth or hair health promoter or as an agent for preventing or treating hair loss, the composition simultaneously increasing light stability, preservability, convenience of administration and therapeutic effects.

Description

멜라토닌을 포함하는 안정성이 개선된 육모, 양모 또는 발모 촉진용 조성물Composition for promoting hair growth, wool or hair growth with improved stability, including melatonin
본 특허출원은 2015년 1월 30일에 대한민국 특허청에 제출된 대한민국 특허출원 제10-2015-0015524호에 대하여 우선권을 주장하며, 상기 특허출원의 개시 사항은 본 명세서에 참조로서 삽입된다.This patent application claims priority to Korean Patent Application No. 10-2015-0015524 filed with the Korean Intellectual Property Office on January 30, 2015, the disclosure of which is incorporated herein by reference.
본 발명은 안정성, 투약 순응도 및 치료효과가 비약적으로 개선된 육모, 양모 또는 발모 촉진용 조성물에 관한 것이다.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.
사람의 탈모주기는 크게 성장기(anagen), 퇴행기(catagen) 및 휴지기 (telogen)로 구분된다. 성장기는 모유도의 활동이 활발하면서 세포분열이 왕성하게 일어나 모발이 빠른 속도로 자라는 시기이다. 성장기의 수명은 털의 종류마다 다르지만 머리카락의 경우, 3-6년 정도이다. 성장기 모발은 전체모발의 80-90%를 차지하며, 탈모가 진행되고 있는 사람은 성장기가 짧아지고 휴지기가 긴 모발주기를 가지게 되어 전체모발에서 성장기모발의 비중이 감소하게 된다. 퇴행기는 모발의 성장기가 끝나고 모발 생성이 점차 느려져 결국 세포분열 및 성장이 멈추는 시기로 퇴행기의 수명은 1-1.5개월 정도이며 전체 모발의 1% 정도가 이 단계에 속한다. 휴지기는 성장의 마지막 단계로서 모낭과 모유두가 완전히 분리되어 모낭은 위축되고 모근은 더욱 위쪽으로 올라가 머리카락이 빠지는 단계이다. 휴지기는 3-4개월간 지속되고 전체모발의 4-14%가 이 단계에 해당된다. 휴지기가 끝나고 다시 모유두의 활동이 활발해지면, 새로운 모발의 모유두가 만들어지면서 휴지기에 있던 모발은 밀려나서 완전히 두피 밖으로 빠져나오게 된다.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. After the rest period, 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.
탈모증의 주요 원인으로는 남성호르몬과 스테로이드 호르몬이 관련되어 있는 것으로 알려져 있으며, 스트레스가 크게 관여한다는 보고도 있고, 최근에는 신장 기능의 장애가 탈모의 직접적인 원인이라는 주장이 제시되고 있으나, 아직까지 정확한 탈모증의 원인이나 발생 기전에 대해서는 알려져 있지 않은 부분이 많다.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.
현재 탈모치료를 위한 제제는 크게 의약품과 의약외품, 그리고 화장품으로 분류된다. 의사의 처방이 있어야 구입이 가능한 전문의약품에는 미국 Merck사에서 개발 판매하고 있는'프로페시아'가 있으며, 이의 주성분인 피나스테라이드(Finasteride)는 1997년 12월 미국 FDA로부터 탈모치료제 승인을 받았다. 피나스테라이드는 테스토스테론을 디하이드로테스토스테론(dihydrotestosterone, DHT)으로 전환하는 5α-리덕테이즈 효소를 억제하는 약제로서 연모를 굵고 긴 모발로 성장하게 하는 역할을 한다. 이는 단기적으로 탈모개선에 효과가 있으나 발기부전, 성기능 감퇴, 남성의 유방비대 등과 같은 부작용이 보고되고 있다. 안전성과 유효성이 인정되어 의사의 처방 없이도 구입이 가능한 약품으로 미녹시딜(Minoxidil)이 있으며, 1997년 12월 미국 FDA로부터 최초의 바르는 탈모 치료제로 승인되었다. 이 약품은 혈액순환을 개선시키고 칼륨 채널을 개방시킴으로써 모발성장을 촉진시키는 효과가 있으나 가려움, 발진 등 국소반응이 올 수 있으며, 빈맥 등이 나타날 수 있다.Currently, drugs for treating hair loss are largely classified into medicines, quasi-drugs, and cosmetics. Specialty drugs that can be purchased only with a doctor's prescription include Propecia, developed and marketed by Merck, USA, and its main ingredient, Finasteride, was approved by the US FDA in December 1997 for hair loss treatment. Finasteride is a drug that inhibits the 5α-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.
멜라토닌은 뇌의 송과선에서 생성, 분비되는 호르몬으로 트립토판(tryptophan)이세로토닌(serotonin)을 거쳐 만들어진다. 멜라토닌은 내분비 조절제로서 모발 성장, 착색 또는 탈피를 조절하는 기능을 가지고 있으며, 모발주기 조절이 가능하고, DNA 회복 유도체로서 모발의 성장을 촉진한다. 이에 멜라토닌은 기존 탈모치료제의 다양한 부작용을 최소화할 수 있는 대안이 될 수 있음에도, 광안정성이 현저하게 떨어지고 용해도가 상대적으로 낮아 외용제 형태로의 제품화에 어려움이 많다. 따라서, 멜라토닌을 약리성분으로 포함하면서도 보관 안정성이 개선되고 복용 편의성이 우수하면서 약물전달 효율 및 약물지속성이 최적화된 약제학적 조성물의 개발이 요구되고 있다.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. Thus, 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.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Throughout this specification, many papers and patent documents are referenced and their citations are indicated. The disclosures of cited papers and patent documents are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.
본 발명자들은 기존의 탈모 치료제에 비해 부작용이 적으면서도 보관 안정성 및 투여 편의성이 우수한 육모, 양모 또는 발모 촉진용 조성물을 개발하고자 예의 연구 노력하였다. 그 결과, 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 일정 함량으로 포함시킬 경우 약리성분인 멜라토닌의광안정성이 개선되고 제제 성상 투명도가 향상되며, 약물흡수, 특히 경피투과흡수가 극대화될 뿐 아니라, 장기간 보관시에도 자외선에 의한 화학적, 물리적 변화가 최소화되어 제제의 안정성이 크게 개선될 수 있음을 발견함으로써, 본 발명을 완성하게 되었다.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. As a result, 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.
따라서 본 발명의 목적은 육모, 양모 또는 발모 촉진용 약제학적 조성물을 제공하는 데 있다.It is therefore an object of the present invention to provide a pharmaceutical composition for promoting hair growth, wool or hair growth.
본 발명의 다른 목적은 육모, 양모 또는 발모 촉진 방법을 제공하는 데 있다.Another object of the present invention to provide a method for promoting hair growth, wool or hair growth.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 조성물을 제공한다.According to one aspect of the invention, 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.
본 발명자들은 기존의 탈모 치료제에 비해 부작용이 적으면서도 보관 안정성 및 투여 편의성이 우수한 육모, 양모 또는 발모 촉진용 조성물을 개발하고자 예의 연구 노력하였다. 그 결과, 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 일정 함량으로 포함시킬 경우 약리성분인 멜라토닌의광안정성이 개선되고 제제 성상 투명도가 향상되며, 약물흡수 개선뿐만 아니라, 장기간 보관시에도 자외선에 의한 화학적, 물리적 변화가 최소화되어 제제의 안정성이 크게 개선될 수 있음을 발견하였다. 또한 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 일정 함량으로 포함시킬 경우 항산화 효과가 극대화 되어 염증 유발을 예방하고 항염증 효과를 보여 줄 수 있다The 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. As a result, 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. In addition, when melatonin, dexpanthenol, biotin and nicotinamide are included in certain amounts, the antioxidant effect can be maximized to prevent inflammation and show anti-inflammatory effects.
본 명세서에서 용어 "육모 촉진", "양모 촉진" 및 "발모 촉진"은 모발의 생성 및 성장을 촉진하여 궁극적으로 전체 모발에서 성장기 모발의 비중을 증가시키는 것을 의미한다. 따라서, 상기 용어는 성장기 모발의 비중이 감소함으로써 유발되는 탈모를 억제하는 것을 의미하므로,"탈모 개선", "탈모 예방" 및 "탈모 치료"와 동일한 의미를 가진다.As used herein, the terms "promoting hair growth", "promoting wool" and "promoting hair growth" mean 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".
본 발명의 구체적인 구현예에 따르면, 본 발명에서 이용되는 멜라토닌(melatonin) 은 본 발명의 조성물 총량에 대해 0.001-1.0 중량%로 포함된다. 보다 구체적으로는, 0.005-0.5 중량%로 포함되며, 보다 더 구체적으로는, 0.01-0.3 중량%로 포함되며, 가장 구체적으로는, 0.05-0.2 중량%로 포함된다. According to a specific embodiment of the present invention, 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.
본 발명의 구체적인 구현예에 따르면, 본 발명에서 이용되는 덱스판테놀(dexpanthenol)은 본 발명의 조성물 총량에 대해 0.01-0.5 중량%로 포함된다. 보다 구체적으로는, 0.02-0.4 중량%로 포함되며, 보다 더 구체적으로는, 0.05-0.3 중량%로 포함되며, 가장 구체적으로는, 0.1-0.2 중량%로 포함된다. According to a specific embodiment of the present invention, 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.
본 발명의 구체적인 구현예에 따르면, 본 발명에서 이용되는 비오틴(biotin)은 본 발명의 조성물 총량에 대해 0.001-0.05 중량%로 포함된다. 보다 구체적으로는, 0.002-0.04 중량 %로 포함되며, 보다 더 구체적으로는, 0.005-0.03 중량%로 포함되며, 가장 구체적으로는, 0.01-0.02 중량%로 포함된다. According to a specific embodiment of the invention, 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.
본 발명의 구체적인 구현예에 따르면, 본 발명에서 이용되는 니코틴산아미드(nicotinamide)는 본 발명의 조성물 총량에 대해 0.006-0.3 중량%로 포함된다. 보다 구체적으로는, 0.012-0.24 중량%로 포함되며, 보다 더 구체적으로는, 0.03-0.18 중량%로 포함되며, 가장 구체적으로는, 0.06-0.12 중량%로 포함된다. According to a specific embodiment of the present invention, 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.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물은 광 안정화제를 추가적으로 포함한다.According to a specific embodiment of the present invention, the composition of the present invention further comprises a light stabilizer.
본 명세서에서 용어 "광안정화제(light stabilizer)"는 제제가 가공, 보관 및 유통 과정에서 태양광에 노출됨으로써 유효성분이 열화, 분해, 산화 또는 변색되어 본래의 효능과 성상에 변화가 오는 것을 차단하는 물질을 의미한다. 본 발명의 광안정화는 라디칼의 포착, 하이드로퍼옥사이드의 분해, 중금속의 포착, 홑겹항산소의 소광에 의한 안정화를 모두 포함하나, 이에 제한되지 않으며 가시광선 및 자외선에의 노출에 의한 가능한 물리 화학적 변화를 차단 또는 완화시키는 일체의 기작을 모두 포함한다. As used herein, the term "light stabilizer" refers to a substance that prevents the active ingredient from deteriorating, degrading, oxidizing or discoloring due to exposure to sunlight in the process of processing, storage and distribution, thereby preventing changes in its original efficacy and properties. Means. 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.
본 발명에서 이용되는 광안정화제는 예를 들어 트리아졸계, 벤조페논계, 힌더드 아민 광안정화제(Hindered Amine Light Stabilizer, HALS), 힌더드페놀성광안정화제(Hindered Phenol Light Stabilizer), Al-Mg(알루미늄-마그네슘)계의 안정제가 있으나, 이에 제한되는 것은 아니다.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.
본 발명의 구체적인 구현예에 따르면, 본 발명에서 이용되는 광안정화제는 벤조페논이다. 보다 구체적으로는, 상기 벤조페논은 본 발명의 조성물 총량에 대해 0.008-0.5 중량%로 포함되며, 보다 더 구체적으로는 0.04-0.3 중량%로 포함되고, 가장 구체적으로는 0.08-0.2 중량%로 포함된다. According to a specific embodiment of the present invention, 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.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물은 제제 안정화제를 추가적으로 포함한다. 제제 안정화제는 예를 들어 파라히드록시벤조산에스테르(parahydroxybenzoic acid ester) 유도체, 피롤리디논(pyrrolidinone) 유도체, 알코올, 페놀 유도체, 티메로살(thimerosal), 아세트산 무수물, 소디움카르복실레이트, 라우릴설페이트(lauryl sulfate), 설파이드 화합물, 아황산염(sulfite), 아스코르빈산, 레티놀(retinol), 토코페롤(tocopherol), 부틸 하이드록시아니솔(butyl hydroxyl anisole)이 있으나, 이에 제한되는 것은 아니다.According to a specific embodiment of the present invention, 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.
본 발명의 구체적인 구현예에 따르면, 본 발명에서 이용되는 제제 안정화제는 메틸-2-피롤리디논(methyl-2-pyrrolidinone)이다. 보다 구체적으로는, 상기 메틸-2-피롤리디논은 본 발명의 조성물 총량에 대해 0.05-2.0 중량%로 포함되며, 보다 더 구체적으로는 0.1-1.5 중량%로 포함되고, 가장 구체적으로는 0.5-1.0 중량%로 포함된다. According to a specific embodiment of the present invention, 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%.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 상술한 유효성분 외에도 약제학적으로 허용되는 담체를 추가적으로 포함할 수 있다.When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the above-described active ingredient.
본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.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. In addition to the above components, 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. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 바람직한 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다.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.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 피부에 국소적으로 도포, 피하 주입, 경피 투여 등으로 투여할 수 있다. 본 발명의 약제학적 조성물이 육모 촉진, 양모 촉진 또는 발모 촉진을 위해 적용되는 점을 감안하면, 투여는 두피에 국소적으로 도포하거나 경피 투여를 통해 이루어지는 것이 바람직하다.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. In view of the fact that the pharmaceutical composition of the present invention is applied for promoting hair growth, promoting wool or promoting hair growth, the administration is preferably applied topically to the scalp or through transdermal administration.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제, 유화액 또는 토너, 로션, 크림 및 샴푸 등형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical 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.
본 발명의 일 구체예에 따르면, 본 발명의 약제학적 조성물은 피부외용 조성물이다. 상기 피부 외용 조성물의 제형은 특별히 한정되지 않으나, 파우더, 젤, 연고, 크림, 액체 또는 에어로졸 제형이 바람직하다.According to one embodiment of the present invention, 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.
본 발명에서 피부외용제형의 겔 기재로는 카르보머(Carbomer), 폴리에틸렌글리콜(Polyethyleneglycol), 폴리프로필렌글리콜(Polypropylene glycol), 폴리아크릴산(Polyacrylic acid), 카르복시메틸셀룰로오스(Carboxymethyl cellulose), 히드록시메틸셀룰로오스(Hydroxymethylcellulose), 폴리비닐피롤리돈 (Polyvinylpyrrolidone), 젤라틴(Gelatine), 알지네이트염(Alginate Salt), 키틴(Chitin) 또는 키토산(Chitosan) 유도체, 히알루론산(hyaluronic acid), 콜라겐(collagen) 중에서 선택된 1종 또는 2종 이상을 사용할 수 있으나, 이에 한정되지 않는다.In the present invention, 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.
상술한 바와 같이 본 발명의 조성물은 두피에 국소적으로 도포하는 형태의 피부외용 조성물로서 이용될 수 있다. As described above, the composition of the present invention can be used as an external skin composition in the form of a topical application to the scalp.
본 발명의 약제학적 조성물은 인간을 포함하는 모든 동물의 육모, 양모, 또는 발모 촉진을 위해 이용될 수 있으며, 그 대상(subject)은 인간으로 한정되지 않는다. 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.
본 발명의 일 구현예에 따르면, 본 발명은 화장료 조성물이다. According to one embodiment of the invention, the invention is a cosmetic composition.
본 발명의 항산화용 조성물은 육모, 양모, 또는 발모 촉진용 화장료 조성물의 형태로 제조될 수 있다. 본 발명의 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 유연 화장수, 영양 화장수, 로션, 영양 크림, 마사지 크림, 에센스, 클렌징 크림, 클렌징 포옴, 클렌징 워터, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.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.
본 발명의 제형이 페이스트, 크림, 로션, 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream, lotion, or gel, 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.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, 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.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매,용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or emulsion, 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.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, 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.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a surfactant-containing cleansing, 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.
본 발명의 화장료 조성물에 포함되는 성분은 유효 성분과 담체 성분 이외에, 화장료 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제를 포함할 수 있다.Ingredients included in the cosmetic composition of the present invention, in addition to the active ingredient and the carrier component, 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.
본 발명의 일 구현예에 있어서, 본 발명은 기능성 식품 조성물이다. 본 발명의 기능성 식품 조성물은 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분 이외에 향미제 또는 천연 탄수화물을 추가 성분으로서 포함시킬 수 있다. 예를 들어, 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등); 디사카라이드(예컨대, 말토스, 수크로오스 등); 올리고당; 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등); 및 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)을 포함한다.In one embodiment of the invention, 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. For example, when prepared with a drink, flavoring agents or natural carbohydrates may be included as additional ingredients in addition to the active ingredient. For example, 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).
향미제로서 천연 향미제(예컨대, 타우마틴, 스테비아 추출물 등) 및 합성 향미제(예컨대, 사카린, 아스파르탐 등)을 이용할 수 있다.As the flavoring agent, natural flavoring agents (e.g., taumartin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.
본 발명의 다른 일 양태에 따르면, 본 발명은 멜라토닌 0.001-1.0 중량%, 덱스판테놀 0.01-0.5 중량%, 비오틴 0.001-0.05 중량% 및 니코틴산아미드 0.006-0.3 중량%를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 약제학적 조성물을 제공한다. According to another aspect of the present invention, 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.
육모, 양모 또는 발모 촉진용 조성물에 관한 본 일 양태는 상기에서 이미 설명한 육모, 양모 또는 발모 촉진용 조성물에 관한 다른 일 양태에서 유효 성분의 함량을 명확히 한정한 것으로서, 상기 다른 일 양태에 대하여 발명의 상세한 설명에 기재된 모든 내용을 원용하며, 중복되는 내용에 대하여는 본 명세서 기재의 과도한 복잡성을 피하기 위해 생략하도록 한다. 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.
본 발명의 다른 일 양태에 따르면, 본 발명은 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 탈모 예방 또는 치료용 조성물을 제공한다. 본 명세서에서 용어 "탈모 예방"은 성장기 모발의 비중을 증가시킴으로서, 성장기 모발의 비중이 감소됨으로써 유발되는 탈모를 예방하는 것을 의미하고, 본 명세서에서 용어 "탈모 치료"는 상술한 성장기 모발의 비중의 증가에 따라, 탈모의 진행을 늦추거나, 탈모 증상을 억제하고, 궁극적으로 모발의 탈락된 상태의 두피 면적을 감소시키는 것을 의미한다. According to another aspect of the present invention, the present invention provides a composition for preventing or treating hair loss comprising melatonin, dexpanthenol, biotin and nicotinamide as an active ingredient. As used herein, the term "alopecia prevention" means increasing the specific gravity of growth hair, thereby preventing hair loss caused by decreasing the specific gravity of the growth phase hair, and the term "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.
본 발명의 일 양태는 상술한 본 발명의 다른 일 양태인 육모, 양모 또는 발모 촉진용 조성물에 대하여 설명한 내용을 원용하며, 중복되는 내용에 대하여는 본 명세서 기재의 과도한 복잡성을 피하기 위해 생략하도록 한다. 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.
본 발명의 다른 일 양태는 멜라토닌 0.001-1.0 중량%, 덱스판테놀 0.01-0.5 중량%, 비오틴 0.001-0.05 중량% 및 니코틴산아미드 0.006-0.3 중량%를 유효성분으로 포함하는 탈모 예방 또는 치료용 약제학적 조성물을 제공한다.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. To provide.
탈모 예방 또는 치료용 조성물에 관한 본 일 양태는 상기에서 이미 설명한 탈모 예방 또는 치료용 조성물에 관한 다른 일 양태에서 유효 성분의 함량을 명확히 한정한 것으로서, 상기 다른 일 양태에 대하여 발명의 상세한 설명에 기재된 모든 내용을 원용하며, 중복되는 내용에 대하여는 본 명세서 기재의 과도한 복잡성을 피하기 위해 생략하도록 한다. This aspect of the 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.
본 발명의 다른 일 양태는 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 조성물의 약제학적 유효량을 이를 필요로 하는 대상(subject)에 투여하는 단계를 포함하는 육모, 양모 또는 발모 촉진 방법을 제공한다. 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. Provides methods for promoting hair growth, wool or hair growth.
본 명세서 상의 용어 "약제학적 유효량"이란 상술한 조성물을 이용하여 대상(subject)의 육모, 양모 또는 발모를 촉진시키고, 탈모 증상을 예방, 경감 또는 치료 효능을 달성하는 데 충분한 양을 의미한다. 본 명세서 상의 용어 "대상(subject)"이란 인간을 포함하는 모든 동물을 의미하는 것으로서 특별히 제한되지 않고, 특히 육모, 양모 또는 발모를 촉진시킬 필요성이 있는 객체를 의미한다. 본 발명의 방법은 상술한 육모, 양모 또는 발모 촉진용 조성물을 대상(subject)에 투여하는 방법에 관한 것이므로, 중복되는 내용을 원용하며, 본 명세서 기재의 과도한 복잡성을 피하기 위해 그 기재를 생략하도록 한다. As used herein, 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. As used herein, 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. .
본 발명의 다른 일 양태는 멜라토닌 0.001-1.0 중량%, 덱스판테놀 0.01-0.5 중량%, 비오틴 0.001-0.05 중량% 및 니코틴산아미드 0.006-0.3 중량%를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 조성물의 약제학적 유효량을 이를 필요로 하는 대상(subject)에 투여하는 단계를 포함하는 육모, 양모 또는 발모 촉진 방법을 제공한다. 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.
본 발명의 방법은 상술한 육모, 양모 또는 발모 촉진용 조성물을 대상(subject)에 투여하는 방법에 관한 것이며, 이미 상술한 육모, 양모 또는 발모 촉진 방법의 구성성분의 함량을 구체적으로 한정하는 발명의 일 양태에 해당하는 바, 중복되는 내용을 원용하며, 본 명세서 기재의 과도한 복잡성을 피하기 위해 그 기재를 생략하도록 한다. 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. In one aspect, overlapping content is used, and the description is omitted to avoid excessive complexity of the description.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 약제학적 조성물, 화장료 조성물 또는 기능성 식품 조성물, 또는 상술한 조성물을 이용한 육모, 양모 또는 발모 촉진 방법을 제공한다. (a) 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.
(b) 본 발명의 조성물은 약리 활성성분인 멜라토닌의광안정성을 개선하면서 제제를 안정화시키고 두피 염증을 유의하게 억제함으로써, 발모 또는 양모 효과를 극대화시킨다.(b) The 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.
(c) 본 발명의 조성물은광안정성, 보존성, 투약 편의성 및 치료효과가 동시에 증대된 효율적인 발모, 양모 촉진제 또는 탈모의 예방 또는 치료제로서 유용하게 이용될 수 있다.(c) The 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.
도 1은 덱사메타손(Dexamethasone) 유도 탈모증(alopecia) C57BL/6 마우스 모델에서 시험물질 처리 후 9일째의 발모효력평가(AREA OF HAIR RESTORATION) 결과를 나타낸다. 도 1의 화살표 처리한 부분은 도포 부위를 디지털카메라로 촬영한 후, ImageJ 소프트웨어 (NIH, Bethesda, MD)를 이용하여 분석한 범위를 표시한 것이다.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.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
실시예Example
실시예Example 제제의 제조 Preparation of the formulation
본 발명에서 이용되는 4종의 복합성분인 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드가 포함된 9가지 제제를 제작하였으며, 상기 제제의 구체적인 성분은 하기의 표 1에 표시하였다.Nine formulations containing melatonin, dexpanthenol, biotin and nicotinic acid amide, which are four complex components used in the present invention, were prepared, and specific components of the formulation are shown in Table 1 below.
실시예 제제의 조성EXAMPLES Composition of Formulation
구분division 실시예1Example 1 실시예2Example 2 실시예3Example 3 실시예4Example 4 실시예5Example 5 실시예6Example 6 실시예7Example 7 실시예8Example 8 실시예9Example 9 실시예10Example 10 실시예11Example 11 비교예1Comparative Example 1
멜라토닌Melatonin 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.010.01 0.20.2 --
덱스판테놀Dexpanthenol -- 0.10.1 -- -- 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1
비오틴Biotin -- -- 0.010.01 -- 0.010.01 0.010.01 0.010.01 0.010.01 0.010.01 0.010.01 0.010.01 0.010.01
니코틴산아미드Nicotinic acid amide -- -- -- 0.060.06 0.060.06 0.060.06 0.060.06 0.060.06 0.060.06 0.060.06 0.060.06 0.060.06
N-메틸-2-피릴리디논N-methyl-2-pyridyridone -- -- -- -- -- 0.50.5 1One 0.50.5 0.50.5 0.50.5 0.50.5 --
벤조페논Benzophenone -- -- -- -- -- -- -- 0.040.04 0.080.08 0.080.08 0.080.08 --
폴리옥실40경화 피마자유(Polyoxyl 40 Hydrogenated Castor Oil)Polyoxyl 40 Hydrogenated Castor Oil 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5 0.50.5
글리세린(Glycerin)Glycerin 33 33 33 33 33 33 33 33 33 33 33 33
l-멘톨(l-Menthol)l-Menthol 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1
dl-캄파(dl-Camphor)dl-Camphor 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05 0.050.05
에데트산나트륨수화물(Disodium Edetate Hydrate)Sodium Edetate Hydrate 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03 0.030.03
파라옥시벤조산메틸(Methylparaben)Methyl paraben (Methylparaben) 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity
파라옥시벤조산 프로필(Propylparaben)Paraoxybenzoic acid propyl (Propylparaben) 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity
착향제Flavor 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity 적량Quantity
에탄올(Ethanol)Ethanol 3535 3535 3535 3535 3535 3535 3535 3535 3535 3535 3535 3535
정제수Purified water 60.4260.42 60.3260.32 60.4160.41 60.3660.36 60.2560.25 59.7559.75 59.2559.25 59.7159.71 59.6759.67 59.7659.76 59.5759.57 60.3560.35
각 제제의 제조 방법How to prepare each formulation
공정명Process Name 작업명Job name
수상조제1Award Preparation 1 정제수, N-메틸-2-피롤리돈, 글리세린, 벤조페논, 덱스판테놀, 비오틴을 넣고 가온 용해한다.Purified water, N-methyl-2-pyrrolidone, glycerin, benzophenone, dexpanthenol, and biotin are added and dissolved by heating.
수상조제2Award Winner 2 수상조제1에 니코틴산아미드, 에데트산나트륨수화물을 투입하여 용해한 뒤 실온으로 냉각한다.Nicotinic acid amide and edetate sodium hydrate are added to the aqueous phase preparation 1 to dissolve, and then cooled to room temperature.
유상조제1Paid Preparation 1 에탄올, 폴리옥실40경화피마자유를 넣고 가온 용해 후 실온으로 냉각한다.Add ethanol and polyoxyl 40 hardened castor oil, and dissolve it after heating to cool to room temperature.
유상조제2Paid Preparation 2 유상조제1에 l-멘톨, dl-캄파, 멜라토닌, 파라옥시벤조산메틸, 파라옥시벤조산프로필, 착향제를 투입하여 교반 용해한다.1-Menthol, dl-campa, melatonin, methyl paraoxybenzoate, propyl paraoxybenzoic acid, and flavoring agent are added to the oily preparation 1 to dissolve by stirring.
혼합mix 수상조제2에 준비된 유상조제2를 투입하여 교반한다.The oily phase preparation 2 prepared in the aqueous phase preparation 2 is added and stirred.
실시예 1 내지 실시예5는 본 발명의 조성물의 효능·효과 및 성상에 적합한 제제 확립을 위한 기본 제제 처방 확립을 위한 것이며, 실시예 6 및 실시예 7은 안정성 확보 및 경피흡수율 증가를 위한 조성의 적용이며, 실시예 8 및 실시예 9는 자외선에 의한 화학적, 물리적 변화로부터 제제의 안정성 확보를 위한 조성의 적용이다.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, Examples 6 and 7 of the composition for ensuring stability and increasing transdermal absorption rate Application, 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.
실험예 1: 항산화 효과(DPPH)의 측정Experimental Example 1 Measurement of Antioxidant Effect (DPPH)
자유 라디칼은노화(예컨대, 탈모, 피부노화)의 원인물질로 간주되고 있는데, 광안정화제 사용에 따른 자유 라디칼 소거 활성 측정을 통하여 항산화효과 정도를 측정하였다. 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.
DPPH 시험군 시료를 제조하기 위하여, 멜라토닌 0.1 중량%, 비오틴 0.01 중량%, 니코틴산아미드 0.06 중량% 및 덱스판테놀 0.1 중량%를 에탄올에 완전히 용해될 때까지 10분간 교반하였다. 그리고, DPPH(1-diphenyl-2-picrylhydrazyl) 용액을 80 ㎍/㎖ 에탄올로 조제하고 이 용액 1 ㎖에 각 분획을 2 ㎎/㎖ 의 농도가 되도록 에탄올에 용해하였다. 그 다음 DPPH의 색변화를 UV스펙트로포토미터를 사용하여 흡수파장 517nm에서의 흡광도를 측정하고 활성의 크기를 측정한 결과치를 아래 수학식에 넣어 억제 효과를 산출하였다: 실험 결과 멜라토닌, 비오틴, 니코틴산아미드 및 덱스판테놀을 포함하는 경우 항산화 효과가 가장 우수하게 측정되었으며, 덱스판테놀, 비오틴, 니코틴산아미드를 각각 단독으로 사용한 경우에는 멜라토닌, 비오틴, 니코틴산아미드 및 덱스판테놀을 모두 포함하는 경우에 비하여 항산화 효과가 유의하게 감소된다는 결과가 도출되었다. 그 결과는 표 3에 나타내었다.To prepare 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 µg / 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. The results are shown in Table 3.
수학식 1Equation 1
Figure PCTKR2016000742-appb-I000001
Figure PCTKR2016000742-appb-I000001
성분명Ingredient Name 멜라토닌+비오틴+니코틴산아미드+ 덱스판테놀Melatonin + Biotin + Nicotinamide + Dexpanthenol 비오틴Biotin 덱스판테놀Dexpanthenol 니코틴산아미드Nicotinic acid amide
억제효과(%)Inhibitory effect (%) 84.984.9 17.017.0 25.025.0 0.00.0
상기 실시예는 Journal of Toxicology and Public Health Vol.23 No.3, 2007.9, 263-269.를 참조하여 수행하였다.This example was performed with reference to Journal of Toxicology and Public Health Vol. 23 No. 3, 2007.9, 263-269.
실험예 2: 제형 조성물의 안정화 효과 측정Experimental Example 2: Determination of Stabilization Effect of Formulation Composition
본 발명의 조성물의 효능·효과 및 성상에 적합한 제제확립을 위해 유효성분인 멜라토닌, 비오틴, 덱스판테놀 및 니코틴산아미드를 포함하는 조성물을 제조하고, 그 유효성분의 조성이 멜라토닌의 안정성에 미치는 효과를 광안정성시험을 통하여 측정하였다. 광안정성 챔버를 이용 ICH(International Conference on Harmonization) 가이드 라인의 Q1b(Stability Testing: Photo stability Testing of New Drug Substances and Products)에 의거하여 VIS 40 klux 조건하에서 시험을 실시하였다.To prepare a formulation suitable for the efficacy, effect and properties of the composition of the present invention, 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.
제형 조성물시험군(실시예1-실시예5)의 제조는 표 2의 방법에 따라 제조하였다. 그리고 펌프타입의 투명용기(HDPE)에 시험군인 시료를 각각 50 g씩 충전하였다. 충전이 완료된 시료를 광안정성 챔버 내의 조사방향으로 배치한 다음 시간대별로 2 mL 씩 샘플링하였다. 샘플링이 완료되면 액체크로마토그래피(HPLC)로 정량분석 하였다. HPLC 분석조건은 검출기로 자외부흡광광도계(파장 225 nm)컬럼은 C18(4.6 mm×50 mm, 1.8 ㅅm) 또는 이와 동등한 칼럼, 이동상은 0.018 mol/L 인산염완충액(pH 3.0): 아세토니트릴(90 : 10) 그리고 유속은 1 mL/min, 주입량은 50 μL, 온도는 25℃, 주입 순서는 표준액(3회), 검액(2회) 순으로 주입하였다. 실험 결과, 제형 조성물의 안정성은 멜라토닌 단독군보다 멜라토닌, 비오틴, 니코틴산아미드 및 덱스판테놀 혼합군이 함량 안정성이 유지되었는 바, 멜라토닌에 대하여 비오틴, 니코틴산아미드 및 덱스판테놀을 혼합하는 것이 함량 안정성 향상에 유의한 효과가 있음을 알 수 있었다. 그 결과는 표 4에 나타내었다.Formulation The preparation of the 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 analysis conditions were the detector, ultraviolet ultraviolet photometer (wavelength 225 nm) column C18 (4.6 mm x 50 mm, 1.8 μm) 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 μL, the temperature was 25 ° C., and the injection order was standard solution (3 times) and sample solution (2 times). As a result of the experiment, 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.
참고로 인산염 완충액은 인산이수소칼륨 2.45 g을 물에 녹여 1 L로 한 다음 20% 인산을 넣어 pH 3.0으로 조정하여 제조하였다.For reference, 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.
실험예3: 멜라토닌의광안정화 효과 측정Experimental Example 3 Measurement of the Light Stabilization Effect of Melatonin
주성분인 멜라토닌은 빛에 취약하여 이에 안정화제 또는 광안정화제를 첨가하는데, 이에 대한 효과를 광안정성 시험을 통하여 측정하였다. 광안정성 챔버를 이용 ICH(International Conference on Harmonization)가이드 라인의 Q1b(Stability Testing: Photo stability Testing of New Drug Substances and Products)에 의거하여 VIS 40 klux 조건하에서 시험을 실시하였다.Melatonin, the main component, is vulnerable to light, and a stabilizer or light stabilizer is added thereto, and its effect was measured through a light stability test. The test was conducted under a VIS 40 klux condition based on the Stability Testing: Photo stability Testing of New Drug Substances and Products (Q1b) of the International Conference on Harmonization (ICH) guideline using a light stability chamber.
안정화제 시험군 시료를 제조하기 위하여, 멜라토닌 0.1 중량%에 각각의 안정화제(메틸-2-피롤리디논, 아스코르빈산, 토코페롤, 부틸 하이드록시아니솔)를 0.1 중량%씩 에탄올에 완전히 용해될 때까지 10분간 교반하였다To prepare a stabilizer test group sample, 0.1% by weight of each stabilizer (methyl-2-pyrrolidinone, ascorbic acid, tocopherol, butyl hydroxyanisole) in 0.1% by weight of melatonin was completely dissolved in ethanol. Stir for 10 minutes until
광안정화제 시험군 시료를 제조하기 위하여, 멜라토닌 0.1 중량%에 각각의 안정화제(벤조페논, 산화아연, 에틸헥실살리실레이트, 산화티탄)를 0.1 중량%씩 에탄올에 완전히 용해될 때까지 10분간 교반하였다.  To prepare a light stabilizer test group sample, 0.1% by weight of 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.
그리고 펌프타입의 투명용기(HDPE)에 시험군인 시료를 각각 50 g씩 충전하였다.And 50g each of the test group was filled in a pump-type transparent container (HDPE).
충전이 완료된 시료를 광안정성 챔버 내의 조사방향으로 배치한 다음 시간대별로 2 mL씩 샘플링하였다. 샘플링이 완료되면 액체크로마토그래피(HPLC)로 정량분석 하였다. HPLC 분석조건은 검출기로 자외부 흡광광도계(파장 225 nm)컬럼은 C18(4.6mm×50mm,1.8ㅅm)또는 이와 동등한 칼럼, 이동상은 0.018 mol/L 인산염완충액(pH 3.0):아세토니트릴(90 : 10) 그리고 유속은 1 mL/min, 주입량은 50 μL, 온도는 25℃, 주입순서는 표준액(3회), 검액(2회) 순으로 주입하였다. 실험 결과, 안정화제 활성은 메틸-2-피롤리디논, 아스코르빈산, 토코페롤, 부틸 하이드록시아니솔 순으로 측정되었으며, 메틸-2-피롤리디논의 안정화 활성이 가장 우수한 바 안정화제로서 가장 바람직하게는 메틸-2-피롤리디논을 이용할 수 있음을 알 수 있었다.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 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 μm) 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 μL, the temperature was 25 ° C, and the injection order was standard solution (3 times) and sample solution (2 times). As a result, 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.
광안정화 활성은 벤조페논, 산화아연, 에틸헥산살리실레이트, 산화티탄 순으로 측정되었으며, 벤조페논의 광안정화 활성이 가장 우수한 바, 광안정화제로서 가장 바람직하게는 벤조페논을 이용할 수 있음을 알 수 있었다. 그 결과는 표 5 및 표 6에 나타내었다.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.
참고로 인산염완충액은 인산이수소칼륨 2.45 g을 물에 녹여 1 L로 한 다음 20% 인산을 넣어 pH 3.0으로 조정하여 제조하였다.For reference, 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.
제형 조성물에 따른 안정성 평가 결과Results of stability evaluation according to the formulation composition
시간(min.)Time (min.) 실시예1Example 1 실시예2Example 2 실시예3Example 3 실시예4Example 4 실시예5Example 5
멜라토닌Melatonin 멜라토닌+덱스판테놀Melatonin + Dexpanthenol 멜라토닌+비오틴Melatonin + Biotin 멜라토닌+니코틴산아미드Melatonin + Nicotinamide 멜라토닌+비오틴+니코틴산아미드+덱스판테놀Melatonin + Biotin + Nicotinamide + Dexpanthenol
00 100.1100.1 100.1100.1 99.799.7 99.799.7 100.0100.0
1515 99.899.8 99.799.7 99.899.8 99.699.6 99.999.9
3030 98.498.4 99.499.4 99.599.5 99.099.0 99.899.8
4545 98.798.7 99.299.2 99.799.7 99.499.4 100.0100.0
6060 97.997.9 98.698.6 99.299.2 98.698.6 100.0100.0
7575 96.796.7 98.298.2 98.098.0 97.797.7 99.899.8
9090 95.695.6 97.797.7 97.297.2 96.596.5 100.3100.3
105105 93.993.9 97.297.2 96.896.8 96.096.0 99.699.6
120120 미검출Not detected 93.793.7 92.492.4 90.790.7 99.399.3
(단위 :멜라토닌 함량(%)) (Unit: Melatonin Content (%))
(보관조건: 25℃, 60RH),(광조건: VIS 40 klux),(Storage condition: 25 ℃, 60RH), (light condition: VIS 40 klux),
제제 안정화제스크리닝 실험 결과Formulation stabilizer screening results
시간(h)Hours (h) 멜라토닌Melatonin 멜라토닌+메틸-2-피롤리디논Melatonin + Methyl-2-pyrrolidinone 멜라토닌+아스코르빈산Melatonin + Ascorbic Acid 멜라토닌+토코페롤Melatonin + Tocopherol 멜라토닌+부틸하이드록시아니솔Melatonin + Butylhydroxyanisole
00 99.799.7 100.2100.2 100.5100.5 100.2100.2 100.9100.9
22 미검출Not detected 100.7100.7 93.793.7 94.794.7 94.994.9
44 미검출Not detected 100.4100.4 92.292.2 93.693.6 93.893.8
66 미검출Not detected 99.899.8 91.591.5 92.392.3 92.492.4
88 미검출Not detected 99.699.6 90.190.1 90.890.8 89.789.7
2424 미검출Not detected 99.599.5 85.685.6 88.188.1 86.586.5
(단위 :멜라토닌 함량 (%))(Unit: Melatonin Content (%))
(보관조건: 25℃, 60 RH, 광조건: VIS 40 klux)(Storage condition: 25 ℃, 60 RH, Light condition: VIS 40 klux)
광안정화제스크리닝 실험 결과Light Stabilizer Screening Experiment Results
시간(h)Hours (h) 멜라토닌Melatonin 멜라토닌+벤조페논Melatonin + Benzophenone 멜라토닌+산화아연Melatonin + Zinc Oxide 멜라토닌+에틸헥실살리실레이트Melatonin + ethylhexyl salicylate 멜라토닌+산화티탄Melatonin + Titanium Oxide
00 99.799.7 99.999.9 100.1100.1 101.5101.5 100.0100.0
22 미검출Not detected 100.0100.0 99.399.3 99.299.2 97.497.4
44 미검출Not detected 99.999.9 98.398.3 97.597.5 95.995.9
66 미검출Not detected 100.1100.1 95.795.7 93.593.5 91.991.9
88 미검출Not detected 99.899.8 91.791.7 88.588.5 87.987.9
2424 미검출Not detected 99.199.1 85.385.3 82.282.2 78.978.9
(단위 :멜라토닌 함량 (%))(Unit: Melatonin Content (%))
(보관조건: 25℃, 60RH, 광조건: VIS 40klux)(Storage condition: 25 ℃, 60RH, light condition: VIS 40klux)
표 4에 나타낸 바와 같이 멜라토닌에 비오틴, 니코틴산아미드 및 덱스판테놀을 모두 추가적으로 포함시키는 경우, 비오틴, 니코틴산아미드 또는 덱스판테놀을 단독으로 추가하는 경우에 비하여 더욱 우수한 함량 안정성을 얻을 수 있었으며, 표 5에 나타낸 바와 같이 메틸-2-피롤리디논을 이용하는 경우 함량 안정성이 가장 우수한 바, 메틸-2-피롤리디논을 적합한 안정화제로서 이용할 수 있음을 보였다. 또한 표 6에 나타낸 바와 같이 벤조페논을 이용하는 경우 함량안정성이 가장 우수한 바, 벤조페논을 적합한 광안정화제로서 이용할 수 있음을 보였다. 그러나 상술한 바와 같이 벤조페논을 우수한 광안정화제로서 이용할 수 있으나, 내분비계를 교란하여 알러지성 질환은 악화 시킬 수 있는 등 종래 알려진 일부의 부작용이 있으므로, 이를 대체하기 위해 비오틴, 니코틴산아미드 및 덱스판테놀 복합군을 멜라토닌에 추가적으로 포함시키거나, 또는 메틸-2-피롤리디논을 이용하거나, 또는 벤조페논의 함량을 줄이면서 이를 보완하기 위해 비오틴, 니코틴산아미드 및 덱스판테놀 복합군 및 메틸-2-피롤리디논을 이용하는 등의 방식으로 멜라토닌의 광안정성을 증대시킬 수 있다.As shown in Table 4, when biotin, nicotinic acid amide, and dexpanthenol were additionally included in the melatonin, more excellent content stability was obtained than in the case of adding biotin, nicotinic acid amide, or dexpanthenol alone. As described above, when methyl-2-pyrrolidinone was used, it was found that methyl-2-pyrrolidinone may be used as a suitable stabilizer. In addition, as shown in Table 6, when benzophenone is used, the content stability is the best, and it was shown that benzophenone can be used as a suitable light stabilizer. However, as described above, 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.
덱스판테놀, 비오틴 및 니코틴산아미드의 복합 성분의 이용만으로도, 멜라토닌의 광안정성은 유의하게 증대되며, 추가적인 안정화제 또는 광안정화제, 예컨대, 메틸-2-피롤리디논, 벤조페논을 추가적으로 포함시켜 더욱 향상된 광안정성을 확보할 수 있다.Even with the use of a combination of dexpanthenol, biotin and nicotinic acid amides, 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.
실험예4Experimental Example 4 : 덱사메타손 유도 탈모증(Dexamethasone-induced alopecia ( alopeciaalopecia ) ) C57BLC57BL /6 모델에서 시험 물질의 발모 효력 평가Evaluation of the regrowth effect of the test substance on the 6/6 model
덱사메타손에 의해 유도된 탈모증(alopecia) C57BL/6 마우스 모델에서 시험물질의 투여가 발모 촉진에 미치는 영향을 평가하기 위해 한국동물의과학연구소에 의뢰하여본 실험을 진행하였다.In order to evaluate the effect of the administration of test substance on hair growth promotion in alopecia C57BL / 6 mouse model induced by dexamethasone, this experiment was conducted by the Korean Institute of Animal Science.
4-1. 시험계4-1. Test system
특정병원균 부재(SPF) C57BL/6 마우스, C57BL/6NCrljOri(오리엔트바이오)는 각종 약효 및 독성시험에 널리 사용되고 있고, 풍부한 시험 기초 자료가 축적되어 있으며, 이러한 자료를 이용하여 시험결과의 해석 및 평가가 용이하기 때문에 본 실험에 이용하기 위한 종 및 계통으로 선택하였다. 5주령의 암컷 100마리를 입수하였으며, 입수 후 7일 간의 검역 및 순화기간을 거쳤고, 암컷 70 마리를 시험에 이용하였다. SPF-free C57BL / 6 mice, C57BL / 6NCrljOri (orient bio) are widely used in various drug efficacy and toxicity tests, and abundant basic test data have been accumulated. Because of its ease, it was chosen as the species and strain to be used in this experiment. 100 females of 5 weeks of age were obtained, and after 7 days of quarantine and purification, 70 females were used for the test.
동물은 순화기간(청색), 투여 및 관찰기간(붉은색) 동안 미부표식법을 사용하여 식별하였다. 사육상자에는 색으로 구별되는 개체식별카드를 부착하고, 사육실 입구에는 동물실 사용기록지를 부착하였다.Animals were identified using unlabeled methods during the period of acclimatization (blue), administration and observation (red). 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.
4-2. 사육환경4-2. Breeding environment
본 시험은 온도 23±3℃, 상대습도 55±15%, 환기횟수 10∼20 회/hr, 조명시간 12 시간(오전 8 시 점등∼오후 8 시 소등) 및 조도 150∼300 Lux로 설정한 주식회사 한국동물의과학연구소 설치류 사육구역 2 호실에서 실시하였다.This test is set to a temperature of 23 ± 3 ℃, 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.
사육기간 중 동물실의 온도, 습도, 환기횟수 및 조도 등의 환경조건은 주 1 회 측정하였다. 환경측정 결과 시험의 결과에 나쁜 영향을 끼칠만한 이상은 관찰되지 않았다.During the breeding period, 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.
사료는 ㈜카길애그리퓨리나에서 생산하는 실험동물용 사료를 드림바이오로부터 공급받아 급이기에 넣고 자유롭게 섭취하도록 하였으며, 물은 정수된 물을 폴리카보네이트제 음수병에 넣고 자유롭게 섭취하도록 하였다. 깔개는 나무깔개를 ㈜새론바이오로부터 공급받아 사용하였다.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.
순화, 투여 및 관찰 기간 동안 설치류용 폴리카보네이트 사육상자(W 170 x L 235 x H 125 mm) 에서 사육상자 당 5 마리 이하로 사육하였다.During the period of acclimation, administration and observation, no more than 5 birds per breeder were raised in a rodent polycarbonate cage (W 170 x L 235 x H 125 mm).
본 시험은 주식회사 한국동물의과학연구소의 동물실험윤리위원회인 KAMSI IACUC의 승인을 받아 실시하였다.This test was conducted with the approval of KAMSI IACUC, Animal Experiment Ethics Committee of Korea Institute of Animal Science.
4-3.시험군의 구성 및 투여량 설정4-3.Configuration of test group and dose setting
시험군의 구성은 하기 표 7에 나타내었다. The configuration of the test group is shown in Table 7.
군group 성별gender 동물수 (마리)Animal count (horses) 동물번호Animal Number 시험물질Test substance 투여액량 (mL/head)Dosage amount (mL / head) 비고Remarks
G1G1 FF 1010 1-101-10 비히클(Vehicle)Vehicle 1.001.00 D-판테놀: 0.1%, 비오틴 : 0.01%, 니코틴산아미드 : 0.06%D-panthenol: 0.1%, biotin: 0.01%, nicotinic acid amide: 0.06%
G2G2 FF 1010 11-2011-20 3 % 미녹시딜(Minoxidil)3% Minoxidil 1.001.00 　
G3G3 FF 1010 21-3021-30 멜라토닌(Melatonin) 0.01%Melatonin 0.01% 1.001.00 D-판테놀: 0.1%, 비오틴 : 0.01%, 니코틴산아미드 : 0.06%D-panthenol: 0.1%, biotin: 0.01%, nicotinic acid amide: 0.06%
G5G5 FF 1010 41-5041-50 멜라토닌 0.1%Melatonin 0.1% 1.001.00 D-판테놀: 0.1%, 비오틴 : 0.01%, 니코틴산아미드 : 0.06%D-panthenol: 0.1%, biotin: 0.01%, nicotinic acid amide: 0.06%
G6G6 FF 1010 51-6051-60 멜라토닌 0.1% 단독Melatonin 0.1% only 1.001.00 　
G7G7 FF 1010 61-7061-70 멜라토닌 0.2%Melatonin 0.2% 1.001.00 D-판테놀: 0.1%, 비오틴 : 0.01%, 니코틴산아미드 : 0.06%D-panthenol: 0.1%, biotin: 0.01%, nicotinic acid amide: 0.06%
제모 후 피부에 상처가 없고 등의 피부색이 분홍색인 동물을 선별하여 무작위로 군분리를 실시하였다. 각 그룹은 군분리 후 부형제대조군, 양성대조군 (3 % 미녹시딜 투여군), HTB005(1)~HTB005(5) 투여군으로 나누어 시험물질을 투여하였다. After depilation, animals 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.
4-4. 투여4-4. administration
임상예정경로인 피부도포를 통해 투여하였고, 시험물질의 경우, 제모 후 7 일째부터 1 회/일, 9 일간 투여하였으며, 덱사메타손의 경우, 제모 후 9 일째부터 1 회/일, 7 일간 투여하였다. 덱사메타손의 경우, 1 mL/head로 도포하였다. 피부 일정 구획에 고루 퍼지도록 스프레이 용기(약 0.18 mL/1회)를 이용하여 도포하였다.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. For 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.
시험물질 및 양성대조물질을 제모된 피부 위에 1.5 cm×1.5 cm 크기의 틀을 올린 후 일정 구획에 고루 퍼지도록 스프레이 용기를 이용하여 도포하였다.The 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.
4-5. 시험방법 및 검사 항목4-5. Test method and inspection item
(1) 모델 제작(1) model making
모든 동물에 대하여 졸레틸 50(Zoletil 50, VIRBAC, France) 및 실라진(xylazine, Rompun®, Bayer AG, Germany)으로 마취를 유도한 후 마우스 등의 털을 제모기를 이용하여 1 차 제모를 실시한 후, 제모크림을 발라 2 차 제모를 실시하였다. 제모 후 피부에 상처가 없고 등의 피부색이 분홍색인 동물을 선별하여 군분리를 실시하였다. 제모 9 일째 (시험물질 투여 2 일째)부터 덱사메타손(Dexamethasone) 약 0.2 mL를 제모된 피부 일정 구획에 고루 퍼지도록 도포하였다.All animals were induced with anesthesia with Zoletil 50 (Zoletil 50, VIRBAC, France) and silazine (xylazine, Rompun®, Bayer AG, Germany), followed by primary hair removal using a hair removal device. 2nd epilation was performed by applying depilatory cream. After depilation, animals with no skin wound and pinkish back color were selected for group separation. From day 9 of hair removal (day 2 of administration of the test substance), about 0.2 mL of dexamethasone was applied to spread the hairs evenly over a section of the epidermis.
(2) 사진 촬영 및 분석(2) taking and analyzing pictures
제모실시일(Day 0), Day 7, 9, 12 및 16 일째에 졸레틸 50 및 실라진으로 마취를 유도한 후 도포 부위를 디지털카메라로 촬영한 후, ImageJ software (NIH, Bethesda, MD)를 이용하여 분석하였다. On day 0, Day 7, 9, 12, and 16, induction of anesthesia with zoletil 50 and silazine was performed, the application site was photographed with a digital camera, and imageJ software (NIH, Bethesda, MD) The analysis was carried out.
(3) 체중 측정: 제모실시일, 그 이후에는 1 회/주 측정하였다.(3) Body weight measurement: It was measured on the day of hair removal, and once / week thereafter.
(4) 부검(4) autopsy
제모 후 16 일째에 시험물질 도포 부위를 적출하여 10 % 중성완충포르말린용액에 고정하였다.At 16 days after depilation, the test substance application site was extracted and fixed in 10% neutral buffered formalin solution.
(5) 조직병리학적 검사(5) histopathological examination
고정된 조직은 삭정, 탈수, 파라핀 포매, 박절 등 일반적인 조직처리 과정을 거쳐 조직병리학적 검사를 위한 검체를 제작한 뒤, H&E(Hematoxylin & Eosin) 염색을 실시하고 모낭의 형성 여부 및 모낭의 생장기 비율에 따른 발모 효력 평가를 실시하였다. 모낭수 및 생장기 비율은 광학 현미경(Olympus BX53, Japan)을 이용하여 사진을 촬영한 후 각 개체당 무작위로 5 장을 선택하여 평가하였다.After fixation, dehydration, paraffin embedding, and cutting of the tissue, 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.
4-6. 통계학적 분석4-6. Statistical analysis
모낭수 및 발모면적에 대하여는 자료의 정규성을 가정하고 모수적인 일원분산분석 (One-way ANOVA)을 적용하였다. ANOVA 결과가 유의하였을 경우, Dunnett's multiple comparison test를 포함하는 사후검정을 실시하여 부형제대조군 및 양성대조군과 유의한 차이를 나타내는 군을 확인하였다.For hair follicle number and hair growth area, we used parametric one-way ANOVA assuming normality of data. When the ANOVA result was significant, a post-test including Dunnett's multiple comparison test was performed to identify the groups that showed significant differences from the excipient control group and the positive control group.
생장기 비율 평가는 순위화한 데이터를 이용하여 비모수적Kruskal-Wallis'H-test를 실시하였으며, 그 결과가 유의할 경우 사후분석인 Dunn's multiple comparison test로 부형제대조군 및 양성대조군과 유의한 차이를 나타내는 군을 확인하였다.For the growth rate evaluation, nonparametric Kruskal-Wallis'H-test was performed using the ranked data. If the results were significant, Dunn's multiple comparison test, a post hoc analysis, showed a significant difference from the excipient control group and the positive control group. Confirmed.
통계학적 분석은 Prism 5.03(GraphPad Software Inc., San Diego, CA, USA)을 이용하였으며, p값이 0.05 미만일 경우, 통계학적으로 유의한 것으로 판정하였다. Statistical analysis was performed using Prism 5.03 (GraphPad Software Inc., San Diego, Calif., USA), and was determined to be statistically significant when the p-value was less than 0.05.
4-7. 실험 결과4-7. Experiment result
본 시험은덱사메타손에 의해 유도된 탈모증 (alopecia) C57BL/6 마우스 모델에서 시험물질의 투여가 발모 촉진에 미치는 영향을 평가하기 위하여 수행하였다(G1: 부형제대조군, G2: 양성대조군 (3 % 미녹시딜(Minoxidil)), G3: 멜라노닌 0.01 % 투여군, G5: 멜라토닌 0.1 % 투여군, G6: 멜라토닌 0.1 % 단독 투여군, G7: 멜라토닌 0.2 % 투여군).This study was performed to evaluate the effect of administration of test substance on hair growth promotion in alopecia C57BL / 6 mouse model induced by dexamethasone (G1: excipient control group, G2: positive control group (3% Minoxidil) )), G3: Melanonin 0.01% administration group, G5: Melatonin 0.1% administration group, G6: Melatonin 0.1% administration group, G7: Melatonin 0.2% administration group).
미녹시딜(Minoxidil)은 남성형 탈모증(androgenetic alopecia)에 효과가 있는 것으로 보고되어 있으며(Messenger AG et al, 2004), 본 시험에서 양성대조군으로 사용하였다. 발모 면적 측정 결과, 시험물질 투여개시 후 7 일째에 모든 시험물질 투여군의 발모 면적은 부형제대조군에 비하여 높은 경향을 나타내었다. 또한, 시험물질 투여개시 후 12 및 16 일째에 멜라토닌(Melatonin) 0.01 % 및 멜라토닌 0.2 % 투여군의 발모 면적은 부형제대조군에 비하여 높은 경향을 보였고, 멜라토닌 0.01 % 및 멜라토닌 0.2 % 투여군의 발모 면적은 양성대조군보다도 높은 경향을 보였기에 시험물질은 발모 촉진에 도움을 주는 것으로 사료된다.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. As a result of the measurement of the hair growth area, 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. In addition, 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.
조직병리학적 검사에서 모낭수 측정 결과 및 생장기 모낭 비율을 분석한 결과, 통계학적으로 유의한 차이는 관찰되지 않았다. 그러나, 생장기 모낭 비율 분석 결과에서 멜라토닌 0.01 % 및 멜라토닌 0.2 % 투여군의생장기 모낭 비율은 양성대조군에 비하여도 높은 경향을 나타내었기에 시험물질의 투여가 생장기 모낭으로의 전환에 영향을 미치는 것으로 사료된다.As a result of analyzing the number of hair follicles and the growth rate of hair follicles in histopathological examination, no statistically significant difference was observed. However, in the hair follicle ratio analysis results, 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.
결론적으로 덱사메타손에 의해 유도된 탈모증 C57BL/6 마우스 모델에 시험물질을 9 일간 피부도포하였을 때, 멜라토닌 0.2 % 투여군의 발모 면적이 모든 측정일에 부형제 대조군 및 양성대조군에 비하여 높은 경향이 관찰되었고, 멜라토닌 0.01% 투여군에서는 9일 째를 제외한 모든 측정일에 부형제 대조군 및 양성대조군에 비하여 높은 경향이 관찰되었다. 또한, 멜라토닌 0.01 % 및 멜라토닌 0.2 % 투여군의 모낭수 및 생장기 모낭 비율은 부형제대조군 및 양성대조군 대비 높은 경향이 관찰되었다.In conclusion, when dermamethasone-induced alopecia C57BL / 6 mouse was coated with the test substance for 9 days, 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. In 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. In addition, 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.
따라서, 본 시험 조건 하에서 덱사메타손에 의해 유도된 탈모증 C57BL/6 마우스 모델에서 시험물질 멜라토닌 0.01 % 및 멜라토닌 0.2 %의 투여는 발모 촉진에 도움을 줄 수 있는 것으로 사료된다.Therefore, administration of 0.01% melatonin and 0.2% melatonin in the alopecia C57BL / 6 mouse model induced by dexamethasone under the present test conditions may help promote hair growth.
재발모 면적Rehair area
단위: %unit: %
그룹group 9 일째9th day
G1G1 1.2571.257
G2G2 22.3322.33
G3 G3 2020
G5G5 10.110.1
G6G6 0.2950.295
G7G7 37.237.2
표 8에서 데이터는 평균으로 나타내었으며, G1은 비히클대조구, G2는 미녹시딜 3% 0.18 ml/head, G3는 멜라토닌 0.01% 0.18 ml/head, G5는 멜라토닌 0.1% 0.18 ml/head, G6는 멜라토닌 0.1% 단독 0.18 ml/head, G7은 멜라토닌 0.2% 0.18 ml/head이다. In Table 8, the data are presented as averages, G1 is vehicle control, G2 is minoxidil 3% 0.18 ml / head, G3 is melatonin 0.01% 0.18 ml / head, G5 is melatonin 0.1% 0.18 ml / head, G6 is melatonin 0.1% 0.18 ml / head alone, G7 is 0.2% 0.18 ml / head of melatonin.
활성 모낭비율(anagen ratio)16일째Active anagen ratio on day 16
G1G1 0.30.3
G2G2 0.40.4
G3G3 0.60.6
G6G6 0.40.4
G7G7 0.70.7
전체 모낭 중 활성 형태 모낭의 수의 비율로 계산하였다. 활성모낭은 발모시험 내 조직병리학적 검사 소견에서 생장기 모낭 및 모발로 전환된 개체의 비율을나타낸다. 조직병리학적 검사에서 생장기, 휴지기 및 퇴행기로 구분을 하며, 전체 중 생장기 모낭의 비율만을 계산한 것이다. 생장기, 휴지기 및 퇴행기는 모낭수, 모낭의 크기 및 모발의 굵기, 형태 등을 현미경 상에서 종합적으로 고려하여 판단하고 결정하였다. 계산방법은 다음과 같다:Calculated as the ratio of the number of active follicles in the total hair follicles. 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:
활성 모낭비율(Anagen ratio) = 제모 부위가 생장기로 전환된 동물수 / 각 시험군의전체동물수 X 100.Active hair follicle ratio (Anagen 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.
즉 비율이 높을수록 발모 면적이 높은 것을 의미한다. In other words, the higher the ratio, the higher the hair growth area.
표 9에서 데이터는 평균으로 나타내었으며, G1은 비히클대조구, G2는 미녹시딜 3% 0.18 ml/head, G3는 멜라토닌 0.01 % 0.18 ml/head, G6는 멜라토닌 0.1% 단독 0.18 ml/head, G7은 멜라토닌 0.2% 0.18 ml/head이다. In Table 9, the data are presented as averages, G1 is vehicle control, G2 is minoxidil 3% 0.18 ml / head, G3 is melatonin 0.01% 0.18 ml / head, G6 is melatonin 0.1% alone 0.18 ml / head, G7 is melatonin 0.2 % 0.18 ml / head.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (16)

  1. 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 약제학적 조성물.Pharmaceutical composition for promoting hair growth, wool or hair growth comprising melatonin, dexpanthenol, biotin and nicotinic acid amide as an active ingredient.
  2. 멜라토닌 0.001-1.0 중량%, 덱스판테놀 0.01-0.5 중량%, 비오틴 0.001-0.05 중량% 및 니코틴산아미드 0.006-0.3 중량%를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 약제학적 조성물. A pharmaceutical composition for promoting hair growth, wool or hair growth 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.
  3. 제 1 항 또는 제2항에 있어서, 상기 조성물은 광안정화제를 추가적으로 더 포함하는 것을 특징으로 하는 조성물.The composition of claim 1 or 2, wherein the composition further comprises a light stabilizer.
  4. 제 3 항에 있어서, 상기 광안정화제는 트리아졸계, 벤조페논계, 힌더드 아민 광안정화제(Hindered Amine Light stabilizer, HALS), 힌더드페놀성 광안정화제(Hindered Phenol Light Stabilizer), 및 Al-Mg(알루미늄-마그네슘)계 안정제로 구성된 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는 조성물.4. The light stabilizer according to claim 3, wherein the light stabilizer is a triazole type, a benzophenone type, a hindered amine light stabilizer (HALS), a hindered phenolic light stabilizer, and an Al-Mg (aluminum). -Magnesium) -based stabilizer, characterized in that any one or more selected from the group consisting of.
  5. 제 4 항에 있어서, 상기 광안정화제는 벤조페논인 것을 특징으로 하는 조성물.5. The composition of claim 4 wherein said light stabilizer is benzophenone.
  6. 제 1 항 또는 제 2 항에 있어서, 상기 조성물은 제제 안정화제를 추가적으로 더 포함하는 것을 특징으로 하는 조성물.The composition of claim 1 or 2, wherein the composition further comprises a formulation stabilizer.
  7. 제 6 항에 있어서, 상기 제제 안정화제는 파라히드록시벤조산에스테르(parahydroxybenzoic acid ester) 유도체, 피롤리디논(pyrrolidinone) 유도체, 알코올, 페놀 유도체, 티메로살(thimerosal), 아세트산 무수물, 소디움카르복실레이트, 라우릴설페이트(lauryl sulfate), 설파이드 화합물, 아황산염(sulfite), 아스코르빈산, 레티놀(retinol), 토코페롤(tocopherol), 및 부틸 하이드록시아니솔(butyl hydroxyl anisole)로 구성된 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는 조성물.The method of claim 6, wherein the formulation stabilizer is a parahydroxybenzoic acid ester derivative, pyrrolidinone derivatives, alcohols, phenol derivatives, thimerosal, acetic anhydride, sodium carboxylate Any one selected from the group consisting of lauryl sulfate, sulfide compounds, sulfites, ascorbic acid, retinol, tocopherol, and butyl hydroxyl anisole The composition characterized by the above.
  8. 제 7 항에 있어서, 상기 제제 안정화제는 메틸-2-피롤리디논인 것을 특징으로 하는 조성물.8. The composition of claim 7, wherein said agent stabilizer is methyl-2-pyrrolidinone.
  9. 제 1 항 또는 제 2 항에 있어서, 상기 조성물은 약제학적 조성물인 것을 특징으로 하는 조성물.The composition of claim 1 or 2, wherein the composition is a pharmaceutical composition.
  10. 제 9 항에 있어서, 상기 조성물은 피부외용 조성물인 것을 특징으로 하는 조성물.10. The composition of claim 9, wherein the composition is an external skin composition.
  11. 제 1 항 또는 제 2 항에 있어서, 상기 조성물은 화장료 조성물인 것을 특징으로 하는 조성물.The composition according to claim 1 or 2, wherein the composition is a cosmetic composition.
  12. 제 1 항 또는 제 2 항에 있어서, 상기 조성물은 기능성 식품 조성물인 것을 특징으로 하는 조성물.The composition of claim 1 or 2, wherein the composition is a functional food composition.
  13. 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 탈모 예방 또는 치료용 조성물.Hair loss prevention or treatment composition comprising melatonin, dexpanthenol, biotin and nicotinic acid amide as an active ingredient.
  14. 멜라토닌 0.001-1.0 중량%, 덱스판테놀 0.01-0.5 중량%, 비오틴 0.001-0.05 중량% 및 니코틴산아미드 0.006-0.3 중량%를 유효성분으로 포함하는 탈모 예방 또는 치료용 약제학적 조성물.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.
  15. 멜라토닌, 덱스판테놀, 비오틴 및 니코틴산아미드를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 조성물의 약제학적 유효량을 이를 필요로 하는 대상(subject)에 투여하는 단계를 포함하는 육모, 양모 또는 발모 촉진 방법.A method for promoting hair growth, wool or hair growth comprising administering to a subject in need thereof a pharmaceutically effective amount of hair growth, wool or hair growth promoting composition comprising melatonin, dexpanthenol, biotin and nicotinamide as an active ingredient. .
  16. 멜라토닌 0.001-1.0 중량%, 덱스판테놀 0.01-0.5 중량%, 비오틴 0.001-0.05 중량% 및 니코틴산아미드 0.006-0.3 중량%를 유효성분으로 포함하는 육모, 양모 또는 발모 촉진용 조성물의 약제학적 유효량을 이를 필요로 하는 대상(subject)에 투여하는 단계를 포함하는 육모, 양모 또는 발모 촉진 방법. A pharmaceutically effective amount of the composition for promoting hair growth, wool or hair growth 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 is required. A method for promoting hair growth, wool or hair growth comprising administering to a subject.
PCT/KR2016/000742 2015-01-30 2016-01-22 Composition for hair health or hair growth promotion, having improved stability and containing melatonin WO2016122172A1 (en)

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