WO2023191515A1 - Composition for preventing hair loss or promoting hair growth comprising indirubin derivative and metabolic activator - Google Patents
Composition for preventing hair loss or promoting hair growth comprising indirubin derivative and metabolic activator Download PDFInfo
- Publication number
- WO2023191515A1 WO2023191515A1 PCT/KR2023/004211 KR2023004211W WO2023191515A1 WO 2023191515 A1 WO2023191515 A1 WO 2023191515A1 KR 2023004211 W KR2023004211 W KR 2023004211W WO 2023191515 A1 WO2023191515 A1 WO 2023191515A1
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- WIPO (PCT)
- Prior art keywords
- hair
- formula
- activator
- alkyl
- group
- Prior art date
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- 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
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Definitions
- the present invention relates to a composition for preventing hair loss or promoting hair growth containing an indirubin derivative and a metabolic activator.
- the anagen phase is the period when hair grows
- the catagen phase is the period when the metabolic process slows down while maintaining the shape of the hair after the growth period ends. During this period, hair growth slows down.
- the catagen stage is a period in which hair follicle cell division stops and rapidly shrinks.
- the final telogen phase is a period in which hair follicle activity completely stops and prepares for hair loss. The telogen hair is pushed out by new growth-phase hair growing at the base and falls out on its own, and is easily removed by physical actions such as combing or washing the hair. This cycle repeats over 3 to 6 years.
- Hair loss refers to a condition in which there is no hair in areas where hair should normally exist.
- the papilla present at the hair root becomes smaller, and as the papilla becomes smaller, the thickness of the hair becomes thinner and at the same time, the hair cycle becomes shorter and new growth occurs.
- the hair that comes out becomes thinner. In other words, as hair loss progresses, the hair turns into fluff and the hair cycle becomes shorter, so the hair grows a little and falls out immediately.
- DHT dihydrotestosterone
- Testosterone a type of male hormone, is activated into DHT by the 5 ⁇ -reductase enzyme, and this DHT is known to induce hair loss.
- DHT causes hair follicles to atrophy, causing vellus hair to become thin and limp.
- hair root-destroying substances are secreted, causing the hair to enter the catagen stage at an early stage, resulting in hair loss.
- Hair loss treatments developed to date include finasteride (brand name: Propecia®), dutasteride (brand name: Avodart®), and minoxidil (brand names: Minoxil® or Rogaine®).
- Minoxidil can cause side effects such as edema, arrhythmia, and hair growth in unwanted areas when applied long-term. It is known that the effect of minoxidil is greatest between 6 months and 1 year after use, and the effect gradually decreases thereafter.
- Finasteride and dutasteride inhibit DHT production by blocking the action of the 5 ⁇ -reductase enzyme, but have side effects such as decreased libido, erectile dysfunction, and loss of driving and performance abilities.
- hair transplant surgery has recently been attempted for patients with severe hair loss, but the high cost and side effects after the procedure have been pointed out as limitations.
- the present inventors conducted repeated research to develop a drug with fewer side effects and excellent hair loss improvement effect, and as a result discovered that indirubin derivatives and metabolic activators have excellent hair loss improvement effect, thereby completing the present invention. .
- Patent Document 1 Republic of Korea Patent Publication No. 10-2022-0032974
- the present invention was devised to solve the above problems, and the object of the present invention is to provide a pharmaceutical composition for preventing or treating hair loss that contains an indirubin derivative and a metabolic activator as active ingredients and has no side effects on the human body.
- the present invention provides a cosmetic composition and food composition for preventing or improving hair loss containing the indirubin derivative and the metabolic activator as active ingredients.
- Another object of the present invention is to provide a method for preventing, improving, or treating hair loss that has an excellent hair loss prevention or treatment effect and includes an indirubin derivative and a metabolic activator as active ingredients.
- the present invention is intended to provide a new use of a composition containing an indirubin derivative and a metabolic activator for the prevention or treatment of hair loss.
- the present invention includes an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients, and the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier)
- a pharmaceutical composition for preventing or treating hair loss which is an inhibitor.
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- R 1 to R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy
- R 4 is hydrogen or C 1 - C 6 alkyl
- R 5 may be any one selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 arylalkyl.
- R 3 and R 4 may be hydrogen.
- R 1 and R 2 may each independently be selected from the group consisting of hydrogen, halogen, and -O-CH 3 .
- R 5 may be any one selected from the group consisting of hydrogen, C 1 -C 3 alkyl, substituted or unsubstituted C 6 -C 10 aryl, and C 7-10 arylalkyl.
- Formula 1 may be any one selected from the following Formulas 1-1 to 1-4.
- the PKM2 (pyruvate kinase M2) activator is 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5 ]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1, It may be any one selected from the group consisting of 4-diazepan-1-ylsulfonyl)aniline (DASA-58) and serine, and the MPC (Mitochondrial pyruvate carrier) inhibitor is (E)-2-Cyano-3- It may be (1-phenyl-1H-indol-3-yl)acrylic acid (UK5099).
- the indirubin derivative and the metabolic activator may be included in a molar ratio of 1:0.1 to 10.
- the present invention includes an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients, and the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) )
- the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier)
- PKM2 pyruvate kinase M2
- MPC Mitochondrial pyruvate carrier
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- the composition may promote the proliferation of dermal papilla cells or hair follicle cells in vitro.
- the cosmetic composition includes hair tonic, hair conditioner, hair essence, hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisture cream, hair massage cream, hair wax, and hair aerosol.
- hair pack, hair nutrition pack, hair soap, hair cleansing foam, hair oil, hair dryer, hair preservation treatment, hair dye, hair waving agent, hair bleach, hair gel, hair glaze, hair dresser, hair lacquer, hair moisturizer It may be any one hair formulation selected from the group consisting of hair mousse and hair spray.
- the present invention includes an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients, and the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate)
- a food composition for preventing or improving hair loss which is characterized as being a carrier inhibitor.
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- the present invention provides a method for preventing or treating hair loss, which includes administering an indirubin derivative represented by the following formula (1) and a metabolic activator to a hair loss patient.
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- the present invention provides a new use of an indirubin derivative and a metabolic activator represented by the following formula (1) as a drug for preventing or treating hair loss.
- the metabolic activator is characterized as being a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) inhibitor.
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- the present invention provides a method for producing a pharmaceutical agent having a hair loss prevention or treatment effect, characterized by using an indirubin derivative and a metabolic activator represented by the following formula (1): .
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- composition according to the present invention can be usefully used as a pharmaceutical composition or cosmetic composition capable of preventing hair loss or promoting hair growth, and can be used in functional cosmetics for preventing hair loss or promoting hair growth, including hair growth promoting agents.
- the mixed composition of an indirubin derivative and a metabolic activator according to the present invention has the advantage of being a safe material that is non-toxic to cells and does not cause inflammation and does not cause side effects to the human body.
- the present invention is a composition that mixes an indirubin derivative and a metabolic activator at a certain ratio, and has the advantage of showing a stronger effect on hair growth, wool growth, and hair loss prevention than a single composition.
- Figure 1 is a micrograph taken after culturing Vibrissa hair follicles treated with indirubin derivatives or metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone for 6 days
- Figure 2 is This is a photomicrograph taken after culturing Vibrissa hair follicles treated with a mixture of indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) for 6 days.
- Figure 3 shows the length change of each Vibrissa hair follicle treated alone or in combination with an indirubin derivative and a metabolic activator (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) and cultured for 6 days. This is the graph shown (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005, NS: not significant vs. VEH or single treat).
- a metabolic activator TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate
- Figure 4 is a micrograph (top) of Vibrissa hair follicles taken in the group administered with various concentrations of serine alone and a graph (bottom) showing the length change (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005, NS: not significant vs. VEH).
- Figure 5 shows the cell viability of human dermal papilla cells treated with indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone or in combination. This is the graph shown (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005 vs VEH).
- Figure 6 is a photograph of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination
- Figure 7 is a photograph of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination. This is a graph showing the hair growth values measured from each treated group (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005, NS: not significant vs VEH or single treat).
- One aspect of the present invention relates to a pharmaceutical composition, cosmetic composition, and food composition for preventing or treating hair loss containing an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients.
- the metabolic activator may be a PKM2 (pyruvate kinase M2) activator or an MPC (Mitochondrial pyruvate carrier) inhibitor.
- Another aspect of the present invention relates to a method of treating hair loss comprising administering an effective amount of an indirubin derivative represented by Formula 1 and a metabolic activator to a hair loss patient.
- Another aspect of the present invention relates to a method of treating hair loss comprising administering a therapeutically effective amount of an indirubin derivative represented by Formula 1 and a metabolic activator to a subject.
- Another aspect of the present invention provides a new use of the indirubin derivative and metabolic activator represented by the following formula (1) as a drug for preventing or treating hair loss.
- another aspect of the present invention provides a method for producing a pharmaceutical agent having a hair loss prevention or treatment effect, characterized by using an indirubin derivative represented by the following formula (1) and a metabolic activator.
- the indirubin derivative and metabolic activator represented by Formula 1 are active ingredients that enable the above method and use to be achieved, and may be in the form of a mixture or mixed composition or composition mixed in a certain ratio.
- the present invention is a composition that mixes an indirubin derivative and a metabolic activator in a certain ratio, and has been confirmed to have excellent effects on preventing hair loss and promoting hair growth, making it possible to prevent hair loss and promote hair growth, and thus can be used in pharmaceuticals, foods, cosmetics, etc. It can be applied to various fields.
- R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- 'halogen' in the present invention refers to bromo, chloro, fluoro, or iodo, and can be used interchangeably with 'halo' and 'halogen'.
- alkyl' in the present invention refers to a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and includes saturated aliphatic groups that may be straight-chain, branched, or cyclic, or a combination thereof. do.
- an alkyl group may have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl).
- alkyls examples include methyl (Me, -CH 3 ), ethyl (Et, -C 2 H 5 ), 1-propyl (n-Pr, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, - CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu,-CH 2 CH(CH 3 ) 2 ) , 2-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl- 2-Butyl(-CH(CH 3 ) 2 CH 2 CH
- 'alkoxy' in the present invention refers to a functional group with -OR in which an alkyl group is attached to the parent compound through an oxygen atom.
- Examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
- the term 'aryl' refers to an optionally substituted benzene ring, or a ring system that can be formed by fusing one or more optional substituents, and the number of carbon atoms is not particularly limited, but is 6 to 6. Substituted or unsubstituted allyl, which is 30, is preferred.
- 'aryl' groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracyl or phenanthryl, and substituted derivatives thereof.
- the substituents include C l - 3 alkyl, C 2 - 3 alkenyl, substituted C 2 - 3 alkynyl, heteroaryl, heterocyclic, aryl, alkoxy, aryloxy, aralkoxy, optionally having 1 to 3 fluorine substituents.
- This ring or ring system may optionally be fused to an aryl ring (eg, a benzene ring), a carbocyclic ring, or a heterocyclic ring, optionally bearing one or more substituents.
- the substituent may be C 1-3 alkyl
- aryl substituted with C 1-3 alkyl refers to an aryl group in which one hydrogen is substituted with an alkyl group.
- the aryl group substituted with C 1-3 alkyl is also called alkylaryl and may be C 7 to C 30 alkylaryl.
- C 7-30 alkylaryl may be methylphenyl, ethylphenyl, n-propylphenyl, iso-propylphenyl, n-butylphenyl, iso-butylphenyl, tert-butylphenyl, or cyclohexylphenyl, and is preferably C It may be 7 to C 10 alkylaryl.
- the arylalkyl group is arylalkyl having 7 to 30 carbon atoms, which may mean a substituent in which one or more hydrogens of alkyl are replaced by aryl. Specifically, it may be C 7-30 arylalkyl, preferably benzyl, phenylpropyl, or phenylhexyl, and more preferably, the C 7-10 arylalkyl may be benzyl or phenylpropyl.
- 'hydroxy' in the present invention refers to the -OH radical.
- R 1 to R 3 may each independently be selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, and R 4 is hydrogen or C It may be 1 -C 6 alkyl, but more preferably, in Formula 1, R 1 and R 2 may each independently be any one selected from the group consisting of hydrogen, halogen, and -O-CH 3 , and the formula In 1, R 3 and R 4 may be hydrogen.
- R 5 may be any one selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 6 -C 10 aryl, but more preferably R 5 is hydrogen, C 1 -C 3 alkyl. , substituted or unsubstituted C 6 -C 10 aryl, and C 7-10 arylalkyl.
- Indirubin represented by Formula 1 is 5-methoxyl indirubin-3'-oxime, indirubin-3'-oxime, 6-bromoindirubin-3'-oxime, 5,6-dichloro indirubin, 5 , 6-dichloro indirubin-3'-oxime, 5,6-dichloro indirubin-3'-methoxime, 5,6-dichloro indirubin-3'-propyl oxime, 6-chloro-5-nitro indirubin, 6-chloro-5-nitroindirubin-3'-oxime, 6-chloroindirubin-3'-methoxime, 5-chloroindirubin-3'-methoxime, 5-bromoindirubin-3'-oxime , 5-bromoindirubin-3'-oxime , 5-bromoindirubin-3'-methoxime, 5-bromoindirubin-3'-ethyloxime, 5,6-dichloroindirubin-3'-oximepropyloxime and 6-
- Formula 1 may be any one selected from the following Formulas 1-1 to 1-4, but is not limited thereto, and can significantly prevent and treat hair loss and hair growth through combined use with a metabolic activator. Alternatively, it may show an improvement effect, but most preferably, an indirubin derivative represented by Formula 1-1 prevents hair loss when administered in combination with a metabolic activator, not only promotes hair growth or hair growth, but also promotes the proliferation of skin cells. By increasing and inducing, a significant effect beyond the synergistic effect can be achieved compared to single administration.
- the metabolic activator may be a PKM2 (pyruvate kinase M2) activator or an MPC (Mitochondrial pyruvate carrier) inhibitor, and the PKM2 (pyruvate kinase M2) activator refers to any substance that can promote the expression or activity of PKM2.
- PKM2 pyruvate kinase M2
- MPC Mitochondrial pyruvate carrier
- 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5] pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4 -diazepan-1-ylsulfonyl)aniline (DASA-58) may be any one selected from the group consisting of serine, and more preferably 6-[(3-aminophenyl)methyl]-4,6-dihydro It may be -4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one (TEPP-46, ML
- MPC mitochondrial pyruvate carrier
- E 2-Cyano- It may be 3-(1-phenyl-1H-indol-3-yl)acrylic acid (UK5099).
- the term 'hair loss' refers to a state in which there is no hair in areas where hair should normally exist, regardless of the cause, for example, male pattern baldness, female pattern baldness, alopecia areata, telogen effluvium, stress-related. It may be hair loss or hair loss caused by chemotherapy drugs.
- the composition of the present invention promotes proliferation of dermal papilla cells and growth of hair length, and therefore may be particularly effective in the treatment of male pattern baldness.
- the indirubin derivative is represented by Formulas 1-1 to 1-4, which shows little toxicity to cells even when treated with cells for a long period of time, and has a significant increase in effect when treated with a metabolic activator. It may be any one or more selected from the group consisting of, and most preferably, it may be an indirubin derivative represented by Formula 1-2. This is because through in vitro experiments, treatment with an indirubin derivative of Chemical Formula 1-2 and a metabolic activator was observed to increase the length of vibrissa by more than 75 to 95% compared to the conventional hair loss treatment agent (minoxidil). Because it has been done.
- the conventional hair loss treatment agent minoxidil
- the composition containing an indirubin derivative and a metabolic activator according to the present invention can be used as a pharmaceutical composition and cosmetic composition that prevents hair loss and promotes hair growth by preventing hair follicles from entering the telogen phase and maintaining the growth phase. You can.
- composition according to the present invention did not show inflammation or other pathological findings and was confirmed to be stable in cytotoxicity tests, and based on this, it can be used as an improvement or treatment for hair loss.
- the indirubin derivative represented by Formula 1 according to the present invention can be used not only as a free substance, but also as a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable polymorph, or pharmaceutically acceptable prodrug. can be provided.
- the salt of the indirubin derivative is not particularly limited as long as it is in a form that can be incorporated into medicines or cosmetics. It contains inorganic salts or organic salts and may be acidic salts or alkaline salts.
- alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; Basic amino acid salts such as arginine and lysine; Ammonium salts such as ammonium salt and tricyclohexylammonium salt; It may be various alkanol amine salts such as monoethanolamine salt, diethanolamine salt, triethanolamine salt, monoisopropanolamine salt, diisopropanolamine salt, and triisopropanolamine salt.
- the salt is an alkali metal salt, and more preferably, it may be a tetrasodium salt.
- the mixing ratio of the indirubin derivative and the metabolic activator is not particularly limited, but may be included at a molar ratio of 1:0.1 to 10, preferably 1:0.1 to 5, and more preferably 1:0.1 to 5. It may be a molar ratio of 0.1 to 3. If it is outside the above range, it is undesirable because the hair loss prevention and hair promotion effects are reduced.
- the term 'comprising an active ingredient' in the present invention means containing an active ingredient in an amount sufficient to prevent hair loss or promote hair growth in the present invention.
- the term 'prevention' refers to any action that inhibits or delays hair loss or hair damage by administering the composition according to the present invention
- 'treatment' refers to improvement of hair loss symptoms by administering the pharmaceutical composition. It means any action that becomes or changes beneficially.
- the term 'improvement' in the present invention means any act of reducing at least the degree of symptoms, for example, parameters related to the hair loss or hair damage condition treated by administration of the composition containing the indirubin derivative and the metabolic activator of the present invention. means.
- the pharmaceutical composition of the present invention can be administered parenterally or orally according to the desired method, and preferably may be parenteral administration or topical administration through application.
- the dosage range varies depending on the patient's weight, age, gender, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.
- the therapeutically effective amount of the composition may vary depending on the administration method, target area, and patient's condition, and when used in the human body, the dosage should be determined as an appropriate amount considering safety and efficiency.
- subject refers to an object for which the disease is to be prevented or treated, and preferably includes humans and animals.
- the upper limit of the dosage is not particularly limited, but the preferred dosage of the composition of the present invention is 0.01 to 1000 mL/kg per day. Preferably, it can be administered at 0.1 to 100 ml/kg, and more preferably at 1 to 10 ml/kg. Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way.
- the pharmaceutical composition of the present invention can be formulated into oral dosage forms such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, and aerosols, skin external preparations such as ointments and creams, suppositories, injections, and the like, respectively, according to conventional methods. It can be formulated and used in any form suitable for pharmaceutical preparations, including sterile injectable solutions.
- excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and diluents commonly used for the formulation.
- excipients that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate.
- cellulose methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc can also be used.
- Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
- Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
- witepsol macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.
- composition according to the present invention may have a dosage form that can be administered by a method such as directly applying or spraying to the skin or wound, for example, a cream, lotion, ointment, aerosol, gel, or pack.
- a method such as directly applying or spraying to the skin or wound, for example, a cream, lotion, ointment, aerosol, gel, or pack.
- Methods for mixing ingredients or formulations suitable for each dosage form are well known in the art. When preparing these preparations, those skilled in the art can appropriately select and use various mixing ingredients used in preparing conventional external preparations.
- such ingredients include white petrolatum, yellow petrolatum, lanolin, bleached beeswax, cetanol, stearyl alcohol, stearic acid, hydrogenated oil, gelling hydrocarbons, polyethylene glycol, and liquid paraffin. , squalane, etc., oleic acid, isopropyl myrstate, glycerin triisooctanoate, crotamiton, diethyl sebacate, diisopropyl adipate, hexyl laurate, fatty acids, fatty acid esters, fatty alcohols, vegetable oils.
- solvents and solubilizers such as tocopherol derivatives, antioxidants such as L-ascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, preservatives such as parahydroxybenzoic acid ester, glycerin, propylene glycol, and sodium hyaluronate.
- Moisturizers such as polyoxyethylene derivatives, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, surfactants such as lecithin, carboxyvinyl polymer, xanthan gum, carboxymethyl cellulose, carboxymethyl cellulose sodium salt, There are thickeners such as hydroxypropylcellulose and hydroxypropylmethylcellulose.
- the present invention relates to a cosmetic composition for alleviating, suppressing or improving hair loss containing an indirubin derivative represented by Formula 1 and a metabolic activator as active ingredients.
- the specific description of the cosmetic composition is the same as the description of the pharmaceutical composition for preventing or treating hair loss containing the indirubin derivative represented by Chemical Formula 1 and the metabolic activator as active ingredients, so please refer to that section for detailed information. .
- ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions in addition to the indirubin derivative and metabolic activator as active ingredients, such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances. It may include common auxiliaries and carriers such as:
- the cosmetic composition of the present invention can be prepared in any formulation commonly prepared in the art, for example, solution, suspension, emulsion, paste, gel, shampoo, rinse, conditioner, lotion, lotion, cream, serum. , essence, gel, pack, cleanser, soap, spray, powder, oil, powder foundation, emulsion foundation, and wax foundation, but is not limited thereto, and specifically hair tonic, hair conditioner, and hair essence. , hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisture cream, hair massage cream, hair wax, hair aerosol, hair pack, hair nutrition pack, hair soap, hair cleansing foam.
- the present invention relates to a food composition for preventing or improving hair loss containing an indirubin derivative represented by Formula 1 and a metabolic activator as active ingredients.
- the specific description of the food composition is the same as the description of the pharmaceutical composition for preventing or treating hair loss containing the indirubin derivative represented by Chemical Formula 1 and the metabolic activator as active ingredients, so please refer to that section for detailed information. .
- the food composition according to the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods.
- Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, confectionery, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, gum, ice cream, vitamin complexes, and health supplements. etc.
- the food composition of the present invention may contain not only the above active ingredients but also ingredients commonly added during food production, including, for example, proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents.
- examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- flavoring agents natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
- thaumatin, stevia extract e.g., rebaudioside A, glycyrrhizin, etc.
- synthetic flavoring agents sacharin, aspartame, etc.
- the food composition of the present invention is manufactured as a drink or beverage
- citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be additionally included in addition to the boratin of the present invention.
- the present invention provides a health functional food containing a food composition for preventing or improving hair loss containing an active ingredient.
- Health functional foods are foods manufactured by adding the active ingredients of indirubin derivatives and metabolic activators represented by Chemical Formula 1 to food ingredients such as beverages, teas, spices, gum, and confectionery, or by encapsulating, powdering, or suspending them. , which means that ingesting it will bring about certain health effects, but unlike regular drugs, it has the advantage of not having any side effects that may occur when taking the drug for a long time since it is made from food.
- the health functional food of the present invention obtained in this way is very useful because it can be consumed on a daily basis.
- the amount of active ingredients added in such health functional foods cannot be uniformly specified as it depends on the type of health functional food being targeted. However, it can be added within a range that does not damage the original taste of the food, and is usually 0.01% for the target food. to 50% by weight, preferably 0.1 to 20% by weight.
- it is usually added in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight.
- the health functional food of the present invention may be in the form of a pill, tablet, capsule, or beverage.
- the present invention provides a composition for promoting the growth of dermal papilla cells or hair follicle cells isolated from mammalian skin, comprising an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients.
- composition for preventing or treating hair loss containing the indirubin derivative represented by Formula 1 and a metabolic activator as active ingredients, so refer to that section for detailed information.
- the composition of the present invention can be used as a composition that can promote the proliferation of dermal papilla cells or hair follicle cells in vitro, and can especially be used as a medium composition that can culture the dermal papilla cells and hair follicle cells in vitro.
- the mammal may be any one selected from the group consisting of humans, cattle, goats, and sheep.
- the present inventors provide a composition that can efficiently and rapidly mass-produce dermal papilla cells or hair follicle cells in vitro in relation to hair loss or hair growth promotion, and the composition only efficiently causes the growth of dermal papilla cells or hair follicle cells.
- the composition only efficiently causes the growth of dermal papilla cells or hair follicle cells.
- large amounts of non-toxic dermal papilla cells and hair follicle cells could be produced at high yield.
- 5,6-dichloroindirubin-3'-propyloxime and 6-chloroindirubin-3'-benzyloxime are 5,6-dichloroindirubin-3'-methoxime or 5-methoxyl indirubin-3'.
- -It was synthesized in the same way as oxime, and was dissolved in dimethyl sulfide (DMSO) and applied to the experiment.
- the metabolic activator used in the present invention is 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[ 2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4-diazepan -1-ylsulfonyl)aniline (DASA-58) and (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid (UK5099) and serine were obtained from Sigma Aldrich (St. Louis, USA) and used.
- Examples 1 to 4 are a mixture of an indirubin derivative represented by Formula 1-2 and a metabolic activator
- Comparative Examples 1 to 9 are a group administered only an indirubin derivative represented by Formula 1-2 or a metabolic activator.
- Comparative Examples 10 and 11 contain dichloroacetate, a PDK activator, not a PKM2 activator, alone or mixed with an indirubin derivative among metabolic activators.
- mice Male mice aged 6 to 8 weeks were sacrificed, and tissues around the mouth were isolated. The separated tissue was placed in 70% ethanol and then washed with PBS (phosphate) containing 1% penicillin (100IU/ml)/streptomycin (100 ⁇ g/ml) (P/S, GIBCO, Grand Island, NY, USA). -buffered saline)pH 7.4, SIGMA, St. Louis, MO, USA) to prepare an emulsion. Using a microscope, vibrissa follicles in the anagen state were separated one by one.
- PBS phosphate
- P/S GIBCO
- SIGMA St. Louis, MO, USA
- the isolated vibrissa follicles were dispensed into each well of a 24-well plate and then treated with medium containing the examples or comparative examples (DMEM serum free 1% P/S + 12.5 ⁇ g/ml gentamycin).
- the plate was cultured at 37°C and 5% CO 2 and observed through a microscope after 6 days. The medium was changed once every two days.
- the hair follicle morphology was photographed under a microscope (SMZ745T, Nikon), and the hair follicle length was measured using image J.
- the average value of hair follicle length change was calculated and compared with the average length of the negative control group or single treatment group to measure the degree of growth.
- the results obtained from the experiment were recorded as the mean and its standard error of the mean (SEM), and significance was determined using the Student's T-test analysis method.
- Figure 1 is a micrograph taken after culturing Vibrissa hair follicles treated with indirubin derivatives or metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone for 6 days
- Figure 2 is This is a photomicrograph taken after culturing Vibrissa hair follicles treated with a mixture of indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) for 6 days.
- Figure 3 shows the length change of each Vibrissa hair follicle treated alone or in combination with an indirubin derivative and a metabolic activator (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) and cultured for 6 days. This is the graph shown (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005, NS: not significant vs. VEH or single treat).
- a metabolic activator TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate
- Figure 4 is a micrograph (top) of Vibrissa hair follicles taken in the group administered with various concentrations of serine alone and a graph (bottom) showing the length change (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005, NS: not significant vs. VEH).
- Examples 1 to 4 which are a mixture of an indirubin derivative represented by Formula 1-2 and a metabolic activator, have a ratio of 75 to 95% or more than minoxidil (MNX), a conventional hair loss treatment agent. It showed an effect of increasing the length of vibrissa, and the length of vibrissa increased compared to Comparative Examples 1 to 9 (single-treatment) in which the indirubin derivative or metabolic activator represented by Formula 1-2 was administered alone. It was confirmed that was 20% to 40% or more.
- MNX minoxidil
- Comparative Examples 1 to 9 in which the indirubin derivative or metabolic activator represented by Formula 1-2 was administered alone, produced an increase effect of only about 1.25 times that of minoxidil (MNX), a conventional hair loss treatment, It can be seen that Examples 1 to 4 achieve significantly more significant effects than the simple synergistic effect of Comparative Examples 1 to 9.
- the mixed composition prepared in Examples 1 to 4 of the present invention can be used as a composition useful for preventing hair loss and promoting hair growth.
- Human dermal papilla cells were fixed at a rate of 2 ⁇ 10 5 per well of a 6-well plate, and when the cells were stably attached, they were treated with the drugs of Examples or Comparative Examples. . After 24 hours, luminescence values were measured using a FLUOstar OPTIMA luminometer (BMG Labtech, Offenburg, Germany) using the Cell Titer-Glo Luminescent Cell Viability Assay kit (Promega, Madison, USA).
- Figure 5 shows the cell viability of human dermal papilla cells treated with indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone or in combination. This is the graph shown (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005 vs VEH).
- the indirubin derivative represented by Formula 1-2 and the metabolic activator did not show cytotoxicity either alone or in combination. That is, in Examples 1 to 4 and Comparative Examples 1 to 12, it was confirmed that the cell viability was more than 100%, confirming that the cell stability was very excellent. However, in the case of minoxidil (MNX), it was confirmed to be 97%, the only one below 100%.
- C57BL/6N mice were used as experimental animals considering ease of experimentation.
- the experimental animals used were 7-week-old male C57BL/6N normal mice weighing approximately 25g purchased from Orient Bio Co., Ltd. Five animals were assigned to each experimental group.
- all hair follicles enter the anagen phase of the hair growth cycle from birth and begin to grow hair. After about 3 weeks, the mouse transitions to the telogen phase and immediately enters the second growth phase. It is known that all hair follicles transition into the telogen phase around 6-7 weeks, so this telogen phase is appropriate for evaluating the efficacy of only the experimental substance since the influence of the test animal's own hair growth factors is excluded.
- the hair on the back of a 7-week-old C57BL/6N mouse was removed using an animal clipper.
- the experiment was conducted by dividing the animals into 5 groups with 5 animals per group. Except for the normal group, 150 ⁇ l of the drug was applied to the back skin once a day for 28 days. Drugs were administered, and 4 weeks later, they were euthanized using carbon dioxide and photographs were taken. To compare the degree of hair growth, hair growth during the anagen phase was observed after 4 weeks by measuring the weight of the regrown hair. Among all areas of hair loss, the weight of the area where hair grew during the anagen phase was measured.
- VHE Normal group
- TEPP46 First comparison group
- Second comparison group (KY19382): 150 ⁇ l of KY19382 (0.5 mM) was applied to the back skin once a day for 28 days.
- MNX Third comparison group
- Figure 6 is a photograph taken of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination
- Figure 7 is a photograph of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination. This is a graph showing the hair growth values measured from each treated group (* P ⁇ 0.05, ** P ⁇ 0.005, *** P ⁇ 0.0005, NS: not significant vs VEH or single treat).
- the composition combining the indirubin derivative (KY19382) and the metabolic activator (TEPP-46) of the present invention was compared and reviewed for hair loss improvement effect with MNX, an existing hair loss improvement agent, and as a result, the indirubin derivative (KY19382) and the metabolic activator were compared. It was confirmed that the composition mixed with the agent (TEPP-46) promoted hair growth during the growth period and showed significantly significant hair growth efficacy. In addition, the mixed composition of indirubin derivative (KY19382) and metabolic activator (TEPP-46) did not show inflammation or other pathological findings and was confirmed to be stable in cytotoxicity tests. Based on this, it was confirmed as an improvement or treatment for hair loss. You can see that it is available.
- Formulation Example 1 Cream-type cosmetic composition for preventing or improving hair loss
- composition of Example 1 an attempt was made to prepare a cream-type cosmetic composition for preventing or improving hair loss containing a mixed composition of an indirubin derivative of Formula 1-2 and a metabolic activator (TEPP-46) as an active ingredient.
- Components including the composition of Example 1 were mixed according to the following amounts to prepare a cream-type cosmetic composition for preventing or improving hair loss.
- Formulation Example 2 Pharmaceutical composition (ointment) for preventing or treating hair loss
- composition for preventing or treating hair loss containing a mixed composition of an indirubin derivative of Formula 1-2 and a metabolic activator (TEPP-46) as an active ingredient.
- Components including the composition of Example 1 were mixed according to the following amounts to prepare a pharmaceutical composition (ointment) for preventing or treating hair loss.
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Abstract
The present invention relates to a composition for preventing hair loss or promoting hair growth, comprising an indirubin derivative and a metabolic activator. The composition, according to the present invention, may be effectively used as a pharmaceutical composition or a cosmetic composition that may prevent hair loss or promote hair growth, and may be used in functional cosmetics with hair growth promotion or hair loss prevention properties exhibited from a hair loss prevention function, including a hair growth promoter.
Description
본 발명은 인디루빈 유도체 및 대사활성화제를 포함하는 탈모 방지 또는 발모 촉진용 조성물에 관한 것이다.The present invention relates to a composition for preventing hair loss or promoting hair growth containing an indirubin derivative and a metabolic activator.
모발은 인체에 약 10만 내지 15만 개 정도 존재하며, 모낭(hair follicle)에서 형성된다. 각각의 모발들은 서로 다른 주기로, 성장기(anagen), 퇴행기(catagen) 및 휴지기(telogen)를 반복한다. 성장기는 모발이 성장하는 시기이고, 퇴행기는 성장기가 끝나고 모발의 형태를 유지하면서 대사과정이 느려지는 시기로, 이 시기에는 모발의 성장이 느려지게 된다. 퇴행기에는 모낭의 세포 분열이 정지되어 급격히 위축되는 시기이다. 마지막 휴지기는 모낭의 활동이 완전히 멈추고 탈모를 준비하는 시기로, 휴지기 모발은 기저부에서 새롭게 자라는 성장기 모발에 의해 밀려나 저절로 빠지게 되고, 빗질이나 머리를 감는 등의 물리적 작용에 의해 쉽게 탈락된다. 이러한 주기는 3~6년에 걸쳐 반복된다. There are about 100,000 to 150,000 hairs in the human body, and they are formed in hair follicles. Each hair cycle repeats the growth phase (anagen), the catagen phase, and the resting phase (telogen) in different cycles. The anagen phase is the period when hair grows, and the catagen phase is the period when the metabolic process slows down while maintaining the shape of the hair after the growth period ends. During this period, hair growth slows down. The catagen stage is a period in which hair follicle cell division stops and rapidly shrinks. The final telogen phase is a period in which hair follicle activity completely stops and prepares for hair loss. The telogen hair is pushed out by new growth-phase hair growing at the base and falls out on its own, and is easily removed by physical actions such as combing or washing the hair. This cycle repeats over 3 to 6 years.
탈모란 정상적으로 모발이 존재해야할 부위에 모발이 없는 상태를 말하는 것으로, 탈모 질환이 진행되는 경우 모근에 존재하는 유두가 작아지고, 모유두가 작아지면 머리털의 굵기도 가늘어지고 동시에 모주기도 짧아지며, 새로 자라나온 털은 더욱 가늘어진다. 즉 탈모가 진행되면 머리털은 솜털로 변하며 모주기는 더욱 짧아져버리기 때문에 모발이 조금 자라고 바로 빠져버리게 되는 것이다.Hair loss refers to a condition in which there is no hair in areas where hair should normally exist. As the hair loss disease progresses, the papilla present at the hair root becomes smaller, and as the papilla becomes smaller, the thickness of the hair becomes thinner and at the same time, the hair cycle becomes shorter and new growth occurs. The hair that comes out becomes thinner. In other words, as hair loss progresses, the hair turns into fluff and the hair cycle becomes shorter, so the hair grows a little and falls out immediately.
탈모의 원인으로는 유전적인 원인, 남성호르몬의 작용뿐만 아니라 내분비 질환, 영양 결핍, 약물 사용, 출산, 발열, 수술 등의 심한 신체적, 정신적 스트레스 등의 요인들이 복합적으로 작용하는 것으로 알려져 있다. 그 중에서도 남성형 탈모는 디히드로테스토스테론(dihydrotestosterone, DHT)의 영향이 큰 것으로 알려져 있다. 남성 호르몬의 일종인 테스토스테론은 5α-reductase 효소에 의해 DHT로 활성화되며, 이 DHT가 탈모를 유도하는 것으로 알려져 있다. DHT는 모낭을 위축시켜 검고 굵은 모발을 가늘고 축 처지게 만드는 연모화 현상을 일으킨다. 또는 모근 파괴물질을 분비시켜 모발을 이른 시기에 퇴행기로 이행시켜 탈모가 진행된다.It is known that the causes of hair loss are not only genetic causes and the action of male hormones, but also a combination of factors such as endocrine diseases, nutritional deficiencies, drug use, childbirth, fever, and severe physical and mental stress such as surgery. Among them, male pattern hair loss is known to be greatly influenced by dihydrotestosterone (DHT). Testosterone, a type of male hormone, is activated into DHT by the 5α-reductase enzyme, and this DHT is known to induce hair loss. DHT causes hair follicles to atrophy, causing vellus hair to become thin and limp. Alternatively, hair root-destroying substances are secreted, causing the hair to enter the catagen stage at an early stage, resulting in hair loss.
현재까지 개발된 탈모 치료제로는 피나스테라이드(finasteride; 상품명 Propecia®), 두타스테라이드(dutasteride; 상품명 Avodart®), 미녹시딜(minoxidil; 상품명 마이녹실® 또는 Rogaine®) 등이 있다. 미녹시딜은 장기 적용 시 부종, 부정맥과 원하지 않는 부위에 털이 나는 등의 부작용을 초래할 수 있으며 미녹시딜의 효과는 사용으로부터 6개월에서 1년 사이에 가장 큰 효과를 보이고 이후에는 서서히 그 효과가 줄어드는 것으로 알려져 있다. 피나스테라이드와 두타스테라이드는 5α-reductase 효소의 작용을 차단해 DHT생성을 억제하지만 성욕감퇴, 발기부전, 운전 및 수행능력 상실 등의 부작용을 나타낸다. 또한 최근 중증 탈모 환자들을 대상으로 모발 이식술이 시도되고 있지만, 고가의 비용과 시술 후 부작용이 한계로 지적되고 있다.Hair loss treatments developed to date include finasteride (brand name: Propecia®), dutasteride (brand name: Avodart®), and minoxidil (brand names: Minoxil® or Rogaine®). Minoxidil can cause side effects such as edema, arrhythmia, and hair growth in unwanted areas when applied long-term. It is known that the effect of minoxidil is greatest between 6 months and 1 year after use, and the effect gradually decreases thereafter. . Finasteride and dutasteride inhibit DHT production by blocking the action of the 5α-reductase enzyme, but have side effects such as decreased libido, erectile dysfunction, and loss of driving and performance abilities. In addition, hair transplant surgery has recently been attempted for patients with severe hair loss, but the high cost and side effects after the procedure have been pointed out as limitations.
이러한 배경하에서, 본 발명자들은 부작용이 적고 탈모 개선 효과가 우수한 약물을 개발하기 위하여 연구를 거듭한 결과, 인디루빈 유도체와 대사활성제가 우수한 탈모 개선 효과를 갖는 것을 발견함으로써, 본 발명을 완성하기에 이르렀다.Against this background, the present inventors conducted repeated research to develop a drug with fewer side effects and excellent hair loss improvement effect, and as a result discovered that indirubin derivatives and metabolic activators have excellent hair loss improvement effect, thereby completing the present invention. .
특허문헌 1. 대한민국 공개특허공보 제10-2022-0032974호 Patent Document 1. Republic of Korea Patent Publication No. 10-2022-0032974
본 발명은 상기와 같은 문제점을 해결하기 위하여 안출된 것으로, 본 발명의 목적은 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하여 인체에 대한 부작용이 없는 탈모 예방 또는 치료용 약학적 조성물을 제공하는 것이다. 또한 본 발명의 상기 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 예방 또는 개선용 화장료 조성물, 식품 조성물을 제공하는 것이다.The present invention was devised to solve the above problems, and the object of the present invention is to provide a pharmaceutical composition for preventing or treating hair loss that contains an indirubin derivative and a metabolic activator as active ingredients and has no side effects on the human body. will be. In addition, the present invention provides a cosmetic composition and food composition for preventing or improving hair loss containing the indirubin derivative and the metabolic activator as active ingredients.
또한 본 발명의 다른 목적은 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 우수한 탈모의 예방 또는 치료 효과를 갖는 탈모 예방, 개선 또는 치료방법을 제공하고자 하는 것이다.Another object of the present invention is to provide a method for preventing, improving, or treating hair loss that has an excellent hair loss prevention or treatment effect and includes an indirubin derivative and a metabolic activator as active ingredients.
또한 본 발명은 탈모의 예방 또는 치료를 위한 인디루빈 유도체 및 대사활성화제를 포함하는 조성물의 신규 용도를 제공하기 위한 것이다.In addition, the present invention is intended to provide a new use of a composition containing an indirubin derivative and a metabolic activator for the prevention or treatment of hair loss.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하고, 상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention includes an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients, and the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) Provided is a pharmaceutical composition for preventing or treating hair loss, which is an inhibitor.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
상기 화학식 1에서, R1 내지 R3은 각각 독립적으로 수소, 할로젠, C1-C6 알킬, C1-C6 알콕시로 이루어진 군으로부터 선택되는 어느 하나이고, R4는 수소 또는 C1-C6 알킬이며, R5는 수소, C1-C6 알킬, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.In Formula 1, R 1 to R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, and R 4 is hydrogen or C 1 - C 6 alkyl, and R 5 may be any one selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 arylalkyl.
상기 화학식 1에서, R3 및 R4는 수소일 수 있다.In Formula 1, R 3 and R 4 may be hydrogen.
상기 화학식 1에서, R1 및 R2는 각각 독립적으로 수소, 할로젠 및 -O-CH3로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.In Formula 1, R 1 and R 2 may each independently be selected from the group consisting of hydrogen, halogen, and -O-CH 3 .
상기 화학식 1에서, R5는 수소, C1-C3 알킬, 치환 또는 비치환된 C6-C10 아릴 및 C7-10 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.In Formula 1, R 5 may be any one selected from the group consisting of hydrogen, C 1 -C 3 alkyl, substituted or unsubstituted C 6 -C 10 aryl, and C 7-10 arylalkyl.
상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-4 중에서 선택되는 어느 하나일 수 있다. Formula 1 may be any one selected from the following Formulas 1-1 to 1-4.
[화학식 1-1][Formula 1-1]
[화학식 1-2][Formula 1-2]
[화학식 1-3][Formula 1-3]
[화학식 1-4][Formula 1-4]
상기 PKM2(pyruvate kinase M2) 활성화제는 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4-diazepan-1-ylsulfonyl)aniline(DASA-58) 및 세린(Serine)로 이루어진 군으로부터 선택되는 어느 하나일 수 있고, 상기 MPC(Mitochondrial pyruvate carrier) 억제제는 (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid(UK5099) 일 수 있다.The PKM2 (pyruvate kinase M2) activator is 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5 ]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1, It may be any one selected from the group consisting of 4-diazepan-1-ylsulfonyl)aniline (DASA-58) and serine, and the MPC (Mitochondrial pyruvate carrier) inhibitor is (E)-2-Cyano-3- It may be (1-phenyl-1H-indol-3-yl)acrylic acid (UK5099).
상기 인디루빈 유도체와 대사활성화제는 1 : 0.1 내지 10의 몰비로 포함되는 것일 수 있다.The indirubin derivative and the metabolic activator may be included in a molar ratio of 1:0.1 to 10.
상기 다른 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하고, 상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모 예방 또는 개선용 화장료 조성물을 제공한다.In order to achieve the above other objects, the present invention includes an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients, and the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) ) Provides a cosmetic composition for preventing or improving hair loss, characterized in that it is an inhibitor.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
상기 조성물은 생체 외에서 모유두세포 또는 모낭세포의 증식을 촉진시키는 것일 수 있다.The composition may promote the proliferation of dermal papilla cells or hair follicle cells in vitro.
상기 화장료 조성물은 헤어토닉, 헤어컨디셔너, 헤어에센스, 헤어로션, 헤어영양로션, 헤어샴푸, 헤어린스,헤어트리트먼트, 헤어크림, 헤어영양크림, 헤어모이스처크림, 헤어맛사지크림, 헤어왁스, 헤어 에어로졸, 헤어팩, 헤어영양팩, 헤어비누, 헤어클렌징폼, 머릿기름, 모발건조제, 모발보존처리제, 모발염색제, 모발용 웨이브제, 모발탈색제, 헤어겔, 헤어글레이즈, 헤어드레싱어, 헤어래커, 헤어모이스처라이저, 헤어무스 및 헤어스프레이로 이루어진 군으로부터 선택되는 어느 하나의 두발용 제형일 수 있다.The cosmetic composition includes hair tonic, hair conditioner, hair essence, hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisture cream, hair massage cream, hair wax, and hair aerosol. , hair pack, hair nutrition pack, hair soap, hair cleansing foam, hair oil, hair dryer, hair preservation treatment, hair dye, hair waving agent, hair bleach, hair gel, hair glaze, hair dresser, hair lacquer, hair moisturizer, It may be any one hair formulation selected from the group consisting of hair mousse and hair spray.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하고, 상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모 예방 또는 개선용 식품 조성물을 제공한다.In order to achieve the above other object, the present invention includes an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients, and the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate) Provided is a food composition for preventing or improving hair loss, which is characterized as being a carrier inhibitor.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
본 발명은 상기 또 다른 목적을 이루기 위해 탈모 환자에게 하기 화학식 1로 표시되는 인디루빈 유도체와 대사활성화제를 투여하는 것을 포함하는 탈모의 예방 또는 치료방법을 제공한다.In order to achieve the above further object, the present invention provides a method for preventing or treating hair loss, which includes administering an indirubin derivative represented by the following formula (1) and a metabolic activator to a hair loss patient.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
본 발명은 상기 또 다른 목적을 이루기 위해 탈모 예방 또는 치료를 위한 약제로써 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제의 신규 용도를 제공한다. 상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 한다.In order to achieve the above-mentioned other object, the present invention provides a new use of an indirubin derivative and a metabolic activator represented by the following formula (1) as a drug for preventing or treating hair loss. The metabolic activator is characterized as being a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) inhibitor.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
본 발명은 상기 또 다른 목적을 이루기 위해, 탈모 예방 또는 치료 효과를 갖는 의약 제제를 생산하기 위한 방법으로써 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 사용하는 것을 특징으로 하는 방법을 제공한다.In order to achieve the above-mentioned further object, the present invention provides a method for producing a pharmaceutical agent having a hair loss prevention or treatment effect, characterized by using an indirubin derivative and a metabolic activator represented by the following formula (1): .
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
본 발명에 따른 조성물은 탈모 방지 또는 발모를 촉진할 수 있는 약학적 조성물 또는 화장료 조성물로 유용하게 이용할 수 있어 발모 촉진제를 비롯하여 탈모 방지 기능으로부터 발휘되는 탈모 방지 또는 발모 촉진 기능성 화장품에 활용될 수 있다.The composition according to the present invention can be usefully used as a pharmaceutical composition or cosmetic composition capable of preventing hair loss or promoting hair growth, and can be used in functional cosmetics for preventing hair loss or promoting hair growth, including hair growth promoting agents.
게다가 본 발명에 따른 인디루빈 유도체와 대사활성화제의 혼합 조성물은 세포에 대한 독성이 없고, 염증을 유발하지 않는 안전한 물질로 인체에 부작용을 나타내지 않는 장점이 있다.In addition, the mixed composition of an indirubin derivative and a metabolic activator according to the present invention has the advantage of being a safe material that is non-toxic to cells and does not cause inflammation and does not cause side effects to the human body.
본 발명은 인디루빈 유도체와 대사활성화제를 일정 비율로 혼합한 조성물로, 단독 조성물에 비해 강력한 발모, 양모, 탈모 방지에 대해 효과를 나타내는 장점이 있다.The present invention is a composition that mixes an indirubin derivative and a metabolic activator at a certain ratio, and has the advantage of showing a stronger effect on hair growth, wool growth, and hair loss prevention than a single composition.
도 1은 인디루빈 유도체 또는 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)를 단독으로 처리한 비브리사 모낭을 6일간 배양한 후 촬영한 현미경 사진이고, 도 2는 인디루빈 유도체와 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)의 혼합물을 처리한 비브리사 모낭을 6일간 배양한 후 촬영한 현미경 사진이다.Figure 1 is a micrograph taken after culturing Vibrissa hair follicles treated with indirubin derivatives or metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone for 6 days, and Figure 2 is This is a photomicrograph taken after culturing Vibrissa hair follicles treated with a mixture of indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) for 6 days.
도 3은 인디루빈 유도체와 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)의 단독 또는 혼합 처리한 비브리사 모낭을 6일간 배양하였을 때, 각각의 길이변화를 측정하여 나타낸 그래프이다(* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH or single treat).Figure 3 shows the length change of each Vibrissa hair follicle treated alone or in combination with an indirubin derivative and a metabolic activator (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) and cultured for 6 days. This is the graph shown (* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH or single treat).
도 4는 다양한 농도의 세린 단독 투여군에 대한 비브리사 모낭을 촬영한 현미경 사진(상)과 길이변화를 측정하여 나타낸 그래프(하)이다(* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH).Figure 4 is a micrograph (top) of Vibrissa hair follicles taken in the group administered with various concentrations of serine alone and a graph (bottom) showing the length change (* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH).
도 5는 인디루빈 유도체와 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)를 단독 또는 혼합하여 처리한 사람의 진피 유두 세포에 대한 세포 생존율(cell viability)을 측정하여 나타낸 그래프이다(* P < 0.05, ** P < 0.005, *** P < 0.0005 vs VEH).Figure 5 shows the cell viability of human dermal papilla cells treated with indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone or in combination. This is the graph shown (* P < 0.05, ** P < 0.005, *** P < 0.0005 vs VEH).
도 6은 인디루빈 유도체와 대사활성화제(TEPP-46)을 단독 또는 혼합하여 처리한 각 군을 촬영한 사진이고, 도 7은 인디루빈 유도체와 대사활성화제(TEPP-46)을 단독 또는 혼합하여 처리한 각 군으로부터 모발 성장치를 측정하여 나타낸 그래프이다(* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs VEH or single treat).Figure 6 is a photograph of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination, and Figure 7 is a photograph of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination. This is a graph showing the hair growth values measured from each treated group (* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs VEH or single treat).
이하에서, 본 발명의 여러 측면 및 다양한 구현예에 대해 더욱 구체적으로 살펴보도록 한다. Below, we will look at various aspects and various implementation examples of the present invention in more detail.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout the specification of the present application, when a part "includes" a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.
본 발명의 일 측면은 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 예방 또는 치료용 약학적 조성물, 화장료 조성물, 식품 조성물에 관한 것이다. 상기 대사활성화제는 상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것일 수 있다.One aspect of the present invention relates to a pharmaceutical composition, cosmetic composition, and food composition for preventing or treating hair loss containing an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients. The metabolic activator may be a PKM2 (pyruvate kinase M2) activator or an MPC (Mitochondrial pyruvate carrier) inhibitor.
또한 본 발명의 다른 측면은 탈모 환자에게 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효량 투여하는 것을 포함하는 탈모의 치료방법에 관한 것이다.Another aspect of the present invention relates to a method of treating hair loss comprising administering an effective amount of an indirubin derivative represented by Formula 1 and a metabolic activator to a hair loss patient.
또한 본 발명의 다른 측면은 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 대상체에게 치료학적 유효량 투여하는 단계를 포함하는 탈모의 치료방법에 관한 것이다.Another aspect of the present invention relates to a method of treating hair loss comprising administering a therapeutically effective amount of an indirubin derivative represented by Formula 1 and a metabolic activator to a subject.
또한 본 발명의 다른 측면은 탈모 예방 또는 치료를 위한 약제로써 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제의 신규 용도를 제공한다.In addition, another aspect of the present invention provides a new use of the indirubin derivative and metabolic activator represented by the following formula (1) as a drug for preventing or treating hair loss.
또한 본 발명의 다른 측면은 탈모 예방 또는 치료 효과를 갖는 의약 제제를 생산하기 위한 방법으로써 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 사용하는 것을 특징으로 하는 방법을 제공한다.In addition, another aspect of the present invention provides a method for producing a pharmaceutical agent having a hair loss prevention or treatment effect, characterized by using an indirubin derivative represented by the following formula (1) and a metabolic activator.
본 발명에서 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제는 상기 방법, 용도를 달성할 수 있도록 하는 유효성분으로써, 일정 비율로 혼합된 혼합물 또는 혼합조성물 또는 조성물 형태일 수 있다.In the present invention, the indirubin derivative and metabolic activator represented by Formula 1 are active ingredients that enable the above method and use to be achieved, and may be in the form of a mixture or mixed composition or composition mixed in a certain ratio.
본 발명은 인디루빈 유도체 및 대사활성화제를 일정 비율로 혼합한 조성물로, 탈모 방지 및 모발 생장 촉진에 대해 탁월한 효과를 나타냄을 확인함으로써 탈모 방지 및 발모 촉진이 가능하므로, 약학, 식품, 화장료 등의 다양한 분야에 적용이 가능하다.The present invention is a composition that mixes an indirubin derivative and a metabolic activator in a certain ratio, and has been confirmed to have excellent effects on preventing hair loss and promoting hair growth, making it possible to prevent hair loss and promote hair growth, and thus can be used in pharmaceuticals, foods, cosmetics, etc. It can be applied to various fields.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
본 발명에서의 용어 '할로젠'은 브로모, 클로로, 플루오로 또는 요오도를 의미하며, '할로' 및 '할로겐'과 혼용하여 사용할 수 있다.The term 'halogen' in the present invention refers to bromo, chloro, fluoro, or iodo, and can be used interchangeably with 'halo' and 'halogen'.
본 발명에서의 용어 '알킬'은 1차, 2차, 3차, 및/또는 4차 탄소 원자를 갖는 탄화수소이며, 직쇄형, 분지형, 또는 환형, 또는 이들의 조합일 수 있는 포화 지방족기를 포함한다. 예를 들어, 알킬기는 1 내지 20개의 탄소원자 (즉, C1-C20 알킬), 1 내지 10개의 탄소 원자 (즉, C1-C10 알킬), 또는 1 내지 6개의 탄소 원자(즉, C1-C6 알킬)를 가질 수 있다. 적합한 알킬의 예로는 메틸(Me, -CH3), 에틸(Et, -C2H5), 1-프로필(n-Pr,-CH2CH2CH3), 2-프로필(i-Pr, -CH(CH3)2), 1-부틸(n-Bu, - CH2CH2CH2CH3), 2-메틸-1-프로필(i-Bu,-CH2CH(CH3)2), 2-부틸(s-Bu, -CH(CH3)CH2CH3), 2-메틸-2-프로필(t-Bu, -C(CH3)3), 1-펜틸(n-펜틸, -CH2CH2CH2CH2CH3), 2-펜틸(-CH(CH3)CH2CH2CH3), 3-펜틸(-CH(CH2CH3)2), 2-메틸-2-부틸(-CH(CH3)2CH2CH3), 3-메틸-2-부틸(-CH(CH3)CH(CH3)2), 3-메틸-1-부틸(-CH2CH2CH(CH3)2), 2-메틸-1-부틸(-CH2CH(CH3)CH2CH3), 1-헥실(-CH2CH2CH2CH2CH2CH3), 2-헥실(-CH(CH3)CH2CH2CH2CH3), 3-헥실 (-CH(CH2CH3)(CH2CH2CH3)), 2-메틸-2-펜틸(-C(CH3)2CH2CH2CH3), 3-메틸-2-펜틸(-CH(CH3)CH(CH3)CH2CH3), 4-메틸-2-펜틸(-CH(CH3)CH2CH(CH3)2), 3-메틸-3-펜틸(-C(CH3)(CH2CH3)2), 2-메틸-3-펜틸(-CH(CH2CH3)CH(CH3)2), 2,3-디메틸-2-부틸(-C(CH3)2CH(CH3)2), 3,3-디메틸2-부틸(-CH(CH3)C(CH3)3), 및 옥틸(-(CH2)7CH3)을 들 수 있고, 바람직하게는 C1-C6 알킬기로 일 수 있으며, 보다 바람직하게는 C1-C3 알킬기로, 메틸(Me, -CH3), 에틸(Et, -C2H5), 1-프로필(n-Pr, -CH2CH2CH3) 중에서 선택되는 어느 하나일 수 있다.The term 'alkyl' in the present invention refers to a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and includes saturated aliphatic groups that may be straight-chain, branched, or cyclic, or a combination thereof. do. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl). Examples of suitable alkyls include methyl (Me, -CH 3 ), ethyl (Et, -C 2 H 5 ), 1-propyl (n-Pr, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, - CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu,-CH 2 CH(CH 3 ) 2 ) , 2-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl- 2-Butyl(-CH(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl(-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl(-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) , 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl(-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl(- CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl(-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl(-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), and octyl (-(CH 2 ) 7 CH 3 ), preferably a C 1 -C 6 alkyl group, more preferably C 1 -C 3 The alkyl group may be any one selected from methyl (Me, -CH 3 ), ethyl (Et, -C 2 H 5 ), and 1-propyl (n-Pr, -CH 2 CH 2 CH 3 ).
본 발명에서의 용어 '알콕시'는 앞서 설명한 바와 같이 알킬기가 산소 원자를 통해 모 화합물에 부착된 것인 -OR을 갖는 작용기를 의미한다. C1-C6알콕시의 예는 메톡시, 에톡시, 프로폭시, 이소프로폭시, 부톡시, 이소부톡시, 펜톡시, 및 헥속시를 포함하지만, 이로 제한되지는 않는다.As described above, the term 'alkoxy' in the present invention refers to a functional group with -OR in which an alkyl group is attached to the parent compound through an oxygen atom. Examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
본 발명에서의 용어 '아릴'은 다른 언급이 없으면 임의적으로 치환된 벤젠 고리를 지칭하거나, 또는 하나 이상의 임의적인 치환기를 융합시킴으로써 형성될 수 있는 고리 시스템을 지칭하며, 탄소수는 특별히 한정되지 않으나 6 내지 30인 치환 또는 비치환된 알릴인 것이 바람직하다. '아릴'기의 예는 비제한적으로 페닐, 나프틸, 테트라하이드로나프틸, 바이페닐, 인단일, 안트라실 또는 페난트릴, 및 이들의 치환된 유도체를 포함한다.In the present invention, the term 'aryl', unless otherwise specified, refers to an optionally substituted benzene ring, or a ring system that can be formed by fusing one or more optional substituents, and the number of carbon atoms is not particularly limited, but is 6 to 6. Substituted or unsubstituted allyl, which is 30, is preferred. Examples of 'aryl' groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracyl or phenanthryl, and substituted derivatives thereof.
상기 치환기는 Cl-3 알킬, C2-3 알케닐, 치환된 C2-3 알킨일, 헤테로아릴, 헤테로환형, 아릴, 임의적으로 1 내지 3개의 불소 치환기를 갖는 알콕시, 아릴옥시, 아르알콕시, 아실, 아로일, 헤테로아로일, 아실옥시, 아로일옥시, 헤테로아로일옥시, 설판일, 설핀일, 설폰일, 아미노설폰일, 설폰일아미노, 카복시아마이드, 아미노카보닐, 카복시, 옥소, 하이드록시, 머캅토, 아미노, 나이트로, 할로겐 또는 우레이도를 포함한다. 이러한 고리 또는 고리 시스템은 임의적으로 하나 이상의 치환기를 갖는 아릴 고리(예컨대, 벤젠 고리), 탄소환 고리 또는 헤테로환형 고리에 임의적으로 융합될 수 있다. 보다 바람직하게 상기 치환기는 C1-3 알킬일 수 있으며, C1-3 알킬로 치환된 아릴은 하나의 수소가 알킬기로 치환된 아릴기를 의미한다. 상기 C1-3 알킬로 치환된 아릴기는 알킬아릴이라고도 하며 C7 내지 C30의 알킬아릴일 수 있다. 구체적으로 C7-30 알킬아릴은 메틸페닐, 에틸페닐, n-프로필페닐, iso-프로필페닐, n-부틸페닐, iso-부틸페닐, tert-부틸페닐 또는 사이클로헥실페닐 등일 수 있고, 바람직하게는 C7 내지 C10의 알킬아릴일 수 있다.The substituents include C l - 3 alkyl, C 2 - 3 alkenyl, substituted C 2 - 3 alkynyl, heteroaryl, heterocyclic, aryl, alkoxy, aryloxy, aralkoxy, optionally having 1 to 3 fluorine substituents. , acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, Includes hydroxy, mercapto, amino, nitro, halogen or ureido. This ring or ring system may optionally be fused to an aryl ring (eg, a benzene ring), a carbocyclic ring, or a heterocyclic ring, optionally bearing one or more substituents. More preferably, the substituent may be C 1-3 alkyl, and aryl substituted with C 1-3 alkyl refers to an aryl group in which one hydrogen is substituted with an alkyl group. The aryl group substituted with C 1-3 alkyl is also called alkylaryl and may be C 7 to C 30 alkylaryl. Specifically, C 7-30 alkylaryl may be methylphenyl, ethylphenyl, n-propylphenyl, iso-propylphenyl, n-butylphenyl, iso-butylphenyl, tert-butylphenyl, or cyclohexylphenyl, and is preferably C It may be 7 to C 10 alkylaryl.
본 발명에서 아릴알킬기는 탄소수 7 내지 30인 아릴알킬로, 이는 알킬의 1 이상의 수소가 아릴에 의하여 치환된 치환기를 의미할 수 있다. 구체적으로, C7-30 아릴알킬일 수 있으며, 바람직하게는 벤질기, 페닐프로필 또는 페닐헥실 등일 수 있고, 보다 바람직하게는 C7-10 아릴알킬기로 벤질기, 페닐프로필일 수 있다.In the present invention, the arylalkyl group is arylalkyl having 7 to 30 carbon atoms, which may mean a substituent in which one or more hydrogens of alkyl are replaced by aryl. Specifically, it may be C 7-30 arylalkyl, preferably benzyl, phenylpropyl, or phenylhexyl, and more preferably, the C 7-10 arylalkyl may be benzyl or phenylpropyl.
본 발명에서의 용어 '히드록시'는 -OH 라디칼을 지칭한다.The term 'hydroxy' in the present invention refers to the -OH radical.
상기 화학식 1에서, R1 내지 R3은 각각 독립적으로 수소, 할로젠, C1-C6 알킬, C1-C6 알콕시로 이루어진 군으로부터 선택되는 어느 하나일 수 있고, R4는 수소 또는 C1-C6 알킬일 수 있으나, 보다 바람직하게 상기 화학식 1에서, R1 및 R2는 각각 독립적으로 수소, 할로젠 및 -O-CH3로 이루어진 군으로부터 선택되는 어느 하나일 수 있으며, 상기 화학식 1에서, R3 및 R4는 수소일 수 있다.In Formula 1, R 1 to R 3 may each independently be selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, and R 4 is hydrogen or C It may be 1 -C 6 alkyl, but more preferably, in Formula 1, R 1 and R 2 may each independently be any one selected from the group consisting of hydrogen, halogen, and -O-CH 3 , and the formula In 1, R 3 and R 4 may be hydrogen.
상기 화학식 1에서, R5는 수소, C1-C6 알킬 및 C6-C10 아릴로 이루어진 군으로부터 선택되는 어느 하나일 수 있으나, 보다 바람직하게는 R5는 수소, C1-C3 알킬, 치환 또는 비치환된 C6-C10 아릴 및 C7-10 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.In Formula 1, R 5 may be any one selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 6 -C 10 aryl, but more preferably R 5 is hydrogen, C 1 -C 3 alkyl. , substituted or unsubstituted C 6 -C 10 aryl, and C 7-10 arylalkyl.
상기 화학식 1로 표시되는 인디루빈은 5-메톡실인디루빈-3'-옥심, 인디루빈-3'-옥심, 6-브로모인디루빈-3'-옥심, 5,6-디클로로인디루빈, 5,6-디클로로인디루빈-3'-옥심, 5,6-디클로로인디루빈-3'-메톡심, 5,6-디클로로인디루빈-3'-프로필옥심, 6-클로로-5-니트로인디루빈, 6-클로로-5-니트로인디루빈-3'-옥심, 6-클로로인디루빈-3'-메톡심, 5-클로로인디루빈-3'-메톡심, 5-브로모인디루빈-3'-옥심, 5-브로모인디루빈-3'-메톡심, 5-브로모인디루빈-3'-에틸옥심, 5,6-디클로로인디루빈-3'-옥심프로필옥심 및 6-클로로인디루빈-3'-벤질옥심으로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.Indirubin represented by Formula 1 is 5-methoxyl indirubin-3'-oxime, indirubin-3'-oxime, 6-bromoindirubin-3'-oxime, 5,6-dichloro indirubin, 5 , 6-dichloro indirubin-3'-oxime, 5,6-dichloro indirubin-3'-methoxime, 5,6-dichloro indirubin-3'-propyl oxime, 6-chloro-5-nitro indirubin, 6-chloro-5-nitroindirubin-3'-oxime, 6-chloroindirubin-3'-methoxime, 5-chloroindirubin-3'-methoxime, 5-bromoindirubin-3'-oxime , 5-bromoindirubin-3'-methoxime, 5-bromoindirubin-3'-ethyloxime, 5,6-dichloroindirubin-3'-oximepropyloxime and 6-chloroindirubin-3' -It may be any one selected from the group consisting of benzyloxime.
가장 바람직하게 상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-4 중에서 선택되는 어느 하나일 수 있는데, 이에 한정되지는 않으며 대사활성화제와의 복합사용을 통해 유의적으로 현저한 탈모, 발모 예방, 치료 또는 개선 효과를 나타낼 수 있으나, 가장 바람직하게는 화학식 1-1로 표시되는 인디루빈 유도체인 것이 대사활성화제와 복합투여시 탈모를 방지하고, 발모 또는 육모를 촉진할 뿐만 아니라, 피부 세포의 증식을 증가 및 유도하여 단독 투여 대비 시너지 효과 이상의 유의적 효과를 달성할 수 있다.Most preferably, Formula 1 may be any one selected from the following Formulas 1-1 to 1-4, but is not limited thereto, and can significantly prevent and treat hair loss and hair growth through combined use with a metabolic activator. Alternatively, it may show an improvement effect, but most preferably, an indirubin derivative represented by Formula 1-1 prevents hair loss when administered in combination with a metabolic activator, not only promotes hair growth or hair growth, but also promotes the proliferation of skin cells. By increasing and inducing, a significant effect beyond the synergistic effect can be achieved compared to single administration.
[화학식 1-1][Formula 1-1]
[화학식 1-2][Formula 1-2]
[화학식 1-3][Formula 1-3]
[화학식 1-4][Formula 1-4]
상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제일 수 있으며, PKM2(pyruvate kinase M2) 활성화제는 PKM2의 발현 또는 활성을 촉진할 수 있는 임의의 물질을 의미하며, 특별히 이에 제한되지 않으나 바람직하게는 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4-diazepan-1-ylsulfonyl)aniline(DASA-58) 및 세린(Serine)로 이루어진 군으로부터 선택되는 어느 하나일 수 있으며, 보다 바람직하게는 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265)일 수 있다.The metabolic activator may be a PKM2 (pyruvate kinase M2) activator or an MPC (Mitochondrial pyruvate carrier) inhibitor, and the PKM2 (pyruvate kinase M2) activator refers to any substance that can promote the expression or activity of PKM2. , but is not particularly limited thereto, preferably 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5] pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4 -diazepan-1-ylsulfonyl)aniline (DASA-58) may be any one selected from the group consisting of serine, and more preferably 6-[(3-aminophenyl)methyl]-4,6-dihydro It may be -4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one (TEPP-46, ML265).
또한 상기 MPC(Mitochondrial pyruvate carrier) 억제제는 미토콘드리아 피루빈산 캐리어(MPC) 억제를 통한 글루코스 또는 피루빈산을 억제하는 임의의 물질을 의미하며, 특별히 이에 제한되지 않으나, (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid(UK5099)일 수 있다.In addition, the MPC (Mitochondrial pyruvate carrier) inhibitor refers to any substance that inhibits glucose or pyruvate through mitochondrial pyruvate carrier (MPC) inhibition, but is not particularly limited thereto, (E)-2-Cyano- It may be 3-(1-phenyl-1H-indol-3-yl)acrylic acid (UK5099).
본 발명에서 용어 '탈모'란, 그 원인과 무관하게, 정상적으로 모발이 존재해야 할 부위에 모발이 없는 상태를 지칭하며, 예를 들어, 남성형 탈모, 여성형 탈모, 원형 탈모, 휴지기성 탈모, 스트레스성 탈모, 또는 화학요법제로 인해 발생한 탈모일 수 있다. 본 발명의 조성물은 모유두 세포의 증식과 모발 길이의 성장을 촉진하므로, 남성형 탈모의 치료에 특히 효과적일 수 있다.In the present invention, the term 'hair loss' refers to a state in which there is no hair in areas where hair should normally exist, regardless of the cause, for example, male pattern baldness, female pattern baldness, alopecia areata, telogen effluvium, stress-related. It may be hair loss or hair loss caused by chemotherapy drugs. The composition of the present invention promotes proliferation of dermal papilla cells and growth of hair length, and therefore may be particularly effective in the treatment of male pattern baldness.
바람직하게 상기 인디루빈 유도체는 장기간 세포에 처리하여도 세포에 대한 독성이 거의 나타나지 않으면서, 대사활성화제와 함께 처리하였을 때 유의한 효과의 증가가 있는 화학식 1-1 내지 화학식 1-4로 표시되는 것 중에서 선택되는 어느 하나 이상의 것일 수 있고, 가장 바람직하게는 화학식 1-2로 표시되는 인디루빈 유도체일 수 있다. 왜냐하면 생체 외(in virto) 실험을 통해 화학식 1-2의 인디루빈 유도체와 대사활성화제를 함께 처리하는 것이 종래 탈모치료제(미녹시딜) 대비 75~95% 이상의 비브리사(vibrissa)의 길이 증가효과가 관찰되었기 때문이다. Preferably, the indirubin derivative is represented by Formulas 1-1 to 1-4, which shows little toxicity to cells even when treated with cells for a long period of time, and has a significant increase in effect when treated with a metabolic activator. It may be any one or more selected from the group consisting of, and most preferably, it may be an indirubin derivative represented by Formula 1-2. This is because through in vitro experiments, treatment with an indirubin derivative of Chemical Formula 1-2 and a metabolic activator was observed to increase the length of vibrissa by more than 75 to 95% compared to the conventional hair loss treatment agent (minoxidil). Because it has been done.
따라서 본 발명에 따른 인디루빈 유도체와 대사활성화제를 포함하는 조성물은 모낭이 휴지기로 접어드는 것을 예방하고, 성장기를 유지할 수 있게 하여 탈모를 방지하고 양모 효능을 촉진시키는 약학적 조성물 및 화장료 조성물 등으로 이용할 수 있다.Therefore, the composition containing an indirubin derivative and a metabolic activator according to the present invention can be used as a pharmaceutical composition and cosmetic composition that prevents hair loss and promotes hair growth by preventing hair follicles from entering the telogen phase and maintaining the growth phase. You can.
또한 본 발명에 따른 조성물은 염증소견이나 기타 병리학적 소견을 나타내지 않았고, 세포 독성 실험에서도 안정한 것으로 확인된 바, 이를 바탕으로 탈모에 대한 개선 또는 치료제로 이용가능하다.In addition, the composition according to the present invention did not show inflammation or other pathological findings and was confirmed to be stable in cytotoxicity tests, and based on this, it can be used as an improvement or treatment for hair loss.
본 발명에 따른 화학식 1로 표시되는 인디루빈 유도체는 유리 물질로서 뿐만 아니라 그의 약학적으로 허용가능한 염, 약학적으로 허용가능한 용매화물, 약학적으로 허용가능한 다형체 또는 약제학적으로 허용 가능한 전구약물로써 제공될 수 있다. 상기 인디루빈 유도체의 염에 있어서는 의약 또는 화장료 내에서 배합할 수 있는 형태이면 특별히 제한되지 않는다. 무기염 또는 유기염을 포함하며, 산성염 또는 알칼리성염일 수 있다. 특히 양이온에 의한 염인 경우 나트륨염이나 칼륨염 등의 알칼리 금속염, 칼슘염, 마그네슘염 및 바륨염 등의 알칼리토류 금속염; 아르기닌이나 라이신 등의 염기성 아미노산염; 암모늄염이나 트리시클로헥실암모늄염 등의 암모늄염; 모노에탄올아민염, 디에탄올아민염, 트리에탄올아민염, 모노이소프로판올아민염, 디이소프로판올아민염 및 트리이소프로판올아민 등의 각종 알칸올 아민염일 수 있다. 바람직하게 상기 염은 알칼리 금속염이며, 더욱 바람직하게는 테트라소듐염일 수 있다.The indirubin derivative represented by Formula 1 according to the present invention can be used not only as a free substance, but also as a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable polymorph, or pharmaceutically acceptable prodrug. can be provided. The salt of the indirubin derivative is not particularly limited as long as it is in a form that can be incorporated into medicines or cosmetics. It contains inorganic salts or organic salts and may be acidic salts or alkaline salts. In particular, in the case of cationic salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; Basic amino acid salts such as arginine and lysine; Ammonium salts such as ammonium salt and tricyclohexylammonium salt; It may be various alkanol amine salts such as monoethanolamine salt, diethanolamine salt, triethanolamine salt, monoisopropanolamine salt, diisopropanolamine salt, and triisopropanolamine salt. Preferably, the salt is an alkali metal salt, and more preferably, it may be a tetrasodium salt.
상기 인디루빈 유도체와 대사활성화제의 혼합비는 특별히 이에 제한되지 않으나, 1 : 0.1 내지 10의 몰비로 포함될 수 있고, 바람직하게는 1 : 0.1 내지 5의 몰비로 포함될 수 있으며, 보다 바람직하게는 1 : 0.1 내지 3 몰비일 수 있다. 상기 범위를 벗어나면 탈모 방지 및 모발 촉진 효과가 저하되기 때문에 바람직하지 못하다.The mixing ratio of the indirubin derivative and the metabolic activator is not particularly limited, but may be included at a molar ratio of 1:0.1 to 10, preferably 1:0.1 to 5, and more preferably 1:0.1 to 5. It may be a molar ratio of 0.1 to 3. If it is outside the above range, it is undesirable because the hair loss prevention and hair promotion effects are reduced.
본 발명에서의 용어 '유효성분으로 포함하는'이란, 본 발명의 탈모 방지 또는 발모 촉진을 치료하는데 충분한 양으로 유효성분을 포함하는 것을 의미한다.The term 'comprising an active ingredient' in the present invention means containing an active ingredient in an amount sufficient to prevent hair loss or promote hair growth in the present invention.
본 발명에서의 용어, '예방'이란 본 발명에 따른 조성물의 투여에 의해 탈모 또는 모발 손상을 억제 또는 지연시키는 모든 행위를 의미하고, '치료'란 상기 약학 조성물의 투여에 의해 탈모의 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미한다. 본 발명의 용어, '개선'이란, 본 발명의 인디루빈 유도체와 대사활성화제를 포함하는 조성물의 투여로 치료되는 탈모 또는 모발 손상 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다. As used herein, the term 'prevention' refers to any action that inhibits or delays hair loss or hair damage by administering the composition according to the present invention, and 'treatment' refers to improvement of hair loss symptoms by administering the pharmaceutical composition. It means any action that becomes or changes beneficially. The term 'improvement' in the present invention means any act of reducing at least the degree of symptoms, for example, parameters related to the hair loss or hair damage condition treated by administration of the composition containing the indirubin derivative and the metabolic activator of the present invention. means.
본 발명의 약학 조성물은 목적하는 방법에 따라 비경구투여 또는 경구 투여할 수 있으며, 바람직하게는 비경구 투여 또는 도포에 의한 국부투여 방식일 수 있다. 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 또한 상기 조성물의 치료적으로 유효한 양은 투여방법, 목적부위, 환자의 상태에 따라 달라질 수 있으며, 인체에 사용시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다.The pharmaceutical composition of the present invention can be administered parenterally or orally according to the desired method, and preferably may be parenteral administration or topical administration through application. The dosage range varies depending on the patient's weight, age, gender, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. In addition, the therapeutically effective amount of the composition may vary depending on the administration method, target area, and patient's condition, and when used in the human body, the dosage should be determined as an appropriate amount considering safety and efficiency.
본 명세서에서 “대상체(subject)”는 상기 질환을 예방 또는 치료하고자 하는 객체를 의미하며, 바람직하게는 인간 및 동물을 포함한다.As used herein, “subject” refers to an object for which the disease is to be prevented or treated, and preferably includes humans and animals.
본 발명의 유효성분은 실험예 2에 측정한 바와 같이 생체에 대한 안정성이 매우 우수하므로, 투여용량의 상한선은 특별히 제한되지 않으나, 본 발명의 조성물의 바람직한 투여량은 1일 0.01 내지 1000 ㎖/kg으로, 바람직하게는 0.1 내지 100 ㎖/kg으로 투여할 수 있고, 보다 바람직하게는 1 내지 10 ㎖/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. Since the active ingredient of the present invention has excellent stability to the living body as measured in Experimental Example 2, the upper limit of the dosage is not particularly limited, but the preferred dosage of the composition of the present invention is 0.01 to 1000 mL/kg per day. Preferably, it can be administered at 0.1 to 100 ml/kg, and more preferably at 1 to 10 ml/kg. Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way.
본 발명의 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 연질 또는 경질 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 연고, 크림 등의 피부 외용제, 좌제, 주사제 및 멸균주사용액 등을 비롯하여 약제학적 제제에 적합한 어떠한 형태로든 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention can be formulated into oral dosage forms such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, and aerosols, skin external preparations such as ointments and creams, suppositories, injections, and the like, respectively, according to conventional methods. It can be formulated and used in any form suitable for pharmaceutical preparations, including sterile injectable solutions.
상기 제제화를 위해 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제, 희석제 등의 부형제를 추가로 포함할 수 있다. 예를 들어, 본 발명의 약학 조성물에 포함될 수 있는 부형제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 메틸히드록시 벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 사용할 수 있으나, 이에 제한되지 않는다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.It may additionally include excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and diluents commonly used for the formulation. For example, excipients that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate. , cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.
본 발명에 따른 조성물은 피부, 상처에 직접 도포 또는 산포하는 등의 방법에 의해 투여할 수 있는 제형, 예를 들어, 크림, 로션, 연고, 에어로졸, 겔, 또는 팩의 제형을 갖는 것일 수 있다. 각각의 제형에 적합한 배합성분이나 제제를 위한 방법은 당업계에 잘 알려져 있다. 당업자들은 이들 제제를 제조할 때, 통상의 외용제를 제조하는 데에 사용되는 각종 배합 성분을 적절히 선택하여 사용할 수 있다.The composition according to the present invention may have a dosage form that can be administered by a method such as directly applying or spraying to the skin or wound, for example, a cream, lotion, ointment, aerosol, gel, or pack. Methods for mixing ingredients or formulations suitable for each dosage form are well known in the art. When preparing these preparations, those skilled in the art can appropriately select and use various mixing ingredients used in preparing conventional external preparations.
그러한 성분으로는 연고제, 크림제, 겔제, 로션제 등의 경우에 있어서는, 백색 바셀린, 황색 바셀린, 라놀린, 표백밀랍, 세탄올, 스테아릴알코올, 스테아르산, 경화유, 겔화 탄화수소, 폴리에틸렌글리콜, 유동 파라핀, 스쿠알란 등의 기제가 있고, 올레산, 미리스트산이소프로필, 트리이소옥탄산글리세린, 크로타미톤, 세바크산디에틸, 아디프산디이소프로필, 라우르산헥실, 지방산, 지방산 에스테르, 지방족 알코올, 식물유 등의 용제 및 용해 보조제가 있으며, 토코페롤 유도체, L-아스코르브산, 디부틸하이드록시톨루엔, 부틸하이드록시아니솔 등의 산화 방지제, 파라하이드록시벤조산에스테르 등의 방부제, 글리세린, 프로필렌글리콜, 히알루론산나트륨 등의 보습제, 폴리옥시에틸렌유도체, 글리세린 지방산 에스테르, 자당 지방산 에스테르, 소르비탄 지방산 에스테르, 프로필렌글리콜 지방산 에스테르, 레시틴 등의 계면 활성제, 카르복시비닐 폴리머, 잔탄검, 카르복시메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨염류, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등의 증점제 등이 있다.In the case of ointments, creams, gels, lotions, etc., such ingredients include white petrolatum, yellow petrolatum, lanolin, bleached beeswax, cetanol, stearyl alcohol, stearic acid, hydrogenated oil, gelling hydrocarbons, polyethylene glycol, and liquid paraffin. , squalane, etc., oleic acid, isopropyl myrstate, glycerin triisooctanoate, crotamiton, diethyl sebacate, diisopropyl adipate, hexyl laurate, fatty acids, fatty acid esters, fatty alcohols, vegetable oils. There are solvents and solubilizers such as tocopherol derivatives, antioxidants such as L-ascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, preservatives such as parahydroxybenzoic acid ester, glycerin, propylene glycol, and sodium hyaluronate. Moisturizers such as polyoxyethylene derivatives, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, surfactants such as lecithin, carboxyvinyl polymer, xanthan gum, carboxymethyl cellulose, carboxymethyl cellulose sodium salt, There are thickeners such as hydroxypropylcellulose and hydroxypropylmethylcellulose.
에어로졸제의 경우에 있어서는, 연고제, 크림제, 겔제, 현탁제, 유제, 액제, 로션제 등의 조제에 사용되는 상기 성분 외에 추가로 각종 안정제, 완충제, 교미제, 현탁화제, 유화제, 방향제, 보존제, 용해 보조제, 그 밖의 적당한 첨가제를 배합할 수 있다.In the case of aerosol preparations, in addition to the above ingredients used in the preparation of ointments, creams, gels, suspensions, emulsions, solutions, lotions, etc., various stabilizers, buffers, corrigants, suspending agents, emulsifiers, fragrances, and preservatives are added. , solubility aids, and other suitable additives can be added.
본 발명은 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 완화, 억제 또는 개선용 화장료 조성물에 관한 것이다. 상기 화장료 조성물에 대한 구체적인 설명은 상술한 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 예방 또는 치료용 약학 조성물의 설명과 같으므로 상세한 내용은 그 부분을 참조하기로 한다.The present invention relates to a cosmetic composition for alleviating, suppressing or improving hair loss containing an indirubin derivative represented by Formula 1 and a metabolic activator as active ingredients. The specific description of the cosmetic composition is the same as the description of the pharmaceutical composition for preventing or treating hair loss containing the indirubin derivative represented by Chemical Formula 1 and the metabolic activator as active ingredients, so please refer to that section for detailed information. .
본 발명의 화장료 조성물에 포함되는 성분은 유효성분으로서의 상기 인디루빈 유도체 및 대사활성화제 이외에 화장료 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.Ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions in addition to the indirubin derivative and metabolic activator as active ingredients, such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances. It may include common auxiliaries and carriers such as:
본 발명의 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 샴푸, 린스, 컨디셔너, 화장수, 로션, 크림, 세럼, 에센스, 젤, 팩, 클렌저, 비누, 스프레이, 파우더, 오일, 분말 파운데이션, 유탁액 파운데이션, 및 왁스 파운데이션 등으로 제형화될 수 있으나, 이에 한정되지 않으며, 구체적으로 헤어토닉, 헤어컨디셔너, 헤어에센스, 헤어로션, 헤어영양로션, 헤어샴푸, 헤어린스,헤어트리트먼트, 헤어크림, 헤어영양크림, 헤어모이스처크림, 헤어맛사지크림, 헤어왁스, 헤어 에어로졸, 헤어팩, 헤어영양팩, 헤어비누, 헤어클렌징폼, 머릿기름, 모발건조제, 모발보존처리제, 모발염색제, 모발용 웨이브제, 모발탈색제, 헤어겔, 헤어글레이즈, 헤어드레싱어, 헤어래커, 헤어모이스처라이저, 헤어무스 및 헤어스프레이로 이루어진 군으로부터 선택되는 어느 하나의 두발용 제형일 수 있다.The cosmetic composition of the present invention can be prepared in any formulation commonly prepared in the art, for example, solution, suspension, emulsion, paste, gel, shampoo, rinse, conditioner, lotion, lotion, cream, serum. , essence, gel, pack, cleanser, soap, spray, powder, oil, powder foundation, emulsion foundation, and wax foundation, but is not limited thereto, and specifically hair tonic, hair conditioner, and hair essence. , hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisture cream, hair massage cream, hair wax, hair aerosol, hair pack, hair nutrition pack, hair soap, hair cleansing foam. Any product selected from the group consisting of hair oil, hair dryer, hair preservative treatment, hair dye, hair waving agent, hair bleach, hair gel, hair glaze, hair dresser, hair lacquer, hair moisturizer, hair mousse, and hair spray. It may be a single hair formulation.
본 발명은 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 예방 또는 개선용 식품 조성물에 관한 것이다. 상기 식품 조성물에 대한 구체적인 설명은 상술한 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 예방 또는 치료용 약학 조성물의 설명과 같으므로 상세한 내용은 그 부분을 참조하기로 한다.The present invention relates to a food composition for preventing or improving hair loss containing an indirubin derivative represented by Formula 1 and a metabolic activator as active ingredients. The specific description of the food composition is the same as the description of the pharmaceutical composition for preventing or treating hair loss containing the indirubin derivative represented by Chemical Formula 1 and the metabolic activator as active ingredients, so please refer to that section for detailed information. .
본 발명에 따른 식품 조성물은 상기 약학 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 알코올 음료류, 과자류, 다이어트바, 유제품, 육류, 초코렛, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 비타민 복합제, 건강보조식품류 등이 있다.The food composition according to the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, confectionery, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, gum, ice cream, vitamin complexes, and health supplements. etc.
본 발명의 식품 조성물은 상기 유효성분뿐 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제와 음료류로 제조되는 경우에는 본 발명의 보라틴 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 및 각종 식물 추출액 등을 추가로 포함시킬 수 있다.The food composition of the present invention may contain not only the above active ingredients but also ingredients commonly added during food production, including, for example, proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents. Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is manufactured as a drink or beverage, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be additionally included in addition to the boratin of the present invention.
본 발명은 유효성분을 포함하는 탈모 예방 또는 개선용 식품 조성물을 포함하는 건강기능식품을 제공한다. 건강기능식품이란, 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제의 유효성분을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있다. 이와 같이 하여 얻어지는 본 발명의 건강기능식품은, 일상적으로 섭취하는 것이 가능하기 때문에 매우 유용하다. 이와 같은 건강기능식품에 있어서의 유효성분의 첨가량은, 대상인 건강기능식품의 종류에 따라 달라 일률적으로 규정할 수 없지만, 식품 본래의 맛을 손상시키지 않는 범위에서 첨가하면 되며, 대상 식품에 대하여 통상 0.01 내지 50 중량%, 바람직하기로는 0.1 내지 20 중량%의 범위이다. 또한, 환제, 과립제, 정제 또는 캡슐제 형태의 건강기능식품의 경우에는 통상 0.1 내지 100 중량% 바람직하기로는 0.5 내지 80 중량%의 범위에서 첨가하면 된다. 한 구체예에서, 본 발명의 건강기능식품은 환제, 정제, 캡슐제 또는 음료의 형태일 수 있다.The present invention provides a health functional food containing a food composition for preventing or improving hair loss containing an active ingredient. Health functional foods are foods manufactured by adding the active ingredients of indirubin derivatives and metabolic activators represented by Chemical Formula 1 to food ingredients such as beverages, teas, spices, gum, and confectionery, or by encapsulating, powdering, or suspending them. , which means that ingesting it will bring about certain health effects, but unlike regular drugs, it has the advantage of not having any side effects that may occur when taking the drug for a long time since it is made from food. The health functional food of the present invention obtained in this way is very useful because it can be consumed on a daily basis. The amount of active ingredients added in such health functional foods cannot be uniformly specified as it depends on the type of health functional food being targeted. However, it can be added within a range that does not damage the original taste of the food, and is usually 0.01% for the target food. to 50% by weight, preferably 0.1 to 20% by weight. In addition, in the case of health functional foods in the form of pills, granules, tablets, or capsules, it is usually added in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the health functional food of the present invention may be in the form of a pill, tablet, capsule, or beverage.
또한 본 발명은 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는, 포유동물의 피부로부터 분리된 모유두세포 또는 모낭세포의 성장 촉진용 조성물을 제공한다.In addition, the present invention provides a composition for promoting the growth of dermal papilla cells or hair follicle cells isolated from mammalian skin, comprising an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients.
상기 조성물에 대한 구체적인 설명은 상술한 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하는 탈모 예방 또는 치료용 약학 조성물의 설명과 같으므로 상세한 내용은 그 부분을 참조하기로 한다.The specific description of the composition is the same as the description of the pharmaceutical composition for preventing or treating hair loss containing the indirubin derivative represented by Formula 1 and a metabolic activator as active ingredients, so refer to that section for detailed information.
본 발명의 조성물은 생체 외에서 모유두세포 또는 모낭세포의 증식을 촉진할 수 있는 조성물로 사용할 수 있으며, 특히 생체 외에서 상기 모유두세포와 모낭세포를 배양할 수 있는 배지조성물로 활용될 수 있다.The composition of the present invention can be used as a composition that can promote the proliferation of dermal papilla cells or hair follicle cells in vitro, and can especially be used as a medium composition that can culture the dermal papilla cells and hair follicle cells in vitro.
상기 포유동물은 인간, 소, 염소 및 양으로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.The mammal may be any one selected from the group consisting of humans, cattle, goats, and sheep.
본 발명자들은 탈모 혹은 발모 촉진과 관련하여 생체 외(ex vivo)에서 모유두세포 혹은 모낭세포를 효율적으로 빠르게 대량생산할 수 있는 조성물을 제공하고, 상기 조성물은 모유두세포 또는 모낭세포의 성장이 효율적으로 일어날 뿐 아니라 독성이 없이 성장한 대량의 모유두세포와 모낭세포를 높은 수율로 생산할 수 있음을 발견하였다.The present inventors provide a composition that can efficiently and rapidly mass-produce dermal papilla cells or hair follicle cells in vitro in relation to hair loss or hair growth promotion, and the composition only efficiently causes the growth of dermal papilla cells or hair follicle cells. In addition, it was discovered that large amounts of non-toxic dermal papilla cells and hair follicle cells could be produced at high yield.
이하에서 실시예 등을 통해 본 발명을 더욱 상세히 설명하고자 하며, 다만 이하에 실시예 등에 의해 본 발명의 범위와 내용이 축소되거나 제한되어 해석될 수 없다. 또한, 이하의 실시예를 포함한 본 발명의 개시 내용에 기초한다면, 구체적으로 실험 결과가 제시되지 않은 본 발명을 통상의 기술자가 용이하게 실시할 수 있음은 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연하다.Hereinafter, the present invention will be described in more detail through examples, etc., but the scope and content of the present invention should not be construed as being reduced or limited by the examples below. In addition, based on the disclosure of the present invention, including the following examples, it is clear that a person skilled in the art can easily implement the present invention for which no specific experimental results are presented, and the patent to which such variations and modifications are attached It is natural that it falls within the scope of the claims.
또한 이하에서 제시되는 실험 결과는 상기 실시예 및 비교예의 대표적인 실험 결과만을 기재한 것이며, 아래에서 명시적으로 제시하지 않은 본 발명의 여러 구현예의 각각의 효과는 해당 부분에서 구체적으로 기재하도록 한다.In addition, the experimental results presented below describe only the representative experimental results of the examples and comparative examples, and the effects of each embodiment of the present invention that are not explicitly presented below will be described in detail in the corresponding section.
제조예 1. 5,6-디클로로인디루빈-3'-메톡심(KY19382)의 합성.Preparation Example 1. Synthesis of 5,6-dichloroindirubin-3'-methoxime (KY19382).
① 중간체 5',6`-다이클로로-[2,3`-바이인돌리닐리딘]-2`3-다이온 ( 5',6'-dichloro-[2,3'-biindolinylidene]-2',3-dione )의 합성① Intermediate 5',6'-dichloro-[2,3'-biindolinylidene]-2'3-dione (5',6'-dichloro-[2,3'-biindolinylidene]-2' ,3-dione) synthesis
250 ㎖ 둥근바닥 플라스크에 5,6-다이클로로이사틴(5,6-dichloroisatin) (500 ㎎, 2.32 m㏖)을 넣고 메탄올(MeOH)(92.80 ㎖)에 녹인 뒤, 인독실아세테이트(indoxyl acetate)(405.48 ㎎, 2.315 mmol)과 탄산나트륨(Na2CO3)(637.83 ㎎, 6.02 mmol)을 첨가하여 65 ℃에서 12시간 동안 교반 한다. TLC(Rf=0.4,에틸아세테이트/헥산 = 1/2 (v/v))를 이용하여 반응의 종결을 확인하고, 생성물을 얼음에서 결정 덩어리가 생길 때까지 식혀준다. 결정체가 생기면 여과시켜 용매를 제거한 후, 여과액은 버리고 생성물을 용매(에탄올/물 = 1/1(v/v))로 여러번 씻어준다. 생성물을 여과하여 진공 펌프에서 건조시킨 다음 추가 정제 없이 다음 단계에서 사용하였다.Add 5,6-dichloroisatin (500 mg, 2.32 mmol) to a 250 ㎖ round bottom flask, dissolve in methanol (MeOH) (92.80 ㎖), and then add indoxyl acetate ( 405.48 mg, 2.315 mmol) and sodium carbonate (Na 2 CO 3 ) (637.83 mg, 6.02 mmol) were added and stirred at 65°C for 12 hours. The completion of the reaction was confirmed using TLC (Rf = 0.4, ethyl acetate/hexane = 1/2 (v/v)), and the product was cooled in ice until crystal lumps formed. If crystals form, filter them to remove the solvent, then discard the filtrate and wash the product several times with solvent (ethanol/water = 1/1 (v/v)). The product was filtered, dried in a vacuum pump and used in the next step without further purification.
② KY19382(화학식 1-2)의 합성② Synthesis of KY19382 (Formula 1-2)
100 ㎖ 둥근바닥 플라스크에 5',6`-다이클로로-[2,3`-바이인돌리닐리딘]-2`3-다이온(5',6'-dichloro-[2,3'-biindolinylidene]-2',3-dione)(600 ㎎, 1.81 m㏖)을 넣고 피리딘(pyridine)(151 ㎖)에 녹인 다음 H2NOCH3·HCl(3026.4 ㎎, 36.24 m㏖)을 첨가한 후, 120 ℃에서 12시간 동안 교반한다. TLC(Rf=0.4, 에틸아세테이트/헥산=1/1(v/v))를 이용하여 반응의 종결을 확인하고 반응용액의 온도를 실온으로 낮춘다. 생성물의 피리딘 용매를 모두 증발한 뒤 물과 에틸아세테이트를 넣어 30분 동안 초음파를 이용하여 생성물을 용해 한 뒤, 에틸아세테이트로 두 번에 걸쳐 추출하고 중조(NaHCO3) 포화용액으로 씻어준다. 추출한 용액을 무수황산마그네슘으로 탈수한 뒤, 용매를 증발시키고 메탄올과 핵산을 이용해 재결정하였다. 생성물을 진공펌프에서 건조시키면 붉은색 고체 KY19382(326 ㎎) 47.94%의 수율로 얻을 수 있다. 1H NMR(400 MHz, DMSO-d6) δ 11.36 (s, 2H), 8.80 (s, 1H), 8.08 (d, 1H, J = 7.7 Hz), 7.46 - 7.41 (m, 2H), 7.07 - 6.99 (m, 2H), 4.38 (s, 3H).5',6'-dichloro-[2,3'-biindolinylidene]-2'3-dione (5',6'-dichloro-[2,3'-biindolinylidene) in a 100 mL round bottom flask. ]-2',3-dione) (600 mg, 1.81 mmol) was added and dissolved in pyridine (151 ml), then H 2 NOCH 3 ·HCl (3026.4 mg, 36.24 mmol) was added, then 120 Stir at ℃ for 12 hours. Confirm the completion of the reaction using TLC (R f = 0.4, ethyl acetate/hexane = 1/1 (v/v)) and lower the temperature of the reaction solution to room temperature. After evaporating all of the pyridine solvent in the product, water and ethyl acetate were added and the product was dissolved using ultrasound for 30 minutes, then extracted twice with ethyl acetate and washed with a saturated solution of sodium bicarbonate (NaHCO 3 ). The extracted solution was dehydrated with anhydrous magnesium sulfate, the solvent was evaporated, and it was recrystallized using methanol and hexane. When the product is dried in a vacuum pump, red solid KY19382 (326 mg) can be obtained with a yield of 47.94%. 1H NMR (400 MHz, DMSO- d6 ) δ 11.36 (s, 2H), 8.80 (s, 1H), 8.08 (d, 1H, J = 7.7 Hz), 7.46 - 7.41 (m, 2H), 7.07 - 6.99 (m, 2H), 4.38 (s, 3H).
제조예 2. 5-메톡실인디루빈-3'-옥심의 합성Preparation Example 2. Synthesis of 5-methoxyl indirubin-3'-oxime
① 중간체 5'-메톡시-[2,3'-바이인돌리닐리딘]-2',3-다이온 (5'-methoxy-[2,3'-biindolinylidene]-2',3-dione)의 합성① Intermediate 5'-methoxy-[2,3'-biindolinylidene]-2',3-dione (5'-methoxy-[2,3'-biindolinylidene]-2',3-dione) synthesis of
250 ㎖ 둥근바닥 플라스크에 5-메톡시이사틴(5-methoxyisatin)(1000 ㎎, 5.65 m㏖)을 넣고 메탄올(MeOH)(225 ㎖)에 녹인 뒤, 인독실아세테이트(indoxyl acetate)(989 ㎎, 5.65 mmol)과 탄산나트륨(Na2CO3)(1496 ㎎, 14.11 mmol)을 첨가하여 65 ℃에서 12시간 동안 교반한다. TLC(Rf=0.4,에틸아세테이트/헥산 = 1/2 (v/v))를 이용하여 반응의 종결을 확인하고, 생성물을 얼음에서 결정 덩어리가 생길 때까지 식혀준다. 결정체가 생기면 여과시켜 용매를 제거한 후, 여과액은 버리고 생성물을 용매(에탄올/물 = 1/1(v/v))로 여러 번 씻어 준다. 생성물을 여과하여 진공 펌프에서 건조시킨 다음 추가 정제 없이 다음 단계에서 사용하였다.Add 5-methoxyisatin (1000 mg, 5.65 mmol) to a 250 mL round bottom flask, dissolve in methanol (MeOH) (225 mL), and then add indoxyl acetate (989 mg, 5.65 mmol). mmol) and sodium carbonate (Na 2 CO 3 ) (1496 mg, 14.11 mmol) were added and stirred at 65°C for 12 hours. The completion of the reaction was confirmed using TLC (Rf = 0.4, ethyl acetate/hexane = 1/2 (v/v)), and the product was cooled in ice until crystal lumps formed. If crystals form, filter them to remove the solvent, then discard the filtrate and wash the product several times with solvent (ethanol/water = 1/1 (v/v)). The product was filtered, dried in a vacuum pump and used in the next step without further purification.
② 5-메톡실인디루빈-3'-옥심(화학식 1-1) 합성② Synthesis of 5-methoxyl indirubin-3'-oxime (Formula 1-1)
100 ㎖ 둥근바닥 플라스크에 5'-메톡시-[2,3'-바이인돌리닐리딘]-2',3-다이온(5'-methoxy-[2,3'-biindolinylidene]-2',3-dione)(670 ㎎, 2.29 m㏖)을 넣고 피리딘(pyridine)(27 ㎖)에 녹인 다음 H2NOH·HCl(3186 ㎎, 45.85 m㏖)을 첨가한 후, 120 ℃에서 12시간 동안 교반 한다. TLC(Rf=0.5, 에틸아세테이트/헥산= 1/1 (v/v))를 이용하여 반응의 종결을 확인하고 반응 용액의 온도를 실온으로 낮춘다. 생성물의 피리딘 용매를 모두 증발한 뒤 물과 에틸아세테이트를 넣어 30분 동안 초음파를 이용하여 생성물을 용해 한 뒤, 에틸아세테이트로 두 번에 걸쳐 추출하고 중조(NaHCO3) 포화용액으로 씻어준다. 추출한 용액을 무수황산마그네슘으로 탈수 한 뒤, 용매를 증발시키고 메탄올과 핵산을 이용해 재결정 해 준다. 생성물을 진공펌프에서 건조시키면 붉은색 고체 5-메톡실인디루빈-3'-옥심(화학식 1-1)(420 ㎎)을 59%의 수율로 얻을 수 있다. 1H NMR(400 MHz, DMSO-d6) δ 13.52 (s, 1H), 11.79 (s, 1H), 10.54 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 2.8 Hz, 2H), 7.08 - 7.00 (m, 1H), 6.82 - 6.71 (m, 2H), 3.78 (s, 3H).5'-methoxy-[2,3'-biindolinylidene]-2',3-dione (5'-methoxy-[2,3'-biindolinylidene]-2', 3-dione) (670 mg, 2.29 mmol) was added and dissolved in pyridine (27 ml), then H 2 NOH·HCl (3186 mg, 45.85 mmol) was added, and stirred at 120°C for 12 hours. do. The completion of the reaction is confirmed using TLC (R f = 0.5, ethyl acetate/hexane = 1/1 (v/v)), and the temperature of the reaction solution is lowered to room temperature. After evaporating all of the pyridine solvent in the product, water and ethyl acetate were added and the product was dissolved using ultrasound for 30 minutes, then extracted twice with ethyl acetate and washed with a saturated solution of sodium bicarbonate (NaHCO 3 ). After dehydrating the extracted solution with anhydrous magnesium sulfate, the solvent is evaporated and recrystallized using methanol and hexane. When the product is dried in a vacuum pump, red solid 5-methoxyl indirubin-3'-oxime (Formula 1-1) (420 mg) can be obtained with a yield of 59%. 1H NMR (400 MHz, DMSO- d6 ) δ 13.52 (s, 1H), 11.79 (s, 1H), 10.54 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 2.8 Hz, 2H), 7.08 - 7.00 (m, 1H), 6.82 - 6.71 (m, 2H), 3.78 (s, 3H).
제조예 3 및 4. 5,6-디클로로인디루빈-3'-옥심프로필옥심 및 6-클로로인디루빈-3'-벤질옥심의 제조Preparation Examples 3 and 4. Preparation of 5,6-dichloroindirubin-3'-oxime propyloxime and 6-chloroindirubin-3'-benzyloxime
5,6-디클로로인디루빈-3'-프로필옥심과 6-클로로인디루빈-3'-벤질옥심은 상기 5,6-디클로로인디루빈-3'-메톡심 또는 5-메톡실인디루빈-3'-옥심과 동일한 방식으로 합성되었고, 이는 황화디메틸(DMSO)에 녹여 실험에 적용하였다. 5,6-dichloroindirubin-3'-propyloxime and 6-chloroindirubin-3'-benzyloxime are 5,6-dichloroindirubin-3'-methoxime or 5-methoxyl indirubin-3'. -It was synthesized in the same way as oxime, and was dissolved in dimethyl sulfide (DMSO) and applied to the experiment.
실시예 및 비교예. 인디루빈 유도체 및 대사활성화제의 혼합물Examples and comparative examples. Mixture of indirubin derivatives and metabolic activators
하기 표 1에서와 같이 인디루빈 유도체와 대사활성화제를 혼합한 혼합물을 제조하였다. 본 발명에서 사용한 대사활성화제 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4-diazepan-1-ylsulfonyl)aniline(DASA-58) 및 (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid(UK5099) 및 세린(Serine)은 Sigma Aldrich(St. Louis, USA)로부터 구입하여 사용하였다.As shown in Table 1 below, a mixture of indirubin derivatives and a metabolic activator was prepared. The metabolic activator used in the present invention is 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[ 2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4-diazepan -1-ylsulfonyl)aniline (DASA-58) and (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid (UK5099) and serine were obtained from Sigma Aldrich (St. Louis, USA) and used.
이때 상용화된 약물인 미녹시딜(MNX) 150 μM은 양성대조군으로 하였고, 혼합물 대신 DMSO를 처리한 것은 음성대조군으로 하였다.At this time, 150 μM of minoxidil (MNX), a commercially available drug, was used as a positive control, and DMSO treated instead of the mixture was used as a negative control.
구분division |
인디루빈 유도체 KY19382Indirubin derivatives KY19382 |
대사활성화제metabolic activator | |
종류type | 함량content | ||
실시예 1Example 1 | 0.5 μM0.5 μM | TEPP-46TEPP-46 | 0.1 μM0.1 μM |
실시예 2Example 2 | 0.5 μM0.5 μM | DASA-58DASA-58 | 0.1 μM0.1 μM |
실시예 3Example 3 | 0.5 μM0.5 μM | SerineSerine | 1 mM1mM |
실시예 4Example 4 | 0.5 μM0.5 μM | UK-5099UK-5099 | 0.1 μM0.1 μM |
비교예 1Comparative Example 1 | 0.5 μM0.5 μM | -- | -- |
비교예 2Comparative Example 2 | -- | TEPP-46TEPP-46 | 0.1 μM0.1 μM |
비교예 3Comparative Example 3 | -- | DASA-58DASA-58 | 0.1 μM0.1 μM |
비교예 4Comparative Example 4 | -- | SerineSerine | 0.1 μM0.1 μM |
비교예 5Comparative Example 5 | -- |
Serine |
1 μM1 μM |
비교예 6Comparative Example 6 | -- |
Serine |
10 μM10 μM |
비교예 7Comparative Example 7 | -- | SerineSerine | 0.1 mM0.1mM |
비교예 8Comparative Example 8 | -- | SerineSerine | 1 mM1mM |
비교예 9Comparative Example 9 | -- | UK-5099UK-5099 | 0.1 μM0.1 μM |
비교예 10Comparative Example 10 | -- | Dichloro-acetateDichloro-acetate | 0.1 μM0.1 μM |
비교예 11Comparative Example 11 | 0.5 μM0.5 μM | Dichloro-acetateDichloro-acetate | 0.1 μM0.1 μM |
실시예 1 내지 4는 화학식 1-2로 표시되는 인디루빈 유도체와 대사활성화제의 혼합물이고, 비교예 1 내지 9는 화학식 1-2로 표시되는 인디루빈 유도체 또는 대사활성화제 단독 투여군이다. 비교예 10 및 11은 대사활성화제 중에서 PKM2 활성화제가 아닌 PDK 활성화제인 Dichloroacetate를 단독 또는 인디루빈 유도체와 혼합한 것이다.Examples 1 to 4 are a mixture of an indirubin derivative represented by Formula 1-2 and a metabolic activator, and Comparative Examples 1 to 9 are a group administered only an indirubin derivative represented by Formula 1-2 or a metabolic activator. Comparative Examples 10 and 11 contain dichloroacetate, a PDK activator, not a PKM2 activator, alone or mixed with an indirubin derivative among metabolic activators.
실험예 1. ex vivo에서의 육모 효능 측정Experimental Example 1. Measurement of hair growth efficacy in ex vivo
생후 6 내지 8 주령의 마우스(mouse) 수컷을 희생시킨 후, 입 주변 조직을 분리하였다. 분리된 조직은 70% 에탄올(ethanol)에 넣은 후 1% 페니실린(100IU/㎖)/스트렙토마이신(100㎍/㎖)(P/S,GIBCO,Grand Island,NY,USA)가 포함된 PBS(phosphate-bufferedsaline)pH 7.4, SIGMA, St. Louis, MO, USA)에 혼합하여 유제액을 제조하였다. 현미경을 이용하여 성장기(anagen) 상태인 비브리사 모낭(vibrissa follicle)을 하나씩 분리하였다. 분리된 비브리사 모낭(vibrissa follicle)은 24 웰 플레이트의 각 웰에 분주한 후, 실시예 또는 비교예가 포함된 배지(DMEM serum free 1% P/S + 12.5 μg/ml gentamycin)를 각각 처리하였다. 상기 플레이트를 37 ℃, 5% CO2 조건 하에서 배양하고, 6일 후 현미경을 통해 관찰하였다. 배지는 2일에 한번씩 교체하였다. 모낭 형태를 현미경(SMZ745T, Nikon)으로 촬영하였고, 모낭 길이는 image J를 사용하여 측정하였다. 모낭 길이 변화의 평균값을 구하고 음성대조군 혹은 단일처리군의 평균길이와 비교하여 성장 정도를 측정하였다. 실험으로부터 얻은 결과는 평균 및 이의 표준오차(SEM, Standard Error of the Mean)로 기록하였고, 유의성 검증은 Student's T-test 분석방법을 이용하여 결정하였다.Male mice aged 6 to 8 weeks were sacrificed, and tissues around the mouth were isolated. The separated tissue was placed in 70% ethanol and then washed with PBS (phosphate) containing 1% penicillin (100IU/ml)/streptomycin (100㎍/ml) (P/S, GIBCO, Grand Island, NY, USA). -buffered saline)pH 7.4, SIGMA, St. Louis, MO, USA) to prepare an emulsion. Using a microscope, vibrissa follicles in the anagen state were separated one by one. The isolated vibrissa follicles were dispensed into each well of a 24-well plate and then treated with medium containing the examples or comparative examples (DMEM serum free 1% P/S + 12.5 μg/ml gentamycin). The plate was cultured at 37°C and 5% CO 2 and observed through a microscope after 6 days. The medium was changed once every two days. The hair follicle morphology was photographed under a microscope (SMZ745T, Nikon), and the hair follicle length was measured using image J. The average value of hair follicle length change was calculated and compared with the average length of the negative control group or single treatment group to measure the degree of growth. The results obtained from the experiment were recorded as the mean and its standard error of the mean (SEM), and significance was determined using the Student's T-test analysis method.
도 1은 인디루빈 유도체 또는 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)를 단독으로 처리한 비브리사 모낭을 6일간 배양한 후 촬영한 현미경 사진이고, 도 2는 인디루빈 유도체와 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)의 혼합물을 처리한 비브리사 모낭을 6일간 배양한 후 촬영한 현미경 사진이다.Figure 1 is a micrograph taken after culturing Vibrissa hair follicles treated with indirubin derivatives or metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone for 6 days, and Figure 2 is This is a photomicrograph taken after culturing Vibrissa hair follicles treated with a mixture of indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) for 6 days.
도 3은 인디루빈 유도체와 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)의 단독 또는 혼합 처리한 비브리사 모낭을 6일간 배양하였을 때, 각각의 길이변화를 측정하여 나타낸 그래프이다(* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH or single treat).Figure 3 shows the length change of each Vibrissa hair follicle treated alone or in combination with an indirubin derivative and a metabolic activator (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) and cultured for 6 days. This is the graph shown (* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH or single treat).
도 4는 다양한 농도의 세린 단독 투여군에 대한 비브리사 모낭을 촬영한 현미경 사진(상)과 길이변화를 측정하여 나타낸 그래프(하)이다(* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH).Figure 4 is a micrograph (top) of Vibrissa hair follicles taken in the group administered with various concentrations of serine alone and a graph (bottom) showing the length change (* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs. VEH).
구분division | * relative vibrissa length* relative vibrissa length | SEMS.E.M. | Comparison to VEHComparison to VEH | Comparison to single-treatmentComparison to single-treatment |
음성대조군 (VEH)Negative control group (VEH) |
100100 | 8.535758.53575 | -- | -- |
양성대조군 (MNX)Positive control group (MNX) |
145.1296145.1296 | 7.9735987.973598 | 0.0021730.002173 | -- |
실시예 1Example 1 | 283.7517283.7517 | 26.2844326.28443 | 1.47E-061.47E-06 | 0.0251560.025156 |
실시예 2Example 2 | 254.5192254.5192 | 18.4062518.40625 | 1.66E-061.66E-06 | 0.0189850.018985 |
실시예 3Example 3 | 280.0675280.0675 | 29.5853829.58538 | 1.29E-061.29E-06 | 0.008050.00805 |
실시예 4Example 4 | 269.6002269.6002 | 17.4283317.42833 | 8.63E-088.63E-08 | 0.0218750.021875 |
비교예 1Comparative Example 1 | 179.1396179.1396 | 8.0838338.083833 | 6.08E-066.08E-06 | -- |
비교예 2Comparative Example 2 | 202.3379202.3379 | 14.2701514.27015 | 1.21E-051.21E-05 | -- |
비교예 3Comparative Example 3 | 193.872193.872 | 12.9731112.97311 | 1.13E-051.13E-05 | -- |
비교예 4Comparative Example 4 | 116.3255116.3255 | 12.4313512.43135 | 0.3696960.369696 | -- |
비교예 5Comparative Example 5 | 117.0565117.0565 | 11.2888911.28889 | 0.3279760.327976 | -- |
비교예 6Comparative Example 6 | 128.6062128.6062 | 17.7321617.73216 | 0.2048130.204813 | -- |
비교예 7Comparative Example 7 | 156.291156.291 | 19.9660419.96604 | 0.0275170.027517 | -- |
비교예 8Comparative Example 8 | 163.103163.103 | 19.6130219.61302 | 0.0049530.004953 | -- |
비교예 9Comparative Example 9 | 202.1371202.1371 | 18.626318.6263 | 0.0002180.000218 | -- |
비교예 10Comparative Example 10 | 160.6009160.6009 | 15.0211215.02112 | 0.0007580.000758 | -- |
비교예 11Comparative Example 11 | 194.1432194.1432 | 10.9987610.99876 | 9.19E-069.19E-06 | 0.127580.12758 |
*) VEH를 기준으로, 상대적인(relative) 비브리사 길이 변화 값*) Relative vibrissa length change value based on VEH
도 1 내지 4 및 표 2에 나타난 바와 같이, 화학식 1-2로 표시되는 인디루빈 유도체와 대사활성화제의 혼합물인 실시예 1 내지 4는 종래 탈모 치료제인 미녹시딜(MNX)보다 75 내지 95% 이상의 비브리사(vibrissa)의 길이 증가효과를 나타내었고, 화학식 1-2로 표시되는 인디루빈 유도체 또는 대사활성화제를 단독으로 투여한 비교예 1 내지 9(single-treatment)보다 비브리사(vibrissa)의 길이 증가가 20% 내지 40% 이상이라는 것을 확인하였다.As shown in Figures 1 to 4 and Table 2, Examples 1 to 4, which are a mixture of an indirubin derivative represented by Formula 1-2 and a metabolic activator, have a ratio of 75 to 95% or more than minoxidil (MNX), a conventional hair loss treatment agent. It showed an effect of increasing the length of vibrissa, and the length of vibrissa increased compared to Comparative Examples 1 to 9 (single-treatment) in which the indirubin derivative or metabolic activator represented by Formula 1-2 was administered alone. It was confirmed that was 20% to 40% or more.
화학식 1-2로 표시되는 인디루빈 유도체 또는 대사활성화제를 단독으로 투여한 비교예 1 내지 9가 종래 탈모 치료제인 미녹시딜(MNX)보다 단지 1.25배 정도의 증가효과만을 도출하고 있다는 점을 고려한다면, 실시예 1 내지 4는 비교예 1 내지 9의 단순 상승효과 이상의 유의적으로 현저한 효과를 달성하고 있다는 것을 알 수 있다.Considering that Comparative Examples 1 to 9, in which the indirubin derivative or metabolic activator represented by Formula 1-2 was administered alone, produced an increase effect of only about 1.25 times that of minoxidil (MNX), a conventional hair loss treatment, It can be seen that Examples 1 to 4 achieve significantly more significant effects than the simple synergistic effect of Comparative Examples 1 to 9.
따라서 본 발명의 실시예 1 내지 4로부터 제조된 혼합 조성물은 탈모 방지 및 발모 촉진에 유용한 조성물로 이용될 수 있음을 알 수 있다.Therefore, it can be seen that the mixed composition prepared in Examples 1 to 4 of the present invention can be used as a composition useful for preventing hair loss and promoting hair growth.
실험예 2. 독성 분석Experimental Example 2. Toxicity Analysis
사람 진피 유두 세포(human dermal papilla cell)를 6 웰 플레이트(well plate)의 각 웰(well)당 2 × 105개씩 고착시킨 후, 세포가 안정하게 부착되었을 때 실시예 또는 비교예의 약물을 처리하였다. 24시간 후 Cell Titer-Glo Luminescent Cell Viability Assay kit(Promega, Madison, USA)를 사용하여 FLUOstar OPTIMA luminometer(BMG Labtech, Offenburg, Germany)를 통해 발광(luminescence)값을 측정하였다.Human dermal papilla cells were fixed at a rate of 2 × 10 5 per well of a 6-well plate, and when the cells were stably attached, they were treated with the drugs of Examples or Comparative Examples. . After 24 hours, luminescence values were measured using a FLUOstar OPTIMA luminometer (BMG Labtech, Offenburg, Germany) using the Cell Titer-Glo Luminescent Cell Viability Assay kit (Promega, Madison, USA).
실험으로부터 얻은 결과는 평균 및 이의 표준오차(SEM, Standard Error of the Mean)로 기록하였고, 유의성 검증은 Student's T-test 분석방법을 이용하여 결정하였다. The results obtained from the experiment were recorded as the mean and its standard error of the mean (SEM), and significance was determined using the Student's T-test analysis method.
도 5는 인디루빈 유도체와 대사활성화제(TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate)를 단독 또는 혼합하여 처리한 사람의 진피 유두 세포에 대한 세포 생존율(cell viability)을 측정하여 나타낸 그래프이다(* P < 0.05, ** P < 0.005, *** P < 0.0005 vs VEH).Figure 5 shows the cell viability of human dermal papilla cells treated with indirubin derivatives and metabolic activators (TEPP-46, DASA-58, Serine, UK-5099, Dichloroacetate) alone or in combination. This is the graph shown (* P < 0.05, ** P < 0.005, *** P < 0.0005 vs VEH).
도 5에 나타난 바와 같이, 화학식 1-2로 표시되는 인디루빈 유도체와 대사활성화제는 단독 또는 혼합 모두에서 세포 독성을 나타내지 않았다. 즉 실시예 1 내지 4 및 비교예 1 내지 12는 모두 세포 생존율이 100% 이상인 것을 확인한 바, 세포 안정성이 매우 우수하다는 것을 확인하였다. 다만 미녹시딜(MNX)의 경우 97%로, 유일하게 100% 이하인 것을 확인하였다.As shown in Figure 5, the indirubin derivative represented by Formula 1-2 and the metabolic activator did not show cytotoxicity either alone or in combination. That is, in Examples 1 to 4 and Comparative Examples 1 to 12, it was confirmed that the cell viability was more than 100%, confirming that the cell stability was very excellent. However, in the case of minoxidil (MNX), it was confirmed to be 97%, the only one below 100%.
실험예 3. 동물실험Experimental Example 3. Animal experiment
실험동물은 실험의 용이성을 고려하여 C57BL/6N 쥐를 사용하였다. 실험동물은 ㈜오리엔트바이오에서 구입한 체중 25g 내외의 수컷 7주령 C57BL/6N 정상생쥐를 이용하였다. 각각의 실험군에는 5마리씩 배정하였다. C57BL/6N 쥐는 생후부터 모든 모낭이 모발성장주기의 성장기로 진입하여 털이 자라기 시작하고, 약 3주경 휴지기로 전이된 다음 바로 2차 성장기로 진입한다. 6-7주쯤 모든 모낭이 휴지기로 전이되는 것으로 알려져 있으므로, 이 휴지기에는 실험동물의 자체적인 모발 성장 인자에 의한 영향이 배제되므로 실험 물질만의 효능을 평가하기 적절하다.C57BL/6N mice were used as experimental animals considering ease of experimentation. The experimental animals used were 7-week-old male C57BL/6N normal mice weighing approximately 25g purchased from Orient Bio Co., Ltd. Five animals were assigned to each experimental group. In C57BL/6N mice, all hair follicles enter the anagen phase of the hair growth cycle from birth and begin to grow hair. After about 3 weeks, the mouse transitions to the telogen phase and immediately enters the second growth phase. It is known that all hair follicles transition into the telogen phase around 6-7 weeks, so this telogen phase is appropriate for evaluating the efficacy of only the experimental substance since the influence of the test animal's own hair growth factors is excluded.
동물실험의 윤리적, 과학적 타당성 검토 및 효율적인 관리를 위하여 연세대학교 동물실험윤리 위원회(Institutional Animal Care and Use Committee : IACUC)의 승인을 받아 수행하였다.To review the ethical and scientific validity and efficient management of animal experiments, this study was conducted with approval from the Institutional Animal Care and Use Committee (IACUC) of Yonsei University.
7 주령의 C57BL/6N 생쥐의 등쪽 체모를 애니멀 글리퍼(animal clipper)로 제거하였다. 각각 군당 5마리씩 모두 5군으로 나누어 실험하였다. 정상군을 제외한 나머지 군은 150 μl씩 약물을 28일 동안 매일 1회씩 등 피부에 도포하였다. 약물을 투여하고, 4주 후 이산화탄소 이용하여 안락사 시킨 후 사진촬영을 실시하였다. 모발 성장 정도를 비교하기 위하여 4주 후 생장기 모발 성장치를 다시 자라난 털의 무게를 측정하여 관찰하였다. 전체 삭모 부위 중 생장기 모발이 자란 부위의 무게를 측정하였다.The hair on the back of a 7-week-old C57BL/6N mouse was removed using an animal clipper. The experiment was conducted by dividing the animals into 5 groups with 5 animals per group. Except for the normal group, 150 μl of the drug was applied to the back skin once a day for 28 days. Drugs were administered, and 4 weeks later, they were euthanized using carbon dioxide and photographs were taken. To compare the degree of hair growth, hair growth during the anagen phase was observed after 4 weeks by measuring the weight of the regrown hair. Among all areas of hair loss, the weight of the area where hair grew during the anagen phase was measured.
실험으로부터 얻은 결과는 평균 및 이의 표준오차(SEM, Standard Error of the Mean)로 기록하였고, 유의성 검증은 Student's T-test 분석방법을 이용하여 결정하였다. The results obtained from the experiment were recorded as the mean and its standard error of the mean (SEM), and significance was determined using the Student's T-test analysis method.
5개 군의 동물모델Animal models from 5 groups
정상군(VHE) : 150 μl PBS를 등 피부에 1일 1회 28일동안 도포함Normal group (VHE): 150 μl PBS was applied to the back skin once a day for 28 days.
실험군(KY+TE) : KY19382(0.5 mM)과 TEPP-46(0.5 mM)을 혼합한 조성물 150 μl를 등 피부에 1일 1회 28일동안 도포함Experimental group (KY+TE): 150 μl of a mixture of KY19382 (0.5mM) and TEPP-46 (0.5mM) was applied to the back skin once a day for 28 days.
제1 비교군(TEPP46) : TEPP-46(0.5 mM) 150 μl를 등 피부에 1일 1회 28일동안 도포함First comparison group (TEPP46): 150 μl of TEPP-46 (0.5 mM) was applied to the back skin once a day for 28 days.
제2 비교군(KY19382) : KY19382(0.5 mM) 150 μl를 등 피부에 1일 1회 28일동안 도포함Second comparison group (KY19382): 150 μl of KY19382 (0.5 mM) was applied to the back skin once a day for 28 days.
제3 비교군(MNX) : 미녹시딜(MNX)(150 mM) 150 μl를 등 피부에 1일 1회 28일동안 도포함Third comparison group (MNX): 150 μl of minoxidil (MNX) (150 mM) was applied to the back skin once a day for 28 days.
도 6은 인디루빈 유도체와 대사활성화제(TEPP-46)를 단독 또는 혼합하여 처리한 각 군을 촬영한 사진이고, 도 7은 인디루빈 유도체와 대사활성화제(TEPP-46)를 단독 또는 혼합하여 처리한 각 군으로부터 모발 성장치를 측정하여 나타낸 그래프이다(* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs VEH or single treat).Figure 6 is a photograph taken of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination, and Figure 7 is a photograph of each group treated with indirubin derivative and metabolic activator (TEPP-46) alone or in combination. This is a graph showing the hair growth values measured from each treated group (* P < 0.05, ** P < 0.005, *** P < 0.0005, NS: not significant vs VEH or single treat).
도 6 및 7에 나타난 바와 같이, 모발 성장치를 다시 자라난 털의 무게를 통해 관찰한 결과 4주 후 실험군의 모발 성장 정도가 MNX군에 비하여 유의성있게 증가하였다는 것을 확인하였다. 인디루빈 유도체와 대사활성화제(TEPP-46)를 혼합처리한 실험군에서 모발 성장 정도는 제1 내지 제2 비교군에 비하여 유의하게 증가하였다.As shown in Figures 6 and 7, hair growth was observed through the weight of regrown hair, and it was confirmed that the degree of hair growth in the experimental group significantly increased compared to the MNX group after 4 weeks. In the experimental group treated with a mixture of indirubin derivative and metabolic activator (TEPP-46), the degree of hair growth significantly increased compared to the first and second comparison groups.
양모의 육안관찰을 위해 도 6의 사진을 분석한 결과, 실험 4주 후 인디루빈 유도체와 대사활성화제(TEPP-46)를 혼합처리한 실험군에서 등 부분의 전체 삭모 부위 중 모발이 자란 부위의 비가 제1 내지 제3 비교군에 비하여 현저히 증가한 것을 확인하였다. 또한 화학식 1-2로 표시되는 인디루빈 유도체와 대사활성화제(TEPP-46)를 혼합처리한 실험군에서는 염증소견이나 기타 병리학적 소견이 확인되지 않았으며, 전체 삭모 부위에서 빈곳없이 모발이 자랐으며, 제모하기 이전보다 모발의 양과 길이가 더 많고 증가하였다.As a result of analyzing the photo in FIG. 6 for visual observation of the wool, in the experimental group treated with a mixture of indirubin derivative and metabolic activator (TEPP-46) 4 weeks after the experiment, the ratio of the area where hair grew out of the total hair loss area on the back was It was confirmed that there was a significant increase compared to the first to third comparison groups. In addition, in the experimental group treated with a mixture of an indirubin derivative represented by Formula 1-2 and a metabolic activator (TEPP-46), no inflammation or other pathological findings were confirmed, and hair grew without gaps in the entire hair loss area. The amount and length of hair increased more than before hair removal.
즉, 본 발명의 인디루빈 유도체(KY19382)와 대사활성화제(TEPP-46)을 혼합한 조성물은 기존 탈모개선제인 MNX와 탈모 개선 효과를 비교 검토하였고, 그 결과 인디루빈 유도체(KY19382)와 대사활성화제(TEPP-46)를 혼합한 조성물은 생장기 모발의 발모를 촉진하여 유의적으로 현저한 양모 효능을 나타낸다는 것을 확인할 수 있었다. 또한 인디루빈 유도체(KY19382)와 대사활성화제(TEPP-46)의 혼합 조성물은 염증소견이나 기타 병리학적 소견을 나타내지 않았고, 세포 독성 실험에서도 안정한 것으로 확인된 바, 이를 바탕으로 탈모에 대한 개선 또는 치료제로 이용가능하다는 것을 알 수 있다.That is, the composition combining the indirubin derivative (KY19382) and the metabolic activator (TEPP-46) of the present invention was compared and reviewed for hair loss improvement effect with MNX, an existing hair loss improvement agent, and as a result, the indirubin derivative (KY19382) and the metabolic activator were compared. It was confirmed that the composition mixed with the agent (TEPP-46) promoted hair growth during the growth period and showed significantly significant hair growth efficacy. In addition, the mixed composition of indirubin derivative (KY19382) and metabolic activator (TEPP-46) did not show inflammation or other pathological findings and was confirmed to be stable in cytotoxicity tests. Based on this, it was confirmed as an improvement or treatment for hair loss. You can see that it is available.
제제예 1: 탈모 예방 또는 개선용 크림형 화장료 조성물Formulation Example 1: Cream-type cosmetic composition for preventing or improving hair loss
본 제제예에서는 화학식 1-2의 인디루빈 유도체 및 대사활성화제(TEPP-46)의 혼합 조성물을 유효성분으로 함유하는 탈모 예방 또는 개선용 크림형 화장료 조성물을 제조하고자 하였다. 실시예 1의 조성물을 포함하는 성분들을 하기 함량에 따라, 혼합하여 탈모 예방 또는 개선용 크림형 화장료 조성물을 제조하였다.In this formulation example, an attempt was made to prepare a cream-type cosmetic composition for preventing or improving hair loss containing a mixed composition of an indirubin derivative of Formula 1-2 and a metabolic activator (TEPP-46) as an active ingredient. Components including the composition of Example 1 were mixed according to the following amounts to prepare a cream-type cosmetic composition for preventing or improving hair loss.
실시예 1의 조성물 4.0 중량%4.0% by weight of the composition of Example 1
글리세린 2.0 중량%Glycerin 2.0% by weight
파라벤 0.2 중량%Paraben 0.2% by weight
알란토인 2.0 중량%Allantoin 2.0% by weight
베타인 3.0 중량%Betaine 3.0% by weight
히아루론산나트륨 1.0 중량%Sodium hyaluronate 1.0% by weight
초산토코페롤 5.0 중량%Tocopherol acetate 5.0% by weight
쉐어버터 2.0 중량%Shea butter 2.0% by weight
트레할로스 1.0 중량%Trehalose 1.0% by weight
방부제 및 향 적량의 중량%Weight percent of preservatives and fragrances
정제수 to 100 중량%Purified water to 100% by weight
합계 100 중량%Total 100% by weight
제제예 2: 탈모 예방 또는 치료용 약학 조성물(연고)Formulation Example 2: Pharmaceutical composition (ointment) for preventing or treating hair loss
본 제제예에서는 화학식 1-2의 인디루빈 유도체 및 대사활성화제(TEPP-46)의 혼합 조성물을 유효성분으로 함유하는 탈모 예방 또는 치료용 약학 조성물(연고)을 제조하고자 하였다. 실시예 1의 조성물을 포함하는 성분들을 하기 함량에 따라, 혼합하여 탈모 예방 또는 치료용 약학 조성물(연고)을 제조하였다.In this formulation example, an attempt was made to prepare a pharmaceutical composition (ointment) for preventing or treating hair loss containing a mixed composition of an indirubin derivative of Formula 1-2 and a metabolic activator (TEPP-46) as an active ingredient. Components including the composition of Example 1 were mixed according to the following amounts to prepare a pharmaceutical composition (ointment) for preventing or treating hair loss.
실시예 1의 조성물 10 중량%10% by weight of the composition of Example 1
디에틸 세바케이트 8 중량%Diethyl sebacate 8% by weight
경납 5 중량%Hard wax 5% by weight
폴리옥시에틸렌올레일에테르 포스페이트 6 중량%Polyoxyethylene oleyl ether phosphate 6% by weight
벤조산 나트륨 적량의 중량% % by weight of sodium benzoate
바셀린 to 100 중량%Vaseline to 100% by weight
합계 100 중량%Total 100% by weight
제제예 3: 헤어토닉의 제조Formulation Example 3: Preparation of hair tonic
실시예 1의 조성물 10.0 중량%10.0% by weight of the composition of Example 1
레조시놀 0.1 중량%Resorcinol 0.1% by weight
멘톨 0.05 중량%Menthol 0.05% by weight
판테놀 0.2 중량%Panthenol 0.2% by weight
살리실산 0.1 중량%Salicylic acid 0.1% by weight
토코페릴 아세테이트 0.1 중량%Tocopheryl acetate 0.1% by weight
염산피리독신 0.1 중량%Pyridoxine hydrochloride 0.1% by weight
피마자유 5.0 중량%Castor oil 5.0% by weight
색소 적량Pigment dosage
향료 적량Spice Proper Amount
에탄올 적량Ethanol dosage
정제수 잔량Purified water remaining
합계 100.0 중량%Total 100.0% by weight
제제예 4: 헤어컨디셔너의 제조Formulation Example 4: Preparation of hair conditioner
실시예 1의 조성물 2.5 중량%2.5% by weight of the composition of Example 1
세탄올 3.5 중량%Cetanol 3.5% by weight
자기유화형 모노스테아린산글리세린 1.5%Self-emulsifying glycerin monostearate 1.5%
프로필렌 글리콜 2.5%Propylene glycol 2.5%
염화스테아릴메틸벤질 암모늄(25%) 7.0%Stearylmethylbenzyl ammonium chloride (25%) 7.0%
파라옥시안식향산메틸 0.3%Methyl paraoxybenzoate 0.3%
색소 적량Pigment dosage
향료 적량Spice Proper Amount
정제수 잔량Purified water remaining
합계 100.0%Total 100.0%
제제예 5: 헤어로션의 제조Formulation Example 5: Preparation of hair lotion
실시예 1의 조성물 5.0 중량%5.0% by weight of the composition of Example 1
레조시놀 2.0%Resorcinol 2.0%
멘톨 2.0%Menthol 2.0%
판테놀 0.5%Panthenol 0.5%
피록톤올아민 0.1%Piroctonolamine 0.1%
향료, 색소 0.5%Fragrance, coloring 0.5%
정제수 잔량Purified water remaining
합계 100.0%Total 100.0%
제제예 6: 헤어비누의 제조Formulation Example 6: Preparation of hair soap
실시예 1의 조성물 0.1 중량%0.1% by weight of the composition of Example 1
이산화티탄 0.2%Titanium dioxide 0.2%
폴리에틸렌글리콜 0.8%Polyethylene glycol 0.8%
글리세린 0.5%Glycerin 0.5%
에틸렌디아민테트라아세트산 0.05%Ethylenediaminetetraacetic acid 0.05%
나트륨 1.0%Sodium 1.0%
색소 적량Pigment dosage
비누향 적량Soap scent appropriate amount
화장비누베이스 (수분 13%, 중량부) 잔량Toilet soap base (moisture 13%, parts by weight) remaining amount
합계 100.0%Total 100.0%
제제예 7: 우유에의 적용Formulation Example 7: Application to milk
우유 99.9 중량%Milk 99.9% by weight
실시예 1의 조성물 0.1 중량%0.1% by weight of the composition of Example 1
제제예 8: 음료의 제조Formulation Example 8: Preparation of beverage
실시예 1의 조성물 10 ㎎10 mg of composition of Example 1
젖산칼슘 50 ㎎ Calcium lactate 50 mg
구연산 5 ㎎Citric acid 5 mg
니코틴산아미드 10 ㎎ Nicotinamide 10 mg
염산리보플라빈나트륨 3 ㎎ Sodium riboflavin hydrochloride 3 mg
염산피리독신 2 ㎎Pyridoxine hydrochloride 2 mg
아르기닌 10 ㎎ Arginine 10 mg
자당지방산에스테르 10 ㎎Sucrose fatty acid ester 10 mg
물 200 ㎖200 ml of water
Claims (14)
- 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하고,Contains an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients,상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물:Pharmaceutical composition for preventing or treating hair loss, characterized in that the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) inhibitor:[화학식 1][Formula 1]상기 화학식 1에서,In Formula 1,R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- 제1항에 있어서,According to paragraph 1,상기 화학식 1에서,In Formula 1,R1 내지 R3은 각각 독립적으로 수소, 할로젠, C1-C6 알킬 및 C1-C6 알콕시로 이루어진 군으로부터 선택되는 어느 하나이고,R 1 to R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy,R4는 수소 또는 C1-C6 알킬이며,R 4 is hydrogen or C 1 -C 6 alkyl,R5는 수소, C1-C6 알킬, 치환 또는 비치환된 C6-C10 아릴 및 C7-10 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물.R 5 is a pharmaceutical for preventing or treating hair loss, characterized in that any one selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, and C 7-10 arylalkyl. Composition.
- 제1항에 있어서,According to paragraph 1,상기 화학식 1에서, R3 및 R4는 수소인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물.In Formula 1, R 3 and R 4 are hydrogen. A pharmaceutical composition for preventing or treating hair loss.
- 제3항에 있어서,According to paragraph 3,상기 화학식 1에서, R1 및 R2는 각각 독립적으로 수소, 할로젠 및 -O-CH3로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물.In Formula 1, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, and -O-CH 3. A pharmaceutical composition for preventing or treating hair loss.
- 제1항에 있어서,According to paragraph 1,상기 화학식 1에서, R5는 수소, C1-C3 알킬, 벤질기 및 페닐프로필기로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물.In Formula 1, R 5 is any one selected from the group consisting of hydrogen, C 1 -C 3 alkyl, benzyl group, and phenylpropyl group. A pharmaceutical composition for preventing or treating hair loss.
- 제1항에 있어서,According to paragraph 1,상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-4 중에서 선택되는 어느 하나인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물.Formula 1 is a pharmaceutical composition for preventing or treating hair loss, characterized in that any one selected from the following Formulas 1-1 to 1-4.[화학식 1-1][Formula 1-1][화학식 1-2][Formula 1-2][화학식 1-3][Formula 1-3][화학식 1-4][Formula 1-4]
- 제1항에 있어서,According to paragraph 1,상기 PKM2(pyruvate kinase M2) 활성화제는 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,4-diazepan-1-ylsulfonyl)aniline(DASA-58) 및 세린(Serine)로 이루어진 군으로부터 선택되는 어느 하나일 수 있고,The PKM2 (pyruvate kinase M2) activator is 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5H-thieno[2',3':4,5 ]pyrrolo[2,3-d]pyridazin-5-one(TEPP-46, ML265), 3-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1, It may be any one selected from the group consisting of 4-diazepan-1-ylsulfonyl)aniline (DASA-58) and serine,상기 MPC(Mitochondrial pyruvate carrier) 억제제는 (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid(UK5099)인 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물.The MPC (Mitochondrial pyruvate carrier) inhibitor is (E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid (UK5099). A pharmaceutical composition for preventing or treating hair loss. .
- 제1항에 있어서,According to paragraph 1,상기 인디루빈 유도체와 대사활성화제는 1 : 0.1 내지 10의 몰비로 포함되는 것을 특징으로 하는 탈모 예방 또는 치료용 약학적 조성물..A pharmaceutical composition for preventing or treating hair loss, characterized in that the indirubin derivative and the metabolic activator are contained in a molar ratio of 1:0.1 to 10.
- 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하고,Contains an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients,상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모 예방 또는 개선용 화장료 조성물:A cosmetic composition for preventing or improving hair loss, wherein the metabolic activator is a PKM2 (pyruvate kinase M2) activator or an MPC (Mitochondrial pyruvate carrier) inhibitor:[화학식 1][Formula 1]상기 화학식 1에서,In Formula 1,R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- 제9항에 있어서,According to clause 9,상기 조성물은 생체 외에서 모유두세포 또는 모낭세포의 증식을 촉진시키는 것을 특징으로 하는 탈모 예방 또는 개선용 화장료 조성물.The composition is a cosmetic composition for preventing or improving hair loss, characterized in that it promotes the proliferation of dermal papilla cells or hair follicle cells in vitro.
- 제9항에 있어서,According to clause 9,상기 화장료 조성물은 헤어토닉, 헤어컨디셔너, 헤어에센스, 헤어로션, 헤어영양로션, 헤어샴푸, 헤어린스,헤어트리트먼트, 헤어크림, 헤어영양크림, 헤어모이스처크림, 헤어맛사지크림, 헤어왁스, 헤어 에어로졸, 헤어팩, 헤어영양팩, 헤어비누, 헤어클렌징폼, 머릿기름, 모발건조제, 모발보존처리제, 모발염색제, 모발용 웨이브제, 모발탈색제, 헤어겔, 헤어글레이즈, 헤어드레싱어, 헤어래커, 헤어모이스처라이저, 헤어무스 및 헤어스프레이로 이루어진 군으로부터 선택되는 어느 하나의 두발용 제형인 것을 특징으로 하는 탈모 예방 또는 개선용 화장료 조성물.The cosmetic composition includes hair tonic, hair conditioner, hair essence, hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisture cream, hair massage cream, hair wax, and hair aerosol. , hair pack, hair nutrition pack, hair soap, hair cleansing foam, hair oil, hair dryer, hair preservation treatment, hair dye, hair waving agent, hair bleach, hair gel, hair glaze, hair dresser, hair lacquer, hair moisturizer, A cosmetic composition for preventing or improving hair loss, characterized in that it is a hair formulation selected from the group consisting of hair mousse and hair spray.
- 하기 화학식 1로 표시되는 인디루빈 유도체 및 대사활성화제를 유효성분으로 포함하고,Contains an indirubin derivative represented by the following formula (1) and a metabolic activator as active ingredients,상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모 예방 또는 개선용 식품 조성물:Food composition for preventing or improving hair loss, characterized in that the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) inhibitor:[화학식 1][Formula 1]상기 화학식 1에서,In Formula 1,R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- 탈모 환자에게 하기 화학식 1로 표시되는 인디루빈 유도체와 대사활성화제를 치료학적 유효량을 투여하는 것을 포함하는 탈모의 치료방법으로,A method of treating hair loss comprising administering a therapeutically effective amount of an indirubin derivative represented by the following formula (1) and a metabolic activator to a hair loss patient,상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 탈모의 치료방법:A method of treating hair loss, characterized in that the metabolic activator is a PKM2 (pyruvate kinase M2) activator or an MPC (Mitochondrial pyruvate carrier) inhibitor:[화학식 1][Formula 1]상기 화학식 1에서,In Formula 1,R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
- 탈모 예방 또는 치료용 의약의 제조를 위한 하기 화학식 1로 표시되는 인디루빈 유도체와 대사활성화제의 용도로,For the use of indirubin derivatives and metabolic activators represented by the following formula (1) for the production of medicines for preventing or treating hair loss,상기 대사활성화제는 PKM2(pyruvate kinase M2) 활성화제 또는 MPC(Mitochondrial pyruvate carrier) 억제제인 것을 특징으로 하는 용도:Uses wherein the metabolic activator is a PKM2 (pyruvate kinase M2) activator or MPC (Mitochondrial pyruvate carrier) inhibitor:[화학식 1][Formula 1]상기 화학식 1에서,In Formula 1,R1 내지 R5는 각각 독립적으로 수소, 할로젠, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, 치환 또는 비치환된 C6-C10 아릴 및 C7-30 아릴알킬로 이루어진 군으로부터 선택되는 어느 하나이다.R 1 to R 5 are each independently hydrogen, halogen, hydroxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, and C 7-30 aryl. It is any one selected from the group consisting of alkyl.
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KR1020230015930A KR20230141447A (en) | 2022-03-29 | 2023-02-07 | composition for preventing of hair loss or promoting hair growth comprising Metabolic activator and Indirubin derivative compound |
KR10-2023-0015930 | 2023-02-07 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20130103148A (en) * | 2012-03-09 | 2013-09-23 | 연세대학교 산학협력단 | A pharmaceutical composition for treating and preventing bonedisease containing methyl vanillate |
US20180186885A1 (en) * | 2015-06-16 | 2018-07-05 | The Regents Of The University Of California | Fzd7 specific antibodies and vaccines to treat cancer and control stem cell function |
KR20190013575A (en) * | 2017-08-01 | 2019-02-11 | 주식회사 씨케이바이오텍 | composition for preventing of hair loss or promoting hair growth |
US20200157093A1 (en) * | 2017-06-30 | 2020-05-21 | The Regents Of The University Of California | Compositions and methods for modulating hair growth |
KR20210003799A (en) * | 2018-04-13 | 2021-01-12 | 노쓰 캐롤라이나 스테이트 유니버시티 | Use of microneedle patch to promote hair growth |
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- 2023-03-29 WO PCT/KR2023/004211 patent/WO2023191515A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20130103148A (en) * | 2012-03-09 | 2013-09-23 | 연세대학교 산학협력단 | A pharmaceutical composition for treating and preventing bonedisease containing methyl vanillate |
US20180186885A1 (en) * | 2015-06-16 | 2018-07-05 | The Regents Of The University Of California | Fzd7 specific antibodies and vaccines to treat cancer and control stem cell function |
US20200157093A1 (en) * | 2017-06-30 | 2020-05-21 | The Regents Of The University Of California | Compositions and methods for modulating hair growth |
KR20190013575A (en) * | 2017-08-01 | 2019-02-11 | 주식회사 씨케이바이오텍 | composition for preventing of hair loss or promoting hair growth |
KR20210003799A (en) * | 2018-04-13 | 2021-01-12 | 노쓰 캐롤라이나 스테이트 유니버시티 | Use of microneedle patch to promote hair growth |
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