KR20190001854A - Composition for promoting growth and restoration of eyebrow or beard - Google Patents
Composition for promoting growth and restoration of eyebrow or beard Download PDFInfo
- Publication number
- KR20190001854A KR20190001854A KR1020170082026A KR20170082026A KR20190001854A KR 20190001854 A KR20190001854 A KR 20190001854A KR 1020170082026 A KR1020170082026 A KR 1020170082026A KR 20170082026 A KR20170082026 A KR 20170082026A KR 20190001854 A KR20190001854 A KR 20190001854A
- Authority
- KR
- South Korea
- Prior art keywords
- group
- lysine
- peptide
- glycine
- present
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
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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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
본 발명은 광감각제-펩타이드를 유효성분으로 포함하며, 눈썹 또는 수염의 발모 및 육모를 촉진하는 다양한 용도의 조성물에 관한 것이다. The present invention relates to a composition for various uses comprising a photosensitizer-peptide as an active ingredient and promoting the hair growth and hair growth of eyebrows or hairs.
화장이란 화장품을 바르고 매만져 곱게 꾸미는 행위로서, 신체의 아름다운 부분은 돋보이도록 하고 약점이나 추한 부분은 수정하거나 위장하는 수단을 뜻한다. 과거에는 화장을 통해 자연 속에서 자신의 안전과 더 나은 삶을 바라는 의미의 행위였다면, 현재는 화장을 통해 사회 속에서 자기표현을 하는 것으로 의미만 바뀌었을 뿐, 미용을 중시하는 것은 예나 지금이나 같아 화장 재료 및 기술에 관하여 빠르게 변화하고 있다.Cosmetics is the act of applying cosmetics and touching and decorating them finely, which means to make the beautiful part of the body stand out and to fix or disguise weakness or ugly part. In the past, if it was an act in the past that meant a desire for safety and a better life in nature through the use of makeup, now it has only changed meaning by self-expression in society through makeup. Cosmetics and technology are changing rapidly.
최근 눈썹을 강조한 메이크업이 신 뷰티 트렌드로 떠오르면서, 눈썹 등 얼굴을 좀 더 아름답고 어려 보이기 위한 시술이나 제품의 수요가 급증하고 있으며, 여성뿐 아니라 남성 또한 눈썹 모양을 다듬는 경우가 늘었다. 풍성하고 고른 눈썹은 풍요와 부유를 상징하기 때문에 사업 등 중요한 일을 앞두고 있을 때나 승진을 앞두고 관상 눈썹 이식을 하기도 한다.As the makeup that emphasizes the eyebrows recently emerged as a new beauty trend, the demand for procedures and products to make the eyebrows look more beautiful and younger has been increasing rapidly, and the number of cases of not only women but also men have been refining their eyebrows. Because rich and balanced eyebrows symbolize abundance and affluence, they sometimes carry out corneal eyebrow transplantation in advance of important business or promotion.
동양인은 서양인에 비해 체모가 상대적으로 적어 눈썹과 속눈썹 또한 옅은 편이다. 눈썹이나 속눈썹이 옅으면 덜 매력적으로 보일 뿐만 아니라 차갑고 귀하지 못한 인상을 주게 된다. 이러한 단점을 커버하기 위해 눈썹 그리기, 눈썹 문신, 속눈썹 연장을 많이 하고 있으나, 시술 후 세균 때문에 눈썹 부위의 피부에 염증 및 건조증이 생기기도 한다. Asians have relatively less hairs than Westerners, and their eyebrows and eyelashes are also light. If your eyebrows or eyelashes are light, it will not only look less attractive, but will also give you a cool and unremarkable impression. To cover these disadvantages, eyebrow drawing, eyebrow tattooing, and eyelash extensions are common. However, after the procedure, inflammation and dryness may occur in the skin of the eyebrow area due to bacteria.
한편, 최근에는 눈썹은 물론, 콧수염, 턱수염, 구레나룻을 짙게 해주는 발모제에 대한 남성들의 관심이 늘어나고 있다. 구체적으로 2013년부터 힙스터 (Hipster) 수염 스타일은 미국, 유럽, 호주에서 트렌드가 되어, 그에 따라 면도기 또는 면도 크림의 판매량이 감소하는 반면, 2015년부터 특히 수염 관리 제품의 시장은 4% 이상 증가하고 있으며, 판매되는 수염 관리 제품에는 수염 샴푸, 수염 에센스, 수염 오일, 왁스 등이 있고 그 중에서도 특히 수염 발모제가 가장 많이 팔리고 있다. On the other hand, men are increasingly interested in eyebrows, baldness, mustache, beard and whiskers that darken the sideburns. Specifically, the Hipster beard style has become a trend in the US, Europe and Australia since 2013, and sales of shaving and shaving creams are accordingly decreasing, while the market for beard care products in particular has increased by more than 4% since 2015 The beard care products sold include beard shampoo, beard essence, beard oil, and wax, among which the beard hair growth agent is the most sold.
국내에서도 상기 트렌드에 발맞추어 바르는 눈썹 및 수염 발모제로 일본산 ‘미크로겐’이 판매되고 있으나, 이는 부작용이 보고되어 수입금지 품목으로 지정되었음에도, 대체할 수 있는 제품이 부족하고, 수염과 눈썹을 기르는데 탁월한 효과가 있다고 하여 현재도 여전히 유통 중 이다. ‘미크로겐’에 함유된 남성호르몬 성분은 가임여성에게 노출되었을 때 기형아를 유발하며, 소아에 노출되었을 때 2차 성징 변화시키는 등의 부작용을 일으킬 수 있다.In Japan, 'microgen' is sold as eyebrows and beard hair growth products that are applied to the above trends. However, even though it has been reported that side effects have been reported and it has been designated as an import prohibited item, It is still in circulation because of its excellent effect. Male hormone components in 'microgen' can cause birth defects when exposed to a child of childbearing, and may cause side effects such as secondary sexual change when exposed to children.
이에, 최근에는 눈썹 또는 수염의 발모 및 육모 효과가 뛰어나면서도 부작용의 위험성이 적은 제품이 요구되고 있다. Recently, there has been a demand for a product which is excellent in hair growth and eye hair growth of eyebrows or whiskers and has a low risk of side effects.
본 발명의 일 목적은 안전하면서도 눈썹 또는 수염의 발모 및 육모 촉진 효과가 뛰어난 약학적 조성물을 제공하고자 한다. It is an object of the present invention to provide a pharmaceutical composition which is safe and has an effect of promoting the hair growth and hair growth of the eyebrows or whiskers.
본 발명의 다른 목적은 안전하면서도 눈썹 또는 수염의 발모 및 육모 촉진 효과가 뛰어난 화장료 조성물을 제공하고자 한다. Another object of the present invention is to provide a cosmetic composition which is safe and has excellent hair and hair growth promoting effect of eyebrows or beard.
본 발명의 발명자들은 5-아미노레불린산(5-Aminolevulin Acid, ALA)과 펩타이드를 유효 성분으로 사용하는 경우 눈썹 또는 수염에 대하여 발모 및 육모 효과가 매우 뛰어날 뿐만 아니라, 부가적으로 주름 개선 효과까지 부여함을 발견하여 본 발명에 본 발명에 이르게 되었다. The inventors of the present invention have found that when 5-aminolevulinic acid (ALA) and a peptide are used as an active ingredient, the hair and hair growth effect is excellent not only on the eyebrows or the beard, but also on the wrinkles And found the present invention to the present invention.
본 발명에서 상기 '발모'는 눈꺼풀 또는 피부의 모낭에서 모발이 나는 것을 의미하고, '육모'는 모발의 길이가 길어지는 것(즉, 모발 성장)을 의미한다. In the present invention, the 'hair growth' means that the hair grows in an eyelid or a skin follicle, and the 'hair growth' means that the hair grows longer (that is, hair growth).
본 발명의 일 구현 예에 따르면, 하기 화학식 1로 표시되는 5-아미노레불린산 또는 그의 염; 및 펩타이드를 유효 성분으로 포함하는, 눈썹 또는 수염의 발모 및 육모 촉진용 약학적 조성물에 관한 것이다: According to one embodiment of the present invention, there is provided a 5-aminolevulinic acid or a salt thereof represented by the following formula 1: And a peptide as an active ingredient. The present invention relates to a pharmaceutical composition for promoting hair growth and hair growth of eyebrows or beard.
[화학식 1][Chemical Formula 1]
본 발명에서 상기 화학식 1로 표시되는 5-아미노레불린산은 광역학적 치료(photodynamic therapy, PDT)에 주로 사용되는 광감각제로, 내재성 포피린(porphyrin) 합성 시 중간 산물로 세포에서 생성되는 물질에 해당한다. 본 발명에서 상기 5-아미노레불린산은 탄소 5개의 지방족 화합물로 생물체 내에 클로로필 및 헴(Heme)을 포함하는 모든 테트라피롤(tetrapyrrole) 생합성 과정의 필수적인 전구체로서, 생체 내에서 테트라피롤은 여러 단계를 거쳐서 헤모글로빈, 클로로필, 비타민 B12 등의 조효소인 헴(Heme)으로 생합성될 수 있다. 상기와 같이 본 발명에서 사용하는 5-아미노레불린산은 천연 생체 물질로서 환경 친화적이며 피부에 도포 시 부작용이 적은 장점이 있다. In the present invention, the 5-aminolevulinic acid represented by the above formula (1) is a photosensitizer which is mainly used for photodynamic therapy (PDT). It is an intermediate product in the synthesis of porphyrin, do. In the present invention, the 5-aminolevulinic acid is an essential precursor of the tetrapyrrole biosynthetic process including five chlorinated aliphatic compounds including chlorophyll and heme in the organism. In vivo, tetrapyrrole is obtained through various steps Hemoglobin, chlorophyll, vitamin B12, and the like. As described above, the 5-aminolevulinic acid used in the present invention is environmentally friendly as a natural biomaterial and has a small side effect when applied to skin.
본 발명에서 상기 5-아미노레불린산은 광원이 조사되어 활성화된 눈썹 또는 수염의 발모 및 육모 촉진 효과에 있어 바람직하다. 보다 상세하게 상기 5-아미노레불린산에 광원이 조사되면 상기 5-아미노레불린산이 활성화되어 에너지를 산소 분자에 전달해 에너지를 받은 활성 산소가 생성되어 이하 기재하겠으나 컨쥬게이트 되는 펩타이드의 활성 또한 보다 향상시킬 수 있다. In the present invention, the 5-aminolevulinic acid is preferable for promoting hair growth and hair growth of eyebrows or whiskers activated by irradiation with a light source. More specifically, when the light source is irradiated to the 5-aminolevulinic acid, the 5-aminolevulinic acid is activated to transfer energy to the oxygen molecule to generate active oxygen which is energized, and the activity of the conjugated peptide is further improved .
본 발명에서 상기 5-아미노레불린산에 조사되는 광원은 자연광 또는 PDT 광원일 수 있다. 여기서, 상기 PDT 광원으로는, 펄스 적외선 및 가시광선이 1-3분 동안 조사될 수 있고, 이때 바람직한 파장은 가시광선 영역인 660 nm일 수 있다. 또한, 상기 광원은 당업계에 잘 알려진 소스를 이용할 수 있으며, 예를 들어 LED(ligh-emitting diodes), 여과된 백색광 소스[예컨대, 백색등, IPL(intense pulsed light), 형광 튜브, 등], 저-강도 협소 또는 광범위한 방전 튜브 등일 수 있다. 바람직하게는 본 발명에서 상기 5-아미노레불린산에 LED 광원을 조사하여 활성화시킬 수 있고, 보다 바람직하게는 650~674 nm의 장파장의 LED 광원을 2~10 cm의 이격된 거리에서 조사함으로써 활성화 정도를 가장 높일 수 있다. In the present invention, the light source irradiated to the 5-aminolevulinic acid may be natural light or a PDT light source. Here, as the PDT light source, pulsed infrared rays and visible rays can be irradiated for 1 to 3 minutes, and the preferable wavelength may be 660 nm, which is a visible ray region. Also, the light source may be a source well known in the art, for example, a light emitting diode (LED), a filtered white light source (e.g., white light, intensified pulsed light (IPL) Low-intensity narrowing or a wide discharge tube. Preferably, the 5-aminolevulinic acid may be activated by irradiating the LED light source to the 5-aminolevulinic acid in the present invention, more preferably by irradiating the LED light source with a long wavelength of 650 to 674 nm at a distance of 2 to 10 cm Can be maximized.
본 발명에서 사용되는 상기 5-아미노레불린산을 제조하는 방법은 특별히 제한하지 않으며, 예를 들어 배아세포를 함유한 옥수수추출물의 당 발효 및 분리정제법과 촉매 반응을 이용한 합성법 연구를 진행하여 수득한 ALA 성분을 수득할 수 있으나, 이에 한정되는 것은 아니다.The method for producing the 5-aminolevulinic acid used in the present invention is not particularly limited. For example, a method of fermentation, separation and purification of a corn extract containing an embryo cell, and a synthesis method using a catalytic reaction, The ALA component may be obtained, but is not limited thereto.
또한, 본 발명에서 상기 펩타이드는 알라닌, 글라이신, 라이신, 히스티딘, 세린, 프롤린, 하이드록시프롤린, 트레오닌, 아르기닌, 글루타민, 메티오닌 및 글루탐산으로 이루어진 군 중에서 선택되는 동일하거나 상이한 3개 내지 7개의 아미노산 잔기가 아미드 결합된 펩타이드일 수 있고, 바람직하게는 글라이신-라이신-히스티딘, 글라이신-히스티딘-라이신, 글라이신-프롤린-히드록시프롤린, 알라닌-라이신-히스티딘, 알라닌-히스티딘-라이신, 라이신-히스티딘-라이신, 라이신-아르기닌-라이신, 또는 라이신-트레오닌-트레오닌-라이신-세린일 수 있으나, 보다 바람직하게는 글라이신, 히스티딘 및 라이신의 아미노산 잔기가 글라이신-히스티딘-라이신의 순서로 아미드 결합된 펩타이드일 수 있다. In addition, in the present invention, the peptide includes 3 to 7 amino acid residues which are the same or different from each other selected from the group consisting of alanine, glycine, lysine, histidine, serine, proline, hydroxyproline, threonine, arginine, glutamine, methionine and glutamic acid Amidine-bonded peptide, preferably glycine-lysine-histidine, glycine-histidine-lysine, glycine-proline-hydroxyproline, alanine-lysine-histidine, alanine-histidine-lysine, lysine- -Arginine-lysine, or lysine-threonine-threonine-lysine-serine, but more preferably the amino acid residues of glycine, histidine and lysine may be amide bonded in the order of glycine-histidine-lysine.
본 발명에서 상기 광감각제인 5-아미노레불린산과 펩타이드는 컨쥬게이트 된 것, 보다 바람직하게는 공유 결합을 통해 결합된 것이 피부 침투력을 높이면서 눈썹 또는 수염의 발모 및 육모를 현저하게 촉진시킬 수 있어 바람직하다.In the present invention, the 5-aminolevulinic acid and the peptide which are conjugated through the covalent bond, 5-aminolevulinic acid and the 5'-aminolevulinic acid may significantly promote the hair growth and hair growth of eyebrows or whiskers while enhancing skin penetration desirable.
본 명세서에서 용어 "펩타이드"는 펩타이드 결합에 의해 아미노산 잔기들이 서로 결합되어 형성된 선형의 분자를 의미한다. 본 발명의 펩타이드는 당업계에 공지된 화학적 합성 방법, 특히 고상 합성 기술(solid-phase synthesis techniques)에 따라 제조될 수 있다(Merrifield, J. Amer. Chem. Soc. 85:2149-54(1963); Stewart, etal., SolidPhasePeptideSynthesis, 2nd. ed., Pierce Chem. Co.: Rockford, 111(1984)).As used herein, the term " peptide " refers to a linear molecule formed by peptide bonds and amino acid residues joined together. The peptides of the present invention can be prepared according to chemical synthesis methods known in the art, particularly solid-phase synthesis techniques (Merrifield, J. Amer. Chem. Soc. 85: 2149-54 (1963) ; Stewart, et al., Solid Phosphate Synthesis, 2nd ed., Pierce Chem. Co .: Rockford, 111 (1984)).
또한, 본 발명에서 상기 펩타이드의 말단은 아세틸기, 플루오레닐 메톡시 카르보닐기, 포르밀기, 팔미토일기, 미리스틸기, 스테아릴기 및 폴리에틸렌글리콜(PEG)로 구성된 군으로부터 선택되는 보호기가 결합될 수 있으며, 상기 변형은 천연(naturally occurring) 펩타이드 보다 안정성이 높은 펩타이드를 제공할 수 있다.Also, in the present invention, the terminal of the peptide is bound to a protecting group selected from the group consisting of an acetyl group, a fluorenylmethoxycarbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group and a polyethylene glycol (PEG) And these modifications can provide peptides that are more stable than naturally occurring peptides.
본 발명에서 상기와 같이 제공되는 5-아미노레불린산과 펩타이드의 컨쥬게이트 화합물은 β-카테닌, Wnt10b(Wigless related MMTV integration site 10b) 및 Ki-67의 발현을 증가시킴으로써 모낭의 발생 및 모발 성장에 중추적 역할을 하는 것으로 밝혀진 Wnt/β-카테닌 신호전달계를 활성화시켜 최종적으로는 인체에 존재하는 모발 중에서도 특히 눈썹과 수염의 발모 또는 육모를 효과적으로 촉진시킬 수 있다. The conjugate compound of 5-aminolevulinic acid and peptide provided as described above in the present invention increases the expression of? -Catenin, Wnt101 related to
뿐만 아니라 본 발명의 상기 5-아미노레불린산과 펩타이드의 컨쥬게이트 화합물은 MMP2 활성을 저해하여 도포되는 부위의 피부 주름 생성을 억제하고 피부 탄력 또한 개선할 수 있다. 여기서 상기 'MMP-2'는 젤라티네이즈 A(gelatinase A) 또는 72 kDa 젤라티네이즈라고도 불리우며, 피부 세포간질 (ECM) 성분들 중 젤라틴, 콜라겐 타입 lV과 타입 V에 대한 분해 활성이 알려져 있다. 따라서 MMP-2 활성을 저해하는 정도가 클수록 주름 형성에 대한 보호 효과가 크며, 젤라틴과 콜라겐을 유지하여 피부의 탄력 등을 개선시킬 수 있다. In addition, the conjugate compound of 5-aminolevulinic acid and peptide of the present invention inhibits MMP2 activity, thereby suppressing the formation of skin wrinkles and improving skin elasticity. Herein, MMP-2 is also known as gelatinase A or 72 kDa gelatinase, and it is known that the degradation activity of gelatin, collagen type 1V and type V among the components of skin cell stroma (ECM) is known. Therefore, the greater the degree of inhibition of MMP-2 activity, the greater the protective effect against wrinkle formation, and the elasticity of skin can be improved by maintaining gelatin and collagen.
본 발명에 있어서, 상기 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be in the form of a capsule, a tablet, a granule, an injection, an ointment, a powder or a drink, and the pharmaceutical composition may be a human.
본 발명의 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학적 조성물은 약제적으로 허용 가능한 담체를 포함할 수 있다. 약제학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형할 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral preparations such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories and sterilized injection solutions according to a conventional method, . The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration. A solubilizing agent, an isotonic agent, a stabilizer and the like may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with a pharmaceutically acceptable carrier as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In the case of injections, they may be formulated in unit dosage ampoules or in multiple dosage forms have. Other, solutions, suspensions, tablets, capsules, sustained-release preparations and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.
본 발명에 따른 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, , Sublingual or rectal. Oral or parenteral administration is preferred.
본 발명에서, "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.
본 발명의 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 약학 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, And the dose of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the mode of administration, the route of administration and the period of time, and is preferably from 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries and suspensions.
본 발명의 다른 구현 예에 따르면, 하기 화학식 1로 표시되는 5-아미노레불린산 또는 그의 염; 및 펩타이드를 유효 성분으로 포함하는, 눈썹 또는 수염의 발모 및 육모 촉진용 화장료 조성물에 관한 것이다: According to another embodiment of the present invention, there is provided a 5-aminolevulinic acid represented by the following general formula (1) or a salt thereof; And a peptide as an active ingredient. The present invention relates to a cosmetic composition for promoting the hair growth and hair growth of eyebrows or beard,
[화학식 1][Chemical Formula 1]
본 발명에서 상기 화학식 1로 표시되는 5-아미노레불린산은 테트라피롤(tetrapyrrole) 생합성 과정에서 생성되는 것으로 천연 생체 물질에 해당하는 바 환경 친화적이며 피부에 도포 시 부작용이 적은 장점이 있다.In the present invention, the 5-aminolevulinic acid represented by the above formula (1) is produced in the process of tetrapyrrole biosynthesis, which is a natural biomaterial and is environmentally friendly and has a small side effect when applied to skin.
본 발명에서 상기 5-아미노레불린산은 광원이 조사되어 활성화된 것이 눈썹 또는 수염의 발모 및 육모 촉진 효과에 있어 바람직하다. 본 발명에서 상기 5-아미노레불린산에 조사되는 광원은 자연광 또는 PDT 광원일 수 있으나, 바람직하게는 LED 광원일 수 있고, 보다 바람직하게는 650~674 nm의 장파장의 LED 광원을 2~10 cm의 이격된 거리에서 조사함으로써 활성화 정도를 가장 높일 수 있다. In the present invention, the 5-aminolevulinic acid is preferably irradiated with a light source to enhance eyebrows or hair growth and promote hair growth. In the present invention, the light source irradiated to the 5-aminolevulinic acid may be a natural light or a PDT light source, but may preferably be an LED light source, more preferably an LED light source having a long wavelength of 650 to 674 nm, The activation level can be maximized.
또한, 본 발명에서 상기 펩타이드는 알라닌, 글라이신, 라이신, 히스티딘, 세린, 프롤린, 하이드록시프롤린, 트레오닌, 아르기닌, 글루타민, 메티오닌 및 글루탐산으로 이루어진 군 중에서 선택되는 동일하거나 상이한 3개 내지 7개의 아미노산 잔기가 아미드 결합된 펩타이드일 수 있고, 바람직하게는 글라이신-라이신-히스티딘, 글라이신-히스티딘-라이신, 글라이신-프롤린-히드록시프롤린, 알라닌-라이신-히스티딘, 알라닌-히스티딘-라이신, 라이신-히스티딘-라이신, 라이신-아르기닌-라이신, 또는 라이신-트레오닌-트레오닌-라이신-세린일 수 있으나, 보다 바람직하게는 글라이신, 히스티딘 및 라이신의 아미노산 잔기가 글라이신-히스티딘-라이신의 순서로 아미드 결합된 펩타이드일 수 있다. In addition, in the present invention, the peptide includes 3 to 7 amino acid residues which are the same or different from each other selected from the group consisting of alanine, glycine, lysine, histidine, serine, proline, hydroxyproline, threonine, arginine, glutamine, methionine and glutamic acid Amidine-bonded peptide, preferably glycine-lysine-histidine, glycine-histidine-lysine, glycine-proline-hydroxyproline, alanine-lysine-histidine, alanine-histidine-lysine, lysine- -Arginine-lysine, or lysine-threonine-threonine-lysine-serine, but more preferably the amino acid residues of glycine, histidine and lysine may be amide bonded in the order of glycine-histidine-lysine.
본 발명에서 상기 광감각제인 5-아미노레불린산과 펩타이드는 공유 결합을 통해 컨쥬게이트된 것이 피부 침투력을 높이면서 눈썹 또는 수염의 발모 및 육모를 현저하게 촉진시킬 수 있어 바람직하다.In the present invention, the 5-aminolevulinic acid and the peptide, which are conjugated through covalent bonding, are preferred because they increase the penetration of the skin and significantly promote the hair growth and hair growth of the eyebrows or whiskers.
또한, 본 발명에서 상기 펩타이드의 말단은 아세틸기, 플루오레닐 메톡시 카르보닐기, 포르밀기, 팔미토일기, 미리스틸기, 스테아릴기 및 폴리에틸렌글리콜(PEG)로 구성된 군으로부터 선택되는 보호기가 결합될 수 있으며, 상기 변형은 천연(naturally occurring) 펩타이드 보다 안정성이 높은 펩타이드를 제공할 수 있다.Also, in the present invention, the terminal of the peptide is bound to a protecting group selected from the group consisting of an acetyl group, a fluorenylmethoxycarbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group and a polyethylene glycol (PEG) And these modifications can provide peptides that are more stable than naturally occurring peptides.
본 발명에서 상기와 같이 제공되는 5-아미노레불린산과 펩타이드의 컨쥬게이트 화합물은 인체에 존재하는 모발 중에서도 특히 눈썹과 수염의 발모 또는 육모를 촉진하는 효과가 뛰어날 뿐만 아니라, 이와 함께 MMP2 활성을 저해하여 도포되는 부위의 피부 주름 또한 개선할 수 있다. In the present invention, the conjugate compound of 5-aminolevulinic acid and peptide provided as described above is excellent not only in promoting the hair growth and hair growth of the eyebrows and whiskers among the hair existing in the human body, but also inhibits the activity of MMP2 It is possible to improve the skin wrinkles of the area to be applied.
본 발명에서 화장료 조성물은 화장수, 영양로션, 영양에센스, 마사지 크림, 미용목욕물첨가제, 바디로션, 바디밀크, 배스오일, 베이비오일, 베이비파우더, 샤워겔, 샤워크림, 선스크린로션, 선스크린크림, 선탠크림, 스킨로션, 스킨크림, 자외선차단용 화장품, 크렌징밀크, 탈모제{화장용}, 페이스 및 바디로션, 페이스 및 바디크림, 피부미백크림, 핸드로션, 헤어로션, 화장용크림, 쟈스민오일, 목욕비누, 물비누, 미용비누, 샴푸, 손세정제(핸드클리너), 약용비누{비의료용}, 크림비누, 페이셜 워시, 전신 세정제, 두피 세정제, 헤어린스, 화장비누, 치아미백용 겔, 치약 등의 형태로 제조될 수 있다. 이를 위해 본 발명의 유효 성분은 화장료 조성물의 제조에 통상적으로 사용하는 용매나, 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The cosmetic composition according to the present invention may be used in cosmetics, nutritional lotions, nutritional essences, massage creams, cosmetic bath additives, body lotions, body milks, bath oils, baby oils, baby powders, shower gels, shower creams, sunscreen lotions, Face and Body Cream, Face and Body Cream, Skin Whitening Cream, Hand Lotion, Hair Lotion, Cosmetic Cream, Jasmine Oil, Face Cream, Skin Cream, Skin Cream, Sunscreen Cosmetics, Bath soap, water soap, soap, shampoo, hand cleanser, medicinal soap {non-medical use}, cream soap, facial wash, whole body cleanser, scalp cleanser, hair rinse, cosmetic soap, tooth whitening gel, . ≪ / RTI > For this purpose, the active ingredient of the present invention may further comprise a solvent commonly used in the production of a cosmetic composition, or a suitable carrier, excipient or diluent.
본 발명의 화장료 조성물 내에 더 추가될 수 있는 용매의 종류는 특별히 한정하지 않으나, 예를 들어, 물, 식염수, DMSO 또는 이들의 조합을 사용할 수 있고, 담체, 부형제 또는 희석제로는 정제수, 오일, 왁스, 지방산, 지방산 알콜, 지방산 에스테르, 계면활성제, 흡습제(humectant), 증점제, 항산화제, 점도 안정화제, 킬레이팅제, 완충제, 저급 알콜 등이 포함되지만, 이에 제한되는 것은 아니다. 또한, 필요에 따라 미백제, 보습제, 비타민, 자외선 차단제, 향수, 염료, 항생제, 항박테리아제, 항진균제를 포함할 수 있다. For example, water, saline solution, DMSO, or a combination thereof may be used. Examples of the carrier, excipient or diluent include purified water, oil, wax But are not limited to, fatty acids, fatty acid alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols and the like. Further, if necessary, it may contain a whitening agent, a moisturizing agent, a vitamin, an ultraviolet screening agent, a perfume, a dye, an antibiotic, an antibacterial agent, and an antifungal agent.
상기 오일로서는 수소화 식물성유, 피마자유, 면실유, 올리브유, 야자인유, 호호바유, 아보카도유가 이용될 수 있으며, 왁스로는 밀랍, 경랍, 카르나우바, 칸델릴라, 몬탄, 세레신, 액체 파라핀, 라놀린이 이용될 수 있다.As the oil, hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil and avocado oil may be used. Examples of the wax include wax, wax, carnauba, candelilla, montan, ceresin, liquid paraffin, Can be used.
지방산으로는 스테아르산, 리놀레산, 리놀렌산, 올레산이 이용될 수 있고, 지방산 알콜로는 세틸 알콜, 옥틸 도데칸올, 올레일 알콜, 판텐올, 라놀린 알콜, 스테아릴 알콜, 헥사데칸올이 이용될 수 있으며 지방산 에스테르로는 이소프로필 미리스테이트, 이소프로필 팔미테이트, 부틸 스테아레이트가 이용될 수 있다. 계면 활성제로는 당업계에 알려진 양이온 계면활성제, 음이온 계면활성제 및 비이온성 계면활성제가 사용가능하며 가능한 한 천연물 유래의 계면활성제가 바람직하다. As the fatty acid, stearic acid, linoleic acid, linolenic acid and oleic acid may be used. As the fatty acid alcohol, cetyl alcohol, octyldodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol and hexadecanol may be used As fatty acid esters, isopropyl myristate, isopropyl palmitate, and butyl stearate may be used. As the surfactant, a cationic surfactant, an anionic surfactant and a nonionic surfactant known in the art can be used, and a surfactant derived from a natural material is preferably used.
그 외에도 화장품 분야에서 널리 알려진 흡습제, 증점제, 항산화제 등을 포함할 수 있으며, 이들의 종류와 양은 당업계에 공지된 바에 따른다. In addition, it may contain a hygroscopic agent, a thickening agent, an antioxidant and the like widely known in the field of cosmetics, and the kind and amount thereof are well known in the art.
본 발명에서 제공하는 조성물은 피부 침투력이 우수하며, 인체의 모발 중에서도 눈썹 및 수염의 발모 및 육모 촉진 효과가 매우 뛰어나고 동시에 도포되는 피부의 주름 형성을 억제하며 탄력을 증진시킬 수 있다. The composition provided in the present invention is excellent in skin penetration ability and is highly effective in promoting the hair growth and hair growth of eyebrows and whiskers among human hair, and can also suppress the formation of wrinkles of the skin to be applied and improve the elasticity.
또한, 본 발명의 조성물은 천연 생체 물질을 이용함으로써 종래에 눈썹 또는 수염 발모제에서 문제되었던 부작용의 위험성을 현저히 줄일 수 있다. In addition, the composition of the present invention can significantly reduce the risk of adverse effects conventionally encountered with eyebrows or hair growth agents by using natural biomaterials.
도 1은 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 모근을 사진으로 나타낸 것이다.
도 2는 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 모근의 총 길이 변화를 그래프로 나타낸 것이다.
도 3은 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 모근을 H&E 염색한 후 광학 현미경으로 촬영한 사진을 나타낸 것이다.
도 4는 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 β-카테닌에 대하여 면역 조직 화학 염색을 수행한 후 광학 현미경으로 촬영한 사진을 나타낸 것이다.
도 5는 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 면역 조직 화학 염색을 통하여 눈썹모 전체에 있어서 β-카테닌의 발현 수준을 확인한 사진을 나타낸 것이다.
도 6은 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 면역 조직 화학 염색을 통하여 눈썹모 전체에 있어서 Wnt 10b의 발현 수준을 확인한 사진을 나타낸 것이다.
도 7은 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 면역 조직 화학 염색을 통하여 눈썹모의 모근구 부위에 있어서 Wnt 10b의 발현 수준을 확인한 사진을 나타낸 것이다.
도 8은 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 DAPI 염색을 통하여 눈썹모 전체에 있어서 Ki67의 발현 수준을 확인한 사진을 나타낸 것이다.
도 9는 실시예 1에서 눈썹 모근에 미처리(A군), 본 발명의 일 실시예에 따른 화합물(B군), 미녹시딜(C군)을 처리한 뒤 7일간 배양 후 DAPI 염색을 통하여 눈썹모의 모근구 부위에 있어서 Wnt 10b의 발현 수준을 확인한 사진을 나타낸 것이다.
도 10은 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 모근을 사진으로 나타낸 것이다.
도 11은 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 모근의 총 길이 변화를 그래프로 나타낸 것이다.
도 12는 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 모근을 H&E 염색한 후 광학 현미경으로 촬영한 사진을 나타낸 것이다.
도 13은 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 β-카테닌에 대하여 면역 조직 화학 염색을 수행한 후 광학 현미경으로 촬영한 사진을 나타낸 것이다.
도 14는 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 면역 조직 화학 염색을 통하여 눈썹모 전체에 있어서 β-카테닌의 발현 수준을 확인한 사진을 나타낸 것이다.
도 15는 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 면역 조직 화학 염색을 통하여 눈썹모 전체에 있어서 Wnt 10b의 발현 수준을 확인한 사진을 나타낸 것이다.
도 16은 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 면역 조직 화학 염색을 통하여 눈썹모의 모근구 부위에 있어서 Wnt 10b의 발현 수준을 확인한 사진을 나타낸 것이다.
도 17은 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 DAPI 염색을 통하여 눈썹모 전체에 있어서 Ki67의 발현 수준을 확인한 사진을 나타낸 것이다.
도 18은 실시예 2에서 턱 수염 모근에 미처리(D군), 본 발명의 일 실시예에 따른 화합물(E군), 미녹시딜(F군)을 처리한 뒤 7일간 배양 후 DAPI 염색을 통하여 눈썹모의 모근구 부위에 있어서 Wnt 10b의 발현 수준을 확인한 사진을 나타낸 것이다.
도 19는 실시예 3에서 섬유아 세포주(fibroblast cell line) 및 CCD-986sk 세포에 아데노신(제1군), 레티놀 처리(제2군), 증류수 처리(제3군) 및 본 발명의 일 실시예에 따른 화합물(제4군)을 처리한 뒤 세포 내 MMP-2 효소의 활성 억제 정도를 그래프로 나타낸 것이다. Fig. 1 is a photograph showing hair roots after treatment for seven days, after treatment of untreated eyebrow roots (group A), compounds according to one embodiment of the present invention (group B), and minoxidil (group C) in Example 1. Fig.
Fig. 2 is a graph showing changes in the total length of the hair roots after treatment for seven days, after treating the eyebrow hair roots untreated (group A), the compound according to one embodiment of the present invention (group B), and minoxidil (group C) Respectively.
FIG. 3 is a graph showing the results of the H & E staining of hair roots after the treatment of untreated eyebrow hair (group A), the compound according to one embodiment of the present invention (group B) and minoxidil (group C) It is a picture taken with a microscope.
Fig. 4 is a graph showing the results of a comparison between the results of Fig. 4 and Fig. 4. Fig. 4 is a graph showing the results of a comparison of the results of Fig. And photographs taken by an optical microscope after performing chemical dyeing.
FIG. 5 is a graph showing the results of a comparison between the eyebrow hair roots (group A), the compound according to one embodiment of the present invention (group B), and minoxidil (group C) The photograph shows the expression level of beta -catenin in the parent hair.
FIG. 6 is a graph showing the results of a comparison between the eyebrow hair roots (group A), the compound according to one embodiment of the present invention (group B), and minoxidil (group C) And the expression level of
FIG. 7 is a graph showing the results of a comparison between the eyebrow hair roots (group A), the compound according to one embodiment of the present invention (group B) and minoxidil (group C) The photograph shows the expression level of
Fig. 8 is a graph showing the results of a comparison between the results of Example 1 and Fig. 8. Fig. 8 is a graph showing the results obtained by treating DAPI after untreated eyebrow hair (group A), compound according to one embodiment of the present invention (group B) and minoxidil In which the expression level of Ki67 was confirmed.
FIG. 9 is a graph showing the results of the treatment of eyebrow hair roots (group A), the compound according to one embodiment of the present invention (group B), and minoxidil (group C) after 7 days of DAPI staining, And the expression level of
FIG. 10 is a photograph showing hair roots after treatment for seven days, after treatment of untreated hair of the beard hair (group D), compound according to one embodiment of the present invention (group E) and minoxidil (group F) .
Fig. 11 is a graph showing changes in the total length of the hair roots after treatment for 7 days, after treatment of untreated hairy roots (group D), compounds according to one embodiment of the present invention (group E) and minoxidil (group F) As shown in the graph.
FIG. 12 is a graph showing the results of treatment of hairless hair roots (group D), compounds according to one embodiment of the present invention (group E), and minoxidil (group F) It is a photograph taken with an optical microscope.
FIG. 13 is a graph showing the results of immunosuppression of β-catenin after treatment for 7 days, after treatment of untreated hair (hairpin group D), compound according to one embodiment of the present invention (group E) and minoxidil The photographs taken by an optical microscope after histochemical staining are shown.
FIG. 14 is a graph showing the results of treatment of the hairless hair roots (D group), the compound according to one embodiment of the present invention (E group) and minoxidil (F group) in Example 2 after 7 days of culture and immunohistochemical staining The photograph shows the expression level of beta -catenin in eyebrows parent hair.
Fig. 15 is a graph showing the results of a comparison between the results of Example 2 and Fig. 15 showing the results of treatment of untreated hair of the beard hair (group D), compound (E group) and minoxidil (group F) according to one embodiment of the present invention, And the expression levels of
Fig. 16 is a graph showing the results of treatment of the hairless hair roots (group D), compound (E group) and minoxidil (group F) according to one embodiment of the present invention after 7 days of culturing and immunohistochemical staining FIG. 2 is a photograph showing the level of expression of
FIG. 17 is a graph showing the results of treatment of eyebrows (group D) after DAPI staining after treatment of untreated hair (hairpin group D), compound according to one embodiment of the present invention (group E) and minoxidil And the expression level of Ki67 was confirmed in the whole.
FIG. 18 is a graph showing the results of a comparison between the untreated hair (hairpin group D), the compound according to one embodiment of the present invention (group E) and minoxidil (group F) after 7 days of DAPI staining, And the expression levels of
FIG. 19 is a graph showing the results of a comparison between the fibroblast cell line and the CCD-986sk cell in Example 3 with adenosine (Group 1), retinol treatment (Group 2), distilled water treatment (Group 3) (Group 4), and the degree of inhibition of the activity of intracellular MMP-2 enzyme.
이하, 본 발명의 바람직한 실시형태들을 설명한다. 그러나, 본 발명의 실시형태는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한, 본 발명의 실시형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다.Hereinafter, preferred embodiments of the present invention will be described. However, the embodiments of the present invention can be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Further, the embodiments of the present invention are provided to more fully explain the present invention to those skilled in the art.
실시예Example
[[ 준비예Preparation Example 1] 5- 1] 5- 아미노레불린산Aminolevulinic acid -- 펩타이드(글라이신-히스티딘-라이신)의Of the peptide (glycine-histidine-lysine) 컨쥬게이트Conjugate 화합물의 제조 Preparation of compounds
필터(0.1 ; Sigma, USA)가 부착된 펩타이드 합성용 유리반응기(대광싸이언스, KOR)에 2-클로로트리틸레진(2-Chlorotrityl resin; MERCK, USA) 14.286 g(치환율, 1.40 mmole/g; 20 mmole), Fmoc-Lys(Boc)-OH 18.742 g(40 mmole; MERCK, USA), DIEA(N,N-diisopropylethylamine) 13.97 ml(80 mmole; MERCK, USA)을 혼합한 후, MC(methylene chloride; MERCK, USA) 400 ml을 첨가하여 5시간 이상 동안 반응시켰다. 상기 반응액에 10 ml 메탄올을 첨가하여 10분 동안 반응시킨 후 용액을 모두 제거하였다. MC, DMF(N,N-Dimethylformamide; MERCK, USA 및 메탄올로 순차적으로 레진을 세척한 후 20% 피페리딘(MERCK, USA) 400 ml을 가하여 20분 동안 2회 반응시켜 Fmoc기를 제거하였다. Fmoc기를 제거한 후 다시 MC 및 DMF로 트리틸레진을 연속적으로 세척하여 용액을 모두 제거하였다. Fmoc기가 제거되는 동안 Fmoc-His(Trt)-OH 24.789 g(40 mmole; MERCK, USA), HOBt(1-hydroxybenzotriazole; MERCK, USA) 5.40 g(40 mmole), DIC(diisopropylcarbodiimide; MERCK, USA) 6.19 ml(40 mmole)을 100 ml의 DMF에 완전히 녹여 40분 동안 활성화시켰다. 활성화시킨 Fmoc-His(Trt)-OH/DMF 용액을 Fmoc을 제거한 레진에 첨가한 후 300 ml의 DMF를 더 첨가하여 5시간 이상 동안 반응시켰다. 5시간 이상 반응 후 용액을 완전히 제거하고, MC 및 DMF로 레진을 연속적으로 세척한 후 20% 피페리딘 400 ml을 가하여 20분 동안 2회 반응시켜 Fmoc기를 제거하였다. Fmoc기를 제거한 후 다시 MC 및 DMF로 트리틸레진을 연속적으로 세척하고 용액을 모두 제거하였다. Fmoc기가 제거되는 동안 Fmoc-Gly-OH 11.892 g(40 mmole; MERCK, USA), HOBt 5.40 g(40 mmole), DIC 6.19 ml(40 mmole)을 100 ml의 DMF에 완전히 녹여 40분 동안 활성화시켰다. 활성화시킨 Fmoc-Gly-OH/DMF 용액을 Fmoc을 제거한 레진에 첨가한 후 300 ml의 DMF를 더 첨가하여 5시간 이상 동안 반응시켰다. 5시간 이상 반응 후 용액을 완전히 제거하고, MC 및 DMF로 레진을 연속적으로 세척한 후 20% 피페리딘 400 ml을 가하여 20분 동안 2회 반응시켜 Fmoc기를 제거하였다. Fmoc기를 제거한 후 다시 MC 및 DMF로 트리틸레진을 세척하고 용액을 모두 제거하였다. Fmoc기가 제거되는 동안 5-아미노레불린산 5.245 g(40 mmole; Sigma, St. Louis, mo, USA)를 100 ml의 DMF에 완전히 녹여 40분 동안 활성화시켰다. 상기 활성화시킨 5-아미노레불린산/DMF 용액을 Fmoc을 제거한 레진에 첨가한 후 300 ml의 DMF를 더 첨가하여 5시간 이상 동안 반응시켰다. 5시간 이상 반응 후 용액을 완전히 제거하고, MC, DMF 및 MC로 레진을 세척한 후 용액을 완전히 제거하였다. 용액을 제거한 레진에 95% TFA(Trifluoroacetic acid) 수용액(MERCK, USA) 600-800 ml 가하여 3시간 동안 반응시킨 후 용액을 별도의 용기에 수집하였다. 냉장(4℃) 에테르(SIGMA, USA)에 수집한 용액을 천천히 가하여 침전을 유도하고, 냉동실에 20분 동안 방치하여 용액 속의 펩타이드가 완전히 침전되도록 하였다. 상기 침전된 펩타이드는 원심분리를 통해 회수하여 남아있는 에테르를 완전히 기화시킨 후 고속액체크로마토그래피(High performance Liquid chromatography, HPLC; WATERS, USA)를 통해 분석 및 정제하였다.14.286 g (substitution ratio, 1.40 mmole / g; 20: 1) of 2-chlorotrityl resin (MERCK, USA) was added to a glass reactor for the synthesis of peptides (Sigma, USA) (methylene chloride, Molecular Cloning, USA) were mixed with 18.742 g (40 mmole; MERCK, USA) of Fmoc-Lys (Boc) -OH and 13.97 ml (80 mmole; MERCK, USA) of DIEA (N-diisopropylethylamine). MERCK, USA) was added and reacted for 5 hours or more. 10 ml of methanol was added to the reaction solution, which was then reacted for 10 minutes, and then the solution was completely removed. After the resin was washed sequentially with MC, DMF (N, N-Dimethylformamide, MERCK, USA and methanol), 400 ml of 20% piperidine (MERCK, USA) was added and the reaction was carried out twice for 20 minutes to remove the Fmoc group. (24 mmHg) was added to the reaction mixture, and the reaction was terminated by the addition of DMF to the reaction mixture. 6.9 g (40 mmole) of hydroxybenzotriazole (MERCK, USA) and 6.19 ml (40 mmole) of DIC (diisopropylcarbodiimide; MERCK, USA) were completely dissolved in 100 ml of DMF for 40 minutes. OH / DMF solution was added to the Fmoc-free resin, and 300 ml of DMF was further added for 5 hours or more. After the reaction was completed for more than 5 hours, the solution was completely removed and the resin was continuously washed with MC and DMF 400 ml of 20% piperidine was added and the mixture was reacted twice for 20 minutes to remove the Fmoc group. After removing the Fmoc group (40 mmole; MERCK, USA), 5.40 g (40 mmole) of HOBt, and 6.19 g of DIC 6.19 (40 mmole), while the Fmoc group was removed. (40 mmole) was completely dissolved in 100 ml of DMF and activated for 40 minutes. The activated Fmoc-Gly-OH / DMF solution was added to the Fmoc-free resin, and 300 ml of DMF was further added thereto for more than 5 hours After the reaction was completed for more than 5 hours, the solution was completely removed, and the resin was washed successively with MC and DMF, and 400 ml of 20% piperidine was added thereto, followed by reaction for 20 minutes twice to remove the Fmoc group. Tritile resin was again washed with MC and DMF and the solution was removed. 5.245 g (40 mmole; Sigma, St. Louis, MO, USA) of 5-aminolevulinic acid was completely dissolved in 100 ml of DMF and allowed to react for 40 minutes while the Fmoc group was removed. The activated 5-aminolevulinic acid / DMF solution was added to the resin from which the Fmoc was removed, and 300 ml of DMF was further added thereto for reaction for 5 hours or more. After the reaction for more than 5 hours, the solution was completely removed and the resin was washed with MC, DMF and MC, and the solution was completely removed. After removing the solution, 600-800 ml of a solution of 95% TFA (Trifluoroacetic acid) (MERCK, USA) was added and reacted for 3 hours. The solution was collected in a separate container. The solution collected in cold (4 ° C) ether (SIGMA, USA) was slowly added to induce precipitation and left in the freezer for 20 minutes to allow the peptide in the solution to settle completely. The precipitated peptide was recovered through centrifugation and the remaining ether was completely vaporized and analyzed and purified through high performance liquid chromatography (HPLC; WATERS, USA).
[실시예 1] 눈썹의 육모 효과 확인[Example 1] Confirmation of eye hair hair growth effect
1. 모근 수집 및 처리 1. Hair root collection and processing
2명의 실험자로부터 총 25개의 눈썹 모근을 채취한 뒤 총 길이를 동일하게 맞춘 후 모근 10개(A군), 10개(B군) 및 5개(C군)의 3군으로 분류하였다. 이후, William E 배지에 상기 3군의 모근을 접종한 뒤 하기 표 1의 조건으로 처리하고 상기 배지에 LED를 5분 동안 처리한 뒤 7일간 배양하였다. A total of 25 eyebrow hair roots were collected from 2 experimental subjects and the total length was sampled. The hair roots were divided into 10 groups (group A), 10 groups (group B), and 5 groups (group C). Then, the hair roots of
2. 모발의 길이 변화 2. Length of hair change
7일 경과 후 각 군별 모근의 변화를 촬영한 사진을 도 1에 나타내었고, 길이를 측정하여 도 2에 그래프로 나타내었다. 또한, 모근을 헤마톡실린 및 에오신(H&E)으로 염색한 뒤 통상적인 방법에 따라 탈수와 투명화를 거친 후 봉입하여 광학현미경으로 관찰한 결과를 도 3에 나타내었다. FIG. 1 shows photographs of changes in hair roots after 7 days, and the lengths of the photographs are shown in FIG. 2 as a graph. In addition, hair roots were dyed with hematoxylin and eosin (H & E), dehydrated and transparentized according to a conventional method, sealed and observed with an optical microscope, and the results are shown in Fig.
도 1 내지 3에서 보는 바와 같이, 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물을 처리한 경우 미처리 또는 미녹시딜을 처리한 경우보다 눈썹 모발의 육모 효과가 현저히 뛰어난 것을 볼 수 있었다. As shown in FIGS. 1 to 3, when the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention is treated, eye hair growth effect of eyebrow hair is lower than that of untreated or minoxidil I could see something remarkable.
3. β-카테닌 및 Wnt 10b의 발현 수준 변화3. Changes in expression levels of β-catenin and Wnt 10b
모발 성장과 관련된 β-카테닌 및 Wnt 10b의 발현 수준의 변화를 관찰하기 위하여, 상기와 같이 7일 배양 후 각 군별 모근에 대하여 β-카테닌 및 Wnt 10b 각각에 대한 1차 항체를 각각 1:50으로 희석한 후 조직 절편에 가하고 실온에서 12시간 동안 반응시켰다. 1차 항체의 희석은 0.1M 포스페이트 완충액(PB)에 1% 정상 고트 혈청(Vector Laboratories Inc.)과 0.3% Triton X-100(Sigma)을 혼합하여 사용하였다. 조직 절편을 실온에서 15분간 2회 0.1M PB로 세척하고, 다시 1:200으로 희석된 2차 항체[비오틴화 항-래빗 IgG(Vector Laboratories Inc.)]와 1시간 동안 실온에서 반응시켰다. 다시 0.1M PB로 15분간 2회의 수세과정을 거친 후 퍼옥시다아제가 표지된 ABC(avidin-biotin complexex) 용액에 담가 실온에서 1시간 동안 반응시켰다. 그 후 다시 0.1M PB로 15분간 2회 수세하고 30 mg의 3-3′디아미노벤지딘(diaminobenzidine)을 150 ml의 0.1M PB에 녹인 용액에서 5분간 반응시킨 후 과산화수소를 0.005% 농도로 첨가하여 약 5분간 갈색 발색반응을 시행하였다. 반응이 끝난 조직들은 다시 0.1M PB로 여러 차례 수세하고 헤마톡실린으로 20초간 대조 염색한 후, 탈수와 투명화를 거친 뒤 봉입하여 광학현미경으로 관찰한 결과를 도 4 내지 7에 나타내었다.In order to observe the changes in the expression levels of β-catenin and Wnt 10b associated with hair growth, the primary antibody against each of β-catenin and Wnt 10b was 1:50 After dilution, the sections were added to tissue sections and allowed to react at room temperature for 12 hours. Dilution of the primary antibody was performed by mixing 1% normal goat serum (Vector Laboratories Inc.) and 0.3% Triton X-100 (Sigma) in 0.1 M phosphate buffer (PB) The tissue sections were washed with 0.1 M PB twice for 15 min at room temperature and then reacted with secondary antibody (biotinylated anti-rabbit IgG (Vector Laboratories Inc.)) diluted 1: 200 for 1 h at room temperature. After washing twice with 0.1 M PB for 15 minutes, the cells were immersed in peroxidase-labeled ABC (avidin-biotin complexex) solution and reacted at room temperature for 1 hour. After washing with 0.1 M PB for 15 minutes twice, 30 mg of 3-3 'diaminobenzidine was dissolved in 150 ml of 0.1 M PB for 5 minutes. Then, hydrogen peroxide was added at a concentration of 0.005% Brown color reaction was performed for about 5 minutes. After completion of the reaction, the tissues were washed again with 0.1 M PB several times, counterstained with hematoxylin for 20 seconds, dehydrated and clarified, sealed, and observed with an optical microscope, and the results are shown in FIGS.
도 4 내지 7에서 보는 바와 같이, 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물을 처리한 경우가 미처리 또는 미녹시딜을 처리한 경우보다, 발모(또는 육모) 촉진 메카니즘으로 알려져 있는 Wnt/β-카테닌 신호전달체계가 활성화됨에 따라 β-카테닌 및 Wnt 10b의 발현 수준이 유의적으로 증가한 것을 볼 수 있었다. As shown in FIGS. 4 to 7, the treatment with the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention is more effective than the treatment with untreated or minoxidil, ) Promoting mechanism of the Wnt / β-catenin signaling pathway, the expression levels of β-catenin and Wnt 10b were significantly increased.
4. Ki67의 발현 수준 변화4. Expression level change of Ki67
7일 배양 후 각 군별 모근을 4 % 포름알데하이드로 고정하고, 모근 조직의 파라핀 제작 후, 3㎛ 두께로 절단한 조직을 슬라이드에 붙이고 파라핀 제거 및 재수화 과정(deparaffinize and rehydrate)을 실시하였다. 이 후 항체 회수(antigen retrieval; citrate buffer, pH 6.0)하고, 0.1% 트리톤(Triton) X-100을 처리하고 정상 당나귀 혈청(normal donkey serum)을 블록킹(blocking)을 거치고 1차 항체를 1:250으로 24시간 처리하였다. 이후 2차 항체를 이용하여 1시간 동안 처리하고 DAPI 염색을 5분간 진행하였다. 벡타실드 마운팅(vectashield mounting medium)제를 이용하여 슬라이드에 고정시킨 후 공초점 현미경(Confocal Microscope)으로 관찰한 결과를 도 8 및 9에 나타내었다. After culturing for 7 days, the hair roots of each group were fixed with 4% formaldehyde. After making the paraffin of the hair follicle tissue, the tissue cut to 3 μm thickness was attached to the slide, and the paraffin removal and rehydration process (deparaffinize and rehydrate) were performed. The cells were treated with 0.1% Triton X-100, blocked with normal donkey serum, and incubated with primary antibody at a ratio of 1: 250 For 24 hours. Then, the cells were treated with a secondary antibody for 1 hour and DAPI staining was performed for 5 minutes. 8 and 9 show the result of observation with a confocal microscope after fixation on a slide using a vector shield mounting medium (vectashield mounting medium).
도 8 및 9에서 보는 바와 같이, 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물을 처리한 경우 미처리 또는 미녹시딜을 처리한 경우보다, 세포 성장을 나타내는 마커인 Ki67의 발현 수준이 증가한 것을 볼 수 있었다. As shown in FIGS. 8 and 9, when the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention was treated, The expression level of Ki67 was increased.
이를 통하여 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물이 눈썹에 대한 발모 및 육모 촉진 효과가 현저히 뛰어남을 확인할 수 있었다. Thus, it was confirmed that the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention is remarkably excellent in hair growth and hair growth promoting effect on eyebrows.
[실시예 2] 수염의 육모 효과 확인[Example 2] Confirmation of hair growth effect of beard
1. 모근 수집 및 처리 1. Hair root collection and processing
4명의 실험자로부터 총 13개의 턱수염 모근을 채취한 뒤 총 길이를 동일하게 맞춘 후 모근 5개(D군), 4개(E군) 및 4개(E군)의 3군으로 분류하였다. 이후, William E 배지에 상기 3군의 모근을 접종한 뒤 하기 표 2의 조건으로 처리하고 상기 배지에 LED를 5분 동안 처리한 뒤 7일간 배양하였다. A total of 13 beard hair roots were sampled from 4 patients and the total length was the same. Five groups of hair follicles (Group D), 4 (E group) and 4 (E group) were classified. Then, the hair roots of
2. 모발의 길이 변화 2. Length of hair change
7일 경과 후 각 군별 모근의 변화를 촬영한 사진을 도 10에 나타내었고, 길이를 측정하여 도 11에 그래프로 나타내었다. 또한, 모근을 헤마톡실린 및 에오신(H&E)으로 염색한 뒤 통상적인 방법에 따라 탈수와 투명화를 거친 후 봉입하여 광학현미경으로 관찰한 결과를 도 12에 나타내었다. FIG. 10 shows photographs of changes in hair roots of each group after 7 days, and the length was measured and shown in FIG. 11 as a graph. The hair roots were dyed with hematoxylin and eosin (H & E), dehydrated and transparentized according to a conventional method, sealed, and observed with an optical microscope. The results are shown in FIG.
도 10 내지 12에서 보는 바와 같이, 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물을 처리한 경우 미처리 또는 미녹시딜을 처리한 경우보다 수염 모발의 육모 효과가 현저히 뛰어난 것을 볼 수 있었다. As shown in FIGS. 10 to 12, when the conjugate compound of the 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention was treated, hair growth of the hair of hair was lower than that of untreated or minoxidil I could see something remarkable.
3. β-카테닌 및 Wnt 10b의 발현 수준 변화3. Changes in expression levels of β-catenin and Wnt 10b
모발 성장과 관련된 β-카테닌 및 Wnt 10b의 발현 수준의 변화를 관찰하기 위하여, 상기와 같이 7일 배양 후 각 군별 모근에 대하여 β-카테닌 및 Wnt 10b 각각에 대한 1차 항체를 각각 1:50으로 희석한 후 조직절편에 가하고 실온에서 12시간 동안 반응시켰다. 1차 항체의 희석은 0.1M 포스페이트 완충액(PB)에 1% 정상 고트 혈청(Vector Laboratories Inc.)과 0.3% Triton X-100(Sigma)을 혼합하여 사용하였다. 조직절편을 실온에서 15분간 2회 0.1M PB로 세척하고, 다시 1:200으로 희석된 2차 항체[비오틴화 항-래빗 IgG(Vector Laboratories Inc.)]와 1시간 동안 실온에서 반응시켰다. 다시 0.1M PB로 15분간 2회의 수세과정을 거친 후 퍼옥시다아제가 표지된 ABC(avidin-biotin complexex) 용액에 담가 실온에서 1시간 동안 반응시켰다. 그 후 다시 0.1M PB로 15분간 2회 수세하고 30 mg의 3-3′디아미노벤지딘(diaminobenzidine)을 150 ml의 0.1M PB에 녹인 용액에서 5분간 반응시킨 후 과산화수소를 0.005% 농도로 첨가하여 약 5분간 갈색 발색반응을 시행하였다. 반응이 끝난 조직들은 다시 0.1M PB로 여러 차례 수세하고 헤마톡실린으로 20초간 대조 염색한 후, 탈수와 투명화를 거친 뒤 봉입하여 광학현미경으로 관찰한 결과를 도 13 내지 16에 나타내었다.In order to observe the changes in the expression levels of β-catenin and Wnt 10b associated with hair growth, the primary antibody against each of β-catenin and Wnt 10b was 1:50 After dilution, the sections were added to tissue sections and allowed to react at room temperature for 12 hours. Dilution of the primary antibody was performed by mixing 1% normal goat serum (Vector Laboratories Inc.) and 0.3% Triton X-100 (Sigma) in 0.1 M phosphate buffer (PB) The tissue sections were washed with 0.1 M PB twice for 15 min at room temperature and then reacted with secondary antibody (biotinylated anti-rabbit IgG (Vector Laboratories Inc.)) diluted 1: 200 for 1 h at room temperature. After washing twice with 0.1 M PB for 15 minutes, the cells were immersed in peroxidase-labeled ABC (avidin-biotin complexex) solution and reacted at room temperature for 1 hour. After washing with 0.1 M PB for 15 minutes twice, 30 mg of 3-3 'diaminobenzidine was dissolved in 150 ml of 0.1 M PB for 5 minutes. Then, hydrogen peroxide was added at a concentration of 0.005% Brown color reaction was performed for about 5 minutes. After the reaction, the tissues were washed again with 0.1 M PB several times, counterstained with hematoxylin for 20 seconds, dehydrated and clarified, sealed, and observed with an optical microscope. The results are shown in FIGS.
도 13 내지 16에서 보는 바와 같이, 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물을 처리한 경우가 미처리 또는 미녹시딜을 처리한 경우보다, 발모(또는 육모) 촉진 메카니즘으로 알려져 있는 Wnt/β-카테닌 신호전달체계가 활성화됨에 따라 β-카테닌 및 Wnt 10b의 발현 수준이 유의적으로 증가한 것을 볼 수 있었다. As shown in FIGS. 13 to 16, the treatment with the conjugate compound of the 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention is more effective than the treatment with untreated or minoxidil, ) Promoting mechanism of the Wnt / β-catenin signaling pathway, the expression levels of β-catenin and Wnt 10b were significantly increased.
4. Ki67의 발현 수준 변화4. Expression level change of Ki67
7일 배양 후 각 군별 모근을 4 % 포름알데하이드로 고정하고, 모근 조직의 파라핀 제작 후, 3㎛ 두께로 절단한 조직을 슬라이드에 붙이고 파라핀 제거 및 재수화 과정(deparaffinize and rehydrate)을 실시하였다. 이 후 항체 회수(antigen retrieval; citrate buffer, pH 6.0)하고, 0.1% 트리톤(Triton) X-100을 처리하고 정상 당나귀 혈청(normal donkey serum)을 블록킹(blocking)을 거치고 1차 항체를 1:250으로 24시간 처리하였다. 이후 2차 항체를 이용하여 1시간 동안 처리하고 DAPI 염색을 5분간 진행하였다. 벡타실드 마운팅(vectashield mounting medium)제를 이용하여 슬라이드에 고정시킨 후 공초점 현미경(Confocal Microscope)으로 관찰한 결과를 도 17 및 18에 나타내었다. After culturing for 7 days, the hair roots of each group were fixed with 4% formaldehyde. After making the paraffin of the hair follicle tissue, the tissue cut to 3 μm thickness was attached to the slide, and the paraffin removal and rehydration process (deparaffinize and rehydrate) were performed. The cells were treated with 0.1% Triton X-100, blocked with normal donkey serum, and incubated with primary antibody at a ratio of 1: 250 For 24 hours. Then, the cells were treated with a secondary antibody for 1 hour and DAPI staining was performed for 5 minutes. The results were observed with a confocal microscope after being fixed on a slide using a vector shield mounting medium (Vectashield mounting medium), and the results are shown in FIGS. 17 and 18. FIG.
도 17 및 18에서 보는 바와 같이, 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물을 처리한 경우 미처리 또는 미녹시딜을 처리한 경우보다, 세포 성장을 나타내는 마커인 Ki67의 발현 수준이 증가한 것을 볼 수 있었다. As shown in FIGS. 17 and 18, when the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention was treated, The expression level of Ki67 was increased.
이를 통하여 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물이 수염에 대한 발모 및 육모 촉진 효과가 현저히 뛰어남을 확인할 수 있었다. Thus, it was confirmed that the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention is remarkably excellent in hair growth and hair growth promoting effect on hair.
[실시예 3] 항주름 효과[Example 3] Anti-wrinkle effect
본 발명에 따른 화합물이 MMP-2의 효소 활성에 미치는 영향을 수행하기 위하여 섬유아 세포주(fibroblast cell line) 및 CCD-986sk 세포의 배양 중, 컨플루언스(confluence)가 30 ~ 40%일 때 하기 표 3의 조건으로 처리하였다. 48시간 추가 배양하여 컨플루언스가 90 ~ 100%에 도달하게 하였다. 이후, 세포 배양액을 회수하여 단백질을 Bradford reagent를 이용하여 계량하고 동량 (15 ug proteins)의 배양 배지 단백질들을 효소 기질인 젤라틴이 함유된 젤을 이용하여 전기영동 하였다. 전기영동 후 developing buffer에서 MMP-2에 의한 젤라틴 분해를 유도한 후, 코마시 블루(comassie blue) 염색 및 탈염색을 수행하였으며, 효소 작용에 의해 희게 반전된 영역의 넓이를 비교하는 방법으로 효소저해 활성을 분석한 결과를 도 19에 그래프로 나타내었다.In order to effect the effect of the compound according to the present invention on the enzymatic activity of MMP-2, when the confluence of the fibroblast cell line and the CCD-986sk cell is 30 to 40% And treated under the conditions shown in Table 3. Additional culture for 48 hours allowed confluence to reach 90-100%. Then, the cell culture was recovered, the proteins were quantified using Bradford reagent, and the same amount of culture medium proteins (15 ug proteins) were electrophoresed using a gel containing gelatin as an enzyme substrate. After electrophoresis, gelatin degradation by MMP-2 was induced in developing buffer, followed by comassie blue staining and de-staining. By comparing the area of the whitened area by enzyme action, the enzyme inhibition The results of analysis of activity are shown in FIG. 19 as a graph.
도 19에서 보는 바와 같이, 본 발명에 따른 화합물을 처리한 경우 미처리한 경우보다는 현저히, 양성 대조군으로 아데노신 또는 레티놀을 처리한 경우보다는 동등 이상의 수준으로 MMP-2의 효소 활성을 억제하는 것을 볼 수 있었다. As shown in FIG. 19, when the compound of the present invention was treated, the enzyme activity of MMP-2 was significantly inhibited to a level equal to or higher than that of adenosine or retinol treated as a positive control group .
이를 통하여 본 발명에 따른 5-아미노레불린산-펩타이드(글라이신-히스티딘-라이신)의 컨쥬게이트 화합물이 피부 주름 개선 및 탄력 증가의 효과가 현저히 뛰어남을 확인할 수 있었다. Thus, it was confirmed that the conjugate compound of 5-aminolevulinic acid-peptide (glycine-histidine-lysine) according to the present invention is remarkably excellent in the effect of improving skin wrinkles and elasticity.
이상, 본 발명을 상기 실시예를 중심으로 하여 설명하였으나 이는 예시에 지나지 아니하며, 본 발명은 본 발명의 기술분야에서 통상의 지식을 가진 자에게 자명한 다양한 변형 및 균등한 기타의 실시 예를 이하에 첨부한 청구범위 내에서 수행할 수 있다는 사실을 이해하여야 한다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.
Claims (16)
[화학식 1]
[Chemical Formula 1]
상기 5-아미노레불린산 또는 그의 염과 상기 펩타이드는 컨쥬게이트된 것인, 약학적 조성물.The method according to claim 1,
Wherein the 5-aminolevulinic acid or salt thereof and the peptide are conjugated.
상기 펩타이드는 알라닌, 글라이신, 라이신, 히스티딘, 세린, 프롤린, 하이드록시프롤린, 트레오닌, 아르기닌, 글루타민, 메티오닌 및 글루탐산으로 이루어진 군 중에서 선택되는 동일하거나 상이한 3개 내지 7개의 아미노산 잔기가 아미드 결합된 펩타이드인, 약학적 조성물. The method according to claim 1,
Wherein the peptide is an amide bonded peptide wherein the same or different 3 to 7 amino acid residues selected from the group consisting of alanine, glycine, lysine, histidine, serine, proline, hydroxyproline, threonine, arginine, glutamine, methionine and glutamic acid , ≪ / RTI >
상기 펩타이드는 글라이신-라이신-히스티딘, 글라이신-히스티딘-라이신, 글라이신-프롤린-히드록시프롤린, 알라닌-라이신-히스티딘, 알라닌-히스티딘-라이신, 라이신-히스티딘-라이신, 라이신-아르기닌-라이신, 또는 라이신-트레오닌-트레오닌-라이신-세린인, 약학적 조성물.The method of claim 3,
The peptide may be a glycine-lysine-histidine, a glycine-histidine-lysine, a glycine-proline-hydroxyproline, an alanine-lysine- Threonine-threonine-lysine-serine.
상기 펩타이드는 글라이신-히스티딘-라이신인, 약학적 조성물.5. The method of claim 4,
Wherein said peptide is glycine-histidine-lysine.
상기 5-아미노레불린산 또는 그의 염은 LED(light-emitting diode) 조사에 의해 활성화된 것인, 약학적 조성물.The method according to claim 1,
Wherein the 5-aminolevulinic acid or a salt thereof is activated by light-emitting diode (LED) irradiation.
상기 5-아미노레불린산 또는 그의 염은 650-675 nm 장파장의 LED 조사에 의해 활성화된 것인, 약학적 조성물.The method according to claim 6,
Wherein the 5-aminolevulinic acid or salt thereof is activated by LED irradiation with a long wavelength of 650-675 nm.
상기 조성물은 β-카테닌, Wnt 10b 및 Ki67 중 적어도 하나의 발현을 증가하거나 MMP-2의 활성을 억제하는, 약학적 조성물. The method according to claim 1,
Wherein said composition increases expression of at least one of? -Catenin, Wnt 10b, and Ki67, or inhibits the activity of MMP-2.
[화학식 1]
[Chemical Formula 1]
상기 5-아미노레불린산 또는 그의 염과 상기 펩타이드는 컨쥬게이트된 것인, 화장료 조성물.10. The method of claim 9,
Wherein the 5-aminolevulinic acid or salt thereof and the peptide are conjugated.
상기 펩타이드는 알라닌, 글라이신, 라이신, 히스티딘, 세린, 프롤린, 하이드록시프롤린, 트레오닌, 아르기닌, 글루타민, 메티오닌 및 글루탐산으로 이루어진 군 중에서 선택되는 동일하거나 상이한 3개 내지 7개의 아미노산 잔기가 아미드 결합된 펩타이드인, 화장료 조성물. 10. The method of claim 9,
Wherein the peptide is an amide bonded peptide wherein the same or different 3 to 7 amino acid residues selected from the group consisting of alanine, glycine, lysine, histidine, serine, proline, hydroxyproline, threonine, arginine, glutamine, methionine and glutamic acid , Cosmetic composition.
상기 펩타이드는 글라이신-라이신-히스티딘, 글라이신-히스티딘-라이신, 글라이신-프롤린-히드록시프롤린, 알라닌-라이신-히스티딘, 알라닌-히스티딘-라이신, 라이신-히스티딘-라이신, 라이신-아르기닌-라이신, 또는 라이신-트레오닌-트레오닌-라이신-세린인, 화장료 조성물.12. The method of claim 11,
The peptide may be a glycine-lysine-histidine, a glycine-histidine-lysine, a glycine-proline-hydroxyproline, an alanine-lysine- Threonine-threonine-lysine-serine.
상기 펩타이드는 글라이신-히스티딘-라이신인, 화장료 조성물.13. The method of claim 12,
Wherein the peptide is glycine-histidine-lysine.
상기 5-아미노레불린산 또는 그의 염은 LED(light-emitting diode) 조사에 의해 활성화된 것인, 화장료 조성물.10. The method of claim 9,
Wherein the 5-aminolevulinic acid or salt thereof is activated by light-emitting diode (LED) irradiation.
상기 5-아미노레불린산 또는 그의 염은 650-675 nm 장파장의 LED 조사에 의해 활성화된 것인, 화장료 조성물.15. The method of claim 14,
Wherein the 5-aminolevulinic acid or salt thereof is activated by LED irradiation with a long wavelength of 650-675 nm.
상기 조성물은 β-카테닌, Wnt 10b 및 Ki67 중 적어도 하나의 발현을 증가하거나 MMP-2의 활성을 억제하는, 화장료 조성물. 10. The method of claim 9,
Wherein the composition increases expression of at least one of? -Catenin, Wnt 10b, and Ki67, or inhibits the activity of MMP-2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20220018191A (en) | 2020-08-06 | 2022-02-15 | 농업회사법인 주식회사 팔공창조농업 | A cosmetic composition for promoting growth of eyelash comprising fermentation product of jujube seed |
| KR20230063478A (en) | 2021-11-02 | 2023-05-09 | 조성은 | Composition for promoting growth of eyebrow comprising Luffa cylindrica sap |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20220018191A (en) | 2020-08-06 | 2022-02-15 | 농업회사법인 주식회사 팔공창조농업 | A cosmetic composition for promoting growth of eyelash comprising fermentation product of jujube seed |
| KR20230063478A (en) | 2021-11-02 | 2023-05-09 | 조성은 | Composition for promoting growth of eyebrow comprising Luffa cylindrica sap |
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