KR20190018108A - Composition Comprising Thymol for Preventing or Treating in Skin Wrinkle or Atopic Dermatitis as Active Ingredient - Google Patents
Composition Comprising Thymol for Preventing or Treating in Skin Wrinkle or Atopic Dermatitis as Active Ingredient Download PDFInfo
- Publication number
- KR20190018108A KR20190018108A KR1020170102423A KR20170102423A KR20190018108A KR 20190018108 A KR20190018108 A KR 20190018108A KR 1020170102423 A KR1020170102423 A KR 1020170102423A KR 20170102423 A KR20170102423 A KR 20170102423A KR 20190018108 A KR20190018108 A KR 20190018108A
- Authority
- KR
- South Korea
- Prior art keywords
- atopic dermatitis
- composition
- skin
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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Abstract
Description
본 발명은 피부 주름 또는 아토피성 피부염의 예방 또는 치료용 조성물에 관한 것으로, 더욱 구체적으로 티몰 화합물을 유효성분으로 함유하는 피부 주름 또는 아토피성 피부염의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating skin wrinkles or atopic dermatitis, and more particularly to a composition for preventing or treating skin wrinkles or atopic dermatitis containing a thymol compound as an active ingredient.
피부 주름은 피부 수분함량, 콜라겐 함량 및 외부 환경에 대한 면역력 등 여러 가지 요소들에 의해 영향을 받는 것으로 알려져 있으며, 이중 주름의 형성에 가장 큰 영향을 미치는 것은 콜라겐의 생성량 및 콜라겐 분해 효소인 콜라게네이즈의 발현과 활성이다. Skin wrinkles are known to be influenced by various factors such as skin moisture content, collagen content and immunity to the external environment. Among them, collagen production and collagenase, collagenase It is the expression and activity of Nath.
콜라겐은 피부 진피층에 존재하는데, 피부 전체 건조 중량의 약 70 내지 80%를 차지하는 엘라스틴과 함께 피부에 탄력을 부여하는 주요 성분으로 알려져 있다. 콜라겐은 자연 노화에 따른 세포활성 저하와 같은 내부 요인에 의해 감소되고, 여러 유해 환경에서의 스트레스 증가나 태양 광선에 의한 활성 산소 종의 증가와 같은 외부 요인에 의하여 생합성이 감소되거나, 분해가 촉진되고 있다.Collagen is present in the dermal layer of the skin and is known to be the main ingredient that imparts elasticity to the skin along with elastin, which accounts for about 70 to 80% of the dry weight of the skin. Collagen is reduced by internal factors such as decreased cell activity due to natural aging, and biosynthesis is reduced or accelerated by external factors such as increased stress in various harmful environments and increase of active oxygen species by sunlight have.
한편, 활성산소종(reactive oxygen species, ROS)의 과생산은 UVB 노출 환경에서 보고된 바 있고, UVB 노출과 연관된 신호전달 체계는 MAPKs(mitogen activated protein kinases), ERK(extracellular signal-regulated kinase), p38 카이나아제, 및 JNK(c-Jun amino-terminal kinase) 등의 단백질과 관련되어 있는데, NF-ĸB 및 AP-1 전사인자의 발현증가를 유도한다. 또한, AP-1 단백질은 MMP(matrix metalloproteinase) 유전자의 활성과 관련되어 있고, NF-ĸB 단백질은 인터루킨과 같은 전염증 사이토카인(proinflammatory cytokines)의 발현에 영향을 미친다. On the other hand, over-production of reactive oxygen species (ROS) has been reported in the UVB exposure environment, and the signaling pathways associated with UVB exposure include mitogen-activated protein kinases (MAPKs), extracellular signal- p38 kinase, and JNK (c-Jun amino-terminal kinase), which induce increased expression of NF-κB and AP-1 transcription factors. In addition, the AP-1 protein is associated with the activity of the MMP (matrix metalloproteinase) gene, and the NF-κB protein affects the expression of proinflammatory cytokines such as interleukins.
노화된 피부에서 콜라겐 및 엘라스틴의 붕괴는 주로 MMP 단백질과 같은 그 분해 효소의 증가된 발현에 의해 야기된다. 또한, 전염증 사이토카인은 콜라겐의 합성을 방해하고, 콜라겐의 붕괴를 촉진시킨다. 타입 I 콜라겐은 연결 조직의 세포외 기질에서 가장 풍부한 단백질이다. 세포외 기질에는 타입 III, V, 및 VII 콜라겐, 엘라스틴, 프로테오글라이칸, 파이브로넥틴과 같은 다른 유형의 단백질을 포함한다. Collapse of collagen and elastin in aged skin is mainly caused by increased expression of its degrading enzyme such as MMP protein. In addition, proinflammatory cytokines interfere with the synthesis of collagen and promote collagen collapse. Type I collagen is the most abundant protein in the extracellular matrix of connective tissue. Extracellular matrix includes other types of proteins such as type III, V, and VII collagen, elastin, proteoglycan, and fibronectin.
타입 I 콜라겐 단백질의 발현 수준을 조절하는 것은 피부 광노화를 예방하는데 있어서 가장 중요한 인자이다. UVB의 조사는 TGF-β/Smad 신호전달 체계의 억제를 통해 피부 섬유아세포에서 콜라겐 전구체인 프로콜라겐(procollagen)의 발현을 감소시키게 된다. 또한, TGF-β1 신호전달 체계는 인간 피부 섬유아세포에서 세포외 기질의 합성을 조절하는 중요한 인자의 하나이다. Controlling the expression level of type I collagen protein is the most important factor in preventing skin photoaging. UVB irradiation reduces the expression of the collagen precursor procollagen in skin fibroblasts by inhibiting the TGF-β / Smad signaling pathway. In addition, the TGF-β1 signaling system is one of the important factors controlling the synthesis of extracellular matrix in human dermal fibroblasts.
따라서, AP-1 및 MAPKs 인자에 의해 조절되는 활성산소종(ROS)의 생성, 및 MMPs, ILs, TGF-β, 및 타입 I 프로콜라겐의 발현은 피부 광노화 연구에 있어서 유용한 마커로 작용한다. Thus, the production of reactive oxygen species (ROS) regulated by AP-1 and MAPKs factors, and the expression of MMPs, ILs, TGF-ss, and type I procollagen serve as markers useful in skin photoaging studies.
이와 같이 콜라겐 감소를 저해하여 피부 주름개선에 효과가 있는 천연물질을 탐색하고자 하는 여러 다양한 시도가 있었다. 콜라겐의 주름개선 효과를 이용하기 위하여 화장품 또는 연고 등과 같은 피부외용제 조성물에 콜라겐을 배합한 제품들이 출시되었으나, 이들 제품들은 콜라겐 자체를 피부 표면에 도포하는 것으로 고분자 물질인 콜라겐의 경피 흡수가 어려워 본질적인 주름개선 효과를 나타낼 수 없었다. 이러한 문제를 해결하기 위하여 콜라겐합성 촉진물질에 대한 관심이 높아졌으며, 종래 알려진 콜라겐합성 촉진물질로는 비타민C, 레티노익산, 형질전환생장인자(transforming growth factor, TGF), 동물태반 유래의 단백질(JP8-231370), 베툴린산(betulinic acid, JP8-208424), 클로렐라 추출물(JP9-40523, JP10-36283, 섬유아세포 증식 촉진작용) 등이 있다. 그러나 상기 물질은 피부 적용시 자극과 발적 등 안전성 문제로 사용량에 제한이 있거나 그 효과가 미미하여 실질적으로 주름개선 효과를 기대할 수 없다는 문제점이 있었다. 따라서, 종래 주름개선용 조성물보다 생체에 안전하고 주름개선 효과가 높은 새로운 주름개선 조성물의 개발이 절실히 요구되고 있다. Thus, there have been various attempts to discover natural substances that inhibit collagen reduction and are effective in improving skin wrinkles. In order to utilize the effect of improving the wrinkles of collagen, products containing collagen as an external composition for skin such as cosmetics or ointment have been marketed. However, since these products are coated with collagen itself on the skin surface, collagen, which is a polymer substance, The improvement effect could not be shown. To solve this problem, there has been a growing interest in collagen synthesis promoting substances. Examples of known collagen synthesis promoting substances include vitamin C, retinoic acid, transforming growth factor (TGF), animal placenta-derived proteins -231370), betulinic acid (JP8-208424), chlorella extract (JP9-40523, JP10-36283, fibroblast proliferation promoting action) and the like. However, there is a problem in that the use amount of the substance is limited or its effect is insufficient due to safety problems such as irritation and reddening when applied to the skin, so that the effect of improving wrinkles can not be expected substantially. Therefore, it is urgently required to develop a novel wrinkle-improving composition which is safer for a living body than a conventional wrinkle-improving composition and has a high wrinkle-reducing effect.
한편, 아토피성 피부염(atopic dermatitis)은 만성적으로 재발하는 가려움성 피부염으로, 영유아기에 흔히 발생하고 환자나 가족 중에 가려움증, 피부건조증 또는 특징적인 습진을 동반하는 질환이다. 아토피성 피부염의 전형적인 증상은 손, 두피, 얼굴, 목, 팔꿈치, 무릎 등에서 나타나며, 피부가 매우 건조해지고 가려움증과 염증이 생기며 비늘처럼 벗겨지다가 심하게 긁으면 피부가 두꺼워지면서 깊게 주름이 잡히는 태선화 현상이다.On the other hand, atopic dermatitis (chronic dermatitis) is a chronic itchy dermatitis that occurs frequently during infancy and is associated with itching, dry skin or characteristic eczema in the patient or family. Typical symptoms of atopic dermatitis occur in the hands, scalp, face, neck, elbow, and knee. The skin becomes very dry, itching and inflammation occurs, and scratched and scratched severely wrinkles deeply as the skin thickens.
이러한 아토피성 피부염이 발생하게 되는 직접적인 원인은 아직까지 명확하지 않기 때문에 이에 대한 연구가 계속적으로 진행되고 있다. 이러한 아토피를 치료하기 위하여, 종래 세라마이드, 리놀레산, 식물유 또는 광물성 오일 등의 성분, 하이드로코티손(hydrocortisone) 등의 스테로이드(steroid) 제제 또는 이들에 항균 및 항염 기능을 강화한 물질들이 제안된 바 있다. 그러나, 상기 스테로이드 제제는 표피의 성장억제나 부작용 등의 역효과를 유발할 수 있으며, 우레아 퍼록사이드 등은 피부의 과다 자극을 야기할 수 있고, 균의 내성(resistance) 및 광과민 등의 부작용을 유발할 가능성이 높은 문제점이 있다. 또한, 장기간 피부에 적용시 모세 혈관 확장증 및/또는 각질층의 두께 증가 내지 확장을 유발하는 등의 심각한 부작용을 발생시킬 염려가 있으며, 최근 아토피 완화에 많이 쓰이는 감마-리놀레산은 쉽게 산화되므로 안정성이 낮을 뿐만 아니라, 피부 자극성이 비교적 강하여 민감한 피부에는 사용하기 곤란한 문제점이 있다.The direct cause of the development of atopic dermatitis has not been clarified yet. In order to treat such atopy, conventionally used ingredients such as ceramide, linoleic acid, vegetable oil or mineral oil, steroid preparations such as hydrocortisone, or substances having enhanced antimicrobial and anti-inflammatory properties have been proposed. However, the above steroid preparations may cause adverse effects such as suppression of epidermal growth or side effects, and urea peroxide may cause excessive skin irritation and may cause side effects such as resistance to bacteria and photosensitivity There is a high problem. In addition, when applied to long-term skin, serious side effects such as increased capillary vasodilatation and / or stratum corneum thickening or expansion may occur. Gamma-linoleic acid, which is recently used for atopic dermatitis, is easily oxidized However, there is a problem that it is difficult to use for sensitive skin due to relatively strong skin irritation.
티몰(Thymol, 2-isopropyl-5-methylphenol)은 많은 약용식물의 정유(essential oils)에서 발견되는 페놀릭 화합물로, 멘톨의 합성원료로 사용되고 있고, 방부제와 살균제로서 치약·비누 등에 사용되는 외에, 분석시약으로서 타이타늄·암모니아 등의 분석에 사용되고 있으며, 의약품으로서 구충제 등에 사용된 바 있다. 티몰은 리아노딘 수용체(ryanodine receptors)를 활성화시키고, 골격 및 평활근에서 칼슘의 방출을 유도하며, 포유류 심실 심장 근세포에서 일시적인 외측 K+ 및 L 타입 Ca2 + 전류를 억제하기 위해 사용되는 강력한 화합물로 알려져 있다. 그리고, 신경 세포에서 저장된 세포내 칼슘의 방출과 티몰의 GABA-A 수용체 특성 강화작용이 보고된바 있다. 또한, 최근 연구들로 기니아 피그 위로부터 분리된 순환 평활근 세포에서 알파1-아드레날린 아고니스트(α1-adrenergic agonist)로서 활성이 보고된 바 있는데, 이는 혀 및 코 상피의 TRPV3(transient receptor potential channel)을 활성화시키고 시험관 내에서 아세틸콜린 에스테라제(acetylcholinesterase) 활성을 저해하는 것으로 알려져 있다. 또한, 항염증 효능으로 COX-1 효소 활성 또는 호중구에 의해 분비된 엘라스타제(elastase)를 중화하는 특성을 보이는 것으로 알려져 있다(Boudry G et al., J Physio Pharmacol 2008; 59(3): 543552). 그러나 이러한 티몰 또는 이의 유도체가 피부 주름 또는 아토피성 피부염에 있어서 어떠한 효과를 나타낼지에 대하여는 아직까지 개시된 바가 없다.Thymol (2-isopropyl-5-methylphenol) is a phenolic compound found in essential oils of many medicinal plants. It is used as a raw material for the synthesis of menthol. It is used as a preservative and disinfectant in toothpaste, soap, It is used as analytical reagent for the analysis of titanium, ammonia, etc., and has been used as a medicine for insect repellent. Thymol is Ria nodin receptor (ryanodine receptors) a greater activation, skeletal, and induces the release of calcium from the smooth muscle, transient outward in mammalian ventricular cardiomyocytes K + and L-type Ca 2 + is known as a powerful compounds to be used in order to suppress the current have. The release of stored intracellular calcium from neurons and thymol enhances GABA-A receptor properties have been reported. Recent studies have also reported activity as an alpha 1-adrenergic agonist in circulating smooth muscle cells isolated from guinea pigs, suggesting that the transient receptor potential channel (TRPV3) of the tongue and nasal epithelium And is known to inhibit acetylcholinesterase activity in vitro. In addition, it has been known that the anti-inflammatory effect exhibits the property of neutralizing COX-1 enzyme activity or elastase secreted by neutrophils (Boudry G et al., J Physio Pharmacol 2008; 59 (3): 543552 ). However, the effect of thymol or its derivatives on skin wrinkles or atopic dermatitis has not yet been disclosed.
이에 본 발명자들은, 천연물 유래 혹은 새로운 화합물의 피부주름 또는 아토피성 피부염 치료제를 개발하기 위하여 예의 노력한 결과, 티몰 또는 이의 유도체가 피부 주름 또는 아토피성 피부염의 예방 또는 치료에 유용하게 사용될 수 있음을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors have made intensive efforts to develop a therapeutic agent for skin wrinkles or atopic dermatitis derived from natural products or new compounds, and as a result, it has been confirmed that thymol or derivatives thereof can be effectively used for preventing or treating skin wrinkles or atopic dermatitis Thus completing the present invention.
따라서, 본 발명의 주된 목적은 피부 주름 또는 아토피성 피부염의 예방 또는 치료에 뛰어난 효과를 갖는 티몰을 유효성분으로 하는 조성물을 제공하는 데 있다.Accordingly, it is a main object of the present invention to provide a composition comprising thymol as an active ingredient, which has an excellent effect in preventing or treating skin wrinkles or atopic dermatitis.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 한 양태에 따르면, 본 발명은 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 피부 주름 또는 아토피성 피부염의 예방 또는 치료용 약학적 조성물을 제공한다:According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating skin wrinkles or atopic dermatitis comprising, as an active ingredient, a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof :
[화학식 1][Chemical Formula 1]
. .
상기 화학식 1의 화합물은 티몰(Thymol, 2-isopropyl-5-methylphenol)이다.The compound of
본 발명에서 용어, "티몰(Thymol)"은 무색 결정이며, 분자량 150.22, 비중 0.97, 녹는점 51℃, 끓는점 232.8℃이다. The term "Thymol" in the present invention is a colorless crystal and has a molecular weight of 150.22, a specific gravity of 0.97, a melting point of 51 ° C, and a boiling point of 232.8 ° C.
본 발명자들은 피부 주름개선 및 아토피 피부염의 방지에 효능이 있는 물질을 찾고자 여러 가지 천연물질들 중에서 유효한 물질을 검색한 결과, 상기 티몰 화합물이 우수한 피부 주름 예방 및 개선 작용의 효과가 있음과 동시에 아토피 피부염의 치료 및 예방에 효과가 있음을 발견하였고, 또한 피부에 적용시 안전성에도 문제가 없음을 확인하였다.The inventors of the present invention searched for a substance effective for the prevention of skin wrinkles and atopic dermatitis and found that the thymol compound has an effect of preventing and improving wrinkles of the skin and at the same time, And it was confirmed that there is no problem in safety when applied to the skin.
상기 티몰 화합물의 약학적으로 허용가능한 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용할 수 있다. 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탈설폰산, 아세트산, 글리콜산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다.Pharmaceutically acceptable salts of the thymol compounds may be acid addition salts formed by pharmaceutically acceptable free acids. As the free acid, organic acid and inorganic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid.
본 발명에 의한 부가염은 통상의 방법, 즉, 상기 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 당량 또는 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조하거나, 또는 용매나 과량의 산을 증발시킨 후 건조하거나 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be obtained by a conventional method, that is, by dissolving the above compound in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding an equivalent amount or excess amount of an organic acid, Precipitation or crystallization, or by evaporating a solvent or excess acid, followed by drying or precipitation of the precipitated salt by suction filtration.
본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염뿐 아니라 이로부터 제조될 수 있는, 동일한 효능을 나타내는 용매화물, 수화물 및 입체이성질체도 모두 본 발명의 범주 내로 포함할 수 있다.The present invention includes all of the solvates, hydrates and stereoisomers which exhibit the same potency as the above compound or a pharmaceutically acceptable salt thereof, which can be prepared therefrom, all within the scope of the present invention.
본 발명의 티몰 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물은, 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형체 또는 희석제를 추가로 포함할 수 있다. 이때, 상기 조성물에 포함되는 화학식 1로 표시되는 티몰 화합물, 또는 이의 약학적으로 허용가능한 염의 함량은 특별히 이에 제한되지 않으나, 조성물 총 중량에 대하여 0.01 중량% 내지 50.0 중량%로, 바람직하게는 0.05 중량% 내지 20 중량%로, 가장 바람직하게는 0.1 중량% 내지 10 중량%로 포함될 수 있다.The pharmaceutical composition comprising the thymol compound of the present invention, or a pharmaceutically acceptable salt thereof, may further comprise an appropriate carrier, adduct or diluent conventionally used in the production of a pharmaceutical composition. In this case, the content of the thymol compound represented by the formula (1) or a pharmaceutically acceptable salt thereof contained in the composition is not particularly limited, but may be 0.01 to 50.0% by weight, preferably 0.05 % To 20% by weight, and most preferably 0.1% to 10% by weight.
본 발명의 일 실시예에서는 티몰 화합물은 UVB 조사된 인간 진피섬유아세포에서 타입 I 프로콜라겐 단백질의 발현을 증가시키고, MMP-1 및 MMP-3 단백질의 발현을 억제하는 효과가 있음이 관찰되었다. 또한, 상기 티몰 화합물은 TNF-a 및 IFN-r 처리된 인간 피부각질세포주에서 염증성 사이토카인인 IL-6과 아토피성 피부염에 특이인자인 TARC(thymus and activation-regulated chemokine)의 발현을 억제하는 것을 확인한 바 있다. In one embodiment of the present invention, it has been observed that the thymol compound has an effect of increasing the expression of type I procollagen protein and suppressing the expression of MMP-1 and MMP-3 protein in UVB-irradiated human dermal fibroblasts. In addition, the thymol compound inhibits the expression of IL-6, an inflammatory cytokine, and TARC (thymus and activation-regulated chemokine), a specific factor in atopic dermatitis, in human dermal keratinocytes treated with TNF-a and IFN- I have confirmed.
본 발명의 티몰 화합물, 또는 이의 약학적으로 허용가능한 염은 타입 I 프로콜라겐 유전자의 발현을 증가시키고, MMP-1 및 MMP-3 유전자의 발현을 억제하는 것을 특징으로 한다. The thymol compound of the present invention, or a pharmaceutically acceptable salt thereof, is characterized in that it increases the expression of type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes.
피부 섬유아세포의 주된 기능으로 세포외기질 합성과 증식을 통한 손상된 피부 조직 재생 등을 들 수 있는데, 광노화와 같은 외인성 노화 요인 또는 유리 산소에 의한 손상 누적, 텔로미어 단절로 인한 세포 노화 등에 따른 내인성 노화 요인들은 진피층 내에 있는 피부섬유아세포의 생리 활성 기능을 저하시키게 된다. 피부 세포외기질 중 95% 이상을 차지하고, 세포의 부착분자(adhesion molecule) 및 세포 골격(cytoskeleton) 등과의 상호 작용과 신호 교류를 통해 섬유아세포의 생리 활성에 매우 주요한 부분을 담당하는 제I형 콜라겐의 합성이 저하될 경우, 피부 조직 내 콜라겐 양이 감소되고, 이에 따라 표면 장력이 감소되어 피부 탄력이 저하되고 피부 주름이 형성될 뿐만 아니라, 세포의 증식 및 재생 기능을 포함하는 생리 활성 기능이 감소하는 악순환의 원인이 된다.The major function of dermal fibroblasts is extracellular matrix synthesis and regeneration of injured skin tissue through proliferation. The factors of extrinsic aging such as photoaging, accumulation of damage by free oxygen, and endogenous aging by cell aging due to telomere breakage Reduce the physiological activity of dermal fibroblasts in the dermal layer. Type I collagen, which accounts for more than 95% of the extracellular matrix and plays a major role in the physiological activity of fibroblasts through interactions and signal interactions with adhesion molecules and cytoskeletons of cells, Is reduced, the amount of collagen in the skin tissue is reduced, whereby the surface tension is reduced, so that the skin elasticity is lowered and the skin wrinkles are formed, and the physiological activity including cell proliferation and regeneration is decreased This causes a vicious circle.
따라서, 피부섬유아세포의 콜라겐은 피부 재생, 피부 탄력, 피부 주름 형성 및 피부 손상 시 조직의 수복 또는 재생과 직접적인 관련이 있다고 볼 수 있다.Therefore, collagen of skin fibroblasts may be directly related to restoration or regeneration of tissue during skin regeneration, skin elasticity, wrinkle formation and skin damage.
즉, 피부 섬유아세포의 콜라겐 또는 프로콜라겐의 합성이 촉진되거나, 콜라겐을 분해하는 기질 단백질 분해효소(matrix metallo-proteinase, 이하 'MMP'라 함)의 합성이 저해되면, 피부 탄력 개선, 피부 재생, 피부 주름 개선, 상처 치유, 손상된 피부 조직의 수복 및 재생; 및 피부 노화 방지 등의 효과를 얻을 수 있다.That is, when the synthesis of collagen or procollagen of skin fibroblast is promoted or the synthesis of matrix metallo-proteinase (hereinafter, referred to as 'MMP'), which degrades collagen, is inhibited, skin elasticity improvement, skin regeneration, Improvement of skin wrinkles, wound healing, restoration and regeneration of damaged skin tissue; And prevention of skin aging can be obtained.
이에, 상기 티몰 화합물이 염증성 사이토카인인 타입 I 프로콜라겐 단백질의 발현을 증가시키고, MMP-1 및 MMP-3 유전자의 발현을 억제함으로써 피부 주름의 예방 또는 치료효과가 있음은 자명하다.It is obvious that the thymol compound has an effect of preventing or treating wrinkles of skin by increasing the expression of type I procollagen protein, which is an inflammatory cytokine, and suppressing the expression of MMP-1 and MMP-3 genes.
본 발명의 티몰 화합물, 또는 이의 약학적으로 허용가능한 염은 IL-6(interleukin-6) 및 TARC(Thymus and activationregulated chemokine) 유전자의 발현을 억제함으로써 아토피 예방 또는 치료 효과를 갖는 것을 특징으로 한다. The thymol compound of the present invention, or a pharmaceutically acceptable salt thereof, is characterized by having an effect of preventing or treating atopy by inhibiting the expression of IL-6 (interleukin-6) and TARC (Thymus and activation regulated chemokine) genes.
아토피성 피부염 환자와 NC/Nga 마우스(아토피성 피부염의 생쥐 모델)를 이용한 실험에서 혈청이나 병변조직에서 나타나는 특정 케모카인을 찾아 향후 아토피성 피부염 관련연구에서 표직인자로 사용할 수 있는가에 대한 연구가 많이 이루어져서 TARC에 관하여 다수의 연구결과가 축적되어 있다(Fujisawa et al., J. Allergy Clin. Immunol., 110(1), 139-146, 2002; H.Furukawa et al., J. Dermatol. Sci., 36, 165-172, 2004; Leung et al., Pediatr. Allergy Immunol., 14,296-301, 2003; Y. Shimada et al., J. Dermatol. Sci., 34, 201-208, 2004; Jahns- Rozyk et. al., Allergy,60, 685-688, 2005). TARC는 케모카인 수용체 4(CCR4)와 결합하며, 이들 간의 결합은 Th2세포가 염증조직으로 이동해 가는데 중요한 역할을 하는 것으로 알려져 있다. TARC의 혈청 농도가 아토피성 피부염과 같은 Th2 세포 관련피부질환과 밀접한 상관관계가 있음이 보고된바 있다(Y. Shimada et al., J. Dermatol. Sci., 34, 201-208,2004). 즉, 아토피성 피부염 환자의 혈청에는 TARC의 농도가 높으며 사이크로스포린 A를 투여한 치료나, 국소용 코르티코스테로이드를 사용한 치료에서 TARC 농도는 현저히 감소하고 질환은 호전됨이 증명된바 있다(Hijnen et. al., J. Allergy Clin. Immunol.. 113(2) 334-340). Many studies have investigated whether a particular chemokine present in serum or lesion tissue can be used as a marker in atopic dermatitis-related studies in patients with atopic dermatitis and NC / Nga mice (a mouse model of atopic dermatitis) Numerous studies have been accumulated on TARC (Fujisawa et al., J. Allergy Clin. Immunol., 110 (1), 139-146, 2002; H. Furukawa et al., J. Dermatol. Sci. Y. Shimada et al., J. Dermatol. Sci., 34, 201-208, 2004, Jahns-Rozyk et al., J. Immunol., 36, 165-172, 2004, Pediatr Allergy Immunol., 14,296-301, et al., Allergy, 60, 685-688, 2005). TARC binds to chemokine receptor 4 (CCR4), and the linkage between them is known to play an important role in the migration of Th2 cells to inflammatory tissues. It has been reported that serum concentrations of TARC are closely related to Th2 cell-related skin diseases such as atopic dermatitis (Y. Shimada et al., J. Dermatol. Sci., 34, 201-208, 2004). In other words, serum TARC concentration in patients with atopic dermatitis is high and treatment with ciclosporin A or topical corticosteroids has been shown to significantly reduce TARC concentration and improve disease (Hijnen et. al., J. Allergy Clin. Immunol. 113 (2) 334-340).
이에 상기 티몰 화합물이 염증성 사이토카인인 IL-6과 아토피성 피부염에 특이인자인 TARC(thymus and activation-regulated chemokine)의 발현을 억제함으로써 아토피성 피부염의 예방 또는 치료효과가 있음은 자명하다.It is clear that the thymol compound has the effect of preventing or treating atopic dermatitis by inhibiting the expression of IL-6, an inflammatory cytokine, and TARC (thymus and activation-regulated chemokine), which is a specific factor in atopic dermatitis.
본 발명에서 용어, "예방"은 본 발명의 조성물의 투여로 피부 주름 또는 아토피성 피부염의 발병을 억제 또는 지연시키는 모든 행위를 의미하며, "치료"는 본 발명의 조성물에 의해 피부 주름 또는 아토피성 피부염에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term " prevention " in the present invention means any action that inhibits or delays the onset of skin wrinkles or atopic dermatitis upon administration of the composition of the present invention, and " treatment " means that the composition of the present invention causes skin wrinkles or atopic It means all the actions that improve or change the symptoms caused by dermatitis.
본 발명에서 용어, "피부 주름"이란, 피부가 쇠하여 생긴 잔줄을 의미하는데, 유전자에 의한 원인, 피부 진피에 존재하는 콜라겐의 감소, 외부 환경 등에 의해 유발될 수 있다.In the present invention, the term " skin wrinkle " means a skin formed by decay of skin, which may be caused by a cause of a gene, a decrease in collagen existing in the skin dermis, or an external environment.
본 발명에서 용어, "아토피성 피부염"은 만성적이고 재발성의 염증성 피부질환으로 가려움증(가려움증)과 피부건조증, 특징적인 홍반 또는 습진을 동반하는 질병을 의미한다. 아토피성 피부염의 급성 병소에서는 혈청 면역글로불린 E(IgE)의 유의한 증가현상이 특징으로 나타나며, 이에 부가하여 병소의 조직병리학적인 변화 및 피부염 병변에 대한 평가 등을 행하여 아토피성 피부염의 진단 및 심각도를 판정하기도 한다. 아토피성 피부염의 정확한 원인은 아직까지 완전히 이해되고 있지 않지만 유전적 소인과 함께 면역학적, 비면역학적 기전이 관여한다고 보고 있다.As used herein, the term " atopic dermatitis " refers to chronic and recurrent inflammatory skin disease, which refers to a disease accompanied by itching (itching) and dry skin, characteristic erythema or eczema. In acute lesions of atopic dermatitis, a significant increase of serum immunoglobulin E (IgE) was noted. In addition, histopathologic changes of lesions and evaluation of dermatitis lesions were performed to evaluate the diagnosis and severity of atopic dermatitis . Although the exact cause of atopic dermatitis has not yet been fully understood, it is believed that immunologic and nonphysiologic mechanisms are involved with genetic predisposition.
상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결 건조제 및 좌제으로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있으며, 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 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.The pharmaceutical composition may be any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, nonaqueous solvents, suspensions, emulsions, And may be oral or parenteral formulations of various forms. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
본 발명의 조성물은 약학적으로 유효한 양으로 투여할 수 있다.The composition of the present invention may be administered in a pharmaceutically effective amount.
본 발명에서 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여경로 및 기간에 따라 다르며, 적합한 총 1일 사용량은 올바른 의학적 판단범위 내에서 처치의에 의해 결정될 수 있으나, 일반적으로 0.001 내지 1000 mg/kg의 양, 바람직하게는 0.05 내지 200 mg/kg, 보다 바람직하게는 0.1 내지 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 상기 조성물은 피부 주름 및/또는 아토피성 피부염의 예방 또는 치료를 목적으로 하는 개체이면 특별히 한정되지 않고, 어떠한 개체이든 적용가능하다. 예를 들면, 원숭이, 개, 고양이, 토끼, 모르모트, 랫트, 마우스, 소, 양, 돼지, 염소 등과 같은 비인간동물 및 인간 등 어느 개체에나 적용할 수 있으며, 투여의 방식은 당업계의 통상적인 방법이라면 제한없이 포함한다. 예를 들어, 국소도포 등을 통한 경피투여 방식을 사용할 수 있으나, 이에 제한되는 것은 아니다.The term " pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will vary depending on the species and severity, age, sex, The type of drug, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art. The preferred dosage of the composition of the present invention will depend on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, and the appropriate total daily dose may be determined by treatment, Generally, an amount of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg, can be administered in a single dose, divided into several times a day. The composition is not particularly limited as long as it is an object for prevention or treatment of skin wrinkles and / or atopic dermatitis, and any object can be applied. For example, it can be applied to any individual such as a monkey, a dog, a cat, a rabbit, a guinea pig, a rat, a mouse, a cattle, a pig, a goat, Including without limitation. For example, transdermal administration through topical application may be used, but is not limited thereto.
또 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 피부 주름 또는 아토피성 피부염의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In another aspect, the present invention provides a health functional food composition for preventing or ameliorating skin wrinkles or atopic dermatitis comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof .
[화학식 1][Chemical Formula 1]
구체적으로, 본 발명의 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 피부 주름 또는 아토피성 피부염의 예방 또는 개선을 목적으로 건강기능식품 조성물에 포함시킬 수 있다.Specifically, the compound represented by
상기 화합물, 약학적으로 허용가능한 염과, 피부 주름 및 아토피성 피부염에 대해서는 상기에서 설명한 바와 같다.The above-mentioned compounds, pharmaceutically acceptable salts, skin wrinkles and atopic dermatitis are as described above.
본 발명에서 용어, "개선"은 상기 조성물을 이용하여 피부 주름과 아토피성 피부염의 의심 및 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다. In the present invention, the term " improvement " refers to any action that alleviates or alleviates the symptoms of skin wrinkles, atopic dermatitis and symptoms of onset individuals using the composition.
본 발명의 조성물을 건강기능식품에 포함하여 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 건강기능식품 또는 건강기능식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합량은 사용 목적에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 바람직하게는 15 중량부 이하, 보다 바람직하게는 10 중량부 이하의 양으로 첨가할 수 있다. 그러나, 건강 조절 및 위생을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용할 수 있다.When the composition of the present invention is incorporated into a health functional food, the composition may be added as it is or may be used together with other health functional foods or health functional food ingredients and suitably used according to a conventional method. The amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use. Generally, the composition of the present invention may be added in an amount of preferably not more than 15 parts by weight, more preferably not more than 10 parts by weight, based on the raw material, in the production of food or beverage. However, in the case of long-term intake for the purpose of health control and hygiene, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
본 발명의 조성물을 포함할 수 있는 건강기능식품의 종류에는 특별한 제한은 없으며, 구체적인 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있고, 통상적인 의미에서의 건강기능식품을 모두 포함할 수 있으며, 동물을 위한 사료로 이용되는 식품을 포함할 수 있다.There is no particular limitation on the kind of health functional food that can contain the composition of the present invention, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gum, Dairy products, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and may include foodstuffs used as food for animals, which may include all health functional foods in the conventional sense.
또한, 본 발명의 건강기능식품 조성물이 음료의 형태로 사용될 경우에는 통상의 음료와 같이 여러 가지 감미제, 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드, 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨, 에리트리톨과 같은 당알콜일 수 있다. 상기 천연 탄수화물의 비율은 이에 제한되지는 않으나, 본 발명의 조성물 100㎖ 당 바람직하게는 약 0.01 내지 0.04g, 보다 바람직하게는 0.02 내지 0.03g일 수 있다. 상기 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제 및 사카린, 아스파르탐과 같은 합성 감미제일 수 있다.In addition, when the health functional food composition of the present invention is used in the form of a drink, it may contain various sweetening agents, flavoring agents, or natural carbohydrates as additional components such as ordinary beverages. The natural carbohydrates may be polysaccharides such as disaccharides such as monosaccharides such as glucose and fructose, maltose, sucrose, dextrin, cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol. The ratio of the natural carbohydrate is not limited thereto, but may be about 0.01 to 0.04 g, more preferably 0.02 to 0.03 g per 100 ml of the composition of the present invention. The sweeteners may be natural sweeteners such as tau martin and stevia extract, and synthetic sweeteners such as saccharin and aspartame.
상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, , Alcohols, carbonating agents used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks.
또 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 피부 주름 또는 아토피성 피부염의 예방 또는 개선용 의약외품 조성물을 제공한다.In another aspect, the present invention provides a quasi-drug composition for preventing or improving skin wrinkles or atopic dermatitis, which comprises, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
구체적으로, 본 발명의 화합물, 또는 이의 약학적으로 허용가능한 염을 피부 주름 또는 아토피성 피부염의 예방 또는 개선을 목적으로 의약외품 조성물에 포함시킬 수 있다.Specifically, the compound of the present invention, or a pharmaceutically acceptable salt thereof, may be included in the quasi-drug composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.
상기 화합물, 약학적으로 허용가능한 염과 피부 주름 및 아토피성 피부염에 대해서는 상기에서 설명한 바와 같다.The above-mentioned compounds, pharmaceutically acceptable salts, skin wrinkles and atopic dermatitis are as described above.
본 발명에서 용어, "의약외품"은 사람이나 동물의 질병을 치료, 경감, 처치 또는 예방할 목적으로 사용되는 섬유, 고무제품 또는 이와 유사한 것, 인체에 대한 작용이 약하거나 인체에 직접 작용하지 않으며, 기구 또는 기계가 아닌 것과 이와 유사한 것, 감염 예방을 위하여 살균, 살충 및 이와 유사한 용도로 사용되는 제제 중 하나에 해당하는 물품으로서, 사람이나 동물의 질병을 진단, 치료, 경감, 처치 또는 예방할 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것 및 사람이나 동물의 구조와 기능에 약리학적 영향을 줄 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것을 제외한 물품을 의미하며, 피부 외용제 및 개인위생용품도 포함한다.The term " quasi-drug " in the present invention means a fiber, a rubber product or the like used for the purpose of treating, alleviating, treating or preventing a disease of a human or an animal, a weak action on the human body, Or products similar to those which are not machinery, preparations used for sterilization, insecticides and similar uses for the prevention of infections, for the purpose of diagnosis, treatment, alleviation, treatment or prevention of diseases of human beings or animals Machinery, or apparatus, and that is not an apparatus, machine, or apparatus of an article used for the purpose of giving pharmacological effects to the structure or function of a person or animal, It also includes supplies.
본 발명의 조성물을 피부 주름 또는 아토피성 피부염의 예방 또는 개선을 목적으로 의약외품에 포함시킬 경우, 상기 조성물을 그대로 포함하여 사용하거나 다른 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합량은 사용 목적에 따라 적합하게 결정할 수 있다.When the composition of the present invention is contained in a quasi-drug for the purpose of preventing or improving skin wrinkles or atopic dermatitis, the composition may be used as it is or may be used together with other quasi-drug components, and may be suitably used according to a conventional method have. The amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use.
상기 피부외용제는 특별히 이에 제한되지 않으나, 예를 들어 연고제, 로션제, 스프레이제, 패치제, 크림제, 산제, 현탁제 또는 젤제의 형태로 제조되어 사용될 수 있다.The external preparation for skin may be prepared and used in the form of, for example, an ointment, a lotion, a spray, a patch, a cream, a powder, a suspension or an ointment.
또 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 피부 주름 또는 아토피성 피부염의 예방 또는 개선용 화장료 조성물을 제공한다.In another aspect, the present invention provides a cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis, which comprises a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
구체적으로, 본 발명의 화합물, 또는 이의 약학적으로 허용가능한 염을 피부 주름 또는 아토피성 피부염의 예방 또는 개선을 목적으로 화장료 조성물에 포함시킬 수 있다.Specifically, the compound of the present invention, or a pharmaceutically acceptable salt thereof, may be included in the cosmetic composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.
상기 화합물, 약학적으로 허용가능한 염과 피부 주름 및 아토피성 피부염에 대해서는 상기에서 설명한 바와 같다.The above-mentioned compounds, pharmaceutically acceptable salts, skin wrinkles and atopic dermatitis are as described above.
본 발명의 피부 주름 또는 아토피성 피부염의 예방 또는 개선용 화장료 조성물은 전체 조성물 중량에 대하여 0.001 내지 50 중량%의 화합물 또는 이의 약학적으로 허용가능한 염을 포함할 수 있으며, 보다 바람직하게는 0.01 내지 20 중량%, 가장 바람직하게는 0.1 중량% 내지 10 중량%의 화합물 또는 이의 약학적으로 허용가능한 염을 포함할 수 있으며, 이에 제한되는 것은 아니다.The cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis according to the present invention may comprise 0.001 to 50% by weight of the compound or a pharmaceutically acceptable salt thereof, more preferably 0.01 to 20% by weight, By weight, most preferably from 0.1% to 10% by weight, of a compound or a pharmaceutically acceptable salt thereof.
또한, 본 발명의 화장료 조성물은 상기 유효성분 이외에 통상적으로 허용되는 성분들을 제한없이 포함할 수 있으며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.In addition, the cosmetic composition of the present invention may include, without limitation, commonly accepted ingredients other than the above-mentioned effective ingredients, and includes conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and carriers can do.
본 발명에 따른 화장료 조성물은 용액, 외용연고, 크림, 폼, 영양화장수, 유연화장수, 팩, 유연수, 유액, 메이크업베이스, 에센스, 비누, 액체 세정료, 입욕제, 선 스크린크림, 선오일, 현탁액, 유탁액, 페이스트, 겔, 로션, 파우더, 비누, 계면활성제-함유 클렌징, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션, 패취 및 스프레이 등의 제형으로 제조할 수 있으나, 이에 제한되는 것은 아니다.The cosmetic composition according to the present invention can be used as a cosmetic composition in the form of a solution, an ointment for external use, a cream, a foam, a nutritional lotion, a softening water, a pack, a soft water, an emulsion, a makeup base, But are not limited to, emulsions, pastes, gels, lotions, powders, soaps, surfactant-containing cleansers, oils, powder foundations, emulsion foundations, wax foundations, patches and sprays.
또한, 본 발명의 화장료 조성물은 일반 피부 화장료에 배합되는 화장품학적으로 허용 가능한 담체를 1종 이상 추가로 포함할 수 있으며, 통상의 성분으로 예를 들면 유분, 물, 계면활성제, 보습제, 저급 알콜, 증점제, 킬레이트제, 색소, 방부제, 향료 등을 적절히 배합할 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 화장료 조성물에 포함되는 화장품학적으로 허용가능한 담체는 제형에 따라 다양하다. In addition, the cosmetic composition of the present invention may further comprise at least one cosmetically acceptable carrier to be incorporated in a general skin cosmetic composition, and examples thereof include oil, water, a surfactant, a moisturizer, A thickening agent, a chelating agent, a coloring matter, an antiseptic, a perfume, and the like may be appropriately compounded, but the present invention is not limited thereto. The cosmetically acceptable carrier to be contained in the cosmetic composition of the present invention varies depending on the formulations.
본 발명의 제형이 연고, 페이스트, 크림 또는 젤인 경우에는, 담체성분으로서 동물성 유, 식물성 유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크, 산화아연 또는 이들의 혼합물이 이용될 수 있다.When the formulation of the present invention is an ointment, a paste, a cream or a gel, the carrier component may be an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide Mixtures of these may be used.
본 발명의 제형이 파우더 또는 스프레이인 경우에는, 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록사이드, 칼슘 실케이트, 폴리아미드 파우더 또는 이들의 혼합물이 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진제를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof may be used as the carrier component, Propellants such as fluorohydrocarbons, propane / butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는, 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되며, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알콜, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일이 이용될 수 있으며, 특히, 목화씨 오일, 땅콩 오일, 옥수수 배종 오일, 올리브 오일, 피마자 오일 및 참깨 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 이용될 수 있다.When the formulation of the present invention is a solution or emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, 1,3-butyl glycol oil may be used, in particular fatty acid esters of cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol aliphatic esters, polyethylene glycols or sorbitan may be used have.
본 발명의 제형이 현탁액인 경우에는, 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알콜, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
본 발명의 제형이 비누인 경우에는 담체 성분으로서 지방산의 알칼리 금속 염, 지방산 헤미에스테르 염, 지방산 단백질 히드롤리제이트, 이세티오네이트, 라놀린 유도체, 지방족 알콜, 식물성 유, 글리세롤, 당 등이 이용될 수 있다.When the formulation of the present invention is a soap, an alkali metal salt of a fatty acid, a fatty acid hemiester salt, a fatty acid protein hydrolizate, isethionate, a lanolin derivative, an aliphatic alcohol, a vegetable oil, glycerol, .
본 발명의 제형이 계면-활성제 함유 클렌징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시테이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 오일, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is an interface-active agent-containing cleansing, the carrier component is selected from the group consisting of aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.
또 하나의 양태로서, 본 발명은 상기 약학적 조성물을 포함하는 아토피성 피부염 치료용 경피투여형 제제를 제공한다.In another embodiment, the present invention provides a transdermal preparation for the treatment of atopic dermatitis comprising the above pharmaceutical composition.
구체적으로, 상기 약학적 조성물을 경피투여형 제제화함으로써 피부 주름 또는 아토피성 피부염의 치료용도로 사용할 수 있다.Specifically, the pharmaceutical composition can be used for treatment of skin wrinkles or atopic dermatitis by transdermal administration.
본 발명의 용어 "경피투여형 제제"는 피부를 통해 약물을 투여하여 효과를 나타내는 제형으로, 피부에 바르는 약, 피부에 붙이는 약 등의 형태로 제형화된다. 경피투여시 활성성분의 피부 투과는 화학포텐셜 즉, 농도기울기에 따른 단순확산에 의해 세포 내, 세포간 또는 땀구멍, 털구멍 등의 부속기관을 통과하여 이루어진다. 손상되지 않은 피부를 통과하는 것이 용이하지는 않다는 단점이 있으나, 약물의 효율, 투여속도의 제어, 환부에 직접적용 가능성 등의 사용상 용이점이 있으며 비교적 일정한 혈중농도 유지, 위장관 독성을 나타내는 물질의 부작용 최소화, 간의 부담 감소 등의 장점이 있다. 활성성분의 피부 투과를 용이하게 하기 위해서는 피부투여 촉진제를 추가적으로 포함하여 제형화할 수 있으며, 본 발명의 화합물은 지용성의 특성으로 인하여 경피투여에 유리할 수 있다.The term " transdermal dosage form " of the present invention is a dosage form that exhibits an effect by administering a drug through the skin, and is formulated in the form of a drug applied to the skin or a drug attached to the skin. In transdermal administration, the skin permeation of the active ingredient is carried out through an intracellular, intracellular, or parenchyma, hairy hole, or the like by simple diffusion according to the chemical potential, that is, the concentration gradient. It is not easy to pass through uninjured skin. However, there are advantages in ease of use such as efficiency of drug, control of administration rate, possibility of direct application to affected part, maintenance of relatively constant blood concentration, minimization of side effects of substances showing gastrointestinal toxicity, And reducing the burden on the liver. In order to facilitate skin permeation of the active ingredient, a skin administration promoter may be additionally formulated, and the compound of the present invention may be advantageous for transdermal administration owing to the lipophilicity characteristics.
본 발명의 경피투여형 제제는 피부의 질환부 표면에 유효 성분을 직접 투여할 수 있는 제형이라면 제한없이 사용될 수 있다. 예를 들어, 연고제, 크림제, 겔제, 로션제, 액제, 유제, 현탁제, 경고제(스틱제), 파스타제, 리니멘트제, 파프제, 테이프제, 에어로졸제 또는 외용산제 등의 제제로 조제하여 사용할 수 있다. 이를 위해 통상의 경피투여형 제제의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The transdermal preparation of the present invention can be used without limitation as long as it is a formulation capable of directly administering the active ingredient to the surface of the diseased part of the skin. For example, preparations such as ointments, creams, gels, lotions, solutions, emulsions, suspensions, warnings (sticks), pastes, liniments, papings, tapes, aerosols or external powders Can be used. To this end, it may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of conventional transdermal dosage forms.
연고제, 크림제, 겔제, 로션제의 경우에 있어서는, 백색 바셀린, 황색 바셀린, 라놀린, 표백밀랍, 세탄올, 스테아릴알코올, 스테아르산, 경화유, 겔화 탄화수소, 폴리에틸렌글리콜, 유동 파라핀, 스쿠알란 등의 기제; 올레산, 미리스트산이소프로필, 트리이소옥탄산글리세린, 크로타미톤, 세바크산디에틸, 아디프산디이소프로필, 라우르산헥실, 지방산, 지방산 에스테르, 지방족 알코올, 식물유 등의 용제 및 용해 보조제; 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 지방산에스테르, 레시틴등의 계면 활성제; 카르복시비닐 폴리머, 잔탄검, 카르복시메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨염류, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등의 증점제 등을 들 수 있다. 또한, 원하는 바에 따라 안정제, 보존제, 흡수 촉진제, pH 조정제, 그 밖의 적당한 첨가제를 배합할 수 있다. 액제 또는 유제인 경우에는 담체 성분으로서 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르 등의 용매, 용매화제 또는 유탁화제가 이용될 수 있다.In the case of ointments, creams, gels and lotions, the base material is selected from the group consisting of white petrolatum, yellow petrolatum, lanolin, bleached beeswax, cetanol, stearyl alcohol, stearic acid, hydrogenated oil, gelled hydrocarbon, polyethylene glycol, liquid paraffin, squalane ; Solvents and dissolution aids such as oleic acid, myristic acid isopropyl, triisooctanoic acid glycerin, crotamiton, diethyl sebacate, diisopropyl adipate, hexyl laurate, fatty acid, fatty acid ester, aliphatic alcohol and vegetable oil; Antioxidants such as tocopherol derivatives, L-ascorbic acid, dibutylhydroxytoluene, and butylhydroxyanisole; Preservatives such as parahydroxybenzoic acid ester; Humectants such as glycerin, propylene glycol and sodium hyaluronate; Surfactants such as polyoxyethylene derivatives, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, and lecithin; Carboxyvinyl polymer, xanthan gum, carboxymethylcellulose, carboxymethylcellulose sodium salt, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. In addition, a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired. In the case of a liquid or an emulsion, the carrier component may be water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan A solvent, a solvent or an emulsifying agent may be used.
현탁제인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제; 에톡실화 이소스테아릴알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제; 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.In the case of a suspension agent, a liquid diluent such as water, ethanol or propylene glycol as a carrier component; Suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters; Microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
경고제인 경우에는 일산화납, 올리브유 및 돈지(lard)를 이용하여, 파스타제인 경우에는 아연화 세말, 살리실산세말, 전분 및 바셀린을 이용하여, 리니멘트제인 경우에는 장뇌유, 올리브유, 메틸 살리실리레이트, 트라가칸타, 소듐 카르복시메틸셀룰로오스, 글리세린 및 산화아연을 이용하여 제제화할 수 있다.In the case of a warning agent, lead monoxide, olive oil and lard are used. In case of pasta starch, zinc sulfate, salicylic acid and starch and petroleum jelly are used. In case of liniment oil, ginger oil, olive oil, methyl salicylate, Sodium carboxymethyl cellulose, glycerin, and zinc oxide.
파프제의 경우에 있어서는, 폴리아크릴산, 폴리아크릴산 공중합체 등의 점착 부여제; 황산알루미늄, 황산칼륨알루미늄, 염화알루미늄, 메타규산알루민산마그네슘, 디하이드록시알루미늄아세테이트 등의 가교제; 폴리아크릴산나트륨, 폴리비닐알코올, 폴리비닐피롤리돈, 젤라틴, 알긴산나트륨, 카르복시메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨염류, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등의 증점제; 글리세린, 폴리에틸렌글리콜 (마크로골), 프로필렌글리콜, 1,3-부탄디올 등의 다가 알코올류; 폴리옥시에틸렌 유도체 등의 계면 활성제; 1-멘톨 등의 향료; 파라하이드록시벤조산에스테르 등의 방부제; 정제수 등을 들 수 있다. 또한, 원하는 바에 따라 안정제, 보존제, 흡수 촉진제, pH 조정제, 그 밖의 적당한 첨가제를 배합할 수 있다.In the case of the PAPE agent, a tackifier such as polyacrylic acid and polyacrylic acid copolymer; A crosslinking agent such as aluminum sulfate, aluminum potassium sulfate, aluminum chloride, magnesium metasilicate aluminate, and dihydroxy aluminum acetate; Thickening agents such as sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, sodium alginate, carboxymethylcellulose, carboxymethylcellulose sodium salts, hydroxypropylcellulose, and hydroxypropylmethylcellulose; Polyhydric alcohols such as glycerin, polyethylene glycol (macrogol), propylene glycol and 1,3-butanediol; Surfactants such as polyoxyethylene derivatives; Fragrances such as 1-menthol; Preservatives such as parahydroxybenzoic acid ester; And purified water. In addition, a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired.
테이프제의 경우에 있어서는, 스티렌, 이소프렌, 스티렌 블록 공중합체(SIS 블록 공중합체)나 아크릴 수지 등의 점착제; 지환족 포화 탄화수소계 수지, 로진계 수지, 테르펜계 수지 등의 점착 부여 수지; 액상 고무, 유동파라핀 등의 연화제; 디부틸하이드록시톨루엔 등의 산화 방지제; 프로필렌글리콜 등의 다가 알코올; 올레산 등의 흡수 촉진제; 폴리옥시에틸렌 유도체 등의 계면 활성제, 그 밖의 적당한 첨가제를 배합할 수 있다. 또한, 폴리아크릴산나트륨이나 폴리비닐알코올과 같은 함수 가능한 고분자와 소량의 정제수를 첨가하여 함수 테이프제로 할 수도 있다. 이 경우에 있어서도, 추가로 원하는 바에 따라 안정제, 보존제, 흡수 촉진제, pH 조정제, 그 밖의 적당한 첨가제를 배합할 수 있다.In the case of the tape, a pressure-sensitive adhesive such as styrene, isoprene, styrene block copolymer (SIS block copolymer) or acrylic resin; A tackifier resin such as an alicyclic saturated hydrocarbon resin, a rosin resin, and a terpene resin; Softeners such as liquid rubber and liquid paraffin; Antioxidants such as dibutyl hydroxytoluene; Polyhydric alcohols such as propylene glycol; Absorption promoters such as oleic acid; A surfactant such as a polyoxyethylene derivative, and other suitable additives. A functional tape such as sodium polyacrylate or polyvinyl alcohol and a small amount of purified water may be added to form a functional tape. In this case as well, a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired.
에어로졸제의 경우에 있어서는, 연고제, 크림제, 겔제, 현탁제, 유제, 액제 및 로션제 등의 조제에 사용되는 백색 바셀린, 황색 바셀린, 라놀린, 표백 밀랍, 세탄올, 스테아릴알코올, 스테아르산, 경화유, 겔화 탄화수소, 폴리에틸렌글리콜, 유동 파라핀, 스쿠알란 등의 기제; 올레산, 미리스트산이소프로필, 아디프산디이소프로필, 세바크산이소프로필, 트리이소옥탄산글리세린, 크로타미톤, 세바크산디에틸, 라우르산헥실, 지방산, 지방산 에스테르, 지방족 알코올, 식물유 등의 용제 및 용해 보조제; 토코페롤 유도체, L-아스코르브산, 디부틸하이드록시톨루엔, 부틸하이드록시아니솔 등의 산화 방지제; 파라하이드록시벤조산에스테르 등의 방부제; 글리세린, 프로필렌글리콜, 히알루론산나트륨 등의 보습제; 폴리옥시에틸렌 유도체, 글리세린 지방산 에스테르, 자당 지방산에스테르, 소르비탄 지방산 에스테르, 프로필렌글리콜 지방산 에스테르, 레시틴 등의 계면 활성제; 카르복시비닐 폴리머, 잔탄검, 카르복시메틸셀룰로오스, 카르복시메틸셀룰로오스 나트륨염류, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등의 증점제; 추가로 각종 안정제, 완충제, 교미제, 현탁화제, 유화제, 방향제, 보존제, 용해 보조제, 그 밖의 적당한 첨가제를 배합할 수 있다. 특히, 틀로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 추가적으로 포함할 수 있다.In the case of the aerosol preparation, the white petrolatum, the yellow petrolatum, the lanolin, the bleached wax, the cetanol, the stearyl alcohol, the stearic acid, the stearic acid, Base oils such as hydrogenated oils, gelled hydrocarbons, polyethylene glycols, liquid paraffin, squalane and the like; Oleic acid, myristic acid isopropyl, diisopropyl adipate, isobutyl sebacate, glycerin triisooctanoate, crotamiton, diethyl sebacate, hexyl laurate, fatty acid esters, aliphatic alcohols and vegetable oils Solvents and dissolution aids; Antioxidants such as tocopherol derivatives, L-ascorbic acid, dibutylhydroxytoluene, and butylhydroxyanisole; Preservatives such as parahydroxybenzoic acid ester; Humectants such as glycerin, propylene glycol and sodium hyaluronate; Surfactants such as polyoxyethylene derivatives, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, and lecithin; Thickening agents such as carboxyvinyl polymer, xanthan gum, carboxymethyl cellulose, carboxymethyl cellulose sodium salts, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like; In addition, various stabilizers, buffers, mating agents, suspending agents, emulsifiers, fragrances, preservatives, solubilizers, and other suitable additives may be added. In particular, it may additionally include propellants such as fluoro-hydrocarbons, propane / butane or dimethyl ether.
외용산제의 경우에 있어서는, 감자 전분, 쌀 전분, 옥수수 전분, 탤크, 산화아연 등의 부형제 또는 그 밖의 적당한 첨가제를 배합할 수 있다. 이 경우에 있어서도, 추가로 원하는 바에 따라 각종 안정제, 보존제, 흡수 촉진제, 그 밖의 적당한 첨가제를 배합할 수 있다.In the case of external preparations, excipients such as potato starch, rice starch, corn starch, talc and zinc oxide or other suitable additives may be added. In this case as well, various stabilizers, preservatives, absorption promoters and other suitable additives may be added as desired.
본 발명이 제공하는 경피투여형 제제를 조제하는 수단은 특별히 한정되지 않고, 원하는 제형에 따라 각 성분 및 필요에 따라 기제 성분을 충분히 혼련하는 등의 통상의 경피투여형 제제를 제조하는 방법을 사용하여 제조될 수 있다. 또, 파프제 및 테이프제의 조제에 있어서는, 혼련한 혼합물을 이형지 상에 전연, 건조시키고, 추가로 유연한 지지체와 첩합시키고, 원하는 크기로 재단함으로써 조제할 수 있다.The means for preparing the transdermal dosage formulations provided by the present invention is not particularly limited, and a method for preparing conventional transdermal dosage forms, such as sufficiently kneading the respective components and the base components as necessary according to a desired formulation, . In the preparation of the papermaking agent and the tape agent, it is possible to prepare the kneaded mixture by preliminarily drying it on a release paper, further kneading it with a flexible support, and cutting it to a desired size.
본 발명이 제공하는 경피투여형 제제는, 예를 들어 연고제, 액제(현탁제, 유제, 로션제 등), 에어로졸제 및 외용산제의 경우에는, 피부 환부에 도포 등에 의해 직접 적용하거나, 혹은 천 등의 지지체에 도포 또는 함침시켜 적용하거나 하는 등의 통상의 사용 방법에 의해 사용될 수 있다. 또, 파프제 혹은 테이프제의 경우에는, 이들 제제를 피부 환부에 직접 첩부하는 방법에 의해 사용될 수 있다.The transdermal dosage form provided by the present invention can be applied directly to the skin affected area by application or the like in the case of ointments, liquid preparations (suspensions, emulsions, lotions and the like), aerosols and external preparations, Or by applying or impregnating the support to a support of the above-mentioned composition. In the case of a papermaking or a tape preparation, these preparations can be used by directly attaching them to the skin affected portion.
본 발명의 경피투여형 제제로 사용되는 경우 경피투과 속도, 세포 흡수력 등을 고려하여 적용량을 설정할 수 있다. 바람직하게는 피부단위면적당 1mg/cm2 내지 50mg/cm2 또는 2mg/cm2 내지 20mg/cm2의 양으로 적용할 것을 권장할 수 있으나 이에 제한되지 않고, 총 조성물의 중량에 대한 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염의 함량을 고려하여, 당업자에 의해 결정될 수 있다. 본 발명의 경피투여형 제제의 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염의 함량은 총 조성물의 중량에 대하여 0.1 내지 10 중량%로 포함하도록 제조할 수 있으나, 이에 제한되지 않고, 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염의 아토피성 피부염의 예방 또는 치료효과가 제공되는 범위에서 당업자에 의해 결정될 수 있다.When used as the transdermal preparation of the present invention, the application amount can be set in consideration of the transdermal permeation rate, the cell absorption capacity, and the like. Preferably 1 mg / cm < 2 > To 50 mg / cm 2, or from 2 mg / cm 2 to 20 mg / cm 2 , based on the weight of the total composition, or a pharmaceutically acceptable salt thereof, May be determined by those skilled in the art, taking into consideration the salt content. The content of the compound represented by the formula (1) of the transdermal formulation of the present invention, or a pharmaceutically acceptable salt thereof, may be from 0.1 to 10% by weight, based on the weight of the total composition, 1, or a pharmaceutically acceptable salt thereof, can be determined by those skilled in the art to the extent that the effect of preventing or treating atopic dermatitis is provided.
또 하나의 양태로서, 본 발명은 상기 약학적 조성물을 피부 주름의 발생 우려가 있는 개체 또는 아토피성 피부염의 의심개체에 투여하는 단계를 포함하는, 피부 주름 또는 아토피성 피부염의 예방 또는 치료 방법을 제공한다.In another aspect, the present invention provides a method for preventing or treating skin wrinkles or atopic dermatitis, comprising the step of administering the pharmaceutical composition to a subject suspected of having skin wrinkles or suspected individuals of atopic dermatitis do.
본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물을 피부 주름의 발생 우려가 있는 개체 또는 아토피성 피부염의 의심 개체에 투여함으로써, 개체를 효율적으로 치료할 수 있다. 피부 주름과 아토피성 피부염에 대해서는 상기에서 설명한 바와 같다.The individual can be efficiently treated by administering a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject suspected of causing skin wrinkles or suspect of atopic dermatitis. Skin wrinkles and atopic dermatitis are as described above.
본 발명에서 용어, "투여"는 어떠한 적절한 방법으로 피부 주름이 발생할 우려가 있는 개체 또는 아토피성 피부염 의심 개체에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다. 구체적으로, 국소도포 등을 통한 경피투여 방식으로 투여될 수 있으나 이에 제한되지 않는다.The term " administering " in the present invention means introducing the pharmaceutical composition of the present invention into a suspected individual or atopic dermatitis susceptible to skin wrinkling in any appropriate manner, and the administration route can reach the target tissue May be administered via various routes of administration, whether oral or parenteral. Specifically, it can be administered by a transdermal administration method such as topical application, but is not limited thereto.
본 발명의 치료 방법은 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물을 약학적 유효량으로 투여하는 것을 포함할 수 있다. 적합한 총 1일 사용량은 올바른 의학적 판단범위 내에서 처치의에 의해 결정될 수 있으며, 일반적으로 0.001 내지 1000mg/kg의 양, 바람직하게는 0.05 내지 200mg/kg, 보다 바람직하게는 0.1 내지 100mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 그러나 본 발명의 목적상, 특정 환자에 대한 구체적인 치료적 유효량은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다.The method of treatment of the present invention may comprise administering a pharmaceutical effective amount of a pharmaceutical composition comprising a compound represented by the above-mentioned formula (1), or a pharmaceutically acceptable salt thereof. Suitable total daily doses may be determined by treatment within the scope of sound medical judgment and are generally in the range of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg May be administered once or several times a day. For purposes of the present invention, however, the specific therapeutically effective amount for a particular patient will depend upon the nature and extent of the reaction to be achieved, the particular composition, including whether or not other agents are used, the age, weight, Sex and diet of the patient, the time of administration, the route of administration and the rate of administration of the composition, the duration of the treatment, the drugs used or concurrently used with the specific composition, and similar factors well known in the medical arts.
이상 설명한 바와 같이, 본 발명의 조성물은 인간 진피 섬유 아세포에서 타입 I 프로콜라겐 단백질의 발현을 증가시키고, MMP-1, 및 MMP-3 단백질의 발현을 억제하며, TNF-a 및 IFN-r 처리된 인간 피부 각질 세포주에서 염증성 사이토카인인 IL-6과 아토피성 피부염에 특이인자인 TARC(thymus and activation-regulated chemokine)의 발현을 효과적으로 억제하여 아토피성 피부염을 예방하고 크게 개선시킬 수 있다. As described above, the composition of the present invention increases the expression of type I procollagen protein in human dermal fibroblasts, inhibits the expression of MMP-1 and MMP-3 proteins, inhibits the expression of TNF-a and IFN-r IL-6, an inflammatory cytokine, and TARC (thymus and activation-regulated chemokine), which are specific for atopic dermatitis, can be effectively inhibited in human keratinocyte cell line, thereby preventing and greatly improving atopic dermatitis.
또한, 본 발명의 조성물은 천연상태에서 분리되는 물질로 인체에 매우 안전할 뿐만 아니라, 안정성도 매우 탁월하다.In addition, the composition of the present invention is a material which is separated in a natural state and is not only very safe for human body but also excellent in stability.
도 1은 티몰 화합물이 처리된 인간섬유아세포에서 세포 독성을 측정한 그래프이다.
도 2는 티몰 화합물이 처리된 인간섬유아세포에서 MMP-1 단백질의 발현 변화를 측정한 나타내는 그래프이다.
도 3은 티몰 화합물이 처리된 인간섬유아세포에서 MMP-3 단백질의 발현 변화를 측정한 나타내는 그래프이다.
도 4는 티몰 화합물이 처리된 인간섬유아세포에서 프로콜라겐 단백질의 발현 변화를 측정한 나타내는 그래프이다.
도 5는 티몰 화합물이 처리된 피부각질세포주에서 TARC의 발현 변화를 측정한 나타내는 그래프이다.
도 6은 티몰 화합물이 처리된 피부각질세포주에서 IL-6의 발현 변화를 측정한 나타내는 그래프이다.
도 7은 NC/Nga 마우스 아토피모델에서 DNCB 용액과 병행하여 티몰을 처리한 후, 피부 수분량을 측정한 결과를 나타내는 그래프이다.
도 8은 NC/Nga 마우스 아토피모델에서 DNCB 용액과 병행하여 티몰을 처리한 후, 피부 홍반을 측정한 결과를 나타내는 그래프이다.
도 9는 NC/Nga 마우스 아토피모델에서 DNCB 용액과 병행하여 티몰을 처리한 후, 피부의 조직학적 변화를 관찰한 사진이다.
도 10은 NC/Nga 마우스 아토피모델에서 DNCB 용액과 병행하여 티몰을 처리한 후, 비장을 적출하고 그 무게를 측정한 그래프이다. 1 is a graph showing cytotoxicity of human fibroblasts treated with thymol compound.
2 is a graph showing changes in the expression of MMP-1 protein in human fibroblasts treated with thymol compound.
3 is a graph showing changes in the expression of MMP-3 protein in human fibroblasts treated with thymol compound.
4 is a graph showing changes in the expression of procollagen protein in human fibroblasts treated with thymol compound.
5 is a graph showing changes in the expression of TARC in keratinocyte lineage treated with thymol compound.
6 is a graph showing changes in expression of IL-6 in keratinocyte lines treated with thymol compound.
FIG. 7 is a graph showing the results of measurement of skin moisture content after treatment of thymol with NCNC / Nga mouse atopic model in parallel with DNCB solution. FIG.
8 is a graph showing the results of measurement of skin erythema after treatment of thymol with NCNC / Nga mouse atopic model in parallel with DNCB solution.
FIG. 9 is a photograph showing histological changes of the skin after treatment of thymol with NCNC / Nga mouse atopic model in parallel with DNCB solution. FIG.
FIG. 10 is a graph showing the spleen extracted and its weight after treatment with thymol in parallel with the DNCB solution in the NC / Nga mouse atopic model. FIG.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예는 단지 본 발명을 예시하기 위한 것이므로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다.Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and thus the scope of the present invention is not construed as being limited by these embodiments.
실험예 1. 세포 독성 확인Experimental Example 1. Cytotoxicity determination
세포독성은 MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 비색정량분석법(colorimetric assay)을 사용하여 측정하였다. MTT(Methyl thiazol tetrazolium) 분석은 세포 생존 능력을 측정하기 위해 사용되는 것으로, MTT가 보라색을 생성하는 포마르잔 염색으로 바꾸는 것이다. 인큐베이션 72시간 후, 배지의 부피는 1㎖로 감소하였고, 1㎎/㎖ MTT의 100㎕는 각 벽에 첨가되었다. 이후, 세포는 37℃에서 2시간 동안 5%의 CO2 및 95%의 O2 존재 하에 배양되었다. 기질-함유 배지는 제거되었고, 1㎖의 DMSO는 포마르잔 결정을 용해시키기 위해 각 벽에 첨가되었다. 또한, 상온에서 30분 동안 오비탈 쉐이커로 플레이트를 흔들었다. 100㎕의 부분 표본의 흡수율은 마이크로플레이트 리더(Molecular Devices E09090; 샌프란시스코, CA, 미국)를 사용하여 570㎚에서 흡수율을 측정함으로써 정량화하였다. 클로로겐산, 루틴 및 그의 조합이 처리된 세포(처리 후 72시간)들의 세포 독성을 확인하고자, UVB 조사된 정상 인간 진피 섬유 아세포들에서 MTT 분석을 실시하였다.Cytotoxicity was measured using a colorimetric assay of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide. MTT (Methyl thiazol tetrazolium) assay is used to measure cell viability, and MTT converts to purple-forming Fomarzan stain. After 72 hours of incubation, the volume of the medium was reduced to 1 ml, and 100 μl of 1 mg / ml MTT was added to each wall. The cells were then incubated at 37 ° C for 2 hours in the presence of 5% CO 2 and 95% O 2 . The substrate-containing medium was removed, and 1 ml of DMSO was added to each wall to dissolve the formalin crystals. The plate was also shaken with an orbital shaker for 30 minutes at room temperature. Absorbance of the 100 μl aliquot was quantified by measuring the absorbance at 570 nm using a microplate reader (Molecular Devices E09090; San Francisco, CA, USA). MTT analysis was performed on normal human dermal fibroblasts irradiated with UVB to confirm cytotoxicity of cells treated with chlorogenic acid, rutin, and combinations thereof (72 hours after treatment).
그 결과, 도 1에 나타난 바와 같이, UVB 조사 전 및 UVB 조사 후 티몰 화합물이 처리된 인간 진피 섬유상세포들의 세포 생존을 억제하지 않고 오히려 세포 생장을 촉진하고 있음을 확인할 수 있었다.As a result, as shown in FIG. 1, it was confirmed that the human dermal fibroblasts treated with the thymol compound before UVB irradiation and after UVB irradiation did not inhibit cell survival but rather promoted cell growth.
실시예 2. MMP-1 및 MMP-3 단밸질 발현 억제Example 2. Inhibition of MMP-1 and MMP-3 protein expression
40mm 세포 배양 접시에 2㎖의 DMEM 배양액을 넣고, 인간섬유아세포를 약 1.2x105의 농도로 접종한 후, 37℃, 5% CO2 환경에서 24시간 동안 배양하였다. 그 후, UVB를 144mJ/cm2 조건으로 조사한 후, 티몰(각각 0.1, 1, 및 10㎍/㎖)을 포함한 배지로 교체하여 3일간 배양하였다. 이후 배양액을 회수(harvest)하여 4℃, 7500rpm 환경에서 5분간 원심분리(centrifuge)하여 ELISA 방법을 이용하여 MMP-1 및 MMP-3(Human Total MMP-1 kit, R&D Systems, Inc., Minneapolis, MN, USA)의 단백질 발현량 변화를 확인하였다.40mm cell into the culture medium of
144mJ/cm2 용량으로 자외선 조사 처리한 인간섬유아세포는 자외선 무처리 군에 비해 MMP-1 단백질의 생성이 3배 정도 증가하였다. 이렇게 자외선 조사 처리로 인한 MMP-1 단백질의 생성 증가는 티몰의 처리에 의해서 감소하는 현상을 나타내었는데, 각각 0.1, 1, 및 10㎍/㎖ 용량에서 2%, 34%, 및 46%, 개선된 MMP-1 단백질의 생성 저해 효과를 나타내었다(도 2). 또한, 자외선 조사 처리로 인한 MMP-3 단백질의 생성 증가는 티몰의 처리에 의해서 감소하는 현상을 나타내었는데, 각각 0.1, 1, 및 10㎍/㎖ 용량에서 18%, 28%, 및 40% 개선된 MMP-3 단백질의 생성 저해 효과를 나타내었다(도 3).Human fibroblasts irradiated with ultraviolet rays at a dose of 144 mJ / cm 2 showed a three-fold increase in the production of MMP-1 protein as compared with the ultraviolet-untreated group. The increase in the production of MMP-1 protein due to the ultraviolet irradiation treatment was reduced by thymol treatment, which was improved by 2%, 34%, and 46% at 0.1, 1, and 10 μg / And showed the inhibitory effect on the production of MMP-1 protein (Fig. 2). In addition, the increase in the production of MMP-3 protein due to ultraviolet irradiation treatment was reduced by the treatment with thymol, which was improved by 18%, 28%, and 40% at 0.1, 1, and 10 μg / Indicating the inhibitory effect of MMP-3 protein (Fig. 3).
상기와 같은 결과를 통해, 본 발명의 티몰은 주름생성의 원인이 되는 MMP-1 및 MMP-3 단백질의 생성을 효과적으로 억제하여 피부 주름의 예방 및 개선에 효과적으로 사용될 수 있음을 알 수 있었다. From the above results, it can be seen that the thymol of the present invention effectively inhibits the production of MMP-1 and MMP-3 proteins, which cause wrinkles, and can be effectively used for prevention and improvement of skin wrinkles.
실시예 3. 타입 1 프로콜라겐 단백질의 합성 촉진Example 3. Promoting the synthesis of
40mm 세포 배양 접시에 2㎖의 DMEM 배양액을 넣고, 인간섬유아세포를 약 1.2x105의 농도로 접종한 후, 37℃, 5% CO2 환경에서 24시간 동안 배양하였다. 그 후, UVB를 144mJ/cm2 조건으로 조사한 후, 티몰(각각 1, 및 10㎍/㎖)을 포함한 배지로 교체하여 3일간 배양하였다. 이후 배양액을 회수(harvest)하여 4℃, 7500rpm 환경에서 5분간 원심분리(centrifuge)하여 ELISA 방법을 이용하여 타입 1 프로콜라겐(Procollagen Type I C Peptide EIA Kit, Takara, Shiga, Japan)의 단백질 발현량 변화를 확인하였다(도 4 참조).40mm cell into the culture medium of
먼저, 자외선 조사 없는 인간섬유아세포 실험에서, 티몰 처리군은 타입 1 프로콜라겐 단백질의 생성을 농도 의존적으로 증가시키고 있음을 알 수 있었다. 티몰 처리군에서는 무처리군 대비 각각 1, 및 10㎍/㎖ 용량에서 146%, 및 177% 개선된 타입 1 프로콜라겐 단백질의 생성 증가를 나타났다(도 4). First, in human fibroblast experiments without ultraviolet irradiation, it was found that the thymol-treated group increased the production of
또한, 144mJ/cm2 용량으로 자외선 조사 처리한 인간섬유아세포는 자외선 무처리 군에 비해 타입 1 프로콜라겐 단백질의 생성이 2.3배 감소하였다. 이렇게 자외선 조사 처리로 인한 타입 1 프로콜라겐 단백질의 생성 감소는 티몰 화합물의 처리에 의해서 다시 증가하는 현상을 나타내었다. 이 때, 티몰 화합물 처리군은 무처리군과 비교할 때 월등한 증가 효과를 나타내는데, 각각 10, 및 100㎍/㎖ 용량에서 ?% 및 ?% 개선된 타입 1 프로콜라겐 단백질의 생성 증가 효과를 나타내었다(도 4).In addition, human fibroblasts irradiated with ultraviolet rays at a dose of 144 mJ / cm 2 showed a 2.3-fold reduction in the production of
실시예 4. TARC 발현 촉진Example 4. Promoting TARC expression
피부각질세포주(HaCaT 5×105/well)를 FBS DMEM 배지에서 24시간 배양 후, FBS 없는 DMEM에 티몰 화합물(각각 1 및 10㎍/㎖)을 30분간 전처리 한 후, TNF-a 및 IFN-r(10ng/mL)을 희석하여 동시 처리하고, 추가 배양하였다. 24시간 경과 후, 각 well의 상층액을 human TARC ELISA kit를 사용하여 정량하였다.Skin horny cell line (HaCaT 5 × 10 5 / well ) and then after 24 hours incubation in FBS DMEM medium, pretreated for 30 minutes thymol compounds (each 1 and 10㎍ / ㎖) in DMEM without FBS, TNF-a and IFN- r (10 ng / mL) were diluted and co-treated and further cultured. After 24 hours, supernatants from each well were quantitated using a human TARC ELISA kit.
그 결과, 도 5에 나타낸 바와 같이, TNF-a 및 IFN-r에 의해 과 발현된 TARC 생성량이 티몰 화합물 처리에 따라 유의적으로 억제됨을 확인할 수 있었다. As a result, as shown in FIG. 5, it was confirmed that the amount of TARC over-expressed by TNF-a and IFN-r was significantly inhibited by thymol compound treatment.
실시예 5. 염증성 사이토카인 생성 억제Example 5 Inflammatory cytokine production inhibition
아토피성 피부염은 염증반응을 통해 더욱 확대되며, 피부 발적, 피부 과민반응, 또는 광과민 반응 등을 통해 임상적으로 아토피성 피부염 증상이 더욱 악화되는 경향을 보인다. 따라서, 아토피성 피부염이 발생한 피부 상태의 효과적인 개선을 위해서 염증반응의 조기 차단은 여드름 증상의 치료에 있어 매우 중요한 요인이다. Atopic dermatitis is further enlarged through an inflammatory reaction, and clinical symptoms of atopic dermatitis tend to be further exacerbated through skin eruption, skin irritation, or photosensitization. Therefore, early prevention of inflammatory reaction is a very important factor in the treatment of acne symptoms in order to effectively improve the skin condition resulting from atopic dermatitis.
티몰 화합물이 염증반응과 면역 활성을 억제하는 효과를 아래와 같은 방법으로 검증하였다. The effect of the thymol compound on inflammation and immunosuppressive activity was verified by the following method.
아토피성 피부염에 의해 발생되는 염증반응 메커니즘에서 IL-6 등의 염증매개 물질들이 관여하게 되며, 염증매개 물질들의 작용에 의해 염증반응이 증폭되게 되며, IL-6의 발현을 억제하는 경우 염증반응을 효과적으로 차단할 수 있게 된다.In the inflammatory reaction mechanism caused by atopic dermatitis, inflammatory mediators such as IL-6 are involved, and the inflammatory response is amplified by the action of inflammatory mediators. In the case of inhibiting the expression of IL-6, It can be effectively blocked.
아토피성 피부염이 IL-6 단백질의 발현에 미치는 영향을 검증하기 위해 피부각질세포주(HaCaT)를 대상을 실험을 수행하였다. HaCaT 세포를 96 well plate에 5.0×105 농도로 접종한 후 24시간 동안, FBS 없는 DMEM에 티몰 화합물(각각 1 및 10㎍/㎖)을 30분간 전처리 한 후, TNF-a 및 IFN-r(10ng/mL)을 희석하여 동시 처리하고, 추가 배양하였다.In order to examine the effect of atopic dermatitis on the expression of IL-6 protein, skin keratinocyte line (HaCaT) was experimented. HaCaT cells were inoculated in a 96-well plate at a concentration of 5.0 × 10 5 , and thymol compounds (1 and 10 μg / ml, respectively) were pre-treated for 30 minutes in DMEM without FBS for 24 hours. TNF-α and IFN- 10 ng / mL) were diluted, co-treated, and further cultured.
배양이 끝나고, 상등액을 취하여 IL-6 단백질 생성량을 효소결합 면역흡수 분석법(ELISA, Enzyme-Linked Immunosorbent Assay) 키트를 사용하여 분석하였다.After the incubation, the supernatant was taken and the amount of IL-6 protein produced was analyzed using an enzyme-linked immunosorbent assay (ELISA) kit.
그 결과, 티몰 화합물 처리시 LPS로 유도된 IL-6 단백질의 생성이 효과적으로 억제되는 것으로 나타났으며, 이러한 IL-6 단백질 생성 억제능은 농도 의존적인 것으로 나타났다(도 6).As a result, it was shown that the production of IL-6 protein induced by LPS was effectively inhibited by thymol compound treatment, and the inhibitory effect on IL-6 protein production was concentration-dependent (FIG. 6).
제조예. 티몰 크림의 제조Production example. Manufacture of thymol cream
유상제조를 위해 티몰, IPM, 유동 파라핀, 세토스테아릴 알코올(Cetostearyl alcohol), 글리세릴 모노스테아레이트(Glyceryl monostearate), Brij 58, Span 60, BHA, 메틸파라벤(Methyl paraben)을 혼합한 후, 이 혼합물의 온도가 70~80℃가 될 때까지 가온하여 균일하게 용해시켰다. 또한 수상제조를 위해 PEG1500, PEG4000, SLS, 잔탄검, 정제수를 혼합한 후 70~80℃에서 용해하였다. 이후, 이들 유상제조물과 수상제조물을 혼합시키기 위하여 20분간 70~80℃에서 교반시켰다. 이후, 냉각 후 정제수로 정용을 하고 실온에서 크림제제를 제조하였다.After mixing with thymol, IPM, liquid paraffin, cetostearyl alcohol, glyceryl monostearate, Brij 58, Span 60, BHA and Methyl paraben for oil phase production, The mixture was heated to uniformly dissolve until the temperature of the mixture reached 70 to 80 占 폚. PEG1500, PEG4000, SLS, xanthan gum, and purified water were mixed and dissolved at 70 to 80 ° C for preparation of the water phase. Then, the mixture was stirred at 70 to 80 ° C for 20 minutes to mix the oil-based product and the water-based product. After cooling, the mixture was poured into purified water, and a cream preparation was prepared at room temperature.
티몰은 유효성분으로 2가지 농도(0.1, 1 중량%)로 첨가하고, 하기 표 1에 기재된 성분과 함량으로 조성 성분들을 잘 유화시키고 탈기, 여과, 냉각함으로써 크림형의 조성물을 제조하였다. 크림제형의 대조군 실험을 위해 티몰을 첨가하지 않은 것을 제외하고는 위와 동일한 방법으로 피부 크림제제를 제조하였다. 상기 제형들은 제형 안정성이 양호하였으며, 피부에 대한 부작용도 없음을 확인하였다.Thymol was added as an active ingredient at two concentrations (0.1, 1% by weight), and the composition components were well emulsified by the ingredients and contents shown in the following Table 1, and deaerated, filtered and cooled to prepare a creamy composition. Skin cream preparations were prepared in the same manner as above except that no thymol was added for the control experiment of cream formulations. The formulations were found to have good formulation stability and no side effects to the skin.
[표 1][Table 1]
실험예 1. 아토피성 피부염에 대한 티몰의 효능(in-vivo)Experimental Example 1. Effectiveness of thymol against atopic dermatitis (in-vivo)
NC/Nga 마우스 아토피모델(7주령, 수컷, 각 군당 8마리, 대한바이오링크)을 이용하여 피부 염증 및 아토피 피부염과의 관계를 실험하였다. 사육은 온도(23±2℃), 습도(50±10%) 및 명암주기(12시간)는 자동으로 조절되도록 하였으며, 실험동물들을 conventional 환경에서 사육하였고 실험동물용 사료를 자유로이 급여하고 cage는 매 3일마다 교체하여 주었다. The relationship between skin inflammation and atopic dermatitis was examined using NC / Nga mouse atopic model (7 weeks old, male, 8 per group, Korea BioLink). Experimental animals were kept in a conventional environment. The animals were fed free of animal feed and cages were fed at a constant temperature (23 ± 2 ℃), humidity (50 ± 10%) and light (12 hours) Replace every 3 days.
마우스의 안정화 기간이 지난 후 마우스의 등을 귀 하단부에서부터 꼬리 상단부까지 전체를 제모하여 24시간 방치하고, 1%의 DNCB 용액(아세톤 : 올리브오일 = 3 : 1) 200㎕를 제모 부위에 1주일 간 5회 도포하였다. 이 후, 2주차부터 10주간 0.4% DNCB 용액 150 ㎕를 주3회 재도포하여 아토피성 피부염을 유발하였다. After the stabilization period of the mice, the entire back of the mouse was removed from the lower part of the ear to the upper part of the tail and allowed to stand for 24 hours. 200 μl of 1% DNCB solution (acetone: olive oil = 3: 1) 5 times. After that, 150 μl of 0.4% DNCB solution was reapplied three times a week for at least 10 weeks to induce atopic dermatitis.
DNCB 용액을 도포하기 시작한지 5주차가 되는 시점에서, DNCB 용액과 병행하여 티몰을 각각 0.1 및 1 중량% 용량으로 병행하여 도포하여 아토피 동물모델에서 티몰의 아토피 증상 개선에 미치는 영향을 관찰하였다. 아토피 질환의 치료제로 임상에서 사용되고 있는 타크롤리무스(tacrolimus) 0.1 중량%를 병행하여 도포한 군을 양성 대조군으로 사용하였다.At the 5th week of application of the DNCB solution, the effect of thymol on the improvement of atopic symptoms of thymol in the atopic animal model was observed in parallel with the DNCB solution at the dose of 0.1 and 1 wt%, respectively. As a positive control group, a group treated with 0.1 wt% of tacrolimus, which is used clinically as a treatment for atopic disease, was used.
1-1. 수분 측정1-1. Moisture measurement
NC/Nga 마우스 아토피모델 사육 10주차에 아토피 피부염의 대표적인 임상증상인 피부건조증에 대한 티몰의 영향을 살펴보기 위하여 피부 수분량을 측정하였다. 수분 측정은 (주)에스디 생명공학에서 보유하고 있는 피부측정장비(Dermalab combo, Cortex Technology, Denmark)를 이용하여 측정하였다. NC / Nga Mouse Atopy Model In order to examine the effect of thymol on dry skin, a typical clinical symptom of atopic dermatitis on the 10th week, we measured skin moisture. Moisture content was measured using a skin measuring device (Dermalab combo, Cortex Technology, Denmark) possessed by SD Biotech.
그 결과, 도 7에 도시한 바와 같이, 티몰을 병행하여 처리한 실험군에서는 피부 수분량이 157 A.U.(0.1 중량% 처리군) 및 134 A.U.(1 중량% 처리군)로 측정되어, 티몰을 처리하지 않는 대조군의 피부 수분량 44 A.U.에 비해 각각 3.6배 및 3배 개선된 수치가 관찰되었다. 본 발명의 티몰을 함유하는 조성물이 아토피 피부염의 대표적인 증상인 피부 건조증의 개선에 매우 효과적임을 알 수 있었다. As a result, as shown in Fig. 7, in the test group treated with the thymol in parallel, the skin moisture amount was measured by 157 AU (0.1 wt% treatment group) and 134 AU (1 wt% treatment group) A 3.6-fold and 3-fold improvement in skin moisture was observed in the control group compared with 44 AU, respectively. It was found that the composition containing thymol of the present invention is very effective for the improvement of dry skin syndrome which is a typical symptom of atopic dermatitis.
1-2. 홍반 측정1-2. Erythema measurement
NC/Nga 마우스 아토피모델 사육 10주차에 아토피 피부염의 대표적인 임상증상인 접촉성 피부염 증상에 대한 티몰의 영향을 살펴보기 위하여 피부 홍반 정도를 측정하였다. 피부 홍반 측정은 (주)에스디 생명공학에서 보유하고 있는 피부측정장비(Dermalab combo, Cortex Technology, Denmark)를 이용하여 측정하였다. NC / Nga mouse atopy model In order to examine the effect of thymol on contact dermatitis, a typical clinical symptom of atopic dermatitis on the 10th week, skin erythema was measured. The skin erythema measurement was performed using a skin measuring device (Dermalab combo, Cortex Technology, Denmark) possessed by SD Biotech.
그 결과, 도 8에 도시한 바와 같이, 티몰을 병행하여 처리한 실험군에서는 피부 홍반이 9 A.U.(0.1 중량% 처리군) 및 8 A.U.(1 중량% 처리군)로 측정되어, 티몰을 처리하지 않는 대조군의 피부 홍반량이 12 A.U.에 비해 개선된 수치가 관찰되었다. 이러한 수치는 본 발명의 티몰을 함유하는 조성물이 아토피 피부염의 대표적인 증상인 접촉성 피부염의 개선에 매우 효과적임을 알 수 있었다. As a result, as shown in Fig. 8, skin erythema was measured in 9 AU (0.1 wt% treated group) and 8 AU (1 wt% treated group) in the experimental group treated with thymol in parallel, An improved level of erythema of the control compared to 12 AU was observed. These values indicate that the composition containing thymol of the present invention is highly effective in improving contact dermatitis, which is a typical symptom of atopic dermatitis.
1-3. 조직학적 관찰1-3. Histological observation
H&E 염색법을 통한 조직학적 결과에서 볼 때 아토피 유발군 마우스는 아토피 비유발군 마우스에 비하여 피부표면의 염증상태가 심하고 형태학적으로 피부장벽이 깨어져 있는 모습을 확인할 수 있다. 하지만 아토피 유발 후 5주 후, DNCB 용액과 병행하여 티몰을 5주간 처리한 군은 피부표면의 염증상태가 아토피 비유발군과 유사하게 보이며, 피부장벽도 깨어져 있지 않은 것으로 관찰 되었다. Histological studies using H & E staining showed that the atopy-induced group mice had a more inflammatory state on the surface of the skin and a morphological breakdown of the skin barrier than the atopic-related non-grouped mice. However, 5 weeks after the atopy induction, the group treated with thymol for 5 weeks in parallel with the DNCB solution showed that the inflammatory state of the skin surface was similar to that of the atopic paralytic group, and the skin barrier was not broken.
아토피성 피부염 유발에 따른 실험동물의 피부(epiderms와 dermis)의 변화를 확인하기 위하여 H&E(hematoxylin&Eosin) 염색을 진행하였다. 실험동물의 피부조직을 적출하여 조직고정액인 4% 파라포름알데하이드(paraformaldehyde) 용액(pH 7.4)에 고정시킨 후 통상적인 조직표본제작법에 따라 파라핀 포매한 후, 5-6㎛ 로 절편하였다. 조직표본은 자일렌(xylene)으로 파라핀을 제거하고 함수 과정을 거친 H&E로 핵과 세포질을 염색하여 광학현미경으로 그 변화를 관찰하였다.H & E (hematoxylin & Eosin) staining was performed to determine the changes of skin (epiderms and dermis) of experimental animals caused by atopic dermatitis. The skin tissue of the experimental animals was extracted and fixed in a 4% paraformaldehyde solution (pH 7.4) as a tissue fixative, and embedded in paraffin according to a conventional tissue preparation method and then cut into 5-6 μm. Tissue samples were stained with nuclear and cytoplasm by H & E which had been treated with xylene to remove paraffin, and observed by optical microscope.
피부의 조직학적 변화를 관찰한 결과, 아토피성 피부염 동물모델의 피부는 대조군과 비교하여 표피층(epidermis)이 비후되어 있으며, 정상에 비해 그 두께가 매우 증가되어 있다. 이는 아토피성 피부염 동물모델이 외형상뿐만 아니라 조직학적으로도 변화가 유발되었음을 의미하며 아토피 기준에 합당한 것으로 판단된다. 이들 모델에서 아토피 유발 후 5주 후, DNCB 용액과 병행하여 티몰을 0.1 및 1 중량%로 5주간 처리한 경우 정상군과 거의 유사한 조직학적 소견을 보였다. 이는 아토피성 피부염 동물모델에서 티몰이 피부의 빠른 재생을 유발하는 효과를 지니고 있음을 시사한다(도 9).As a result of observing the histological changes of the skin, skin of the atopic dermatitis animal model has thickened epidermis compared to the control group and its thickness is greatly increased compared with the normal skin. This indicates that the atopic dermatitis animal model was not only changed in appearance but also histologically, it was judged to be appropriate to the atopic criteria. In these models, 5 weeks after the induction of atopy, when treated with 0.1 and 1% by weight of thymol in combination with DNCB solution, histological findings similar to those of the normal group were obtained. This suggests that thymol has an effect of inducing rapid regeneration of skin in an atopic dermatitis animal model (Fig. 9).
1-4. Spleen 무게 측정1-4. Spleen weighing
외부에서 알레르기 원인물질이 피부로 들어오면 특정한 T림프구에서 염증반응을 일으키는 Cytokine을 분비한다. 이로 인해 면역글로불린 E(IgE)가 증가하게 되고 이는 호산구의 증가로 이어져 아토피 질환의 각종 증상이 발생하게 된다. 이와 같이 아토피가 유발되면 호산구가 증가하게 되는데 호산구는 비장에 저장되므로 비장의 무게를 측정함으로 호산구의의 변화를 알아보았다(도 10). DNCB에 대한 마우스의 면역반응을 검토하기 위하여 실험종료일에 마우스를 희생시켜 비장을 적출하고 무게를 측정하였다. 실험결과 DNCB로 아토피를 유발시킨 군에서는 비장의 무게가 정상군에 비해 약 1.5배 정도의 증가한 것으로 나타났다. 이는 아토피 피부염으로 인해 호산구수가 정상수치보다 비정상적으로 늘어났음을 나타내는 것이다. 이러한 비장의 무게가 증가하는 현상은 티몰 0.1 및 1 중량%를 처리한 군에서는 관찰되지 않았는데, 티몰 0.1 및 1 중량%를 처리한 군에서는 정상군과 거의 동일한 무게를 갖는 것으로 관찰되었다. 상기와 같은 결과를 통해서 본 발명의 티몰을 유효성분으로 함유하는 조성물은 T림프구의 억제능이 우수하고, 면역글로불린의 생성을 억제함으로써 아토피 피부염의 예방 및 개선에 효과가 있음을 알 수 있었다.When an exogenous allergen enters the skin, it secretes a cytokine that causes an inflammatory response in a specific T lymphocyte. This leads to an increase in immunoglobulin E (IgE), which leads to an increase in eosinophils, leading to various symptoms of atopic disease. The eosinophil count was increased when the atopy was induced, and the eosinophil count was measured by measuring the weight of the spleen (Fig. 10). To examine the immune response of the mouse to DNCB, the mice were sacrificed at the end of the experiment and the spleen was excised and weighed. As a result, the weight of spleen was increased about 1.5 times as compared with that of normal group in DNCB induced group. This indicates that the eosinophil count is abnormally higher than the normal level due to atopic dermatitis. The increase in the weight of the spleen was not observed in the groups treated with 0.1 and 1 wt.% Of thymol. It was observed that the groups treated with 0.1 and 1 wt. These results indicate that the composition containing thymol as an active ingredient of the present invention has an excellent inhibitory effect on T lymphocytes and is effective in preventing and improving atopic dermatitis by inhibiting the production of immunoglobulin.
Claims (13)
[화학식 1]
.A pharmaceutical composition for preventing or treating skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
.
상기 조성물은 약학적으로 허용가능한 담체를 추가로 포함하는 것을 특징으로 하는 조성물.The method according to claim 1,
Wherein said composition further comprises a pharmaceutically acceptable carrier.
상기 화합물, 또는 이의 약학적으로 허용가능한 염의 농도는 0.1 내지 10 중량%인 것을 특징으로 하는 조성물.The method according to claim 1,
Wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof, is 0.1 to 10% by weight.
상기 화합물, 또는 이의 약학적으로 허용가능한 염은 타입 I 프로콜라겐 유전자의 발현을 증가시키고, MMP-1 및 MMP-3 유전자의 발현을 억제하는 것을 특징으로 하는 조성물.The method according to claim 1,
Wherein said compound, or a pharmaceutically acceptable salt thereof, increases expression of a type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes.
상기 화합물, 또는 이의 약학적으로 허용가능한 염은 IL-6(interleukin-6) 및 TARC(Thymus and activationregulated chemokine) 유전자의 발현을 억제하는 것을 특징으로 하는 조성물.The method according to claim 1,
Wherein said compound, or a pharmaceutically acceptable salt thereof, inhibits the expression of IL-6 (interleukin-6) and TARC (Thymus and activation regulated chemokine) genes.
[화학식 1]
.A health functional food composition for preventing or ameliorating skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
.
[화학식 1]
.A quasi-drug composition for prevention or improvement of skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
.
[화학식 1]
.A cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
.
상기 화합물, 또는 이의 약학적으로 허용가능한 염의 농도는 0.1 내지 10 중량%인 것을 특징으로 하는 조성물.9. The method according to any one of claims 6 to 8,
Wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof, is 0.1 to 10% by weight.
상기 화합물, 또는 이의 약학적으로 허용가능한 염은 타입 I 프로콜라겐 유전자의 발현을 증가시키고, MMP-1 및 MMP-3 유전자의 발현을 억제하는 것을 특징으로 하는 조성물.9. The method according to any one of claims 6 to 8,
Wherein said compound, or a pharmaceutically acceptable salt thereof, increases expression of a type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes.
상기 경피투여형 제제는 연고제, 크림제, 겔제, 로션제, 액제, 유제, 현탁제, 스틱제, 파스타제, 리니멘트제, 파프제, 테이프제, 에어로졸제 또는 외용산제인 것을 특징으로 하는 경피투여형 제제.12. The method of claim 11,
Wherein the transdermal preparation is an ointment, a cream, a gel, a lotion, a liquid, an oil, a suspension, a stick, a pasta, a liniment, a papermaking, a tape, an aerosol or an external acid. Dosage formulations.
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PCT/KR2017/013373 WO2019031655A1 (en) | 2017-08-11 | 2017-11-22 | Composition comprising thymol as effective ingredient for preventing or treating skin wrinkle or atopic dermatitis |
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KR20210013380A (en) * | 2019-07-23 | 2021-02-04 | (주)유스케어팜 | Composition for preventing or treating atopic dermatitis comprising extracts of Artemisia capillaris, Cinnamomum cassia, Scutellaria baicalensis and Coptis japonica |
KR20210060831A (en) | 2019-11-19 | 2021-05-27 | 대구한의대학교산학협력단 | Cosmetic composition for improving skin inflammation and wrinkles comprising Aaronia pomace extract |
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US20060263452A1 (en) * | 2005-05-17 | 2006-11-23 | Alwyn Dowell | Topical composition containing essential oils |
KR100682979B1 (en) * | 2005-07-27 | 2007-02-15 | 경북대학교 산학협력단 | Composition for precaution treatment having synergism for antimicrobial infection and antiinflammatory action and treatment for athletes foot provided by using them |
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KR20210013380A (en) * | 2019-07-23 | 2021-02-04 | (주)유스케어팜 | Composition for preventing or treating atopic dermatitis comprising extracts of Artemisia capillaris, Cinnamomum cassia, Scutellaria baicalensis and Coptis japonica |
KR20210060831A (en) | 2019-11-19 | 2021-05-27 | 대구한의대학교산학협력단 | Cosmetic composition for improving skin inflammation and wrinkles comprising Aaronia pomace extract |
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