KR101855894B1 - A pharmaceutical composition having the effect of preventing or treating of respiratory disease comprising the p-coumaric acid - Google Patents
A pharmaceutical composition having the effect of preventing or treating of respiratory disease comprising the p-coumaric acid Download PDFInfo
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- KR101855894B1 KR101855894B1 KR1020170044184A KR20170044184A KR101855894B1 KR 101855894 B1 KR101855894 B1 KR 101855894B1 KR 1020170044184 A KR1020170044184 A KR 1020170044184A KR 20170044184 A KR20170044184 A KR 20170044184A KR 101855894 B1 KR101855894 B1 KR 101855894B1
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- Prior art keywords
- respiratory
- disease
- coumaric acid
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- pharmaceutical composition
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Abstract
본 발명은 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 예방 또는 치료용 약학적 조성물에 관한 것으로, 담배연기에 노출시킨 마우스의 폐 조직에서 폐포의 확장 또는 세기관지 주변부의 염증세포 침윤이 증가하였으나, 본 발명의 쿠마릭산을 담배연기에 노출시키기 전에 경구 투여한 경우 폐포의 불규칙적인 확장이나 염증세포의 침윤이 완화됨을 확인하였다.The present invention relates to a pharmaceutical composition for the prevention or treatment of respiratory diseases, which comprises a p-coumaric acid compound or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention relates to a pharmaceutical composition for preventing or treating respiratory diseases, Or inflammatory cell infiltration at the periphery of the bronchioles. However, it was confirmed that irregular expansion of alveoli or infiltration of inflammatory cells was alleviated when oral administration of coumaric acid of the present invention before exposure to tobacco smoke.
Description
본 발명은 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 예방 및 치료용 약학적 조성물, 호흡기 질환 개선용 건강기능식품 및 면역 증강용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for the prevention and treatment of respiratory diseases comprising a p-coumaric acid compound or a pharmaceutically acceptable salt thereof as an active ingredient, a health functional food for improving respiratory diseases, and a pharmaceutical composition for enhancing immunity .
호흡기질환(respiratory disease)은 기침, 가래, 호흡곤란 및 발열 등을 동반하는 기도, 기관지 및 폐에 만성적인 염증을 유발하는 질환으로, 미세먼지 등 대기 오염 물질의 증가와 흡연 인구의 증가 등으로 인해 그 사망률이 계속적으로 증가하는 추세이다. 특히, 흡연은 호흡기질환 중 하나인 만성 기침을 야기하는 천식 이외에 만성기관지염과 만성폐쇄성폐 질환(COPD)의 원인이 되는 폐기종을 유발하는데, 이러한 폐기종의 조직병리학적 변화는 종말모세기관지 이하의 조직에 탄성조직의 소실로 폐포벽이 파괴되어 불규칙적인 폐포의 확장과 기도폐쇄를 일으키게 되는 것이다. 또한 흡연은 폐암의 주요 원인임은 주지의 사실이다. Respiratory disease is a disease that causes chronic inflammation in airways, bronchi and lungs accompanied by cough, sputum, dyspnea and fever. It is caused by the increase of air pollutants such as fine dust and the increase of the smoking population The mortality rate is on the rise. In addition, asthma causes chronic bronchitis and chronic obstructive pulmonary disease (COPD), as well as asthma, which is one of the respiratory diseases, which is one of the respiratory diseases. Histopathologic changes of these emphysema occur in the tissues below the endocardial bronchus The loss of elastic tissue destroys the alveolar wall, causing irregular alveolar expansion and airway obstruction. It is well known that smoking is a major cause of lung cancer.
지난 2008년 10월부터 2009년 6월까지 평생건강증진센터에서 폐기능검사와 저선량흉부 CT를 시행한 274명을 추적 조사한 결과, 정상 폐기능을 가진 건강한 흡연자(191명)의 25.6%(49명)에서 폐기종이 발견되었고, 흡연자의 폐기종 발병률은 비흡연자(83명)의 2.4%(2명)에서 폐기종이 발견된 것보다 10배 이상 높은 수치를 나타내었다.From October 2008 to June 2009, 274 patients who underwent pulmonary function tests and low-dose chest CT scans at the Lifelong Health Promotion Center showed that 25.6% of healthy smokers (191) ), And the incidence of emphysema of smokers was 10 times higher than that of emphysema in 2.4% (n = 2) of nonsmokers (83).
이러한 호흡기질환은 크게 상기도 질환과 하기도 질환으로 분류되는데, 상기도 질환은 기도에서부터 기관지, 후두, 인두, 비강까지 발생하는 질환으로 감기, 인두염, 후두염 및 편도염 등이 이에 속하고, 하기도 질환은 기관지 또는 폐에 발생하는 모든 질환으로 기관지염이나 폐렴 등과 같은 염증성 질환과 천식, 폐기종, 만성기관지염 및 COPD 등과 같은 기도질환, 그리고 악성 종양으로 나누게 된다. 특히, 하기도 질환의 90%가 흡연에 의한 것으로, WHO 통계에 따르면 호흡기질환인 COPD가 전체 사망률 4위를 차지 한다고 밝혔다. These respiratory diseases are classified into the upper respiratory tract diseases and the lower respiratory tract diseases. The respiratory diseases include airways, larynx, pharynx, nasal cavity, cold, pharyngitis, laryngitis and tonsillitis, Or pulmonary diseases, inflammatory diseases such as bronchitis and pneumonia, airway diseases such as asthma, emphysema, chronic bronchitis and COPD, and malignant tumors. Particularly, 90% of the lower-grade diseases are due to smoking, and according to WHO statistics, COPD, respiratory disease, is the fourth highest overall mortality rate.
천식(asthma)은 기도, 특별히, 기관지에 생기는 만성 염증을 일컫는다. 천식으로 인해 유발되는 염증은 매연, 알레르기성 항원, 찬바람, 운동, 호흡기 감염 등 매우 다양한 소인에 의하여 악화될 수 있으며, 지속적인 염증은 기도의 변형 및 기도의 과민성(hyper-responsiveness)을 야기한다. 이러한 원인들에 의하여 천명(wheezing, 기도가 좁아져 쌕쌕거리거나 가랑가랑하는 호흡음이 나타나는 증상)이나, 숨이 차고 기침이 나며, 과도한 객담이 배출되는 등의 일반적인 증상이 나타난다.Asthma refers to chronic inflammation of the airways, especially the bronchi. Inflammation caused by asthma can be exacerbated by a wide variety of scrapes, including smoke, allergic antigens, cold winds, exercise, and respiratory infections, and persistent inflammation causes airway deformation and hyper-responsiveness. These causes include general symptoms such as wheezing (wheezing, narrowing of the airways, wheezing or cramps), breathing, coughing, and excessive sputum production.
천식은 네 가지 병적 증상으로 요약될 수 있는데, 기도 내의 호산구(eosinophils)의 유입이 현저하게 증가하고, 점액(mucus)이 과다하게 분비되며, 부종(edema)이 관찰되기도 하고, 무엇보다 기도(airway)가 좁아지는 것을 특징적인 소견으로 하고 있다.Asthma can be summarized by four pathological symptoms: the inflow of eosinophils in the airways is markedly increased, mucus is excessively secreted, edema is observed, and airway ) Is narrowed.
호흡기도는 크게 점막과 기관지평활근이라는 근육으로 이루어져 있고 점막에는 많은 분비샘들이 있어 필요한 분비물을 계속 분비하고 있으며 기관지 평활근이 수축하면 호흡기도가 좁아지게 된다. 매연, 알레르기성 항원, 찬바람, 운동, 호흡기 감염 등 매우 다양한 소인에 의하여 염증반응이 일어나면 분비샘에서 나오는 분비물이 더욱 증가하게 되고 이 분비물이 기도를 막아 점막이 기도 안쪽으로 부어오르게 되어 기도를 더욱 좁게 만든다. 이로 인해, 천명을 동반한 발작적인 기침과 호흡곤란이 심하게 나타나며, 발작 시에는 마른기침이 발생되고 흉부압박감을 느끼게 된다. 천명이 없이 만성적 기침과 흉부압박감이 있는 원인을 알 수 없는 호흡곤란 증상만 있는 천식도 많은데 이 증상들은 일상생활 중에서 갑자기 발작적으로 나타나는 경향이 있다.The respiratory tract is composed of the muscles of the mucous membrane and the bronchial smooth muscle, and there are many secretory glands in the mucous membrane, which keeps secretion of necessary secretions. When the bronchial smooth muscle contracts, the respiratory rate becomes narrower. When inflammation occurs due to a wide variety of scabies such as soot, cold allergy, exercise, and respiratory infections, the secretions from the secretory glands are further increased and this secretion blocks the airway and causes the mucosa to swell inward to narrow the airway . As a result, seizure coughing and dyspnea accompanied by lethargy are severe, and when seizure occurs, dry coughing occurs and chest tightness is felt. There are many asthmatics with symptoms of respiratory distress that can not be diagnosed with chronic coughing and chest tightness without any symptoms. These symptoms tend to appear suddenly in their everyday lives.
현재, 천식은 기관지 협착증에서 만성적인 기관지 염증질환으로 개념이 새로 정립되었으며, 증상이 있을 때에 이를 완화시키는 것도 중요하지만 장기적으로 염증을 관리하는 근본적인 치료방법이 중요하다.At present, asthma is a chronic bronchitic inflammatory disease in bronchial stenosis, and it is important to alleviate it when symptoms are present, but it is important to treat inflammation in a long term.
천식을 병태/생리학적 원인으로 보면, 기도염증(airway inflammation), 기도과민성(airwayhyperresponsiveness: AHR), 점막단백 과다분비(mucin hypersecretion)가 일어나는 질환이며, 면역학적으로는 호산구(eosinophils)의 침윤, Th1 세포수에 비해 Th2 세포수의 증가, 활성화 비만 세포(mast cell) 수가 증가되는 것을 특징으로 하는 만성기도 염증질환이다. 천식의 증상으로는 기도에 백혈구 중 과립구(granulocyte) 계통인 호산구가 침윤되는 것이 대표적인 특징으로, 호산구는 기도염증과 기관지 수축을 촉진하는 여러 유발물질을 생성하여 천식의 병태/생리에 매우 중요한 역할을 수행한다. 천식을 일으키는 항원은 T 세포를 Th2 세포로의 분화를 일으키며, Th2 세포는 IL(interleukin)-5, GM-CSF(granulocyte-macrophage stimulating factor), IL-3, IL-13, IL-4 등의 사이토카인(cytokine)을 분비하고, IL-4는 B 세포에 작용하여 IgE의 생성을 촉진시키며, 비만 세포를 활성화시킨다. 비만세포 등의 염증세포가 활성화되면 다양한 염증 매개인자를 유리하며, 기도에서 기관지수축, 혈관확장, 감각신경 감작화, 콜린성 기관지수축 등의 급성 염증반응을 일으키게 된다. 대부분의 천식은 가역적이지만 일부 환자의 경우, 천식이 진행됨에 따라 상치하세포의 섬유화, 혈관수 및 점액분비 세포수의 증가 및 기도 평활근의 비후에 의한 기도 구조변화로 리모델링이 일어나며, 만성폐쇄성폐 질환(Chronic Obstructive Pulmonary Disease, COPD)에서 나타나는 기도폐쇄도 일어날 수 있다.Airway inflammation, airwayhyperresponsiveness (AHR), and mucin hypersecretion are the causes of asthma. Physiologically, eosinophils infiltrate, Th1 It is a chronic airway inflammation disease characterized by an increase in the number of Th2 cells and an increase in the number of activated mast cells compared to the number of cells. As a symptom of asthma, eosinophil infiltration of the granulocyte lineage of white blood cells is typical characteristic of eosinophils, and eosinophils play a very important role in asthma's condition / physiology by producing various inducers that promote airway inflammation and bronchoconstriction . The asthma-inducing antigens induce the differentiation of T cells into Th2 cells, and Th2 cells produce IL-5, granulocyte-macrophage stimulating factor (GM-CSF), IL-3, IL-13 and IL-4 Secrete cytokines, and IL-4 acts on B cells to stimulate the production of IgE and activate mast cells. Activation of inflammatory cells, such as mast cells, is advantageous for various inflammatory mediators and causes acute inflammatory responses such as bronchoconstriction, vasodilation, sensory neuropathy, and cholinergic bronchoconstriction in the airways. Most asthma is reversible, but in some patients remodeling occurs due to changes in the airway structure due to fibrosis, elevation of vascular and mucus secretory cells and thickening of the airway smooth muscle as the asthma progresses, and chronic obstructive pulmonary disease (COPD) may also occur in patients with chronic obstructive pulmonary disease (COPD).
만성폐쇄성폐 질환(chronic obstructive pulmonary disease, COPD)은 원인이 되는 폐 질환이나 심장질환이 없이 기도폐쇄가 발생하여 기류의 속도가 감소하는 질환군을 일컫는다. 임상적으로는 만성적으로 객담을 동반하는 기침을 하는 만성기관지염과 종말세기관지 이하의 폐포들이 비정상적으로 늘어나고 폐포격벽이 파괴되는 폐기종이 혼합되어 구분이 힘든 경우에, 이들을 총칭하여 만성폐쇄성폐 질환이라고 한다. 만성폐쇄성폐 질환은 천식과 비슷하게 호흡곤란, 기침, 가래 등의 기도 질환 증상을 나타내다가 폐 기능을 악화시켜 결국에는 사망에 이르게 된다. 발병 주요 원인은 흡연으로, 이외에도 공해와 선천적 질환, 호흡기 감염증 등이 원인이 되며, 호중성구(neutrophils) 및 대식세포(macrophage)에 의해 유도된다고 알려져 있다. 호중성구는 대표적인 염증세포로서 여러 종류의 단백분해효소를 분비하여 폐실질의 파괴와 만성적인 점액분비를 일으키며, 대식세포는 최근 IFN-γ(interferon-γ), IL-13 과발현의 중요한 염증세포로 대두되고 있고, 이는 조직손상을 일으키는 매개체(ROS[reactive oxygen species], NO[nitric oxide] 대사산물 등)를 분비할 뿐만 아니라 상처치유에 관여하는 매개체(TGF-β[transforming growth factor-β], FGF2[fibroblast growth factor 2], VEGF[endothelial growth factor] 등)를 분비하는 만성염증을 일으키는 주 원인이 되는 세포이다. 비가역적 기도폐색은 폐포의 파괴로 인해 주변 기도가 막혀 발생하는 폐기종과, 소기도인 세기관지의 염증과 이에 따른 반복적인 손상에 의해 섬유화를 특징으로 발생하는 만성폐쇄성세기관지염(small airway fibrosis, obstructive bronchiolitis)이 있다. 이러한 질환의 환자들에게는 대부분 폐기종과 함께 소기도의 염증과 섬유화가 동반하여 나타난다.Chronic obstructive pulmonary disease (COPD) refers to a group of diseases in which the air velocity decreases due to airway obstruction without causing lung or heart disease. Chronic obstructive pulmonary disease (COPD) is defined as chronic bronchitis with chronic sputum accompanied by sputum, and abnormal pulmonary vesicles with end-bronchial organs that are abnormally enlarged and pulmonary alveoli destroyed. Chronic obstructive pulmonary disease, like asthma, manifests as airway disease symptoms such as dyspnea, cough, and sputum, which then exacerbate lung function and eventually lead to death. The major cause of the disease is smoking, and it is known to be caused by pollutants, congenital diseases, respiratory infections, and by neutrophils and macrophages. This is a major inflammatory cell that secretes many kinds of proteolytic enzymes, resulting in destruction of lung parenchyma and chronic mucus secretion. Macrophages have recently become important inflammatory cells of IFN-γ (interferon-γ) and IL-13 overexpression (TGF-β [transforming growth factor-β]], which is involved in wound healing, as well as secretes mediators (ROS [reactive oxygen species], nitric oxide metabolites, FGF2 [fibroblast growth factor 2], VEGF [endothelial growth factor], and the like. The irreversible airway obstruction is characterized by emphysema of the airway obstruction due to destruction of the alveoli, small airway fibrosis (obstructive bronchiolitis) characterized by fibrosis due to inflammation of the bronchus bronchus and subsequent repetitive damage. . Most patients with these diseases are accompanied by inflammation and fibrosis of the lower airways with emphysema.
천식과 만성폐쇄성폐 질환은 모두 호흡곤란, 기침, 가래 등의 기도 질환 증상을 나타내며, 현재까지 질환 자체에 대한 원인치료제는 없다는 공통점이 있다. 현재 사용되는 천식의 치료제로는 염증을 억제하는 조절제(controller)와 호흡곤란증상을 완화시켜주는 완화제(reliever) 두 가지 뿐으로 아직까지는 원인 치료제가 없는 상황이다. 이는 천식이 매우 다양한 발병요인 및 유발인자에 의하여 발생하는 데에 비하여 나타나는 외형상의 증세는 비슷하기 때문이다. 또한 질환자체에 대한 연구가 어렵기 때문일 것으로 생각된다. 특히, 천식 관련 총사망률과 경제부담의 상당부분을 차지하고 있는 중증의 천식(severe persistent)의 대부분은 고용량 스테로이드를 포함한 치료법을 받고 있지만, 여전히 천식이 잘 조절되지 않는다는 문제가 있다. 천식치료는 약물요법, 환경요법(회피요법), 면역요법을 병행하여야 하고, 천식을 오랫동안 방치하면 기관지의 점막에 흉터가 생기는 데 이것은 회복이 불가능하며 이로 인해 천식이 더 악화되는 경우가 많으므로 초기에 치료하는 것이 중요하며 증상이 없어져도 기관지 점막의 염증은 계속 진행되어 기관지 손상을 초래하기 때문에 철저한 치료가 필요하다. 천식은 만성적이고 일시적으로 호전되었다가도 재발할 수 있으며 치료 중이라도 더 나빠질 수 있기 때문에 특히 소아천식의 경우 초기에 적극적으로 치료해서 천식 발작의 횟수를 줄이고 발작 정도도 경감시켜야 완치하기가 쉽다. 천식은 알레르기 질환이기에 치료하기가 쉽지 않고 근본치료가 되지 않는 한 유발환경에 노출되면 쉽게 재발하기 때문에 약물요법 등 철저한 환경관리가 요구된다.Both asthma and chronic obstructive pulmonary disease are symptoms of airway diseases such as dyspnea, cough, and sputum, and there is no common cause for the disease itself. Currently, there are only two treatments for asthma: a controller that suppresses inflammation and a reliever that relieves dyspnea. This is because asthma is caused by a wide variety of oncogenic factors and inducers, compared with the appearance of the symptoms. It is thought that it is difficult to study the disease itself. In particular, most of the severe persistent asthma-related mortality and economic burden, which are a significant part of the economic burden, have been treated with high-dose steroids, but asthma is still not well controlled. Asthma treatment should be accompanied by medication, environmental therapy (avoiding therapy) and immunotherapy. If left for a long time, scarring occurs in the mucous membrane of the bronchial tube, which can not be recovered. It is important to treat the bronchial mucosa, and even if the symptoms disappear, the inflammation of the bronchial mucosa continues, leading to bronchial damage. Therefore, thorough treatment is necessary. Asthma is chronic and temporarily reversible and may recur, and even worse during treatment, especially in pediatric asthma, it is often easier to cure by reducing the number of asthma attacks and reducing the severity of seizures. Because asthma is an allergic disease, it is not easy to treat it. If it is not a fundamental treatment, it will recur easily when exposed to a triggering environment.
또 다른 대표적인 호흡기질환인 알레르기비염(allergic rhinitis)은 코 알레르기 또는 알레르기성 비염이라고도 하며, 증세는 갑자기 연속적으로 재채기를 하고, 맑은 콧물이 다량으로 나오고 코가 막히며, 또한 동시에 머리가 무겁고 눈물이 나오기도 한다. 증세가 아주 비슷하면서 항원이 분명하지 않은 것을 혈관운동신경성 비염이라 한다. 즉, 하루 중 아침에 일어나서 몸이 일시적으로 식었을 때에 앞에서 말한 바와 같은 증세가 일어났다가 수 시간 만에 낫는 것도 있으며, 1년 중 환절기라든지 추운 계절에 많이 나타난다. 흔히 코감기로 혼동되는데 감기와는 다르며, 천식이나 두드러기를 동반하는 경우가 많다.Another common respiratory disease, allergic rhinitis, is also known as nasal allergies or allergic rhinitis. Sudden onset, sneezing suddenly, a lot of clear nasal discharge, nasal obstruction, and head heavy and tear Also. It is called vasomotor rhinitis, a condition in which the symptoms are very similar and the antigen is not clear. In other words, when you get up in the morning of the day and your body temporarily cools down, the symptoms mentioned above may be recovered within a few hours, and many occur during the turn of the year or during the cold season. It is often confused with a cold, which is different from a cold, often accompanied by asthma or urticaria.
알레르기성 비염의 알레르기 반응은 일종의 항원과 항체 과민반응, 비만세포와 호염구의 세포막에서 히스타민이 유리되고, 아라키돈산(arachidonic acid)이 유리되어 싸이클로옥시게나제(cyclooxygenase, COX)와 5-리폭시게나제(5-lipoxygenase, 5-LO)에 의해 프로스타글란딘류와 루코트리엔을 생성시켜, 항원 노출 2 내지 90분 사이에 나타나는 초기 반응과 4 내지 8시간 이후에 나타나는 후기 반응을 매개한다. 초기 반응은 주로 매개물질에 의해, 후기 반응은 주로 세포의 침윤에 의해 나타난다. 또한, 알레르기성 및 비알레르기성 비염은 모두 천식 발병의 위험인자로 작용한다. 알레르기비염의 치료는 항원이 분명할 때는 탈감작요법을 행하고, 기타 약물요법, 수술적 요법, 이학적 요법 등이 있지만 완전히 낫기는 어렵다.Allergic reactions of allergic rhinitis are caused by a type of antigen and antibody hypersensitivity, histamine in the cell membrane of mast cells and basophils is liberated, arachidonic acid is released, cyclooxygenase (COX) and 5-lipoxygenase (5-lipoxygenase, 5-LO) to mediate prostaglandins and rucotrienes, which show an initial response between 2 and 90 minutes of antigen exposure and a late response after 4 to 8 hours. The initial response is mainly mediated by the mediator, and the late response is mainly by cellular infiltration. In addition, both allergic and nonallergic rhinitis act as risk factors for the development of asthma. Treatment of allergic rhinitis is performed when desensitization is performed when the antigen is evident, and other drug therapy, surgical therapy, and physical therapy, but it is difficult to be completely cured.
농흉(pyothorax)은 흉곽과 폐를 둘러싸는 늑막 사이의 공간인 늑막강에 고름이 괴는 현상이다. 주된 원인은 포도상구균성 폐렴에 의한 것이 가장 많고, 그 다음이 폐렴구균, 독감균에 의한 것 등으로서, 폐에 침입한 세균이 주위의 늑막강으로 퍼져서 발생한다.Pyothorax is a phenomenon of pus in the pleural cavity, which is the space between the pleura surrounding the thorax and the lung. The most common cause is staphylococcal pneumonia, followed by pneumococci, influenza, and the like. Bacteria entering the lungs spread to the surrounding pleural cavity.
기침, 가래는 찬공기, 병원성 미생물을 포함한 외부 이물질, 대기 오염 물질, 알레르기 유발 물질 등과 같은 물리 화학적 요인 등에 의해 발생된다. 기침은 기도 점막 자극에 의해 반사적으로 일어나는 방어기전으로, 지나친 자극에 의한 지속적인 기침이 유발될 경우, 환자의 삶의 질을 경감시키고 악화시키게 된다. 또한, 기침과 같은 원리로 외부에서 먼지나 자극 물질 등이 유입되면 우리 몸의 기관지에서는 타액과 함께 근육운동을 해서 외부로 밀어내게 되는데, 이것이 객담(가래) 형성의 원인이며 폐 등 기관지 염증에 의해서 짙은 화농성 객담이 생기게 된다. 이 때, 기침을 억제하는 치료법을 진해(鎭咳)라 하고, 가래를 억제하는 치료법을 거담(祛痰)이라 한다.Cough, sputum is caused by cold air, external foreign substances including pathogenic microorganisms, physicochemical factors such as air pollutants and allergens. Coughing is a defense mechanism that occurs reflexively by airway mucosal stimulation. If persistent coughing is induced by excessive stimuli, the quality of life of the patient is reduced and worsened. In addition, when dust or irritant substances are introduced from the outside by the same principle as coughing, the bronchus of our body pushes out with the saliva along with the saliva, which causes the formation of sputum (sputum) There will be a dense purulent sputum. At this time, the cure-suppressing treatment is called Jinseong (鎭 咳), and the treatment for suppressing the sputum is called gutum (祛痰).
급성기관지염(acute bronchitis)은 독립된 질환이 아니라 다른 상하기도의 질환과 수반되어 나타난다. 급성기관지염은 흔히 비인두염과 같은 상기도 감염 및 인플루엔자, 백일해, 홍역, 장티푸스, 디프테리아, 성홍열 감염과 함께 오며, 세균성 질환을 제외하고는 모두 바이러스 감염에서 기인된다. 가끔 객담에서 폐렴 구균, 포도상 구균, 헤모필루스 인플루엔자, 여러 형태의 연구균이 발견되지만 이는 세균 감염이 원인이라는 뜻이 아니며, 아울러 항생제 치료가 병의 경과에 영향을 주지 않는다. 주 증상으로는 기관지점막에 발적, 종창, 건조 등이 있고, 기관지에서 점액성 또는 농성(膿性)의 분비물을 볼 수 있다. 보통은 합병증을 일으키는 일이 없이 회복되지만, 만성으로 이행되면 점막의 종창(腫脹), 비후(肥厚), 위축을 초래하는데, 오래되면 섬유의 증식이 생기고 기관지 협착을 일으키거나 폐기종 등이 속발되기도 한다.Acute bronchitis is not an independent disease but is accompanied by other illnesses. Acute bronchitis often accompanies upper respiratory infections such as nasopharyngitis and influenza, pertussis, measles, typhoid, diphtheria, and scarlet fever, all of which are caused by viral infection except bacterial diseases. Staphylococcus aureus, Staphylococcus aureus, Hemophilus influenza, and several types of laboratory bacterium are found in sputum, but this does not mean that it is caused by bacterial infection, and antibiotic treatment does not affect the course of the disease. Main symptoms include redness, swelling, and dryness of the bronchial mucosa, and mucus or purulent secretions from the bronchi. It usually resolves without causing any complications, but chronic progression can lead to swelling, thickening, and atrophy of the mucous membranes. Prolonged fibrosis, bronchopulmonary stenosis, or emphysema may occur in the long term .
만성기관지염(chronic bronchitis)은 2년 연속, 1년에 3개월 이상 가래가 있고 기침이 지속되는 질환이다. 흡연, 대기 오염, 직업적 노출 등의 자극이 기관지 손상을 일으켜 이로 인해 만성 기관지염이 발병하는 것으로 추정하고 있으며, 만성 기침, 가래, 운동 시 호흡곤란이 주 증상이다. 병이 진행할 경우 비교적 수개월에서 수년에 걸쳐 서서히 호흡곤란이 심해져 약간의 활동에도 호흡곤란을 느끼게 된다.Chronic bronchitis is a disease that lasts for 2 consecutive years, has sputum more than 3 months in a year, and persists coughing. It is estimated that smoking, air pollution, occupational exposure, and other stimuli cause bronchial injury, resulting in chronic bronchitis. Chronic cough, sputum and dyspnea are the main symptoms. When the disease progresses, the respiratory difficulty gradually increases over a period of several months to several years, so that even a little activity causes difficulty in breathing.
후두염(laryngitis)은 바이러스나 세균 등의 감염에 의해 후두 자체에 염증이 생기거나, 인두염, 편도염 등과 같은 주변 조직의 염증이 후두로 파급되어 발생한다. 감기의 부분 증상으로 나타나는 경우가 많으며, 대부분 코감기(급성 비염)나 인두염을 동반하고 기침이 발생하며 목소리가 변하게 된다. 후두염은 상기도 호흡기 질환으로 통칭되는 감염성 질환으로 인두염, 후두염, 기관지염과 명확히 구분하는 것은 어렵다.Laryngitis is caused by inflammation of the larynx itself caused by infection with viruses or bacteria, or by inflammation of surrounding tissues such as pharyngitis and tonsillitis, which are spread to the larynx. It is often a partial symptom of cold. Most of them are accompanied by nose cold (acute rhinitis) or pharyngitis, coughing occurs and voices change. Laryngitis is an infectious disease commonly referred to as respiratory disease, and it is difficult to clearly distinguish it from pharyngitis, laryngitis, and bronchitis.
세기관지염(bronchiolitis)은 허파꽈리에 염증이 생겨서 호흡곤란을 일으키는 질환으로 기관지초염이라고도 한다. 세기관지 내벽에 염증이 생겨서 내벽 세포가 뭉치거나 부어서 내강이 좁아지고 그에 따라 호흡곤란을 일으키는 질환으로, 전염성이며 종종 유행하기도 한다. 세기관지는 기관지로부터 폐포로 공기를 운반하고 폐포는 혈액에 산소를 공급해 주는 역할을 한다. 원인은 바이러스나 세균에 감염되거나 동시에 둘 다에 감염된 경우를 들 수 있다. 어떤 경우에는 감기에 걸릴 때마다 질환이 발생하는 경우도 있다. 위험요인으로는 저항성을 감소시키는 질환 중 특히 호흡기 감염과 알레르기 질환 가족력, 비만증 등을 들 수 있다. 합병증으로 영구적인 폐 질환으로 만성 기관지염, 폐의 부분적 붕괴, 기관지 확장증, 폐렴 재발 등이 일어날 수 있고 드물게는 만성폐쇄성폐 질환을 일으키기도 한다.Bronchiolitis (bronchiolitis) is a disease that causes irritation of the lining of the lungs, causing bronchiolitis. The inflammation of the inner lining of the bronchial tube causes the inner wall cells to clump or swell, narrowing the lumen and causing dyspnea, which is contagious and often prevalent. Bronze bronchus carries air from the bronchi to the alveoli and alveoli supply oxygen to the blood. Causes can be infected with viruses or bacteria, or both. In some cases, the illness may occur every time a person catches a cold. Risk factors include respiratory infections, family history of allergic diseases, and obesity, among other diseases that reduce resistance. Complications include persistent pulmonary disease, chronic bronchitis, partial collapse of the lung, bronchiectasis, recurrence of pneumonia, and rarely cause chronic obstructive pulmonary disease.
인후염(laryngopharyngitis)은 흔히 말하는 감기, 목 감기, 상기도 감염에 해당하는 질병이다. 베타 용혈성 사슬알균, 포도알균, 폐렴알균, 헤모필루스균과 혐기성 균주와 같은 세균 또는 인플루엔자 바이러스, 단순포진 바이러스, 파라인플루엔자 바이러스, 콕사키 바이러스, 에코 바이러스 등과 같은 바이러스 등이나 세균 등에 감염되어 인두, 후두를 포함한 상기도 점막에 염증이 생긴 경우를 말하며 급성과 만성이 있다. 급성은 급격한 기온변화, 감기, 열성질환, 과로, 허약한 체질, 세균 감염 등의 원인으로 발생하고, 만성은 급성인후염이 반복해서 재발하거나 지나친 흡연, 음주, 과로, 자극성 음식 섭취, 목의 혹사, 인후두 역류질환 등이 원인이 되어 나타난다. 드물게는 자극성 가스나 화학물질, 화학증기를 들이마시거나 부비동 등 인접 부위로부터 염증이 파급되어 생길 수도 있다.Laryngopharyngitis is a common cold, throat and upper respiratory infection. Beta hemolytic streptococcus, staphylococcus aureus, pneumococcus, bacteria such as hemophilus and anaerobic strain, or viruses such as influenza virus, herpes simplex virus, parainfluenza virus, coxsack virus, It is acute and chronic. It is acute and chronic. Acute is caused by sudden temperature changes, cold, febrile disease, overwork, weak constitution, bacterial infection, chronic, acute sore throat repeatedly recurrence or excessive smoking, drinking, overwork, irritating food intake, Laryngopharyngeal reflux disease and other causes. In rare cases, irritating gases, chemicals, chemical vapors, or inflammation may spread from adjacent areas, such as the sinuses.
2006년 기준으로 전 세계의 천식, 만성기관지염 및 폐기종 등과 같은 염증성 호흡기질환을 치료하기 위하여 사용되는 약물로는 스테로이드성 면역억제제, 테오필린과 항콜린제 등의 기관지 확장제 등이 사용되고 있지만, 이러한 약물들은 개개인에 따라 치료효과의 차이가 있으며 그 효과 또한 미미할 뿐만 아니라 구토, 설사, 두통, 어지럼증 및 체중감소 등의 극심한 부작용을 유발하기 때문에 새로운 치료제의 개발이 요구되어지고 있는 실정이다. In 2006, medications used to treat inflammatory respiratory diseases such as asthma, chronic bronchitis and emphysema all over the world are steroid immunosuppressants, bronchodilators such as theophylline and anticholinergics, Therefore, there is a need for the development of a new therapeutic agent because it causes a severe side effect such as vomiting, diarrhea, headache, dizziness and weight loss.
임상실험에서 폐 염증에 의한 호흡기질환을 연구하는데 있어, 양성대조군으로 많이 사용되어지는 약물인 roflumilast(ROF)는 선택적인 PDE4 억제제로 COPD의 항염증성 치료제로 많이 사용되어지고 있다. 그러나 구토, 설사, 체중감소, 두통 및 어지럼증 등의 부작용을 나타내는 한계가 있다.In clinical trials, roflumilast (ROF), a drug commonly used as a positive control in the study of respiratory diseases caused by pulmonary inflammation, is a selective PDE4 inhibitor and is widely used as an anti - inflammatory drug for COPD. However, there is a limit to the side effects such as vomiting, diarrhea, weight loss, headache and dizziness.
이에, 본 발명자들은 부작용을 최소화하면서 그 효과가 우수한 천연물로부터 유래된 p-coumaric acid 단일화합물이 폐의 염증을 억제하고, 치료효과를 나타내는 것을 확인함으로써 본 발명을 완성하였다.Thus, the inventors of the present invention have completed the present invention by confirming that a single compound of p-coumaric acid derived from a natural product having excellent effects while minimizing side effects suppresses inflammation of the lungs and shows a therapeutic effect.
본 발명의 목적은 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 예방 및 치료용 약학적 조성물, 호흡기 질환 개선용 건강기능식품 및 면역 증강용 약학적 조성물을 제공하는데 있다. It is an object of the present invention to provide a pharmaceutical composition for the prevention and treatment of respiratory diseases comprising a p-coumaric acid compound or a pharmaceutically acceptable salt thereof as an active ingredient, a health functional food for improving respiratory diseases, And to provide a solid composition.
상기 목적을 달성하기 위하여, 본 발명은 In order to achieve the above object,
하기 화학식 1로 표시되는 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 예방 및 치료용 약학적 조성물을 제공한다:There is provided a pharmaceutical composition for the prevention and treatment of respiratory diseases comprising, as an active ingredient, a p-coumaric acid compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
. .
또한, 본 발명은 상기 화학식 1로 표시되는 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for improving respiratory diseases, which comprises the p-coumaric acid compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
아울러, 본 발명은 상기 화학식 1로 표시되는 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 면역 증강용 약헉적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for immune enhancement comprising, as an active ingredient, a p-coumaric acid compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
본 발명은 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 예방 및 치료용 약학적 조성물에 관한 것으로, 담배연기에 노출시킨 마우스의 폐 조직에서 폐포의 확장 또는 세기관지 주변부의 염증세포 침윤이 증가하였으나, 본 발명의 쿠마릭산을 담배연기에 노출시키기 전에 경구 투여한 경우 폐포의 불규칙적인 확장이나 염증세포의 침윤이 완화됨을 확인하였다.The present invention relates to a pharmaceutical composition for the prevention and treatment of respiratory diseases, comprising a p-coumaric acid compound or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention relates to a pharmaceutical composition for preventing and treating respiratory diseases, Or inflammatory cell infiltration at the periphery of the bronchioles. However, it was confirmed that irregular expansion of alveoli or infiltration of inflammatory cells was alleviated when oral administration of coumaric acid of the present invention before exposure to tobacco smoke.
도 1은 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 체중 감소 억제 효과를 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배연기에 노출시킨 실험군.
도 2는 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 BALF 내 전체 염증세포 수와 각 염증세포(macrophage, neutrophil 및 lymphocyte) 수의 감소 효과를 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군.
도 3는 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 BALF 내 염증성 사이토카인 IL-1B, IL-6, TNF-α 및 MCP-1의 발현량을 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배연기에 노출시킨 실험군.
도 4는 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 폐 조직에서 폐포의 불규칙적인 확장상태를 조직학적으로 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군
도 5은 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 폐포의 확장 정도를 넓이값으로 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군
도 6은, 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 기관지 주위로의 염증세포 침윤정도를 조직학적으로 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군.
도 7은, 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 염증 정도를 점수로 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군.
도 8은, 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 TNF-α 및 MIP-3α의 mRNA 량을 real-time PCR을 이용하여 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군.
도 9는, 쿠마릭산(p-coumaric acid) 화합물의 투여를 통한 염증성 폐 질환 마우스 모델의 폐에서 NF-κB 및 MMP-12 단백질 발현양을 나타낸 도이다:
CON : 담배연기에 노출되지 않은 정상대조군;
CS : 담배연기에 노출시킨 음성대조군;
ROF : roflumilast를 처리한 후 담배연기에 노출시킨 양성대조군;
P-CA 5 : 쿠마릭산(p-coumaric acid) 화합물 5 mg/kg를 처리한 후 담배연기에 노출시킨 실험군; 및
P-CA 10 : 쿠마릭산(p-coumaric acid) 화합물 10 mg/kg를 처리한 후 담배 연기에 노출시킨 실험군.Brief Description of the Drawings Fig. 1 is a graph showing an effect of suppressing weight loss of a mouse model of inflammatory lung disease through administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
FIG. 2 is a graph showing the effect of decreasing the total number of inflammatory cells and the number of macrophages, neutrophils and lymphocytes in the BALF of a mouse model of inflammatory lung disease through administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
FIG. 3 shows the expression levels of the inflammatory cytokines IL-1B, IL-6, TNF-α and MCP-1 in BALF of a mouse model of inflammatory lung disease through administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
Figure 4 is a histological illustration of the irregular enlargement of the alveoli in the lung tissue of an inflammatory lung disease mouse model through the administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke
Figure 5 shows the extent of expansion of alveoli in an inflammatory lung disease mouse model through the administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke
6 is a histological diagram showing the degree of inflammatory cell infiltration around the bronchi of a mouse model of inflammatory lung disease through the administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
FIG. 7 is a graph showing the degree of inflammation of a mouse model of inflammatory lung disease through the administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
8 is a diagram showing the amount of mRNA of TNF-? And MIP-3? In a mouse model of inflammatory lung disease through administration of a p-coumaric acid compound using real-time PCR:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
9 is a graph showing the amount of NF-κB and MMP-12 protein expression in the lung of an inflammatory lung disease mouse model through administration of a p-coumaric acid compound:
CON: normal controls not exposed to tobacco smoke;
CS: Negative control exposed to cigarette smoke;
ROF: Positive control after exposure to roflumilast and exposure to tobacco smoke;
P-CA 5: Experimental group treated with 5 mg / kg of p-coumaric acid compound and exposed to cigarette smoke; And
P-CA 10: Experimental group treated with 10 mg / kg of p-coumaric acid compound and exposed to cigarette smoke.
이하, 본 발명에서 사용한 용어를 설명한다.Hereinafter, terms used in the present invention will be described.
본 발명에서 사용되는 용어 "예방"은 본 발명의 조성물의 투여로 만성폐쇄성 폐 질환(chronic obstructive pulmonary disease, COPD)을 억제시키거나 진행을 지연시키는 모든 행위를 의미한다.The term " prophylactic " as used herein refers to all actions that inhibit or delay the progression of chronic obstructive pulmonary disease (COPD) by administration of the composition of the present invention.
본 발명에서 사용되는 용어 "치료" 및 "개선"은 본 발명의 조성물의 투여로 만성폐쇄성 폐 질환의 증상이 호전 또는 이롭게 변경되는 모든 행위를 의미한다.As used herein, the terms " treatment " and " improvement " refer to all actions by which administration of the composition of the present invention improves or alleviates symptoms of COPD.
본 발명에서 사용되는 용어 "투여"는 임의의 적절한 방법으로 개체에 소정의 본 발명의 조성물을 제공하는 것을 의미한다.The term " administering " as used herein is meant to provide any desired composition of the invention to an individual by any suitable method.
본 발명에서 사용되는 용어 "개체"는 본 발명의 조성물을 투여하여 만성폐쇄성 폐 질환의 증상이 호전될 수 있는 질환을 가진 인간, 원숭이, 개, 염소, 돼지 또는 쥐 등 모든 동물을 의미한다.The term " individual " as used herein refers to all animals such as humans, monkeys, dogs, goats, pigs or rats having a disease in which symptoms of chronic obstructive pulmonary disease can be improved by administering the composition of the present invention.
본 발명에서 사용되는 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜 또는 위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 이는 개체의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시에 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 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The term " pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit or risk rate applicable to medical treatment, including the type of disease, severity, activity of the drug, The time of administration, the route and rate of excretion of the drug, the duration of the treatment, factors including drugs used simultaneously and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. 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 side effects, which can be easily determined by those skilled in the art.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 예방 및 치료용 약학적 조성물을 제공한다:The present invention provides a pharmaceutical composition for the prevention and treatment of respiratory diseases comprising, as an active ingredient, a p-coumaric acid compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
. .
상기 화합물은 죽여(Bambusae Caulis in Taeniam)로부터 분리된 것이 바람직하나 이에 한정되지 않는다.The compound is preferably isolated from Bambusae Caulis in Taeniam, but is not limited thereto.
상기 호흡기 질환은 호흡기 염증성 폐 질환, 만성 폐쇄성 폐 질환 (COPD), 부비강염, 알레르기성 비염, 하기도 감염증, 급만성기관지염, 폐기종, 폐렴, 기관지 천식, 기관지 확장증, 폐기종, 폐결핵 후유증, 급성 호흡 궁박증후군(窮迫症候群), 낭포성 섬유증, 중이염 및 폐섬유증으로 이루어진 군으로부터 선택되는 하나 이상의 질환인 것이 바람직하나 이에 한정되지 않는다. The respiratory disease is selected from the group consisting of respiratory inflammatory lung disease, chronic obstructive pulmonary disease (COPD), sinusitis, allergic rhinitis, lower respiratory tract infection, acute chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, pulmonary tuberculosis, acute respiratory distress syndrome Atherosclerotic syndrome), cystic fibrosis, otitis media, and pulmonary fibrosis, but is not limited thereto.
상기 조성물은 폐포의 불규칙적인 확장 또는 염증세포의 침윤을 감소시키는 것이 바람직하다.The composition preferably reduces irregular enlargement of the alveoli or infiltration of inflammatory cells.
본 발명의 구체적인 실시 예에서, 본 발명자들은 염증성 폐 질환 동물모델을 제조하기 위해 담배연기 노출을 통해 동물 모델을 제조하였고, 담배연기에 노출시키지 않은 정상대조군(Control, CON), 담배연기를 노출시킨 음성대조군(Cigarette Smoking, cs), roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)으로 구별하여 각 그룹 당 6마리씩 나누었고, 쿠마릭산의 담배 연기 노출로 인한 체중 감소의 억제 효과를 확인한 결과, 담배연기를 노출시킨 음성대조군 그룹(cs)이 대조군 그룹(CON)에 비해서 마우스의 체중이 감소하는 것을 확인하였으며, p-coumaric acid(P-CA)를 각 5, 10 mg/kg 농도별로 투여한 그룹이 담배연기를 노출시킨 음성대조군 그룹(cs)에 비해서 농도에 의존적으로 체중이 덜 감소하는 것을 확인하였다(도 1 참조).In a specific embodiment of the present invention, we prepared an animal model through tobacco smoke exposure to produce an animal model of inflammatory lung disease and compared with a normal control (Control, CON), tobacco smoke exposed (ROF), p-coumaric acid, or 10 mg / kg of cigarette smoke after cigarette smoking (cigarette smoking, cs) and roflumilast (Cs) were exposed to tobacco smoke. The control group (cs) exposed to cigarette smoke was divided into control group (control group) and control group (Cc), which was exposed to cigarette smoke, showed a decrease in the body weight of the mice compared to the control group (CON), and a group administered with p-coumaric acid (P-CA) Depend on concentration It was confirmed that a less weight loss (see Fig. 1).
또한, BALF 내 전체 염증세포와 macrophage, neutrophil 및 lymphocyte 수의 감소를 확인한 결과, 담배연기로 자극을 주었을 경우 전체 염증세포의 수가 증가하였고, P-CA를 각각 5, 10 mg/kg 농도로 투여한 후 담배연기에 노출시킨 그룹은 담배연기를 노출시킨 음성대조군 그룹(cs)과 비교하여 유의성 있게 감소하였다(도 2 참조).In addition, the reduction of total inflammatory cells and macrophage, neutrophil and lymphocyte counts in BALF showed that the total number of inflammatory cells increased when stimulated with tobacco smoke and that P-CA was administered at 5 and 10 mg / kg, respectively The group exposed to post-cigarette smoke decreased significantly compared to the negative control group (cs) exposed to cigarette smoke (see FIG. 2).
또한, P-CA를 각각 5, 10 mg/kg 농도로 투여한 후 담배연기에 노출시킨 그룹은 담배연기를 노출시킨 음성대조군 그룹(cs)과 비교하여 IL-1B, IL-6, TNF-α 및 MCP-1의 발현량이 유의하게 감소하였다(도 3 참조).In addition, the groups exposed to tobacco smoke after administration of P-CA at 5 and 10 mg / kg, respectively, showed higher levels of IL-1B, IL-6 and TNF-α compared to the negative control group (cs) And the expression level of MCP-1 was significantly decreased (see FIG. 3).
또한, 담배 연기에 노출시킨 음성대조군 그룹(CS)에서는 담배연기에 노출시키지 않은 정상대조군(CON) 그룹과 비교하여 폐포 파괴에 의한 비정상적인 큰 폐포 공간으로의 확장을 보였으며(도 4 참조), 폐 기관지 주위로 염증세포들의 침윤이 일어난 것으로 보아 폐의 손상이 되었음을 확인할 수 있었다(도 6 참조). 이를, 폐포의 불규칙적인 확장 정도와 폐 기관지 주위로의 염증세포의 침윤 정도를 점수로 매긴 결과는 정상대조군(CON) 그룹에서 가장 작은 수치를 보였으며 roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 경우에는 유의성 있게 감소하는 것을 확인하였다(도 5 및 도 7 참조).In addition, in the negative control group (CS) exposed to the cigarette smoke, the group expanded to abnormal large alveolar space due to alveolar destruction (see FIG. 4) as compared with the normal control group (CON) The infiltration of inflammatory cells around the bronchus showed that the lungs were damaged (see FIG. 6). The results were as follows: The number of irregular enlargement of the alveoli and the degree of infiltration of inflammatory cells around the lung bronchus were the lowest in the control group (CON) group. The positive control group, which received roflumilast, (P-
또한, 폐 조직 내의 TNF-α 및 MIP-3α mRNA 량을 확인한 결과, 담배연기를 노출시킨 그룹(CS)과 비교하여 양성대조군(ROF)과 p-coumaric acid 5 mg/kg 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 경우에는 유의성 있게 감소하는 것을 확인하였고(도 8 참조), 폐 조직 내의 NF-κB 및 MMP-12 protein 량을 확인한 결과에서도 실험군(P-CA 5 또는 P-CA 10) 그룹에서 유의성 있게 감소한 것을 확인할 수 있었다(도 9 참조).In addition, the amounts of TNF-α and MIP-3α mRNA in lung tissues were examined. As a result, positive control (ROF) and p-
따라서, 본 발명의 쿠마릭산 화합물을 담배연기에 노출되기 전에 경구 투여하면 체중 감소가 억제되고 염증성 사이토카인이 감소하며 폐포의 불규칙적인 확장이나 염증세포의 침윤이 완화되므로, 쿠마릭산 화합물을 유효성분으로 함유하는 조성물을 호흡기 질환 예방 또는 치료용 약학적 조성물, 건강기능식품 또는 면역 증강용 조성물로 사용할 수 있다.Therefore, oral administration of the coumaric acid compound of the present invention before exposure to tobacco smoke inhibits weight loss, decreases inflammatory cytokines, and alleviates irregular enlargement of alveoli or infiltration of inflammatory cells. Therefore, a coumaric acid compound as an active ingredient May be used as a pharmaceutical composition for the prevention or treatment of respiratory diseases, a health functional food, or a composition for enhancing immunity.
본 발명의 상기 [화학식 1]로 기재되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.The compound represented by the above formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면 메탄올, 에탄올, 아세톤 또는 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method such as methanol, ethanol, acetone or methylene chloride, acetonitrile and the like, which is obtained by filtering and drying the precipitate formed by adding an organic acid or an inorganic acid, Followed by distillation under reduced pressure, followed by drying or crystallization in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
나아가, 본 발명은 상기 [화학식 1]로 기재되는 화합물 또는 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 이성질체 등을 모두 포함한다.Further, the present invention includes all solvates, hydrates, isomers, and the like, which can be prepared therefrom, as well as a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.
상기 [화학식 1]로 기재되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 일반적인 의약품 제제의 형태로 사용될 수 있다.The pharmaceutical composition containing the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient may be used in the form of a general pharmaceutical preparation.
상기 약학적 조성물은 약제학적으로 허용가능한 첨가제를 추가적으로 포함할 수 있으며, 이때 약제학적으로 허용가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨, 탈크 등이 사용될 수 있다. 본 발명에 따른 약제학적으로 허용가능한 첨가제는 상기 조성물에 대해 0.1 - 90 중량부 포함되는 것이 바람직하다.The pharmaceutical composition may further comprise a pharmaceutically acceptable additive, wherein pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose Starch glycolate, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, calcium stearate, , White sugar, dextrose, sorbitol, talc, and the like. The pharmaceutically acceptable additives according to the present invention are preferably contained in an amount of 0.1 to 90 parts by weight based on the composition.
상기 약학적 조성물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 크라이토싸이빈 유도체 또는 이의 약학적으로 허용가능한 염에 적어도 하나 이상의 부형제 예를들면, 전분, 칼슘카보네이트(Calcium carbonate), 수크로스(Sucrose) 또는 락토오스(Lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성 용제, 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, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition may be administered orally or parenterally in various clinical formulations. In the case of pharmaceutical preparations, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, ≪ / RTI > Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain at least one excipient such as starch, Calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions and syrups, and various excipients such as wetting agents, sweetening agents, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
상기 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여할 수 있으며, 비경구 투여시 피부 외용 또는 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식을 선택하는 것이 바람직하다. 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다.The pharmaceutical composition may be administered orally or parenterally in accordance with the desired method. In the case of parenteral administration, the composition may be administered by external or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, . The dosage varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
상기 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여할 수 있으며, 비경구 투여시 피부 외용 또는 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식을 선택하는 것이 바람직하다. 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다.The pharmaceutical composition may be administered orally or parenterally in accordance with the desired method. In the case of parenteral administration, the composition may be administered by external or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, . The dosage varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
상기 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하며, 일일 투여량은 본 발명의 추출물 또는 이의 분획물의 양을 기준으로 0.0001 내지 100 ㎎/㎏이고, 바람직하게는 0.001 내지 10 ㎎/㎏이며, 하루 1 ~ 6 회 투여될 수 있다.The dosage of the pharmaceutical composition varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. Preferably 0.001 to 10 mg / kg, based on the amount of the fractions thereof, and may be administered 1 to 6 times per day.
상기 약학적 조성물은 염증성 질환의 예방 및 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The pharmaceutical composition may be used alone or in combination with methods for the prevention and treatment of inflammatory diseases or using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
또한, 본 발명은 상기 [화학식 1]로 표시되는 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 호흡기 질환 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for improving respiratory diseases comprising, as an active ingredient, a p-coumaric acid compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof.
상기 화합물은 죽여(Bambusae Caulis in Taeniam)로부터 분리된 것이 바람직하나 이에 한정되지 않는다. The compound is preferably isolated from Bambusae Caulis in Taeniam, but is not limited thereto.
상기 호흡기 질환은 호흡기 염증성 폐 질환, 만성 폐쇄성 폐 질환 (COPD), 부비강염, 알레르기성 비염, 하기도 감염증, 급만성기관지염, 폐기종, 폐렴, 기관지 천식, 기관지 확장증, 폐기종, 폐결핵 후유증, 급성 호흡 궁박증후군(窮迫症候群), 낭포성 섬유증, 중이염 및 폐섬유증으로 이루어진 군으로부터 선택되는 하나 이상의 질환인 것이 바람직하나 이에 한정되는 것은 아니다.The respiratory disease is selected from the group consisting of respiratory inflammatory lung disease, chronic obstructive pulmonary disease (COPD), sinusitis, allergic rhinitis, lower respiratory tract infection, acute chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, pulmonary tuberculosis, acute respiratory distress syndrome And chronic obstructive pulmonary disease), cystic fibrosis, otitis media, and pulmonary fibrosis, but is not limited thereto.
상기 조성물은 폐포의 불규칙적인 확장 또는 염증세포의 침윤을 감소시키는 것이 바람직하다.The composition preferably reduces irregular enlargement of the alveoli or infiltration of inflammatory cells.
본 발명의 [화학식 1]로 기재되는 화합물 또는 이의 약학적으로 허용 가능한 염을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다.The compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof may be directly added or used together with other food or food ingredients, and may be suitably used according to a conventional method.
본 발명의 건강식품은 식품 제조시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다.The health food of the present invention includes components that are ordinarily added at the time of food production, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings.
상기 식품의 종류에는 특별한 제한은 없다. 상기 쿠마릭산(p-coumaric acid) 화합물 또는 이의 약학적으로 허용 가능한 염을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of foods to which the p-coumaric acid compound or a pharmaceutically acceptable salt thereof can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, Dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.
본 발명의 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 0.01 ~0.04 g, 바람직하게는 약 0.02 ~ 0.03 g 이다.The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 [화학식 1]로 기재되는 화합물 또는 이의 약학적으로 허용 가능한 염은 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. 그 밖에 본 발명의 쿠마릭산(p-coumaric acid) 화합물 유도체 또는 이의 약학적으로 허용 가능한 염은 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다.In addition to the above, the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof may be in the form of various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, Colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the p-coumaric acid compound derivative or pharmaceutically acceptable salt thereof of the present invention may contain flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination.
이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부당 0.01 - 0.1 중량부의 범위에서 선택되는 것이 일반적이다.The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
이하, 본 발명을 하기의 실시예 및 제조예에 의하여 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail with reference to the following Examples and Preparation Examples.
단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.
담배 연기(Cigarettes smoking)로 유발된 염증성 폐 질환 동물모델의 제조Manufacture of Animal Model of Inflammatory Pulmonary Disease Induced by Cigarette Smoking
본 발명자들은 염증성 폐 질환 동물모델을 제조하기 위해 하기와 같이 담배 연기 노출을 통해 동물 모델을 제조하였다.To produce an animal model of inflammatory lung disease, the present inventors produced animal models through tobacco smoke exposure as follows.
구체적으로, 마우스는 체중 18-20 g의 7주령 암컷 C57BL/6 (Orient Bio Inc, South Korea)을 사용하였다. 염증성 폐 질환 모델 제작을 위해, Smoking chamber를 이용해서 C57BL/6 마우스에 담배 연기를 노출 시켰다. Reference cigarette 3R4F (University of Kentucky, Lexington, Kentuchy)를 하루에 5 개피 씩 피운 연기에 마우스에 30분간 노출 시킨 후 air 상태에서 30분간 휴식시간을 주었다. 이와 동일한 방법으로 4번 반복하였고 일주일에 5일 4주 동안 연기에 노출 시킨 후에 실험동물을 희생시켜 다음 실험을 진행하였다.Specifically, mice were 7-week old female C57BL / 6 (Orient Bio Inc, South Korea) weighing 18-20 g. To construct an inflammatory lung disease model, C57BL / 6 mice were exposed to cigarette smoke using a smoking chamber. A reference cigarette 3R4F (University of Kentucky, Lexington, Kentucky) was exposed to 5 cigarettes a day for 30 minutes and then allowed to rest for 30 minutes in air. The same procedure was repeated four times. After 5 days and 4 weeks of exposure to smoke, the experimental animals were sacrificed and the following experiment was carried out.
본 발명의 하기 실험을 위해 담배연기에 노출시키지 않은 정상대조군(Control, CON), 담배연기를 노출시킨 음성대조군(Cigarette Smoking, cs), roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 p-coumaric acid 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)으로 구별하여 각 그룹당 6마리씩 나누었다. 물과 사료는 자유롭게 먹도록 하였으며, 사육실 내의 온도는 21 내지 24℃ 습도는 55% 내지 60%로 유지하였고 낮과 밤 주기는 각각 12시간으로 하였다.(Control, CON), a negative control group (Cigarette Smoking, cs) exposed to tobacco smoke, a positive control group (ROF) exposed to cigarette smoke after administration of roflumilast, (P-
쿠마릭산(p-coumaric acid)의 체중 감소 억제 효과 확인 OK Kumar acid weight loss inhibition of (p-coumaric acid) effect
중등도 이상의 호흡기질환의 가장 두드러진 특징 중 하나는 체중 변화량이다. 본 발명자들은 p-coumaric acid가 담배 연기(Cigarettes smoking)를 노출시킨 마우스의 감소된 체중을 개선시키는지 확인하기 위하여 하기와 같은 실험을 수행하였다.One of the most prominent features of moderate to severe respiratory disease is weight change. The present inventors conducted the following experiment to confirm that p-coumaric acid improves the reduced body weight of mice exposed to cigarette smoke.
구체적으로, 본 연구에 사용된 p-coumaric acid 파우더(CoreSciences Co., Republic of Korea)를 농도 5 및 10 mg/kg로 각각 인산화 식염수(phosphate buffered saline, PBS)에 녹여 여과한 다음 냉장 보관하여 사용하였다. 마우스의 체중은 실험 시작일에 담배 연기(Cigarettes smoking)으로 자극을 주기 전에 저울(정밀 저울 E06120)을 이용해서 측정하였고, 그 이후로는 담배 연기로 자극을 준 후에 체중 변화량을 측정하였다. Specifically, the p-coumaric acid powder (CoreSciences Co., Republic of Korea) used in this study was dissolved in phosphate buffered saline (PBS) at a concentration of 5 and 10 mg / kg, Respectively. The weight of the mouse was measured using a scale (Precision Balance E06120) before stimulation with cigarette smoke at the beginning of the experiment, and thereafter the change in weight was measured after stimulation with tobacco smoke.
그 결과, 도 1에 나타낸 바와 같이 실험 시작일을 기준으로 담배연기에 노출되지 않은 정상대조군 그룹(CON)의 체중은 약 15% 정도 증가한 반면, 담배연기를 노출시킨 음성대조군 그룹(cs)은 약 3% 정도의 체중 감소를 나타내었다. 또한, p-coumaric acid(P-CA)를 각 5 또는 10 mg/kg의 농도로 투여한 후 담배연기에 노출시킨 그룹이 음성대조군 그룹(cs)에 비해서 농도 의존적으로 체중이 덜 감소하였고 양성대조군 그룹(ROF)과 비교하여도 체중 감소의 개선(예방) 효과가 우수한 것을 확인할 수 있었다(도 1).As a result, as shown in FIG. 1, the body weight of the normal control group (CON) not exposed to the cigarette smoke increased by about 15% on the basis of the experiment start date, while the negative control group (cs) % Body weight loss. In addition, the group exposed to tobacco smoke after administration of p-coumaric acid (P-CA) at a concentration of 5 or 10 mg / kg reduced the body weight in a dose-dependent manner compared to the negative control group (cs) It was confirmed that the improvement (prevention) effect of weight loss was excellent even in comparison with the group (ROF) (Fig. 1).
쿠마릭산(p-coumaric acid)의 면역세포 억제 효과 확인 OK Kumar acid inhibition of immune cells (p-coumaric acid) effect
본 발명자들은 담배 연기를 노출시킨 마우스의 면역세포의 수의 변화에 있어서 p-coumaric acid의 투여가 미치는 영향을 확인하기 위하여 하기와 같이 폐세척액(bronchoalveloar lavage fluid, BALF)의 면역세포 분석을 수행하였다.The present inventors carried out immunocytochemical analysis of bronchoalveloar lavage fluid (BALF) as follows to confirm the effect of administration of p-coumaric acid on the number of immune cells in a mouse exposed to tobacco smoke .
구체적으로, 담배연기에 노출시키지 않은 정상대조군(Control, CON), 담배연기를 노출시킨 음성대조군(Cigarette Smoking, cs), roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 p-coumaric acid 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 기도에 캐눌라(Cannula)를 삽입한 다음 천천히 인산완충식염수(phosphate buffered saline)를 주입한 후, 폐를 세척하여 폐세척액(bronchoalveloar lavage fluid; BALF)을 수득하였다. 그런 다음, 혈구계수기(hemacytometer)를 이용하여 폐세척액속의 면역세포를 슬라이드글라스에 부착한 후, 폐세척액(BAL fluid) 내 전체 염증세포와 macrophage, neutrophil, lymphocyte의 염증세포 수를 분석하였다.(Control, CON), a negative control (Cigarette Smoking, cs) exposed to cigarette smoke, a positive control (ROF) exposed to cigarette smoke after administration of roflumilast, p-coumaric (P-
그 결과, 도 2에 나타낸 바와 같이 담배연기에 노출시킨 음성대조군의 경우 air 상태의 정상대조군(control) 그룹에 비해서 전체 염증세포의 수, macrophage, neutrophil, 및 lymphocyte의 수가 증가하였고, p-coumaric acid를 5 또는 10 mg/kg 농도로 투여한 후 담배연기에 노출시킨 그룹은 음성대조군 그룹(cs)과 비교하여 전체 염증세포의 수, macrophage, neutrophil, 및 lymphocyte의 수가 유의성 있게 감소하였다(도 2).As a result, as shown in FIG. 2, the number of total inflammatory cells, macrophage, neutrophil, and lymphocyte was increased in the negative control group exposed to the cigarette smoke as compared with the control group in the air state, and p-coumaric acid The number of total inflammatory cells, macrophage, neutrophil, and lymphocyte was significantly reduced in the group exposed to tobacco smoke after administration of 5 or 10 mg / kg (Fig. 2) compared with the negative control group (cs) .
쿠마릭산(p-coumaric acid)의 염증성-사이토카인의 발현량 감소 효과 확인 Determine the effect of reduced expression level of cytokine-inflammatory Kumar acid (p-coumaric acid)
담배 연기로 유발된 염증성 폐 질환 마우스에서 항염증성-사이토카인 발현량(pro-inflammatory cytokine level)에 있어서 p-coumaric acid의 투여가 미치는 영향을 확인하기 위하여 하기와 같이 폐 조직을 분쇄하여 단백질(protein) 추출 후 ELISA(Enzyme-Linked ImmunoSorbent Assay) 분석을 수행하였다. To confirm the effect of p-coumaric acid administration on the pro-inflammatory cytokine level in inflammatory lung disease mice induced by tobacco smoke, pulmonary tissues were pulverized to obtain protein (protein ), Followed by ELISA (Enzyme-Linked ImmunoSorbent Assay) analysis.
ELISA 분석을 통하여 폐 조직 내의 면역신호전달물질인 IL-1B, IL-6, TNF-α 및 MCP-1의 발현량을 Quantitative sandwich enzyme-linked immunoassay kit (BD,USA)을 이용하여 측정하였다. OptEIA (BD Bioscience, San Diego, CA, USA)의 protocol을 이용하되 포획 항체(capture antibody)를 코팅 버퍼(coating buffer)(0.1M Carbonate, pH 9.5)로 희석하여 96-well plate에 100 ㎕씩 분주한 후 4℃에 overnight 동안 코팅(coating)하였다. 코팅한 plate를 wash buffer (PBS/Tween-20 0.05%)로 3번 washing 한 후 assay diluent(BD Bioscience, San Diego, CA, USA)를 200 ㎕/well 씩 분주한 후 실온에서 1시간 동안 blocking 하였다. 이후 다시 wash buffer로 3번 washing하고 standard와 sample을 각각 100 ㎕씩 분주한 후 실온에서 2시간 반응시킨다. Wash buffer로 5번 washing 하고 working detector(Detection antibody+Avidin-HRP) 100 ㎕씩 각 well에 첨가하였다. 실온에서 1시간 반응 후 wash buffer로 7번 washing 한 후 substrate solution(TMB Substrate Reagent; Pharmingen, BD Bioscience, San Diego, CA, USA) set을 각 well 마다 100 ㎕씩 첨가하였다. 실온의 어두운 곳에서 30분 동안 반응시킨 후 2N H2SO4를 50 ㎕ 첨가하였다. 30분 안에 micropalte reader (Molecular Devices, Sunnyvale, CA, USA)로 450 nm/570 nm로 측정하였다. The expression levels of IL-1B, IL-6, TNF-α and MCP-1 in lung tissues were measured by ELISA using a quantitative sandwich enzyme-linked immunoassay kit (BD, USA). The capture antibody was diluted with a coating buffer (0.1 M carbonate, pH 9.5) using OptEIA (BD Bioscience, San Diego, Calif., USA) And then coated overnight at 4 ° C. The coated plates were washed 3 times with wash buffer (PBS / Tween-20, 0.05%) and 200 μl / well of assay diluent (BD Bioscience, San Diego, CA, USA) . After washing 3 times with wash buffer, 100 μl of standard and sample are dispensed, and reacted at room temperature for 2 hours. After washing 5 times with Wash Buffer, 100 μl of working detector (Detection antibody + Avidin-HRP) was added to each well. After washing for 1 hour at room temperature, the plate was washed 7 times with wash buffer and 100 μl of substrate solution (TMB Substrate Reagent; Pharmingen, BD Bioscience, San Diego, CA, USA) was added to each well. After reacting for 30 minutes in a dark place at room temperature, 50 ㎕ of 2N H 2 SO 4 was added. Was measured at 450 nm / 570 nm with a micropalte reader (Molecular Devices, Sunnyvale, Calif., USA) within 30 min.
그 결과, 도 3에 나타낸 바와 같이 담배연기를 노출시킨 음성대조군의 경우 air 상태의 정상대조군(control) 그룹에 비해서 IL-1B, IL-6, TNF-α 및 MCP-1의 발현량이 모두 증가하였고, roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid를 5 또는 10 mg/kg의 농도로 투여한 후 담배연기에 노출시킨 실험군의 경우는 음성대조군 그룹(cs)과 비교하여 유의성 있게 감소하였다(도 3).As a result, as shown in FIG. 3, the expression levels of IL-1B, IL-6, TNF-α and MCP-1 were increased in the negative control group exposed to the cigarette smoke compared to the normal control group in the air state , roflumilast, rosiglitazone (rof), and p-coumaric acid were administered at a dose of 5 or 10 mg / kg. (Fig. 3).
쿠마릭산(p-coumaric acid)의 폐포의 불규칙적인 확장 감소 효과 확인 Kumar acid make irregular expansion decreased the effects of the closure (p-coumaric acid)
담배 연기로 유발된 염증성 폐 질환 마우스의 폐 손상에 p-coumaric acid의 투여가 미치는 영향을 확인하기 위하여 상기 <실시예 3>에서와 같이 담배연기에 노출시키지 않은 정상대조군(Control, CON), 담배연기를 노출시킨 음성대조군(Cigarette Smoking, cs), roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 p-coumaric acid 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)에서 폐 조직을 적출하여 10% paraformaldehyde의 고정액에서 고정한 후 알콜로 탈수한 다음 파라핀 블럭을 만들었다. 파라핀에 고정된 조직을 4 ㎛의 두께로 자른 후 슬라이드글라스에 붙였다. 파라핀을 제거한 후 헤마톡실린과 에오신(Hematoxylin and Eosin, H&E)으로 염색하여 canadabalsam(ShowaChemicalCo.Ltd.,Japan)으로 고정하였다.To confirm the effect of p-coumaric acid administration on pulmonary injury in lungs of inflammatory lung diseases induced by tobacco smoke, the control group (Control, CON), tobacco smoke After administration of cigarette smoking (cs), roflumilast, a positive control (ROF) exposed to cigarette smoke, p-
그 결과, 도 4에 나타낸 바와 같이 담배 연기에 노출시킨 음성대조군 그룹(CS)에서는 담배연기에 노출시키지 않은 정상대조군(control) 그룹과 비교하여 폐포 무너짐에 의한 비정상적인 큰 폐포로의 확장이 많이 진행되어 폐의 손상이 되었음을 확인하였다(도 4).As a result, as shown in FIG. 4, in the negative control group (CS) exposed to the cigarette smoke, compared with the control group which was not exposed to the cigarette smoke, the alveolar collapse greatly extended to abnormal abnormal large alveoli The lungs were damaged (Fig. 4).
또한, 도 5에 나타난 바와 같이 폐포 무너짐에 의한 큰 폐포로 확장된 공간의 넓이를 분석한 결과, 담배 연기에 노출시킨 음성대조군 그룹(CS)에서 정상대조군과 비교하여 넓이가 크게 증가한 것을 확인하였으며, roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid를 5 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 경우에는 그 넓이가 유의성 있게 감소하는 것을 확인하였다(도 5).As shown in FIG. 5, the width of the area extended to the large alveoli due to the alveolar collapse was analyzed. As a result, it was confirmed that the area of the negative control group (CS) exposed to the cigarette smoke increased greatly compared with the normal control group, (ROF) exposed to tobacco smoke after administration of roflumilast, and the experimental group (P-
쿠마릭산(p-coumaric acid)의 폐 염증세포의 침윤 감소 효과 확인 OK reduced infiltration of pulmonary inflammatory effect of Kumar acid (p-coumaric acid)
담배 연기로 유발된 염증성 폐 질환 마우스의 폐 염증세포 침윤에 p-coumaric acid의 투여가 미치는 영향을 확인하기 위하여 상기 <실시예 3>에서와 같이 담배연기에 노출시키지 않은 정상대조군(Control, CON), 담배연기를 노출시킨 음성대조군(Cigarette Smoking, cs), roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)에서 폐 조직을 적출하여 10% paraformaldehyde의 고정액에서 고정한 후 알콜로 탈수한 다음 파라핀 블럭을 만들었다. 파라핀에 고정된 조직을 4 ㎛의 두께로 자른 후 슬라이드글라스에 붙였다. 파라핀을 제거한 후 헤마톡실린과 에오신(Hematoxylin and Eosin, H&E)으로 염색하여 canadabalsam(ShowaChemicalCo.Ltd.,Japan)으로 고정하였으며, 이후 조직의 손상 정도에 따라 점수를 주었다. 상기 점수의 기준은 다음과 같다: 0점, 없음; 2점, 10% 미만; 4점, 10 내지 25%; 6점, 25 내지 50%; 8점, 50 내지 75%; 및 10점, 75% 이상. In order to examine the effect of p-coumaric acid on pulmonary inflammatory cell infiltration in inflammatory lung disease mice induced by tobacco smoke, a control group (Control, CON), which was not exposed to tobacco smoke as in Example 3, , Cigarette smoking (cs), roflumilast, cigarette smoke-exposed positive control (ROF), p-
그 결과, 도 6에 나타낸 바와 같이 담배 연기에 노출시킨 음성대조군 그룹(CS)에서는 담배연기에 노출시키지 않은 정상대조군(control) 그룹과 비교하여 폐포 주위로의 염증세포들의 침윤(infiltration)이 많이 나타난 것을 확인할 수 있었다(도 6).As a result, as shown in FIG. 6, in the negative control group (CS) exposed to the cigarette smoke, infiltration of inflammatory cells around the alveoli was more frequent compared with the control group not exposed to the cigarette smoke (Fig. 6).
또한, 도 7에 나타난 바와 같이 조직의 염증 정도에 따라 점수를 매긴 결과, 담배연기를 노출시킨 음성대조군(CS) 그룹에서 가장 큰 점수를 나타냈으며 roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid를 5 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 경우에는 유의성 있게 감소하는 것을 확인하였다(도 7).As shown in FIG. 7, the scores were scored according to the degree of inflammation of the tissues. As a result, the highest score was obtained in the negative control group (CS) group exposed to the cigarette smoke, and the positive control group in which roflumilast was administered and the cigarette smoke was exposed (P-
쿠마릭산(p-coumaric acid)의 염증 관련 인자 억제 효과 확인 OK Kumar acid inflammatory factor inhibition of (p-coumaric acid) effect
담배 연기로 유발된 염증성 폐 질환 마우스의 폐조직에서 p-coumaric acid의 투여가 미치는 영향을 확인하기 위하여 상기 <실시예 3>에서와 같이 담배연기에 노출시키지 않은 정상대조군(Control, CON), 담배연기를 노출시킨 음성대조군(Cigarette Smoking, cs), roflumilast를 투여한 후 담배연기를 노출시킨 양성대조군(ROF), p-coumaric acid 5 mg/kg 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)에서 폐 조직을 적출, 파쇄한 후 real time PCR 및 western blot을 이용하여 TNF-α, MIP-3α, NF-κB 및 MMP-12의 mRNA 또는 단백질 발현량을 확인하였다In order to confirm the effect of p-coumaric acid administration on the lung tissue of inflammatory lung disease mice induced by tobacco smoke, the control group (Control, CON), tobacco smoke Cigarette Smoking (cs), roflumilast, cigarette smoke exposure, positive control (ROF), p-
그 결과, 도 8에 나타낸 바와 같이 담배연기를 노출시킨 음성대조군의 경우 TNF-α 및 MIP-3α의 발현량이 증가한 반면, 양성대조군(ROF), p-coumaric acid를 5 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 경우에는 TNF-α 및 MIP-3α의 발현량이 유의성 있게 감소하였다(도 8).As a result, as shown in FIG. 8, the expression of TNF-α and MIP-3α was increased in the negative control group exposed to the cigarette smoke while the positive control (ROF) and 5 or 10 mg / kg of p-coumaric acid were administered (P-
또한, 도 9에 나타낸 바와 같이 담배연기를 노출시킨 음성대조군의 경우 NF-κB 및 MMP-12의 발현량이 증가한 반면, 양성대조군(ROF), p-coumaric acid를 5 또는 10 mg/kg를 투여한 후 담배연기를 노출시킨 실험군(P-CA 5 또는 P-CA 10)의 경우에는 NF-κB 및 MMP-12의 발현량이 유의성 있게 감소하였다(도 9).9, the expression of NF-κB and MMP-12 was increased in the negative control group exposed to the cigarette smoke while the positive control (ROF) and 5 or 10 mg / kg of p-coumaric acid were administered The expression levels of NF-κB and MMP-12 were significantly decreased in the experimental group (P-
<< 제조예Manufacturing example 1> 약제의 제조 1> Manufacture of Pharmaceuticals
1. 산제의 제조1. Manufacturing of powder
본 발명의 쿠마릭산(p-coumaric acid) 화합물 500 ng500 ng of the p-coumaric acid compound of the present invention
유당 1 gLactose 1 g
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above components were mixed and packed in airtight bags to prepare powders.
2. 정제의 제조2. Preparation of tablets
본 발명의 쿠마릭산(p-coumaric acid) 화합물 500 ng500 ng of the p-coumaric acid compound of the present invention
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
3. 캡슐제의 제조3. Preparation of capsules
본 발명의 쿠마릭산(p-coumaric acid) 화합물 500 ng500 ng of the p-coumaric acid compound of the present invention
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
4. 주사제의 제조4. Preparation of injections
본 발명의 쿠마릭산(p-coumaric acid) 화합물 500 [0189] ngThe p-
만니톨 180 mg180 mg mannitol
Na2HPO42H2O 26 mgNa 2 HPO 4 2H 2 O 26 mg
증류수 2974 mgDistilled water 2974 mg
통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.
<제조예 2> 건강기능식품의 제조≪ Preparation Example 2 > Preparation of health functional foods
1. 건강식품의 제조1. Manufacture of health food
본 발명의 쿠마릭산(p-coumaric acid) 화합물 500 ng500 ng of the p-coumaric acid compound of the present invention
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 ㎍70 [mu] g of vitamin A acetate
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 0.13 mg0.13 mg of vitamin
비타민 B2 0.15 mg0.15 mg of vitamin B2
비타민 B6 0.5 mgVitamin B6 0.5 mg
비타민 B12 0.2 ㎍0.2 [mu] g vitamin B12
비타민 C 10 mg
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 mgNicotinic acid amide 1.7 mg
엽산 50 mg
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75 mg1.75 mg of ferrous sulfate
산화아연 0.82 mg0.82 mg of zinc oxide
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mgPotassium monophosphate 15 mg
제2인산칼슘 55 mgSecondary calcium phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mg
염화마그네슘 24.8 mgMagnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
2. 건강 음료의 제조2. Manufacture of health drinks
본 발명의 쿠마릭산(p-coumaric acid) 화합물 500 ng500 ng of the p-coumaric acid compound of the present invention
구연산 1000 mg
올리고당 100 g100 g of oligosaccharide
매실농축액 2 gPlum concentrate 2 g
타우린 1 gTaurine 1 g
정제수를 가하여 전체 900 mlPurified water was added and the entire 900 ml
통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2l 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 음료 조성물 제조에 사용하였다.The above ingredients were mixed according to the usual health drink manufacturing method, and the mixture was stirred and heated at 85 for about 1 hour. The resulting solution was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, And used for manufacturing.
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
Claims (10)
[화학식 1]
.
1. A pharmaceutical composition for the prevention or treatment of respiratory diseases comprising, as an active ingredient, a p-coumaric acid compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
.
The pharmaceutical composition for preventing or treating respiratory diseases according to claim 1, wherein the compound is isolated from Bambusae Caulis in Taeniam.
The method of claim 1, wherein the respiratory disease is selected from the group consisting of respiratory inflammatory lung disease, chronic obstructive pulmonary disease (COPD), sinusitis, allergic rhinitis, lower respiratory tract infection, acute chronic bronchitis, emphysema, pneumonia, bronchial asthma, Wherein the composition is at least one disease selected from the group consisting of emphysema, pulmonary tuberculosis, acute respiratory distress syndrome, cystic fibrosis, otitis media and pulmonary fibrosis.
The pharmaceutical composition for preventing or treating respiratory diseases according to claim 1, wherein the composition reduces irregular expansion of alveoli.
The pharmaceutical composition for preventing or treating respiratory diseases according to claim 1, wherein the composition reduces the infiltration of inflammatory cells.
[화학식 1]
.
A health functional food for improving respiratory diseases comprising, as an active ingredient, a p-coumaric acid compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
.
The health functional food for respiratory diseases according to claim 6, wherein said compound is isolated from Bambusae Caulis in Taeniam.
The method of claim 6, wherein the respiratory disease is selected from the group consisting of respiratory inflammatory lung disease, chronic obstructive pulmonary disease (COPD), sinusitis, allergic rhinitis, lower respiratory tract infection, acute chronic bronchitis, emphysema, pneumonia, bronchial asthma, Wherein the disease is one or more diseases selected from the group consisting of emphysema, pulmonary tuberculosis, acute respiratory distress syndrome, cystic fibrosis, otitis media and pulmonary fibrosis.
The health functional food for improving respiratory diseases according to claim 6, wherein the health functional food reduces irregular expansion of alveoli.
The health functional food for respiratory diseases according to claim 6, wherein the health functional food reduces infiltration of inflammatory cells.
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KR20040054940A (en) * | 2002-12-18 | 2004-06-26 | 주식회사 엘지생활건강 | Cinnamic aldehyde containing composition having suppressive effect on inducible nitric oxide synthase and pro-inflammatory cytokine |
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