KR20110038499A - Pharmaceutical composition for treatment and prevention of common cold comprising extract or fraction from polygonum cuspidatum or stilbene compound - Google Patents
Pharmaceutical composition for treatment and prevention of common cold comprising extract or fraction from polygonum cuspidatum or stilbene compound Download PDFInfo
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- KR20110038499A KR20110038499A KR1020090095814A KR20090095814A KR20110038499A KR 20110038499 A KR20110038499 A KR 20110038499A KR 1020090095814 A KR1020090095814 A KR 1020090095814A KR 20090095814 A KR20090095814 A KR 20090095814A KR 20110038499 A KR20110038499 A KR 20110038499A
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- composition
- extract
- resveratrol
- cold
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Abstract
Description
본 발명은 호장근 추출물 또는 이의 분획물, 또는 이들로부터 유래된 스틸벤계 화합물을 유효성분으로 하는 감기증상의 개선 또는 감기의 예방 또는 치료용 조성물에 관한 것이다. 또한, 본 발명은 상기 조성물을 포함하는 피부 외용제, 식료품 및 개인위생용품에 관한 것이다.The present invention relates to a composition for improving cold symptoms or for preventing or treating cold symptoms using as an active ingredient, e.g., root extract or fractions thereof. The present invention also relates to external skin preparations, foodstuffs and personal care products containing the composition.
감기(感氣, common cold)란 코, 목구멍, 기관지 등 호흡기 점막의 급성 염증성 질환이나 알레르기성 질환의 총칭으로서, 급성비염, 급성인두염, 급성후두염, 급성편도염, 기관지염, 그 밖의 바이러스성 상기도 감염증 등을 포함한다. 감기의 원인으로서는 여러 종류의 바이러스, 세균에 의한 감염, 한랭이나 먼지 등의 자극, 체온 분포의 불균형, 알레르기원 등이 원인이 되나 이들 중 한 가지만이 원인이 되는 경우는 적고, 대부분은 한랭이나 먼지의 자극, 체온 분포의 불균형 등의 복합적 인 원인이 되어 바이러스 감염이 일어나 감기가 유발되는 것으로 알려져 있다. 감기의 병원이 되는 바이러스는 50여종에 이르나, 주요한 것은 인플루엔자 바이러스(Influenza Virus), 아데노바이러스(Adenovirus), 호흡기 신시치아 바이러스(Respiratory Syncytial Virus), 리노바이러스(Rhinovirus) 등이다. 이들 바이러스에 의한 질환은 콧물, 재채기, 기침, 발열이나 목이 아픈 증세 등 감기증후군이라고 할 수 있는 공통점이 많아 이들을 통틀어 '감기'라고 하기도 하였으나, 최근에는 의학의 발달에 따라 원인 및 증상이 확실한 것은 인플루엔자, 알레르기성 비염 등과 같은 독립된 병명으로 부르는 경향이 생겨, 현재 감기라고 하면 좁은 의미의 감기, 즉 인플루엔자 외의 바이러스성 감기를 뜻한다.Common cold is a generic term for acute inflammatory or allergic diseases of the respiratory mucosa, such as the nose, throat, and bronchus. Acute rhinitis, acute pharyngitis, acute laryngitis, acute tonsillitis, bronchitis, and other viral upper respiratory tract infections And the like. The causes of the common cold are caused by various kinds of viruses, bacteria, irritation of cold and dust, imbalance of body temperature distribution and allergens, but only one of them is caused by cold and dust. It is known that the virus is caused by a complex cause such as irritation and imbalance of body temperature distribution, causing a cold. There are about 50 kinds of viruses that cause colds, but the main ones are influenza virus, adenovirus, respiratory syncytial virus, and rhinovirus. The diseases caused by these viruses have a common common cold syndrome such as runny nose, sneezing, coughing, fever or sore throat, but they are collectively referred to as 'cold', but recently, the cause and symptoms are obvious with the development of medicine. In addition, there is a tendency to call an independent disease, such as allergic rhinitis, and the current cold means a cold in a narrow sense, that is, a viral cold other than influenza.
감기와 독감은 특히 합병증에서 차이가 많이 난다는 점에서 구별되는데, 감기의 경우 리노바이러스, 독감의 경우 인플루엔자 바이러스가 주된 원인이다. 유행성 독감을 일으키는 인플루엔자 바이러스는 항원형에 따라 A, B, C 의 세 가지 유형으로 분류하는데, 이 중 A형이 가장 항원 변이를 자주 일으키며 범세계적인 대유행을 일으키는 원인 바이러스 중 90% 를 차지하는 것으로 알려져 있다. 이와 같은 독감 바이러스는 매년 전 세계적으로 발생하여 호흡기 질환을 일으키는데, 고열에 의한 오한과 근육통, 무기력증, 호흡기 통증, 두통, 복통 등을 수반하는 등 몸이 무겁고 괴로운 증상을 호소하게 되며, 면역 능력이 약한 어린이와 노인들에 대해 치사율이 높고, 합병증으로 폐렴, 심폐질환 등의 기관지 질환들을 수반하는 경우 치사율이 더욱 높아져 국민 보건에 미치는 영향이 크다고 할 수 있다.Colds and influenza are distinguished, especially in complications, with rhinoviruses for colds and influenza viruses for flus. Influenza viruses that cause pandemic influenza are classified into three types, A, B, and C, depending on the antigen type, of which A is the most common antigen mutation and accounts for 90% of the worldwide pandemic virus. . These flu viruses occur worldwide every year and cause respiratory illnesses. They cause severe and painful symptoms such as chills, myalgia, lethargy, respiratory pain, headache, and abdominal pain caused by high fever. If mortality is high for children and the elderly, and complications involving bronchial diseases such as pneumonia and cardiopulmonary disease, the mortality rate is higher.
한편, 리노바이러스(Rhinovirus)는 성인 감기 원인의 30-35% 를 차지하며, 100 여가지의 항원형을 가지고 있다. 감염된 리노바이러스는 몸 안으로 들어가지 않고 상기도의 상피 세포에 4일~2주 붙어서 생존한다. 폐렴을 일으키고 감염자를 사망에 이르게 하는 독감 바이러스와는 달리, 리노바이러스는 콧물, 오한, 두통, 권태감 등의 증상을 유발하나 인체에 큰 해를 끼치지는 않는 것으로 알려져 있다. 즉, 사람과 공생하면서 사는 덕분에 쉽게 증식할 수 있으며 천식, 만성기관지염 등의 급성 호흡질환을 유발시키기도 하는 것으로 알려져 있다. 리노바이러스는 초가을, 봄, 여름에 활발히 활동한다. 중합효소연쇄반응(PCR) 연구에 대한 조사에서는 일반 감기 증후군에 연루된 리노바이러스 감염에 대한 실제 범위가 통상적인 세포배양기술을 통해 관찰된 것과 비교하여 최소 두 배가 높다고 한다(Johnston, Journal of clinical microbiology, 111-117, 1993). 이는 일반 감기에 걸린 모든 환자의 70-75% 까지가 단일 감염이나 공감염으로써 진행중인 리노바이러스 감염이 있다는 것을 나타낸다. On the other hand, rhinoviruses account for 30-35% of the causes of adult colds and have more than 100 antigenic types. Infected rhinoviruses do not enter the body and survive by attaching to epithelial cells of the upper airway for 4 to 2 weeks. Unlike the flu virus, which causes pneumonia and kills infected people, rhinoviruses are known to cause runny nose, chills, headaches, and malaise, but they do not harm the body. In other words, living together while living symbiosis is easy to multiply and is known to cause acute respiratory diseases such as asthma, chronic bronchitis. Renovirus is active in early autumn, spring and summer. Investigations into polymerase chain reaction (PCR) studies have shown that the actual range of rhinovirus infections involved in common cold syndrome is at least twice as high as those observed through conventional cell culture techniques (Johnston, Journal of clinical microbiology, 111-117, 1993). This indicates that up to 70-75% of all patients with common cold have ongoing rhinovirus infection as a single infection or as a co-infection.
현재 일반 감기 환자를 위한 효과적인 치료는 없다. 몇몇 제공된 치료는 일반 감기를 더 악화시키기도 하는데, 예컨대, 아스피린 및 아세트아미노펜의 투여는 일반 감기 치료에 해로운 영향을 끼칠 수 있으며 항체를 중화시키고 코기관 문제를 증가시킬 수 있다고 보고된 바 있다(Graham, J.Infect.Dis, 162:1277-1282, 1990). 경구알파-작용제는 많은 개체에게 충혈을 경감시킬 수 있고 항히스타민제는 도움을 줄 수 있는 가능성이 있지만, 실제 치료는 조사된 바 없다. 인조 가용성 수용체(artificial soluble receptors)로 예방하거나 치료하는 것은 기대했던 것 만큼 성공하지 못하였다(Hayden, Antiviral Res., 9:233-237, 1988). 인터페론으로 일반 감기 환자를 치료하는 여러가지 시도도 부정적이었다(Monto, Antimicrobial agents and chemotherapy 33(3):387-930, 1989; Sperber, J. Infectious Dis. 160:700-705, 1989). 최근에는 부착 부위를 통해 리노바이러스의 결합을 억제시키는 Plecarnil 도 역시 부정적인 것으로 보고되었다. 따라서, 효과적인 감기 치료제의 개발이 시급한 실정이다.There is no effective treatment for common cold patients at this time. Some provided therapies have worsened the common cold, such as the administration of aspirin and acetaminophen, which have been reported to have a detrimental effect on the treatment of common cold and can neutralize antibodies and increase nasal organ problems (Graham, J. Infect. Dis, 162: 1277-1282, 1990). Oral alpha-agonists can alleviate hyperemia in many individuals and antihistamines may help, but no actual treatment has been investigated. Prevention or treatment with artificial soluble receptors has not been as successful as expected (Hayden, Antiviral Res., 9: 233-237, 1988). Several attempts to treat patients with common cold with interferon were also negative (Monto, Antimicrobial agents and chemotherapy 33 (3): 387-930, 1989; Sperber, J. Infectious Dis. 160: 700-705, 1989). Recently, Plecarnil®, which inhibits the binding of rhinoviruses through attachment sites, has also been reported to be negative. Therefore, the development of an effective cold treatment agent is urgently needed.
한편, 호장근(Polygonum Cuspidatum , Japanese Knotweed )은 우리나라 산야에서 자라는 마디풀과의 다년초 식물로 한국, 일본, 타이완 및 중국 등지에서 분포한다. 호장근은 민간에서 이뇨, 통경제, 진정제로 사용되어 왔으며, 완화, 이뇨, 통경, 화농성 피부염, 요도염, 방광염, 고혈압, 암, 동맥경화 등 여러 질병을 치료하기 위하여 우리나라를 비롯하여 동양권의 전통의학에서 이용되어 왔다. On the other hand, Polygonum Cuspidatum , Japanese Knotweed ) Is a perennial plant of the genus Madaceae, which grows in the mountains of Korea. It is distributed in Korea, Japan, Taiwan, and China. Ho Jang-geun has been used as a diuretic, pain economy, and sedative in the private sector, and in traditional medicine in Korea and other Asian regions Has been used.
이에, 본 발명자들은 천연물에서 감기 예방 및 치료용 조성물을 검색하던 중, 호장근 추출물 또는 그 분획물, 또는 이로부터 분리한 레스베라트롤이 리노바이러스에 대하여 항바이러스 활성을 나타냄으로써 감기의 예방 및 치료용 조성물로 사용될 수 있음을 규명함으로써 본 발명을 완성하였다.Accordingly, the inventors of the present invention, while searching for a composition for preventing and treating colds in natural products, resveratrol isolated from the extracts or fractions thereof, or resveratrol isolated therefrom, have antiviral activity against rhinoviruses, thereby providing a composition for preventing and treating colds. The present invention has been completed by identifying that it can be used.
본 발명의 목적은 호장근 추출물 또는 이의 분획물을 유효성분으로 포함하는 감기 증상의 개선 또는 감기의 예방 또는 치료용 조성물을 제공하는 것이다.It is an object of the present invention to provide a composition for improving or preventing or treating the symptoms of a cold, comprising an extract of E. coli muscle or a fraction thereof as an active ingredient.
본 발명의 다른 목적은 상기 조성물을 포함하는 피부 외용제, 식료품 및 개인위생용품을 제공하는 것이다.Another object of the present invention is to provide an external preparation for skin, foodstuffs and personal care products containing the composition.
하나의 양태로서, 본 발명은 호장근 추출물 또는 이의 분획물을 유효성분으로 포함하는 감기 증상의 개선 또는 감기의 예방 또는 치료용 조성물에 관한 것이다.In one embodiment, the present invention relates to a composition for improving or preventing or treating cold symptoms, including cold root extract or fractions thereof as an active ingredient.
본 발명에서, 상기 호장근 추출물은 물, 탄소수 1 내지 4의 저급 알콜 및 이들의 혼합 용매로 구성되는 군으로부터 선택되는 용매, 바람직하게는 메탄올, 에탄올 또는 부탄올로 추출한 것을 포함한다. 또한, 본 발명에 있어서, 상기 추출물에는, 추출처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 또는 이들 조정제물 또는 정제물 중 어느 하나도 포함하는 것으로 한다.In the present invention, the E. coli extract is extracted with a solvent selected from the group consisting of water, a lower alcohol having 1 to 4 carbon atoms and a mixed solvent thereof, preferably methanol, ethanol or butanol. In addition, in this invention, the said extract shall contain the extract obtained by an extraction process, the dilution or concentrate of an extract, the dried material obtained by drying an extract, or any of these modifiers or refined products.
본 발명에서 호장근 추출물을 얻기 위한 방법은 다음과 같다. 호장근 분쇄물을 건조 중량의 약 2 내지 20배, 바람직하게는 약 3 내지 5배에 달하는 부피의 물, 메탄올, 에탄올 및 부탄올 등과 같은 탄소수 1(C1) 내지 4(C4)의 저급 알콜의 극성 용매 또는 이들의 약 1:0.1 내지 1:10의 혼합비를 갖는 혼합용매를 용출 용매로써 사용하고, 추출 온도는 20 내지 100℃, 바람직하게는 실온에서, 추출 기간은 약 12시간 내지 10일, 바람직하게는 3일 내지 7일 동안 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 추출방법을 사용하여 추출한다. 바람직하게는 냉침추출로 1회 내지 5회 연속 추출하여 감압여과하고, 그 여과추출물을 진공회전농축기로 20 내지 100℃, 바람직하게는 실온에서 감압농축하여 물, 저급 알콜 또는 이들의 혼합용매에 가용한 호장근 조추출물을 수득할 수 있다.In the present invention, a method for obtaining Hojanggeun extract is as follows. The low-strength alcohols of C 1 -C 4 to C 4 , such as water, methanol, ethanol and butanol, in volume of about 2 to 20 times, preferably about 3 to 5 times, dry weight Using a polar solvent or a mixed solvent having a mixing ratio of about 1: 0.1 to 1:10 as the elution solvent, the extraction temperature is 20 to 100 ℃, preferably at room temperature, the extraction period is about 12 hours to 10 days Preferably, the extraction is performed using extraction methods such as hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction for 3 days to 7 days. Preferably, the extract is filtered 1 to 5 times by cold extraction and subjected to filtration under reduced pressure, and the filtrate is concentrated under reduced pressure at 20 to 100 ° C., preferably at room temperature using a vacuum rotary condenser, and soluble in water, lower alcohols, or a mixed solvent thereof. One colic root extract can be obtained.
감기의 예방 및 치료 활성을 갖는 상기 호장근 추출물은 천연, 잡종, 변종 식물의 다양한 기관으로부터 추출될 수 있고, 예를 들어 뿌리, 줄기, 잎, 꽃, 열매의 몸통, 열매의 껍질뿐만 아니라 식물 조직 배양물로부터 추출 가능하며 호장근의 뿌리에서 추출하는 것이 가장 바람직하다. The extract of K. koji with the prophylactic and therapeutic activity of the common cold can be extracted from various organs of natural, hybrid, and mutant plants, for example roots, stems, leaves, flowers, trunks of berries, peels of berries, as well as plant tissues. Extractable from the culture and most preferably from the roots of the roots
본 발명에서, 호장근 추출물의 용매분획물은 호장근 추출물을 물로 현탁한 후 n-헥산, 에틸 아세테이트 또는 클로로포름과 같은 비극성 용매를 사용하여 분획함으로써 극성 용매 분획물과 비극성 용매 분획물을 각각 수득할 수 있다. 본 발명에서, 구체적인 일 양태로서 용매분획물로는 물 분획물, n-헥산 분획물, 에틸 아세테이트 분획물 또는 클로로포름 분획물이 제공된다.In the present invention, the solvent fractions of the extracts of the roots of the extract may be obtained by suspending the extract of the roots of the extract with water using a nonpolar solvent such as n -hexane, ethyl acetate or chloroform, respectively, to obtain a polar solvent fraction and a nonpolar solvent fraction. In the present invention, as a specific aspect, the solvent fraction is provided with water fraction, n -hexane fraction, ethyl acetate fraction or chloroform fraction.
본 발명에서 호장근 추출물의 분획물을 얻기 위한 방법은 다음과 같다. 상기에서 얻은 호장근 조추출물을 증류수에 현탁한 후, 현탁액의 약 1 내지 100배, 바 람직하게는 약 1 내지 5배 부피의 헥산, 에틸아세테이트 또는 클로로포름과 같은 비극성 용매를 가하여 1회 내지 10회, 바람직하게는 2회 내지 5회에 걸쳐 비극성 용매 가용층을 추출, 분리하여 수득할 수 있다. 또한 추가로 통상의 분획 공정을 수행할 수도 있다(Harborne J.B. Phytochemical methods: A guide to modern techniques of plant analysis , 3rd Ed. p6-7, 1998). 구체적으로, 상기 호장근 조추출물을 물에 현탁한 후, 등량의 n-헥산 및 클로로포름을 용매를 이용하여 연속 추출로 호장근 각 용매 가용 추출물을 수득할 수 있고, 더욱 구체적으로는 호장근 조추출물을 물에 현탁한 후, 동량의 n-헥산을 혼합한 후 분획하여 n-헥산 가용성 분획물 및 수가용성 분획물을 수득할 수 있으며, 이 수가용성 분획물에 클로로포름을 가하여 클로로포름 가용성 분획물 및 수가용성 분획물을 수득할 수 있다.In the present invention, a method for obtaining a fraction of the extract of Hojang root is as follows. Suspended crude extract of the above-mentioned roots in distilled water, and then 1 to 10 times by adding a non-polar solvent such as hexane, ethyl acetate or chloroform in a volume of about 1 to 100 times, preferably about 1 to 5 times the suspension. Preferably, the mixture can be obtained by extracting and separating the nonpolar solvent soluble layer over two to five times. It is also possible to further carry out conventional fractionation processes (Harborne JB Phytochemical methods: A guide to modern techniques of plant analysis , 3rd Ed. p6-7, 1998). Specifically, after suspending the crude root extract in water, an equivalent amount of n-hexane and chloroform can be obtained by continuous extraction using a solvent to obtain a soluble extract of each solvent of the root extract, and more specifically, the crude extract of After suspending in water, the same amount of n-hexane was mixed and fractioned to obtain n-hexane soluble fraction and water soluble fraction, and chloroform was added to the water soluble fraction to obtain chloroform soluble fraction and water soluble fraction. can do.
본 발명은 호장근 추출물 및 그의 분획물은 하기 화학식 1 로 표시되는 스틸벤계 화합물인 레스베라트롤을 함유함을 특징으로 한다.The present invention is characterized in that the extract of Kojang-geun and its fractions contain resveratrol, a stilbene compound represented by the following formula (1).
[화학식 1][Formula 1]
본 발명의 호장근의 에탄올 추출물 및 분획물은 리노바이러스의 다양한 주(HRV-2, HRV-3)에 대하여 적은 농도에도 높은 항바이러스 효능을 보였다 (표 3). 또한, 호장근의 추출물 및 분획물은 각각 높은 함량의 레스베라트롤의 함량을 보였 는데, 레스베라트롤은 높은 수준의 항리노바이러스 활성을 보였으므로(도 6 내지 도 8), 레스베라트롤을 함유하는 호장근 추출물 및 분획물 역시 감기의 예방 및 치료에 적합함을 알 수 있다.Ethanol extracts and fractions of E. coli of the present invention showed high antiviral efficacy at low concentrations against various strains of rhinovirus (HRV-2, HRV-3) (Table 3). In addition, the extracts and fractions of renal vera muscle each showed a high content of resveratrol. Since resveratrol showed a high level of antilinovirus activity (FIGS. 6 to 8), resveratrol-containing renal vera extract and fractions were also present. It can be seen that it is suitable for the prevention and treatment of colds.
다른 하나의 양태로서, 본 발명은 화학식 1로 표시되는 레스베라트롤을 유효성분으로 포함하는 감기증상의 개선 또는 감기의 예방 또는 치료용 조성물에 관한 것이다.As another aspect, the present invention relates to a composition for improving or preventing or treating cold symptoms, including resveratrol represented by Formula 1 as an active ingredient.
본 발명의 조성물이 레스베라트롤을 유효성분으로 포함하는 경우, 레스베라트롤은 약학적으로 허용가능한 염의 형태로 사용될 수 있으며, 통상의 방법에 의해 제조되는 모든 염, 수화물 및 용매화물이 포함된다. When the composition of the present invention includes resveratrol as an active ingredient, resveratrol may be used in the form of a pharmaceutically acceptable salt, and includes all salts, hydrates, and solvates prepared by conventional methods.
염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산 부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알콜(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다. 이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산 (propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘 산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 히드로아이오딕산 등을 사용할 수 있으며, 이들에 제한되지 않는다.As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered. In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid may be used as the organic acid. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glyconic Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like can be used. It is not limited to.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salt, but is not limited thereto. Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
상기 레스베라트롤의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 레스베라트롤의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며 당업계에서 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of resveratrol include salts of acidic or basic groups which may be present in the compound of resveratrol, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and the like. It can be prepared through.
본 발명에서 용어, "감기증상의 개선 또는 감기의 예방 또는 치료"란, 감기의 예방 및 완전한 또는 부분적인 치료를 포함한다. 이는 또한 감기 증상의 감소, 감기 증상의 개선, 감기 또는 그 증상의 고통 경감, 감기 발생율 감소 또는 치료결과를 증가시키는 환자의 어떠한 다른 변화를 포함한다.As used herein, the term "amelioration of cold symptoms or prevention or treatment of a cold" includes the prevention and complete or partial treatment of a cold. It also includes reducing cold symptoms, ameliorating cold symptoms, alleviating the pain of a cold or its symptoms, reducing the incidence of colds, or any other change in a patient that increases treatment outcome.
본 발명의 상기 조성물이 효과가 있는 감기의 증상은 재채기, 콧물, 비강폐색(nasal obstruction), 코막힘, 후두염 또는 목의 통증, 기침, 목이쉼, 천식악화 및 두통, 열, 한기 및 컨디션이 좋지 않은 것과 같은 일반적인 증상 중 하나 또는 그 이상을 포함한다. 따라서 본 발명은 기침, 재채기, 콧물, 근육통, 인후염, 비강폐색, 후두염, 목의 통증, 쉰소리, 천식악화, 두통, 부비강에 대한 통증, 비염, 점막 종기, 인두염, 기관지염 오한, 한기 및 권태감 중 하나 또는 그 이상의 개선, 치료 또는 예방에 효과가 있다.Symptoms of a cold in which the composition of the present invention is effective are sneezing, runny nose, nasal obstruction, nasal congestion, laryngitis or sore throat, cough, sore throat, asthma and headache, fever, chills and poor condition It includes one or more of the common symptoms, such as ones that do not. Therefore, the present invention is a cough, sneezing, runny nose, myalgia, sore throat, nasal obstruction, laryngitis, sore throat, hoarseness, asthma, headache, sinus pain, rhinitis, mucosal boil, pharyngitis, bronchitis chills, chills and nausea It is effective in one or more amelioration, treatment or prevention.
본 발명의 레스베라트롤은 감기 바이러스인 리노바이러스(rhinovirus)에 의한 감기에 예방 및 치료에 적합하다. Resveratrol of the present invention is suitable for the prevention and treatment of colds by rhinovirus, a cold virus.
본 발명의 구체적인 실시예에서는, 레스베라트롤의 리노바이러스에 대한 저해 효과를 측정하였는바, 레스베라트롤을 바이러스와 섞어 1시간 반응 후 세포에 접종한 경우와, 바이러스를 먼저 세포에 접종하고 1시간 후 레스베라트롤을 첨가(after 1h)한 경우에 모두 리노바이러스(HRV2) 저해활성이 우수하였으므로, 레스베라트롤이 리노바이러스에 직접 작용하여 항바이러스 효능 및 바이러스 감염 예방 효과도 함께 나타낸다는 것을 확인할 수 있다(도 6 내지 도 8).In a specific embodiment of the present invention, the inhibitory effect of resveratrol on rhinovirus was measured. When resveratrol was mixed with a virus and inoculated into cells after 1 hour of reaction, the virus was first inoculated into cells and after 1 hour, resveratrol was added. In the case of (after 1h), renovirus (HRV2) inhibitory activity was excellent in all cases, and thus resveratrol directly acts on the renovirus, indicating that the antiviral effect and the viral infection prevention effect are also shown (FIGS. 6 to 8). .
본 발명의 감기증상의 개선 또는 감기의 예방 또는 치료용 조성물은 사람 및 동물용 식료품, 제약학상 제품, 수의학용 제품, 화장품, 개인 위생 제품 및 가정 용품을 포함하는 다양한 제품에 사용될 수 있다.The composition for improving or preventing or treating cold symptoms of the present invention can be used in a variety of products including foodstuffs for humans and animals, pharmaceutical products, veterinary products, cosmetics, personal care products and household products.
구체적으로, 본 발명의 상기 조성물은 피부 외용제로 사용할 수 있으며, 바람직하게는 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태의 피부 외용제로 사용할 수 있다.Specifically, the composition of the present invention can be used as an external preparation for skin, and preferably used as an external preparation for skin in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel or gel.
또한, 본 발명의 상기 조성물은 식료품으로 사용할 수 있으며, 바람직하게는 마아가린, 지방 지속성(fat continuous) 또는 물 지속성(water continuous) 또는 양쪽 지속성(bicontinuous) 스프레드, 지방 감소된 스프레드, 초콜렛, 또는 초콜렛 코팅 또는 초콜렛 속(fillings) 또는 베이커리 속과 같은 과자류, 과자, 껌, 아이스크림, 아이스크림 코팅, 아이스크림 함유물, 드레싱, 마요네즈, 치즈, 크림 대체물, 건조 스프, 드링크, 시리얼 바, 소스, 스낵바, 유제품, 임상 영양식품 또는 소아 제제로 사용할 수 있다.In addition, the compositions of the present invention can be used in foodstuffs, preferably margarine, fat continuous or water continuous or bicontinuous spreads, fat reduced spreads, chocolate, or chocolate coating Or confectionery such as chocolate fillings or bakery, confectionery, gum, ice cream, ice cream coatings, ice cream ingredients, dressings, mayonnaise, cheese, cream substitutes, dry soups, drinks, cereal bars, sauces, snack bars, dairy products, clinical It can be used as a nutritional or pediatric preparation.
또한, 본 발명의 상기 조성물은 개인위생용품으로 사용할 수 있으며, 바람직하게는 비누, 화장품, 물티슈, 휴지, 샴푸, 구강청정제, 피부 크림, 얼굴 크림, 치약, 립스틱, 향수, 메이크-업, 파운데이션, 볼터치, 마스카라, 아이섀도우, 선스크린 로션, 모발 손질 제품, 에어프레쉬너 또는 세정 겔로 사용할 수 있다.In addition, the composition of the present invention can be used as personal hygiene products, preferably soap, cosmetics, wet wipes, tissue paper, shampoo, mouthwash, skin cream, face cream, toothpaste, lipstick, perfume, make-up, foundation, It can be used as a ball touch, mascara, eye shadow, sunscreen lotion, hair care product, air freshener or cleansing gel.
본 발명의 호장근 추출물 또는 이의 분획물, 또는 레스베라트롤은 오랫동안 생약으로 사용되어 오던 약제인 호장근으로부터 유래한 것이므로 독성 및 부작용 등의 문제가 없다.E. coli extract of the present invention or a fraction thereof, or resveratrol is derived from e.g. root, a drug that has been used for a long time as a herbal, there is no problem such as toxicity and side effects.
본 발명의 감기의 예방 및 치료용 약학조성물은, 조성물 총 중량에 대하여 상기 추출물 및 그 분획물 또는 화합물 1을 0.0001 내지 10 중량%로, 바람직하게는 0.001 내지 1 중량%를 포함할 수 있다.The pharmaceutical composition for the prevention and treatment of colds of the present invention may comprise 0.0001 to 10% by weight, preferably 0.001 to 1% by weight of the extract and its fractions or
본 발명의 호장근 추출물, 그 분획물 또는 스틸벤계 화합물을 포함하는 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The pharmaceutical composition comprising E. coli extract, fractions thereof, or stilbene compound of the present invention may further include appropriate carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions.
본 발명의 호장근 추출물, 그 분획물 또는 스틸벤계 화합물은 단독으로 또는 타 약학적 활성 추출물, 분획물 또는 화합물과의 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. E. coli extracts, fractions or stilbene compounds of the present invention may be used alone or in combination with other pharmaceutically active extracts, fractions or compounds as well as in a suitable collection.
본 발명에 따른 호장근 추출물, 그 분획물 또는 스틸벤계 화합물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명에서, 호장근 추출물, 그 분획물 또는 스틸벤계 화합물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 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 상기 호장근 추출물, 이의 분획물 또는 이로부터 분리된 레스베라트롤에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로 스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 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, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The composition comprising the extract of E. coli according to the present invention, its fractions or stilbene compounds, oral formulations, external preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. It can be formulated in the form of suppositories and sterile injectable solutions. In the present invention, carriers, excipients, and diluents that may be included in the composition comprising the extract of K. koji, its fractions or stilbene-based compounds include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, and starch. , Acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil Can be mentioned. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, in the renal vera extract, fractions thereof, or resveratrol separated therefrom. It is prepared by mixing calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 호장근 추출물, 그 분획물 또는 레스베라트롤의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 호장근 추출물 또는 그 분획물은 1일 0.0001 내지 100 mg/kg으로, 바람직하게는 0.001 내지 100mg/kg으로 투여하는 것이 좋으며, 레스베라트롤은 1일 0.0001 내지 10mg/kg으로, 바람직하게는 0.001 내지 10mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.Preferred dosages of E. coli extract, fractions thereof, or resveratrol of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer Escherichia coli extract or fractions of the present invention at 0.0001 to 100 mg / kg per day, preferably at 0.001 to 100 mg / kg, and resveratrol at 0.0001 to 10 mg / kg per day. As an example, it is preferable to administer at 0.001 to 10mg / kg. Administration may be administered once a day or may be divided several times.
본 발명의 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention can be administered to various mammals such as rats, mice, livestock, humans, and the like. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명의 호장근 추출물, 이의 분획물 및 이로부터 분리한 스틸벤계 화합물은 리노바이러스 등에 의한 감기 증상의 개선 또는 감기의 예방 및 치료에 우수한 효과를 나타내므로, 피부 외용제, 식료품, 화장품 및 개인위생용품 등에 폭넓게 적용할 수 있다.E. coli extract, fractions thereof, and stilbene compounds isolated therefrom exhibit excellent effects on improving cold symptoms or preventing and treating cold symptoms caused by rhinoviruses, and the like for external skin preparations, foodstuffs, cosmetics and personal hygiene products. It is widely applicable.
이하, 본 발명을 실시 예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시 예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시 예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.
실시예 1. 호장근 추출물 및 분획물 제조Example 1. Preparation of Keun-Geun Extract and Fraction
호장근은 물로 깨끗이 세척하여 그늘에서 건조한 후, 와링 브랜드로 분말화 시켰다. 분말화된 호장근 3.6 ㎏을 에탄올 20 ℓ에 넣고 실온에서 7일간 냉침 추출한 후, 여지(와트만사, 미국)로 감압 여과한 다음, 여과 추출물은 진공회전농축기로 실온에서 에탄올 용매를 제거한 후 추출된 잔사로서 호장근 조추출물 146g을 수득하였다.Ho Jang Keun was washed with water, dried in the shade, and then powdered with Waring brand. 3.6 kg of powdered rye roots were added to 20 l of ethanol, followed by cold extraction at room temperature for 7 days, followed by filtration under reduced pressure with Wattman (Watman, USA). As a residue, 146 g of KJ extract was obtained.
상기 조추출물은 물 1 ℓ 에 현탁 시킨 후 동량의 에틸아세테이트를 가하여 혼합하여 분획하였으며, 이 과정을 4회 반복하여 에틸아세테이트 분획 물 4 ℓ를 수득하였다. 이 에틸아세테이트 가용성 분획 물을 감압 농축하여 에틸아세테이트 가용 추출물 80 g 을 수득하였다.The crude extract was suspended in 1 L of water and mixed with the same amount of ethyl acetate. The crude extract was repeated four times to obtain 4 L of ethyl acetate fraction. The ethyl acetate soluble fraction was concentrated under reduced pressure to obtain 80 g of an ethyl acetate soluble extract.
상기에서 얻은 에틸아세테이트 가용 추출물 중 40 g 을, 클로로포름:메탄올 = (100/0 ~ 1/1)로 구성된 단계농도 구배(step gradient) 용매 시스템을 이용하여 실리카겔 컬럼 크로마토그래피를 행하여 레스베라트롤이 함유된 클로로포름:메탄올 = 20:1 분획 830 mg 을 수득하였다.40 g of the ethyl acetate soluble extract obtained above was subjected to silica gel column chromatography using a step gradient solvent system consisting of chloroform: methanol = (100/0 to 1/1) to give chloroform containing resveratrol. Methanol = 20: 1 fraction 830 mg was obtained.
상기에서 얻어진 호장근 에탄올추출물 및 에틸아세테이트 분획물, 그리고 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획에 대하여 레스베라트롤 함유 정도를 확인하기 위하여 LC-MS를 이용하여 분석을 수행하였다. The chloroform: methanol = 20: 1 fraction in the E. coli ethanol extract, ethyl acetate fraction, and ethyl acetate fraction column chromatography obtained above was analyzed using LC-MS to determine the resveratrol content.
실시예Example 2. 2. 호장근Ho Jang Geun 추출물 및 Extract and 분획물의Fraction 레스베라트롤Resveratrol 함량 분석 Content analysis
2-1. 2-1. 레스베라트롤Resveratrol 표준정량곡선 Standard Quantitative Curve
표준품의 분석 조건을 살펴보면, HPLC는 Agilent Technologies 1200 series를 사용하였고, 분석용 컬럼은 ZORBAX SB-C18 (Agilent, 5 μm, 4.6x150 mm), 60% 메탄올을 분석용매로 사용하였다. 210nm에서 분석하였으며, 유속은 0.2 mℓ /min을 흘려 주었으며, 시료는 2 μℓ 을 injection 후 분석하였다. 레스베라트롤 표준화합물은 1.25 mg/mℓ , 0.63 mg/mℓ, 0.31 mg/mℓ, 0.16 mg/mℓ, 0.08 mg/mℓ, 0.04 mg/mℓ 농도로 조제 후 2 μL을 injection하여 HPLC로 분석하였다. 분석 된 크로마토그램에서 레스베라트롤 표준품의 peak는 11분대에 관찰되었으며, 분석된 peak의 면적과 injection 된 레스베라트롤의 양으로부터 표준 정량곡선 및 직선의 방정식을 얻었다 (도 1).In the analysis conditions of the standard, HPLC was used Agilent Technologies 1200 series, analytical column was ZORBAX SB-C18 (Agilent, 5 μm, 4.6x150 mm), 60% methanol as the analytical solvent. The analysis was performed at 210 nm, and the flow rate was 0.2 mℓ / min, and the sample was analyzed after injection of 2 μℓ. Resveratrol standard compounds were prepared at concentrations of 1.25 mg / ml, 0.63 mg / ml, 0.31 mg / ml, 0.16 mg / ml, 0.08 mg / ml, and 0.04 mg / ml, and analyzed by HPLC. The peak of the resveratrol standard in the analyzed chromatogram was observed in 11 minutes, and the standard quantitative curve and the linear equation were obtained from the area of the analyzed peak and the amount of injected resveratrol (Fig. 1).
2-2. 2-2. 호장근Ho Jang Geun 에탄올 추출물에 대한 For ethanol extract 레스베라트롤Resveratrol 함량 분석 Content analysis
호장근 에탄올 추출물에 대한 분석 조건으로는, Agilent Technologies 1200 series의 HPLC를 사용하였고, 분석용 컬럼은 ZORBAX SB-C18 (Agilent, 5 μm, 4.6x150 mm), 50~90% 메탄올을 분석용매로 사용하였다 (표 1-용매분석조건). 분석 파장은 210nm, 유속은 0.2 mℓ/min을 흘려 주었으며, 시료는 2 μℓ을 injection 후 분석하였다. 상기에서 얻어진 호장근 에탄올 추출물에 대하여 레스베라트롤 함량을 확인하기 위하여, 시료는 10 mg/mℓ 농도로 제조 후 2 μℓ를 injection하여 LC-MS를 이용하여 분석을 수행하였다. HPLC 크로마토그래피 분석 결과 레스베라트롤의 peak는 17분대에서 관찰되었으며, MS 분석 결과 m/z 227 [M-H]+의 분자 peak를 확인 할 수 있었다 (도 2). 분석된 peak의 면적을 표준정량곡선에서 얻어진 직선의 방정식에 대입해본 결과, 호장근 에탄올 추출물 1g 안에는 12 mg의 레스베라트롤을 함유하고 있는 것으로 밝혀졌다 (도 2).As analytical conditions for E. coli ethanol extract, HPLC of Agilent Technologies 1200 series was used, and the analytical column was ZORBAX SB-C18 (Agilent, 5 μm, 4.6x150 mm) and 50-90% methanol as an analyte. (Table 1-Solvent analysis conditions). The analysis wavelength was 210nm and the flow rate was 0.2 mℓ / min, and the sample was analyzed after injection of 2 μℓ. In order to confirm the resveratrol content of the E. coli ethanol extract obtained above, the sample was prepared at a concentration of 10 mg / ml and then injected into 2 μl and analyzed using LC-MS. As a result of HPLC chromatography, the peak of resveratrol was observed at 17 minutes, and MS analysis showed a molecular peak of m / z 227 [MH] + (FIG. 2). As a result of substituting the area of the analyzed peak into the equation of the straight line obtained from the standard quantitative curve, it was found that 1 g of renal ethanol extract contained 12 mg of resveratrol (FIG. 2).
2-3. 2-3. 호장근Ho Jang Geun 에틸아세테이트 Ethyl acetate 분획물Fraction 및 에틸아세테이트 분획 And ethyl acetate fraction 컬럼column 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획에 대한 For chloroform: methanol = 20: 1 fraction in chromatography 레스베라트롤Resveratrol 분석 analysis
상기에서 얻어진 호장근 에틸아세테이트 분획물은 호장근 에탄올 추출물과 동일한 방업으로 분석을 수행하였다. HPLC 크로마토그래피 분석 결과 레스베라트롤의 peak는 17분대에서 관찰되었으며, MS 분석 결과 m/z 227 [M-H]+의 분자 peak를 확인 할 수 있었다 (도 3). The obtained E. coli ethyl acetate fraction was analyzed in the same manner as E. coli ethanol extract. As a result of HPLC chromatography, the peak of resveratrol was observed at 17 minutes, and MS analysis showed a molecular peak of m / z 227 [MH] + (FIG. 3).
상기에서 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획은 레스베라트롤 표준품 분석과 동일한 방법으로 분석을 수행하였다. HPLC 크로마토그래피 분석 결과 레스베라트롤의 peak는 11분대에서 관찰되었으며, MS 분석 결과 m/z 227 [M-H]+의 분자 peak를 확인 할 수 있었다 (도 4). The chloroform: methanol = 20: 1 fraction in the ethyl acetate fraction column chromatography was analyzed in the same manner as the resveratrol standard assay. As a result of HPLC chromatography, the peak of resveratrol was observed in 11 minutes, and MS analysis showed a molecular peak of m / z 227 [MH] + (FIG. 4).
이상의 호장근 에탄올추출물 및 에틸아세테이트 분획물, 그리고 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획에 대한 LC-MS 분석결과, 각각의 시료에는 레스베라트롤이 1.2 %, 4.6 %, 7.1 % 함유하고 있음을 확인하였으며, 이를 기준으로 환산한 결과, 호장근 생약 1kg 에 함유된 레스베라트롤은 2.4 g으로 건조중량의 0.24 %를 차지하였다 (표 2-레스베라트롤 함량). LC-MS analysis of chloroform: methanol = 20: 1 fractions in ethanol extract and ethyl acetate fraction and ethyl acetate fraction column chromatography showed that resveratrol contained 1.2%, 4.6% and 7.1% in each sample. As a result, it was found that resveratrol contained in 1 kg of Kwonjeok herbal medicine accounted for 2.44 g of 0.24% of dry weight (Table 2-Resveratrol content).
2-4. 산 처리 후 2-4. After acid treatment 레스베라트롤Resveratrol 함량 변화 분석 Content change analysis
호장근 에탄올 추출물 (200 mg) 은 9 mℓ 의 메탄올에 녹인 후 1 mℓ 의 3M 황산 용액을 첨가하여 둥근바닥 플라스크 에 넣는다. 이 플라스크는 70 ℃ 물중탕에서 12 시간 동안 반응 후, 에틸아세테이트로 반응을 종결시킨다. 이 에틸아세테이트 분획 (100 mg)에 들어 있는 레스베라트롤의 함량 변화를 분석하기 위하여, 10 mg/mℓ 농도로 제조 후 2 μℓ를 injection하여 LC-MS를 이용하여 분석을 수행하였다. 그림-5를 살펴보면, 에탄올 추출물 HPLC 크로마토그램에서는 resveratrol-3-O-β-D-glucoside peak (11분대)의 면적은 41,363 mAU로 관찰되나, 12시간 산 처리 후 26,400 mAU 로 감소 되는 것을 확인 할 수 있었다. 또한, 레스베라트롤 peak (17분대)의 면적은 5,618 mAU에서 23,380 mAU로 증가하는 것을 확인 할 수 있다 (도 5). 호장근 에탄올 추출물의 레스베라트롤 함량은 12 mg/g (에탄올 추출물) 로 측정되었고 (표 2), 산 처리 12시간 후 레스베라트롤의 함량은 50 mg/g (에탄올 추출물)로 약 4배 증가 하였다.E. coli ethanol extract (200 mg) was dissolved in 9 ml of methanol and added to 1 ml of 3M sulfuric acid solution into a round bottom flask. The flask was reacted in a 70 ° C. water bath for 12 hours and then terminated with ethyl acetate. In order to analyze the change in the content of resveratrol contained in the ethyl acetate fraction (100 mg), after preparing at 10 mg / ml concentration was injected 2 μl and analyzed using LC-MS. Figure 5 shows that the area of resveratrol-3-O-β-D-glucoside peak (11 minutes) was 41,363 mAU in the ethanol extract HPLC chromatogram, but after 12 hours of acid treatment it was reduced to 26,400 mAU. Could. In addition, it can be seen that the area of the resveratrol peak (17 components) increases from 5,618 mAU to 23,380 mAU (FIG. 5). The resveratrol content of K. ethanol extract was measured as 12 mg / g (ethanol extract) (Table 2), and after 12 hours of acid treatment, the resveratrol content increased about 4 times to 50 mg / g (ethanol extract).
실시예Example 3. 3. 호장근Ho Jang Geun 추출물 및 Extract and 분획물의Fraction 리노바이러스에Renovirus 대한 저해 효과 측정 Measurement of inhibitory effects
호장근 에탄올추출물 및 에틸아세테이트 분획물 그리고 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획의 리노바이러스 (HRV-2, 3)에 대한 저해효과를 측정하기 위하여, 사람의 폐포 섬유아세포주(human lung fibroblast)인 WI-38 (ATCC: CCL-75)을 이용하여 다음과 같은 in vitro 실험을 수행하였다. In order to measure the inhibitory effect of chloroform: methanol = 20: 1 fraction on rhinovirus (HRV-2, 3) in ethanol extract, ethyl acetate fraction and ethyl acetate fraction column chromatography, human lung fibroblast) of WI-38 (ATCC: following in the same using the CCL-75) In vitro experiments were performed.
먼저, 96 웰 마이크로플레이트에 WI-38 세포를 각 웰 당 1 X 105 cells/ well 이 되도록 넣고 배지 EMEM (penicillin 100 units, streptomycin 100 μg, 10% FBS)로 배양하였다. WI-38 세포가 monolayer가 되면 항생제만 포함된 EMEM 배지로 2회 세척하였다. HRV-2, HRV-3주를 각각 100 TCID50이 되도록 희석하여 EP 튜브에 담아 두었다. 여기에 DMSO (dimethylsulfoxide)로 희석한 호장근 에탄올추출물 및 에틸아세테이트 분획물 그리고 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획의 최종 농도가 100 μg/mℓ, 60 μg/mℓ, 30 μg/mℓ, 10 μg/mℓ, 1 μg/mℓ로 각 튜브에 넣은 후 4℃에서 1시간 동안 반응 시켰다. 1시간 후 미리 세척한 WI-38 세포에 한 농도 당 3 웰에 각각 접종하였다. First, WI-38 cells were placed in 96 well microplates at 1
한편, 항바이러스 효과가 알려진 인터페론 알파(INF-α)와 비감염, 비투여 대조군(Control) 및 감염, 비투여 대조군(Virus control)을 동일한 조건에서 1시간 반응 후 WI-38 세포에 접종하여 33℃에서 배양한다. 감염, 비투여 대조군에서 완전히 세포변성효과(Cytopathic effect, CPE)가 나올 때 까지 3-4일간 배양하였다. 도립현미경으로 매일 세포 상태를 배율 50X 관찰하여 사진을 찍었다. 배양 3-4일 후 세포 생존률을 알아보기 위하여 Cell Counting kit-8 (Dojin, Japan, tetrazolium salt WST-8)을 각 웰당 10 μℓ 씩 넣은 후 33℃에서 2시간 반응시킨 후 450 nm에서 흡광도를 측정하였다. 이때, DMSO만 처리한 세포와 DMSO 및 HRV-2, HRV-3를 처리한 세포를 대조군으로 사용하여 비교한 본 발명의 화합물이 나타내는 리노바이러스 저해 효과를 결정하였다. Meanwhile, interferon alpha (INF-α), which is known for its antiviral effect, and non-infected, non-administered control, and infected and non-administered control, were inoculated into WI-38 cells after 1 hour of reaction under the same conditions. Incubate in. Infected and non-administered controls were incubated for 3-4 days until complete cytopathic effect (CPE). The cells were photographed by observing the magnification of 50X daily with an inverted microscope. To determine cell viability after 3-4 days of incubation, 10 μl of Cell Counting kit-8 (Dojin, Japan, tetrazolium salt WST-8) was added to each well, followed by reaction at 33 ° C. for 2 hours, and then absorbance at 450 nm. It was. At this time, the rhinovirus inhibitory effect of the compound of the present invention was determined using DMSO-only cells and DMSO, HRV-2, and HRV-3 treated cells as controls.
본 발명의 호장근 에탄올추출물 및 에틸아세테이트 분획물 그리고 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획에 대한 항바이러스 활성 측정 결과, HRV-2의 경우 EC50 값이 각각 >60 μg/mℓ, 37.2 μg/mℓ, 11.5 μg/mℓ로 측정되었으며, HRV-3주의 경우 EC50 값이 47.8 μg/mℓ, 44.4 μg/mℓ, 11.3 μg/mℓ의 측정되었다 (표 3-CPE reduction effects of HRV). The antiviral activity of the chloroform: methanol = 20: 1 fraction in ethanol extract, ethyl acetate fraction and ethyl acetate fraction column chromatography of the present invention was determined that the EC 50 value was> 60 μg / ml for HRV-2. , 37.2 μg / ml, 11.5 μg / ml and EC 50 values of HRV-3 strains were 47.8 μg / ml, 44.4 μg / ml, and 11.3 μg / ml (Table 3-CPE reduction effects of HRV). .
이상의 결과로부터, 호장근 에탄올추출물 및 에틸아세테이트 분획물 그리고 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획은 감기바이러스인 리노바이러스의 다양한 주 (HRV-2, HRV-3)에 모두 좋은 항바이러스 효능을 확인할 수 있었으며, 또한 바이러스에 직접 작용하여 바이러스 감염 예방효과도 함께 나타내는 것으로 판단된다. From the above results, the chloroform: methanol = 20: 1 fractions in E. coli ethanol extract, ethyl acetate fraction and ethyl acetate fraction column chromatography were good for all strains of rhinovirus (HRV-2, HRV-3). Viral efficacy was confirmed, and it is also judged to have a direct effect on the virus and also show a virus infection prevention effect.
(mg/mL)EC 50 a
(mg / mL)
(mg/mL)EC 50 a
(mg / mL)
a EC50, mean (50%) value from concentration of inhibitory effect a EC 50 , mean (50%) value from concentration of inhibitory effect
실시예Example 4. 4. 레스베라트롤의Resveratrol 화합물의 Compound 리노바이러스에Renovirus 대한 저해 효과 측정 Measurement of inhibitory effects
레스베라트롤의 리노바이러스 (HRV-2, 3, 14)에 대한 저해효과를 측정하기 위하여, 사람의 폐포 섬유아세포주(human lung fibroblast)인 WI-38 (ATCC: CCL-75)을 이용하여 다음과 같은 in vitro 실험을 수행하였다. In order to measure the inhibitory effect of resveratrol against rhinoviruses (HRV-2, 3, 14), the human lung fibroblast WI-38 (ATCC: CCL-75) was used as follows. in In vitro experiments were performed.
먼저, 96 웰 마이크로플레이트에 WI-38 세포를 각 웰 당 1 X 105 cells/ well 이 되도록 넣고 배지 EMEM (penicillin 100 units, streptomycin 100 μg, 10% FBS)로 배양하였다. WI-38 세포가 monolayer가 되면 항생제만 포함된 EMEM 배지로 2회 세척하였다. HRV-2, HRV-3, HRV-14주를 각각 100 TCID50이 되도록 희석하여 EP 튜브에 담아 두었다. 여기에 DMSO (dimethylsulfoxide)로 희석한 레스베라트롤이 최종 농도가 100 μM, 60 μM, 30 μM, 10 μM, 1 μM로 각 튜브에 넣은 후 4℃에서 1시간 동안 반응 시켰다. 1시간 후 미리 세척한 WI-38 세포에 한 농도 당 3 웰에 각각 접종하였다. First, WI-38 cells were placed in 96 well microplates at 1
한편, 항바이러스 효과가 알려진 인터페론 알파(INF-α)와 비감염, 비투여 대조군(Control) 및 감염, 비투여 대조군(Virus control)을 동일한 조건에서 1시간 반응 후 WI-38 세포에 접종하여 33℃에서 배양한다. 감염, 비투여 대조군에서 완전히 세포변성효과(Cytopathic effect, CPE)가 나올 때 까지 3-4일간 배양하였다. 도립현미경으로 매일 세포 상태를 배율 50X 관찰하여 사진을 찍었다. 배양 3-4일 후 세포 생존률을 알아보기 위하여 Cell Counting kit-8 (Dojin, Japan, tetrazolium salt WST-8)을 각 웰당 10 μℓ 씩 넣은 후 33℃에서 2시간 반응시킨 후 450 nm에서 흡광도를 측정하였다. 이때, DMSO만 처리한 세포와 DMSO 및 HRV-2, HRV-3, HRV-14를 처리한 세포를 대조군으로 사용하여 비교한 레스베라트롤이 나타내는 리노바이러스 저해 효과를 결정하였다. Meanwhile, interferon alpha (INF-α), which is known for its antiviral effect, and non-infected, non-administered control, and infected and non-administered control, were inoculated into WI-38 cells after 1 hour of reaction under the same conditions. Incubate in. Infected and non-administered controls were incubated for 3-4 days until complete cytopathic effect (CPE). The cells were photographed by observing the magnification of 50X daily with an inverted microscope. To determine cell viability after 3-4 days of incubation, 10 μl of Cell Counting kit-8 (Dojin, Japan, tetrazolium salt WST-8) was added to each well, followed by reaction at 33 ° C. for 2 hours, and then absorbance at 450 nm. It was. At this time, the renovirus inhibitory effect of resveratrol compared with DMSO-only cells and DMSO, HRV-2, HRV-3, HRV-14 treated cells as a control group was determined.
그 결과, 양성 대조군으로 사용한 인터페론 알파(INF-α)는 HRV-2에서는 22%로 낮은 저해 능력을 보였고, HRV-3와 HRV-14에서는 각각 55.6%, 80.8%로 저해 능력을 나타내었다. 본 발명의 레스베라트롤은 HRV-2와 HRV-3에서는 60 μM에서 각각 100%, 78%의 높은 저해 활성을 나타내었으며, HRV-14주의 경우 90 μM에서 100% 저해 활성을 나타내었다(도 6). 또한 도립현미경 상에서 세포 형태를 관찰한 결과, 바이러스만을 접종한 것 (HRV-2, 3, 14)은 WI-38세포가 거의 파괴되어 100% 세포 변성효과가 나왔으나, 바이러스와 레스베라트롤을 100 μM를 처리한 군은 WI-38 세포가 아무것도 처리하지 않은 대조군과 유사한 것을 확인하였다(도 8).As a result, the interferon alpha (INF-α) used as a positive control showed a low inhibitory capacity of 22% in HRV-2, and 55.6% and 80.8% in HRV-3 and HRV-14, respectively. Resveratrol of the present invention showed high inhibitory activity of 100% and 78% at 60 μM, respectively, in HRV-2 and HRV-3, and 100% inhibitory activity at 90 μM in HRV-14 strains (FIG. 6 ). In addition, as a result of observing the cell morphology on the inverted microscope, virus inoculation alone (HRV-2, 3, 14) showed almost 100% cell denaturation effect due to almost destruction of WI-38 cells, but 100 μM of virus and resveratrol. The treated group confirmed that the WI-38 cells were similar to the control group treated with nothing (FIG. 8).
또한, 레스베라트롤을 HRV-2주의 감염 전과 감염 후 투여를 비교한 실험을 수행하기 위하여, 감염 후 레스베라트롤의 바이러스 저해 활성을 알아보았다. 이를 위하여, 항생제만 포함된 EMEM 배지로 2회 세척한 WI-38 세포 리노바이러스(HRV-2)를 접종하여 1시간 동안 33℃에서 배양하였다. 1시간 후 접종한 바이러스액을 모두 제거하고, 레스베라트롤의 최종 농도가 100 μM, 60 μM, 30 μM, 10 μM 1 μM 가 되도록 배지에 첨가하여 바이러스가 접종된 WI-38 세포에 넣어주었다. 이후, 위와 동일한 방법으로 본 발명의 화합물이 나타내는 리노바이러스 저해 효과를 결정하였다. In addition, in order to perform an experiment comparing resveratrol with pre- and post-infection of HRV-2 strain, the virus inhibitory activity of resveratrol after infection was examined. To this end, WI-38 cell linovirus (HRV-2) washed twice with EMEM medium containing only antibiotics was inoculated and incubated at 33 ° C. for 1 hour. After 1 hour, all the inoculated virus solution was removed, and the final concentration of resveratrol was 100 μM, 60 μM, 30 μM, 10 μM, and 1 μM was added to the medium, and the virus was inoculated into WI-38 cells. Then, the linovirus inhibitory effect represented by the compound of the present invention was determined in the same manner as above.
그 결과, HRV-2를 레스베라트롤과 먼저 1시간 동안 반응시킨 후 감염 시킨 경우 60 μM에서 100% 바이러스 억제 활성을 보였으며 IC50 값은 13 μM이었다. 또한 바이러스를 먼저 감염시키고 1시간 후에 레스베라트롤을 투여한 경우 같은 농도에서 71.6% 억제 활성을 보였으며 IC50 값은 36 μM이었다. (도 7). As a result, when HRV-2 was first reacted with resveratrol for 1 hour and then infected, it showed 100% virus inhibition activity at 60 μM and IC 50 value was 13 μM. In addition, when the virus was first infected and resveratrol was administered 1 hour later, 71.6% of inhibitory activity was observed at the same concentration, and the IC 50 value was 36 μM. (FIG. 7).
이상의 결과로부터, 레스베라트롤은 감기바이러스인 리노바이러스의 다양한 주 (HRV-2, HRV-3, HRV-14)에 모두 좋은 항바이러스 효능을 확인할 수 있었으며, 또한 바이러스에 직접 작용하여 바이러스 감염 예방효과도 함께 나타내는 것으로 판단된다. From the above results, resveratrol was able to confirm good antiviral efficacy in various strains of rhinovirus (HRV-2, HRV-3, HRV-14) of cold virus, and also acts directly on the virus to prevent viral infection. It is judged to indicate.
도 1은 레스베라트롤 표준정량곡선을 나타낸 도이다.1 is a diagram showing a resveratrol standard quantity curve.
도 2는 호장근 에탄올 추출물 크로마토그램 및 MS 스펙트럼을 나타낸 도이다.Figure 2 is a diagram showing chromatogram and MS spectrum of Escherichia coli ethanol extract.
도 3은 호장근 에틸아세테이트 분획물의 크로마토그램 및 MS 스펙트럼을 나타낸 도이다.Figure 3 is a diagram showing the chromatogram and MS spectrum of E. coli ethyl acetate fraction.
도 4는 호장근 에틸아세테이트 분획 컬럼 크로마토그래피 중 클로로포름:메탄올 = 20:1 분획의 크로마토그램 및 MS 스펙트럼을 나타낸 도이다.FIG. 4 is a diagram showing chromatogram and MS spectrum of chloroform: methanol = 20: 1 fraction in Escherichia coli ethyl acetate fraction column chromatography.
도 5는 호장근 에탄올 추출물 및 12 시간 산 처리 후 크로마토그램을 나타낸 도이다.Figure 5 is a diagram showing the chromatogram after treatment with E. coli ethanol extract and 12 hours acid.
도 6은 레스베라트롤의 리노바이러스 (HRV-2, 3, 14) 저해활성을 나타낸 도이다.6 is a diagram showing the inhibitory activity of renovirus (HRV-2, 3, 14) of resveratrol.
도 7은 레스베라트롤을 바이러스와 섞어 1시간 반응 후 세포에 접종한 것(before 1h)과 바이러스를 먼저 세포에 접종하고 1시간 후 레스베라트롤을 첨가(after 1h)하여 리노바이러스(HRV2) 저해활성을 나타낸 도이다.7 is a diagram showing renovirus (HRV2) inhibitory activity by mixing resveratrol with a virus and inoculating cells after 1 hour of reaction (before 1h) and inoculating the cells first and then adding resveratrol after 1 hour (after 1h). to be.
도 8은 WI-38 세포주에 바이러스를 접종하지 않은 현미경 사진과 각 HRV-2, HRV-3, HRV-14주를 접종한 현미경사진, 그리고 각각의 바이러스와 레스베라트롤을 100 μM 첨가하였을 때의 현미경 사진을 나타낸 도이다.FIG. 8 shows micrographs of no vaccinated WI-38 cell lines, micrographs inoculated with each of HRV-2, HRV-3, and HRV-14, and micrographs of 100 μM of each virus and resveratrol. Is a diagram showing.
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US9125932B2 (en) | 2011-05-30 | 2015-09-08 | Korea Institute Of Oriental Medicine | Composition comprising herbal extracts or fermented products thereof having lactic acid bacteria for preventing or treating respiratory diseases |
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