KR101493461B1 - Composition Comprising Deoxypergularinine and the Extract of Cynanchum atratum against tuberculosis - Google Patents
Composition Comprising Deoxypergularinine and the Extract of Cynanchum atratum against tuberculosis Download PDFInfo
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- KR101493461B1 KR101493461B1 KR20140058108A KR20140058108A KR101493461B1 KR 101493461 B1 KR101493461 B1 KR 101493461B1 KR 20140058108 A KR20140058108 A KR 20140058108A KR 20140058108 A KR20140058108 A KR 20140058108A KR 101493461 B1 KR101493461 B1 KR 101493461B1
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/24—Apocynaceae (Dogbane family), e.g. plumeria or periwinkle
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
Abstract
Description
본 발명은 백미(Cynanchum atratum)의 디옥시퍼굴라리닌(deoxypergularinine)을 유효성분으로 하는 결핵치료용 약학조성물에 관한 것이다.
The present invention relates to a pharmaceutical composition for treating tuberculosis comprising deoxypergularinine of Cynanchum atratum as an active ingredient.
결핵(tuberculosis)은 하이델베르크에서 발견된 석기시대 사람의 척추뼈에서도 흔적이 발견되었고, BC 3,000년경 고대 이집트 미라에서도 흔적이 발견되었다. 오랜 역사를 가지는 결핵은 현재 전 세계인구의 1/3이 감염되어 있으며, 이들은 면역기능이 저하되는 경우 언제든지 결핵환자가 될 수 있다. 현재 전 세계적으로 1,600만 명의 환자가 결핵으로 고통을 받고 있고, 매년 8백만 명의 새로운 결핵환자가 발생되며, 그 중 매년 2백만 명이 사망하고 있다. Tuberculosis was also found in the vertebral bones of Stone Age people found in Heidelberg, and traces were found in ancient Egyptian mummies around 3,000 BC. Tuberculosis with a long history is now infected with one-third of the world's population, and they can become TB patients whenever their immune function deteriorates. Currently, 16 million people worldwide suffer from tuberculosis, and 8 million new TB patients are born each year, of which 2 million die each year.
선진국의 결핵감염률은 0.1% 이하이고, 질병발생률이 25% 이하이다. 우리나라는 활동성 폐결핵 유병률(엑스선 촬영에 의한 유병률)이 1965년 5.1%에서 1995년 1.0%로 감소하였으며, 균양성 유병률은 0.94%에서 0.22%로, 연간 결핵감염위험률은 5.3%에서 0.5%로 감소하였다. 인구 10만 명당 사망률은 1991년 10.4%에서 2001년 6.3명으로 감소하였으나, 아직도 결핵은 10대 사망원인 중의 하나로 치료 원칙은 초치료는 6개월 단기요법을 원칙으로 한다.Tuberculosis infection rates in developed countries are less than 0.1%, and disease incidence is less than 25%. In Korea, the prevalence of active pulmonary tuberculosis (prevalence due to x-ray) decreased from 5.1% in 1965 to 1.0% in 1995, and the bacterial prevalence decreased from 0.94% to 0.22% and the annual tuberculosis infection rate decreased from 5.3% to 0.5% . The mortality rate per 100,000 population declined from 10.4% in 1991 to 6.3 in 2001. However, tuberculosis is still one of the causes of death among teenagers. The principle of treatment is based on short-term therapy for 6 months.
일차항결핵제인 rifampin(RFP), isoniazid(INH), pyrazinamide(PZA), ethambutol(EMB)의 4제 병용, 2개월 후 RFP, INH 및 EMB의 3제를 4개월간 유지 치료한다. 초기 집중치료 2개월간 EMB 대신에 streptomycin을 쓸 수 있다. 이 경우 유지치료는 RFP 및 INH를 투여한다. 재발환자에 대한 재치료는 처음 치료약제에 대하여 대부분 감수성이 남아 있으므로 원래 약제를 다시 사용하는 것이 원칙이며 정해진 처음치료 기간보다 3개월을 더 연장하여 치료한다. 처음치료 실패자에 대한 재치료는 약제 감수성검사를 시행하여 처음치료에 사용한 약제를 모두 제외시키고, 과거에 사용하지 않았던 새로운 감수성 약제를 최소한 3제, 가능하면 4제 또는 그 이상을 병용하여 치료하며 원칙적으로 18개월 이상 치료한다.Four months of combined treatment with rifampin (RFP), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB), and three months with RFP, INH and EMB are treated for 4 months. Initial intensive therapy For 2 months, streptomycin can be used instead of EMB. In this case, maintenance therapy is administered with RFP and INH. The re-treatment for relapsed patients is mostly susceptible to the first-line treatment, so the original drug should be used again and the treatment should be extended by 3 months beyond the initial treatment period. Re-treatment for the first-time failing person is done by taking a drug susceptibility test to exclude all the drugs used for the first treatment and to treat the new susceptible drugs that have not been used in the past with at least 3 drugs, possibly 4 drugs or more, Treat for 18 months or more.
폐결핵의 치료는 통원치료와 내성획득을 예방하기 위하여 4제를 병용하는 것을 원칙으로 한다. 항결핵제 내성균은 약 106 세포분열마다 한 개의 빈도로 돌연변이주가 출현한다. 그러므로 최소한 2개 이상의 항결핵제를 같이 사용하는 다제병합요법의 원칙이 지켜져야 한다. 폐공동내에는 보통 107 ∼ 109의 결핵균이 있으며, 이런 병소 내에는 결핵균의 streptomycin, INH 및 RFP에 대한 약제 내성률은 각각 10-6, 10-5 및 10-8이다.The treatment of pulmonary tuberculosis is based on the principle of using 4 agents in order to prevent hospitalization and acquisition of tolerance. Line drugs are resistant mutant price emerges as a single frequency of about every 10 6 cell divisions. Therefore, the principle of multidrug combination therapy using at least two antituberculous drugs should be observed. There are usually 10 7 to 10 9 mycobacteria in the pulmonary tunnel, and drug resistance rates for streptomycin, INH and RFP in these lesions are 10 -6 , 10 -5 and 10 -8, respectively.
결핵치료의 가장 큰 문제점은 일차항결핵제에 대한 내성이 생기는 경우 특별한 치료방법이 없다는 것이다. 실제 효과적인 항결핵제의 개발과 체계적인 관리로 결핵의 발생과 사망이 급격히 감소하였지만 최근 다제내성결핵(multi-drug resistant tuberculosis, MDR-TB)의 발생과 후천성면역결핍증(AIDS) 유행으로 결핵이 증가하고 있는 추세이다. MDR-TB란 INH, RFP를 포함하여 최소한 두 가지 이상 약제에 동시내성이 발생된 것을 말한다. 판정의 기준은 약제가 포함된 배지에서 자란 결핵균주의 수가 약제가 포함되지 않은 배지에서 자란 균주 수의 1%를 초과할 때로 하고 있다.The biggest problem of tuberculosis treatment is that there is no special treatment method in case of resistance to primary anti-tuberculosis drugs. Although the incidence and mortality of tuberculosis has decreased dramatically due to the development of effective antituberculous drugs and the systematic management of tuberculosis, the recent trend of tuberculosis due to the development of multi-drug resistant tuberculosis (MDR-TB) and acquired immunodeficiency syndrome (AIDS) to be. MDR-TB refers to simultaneous resistance to at least two drugs including INH and RFP. The criteria for the determination are that the number of M. tuberculosis strains grown on a medium containing the drug exceeds 1% of the number of strains grown on media containing no drug.
현재 다제내성결핵은 심각한 보건문제로 대두되고 있다. 최근 몇 년 동안 우리나라는 결핵감염률이 더 이상 감소하지 않고 있으며 이는 다제내성 결핵환자가 감소하지 않고 있는 사실과 밀접한 관련이 있다. 또한 다제내성 결핵환자의 50%가 사망한다고 알려져 있다. 따라서 결핵으로 사망하는 원인의 상당수는 다제내성결핵으로 기인한다. 1995년 우리나라 결핵 실태조사에서 INH에 대한 내성률은 9.2% 이었다. 한 가지 이상의 약제에 대한 내성은 9.9%이었으며, INH 와 RFP를 포함한 두 가지 이상의 약제에 대한 내성률은 5.3%이었다. 이들은 지속적으로 약제내성균을 지역사회로 퍼트리는 근원이 되고 있다. 현재 몇 종의 2차 항결핵제가 개발되었지만 효과면에서 일차약제를 대체할 수 있는 약제는 없다.Currently, multidrug - resistant tuberculosis is emerging as a serious health problem. In recent years, the incidence of tuberculosis infection has not decreased further in Korea, which is closely related to the fact that patients with multidrug-resistant tuberculosis are not decreasing. It is also known that 50% of patients with multidrug - resistant tuberculosis die. Therefore, many of the causes of tuberculosis death are caused by multidrug-resistant tuberculosis. In 1995, the rate of resistance to INH in Korea was 9.2%. Resistance to one or more drugs was 9.9%, and resistance to two or more drugs including INH and RFP was 5.3%. They are the source of persistent drug-resistant bacteria to the community. Although a number of second-line anti-tuberculosis drugs have been developed, there are no drugs that can replace primary drugs in terms of efficacy.
따라서 기존 약제와 작용기전이 다른 새로운 항결핵제의 개발은 매우 시급한 과제이다. 이상적으로 다음과 같은 요구를 충족시키는 항결핵제 개발이 연구자들의 목표가 되고 있다. 즉 결핵치료기간을 단축시킬 수 있거나, 일차항결핵제에 내성이 생기는 경우 대치할 수 있는 약제 및 부작용이 상대적으로 적은 약제 개발이 요구된다. 더 나아가서는 언제든지 재활성화에 의해 환자가 될 수 있는 잠복결핵에 효과가 있는 약제개발이 요구된다.
Therefore, the development of new anti-tuberculosis drugs, which have different mechanisms of action from existing drugs, is an urgent task. Ideally, the development of anti-tuberculosis drugs that meet the following needs is the goal of researchers. Therefore, it is necessary to develop drugs that can shorten the duration of tuberculosis therapy, or replace drugs that are resistant to primary antituberculous drugs and drugs with relatively few side effects. Furthermore, development of drugs that are effective for latent tuberculosis, which can be a patient by reactivation at any time, is required.
본 발명은 백미추출물 또는 디옥시퍼굴라리닌(deoxypergularinine)을 유효성분으로 하는 새로운 결핵치료용 선도물질, 약학조성물 및 백미 추출물을 제공하는 것을 목적으로 한다.The present invention aims at providing a new drug for treating tuberculosis, a pharmaceutical composition and a white rice extract containing as an active ingredient a white rice extract or deoxypergularinine.
본 발명의 다른 목적으로는 식품학적으로 허용 가능한 담체를 포함하는 결핵치료 또는 예방을 위한 건강기능성식품을 제공하는 것이다.
Another object of the present invention is to provide a health functional food for treating or preventing tuberculosis comprising a pharmaceutically acceptable carrier.
상기의 목적을 달성하기 위하여, 본 발명에 따른 백미 추출물의 디옥시퍼굴라리닌을 유효성분으로 하는 결핵치료용 약학조성물은,
In order to accomplish the above object, the present invention provides a pharmaceutical composition for treating tuberculosis comprising, as an active ingredient, dioxypyrrolurinin,
본 발명에 따르면, 새로운 결핵치료용 선도물질, 약학조성물 및 건강보조식품을 얻을 수 있다.According to the present invention, a novel substance for treating tuberculosis, a pharmaceutical composition and a health supplement can be obtained.
본 발명에 따르면, 식품학적으로 허용 가능한 담체를 포함하는 결핵치료 또는 예방을 위한 건강기능성식품을 얻을 수 있다.
According to the present invention, a health-functional food for the treatment or prevention of tuberculosis comprising a pharmaceutically acceptable carrier can be obtained.
도 1은 백미의 메탄올 및 물 추출물의 디옥시퍼굴라리닌(deoxypergularinine)의 함량에 대한 HPLC 비교분석 결과를 나타내고 자외선 흡광도분석 결과를 나타내었다.
도 2는 백미로부터 분리한 디옥시퍼굴라리닌(deoxypergularinine)의 농도에 따를 항결핵 효과를 측정한 결과 MIC(최소억제농도) 값이 6 ㎍/ml을 나타내었다.
도 3은 디옥시퍼굴라리닌(deoxypergularinine)에 대한 배양된 표준결핵균주를 접종하여 항결핵제 내성균주에 대한 항결핵 활성을 측정하여 결과를 나타낸다.FIG. 1 shows HPLC analysis results of the content of deoxypergularinine in methanol and water extract of white rice, and the results of ultraviolet absorbance analysis are shown.
FIG. 2 shows MIC (minimum inhibitory concentration) value of 6 / / ml as measured by anti-tuberculosis effect according to the concentration of deoxypergularinine isolated from white rice.
FIG. 3 shows the results of measuring anti-tuberculosis activity against anti-tuberculosis resistant strains by inoculating cultured standard tubercle bacilli for deoxypergularinine.
백미(Cynanchum atratum)는 쌍떡잎식물, 용담목으로서 아마존이라고도 한다. 산과 들에서 자라며 높이는 약 50cm이다. 가지가 없으며 전체에 잎과 털이 빽빽이 나며 줄기는 곧게 선다. 잎은 마주나고 타원형이며 가장자리가 밋밋하고 짧은 잎자루가 있다. 잎 길이 615cm, 나비 48cm이며 끝이 뾰족하고 밑은 둥근 모양이다. 잎자루는 길이 812mm이다. 꽃은 5∼7월에 피고 검은 자주색이며 잎겨드랑이에서 산형(傘形)으로 갈라진 작은꽃자루 끝에 달린다. 꽃받침은 녹색이고 5개로 갈라진다. White rice ( Cynanchum atratum ) is a dicotyledonous plant, which is also called Amazon. It grows in mountains and fields and is about 50cm high. There are no branches, the leaves and hairs are dense throughout, and the stems are straight. Leaves are opposite and oval, with flat edges and short petiole. Leaf length 615cm, Butterfly 48cm, with pointed end and rounded bottom. The petiole is 812mm long. Flowers bloom in May-July, black purple, hanging on the end of a small peduncle, which is divided into umbrella-shaped from leaf axil. Calyx is green and cracks into 5 pieces.
화관(花冠)은 겉에 털이 드문드문 나고 안쪽은 털이 없으며 짙은 자주색이고 5개로 깊게 갈라진다. 부화관조각은 타원형이고 암술대와 같은 길이이다. 열매는 골돌과로서 넓은 바소꼴이고 9∼10월에 익는다. 길이 78cm이고 겉에 털이 빽빽이 나며 종자에도 길고 흰 털이 난다.Corolla (corolla) is sparse on the outside, has no hairs on the inside, is dark purple, and is deeply divided into 5 pieces. The bulbous sculpture is elliptical and has the same length as the style. The fruit is broad-leaved and has ripen in September-October. It is 78cm long and has dense hairs on the surface and long white hairs on the seeds.
한방에서는 뿌리와 뿌리줄기를 해열, 이뇨, 부종에 처방하며 민간에서는 잎을 강장제로 쓴다. 한국, 일본, 중국, 우수리강, 헤이룽강, 몽골에 분포한다. 유사종으로 꽃이 녹색빛이 도는 것을 푸른백미꽃(Cynanchum atratum for. viridescens Ohwi)이라 한다. 한방에서는 뿌리를 말린 것을 백미라 하여 해열, 이뇨, 토산제 등에 사용한다. 또 민간에서는 잎을 강장제로 사용한다.In one room, roots and rootstocks prescribe for fever, diuretic, edema, and in private, leaves are used as tonic. It is distributed in Korea, Japan, China, Siberian River, Heilong River, Mongolia. It is called a blue rice flower ( Cynanchum atratum for viridescens Ohwi). In one room, dried root is called white rice, and it is used for fever, diuretic, and tocetic acid. In the private sector, leaves are used as tonic.
백미(Cynanchum atratum)로부터 분리된 화합물로는 Steroidal glycosides인 cynanosides P1-P5, Q1-Q3, R1-R3, Cynanoside S와 Atratoside C, Sublanceoside E3, Chekiangensoside C, Cynatroside B, 2,4-dihyroxyacetophenone, 2,6-dihyroxyacetophenone, 4-hydroxybenzenemethanol, Benzoic acid, Beta-amyrin acetate, Palmitic acid, Beta-sitosterol, Beta-daucosterol, GlaucogeninC-3-O-alpha-D- oleandropyranosyl-(1->4)- beta-D-digitoxopyranosyl-(1->4)- alpha-D-oleandropyranoside, Cynascyroside C, Sublanceoside E, Sublanceoside I, Atratoside A, Atratoside B, Biphenylneolignan, 2,6,2',6'-tetramethoxy-4,4'-bis (2,3-epoxy-1-hydroxypropyl)biphenyl, Atratoglaucosides A 및 B, Cynatratoside-A, -B, -C, -D, -E 등이 알려져 있으나 디옥시퍼굴라리닌(deoxypergularinine)은 현재까지 보고된바 없다. Compounds isolated from Cynanchum atratum include the steroidal glycosides cynanosides P1-P5, Q1-Q3, R1-R3, Cynanoside S and Atratoside C, Sublanceoside E3, Chekiangensoside C, Cynatroside B, 2,4- dihyroxyacetophenone, D-oleandropyranosyl- (1- > 4) -beta-D-glucopyranoside, 6-dihydroxyacetophenone, 4-hydroxybenzenemethanol, Benzoic acid, Beta-amyrin acetate, Palmitic acid, Beta-sitosterol, Beta-daucosterol, GlaucogeninC- Cynascyroside C, Sublanceoside E, Sublanceoside I, Atratoside A, Atratoside B, Biphenylneolignan, 2,6,2 ', 6'-tetramethoxy-4,4'-bis (2,3-epoxy-1-hydroxypropyl) biphenyl, Atratoglaucosides A and B, Cynatratoside-A, -B, -C, -D and -E. However, deoxypergularinine has been reported to date There is no way.
또한 백미의 효능에 대한 학술적 연구보고는 항-골다공증, 신경보호작용, 항-담배모자이크바이러스에 대한 효능이 알려져 있으나 결핵균에 대한 효과 또한 현재까지 알려진 바 없다. 따라서 본 발명자들은 천연물로부터 부작용이 적은 항결핵균 감염치료제를 개발하기 위해 연구하던 중 백미 추출물 및 백미의 유효성분인 디옥시퍼굴라리닌(deoxypergularinine)이 표준결핵균주와 다제내성 결핵균주의 증식을 억제하는 것을 발견하여 본 발명을 완성하였다.
In addition, the scientific research report on the efficacy of white rice has been known to be effective against anti-osteoporosis, neuroprotection, and anti-tobacco mosaic virus. Therefore, the inventors of the present invention have been studying to develop anti-tuberculosis infection therapeutic agents which have less adverse effects from natural products, and that deoxypergularinine, an active ingredient of white rice extract and white rice, inhibits the proliferation of standard tubercle bacillus and multidrug- And completed the present invention.
본 발명은 표준(wild type) 결핵균주와 다제내성결핵균주의 증식억제효과를 갖는 백미추출물 및 디옥시퍼굴라리닌(deoxypergularinine)을 유효성분으로 하는 결핵치료용 선도물질, 약학조성물, 결핵치료 및 예방용 건강기능성식품에 관한 것으로, 본 발명에 따른 디옥시퍼굴라리닌(deoxypergularinine)과 백미의 물 및 유기용매 추출물 또는 이들의 혼합용매로부터 추출된 것을 특징으로 하며, 더욱 상세하게는 디옥시퍼굴라리닌(deoxypergularinine)과 물, 메탄올, 에탄올에 의하여 추출된 분획을 핵산과 디클로로메탄으로 추출하여 수득된 디클로로메탄 추출물인 것이다.The present invention relates to a medicament for the treatment of tuberculosis comprising a white rice extract and a deoxypergularinine having the effect of inhibiting the growth of wild type Mycobacterium tuberculosis and multidrug-resistant Mycobacterium tuberculosis as active ingredients, a pharmaceutical composition for the treatment and prevention of tuberculosis The present invention relates to a health functional food and is characterized in that it is extracted from deoxypergularinine, water and organic solvent extract of white rice, or a mixed solvent thereof, more specifically, deoxyperfuccurarinin deoxypergularinine) and extracts of dichloromethane obtained by extracting fractions extracted with water, methanol and ethanol with nucleic acid and dichloromethane.
또한, 결핵치료 또는 예방을 위한 건강기능식품은 분말, 과립, 정제, 캡슐 또는 음료형태로부터 선택되는 것임을 특징으로 한다. In addition, the health functional food for treatment or prevention of tuberculosis is characterized in that it is selected from powders, granules, tablets, capsules or beverage forms.
본 발명에 따른 백미추출물에 사용되는 백미 식물로부터 유래한 백미 뿌리, 지상부, 전초 등을 포함하며, 백미의 뿌리를 사용하는 것이 바람직하다.It is preferable to use white rice roots, which include white rice root, ground portion, outpost, etc. derived from white rice plants used in the white rice extract according to the present invention.
본 발명에 따른 백미추출물은 물 추출물, 유기용매추출물들이 모두 사용될 수 있으나, 유기용매추출물이 결핵균 증식억제에 더 효과적이며, 바람직한 유기용매는 메탄올, 에탄올, 프로판올, 부탄올, 또는 아세톤 등의 극성용매와 디클로로메탄, 클로로포름, 메틸렌클로라이드, 에테르 또는 헥산 등의 무극성용매이다. Although the water extract and the organic solvent extract according to the present invention can be used, the organic solvent extract is more effective in inhibiting the growth of the tubercle bacilli. The preferred organic solvent is a polar solvent such as methanol, ethanol, propanol, butanol, Non-polar solvents such as dichloromethane, chloroform, methylene chloride, ether or hexane.
특히 바람직하기로는 메탄올 또는 에탄올 등 극성용매에 의하여 추출된 분획을 핵산과 디클로로메탄으로 추출하여 수득된 디클로로메탄 분획이다.
Particularly preferred is a dichloromethane fraction obtained by extracting a fraction extracted with a polar solvent such as methanol or ethanol with a nucleic acid and dichloromethane.
이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명에 따른 백미추출물은 백미 1kg 당 2ℓ 내지 10ℓ의 비율로 물 또는 메탄올, 에탄올과 같은 저급알콜 또는 이들의 혼합용매를 가하여 20℃ 내지 70℃, 바람직하게는 20℃ 내지 30℃의 추출온도에서 10분 내지 5시간동안 열수추출, 냉침추출, 환류 냉각 추출 또는 초음파 추출 등의 추출방법으로 추출 및 여과한 후 이를 감압 농축하여 백미추출물을 얻을 수 있다.The white rice extract according to the present invention may be prepared by adding water or a lower alcohol such as methanol or ethanol or a mixed solvent thereof at a ratio of 2 to 10 liters per kg of white rice at an extraction temperature of 20 to 70 캜, preferably 20 to 30 캜 Extraction and filtration using an extraction method such as hot water extraction, cold extraction, reflux cooling extraction or ultrasonic extraction for 10 minutes to 5 hours, and then concentrated under reduced pressure to obtain a white rice extract.
상기의 백미추출물은 물에 현탁한 후 n-헥산, 디클로로메탄의 비극성용매를 이용하여 분획을 얻을 수 있으며, 특히 본 발명에 따른 백미추출물은 저급알콜에 의한 추출 후 물과 디클로로메탄으로 분획하여 수득한 디클로로메탄 분획이 가장 결핵균에 대한 활성이 높다. 수득된 상기 핵산 및 디클로로메탄 분획을 실리카겔 컬럼 크로마토그래피와 Sephadex LH-20을 이용한 크로마토그래피를 수행함으로써, 순수화합물로서 디옥시퍼굴라리닌(deoxypergularinine)을 수득할 수 있다.The white rice extract of the present invention can be obtained by suspending it in water and then using a nonpolar solvent of n-hexane or dichloromethane. In particular, the white rice extract according to the present invention can be obtained by extracting with lower alcohol and fractionating with water and dichloromethane One dichloromethane fraction has the highest activity against M. tuberculosis. The obtained nucleic acid and the dichloromethane fraction are subjected to chromatography using silica gel column chromatography and Sephadex LH-20 to obtain deoxypergularinine as a pure compound.
추출물의 활성을 조사한 결과 50 ㎍/ml 이상의 저농도에서 표준결핵균주에 대하여 항살균 활성의 효과가 있었으며, 활성에 기초한 컬럼크로마토그래피를 통하여 백미의 성분 중 디옥시퍼굴라리닌(deoxypergularinine)이 결핵균주에의 유효활성성분임을 확인하였다.
As a result of the activity of extracts, antimicrobial activity against standard tubercle bacilli was observed at a low concentration of 50 ㎍ / ml or more, and deoxypergularinine, a component of white rice, Was found to be an active active ingredient.
본 발명에 따른 분석된 화합물인 디옥시퍼굴라리닌(deoxypergularinine에 대한 화학식은 다음과 같다.
The formula for deoxypergularinine, an analyte compound according to the present invention, is as follows.
[화학식 1][Chemical Formula 1]
본 발명에 따른 결핵치료용 약학조성물에는 디옥시퍼굴라리닌(deoxypergularinine)을 60mg 내지 6g 를 함유하거나, 또는 백미 추출물을 0.1 내지 80% 중량 함유되는 것을 특징으로 한다.The pharmaceutical composition for treating tuberculosis according to the present invention is characterized by containing 60 mg to 6 g of deoxypergularinine or 0.1 to 80% by weight of white rice extract.
또한, 본 발명의 백미 추출물을 포함하는 조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.
In addition, the composition comprising the white rice extract of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the production of pharmaceutical compositions.
본 발명의 화합물, 추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토오즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오즈, 메틸셀룰로오즈, 미정질 셀룰로오즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 본 발명에 따른 화합물 및 추출물을 포함하는 약학조성물은 각각 통상의 방법에 따라 산제, 과립제, 캡슐제, 현탁액, 에멀젼, 시럽 등의 경구형 제형, 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제제화 할 경우 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. Examples of the carrier, excipient and diluent which can be contained in the composition containing the compound of the present invention and the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The pharmaceutical composition containing the compound and the extract according to the present invention can be formulated in the form of powders, granules, capsules, oral preparations such as suspensions, emulsions and syrups, and sterilized injection solutions according to conventional methods. When it is formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are generally used.
본 발명에 디옥시퍼굴라리닌(deoxypergularinine) 및 백미 추출물을 함유하는 결핵치료용 약학조성물의 용량은 환자의 나이, 성별, 체중에 따라 달라질 수 있다. 약학조설뭉실은 용량은 0.1 내지 100 mg/kg의 양을 1 일 1 회 내지 수회 투여할 수 있으며, 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.
The dosage of the pharmaceutical composition for treating tuberculosis containing deoxypergularinine and white spirit extract according to the present invention may vary depending on the age, sex, and body weight of the patient. The dosage may be in the range of 0.1 to 100 mg / kg once or several times a day, and the dose may be increased or decreased depending on the administration route, disease severity, sex, weight, age, and the like. The dose is not intended to limit the scope of the invention in any way.
본 발명의 디옥시퍼굴라리닌(deoxypergularinine) 또는 백미 추출물은 결핵의 예방 또는 치료의 효과를 위한 건강보조식품으로 다양하게 이용될 수 있다. 본 발명에 따른 deoxypergularinine 및 백미 추출물을 첨가할 수 있는 식품으로는 분말, 과립, 정제, 캡슐형태의 각종 식품류, 음료, 껌, 차 등을 들 수 있다. The deoxypergularinine or white rice extract of the present invention can be used variously as a health supplement for the prevention or treatment of tuberculosis. Foods to which deoxypergularinine and white rice extract according to the present invention can be added include powders, granules, tablets, various foods in the form of capsules, beverages, gums and tea.
이 때, 식품 또는 음료 중의 상기 추출물의 양, 즉 일반적으로 본 발명의 건강기능성식품 조성물은 전체 식품 중량의 0.01 내지 20% 중량으로 가할 수 있으며, 건강 음료 조성물은 100 를 기준으로 0.01 내지 20 g, 바람직하게는 0.2 내지 2 g의 비율로 가할 수 있다.
In this case, the amount of the above-mentioned extract in the food or beverage, that is, the health functional food composition of the present invention can be generally 0.01 to 20% by weight of the total food weight, and the health beverage composition is 0.01 to 20 g, Preferably at a ratio of 0.2 to 2 g.
본 발명의 건강 음료 조성물은 지시된 비율로, 필수 성분으로서 상기 추출물을 함유하는 외에는 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 포도당, 과당, 말토스, 슈크로스, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 및 합성 향미제를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 10 g이다.
The health beverage composition of the present invention is not limited to liquid ingredients other than those containing the extract as an essential ingredient in the indicated ratios and may contain various flavors or natural carbohydrates such as ordinary beverages as an additional ingredient. Examples of the above-mentioned natural carbohydrates are conventional sugars such as glucose, fructose, maltose, sucrose, dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors and synthetic flavors can be advantageously used as flavors other than those described above. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 10 g per 100 g of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.
In addition to the above, the composition of the present invention can be used in various forms such as flavorings such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, PH adjusters, stabilizers, antiseptics, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination.
본 발명의 추출물 자체는 1,000 mg/kg의 용량으로 쥐에게 경구 투여하였을 때 독성이 거의 없는 것으로 나타났으며, 표준균주 및 내성균주 모두에 대하여 유의미한 효과를 나타난바, 백미 조추출물을 함유한 약학조성물 또는 건강보조식품은 결핵의 예방 및 치료에 유용하다.
The extract of the present invention itself showed little toxicity when administered orally to rats at a dose of 1,000 mg / kg and showed a significant effect on both the standard strain and the resistant strain, and the pharmaceutical composition containing the white rice extract Or health supplements are useful for the prevention and treatment of tuberculosis.
이하 실시예에 의하여 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to examples.
단, 하기 실시예는 본 발명을 예시하는 것으로, 본 발명의 범위가 이에 한정되는 것은 아니다.
However, the following examples are illustrative of the present invention, and the scope of the present invention is not limited thereto.
<실시예 1>≪ Example 1 >
본 발명에 따른 백미 물 추출물의 제조백미 1kg에 물 2 내지 10L를 가하고 90℃ 내지 95℃에서 2 시간 동안 3회 추출한 후 여과지로 여과하고, 감압 농축하여 백미 추출물 210 g을 제조하였다. 도 1은 백미 물추출물에 대한 HPLC 결과를 나타낸다.
Preparation of White Rice Water Extract According to the Present Invention Water (2 to 10 L) was added to 1 kg of white rice, and extracted three times at 90 ° C to 95 ° C for 2 hours. Then, the mixture was filtered through filter paper and concentrated under reduced pressure to obtain 210 g of white rice extract. Figure 1 shows the HPLC results for white rice water extract.
<실시예 2>≪ Example 2 >
본 발명에 따른 백미 메탄올 추출물의 제조 백미 1kg에 2L내지 20L의 메탄올을 가하고 실온에서 냉침하여 3회 추출한 후 여과하고, 여액을 감압 농축하여 백미메탄올 추출물 240 g을 제조하였다. 도 1은 백미 메탄올 추출물에 대한 HPLC 결과를 나타낸다.
Preparation of White Rice Methanol Extract According to the Present Invention 2 L to 20 L of methanol was added to 1 kg of white rice, and the mixture was cooled at room temperature for 3 times and filtered. The filtrate was concentrated under reduced pressure to obtain 240 g of methanol extract. Fig. 1 shows the HPLC results for methanol extract of white rice.
<실시예 3> 본 발명에 따른 백미의 추출물 활성분석<Example 3> Analysis of extract activity of white rice according to the present invention
- Resazurin microtiter assay- Resazurin microtiter assay
Resazurin 용액은 40 ml의 멸균된 물에 resazurin sodium salt를 4 mg 넣어 0.01%로 제조한 다음, 0.45 m의 필터로 여과하여 냉장 보관한 뒤 사용하였다. 7H9 media를 100㎕씩 분주한 96well에 100㎕의 디옥시퍼굴라리닌(deoxypergularinine)을 더한 뒤 연속희석(serial dilution, 1.5㎍/ml ∼ 50 ㎍/ml)한 다음, M.tuberculosis H37Ra (5x10cells/ml)를 100㎕씩 첨가하였다. 일주일 후, resazurin 용액 30㎕씩을 각 well에 첨가하여 항결핵 활성을 확인하였다. 양성대조군으로 isoniazid와 rifampin을 0.5∼2 ㎍/ml로 설정해서 넣어주었고, 음성대조군으로는 동량의 DMSO를 사용하였다. 도 2는 화합물인 디옥시퍼굴라리닌(deoxypergularinine)에 대한 항-결핵 활성결과를 나타낸다. MIC는 약 6 ㎍/ml로 나타났다.
Resazurin solution was prepared by adding 4 mg of resazurin sodium salt to 40 ml of sterilized water to make 0.01%, then filtered with 0.45 m filter, and stored in the refrigerator. After dilution (serial dilution, 1.5 ㎍ / ml to 50 ㎍ / ml), 100 μl of deoxypergularinine was added to 96 wells containing 100 μl of 7H9 media, followed by addition of M.tuberculosis H37Ra (5 × 10cells / ml). One week later, 30 μl of resazurin solution was added to each well to confirm antituberculous activity. As a positive control, isoniazid and rifampin were added at a dose of 0.5 ~ 2 ㎍ / ml, and the same amount of DMSO was used as a negative control. Figure 2 shows the results of anti-tuberculosis activity against the compound deoxypergularinine. MIC was about 6 ㎍ / ml.
<실시예 4> 본 발명에 따른 백미의 추출물 활성분석 재검<Example 4> Analysis of the extract activity of white rice according to the present invention
- MGIT assay - MGIT assay
본 실험은 Resazurin microtiter assay에서 활성이 확인된 디옥시퍼굴라리닌(deoxypergularinine)의 결핵균 생장억제 능력을 확인하기 위해 MGIT 960 System을 이용하여 수행되었다. MGIT tube에 든 7 ml의 media에 추가로 740∼820㎕의 growth supplement를 첨가한 뒤, 디옥시퍼굴라리닌(1 mg/ml)를 최종농도 3∼12 ㎍/ml로 맞추었다. 그 후, M.tuberculosis H37Ra (6.4x10cells/ml)를 100 ㎕ 넣은 다음 MGIT 기기로 결핵균의 생장을 매일 측정하여 디옥시퍼굴라리닌의 생장억제 활성을 측정하였다. 양성대조군으로는 rifampin (5㎍/ml)을 사용하였고, 음성대조군으로는 동량의 DMSO를 사용하였다. 도 3은 화합물인 디옥시퍼굴라리닌(deoxypergularinine)에 대한 항-결핵 활성결과를 나타낸다.
This experiment was performed using the MGIT 960 system to confirm the ability of deoxypergularinine to inhibit growth of M. tuberculosis in the Resazurin microtiter assay. After addition of 740 to 820 μl of growth supplement to 7 ml of media in the MGIT tube, deoxypyrrolinin (1 mg / ml) was adjusted to a final concentration of 3-12 μg / ml. After that, 100 쨉 l of M. tuberculosis H37Ra ( 6.4 x 10cells / ml) was added, and then the growth inhibitory activity of dioxypyrrolurinin was measured by measuring the growth of Mycobacterium tuberculosis with an MGIT instrument on a daily basis. Rifampin (5 μg / ml) was used as a positive control and DMSO was used as a negative control. Figure 3 shows the results of anti-tuberculosis activity against the compound deoxypergularinine.
이하, 백미의 메탄올 추출물로부터 컬럼크로마토그래피를 통하여 순수 분리한 화합물의 1H-NMR, 13C-NMR, MASS 분석 결과를 나타내었다.Hereinafter, the results of 1 H-NMR, 13 C-NMR and MASS analyzes of the compound purely separated from the methanol extract of white rice through column chromatography are shown.
1H-NMR (CDCl3, 500 MHz) δ: 7.91 (1H, d, J = 9.2Hz, H-1), 7.88 (1H, s, H-5), 7.86 (1H, d, J = 2.5Hz, H-4), 7.21 (1H, dd, J = 9.2, 2.5Hz, H-2), 7.09 (1H, s, H-8), 4.62 (1H, d, J = 14.5 Hz, H-9), 4.09 (3H, s, OCH3-7), 4.03 (3H, s, OCH3-6), 4.01 (3H, s, OCH3-3), 3.72 (1H, d, J = 14.5 Hz, H-9), 3.47 (1H, td, J = 8.1, 2.0 Hz, H-11), 3.40 (1H, dd, J = 16.5, 3.0 Hz,H-14), 3.00 (1H, dd, J = 16.5, 10.5 Hz, H-14), 2.59 (1H, m, H-13a), 2.58 (1H, dd, J = 8.1, 8.1Hz, H-11), 2.25 (1H, m, H-13), 2.06 (1H, m, H-12), 1.96 (1H, m, H-12), 1.82 (1H, m, H-13).
1 H-NMR (CDCl 3, 500 MHz)?: 7.91 (1H, d, J = 9.2 Hz, H-1), 7.88 D, J = 9.2, 2.5 Hz, H-2), 7.09 (1H, s, H-8), 4.62 4H), 4.09 (3H, s, OCH3-7), 4.03 (3H, s, OCH3-6), 4.01 (1H, dd, J = 16.5, 10.5 Hz, H), 3.47 (1H, dd, J = 8.1, 2.0 Hz, H- M, H-13), 2.06 (1H, m, H-13), 2.59 (1H, d, J = H-12), 1.96 (1H, m, H-12), 1.82 (1H, m, H-13).
13C-NMR (CDCl3, 500 MHz) δ: 157.7 (C-3), 149.4 (C-7), 148.3 (C-6), 130.4 (C-4b), 126.6 (C-8b), 125.3 (C-14b), 125.2 (C-14a), 125.1 (C-1), 124.2 (C-8a), 123.4 (C-4a), 114.9 (C-2), 104.6 (C-4), 103.8 (C-5), 102.9 (C-8), 60.2 (C-13a), 56.0 (OCH3-7), 55.9 (OCH3-6), 55.5 (OCH3-3), 55.4 (C-11), 53.1 (C-9), 32.6 (C-14), 30.9 (C-13), 21.5 (C-12).
13 C-NMR (CDCl 3 , 500 MHz)?: 157.7 (C-3), 149.4 (C-7), 148.3 (C-6), 130.4 C-14b), 125.2 (C-14a), 125.1 (C-1), 124.2 (C-8a), 123.4 -5), 102.9 (C-8), 60.2 (C-13a), 56.0 (OCH3-7), 55.9 (OCH3-6), 55.5 (OCH3-3), 55.4 9), 32.6 (C-14), 30.9 (C-13), 21.5 (C-12).
EIMS m/z : 363(C23H25NO3)
EIMS m / z: 363 (C 23 H 25 NO 3 )
Claims (7)
상기 백미 추출물은 물, 유기용매 또는 이들의 혼합용매로부터 추출된 것임을 특징으로 하는 결핵치료용 약학조성물.The method according to claim 1,
Wherein the white rice extract is extracted from water, an organic solvent or a mixed solvent thereof.
유기용매는 메탄올, 에탄올, 핵산, 디클로로메탄, 또는 에틸아세테이트를 특징으로 하는 결핵치료용 약학조성물.3. The method of claim 2,
Wherein the organic solvent is methanol, ethanol, nucleic acid, dichloromethane, or ethyl acetate.
메탄올 및 물에 의하여 추출된 분획을 핵산과 디클로로메탄을 가하여 수득된 핵산 및 디클로로메탄 분획인 것을 특징으로 하는 결핵치료용 약학조성물.The method of claim 3,
Wherein the fraction is a nucleic acid and a dichloromethane fraction obtained by adding nucleic acid and dichloromethane to the fraction extracted by methanol and water.
상기 디옥시퍼굴라리닌(deoxypergularinine)은 하기의 화학식인 것을 특징으로 하는 결핵치료용 약학조성물.
[화학식]
The method according to claim 1,
Wherein the deoxypergularinine is of the following formula:
[Chemical Formula]
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| KR20180102851A (en) * | 2017-03-08 | 2018-09-18 | 에이제이 주식회사 | Preservative composition comprising Cynanchum atratum Bunge extract as active ingredient and method of manufacturing the same |
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