KR20230171852A - Pharmaceutical composition for preventing or treating respiratory inflammatory disease - Google Patents
Pharmaceutical composition for preventing or treating respiratory inflammatory disease Download PDFInfo
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- KR20230171852A KR20230171852A KR1020220166482A KR20220166482A KR20230171852A KR 20230171852 A KR20230171852 A KR 20230171852A KR 1020220166482 A KR1020220166482 A KR 1020220166482A KR 20220166482 A KR20220166482 A KR 20220166482A KR 20230171852 A KR20230171852 A KR 20230171852A
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- ginseng
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Abstract
본 발명은 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물을 개시한다. 본 발명에 따른 약학적 조성물은 종래 호흡기 염증 질환의 예방 또는 치료에 효과가 있다고 알려져 있으며, 특히 진해·거담 작용을 갖는다고 알려진 마황과 길경의 혼합 추출물 보다 항염증 인자인 NO(nitric oxide), IL-1β, IL-6 및 TNF-α과, 전 염증성 물질인 류코트리엔 B4(leukotriene B4; LTB4)의 억제 효과가 우수하며, 점액 생성 유전자인 뮤신 5AC(Mucin 5AC; MUC5AC)의 억제 효과가 우수하여 호흡기 염증 질환 예방 또는 치료제 및 진해·거담제를 위한 의약품 등에 적용될 수 있다.The present invention discloses a pharmaceutical composition for preventing or treating respiratory inflammatory diseases. The pharmaceutical composition according to the present invention is known to be effective in preventing or treating conventional respiratory inflammatory diseases, and in particular, it contains NO (nitric oxide), IL, which are anti-inflammatory factors, rather than the mixed extract of Ephedra and Gilge Gyeong, which are known to have antitussive and expectorant effects. -1β, IL-6, TNF-α, and the pro-inflammatory substance leukotriene B4 (LTB4) are highly suppressive, and the mucus-generating gene Mucin 5AC (MUC5AC) is suppressed, thereby improving respiratory health. It can be applied to medicines for preventing or treating inflammatory diseases and as an antitussive or expectorant.
Description
본 발명은 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물에 관한 것으로서, 본 발명에 따른 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물은 진해 및 거담 작용을 갖는 것을 특징으로 한다.The present invention relates to a pharmaceutical composition for preventing or treating respiratory inflammatory diseases. The pharmaceutical composition for preventing or treating respiratory inflammatory diseases according to the present invention is characterized by having antitussive and expectorant effects.
COVID-19(신종 코로나바이러스 감염증) 호흡기 증후군 회복 환자의 경우 유전자 전사나 물질대사와 관련해 대식세포(macrophage)에 각인된 전(前) 염증성 특징이 5개월 가량 유지되며, 코로나 회복 이후에도 일정기간 동안은 면역계의 염증에 대한 민감성이 높게 지속된다.In patients recovering from COVID-19 (novel coronavirus infection) respiratory syndrome, the pre-inflammatory characteristics imprinted on macrophages related to gene transcription and metabolism are maintained for about 5 months, and for a certain period of time even after recovery from COVID-19. The immune system remains highly susceptible to inflammation.
이러한 증상을 장기 후유증, 일명 장기 코로나(long COVID), 포스트 코로나 컨디션 또는 포스트 코로나 19 증후군이라고 한다.These symptoms are called long-term sequelae, also known as long COVID, post-COVID condition, or post-COVID-19 syndrome.
통계 상 COVID-19 감염자의 약 30%가 수 개월후에도 장기 코로나(long COVID)를 겪는 것으로 알려져 있으며, 일반적인 코로나 19의 회복 기간을 넘어 몇 주 혹은 몇 달에 걸쳐 후유증이 지속되는 특징을 보이며, 이의 후유증의 일 예로는 피로감, 수면장애, 이명, 인지장애(브레인포그)를 비롯해 지속적인 기침, 가래, 호흡곤란 등의 호흡기 염증 질환을 들 수 있다. 이러한 장기 코로나(long COVID) 의심 징후가 나타나는 경우 이에 대한 치료가 필요하다고 볼 수 있다.Statistically, about 30% of COVID-19 infected people are known to suffer from long COVID even after several months, and the aftereffects are characterized by lasting for weeks or months beyond the normal recovery period of COVID-19. Examples of aftereffects include fatigue, sleep disorders, tinnitus, cognitive impairment (brain fog), and respiratory inflammatory diseases such as persistent coughing, phlegm, and difficulty breathing. If these signs of long COVID appear, treatment may be necessary.
경증 COVID-19 회복 환자 36명의 혈액 샘플 분석 결과 염증성 에이코사노이드(eicosanoid)의 생성이 증가함에 따라 류코트리엔 B4(Leukotriene B4; LTB4)가 높은 수위로 3~5개월간 유지되는 결과를 나타났다고 보고되었다 (Mucosal Immunology volume 15, pages515-524 (2022)).As a result of analyzing blood samples from 36 recovered patients from mild COVID-19, it was reported that leukotriene B4 (LTB4) remained at high levels for 3 to 5 months as the production of inflammatory eicosanoids increased (Mucosal Immunology volume 15, pages515-524 (2022)).
회복 후 수개월이 지날 때까지 류코트리엔 B4(Leukotriene B4; LTB4)의 높은 수준의 유지는 호흡기 염증의 민감성을 높일 수 있는 부분으로서 COVID-19에서 회복한 뒤에도 류코트리엔 B4(Leukotriene B4; LTB4)가 증가세를 유지하면 호흡기 염증의 민감성이 높아질 수 있는 문제가 있다.Maintaining high levels of Leukotriene B4 (LTB4) even months after recovery may increase susceptibility to respiratory inflammation, and Leukotriene B4 (LTB4) remains elevated even after recovery from COVID-19. There is a problem that this may increase the sensitivity to respiratory inflammation.
따라서, 본 발명은 장기 코로나 후유증으로부터 벗어날 수 있도록 류코트리엔 B4(Leukotriene B4; LTB4)의 억제에 효과적인 생약 성분 및 이들의 최적화된 배합비율을 선정하여 호흡기 염증 질환의 예방 또는 치료에 효과가 있으며, 특히 진해·거담 작용을 갖는 약학적 조성물을 개발하고자 한다.Therefore, the present invention is effective in preventing or treating respiratory inflammatory diseases by selecting herbal ingredients and their optimized mixing ratios that are effective in suppressing leukotriene B4 (LTB4) to avoid long-term Corona aftereffects. ·We seek to develop a pharmaceutical composition with expectorant action.
이에, 본 발명자들은 부작용이 많은 합성 약물들을 대체할 만한 안전하면서 효능이 과학적으로 입증된 천연물 유래의 의약품 또는 식품을 개발하기 위하여 연구한 결과, 마황, 길경, 오미자 및 인삼의 혼합 추출물의 경우, 종래 호흡기 염증 질환의 예방 또는 치료에 효과가 있으며, 특히 진해·거담 작용을 갖는다고 있다고 알려진 마황과 길경의 혼합 추출물 보다 항염증 인자인 NO(nitric oxide), 인터루킨-1β(Interleukin-1β; IL-1β), 인터루킨-6(Interleukin-6; IL-6) 및 종양괴사인자-α(tumor necrosis factor-α; TNF-α)과, 전 염증성 물질인 류코트리엔 B4(leukotriene B4; LTB4)의 억제 효과가 우수하며, 점액 생성 유전자인 뮤신 5AC(Mucin 5AC; MUC5AC)의 억제 효과가 우수함을 확인하고, 본 발명을 완성하였다.Accordingly, the present inventors conducted research to develop medicines or foods derived from natural products that are safe and scientifically proven to be effective as substitutes for synthetic drugs with many side effects. As a result, in the case of mixed extracts of ephedra, Gilgyeong, Schisandra chinensis, and ginseng, It is effective in preventing or treating respiratory inflammatory diseases, and in particular, it contains anti-inflammatory factors such as NO (nitric oxide), interleukin-1β (IL-1β), and anti-inflammatory factors, rather than the mixed extract of ephedra and gilgye, which are known to have antitussive and expectorant properties. ), Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and leukotriene B4 (LTB4), a pro-inflammatory substance. In addition, it was confirmed that the inhibitory effect of Mucin 5AC (MUC5AC), a mucus production gene, was excellent, and the present invention was completed.
따라서, 본 발명은 마황, 길경, 오미자 및 인삼의 혼합 추출물을 유효성분으로 포함하는 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것을 구체적인 해결과제로 한다.Therefore, the specific problem of the present invention is to provide a pharmaceutical composition for the prevention or treatment of respiratory inflammatory diseases containing mixed extracts of ephedra, gilgyeong, Schisandra chinensis, and ginseng as active ingredients.
구체적으로, 본 발명에 따른 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물의 경우 진해·거담 작용을 갖는 것을 구체적인 해결과제로 한다.Specifically, in the case of the pharmaceutical composition for preventing or treating respiratory inflammatory diseases according to the present invention, having antitussive and expectorant effects is a specific problem to be solved.
나아가, 본 발명은 마황, 길경, 오미자 및 인삼의 혼합 추출물이 약리학적으로 가장 우수한 상승 효과를 나타낼 수 있는 비율로 생약 1일 복용량 기준 함량이 포함되도록 혼합된 혼합 추출물을 유효성분으로 제공하는 것을 특별한 해결과제로 한다.Furthermore, the present invention provides, as an active ingredient, a mixed extract of ephedra, gilgyeong, Schisandra chinensis, and ginseng mixed in a ratio that can exhibit the best pharmacological synergistic effect and contains the standard daily dose of herbal medicine. Make it a problem to solve.
이 때, 1일 복용량 기준 함량은 1일 3회 투여를 기준으로 산정한 것이다.At this time, the daily dose standard content is calculated based on administration three times a day.
상기 목적을 달성하기 위하여, 본 발명은 마황, 길경, 오미자 및 인삼의 혼합 추출물을 유효성분으로 포함하는 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of respiratory inflammatory diseases containing a mixed extract of ephedra, gilgyeong, Schisandra chinensis, and ginseng as an active ingredient.
본 발명에 따른 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물은 우수한 항염증 효과 및 진해·거담 활성을 가지며, 이는 유효성분으로 마황 및 길경의 혼합 추출물, 마황, 길경 및 오미자의 혼합 추출물, 그리고 마황, 길경 및 인삼의 혼합 추출물 보다 우수한 효과를 갖는다.The mixed extract of ephedra, gilgyeong, Schisandra chinensis and ginseng, which are active ingredients according to the present invention, has excellent anti-inflammatory effects and antitussive and expectorant activities, and the active ingredients include mixed extracts of ephedra and gilgyeong, mixed extracts of ephedra, gilgyeong and Schisandra chinensis, And it has a superior effect than the mixed extract of ephedra, gilgyeong, and ginseng.
또한, 본 발명의 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물은 생약 중량 기준으로 최적의 중량비를 포함함으로써 항염증 효과 및 진해·거담 활성을 갖는 덱사메타손 대비 동등 또는 이상의 억제 효과를 갖는다.In addition, the mixed extract of ephedra, gilgyeong, Schisandra chinensis, and ginseng, which are active ingredients of the present invention, contains an optimal weight ratio based on the weight of herbal medicine, and has an inhibitory effect equal to or greater than that of dexamethasone, which has anti-inflammatory effects and antitussive and expectorant activities.
또한, 본 발명의 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물은 호흡기 염증 질환, 특히 비인두염, 후두염, 만급성 기관지염, 염증성 폐 질환, 폐기종, 천식, 만성 폐쇄성 폐질환, 중이염, 부비강염, 편도선염 및 알레르기성 비염 질환의 개선 또는 치료에 매우 유용하며, 진해·거담제로의 적용이 가능하다.In addition, the mixed extract of ephedra, gilgyeong, Schisandra chinensis and ginseng, which are the active ingredients of the present invention, can be used to treat respiratory inflammatory diseases, especially nasopharyngitis, laryngitis, acute bronchitis, inflammatory lung disease, emphysema, asthma, chronic obstructive pulmonary disease, otitis media, sinusitis, It is very useful in improving or treating tonsillitis and allergic rhinitis diseases, and can be applied as an antitussive and expectorant.
본 발명의 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물은 부작용이 알려지지 않은 안전성이 뛰어난 유효성분으로 건강기능(성)식품, 식품첨가물, 음료, 의약품 등에 널리 사용될 수 있는 이점이 있다.The mixed extract of ephedra, gilgyeong, Schisandra chinensis, and ginseng, which are the active ingredients of the present invention, is an effective ingredient with excellent safety with no known side effects, and has the advantage of being widely used in health functional (sexual) foods, food additives, beverages, pharmaceuticals, etc.
본 발명의 효과는 이상에서 언급한 효과들로 제한되지 않으며, 이하에서 설명할 내용으로부터 통상의 기술자에게 자명한 범위 내에서 다양한 효과들이 포함될 수 있다.The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within the scope apparent to those skilled in the art from the contents described below.
도 1은 실시예 1 내지 9, 비교예 1 내지 8에 따른 약학적 조성물의 산화질소 (nitric oxide; NO) 억제 효과를 나타낸 그래프이다.
도 2는 본 발명의 호흡기 염증 질환 예방 또는 치료제 및 진해·거담 작용제의 유효성분인 마황 추출물, 길경 추출물, 오미자 추출물 및 인삼 추출물에 대한 조합의 용량 범위를 도출하기 위한 도면이다.Figure 1 is a graph showing the nitric oxide (NO) inhibition effect of pharmaceutical compositions according to Examples 1 to 9 and Comparative Examples 1 to 8.
Figure 2 is a diagram for deriving the dosage range of the combination of ephedra extract, Gilgyeong extract, Schisandra chinensis extract and ginseng extract, which are active ingredients of the respiratory inflammatory disease prevention or treatment and antitussive and expectorant agent of the present invention.
이하, 본 명세서에 대하여 더욱 상세히 설명한다.Hereinafter, this specification will be described in more detail.
이를 구체적으로 설명하면 다음과 같다. 본 명세서에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.This is explained in detail as follows. The terms used in this specification are general terms that are currently widely used as much as possible while considering the function in the present invention, but this may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than simply the name of the term.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the technical field to which the present invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless clearly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.
수치 범위는 상기 범위에 정의된 수치를 포함한다. 본 명세서에 걸쳐 주어진 모든 최대의 수치 제한은 낮은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 낮은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 최소의 수치 제한은 더 높은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 높은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 수치 제한은 더 좁은 수치 제한이 명확히 쓰여져 있는 것처럼, 더 넓은 수치 범위 내의 더 좋은 모든 수치 범위를 포함할 것이다.The numerical range includes the values defined in the range above. Every maximum numerical limit given throughout this specification includes all lower numerical limits as if the lower numerical limit were explicitly written out. Every minimum numerical limit given throughout this specification includes every higher numerical limit as if such higher numerical limit was clearly written. All numerical limits given throughout this specification will include all better numerical ranges within the broader numerical range, as if the narrower numerical limits were clearly written.
이하, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각에 대한 다른 설명 및 실시형태에도 적용될 수 있다. 즉, 본 발명에 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기에 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description set forth below.
본 명세서에서 사용되는 「포함하는」과 같은 표현은, 해당 표현이 포함되는 문구 또는 문장에서 특별히 다르게 언급되지 않는 한, 다른 실시예를 포함할 가능성을 내포하는 개방형 용어(open-ended terms)로 이해되어야 한다.Expressions such as “comprising” used in this specification are understood as open-ended terms that imply the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence containing the expression. It has to be.
본 발명의 발명자들은, 호흡기 염증 질환의 예방 또는 치료제 및 진해·거담 작용제(진해·거담제)를 개발하기 위해 연구 개발 하던 중, 마황, 길경, 오미자 및 인삼의 혼합 추출물을 유효성분으로 포함할 경우 종래 호흡기 염증 질환의 예방 또는 치료에 효과가 있으며, 특히 진해·거담 작용에 효과가 있다고 알려진 마황과 길경의 혼합 추출물 보다 항염증 인자인 산화질소(nitric oxide; NO), 인터루킨-1β(Interleukin-1β; IL-1β), 인터루킨-6(Interleukin-6; IL-6) 및 종양괴사인자-α(tumor necrosis factor-α; TNF-α)과, 전 염증성 물질인 류코트리엔 B4(leukotriene B4; LTB4)의 억제 효과가 우수하며, 점액 생성 유전자인 뮤신 5AC(Mucin 5AC; MUC5AC)의 억제 효과가 우수함을 확인함으로써, 본 발명을 완성하게 되었다.The inventors of the present invention, while conducting research and development to develop a preventive or therapeutic agent for respiratory inflammatory diseases and an antitussive/exposure agent (antitussive/expectant), found that mixed extracts of ephedra, gilgyeong, Schisandra chinensis, and ginseng as active ingredients were used as active ingredients. It is effective in preventing or treating respiratory inflammatory diseases, and is especially effective in anti-tussive and expectorant action, including the anti-inflammatory factors nitric oxide (NO) and interleukin-1β (Interleukin-1β), rather than the mixed extract of ephedra and gilgyeong, which are known to be effective in antitussive and expectorant action. Inhibition of IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and leukotriene B4 (LTB4), a pro-inflammatory substance. The present invention was completed by confirming that the effect was excellent and that the inhibitory effect of Mucin 5AC (MUC5AC), a mucus production gene, was excellent.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
호흡기 염증 질환의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating respiratory inflammatory diseases
본 발명은 하기와 같은 약학적 조성물을 개시한다.The present invention discloses the following pharmaceutical composition.
구체적으로, 본 발명은 마황, 길경, 오미자 및 인삼의 혼합 추출물을 유효성분으로 포함하는 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물에 대한 것이다.Specifically, the present invention relates to a pharmaceutical composition for the prevention or treatment of respiratory inflammatory diseases containing mixed extracts of ephedra, gilgyeong, Schisandra chinensis, and ginseng as active ingredients.
본 발명에 있어서, 용어 「마황(Ephedra sinica)」이란, 마황과의 초마황(Ephedra sinica Stepf) 또는 동속식물의 부드러운 줄기(초질경)를 사용해 만든 약재로, 혀를 약하게 마비시키는 성질이 있으며 맛은 떫고 맵고 쓰며, 성질은 따뜻하다. 풍한을 소산시키고, 발한해표, 오한발열, 두통, 천식, 해수, 수종, 신체상부 마비, 피부마비, 충혈, 어혈에 쓰이고 있다.In the present invention, the term "Ephedra sinica" refers to a medicine made using Ephedra sinica Stepf of the Ephedra family or the soft stem (Ephedra sinica) of the same plant, which has the property of slightly paralyzing the tongue and has a pleasant taste. is astringent, spicy and bitter, and warm in nature. It is used to dissipate wind chills, sweating, fever, headache, asthma, seawater, dropsy, paralysis of the upper body, skin paralysis, congestion, and blood stagnation.
본 발명에 있어서, 용어 「길경」이란, 초롱꽃과의 도라지(Platycodon grandiflorum A. De Candolle)의 뿌리 또는 주피를 제거하여 만든 약재로, 냄새가 약간 있고 맛은 쓰고 성질은 어느 한쪽으로 치우치지 않고 평하다. 인후통, 감기로 인한 기침, 가래, 코막힘, 천식, 기관지염증, 흉막염, 두통, 오한, 편도선염 등에 사용되고 있으며, 약리작용으로는 거담 작용, 혈당강하 작용, 콜레스테롤 강하 작용, 개선균 억제 작용이 보고되어 있다.In the present invention, the term "Gilgyeong" refers to a medicinal herb prepared by removing the roots or pericarp of Bellflower (Platycodon grandiflorum A. De Candolle) of the Campanula family. It has a slight odor, a bitter taste, and is flat in nature without being biased to either side. do. It is used for sore throat, cough due to cold, phlegm, nasal congestion, asthma, bronchial inflammation, pleurisy, headache, chills, tonsillitis, etc. It has been reported that its pharmacological effects include expectorant action, blood sugar lowering effect, cholesterol lowering effect, and suppressive effect on improving bacteria. there is.
본 발명에 있어서, 용어 「오미자(Schisandra Fruit)」란, 오미자과(Schizandraceae)에 속하는 낙엽성 목본인 덩굴식물이며 붉은 색의 과실을 생약제 및 식품원료로 이용하는 주요 약용식물이다. 오미자나무과에는 2속 3종이 국내에 분포하고 있는데, 오미자의 효능으로는 혈압강하작용 및 알콜 해독작용이 있는 것으로 알려져 있고 암 예방 활성, 노화 억제 활성, 면역 조절 작용 및 항균활성 등 다양한 생리적 기능이 보고되고 있다. 오미자의 과실에 함유된 성분은 쉬잔드린(schizandrin), 고미신 A(gomisin A), 고미신 N(gomisin N) 등 주로 리그난 화합물이 있으며 그 외에 정유, 색소 등 다양한 성분이 함유되어 있다. 특히 쉬잔드린(schizandrin)은 혈당저하작용, 항궤양작용, 만성간염치료효과, 중추신경흥분작용 및 간 보호 등의 효능이 있는 것으로 알려져 있다.In the present invention, the term "Schisandra Fruit" is a deciduous woody vine belonging to the Schizandraceae family and is a major medicinal plant whose red fruits are used as herbal medicine and food raw materials. There are 2 genera and 3 species of Schisandra family distributed in Korea. Schisandra chinensis is known to have a blood pressure lowering effect and alcohol detoxification effect, and has various physiological functions such as cancer prevention activity, anti-aging activity, immunomodulatory activity, and antibacterial activity. It is becoming. The ingredients contained in the fruit of Schisandra chinensis are mainly lignan compounds such as schizandrin, gomisin A, and gomisin N, and also contain various ingredients such as essential oils and pigments. In particular, schizandrin is known to have effects such as blood sugar lowering effect, anti-ulcer effect, chronic hepatitis treatment effect, central nervous stimulating effect, and liver protection.
본 발명에 있어서, 용어 「인삼(Ginseng Radix)」이란, 식품분류학상 오가피과(Panax)의 인삼속에 속하는 다년생 숙근초로서 지금까지 콜레스테롤 저하, 혈압강하, 혈류증가, 항산화 작용, 항노화 작용, 항암제 등의 활성을 가지고 있는 것으로 알려져 있다.In the present invention, the term "ginseng (Ginseng Radix)" refers to a perennial root herb belonging to the genus Panax in food taxonomy, and has been used to lower cholesterol, lower blood pressure, increase blood flow, antioxidant effect, anti-aging effect, anti-cancer agent, etc. It is known to be active.
본 발명에 있어서, 용어 「생약(crude drug)」이란, 용매, 초임계 또는 초음파 추출 처리되지 않은 마황, 길경, 오미자 및 인삼의 일부 또는 전부를 의미한다.In the present invention, the term “crude drug” refers to some or all of ephedra, agilite, Schisandra chinensis, and ginseng that have not been subjected to solvent, supercritical, or ultrasonic extraction.
본 발명에 있어서, 용어 「추출물」이란, 당업계에서 조추출물(crude extract)로 통용되는 의미를 갖지만, 광의적으로는 상기 조추출물을 추가적으로 분획(fractionation)한 분획물도 포함하는 의미이다. 즉, 본 발명의 추출물은 상술한 추출 용매를 이용하여 얻은 것뿐만 아니라, 여기에 정제과정을 추가적으로 적용하여 얻은 분획물도 포함한다. 예컨대, 상기 추출물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리, 상기 설명된 추출 용매에 의한 2차 또는 3차의 추가적인 추출 분획 등, 추가적으로 실시된 다양한 정제 방법을 통해 얻어진 분획도 본 발명의 추출물에 포함되는 것이다.In the present invention, the term “extract” has a meaning commonly used in the art as a crude extract, but in a broad sense also includes fractions obtained by additional fractionation of the crude extract. That is, the extract of the present invention includes not only those obtained using the above-described extraction solvent, but also fractions obtained by additionally applying a purification process. For example, fractions obtained by passing the extract through an ultrafiltration membrane with a certain molecular weight cut-off value, separation by various chromatographs (designed for separation according to size, charge, hydrophobicity or affinity), extraction solvents as described above. Fractions obtained through various additional purification methods, such as secondary or tertiary additional extraction fractions, are also included in the extract of the present invention.
본 발명에 있어서, 약학적 조성물은 마황, 길경, 오미자 및 인삼의 혼합 추출물을 포함하는 것인데, 이때 혼합 추출물은 각각의 마황, 길경, 오미자 및 인삼을 용매 추출, 열수 추출, 초임계 추출 또는 초음파 추출에 의해 추출하여 얻어진 마황 추출물, 길경 추출물, 오미자 추출물 및 인삼 추출물의 혼합물과, 마황, 길경, 오미자 및 인삼의 혼합물을 상기 방법에 의해 추출하여 얻어진 추출물을 모두 의미한다.In the present invention, the pharmaceutical composition contains a mixed extract of ephedra, gilgyeong, Schisandra chinensis, and ginseng. In this case, the mixed extract includes each of ephedra, gilgyeong, Schisandra chinensis, and ginseng through solvent extraction, hot water extraction, supercritical extraction, or ultrasonic extraction. It refers to both the mixture of ephedra extract, Gilgyeong extract, Schisandra chinensis extract and ginseng extract obtained by extraction, and the extract obtained by extracting the mixture of ephedra, Gilgyeong, Schisandra chinensis and ginseng by the above method.
본 발명에 있어서, 용어 「용매 추출법」이란, 특정 물질인 마황, 길경, 오미자 및 인삼에 포함된 추출 대상 물질을 액체 용매에 용해시킨 후, 추출 대상 물질이 용해된 용매를 분리하여 정제하는 방법을 의미한다.In the present invention, the term "solvent extraction method" refers to a method of dissolving substances to be extracted contained in specific substances such as ephedra, gilgyeong, Schisandra chinensis and ginseng in a liquid solvent, and then separating and purifying the solvent in which the substances to be extracted are dissolved. it means.
본 발명에서 용어 「열수 추출법」이란, 뜨거운 물(80 내지 100℃)을 이용하여 특정 물질인 마황, 길경, 오미자 및 인삼에 포함된 추출 대상 물질을 용출시켜 추출하는 것을 의미한다.In the present invention, the term “hot water extraction method” refers to extraction by eluting the extraction target substances contained in specific substances such as ephedra, gilgyeong, Schisandra chinensis, and ginseng using hot water (80 to 100°C).
본 발명에 있어서, 용어 「초임계 추출법」이란, 마황, 길경, 오미자 및 인삼을 추출조에 주입시키고 초임계 상태의 조건에서 초임계 유체 단독, 또는 초임계 유체와 보조용매를 추출조에 통과시켜 마황, 길경, 오미자 및 인삼 내에 존재하는 특정물질을 추출하는 것을 의미한다. 상기 추출조에 유입되는 초임계 유체에 의해 상기 마황, 길경, 오미자 및 인삼으로부터 추출된 물질은 분리조에 포집된다. 추출 수율은 추출변수인 온도, 압력, 유량, 원료 입자의 크기, 추출시간, 수분함량에 의존한다. 추출이 끝난 후 분리조에 포집된 추출물질은 회수된다.In the present invention, the term "supercritical extraction method" refers to injecting ephedra, Gilgyeong, Schisandra chinensis, and ginseng into an extraction tank and passing the supercritical fluid alone or the supercritical fluid and auxiliary solvent through the extraction tank under supercritical conditions to extract ephedra, This means extracting specific substances present in Gilgyeong, Schisandra chinensis, and ginseng. The substances extracted from the ephedra, gilgyeong, Schisandra chinensis and ginseng by the supercritical fluid flowing into the extraction tank are collected in the separation tank. Extraction yield depends on extraction variables such as temperature, pressure, flow rate, raw material particle size, extraction time, and moisture content. After extraction is completed, the extracts collected in the separation tank are recovered.
본 발명에 있어서, 용어 「초음파 추출법」이란, 용매를 이용하는 추출에 있어 20 kHz 이상의 높은 주파수의 초음파를 가하는 공법을 의미한다. 이 경우, 적정 수준의 초음파가 용매를 통과함에 따라 발생하는 공동화현상(Cavitation)으로 인하여 높은 에너지를 발생시켜 세포 벽 및 세포 내부 구조를 파열시킴으로써, 용매가 세포로 침투하게 되어 추출 효율이 증가된다.In the present invention, the term “ultrasonic extraction method” refers to a method of applying ultrasonic waves of a high frequency of 20 kHz or more in extraction using a solvent. In this case, cavitation, which occurs as an appropriate level of ultrasound passes through the solvent, generates high energy and ruptures the cell wall and internal cell structure, allowing the solvent to penetrate into the cells and increasing extraction efficiency.
본 발명에 있어서, 용어 「유효성분」이란, 내재된 약리작용에 의해 그 조성물의 효능 효과를 직접 또는 간접적으로 발현한다고 기대되는 물질 또는 물질군(약리학적 활성성분 등이 밝혀지지 않은 생약 등을 포함한다)으로서 주성분을 포함하는 것을 의미한다.In the present invention, the term “active ingredient” refers to a substance or group of substances expected to directly or indirectly express the efficacy and effect of the composition through inherent pharmacological action (including herbal medicines, etc. whose pharmacologically active ingredients, etc. are unknown). means that it contains the main ingredient.
본 발명에 있어서, 용어 「예방」이란, 상기 약학적 조성물의 투여에 의해 호흡기 염증 질환 등을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, the term “prevention” refers to all actions that suppress or delay respiratory inflammatory diseases, etc. by administering the pharmaceutical composition.
본 발명에 있어서, 용어 「치료」란, 상기 약학적 조성물의 투여에 의해 호흡기 염증 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, the term “treatment” refers to any action in which the symptoms of an individual suspected or affected by a respiratory inflammatory disease are improved or beneficially changed by administration of the pharmaceutical composition.
본 발명에 있어서, 마황, 길경, 오미자 및 인삼의 혼합 추출물을 유효성분으로 포함하는 호흡기 염증 질환의 예방 또는 치료용 약학적 조성물은 진해 및 거담 작용을 갖는 것일 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the pharmaceutical composition for preventing or treating respiratory inflammatory diseases containing mixed extracts of ephedra, gilgyeong, Schisandra chinensis, and ginseng as active ingredients may have antitussive and expectorant effects, but is not limited thereto.
본 발명에 있어서, 용어 「진해」란, 기침을 그치게 하는 것을 의미하고, 용어 「거담」이란, 객담을 배출하는 것을 의미하며, 기도 내 점액질의 저류를 완화, 개선 또는 치료하는 것을 포함한다.In the present invention, the term “antitussive” means to stop coughing, and the term “exposure” means to expel sputum, and includes alleviating, improving, or treating mucus retention in the respiratory tract.
본 발명에 있어서, 마황 추출물과 길경 추출물은 생약 1일 복용량 기준 각각 1.50 내지 2.40 g의 마황과 길경을 포함할 수 있으며, 바람직하게는 생약 1일 복용량 기준 1.95 내지 2.10 g의 마황과 길경을 포함할 수 있고, 이에 한정되는 것은 아니다.In the present invention, the ephedra extract and gilgyeong extract may each contain 1.50 to 2.40 g of ephedra and gilgyeong based on a daily dose of herbal medicine, and preferably include 1.95 to 2.10 g of ephedra and gilgyeong based on a daily dose of herbal medicine. It can be done, but it is not limited to this.
본 발명에 있어서, 오미자 추출물은 생약 1일 복용량 기준 0.51 내지 2.50 g의 오미자를 포함할 수 있으며, 바람직하게는 생약 1일 복용량 기준 1.50 내지 2.50 g의 오미자를 포함할 수 있고, 이에 한정되는 것은 아니다.In the present invention, the Schisandra chinensis extract may include 0.51 to 2.50 g of Schisandra chinensis based on a daily dose of herbal medicine, and preferably may include 1.50 to 2.50 g of Schisandra chinensis based on a daily dose of herbal medicine, but is not limited thereto. .
본 발명에 있어서, 인삼 추출물은 생약 1일 복용량 기준 0.60 내지 3.00 g의 인삼을 포함할 수 있으며, 바람직하게는 생약 1일 복용량 기준 1.50 내지 3.00 g의 인삼을 포함할 수 있고, 이에 한정되는 것은 아니다.In the present invention, the ginseng extract may include 0.60 to 3.00 g of ginseng based on a daily dose of herbal medicine, and preferably may include 1.50 to 3.00 g of ginseng based on a daily dose of herbal medicine, but is not limited thereto. .
본 발명에 있어서, 추출물 형태는 유동엑스(용액), 연조엑스(농축물) 또는 건조분말 상태일 수 있으며, 구체적으로 마황, 길경 및 오미자 추출물은 연조엑스 형태이고, 인삼 추출물은 유동엑스 형태일 수 있고, 이에 한정되는 것은 아니다.In the present invention, the extract form may be in the form of liquid extract (solution), soft extract (concentrate), or dry powder. Specifically, ephedra, Gilgyeong, and Schisandra chinensis extracts may be in the form of soft extract, and the ginseng extract may be in the form of liquid extract. There is, and it is not limited to this.
본 발명에 있어서, 유동엑스(용액)란, 생약의 침출액으로서 보통 1 mL 중에 생약 1 g 중의 가용성 성분을 함유하도록 만든 액상의 제제를 의미하고, 연조엑스(농축물)이란, 생약의 추출물을 농축하여 물엿과 같은 점조도로 만든 제형을 의미한다.In the present invention, fluid extract (solution) refers to a liquid preparation made to contain the soluble components of 1 g of herbal medicine in 1 mL as a leachate of a herbal medicine, and soft extract (concentrate) refers to a concentrated extract of a herbal medicine. This refers to a formulation made with the same consistency as starch syrup.
본 발명에 있어서, 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물의 항염증 및 진해·거담 작용의 상승효과를 최대화하기 위하여, 생약 중량 기준으로 마황, 길경, 오미자 및 인삼이 1 : 0.5~1.5 : 0.15~2.0 : 0.1~2.0의 중량비로 포함될 때, 바람직하게는 마황, 길경, 오미자 및 인삼이 1 : 1 : 0.5~1.5 : 0.2~1.8의 중량비로 포함될 때, 더 바람직하게는 마황, 길경, 오미자 및 인삼이 1 : 1 : 0.75~1.25 : 0.9~1.5의 중량비로 포함될 때 현저히 우수한 효과를 나타내는 것을 확인할 수 있으며, 덱사메타손과 비교 시 동등 또는 이상의 우수한 효과를 나타낼 수 있다.In the present invention, in order to maximize the synergistic effect of the anti-inflammatory and antitussive and expectorant effects of the mixed extract of the active ingredients ephedra, gilgyeong, Schisandra chinensis and ginseng, the amount of ephedra, gilgyeong, Schisandra chinensis and ginseng is 1:0.5~1, based on the weight of the herbal medicine. When included in a weight ratio of 1.5:0.15~2.0:0.1~2.0, preferably ephedra, Gilgyeong, Schisandra chinensis, and ginseng in a weight ratio of 1:1:0.5~1.5:0.2~1.8, more preferably ephedra, Gilgyeong , it can be confirmed that it shows a significantly superior effect when Schisandra chinensis and ginseng are included in a weight ratio of 1:1:0.75~1.25:0.9~1.5, and when compared to dexamethasone, it can show an equally or better effect.
구체적으로, 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물은 종래 호흡기 염증 질환의 치료에 효과가 있으며, 특히 진해·거담 작용을 갖는다고 알려진 마황과 길경의 혼합 추출물, 그리고 마황과 길경에 인삼과 오미자를 각각 조합한 혼합 추출물 대비 항염증 인자인 산화질소(nitric oxide; NO), 인터루킨-1β(Interleukin-1β; IL-1β), 인터루킨-6(Interleukin-6; IL-6) 및 종양괴사인자-α(tumor necrosis factor-α; TNF-α)과, 전 염증성 물질인 류코트리엔 B4(leukotriene B4; LTB4)의 억제 효과가 우수하며, 점액 생성 유전자인 뮤신 5AC(Mucin 5AC; MUC5AC)의 억제 효과가 우수한 효과를 제공할 수 있다.Specifically, the mixed extract of the active ingredients ephedra, gilgyeong, Schisandra chinensis, and ginseng is effective in the treatment of conventional respiratory inflammatory diseases, and in particular, the mixed extract of ephedra and gilgyeong, which are known to have antitussive and expectorant effects, and ginseng mixed with ephedra and gilgyeong. Compared to the mixed extract of Schisandra chinensis and Schisandra chinensis, the anti-inflammatory factors nitric oxide (NO), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and tumor necrosis Excellent inhibitory effect on tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), a pro-inflammatory substance, and mucin 5AC (MUC5AC), a mucus producing gene. can provide excellent effects.
본 발명에 있어서, 마황, 길경, 오미자 및 인삼은 물, 탄소수 1 내지 4개로 이루어진 저급 알코올 또는 이의 수용액으로 추출될 수 있으며, 이에 제한되지 않는다.In the present invention, ephedra, gilgyeong, Schisandra chinensis, and ginseng can be extracted with water, a lower alcohol having 1 to 4 carbon atoms, or an aqueous solution thereof, but is not limited thereto.
본 발명에 있어서, 마황, 길경, 오미자 및 인삼의 혼합 추출물은 마황, 길경, 오미자 및 인삼을 물, 탄소수 1 내지 4개로 이루어진 저급 알코올, 또는 이의 수용액으로 추출하여 얻어진 조추출물(1차 추출물) 또는 이의 농축물일 수 있다. 상기 탄소수 1 내지 4개의 저급 알코올은 메탄올, 에탄올, 프로판올, 이소프로판올 및 sec-부탄올 중에서 선택될 수 있다.In the present invention, the mixed extract of ephedra, gilgyeong, Schisandra chinensis, and ginseng is a crude extract (primary extract) obtained by extracting ephedra, gilgyeong, Schisandra chinensis, and ginseng with water, a lower alcohol having 1 to 4 carbon atoms, or an aqueous solution thereof. It may be a concentrate thereof. The lower alcohol having 1 to 4 carbon atoms may be selected from methanol, ethanol, propanol, isopropanol, and sec-butanol.
특히, 본 발명에서 생약인 마황, 길경, 오미자 및 인삼은 물 또는 에탄올 수용액으로 추출될 수 있으며, 에탄올 수용액일 경우 바람직하게 10 내지 90% 에탄올 수용액으로 추출될 수 있다.In particular, in the present invention, the herbal medicines ephedra, gilgyeong, Schisandra chinensis, and ginseng can be extracted with water or an aqueous ethanol solution, and in the case of an aqueous ethanol solution, they can preferably be extracted with a 10 to 90% ethanol aqueous solution.
본 발명에 있어서, 추출 온도는 40 내지 120℃, 바람직하게는 60 내지 90℃이며, 추출시간은 2 내지 48시간, 바람직하게는 4 내지 24시간이다.In the present invention, the extraction temperature is 40 to 120°C, preferably 60 to 90°C, and the extraction time is 2 to 48 hours, preferably 4 to 24 hours.
본 발명에 따른 약학적 조성물은 실제 임상투여 시에 경구로 투여될 수 있다. 본 발명의 조성물은 각각 통상의 방법에 따라 정제(츄어블정, 발포정 포함), 캡슐제(연질캡슐제 포함), 산제, 과립제, 환제, 트로키제 및 내용액제(엘릭서제 및 주정제는 제외, 시럽 또는 현탁제 포함)로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention can be administered orally during actual clinical administration. The composition of the present invention can be prepared into tablets (including chewable tablets and effervescent tablets), capsules (including soft capsules), powders, granules, pills, troches, and oral solutions (excluding elixirs and spirits) according to conventional methods. It can be formulated and used as a syrup or suspension).
본 발명에 있어서, 상기 약학적 조성물이 의약품, 건강기능(성)식품, 식품, 음료 및 식품 첨가물 등에 사용될 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the pharmaceutical composition can be used in medicines, health functional foods, foods, beverages, food additives, etc., but is not limited thereto.
본 발명에 있어서, 용어 「의약품」이란, 호흡기 염증 질환, 진해·거담 의 진단과 치료, 경감, 예방을 목적으로 사용되거나 인체의 구조와 기능에 약리적인 영향을 주는 것을 의미하며, 상술한 바와 같이 통상의 방법에 따라 정제, 캡슐제, 산제, 과립제, 환제, 트로키제 및 내용액제 등으로 제형화 된 것을 의미한다.In the present invention, the term “drug” refers to a product used for the purpose of diagnosis, treatment, alleviation, and prevention of respiratory inflammatory diseases, coughing and expectoration, or having a pharmacological effect on the structure and function of the human body, as described above. It means that it is formulated into tablets, capsules, powders, granules, pills, troches, and oral solutions according to conventional methods.
본 발명에 있어서, 용어 「건강기능(성)식품」이란, 건강기능(성)식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, 「기능성」이라 함은, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 건강기능(성)식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 의약품과는 달리 현재 섭식되는 생약을 원료로 하여 의약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능(성)식품은 호흡기 염증 질환의 개선 효과를 증진시키거나 진해·거담제를 위한 보조제로 섭취가 가능하다.In the present invention, the term "health functional food" refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Act on Health Functional Food, and "functional" 」means ingestion for the purpose of controlling nutrients for the structure and function of the human body or obtaining useful effects for health purposes such as physiological effects. Health functional (sex) foods can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. In addition, unlike general medicines, the health functional (sexual) food of the present invention has the advantage of being made from currently consumed herbal medicines as raw materials, so there are no side effects that may occur when taking medicines for a long period of time, and is highly portable, so the health functional (sexual) food of the present invention can improve respiratory inflammatory diseases. It can be taken as an adjuvant to enhance the effect or as an antitussive or expectorant.
본 발명에 있어서, 식품의 종류에는 특별한 제한은 없다. 상기 약학적 조성물이 식품으로 사용될 경우 정제, 경질 또는 연질 캅셀제, 액제, 현탁제 등과 같은 경구투여용 제제의 형태로 이용될 수 있으며, 이들 제제는 허용 가능한 통상의 식품 첨가물을 더 포함할 수 있다. 상기 용어 「식품 첨가물」이란, 각 제형의 건강기능(성)식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품 첨가물의 예로는 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 등이 포함되지만, 상기 예들에 의해 본 발명의 식품 첨가물의 종류가 제한되는 것은 아니다.In the present invention, there is no particular limitation on the type of food. When the pharmaceutical composition is used as a food, it can be used in the form of preparations for oral administration such as tablets, hard or soft capsules, solutions, suspensions, etc., and these preparations may further contain acceptable common food additives. The term “food additive” refers to something added in manufacturing health functional (sex) food of each dosage form, and can be appropriately selected and used by a person skilled in the art. Examples of food additives include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. are included, but the types of food additives of the present invention are not limited to the above examples.
상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 조성물과 함께 사용될 수 있으며, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 그의 사용 목적(예방, 개선 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.The composition can be added as is or used together with other foods or food compositions, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, improvement or therapeutic treatment).
본 발명에 있어서, 음료는 식품의 일 예로서, 음료 100을 기준으로 0.01 내지 5.0 g, 바람직하게는 0.01 내지 1.0 g의 비율로 첨가할 수 있다. 그러나 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다. 본 발명의 약학적 조성물이 음료로 사용 시 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어, 말토스, 수크로즈 등 및 폴리사카라이드, 예를 들어, 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리스리톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마킨, 스테비아 추출물 등), 및 합성 향미제(사카린, 아스파르탄 등)를 유리하게 사용할 수 있다. 또한, 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 당 일반적으로 약 0.1 내지 2.0 g, 바람직하게는 약 0.1 내지 1.0 g이다. In the present invention, a beverage is an example of a food and can be added at a rate of 0.01 to 5.0 g, preferably 0.01 to 1.0 g, based on 100 beverages. However, in the case of long-term intake for the purpose of health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range. When the pharmaceutical composition of the present invention is used as a beverage, other than containing the above compounds as essential ingredients in the indicated ratio, there are no particular restrictions on other ingredients, and various flavoring agents or natural carbohydrates can be contained as additional ingredients like ordinary beverages. there is. Examples of such natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Common sugars such as disaccharides, such as maltose, sucrose, etc., and polysaccharides, such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (thaumaquine, stevia extract, etc.) and synthetic flavoring agents (saccharin, aspartane, etc.) can be advantageously used. Additionally, the proportion of the natural carbohydrate is generally about 0.1 to 2.0 g, preferably about 0.1 to 1.0 g, per 100 of the composition of the present invention.
본 발명에 있어서, 호흡기 염증 질환은 비인두염, 후두염, 만급성 기관지염, 염증성 폐 질환, 폐기종, 천식, 만성 폐쇄성 폐질환, 중이염, 부비강염, 편도선염 및 알레르기성 비염으로 이루어진 군으로부터 선택되는 것일 수 있으며, 이에 한정되는 것은 아니다. In the present invention, the respiratory inflammatory disease may be selected from the group consisting of nasopharyngitis, laryngitis, acute bronchitis, inflammatory lung disease, emphysema, asthma, chronic obstructive pulmonary disease, otitis media, sinusitis, tonsillitis and allergic rhinitis, It is not limited to this.
본 발명에 있어서, 약학적 조성물은 산화질소(nitric oxide; NO), 인터루킨-1β(Interleukin-1β; IL-1β), 인터루킨-6(Interleukin-6; IL-6), 종양괴사인자-α(tumor necrosis factor-α; TNF-α) 또는 류코트리엔 B4(leukotriene B4; LTB4)의 생성을 억제하여 호흡기 염증 질환을 치료하는 것일 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the pharmaceutical composition contains nitric oxide (NO), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α ( It may be used to treat respiratory inflammatory diseases by inhibiting the production of tumor necrosis factor-α (TNF-α) or leukotriene B4 (LTB4), but is not limited thereto.
본 발명에 있어서, 약학적 조성물은 점액 관련 유전자인 뮤신 5AC(Mucin 5AC; MUC5AC)의 발현을 억제하여 진해·거담 작용을 하는 것일 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the pharmaceutical composition may have an antitussive or expectorant effect by suppressing the expression of Mucin 5AC (MUC5AC), a mucus-related gene, but is not limited thereto.
본 발명에 있어서, 약학적 조성물은 1일 3회 투여하는 것일 수 있으며, 구체적으로 1일 3회 경구투여 할 수 있고, 이에 한정되는 것은 아니다. 본 발명에 있어서 약학적 조성물을 1일 3회 경구투여 시, 생약 1일 기준 용량에 부합하도록 마황, 길경, 오미자 및 인삼의 혼합 추출물을 유효성분으로 사용함으로써 항염증 인자, 전 염증성 물질, 그리고 점액 생성 유전자를 억제하여 호흡기 염증 질환의 치료용, 및/또는 진해·거담제로 사용할 수 있다.In the present invention, the pharmaceutical composition may be administered three times a day, and specifically may be administered orally three times a day, but is not limited thereto. In the present invention, when the pharmaceutical composition is administered orally three times a day, mixed extracts of ephedra, Gilgeria, Schisandra chinensis, and ginseng are used as active ingredients to meet the standard daily dose of herbal medicine, thereby reducing anti-inflammatory factors, pro-inflammatory substances, and mucus. It can be used for the treatment of respiratory inflammatory diseases and/or as an antitussive and expectorant by suppressing the gene that produces it.
이하, 실시예 및 비교예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예 및 비교예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술 분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다.Hereinafter, the present invention will be described in more detail using examples and comparative examples. These Examples and Comparative Examples are only for illustrating the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.
실시예 및 비교예: 약학적 조성물의 제조Examples and Comparative Examples: Preparation of Pharmaceutical Compositions
길경 연조엑스 (구입처: 한풍제약), 오미자 연조엑스 (구입처: 한풍제약), 인삼 유동엑스 (구입처: 보락) 및 마황 연조엑스 (구입처: 한풍제약)를 하기 표 1 및 2와 같이 생약 1일 기준 용량 (1일 3회 투여 기준)이 포함되도록 혼합하여 혼합 추출물을 유효성분으로 포함하는 약학적 조성물을 제조하였다.Gilgyeong Yeonjo Ex (Purchase: Hanpoong Pharmaceutical), Schisandra chinensis Ex (Purchase: Hanpoong Pharmaceutical), Ginseng Dongdong Ex (Purchase: Borak), and Ephedra Yeonjo Ex (Purchase: Hanpoong Pharmaceutical) are used as herbal medicines per day as shown in Tables 1 and 2 below. A pharmaceutical composition containing the mixed extract as an active ingredient was prepared by mixing the mixture to contain the dosage (based on administration three times a day).
이 때, 유효성분인 마황, 길경, 오미자 및 인삼의 혼합 추출물에서, 생약 1일 기준 마황 2.00 g을 포함하는 마황 연조엑스의 양은 0.82 mL 이고, 생약 1일 기준 길경 2.00 g을 포함하는 길경 연조엑스의 양은 0.79 mL 이며, 생약 1일 기준 오미자 0.51 g, 1.50 g 및 2.50 g을 포함하는 오미자 연조엑스의 양은 각각 0.32 mL, 0.94 mL 및 1.56 mL 이고, 생약 1일 기준 인삼 0.60 g, 1.80 g 및 3.00 g을 포함하는 인삼 유동엑스의 양은 각각 0.60 mL, 1.80 mL 및 3.00 mL 이다.At this time, in the mixed extract of the active ingredients ephedra, gilgyeong, Schisandra chinensis, and ginseng, the amount of ephedra extract containing 2.00 g of ephedra per day is 0.82 mL, and the amount of ephedra extract containing 2.00 g of ephedra per day is 0.82 mL. The amount is 0.79 mL, and the amounts of Schisandra chinensis extract containing 0.51 g, 1.50 g, and 2.50 g of Schisandra chinensis per day are 0.32 mL, 0.94 mL, and 1.56 mL, respectively, and the amounts of ginseng per day are 0.60 g, 1.80 g, and 3.00 g, respectively. The amounts of ginseng liquid extract containing g are 0.60 mL, 1.80 mL, and 3.00 mL, respectively.
양성대조물질
(덱사메타손)Comparative Example 1
positive control material
(dexamethasone)
실험예Experiment example
실험예 1: 항염증 활성 평가Experimental Example 1: Evaluation of anti-inflammatory activity (in-vitro (in-vitro 효력 평가) efficacy evaluation)
평가 방법Assessment Methods
상기 실시예에 따른 약학적 조성물의 항염증 활성 평가를 평가하기 위해 마우스 유래 대식세포주인 RAW264.7 세포를 대상으로 하는 실험을 수행하였다. 먼저, 10% 우태아혈청(FBS), 1% 페니실린/스트렙토마이신이 첨가된 DMEM(Dulbecco's Modified Eagle Medium) 배지를 사용하여 2일 간격으로 계대 배양하였다(37℃, 5% CO2 incubator, 90% 이상 습도).To evaluate the anti-inflammatory activity of the pharmaceutical composition according to the above example, an experiment was performed on RAW264.7 cells, a mouse-derived macrophage cell line. First, subculture was performed at 2-day intervals using DMEM (Dulbecco's Modified Eagle Medium) medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (37°C, 5% CO 2 incubator, 90% abnormal humidity).
대식세포가 안정화된 후에, (1) 무처리군(Vehicle) 및 (2) 비교예 1에 따른 양성대조물질(덱사메타손, Dexamethasone; Dex)을 20 ug/mL (50 μM), 비교예 2 내지 8, 실시예 1 내지 9에 따른 약학적 조성물을 1 mg/mL를 처리하고, 염증유발물질인 리포폴리사카라이드 (Lipopolysaccharide; LPS) 100 ng/mL를 넣은 후 약 20~24시간 동안 배양하였다. 배양을 종료한 후 100 μl의 배양액을 취하여 동일 부피의 그리에스(Griess) 시약과 혼합한 후 540 nm의 흡광도로 측정하였다. 동일 배지에 녹인 여러 농도의 아질산나트륨(sodium nitrite) 표준 곡선을 이용하여 시료의 아질산염(nitrite) 양을 정량하여, 세포 배양 상등액에서 평가인자인 NO(nitric oxide) 농도를 확인하였고, 상기와 같이 분리한 배양액에서 ELISA kit(BD Biosciences, U.S.A.)를 이용하여 제조사의 절차에 따라 항염증 인자인 TNF-α 생성량의 분석을 통해 항염증 인자(TNF-α) 억제 경향성을 확인하였다. 나아가, 오미자와 인삼의 유무에 따라 비교예 2, 5, 8 및 실시예 9를 선정하여 상기와 같이 분리한 배양액에서 ELISA kit(BD Biosciences, U.S.A.)를 이용하여 제조사의 절차에 따라 항염증 인자인 IL-1β 및 IL-6, 그리고 전 염증성 물질인 류코트리엔 B4(leukotriene B4; LTB4)의 생성량의 분석을 통하여 억제 경향성 확인하였다.After the macrophages were stabilized, (1) untreated group (Vehicle) and (2) positive control material (Dexamethasone; Dex) according to Comparative Example 1 at 20 ug/mL (50 μM), Comparative Examples 2 to 8 , 1 mg/mL of the pharmaceutical composition according to Examples 1 to 9 was treated, 100 ng/mL of lipopolysaccharide (LPS), an inflammatory substance, was added, and cultured for about 20 to 24 hours. After completing the culture, 100 μl of the culture medium was mixed with an equal volume of Griess reagent and the absorbance was measured at 540 nm. The amount of nitrite in the sample was quantified using a standard curve of various concentrations of sodium nitrite dissolved in the same medium, and the concentration of NO (nitric oxide), an evaluation factor, was confirmed in the cell culture supernatant, and separated as above. The tendency to suppress anti-inflammatory factor (TNF-α) was confirmed by analyzing the amount of anti-inflammatory factor (TNF-α) produced in one culture using an ELISA kit (BD Biosciences, U.S.A.) according to the manufacturer's procedure. Furthermore, Comparative Examples 2, 5, 8, and Example 9 were selected depending on the presence or absence of Schisandra chinensis and ginseng, and the anti-inflammatory factor was extracted from the culture medium isolated as above using an ELISA kit (BD Biosciences, U.S.A.) according to the manufacturer's procedure. The inhibition tendency was confirmed through analysis of the production amount of IL-1β, IL-6, and leukotriene B4 (LTB4), a pro-inflammatory substance.
- 음성대조군: LPS만을 처리- Negative control group: treated only with LPS
- 비교예 1: 양성대조물질(덱사메타손, Dexamethasone; Dex, 제조사: Sigma-Aldrich, 제품 번호: D2915)을 처리- Comparative Example 1: Treatment of positive control material (Dexamethasone; Dex, manufacturer: Sigma-Aldrich, product number: D2915)
- 실험군: 실시예 1 내지 9, 비교예 2 내지 8에 따른 혼합 추출물을 유효성분으로 포함하는 약학적 조성물을 처리-Experimental group: treated with a pharmaceutical composition containing the mixed extract according to Examples 1 to 9 and Comparative Examples 2 to 8 as an active ingredient
평가 결과Evaluation results
도 1 및 표 3, 4를 참조하면, 실시예 9에 따른 약학적 조성물에서 NO (nitric oxide) 억제효과가 가장 우수함을 확인하였고, 비교예 1인 덱사메타손과 동등 또는 이상의 NO (nitric oxide) 억제효과가 있음을 확인하였다.Referring to Figure 1 and Tables 3 and 4, it was confirmed that the pharmaceutical composition according to Example 9 had the best NO (nitric oxide) inhibitory effect, and the NO (nitric oxide) inhibitory effect was equal to or greater than that of dexamethasone in Comparative Example 1. It was confirmed that there is.
표 5 및 6을 참조하면, 실시예 1, 4, 9에 따른 약학적 조성물에서 항염증 인자인 TNF-α의 억제효과가 비교예 2 내지 8의 약학적 조성물 보다 우수함을 확인하였다. 특히, 실시예 9에 따른 약학적 조성물의 경우, 비교예 1인 덱사메타손과 비교하더라도 동등한 수준의 억제 효과가 있음을 확인하였다.Referring to Tables 5 and 6, it was confirmed that the pharmaceutical compositions according to Examples 1, 4, and 9 had better inhibitory effects on TNF-α, an anti-inflammatory factor, than the pharmaceutical compositions of Comparative Examples 2 to 8. In particular, in the case of the pharmaceutical composition according to Example 9, it was confirmed that the inhibitory effect was at the same level as that of dexamethasone in Comparative Example 1.
표 7을 참조하면, 실시예 9에 따른 약학적 조성물은 오미자 및/또는 인삼을 포함하지 않는 비교예 2, 5 및 8의 약학적 조성물 대비 전체적인 항염증 인자(IL-1β 및 IL-6) 및 전 염증성 물질인 류코트리엔 B4(LTB4)의 억제효과가 우수함을 확인하였고, 특히 비교예 1인 덱사메타손과 비교하더라도 동등 또는 이상의 억제 효과가 있음을 확인하였다.Referring to Table 7, the pharmaceutical composition according to Example 9 has overall anti-inflammatory factors (IL-1β and IL-6) and It was confirmed that the inhibitory effect of leukotriene B4 (LTB4), a pro-inflammatory substance, was excellent, and in particular, it was confirmed that the inhibitory effect was equal to or greater than that of dexamethasone, Comparative Example 1.
(LTB4)leukotriene B4
(LTB4)
실험예 2: 점액 생성 유전자 발현 평가Experimental Example 2: Evaluation of mucus production gene expression
평가 방법Assessment Methods
점액유전자인 MUC5AC(Mucin 5AC)는 염증성 점액단백질로, LPS와 같은 물질의 자극에 의해 분비되며, 이들의 과다분비는 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease, COPD)을 유발하는 것으로 알려져 있다. 이에, 상기 실시예에 따른 약학적 조성물이 사람 호흡기 점액상피양 암세포주에서의 발현 정도를 평가하기 위해 포르볼 12-미리스테이트 13-아세테이트(phorbol 12-myristate 13-acetate; PMA)로 MUC5AC 분비를 유도한 사람 호흡기 점액상피양 암세포주에서 점액유전자(MUC5AC)의 분비량을 qRT-PCR로 분석하여 측정하였다.Mucin 5AC (MUC5AC), a mucus gene, is an inflammatory mucus protein that is secreted upon stimulation by substances such as LPS, and its hypersecretion is known to cause chronic obstructive pulmonary disease (COPD). Accordingly, in order to evaluate the expression level of the pharmaceutical composition according to the above example in human respiratory mucoepithelial cancer cell lines, MUC5AC secretion was tested with phorbol 12-myristate 13-acetate (PMA). The secretion amount of the mucin gene (MUC5AC) from the induced human respiratory mucoepithelial cancer cell line was measured by qRT-PCR.
구체적으로, 사람 호흡기 점액상피양 암세포주인 NCI-H292 세포를 대상으로 하는 실험을 수행하였다. 먼저, 10% (v/v) FBS, 1% 페니실린/스트렙토마이신을 함유하는 RPMI-1640 배지 (Gibco, #A10491)를 사용하여 3일 간격으로 계대 배양하였다(37℃, 5% CO2 incubator, 90% 이상 습도).Specifically, an experiment was performed on NCI-H292 cells, a human respiratory mucoepithelial cancer cell line. First, subculture was performed at 3-day intervals using RPMI-1640 medium (Gibco, #A10491) containing 10% (v/v) FBS and 1% penicillin/streptomycin (37°C, 5% CO 2 incubator, Humidity above 90%).
이후 세포에 실시예 1 내지 9, 비교예 2 내지 8에 따른 약학적 조성물 및 비교예 1에 따른 양성대조물질(덱사메타손)을 각각 0.1 mg/mL 및 4 ng/mL (10 nM) 처리하고, 1시간 뒤 점액 생성 유전자 발현 물질인 포르볼 12-미리스테이트 13-아세테이트(phorbol 12-myristate 13-acetate; PMA)를 100 nM로 처리하여 점액유전자(MUC5AC)의 분비(secretion) 및 생성(production)을 유도한 후, 24시간 배양한 다음에 상등액을 제거하고 남은 세포에서 RNeasy Mini kit(QIAGEN, USA) 를 통해 제조사의 프로토콜에 따라 진행하여 RNA를 추출하였고, cDNA 합성은 cDNA Synthesis kit(Thermo Fisher Scientific, USA)를 사용하였으며, AccuPower® 2X GreenStar™ qPCR Master Mix(Bioneer, Korea)를 사용하여 유전자를 증폭하였다. 분석에는 MUC5AC primer (Sense: TCCACCATATACCGCCACAGA, Antisense: TGGACGGACAGTCACTGTCAAC)를 사용하였다. 점액유전자(MUC5AC)의 mRNA 발현을 qRT-PCR(50℃에서 2분; 95℃에서 10분; 95℃에서 15초, 60℃에서 1분, 95℃에서 15초, 40 사이클; 60℃에서 1분; 95℃에서 15초 반응)로 분석하여 결과를 표 8 및 9에 나타내었다. 표 8 및 9에서의 결과 값은 아무것도 처리하지 않은 음성대조군 세포를 기준으로 하였을 때 PMA에 의한 MUC5AC의 생성능 대비 비교예 1과 실험군의 처리 시 억제된 정도를 나타낸 것이다.Afterwards, the cells were treated with 0.1 mg/mL and 4 ng/mL (10 nM) of the pharmaceutical compositions according to Examples 1 to 9 and Comparative Examples 2 to 8 and the positive control substance (dexamethasone) according to Comparative Example 1, respectively, and 1 After some time, phorbol 12-myristate 13-acetate (PMA), a mucus production gene expression material, was treated with 100 nM to induce secretion and production of the mucus gene (MUC5AC). After induction, culture was performed for 24 hours, the supernatant was removed, and RNA was extracted from the remaining cells using the RNeasy Mini kit (QIAGEN, USA) according to the manufacturer's protocol. cDNA synthesis was performed using the cDNA Synthesis kit (Thermo Fisher Scientific, USA) was used, and the gene was amplified using AccuPower ® 2X GreenStar™ qPCR Master Mix (Bioneer, Korea). MUC5AC primer (Sense: TCCACCATATACCGCCACAGA, Antisense: TGGACGGACAGTCACTGTCAAC) was used in the analysis. The mRNA expression of the mucin gene (MUC5AC) was measured by qRT-PCR (2 min at 50°C; 10 min at 95°C; 15 s at 95°C, 1 min at 60°C, 40 cycles; 15 s at 95°C; 1 at 60°C). minutes; 15 second reaction at 95°C) and the results are shown in Tables 8 and 9. The results in Tables 8 and 9 show the degree of inhibition in the treatment of Comparative Example 1 and the experimental group compared to the production ability of MUC5AC by PMA, based on the negative control cells that were not treated with anything.
- 음성대조군: PMA 만을 처리- Negative control group: treated with PMA only
- 비교예 1: 양성대조물질(덱사메타손, Dexamethasone; Dex, 제조사: Sigma-Aldrich, 제품 번호: D2915)을 처리- Comparative Example 1: Treatment of positive control material (Dexamethasone; Dex, manufacturer: Sigma-Aldrich, product number: D2915)
- 실험군: 실시예 1 내지 9, 비교예 2 내지 8에 따른 약학적 조성물을 처리-Experimental group: treated with pharmaceutical compositions according to Examples 1 to 9 and Comparative Examples 2 to 8
평가 결과Evaluation results
표 8 및 9를 참조하면, 실시예 5에 따른 약학적 조성물을 처리할 경우 점액 생성 유전자인 MUC5AC의 억제효과가 가장 높음을 확인하였고, 비교예 1인 덱사메타손과 비교하더라도 현저히 우수한 MUC5AC의 억제효과가 있음을 확인하였다.Referring to Tables 8 and 9, it was confirmed that the inhibitory effect of MUC5AC, a mucus production gene, was the highest when treated with the pharmaceutical composition according to Example 5, and the inhibitory effect of MUC5AC was significantly superior even compared to dexamethasone in Comparative Example 1. It was confirmed that it exists.
실험예 3: 실험계획법(Design of experiment, DOE)Experimental Example 3: Design of experiment (DOE)
DOE를 통한 설계가용영역(Design space, DS) 도출 방법How to derive design space (DS) through DOE
DS는 목표로 하는 출력변수(Ys)를 만족시키는 입력변수(Xs)의 수준을 영역으로 나타낸 것, 즉 설계 가용 영역이며 DS 안에서의 Xs 변동은 목표로 하는 Ys의 품질 저하를 초래하지 않음을 의미한다. 또한, DOE는 Xs와 Ys 간의 함수관계를 규명하는데 매우 효과적인 방법이며, 이를 기반으로 Xs와 Ys 간의 추정 회귀식을 이용하여 DS를 도출한다. DS represents the level of the input variable (Xs) that satisfies the target output variable (Ys) as an area, that is, the design availability area, and means that changes in Xs within the DS do not cause a decrease in the quality of the target Ys. do. In addition, DOE is a very effective method for identifying the functional relationship between Xs and Ys, and based on this, DS is derived using an estimated regression equation between Xs and Ys.
DOE 방법 중 하나인 요인 설계(Factorial design)는 선형 또는 다항 회귀식(제곱항 회귀식 제외)으로 나타나고, 반응표면법(Response surface methodology, RSM)은 제곱항을 포함한 다항 회귀식으로 나타난다.Factorial design, one of the DOE methods, appears as a linear or polynomial regression equation (excluding square term regression), and response surface methodology (RSM) appears as a polynomial regression equation including square terms.
본 발명에 있어서, DS 도출을 위한 추정 회귀식은 FD 방법과 RSM 방법을 통해 나타내었고, 통계 프로그램인 Minitab Statistical Software를 사용하였다.In the present invention, the estimated regression equation for deriving DS was expressed through the FD method and the RSM method, and the statistical program Minitab Statistical Software was used.
RSM의 면중심합성법(Central composite face-centerd, CCF)을 통한 추정 회귀식 도출Derivation of estimated regression equation through RSM's central composite face-centered (CCF) method
하기 표 10과 같이 CCF의 표준실험설계표를 작성하고, 표 11에 따라 Ys의 기준을 설정한 후 런 순서대로 실험을 진행하였다. 실험 결과를 분산분석(Analysis of variance, ANOVA)을 통해 통계적 유의성을 검증하였고, 제곱항을 포함하는 추정 회귀식을 도출하였다.A standard experimental design table for CCF was created as shown in Table 10 below, the standard for Ys was set according to Table 11, and the experiment was conducted in run order. The experimental results were verified for statistical significance through analysis of variance (ANOVA), and an estimated regression equation including square terms was derived.
요인 설계의 완전요인실험(Full factorial design, FD)을 통한 추정 회귀식Estimated regression equation through full factorial design (FD)
하기 표 12과 같이 FD의 표준실험설계표를 작성하고, 표 13과 같이 Ys의 기준을 설정한 후 런 순서대로 실험을 진행하였다. 실험 결과를 분산분석(Analysis of variance, ANOVA)을 통해 통계적 유의성을 검증하였고, 선형의 추정 회귀식을 도출하였다.A standard experimental design table for FD was prepared as shown in Table 12 below, and the standard for Ys was set as shown in Table 13, and then the experiment was conducted in run order. The experimental results were verified for statistical significance through analysis of variance (ANOVA), and a linear regression equation was derived.
설계가용영역(Design space, DS) 도출Derivation of design space (DS)
도 2의 결과와 같이 DS를 도출하였고, 안전가용공간(Operating space, OS)으로 X축의 오미자 생약은 1.50 ~ 2.50 g, Y축의 인삼 생약은 1.50 ~ 3.00 g의 범위에서는 출력변수(Ys)의 상한 값 설정 기준에 모두 만족하다고 판단하였다.DS was derived as shown in the results in Figure 2, and the upper limit of the output variable (Ys) is in the safe operating space (OS) range of 1.50 to 2.50 g for Schisandra chinensis herbal medicine on the X-axis and 1.50 to 3.00 g for ginseng herbal medicine on the Y-axis. It was determined that all value setting standards were satisfied.
설정된 오미자와 인삼의 용량범위를 바탕으로 호흡기 염증 질환, 특히 진해·거담 작용에 효과적인 4가지 성분 조합의 1일 복용 용량범위를 하기와 같이 설정하였다.Based on the established dosage range of Schisandra chinensis and ginseng, the daily dosage range of the four ingredient combinations that are effective for respiratory inflammatory diseases, especially antitussive and expectorant effects, was set as follows.
마황: 1.95 ~ 2.10 gEphedra: 1.95 to 2.10 g
길경: 1.95 ~ 2.10 gGilgyeong: 1.95 ~ 2.10 g
오미자: 1.50 ~ 2.50 g 및Schisandra chinensis: 1.50 to 2.50 g and
인삼: 1.50 ~ 3.00 gGinseng: 1.50 to 3.00 g
(※ 출력변수(Ys) MUC5AC의 경우 ANOVA 결과 p-value > 0.05 로 통계적으로 유의하지 않은 결과가 도출되어 DS 도출 시 제외됨.(※ In the case of the output variable (Ys) MUC5AC, the ANOVA result showed a statistically insignificant result with p-value > 0.05, so it was excluded when deriving DS.
※ 출력변수(Ys) 인터루킨-6(Interleukin-6; IL-6), 인터루킨-1β(Interleukin-1β; IL-1β), 류코트리엔 B4(Leukotriene B4; LTB4)의 경우 상한 값 기준을 유발군 대비 50% 개선 값으로 설정하였으며, 모든 DS 영역에서 기준에 만족하기 때문에 DS 도출 시 도 2에는 표기가 되지 않았다.)※ In the case of output variables (Ys) Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Leukotriene B4 (LTB4), the upper limit value standard is 50% compared to the induced group. It was set as a % improvement value, and because it satisfies the standards in all DS areas, it is not indicated in Figure 2 when deriving DS.)
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 관련 기술 분야의 통상의 지식을 가진 자에게 있어 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구범위와 그의 등가물에 의하여 정의될 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (13)
혼합 추출물은 생약 중량 기준으로 마황, 길경, 오미자 및 인삼이 1 : 0.5~1.5 : 0.15~2.0 : 0.1~2.0의 중량비로 혼합된 혼합 추출물인 것을 특징으로 하는 약학적 조성물.According to paragraph 1,
The mixed extract is a pharmaceutical composition characterized in that it is a mixed extract in which ephedra, gilgyeong, Schisandra chinensis, and ginseng are mixed in a weight ratio of 1:0.5-1.5:0.15-2.0:0.1-2.0 based on the weight of the herbal medicine.
상기 약학적 조성물은 산화질소(nitric oxide; NO), 인터루킨-1β(IL-1β), 인터루킨-6(IL-6), 종양괴사인자-α(TNF-α) 또는 류코트리엔 B4 (leukotriene B4)의 생성을 억제하여 호흡기 염증 질환을 치료하는 것인 약학적 조성물.According to paragraph 1,
The pharmaceutical composition contains nitric oxide (NO), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), or leukotriene B4. A pharmaceutical composition for treating respiratory inflammatory diseases by inhibiting production.
상기 약학적 조성물은 점액 관련 유전자인 MUC5AC의 발현을 억제하여 진해·거담 작용을 하는 것인 약학적 조성물.According to paragraph 1,
The pharmaceutical composition is a pharmaceutical composition that suppresses the expression of MUC5AC, a mucus-related gene, and acts as an antitussive and expectorant.
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