KR20230105146A - Herbal composition with intestinal immunity and systemic immunity activity - Google Patents
Herbal composition with intestinal immunity and systemic immunity activity Download PDFInfo
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- KR20230105146A KR20230105146A KR1020220000346A KR20220000346A KR20230105146A KR 20230105146 A KR20230105146 A KR 20230105146A KR 1020220000346 A KR1020220000346 A KR 1020220000346A KR 20220000346 A KR20220000346 A KR 20220000346A KR 20230105146 A KR20230105146 A KR 20230105146A
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Abstract
과제: 장관면역 및 전신면역능 활성을 갖는 생약 조성물 및 그 제조방법을 제공하는 것.
또한, 경구투여된 생약 조성물에 의하여 장관뿐 아니라 전신으로 감염되는 여러 감염원에 대하여 방어기전을 가지는 면역 성분의 생산을 증진시키는 기능을 가진 식품 혹은 약학 조성물로 응용하는 것.
해결수단: 본 발명은 장관면역 및 전신면역능 활성을 갖는 생약 조성물 및 그 제조방법에 관한 것으로서, 좀 더 자세히는 가시오가피, 진피 및 구기자는 각 20 내지 40 중량%, 감초, 생강 및 용안육은 각각 2 내지 10 중량%로 함유하는 추출물을 유효성분으로 함유하는 장관면역 및 전신면역능 활성을 갖는 생약 조성물 및 그 제조방법에 관한 것이다. 또한, 본 발명의 장관면역 및 전신면역능 활성을 갖는 생약 조성물은 장관면역계를 활성화시켜 장내의 IgA 생산 증가는 물론 혈청 IgA의 생산 증가를 통한 전신면역능을 활성화를 나타낸다. 또한, 본 발명의 장관면역 및 전신면역능 활성을 갖는 생약 조성물은 식품 및 약학 조성물로 응용 가능하다. Objective: To provide a herbal composition having intestinal immunity and systemic immunity activity and a manufacturing method thereof.
In addition, to be applied as a food or pharmaceutical composition having a function of enhancing the production of immune components having a defense mechanism against various infectious agents that are infected systemically as well as the intestinal tract by the orally administered herbal composition.
Solution: The present invention relates to a herbal composition having intestinal and systemic immune activity and a method for producing the same. It relates to a herbal composition containing an extract containing 10% by weight as an active ingredient and having intestinal and systemic immune activity and a method for preparing the same. In addition, the herbal composition having intestinal immunity and systemic immune activity of the present invention activates the intestinal immune system to increase intestinal IgA production as well as activate systemic immunity through increased serum IgA production. In addition, the herbal composition having intestinal and systemic immune activity of the present invention can be applied as a food and pharmaceutical composition.
Description
본 발명은 장관면역 및 전신면역능 활성을 갖는 생약 조성물에 관한 것으로서, 좀 더 자세히는 장관면역계를 활성화시켜 장내의 IgA 생산 증가는 물론 혈청 IgA의 생산 증가를 통한 전신면역능을 활성화시키는 가시오가피 추출물, 진피 추출물 및 구기자 추출물을 유효성분으로 함유하는 식품 조성물 및 약학 조성물에 관한 것이다.The present invention relates to a herbal composition having intestinal immunity and systemic immune function activity, and more particularly, to activating the intestinal immune system to increase intestinal IgA production as well as systemic immune function by increasing serum IgA production. And it relates to a food composition and a pharmaceutical composition containing goji berry extract as an active ingredient.
위장관은 식품에 함유된 여러 가지 감염원이 생체 내로 가장 많이 들어오는 장소이다. 장관면역계는 점막면역계의 한 종류로서 장관으로 이입된 병원균에 대한 최초의 감염방어 기구이다. 또한, 장관면역계의 활성화는 장관조직에서 유도된 면역기능이 국소적인 장관조직에 국한되지 않고, 전신을 순환하며 전신성 면역을 상승시킬 수 있는 장점을 가지고 있다. 장관면역계의 활성화는 개시기관인 소장의 파이엘 판 (Peyer's patch)을 구성하는 M 세포에 의하여 유도되며, 장관으로 들어온 병원균 또는 면역증강 성분은 이 경로를 통하여 장관면역계를 활성화시킨다. 장관면역계가 생산하는 분비형 IgA(secretory IgA) 항체는 가장 중요한 면역 성분으로 인정되고 있다. The gastrointestinal tract is the place where various infectious agents contained in food enter the body the most. The intestinal immune system is a type of mucosal immune system and is the first infection defense mechanism against pathogens introduced into the intestinal tract. In addition, the activation of the intestinal immune system has the advantage that the immune function induced in the intestinal tissue is not limited to the local intestinal tissue, but circulates throughout the body to increase systemic immunity. Activation of the intestinal immune system is induced by M cells constituting the Peyer's patch of the small intestine, which is an initiator, and pathogens or immune enhancing components entering the intestinal tract activate the intestinal immune system through this pathway. Secretory IgA antibodies produced by the intestinal immune system are recognized as the most important immune component.
한편, 감염성 세균이나 바이러스 등의 병원체들은 주로 식도, 호흡기, 소화기, 비뇨생식기 계통의 점막 부위를 통하여 생체 내로 들어와서 전신순환을 하며 전신적인 감염을 유도한다. 장관의 병원성 성분은 장관 내에서 생성된 IgA에 의하여 중화 기전을 통하여 제거될 수 있으나, 전신으로 전이된 병원균의 억제를 위하여는 전신적인 면역계가 활성화되어야 하고 이때는 혈액 중의 IgG 및 IgA 항체가 방어역할을 담당한다. 따라서, 장관면역 증진에 의한 전신면역의 증진을 촉진하는 식품 조성물 및 약학 조성물의 제공은 감염에 대한 생체 항상성 유지에 중요한 도구가 될 수 있다.On the other hand, pathogens such as infectious bacteria or viruses enter the living body mainly through the mucosal parts of the esophagus, respiratory, digestive, and genitourinary systems, circulate systemically, and induce systemic infection. Pathogenic components of the intestinal tract can be removed through a neutralization mechanism by IgA produced in the intestinal tract, but the systemic immune system must be activated to suppress pathogens that have spread throughout the body. At this time, IgG and IgA antibodies in the blood play a protective role. take charge Therefore, the provision of food compositions and pharmaceutical compositions that promote the enhancement of systemic immunity by enhancing intestinal immunity can be an important tool for maintaining homeostasis against infection.
본 발명의 생약 조성물에 함유되는 가시오가피 (Eleutherococcus senticosus)는 한방에서는 주로 간, 순환계 및 신경계에 작용하는 생약으로 알려져 있다. 구소련에서는 시베리아 진생으로 불렸으며, 약리학적 효능으로 피로, 스트레스 등에 작용하여 생체 항상성을 유지시키는 adaptgen으로서의 효과가 있음이 알려져 있다. Eleutherococcus senticosus ) contained in the herbal composition of the present invention is known as a herbal medicine that mainly acts on the liver, circulatory system and nervous system in oriental medicine. In the former Soviet Union, it was called Siberian ginseng, and it is known to have an effect as an adaptgen that maintains body homeostasis by acting on fatigue and stress as a pharmacological effect.
진피는 감귤 과피를 건조한 것으로 한방에서는 감기, 소화불량, 소갈증, 해열 등을 포함하여 주로 호흡기 및 위장관 건강에 사용하는 것으로 알려져 있다. The dermis is dried tangerine peel, and in oriental medicine, it is known that it is mainly used for respiratory and gastrointestinal health, including colds, indigestion, small thirst, and fever.
구기자는 구기자 나무의 열매를 말린 것으로 주로 신진대사를 다스리며 항산화 활성과 간 건강에 대한 기능이 알려져 있다.Gojija is the dried fruit of the gojija tree. It mainly regulates metabolism and is known for its antioxidant activity and liver health.
본 발명은 상기 생약들을 적절한 비율로 혼합하여 제조한 것이다. The present invention is prepared by mixing the herbal medicines in an appropriate ratio.
본 발명과 유사한 성격의 장관면역기능을 활성화시키는 식품소재 및 혼합물로는 대한민국 공개특허 제2017-0020952호에 상심자 추출물을 유효성분으로 함유한 경구용 면역 보조제가 개시되어 있다. 그러나, 본 발명은 상기 공개특허와는 별개의 생약 소재이며, 장관면역 기능 및 전신면역능 활성 증진 기능을 가지는 식품 및 약학 조성물 개발은 미진한 실정이다.Korean Patent Publication No. 2017-0020952 discloses an oral immune adjuvant containing a heartworm extract as an active ingredient as a food material and mixture that activates the intestinal immune function of a similar nature to that of the present invention. However, the present invention is a herbal medicine material separate from the above published patents, and the development of food and pharmaceutical compositions having a function of enhancing intestinal immune function and systemic immune function activity is insufficient.
대한민국 공개특허 제2013-39309호에는 마늘과 난황의 복합 활성물질을 건강개선 기능성 약효제로 포함하는 식품조성물과 그 제조방법이 개시되어 있고, 부가적으로 다양한 생약재들의 기능이 개시되어 있다. 용안육은 심혈관계에 작용하는 약재로, 면역계에 작용하는 약재 중 한 가지로 오가피가, 소화기계에 작용하는 약재로 진피, 구기자, 생강이, 기를 보하는 약재로 감초, 오가피, 진피 등이 개시되어 있다. 이 발명에는 백여 종의 약재들이 나열되어 있으나, 본 발명의 조성과 같이 특별히 장관면역기능 및 전신면역기능을 활성화하는 생약 조성물에 대하여는 개시하고 있지 않다.Korean Patent Publication No. 2013-39309 discloses a food composition containing a complex active substance of garlic and egg yolk as a health-improving functional drug and a method for manufacturing the same, and additionally discloses the functions of various herbal medicines. Yongan Yuk is a medicinal material that acts on the cardiovascular system, and five peels are one of the medicines that act on the immune system. there is. In this invention, about one hundred kinds of medicinal materials are listed, but, like the composition of the present invention, a herbal composition that specifically activates intestinal immune function and systemic immune function is not disclosed.
본 발명은 장관면역 및 전신면역능 활성을 갖는 생약 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a herbal composition having intestinal immunity and systemic immunological activity.
또한, 본 발명은 경구투여된 본 발명의 조성물에 의하여 장관계뿐만 아니라 전신으로 감염되는 여러 감염원에 대하여 방어기전을 가지는 면역 성분의 생산을 증진시키는 기능을 가진 식품 조성물 또는 약학 조성물로 응용하는 것을 목적으로 한다.In addition, the present invention is intended to be applied to a food composition or pharmaceutical composition having a function of enhancing the production of immune components having a defense mechanism against various infectious agents that are infected systemically as well as the intestinal system by the composition of the present invention administered orally. to be
감염원에 대하여 생체방어능을 가지는 면역의 특성은 염증반응을 기초로 한다. 즉, 초기 감염원이 침입한 경우 대식세포는 친-염증성 사이토카인인 TNF-a, IL-6을 포함하는 염증매개물질을 생산하고, 이러한 성분은 감염부위에 면역세포를 모이게 하는 작용을 하면서 국소적인 염증반응을 일으킨다. 그러나 감염원이 초기 면역반응에 의하여 제거되지 않고 계속 남아있을 경우, 지속적인 염증반응을 일으키게 되고 이것은 질병의 원인이 된다. 예를 들어 간염 바이러스의 감염은 간암의 원인되고, 활성산소에 의한 지속적인 염증반응은 결국 인체에서 동맥경화, 당뇨 및 암과 같은 성인병의 발생원인이 된다. 한편, 염증 조절 기능을 가지는 성분들은 항염증반응을 유도하고 이러한 성분은 주로 항산화 기능을 가지고 있다. 따라서 생체의 항상성유지를 위하여 중요한 것은 염증반응을 조절하는 것이다. 예를 들어 감염성 미생물의 침입에 대하여 급성 염증반응을 유도함으로 감염원을 제거하고 감염원이 제거되면 생체는 IL-10과 같은 면역억제 성분을 생산하여 면역반응을 종결시킴으로서 항상성을 유지하게 한다. 따라서 면역조절 기능은 생체건강유지를 위하여 매우 중요한 요소가 된다. 따라서 본 발명자는 이러한 사실에 기초하여 강한 면역자극 활성과 면역조절 기능을 가지는 생약들의 효능을 연구하던 중 생약제의 혼합에 의한 생체 조절 기능을 가지는 혼합성분을 완성하였다.The characteristics of immunity with biological defense against infectious agents are based on the inflammatory response. In other words, when an initial infectious agent invades, macrophages produce inflammatory mediators including TNF-a and IL-6, which are pro-inflammatory cytokines, and these components act to gather immune cells at the site of infection and cause an inflammatory response However, if the infectious agent is not eliminated by the initial immune response and remains, it causes a continuous inflammatory response, which causes disease. For example, hepatitis virus infection causes liver cancer, and a continuous inflammatory reaction caused by reactive oxygen species eventually causes adult diseases such as arteriosclerosis, diabetes, and cancer in the human body. On the other hand, components having an inflammatory control function induce an anti-inflammatory response, and these components mainly have an antioxidant function. Therefore, it is important to control the inflammatory response to maintain the homeostasis of the living body. For example, by inducing an acute inflammatory response against the invasion of infectious microorganisms, the infectious agent is removed, and when the infectious agent is removed, the living body produces immunosuppressive components such as IL-10 to terminate the immune response to maintain homeostasis. Therefore, the immunoregulatory function is a very important factor for the maintenance of biological health. Therefore, the present inventors, while studying the efficacy of herbal medicines having strong immunostimulatory activity and immunomodulatory function based on these facts, completed a mixed component having a biomodulatory function by mixing herbal medicines.
본 발명은 상기 목적을 달성하기 위한 것으로 가시오가피 추출물, 진피 추출물 및 구기자 추출물을 유효성분으로 포함하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다. The present invention relates to a herbal composition for activating intestinal immunity and systemic immunity, comprising an extract of ginseng ginseng, a dermis extract, and a goji berry extract as active ingredients to achieve the above object.
또한, 본 발명은 가시오가피 추출물 20~40 중량%, 진피 추출물 20~40 중량% 및 구기자 추출물 20~40 중량%를 포함하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다.In addition, the present invention relates to a herbal composition for activating intestinal immunity and systemic immunity, comprising 20 to 40% by weight of a prickly pear extract, 20 to 40% by weight of a dermal extract, and 20 to 40% by weight of a goji berry extract.
또한, 본 발명은 상기 가시오가피 추출물이 30~40 중량%인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다.In addition, the present invention relates to a herbal composition for activating intestinal immunity and systemic immune function, characterized in that the extract of ginseng cinnamonaceae is 30 to 40% by weight.
또한, 본 발명은 상기 진피 추출물이 20~30 중량%인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다.In addition, the present invention relates to a herbal composition for activating intestinal immunity and systemic immunity, characterized in that the dermal extract is 20 to 30% by weight.
가시오가피 추출물, 진피 추출물 및 구기자 추출물은 각각 20~40중량%, 바람직하게는 가시오가피 추출물 30~40중량%, 진피 추출물 20~30중량% 및 구기자 추출물 20~40중량% 범위일 때 장관면 역 및 전신면역 활성화 효과가 우수하다 (데이터 나타내지 않음). 가시오가피, 진피 및 구기자 추출물이 각각 20 중량% 미만인 경우에는 효능이 미약하고, 가시오가피, 진피 및 구기자 추출물이 각각 40 중량%를 초과할 경우에는 효능 증가가 크지 않으므로 효능과 경제적인 문제 등을 고려하여 상기 범위 내로 사용하는 것이 좋다.When the amount of Pacillus cinnamon extract, dermal extract and Goji berry extract is in the range of 20 to 40% by weight, preferably 30 to 40% by weight of Prickly pear extract, 20 to 30% by weight of dermal extract and 20 to 40% by weight of Goji berry extract, intestinal immunity and systemic The immune activation effect is excellent (data not shown). If the amount of cinnamon bark, dermis, and goji berry extract is less than 20% by weight, respectively, the efficacy is weak, and if the amount of cinnamon bark, dermis, and goji berry extract exceeds 40% by weight, respectively, the increase in efficacy is not significant. It is good to use within the range.
또한, 본 발명은 상기 생약 조성물이 경구 투여용인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다.In addition, the present invention relates to a herbal composition for activating intestinal immunity and systemic immunity, characterized in that the herbal composition is for oral administration.
또한, 본 발명은 상기 생약 조성물이 감초 추출물, 생강 추출물 및 용안육 추출물로 구성되는 군으로부터 선택되는 하나 이상을 추가로 포함하는 것으로 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다.In addition, the present invention relates to a herbal composition for activating intestinal immunity and systemic immunity, characterized in that the herbal composition further comprises at least one selected from the group consisting of licorice extract, ginger extract and longan yuk extract.
또한, 본 발명은 추가로 포함되는 감초 추출물, 생강 추출물 또는 용안육 추출물이 각각 2~10중량%인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물에 관한 것이다. 감초 추출물, 생강 추출물 또는 용안육 추출물이 각각 2중량% 미만 첨가될 경우에는 효능이 미약하고, 감초 추출물, 생강 추출물 또는 용안육 추출물이 각각 10중량%를 초과할 경우에는 효능 증가가 크지 않으므로 효능과 경제적인 문제 등을 고려하여 상기 범위 내로 사용하는 것이 좋다.In addition, the present invention relates to a herbal composition for activating intestinal immunity and systemic immunity, characterized in that the licorice extract, ginger extract or longan yuk extract additionally contained are 2 to 10% by weight, respectively. When the licorice extract, ginger extract or longan yuk extract is added in an amount of less than 2% by weight, respectively, the efficacy is weak, and when the licorice extract, ginger extract, or longan yuk extract is added in an amount of more than 10% by weight, the efficacy does not increase significantly. It is good to use it within the above range in consideration of problems and the like.
또한, 본 발명은 상기 생약 조성물을 유효성분으로 포함하는 장관면역 및 전신면역 증강용 약학 조성물에 관한 것이다.In addition, the present invention relates to a pharmaceutical composition for enhancing intestinal immunity and systemic immunity comprising the herbal composition as an active ingredient.
또한, 본 발명은 상기 생약 조성물을 유효성분으로 포함하는 장관면역 및 전신면역 증강용 식품 조성물에 관한 것이다.In addition, the present invention relates to a food composition for enhancing intestinal immunity and systemic immunity comprising the herbal composition as an active ingredient.
본 발명에서 사용된 용어 "식품"이란 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하며, 바람직하게는 어느 정도의 가공 공정을 거쳐 직접 먹을 수 있는 상태가 된 것을 의미하며, 통상적인 의미로서, 식품, 식품 첨가제, 기능성식품, 건강기능식품, 건강보조식품 및 음료 등을 모두 포함할 수 있다. 본 발명의 식품 조성물은 비제한적으로 각종 음료, 차, 과자, 비타민 복합체, 건강 보조식품 등의 형태로 제조될 수 있다. 본 발명의 식품 조성물의 바람직한 섭취량은 섭취하는 사람의 상태, 체중, 증상의 정도, 식품 형태, 섭취 기간에 따라 다르며, 적절하게 선택될 수 있다. 본 발명의 식품 조성물은 유효 성분이 1일 0.1㎎/㎏ 내지 500㎎/㎏으로 섭취되도록 하는 것이 최적의 효과를 위해 바람직하다.The term "food" used in the present invention means a natural product or processed product containing one or more nutrients, and preferably means a product that can be eaten directly through a certain degree of processing process. As a meaning, it may include all foods, food additives, functional foods, health functional foods, health supplement foods, and beverages. The food composition of the present invention may be prepared in the form of various beverages, tea, sweets, vitamin complexes, health supplements, and the like, without limitation. The preferred intake amount of the food composition of the present invention varies depending on the condition, body weight, severity of symptoms, food type, and intake period of the person who consumes it, and may be appropriately selected. In the food composition of the present invention, it is preferable for optimal effect that the active ingredient be ingested at 0.1 mg/kg to 500 mg/kg per day.
상기 생약 조성물을 유효성분으로 포함하는 장관면역 및 전신면역 증강용 약학 조성물은 약제학적 분야에서 통상적으로 허용되는 담체와 함께 배합하여 통상적인 방법에 의해 주사형태, 경구투여, 도포제 형태 등으로 제형화할 수 있다. 예를 들면 액제, 시럽제, 캡슐제, 과립제, 분말, 연고, 에멀젼, 겔, 크림 등으로 제제화할 수 있으며, 이를 여러 경로로 투여할 수 있다. 여러 가지 제형 중 예컨대, 주사용 조성물은 등장성 수용액 또는 현탁액이 바람직하고, 언급한 조성물은 멸균되고/되거나 보조제(예: 방부제, 안정화제, 습윤제 또는 유화제 용액 촉진제, 삼투압 조절을 위한 염/또는 완충제)를 함유한다. 또한, 이들은 기타 치료적으로 유용한 물질을 함유할 수 있다. 약제학적으로 허용 가능한 담체에는 유당, 포도당, 자당, 소르비톨, 마니톨, 전분, 검 아카시아, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미세결정 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 미네랄 오일 등이 포함된다. 상기 조성물에는 또한 윤활제, 웨팅제, 풍미제, 유화제 및 방부제 등이 더 포함될 수 있다. 본 발명의 조성물은 과립제, 산제, 액제, 정제, 캅셀제 또는 건조 시럽제 등의 경구용 제제 또는 주사제 등의 비경구용 제형으로 제제화할 수 있으나, 이러한 제형에 한정되는 것은 아니다.The pharmaceutical composition for enhancing enteral immunity and systemic immunity containing the herbal composition as an active ingredient can be formulated in the form of an injection, oral administration, coating, etc. by a conventional method by blending with a carrier generally accepted in the pharmaceutical field. there is. For example, it can be formulated into a liquid, syrup, capsule, granule, powder, ointment, emulsion, gel, cream, etc., and can be administered through various routes. Among the various dosage forms, for example, injectable compositions, preferably isotonic aqueous solutions or suspensions, the mentioned compositions are sterile and/or contain additives such as preservatives, stabilizers, wetting agents or emulsifiers, solution accelerators, salts and/or buffers for regulating osmotic pressure. ) contains In addition, they may contain other therapeutically useful substances. Pharmaceutically acceptable carriers include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, These include methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition may further include lubricants, wetting agents, flavoring agents, emulsifying agents and preservatives. The composition of the present invention may be formulated into oral formulations such as granules, powders, solutions, tablets, capsules, or dry syrups, or parenteral formulations such as injections, but is not limited to these formulations.
이와 같이 제조된 약제학적 제제는 목적하는 바에 따라 피하 투여, 근육 투여 또는 경구투여, 정맥 투여, 피부 도포, 구강 도포 등으로 투여할 수 있으며, 용량은 일일 투여량이 0.001㎍/㎏~100㎎/㎏의 양을 1 내지 수회에 나누어 투여할 수 있다. 특정 환자에 대한 투여용량 수준은 환자의 체중, 연령, 성별, 건강상태, 투여시간, 투여방법, 질환의 중증도 등에 따라 변화될 수 있다.The pharmaceutical preparation prepared as described above may be administered by subcutaneous administration, intramuscular administration or oral administration, intravenous administration, skin application, oral application, etc., depending on the purpose, and the daily dose is 0.001 μg/kg to 100 mg/kg. The amount of may be divided into 1 to several times and administered. The dosage level for a specific patient may vary depending on the patient's weight, age, sex, health condition, administration time, administration method, severity of disease, and the like.
본 발명의 주요 구성 재료 물질인 가시오가피, 진피 및 구기자 각각의 기능에 대한 과학적인 증거는 많이 있다.There is a lot of scientific evidence for the function of each of the main constituent materials of the present invention, cinnamon bark, dermis, and goji berry.
본 발명에 사용된 생약은 식품의약품안전처에서 식품 원료로의 사용이 가능한 것으로 구성되었다. 대표 원료인 가시오가피는 아칸소사이드 배당체 및 다당류를 주성분으로 하며 면역조절, 간기능 개선, 염증 억제 효과가 알려져 있다. 진피는 헤스페리딘 배당체를 주성분으로 하며 항염 작용이 보고되고 있다. 구기자는 베타인, 제아잔틴과 같은 성분을 함유함으로써 간기능, 혈관건강 및 피부건강 및 생체 단백질 합성을 촉진하는 기능을 가지는 것으로 알려져 있다.The crude drug used in the present invention was configured to be usable as a food raw material by the Ministry of Food and Drug Safety. As a representative raw material, prickly pear has Arkansoside glycosides and polysaccharides as its main components, and is known to have immunomodulatory, liver function improvement, and anti-inflammatory effects. The dermis has hesperidin glycoside as the main component, and anti-inflammatory action has been reported. Goji berry is known to have a function of promoting liver function, vascular health, skin health, and biological protein synthesis by containing components such as betaine and zeaxanthin.
또한, 본 발명의 생약 조성물은 경구투여에 의한 생체의 방어기능 증진을 자극하는 특징을 가지며, 상기 대표 생약으로서 가시오가피, 진피 및 구기자의 혼합은 장관 및 전신면역 기능을 자극하기 위하여 최적의 비율로 혼합되어 있다.In addition, the herbal composition of the present invention has the characteristic of stimulating the enhancement of the body's defense function by oral administration, and as the representative herbal medicine, the mixture of ginseng ginseng, dermis, and goji berry is mixed in an optimal ratio to stimulate the intestinal tract and systemic immune function. has been
본 발명의 부가적 구성 생약재인 감초, 생강 및 용안육의 특징과 기능은 다음과 같다.The characteristics and functions of licorice, ginger, and longan meat, which are additional constituent herbal medicines of the present invention, are as follows.
감초 (Chinese liquorice)는 콩과에 속하는 여러해살이풀로 중국 북동부와 시베리아, 몽골, 중국 북부 등지에 분포한다. 모든 약물과 배합이 잘 되어 중화작용을 하므로 뿌리는 건조하여 한약재로 사용한다.Licorice ( Chinese liquorice ) is a perennial plant belonging to the leguminous family and is distributed in northeastern China, Siberia, Mongolia, and northern China. It is well mixed with all drugs and has a neutralizing effect, so the root is dried and used as a herbal medicine.
생강 (Zingiber officinale)은 생강과에 속하는 여러해살이풀로서 동남아시아가 원산지이다. 몸을 따뜻하게 해주어 감기 예방에 탁월하며, 혈관에 쌓인 콜레스테롤을 몸 밖으로 배출해 동맥경화나 고혈압 등 성인병 예방과 수족냉증, 복부냉증 해소에 도움이 되는 한약재이다.Ginger ( Zingiber officinale ) is a perennial plant belonging to the ginger family and is native to Southeast Asia. It is excellent for preventing colds by warming the body, and it is a herbal medicine that helps prevent adult diseases such as arteriosclerosis and high blood pressure by discharging cholesterol accumulated in blood vessels out of the body, and relieves cold hands and feet and cold stomach.
용안육 (Euphoria longana)은 무환자나무과에 속하는 상록교목인 용안의 과실을 따서 과피를 제거하고 과육만 말린 것인데 과실이 둥글면서 용(龍)의 눈(眼)과 비슷하게 생겼기 때문에 용안육이라고 부른다. 중국 남부지역, 인도, 동남아시아와 열대 아메리카에 널리 분포하고 있다. 기운과 혈액을 보충해주고 몸과 마음을 편안하게 해주어 불안, 초조, 피로 개선 등에 사용되는 한약재이다.Longan meat ( Euphoria longana ) is obtained by picking the fruit of the longan, an evergreen tree belonging to the Euphoria longana family, removing the skin and drying only the flesh. It is widely distributed in southern China, India, Southeast Asia and tropical America. It is a herbal medicine used to improve anxiety, nervousness, and fatigue by replenishing energy and blood and relaxing the body and mind.
본 발명의 생약 조성물은 가시오가피, 진피 및 구기자가 각 20 내지 40 중량%, 선택적으로 감초, 생강 및 용안육은 각각 2 내지 10 중량%로 함유하는 추출물인 것을 특징으로 한다.The herbal composition of the present invention is characterized in that it is an extract containing 20 to 40% by weight of ginseng ginseng, dermis and wolfberry, and optionally 2 to 10% by weight of each of licorice, ginger and longan meat.
또한, 본 발명의 생약 조성물은 부형제로서 비타민, 무기질, 락토오스, 덱스트로스, 전분, 수크로스 또는 이들의 혼합물을 더 포함할 수 있는 것을 특징으로 한다.In addition, the herbal composition of the present invention is characterized in that it may further contain vitamins, minerals, lactose, dextrose, starch, sucrose or a mixture thereof as an excipient.
또한, 본 발명의 생약 조성물은 정제, 경질 또는 연질 캅셀제, 액제, 현탁제 등과 같은 경구투여용 제제의 형태로 이용될 수 있으며, 이들 제제는 허용 가능한 담체, 예를 들어 경구투여용 제제의 경우에는 부형제, 결합제, 붕해제, 활택제, 가용화제, 현탁화제, 보존제 또는 증량제 등을 사용하여 조제할 수 있다.In addition, the herbal composition of the present invention can be used in the form of preparations for oral administration such as tablets, hard or soft capsules, solutions, suspensions, etc., and these preparations are acceptable carriers, for example, in the case of preparations for oral administration It can be prepared using excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or bulking agents.
또한, 본 발명의 생약 조성물은 외래의 물질에 대한 방어력을 높임으로써 생체의 항상성 유지와 관련되는 면역기능 증진 활성을 나타내는 것을 특징으로 한다.In addition, the herbal composition of the present invention is characterized in that it exhibits an immune function enhancement activity related to the maintenance of homeostasis of the living body by increasing the defense against foreign substances.
또한, 본 발명의 생약 조성물은 각각의 생약 성분이 대식세포를 직접 자극하여 NO 및 사이토카인을 생산하는 면역자극 활성을 보였으며 그 효과는 본 발명의 실시예에 잘 나타나 있다.In addition, the herbal composition of the present invention showed immunostimulatory activity in that each herbal medicine component directly stimulates macrophages to produce NO and cytokines, and the effect is well shown in the examples of the present invention.
본 발명의 일 실시예에서 본 발명 생약 조성물의 경구투여는 각각의 생약 약용식물에 비하여 외래물질로서 암의 전이를 현저히 억제하였고, 이 결과는 본 발명 생약조성물이 장관면역기구의 활성화와 연관되는 것임을 제시한다.In one embodiment of the present invention, oral administration of the herbal composition of the present invention significantly inhibited metastasis of cancer as a foreign substance compared to each herbal medicinal plant, and this result indicates that the herbal composition of the present invention is associated with the activation of the intestinal immune system. present.
특정 항원이 선천면역계의 장벽을 극복할 경우에 생체는 그에 대한 적응면역계를 작동시켜 외래물질을 무력화한다. 이러한 적응면역계로는 외인성 항원에 대한 체액성 면역과 내인성 항원에 대한 세포성 면역계가 있다. 적응면역은 선천면역에 비하여 항원 특이적인 면역반응을 나타내므로, 특정 항원에 대하여 선천면역계에 비하여 더 높은 방어력을 가진다. 전신적으로 들어온 외인성 항원은 체액성 면역계를 구성하는 세포인 B-세포가 생산하는 항체에 의하여 제거된다. 이때 관여하는 항체는 주로 IgG 형의 항체로 혈액을 순환하며 외부로부터 들어온 항원을 제거하는 기능을 가진다. 혈액의 IgG는 혈액 항체의 약 80%를 구성하고 있는 중요한 성분이며, IgA가 약 15% 이하로 구성되어 있다. When a specific antigen overcomes the barrier of the innate immune system, the living body activates the adaptive immune system to neutralize the foreign substance. These adaptive immune systems include humoral immunity against exogenous antigens and cellular immune system against endogenous antigens. Adaptive immunity exhibits an antigen-specific immune response compared to innate immunity, so it has a higher defense against a specific antigen than the innate immune system. Exogenous antigens introduced systemically are removed by antibodies produced by B-cells, which are cells of the humoral immune system. Antibodies involved in this case are mainly IgG-type antibodies that circulate in the blood and have the function of removing antigens from the outside. Blood IgG is an important component constituting about 80% of blood antibodies, and IgA constitutes about 15% or less.
IgA의 원래의 기능은 주로 점막조직에서 생성되는 항체로서 점막면역에 관여하고 있다. 일반적으로 장내 IgA의 생산 증가는 다음과 같은 기전에 의한다. 소화기 장관을 포함하여 호흡기, 생식기로 구성되는 점막 면역 조직 (mucosal immune tissue)은 점막으로 덮여있는 조직들로, 외부 환경과 직접 연결되어 외부항원 및 병원체에 쉽게 노출된다. 특히, 장관의 점막조직은 식품과 함께 끊임없이 외부로부터 들어오는 병원체에 대처하기 위해 면역반응을 유도하거나 관용 (tolerance)을 유도함으로써 인체의 항상성을 유지하고 있다. 장관면역의 유도에서 가장 큰 특징은 장내에 거주하는 상주세균에 대하여 면역 관용을 유도함으로 인하여 공생균에 대한 면역반응이 유발되지 않는다는 것이다. 한편 식품 등으로 들어오는 외래 감염균 또는 이물질에 대하여 상피세포 표면의 점막층은 장내에 이입된 감염균의 조직침범 가능성을 줄인다. 둘째, 장조직에 침투한 박테리아의 신속한 탐지 및 사멸을 유도하는 면역반응의 유도이다. 장관면역계는 면역세포들의 집합적 조직인 파이엘 판 (Peyer's patch) 및 고유판 (Lamina propria)에 존재하는 장간막 림프절 (mesentric lymph node)로 구성된다. 장관내 파이엘 판의 M 세포는 림프성 섬유가 겹쳐지는 전문화된 상피세포로, 표면에 점액이 없기 때문에 내강에 침입한 항원은 M 세포를 쉽게 통과하여 상피 수지상 세포 (epithelial Dendritic Cells)에 의하여 포획된다. 수지상 세포는 항원을 PP 혹은 장간막림프절 (mesenteric lymph nodes; MLN)로 운반하여 특정 T와 B 세포와 반응하게 한다. 장관면역계의 T cell은 Th1, Th2, Th17 및 Tregs 등으로 구분되며, B-세포는 dimeric IgA를 생산하는 형질세포 (plasma cells)로 분화되고 상피세포의 특정 수용체인 pIgR을 통해 상피세포 (epithelial cells)층을 통과하여 분비형 항체 (sIgA)로서 장 내강에 들어가 감염성 물질을 중화하는 역할을 한다. 종합적으로는 장 상피층, 점액층, 면역세포이 생산하는 항균성 단백질들이 협력하여 감염을 억제하고 있으며, 이들이 생산하는 여러 가지 사이토카인들이나 케모카인들은 장을 구성하는 상피세포 및 면역세포의 기능을 조절하는 작용을 하고, B 세포가 생산하는 IgA 항체는 감염원을 직접적으로 제거하는 역할을 하는 것이다. 결국, 외래물질에 대하여 B 세포가 생산하여 내강에 이입되어 감염성 성분과 결합하는 항체인 분비형 IgA (secretoty IgA; sIgA)는 장관의 항상성 유지를 위한 가장 중요한 면역학적 기구로 인정되고 있다.The original function of IgA is mainly involved in mucosal immunity as an antibody produced in mucosal tissues. In general, increased production of IgA in the intestine is due to the following mechanisms. Mucosal immune tissues composed of the respiratory tract and genital organs, including the digestive tract, are tissues covered with mucous membranes, and are directly connected to the external environment and easily exposed to external antigens and pathogens. In particular, the mucosal tissue of the intestinal tract maintains homeostasis of the human body by inducing an immune response or inducing tolerance in order to cope with pathogens constantly entering from the outside along with food. The most significant feature of induction of intestinal immunity is that immune response against commensal bacteria is not induced by inducing immune tolerance against resident bacteria residing in the intestine. On the other hand, the mucosal layer on the surface of the epithelial cell reduces the possibility of invading the tissue of the infectious bacteria imported into the intestine with respect to foreign infectious bacteria or foreign substances entering the food. Second, it is the induction of an immune response that induces rapid detection and death of bacteria infiltrating the intestinal tissue. The intestinal immune system consists of Peyer's patches, which are collective tissues of immune cells, and mesentric lymph nodes present in the lamina propria. M cells of the intestinal tract's Peyer's plate are specialized epithelial cells in which lymphatic fibers overlap. Since there is no mucus on the surface, antigens that invade the lumen easily pass through the M cells and are captured by epithelial dendritic cells. do. Dendritic cells transport antigens to PPs or mesenteric lymph nodes (MLNs) where they react with specific T and B cells. T cells in the intestinal immune system are classified into Th1, Th2, Th17, and Tregs, and B-cells differentiate into plasma cells that produce dimeric IgA, and epithelial cells (epithelial cells) through pIgR, a specific receptor for epithelial cells. ) layer to enter the intestinal lumen as a secreted antibody (sIgA) and play a role in neutralizing infectious substances. Overall, antimicrobial proteins produced by the intestinal epithelial layer, mucous layer, and immune cells cooperate to suppress infection, and various cytokines or chemokines produced by them act to regulate the functions of epithelial cells and immune cells constituting the intestine. , IgA antibodies produced by B cells play a role in directly eliminating infectious agents. As a result, secretory IgA (sIgA), an antibody that is produced by B cells against a foreign substance, is introduced into the lumen, and binds to an infectious component, is recognized as the most important immunological mechanism for maintaining intestinal homeostasis.
한편, 혈액의 IgA에 대한 기능은 IgG에 비하여 잘 알려져 있지 않다. 다만 최근에 혈액의 IgA는 주로 단량체로 존재하고 점막에서 생성된 IgA가 인식하는 항원의 항원 결정기 (epitope)를 동시에 인식할 수 있다는 것이 규명되었다. 이것은 점막으로 들어온 항원이 림프관이나 장관내 혈액을 통하여 전신적으로 순환할 때 혈액내 IgA와 이들 미생물의 방어작용에 관여할 수 있음을 시사하는 것이고 실제로 ADCC와 같은 기전을 통하여 항원을 제거하는 기능이 있다는 것이 보고되고 있다. 한편, 구강 및 비강과 같은 점막조직으로 들어온 병원성 미생물은 점막조직의 고유한 면역기관 (mucosal-associated lymphoid tissue)에 의하여 인식되며 특히 구강을 통하여 들어온 외래물질은 점막면역계의 일부인 장관면역계를 구성하는 파이엘 판 및 MLN (mensentric lymph node)에 의하여 생산되는 분비형 IgA에 의하여 제거된다. 분비형 IgA는 주로 2량체로 구성되며 장 내강으로 분비되어 이곳의 병원균을 제거하는 기능을 가진다. 따라서 경구투여를 통하여 장관면역계의 작동분자인 IgA 항체 생산의 증진시키는 기능이 있는 성분의 탐색은 건강유지를 위한 중요한 도구가 될 수 있다.On the other hand, the function of blood IgA is not well known compared to IgG. However, it has recently been found that blood IgA mainly exists as a monomer and can simultaneously recognize antigenic epitopes recognized by IgA produced in the mucous membrane. This suggests that when antigens entering the mucous membrane circulate systemically through lymphatic vessels or blood in the intestinal tract, they can be involved in the defense of IgA and these microorganisms in the blood, and that they actually have the function of removing antigens through a mechanism such as ADCC. something is being reported. On the other hand, pathogenic microorganisms that enter mucosal tissues such as the oral cavity and nasal cavity are recognized by the mucosal-associated lymphoid tissue, and in particular, foreign substances entering through the oral cavity are part of the mucosal immune system, which constitutes the intestinal immune system. It is removed by secretory IgA produced by the L plate and MLN (mensentric lymph node). Secretory IgA mainly consists of dimers and is secreted into the intestinal lumen to eliminate pathogens there. Therefore, searching for components that have the function of enhancing the production of IgA antibodies, which are effector molecules of the intestinal immune system through oral administration, can be an important tool for maintaining health.
마우스를 이용한 실험에서 상기한 본 발명은 장관면역계인 PP를 구성하는 세포의 증식활성은 물론 PP를 통한 골수세포의 증식활성을 보였으며, 상기 약용식물 혼합물의 경구투여는 장내에서 특정 단백질 항원 (OVA)에 대한 IgA의 생산을 투여농도 의존적으로 증진시키는 활성이 있었다. 또한, 본 발명 생약 조성물의 경구투여는 혈액의 IgA 및 IgG의 항체가를 높이는 기능을 나타내었다. 따라서 본 발명 생약 조성물의 경구투여는 장관면역뿐 아니라 전신면역계를 활성화하는 기능이 있었고 이러한 결과는 실시예에 잘 나타나 있다.In experiments using mice, the above-described present invention showed proliferative activity of cells constituting PP, the intestinal immune system, as well as proliferative activity of bone marrow cells through PP, and oral administration of the medicinal plant mixture showed specific protein antigen (OVA) in the intestine. ) had the activity of enhancing the production of IgA in a dose-dependent manner. In addition, oral administration of the herbal composition of the present invention showed a function of increasing the antibody titer of IgA and IgG in the blood. Therefore, oral administration of the herbal composition of the present invention had the function of activating the systemic immune system as well as the intestinal immunity, and these results are well shown in the Examples.
선천면역계를 구성하는 또 다른 중요한 세포로 NK 세포가 있다. NK 세포는 바이러스 감염세포, 암을 포함하는 변형된 자기세포를 제거하는 기능을 가지며, 대식세포 혹은 수지상세포가 생산하는 사이토카인s에 의하여 활성화된다. 본 발명의 경구투여는 NK 세포의 세포독성 효과를 높이는 기능에 의한다는 것을 확인하였다. 따라서 본 발병의 경구투여는 전신적인 면역증강활성이 있음을 강하게 제시하였다. NK cells are another important cell that constitutes the innate immune system. NK cells have the function of removing virus-infected cells and transformed self cells including cancer cells, and are activated by cytokines produced by macrophages or dendritic cells. It was confirmed that the oral administration of the present invention is due to the function of increasing the cytotoxic effect of NK cells. Therefore, it was strongly suggested that the oral administration of the present invention has a systemic immune-enhancing activity.
특정 항원에 대한 적응면역 반응으로 T 세포가 관여하는 세포성 면역은 내인성 항원의 제거에 중요한 기구가 된다. 내인성 항원은 바이러스 감염 혹은 암에 대한 방어기능으로 주로 CTL (cytotoxic T-lymphocyte)이 관여한다. CTL이 표적세포를 살해하는 기구는 CTL의 MHC-I이 특정세포에서 발현하는 항원을 인식 및 CTL의 CD8과 표적세포와의 결합을 통하여 이루어진다. 이러한 결합은 CTL로 하여금 퍼포린 (perforin) 및 그랜자임 (granzyme)의 분비를 유도하고 이들 성분은 감염세포 혹은 암세포를 살해하게 한다. 따라서 CTL 활성을 증진시키는 성분은 내인성 항원의 제거를 위한 중요한 기구가 될 수 있다. Cellular immunity in which T cells are involved in an adaptive immune response to a specific antigen is an important mechanism for the elimination of endogenous antigens. Endogenous antigen is mainly involved in CTL (cytotoxic T-lymphocyte) as a defense function against viral infection or cancer. The mechanism by which CTLs kill target cells is achieved through the recognition of antigens expressed by MHC-I of CTLs on specific cells and the binding of CD8 of CTLs to target cells. This combination induces CTL to secrete perforin and granzyme, and these components kill infected cells or cancer cells. Thus, components that enhance CTL activity can be important mechanisms for clearance of endogenous antigens.
스트레스에 의하여 살해된 암세포와 본 발명의 약용식물 혼합물의 면역능은 스트레스에 의하여 살해된 암세포 만의 면역에 비하여 유의하게 높은 암의 전이 억제효과를 유도하였고 면역 마우스로부터 얻은 CTL 활성을 조사한 바 본 발명은 높은 CTL 활성 및 관련 성분의 증진 효과를 유도하였다. 이에 대한 결과는 실시예에 잘 나타나 있다.The immune ability of cancer cells killed by stress and the medicinal plant mixture of the present invention induced a significantly higher cancer metastasis inhibitory effect compared to the immunity of only cancer cells killed by stress, and CTL activity obtained from immunized mice was investigated. The enhancing effect of CTL activity and related components was induced. The results of this are well shown in the Examples.
본 발명의 장관면역 및 전신면역능 활성을 갖는 생약 조성물은 선천면역계의 자극 활성을 가지며 경구투여에 의하여 NK 세포의 활성화를 유도하는 선천면역계 활성화 기능을 나타냄과 동시에 특정 항원에 대하여 장관면역계를 구성하는 중요성분인 IgA의 생산 기능을 나타낸다.The herbal composition having intestinal and systemic immune activity of the present invention has a stimulating activity of the innate immune system and exhibits an innate immune system activating function by inducing activation of NK cells by oral administration, and at the same time, it is an important component of the intestinal immune system for a specific antigen. Indicates the production function of the component IgA.
또한, 본 발명의 장관면역 및 전신면역능 활성을 갖는 생약 조성물은 경구투여하는 경우 혈액을 통하여 전신적으로 순환되는 IgA의 항체가를 높이는 기능을 나타냄으로써 장관면역계 활성화를 통하여 특정 항원에 대한 전신면역계의 작동력을 높힐 수 있다.In addition, the herbal composition having intestinal and systemic immune activity of the present invention exhibits a function of increasing the antibody titer of IgA systemically circulating through the blood when administered orally, thereby activating the systemic immune system against a specific antigen through the activation of the intestinal immune system. can raise
또한, 본 발명의 장관면역 및 전신면역능 활성을 갖는 생약 조성물의 경구투여는 내인성 항원에 대한 세포성 면역기능을 가지는 면역증강제로서의 가능성이 제시되었다.In addition, the oral administration of the herbal composition having intestinal and systemic immune activity of the present invention has been suggested as an immune enhancer having a cellular immune function against endogenous antigens.
도 1은 가시오가피 추출물, 진피 추출물, 구기자 추출물 및 본 발명의 조성물이 농도에 따라 NO 생산에 미치는 효과를 나타낸 그래프이다.
도 2는 가시오가피 추출물, 진피 추출물, 구기자 추출물 및 본 발명의 조성물이 농도에 따라 TNF-α의 생산에 미치는 효과를 나타낸 그래프이다.
도 3은 가시오가피 추출물, 진피 추출물, 구기자 추출물 및 본 발명의 조성물이 농도에 따라 IL-12의 생산에 미치는 효과를 나타낸 그래프이다.
도 4는 암 전이모델에서 본 발명의 조성물 경구투여에 의한 종양전이 억제효과를 나타낸 그래프이다.
도 5는 본 발명의 조성물 경구투여에 의한 NK-세포의 활성화 및 인터페론 감마 (IFN-γ) 생산량에 미치는 영향을 나타낸 그래프이다.
도 6은 본 발명의 조성물 투여시 파이엘 판 세포 활성화에 의한 골수세포 증식능을 나타낸 그래프이다.
도 7은 항원의 경구투여에 의한 장관내 항원특이적 IgA의 생산효과에 미치는 본 발명의 조성물의 영향을 나타낸 그래프이다.
도 8은 항원 경구투여에 의한 혈중 항원특이적 IgA 및 IgG의 생산효과에 미치는 본 발명의 조성물의 영향을 나타낸 그래프이다.Figure 1 is a graph showing the effect of a prickly pear extract, a dermal extract, a goji berry extract, and the composition of the present invention on NO production according to the concentration.
Figure 2 is a graph showing the effect of the prickly pear extract, dermal extract, goji berry extract, and the composition of the present invention on the production of TNF-α according to the concentration.
Figure 3 is a graph showing the effect of the prickly pear extract, the dermal extract, the goji berry extract, and the composition of the present invention on the production of IL-12 according to the concentration.
Figure 4 is a graph showing the tumor metastasis inhibitory effect by oral administration of the composition of the present invention in a cancer metastasis model.
5 is a graph showing the effect of oral administration of the composition of the present invention on NK-cell activation and interferon gamma (IFN-γ) production.
6 is a graph showing myeloid cell proliferative ability by activation of Pail's plate cells upon administration of the composition of the present invention.
Figure 7 is a graph showing the effect of the composition of the present invention on the production of antigen-specific IgA in the intestinal tract by oral administration of the antigen.
8 is a graph showing the effect of the composition of the present invention on the production of antigen-specific IgA and IgG in the blood by oral antigen administration.
이하, 실시예를 통해 본 발명을 좀 더 구체적으로 설명한다. 단, 하기 실시예는 본 발명의 예시적인 기재일 뿐이며, 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, the following examples are merely exemplary descriptions of the present invention, and the scope of the present invention is not limited to the following examples.
실시예 1: 생약 조성물의 제조Example 1: Preparation of herbal composition
실시예 1에서 사용된 각각의 생약은 경동시장에서 구입하여 사용하였으며 혼합물의 배합비율은 표 1에 나타내었다.Each herbal medicine used in Example 1 was purchased from Gyeongdong Market and used, and the blending ratio of the mixture is shown in Table 1.
상기 표 1의 생약 재료를 엄선한 후 세척하여 이물을 제거 후, 원료 대비 20배의 정제수를 가하여 100℃에서 5시간 추출하면서 원료 대비 10배의 부피가 되도록 농축하였다. 열수 추출물은 4℃, 10,000 RPM, 20분 원심분리 후 0.4 um 기공 크기의 필터를 이용하여 여과 후 이하 실시예 2 내지 6의 실험을 실시하였다.After carefully selecting the herbal medicine materials in Table 1, washing them to remove impurities, adding 20 times more purified water than the raw materials and extracting at 100° C. for 5 hours while concentrating the mixture to a
또한, 본 발명의 생약 조성물은 상기 성분 이외에 조성물의 안정성 및 생체조절기구를 활성화시킬 수 있는 비타민류 및/또는 무기질을 첨가할 수 있다. 동시에 본 생약 조성물은 약학적 혹은 생리학적으로 허용된 담체 즉, 락토스, 덱스트로스, 전분 및 수크로스 등의 성분을 추가할 수 있다.In addition, vitamins and/or minerals capable of activating the stability and bioregulatory mechanism of the composition may be added to the herbal composition of the present invention in addition to the above ingredients. At the same time, pharmaceutically or physiologically acceptable carriers such as lactose, dextrose, starch and sucrose may be added to the herbal composition.
본 발명에 따른 생약 조성물의 1일 인체 섭취량은 1 내지 10 g인 경우가 바람직하나 실제 투여량은 각 개인의 나이, 성별, 체중 및 증상에 따라 결정되어야 하며, 이 농도는 본 발명의 범위를 한정하지는 않는다. 따라서 상기 본 발명 생약 조성물은 개인별로 적절한 양을 섭취하며, 액상차의 형태로는 150 내지 300 ml, 농축액의 경우 30 내지 70 ml, 환의 형태로는 2 내지 5 g을 섭취하는 것이 바람직하다.The daily intake of the herbal composition according to the present invention is preferably 1 to 10 g, but the actual dosage should be determined according to the age, sex, weight and symptoms of each individual, and this concentration limits the scope of the present invention. I don't. Therefore, the herbal composition of the present invention is ingested in an appropriate amount for each individual, preferably 150 to 300 ml in the form of a liquid tea, 30 to 70 ml in the case of a concentrate, and 2 to 5 g in the form of a pill.
실시예 2: RAW 264.7 대식세포 자극에 의한 면역매개물질 생산Example 2: Production of immune mediators by stimulation of RAW 264.7 macrophages
본 실시예에 사용된 대식세포인 Raw 264.7 세포주 (KTCC No. 40071)는 한국 세포주은행 (KTCC, Seoul)에서 분양받아 사용하였다. 배지는 RPMI-1640 배지에 8% (v/v) FBS와 1% (v/v) 페니실린-스트렙토마이신을 혼합해 사용하였다. 본 발명의 대식세포에 대한 직접적인 세포독성 효과를 관찰하기 위하여 96-웰 플레이트의 각 웰에 대식세포를 2×104/well/0.1 ml의 밀도로 접종한 후, 시료의 최종농도가 2 ㎎/㎖부터 4배 희석법으로 희석하여 16 ㎍/㎖가 되게 조정 후 24시간 배양하였다. 각 물질의 세포독성 효과는 WST를 이용하는 cell counting kit (EZ-Cytox, Daeil Lab. Seoul, Korea)를 이용하여 제조사의 지침에 따라 450 nm에서 흡광도를 측정하였다. 실험 결과, 실험에 적용한 모든 시료는 대식세포에 직접적인 독성효과를 일으키지 않았다. 따라서 이후의 대식세포 자극 효과에 대한 실험은 동일한 조건에서 실시하였다. 대식세포의 자극 활성에 대한 양성 대조군으로 지질다당체 성분인 lipopolysaccharide (LPS; 최종농도 0.5 ㎍/mL)를 사용하였다. 각 사이토카인에 대한 ELISA kit (Pharm-in-gen, San Jose, CA, USA)를 구입하여 제조사의 지침에 따라 측정하였고, NO의 생산능 측정은 대식세포의 세포배양 상등액 0.1 ㎖과 동량의 Griess 시약 (Sigma-Aldrich, St. Louis, MO, USA)을 혼합하여 10분간 반응 후 540 nm에서 측정한 다음, sodium nitrite (NaNO2)에 대한 표준 곡선에 대입하여 측정하였다.Raw 264.7 cell line (KTCC No. 40071), a macrophage used in this example, was purchased from Korea Cell Line Bank (KTCC, Seoul) and used. The medium was used by mixing 8% (v/v) FBS and 1% (v/v) penicillin-streptomycin in RPMI-1640 medium. In order to observe the direct cytotoxic effect on macrophages of the present invention, macrophages were inoculated into each well of a 96-well plate at a density of 2×10 4 /well/0.1 ml, and the final concentration of the sample was 2 mg/well. It was diluted from ㎖ by a 4-fold dilution method, adjusted to 16 μg/ml, and cultured for 24 hours. For the cytotoxic effect of each substance, absorbance was measured at 450 nm using a cell counting kit (EZ-Cytox, Daeil Lab. Seoul, Korea) using WST according to the manufacturer's instructions. As a result of the experiment, all samples applied to the experiment did not cause direct toxic effects on macrophages. Therefore, subsequent experiments on the macrophage stimulating effect were conducted under the same conditions. Lipopolysaccharide (LPS; final concentration: 0.5 μg/mL), a lipopolysaccharide component, was used as a positive control for the stimulatory activity of macrophages. An ELISA kit (Pharm-in-gen, San Jose, CA, USA) for each cytokine was purchased and measured according to the manufacturer's instructions, and NO production capacity was measured using the same amount of Griess as 0.1 ml of cell culture supernatant of macrophages. Reagents (Sigma-Aldrich, St. Louis, MO, USA) were mixed, reacted for 10 minutes, measured at 540 nm, and then substituted into a standard curve for sodium nitrite (NaNO 2 ).
선천면역계를 구성하는 대식세포는 체내에서 생성되는 노폐물 제거 및 외부 항원의 포식과 같은 작용을 하며 이러한 과정에서 면역조절능력을 가지는 NO를 포함하여 여러 가지 사이토카인을 유도함으로써 자신의 활성 증가를 포함하는 여러 가지 면역기능을 조절한다. 대식세포가 생산하는 NO는 TNF-α와 함께 염증의 유발을 통하여 혈관투과성을 촉진함으로서 감염부위에 면역세포를 모이게 하는 기능을 가진다. TNF-α는 여러 가지 기능을 가진 사이토카인으로 염증을 통한 면역반응의 개시 및 미성숙 수지상 세포의 표면에 MHC (Major Histocompatibility Complex) 또는 보조자극인자 (co-stimulatory molecule)의 발현을 촉진하므로 성숙한 형태의 수지상 세포로 전환하는 작용을 함으로써 외래물질의 항원제시를 통한 적응면역반응을 증진하는 역할을 한다. IL-12는 자연살해세포 (NK-cell) 및 Th1 세포에 작용하여 IFN-γ의 생산을 유도함으로써 세포성 면역인 NK 세포 및 T 세포가 감염세포를 살해하는 effector 형태로 분화하게 하는 작용을 한다. 따라서 대식세포로부터 IL-12의 생산능은 항원에 대항하는 자연 및 획득면역계의 활성화에 중요한 요소로 작용하는 사이토카인으로 간주되고 있다.Macrophages constituting the innate immune system have functions such as elimination of waste products generated in the body and phagocytosis of external antigens. Regulates several immune functions. NO produced by macrophages promotes vascular permeability through the induction of inflammation along with TNF-α, and has the function of gathering immune cells at the site of infection. TNF-α is a cytokine with multiple functions, which promotes the initiation of immune responses through inflammation and the expression of MHC (Major Histocompatibility Complex) or co-stimulatory molecules on the surface of immature dendritic cells. By converting into dendritic cells, it plays a role in enhancing the adaptive immune response through antigen presentation of foreign substances. IL-12 acts on natural killer cells (NK-cells) and Th1 cells to induce the production of IFN-γ, so that NK cells and T cells, which are cellular immunity, differentiate into effector types that kill infected cells. . Therefore, the ability to produce IL-12 from macrophages is regarded as a cytokine that acts as an important factor in activating the natural and acquired immune systems against antigens.
상기 결과에서 NO 및 TNF-α의 생산은 구기자와 실시예 1의 생약 조성물이 가장 높은 생산활성을 보였고, IL-12의 생산 효과는 실시예 1의 생약 조성물, 가시오가피, 구기자의 순으로 생산 활성이 높았다. 본 실험이 NO 또는 사이토카인의 기능보다는 시료 자체가 직접 대식세포와 반응하여 면역매개물질을 생산하는 자극효과에 주목한 연구임을 볼 때 실시예 1의 생약 조성물의 경우가 가장 다양하게 대식세포로부터 면역매개성분을 생산하는 기능이 있음을 확인하였다.From the above results, the production of NO and TNF-α showed the highest production activity of Gojija and the herbal composition of Example 1, and the production of IL-12 showed the highest production activity in the order of the herbal composition of Example 1, Goji gapi, and Goji japonica. It was high. Considering that this experiment focused on the stimulating effect of the sample itself reacting with macrophages to produce immune mediators rather than the function of NO or cytokines, the herbal composition of Example 1 was the most diverse in immunity from macrophages. It was confirmed that there is a function to produce mediating components.
실시예 3: 암 전이모델에서 실시예 1 생약 조성물 경구투여에 의한 종양전이 억제효과Example 3: Inhibition of tumor metastasis by oral administration of herbal composition of Example 1 in cancer metastasis model
실시예 1의 생약 조성물 경구투여가 전신적으로 들어오는 외래물질에 대한 감염방어를 억제하는지에 대한 실험을 진행하였다. 감염성 외래물질로는 암세포를 사용하였다. 즉, 배양 중인 마우스 유래 암세포인 colon26-M3.1 carcinoma를 혈관주사법으로 접종하였을 때 시료의 경구투여에 의한 암의 전이 억제력을 검토한 것이다.An experiment was conducted to see whether the oral administration of the herbal composition of Example 1 suppresses the systemic infection defense against foreign substances entering the body. Cancer cells were used as infectious foreign substances. That is, when colon26-M3.1 carcinoma, a mouse-derived cancer cell in culture, was inoculated by intravascular injection, the ability to suppress cancer metastasis by oral administration of the sample was examined.
항종양 효과는 colon26으로부터 얻은 고전이성 세포주인 colon26-M3.1 carcinoma를 이용하는 실험동물 종양전이 모델을 이용하였다. 각 군당 5마리의 Balb/C (자성, 6주령)를 사용하였으며 암의 전이를 위하여 colon26-M3.1 carcinoma (3 × 104 cells)를 혈관 주사하였다. 각 시험물질은 암의 접종 10일 전부터 매일 1회 경구투여하였고, 암세포를 접종 14일 후에 종양의 표적기관인 폐를 적출하여 Bouin's 용액에서 전이된 종양을 고정시킨 후, 종양의 군집 수를 측정하였다.For the antitumor effect, an experimental animal tumor metastasis model using colon26-M3.1 carcinoma, a highly metastatic cell line obtained from colon26, was used. Five Balb/C (female, 6 weeks old) were used for each group, and colon26-M3.1 carcinoma (3 × 10 4 cells) were intravascularly injected for cancer metastasis. Each test substance was orally administered once daily from 10 days before cancer inoculation, and after 14 days of cancer cell inoculation, the lungs, the target organs of tumors, were removed, and the metastasized tumors were fixed in Bouin's solution, and the number of tumor clusters was measured.
암의 증식과 전이에 있어서 면역자극과 염증의 유발은 중요한 요인이 된다. 암의 개시단계에서의 염증, 즉, 친-염증성 사이토카인을 포함하는 염증매개 성분은 면역세포의 활성화를 통하여 암의 개시를 억제하는 역할을 하지만 암의 진행과정에서 염증은 면역세포를 억제하는 기능을 가지는 쪽으로 유도하기에 염증은 암의 발전을 촉진시키는 역할을 한다. 실시예 2의 실험에서 시료에 의한 대식세포의 자극활성은 실시예 1의 생약 조성물, 가시오가피 추출물의 순으로 자극활성이 높았다. 실시예 1의 생약 조성물을 구성하는 또 다른 재료인 진피의 경우는 주로 염증의 억제 작용만을 유도하였고, 구기자의 경우 일부의 면역자극과 염증억제활성을 보였다. 따라서 이러한 특성을 가지는 각각의 구성물이 혼합된 실시예 1의 생약 조성물은 각각의 성분에 비하여 외래물질의 방어에 대하여 실시예 1의 생약 조성물이 상승작용을 유도하는 데 필요한 성분임이 강하게 시사되었다.In the proliferation and metastasis of cancer, immune stimulation and induction of inflammation are important factors. Inflammation at the initiation stage of cancer, that is, inflammation-mediated components including pro-inflammatory cytokines play a role in suppressing the initiation of cancer through the activation of immune cells, but inflammation in the process of cancer suppresses immune cells. Inflammation plays a role in promoting the development of cancer. In the experiment of Example 2, the stimulating activity of macrophages by the sample was high in the herbal composition of Example 1, and the stimulating activity was higher in the order of the extract of Ginseng. In the case of the dermis, which is another material constituting the herbal composition of Example 1, only the inhibitory action of inflammation was mainly induced, and in the case of goji berry, some immunostimulatory and anti-inflammatory activities were shown. Therefore, it was strongly suggested that the herbal composition of Example 1, in which each component having these properties was mixed, was a component necessary for inducing synergistic action of the herbal composition of Example 1 against foreign substances compared to each component.
실험 결과 구기자 및 진피 추출물의 경우 경구투여에 의한 유의미한 전이 억제활성은 보이지 않았으나, 가시오가피와 상기 실시예 1의 생약 조성물의 경우 대조군에 비하여 경구투여에 의한 유의미한 전이억제 효과가 인정되었고, 실시예 1의 생약 조성물의 경우가 더 높은 항-종양전이 활성을 보였다. 이러한 실험결과의 도출은 크게 두 가지로 설명이 가능하였다. 첫째, 실시예 1의 생약 조성물의 투여가 암세포를 살해하는 능력을 가진 NK-cell을 활성화하는 측면이다. 즉, NK-cell은 혈액내에서 암세포를 인식하고 살해하는 기능을 가진다. 따라서 만약에 실시예 1의 생약 조성물 경구투여에 의하여 NK cell의 활성화가 유도된다면 실시예 1의 생약 조성물 경구투여 후 혈액으로 접종된 암세포가 그의 목표기관인 폐에 부착하기 전에 살해함으로써 결국 암의 전이를 억제할 수 있다는 가능성이다. 둘째, 실시예 1의 생약 조성물 경구투여에 의하여 장관면역계의 활성화와 이에 의한 전신면역기능의 상승효과이다. 즉, 장관의 파이엘 판을 경유하는 골수세포의 활성화 기전은 암전이 억제 결과를 해석할 수 있는 또 다른 기전이 될 수 있다. 따라서 이 두 가지 기전에 대한 실험을 진행하였다.As a result of the experiment, in the case of goji berry and dermal extract, no significant metastasis inhibitory activity was observed by oral administration, but in the case of the herbal medicine composition of Example 1, as well as the Goji ginseng extract, a significant metastasis inhibitory effect was recognized by oral administration compared to the control group, and in Example 1 The herbal composition showed higher anti-tumor activity. The derivation of these experimental results could be largely explained in two ways. First, administration of the herbal composition of Example 1 is an aspect of activating NK-cells having the ability to kill cancer cells. That is, NK-cells have the function of recognizing and killing cancer cells in the blood. Therefore, if NK cell activation is induced by oral administration of the herbal composition of Example 1, cancer cells inoculated with blood after oral administration of the herbal composition of Example 1 are killed before attaching to their target organ, the lung, eventually preventing cancer metastasis. possibility that it can be suppressed. Second, the activation of the intestinal immune system by oral administration of the herbal composition of Example 1 and the resulting synergistic effect on systemic immune function. In other words, the activation mechanism of myeloid cells via the intestinal tract's plate of Peyer can be another mechanism that can interpret the results of inhibition of cancer metastasis. Therefore, experiments on these two mechanisms were conducted.
실시예 4: 실시예 1의 생약 조성물 경구투여에 의한 NK-세포의 활성화Example 4: Activation of NK-cells by oral administration of the herbal composition of Example 1
NK-세포는 주로 혈액에 존재하는 세포로서 바이러스 감염세포 혹은 암세포 등의 비자기 (non-self) 세포를 살해하는 세포성 면역활성을 나타낸다. NK-cells의 활성화, 즉, 암세포에 대한 살해능은 주로 대식세포가 생산하는 사이토카인 중 하나인 IL-12에 의한 것으로 알려져 있다. 활성화된 NK-세포는 IFN-γ 생산능이 높아지고 이렇게 생성된 IFN-γ는 감염원이 있는 장소의 대식세포에 대하여 수지상 세포와 같이 항원제시능을 획득하게 하는 작용을 한다.NK-cells are cells mainly present in the blood and exhibit cellular immune activity to kill non-self cells such as virus-infected cells or cancer cells. It is known that the activation of NK-cells, that is, the ability to kill cancer cells is mainly caused by IL-12, one of the cytokines produced by macrophages. Activated NK-cells increase the ability to produce IFN-γ, and the IFN-γ produced in this way acts to acquire antigen presenting ability, like dendritic cells, against macrophages at the site of infection.
본 실시예에서는 실시예 1의 생약 조성물을 경구투여한 마우스로부터 시료에 의한 NK-cell 활성화를 조사하기 위하여 실시예 1의 생약 조성물이 주사된 마우스의 비장세포와 NK-민감성 세포로 알려진 YAC-1 세포를 동시 배양한 후, YAC-1의 살해 정도를 측정하였다. 즉, 6주령의 Balb/c 마우스에 10 및 0.4 mg의 시료를 10일간 매일 경구투여하고 최종 투여 3일 후에 마우스의 비장을 멸균적으로 취하여 비장세포 (effector cell; E)를 준비하였다. U-bottomed 96-well plate에 마우스로부터 얻은 비장세포와 NK-민감성 세포로 알려진 YAC-1 세포 (target cell; T)를, E/T 비가 각각 50:1, 25:1이 되도록 조정하여 6시간 동안 공동 배양하였다. 배양종료 후 원심분리를 통하여 배양상등액을 취한 후 살해된 암세포가 유리한 LDH의 양을 kit를 이용하여 제조사 (Promega)의 지침에 따라 측정하였다.In this example, in order to investigate NK-cell activation by samples from mice orally administered with the herbal composition of Example 1, splenocytes of mice injected with the herbal composition of Example 1 and YAC-1 known as NK-sensitive cells After the cells were co-cultured, the degree of killing of YAC-1 was measured. That is, 10 and 0.4 mg of the sample were orally administered to 6-week-old Balb/c mice daily for 10 days, and 3 days after the final administration, the spleen of the mouse was sterilized to prepare effector cells (E). Splenocytes obtained from mice and YAC-1 cells (target cells; T), known as NK-sensitive cells, were placed in a U-bottomed 96-well plate for 6 hours by adjusting the E/T ratios to 50:1 and 25:1, respectively. during co-culture. After the end of the culture, the culture supernatant was taken through centrifugation, and the amount of LDH that was beneficial to the killed cancer cells was measured using a kit according to the instructions of the manufacturer (Promega).
세포독성 (%) = [(실험 배출량 - 자연 배출량)/(최대 배출량 - 자연 배출량)] X 100Cytotoxicity (%) = [(Experimental Emissions - Natural Emissions)/(Maximum Emissions - Natural Emissions)]
실험결과, 본 발명 생약 조성물 10 mg의 경구투여는 유의미한 YAC-1 세포의 살해효과를 유도하였으며, 세포독성 활성은 YCA-1 세포에 적용한 비장세포 의존적인 결과를 보였다. 동시에 배양 상등액에 생산된 IFN-γ의 양을 측정한 결과 YAC-1 세포에 대한 세포독성 결과와 동일한 패턴의 IFN-γ 생산활성을 보였다. 따라서 이러한 결과를 통하여 실시예 1 생약 조성물의 경구투여는 NK-세포의 활성화를 유도하는 기능이 있음을 확인하였다. 이러한 결과는 결국 실시예 1 생약 조성물이 PP를 경유하는 전신적인 생체방어력을 증진시킨다는 결과를 지지하였으며, 실시예 3의 암 전이 억제결과는 시료의 경구투여에 의한 NK-세포의 활성화가 중요한 요소로 작용함을 강하게 시사한다.As a result of the experiment, oral administration of 10 mg of the herbal composition of the present invention induced a significant YAC-1 cell killing effect, and the cytotoxic activity showed splenocyte-dependent results when applied to YCA-1 cells. At the same time, as a result of measuring the amount of IFN-γ produced in the culture supernatant, the same pattern of IFN-γ production activity as the result of cytotoxicity to YAC-1 cells was shown. Therefore, through these results, it was confirmed that oral administration of the herbal composition of Example 1 has the function of inducing activation of NK-cells. These results eventually supported the result that the herbal composition of Example 1 enhances the systemic biodefense through PP, and the cancer metastasis inhibition result of Example 3 shows that the activation of NK-cells by oral administration of the sample is an important factor. strongly suggest that it works.
실시예 5: 실시예 1 생약 조성물의 파이엘 판 세포 활성화 기능에 의한 골수세포 증식능Example 5: Bone marrow cell proliferation ability of Example 1 herbal composition by Paiel's plate cell activating function
Balb/C 마우스에 실시예 1의 생약 조성물을 10일간 경구투여한 후, 암세포 (colon26-M3.1 carcinoma)를 혈관주사법으로 접종하였다. 암세포 접종 후 2일 간격으로 실시예 1의 생약 조성물을 계속 경구투여하였다. 암세포 접종 14일 후 각각의 마우스의 소장으로부터 파이엘 판 (Peyer’s patch; PP)을 적출 후, PP를 구성하는 세포 (T 세포, B 세포, 대식세포와 수지상 세포 등)를 준비하여 96-웰 플레이트에서 3일간 배양 (3×105 cells/well)하였다. PP 배양 상등액의 골수세포 증식능을 조사하였다. 골수세포 증식능 분석은 PP 배양 상등액 (50 ul)을 Balb/C로부터 얻은 골수세포 (2.5×105 cells/ well)와 함께 5일간 배양 후 EZ cytox를 이용하여 흡광도 (450 nm)를 측정하여 수행하였다.After orally administering the herbal composition of Example 1 to Balb/C mice for 10 days, cancer cells (colon26-M3.1 carcinoma) were inoculated by intravascular injection. After cancer cell inoculation, the herbal composition of Example 1 was continuously orally administered every 2 days. After 14 days of cancer cell inoculation, Peyer's patch (PP) was extracted from the small intestine of each mouse, and cells constituting the PP (T cells, B cells, macrophages, dendritic cells, etc.) were prepared and placed in a 96-well plate. and cultured for 3 days (3×10 5 cells/well). The bone marrow cell proliferation ability of the PP culture supernatant was investigated. Analysis of bone marrow cell proliferative capacity was performed by measuring absorbance (450 nm) using EZ cytox after incubating PP culture supernatant (50 ul) with bone marrow cells (2.5×10 5 cells/ well) obtained from Balb/C for 5 days. .
실험 결과, PP 상등액을 골수세포와 동시 배양한 결과 유의한 골수세포 증식능이 인정되었는바 이 결과는 실시예 1의 생약 조성물의 경구투여가 혈액의 골수세포를 생체방어기구에 관여하는 백혈구로 분화하도록 촉진하는 기능을 발휘하여 전신면역능을 높일 수 있음을 강하게 시사하였고, 이러한 결과가 실시예 1 생약 조성물의 경구투여에 의한 암전이 억제 활성을 설명하는 하나의 기작으로 추측된다.As a result of the experiment, as a result of co-culturing the PP supernatant with bone marrow cells, significant bone marrow cell proliferative ability was recognized. It was strongly suggested that systemic immunity could be increased by exerting a stimulating function, and this result is presumed to be one mechanism explaining the activity of suppressing cancer metastasis by oral administration of the herbal composition of Example 1.
실시예 6: 실시예 1 생약 조성물의 경구투여에 의한 장관내 및 혈중 항체 생산에 미치는 효과Example 6: Effect of Oral Administration of Example 1 Herbal Composition on Intestinal and Blood Antibody Production
1) 항원 경구투여에 의한 장관내 항원특이적 IgA의 생산효과1) Effect of antigen-specific IgA production in the intestinal tract by oral administration of antigen
실시예 1 생약 조성물의 경구투여가 장관면역계를 활성화하는지 확인하기 위하여 Balb/c 마우스를 이용한 동물실험을 실시하였다. 6주령의 암컷 Balb/c 마우스에 생리식염수로 녹인 실시예 1 생약 조성물을 20, 100 및 500 mg/kg의 양 (0.4, 2, 10 mg/mouse)으로 2일 간격으로 총 7회 경구투여하였다. 항원으로는 OVA (ovoalbumin, 10 mg/kg)를 사용하였으며, 4일 간격으로 총 3회 경구투여하였다. 항원 투여 후 실시예 1의 생약 조성물은 2일 간격으로 5회 더 경구투여하였고 항원 최종 경구투여 14일 후 마우스를 희생시키고 장세척액을 준비하여 실험에 적용하였다. 장 내용물 중 IgA의 함량은 ELISA법으로 제조된 IgA 분석 키트를 이용하여 제조사의 지침에 따라 분석하였다. 소장의 파이엘 판 (PP)은 식품과 함께 이입되는 다양한 항원들 (미생물 및 식품 유래 항원)과 늘 접하고 있기 때문에 지속적으로 항원에 노출된다는 특징이 있다. 소장으로 이입된 항원은 특수화된 M 상피 세포 (microfold epithelial cell)에 의해 PP에 전달되고 PP 내의 상주 수지상 세포 (DC)에 의해 포획 및 제시함으로써 PP의 종자 중심 (germinal center)에 존재하는 B 세포를 항체 생산 형질 세포로 분화시켜 IgA를 생산하게 한다. 실험 결과, 실시예 1 생약 조성물의 경구투여는 항원 OVA 단독 투여의 경우와 비교하여 투여농도 의존적인 IgA의 생산활성이 관찰되었다. 따라서, 실시예 1 생약 조성물의 경구투여는 장관면역을 증진시키는 기능이 있음이 확인되었다.Example 1 Animal experiments using Balb/c mice were conducted to confirm whether oral administration of the herbal composition activates the intestinal immune system. The herbal composition of Example 1 dissolved in physiological saline was orally administered to 6-week-old female Balb/c mice at 20, 100, and 500 mg/kg (0.4, 2, and 10 mg/mouse) for a total of 7 times at 2-day intervals. . OVA (ovoalbumin, 10 mg/kg) was used as an antigen, and it was orally administered three times at 4-day intervals. After antigen administration, the herbal composition of Example 1 was orally administered 5 more times at 2-day intervals, and mice were sacrificed 14 days after the final oral administration of antigen, and intestinal washings were prepared and applied to the experiment. The content of IgA in the intestinal contents was analyzed using an IgA assay kit prepared by ELISA method according to the manufacturer's instructions. The small intestine's Peyer's plate (PP) is characterized by continuous exposure to antigens because it is always in contact with various antigens (microbial and food-derived antigens) introduced with food. Antigens translocated into the small intestine are delivered to the PP by specialized M epithelial cells (microfold epithelial cells), captured and presented by resident dendritic cells (DCs) in the PP, thereby targeting B cells present in the germinal center of the PP. Differentiate into antibody-producing plasma cells to produce IgA. As a result of the experiment, the oral administration of the herbal composition of Example 1 showed an administration concentration-dependent IgA production activity compared to the case of antigen OVA alone administration. Therefore, it was confirmed that oral administration of the herbal composition of Example 1 has a function of enhancing intestinal immunity.
비장, PP 등의 이차 림프 조직은 항원과 항원 특이적 림프구를 결합하여 적응 면역 반응의 유도 및 반응을 나타내는 중요한 기능을 한다. 따라서 특정 항원에 감작된 이들 이차 림프조직은 시험관 내에서 동일한 항원에 노출될 경우 세포의 증식을 포함하는 세포의 활성화가 이루어진다. 따라서 상기 IgA 실험을 실시한 마우스의 PP 세포를 채취하여 시험관 내에서 동일한 항원인 OVA로 노출 후 PP 세포의 증식활성을 조사하였다. 그 결과, OVA 단독으로 노출된 마우스에 비하여 실시예 1 생약 조성물을 동시에 투여한 마우스의 PP 세포는 OVA의 재자극에 의하여 항원농도 의존적인 세포증식활성이 유도되었다. 그리고 PP 세포의 증식활성은 IgA의 생산활성과 같은 패턴으로, 실시예 1의 생약 조성물 투여농도 의존적인 결과를 얻었다. 동시에 PP 상등액을 골수세포에 적용한 결과, 실시예 5의 경우와 동일하게 투여농도 의존적인 골수세포 증식능을 유도하였다. 이러한 결과는 실시예 1 생약 조성물의 경구투여가 경구적으로 투여한 항원에 대한 전신적인 면역반응 유도 가능성을 제시하였다.Secondary lymphoid tissue, such as the spleen and PP, plays an important role in inducing and responding to an adaptive immune response by binding antigens and antigen-specific lymphocytes. Therefore, when these secondary lymphoid tissues sensitized to a specific antigen are exposed to the same antigen in vitro, cell activation including cell proliferation is achieved. Therefore, the PP cells of the mice subjected to the IgA experiment were collected and exposed to the same antigen, OVA, in vitro, and then the proliferative activity of the PP cells was examined. As a result, compared to mice exposed to OVA alone, PP cells of mice simultaneously administered with the herbal composition of Example 1 induced antigen concentration-dependent cell proliferation activity by restimulation with OVA. In addition, the proliferative activity of PP cells was in the same pattern as the IgA production activity, and the concentration-dependent result of the herbal composition of Example 1 was obtained. At the same time, as a result of applying the PP supernatant to the bone marrow cells, the same as in Example 5, the dose-dependent proliferation capacity of the bone marrow cells was induced. These results suggest the possibility that oral administration of the herbal composition of Example 1 induces a systemic immune response to an orally administered antigen.
2) 실시예 1 생약 조성물의 경구투여에 의한 혈중 항원특이적 IgA 및 IgG의 생산효과2) Effect of production of antigen-specific IgA and IgG in the blood by oral administration of the herbal composition of Example 1
상기 실시예 6의 1) 실험에서 항원 OVA와 실시예 1 생약 조성물의 경구투여는 장관내에서 유의하게 높은 IgA의 생산활성을 보여주었고, 이를 통해 본 발명 생약 조성물이 장관면역계를 증진시키는 기능이 있음을 확인하였다. 본 실험은 동일한 마우스에서 혈액의 항체 생산에 미치는 효과를 검토하기 위하여 혈중 IgA 및 IgG 항체의 생산효과를 ELISA법으로 분석한 것이다. 각 항체의 생산 측정을 위하여 항원 OVA의 coating (20 ug/well), skim milk (3%)를 이용한 blocking, 희석된 각각의 혈청, 그리고 IgA 및 IgG에 대한 2차 항체 HRP를 순차적으로 반응시킨 후 TMB 용액으로 발색 후 2N 황산을 이용하여 반응을 정지하고, 450 nnm에서 흡광도를 조사하였다. 실험 결과 혈청의 IgA는 농도 의존적으로 실시예 1 생약 조성물의 경구투여군에서 높은 생산활성을 보였으며, IgG 항체 생산은 실시예 1 생약 조성물 10 mg의 투여군에서 일부의 항체생산 증가효과가 관찰되었으나 통계적인 유의성은 없었다.Oral administration of the antigen OVA and the herbal composition of Example 1 in the 1) experiment of Example 6 showed significantly high IgA production activity in the intestinal tract, through which the herbal composition of the present invention has the function of enhancing the intestinal immune system. confirmed. In this experiment, the production effect of IgA and IgG antibodies in blood was analyzed by ELISA method to examine the effect on blood antibody production in the same mouse. To measure the production of each antibody, coating of antigen OVA (20 ug/well), blocking using skim milk (3%), diluted serum, and secondary antibody HRP for IgA and IgG were sequentially reacted After color development with TMB solution, the reaction was stopped using 2N sulfuric acid, and absorbance was examined at 450 nm. As a result of the experiment, serum IgA showed high production activity in the oral administration group of the herbal composition of Example 1 in a concentration-dependent manner, and the production of IgG antibodies was partially increased in the group administered with 10 mg of the herbal composition of Example 1, but statistically There was no significant.
실험 결과, 혈청의 IgA의 역가가 실시예 1 생약 조성물의 경구투여로 유의미하게 증가한 것은 경구로 들어온 항원에 대하여 실시예 1 생약 조성물이 항원 특이적으로 전신적인 면역반응을 유의미하게 증가시켰음을 제시한다. 전통적으로 전신면역계에서 가장 중요한 면역기구인 IgG 항체의 생산활성이 실시예 1 생약 조성물 10 mg 투여군에서 증강된 결과는, 만약 항원이 혈관계를 통하여 전신적으로 순환할 경우 실시예 1 생약 조성물의 투여가 혈청 IgG에 대한 반응성을 증가시킬 수 있음을 시사하는 것이다. 혈액의 IgA의 기능은 IgG의 기능에 비하여 잘 알려 있지는 않다. 비록 장관 또는 혈액에서 IgA를 생산하는 B 세포의 원천은 다르다는 것이 시사되고 있지만 장관과 혈액의 IgA는 항원에 있는 동일한 항원 결정기를 인식하는 것으로 보고되고 있다. 따라서 항원이 전신적으로 침입할 경우, 실시예 1 생약 조성물의 경구투여는 혈액의 IgA 항체 생산 증가는 물론 장관내의 IgA 생산에도 분명하게 관여할 것으로 사료된다. 혈액의 IgA는 특정 항원에 대하여 opsonization 작용에 의한 항원의 제거능이 보고되었다. 따라서 암을 포함한 감염성 질병억제에 관여하는 것이 제시되었고, 최근 (코로나) 바이러스 감염에 대한 방어에서 혈액 IgA는 감염 초기에 IgG에 비하여 유의하게 높은 방어기구로 작용함이 보고되었다. 결론적으로 실시예 1 생약 조성물의 경구투여는 장관내의 IgA 생산은 물론 혈액내 IgA 항체의 생산을 증가시킴으로써 장관면역계는 물론 전신면역계에 의한 생체방어 활성을 증가시키는 기능이 있는 것으로 확인되었다.As a result of the experiment, the fact that the serum IgA titer was significantly increased by oral administration of the herbal composition of Example 1 suggests that the herbal composition of Example 1 significantly increased the antigen-specific systemic immune response to the orally administered antigen. . The result of the enhancement of the production activity of IgG antibody, which is traditionally the most important immune mechanism in the systemic immune system, in the 10 mg administration group of the herbal composition of Example 1 is that if the antigen circulates systemically through the vascular system, the administration of the herbal composition of Example 1 is effective in serum This suggests that the reactivity to IgG can be increased. The function of blood IgA is less well known than that of IgG. It has been reported that intestinal and blood IgA recognize the same antigenic determinant on the antigen, although it has been suggested that the sources of IgA-producing B cells in the intestinal tract or blood are different. Therefore, when the antigen invades systemically, oral administration of the herbal composition of Example 1 is considered to be clearly involved in IgA production in the intestinal tract as well as increased blood IgA antibody production. It has been reported that blood IgA has the ability to remove antigens by opsonization against specific antigens. Therefore, it has been suggested to be involved in suppressing infectious diseases, including cancer, and it has recently been reported that blood IgA acts as a significantly higher defense mechanism than IgG in the defense against (corona) virus infection in the early stage of infection. In conclusion, it was confirmed that oral administration of the herbal composition of Example 1 increases the production of IgA antibodies in the blood as well as the production of IgA in the intestinal tract, thereby increasing the biodefense activity by the systemic immune system as well as the intestinal immune system.
Claims (8)
A herbal composition for activating intestinal immunity and systemic immunity, comprising 20 to 40% by weight of a prickly pear extract, 20 to 40% by weight of a dermal extract, and 20 to 40% by weight of a goji berry extract.
상기 가시오가피 추출물은 30~40 중량%인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물.
The method of claim 1,
The herbal composition for activating intestinal immunity and systemic immunity, characterized in that the extract of ginseng cinnamonella is 30 to 40% by weight.
상기 진피 추출물은 20~30 중량%인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물.
The method of claim 1,
The dermal extract is a herbal composition for activating intestinal immunity and systemic immunity, characterized in that 20 to 30% by weight.
상기 생약 조성물은 경구 투여용인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물.
The method of claim 1,
The herbal composition is a herbal composition for activating intestinal immunity and systemic immunity, characterized in that for oral administration.
상기 생약 조성물은 감초 추출물, 생강 추출물 및 용안육 추출물로 구성되는 군으로부터 선택되는 하나 이상을 추가로 포함하는 것으로 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물.
The method of claim 1,
The herbal composition is a herbal composition for activating intestinal immunity and systemic immunity, characterized in that it further comprises at least one selected from the group consisting of licorice extract, ginger extract and longan yuk extract.
감초 추출물, 생강 추출물 또는 용안육 추출물은 2~10중량%인 것을 특징으로 하는 장관면역 및 전신면역능을 활성화하는 생약 조성물.
The method of claim 5,
A herbal composition for activating intestinal immunity and systemic immunity, characterized in that the licorice extract, ginger extract or longan yuk extract is 2 to 10% by weight.
A pharmaceutical composition for enhancing intestinal immunity and systemic immunity, comprising the herbal composition according to any one of claims 1 to 6 as an active ingredient.
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