KR20220163843A - Extracellular Vesicles Derived from Lactobacillus rhamnosus and uses thereof - Google Patents
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- KR20220163843A KR20220163843A KR1020210173139A KR20210173139A KR20220163843A KR 20220163843 A KR20220163843 A KR 20220163843A KR 1020210173139 A KR1020210173139 A KR 1020210173139A KR 20210173139 A KR20210173139 A KR 20210173139A KR 20220163843 A KR20220163843 A KR 20220163843A
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Abstract
Description
본 발명은 락토바실러스 람노수스(Lactobacillus rhamnosus) 유래 소포를 유효성분으로 포함하는 면역질환 및 세포 노화 관련 질환의 예방, 개선, 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for preventing, improving, or treating immune diseases and diseases related to cellular aging, comprising Lactobacillus rhamnosus -derived vesicles as an active ingredient.
21세기에 들어서면서 과거 전염병으로 인식되던 급성 감염성 질환의 중요성은 감소되었다. 반면, 우리 몸의 주요 장기에 발생하는 면역기능 이상 및 세포 노화로 인한 만성질환이 삶의 질 감소와 인간 수명을 결정하는 주요 질환으로 질병 패턴이 바뀌었다. 이러한 질병 패턴의 변화는 식이 패턴의 변화와 밀접한 관련이 있는데, 과거에 영양 상태가 부족했던 시절에는 영양실조로 인한 급성 감염성 질환이 주요 사망원인이었지만, 최근 영양이 풍부해지면서 영양 과잉으로 발생하는 면역기능 이상 및 세포 노화와 관련된 만성질환이 주요한 문제가 되고 있다.Entering the 21st century, the importance of acute infectious diseases, which were recognized as infectious diseases in the past, has decreased. On the other hand, chronic diseases caused by abnormal immune function and cellular aging that occur in major organs of the body have changed the pattern of diseases as major diseases that determine the decrease in quality of life and human lifespan. Changes in these disease patterns are closely related to changes in dietary patterns. In the past, acute infectious diseases caused by malnutrition were the main cause of death in the past when nutritional status was insufficient. Chronic diseases associated with functional abnormalities and cellular aging are becoming major problems.
영양 과잉으로 인해 지방이 정상적으로 저장되는 장소인 지방조직뿐만 아니라 혈관, 심장, 간, 신장, 근육 등에 축적되면서 지방 독성 (lipotoxicity)이 초래되고, 이로 인해 염증 및 세포의 노화가 발생한다. 즉, 탄수화물 또는 지질 대사 장애에 의해 혈중 지질과 지방산이 증가하고, 세포 내에 지방산이 많아지면서 지방산에 의한 염증반응이 발생하게 되고, 염증반응은 세포 노화 및 사멸을 일으켜 심혈관, 간, 신장, 근육, 뇌 등의 장기의 기능 장애가 발생하게 된다. 이러한 병인에 의해 발생하는 질환으로 협심증, 혈전색전증, 심근경색, 심근병증, 뇌졸중 등의 심혈관질환, 만성 신증, 신부전 등의 신장질환, 골관절염, 통풍, 골다공증 등의 근골격계질환, 알츠하이머병, 파킨슨병 등의 퇴행성 뇌질환 등이 포함된다.Excessive nutrition causes fat to accumulate in blood vessels, heart, liver, kidneys, muscles, etc. as well as adipose tissues, which are normally stored, resulting in lipotoxicity, which causes inflammation and cellular aging. In other words, blood lipids and fatty acids increase due to carbohydrate or lipid metabolism disorders, and fatty acids increase in cells, resulting in inflammatory reactions caused by fatty acids. Functional disorders of organs such as the brain may occur. Diseases caused by these etiologies include cardiovascular diseases such as angina pectoris, thromboembolism, myocardial infarction, cardiomyopathy, and stroke, kidney diseases such as chronic nephropathy and renal failure, musculoskeletal diseases such as osteoarthritis, gout, and osteoporosis, Alzheimer's disease, Parkinson's disease, etc. of degenerative brain diseases, etc.
면역(immunity)은 생물학적, 화학적, 물리적, 정신적 스트레스에 대한 세포의 방어 기작으로, 선천면역(innate immunity)과 후천면역(adaptive immunity)을 통해 일어나게 된다. 특히 병원성 인자에 반복적으로 노출 시에 부적절한 면역반응이 일어나면 만성염증반응의 결과로 질병이 발생하는데, 대표적인 예로 환경적인 병원성 인자에 의한 면역 과민 반응에 의한 알레르기 질환 및 내부적으로 생성되는 병원성 위험인자에 의한 과민반응의 결과로 발생하는 자가면역질환이 대표적이다. 또한, 최근 면역기능이 세포의 대사기능과 밀접히 연관되어 있음이 밝혀졌는데, 영양 과잉에 의한 면역기능 장애의 병인과 관련해서 세포질 내 지방산, 요산 등의 대사산물이 위험 신호로 작용하여 세포질 내에 존재하는 패턴인식수용체(pattern recognition receptor)인 NLRP(Nucleotide-binding oligomerization domain)에 의해 인지된다. 이는 인플라마좀을 형성하여 세포사멸을 유도함과 동시에 염증성 매개체를 분비하여 염증세포 침윤을 유도한다는 사실이 알려져 있다.Immunity is a defense mechanism of cells against biological, chemical, physical, and mental stresses, and occurs through innate immunity and adaptive immunity. In particular, when an inappropriate immune response occurs when repeatedly exposed to pathogenic factors, diseases occur as a result of chronic inflammatory reactions. Representative examples include allergic diseases caused by immune hypersensitivity reactions caused by environmental pathogenic factors and pathogenic risk factors generated internally. An autoimmune disease that occurs as a result of a hypersensitivity reaction is representative. In addition, it has recently been found that immune function is closely related to the metabolic function of cells. In relation to the pathogenesis of immune dysfunction caused by nutrient overload, metabolites such as fatty acids and uric acid in the cytoplasm act as a danger signal, causing It is recognized by the pattern recognition receptor, NLRP (Nucleotide-binding oligomerization domain). It is known that this induces apoptosis by forming inflammasomes and simultaneously secretes inflammatory mediators to induce inflammatory cell infiltration.
한편, 인체에 공생하는 미생물은 100조에 이르러 인간 세포보다 많으며, 미생물의 유전자수는 인간 유전자수의 100배가 넘는 것으로 알려지고 있다. 미생물총(microbiota 혹은 microbiome)은 주어진 거주지에 존재하는 진정세균(bacteria), 고세균(archaea), 진핵생물(eukarya)을 포함한 미생물 군집(microbial community)을 말한다. On the other hand, it is known that the number of microorganisms symbiotic with the human body is 100 trillion, which is more than human cells, and the number of genes of microorganisms is more than 100 times the number of human genes. The microbiota or microbiome refers to the microbial community, including bacteria, archaea, and eukarya, present in a given habitat.
우리 몸에 공생하는 세균 및 주변 환경에 존재하는 세균은 다른 세포로의 유전자, 저분자화합물, 단백질 등의 정보를 교환하기 위하여 나노미터 크기의 소포(vesicle)를 분비한다. 점막은 200 나노미터(nm) 크기 이상의 입자는 통과할 수 없는 물리적인 방어막을 형성하여 점막에 공생하는 세균인 경우에는 점막을 통과하지 못하지만, 세균 유래 소포는 크기가 200 나노미터 크기 이하라서 비교적 자유롭게 점막을 통하여 상피세포를 통과하여 우리 몸에 흡수된다. 이와 같이, 세균 유래 소포는 세균에서 분비된 것이지만, 세균과 구성 성분, 체내 흡수율, 부작용 위험성 등이 서로 상이하며, 이로 인하여 세균 유래 소포를 사용하는 것은 살아있는 세균을 사용하는 것과는 전혀 상이하거나 현저한 효과를 나타낸다.Bacteria that live symbiotically in our bodies and those that exist in the surrounding environment secrete nanometer-sized vesicles to exchange information such as genes, low-molecular-weight compounds, and proteins with other cells. The mucous membrane forms a physical barrier that does not allow particles larger than 200 nanometers (nm) to pass through, so bacteria that live symbiotically on the mucous membrane cannot pass through the mucous membrane, but bacterial-derived vesicles are relatively free because they are less than 200 nanometers in size. It passes through the epithelial cells through the mucous membrane and is absorbed into our body. In this way, bacterial-derived vesicles are secreted from bacteria, but are different from bacteria in terms of composition, absorption rate in the body, risk of side effects, etc. indicate
국소적으로 분비된 세균 유래 소포는 점막의 상피세포를 통해 흡수되어 국소 염증반응을 유도할 뿐만 아니라, 상피세포를 통과한 소포는 림프관을 통해 전신적으로 흡수되어 각 장기로 분포하고, 분포된 장기에서 대사기능과 면역기능을 조절한다. 예를 들어, 대장균(Eshcherichia coli)와 같은 병원성 그람음성세균에서 유래하는 소포는 병원성 나노 입자로서 국소적으로 대장염이나 식중독 등을 일으키고, 혈관으로 흡수된 경우에는 혈관 내피세포에 흡수되어 염증반응을 유도하여 전신적인 염증반응 및 혈액응고를 촉진시키고, 또한 인슐린이 작용하는 근육세포 등에 흡수되어 인슐린 저항성과 당뇨병 등과 같은 대사질환을 유발한다. 반면, 유익한 세균에서 유래하는 소포는 병원성 소포에 의한 면역기능 및 대사기능 이상을 조절하여 질병을 조절할 수 있다.Bacterial-derived vesicles secreted locally are absorbed through the epithelial cells of the mucous membrane and induce a local inflammatory response. The vesicles that have passed through the epithelial cells are absorbed systemically through the lymphatic vessels and distributed to each organ. Regulates metabolic and immune functions. For example, vesicles derived from pathogenic Gram-negative bacteria such as Escherichia coli are pathogenic nanoparticles that cause colitis or food poisoning locally, and when absorbed into blood vessels, are absorbed by vascular endothelial cells to induce an inflammatory response. It promotes systemic inflammatory response and blood coagulation, and also causes metabolic diseases such as insulin resistance and diabetes by being absorbed into muscle cells where insulin acts. On the other hand, vesicles derived from beneficial bacteria can control diseases by regulating immune and metabolic abnormalities caused by pathogenic vesicles.
락토바실러스 속 세균은 유산을 분비하는 대표적인 유익균으로 알려져 있다. 이중, 락토바실러스 람노수스(Lactobacillus rhamnosus)는 그람양성 간균으로서 혐기성 환경뿐만 아니라 호기성 환경에서도 잘 자라고, 우리 몸에도 공생하는 세균이고, 발효과정에서도 중요한 세균으로 알려져 있다. 락토바실러스 람노수스와 같은 그람양성균(gram-positive bacteria) 유래 소포는 세균 유래 단백질, 대사체 및 핵산 외에도 세균의 세포벽 구성성분인 펩티도글리칸(peptidoglycan)과 리포테이코산(lipoteichoic acid)을 가지고 있다. Bacteria of the genus Lactobacillus are known as representative beneficial bacteria that secrete lactic acid. Among them, Lactobacillus rhamnosus is a Gram-positive bacillus that grows well in an aerobic as well as anaerobic environment, is a bacterium symbiotic with our body, and is known as an important bacterium in the fermentation process. Vesicles derived from gram-positive bacteria, such as Lactobacillus rhamnosus, contain peptidoglycan and lipoteichoic acid, which are components of bacterial cell walls, in addition to bacterial-derived proteins, metabolites, and nucleic acids. .
그러나, 락토바실러스 람노수스에서 분비되는 소포가 면역기능 장애 및 세포 노화 관련 질환의 예방, 또는 치료를 위해 이용된 경우는 없는 실정이다.However, there is no case in which vesicles secreted from Lactobacillus rhamnosus have been used for the prevention or treatment of immune dysfunction and diseases related to cellular aging.
본 발명자들은 상기와 같은 종래의 문제점을 해결하기 위해 예의 연구한 결과, 락토바실러스 람노수스 유래 소포가 면역질환 및 세포 노화 관련 질환의 치료 효과가 있음을 확인하여 본 발명을 완성하였다.As a result of intensive research to solve the above conventional problems, the inventors of the present invention confirmed that Lactobacillus rhamnosus-derived vesicles are effective in treating immune diseases and cellular aging-related diseases, thereby completing the present invention.
이에, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 함유하는, 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방, 개선 또는 치료용 약학적 조성물을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing, improving, or treating at least one selected from the group consisting of immune diseases and cellular aging-related diseases, containing vesicles derived from Lactobacillus rhamnosus as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명자들은 락토바실러스 람노수스 세균을 배양하여 배양액에서 소포를 분리하고, 분리된 소포를 고지방 식이에 의한 세포 노화 관련 질환 마우스에 경구 투여한 결과, 체중 증가가 억제되고, 신기능 및 폐기능이 호전되며, 이러한 작용은 Th17 및 Th2 과민반응의 억제와 관련이 있음을 확인하였다. 또한, 본 발명의 소포가 금식(starvation), 운동 등과 같은 ATP 생성이 잘 일어나지 않는 스트레스(metabolic stress) 상황에서 자가포식(autophagy)을 통해 세포의 항상성을 유도하는 핵심 신호인 AMPK (AMP-activated kinase)의 활성화를 증가시킴을 확인하였다. 또한, 바이러스성 병원 원인 인자인 poly(I:C)에 의해 유도된 면역질환 마우스 모델에 상기 소포를 경구로 투여하였을 때, 인터페론-감마 및 IL-6을 매개로 하는 면역 과민 반응에 의한 전신 염증 반응이 억제되고, 국소적으로는 TNF-α 및 IL-6를 매개로 하는 면역 과민 반응에 의한 폐 염증이 유의하게 억제됨을 확인하였다. 또한, 상기의 바이러스성 원인 인자에 의한 면역 과민 반응은 상기 소포가 NF-κB 신호 및 이의 하부 신호인 inducible NOS(iNOS) 발현을 억제하여 작용하는 것을 확인하였다.In order to achieve the object of the present invention as described above, the present inventors cultured Lactobacillus rhamnosus bacteria to separate vesicles from the culture medium, and orally administered the separated vesicles to mice with cellular aging-related diseases caused by a high-fat diet. It was confirmed that the increase is suppressed, and renal and lung functions are improved, and that these actions are related to suppression of Th17 and Th2 hypersensitivity reactions. In addition, the vesicles of the present invention are AMPK (AMP-activated kinase), a key signal that induces cell homeostasis through autophagy in situations of metabolic stress where ATP generation does not occur, such as starvation and exercise. ) was confirmed to increase the activation. In addition, when the vesicles were orally administered to a mouse model of immune disease induced by poly(I:C), a viral pathogen causative factor, systemic inflammation caused by immune hypersensitivity mediated by interferon-gamma and IL-6 It was confirmed that the reaction was suppressed, and pulmonary inflammation caused by an immune hypersensitivity reaction mediated by TNF-α and IL-6 was significantly suppressed locally. In addition, it was confirmed that the immune hypersensitivity reaction caused by the viral causative factor acts by suppressing the expression of the NF-κB signal and inducible NOS (iNOS), which is a downstream signal thereof.
따라서, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 함유하는, 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방 또는 치료용 약학적 조성물을 제공한다. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating at least one selected from the group consisting of immune diseases and cellular aging-related diseases, containing Lactobacillus rhamnosus-derived vesicles as an active ingredient.
본 발명의 일 구현예에서, 상기 면역질환은 바이러스 감염 질환, 알레르기성 면역질환, 및 자가면역질환으로 이루어진 군으로부터 선택된 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the immune disease may be at least one selected from the group consisting of a viral infection disease, an allergic immune disease, and an autoimmune disease, but is not limited thereto.
본 발명의 다른 구현에에서, 상기 바이러스 감염 질환은 바이러스성 폐렴, 바이러스성 간염, 바이러스성 심장염, 바이러스성 장염, 바이러스성 신장염, 바이러스성 혈전색전증, 대상포진, 및 메니에르병으로 이루어진 군으로부터 선택된 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the viral infectious disease is from the group consisting of viral pneumonia, viral hepatitis, viral carditis, viral enteritis, viral nephritis, viral thromboembolism, herpes zoster, and Meniere's disease It may be one or more selected ones, but is not limited thereto.
본 발명의 또 다른 구현에에서, 상기 자가면역질환은 전신성홍반성낭창, 류마티스관절염, 쇼그렌증후군, 베체트병, 강직성척추염, 및 다발성경화증으로 이루어진 군으로부터 선택된 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the autoimmune disease may be at least one selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Behçet's disease, ankylosing spondylitis, and multiple sclerosis, but is not limited thereto .
본 발명의 또 다른 구현에에서, 상기 알레르기성 면역질환은 아토피피부염, 건선, 알레르기성 결막염, 알레르기 비염, 알레르기 천식, 과민성 폐렴, 식품알레르기, 셀리악병, 과민성 장증후군, 및 아나필락시스로 이루어진 군으로부터 선택된 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the allergic immune disease is selected from the group consisting of atopic dermatitis, psoriasis, allergic conjunctivitis, allergic rhinitis, allergic asthma, hypersensitivity pneumonitis, food allergy, celiac disease, irritable bowel syndrome, and anaphylaxis. It may be one or more, but is not limited thereto.
본 발명의 또 다른 구현에에서, 상기 세포 노화 관련 질환은 협심증, 심근경색, 심근병증, 혈전색전증, 및 뇌졸중으로 이루어진 군으로부터 선택된 하나 이상의 심혈관질환; 알코올성 지방간염, 간경변, 만성담도염, 만성담낭염, 및 만성췌장염으로 이루어진 군으로부터 선택된 하나 이상의 간-담도-췌장질환; 통풍, 골관절염, 골다공증으로 이루어진 군으로부터 선택된 하나 이상의 근골격계질환; 및 알츠하이머병, 파킨슨병, 및 황반변성으로 이루어진 군으로부터 선택된 하나 이상의 신경질환으로 이루어진 군으로부터 선택된 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the cellular senescence-associated disease is at least one cardiovascular disease selected from the group consisting of angina pectoris, myocardial infarction, cardiomyopathy, thromboembolism, and stroke; at least one hepato-biliary-pancreatic disease selected from the group consisting of alcoholic steatohepatitis, cirrhosis, chronic cholangitis, chronic cholecystitis, and chronic pancreatitis; one or more musculoskeletal disorders selected from the group consisting of gout, osteoarthritis, and osteoporosis; And it may be at least one selected from the group consisting of one or more neurological diseases selected from the group consisting of Alzheimer's disease, Parkinson's disease, and macular degeneration, but is not limited thereto.
본 발명의 또 다른 구현에에서, 상기 소포는 평균 직경이 10~1000 nm인 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the vesicles may have an average diameter of 10 to 1000 nm, but are not limited thereto.
본 발명의 또 다른 구현에에서, 상기 소포는 락토바실러스 람노수스 배양액에서 분리되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the vesicles may be isolated from Lactobacillus rhamnosus culture, but are not limited thereto.
본 발명의 또 다른 구현에에서, 상기 소포는 락토바실러스 람노수스를 첨가하여 제조된 식품에서 분리되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the vesicles may be separated from food prepared by adding Lactobacillus rhamnosus, but is not limited thereto.
본 발명의 또 다른 구현에에서, 상기 소포는 락토바실러스 람노수스에서 자연적으로 또는 인공적으로 분비되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the vesicles may be naturally or artificially secreted from Lactobacillus rhamnosus, but are not limited thereto.
또한, 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는, 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방 또는 개선용 식품 조성물을 제공한다.In addition, a food composition for preventing or improving at least one selected from the group consisting of immune diseases and cellular aging-related diseases, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient, is provided.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는, 노화 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는, 노화 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는, 노화 예방 또는 개선용 화장료 조성물을 제공한다.In addition, the present invention provides a cosmetic composition for preventing or improving aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는 조성물을 개체에 투여하는 단계를 포함하는, 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방 또는 치료방법을 제공한다. In addition, the present invention provides at least one preventive or therapeutic method selected from the group consisting of immune diseases and cellular senescence-related diseases, comprising administering to a subject a composition containing Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는 조성물의 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방 또는 치료용도를 제공한다. In addition, the present invention provides a preventive or therapeutic use of at least one selected from the group consisting of immune diseases and cellular senescence-related diseases of a composition comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 치료용 약제 제조를 위한 락토바실러스 람노수스 유래 소포의 용도를 제공한다. In addition, the present invention provides a use of Lactobacillus rhamnosus-derived vesicles for the manufacture of at least one therapeutic agent selected from the group consisting of immune diseases and cellular senescence-related diseases.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는 조성물을 개체에 투여하는 단계를 포함하는, 노화의 예방 또는 치료방법을 제공한다. In addition, the present invention provides a method for preventing or treating aging, comprising administering to a subject a composition containing Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는 조성물의 노화의 예방 또는 치료용도를 제공한다. In addition, the present invention provides a composition containing Lactobacillus rhamnosus-derived vesicles as an active ingredient for preventing or treating aging.
또한, 본 발명은 노화 치료용 약제 제조를 위한 락토바실러스 람노수스 유래 소포의 용도를 제공한다. In addition, the present invention provides the use of vesicles derived from Lactobacillus rhamnosus for the manufacture of a drug for the treatment of aging.
본 발명에 따른 락토바실러스 람노수스 세균 유래 소포를 고지방 식이에 의한 세포 노화 관련 질환 마우스 모델에 경구 투여 시 체중 증가가 억제되었고, 신기능 및 폐기능이 호전됨을 확인하였다. 또한, ATP 생성이 잘 일어나지 않는 에너지 대사 스트레스 상황에서 자가포식을 통해 세포의 항상성을 유도하는 핵심 신호인 AMPK를 상기 소포가 활성화시킴을 확인하였다. It was confirmed that when the Lactobacillus rhamnosus bacterium-derived vesicles according to the present invention were orally administered to a mouse model of a cellular senescence-related disease by a high-fat diet, weight gain was suppressed and renal and lung functions improved. In addition, it was confirmed that the vesicle activates AMPK, a key signal that induces cell homeostasis through autophagy in an energy metabolism stress situation where ATP production does not occur well.
이에 더하여, 바이러스성 병원성 인자인 poly(I:C)에 의해 유도된 면역기능 장애 관련 질환 마우스 모델에 상기 소포를 경구로 투여하였을 때, 면역 과민 반응에 의한 전신적인 염증반응이 억제되었고, 국소적으로도 바이러스성 원인 인자에 의한 면역 과민 반응에 의한 폐염증이 유의하게 억제되었다. 또한, 상기 바이러스성 원인 인자에 의한 면역 과민 반응은 상기 소포가 NF-κB 신호 및 이의 하부 신호인 iNOS 발현을 억제하여 작용하는 것으로 확인되었다. In addition, when the vesicles were orally administered to a mouse model of immune dysfunction-related diseases induced by the viral pathogenic factor poly(I:C), the systemic inflammatory response caused by the immune hypersensitivity reaction was suppressed, and the local Pulmonary inflammation caused by immune hypersensitivity reaction caused by viral causative factors was also significantly suppressed. In addition, it was confirmed that the immune hypersensitivity reaction by the viral causative factor acts by the vesicles suppressing the expression of the NF-κB signal and iNOS, a downstream signal thereof.
따라서, 본 발명에 따른 락토바실러스 람노수스 유래 소포는 바이러스 감염 질환, 알레르기성 면역질환, 및 자가면역질환을 포함하는 면역질환, 및 세포 노화 관련 질환을 예방, 증상 개선, 또는 치료하기 위한 의약품 또는 건강기능식품 등의 개발에 유용하게 이용될 수 있을 것으로 기대된다. Therefore, the Lactobacillus rhamnosus-derived vesicles according to the present invention are pharmaceuticals or health products for preventing, improving symptoms, or treating immune diseases, including viral infections, allergic immune diseases, and autoimmune diseases, and cellular aging-related diseases. It is expected that it can be usefully used in the development of functional foods.
도 1은 고지방 식이에 의해 유도된 세포 노화 관련 질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 세포 노화 관련 질환에 대한 치료효과를 평가하기 위한 실험 프로토콜이다.
도 2는 고지방 식이에 의한 세포 노화 관련 질환 마우스 모델에서 락토바실러스 람노수스 유래 소포를 경구로 투여하여 체중 감소 효과를 평가한 결과이다.
도 3a 및 도 3b는 고지방 식이에 의한 세포 노화 관련 질환 마우스 모델에서 락토바실러스 람노수스 유래 소포를 경구로 투여하여 혈청 내 신장기능검사(BUN, 크레아티닌) 수치를 확인한 결과이다.
도 4는 고지방 식이에 의한 세포 노화 관련 질환 마우스 모델에서 락토바실러스 람노수스 유래 소포를 경구로 투여하여 폐기능의 변화를 관찰한 결과이다.
도 5a 및 도 5b는 고지방 식이에 의한 세포 노화 관련 질환 마우스 모델에서 락토바실러스 람노수스 유래 소포를 경구로 투여하여 기도세척액 내 Th17 및 Th2 관련 사이토카인 수치를 확인한 결과이다.
도 6은 락토바실러스 람노수스 유래 소포가 근육세포 내에서 AMPK 활성화를 통해 세포 항상성 유지에 미치는 영향을 평가한 결과이다.
도 7은 바이러스 감염에 의한 면역질환을 모사하는 원인 인자인 poly(I:C)를 비강으로 투여하여 유도한 면역기능 장애 관련 질환 마우스에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 면역질환에 대한 치료 효과를 평가하기 위한 실험 프로토콜이다.
도 8a 및 도 8b는 poly(I:C)를 비강으로 투여하여 유도한 면역질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 기도세척액 내 총 염증세포수 (a) 및 대식세포 및 림프구 수 (b) 변화를 관찰한 결과이다.
도 9a 및 도 9b는 poly(I:C)를 비강으로 투여하여 유도한 면역질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 H&E 염색을 통한 폐 조직학적 변화를 관찰한 결과이다.
도 10은 poly(I:C)를 비강으로 투여하여 유도한 면역질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 혈중 염증지표인 hs-CRP 수치를 확인한 결과이다.
도 11a 및 도 11b는 poly(I:C)를 비강으로 투여하여 유도한 면역질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 기도세척액 내 염증성 사이토카인(TNF-α, IL-6) 수치를 확인한 결과이다.
도 12a 및 도 12b는 poly(I:C)를 비강으로 투여하여 유도한 면역질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여한 후 얻은 비장 T세포에서 항-CD3 및 항-CD28 항체로 T세포를 자극한 후, T세포에서 분비되는 염증성 사이토카인(IFN-γ, IL-6) 수치를 확인한 결과이다.
도 13은 poly(I:C)를 비강으로 투여하여 유도한 면역질환 마우스 모델에 락토바실러스 람노수스 유래 소포를 경구로 투여한 후 얻은 폐 조직에서 NF-κB 및 iNOS의 발현을 확인한 결과이다.
도 14는 면역질환 및 대사질환에 대한 락토바실러스 람노수스의 작용 기전을 분자생물학적 수준에서 요약한 그림이다.1 is an experimental protocol for evaluating the therapeutic effect on cellular senescence-related diseases by orally administering Lactobacillus rhamnosus-derived vesicles to a mouse model of cellular senescence-related diseases induced by a high-fat diet.
Figure 2 is a result of evaluating the weight loss effect by orally administering Lactobacillus rhamnosus-derived vesicles in a mouse model of cellular senescence-related diseases caused by a high-fat diet.
3a and 3b are results of confirming the level of renal function test (BUN, creatinine) in serum by orally administering Lactobacillus rhamnosus-derived vesicles in a mouse model of cellular senescence-related diseases caused by a high-fat diet.
4 is a result of observing changes in lung function by orally administering Lactobacillus rhamnosus-derived vesicles in a mouse model of cellular senescence-related diseases caused by a high-fat diet.
5a and 5b show the results of confirming the levels of Th17 and Th2-related cytokines in airway lavage fluid by orally administering Lactobacillus rhamnosus-derived vesicles in a mouse model of cellular senescence-related diseases caused by a high-fat diet.
6 is a result of evaluating the effect of Lactobacillus rhamnosus-derived vesicles on maintaining cell homeostasis through AMPK activation in muscle cells.
Figure 7 is a causative factor that mimics immune diseases caused by viral infection poly (I: C) induced by intranasal administration of immune dysfunction-related disease mice by orally administering Lactobacillus rhamnosus-derived vesicles to immunological diseases It is an experimental protocol to evaluate the treatment effect.
8a and 8b show the total number of inflammatory cells (a) and macrophages and lymphocytes in airway lavage fluid by orally administering Lactobacillus rhamnosus-derived vesicles to a mouse model of immune disease induced by intranasal administration of poly(I:C). This is the result of observing the change in number (b).
9a and 9b show the results of observing lung histological changes through H&E staining after orally administering Lactobacillus rhamnosus-derived vesicles to an immune disease mouse model induced by nasally administering poly(I:C).
10 is a result of confirming the level of hs-CRP, an inflammatory marker in the blood, by orally administering Lactobacillus rhamnosus-derived vesicles to a mouse model of immune disease induced by intranasal administration of poly(I:C).
11a and 11b show inflammatory cytokines (TNF-α, IL-6) in airway lavage fluid by orally administering Lactobacillus rhamnosus-derived vesicles to a mouse model of immune disease induced by intranasal administration of poly(I:C). This is the result of checking the numbers.
12a and 12b show anti-CD3 and anti-CD28 antibodies in splenic T cells obtained after orally administering Lactobacillus rhamnosus-derived vesicles to a mouse model of immune disease induced by intranasal administration of poly(I:C). This is the result of confirming the levels of inflammatory cytokines (IFN-γ, IL-6) secreted from T cells after stimulating T cells.
13 shows the results of confirming the expression of NF-κB and iNOS in lung tissue obtained after orally administering Lactobacillus rhamnosus-derived vesicles to a mouse model of immune disease induced by nasal administration of poly(I:C).
14 is a diagram summarizing the mechanism of action of Lactobacillus rhamnosus on immune and metabolic diseases at the molecular biological level.
본 발명은 락토바실러스 람노수스 유래 소포 및 이의 용도에 관한 것이다. The present invention relates to vesicles derived from Lactobacillus rhamnosus and uses thereof.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명자들은 고지방 식이에 의한 세포 노화를 유도한 만성질환 마우스에 락토바실러스 람노수스 세균을 배양하여 배양액에서 소포를 분리하여 경구로 투여하였을 때, 체중 증가가 억제되었고, 신기능 및 폐기능이 호전됨을 확인하였으며, 이러한 작용은 Th17 및 Th2 세포에 의한 면역 과민 반응의 억제와 관련이 있음을 확인하였다(실시예 2 및 3 참조).The present inventors cultured Lactobacillus rhamnosus bacteria in mice with chronic diseases in which cellular senescence was induced by a high-fat diet, separated vesicles from the culture medium, and orally administered it. It was confirmed that weight gain was suppressed and renal and lung functions improved. It was confirmed that this action was related to suppression of immune hypersensitivity by Th17 and Th2 cells (see Examples 2 and 3).
또한, 본 발명의 소포가 ATP 생성이 잘 일어나지 않는 에너지 대사 스트레스 상황에서 자가포식을 통해 세포의 항상성을 유도하는 핵심 신호인 AMPK를 활성화시킴을 확인하였다(실시예 4 참조). In addition, it was confirmed that the vesicle of the present invention activates AMPK, a key signal that induces cell homeostasis through autophagy in an energy metabolism stress situation where ATP production does not occur well (see Example 4).
또한, 바이러스성 병원성 인자인 poly(I:C)에 의해 유도된 면역질환 마우스 모델에 상기 소포를 경구로 투여하였을 때, 전신적인 염증 반응이 억제되었고, 국소적으로도 바이러스성 원인 인자에 의한 폐 염증이 유의하게 억제되었음을 확인하였다(실시예 5 및 6 참조). In addition, when the vesicles were orally administered to a mouse model of immune disease induced by the viral pathogenic factor poly(I:C), the systemic inflammatory response was suppressed, and the lungs caused locally by the viral causative factor. It was confirmed that inflammation was significantly inhibited (see Examples 5 and 6).
또한, 상기 바이러스성 원인 인자에 의한 면역 과민 반응은 상기 소포가 NF-κB 신호 및 이의 하부 신호인 iNOS 발현을 억제하여 작용함을 확인한 바(실시예 7 참조), 본 발명에 따른 락토바실러스 람노수스 세균 유래 소포는 면역질환 및 세포 노화 관련 신경질환에 대한 예방용 혹은 치료용 조성물로 유용하게 이용할 수 있음을 확인하였다.In addition, it was confirmed that the immune hypersensitivity reaction caused by the viral causative factor acts by suppressing the expression of the NF-κB signal and iNOS, a lower signal thereof (see Example 7), Lactobacillus rhamnosus according to the present invention It was confirmed that the bacterial-derived vesicles can be usefully used as a preventive or therapeutic composition for immune diseases and neurological diseases related to cell aging.
이에, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 함유하는, 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating at least one selected from the group consisting of immune diseases and cellular aging-related diseases, containing Lactobacillus rhamnosus-derived vesicles as an active ingredient.
본 발명에서 사용되는 용어, “세포외소포 또는 소포(extracellular vesicle)”는 다양한 세균에서 분비되는 나노 크기의 지질 막으로 된 구조물을 의미하며, 본 발명에서는 락토바실러스 람노수스로부터 자연적으로 분비되거나, 인공적으로 생산된 막으로 된 모든 구조물을 총칭한다. As used herein, the term “extracellular vesicle” refers to a structure made of nano-sized lipid membrane secreted by various bacteria, and in the present invention, naturally secreted from Lactobacillus rhamnosus or artificially It is a generic term for all structures made of membranes produced by
본 발명에서는, 상기 소포는 락토바실러스 람노수스로부터 자연적으로 분비되거나, 인공적으로 생산된 막으로 된 모든 구조물을 총칭한다. In the present invention, the vesicle is a generic term for all membrane structures secreted naturally or artificially produced from Lactobacillus rhamnosus.
상기 소포는 락토바실러스 람노수스 배양과정에서 열처리, 고압처리 하거나, 상기 세균 배양액을 원심분리, 초고속 원심분리, 고압처리, 압출, 초음파분해, 세포 용해, 균질화, 냉동-해동, 전기천공, 기계적 분해, 화학물질 처리, 필터에 의한 여과, 겔 여과 크로마토그래피, 프리-플로우 전기영동, 및 모세관 전기영동으로 이루어진 군에서 선택된 하나 이상의 방법을 사용하여 분리할 수 있다. 또한, 불순물의 제거를 위한 세척, 수득된 소포의 농축 등의 과정을 추가로 포함할 수 있다. The vesicles are subjected to heat treatment or high-pressure treatment in the process of culturing Lactobacillus rhamnosus, or centrifugation, ultra-high-speed centrifugation, high-pressure treatment, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical degradation, Separation may be performed using one or more methods selected from the group consisting of chemical treatment, filtration through a filter, gel filtration chromatography, free-flow electrophoresis, and capillary electrophoresis. In addition, processes such as washing to remove impurities and concentration of the obtained vesicles may be further included.
본 발명의 상기 락토바실러스 람노수스의 배양액 또는 발효식품에서 소포를 분리하는 방법은 소포를 포함한다면, 특별히 제한되지 않는다. 예컨대 원심분리, 초고속 원심분리, 필터에 의한 여과, 겔 여과 크로마토그래피, 프리-플로우 전기영동, 또는 모세관 전기영동 등의 방법, 및 이들의 조합을 이용하여 소포를 분리할 수 있으며, 또한 불순물의 제거를 위한 세척, 수득된 소포의 농축 등의 과정을 추가로 포함할 수 있다. The method of separating vesicles from the culture broth or fermented food of Lactobacillus rhamnosus of the present invention is not particularly limited as long as vesicles are included. For example, vesicles can be separated using methods such as centrifugation, ultra-high-speed centrifugation, filter filtration, gel filtration chromatography, free-flow electrophoresis, or capillary electrophoresis, and combinations thereof, and also removal of impurities. It may further include a process of washing for, concentration of the obtained vesicles, and the like.
본 발명의 상기 소포는 락토바실러스 람노수스의 배양액 또는 락토바실러스 람노수스를 첨가하여 제조된 식품에서 분리될 수 있으며, 락토바실러스 람노수스로부터 자연적으로 또는 인공적으로 분비된 것일 수 있으나, 이에 제한되는 것은 아니다. The vesicles of the present invention may be isolated from a culture medium of Lactobacillus rhamnosus or a food prepared by adding Lactobacillus rhamnosus, and may be secreted naturally or artificially from Lactobacillus rhamnosus, but is not limited thereto. .
본 발명에서 상기 방법에 의하여 분리된 소포는 평균 직경이 10~1000 nm, 10~900 nm, 10~800 nm, 10~700 nm, 10~600 nm, 10~500 nm, 10~400 nm, 10~300 nm, 10~200 nm, 10~100 nm, 10~90 nm, 10~80 nm, 10~70 nm, 10~60 nm, 10~50 nm, 10~40 nm, 또는 20~40 nm 일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the vesicles isolated by the above method have an average diameter of 10-1000 nm, 10-900 nm, 10-800 nm, 10-700 nm, 10-600 nm, 10-500 nm, 10-400 nm, 10 ~300 nm, 10-200 nm, 10-100 nm, 10-90 nm, 10-80 nm, 10-70 nm, 10-60 nm, 10-50 nm, 10-40 nm, or 20-40 nm It may be, but is not limited thereto.
본 발명에서 사용되는 용어, “면역 질환 (immune disease)”이란, 생체 내에서의 면역기능 장애에 의해 발생하는 질환을 총칭한다. 일반적으로 면역 질환은 병원성 원인 인자에 의해 염증이 발생하고, 이의 결과로 세포사멸 및 염증성 매개체에 의한 염증세포 침윤이 유도된다. 또한, 본 발명의“면역기능 장애 관련 질환(immune dysfunction related disease) 또는 면역질환(immune disease)”이란, 외부 인자 또는 내부 인자에 의한 면역 과민 반응을 특징으로 하는 면역기능 장애에 의해 발생하는 질환을 총칭한다. 일반적으로 바이러스, 알레르겐과 같은 외부 인자에 대한 과민반응을 특징으로 하는 면역기능 장애에 의해 바이러스 감염 질환 및 알레르기성 면역질환이 발생하고, 자가 항원과 같은 내부 원인 인자에 대한 면역기능 장애에 의해 자가면역질환이 발생한다. 상기 면역기능 장애 관련 질환 또는 면역질환으로는 바이러스 감염 질환, 알레르기성 면역질환, 및 자가면역질환 등이 있다.As used herein, the term "immune disease" refers to diseases caused by immune dysfunction in vivo. In general, immune diseases cause inflammation by pathogenic factors, and as a result, apoptosis and inflammatory cell infiltration by inflammatory mediators are induced. In addition, the term "immune dysfunction related disease or immune disease" of the present invention refers to a disease caused by an immune dysfunction characterized by an immune hypersensitivity reaction caused by an external factor or an internal factor. collectively In general, viral infection diseases and allergic immune diseases occur due to immune dysfunction characterized by hypersensitivity to external factors such as viruses and allergens, and autoimmunity is caused by immune dysfunction against internal causative factors such as self antigens. disease occurs Examples of the immune dysfunction-related diseases or immune diseases include viral infections, allergic immune diseases, and autoimmune diseases.
본 발명에서, 상기 바이러스 감염 질환은 바이러스에 의한 폐렴, 폐결핵, 결핵, 감기, 인플루엔자, 기도 감염, 비염, 비인두염, 중이염, 기관지염, 임파선염, 이하선염, 림프절염, 구순염, 구내염, 관절염, 근육염, 피부염, 혈관염, 치은염, 치근막염, 각막염, 결막염, 창상 감염, 복막염, 간염, 골수염, 봉소염, 수막염, 뇌염, 뇌농양, 뇌척수염, 뇌막염, 골수염, 신장염, 심장염, 심내막염, 장염, 위염, 식도염, 십이지장염, 대장염, 요로염, 방광염, 질염, 자궁경부염, 난관염, 감염성 홍반, 세균성 이질, 농양 및 궤양, 균혈증, 설사, 이질, 위장염, 위장관염, 비뇨생식기 농양, 개방성 창상 또는 상처의 감염, 화농성 염증, 농양, 종기, 농피증, 농가진, 모낭염, 봉소염, 수술 후 상처 감염, 피부열상증후군, 피부화상증후군, 혈전성 혈소판 감소증, 용혈성 요독 증후군, 신부전증, 신우신염, 사구체신염, 신경계 농양, 중이염, 부비동염, 인두염, 편도선염, 유양돌기염, 연조직염, 치성 감염, 누낭염, 늑막염, 복부 농양, 간농양, 담낭염, 비장 농양, 심낭염, 심근염, 태반염, 양수염, 유방염,패혈성 쇼크(septic shock), 전신성 염증반응 증후군(systemic inflammatory response syndrome, SIRS), 다장기 기능장애 증후군(multiple organ dysfunction syndrome, MODS), 혈전색전증, 대상포진, 및 메니에르병으로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the viral infectious disease is pneumonia caused by a virus, pulmonary tuberculosis, tuberculosis, cold, influenza, airway infection, rhinitis, nasopharyngitis, otitis media, bronchitis, lymphadenitis, mumps, lymphadenitis, cheilitis, stomatitis, arthritis, myositis, dermatitis , vasculitis, gingivitis, periodontitis, keratitis, conjunctivitis, wound infection, peritonitis, hepatitis, osteomyelitis, cellulitis, meningitis, encephalitis, brain abscess, encephalomyelitis, meningitis, osteomyelitis, nephritis, carditis, endocarditis, enteritis, gastritis, esophagitis, duodenitis , colitis, urinary tractitis, cystitis, vaginitis, cervicitis, salpingitis, erythema infectious, dysentery, abscesses and ulcers, bacteremia, diarrhea, dysentery, gastroenteritis, gastroenteritis, genitourinary abscess, infection of open wounds or wounds, purulent inflammation, Abscess, abscess, pyoderma, impetigo, folliculitis, cellulitis, postoperative wound infection, skin laceration syndrome, skin burn syndrome, thrombotic thrombocytopenia, hemolytic uremic syndrome, renal failure, pyelonephritis, glomerulonephritis, nervous system abscess, otitis media, sinusitis, pharyngitis , tonsillitis, mastoiditis, cellulitis, odontogenic infection, dacryocystitis, pleurisy, abdominal abscess, liver abscess, cholecystitis, splenic abscess, pericarditis, myocarditis, placenta, amniotitis, mastitis, septic shock, systemic inflammation It may be one or more selected from the group consisting of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thromboembolism, herpes zoster, and Meniere's disease, but is not limited thereto. .
본 발명에서, 상기 자가면역질환은 패혈증, 동맥경화, 균혈증, 전신염증반응증후군, 다장기기능부전, 골다공증, 치주염, 전신성 홍반성 루푸스, 류마티스성 관절염, 골관절염, 유년형 만성 관절염, 척추관절증, 다발성 경화증, 전신성 경화증, 특발성 염증성 근장애, 쇼그렌 증후군(Sjogren's syndrome), 전신성 맥관염, 유육종증(sarcoidosis), 자가면역 용혈성 빈혈, 자가면역성 혈소판감소증, 갑상선염, 진성당뇨병, 면역매개성 신장질환, 중추신경계 또는 말초신경계의 탈수초 질환, 특발성 탈수초 다발성 신경염, 길랑-바레 증후군(Guillain-Barre syndrome), 만성 염증성 탈수초 다발성 신경염, 간담즙성 질환, 감염성 또는 자가면역성 만성 활성 간염, 원발성 담즙성 간경변, 육아종성 간염, 경화성 담관염, 염증성 장질환(inflammatory bowel disease, IBD), 궤양성 대장염(ulcerative colitis), 크론병(Crohn's disease), 과민성 대장 증후군(irritable bowel syndrome), 글루텐(gluten) 민감성 장질환, 휘플병(Whipple's disease), 자가면역성 또는 면역매개성 피부질환, 수포성 피부질환 다형홍반, 접촉성 피부염, 건선, 알레르기성 면역질환, 천식, 알레르기성 비염, 아토피성 피부염, 음식물 과민증, 여드름, 두드러기, 폐의 면역질환, 호산구성 폐렴, 특발성 폐 섬유증, 과민성 폐렴으로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the autoimmune disease is sepsis, arteriosclerosis, bacteremia, systemic inflammatory response syndrome, multiple organ dysfunction, osteoporosis, periodontitis, systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, spondyloarthrosis, multiple Sclerosis, systemic sclerosis, idiopathic inflammatory myopathy, Sjogren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus, immune-mediated renal disease, central nervous system or Demyelinating disease of the peripheral nervous system, idiopathic demyelinating polyneuritis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuritis, hepatobiliary disease, infectious or autoimmune chronic active hepatitis, primary biliary cirrhosis, granulation Hepatitis, sclerosing cholangitis, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, irritable bowel syndrome, gluten sensitive bowel disease, Whipple's disease, autoimmune or immune-mediated skin disease, bullous skin disease erythema multiforme, contact dermatitis, psoriasis, allergic immune disease, asthma, allergic rhinitis, atopic dermatitis, food intolerance, acne, urticaria, It may be at least one selected from the group consisting of pulmonary immune disease, eosinophilic pneumonia, idiopathic pulmonary fibrosis, and hypersensitivity pneumonitis, but is not limited thereto.
본 발명에서, 상기 알레르기성 면역질환은 아토피피부염, 알레르기성 결막염, 알레르기성 비염, 알레르기 천식, 과민성 폐렴, 식품알레르기, 셀리악병, 과민성대장증후군, 및 아나필락시스로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the allergic immune disease may be one or more selected from the group consisting of atopic dermatitis, allergic conjunctivitis, allergic rhinitis, allergic asthma, hypersensitivity pneumonitis, food allergy, celiac disease, irritable bowel syndrome, and anaphylaxis. It is not limited.
본 발명에서 사용되는 용어, “세포 노화 관련 질환(cellular aging related disease)”이란, 영양 과잉으로 생체 내에서의 에너지 대사 스트레스에 의해 세포 노화가 촉진되어 발생하는 질환을 총칭한다. 상기 세포 노화 관련 질환은 고혈압, 동맥경화, 협심증, 고지혈증, 심부전, 심근경색, 심근병증, 혈전색전증, 및 뇌졸중으로 이루어진 군으로부터 선택된 하나 이상의 심혈관질환;As used in the present invention, the term "cellular aging related disease" is a general term for diseases caused by accelerated cellular aging due to energy metabolism stress in vivo due to nutrient excess. The cellular aging-related disease is one or more cardiovascular diseases selected from the group consisting of hypertension, arteriosclerosis, angina pectoris, hyperlipidemia, heart failure, myocardial infarction, cardiomyopathy, thromboembolism, and stroke;
비알코올성 지방간염(non-alcoholic steatohepatitis, NASH), 알코올성 지방간염(alcoholic steatohepatitis), 간경변(liver cirrhosis), 담도염(cholangitis), 담낭염(cholecystitis), 및 췌장염(pancreatitis)으로 이루어진 군으로부터 선택된 하나 이상의 간-담도-췌장질환;At least one liver selected from the group consisting of non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, liver cirrhosis, cholangitis, cholecystitis, and pancreatitis -biliary-pancreatic disease;
사구체신염(glomerulonephritis), 및 만성신증(chronic nephropathy)으로 이루어진 군으로부터 선택된 하나 이상의 신장질환; one or more kidney diseases selected from the group consisting of glomerulonephritis and chronic nephropathy;
긴장감퇴증(atony), 근위축증(muscular artrophy), 근이영양증(muscular dystrophy), 근무력증, 악액질(cachexia), 통풍(Gout), 근감소증(sarcopenia), 골다공증(osteoporosis), 파제트병(Paget's disease), 류마티스관절염(rheumatoid arthritis), 및 골관절염(osteoarthritis)으로 이루어진 군으로부터 선택된 하나 이상의 근골격계질환;Atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, Gout, sarcopenia, osteoporosis, Paget's disease, one or more musculoskeletal disorders selected from the group consisting of rheumatoid arthritis and osteoarthritis;
경도인지장애 (mild cognitive impairment), 치매 (dementia), 알츠하이머병 (Alzheimer’s disease), 파킨슨병 (Parkinson’s disease), 헌팅톤병 (Huntington’s disease), 루게릭병 (Amyotrophic lateral sclerosis. ALS), 바튼병 (Batten disease), 컨스-세이어증후군 (Kearns-Sayre syndrome, KSS), 만성 진행성 외안근마비 (chronic progressive external ophthalmoplegia, CPEO), 멜라스증후군 (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, MELAS), MERRF증후군 (myoclonic epilepsy with ragged-red fibers, MERRF), NARP증후군 (neurogenic weakness with ataxia and retinitis pigmentosa, NARP), 레이증후군 (Leigh syndrome, LS), MIRAS증후군 (mitochondrial recessive ataxia syndrome), 루이소체치매(Dementia with Lewy Bodies, DLB), 다발성경색치매(Multi-Infarct Dementia, MID), 전두측두엽변성증(frontotemporal lobar degeneration, FTLD), 픽병(Pick's disease), 피질기조퇴행(Corticobasal degeneration, CBD), 퇴행성핵상마비(progressive supranuclear palsy, PSP), 황반변성(age-related macular degeneration, AMD), 후각장애(dysosmia), 청각장애(deafness), 및 당뇨병성망막증(diabetic retinopathy)으로 이루어진 군으로부터 선택된 하나 이상의 신경질환 등이 있다.Mild cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), Batten disease ), Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), MERRF syndrome ( myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), Leigh syndrome (LS), mitochondrial recessive ataxia syndrome (MIRAS syndrome), Dementia with Lewy Bodies (DLB), Multi-Infarct Dementia (MID), frontotemporal lobar degeneration (FTLD), Pick's disease, Corticobasal degeneration (CBD), progressive supranuclear palsy palsy (PSP), age-related macular degeneration (AMD), dysosmia, deafness, and at least one neurological disease selected from the group consisting of diabetic retinopathy.
본 발명의 조성물 내의 상기 소포의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 또는 0.001 내지 50중량%일 수 있으나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다.The content of the vesicles in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progress of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight, or 0.001 to 50% by weight based on the total weight of the composition. It may, but is not limited thereto. The content ratio is a value based on the dry amount after removing the solvent.
본 발명에 따른 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 상기 부형제는 예를 들어, 희석제, 결합제, 붕해제, 활택제, 흡착제, 보습제, 필름-코팅 물질, 및 제어방출첨가제로 이루어진 군으로부터 선택된 하나 이상일 수 있다. The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.
본 발명에 따른 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 서방형 과립제, 장용과립제, 액제, 점안제, 엘실릭제, 유제, 현탁액제, 주정제, 트로키제, 방향수제, 리모나아데제, 정제, 서방형정제, 장용정제, 설하정, 경질캅셀제, 연질캅셀제, 서방캅셀제, 장용캅셀제, 환제, 틴크제, 연조엑스제, 건조엑스제, 유동엑스제, 주사제, 캡슐제, 관류액, 경고제, 로션제, 파스타제, 분무제, 흡입제, 패취제, 멸균주사용액, 또는에어로졸 등의 외용제 등의 형태로 제형화하여 사용될 수 있으며, 상기 외용제는 크림, 젤, 패치, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 등의 제형을 가질 수 있다. The pharmaceutical compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, and limonadese, respectively, according to conventional methods. , tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusate, It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta agents, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external agents are creams, gels, patches, sprays, ointments, and warning agents. , lotion, liniment, pasta, or cataplasma may have formulations such as the like.
본 발명에 따른 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
본 발명에 따른 정제, 산제, 과립제, 캡슐제, 환제, 트로키제의 첨가제로 옥수수전분, 감자전분, 밀전분, 유당, 백당, 포도당, 과당, 디-만니톨, 침강탄산칼슘, 합성규산알루미늄, 인산일수소칼슘, 황산칼슘, 염화나트륨, 탄산수소나트륨, 정제 라놀린, 미결정셀룰로오스, 덱스트린, 알긴산나트륨, 메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 카올린, 요소, 콜로이드성실리카겔, 히드록시프로필스타치, 히드록시프로필메칠셀룰로오스(HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, 프로필렌글리콜, 카제인, 젖산칼슘, 프리모젤 등 부형제; 젤라틴, 아라비아고무, 에탄올, 한천가루, 초산프탈산셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스칼슘, 포도당, 정제수, 카제인나트륨, 글리세린, 스테아린산, 카르복시메칠셀룰로오스나트륨, 메칠셀룰로오스나트륨, 메칠셀룰로오스, 미결정셀룰로오스, 덱스트린, 히드록시셀룰로오스, 히드록시프로필스타치, 히드록시메칠셀룰로오스, 정제쉘락, 전분호, 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 폴리비닐알코올, 폴리비닐피롤리돈 등의 결합제가 사용될 수 있으며, 히드록시프로필메칠셀룰로오스, 옥수수전분, 한천가루, 메칠셀룰로오스, 벤토나이트, 히드록시프로필스타치, 카르복시메칠셀룰로오스나트륨, 알긴산나트륨, 카르복시메칠셀룰로오스칼슘, 구연산칼슘, 라우릴황산나트륨, 무수규산, 1-히드록시프로필셀룰로오스, 덱스트란, 이온교환수지, 초산폴리비닐, 포름알데히드처리 카제인 및 젤라틴, 알긴산, 아밀로오스, 구아르고무(Guar gum), 중조, 폴리비닐피롤리돈, 인산칼슘, 겔화전분, 아라비아고무, 아밀로펙틴, 펙틴, 폴리인산나트륨, 에칠셀룰로오스, 백당, 규산마그네슘알루미늄, 디-소르비톨액, 경질무수규산 등 붕해제; 스테아린산칼슘, 스테아린산마그네슘, 스테아린산, 수소화식물유(Hydrogenated vegetable oil), 탈크, 석송자, 카올린, 바셀린, 스테아린산나트륨, 카카오지, 살리실산나트륨, 살리실산마그네슘, 폴리에칠렌글리콜 4000, PEG 6000, 유동파라핀, 수소첨가대두유(Lubri wax), 스테아린산알루미늄, 스테아린산아연, 라우릴황산나트륨, 산화마그네슘, 마크로골(Macrogol), 합성규산알루미늄, 무수규산, 고급지방산, 고급알코올, 실리콘유, 파라핀유, 폴리에칠렌글리콜지방산에테르, 전분, 염화나트륨, 초산나트륨, 올레인산나트륨, dl-로이신, 경질무수규산 등의 활택제;가 사용될 수 있다.Corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, phosphoric acid as additives for tablets, powders, granules, capsules, pills, and troches according to the present invention Calcium monohydrogen, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethyl Excipients such as cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose phthalate acetate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin Binders such as hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, purified shellac, starch arc, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone may be used, Hydroxypropyl Methyl Cellulose, Corn Starch, Agar Powder, Methyl Cellulose, Bentonite, Hydroxypropyl Starch, Sodium Carboxymethyl Cellulose, Sodium Alginate, Calcium Carboxymethyl Cellulose, Calcium Citrate, Sodium Lauryl Sulfate, Silicic Anhydride, 1-Hydroxy Propyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopod, kaolin, vaseline, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil ( Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acid, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride , lubricants such as sodium acetate, sodium oleate, dl-leucine, light anhydrous silicic acid; may be used.
본 발명에 따른 액제의 첨가제로는 물, 묽은 염산, 묽은 황산, 구연산나트륨, 모노스테아린산슈크로스류, 폴리옥시에칠렌소르비톨지방산에스텔류(트윈에스텔), 폴리옥시에칠렌모노알킬에텔류, 라놀린에텔류, 라놀린에스텔류, 초산, 염산, 암모니아수, 탄산암모늄, 수산화칼륨, 수산화나트륨, 프롤아민, 폴리비닐피롤리돈, 에칠셀룰로오스, 카르복시메칠셀룰로오스나트륨 등이 사용될 수 있다.Additives for the liquid formulation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like may be used.
본 발명에 따른 시럽제에는 백당의 용액, 다른 당류 혹은 감미제 등이 사용될 수 있으며, 필요에 따라 방향제, 착색제, 보존제, 안정제, 현탁화제, 유화제, 점조제 등이 사용될 수 있다.In the syrup according to the present invention, a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.
본 발명에 따른 유제에는 정제수가 사용될 수 있으며, 필요에 따라 유화제, 보존제, 안정제, 방향제 등이 사용될 수 있다.Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.
본 발명에 따른 현탁제에는 아카시아, 트라가칸타, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 미결정셀룰로오스, 알긴산나트륨, 히드록시프로필메칠셀룰로오스(HPMC), HPMC 1828, HPMC 2906, HPMC 2910 등 현탁화제가 사용될 수 있으며, 필요에 따라 계면활성제, 보존제, 안정제, 착색제, 방향제가 사용될 수 있다.Suspension agents according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Agents may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.
본 발명에 따른 주사제에는 주사용 증류수, 0.9%염화나트륨주사액, 링겔주사액, 덱스트로스주사액, 덱스트로스+염화나트륨주사액, 피이지(PEG), 락테이티드 링겔주사액, 에탄올, 프로필렌글리콜, 비휘발성유-참기름, 면실유, 낙화생유, 콩기름, 옥수수기름, 올레인산에칠, 미리스트산 이소프로필, 안식향산벤젠과 같은 용제; 안식향산나트륨, 살리실산나트륨, 초산나트륨, 요소, 우레탄, 모노에칠아세트아마이드, 부타졸리딘, 프로필렌글리콜, 트윈류, 니정틴산아미드, 헥사민, 디메칠아세트아마이드와 같은 용해보조제; 약산 및 그 염(초산과 초산나트륨), 약염기 및 그 염(암모니아 및 초산암모니움), 유기화합물, 단백질, 알부민, 펩 톤, 검류와 같은 완충제; 염화나트륨과 같은 등장화제; 중아황산나트륨(NaHSO3) 이산화탄소가스, 메타중아황산나트륨(Na2S2O5), 아황산나트륨(Na2SO3), 질소가스(N2), 에칠렌디아민테트라초산과 같은 안정제; 소디움비설파이드 0.1%, 소디움포름알데히드 설폭실레이트, 치오우레아, 에칠렌디아민테트라초산디나트륨, 아세톤소디움비설파이트와 같은 황산화제; 벤질알코올, 클로로부탄올, 염산프로카인, 포도당, 글루콘산칼슘과 같은 무통화제; 시엠시나트륨, 알긴산나트륨, 트윈 80, 모노스테아린산알루미늄과 같은 현탁화제를 포함할 수 있다.Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumins, peptones, and gums; tonicity agents such as sodium chloride; Stabilizers such as sodium bisulfite (NaHSO 3 ) carbon dioxide gas, sodium metabisulfite (Na 2 S 2 O 5 ), sodium sulfite (Na 2 SO 3 ), nitrogen gas (N 2 ), ethylenediaminetetraacetic acid; Sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, ethylenediamine disodium tetraacetate, acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; Suspending agents such as Siemesis sodium, sodium alginate, Tween 80, aluminum monostearate may be included.
본 발명에 따른 좌제에는 카카오지, 라놀린, 위텝솔, 폴리에틸렌글리콜, 글리세로젤라틴, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 스테아린산과 올레인산의 혼합물, 수바날(Subanal), 면실유, 낙화생유, 야자유, 카카오버터+콜레스테롤, 레시틴, 라네트왁스, 모노스테아린산글리세롤, 트윈 또는 스판, 임하우젠(Imhausen), 모놀렌(모노스테아린산프로필렌글리콜), 글리세린, 아뎁스솔리두스(Adeps solidus), 부티룸 태고-G(Buytyrum Tego-G), 세베스파마 16(Cebes Pharma 16), 헥사라이드베이스 95, 코토마(Cotomar), 히드록코테 SP, S-70-XXA, S-70-XX75(S-70-XX95), 히드록코테(Hydrokote) 25, 히드록코테 711, 이드로포스탈(Idropostal), 마사에스트라리움(Massa estrarium, A, AS, B, C, D, E, I, T), 마사-MF, 마수폴, 마수폴-15, 네오수포스탈-엔, 파라마운드-B, 수포시로(OSI, OSIX, A, B, C, D, H, L), 좌제기제 IV 타입(AB, B, A, BC, BBG, E, BGF, C, D, 299), 수포스탈(N, Es), 웨코비(W, R, S, M ,Fs), 테제스터 트리글리세라이드 기제(TG-95, MA, 57)와 같은 기제가 사용될 수 있다.The suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lannet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolen (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Buytyrum Tego-G -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxycote SP, S-70-XXA, S-70-XX75 (S-70-XX95),
경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc. ) or by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.
본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 본 발명이 속하는 기술분야에 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구 복용, 피하 주사, 복강 투여, 정맥 주사, 근육 주사, 척수 주위 공간(경막내) 주사, 설하 투여, 볼점막 투여, 직장 내 삽입, 질 내 삽입, 안구 투여, 귀 투여, 비강 투여, 흡입, 입 또는 코를 통한 분무, 피부 투여, 경피 투여 등에 따라 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
본 발명의 약학적 조성물은 치료할 질환, 투여 경로, 환자의 연령, 성별, 체중 및 질환의 중등도 등의 여러 관련 인자와 함께 활성성분인 약물의 종류에 따라 결정된다. 구체적으로, 본 발명에 따른 조성물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.001 내지 150 mg, 바람직하게는 0.01 내지 100 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient. Specifically, the effective amount of the composition according to the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg per day or every other day, or 1 It can be administered in 1 to 3 divided doses per day. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
본 발명에서 “개체”란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐(mouse), 쥐(rat), 개, 고양이, 말, 및 소 등의 포유류일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "subject" means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, etc. It may be a mammal of, but is not limited thereto.
본 발명에서 “투여”란 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.In the present invention, "administration" means providing a given composition of the present invention to a subject by any suitable method.
본 발명에서 “예방”이란 목적하는 질환의 발병을 억제하거나 지연시키는 모든 행위를 의미하고, “치료”란 본 발명에 따른 약학적 조성물의 투여에 의해 목적하는 질환과 그에 따른 대사 이상 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미하며, “개선”이란 본 발명에 따른 조성물의 투여에 의해 목적하는 질환과 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다. In the present invention, “prevention” refers to any action that suppresses or delays the onset of a desired disease, and “treatment” means that the desired disease and its resulting metabolic abnormality are improved or improved by administration of the pharmaceutical composition according to the present invention. All actions that are advantageously altered are meant, and "improvement" means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administration of the composition according to the present invention.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는 면역질환 및 세포 노화 관련 질환으로 이루어진 군으로부터 선택된 하나 이상의 예방 또는 개선용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for preventing or improving at least one selected from the group consisting of immune diseases and cellular aging-related diseases, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
상기 식품 조성물은 건강기능성 식품 조성물일 수 있으나, 이에 제한되는 것은 아니다.The food composition may be a health functional food composition, but is not limited thereto.
본 발명의 상기 소포를 식품 첨가물로 사용할 경우, 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시 본 발명의 소포는 원료에 대하여 15 중량% 이하, 또는 10 중량% 이하의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When the vesicle of the present invention is used as a food additive, it can be added as it is or used together with other foods or food ingredients, and can be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment). In general, the antifoam of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less based on the raw material when preparing food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the type of food. Examples of foods to which the above substances can be added include meat, sausages, bread, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice creams, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and includes all health functional foods in a conventional sense.
본 발명에 따른 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당 및 과당과 같은 모노사카라이드, 말토오스 및 수크로오스와 같은 디사카라이드, 덱스트린 및 시클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨 및 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 0.01-0.20g, 또는 약 0.04-0.10g 이다.The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional components, like conventional beverages. The aforementioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01-0.20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, A carbonation agent used in carbonated beverages and the like may be contained. In addition, the composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination. The ratio of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는 노화 또는 노화관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.In addition, the present invention relates to a pharmaceutical composition for preventing or treating aging or aging-related diseases comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는, 노화 예방 또는 개선용 식품 조성물에 관한 것이다.In addition, the present invention relates to a food composition for preventing or improving aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
또한, 본 발명은 락토바실러스 람노수스 유래 소포를 유효성분으로 포함하는, 노화 예방 또는 개선용 화장료 조성물에 관한 것이다.In addition, the present invention relates to a cosmetic composition for preventing or improving aging, comprising vesicles derived from Lactobacillus rhamnosus as an active ingredient.
본 발명에서 “노화”란 시간이 지남에 따라 일어나는 신체의 모든 생리적 변화를 통칭하는 것으로 개체에 따라 수많은 요인에 의해 매우 다양하게 일어나는 생명 현상을 의미한다. 노화 현상을 구체적으로 살펴보면 각 구성 기관 및 조직의 기능 변화가 일어나는 것으로, 개체의 노화는 결국 그 개체를 구성하는 세포들의 노화에 기인한다. 본 발명에서, 상기 노화는 뇌, 간, 폐, 신장, 근육, 피부 또는 이들 장기의 세포 노화에 의한 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "aging" refers to all physiological changes in the body that occur over time, and refers to a life phenomenon that occurs in a variety of ways due to numerous factors depending on the individual. Looking specifically at the aging phenomenon, changes in the function of each constituent organ and tissue occur, and the aging of an individual is ultimately caused by the aging of cells constituting the individual. In the present invention, the aging may be due to brain, liver, lung, kidney, muscle, skin, or cellular aging of these organs, but is not limited thereto.
본 발명에서 “노화 관련 질환(age-related disease)”이란 뇌, 간, 폐, 신장, 심장, 근육, 피부 등의 장기에 존재하는 세포의 노화에 의해 발생하는 질환일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "age-related disease" may be a disease caused by aging of cells present in organs such as the brain, liver, lungs, kidneys, heart, muscle, skin, etc., but is not limited thereto. not.
본 발명에 따른 화장료 조성물의 제형은 스킨로션, 스킨소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스쳐 로션, 영양로션, 맛사지크림, 영양크림, 미스트, 모이스쳐 크림, 핸드크림, 핸드로션, 파운데이션, 에센스, 영양에센스, 팩, 비누, 클렌징폼, 클렌징로션, 클렌징크림, 클렌징오일, 클렌징밤, 바디로션 또는 바디클렌저의 형태일 수 있다.The formulation of the cosmetic composition according to the present invention is skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrient lotion, massage cream, nutrient cream, mist, moisture cream, hand cream, hand lotion, foundation, It may be in the form of essence, nutritional essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion, or body cleanser.
본 발명의 화장료 조성물은 수용성 비타민, 유용성 비타민, 고분자 펩티드, 고분자 다당, 및 스핑고 지질로 이루어진 군에서 선택된 조성물을 더 포함할 수 있다.The cosmetic composition of the present invention may further include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high-molecular peptides, high-molecular polysaccharides, and sphingolipids.
수용성 비타민으로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 비타민 B1, 비타민 B2, 비타민 B6, 피리독신, 염산피리독신, 비타민 B12, 판토텐산, 니코틴산, 니코틴산아미드, 엽산, 비타민 C, 비타민 H 등을 들 수 있으며, 그들의 염 (티아민염산염, 아스코르빈산나트륨염 등)이나 유도체 (아스코르빈산-2-인산나트륨염, 아스코르빈산-2-인산마그네슘염 등)도 본 발명에서 사용할 수 있는 수용성 비타민에 포함된다. 수용성 비타민은 미생물 변환법, 미생물의 배양물로부터의 정제법, 효소법 또는 화학 합성법 등의 통상의 방법에 의해 수득할 수 있다.Any water-soluble vitamin can be used as long as it can be incorporated into cosmetics, but examples include vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine hydrochloride, vitamin B12, pantothenic acid, nicotinic acid, nicotinic acid amide, folic acid, vitamin C, and vitamin H. salts (thiamin hydrochloride, sodium ascorbate, etc.) or derivatives (sodium ascorbic acid-2-phosphate, magnesium salt of ascorbic acid-2-phosphate, etc.) included Water-soluble vitamins can be obtained by conventional methods such as a microbial transformation method, a purification method from a microbial culture, an enzymatic method, or a chemical synthesis method.
유용성 비타민으로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 비타민 A, 카로틴, 비타민 D2, 비타민 D3, 비타민 E (d1-알파 토코페롤, d-알파 토코페롤, d-알파 토코페롤) 등을 들 수 있으며, 그들의 유도체 (팔미틴산아스코르빈, 스테아르산아스코르빈, 디팔미틴산아스코르빈, 아세트산dl-알파 토코페롤, 니코틴산dl-알파 토코페롤비타민 E, DL-판토테닐알코올, D-판토테닐알코올, 판토테닐에틸에테르 등) 등도 본 발명에서 사용되는 유용성 비타민에 포함된다. 유용성 비타민은 미생물 변환법, 미생물의 배양물로부터의 정제법, 효소 또는 화학 합성법 등의 통상의 방법에 의해 취득할 수 있다.Any useful vitamin can be used as long as it can be formulated into cosmetics, but examples include vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (d1-alpha tocopherol, d-alpha tocopherol, d-alpha tocopherol), etc. , their derivatives (ascorbine palmitate, ascorbine stearate, ascorbine dipalmitate, dl-alpha tocopherol acetate, dl-alpha tocopherol nicotinate, vitamin E, DL-pantothenyl alcohol, D-pantothenyl alcohol, pantothenylethyl ether, etc.) and the like are also included in the useful vitamins used in the present invention. The useful vitamins can be obtained by conventional methods such as microbial transformation, purification from microbial culture, enzymatic or chemical synthesis.
고분자 펩티드로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 콜라겐, 가수 분해 콜라겐, 젤라틴, 엘라스틴, 가수 분해 엘라스틴, 케라틴 등을 들 수 있다. 고분자 펩티드는 미생물의 배양액으로부터의 정제법, 효소법 또는 화학 합성법 등의 통상의 방법에 의해 정제 취득할 수 있으며, 또는 통상 돼지나 소 등의 진피, 누에의 견섬유 등의 천연물로부터 정제하여 사용할 수 있다.Any polymer peptide may be used as long as it can be incorporated into cosmetics, and examples thereof include collagen, hydrolyzed collagen, gelatin, elastin, hydrolyzed elastin, and keratin. Polymer peptides can be purified and obtained by conventional methods such as a purification method from a culture medium of microorganisms, an enzyme method, or a chemical synthesis method, or can be used after being purified from natural products such as pig or cow dermis or silkworm silk fibers.
고분자 다당으로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 히드록시에틸셀룰로오스, 크산탄검, 히알루론산나트륨, 콘드로이틴 황산 또는 그 염 (나트륨염 등) 등을 들 수 있다. 예를 들어, 콘드로이틴 황산 또는 그 염 등은 통상 포유 동물이나 어류로부터 정제하여 사용할 수 있다.The polymeric polysaccharide may be any material as long as it can be incorporated into cosmetics, and examples thereof include hydroxyethyl cellulose, xanthan gum, sodium hyaluronate, chondroitin sulfate or salts thereof (sodium salt, etc.). For example, chondroitin sulfate or a salt thereof can be used after being purified from mammals or fish.
스핑고 지질로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 세라미드, 피토스핑고신, 스핑고당지질 등을 들 수 있다. 스핑고 지질은 통상 포유류, 어류, 패류, 효모 또는 식물 등으로부터 통상의 방법에 의해 정제하거나 화학 합성법에 의해 취득할 수 있다.Any sphingolipid can be used as long as it can be incorporated into cosmetics, and examples thereof include ceramide, phytosphingosine, and sphingoglycolipid. Sphingolipids can be purified by conventional methods or obtained by chemical synthesis from mammals, fish, shellfish, yeast, or plants.
본 발명의 화장료 조성물에는 상기 필수 성분과 더불어 필요에 따라 통상 화장품에 배합되는 다른 성분을 배합해도 된다.In the cosmetic composition of the present invention, in addition to the above essential ingredients, other ingredients normally formulated in cosmetics may be blended as necessary.
이외에 첨가해도 되는 배합 성분으로서는 유지 성분, 보습제, 에몰리엔트제, 계면 활성제, 유기 및 무기 안료, 유기 분체, 자외선 흡수제, 방부제, 살균제, 산화 방지제, 식물 추출물, pH 조정제, 알콜, 색소, 향료, 혈행 촉진제, 냉감제, 제한(制汗)제, 정제수 등을 들 수 있다.Other ingredients that may be added include fats and oils, humectants, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, fragrances, A blood circulation accelerator, a cooling agent, an antiperspirant, purified water, etc. are mentioned.
유지 성분으로서는 에스테르계 유지, 탄화수소계 유지, 실리콘계 유지, 불소계 유지, 동물 유지, 식물 유지 등을 들 수 있다.Examples of the oil and fat component include ester oils, hydrocarbon oils, silicone oils, fluorine oils, animal fats and vegetable oils.
에스테르계 유지로서는 트리2-에틸헥산산글리세릴, 2-에틸헥산산세틸, 미리스틴산이소프로필, 미리스틴산부틸, 팔미틴산이소프로필, 스테아르산에틸, 팔미틴산옥틸, 이소스테아르산이소세틸, 스테아르산부틸, 리놀레산에틸, 리놀레산이소프로필, 올레인산에틸, 미리스틴산이소세틸, 미리스틴산이소스테아릴, 팔미틴산이소스테아릴, 미리스틴산옥틸도데실, 이소스테아르산이소세틸, 세바신산디에틸, 아디핀산디이소프로필, 네오펜탄산이소알킬, 트리(카프릴, 카프린산)글리세릴, 트리2-에틸헥산산트리메틸롤프로판, 트리이소스테아르산트리메틸롤프로판, 테트라2-에틸헥산산펜타엘리슬리톨, 카프릴산세틸, 라우린산데실, 라우린산헥실, 미리스틴산데실, 미리스틴산미리스틸, 미리스틴산세틸, 스테아르산스테아릴, 올레인산데실, 리시노올레인산세틸, 라우린산이소스테아릴, 미리스틴산이소트리데실, 팔미틴산이소세틸, 스테아르산옥틸, 스테아르산이소세틸, 올레인산이소데실, 올레인산옥틸도데실, 리놀레산옥틸도데실, 이소스테아르산이소프로필, 2-에틸헥산산세토스테아릴, 2-에틸헥산산스테아릴, 이소스테아르산헥실, 디옥탄산에틸렌글리콜, 디올레인산에틸렌글리콜, 디카프린산프로필렌글리콜, 디(카프릴,카프린산)프로필렌글리콜, 디카프릴산프로필렌글리콜, 디카프린산네오펜틸글리콜, 디옥탄산네오펜틸글리콜, 트리카프릴산글리세릴, 트리운데실산글리세릴, 트리이소팔미틴산글리세릴, 트리이소스테아르산글리세릴, 네오펜탄산옥틸도데실, 옥탄산이소스테아릴, 이소노난산옥틸, 네오데칸산헥실데실, 네오데칸산옥틸도데실, 이소스테아르산이소세틸, 이소스테아르산이소스테아릴, 이소스테아르산옥틸데실, 폴리글리세린올레인산에스테르, 폴리글리세린이소스테아르산에스테르, 시트르산트리이소세틸, 시트르산트리이소알킬, 시트르산트리이소옥틸, 락트산라우릴, 락트산미리스틸, 락트산세틸, 락트산옥틸데실, 시트르산트리에틸, 시트르산아세틸트리에틸, 시트르산아세틸트리부틸, 시트르산트리옥틸, 말산디이소스테아릴, 히드록시스테아르산 2-에틸헥실, 숙신산디2-에틸헥실, 아디핀산디이소부틸, 세바신산디이소프로필, 세바신산디옥틸, 스테아르산콜레스테릴, 이소스테아르산콜레스테릴, 히드록시스테아르산콜레스테릴, 올레인산콜레스테릴, 올레인산디히드로콜레스테릴, 이소스테아르산피트스테릴, 올레인산피트스테릴, 12-스테알로일히드록시스테아르산이소세틸, 12-스테알로일히드록시스테아르산스테아릴, 12-스테알로일히드록시스테아르산이소스테아릴 등의 에스테르계 등을 들 수 있다.Examples of ester oils include glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, and stearic acid. Butyl, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, adipine Diisopropyl acid, isoalkyl neopentanoate, tri(capryl, capric acid) glyceryl, trimethylolpropane tri2-ethylhexanoate, trimethylolpropane triisostearate, pentaelislitol tetra2-ethylhexanoate , Cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinooleate, isostea laurate Lil, isotridecyl myristate, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isopropyl isostearate, 2-ethylhexanoate Aryl, 2-ethyl stearyl hexanoate, hexyl isostearate, ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicaprate, di(caprylic, capric acid) propylene glycol, propylene glycol dicaprylate, dicap Neopentyl glycol prinate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate , Octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin oleate, polyglycerin isostearate, Triisocetyl citrate, triisoalkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, trioctyl citrate, dimalate Isostearyl, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, Cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phyteryl isostearate, phyteryl oleate, 12-stealoyl and esters such as isocetyl hydroxystearate, stearyl 12-stealoylhydroxystearate, and isostearyl 12-stealoylhydroxystearate.
탄화 수소계 유지로서는 스쿠알렌, 유동 파라핀, 알파-올레핀올리고머, 이소파라핀, 세레신, 파라핀, 유동 이소파라핀, 폴리부덴, 마이크로크리스탈린왁스, 와셀린 등의 탄화 수소계 유지 등을 들 수 있다.Examples of hydrocarbon-based fats and oils include hydrocarbon-based fats and oils such as squalene, liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybuden, microcrystalline wax, and vaseline.
실리콘계 유지로서는 폴리메틸실리콘, 메틸페닐실리콘, 메틸시클로폴리실록산, 옥타메틸폴리실록산, 데카메틸폴리실록산, 도데카메틸시클로실록산, 디메틸실록산ㆍ메틸세틸옥시실록산 공중합체, 디메틸실록산ㆍ메틸스테알록시실록산 공중합체, 알킬 변성 실리콘유, 아미노 변성 실리콘유 등을 들 수 있다.Examples of silicone oils include polymethylsilicone, methylphenylsilicone, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, dimethylsiloxane/methylcetyloxysiloxane copolymer, dimethylsiloxane/methylstealoxysiloxane copolymer, alkyl Modified silicone oil, amino modified silicone oil, etc. are mentioned.
불소계 유지로서는 퍼플루오로폴리에테르 등을 들 수 있다.Examples of fluorine-based fats and oils include perfluoropolyether and the like.
동물 또는 식물 유지로서는 아보카도유, 아르몬드유, 올리브유, 참깨유, 쌀겨유, 새플라워유, 대두유, 옥수수유, 유채유, 행인(杏仁)유, 팜핵유, 팜유, 피마자유, 해바라기유, 포도종자유, 면실유, 야자유, 쿠쿠이너트유, 소맥배아유, 쌀 배아유, 시아버터, 월견초유, 마커데이미아너트유, 메도홈유, 난황유, 우지(牛脂), 마유, 밍크유, 오렌지라피유, 호호바유, 캔데리러왁스, 카르나바왁스, 액상 라놀린, 경화피마자유 등의 동물 또는 식물 유지를 들 수 있다.Animal or vegetable oils include avocado oil, almond oil, olive oil, sesame oil, rice bran oil, birdflower oil, soybean oil, corn oil, rapeseed oil, algae oil, palm kernel oil, palm oil, castor oil, sunflower oil, grape seed oil , cottonseed oil, palm oil, kukui nut oil, wheat germ oil, rice germ oil, shea butter, moonshine colostrum, marker damian nut oil, meadowsweet oil, egg yolk oil, beef tallow, horse oil, mink oil, orange raffia oil, jojoba oil , animal or plant fats and oils such as candelilla wax, carnaba wax, liquid lanolin, and hydrogenated castor oil.
보습제로서는 수용성 저분자 보습제, 지용성 분자 보습제, 수용성 고분자, 지용성 고분자 등을 들 수 있다.Examples of the moisturizer include water-soluble low-molecular moisturizers, fat-soluble molecular moisturizers, water-soluble polymers, and oil-soluble polymers.
수용성 저분자 보습제로서는 세린, 글루타민, 솔비톨, 만니톨, 피롤리돈-카르복실산나트륨, 글리세린, 프로필렌글리콜, 1,3-부틸렌글리콜, 에틸렌글리콜, 폴리에틸렌글리콜B(중합도 n = 2 이상), 폴리프로필렌글리콜(중합도 n = 2 이상), 폴리글리세린B(중합도 n = 2 이상), 락트산, 락트산염 등을 들 수 있다.Examples of water-soluble low-molecular moisturizers include serine, glutamine, sorbitol, mannitol, pyrrolidone-sodium carboxylate, glycerin, propylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol B (polymerization degree n = 2 or more), polypropylene Glycol (polymerization degree n = 2 or more), polyglycerol B (polymerization degree n = 2 or more), lactic acid, lactate, etc. are mentioned.
지용성 저분자 보습제로서는 콜레스테롤, 콜레스테롤에스테르 등을 들 수 있다.Cholesterol, cholesterol ester, etc. are mentioned as a fat-soluble low-molecular moisturizer.
수용성 고분자로서는 카르복시비닐폴리머, 폴리아스파라긴산염, 트라가칸트, 크산탄검, 메틸셀룰로오스, 히드록시메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 카르복시메틸셀룰로오스, 수용성 키틴, 키토산, 덱스트린 등을 들 수 있다.Examples of water-soluble polymers include carboxyvinyl polymer, polyaspartate, tragacanth, xanthan gum, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, water-soluble chitin, chitosan, dextrin, and the like. can
지용성 고분자로서는 폴리비닐피롤리돈ㆍ에이코센 공중합체, 폴리비닐피롤리돈ㆍ헥사데센 공중합체, 니트로셀룰로오스, 덱스트린지방산에스테르, 고분자 실리콘 등을 들 수 있다.Examples of the fat-soluble polymer include polyvinylpyrrolidone/eicosene copolymer, polyvinylpyrrolidone/hexadecene copolymer, nitrocellulose, dextrin fatty acid ester, and high molecular silicone.
에몰리엔트제로서는 장쇄아실글루타민산콜레스테릴에스테르, 히드록시스테아르산콜레스테릴, 12-히드록시스테아르산, 스테아르산, 로진산, 라놀린지방산콜레스테릴에스테르 등을 들 수 있다.Examples of the emollient agent include long-chain acyl glutamic acid cholesteryl ester, hydroxystearic acid cholesteryl, 12-hydroxystearic acid, stearic acid, rosin acid, lanolin fatty acid cholesteryl ester, and the like.
계면 활성제로서는 비이온성 계면 활성제, 음이온성 계면 활성제, 양이온성 계면 활성제, 양성 계면 활성제 등을 들 수 있다.Examples of the surfactant include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.
비이온성 계면 활성제로서는 자기 유화형 모노스테아르산글리세린, 프로필렌글리콜지방산에스테르, 글리세린지방산에스테르, 폴리글리세린지방산에스테르, 솔비탄지방산에스테르, POE (폴리옥시에틸렌)솔비탄지방산에스테르, POE 솔비트지방산에스테르, POE 글리세린지방산에스테르, POE 알킬에테르, POE 지방산에스테르, POE 경화피마자유, POE 피마자유, POEㆍPOP (폴리옥시에틸렌ㆍ폴리옥시프로필렌) 공중합체, POEㆍPOP 알킬에테르, 폴리에테르변성실리콘, 라우린산알카놀아미드, 알킬아민옥시드, 수소첨가대두인지질 등을 들 수 있다.Nonionic surfactants include self-emulsifying glycerin monostearate, propylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, POE (polyoxyethylene) sorbitan fatty acid esters, POE sorbitan fatty acid esters, POE Glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hydrogenated castor oil, POE castor oil, POE·POP (polyoxyethylene·polyoxypropylene) copolymer, POE·POP alkyl ether, polyether modified silicone, lauric acid alkanolamides, alkylamine oxides, hydrogenated soybean phospholipids, and the like.
음이온성 계면 활성제로서는 지방산비누, 알파-아실술폰산염, 알킬술폰산염, 알킬알릴술폰산염, 알킬나프탈렌술폰산염, 알킬황산염, POE 알킬에테르황산염, 알킬아미드황산염, 알킬인산염, POE 알킬인산염, 알킬아미드인산염, 알킬로일알킬타우린염, N-아실아미노산염, POE 알킬에테르카르복실산염, 알킬술포숙신산염, 알킬술포아세트산나트륨, 아실화 가수분해 콜라겐펩티드염, 퍼플루오로알킬인산에스테르 등을 들 수 있다.Anionic surfactants include fatty acid soaps, alpha-acyl sulfonates, alkyl sulfonates, alkyl allyl sulfonates, alkyl naphthalene sulfonates, alkyl sulfates, POE alkyl ether sulfates, alkyl amide sulfates, alkyl phosphates, POE alkyl phosphates, and alkyl amide phosphates. , alkyloylalkyl taurine salts, N-acylamino acid salts, POE alkyl ether carboxylate salts, alkyl sulfosuccinic acid salts, sodium alkyl sulfoacetate, acylated hydrolyzed collagen peptide salts, perfluoroalkyl phosphate esters, and the like. .
양이온성 계면 활성제로서는 염화알킬트리메틸암모늄, 염화스테아릴트리메틸암모늄, 브롬화스테아릴트리메틸암모늄, 염화세토스테아릴트리메틸암모늄, 염화디스테아릴디메틸암모늄, 염화스테아릴디메틸벤질암모늄, 브롬화베헤닐트리메틸암모늄, 염화벤잘코늄, 스테아르산디에틸아미노에틸아미드, 스테아르산디메틸아미노프로필아미드, 라놀린 유도체 제 4급 암모늄염 등을 들 수 있다.As the cationic surfactant, alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, chloride Benzalkonium, stearic acid diethylaminoethylamide, stearic acid dimethylaminopropylamide, lanolin derivative quaternary ammonium salt, etc. are mentioned.
양성 계면 활성제로서는 카르복시베타인형, 아미드베타인형, 술포베타인형, 히드록시술포베타인형, 아미드술포베타인형, 포스포베타인형, 아미노카르복실산염형, 이미다졸린 유도체형, 아미드아민형 등의 양성 계면 활성제 등을 들 수 있다.Amphoteric surfactants include carboxybetaine type, amidebetaine type, sulfobetaine type, hydroxysulfobetaine type, amide sulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, amideamine type, etc. An amphoteric surfactant etc. are mentioned.
유기 및 무기 안료로서는 규산, 무수규산, 규산마그네슘, 탤크, 세리사이트, 마이카, 카올린, 벵갈라, 클레이, 벤토나이트, 티탄피막운모, 옥시염화비스무트, 산화지르코늄, 산화마그네슘, 산화아연, 산화티탄, 산화알루미늄, 황산칼슘, 황산바륨, 황산마그네슘, 탄산칼슘, 탄산마그네슘, 산화철, 군청, 산화크롬, 수산화크롬, 칼라민 및 이들의 복합체등의 무기 안료; 폴리아미드, 폴리에스테르, 폴리프로필렌, 폴리스티렌, 폴리우레탄, 비닐수지, 요소수지, 페놀수지, 불소수지, 규소수지, 아크릴수지, 멜라민수지, 에폭시수지, 폴리카보네이트수지, 디비닐벤젠ㆍ스티렌 공중합체, 실크파우더, 셀룰로오스, CI 피그먼트옐로우, CI 피그먼트오렌지 등의 유기 안료 및 이들의 무기 안료와 유기 안료의 복합 안료 등을 들 수 있다.As organic and inorganic pigments, silicic acid, silicic anhydride, magnesium silicate, talc, sericite, mica, kaolin, bengala, clay, bentonite, titanium-coated mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, aluminum oxide inorganic pigments such as calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, iron oxide, ultramarine blue, chromium oxide, chromium hydroxide, calamine and complexes thereof; Polyamide, polyester, polypropylene, polystyrene, polyurethane, vinyl resin, urea resin, phenolic resin, fluororesin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, divinylbenzene/styrene copolymer, organic pigments such as silk powder, cellulose, CI pigment yellow and CI pigment orange, and composite pigments of these inorganic pigments and organic pigments.
유기 분체로서는 스테아르산칼슘 등의 금속비누; 세틸린산아연나트륨, 라우릴린산아연, 라우릴린산칼슘 등의 알킬인산금속염 ; N-라우로일-베타-알라닌칼슘, N-라우로일-베타-알라닌아연, N-라우로일글리신칼슘 등의 아실아미노산 다가금속염 ; N-라우로일-타우린칼슘, N-팔미토일-타우린칼슘 등의 아미드술폰산 다가금속염 ; N-엡실론-라우로일-L-리진, N-엡실론-팔미토일리진, N-알파-파리토일올니틴, N-알파-라우로일아르기닌, N-알파-경화우지지방산아실아르기닌 등의 N-아실염기성아미노산 ; N-라우로일글리실글리신 등의 N-아실폴리펩티드 ; 알파-아미노카프릴산, 알파-아미노라우린산 등의 알파-아미노지방산 ; 폴리에틸렌, 폴리프로필렌, 나일론, 폴리메틸메타크릴레이트, 폴리스티렌, 디비닐벤젠ㆍ스티렌 공중합체, 사불화에틸렌 등을 들 수 있다.Examples of the organic powder include metal soaps such as calcium stearate; Alkyl phosphate metal salts, such as zinc sodium cetylrate, zinc laurylate, and calcium laurylate; polyvalent metal salts of acyl amino acids such as N-lauroyl-beta-alanine calcium, N-lauroyl-beta-alanine zinc, and N-lauroyl glycine calcium; polyvalent metal salts of amide sulfonic acids such as N-lauroyl-taurine calcium and N-palmitoyl-taurine calcium; N-epsilon-lauroyl-L-lysine, N-epsilon-palmitoylizine, N-alpha-paritoylolnithine, N-alpha-lauroylarginine, N-alpha-hardened beef fatty acid acylarginine, etc. -acyl basic amino acids; N-acyl polypeptides such as N-lauroyl glycyl glycine; alpha-amino fatty acids such as alpha-aminocaprylic acid and alpha-aminolauric acid; polyethylene, polypropylene, nylon, polymethyl methacrylate, polystyrene, divinylbenzene/styrene copolymer, tetrafluoroethylene, and the like.
자외선 흡수제로서는 파라아미노벤조산, 파라아미노벤조산에틸, 파라아미노벤조산아밀, 파라아미노벤조산옥틸, 살리실산에틸렌글리콜, 살리신산페닐, 살리신산옥틸, 살리신산벤질, 살리신산부틸페닐, 살리신산호모멘틸, 계피산벤질, 파라메톡시계피산-2-에톡시에틸, 파라메톡시계피산옥틸, 디파라메톡시계피산모노-2-에틸헥산글리세릴, 파라메톡시계피산이소프로필, 디이소프로필ㆍ디이소프로필계피산에스테르 혼합물, 우로카닌산, 우로카닌산에틸, 히드록시메톡시벤조페논, 히드록시메톡시벤조페논술폰산 및 그 염, 디히드록시메톡시벤조페논, 디히드록시메톡시벤조페논디술폰산나트륨, 디히드록시벤조페논, 테트라히드록시벤조페논, 4-tert-부틸-4'-메톡시디벤조일메탄, 2,4,6-트리아닐리노-p-(카르보-2'-에틸헥실-1'-옥시)-1,3,5-트리아진, 2-(2-히드록시-5-메틸페닐)벤조트리아졸 등을 들 수 있다.Examples of UV absorbers include para-aminobenzoic acid, ethyl para-aminobenzoate, amyl para-aminobenzoate, octyl para-aminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, butylphenyl salicylate, homomenthyl salicylate, and benzyl cinnamate. , paramethoxycinnamic acid-2-ethoxyethyl, paramethoxycinnamic acid octyl, diparamethoxycinnamic acid mono-2-ethylhexane glyceryl, paramethoxycinnamic acid isopropyl, diisopropyl-diisopropylcinnamic acid ester mixture, uro Cannic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenonesulfonic acid and its salts, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone , tetrahydroxybenzophenone, 4-tert-butyl-4'-methoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2'-ethylhexyl-1'-oxy)-1 ,3,5-triazine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, etc. are mentioned.
살균제로서는 히노키티올, 트리클로산, 트리클로로히드록시디페닐에테르, 크로르헥시딘글루콘산염, 페녹시에탄올, 레조르신, 이소프로필메틸페놀, 아줄렌, 살리칠산, 진크필리티온, 염화벤잘코늄, 감광소 301 호, 모노니트로과이어콜나트륨, 운데시렌산 등을 들 수 있다.Bactericides include hinokitiol, triclosan, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zincophylthione, benzalkonium chloride, photosensitizer So No. 301, mononitroguacol sodium, undecyrenic acid, etc. are mentioned.
산화 방지제로서는 부틸히드록시아니솔, 갈릭산프로필, 엘리소르빈산 등을 들 수 있다.Examples of antioxidants include butylhydroxyanisole, propyl gallic acid, and elisorbic acid.
pH 조정제로서는 시트르산, 시트르산나트륨, 말산, 말산나트륨, 프말산, 프말산나트륨, 숙신산, 숙신산나트륨, 수산화나트륨, 인산일수소나트륨 등을 들 수 있다.Examples of the pH adjuster include citric acid, sodium citrate, malic acid, sodium malate, fumaric acid, sodium fumalate, succinic acid, sodium succinate, sodium hydroxide, and sodium monohydrogenphosphate.
알코올로서는 세틸알코올 등의 고급 알코올을 들 수 있다.Examples of alcohol include higher alcohols such as cetyl alcohol.
또한, 이외에 첨가해도 되는 배합 성분은 이에 한정되는 것은 아니며, 또, 상기 어느 성분도 본 발명의 목적 및 효과를 손상시키지 않는 범위 내에서 배합 가능하지만, 총중량에 대하여 0.01-5% 중량 백분율 또는 0.01-3% 중량 백분율로 배합될 수 있다.In addition, the blending components that may be added are not limited to these, and any of the above ingredients can be blended within a range not impairing the objects and effects of the present invention, but 0.01 to 5% by weight percent or 0.01 to 3% based on the total weight. Can be formulated in % weight percentage.
본 발명의 제형이 로션, 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물섬유, 식물섬유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a lotion, paste, cream or gel, animal fiber, vegetable fiber, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide as a carrier component can be used
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydrocarbon, propane / May contain a propellant such as butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액의 경우에는 담체 성분으로서 용매, 용매화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or emulsion, a solvent, solvating agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol oil, fatty acid esters of glycerol, polyethylene glycol or sorbitan.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar or tracanth and the like may be used.
본 발명의 제형이 계면-활성제 함유 클렌징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 리놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is surfactant-containing cleansing, as carrier components, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolin derivatives, or ethoxylated glycerol fatty acid esters may be used.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, a preferred embodiment is presented to aid understanding of the present invention. However, the following examples are provided to more easily understand the present invention, and the content of the present invention is not limited by the following examples.
[실시예][Example]
실시예 1. 락토바실러스 람노수스 유래 소포의 분리Example 1. Isolation of vesicles derived from Lactobacillus rhamnosus
락토바실러스 람노수스(Lactobacillus rhamnosus) 유래 소포(extracellular vesicle; EV)를 분리하기 위하여, 락토바실러스 람노수스 균주를 자체 개발한 배지에 접종하여 혐기성 환경에서 배양하였다. 37 ℃에서 흡광도(OD600nm)가 1.0 내지 1.5가 될 때까지 정치 배양한 후에, 배지에 재접종하여 배양하였다. 그리고 균체가 포함되어 있는 배양액을 회수하여 13,000 g로 4℃에서 15분 동안 원심분리하여 균체를 제거된 상층액을 획득하였다. 획득된 상층액은 다시 0.22 μm의 필터를 이용하여 여과시키고, 여과시킨 상층액은 100 kDa Pellicon 2 Cassette 필터 멤브레인(Merck Millipore)과 MasterFlex pump system(Cole-Parmer)을 이용하여 50 mL 이하의 부피로 농축하였다. 농축시킨 상층액은 다시 0.22 μm의 필터를 이용하여 여과시켜, 락토바실러스 람노수스 유래 소포(MDH-003)를 분리하였다. 이하의 실시예에서는 분리된 상기 소포를 이용하여 실험을 진행하였다.In order to isolate Lactobacillus rhamnosus -derived extracellular vesicles (EVs), a Lactobacillus rhamnosus strain was inoculated into a self-developed medium and cultured in an anaerobic environment. After stationary culture at 37 °C until the absorbance (OD 600nm ) is 1.0 to 1.5, the medium was re-inoculated and cultured. Then, the culture medium containing the cells was collected and centrifuged at 13,000 g at 4° C. for 15 minutes to obtain a supernatant from which the cells were removed. The obtained supernatant was filtered again using a 0.22 μm filter, and the filtered supernatant was reduced to a volume of 50 mL or less using a 100 kDa
실시예 2. 영양 과잉으로 유도된 세포 노화 관련 질환 마우스에서 락토바실러스 람노수스 유래 소포의 치료 효과Example 2. Therapeutic effect of Lactobacillus rhamnosus-derived vesicles in mice with cellular senescence-related diseases induced by overnutrition
영양 과잉으로 인해 비만이 발생하고, 비만은 낮은 수준의 전신성 만성 염증 상태로서 영양 과잉에 의해 체내에서 비정상 대사산물이 만들어져서 염증성 매개체가 분비되어 만성 염증을 유발시킨다. 또한, 영양 과잉에 의해 에너지 대사 스트레스 상황에서 세포의 항상성을 유지하는 AMPK 신호가 억제되어 세포 노화가 촉진됨에 따라 세포 노화 관련 질환이 발생할 수 있다. 특히, 비만은 천식의 발생 및 폐기능 저하에 관여하는 위험 인자라는 연구 결과들이 많이 알려져 있다. 따라서, 고지방 식이로 영양 과잉을 유도한 마우스에서 락토바실러스 람노수스 유래 소포(MDH-003)의 치료 효과를 평가하기 위하여 다음과 같은 방법으로 실험을 수행하였다. Obesity occurs due to overnutrition, and obesity is a low-level systemic chronic inflammatory state. Abnormal metabolites are produced in the body due to overnutrition, and inflammatory mediators are secreted to induce chronic inflammation. In addition, as AMPK signaling, which maintains cell homeostasis, is suppressed by excessive nutrition in an energy metabolism stress situation, cell senescence is accelerated, and thus cell senescence-related diseases may occur. In particular, it is well known that obesity is a risk factor involved in the development of asthma and lung function decline. Therefore, in order to evaluate the therapeutic effect of Lactobacillus rhamnosus-derived vesicles (MDH-003) in mice induced to overnutrition by a high-fat diet, an experiment was performed as follows.
구체적으로, BALB/c 6주령 암컷 마우스에 22주간 고지방 식이(Harlan, adjusted calories diet)를 급여하여 비만을 유도한 뒤, 23주부터 26주까지 4주간 지속적으로 고지방 식이를 급여함과 동시에 락토바실러스 람노수스 유래 소포를 1회 50μg 용량으로 주 4회 경구 투여하여 락토바실러스 람노수스 유래 소포 효능평가를 진행하였다(도 1 참조). Specifically, BALB/c 6-week-old female mice were fed a high-fat diet (Harlan, adjusted calories diet) for 22 weeks to induce obesity, and then continuously fed a high-fat diet for 4 weeks from 23 weeks to 26 weeks, while feeding Lactobacillus Rhamnosus-derived vesicles were orally administered four times a week at a dose of 50 μg once, and the efficacy of Lactobacillus rhamnosus-derived vesicles was evaluated (see FIG. 1).
2-1. 체중 감소 효과 확인2-1. Check the weight loss effect
24주 내지 27주차 고지방 식이 마우스의 체중을 측정하였다.At 24 to 27 weeks, the body weight of mice on a high-fat diet was measured.
그 결과, 도 2에 나타난 바와 같이, 26주부터 비만 그룹(Obese)에 비해 락토바실러스 람노수스 유래 소포 투여 그룹(MDH-003)에서 체중 감소 효과가 관찰되었다. As a result, as shown in FIG. 2, a weight loss effect was observed in the group administered with Lactobacillus rhamnosus-derived vesicles (MDH-003) compared to the obese group (Obese) from 26 weeks.
2-2. 신장 기능 개선 효과 확인2-2. Check the effect of improving kidney function
신장 손상 마커인 혈청 내 Blood urea nitrogen(BUN, 혈액요소질소) 및 Creatinine(Cr, 크레아티닌) 수치 검사를 통해 신장 기능을 평가하였다.Renal function was evaluated through blood urea nitrogen (BUN) and creatinine (Cr, creatinine) level tests in serum, which are kidney damage markers.
혈청에서 크레아티닌, 및 BUN은 현재 판매 중인 어세이 키트(Pointe Sceintific, Linclon Park, MI)를 통해 측정하였다.Creatinine and BUN in serum were measured using a commercially available assay kit (Pointe Sceintific, Linclon Park, MI).
도 3a 및 도 3b에 나타난 바와 같이, 27주간 고지방 식이를 섭취한 마우스에서는 BUN 및 Cr 수치가 증가하였고, 고지방 식이에 의해 유도된 신장 기능 이상, 즉 신자으이 손상이 락토바실러스 람노수스 유래 소포를 투여한 그룹에서는 회복되었다.As shown in Figures 3a and 3b, BUN and Cr levels increased in mice fed a high-fat diet for 27 weeks, and renal dysfunction induced by the high-fat diet, that is, damage to the kidneys, was reduced by administration of Lactobacillus rhamnosus-derived vesicles. One group recovered.
2-3. 폐 기능 개선 효과 확인2-3. Check the lung function improvement effect
고지방 식이에 의한 폐 기능의 변화를 평가하였다. 구체적으로 flexiVent(SCIREQ, Canada)를 사용하여 기도과민성(AHR, Airway hyperresponsiveness)을 측정하였다. 이는 Invasive method로 마우스의 마취상태에서, 메타콜린 (Methacholine) 농도(0, 5, 10, 25, 50 mg/㎖)의 변화에 따른 airway resistance (Rrs) 값을 측정하였다. 마우스는 메타콜린을 흡입시키기 전에 0.9% 생리식염수를 10초간 분무시켜 기저(Basal control) 기도 과민성을 측정하였고, 메타콜린에 대한 기도 반응의 차이를 확인하기 위하여 각 마우스에게 초음파분무기를 이용하여 메타콜린의 농도를 증가시키며 측정하였다. 각 농도의 메타콜린 투여 후, 3분 간 Rrs 값을 측정하여 평균값을 사용하였다. 기도 기능의 변화 정도는 0.9% 생리식염수 흡입 후 얻어진 기저 Rrs 값을 기준으로 그 차이를 백분율로 표현하였다.Changes in lung function by high-fat diet were evaluated. Specifically, airway hyperresponsiveness (AHR) was measured using flexiVent (SCIREQ, Canada). The airway resistance (Rrs) value was measured according to the change in methacholine concentration (0, 5, 10, 25, 50 mg/ml) under anesthesia of the mouse by the Invasive method. Before inhaling methacholine, mice were sprayed with 0.9% saline for 10 seconds to measure basal control airway hyperresponsiveness. It was measured by increasing the concentration of After administration of methacholine at each concentration, the Rrs value was measured for 3 minutes and the average value was used. The degree of change in airway function was expressed as a percentage based on the baseline Rrs value obtained after inhalation of 0.9% saline solution.
도 4에 나타난 바와 같이, 비만 그룹은 음성 대조군 대비 기도과민성이 증가되었고, 이렇게 증가된 기도과민성은 락토바실러스 람노수스 유래 소포를 투여한 그룹에서 개선된 것을 확인하였다.As shown in FIG. 4, it was confirmed that airway hyperresponsiveness was increased in the obese group compared to the negative control group, and airway hyperresponsiveness was improved in the group administered with Lactobacillus rhamnosus-derived vesicles.
이상의 결과에서 영양 과잉으로 세포 노화가 촉진되어 발생하는 신장 기능 및 폐 기능 장애를 락토바실러스 람노수스 유래 소포가 효율적으로 치료할 수 있음을 알 수 있다.From the above results, it can be seen that Lactobacillus rhamnosus-derived vesicles can efficiently treat kidney and lung dysfunctions caused by accelerated cell aging due to nutrient excess.
실시예 3. 영양 과잉에 의해 유도된 세포 노화 관련 질환 마우스에서 락토바실러스 람노수스 유래 소포의 면역기능 조절 효과Example 3. Effects of Lactobacillus rhamnosus-derived vesicles on regulating immune function in mice with cellular senescence-related diseases induced by nutrient overload
면역은 선천면역(innate immunity)과 적응면역(adaptive immunity)으로 구분할 수 있으며, 외부 또는 내부 인자에 대한 면역기능의 이상이 발생할 경우 질병이 발생한다. 특히, 후천면역 반응에 중요한 T세포는 사이토카인을 분비하여 면역질환을 유도하는데, 특히 Th17 세포는 주로 IL-17, IL-6 등을 분비하며 호중구성 염증을 특징으로 하는 염증질환을 유도하고, Th2 세포는 IL-4, IL-5 등을 분비하여 호산구성 염증을 특징으로 하는 염증질환을 유도한다. Immunity can be divided into innate immunity and adaptive immunity, and diseases occur when abnormalities in immune function against external or internal factors occur. In particular, T cells, which are important for the acquired immune response, induce immune diseases by secreting cytokines. In particular, Th17 cells secrete mainly IL-17 and IL-6, and induce inflammatory diseases characterized by neutrophilic inflammation. Th2 cells induce inflammatory diseases characterized by eosinophilic inflammation by secreting IL-4 and IL-5.
이에, 락토바실러스 람노수스 유래 소포가 Th17 및 Th2 세포에 의한 과민반응에 대한 치료 효과를 평가하였다. 구체적으로, 실시예 2의 방법과 같이 고지방 식이로 영양 과잉을 유도한 마우스에 락토바실러스 람노수스 유래 소포를 경구로 투여하여 기도세척액 내 Th17 및 Th2 관련 사이토카인(IL-17, IL-4, 및 IL-5) 수치를 Enzyme-Linked ImmunoSorbent Assay(ELISA, R&D Systems) 방법으로 측정하였다. ELISA 분석을 위해, Capture 항체를 PBS에 희석시켜 96-well 폴리스티렌 플레이트에 작용 농도에 맞게 50 μl 씩 분주한 후 4 ℃에서 밤새 반응시켰다. 이후 PBST (0.05 % tween-20이 들어있는 PBS) 용액 100 μl로 두 번씩 씻어준 후, RD(1 % BSA 가 들어있는 PBST) 용액 100 μl을 분주하여 상온에서 1시간 동안 차단(blocking)한 후, 다시 PBST 100 μl로 두 번 씻어준 후, 샘플 및 standard를 농도에 맞게 50 μl씩 분주하고 상온에서 2시간 동안 반응시켰다. 다시 PBST 100 μl로 두 번 씻어준 후, detection 항체를 RD에 희석시켜 작용 농도에 맞게 50 μl씩 분주하여 상온에서 2시간 동안 반응시켰다. 또 다시 PBST 100 μl로 두 번 씻어준 후, Strpetavidin-HRP를 RD에 1/200으로 희석시켜 50 μl씩 분주하여 상온에서 30분간 반응시켰다. 마지막으로 PBST 100 μl로 세 번 씻어준 후, TMB 기질과 0.04 % 과산화수소수를 1:1 혼합한 용액 50 μl를 분주한 후 발색을 기다리다가 5분에서 20분 후 발색이 진행되었을 때, 1 M 황산용액을 50 μl씩 분주해 반응을 멈추고 Synergy™ HT multi-detection microplate reader를 이용해 (BioTek, USA) 450 nm에서 흡광도를 측정하였다.Thus, the therapeutic effect of Lactobacillus rhamnosus-derived vesicles on hypersensitivity by Th17 and Th2 cells was evaluated. Specifically, Lactobacillus rhamnosus-derived vesicles were orally administered to mice induced to overnutrition by a high-fat diet as in the method of Example 2, and Th17 and Th2-related cytokines (IL-17, IL-4, and IL-5) levels were measured by the Enzyme-Linked ImmunoSorbent Assay (ELISA, R&D Systems) method. For ELISA analysis, Capture antibody was diluted in PBS, dispensed in 50 μl each according to the working concentration in a 96-well polystyrene plate, and reacted overnight at 4 °C. After washing twice with 100 μl of PBST (PBS containing 0.05% tween-20) solution, 100 μl of RD (PBST containing 1% BSA) solution was dispensed and blocked for 1 hour at room temperature. , After washing again with 100 μl of PBST twice, the sample and standard were dispensed in 50 μl each according to the concentration and reacted at room temperature for 2 hours. After washing again with 100 μl of PBST twice, the detection antibody was diluted in RD, dispensed by 50 μl according to the working concentration, and reacted at room temperature for 2 hours. After washing again with 100 μl of PBST twice, Strpetavidin-HRP was diluted 1/200 in RD, dispensed by 50 μl, and reacted at room temperature for 30 minutes. Finally, after washing three times with 100 μl of PBST, dispensing 50 μl of a 1:1 mixture of TMB substrate and 0.04% hydrogen peroxide solution, wait for color development, and when color development proceeds after 5 to 20 minutes, 1 M The reaction was stopped by dispensing 50 μl of the sulfuric acid solution, and absorbance was measured at 450 nm using a Synergy™ HT multi-detection microplate reader (BioTek, USA).
그 결과, 도 5a 및 도 5b에 나타낸 바와 같이, 비만 그룹인 경우에는 정상 영양 상태의 마우스에 비하여 기도세척액 내 Th17 사이토카인인 IL-17, 및 Th2 사이토카인인 IL-4 및 IL-5가 현저히 증가되어 있었다. 반면, 락토바실러스 람노수스 유래 소포를 투여한 그룹에서는 기도세척액 내의 Th17 및 Th2 사이토카인의 수치가 정상 수준으로 감소되었다. As a result, as shown in FIGS. 5A and 5B , in the case of the obese group, IL-17, a Th17 cytokine, and IL-4 and IL-5, a Th2 cytokines, in the airway lavage fluid were significantly decreased compared to mice in a normal nutritional state. had been increased On the other hand, in the group administered with Lactobacillus rhamnosus-derived vesicles, the levels of Th17 and Th2 cytokines in airway lavage fluid were reduced to normal levels.
이상의 결과를 통해, 영양 과잉에 의해 유도되는 면역기능 이상이 락토바실러스 람노수스 유래 소포에 의해 효율적으로 억제 및 개선됨을 알 수 있다.Through the above results, it can be seen that the abnormal immune function induced by nutrient excess is efficiently suppressed and improved by Lactobacillus rhamnosus-derived vesicles.
실시예 4. 에너지 대사 스트레스에 대한 세포의 항상성 유지에 락토바실러스 람노수스 유래 소포의 치료 효과Example 4. Therapeutic effect of Lactobacillus rhamnosus-derived vesicles on maintaining cellular homeostasis against energy metabolism stress
세포 노화는 반복적인 물리적, 화학적, 생물학적, 정신적 스트레스에 의해 세포의 분열 능력이 소실되는 것으로 정의되며, 반복적인 스트레스에 의해 세포의 노화와 함께 세포 재생 능력이 떨어져서 세포 노화 및 노화 관련 질병이 발생한다. 특히 세포는 ATP 생성이 떨어지는 대사 스트레스 상황에서 세포 내 신호전달경로로서 AMPK 단백질을 활성화하여 세포의 항상성(metabolic homeostasis)을 유도함에 따라 세포 노화 및 사멸을 억제하게 된다. Cellular aging is defined as the loss of cell division ability due to repetitive physical, chemical, biological, and mental stress, and cell aging and aging-related diseases occur because cell regeneration ability decreases along with aging of cells due to repeated stress. . In particular, cells activate AMPK protein as an intracellular signaling pathway under metabolic stress situations where ATP production is reduced to induce cellular homeostasis, thereby suppressing cell aging and apoptosis.
이에, 락토바실러스 람노수스 유래 소포(MDH-003)가 세포 내에서 AMPK 활성화를 통해 세포 노화에 미치는 영향을 평가하기 위하여 다음과 같은 방법으로 실험을 수행하였다. 즉, 근육세포에서 락토바실러스 람노수스 유래 소포 처리 농도에 따른 AMPK 활성을 평가하기 위해, 세포에 락토바실러스 람노수스 유래 소포를 0, 0.1, 1, 및 10 μg/ml의 농도로 1시간 동안 처리하였다. 대조군으로는 노화를 억제하는 메트포민(metformin)을 10 μg/ml 농도로 사용하였다. 상기 약물을 세포에 처리한 후 AMPK 신호전달에서 중요한 지표인 pAMPK의 양 차이를 웨스턴 블롯으로 측정하였다. Accordingly, in order to evaluate the effect of Lactobacillus rhamnosus-derived vesicles (MDH-003) on cellular senescence through AMPK activation in cells, the following experiment was performed. That is, in order to evaluate AMPK activity according to the treatment concentration of Lactobacillus rhamnosus-derived vesicles in muscle cells, cells were treated with Lactobacillus rhamnosus-derived vesicles at concentrations of 0, 0.1, 1, and 10 μg/ml for 1 hour. . As a control, metformin, which inhibits aging, was used at a concentration of 10 μg/ml. After treatment with the drug, the difference in the amount of pAMPK, which is an important indicator in AMPK signaling, was measured by Western blotting.
그 결과, 도 6에 나타낸 바와 같이, AMPK의 인산화(pAMPK)가 락토바실러스 람노수스 유래 소포를 처리한 경우에 메트포민과 유사하게 증가되었으며, 이러한 효과는 본 발명 소포의 농도에 의존적으로 증가되었다. As a result, as shown in FIG. 6, AMPK phosphorylation (pAMPK) was increased similarly to metformin when Lactobacillus rhamnosus-derived vesicles were treated, and this effect was increased in a concentration-dependent manner of the vesicles of the present invention.
이상의 결과를 통해 락토바실러스 람노수스 유래 소포는 AMPK 신호를 활성화하여 대사 스트레스에 대한 세포의 항상성을 증가시킴에 따라 세포의 생존능력을 항진시키고 노화를 예방함을 알 수 있다.Through the above results, it can be seen that Lactobacillus rhamnosus-derived vesicles activate AMPK signals to increase cell homeostasis against metabolic stress, thereby enhancing cell viability and preventing aging.
실시예 5. 바이러스성 원인 인자인 poly(I:C)에 의해 유도된 면역질환 마우스 모델에서 락토바실러스 람노수스 유래 소포의 염증 억제 효과Example 5. Anti-inflammatory effect of Lactobacillus rhamnosus-derived vesicles in mouse models of immune diseases induced by viral causative factor poly(I:C)
Poly(I:C)는 인공적으로 합성된 이중 구조의 리보뉴클레오타이드 중합체로서 일부 바이러스에 존재하는 dsRNA와 구조적으로 유사하여 다양한 염증성 신호전달 경로를 활성화하여 바이러스 감염 질환을 유발한다. Poly(I:C) is an artificially synthesized double-structured ribonucleotide polymer that is structurally similar to dsRNA present in some viruses and activates various inflammatory signaling pathways to cause viral infections.
이에, 바이러스성 원인 인자에 의한 면역질환 모델에서 락토바실러스 람노수스 유래 소포의 치료 효과를 평가하기 위하여 다음과 같은 방법으로 실험을 수행하였다. 즉, 도 7에 나타난 바와 같이, C57BL/6 6주령 수컷 마우스에 바이러스성 원인 인자인 poly(I:C)를 2주간 격일로 비강 투여하여 면역질환 마우스 모델을 제작하였다. 락토바실러스 람노수스 유래 소포는 poly(I:C) 투여 6일 전부터 2주간 격일로 경구투여하였다. 대조 약물로는 덱사메타손을 2 mg/kg의 용량으로 복강 투여하였다. Accordingly, in order to evaluate the therapeutic effect of Lactobacillus rhamnosus-derived vesicles in an immune disease model caused by viral causative factors, an experiment was performed as follows. That is, as shown in FIG. 7, a viral causative factor, poly(I:C), was intranasally administered to C57BL/6 6-week-old male mice every other day for 2 weeks to prepare an immune disease mouse model. Lactobacillus rhamnosus-derived vesicles were orally administered every other day for 2 weeks from 6 days before poly(I:C) administration. As a control drug, dexamethasone was intraperitoneally administered at a dose of 2 mg/kg.
5-1. 증가된 염증세포 감소 효과 확인5-1. Confirmation of increased inflammatory cell reduction effect
투여 후 마우스의 기도세척액을 획득하고, 염증세포의 수를 평가하였다.After administration, airway washing fluid of the mouse was obtained, and the number of inflammatory cells was evaluated.
그 결과, 도 8a 및 도 8b에 나타난 바와 같이, 기도세척액 내 염증 세포 수 변화를 관찰한 결과, poly(I:C)를 투여한 경우에는 기도세척액 내 염증세포의 수가 증가하였고, 특히 대식세포와 림프구 수가 증가하였다. 한편, poly(I:C)에 의해 증가된 기도세척액 내 염증세포의 수는 덱사메타손(Dex) 치료와 유사하게 락토바실러스 람노수스 유래 소포에 의해 유의하게 억제되었다. As a result, as shown in FIGS. 8a and 8b, as a result of observing changes in the number of inflammatory cells in the airway lavage fluid, when poly(I:C) was administered, the number of inflammatory cells in the airway lavage fluid increased, especially macrophages and The number of lymphocytes increased. On the other hand, the number of inflammatory cells in airway lavage fluid increased by poly(I:C) was significantly suppressed by Lactobacillus rhamnosus-derived vesicles, similar to dexamethasone (Dex) treatment.
5-2. 폐 조직 손상 개선 효과 확인5-2. Confirmation of lung tissue damage improvement effect
Hematoxylin and Eosin(H&E) 염색으로 폐 조직의 변화를 평가하였다.Changes in lung tissue were evaluated by Hematoxylin and Eosin (H&E) staining.
도 9a에 나타난 바와 같이, 정상군의 폐 조직에서는 작은 크기의 폐포가 균일하게 관찰되었으나, poly(I:C) 투여 그룹에서는 폐포 주변으로 세포들이 많이 몰려있는 것이 관찰되었다. 또한, 덱사메타손을 처리한 그룹과 락토바실러스 람노수스 유래 소포를 투여한 그룹에서는 비교적 폐포의 형태가 균일하게 유지되었다.As shown in FIG. 9a , small-sized alveoli were uniformly observed in the lung tissue of the normal group, but a large number of cells were observed around the alveoli in the poly(I:C)-administered group. In addition, in the group treated with dexamethasone and the group administered with Lactobacillus rhamnosus-derived vesicles, the morphology of the alveoli was maintained relatively uniformly.
또한, 도 9b에 나타난 바와 같이, 기도 주변에 면역세포의 침윤이 감소하는 것을 확인하였다.In addition, as shown in Figure 9b, it was confirmed that the infiltration of immune cells around the airway was reduced.
5-3. 전신 염증반응 억제 효과 확인5-3. Confirmation of systemic inflammatory response inhibitory effect
바이러스성 원인 인자에 의한 전신적인 염증반응을 혈중 고감도C반응단백(hsCRP) 수치를 통해 평가하였다. CRP는 급성기 반응 단백질로서 전신 염증 반응의 표지자로 사용되어 왔으며, hsCRP는 심혈관 질환의 단순한 표지자가 아니라 독립적 위험인자로서, hsCRP 검사는 표준 CRP 검사보다 낮은 농도의 해당 단백질을 더 정확히 검출할 수 있고, 혈관내피세포의 기능장애 촉진, 혈전 형성 증진 등의 작용을 통해 동맥경화와 그로 인한 합병 질환의 발생에 중요한 역할을 한다고 받아들여지고 있다. 본 실시예에서는 Immunonephelometric assay 방법으로 hsCRP 농도를 측정하였다. The systemic inflammatory response caused by viral causative factors was evaluated through blood high sensitivity C-reactive protein (hsCRP) levels. CRP has been used as a marker of the systemic inflammatory response as an acute-phase response protein, and hsCRP is not a simple marker of cardiovascular disease but an independent risk factor. It is accepted that it plays an important role in the occurrence of arteriosclerosis and associated diseases by promoting dysfunction of vascular endothelial cells and promoting thrombus formation. In this Example, hsCRP concentration was measured by Immunonephelometric assay method.
도 10에 나타난 바와 같이, 락토바실러스 람노수스 유래 소포에 의해 hsCRP 수치가 감소하였다.As shown in FIG. 10, the level of hsCRP was decreased by Lactobacillus rhamnosus-derived vesicles.
이상의 결과들을 통해 poly(I:C)에 의해 유도된 전신적인 염증 반응, 및 폐 질환이 락토바실러스 람노수스 유래 소포에 의해 효과적으로 치료될 수 있음을 알 수 있다.Through the above results, it can be seen that the systemic inflammatory response and lung diseases induced by poly(I:C) can be effectively treated by Lactobacillus rhamnosus-derived vesicles.
실시예 6. 바이러스성 원인 인자인 poly(I:C)에 의해 유도된 면역질환 마우스 모델에서 락토바실러스 람노수스 유래 소포의 면역조절 효과Example 6. Immunomodulatory effect of Lactobacillus rhamnosus-derived vesicles in mouse models of immune diseases induced by viral causative factor poly(I:C)
6-1. 기도세척액에서 염증성 사이토카인 분비 확인6-1. Confirmation of secretion of inflammatory cytokines in airway lavage fluid
염증세포가 분비하는 TNF-α와 IL-6는 병원성 원인 인자에 의한 염증질환을 유도하는 대표적인 염증성 매개체이다. 본 실시예에서는 바이러스성 원인 인자에 의한 면역기능 이상에 대한 락토바실러스 람노수스 유래 소포의 면역조절 효과를 평가하기 위하여 다음과 같은 방법으로 실험을 수행하였다. 즉, 실시예 5에 기술된 면역질환 마우스 모델에서 기도세척액 내 염증성 사이토카인 TNF-α, 및 IL-6을 ELISA 방법으로 측정하였다. ELISA 방법은 전술한 방법을 사용하였다.TNF-α and IL-6 secreted by inflammatory cells are typical inflammatory mediators that induce inflammatory diseases by pathogenic causative factors. In this Example, in order to evaluate the immunoregulatory effect of Lactobacillus rhamnosus-derived vesicles on immune dysfunction caused by viral causative factors, the following experiment was performed. That is, in the immunological disease mouse model described in Example 5, the inflammatory cytokines TNF-α and IL-6 in airway lavage fluid were measured by ELISA method. The ELISA method was used as described above.
그 결과, 도 11a 및 도 11b에 나타낸 바와 같이, 기도세척액 내 TNF-α와 IL-6 농도가 poly(I:C) 투여 그룹에서 음성 대조군(NC) 대비 증가되었다. 반면, 락토바실러스 람노수스 유래 소포 투여 그룹에서 poly(I:C)에 의해 증가된 TNF-α와 IL-6 분비가 음성 대조군 수준으로 유의미하게 감소되었고, 이는 덱사메타손(Dexa) 투여 그룹보다 억제효과가 우수하였다.As a result, as shown in FIGS. 11a and 11b, the concentrations of TNF-α and IL-6 in the airway lavage fluid were increased in the poly(I:C) administration group compared to the negative control group (NC). On the other hand, in the group administered with Lactobacillus rhamnosus-derived vesicles, the secretion of TNF-α and IL-6, which was increased by poly(I:C), was significantly reduced to the level of the negative control group, which had an inhibitory effect compared to the group administered with dexamethasone (Dexa). Excellent.
6-2. 비장 T세포에서의 염증성 사이토카인 분비 확인6-2. Confirmation of inflammatory cytokine secretion from splenic T cells
비장 T세포에서 사이토카인 분비 양상을 평가하여 poly(I:C)에 의한 전신적인 면역기능 이상에 락토바실러스 람노수스 유래 소포의 치료 효과를 평가하였다. The therapeutic effect of Lactobacillus rhamnosus-derived vesicles on systemic immune dysfunction caused by poly(I:C) was evaluated by evaluating cytokine secretion patterns in splenic T cells.
도 12a 및 도 12b에 나타난 바와 같이, poly(I:C) 투여 그룹에서 Th1 사이토카인인 IFN-γ 및 Th17 사이토카인인 IL-6의 분비가 음성 대조군 대비 증가되었다. 반면, 락토바실러스 람노수스 유래 소포에 의해 증가된 IFN-γ 및 IL-6이 유의미하게 억제되었다. 한편, 덱사메타손(Dexa)은 효과가 없었다.As shown in FIGS. 12A and 12B , secretion of IFN-γ, a Th1 cytokine, and IL-6, a Th17 cytokine, was increased in the poly(I:C) administration group compared to the negative control group. On the other hand, the increased IFN-γ and IL-6 by Lactobacillus rhamnosus-derived vesicles were significantly suppressed. On the other hand, dexamethasone (Dexa) was ineffective.
이상의 결과를 통해, 락토바실러스 람노수스 유래 소포는 바이러스성 원인 인자에 의한 면역기능 이상을 효율적으로 억제할 수 있고, 이는 기존의 면역억제제인 덱사메타손 보다 우수한 치료효과가 있음을 알 수 있다.Through the above results, it can be seen that the Lactobacillus rhamnosus-derived vesicles can efficiently suppress immune dysfunction caused by viral causative factors, and have a superior therapeutic effect than dexamethasone, a conventional immunosuppressive agent.
실시예 7. 바이러스성 원인 인자인 poly(I:C)에 의한 면역기능 장애 조절에 대한 락토바실러스 람노수스 유래 소포의 분자생물학적 작용기전 확인Example 7. Confirmation of the molecular biological mechanism of action of Lactobacillus rhamnosus-derived vesicles for the control of immune dysfunction by poly(I:C), a viral causative factor
핵 전사 인자인 nuclear factor-κB(NF-κB)는 염증 조절 인자로서 inducible nitric oxide synthase(iNOS)의 전사를 유도하며 다양한 전염증성 사이토카인의 분비를 증가시킨다. Nuclear factor-κB (NF-κB), a nuclear transcription factor, induces the transcription of inducible nitric oxide synthase (iNOS) as an inflammatory regulator and increases the secretion of various pro-inflammatory cytokines.
이에, 락토바실러스 람노수스 유래 소포가 NF-κB 활성화를 통해 염증반응에 미치는 영향을 평가하기 위하여, 마우스 폐 조직을 이용한 western blot 방법으로 실험을 수행하였다. Accordingly, in order to evaluate the effect of Lactobacillus rhamnosus-derived vesicles on the inflammatory response through NF-κB activation, an experiment was performed using a western blot method using mouse lung tissue.
도 13에 나타난 바와 같이, NF-κB의 인산화(p-NF-κB, p-p65) 및 iNOS 발현이 poly(I:C)를 투여한 경우에 증가하였다. 또한, poly(I:C)에 의해 증가된 NF-κB의 인산화(p-NF-κB, p-p65)는 덱사메타손(Dex) 및 락토바실러스 람노수스 유래 소포에 의해 억제되었다. 또한, 락토바실러스 람노수스 유래 소포를 투여한 경우 덱사메타손보다 poly(I:C)에 의해 증가된 iNOS 발현을 효율적으로 억제하였다. As shown in FIG. 13, NF-κB phosphorylation (p-NF-κB, p-p65) and iNOS expression increased when poly(I:C) was administered. In addition, NF-κB phosphorylation (p-NF-κB, p-p65) increased by poly(I:C) was inhibited by dexamethasone (Dex) and Lactobacillus rhamnosus-derived vesicles. In addition, when vesicles derived from Lactobacillus rhamnosus were administered, iNOS expression, which was increased by poly(I:C), was more efficiently suppressed than dexamethasone.
이상의 결과를 통해 락토바실러스 람노수스 유래 소포가 병원성 원인 인자에 의한 면역기능 이상의 핵심인 NF-κB 신호 및 이의 하부 신호인 iNOS의 발현을 효율적으로 억제하여 바이러스성 원인 인자에 의한 면역 과민 반응을 조절함을 알 수 있다.Through the above results, Lactobacillus rhamnosus-derived vesicles effectively suppress the expression of NF-κB signal, which is the core of immune function abnormality caused by pathogenic causative factors, and iNOS, a lower signal thereof, to regulate immune hypersensitivity reactions caused by viral causative factors. can know
상기 결과들을 통하여, 본 발명의 락토바실러스 람노수스 유래 소포는 AMPK 신호를 통해 세포의 항상성을 증가시켜 세포 노화 및 세포사멸을 억제할 뿐만 아니라, 생물학적 원인 인자에 의한 면역기능 이상을 NF-κB 신호를 억제하여 염증의 발생을 억제함으로써 면역질환 및 세포 노화 관련 질병을 효율적으로 치료할 수 있음을 확인한 바(도 14 참조), 본 발명의 락토바실러스 람노수스 유래 소포는 면역기능 장애 및 세포 노화 관련 질환의 개선, 예방, 또는 치료 용도로서 사용될 수 있을 것으로 기대된다.Through the above results, the Lactobacillus rhamnosus-derived vesicles of the present invention not only inhibit cell aging and apoptosis by increasing cell homeostasis through AMPK signaling, but also suppress immune function abnormalities caused by biological causative factors through NF-κB signaling. As it was confirmed that immune diseases and cellular senescence-related diseases can be effectively treated by suppressing the occurrence of inflammation (see FIG. 14), the Lactobacillus rhamnosus-derived vesicles of the present invention improve immune function disorders and cellular senescence-related diseases , prophylactic, or therapeutic use is expected.
상기 진술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention described above is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. There will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.
Claims (18)
A pharmaceutical composition for preventing or treating at least one selected from the group consisting of immune diseases and cellular aging-related diseases, containing Lactobacillus rhamnosus-derived vesicles as an active ingredient.
상기 면역질환은 바이러스 감염 질환, 알레르기성 면역질환, 및 자가면역질환으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The immune disease is a pharmaceutical composition, characterized in that at least one selected from the group consisting of viral infection diseases, allergic immune diseases, and autoimmune diseases.
상기 바이러스 감염 질환은 바이러스성 폐렴, 바이러스성 간염, 바이러스성 심장염, 바이러스성 장염, 바이러스성 신장염, 바이러스성 혈전색전증, 대상포진, 및 메니에르병으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
According to claim 2,
Characterized in that the viral infectious disease is at least one selected from the group consisting of viral pneumonia, viral hepatitis, viral carditis, viral enteritis, viral nephritis, viral thromboembolism, herpes zoster, and Meniere's disease, pharmaceutical composition.
상기 자가면역질환은 전신성홍반성낭창, 류마티스관절염, 쇼그렌증후군, 베체트병, 강직성척추염, 및 다발성경화증으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
According to claim 2,
The autoimmune disease is a pharmaceutical composition, characterized in that at least one selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease, ankylosing spondylitis, and multiple sclerosis.
상기 알레르기성 면역질환은 아토피피부염, 건선, 알레르기성 결막염, 알레르기 비염, 알레르기 천식, 과민성 폐렴, 식품알레르기, 셀리악병, 과민성 장증후군, 및 아나필락시스로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
According to claim 2,
The allergic immune disease is characterized in that at least one selected from the group consisting of atopic dermatitis, psoriasis, allergic conjunctivitis, allergic rhinitis, allergic asthma, hypersensitivity pneumonitis, food allergy, celiac disease, irritable bowel syndrome, and anaphylaxis. composition.
상기 세포 노화 관련 질환은 협심증, 심근경색, 심근병증, 혈전색전증, 및 뇌졸중으로 이루어진 군으로부터 선택된 하나 이상의 심혈관질환;
알코올성 지방간염, 간경변, 만성담도염, 만성담낭염, 및 만성췌장염으로 이루어진 군으로부터 선택된 하나 이상의 간-담도-췌장질환; 및
통풍, 골관절염, 골다공증 등의 근골격계질환, 알츠하이머병, 파킨슨병, 황반변성으로 이루어진 군으로부터 선택된 하나 이상의 신경질환으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The cellular aging-related diseases include at least one cardiovascular disease selected from the group consisting of angina pectoris, myocardial infarction, cardiomyopathy, thromboembolism, and stroke;
at least one hepato-biliary-pancreatic disease selected from the group consisting of alcoholic steatohepatitis, cirrhosis, chronic cholangitis, chronic cholecystitis, and chronic pancreatitis; and
Characterized in that at least one selected from the group consisting of one or more neurological diseases selected from the group consisting of musculoskeletal disorders such as gout, osteoarthritis and osteoporosis, Alzheimer's disease, Parkinson's disease and macular degeneration, a pharmaceutical composition.
상기 소포는 평균 직경이 10~1000 nm인 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The vesicles are characterized in that the average diameter is 10 ~ 1000 nm, the pharmaceutical composition.
상기 소포는 락토바실러스 람노수스 배양액에서 분리되는 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The pharmaceutical composition, characterized in that the vesicles are separated from the Lactobacillus rhamnosus culture medium.
상기 소포는 락토바실러스 람노수스를 첨가하여 제조된 식품에서 분리되는 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The pharmaceutical composition, characterized in that the vesicles are separated from food prepared by adding Lactobacillus rhamnosus.
상기 소포는 락토바실러스 람노수스에서 자연적으로 또는 인공적으로 분비되는 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The pharmaceutical composition, characterized in that the vesicles are secreted naturally or artificially from Lactobacillus rhamnosus.
A food composition for preventing or improving at least one selected from the group consisting of immune diseases and cellular aging-related diseases, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
상기 면역질환은 바이러스 감염 질환, 알레르기성 면역질환, 및 자가면역질환으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 식품 조성물.
According to claim 11,
The immune disease is a food composition, characterized in that at least one selected from the group consisting of viral infection diseases, allergic immune diseases, and autoimmune diseases.
상기 소포는 락토바실러스 람노수스 배양액에서 분리되는 것을 특징으로 하는, 식품 조성물.
According to claim 11,
Characterized in that the vesicles are separated from the Lactobacillus rhamnosus culture medium, the food composition.
상기 소포는 락토바실러스 람노수스를 첨가하여 제조된 식품에서 분리되는 것을 특징으로 하는, 식품 조성물.
According to claim 11,
The food composition, characterized in that the vesicles are separated from the food prepared by adding Lactobacillus rhamnosus.
상기 소포는 락토바실러스 람노수스에서 자연적으로 또는 인공적으로 분비되는 것을 특징으로 하는, 식품 조성물.
According to claim 11,
The food composition, characterized in that the vesicles are secreted naturally or artificially from Lactobacillus rhamnosus.
A pharmaceutical composition for preventing or treating aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
A food composition for preventing or improving aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
A cosmetic composition for preventing or improving aging, comprising Lactobacillus rhamnosus-derived vesicles as an active ingredient.
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