KR20220069248A - Composition for Theragnosis of Scleroderma containing Bifidobacterium sp. as Active Ingredient - Google Patents
Composition for Theragnosis of Scleroderma containing Bifidobacterium sp. as Active Ingredient Download PDFInfo
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- KR20220069248A KR20220069248A KR1020200156183A KR20200156183A KR20220069248A KR 20220069248 A KR20220069248 A KR 20220069248A KR 1020200156183 A KR1020200156183 A KR 1020200156183A KR 20200156183 A KR20200156183 A KR 20200156183A KR 20220069248 A KR20220069248 A KR 20220069248A
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- bifidobacterium
- cells
- scleroderma
- composition
- skin
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Abstract
Description
본 발명은 비피도박테리움 속을 유효성분으로 포함하는 피부경화증에 대한 테라그노시스용 조성물에 관한 것이다. The present invention relates to a composition for theragnosis for scleroderma comprising the genus Bifidobacterium as an active ingredient.
면역질환은 포유류 면역계의 구성성분들이 포유류의 병리상태를 야기하거나, 매개하거나 또는 기타 공헌하는 질환으로서, 특히 염증성 장애는 전 세계에서 가장 중요한 건강 문제 중 하나이다. 염증은 일반적으로 외부 물질 또는 해로운 자극에 의한 숙주 침입에 대해 신체 조직의 국소화된 보호 반응이다. 염증의 원인은 박테리아, 바이러스 및 기생충과 같은 감염성 원인; 화상 또는 방사선 조사와 같은 물리적 원인; 독소, 약물 또는 산업적 제제와 같은 화학약품; 알레르기 및 자가면역 반응과 같은 면역적 반응, 또는 산화성 스트레스와 연관된 상태일수 있다.Immune diseases are diseases in which components of the mammalian immune system cause, mediate or otherwise contribute to the pathology of mammals. In particular, inflammatory disorders are one of the most important health problems in the world. Inflammation is generally a localized protective response of body tissues against host invasion by foreign substances or noxious stimuli. Inflammation can be caused by infectious causes such as bacteria, viruses, and parasites; physical causes such as burns or radiation; chemicals such as toxins, drugs or industrial agents; immune responses, such as allergies and autoimmune responses, or conditions associated with oxidative stress.
각종 병원체에 대한 생체 방어 시스템으로 면역계에서 중심적 역할을 담당하는 세포군의 하나로 T 세포가 있다. T 세포는 인체의 흉선에서 생성되며 일련의 분화 과정을 거치면서 고유의 특성을 지닌 T 세포로 분화하게 되는데, 분화를 완료한 T 세포는 그 기능에 따라 크게 1형 보조 세포(Th1)와 2형 보조 세포(Th2)로 구분된다. 이 중에서 Th1 세포의 주된 기능은 세포 매개성 면역에 관여하고, Th2 세포는 체액성 면역에 관여하며, 면역계에서 이러한 두 세포 집단은 서로 과 활성화되지 않도록 서로 견제를 통해 면역계의 균형을 유지하고 있다. 따라서 면역질환의 대부분은 이러한 두 가지 면역 세포간의 불균형에 기인하는 것으로 볼 수 있는데, 예를 들어 Th1 세포의 활성이 비정상적으로 증가하는 경우 자가면역질환이 발생할 수 있고, Th2 세포의 활성이 비정상적으로 증가하는 경우 과민반응에 의한 면역질환이 발생하는 것으로 알려져 있다. 한편, Th1 세포의 분화에 대한 최근 연구 결과에 따르면, Th1 세포의 활성을 조절할 수 있는 새로운 그룹인 면역조절 T 세포(Treg)의 존재가 알려지면서 이를 이용한 면역질환의 치료에 대한 연구가 대두되고 있는데, Treg 세포는 비정상적으로 활성화된 면역세포의 기능을 억제하여 염증 반응을 제어하는 특성이 있어, Treg 세포의 활성을 증가시키는 작용을 통해 면역질환을 치료하고자 하는 연구들이 많이 진행되고 있다. 또한, Treg 세포 이 외에 T 세포의 분화 과정에서 만들어지는 또 다른 그룹으로 Th17 세포가 있는데, Th17 세포는 미분화 T세포의 분화 과정에서 Treg 세포의 분화와 유사한 과정을 거치며 형성되는 것으로 알려져 있다. 즉, Treg 세포와 Th17 세포의 분화는 공통적으로 TGF-β의 존재 하에서 이루어지지만, Treg 세포의 경우 IL-6을 필요로 하지 않는 반면, Th17 세포의 경우에는 TGF-β와 함께 IL-6가 존재하는 상황에서 분화를 한다. 또한, 분화된 Th17 세포는 IL-17을 분비하는 것을 특징으로 한다. Th17 세포는 Treg 세포와는 달리 면역질환에서 보이는 염증반응의 최전방에서 관여하여 염증 반응의 신호를 최대화시켜 질병의 진행을 가속화시키는 것이 밝혀지고 있다. 그러므로 자가면역질환 중 Treg 세포에 의해 제어되지 않는 자가면역질환의 경우, Th17 세포 활성의 억제를 표적으로 한 자가면역질환의 치료제 개발이 크게 부각 되고 있다.T cells are one of the cell groups that play a central role in the immune system as a biological defense system against various pathogens. T cells are generated in the thymus of the human body and differentiate into T cells with unique characteristics through a series of differentiation processes. differentiated into helper cells (Th2). Among them, the main function of Th1 cells is involved in cell-mediated immunity, Th2 cells are involved in humoral immunity, and in the immune system, these two cell populations maintain the balance of the immune system by checking each other so that they do not overactivate each other. Therefore, it can be seen that most of the immune diseases are due to the imbalance between these two immune cells. For example, if the activity of Th1 cells is abnormally increased, autoimmune diseases may occur, and the activity of Th2 cells is abnormally increased. It is known that immune diseases caused by hypersensitivity reactions occur. On the other hand, according to the results of recent studies on the differentiation of Th1 cells, as the existence of a new group of immunoregulatory T cells (Tregs) that can regulate the activity of Th1 cells is known, research on the treatment of immune diseases using them is emerging. , Treg cells have the characteristic of controlling the inflammatory response by suppressing the function of abnormally activated immune cells, and many studies are being conducted to treat immune diseases by increasing the activity of Treg cells. In addition to Treg cells, there are Th17 cells as another group created in the differentiation process of T cells. Th17 cells are known to be formed through a process similar to the differentiation of Treg cells in the differentiation process of undifferentiated T cells. That is, Treg cells and Th17 cells are differentiated in the presence of TGF-β in common, but Treg cells do not require IL-6, whereas in Th17 cells, IL-6 is present together with TGF-β. differentiate in a situation where In addition, differentiated Th17 cells are characterized in that they secrete IL-17. It has been found that Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases and accelerate disease progression by maximizing the signal of the inflammatory response. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, the development of therapeutic agents for autoimmune diseases targeting the inhibition of Th17 cell activity has been highlighted.
한편, 피부경화증(Systemic scleroderma)은 피부 섬유모세포에 의한 세포외 매트릭스 내로의 과도한 단백질 침착을 특징으로 하는, 피부 섬유증으로도 지칭되는 진행성 쇠약화 자가면역 장애로, 피부에서의 만연된 미세혈관 손상 및 진행성 섬유증을 특징으로 한다. 일반적으로 가장 명확한 임상적 증상은 예를 들어, 피부가 딱딱해지거나, 홍조를 띠거나, 또는 벗겨지는 등의 피부 경화 및 이와 관련된 상흔이다. SSc는 활성화된 섬유아세포(fibroblast)가 콜라겐(collagen) 등의 결합조직 구성물질을 과도하게 생성하는데 기인하며, 피부의 결합 조직에 변화를 일으켜 그 기능의 결함을 초래한다. SSc는 그 발병 부위에 따라, 피부 경화가 팔꿈지 이하의 손, 무릎 이하의 발, 얼굴에서만 발생되는 제한성(limited) 타입과, 이보다 더 많은 부위, 즉 팔꿈치 이상, 무릎 이상의 피부와 몸통에서도 피부가 딱딱해지는 변화가 나타나면서 신장, 폐 등의 내부 장기 침범이 동반되는 확산성(diffuse) 타입으로 크게 분류된다. 제한성 SSc를 보이는 환자는 90% 이상의 5년 생존율을 보이나, 미만성 SSc를 보이는 환자의 예후는 좋지 않아 50∼70% 정도에 그치는 5년 생존율을 나타낸다. 확산성 피부 질환을 갖는 환자는 종종 피부에서 독특한 마커, 예컨대, I형 인터페론(IFN)-유도된 유전자의 상향조절을 보여준다. IFN이 피부 섬유증에서 일정한 역할을 수행한다는 가설을 만성 바이러스 감염에 대한 IFN 치료를 받은 환자에서 발생하는 피부경화증의 최근 보고가 뒷받침한다 (Varga & Abraham (2007) J. Clin. Invest. 117:557-567 및 Coelho et al. (2008) Immunol. Lett. 118:110-115). SSc의 병변은 조직의 섬유증(tissue fibrosis), 세소혈관(細小血管, small blood vessel)의 맥관 장애(vasculopathy), 자가항체에 의한 특이적 자가면역반응 (autoimmune disease) 등의 증상으로 특징될 수 있다. On the other hand, Systemic scleroderma is a progressive, debilitating autoimmune disorder, also referred to as dermal fibrosis, characterized by excessive protein deposition into the extracellular matrix by skin fibroblasts, with widespread microvascular damage in the skin and It is characterized by progressive fibrosis. In general, the most obvious clinical symptoms are hardening of the skin and associated scarring, for example, hardening, redness, or peeling of the skin. SSc is caused by activated fibroblasts that excessively produce connective tissue constituents such as collagen, and causes changes in the connective tissue of the skin, resulting in a defect in its function. SSc is a limited type in which skin hardening occurs only on the hands below the elbow, feet below the knee, and face, depending on the site of the onset, and skin in more areas, i.e., above the elbow, above the knee, and the body, as well as the skin It is broadly classified as a diffuse type accompanied by invasion of internal organs such as the kidneys and lungs with changes in hardness. Patients with restricted SSc have a 5-year survival rate of more than 90%, but the prognosis of patients with diffuse SSc is poor, showing a 5-year survival rate of only 50-70%. Patients with diffuse skin disease often show upregulation of unique markers in the skin, such as type I interferon (IFN)-induced genes. The hypothesis that IFN plays a role in skin fibrosis is supported by a recent report of scleroderma in patients treated with IFN for chronic viral infection (Varga & Abraham (2007) J. Clin. Invest. 117:557- 567 and Coelho et al. (2008) Immunol. Lett. 118:110-115). The lesion of SSc can be characterized by symptoms such as tissue fibrosis, vasculopathy of small blood vessels, and autoimmune disease specific to autoantibodies. .
프로바이오틱스(probiotics)란 다양한 미생물이 존재하는 사람의 장내에서 우세균으로 분포하고 체내 유익균의 성장을 촉진하는 생균활성제로써, 인체의 소화계에 공생하면서 섬유질 및 복합 단백질을 분해하여 중요한 영양 성분으로 만드는 역할을 담당한다. 또한 장내 pH를 산성으로 유지시켜 대장균이나 Chlostridum sp와 같은 유해균의 번식을 억제하고 설사와 변비를 개선하며 비타민 합성, 혈중 콜레스테롤 저하 등의 역할을 한다. 프로바이오틱스는 특히 장의 점막과 상피 세포에 강하게 결합할 수 있는 특성이 있어 정장 작용에 많은 도움을 준다. 또한, 프로바이오틱스는 대식세포의 증식을 촉진하여 대식세포(macrophage)의 장내 유해 세균에 대한 인지능력, 살균능력을 강화시킨다.Probiotics are probiotics that are distributed as dominant bacteria in the human intestine where various microorganisms exist and promote the growth of beneficial bacteria in the body. do. In addition, it maintains the pH of the intestine to be acidic, inhibits the growth of harmful bacteria such as E. coli and Chlostridum sp, improves diarrhea and constipation, and plays a role in vitamin synthesis and lowering blood cholesterol. In particular, probiotics have the ability to bind strongly to the intestinal mucosa and epithelial cells, and thus help the intestinal tract. In addition, probiotics promote the proliferation of macrophages, thereby enhancing the recognition and sterilization ability of macrophages against harmful intestinal bacteria.
이에 본 발명자는 가 정상인 및 피부경화증 환자의 장내 균총을 분석한 결과, 프로바이오틱스 중 하나인 비피도박테리움 속(Bifidobacterium) 균주의 차이가 현저함을 확인하였고, 이를 처리 시, 피부경화증 예방 및 치료에 효과적임을 확인하였다. 또한, 종래 피부경화증 치료 약물을 처리 후, 장내 비피도박테리움의 증가/감소 정도를 효과적으로 확인하여, 이를 바탕으로 치료 약물의 치료 정도 판별 및 진단 지표로서 이용 가능함을 확인하여, 본 발명의 피비도박테리움 속 균주는 질병을 조기에 진단하고 동시에 치료를 수행하는 신개념 진단/치료 기술에 적용 가능한 가치가 높음을 확인하여, 본 발명을 완성하였다. Accordingly, the present inventors analyzed the intestinal flora of normal individuals and patients with scleroderma, and confirmed that the difference between the Bifidobacterium strain, one of the probiotics, was significant, and when treated, It was confirmed to be effective. In addition, after treatment with the conventional skin sclerosis treatment drug, the increase/decrease degree of intestinal bifidobacterium was effectively confirmed, and based on this, it was confirmed that the therapeutic drug can be used as a therapeutic level discrimination and diagnostic index, The present invention was completed by confirming that the terium sp. strain has a high value applicable to a new concept diagnosis/treatment technology for diagnosing diseases at an early stage and performing treatment at the same time.
상기 목적을 달성하기 위하여, 본 발명은 비피도박테리움 속(Bifidobacterium sp.) 균주; 이의 배양액; 또는 그 건조분말을 유효성분으로 포함하는 피부경화증(Scleroderma)의 예방 또는 치료용 약학적 조성물을 제공할 수 있다.In order to achieve the above object, the present invention is a Bifidobacterium sp. strain; its culture; Or it may provide a pharmaceutical composition for preventing or treating skin sclerosis (Scleroderma) comprising the dry powder as an active ingredient.
또한, 본 발명은 비피도박테리움 속 균주; 이의 배양액; 또는 그 건조분말;을 유효성분으로 포함하는 피부경화증의 예방 또는 개선용 식품 조성물을 제공할 수 있다.In addition, the present invention is a Bifidobacterium sp. strain; its culture; Or it can provide a food composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
또한, 본 발명은 비피도박테리움 속 균주; 이의 배양액; 또는 그 건조분말을 유효성분으로 포함하는 피부경화증의 예방 또는 개선용 의약외품 조성물을 제공할 수 있다.In addition, the present invention is a Bifidobacterium sp. strain; its culture; Or it can provide a quasi-drug composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
본 발명은 비피도박테리움 속(Bifidobacterium sp.) 균주; 이의 배양액; 또는 그 건조분말을 유효성분으로 포함하는 피부경화증(Scleroderma)의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention is a Bifidobacterium sp. strain; its culture; Or it provides a pharmaceutical composition for the prevention or treatment of skin sclerosis (Scleroderma) comprising the dry powder as an active ingredient.
또한, 본 발명은 비피도박테리움 속 균주; 이의 배양액; 또는 그 건조분말;을 유효성분으로 포함하는 피부경화증의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention is a Bifidobacterium sp. strain; its culture; Or its dry powder; provides a food composition for preventing or improving skin sclerosis comprising as an active ingredient.
또한, 본 발명은 비피도박테리움 속 균주; 이의 배양액; 또는 그 건조분말을 유효성분으로 포함하는 피부경화증의 예방 또는 개선용 의약외품 조성물을 제공한다.In addition, the present invention is a Bifidobacterium sp. strain; its culture; Or it provides a quasi-drug composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
본 발명의 비피도박테리움 속(Bifidobacterium sp.) 균주는 Th1 세포, Th2 세포 및 Th17 세포를 감소시켜 면역 기능을 조절하고, 장내균총 분석 시 비피도박테리움의 총균수가 감소된 피부경화증 환자에게 투여하면, 장내총균 증가를 유도하는 효과가 우수하다. 따라서, 본 발명의 비피도박테리아 속 균주는 피부의 두께를 감소시키며, 피부 섬유화를 억제하여 피부경화증을 예방 및 치료하는 효과가 우수함을 확인하였다. 또한, 종래 피부경화증 치료 약물을 처리 후, 장내 비피도박테리움의 증가/감소 정도를 효과적으로 확인하여, 이를 바탕으로 치료 약물의 치료 정도 판별 및 진단 지표로서 이용 가능함을 확인하였다. 따라서, 본 발명의 비피도박테리움 속 균주는 피부경화증과 같은 면역 질환을 조기에 진단하고 동시에 치료를 수행하는 신개념 진단/치료 기술에 적용 가능한 "테라그노시스(Theragnosis)" 기술에 적용 가능하고 그 가치가 높음을 확인하여, 본 발명을 완성하였다. The Bifidobacterium sp. strain of the present invention regulates immune function by reducing Th1 cells, Th2 cells and Th17 cells, and in the intestinal flora analysis, the total number of Bifidobacterium bacteria is reduced in skin sclerosis patients. When administered, the effect of inducing an increase in intestinal flora is excellent. Therefore, it was confirmed that the Bifidobacterium sp. strain of the present invention is excellent in preventing and treating skin sclerosis by reducing the thickness of the skin and inhibiting skin fibrosis. In addition, after treatment with the conventional skin sclerosis treatment drug, the increase/decrease degree of intestinal bifidobacterium was effectively confirmed, and based on this, it was confirmed that the therapeutic drug could be used as a therapeutic level discrimination and diagnostic index. Therefore, the Bifidobacterium spp. strain of the present invention is applicable to "Theragnosis" technology applicable to a new concept diagnosis/treatment technology for diagnosing and simultaneously treating immune diseases such as scleroderma at an early stage, and its value By confirming that is high, the present invention was completed.
도 1은 정상인 28명 및 환자 24명에서 장내균총을 분석하여 비피도박테리움 속(genus)의 분포를 확인한 도이다.
도 2는 정상인 28명 및 환자 24명에서 장내균총을 분석하여 비피도박테리움 속(genus)의 종(Species) 분포를 확인한 도이다.
도 3은 정상인 28명 및 환자 24명에서 장내균총을 분석하여, 속(genus) 수준에서 비피도박테리움 속을 포함하는 다양한 속(genus)의 분포를 비교하여 나타낸 도이다.
도 4는 정상인 28명 및 환자 24명에서 장내균총을 분석하여 종(Species) 수준에서 비피도박테리움 롱검(Bifidobacterium longum)을 포함하는 다양한 종(Species)의 분포를 비교하여 나타낸 도이다.
도 5는 정상인 28명 및 환자 24명에서 장내균총을 분석하여 종(Species) 수준에서 비피도박테리움 카테눌라툼(Bifidobacterium catenulatum)을 포함하는 다양한 종(Species)의 분포를 비교하여 나타낸 도이다.
도 6은 정상인 28명 및 환자 24명에서 장내균총을 분석하여 종(Species) 수준에서 비피도박테리움 아돌레센티스(Bifidobacterium adolescentis)을 포함하는 다양한 종(Species)의 분포를 비교하여 나타낸 도이다.
도 7은 피부경화증 동물 모델에 비피도박테리움 롱검 투여에 따른 피부 두께 감소를 나타낸 도이다.
도 8은 피부경화증 동물 모델에 비피도박테리움 롱검 투여에 따른 피부 두께 감소 정도를 MT(masson's trichrome stain) 염색하여 확인한 결과를 나타낸 도이다.
도 9는 피부경화증 동물 모델에 비피도박테리움 롱검 투여에 따른 Th1, Th2, Th17 억제 효과를 나타낸 도이다.
도 10은 피부경화증 동물 모델에 비피도박테리움 롱검 투여에 따른 CD8+IL-17+ 억제 효과 및 CD8+IFN-r 증강 효과를 나타낸 도이다.
도 11은 피부경화증 동물 모델에 종래 치료 약물(메트포민(Metfomin) 또는 타크로리무스(FK506))을 처리한 후, 비피도박테리움 속의 증가를 확인하여, 종래 치료 약물의 치료효과 정도를 진단하고자 하는 도이다. 1 is a diagram confirming the distribution of Bifidobacterium genus by analyzing the intestinal flora in 28 normal subjects and 24 patients.
Figure 2 is a diagram confirming the distribution of species (Species) of the genus Bifidobacterium (genus) by analyzing the intestinal flora in 28 normal and 24 patients.
3 is a diagram showing the comparison of the distribution of various genera including the genus Bifidobacterium at the genus level by analyzing the intestinal flora in 28 normal patients and 24 patients.
Figure 4 is a diagram showing the comparison of the distribution of various species (Species) including Bifidobacterium longum ( Bifidobacterium longum ) at the level of the species (Species) by analyzing the intestinal flora in 28 normal and 24 patients.
5 is a diagram showing the comparison of the distribution of various species including Bifidobacterium catenulatum at the species level by analyzing the intestinal flora in 28 normal and 24 patients.
6 is a diagram showing comparison of the distribution of various species (Species) including Bifidobacterium adolescentis at the species level by analyzing the intestinal flora in 28 normal people and 24 patients.
7 is a diagram showing a decrease in skin thickness according to the administration of Bifidobacterium longum to an animal model of scleroderma.
8 is a diagram showing the results confirmed by MT (masson's trichrome stain) staining the degree of skin thickness reduction according to the administration of Bifidobacterium longum to an animal model of scleroderma.
9 is a diagram showing the Th1, Th2, Th17 inhibitory effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
10 is a diagram showing the CD8+IL-17+ inhibitory effect and CD8+IFN-r enhancing effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
11 is a diagram to diagnose the degree of therapeutic effect of conventional therapeutic drugs by confirming an increase in the genus of Bifidobacterium after treatment of a conventional therapeutic drug (Metfomin or tacrolimus (FK506)) in an animal model of scleroderma .
본 발명은 비피도박테리움 속(Bifidobacterium sp.) 균주; 이의 배양액; 또는 그 건조분말을 유효성분으로 포함하는 피부경화증(Scleroderma)의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention is a Bifidobacterium sp. strain; its culture; Or it provides a pharmaceutical composition for the prevention or treatment of skin sclerosis (Scleroderma) comprising the dry powder as an active ingredient.
본 발명의 일실시예에서, 정상인 28명 및 환자 24명에서 장내균총을 분석하여 비피도박테리움 속(genus)의 분포를 살펴본 결과, 비피도박테리움 속의 분포가 차이가 있음을 확인하였다. 이에, 종(Species) 수준에서 다양한 종(Species)의 분포를 살펴본 결과, 비피도박테리움은 비피도박테리움 롱검(Bifidobacterium longum), 비피도박테리움은 비피도박테리움 카테눌라툼(Bifidobacterium catenulatum), 비피도박테리움 아돌레센티스(Bifidobacterium adolescentis)이 정상인 및 환자의 분포에 차이가 있음을 확인하였다. 따라서, 본 발명은 비피도박테리움 속(genus), 바람직하게는 비피보박테리움 롱검을 유효성분으로 이용할 수 있다. In one embodiment of the present invention, as a result of examining the distribution of the genus Bifidobacterium by analyzing the intestinal flora in 28 normal subjects and 24 patients, it was confirmed that there was a difference in the distribution of the Bifidobacterium genus. Accordingly, as a result of examining the distribution of various species at the species level, Bifidobacterium is Bifidobacterium longum ( Bifidobacterium longum ), Bifidobacterium is Bifidobacterium catenulatum ( Bifidobacterium catenulatum ) , Bifidobacterium adolescentis ( Bifidobacterium adolescentis ) It was confirmed that there is a difference in the distribution of normal people and patients. Therefore, in the present invention, Bifidobacterium genus, preferably Bifidobacterium longum, can be used as an active ingredient.
상기 피부경화증은 Th1 세포, Th2 세포 및 Th17 세포가 증가되고, CD8+IL17+ T 세포가 증가되며하고, CD8+IFN-r+ 세포가 감소되어, 피부의 두께가 두꺼워지고, 피부 섬유화가 진행된 특징이 있다. The scleroderma is characterized by an increase in Th1 cells, Th2 cells and Th17 cells, an increase in CD8+IL17+ T cells, and a decrease in CD8+IFN-r+ cells, resulting in thickening of the skin, and advanced skin fibrosis. .
상기 본 발명의 비피도박테리움 속은 Th1 세포, Th2 세포 및 Th17 세포를 감소시키고, CD8+IL17+ T 세포를 억제하며, CD8+IFN-r+ 세포를 증가시킴으로서, 피부의 두께를 감소시키며, 피부 섬유화를 억제시키는 것으로, 피부 경화증을 치료 및 예방할 수 있다.The genus Bifidobacterium of the present invention reduces Th1 cells, Th2 cells and Th17 cells, inhibits CD8+IL17+ T cells, and increases CD8+IFN-r+ cells, thereby reducing the thickness of the skin and reducing skin fibrosis. By suppressing it, skin sclerosis can be treated and prevented.
또한, 종래 피부경화증 치료 약물을 처리 후, 장내 비피도박테리움의 증가/감소 정도를 효과적으로 확인하여, 이를 바탕으로 치료 약물의 치료 정도 판별 및 진단 지표로서 이용 가능할 수 있다.In addition, after treatment with the conventional skin sclerosis treatment drug, the increase/decrease degree of intestinal bifidobacterium can be effectively checked, and based on this, it can be used as a therapeutic level discrimination and diagnostic index of the treatment drug.
본 발명의 비피도박테리움 속 균주는 배양 배지에서 배양하여 수득한 발효액, 농축 발효액, 발효액 의 건조물, 배양 여과액, 농축 배양 여과액, 또는 배양 여과액의 건조물을 의미하는 것으로, 상기 균주를 포함하는 것 또는 배양한 후 균주를 제거한 배양 여액일 수 있다. 또한 상기 배양물은 그 제형이 한정되지 아니하고, 일 예로 액체, 에멀젼, 또는 고체일 수 있다.The Bifidobacterium sp. strain of the present invention refers to a fermentation broth obtained by culturing in a culture medium, a concentrated fermentation broth, a dried product of the fermentation broth, a culture filtrate, a concentrated culture filtrate, or a dried product of the culture filtrate, including the strain It may be a culture filtrate from which the strain is removed after culturing. In addition, the formulation of the culture is not limited, and may be, for example, a liquid, an emulsion, or a solid.
본 발명에서 용어 "배양"은 미생물을 적당히 인공적으로 조절한 환경조건에서 생육시키는 것을 의미한다. In the present invention, the term "cultivation" means to grow microorganisms in an appropriately artificially controlled environmental condition.
상기 균주는 통상의 배지에서 생육 가능하며, 배지는 특정 미생물을 배양하기 위하여 배양대상 즉 배양체가 되는 미생물이 필요로 하는 영양물질을 포함하는 것으로 특수한 목적을 위한 물질이 추가로 첨가되어 혼합된 것일 수 있다. 상기 배지는 배양기 또는 배양액이라고도 하며, 천연배지, 합성배지 또는 선택배지를 모두 포함하는 개념이며, 통상의 배양방법에 따라 배양할 수 있다.The strain can grow in a normal medium, and the medium contains nutrients required by the microorganism to be a culture target, that is, a culture body to cultivate a specific microorganism. have. The medium is also referred to as an incubator or culture medium, and is a concept including all of natural medium, synthetic medium or selective medium, and can be cultured according to a conventional culture method.
배양에 사용되는 배지는 적당한 탄소원, 질소원, 아미노산, 비타민 등을 함유한 통상의 배지 내에서 온도, pH 등을 조절하면서 적절한 방식으로 특정 균주의 요건을 충족해야 한다. 사용될 수 있는 탄소원으로는 글루코즈 및 자일로즈의 혼합당을 주 탄소원으로 사용하며 이외에 수크로즈, 락토즈, 프락토즈, 말토즈, 전분, 셀룰로즈와 같은 당 및 탄수화물, 대두유, 해바라기유, 피마자유, 코코넛유 등과 같은 오일 및 지방, 팔미트산, 스테아린산, 리놀레산과 같은 지방산, 글리세롤, 에탄올과 같은 알코올, 아세트산과 같은 유기산이 포함된다. 이들 물질은 개별적으로 또는 혼합물로서 사용될 수 있다. 사용될 수 있는 질소원으로는 암모니아, 황산암모늄, 염화암모늄, 초산암모늄, 인산암모늄, 탄산안모늄, 및 질산암모늄과 같은 무기질소원; 글루탐산, 메티오닌, 글루타민과 같은 아미노산 및 펩톤, NZ-아민, 육류 추출물, 효모 추출물, 맥아 추출물, 옥수수 침지액, 카세인 가수분해물, 어류 또는 그의 분해생성물, 탈지 대두 케이크 또는 그의 분해생성물 등 유기질소원이 사용될 수 있다. 이들 질소원은 단독 또는 조합되어 사용될 수 있다. 상기 배지에는 인원으로서 인산 제1칼륨, 인산 제2칼륨 및 대응되는 소듐-함유 염이 포함될 수 있다. 사용될 수 있는 인원으로는 인산이수소칼륨 또는 인산수소이칼륨 또는 상응하는 나트륨-함유 염이 포함된다. 또한, 무기화합물로는 염화나트륨, 염화칼슘, 염화철, 황산마그네슘, 황산철, 황산망간 및 탄산칼슘 등이 사용될 수 있다. 마지막으로, 상기 물질에 더하여 아미노산 및 비타민과 같은 필수 성장 물질이 사용될 수 있다.The medium used for culture must meet the requirements of a specific strain in an appropriate manner while controlling temperature, pH, etc. in a conventional medium containing an appropriate carbon source, nitrogen source, amino acids, vitamins, and the like. As a carbon source that can be used, a mixed sugar of glucose and xylose is used as the main carbon source, in addition to sugars and carbohydrates such as sucrose, lactose, fructose, maltose, starch, cellulose, soybean oil, sunflower oil, castor oil, coconut Oils and fats such as oil, fatty acids such as palmitic acid, stearic acid and linoleic acid, alcohols such as glycerol, ethanol, and organic acids such as acetic acid are included. These substances may be used individually or as a mixture. Examples of the nitrogen source that can be used include inorganic nitrogen sources such as ammonia, ammonium sulfate, ammonium chloride, ammonium acetate, ammonium phosphate, anmonium carbonate, and ammonium nitrate; Amino acids such as glutamic acid, methionine, and glutamine, and organic nitrogen sources such as peptone, NZ-amine, meat extract, yeast extract, malt extract, corn steep liquor, casein hydrolyzate, fish or its degradation products, defatted soybean cake or its degradation products, etc. can These nitrogen sources may be used alone or in combination. The medium may contain monopotassium phosphate, dipotassium phosphate and the corresponding sodium-containing salt as phosphorus. The phosphorus that can be used includes potassium dihydrogen phosphate or dipotassium hydrogen phosphate or the corresponding sodium-containing salt. In addition, sodium chloride, calcium chloride, iron chloride, magnesium sulfate, iron sulfate, manganese sulfate, calcium carbonate, etc. may be used as the inorganic compound. Finally, in addition to the above substances, essential growth substances such as amino acids and vitamins can be used.
또한, 배양 배지에 적절한 전구체들이 사용될 수 있다. 상기된 원료들은 배양과정에서 배양물에 적절한 방식에 의해 회분식, 유가식 또는 연속식으로 첨가될 수 있으나, 특별히 이에 제한되지는 않는다. 수산화나트륨, 수산화칼륨, 암모니아와 같은 기초 화합물 또는 인산 또는 황산과 같은 산 화합물을 적절한 방식으로 사용하여 배양물의 pH를 조절할 수 있다.In addition, precursors suitable for the culture medium may be used. The above-mentioned raw materials may be added in a batch, fed-batch or continuous manner by an appropriate method to the culture during the culturing process, but is not particularly limited thereto. Basic compounds such as sodium hydroxide, potassium hydroxide, ammonia or acid compounds such as phosphoric acid or sulfuric acid may be used in an appropriate manner to adjust the pH of the culture.
본 발명의 약학 조성물에는 유효성분 이외에 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 면역성을 증가시킬 수 있다. The pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient. The adjuvant may be used without limitation as long as it is known in the art, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
본 발명에 따른 약학 조성물은 유효성분을 약학적으로 허용된 담체에 혼입시킨 형태로 제조될 수 있다. 여기서, 약학적으로 허용된 담체는 제약 분야에서 통상 사용되는 담체, 부형제 및 희석제를 포함한다. 본 발명의 약학 조성물에 이용할 수 있는 약학적으로 허용된 담체는 이들로 제한되는 것은 아니지만, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition according to the present invention may be prepared in a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. .
제제화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 그러한 고형 제제는 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카르보네이트, 수크로스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 일반적으로 사용되는 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수용성용제, 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As the base of the suppository, witepsol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명에 따른 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
본 발명에 따른 약학 조성물의 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학 조성물에 0.01 ~ 5,000 ㎍/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 5,000 ㎍/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The dosage of the pharmaceutical composition according to the present invention is selected in consideration of the individual's age, weight, sex, physical condition, and the like. It is self-evident that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg/ml. If the concentration is less than 0.01 μg/ml, pharmaceutical activity may not appear, and if it exceeds 5,000 μg/ml, it may be toxic to the human body.
상기 약학 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화될 수 있다.The pharmaceutical composition may be formulated in various oral or parenteral dosage forms.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경질, 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 추가로 포함할 수 있다. 또한, 상기 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다.Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). In addition, the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or a disintegrant such as its sodium salt or a boiling mixture and/or absorbent, coloring, flavoring and sweetening agent. The formulation may be prepared by conventional mixing, granulating or coating methods.
또한, 비경구 투여용 제형의 대표적인 것은 주사용 제제이며, 주사용 제제의 용매로서 물, 링거액, 등장성 생리식염수 또는 현탁액을 들 수 있다. 상기 주사용 제제의 멸균 고정 오일은 용매 또는 현탁 매질로서 사용할 수있으며 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있다.In addition, a representative formulation for parenteral administration is an injection formulation, and examples of the solvent for the injection formulation include water, Ringer's solution, isotonic saline, or suspension. The sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose.
또한, 상기 주사용 제제는 올레산과 같은 지방산을 사용할 수 있다.In addition, the injection preparation may use a fatty acid such as oleic acid.
또한, 본 발명은 비피도박테리움 속 균주; 이의 배양액; 또는 그 건조분말;을 유효성분으로 포함하는 피부경화증의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention is a Bifidobacterium sp. strain; its culture; Or its dry powder; provides a food composition for preventing or improving skin sclerosis comprising as an active ingredient.
본 발명의 식품 조성물은 유효성분을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition to containing the active ingredient, the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional food composition.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨,소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 본 발명의 식품 조성물은 상기 약학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등이 있다.Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The above-mentioned flavoring agents can advantageously use natural flavoring agents (Taumatine), stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements. There is this.
또한 상기 식품 조성물은 유효성분인 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition includes, in addition to the active ingredient extract, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.
본 발명의 기능성 식품 조성물은, 정제,캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공될 수 있다. 본 발명에서 '건강기능성 식품 조성물'이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 '식품 첨가물 공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다. 캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 건강기능식품은 본 발명의 유효성분과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다. 과립 형태의 건강기능식품은 본 발명의 유효성분의 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The functional food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like. In the present invention, the term 'health functional food composition' refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and It refers to ingestion for the purpose of obtaining useful effects for health purposes, such as regulating nutrients or physiological effects. The health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards. The items listed in the 'Food Additives Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations, such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar color preparation, etc. are mentioned. For example, a health functional food in tablet form is granulated by a conventional method by mixing a mixture of the active ingredient of the present invention with an excipient, binder, disintegrant and other additives, followed by compression molding by putting a lubricant, etc., or The mixture can be compression molded directly. In addition, the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary. Among health functional foods in capsule form, hard capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients in a conventional hard capsule. It can be prepared by filling the mixture mixed with the capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary. A health functional food in the form of a ring can be prepared by molding a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc. by a known method, Alternatively, the surface may be coated with a material such as starch or talc. The health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing a mixture of the active ingredient excipients, binders, disintegrants, etc. of the present invention, and may contain flavoring agents, flavoring agents, etc. as needed can
또한, 본 발명은 비피도박테리움 속 균주; 이의 배양액; 또는 그 건조분말을 유효성분으로 포함하는 피부경화증의 예방 또는 개선용 의약외품 조성물을 제공한다.In addition, the present invention is a Bifidobacterium sp. strain; its culture; Or it provides a quasi-drug composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
본 발명에서 사용되는 용어 "의약외품"은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미하는 것으로, 예를 들어 약사법에 따르면 의약외품이란 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람ㆍ동물의 질병 치료나 예방에 쓰이는 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않는 제품 등이 포함된다.The term "quasi-drug" as used in the present invention refers to articles with a milder action than pharmaceuticals among articles used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases of humans or animals, for example, in the Pharmaceutical Affairs Act. According to the report, quasi-drugs exclude products used for medicinal purposes, and include products used for the treatment or prevention of diseases in humans and animals, and products with minor or no direct action on the human body.
본 발명의 상기 의약외품 조성물은 바디 클렌저, 소독 청결제, 세정제, 주방용 세정제, 청소용 세정제, 치약, 가글제, 물티슈, 세제, 비누, 핸드 워시, 헤어세정제, 헤어 유연제, 가습기 충진제, 마스크, 연고제 및 필터 충 진제로 이루어진 군에서 선택되는 제형으로 제조할 수 있으나, 이에 제한되는 것은 아니다.The quasi-drug composition of the present invention is a body cleanser, disinfectant cleaner, detergent, kitchen cleaner, cleaning agent, toothpaste, gargle, wet tissue, detergent, soap, hand wash, hair cleaner, hair softener, humidifier filler, mask, ointment and filter filling It may be prepared in a formulation selected from the group consisting of agents, but is not limited thereto.
<실시예 1> 정상인 및 피부경화증 환자에서의 장내균총 분석<Example 1> Analysis of intestinal flora in normal persons and patients with scleroderma
1-1. 정상인 및 피부경화증 환자에서의 장내균총 내 속(genus)의 분포 확인1-1. Confirmation of the distribution of genus in the intestinal flora in normal persons and patients with scleroderma
정상인 및 피부경화증 환자 에서 장내 균총을 내 속(genus)의 분포를 확인하기 위하여, 정상인 28명과 한국인 피부경화증 환자 42명을 대상으로 분변 샘플을 수집하고 -80℃에서 보관하였다. 그 후, 분변을 시료로 차세대염기서열 분석 (Next Generation Sequencing)을 시행하기 위하여, 시료에서 박테리아 유전체 DNA (bacterial genomic DNA)를 분리하여 그 중 미생물에 특이적인 16S rRNA 유전자를 증폭시켜 라이브러리를 제작하였다. 라이브러리의 16S rRNA 유전자는 Illumina 사의 Misep를 이용하여 염기서열을 해독하였다. 해독된 서열은 QllME1.9.1 (open-source bioinformatic pipeline)을 이용하여 생물정보학적 분석을 시행하였다.To confirm the distribution of genus in the intestinal flora in normal subjects and scleroderma patients, fecal samples were collected from 28 normal subjects and 42 Korean scleroderma patients and stored at -80°C. After that, in order to perform next generation sequencing with the fecal sample, bacterial genomic DNA was isolated from the sample and the 16S rRNA gene specific to the microorganism was amplified among them to prepare a library. . The 16S rRNA gene of the library was sequenced using Illumina's Misep. The decoded sequence was subjected to bioinformatic analysis using QllME1.9.1 (open-source bioinformatic pipeline).
그 결과, 장내 균총 분석 결과를 살펴보면, 피부경화증 환자 환자군에서 정상인에 비해 비피도박테리움 속 (Bifidobacterium genus)균주가 현저히 감소한 것을 확인할 수 있었다(도 1, 도 3)(HC_CMC: 정상인, SSc cohort CMC_SCH: 피부경화증 환자).As a result, looking at the results of the intestinal flora analysis, it was confirmed that the Bifidobacterium genus strain was significantly reduced in the scleroderma patient group compared to the normal person (FIG. 1, FIG. 3) (HC_CMC: normal person, SSc cohort CMC_SCH : skin sclerosis patients).
1-2. 정상인 및 피부경화증 환자에서의 장내균총 내 종(Species)의 분포 확인1-2. Confirmation of the distribution of species in the intestinal flora in normal persons and patients with scleroderma
정상인 및 피부경화증 환자에서의 장내 균총 내에서 종(Species)의 분포를 확인하기 위하여, 상기 실시예 1-1과 같은 방법으로, 정상인과 한국인 피부경화증 환자의 생물학적 분석을 시행하였다.In order to confirm the distribution of species in the intestinal flora in normal people and patients with scleroderma, biological analysis of normal people and Korean patients with scleroderma was performed in the same manner as in Example 1-1.
그 결과, 피부경화증 환자 환자군에서 정상인에 비해 비피도박테리움 롱검(Bifidobacterium longum)의 균주가 현저히 감소함을 확인하였다(도 2, 도 4). 또한, 피부경화증 환자 환자군에서 정상인에 비해 비피도박테리움 카테눌라툼(Bifidobacterium catenulatum)의 균주가 다른 종의 균주보다 현저히 감소하였고(도 5), 비피도박테리움 아돌레센티스(Bifidobacterium adolescentis)의 균주 또한 다른 종의 균주보다 현저히 감소함을 확인하였다(도 6).As a result, it was confirmed that the strain of Bifidobacterium longum was significantly reduced in the skin sclerosis patient group compared to normal people ( FIGS. 2 and 4 ). In addition, in the skin sclerosis patient group, the strain of Bifidobacterium catenulatum was significantly reduced than that of other species compared to normal people ( FIG. 5 ), and the strain of Bifidobacterium adolescentis ( Bifidobacterium adolescentis ) In addition, it was confirmed that the strain of other species was significantly reduced (FIG. 6).
<실시예 2> 피부경화증 동물 모델에서 비피도박테리움 롱검 투여에 따른 피부 두께 및 섬유화 억제 효과<Example 2> Skin thickness and fibrosis inhibitory effect according to the administration of Bifidobacterium longum in an animal model of scleroderma
C57BL/6 혹은 balb/c 정상 마우스 등털을 제모한 뒤 미리 준비해둔 블레오마이신(bleomycin)을 0.9% 염화나트륨에 녹인 후 (1mg/ml), 100ul씩 매일 총 4주 동안 목부터 등 부위(정사각형 모양의 각 네 귀퉁이)에 피하주사를 하여 피부경화증 모델을 제작하였다.After depilating C57BL/6 or balb/c normal mouse back hair, bleomycin prepared in advance was dissolved in 0.9% sodium chloride (1 mg/ml), 100ul each daily for a total of 4 weeks from the neck to the back (square shape). A scleroderma model was prepared by subcutaneous injection in each of the four corners).
또한, 비피도박테리움 롱검은 ㈜씨티씨바이오에서 구입하였다.In addition, Bifidobacterium long gum was purchased from CTC Bio.
그 후 상기 마우스 모델에 본 발명의 비피도박테리움 롱검을 유체 역학 주입(hydrodynamic injection)하고, 2 주부터 5주까지 주 1회 총 3회 주입하였다. 그 후, 무처리 마우스군 (대조군), 400mg/kg 비피도박테리움 롱검 투여 피부경화증 마우스군 (실험군)의 피부를 경화증 유도 35일 후에 각각 10% 포르말린으로 고정시켜 파라핀으로 블록을 제조하였다. 이로부터 피부 절편을 준비하여 슬라이드에 부착하였고, 자일렌을 이용하여 탈 파라핀 과정을 거친 뒤, 고농도 및 저농도 에탄올을 이용하여 함수시켰으며, 헤마톡실린과 에오신으로 피부 절편을 염색하였다. 또한, 교원질 섬유의 밀도를 알아보기 위해 메이슨스 트리크롬(Masson's Trichrome, MT)으로 피부 절편을 염색하였다. 각 처리군에 대한 피부 두께 및 섬유화정도를 확인하였다.After that, the Bifidobacterium longum of the present invention was hydrodynamically injected into the mouse model, and injected once a week from 2 weeks to 5 weeks, a total of 3 times. Thereafter, the skin of the untreated mouse group (control group) and the 400 mg/kg Bifidobacterium longum-administered scleroderma mouse group (experimental group) were fixed with 10% formalin each 35 days after sclerosis induction to prepare a block with paraffin. From this, a skin section was prepared and attached to a slide, and after deparaffinization using xylene, it was hydrated using high and low concentration ethanol, and the skin section was stained with hematoxylin and eosin. In addition, the skin sections were stained with Masson's Trichrome (MT) to determine the density of collagen fibers. The skin thickness and fibrosis degree for each treatment group were checked.
그 결과, 대조군과 비교하여 비피도박테리움 롱검이 처리된 피부경화증 마우스 모델의 피부 두께 및 진피 내 교원질 섬유의 밀도가 조밀하고 공간이 없어졌으며, 모낭의 크기가 현저히 감소되고 혈관의 위치가 밑으로 쳐저 있어 손상되어 있었으나, 비피도박테리움 롱검 처리에 의해 피부 두께가 감소하고 피부 섬유화가 현저히 감소함에 따라, 현저히 피부경화증의 증상이 완화된 것으로 나타났다(도 7, 도 8).As a result, compared to the control group, the thickness of the skin and the density of collagen fibers in the dermis of the scleroderma mouse model treated with Bifidobacterium longum were dense and space was lost, and the size of the hair follicles was significantly reduced and the location of the blood vessels was lowered. Although it was damaged due to drooping, as the skin thickness was reduced and skin fibrosis was significantly reduced by the treatment of Bifidobacterium longum, the symptoms of scleroderma were remarkably alleviated ( FIGS. 7 and 8 ).
<실시예 3> 피부경화증 동물 모델에서 비피도박테리움 롱검 투여에 따른 Th1, Th2, Th17 억제 효과 확인<Example 3> Confirmation of Th1, Th2, Th17 inhibitory effect according to the administration of Bifidobacterium longum in an animal model of scleroderma
T 세포 반응은 Th1(T helper 1 cell)/IFN-감마, Th2(T helper 2 cell)/IL-4(Interleukin 4), Th17(T helper 17 cell)/IL-17(Interleukin 17)의 활성을 조절하고, 상기 IFN-감마, IL-4, IL-17는 염증성 세포로 분류된다.The T cell response suppresses the activity of Th1 (
본 발명의 비피도박테리움 롱검 투여에 따른 Th1, Th2, Th17 억제 효과를 확인하기 위하여, 무처리 피부경화증 마우스(대조군), 비피도박테리움 롱검 처리된 피부경화증 마우스(실험군)의 시료를 유세포 분석 방법에 Th1, Th2, Th17 세포를 분석하였다. 실험종료 시점에 각 그룹의 비장세포를 얻어, 유세포 분석을 통해 Th1 세포는 CD4+IFN-r+ 세포를, Th2 세포는 CD4+IL-4+ 세포를, Th17 세포는 CD4+IL-17+ 로 분석 하였다. In order to confirm the Th1, Th2, Th17 inhibitory effect according to the administration of Bifidobacterium longum of the present invention, flow cytometry analysis of samples of untreated scleroderma mice (control group) and Bifidobacterium longum-treated scleroderma mice (experimental group) Th1, Th2, Th17 cells were analyzed in the method. At the end of the experiment, splenocytes from each group were obtained, and Th1 cells were analyzed as CD4+IFN-r+ cells, Th2 cells as CD4+IL-4+ cells, and Th17 cells as CD4+IL-17+ cells through flow cytometry. did
그 결과, 대조군과 비교하여 비피도박테리움 롱검이 처리된 피부경화증 마우스 모델에서 Th1, Th2, Th17 세포의 억제 효과가 매우 우수함을 확인하였다(도 9).As a result, it was confirmed that the inhibitory effect of Th1, Th2, and Th17 cells was very excellent in the scleroderma mouse model treated with Bifidobacterium longum compared to the control group (FIG. 9).
<실시예 4> 피부경화증 동물 모델에서 비피도박테리움 롱검 투여에 따른 CD8+IL-17+ 억제 효과 및 CD8+IFN-r 증강 효과<Example 4> CD8+IL-17+ inhibitory effect and CD8+IFN-r enhancement effect according to the administration of Bifidobacterium longum in an animal model of scleroderma
본 발명의 비피도박테리움 롱검 투여에 따른 CD8+IL-17+ 억제 효과 및 CD8+IFN-r 억제 효과를 확인하기 위하여, 무처리 피부경화증 마우스(대조군), 비피도박테리움 롱검 처리된 피부경화증 마우스(실험군)의 실험종료 시점에 비장세포를 얻어 유세포 분석 방법에 따라 배양된 CD8+IL-17+ 및 CD8+IFN-r+ 세포를 분석하였다.In order to confirm the CD8+IL-17+ inhibitory effect and CD8+IFN-r inhibitory effect according to the administration of Bifidobacterium longum of the present invention, untreated scleroderma mice (control group), Bifidobacterium longum-treated scleroderma At the end of the experiment in mice (experimental group), splenocytes were obtained and cultured CD8+IL-17+ and CD8+IFN-r+ cells were analyzed according to flow cytometry.
그 결과, 대조군과 비교하여 비피도박테리움 롱검이 처리된 피부경화증 마우스 모델에서 CD8+IL-17+ 억제 효과 및 CD8+IFN-r 증강 효과가 매우 우수함을 확인하였다(도 10). As a result, it was confirmed that the CD8+IL-17+ inhibitory effect and the CD8+IFN-r enhancing effect were very excellent in the scleroderma mouse model treated with Bifidobacterium longum compared to the control group ( FIG. 10 ).
<실시예 5> 피부경화증 동물 모델에 종래 치료 약물 처리 후 비피도박테리움 속의 분포 변화 확인<Example 5> Confirmation of distribution changes in Bifidobacterium genus after treatment with conventional therapeutic drugs in an animal model of scleroderma
종래 피부경화증 치료를 위하여, 면역억제제인 메트포민(Metfomin), 타크로리무스(FK506)등이 이용되고 있으며, 상기 면역억제제의 처리 후, 특정 장내 균총의 변화에 대한 확인은 전무한 실정이다. 따라서, 피부경화증 동물 모델에 메트포민(Metfomin), 타크로리무스(FK506)를 처리하고, 장내 균총, 특히 비피도박테리움 속의 변화를 확인하였다.Conventional immunosuppressive agents metformin (Metfomin), tacrolimus (FK506), etc. are used for the treatment of scleroderma, and after treatment with the immunosuppressant, there is no confirmation of a change in a specific intestinal flora. Therefore, the scleroderma animal model was treated with metformin (Metfomin) and tacrolimus (FK506), and changes in the intestinal flora, particularly Bifidobacterium genus, were confirmed.
구체적으로, 무처리 피부경화증 마우스(대조군), 메트포민 처리된 피부경화증 마우스 또는 타크로리무스 처리된 피부경화증 마우스의 분변 샘플을 수집하고 -80℃에서 보관하였다. 그 후, 분변을 시료로 차세대염기서열 분석 (Next Generation Sequencing)을 시행하기 위하여, 시료에서 박테리아 유전체 DNA (bacterial genomic DNA)를 분리하여 그 중 미생물에 특이적인 16S rRNA 유전자를 증폭시켜 라이브러리를 제작하였다. 라이브러리의 16S rRNA 유전자는 Illumina 사의 Misep를 이용하여 염기서열을 해독하였다. 해독된 서열은 QllME1.9.1 (open-source bioinformatic pipeline)을 이용하여 생물정보학적 분석을 시행하였다.Specifically, fecal samples from untreated scleroderma mice (control), metformin-treated scleroderma mice or tacrolimus-treated scleroderma mice were collected and stored at -80°C. After that, in order to perform Next Generation Sequencing with the fecal sample, bacterial genomic DNA was isolated from the sample, and the 16S rRNA gene specific to the microorganism was amplified among them to prepare a library. . The 16S rRNA gene of the library was sequenced using Illumina's Misep. The decoded sequence was subjected to bioinformatic analysis using QllME1.9.1 (open-source bioinformatic pipeline).
그 결과, 무처리 피부경화증 마우스 대조군과 비교하여, 메트포민 처리된 피부경화증 마우스 또는 타크로리무스 처리된 피부경화증 마우스에서 비피도박테리움 속이 증가되고, 최대 10배 이상 차이가 나타남을 확인하였다. 따라서, 피부 경화증이 완화되면, 장 내 비피도박테리움이 장 세포 내 부착능이 높아져 비피도박테리움 속이 증가된 것임을 알 수 있다(도 11). As a result, it was confirmed that the genus of Bifidobacterium was increased in the metformin-treated scleroderma mouse or tacrolimus-treated scleroderma mouse compared with the untreated sclerosis mouse control group, and a difference of up to 10 times or more was observed. Therefore, it can be seen that when the skin sclerosis is alleviated, the ability of intestinal Bifidobacterium to adhere to the intestinal cells is increased, thereby increasing the genus of Bifidobacterium (FIG. 11).
또한, 본 발명의 결과에 따르면, 피부경화증 진행 시, 비피도박테리움 속이 감소되고, 치료 약물 처리시 증가된 결과가 나타나는 바, 비피도박테리움 정량에 따라 피부경화증에 대한 진단 또한 가능할 것임을 시사한다. 여기에, 치료 약물 처리에 대한 효과 또한 비피도박테리움 속의 정량 또는 증가에 따라 파악할 수 있어, 향후 관련 후보 약물에 대한 스크리닝 지표로서도 사용할 수 있음을 알 수 있어, 본 발명의 비피도박테리움 속 균주는 피부경화증과 같은 면역 질환을 조기에 진단하고 동시에 치료를 수행하는 신개념 진단/치료 기술에 적용 가능한 "테라그노시스(Theragnosis)" 기술에 적용 가능하고 그 가치가 높음을 확인하였다.In addition, according to the results of the present invention, the genus of Bifidobacterium is decreased during the progression of scleroderma, and results increased during treatment with therapeutic drugs, suggesting that the diagnosis of scleroderma will also be possible depending on the quantity of Bifidobacterium. . Here, it can be seen that the effect on the treatment drug treatment can also be determined according to the quantity or increase of the Bifidobacterium genus, and can be used as a screening index for related candidate drugs in the future, so that the Bifidobacterium sp. strain of the present invention confirmed that it can be applied to the "Theragnosis" technology, which can be applied to a new concept diagnosis/treatment technology that diagnoses immune diseases such as scleroderma at an early stage and performs treatment at the same time, and has high value.
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