KR102372552B1 - Composition for preventing or treating immune disease comprising Alphalipoic acid and metformin - Google Patents
Composition for preventing or treating immune disease comprising Alphalipoic acid and metformin Download PDFInfo
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- KR102372552B1 KR102372552B1 KR1020170051048A KR20170051048A KR102372552B1 KR 102372552 B1 KR102372552 B1 KR 102372552B1 KR 1020170051048 A KR1020170051048 A KR 1020170051048A KR 20170051048 A KR20170051048 A KR 20170051048A KR 102372552 B1 KR102372552 B1 KR 102372552B1
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- lipoic acid
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Abstract
본 발명은 면역반응의 이상으로 유발되는 면역질환을 예방 또는 치료할 수 있는 알파리포익산 및 메트포민의 약학적 용도에 관한 것이다. 본 발명에 따른 알파리포익산 및 메트포민은 염증성 사이토카인의 생성 및 분비를 억제하는 활성을 가지며 STAT3 발현 또는 활성을 억제하여 각종 면역반응의 조절 이상으로 유발되는 자가면역질환, 염증성질환 및 이식거부질환과 같은 면역질환을 예방 또는 치료할 수 있는 약학적 조성물 또는 건강기능성 식품의 유효성분으로 유용하게 사용할 수 있다.The present invention relates to the pharmaceutical use of alpha lipoic acid and metformin, which can prevent or treat immune diseases caused by abnormal immune responses. Alpha lipoic acid and metformin according to the present invention have an activity of inhibiting the production and secretion of inflammatory cytokines, and inhibit STAT3 expression or activity to cause autoimmune diseases, inflammatory diseases and transplant rejection diseases caused by abnormal regulation of various immune responses It can be usefully used as an active ingredient in a pharmaceutical composition or health functional food capable of preventing or treating the same immune disease.
Description
본 발명은 면역반응의 이상으로 유발되는 면역질환을 예방 또는 치료할 수 있는 알파리포익산 및 메트포민의 약학적 용도에 관한 것이다.The present invention relates to the pharmaceutical use of alpha lipoic acid and metformin, which can prevent or treat immune diseases caused by abnormal immune responses.
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 상태일 수 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.
염증은 통증, 적화현상, 부기, 열 및 감염된 영역의 궁극적인 기능 손실을 그 특징으로 한다. 이들 증상은 면역계의 세포 사이에서 일어나는 일련의 복잡한 상호작용의 결과이다. 세포의 반응으로 인해 결과적으로 여러 그룹의 염증 매개자의 상호작용 네트워크가 생성된다: 단백질(예를 들면, 사이토카인, 효소(예를 들면 프로테아제, 퍼옥시다제), 주요 염기성 단백질, 점착 분자(ICAM, VCAM), 지질 매개자(예를 들면, 에이코사노이드, 프로스타글란딘, 류코트라이엔, 혈소판 활성화 인자(PAF)), 반응성 산소 종(예를 들면, 하이드로퍼옥사이드, 슈퍼옥사이드 음이온 O2-, 산화질소(NO) 등). 그러나 염증의 이들 매개자중 대부분은 또한 정상적인 세포 활성의 조절자이다. 따라서 염증 반응의 결핍으로 인해 숙주가 제어되지 않으면서 손상(즉, 감염)되고, 따라서 만성 염증으로 인해 부분적으로는 상기 언급된 매개자중 여럿이 과다 생성됨으로써 매개되는 염증성 질환이 야기된다.Inflammation is characterized by pain, redness, swelling, fever, and eventual loss of function of the affected area. These symptoms are the result of a complex series of interactions between the cells of the immune system. The cellular response results in an interactive network of several groups of inflammatory mediators: proteins (eg cytokines, enzymes (eg proteases, peroxidases), major basic proteins, adhesion molecules (ICAM, VCAM), lipid mediators (e.g., eicosanoids, prostaglandins, leukotrienes, platelet activating factor (PAF)), reactive oxygen species (e.g., hydroperoxide, superoxide anion O2-, nitric oxide (NO) ) etc.) However, most of these mediators of inflammation are also modulators of normal cellular activity, so the lack of an inflammatory response leads to uncontrolled damage (i.e. infection) of the host, and thus chronic inflammation in part Overproduction of several of the above-mentioned mediators results in mediated inflammatory diseases.
또한, 면역질환 중 하나인 자가면역질환은 면역 체계가 그 자신의 기관을 공격하여 자발적인 반응을 일으키는 것을 특징으로 한다. 이러한 반응들은 T 림프구에 의한 자가항원(auto-antigen)의 인식에 기인하며, 이로 인하여 체액상(자가항원 생성) 및 세포상 (림프구 및 대식세포 세포독성 활성 증가) 면역 반응이 유발된다. 자가면역질환으로서는 다음과 같은 것들을 들 수 있다: 류마티스성 질환, 건선, 전신성 피부근염, 다발성 경화증, 홍반성 낭창, 또는 항원에 의한 면역반응 악화, 즉, 천식, 약물 또는 음식에 대한 알레르기 등 이러한 질환들은 모두 제한성이고 만성인 질환들이며, 경우에 따라서는 치명적이고 현재까지 상기 질환들을 치료할 수 있는 효과적인 치료 방법이 존재하지 않는 실정이다. 그러므로 이들 질환의 진행 중에 질환을 경감시키거나 완화시킬 수 있는 약물, 의약 또는 매체라면 환자의 건강을 위해서 중요한 해결 수단이 된다고 할 것이다.In addition, autoimmune disease, which is one of the immune diseases, is characterized in that the immune system attacks its own organs and causes a spontaneous reaction. These responses are due to the recognition of auto-antigens by T lymphocytes, which provokes humoral (autoantigen production) and cellular (increased lymphocyte and macrophage cytotoxic activity) immune responses. Autoimmune diseases include: rheumatoid disease, psoriasis, systemic dermatomyositis, multiple sclerosis, lupus erythematosus, or worsening of the immune response to an antigen, i.e. asthma, allergy to drugs or food, etc. These diseases These are all limited and chronic diseases, in some cases fatal, and there is no effective treatment method for treating the diseases to date. Therefore, any drug, drug or medium capable of alleviating or alleviating the disease during the course of these diseases will be an important solution for the health of the patient.
많은 연구자들은 자가면역질환의 치료방법을 탐색하여 적당한 약물과 방법을 찾고자 집중적인 노력을 해왔으며, 오늘날, 자가면역질환의 치료는 주로 면역억제 약물, 예컨대 글루코코르티코이드(glucocorticoids), 칼시뉴린 억제제(calcineurin inhibitors) 및 증식억제제-대사물 작용 억제제(antiproliferatives-antimetabolites)의 사용에 근거한 것이다. 그러나 이와 같은 약리 요법은 다양한 표적들에 대하여 작용하므로, 전체적으로는 면역기능을 저하시킬 수 있다. 그렇지 않으면, 이러한 약리 요법을 장기간 사용하였을 경우 여러 가지 세포 독성 작용이 문제가 되어, 면역 체계를 비특이적인 방식으로 억제함으로써, 환자를 감염증 및 암에 걸릴 위험에 노출시킬 수 있다. 칼시뉴린과 글루코코르티코이드는, 그들의 신독성과 당뇨병 유발 특성에 기인하여 또 다른 문제점을 나타내기 때문에, 몇 가지 임상학적 증상의 경우(예: 신기능 부전, 당뇨병 등)에는 그 사용이 제한된다.Many researchers have made intensive efforts to find suitable drugs and methods by exploring methods of treating autoimmune diseases. inhibitors) and antiproliferatives-antimetabolites. However, since such pharmacological therapy acts on a variety of targets, the overall immune function may be reduced. Otherwise, when such pharmacological therapy is used for a long time, various cytotoxic actions become a problem, suppressing the immune system in a non-specific way, thereby exposing the patient to the risk of infection and cancer. Because calcineurin and glucocorticoids present another problem due to their nephrotoxicity and diabetes-inducing properties, their use is limited in some clinical conditions (eg renal insufficiency, diabetes, etc.).
따라서 자가면역질환, 염증성 질환, 이식거부반응 등과 같은 면역질환을 치료할 수 있는 물질로서, 부작용이 없으면서도 치료 효과가 우수한 새로운 치료제의 개발이 필요한 실정이다.Therefore, there is a need to develop a new therapeutic agent capable of treating immune diseases such as autoimmune diseases, inflammatory diseases, and transplantation rejection, which has no side effects and has excellent therapeutic effects.
이에 본 발명자들은 알파리포익산 및 메트포민을 함께 투여시, 염증성 사이토카인의 생성을 효과적으로 억제할 수 있으며, STAT3의 활성억제와 함께 동종반응을 억제할 수 있어, 면역질환 특히 자가면역질환; 염증성 질환; 또는 세포, 조직 또는 기관의 이식거부반응을 예방 또는 치료할 수 있는 새로운 치료제로서의 사용 가능성을 확인함으로써 본 발명을 완성하였다.Therefore, the present inventors can effectively inhibit the generation of inflammatory cytokines when administered together with alpha lipoic acid and metformin, and can suppress the homologous reaction together with inhibition of STAT3 activity, immune diseases, especially autoimmune diseases; inflammatory diseases; Alternatively, the present invention was completed by confirming the possibility of use as a new therapeutic agent capable of preventing or treating transplant rejection of cells, tissues or organs.
따라서 본 발명의 목적은 알파리포익산 및 메트포민을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a composition for preventing or treating immune diseases comprising alpha lipoic acid and metformin as active ingredients.
또한, 본 발명의 다른 목적은 알파리포익산 및 메트포민을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 건강기능성 식품을 제공하는 것이다.Another object of the present invention is to provide a functional health food for the prevention or improvement of immune diseases comprising alpha lipoic acid and metformin as active ingredients.
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상기 목적을 달성하기 위하여, 본 발명은 알파리포익산 및 메트포민을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물을 제공한다.
본 발명의 일실시예에 있어서, 상기 알파리포익산 및 메트포민은 알파리포익산이 10 내지 1000nM의 농도, 메트포민이 100 내지 1000uM로 상기 조성물에 함유되어 있을 수 있다.
본 발명의 일실시예에 있어서, 상기 알파리포익산 및 메트포민은 염증성 사이토카인의 생성을 감소 또는 억제시키고, STAT3의 활성을 감소 도는 억제시키는 기작을 통해 치료 효과를 나타내는 것일 수 있다.
본 발명의 일실시예에 있어서, 상기 염증성 사이토카인은 IL-17, IFN-r, IL-27 또는 IL-37일 수 있다.
본 발명의 일실시예에 있어서, 상기 면역질환은 자가면역질환; 염증성질환 또는 세포, 조직 또는 기관의 이식거부반응으로 이루어진 군 중에서 선택되는 것일 수 있다.
본 발명의 일실시예에 있어서, 상기 자가면역질환은 류마티스 관절염 (Rheumatoid Arthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis) 및 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 암 전이 및 소동맥 질환으로 이루어진 군으로부터 선택되는 것일 수 있다.
본 발명의 일실시예에 있어서, 상기 세포, 조직 또는 기관의 이식거부반응은 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부이식의 거부반응으로 이루어진 군 중에서 선택되는 것일 수 있다.
또한, 본 발명은 알파리포익산 및 메트포민을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 건강기능성 식품을 제공한다In order to achieve the above object, the present invention provides a composition for preventing or treating immune diseases comprising alpha lipoic acid and metformin as active ingredients.
In one embodiment of the present invention, the alpha lipoic acid and metformin may be contained in the composition at a concentration of 10 to 1000 nM of alpha lipoic acid and 100 to 1000 uM of metformin.
In one embodiment of the present invention, the alpha lipoic acid and metformin may reduce or inhibit the production of inflammatory cytokines and exhibit a therapeutic effect through a mechanism of reducing or inhibiting the activity of STAT3.
In one embodiment of the present invention, the inflammatory cytokine may be IL-17, IFN-r, IL-27 or IL-37.
In one embodiment of the present invention, the immune disease is an autoimmune disease; It may be selected from the group consisting of inflammatory diseases or transplant rejection of cells, tissues or organs.
In one embodiment of the present invention, the autoimmune disease is Rheumatoid Arthritis, Asthma, Dermititis, Psoriasis, Cystic Fibrosis, Multiple Sclerosis, Systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease, vitiligo, pernicious anemia pernicious anemia, glomerulonephritis and pulmonary fibrosis, Inflammatory Bowel Dieseses, Autoimmune Diabetes, Diabetic retinopathy, Rhinitis, Lung blood-reperfusion injury (Ischemia-reperfusion injury), Post-angioplasty restenosis, Chronic obstructive pulmonary diseases (COPD), Graves disease, Gastrointestinal allergies, Conjunctivitis ), atherosclerosis, coronary artery disease, angina, cancer metastasis and arteriolar disease may be selected from the group consisting of.
In one embodiment of the present invention, the transplant rejection reaction of the cells, tissues or organs is bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreatic transplantation, kidney transplantation and skin transplantation rejection. It may be selected from the group consisting of.
In addition, the present invention provides a health functional food for the prevention or improvement of immune diseases comprising alpha lipoic acid and metformin as active ingredients
본 발명에 따른 알파리포익산 및 메트포민은 염증성 사이토카인의 생성 및 분비를 억제하는 활성을 가지며 STAT3을 발현 또는 활성을 억제하여 각종 면역반응의 조절 이상으로 유발되는 자가면역질환, 염증성질환 및 이식거부질환과 같은 면역질환을 예방 또는 치료할 수 있는 약학적 조성물 또는 건강기능성 식품의 유효성분으로 유용하게 사용할 수 있다.Alpha-lipoic acid and metformin according to the present invention have an activity of inhibiting the production and secretion of inflammatory cytokines, and suppress STAT3 expression or activity to cause autoimmune diseases, inflammatory diseases and transplant rejection diseases caused by abnormal regulation of various immune responses It can be usefully used as an active ingredient in a pharmaceutical composition or health functional food that can prevent or treat immune diseases, such as.
도 1은 정상인의 PBMC에서 알파리포익산 및 메트포민을 함께 투여하는 경우, IL-17의 억제효과를 확인한 도이다.
도 2는 정상인의 PBMC에서 알파리포익산 및 메트포민을 함께 투여하는 경우, STAT3의 억제효과를 확인한 도이다.
도 3은 정상인의 PBMC에서 알파리포익산 및 메트포민을 함께 투여하는 경우, IL-17의 억제효과를 확인한 도이다.
도 4는 간암환자에서 알파리포익산 및 메트포민을 함께 투여하는 경우, IL-17의 억제효과를 확인한 도이다.
도 5는 간암환자에서 알파리포익산 및 메트포민을 함께 투여하는 경우, IFN-r의 억제효과를 확인한 도이다.
도 6은 이식환자에서 정상인의 PBMC에서 알파리포익산 및 메트포민을 함께 투여하는 경우, IL-17의 억제효과를 확인한 도이다.1 is a diagram confirming the inhibitory effect of IL-17 when alpha-lipoic acid and metformin are administered together in PBMC of normal persons.
Figure 2 is a diagram confirming the inhibitory effect of STAT3 when administered together with alpha-lipoic acid and metformin in PBMC of normal people.
3 is a diagram confirming the inhibitory effect of IL-17 when alpha-lipoic acid and metformin are administered together in PBMC of normal persons.
4 is a diagram confirming the inhibitory effect of IL-17 when alpha-lipoic acid and metformin are administered together in a liver cancer patient.
5 is a diagram confirming the inhibitory effect of IFN-r when alpha-lipoic acid and metformin are administered together in a liver cancer patient.
6 is a diagram confirming the inhibitory effect of IL-17 when alpha-lipoic acid and metformin are co-administered in PBMCs of normal persons in transplant patients.
본 발명은 면역질환을 효과적으로 예방 또는 치료할 수 있는 새로운 치료제로서 알파리포익산 및 메트포민을 사용할 수 있음을 최초로 규명한 점에 특징이 있다. The present invention is characterized in that it was first identified that alpha lipoic acid and metformin can be used as new therapeutic agents that can effectively prevent or treat immune diseases.
알파리포익산은 하기 화학식을 갖는 화합물로서, 항당뇨 활성이 있고, 지방 분해 활성에 따른 비만 치료제 가능성에 대한 연구가 보고된 바 있을 뿐, 본원발명과 같이 면역질환의 치료 효과에 대해서는 연구된 바가 없다.Alpha lipoic acid is a compound having the following formula, has antidiabetic activity, and studies on the possibility of an anti-obesity treatment according to lipolytic activity have been reported, but there has been no study on the therapeutic effect of immune diseases as in the present invention. .
한편, 메트포민은 면역질환에 대한 치료제로 알려져있지만, 알파리포익산과의 상승효과에 대하여서는 전혀 연구된 바가 없다.On the other hand, metformin is known as a therapeutic agent for immune diseases, but there has been no study on its synergistic effect with alpha lipoic acid.
<알파리포익산 화합물의 화학식><Chemical formula of alpha lipoic acid compound>
이에 본 발명자들은 알파리포익산 및 메트포민을 함께 투여하는 경우 면역질환의 치료 효과에 상승효과가 있음을 최초로 규명하였다.Accordingly, the present inventors first identified that when alpha lipoic acid and metformin are administered together, there is a synergistic effect on the therapeutic effect of immune diseases.
구체적으로 본 발명의 일실시예에 따르면, 본 발명의 알파리포익산 및 메트포민은 인간의 말초단핵구세포에서 염증성인자를 유발시키는 anti-CD3에 의한 염증성사이토카인의 생성 정도를 효과적으로 억제할 수 있음을 확인하였다.Specifically, according to one embodiment of the present invention, it was confirmed that the alpha-lipoic acid and metformin of the present invention can effectively inhibit the production of inflammatory cytokines by anti-CD3 that induces inflammatory factors in human peripheral mononuclear cells. did
또한, 본 발명의 다른 일실시예에 따르면, 정상, 간암 환자 또는 이식환자로부터 분리한 말초단핵구 세포를 대상으로 염증유발 인자에 의한 염증반응 유도조건 하에서 알파리포익산 및 메트포민을 처리할 경우, 단독 또는 처리하지 않은 대조군에 비해 염증성 사이토카인의 생성 및 STAT3의 발현을 현저하게 감소시키는 것도 확인할 수 있었다.In addition, according to another embodiment of the present invention, when alpha-lipoic acid and metformin are treated under conditions of inducing an inflammatory response by an inflammatory factor in normal, liver cancer patients or peripheral mononuclear cells isolated from transplanted patients, alone or It was also confirmed that the production of inflammatory cytokines and the expression of STAT3 were significantly reduced compared to the untreated control group.
따라서 이러한 결과를 통해 본 발명자들은 알파리포익산 및 메트포민을 동시에 투여하는 경우, 면역질환을 효과적으로 치료할 수 있는 새로운 치료방법으로서의 가능성을 확인할 수 있었다.Therefore, through these results, the present inventors were able to confirm the possibility as a new treatment method that can effectively treat immune diseases when alpha lipoic acid and metformin are administered at the same time.
그러므로 본 발명은 알파리포익산 및 메트포민을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물을 제공할 수 있다.Therefore, the present invention can provide a composition for preventing or treating immune diseases comprising alpha lipoic acid and metformin as active ingredients.
한편, 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. Meanwhile, 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.
따라서 면역 질환의 대부분은 이러한 두 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. Therefore, it can be seen that most of the immune diseases are caused by the imbalance between these two immune cells. For example, when 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 autoimmune diseases are caused by hypersensitivity reactions.
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 치료하는 실험들이 많이 보고되고 있다. 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 experiments for treating immune diseases through the action of increasing the activity of Treg cells have been reported.
또한, Treg 세포 이 외에 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-의 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. In addition to Treg cells, there are Th17 cells as another group created in the differentiation process. 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-, but Treg cells do not require IL-6, whereas in Th17 cells, IL-6 is present together with TGF-β. differentiate from In addition, differentiated Th17 cells are characterized in that they secrete IL-17.
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 하는 자가면역질환의 치료제 개발이 크게 부각되고 있다. 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 that target inhibition of Th17 cell activity has been highlighted.
그러나 현재 사용되고 있는 면역질환치료제로는 T 세포에서의 신호변환 경로를 차단하는 면역 억제제가 가장 많이 사용되고 있는데, 이러한 면역억제제들은 독성, 감염, 임파종, 당뇨병, 진전(tremor), 두통, 설사, 고혈압, 오심, 신기능 장애 등의 부작용이 발생하는 문제점이 있다.However, immunosuppressants that block the signal transduction pathway in T cells are the most used as currently used immunosuppressive drugs, and these immunosuppressants are toxic, infection, lymphoma, diabetes, tremor, headache, diarrhea, hypertension, There is a problem that side effects such as nausea and renal dysfunction occur.
또한, T 세포의 활성화를 억제하는 방법을 통해 면역질환을 치료하는 방법 이외에도 면역 세포로부터 분비되는 사이토카인의 양을 조절하는 치료법 및 면역 세포로부터 분비되는 사이토카인을 표적으로 하는 항체를 이용한 치료법이 개발 중에 있다. In addition to the method of treating immune diseases through the method of inhibiting the activation of T cells, a treatment method that controls the amount of cytokines secreted from immune cells and a treatment method using antibodies targeting cytokines secreted from immune cells have been developed. is in the middle
이러한 점에서 본 발명에 따른 알파리포익산 및 메트포민의 공동 투여는, 염증성 사이토카인 생성 억제 효과가 우수하고 동시에 STAT3 억제 활성이 종래 치료제보다 효과적으로 면역질환을 치료할 수 있을 것으로 보인다. In this regard, co-administration of alpha-lipoic acid and metformin according to the present invention is expected to have an excellent inhibitory effect on inflammatory cytokine production and at the same time, STAT3 inhibitory activity, to treat immune diseases more effectively than conventional therapeutic agents.
본 발명의 알파리포익산 및 메트포민이 억제할 수 있는 염증성사이토카인으로는 염증 반응 또는 면역질환을 유발할 수 있는 사이토카인이라면 모두 포함할 수 있으며, 이에 제한되지는 않으나, IL-17, IFN-r, IL-27, IL-37일 수 있다.The inflammatory cytokines that can be inhibited by alpha lipoic acid and metformin of the present invention may include any cytokine that can induce an inflammatory response or immune disease, but are not limited thereto, but IL-17, IFN-r, IL-27 or IL-37.
앞서 기술한 바와 같이, 본 발명의 일실시예의 결과를 보면, 본 발명의 조성물이 STAT3의 활성을 억제하는 작용이 있음을 확인할 수 있었는데, 최근에는 다양한 암 종에서 STAT1, STAT3 및 STAT5의 활성화된 형태가 발견되고 있으며, STAT3는 백혈병과 같은 혈액암 뿐만 아니라, 유방암, 두부경부암, 흑색종, 난소암, 폐암, 췌장암, 전립선암과 같은 다양한 고형암에서 활성화되어 있어 중요한 항암 타겟이 되고 있다(Hua Yu and Richard Jove, Nature Review Cancer.,2004, 8, 945). As described above, looking at the results of one embodiment of the present invention, it was confirmed that the composition of the present invention had an action of inhibiting the activity of STAT3. Recently, activated forms of STAT1, STAT3 and STAT5 in various cancer types has been discovered, and STAT3 is active in various solid cancers such as breast cancer, head and neck cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer, and prostate cancer, as well as blood cancer such as leukemia, making it an important anticancer target (Hua Yu and Richard Jove, Nature Review Cancer ., 2004, 8, 945).
또한, STAT3의 활성은 세포사멸을 억제하고, 신생혈관(angiogenesis)을 유도하며, 면역회피를 유도하는 것으로 알려진 바 있다((Wang T. et al., Nature Medicine., 2004, 10, 48). 따라서 STAT3 활성 억제는 복합적인 항암 기작으로 종양을 제어할 수 있는 효과가 있고, STAT3 단백질은 종양뿐만 아니라 다양한 세포내 기능에도 관여하므로 이의 저해제 발굴은 면역질환, 특히 자가면역질환 및 이식거부반응의 치료를 위한 면역억제제로의 개발도 가능하다. In addition, the activity of STAT3 is known to inhibit apoptosis, induce angiogenesis, and induce immune evasion (Wang T. et al., Nature Medicine ., 2004, 10, 48). Therefore, inhibition of STAT3 activity has the effect of controlling tumors with a complex anticancer mechanism, and STAT3 protein is involved not only in tumors but also in various intracellular functions. It is also possible to develop an immunosuppressive agent for
면역계는 정상상태에서는 자가 항원에 대한 특이적 면역반응을 제어하고 있으며, 외부항원에 대한 면역반응도 억제하고 있는 경우가 있는데, 예컨대 임산부의 태아에 대한 반응 및 만성감염상태에 있는 미생물에 대한 면역반응을 들 수 있다. 이러한 현상들은 항원 특이적 면역관용이 유도될 수 있는 기전으로 클론 제거(clonal deletion), 클론 무반응(anergy) 및 면역조절 T 세포(Treg)에 의한 능동적 통제에 의해 유도되는 것으로 알려져 있다. 이식항원에 대한 면역관용이 우연히 획득된 일부 환자나 실험적으로 면역관용을 유도한 동물모델을 조사해 보면 위의 세 가지 기전 모두 이식면역관용에 관여한다는 사실이 확인되고 있고, 특히 최근에는 면역조절 T 림프구가 이식면역반응 뿐만 아니라 자가면역, 종양면역, 감염면역반응 등 생체의 거의 모든 면역반응을 통제하는데 관여하는 중요한 세포로 주목받고 있다.In normal state, the immune system controls specific immune responses to self-antigens, and in some cases also suppresses immune responses to external antigens. can be heard These phenomena are known to be induced by clonal deletion, clonal anergy, and active control by immunoregulatory T cells (Tregs) as mechanisms by which antigen-specific immune tolerance can be induced. When examining some patients who acquired immune tolerance to a transplant antigen accidentally or an animal model that experimentally induced immune tolerance, it was confirmed that all three mechanisms are involved in transplant immunity. is attracting attention as an important cell involved in controlling almost all immune responses in the body, such as autoimmunity, tumor immunity, and infection immune response as well as transplant immune response.
그러므로 본 발명에서 제공하는 상기 면역질환의 예방 또는 치료용 약학적 조성물은, 알파리포익산 및 메트포민을 유효성분으로 포함하며, 알파리포익산은 10~1000nM의 농도, 메트포민은 100 내지 1000uM로 상기 조성물에 함유되어 있을 수 있다.Therefore, the pharmaceutical composition for the prevention or treatment of immune diseases provided in the present invention includes alpha lipoic acid and metformin as active ingredients, alpha lipoic acid at a concentration of 10 to 1000 nM, and metformin at a concentration of 100 to 1000 uM in the composition may contain.
상기 염은 바람직하게는 약학적으로 허용 가능한 염의 형태로 사용될 수 있는데, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다. The salt is preferably used in the form of a pharmaceutically acceptable salt. The salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid, and the free acid is an organic acid and Inorganic acids may be used. The organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid. In addition, the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
본 발명에 따른 화합물은 천연으로부터 분리되거나 당업계에 공지된 화학적 합성법으로 제조된 것을 사용할 수 있다. The compound according to the present invention may be isolated from nature or prepared by chemical synthesis known in the art.
본 발명에서 상기 "면역질환"은 포유류 면역계의 구성성분들이 포유류의 병리상태를 야기하거나, 매개하거나 또는 기타 공헌하는 질환을 의미한다. 또한, 면역 반응의 자극 또는 중단이 그 질병의 진행에 보상적인 효과를 갖는 질환을 모두 포함할 수 있는데, 본 발명에서는 과민성 면역반응으로 인해 야기되는 질환들을 포함할 수 있다. 이러한 면역질환의 예로는 이에 제한되지는 않으나, 자가면역질환; 염증성질환; 및 세포, 조직 또는 기관의 이식거부(transplantation rejection)질환 등을 모두 포함할 수 있다.In the present invention, the "immune disease" refers to a disease in which components of the mammalian immune system cause, mediate, or otherwise contribute to the mammalian pathology. In addition, all diseases in which stimulation or interruption of an immune response has a compensatory effect on the progression of the disease may be included, and the present invention may include diseases caused by an overactive immune response. Examples of such immune diseases include, but are not limited to, autoimmune diseases; inflammatory diseases; and transplantation rejection disease of cells, tissues or organs.
또한, 모든 정상 개체에 있어서 가장 중요한 특성 중의 하나는 자기(self)를 구성하고 있는 항원물질에 대해서는 해롭게 반응하지 않는 반면, 비자기(non-self) 항원들에 대해서는 이를 인식하고 반응하여 제거할 수 있는 능력을 가지고 있다. 이처럼 자기항원에 대한 생체의 무반응을 면역학적 무반응성(immunologic unresponsiveness) 또는 관용(tolerance)이라고 한다.In addition, one of the most important characteristics of all normal individuals is that they do not react harmfully to antigenic substances constituting self, whereas non-self antigens can be recognized, reacted and eliminated. have the ability As such, the non-response of the living body to the self-antigen is called immunologic unresponsiveness or tolerance.
그러나 이러한 자기관용을 유도하거나 계속 유지하는데 있어서 문제가 생기게 되면 자기항원에 대하여 면역반응이 일어나게 되고, 이로 인하여 자신의 조직을 공격하는 현상이 발생하는데 이러한 과정에 의해 발생되는 질환을 "자가면역질환"이라고 한다.However, if there is a problem in inducing or maintaining self-tolerance, an immune response to the self-antigen occurs, which causes an attack on one's own tissue. The disease caused by this process is called "autoimmune disease" It is said
또한, "염증성 질환"이란 염증유발인자 또는 방사선조사 등 유해한 자극으로 인해 인체 면역체계를 과도하게 항진시켜 대식세포와 같은 면역세포에서 분비되는 TNF-(tumor necrosis factor-), LPS, IL-17, IL-10, IFN-r, IL-1(interleukin-1), IL-6, 프로스타글란딘(prostagladin), 루코트리엔(luecotriene) 또는 산화질소(nitric oxide, NO)와 같은 염증유발물질(염증성 사이토카인)에 의해 유발되는 질환을 말한다.In addition, "inflammatory disease" means TNF- (tumor necrosis factor-), LPS, IL-17, Inflammatory substances such as IL-10, IFN-r, IL-1 (interleukin-1), IL-6, prostaglandin, luecotriene, or nitric oxide (NO) disease caused by Cain).
또한 성공적인 장기 이식을 위해서는 이식할 세포 및 장기에 대한 수혜자의 면역 거부반응을 극복해야 한다. 이식면역거부반응의 주요 매개체는 T 세포로서, 이식편(graft)에 발현되어져 있는 주조직적합성분자(major histocompatibility complex, MHC)를 T 세포 수용체(T cell receptor)가 인지함으로써 면역반응이 유도되어 이식거부반응이 발생되게 된다. 주조직적합성분자는 당단백 항원의 종류에 따라 결정되는데, 조직적합항원이 일치하지 않아서 일어나는 면역반응은 성공적인 이식을 가로막는 장애가 되고 있어, 조직적합항원 검사의 정확성과 일치 여부의 조사는 매우 중요한 요소이다. In addition, successful organ transplantation requires overcoming the recipient's immune rejection of the cells and organs to be transplanted. The main mediator of the transplant immune rejection response is T cells, and the T cell receptor recognizes the major histocompatibility complex (MHC) expressed in the graft, thereby inducing an immune response to reject the transplant. reaction will occur. The main histocompatibility molecule is determined according to the type of glycoprotein antigen, and the immune response caused by the mismatch of the histocompatibility antigen is an obstacle to successful transplantation.
사람에게는 여러 종류의 조직적합항원이 있는데, 그 중 HLA-A, -B, -C를 포함하는 Class I 항원이 있고, HLA-DR,-DP, -DQ를 포함하는 Class II 항원이 있다. 이들 항원의 생물학적 기능은 T 림프구에게 항원을 전달하며, Class I 항원은 대부분의 유핵세포에서 발현되며 이를 통해 전달되는 항원들은 CD8+ 세포독성 T 림프구에 의해 인식된다. Class II 항원은 항원제시세포로 알려진 수지상세포, B 림프구, 활성화된 T 림프구, 큰포식세포 등에서 발현되며, CD4+ T 림프구에게 항원을 전달하는 기능을 한다. T 림프구에 전달된 항원들은 T 림프구 수용체에 결합함으로써 T 림프구가 항원을 인식하게 되는데 이식하는 과정에서 자신의 것이 아닌 다른 사람으로부터 유래한 조직적합항원을 높은 빈도로 인식하게 된다. 공여자 또는 환자의 전체 T 림프구 중 1~10% 정도가 환자 또는 공여자로부터 유래한 조직적합항원을 인식하여 이에 대한 반응으로 증식하게 되고, 일련의 면역반응을 일으키게 되는데 이를 "동종반응(Alloresponse)"라고 한다. 또한 공여자의 T 림프구가 환자의 조직적합항원에 대하여 면역반응을 일으키는 것을 이식편대숙주질환(GVDH)"라고 하며, 반대로 환자의 T 림프구가 공여자의 조직적합항원에 대하여 일으키는 반응을 이식거부반응(graft rejection)"이라고 한다.There are several types of histocompatibility antigens in humans. Among them, there are Class I antigens including HLA-A, -B, and -C, and Class II antigens including HLA-DR, -DP and -DQ. The biological function of these antigens is to deliver antigens to T lymphocytes, and Class I antigens are expressed in most nucleated cells, and the antigens delivered through them are recognized by CD8+ cytotoxic T lymphocytes. Class II antigens are expressed in dendritic cells, B lymphocytes, activated T lymphocytes, macrophages, etc. known as antigen presenting cells, and function to deliver antigens to CD4+ T lymphocytes. The antigens delivered to the T lymphocytes bind to the T lymphocyte receptor and the T lymphocytes recognize the antigen. About 1 to 10% of the donor or patient's total T lymphocytes recognize the patient or donor-derived histocompatibility antigen and proliferate in response thereto, causing a series of immune responses, which is called "Alloresponse". do. Graft-versus-host disease (GVDH) is when the donor's T lymphocytes provoke an immune response to the patient's histocompatible antigen. rejection)".
본 발명에서 예방 및 치료할 수 있는 상기 면역질환에서, 상기 자가면역질환은 이에 제한되지는 않으나, 류마티스 관절염 (Rheumatoid Arthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis) 및 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 암 전이 및 소동맥 질환 등을 포함할 수 있다.In the immune diseases that can be prevented and treated in the present invention, the autoimmune diseases include, but are not limited to, Rheumatoid Arthritis, Asthma, Dermititis, Psoriasis, Cystic Fibrosis, Multiple Sclerosis, systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease ), vitiligo, pernicious anemia, glomerulonephritis and pulmonary fibrosis, Inflammatory Bowel Dieseses, Autoimmune Diabetes, Diabetic retinopathy , Rhinitis, Ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary diseases (COPD), Graves disease, Gastrointestinal allergies, Conjunctivitis, Atherosclerosis, Coronary artery disease, Angina, cancer metastasis and arteriole disease may include.
또한, 상기 세포, 조직 또는 기관의 이식거부반응은 이에 제한되지는 않으나, 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부이식의 거부반응을 포함할 수 있다. In addition, the transplant rejection reaction of the cell, tissue or organ includes, but is not limited to, rejection of bone marrow transplantation, heart transplantation, corneal transplantation, intestine transplantation, liver transplantation, lung transplantation, pancreatic transplantation, kidney transplantation and skin transplantation. can do.
그러므로 본 발명에 따른 상기 조성물은 면역질환을 예방 또는 치료할 수 있는 약학적 조성물로 사용될 수 있고, 상기 "치료"란, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미하며, 본원에서 사용된 상기 치료란 용어는 "치료하는"이 상기와 같이 정의될 때 치료하는 행위를 말한다. 따라서 포유동물에 있어서 면역질환의 "치료" 또는 "치료요법"은 하기의 하나 이상을 포함할 수 있다:Therefore, the composition according to the present invention can be used as a pharmaceutical composition capable of preventing or treating an immune disease, and the "treatment" means a disease or disease to which the term applies, or the disease or disease, unless otherwise stated. means reversing, alleviating, inhibiting the progression, or preventing one or more symptoms of say Accordingly, "treatment" or "therapeutic therapy" of an immune disease in a mammal may include one or more of the following:
(1) 면역질환의 성장을 저해함, 즉, 그 발달을 저지시킴,(1) inhibit the growth of immune diseases, that is, arrest their development;
(2) 면역질환의 확산을 예방함, 즉, 전이를 예방함,(2) prevent the spread of immune diseases, that is, prevent metastasis;
(3) 면역질환을 경감시킴.(3) Alleviate immune diseases.
(4) 면역질환의 재발을 예방함, 및(4) preventing recurrence of immune diseases, and
(5) 면역질환의 증상을 완화함(palliating)(5) alleviating symptoms of immune diseases (palliating)
본 발명에 따른 면역질환의 예방 또는 치료용 조성물은 약학적으로 유효한 양의 알파리포익산 및 메트포민을 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다. 상기에서 약학적으로 유효한 양이란 면역질환의 증상을 예방, 개선 및 치료하기에 충분한 양을 말한다.The composition for preventing or treating immune diseases according to the present invention may contain pharmaceutically effective amounts of alpha-lipoic acid and metformin, or may contain one or more pharmaceutically acceptable carriers, excipients or diluents. In the above, the pharmaceutically effective amount refers to an amount sufficient to prevent, improve, and treat symptoms of immune diseases.
본 발명에 따른 알파리포익산 및 메트포민의 양은 면역질환 증상의 정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있다.The amounts of alpha-lipoic acid and metformin according to the present invention may be appropriately changed depending on the severity of symptoms of immune disease, the age, weight, health status, sex, administration route, and treatment period of the patient.
또한, 상기에서 약학적으로 허용되는이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. In addition, in the above, pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, fillers, anti-agglomeration agents, lubricants, wetting agents, flavoring agents, emulsifiers and preservatives and the like may be further included.
또한, 본 발명의 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다. In addition, the compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, or sterile powders.
또한, 본 발명에 따른 면역질환의 예방 또는 치료용 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있고, 본 발명에 따른 면역질환의 예방 또는 치료용 조성물은 면역질환의 증상을 예방, 개선 또는 치료하는 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다.In addition, the composition for preventing or treating immune diseases according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient depends on the route of administration, age, sex, and age of the patient. It can be appropriately selected according to various factors such as body weight and the severity of the patient, and the composition for preventing or treating immune diseases according to the present invention can be used in combination with known compounds having an effect of preventing, improving or treating symptoms of immune diseases. can be administered.
본 발명은 또한, 포유동물에게 치료상 유효량의 본 발명의 약제학적 조성물을 투여하는 것을 포함하는 면역질환의 예방 또는 치료방법을 제공한다.The present invention also provides a method for preventing or treating an immune disease comprising administering to a mammal a therapeutically effective amount of the pharmaceutical composition of the present invention.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term "mammal" refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
여기에서 사용된 용어 "치료상 유효량"은 연구자, 수의사, 의사 또는 기타 임상에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 치료상 유효 투여량 및 투여횟수는 원하는 효과에 따라 변화될 것임은 당업자에게 자명하다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다.As used herein, the term “therapeutically effective amount” refers to an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human as conceived by a researcher, veterinarian, physician or other clinician, which an amount that induces amelioration of the symptoms of the disease or disorder being treated. It is apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration for the active ingredient of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by those skilled in the art, and the type of disease, the severity of the disease, the content of active ingredients and other components contained in the composition, the type of formulation, and the age, weight, and general health of the patient It can be adjusted according to various factors including state, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs.
또한, 본 발명은 알파리포익산 및 메트포민을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for the prevention or improvement of immune diseases comprising alpha lipoic acid and metformin as active ingredients.
본 발명의 건강기능식품은 면역질환의 예방 또는 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or improving immune diseases.
본 발명에서 건강기능식품이라 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 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.In the present invention, health functional food refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Health Functional Food Act No. 6727, and nutrients are controlled for the structure and function of the human body. It means to consume for the purpose of obtaining useful effects for health purposes, such as physiological action or the like.
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.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.
상기 식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다.The items listed in the Food Additives Codex 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; and mixed preparations such as sodium L-glutamate preparations, noodles-added alkalis, preservatives, and tar dye preparations.
예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분인 알파리포익산 및 메트포민을 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.For example, health functional food in tablet form is granulated in a conventional manner by mixing a mixture of alpha-lipoic acid and metformin, which are the active ingredients of the present invention, with excipients, binders, disintegrants and other additives, and then, a lubricant, etc. It can be compression-molded by putting it in, or the mixture can be directly compression-molded. In addition, the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분인 알파리포익산 및 메트포민을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 알파리포익산 및 메트포민을 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.Among health functional foods in the form of capsules, hard capsules can be prepared by filling a conventional hard capsule with a mixture of alpha-lipoic acid and metformin, which are the active ingredients of the present invention, with additives such as excipients, and soft capsules include alpha-lipoic acid and It can be prepared by filling a mixture of metformin with additives such as excipients in a 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.
환 형태의 건강기능식품은 본 발명의 유효성분인 알파리포익산 및 메트포민을 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.A health functional food in the form of a ring can be prepared by molding a mixture of alpha-lipoic acid and metformin, which are the active ingredients of the present invention, as an excipient, a binder, a disintegrant, etc. by a conventionally known method. It can be coated with a skinning agent, or the surface can be coated with a material such as starch or talc.
과립 형태의 건강기능식품은 본 발명의 유효성분인 알파리포익산 및 메트포민과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.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 alpha lipoic acid and metformin, which are the active ingredients of the present invention, and excipients, binders, and disintegrants, and, if necessary, a flavoring agent, It may contain a corrosive agent and the like.
상기 건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다.The health functional food may be beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements.
이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail by way of Examples. These examples are merely for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited to these examples.
[실시예 1]정상인의 말초단핵구세포에서 알파리포익산 및 메트포민 투여의 IL-17 억제효과 확인[Example 1] Confirmation of IL-17 inhibitory effect of alpha-lipoic acid and metformin administration in normal human peripheral mononuclear cells
정상인으로부터 말초단핵구세포(peripheral blood mononuclear cells, PBMC)를 Ficoll Paque TM으로 원심분리기로 비중차를 이용하여 분리하였다. 분리한 말초단핵구세포를 대상으로 알파리포익산 100nM, 메트포민 500uM, 메트포민 500uM 및 알파리포익산 100nM를 각각 2시간 동안 배양한 후, anti-CD3(1ug/ml)로 세포자극을 유도한 후, 3일 동안 배양한 다음, 세포배양액을 수득하여 ELISA 방법을 통해 IL-17의 농도를 측정하였다. 이때 대조군으로는 anti-CD3(1ug/ml)만 단독 처리한 군을 사용하였다. 이의 결과를 도 1에 나타내었다.Peripheral blood mononuclear cells (PBMC) from normal individuals were separated using a Ficoll Paque TM centrifuge using a specific gravity difference. After incubating the isolated peripheral mononuclear cells with 100 nM of alpha-lipoic acid, 500 uM of metformin, 500 uM of metformin, and 100 nM of alpha-lipoic acid for 2 hours each, anti-CD3 (1ug/ml) was used to induce cell stimulation, and then 3 days. After culturing for a while, a cell culture medium was obtained and the concentration of IL-17 was measured through an ELISA method. In this case, a group treated with only anti-CD3 (1ug/ml) was used as a control group. The results are shown in FIG. 1 .
도 1에 나타낸 바와 같이, 알파리포익산 및 메트포민의 처리에 의해 anti-CD3 자극에 따른 염증성 사이토카인인 IL-17의 생성이 알파리포익산 또는 메트포민을 단독 투여한 경우와 비교하여, 현저히 억제되는 것을 확인하였다.As shown in FIG. 1, the production of IL-17, an inflammatory cytokine, according to anti-CD3 stimulation by treatment with alpha-lipoic acid and metformin was significantly inhibited compared to the case where alpha-lipoic acid or metformin was administered alone. Confirmed.
[실시예 2]알파리포익산 및 메트포민 투여의 STAT3 발현 억제효과 확인 [Example 2] Confirmation of STAT3 expression inhibitory effect of alpha poic acid and metformin administration
알파리포익산 및 메트포민이 STAT3의 발현을 억제하는 작용이 있는지 분석하였다. 이를 위해 STAT3 luciferase 벡터로 형질 전환된 세포주인 HeLa 세포주를 사용하였다. 대조군으로는 아무것도 도입하지 않은 HeLa 세포주를 사용하였다. 상기 HeLa 세포주에 메트포민 500uM, 알파리포익산 100nM 또는 메트포민 500uM 및 알파리포익산 100uM을 48시간 동안 함께 투여하였고, 이의 결과를 도 2에 나타내었다.It was analyzed whether alpha lipoic acid and metformin had the effect of inhibiting the expression of STAT3. For this purpose, the HeLa cell line transformed with the STAT3 luciferase vector was used. As a control, a HeLa cell line into which nothing was introduced was used.
도 2에 나타낸 바와 같이, 알파리포익산 및 리포익산을 함께 투여한 경우, 각각을 투여한 경우보다 STAT3 프로모터 억제효과가 우수함을 확인하였다.As shown in Figure 2, when alpha-lipoic acid and lipoic acid were administered together, it was confirmed that the STAT3 promoter inhibitory effect was superior to that when each was administered.
[실시예 3]알파리포익산 및 메트포민 투여의 IL-17 프로모터 억제효과 확인[Example 3] Confirmation of IL-17 promoter inhibitory effect of alpha poic acid and metformin administration
알파리포익산 및 메트포민이 IL-17의 발현을 억제하는 작용이 있는지 분석하였다. 이를 위해 h293 세포에 IL-17 luciferase 벡터를 형질전환 하여 사용하였으며, 대조군으로는 IL-17 luciferase 벡터의 backbone이 되는 empty 벡터를 형질전환 하여 사용하였다. 상기 세포주에 메트포민 500uM, 알파리포익산 100nM 또는 메트포민 500uM 및 알파리포익산 100uM을 48시간 동안 함께 투여하였고, 이의 결과를 도 2에 나타내었다.It was analyzed whether alpha lipoic acid and metformin had the effect of inhibiting the expression of IL-17. For this purpose, h293 cells were transformed with IL-17 luciferase vector and used as a control, and an empty vector serving as the backbone of the IL-17 luciferase vector was transformed and used. Metformin 500uM, alpha-lipoic acid 100nM, or metformin 500uM and alpha-lipoic acid 100uM were co-administered to the cell line for 48 hours, and the results are shown in FIG. 2 .
도 3에 나타낸 바와 같이, 알파리포익산 및 리포익산을 함께 투여한 경우, 각각을 투여한 경우보다 IL-17 프로모터 억제효과가 우수함을 확인하였다.As shown in Figure 3, when alpha-lipoic acid and lipoic acid were administered together, it was confirmed that the IL-17 promoter inhibitory effect was superior to that when each was administered.
[실시예 4]간암환자에서 알파리포익산 및 메트포민 투여의 염증성 사이토카인 억제효과 확인[Example 4] Confirmation of inflammatory cytokine inhibitory effect of alpha-lipoic acid and metformin administration in liver cancer patients
1.IL-17 억제효과 확인1.IL-17 inhibitory effect confirmation
간암환자로부터 말초단핵구세포(peripheral blood mononuclear cells, PBMC)를 Ficoll Paque TM으로 원심분리기로 비중차를 이용하여 분리하였다. 분리한 말초단핵구세포를 대상으로 알파리포익산 100nM, 메트포민 500uM, 메트포민 500uM 및 알파리포익산 100nM를 각각 2시간동안 배양한 후, anti-CD3(1ug/ml)로 세포자극을 유도한 후, 3일 동안 배양한 다음, 세포배양액을 수득하여 ELISA 방법을 통해 IL-17의 농도를 측정하였다. 이때 대조군으로는 anti-CD3(1ug/ml)만 단독 처리한 군을 사용하였다. 이의 결과를 도 4에 나타내었다.Peripheral blood mononuclear cells (PBMC) from liver cancer patients were isolated using a Ficoll Paque TM centrifuge using a specific gravity difference. After incubating the isolated peripheral mononuclear cells with alpha
도 4에 나타난 바와 같이, 간암환자에서, 알파리포익산 및 메트포민의 처리에 의해 anti-CD3 자극에 따른 염증성 사이토카인인 IL-17의 생성이 알파리포익산 또는 메트포민을 단독 투여한 경우와 비교하여, 현저히 억제되는 것을 확인하였다.As shown in Fig. 4, in liver cancer patients, the production of IL-17, an inflammatory cytokine, according to anti-CD3 stimulation by treatment with alpha-lipoic acid and metformin compared with the case of administering alpha-lipoic acid or metformin alone, It was confirmed that it was significantly suppressed.
2.IFN-r 억제효과 확인2. Confirmation of IFN-r inhibitory effect
상기와 같은 방법으로, IFN-r의 억제효과를 도 5에 나타내었다.In the same manner as described above, the inhibitory effect of IFN-r is shown in FIG. 5 .
도 5에 나타난 바와 같이, 알파리포익산 및 메트포민의 처리에 의해 anti-CD3 자극에 따른 염증성 사이토카인인 IFN-r의 생성이 알파리포익산 또는 메트포민을 단독 투여한 경우와 비교하여, 현저히 억제되는 것을 확인하였다.As shown in FIG. 5 , the production of IFN-r, an inflammatory cytokine according to anti-CD3 stimulation, was significantly inhibited by treatment with alpha lipoic acid and metformin compared to the case of administering alpha lipoic acid or metformin alone. Confirmed.
[실시예 5]이식환자에서 알파리포익산 및 메트포민 투여의 염증서 사이토카인 IL-17 억제효과 확인[Example 5] Confirmation of the inhibitory effect of alpha-lipoic acid and metformin on the inflammatory cytokine IL-17 in transplant patients
이식환자로부터 말초단핵구세포(peripheral blood mononuclear cells, PBMC)를 Ficoll Paque TM으로 원심분리기로 비중차를 이용하여 분리하였다. 분리한 말초단핵구세포를 대상으로 알파리포익산 100nM, 메트포민 500uM, 메트포민 500uM 및 알파리포익산 100nM를 각각 2시간 동안 배양한 후, anti-CD3(1ug/ml)로 세포자극을 유도한 후, 3일 동안 배양한 다음, 세포배양액을 수득하여 ELISA 방법을 통해 IL-17의 농도를 측정하였다. 이때 대조군으로는 anti-CD3(1ug/ml)만 단독 처리한 군을 사용하였다. 이의 결과를 도 6에 나타내었다.Peripheral blood mononuclear cells (PBMC) from transplanted patients were separated using a Ficoll Paque TM centrifuge using a specific gravity difference. After incubating the isolated peripheral mononuclear cells with 100 nM of alpha-lipoic acid, 500 uM of metformin, 500 uM of metformin, and 100 nM of alpha-lipoic acid for 2 hours each, anti-CD3 (1ug/ml) was used to induce cell stimulation, and then 3 days. After culturing for a while, a cell culture medium was obtained and the concentration of IL-17 was measured through an ELISA method. In this case, a group treated with only anti-CD3 (1ug/ml) was used as a control group. The results are shown in FIG. 6 .
도 6에 나타난 바와 같이, 이식환자에서, 알파리포익산 및 메트포민의 처리에 의해 anti-CD3 자극에 따른 염증성 사이토카인인 IL-17의 생성이 알파리포익산 또는 메트포민을 단독 투여한 경우와 비교하여, 현저히 억제되는 것을 확인하였다.As shown in FIG. 6 , in transplant patients, the production of IL-17, an inflammatory cytokine, according to anti-CD3 stimulation by treatment with alpha lipoic acid and metformin compared with the case of single administration of alpha lipoic acid or metformin, It was confirmed that it was significantly suppressed.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been looked at with respect to preferred embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (11)
상기 알파리포익산(alpha lipoic acid) 및 메트포민은 1:5000의 몰농도비로 혼합되는 것인, 이식거부질환의 예방 및 치료용 약학적 조성물.
As a pharmaceutical composition for the prevention and treatment of transplant rejection disease comprising alpha lipoic acid and metformin as active ingredients,
The alpha lipoic acid (alpha lipoic acid) and metformin will be mixed in a molar ratio of 1:5000, a pharmaceutical composition for the prevention and treatment of transplant rejection disease.
상기 알파리포익산 및 메트포민은 염증성 사이토카인의 생성을 감소 또는 억제시키고, STAT3의 발현을 감소 또는 억제시키는 기작을 통해 치료 효과를 나타내는 것을 특징으로 하는 이식거부질환의 예방 및 치료용 약학적 조성물.The method of claim 1,
The alpha lipoic acid and metformin reduce or inhibit the production of inflammatory cytokines, and a pharmaceutical composition for the prevention and treatment of transplant rejection disease, characterized in that it exhibits a therapeutic effect through a mechanism of reducing or inhibiting the expression of STAT3.
상기 염증성 사이토카인은 IL-17 및 IFN-r인 것을 특징으로 하는 이식거부질환의 예방 및 치료용 약학적 조성물.4. The method of claim 3,
The inflammatory cytokine is a pharmaceutical composition for the prevention and treatment of transplant rejection disease, characterized in that IL-17 and IFN-r.
상기 세포, 조직 또는 기관의 이식거부반응은 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부 이식의 거부반응 으로 이루어진 군 중에서 선택되는 것을 특징으로 하는 이식거부질환의 예방 및 치료용 약학적 조성물.The method of claim 1,
The cell, tissue or organ transplant rejection is selected from the group consisting of bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreatic transplantation, kidney transplantation and skin transplantation. A pharmaceutical composition for the prevention and treatment of transplant rejection disease.
상기 알파리포익산(alpha lipoic acid) 및 메트포민은 1:5000의 몰농도비로 혼합되는 것인, 이식거부질환의 예방 및 개선용 식품 조성물.As a food composition for preventing and improving transplant rejection disease comprising alpha lipoic acid and metformin as active ingredients,
The alpha lipoic acid and metformin are mixed in a molar ratio of 1:5000, a food composition for preventing and improving transplant rejection disease.
상기 세포, 조직 또는 기관의 이식거부반응은 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부이식의 거부반응 으로 이루어진 군 중에서 선택되는 것을 특징으로 하는 이식거부질환의 예방 및 개선용 식품 조성물.9. The method of claim 8,
The cell, tissue or organ transplant rejection is selected from the group consisting of bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreatic transplantation, kidney transplantation, and skin transplantation. A food composition for the prevention and improvement of transplant rejection disease.
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