KR20210083632A - Composition containing artesunate for preventing, improving or treating cancer cachexia - Google Patents
Composition containing artesunate for preventing, improving or treating cancer cachexia Download PDFInfo
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- KR20210083632A KR20210083632A KR1020190176110A KR20190176110A KR20210083632A KR 20210083632 A KR20210083632 A KR 20210083632A KR 1020190176110 A KR1020190176110 A KR 1020190176110A KR 20190176110 A KR20190176110 A KR 20190176110A KR 20210083632 A KR20210083632 A KR 20210083632A
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- South Korea
- Prior art keywords
- cachexia
- artesunate
- cancer
- composition
- preventing
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Abstract
Description
본 발명은 아르테수네이트를 함유하는 암성 악액질 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating cancer cachexia containing artesunate.
악액질(cachexia)은 암, 심부전증, 만성 폐쇄성 폐 질환, 만성 신장 질환, 에이즈 등의 다양한 질병에 의해 지속적인 근육 손실을 일으키는 복잡한 증후군을 가리킨다. 이 중 암성 악액질(cancer cachexia)은 악성 종양을 수반하는 복합 대사 증후군으로서, 암이 발생하고 6개월 내에 근육과 지방의 손실에 의해 체중의 5% 이상 감소하는 것으로 정의된다. 악액질은 다양한 의학적 상태에서 일어날 수 있으나 암성 악액질은 말기 암과 밀접한 관계를 가지고 있다. 전체 암 환자의 약 50%, 특히 암 말기 환자의 약 80%가 암성 악액질의 영향을 받으며 근육과 지방의 손실로 인한 삶의 저하 및 사망률 증가로 인해 고통받고 있다. 암성 악액질은 근육량 및 지방조직의 현저한 손실을 통해 체중 감소가 특징이며, 식욕 억제를 통한 근육 및 지방 손실과는 다른 특징을 지니고 있다.Cachexia refers to a complex syndrome that causes persistent muscle loss by various diseases such as cancer, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, AIDS, and the like. Among them, cancer cachexia is a complex metabolic syndrome accompanied by malignant tumors, and is defined as a loss of more than 5% of body weight due to muscle and fat loss within 6 months of the onset of cancer. Cachexia can occur in a variety of medical conditions, but cancerous cachexia is closely related to terminal cancer. About 50% of all cancer patients, especially about 80% of terminal cancer patients, are affected by cancerous cachexia and suffer from decreased life and increased mortality due to loss of muscle and fat. Cancer cachexia is characterized by weight loss through significant loss of muscle mass and adipose tissue, and has different characteristics from muscle and fat loss through appetite suppression.
암성악액질 진단기준은 체중 감소가 5%이상 감소, 혈청 레벨에서 높은 수준의 염증성 마커 발현 (IL6, CRP1, TNFr), 운동 능력 저하, 식욕 부진 등이 있다. 암성 악액질의 정확한 메커니즘은 밝혀져 있지 않지만, IL-6, TNF-α, CRP1(C-reactive protein 1)과 같은 염증성 사이토카인이 근육 및 지방 감소에 중심적인 역할을 하는 것으로 알려져있다. The diagnostic criteria for cancer cachexia include a reduction in weight loss of 5% or more, high levels of inflammatory marker expression in serum levels (IL6, CRP1, TNFr), decreased exercise capacity, and anorexia. Although the exact mechanism of cancer cachexia is not known, inflammatory cytokines such as IL-6, TNF-α, and C-reactive protein 1 (CRP1) are known to play a central role in muscle and fat loss.
염증반응에 기인된 골격근 중량 감소 및 근육소모는 유비퀴틴-프로테아좀(ubiquitin-proteasome) 단백질 분해 경로 및 오토파지/리소좀(autophagic/lysosomal) 단백질 분해 경로를 활성화하며 근육의 단백질이 분해된다. 특히 MAFbx/Atrogin-1(muscle atrophy F-Box) 와 MuRF1(muscle RING finger-1)등의 유비퀴틴 리가아제(ubiquitin ligases) 증가, 그리고 Bnip3등의 오토파지(autophagy) 연관 유전자의 발현증가가 근육의 단백질분해에 직접 연관되어 있다.Skeletal muscle weight loss and muscle wasting due to the inflammatory response activate the ubiquitin-proteasome proteolytic pathway and the autophagic/lysosomal proteolytic pathway, and muscle protein is degraded. In particular, increases in ubiquitin ligases such as MAFbx/Atrogin-1 (muscle atrophy F-Box) and MuRF1 (muscle RING finger-1), and autophagy-related genes such as Bnip3 It is directly involved in proteolysis.
암성악액질의 치료제에는 NSAIDs (non-steroidal anti-inflammatory drugs), β2-adrenergic agonists, corticosteroid, ghrelin 등이 있으며, 현재까지 시판되고 있는 암성 악액질 치료에 가장 많이 사용되는 약물은 COX-2 억제제와 TNF-α 억제제가 있다.Treatments for cancer cachexia include NSAIDs (non-steroidal anti-inflammatory drugs), β2-adrenergic agonists, corticosteroids, and ghrelin. There are α inhibitors.
COX-2 억제제는 암 조직에서 다량 발생되는 염증 물질인 프로스타글란딘(prostaglandins)의 생성에 관여하는 COX-2를 억제하여 골격근의 손실을 감소시키는 약물이다. COX-2 억제제로서 시중에는 셀레콕시브(celecoxib)가 판매되고 있다. 그러나 셀레콕시브(celecoxib)는 빈혈, 위궤양, 알레르기, 심장 마비 및 뇌졸중 등의 부작용이 보고되어 있다.A COX-2 inhibitor is a drug that reduces the loss of skeletal muscle by inhibiting COX-2, which is involved in the production of prostaglandins, which are inflammatory substances generated in large amounts in cancer tissues. As a COX-2 inhibitor, celecoxib is commercially available. However, side effects such as anemia, gastric ulcer, allergy, heart attack and stroke have been reported with celecoxib.
TNF-α 억제제는 암성 악액질 환자의 혈정에서 많이 발현되는 TNF-α 의 발현을 감소시켜 암세포를 사멸시키는 약물이다. TNF-α 억제제로서 시중에는 탈리도마이드(Thalidomide)가 판매되고 있다. 그러나 이들 약물은 암성 악액질 치료제로서의 효과가 적으며, 우울증, 심부전, 호흡 곤란, 구토, 발진, 고혈압 및 임신 시 기형아를 낳게 되는 부작용이 있다.A TNF-α inhibitor is a drug that kills cancer cells by reducing the expression of TNF-α, which is widely expressed in the bloodstream of patients with cancer cachexia. Thalidomide is commercially available as a TNF-α inhibitor. However, these drugs have little effect as a treatment for cancer cachexia, and have side effects such as depression, heart failure, breathing difficulties, vomiting, rash, high blood pressure, and birth defects during pregnancy.
이와 같이 현재까지 개발 중이거나 시판되고 있는 약물은 대부분 부작용이 많이 나타나며, 치료 효과에 대한 근거가 부족하다. 따라서 새로운 기전의 암성 악액질 치료제 개발이 절실한 상황이다.As such, most of the drugs being developed or marketed up to now have many side effects and lack of evidence for their therapeutic effect. Therefore, there is an urgent need to develop a treatment for cancer cachexia with a new mechanism.
한편, 아르테수네이트는 중국에서 2,000년 이상 해열제로 사용되어 온 한약인 청호의 성분으로, 수용성이며 항말라리아 원충 효과가 있음. 또한 World Health Organization의 Essential Medicines에 등재된 약물이다.On the other hand, Artesunate is a component of Cheongho, a herbal medicine that has been used as an antipyretic agent in China for more than 2,000 years, and is water-soluble and has anti-malarial effects. It is also a drug listed in Essential Medicines of the World Health Organization.
본 발명자들은 천연물, 특히 식품에서 유래한 성분인 아르테수네이트 화합물이 CT26 세포 주입으로 암성 악액질을 유도한 마우스 모델에서 유의성 있는 암성 악액질 개선 효과가 있음을 확인하여, 본 발명을 완성하였다.The present inventors have completed the present invention by confirming that artesunate compound, which is a component derived from natural products, particularly food, has a significant improvement in cancer cachexia in a mouse model in which cancer cachexia is induced by injection of CT26 cells.
본 발명의 목적은, 아르테수네이트(Artesunate) 또는 이의 약학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating cachexia comprising Artesunate or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은, 아르테수네이트(Artesunate) 또는 이의 식품학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for preventing or improving cachexia comprising artesunate or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은, 아르테수네이트(Artesunate) 또는 이의 식품학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 개선용 건강식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health food composition for preventing or improving cachexia comprising artesunate or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은, 상기 악액질 예방 또는 치료용 약학적 조성물을 포함하는 항암 보조제 조성물을 제공하는 것이다.Another object of the present invention is to provide an anti-cancer adjuvant composition comprising the pharmaceutical composition for preventing or treating cachexia.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은, 아르테수네이트(Artesunate) 또는 이의 약학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cachexia comprising Artesunate or a pharmaceutically acceptable salt thereof.
본 발명의 일실시예에 있어서, 상기 악액질은 암에 의해 유발되는 것일 수 있다.In one embodiment of the present invention, the cachexia may be caused by cancer.
또한, 본 발명은, 아르테수네이트(Artesunate) 또는 이의 식품학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cachexia comprising artesunate or a pharmaceutically acceptable salt thereof.
본 발명의 일실시예에 있어서, 상기 악액질은 암에 의해 유발되는 것일 수 있다.In one embodiment of the present invention, the cachexia may be caused by cancer.
나아가, 본 발명은, 아르테수네이트(Artesunate) 또는 이의 식품학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 개선용 건강식품 조성물을 제공한다.Furthermore, the present invention provides a health food composition for preventing or improving cachexia comprising artesunate or a pharmaceutically acceptable salt thereof.
본 발명의 일실시예에 있어서, 상기 악액질은 암에 의해 유발되는 것일 수 있다.In one embodiment of the present invention, the cachexia may be caused by cancer.
더 나아가, 본 발명은, 상기 악액질 예방 또는 치료용 약학적 조성물을 포함하는 항암 보조제 조성물을 제공한다.Furthermore, the present invention provides an anti-cancer adjuvant composition comprising the pharmaceutical composition for preventing or treating cachexia.
본 발명의 아르테수네이트(Artesunate)은 대장암 세포주인 CT26을 사타구니에 주입하여 유발한 암성 악액질 마우스 모델에서 유의성 있는 체중 감소 개선 효과를 보였으며, 암성 악액질의 주요 지표 인자로서 작용하는 IL6, CRP 및 TNF-α의 혈청 농도의 발현을 억제하였고, 암성 악액질에 의한 근육 조직의 크기 및 무게 감소를 억제하는 효과를 나타내므로, 암성 악액질 예방, 개선 또는 치료용 조성물로 유용할 수 있다.Artesunate of the present invention showed a significant weight loss improvement effect in a mouse model of cancer cachexia induced by injection of CT26, a colorectal cancer cell line, into the groin, and IL6, CRP and Since it inhibits the expression of serum concentration of TNF-α and has the effect of inhibiting the reduction in the size and weight of muscle tissue caused by cancerous cachexia, it may be useful as a composition for preventing, improving or treating cancerous cachexia.
도 1은 아르테수네이트의 암성 악액질에 의한 체중 감소에 대한 억제 효과를 나타낸 것이다.
도 2는 아르테수네이트의 암성 악액질에 의한 혈청내 염증성 사이토카인(CRP, TNF-α 및 IL-6) 발현에 대한 억제 효과를 나타낸 것이다.
도 3은 아르테수네이트의 암성 악액질에 의한 근육조직 감소 억제 효과를 나타낸 것이다.
도 4는 아르테수네이트의 근육세포에서 근세포 손실 억제 효과를 나타낸 것이다.1 shows the inhibitory effect of artesunate on weight loss caused by cancerous cachexia.
2 shows the inhibitory effect of artesunate on the expression of inflammatory cytokines (CRP, TNF-α and IL-6) in the serum by cancer cachexia.
3 shows the inhibitory effect of artesunate on muscle tissue reduction due to cancerous cachexia.
4 shows the inhibitory effect of artesunate on muscle cell loss in muscle cells.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
악액질(cachexia) 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating cachexia
본 발명은 아르테수네이트(Artesunate) 또는 이의 약학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cachexia comprising Artesunate or a pharmaceutically acceptable salt thereof.
본 명세서에 사용된 용어, '악액질'은 암, 결핵, 당뇨병, 후천성면역결핍증(Acquired immunodeficiency syndrome, AIDS) 등의 말기에서 볼 수 있는 고도의 전신쇠약증세를 말하며, 위암이나 식도암, 대장암 등 소화기암 환자와 폐암 환자에서 자주 나타난다. 식욕 감소, 근육 및 지방 감소에 따른 체중 및 체력의 감소, 빈혈, 무기력, 소화 불량 등의 증상 등을 나타내며, 특히 식욕이 감소하여 정상적인 음식 섭취가 어려운 상태를 보이거나 또는 정상적으로 음식을 섭취하더라도 체중이 감소하는 상태를 나타낸다. 악액질이 발생하면 항암 화학요법이나 방사선 치료에 대해 낮은 반응을 보이므로 환자의 삶의 질이 저하되고, 기대 여명의 단축을 초래하며, 전체 암환자의 10 내지 20%에서 체중 감소로 인한 사망을 유발한다.As used herein, the term 'cachexia' refers to a high degree of general weakness that can be seen in the late stages of cancer, tuberculosis, diabetes, acquired immunodeficiency syndrome, AIDS, etc., and digestive organs such as stomach cancer, esophageal cancer, colon cancer, etc. It is often seen in cancer patients and lung cancer patients. It shows symptoms such as decreased appetite, decreased body weight and stamina due to muscle and fat reduction, anemia, lethargy, and indigestion. indicates a declining state. When cachexia develops, it shows a low response to chemotherapy or radiation therapy, which reduces the quality of life of patients, shortens life expectancy, and causes death due to weight loss in 10 to 20% of all cancer patients. do.
본 발명에 따른 약학적 조성물에 있어서, 상기 악액질은 암에 의해 유발되는 것일 수 있다.In the pharmaceutical composition according to the present invention, the cachexia may be caused by cancer.
본원에서 정의되는 암은 백혈병, 림프종, 골수종, 골수이형성증후군, 유방암, 두경부암, 식도암, 위암, 대장암(=결장암), 직장암, 항문암, 간세포간암, 담관암, 담낭암, 췌장암, 폐암(비소세포성 폐암, 소세포성 폐암), 흉선암, 신장암, 방광암, 전립선암, 고환암, 난소암, 자궁경부암, 육종, 위장관 기질성 종양(GIST, 기스트), 원발부위불명암, 중피종, 흑색종, 신경내분비 종양, 피부암, 혈액암 등을 포함하는 것일 수 있다.Cancer as defined herein is leukemia, lymphoma, myeloma, myelodysplastic syndrome, breast cancer, head and neck cancer, esophageal cancer, stomach cancer, colorectal cancer (= colon cancer), rectal cancer, anal cancer, hepatocellular liver cancer, bile duct cancer, gallbladder cancer, pancreatic cancer, lung cancer (non-small cell) Lung cancer, small cell lung cancer), thymus cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, sarcoma, gastrointestinal stromal tumor (GIST, GIST), cancer of unknown primary site, mesothelioma, melanoma, It may include neuroendocrine tumors, skin cancers, blood cancers, and the like.
본 발명에 따른 상기 약학적 조성물은 식욕 감소, 체중 감소, 피로도 증가, 염증 증가, 근육 손실, 지방 손실 및 조혈 독성으로 이루어진 군에서 선택되는 1종 이상의 증상을 개선하는 것일 수 있고, 바람직하게는 체중 감소, 근육 손실 및 지방 손실로 이루어진 군에서 선택되는 1종 이상의 증상을 개선하는 것일 수 있다.The pharmaceutical composition according to the present invention may improve one or more symptoms selected from the group consisting of decreased appetite, weight loss, increased fatigue, increased inflammation, muscle loss, fat loss, and hematopoietic toxicity, preferably weight loss. It may be to improve one or more symptoms selected from the group consisting of reduction, muscle loss, and fat loss.
또한, 본 발명에 따른 상기 약학적 조성물은 시상하부, 혈액 또는 골수에서의 염증성 사이토카인의 발현을 감소시키는 것일 수 있다. 이때, 상기 염증성 사이토카인은 CRP, TNF-α, IL-1β, IL-6, 및 IL-17로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있다.In addition, the pharmaceutical composition according to the present invention may be to reduce the expression of inflammatory cytokines in the hypothalamus, blood or bone marrow. In this case, the inflammatory cytokine may be one or more selected from the group consisting of CRP, TNF-α, IL-1β, IL-6, and IL-17.
본 발명의 일실시예에 따르면, 아르테수네이트(Artesunate)가 대장암 세포주인 CT26을 사타구니에 주입하여 유발한 암성 악액질 마우스 모델에서 체중 감소 개선 효과를 보였고, 암성 악액질의 주요 지표 인자로서 작용하는 IL6, CRP 및 TNF-α의 혈청 농도의 발현을 억제하는 효과를 나타내었으며, 암성 악액질에 의한 근손실이 아르테수네이트에 의해 감소되는 효과를 확인하였다(실시예 1 내지 5 참조).According to one embodiment of the present invention, Artesunate showed an effect of improving weight loss in a mouse model of cancer cachexia induced by injection of CT26, a colorectal cancer cell line, into the groin, and IL6 acting as a major indicator of cancer cachexia , showed the effect of inhibiting the expression of serum concentrations of CRP and TNF-α, and confirmed the effect of reducing muscle loss due to cancer cachexia by artesunate (see Examples 1 to 5).
본 발명에 따른 약학적 조성물에 있어서, 약학적으로 허용가능한 염이란 표현은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 아르테수네이트의 이로운 효능을 떨어뜨리지 않는 아르테수네이트의 어떠한 유기 또는 무기 부가염을 의미한다. 이들 염은 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 질산, 황산, 과염소산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 말레산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 타타르산, 갈룩투론산, 엠본산, 글루탐산, 아스파르트산, 옥살산, (D) 또는 (L) 말산, 말레산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산 또는 말론산 등을 사용할 수 있다. 또한, 이들 염은 알칼리 금속염(나트륨염, 칼륨염 등) 및 알칼리 토금속염(칼슘염, 마그네슘염 등) 등을 포함한다. 예를 들면, 산부가염으로는 아세테이트, 아스파테이트, 벤즈에이트, 베실레이트, 바이카보네이트/카보네이트, 바이설페이트/설페이트, 보레이트, 캄실레이트, 시트레이트, 에디실레이트, 에실레이트, 포메이트, 퓨마레이트, 글루셉테이트, 글루코네이트, 글루큐로네이트, 헥사플루오로포스페이트, 하이벤제이트, 하이드로클로라이드/클로라이드, 하이드로브로마이드/브로마이드, 하이드로요오디드/요오디드, 이세티오네이트, 락테이트, 말레이트, 말리에이트, 말로네이트, 메실레이트, 메틸설페이트, 나프틸레이트, 2-나프실레이트, 니코티네이트, 나이트레이트, 오로테이트, 옥살레이트, 팔미테이트, 파모에이트, 포스페이트/수소 포스페이트/이수소 포스페이트, 사카레이트, 스테아레이트, 석시네이트, 타르트레이트, 토실레이트, 트리플루오로아세테이트, 알루미늄, 알기닌, 벤자틴, 칼슘, 콜린, 디에틸아민, 디올아민, 글라이신, 라이신, 마그네슘, 메글루민, 올아민, 칼륨, 나트륨, 트로메타민, 아연염 등이 포함될 수 있다.In the pharmaceutical composition according to the present invention, the expression pharmaceutically acceptable salt is a concentration having an effective action that is relatively non-toxic and harmless to the patient, and the side effects caused by the salt do not reduce the beneficial efficacy of Artesunate. any organic or inorganic addition salt of sunate. For these salts, inorganic acids and organic acids can be used as free acids, and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, fumarin, etc. can be used as organic acids. Acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid Phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid may be used. Further, these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salt (calcium salt, magnesium salt, etc.) and the like. For example, acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hebenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malate ate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate Late, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salts and the like may be included.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 아르테수네이트을 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜셔 제조할 수 있다.The acid addition salt according to the present invention is prepared by a conventional method, for example, dissolving artesunate in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid to filter and dry the resulting precipitate. or by distilling the solvent and excess acid under reduced pressure and then drying or crystallizing in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
나아가, 본 발명은 상기 아르테수네이트 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 이성질체, 광학 이성질체 등을 모두 포함하는 것일 수 있다.Furthermore, the present invention may include all possible solvates, hydrates, isomers, optical isomers, etc. that can be prepared therefrom, as well as the artesunate and pharmaceutically acceptable salts thereof.
본 발명에 따른 상기 약학적 조성물은 경구 투여용, 근육내 투여용, 정맥내 투여용, 복강내 투여용, 피하 투여용, 피내 투여용, 또는 국소 투여용으로 제제화되는 것일 수 있다.The pharmaceutical composition according to the present invention may be formulated for oral administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, intradermal administration, or topical administration.
본 발명의 아르테수네이트 또는 이의 약학적으로 허용되는 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.Artesunate or a pharmaceutically acceptable salt thereof of the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrants, It is prepared using a diluent or excipient such as a surfactant.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 아르테수네이트 또는 이의 약학적으로 허용되는 염에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and these solid preparations include at least one excipient in one or more artesunate of the present invention or a pharmaceutically acceptable salt thereof. For example, it is prepared by mixing starch, calcium carbonate, sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
상기 약학적 조성물은 담체, 부형제 또는 희석제를 더 포함할 수 있다. 담체, 부형제, 또는 희석제는 예를 들어, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 또는 광물유를 포함할 수 있다.The pharmaceutical composition may further include a carrier, excipient or diluent. Carriers, excipients, or diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
또한, 상기 약학적 조성물은 암성 악액질 예방 또는 치료 활성을 갖는 공지의 유효성분을 더 포함할 수 있다.In addition, the pharmaceutical composition may further include a known active ingredient having a preventive or therapeutic activity for cancer cachexia.
본 발명의 아르테수네이트 또는 이의 약학적으로 허용되는 염의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001~100 mg/kg/일이며, 바람직하게는 0.01~35 mg/kg/일이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07~7000 mg/일이며, 바람직하게는 0.7~2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.The effective dose for the human body of artesunate or a pharmaceutically acceptable salt thereof of the present invention may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and is generally about 0.001 to 100 mg. /kg/day, preferably 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and once a day at regular time intervals according to the judgment of a doctor or pharmacist It may be administered in several divided doses.
악액질(cachexia) 예방 또는 개선용 건강기능식품 및 건강식품 조성물Health functional food and health food composition for preventing or improving cachexia
또한, 본 발명은 아르테수네이트(Artesunate) 또는 이의 식품학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cachexia comprising artesunate or a pharmaceutically acceptable salt thereof.
본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캡슐제, 환제, 액제, 분말 및 과립 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 건강기능식품 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 암성 악액질 치료제 또는 항암제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The term "health functional food" used in the present invention refers to food manufactured and processed in the form of tablets, capsules, pills, liquids, powders and granules, etc. using raw materials or ingredients having useful functions in the human body. Here, the term 'functionality' refers to obtaining useful effects for health purposes such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be manufactured by a method commonly used in the conventional technical field, and at the time of the production, it can be prepared by adding raw materials and components commonly added in the conventional technical field. In addition, the dosage form of the health functional food may also be manufactured without limitation as long as it is a dosage form recognized as a health functional food. The health functional food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur when taking the drug for a long period of time by using food as a raw material, and it has excellent portability, The health functional food of the present invention can be ingested as an adjuvant for enhancing the effect of a cancer cachexia therapeutic agent or an anticancer agent.
나아가, 본 발명은 아르테수네이트(Artesunate) 또는 이의 식품학적으로 허용가능한 염을 포함하는 악액질(cachexia) 예방 또는 개선용 건강기능식품 조성물을 제공한다.Furthermore, the present invention provides a health functional food composition for preventing or improving cachexia comprising artesunate or a pharmaceutically acceptable salt thereof.
본 발명에 따른 상기 건강기능식품 조성물 또는 건강식품 조성물은 암성 악액질을 예방 또는 개선시키기 위한 목적으로 상기 아르테수네이트 또는 이의 식품학적으로 허용가능한 염을 식품, 음료 등의 건강기능식품 또는 건강식품에 첨가할 수 있다.In the health functional food composition or health food composition according to the present invention, the artesunate or a pharmaceutically acceptable salt thereof is added to health functional food or health food such as food and beverage for the purpose of preventing or improving cancerous cachexia. can do.
상기 식품의 종류에는 특별한 제한은 없다. 본 발명에 따른 아르테수네이트 또는 이의 식품학적으로 허용가능한 염을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강식품 및 건강기능식품을 모두 포함한다.There is no particular limitation on the type of the food. Examples of foods to which artesunate or a pharmaceutically acceptable salt thereof according to the present invention can be added include drinks, meat, sausage, bread, biscuits, rice cake, chocolate, candy, snacks, confectionery, pizza, ramen, and other noodles. , gums, dairy products including ice cream, various soups, beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and includes both health food and health functional food in the ordinary sense.
본 발명에 따른 상기 건강기능식품 및 건강식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 본 발명에 따른 상기 아르테수네이트 또는 이의 식품학적으로 허용가능한 염의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 및 건강기능식품 중의 상기 아르테수네이트 또는 이의 식품학적으로 허용가능한 염의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 유지를 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The health functional food and health food composition according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the artesunate or a pharmaceutically acceptable salt thereof according to the present invention may be appropriately determined depending on the purpose of its use (for prevention or improvement). In general, the amount of artesunate or a pharmaceutically acceptable salt thereof in health food and health functional food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for health maintenance or health control, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 건강식품 및 건강기능식품 조성물은 지시된 비율로 필수 성분으로서 본 발명에 따른 아르테수네이트 또는 이의 식품학적으로 허용가능한 염을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 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, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능성 식품 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health food and health functional food composition of the present invention is not particularly limited in other ingredients except for containing the artesunate according to the present invention or a pharmaceutically acceptable salt thereof as an essential ingredient in the indicated ratio, and various Eggplant flavoring agents or natural carbohydrates may be contained as additional ingredients. 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. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the nutraceutical composition of the present invention.
상기 외에 본 발명에 따른 아르테수네이트 또는 이의 식품학적으로 허용가능한 염을 함유하는 건강식품 및 건강기능식품 조성물은 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, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강식품 및 건강기능식품 조성물은 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health food and health functional food composition containing artesunate or a pharmaceutically acceptable salt thereof according to the present invention is a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents, and natural flavoring agents. , colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, etc. may contain. In addition, the health food and health functional food composition of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 이에 제한되지는 않으나, 본 발명의 유효물질을 함유하는 건강식품 및 건강기능식품 조성물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. The proportion of these additives is not limited thereto, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.
항암 보조제 조성물Anti-cancer adjuvant composition
또한, 본 발명은 상기 악액질(cachexia) 예방 또는 치료용 약학적 조성물을 포함하는 항암 보조제 조성물을 제공한다.In addition, the present invention provides an anti-cancer adjuvant composition comprising a pharmaceutical composition for preventing or treating cachexia.
본 발명에서 사용되는 용어 "항암보조제"는 항암 치료 효과를 증대시키고, 항암제의 부작용을 억제하거나 개선시키기 위하여 사용될 수 있으며, 항암제와 병용하여 환자에게 투여될 수 있다. The term "anticancer adjuvant" used in the present invention may be used to increase the anticancer therapeutic effect, suppress or improve the side effects of anticancer agents, and may be administered to a patient in combination with an anticancer agent.
본 발명의 상기 항암 보조제 조성물은, 암에 의해 유발되는 근 손실, 체중 감소, 지방 감소, 조혈 도성, 식욕 감소 등의 악액질 증상을 억제하거나 개선시키는 효과를 나타내어 항암제의 항암효과를 증대시키는 것일 수 있다.The anticancer adjuvant composition of the present invention exhibits an effect of suppressing or improving cachexia symptoms such as muscle loss, weight loss, fat reduction, hematopoiesis, and decreased appetite caused by cancer, thereby increasing the anticancer effect of the anticancer agent. .
본원에서 정의되는 기존 항암제는 시클로포스파미드(Cyclophosphamide), 메토트랙세이트 (methotrexate), 5-플루오로우라실(fluorouracil), 독소루비신(Doxorubicin), 무스틴(Mustine), 비크리스틴(vincristine), 프로카바진(procarbazine), 프레드니솔론(prednisolone), 블레오마이신(bleomycin), 빈블라스틴(vinblastine), 다카르바진(dacarbazine), 에토포시드 (etoposide), 시스플라틴(cisplatin), 에피루비신(Epirubicin), 시스플라틴(cisplatin), 카페시타빈(capecitabine), 옥살리플라틴(oxaliplatin) 등을 포함하는 것일 수 있다.Existing anticancer agents as defined herein include cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarba Procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, cisplatin ( cisplatin), capecitabine, oxaliplatin, and the like.
상기 항암 보조제 조성물은 유효성분으로 아르테수네이트 또는 이의 약학적으로 허용가능한 염을 포함하는 이외에 동일 또는 유사한 기능을 나타내는 유효성분을 추가로 1종 이상 포함할 수 있다. 상기 항암 보조제는 임상 투여 시에 경구 또는 비경구로 투여가 가능하며, 비경구 투여 시 복강 내 주사, 직장 내 주사, 피하주사, 정맥주사, 근육 내 주사, 자궁 내 경막주사, 뇌혈관 내 주사 또는 흉부 내 주사에 의해 투여될 수 있고, 일반적인 의약품 제제의 형태로 사용될 수 있다.The anti-cancer adjuvant composition may further include at least one active ingredient exhibiting the same or similar function in addition to including artesunate or a pharmaceutically acceptable salt thereof as an active ingredient. The anticancer adjuvant can be administered orally or parenterally during clinical administration, and when administered parenterally, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrauterine dural injection, intracerebrovascular injection, or chest It can be administered by internal injection, and can be used in the form of a general pharmaceutical preparation.
상기 항암 보조제는 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다. 상기 항암 보조제의 일일 투여량은 약 0.0001 내지 1000 ㎎/㎏이고, 바람직하게는 1 내지 100 ㎎/㎏이며, 하루 1회 내지 수회 나누어 투여하는 것이 바람직하나 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여 방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 항암 보조제는 실제 임상 투여 시에 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The anticancer adjuvant may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers. The daily dose of the anticancer adjuvant is about 0.0001 to 1000 mg/kg, preferably 1 to 100 mg/kg, and it is preferable to divide and administer it once to several times a day, but the patient's weight, age, sex, health condition, The range varies depending on the diet, administration time, administration method, excretion rate, and the severity of the disease. The anticancer adjuvant of the present invention may be administered in various parenteral formulations during actual clinical administration. When formulated, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, etc. is prepared Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.
<실시예 1> 암성 악액질 유발 마우스 모델의 준비<Example 1> Preparation of a cancerous cachexia-induced mouse model
암성 악액질을 유발하기 위해 BALB/c 마우스를 4군(각 군당 9마리)으로 나누어 정상군을 제외한 2군은 1주간 CT26(10mg/kg/day)를 마우스 오른쪽 허벅지에 주사하고, 1주간의 암성 악액질 유발 하였다. 그후, 3주간 정상군과 악액질유발군은 물을, 약물군은 아르테수네이트(100mg/kg/day)을 주입한 실험군으로 처치를 달리하여 실험을 진행하였다. 이때 아르테수네이트는 시그마 알드리치(카탈로그 넘버: A3731)에서 구입하여 사용하였다.In order to induce cancerous cachexia, BALB/c mice were divided into 4 groups (9 mice in each group), and CT26 (10mg/kg/day) was injected into the right thigh for 1 week in group 2 except for the normal group, and cancerous for 1 week. cachexia induced. After that, the normal group and the cachexia-inducing group were treated with water, and the drug group was treated with artesunate (100 mg/kg/day) for 3 weeks. At this time, artesunate was purchased from Sigma Aldrich (catalog number: A3731) and used.
<실시예 2> 아르테수네이트의 암성 악액질에 의한 체중 감소 개선 효과<Example 2> Effects of Artesunate on Weight Loss Improvement by Cancer Cachexia
암성 악액질의 유발 및 아르테수네이트의 개선 효과를 확인하기 위해 상기 실시예 1과 같은 방법으로 총 4주간의 처치 후 마우스들의 체중을 측정하였다. 이때, 마우스에서 유발된 암의 무게를 제거한 후 체중을 측정하였다. In order to confirm the induction of cancerous cachexia and the improvement effect of artesunate, the weights of the mice were measured after treatment for a total of 4 weeks in the same manner as in Example 1. At this time, the weight was measured after removing the weight of cancer induced in the mouse.
암성 악액질에 의한 체중 감소 억제에 대한 아르테수네이트의 효과를 실험한 결과는 도 1에 나타난 바와 같다.The experimental results of the effect of artesunate on weight loss inhibition caused by cancer cachexia are shown in FIG. 1 .
그 결과, 악액질 유발군과 아르테수네이트를 처리한 군(약물군)을 비교해 봤을 때, 암의 무게를 제외한 마우스의 체중이 증가하였으며, 아르테수네이트가 암성 악액질 유발 모델에서 체중 감소를 유의하게 억제하는 것을 확인하였다(도 1참조).As a result, when the cachexia-inducing group and the artesunate-treated group (drug group) were compared, the weight of mice excluding the weight of cancer increased, and artesunate significantly inhibited weight loss in the cancerous cachexia induction model. was confirmed (see FIG. 1).
<실시예 3> 아르테수네이트의 암성 악액질 지표 인자에 대한 발현 개선 효과<Example 3> Expression improvement effect of artesunate on cancer cachexia indicator factor
암성 악액질의 유발 및 아르테수네이트의 개선 효과를 확인하기 위해 상기 실시예 1과 같은 방법으로 총 4주간 처치한 후, 마우스들의 혈액을 채취하여 에틸렌다이아민테트라아세트산(ethylenediaminetetraacetic acid, EDTA)가 들어있는 튜브에 넣은 다음, 잘 섞이도록 tapping해 주었다. 그 다음, 13000 RPM, 30분 동안 원심분리기를 이용하여 혈청(serum)을 분리해낸 뒤 IL-6, CRP, TNF-α가 코팅된 Plate에 혈청을 넣고 반응시킨 뒤 2차 항체를 붙여 반응 시킨 후 그 발현량에 따른 색의 차이를 ELISER 분석기(VERSAmax microplate reader, Molecular Devices, CA, USA)를 이용하여 분석하였다.In order to confirm the induction of cancerous cachexia and the improvement effect of artesunate, after a total of 4 weeks of treatment in the same manner as in Example 1, blood was collected from mice and containing ethylenediaminetetraacetic acid (EDTA). After putting it in a tube, it was tapped to mix well. Then, after separating the serum using a centrifuge at 13000 RPM for 30 minutes, the serum was put on a plate coated with IL-6, CRP, and TNF-α and reacted, followed by reaction with a secondary antibody. The difference in color according to the expression level was analyzed using an ELISER analyzer (VERSAmax microplate reader, Molecular Devices, CA, USA).
암성 악액질이 발생하는 과정에서 일어나는 염증성 사이토카인의 변화에 대한 아르테수네이트의 효과를 실험한 결과를 도 2에 나타내었다.2 shows the results of an experiment on the effect of artesunate on changes in inflammatory cytokines that occur in the process of cancerous cachexia.
그 결과, 아르테수네이트는 혈청 CRP, 혈청 TNF-α 및 혈청 IL-6에서 모두 암성 악액질로 유발되는 염증성 사이토카인의 변화에 대하여 개선 효과를 보임을 확인하였다.As a result, it was confirmed that artesunate showed an improvement effect on changes in inflammatory cytokines induced by cancer cachexia in all of serum CRP, serum TNF-α and serum IL-6.
<실시예 4> 아르테수네이트의 암성 악액질에 의한 근육조직 감소 억제 효과<Example 4> Artesunate inhibitory effect on muscle tissue reduction due to cancerous cachexia
암성 악액질의 유발 및 아르테수네이트의 개선 효과를 확인하기 위해 상기 실시예 1과 같은 방법으로 총 4주간의 처치 후, 마우스들의 장딴지근(GAS; gastrocnemius) 및 전경골근(TA; tibialis anterior) 근육조직의 부피 및 무게를 측정하였다.To confirm the induction of cancerous cachexia and the improvement effect of artesunate, after a total of 4 weeks of treatment in the same manner as in Example 1, the gastrocnemius (GAS) and tibialis anterior (TA) muscle tissues of mice The volume and weight of the were measured.
근육조직의 감소 억제에 대한 아르테수네이트의 효과를 실험한 결과를 도 3에 나타내었다.The experimental results of the effect of artesunate on the inhibition of muscle tissue reduction are shown in FIG. 3 .
그 결과, 아르테수네이트 암성 악액질의 발병 과정에 일어나는 근육 감소에 있어서 개선 효과를 확인하였으며, 질병대조군에 비해, 근육조직의 무게가 유의하게 증가하는 것을 확인하였다.As a result, it was confirmed that artesunate had an improvement effect on muscle reduction occurring during the onset of cancerous cachexia, and the weight of muscle tissue was significantly increased compared to the disease control group.
<실시예 5> 아르테수네이트의 암성 악액질에 의한 근세포 손실 억제 효과<Example 5> Artesunate inhibits muscle cell loss due to cancerous cachexia
암성 악액질의 유발 및 아르테수네이트의 개선 효과를 확인하기 위해 근육세포인 C2C12를 2% Horse Serum으로 분화시켜 Myosin heavy chains (MYH)항체를 붙여 형광염색을 하여 형광현미경으로 관찰하였다.In order to confirm the induction of cancerous cachexia and the improvement effect of artesunate, muscle cells, C2C12, were differentiated into 2% Horse Serum, Myosin heavy chains (MYH) antibody was attached, fluorescence staining was performed, and observed with a fluorescence microscope.
근세포 손실 억제에 대한 아르테수네이트의 효과를 실험한 결과를 도 4에 나타내었다.The experimental results of the effect of artesunate on the inhibition of muscle cell loss are shown in FIG. 4 .
그 결과, 아르테수네이트는 암성 악액질이 유발된 세포 모델에서 줄어든 세포의 두께를 아르테수네이트 처리에 의해 근육세포의 두께가 정상군과 유사하게 되는 것을 확인하였으며, 또한 MYH의 발현이 암성 악액질 모델과 비교하여 아르테수네이트 처리 시 높게 발현되는 것을 확인하였다. As a result, artesunate confirmed that the muscle cell thickness was similar to that of the normal group by artesunate treatment with the reduced cell thickness in the cancerous cachexia-induced cell model. Also, the expression of MYH was similar to that of the cancerous cachexia model. By comparison, it was confirmed that high expression was observed during artesunate treatment.
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 특허 청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. 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 in the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (12)
상기 악액질은 암에 의해 유발되는 것을 특징으로 하는, 약학적 조성물.According to claim 1,
The cachexia is characterized in that caused by cancer, a pharmaceutical composition.
상기 조성물은 식욕 감소, 체중 감소, 피로도 증가, 염증 증가, 근육 손실, 지방 손실 및 조혈 독성으로 이루어진 군에서 선택되는 1종 이상의 증상을 개선하는 것을 특징으로 하는, 약학적 조성물.According to claim 1,
The composition is characterized in that it improves one or more symptoms selected from the group consisting of decreased appetite, weight loss, increased fatigue, increased inflammation, muscle loss, fat loss, and hematopoietic toxicity.
상기 조성물은 시상하부, 혈액 또는 골수에서의 염증성 사이토카인의 발현을 감소시키는 것을 특징으로 하는, 약학적 조성물.According to claim 1,
The composition is characterized in that it reduces the expression of inflammatory cytokines in the hypothalamus, blood or bone marrow, a pharmaceutical composition.
상기 염증성 사이토카인은 CRP, TNF-α, IL-1β, IL-6, 및 IL-17로 이루어진 군으로부터 선택되는 1종 이상인 것을 특징으로 하는, 약학적 조성물.5. The method of claim 4,
The inflammatory cytokine is one or more selected from the group consisting of CRP, TNF-α, IL-1β, IL-6, and IL-17, a pharmaceutical composition.
상기 악액질은 암에 의해 유발되는 것을 특징으로 하는, 건강기능식품 조성물.7. The method of claim 6,
The cachexia is a health functional food composition, characterized in that caused by cancer.
상기 건강기능식품은 정제, 캡슐제, 환제 또는 액제 형태의 식품인 것을 특징으로 하는, 건강기능식품 조성물.7. The method of claim 6,
The health functional food is a health functional food composition, characterized in that the food in the form of tablets, capsules, pills or liquids.
상기 악액질은 암에 의해 유발되는 것을 특징으로 하는, 건강식품 조성물.10. The method of claim 9,
The cachexia is characterized in that caused by cancer, health food composition.
상기 건강식품은 각종 드링크제, 육류, 소세지, 빵, 캔디류, 스넥류, 면류, 아이스크림, 유제품, 스프, 이온음료, 음료수, 알코올 음료, 껌, 차 및 비타민 복합제에서 선택되는 것을 특징으로 하는, 건강식품 조성물.10. The method of claim 9,
The health food is selected from various drinks, meat, sausages, bread, candy, snacks, noodles, ice cream, dairy products, soups, ionic beverages, beverages, alcoholic beverages, gum, tea and vitamin complexes, health food composition .
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