KR101968398B1 - Pharmaceutical composition for treating cancer with suppressed side effects in the immune system - Google Patents
Pharmaceutical composition for treating cancer with suppressed side effects in the immune system Download PDFInfo
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- KR101968398B1 KR101968398B1 KR1020170023104A KR20170023104A KR101968398B1 KR 101968398 B1 KR101968398 B1 KR 101968398B1 KR 1020170023104 A KR1020170023104 A KR 1020170023104A KR 20170023104 A KR20170023104 A KR 20170023104A KR 101968398 B1 KR101968398 B1 KR 101968398B1
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- Prior art keywords
- coumarin
- immune system
- side effects
- present
- cancer
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 항암제에 의하여 유발된 면역계 부작용을 예방 또는 치료할 수 있는 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 암치료 보조용 약학 조성물, 상기 쿠마린 또는 이의 약학적으로 허용되는 염 및 항암제를 포함하여, 부작용이 억제되어 안전성이 증가된 암치료용 약학 조성물, 및 상기 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 항암제에 의하여 유발된 면역계 부작용의 예방 또는 개선용 건강기능성 식품 조성물에 관한 것이다. 본 발명에서 제공하는 쿠마린은 다양한 플라틴계 항암제의 투여에 의하여 유발되는 면역계 부작용을 감소시킬 수 있으므로, 플라틴계 항암제를 사용한 안전한 암치료에 널리 활용될 수 있을 것이다.The present invention relates to a pharmaceutical composition for cancer treatment comprising coumarin or a pharmaceutically acceptable salt thereof as an active ingredient capable of preventing or treating immune system side effects induced by an anti-cancer agent, a pharmaceutical composition for the treatment of cancer which comprises coumarin or a pharmaceutically acceptable salt thereof and an anti- , A pharmaceutical composition for treating cancer in which side effects are suppressed and safety is increased and a health functional food for preventing or ameliorating side effects of the immune system induced by an anticancer agent containing coumarin or a pharmaceutically acceptable salt thereof as an active ingredient ≪ / RTI > The coumarin provided by the present invention can reduce the immune system side effects caused by administration of various platinic anticancer drugs, and thus can be widely used for safe cancer treatment using platinic anticancer drugs.
Description
본 발명은 면역계 부작용이 억제된 암치료용 약학 조성물에 관한 것으로, 보다 구체적으로 본 발명은 항암제에 의하여 유발된 면역계 부작용을 예방 또는 치료할 수 있는 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 암치료 보조용 약학 조성물, 상기 쿠마린 또는 이의 약학적으로 허용되는 염 및 항암제를 포함함으로써, 상기 항암제에 의한 면역계 부작용이 억제되어 안전성이 증가된 암치료용 약학 조성물, 및 상기 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 항암제에 의하여 유발된 면역계 부작용의 예방 또는 개선용 건강기능성 식품 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for treating cancer in which immune system side effects are suppressed. More specifically, the present invention relates to a pharmaceutical composition for treating cancer, wherein coumarin or its pharmaceutically acceptable salt capable of preventing or treating immune system side- Which comprises the above-mentioned coumarin or a pharmaceutically acceptable salt thereof and an anticancer agent, wherein the anticancer agent suppresses side effects of the immune system and thereby increases the safety, and a pharmaceutical composition for treating cancer which comprises the coumarin or its pharmaceutical To a health functional food composition for preventing or ameliorating the side effects of the immune system induced by an anticancer agent containing an effective ingredient as a salt.
최근 전체 사망원인 중 암으로 사망하는 원인은 4명 중 1명 꼴로 이는 계속 증가하는 추세에 있다. 이와 같이 사망원인의 대부분을 차지하는 암의 치료방법으로는 외과수술, 방사선 요법, 생물요법 및 화학요법등이 있다. 이 중에서도, 암치료를 위한 대부분의 화학요법제(chemotherapeutics)는 빠르게 분열, 증식하는 암세포를 사멸시키지만, 분열하는 세포의 DNA 합성과정에 영향을 미치기 때문에 암세포는 물론 골수, 면역세포 및 장상피에 독성을 나타낸다. 특히, 골수독성은 조혈기능 소실로 빈혈의 원인이 되며, 면역세포 독성은 면역력 감퇴를, 그리고 장관손상은 영양결핍, 탈수 및 감염에 대한 이환율 상승으로 사망의 주요 원인이 된다. 예를 들어, 시스플라틴(Cisplatin)을 포함하는 플라틴계열의 항암제는 중심에 백금(platinum II)을 함유한 대표적인 백금 착화 항암제로서, 다양한 종양 치료에 사용되고 있는 광범위 화학요법제의 하나로 비교적 우수한 항암효과를 나타내왔다. 그러나, 소화관 내에 존재하는 내분비세포 세포의 세로토닌 합성 및 세로토닌 5-HT3 수용체를 활성화시켜, 위장관의 손상과 함께 위배출능을 현저히 억제하여, 음식물의 위내 정체를 초래하는 등의 다양한 위장관 독성과 함께, 신장조직 손상, 신장기능장애, 전염증성 사이토카인 증가, 대식구 세포증가 등의 신장독성 부작용 또는 냉이질통, 기계적 이질통 등의 신경병증 부작용, 혈액순환 저해 및 이로 인한 부종 등의 심혈관성 부작용, 청신경 마비, 난청 유발 등의 이독성 등을 나타내는 것으로 알려져 있다. 특히, 옥살리플라틴은 부작용빈도가 가장 높은 수준인 것으로 알려져 있는데, 임상 증상으로는 과민반응, 오심, 발진이 높은 빈도로 나타난다고 알려져 있다.The cause of cancer deaths among all causes of deaths in recent years is one in four, which continues to increase. Thus, surgical treatment, radiation therapy, biotherapy, and chemotherapy are the treatment methods of cancer that account for most of the causes of death. Among them, most chemotherapeutics for cancer treatment rapidly kill cancer cells that divide and multiply, but it affects the DNA synthesis process of the dividing cells. Therefore, the cancer cells, as well as toxins . In particular, bone marrow toxicity causes hematopoiesis due to loss of hematopoiesis, immune cell toxicity is a cause of immune decline, and intestinal damage is a major cause of death due to malnutrition, dehydration and increased morbidity for infection. For example, a platinum-based chemotherapeutic agent including cisplatin is a representative platinum-complexing chemotherapeutic agent containing platinum (II) at the center. It is a broad-spectrum chemotherapeutic agent used in various tumor treatments. Have shown. However, in addition to various gastrointestinal toxicities such as serotonin synthesis and endothelialization of food by activating serotonin 5-HT3 receptor in gastrointestinal endocytic cell cells present in the gastrointestinal tract, Nephropathy side effects such as renal tissue damage, renal dysfunction, proinflammatory cytokine increase, increase of macrophage cells, or side effects such as coughing pain and mechanical allodynia, cardiovascular side effects such as blood circulation inhibition and edema, And is known to exhibit toxicity such as induction of hearing loss. In particular, oxaliplatin is known to have the highest frequency of adverse events, and clinical symptoms are known to be high frequency of hypersensitivity reactions, nausea, and rash.
이에 따라, 플라틴계열의 항암제를 사용한 암치료시에는, 다양한 부작용을 억제하는 것이 상기 약물의 강력한 항암효과를 활용하는데 매우 중요한 관점이 되고 있다. 예를 들어, 한국특허등록 제697212호에는 황기 및 당귀의 혼합 생약재 추출물을 유효성분으로 하는, 항암제 투여에 의해 유발되는 부작용 치료용 조혈 촉진제가 개시되어 있고, 한국특허등록 제1133837호에는 백두옹 추출물을 유효성분으로 포함하는 항암제 투여로 인한 신장독성 억제용 조성물이 개시되어 있으며, 한국특허등록 제1350143호에는 반하 및 황금 생약 추출물을 유효성분으로 포함하는 항암제로 인한 부작용의 경감용 조성물이 개시되어 있다. 그러나, 이들 대부분의 부작용 억제효과는 항암제의 항암활성에 간섭하여, 상기 항암활성을 일정부분 감소시킨다는 문제점이 있었다.Accordingly, when treating cancer using a platinum-based anticancer agent, suppressing various side effects is a very important aspect for utilizing the strong anticancer effect of the drug. For example, Korean Patent Registration No. 697212 discloses a hematopoietic promoter for treating side effects caused by the administration of an anticancer drug, which comprises an extract of a mixed herbal medicine of Hwanggi and Angelica gigas as an active ingredient. In Korean Patent Registration No. 1133837, Discloses a composition for inhibiting renal toxicity by administration of an anticancer agent comprising as an active ingredient, and Korean Patent Registration No. 1350143 discloses a composition for alleviating side effects due to an anticancer agent comprising an anti-cancer and golden herbal extract as an active ingredient. However, most of these side effect inhibiting effects interfere with the anticancer activity of the anticancer drug, which has a problem that the anticancer activity is partially reduced.
이러한 배경하에서, 본 발명자들은 상기 항암제의 항암활성을 경감시키지 않으면서도 항암제에 의하여 유발되는 부작용을 예방 또는 치료하여, 보다 안전한 암치료를 도모할 수 있는 방법을 개발하고자 예의 연구노력한 결과, 계피로부터 유래된 쿠마린이 플라틴계 항암제의 투여에 의하여 유발되는 면역계 부작용을 예방 또는 치료할 수 있음을 확인하고, 본 발명을 완성하였다.Under these circumstances, the inventors of the present invention have made efforts to develop a method for preventing cancer treatment by preventing or treating the side effects caused by the anticancer drug without reducing the anticancer activity of the anticancer drug. As a result, The inventors have confirmed that coumarin can prevent or treat immune system side effects caused by the administration of a platinic anticancer drug, thereby completing the present invention.
본 발명의 하나의 목적은 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는, 암치료 보조용 약학 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for assisting in the treatment of cancer, which comprises coumarin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 목적은 항암제; 및 쿠마린 또는 이의 약학적으로 허용되는 염을 포함하는, 암치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide an anti-cancer agent; And coumarine or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 항암제에 의하여 유발된 면역계 부작용의 예방 또는 개선용 건강기능성 식품 조성물을 제공하는 것이다.It is still another object of the present invention to provide a health functional food composition for preventing or ameliorating side effects of immune system induced by an anticancer agent comprising coumarin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명자들은 옥살리플라틴을 이용한 암치료시에 발생되는 부작용을 감소시킬 수 있는 방법을 개발하기 위하여 다양한 연구를 수행하던 중, 계피에 포함된 주요성분 중의 하나인 쿠마린이 옥살리플라틴의 투여에 의하여 유발되는 면역계 부작용을 억제할 수 있음을 규명하였다. 구체적으로, 교세포의 일종인 성상세포에 옥살리플라틴을 처리하면, 상기 성상세포에서 염증성 사이토카인의 일종인 TNF-α 분비량이 급격히 증가되는데, 상기 성상세포에 쿠마린을 처리하면, 증가된 TNF-α 분비량이 감소됨을 확인하였다. 이러한 TNF-α 분비량 감소효과는 쿠마린에 의해 특이적으로 나타나는 것으로서, 동일한 성상세포에 상기 쿠마린을 포함하는 것으로 알려진 육계(계피)를 처리한 경우에는 TNF-α 분비량이 감소되지 않음은 물론, 오히려 TNF-α 분비량이 증가됨을 확인하였다. The present inventors have conducted various studies to develop a method for reducing side effects caused by oxaliplatin-induced cancer, and have found that coumarin, one of the major components contained in cinnamon, Of the total number of patients. Specifically, when oxaliplatin is treated as an astrocytic cell, the amount of TNF-α secreted as an inflammatory cytokine in the astrocytes is rapidly increased. When the astrocytes are treated with coumarin, an increased secretion amount of TNF-α Respectively. The effect of decreasing the amount of TNF-α secretion is specifically expressed by coumarin. When the broiler (cinnamon) treated with the same astrocytes is known to contain coumarin, the amount of TNF-α secretion is not reduced, -α secretion was increased.
한편, 이러한 쿠마린의 효과는 옥살리플라틴의 처리에 특이적임을 확인하였다. 구체적으로, 교세포의 일종인 BV-2 미세아교세포에 ATP를 과량으로 처리하면, 상기 BV-2 미세아교세포에서 TNF-α 분비량이 급격히 증가되는데, 상기 BV-2 미세아교세포에는 쿠마린을 처리하여도 TNF-α 분비량이 감소되지 않음은 물론, 오히려 TNF-α 분비량이 증가됨을 확인하였다.On the other hand, it was confirmed that the effect of coumarin was specific to the treatment of oxaliplatin. Specifically, treatment of BV-2 microglial cells, which is a type of glia, with ATP excessively increases the amount of TNF-a secreted in the BV-2 microglia. The BV-2 microglia cells are treated with coumarin , The amount of TNF-α secretion was not decreased, and the amount of TNF-α secretion was increased.
따라서, 상기 쿠마린은 옥살리플라틴의 투여로 인하여 발생되는 면역계 부작용을 억제시키는 효과를 나타낼 수 있으며, 이러한 효과는 옥살리플라틴 이외의 다양한 플라틴계 항암제의 투여시에도 유사하게 나타날 수 있을 것으로 예상되었다.Therefore, the coumarin may have an effect of suppressing the immune system side effect caused by the administration of oxaliplatin, and this effect is expected to be similar to the administration of various platinous anticancer drugs other than oxaliplatin.
따라서, 쿠마린은 플라틴계 항암제를 사용한 안전한 암치료에 사용될 수 있고, 이러한 연구결과는 종래의 어떠한 연구결과로부터도 나타나지 않은 새로운 효과이며, 이는 본 발명자에 의하여 최초로 규명되었다.Therefore, coumarin can be used for safe cancer treatment using platinic anticancer agents, and the results of these studies are new effects not revealed from any conventional research results, and were first identified by the present inventor.
상기 목적을 달성하기 위한 일 실시양태로서, 본 발명은 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는, 암치료 보조용 약학 조성물을 제공한다.As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for assisting in the treatment of cancer, comprising coumarin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 용어 "쿠마린(coumarin)"이란, o-옥시신남산의 락톤에 해당하고, "벤조-α-피론"이라고도 호칭되며, C9H6O2의 화학식으로 표시되고, 하기 화학식 1로 표시되는 구조를 갖는 화합물을 의미한다. 상기 쿠마린은 육계(계피)를 비롯한 다양한 천연식물에 미량으로 포함되어 있는데, 무색의 결정이며, 분자량 146.15, 녹는점 71℃, 끓는점 301.7℃ 및 비중 0.935의 특성을 갖는다. The term "coumarin " of the present invention corresponds to a lactone of o-oxysinnamic acid and is also referred to as" benzo-a-pyrone ", and is represented by the formula C 9 H 6 O 2 , Means a compound having the structure shown. The coumarin is a colorless crystal having a molecular weight of 146.15, a melting point of 71 ° C, a boiling point of 301.7 ° C and a specific gravity of 0.935, which are contained in trace amounts in various natural plants including broilers (cinnamon).
본 발명에 있어서, 상기 쿠마린은 항암제에 의하여 유발된 면역계 부작용을 예방, 개선 또는 치료하는 유효성분으로서 사용될 수 있다.In the present invention, the coumarin can be used as an active ingredient for preventing, ameliorating or treating an immune system side effect caused by an anticancer drug.
본 발명에서 제공하는 쿠마린은 항암제의 투여에 의하여 유발되는 면역계 부작용을 예방 또는 치료할 수 있는 효과를 나타내므로, 상기 쿠마린은 통상적인 항암제와 함께 또는 항암제의 투여 이전에 암환자에게 투여되어, 항암제로 인한 면역계 부작용을 발생을 예방, 억제 또는 감소시킬 수 있다. The coumarin provided in the present invention has an effect of preventing or treating the side effects of the immune system caused by the administration of the anticancer agent. Therefore, the coumarin is administered to the cancer patient together with the conventional anticancer agent or before administration of the anticancer agent, It is possible to prevent, inhibit or reduce the occurrence of immune system side effects.
본 발명의 쿠마린에 의하여 부작용의 발생이 억제되는 항암제는 특별히 이에 제한되지 않으나, 부작용을 나타내는 모든 항암제가 포함될 수 있고, 바람직하게는 옥살리플라틴(oxaliplatin), 시스플라틴(cisplatin), 테트라플라틴(tetraplatin), 헵타플라틴(heptaplatin), 파라플라틴(paraplatin), 카보플라틴(carboplatin), 나노플라틴(nanoplatin) 등의 플라틴계 항암제가 될 수 있으며, 보다 바람직하게는, 옥살리플라틴이 될 수 있다.The anticancer agent that suppresses the occurrence of side effects by the coumarin of the present invention is not particularly limited, but may include all anticancer drugs exhibiting side effects, preferably oxaliplatin, cisplatin, tetraplatin, It may be a platinum-based anticancer drug such as heptaplatin, paraplatin, carboplatin, nanoplatin and the like, more preferably oxaliplatin.
또한, 항암제의 투여에 의하여 유발되어 본 발명의 쿠마린에 의하여 억제되는 면역계 부작용은 특별히 이에 제한되지 않으나, 바람직하게는, 개체의 사망, 면역계 과활성에 의한 자가면역질환, 염증성 사이토카인의 과분비에 의한 염증성 질환 등이 될 수 있다. The immune system side effects induced by the administration of the anticancer drug and inhibited by coumarin of the present invention are not particularly limited, but preferably include autoimmune diseases due to death of the individual, immune system and activity, and hypersecretion of the inflammatory cytokine Inflammatory disease, and the like.
따라서, 본 발명의 쿠마린은 옥살리플라틴(oxaliplatin), 시스플라틴(cisplatin), 테트라플라틴(tetraplatin), 헵타플라틴(heptaplatin), 파라플라틴(paraplatin), 카보플라틴(carboplatin), 나노플라틴(nanoplatin) 등의 플라틴계 항암제의 투여에 의하여 발생할 수 있는 개체의 사망, 면역계 과활성에 의한 자가면역질환, 염증성 사이토카인의 과분비에 의한 염증성 질환 등의 증상을 예방 또는 치료할 수 있는 효과를 나타낼 수 있다.Thus, the coumarin of the present invention can be used in combination with oxaliplatin, cisplatin, tetraplatin, heptaplatin, paraplatin, carboplatin, nanoplatin, ), An autoimmune disease caused by an immune system and an activity, and an inflammatory disease caused by an hypersecretion of an inflammatory cytokine, which may be caused by the administration of a platinum-based anticancer drug.
본 발명의 용어 "약학적으로 허용되는 염"이란, 양이온과 음이온이 정전기적인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하는데, 통상적으로 금속염, 유기 염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기 염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다.The term "pharmaceutically acceptable salt " of the present invention means salts in which the cation and the anion are pharmaceutically usable among the salts in which they are bound by an electrostatic attraction. Usually, the salt is a metal salt, an organic base, Salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt and the like; Examples of salts with organic bases include salts with organic bases such as triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, And the like; The salt with the inorganic acid may be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; Salts with organic acids may be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; Salts with basic amino acids may be salts with arginine, lysine, ornithine and the like; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid and the like.
본 발명의 용어 "예방"이란, 본 발명에 따른 조성물의 투여로 항암제에 의하여 유발된 면역계 부작용을 억제 또는 지연시키는 모든 행위를 의미한다.The term "prevention" of the present invention means any action that inhibits or delays the immune system side effects caused by an anti-cancer drug by administration of the composition according to the present invention.
본 발명의 용어 "치료"란, 본 발명에 따른 조성물의 투여로 항암제에 의하여 유발된 면역계 부작용을 완화 또는 경감시키는 모든 행위를 의미한다.The term "treatment" of the present invention means any action that alleviates or alleviates the side effects of the immune system caused by an anticancer drug by administration of the composition according to the present invention.
본 발명의 약학 조성물은 단일제제로도 사용할 수 있으며, 공인된 항암제에 의하여 유발된 면역계 부작용을 예방 또는 치료하는 효과를 가진다고 알려진 약물을 추가로 포함하여 복합제제로 제조하여 사용할 수 있다.The pharmaceutical composition of the present invention can also be used as a single agent and can be used as a combined preparation containing a drug known to have an effect of preventing or treating immune system side effects caused by an approved anticancer drug.
본 발명의 용어 "암치료 보조"란, 암치료용 약학 조성물의 투여에 의하여 유발될 수 있는 부작용을 예방 또는 치료하여, 보다 안전한 암치료를 도모할 수 있는 효과를 의미한다.The term "cancer treatment aid" of the present invention means an effect of preventing or treating side effects that may be caused by the administration of the pharmaceutical composition for cancer treatment, thereby achieving safer cancer treatment.
본 발명에 있어서, 상기 암치료 보조는 쿠마린의 투여에 의하여 수행되므로, 상기 쿠마린은 항암 보조제로 작용하는 것으로 해석될 수 있다. In the present invention, since the cancer treatment aid is performed by the administration of coumarin, the coumarin can be interpreted as acting as an anti-cancer adjuvant.
본 발명에서는 상기 쿠마린이 항암 보조제로 작용할 수 있는지에 관하여 다양한 효능 및 관점에서 이를 확인하였다.In the present invention, it has been confirmed from various efficacy and viewpoints as to whether coumarin can act as an anticancer adjuvant.
이처럼 항암 보조제로 작용하는 쿠마린의 기본적인 효과는 항암제의 투여로 인하여 유발되는 부작용을 억제하는 것이다.The basic effect of coumarin, which acts as a chemotherapeutic adjuvant, is to inhibit side effects caused by administration of anticancer drugs.
본 발명의 일 실시예에 의하면, 교세포의 일종인 성상세포에 옥살리플라틴을 처리하면, 상기 성상세포에서 염증성 사이토카인의 일종인 TNF-α 분비량이 급격히 증가한다. 이처럼 옥살리플라틴이 처리된 성상세포에 쿠마린 또는 쿠마린 성분을 포함하는 육계(계피) 추출물을 처리한 결과, 쿠마린을 처리한 경우에는 옥살리플라틴의 처리에 의해 증가된 TNF-α 분비량이 감소되었으나, 육계 추출물을 처리한 경우에는 옥살리플라틴의 처리에 의해 증가된 TNF-α 분비량이 더욱 증가됨을 확인하였다.According to one embodiment of the present invention, when oxaliplatin is treated to astrocytes, which are a kind of glioblastoma, the secretion amount of TNF-a, which is a type of inflammatory cytokine, in the astrocytes is increased sharply. As a result of treating the broth (cinnamon) extract containing the coumarin or coumarin component with oxaliplatin-treated astrocytes, the amount of TNF-α secreted by the treatment with coumarin decreased by the treatment with oxaliplatin, but the broth extract In one case, the amount of TNF-α secretion increased by oxaliplatin treatment was further increased.
본 발명의 다른 실시예에 의하면, 교세포의 일종인 BV-2 미세아교세포에 손상신호전달 물질의 일종인 ATP를 처리하면 ATP의 농도의존적으로 상기 BV-2 미세아교세포에서 TNF-α 분비량이 증가한다. 이처럼 ATP가 처리된 BV-2 미세아교세포에 쿠마린 또는 쿠마린 성분을 포함하는 육계 추출물을 처리한 결과, 육계 추출물을 처리한 경우에는 ATP의 처리에 의해 증가된 TNF-α 분비량이 감소되었으나, 쿠마린을 처리한 경우에는 ATP의 처리에 의해 증가된 TNF-α 분비량이 더욱 증가됨을 확인하였다.According to another embodiment of the present invention, the treatment of ATP, which is a kind of damaged signal transduction material, in BV-2 microglia, which is one kind of giant cells, increases the secretion amount of TNF-a in the BV-2 microglia do. As a result of treatment with ATP-treated broth extract of broiler chickens containing BVP-2 microglial cells containing coumarin or coumarin, the amount of TNF-α secreted increased by ATP treatment, but the amount of coumarin It was confirmed that the amount of TNF-a secretion increased by ATP treatment was further increased.
상기 결과로부터, 쿠마린이 교세포에서 비정상적으로 분비되는 염증성 사이토카인의 분비량을 감소시키는 효과를 나타낼 수 있지만, 이러한 효과는 항암제의 처리에 의한 염증성 사이토카인의 분비량에만 특이적으로 나타나는 효과임을 알 수 있었다.From the above results, it can be seen that coumarin may have an effect of reducing the secretion amount of inflammatory cytokines abnormally secreted from the glioblastoma cells, but this effect is shown to be a specific effect only on the secretion amount of the inflammatory cytokine by the treatment with the anticancer drug.
따라서, 상기 쿠마린은 플라틴계 항암제의 투여에 의하여 유발되는 부작용을 감소시킬 수 있으므로, 플라틴계 항암제를 사용한 안전한 암치료에 널리 활용될 수 있음을 알 수 있었다.Therefore, it has been found that coumarin can be widely used for safe cancer treatment using platinum-based anticancer drugs because it can reduce adverse effects caused by administration of platinic anticancer drugs.
본 발명의 암치료 보조용 약학 조성물은, 약학 조성물의 제조에 통상적으로 사용하는 적절한 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. The pharmaceutical composition for adjuvant therapy for cancer of the present invention may further comprise a suitable pharmaceutically acceptable carrier, excipient or diluent conventionally used in the production of a pharmaceutical composition.
상기 "약학적으로 허용가능한"이란 생물체를 상당히 자극하지 않고 투여 활성 물질의 생물학적 활성 및 특성을 저해하지 않는 것을 의미한다.By "pharmaceutically acceptable" as used herein is meant not significantly irritating the organism and not interfering with the biological activity and properties of the administered active substance.
상기 담체는 자연적이거나 또는 비자연적인 담체가 될 수 있는데, 제형에 따라, 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제와 같은 다양한 담체를 사용하여 제제화 할 수 있다. 예를 들어, 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 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, 글리세로젤라틴 등이 사용될 수 있다.The carrier may be a natural or an unnatural carrier. Depending on the formulation, it may be formulated using various carriers such as fillers, extenders, binders, wetting agents, disintegrants, diluents such as surfactants or excipients. For example, solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
본 발명의 암치료 보조용 약학 조성물에 포함된 상기 쿠마린 또는 이의 약학적으로 허용되는 염의 함량은 특별히 이에 제한되지 않으나, 최종 조성물 총 중량을 기준으로 0.0001 내지 50 중량%, 보다 바람직하게는 0.01 내지 20 중량%의 함량으로 포함될 수 있다. The content of the coumarin or the pharmaceutically acceptable salt thereof contained in the pharmaceutical composition for cancer treatment adjuvant of the present invention is not particularly limited but is preferably 0.0001 to 50% by weight, more preferably 0.01 to 20% by weight, % ≪ / RTI > by weight.
상기 본 발명의 암치료 보조용 약학 조성물은 부작용을 유발할 수 있는 항암제와 동시에 또는 상기 항암제의 투여 이전 또는 이후에 개별적으로 약제학적으로 유효한 양으로 투여될 수 있는데, 본 발명의 용어 "약제학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 암치료 보조용 약학 조성물은 개별 치료제로 투여하거나 항암제의 부작용을 억제할 수 있는 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.The pharmaceutical composition for adjunctive cancer therapy of the present invention may be administered in an effective amount in combination with an anticancer agent capable of causing side effects or individually or after administration of the anticancer agent. The term "pharmaceutically effective amount Amount "means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention, and the effective dose level will depend on the severity of the disease, the activity of the drug, the age, weight, , The sensitivity of the patient to the drug, the time of administration of the composition of the present invention, the route of administration and the rate of excretion of the drug, the duration of the treatment, factors including drugs used in combination with or co- Can be determined accordingly. The pharmaceutical composition for adjuvant therapy for cancer of the present invention may be administered in combination with another therapeutic agent which can be administered as an individual therapeutic agent or a side effect of an anti-cancer agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered singly or multiply. It is important to take into account all of the above factors and administer an amount that will achieve the maximum effect in the least amount without side effects.
본 발명의 암치료 보조용 약학 조성물의 투여량은 예를 들어, 본 발명의 암치료 보조용 약학 조성물을 사람을 포함하는 포유동물에 하루 동안 0.1 내지 500 mg/체중 kg으로 투여함이 바람직하다. 본 발명의 암치료 보조용 약학 조성물의 투여 빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.For example, the dosage of the pharmaceutical composition for adjuvant therapy of cancer of the present invention is preferably 0.1 to 500 mg / kg of body weight per day to a mammal including human. The frequency of administering the pharmaceutical composition for cancer therapy of the present invention is not particularly limited, but may be administered once a day or divided into several doses. The dose is not intended to limit the scope of the invention in any way.
상기 목적을 달성하기 위한 다른 실시양태로서, 본 발명은 항암제; 및 쿠마린 또는 이의 약학적으로 허용되는 염을 포함하는, 암치료용 약학 조성물을 제공한다.As another embodiment for achieving the above object, the present invention provides an anticancer agent; And coumarin or a pharmaceutically acceptable salt thereof.
상술한 바와 같이, 상기 쿠마린은 항암제의 투여에 의하여 유발되는 면역계 부작용을 예방 또는 치료할 수 있는 효과를 나타내므로, 상기 부작용 유발이 우려되는 항암제; 및 쿠마린 또는 이의 약학적으로 허용되는 염을 동시에 포함하는 복합적 암치료용 약학 조성물은 항암제에 의한 부작용의 발생이 억제될 수 있어, 보다 안전한 암치료에 활용될 수 있다. 이때, 사용되는 쿠마린 또는 이의 약학적으로 허용되는 염은 항암제에 의하여 유발되는 부작용을 억제하여 암치료를 보조하는 역할을 수행하는 항암 보조제로 해석될 수 있다.As described above, the coumarin exhibits an effect of preventing or treating the side effects of the immune system caused by the administration of the anticancer agent, and thus, the anticancer agent which is liable to cause side effects; And coumarin or a pharmaceutically acceptable salt thereof, can inhibit the occurrence of side effects caused by anticancer drugs, and thus can be used for safer cancer treatment. At this time, coumarin or a pharmaceutically acceptable salt thereof may be interpreted as an anticancer adjuvant which plays a role of supporting the cancer treatment by inhibiting side effects caused by the anticancer agent.
이때, 상기 항암제, 쿠마린 또는 이의 약학적으로 허용되는 염 등은 상술한 바와 동일하고, 상기 암치료용 약학 조성물에 포함될 수 있는 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제 역시 상술한 바와 동일하며, 상기 약학 조성물에 포함되는 항암제 및 쿠마린 또는 이의 약학적으로 허용되는 염의 함량은 상술한 바와 같이, 암환자에게서 발병된 암질환의 종류, 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The carrier, excipient or diluent which is usually used in the production of the pharmaceutical composition which can be contained in the pharmaceutical composition for cancer therapy is the same as the above-mentioned one, And the content of the anticancer agent and coumarin or pharmaceutically acceptable salt thereof contained in the pharmaceutical composition is, as described above, the kind of the cancer disease, the severity of the disease, the activity of the drug, the age of the patient, The composition of the present invention can be used in combination with the composition of the present invention, including drugs used in combination with the composition of the present invention, and other medical fields including, for example, body weight, health, sex, sensitivity of the patient to the drug, May be determined according to well known factors.
상기 목적을 달성하기 위한 또 다른 실시양태로서, 본 발명은 상기 암치료 보조용 약학 조성물 또는 암치료용 약학 조성물을 약제학적으로 유효한 양으로 암질환이 발병될 가능성이 있거나 또는 발병된 개체에 투여하는 단계를 포함하는 암질환의 예방 또는 치료방법을 제공한다.In another aspect of the present invention, the present invention provides a pharmaceutical composition for cancer therapy or a pharmaceutical composition for cancer therapy, which comprises a pharmaceutically effective amount of a compound of the present invention, The method comprising the steps of:
상술한 바와 같이, 본 발명에서 제공하는 상기 쿠마린 또는 이의 약학적으로 허용되는 염은 항암제의 면역계 부작용을 예방 또는 치료할 수 있으므로, 상기 쿠마린 또는 이의 약학적으로 허용되는 염을 포함하는 암치료 보조용 약학 조성물을 항암제와 개별적으로 환자에게 투여하거나 또는 항암제; 및 쿠마린 또는 이의 약학적으로 허용되는 염을 동시에 포함하는 안전성이 증가된 암치료용 약학 조성물을 환자에게 투여함으로써, 보다 안전하게 암질환을 예방 또는 치료하는데 사용될 수 있다.As described above, the coumarin or its pharmaceutically acceptable salt provided by the present invention can prevent or treat the immune system side effect of the anticancer agent. Therefore, it is possible to provide a therapeutic agent for cancer treatment comprising coumarin or a pharmaceutically acceptable salt thereof Administering the composition separately to the patient with the anti-cancer agent, or administering the anti-cancer agent; And coumarin or a pharmaceutically acceptable salt thereof, can be administered to a patient in order to more safely prevent or treat cancer diseases.
본 발명의 용어 "개체"란 암질환이 발병될 가능성이 있거나 또는 발병된 쥐, 가축, 인간 등을 포함하는 포유동물을 제한 없이 포함한다.The term "individual" of the present invention includes, without limitation, mammals, including rats, cattle, humans,
본 발명의 암질환을 치료하는 방법에 있어서, 상기 약학 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여도 투여될 수 있다. 본 발명의 약학 조성물은 특별히 이에 제한되지 않으나, 목적하는 바에 따라 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 비내 투여, 폐내 투여, 직장내 투여 등의 경로를 통해 투여 될 수 있다. 다만, 경구 투여 시에는 위산에 의하여 상기 쿠마린 또는 이의 약학적으로 허용되는 염이 변성될 수 있기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화 되어야 한다. 또한, 상기 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다. In the method of treating cancer diseases of the present invention, the administration route of the pharmaceutical composition may be administered through any ordinary route as long as it can reach the target tissues. The pharmaceutical composition of the present invention is not particularly limited, but may be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, intrapulmonary administration, rectal administration and the like ≪ / RTI > However, since the coumarin or its pharmaceutically acceptable salt may be denatured by gastric acid upon oral administration, the oral composition should be formulated so as to coat the active agent or protect it from decomposition at the top. In addition, the composition may be administered by any device capable of transferring the active agent to the target cell.
상기 목적을 달성하기 위한 또 다른 실시양태로서, 본 발명은 쿠마린 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 항암제에 의하여 유발된 면역계 부작용의 예방 또는 개선용 건강기능성 식품 조성물을 제공한다.In another aspect of the present invention, there is provided a health functional food composition for preventing or ameliorating an immune system side effect caused by an anticancer agent comprising coumarin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 용어 "개선"이란, 상기 조성물을 이용하여 항암제에 의하여 유발된 면역계 부작용의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다. The term "improvement" of the present invention refers to any action that improves or alleviates symptoms of an immune system side effect caused by an anticancer drug using the composition.
본 발명의 식품 조성물은 식품학적으로 허용가능한 담체를 추가로 포함하는 것일 수 있다.The food composition of the present invention may further comprise a pharmaceutically acceptable carrier.
상기 식품 조성물은 항암제에 의하여 유발된 면역계 부작용의 억제에 도움을 주는 기능을 가질 수 있다.The food composition may have a function to help suppress the immune system side effects caused by the anticancer agent.
본 발명의 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함하며, 본 발명의 쿠마린 또는 이의 약학적으로 허용되는 염을 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다.The food composition of the present invention includes forms such as pills, powders, granules, infusions, tablets, capsules or liquid preparations, and there is no particular restriction on the kinds of foods in which coumarin or its pharmaceutically acceptable salts of the present invention can be added Such as various beverages, gums, tea, vitamin complex, and health supplement foods.
상기 식품 조성물에는 쿠마린 또는 이의 약학적으로 허용되는 염 이외에도 항암제에 의하여 유발된 면역계 부작용의 억제활성에 방해가 되지 않는 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition to coumarin or a pharmaceutically acceptable salt thereof, the food composition may further include other ingredients that do not interfere with the inhibitory activity of the immune system side effects induced by the anticancer agent, and the kind thereof is not particularly limited. For example, various herbal medicine extracts, food-acceptable food-aid additives or natural carbohydrates, such as ordinary foods, may be added as an additional ingredient.
본 발명의 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term "food-aid additive " of the present invention means a component which can be added to foods in a supplementary manner, and is appropriately selected and used by those skilled in the art as added to produce health functional foods of each formulation. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated beverage. However, the types of the food auxiliary additives of the present invention are not limited by the above examples.
상기 천연 탄수화물의 예는 포도당, 과당 등의 단당류; 말토스, 수크로스 등의 이당류; 및 덱스트린, 시클로덱스트린 등의 다당류와, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 Ａ, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose and the like; And polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above .
본 발명의 식품 조성물은 건강기능성 식품의 제조를 위하여 사용되거나, 건강기능성 식품에 포함될 수 있다. The food composition of the present invention may be used for the production of health functional foods or may be included in health functional foods.
본 발명의 용어 "건강기능성 식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 기능성이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능성 식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다.The term " health functional food "of the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings using raw materials and components having useful functions in the human body. Here, the term "functionality" means that the structure and function of the human body are controlled to obtain nutritional effects or effects useful for health use such as physiological actions. The health functional food of the present invention can be manufactured by a method commonly used in the art and can be prepared by adding raw materials and ingredients which are conventionally added in the art. Also, unlike general medicine, there is an advantage that there is no side effect that can occur when a medicine is used for a long time by using food as a raw material, and it is excellent in portability.
본 발명의 조성물을 건강기능식품에 포함하여 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 건강기능식품 또는 건강기능식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. When the composition of the present invention is incorporated into a health functional food, the composition may be added as it is or may be used together with other health functional foods or health functional food ingredients and suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment).
일반적으로, 식품의 제조 시에 본 발명의 쿠마린 또는 이의 약학적으로 허용되는 염은 원료 조성물 중 1 내지 10 중량%, 바람직하게는 5 내지 10 중량%의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다.Generally, coumarin or a pharmaceutically acceptable salt thereof of the present invention may be added in an amount of 1 to 10% by weight, preferably 5 to 10% by weight of the raw material composition in the production of food. However, in the case of long-term ingestion intended for health and hygiene purposes or for the purpose of controlling health, the above amount can also be used below the above-mentioned range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능성 식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include health functional foods in a conventional sense.
본 발명의 조성물을 포함할 수 있는 건강기능식품의 종류에는 특별한 제한은 없으며, 구체적인 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있고, 통상적인 의미에서의 건강기능식품을 모두 포함할 수 있으며, 동물을 위한 사료로 이용되는 식품을 포함할 수 있다.There is no particular limitation on the kind of health functional food that can contain the composition of the present invention, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gum, Dairy products, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and may include foodstuffs used as food for animals, which may include all health functional foods in the conventional sense.
또한, 본 발명의 건강기능식품 조성물이 음료의 형태로 사용될 경우에는 통상의 음료와 같이 여러 가지 감미제, 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드, 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨, 에리트리톨과 같은 당알콜일 수 있다. 상기 천연 탄수화물의 비율은 이에 제한되지는 않으나, 본 발명의 조성물 100 ㎖ 당 바람직하게는 약 0.01 내지 0.04g, 보다 바람직하게는 0.02 내지 0.03g일 수 있다. 상기 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제 및 사카린, 아스파르탐과 같은 합성 감미제일 수 있다.In addition, when the health functional food composition of the present invention is used in the form of a drink, it may contain various sweetening agents, flavoring agents, or natural carbohydrates as additional components such as ordinary beverages. The natural carbohydrates may be polysaccharides such as disaccharides such as monosaccharides such as glucose and fructose, maltose, sucrose, dextrin, cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol. The ratio of the natural carbohydrate is not limited thereto, but may be about 0.01 to 0.04 g, more preferably 0.02 to 0.03 g per 100 ml of the composition of the present invention. The sweeteners may be natural sweeteners such as tau martin and stevia extract, and synthetic sweeteners such as saccharin and aspartame.
상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, , Alcohols, carbonating agents used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks.
본 발명에서 제공하는 쿠마린은 다양한 플라틴계 항암제의 투여에 의하여 유발되는 면역계 부작용을 감소시킬 수 있으므로, 플라틴계 항암제를 사용한 안전한 암치료에 널리 활용될 수 있을 것이다.The coumarin provided by the present invention can reduce the immune system side effects caused by administration of various platinic anticancer drugs, and thus can be widely used for safe cancer treatment using platinic anticancer drugs.
도 1은 옥살리플라틴이 처리된 성상세포에서 분비되는 TNF-α의 함량에 미치는 쿠마린과 육계추출물의 효과를 분석한 결과를 나타내는 그래프이다.
도 2는 ATP가 처리된 BV-2 미세아교세포에서 분비되는 TNF-α의 함량에 미치는 쿠마린과 육계추출물의 효과를 분석한 결과를 나타내는 그래프이다.FIG. 1 is a graph showing the results of analysis of the effect of coumarin and broiler chick extract on the content of TNF-.alpha. Secreted from oxaliplatin-treated astrocytes.
FIG. 2 is a graph showing the results of analysis of the effect of coumarin and broiler chick extract on the content of TNF-.alpha. Secreted from ATP-treated BV-2 microglia.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예Example 1: One: 옥살리플라틴의Oxaliplatin 처리에 따른 Depending on the treatment TNFTNF -α의 과분비에 미치는 쿠마린의 효과Effect of coumarin on the hypersecretion of -α
마취시킨 유아기 마우스를 희생시키고, 그의 머리부분을 70% 에탄올로 세척한 다음, 뇌를 적출하였다. 적출된 뇌에서 후각신경구, 소뇌 및 선조체를 제거한 후, 차가운 PBS에 침지하였다. 이어, 상기 뇌에서 뇌척수막을 제거한 다음, 세절하고, 세절된 뇌에 0.5% 트립신용액 5ml을 가하고, 37 ℃에서 10분동안 반응시켰다. 그런 다음, 말혈청 5ml을 가하여 트립신 반응을 종료시키고, 여과한 다음, 원심분리하고(1000 rpm, 10분), 침전된 혼합 교세포를 수득하였다.Anesthetized infant mice were sacrificed, their heads were washed with 70% ethanol and the brain was harvested. The olfactory nerves, cerebellum and striatum were removed from the extracted brain and then immersed in cold PBS. Then, the cerebrospinal fluid was removed from the brain, and the brain was cut, and 5 ml of 0.5% trypsin solution was added to the chopped brain, followed by reaction at 37 ° C for 10 minutes. Then, 5 ml of horse serum was added to terminate the trypsin reaction, followed by filtration, followed by centrifugation (1000 rpm, 10 minutes) to obtain precipitated mixed gypsum.
상기 수득한 혼합 교세포에 DMEM 배지(10% horse serum, 10% FBS, 1% penicillin-streptomycin)를 가하고, 3일마다 배지를 교체하면서 1주일 동안 배양하였다.DMEM medium (10% horse serum, 10% FBS, 1% penicillin-streptomycin) was added to the mixed cultured cells obtained above and cultured for one week while changing the medium every three days.
상기 혼합 교세포 배양물로부터 성상세포를 분리하기 위하여, 다음과 같은 실험을 수행하였다.In order to isolate astrocytes from the mixed cultured cells, the following experiment was conducted.
상기 배양물을 37 ℃에서 2시간 동안 100 rpm의 속도로 진탕시킨 후, 배지를 제거하고 PBS로 2회 세척하였다. 세척된 세포에 0.5% 트립신용액 5ml을 가하여 2분 동안 반응시킨 후, 반응용기에 충격을 가하였다. 이어, 말혈청 5ml을 가하고, 원심분리(1000 rpm, 10분)한 다음, 침전된 세포를 10ml DMEM 배지에 현탁시키고, 24웰 플레이트에 접종하였다. 상기 접종된 세포를 4일 동안 배양하여, 성상세포를 수득하였다.The culture was shaken at 37 ° C for 2 hours at 100 rpm, then the medium was removed and washed twice with PBS. To the washed cells, 5 ml of 0.5% trypsin solution was added and allowed to react for 2 minutes, after which the reaction vessel was shocked. Then, 5 ml of horse serum was added, centrifuged (1000 rpm, 10 minutes), and the precipitated cells were suspended in 10 ml of DMEM medium and inoculated into a 24-well plate. The inoculated cells were cultured for 4 days to obtain astrocytes.
상기 수득한 성상세포에, 0.1mM 옥살리플라틴을 포함하는 무혈청 DMEM 배지; 0.1mM 옥살리플라틴과 0.1mM 쿠마린을 포함하는 무혈청 DMEM 배지; 또는 0.1mM 옥살리플라틴과 0.1mM 육계추출물을 포함하는 무혈청 DMEM 배지로 교체한 후, 48시간 동안 배양하였다. 배양이 종료된 후, 배지를 회수하고, 회수된 배지에 포함된 TNF-α의 함량을 ELISA를 통해 분석하였다(도 1).To the obtained astrocytic cells, serum-free DMEM medium containing 0.1 mM oxaliplatin; Serum-free DMEM medium containing 0.1 mM oxaliplatin and 0.1 mM coumarin; Or with serum-free DMEM medium containing 0.1 mM oxaliplatin and 0.1 mM broiler extract, and then cultured for 48 hours. After the incubation was completed, the medium was recovered and the content of TNF-? Contained in the recovered medium was analyzed by ELISA (Fig. 1).
도 1은 옥살리플라틴이 처리된 성상세포에서 분비되는 TNF-α의 함량에 미치는 쿠마린과 육계추출물의 효과를 분석한 결과를 나타내는 그래프이다. 도 1에서 보듯이, 신경세포의 일종인 성상세포에 옥살리플라틴을 처리하면, 상기 성상세포에서 염증성 사이토카인의 일종인 TNF-α 분비량이 급격히 증가함을 확인하였다. 이처럼 옥살리플라틴이 처리된 성상세포에 쿠마린 또는 쿠마린 성분을 포함하는 육계(계피) 추출물을 처리한 결과, 옥살리플라틴과 쿠마린을 함께 처리한 경우에는 옥살리플라틴의 처리에 의해 증가된 TNF-α 분비량이 감소되었으나, 옥살리플라틴과 육계 추출물을 함께 처리한 경우에는 옥살리플라틴의 처리에 의해 증가된 TNF-α 분비량이 더욱 증가됨을 확인하였다.FIG. 1 is a graph showing the results of analysis of the effect of coumarin and broiler chick extract on the content of TNF-.alpha. Secreted from oxaliplatin-treated astrocytes. As shown in FIG. 1, when oxaliplatin was treated with astrocytes, which are a kind of nerve cells, it was confirmed that the amount of TNF-a secreted as an inflammatory cytokine in the astrocytes increased sharply. As a result of treating the broth (cinnamon) extract containing coumarin or coumarin with oxaliplatin-treated astrocytes, when oxaliplatin and coumarin were treated together, the increased amount of TNF-α secreted by oxaliplatin treatment was reduced. However, oxaliplatin And broiler body extracts, the amount of TNF-α secretion increased by oxaliplatin treatment was further increased.
따라서, 옥살리플라틴의 처리에 의하여 증가되는 TNF-α의 수준을 쿠마린에 의해 감소시킬 수 있음을 확인하였다.Therefore, it was confirmed that the level of TNF-a increased by treatment with oxaliplatin can be reduced by coumarin.
비교실시예Comparative Example 1: ATP의 처리에 따른 1: ATP treatment TNFTNF -α의 과분비에 미치는 쿠마린의 효과Effect of coumarin on the hypersecretion of -α
교세포의 일종인 BV-2 미세아교세포에, 손상신호전달 물질의 일종인 ATP를 0.1mM 또는 1mM로 포함하는 무혈청 DMEM 배지; 1mM ATP와 1mM 육계추출물을 포함하는 무혈청 DMEM 배지; 또는 1mM ATP와 1mM 쿠마린을 무혈청 DMEM 배지를 가하고, 48시간 동안 배양하였다. 배양이 종료된 후, 배지를 회수하고, 회수된 배지에 포함된 TNF-α의 함량을 ELISA를 통해 분석하였다(도 2).Serum-free DMEM medium containing BV-2 microglia as a kind of glia, containing 0.1 mM or 1 mM of ATP, a kind of damage signaling substance; Serum-free DMEM medium containing 1 mM ATP and 1 mM broiler chick extract; Or 1 mM ATP and 1 mM coumarin were added to serum-free DMEM medium and cultured for 48 hours. After the culture was completed, the medium was recovered and the content of TNF-? Contained in the recovered medium was analyzed by ELISA (Fig. 2).
도 2는 ATP가 처리된 BV-2 미세아교세포에서 분비되는 TNF-α의 함량에 미치는 쿠마린과 육계추출물의 효과를 분석한 결과를 나타내는 그래프이다. 도 2에서 보듯이, 교세포의 일종인 BV-2 미세아교세포에 손상신호전달 물질의 일종인 ATP를 처리하면 ATP의 농도의존적으로 상기 BV-2 미세아교세포에서 TNF-α 분비량이 증가함을 확인하였다. 이처럼 ATP가 처리된 BV-2 미세아교세포에 쿠마린 또는 쿠마린 성분을 포함하는 육계 추출물을 처리한 결과, 육계 추출물을 처리한 경우에는 ATP의 처리에 의해 증가된 TNF-α 분비량이 감소되었으나, 쿠마린을 처리한 경우에는 ATP의 처리에 의해 증가된 TNF-α 분비량이 더욱 증가됨을 확인하였다.FIG. 2 is a graph showing the results of analysis of the effect of coumarin and broiler chick extract on the content of TNF-.alpha. Secreted from ATP-treated BV-2 microglia. As shown in FIG. 2, when ATP, which is a kind of damage signal transduction material, was treated to BV-2 microglia, which is one kind of giant cell, it was confirmed that the secretion amount of TNF-α was increased in BV-2 microglia Respectively. As a result of treatment with ATP-treated broth extract of broiler chickens containing BVP-2 microglial cells containing coumarin or coumarin, the amount of TNF-α secreted increased by ATP treatment, but the amount of coumarin It was confirmed that the amount of TNF-a secretion increased by ATP treatment was further increased.
따라서, ATP의 처리에 의하여 증가되는 TNF-α의 수준은 쿠마린에 의해 감소시킬 수 없음을 확인하였다.Thus, it was confirmed that the level of TNF-a increased by treatment with ATP can not be reduced by coumarin.
상기 도 1 및 2의 결과를 종합하면, 쿠마린은 옥살리플라틴의 처리에 의해 증가되는 염증성 사이토카인의 수준을 특이적으로 감소시키는 효과를 나타냄을 알 수 있었다.1 and 2, it can be seen that coumarin has an effect of specifically reducing the level of inflammatory cytokine which is increased by treatment with oxaliplatin.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
Claims (12)
Wherein said cancer therapeutic aid is for the prevention of adverse side effects caused by oxaliplatin in the immune system and said immune system side effect is a side effect of pain , ≪ / RTI >
상기 통증 부작용은 염증성 사이토카인 분비수준이 증가되는 것인, 약학 조성물.
The method according to claim 1,
Wherein said pain adverse effect is an increased level of inflammatory cytokine secretion.
상기 부작용은 신경세포에서 염증성 사이토카인의 분비수준이 증가되는 것인, 약학 조성물.
The method according to claim 1,
Wherein said side effect is an increased secretion level of inflammatory cytokines in neurons.
상기 염증성 사이토카인은 종양괴사인자-α(TNF-α)인 것인, 약학 조성물.
6. The method of claim 5,
Wherein said inflammatory cytokine is tumor necrosis factor-alpha (TNF-a).
상기 조성물은 약학적으로 허용가능한 담체를 추가로 포함하는 것인, 약학 조성물.
The method according to claim 1,
Wherein the composition further comprises a pharmaceutically acceptable carrier.
Oxaliplatin; And coumarin or a pharmaceutically acceptable salt thereof, wherein the composition is for inhibiting the immune system side effect induced by oxaliplatin, wherein the immune system side effect is a pain adverse effect.
상기 통증 부작용은 염증성 사이토카인 분비수준이 증가되는 것인, 약학 조성물.
9. The method of claim 8,
Wherein said pain adverse effect is an increased level of inflammatory cytokine secretion.
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