KR102228012B1 - Composition for enhancing radiosensitization effect of aripiprazole comprising D2 dopamine receptor antagonist - Google Patents
Composition for enhancing radiosensitization effect of aripiprazole comprising D2 dopamine receptor antagonist Download PDFInfo
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- KR102228012B1 KR102228012B1 KR1020190028720A KR20190028720A KR102228012B1 KR 102228012 B1 KR102228012 B1 KR 102228012B1 KR 1020190028720 A KR1020190028720 A KR 1020190028720A KR 20190028720 A KR20190028720 A KR 20190028720A KR 102228012 B1 KR102228012 B1 KR 102228012B1
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- cancer
- aripiprazole
- radiation
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- dopamine
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Abstract
본 발명은 도파민 D2 수용체 저해제를 유효성분으로 함유하는 아리피프라졸의 방사선 민감화 효과 증진용 조성물로서, 보다 구체적으로는 도파민 D2 수용체 저해제를 아리피프라졸과 병용 치료 시 방사선 민감제로서 작용하여 암을 치료할 수 있는 아리피프라졸의 방사선 민감화 효과 증진용 조성물에 관한 것이다. 본 발명에 따른 유효량의 도파민 수용체 저해제를 아리피프라졸에 병용하여 투여함으로써, MCF-7 세포 및 BT-474 세포 내에서 암세포의 생존도를 감소시키며 암세포 고사를 유도하는 등 아리피프라졸의 방사선 민감화 효능의 증진 효과가 우수하므로, 아리피프라졸 방사선 민감화 효능 증진제로 사용될 수 있다.The present invention is a composition for enhancing the radiation-sensitizing effect of aripiprazole containing a dopamine D2 receptor inhibitor as an active ingredient, and more specifically, of aripiprazole that can treat cancer by acting as a radiation sensitizer when a dopamine D2 receptor inhibitor is combined with aripiprazole. It relates to a composition for enhancing the radiation sensitizing effect. By administering an effective amount of a dopamine receptor inhibitor according to the present invention in combination with aripiprazole, the effect of enhancing the radiation-sensitizing efficacy of aripiprazole, such as reducing the viability of cancer cells in MCF-7 cells and BT-474 cells, and inducing cancer cell death. Since it is excellent, it can be used as an enhancer of aripiprazole radiation sensitization efficacy.
Description
본 발명은 도파민 D2 수용체 저해제를 유효성분으로 함유하는 아리피프라졸의 방사선 민감화 효과 증진용 조성물로서, 보다 구체적으로는 도파민 D2 수용체 저해제를 아리피프라졸과 병용 치료 시 방사선 민감제로서 작용하여 암을 치료할 수 있는 아리피프라졸의 방사선 민감화 효과 증진용 조성물에 관한 것이다.The present invention is a composition for enhancing the radiation-sensitizing effect of aripiprazole containing a dopamine D2 receptor inhibitor as an active ingredient, and more specifically, of aripiprazole that can treat cancer by acting as a radiation sensitizer when a dopamine D2 receptor inhibitor is combined with aripiprazole. It relates to a composition for enhancing the radiation sensitizing effect.
암의 치료법은 수술, 방사선치료법, 항암화학요법으로 크게 나눌 수 있는데, 전 세계적으로 방사선치료를 받는 암환자의 수가 매년 증가하고 있는 추세에 있어 암치료에 있어 방사선치료의 중요성 또한 증가하고 있지만, 암세포의 방사선내성 획득, 고선량 방사선 치료시 정상 조직의 손상 등이 치료의 효율을 떨어뜨리는 부작용을 수반한다. 방사선의 부작용을 줄이고 내성을 극복하기 위해 방사선과 병용하여 투여할 때 방사선의 항암 효과를 증가시키는 방사선 민감제에 관한 연구 개발이 이루어지고 있다. Cancer treatments can be broadly divided into surgery, radiation therapy, and chemotherapy. As the number of cancer patients receiving radiation therapy worldwide is increasing every year, the importance of radiation therapy in cancer treatment is also increasing, but cancer cells Acquisition of radiation resistance and damage to normal tissues during high-dose radiation treatment are accompanied by side effects that reduce the effectiveness of treatment. In order to reduce the side effects of radiation and overcome resistance, research and development on radiation sensitizers that increase the anticancer effect of radiation when administered in combination with radiation are being conducted.
아리피프라졸은 그 화학명이 7-{4-[4-(2,3-디클로로페닐)-1-피페라지닐]-부톡시}-3,4-디히드로 카르보스티릴 또는 7-{4-[4-(2,3-디클로로페닐)-1-피페라지닐]-부톡시}-3,4-디히드로-2(1H)-퀴놀리논이다. 아리피프라졸은 도파민 D2 수용체의 강력한 부분효능제(partial agonist)로, 향정신병 치료제로서 정신분열증(schizophrenia), 양극성 장애(bipolar disorder), 임상우울증(clinical depression) 등의 치료에 유용한 것으로 알려져 있다. 지금까지 아리피프라졸에 대한 약리작용으로는 중추신경계 및 신경질환에 대해서만 한정되어 연구되어 왔으며, 그 기술 또한 약물의 용해도 및 흡수율을 높이는 데에만 초점을 맞추어 연구되어 왔다. 최근 아리피프라졸 단독 처리에 의한 항암 효과, 기존 항암제와 병용 처리 시 기존 항암제의 항암 효능을 증진시키고, 또한 방사선과 병용 처리 시에도 아리피프라졸이 방사선 민감제로 작용하여 암을 치료할 수 있는 것으로 알려져 있다. 이러한 항암 효능에 도파민 수용체의 관여 또는 역할은 전혀 알려져 있지 않다. 따라서, 도파민 수용체 저해제의 아리피프라졸 항암 효능 증진에 대한 연구 및 개발의 필요성이 절실히 요구되고 있다.Aripiprazole has the chemical name 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyryl or 7-{4-[4 -(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone. Aripiprazole is a strong partial agonist of the dopamine D2 receptor, and is known to be useful in the treatment of schizophrenia, bipolar disorder, and clinical depression as a psychotropic drug. Until now, the pharmacological action of aripiprazole has been limitedly studied for central nervous system and neurological diseases, and its technology has also been studied focusing only on increasing the solubility and absorption of drugs. Recently, it is known that the anticancer effect of aripiprazole alone treatment, the anticancer efficacy of existing anticancer drugs when combined with the existing anticancer drugs, and even when combined with radiation, aripiprazole acts as a radiation sensitizer to treat cancer. The involvement or role of dopamine receptors in these anticancer efficacy is not known at all. Therefore, there is an urgent need for research and development on the improvement of anticancer efficacy of aripiprazole of dopamine receptor inhibitors.
본 발명의 목적은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아리피프라졸의 방사선 민감화 효과 증진용 조성물을 제공하는 데에 있다.An object of the present invention is to provide a composition for enhancing the radiation sensitizing effect of aripiprazole containing a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 목적은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염; 및 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 약학조성물 또는 건강기능식품 조성물을 제공하는 데에 있다.In addition, an object of the present invention is a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof; And aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아리피프라졸의 방사선 민감화 효과 증진용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for enhancing the radiation sensitizing effect of aripiprazole containing a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염; 및 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 약학조성물을 제공한다.In addition, the present invention is a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for adjuvant radiotherapy for cancer containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염; 및 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 건강기능식품 조성물을 제공한다.In addition, the present invention is a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof; And aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a health functional food composition for adjuvant radiotherapy for cancer.
본 발명은 도파민 D2 수용체 저해제를 유효성분으로 함유하는 아리피프라졸의 방사선 민감화 효과 증진용 조성물로서, 보다 구체적으로는 도파민 D2 수용체 저해제를 아리피프라졸과 병용 치료 시 방사선 민감제로서 작용하여 암을 치료할 수 있는 아리피프라졸의 방사선 민감화 효과 증진용 조성물에 관한 것이다. 본 발명에 따른 유효량의 도파민 수용체 저해제를 아리피프라졸에 병용하여 투여함으로써, MCF-7 세포 및 BT-474 세포 내에서 암세포의 생존도를 감소시키며 암세포 고사를 유도하는 등 아리피프라졸의 방사선 민감화 효능의 증진 효과가 우수하므로, 아리피프라졸 방사선 민감화 효능 증진제로 사용될 수 있다.The present invention is a composition for enhancing the radiation-sensitizing effect of aripiprazole containing a dopamine D2 receptor inhibitor as an active ingredient, and more specifically, of aripiprazole that can treat cancer by acting as a radiation sensitizer when a dopamine D2 receptor inhibitor is combined with aripiprazole. It relates to a composition for enhancing the radiation sensitizing effect. By administering an effective amount of the dopamine receptor inhibitor according to the present invention in combination with aripiprazole, the effect of enhancing the radiation-sensitizing efficacy of aripiprazole, such as reducing the viability of cancer cells in MCF-7 cells and BT-474 cells, and inducing cancer cell death. Since it is excellent, it can be used as an enhancer of aripiprazole radiation sensitization efficacy.
도 1은 MCF-7 세포 내에서 티오리다진 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 티오리다진과 아리피프라졸을 동시에 방사선과 병용처리한 후 PARP 절단(cleavage)을 평가한 결과를 나타낸다.
도 2는 MCF-7 또는 BT-474 세포 내에서 티오리다진 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 티오리다진과 아리피프라졸을 동시에 방사선과 병용처리한 후 DNA 단편화(fragmentation)를 평가한 결과를 나타낸다.
도 3은 MCF-7 세포 내에서 할로페리돌 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 할로페리돌과 아리피프라졸을 동시에 방사선과 병용처리한 후 PARP 절단(cleavage)을 평가한 결과를 나타낸다.
도 4는 MCF-7 또는 BT-474 세포 내에서 할로페리돌 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 할로페리돌과 아리피프라졸을 동시에 방사선과 병용처리한 후 DNA 단편화(fragmentation)를 평가한 결과를 나타낸다.FIG. 1 shows the results of evaluating PARP cleavage after treatment in combination with radiation of thioridazine or aripiprazole in MCF-7 cells, respectively, or treatment of thioridazine and aripiprazole in combination with radiation at the same time.
Figure 2 shows the results of evaluating DNA fragmentation in MCF-7 or BT-474 cells after treatment with radiation in combination with thioridazine or aripiprazole, respectively, or treatment with radiation in combination with thioridazine and aripiprazole at the same time.
FIG. 3 shows the results of evaluating PARP cleavage after treatment of haloperidol or aripiprazole in combination with radiation, respectively, or haloperidol and aripiprazole in combination with radiation in MCF-7 cells.
4 shows the results of evaluating DNA fragmentation after treatment with radiation in combination with haloperidol or aripiprazole, respectively, or haloperidol and aripiprazole in combination with radiation in MCF-7 or BT-474 cells.
본 발명은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아리피프라졸의 방사선 민감화 효과 증진용 조성물을 제공한다.The present invention provides a composition for enhancing the radiation sensitizing effect of aripiprazole containing a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
바람직하게는, 상기 도파민 수용체 저해제는 티오리다진 또는 할로페리돌일 수 있으나, 이에 제한되는 것은 아니다.Preferably, the dopamine receptor inhibitor may be thioridazine or haloperidol, but is not limited thereto.
바람직하게는, 상기 조성물은 방사선 조사에 의한 암세포의 세포고사(apoptosis)를 유도할 수 있으며, 보다 바람직하게는, 상기 조성물은 암세포의 PARP 절단(cleavage) 또는 DNA 단편화(fragmentation)를 유도할 수 있다.Preferably, the composition can induce apoptosis of cancer cells by irradiation, and more preferably, the composition can induce PARP cleavage or DNA fragmentation of cancer cells. .
바람직하게는, 상기 조성물은 암 치료시 방사선 조사와 병용하여 투여될 수 있다. 보다 바람직하게는, 상기 암은 유방암, 폐암, 골암, 췌장암, 피부암, 구강암, 구강인두암, 자궁암, 난소암, 직장암, 위암, 자궁내막암종, 자궁경부암종, 질암종, 소장암, 갑상선암, 부갑상선암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장암, 간암, 대장암 또는 뇌종양일 수 있으나, 이에 제한되는 것은 아니다.Preferably, the composition may be administered in combination with irradiation during cancer treatment. More preferably, the cancer is breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, small intestine cancer, thyroid cancer, part Thyroid cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney cancer, liver cancer, colon cancer, or brain tumor, but are not limited thereto.
또한, 본 발명은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염; 및 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 약학조성물을 제공한다.In addition, the present invention is a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for adjuvant radiotherapy for cancer containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
바람직하게는, 상기 도파민 수용체 저해제는 티오리다진 또는 할로페리돌일 수 있으나, 이에 제한되는 것은 아니다.Preferably, the dopamine receptor inhibitor may be thioridazine or haloperidol, but is not limited thereto.
또한, 본 발명은 도파민 D2 수용체 저해제 또는 이의 약학적으로 허용가능한 염; 및 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 건강기능식품 조성물을 제공한다.In addition, the present invention is a dopamine D2 receptor inhibitor or a pharmaceutically acceptable salt thereof; And aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a health functional food composition for adjuvant radiotherapy for cancer.
바람직하게는, 상기 도파민 수용체 저해제는 티오리다진 또는 할로페리돌일 수 있으나, 이에 제한되는 것은 아니다.Preferably, the dopamine receptor inhibitor may be thioridazine or haloperidol, but is not limited thereto.
본 발명에서 용어, "약학적으로 허용가능한 염"은 인간에게 투여하기에 적합한 안전성 및 효능 프로파일을 갖는 염을 의미한다. 구체적으로는, 아리피프라졸의 제약상 허용되는 염으로서, 구체적인 형태로는 무기 산, 예컨대 염산, 질산, 인산, 황산, 브로민화수소산, 아이오딘화수소산, 아인산 및 이들의 혼합물로부터 유도된 염 뿐만 아니라 유기산, 예컨대 지방족 모노- 및 디카르복실산, 페닐-치환된 알칸산, 히드록시 알칸산, 알칸디오산, 방향족 산, 및 지방족 및 방향족 술폰산으로부터 유도된 염을 포함할 수 있으나, 이에 제한되지는 않는다.As used herein, the term "pharmaceutically acceptable salt" refers to a salt having a safety and efficacy profile suitable for administration to humans. Specifically, as a pharmaceutically acceptable salt of aripiprazole, in specific forms, as well as salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and mixtures thereof, as well as organic acids , For example, aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanic acids, hydroxy alkanic acids, alkanedioic acids, aromatic acids, and salts derived from aliphatic and aromatic sulfonic acids, but are not limited thereto. .
본 발명에서 용어, "방사선 민감성" 또는 "방사선 민감화"는 방사선 용량에 기초한 생존하는 세포수를 의미한다. 본 발명에서는 방사선 민감성을 측정하기 위하여, 방사선을 용량별로 조사한 후 형성된 콜로니의 수를 측정하는 방법을 사용하여 확인하였다.In the present invention, the term "radiation sensitivity" or "radiation sensitization" refers to the number of surviving cells based on radiation dose. In the present invention, in order to measure radiation sensitivity, it was confirmed using a method of measuring the number of colonies formed after irradiating radiation by dose.
본 발명에서 용어, "증진"은 어떤 방사선 용량에서 생존하는 세포수의 감소, 치사량에 필요한 방사선 용량의 감소, 또는 이들의 조합을 의미하나, 다른 통상적으로 의미하는 증진도 포함한다. 구체적으로, 본 발명에서 상기 방사선의 민감성이 증진된다는 것은 방사선을 용량별로 조사한 후 형성된 콜로니의 수를 측정하였을 때, 방사선 농도에 따라 그 콜로니의 수가 감소하거나, 상기 작성된 선형 모델의 기울기의 값이 증가하는 것을 의미한다.In the present invention, the term "enhancement" refers to a decrease in the number of cells surviving at a certain radiation dose, a decrease in radiation dose required for a lethal dose, or a combination thereof, but also includes other commonly meant enhancement. Specifically, in the present invention, the increased sensitivity of the radiation means that when the number of colonies formed after radiation is irradiated by dose is measured, the number of colonies decreases according to the radiation concentration, or the value of the slope of the created linear model increases. Means to do.
본 발명에서 용어, "방사선 조사"는 악성 세포의 DNA를 손상시키는 국소 치료 방법을 의미한다. 정상 세포는 종양 세포에 비해 이런 손상을 수선하는 능력이 더 크다. 방사선 조사는 이런 차이를 이용하는 치료를 의미하며, 통상적으로 의미하는 방사선을 이용하여 치료하는 방법을 포함한다.In the present invention, the term "irradiation" refers to a local treatment method that damages the DNA of malignant cells. Normal cells have a greater ability to repair this damage than tumor cells. Radiation irradiation refers to treatment using these differences, and includes a method of treatment using radiation, which is usually meant.
방사선 조사는 국소 요법의 형태이므로, 일반적으로 부작용은 치료된 부위에 제한된다. 그러나 공통된 전신 증상으로서 피로감이 있다. 많은 유전적 요인들이 일부 환자에서 2차 암의 소인이 되는 것이 사실이지만, 방사선 또한 관련 위험의 증가에 기여한다. 본 발명에 따른 방사선 민감성 증가용 조성물은 방사선의 필요량을 감소시킴으로써 이러한 부작용을 줄일 수 있다. 또한, 방사선에 민감한 암세포뿐만 아니라, 방사선에 저항성이 있는 암세포에서도 방사선 민감도를 증가시킬 수 있다.Since irradiation is a form of topical therapy, side effects are usually limited to the treated area. However, there is a feeling of fatigue as a common systemic symptom. It is true that many genetic factors predispose to secondary cancer in some patients, but radiation also contributes to the increased risk involved. The composition for increasing radiation sensitivity according to the present invention can reduce such side effects by reducing the required amount of radiation. In addition, radiation sensitivity can be increased not only in radiation-sensitive cancer cells, but also in radiation-resistant cancer cells.
본 발명에서 용어, "병용하여 투여"는 다양한 종류의 암세포를 치료하는 항암 과정에서 방사선 조사를 함께 투여하는 것을 의미한다. 구체적으로는, 폐암, 유방암, 대장암, 난소암, 두경부암, 뇌암 등의 고형암과 같은 암세포를 치료하는 항암 과정에서 방사선 조사 치료법을 병용 처리되는 것일 수 있다.In the present invention, the term "administered in combination" means administering radiation irradiation together in an anticancer process to treat various types of cancer cells. Specifically, it may be a combination treatment of radiation irradiation therapy in an anticancer process for treating cancer cells such as solid cancer such as lung cancer, breast cancer, colon cancer, ovarian cancer, head and neck cancer, and brain cancer.
본 발명의 조성물이 약학조성물인 경우, 상기 약학적 조성물은 도파민 D2 수용체 저해제 또는 아리피프라졸 이외에 약제학적으로 허용되는 담체를 포함할 수 있는데, 이러한 약학적으로 허용되는 담체는 약품 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘, 미네랄 오일 등을 포함할 수 있으나, 이에 한정되는 것은 아니다. 또한, 상기 약학적 조성물은 첨가제로서 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.When the composition of the present invention is a pharmaceutical composition, the pharmaceutical composition may include a pharmaceutically acceptable carrier other than a dopamine D2 receptor inhibitor or aripiprazole. Such a pharmaceutically acceptable carrier is commonly used in pharmaceutical formulations. As such, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, Methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. may be included, but the present invention is not limited thereto. In addition, the pharmaceutical composition may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like as an additive.
상기 약학적 조성물은 증상 정도에 따라 투여 방법이 결정되는데, 통상적으로는 국소 투여 방식이 바람직하다. 또한, 상기 약학적 조성물 중 유효성분의 투여량은 투여경로, 질병의 정도, 환자의 나이, 성별, 체중 등에 따라 달라질 수 있으며, 일일 1회 내지 수회 투여할 수 있다.The method of administration of the pharmaceutical composition is determined according to the degree of symptoms, and a topical administration method is usually preferred. In addition, the dosage of the active ingredient in the pharmaceutical composition may vary depending on the route of administration, the severity of the disease, the patient's age, sex, weight, etc., and may be administered once to several times a day.
상기 약학적 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내(intracerebroventricular)주사에 의해 투여될 수 있다.The pharmaceutical composition may be administered to mammals such as mice, mice, livestock, and humans by various routes. All modes of administration can be expected, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or by intracerebroventricular injection.
상기 약학적 조성물은 약학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때, 제형은 용액, 현탁액 또는 유화액 형태이거나 엘렉시르제, 엑스제, 분말제, 과립제, 정제, 경고제, 로션제, 연고제 등의 형태일 수 있다.The pharmaceutical composition may be prepared in unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient, or may be prepared by incorporating it into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, or emulsion, or may be in the form of an elexir, an extract, a powder, a granule, a tablet, a warning agent, a lotion, an ointment, and the like.
또한, 본 발명의 조성물이 건강기능식품 조성물인 경우, 상기 건강기능식품 조성물은 분말, 과립, 정제, 캡슐, 시럽, 음료 또는 환의 형태로 제공될 수 있으며, 상기 건강기능식품 조성물은 유효성분인 본 발명에 따른 도파민 D2 수용체 저해제 또는 아리피프라졸 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.In addition, when the composition of the present invention is a health functional food composition, the health functional food composition may be provided in the form of powder, granules, tablets, capsules, syrup, beverages or pills, and the health functional food composition is an active ingredient. In addition to the dopamine D2 receptor inhibitor or aripiprazole according to the invention, it may be used together with other foods or food additives, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use, for example, prevention, health or therapeutic treatment.
상기 건강기능식품 조성물에 함유된 도파민 D2 수용체 저해제 또는 아리피프라졸의 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the dopamine D2 receptor inhibitor or aripiprazole contained in the health functional food composition can be used in accordance with the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or health control It may be less than the above range, and since there is no problem in terms of safety, the active ingredient can be used in an amount greater than the above range.
상기 건강기능식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There are no particular restrictions on the types of health functional foods, examples of which include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea. , Drinks, alcoholic beverages, and vitamin complexes.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
<< 실시예Example 1> 암세포 내에서 도파민 수용체 저해제인 1> Dopamine receptor inhibitors in cancer cells 티오리다진과Thiori chopped fruit 아리피프Aripipe 라졸이 방사선 유도 세포고사(PARP 절단 정도)에 미치는 영향Effect of razol on radiation-induced apoptosis (degree of PRP cleavage)
암세포 내에서 도파민 수용체 저해제와 아리피프라졸이 방사선 유도 세포고사에 미치는 영향을 확인하기 위하여, MCF-7 세포에 티오리다진 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 티오리다진과 아리피프라졸을 동시에 방사선과 병용처리하였다. 24 시간 후 PBS로 세척한 후 세포로부터 단백질을 추출하여 웨스턴블랏으로 PARP 절단(cleavage) 정도를 확인하였다.To confirm the effect of dopamine receptor inhibitors and aripiprazole on radiation-induced apoptosis in cancer cells, thioridazine or aripiprazole was treated in combination with radiation, respectively, or thioridazine and aripiprazole were treated in combination with radiation on MCF-7 cells. After 24 hours, after washing with PBS, proteins were extracted from the cells, and the degree of PARP cleavage was confirmed by Western blot.
도 1에 나타난 바와 같이, '티오리다진과 방사선 병용처리' 또는 '아리피프라졸과 방사선 병용처리' 각각의 처리에 의한 PARP 절단(cleavage) 유도 효과 보다 티오리다진과 아리피프라졸을 동시에 방사선과 병용 처리할 때에 보다 우수한 PARP 절단(cleavage) 유도 효과를 나타내는 것으로 밝혀졌다. As shown in Fig. 1, compared to the effect of inducing PARP cleavage by the treatment of'combination of thiolidazine and radiation' or'combination of aripiprazole and radiation', than when the combination treatment of thioridazine and aripiprazole with radiation at the same time It has been found to exhibit excellent PARP cleavage induction effect.
<< 실시예Example 2> 암세포 내에서 도파민 수용체 저해제인 2> Dopamine receptor inhibitors in cancer cells 티오리다진과Thiori chopped fruit 아리피프Aripipe 라졸이 방사선 유도 세포고사(DNA 단편화)에 미치는 영향Effect of Razol on Radiation-induced Apoptosis (DNA Fragmentation)
MCF-7 세포 또는 BT-474 세포를 5000 cells/well의 농도로 조절한 후, 96 웰 플레이트에 접종하고 24시간 동안 전배양하였다. 이후 배지를 제거하고 티오리다진 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 티오리다진과 아리피프라졸을 동시에 방사선과 병용처리하였다. 24시간 후 로슈사의 Cell Death Detection ELISA plus 키트를 이용하여 DNA 단편화(fragmentation) 정도를 확인하였다.After the MCF-7 cells or BT-474 cells were adjusted to a concentration of 5000 cells/well, they were inoculated into a 96-well plate and pre-cultured for 24 hours. Thereafter, the medium was removed, and thioridazine or aripiprazole was treated in combination with radiation, respectively, or thioridazine and aripiprazole were treated in combination with radiation at the same time. After 24 hours, the degree of DNA fragmentation was confirmed using a Roche Cell Death Detection ELISA plus kit.
도 2에 나타난 바와 같이, 티오리다진과 아리피프라졸을 동시에 방사선 과 병용 처리 할 때에 '티오리다진과 방사선 병용 처리' 또는 '아리피프라졸과 방사선 병용 처리' 각각의 처리를 더한 효과보다 우수한 DNA 단편화(fragmentation) 유도 효과를 나타내는 것으로 밝혀졌다.As shown in Fig. 2, when thioridazine and aripiprazole are simultaneously treated with radiation, DNA fragmentation is superior to the effect of adding the treatment of each of'thioridazine and radiation combined treatment' or'aripiprazole and radiation combined treatment'. It has been found to exhibit an induction effect.
<< 실시예Example 3> 암세포 내에서 도파민 수용체 저해제인 3> Dopamine receptor inhibitors in cancer cells 할로페리돌과Haloperidolaceae 아리피프Aripipe 라졸이 방사선 유도 세포고사(PARP 절단 정도)에 미치는 영향Effect of razol on radiation-induced apoptosis (degree of PRP cleavage)
암세포 내에서 도파민 수용체 저해제와 아리피프라졸이 방사선 유도 세포고사에 미치는 영향을 확인하기 위하여, MCF-7 세포에 할로페리돌 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 할로페리돌과 아리피프라졸을 동시에 방사선과 병용처리하였다. 24 시간 후 PBS로 세척한 후 세포로부터 단백질을 추출하여 웨스턴블랏으로 PARP 절단(cleavage) 정도를 확인하였다.To confirm the effect of dopamine receptor inhibitors and aripiprazole on radiation-induced apoptosis in cancer cells, MCF-7 cells were treated with haloperidol or aripiprazole in combination with radiation, respectively, or haloperidol and aripiprazole in combination with radiation. After 24 hours, after washing with PBS, proteins were extracted from the cells, and the degree of PARP cleavage was confirmed by Western blot.
도 3에 나타난 바와 같이, '할로페리돌과 방사선 병용처리' 또는 '아리피프라졸과 방사선 병용처리' 각각의 처리에 의한 PARP 절단(cleavage) 유도 효과 보다 할로페리돌과 아리피프라졸을 동시에 방사선과 병용 처리할 때에 보다 우수한 PARP 절단(cleavage) 유도 효과를 나타내는 것으로 밝혀졌다. As shown in FIG. 3, PARP cleavage is more excellent when haloperidol and aripiprazole are simultaneously treated with radiation than the PARP cleavage-inducing effect by each treatment of'haloperidol and radiation combination treatment' or'aripiprazole and radiation combination treatment'. cleavage) inducing effect.
<< 실시예Example 4> 암세포 내에서 도파민 수용체 저해제인 4> Dopamine receptor inhibitors in cancer cells 할로페리돌과Haloperidolaceae 아리피프Aripipe 라졸이 방사선 유도 세포고사(DNA 단편화)에 미치는 영향Effect of Razol on Radiation-induced Apoptosis (DNA Fragmentation)
MCF-7 세포 또는 BT-474 세포를 5000 cells/well의 농도로 조절한 후, 96 웰 플레이트에 접종하고 24시간 동안 전배양하였다. 이후 배지를 제거하고 할로페리돌 또는 아리피프라졸을 각각 방사선과 병용 처리하거나 할로페리돌과 아리피프라졸을 동시에 방사선과 병용처리하였다. 24시간 후 로슈사의 Cell Death Detection ELISA plus 키트를 이용하여 DNA 단편화(fragmentation) 정도를 확인하였다.After the MCF-7 cells or BT-474 cells were adjusted to a concentration of 5000 cells/well, they were inoculated into a 96-well plate and pre-cultured for 24 hours. Thereafter, the medium was removed, and haloperidol or aripiprazole was treated in combination with radiation, respectively, or haloperidol and aripiprazole were treated in combination with radiation at the same time. After 24 hours, the degree of DNA fragmentation was confirmed using a Roche Cell Death Detection ELISA plus kit.
도 4에 나타난 바와 같이, 할로페리돌과 아리피프라졸을 동시에 방사선과 병용 처리할 때에 '할로페리돌과 방사선 병용 처리' 또는 '아리피프라졸과 방사선 병용 처리' 각각의 처리를 더한 효과보다 우수한 DNA 단편화(fragmentation) 유도 효과를 나타내는 것으로 밝혀졌다.As shown in FIG. 4, when haloperidol and aripiprazole are simultaneously treated with radiation, the effect of inducing DNA fragmentation is better than the effect of adding the respective treatments of'haloperidol and radiation combined treatment' or'aripiprazole and radiation combined treatment'. It turned out.
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| EP19796396.0A EP3789029B1 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as active ingredient |
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| PL19796396.0T PL3789029T3 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as active ingredient |
| CN201980029987.0A CN112074273B (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition comprising aripiprazole as active ingredient |
| CN202310699745.0A CN116726169A (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition comprising aripiprazole as active ingredient |
| ES22176241T ES2959158T3 (en) | 2018-05-04 | 2019-04-23 | Composition for enhancing radiation sensitivity containing aripiprazole as the active ingredient |
| US17/050,462 US20210236482A1 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as active ingredient |
| PCT/KR2019/004900 WO2019212185A1 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as active ingredient |
| JP2021512344A JP7059444B2 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as an active ingredient |
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