KR102008931B1 - Composition for enhancing radiation sensitivity comprising aripiprazole - Google Patents
Composition for enhancing radiation sensitivity comprising aripiprazole Download PDFInfo
- Publication number
- KR102008931B1 KR102008931B1 KR1020180051702A KR20180051702A KR102008931B1 KR 102008931 B1 KR102008931 B1 KR 102008931B1 KR 1020180051702 A KR1020180051702 A KR 1020180051702A KR 20180051702 A KR20180051702 A KR 20180051702A KR 102008931 B1 KR102008931 B1 KR 102008931B1
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- KR
- South Korea
- Prior art keywords
- cancer
- radiation
- pharmaceutical composition
- aripiprazole
- cells
- Prior art date
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Abstract
Description
본 발명은 아리피프라졸을 유효성분으로 함유하는 방사선 민감성 증진용 조성물로서, 보다 구체적으로는 방사선과 병용 치료 시 아리피프라졸이 방사선 민감제로서 작용하여 암을 치료할 수 있는 방사선 민감성 증진용 조성물에 관한 것이다.The present invention relates to a composition for enhancing radiation sensitivity containing aripiprazole as an active ingredient, and more particularly, to a composition for enhancing radiation sensitivity in which aripiprazole acts as a radiation sensitizer when treating a combination with radiation.
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 treatment can be divided into surgery, radiation therapy, and chemotherapy. Since the number of cancer patients receiving radiation therapy is increasing every year, the importance of radiation therapy in cancer treatment is increasing. Acquisition of radiation resistance and damage to normal tissues during high-dose radiation are accompanied by side effects that reduce the effectiveness of treatment. In order to reduce the side effects of radiation and overcome the resistance, research and development are being conducted on radiation sensitizers that increase the anticancer effect of radiation when administered in combination with radiation.
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)로서, 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 있을 뿐, 아리피프라졸의 방사선 민감화 효과에 대해서는 전혀 알려져 있지 않으며, 이에 대한 연구도 전무한 상태이다. 따라서, 아리피프라졸의 방사선 민감화 효과에 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 potent partial agonist of the dopamine D2 receptor, and is known to be useful for the treatment of schizophrenia, bipolar disorder, clinical depression, etc. Until now, the pharmacological action of aripiprazole has been limited to only the central nervous system and neurological diseases, and the technique has been focused only on increasing the solubility and absorption rate of the drug. It is not known and there is no research on this. Therefore, there is an urgent need for research and development on the radiation sensitization effect of aripiprazole.
본 발명의 목적은 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 방사선 민감성 증진용 조성물을 제공하는 데에 있다.An object of the present invention is to provide a composition for enhancing radiation sensitivity containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
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상기 목적을 달성하기 위하여, 본 발명은 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 방사선 민감성 증진용 조성물, 암에 대한 방사선 치료 보조용 약학조성물 또는 암에 대한 방사선 치료 보조용 건강기능식품 조성물을 제공한다.In order to achieve the above object, the present invention is a composition for enhancing radiation sensitivity containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for assisting radiation therapy for cancer or a radiation therapy assisting health function for cancer Provide a food composition.
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본 발명은 아리피프라졸을 유효성분으로 함유하는 방사선 민감성 증진용 조성물로서, 보다 구체적으로는 방사선과 병용 치료 시 아리피프라졸이 방사선 민감제로서 작용하여 암을 치료할 수 있는 방사선 민감성 증진용 조성물에 관한 것이다. 본 발명에 따른 유효량의 아리피프라졸을 방사선 조사에 병용하여 투여함으로써, 암세포의 생존도를 감소시키며 암세포 고사를 유도하는 등 방사선 민감성 증진 효과가 우수하므로, 방사선 민감성 증진제로 유용하게 이용될 수 있다.The present invention relates to a composition for enhancing radiation sensitivity containing aripiprazole as an active ingredient, and more particularly, to a composition for enhancing radiation sensitivity in which aripiprazole acts as a radiation sensitizer when treating a combination with radiation. By administering an effective amount of aripiprazole according to the present invention in combination with radiation, it is excellent in radiation sensitivity enhancement effects such as reducing cancer cell viability and inducing cancer cell death, and thus may be useful as a radiation sensitivity enhancer.
도 1은 MCF-7 세포 내에서 321 종류의 약물 단독 또는 방사선과 병용처리가 세포생존율에 미치는 영향을 나타낸다.
도 2는 MCF-7 세포 내에서 여러 농도의 아리피프라졸 단독 또는 방사선과 병용처리가 세포생존율에 미치는 영향을 나타낸다.
도 3은 MCF-7 세포 내에서 아리피프라졸 단독 또는 방사선과 병용처리가 PARP 절단(cleavage)에 미치는 영향을 나타낸다.
도 4는 MCF-7 또는 U251 세포 내에서 아리피프라졸 단독 또는 방사선과 병용처리가 DNA 단편화(fragmentation)에 미치는 영향을 나타낸다.Figure 1 shows the effect of 321 types of drugs alone or radiation treatment in MCF-7 cells on the cell survival rate.
Figure 2 shows the effect of different concentrations of aripiprazole alone or in combination with radiation in MCF-7 cells on the cell survival rate.
3 shows the effect of aripiprazole alone or in combination with radiation in MCF-7 cells on PARP cleavage.
4 shows the effect of aripiprazole alone or in combination with radiation on MCF-7 or U251 cells on DNA fragmentation.
본 발명은 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 방사선 민감성 증진용 조성물을 제공한다.The present invention provides a composition for enhancing radiation sensitivity containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
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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 may induce apoptosis of cancer cells by irradiation, and more preferably, the composition may 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 radiation when treating cancer. 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, vice Thyroid cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney cancer, liver cancer, colon cancer or brain tumors, but is not limited thereto.
또한, 본 발명은 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 약학조성물을 제공한다.The present invention also provides a pharmaceutical composition for adjuvant radiation therapy for cancer containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
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또한, 본 발명은 아리피프라졸 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암에 대한 방사선 치료 보조용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a dietary supplement for radiation therapy for cancer containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
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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 salts” means salts having a safety and efficacy profile suitable for administration to humans. Specifically, pharmaceutically acceptable salts of aripiprazole, in particular forms of organic acids 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 Such as, but not limited to, aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, and salts derived from aliphatic and aromatic sulfonic acids. .
본 발명에서 용어, "방사선 민감성"은 방사선 용량에 기초한 생존하는 세포수를 의미한다. 본 발명에서는 방사선 민감성을 측정하기 위하여, 방사선을 용량별로 조사한 후 형성된 콜로니의 수를 측정하는 방법을 사용하여 확인하였다.As used herein, the term "radiation sensitivity" refers to the number of viable cells based on radiation dose. In the present invention, in order to measure the 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.As used herein, the term "enhancing" means a decrease in the number of cells surviving at a certain radiation dose, a reduction in the radiation dose required for lethal dose, or a combination thereof, but also includes other commonly meant enhancements. Specifically, in the present invention, the sensitivity of the radiation is improved, when the number of colonies formed after irradiation of radiation by dose is measured, the number of colonies decreases according to the radiation concentration, or the value of the slope of the linear model prepared increases. I mean.
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.As used herein, the term "radiation irradiation" means a topical treatment method that damages the DNA of malignant cells. Normal cells have a greater ability to repair these damages than tumor cells. Irradiation means treatment using these differences and includes methods of treatment using radiation, which is commonly 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 radiation is a form of topical therapy, side effects are generally limited to the treated area. However, a common systemic symptom is fatigue. While many genetic factors are prevalent in secondary cancers in some patients, radiation also contributes to an increased risk. The composition for increasing radiation sensitivity according to the present invention can reduce these side effects by reducing the required amount of radiation. In addition, radiation sensitivity can be increased not only in cancer cells that are sensitive to radiation, but also in cancer cells that are resistant to radiation.
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.As used herein, the term "combined administration" refers to the administration of irradiation together in the anti-cancer process of treating various types of cancer cells. Specifically, radiation therapy may be used in combination with an anti-cancer process for treating cancer cells such as solid cancers 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 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 in addition to aripiprazole, such a pharmaceutically acceptable carrier is commonly used in pharmaceutical formulations, lactose, deck Straw, Sucrose, Sorbitol, Mannitol, Starch, Acacia Rubber, Calcium Phosphate, Alginate, Gelatin, Calcium Silicate, Microcrystalline Cellulose, Polyvinylpyrrolidone, Cellulose, Water, Syrup, Methyl Cellulose, Methylhydroxybenzoate , But may include, but is not limited to, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, the pharmaceutical composition may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, 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 depending on the degree of symptoms, usually topical administration is preferred. In addition, the dosage of the active ingredient in the pharmaceutical composition may vary depending on the route of administration, the degree of the disease, the age, sex, and weight of the patient, and may be administered once to several times daily.
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 various mammals such as rats, mice, livestock, humans, and the like. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or 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 compositions may be prepared in unit dose form or formulated using pharmaceutically acceptable carriers and / or excipients or may be prepared within 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 exercicide, extract, powder, granule, tablet, warning, lotion, ointment, or 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 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 dietary supplement composition, the dietary supplement composition may be provided in the form of powder, granules, tablets, capsules, syrups, beverages or pills, the dietary supplement composition is an active ingredient In addition to aripiprazole according to the invention, it is used together with other food or food additives, and may be suitably used according to a conventional method. The mixed amount of the active ingredient can be suitably determined depending on the purpose of use thereof, for example, prophylactic, health or therapeutic treatment.
상기 건강기능식품 조성물에 함유된 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 aripiprazole contained in the dietary supplement composition may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for long term intake for health and hygiene purposes or for health control purposes. However, since the active ingredient has no problem in terms of safety, it is evident that it can be used in an amount above 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 limitations on the types of dietary supplements, for example, meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, drinks, tea , A drink, an alcoholic beverage, and a vitamin complex.
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 with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
<< 실시예Example 1> 유방암세포 내에서 방사선 1> radiation within breast cancer cells 민감제Sensitizer 검색 Search
방사선 저항성을 가진 유방암세포 내에서의 단독 처리에서는 세포독성이 관찰되지 않지만 방사선과 병용처리에서 방사선 민감도를 증강시키는 방사선 민감제 후보약물을 엔조사의 약물라이브러리에서 검색하였다.Cytotoxicity was not observed in treatment alone in radiation-resistant breast cancer cells, but candidates for radiation sensitizers that enhance radiation sensitivity in combination with radiation were searched for in the NRI drug library.
인간 유방암 세포주인 MCF-7 세포를 5000 cells/well의 농도로 조절한 후, 96 웰 플레이트에 접종하고 24시간 동안 전배양하였다. 이후 배지를 제거하고 엔조사 약물라이브러리의 각 약물을 5 mM 농도로 단독처리하거나 방사선과 병용처리하였다. 96시간 후 도젠사의 EZ-Cytox Cell Viability Assay 키트로 세포의 생존율을 측정하였다.MCF-7 cells, which are human breast cancer cell lines, were adjusted to a concentration of 5000 cells / well, and then inoculated into 96 well plates and precultured for 24 hours. The medium was then removed and each drug in the Enzyme Drug Library was treated alone or in combination with radiation at a 5 mM concentration. After 96 hours, the viability of the cells was measured by Dozen's EZ-Cytox Cell Viability Assay kit.
도 1에 나타난 바와 같이, 약물 단독처리에서는 세포의 생존율에 영향이 없지만 방사선과 병용하여 처리할 때에 방사선 저항성 세포의 생존율을 떨어뜨리는 방사선 민감제로 아리피프라졸을 발굴하였다. As shown in Figure 1, the drug alone treatment has no effect on the survival rate of the cells, but when treated in combination with radiation to detect aripiprazole as a radiation-sensitive agent that reduces the survival rate of radiation-resistant cells.
<< 실시예Example 2> 2> 아리피프라졸이Aripiprazole 암세포 방사선 민감도에 미치는 영향 Effect on cancer cell radiation sensitivity
암세포 내에서 아리피프라졸이 방사선 민감도에 미치는 영향을 확인하기 위하여, 방사선 저항성을 가진 유방암세포 내에서 MTT 어세이를 이용하여 세포생존율 측정 실험을 하기와 같이 수행하였다.In order to confirm the effect of aripiprazole on radiation sensitivity in cancer cells, cell viability measurement experiments were performed using MTT assay in radiation resistant breast cancer cells as follows.
MCF-7 세포를 5000 cells/well의 농도로 조절한 후, 96 웰 플레이트에 접종하고 24시간 동안 전배양하였다. 이후 배지를 제거하고 아리피프라졸 (5, 10, 20 μM)을 단독처리하거나 방사선과 병용처리하였다. 96시간 후 도젠사의 EZ-Cytox Cell Viability Assay 키트로 세포의 생존율을 측정하였다. MCF-7 cells were adjusted to a concentration of 5000 cells / well, then seeded in 96 well plates and precultured for 24 hours. The medium was then removed and aripiprazole (5, 10, 20 μM) alone or in combination with radiation. After 96 hours, the viability of the cells was measured by Dozen's EZ-Cytox Cell Viability Assay kit.
도 2에 나타난 바와 같이, 아리피프라졸 단독 처리에 의한 생존율 저감 효과 보다 방사선과 병용하여 처리할 때에 보다 우수한 생존율 저감 효과를 나타내는 것으로 밝혀졌다. 아리피프라졸은 농도 의존적으로 방사선 민감화 효과가 우수한 것으로 밝혀졌다.As shown in FIG. 2, it was found to exhibit a better survival rate reduction effect when treated in combination with radiation than the survival rate reduction effect by aripiprazole alone. Aripiprazole has been found to have excellent radiation sensitizing effects in a concentration dependent manner.
<< 실시예Example 3> 암세포 내에서 3> within cancer cells 아리피프라졸이Aripiprazole 방사선 유도 Radiation induction 세포고사에On a cell test 미치는 영향 Impact
암세포 내에서 아리피프라졸은 세포고사(apoptosis)를 유도할 수 있다고 최근 보고되었는데, 암세포에서 아리피프라졸이 방사선 유도 세포고사에 미치는 영향을 확인하기 위하여, 암세포 내에서 PARP 절단(cleavage) 및 DNA 단편화(fragmentation) 측정 실험을 하기와 같이 수행하였다.Aripiprazole may induce apoptosis in cancer cells. To determine the effect of aripiprazole on radiation-induced apoptosis in cancer cells, measurement of PARP cleavage and DNA fragmentation in cancer cells The experiment was performed as follows.
MCF-7 세포에 아리피프라졸 (1, 5, 10, 20μM)을 단독처리하거나 방사선과 병용처리하였다. 24시간 후 PBS로 세척한 후 세포로부터 단백질을 추출하여 웨스턴블랏으로 PARP 절단(cleavage) 정도를 확인하였다.Aripiprazole (1, 5, 10, 20 μM) was treated with MCF-7 cells alone or in combination with radiation. After 24 hours, the cells were washed with PBS, and proteins were extracted from the cells. The degree of PARP cleavage was confirmed by Western blot.
도 3에 나타난 바와 같이, 아리피프라졸 단독 처리에 의한 PARP 절단(cleavage) 유도 효과 보다 방사선과 병용하여 처리할 때에 보다 우수한 PARP 절단(cleavage) 유도 효과를 나타내는 것으로 밝혀졌다. 아리피프라졸은 농도 의존적으로 방사선 처리된 암세포에서 세포고사를 유도하는 것으로 밝혀졌다.As shown in FIG. 3, it was found that PARP cleavage induction effect was better when combined with radiation than PARP cleavage induction effect by Aripiprazole alone treatment. Aripiprazole has been shown to induce apoptosis in concentration-dependently treated cancer cells.
MCF-7 세포 또는 U251 세포를 5000 cells/well의 농도로 조절한 후, 96 웰 플레이트에 접종하고 24시간 동안 전배양하였다. 이후 배지를 제거하고 아리피프라졸을 단독처리하거나 방사선과 병용처리하였다. 24시간 후 로슈사의 Cell Death Detection ELISA plus 키트를 이용하여 DNA 단편화(fragmentation) 정도를 확인하였다.MCF-7 cells or U251 cells were adjusted to a concentration of 5000 cells / well, then seeded in 96 well plates and pre-cultured for 24 hours. The medium was then removed and treated with aripiprazole alone or in combination with radiation. After 24 hours, DNA fragmentation was confirmed using Roche's Cell Death Detection ELISA plus kit.
도 4에 나타난 바와 같이, 아리피프라졸과 방사선을 병행하여 처리할 때에 각각의 처리를 더한 효과보다 우수한 DNA 단편화(fragmentation) 유도 효과를 나타내는 것으로 밝혀졌다. 단독 처리에 의한 DNA 단편화(fragmentation) 유도 효과보다 두 개의 처리를 동시 병용하였을 때 보다 우수한 세포고사 유도효과를 나타내는 것으로 밝혀졌다. As shown in FIG. 4, it was found that when the aripiprazole and radiation were treated in parallel, the DNA fragmentation induction effect was superior to that of the treatment. It was found to exhibit better apoptosis induction effect when two treatments were used at the same time than the induction effect of DNA fragmentation by treatment alone.
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| KR1020180051702A KR102008931B1 (en) | 2018-05-04 | 2018-05-04 | Composition for enhancing radiation sensitivity comprising aripiprazole |
| JP2021512344A JP7059444B2 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as an 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 |
| CN201980029987.0A CN112074273B (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition comprising aripiprazole as active ingredient |
| EP19796396.0A EP3789029A4 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as active ingredient |
| US17/050,462 US20210236482A1 (en) | 2018-05-04 | 2019-04-23 | Radiation sensitivity enhancing composition containing aripiprazole as active ingredient |
| EP22176241.2A EP4074315B1 (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 |
| US17/937,778 US20230025625A1 (en) | 2018-05-04 | 2022-10-03 | Radiation sensitivity enhancing comoposition containing aripiprazole as active ingredient |
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| KR102328367B1 (en) | 2019-11-05 | 2021-11-18 | 한국해양과학기술원 | Composition for Enhancing Radiation Sensitivity comprising Ageloxime D |
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