KR102437152B1 - A pharmaceutical composition comprising loganic acid for preventing or treating cognitive impairment related disease - Google Patents
A pharmaceutical composition comprising loganic acid for preventing or treating cognitive impairment related disease Download PDFInfo
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- KR102437152B1 KR102437152B1 KR1020200024697A KR20200024697A KR102437152B1 KR 102437152 B1 KR102437152 B1 KR 102437152B1 KR 1020200024697 A KR1020200024697 A KR 1020200024697A KR 20200024697 A KR20200024697 A KR 20200024697A KR 102437152 B1 KR102437152 B1 KR 102437152B1
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- disease
- cognitive impairment
- preventing
- acid
- pharmaceutical composition
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- 230000001537 neural effect Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000021317 sensory perception Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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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
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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Abstract
본 발명은 초석잠으로부터 분리된 로가닉산을 포함하는 인지장애 관련 질환의 예방 또는 치료용 조성물에 관한 것으로, 상기 화합물은 뇌세포보호 효과가 우수하여 인지장애 관련 질환의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.The present invention relates to a composition for preventing or treating cognitive impairment-related diseases, comprising rorganic acid isolated from Choseokjam, and the compound is useful as a composition for preventing or treating cognitive impairment-related diseases due to its excellent brain cell protection effect. can be used
Description
본 발명은 로가닉산을 포함하는 인지장애 관련 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cognitive impairment-related diseases, including rorganic acid.
뇌는 신경세포가 하나의 큰 덩어리를 이루고 있는 모든 동물의 신경계 최고 중추 기관으로서, 운동기능, 감각정보 처리 기능, 언어 기능, 학습과 기억 기능, 항상성 유지 및 호르몬 분비에 관련한다. 뇌 기능에 이상이 생겨 뇌에서 발생하는 질환으로는 인지장애(cognitive impairment)가 있으며, 주의력 감소, 학습능력의 감소, 기억력 감퇴, 감각인지기능(perception)의 장애 등을 나타낸다. The brain is the highest central organ of the nervous system of all animals, in which nerve cells form a single mass, and is involved in motor functions, sensory information processing functions, language functions, learning and memory functions, homeostasis maintenance, and hormone secretion. Diseases that occur in the brain due to abnormalities in brain function include cognitive impairment, which indicates a decrease in attention, a decrease in learning ability, a decrease in memory, and impairment in sensory perception.
신경퇴행성 질환(neurodegenerative disease)은 나이가 들어감에 따라 발생하는 뇌질환으로 환경적, 유전적 요인의 누적으로 인하여 발병하는 것으로 알려져 있다. 중추 신경계의 신경세포에 점진적이고 꾸준한 사멸로 인한 퇴행성 변화가 나타나면서 여러 가지 증상을 유발하는 질환을 통칭하며, 세포손상과 기억장애를 포함하는 신경구조와 기능의 손실이 특징적이다. 대표적인 예로는, 알츠하이머병(alzheimer's disease), 파킨슨병(parkinson's disease), 헌팅턴병(huntington's disease), 근위축성 축삭경화증(amyotrophic lateral sclerosis) 등을 들 수 있다.Neurodegenerative disease (neurodegenerative disease) is a brain disease that occurs with aging, it is known to occur due to the accumulation of environmental and genetic factors. It is a collective term for a disease that causes various symptoms as degenerative changes due to gradual and steady death occur in nerve cells of the central nervous system, and is characterized by loss of neural structure and function, including cell damage and memory impairment. Representative examples include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
글루타메이트(glutamate)는 중추 신경계에서 신경성 세포 손실을 야기하는 것으로 알려져 있으며, 발작, 알츠하이머병, 파킨슨병, 허혈 및 척수 외상(ischemia and spinal cord trauma) 등의 신경계 질환에 관여될 수 있다. 이와 관련하여, 알츠하이머병 치료제 중 메만틴(memantine)은 흥분성 신경전달물질인 글루타메이트를 차단하는 것으로, 글루타메이트는 뇌의 신경을 과도하게 자극하여 뇌신경세포 내의 지나친 칼슘 유입을 초래해 뇌신경의 손상, 사멸을 일으키는데, 메만틴은 이를 방지하는 것으로 알려져 있다. 그러나, 이러한 화학약제 및 천연 조성물이 시중에 나와 있음에도 불구하고, 아직은 효능이 확실한 우수한 제제가 개발되지 못하고 있는 실정이며, 또한, 시판중인 약제들은 간독성, 불면증, 고혈압, 구토 등의 많은 부작용을 유발하고 있다. 따라서, 다양한 원인에 의해 나타나는 인지장애 관련 질환 및 신경퇴행성 질환에 있어서, 뇌세포 파괴와 노화를 지연시켜 뇌세포를 보호하고 인지기능을 회복시키며 부작용이 적고 질환의 진행 과정을 막아 줄 수 있는 치료제의 개발이 시급한 과제가 되고 있다. Glutamate is known to cause neuronal cell loss in the central nervous system and may be involved in neurological diseases such as seizures, Alzheimer's disease, Parkinson's disease, ischemia and spinal cord trauma. In this regard, memantine among Alzheimer's disease drugs blocks glutamate, an excitatory neurotransmitter, and glutamate overstimulates nerves in the brain and causes excessive calcium influx into cranial nerve cells, thereby preventing damage and death of cranial nerves. Memantine is known to prevent this. However, despite the fact that such chemical agents and natural compositions are available on the market, an excellent formulation with a certain efficacy has not yet been developed, and in addition, commercially available drugs cause many side effects such as hepatotoxicity, insomnia, high blood pressure, and vomiting. have. Therefore, in cognitive disorder-related diseases and neurodegenerative diseases caused by various causes, it is possible to delay brain cell destruction and aging to protect brain cells, restore cognitive function, and have fewer side effects and prevent the progression of diseases. development has become an urgent task.
한편, 인지장애 관련 질환의 예방 또는 치료용 조성물과 관련된 종래 선행문헌으로서, 한국등록특허 제10-2064610호에는 초석잠 소재 및 흑삼 소재를 유효성분으로 함유하는 인지능 개선용 조성물이 개시되었으며, 한국등록특허 제10-0890179호에는 현삼 추출물을 유효성분으로 함유하는 인지기능 장애 관련질환의 예방 및 치료용 조성물이 개시되었고, 한국공개특허 제10-2020-0000048호에는 체불라닌을 포함하는 인지장애 관련 질환의 예방 또는 치료용 조성물이 개시된 바 있다. 그러나 본 발명과 같이 로가닉산의 인지장애 관련 질환의 예방 또는 치료 효과를 확인한 이전 보고는 없다.On the other hand, as a prior art related to a composition for the prevention or treatment of cognitive impairment-related diseases, Korea Patent No. 10-2064610 discloses a composition for improving cognitive ability containing choseokjam and black ginseng as active ingredients. Registered Patent No. 10-0890179 discloses a composition for preventing and treating cognitive dysfunction-related diseases containing ginseng extract as an active ingredient, and Korean Patent Publication No. 10-2020-0000048 discloses cognitive impairment-related diseases containing chebulanin. A composition for preventing or treating a disease has been disclosed. However, as in the present invention, there is no previous report confirming the preventive or therapeutic effect of rorganic acid for cognitive impairment-related diseases.
이에 따라 본 발명자들은 초석잠의 성분을 연구하는 과정에서, 특히 로가닉산의 뇌신경세포 보호효과가 우수함을 확인함으로써 본 발명을 완성할 수 있었다.Accordingly, the present inventors were able to complete the present invention by confirming that, in the course of studying the components of Choseokjam, particularly, the protective effect of rorganic acid on brain nerve cells was excellent.
본 발명의 목적은 초석잠(Stachys sieboldii)으로부터 분리된 로가닉산을 포함하는 인지장애 관련 질환의 예방 또는 치료용 약학 조성물을 제공하는 데 있다.It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cognitive impairment-related diseases comprising rorganic acid isolated from Stachys sieboldii .
본 발명은 로가닉산을 포함하는 인지장애 관련 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cognitive impairment-related diseases, including rorganic acid.
상기 화합물은 당해 기술 분야에서 통상적인 방법에 따라 합성하는 것도 가능하며 약학적으로 허용 가능한 염으로 제조될 수도 있으나, 바람직하게는 초석잠(Stachys sieboldii) 추출물로부터 크로마토그래피로 분획하여 얻는다.The compound may be synthesized according to a conventional method in the art and may be prepared as a pharmaceutically acceptable salt, but is preferably obtained by fractionation by chromatography from an extract of Stachys sieboldii .
상기 초석잠은 꿀풀과(Labiatae) 석잠풀속(Stachys Linne)의 석잠풀(Stachys sieboldii Miq)이 기원식물로, 뿌리 모양이 골뱅이 모양을 닮았다고 하여 골뱅이형 초석잠이라고 불리운다. 꿀풀과 석잠풀속의 식물은 우리나라에서는 우단석잠풀(S. oblongifolia Benth.), 석잠풀(S. sieboldii Miq), 개석잠풀(S. japonica var. hispidula (Hara), 털석잠풀(S.japonica var. villosa (Kudo) Ohwi) 등이 포함된다. The plant is derived from Stachys sieboldii Miq of the family Labiatae, the genus Stachys Linne, and the root shape resembles the shape of a golbaengi, so it is called a golbaengi-type choseokjam. Plants of the genus Lamiaceae are S. oblongifolia Benth., S. sieboldii Miq, S. japonica var. hispidula (Hara), and S. japonica var villosa (Kudo) Ohwi) and others.
상기 초석잠 추출물은 초석잠을 물, C1 내지 C4 알코올 또는 이들의 혼합 용매로 추출한 것이며, 상기 C1 내지 C4의 알코올은 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올 및 이소부탄올로 이루어진 군에서 선택될 수 있다. 보다 바람직하게는 초석잠을 알코올 또는 알코올 수용액으로 추출하고 농축 및 물에 현탁한 다음 에틸아세테이트, n-부탄올, n-헥산으로 이루어진 군에서 선택되는 1종 이상의 용매로 분획한 분획물을 사용한다.The Choseokjam extract is water, C1 to C4 alcohol, or a mixed solvent thereof, and the C1 to C4 alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and isobutanol. . More preferably, a fraction obtained by extraction with alcohol or an aqueous alcohol solution, concentration and suspension in water, and then fractionation with one or more solvents selected from the group consisting of ethyl acetate, n-butanol, and n-hexane is used.
추출시 사용되는 물, C1 내지 C4의 알코올 또는 이들의 혼합용액은 사용되는 초석잠 중량 대비 1~100배 부피를 사용할 수 있으며 상기 과정을 1~5회 반복하는 것도 가능하다.Water, C1 to C4 alcohol, or a mixed solution thereof used for extraction can be used in an amount of 1 to 100 times the weight of choseokjam used, and it is also possible to repeat the above process 1 to 5 times.
상기 추출물의 추출시간은 특별히 제한되는 것은 아니나, 10분 내지 1일 이내에 추출하는 것이 바람직하고, 추출방법은 통상적으로 사용되는 모든 추출방법, 예컨대, 가압 추출, 침지(냉침, 온침), 초음파 추출, 환류 추출법 등을 사용할 수 있으며, 추출용 기기로는 통상의 추출기기, 초음파분쇄추출기 또는 분획기를 이용할 수 있다. The extraction time of the extract is not particularly limited, but extraction is preferably performed within 10 minutes to 1 day, and the extraction method includes all commonly used extraction methods, for example, pressure extraction, immersion (cold-chilling, warm-chilling), ultrasonic extraction, A reflux extraction method, etc. can be used, and as an extraction device, a conventional extraction device, an ultrasonic pulverization extractor, or a fractionator can be used.
또한, 상기 추출물은 상기 추출 과정으로부터 얻은 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함한다.In addition, the extract is formed using the extract itself and the extract, such as an extract obtained from the extraction process, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, a prepared or purified product of the extract, or a mixture thereof. All possible formulations of extracts are included.
상기 크로마토그래피는 실리카겔 컬럼 크로마토그래피(silica gel column chromatography), 플래쉬 컬럼 크로마토그래피(flash column chromatography), 세파덱스 LH-20 컬럼 크로마토그래피(sephadex LH-20 column chromatography), RP-18 컬럼 크로마토그래피(RP-18 column chromatography), 박층 크로마토그래피(thin layer chromatography, TLC), 중압 액체 크로마토그래피(medium pressure liquid chromatography) 및 고성능 액체 크로마토그래피(high performance liquid chromatography, HPLC) 등을 사용할 수 있고 특별히 이에 제한되지 않는다.The chromatography is silica gel column chromatography (silica gel column chromatography), flash column chromatography (flash column chromatography), sephadex LH-20 column chromatography (sephadex LH-20 column chromatography), RP-18 column chromatography (RP) -18 column chromatography), thin layer chromatography (TLC), medium pressure liquid chromatography, and high performance liquid chromatography (HPLC) may be used, but is not particularly limited thereto .
상기 인지장애 관련 질환은 기억력, 공간지각력, 판단력, 집행기능, 언어능력 등의 기능 저하로부터 발생되는 질환을 의미하는 것으로, 바람직하게는 학습장애, 기억력 장애, 건망증, 경도인지장애 또는 신경퇴행성 질환으로 이루어진 군에서 선택되는 질환이고, 상기 신경퇴행성 질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 피크병, 근위축성 축삭경화증 및 크로이츠펠트-야콥병으로 이루어진 군에서 선택되는 질환이다. 그러나 특별히 이에 제한되지 않고 다양한 원인에 기인한 인지장애 관련 질환이라면 모두 포함될 수 있다.The cognitive impairment-related disease refers to a disease resulting from a decrease in functions such as memory, spatial perception, judgment, executive function, and language ability, preferably learning disability, memory impairment, forgetfulness, mild cognitive impairment or neurodegenerative disease. It is a disease selected from the group consisting of, and the neurodegenerative disease is a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis, and Creutzfeldt-Jakob disease. However, it is not particularly limited thereto, and any cognitive impairment-related disease caused by various causes may be included.
본 발명에 따른 약학 조성물은 일반적으로 사용되는 약학적으로 허용 가능한 담체와 함께 적합한 형태로 제형화될 수 있다. "약학적으로 허용 가능"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 또한, 상기 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. In addition, the composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively.
상기 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로즈, 수크로스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아라비아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미결정셀룰로오스, 폴리비닐 피롤리돈, 물, 파라옥시벤조산메틸, 파라옥시벤조산프로필, 탈크, 스테아르산마그네슘 및 광물유를 포함할 수 있으나, 이에 한정되는 것은 아니다. 제제화할 경우에는 보통 사용하는 충진제, 안정화제, 결합제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 미결정셀룰로오스, 수크로스 또는 락토오스, 저치환도히드록시프로필셀룰로오스, 히프로멜로오스 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아르산마그네슘, 탈크 같은 활택제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 유동파라핀 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, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다. 비경구 투여용 제형으로 제제화하기 위하여 상기 화합물 또는 이의 약학적으로 허용되는 염을 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질과 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다.Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. In the case of formulation, it is prepared using diluents or excipients such as fillers, stabilizers, binders, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient, for example, starch, microcrystalline cellulose, sucrose or lactose, to the compound of the present invention; It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used. In order to formulate a formulation for parenteral administration, the compound or a pharmaceutically acceptable salt thereof is sterilized and/or adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other treatments It can be prepared as a solution or suspension by mixing it with water with useful substances, and it can be prepared in ampoules or vial unit dosage form.
본 발명에 개시된 화합물을 유효성분으로 포함하는 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. 투여량은 치료받을 대상의 연령, 성별, 체중, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여시간, 투여경로, 약물의 흡수, 분포 및 배설률, 사용되는 다른 약물의 종류 및 처방자의 판단 등에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The pharmaceutical composition comprising the compound disclosed in the present invention as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes. All modes of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection. The dosage may vary depending on the age, sex, weight, specific disease or pathology to be treated, the severity of the disease or pathology, administration time, administration route, absorption, distribution and excretion rate of the drug, the type of other drugs used and the prescriber's It will depend on judgment, etc. Dosage determination based on these factors is within the level of one of ordinary skill in the art, and dosages generally range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
또 다른 일면에 있어서, 본 발명은 로가닉산을 포함하는 인지장애 관련 질환의 예방 또는 개선용 건강기능식품에 관한 것이다.In another aspect, the present invention relates to a health functional food for preventing or improving cognitive impairment-related diseases, including rorganic acid.
상기 건강기능식품은 유용한 기능성을 가진 원료나 성분을 사용하여 제조 또는 가공한 식품을 지칭하는 것으로, 예를 들어 건강보조식품, 기능성 식품, 영양제, 보조제 등을 모두 포함한다.The health functional food refers to a food manufactured or processed using raw materials or ingredients having useful functionality, and includes, for example, health supplements, functional foods, nutritional supplements, supplements, and the like.
상기 로가닉산은 전체 건강기능식품 총 중량에 대하여 바람직하게는 0.001중량% 내지 50중량%, 더 바람직하게는 0.001중량% 내지 30중량%, 가장 바람직하게는 0.001중량% 내지 10중량%로 하여 첨가될 수 있다.The rorganic acid is preferably added in an amount of 0.001% to 50% by weight, more preferably 0.001% to 30% by weight, and most preferably 0.001% to 10% by weight based on the total weight of the health functional food. can be
본 발명의 건강기능식품은 정제, 캡슐제, 환제 및 액제 등의 형태를 포함하며, 본 발명 로가닉산을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제 등이 있다.The health functional food of the present invention includes the form of tablets, capsules, pills and liquids, and the like, and the food to which rorganic acid of the present invention can be added includes, for example, various foods, beverages, gum, tea, vitamins. combination drugs, etc.
본 발명은 초석잠으로부터 분리된 로가닉산을 포함하는 인지장애 관련 질환의 예방 또는 치료용 조성물에 관한 것으로, 상기 화합물은 뇌세포보호 효과가 우수하여 인지장애 관련 질환의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.The present invention relates to a composition for preventing or treating cognitive impairment-related diseases, comprising rorganic acid isolated from Choseokjam, and the compound is useful as a composition for preventing or treating cognitive impairment-related diseases due to its excellent brain cell protection effect. can be used
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.
<실시예 1. 초석잠으로부터 로가닉산의 분리><Example 1. Separation of Loganic Acid from Choseokjam>
초석잠(Stachys sieboldii)의 건조된 뿌리 2.5kg을 35±3℃에서 에탄올로 3번 환류 추출한 다음 용매를 감압 조건하에서 제거하여 에탄올 추출물(100g)을 얻었다. 상기 에탄올 추출물을 증류수에 현탁하고 에틸아세테이트와 물로 분획하여 각각의 분획물을 얻었다. 상기 분획물 중 초석잠 에틸아세테이트 분획물(7.0g)을 실리카겔 컬럼 크로마토그래피(CH2Cl2:MeOH:H2O, 7:1:0.1→5:1:0.1→3:1:0.1→1:1:0.1→1:2:0.1)하여 15개의 소 분획물(FE1-FE15)을 얻었다. 상기 소 분획물 중 FE7을 RP-18 실리카겔 컬럼 크로마토그래피(MeOH:H2O, 2:1→1:1)하여 하기 화학 구조의 로가닉산(20.0㎎)을 얻었다.2.5 kg of dried roots of Stachys sieboldii were extracted under reflux three times with ethanol at 35±3° C., and then the solvent was removed under reduced pressure to obtain an ethanol extract (100 g). The ethanol extract was suspended in distilled water and fractionated with ethyl acetate and water to obtain each fraction. Among the fractions, the ethylacetate fraction (7.0 g) of choseokjam was subjected to silica gel column chromatography (CH 2 Cl 2 :MeOH:H 2 O, 7:1:0.1→5:1:0.1→3:1:0.1→1:1). :0.1→1:2:0.1) to obtain 15 small fractions (FE1-FE15). FE7 in the small fraction was subjected to RP-18 silica gel column chromatography (MeOH:H 2 O, 2:1→1:1) to obtain rorganic acid (20.0 mg) having the following chemical structure.
1H-NMR (CD3OD, 400 MHz) : δ 5.20 (1H, d, J = 4.3 Hz, H-1), 7.31 (1H, s, H-3), 3.02 (1H, m, H-5), 2.16 (1H, m, H-6a), 1.59 (1H, m, H-6b), 3.92 (1H, m, H-7), 1.79 (1H, m, H-8), 1.95 (1H, m, H-9), 1.01 (3H, d, J = 6.8 Hz, H-10), 4.57 (1H, d, J = 7.9 Hz, H-1´), 3.14 (1H, m, H-2´), 3.56 (1H, m, H-3´), 3.29 (1H, m, H-4´), 3.40 (1H, m, H-5´), 3.83 (1H, m, H-6a´), 3.70 (1H, m, H-6b´); 1 H-NMR (CD 3 OD, 400 MHz): δ 5.20 (1H, d, J = 4.3 Hz, H-1), 7.31 (1H, s, H-3), 3.02 (1H, m, H-5 ), 2.16 (1H, m, H-6a), 1.59 (1H, m, H-6b), 3.92 (1H, m, H-7), 1.79 (1H, m, H-8), 1.95 (1H, m, H-9), 1.01 (3H, d, J = 6.8 Hz, H-10), 4.57 (1H, d, J = 7.9 Hz, H-1′), 3.14 (1H, m, H-2′) ), 3.56 (1H, m, H-3′), 3.29 (1H, m, H-4′), 3.40 (1H, m, H-5′), 3.83 (1H, m, H-6a′), 3.70 (1H, m, H-6b');
13C-NMR (CD3OD, 100 MHz) : δ 97.8 (C-1), 152.4 (C-3), 114.4 (C-4), 32.3 (C-5), 42.8 (C-6), 75.3 (C-7), 42.3 (C-8), 46.7 (C-9), 13.6 (C-10), 171.3 (CO), 100.2 (C-1´), 74.9 (C-2´), 78.2 (C-3´), 71.8 (C-4´), 78.5 (C-5´), 62.9 (C-6´). 13 C-NMR (CD 3 OD, 100 MHz): δ 97.8 (C-1), 152.4 (C-3), 114.4 (C-4), 32.3 (C-5), 42.8 (C-6), 75.3 (C-7), 42.3 (C-8), 46.7 (C-9), 13.6 (C-10), 171.3 (CO), 100.2 (C-1′), 74.9 (C-2′), 78.2 ( C-3′), 71.8 (C-4′), 78.5 (C-5′), 62.9 (C-6′).
<실시예 2. 뇌신경세포 보호 활성 확인> <Example 2. Confirmation of brain nerve cell protective activity>
HT22 세포에서 신경세포 독성을 유도(글루타메이트 처리)하여 세포 생존률을 확인한 실험은 뇌신경보호활성 평가를 위한 in vitro 모델로써 널리 사용되어왔다. 따라서 본 발명 로가닉산의 뇌신경세포 보호 활성을 확인하고자 다음과 같이 실시하였다.The experiment to confirm the cell viability by inducing neuronal toxicity (glutamate treatment) in HT22 cells has been widely used as an in vitro model for the evaluation of neuroprotective activity. Therefore, in order to confirm the brain nerve cell protective activity of the present invention rorganic acid, it was carried out as follows.
HT22 세포를 4.5×104cells/㎖로 96-웰 플레이트에 접종하고, 23시간 동안 배양한 다음 로가닉산을 첨가하였다. 1시간 후 3mM 글루타메이트를 처리하고 24시간 추가 배양함에 따라 신경세포 독성을 유도하여 세포가 사멸되도록 한 후, WST assay로 세포 생존율을 측정하였다. 양성대조군으로는 트롤룩스(trolox)를 사용하였으며, 세포 생존율 측정 결과는 하기 표 1에 나타내었다. HT22 cells were inoculated in a 96-well plate at 4.5×10 4 cells/ml, incubated for 23 hours, and then rorganic acid was added. After 1 hour, 3mM glutamate was treated and the cells were killed by inducing neuronal toxicity by further culturing for 24 hours, and then cell viability was measured by WST assay. As a positive control, trolox was used, and the cell viability measurement results are shown in Table 1 below.
상기 표 1을 살펴보면, 본 발명 화합물은 뇌신경세포 보호 효과가 양성대조군인 트롤룩스에 비해 현저하게 우수하였음을 확인할 수 있었다. Referring to Table 1, it was confirmed that the compound of the present invention had a significantly superior effect on protecting brain neurons compared to the positive control, Trolux.
신경세포가 손상되면 정상적인 뇌기능을 수행할 수 없게 되고, 특히 뇌세포는 다른 세포와는 달리 일단 손상되면 다시 만들어지지 않는다고 알려져 있으므로, 상기와 같은 결과로부터 본 발명 로가닉산은 뇌신경세포 보호 효과가 우수하여 인지장애 관련 질환의 예방 및 치료제로서 유용하게 사용될 수 있음을 알 수 있었다.When nerve cells are damaged, normal brain functions cannot be performed, and in particular, brain cells are known not to be remade once damaged, unlike other cells. It was found that it can be usefully used as a preventive and therapeutic agent for cognitive impairment-related diseases.
<제제예 1. 정제의 제조><Formulation Example 1. Preparation of tablets>
본 발명 로가닉산 20g을 각각 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다. 20 g of loganic acid of the present invention was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid, respectively. After adding a 10% gelatin solution to this mixture, it was ground and passed through a 14 mesh sieve. This was dried, and 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate were added thereto, and the resulting mixture was made into tablets.
<제제예 2. 캡슐제의 제조><Formulation Example 2. Preparation of capsules>
본 발명 로가닉산 100㎎, 옥수수전분 100㎎, 유당 100㎎ 및 스테아린산 마그네슘 2㎎을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing 100 mg of loganic acid of the present invention, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method and filled in a gelatin capsule to prepare a capsule.
<제제예 3. 주사제의 제조><Formulation Example 3. Preparation of Injection>
본 발명 로가닉산 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.1 g of rorganic acid of the present invention, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20° C. for 30 minutes.
Claims (6)
상기 신경퇴행성 질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 피크병, 근위축성 축삭경화증 및 크로이츠펠트-야콥병으로 이루어진 군에서 선택되는 것을 특징으로 하는 인지장애 관련 질환의 예방 또는 치료용 약학 조성물.The method of claim 1,
The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis and Creutzfeldt-Jakob disease.
상기 신경퇴행성 질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 피크병, 근위축성 축삭경화증 및 크로이츠펠트-야콥병으로 이루어진 군에서 선택되는 것을 특징으로 하는 인지장애 관련 질환의 예방 또는 개선용 건강기능식품.5. The method of claim 4,
The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis and Creutzfeldt-Jakob disease.
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