KR20190121569A - Pharmaceutical Composition for Improving Fragile X Syndrome Comprising Agmatine or its derivatives - Google Patents
Pharmaceutical Composition for Improving Fragile X Syndrome Comprising Agmatine or its derivatives Download PDFInfo
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- KR20190121569A KR20190121569A KR1020180045046A KR20180045046A KR20190121569A KR 20190121569 A KR20190121569 A KR 20190121569A KR 1020180045046 A KR1020180045046 A KR 1020180045046A KR 20180045046 A KR20180045046 A KR 20180045046A KR 20190121569 A KR20190121569 A KR 20190121569A
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- South Korea
- Prior art keywords
- agmatine
- syndrome
- fxs
- fragile
- pharmaceutical composition
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Classifications
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- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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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
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
Abstract
Description
본 발명은 아그마틴 (agmatine) 또는 이의 약학적으로 허용 가능한 염을 포함하는 집중력 향상, 인지기능 장애, 사회성과 의사소통 결여, 과잉행동, 반복적인 행동 등과 같은 (정신)신경이상행동에 관한 예방 및 치료용 약학 조성물에 관한 것이다. 보다 구체적으로 본 발명은 취약 X 증후군 (Fragile X Syndrome; FXS)의 원인 유전자인 Fragile X mental retardation protein (FMRP)을 Knock-out한 마우스를 대상으로 아그마틴을 투여한 결과, 상기 FMRP Knock-out에 아그마틴을 투여한 군은 반복행동이상과 사회성 및 인지능 문제점 등이 개선되는 것을 확인하여, 아그마틴이 취약 X 증후군 (Fragile X Syndrome; FXS)를 포함한 정신신경질환에 있어 효과적으로 예방 또는 치료할 수 있음을 확인하였다. The present invention relates to the prevention and prevention of (mental) neurological abnormalities such as concentration improvement, cognitive impairment, lack of social and communication, hyperactivity, repetitive behavior, and the like, including agmatine or a pharmaceutically acceptable salt thereof. It relates to a therapeutic pharmaceutical composition. More specifically, the present invention is a result of administering agmatine to mice knocked out of Fragile X mental retardation protein (FMRP), which is the cause gene of Fragile X Syndrome (FXS), to the FMRP knock-out. Agmatine group was found to improve repetitive behavioral problems and social and cognitive problems, and can effectively prevent or treat agmatine in mental neurological diseases including Fragile X Syndrome (FXS). It was confirmed.
취약 X 증후군 (Fragile X Syndrome; FXS)은 Fragile X mental retardation protein (FMRP)의 발현이 나타나지 않아 발병하는 유전질환으로써, 학습과 기억을 비롯한 인지능력 저하, 사회성 문제, 의사소통의 어려움, 과잉행동 등과 같은 다양한 신경행동학적 증상과 신체적 기형 등을 특징으로 한다. 특히, X 유전자에 위치하고 있어 성별 간 유병률에 있어 큰 차이를 나타난다(남자의 경우, 2-3배 높은 유병률). 상기 자폐성 범주의 질환(자폐성, 아스퍼거 증후군, 아동기 붕괴성 장애 및 전반적 발달장애)은 질병분류코드의 F에 해당하는 정신 및 행동 장애인 반면에, FXS는 질병분류코드의 Q에 해당하는 유전자 X염색체의 장완(long arm) 말단부위가 끊어져서 생기는 선천 기형, 변형 및 염색체이상의 질환으로, FXS는 자폐성 범주의 질환(자폐성, 아스퍼거 증후군, 아동기 붕괴성 장애 및 전반적 발달장애)와는 전혀 다른 질병이다. 그러나, FXS는 전세계적으로 유병률이 증가하고 있는 발달장애의 일종인 자폐증이나 ADHD, 조현병 등의 정신신경질환에서 나타나는 이상행동들과 동반질병 (comorbidity)을 보인다. 따라서 FXS의 예방 및 치료에 적응 가능한 기능성 물질 혹은 약물, 식품 등의 개발에 대한 요구가 증대되고 있는 실정이다. Fragile X Syndrome (FXS) is a hereditary disease caused by the absence of the expression of Fragile X mental retardation protein (FMRP) .Fragile X Syndrome (FXS) is a disorder of cognitive ability including learning and memory, social problems, communication difficulties, and hyperactivity. It is characterized by various neurobehavioral symptoms and physical malformations. In particular, because it is located in the X gene, there is a big difference in the prevalence between genders (2-3 times higher prevalence in men). Diseases of the autism category (autism, Asperger's syndrome, childhood disruptive disorders and general developmental disorders) are mental and behavioral disorders corresponding to F of the disease classification code, whereas FXS represents the gene X chromosome corresponding to Q of the disease classification code. Congenital malformations, deformities and chromosomal aberrations caused by breaking of the long arm distal end. FXS is a completely different disease from the autistic category of disorders (autism, Asperger's syndrome, childhood decay and overall developmental disability). However, FXS shows comorbidity and abnormal behaviors that occur in mental disorders such as autism, ADHD, and schizophrenia, which are a type of developmental disorder that is increasing worldwide. Therefore, there is an increasing demand for the development of functional substances, drugs, and foods that are adaptable to the prevention and treatment of FXS.
FXS는 생후 3년 이내에 발병하는 발달장애의 일종으로 과잉행동, 학습과 기억의 어려움, 충동성, 사회성이나 의사소통의 어려움 등의 다양한 대뇌 및 해마 기능의 장애가 보고되어 있다. 어린 나이에 발병해 성인에 이르기까지 증상이 지속되기에 환자 뿐 아니라 사회 전반적으로 치료와 시간 등에 있어 사회비용이 큰 편이다. FXS의 발병기전은 다른 신경질환에 비해 비교적 잘 알려져 있지만, 현재까지 승인되어 사용되는 치료제는 아직 개발되어 있지 않다. 중추신경계의 mGluR 신호전달 및 기능의 과활성이 공통적으로 나타나기에, 그 치료를 위해서는 이의 길항제를 투여하거나 GABAergic 신호의 기능 항진제를 투여하여 뇌의 E/I balance를 맞춰주는 치료방법이 널리 사용되어 왔다. 대표적인 약물로는 AFQ056(mGluR5 antagonist), sertraline (SSRI), aripiprazole, arbaclofen(GABAB agonist) 등이다. 이들은 모두 병의 진행을 늦출 뿐 직접적인 치료에는 별 효과가 없고 또한 발병 초기에 제한된 치료 범위를 가지고 있기 때문에 FXS의 근본적인 원인을 치료하는 약을 개발하고자 하는 노력이 이루어져 왔다(Drugs. 2016 Mar;76(4):431; Dev Neurobiol. 2016 Jul 13. doi: 10.1002/dneu.22419; Neuropsychopharmacology. 2016 Nov 9. doi: 10.1038/npp.2016.237; J Dev Behav Pediatr. 2016 Oct;37(8):619). FXS is a type of developmental disorder that develops within three years of life and has been reported to have various cerebral and hippocampal dysfunctions, including hyperactivity, difficulty learning and memory, impulsivity, and social or communication difficulties. Symptoms persist at an early age and continue to adulthood, resulting in high social costs not only for patients but also for the treatment and time of society as a whole. The pathogenesis of FXS is relatively well known compared to other neurological diseases, but therapies currently approved and used have not been developed. Since mGluR signaling and functional overactivity of the central nervous system are common, the treatment method that adjusts the brain's E / I balance by administering its antagonist or GABAergic signal dysfunction has been widely used. . Representative drugs include AFQ056 (mGluR5 antagonist), sertraline (SSRI), aripiprazole, arbaclofen (GABA B agonist). All of these have slowed disease progression, have little effect on direct treatment, and have a limited range of treatment at the outset, and efforts have been made to develop drugs to treat the underlying cause of FXS (Drugs. 2016 Mar; 76 ( 4): 431; Dev Neurobiol. 2016 Jul 13. doi: 10.1002 / dneu.22419; Neuropsychopharmacology. 2016 Nov 9. doi: 10.1038 / npp.2016.237; J Dev Behav Pediatr. 2016 Oct; 37 (8): 619).
본 발명의 아그마틴(Agmatine)은 NMDA receptor blocker로 보고되어 있으며, L-arginine decarboxylation 으로 형성되는 내인성 생체 아민이다. 아그마틴(Agmatine)은 신경보호 기능과 신경전달물질, 신경조절물질로서의 작용을 담당할 수 있음이 발표되어있다. 이에, 본 발명자들은 FXS와 같은 정신신경질환을 예방 또는 치료하고 학습능력이나 사회성을 증진시킬 수 있는 효과적인 치료제를 개발하기 위하여 연구하던 중, 기억 및 인지능력을 효과적으로 증진시키고 사회성을 향상시킬 수 있으며, 충동성과 과잉행동을 완화시킬 수 있는 유효 성분을 발견하고 본 발명을 완성하였다. Agmatine of the present invention is reported as an NMDA receptor blocker and is an endogenous bioamine formed by L-arginine decarboxylation. Agmatine is reported to be responsible for neuroprotective functions, neurotransmitters and neuromodulators. Accordingly, the present inventors can effectively improve memory and cognitive ability and improve sociality while researching to develop an effective therapeutic agent that can prevent or treat mental neurological diseases such as FXS and improve learning ability or sociality. The present invention was completed by finding an active ingredient that can alleviate impulsiveness and hyperactivity.
본 발명의 목적은 아그마틴 또는 이의 약학적으로 허용되는 염을 유효성분으로 함유하는 취약 X 증후군 (Fragile X Syndrome; FXS) 또는 이와 관련된 질병의 예방 또는 치료용 약학조성물을 제공하는 것이다. An object of the present invention is to provide a pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) or related diseases containing Agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 아그마틴 또는 이의 약학적으로 허용되는 염을 유효성분으로 함유하는 취약 X 증후군 (Fragile X Syndrome; FXS) 또는 이와 관련된 질병의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다. Still another object of the present invention is to provide a nutraceutical composition for the prevention or improvement of Fragile X Syndrome (FXS) or related diseases containing Agmatine or a pharmaceutically acceptable salt thereof as an active ingredient. .
본 발명은 아그마틴 또는 이의 약학적으로 허용되는 염을 유효성분으로 함유하는 취약 X 증후군 (Fragile X Syndrome; FXS) 또는 이와 관련된 질병의 예방 또는 치료용 약학조성물에 대한 것이다. The present invention relates to a pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) or a related disease containing Agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.
아그마틴은 하기 화학식 1로 표시되는 화합물이다. Agmatine is a compound represented by the following formula (1).
[화학식 1][Formula 1]
상기 아그마틴은 하기 화학식 2과 같은 이의 유도체를 포함할 수 있다.The agmatine may include a derivative thereof, such as the following Formula 2.
[화학식 2] [Formula 2]
상기 R1, R2, R3은 각각 독립적으로 수소 또는 할로겐 원자 또는 치환되거나 치환되지 않은 알킬, 알콕시, 알케닐, 알키닐, 알카디에닐, 아릴, 아릴옥시, 헤테로아릴, 사이클로알킬, 사이클로알케닐, 비사이클로알킬 또는 헤테로사이클릴 그룹을 나타낸다.R 1 , R 2 and R 3 are each independently hydrogen or a halogen atom or substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, alkadienyl, aryl, aryloxy, heteroaryl, cycloalkyl, cycloal A kenyl, bicycloalkyl or heterocyclyl group.
상기 화학식으로 표시되는 아그마틴 또는 이의 약학적으로 허용되는 염은 취약 X 증후군 (Fragile X Syndrome; FXS)에서 취약 X 증후군 (Fragile X Syndrome; FXS)에서 나타내는 반복행동증상, 과잉행동 증상, 사회성 결여 증상, 학습능력감소 또는 선행자극 억제의 감소 증상을 예방 또는 치료할 수 있다. 보다 구체적으로, 상기 화학식으로 표시되는 아그마틴 및 이의 약학적으로 혀용되는 염은 반복행동을 감소시키고, 과잉행동을 억제시키며, 사회성과 학습 능력을 향상시키고 선행자극억제를 증가시켜 취약 X 증후군 (Fragile X Syndrome; FXS) 또는 이와 관련된 질병의 예방 또는 치료할 수 있다. 또한, 본 발명의 상기 화학식으로 표시되는 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물은 독성 및 부작용이 없으므로 예방 또는 치료 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다. Agmatine or a pharmaceutically acceptable salt thereof represented by the above formula is a symptom of repetitive behavior, hyperactivity, and social deficiency in Fragile X Syndrome (FXS) in Fragile X Syndrome (FXS). This can prevent or treat symptoms of decreased learning ability, or decreased pre-stimulation. More specifically, Agmatine and its pharmaceutically acceptable salts represented by the above formula decreases repetitive behavior, suppresses hyperactivity, improves social and learning ability, and increases pre-stimulation inhibition, thereby fragile X syndrome (Fragile). X Syndrome (FXS) or related diseases can be prevented or treated. In addition, the pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof represented by the above formula of the present invention has no toxicity and side effects, and thus can be used safely for long-term administration for prophylactic or therapeutic purposes.
본 발명의 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학적 조성물에 있어 상기 아그마틴 또는 이의 약학적으로 허용되는 염은 약 성인 1일 1 mg 내지 1 g의 용량으로 단 회 내지 수 회 투여가 가능하며, 바람직하게는 30 mg 내지 120 mg의 용량으로 단 회 내지 수 회 투여가 가능하다. 그러나 상기 아그마틴 또는 이의 약학적으로 허용되는 염의 투여량은 환자의 중증, 나이, 성별, 체중 등의 환자의 상태와 약물의 제형, 투여경로 및 투여 기간에 따라 적절하게 조절가능하다. In the pharmaceutical composition comprising the agmatine or a pharmaceutically acceptable salt thereof of the present invention, the agmatine or a pharmaceutically acceptable salt thereof is used once or several times at a dose of 1 mg to 1 g per adult. Administration is possible, preferably from single to several dosages of 30 mg to 120 mg. However, the dosage of the agmatine or a pharmaceutically acceptable salt thereof may be appropriately adjusted according to the patient's condition such as the severity, age, sex, and weight of the patient and the formulation, route of administration, and duration of administration of the drug.
본 발명의 약학 조성물은 상기 유효물질을 조성물 총 중량에 대하여 0.1 내지 50중량%로 포함할 수 있다. 그러나 상기 함유량은 반드시 이에 한정되는 것은 아니고 환자의 상태 및 질환의 종류 및 진행 정도에 따라 변할 수 있다.The pharmaceutical composition of the present invention may include 0.1 to 50% by weight of the active substance based on the total weight of the composition. However, the content is not necessarily limited thereto, and may vary depending on the condition of the patient and the type and extent of the disease.
상기 취약 X 증후군 (Fragile X Syndrome; FXS) 관련된 질병은 자폐 범주성 질병일 수 있으며, 상기 자폐 범주성 질병은 자폐증, 아스퍼거 증후군, 아동기 붕괴성 장애 및 전반적 발달장애(PDD-NOS)일 수 있다. The Fragile X Syndrome (FXS) related disease may be autism categorical disease, and the autism categorical disease may be autism, Asperger's syndrome, childhood disruptive disorder and general developmental disability (PDD-NOS).
본 발명의 유효성분을 포함하는 취약 X 증후군 (Fragile X Syndrome; FXS) 관련된 질병의 예방 또는 치료용 약학 조성물에 있어 상기 유효물질은 약 성인 1일 1 mg 내지 1 g의 용량으로 단 회 내지 수 회 투여가 가능하며, 바람직하게는 30 mg 내지 120 mg의 용량으로 단 회 내지 수 회 투여가 가능하다. 그러나 상기 약물의 투여량은 환자의 중증, 나이, 성별, 체중 등의 환자의 상태와 약물의 제형, 투여경로 및 투여 기간에 따라 적절하게 조절될 수 있다. In the pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) -related diseases comprising the active ingredient of the present invention, the active substance is used once or several times at a dose of 1 mg to 1 g per adult. Administration is possible, preferably from single to several dosages of 30 mg to 120 mg. However, the dosage of the drug may be appropriately adjusted according to the patient's condition such as the patient's severity, age, sex, and weight, and the formulation, route of administration, and duration of administration of the drug.
본 발명에 따른 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물은 집중력의 저하, 충동성 및 사회성 등의 증상을 보이는 정신신경질환을 예방 또는 치료하기 위하여 단독 또는 호르몬 치료, 약물 치료 등의 다양한 방법들과 병용하여 사용될 수 있다. The pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof according to the present invention may be used alone or in hormonal therapy, drug therapy, or the like to prevent or treat mental neurological disorders such as decreased concentration, impulsivity and social symptoms. It can be used in combination with various methods.
본 발명의 상기 화학식 1로 표시되는 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물은 본 발명의 효과를 해치치 않는 범위 안에서 약학적으로 허용 가능한 희석제, 결합제, 붕해제, 윤활제, pH 조절제, 산화방지제, 용해 보조제 등의 첨가제를 포함할 수 있다. 희석제는 슈가, 전분, 미결정셀룰로오스, 유당(유당수화물), 포도당, 디-만니톨, 알기네이트, 알칼리토금속류염, 클레이, 폴리에틸렌글리콜, 무수인산수소칼슘, 또는 이들의 혼합물 등을 사용할 수 있으며; 결합제는 전분, 미결정셀룰로오스, 고분산성 실리카, 만니톨, 디-만니톨, 자당, 유당수화물, 폴리에틸렌글리콜, 폴리비닐피롤리돈(포비돈), 폴리비닐피롤리돈 공중합체(코포비돈), 히프로멜로오스, 히드록시프로필셀룰로오스, 천연검, 합성검, 코포비돈, 젤라틴, 또는 이들의 혼합물 등을 사용할 수 있다. 붕해제는 전분글리콘산나트륨, 옥수수전분, 감자전분 또는 전호화전분 등의 전분 또는 변성전분; 벤토나이트, 몬모릴로나이트, 또는 비검(veegum) 등의 클레이; 미결정셀룰로오스, 히드록시프로필셀룰로오스 또는 카르복시메틸셀룰로오스 등의 셀룰로오스류; 알긴산나트륨 또는 알긴산 등의 알긴류; 크로스카멜로스(croscarmellose)나트륨 등의 가교 셀룰로오스류; 구아검, 잔탄검 등의 검류; 가교 폴리비닐피롤리돈(crospovidone) 등의 가교 중합체; 중탄산나트륨, 시트르산 등의 비등성 제제, 또는 이들의 혼합물을 사용할 수 있다. 윤활제는 탈크, 스테아린산, 스테아린산 마그네슘, 스테아린산 칼슘, 라우릴설페이트나트륨, 수소화식물성오일, 나트륨벤조에이트, 나트륨스테아릴푸마레이트, 글리세릴 베헤네이트, 글리세릴 모노레이트, 글리세릴모노스테아레이트, 글리세릴 팔미토스테아레이트, 콜로이드성 이산화규소 또는 이들의 혼합물 등을 사용할 수 있다. pH 조절제는 초산, 아디프산, 아스코르빈산, 아스코르빈산 나트륨, 에테르산 나트륨, 사과산, 숙신산, 주석산, 푸마르산, 구연산(시트르산)과 같은 산성화제와 침강 탄산 칼슘, 암모니아수, 메글루민, 탄산 나트륨, 산화 마그네슘, 탄산 마그네슘, 구연산 나트륨, 삼염기칼슘인산염과 같은 염기성화제 등을 사용할 수 있다. 산화방지제는 디부틸 히드록시 톨루엔, 부틸레이티드 히드록시아니솔, 초산 토코페롤, 토코페롤, 프로필 갈레이트, 아황산수소나트륨, 피로아황산나트륨 등을 사용할 수 있다.본 발명의 선방출성 구획에서, 용해보조제는 라우릴황산나트륨, 폴리소르베이트 등의 폴리옥시에틸렌 소르비탄 지방산 에스테류, 도큐세이트 나트륨, 폴록사머(poloxamer) 등을 사용할 수 있다. A pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof represented by Chemical Formula 1 of the present invention is a pharmaceutically acceptable diluent, binder, disintegrant, lubricant, pH within a range that does not impair the effects of the present invention. Additives such as modifiers, antioxidants, dissolution aids, and the like. The diluent may be sugar, starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof; Binders, starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose , Hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof. The disintegrating agent may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used. Lubricants include talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, mixtures thereof, and the like. pH adjusters include acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, ammonia water, meglumine, carbonate Basic agents, such as sodium, magnesium oxide, magnesium carbonate, sodium citrate, and calcium tribasic phosphate, etc. can be used. The antioxidant may be dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, etc. In the pre-release compartment of the present invention, dissolution aids Polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, sodium docusate, poloxamer and the like.
본 발명의 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학적 조성물은 경구투여를 위하여 정제, 환제, 산제, 과립제, 캡슐제 등의 고형제제로 제제화될 수 있으며, 이러한 고형제제는 상기 아그마틴 함유 화합물과 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 제조될 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 함께 사용될 수 있다. 또한 상기 약학 조성물이 경구를 위한 현탁제, 내용액제, 유제, 시럽제 등의 액상제제로 제제화될 수 있으며, 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 사용하여 액상제제로 제제화될 수 있다.The pharmaceutical composition comprising the agmatine of the present invention or a pharmaceutically acceptable salt thereof may be formulated into solid preparations such as tablets, pills, powders, granules, capsules, or the like for oral administration, and such solid preparations may be It may be prepared by mixing a martin-containing compound with at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc may also be used. In addition, the pharmaceutical composition may be formulated as a liquid preparation such as oral suspensions, liquid solutions, emulsions, and syrups, and in addition to water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be used. It may be formulated as a liquid formulation.
본 발명의 Agmatine 및 그 유도체 또는 이를 포함하는 약학 조성물은 비경구 투여를 위한 제제화를 위하여 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함할 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Agmatine and its derivatives or pharmaceutical compositions comprising the same of the present invention may contain sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories for formulation for parenteral administration. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명에서 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 FXS와 같은 일종의 발달장애나 정신신경질환 등에 있어 예방 및 치료용 조성물을 도입하는 것을 의미하며, 본 발명의 학습능력 및 사회성 향상 및 발달장애나 정신신경질환 예방 및 치료용 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 경구 투여, 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피 내 투여, 비 내 투여, 폐내 투여, 직장 내 투여, 강 내 투여, 복강 내 투여, 경막 내 투여될 수 있으나, 이에 제한되지는 않는다. 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 (intracerebroventricular) 주사에 의해 투여될 수 있다. In the present invention, the term "administration" means introducing a composition for prevention and treatment in a kind of developmental disorder or mental neurological disease such as FXS of the present invention to the patient by any suitable method, and improve the learning ability and sociality of the present invention. And the route of administration of the composition for the prevention and treatment of developmental disorders or mental neurological diseases can be administered through any general route as long as the target tissue can be reached. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, pulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intradural administration, but not limited thereto. It doesn't work. For example, it can be administered by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명은 아그마틴 또는 이의 약학적으로 허용되는 염을 유효성분으로 함유하는 취약 X 증후군 (Fragile X Syndrome; FXS) 또는 이와 관련된 질병의 예방 또는 개선용 건강기능식품조성물을 제공할 수 있다. The present invention can provide a nutraceutical composition for the prevention or amelioration of fragile X syndrome (Fragile X Syndrome; FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화학식으로 표시되는 아그마틴 또는 이의 약학적으로 허용되는 염은 취약 X 증후군 (Fragile X Syndrome; FXS)에서 나타내는 반복행동증상, 과잉행동 증상, 사회성 결여 증상, 학습능력감소 또는 선행자극 억제의 감소 증상을 예방 또는 개선할 수 있다. 구체적으로, 상기 화학식으로 표시되는 아그마틴 및 이의 약학적으로 허용되는 염은 반복행동을 감소시키고, 과잉행동을 억제시키며, 사회성과 학습 능력을 향상시키고 선행자극억제를 증가시켜 취약 X 증후군 (Fragile X Syndrome; FXS) 또는 이와 관련된 질병의 예방 또는 개선할 수 있다. 본 발명의 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학조성물은 마우스의 이상행동을 특별한 부작용 없이 효과적으로 치료하고 향상시킬 수 있다. Agmatine represented by the above formula or a pharmaceutically acceptable salt thereof is a symptom of repetitive behavior, hyperactivity, social deficiency, decreased learning ability or suppression of pro-stimulation in Fragile X Syndrome (FXS). Can be prevented or improved. Specifically, Agmatine and its pharmaceutically acceptable salts represented by the above formulas reduce fragile behavior, inhibit hyperactivity, improve social and learning ability, and increase pre-stimulation inhibition, thereby fragile X syndrome. Syndrome (FXS) or related diseases can be prevented or ameliorated. The pharmaceutical composition comprising the agmatine or a pharmaceutically acceptable salt thereof of the present invention can effectively treat and improve the abnormal behavior of mice without any special side effects.
상기 취약 X 증후군 (Fragile X Syndrome; FXS) 관련된 질병은 자폐 범주성 질병일 수 있고, 상기 자폐 범주성 질병은 자폐증, 아스퍼거 증후군, 아동기 붕괴성 장애 및 전반적 발달장애(PDD-NOS)일 수 있다. The Fragile X Syndrome (FXS) related disease may be autism categorical disease, and the autism categorical disease may be autism, Asperger's syndrome, childhood disruptive disorder and general developmental disability (PDD-NOS).
본 발명은 상기 화학식으로 표시되는 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물은 집중력 저하, 충동성 및 사회성 등의 증상을 보이는 정신신경질환을 예방 또는 개선용 식품 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof, represented by the above formula, relates to a food composition for preventing or improving a mental neurological disease exhibiting symptoms such as decreased concentration, impulsiveness and sociality.
본 발명에 따른 상기 식품 조성물은 식품 조성물, 건강기능식품 또는 음료에 통상적으로 첨가제 등을 더 포함할 수 있다. 예를 들면, 본 발명의 식품 조성물은 백당, 결정과당, 포도당, D-솔비톨, 만니톨, 이소말토올리고당, 스테비오사이드, 아스파탐, 아세설팜칼륨, 수크랄로오스 등의 감미제, 무수구연산, DL-사과산, 호박산 및 그의 염 등의 산미제, 안식향산 및 그의 유도체 등의 보존제, 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 또한, 본 발명의 식품 조성물들은 천연 과일 쥬스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 첨가제의 비율은 본 발명의 식품 조성물 100 중량부 당 약 20 중량부 이하의 범위에서 사용될 수 있다. 본 발명의 식품 조성물이 음료인 경우, 음료에 통상적으로 포함되는 향미제 또는 천연 탄수화물을 더 포함할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토오스, 슈크로스와 같은 디사카라이드, 덱스트린, 시크롤덱스크린과 같은 폴리사카라이드 또는 자일리톨, 소르비톨, 에리쓰리톨과 같은 당 알콜일 수 있다. 또한, 상기 향미제로는 타우마틴, 스테비아 추출물(레바우디오시드 A, 글리시르히진 등)의 천연 향미제 또는 사카린, 아스파탐 등의 합성 향미제일 수 있다. 상기 식품 조성물이 음료인 경우 천연 탄수화물은 조성물 100 ml 당 일반적으로 약 1 g 내지 20 g, 바람직하게는 약 5 g 내지 12g 포함될 수 있다. 본 발명의 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 식품 조성물은 분말, 과립, 정제, 캡슐 또는 음료인 형태로 제조되어 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류로 이용될 수 있다. 본 발명의 아그마틴 또는 이의 약학적으로 허용되는 염을 포함하는 조성물은 학습능력 향상 및 과잉행동이나 사회적 의사소통 문제점 등을 예방 또는 개선하기 위한 약제, 식품 및 음료 등에 첨가될 수 있다. 예를 들면, 본 발명의 Agmatine 및 그 유도체 또는 이를 포함하는 조성물은 식품, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등에 첨가될 수 있다. 본 발명의 조성물은 식품 전체 중량의 1 중량% 내지 5 중량%로 첨가될 수 있으며, 음료 100 ml에 0.02 g 내지 10 g, 바람직하게는 0.3 g 내지 1 g의 비율로 첨가될 수 있다. The food composition according to the present invention may further include additives, such as food composition, health functional food or beverages. For example, the food composition of the present invention is a sweetener such as white sugar, fructose, glucose, D-sorbitol, mannitol, isomaltoligosaccharide, stevioside, aspartame, acesulfame potassium, sucralose, citric anhydride, DL- Preservatives such as malic acid, succinic acid and salts thereof, preservatives such as benzoic acid and derivatives thereof, various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, such as colorants and neutralizing agents (cheese, chocolate) Etc.), and the salts of pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonated drinks used in carbonated beverages and the like. In addition, the food compositions of the present invention may contain pulp for the production of natural fruit juices and vegetable drinks. The proportion of such additives may be used in the range of about 20 parts by weight or less per 100 parts by weight of the food composition of the present invention. When the food composition of the present invention is a beverage, it may further include a flavor or natural carbohydrate that is commonly included in the beverage. The natural carbohydrate may be a monosaccharide such as glucose, fructose, a disaccharide such as maltose, sucrose, a polysaccharide such as dextrin, a cyclodexscreen or a sugar alcohol such as xylitol, sorbitol, erythritol. In addition, the flavourant may be a natural flavourant such as taumartin, stevia extract (rebaudioside A, glycyrzin, etc.) or synthetic flavors such as saccharin and aspartame. When the food composition is a beverage, natural carbohydrates may generally comprise about 1 g to 20 g, preferably about 5 g to 12 g per 100 ml of the composition. The food composition comprising the agmatine or a pharmaceutically acceptable salt thereof of the present invention is prepared in the form of a powder, granule, tablet, capsule or beverage to be used as foods, beverages, gums, teas, vitamin complexes, dietary supplements Can be. The composition containing the agmatine or a pharmaceutically acceptable salt thereof of the present invention may be added to drugs, foods and beverages for improving or improving learning ability and preventing or improving problems such as excessive behavior or social communication. For example, Agmatine of the present invention and its derivatives or compositions comprising the same may be added to foods, beverages, gums, teas, vitamin complexes, dietary supplements, and the like. The composition of the present invention may be added in an amount of 1% to 5% by weight of the total weight of the food, and may be added to 100 ml of the beverage at a ratio of 0.02 g to 10 g, preferably 0.3 g to 1 g.
본 발명에 따른 agmatine 및 그 유도체 혹은 상기 화합물의 일부를 포함하는 약학조성물은 집중력 향상, 인지기능 장애, 사회성과 의사소통, 반복적인 행동 등과 같은 (정신)신경이상행동 및 질환을 효과적으로 예방 및 치료할 수 있다. 구체적으로, 본 발명에 따른 아그마틴 또는 이의 약학적으로 허용 가능한 염을 포함하는 약학조성물은 반복행동이상과 사회성 및 인지능 문제점 등을 개선시켜 취약 X 증후군 (Fragile X Syndrome; FXS)을 효과적으로 예방 및 치료할 수 있다. The pharmaceutical composition comprising agmatine and its derivatives or a part of the compound according to the present invention can effectively prevent and treat (psychiatric) neuropathy and diseases such as concentration improvement, cognitive impairment, social and communication, repetitive behavior, etc. have. Specifically, the pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof according to the present invention effectively prevents fragile X syndrome (FXS) by improving repetitive behavior abnormalities and social and cognitive problems. It can be cured.
도 1은 본 발명의 Agmatine의 구조식을 보여준다.
도 2는 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 반복행동 내지 충동성을 완화시켜주는 효과를 나타내는 도이다.
도 3은 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 과잉행동에 유효함을 시사하는 도이다.
도 4는 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 사회성 및 인지 기억 향상 효과를 보여주는 결과로서, 빈 공간과 동 종의 동물에 대한 탐색시간을 나타내었으며 그에 따른 “사회성 지표”(동물/빈 공간에 머무르는 시간)을 산출한 결과이다.
도 5는 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 사회성 및 인지 기억 향상 효과를 보여주는 결과로서, 친숙한 동물과 낯선 동물에서의 탐색시간을 표시한 결과이며, 그에 따른 “사회인지능 내지는 선호도 지표”(낯선 동물/친한 동물의 탐색시간)을 산출한 결과이다.
도 6 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 학습 및 기억 향상 효과를 나타내는 결과로서, 타겟 지점을 기억해 들어가기까지 걸린 시간(Latency)을 표시하여 기억의 학습기간에 미치는 영향을 정리한 결과이다.
도 7은 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 학습 및 기억 향상 효과를 나타내는 결과로서, 기억이 형성된 이후, 90초간 시험동물의 공간기억능을 평가한 지표로, 전체 사 사분면 중 타겟 지점에 머무르는 시간을 정리한 결과이다.
도 8은 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 선행자극억제 효과를 보여주는 도이다.
도 9는 본 발명에 따른 아그마틴을 포함하는 약학 조성물의 (사회적) 의사소통에 개선효과를 나타내는 도이다. Figure 1 shows the structural formula of Agmatine of the present invention.
Figure 2 is a view showing the effect of reducing the repetitive behavior to impulse of the pharmaceutical composition comprising agmatine according to the present invention.
Figure 3 suggests that it is effective in the excessive action of the pharmaceutical composition comprising agmatine according to the present invention.
4 is a result showing the social and cognitive memory improving effect of the pharmaceutical composition containing agmatine according to the present invention, showing the search time for the animal of the same space and the same species and accordingly "social indicator" (animal / bin) Time spent in space).
5 is a result showing the social and cognitive memory improving effect of the pharmaceutical composition containing agmatine according to the present invention, it is a result showing the search time in familiar animals and strangers, according to "social cognition or preference indicators" It is the result of (Searching time of unfamiliar / friendly animal).
6 is a result showing the learning and memory improving effect of the pharmaceutical composition comprising agmatine according to the present invention, it is a result of summarizing the effect on the learning period of memory by displaying the time (Latency) to remember the target point .
Figure 7 is a result showing the learning and memory improvement effect of the pharmaceutical composition comprising agmatine according to the present invention, the index for evaluating the spatial memory capacity of the test animal for 90 seconds after the memory is formed, the target point of the four quadrants This is the result of staying in time.
Figure 8 is a view showing the effect of pre-stimulation of the pharmaceutical composition comprising agmatine according to the present invention.
9 is a view showing an improvement effect on the (social) communication of the pharmaceutical composition comprising agmatine according to the present invention.
하기 제조예 및 실험예는 본 발명을 보다 구체적으로 설명하고자 한다. 이들 제조예 및 실험예는 본 발명을 설명하기 위한 것일 뿐, 본 발명의 범위가 하기 제조예 및 실험예에 의해 한정되는 것은 아니다. 또한, 이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma사로부터 구입한 것이다. The following Preparation Examples and Experimental Examples are intended to explain the present invention in more detail. These preparation examples and experimental examples are only for illustrating the present invention, the scope of the present invention is not limited by the following preparation examples and experimental examples. In addition, the reagents and solvents mentioned below were purchased from Sigma unless otherwise stated.
실험예: Agmatine의 신경약리효능 확인Experimental Example: Confirmation of Neuropharmacological Effects of Agmatine
아그마틴을 포함하는 약물의 FXS를 포함하는 정신신경질환의 치료효능을 확인하기 위하여 FMRP 단백질이 결핍된 유전형질전환 동물 (Fmr1 KO mouse)를 사용하여, 하기의 실험들을 수행하였으며, 구체적인 실험방법과 결과는 아래와 같다. The following experiments were carried out using a genetically transgenic animal (Fmr1 KO mouse) deficient in FMRP protein to confirm the therapeutic efficacy of FXS-containing psychoactive neuropathy-containing drugs. The result is shown below.
준비예 1 실험동물의 준비Preparation Example 1 Preparation of Experiment Animal
약 26g 내지 28g의 6-9주령 FVB계 Fmr1 KO mouse(Jackson Laboratory, 미국)를 물과 사료를 자유롭게 섭취하도록 하면서 온도 약 23± 2℃, 습도 약 55± 10% 및 명암주기가 12시간인 환경 하에서 적응시켜 사육(경희대학교 약학대학의 동물 실험실)한 후 실험에 사용하였다. 동물실험의 심의승인번호는 아래와 같다. KHUASP(SE)15-119A 6-9-week-old FVB-based Fmr1 KO mouse (Jackson Laboratory, USA) of about 26 g to 28 g freely consumes water and feed, and has a temperature of about 23 ± 2 ° C, a humidity of about 55 ± 10%, and a contrast cycle of 12 hours. It was adapted for the rearing (animal laboratory of the College of Pharmacy, Kyung Hee University) and used for the experiment. The deliberation approval number of the animal experiment is as follows. KHUASP (SE) 15-119
준비예 2 약물처리Preparation Example 2 Drug Treatment
모든 동물은 FMRP 발현이 정상적으로 나타나는 WT과 FMRP 발현이 결핍된 KO 수컷 생쥐(약 X 증후군 (Fragile X Syndrome; FXS)을 유도함)를 사용하였으며, 주령을 맞추어 장기투약 및 실험을 실시하였다. 투약은 동일한 시간대에 진행하였으며, 매주 몸무게를 측정하여 약물에 의한 스트레스, 독성 등을 확인하였다. 투약 1주 후부터 행동실험을 진행하였으며, 지속적으로 4주 동안 투약이 진행되었다. FMRP 발현이 결핍 시킨 Knock-Out 마우스에 아그마틴을 각각 30 mg/kg (실시예 1) 또는 100 mg/kg (실시예 2)을 투여한 그룹, Wild Type 마우스에 아그마틴을 각각 30 mg/kg (대조군 1) 또는 100 mg/kg (대조군 2)을 투여한 그룹, Wild Type 마우스에 0.9%의 생리 식염수(saline 용액)을 투여한 그룹 (대조군 3) 및 FMRP 발현이 결핍 시킨 Knock-Out 마우스에 0.9%의 생리 식염수(saline 용액)을 투여한 그룹 (비교예 1)으로 나누어 한 군당 4-10 마리로 준비하였다. 상기 약물투여군에 대해서는 아그마틴을 0.9%의 생리 식염수(saline 용액)에 용해시킨 후 30, 100 mg/kg의 용량으로 복강 투여하였다. 한편, 대조군에는 0.9%의 생리 식염수(saline 용액)을 복강 투여하였다. All animals used WT with normal FMRP expression and KO male mice lacking FMRP expression (inducing Fragile X Syndrome (FXS)). Dosing was carried out at the same time, and the weight was measured every week to check the stress and toxicity caused by the drug. Behavioral tests were conducted one week after the administration, and the administration was continued for four weeks. Knock-Out mice lacking FMRP expression were treated with 30 mg / kg of Agmatine (Example 1) or 100 mg / kg (Example 2), respectively. (Control 1) or 100 mg / kg (Control 2) group, Wild type mice received 0.9% physiological saline (saline solution) group (Control 3) and FMRP expression deficient Knock-Out mice 4-10 rats were prepared per group divided into groups (Comparative Example 1) administered 0.9% saline solution (saline solution). The drug administration group was dissolved in 0.9% physiological saline (saline solution) and then intraperitoneally administered at a dose of 30, 100 mg / kg. Meanwhile, 0.9% of saline solution (saline solution) was intraperitoneally administered to the control group.
실험예 1: Marble burying testExperimental Example 1: Marble burying test
실험을 위하여 깔집이 준비된 케이지에 구슬을 배열해 준비하였다. 상기 3)에서 준비된 마우스들을 구슬이 들어있는 케이지에 넣은 후 30분 동안 행동을 관찰하였다. 실험 종료 후, 각 구슬의 남아있는 모습을 사진 찍고 숫자를 기록하였다. 숨긴 구슬의 숫자가 많을수록 반복행동이 증가되어 있음을 나타낸다. 각 군의 마우스들의 평균 숨긴 구슬의 숫자를 표 1 및 도 2에 나타내었다.For the experiment was prepared by arranging the beads in a cage prepared with a rug. The mice prepared in 3) were placed in a cage containing beads and observed for 30 minutes of action. After the end of the experiment, each ball was photographed and the number was recorded. The higher the number of hidden marbles, the greater the repetitive behavior. The average number of hidden beads of the mice in each group is shown in Table 1 and FIG.
(Wild Type; 아그마틴 30 mg/kg)
(Wild Type;
(Wild Type; 아그마틴 100 mg/kg)
(Wild Type;
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 30 mg/kg)Example 1
Knock-Out Deficient in FMRP Expression
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 100 mg/kg)Example 2
Knock-Out Deficient in FMRP Expression
(Wild Type; Vehicle)
(Wild Type; Vehicle)
(FMRP 발현이 결핍 시킨 Knock-Out Vehicle)Comparative Example 1
Knock-Out Vehicle Deficient in FMRP Expression
상기 표 1 및 도 2에서 볼 수 있는 바와 같이, KO 군의 경우에서 아그마틴을 투여한 실시예 1 및 실시예 2은 vehicle을 투여한 비교예 1에 비하여 반복행동이 현저하게 감소하였다. 반면, 정상동물인 WT군의 경우에서는 아그만틴 투여군인 대조군 1 및 대조군 2은 vehicle을 투여한 대조군 3에 비해 유의적인 차가 없었으므로, 약물투약에 의해 행동학적으로 유의적인 영향을 받지 않았음을 알 수 있다. 이로부터 아그마틴이 반복행동을 보이는 FXS 및 이와 관련된 발달장애나 정신신경질환을 효과적으로 예방 또는 치료 할 수 있음을 알 수 있었다.As can be seen in Table 1 and Figure 2, in the case of KO group, Example 1 and Example 2 administered with agmat markedly reduced repetitive behavior compared to Comparative Example 1 administered a vehicle. On the other hand, in the WT group of normal animals, the
실험예 2: Open field testExperimental Example 2: Open field test
준비예 2와 같이 마우스를 그룹으로 나누고, wild typ 또는 FMRP 발현이 결핍 시킨 Knock-Out 마우스에 0.9%의 생리 식염수(saline 용액) 또는 아그마틴을 각각의 그룹 함량으로 복강 투여하였다. 이후 open field test를 실시하였다. 상기 실험의 결과는 하기 표 2 및 도 3에 도시하였다. Mice were divided into groups as in Preparation Example 2, and 0.9% physiological saline (saline solution) or agmatine was intraperitoneally administered to Knock-Out mice lacking wild typ or FMRP expression. After that, open field test was performed. The results of the experiment are shown in Table 2 and FIG. 3.
(Wild Type; 아그마틴 30 mg/kg)
(Wild Type;
(Wild Type; 아그마틴 100 mg/kg)
(Wild Type;
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 30 mg/kg)Example 1
Knock-Out Deficient in FMRP Expression
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 100 mg/kg)Example 2
Knock-Out Deficient in FMRP Expression
(Wild Type; Vehicle)
(Wild Type; Vehicle)
(FMRP 발현이 결핍 시킨 Knock-Out Vehicle)Comparative Example 1
Knock-Out Vehicle Deficient in FMRP Expression
상기 표 2 및 도 3에서 볼 수 있는 바와 같이, KO 군의 경우에서 아그마틴을 투여한 실시예 1 및 실시예 2은 vehicle을 투여한 비교예 1에 비하여 이동한 거리가 현저하게 감소하였다. 반면, 정상동물인 WT군의 경우에서는 아그만틴 투여군인 대조군 1 및 대조군 2은 vehicle을 투여한 대조군 3에 비해 유의적인 차가 없었으므로, 약물투약에 의해 행동학적으로 유의적인 영향을 받지 않았음을 알 수 있다. 이로부터 아그마틴 투여가 과잉행동과 같은 취약 X 증후군 (Fragile X Syndrome; FXS) 및 이와 관련된 발달장애나 정신신경질환을 효과적으로 예방 또는 치료 할 수 있음을 알 수 있었다. As can be seen in Table 2 and Figure 3, in the case of KO group Example 1 and Example 2 administered with agmat it was significantly reduced the distance traveled compared to Comparative Example 1 administered a vehicle. On the other hand, in the WT group of normal animals, the
실험예 3: Social interaction test (Three chamber task)Experimental Example 3: Social interaction test (Three chamber task)
준비예 2와 같이 마우스를 그룹으로 나누고, wild typ 또는 FMRP 발현이 결핍 시킨 Knock-Out 마우스에 0.9%의 생리 식염수(saline 용액) 또는 아그마틴을 각각의 그룹 함량으로 복강 투여하였다. 이후 Three chamber를 이용해 social interaction test를 실시하였다. 상기 실험의 결과는 하기 표 3 및 도 4-5에 도시하였다. Mice were divided into groups as in Preparation Example 2, and 0.9% physiological saline (saline solution) or agmatine was intraperitoneally administered to Knock-Out mice lacking wild typ or FMRP expression. Then, social interaction test was performed using three chambers. The results of the experiment are shown in Table 3 below and FIGS. 4-5.
(Wild Type; 아그마틴 30 mg/kg)
(Wild Type;
(Wild Type; 아그마틴 100 mg/kg)
(Wild Type;
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 30 mg/kg)Example 1
Knock-Out Deficient in FMRP Expression
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 100 mg/kg)Example 2
Knock-Out Deficient in FMRP Expression
(Wild Type; Vehicle)
(Wild Type; Vehicle)
(FMRP 발현이 결핍 시킨 Knock-Out Vehicle)Comparative Example 1
Knock-Out Vehicle Deficient in FMRP Expression
상기 표 3 및 도 4-5에서 볼 수 있는 바와 같이, KO 군의 경우에서 아그마틴을 투여한 실시예 1 및 실시예 2은 vehicle을 투여한 비교예 1에 비하여 사회성 및 인지능이 현저하게 증가하였다. 반면, 정상동물인 WT군의 경우에서는 아그마틴 투여군인 대조군 1 및 대조군 2은 vehicle을 투여한 대조군 3에 비해 유의적인 차가 없었으므로, 약물투약에 의해 행동학적으로 유의적인 영향을 받지 않았음을 알 수 있다. 이로부터 아그마틴 투여가 사회성 저하와 같은 취약 X 증후군 (Fragile X Syndrome; FXS) 및 이와 관련된 발달장애나 정신신경질환을 효과적으로 예방 또는 치료 할 수 있음을 알 수 있었다. As can be seen in Table 3 and Figures 4-5, in the case of KO group, Example 1 and Example 2 to which agmatine was administered significantly increased social and cognitive abilities compared to Comparative Example 1 to which vehicle was administered. . On the other hand, in the WT group of normal animals, the
실험예Experimental Example 4: Barnes maze test 4: Barnes maze test
준비예 2와 같이 마우스를 그룹으로 나누고, wild typ 또는 FMRP 발현이 결핍 시킨 Knock-Out 마우스에 0.9%의 생리 식염수(saline 용액) 또는 아그마틴을 각각의 그룹 함량으로 복강 투여하였다. 이후 Barnes maze를 이용해 학습 및 기억을 평가하였다. 상기 실험의 결과는 하기 표 4 및 도 6-7에 도시하였다. Mice were divided into groups as in Preparation Example 2, and 0.9% physiological saline (saline solution) or agmatine was intraperitoneally administered to Knock-Out mice lacking wild typ or FMRP expression. We then used Barnes maze to evaluate learning and memory. The results of the experiment are shown in Table 4 below and FIGS. 6-7.
(Wild Type; 아그마틴 30 mg/kg)Control group 1
(Wild Type;
(Wild Type; 아그마틴 100 mg/kg)
(Wild Type;
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 30 mg/kg)Example 1
Knock-Out Deficient in FMRP Expression
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 100 mg/kg)Example 2
Knock-Out Deficient in FMRP Expression
(Wild Type; Vehicle)
(Wild Type; Vehicle)
(FMRP 발현이 결핍 시킨 Knock-Out Vehicle)Comparative Example 1
Knock-Out Vehicle Deficient in FMRP Expression
상기 표 4 및 도 6-7에서 볼 수 있는 바와 같이, KO 군의 경우에서 아그마틴을 투여한 실시예 1 및 실시예 2은 vehicle을 투여한 비교예 1에 비하여 4일간의 훈련 기간 동안 타깃 지점에 도달하기까지 걸리는 시간이 현저하게 감소하였다. 또한, 시험 당일, 타깃 지점에 머무르는 시간이 유의적으로 증가하였다. 반면, 정상동물인 WT군의 경우에서는 아그마틴 투여군인 대조군 1 및 대조군 2은 vehicle을 투여한 대조군 3에 비해 유의적인 차가 없었으므로, 약물투약에 의해 행동학적으로 유의적인 영향을 받지 않았음을 알 수 있다. 이로부터 아그마틴 투여가 학습 및 기억의 저하와 같은 인지능 질환을 효과적으로 예방 또는 치료 할 수 있음을 알 수 있었다. As can be seen in Table 4 and Figures 6-7, Example 1 and Example 2 administered with Agmatine in the case of KO group compared to the target Example 1 administered the vehicle during the four-day training period The time to reach was significantly reduced. In addition, on the test day, the time to stay at the target point increased significantly. On the other hand, in the WT group of normal animals, the
실험예 5: Prepulse inhibition testExperimental Example 5: Prepulse inhibition test
준비예 2와 같이 마우스를 그룹으로 나누고, wild typ 또는 FMRP 발현이 결핍 시킨 Knock-Out 마우스에 0.9%의 생리 식염수(saline 용액) 또는 아그마틴을 각각의 그룹 함량으로 복강 투여하였다. 이후 선행자극억제시험을 통해 sensorimotor gating을 평가하였다. 상기 실험의 결과는 아래와 같은 수학식1에 의해 환산하였으며 그 결과는 하기 표 5 및 도 8에 도시하였다. Mice were divided into groups as in Preparation Example 2, and 0.9% physiological saline (saline solution) or agmatine was intraperitoneally administered to Knock-Out mice lacking wild typ or FMRP expression. Subsequent sensorimotor gating was assessed through a prior stimulation suppression test. The results of the experiment was converted by
상기 수학식 1에 의해 환산된 선행자극억제능을 하기 표5 및 도 8에 나타내었다. The preceding stimulatory inhibitory capacity converted by
(Wild Type; 아그마틴 30 mg/kg)Control group 1
(Wild Type;
(Wild Type; 아그마틴 100 mg/kg)
(Wild Type;
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 30 mg/kg)Example 1
Knock-Out Deficient in FMRP Expression
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 100 mg/kg)Example 2
Knock-Out Deficient in FMRP Expression
(Wild Type; Vehicle)
(Wild Type; Vehicle)
(FMRP 발현이 결핍 시킨 Knock-Out; Vehicle)Comparative Example 1
(Knock-Out; Vehicle Deficient in FMRP Expression)
상기 표 5 및 도 8에서 볼 수 있는 바와 같이, KO 군의 경우에서 아그마틴을 투여한 실시예 1 및 실시예 2은 vehicle을 투여한 비교예 1에 비하여 선행자극억제가 증가하였다. 반면, 정상동물인 WT군의 경우에서는 아그마틴 투여군인 대조군 1 및 대조군 2은 vehicle을 투여한 대조군 3에 비해 유의적인 차가 없었으므로, 약물투약에 의해 행동학적으로 유의적인 영향을 받지 않았음을 알 수 있다. 이로부터 아그마틴 투여가 sensorimotor gating deficit으로 대표되는 선행자극억제이상을 나타내는 정신신경질환을 효과적으로 예방 또는 치료 할 수 있음을 알 수 있었다.As can be seen in Table 5 and Figure 8, in the case of the KO group, Example 1 and Example 2 administered with agmatin compared to Comparative Example 1 administered a vehicle increased the pre-stimulation inhibition. On the other hand, in the WT group of normal animals, the
실험예 6: Ultrasonic vocalization testExperimental Example 6: Ultrasonic vocalization test
준비예 2와 같이 마우스를 그룹으로 나누고, wild typ 또는 FMRP 발현이 결핍 시킨 Knock-Out 마우스에 0.9%의 생리 식염수(saline 용액) 또는 아그마틴을 각각의 그룹 함량으로 복강 투여하였다. 이후 Sonotrack을 이용해 ultrasonic vocalization을 평가하였다. 상기 실험의 결과는 하기 표 6 및 도 9에 도시하였다. Mice were divided into groups as in Preparation Example 2, and 0.9% physiological saline (saline solution) or agmatine was intraperitoneally administered to Knock-Out mice lacking wild typ or FMRP expression. Then, ultrasonic vocalization was evaluated using Sonotrack. The results of the experiment are shown in Table 6 and FIG. 9.
(Wild Type; 아그마틴 30 mg/kg)Control group 1
(Wild Type;
(FMRP 발현이 결핍 시킨 Knock-Out
아그마틴 30 mg/kg)Example 1
Knock-Out Deficient in FMRP Expression
(Wild Type; Vehicle)
(Wild Type; Vehicle)
(FMRP 발현이 결핍 시킨 Knock-Out; Vehicle)Comparative Example 1
(Knock-Out; Vehicle Deficient in FMRP Expression)
상기 표 6 및 도 9에서 볼 수 있는 바와 같이, KO 군의 경우에서 아그마틴을 투여한 실시예 1은 vehicle을 투여한 비교예 1에 비하여 총 초음파 발생 횟수가 증가하였다. 즉, 서로 간에 의사소통이 활발하게 이루어지고 있음을 알 수 있다. 반면, 정상동물인 대조군 3의 경우에서는 약물투약에 의해 유의적인 영향을 받지 않았음을 알 수 있다. 이로부터 아그마틴 투여가 의사소통이나 사회성 문제를 나타내는 발달장애나 정신신경질환을 효과적으로 예방 또는 치료 할 수 있음을 알 수 있었다.As can be seen in Table 6 and FIG. 9, in the case of KO group, Example 1 in which agmatine was administered increased as compared with Comparative Example 1 in which a vehicle was administered. In other words, it can be seen that the communication between each other is active. On the other hand, in the case of
Claims (7)
The health functional food composition for preventing or ameliorating Fragile X Syndrome (FXS) or a related disease according to claim 5, wherein the disease related to Fragile X Syndrome (FXS) is autistic categorical disease.
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| PCT/KR2019/004439 WO2019203509A1 (en) | 2018-04-18 | 2019-04-12 | Pharmaceutical composition, comprising agmatine or pharmaceutically acceptable salt thereof, for prevention or treatment of fragile x syndrome |
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