KR20200117506A - Pharmaceutical composition for the prevention or treatment of depressive or anxiety symptoms through nasal administration of GABA-B receptor antagonists or agonists - Google Patents
Pharmaceutical composition for the prevention or treatment of depressive or anxiety symptoms through nasal administration of GABA-B receptor antagonists or agonists Download PDFInfo
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- KR20200117506A KR20200117506A KR1020190039693A KR20190039693A KR20200117506A KR 20200117506 A KR20200117506 A KR 20200117506A KR 1020190039693 A KR1020190039693 A KR 1020190039693A KR 20190039693 A KR20190039693 A KR 20190039693A KR 20200117506 A KR20200117506 A KR 20200117506A
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- A—HUMAN NECESSITIES
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Abstract
Description
본 발명은 GABA-B 수용체 길항제 또는 효능제의 비강 투여를 통한 우울 또는 불안 증세 치료용 약학적 조성물로서, 보다 구체적으로 상기 길항제의 비강 투여로 불안 증세인 불안감을 감소시킬 수 있으며, 상기 효능제의 비강 투여로 불안 장애와 다른 양상으로 나타나는 우울 증세를 완화할 수 있는 약학적 조성물을 제공하는 것이다. The present invention is a pharmaceutical composition for the treatment of depression or anxiety symptoms through nasal administration of a GABA-B receptor antagonist or an agonist, and more specifically, the nasal administration of the antagonist can reduce anxiety, which is an anxiety symptom, and of the agonist It is to provide a pharmaceutical composition that can relieve anxiety disorders and other depression symptoms by nasal administration.
불안장애와 우울장애는 매우 흔한 정신질환이다. 역학 조사에 의하면 정신 질환 중 각각 1위와 2위를 차지할 만큼 그 유병률이 높다. 불안장애와 우울장애는 각각 구분된 진단 범주로 나뉘어져 있지만, 임상 양상과 진단 기준에 있어 유사 하거나 공통되는 경향이 있다. 우울 삽화의 경우 초조, 범불안장애의 피로감, 불면증, 집중 곤란, 외상후 스트레스장애의 흥미 상실 등을 그 예로들 수 있다. 더욱이 이 두 질환은 한 사람한테 동시에 진단되는 공존율이 높다. 그러나, 불안장애와 우울장애는 질적으로 다른 질환이며 위험인자, 자연경과, 정신병리적 특징도 상이하다. 불안과 우울의 공존은 1차적으로 불안장애가 발병한 이후에 우울증상은 여러 요소들이 용량-반응 관계로 작용하여 나타나는 것이라고 보는 견해가 지배적이다. 이에, 불안감과 우울감을 각각 독립적으로 조절할 수 있는 방법의 개발이 요구되고 있다.Anxiety disorders and depressive disorders are very common mental disorders. According to epidemiological surveys, the prevalence is high enough to occupy the first and second place among mental disorders, respectively. Anxiety disorders and depressive disorders are classified into separate diagnostic categories, but they tend to be similar or common in clinical manifestations and diagnostic criteria. In the case of depressive episodes, anxiety, fatigue from generalized anxiety disorder, insomnia, difficulty concentrating, and loss of interest in post-traumatic stress disorder are examples. Moreover, these two diseases have a high coexistence rate, which is diagnosed by one person at the same time. However, anxiety disorder and depressive disorder are qualitatively different diseases, and their risk factors, natural course, and psychopathological characteristics are also different. The dominant view is that the coexistence of anxiety and depression is primarily due to the onset of anxiety disorder and that the depressive image appears as a result of a dose-response relationship. Accordingly, there is a need to develop a method that can independently control anxiety and depression.
우울증 치료는 정신치료적 접근과 함께 약물 치료가 병행되고 있으나, 약물 치료에 이용되는 약물은 1950년대에 개발된 모노아민 재흡수 억제 약물 이후로는 획기적인 기전의 약물이 개발되지 않고 있다. 최근 신경전달물질 체계에 따라 SSRI, NDRI, SNRI 등 다양한 계열의 약물들이 개발되어 왔으나 아직 임상실험 단계에 머무르고 있다. 또한, 항우울제는 일반적으로 효능이 수일에서 수주에 걸쳐 나타나므로 복용 후 최소 4 내지 6 주가 지나야 약물의 효과를 확인할 수 있고, 경우에 따라서는 약물 용량을 늘리거나 약물 교체 등으로 인하여 호전되기 까지 오랜 시간이 걸릴 수도 있다. 이에, 보다 즉각적으로 효과를 나타내면서도 부작용이 적은 약물의 개발이 필요한 실정이다. The treatment of depression is accompanied by a psychotherapeutic approach and drug treatment, but the drug used for drug treatment has not been developed with a breakthrough mechanism since the monoamine reuptake inhibitory drug developed in the 1950s. Recently, a variety of drugs such as SSRI, NDRI, and SNRI have been developed according to the neurotransmitter system, but they are still in the clinical trial stage. In addition, antidepressants generally show efficacy over several days to several weeks, so the effect of the drug can be confirmed after at least 4 to 6 weeks after taking it, and in some cases, it will take a long time to improve due to an increase in the drug dose or drug replacement. It might take. Accordingly, it is necessary to develop a drug that exhibits more immediate effects and has less side effects.
한편, 뇌는 약 150ml의 뇌척수액(Cerebrospinal Fluid, CSF) 내에 떠있으며, 뇌척수액은 4개의 뇌실 사이와 지주막 아래의 공간 사이를 천천히 순환하고, 지주막 융모(arachnoid vili.)를 통해 대뇌 정맥 내로 빠져나간다. 뇌에는 림프계가 없기 때문에 뇌척수액이 부분적으로 이를 대체한다. 뇌와 뇌척수액은 어느 정도 투과성을 갖는 유막에 의해 분리되어 있어서, 뇌-뇌척수액간 장벽(blood-cerebrospinal fluid barrier)과 혈-뇌간 장벽 (blood-brain barrier: BBB)은 바람직하지 않은 혈액물질의 생성을 차단한다. 혈-뇌간 장벽은 뇌를 보호하는 화학적 환경을 만들어내는데, 거기에서 어떤 분자들은 그 분자들이 몸의 다른 곳 에서 수행하는 기능과 독립적인 기능을 수행할 수 있다. On the other hand, the brain is floating in about 150ml of cerebrospinal fluid (CSF), and the cerebrospinal fluid slowly circulates between the four ventricles and the space under the arachnoid, and exits into the cerebral vein through the arachnoid vili. Since there is no lymphatic system in the brain, cerebrospinal fluid partially replaces it. Since the brain and cerebrospinal fluid are separated by an oil membrane that has some degree of permeability, the blood-cerebrospinal fluid barrier and the blood-brain barrier (BBB) prevent the production of undesirable blood substances. Block. The blood-brainstem barrier creates a chemical environment that protects the brain, where certain molecules can perform functions independent of what they do elsewhere in the body.
이에, 중추신경계(central nervous system, CNS)의 장애에 효과적인 약을 개발하기 위해, 비강전달이 연구되어 왔다. 약물의 비강전달은 많은 장점을 갖고 있는데, 뇌로의 직접적인 접근이 가능하고, 코에 있는 풍부한 모세혈관 때문에 흡수가 빠르고, 작용시작이 빠르고, 간장의 초회 통과(first-pass) 대사작용을 회피할 수 있고, 만성 약물 치료에 효과가 있으며, 쉽게 투여할 수 있다. 또한 큰 분자들 및/또는 이온화된 분자들과는 대조되게, 충분히 작은 분자량을 가진 친유성 제약 화합물은 일반적으로 코의 점막에 의해 쉽게 흡수된다고 알려져 있다.Thus, in order to develop a drug effective against disorders of the central nervous system (CNS), nasal delivery has been studied. Nasal delivery of drugs has many advantages. Direct access to the brain is possible, absorption is fast due to the abundant capillaries in the nose, the initiation of action is quick, and the first-pass metabolism of the liver can be avoided. It is effective in chronic drug treatment, and can be easily administered. It is also known that, in contrast to large molecules and/or ionized molecules, lipophilic pharmaceutical compounds with sufficiently small molecular weight are generally readily absorbed by the mucous membrane of the nose.
감마아미노뷰티르산(GABA)은 중추신경계에 작용하는 대표적인 억제성 신경전달물질이며, GABA에 의한 대뇌변연계(limbic system)의 억제성 조절이 상실되는 경우에 공격성을 보이는 것으로 알려져 있다. 또한 벤조디아제핀(benzodiazepine) 등의 GABA-A 수용체 효능제(agonist)는 주로 불안증세나 근육경련(muscle spasm)을 줄이기 위해 처방되고 있다. 또한, GABA-B 수용체는 리간드(ligand) 수용체로 바클로펜(baclofen) 등의 GABA-B 수용체 효능제는 주로 척추 손상이나 다발성 경화증과 같은 근육경련 치료를 위해 처방되어 왔으며, SCH-50911 등과 같은 GABA-B 수용체 길항제(antagonist)는 항경련제로 처방되어 왔다. 최근 GABA-B 수용체가 약물 중독, 우울증, 불안 장애 등의 정신질환에 영향을 미치는 것으로 보고되었으나, 구체적인 작용기전에 대한 연구가 미진하여, 이의 기능을 조절할 수 있는 물질의 적절한 투여방법과 투여용량에 대한 연구가 필요하다. Gammaaminobutyric acid (GABA) is a representative inhibitory neurotransmitter acting on the central nervous system, and is known to show aggressiveness when the inhibitory regulation of the limbic system by GABA is lost. In addition, GABA-A receptor agonists such as benzodiazepine are mainly prescribed to reduce anxiety symptoms and muscle spasm. In addition, GABA-B receptor is a ligand receptor, and GABA-B receptor agonists such as baclofen have been mainly prescribed for the treatment of muscle spasms such as spinal injury or multiple sclerosis, and such as SCH-50911. GABA-B receptor antagonists have been prescribed as anticonvulsants. Recently, GABA-B receptors have been reported to have an effect on mental disorders such as drug addiction, depression, and anxiety disorders. However, studies on specific mechanisms of action have been insufficient, so the appropriate administration method and dosage of substances capable of regulating its function have been investigated. Research is needed.
이에, 본 발명자들은 GABA-B 수용체를 타겟으로 하고 상기 수용체의 길항제 또는 효능제를 비강 또는 복강에 투여 하여 불안장애와 우울장애의 증상에 미치는 영향을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors targeted the GABA-B receptor and administered the antagonist or agonist of the receptor to the nasal cavity or intraperitoneally to confirm the effect on the symptoms of anxiety disorder and depressive disorder, and completed the present invention.
본 발명이 이루고자 하는 기술적 과제는 우울장애 또는 불안장애의 예방 또는 치료를 위하여 GABA-B 수용체 특이적인 효능제 또는 길항제를 포함하는 약학적 조성물의 최적의 투여방법 및 투여용량을 제공하는 것이다.The technical task of the present invention is to provide an optimal administration method and dosage of a pharmaceutical composition containing a GABA-B receptor-specific agonist or antagonist for the prevention or treatment of depressive disorder or anxiety disorder.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당해 기술분야의 통상의 기술자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.
상기 과제를 해결하기 위하여, 본 발명은 GABA-B 수용체에 특이적인 효능제(agonist)를 유효성분으로 포함하고 항우울 효과를 갖는 비강 투여용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for nasal administration comprising an agonist specific to GABA-B receptor as an active ingredient and having an antidepressant effect.
본 발명의 일 구현예로서, 상기 조성물은 1일 1회 투여하되, 단위 kg당 GABA-B 수용체에 특이적인 효능제를 1 내지 4 mg, 바람직하게는 1.4 내지 1.8 mg, 더욱 바람직하게는 1.6 mg 투여하도록 GABA-B 수용체에 특이적인 효능제를 포함할 수 있다. In one embodiment of the present invention, the composition is administered once a day, but 1 to 4 mg, preferably 1.4 to 1.8 mg, more preferably 1.6 mg of an agonist specific to the GABA-B receptor per unit kg An agonist specific for the GABA-B receptor may be included for administration.
본 발명의 다른 구현예로서, 상기 항우울 효과는 절망감 완화에 의한 것일 수 있다. As another embodiment of the present invention, the antidepressant effect may be due to alleviation of hopelessness.
본 발명의 또 다른 구현예로서, 상기 GABA-B 수용체에 특이적인 효능제는 Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen 및 Arbaclofen Placarbil으로 이루어진 군으로부터 선택되는 하나 이상일 수 있으나, 바람직하게는 baclofen일 수 있다. In another embodiment of the present invention, the GABA-B receptor-specific agonist is Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen, and Arbaclofen Placarbil. It may be one or more selected from the group, preferably baclofen.
또한, 본 발명은 GABA-B 수용체에 특이적인 길항제를 유효성분으로 포함하고 항불안 효과를 갖는 비강 투여용 약학적 조성물을 제공할 수 있다. In addition, the present invention can provide a pharmaceutical composition for nasal administration containing an antagonist specific for GABA-B receptor as an active ingredient and having an anti-anxiety effect.
본 발명의 일 구현예로서, 상기 조성물은 불안 증세는 완화시키지만 우울 증세에는 영향을 미치지 않는 것일 수 있다.As an embodiment of the present invention, the composition may relieve anxiety symptoms but not affect depression symptoms.
본 발명의 다른 구현예로서, 상기 조성물은 1일 1회 투여하되, 단위 kg당 GABA-B 수용체에 특이적인 길항제를 2 내지 4 mg 투여하도록 GABA-B 수용체에 특이적인 길항제를 포함할 수 있다. In another embodiment of the present invention, the composition may be administered once a day, but may include an antagonist specific to the GABA-B receptor such that 2 to 4 mg of an antagonist specific to the GABA-B receptor per kg is administered.
본 발명의 또 다른 구현예로서, 상기 GABA-B 수용체에 특이적인 길항제는 CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, 및 SCH50911일 수 있으나, 바람직하게는 SCH50911일 수 있다. In another embodiment of the present invention, the GABA-B receptor specific antagonist may be CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, and SCH50911, but preferred For example, it may be SCH50911.
또한, 본 발명은 개체의 비강에 GABA-B 수용체에 특이적인 효능제를 투여하는 단계를 포함하는 우울 장애 예방 또는 치료 방법을 제공한다. In addition, the present invention provides a method for preventing or treating depressive disorder comprising administering an agonist specific for GABA-B receptor to the nasal cavity of an individual.
또한, 본 발명은 개체의 비강에 GABA-B 수용체에 특이적인 길항제를 투여하는 단계를 포함하는 불안 장애의 예방 또는 치료 방법을 제공한다. In addition, the present invention provides a method for preventing or treating anxiety disorders comprising administering an antagonist specific to the GABA-B receptor to the nasal cavity of an individual.
본 발명의 일 구현예로서, 상기 개체의 비강에 투여되는 GABA-B 수용체에 특이적인 효능제는 개체의 단위 kg 당 1 내지 4 mg일 수 있으며, 이를 1일 1회 투여하는 것일 수 있다. As an embodiment of the present invention, the GABA-B receptor-specific agonist administered to the nasal cavity of the individual may be 1 to 4 mg per kg of the individual, and may be administered once a day.
본 발명의 다른 구현예로서, 상기 개체의 비강에 투여되는 GABA-B 수용체에 특이적인 길항제는 개체의 단위 kg 당 2 내지 4 mg일 수 있으며, 이를 1일 1회 투여하는 것일 수 있다. In another embodiment of the present invention, the GABA-B receptor specific antagonist administered to the nasal cavity of the subject may be 2 to 4 mg per kg of the subject, and may be administered once a day.
또한, 본 발명은 우울 장애 예방 또는 치료 효과를 갖는 비강 투여용 약물의 제조를 위한 GABA-B 수용체에 특이적인 효능제의 용도를 제공한다. In addition, the present invention provides the use of an agonist specific to the GABA-B receptor for the manufacture of a drug for nasal administration having an effect of preventing or treating depressive disorder.
또한, 본 발명은 불안 장애 예방 또는 치료 효과를 갖는 비강 투여용 약물의 제조를 위한 GABA-B 수용체에 특이적인 길항제의 용도를 제공한다.In addition, the present invention provides the use of a GABA-B receptor specific antagonist for the manufacture of a drug for nasal administration having an anxiety disorder prevention or treatment effect.
본 발명은 GABA-B 수용체 효능제의 비강 투여를 통해, 복강 투여의 경우와 달리 절망감을 감소시키는 효과를 얻을 수 있음을 확인하였고, GABA-B 수용체 길항제의 비강 투여를 통해, 복강 투여의 경우보다 우수한 불안 증세 감소 효과를 확인할 수 있었는바, 본 발명의 제공에 의해, 보다 적은 양의 약물을 이용하여 효과적으로 우울 및/또는 불안 장애의 예방 또는 치료가 가능하다는 장점이 있다. 또한 비강 투여를 통해 약물이 직접 뇌로 전달되기 때문에 간에 무리가 없으며, 전신부작용이 없거나 적은 장점이 있다.The present invention confirmed that the effect of reducing hopelessness can be obtained through nasal administration of a GABA-B receptor agonist, unlike intraperitoneal administration, and through nasal administration of a GABA-B receptor antagonist, compared to intraperitoneal administration. Excellent anxiety symptom reduction effect was confirmed, and by the provision of the present invention, there is an advantage that it is possible to effectively prevent or treat depression and/or anxiety disorders using a smaller amount of drugs. In addition, since the drug is directly delivered to the brain through nasal administration, there is no problem with the liver, and there is no or little side effects.
도 1은 비강 투여 방법과 비강 투여 약물의 작용을 도식화한 도면이다.
도 2는 baclofen을 비강 투여한 마우스의 행동 실험 결과 그래프로서, 구체적으로 꼬리 현수법과 강제 수영실험에서 baclofen을 비강 투여한 마우스는 부동성(A 및 B)이 감소함을 확인하고 있다.
도 3은 SCH50911을 비강 투여한 마우스의 행동 실험 결과 그래프로서, 구체적으로 고도 제로 미로 테스트에서 SCH50911을 비강 투여한 마우스는 열린 공간에서 머무는 시간(A)과 열린 공간으로 방문 횟수(B) 모두 증가함을 확인하고 있다.
도 4는 SCH50911을 복강 투여한 마우스의 행동 실험 결과 그래프로서, SCH50911을 복강 투여한 마우스는 고도 제로 미로 테스트, 꼬리 현수법, 강제 수영실험 모두에서 약물의 투여에 따른 행동 변화에 있어 통계적 차이를 나타내지 않음을 확인하고 있다.
도 5은 비강으로 투여되는 SCH50911의 양에 따른 효능을 확인한 도면으로, 구체적으로 투여 대상 개체의 단위 무게(1kg) 당 2mg 미만의 약물을 투여하는 경우 불안 증세 완화에 효과가 미미함을 확인한 도면이다.1 is a diagram illustrating a nasal administration method and an action of a nasal drug.
FIG. 2 is a graph of the results of a behavioral experiment of mice administered with baclofen nasally. Specifically, it was confirmed that the mice to which baclofen was administered nasally in the tail suspension method and forced swimming experiment decreased immobility (A and B).
FIG. 3 is a graph of the results of a behavioral experiment of a mouse administered SCH50911 nasally. Specifically, in a high zero maze test, a mouse nasal administration of SCH50911 increased both the time to stay in the open space (A) and the number of visits to the open space (B). Are checking.
4 is a graph of the results of behavioral experiments of mice administered intraperitoneally with SCH50911, and mice administered with SCH50911 intraperitoneally show statistical differences in behavioral changes according to drug administration in all of the high-level zero maze test, tail suspension, and forced swimming experiments. It is confirming that it is not.
FIG. 5 is a view confirming the efficacy according to the amount of SCH50911 administered to the nasal cavity. Specifically, it is a view confirming that the effect on relieving anxiety symptoms is insignificant when a drug of less than 2 mg per unit weight (1 kg) of the subject to be administered is administered. .
본 발명자들은 우울증 및 불안장애의 효과적인 치료 방법에 대해 예의 연구한 결과, GABA-B 수용체를 타겟으로 하여 상기 수용체의 길항제 또는 효능제를 비강을 통해 투여함으로써 적은 양의 약물만으로도 신경불안 증세와 우울 증세를 효과적으로 완화시킴을 확인하여 본 발명을 완성하였다. As a result of intensive research on effective treatment methods for depression and anxiety disorders, the present inventors showed neuro anxiety symptoms and depression symptoms with only a small amount of drugs by administering an antagonist or agonist of the receptor targeting the GABA-B receptor through the nasal cavity. It was confirmed that it effectively alleviates the present invention.
본 발명의 억제 또는 활성 타겟인 GABA-B 수용체는 중추신경계에 작용하는 대표적인 억제성 신경전달물질인 감마아미노뷰티르산(gamma-Aminobutyric acid: GABA)의 수용체(receptor)로서 최근 약물 중독, 우울증, 불안 장애 등의 정신질환에 영향을 미치는 것으로 밝혀졌으나, 상기 수용체의 적절한 활성 조절 방법이 아직 개발되지 않았다. GABA-B receptor, an inhibitory or active target of the present invention, is a receptor for gamma-Aminobutyric acid (GABA), a representative inhibitory neurotransmitter acting on the central nervous system. Although it has been found to affect mental disorders such as disability, a method for controlling the appropriate activity of the receptor has not yet been developed.
본 발명의 GABA-B 수용체 효능제(agonist)는 상기 수용체의 활성을 활발하게 하는 것으로서, 그 비제한적인 예로는 Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen 및 Arbaclofen Placarbil 등이 있으나, 본 발명의 구체적인 실시예에서는 baclofen을 이용하여 상기 효능제가 비강을 통해 투여되는 경우 우울 증세를 완화시키는 효과가 있음을 확인하였다(실시예 3-1 참조).The GABA-B receptor agonist of the present invention activates the activity of the receptor, and non-limiting examples thereof include Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102 , Tolgabide, baclofen, and Arbaclofen Placarbil, etc., but in a specific embodiment of the present invention, it was confirmed that baclofen is used to relieve depression when the agonist is administered through the nasal cavity (see Example 3-1). .
한편, 본 발명의 구체적인 실시예에서 이용하고 있는 GABA-B 수용체 효능제인 baclofen은 하기의 구조를 갖는 베타-(4-클로로페닐)-감마-아미노뷰트릭산(βγacid)이다. Baclofen은 척추 손상이나 다발성 경화증과 같은 근육경련(muscle spasm) 치료를 위한 약물로 이용되어 왔으며, 구강 투여 또는 척수관 주사를 통한 투여로만 이용되어, baclofen의 비강 투여로 나타나는 효과에 대해서는 밝혀진바가 없다.On the other hand, baclofen, a GABA-B receptor agonist used in a specific example of the present invention, is beta-(4-chlorophenyl)-gamma-aminobutric acid (βγacid) having the following structure. Baclofen has been used as a drug for the treatment of muscle spasm such as spinal injuries or multiple sclerosis, and has been used only by oral administration or administration through spinal canal injection, and the effects of baclofen's nasal administration have not been revealed.
[구조식 1][Structural Formula 1]
또한, 본 발명의 GABA-B 수용체 길항제(antagonist)는 상기 수용체의 활성을 직접 및/또는 간접적으로 억제하는 것으로서, 그 비제한적인 예로는 CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, 및 SCH-50911 등이 있으나, 본 발명의 구체적인 실시예에서는 SCH-50911을 이용하여 상기 길항제가, 복강 투여되는 경우와 달리, 비강을 통해 투여되는 경우 우울 증세에는 영향을 미치지 않으면서 불안 증세를 완화시키는 효과가 있음을 확인하였다(실시예 3-2 및 3-3 참조).In addition, the GABA-B receptor antagonist of the present invention directly and/or indirectly inhibits the activity of the receptor, and non-limiting examples thereof include CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP -35348, Homotaurine, Phaclofen, Saclofen, and SCH-50911, etc., but in a specific embodiment of the present invention, the antagonist using SCH-50911, unlike the case of intraperitoneal administration, when administered through the nasal cavity, the symptoms of depression It was confirmed that there is an effect of alleviating anxiety symptoms without affecting (see Examples 3-2 and 3-3).
본 발명에서 GABA-B 수용체 길항제가 비강 투여되어 우울 증세에 영향을 미치지 않는다는 것은 상기 길항제가 투여 전과 투여 후 우울 증세의 상태 및/또는 그 정도에 유의한 변화를 야기하지 못함을 의미한다.In the present invention, that the GABA-B receptor antagonist is intranasally administered and does not affect depression symptoms means that the antagonist does not cause a significant change in the state and/or the degree of depression before and after administration.
한편, 본 발명의 구체적인 실시예에서 이용하고 있는 GABA-B 수용체 길항제인 SCH-50911는 하기의 구조를 갖는 2-[(2S)-5,5-디메틸모르폴린-2-일]아세트산(2-[(2S)-5,5-dimethylmorpholin-2-yl]acetic acid)이다. SCH-50911는 항경련제로 이용되어 왔으나, 우울증 또는 불안장애와 관련되어 영향을 미침에 대해서는 아직까지 밝혀진바 없다. On the other hand, SCH-50911, a GABA-B receptor antagonist used in specific examples of the present invention, has the following structure: 2-[(2 S )-5,5-dimethylmorpholin-2-yl]acetic acid (2 -[(2 S )-5,5-dimethylmorpholin-2-yl]acetic acid). Although SCH-50911 has been used as an anticonvulsant, it has yet to be known about its effect in relation to depression or anxiety disorder.
[구조식 2][Structural Formula 2]
본 발명의 조성물이 예방 또는 치료의 대상으로 하는 불안장애(Anxiety disorder)와 우울장애(depressive disorder)는 매우 흔한 정신질환으로, 임상 양상과 진단 기준에 있어 유사하거나 공통되는 경향이 있으나, 불안장애와 우울장애는 각각 구분되는 진단범주로 나뉘어져 있다.Anxiety disorder and depressive disorder, which the composition of the present invention is the target of prevention or treatment, are very common mental disorders, and tend to be similar or common in clinical manifestations and diagnostic criteria. Depressive disorders are divided into separate diagnostic categories.
흔히, 우울증이라고 불리는 우울장애는 의욕 저하와 우울감을 주요 증상으로 하여 다양한 인지 및 정신 신체적 증상을 일으켜 기능의 저하를 가져오는 질환을 의미하며, 불안장애는 다양한 형태의 비정상적, 병적인 불안과 공포로 인하여 일상 샐활에 장애를 일으키는 정신 질환의 통칭으로서 불안과 공포가 정상적인 범위를 넘어서면서 정신적 고통과 신체적 증상을 초래하는 것을 의미한다. Depressive disorder, commonly referred to as depression, refers to a disease that causes a variety of cognitive and psychosomatic symptoms, resulting in a decrease in function, with decreased motivation and depression as the main symptoms, and anxiety disorder is caused by various types of abnormal, pathological anxiety and fear. As a result, it is a collective term for mental disorders that cause disorders in daily life, which means that anxiety and fear exceed the normal range, causing mental pain and physical symptoms.
본 발명은 불안장애와 우울장애를 구분하여 치료에 접근할 수 있도록 보다 섬세한 실험 결과를 제시하고 있으며, 구체적으로 우울감 정도를 확인하기 위한 실험 기법으로는 꼬리 현수법(Tail suspension test, TST)과 강제 수영 실험(Forced swim test, FST)을 수행하였으며, 불안감 정도를 확인하기 위하여 고도 제로 미로 테스트(Elevated zero maze test, EZM)를 수행하였다. The present invention presents more detailed experimental results to allow access to treatment by distinguishing between anxiety disorders and depressive disorders, and specifically, as an experimental technique for confirming the degree of depression, the tail suspension test (TST) and forced A forced swim test (FST) was performed, and an elevated zero maze test (EZM) was performed to confirm the degree of anxiety.
또한, 본 발명은 GABA-B 수용체의 효능제가 비강을 통해 투여되는 경우 불안 증세는 악화시키고 우울 증세는 완화시키는 효과가 있음을 확인하고 있는바, 개체의 상기 효능제의 비강 투여 후 나타나는 증상의 변화를 관찰하여 우울장애를 감별진단하는 것에 이용될 수 있다. 마찬가지로 GABA-B 수용체의 길항제는 비강을 통해 투여되는 경우 우울 증세에는 무관하고 불안 증세는 완화시키는 효과가 있는바, 개체에 상기 길항제의 비강 투여 후 나타나는 증상의 완화 정도를 관찰하여 불안장애를 감별진단하는 것에 이용될 수도 있다. In addition, the present invention has confirmed that when an agonist of the GABA-B receptor is administered through the nasal cavity, it has been confirmed that anxiety symptoms are aggravated and depressive symptoms are alleviated. Changes in symptoms appearing after nasal administration of the agonist It can be used for differential diagnosis of depressive disorder by observing. Likewise, when an antagonist of GABA-B receptor is administered through the nasal passages, it is irrelevant to the symptoms of depression and has the effect of alleviating the symptoms of anxiety.The degree of remission of symptoms after nasal administration of the antagonist to the individual is observed to differentiate anxiety disorders. It can also be used for doing.
한편, 본 발명자들은 GABA-B 수용체의 길항제 또는 효능제가 비강을 통해 그 효과를 나타냄에 있어 최적의 용량은 투여되는 개체의 단위 무게(1kg) 기준으로, 길항제의 경우 2 내지 4mg, 효능제의 경우 1 내지 4mg임을 확인하였다. 상기 용량보다 적은 경우 약물의 효과를 기대하기 어려우며, 상기 용량보다 많은 양을 투여하는 경우 약물의 과잉투여로 인한 비특이적인 부작용 또는 치료 효능의 감소가 나타나는 문제가 있다.On the other hand, the present inventors believe that the antagonist or agonist of the GABA-B receptor exhibits its effect through the nasal cavity, so the optimal dose is based on the unit weight (1 kg) of the administered individual, 2 to 4 mg for the antagonist, and 2 to 4 mg for the agonist. It was confirmed that it was 1 to 4 mg. If the dose is less than the above dose, it is difficult to expect the effect of the drug, and if the dose is administered in a larger amount than the above dose, there is a problem that non-specific side effects or decrease in therapeutic efficacy due to overdose of the drug appear.
아울러, 본 발명에 있어서 “개체”란 우울장애 또는 불안장애 증상을 나타내는 포유류를 의미하며, 바람직하게는 인간 또는 가축을 의미한다. In addition, in the present invention, "individual" means a mammal showing symptoms of a depressive disorder or an anxiety disorder, and preferably means a human or livestock.
또한, 본 발명에서 “예방”이란 본 발명에 따른 조성물의 투여에 의해 불안, 공포, 우울감이 정상적인 범주에서 벗어나지 않게 하거나, 삶에 대한 흥미 및 관심이 유지되도록 하여 우울증 또는 우울장애 발생을 지연시키는 모든 행위를 의미하고, “치료”란 본 발명에 따른 조성물의 투여에 의해 불안장애 또는 우울장애 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미하며, “개선”이란 본 발명에 따른 조성물의 투여에 의해 우울장애 또는 불안장애와 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다. In addition, the term "prevention" in the present invention means that anxiety, fear, and depression do not deviate from the normal range by administration of the composition according to the present invention, or any interest and interest in life are maintained to delay the occurrence of depression or depressive disorder. It means an action, and "treatment" means any action in which symptoms of anxiety disorder or depressive disorder are improved or advantageously changed by the administration of the composition according to the present invention, and "improvement" means depression by administration of the composition according to the present invention. Any action that reduces the severity of a disability or an anxiety disorder-related parameter, e.g. symptoms.
본 발명에서 약학적 조성물 (pharmaceutical composition)은 약학적 조성물의 제조에 통상적으로 사용되는 적절한 담체, 부형제, 및 희석제를 더 포함할 수 있다. In the present invention, the pharmaceutical composition (pharmaceutical composition) may further include a suitable carrier, excipient, and diluent commonly used in the preparation of the pharmaceutical composition.
본 발명에서 "담체 (carrier)"란 비이클 (vehicle)이라고도 불리우며, 세포 또는 조직 내로의 단백질 또는펩타이드의 부가를 용이하게 하는 화합물을 의미하는 것으로서, 예를 들어, 디메틸술폭사이드 (DMSO)는 생물체의 세포 또는 조직 내로의 많은 유기물의 투입을 용이하게 하는 통상 사용되는 담체이다.In the present invention, the term "carrier" is also called a vehicle, and refers to a compound that facilitates the addition of proteins or peptides into cells or tissues. For example, dimethyl sulfoxide (DMSO) is It is a commonly used carrier that facilitates the introduction of a large number of organic substances into cells or tissues.
본 발명에서 "희석제 (diluent)"란 대상 단백질 또는 펩타이드의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 단백질 또는 펩타이드를 용해시키게 되는 물에서 희석되는 화합물로 정의된다. 버퍼 용액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 버퍼 용액은 포스페이트 버퍼 식염수이며, 이는 인간 용액의 염 상태를 모방하고 있기 때문이다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형하는 일은 드물다. 여기에 사용된 아젤라산을 함유하는 화합물들은 인간 환자에게 그 자체로서, 또는 결합 요법에서와 같이 다른 성분들과 함께 또는 적당한 담체나 부형제와 함께 혼합된 약제학적 조성물로서 투여될 수 있다.In the present invention, "diluent" is defined as a compound diluted in water that not only stabilizes the biologically active form of the protein or peptide of interest, but also dissolves the protein or peptide. Salts dissolved in buffer solutions are used as diluents in the art. The commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely alter the biological activity of a compound. The compounds containing azelaic acid as used herein can be administered to a human patient as such, or as a pharmaceutical composition mixed with other ingredients, such as in combination therapy, or with a suitable carrier or excipient.
본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 이하 특정 실시예들을 도면에 예시하고 상세한 설명에 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.In the present invention, various transformations can be applied and various embodiments can be applied, and specific embodiments are illustrated in the drawings and described in detail in the detailed description below. However, this is not intended to limit the present invention to a specific embodiment, it is to be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.
[실시예][Example]
실시예 1. 실험 동물의 준비Example 1. Preparation of experimental animals
동물을 이용한 모든 실험 절차는 고려대학교 동물 관리 및 사용 위원회의 승인과 고려대학교의 지침에 따라 수행되었다. 실험동물은 C57BL/6 수컷 마우스(Japan SLC, Inc., 일본)를 사용하였으며, 실험동물을 실험 전 일주일간 길들인 후, 임의로 시험군(Baclofen 또는 SCH50911 투약)과 대조군(PBS 주입)으로 구분하였다.All experimental procedures using animals were approved by the Animal Care and Use Committee of Korea University and were performed in accordance with the guidelines of Korea University. Experimental animals were C57BL/6 male mice (Japan SLC, Inc., Japan), and after taming the experimental animals for one week before the experiment, they were randomly divided into a test group (administered with Baclofen or SCH50911) and a control group (injected with PBS).
실시예 2. 실험 동물에 약물 투여Example 2. Drug administration to experimental animals
실험용 마우스에게 비강으로 약물을 투여하기 위하여, 4% 이소플루란(isoflurane)으로 호흡마취를 시행하였다. 마취된 생쥐는 도 1에 나타낸 바와 같이 비강이 충분히 확보되도록 머리가 아래쪽을 향하도록 파지한 후, 마이크로 피펫을 이용하여 한방울에 2.5 μl씩 넣어서 최종적으로 10 μl 정도가 비강으로 들어가도록 하였다. 마취시간은 투약을 완료하기에 충분한 최소 시간 동안 무의식 상태를 유도하도록 선택하였다. Baclofen과 SCH50911의 투여량은 복강내 주사방법에 사용된 양을 고려하여 각각 마우스당 1.6 mg/kg과 4 mg/kg으로 결정하였다. 마우스는 약물의 비강내 투여 후 1~2분 사이에 의식이 돌아오며, 완전한 회복까지 30분이면 충분하였다. 충분히 회복된 마우스로 동물행동 테스트를 실시하였다.Respiratory anesthesia was performed with 4% isoflurane in order to administer the drug to the experimental mice nasally. As shown in FIG. 1, the anesthetized mice were gripped with their heads facing downwards so that the nasal cavity was sufficiently secured, and then 2.5 μl of each drop was added to each drop using a micropipette, so that about 10 μl of the anesthetized mice finally entered the nasal cavity. Anesthesia time was chosen to induce an unconscious state for a minimum time sufficient to complete dosing. The dosage of Baclofen and SCH50911 was determined to be 1.6 mg/kg and 4 mg/kg per mouse, respectively, taking into account the amount used in the intraperitoneal injection method. Mice returned to consciousness within 1-2 minutes after intranasal administration of the drug, and 30 minutes was sufficient for complete recovery. Animal behavior tests were performed with sufficiently recovered mice.
실험용 마우스에게 GABA-B 수용체 특이적 길항제인 SCH50911을 복강으로 약물을 투여하기 위하여, PBS(Phosphate-buffered saline)에 희석하여 주사 가능한 SCH50911 용액을 제조하여 마우스당 4 mg/kg을 투약하였다.In order to intraperitoneally administer SCH50911, a GABA-B receptor-specific antagonist, to experimental mice, an injectable SCH50911 solution was prepared by diluting in PBS (Phosphate-buffered saline) and administered 4 mg/kg per mouse.
실시예 3. 동물 행동 실험Example 3. Animal behavior experiment
3-1. 고도 제로 미로 테스트(Elevated zero maze test, EZM)3-1. Elevated zero maze test (EZM)
마우스를 원형이면서 서로 마주보는 두 사분면은 벽으로 막혀 있는 닫힌 구역(closed arm), 나머지 두 사분면은 벽이 없는 열린 구역(open arm)인 고도 제로 미로의 닫힌 구역에 놓고 5분 동안 미로를 탐사하도록 허용하였다. 전체 테스트 시간동안 동물의 움직임은 비디오 분석을 위해 기록하였으며, 행동 측정은 열린 구역에서 보낸 시간의 비율과 열린 구역으로 들어가는 빈도로 구성되었다. 4개의 모든 발이 열린 구역에 있을 때, 마우스는 열린 구역에 있는 것으로 분석되었다. 열린 구역은 개방이 되어 있어 생쥐에게 불안감을 유발하므로, 열린 구역에 머무는 시간이나 방문 횟수가 증가한 경우 불안감이 감소된 것으로 볼 수 있다.Place the mouse in the closed area of the altitude zero maze, which is an open arm with two round and facing quadrants with walls, and the other two quadrants and explore the maze for 5 minutes. Allowed. Animal movements during the entire test period were recorded for video analysis, and behavioral measurements consisted of the percentage of time spent in the open area and frequency of entering the open area. When all four paws were in the open area, the mice were analyzed as being in the open area. Since the open area is open, it causes anxiety in the mice, so if the time spent in the open area or the number of visits increases, it can be seen that anxiety decreases.
3-2. 꼬리 현수법(Tail suspension test, TST)3-2. Tail suspension test (TST)
꼬리 현수법 장치에는 4개의 구획이 불투명한 칸막이로 나뉘어져 있으며, 전체 장치는 무광택 아크릴로 만들어져 있다. 각 마우스는 테이프를 사용하여 꼬리를 고정시켜 주변 표면을 잡거나 탈출할 수 없도록 6분간 공중에 부유시켰다. 부동성(immobility)은 사지의 움직임이 전혀 없는 상태로 정의하였다. 6분간의 시험 기간 동안, 마지막 4분 동안 부동성을 기록하였다. 마우스가 부동자세로 있는 시간이 길수록 절망감이 심한 것으로 볼 수 있다.The tail suspension device has four compartments divided into opaque partitions, and the entire device is made of matte acrylic. Each mouse was suspended in the air for 6 minutes so that the tail was fixed with a tape so that it could not grab the surrounding surface or escape. Immobility was defined as a state in which the limb had no movement. During the 6 minute test period, immobility was recorded for the last 4 minutes. The longer the mouse is in the immobile position, the greater the feeling of despair.
3-3. 강제 수영 실험(Forced swim test, FST)3-3. Forced swim test (FST)
강제 수영 실험의 경우, 섭씨 24~25도의 수돗물로 부분적으로 채워진 깨끗한 실린더(직경 12cm, 높이 24cm)에 마우스를 넣었다. 능동적(수영 또는 등반) 또는 수동적(부동성) 행동의 측정을 위해 물의 깊이는 뒷다리 또는 꼬리가 실린더 바닥에 닿지 않도록 설정하였다. 행동은 6분동안 적외선 카메라를 사용하여 기록하였다. 부동성(immobility)은 물 위로 머리를 떠올리기 위해 필요한 최소한의 움직임을 제외하고는 아무런 움직임도 없는 상태로 정의하였다. 6분간의 시험 기간 중 마지막 4분 동안 움직이지 않는 행동의 지속시간을 기록하였다. 마우스가 부동자세로 있는 시간이 길수록 절망감이 심한 것으로 볼 수 있다.In the case of the forced swimming experiment, the mouse was placed in a clean cylinder (diameter 12 cm, height 24 cm) partially filled with tap water at 24 to 25 degrees Celsius. For the measurement of active (swimming or climbing) or passive (floating) behavior, the depth of water was set so that the hind legs or tail did not touch the bottom of the cylinder. Actions were recorded using an infrared camera for 6 minutes. Immobility was defined as a state in which there was no movement except for the minimum movement required to float the head above the water. The duration of motionless behavior was recorded during the last 4 minutes of the 6-minute test period. The longer the mouse is in the immobile position, the greater the feeling of despair.
3-4. GABA-B 수용체의 효능제 비강 투여 결과3-4. Results of nasal administration of GABA-B receptor agonists
GABA-B 수용체 특이적 효능제인 baclofen의 비강을 통한 약물 전달 후 실시한 꼬리 현수법에서 baclofen이 투약된 마우스는 PBS가 투여된 대조군 마우스에 비해서 부동성이 감소하는 결과를 보여 우울증의 핵심 증상인 절망감이 감소함을 확인할 수 있었다 (도 2 참조). 즉, baclofen의 비강 투여를 통해 절망감을 감소시키는 효과를 얻을 수 있음을 알 수 있었다. 이러한 결과는 기존의 복강 주사를 통한 baclofen이 불안증세는 완화시키며, 절망감은 증가시킨다는 결과와 완전히 상반되는 것이다.In the tail suspension performed after nasal delivery of baclofen, a GABA-B receptor-specific agonist, mice treated with baclofen showed a lower immobility compared to control mice administered with PBS, reducing hopelessness, a key symptom of depression. It could be confirmed that (see Fig. 2). In other words, it was found that the effect of reducing hopelessness can be obtained through nasal administration of baclofen. This result is completely contrary to the result that baclofen through intraperitoneal injection relieves anxiety symptoms and increases hopelessness.
3-4. GABA-B 수용체의 길항제 비강 투여 결과3-4. Results of nasal administration of GABA-B receptor antagonist
GABA-B 수용체 특이적 길항제인 SCH50911의 비강을 통한 약물 전달 후 실시한 고도 제로 미로 테스트에서 SCH50911이 투약된 마우스는 PBS가 투여된 대조군 마우스에 비해서 열린 구역에 머무는 시간과 열린 구역으로의 이동 횟수 모두 통계적으로 증가하는 결과로부터 불안증이 감소함을 확인할 수 있었다 (도 3 참조). 꼬리 현수법과 강제 수영 실험에서는 아무런 차이를 보이지 않음으로써 절망감과 관련된 파라미터에는 영향을 미치지 않는 것으로 판단되었다. 이러한 결과는 기존의 복강 주사를 통한 SCH50911이 불안증세는 감소시키는 결과와 일치하였으나, 강제 수영 검사에서 부동성을 감소시킴으로서 항우울 효능이 있다는 결과와는 차이가 있다. In the high zero maze test conducted after nasal drug delivery of SCH50911, a GABA-B receptor-specific antagonist, mice administered with SCH50911 were statistically statistically significant in terms of time to stay in the open area and the number of movements to the open area compared to control mice administered with PBS. It was confirmed that anxiety decreased from the result of increasing by (see FIG. 3). There was no difference between the tail suspension method and the forced swimming experiment, so it was judged that the parameters related to the feeling of hopelessness were not affected. These results are consistent with the results of the conventional intraperitoneal injection of SCH50911 to reduce anxiety symptoms, but are different from the results of antidepressant efficacy by reducing immobility in the forced swimming test.
3-4. GABA-B 수용체의 길항제 복강 투여 결과3-4. Results of intraperitoneal administration of GABA-B receptor antagonists
GABA-B 수용체 특이적 길항제인 SCH50911을 복강을 통한 약물 전달 후 실시한 동물행동평가에서는 고도 제로 미로 테스트, 꼬리 현수법, 강제 수영 실험 모두에 아무런 통계적 차이를 보이지 않았다 (도 4 참조). 따라서 복강을 통한 약물 투약보다는 비강을 통한 약물 투약이 우울증 관련 행동 변화에 효과가 더 우수한 것으로 판단된다. In the animal behavior evaluation conducted after drug delivery of the GABA-B receptor-specific antagonist SCH50911 through the intraperitoneal cavity, there was no statistical difference in all of the high zero maze test, tail suspension method, and forced swimming experiment (see FIG. 4). Therefore, it is judged that nasal drug administration is more effective in depression-related behavioral changes than drug administration through abdominal cavity.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As described above, a specific part of the present invention has been described in detail, and for those of ordinary skill in the art, it is obvious that this specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.
Claims (8)
상기 조성물은 비강 투여용인 것을 특징으로 하는, 약학적 조성물.
As a pharmaceutical composition containing a GABA-B receptor-specific agonist as an active ingredient and having an antidepressant effect,
The composition is characterized in that for nasal administration, pharmaceutical composition.
상기 조성물은 1일 1회 투여하되, 단위 kg당 GABA-B 수용체에 특이적인 효능제를 1 내지 4 mg 투여하도록 GABA-B 수용체에 특이적인 효능제를 포함하는 것을 특징으로 하는, 약학적 조성물.
The method of claim 1,
The composition is administered once a day, characterized in that it comprises a GABA-B receptor-specific agonist to administer 1 to 4 mg of an agonist specific to the GABA-B receptor per kg.
상기 항우울 효과는 절망감 완화에 의한 것을 특징으로 하는, 약학적 조성물.
The method of claim 1,
The antidepressant effect is characterized in that by relieving the feeling of hopelessness, pharmaceutical composition.
상기 GABA-B 수용체에 특이적인 효능제는 Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen 및 Arbaclofen Placarbil으로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 하는, 약학적 조성물.
The method of claim 1,
The GABA-B receptor-specific agonist is at least one selected from the group consisting of Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen and Arbaclofen Placarbil. To, pharmaceutical composition.
상기 조성물은 비강 투여용인 것을 특징으로 하는, 약학적 조성물.
As a pharmaceutical composition containing an antagonist specific to GABA-B receptor as an active ingredient and having an anti-anxiety effect,
The composition is characterized in that for nasal administration, pharmaceutical composition.
상기 조성물은 우울 증세에는 영향을 미치지 않으면서 불안 증세 완화 효과를 갖는 것을 특징으로 하는, 약학적 조성물.
The method of claim 5,
The composition is characterized in that it has an effect of reducing anxiety symptoms without affecting the symptoms of depression, pharmaceutical composition.
상기 조성물은 1일 1회 투여하되, 단위 kg당 GABA-B 수용체에 특이적인 길항제를 2 내지 4 mg 투여하도록 GABA-B 수용체에 특이적인 길항제를 포함하는 것을 특징으로 하는, 약학적 조성물.
The method of claim 5,
The composition is administered once a day, but comprises a GABA-B receptor specific antagonist to administer 2 to 4 mg of an antagonist specific to the GABA-B receptor per kg.
상기 GABA-B 수용체에 특이적인 길항제는 CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, 및 SCH-50911으로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 하는, 약학적 조성물.The method of claim 5,
The GABA-B receptor specific antagonist is at least one selected from the group consisting of CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, and SCH-50911. , Pharmaceutical composition.
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US20050215521A1 (en) | 2003-12-22 | 2005-09-29 | Karim Lalji | Modafinil combination therapy for improving sleep quality |
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CN117257815A (en) * | 2023-11-20 | 2023-12-22 | 中国人民解放军军事科学院军事医学研究院 | New application of CGP35348 in preparation of antidepressant drugs |
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