JP4012994B2 - Anxiolytic - Google Patents
Anxiolytic Download PDFInfo
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- JP4012994B2 JP4012994B2 JP11375996A JP11375996A JP4012994B2 JP 4012994 B2 JP4012994 B2 JP 4012994B2 JP 11375996 A JP11375996 A JP 11375996A JP 11375996 A JP11375996 A JP 11375996A JP 4012994 B2 JP4012994 B2 JP 4012994B2
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Description
【0001】
【発明の属する技術分野】
本発明は、抗不安薬に関する。
【0002】
【発明が解決しようとする課題】
本発明の有効成分であるカルボスチリルに類似する化合物は、例えば特開昭55−127371号公報、特開昭56−46812号公報、特開昭55−124766号公報等に記載されている。これらの化合物の中には、抗不安薬としての用途の示唆されたものもある(特開昭56−46812号公報)。しかしながら、本発明者がこれらの化合物について、抗不安作用の強さをラットVogel型コンフリクト行動に対する作用で調べたところ、前記各公報に開示されたカルボスチリル化合物は、いずれも抗不安作用が弱すぎ、所望の治療効果が発現され難く、抗不安薬として実用的でないことが判明した。
【0003】
一方、本発明の有効成分であるジヒドロカルボスチリルは、特開平2−191256号公報に記載されており、該ジヒドロカルボスチリルが精神分裂病治療剤として有用であることも知られている。
【0004】
【課題を解決するための手段】
本発明者らは、上記ジヒドロカルボスチリルにつき引続き研究を重ねた結果、該ジヒドロカルボスチリルが精神分裂病治療作用からは予測できない抗不安作用、特にラットVogel型コンフリクト行動に対する抗不安作用を有しており、しかもこの種の抗不安作用が上記各公報に記載の化合物のそれに比し格段に優れたものであることを見い出した。本発明は、斯かる知見に基づき完成されたものである。
【0005】
即ち、本発明は、7−{4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]ブトキシ}−3,4−ジヒドロカルボスチリル及びその塩からなる群より選ばれた少なくとも1種を含有することを特徴とする抗不安薬に係る。
【0006】
本発明の抗不安薬は、優れた抗不安作用、特にラットVogel型コンフリクト行動に対する抗不安作用を有している。
【0007】
【発明の実施の形態】
本発明の抗不安薬は、7−{4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]ブトキシ}−3,4−ジヒドロカルボスチリル及びその塩からなる群より選ばれた少なくとも1種を有効成分として含有するものである。
【0008】
7−{4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]ブトキシ}−3,4−ジヒドロカルボスチリルは、これに医薬的に許容される酸を作用させることにより容易に酸付加塩とすることができる。該酸としては例えば塩酸、硫酸、リン酸、臭化水素酸等の無機酸、シュウ酸、マレイン酸、フマール酸、リンゴ酸、酒石酸、クエン酸、安息香酸等の有機酸を挙げることができる。
【0009】
斯くして得られる塩形態の本発明化合物は、通常の分離手段により反応混合物から容易に単離精製することができる。該分離手段としては、例えば溶媒抽出法、稀釈法、再結晶法、カラムトグラフィー等、プレパラティブ薄層クロマトグラフィー等を例示できる。
【0010】
本発明の有効成分化合物は、通常一般的な医薬製剤の形態で用いられる。製剤は通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤等の稀釈剤或いは賦形剤を用いて調製される。この医薬製剤としては各種の形態が治療目的に応じて選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤(液剤、懸濁剤等)等が挙げられる。錠剤の形態に成形するに際しては、担体としてこの分野で従来公知の各種のものを広く使用することが使用でき、例えば乳剤、白糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸カリシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤、乾燥デンプン、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤、白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤、第四級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、デンプン等の保湿剤、デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、精製タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコール等の滑沢剤等を使用できる。更に錠剤は必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠或いは二重錠、多層錠とすることができる。丸剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤、ラミナランカンテン等の崩壊剤等を使用できる。坐剤の形態に成形するに際しては、担体として従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等を挙げることができる。注射剤として調製される場合には、液剤及び懸濁剤は殺菌され、且つ血液と等張であるのが好ましく、これら液剤、丸剤及び懸濁剤の形態に成形するに際しては、希釈剤としてこの分野において慣用されているものを全て使用でき、例えば水、エチルアルコール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。尚、この場合等張性の溶液を調製するに充分な量の食塩、ブドウ糖或いはグリセリンを本発明薬剤中に含有せしめてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。更に必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を該薬剤中に含有せしめてもよい。
【0011】
本発明の抗不安薬中に含有されるべき本発明の有効成分化合物の量は、特に限定されず広い範囲内から適宜選択されるが、通常全組成物中約1〜70重量%、好ましくは約1〜30重量%である。
【0012】
本発明の抗不安薬の投与方法は特に制限はなく、各種製剤形態、患者の年齢、性別その他の条件、疾患の程度等に応じた方法で投与される。例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤及びカプセル剤の場合には、経口投与される。また注射剤の場合には単独で或いはブドウ糖、アミノ酸等の通常の補液と混合して静脈内投与され、更には必要に応じて単独で筋肉内、皮内、皮下もしくは腹腔内投与される。坐剤の場合には直腸内投与される。
【0013】
本発明の抗不安薬の投与量は、用法、患者の年齢、性別その他の条件、疾患の程度等により適宜選択されるが、通常本発明の有効成分化合物の量は、1日当り体重1kg当り約0.1〜10mg程度とするのがよい。また投与単位形態中に有効成分化合物を1〜200mg含有するのがよい。
【0014】
【実施例】
以下に、薬理試験結果及び製剤例を掲げる。
【0015】
下記の薬理試験には、供試化合物として次の化合物を使用した。
【0016】
供試化合物
1.7−{4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]ブトキシ}−3,4−ジヒドロカルボスチリル
2.7−{3−[4−(2,3−ジメチルフェニル)−1−ピペラジニル]プロポキシ}カルボスチリル(特開昭55−127371号公報、特開昭56−46812号公報及び特開昭55−124766号公報に開示されている化合物)
薬理試験1(ラットVogel型コンフリクト行動に対する作用)
Vogel et al.(Psychopharmacologia Berl.21:1,1971)の方法に準じて行った。即ち、本試験2日前午前10時30分頃より、ラットを絶水状態で飼育した。本試験前日に給水瓶よりドリンコメーターを介したチューブが連結しているラット用水吸い口が内部に備わっているスキナーボックス内で10分間の飲水訓練を行った。本試験午前中にも5分間の飲水訓練を行い、その後群分けを行って、午後より供試化合物を経口投与し、その1時間後より本試験を開始した。ラットが水吸い口より水を呑むことによってドリンコメーター内で落下する水滴数を飲水反応数として測定し、本試験では、実験開始後始めの10飲水反応数で床のグリッドを介してラットへ1発の電気ショック(0.6〜0.7mA、ショック時間0.2秒)がかかり、その後は5飲水反応数ごとに1発づつの電気ショックがかかる様にコンピューターシステム(BIO MEDICA製)でプログラムされている。ドリンコメーター内の飲水反応数の記録時間は5分間とし、最初の1発目の電気ショック後の総飲水反応数を同コンピューターシステムにて記録、保存した。結果を表1に示す。
【0017】
【表1】
【0018】
薬理試験2(自由飲水行動に対する作用)
薬理試験1と同じ様に、ラットを絶水状態で飼育し、まず飲水訓練を行った。同様に、本試験午前中にも5分間の飲水訓練を行い、その後群分けを行って、午後より供試化合物を経口投与し、その1時間後より本試験を開始した。本試験では電気ショックがかからない条件下で5分間の総飲水反応数を同コンピューターシステムにて記録、保存した。結果を表2に示す。
【0019】
薬理試験3(電気ショックに対する感受性に対する試験)
スキナーボックス内の床のグリッドを介して、ラットへ電気ショックを与えた。即ち、電流を0.1mAから0.2mAづつ上げて行き、ラットがすくみ反応を示す電流を求め、この閾値電流を指標としてラットの電気ショックに対する感受性に対する供試化合物の影響を検討した。結果を表2に示す。
【0020】
【表2】
【0021】
薬理試験4(ラットVogel型コンフリクト行動に対する作用)
Vogel et al.(Psychopharmacologia Berl.21:1,1971)の方法に準じて行った。即ち、本試験2日前午前10時30分頃より、ラットを絶水状態で飼育した。本試験前日に給水瓶よりドリンコメーターを介したチューブが連結しているラット用水吸い口が内部に備わっているスキナーボックス内で10分間の飲水訓練を行った。本試験午前中にも5分間の飲水訓練を行い、その後群分けを行って、午後より供試化合物を経口投与し、その1時間後より本試験を開始した。ラットが水吸い口より水を呑むことによってドリンコメーター内で落下する水滴数を飲水反応数として測定し、本試験では、実験開始後始めの10飲水反応数で床のグリッドを介してラットへ1発の電気ショック(0.6〜0.7mA、ショック時間0.2秒)がかかり、その後は5飲水反応数ごとに1発づつの電気ショックがかかる様にコンピューターシステム(BIO MEDICA製)でプログラムされている。ドリンコメーター内の飲水反応数の記録時間は5分間とし、最初の1発目の電気ショック後の総飲水反応数を同コンピューターシステムにて記録、保存した。結果を表3に示す。
【0022】
【表3】
【0023】
上記薬理試験より次のことが判る。
【0024】
本発明の有効成分化合物(供試化合物1)は、電気ショックによる飲水反応数の低下を有意に抑制し、優れた抗コンフリクト作用、即ち抗不安作用を有している。
【0025】
本発明の有効成分化合物は、非電気ショック下の飲水反応数及びすくみ反応の閾値電流に有意な影響を及ぼさなかった。従って本発明の有効成分化合物の優れた抗不安作用は、有効成分化合物が飲水欲望を亢進及び電気ショックに対する感受性を低下させた結果生じた虚偽陽性反応(false positive)ではないことが証明された。
【0026】
本発明の有効成分化合物は、比較化合物(供試化合物2)に対して、抗不安作用において有意に且つ極めて優れている。
【0027】
常法により、1錠中に上記組成を含有する錠剤を製造した。
【0028】
上記パラベン類、メタ重亜硫酸ナトリウム及び塩化ナトリウムを攪拌しながら89℃で上記の蒸留水に溶解した。得られた溶液を40℃まで冷却し、本発明有効成分化合物、ポリエチレングリコール及びポリオキシエチレンソルビタンモノオレートを順次溶解させ、次のその溶液に注射用蒸留水を加えて最終の容量に調整し、適当なフィルターペーパーを用いて滅菌濾過して1mlずつアンプルに分注し、注射剤を調製した。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an anxiolytic drug.
[0002]
[Problems to be solved by the invention]
Compounds similar to carbostyril, which is an active ingredient of the present invention, are described in, for example, JP-A-55-127371, JP-A-56-46812, JP-A-55-124766, and the like. Some of these compounds have been suggested for use as anxiolytic drugs (Japanese Patent Laid-Open No. 56-46812). However, when the present inventor examined the strength of the anxiolytic action of these compounds by the action on rat Vogel type conflict behavior, all of the carbostyril compounds disclosed in the above publications have too weak anxiolytic action. Thus, it has been found that the desired therapeutic effect is hardly expressed and is not practical as an anxiolytic drug.
[0003]
On the other hand, dihydrocarbostyril, which is an active ingredient of the present invention, is described in JP-A-2-191256, and it is also known that the dihydrocarbostyril is useful as a therapeutic agent for schizophrenia.
[0004]
[Means for Solving the Problems]
As a result of continuous research on the above-mentioned dihydrocarbostyril, the present inventors have shown that the dihydrocarbostyril has an anxiolytic action that cannot be predicted from a schizophrenia treatment action, in particular, an anti-anxiety action against rat Vogel type conflict behavior. In addition, it has been found that this type of anxiolytic action is much superior to that of the compounds described in the above publications. The present invention has been completed based on such findings.
[0005]
That is, the present invention provides at least one selected from the group consisting of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril and salts thereof. It relates to an anxiolytic drug characterized by containing.
[0006]
The antianxiety drug of the present invention has an excellent anxiolytic action, particularly an anxiolytic action against rat Vogel type conflict behavior.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The anti-anxiety drug of the present invention is at least one selected from the group consisting of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril and salts thereof. It contains seeds as an active ingredient.
[0008]
7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril is easily acidified by reacting it with a pharmaceutically acceptable acid. It can be a salt. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid.
[0009]
The thus obtained compound of the present invention in the form of a salt can be easily isolated and purified from the reaction mixture by ordinary separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like.
[0010]
The active ingredient compound of the present invention is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using a commonly used diluent or excipient such as a filler, a filler, a binder, a moistening agent, a disintegrant, a surfactant, a lubricant and the like. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). When forming into a tablet form, various carriers conventionally known in this field can be widely used as a carrier. For example, emulsion, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose , Excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate , Kanteng powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc., sucrose, stearin, cacao butter, hydrogenated Disintegration inhibitors such as oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, Lubricants such as stearate, boric acid powder and polyethylene glycol can be used. Furthermore, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. In molding into a pill form, conventionally known carriers can be widely used as carriers, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, A binder such as tragacanth powder, gelatin, ethanol or the like, a disintegrant such as lamina lankanten, or the like can be used. In molding into a suppository, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like. When prepared as injections, the solutions and suspensions are preferably sterilized and isotonic with blood, and when formed into these solutions, pills and suspensions, as diluents Any of those commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the drug of the present invention to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. are added. May be. Furthermore, if necessary, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the drug.
[0011]
The amount of the active ingredient compound of the present invention to be contained in the anxiolytic drug of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 1 to 70% by weight in the total composition, preferably About 1 to 30% by weight.
[0012]
The administration method of the anxiolytic drug of the present invention is not particularly limited, and it is administered according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal fluid such as glucose or amino acid, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally.
[0013]
The dose of the anxiolytic drug of the present invention is appropriately selected depending on the usage, patient age, sex and other conditions, the degree of disease, etc. Usually, the amount of the active ingredient compound of the present invention is approximately about 1 kg of body weight per day. It is good to set it as about 0.1-10 mg. Moreover, it is good to contain 1-200 mg of active ingredient compounds in a dosage unit form.
[0014]
【Example】
The pharmacological test results and formulation examples are listed below.
[0015]
The following compounds were used as test compounds in the following pharmacological tests.
[0016]
Test compound 1.7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril 2.7- {3- [4- (2,3- Dimethylphenyl) -1-piperazinyl] propoxy} carbostyril (compounds disclosed in JP-A-55-127371, JP-A-56-46812 and JP-A-55-124766)
Pharmacological study 1 (effect on rat Vogel conflict behavior)
This was performed according to the method of Vogel et al. (Psychopharmacologia Berl. 21 : 1, 1971). That is, the rats were bred in a water-free state from about 10:30 am two days before the test. On the day before this test, a water training for 10 minutes was performed in a skinner box equipped with a water suction mouth for a rat connected to a tube through a drink meter from a water bottle. In the morning of this test, a 5-minute drinking training was conducted, and then grouping was performed. The test compound was orally administered in the afternoon, and the test was started 1 hour later. The number of water drops falling in the drink meter when the rat swallows water from the water mouth is measured as the number of drinking reactions. In this study, the number of drinking reactions at the first 10 after the start of the experiment is 1 to the rat via the floor grid. A computer system (manufactured by BIO MEDICA) is programmed so that an electric shock (0.6-0.7 mA, shock time 0.2 seconds) is applied, and then one electric shock is applied every 5 drinking reactions. Has been. The recording time of the number of drinking reactions in the drink meter was 5 minutes, and the total number of drinking reactions after the first electric shock was recorded and stored with the same computer system. The results are shown in Table 1.
[0017]
[Table 1]
[0018]
Pharmacological test 2 (effect on free drinking behavior)
In the same manner as in Pharmacological Test 1, the rats were bred in a water-absent state, and were first subjected to drinking training. Similarly, in the morning of this study, a 5-minute water drinking training was conducted, and then grouping was performed. The test compound was orally administered in the afternoon, and the study was started 1 hour later. In this test, the total drinking water reaction number for 5 minutes was recorded and stored with the same computer system under conditions where no electric shock was applied. The results are shown in Table 2.
[0019]
Pharmacological test 3 (test for sensitivity to electric shock)
Rats were given an electric shock through the floor grid in the skinner box. That is, the current was increased from 0.1 mA by 0.2 mA, a current indicating a rat's freezing reaction was determined, and the influence of the test compound on the rat's sensitivity to electric shock was examined using this threshold current as an index. The results are shown in Table 2.
[0020]
[Table 2]
[0021]
Pharmacological test 4 (effect on rat Vogel conflict behavior)
This was performed according to the method of Vogel et al. (Psychopharmacologia Berl. 21 : 1, 1971). That is, the rats were bred in a water-free state from about 10:30 am two days before the test. On the day before this test, a water training for 10 minutes was performed in a skinner box equipped with a water suction mouth for a rat connected to a tube through a drink meter from a water bottle. In the morning of this test, a 5-minute drinking training was conducted, and then grouping was performed. The test compound was orally administered in the afternoon, and the test was started 1 hour later. The number of water drops falling in the drink meter when the rat swallows water from the water mouth is measured as the number of drinking reactions. In this study, the number of drinking reactions at the first 10 after the start of the experiment is 1 to the rat via the floor grid. A computer system (manufactured by BIO MEDICA) is programmed so that an electric shock (0.6-0.7 mA, shock time 0.2 seconds) is applied, and then one electric shock is applied every 5 drinking reactions. Has been. The recording time of the number of drinking reactions in the drink meter was 5 minutes, and the total number of drinking reactions after the first electric shock was recorded and stored with the same computer system. The results are shown in Table 3.
[0022]
[Table 3]
[0023]
The following can be seen from the above pharmacological test.
[0024]
The active ingredient compound of the present invention (test compound 1) significantly suppresses the decrease in the number of drinking reactions caused by electric shock, and has an excellent anti-conflict action, that is, an anxiolytic action.
[0025]
The active ingredient compound of the present invention did not significantly affect the number of drinking responses under non-electric shock and the threshold current of freezing response. Therefore, it was proved that the excellent anti-anxiety action of the active ingredient compound of the present invention was not a false positive reaction that occurred as a result of the active ingredient compound enhancing the desire to drink and reducing the sensitivity to electric shock.
[0026]
The active ingredient compound of the present invention is significantly and extremely superior in anti-anxiety action over the comparative compound (Test Compound 2).
[0027]
A tablet containing the above composition in one tablet was produced by a conventional method.
[0028]
The parabens, sodium metabisulfite and sodium chloride were dissolved in the distilled water at 89 ° C. with stirring. The obtained solution is cooled to 40 ° C., the active ingredient compound of the present invention, polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in order, and the final volume is adjusted by adding distilled water for injection to the next solution, Sterile filtration was performed using an appropriate filter paper, and 1 ml was dispensed into ampoules to prepare an injection.
Claims (1)
Priority Applications (1)
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JP11375996A JP4012994B2 (en) | 1996-05-08 | 1996-05-08 | Anxiolytic |
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JP11375996A JP4012994B2 (en) | 1996-05-08 | 1996-05-08 | Anxiolytic |
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JPH09301867A JPH09301867A (en) | 1997-11-25 |
JP4012994B2 true JP4012994B2 (en) | 2007-11-28 |
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US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
AR032641A1 (en) * | 2001-01-29 | 2003-11-19 | Otsuka Pharma Co Ltd | RECEIVER SUBTIPE AGONIST 5-HT 1A. |
AR033485A1 (en) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME |
US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
SI1542668T1 (en) | 2002-08-20 | 2009-08-31 | Bristol Myers Squibb Co | Aripiprazole complex formulation and method |
TWI589301B (en) * | 2010-08-24 | 2017-07-01 | 大塚製藥股份有限公司 | Suspension and cake composition containing carbostyryl derivative and silicone oil and/or silicone oil derivative |
JOP20200109A1 (en) | 2012-04-23 | 2017-06-16 | Otsuka Pharma Co Ltd | Injectable preparation |
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1996
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