JP2002524508A - New composition - Google Patents
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- JP2002524508A JP2002524508A JP2000569802A JP2000569802A JP2002524508A JP 2002524508 A JP2002524508 A JP 2002524508A JP 2000569802 A JP2000569802 A JP 2000569802A JP 2000569802 A JP2000569802 A JP 2000569802A JP 2002524508 A JP2002524508 A JP 2002524508A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
(57)【要約】 本発明は(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチルアミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カルボキサミド1水和物である第1の成分(a)および遊離の塩基または製薬上許容しうる塩および/またはその溶媒和物の形態のパロキセチンである第2の成分(b)を含有する組成物、その調製方法、その組成物を含む医薬組成物、その組成物の使用およびこれを用いた気分障害および不安障害のような感情障害の治療方法並びにその組成物を含むキットに関する。 (57) [Summary] The present invention relates to (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate. A composition comprising a first component (a) and a second component (b) which is paroxetine in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof, a process for preparing the same, The present invention relates to a pharmaceutical composition comprising the composition, a use of the composition and a method for treating emotional disorders such as mood disorders and anxiety disorders using the composition, and a kit comprising the composition.
Description
【0001】[0001]
本発明は(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチルアミノ
−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カルボキサ
ミド1水和物である第1の成分(a)およびパロキセチンまたは製薬上許容しう
るその塩および/または溶媒和物である第2の成分(b)を含有する組成物に関
する。本発明はまた、本発明の組成物の調製方法、その組成物を含む医薬組成物
、鬱病、不安、強迫障害(OCD)等のような感情障害の治療の改良法としての
同時投与または個別投与の何れかによる上記組成物の使用に関する。The present invention relates to (2R, 3R) -hydrogen (R) -3-tartrate-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate. A composition comprising a first component (a) and a second component (b) that is paroxetine or a pharmaceutically acceptable salt and / or solvate thereof. The present invention also relates to methods of preparing the compositions of the invention, pharmaceutical compositions containing the compositions, co-administration or separate administration as an improved method of treating emotional disorders such as depression, anxiety, obsessive-compulsive disorder (OCD) and the like. The use of the above composition according to any of the above.
【0002】[0002]
近年一般的には抗欝剤が完全な臨床作用を発揮するためには2〜4週間を要す
ると考えられている。一方、副作用は即座に生じる。即ち、抗欝剤の作用の発現
が遅いため、患者には副作用は経験するが薬剤の治療作用は経験できない過酷な
期間が与えられる。この期間に治療を継続するように患者を説得することは担当
医に重い負担を与える。更にまた、自殺の恐れの有る患者においては、作用の発
現が緩徐であるため、症状の完全な退行を経験することなく決断力が回復し、自
殺の危険性が残り、入院の必要性が頻発する。作用が急速に発現する抗欝剤はよ
り急速な症状の低減により有益であるのみならず、患者および医師がより許容し
やすいものであり、入院の必要性および期間を低減する。同じように長い完全臨
床作用に至るまでの時間は不安およびOCDのような他の感情障害の治療において
も認められている。In recent years, it is generally considered that it takes 2 to 4 weeks for an antidepressant to exert its full clinical effect. On the other hand, side effects are immediate. That is, since the onset of the action of the antidepressant is slow, the patient is given a severe period in which he / she can experience side effects but cannot experience the therapeutic action of the drug. Convincing the patient to continue treatment during this period places a heavy burden on the attending physician. Furthermore, in patients at risk of suicide, the onset of action is slow, so decision-making is restored without experiencing complete regression of the symptoms, the risk of suicide remains, and the need for hospitalization is frequent. I do. Antidepressants with rapid onset of action not only benefit from more rapid symptom reduction, but are also more tolerated by patients and physicians, reducing the need and duration of hospitalization. An equally long time to full clinical effect has been observed in the treatment of anxiety and other affective disorders such as OCD.
【0003】[0003]
WO96/33710号において、5−HT受容体に対して高い親和性を有し、5−
HT1A媒介応答を拮抗する化合物(R)−5−カルバモイル−8−フルオロ−3−
N,N−ジシクロブチルアミノ−3,4−ジヒドロ−2H−1−ベンゾピランがセ
ロトニン再取り込み抑制剤を投与した鬱病患者の急速な改善をもたらすことが開
示されている。WO 96/33710, which has a high affinity for the 5-HT receptor,
Compound (R) -5-carbamoyl-8-fluoro-3- which antagonizes HT 1A mediated response
It is disclosed that N, N-dicyclobutylamino-3,4-dihydro-2H-1-benzopyran provides rapid improvement in depressed patients receiving serotonin reuptake inhibitors.
【0004】[0004]
本発明は特異的5−HT1A拮抗剤(2R,3R)−酒石酸水素(R)−3−N,N−
ジシクロブチルアミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピ
ラン−5−カルボキサミド1水和物である第1の成分(a)および遊離の塩基ま
たは製薬上許容しうる塩および/またはその溶媒和物の形態のパロキセチンであ
る第2の成分(b)を含有する新しい組成物に関する。この組成物はより急速な
作用の発現を示し、その結果、感情障害、特に鬱病に罹患した患者のより効果的
な治療を可能にする。The present invention provides a specific 5-HT 1A antagonist (2R, 3R) -hydrogen tartrate (R) -3-N, N-
A first component (a) which is dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate and a free base or a pharmaceutically acceptable salt and / or Or a new composition comprising a second component (b) which is paroxetine in the form of a solvate thereof. This composition exhibits a more rapid onset of action, which allows for more effective treatment of patients suffering from emotional disorders, especially depression.
【0005】 動物実験において、選択的5−HT再取り込み抑制剤(SSRI)の急性の投
与は縫線核における側副5−HTアクソン放出5−HTにより恐らくは媒介され
る負方向のフィードバック反応を介した5−HTニューロンにおける電気インパ
ルス伝播を低減させることがわかっている。縫線核における体樹状突起(somato
dendritic)5−HT1A自己受容体を抑制することにより、選択的拮抗剤は5−
HT再取り込み抑制剤により生じた伝播の低下に対抗して作用する。このことは
、体樹状突起自己受容体の選択的遮断、即ち、5−HT1A拮抗剤は5−HT再取
り込み抑制剤(SSRI)の作用を改善する臨床的可能性を有し、感情障害の治療にお
ける作用、例えば抗欝作用の急速な発現のための新しい基盤を与えることを示し
ている。In animal studies, acute administration of a selective 5-HT reuptake inhibitor (SSRI) is via a negative feedback response, possibly mediated by collateral 5-HT axon release 5-HT in the raphe nucleus. Have been shown to reduce electrical impulse propagation in 5-HT neurons. Somato dendrites in the raphe nucleus (somato
dendritic) By inhibiting 5-HT 1A autoreceptors, selective antagonists
Acts against the reduced transmission caused by HT reuptake inhibitors. This suggests that selective blockage of somatic dendritic autoreceptors, ie, 5-HT 1A antagonists have clinical potential to improve the effects of 5-HT reuptake inhibitors (SSRIs), affect emotional disorders Has shown a new basis for the rapid onset of action in the treatment of, for example, antidepressant effects.
【0006】 本明細書に開示する化合物(2R,3R)−酒石酸水素(R)−3−N,N−ジ
シクロブチルアミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラ
ン−5−カルボキサミド1水和物(NAD 299)は選択的5−HT1A受容体
拮抗剤として J. Pharmacol. Exp. Ther., 283, 216-225(1997) に記載されてい
る。The compounds disclosed herein (2R, 3R) -hydrogen (R) -3-tartrate-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 -Carboxamide monohydrate (NAD 299) is described as a selective 5-HT 1A receptor antagonist in J. Pharmacol. Exp. Ther., 283, 216-225 (1997).
【0007】 (2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチルアミノ−8−フル
オロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カルボキサミド1水和
物はCNSにおける5−HT1A受容体の特定のサブグループに対して高い親和性を
有しており、その5−HT1A受容体に対して拮抗剤として作用し、また、経口投
与後に良好な生体利用性を示す。(2R, 3R) -Hydrogen bitartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate is Has high affinity for certain subgroups of 5-HT 1A receptors in the CNS, acts as an antagonist for the 5-HT 1A receptor, and has good bioavailability after oral administration Shows sex.
【0008】 パロキセチンは市販されている5−HT再取り込み抑制剤(SSRI)である
。塩酸塩、臭化水素酸塩、マレイン酸塩、酒石酸塩、酢酸塩等のようなパロキセ
チンの製薬上許容しうる塩も本発明組成物に包含される。塩の水和物および半水
和物のような水和物形態も包含される。[0008] Paroxetine is a commercially available 5-HT reuptake inhibitor (SSRI). Pharmaceutically acceptable salts of paroxetine such as hydrochloride, hydrobromide, maleate, tartrate, acetate and the like are also included in the compositions of the present invention. Hydrate forms such as salt hydrates and hemihydrates are also included.
【0009】 本発明の組成物は成分(a)および成分(b)を含有する1種の医薬組成物中
に存在するか、または、1つが成分(a)を、もう1つが成分(b)を含有する
2種の医薬組成物中に存在してもよい。医薬組成物は、錠剤またはカプセル、散
剤、混合物、溶液または他の適当な医薬品の剤形、例えばパッチ剤または鼻用製
剤の形態であってよい。The composition of the present invention is present in one pharmaceutical composition containing component (a) and component (b), or one is component (a) and the other is component (b) May be present in two pharmaceutical compositions containing The pharmaceutical compositions may be in the form of tablets or capsules, powders, mixtures, solutions or other suitable pharmaceutical forms such as patches or nasal preparations.
【0010】 本発明の組成物は、例えば従来の方法で混合することにより成分(b)と同じ
医薬組成物中に成分(a)を配合して調製することができる。 本発明はまた(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチルアミ
ノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カルボキ
サミド1水和物およびパロキセチンを含有する組成物を同時投与することにより
治療作用の発現を改善する方法も包含する。The composition of the present invention can be prepared, for example, by mixing the component (a) into the same pharmaceutical composition as the component (b) by mixing by a conventional method. The invention also relates to (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate And a method for improving the onset of a therapeutic effect by co-administering a composition containing paroxetine.
【0011】 本発明の別の実施態様は、場合により取り扱い説明書と共に(2R,3R)−酒
石酸水素(R)−3−N,N−ジシクロブチルアミノ−8−フルオロ−3,4−ジヒ
ドロ−2H−1−ベンゾピラン−5−カルボキサミド1水和物の投与単位および
パロキセチンの投与単位を含むキットである。Another embodiment of the present invention is a process for preparing (2R, 3R) -hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydrogen, optionally with instructions for use. It is a kit comprising a dosage unit of -2H-1-benzopyran-5-carboxamide monohydrate and a dosage unit of paroxetine.
【0012】 医薬組成物 本発明によれば組成物中の化合物は通常は製薬上許容しうる剤形中に活性成分
を含有する医薬組成物の形態で、経口、直腸内、経皮、経鼻または注射により投
与される。剤形は固体、半固体または液体の製剤であってよい。通常は活性物質
は製剤の0.1〜99重量%を構成し、特に、注射用製剤では0.5〜20重量%
、経口投与用製剤では0.2〜50重量%を構成する。 医薬組成物は、場合により補助剤、賦形剤、例えば、希釈剤および/または不
活性担体と組合せて活性成分を含有する。Pharmaceutical Compositions According to the present invention, the compounds in the compositions are orally, rectally, transdermally, nasally, in the form of pharmaceutical compositions containing the active ingredient, usually in a pharmaceutically acceptable dosage form. Or it is administered by injection. The dosage form may be a solid, semi-solid or liquid formulation. Usually the active substance will comprise from 0.1 to 99% by weight of the formulation, especially from 0.5 to 20% by weight in injectable formulations
In oral preparations, it constitutes 0.2 to 50% by weight. The pharmaceutical composition will contain the active ingredient optionally in combination with adjuvants, excipients, for example, diluents and / or inert carriers.
【0013】 経口投与用の投与単位形態の本発明の組成物の医薬組成物を調製するためには
、選択された化合物を固体の賦形剤、例えば乳糖、サッカロース、ソルビトール
、マンニトール、澱粉、例えばバレイショ澱粉、コーンスターチまたはアミロペ
クチン、セルロース誘導体、バインダー、例えばゼラチンまたはポリビニルピロ
リドン、錠剤崩壊剤、例えばグリコール酸澱粉ナトリウム、交差結合PVPおよび
クロスカラメロースナトリウムおよび潤滑剤、例えばステアリン酸マグネシウム
、ステアリン酸カルシウム、ポリエチレングリコール、ワックス、パラフィン等
、および、抗付着剤、例えばタルクまたはコロイド状二酸化ケイ素と混合し、次
に圧縮成形して錠剤とする。コーティングされた錠剤が必要である場合は、上記
したとおり調製したコア部を当業者の知る重合体、例えば、HPMC、HCまた
は他のセルロース誘導体またはPVPでコーティングしてよく、その際、重合体
は水または容易に揮発する有機溶媒または有機溶媒の混合物に溶解する。或いは
、例えばアラビアゴム、ゼラチン、タルカム、二酸化チタン等を含有してよい濃
厚糖溶液で錠剤をコーティングすることができる。これらのコーティングには、
例えば異なる活性物質または異なる量の活性化合物を含有する錠剤間の識別を容
易にするために染料を添加してよい。For preparing pharmaceutical compositions of the compositions of the present invention in dosage unit form for oral administration, the selected compound (s) may be a solid excipient such as lactose, saccharose, sorbitol, mannitol, starch, eg, Potato starch, corn starch or amylopectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, tablet disintegrants such as sodium starch glycolate, cross-linked PVP and sodium croscaramellose and lubricants such as magnesium stearate, calcium stearate, polyethylene glycol , Wax, paraffin and the like, and an anti-adhesion agent, such as talc or colloidal silicon dioxide, and then compressed into tablets. If a coated tablet is required, the core prepared as described above may be coated with a polymer known to those skilled in the art, for example, HPMC, HC or other cellulose derivatives or PVP, wherein the polymer is Dissolves in water or readily volatile organic solvents or mixtures of organic solvents. Alternatively, tablets can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talcum, titanium dioxide, and the like. These coatings include:
Dyes may be added, for example, to facilitate differentiation between tablets containing different active substances or different amounts of active compound.
【0014】 ソフトゼラチンカプセルの調製のためには、活性物質を例えば植物油またはポ
リエチレングリコールと混合してよい。ハードゼラチンカプセルは前述した錠剤
用の賦形剤の何れか、例えば乳糖、サッカロース、ソルビトール、マンニトール
、澱粉(例えばバレイショ澱粉、コーンスターチまたはアミロペクチン)、セル
ロース誘導体、可塑剤、ポリエチレングリコール、ワックス、脂質またはゼラチ
ンを用いて活性物質の顆粒を含有させてよい。液体または半固体の薬剤をハード
ゼラチンカプセルに充填することもできる。For the preparation of soft gelatin capsules, the active substances may be mixed with, for example, vegetable oils or polyethylene glycols. Hard gelatin capsules may contain any of the above-mentioned excipients for tablets, such as lactose, saccharose, sorbitol, mannitol, starch (eg, potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyethylene glycol, wax, lipids or gelatin. May be used to contain the granules of the active substance. Liquid or semisolid drugs can also be filled into hard gelatin capsules.
【0015】 直腸投与用の投与単位は溶液または懸濁液であることができ、または、中性脂
肪の基剤との混合物として活性物質を含有する坐薬または植物油またはパラフィ
ン油との混合物として活性物質を含有するゼラチン直腸カプセルの形態で調製す
ることができる。経口用液体製剤は溶液、シロップまたは懸濁液、例えば上記し
た活性物質約0.2〜約20重量%および残余分として糖類およびエタノール、
水、グリセロールおよびポリエチレングリコールの混合物を含有する溶液の形態
であることができる。場合によりこのような液体製剤は着色料、フレーバー剤、
サッカリンおよび濃厚化剤としてのカルボキシメチルセルロース、または、当業
者の知る他の賦形剤を含有してよい。The dosage unit for rectal administration can be a solution or suspension, or the suppository containing the active substance as a mixture with a base of neutral fat or the active substance as a mixture with a vegetable or paraffin oil. Can be prepared in the form of gelatin rectal capsules. Oral liquid preparations may be solutions, syrups or suspensions, for example from about 0.2 to about 20% by weight of the above active substance and the balance being sugar and ethanol,
It can be in the form of a solution containing a mixture of water, glycerol and polyethylene glycol. In some cases, such liquid preparations may contain colorants, flavors,
It may contain saccharin and carboxymethylcellulose as a thickening agent, or other excipients known to those skilled in the art.
【0016】 注射による非経腸投与用の溶液は好ましくは約0.5〜約10重量%の濃度の
活性物質の水溶性の製薬上許容しうる塩の水溶液として調製することができる。
これらの溶液はまた安定化剤および/または緩衝剤を含有してよく、そして、種
々の投与単位アンプル中に好都合に供してよい。Solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.5 to about 10% by weight.
These solutions may also contain stabilizers and / or buffers and may conveniently be provided in various dosage unit ampoules.
【0017】 ヒトの治療における本発明の組成物中の活性化合物の適当な一日当たり用量は
経口投与で約0.01〜100mg/kg体重、非経腸投与で0.001〜100mg/
kg体重である。活性成分(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブ
チルアミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−
カルボキサミド1水和物の一日当たり用量は活性成分パロキセチンの一日当たり
用量とは大きな差があってもよいが、用量は活性成分双方で同じであることもで
きる。[0017] Suitable daily doses of the active compound in the composition according to the invention in the treatment of humans are about 0.01 to 100 mg / kg body weight for oral administration and 0.001 to 100 mg / kg for parenteral administration.
kg weight. Active ingredient (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-
The daily dose of carboxamide monohydrate can vary significantly from the daily dose of active ingredient paroxetine, but the dose can be the same for both active ingredients.
【0018】 医薬用途 別の特徴において本発明は、感情障害のような5-ヒドロキシトリプタミン媒介
障害の治療における(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチル
アミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カル
ボキサミド1水和物である第1の成分(a)およびパロキセチンである第2の成
分(b)を含有する組成物の使用を提供する。感情障害の例は気分障害(鬱病、
主要鬱症状、気分変調、季節性感情障害、双極性障害における鬱期)、不安障害
(強迫性障害、広場恐怖症を伴うかまたは伴わないパニック障害、社会嫌悪症、
特異的嫌悪症、全般的不安障害、外傷後ストレス障害)、人格障害(抑制障害、
トリコチロマニー)および睡眠障害のようなCNSにおける障害である。CNS
におけるその他の障害、例えば摂食障害(肥満、食欲不振、過食症)、月経前症
候群、性障害、アルコール症、喫煙過多、自閉症、注意力欠如、活動亢進症、偏
頭痛、記憶障害(加齢性記憶障害、前老人性および老人性痴呆症、例えばアルツ
ハイマー病)、病的攻撃性、分裂病、内分泌障害(例えば過プロラクチン血症)
、卒中、運動障害、パーキンソン病、体温調節障害、疼痛および高血圧症もまた
本明細書に記載の組み合わせにより治療してよい。他のヒドロキシトリプタミン
媒介障害の例は、尿失禁、血管痙攣および腫瘍(例えば肺癌)の生育制御であり
、これらもまた本明細書に記載の組み合わせにより治療することができる場合が
ある。Pharmaceutical Uses In another aspect, the invention is directed to the use of (2R, 3R) -hydrogentartrate (R) -3-N, N-dicyclobutylamino- in the treatment of 5-hydroxytryptamine-mediated disorders such as affective disorders. Use of a composition containing a first component (a) that is 8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate and a second component (b) that is paroxetine I will provide a. Examples of emotional disorders are mood disorders (depression,
Major depressive symptoms, mood swings, seasonal affective disorder, depression in bipolar disorder), anxiety disorders (obsessive-compulsive disorder, panic disorder with or without agoraphobia, social aversion,
Specific aversion, general anxiety disorder, post-traumatic stress disorder), personality disorder (suppression disorder,
Trichothyromanny) and sleep disorders. CNS
Other disorders in, such as eating disorders (obesity, anorexia, bulimia), premenstrual syndrome, sexual dysfunction, alcoholism, excessive smoking, autism, lack of attention, hyperactivity, migraine, memory impairment ( Age-related memory impairment, presenile and senile dementia such as Alzheimer's disease, pathological aggression, schizophrenia, endocrine disorders (eg hyperprolactinemia)
, Stroke, movement disorders, Parkinson's disease, thermoregulatory disorders, pain and hypertension may also be treated with the combinations described herein. Examples of other hydroxytryptamine-mediated disorders are urinary incontinence, vasospasm and growth control of tumors (eg, lung cancer), which may also be treatable with the combinations described herein.
【0019】 薬理 パロキセチンで誘発される後方縫線ファイアリング(dorsal raphe firing)抑
制の(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチルアミノ−8−フ
ルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カルボキサミド1水
和物(NAD 299)による拮抗作用 材料および方法 成熟雄性 Sprague Dawley ラット(B & K Universal, Sollentuna, Sweden)
を制御された気象条件下に飼育した。標準的操作法に従って電子生理学的記録が
行なえるように動物の準備を行なった。即ち、抱水クロラールでラットを深く麻
酔し、定位フレームに置いた。細胞外記録電極を定位縦軸に沿って後方縫線内に
下ろし、標的ニューロンをこの核内のセロトニンニューロンのファイアリング特
性により検出した。動物は実験中を通じて麻酔し、薬剤は尾静脈カテーテルを介
して静脈内投与した。パロキセチン(0.1mg kg-1iv)はNAD 299(50n
mol kg-1iv)の投与前3分に投与した。Pharmacology (2R, 3R) -hydrogen bitartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3, inhibits paroxetine-induced inhibition of dorsal raphe firing. Antagonism by 4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate (NAD 299) Materials and Methods Mature male Sprague Dawley rats (B & K Universal, Sollentuna, Sweden)
Were bred under controlled weather conditions. Animals were prepared for electrophysiological recordings according to standard procedures. Briefly, rats were deeply anesthetized with chloral hydrate and placed in a stereotaxic frame. The extracellular recording electrode was lowered into the posterior raphe along the stereotactic axis and target neurons were detected by the firing properties of serotonin neurons in this nucleus. Animals were anesthetized throughout the experiment and drugs were administered intravenously via a tail vein catheter. Paroxetine (0.1 mg kg -1 iv) is NAD 299 (50 n
It was administered 3 minutes before the administration of mol kg -1 iv).
【0020】 結果 NAD 299はパロキセチンにより誘発されたラットセロトニン作動性後方
縫線ニューロンにおけるファイアリングの抑制を拮抗することができた(図1)
。図1は群当たり5匹より得た記録値に基づいた中央値±半四分位数間の範囲を
示している。Mann-Whitney μ−検定により行なった投与群と対照との間の差の
統計学的評価もまた図1に示す。更に、パロキセチン誘発抑制はNAD 299
投与により統計学的に有意に拮抗された(p<0.05)。Results NAD 299 was able to antagonize paroxetine-induced suppression of firing in rat serotonergic posterior raphe neurons (FIG. 1).
. FIG. 1 shows the range between the median ± quartile based on recorded values obtained from 5 animals per group. The statistical evaluation of the difference between the administration group and the control, performed by the Mann-Whitney μ-test, is also shown in FIG. In addition, paroxetine-induced suppression was due to NAD 299
Administration was statistically significantly antagonized (p <0.05).
【0021】 考察および結論 パロキセチンのような選択的セロトニン再取り込み抑制剤(SSRI)はその
抗欝作用を中脳縫線核からのセロトニン作動性突出部の前頭部標的領域における
セロトニンのシナプス利用性を増強させるその能力に依っている。しかしながら
、影響を受けた5−ヒドロキシトリプタミン(5−HT)輸送蛋白質が体樹状突
起部と末端領域の双方に存在し、最初は前者の領域のセロトニンの利用性の増大
により、抑制性5−HT1A自己受容体の活性化を介してニューロンの活性並びに
前頭部の5−HTの合成と放出が抑制される。これらの受容体が経時的に感受性
低下を起こすに従い、動物実験で観察された通り前頭部のセロトニンの放出が徐
々に増大し、そして、この現象の経時的挙動は恐らくは抗欝剤の作用が遅延して
発現することを臨床的に説明していると考えられる。DISCUSSION AND CONCLUSIONS Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine exert their antidepressant effects on the synaptic availability of serotonin in the frontal target area of serotonergic protrusions from the midbrain raphe nucleus It depends on its ability to enhance. However, the affected 5-hydroxytryptamine (5-HT) transport protein is present in both the somatic dendrites and terminal regions, and initially the inhibitory 5-hydroxytryptamine (5-HT) transport protein is increased due to increased availability of serotonin in the former regions. Activation of HT 1A autoreceptors suppresses neuronal activity and the synthesis and release of frontal 5-HT. As these receptors become desensitized over time, the release of serotonin in the forehead gradually increases, as observed in animal studies, and the time course of this phenomenon is probably due to the action of antidepressants. This is considered to explain clinically the delayed onset.
【0022】 抑制性5−HT1A自己受容体の遮断によるSSRIの自己抑制作用の脱抑制が
より急速な作用の発現をもたらし、そしてまた、これらの薬剤の効果を一般に増
大させるという仮説が存在する。 データによれば、(2R,3R)−酒石酸水素(R)−3−N,N−ジシクロブチル
アミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カル
ボキサミド1水和物(NAD299)はラットにおけるパロキセチンの急性投与により誘
発されたセロトニン作動性ニューロンにおけるファイアリングの抑制を効果的に
拮抗する。 以下の非限定的な実施例により本発明を説明する。There is a hypothesis that de-suppression of the self-suppressive effect of SSRIs by blocking inhibitory 5-HT 1A autoreceptors results in a more rapid onset of action and also generally increases the effects of these drugs. . According to the data, (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate (NAD299) effectively antagonizes the suppression of firing in serotonergic neurons induced by acute administration of paroxetine in rats. The following non-limiting examples illustrate the invention.
【0023】 実施例 単回投与剤形中に第1の成分(a)成分および第2の成分(b)を含有する適
当な医薬組成物は以下の成分を含む。 組成物 mg/錠 活性薬剤成分(a) 5 活性薬剤成分(b) 20 微結晶セルロース 100 コーンスターチ 40 ポビドン 4 水 50 グリコール酸澱粉ナトリウム 8 ステアリン酸マグネシウム 1EXAMPLES A suitable pharmaceutical composition containing a first component (a) and a second component (b) in a single dosage form comprises the following components: Composition: mg / tablet Active pharmaceutical ingredient (a) 5 Active pharmaceutical ingredient (b) 20 Microcrystalline cellulose 100 Corn starch 40 Povidone 4 Water 50 Sodium starch glycolate 8 Magnesium stearate 1
【図1】 群当たり5匹より得た記録値に基づいた中央値±半四分位数間の範囲を示す。
また Mann-Whitney μ−検定により行なった投与群と対照との間の差の統計的評
価も示す。FIG. 1 shows the range between median ± quartile based on recorded values obtained from 5 animals per group.
In addition, the statistical evaluation of the difference between the administration group and the control performed by the Mann-Whitney μ-test is also shown.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61P 43/00 A61P 43/00 // C07D 311/04 C07D 311/04 405/12 405/12 (81)指定国 EP(AT,BE,CH,CY, DE,DK,ES,FI,FR,GB,GR,IE,I T,LU,MC,NL,PT,SE),OA(BF,BJ ,CF,CG,CI,CM,GA,GN,GW,ML, MR,NE,SN,TD,TG),AP(GH,GM,K E,LS,MW,SD,SL,SZ,UG,ZW),E A(AM,AZ,BY,KG,KZ,MD,RU,TJ ,TM),AE,AL,AM,AT,AU,AZ,BA ,BB,BG,BR,BY,CA,CH,CN,CR, CU,CZ,DE,DK,DM,EE,ES,FI,G B,GD,GE,GH,GM,HR,HU,ID,IL ,IN,IS,JP,KE,KG,KP,KR,KZ, LC,LK,LR,LS,LT,LU,LV,MD,M G,MK,MN,MW,MX,NO,NZ,PL,PT ,RO,RU,SD,SE,SG,SI,SK,SL, TJ,TM,TR,TT,UA,UG,US,UZ,V N,YU,ZA,ZW (72)発明者 セト−ウーロフ・トールベルイ スウェーデン国エス−151 85セーデルテ イエ.アストラゼネカ.アール・アンド・ ディー・セーデルテイエ Fターム(参考) 4C062 EE99 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA01 AA02 BA08 BC21 GA02 GA07 GA15 MA02 MA03 MA04 MA05 NA05 ZA05 ZA18 ZA84 ZC42 ZC75 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification code FI Theme coat ゛ (Reference) A61P 43/00 A61P 43/00 // C07D 311/04 C07D 311/04 405/12 405/12 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), E A (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, R, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW. AstraZeneca. R & D Söderteier F-term (reference) 4C062 EE99 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA01 AA02 BA08 BC21 GA02 GA07 GA15 MA02 MA03 MA04 MA05 NA05 ZA05 ZA18 ZA84 ZC42 ZC75
Claims (22)
アミノ−8−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−5−カル
ボキサミド1水和物である第1の成分(a)および遊離の塩基または製薬上許容
しうる塩および/またはその溶媒和物の形態のパロキセチンである第2の成分(
b)を含有する組成物。(1) (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate (A) and paroxetine in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof (
A composition containing b).
載の組成物の使用。2. Use of a composition according to claim 1 for the manufacture of a medicament for the treatment of a 5-HT mediated disorder.
の使用。3. Use of a composition according to claim 2 for the manufacture of a medicament for the treatment of emotional disorders.
2記載の使用。6. Use according to claim 2, for the manufacture of a medicament in the prevention or treatment of urinary incontinence.
者に投与することによるその障害の治療方法。7. A method for treating a 5-HT-mediated disorder by administering the composition of claim 1 to the patient.
改善方法。12. A method for improving the expression of a therapeutic effect by co-administration of the composition according to claim 1.
活性担体と組み合わされた請求項1記載の組成物中の物質である医薬製剤。13. Pharmaceutical formulation, wherein the active ingredient is a substance in the composition according to claim 1, optionally in combination with auxiliaries, excipients and / or inert carriers.
請求項13記載の医薬製剤。14. The pharmaceutical preparation according to claim 13, wherein the first component (a) is administered simultaneously with the second component (b).
13または14に記載の医薬製剤。15. The pharmaceutical preparation according to claim 13 or 14 for use in the treatment of a 5-HT mediated disorder.
14に記載の医薬製剤。16. The pharmaceutical preparation according to claim 13 or 14 for use in treating an emotional disorder.
14に記載の医薬製剤。17. The pharmaceutical preparation according to claim 13 or 14 for use in the treatment of a mood disorder.
に記載の医薬製剤。18. The method of claim 13 or 14 for use in treating depression.
Pharmaceutical preparation of Claim.
4に記載の医薬製剤。19. Use according to claim 13 or 1 for use in the treatment of urinary incontinence.
5. The pharmaceutical preparation according to 4.
合する請求項1記載の組成物の調製方法。20. The method for preparing a composition according to claim 1, wherein the first component (a) is blended with the same pharmaceutical preparation as the second component (b).
の医薬製剤中に有る第2の成分(b)と組み合わされる請求項1記載の組成物の
調製方法。21. The method of preparing a composition according to claim 1, wherein the first component (a) is in one pharmaceutical formulation and is combined with the second component (b) in another pharmaceutical formulation. .
水素(R)−3−N,N−ジシクロブチルアミノ−8−フルオロ−3,4−ジヒドロ
−2H−1−ベンゾピラン−5−カルボキサミド1水和物である第1の成分(a)
の投与単位および遊離の塩基または製薬上許容しうる塩および/またはその溶媒
和物の形態のパロキセチンである第2の成分(b)の投与単位を含むキット。22. (2R, 3R) -hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran, optionally with instructions for use. First component (a) which is -5-carboxamide monohydrate
And a dosage unit of the second component (b), which is paroxetine in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9803156A SE9803156D0 (en) | 1998-09-16 | 1998-09-16 | A new composition |
SE9803156-0 | 1998-09-16 | ||
PCT/SE1999/001597 WO2000015218A1 (en) | 1998-09-16 | 1999-09-13 | A new composition |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2002524508A true JP2002524508A (en) | 2002-08-06 |
Family
ID=20412627
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000569802A Pending JP2002524508A (en) | 1998-09-16 | 1999-09-13 | New composition |
Country Status (21)
Country | Link |
---|---|
EP (1) | EP1128825A1 (en) |
JP (1) | JP2002524508A (en) |
KR (1) | KR20010099647A (en) |
CN (1) | CN1317964A (en) |
AR (1) | AR021808A1 (en) |
AU (1) | AU6378099A (en) |
BR (1) | BR9913748A (en) |
CA (1) | CA2342341A1 (en) |
CZ (1) | CZ2001961A3 (en) |
EE (1) | EE200100157A (en) |
HU (1) | HUP0103544A3 (en) |
ID (1) | ID28785A (en) |
IL (1) | IL141519A0 (en) |
IS (1) | IS5879A (en) |
NO (1) | NO20011312L (en) |
PL (1) | PL346763A1 (en) |
SE (1) | SE9803156D0 (en) |
SK (1) | SK3262001A3 (en) |
TR (1) | TR200100779T2 (en) |
WO (1) | WO2000015218A1 (en) |
ZA (1) | ZA200101946B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE334979T1 (en) | 2000-10-13 | 2006-08-15 | Neurosearch As | TREATMENT OF AFFECTIVE DISORDERS BY THE COMBINED ACTION OF A NICOTINIC RECEPTOR AGONIST AND A MONOAMINERGIC SUBSTANCE |
EP1859807A4 (en) * | 2005-03-04 | 2008-04-23 | Univ Tokyo Medical & Dental | Recurrence preventive therapeutic agent for psychostimulant-induced psychosis and schizophrenia |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9501567D0 (en) * | 1995-04-27 | 1995-04-27 | Astra Ab | A new combination |
-
1998
- 1998-09-16 SE SE9803156A patent/SE9803156D0/en unknown
-
1999
- 1999-09-13 TR TR2001/00779T patent/TR200100779T2/en unknown
- 1999-09-13 CN CN99811010A patent/CN1317964A/en active Pending
- 1999-09-13 BR BR9913748-8A patent/BR9913748A/en not_active Application Discontinuation
- 1999-09-13 WO PCT/SE1999/001597 patent/WO2000015218A1/en not_active Application Discontinuation
- 1999-09-13 HU HU0103544A patent/HUP0103544A3/en unknown
- 1999-09-13 IL IL14151999A patent/IL141519A0/en unknown
- 1999-09-13 ID IDW20010581A patent/ID28785A/en unknown
- 1999-09-13 KR KR1020017003337A patent/KR20010099647A/en not_active Application Discontinuation
- 1999-09-13 EP EP99951319A patent/EP1128825A1/en not_active Withdrawn
- 1999-09-13 PL PL99346763A patent/PL346763A1/en unknown
- 1999-09-13 CZ CZ2001961A patent/CZ2001961A3/en unknown
- 1999-09-13 EE EEP200100157A patent/EE200100157A/en unknown
- 1999-09-13 JP JP2000569802A patent/JP2002524508A/en active Pending
- 1999-09-13 SK SK326-2001A patent/SK3262001A3/en unknown
- 1999-09-13 AU AU63780/99A patent/AU6378099A/en not_active Abandoned
- 1999-09-13 CA CA002342341A patent/CA2342341A1/en not_active Abandoned
- 1999-09-15 AR ARP990104626A patent/AR021808A1/en not_active Application Discontinuation
-
2001
- 2001-03-07 IS IS5879A patent/IS5879A/en unknown
- 2001-03-08 ZA ZA200101946A patent/ZA200101946B/en unknown
- 2001-03-15 NO NO20011312A patent/NO20011312L/en unknown
Also Published As
Publication number | Publication date |
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PL346763A1 (en) | 2002-02-25 |
ZA200101946B (en) | 2002-06-10 |
CZ2001961A3 (en) | 2001-08-15 |
HUP0103544A2 (en) | 2002-05-29 |
EE200100157A (en) | 2002-08-15 |
AU6378099A (en) | 2000-04-03 |
ID28785A (en) | 2001-07-05 |
WO2000015218A1 (en) | 2000-03-23 |
KR20010099647A (en) | 2001-11-09 |
SK3262001A3 (en) | 2001-08-06 |
NO20011312D0 (en) | 2001-03-15 |
IL141519A0 (en) | 2002-03-10 |
HUP0103544A3 (en) | 2003-12-29 |
AR021808A1 (en) | 2002-08-07 |
CA2342341A1 (en) | 2000-03-23 |
NO20011312L (en) | 2001-05-16 |
TR200100779T2 (en) | 2001-10-22 |
EP1128825A1 (en) | 2001-09-05 |
SE9803156D0 (en) | 1998-09-16 |
CN1317964A (en) | 2001-10-17 |
IS5879A (en) | 2001-03-07 |
BR9913748A (en) | 2001-07-10 |
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