CN1041727C - 瑞斯哌东双羟萘酸盐其制备方法和含该化合物的药物组合物 - Google Patents
瑞斯哌东双羟萘酸盐其制备方法和含该化合物的药物组合物 Download PDFInfo
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Abstract
本发明涉及瑞斯哌利酮与双羟萘酸的加成盐化合物、含有该化合物的组合物以及制备所述化合物和组合物的方法。
Description
EP-0,196,132公开的化合物3-[2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮,通常也称为瑞斯哌东(risperidone),是一种有效的精神抑制药。但遗憾的是目前配制的瑞斯哌东药剂只能在有限的时间范围内达到有效血浆水平。长效可注射用瑞斯哌东剂型对于维持治疗及提高病人的依顺性是非常有用的。
目前已有的长效精神抑制药包括难溶于水的抑制精神的化合物的酯类衍生物的油溶液,如芝麻油溶液。为延长一些特殊吩噻嗪类精神抑制药的有效期,曾用其难溶于水的盐(如双羟萘酸盐)进行实验,结果证明是不成功的(如Florence等,1976,J.Pharm.Sci.,65(11),1665-1668)。然而出乎意料的是当对狗用瑞斯哌东的双羟萘酸盐进行实验时发现瑞斯哌东的释放被大大延长,可以在几个星期内产生可有效地抑制由阿扑吗啡引起的呕吐的瑞斯哌东及其活性代谢物的血浆水平。
因此,本发明涉及瑞斯哌东与双羟萘酸的加成盐化合物,具体地说,本发明涉及下式化合物:得到有效血浆水平的时间取决于双羟萘酸瑞斯哌东盐粉末的物理性质,如粒子大小及结晶形态。
瑞斯哌东、其制备及其药理活性已在EP-0,196,132中描述。瑞斯哌东的双羟萘酸盐可用双羟萘酸或其盐类衍生物(如双羟萘酸二钠)在反应惰性溶剂中处理瑞斯哌东来制备。具体地说,双羟萘酸瑞斯哌东盐可由下法制备:将瑞斯哌东溶于适当溶剂(如乙醇)中,将该溶液加入到双羟萘酸在适当溶剂(如N,N-二甲基甲酰胺)中的溶液中,搅拌混和物直到双羟萘酸瑞斯哌东盐沉淀出来。然后可将反应产物从反应介质中分离出来,必要的话,也可用萃取、结晶和色谱法等本领域公知的方法进一步纯化。得到的主题化合物可用本领域已知的微粒化技术(如用碾磨机碾磨并用适当的筛子筛分等)制成微粒形式。
在一个具体的方面中,本发明涉及瑞斯哌东与双羟萘酸盐的混合加成盐,如瑞斯哌东的双羟萘酸一钠盐。
主题化合物是神经传递介质、尤其是多巴胺的有效的拮抗剂。拮抗所述神经传递介质可抑制由于多巴胺释放尤其是过量释放所引起的一系列症状。已知中枢多巴胺受体阻滞剂具有抑制精神的性质,如它们可以对抗精神分裂症的阳性症状,如幻觉、妄想、超常兴奋及异常行为。因此使用此化合物的治疗适应症主要是中枢神经系统(CNS)方面,具体地说是作为有效的精神抑制药、特别是用作治疗慢性神经病的药剂。另外,此化合物还具有中枢血清素拮抗作用。对中枢血清素起作用的拮抗剂可以改善精神分裂症患者的阴性症状,如无反应性、情感淡漠、孤僻和抑郁情绪,它也可以降低用常规精神抑制剂(如多巴胺拮抗剂)进行维持治疗时产生的锥体束外副作用(EPS)的发生率。因此,多巴胺-血清素复合拮抗剂尤为引人注目,因为它们能同时减轻精神分裂症的阳性及阴性症状,且EPS小。
主题化合物的优点在于它是一类长效的多巴胺拮抗剂,它通过从难溶于水的双羟萘酸盐中持续释放瑞斯哌东来达到目的。下面的实验证明了这一点。例如,对狗进行肌内或皮下用药后测量血浆水平及对于用多巴胺促效药阿扑吗啡刺激的狗表现出的长效止吐作用。因此,使用主题化合物可以较长的间隔(例如几周)用药,当然实际的用药时间还取决于所用化合物的物理性质及受治者的状况。所以,该化合物便于更为有效的治疗:瑞斯哌东的缓释使之在血浆中的浓度稳定在无毒且有效的水平,用药的方式也提高了受治者对实施的药疗法的依顺性。
目前所用的大多数长效精神抑制药通常是在油中配制的,只适于肌内用药;与它们不同本化合物的优点在于它既可以在亲油性溶剂(如油)也可以在憎油性溶剂(如水)中配制,而且可以各种方式用药,如肌内或皮下。
主题化合物有用的药理特性使之可以配制成各种药剂形式以满足不同的用药目的。为制备本发明的药物组合物,只需将有效量的主题化合物作为活性成分与一种可药用载体充分混合为混合物,所述载体可依所需的给药剂型采取各种形式。这些药物组合物最好制成适于皮下或肌内用药的单剂形式。对于肌内用药,最好将主题化合物悬浮于含水溶剂中,这种含水溶剂还可含有下面的组分:一种润湿剂;如脱水山梨醇酯的聚氧乙烯类衍生物(如多乙氧基醚80(吐温80)和多乙氧基醚20(吐温20))、卵磷脂、聚氧乙烯醚、聚氧丙烯醚、脱氧胆酸钠等;一种悬浮剂,如纤维素衍生物(如甲基纤维素、羧甲基纤维素钠和羟丙基甲基纤维素)、聚乙烯基吡咯烷酮、藻酸盐、壳多糖、葡聚糖、明胶、聚乙二醇、聚氧乙烯醚和聚氧丙烯醚等;一种酸,如盐酸等;一种碱,如氢氧化钠等;一种缓冲剂,包含适量的酸(如磷酸、琥珀酸、酒石酸、乳酸、乙酸、马来酸或柠檬酸)和碱(如氢氧化钠、磷酸、氢二钠)的混合物;一种防腐剂,如苯甲酸、苄醇、丁基化羟基苯甲醚、丁基化羟基甲苯、三氯甲基叔丁醇、棓酸盐、羟基苯甲酸酯、EDTA、苯酚、氯甲酚、间甲酚、benzothonium chloride、十四烷基-γ-piccolinium chloride、乙酸苯汞、乙基汞硫代水杨酸钠等;一种紧张调节剂,如氯化钠、葡萄糖、甘露糖醇、山梨醇、乳糖、硫酸钠等。另外,主题化合物也可在油中配制,合适的油类是固定油类,如花生油、芝麻油、棉籽油、谷物油、红花油、蓖麻油、油酸乙酯、豆油、合成长链或中等链长脂肪酸的甘油酯,以及它们与其他油类的混合物。组合物中也可加入增稠剂,如一硬脂酸铝、乙基纤维素、甘油三酯、氢化蓖麻油等。
显而易见,鉴于主题化合物在治疗精神病方面的用途,本发明提供了一种治疗患精神病的温血动物、尤其是人的方法,所述方法包括施与药学上有效量的主题化合物与一种可药用载体的混合物。在另一方面中,本发明涉及主题化合物作为药物、尤其是精神抑制药的用途。通常,这类药物的有效量为0.05mg/kg到50mg/kg体重,更优选0.5mg/kg到10mg/kg体重。
下面的实施例旨在说明而不是限制本发明的范围。实施例1
将0.048摩尔3-[2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮在600毫升乙醇中的溶液加入到0.048摩尔双羟萘酸在400毫升N,N-二甲基甲酰胺中的溶液中。将混合物搅拌3小时。将沉淀抽滤,用乙醇洗涤并干燥,得到31克(产率81%)3-[2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮4,4′-亚甲基双[3-羟基-2-萘甲酸盐](1∶1);熔点为269.2℃。实施例2F1:水悬浮液
瑞斯哌东单双羟萘酸盐 25毫克
多乙氧基醚20 1毫克
苄醇 10毫克
净化水 适量1毫升将瑞斯哌东单双羟萘酸盐、多乙氧基醚20、苄醇和净化水充分混和并匀化,得到水悬浮液。按相同的方法制备:F2:水悬浮液
瑞斯哌东单双羟萘酸盐 50毫克
多乙氧基醚20 2毫克
苄醇 15毫克
羧甲基纤维素钠 20毫克
净化水 适量1毫升F3:油悬浮液
瑞斯哌东单双羟萘酸盐 50毫克
芝麻油 适量1毫升实施例3
与瑞斯哌东游离碱相比,瑞斯哌东单双羟萘酸盐的长效作用可通过下面的实验来鉴定。对狗的阿扑吗啡试验
所用方法参见P.A.J.Janssen和C.J.E.Niemegeers在Arzneim.-Forsch.(Drug.Res.),9,765-767(1959)。将瑞斯哌东游离碱的芝麻油悬浮液及瑞斯哌东单双羟萘酸盐组合物F1、F2和F3分别以2-2.5mg/kg的剂量给3只不同的小猎兔犬用药。其中,将瑞斯哌东游离碱制剂及F1和F3肌内给药,而将F2皮下给药,给药不同时间后,分别用标准剂量0.31mg/kg(皮下给药)的阿扑吗啡刺激狗,阿扑吗啡是一种有效的多巴胺促效药并会引起呕吐。试验化合物对狗的止吐作用将作为衡量其效能的表征。
下表总结了在三只试验动物中得到的平均有效期(天数)。
平均有效期(天)
瑞斯哌东芝麻油悬浮液 3
F1 22
F2 18
F3 12
由此表可以清楚地看出,与用瑞斯哌东游离碱给药相比,用双羟萘酸瑞斯哌东盐给药使有效期大大延长。
Claims (7)
1.一种式(Ⅰ)所示的化合物,该化合物为瑞斯哌东与双羟萘酸的加成盐,式(Ⅰ)为:
2.一种组合物,该组合物包括药学上有效量的作为活性成分的权利要求1的化合物和一种可药用的载体。
3.按照权利要求2的组合物,所述组合物为可注射剂型。
4.按照权利要求3的组合物,所述组合物为水悬浮液的形式。
5.按照权利要求4的组合物,该组合物还含有苄醇、一种脱水山梨醇酯和水。
6.按照权利要求5的组合物,该组合物还含有一种纤维素衍生物。
7.权利要求1的化合物的制备方法,其特征在于在惰性溶剂中用双羟萘酸处理3-[2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-2-甲基4H-吡啶并[1,2-a]嘧啶-4-酮而得到的。
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EP93201216 | 1993-04-28 | ||
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE288270T1 (de) * | 1993-11-19 | 2005-02-15 | Janssen Pharmaceutica Nv | Mikroverkapselte 1,2-benzazole |
US5453425A (en) * | 1994-07-11 | 1995-09-26 | Janssen Pharmaceutica N.V. | Risperidone oral formulation |
TW487572B (en) * | 1996-05-20 | 2002-05-21 | Janssen Pharmaceutica Nv | Aqueous suspensions of 9-hydroxyrisperidone fatty acid esters |
UA73715C2 (en) * | 1997-09-30 | 2005-09-15 | Lilly Co Eli | Pharmaceutically acceptable formulation of olanzapine pamoate and its use for treatment |
US6617321B2 (en) * | 1997-09-30 | 2003-09-09 | Eli Lilly And Company | 2-methyl-thieno-benzodiazepine formulation |
UA72189C2 (uk) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Фармацевтична композиція, що містить водну суспензію субмікронних ефірів 9-гідроксирисперидон жирних кислот |
EA002580B1 (ru) * | 1998-09-30 | 2002-06-27 | Эли Лилли Энд Компани | Готовая препаративная форма 2-метил-тиено-бензодиазепина |
CA2349700A1 (en) * | 1998-11-12 | 2000-05-18 | Merck & Co., Inc. | Therapeutic polymorphs of a gaba-a alpha-5 inverse agonist and pamoate formulations of the same |
FR2802101B1 (fr) | 1999-12-10 | 2003-02-28 | Aventis Pharma Sa | Association de cymemazine et d'un neuroleptique atypique |
US6770478B2 (en) * | 2000-02-10 | 2004-08-03 | The Regents Of The University Of California | Erythrocytic cells and method for preserving cells |
US6495164B1 (en) | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
WO2002043766A1 (fr) * | 2000-11-29 | 2002-06-06 | Takeda Chemical Industries, Ltd. | Compositions medicinales et leur procede de preparation |
US20050232995A1 (en) | 2002-07-29 | 2005-10-20 | Yam Nyomi V | Methods and dosage forms for controlled delivery of paliperidone and risperidone |
US20060148826A1 (en) * | 2002-08-23 | 2006-07-06 | Ashish Gogia | Stable aqueous solutions of risperidone and methods for their preparation |
KR20040034996A (ko) * | 2002-10-18 | 2004-04-29 | 한미약품 주식회사 | 리스페리돈의 개선된 제조방법 |
EP1615923A1 (en) * | 2003-04-22 | 2006-01-18 | Synthon B.V. | Risperidone monohydrochloride |
US6987111B2 (en) * | 2003-08-06 | 2006-01-17 | Alkermes Controlled Therapeutics, Ii | Aripiprazole, olanzapine and haloperidol pamoate salts |
ES2315721T5 (es) | 2003-10-23 | 2012-08-24 | Otsuka Pharmaceutical Co., Ltd. | Formulación de aripiprazol inyectable estéril de liberación controlada y procedimiento |
PL1708790T3 (pl) * | 2003-12-02 | 2010-10-29 | Pharmaneuroboost N V | Zastosowanie pipamperonu oraz antagonisty receptora D2 lub antagonisty receptora serotoniny/dopaminy do leczenia zaburzeń psychotycznych |
US7884096B2 (en) * | 2003-12-02 | 2011-02-08 | Pharmaneuroboost N.V. | Method of treating mental disorders using of D4 and 5-HT2A antagonists, inverse agonists or partial agonists |
WO2005072705A1 (en) * | 2004-01-29 | 2005-08-11 | Neuromolecular, Inc. | Combination of a nmda receptor antagonist and a mao-inhibitor or a gadpf-inhibitor for the treatment of central nervous system-related conditions |
ATE511512T1 (de) * | 2005-01-05 | 2011-06-15 | Lilly Co Eli | Olanzapinpamoat-dihydrat |
EP1695973A1 (en) * | 2005-02-24 | 2006-08-30 | Neuro3D | Ocaperidone salt and pharmaceutical compositions containing the same |
AR055099A1 (es) * | 2005-07-28 | 2007-08-08 | Alza Corp | Formulaciones liquidas para la administracion controlada de derivados de bencisoxazol |
JP2009508859A (ja) * | 2005-09-15 | 2009-03-05 | エラン ファーマ インターナショナル リミテッド | ナノ粒子アリピプラゾール製剤 |
US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
BRPI0811319A2 (pt) | 2007-05-25 | 2015-02-10 | Tolmar Therapeutics Inc | Composição fluida, método de formação de uma composição fluida, implante biodegrádavel formado in situ, método de formação de um implante biodegradável in situ, kit, implante e método de trataento |
PT2170279T (pt) * | 2007-07-31 | 2018-04-06 | Otsuka Pharma Co Ltd | Métodos para produção de suspensão de aripiprazole e formulação liofilizada |
EP3909585A1 (en) * | 2007-12-19 | 2021-11-17 | Janssen Pharmaceutica NV | Dosing regimen associated with long acting injectable paliperidone esters |
US9034867B2 (en) | 2011-03-18 | 2015-05-19 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising sorbitan esters |
EP2702060B1 (en) * | 2011-04-26 | 2015-12-30 | Torrent Pharmaceuticals Limited | Acid addition salts of risperidone and pharmaceutical compositions thereof |
JP6471089B2 (ja) | 2012-03-19 | 2019-02-13 | アルカームス ファーマ アイルランド リミテッド | 脂肪酸エステルを含む医薬組成物 |
JP6219918B2 (ja) | 2012-03-19 | 2017-10-25 | アルカームス ファーマ アイルランド リミテッド | グリセロールエステルを含む医薬組成物 |
CA2867137C (en) | 2012-03-19 | 2020-12-08 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising aripiprazole prodrugs and benzyl alcohol |
AU2013245008B2 (en) | 2012-04-04 | 2017-03-30 | Intervet International B.V. | Soft chewable pharmaceutical products |
CN102659577B (zh) * | 2012-04-07 | 2014-07-02 | 安徽绩溪县徽煌化工有限公司 | 一种亚甲基双羟基萘酸的制备方法 |
ES2792149T3 (es) | 2012-09-19 | 2020-11-10 | Alkermes Pharma Ireland Ltd | Composiciones farmacéuticas que tienen estabilidad de almacenamiento mejorada |
US9375433B2 (en) | 2012-09-26 | 2016-06-28 | Tangent Reprofiling Limited | Modulators of androgen synthesis |
BR112015006727B1 (pt) | 2012-09-26 | 2022-08-16 | Tangent Reprofiling Limited | Uso de uma composição farmacêutica |
MX2016012041A (es) | 2014-03-20 | 2017-01-19 | Alkermes Pharma Ireland Ltd | Formulaciones de aripiprazol que tienen mayores velocidades de inyeccion. |
CN106831594B (zh) * | 2017-01-18 | 2018-02-02 | 力赛生物医药科技(厦门)有限公司 | 可乐定双羟萘酸盐及其制备方法 |
JP7384812B2 (ja) | 2018-03-05 | 2023-11-21 | アルカームス ファーマ アイルランド リミテッド | アリピプラゾール投与戦略 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0196132A2 (en) * | 1985-03-27 | 1986-10-01 | Janssen Pharmaceutica N.V. | 1,2-Benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives |
-
1994
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- 1995-10-26 NO NO954275A patent/NO305083B1/no not_active IP Right Cessation
- 1995-10-27 FI FI955166A patent/FI109125B/fi not_active IP Right Cessation
-
1996
- 1996-12-24 US US08/773,737 patent/US5723467A/en not_active Expired - Lifetime
-
1998
- 1998-02-26 GR GR980400198T patent/GR3026028T3/el unknown
- 1998-06-11 HK HK98105164A patent/HK1006059A1/xx not_active IP Right Cessation
- 1998-06-16 CY CY9800009A patent/CY2107B1/xx unknown
-
1999
- 1999-02-24 LV LVP-99-32A patent/LV12315B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0196132A2 (en) * | 1985-03-27 | 1986-10-01 | Janssen Pharmaceutica N.V. | 1,2-Benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives |
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