CN1196932A - (+)－o－去甲基反胺苯环醇作为止痛药的口服应用 - Google Patents
(+)－o－去甲基反胺苯环醇作为止痛药的口服应用 Download PDFInfo
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Abstract
说明书记载了(+)－O－去甲基反胺苯环醇在治疗剧痛、锐痛和/或慢性疼痛中的口服给药用途。
Description
本发明涉及(+〕-O-去甲基反胺苯环醇在治疗剧痛、锐痛和/或严重的慢性疼痛中的口服应用。
在疼痛的治疗中，鸦片样物质治疗严重疼痛有不容否认的优越性(Zenz，M.，Jurna I.(1993)Lehrbuch der Schmerztherapic，WissenschaftlicheVerlagsgesellschaft Stuttgart)。在治疗锐痛和慢性疼痛的应用中，鸦片样物质的副作用是公认的，如呼吸系统机能抑制、顽固性便秘，尤其是在治疗慢性疼痛时发生的耐药性和依赖性。医疗实践显示口服药相对于注射剂型来说尤其适用于慢性疼痛的治疗，因为可以方便地确定服用剂量，可以由病人和/或护理人员直接用药，而不需要特别的方式和辅助设施(Cherny，N.J.，et al.，Medikamentose Therapie von Tumorschmerzen II，Anwendung vonOpioiden，Der Schmerz 9，3-19(1995)；Evans，P.J.Opiates in the Managementof Chronic Pain in Clinics and Anaestheology Vol.1，No.1，71-94)。口服使用的先决条件是药物显示出好的口服利用率，并具有充分地持续的功效。如果与药用辅料同用使其功效能够充分持续，如制成沉积制剂，那么每天的用药次数可以减少，而不会导致最佳治疗所必须的药物功效的均匀水平的降低(Strubelt，O.，Pharmakologic，Toxikologic und Verschreibung vonOpioids，Internist 3b，185-191(1994))。
近年来已日益增多地将口服、延迟释放的吗啡用于严重慢性疼痛的治疗(Zenz，et al，(1989)，Retardiertes Morphin zur Langzeittherapicschwerer Tumorschmerzen，Dtsch.med.Wschr.114，43-47；Zenz，et al，(1990)，Oral Opiattherapic bei Patienten mit“nicht-malignen”Schmerzen，Der Schmerz 4，14；Ventafridda，et al，(1990)，Side-effectsand Limits of Long-Term Oral Morphine Therapy，in：Treatment of ChronicPain pp.256-269，M.Mumenthaler，P.A.van Zwieten，J.M.Falcot Eds：Harwood Academic Publishers，Chur(1990))。因此口服吗啡制剂现在已成为常规的选择，但它有一系列不利的性质。吗啡的一大显著缺点，是它在肠壁内和经过肝脏时可观的首程失活效应使口服利用率降低。病人的年龄和病情导致的代谢能力的变化，会相应地改变吗啡的口服利用率，还要制订具有特别针对性的剂量以防止不恰当的服用量。吗啡的另一个负效应是其产生严重的顽固性便秘的副作用，当使用口服吗啡治疗时产生便秘，必须同时使用轻泻剂(Cherny，et al.1995 loc.cit.)。更为严重的副作用是产生耐受性和生理、心理的依赖性，这一点导致有关麻醉剂立法中禁止使用吗啡。
吗啡的低口服利用率需要一种特别的药物剂型，如以延迟释放方式使吗啡适用于口服。吗啡的低口服利用率是由其酚羟基引起的。已发现结构类似于吗啡的许多其它化合物也有低的口服利用率，如环丁甲羟氢吗啡、纳洛酮和环丙甲羟二氢吗啡酮，它们也含有一个酚基。
本发明的首要目的是提供一个化合物，用于口服药中治疗剧痛、锐痛和/或慢性疼痛，与吗啡相比它有显著的作用强度，而没有如前所述的副作用。
意外的发现O-去甲基反胺苯环醇的(+)对映异构体和其生理学上适用的盐，有显著的作用强度并显示可观的止痛效果，尽管有酚羟基，但显示出的口服利用率显著优于传统的鸦片类似化合物。这使较低的使用剂量和增加的剂量安全性成为可能。
另外从动物实验发现(+)-去甲基反胺苯环醇与吗啡相比有轻的致便秘作用。并且在长期治疗过程中发生心理依赖性的危险小于使用吗啡。
根据本发明将(+)O-去甲基反胺苯环醇作为活性成分在药物中使用，已在小鼠和大鼠的止痛实验中证实有好的口服利用率和止痛效果。
药理学实验按以下方式进行：
采用小鼠扭体试验法进行的止痛实验
在小鼠身上采用苯基苯醌诱发扭体法进行止痛实验(按I.C.Hendershot，J.Forsaith，J.Pharmacol.Exp.Ther.125，237-240(1959)改进)。使用雄性NMRI小鼠，体重25-30克。药物的每一剂量设一组，每组10只动物。口服本发明的化合物后10分钟和30分钟，每只小鼠腹腔注射0.02％苯基苯醌水溶液0.3ml(苯基苯醌：Sigma，Deisenhofen公司生产，加入5％乙醇并水浴保温45℃制成溶液)。动物单独放于观察用的鼠笼中，用按钮式计数器记录服用苯基苯醌后5-20分钟诱发疼痛导致的强直运动的数目(所谓的扭体运动，也就是伸展后肢端使身体拉平)。通过与平行对照组和仅服用苯基苯醌组比较，得到扭体反应减弱的剂量依赖关系，由此经回归分析(Martens EDVService，Eckental提供的计算程序)计算出药物抑制扭体反应的ED50值。
采用大鼠和小鼠照尾法进行的止痛试验
本发明所述化合物的止痛试验按D1Amour and Smith法(J.Pharm.Exp.Ther.72，74-79(1941))以鼠热辐射(摇尾)方式进行。实验动物为体重20-25g的雄性NMRI小鼠或体重120-160g的雌性Sprague Dawley大鼠。动物单独放于观察用的鼠笼中，尾底部暴露于电灯(Rhema Analgesiemeter)的热辐射焦点处。调节灯的强度，使治疗前动物从开灯至突然抽走尾巴(疼痛潜伏期)的时间为3-6秒。服用本发明的化合物前5分钟内测定2次，计算所得平均值作为试验前平均值。静脉注射后20、40、60分钟和口服用药后30、60、90、120分钟后进行疼痛测量。随着疼痛潜伏期的增加，暴露于辐射下的最大时间被控制在12秒，潜伏期增加到大于治疗前平均值的150％作为止痛有效。为测定剂量依赖性，化合物服用剂量按对数方式增加到3-5倍，此剂量每次包括阈值和最大作用剂量。用Litchfield and Wilcoxon法(J.Pharm.Ex.Ther.96，99-113(1949))从显示止痛效果的动物数计算ED50值。按每例动物静脉注射后20分钟和口服后30分钟的最大有效值计算ED50。
通过静脉注射(i.v.)和口服(p.o.)的ED50值的比值计算有效的口服利用率。表1 吗啡和(+)-O-去甲基反胺苯环醇的止痛效果和口服利用率
| 试验方式 | ED50值(mg/kg) | |
| (+)-O-去甲基反胺苯环醇 | 吗啡 | |
| 摇尾实验，小鼠，i.v.摇尾实验，小鼠，p.o.口服利用率 | 14.13.750.38 | 1.0518.900.06 |
| 扭体实验，小鼠，i.v.扭体实验，小鼠，p.o.口服利用率 | 0.491.870.26 | 0.334.700.07 |
| 摇尾实验，大鼠，i.v.摇尾实验，大鼠，p.o.口服利用率 | 1.014.900.21 | 0.9375.000.01 |
在小鼠扭体实验和大鼠摇尾实验中本发明的(+)-去甲基反胺苯环醇显示明确的止痛效果。吗啡的有效口服利用率在小鼠摇尾实验中只有0.06，在小鼠扭体实验中只有0.07，在大鼠摇尾实验中只有0.01；而(+)-O-去甲基反胺苯环醇的有效口服利用率在小鼠摇尾实验中为0.38，在小鼠扭体实验中为0.26，在大鼠扭体实验中为0.21。本发明所用的化合物用于小鼠的口服利用率比吗啡高5倍，用于大鼠的口服利用率比吗啡高20倍，因此口服止痛效果显著优于吗啡。
当按照本发明将(+)-O-去甲基反胺苯环醇作为止痛活性成分用于药物中时，此药物含有载体物质、填充剂、溶剂、稀释剂、着色剂和/或粘合剂，以及去甲基反胺苯环醇的(+)对映体和/或至少一种生理学可以接受的(+)-O-去甲基反胺苯环醇的盐。在口服制剂中，(+)-O-去甲基反胺苯环醇既可以为游离碱的形态，也可以为无机或有机酸盐的形态，例如与苯甲酸、苯乙酸等芳香羧酸形成的盐。尤其优选亲脂性的有机酸盐，如硬脂酸、棕榈酸等C8-C22脂肪酸形成的盐。(+)-O-去甲基反胺苯环醇与亲脂性有机酸形成的盐尤其适用于药物的延迟释放剂型，可以按延迟方式释放本发明的化合物。
在延迟释放剂型中，(+)-O-去甲基反胺苯环醇最好制成基质片剂。在20℃重量含量为2％的水溶液中具有粘度10,000-150,000mPas的纤维素醚和/或纤维素酯尤其适合作为基质。药物学可以接受的基质从包括甲基羟丙基纤维素、羟乙基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素和羧甲基纤维素的组中优选，并进一步从包括甲基羟丙基纤维素、羟乙基纤维素和羟丙基纤维素的组中优选。
在将被使用的药物中，延迟释放的活性物质的重量含量优选在10-85％之间，药学可以接受的基质的重量含量为10-40％。进一步优选含有25-70％重量的延迟的释放活性物质和10-40％重量的基质的药物。
按本发明制备的药物，还可以含有作为进一步的组分的药学惯用辅料，如乳糖、微晶纤维素或磷酸氢钙等填充剂，及崩解剂、润滑剂、助流剂，如微粉化二氧化硅、滑石、硬脂酸镁和/或硬脂酸。它们在片剂中的总含量为0-80wt％，优选为5-25wt％。
活性物质的给药量根据病人的体重、给药途径、病人临床表现和病情严重程度而变化。(+)-O-去甲基反胺苯环醇的常用给药量为10-400mg/kg体重，优选10-200mg/kg体重。
进一步地，在口服固体剂型中，本发明的(+)-O-去甲基反胺苯环醇可以采用游离碱和/或生理学可以接受的盐的形态制成粉剂、颗粒剂、丸剂、片剂、糖衣药丸、胶囊剂。所述药物剂型的成分组成和制备过程的选择，可以按已知的药学技术规范进行。
在片剂剂型中，既可以采用简单片剂，也可以采用包衣片剂，如薄膜包衣片剂或糖衣片。包衣片还可以采用一层或多层包衣片剂。
Claims (7)
1.(+)-O-去甲基反胺苯环醇以游离碱和/或生理学可接受的盐的形态，口服治疗剧痛、锐痛和/或慢性疼痛的用途。
2.根据权利要求1的用途，其特征在于(+)-O-去甲基反胺苯环醇与有机酸，尤其是C8-C22脂肪酸和芳香羧酸形成盐。
3.根据权利要求1或2的(+)-O-去甲基反胺苯环醇，在活性成分延迟释放的片剂药物中的用途。
4.根据权利要求3的用途，其特征在于此片剂为基质片。
5.根据权利要求3的用途，其特征在于至少含有一种在20℃重量含量为2％的水溶液中具有粘度3,000-150,000mPas，尤其是10,000-150,000mPas的纤维素醚和/或纤维素酯作为药学可以接受的基质。
6.根据权利要求3-5的用途，其特征在于用至少一种从包括甲基羟丙基纤维素、羟乙基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素和羧甲基纤维素的组中选择的物质作为药学可以接受的基质。
7.根据权利要求3-6的用途，其特征在于被延迟释放的活性物质的重量含量在10-85％，优选在25-70％，药学可以接受的基质的重量含量在10-40％。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712398.8 | 1997-03-25 | ||
| DE19712398A DE19712398A1 (de) | 1997-03-25 | 1997-03-25 | Orale Anwendung von (+)-0-Demethyltramadol als Schmerzmittel |
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| Publication Number | Publication Date |
|---|---|
| CN1196932A true CN1196932A (zh) | 1998-10-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98107860A Pending CN1196932A (zh) | 1997-03-25 | 1998-03-21 | (+)－o－去甲基反胺苯环醇作为止痛药的口服应用 |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0870499A1 (zh) |
| JP (1) | JPH1112166A (zh) |
| KR (1) | KR19980080580A (zh) |
| CN (1) | CN1196932A (zh) |
| AU (1) | AU5951798A (zh) |
| BR (1) | BR9801839A (zh) |
| CA (1) | CA2232930A1 (zh) |
| DE (1) | DE19712398A1 (zh) |
| HU (1) | HUP9800623A3 (zh) |
| IL (1) | IL123788A0 (zh) |
| NO (1) | NO981320L (zh) |
| PE (1) | PE62399A1 (zh) |
| PL (1) | PL325509A1 (zh) |
| UY (1) | UY24934A1 (zh) |
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| PE20010623A1 (es) * | 1999-10-05 | 2001-07-07 | Gruenenthal Chemie | Uso de (+)-tramadol y/o o-demetiltramadol para tratamiento de urgencia urinaria incrementada y/o incontinencia urinaria |
| DE10108123A1 (de) * | 2001-02-21 | 2002-10-02 | Gruenenthal Gmbh | Wirkstoffkombination |
| EP2545027A1 (de) | 2010-03-10 | 2013-01-16 | Grünenthal GmbH | Kristalline salze und/oder cokristalle von o-desmethyltramadol |
| US10702485B2 (en) | 2011-07-09 | 2020-07-07 | Syntrix Biosystems Inc. | Compositions and methods for overcoming resistance to tramadol |
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| MX9205106A (es) * | 1991-09-06 | 1993-05-01 | Johnson & Johnson | Composiciones que comprenden un material de tramadol y cualquiera de codeina, oxicodona o hidrocodona y su uso |
| AU661723B2 (en) * | 1991-10-30 | 1995-08-03 | Mcneilab, Inc. | Composition comprising a tramadol material and a non-steroidal anti-inflammatory drug |
| DE4315525B4 (de) * | 1993-05-10 | 2010-04-15 | Euro-Celtique S.A. | Pharmazeutische Zusammensetzung |
| DE4329794C2 (de) * | 1993-09-03 | 1997-09-18 | Gruenenthal Gmbh | Tramadolsalz enthaltende Arzneimittel mit verzögerter Wirkstofffreisetzung |
| DE19525137C2 (de) * | 1995-07-11 | 2003-02-27 | Gruenenthal Gmbh | 6-Dimethylaminomethyl-1-phenyl-cyclohexanverbin -dungen als Zwischenprodukte zur Herstellung pharmazeutischer Wirkstoffe |
| DE19601744C2 (de) * | 1996-01-19 | 1998-04-16 | Gruenenthal Gmbh | Verfahren zur Herstellung der Enantiomeren von O-Demethyltramadol |
-
1997
- 1997-03-25 DE DE19712398A patent/DE19712398A1/de not_active Ceased
-
1998
- 1998-03-05 EP EP98103874A patent/EP0870499A1/de not_active Withdrawn
- 1998-03-21 CN CN98107860A patent/CN1196932A/zh active Pending
- 1998-03-23 IL IL12378898A patent/IL123788A0/xx unknown
- 1998-03-23 CA CA002232930A patent/CA2232930A1/en not_active Abandoned
- 1998-03-23 HU HU9800623A patent/HUP9800623A3/hu unknown
- 1998-03-24 PE PE1998000210A patent/PE62399A1/es not_active Application Discontinuation
- 1998-03-24 UY UY24934A patent/UY24934A1/es not_active Application Discontinuation
- 1998-03-24 KR KR1019980010058A patent/KR19980080580A/ko not_active Application Discontinuation
- 1998-03-24 PL PL98325509A patent/PL325509A1/xx unknown
- 1998-03-24 JP JP10075995A patent/JPH1112166A/ja not_active Withdrawn
- 1998-03-24 NO NO981320A patent/NO981320L/no unknown
- 1998-03-25 BR BR9801839-6A patent/BR9801839A/pt not_active Application Discontinuation
- 1998-03-25 AU AU59517/98A patent/AU5951798A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU5951798A (en) | 1998-10-01 |
| HU9800623D0 (en) | 1998-05-28 |
| DE19712398A1 (de) | 1998-10-01 |
| NO981320L (no) | 1998-09-28 |
| PL325509A1 (en) | 1998-09-28 |
| NO981320D0 (no) | 1998-03-24 |
| EP0870499A1 (de) | 1998-10-14 |
| HUP9800623A2 (hu) | 1999-01-28 |
| KR19980080580A (ko) | 1998-11-25 |
| CA2232930A1 (en) | 1998-09-25 |
| PE62399A1 (es) | 1999-07-10 |
| BR9801839A (pt) | 2000-01-18 |
| HUP9800623A3 (en) | 1999-03-29 |
| UY24934A1 (es) | 1998-04-21 |
| IL123788A0 (en) | 1998-10-30 |
| JPH1112166A (ja) | 1999-01-19 |
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