CN1074918C - 罗哌卡因在具有最小运动神经阻断的止痛作用的药物制造中的应用 - Google Patents
罗哌卡因在具有最小运动神经阻断的止痛作用的药物制造中的应用 Download PDFInfo
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- CN1074918C CN1074918C CN94192664A CN94192664A CN1074918C CN 1074918 C CN1074918 C CN 1074918C CN 94192664 A CN94192664 A CN 94192664A CN 94192664 A CN94192664 A CN 94192664A CN 1074918 C CN1074918 C CN 1074918C
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明公开了可药用的罗哌卡因盐在制备具有感觉神经阻断且具有最小运动神经阻断的药物制剂中的应用。
Description
发明领域
本发明涉及低浓度的药用罗哌卡因盐在药物制剂中的应用，该制剂用于减轻手术和分娩后的疼痛。
发明背景
手术后疼痛的减轻一直是近代手术中的一个问题。据新公开的研究资料，约70％的手术病人的手术后感到中度至重度疼痛。
在手术后头24小时期间对于有效的疼痛减轻是最需要的。冶疗这些病人的传统方法是肌肉或静脉注射麻醉剂。这样治疗通常是不适当的，因麻醉止痛剂有许多副作用。缺点之一是给药后可发生呼吸抑制作用，这意味着必须由专家加强对病人的照看。
用***治疗过的病人是疲劳而淡漠的，且常感到虚弱。病人对其周围的事没有兴趣，因此照看这些病人和使其参加减轻痛苦的锻炼和预防血栓形成是困难的。
方法之一是通过局部麻醉剂的灌注或间歇注射的硬膜外给药。这种治疗只能由专门训练过的人员用于加强护理时或手术之后被照看的具有导管的病人。
因此在监护方面一直迫切需要一种能给予大多数病人有效减轻疼痛的方法，例如通过局部麻醉剂的输注代替***制剂。
通常，使用局部麻醉剂可获得很好的疼痛阻断。缺点是腿部运动神经阻断。这将影响病人，使其放弃疼痛减轻治疗。在其它的一些影响中，运动神经阻断意味着由于腿不能承重，病人没有帮助离不开床。
本发明概述
根据本发明，已惊奇地发现：例如在WO/85/00599中描述的局部麻醉剂罗哌卡因盐酸盐以一种剂量给予病人，能使疼痛减轻，且具有对运动神经功能最小的影响。所述剂量小于0.5％(重量)，尤其是0.01％-0.45％(重量)。这样低的剂量通常是被认为无效的。常用剂量是0.5～2％(重量)。
本发明所用的局部麻醉化合物是其可药用盐形式。特别优选使用罗哌卡因盐酸盐。
所述局部麻醉剂掺入溶液中。
本发明的局部麻醉组合物含有少于0.5％(重量)的局部麻醉化合物，优选0.01～0.45％(重量)，更优选0.1～0.3％(重量)。药物制剂
实施例1～3溶液：5mg/ml,3mg/ml,2mg/ml
实施例
1 2 3罗哌卡因盐酸盐-水合物 0.53kg 0.32kg 0.21kg2MNaOH调pH至5.6～6.0纯水 加至 100kg 100kg 100kg
将罗哌卡因溶于水，加入NaOH使pH5.0～6.0，得到的溶液高压釜灭菌。
目前实施本发明最好的方式已知是使用实施例3的制剂。生物学试验
在健康男性自愿者的连续硬膜外输注期间，用0.1％、0.2％、0.3％罗哌卡因和0.25％丁哌卡因进行感觉和运动神经阻断的双盲研究。
研究的目的是要发现在连续的硬膜外输注期间能给出足够的感觉神经阻断，但很少有或完全没有运动神经阻断的一个罗哌卡因低浓度。该研究是发现罗哌卡因低浓度的第一步，然后将该浓度用于病人的手术后疼痛的治疗。37名自愿者参加了此研究，将他们分成5个治疗组，分别接受0.1％、0.2％或0.3％罗哌卡因或0.25％丁哌卡因，对照组接受0.9％盐水。所有的溶液首先均以10ml溶液剂给药，然后以每小时10ml的速率输注21小时。在输注期间用不同的方法试验运动神经和感觉神经阻断。还评价了自愿受试者的状态稳定性。初步结果
第一组：接受盐水的自愿受试者没有运动和感觉神经阻断。
第二组：丁哌卡因0.25％组的输注期间给出良好的分段分布的感觉神经阻断(从腹部的下部至下肢的下部)。所有自愿受试者均有高程度的运动神经阻断，在整个输注期间75％(6/8)的人不能站立。
第三组：罗哌卡因0.3％组，与丁哌卡因0.25％组比较，给出相等的延续时间，上部份感觉神经阻断的分布稍高于丁哌卡因。下部分感觉神经阻断的分布与丁哌卡因比较在连续输注10小时后仅移至膝以下，且在输注完毕时发现在膝以上。运动神经阻断与丁哌卡因比较稍有差别，7名自愿受试者中有5名在输注期完全不能站立以进行状态稳定性试验。
第四组：罗哌卡因0.2％组，与丁哌卡因比较，在腹部的下部给出相同的感觉神经阻断，但在ancles周围显示出较少的感觉神经阻断。连续输注10小时后，感觉神经的阻断少于罗哌卡因0.3％组和丁哌卡因组。与0.3％罗哌卡因和0.25％丁哌卡因组比较，运动神经阻断较轻，25％自愿受试者(2/8)完全不能站立，而其余人(6/8)在输注期间的某一时间点可进行某些状态试验。
第五组：罗哌卡因0.1％组，在输注的头5小时期间与0.2％罗哌卡因溶液组比较，给出较狭窄分布的感觉神经阻断。在硬膜外输注8小时后恢复正常感觉。
在各试验组没有发现严重的或不期望的副作用。
发现丁哌卡因给出75％的运动神经阻断，比罗哌卡因高，后者在可比较的剂量水平仅给出25％。
罗哌卡因在0.3％和0.2％剂量时给出大约相同的运动神经阻断，在0.1％剂量时，对运动神经的阻断更小。结论
从罗哌卡因独特的效果，可得出结论：该化合物特别适合于以低剂量给予手术和分娩后需要减轻疼痛治疗的病人，它在足够的感觉神经阻断和期望的最小程度的运动神经阻断之间具有良好的平衡。
Claims (4)
1．罗哌卡因的可药用盐在制备治疗急性疾痛且具有感觉神经阻断和最小的运动神经阻断的药物中的用途，其中该罗哌卡因的浓度低于0.5％(重量)。
2．按权利要求1的用途，其中所述罗哌卡因是其盐酸盐形式。
3．按权利要求1的用途，其中所述罗哌卡因的浓度是0.01～0.45％(重量)。
4．按权利要求3的用途，其中所述罗哌卡因的浓度是0.2％(重量)。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE19939302218A SE9302218D0 (sv) | 1993-06-28 | 1993-06-28 | New use |
| SE9302218-4 | 1993-06-28 | ||
| SE93022184 | 1993-06-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1126435A CN1126435A (zh) | 1996-07-10 |
| CN1074918C true CN1074918C (zh) | 2001-11-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94192664A Expired - Fee Related CN1074918C (zh) | 1993-06-28 | 1994-05-26 | 罗哌卡因在具有最小运动神经阻断的止痛作用的药物制造中的应用 |
Country Status (33)
| Country | Link |
|---|---|
| US (2) | US5670524A (zh) |
| EP (1) | EP0706395B1 (zh) |
| JP (1) | JP3725541B2 (zh) |
| CN (1) | CN1074918C (zh) |
| AT (1) | ATE216237T1 (zh) |
| BR (1) | BR9406865A (zh) |
| CA (1) | CA2165446C (zh) |
| CZ (1) | CZ283300B6 (zh) |
| DE (2) | DE706395T1 (zh) |
| DK (1) | DK0706395T3 (zh) |
| EE (1) | EE03205B1 (zh) |
| ES (1) | ES2099048T3 (zh) |
| FI (1) | FI956269A0 (zh) |
| GR (1) | GR970300013T1 (zh) |
| HK (1) | HK1010344A1 (zh) |
| HU (1) | HU218949B (zh) |
| IL (1) | IL110006A (zh) |
| IS (1) | IS4174A (zh) |
| LT (1) | LT3449B (zh) |
| LV (1) | LV12918B (zh) |
| MY (1) | MY119360A (zh) |
| NO (1) | NO955313L (zh) |
| NZ (1) | NZ268110A (zh) |
| PH (1) | PH31258A (zh) |
| PL (1) | PL175518B1 (zh) |
| PT (1) | PT706395E (zh) |
| RU (1) | RU2152215C1 (zh) |
| SA (1) | SA94150010B1 (zh) |
| SE (1) | SE9302218D0 (zh) |
| SG (1) | SG49078A1 (zh) |
| SK (1) | SK280111B6 (zh) |
| TW (1) | TW285640B (zh) |
| WO (1) | WO1995000148A1 (zh) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9302218D0 (sv) * | 1993-06-28 | 1993-06-28 | Ab Astra | New use |
| EP0998286A2 (en) * | 1997-07-21 | 2000-05-10 | Darwin Discovery Limited | Use of levobupivacaine |
| US20060270708A1 (en) * | 2005-05-25 | 2006-11-30 | Navinta Llc | Novel process for preparation of isotonic aqueous injection of ropivacaine |
| EP2209450A4 (en) * | 2007-11-07 | 2013-09-25 | Svip5 Llc | SLOW RELEASE OF LOCAL ANESTHESIC ORGANIC SALTS FOR PAIN RELIEF |
| CA2871820C (en) * | 2012-05-10 | 2020-11-03 | Painreform Ltd. | Depot formulations of a hydrophobic active ingredient and methods for preparation thereof |
| CN105612155A (zh) * | 2012-05-10 | 2016-05-25 | 塞利克斯比奥私人有限公司 | 治疗局部疼痛的组合物和方法 |
| ES2699257T3 (es) | 2013-02-28 | 2019-02-08 | Dermira Inc | Sales de glicopirrolato |
| US8558008B2 (en) | 2013-02-28 | 2013-10-15 | Dermira, Inc. | Crystalline glycopyrrolate tosylate |
| US9006462B2 (en) | 2013-02-28 | 2015-04-14 | Dermira, Inc. | Glycopyrrolate salts |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0151110B1 (en) * | 1983-08-01 | 1989-03-01 | Astra Läkemedel Aktiebolag | L-n-n-propylpipecolic acid-2,6-xylidide and method for preparing the same |
| SE9302218D0 (sv) * | 1993-06-28 | 1993-06-28 | Ab Astra | New use |
-
1993
- 1993-06-28 SE SE19939302218A patent/SE9302218D0/xx unknown
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1994
- 1994-05-26 SK SK1646-95A patent/SK280111B6/sk not_active IP Right Cessation
- 1994-05-26 DE DE0706395T patent/DE706395T1/de active Pending
- 1994-05-26 DE DE69430427T patent/DE69430427T2/de not_active Expired - Lifetime
- 1994-05-26 HU HU9503692A patent/HU218949B/hu not_active IP Right Cessation
- 1994-05-26 CZ CZ953364A patent/CZ283300B6/cs not_active IP Right Cessation
- 1994-05-26 AT AT94919912T patent/ATE216237T1/de not_active IP Right Cessation
- 1994-05-26 NZ NZ268110A patent/NZ268110A/xx not_active IP Right Cessation
- 1994-05-26 PT PT94919912T patent/PT706395E/pt unknown
- 1994-05-26 BR BR9406865A patent/BR9406865A/pt not_active Application Discontinuation
- 1994-05-26 EP EP94919912A patent/EP0706395B1/en not_active Expired - Lifetime
- 1994-05-26 SG SG1996005829A patent/SG49078A1/en unknown
- 1994-05-26 PL PL94312198A patent/PL175518B1/pl not_active IP Right Cessation
- 1994-05-26 DK DK94919912T patent/DK0706395T3/da active
- 1994-05-26 RU RU96101169/14A patent/RU2152215C1/ru not_active IP Right Cessation
- 1994-05-26 WO PCT/SE1994/000496 patent/WO1995000148A1/en active IP Right Grant
- 1994-05-26 CA CA002165446A patent/CA2165446C/en not_active Expired - Fee Related
- 1994-05-26 ES ES94919912T patent/ES2099048T3/es not_active Expired - Lifetime
- 1994-05-26 JP JP50268795A patent/JP3725541B2/ja not_active Expired - Fee Related
- 1994-05-26 CN CN94192664A patent/CN1074918C/zh not_active Expired - Fee Related
- 1994-05-26 US US08/256,319 patent/US5670524A/en not_active Expired - Lifetime
- 1994-06-01 TW TW083105008A patent/TW285640B/zh not_active IP Right Cessation
- 1994-06-08 IS IS4174A patent/IS4174A/is unknown
- 1994-06-09 PH PH48413A patent/PH31258A/en unknown
- 1994-06-13 IL IL11000694A patent/IL110006A/en not_active IP Right Cessation
- 1994-06-14 SA SA94150010A patent/SA94150010B1/ar unknown
- 1994-06-17 LT LTIP1958A patent/LT3449B/lt not_active IP Right Cessation
- 1994-06-27 MY MYPI94001663A patent/MY119360A/en unknown
- 1994-11-03 EE EE9400347A patent/EE03205B1/xx not_active IP Right Cessation
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1995
- 1995-12-27 FI FI956269A patent/FI956269A0/fi not_active Application Discontinuation
- 1995-12-27 NO NO955313A patent/NO955313L/no not_active Application Discontinuation
-
1997
- 1997-05-05 US US08/851,062 patent/US5834489A/en not_active Expired - Lifetime
- 1997-05-30 GR GR970300013T patent/GR970300013T1/el unknown
-
1998
- 1998-10-19 HK HK98111303A patent/HK1010344A1/xx not_active IP Right Cessation
-
2002
- 2002-07-15 LV LVP-02-131A patent/LV12918B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| ANESTHESIA AND ANALGESIA,V01.70, 1990.1.1 M.CONCEPCION,MD等,"A NEW LOCAL ANESTHETIC ROPIVACAINE". * |
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