CN115317481A - 局部麻醉药物组合物及其制备方法 - Google Patents
局部麻醉药物组合物及其制备方法 Download PDFInfo
- Publication number
- CN115317481A CN115317481A CN202210435815.7A CN202210435815A CN115317481A CN 115317481 A CN115317481 A CN 115317481A CN 202210435815 A CN202210435815 A CN 202210435815A CN 115317481 A CN115317481 A CN 115317481A
- Authority
- CN
- China
- Prior art keywords
- solution
- acid
- pharmaceutical composition
- ropivacaine
- local anesthetic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000003589 local anesthetic agent Substances 0.000 title claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 claims abstract description 32
- 229960001549 ropivacaine Drugs 0.000 claims abstract description 32
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 21
- 239000002504 physiological saline solution Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000008215 water for injection Substances 0.000 claims abstract description 17
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 50
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
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Abstract
公开了局部麻醉药物组合物，其包含罗哌卡因或其药物可接受的盐、碳酸氢钠以及生理盐水或注射用水，其中所述罗哌卡因或其药物可接受的盐与碳酸氢钠的质量比为2.5:0.1～2.5:1。
Description
领域
本公开大体上属于医药领域，更具体地，本公开属于药物组合物领域。
背景
早在1995年，美国疼痛学会(APS)就提出“将疼痛列为第五大生命体征”，疼痛对患者的影响是多维度的，从生理-心理-社会三层面对患者产生恶劣影响。目前针对疼痛多采用神经阻滞、口服药物、静脉药物等方式。使用阿片类药物不可避免的带来其他的副作用，诸如恶心呕吐、头晕、便秘等。对于疼痛的治疗，除药物治疗、物理治疗外，椎旁神经阻滞、肋间神经阻滞等区域神经阻滞被广泛采用。区域神经阻滞采用局麻药物，其种类很多，按化学结构可分为酯类和酰胺类，常用的有酯类的普鲁卡因、丁卡因，酰胺类的利多卡因、罗哌卡因等。酰胺类局部麻醉药通过阻断神经细胞膜上的电压门控性Na+通道，使传导阻滞，产生局麻作用。在碱性条件下，碱基比率增加,可增强局部麻醉药通透神经膜的能力。酰胺类局部麻醉药溶液中，处在动态平衡的阳离子与碱基的多少取决于溶液的pH值,pH值越大，脂溶性碱基所占比例越大，镇痛效果越好、镇痛时间越长。目前碳酸利多卡因注射液已经在临床应用，镇痛效果由于盐酸利多卡因注射液。目前尚无关于罗哌卡因联合碳酸氢钠复合制剂。其难点在于具体罗哌卡因和碳酸氢钠配比并没有统一固定配方。同时局部麻醉药物随着溶液PH值的升高可延长麻醉时间、增强麻醉效果，但因PH过高罗哌卡因会产生物理沉淀。本发明为一种新型无沉淀的局部麻醉药物组合物及其制备方法。
概述
一方面，本公开涉及局部麻醉药物组合物，其包含罗哌卡因或其药物可接受的盐、碳酸氢钠以及生理盐水，其中所述罗哌卡因或其药物可接受的盐与碳酸氢钠的质量比为2.5:0.1～2.5:1。
另一方面，本公开涉及制备局部麻醉药物组合物的方法，包括：提供罗哌卡因或其药物可接受的盐的溶液和碳酸氢钠溶液；向罗哌卡因或其药物可接受的盐的溶液中加入生理盐水，从而得到第一溶液；向碳酸氢钠溶液中加入生理盐水，从而得到第二溶液；以及将所述第一溶液和第二溶液混合，从而得到所述局部麻醉药物组合物，其中所述罗哌卡因或其药物可接受的盐、碳酸氢钠和生理盐水或注射用水的质量比为2.5:0.1～2.5:1。
又一方面，本公开涉及周围神经阻滞麻醉或局部浸润麻醉。
在某些实施方案中，本公开的局部麻醉药物组合物可以延长麻醉时间。
在某些实施方案中，本公开的局部麻醉药物组合物的制备方法便捷，可于围术期或其他临床镇痛需要时混合后立即使用。
在某些实施方案中，本公开的局部麻醉药物组合物可以延长罗哌卡因的镇痛时间，减少使用阿片类药物、静脉泵镇痛等，降低阿片类药物副作用，减少患者费用。
在某些实施方案中，本公开的局部麻醉药物组合物可以减少因使用大量静脉麻醉药物带来的副作用。
在某些实施方案中，本公开的局部麻醉药物组合物没有罗哌卡因或其药物可接受的盐的析出。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下仍实现实施方案。
除非本申请中另有要求，在整个说明书和所附的权利要求书中，词语“包括”、“包含”、“含有”和“具有”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个说明书中提到的“一实施方案”、“实施方案”、“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
定义
在本公开中，术语“药物可接受的盐”包括“可以接受的酸加合盐”和“可以接受的碱加合盐”。
在本公开中，术语“可以接受的酸加合盐”系指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
在本公开中，术语“可以接受的碱加合盐”系指保持游离酸的生物学有效性和性质的那些盐，所述碱加合盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。在某些实施方案中，无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。在某些实施方案中，有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
在本公开中，术语“生理盐水”系指渗透压与人体血浆的渗透压基本相等的氯化钠溶液。
在本公开中，术语“α2肾上腺素受体激动剂”系指与α2肾上腺素收结合并激活α2肾上腺素受体，产生类似肾上腺素作用的物质。
具体实施方式
一方面，本公开涉及局部麻醉药物组合物，其包含罗哌卡因或其药物可接受的盐、碳酸氢钠以及生理盐水或注射用水，其中罗哌卡因或其药物可接受的盐、碳酸氢钠和生理盐水或注射用水的质量比为2.5:0.1～2.5:1。
在某些实施方案中，生理盐水为浓度为0.9％(g/mL)的氯化钠溶液。
在某些实施方案中，能够用于本公开的注射用水的示例性实例包括但不限于灭菌注射用水。
在某些实施方案中，罗哌卡因或其药物可接受的盐、碳酸氢钠和生理盐水或注射用水的质量比为2.5:0.1～1:540～600。
在某些实施方案中，局部麻醉药物组合物还包含氯胺酮或α2肾上腺素受体激动剂。
在某些实施方案中，能够用于本公开的α2肾上腺素受体激动剂的示例性实例包括但不限于右美托咪定。
在某些实施方案中，局部麻醉药物组合物的pH值小于7.0。
另一方面，本公开涉及制备局部麻醉药物组合物的方法，包括：
提供罗哌卡因或其药物可接受的盐的溶液和碳酸氢钠溶液；
向罗哌卡因或其药物可接受的盐的溶液中加入生理盐水或注射用水，从而得到第一溶液；
向碳酸氢钠溶液中加入生理盐水或注射用水，从而得到第二溶液；以及
将所述第一溶液和第二溶液混合，从而得到所述局部麻醉药物组合物，
其中所述罗哌卡因或其药物可接受的盐与碳酸氢钠的质量比为2.5:0.1～2.5:1。
在某些实施方案中，罗哌卡因或其药物可接受的盐的溶液的pH至为4至7.0。
在某些实施方案中，罗哌卡因或其药物可接受的盐、碳酸氢钠和生理盐水或注射用水的质量比为2.5:0.1～1:540～600。
在某些实施方案中，制备本公开的局部麻醉药物组合物的过程中不产生肉眼可见沉淀，建议配置后尽快使用，最好在10分钟内完成。
又一方面，本公开涉及麻醉方法，其包括周围神经阻滞或局部浸润麻醉。
下文中，本公开将通过如下实施例进行详细解释以便更好地理解本申请的各个方面及其优点。然而，应当理解，以下的实施例是非限制性的而且仅用于说明本申请的某些实施方案。
实施例
实施例1
向1％罗哌卡因的溶液5mL中加入生理盐水6mL，从而得到第一溶液；向5％碳酸氢钠溶液0.1mL中加入生理盐水6mL，从而得到第二溶液；以及将所述第一溶液和第二溶液混合，从而得到所述局部麻醉药物组合物，无肉眼可见的沉淀。
实施例2
向1％罗哌卡因的溶液5mL中加入注射用水6mL，从而得到第一溶液；向5％碳酸氢钠溶液0.4mL中加入注射用水6mL，从而得到第二溶液；以及将所述第一溶液和第二溶液混合，从而得到所述局部麻醉药物组合物，无肉眼可见的沉淀。
实施例3
向1％罗哌卡因的溶液5mL中加入生理盐水6mL，从而得到第一溶液；向5％碳酸氢钠溶液1mL中加入生理盐水6mL，从而得到第二溶液；以及将所述第一溶液和第二溶液混合，从而得到所述局部麻醉药物组合物，肉眼可见大量沉淀。
实施例4
使用实施例1的组合物行肋间神经阻滞。术后2小时、术后24小时、术后48小时、术后72小时患者疼痛评分分别为2、5、4、4分(满分10分)。
实施例5
使用实施例2的组合物行肋间神经阻滞。术后2小时、术后24小时、术后48小时、术后72小时患者疼痛评分分别为2、2、2、2分(满分10分)。
实施例6
实施例3的组合物大量沉淀形成，未用于神经阻滞注射。
上述实施例中，实施例1的镇痛效果不理想，初始镇痛强度可，但维持时间短，实施例2的镇痛效果理想，镇痛强度大，维持时间长达72小时。但是实施例3的组合物出现大量肉眼可见结晶沉淀，结晶沉淀在实际注射应用中存在注入血管可能，将造成血管栓塞风险，不宜临床使用。
在本公开中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
从前述中可以理解，尽管为了示例性说明的目的描述了本公的具体实施方案，但是在不偏离本公开的精神和范围的条件下，本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本公开所附权利要求的范围。
Claims (9)
1.局部麻醉药物组合物，其包含罗哌卡因或其药物可接受的盐、碳酸氢钠以及生理盐水或注射用水，其中所述罗哌卡因或其药物可接受的盐与碳酸氢钠的质量比为2.5:0.1～2.5:1。
2.如权利要求1所述的局部麻醉药物组合物，其中所述生理盐水为浓度为0.9％(g/mL)的氯化钠溶液，注射用水为灭菌注射用水。
3.如权利要求2所述的局部麻醉药物组合物，其中所述罗哌卡因或其药物可接受的盐、碳酸氢钠和生理盐水或注射用水的质量比为2.5:0.1～1:540～600。
4.如权利要求1至3中任一权利要求所述的局部麻醉药物组合物，其还包含氯胺酮或α2肾上腺素受体激动剂，优选右美托咪定。
5.如权利要求1至4中任一权利要求所述的局部麻醉药物组合物，其中所述药物组合物的pH值小于或等于7.0。
6.制备局部麻醉药物组合物的方法，包括：
提供罗哌卡因或其药物可接受的盐的溶液和碳酸氢钠溶液；
向罗哌卡因或其药物可接受的盐的溶液中加入生理盐水或注射用水，从而得到第一溶液；
向碳酸氢钠溶液中加入生理盐水或注射用水，从而得到第二溶液；以及
将所述第一溶液和第二溶液混合，从而得到所述局部麻醉药物组合物，
其中所述罗哌卡因或其药物可接受的盐与碳酸氢钠的质量比为2.5:0.1～2.5:1。
7.如权利要求6所述的方法，其中所述罗哌卡因或其药物可接受的盐的溶液的pH至为4至7。
8.如权利要求6或7所述的方法，其中所述罗哌卡因或其药物可接受的盐、碳酸氢钠和生理盐水或注射用水的质量比为2.5:0.1～1:540～600。
9.如权利要求6至8中任一权利要求所述的方法，其中不产生任何沉淀。
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