CN102006867A - 含有扑热息痛和布洛芬的口服药物混悬剂 - Google Patents
含有扑热息痛和布洛芬的口服药物混悬剂 Download PDFInfo
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- CN102006867A CN102006867A CN2008801275358A CN200880127535A CN102006867A CN 102006867 A CN102006867 A CN 102006867A CN 2008801275358 A CN2008801275358 A CN 2008801275358A CN 200880127535 A CN200880127535 A CN 200880127535A CN 102006867 A CN102006867 A CN 102006867A
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- Prior art keywords
- suspensoid
- oral drugs
- sodium
- ibuprofen
- acetaminophen
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Abstract
本发明涉及一种包含扑热息痛和布洛芬的口服药物混悬剂。本发明也涉及一种通过给予受试者治疗有效量的包括扑热息痛和布洛芬的口服药物混悬剂治疗围手术期或术后疼痛的方法。
Description
发明领域
本发明涉及一种含有扑热息痛和布洛芬的口服药物混悬剂，所述混悬剂用于治疗术前，围手术期或术后疼痛。
发明背景
扑热息痛或者对乙酰氨基酚或者4’-羟基乙酰苯胺，是一种非阿片类，非水杨酸盐类镇痛解热药物。它具有外周镇痛作用，口服吸收良好。扑热息痛通过提高痛阈产生镇痛作用，通过作用于下丘脑的热调节中心产生退热作用。对乙酰氨基酚化学名为N-(4-羟基苯基)乙酰胺，如式Ⅰ所示。它暂时缓解轻度疼痛和胃灼热或者酸性消化不良引起的疼痛，以及和这些症状相关的胃部不适。
式Ⅰ
布洛芬，一种非甾体抗炎药，具有镇痛解热活性。它的作用模式是抑制***素合成酶。布洛芬的化学名是(±)-2-(对异丁基苯基)丙酸，如式Ⅱ所示。它的治疗作用为缓解类风湿性关节炎和骨关节炎的病征和症状，轻到中度疼痛以及治疗原发性痛经。
式Ⅱ
扑热息痛和布洛芬的混悬剂剂型商业销售的商标名为Ibugesic
(100mg布洛芬和162.5mg扑热息痛)，
(100mg布洛芬和125mg扑热息痛)和(100mg布洛芬和125mg扑热息痛)。
欧洲申请EP0109281记载了flubriprofen或者布洛芬和对乙酰氨基酚的药物组合物
国际(PCT)公布WO2006004449记载了用于治疗疼痛的含有布洛芬和扑热息痛的药物组合物。
Swallow J等，Journal of child health care：for professionals working with children in the hospital and community(2000)，4(3)：第93-8页报道了针对所有进行了扁桃体切除术的儿童的扑热息痛和布洛芬的出院处方。
Homer等，The Journal of laryngology and otology(2001)，115(3)：第205-8页报道了扑热息痛和布洛芬对于接受扁桃体切除术的儿童(没有哮喘症)是一个有效的镇痛组合物。
Pickering等，British Journal of Anaesthesia(2002)，88(1)：第72-77页报道了一个围手术期的布洛芬和扑热息痛的组合物，作为一个策略，用于经历了扁桃体切除术的儿童。
Hyllested，M等，British Journal of Anaesthesia(2002)，88(2)：第199-214页报道了加入非甾体抗炎药物(NSAID)到扑热息痛中后，与单独使用扑热息痛相比，可以产生额外的镇痛效果，并且也认为当扑热息痛被加入到非甾体抗炎药物中时，与单独使用非甾体抗炎药物相比，扑热息痛可以增强镇痛作用。
Kokki Hannu Paediatric drugs(2003)，5(2)：第103-23页报道了扑热息痛和布洛芬的组合物在经历了扁桃体切除术的儿童中改善了镇痛作用。
Menhinick K A等，International endodontic journal(2004)，37(8)：第531-41页报道了布洛芬与对乙酰氨基酚的组合物在处理术后的牙髓疼痛方面与单独使用布洛芬相比更有效果。
Gazal Giath等，International journal of paediatric dentistry/the British Paedodontic Society[and]the International Association of Dentistry for Children (2007)，17(3)：第169-77页报道的证据支持单独口服布洛芬或者布洛芬和扑热息痛的组合，可用于在全麻下拔牙的儿童的手术后镇痛。
几种其它的非专利参考文献报道了在治疗疼痛中使用扑热息痛和布洛芬的组合物。
发明简述
本发明的一方面是提供一种口服药物混悬剂，包括100-500mg/5ml的扑热息痛，40-80mg/5ml的布洛芬和一种或多种药学上可接受的赋形剂。
本发明的另一方面是提供一种口服药物混悬剂，包括200-450mg/5ml的扑热息痛，100-200mg/5ml的布洛芬和一种或多种药学上可接受的赋形剂。
本发明的药物混悬剂可以包括扑热息痛或其盐或者它的衍生物和布洛芬或其盐或者它的衍生物作为活性成分。
药物混悬剂具体实施方式可以包括一种或多种下列的成分。例如，药物混悬剂可以包括一种或多种的药学上可接受的赋形剂。药学上可接受的赋形剂可以包括一种或多种的助悬或者增稠剂，甜味剂，缓冲剂，防腐剂，润湿剂，芳香剂，溶剂等等。
本发明另一方面提供一种治疗手术前、围手术期或手术后疼痛的方法，通过给予受试者治疗有效量的包括100-500mg/5ml的扑热息痛和40-80mg/5ml的布洛芬的口服药物混悬剂。
本发明另一方面提供一种治疗手术前、围手术期或手术后疼痛的方法，通过给予受试者治疗有效量的包括200-450mg/5ml的扑热息痛和100-200mg/5ml的布洛芬的口服药物混悬剂。
这里使用的术语“受试者”指哺乳动物。
治疗手术前，围手术期，手术后疼痛方法的具体实施方案可以包括一种或多种下列的特征。例如，手术前、围手术期或者手术后的疼痛可以是与一种或多种外科手术相关。外科手术可以包括一种或多种的咽喉(像扁桃体切除术、增值腺切除术)，牙齿(像牙周)，耳朵(像鼓膜切开术)，鼻等等。
在下面的说明书中阐述本发明的一种或多种具体实施方式的详细内容。本发明的其它特征、目标和优点在说明书和权利要求中明显的体现。
发明详述
为了控制疼痛，适当有效的手术前、围手术期、手术后的镇痛是必须的。没有适当的控制疼痛会导致不愿意或者拒绝饮食；这样会阻碍恢复和及早出院。出院后的糟糕的疼痛处理持续削弱病人的饮食能力，带来脱水、感染和继发性出血的风险。
现有技术中使用非甾体抗炎药物控制疼痛是众所周知的。使用非甾体抗炎药物(NSAIDS)如布洛芬，会带来许多副作用。来自布洛芬的最常见的副作用是皮疹、耳鸣、头痛、头晕、嗜睡、腹痛、恶心、腹泻、便秘和胃灼热。据报道，非甾体抗炎药物会降低血液的凝结能力，因此增加了伤后出血。布洛芬可以导致胃或肠道溃疡，溃疡可以引起出血。另据报道，非甾体抗炎药物会降低到肾脏的血流量并且损害肾脏的功能，对于布洛芬和其它非甾体抗炎药物，患有哮喘的人更可能经历过敏反应。液体滞留(水肿)，血液凝块，心脏病，高血压和心力衰竭也和使用非甾体抗炎药物有关。
本发明人在研制扑热息痛和布洛芬的混悬剂制剂时注意到，当低剂量范围的布洛芬，即在40-80mg/5ml，与100-500mg/ml的扑热息痛组合时，与单独使用布洛芬(100mg/5ml或者更高含量)相比，可以更好的处理手术前、围手术期和手术后疼痛，并且降低布洛芬(非甾体抗炎药物)的副作用。本发明人也注意到包括100-200mg/5ml布洛芬和200-450mg/5ml扑热息痛的口服混悬剂制剂能够用来治疗和处理与外科手术有关的手术前、围手术期和手术后疼痛。
本发明人进一步注意到本发明的混悬剂剂型提供相当好的外科手术后的疼痛处理，缓解由于水肿、发炎或者肌肉痉挛引起的不适、早期恢复和出院，克服这两种药物各自使用带来的问题，改善在围手术期，手术后和其它情况下的镇痛效果。
本发明的药物口服混悬剂组合物包括扑热息痛和布洛芬作为活性成分。本发明的组合物能够通过加入扑热息痛，布洛芬和药学上可接受的赋形剂到纯水中，然后进行混合来制备。获得的混悬剂的pH通过使用适当的药学上可接受的赋形剂调节至2-6，然后加入合适的芳香剂。
药学上可接受的赋形剂可以包括一种或多种的助悬或者增稠剂，甜味剂，缓冲剂，防腐剂，润湿剂，芳香剂，溶剂等。
合适的助悬或者增稠剂可以包括一种或多种的黄原胶，瓜尔豆胶，黄蓍胶，***胶，明胶，卡拉胶，琼脂，聚维酮，海藻酸，海藻酸钠，海藻酸丙二醇酯，卡波姆，硅酸铝镁，羧甲基纤维素钙，钠羧甲基纤维素，乙基纤维素，甲基纤维素，羟丙基甲级纤维素，羟乙基纤维素，羟丙基纤维素，微晶纤维素，聚葡萄糖，蔗糖，山梨醇，木糖醇，葡萄糖，果糖，麦芽糖醇，膨润土，聚乙烯醇，胶态二氧化硅等。
合适的甜味剂可以包括一种或多种的蔗糖，山梨醇，木糖醇，葡萄糖，果糖，麦芽糖醇，乙酰磺胺酸钾，阿斯巴甜，糖精，糖精钠，液体麦芽糖醇，液体葡萄糖，环己氨基磺酸盐(cyclamate)，环己氨基磺酸钠(sodium cyclamate)等。
合适的缓冲剂可以包括一种或多种的柠檬酸，柠檬酸钠，磷酸钠，柠檬酸钾等。
合适的防腐剂可以包括一种或多种的苯甲酸钠，苯甲酸，乙二胺四乙酸四钠，山梨酸，溴硝丙二醇，尼泊金丁酯，尼泊金甲酯，尼泊金乙酯，尼泊金丙酯，丙酸钠，洗必泰，山梨酸钾，丙二醇，亚硫酸氢钠，焦亚硫酸钠，羟基苯甲酸钠等。
合适的润湿剂可以包括一种或多种的聚乙二醇，聚山梨醇酯，脱水山梨糖醇酯等。
合适的芳香剂可以包括一种或多种的人造草莓香料，人造奶油香料，香草，樱桃，树莓等。
适当的溶剂可以包括一种或多种的水，甘油，丙二醇，聚乙二醇，乙醇等。
下述提供的实施例是对本发明的进一步说明，仅仅是本发明的具体实施方式，不限制本发明的范围。相对于本领域技术人员而言明显的修改和等效方式包括在本发明的范围之内。
实施例1和2：
表1提供了本发明批次的组合物
表1
方法：通过加入扑热息痛，布洛芬，硅酸铝镁，黄原胶，液体麦芽糖醇，苯甲酸钠，糖精钠，吐温80和山梨醇油酸酯到纯水中，接着进行混合得到混悬剂来制备实施例1和2公开的组合物。使用柠檬酸调节获得的混悬剂的pH在2-6之间，加入适当的香料。
实施例3和4
表2提供了本发明批次的组合物
表2
方法：通过加入扑热息痛，布洛芬，硅酸铝镁，黄原胶，液体麦芽糖醇，苯甲酸钠，糖精钠，吐温80和山梨醇油酸酯到纯水中，接着进行混合得到混悬剂来制备实施例3和4公开的组合物。使用柠檬酸调节获得的混悬剂的pH在2-6之间，加入适当的香料。
实施例5和6
表3提供了本发明批次的组合物
表3
方法：通过加入扑热息痛，布洛芬，硅酸铝镁，黄原胶，液体麦芽糖醇，苯甲酸钠，糖精钠，吐温80和山梨醇油酸酯到纯水中，接着进行混合得到混悬剂来制备实施例5和6公开的组合物。使用柠檬酸调节获得的混悬剂的pH在2-6之间，加入适当的香料。
虽然本发明通过具体实施方式描述，但是相对于本领域技术人员而言明显的修改和等效方式包括在本发明的范围之内。
Claims (30)
1.一种口服药物混悬剂，包括100-500mg/5ml的扑热息痛，40-80mg/5ml的布洛芬和一种或多种药学上可接受的赋形剂。
2.权利要求1的口服药物混悬剂，其中混悬剂包括120mg/5ml的扑热息痛和60mg/5ml的布洛芬。
3.权利要求1的口服药物混悬剂，其中的药学上可接受的赋形剂包括一种或多种的助悬或者增稠剂，甜味剂，缓冲剂，防腐剂，润湿剂，芳香剂，溶剂。
4.权利要求3的口服药物混悬剂，其中的助悬或者增稠剂包括一种或多种的黄原胶，瓜尔豆胶，黄蓍胶，***胶，明胶，卡拉胶，琼脂，聚维酮，海藻酸，海藻酸钠，海藻酸丙二醇酯，卡波姆，硅酸铝镁，羧甲基纤维素钙，钠羧甲基纤维素，乙基纤维素，甲基纤维素，羟丙基甲级纤维素，羟乙基纤维素，羟丙基纤维素，微晶纤维素，聚葡萄糖，蔗糖，山梨醇，木糖醇，葡萄糖，果糖，麦芽糖醇，膨润土，聚乙烯醇，胶态二氧化硅。
5.权利要求3的口服药物混悬剂，其中的甜味剂包括一种或多种的蔗糖，山梨醇，木糖醇，葡萄糖，果糖，麦芽糖醇，乙酰磺胺酸钾，阿斯巴甜，糖精，糖精钠，液体麦芽糖醇，液体葡萄糖，环己氨基磺酸盐，环己氨基磺酸钠。
6.权利要求3的口服药物混悬剂，其中的缓冲剂包括一种或多种的柠檬酸，柠檬酸钠，磷酸钠，柠檬酸钾。
7.权利要求3的口服药物混悬剂，其中的防腐剂包括一种或多种的苯甲酸钠，苯甲酸，乙二胺四乙酸四钠，山梨酸，溴硝丙二醇，尼泊金丁酯，尼泊金甲酯，尼泊金乙酯，尼泊金丙酯，丙酸钠，洗必泰，山梨酸钾，丙二醇，亚硫酸氢钠，焦亚硫酸钠，羟基苯甲酸钠。
8.权利要求3的口服药物混悬剂，其中的润湿剂包括一种或多种的聚乙二醇，聚山梨醇酯，脱水山梨糖醇酯。
9.权利要求3的口服药物混悬剂，其中的芳香剂包括一种或多种的人造草莓香料，人造奶油香料，香草，樱桃，树莓。
10.权利要求3的口服药物混悬剂，其中的溶剂包括一种或多种的水，甘油，丙二醇，聚乙二醇，乙醇。
11.权利要求1的口服药物混悬剂，其中混悬剂的pH是2-6。
12.一种口服药物混悬剂，包括200-450mg/5ml的扑热息痛，100-200mg/5ml的布洛芬和一种或多种药学上可接受的赋形剂。
13.权利要求12的口服药物混悬剂，其中混悬剂包括250mg/5ml的扑热息痛和120mg/5ml的布洛芬。
14.权利要求12的口服药物混悬剂，其中的药学上可接受的赋形剂包括一种或多种的助悬或者增稠剂，甜味剂，缓冲剂，防腐剂，润湿剂，芳香剂，溶剂。
15.权利要求14的口服药物混悬剂，其中的助悬或者增稠剂包括一种或多种的黄原胶，瓜尔豆胶，黄蓍胶，***胶，明胶，卡拉胶，琼脂，聚维酮，海藻酸，海藻酸钠，海藻酸丙二醇酯，卡波姆，硅酸铝镁，羧甲基纤维素钙，钠羧甲基纤维素，乙基纤维素，甲基纤维素，羟丙基甲级纤维素，羟乙基纤维素，羟丙基纤维素，微晶纤维素，聚葡萄糖，蔗糖，山梨醇，木糖醇，葡萄糖，果糖，麦芽糖醇，膨润土，聚乙烯醇，胶态二氧化硅。
16.权利要求14的口服药物混悬剂，其中的甜味剂包括一种或多种的蔗糖，山梨醇，木糖醇，葡萄糖，果糖，麦芽糖醇，乙酰磺胺酸钾，阿斯巴甜，糖精，糖精钠，液体麦芽糖醇，液体葡萄糖，环己氨基磺酸盐，环己氨基磺酸钠。
17.权利要求14的口服药物混悬剂，其中的缓冲剂包括一种或多种的柠檬酸，柠檬酸钠，磷酸钠，柠檬酸钾。
18.权利要求14的口服药物混悬剂，其中的防腐剂包括一种或多种的苯甲酸钠，苯甲酸，乙二胺四乙酸四钠，山梨酸，溴硝丙二醇，尼泊金丁酯，尼泊金甲酯，尼泊金乙酯，尼泊金丙酯，丙酸钠，洗必泰，山梨酸钾，丙二醇，亚硫酸氢钠，焦亚硫酸钠，羟基苯甲酸钠。
19.权利要求14的口服药物混悬剂，其中的润湿剂包括一种或多种的聚乙二醇，聚山梨醇酯，脱水山梨糖醇酯。
20.权利要求14的口服药物混悬剂，其中的芳香剂包括一种或多种的人造草莓香料，人造奶油香料，香草，樱桃，树莓。
21.权利要求14的口服药物混悬剂，其中的溶剂包括一种或多种的水，甘油，丙二醇，聚乙二醇，乙醇。
22.权利要求14的口服药物混悬剂，其中混悬剂的pH是2-6。
23.一种治疗手术前、围手术期或手术后疼痛的方法，通过给予受试者治疗有效量的包括100-500mg/5ml的扑热息痛和40-80mg/5ml的布洛芬的口服药物混悬剂。
24.权利要求23的方法，其中的手术前、围手术期或手术后疼痛和一种或多种外科手术相关。
25.权利要求24的方法，其中的外科手术包括：一种或多种的咽喉，牙齿，耳朵或鼻的外科手术。
26.权利要求23的方法，其中所述的受试者是哺乳动物。
27.一种治疗手术前、围手术期或手术后疼痛的方法，通过给予受试者治疗有效量的包括200-450mg/5ml的扑热息痛和100-200mg/5ml的布洛芬的口服药物混悬剂。
28.权利要求27的方法，其中的手术前、围手术期或手术后疼痛和一种或多种外科手术相关。
29.权利要求28的方法，其中的外科手术包括：一种或多种的咽喉，牙齿，耳朵或鼻的外科手术。
30.权利要求27的方法，其中所述的受试者是哺乳动物。
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| PCT/IB2008/000005 WO2009083759A1 (en) | 2008-01-03 | 2008-01-03 | Oral pharmaceutical suspension comprising paracetamol and ibuprofen |
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| CN103961312A (zh) * | 2014-05-26 | 2014-08-06 | 王学重 | 一种扑热息痛口服液及其制备方法 |
| CN106361695A (zh) * | 2016-08-26 | 2017-02-01 | 湖北唯森制药有限公司 | 一种右旋布洛芬的研磨方法及其混悬液的制备方法 |
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| CN102448499A (zh) * | 2009-04-27 | 2012-05-09 | 药效学应用实验室股份有限公司 | 赖氨酸布洛芬口服混悬剂 |
| CN101991531B (zh) * | 2010-11-09 | 2012-06-27 | 武汉人福药业有限责任公司 | 布洛芬口服混悬液及其制备方法 |
| AU2012295397A1 (en) * | 2011-08-16 | 2014-02-20 | Merck Sharp & Dohme Corp. | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
| FR2999934B1 (fr) * | 2012-12-21 | 2015-02-20 | Servier Lab | Composition pharmaceutique sous la forme d'une suspension orale comprenant une fraction flavonoique et de la gomme xanthane |
| EP2938348A4 (en) | 2012-12-30 | 2016-07-27 | Hadasit Med Res Service | ALGINATE COMPOSITIONS AND USES THEREOF |
| CN111904924A (zh) * | 2013-11-13 | 2020-11-10 | 财团法人国际教育基金会 | 化合物降低对乙酰氨基酚引起的肝毒性的用途及复方组合 |
| WO2016008546A1 (en) | 2014-07-18 | 2016-01-21 | Everbright Pharmaceuticals S.A.R.L. | Aqueous formulation comprising paracetamol and ibuprofen |
| DE102016203146A1 (de) | 2016-02-26 | 2017-08-31 | Ivoclar Vivadent Ag | Antibakterielle Mundpflegegele |
| WO2018192664A1 (en) | 2017-04-20 | 2018-10-25 | Hyloris Developments Sa | METHOD FOR PREPARING A COMPOSITION WITH A LOW DISSOLVED OXYGEN CONTENT, COMPRISING ACETAMINOPHEN, AND OPTIONALLY ONE OR MORE NSAIDs, AND A COMPOSITION OBTAINED THEREOF |
| KR102642847B1 (ko) * | 2017-07-10 | 2024-03-04 | 젤 캡 테크놀로지스 엘엘씨 | 이중 방출 투여형 캡슐 및 이를 제조하기 위한 방법, 장치 및 시스템 |
| JP7346425B2 (ja) * | 2018-01-11 | 2023-09-19 | セントラス セラピューティクス | 疾患を治療するためのジヒドロセラミドデサチュラーゼ阻害剤 |
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| JP6858729B2 (ja) * | 2018-05-25 | 2021-04-14 | ▲財▼▲団▼法人国防教育研究基金会Ｎａｔｉｏｎａｌ Ｄｅｆｅｎｓｅ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ | 肝臓に対する副作用がない、新しいアセトアミノフェン複合組成 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103961312A (zh) * | 2014-05-26 | 2014-08-06 | 王学重 | 一种扑热息痛口服液及其制备方法 |
| CN106361695A (zh) * | 2016-08-26 | 2017-02-01 | 湖北唯森制药有限公司 | 一种右旋布洛芬的研磨方法及其混悬液的制备方法 |
| CN106361695B (zh) * | 2016-08-26 | 2017-12-19 | 湖北唯森制药有限公司 | 一种右旋布洛芬的研磨方法及其混悬液的制备方法 |
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| JP2011508768A (ja) | 2011-03-17 |
| AU2008345456A1 (en) | 2009-07-09 |
| ZA201004650B (en) | 2011-09-28 |
| EP2231138A1 (en) | 2010-09-29 |
| WO2009083759A1 (en) | 2009-07-09 |
| MX2010007358A (es) | 2011-05-25 |
| CA2711211A1 (en) | 2009-07-09 |
| KR20110065417A (ko) | 2011-06-15 |
| MA32056B1 (fr) | 2011-02-01 |
| US20110124730A1 (en) | 2011-05-26 |
| BRPI0821871A2 (pt) | 2015-06-16 |
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