CN102813621A - 帕洛诺司琼液体药物配方 - Google Patents
帕洛诺司琼液体药物配方 Download PDFInfo
- Publication number
- CN102813621A CN102813621A CN2012102874523A CN201210287452A CN102813621A CN 102813621 A CN102813621 A CN 102813621A CN 2012102874523 A CN2012102874523 A CN 2012102874523A CN 201210287452 A CN201210287452 A CN 201210287452A CN 102813621 A CN102813621 A CN 102813621A
- Authority
- CN
- China
- Prior art keywords
- palonosetron
- solution
- pharmaceutically acceptable
- acid
- hydrochloride
- 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.)
- Pending
Links
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- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 claims description 23
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- XIEGSJAEZIGKSA-LUNMCBQDSA-N tropisetron hydrochloride Chemical compound Cl.C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 XIEGSJAEZIGKSA-LUNMCBQDSA-N 0.000 description 1
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- 210000003462 vein Anatomy 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及在保存期限内稳定存放的帕洛诺司琼(Palonosetron)液体药物配方,该配方使用帕洛诺司琼减轻化学治疗和放射治疗所诱发的呕吐。该配方主要用于配制静脉注射药物和口服药物。
Description
本申请是申请日为2004年1月30日,申请号为200480006322.1,发明名称为“帕洛诺司琼液体药物配方”的发明专利申请的分案申请。
技术领域
本发明涉及在保存期限内稳定存放的帕洛诺司琼(Palonosetron)液体药物配方,该药物主要用于配制可注射药物和口服药物。
背景技术
呕吐是细胞毒素治疗、放射治疗及术后环境的预期后果,严重影响了治疗后患者的生活质量。近年来业已开发了一类称为5-HT3(5-羟色胺)受体拮抗剂的药物,其通过拮抗与5-HT3受体相关的大脑功能以治疗呕吐。参见Drugs Acting on 5-Hydroxytryptamine Receptors:The Lancet Sep.23,1989和该文所引用的参考文献。这类药物包括昂丹司琼(ondansetron)、格拉司琼(granisetron)、阿洛司琼(alosetron)、托烷司琼(tropisetron)、多拉司琼(dolasetron)。这些5-HT3拮抗剂通常在化学治疗或放射治疗开始之前不久通过静脉内给予,并且在化学治疗或放射治疗的一个周期内可给予多次。此外,它们通常以片剂或者口服酏剂提供,既是对静脉给药的补充,也便于那些自己进行化学治疗的患者在家使用。
由于一些化学治疗试剂即使使用一次也会导致长达几天的呕吐,所以需要每天服用呕吐抑制药物(例如5-HT3拮抗剂)直到呕吐症状明显减轻。然而由于目前市售的5-HT3受体拮抗剂已被证明控制迟发型恶心和呕吐的效果不如控制急性呕吐的效果,因此现有的5-HT3拮抗剂并不被认为能特别有助于符合该需求。Sabra,K,Choice of a 5HT3 Receptor Antagonist for theHospital Formulary.EHP,Oct.1996;2(suppl 1):S 19-24)。
近来,业已进行了关于帕洛诺司琼(Palonosetron)的临床研究,帕洛诺司琼是一种新型5-HT3受体拮抗剂,报道于美国专利号5,202,233中。这些研究表明该药物较目前大部分的5-HT3受体拮抗剂具更有效的数量级,拥有惊人的约40小时的半衰期,对于缓解化学治疗试剂所引起的迟发型恶心很有效。然而,在液体配方中配制帕洛诺司琼并不是一件容易的事情,具体是由于贮存稳定性的问题。美国专利号5,202,233的实施例13中公开了用于静脉内给药的帕洛诺司琼配方,包括如下成分:
成分 | Mg |
帕洛诺司琼盐酸化物 | 10-100mg. |
葡萄糖一水合物 | 适量至等渗 |
柠檬酸一水合物 | 1.05mg. |
氢氧化钠 | 0.18mg. |
WFJ | 至1.0ml. |
该配方pH为3.7,其贮存稳定性小于各国卫生管理机构所要求的1-2年。
昂丹司琼(Ondansetron),其用途及用其所配制的药剂公开于美国专利号4,695,578、4,753,789、4,929,632、5,240,954、5,344,658、5,578,628、5,578,632、5,922,749、5,622,720、5,955,488和6,063,802中。由GlaxoSmithKline以进行商品销售,注明可预防术后的恶心和呕吐(PONV)、癌化学治疗所引起的恶心和呕吐(CINV)及放射治疗所引起的恶心和呕吐(RINV),可以注射剂、片剂、溶液和Zofran(昂丹司琼)口服崩解片剂形式来使用。
格拉司琼(Granisetron),其用途及用其所配制的药剂公开于美国专利号4,886,808、4,937,247、5,034,398、6,294,548中。由Roche LaboratoriesInc.以进行商品销售,注明可预防与化学治疗或放射治疗相关的恶心和呕吐,以片剂、口服溶液和注射剂形式提供。
托烷司琼(Tropisetron)的市售产品商标为(Novartis)CAS-89565-68-4(托烷司琼);CAS-105826-92-4(托烷司琼盐酸化物),注明可用于治疗PONV和CINV。
多拉司琼(Dolasetron),其用途及用其所配制的药剂公开于美国专利号5,011,846和4,906,755中。由Aventis Pharmaceuticals Inc.以进行商品销售,注明可预防PONV和CINV,以片剂或静脉注射用溶液形式提供。
因此,目前需要具有增强的稳定性并因此增加了保存期限的帕洛诺司琼配方。也需要适当浓度范围的5-HT3受体拮抗剂及其药学上可接受载体,将有助于提高配方的稳定性。
本发明的一个目的是提供一种用于预防和/或减轻呕吐的具有增强的药物稳定性的洛诺司琼盐酸化物配方。
本发明的另一个目的是提供一个可稳定含有帕洛诺司琼盐酸化物配方的可接受的浓度范围。
本发明的进一步目的是提供一种帕洛诺司琼配方,其可供延长贮存之用。
本发明的再一目的是提供一种帕洛诺司琼配方,其允许进行成品灭菌。
发明内容
本发明人已获得许多发现来支持使用帕洛诺司琼治疗和预防呕吐的这一高效和通用的配方。这些配方在室温下贮存稳定期大于24个月,因此无需冷藏,并可使用非无菌,末期消毒的方法制备。
在一方面,本发明人已发现在一些病例中,所需含有活性帕洛诺司琼成分配方的用量仅是先前已知用于治疗呕吐的化合物的1/10,令人惊奇的是,帕洛诺司琼的使用浓度远低于通常所预计的量。因此,在本发明一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包含a)约0.01mg/mL至约5mg/mL的帕洛诺司琼或其药学上可接受的盐;和b)药学上可接受载体。
本发明人已进一步发现通过调节配方的pH值和/或赋形剂浓度,就可以增强帕洛诺司琼配方的稳定性。因此,在本发明另一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包含a)帕洛诺司琼或其药学上可接受的盐;和b)药学上可接受载体,pH值为约4.0至约6.0。在本发明另一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包含约0.01至约5.0mg/ml的帕洛诺司琼或其药学上可接受的盐;约10至约100毫摩尔的柠檬酸盐缓冲液;和约0.005至约1.0mg/ml的EDTA。
本发明人已进一步发现添加甘露醇和螯合剂可增强帕洛诺司琼配方的稳定性。因此,还在本发明另一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包含a)帕洛诺司琼或其药学上可接受的盐和b)药学上可接受载体,其中药学上可接受载体包含螯合剂和甘露醇。
具体实施方式
定义
“管形瓶”指用最合适的塞子和封蜡密封的小玻璃容器,也可以使用其它合适的初选容器,例如,但不限于,预装注射器。管形瓶也指装有药物的密封容器,其仅可一次性使用,包括易碎和不易碎的玻璃管形瓶、易碎的塑料管形瓶,小型带螺旋口的广口瓶及其它类型的容器,其尺寸刚好仅能容纳一单位剂量的帕洛诺司琼(通常约5毫升)。
在说明书全文中术语“包括(comprise)”,或诸如“comprises”或“comprising”的变化应当理解为意味着包括所规定的元素、总体或步骤,或元素、总体或步骤的组,但不排除其它元素、总体或步骤,或元素、总体或步骤的组。
“帕洛诺司琼”指的是(3aS)-2,3,3a,4,5,6-六氢-2-[(S)-1-氮杂二环[2.2.2]八-3-基]2,3,3a,4,5,6-六氢-1-氧-lH苯[脱]异喹啉,优选以单盐酸化物存在。帕洛诺司琼单盐酸化物的化学结构如下:
浓度--本文中所提及的帕洛诺司琼浓度是根据游离碱的重量测得的。其他成分的浓度是基于添加到溶液中的该成分重量。
“药学上可接受的”指在制备药物组合物中使用的,通常是安全、无毒以及既不是生物学上的也不是其它方面所不期望的,并包括对于兽医用途和人制药用途可接受的。
“药学上可接受的盐”指其是药学上可接受的盐,如上所定义,具有所需的药理学活性。这样的盐包括无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或有机酸形成的酸加成盐,所述有机酸例如醋酸、丙酸、己酸、庚酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、o-(4-羟基苯甲酰基)苯甲酸、苯丙烯酸、苯乙醇酸、甲磺酸、乙烯磺酸,1,2,-乙烯磺酸、2-羟基乙烯磺酸、苯磺酸、对-氯苯磺酸、2-奈磺酸,对-甲苯磺酸、樟脑磺酸、4-甲基二环[2.2.2]八-2-烯-1-羧酸、葡庚糖酸、4,4'-亚甲基双(3-羟基-2-烯-1-羧酸)、3-苯基丙酸、三甲基乙酸、叔己酸、月桂酸、葡糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、粘庚酸等。
此外,当存在的酸性质子能与无机或有机碱反应时,形成了其药学上可接受的盐。可接受的无机碱包括氢氧化钠、碳酸钠、氢氧化钾、氢氧化铝和氢氧化钙。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、N-甲基葡糖胺等。
讨论
事实是在一些病例中,所需含有活性帕洛诺司琼成分配方的用量仅是先前已知用于治疗呕吐的化合物的1/10,令人惊奇的是,帕洛诺司琼的使用浓度远低于通常所预计的量。因此,在本发明一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包含a)约0.01mg/mL至约5mg/mL的帕洛诺司琼或其药学上可接受的盐;和b)药学上可接受载体。类似地,在本发明另一个实施方案中提供了一种配制帕洛诺司琼药学上稳定的溶液的方法,包括将约0.01mg/mL至约5mg/mL的帕洛诺司琼或其药学上可接受的盐与药学上可接受载体混合。在可选择的实施方案中,所述配方包括帕洛诺司琼或其药学上可接受的盐,浓度为约0.02mg/mL至约1.0mg/mL、约0.03mg/mL至约0.2mg/mL,最优选为约0.05mg/ml。
较低剂量地进行帕洛诺司琼静脉内给药的突出优点是能在短且不连续的时间段内以单次静脉快速注射的形式给予该药物。该时间段通常为约10至约60秒,或约10至约40秒,最优选为约10至约30秒。在一个具体实施方案中,将帕洛诺司琼封装在能容纳5ml溶液的管形瓶中,相当于约0.05mg/ml浓度的约0.25mg帕洛诺司琼。
本发明人已进一步发现通过调节配方的pH值和/或赋形剂浓度,就可以增强帕洛诺司琼配方的稳定性。因此,在另一个实施方案中,本发明提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包括a)帕洛诺司琼或其药学上可接受的盐;和b)药学上可接受载体,pH值为约4.0至约6.0。类似地,在本发明另一个实施方案中提供了一种配制帕洛诺司琼药学上稳定的溶液的方法,包括在pH值为约4.0至约6.0下,混合a)帕洛诺司琼或其药学上可接受的盐;和b)药学上可接受载体。在可选择的实施方案中,pH值为约4.5至约5.5,最优选为约5.0。对于本领域技术人员而言,有许多合适的溶液可用于调节配方pH值。两种例证性的溶液是氢氧化钠和盐酸溶液,都可用于调节配方的pH值。
在本发明另一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包括约0.01至约5.0mg/ml的帕洛诺司琼或其药学上可接受的盐和(i)约10至约100毫摩尔的柠檬酸盐缓冲液,和/或(ii)约0.005至约1.0mg/ml的EDTA。类似地,在本发明另一个实施方案中提供了一种配制帕洛诺司琼药学上稳定的溶液的方法,包括将约0.01至约5.0mg/ml的帕洛诺司琼或其药学上可接受的盐与(i)约10至100毫摩尔的柠檬酸盐缓冲液,和/或(ii)约0.005至约1.0mg/ml的EDTA混合。柠檬酸盐缓冲液可以是柠檬酸和/或诸如柠檬酸三钠的柠檬酸盐形式。在不同实施方案中,一种或多种前述成分的范围可作如下调整:
·所述配方可包含帕洛诺司琼或其药学上可接受的盐,帕洛诺司琼盐酸化物浓度为约0.02mg/mL至约1.0mg/mL,约0.03mg/mL至约0.2mg/mL,最优选浓度为约0.05mg/ml。
·所述配方可包含柠檬酸盐缓冲液,浓度为约10至约40毫摩尔,或约15至约30毫摩尔。
·所述配方可包含EDTA,其浓度为约0.005mg/ml至约1.0mg/ml,或约0.3至约0.7mg/ml,最优选浓度为约0.5mg/ml。
本发明人已进一步发现添加甘露醇和螯合剂可增强帕洛诺司琼配方的稳定性。因此,还在本发明另一个实施方案中提供了一种用于预防或减轻呕吐的药学上稳定的溶液,包含a)帕洛诺司琼或其药学上可接受的盐和b)药学上可接受载体,其中药学上可接受载体包含螯合剂和甘露醇。类似地,在本发明另一个实施方案中提供了一种配制帕洛诺司琼药学上稳定的溶液的方法,包括混合a)帕洛诺司琼或其药学上可接受的盐和b)药学上可接受载体,其中药学上可接受载体包含螯合剂和甘露醇。螯合剂优选EDTA,在不同的实施方案中,所述螯合剂浓度为约0.005至约1.0mg/mL,或约0.05mg/mL至约1.0mg/mL,或约0.3至约0.7mg/ml,或最优选约0.5mg/ml。在不同的实施方案中,所述甘露醇浓度为约10.0mg/ml至约80.0mg/ml,或约20.0mg/mL至约60.0mg/ml,或约40.0至约45.0mg/ml。
可注射的配方通常配制为水溶液,其中水是主要的赋形剂。口服配方与可注射配方不同,其通常添调味剂、着色剂或增稠剂。天然或合成的甜味剂包括,其中有甘露醇、山梨糖醇、蔗糖、糖精、阿斯巴特(糖精)、萘嵌戊酯K或环己氨基磺酸盐。当作为甜味剂时,与在本发明某些实施方案中所描述的甘露醇的浓度41.5mg/ml相比,其浓度通常超过100mg/ml或250mg/ml,其中所述甘露醇只作为张力调节剂。
本发明的配方特别适用于可注射和口服的液体配方,但应当理解所述溶液具备可选择的用途。例如,在制备其它药学上的剂型时可作为中间物。类似地,其可有其它的给药途径,包括鼻内给药或吸入给药。可注射配方可以采用包括肌肉注射、静脉注射或皮下注射的任一途径。
进一步实施方案涉及对帕洛诺司琼配方更易于储存或制备的改进。具体而言,本发明人业已发现本发明的配方在室温下可允许延长产品贮存的时间。因此,在本发明另一个实施方案中提供了一种贮存一个或多个容器的方法,所述容器包含帕洛诺司琼或其药学上可接受的盐的溶液,该方法包括:a)提供一个容纳所述一个或多个容器的空间;b)调节或保持室温在约10、15、或20摄氏度以上;c)将所述容器在所述空间内贮存1个月、3个月、6个月、1年、18个月、24个月或更久(但优选不超过36个月),其中(i)帕洛诺司琼或其药学上可接受的盐的浓度为约0.01mg/mL至约5.0mg/mL,(ii)溶液的pH值为约4.0至约6.0,(iii)溶液包含约0.01至约5.0mg/ml的帕洛诺司琼或其药学上可接受的盐,约10至约100毫摩尔的柠檬酸盐缓冲液和约0.005至约1.0mg/ml的EDTA,(iv)溶液包含螯合剂,或(v)溶液包含约10至约100毫摩尔的柠檬酸盐缓冲液。
上述配方的稳定性还要适用于制造方法中的成品灭菌过程。因此,还在本发明另一个实施方案中提供了一种填充容器的方法,所述容器包含帕洛诺司琼溶液或其药学上可接受的盐,该方法包括:a)提供一个或多个无菌开口容器(优选5ml管形瓶);b)在非无菌环境下将帕洛诺司琼溶液装入到前述容器内;c)密封所述填满的容器;和d)对上述密封的、填满的容器进行灭菌,其中(i)帕洛诺司琼或其药学上可接受的盐的浓度为约0.01mg/mL至约5.0mg/mL,(ii)溶液的pH值为约4.0至约6.0,(iii)溶液包含约0.01至约5.0mg/ml的帕洛诺司琼或其药学上可接受的盐,约10至约100毫摩尔的柠檬酸盐缓冲液和约0.005至约1.0mg/ml的EDTA,(iv)溶液包含螯合剂,或(v)溶液包含约10至约100毫摩尔的柠檬酸盐缓冲液。
实施例
实施例1:稳定的pH
进行研究以确定pH值对含有帕洛诺司琼盐酸化物配方的影响,在80℃,pH 2.0、5.0、7.4和10.0时测定稳定性。结果表明,帕洛诺司琼盐酸化物在pH5.0时最稳定。
实施例2:稳定的浓度范围
使用试验设计软件进行配方优化研究。分析24批药品以研究帕洛诺司琼盐酸化物(0.05mg/mL至5.0mg/mL)、柠檬酸盐缓冲液(0至80mM)和EDTA(0至0.10%)适当的浓度范围。基于优化配方来选择EDTA和柠檬酸盐缓冲液水平,显示在pH 5.0时配方中EDTA为0.05%、柠檬酸盐缓冲液为20mM。该研究结果表明帕洛诺司琼浓度也是化学稳定性的关键因素,可以看到在最低的帕洛诺司琼浓度下具有最高的稳定性。
实施例3:张力调节剂
在柠檬酸盐缓冲液中制备的帕洛诺司琼盐酸化物配方包括a)氯化钠或b)甘露醇。包括甘露醇的帕洛诺司琼盐酸化物配方显示出较高的稳定性。已发现等渗溶液所需的甘露醇最佳水平为4.15%。
实施例4:配方I
如下是一包含帕洛诺司琼的代表性药物配方,其用于静脉内给药配方或该药物的其它液体配方。
成分 | mg/mL |
帕洛诺司琼盐酸化物 | 0.05* |
甘露醇 | 41.5 |
EDTA | 0.5 |
柠檬酸三钠 | 3.7 |
柠檬酸 | 1.56 |
WFJ | 适量至1ml |
氢氧化钠溶液和/或盐酸溶液 | pH5.0±0.5 |
*以游离碱计算
实施例5:配方II
如下是一包含帕洛诺司琼的代表性药物配方,其用于口服给药配方或药物的其它液体配方。
成分 | mg/mL |
帕洛诺司琼盐酸化物 | 0.05* |
甘露醇 | 150 |
EDTA | 0.5 |
柠檬酸三钠 | 3.7 |
柠檬酸 | 1.56 |
WFJ | 适量至1ml |
氢氧化钠溶液和/或盐酸溶液 | pH5.0±0.5 |
调味剂 | 适量 |
*以游离碱计算
实施例6:不含地塞米松时帕洛诺司琼的稳定性
在5%葡萄糖注射液、0.9%氯化钠注射液、含5%葡萄糖的0.45%氯化钠注射液以及含5%葡萄糖的乳酸林格氏(Ringer’s)注射液中,研究浓度为5μg/mL和30μg/mL的帕洛诺司琼盐酸化物的物理和化学稳定性。该混合物在4℃的黑暗条件下观察14天,并在23℃荧光灯下观察48小时。
在聚氯乙烯(PVC)袋中制备帕洛诺司琼盐酸化物测试样品,注入溶液的浓度为5和30μg/mL。立即评估其物理和化学稳定性,并在4℃贮存1、3、5、7、14天后以及在23℃贮存1、4、24、48小时后评估其物理和化学稳定性。物理稳定性采用了目测观察的评估方法,是在正常室内光线条件下并使用高亮度的单向性光束进行的。此外,使用电子仪器测量混浊度和离子含量。通过使用具有稳定性指示的高效液相色谱(HPLC)分析技术评估药物的化学稳定性。
在整个研究过程中所有样品都保持物理稳定。溶液保持澄清,发现微粒负荷和混浊水平几乎没有改变。此外,在整个研究过程中在任何样品中的帕洛诺司琼盐酸化物几乎没有出现损失。
实施例7:含地塞米松时帕洛诺司琼的稳定性
0.25mg的帕洛诺司琼盐酸化物可在聚氯乙烯(PVC)微型袋中,在5%葡萄糖注射液或0.9%氯化钠注射液中与10mg或20mg的地塞米松(为磷酸钠)混合,也可在聚丙烯注射器中,在5%葡萄糖注射液或0.9%氯化钠注射液中与3.3mg的地塞米松(为磷酸钠)混合,在4℃的黑暗条件下放置14天并在23℃暴露于常用的实验室荧光灯超过48小时,以研究帕洛诺司琼盐酸化物的物理和化学稳定性。
在每种注入溶液的聚氯乙烯(PVC)微型袋中制备5μg/mL帕洛诺司琼盐酸化物与0.2mg/mL和0.4mg/mL地塞米松(为磷酸钠)混合的测试样品。此外,在20mL聚丙烯注射器中,在每种注入溶液中制备25μg/mL帕洛诺司琼盐酸化物与0.33mg/mL地塞米松(为磷酸钠)混合的10mL测试溶液。立即评估其物理和化学稳定性,并在4℃贮存1、3、5、7、14天后以及在23℃贮存1、4、24、48小时后评估其物理和化学稳定性。物理稳定性采用了目测观察的评估方法,是在正常室内光线条件下并使用高亮度的单向性光束进行的。此外,使用电子仪器测量混浊度和离子含量。通过使用具有稳定性指示的高效液相色谱(HPLC)分析技术评估药物的化学稳定性。
在整个研究过程中所有样品都保持物理相容性。溶液保持澄清,发现微粒负荷和混浊水平几乎没有改变。此外,在整个研究过程中在任一温度下任何样品中的帕洛诺司琼盐酸化物和地塞米松几乎没有出现损失。
本发明业已根据其优选的实施例进行描述。对于本领域技术人员而言,根据本发明前述的详细描述,本发明的变化和改进是显而易见的。
Claims (11)
1.一种用于预防或减轻呕吐的药学上稳定的溶液,包含:
a)0.03mg/mL至0.2mg/mL帕洛诺司琼或在其药学上可接受的盐;和
b)药学上可接受的载体,
其中,pH值为4.5至5.5。
2.权利要求1所述的溶液,其中帕洛诺司琼或其药学上可接受的盐浓度为0.05mg/mL。
3.权利要求1所述的溶液,包含帕洛诺司琼盐酸化物。
4.权利要求1所述的溶液,其中药学上可接受的载体包含螯合剂。
5.权利要求1所述的溶液,其中药学上可接受的载体包含0.005mg/ml至1.0mg/ml的EDTA。
6.权利要求1所述的溶液,所述药学上可接受的载体包含甘露醇。
7.权利要求1所述的溶液,适用于静脉内给药。
8.权利要求1所述的溶液,适用于口服给药。
9.如权利要求1所述的一种用于预防或减轻呕吐的药学上稳定的溶液,其中帕洛诺司琼封装在能容纳5ml溶液的容器内,以帕洛诺司琼碱的重量计,帕洛诺司琼浓度为0.05mg/ml。
10.权利要求1或6的溶液,进一步包含0.005-1.0mg/ml EDTA,其中所述a)组分为0.03-0.2mg/ml帕洛诺司琼盐酸化物,所述溶液为帕洛诺司琼盐酸化物的可注射等渗水溶液制剂形式。
11.权利要求1的溶液,进一步包含0.005-1.0mg/ml EDTA、10-80mg/ml甘露醇和10-100mM柠檬酸盐缓冲液,其中所述a)组分为0.05mg/ml帕洛诺司琼盐酸化物,所述溶液为帕洛诺司琼盐酸化物的可注射等渗水溶液制剂形式。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44435103P | 2003-01-30 | 2003-01-30 | |
US60/444,351 | 2003-01-30 |
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KR101802183B1 (ko) * | 2016-11-16 | 2017-11-28 | 주식회사 유영제약 | 팔로노세트론을 활성성분으로 함유하는 약제학적 조성물 |
WO2019038656A1 (en) | 2017-08-21 | 2019-02-28 | Leiutis Pharmaceuticals Pvt, Ltd | NEW TRIPLE COMBINATION FORMULATIONS FOR ANTIEMETIC THERAPY |
ES2943933T3 (es) * | 2018-01-12 | 2023-06-16 | Orion Corp | Colirios de palonosetrón para el tratamiento o la prevención de náuseas y vómitos |
JP7090845B2 (ja) * | 2018-08-03 | 2022-06-27 | 高田製薬株式会社 | パロノセトロン含有液体組成物 |
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