CN1775207A - 艾司洛尔制剂 - Google Patents
艾司洛尔制剂 Download PDFInfo
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- CN1775207A CN1775207A CNA2005101184817A CN200510118481A CN1775207A CN 1775207 A CN1775207 A CN 1775207A CN A2005101184817 A CNA2005101184817 A CN A2005101184817A CN 200510118481 A CN200510118481 A CN 200510118481A CN 1775207 A CN1775207 A CN 1775207A
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- 238000009472 formulation Methods 0.000 title description 13
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- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 title description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
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Classifications
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Abstract
一种含水的、适用于经非肠道给药的治疗心脏疾病的无菌药物组合物，该组合物含有3－[4－(2－羟基－3－异丙基氨基)丙氧基]苯基丙酸甲酯盐酸盐(盐酸艾司洛尔)、缓冲剂以及渗透调节剂，同时该组合物的制备方法也在本发明中公开。
Description
本申请是中国专利申请第02800067.6号的分案申请。
发明背景
盐酸艾司洛尔是一种用于治疗或预防哺乳动物心脏疾病的短效β-受体阻断剂。目前多数有效的β-受体阻断剂都是在相对较长的时间内施用于心脏病患者的稳定的药物。然而，在治疗危重病人时经常需要在危险期快速降低心脏负荷或改善心脏的节律性，例如，在心肌梗塞发生时或发生不久。传统的β-受体阻断剂可以被用于上述治疗，但是它们较长的作用时间会引起不希望的副作用。
盐酸艾司洛尔含有一个酯官能团，并且具有典型的β-肾上腺素能阻断活性。然而，与传统的β-受体阻断化合物不同的是，由于酯官能团的存在，盐酸艾司洛尔在体内有较短的作用周期。这样，盐酸艾司洛尔由于其独特的短效活性而具有相对于传统的β-受体阻断剂的优点。但是，盐酸艾司洛尔的酯官能团由于极易水解降解而在含水环境中不稳定。
艾司洛尔在水中的稳定性是由不稳定的脂肪族的甲酯基团的酸/碱水解速率所决定。在过去，盐酸艾司洛尔的降解速率的降低是由于使用作为缓冲剂的醋酸盐，尽可能维持体系的pH值在5.0左右，降低艾司洛尔在溶液中的浓度，以及降低所用缓冲液的浓度来实现的。现有技术的制剂可以保持适当长的贮存期限，然而，在高压灭菌时它们降解严重。因此，现有技术的制剂均是在无菌条件下制备的。参见美国专利申请4857552和5107609。美国专利4857552披露了一种适合于小瓶包装的含有置于含水缓冲剂中的艾司洛尔的成品制剂。美国专利5107609披露了一种适合于安瓿包装的含有置于含水缓冲剂中的艾司洛尔的浓缩制剂，并使用丙二醇和乙醇来增加艾司洛尔的溶解度。在使用时，将安瓿制剂用适当的等渗溶液如包含葡萄糖、乳酸化的林格氏溶液、氯化钠或氯化钾的溶液，稀释到应用的剂量水平。
但是，在稀释/无菌操作过程中，无论是小瓶还是安瓿装，产品都有可能被微生物污染。因此，最终灭菌是权威机构规定的首选的降低微生物含量、保证最终产品的安全的途径。
发明概述
本发明涉及一种适合非肠道给药治疗心脏病的、含水的、无菌药物组合物，该组合物包含3-[4-(2-羟基-3-异丙基氨基)丙氧基]苯基丙酸甲酯盐酸盐(盐酸艾司洛尔)、缓冲剂以及渗透调节试剂。本发明进一步涉及将上述组合物在容器中制备的方法。
发明详述
本发明提供一种稳定的、经非肠道给药的组合物，该组合物包含盐酸艾司洛尔、可药用的缓冲剂、以及调节溶液张力的渗透调节剂。该组合物封装在密封容器中，并经高压灭菌法进行最终灭菌以降低制剂的微生物含量。现有技术的盐酸艾司洛尔制剂不能经受高压灭菌。本发明的制剂稳定，不会发生水解降解和其它化学副反应，并且具有药学上适宜的贮存期限。
本申请所提到的术语“稳定”，意思是保持适于为患者用药的状态或条件。本发明的制剂在室温下可至少保持稳定达12个月，通常可以在室温下保持稳定达12-24个月。
本申请所提到的术语“无菌”组合物，意思是药物组合物保持无菌状态并不会暴露于被微生物污染的环境中，也就是说盛放无菌组合物的容器不会被破坏。无菌组合物的制备通常是按照美国FDA所规定的通用的《药品生产质量管理规范》(cGMP)由药品制造商生产。
本产品可以制成用于输注的无菌的成品制剂形式。这样就避免了在输注前将浓缩的小体积非肠道艾司洛尔制剂稀释成用于输注的形式，也就避免了在无菌操作中可能的微生物污染的风险，以及可能的稀释或计算误差。这种不是由浓缩产品稀释的制剂，基本上不含有丙二醇和乙醇。本产品也可以制成给药前要稀释的浓缩制剂形式。
本发明的含水无菌药物组合物适合于对患者非肠道给药。例如，组合物可以以大注射剂或静脉输注形式给药。合适的非肠道给药途径包括静脉、皮下、皮内、肌内、关节内以及鞘内。本发明的成品制剂优选静脉输注。
本发明合适的容器均是现有技术中常用的。它们包括小瓶、注射器、袋、瓶以及安瓿等。容器可以由玻璃或聚合物材料制备。成品制剂通常用小瓶、注射器、袋以及瓶包装，浓缩制剂通常用安瓿包装。
组合物的pH值会对产品的稳定性有很大影响。pH值应在3.5到6.5之间，优选在4.5到5.5之间，更优选是大约5.0。pH值可以通过众所周知的加入氢氧化钠或盐酸来进行调节。
盐酸艾司洛尔在本发明组合物中的含量范围在0.1-500mg/ml。成品制剂中可含有0.1-100mg/ml，优选1-20mg/ml，更优选1-10mg/ml。浓缩制剂可含有100-500mg/ml，优选100-250mg/ml。
合适的缓冲剂是现有技术公知的那些，在药物组合物中的浓度范围是0.01-2M。成品制剂中的缓冲剂浓度通常是0.01-0.5M，优选为0.02-0.1M。浓缩制剂中的缓冲剂浓度通常是0.5-2M。缓冲剂包括醋酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡萄糖酸盐、磷酸盐以及甘氨酸。优选的缓冲剂包括醋酸钠和冰醋酸的组合。
合适的渗透调节剂是现有技术公知的那些，在本申请药物组合物中的含量范围是1-500mg/ml。渗透调节剂包括氯化钠、葡萄糖、碳酸氢钠、氯化钙、氯化钾、乳酸钠、林格氏溶液以及乳酸化的林格氏溶液。优选是氯化钠和葡萄糖。成品制剂可含有1-100mg/ml渗透调节剂；优选4-60mg/ml氯化钠，更优选4-10mg/ml氯化钠；或含或不含氯化钠的25-60mg/ml葡萄糖。本发明的组合物中的葡萄糖优选与氯化钠组合不超过5％(重量比)。浓缩制剂可含有50-500mg/ml的渗透调节剂。
本发明的药物组合物可以制成小体积非肠道给药剂型(SVP)和大体积非肠道给药剂型(LVP)。药物剂型可以装于任何合适的容器中。合适的容器包括如玻璃或聚合物材料的小瓶、安瓿、注射器或袋，容积从1ml到500ml。SVP的成品溶液通常装在1-100ml的安瓿和小瓶中。另外，注射器可以用于成品SVP的包装，作为“预装注射器”出售。LVP则可装于袋或瓶中。
聚合物材料的容器优选具有挠性，可含或不含聚氯乙烯(PVC)。优选的容器不含有聚氯乙烯，如那些美国专利5849843和5998019所公开的。聚合物材料的容器可进一步含有湿气屏障作为二级包装系统，以防止在贮存过程中水分的丢失，并进而确保产品的稳定性。优选的湿气屏障为铝的罩袋(overpouch)。
将本发明的药物组合物填充入容器的步骤以及随后的加工过程都是现有技术公知的。这些步骤都是用于生产为健康服务的无菌药物产品的。这些工艺技术优选使用消灭或清除任何在制备过程中存在于艾司洛尔制剂中的微生物的无菌操作过程。例如，最终灭菌可以用于消灭存在于盛放艾司洛尔制剂的最终封装容器中的所有活的微生物。高压灭菌器通常用于完成药物产品在最终包装中的最终热灭菌操作。
高压灭菌过程在制药工业中完成对最终产品的最终灭菌条件是在121℃达15分钟。本发明的盐酸艾司洛尔药物组合物可以在高压灭菌温度范围115-130℃进行5-40分钟而保持可接受的稳定性。高压灭菌的优选温度范围是119-122℃，时间是10-36分钟。
另外，根据本发明的无菌药物组合物可以使用无菌工艺进行制备。无菌灌注通常用于制备那些不能进行热灭菌且要求组分为无菌的药品。通过使用无菌材料和控制工作条件来保持药品的无菌。所有的容器和器械都要在灌装前灭菌消毒，优选作热灭菌处理。容器(如小瓶、安瓿、袋、瓶子、或注射器)都要在无菌条件下灌装。
以下的实施例进一步说明本发明，但是并不以任何方式来限制本发明的范围。
实施例1
以下描述的是本发明的包含10mg/ml盐酸艾司洛尔溶液的成品输液袋的制备。组合物中每种组分的浓度如下：
| 组分 | 含量/ml溶液 |
| 盐酸艾司洛尔 | 11mg/ml |
| 氯化钠(渗透调节剂) | 5.9mg/ml |
| 三水合醋酸钠(缓冲剂) | 2.8mg/ml(0.02M) |
| 冰醋酸(缓冲剂) | 0.546mg/ml(0.01M) |
| 氢氧化钠/盐酸 | 调节pH值至5.0 |
| 注射用水，USP | 适量 |
所有混和、过滤以及灌装的设备和玻璃器皿均适度清洗烘干。过滤装置、填料管装置以及其它部件和设备均进行消毒处理。
80％的产品最终体积的冷注射用水加入经过校准的混和罐中。将氯化钠加入罐中，溶液搅拌直至氯化钠溶解。随后加入冰醋酸和醋酸钠。溶液进一步搅拌直至加入的赋形剂溶解。用注射用水加至最终体积的90％，再混和搅拌。此溶液(缓冲溶液)大约用2升用于制备浆状溶液。称量盐酸艾司洛尔并加入2升缓冲溶液形成浆状溶液。此浆状物随后加入混和罐中混和。溶液用1N的氢氧化钠或盐酸调pH值至5.0。再用注射用水加至最终产品的体积，混和。
溶液随即灌入250ml非聚氯乙烯的挠性袋(IntraViaTM挠性塑料容器(PL2408-3非PVC多层塑料膜)，和一个标准的PL 146PVC薄膜管，一个PL 2409-3多层塑料共挤出给药端口管，一个PL 141 PVC蓝尖封端(给药端口保护器)，来自Baxter Healthcare Corporation)。这些袋密封在铝箔罩袋中。产品随后放入高压灭菌器中在121℃下灭菌36分钟。
已灭菌产品要进行检测和释放试验。选择以上制备的袋产品进行稳定性试验。在每一次稳定检测的时间，对每一溶液的一个袋检测pH值、效能、重量克分子渗透浓度、物理外观以及微粒物质。药物的浓度用高效液相色谱(HPLC)法测定。结果如下：
| I.不同温度和时间下贮存的袋的稳定性 | ||||||
| 检测时间 | 效能(mg/ml) | pH | 重量克分子渗透浓度(mosm/kg) | 外观检测 | 微粒物质 | |
| 颗粒≥10μm | 颗粒≥25μm | |||||
| 25℃/35％RH * | ||||||
| 初始3个月6个月 | 10.910.710.6 | 4.94.94.9 | 304303302 | 合格**合格合格 | 000 | 000 |
| 30℃/35％RH * | ||||||
| 初始3个月6个月 | 10.910.610.4 | 4.94.94.8 | 304304304 | 合格合格合格 | 000 | 000 |
| 40℃/15％RH * | ||||||
| 初始1个月2个月3个月6个月 | 10.910.710.510.49.9 | 4.94.94.94.94.8 | 304304304306308 | 合格合格合格合格合格 | 00000 | 00000 |
*贮存温度和湿度条件。RH＝相对湿度
**合格：无色透明溶液。
实施例2
用下列配方重复实施例1的操作：
| 组分 | 含量/ml溶液 |
| 盐酸艾司洛尔 | 11mg/ml |
| 葡萄糖 | 50mg/ml |
| 三水合醋酸钠 | 2.8mg/ml(0.02M) |
| 冰醋酸 | 0.546mg/ml(0.01M) |
| 氢氧化钠/盐酸 | 调节pH值至5.0 |
| 注射用水，USP | 适量 |
实施例3
用下列配方重复实施例1的操作：
| 组分 | 含量/ml溶液 |
| 盐酸艾司洛尔 | 11mg/ml |
| 葡萄糖 | 25mg/ml |
| 氯化钠 | 2.95mg/ml |
| 三水合醋酸钠 | 2.8mg/ml(0.02M) |
| 冰醋酸 | 0.546mg/ml(0.01M) |
| 氢氧化钠/盐酸 | 调节pH值至5.0 |
| 注射用水，USP | 适量 |
在这里所引用的所有参考文献，包括出版物、专利申请和专利文献，都在此引入作为参考，如同每个文献都单独并具体地指明引入作为参考并且在此全文给出一样。
Claims (10)
1.一种含水的、适用于经非肠道给药的治疗心脏疾病的无菌药物组合物，该组合物具有3.5-6.5的pH值，并含有：
a.100-250mg/ml的3-[4-(2-羟基-3-异丙基氨基)丙氧基]苯基丙酸甲酯盐酸盐；
b.0.01-2M缓冲剂；和
c.1-500mg/ml渗透调节剂。
2.如权利要求1的药物组合物，其中pH值在4.5-5.5。
3.如权利要求1或2的药物组合物，其中所述缓冲剂含有醋酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡萄糖酸盐、磷酸盐以及甘氨酸中的至少一种，渗透调节剂含有氯化钠、葡萄糖、碳酸氢钠、氯化钙、氯化钾、乳酸钠、林格氏溶液以及乳酸化的林格氏溶液中的至少一种。
4.如权利要求1或2所述的药物组合物，其中组合物是由经热灭菌消毒的容器所提供。
5.如权利要求1或2所述的药物组合物，其中组合物的pH值大约为5，并含有0.01-0.5M的缓冲剂和1-100mg/ml的渗透调节剂。
6.如权利要求1或2所述的药物组合物，其中组合物的pH值大约为5，并含有0.5-2M的缓冲剂和50-500mg/ml的渗透调节剂。
7.如权利要求1或2所述的药物组合物，其中组合物基本不含丙二醇和乙醇。
8.一种制备含水的、适用于静脉给药的治疗心脏疾病的无菌药物组合物的方法，包括在密封的容器中形成具有3.5-6.5pH值的含水组合物，该组合物含有100-250mg/ml 3-[4-(2-羟基-3-异丙基氨基)丙氧基]苯基丙酸甲酯盐酸盐、0.01-2M缓冲剂和1-500mg/ml渗透调节剂；以及进行高压灭菌，高压灭菌的时间足以使组合物无菌。
9.权利要求8所述的方法，其中组合物具有4.5-5.5的pH值。
10.权利要求8或9的方法，其中所述高压灭菌是在115-130℃温度下进行5-40分钟。
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| KR20140034729A (ko) | 2011-01-27 | 2014-03-20 | 백스터 인터내셔널 인코포레이티드 | 저혈압을 최소화 및/또는 제어하면서 심계항진을 치료 및/또는 심박동수를제어하는 방법 |
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| JPH0720861B2 (ja) * | 1984-04-09 | 1995-03-08 | ザ デュポン マーク ファーマソウテイカル カンパニー | 心臓障害の処置または予防用の医薬組成物および方法 |
| US4857552A (en) * | 1988-06-08 | 1989-08-15 | E. I. Du Pont De Nemours And Co. | Stable pharmaceutical composition |
| TWI277414B (en) * | 2001-01-12 | 2007-04-01 | Baxter Int | Esmolol formulation |
| US6310094B1 (en) * | 2001-01-12 | 2001-10-30 | Baxter International Inc. | Ready-to-use esmolol solution |
-
2001
- 2001-01-12 US US09/759,547 patent/US6310094B1/en not_active Expired - Lifetime
- 2001-10-30 US US10/016,260 patent/US6528540B2/en not_active Expired - Lifetime
-
2002
- 2002-01-02 KR KR1020027011900A patent/KR100889090B1/ko not_active Expired - Lifetime
- 2002-01-02 EP EP06016319A patent/EP1738756A3/en not_active Withdrawn
- 2002-01-02 CN CNA2005101184817A patent/CN1775207A/zh active Pending
- 2002-01-02 PT PT02736473T patent/PT1368019E/pt unknown
- 2002-01-02 CN CN2006101685054A patent/CN1981739B/zh not_active Expired - Lifetime
- 2002-08-21 ZA ZA200206688A patent/ZA200206688B/en unknown
-
2009
- 2009-11-02 JP JP2009252474A patent/JP5778384B2/ja not_active Expired - Lifetime
-
2013
- 2013-05-15 JP JP2013102769A patent/JP2013151572A/ja active Pending
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2014
- 2014-10-14 AR ARP140103809A patent/AR098013A2/es unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106729661A (zh) * | 2016-12-02 | 2017-05-31 | 广东天普生化医药股份有限公司 | 人尿激肽原酶的新用途及含有人尿激肽原酶的药物组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100889090B1 (ko) | 2009-03-17 |
| US6310094B1 (en) | 2001-10-30 |
| AR098013A2 (es) | 2016-04-27 |
| EP1738756A2 (en) | 2007-01-03 |
| JP5778384B2 (ja) | 2015-09-16 |
| CN1981739B (zh) | 2010-12-08 |
| JP2013151572A (ja) | 2013-08-08 |
| PT1368019E (pt) | 2007-01-31 |
| US6528540B2 (en) | 2003-03-04 |
| EP1738756A3 (en) | 2009-01-14 |
| KR20020093839A (ko) | 2002-12-16 |
| JP2010024249A (ja) | 2010-02-04 |
| CN1981739A (zh) | 2007-06-20 |
| ZA200206688B (en) | 2004-03-10 |
| US20020147239A1 (en) | 2002-10-10 |
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