CN1298310A - 稳定的米托蒽醌溶液 - Google Patents
稳定的米托蒽醌溶液 Download PDFInfo
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Abstract
本发明涉及稳定的米托蒽醌溶液,其中含有用于稳定作用的0.001—0.15%乙二胺四乙酸钠。本发明注射液不含亚硫酸盐化合物,因此当非胃肠道给药时不会引起与亚硫酸盐化合物有关的副作用。
Description
技术领域
本发明涉及米托蒽醌溶液,其中除了含有活性化合物米托蒽醌(1,4-二羟基-5,8-二[[2-[(2-羟基乙基)氨基]乙基]氨基]蒽醌盐酸盐)之外,还含有稳定剂,并且不含有亚硫酸盐化合物,本发明还涉及这些溶液作为注射液和作为输液浓缩物的应用。
现有技术
米托蒽醌具有抗肿瘤、抗病毒、抗原生动物、和免疫调节特性。该化合物是很强的细胞抑制剂,尤其可用于治疗乳腺癌、恶性淋巴瘤、急性白血病、原发性肝细胞癌和卵巢癌。
作为药物制剂,米托蒽醌的水溶液获得了使用批准。然而,米托蒽醌在水溶液中的稳定性很有限。已知如果不采取措施来降低米托蒽醌降解或最好是阻止其降解的话,该化合物易于氧化分解。尤其是金属离子甚至在很低的浓度下也能加速米托蒽醌降解。
据表明通过使用抗氧化剂可抵制米托蒽醌的氧化分解。
EP-B-0236822中描述了一种制剂,其中是通过加入具有固定pH值的抗氧化剂偏亚硫酸氢钠、以及加入螯合剂乙二胺四乙酸二钠和甘氨酸来稳定该制剂的。
虽然该制剂是稳定的,但是从添加剂的副作用这个角度来看,该制剂不能令人满意。这种制剂的缺点是使用了通常是非常有效的稳定剂的偏亚硫酸氢钠。
声称加入了亚硫酸盐的含有米托蒽醌的溶液是市售产品。据报道,当使用含有常规浓度的亚硫酸盐的制剂时,会在人体中产生过敏反应,在有些情况下还会产生严重的副作用。对于具有亚硫酸盐敏感性的哮喘,已经提及过的有例如危及生命的并发症。
不仅如此,使用至少两种螯合剂的金属离子结合组合又向制剂中补充了其它组分。
低于3的强酸性pH范围也对使用中的可耐受性和稳定性有不利影响(WANG,Da-Peng;LIANG,Gow-Zaw;TU,Yu-Hsing;米托蒽醌盐酸盐在溶液中的稳定性,Drug Development and Industrial Pharmacy,20(11),1895-1903(1994))。
本发明的目的是避免这些副作用,并提供不含有亚硫酸盐化合物、于正常贮存条件下和30℃的高温下在相当长时间内保持稳定的含水制剂。
发明描述
与引用的专利EP-B-0236822相反,我们惊奇地发现,实际上乙二胺四乙酸钠自身足以在水溶液中稳定米托蒽醌。
依据本发明,通过提供由1-5mg/ml溶液的盐酸米托蒽醌、0.001-0.15%乙二胺四乙酸钠、氯化钠、乙酸钠和乙酸组成的含水制剂,本发明的目的得以实现。本发明制剂所达到的pH为3.0-4.5。
乙二胺四乙酸钠的用量优选为0.04%。
本发明药物制剂可以用作注射液或输液浓缩物来对上述癌症进行化疗。本发明药物制剂避免了上述副作用,并表现出药物制剂所需的稳定性。
实施本发明的方法
为了制备本发明溶液,将氯化钠和乙酸钠、乙酸和乙二胺四乙酸钠加到低氧水中并溶解。将盐酸米托蒽醌加到一部分该溶液中并溶解。将该活性化合物溶液加到具有所述辅料的溶液中,并用低氧水调至终体积。
将由此所获得的溶液过滤,然后装到注射瓶中,密封并卷曲封盖。
为了进行灭菌,使用常规防菌滤器,例如孔径为0.2μm的膜滤器。在使用前通过常规方法将所用容器灭菌。所用的水必须是无菌的,并且不含热原,以及符合欧洲药典1997的要求。注射容器由依据欧洲药典1997的要求的I型玻璃方便地制成。
各容器中溶液的量为2.5ml-50ml/容器、优选为5ml-15ml/容器。每个容器中米托蒽醌的量为5-100mg、优选为10-30mg。
当在无菌条件下装配注射液时,将注射瓶适当地冲洗以除去氧,用注射塞子密封并卷曲封盖。
下述实施例是为了更详细地举例说明本发明。
实施例1
含有5ml 0.2%浓度米托蒽醌注射液的注射瓶。组合物1ml注射液含有:盐酸米托蒽醌 2.328mg氯化钠 8.000mg乙酸钠×3H2O 0.085mg乙二胺四乙酸二钠 0.040mg1N乙酸 7.680μl注射用水 至1ml制备该溶液
为了制备该注射液,将氯化钠、乙酸钠、乙酸和乙二胺四乙酸二钠加到水中并溶解。预先以适当方式将水中的氧含量降低。将该溶液分开,把盐酸米托蒽醌溶于其中一部分溶液。将含有米托蒽醌的溶液与剩余溶液混合在一起,用低氧水调至终体积。
然后通过经由膜滤器过滤来将所得溶液灭菌。
实施例2
含有12.5ml 0.2%浓度米托蒽醌注射液的注射瓶。
该米托蒽醌溶液的组成与制备与实施例1一致。
Claims (7)
1.稳定的米托蒽醌溶液,其中含有1-5mg/ml溶液的盐酸米托蒽醌、0.001-0.15%乙二胺四乙酸钠、以及作为其它组分的氯化钠、乙酸钠和乙酸。
2.权利要求1的稳定的米托蒽醌注射液,其特征在于,乙二胺四乙酸钠的含量优选为0.04%。
3.制备权利要求1或2的稳定的米托蒽醌溶液的方法,其特征在于,将氯化钠、乙酸钠、乙酸和乙二胺四乙酸钠溶于低氧水中,将盐酸米托蒽醌置于一部分该溶液中,将溶液合并,并调节至含有1-5mg盐酸米托蒽醌/ml溶液、和0.001-0.15%乙二胺四乙酸钠/ml溶液的终体积。
4.权利要求3的方法,其特征在于,优选加入0.04%乙二胺四乙酸钠。
5.权利要求1的稳定的米托蒽醌溶液在制备用于治疗癌症的药物中的应用。
6.用于治疗癌症的药物,其特征在于,所述药物含有1-5mg的盐酸米托蒽醌/ml溶液、0.001-0.15%乙二胺四乙酸钠、以及作为其它组分的氯化钠、乙酸钠和乙酸,其中所述百分比是按盐酸米托蒽醌溶液计的。
7.权利要求6的药物,其特征在于,所述药物优选含有0.04%乙二胺四乙酸钠。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19818802.1 | 1998-04-27 | ||
DE19818802A DE19818802A1 (de) | 1998-04-27 | 1998-04-27 | Stabile Mitoxantron-Lösungen |
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CN1298310A true CN1298310A (zh) | 2001-06-06 |
CN1195548C CN1195548C (zh) | 2005-04-06 |
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Application Number | Title | Priority Date | Filing Date |
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CNB998055794A Expired - Fee Related CN1195548C (zh) | 1998-04-27 | 1999-04-01 | 稳定的米托蒽醌溶液 |
Country Status (18)
Country | Link |
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US (1) | US6143795A (zh) |
EP (1) | EP1073469B1 (zh) |
JP (1) | JP2002512981A (zh) |
CN (1) | CN1195548C (zh) |
AR (1) | AR018198A1 (zh) |
AT (1) | ATE282431T1 (zh) |
AU (1) | AU744502B2 (zh) |
BG (1) | BG64767B1 (zh) |
BR (1) | BR9909981A (zh) |
CA (1) | CA2270004C (zh) |
CO (1) | CO5021217A1 (zh) |
DE (2) | DE19818802A1 (zh) |
HK (1) | HK1036012A1 (zh) |
HU (1) | HUP0102075A3 (zh) |
NZ (1) | NZ507407A (zh) |
RU (1) | RU2219917C2 (zh) |
TW (1) | TWI224003B (zh) |
WO (1) | WO1999055375A1 (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102397561A (zh) * | 2011-09-26 | 2012-04-04 | 沈阳药科大学 | 米托蒽醌作为淋巴示踪剂的应用 |
CN107149592A (zh) * | 2017-06-23 | 2017-09-12 | 沈阳天邦药业有限公司 | 具有淋巴靶向功能的生物自组装纳米晶注射剂及制备方法 |
CN113730603A (zh) * | 2020-05-27 | 2021-12-03 | 深圳华润九创医药有限公司 | 米托蒽醌制剂在制备诊治与甲状腺切除相关的疾病的药物中的应用 |
CN114601791A (zh) * | 2020-12-08 | 2022-06-10 | 成都倍特药业股份有限公司 | 一种盐酸米托蒽醌液体制剂及其制备方法 |
WO2023184818A1 (zh) * | 2022-03-27 | 2023-10-05 | 苏州大学 | 米托蒽醌在制备预防或治疗急性移植物抗宿主病药物中的应用 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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GB0005703D0 (en) | 2000-03-09 | 2000-05-03 | Alpharma As | Compounds |
ES2528631T3 (es) | 2003-04-08 | 2015-02-11 | Progenics Pharmaceuticals, Inc. | Formulaciones farmacéuticas que contienen metilnaltrexona |
JP5589110B1 (ja) * | 2013-03-08 | 2014-09-10 | 株式会社ポーラファルマ | 晶癖を有する結晶及び該結晶を有効成分として含有する医薬組成物 |
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US3248291A (en) * | 1963-08-19 | 1966-04-26 | Hoffmann La Roche | Stabilized thioxanthene derivatives and method of using the same |
ATE59290T1 (de) * | 1986-03-07 | 1991-01-15 | American Cyanamid Co | Stabile injizierbare arzneiformulierung des 1,4- dihydroxy-5,8-bis((2-(hydroxyaethylamino)|thyl)amino)anthrachinondihydrochlorids. |
IL83086A (en) * | 1987-07-06 | 1991-03-10 | Teva Pharma | Stable,injectable solutions of vincristine salts |
DE3825374A1 (de) * | 1988-07-26 | 1990-02-01 | Schwendener Reto Dipl Apotheke | Komplex aus mindestens einer lipophilen saeure und mitoxantron und/oder bisantren |
WO1994013274A1 (en) * | 1992-12-10 | 1994-06-23 | Abbott Laboratories | Stabilized catecholamine solutions |
FR2758264B1 (fr) * | 1997-01-16 | 1999-03-26 | Charles Dumontet | Compositions medicamenteuses contenant de l'edta ou un de ses derives pour la prevention de la toxicite cutanee et sous-cutanee des anthracyclines et de leurs derives |
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- 1998-04-27 DE DE19818802A patent/DE19818802A1/de not_active Ceased
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- 1999-04-01 HU HU0102075A patent/HUP0102075A3/hu unknown
- 1999-04-01 BR BR9909981-0A patent/BR9909981A/pt not_active Application Discontinuation
- 1999-04-01 CN CNB998055794A patent/CN1195548C/zh not_active Expired - Fee Related
- 1999-04-01 AT AT99916906T patent/ATE282431T1/de not_active IP Right Cessation
- 1999-04-01 JP JP2000545572A patent/JP2002512981A/ja active Pending
- 1999-04-01 AU AU35225/99A patent/AU744502B2/en not_active Ceased
- 1999-04-01 RU RU2000129666/14A patent/RU2219917C2/ru active
- 1999-04-01 DE DE59911099T patent/DE59911099D1/de not_active Expired - Fee Related
- 1999-04-01 EP EP99916906A patent/EP1073469B1/de not_active Expired - Lifetime
- 1999-04-01 WO PCT/EP1999/002290 patent/WO1999055375A1/de active IP Right Grant
- 1999-04-01 NZ NZ507407A patent/NZ507407A/xx unknown
- 1999-04-07 CO CO99020294A patent/CO5021217A1/es unknown
- 1999-04-23 TW TW088106569A patent/TWI224003B/zh not_active IP Right Cessation
- 1999-04-26 CA CA002270004A patent/CA2270004C/en not_active Expired - Fee Related
- 1999-04-26 US US09/299,131 patent/US6143795A/en not_active Expired - Fee Related
- 1999-04-27 AR ARP990101932A patent/AR018198A1/es unknown
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- 2000-10-12 BG BG104850A patent/BG64767B1/bg unknown
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102397561A (zh) * | 2011-09-26 | 2012-04-04 | 沈阳药科大学 | 米托蒽醌作为淋巴示踪剂的应用 |
CN102397561B (zh) * | 2011-09-26 | 2013-03-06 | 沈阳药科大学 | 米托蒽醌作为淋巴示踪剂的应用 |
CN107149592A (zh) * | 2017-06-23 | 2017-09-12 | 沈阳天邦药业有限公司 | 具有淋巴靶向功能的生物自组装纳米晶注射剂及制备方法 |
WO2018233095A1 (zh) * | 2017-06-23 | 2018-12-27 | 沈阳天邦药业有限公司 | 具有淋巴靶向功能的生物自组装纳米晶注射剂及制备方法 |
CN107149592B (zh) * | 2017-06-23 | 2019-10-08 | 沈阳天邦药业有限公司 | 具有淋巴靶向功能的生物自组装纳米晶注射剂及制备方法 |
CN113730603A (zh) * | 2020-05-27 | 2021-12-03 | 深圳华润九创医药有限公司 | 米托蒽醌制剂在制备诊治与甲状腺切除相关的疾病的药物中的应用 |
CN113730603B (zh) * | 2020-05-27 | 2023-01-24 | 深圳华润九创医药有限公司 | 米托蒽醌制剂在制备诊治与甲状腺切除相关的疾病的药物中的应用 |
CN114601791A (zh) * | 2020-12-08 | 2022-06-10 | 成都倍特药业股份有限公司 | 一种盐酸米托蒽醌液体制剂及其制备方法 |
CN114601791B (zh) * | 2020-12-08 | 2023-09-19 | 成都倍特药业股份有限公司 | 一种盐酸米托蒽醌液体制剂及其制备方法 |
WO2023184818A1 (zh) * | 2022-03-27 | 2023-10-05 | 苏州大学 | 米托蒽醌在制备预防或治疗急性移植物抗宿主病药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
WO1999055375A1 (de) | 1999-11-04 |
CN1195548C (zh) | 2005-04-06 |
DE19818802A1 (de) | 1999-10-28 |
DE59911099D1 (de) | 2004-12-23 |
HUP0102075A2 (hu) | 2002-05-29 |
HK1036012A1 (en) | 2001-12-21 |
BR9909981A (pt) | 2000-12-26 |
AU3522599A (en) | 1999-11-16 |
ATE282431T1 (de) | 2004-12-15 |
AU744502B2 (en) | 2002-02-28 |
CA2270004A1 (en) | 1999-10-27 |
US6143795A (en) | 2000-11-07 |
EP1073469A1 (de) | 2001-02-07 |
HUP0102075A3 (en) | 2002-10-28 |
BG104850A (en) | 2001-05-31 |
EP1073469B1 (de) | 2004-11-17 |
CA2270004C (en) | 2004-06-01 |
AR018198A1 (es) | 2001-10-31 |
NZ507407A (en) | 2002-08-28 |
TWI224003B (en) | 2004-11-21 |
JP2002512981A (ja) | 2002-05-08 |
RU2219917C2 (ru) | 2003-12-27 |
BG64767B1 (bg) | 2006-03-31 |
CO5021217A1 (es) | 2001-03-27 |
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