CN1923285B - 含有至少两种活性成分的注射用无菌药物制剂 - Google Patents

含有至少两种活性成分的注射用无菌药物制剂 Download PDF

Info

Publication number
CN1923285B
CN1923285B CN200610126685XA CN200610126685A CN1923285B CN 1923285 B CN1923285 B CN 1923285B CN 200610126685X A CN200610126685X A CN 200610126685XA CN 200610126685 A CN200610126685 A CN 200610126685A CN 1923285 B CN1923285 B CN 1923285B
Authority
CN
China
Prior art keywords
sodium
mixture
temperature
salify
acetate
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.)
Expired - Fee Related
Application number
CN200610126685XA
Other languages
English (en)
Other versions
CN1923285A (zh
Inventor
M·泽诺尼
A·G·凯特尼奥
L·马斯里
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ACS Dobfar SpA
Original Assignee
ACS Dobfar SpA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ACS Dobfar SpA filed Critical ACS Dobfar SpA
Publication of CN1923285A publication Critical patent/CN1923285A/zh
Application granted granted Critical
Publication of CN1923285B publication Critical patent/CN1923285B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

含有至少两种活性成分的混合物，其中至少一种成分是钠盐，所述混合物从含有成盐或未成盐酸形式的所述相同活性成分的有机溶液中沉淀析出。

Description

含有至少两种活性成分的注射用无菌药物制剂
最常用的抗生素毫无疑问是那些属于β-内酰胺类的抗生素。已知很多年以来，当这些抗生素用于临床治疗时，由于β-内酰胺酶能够降解β-内酰胺环，因而导致后者的“体内”效力逐渐消失。幸运的是，据发现某些物质能够抑制前述酶的活性，该发现使得某些单独使用无效的β-内酰胺抗生素通过与上述抑制剂联合使用仍然可以得到利用。这些抗生素包括以钠盐形式通过注射给药的哌拉西林。在其疗效由于前述原因被延迟之后，将哌拉西林与三唑巴坦钠联合。如US 4477452和US 4534977所述，哌拉西林钠通常由冻干制备得到，所得到的非常柔软的冻干产品可以确保快速溶解。其表明，冻干哌拉西林或者冻干其中哌拉西林以较大比例存在的混合物所得到的产率很低，这正是因为上述操作必须是在极稀的溶液中进行。另一方面，将哌拉西林钠与单独冻干的三唑巴坦钠进行混合时也会出现问题，这是因为这两种组分具有不同的密度：关于这方面，在非均匀分布的粉末混合物中，注意到密度比哌拉西林钠大的三唑巴坦钠倾向于分散在混合物的下层中。
US 5763603要求保护三唑巴坦(tazobactam)的结晶钠盐，但是在使用这种结晶盐时，很明显哌拉西林和三唑巴坦钠盐的机械混合物所存在的均匀性问题没有得到解决，这是由于冻干的哌拉西林钠密度低的缘故。显然，上述事实意味着哌拉西林钠和三唑巴坦钠的混合物不能以高于其单独注射剂量的含量制备。
为了解决上述类型的问题(其是通用的，并不仅仅限于哌拉西林钠+三唑巴坦钠组合)，本发明人最终寻求到一种解决办法，本发明人意外地发现含有成盐形式的活性成分的药物制剂可以在无菌条件下制备并沉淀析出，因此该成盐形式的活性成分并不是水溶液形式，但是其极溶于水且具有最大的稳定性。根据本发明的固体无菌药物制剂由至少两种活性成分形成，其中至少一种成分与选自碳酸钠、2-乙基-己酸钠、乙酸钠、柠檬酸钠、乳酸钠、甲醇钠、乙醇钠的钠盐成盐。
所述制剂通过下述方法制得：将至少一种酸形式的活性成分在-10℃至+25℃的温度下溶解于由至少两种选自水、丙酮、甲醇、异丙醇、乙醇的溶剂组成的溶剂中，然后通过加入选自碳酸钠、2-乙基-己酸钠、乙酸钠、柠檬酸钠、乳酸钠、甲醇钠、乙醇钠的适宜钠盐成盐使混合物成盐，所得到的溶液无菌过滤后，通过将该无菌溶液逐滴进料入温度为0℃-50℃的至少一种选自异丙醇、乙醇、乙酸甲酯、乙酸乙酯、丙酮、二氯甲烷的有机溶剂中，使成盐混合物沉淀析出，过滤所得到的盐混合物，最后将其在20℃-75℃的温度下真空干燥。
并不一定要求各活性成分同时进行沉淀，只要它们是在同一反应容器中进行沉淀即可，甚至可以是在连续的时间点上。对于哌拉西林+三唑巴坦组合而言，所得到的产品是无定形形式并且稳定的，其看上去并且表现得就好像是由单一组分组成的，这使得其在以单剂量或多剂量包装时不存在任何区别，并且不会出现因各组分之间存在密度差异而引起的问题。
实施例1
将7g 2-乙基己酸钠溶解于冷却至0℃的含有17ml水和30ml甲醇的混合物中。然后加入20g哌拉西林酸单水合物，混合物保持搅拌直到完全溶解。加入1.5g 2-乙基己酸钠之后，再加入2.5g三唑巴坦酸。混合物在0℃至+5℃下保持搅拌90分钟，所得到的悬浮液过滤后，同时保持上述温度不变，在至少30分钟内逐滴进料至35℃的400ml异丙醇中。在35℃下继续搅动30分钟，过滤混合物，产物用异丙醇洗涤并在75℃下真空干燥24小时。混合物中所使用的用于溶解2-乙基己酸钠的甲醇可以部分地或几乎全部地被异丙醇所替代。
得到具有下述分析数据的18.6g产物：
相当于14.47g酸的哌拉西林钠；
相当于1.73g酸的三唑巴坦钠；
K.F.：3.5％。
异丙醇：基本上没有
复水溶液的pH：5.6。
实施例2
将6.9g 2-乙基己酸钠溶解于冷却至0℃的含有20ml水和20ml甲醇的混合物中。然后加入20g哌拉西林酸单水合物，混合物保持搅拌直到完全溶解。加入2.5g三唑巴坦酸之后，再加入1.5g 2-乙基己酸钠。反应瓶壁用0℃的10ml甲醇洗涤。混合物在0℃至+5℃下保持搅拌90分钟，所得到的悬浮液过滤后，同时保持上述温度不变，在45分钟内逐滴进料至35℃的400ml异丙醇中。在35℃下继续搅拌30分钟，混合物冷却至+15℃，同时搅拌30分钟。过滤后，产物用30ml异丙醇洗涤并在75℃下真空干燥90分钟。混合物中所使用的用于溶解2-乙基己酸钠的甲醇可以部分地或几乎全部地被异丙醇所替代。
得到具有下述分析数据的18.6g产物：
相当于14.47g酸的哌拉西林钠；
相当于1.73g酸的三唑巴坦钠；
K.F.：3.5％。
异丙醇：基本上没有
复水溶液的pH：5.6。

Claims (3)

1.由至少两种活性成分形成的固体无菌药物制剂，其中至少一种成分与选自碳酸钠、2-乙基-己酸钠、乙酸钠、柠檬酸钠、乳酸钠、甲醇钠、乙醇钠的钠盐成盐，所述活性成分为至少一种抗生素和β-内酰胺抑制剂，所述固体无菌药物制剂通过以下方法制备：将至少一种酸形式的活性成分在-10℃至+25℃的温度下溶解于由至少两种选自水、丙酮、甲醇、异丙醇、乙醇的溶剂组成的溶剂中，然后通过加入选自碳酸钠、2-乙基-己酸钠、乙酸钠、柠檬酸钠、乳酸钠、甲醇钠、乙醇钠的适宜钠盐使混合物成盐，所得到的溶液无菌过滤后，通过将该无菌溶液逐滴进料至温度为0℃-50℃的至少一种选自异丙醇、乙醇、乙酸甲酯、乙酸乙酯、丙酮、二氯甲烷的有机溶剂中，使成盐混合物沉淀析出，过滤所得到的盐混合物，最后将其在20℃-75℃的温度下真空干燥。
2.如权利要求1所述的药物制剂，其特征在于所述抗生素是哌拉西林，并且所述β-内酰胺抑制剂是三唑巴坦。
3.制备如权利要求1所述制剂的方法，其特征在于：将至少一种酸形式的活性成分在-10℃至+25℃的温度下溶解于由至少两种选自水、丙酮、甲醇、异丙醇、乙醇的溶剂组成的溶剂中，然后通过加入选自碳酸钠、2-乙基-己酸钠、乙酸钠、柠檬酸钠、乳酸钠、甲醇钠、乙醇钠的适宜钠盐使混合物成盐，所得到的溶液无菌过滤后，通过将该无菌溶液逐滴进料至温度为0℃-50℃的至少一种选自异丙醇、乙醇、乙酸甲酯、乙酸乙酯、丙酮、二氯甲烷的有机溶剂中，使成盐混合物沉淀析出，过滤所得到的盐混合物，最后将其在20℃-75℃的温度下真空干燥。
CN200610126685XA 2005-09-02 2006-09-01 含有至少两种活性成分的注射用无菌药物制剂 Expired - Fee Related CN1923285B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT001630A ITMI20051630A1 (it) 2005-09-02 2005-09-02 Formulazione farmaceutica sterile iniettabile contenente almeno due principi attivi
ITMI2005A001630 2005-09-02

Publications (2)

Publication Number Publication Date
CN1923285A CN1923285A (zh) 2007-03-07
CN1923285B true CN1923285B (zh) 2010-06-23

Family

ID=37402634

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200610126685XA Expired - Fee Related CN1923285B (zh) 2005-09-02 2006-09-01 含有至少两种活性成分的注射用无菌药物制剂

Country Status (7)

Country Link
US (1) US7964589B2 (zh)
EP (1) EP1759697A1 (zh)
JP (1) JP5060747B2 (zh)
KR (1) KR20070026187A (zh)
CN (1) CN1923285B (zh)
CA (1) CA2554859A1 (zh)
IT (1) ITMI20051630A1 (zh)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20070568A1 (it) * 2007-03-22 2008-09-23 Acs Dobfar Spa Comosizione farmaceutica sterile iniettabile avente piperacillina sodica e tazobactam sodico come principi attivi
WO2013014544A1 (en) * 2011-07-25 2013-01-31 Vardhman Chemtech Limited Method for preparation of composition of piperacillin sodium and tazobactam sodium
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
KR101816798B1 (ko) * 2012-10-19 2018-01-10 주식회사유한양행 피페라실린 또는 그의 염, 타조박탐 또는 그의 염 및 덱사메타손 포스페이트 또는 그의 염을 포함하는 국소투여용 약학 조성물
US20140275000A1 (en) 2013-03-15 2014-09-18 Cubist Pharmaceuticals, Inc. Ceftolozane pharmaceutical compositions
MX2020004205A (es) 2013-03-15 2021-11-16 Merck Sharp & Dohme Llc Composiciones antibioticas de ceftolozano.
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
WO2015035376A2 (en) 2013-09-09 2015-03-12 Calixa Therapeutics, Inc. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US20150094293A1 (en) 2013-09-27 2015-04-02 Calixa Therapeutics, Inc. Solid forms of ceftolozane
CN112409381B (zh) * 2020-12-03 2022-03-01 山东安信制药有限公司 一种哌拉西林钠他唑巴坦钠共无定形物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4477452A (en) * 1981-03-26 1984-10-16 American Cyanamid Company Composition of matter comprising a lyophilized preparation of a penicillin derivative
US20040204372A1 (en) * 2003-04-14 2004-10-14 Wyeth Holdings Corporation Compositions containing pipercillin and tazobactam sodium useful for injection
WO2004098643A1 (en) * 2003-04-14 2004-11-18 Wyeth Holdings Corporation Compositions containing piperacillin and tazobactam useful for injection
CN1802179A (zh) * 2003-04-14 2006-07-12 惠氏控股公司 含有哌拉西林和三唑巴坦的注射用组合物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2925963A1 (de) * 1979-06-27 1981-01-22 Bayer Ag Penicillin-1,1-dioxide, ihre herstellung und ihre verwendung als arzneimittel
CA1209477A (en) * 1981-03-26 1986-08-12 Bruce E. Haeger Composition of matter comprising a lyophilized preparation of a penicillin derivative
CA1222691A (en) * 1981-12-29 1987-06-09 Wilhelmus T. Goedemans Method of preparing radionuclide-labelled proteins, in particular antibodies or antibody fragments
JPS58135823A (ja) * 1982-02-05 1983-08-12 Chugai Pharmaceut Co Ltd 抗生物質組成物およびその製法
IT1255716B (it) * 1992-10-05 1995-11-10 Procedimento per la preparazione di antibiotici beta-lattamici sterili

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4477452A (en) * 1981-03-26 1984-10-16 American Cyanamid Company Composition of matter comprising a lyophilized preparation of a penicillin derivative
US20040204372A1 (en) * 2003-04-14 2004-10-14 Wyeth Holdings Corporation Compositions containing pipercillin and tazobactam sodium useful for injection
WO2004098643A1 (en) * 2003-04-14 2004-11-18 Wyeth Holdings Corporation Compositions containing piperacillin and tazobactam useful for injection
CN1802179A (zh) * 2003-04-14 2006-07-12 惠氏控股公司 含有哌拉西林和三唑巴坦的注射用组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
说明书第13页第3行至第21行.

Also Published As

Publication number Publication date
JP5060747B2 (ja) 2012-10-31
KR20070026187A (ko) 2007-03-08
CA2554859A1 (en) 2007-03-02
JP2007070341A (ja) 2007-03-22
EP1759697A1 (en) 2007-03-07
US7964589B2 (en) 2011-06-21
ITMI20051630A1 (it) 2007-03-03
US20070054889A1 (en) 2007-03-08
CN1923285A (zh) 2007-03-07

Similar Documents

Publication Publication Date Title
CN1923285B (zh) 含有至少两种活性成分的注射用无菌药物制剂
KR20130019383A (ko) 5-아미노-2,3-디히드로프탈라진-1,4-디온 나트륨염에 대한 결정 형태, 이를 함유하는 약제학적 제제 및 상기 형태를 제조하기 위한 방법
AU2019201392A1 (en) Methods for treatment of diseases
JP2017526699A (ja) （６ｓ）−５−メチルテトラヒドロ葉酸又はその塩の組成物及びその調製と応用
JP6461945B2 (ja) ある含有量のマイトマイシンｃを有する凍結乾燥医薬組成物を製造する方法
US8765190B2 (en) Injectable sterile pharmaceutical composition with piperacillin sodium and tazobactam sodium as active principles
CA2894516A1 (en) Injectable depot formulation comprising optically active tolvaptan and process of producing the same
CN103705473A (zh) 一种兰索拉唑冻干粉针剂及其制备方法
JP2022503804A (ja) キレート化剤の非晶質形態及びそれを調製する方法
CN111718299B (zh) 一种左西孟旦钠晶型b及其制备方法
EP3503885B1 (en) Pharmaceutical composition and methods of uses
US5010064A (en) Inclusion complexes of dipyridamole with cyclodextrins
US3558773A (en) Crystalline kallikrein-inactivator and process for preparing the same
CN101654427A (zh) 抗凝化合物、组合物及其用途
CN103349644B (zh) 一种注射用兰索拉唑复合胶束药物组合物及其制备方法
US20210401819A1 (en) Pharmaceutical composition and preparation method therefor
CN102793929B (zh) 一种制备稳定非晶态药物制剂的方法
CN103304580A (zh) 一种盐酸头孢吡肟化合物、其制备方法及其药物组合物
TW202432120A (zh) 注射用組合物、包含其之醫藥調配物以及製備該組合物之方法
CN102304088A (zh) 一种伊伐布雷定化合物、制备方法及其药物组合物
CN103083243A (zh) 一种多拉菌素可溶性粉及其制备方法
CN117771191A (zh) 一种盐酸雷莫司琼注射冻干粉及其制备方法
JP4269580B2 (ja) 注射用キット製剤
KR20240121186A (ko) 주사용 조성물, 이를 포함하는 약학적 제제 및 이의 제조 방법
KR20090052073A (ko) 칼슘이 함유된 전해질 용액에서 안정한 세프트리악손디소디움염 헤미헵타하이드레이트의 제조방법

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20100623

Termination date: 20130901