CN107281187B - 一种注射用头孢哌酮钠他唑巴坦钠及其制备方法 - Google Patents

一种注射用头孢哌酮钠他唑巴坦钠及其制备方法 Download PDF

Info

Publication number
CN107281187B
CN107281187B CN201710559091.6A CN201710559091A CN107281187B CN 107281187 B CN107281187 B CN 107281187B CN 201710559091 A CN201710559091 A CN 201710559091A CN 107281187 B CN107281187 B CN 107281187B
Authority
CN
China
Prior art keywords
sodium
cefoperazone
tazobactam
preparation
injection
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.)
Active
Application number
CN201710559091.6A
Other languages
English (en)
Other versions
CN107281187A (zh
Inventor
张健
徐军
华军杰
顾利芬
何星慧
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.)
Suzhou Erye Pharmaceutical Co Ltd
Original Assignee
Suzhou Erye Pharmaceutical Co Ltd
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 Suzhou Erye Pharmaceutical Co Ltd filed Critical Suzhou Erye Pharmaceutical Co Ltd
Priority to CN201710559091.6A priority Critical patent/CN107281187B/zh
Publication of CN107281187A publication Critical patent/CN107281187A/zh
Application granted granted Critical
Publication of CN107281187B publication Critical patent/CN107281187B/zh
Active 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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明涉及一种注射用头孢哌酮钠他唑巴坦钠及其制备工艺。本发明采用焦亚硫酸钠和甘氨酸组成的稳定剂，吐温80、胆固醇作为乳化剂，去氧胆酸钠作为助乳化剂，海藻糖作为冻干支持剂，有效地提高了头孢哌酮钠和他唑巴坦钠在制备和存储过程中的稳定性，且制剂溶解快速，不产生结晶和浑浊现象，保证了临床使用的疗效和安全性。

Description

一种注射用头孢哌酮钠他唑巴坦钠及其制备方法
技术领域
本发明涉及医药领域，具体涉及一种注射用头孢哌酮钠他唑巴坦钠的制备工艺。
背景技术
头孢哌酮为第三代广谱半合成头孢菌素，能对抗多种β-内酰胺酶的降解作用，抗菌谱广，对革兰阳性菌及阴性菌均有作用。然而，头孢哌酮易被β-内酰胺酶破坏，失去药效。
目前，为了抑制此类酶对β-内酰胺类抗生素的作用，除了开发能抵抗酶水解的β-内酰胺类抗生素外，还发展了β-内酰胺酶抑制剂与β-内酰胺类抗生素的药物组合物。酶抑制剂与β-内酰胺类抗生素的组合不但增强了抗生素的活性，还增大了其抗菌谱，提高了对感染的治疗效果。他唑巴坦为一种不可逆竞争型的β-内酰胺酶抑制剂，其自身无抗菌活性，但具有强效的抑酶作用，与头孢哌酮合用可增强其药效并延长其作用时间，有明显的协同作用。
注射用头孢哌酮钠他唑巴坦钠的复方于2003获批准上市。由于头孢派酮钠的稳定性较差，为保证在有效期内产品合格，必须在干燥冷处保存。在与他唑巴坦钠组合成复方后，稳定性并没得到改善。这是头孢哌酮钠所有复方制剂的不足之处。
发明内容
为了解决现有的注射用头孢哌酮钠他唑巴坦钠稳定性差的问题，本发明提供了一种稳定的头孢哌酮钠他唑巴坦钠复方制剂，并且提供了其制备方法。
本发明提供一种注射用头孢哌酮钠他唑巴坦钠组合物，其按重量份计包括如下组分：
头孢哌酮钠 4-8份；
他唑巴坦钠 1份；
吐温80 5-15份 ；
胆固醇 2-5份 ；
去氧胆酸钠 1-5份 ；
焦亚硫酸钠 2-5份；
甘氨酸 5-10份；
海藻糖 5-20份。
本发明采用焦亚硫酸钠和甘氨酸组成的稳定剂，吐温80、胆固醇作为乳化剂，去氧胆酸钠作为助乳化剂，海藻糖作为冻干支持剂，有效地提高了头孢哌酮钠和他唑巴坦钠在制备和存储过程中的稳定性，且制剂溶解快速，不产生结晶和浑浊现象，保证了临床使用的疗效和安全性。
本发明的制备方法如下：
步骤(1)在惰性气体保护下，将吐温80、胆固醇、去氧胆酸钠、焦亚硫酸钠、甘氨酸用注射用水溶剂，然后加入头孢哌酮钠和他唑巴坦钠，混合均匀，90℃水浴加热搅拌至熔融状态；
步骤(2)将上述液体保温70-90℃条件下采用组织捣碎器剪切搅拌10min，转速 15000r/min，得初乳液，再经高压乳匀机循环乳化4次，得乳化液；
步骤(3)向乳化液中加入海藻糖，溶解后过滤分装，冷冻干燥，得头孢哌酮钠他唑巴坦钠混悬粉针剂。
具体实施方式
实施例1 头孢哌酮钠他唑巴坦钠（4:1）混悬粉针剂的制备
处方(100瓶)：
头孢哌酮钠 100g
他唑巴坦钠 25g
吐温80 150g
胆固醇 75g
去氧胆酸钠 37.5g
焦亚硫酸钠 100g
甘氨酸 150g
海藻糖 100g
制备方法
在惰性气体保护下，将吐温80、胆固醇、去氧胆酸钠、焦亚硫酸钠、甘氨酸用注射用水溶剂，然后加入头孢哌酮钠和他唑巴坦钠，混合均匀，90℃水浴加热搅拌至熔融状态。将上述液体保温70-90℃条件下采用组织捣碎器剪切搅拌10min，转速 1 5000r/min，得初乳液，再经高压乳匀机循环乳化4次，得乳化液。向乳化液中加入海藻糖，溶解后过滤分装，冷冻干燥，得头孢哌酮钠他唑巴坦钠混悬粉针剂。
长期稳定性试验
批号1：100601 批量：5000支 规格：1.0g/瓶 包装：西林瓶
考察条件：25±2℃/60±10%RH
实施例2 头孢哌酮钠他唑巴坦钠（8:1）混悬粉针剂的制备
处方(100瓶)：
头孢哌酮钠 200g
他唑巴坦钠 25g
吐温80 300g
胆固醇 150g
去氧胆酸钠 75g
焦亚硫酸钠 200g
甘氨酸 300g
海藻糖 200g
制备方法
在惰性气体保护下，将吐温80、胆固醇、去氧胆酸钠、焦亚硫酸钠、甘氨酸用注射用水溶剂，然后加入头孢哌酮钠和他唑巴坦钠，混合均匀，90℃水浴加热搅拌至熔融状态。将上述液体保温70-90℃条件下采用组织捣碎器剪切搅拌10min，转速 20000r/min，得初乳液，再经高压乳匀机循环乳化4次，得乳化液。向乳化液中加入海藻糖，溶解后过滤分装，冷冻干燥，得头孢哌酮钠他唑巴坦钠混悬粉针剂。
长期稳定性试验
批号1：100501 批量：4212瓶 规格：1.125g/瓶 包装：西林瓶
考察条件：25±2℃/60±10%RH
Figure DEST_PATH_IMAGE001
通过长期稳定性试验可以发现，本发明的头孢哌酮钠和他唑巴坦钠在制备和存储过程中具有良好的稳定性，保证了临床使用的疗效和安全性。

Claims (1)

1.一种头孢哌酮钠他唑巴坦钠混悬粉针，其组成如下：
Figure FDA0002696141440000011
以上各组分的重量以100瓶计；
该混悬粉针的制备方法为：在惰性气体保护下，将吐温80、胆固醇、去氧胆酸钠、焦亚硫酸钠、甘氨酸用注射用水溶解，然后加入头孢哌酮钠和他唑巴坦钠，混合均匀，90℃水浴加热搅拌至熔融状态；将上述液体保温70-90℃条件下采用组织捣碎器剪切搅拌10min，转速15000r/min，得初乳液，再经高压乳匀机循环乳化4次，得乳化液；向乳化液中加入海藻糖，溶解后过滤分装，冷冻干燥，得头孢哌酮钠他唑巴坦钠混悬粉针剂。
CN201710559091.6A 2017-07-11 2017-07-11 一种注射用头孢哌酮钠他唑巴坦钠及其制备方法 Active CN107281187B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710559091.6A CN107281187B (zh) 2017-07-11 2017-07-11 一种注射用头孢哌酮钠他唑巴坦钠及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710559091.6A CN107281187B (zh) 2017-07-11 2017-07-11 一种注射用头孢哌酮钠他唑巴坦钠及其制备方法

Publications (2)

Publication Number Publication Date
CN107281187A CN107281187A (zh) 2017-10-24
CN107281187B true CN107281187B (zh) 2020-11-17

Family

ID=60101562

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710559091.6A Active CN107281187B (zh) 2017-07-11 2017-07-11 一种注射用头孢哌酮钠他唑巴坦钠及其制备方法

Country Status (1)

Country Link
CN (1) CN107281187B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110772486A (zh) * 2019-11-27 2020-02-11 苏州二叶制药有限公司 一种头孢哌酮组合制剂及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101632677A (zh) * 2009-08-26 2010-01-27 海南永田药物研究院有限公司 一种头孢哌酮钠他唑巴坦钠药物组合物混悬粉针剂及其新应用
CN102274233A (zh) * 2011-09-05 2011-12-14 周晓东 一种头孢哌酮钠他唑巴坦钠药物组合物
CN104013629A (zh) * 2014-06-18 2014-09-03 重庆福安药业集团庆余堂制药有限公司 头孢哌酮钠他唑巴坦钠的复方药物组合物及其制备工艺
US20150112057A1 (en) * 2011-06-23 2015-04-23 Dsm Sinochem Pharmaceuticals Netherlands B.V. Novel crystalline cefoperazone intermediate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101632677A (zh) * 2009-08-26 2010-01-27 海南永田药物研究院有限公司 一种头孢哌酮钠他唑巴坦钠药物组合物混悬粉针剂及其新应用
US20150112057A1 (en) * 2011-06-23 2015-04-23 Dsm Sinochem Pharmaceuticals Netherlands B.V. Novel crystalline cefoperazone intermediate
CN102274233A (zh) * 2011-09-05 2011-12-14 周晓东 一种头孢哌酮钠他唑巴坦钠药物组合物
CN104013629A (zh) * 2014-06-18 2014-09-03 重庆福安药业集团庆余堂制药有限公司 头孢哌酮钠他唑巴坦钠的复方药物组合物及其制备工艺

Also Published As

Publication number Publication date
CN107281187A (zh) 2017-10-24

Similar Documents

Publication Publication Date Title
CN101648016A (zh) 稳定性高的药物组合物
CA2948148C (en) Formulations of cyclophosphamide liquid concentrate
CN107281187B (zh) 一种注射用头孢哌酮钠他唑巴坦钠及其制备方法
TW202247842A (zh) 用於預防或治療眼科疾病的滴眼劑組合物及其製備方法
CN101646441B (zh) 含有氟米龙的混悬型滴眼剂
CN104644610A (zh) 一种头孢氨苄胶囊
WO2013042140A2 (en) Non antibiotic,non peptide compounds for antibiotic efficacy & safety enhancement
CN107638394B (zh) 一种哌拉西林钠舒巴坦钠化合物的药物组合物
CN101890022B (zh) 一种头孢哌酮钠他唑巴坦钠药物组合物脂质体注射剂
CA3055116C (en) Orodispersible tablet containing burlulipase and pharmaceutical composition produced therefrom
AU2012359296B2 (en) Antibiotic formulations
KR102459416B1 (ko) 포스네투피탄트의 생리학적으로 균형잡힌 주사가능 제제
CN107625772A (zh) 一种哌拉西林钠他唑巴坦钠化合物的药物组合物
CN101919863A (zh) 头孢拉宗组合物
CN107496366B (zh) 一种美洛西林钠舒巴坦钠化合物的药物组合物
CN103059045B (zh) 一种阿莫西林钠克拉维酸钾化合物及其药物组合物
CN101890014B (zh) 一种哌拉西林钠舒巴坦钠药物组合物脂质体注射剂
CN107569458B (zh) 一种阿莫西林钠克拉维酸钾化合物的药物组合物
CN104958302B (zh) 一种注射用头孢哌酮钠他唑巴坦钠药物组合物及其制备工艺
TWI465236B (zh) 含有吡諾克辛之懸浮型水性液劑
CN101697973B (zh) 一种注射用头孢硫脒制剂及其制备方法
CN114652719B (zh) 一种氨苄西林钠舒巴坦钠药物组合物及其制备方法
Oliveira Effectiveness of hyaluronidase on degrading hyaluronic acid
EP2114372A1 (en) Pharmaceutical carrier composition and pharmaceutical composition
CN104887679A (zh) 一种哌拉西林钠舒巴坦钠无菌粉针剂及其制备方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant