CN114767627B - Preparation method of ciprofloxacin lactate sodium chloride injection - Google Patents
Preparation method of ciprofloxacin lactate sodium chloride injection Download PDFInfo
- Publication number
- CN114767627B CN114767627B CN202210532029.9A CN202210532029A CN114767627B CN 114767627 B CN114767627 B CN 114767627B CN 202210532029 A CN202210532029 A CN 202210532029A CN 114767627 B CN114767627 B CN 114767627B
- Authority
- CN
- China
- Prior art keywords
- sodium chloride
- ciprofloxacin
- injection
- preparation
- lactic acid
- 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
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- NRBJWZSFNGZBFQ-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;2-hydroxypropanoic acid Chemical compound CC(O)C(O)=O.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 NRBJWZSFNGZBFQ-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 229960004055 ciprofloxacin lactate Drugs 0.000 title claims abstract description 34
- 239000008354 sodium chloride injection Substances 0.000 title claims abstract description 29
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 90
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000000243 solution Substances 0.000 claims abstract description 44
- 239000004310 lactic acid Substances 0.000 claims abstract description 43
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 42
- 239000007788 liquid Substances 0.000 claims abstract description 41
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 25
- 229960003405 ciprofloxacin Drugs 0.000 claims abstract description 24
- 239000008215 water for injection Substances 0.000 claims abstract description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 230000001954 sterilising effect Effects 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 10
- 239000002510 pyrogen Substances 0.000 claims abstract description 8
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 7
- 238000004140 cleaning Methods 0.000 claims abstract description 6
- 239000011780 sodium chloride Substances 0.000 claims description 15
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 9
- 238000011010 flushing procedure Methods 0.000 claims description 9
- 238000005070 sampling Methods 0.000 claims description 9
- 238000002791 soaking Methods 0.000 claims description 9
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 7
- 239000012510 hollow fiber Substances 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 6
- 238000007599 discharging Methods 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 238000007789 sealing Methods 0.000 claims description 5
- 230000001502 supplementing effect Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 2
- 238000007689 inspection Methods 0.000 abstract description 6
- 239000008280 blood Substances 0.000 abstract description 5
- 210000004369 blood Anatomy 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052791 calcium Inorganic materials 0.000 abstract description 4
- 239000011575 calcium Substances 0.000 abstract description 4
- GGPJJOKKXXPKDX-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;sodium Chemical compound [Na].C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 GGPJJOKKXXPKDX-UHFFFAOYSA-N 0.000 abstract description 3
- 238000010306 acid treatment Methods 0.000 abstract description 3
- 230000000536 complexating effect Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 238000005538 encapsulation Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 229910021645 metal ion Inorganic materials 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- 241000289690 Xenarthra Species 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 239000008139 complexing agent Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 239000004626 polylactic acid Substances 0.000 description 3
- OZZQHCBFUVFZGT-UHFFFAOYSA-N 2-(2-hydroxypropanoyloxy)propanoic acid Chemical compound CC(O)C(=O)OC(C)C(O)=O OZZQHCBFUVFZGT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 239000013638 trimer Substances 0.000 description 2
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010069918 Bacterial prostatitis Diseases 0.000 description 1
- 206010005940 Bone and joint infections Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101000777138 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 42 Proteins 0.000 description 1
- NGWKGSCSHDHHAJ-YPFQVHCOSA-N Liquoric acid Chemical compound C1C[C@H](O)C(C)(C)C2CC[C@@]3(C)[C@]4(C)C[C@H]5O[C@@H]([C@](C6)(C)C(O)=O)C[C@@]5(C)[C@@H]6C4=CC(=O)C3[C@]21C NGWKGSCSHDHHAJ-YPFQVHCOSA-N 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 102100031310 Ubiquitin carboxyl-terminal hydrolase 42 Human genes 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 241000607272 Vibrio parahaemolyticus Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000688 enterotoxigenic effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- KMPHTYSTEHXSTL-UHFFFAOYSA-M sodium;2-hydroxypropanoate;2-hydroxypropanoic acid Chemical compound [Na+].CC(O)C(O)=O.CC(O)C([O-])=O KMPHTYSTEHXSTL-UHFFFAOYSA-M 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- 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)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of ciprofloxacin lactate sodium chloride injection, belonging to the field of pharmaceutical preparations. The preparation method of the invention comprises the following steps: the preparation method comprises the steps of cleaning a liquid preparation system and a liquid medicine conveying pipeline by using an edetate disodium solution, performing depolymerization on lactic acid under the acidic condition of hydrochloric acid, fully stirring and uniformly mixing ciprofloxacin serving as a raw material with lactic acid, sodium chloride and water for injection after acid treatment, adjusting the volume of the liquid preparation, and finally performing ultrafiltration pyrogen removal, sterilization filtration, encapsulation, tightness detection, high-pressure sterilization, inspection and the like to obtain the ciprofloxacin sodium chloride injection. The method has the advantages that the formula is simple, the prepared product does not contain edetate disodium, and the risk of complexing calcium blood is avoided; the pH value of the liquid medicine is not required to be regulated, the process is simple, and the reproducibility is good; the ultrafiltration pyrogen is adopted to ensure the medication safety of patients and the like. The ciprofloxacin lactate sodium chloride injection prepared by the method has good stability and excellent product quality.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of ciprofloxacin lactate sodium chloride injection.
Background
Ciprofloxacin lactate (ciprofloxacin lactate), a third-generation quinolone broad-spectrum high-efficiency antibacterial agent, and oral and injection solutions are developed and marketed by the germany bayer company, and are clinically used for treating genitourinary system infection caused by sensitive bacteria, including simple, complex urinary tract infection, bacterial prostatitis, neisseria gonorrhoeae urethritis or cervicitis; can also be used for treating respiratory tract infection, including acute attack of bronchial infection and pulmonary infection caused by sensitive gram-negative bacillus; treating gastrointestinal tract infection caused by Shigella, salmonella, enterotoxigenic Escherichia coli, hydrophilic aeromonas, vibrio parahaemolyticus, etc.; can also be used for treating systemic infection such as typhoid fever, bone and joint infection, skin soft tissue infection septicemia, etc., with definite curative effect.
At present, there are two ways of producing ciprofloxacin lactate and sodium chloride injection in China, namely, firstly, ciprofloxacin lactate bulk drug and sodium chloride are adopted to directly prepare, such as patent application CN 102274169, secondly, the ciprofloxacin lactate is treated by alkali liquor and then water is added to prepare the ciprofloxacin lactate and the sodium chloride, such as patent application CN 102716072.
Both methods have disadvantages. The ciprofloxacin lactate sold in China is obtained by salifying and refining ciprofloxacin, a large amount of organic solvent is consumed, the production cost is increased, more serious organic residues possibly influence the product quality, the medication risk is increased, the environmental pollution problem is also increased, and the benign development of enterprises and society is seriously influenced.
The second part of the Chinese pharmacopoeia 2020 provides that the lactic acid is 2-hydroxy propionic acid and condensate thereof, and the content of the lactic acid is calculated by C 3H6O3 and is 85.0% -92.0%; the U.S. pharmacopoeia USP42 specifies that the ciprofloxacin lactate sodium chloride injection contains 0.288 mg-0.352 mg of lactic acid per 1mg ciprofloxacin, and the detection method is high performance liquid chromatography (sodium lactate (mono lactic acid) is used as a reference substance and calculated as peak area according to an external standard method). Therefore, in the production process of ciprofloxacin lactate sodium chloride injection, the depolymerization of polylactic acid (2-hydroxypropionic acid condensate) in lactic acid raw material (mixture) into mono-lactic acid (2-hydroxypropionic acid) is a problem that must be solved by the formulation process. At present, in the production of ciprofloxacin lactate, there is a preparation method for depolymerizing polylactic acid (2-hydroxypropionic acid condensate) in lactic acid by alkali liquor treatment, but because a large amount of alkali liquor and hydrochloric acid are used in the production process, the operation process has high risk, and more importantly, acid and alkali cause corrosion to a liquid preparation system (a stainless steel liquid preparation tank and the like), so that metal ions escape into liquid medicine. And due to the structural characteristics, ciprofloxacin is easy to complex with metal ions, so that the curative effect is reduced, and the product quality (the color of a solution is changed) is also influenced. Therefore, the existing production process is to add the ciprofloxacin after the edetate disodium is firstly added to complex with metal ions, as shown in the claim of CN 102716072. However, edetate disodium is used as a strong complexing agent, and after entering human blood, the edetate disodium is complexed with blood calcium to reduce blood calcium of a patient to be dosed, and adverse reactions may occur. The administration of the Chinese food and drug administration has prohibited intravenous injection from adding disodium edetate. Therefore, how to improve the process and reduce the operation risk, and how to prepare ciprofloxacin lactate sodium chloride injection which does not contain edetate disodium and has good stability becomes a problem to be solved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method for preparing ciprofloxacin lactate sodium chloride injection with qualified quality and good stability by directly taking ciprofloxacin and lactic acid as raw materials, adjusting isotonicity by sodium chloride and not adding edetate disodium complexing agent, which comprises the following steps:
Step a, soaking a liquid preparation tank by using an edetate disodium solution; then opening a blanking valve, discharging the edetate disodium solution to a liquid medicine conveying pipeline, cleaning the pipeline for at least 30 minutes, and then flushing the pipeline and a liquid preparation tank by using water for injection until the flushing liquid does not contain edetate disodium;
Step b, adding lactic acid and hydrochloric acid into water for injection to prepare lactic acid: hydrochloric acid is 1:0.03-0.3 (molar ratio), and heat treatment is carried out for more than 30 minutes at 115-121 ℃;
C, dispersing a predetermined amount of ciprofloxacin into the water for injection in the liquid preparation tank treated in the step a, adding the lactic acid solution prepared in the step b, and stirring to dissolve the ciprofloxacin;
step d, adding a predetermined amount of sodium chloride into the solution in the step c, and stirring for dissolution;
Step e, supplementing water for injection to a preset amount;
F, sampling and detecting the pH value, ciprofloxacin and sodium chloride content;
Step g, filtering the qualified liquid medicine checked in the step f;
and h, filling, sealing and sterilizing the liquid medicine filtered in the step g to obtain the ciprofloxacin lactate sodium chloride injection.
Preferably, the molar concentration of the disodium edentate solution in step a is between 0.02% and 0.2%, possibly 0.02％、0.03％、0.04％、0.05％、0.06％、0.07％、0.08％、0.09％、0.1％、0.11％、0.12％、0.13％、0.14％、0.15％、0.16％、0.17％、0.18％、0.19％、0.2％,% and more preferably 0.05%; the time for soaking the liquid preparation tank is 20-60 min, which can be 20min, 30min, 40min, 50min, 60min, and more preferably 40 min. Ciprofloxacin is easily complexed with metal ions, yellowing the solution, and does not meet pharmacopoeia standards, so complexing with complexing agents is required to reduce the metal ions in the system. The concentration of edetate disodium solution is lower than 0.02% which can lead to incomplete complexation with metal ions, and the residual metal ions in the system are excessive to affect the quality of the product, while the edetate disodium solution higher than 0.2% requires a large amount of water for injection to clean after soaking, and also causes waste. The soaking time can be adjusted according to the concentration of disodium edentate. The method can greatly reduce the residual metal ions and edetate disodium in the liquid preparation tank, and provides a good reaction environment for the subsequent preparation of ciprofloxacin lactate sodium chloride injection without edetate disodium.
Preferably, the pH of the liquid medicine in the step f must meet the requirements of Chinese pharmacopoeia, and the pH value is 3.5-4.5.
Preferably, step g specifically comprises the steps of:
g1. carrying out pyrogen removal filtration through a hollow fiber ultrafiltration system;
g2. filtering through a 4.5 μm filter;
g3. Filtered through a 0.2 μm sterilizing filter.
Preferably, the hollow fiber ultrafiltration system used in the step g1 is made of a material with an interception molecular weight of 6000 or more.
Preferably, the step h further comprises a step of detecting the tightness of the step h by a vacuum decay method.
Preferably, the sterilization conditions in step h are autoclaving for 30 minutes at 115-121 ℃.
Preferably, the mass ratio of the lactic acid to the ciprofloxacin to the sodium chloride to the water for injection is 0.64:2:9:1000.
In the step b, lactic acid depolymerization is carried out by a very small amount of hydrochloric acid, so that an alkaline hydrolysis polymerization method is replaced, the use of strong acid and strong alkali is reduced, the corrosion to a reaction container is avoided, and the escape of metal ions is reduced, so that disodium edetate is not needed to be used again in the subsequent step, and the finished product can meet pharmacopoeia standards under the condition of no disodium edetate and has good stability. At the same time, the method of depolymerizing lactic acid with a very small amount of hydrochloric acid reduces the operational risk of understanding polylactic acid.
The method has simple formula, and the prepared product does not contain edetate disodium, so that the risk of complexing calcium blood does not exist; the pH value of the liquid medicine is not required to be regulated, the process is simple, and the reproducibility is good; the ultrafiltration pyrogen is adopted to ensure the medication safety of patients and the like. The ciprofloxacin lactate sodium chloride injection prepared by the method has good stability and excellent product quality.
Drawings
FIG. 1 is a HPLC chart of the test results of example 4.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the embodiments of the present invention are only for illustrating the present invention, and not for limiting the present invention, and simple modifications of the present invention under the premise of the concept of the present invention are all included in the scope of the claimed invention. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase by regular vendors without the manufacturer's attention.
Example 1 ciprofloxacin lactate sodium chloride injection and preparation example thereof
Prescription:
The preparation process comprises the following steps:
step a, preparing 0.05% edetate disodium solution, and soaking a preparation tank for 40 minutes; then opening a blanking valve, discharging the edetate disodium solution to a liquid medicine conveying pipeline, cleaning the pipeline for 30 minutes, and then flushing the pipeline and a liquid preparation tank by using water for injection until the flushing liquid does not contain edetate disodium;
Step b, adding 5L of water for injection into the lactic acid and the hydrochloric acid to prepare a solution, and performing heat treatment for 30 minutes at the temperature of 121 ℃;
C, dispersing ciprofloxacin in the water for injection in the liquid preparation tank treated in the step a, adding the lactic acid solution in the step b, and stirring to dissolve the ciprofloxacin;
Step d, adding sodium chloride into the solution in the step c, and stirring for dissolution;
step e, supplementing water for injection to 1000L;
step f, sampling and detecting the pH value, ciprofloxacin and sodium chloride content according to the regulation of the ciprofloxacin lactate injection item of the 2020 edition of Chinese pharmacopoeia;
step g, after the inspection is qualified, carrying out pyrogen removal filtration on the liquid medicine through a hollow fiber ultrafiltration system with an interception molecular weight of 6000 channels, then filtering through a 4.5 mu m filter, and then filtering through a 0.2 mu m sterilization filter;
Step h, filling the filtered liquid medicine into a glass bottle, adding a plug, and sealing an aluminum cover;
Step i, detecting tightness by adopting a vacuum attenuation micro leakage tightness detector Leak-S;
And j, sterilizing the filled glass bottle under high pressure at 121 ℃ for 30 minutes, sampling and performing finished product inspection to obtain the ciprofloxacin lactate sodium chloride injection.
Example 2 ciprofloxacin lactate sodium chloride injection and preparation example thereof
Prescription:
The preparation process comprises the following steps:
step a, preparing 0.02% edetate disodium solution, and soaking a preparation tank for 60 minutes; then opening a blanking valve, discharging the edetate disodium solution to a liquid medicine conveying pipeline, cleaning the pipeline for 30 minutes, and then flushing the pipeline and a liquid preparation tank by using water for injection until the flushing liquid does not contain edetate disodium;
step b, adding 5L of water for injection into the lactic acid and the hydrochloric acid to prepare a solution, and performing heat treatment for 45 minutes at 115 ℃;
C, dispersing ciprofloxacin in the water for injection in the liquid preparation tank treated in the step a, adding the lactic acid solution in the step b, and stirring to dissolve the ciprofloxacin;
Step d, adding sodium chloride into the solution in the step c, and stirring for dissolution;
step e, supplementing water for injection to 1000L;
step f, sampling and detecting the pH value, ciprofloxacin and sodium chloride content according to the regulation of the ciprofloxacin lactate injection item of the 2020 edition of Chinese pharmacopoeia;
step g, after the inspection is qualified, carrying out pyrogen removal filtration on the liquid medicine through a hollow fiber ultrafiltration system with an interception molecular weight of 6000 channels, then filtering through a 4.5 mu m filter, and then filtering through a 0.2 mu m sterilization filter;
Step h, filling the filtered liquid medicine into a glass bottle, adding a plug, and sealing an aluminum cover;
Step i, detecting tightness by adopting a vacuum attenuation micro leakage tightness detector Leak-S;
and j, sterilizing the filled glass bottle under high pressure at 115 ℃ for 30 minutes, sampling and performing finished product inspection to obtain the ciprofloxacin lactate sodium chloride injection.
EXAMPLE 3 product quality and stability Studies
The ciprofloxacin lactate sodium chloride injection prepared in example 1 and example 2 was left for 24 months under normal temperature conditions (product storage conditions), sampled for 0,3,6,9, 12, 18 and 24 months, and each quality index of the injection was measured according to the 2020 edition of chinese pharmacopoeia standard, and the results are shown in tables 1 and 2 below.
TABLE 1 example 1 finished product and stability results
TABLE 2 example 2 finished product and stability results
The result shows that the ciprofloxacin lactate sodium chloride injection is stored for 24 months under the condition of product storage, and has stable quality.
Example 4 edetate disodium residual detection
Taking the finished products of the example 1 and the example 2, detecting the content of disodium edentate by adopting an HPLC method, taking a reference substance solution and a test substance solution according to the following chromatographic conditions, and sampling and detecting, wherein the result is shown in figure 1, and the disodium edentate is not detected.
Chromatographic conditions:
the chromatographic column is a C18 column; the detection wavelength is 254nm; the flow rate is 1.0ml/min; the column temperature is 30 ℃; the sample loading was 20. Mu.l.
Mobile phase: acetonitrile-buffer (6 ml of 10% tetrabutylammonium hydroxide solution), diluted to 200ml with water, and adjusted to pH 6.5) -water (20:20:60).
Preparing a reference substance solution: dissolving edetate disodium reference substance in water, diluting to obtain solution containing 0.25mg per 1ml, shaking, precisely measuring 5ml, placing into 50ml volumetric flask, adding 10ml of 0.25% copper sulfate solution, diluting to scale with water, and shaking.
Sample solution preparation: taking 5ml of ciprofloxacin lactate sodium chloride injection, placing into a 50ml volumetric flask, adding 10ml of 0.25% copper sulfate solution, adding water to dilute to scale, and shaking uniformly.
EXAMPLE 5 content Change before and after lactic acid treatment
The lactic acid content was determined by HPLC using the lactic acid before and after the treatment of step b of example 1, and the chromatographic conditions were as follows:
The chromatographic column is Polyspher OAKC (E, merck) or a column with a suitable packing; the flow rate is 0.4ml/min; column temperature is 50 ℃; the detection wavelength is 208nm; the sample loading was 20. Mu.l.
Mobile phase: 0.0025mol/L sulfuric acid solution: acetonitrile=85: 15
System applicability: the tailing factor of the main peak of the reference substance solution is not more than 2.0, and the relative standard deviation of 3 repeated sample injections is not more than 2.0%.
Preparing a reference substance solution: accurately weighing about 80mg of sodium lactate reference substance, placing into a 100ml volumetric flask, adding 40ml of water for dissolution, diluting with water to scale, and shaking.
Sample solution preparation: taking 1ml of lactic acid solution before and after treatment, adding into a volumetric flask of 200ml, and adding water to 200ml to obtain the product.
The content of mono-lactic acid and lactic acid polymer was calculated by area normalization.
TABLE 3 lactic acid component content in solution before and after lactic acid treatment
| Sample of | Lactic acid content | Lactic acid dimer | Lactic acid trimer |
| EXAMPLE 1 step b Pre-treatment solution | 68.4％ | 23.8％ | 6.5％ |
| Example 1 post-treatment solution from step b | 99.8％ | / | 0.2％ |
It is therefore necessary to treat commercially available lactic acid to increase the lactic acid content.
EXAMPLE 6 lactic acid content of ciprofloxacin sodium chloride injection prepared with direct lactic acid feeding (without step b)
Prescription:
The preparation process comprises the following steps:
step a, preparing 0.05% edetate disodium solution, and soaking a preparation tank for 40 minutes; then opening a blanking valve, discharging the edetate disodium solution to a liquid medicine conveying pipeline, cleaning the pipeline for 30 minutes, and then flushing the pipeline with a proper amount of water for injection;
step b, dispersing ciprofloxacin in water for injection, adding the prescribed amount of lactic acid and hydrochloric acid, and stirring to dissolve the ciprofloxacin;
c, adding sodium chloride into the solution in the step b, and stirring for dissolution;
Step d, supplementing water for injection to 1000L;
Step e, sampling and detecting the pH value, ciprofloxacin and sodium chloride content;
Step f, carrying out pyrogen removal filtration on the liquid medicine through a hollow fiber ultrafiltration system with the interception molecular weight of 6000 channels, then filtering through a 4.5 mu m filter, and then filtering through a 0.2 mu m sterilization filter;
step g, filling the filtered liquid medicine into a glass bottle, adding a plug, and sealing an aluminum cover;
Step h, detecting tightness by adopting a vacuum attenuation micro leakage tightness detector Leak-S;
And i, sterilizing the filled glass bottle under high pressure at 121 ℃ for 30 minutes, sampling and performing finished product inspection to obtain the ciprofloxacin lactate sodium chloride injection.
The lactic acid content of the finished product was measured by the method for measuring lactic acid content in example 5 (the sample solution was directly taken from the sample solution).
TABLE 4 lactic acid direct feed (without step b) preparation of ciprofloxacin sodium chloride injection lactic acid content
Therefore, the lactic acid dimer and lactic acid trimer impurities in the ciprofloxacin lactate sodium chloride injection can be greatly reduced by using acid to treat the depolymerized lactic acid polymer, and the quality of the ciprofloxacin lactate sodium chloride injection is improved as a whole.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art who is skilled in the art to which the present invention pertains should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof within the scope of the present invention.
Claims (8)
1. The preparation method of the ciprofloxacin lactate sodium chloride injection is characterized by comprising the following steps:
Step a, soaking a liquid preparation tank by using an edetate disodium solution; then opening a blanking valve, discharging the edetate disodium solution to a liquid medicine conveying pipeline, cleaning the pipeline for at least 30 minutes, and then flushing the pipeline and a liquid preparation tank with water for injection until the flushing liquid is free of edetate disodium;
Step b, adding lactic acid and hydrochloric acid into water for injection to prepare lactic acid: the solution with the molar ratio of hydrochloric acid of 1:0.03-0.3 is subjected to heat treatment for more than 30 minutes at the temperature of 115-121 ℃;
C, dispersing a predetermined amount of ciprofloxacin into the water for injection in the liquid preparation tank treated in the step a, adding the lactic acid solution prepared in the step b, and stirring to dissolve the ciprofloxacin;
d, adding a predetermined amount of sodium chloride into the solution prepared in the step c, and stirring for dissolution;
Step e, supplementing water for injection to a preset amount;
F, sampling and detecting the pH value, ciprofloxacin and sodium chloride content;
step g, filtering the liquid medicine checked in the step f;
and h, filling, sealing and sterilizing the liquid medicine filtered in the step g to obtain the ciprofloxacin lactate sodium chloride injection.
2. The preparation method according to claim 1, wherein the concentration of the edetate disodium solution in the step a is 0.02% -0.2%, and the soaking time is 20-60 minutes.
3. The method according to claim 1, wherein the pH of the liquid in step f is 3.5-4.5.
4. The preparation method according to claim 1, wherein the step g comprises the following steps:
g1. carrying out pyrogen removal filtration through a hollow fiber ultrafiltration system;
g2. filtering through a 4.5 μm filter;
g3. Filtered through a 0.2 μm sterilizing filter.
5. The process according to claim 4, wherein the hollow fiber ultrafiltration system used in step g1 is made of a material having an interception molecular weight of 6000 or more.
6. The method of claim 1, wherein step h further comprises the step of detecting the tightness using a vacuum decay method.
7. The process according to claim 1, wherein the sterilization conditions in step h are autoclaving at 115-121 ℃ for 30min.
8. The preparation method according to claim 1, wherein the mass ratio of the lactic acid to the ciprofloxacin to the sodium chloride to the water for injection is 0.64:2:9:1000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210532029.9A CN114767627B (en) | 2022-05-17 | 2022-05-17 | Preparation method of ciprofloxacin lactate sodium chloride injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210532029.9A CN114767627B (en) | 2022-05-17 | 2022-05-17 | Preparation method of ciprofloxacin lactate sodium chloride injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114767627A CN114767627A (en) | 2022-07-22 |
| CN114767627B true CN114767627B (en) | 2024-05-31 |
Family
ID=82437743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210532029.9A Active CN114767627B (en) | 2022-05-17 | 2022-05-17 | Preparation method of ciprofloxacin lactate sodium chloride injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114767627B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1115641A (en) * | 1995-07-06 | 1996-01-31 | 东北制药总厂 | Prepn of cyclopropyloxacini injecta |
| CN102716072A (en) * | 2012-06-13 | 2012-10-10 | 广州南新制药有限公司 | Method for preparing ciprofloxacin lactate sodium chloride injection |
| CN106109407A (en) * | 2016-08-25 | 2016-11-16 | 安徽环球药业股份有限公司 | The compound method of antofloxacin hydrochloride sodium chloride injection |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10048510A1 (en) * | 2000-09-29 | 2002-05-16 | Fresenius Kabi De Gmbh | Storage-stable infusion solution of ciprofloxacin with reduced acidity |
-
2022
- 2022-05-17 CN CN202210532029.9A patent/CN114767627B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1115641A (en) * | 1995-07-06 | 1996-01-31 | 东北制药总厂 | Prepn of cyclopropyloxacini injecta |
| CN102716072A (en) * | 2012-06-13 | 2012-10-10 | 广州南新制药有限公司 | Method for preparing ciprofloxacin lactate sodium chloride injection |
| CN106109407A (en) * | 2016-08-25 | 2016-11-16 | 安徽环球药业股份有限公司 | The compound method of antofloxacin hydrochloride sodium chloride injection |
Non-Patent Citations (1)
| Title |
|---|
| 乳酸环丙沙星注射液制备工艺的改进;蒋晓燕;《中国厂矿医学》;20031231;第16卷(第1期);第65页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114767627A (en) | 2022-07-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2133253C1 (en) | Purified heparin fraction, method of its preparing and pharmaceutical composition containing on said | |
| CN110638751A (en) | Stable sugammadex sodium injection and preparation method thereof | |
| CN109432123B (en) | Compound electrolyte glucose injection and preparation method thereof | |
| CN103550143A (en) | Preparation method of levetiracetam injection | |
| CN103989630B (en) | Moxifloxacin hydrochloride injection and preparation method thereof | |
| CN105640876B (en) | A kind of preparation process of moxifloxacin hydrochloride injection | |
| CN114767627B (en) | Preparation method of ciprofloxacin lactate sodium chloride injection | |
| CN105147599B (en) | Netilmicin sulfate injection and preparation method | |
| CN109908077A (en) | A kind of preparation method of Irinotecan hydrochloride injection | |
| CN113143855B (en) | Bromhexine hydrochloride oral liquid and preparation method thereof | |
| CN114557961A (en) | Slow-release enrofloxacin suspension and preparation method thereof | |
| CN105213301B (en) | Netilmicin sulfate injection and its quality control method | |
| CN105193712B (en) | Ambroxol hydrochloride injection and preparation method | |
| CN113018299A (en) | Tirofiban hydrochloride sodium chloride injection and preparation method thereof | |
| CN103239394A (en) | Small-volume moxifloxacin hydrochloride injection and preparation method thereof | |
| CN101664385B (en) | Ibutilide fumarate injection and preparation method thereof | |
| CN102988281A (en) | Injection of ambroxol hydrochloride and preparation method thereof | |
| CN107198676B (en) | Ibuprofen injection for intravenous administration | |
| CN113116921B (en) | Sodium bicarbonate injection and preparation method thereof | |
| CN108743551A (en) | A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method | |
| CN108567739A (en) | Injection for animals and preparation method thereof | |
| CN103479605B (en) | Dilutable ibuprofen pharmaceutical composition and preparation method thereof | |
| CN103877015B (en) | A kind of preparation method of Bisolvon glucose injection | |
| CN115671044A (en) | Netilmicin sulfate injection and preparation method thereof | |
| CN115844922A (en) | Carboxyl maltose iron complex and preparation method thereof |
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 |