CN114767627A - Preparation method of ciprofloxacin lactate and sodium chloride injection - Google Patents
Preparation method of ciprofloxacin lactate and sodium chloride injection Download PDFInfo
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- CN114767627A CN114767627A CN202210532029.9A CN202210532029A CN114767627A CN 114767627 A CN114767627 A CN 114767627A CN 202210532029 A CN202210532029 A CN 202210532029A CN 114767627 A CN114767627 A CN 114767627A
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- sodium chloride
- ciprofloxacin
- injection
- lactic acid
- solution
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- 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 39
- 229960004055 ciprofloxacin lactate Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 239000008354 sodium chloride injection Substances 0.000 title claims abstract description 33
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 97
- 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 52
- 239000000243 solution Substances 0.000 claims abstract description 49
- 239000004310 lactic acid Substances 0.000 claims abstract description 46
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 45
- 239000007788 liquid Substances 0.000 claims abstract description 39
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 34
- 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
- 229960003405 ciprofloxacin Drugs 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 26
- 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 21
- 239000008215 water for injection Substances 0.000 claims abstract description 15
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- 238000000108 ultra-filtration Methods 0.000 claims abstract description 10
- 230000001954 sterilising effect Effects 0.000 claims abstract description 9
- 239000002510 pyrogen Substances 0.000 claims abstract description 8
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 3
- 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 7
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 238000007789 sealing Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 9
- 238000007599 discharging Methods 0.000 claims description 9
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- 238000011010 flushing procedure Methods 0.000 claims description 8
- 238000005070 sampling Methods 0.000 claims description 8
- 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
- 238000004140 cleaning Methods 0.000 claims description 5
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- 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
- 229940079593 drug Drugs 0.000 abstract description 4
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 29
- 239000000047 product Substances 0.000 description 15
- 229910021645 metal ion Inorganic materials 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
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- 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
- 208000015181 infectious disease Diseases 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 239000004626 polylactic acid Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 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
- 238000010668 complexation 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
- 230000000694 effects Effects 0.000 description 2
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- 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
- 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 1
- 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
- 241000607528 Aeromonas hydrophila Species 0.000 description 1
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- 206010005940 Bone and joint infections Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 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
- 241000588653 Neisseria Species 0.000 description 1
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- 102100031310 Ubiquitin carboxyl-terminal hydrolase 42 Human genes 0.000 description 1
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- 241000607272 Vibrio parahaemolyticus Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
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- 244000052616 bacterial pathogen Species 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
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940009662 edetate Drugs 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
- 239000012535 impurity Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000009972 noncorrosive effect Effects 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
- 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
- 239000012488 sample solution Substances 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
- 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
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
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- 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
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Abstract
The invention provides a preparation method of ciprofloxacin lactate sodium chloride injection, belonging to the field of pharmaceutical preparations. The preparation method comprises the following steps: the preparation system and the liquid medicine conveying pipeline are cleaned by using edetate disodium solution, lactic acid is depolymerized under the acidic condition of hydrochloric acid, ciprofloxacin is taken as a raw material, the lactic acid, sodium chloride and water for injection after acid treatment are fully stirred and mixed uniformly, the size of the prepared liquid is adjusted, and finally the ciprofloxacin lactate sodium chloride injection can be prepared through the steps of ultrafiltration pyrogen removal, sterilization and filtration, encapsulation, tightness detection, autoclaving, inspection and the like. The method has the advantages that the formula is simple, the prepared product does not contain edetate disodium, and the risk of complexing calcium in blood is avoided; the pH value of the liquid medicine does not need to be adjusted, the process is simple, and the repeatability is good; the adoption of ultrafiltration for removing pyrogen ensures the safety of the drug use of patients. 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 particularly relates to a preparation method of ciprofloxacin lactate and sodium chloride injection.
Background
Ciprofloxacin lactate (ciprofloxacin lactate), third-generation quinolone broad-spectrum high-efficiency antibacterial drugs, oral administration and injection, developed and marketed by Bayer company in Germany, are clinically used for treating urogenital system infection caused by sensitive bacteria, including simple and complex urinary tract infection, bacterial prostatitis, gonorrhoea neisseria 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 bacilli; treating gastrointestinal infections caused by Shigella, Salmonella, enterotoxigenic Escherichia coli, Aeromonas hydrophila, Vibrio parahaemolyticus, etc.; can also be used for treating typhoid fever, bone and joint infection, skin soft tissue infection septicemia and other systemic infections, and has definite curative effect.
At present, the domestic production of ciprofloxacin lactate sodium chloride injection has two modes, one mode is that ciprofloxacin lactate raw material and sodium chloride are directly prepared, for example, in patent application CN 102274169, and the other mode is that lactic acid is treated by adding alkali liquor and then is prepared by adding water into ciprofloxacin raw material, sodium chloride and the like, for example, in granted patent CN 102716072.
Both methods have disadvantages. The domestic ciprofloxacin lactate is obtained by salifying and refining ciprofloxacin, a large amount of organic solvents are consumed, the production cost is increased, more seriously, organic residues possibly influence the product quality, the medication risk is increased, meanwhile, the problem of environmental pollution is also increased, and the benign development of enterprises and the society is seriously influenced.
The two parts of the 2020 edition of Chinese pharmacopoeia stipulates that lactic acid is 2-hydroxypropionic acid and its condensate, and contains lactic acid and C3H6O3Calculated, 85.0% -92.0%; the content of lactic acid in the ciprofloxacin lactate sodium chloride injection is 0.288 mg-0.352 mg of lactic acid in each 1mg of ciprofloxacin according to the specification of United states pharmacopoeia USP42, and the detection method is high performance liquid chromatography [ sodium lactate (mono-lactic acid) is used as a reference ]Product, calculated as peak area by external standard method ]. Therefore, in the production process of ciprofloxacin lactate sodium chloride injection, the problem that the preparation process must solve is to depolymerize polylactic acid (2-hydroxypropionic acid condensate) in a lactic acid raw material (mixture) into mono-lactic acid (2-hydroxypropionic acid). At present, in the production of ciprofloxacin lactate, a preparation method for depolymerizing polylactic acid (2-hydroxypropionic acid condensation compound) in lactic acid by alkali liquor treatment is adopted, but the operation process is high in danger due to the fact that a large amount of alkali liquor and hydrochloric acid are used in the production process, and more importantly, acid and alkali corrode a liquid preparation system (a stainless steel liquid preparation tank and the like), so that metal ions escape into liquid medicine. Due to the structural characteristics of ciprofloxacin, complexation is easily generated between ciprofloxacin and metal ions, so that the curative effect is reduced, and the product quality is also influenced (the color of the solution is changed). Therefore, the conventional production process is to add edetate disodium and complex with metal ions before ciprofloxacin can be added, as claimed in CN 102716072. However, disodium edetate is used as a strong complexing agent, and is complexed with blood calcium after entering human blood, so that the blood calcium of a patient taking the medicine is reduced, and adverse reactions may occur. The addition of edetate disodium to intravenous injection has been prohibited by the Chinese food and drug administration. Therefore, how to improve the process and reduce the operation risk becomes a problem to be solved, and the preparation of the ciprofloxacin lactate sodium chloride injection which does not contain edetate disodium and has good stability is required to be prepared.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of ciprofloxacin lactate sodium chloride injection with qualified quality and good stability, which directly takes ciprofloxacin and lactic acid as raw materials and adopts sodium chloride to adjust isotonic without adding an edetate disodium complexing agent, and comprises the following steps:
step a, soaking a liquid preparation tank with a edetate disodium solution; then opening a discharging 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 injection water until the flushing liquid does not contain edetate disodium;
and step b, adding lactic acid and hydrochloric acid into water for injection to prepare lactic acid: the solution of hydrochloric acid with the molar ratio of 1:0.03-0.3 is thermally treated for more than 30 minutes at the temperature of 115-121 ℃;
c, dispersing a predetermined amount of ciprofloxacin in 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 obtained in the step c, and stirring for dissolving;
step e, supplementing the injection water to a preset amount;
step f, sampling and detecting the pH value and the contents of ciprofloxacin and sodium chloride;
step g, filtering the qualified liquid medicine from the step f;
and step h, filling, sealing and sterilizing the filtered liquid medicine obtained in the step g to obtain the ciprofloxacin lactate sodium chloride injection.
Preferably, the molar concentration of the edetate disodium solution in step a is 0.02% -0.2%, and may be 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%, more preferably 0.05%; the soaking time of the liquid preparation tank is 20-60 min, and can be 20min, 30min, 40min, 50min, 60min, more preferably 40 min. Ciprofloxacin is easily complexed with metal ions, so that the solution turns yellow and does not meet pharmacopeia standards, and therefore complexing agents are required to be used for complexing so as to reduce the metal ions in the system. The concentration of the edetate disodium solution is lower than 0.02%, which can cause incomplete complexation with metal ions and excessive residual metal ions in the system, thereby affecting the quality of the product, and the edetate disodium solution higher than 0.2% needs 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 edetate disodium. Through the steps, the metal ions and edetate disodium remained in the solution preparation tank can be greatly reduced, and an excellent reaction environment is provided for the subsequent preparation of the edetate disodium-free ciprofloxacin lactate sodium chloride injection.
Preferably, the pH of the liquid medicine in the step f is required to meet the requirements of Chinese pharmacopoeia, and the pH value is 3.5-4.5.
Preferably, step g specifically comprises the following steps:
g1. performing pyrogen removal filtration through a hollow fiber ultrafiltration system;
g2. filtering with 4.5 μm filter;
g3. filtered through a 0.2 μm sterile filter.
Preferably, the hollow fiber ultrafiltration system used in step g1 is made of material with interception molecular weight more than or equal to 6000.
Preferably, step h further comprises the step of detecting the tightness of step h by using a vacuum decay method.
Preferably, the sterilization conditions in step h are 115-121 ℃ autoclaving for 30 minutes.
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 instead of an alkaline depolymerization method, so that the use of strong acid and strong alkali is reduced, the reaction vessel is non-corrosive, the escape of metal ions is reduced, edetate disodium is not required to be reused in the subsequent steps, the final product can meet pharmacopoeia standards under the condition of not containing edetate disodium, and the stability is good. Meanwhile, the method of depolymerizing the lactic acid with a very small amount of hydrochloric acid reduces the operational risk of understanding the polylactic acid.
The method has simple formula, and the prepared product does not contain edetate disodium, so that the risk of complexing calcium in blood is avoided; the pH value of the liquid medicine does not need to be adjusted, the process is simple, and the repeatability is good; the adoption of ultrafiltration for removing pyrogen ensures the safety of the drug use of patients. The ciprofloxacin lactate sodium chloride injection prepared by the method has good stability and superior product quality.
Drawings
FIG. 1 is an HPLC chromatogram of the test results of example 4.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the examples are for illustrative purposes only and are not intended to limit the invention, and that various modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
Example 1 ciprofloxacin lactate sodium chloride injection and preparation example thereof
Prescription:
the preparation process comprises the following steps:
step a, preparing 0.05 percent of edetate disodium solution, and soaking the solution preparation tank for 40 minutes; then opening a discharging 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 injection water until the flushing liquid does not contain edetate disodium;
step b, adding 5L of water for injection into lactic acid and hydrochloric acid to prepare a solution, and carrying out heat treatment at 121 ℃ for 30 minutes;
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;
d, adding sodium chloride into the solution obtained in the step c, and stirring for dissolving;
step e, supplementing the water for injection to 1000L;
step f, sampling and detecting the pH value and the contents of ciprofloxacin and sodium chloride according to the regulations of ciprofloxacin lactate injection in the 2020 version of Chinese pharmacopoeia;
step g, after the inspection is qualified, the liquid medicine is subjected to pyrogen removal filtration by a hollow fiber ultrafiltration system with the intercepted molecular weight of 6000 channels, then is filtered by a 4.5 mu m filter, and is filtered by a 0.2 mu m sterilizing filter;
step h, filling the filtered liquid medicine into a glass bottle, plugging, and sealing an aluminum cover;
step i, detecting the sealing performance by adopting a vacuum attenuation micro-leakage sealing performance detector Leak-S;
and j, autoclaving the filled glass bottle at 121 ℃ for 30 minutes, sampling, and inspecting 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 the solution preparation tank for 60 minutes; then opening a discharging 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 injection water until the flushing liquid does not contain edetate disodium;
step b, adding 5L of water for injection into lactic acid and hydrochloric acid to prepare a solution, and carrying out heat treatment at 115 ℃ for 45 minutes;
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;
d, adding sodium chloride into the solution obtained in the step c, and stirring for dissolving;
step e, supplementing the water for injection to 1000L;
step f, sampling and detecting the pH value and the contents of ciprofloxacin and sodium chloride according to the regulations of ciprofloxacin lactate injection in the 2020 version of Chinese pharmacopoeia;
step g, after the inspection is qualified, the liquid medicine is subjected to pyrogen removal filtration by a hollow fiber ultrafiltration system with the intercepted molecular weight of 6000 channels, then is filtered by a 4.5 mu m filter, and is filtered by a 0.2 mu m sterilizing filter;
step h, filling the filtered liquid medicine into a glass bottle, plugging, and sealing an aluminum cap;
step i, detecting the sealing performance by adopting a vacuum attenuation micro-leakage sealing performance detector Leak-S;
and j, autoclaving the filled glass bottle at the temperature of 115 ℃ for 30 minutes, sampling, making a finished product, and inspecting to obtain the ciprofloxacin lactate sodium chloride injection.
EXAMPLE 3 product quality and stability Studies
The ciprofloxacin lactate sodium chloride injection prepared in the example 1 and the example 2 is placed for 24 months at normal temperature (product storage condition), samples are taken at 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months, and each quality index of the injection is detected according to the standard of 2020 version Chinese pharmacopoeia, and the results are shown in the following tables 1 and 2.
TABLE 1 example 1 Final 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 product storage condition and has stable quality.
Example 4 edetate disodium residual detection
And (3) taking the finished products of the example 1 and the example 2, detecting the content of the edetate disodium by an HPLC method, and taking the reference substance solution and the test substance solution according to the following chromatographic conditions for sample injection detection, wherein the results are shown in figure 1, and the edetate disodium is not detected.
Chromatographic conditions are as follows:
the chromatographic column is a C18 column; the detection wavelength is 254 nm; the flow rate is 1.0 ml/min; the column temperature is 30 ℃; the amount of sample was 20. mu.l.
Mobile phase: acetonitrile-buffer (6 ml of 10% tetrabutylammonium hydroxide solution, diluted to 200ml with water, pH adjusted to 6.5) -water (20:20: 60).
Preparation of a control solution: dissolving appropriate amount of edetate disodium in water, diluting to obtain solution containing 0.25mg per 1ml, shaking, precisely measuring 5ml, placing in 50ml volumetric flask, adding 0.25% copper sulfate solution 10ml, diluting with water to desired volume, and shaking.
Preparing a test solution: taking 5ml of ciprofloxacin lactate sodium chloride injection, putting the ciprofloxacin lactate sodium chloride injection into a 50ml volumetric flask, adding 10ml of 0.25% copper sulfate solution, adding water to dilute to the scale, and shaking up uniformly.
Example 5 content Change before and after lactic acid treatment
The lactic acid before and after the treatment in step b of example 1 was taken and the content of lactic acid was measured by HPLC under the following chromatographic conditions:
the chromatographic column is Polysphere OAKC (E, Merck) or a column suitable for packing; the flow rate is 0.4 ml/min; the column temperature is 50 ℃; the detection wavelength is 208 nm; the sample volume was 20. mu.l.
Mobile phase: 0.0025mol/L sulfuric acid solution: acetonitrile 85: 15
The system applicability is as follows: the tailing factor of the main peak of the control solution should not be more than 2.0, and the relative standard deviation of 3 repeated injections should not be more than 2.0%.
Preparation of a control solution: precisely weighing about 80mg of sodium lactate as a reference substance, placing the reference substance into a 100ml volumetric flask, adding 40ml of water for dissolving, diluting with water to a scale, and shaking up.
Preparing a test solution: adding 1ml of lactic acid solution before and after treatment into a volumetric flask of 200ml, and adding water to 200ml to obtain the lactic acid.
The contents of the mono-lactic acid and the lactic acid polymer were calculated by area normalization.
TABLE 3 lactic acid component content in solution before and after lactic acid treatment
| Sample (I) | Lactic acid content | Lactic acid dimers | Lactic acid trimer |
| Example 1 step b Pre-treatment solution | 68.4％ | 23.8％ | 6.5％ |
| Example 1 step b treated solution | 99.8％ | / | 0.2％ |
It is therefore necessary to treat commercially available lactic acid to increase the lactic acid content.
Example 6 preparation of lactic acid content of ciprofloxacin lactate sodium chloride injection Using direct feeding of lactic acid (without step b)
Prescription:
the preparation process comprises the following steps:
step a, preparing 0.05 percent edetate disodium solution, and soaking the solution 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 washing the pipeline by using a proper amount of injection water;
step b, dispersing ciprofloxacin in water for injection, adding lactic acid and hydrochloric acid with the prescription amount, and stirring to dissolve ciprofloxacin;
step c, adding sodium chloride into the solution obtained in the step b, and stirring for dissolving;
d, supplementing the injection water to 1000L;
step e, sampling and detecting the pH value and the contents of ciprofloxacin and sodium chloride;
f, filtering the liquid medicine by a hollow fiber ultrafiltration system with the intercepted molecular weight of 6000 channels to remove pyrogen, then filtering by a 4.5 mu m filter, and filtering by a 0.2 mu m sterilizing filter;
step g, filling the filtered liquid medicine into a glass bottle, plugging, and sealing an aluminum cap;
step h, adopting a vacuum attenuation micro-leakage tightness detector Leak-S to detect the tightness;
and (i) autoclaving the filled glass bottle at 121 ℃ for 30 minutes, sampling, and inspecting to obtain the ciprofloxacin lactate sodium chloride injection.
The content of lactic acid in the finished product was determined by the method for determining the content of lactic acid in example 5 (the sample solution was directly taken).
TABLE 4 lactic acid direct feeding (without step b) preparation of ciprofloxacin lactate 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 the acid to process and depolymerize the lactic acid polymer, and the quality of the ciprofloxacin lactate sodium chloride injection is integrally improved.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical scope of the present invention and the equivalent alternatives or modifications according to the technical solution and the inventive concept of the present invention within the technical scope of the present invention.
Claims (9)
1. A preparation method of ciprofloxacin lactate and 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 discharging 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 injection water 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: heat treating the solution with the hydrochloric acid molar ratio of 1:0.03-0.3 for more than 30 minutes at the temperature of 115-121 ℃;
c, dispersing a predetermined amount of ciprofloxacin in 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 dissolving;
step e, supplementing the injection water to a preset amount;
f, sampling and detecting the pH value, the ciprofloxacin content and the sodium chloride content;
step g, filtering the liquid medicine detected in the step f;
and step h, filling, sealing and sterilizing the filtered liquid medicine obtained in the step g to obtain the ciprofloxacin lactate sodium chloride injection.
2. The assay method according to claim 1, wherein the concentration of the edetate disodium solution in step a is 0.02% -0.2%, and the soaking time is 20-60 minutes.
3. The method of claim 1, wherein the pH of the liquid medicine in step f is 3.5 to 4.5.
4. The assay method according to claim 1, wherein step g comprises the steps of:
g1. performing pyrogen removal filtration through a hollow fiber ultrafiltration system;
g2. filtering through a 4.5-micron filter;
g3. filtered through a 0.2 μm sterilizing filter.
5. The method 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 according to claim 1, wherein the step h further comprises a step of detecting the sealing property by a vacuum decay method.
7. The assay method according to claim 1, wherein the sterilization conditions in step h are autoclaving at 115-121 ℃ for 30 min.
8. The 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.
9. The ciprofloxacin lactate sodium chloride injection prepared by the preparation method of the ciprofloxacin lactate sodium chloride injection according to any one of claims 1 to 9, wherein the prepared ciprofloxacin lactate sodium chloride injection does not contain edetate disodium.
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Citations (4)
| 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 |
| US20040082593A1 (en) * | 2000-09-29 | 2004-04-29 | Klaus Sommermeyer | Infusion of ciprofloxacin having reduced acid content and being stable in storage |
| 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 |
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Patent Citations (4)
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|---|---|---|---|---|
| CN1115641A (en) * | 1995-07-06 | 1996-01-31 | 东北制药总厂 | Prepn of cyclopropyloxacini injecta |
| US20040082593A1 (en) * | 2000-09-29 | 2004-04-29 | Klaus Sommermeyer | Infusion of ciprofloxacin having reduced acid content and being stable in storage |
| 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 |
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