CN117503715A - Vincristine sulfate freeze-dried composition for injection, and preparation method and application thereof - Google Patents
Vincristine sulfate freeze-dried composition for injection, and preparation method and application thereof Download PDFInfo
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- CN117503715A CN117503715A CN202311729653.9A CN202311729653A CN117503715A CN 117503715 A CN117503715 A CN 117503715A CN 202311729653 A CN202311729653 A CN 202311729653A CN 117503715 A CN117503715 A CN 117503715A
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- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 title claims abstract description 41
- 229960002110 vincristine sulfate Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 238000002347 injection Methods 0.000 title claims abstract description 30
- 239000007924 injection Substances 0.000 title claims abstract description 30
- 238000001914 filtration Methods 0.000 claims abstract description 89
- 239000007788 liquid Substances 0.000 claims abstract description 73
- 239000003814 drug Substances 0.000 claims abstract description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000008215 water for injection Substances 0.000 claims abstract description 45
- 239000000706 filtrate Substances 0.000 claims abstract description 17
- 238000004108 freeze drying Methods 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 11
- 206010000830 Acute leukaemia Diseases 0.000 claims abstract description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims abstract description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 23
- 239000011148 porous material Substances 0.000 claims description 21
- 238000011049 filling Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 238000003825 pressing Methods 0.000 claims description 13
- 239000004695 Polyether sulfone Substances 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 239000011261 inert gas Substances 0.000 claims description 7
- 229920006393 polyether sulfone Polymers 0.000 claims description 7
- 238000005070 sampling Methods 0.000 claims description 7
- 230000000704 physical effect Effects 0.000 claims description 3
- 238000011085 pressure filtration Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000004480 active ingredient Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 244000005700 microbiome Species 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 4
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 3
- 108010024976 Asparaginase Proteins 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 238000010979 pH adjustment Methods 0.000 description 3
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- -1 bisindole alkaloid compound Chemical class 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 229960002790 phenytoin sodium Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 208000019736 Cranial nerve disease Diseases 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241001411320 Eriogonum inflatum Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 241000207834 Oleaceae Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 208000014826 cranial nerve neuropathy Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000031864 metaphase Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
- A61K9/14—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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0017—Filtration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
- A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a vincristine sulfate freeze-dried composition for injection, which comprises the following steps: taking the medicine, auxiliary materials and water for injection according to the formula amount, and dividing the water for injection according to the formula amount into first water for injection and second water for injection; dissolving the medicine and auxiliary materials in the formula amount in first water for injection, performing rough filtration to obtain rough filtrate, adding second water for injection to obtain intermediate liquid, adjusting the pH value of the intermediate liquid, and performing multi-stage filtration to obtain liquid medicine; and then carrying out freeze-drying treatment on the liquid medicine to obtain the freeze-dried composition. The invention also relates to a vincristine sulfate freeze-dried composition for injection prepared by the preparation method, and application of the freeze-dried composition in preparation of medicines for treating tumor, acute leukemia or chronic lymphocytic leukemia. The preparation method can reduce the generation of impurities, ensure the content of the active ingredients of the medicine, improve the preparation efficiency and has wide application.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a preparation method of a vincristine sulfate freeze-dried composition for injection, the freeze-dried composition and application.
Background
Vincristine (VCR) is an effective component extracted from herba Catharanthi rosei of oleaceae, belongs to bisindole alkaloid compound, and has the action target of microtubule, and is mainly used for inhibiting polymerization of tubulin to influence formation of spindle microtubule, so that mitosis is stopped in metaphase; it also can interfere with protein metabolism and inhibit RNA polymerase activity, and inhibit synthesis of cell membrane lipid and amino acid transport on cell membrane. Vincristine has a greater inhibitory effect on transplanted tumors than vinca alkaloid and a broad antitumor spectrum, is particularly effective on hematopoietic tumors, has an effect on mouse ridge osteosarcoma, mecca lymphosarcoma, X-5563 myeloma and the like, and is clinically mainly applied to the treatment of acute leukemia, malignant lymphoma, neuroblastoma, chronic lymphocytic leukemia and other diseases
In the existing administration, vincristine is usually administered in the form of its sulfate (i.e. vincristine sulfate), and in practice, in order to promote the therapeutic effect, vincristine sulfate is often used together with other drugs, but when used together with other drugs, certain side effects are brought about, such as: the side effects of the muscular nervous system are increased by the combination with pyrrole antifungal agent (itraconazole); can be used together with phenytoin sodium to reduce phenytoin sodium absorption or promote metabolism; the combination with platinum-containing anti-sub-malignant tumor agents may enhance the 8 th pair of cranial nerve disorder; the combination with L-asparaginase may enhance neurological and blood disorders.
In order to reduce the toxicity or side effects of the combination, it is possible to administer vincristine sulfate at intervals, for example, 12-24 hours before administration of L-asparaginase when it is used with L-asparaginase, but this interval administration is affected by the instability of vincristine sulfate. Therefore, in practice, a dosage form capable of keeping the stability of vincristine sulfate in vincristine sulfate injection is needed, people throw eye light to a freeze-drying agent, and the freeze-drying agent is convenient to store and transport, and can keep the stability of vincristine sulfate in medicines better, and is also convenient to use. However, in the existing preparation process of vincristine sulfate injection freeze-drying agent, medicinal active carbon is generally added to remove microorganisms, so that great difficulty is brought to production, and in the preparation process, the medicinal active carbon also adsorbs part of vincristine sulfate, so that the medicine content is reduced; in the filter pressing link, the production time is greatly prolonged, so that impurities in the medicine can be increased to a certain extent; in addition, in the existing production process, equipment with different specifications is contacted with materials, the generated dynamic effect and thermal effect can also cause the increase of impurities, and the stability of vincristine sulfate can also be influenced by the overhigh temperature. Therefore, a preparation method of vincristine sulfate freeze-dried preparation for injection capable of reducing impurities and ensuring the content of medicines is required.
Disclosure of Invention
The invention aims to provide a preparation method of a vincristine sulfate freeze-dried composition for injection, which can reduce impurity content and ensure medicine content, and simultaneously provides the vincristine sulfate freeze-dried composition for injection prepared by the preparation method and application of the composition.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a preparation method of a vincristine sulfate freeze-dried composition for injection comprises the following steps: taking the medicine, auxiliary materials and water for injection according to the formula, dividing the water for injection according to the formula into two parts, namely first water for injection and second water for injection respectively; dissolving the medicine and auxiliary materials in the formula amount in first water for injection, performing rough filtration to obtain rough filtrate, adding second water for injection to obtain intermediate liquid, adjusting the pH value of the intermediate liquid to be 4.7-5.7, and performing multi-stage filtration to obtain liquid medicine; then carrying out freeze-drying treatment on the liquid medicine to obtain a freeze-dried composition; the mass ratio of the first water for injection to the water for injection is 7-8:10; the multi-stage filtration has a filtration pore size smaller than that of the coarse filtration, and the multi-stage filtration has a filtration pore size smaller than or equal to 0.22 μm; the rough filtration and the multistage filtration are both carried out by adopting inert gas for filter pressing, and the temperature of the rough filtrate, the intermediate liquid and the liquid medicine is controlled to be less than or equal to 25 ℃ in the filter pressing process.
In the present invention, it is further preferable that the filtration pore size of the rough filtration is 0.4 to 0.5. Mu.m, and the filtration pore size of the multistage filtration is 0.1 to 0.22. Mu.m.
In the invention, the pH of the intermediate solution is further preferably regulated by adopting a sodium hydroxide aqueous solution, and the concentration of the sodium hydroxide aqueous solution is 0.3-0.7mol/L.
In the invention, a further preferable scheme is that the rough filtration and the multistage filtration are both carried out by adopting a polyether sulfone filter element.
In the present invention, it is further preferable that the pressure of the press filtration is 0.2MPa or less.
In the present invention, it is further preferable that the liquid medicine is filled before the lyophilization treatment.
In the invention, the intermediate liquid is sampled and detected before the multistage filtration treatment, wherein the sampling and detection is used for detecting the pH value of the intermediate liquid, the vincristine sulfate content and/or the physical property of the intermediate liquid.
In the present invention, it is further preferable that the temperatures of the first water for injection and the second water for injection are 25 ℃ or less.
The invention also claims a vincristine sulfate freeze-dried composition for injection prepared by the preparation method; and the freeze-dried composition of the vincristine sulfate for injection is claimed to be applied to the preparation of medicines for treating tumors, acute leukemia or chronic lymphocytic leukemia.
Compared with the prior art, the invention has the following advantages: by adopting the preparation method, the combination of coarse filtration and multistage filtration is adopted, wherein the aperture of the multistage filtration is smaller than or equal to 0.22 mu m, most microorganisms (such as bacteria, fungi and the like) in the coarse filtrate and the intermediate liquid can be removed, and the microorganism content in the liquid medicine is greatly reduced, so that medicinal active carbon in the traditional preparation process is not required, the adsorption of vincristine sulfate by the active carbon and impurities are reduced, the preparation time is shortened, the production efficiency is improved, and the production cost is reduced and the operation is more convenient; in addition, because smaller filter pore diameter is adopted, in the filtering operation link, inert gas is adopted for filter pressing, certain heat is generated, the temperature is increased, and in addition, because the pipelines (such as the size and the length) for transferring liquid before and after filtering are different from the temperature, heat transfer is generated, so that the stability of the medicine in the medicine liquid (or coarse filtrate or intermediate liquid) is influenced to a certain extent, the temperature of the coarse filtrate, the intermediate liquid and the medicine liquid is controlled to be less than or equal to 25 ℃ in the filter pressing process in order to ensure the stability of the medicine and avoid/reduce the impurity, and the quality and the efficiency of the medicine production are improved.
The present invention will be described in detail with reference to the following specific embodiments.
Detailed Description
The present invention will be further described with reference to specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be arbitrarily combined between the embodiments or technical features described below. Examples and experimental examples of the present invention, except as specifically illustrated, where equipment and reagent materials were obtained from commercial sources, are given by way of illustration only and are not to be construed as limiting the scope of the present application.
A preparation method of a vincristine sulfate freeze-dried composition for injection comprises the following steps: taking the medicine, auxiliary materials and water for injection according to the formula, dividing the water for injection according to the formula into two parts, namely first water for injection and second water for injection respectively; dissolving the medicine and auxiliary materials in the formula amount in first water for injection, performing rough filtration to obtain rough filtrate, adding second water for injection to obtain intermediate liquid, adjusting the pH value of the intermediate liquid to be 4.7-5.7, and performing multi-stage filtration to obtain liquid medicine; then carrying out freeze-drying treatment on the liquid medicine to obtain a freeze-dried composition; the mass ratio of the first water for injection to the water for injection is 7-8:10; the multi-stage filtration has a filtration pore size smaller than that of the coarse filtration, and the multi-stage filtration has a filtration pore size smaller than or equal to 0.22 μm; the rough filtration and the multistage filtration are both carried out by adopting inert gas for filter pressing, and the temperature of the rough filtrate, the intermediate liquid and the liquid medicine is controlled to be less than or equal to 25 ℃ in the filter pressing process.
By adopting the preparation method, the combination of coarse filtration and multistage filtration is adopted, wherein the aperture of the multistage filtration is smaller than or equal to 0.22 mu m, most microorganisms (such as bacteria, fungi and the like) in the coarse filtrate and the intermediate liquid can be removed, and the microorganism content in the liquid medicine is greatly reduced, so that medicinal active carbon in the traditional preparation process is not required, the adsorption of vincristine sulfate by the active carbon and impurities are reduced, the preparation time is shortened, the production efficiency is improved, and the production cost is reduced and the operation is more convenient; in addition, because smaller filter pore diameter is adopted, in the filtering operation link, inert gas is adopted for filter pressing, certain heat is generated, the temperature is increased, and in addition, because the pipelines (such as the size and the length) for transferring liquid before and after filtering are different from the temperature, heat transfer is generated, so that the stability of the medicine in the medicine liquid (or coarse filtrate or intermediate liquid) is influenced to a certain extent, the temperature of the coarse filtrate, the intermediate liquid and the medicine liquid is controlled to be less than or equal to 25 ℃ in the filter pressing process in order to ensure the stability of the medicine and avoid/reduce the impurity, and the quality and the efficiency of the medicine production are improved.
The inert gas used in the press filtration process of the present invention is not limited to rare gas such as helium, but may be inert gas such as nitrogen, which does not react with the drug in the liquid medicine at room temperature, or which is insoluble in water.
The multi-stage filtration in the present invention is specifically described to include two-stage filtration and filtration of two or more stages; furthermore, for multi-stage filtration, the arrangement of gradually decreasing the filtration pore diameter can be made from the liquid inlet end to the liquid outlet end; for the pore size of multistage filtration, the preferred range of the filtration pore size is 0.1-0.22 μm, the filtration pore size is more than 0.22 μm, part of bacteria or fungi cannot be filtered, the filtration pore size is less than 0.1 μm, the pressure required for pressure filtration will become large, on one hand, the energy consumption in the production process will be increased, on the other hand, the heat generated in the pressure filtration process will be increased too quickly, the temperature control is inconvenient, and the solution will cause the generation of impurities.
For the filtration pore size of the rough filtration, a filtration pore size smaller than that of the multistage filtration may be selected based on the necessity, and in order to enhance the filtration efficiency, the filtration pore size of the rough filtration may be set to 0.4 to 0.5 μm.
For the adjustment of the pH value of the intermediate liquid in the invention, alkaline substances acceptable by injection medicaments can be adopted for adjustment, and sodium hydroxide and potassium hydroxide are preferred; further, the pH of the crude filtrate is regulated by adopting sodium hydroxide aqueous solution, and the concentration of the sodium hydroxide aqueous solution can be selected to be 0.3-0.7mol/L.
For multi-stage filtration and rough filtration, a filter element, a filter membrane and the like can be adopted; still more preferably, the rough filtration and the multistage filtration are both carried out by adopting a polyether sulfone filter core, and the filter core made of polyether sulfone material has good heat resistance and mechanical property, and can reduce the influence of thermal expansion and cold contraction under temperature change on the filtering aperture and the filtering effect.
In the present invention, it is further preferable that the pressure of the press filtration is 0.2MPa or less.
In order to facilitate subsequent processing, storage and transportation, such an arrangement may be made that the liquid medicine is subjected to a filling process prior to the lyophilization process. For filling, the filling machine can be adopted to fill corresponding liquid medicine into the liquid medicine container, and the bottle stopper can be pressed on the liquid medicine container; in order to further reduce the microbial content in the medical fluid container, the filling is performed in a sterile environment; further, a filter element with a filter pore diameter of 0.2 μm or less is mounted on the filling head. In order to ensure the stability of vincristine sulfate in the liquid medicine and avoid the entry of impurities, the time interval from the end of the liquid medicine preparation to the completion of filling is not more than 10 hours.
In order to further ensure the quality of the liquid medicine, the intermediate liquid can be sampled and detected before the multistage filtering treatment, wherein the sampling and detection is used for detecting the pH value of the intermediate liquid, the vincristine sulfate content and/or the physical property of the intermediate liquid.
In order to avoid the influence of the temperature on the stability of vincristine sulfate and to facilitate the control of the temperature in the filter pressing process, the temperatures of the first water for injection and the second water for injection are less than or equal to 25 ℃.
After freeze-drying, the process of pressing plug and rolling aluminum cover can be carried out to ensure the sealing performance of the liquid medicine package.
The invention also claims a vincristine sulfate freeze-dried composition for injection prepared by the preparation method; and the freeze-dried composition of the vincristine sulfate for injection is claimed to be applied to the preparation of medicines for treating tumors, acute leukemia or chronic lymphocytic leukemia.
Example 1
0.5mol/L sodium hydroxide solution: 10g of sodium hydroxide was weighed, dissolved completely in 0.5kg of water for injection, cooled to room temperature and used for pH adjustment.
Adding water for injection (150L) with the dosage not less than the prescription amount into a concentrated preparation tank (300L), and cooling to 25 ℃ for standby. Transferring 16kg of injection water (first injection water) accounting for 80% of the prescription amount into a concentrated preparation tank (100L) with 20kg of injection water, adding 52g of vincristine sulfate and 500g of mannitol in the prescription amount, stirring for 10min to dissolve, adding 25g of medicinal active carbon (for injection), stirring for 10min, then coarsely filtering the mixture to a diluted preparation tank (200L) by using nitrogen through 0.45 mu m (polyethersulfone), filtering for 1h and 50min, obtaining coarse filtrate under the pressure of 0.2MPa, adding the rest injection water to 20kg (namely 4kg of second injection water) to obtain intermediate solution, and then regulating the pH value of the intermediate solution to 5.01 by using the prepared sodium hydroxide solution; then, stirring for 10 minutes, sampling, delivering the property, the pH value and the content of the intermediate liquid, filtering the intermediate liquid by using nitrogen through a two-stage 0.22 mu m-level filter element after the intermediate liquid is inspected to be qualified, obtaining the liquid, then delivering the liquid to a filling room for filling, and performing freeze-drying treatment after filling.
Example 2
0.5mol/L sodium hydroxide solution: 10g of sodium hydroxide was weighed, dissolved completely in 0.5kg of water for injection, cooled to room temperature and used for pH adjustment.
Adding water for injection (150L) with the dosage not less than the prescription amount into a concentrated preparation tank (300L), and cooling to 25 ℃ for standby. Transferring 16kg of injection water (first injection water) with the formula amount of 80% into a concentrated preparation tank (100L), adding 52g of vincristine sulfate and 500g of mannitol with the formula amount, stirring for 10min to dissolve, and coarsely filtering with nitrogen gas to obtain coarse filtrate with the total filtering time of 15min and the pressure of 0.15MPa in a dilute preparation tank (200L) with 0.45 μm (polyethersulfone); then adding the rest water for injection to 20kg (namely 4kg for the second water for injection) to obtain an intermediate solution, and then adjusting the pH value of the intermediate solution to 4.91 by using the prepared sodium hydroxide solution; and then stirring for 10 minutes, sampling, delivering the property, the pH value and the content of the intermediate liquid, filtering the intermediate liquid by using a two-stage 0.2 mu m-level filter element by using nitrogen after the intermediate liquid is inspected to be qualified, obtaining a liquid medicine, delivering the liquid medicine to a filling room for filling, and performing freeze-drying treatment after filling.
Example 3
0.5mol/L sodium hydroxide solution: 10g of sodium hydroxide was weighed, dissolved completely in 0.5kg of water for injection, cooled to room temperature and used for pH adjustment.
Adding water for injection (150L) with the dosage not less than the prescription amount into a concentrated preparation tank (300L), and cooling to 24 ℃ for standby. Transferring 16kg of injection water (first injection water) with the formula amount of 80% into a concentrated preparation tank (100L), adding 52g of vincristine sulfate and 500g of mannitol with the formula amount, stirring for 10min to dissolve, and coarsely filtering with nitrogen gas to obtain coarse filtrate with the total filtration time of 11min and the pressure of 0.2MPa in a dilute preparation tank (200L) with 0.45 μm (polyethersulfone); then adding the rest water for injection to 20kg (namely 4kg for the second water for injection) to obtain an intermediate solution, and regulating the pH value of the intermediate solution to 5.10 by using the prepared sodium hydroxide solution; and then stirring for 10 minutes, sampling, delivering the property, the pH value and the content of the intermediate liquid, filtering the intermediate liquid by using a two-stage 0.2 mu m-level filter element by using nitrogen after the intermediate liquid is inspected to be qualified, obtaining a liquid medicine, delivering the liquid medicine to a filling room for filling, and performing freeze-drying treatment after filling.
Experimental example 1
The physical shape, pH value and vincristine sulfate content of the intermediate solutions in examples 1 to 3 were sampled and examined, and the examination results are shown in Table 1 below:
table 1: intermediate liquid detection data sheet of examples 1-3
The pH, vincristine sulfate content, impurity content, bacterial endotoxin, microbial compliance, insoluble particulates, sterility requirements, etc. of vincristine sulfate raw material, intermediate solution, and liquid medicine before filling and lyophilized composition products used in examples 1-3 were tested by the method referred to ch.p 2020 (chinese pharmacopoeia 2020 edition), and the test results are shown in table 2 below:
table 2: table of detection data for raw materials, intermediate solutions, medicinal solutions and lyophilized compositions of examples 1 to 3
From the detection data of examples 1-3 and the contents of examples 1-3, it is evident that examples 2 and 3 without adding pharmaceutically active carbon have shorter filtration time, lower production time, and higher vincristine sulfate content in examples 2 and 3; through the secondary filtration, the impurity is not detected, and the generation of the impurity can be effectively avoided.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (10)
1. The preparation method of the vincristine sulfate freeze-dried composition for injection is characterized by comprising the following steps: taking the medicine, auxiliary materials and water for injection according to the formula, dividing the water for injection according to the formula into two parts, namely first water for injection and second water for injection respectively; dissolving the medicine and auxiliary materials in the formula amount in first water for injection, performing rough filtration to obtain rough filtrate, adding second water for injection to obtain intermediate liquid, adjusting the pH value of the intermediate liquid to be 4.7-5.7, and performing multi-stage filtration to obtain liquid medicine; then carrying out freeze-drying treatment on the liquid medicine to obtain a freeze-dried composition; the mass ratio of the first water for injection to the water for injection is 7-8:10; the multi-stage filtration has a filtration pore size smaller than that of the coarse filtration, and the multi-stage filtration has a filtration pore size smaller than or equal to 0.22 μm; the rough filtration and the multistage filtration are both carried out by adopting inert gas for filter pressing, and the temperature of the rough filtrate, the intermediate liquid and the liquid medicine is controlled to be less than or equal to 25 ℃ in the filter pressing process.
2. The method of preparing a lyophilized composition according to claim 1, wherein the straining has a filtration pore size of 0.4-0.5 μm and the multi-stage filtration has a filtration pore size of 0.1-0.22 μm.
3. The method for preparing a lyophilized composition according to claim 1, wherein the pH of the intermediate solution is adjusted with an aqueous sodium hydroxide solution having a concentration of 0.3 to 0.7mol/L.
4. The method of claim 1, wherein the rough filtration and the multistage filtration are both performed using a polyethersulfone filter.
5. The method of claim 1, wherein the pressure of the pressure filtration is 0.2MPa or less.
6. The method for preparing a lyophilized composition according to claim 1, wherein the liquid medicine is subjected to a filling treatment before the lyophilization treatment.
7. The method for preparing a freeze-dried composition according to claim 1, wherein the intermediate solution is subjected to sampling detection prior to the multistage filtration treatment, wherein the sampling detection is used for detecting the pH value of the intermediate solution, the vincristine sulfate content and/or the physical properties of the intermediate solution.
8. The method of preparing a lyophilized composition according to claim 1, wherein the first and second water for injection each have a temperature of 25 ℃ or less.
9. A vincristine sulfate freeze-dried composition for injection prepared by the preparation method of any one of claims 1 to 8.
10. The use of vincristine sulfate freeze-dried composition for injection as claimed in claim 9, for preparing medicine for treating tumor, acute leukemia or chronic lymphocytic leukemia.
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