CN114699367A - Amsacrine product and production process thereof - Google Patents
Amsacrine product and production process thereof Download PDFInfo
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- CN114699367A CN114699367A CN202210266675.5A CN202210266675A CN114699367A CN 114699367 A CN114699367 A CN 114699367A CN 202210266675 A CN202210266675 A CN 202210266675A CN 114699367 A CN114699367 A CN 114699367A
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- amsacrine
- lactic acid
- injection
- production process
- solution
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- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 title claims abstract description 150
- 229960001220 amsacrine Drugs 0.000 title claims abstract description 150
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 55
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims abstract description 246
- 238000002347 injection Methods 0.000 claims abstract description 107
- 239000007924 injection Substances 0.000 claims abstract description 107
- 239000000243 solution Substances 0.000 claims abstract description 107
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000001914 filtration Methods 0.000 claims abstract description 31
- 238000004806 packaging method and process Methods 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 238000007670 refining Methods 0.000 claims abstract description 10
- 230000001954 sterilising effect Effects 0.000 claims abstract description 8
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims description 45
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 42
- 238000003756 stirring Methods 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000008215 water for injection Substances 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 238000001179 sorption measurement Methods 0.000 claims description 8
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 239000003957 anion exchange resin Substances 0.000 claims description 6
- 239000003729 cation exchange resin Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000005342 ion exchange Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 239000004310 lactic acid Substances 0.000 description 15
- 238000011049 filling Methods 0.000 description 12
- 238000002372 labelling Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 10
- 229940023913 cation exchange resins Drugs 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000007689 inspection Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 3
- HJCUTNIGJHJGCF-UHFFFAOYSA-N 9,10-dihydroacridine Chemical compound C1=CC=C2CC3=CC=CC=C3NC2=C1 HJCUTNIGJHJGCF-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- FFKUHGONCHRHPE-UHFFFAOYSA-N 5-methyl-1h-pyrimidine-2,4-dione;7h-purin-6-amine Chemical compound CC1=CNC(=O)NC1=O.NC1=NC=NC2=C1NC=N2 FFKUHGONCHRHPE-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 150000001251 acridines Chemical class 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002904 solvent Substances 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
-
- 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
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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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
- A61K9/0012—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
- 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
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses an amsacrine product and a production process thereof, wherein the production process comprises the production process of an amsacrine injection, the production process of an L-lactic acid injection and combination and packaging; the production process of the amsacrine injection comprises the refining treatment of N, N-dimethylacetamide, the preparation of an amsacrine solution, the sterilization filtration of the amsacrine solution and the post-treatment of the amsacrine solution; the production process of the L-lactic acid injection comprises the refining treatment of L-lactic acid, the preparation of an L-lactic acid solution, the sterilization and filtration of the L-lactic acid solution and the post treatment of the L-lactic acid solution; the amsacrine product has the advantages that the amsacrine injection and the L-lactic acid injection are pertinently optimized in the production process, so that the purity of the injection is higher, the concentration of the injection is more accurate, the solubility of the amsacrine injection in the L-lactic acid injection is better, insoluble substances cannot occur, the clarity is good, and the medication safety is higher.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an amsacrine product and a production process thereof.
Background
Amsacrine (Ams) is the first synthetic acridine derivative in Cain et al 1974, as a cytostatic agent; the anticancer mechanism is similar to that of anthracyclines, which interact with adenine-thymine base pair to prevent DNA from being used as template for DNA replication and RNA synthesis and is mainly used in treating acute leukemia and malignant lymphoma.
The amsacrine injection is a commonly used amsacrine injection product, however, amsacrine is insoluble in water, so the amsacrine injection is prepared by taking N, N-dimethylacetamide as a solvent, and when amsacrine is used, the amsacrine injection and an L-lactic acid solution are mixed to be injected, so the amsacrine injection and the L-lactic acid solution are used together and are indispensable. However, the concentration of the L-lactic acid solution special for the amsacrine injection cannot meet the optimal requirement due to the influence of the preparation process, the purity is not high enough, the solubility of the amsacrine injection in the L-lactic acid solution is poor, insoluble substances are possibly generated, and the clarity is reduced, so that the drug effect and the drug safety of amsacrine are seriously influenced.
Disclosure of Invention
The invention aims to overcome the defect of poor solubility of the existing amsacrine injection in an L-lactic acid solution, and provides an amsacrine product and a production process thereof; the amsacrine product has the advantages that the amsacrine injection and the L-lactic acid injection are purposefully optimized in production process, so that the injection is higher in purity and more accurate in concentration, the solubility of the amsacrine injection in the L-lactic acid injection is better, insoluble substances cannot occur, the clarity is good, and the medication safety is higher.
In order to realize the aim, the invention provides a production process of an amsacrine product, which comprises a production process of an amsacrine injection, a production process of an L-lactic acid injection and combination packaging; the amsacrine injection is prepared by mixing 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine according to a ratio; the L-lactic acid injection is prepared by mixing 13.5ml of water for injection and 42.93mg of L-lactic acid according to the proportion; the production process of the amsacrine injection comprises the refining treatment of N, N-dimethylacetamide, the preparation of an amsacrine solution, the sterilization filtration of the amsacrine solution and the post-treatment of the amsacrine solution; the production process of the L-lactic acid injection comprises the refining treatment of the L-lactic acid, the preparation of the L-lactic acid solution, the sterilization and filtration of the L-lactic acid solution and the post treatment of the L-lactic acid solution.
Among them, the preferable refining method of the N, N-dimethylacetamide is as follows: distilling N, N-dimethylacetamide under atmospheric pressure at 165 ℃ to obtain refined N, N-dimethylacetamide; the N, N-dimethylacetamide is purified by distillation treatment, and the purity is higher, so that the amsacrine is favorably dissolved, and the amsacrine is favorably dissolved in L-lactic acid during use.
Preferably, the preparation method of the amsacrine solution comprises the following steps: dissolving amsacrine into the refined N, N-dimethylacetamide solution by stirring to obtain an amsacrine solution; the preparation method is simple and reliable, and is convenient for industrial production.
Preferably, the amsacrine solution sterilization filtration method comprises the following steps: adding 0.1wt% of activated carbon into the amsacrine solution, stirring and adsorbing at room temperature for 30min, and sequentially filtering by using a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution; the insoluble substances and bacteria in the solution can be effectively removed through the adsorption of the active carbon and the multiple filtration treatment.
Wherein, the preferable post-treatment method of the amsacrine solution comprises the following steps: after the filtered amsacrine solution is detected to be qualified, filling, corking, capping, lamp detecting and labeling are carried out to obtain an amsacrine injection product; the detection items at least comprise amsacrine content, visible foreign matters, clarity and bacterial endotoxin.
Among them, the preferred purification treatment method of the L-lactic acid is: distilling L-lactic acid at 120 deg.C under normal pressure, cooling the distillation product to 65-70 deg.C, adding 0.2wt% of active carbon, stirring for adsorption for 30min, and filtering with 0.45 μm filter element to remove carbon; carrying out ion exchange treatment on the filtrate by using a mixed bed consisting of 734 cation exchange resins and 701 anion exchange resins to obtain refined L-lactic acid; through the refining treatment, the L-lactic acid is purified, the purity is higher, and the concentration of the prepared L-lactic acid solution is more accurate, so that the dissolving of amsacrine and the medication safety are facilitated.
Preferably, the preparation method of the L-lactic acid solution comprises the following steps: dissolving the refined L-lactic acid into water for injection by stirring to obtain an L-lactic acid solution; the preparation method is simple and reliable, and is convenient for industrial production;
wherein, preferably, the pH value of the L-lactic acid solution is 2.3-2.7; the pH value of the L-lactic acid solution is preferably selected, the concentration of the L-lactic acid solution is optimal, and the amsacrine injection has the best solubility in the L-lactic acid solution.
Preferably, the method for sterilizing and filtering the L-lactic acid solution comprises the following steps: adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with the diameter of 0.45 μm for 1 time and a microporous filter element with the diameter of 0.22 μm for 2 times to obtain a filtered L-lactic acid solution; the insoluble substances and bacteria in the solution can be effectively removed through the adsorption of the active carbon and the multiple filtration treatment.
Among them, preferably, the post-treatment method of the L-lactic acid solution is as follows: after the filtered L-lactic acid solution is detected to be qualified, filling, corking, capping, lamp detecting and labeling are carried out to obtain an L-lactic acid injection product; the detection items at least comprise L-lactic acid content, pH value, visible foreign matters, clarity, color and bacterial endotoxin.
Preferably, the combined package is that a plurality of amsacrine injections and a plurality of L-lactic acid injections are matched and packaged one by one according to the proportion of 75mg amsacrine to 42.93mg L-lactic acid.
Further, in order to achieve the above object, the present invention also provides an amsacrine product, which is prepared by the above preparation method. The amsacrine product is simple and convenient to use, and the amsacrine injection has good solubility and high safety in an L-lactic acid injection.
Compared with the prior art, the invention has the beneficial effects that:
1. the production process of the invention has the advantages that the N, N-dimethylacetamide and L-lactic acid are refined, so that the injection has higher purity and more accurate concentration, the amsacrine injection has better solubility in the L-lactic acid injection, insoluble substances are avoided, the clarity is good, and the medication safety is higher.
2. The production process is mature, feasible, safe and effective, and is suitable for large-scale industrial production of the acridine product.
3. The amsacrine product is simple and convenient to use, and the amsacrine injection has good solubility and high safety in an L-lactic acid injection.
Detailed Description
The present invention will be described in further detail with reference to test examples and specific embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and any technique realized based on the contents of the present invention falls within the scope of the present invention.
Example 1:
amsacrine product: comprises 5 amsacrine injection solutions prepared from 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine; 5L-lactic acid injection solutions prepared from 13.5ml of water for injection and 42.93mg of L-lactic acid;
the production process of the amsacrine product comprises the production process of amsacrine injection, the production process of L-lactic acid injection, combination and packaging;
the production process of the amsacrine injection comprises the following steps:
(1) distilling N, N-dimethylacetamide under atmospheric pressure at 165 ℃ to obtain refined N, N-dimethylacetamide;
(2) dissolving amsacrine into the refined N, N-dimethylacetamide solution by stirring to obtain an amsacrine solution;
(3) adding 0.01wt% of activated carbon into the amsacrine solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by using a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution;
(4) and (4) detecting the filtered amsacrine solution to be qualified, and then carrying out filling, tamponade, capping, lamp detection and label pasting to obtain amsacrine injection products (each volume of 1.5ml of N, N dimethylacetamide and 75mg of amsacrine).
The production process of the L-lactic acid injection comprises the following steps:
(1) distilling L-lactic acid at 120 deg.C under normal pressure, cooling the distillation product to 68 deg.C, adding 0.2wt% of active carbon, stirring for adsorption for 30min, and filtering with 0.45 μm filter element to remove carbon; performing ion exchange treatment on the filtrate by using a mixed bed consisting of 734 cation exchange resins and 701 anion exchange resins to obtain refined L-lactic acid;
(2) dissolving the refined L-lactic acid into water for injection by stirring to obtain an L-lactic acid solution;
(3) adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with the diameter of 0.45 μm for 1 time and a microporous filter element with the diameter of 0.22 μm for 2 times to obtain a filtered L-lactic acid solution;
(4) and (3) detecting the filtered L-lactic acid solution to be qualified, filling, corking, capping, performing lamp inspection and labeling to obtain an L-lactic acid injection product (each volume of 13.5ml of water for injection and 42.93 mgL-lactic acid).
Merging and packaging: and matching and packaging the 5 amsacrine injections and the 5L-lactic acid injections to obtain the amsacrine product.
Comparative example 1:
amsacrine product: comprises 5 amsacrine injection solutions prepared from 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine; 5L-lactic acid injection solutions prepared from 13.5ml of water for injection and 42.93mg of L-lactic acid;
the production process of the amsacrine product comprises the production process of amsacrine injection, the production process of L-lactic acid injection, combination and packaging;
the production process of the amsacrine injection comprises the following steps:
(1) dissolving amsacrine into an N, N-dimethylacetamide solution by stirring to obtain an amsacrine solution;
(2) adding 0.1wt% of activated carbon into the amsacrine solution, stirring and adsorbing at room temperature for 30min, and sequentially filtering by using a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution;
(3) and (3) detecting the filtered amsacrine solution to be qualified, filling, corking, capping, performing lamp detection and labeling to obtain amsacrine injection products (each volume is 1.5ml N, N-dimethylacetamide and 75mg amsacrine).
The production process of the L-lactic acid injection comprises the following steps:
(1) distilling L-lactic acid at 120 deg.C under normal pressure, cooling the distillation product to 68 deg.C, adding 0.2wt% of active carbon, stirring for adsorption for 30min, and filtering with 0.45 μm filter element to remove carbon; performing ion exchange treatment on the filtrate by using a mixed bed consisting of 734 cation exchange resins and 701 anion exchange resins to obtain refined L-lactic acid;
(2) dissolving the refined L-lactic acid into water for injection by stirring to obtain an L-lactic acid solution;
(3) adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with the diameter of 0.45 μm for 1 time and a microporous filter element with the diameter of 0.22 μm for 2 times to obtain a filtered L-lactic acid solution;
(4) and (3) detecting the filtered L-lactic acid solution to be qualified, filling, corking, capping, performing lamp inspection and labeling to obtain an L-lactic acid injection product (each volume of 13.5ml of water for injection and 42.93 mgL-lactic acid).
Merging and packaging: and matching and packaging the 5 amsacrine injections and the 5L-lactic acid injections to obtain the amsacrine product.
Comparative example 2:
amsacrine product: comprises 5 amsacrine injection solutions prepared from 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine; 5L-lactic acid injection solutions prepared from 13.5ml of water for injection and 42.93mg of L-lactic acid;
the production process of the amsacrine product comprises the production process of amsacrine injection, the production process of L-lactic acid injection, combination and packaging;
the production process of the amsacrine injection comprises the following steps:
(1) distilling N, N-dimethylacetamide under atmospheric pressure at 165 ℃ to obtain refined N, N-dimethylacetamide;
(2) dissolving amsacrine into the refined N, N-dimethylacetamide solution by stirring to obtain an amsacrine solution;
(3) adding 0.1wt% of activated carbon into the amsacrine solution, stirring and adsorbing at room temperature for 30min, and sequentially filtering by using a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution;
(4) and (3) detecting the filtered amsacrine solution to be qualified, filling, corking, capping, performing lamp detection and labeling to obtain amsacrine injection products (each volume is 1.5ml N, N-dimethylacetamide and 75mg amsacrine).
The production process of the L-lactic acid injection comprises the following steps:
(1) dissolving L-lactic acid into water for injection by stirring to obtain an L-lactic acid solution;
(2) adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with the diameter of 0.45 μm for 1 time and a microporous filter element with the diameter of 0.22 μm for 2 times to obtain a filtered L-lactic acid solution;
(3) and (3) detecting the filtered L-lactic acid solution to be qualified, filling, corking, capping, performing lamp detection and labeling to obtain an L-lactic acid injection product (each volume of 13.5ml of water for injection and 42.93 mgL-lactic acid).
Merging and packaging: and matching and packaging the 5 acridan injection and the 5L-lactic acid injection to obtain an amsacrine product.
Comparative example 3:
amsacrine product: comprises 5 amsacrine injection solutions prepared from 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine; 5L-lactic acid injection solutions prepared from 13.5ml of water for injection and 42.93mg of L-lactic acid;
the production process of the amsacrine product comprises the production process of amsacrine injection, the production process of L-lactic acid injection, combination and packaging;
the production process of the amsacrine injection comprises the following steps:
(1) distilling N, N-dimethylacetamide under atmospheric pressure at 165 ℃ to obtain refined N, N-dimethylacetamide;
(2) dissolving amsacrine into the refined N, N-dimethylacetamide solution by stirring to obtain an amsacrine solution;
(3) adding 0.1wt% of activated carbon into the amsacrine solution, stirring and adsorbing at room temperature for 30min, and sequentially filtering by using a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution;
(4) and (3) detecting the filtered amsacrine solution to be qualified, filling, corking, capping, performing lamp detection and labeling to obtain amsacrine injection products (each volume is 1.5ml N, N-dimethylacetamide and 75mg amsacrine).
The production process of the L-lactic acid injection comprises the following steps:
(1) distilling L-lactic acid at 125 deg.C under normal pressure, cooling the distillation product to 68 deg.C, adding 0.2wt% of active carbon, stirring for adsorption for 30min, and filtering with 0.45 μm filter element to remove carbon; performing ion exchange treatment on the filtrate by using a mixed bed consisting of 734 cation exchange resins and 701 anion exchange resins to obtain refined L-lactic acid;
(2) dissolving the refined L-lactic acid into water for injection by stirring to obtain an L-lactic acid solution;
(3) adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with the diameter of 0.45 μm for 1 time and a microporous filter element with the diameter of 0.22 μm for 2 times to obtain a filtered L-lactic acid solution;
(4) and (3) detecting the filtered L-lactic acid solution to be qualified, filling, corking, capping, performing lamp inspection and labeling to obtain an L-lactic acid injection product (each volume of 13.5ml of water for injection and 42.93 mgL-lactic acid).
Merging and packaging: and matching and packaging the 5 amsacrine injections and the 5L-lactic acid injections to obtain the amsacrine product.
Comparative example 5:
amsacrine product: comprises 5 amsacrine injection solutions prepared from 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine; 5L-lactic acid injection solutions prepared from 13.5ml of water for injection and 42.93mg of L-lactic acid;
the production process of the amsacrine product comprises the production process of amsacrine injection, the production process of L-lactic acid injection, combination and packaging;
the production process of the amsacrine injection comprises the following steps:
(1) distilling N, N-dimethylacetamide under atmospheric pressure at 165 ℃ to obtain refined N, N-dimethylacetamide;
(2) dissolving amsacrine into the refined N, N-dimethylacetamide solution by stirring to obtain an amsacrine solution;
(3) adding 0.1wt% of activated carbon into the amsacrine solution, stirring and adsorbing at room temperature for 30min, and sequentially filtering by using a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution;
(4) and (3) detecting the filtered amsacrine solution to be qualified, filling, corking, capping, performing lamp detection and labeling to obtain amsacrine injection products (each volume is 1.5ml N, N-dimethylacetamide and 75mg amsacrine).
The production process of the L-lactic acid injection comprises the following steps:
(1) distilling L-lactic acid at 120 deg.C under normal pressure, cooling the distillation product to normal temperature, adding 0.2wt% of active carbon, stirring for adsorption for 30min, and filtering with 0.45 μm filter element to remove carbon; performing ion exchange treatment on the filtrate by using a mixed bed consisting of 734 cation exchange resins and 701 anion exchange resins to obtain refined L-lactic acid;
(2) dissolving the refined L-lactic acid into water for injection by stirring to obtain an L-lactic acid solution;
(3) adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with the diameter of 0.45 μm for 1 time and a microporous filter element with the diameter of 0.22 μm for 2 times to obtain a filtered L-lactic acid solution;
(4) and (3) detecting the filtered L-lactic acid solution to be qualified, filling, corking, capping, performing lamp inspection and labeling to obtain an L-lactic acid injection product (each volume of 13.5ml of water for injection and 42.93 mgL-lactic acid).
Merging and packaging: and matching and packaging the 5 amsacrine injections and the 5L-lactic acid injections to obtain the amsacrine product.
Experimental example:
the amsacrine injection and the L-lactic acid injection prepared in example 1 and comparative examples 1 to 5 were respectively detected, and the amsacrine injection and the L-lactic acid injection were mixed and then detected, and the detection results were as follows:
according to the detection results, the amsacrine injection and the L-lactic acid injection prepared by the method have higher purity and better clarity, and the amsacrine injection has better solubility and higher medication safety in the L-lactic acid injection.
Claims (8)
1. The production process of the amsacrine product is characterized by comprising the production process of amsacrine injection, the production process of L-lactic acid injection and combination and packaging; the amsacrine injection is prepared by mixing 1.5ml of N, N-dimethylacetamide and 75mg of amsacrine according to a ratio; the L-lactic acid injection is prepared by mixing 13.5ml of water for injection and 42.93mg of L-lactic acid according to the proportion; the production process of the amsacrine injection comprises the refining treatment of N, N-dimethylacetamide, the preparation of an amsacrine solution, the sterilization filtration of the amsacrine solution and the post-treatment of the amsacrine solution; the production process of the L-lactic acid injection comprises the refining treatment of L-lactic acid, the preparation of an L-lactic acid solution, the sterilization and filtration of the L-lactic acid solution and the post treatment of the L-lactic acid solution.
2. The production process according to claim 1, wherein the refining treatment method of the N, N-dimethylacetamide comprises the following steps: distilling N, N-dimethylacetamide under atmospheric pressure at 165 ℃ to obtain refined N, N-dimethylacetamide.
3. The production process according to claim 1, wherein the amsacrine solution is sterilized and filtered by the following method: adding 0.1wt% of activated carbon into the amsacrine solution, stirring and adsorbing at room temperature for 30min, and sequentially filtering with a PTFE0.45 μm filter element for 1 time and a PTFE0.22 μm filter element for 2 times to obtain a filtered amsacrine solution.
4. The production process according to claim 1, wherein the refining treatment method of the L-lactic acid comprises the following steps: distilling L-lactic acid at 120 deg.C under normal pressure, cooling the distillation product to 65-70 deg.C, adding 0.2wt% of active carbon, stirring for adsorption for 30min, and filtering with 0.45 μm filter element to remove carbon; the filtrate was subjected to ion exchange treatment with a mixed bed composed of 734 cation exchange resin and 701 anion exchange resin to obtain purified L-lactic acid.
5. The production process according to claim 1, wherein the pH of the L-lactic acid solution is 2.3 to 2.7.
6. The production process according to claim 1, wherein the L-lactic acid solution is sterilized by filtration: adding 0.3wt% of activated carbon into the L-lactic acid solution, stirring and adsorbing for 30min at room temperature, and sequentially filtering by a titanium rod filter element with 0.45 mu m for 1 time and a microporous filter element with 0.22 mu m for 2 times to obtain the filtered L-lactic acid solution.
7. The production process according to claim 1, wherein the combined packaging is that the amsacrine injection and the L-lactic acid injection are packaged in a one-to-one matching way according to the proportion of 75mg amsacrine to 42.93mg L-lactic acid.
8. An amsacrine product prepared by the process of any one of claims 1 to 7.
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| JP2009050178A (en) * | 2007-08-24 | 2009-03-12 | Toray Ind Inc | Method for producing chemicals by continuous fermentation |
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| JP2009050178A (en) * | 2007-08-24 | 2009-03-12 | Toray Ind Inc | Method for producing chemicals by continuous fermentation |
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| 杨瑞领: "二甲基乙酰胺合成反应精馏工艺研究" * |
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| CN115869286A (en) * | 2022-11-10 | 2023-03-31 | 海南卓泰制药有限公司 | Amsacrine-containing encapsulating composition and preparation method thereof |
| CN115869286B (en) * | 2022-11-10 | 2023-08-18 | 海南卓泰制药有限公司 | Encapsulation composition containing amsacrine and preparation method thereof |
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