CN103284961A - Preparing method of cobamamide freeze-drying formulation for injection - Google Patents
Preparing method of cobamamide freeze-drying formulation for injection Download PDFInfo
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- CN103284961A CN103284961A CN2013102452780A CN201310245278A CN103284961A CN 103284961 A CN103284961 A CN 103284961A CN 2013102452780 A CN2013102452780 A CN 2013102452780A CN 201310245278 A CN201310245278 A CN 201310245278A CN 103284961 A CN103284961 A CN 103284961A
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- 239000011789 cobamamide Substances 0.000 title claims abstract description 32
- ZIHHMGTYZOSFRC-UWWAPWIJSA-M cobamamide Chemical compound C1(/[C@](C)(CCC(=O)NC[C@H](C)OP(O)(=O)OC2[C@H]([C@H](O[C@@H]2CO)N2C3=CC(C)=C(C)C=C3N=C2)O)[C@@H](CC(N)=O)[C@]2(N1[Co+]C[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C3=NC=NC(N)=C3N=C1)O)[H])=C(C)\C([C@H](C/1(C)C)CCC(N)=O)=N\C\1=C/C([C@H]([C@@]\1(CC(N)=O)C)CCC(N)=O)=N/C/1=C(C)\C1=N[C@]2(C)[C@@](C)(CC(N)=O)[C@@H]1CCC(N)=O ZIHHMGTYZOSFRC-UWWAPWIJSA-M 0.000 title claims abstract description 32
- 235000006279 cobamamide Nutrition 0.000 title claims abstract description 32
- 229960005452 cobamamide Drugs 0.000 title claims abstract description 31
- 238000004108 freeze drying Methods 0.000 title claims abstract description 12
- 238000002347 injection Methods 0.000 title claims abstract description 11
- 239000007924 injection Substances 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000009472 formulation Methods 0.000 title claims abstract description 9
- 239000000203 mixture Substances 0.000 title claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 14
- 239000008215 water for injection Substances 0.000 claims abstract description 14
- 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 claims abstract description 12
- 229930195725 Mannitol Natural products 0.000 claims abstract description 12
- 239000000594 mannitol Substances 0.000 claims abstract description 12
- 235000010355 mannitol Nutrition 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012528 membrane Substances 0.000 claims abstract description 5
- 238000005303 weighing Methods 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 13
- 238000000859 sublimation Methods 0.000 claims description 9
- 230000008022 sublimation Effects 0.000 claims description 9
- 238000003556 assay Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000011068 loading method Methods 0.000 claims description 8
- 238000012856 packing Methods 0.000 claims description 5
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003610 charcoal Substances 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000005057 refrigeration Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 abstract description 8
- 239000011261 inert gas Substances 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract 2
- 238000005261 decarburization Methods 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 238000004806 packaging method and process Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 4
- 206010029240 Neuritis Diseases 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- -1 cobalt amine Chemical class 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LJUQGASMPRMWIW-UHFFFAOYSA-N 5,6-dimethylbenzimidazole Chemical compound C1=C(C)C(C)=CC2=C1NC=N2 LJUQGASMPRMWIW-UHFFFAOYSA-N 0.000 description 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 206010037779 Radiculopathy Diseases 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 206010030875 ophthalmoplegia Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000019629 polyneuritis Diseases 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 206010061928 radiculitis Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000017443 reproductive system disease Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to a cobamamide freeze-drying formulation for injection and a preparing method thereof. According to a specific amount, the amount ratio of adenosylcobalamin, mannitol and water for injection is 0.52 g: 25 g: 500 ml. The preparing method comprises: operating in a dark environment, weighing mannitol according to a prescribed amount, adding the water for injection in an amount of about 90%, then stirring to achieve complete dissolution, adding cobamamide, and stirring to achieve complete dissolution; adding the water for injection to the full amount, stirring evenly, adding activated carbon in a preparation amount of 0.02% (W/V), and fully stirring; performing coarsely filtered decarburization of the obtained solution, then performing refined filtration with a 0.22 [mu]m microporous filtering membrane, determining the content, and calculating a package amount; sub-packaging; and performing freeze drying to obtain the final product. The method is simple in operation, has no need of any additional stabilizers and inert gas for protection, and has high product stability.
Description
Technical field:
The present invention relates to the preparation method of pharmaceutical preparation, specifically a kind of injection cobamamide lyophilized formulations with and preparation method thereof.
Background technology:
Cobamamide claims Cobamamide again, and chemistry 5,6-dimethylbenzimidazole base by name-5-deoxyadenosine base cobalt amine is one of active coenzyme form of vitamin B12.The cobamamide initial stage is mainly used in treating pernicious anemia, also share with folic acid, is used for the treatment of anemia that various megaloblastic anemias, antifolic cause etc., and it also is used for nervous system disease.Its range of application is constantly expanded in recent ten years, now also is usually used in treating diseases such as radiculitis, polyneuritis, peripheral neuritis, ophthalmoplegia.Its application in fields such as hepatopathy, cancer, chronic atrophic gastritis, reproductive system diseases has also had new progress.The cobamamide dosage form comprises cobamamide tablet and injection cobamamide lyophilized injectable powder.Since cobamamide crude drug poor chemical stability, especially to photaesthesia, thereby, when preparation injection cobamamide lyophilized injectable powder, to add multiple stabilizing agents such as antibacterial, chelating agent usually, and in the lucifuge environment, prepare at present.But because operator can not carry out work under the environment of complete lucifuge, and the bad control of lucifuge condition, so sometimes also need to feed inert gas shielding and add stabilizing agent.Even but under the situation that adds stabilizing agent, the stability of product is still not ideal enough.Moreover stabilizing agent can be brought potential hazard to health.Therefore, clinical needing badly obtains a kind of preparation simply, do not contain stabilizing agent, and the more stable cobamamide lyophilized injectable powder of product quality.
Summary of the invention:
Purpose of the present invention is exactly that a kind of new method for preparing injection cobamamide lyophilized formulations will be provided, in the hope of providing a kind of and not containing stabilizing agent for clinical, and the more stable cobamamide lyophilized injectable powder of product quality.Applicant of the present invention gropes by the screening of a large amount of reagent and a large amount of experiment, has finally determined to have proportioning and the preparation method of the cobamamide lyophilized formulations of optimum stability.
The object of the present invention is achieved like this:
The preparation method of injection cobamamide lyophilized formulations provided by the present invention may further comprise the steps:
1, drug component
Cobamamide, mannitol, water for injection, its amount ratio is: 0.52g:25g:500ml.By every batch of 1000 calculating, its consumption part is such as following table:
Prescription is formed
| Specification | 0.5mg | 1.0mg | 1.5mg |
| Cobamamide * | 0.52g | 1.04g | 1.56g |
| Mannitol | 25g | 50g | 75g |
| Water for injection | 500ml | 1000ml | 1500ml |
| The packing volume | 0.5ml | 1.0ml | 1.5ml |
*: the cobamamide consumption needs conversion moisture and content for pressing the theoretical value that dry product calculates in feeding intake.
2, solution preparation
Operate under the lucifuge environment, take by weighing mannitol by recipe quantity, add the water for injection of recipe quantity about 90%, stirring makes molten entirely, adds cobamamide, and stirring makes molten entirely; Add to the full amount of water for injection, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir.Solution after coarse filtration is taken off charcoal, reuse 0.22um microporous filter membrane fine straining; Regulate pH value 5.5-7.0.
3, assay, pH value, visible foreign matters, calculating loading amount
4, aseptic filtration, fill
Filter with 0.22um and to draw aseptic filtration liquid, filtrate advances through pipeline behind the diverter of filling machine to the fill syringe needle, gets medicinal liquid 20 times.With aseptic filtration liquid debugging loading amount;
Carry out packing according to the assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg(theoretical volume should be respectively 0.5ml, 1.0ml, 1.5ml) embedding is to the brown cillin bottle of 2ml.
5, lyophilization
(1) pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to about-40 ℃, kept 5 hours;
(2) sublimation drying: open vacuum pump, sublimation drying;
A. phase I: it is 5 ℃/hour that the flaggy heating rate is set, and is warming up to-20 ℃, keeps this temperature and rises fully to solid ice and eliminate;
B. second stage: it is 5 ℃/hour that the flaggy heating rate is set, and sample temperature is risen to 25 ℃, keeps 25 ℃ and reaches requirement to sample moisture, checks drying baker vacuum, does not become to having obviously.
6, compress plug in the case, put into pure air and make and reach normal pressure, take out product
Chemical stabilizers such as bacteriostatic agent, chelating agent, opacifier not in the inventive method, but ratio and the rational technology controlling and process of cobamamide and mannitol and water by the best, the adjuvant amount that makes this product use is less, to the less i.e. stability of the influence of principal agent better; Preparation simultaneously is simple, does not need to feed inert gas shielding in the whole process.The main component of lyophilizing liquid is that mannitol is easy to lyophilizing, adopt the method for gradient sublimation drying during lyophilization, assurance can distil and unlikelyly make too fast distillation and make proppant distortion, can be good at controlling the moisture in the final products, has therefore further improved the stability of product again.
The specific embodiment:
The first step: solution preparation
Take by weighing mannitol 50g by recipe quantity, add the water for injection of the about 900ml of recipe quantity, stirring makes molten entirely, adds cobamamide 1.02g, and stirring makes molten entirely; Add the injection water to 1000ml, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir.Solution is after coarse filtration is taken off charcoal, and reuse 0.22um microporous filter membrane fine straining is regulated pH value 5.5-7.0.
Second step: assay, pH value, visible foreign matters, calculating loading amount
The lucifuge operation.Get cobamamide reference substance 25mg, accurate claim surely, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, precision is measured 2ml, puts in the 10ml measuring bottle, and thin up shakes up to scale, in contrast product solution; Get 10 of this product, be dissolved in water and move in the 250ml measuring bottle, water gradation washing container, washing liquid is incorporated in the measuring bottle, and is diluted to scale, shakes up, as need testing solution.Get each 10 μ l of reference substance solution and need testing solution respectively, inject chromatograph of liquid, the record chromatogram is pressed external standard method with calculated by peak area content.
The 3rd step: aseptic filtration, fill
Filter with 0.22um and to draw aseptic filtration liquid, filtrate advances through pipeline behind the diverter of filling machine to the fill syringe needle, gets medicinal liquid 20 times.With aseptic filtration liquid debugging loading amount;
Carry out packing according to the assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg(theoretical volume should be respectively 0.5ml, 1.0ml, 1.5ml) embedding is to the brown cillin bottle of 2ml.
The 4th step: lyophilization
(1) pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to about-40 ℃, kept 5 hours;
(2) sublimation drying: open vacuum pump, sublimation drying;
A. phase I: it is 5 ℃/hour that the flaggy heating rate is set, and is warming up to-20 ℃, keeps this temperature and rises fully to solid ice and eliminate;
B. second stage: it is 5 ℃/hour that the flaggy heating rate is set, and sample temperature is risen to 25 ℃, keeps 25 ℃ and reaches requirement to sample moisture, checks drying baker vacuum, to there not being significant change.
The 5th step: compress plug in the case, put into pure air and make and reach normal pressure, take out product.
The 6th step: examine entirely by standard.
The 7th step: label dress box, vanning, warehouse-in after qualified.
It should be noted that at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although with reference to preferred embodiment the present invention is had been described in detail, those of ordinary skill in the art is to be understood that, can make amendment or be equal to replacement technical scheme of the present invention, and not breaking away from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of the claim scope of the present invention.
Claims (2)
1. injection cobamamide lyophilized formulations is characterized in that: cobamamide, mannitol, water for injection, and its amount ratio is: 0.52g:25g:500ml; And adopt following method to prepare:
(1) solution preparation;
Operate under the lucifuge environment, take by weighing mannitol by recipe quantity, add the water for injection of recipe quantity about 90%, stirring makes molten entirely, adds cobamamide, and stirring makes molten entirely; Add to the full amount of water for injection, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir, solution after coarse filtration is taken off charcoal, reuse 0.22um microporous filter membrane fine straining; Regulate pH value 5.5-7.0;
(2) assay, pH value, visible foreign matters, calculating loading amount;
(3) aseptic filtration, fill;
Filter with 0.22um and to draw aseptic filtration liquid, filtrate advances through pipeline behind the diverter of filling machine to the fill syringe needle, gets medicinal liquid 20 times, with aseptic filtration liquid debugging loading amount;
Carry out packing according to the assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg embedding is to the brown cillin bottle of 2ml;
(4) lyophilization;
1. pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to about-40 ℃, kept 5 hours;
2. sublimation drying: open vacuum pump, sublimation drying;
A. phase I: it is 5 ℃/hour that the flaggy heating rate is set, and is warming up to-20 ℃, keeps this temperature and rises fully to solid ice and eliminate;
B. second stage: it is 5 ℃/hour that the flaggy heating rate is set, and sample temperature is risen to 25 ℃, keeps 25 ℃ and reaches requirement to sample moisture, checks drying baker vacuum, to there not being significant change;
(5) compress plug in the case, put into pure air and make and reach normal pressure, take out product.
2. method for preparing injection cobamamide lyophilized formulations, its feature is as follows:
(1) drug component: cobamamide, mannitol, water for injection, its amount ratio is: 0.52g:25g:500ml;
(2) solution preparation;
Operate under the lucifuge environment, take by weighing mannitol by recipe quantity, add the water for injection of recipe quantity about 90%, stirring makes molten entirely, adds cobamamide, and stirring makes molten entirely; Add to the full amount of water for injection, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir, solution after coarse filtration is taken off charcoal, reuse 0.22um microporous filter membrane fine straining; Regulate pH value 5.5-7.0;
(3) assay, pH value, visible foreign matters, calculating loading amount;
(4) aseptic filtration, fill;
Filter with 0.22um and to draw aseptic filtration liquid, filtrate advances through pipeline behind the diverter of filling machine to the fill syringe needle, gets medicinal liquid 20 times, with aseptic filtration liquid debugging loading amount;
Carry out packing according to the assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg embedding is to the brown cillin bottle of 2ml;
(5) lyophilization;
1. pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to about-40 ℃, kept 5 hours;
2. sublimation drying: open vacuum pump, sublimation drying;
A. phase I: it is 5 ℃/hour that the flaggy heating rate is set, and is warming up to-20 ℃, keeps this temperature and rises fully to solid ice and eliminate;
B. second stage: it is 5 ℃/hour that the flaggy heating rate is set, and sample temperature is risen to 25 ℃, keeps 25 ℃ and reaches requirement to sample moisture, checks drying baker vacuum, to there not being significant change;
(6) compress plug in the case, put into pure air and make and reach normal pressure, take out product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267161A (en) * | 2015-11-24 | 2016-01-27 | 河北智同生物制药有限公司 | Cobamamide freeze-drying preparation composition for injection and preparing method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101785780A (en) * | 2010-04-07 | 2010-07-28 | 海南资福医药有限公司 | Preparation of cyanocobalamine and adenosine composition and preparation method thereof |
| CN102379851A (en) * | 2010-09-03 | 2012-03-21 | 华北制药股份有限公司 | Preparation method of cobamamide lyophilized preparation for injection |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101785780A (en) * | 2010-04-07 | 2010-07-28 | 海南资福医药有限公司 | Preparation of cyanocobalamine and adenosine composition and preparation method thereof |
| CN102379851A (en) * | 2010-09-03 | 2012-03-21 | 华北制药股份有限公司 | Preparation method of cobamamide lyophilized preparation for injection |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267161A (en) * | 2015-11-24 | 2016-01-27 | 河北智同生物制药有限公司 | Cobamamide freeze-drying preparation composition for injection and preparing method thereof |
| CN105267161B (en) * | 2015-11-24 | 2019-05-14 | 河北智同生物制药股份有限公司 | A kind of cobamamide lyophilized preparation for injection composition and preparation method thereof |
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| CN103284961B (en) | 2014-06-18 |
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