CN102462659B - Citicoline sodium injection and preparation method thereof - Google Patents
Citicoline sodium injection and preparation method thereof Download PDFInfo
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- CN102462659B CN102462659B CN 201010546637 CN201010546637A CN102462659B CN 102462659 B CN102462659 B CN 102462659B CN 201010546637 CN201010546637 CN 201010546637 CN 201010546637 A CN201010546637 A CN 201010546637A CN 102462659 B CN102462659 B CN 102462659B
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Abstract
The invention discloses a citieoline sodium injection with good quality and low cost, and provides a method for preparing the injection simultaneously. The citieoline sodium injection provided by the invention is prepared from 1,000-5,000g of citieoline sodium, 5g of versene disodium and 20,000ml of water for injection, and is 2-5ml per tube. The preparation method comprises the following steps of: weighing each component; heating the water for injection to 28-30 DEG C, adding 0.02-0.05 percent of injection active carbon, adsorbing for 20-30 minutes, and filtering; and heating a feed liquid to 60-65 DEG C, preserving heat for 8-10 minutes, adding 0.02 percent of injection active carbon, stirring, dissolving, decarburizing, filtering, lowering temperature of the feed liquid to be below 40 DEG C, and performing split charging. Due to the adoption of the method, the pollution levels and endotoxin levels of relevant substances of a product and microorganisms are effectively controlled, and the stability and light inspection yield of the product are increased.
Description
Technical field
The present invention relates to pharmaceutical product and preparation method thereof, specifically a kind of Citicoline sodium injection and preparation technology thereof.
Background technology
The Citicoline sodium injection main component is C14H25N4NaO11P2, and chemical name is single sodium salt of choline cytidine diphosphate ester.C14H25N4NaO11P2 is nucleoside derivates, because it can reduce cerebral vascular resistance, increases cerebral blood flow and promotes metabolism of brain, improves cerebral circulation, is used for the treatment of clinically the disturbance of consciousness that causes after the operation of Acute Brain Injury and brain.C14H25N4NaO11P2 is the derivant of karyon thuja acid, it is necessary coenzyme during lecithin synthesizes, have and strengthen the reticular formation of brain stem function relevant with consciousness, tractus pyramidalis is played excited effect, impel damaged cell to recover, can also strengthen cerebrovascular tension force, and strengthen cerebral blood flow, strengthen the function of cell membrane, improve the brain metabolism.Be mainly used in clinically function and disturbance of consciousness that central nervous system's acute injury causes.Nerve injury, disturbance of consciousness to causing behind Acute Stroke, the surgical operation have obvious therapeutical effect to parkinsonism, dementia, glaucoma etc.
Citicoline sodium injection has the several formulations such as intravenous fluid, lyophilized injectable powder at present.The stability of China's biochemical drug magazine the 23rd volume the 4th interim " study on the stability of injection C14H25N4NaO11P2 and Citicoline sodium injection " research in 2002 report citicoline sodium freeze-dried powder injection is better than Citicoline sodium injection.But the applicant's actual investigation result is opposite with it.Also may be because the C14H25N4NaO11P2 water absorption is strong, make lyophilized preparation after its moisture can not guarantee, thereby cause that it is oxidized, rotten.CN02135377.8 discloses a kind of citicoline sodium injection for intravenous injection and preparation method thereof, mentions the intravenous fluid convenient drug administration in this patent application specification, excellent and small-volume injection.But the injection products quality of the method preparation is unstable, and its loading amount is large, and visible foreign matters is easily introduced in the bad control of production process in the medicinal liquid, and the undetected probability of lamp inspection is large.After undetected microgranule injected human body, larger can stop up blood capillary, will cause encirclement and the propagation of organizing thromboembolism and macrophage if invade the positions such as brain, eye, formed the harm such as granuloma.In addition, because loading amount is large, the filling time is long, and medicinal liquid open-assembly time in air is long, and aseptic bad control needs high temperature sterilize.But but some bacterium colonies such as actinomycetes need to be in the just deactivations in 15-20 minute of going out more than 140 ℃, and traditional sterilization process has certain risk concerning the production of infusion solutions.And high temperature can cause the related substance of product to increase, and particulate matter increases, thereby increases the untoward reaction of Citicoline sodium injection.Consider from production cost, the bottle utilization rate of infusion solutions, the rate of qualifiid of the lamp inspection all will be well below small-volume injections.China's biochemical medical magazine the 6th phase of the 25th volume in 2004 is mentioned in " improvement of preparation of citicoline sodium injection ": second adsorption technique is controlled the thermal source of Citicoline sodium injection, the preparing process that boils during dosing, and it is all qualified to make study on the stability outward appearance, content, pH value, clarity.But in fact the boiling water batching causes the unstable of product, and increases related substance; Set up on the second adsorption technology theory, inadvisable from actual fabrication because the prescription in without any adjuvant, 0.1% active carbon second adsorption can make medicinal liquid content lower 6-10%, if for making content up to standard, must strengthen dosage, therefore increased production cost.
Summary of the invention
The object of the present invention is to provide the Citicoline sodium injection that a kind of quality is good, cost is low, a kind of method for preparing this injection is provided simultaneously.
The object of the present invention is achieved like this:
Citicoline sodium injection provided by the invention is made by following prescription: C14H25N4NaO11P2 1000～5000g, disodium edetate (being called for short following EDTA-2Na) 5g water for injection 20000ml, every 2～5ml.
Concrete description is 0.1g/2ml, 0.25g/2ml, 0.5g/2ml.
The preparation method of Citicoline sodium injection provided by the invention may further comprise the steps:
A, take by weighing each component according to following prescription:
C14H25N4NaO11P2 2500g, EDTA-2Na 5g water for injection 20000ml;
B, under ten thousand grades of environment, prepare, at first water for injection is heated to 28～30 ℃, add 0.02～0.05% injection-use activated carbon, adsorb after 20～30 minutes, filter, then adding C14H25N4NaO11P2, stir, dissolve, is 5～10% sodium sulfite solution adjust pH 6.0-8.0 with mass volume ratio concentration;
C, the feed liquid for preparing is heated to 60-65 ℃; be incubated 8～10 minutes; and then add 0.02% injection-use activated carbon and EDTA-2Na; after stirring, dissolving, the decarburization; use the 0.2um double filter to filter; after feed temperature is down to below 40 ℃, under hundred grades of environment, is distributed into 2ml/ and props up, minute process of assembling nitrogen protection.
Said in the said method is that the preferable range of 5～10% sodium sulfite solution adjust pH is 6.5-7.5 with mass volume ratio concentration.
Innovation of the present invention and beneficial effect show:
(1) preparation is carried out water temperature control with water for injection, and before feeding intake, use first activated carbon adsorption, thereby
The related substance of product and level of pollution and the level of endotoxin of microorganism have effectively been controlled.
(2) feed liquid for preparing is heated to 60-65 ℃, the insulation regular hour, and then use activated carbon adsorption, add simultaneously antibacterial EDTA-2Na, after decarburization, the ultrafiltration, use the 0.2um double filter to filter, reduce as far as possible the micro organism quantity in the feed liquid, guarantee that product is aseptic.
(3) packing under hundred grades of environment after feed temperature is down to below 40 ℃, the stability of product has been controlled in minute process of assembling nitrogen protection effectively, has improved the rate of qualifiid of the lamp inspection.
The specific embodiment
Embodiment 1
A, take by weighing C14H25N4NaO11P2 2.5Kg, EDTA-2Na5g, water for injection 20000ml;
B, under ten thousand grades of environment, prepare, at first water for injection is heated to 30 ℃, add 0.05% injection active carbon, adsorb after 20 minutes, filter, then add C14H25N4NaO11P2, stirring, dissolve, is 10% sodium sulfite solution adjust pH 6.5 with mass volume ratio concentration;
C, the feed liquid that the b step is prepared are heated to 65 ℃; be incubated 10 minutes; and then add 0.05% injection active carbon (according to material liquid volume and quality of activated carbon than meter) and EDTA-2Na; after stirring, dissolving, the decarburization; use the 0.2um double filter to filter, after feed temperature is down to below 40 ℃, under hundred grades of environment, is distributed into 2ml/ and props up; filling and sealing (nitrogen protection), leak detection, lamp inspection, packing obtain the Citicoline sodium injection that specification is 2ml: 0.25g.
Embodiment 2:
A, take by weighing C14H25N4NaO11P2 5Kg, EDTA-2Na5g, water for injection 20000ml;
B, under ten thousand grades of environment, prepare, at first water for injection is heated to 28 ℃, add 0.02% injection active carbon, adsorb after 30 minutes, filter, then add C14H25N4NaO11P2, stirring, dissolve, is 5% sodium sulfite solution adjust pH 7.0 with mass volume ratio concentration;
C, the feed liquid that the b step is prepared are heated to 60 ℃; be incubated 8 minutes; and then add 0.02% injection active carbon (according to material liquid volume and quality of activated carbon than meter) and EDTA-2Na; after stirring, dissolving, the decarburization; use the 0.2um double filter to filter, after feed temperature is down to below 40 ℃, under hundred grades of environment, is distributed into 2ml/ and props up; filling and sealing (nitrogen protection), leak detection, lamp inspection, packing obtain the Citicoline sodium injection that specification is 2ml: 0.5g.
Embodiment 3:
A, take by weighing C14H25N4NaO11P2 0.1Kg, EDTA-2Na 5g, water for injection 20000ml;
B, under ten thousand grades of environment, prepare, at first water for injection is heated to 30 ℃, add 0.04% injection active carbon, adsorb after 25 minutes, filter, then add C14H25N4NaO11P2, stirring, dissolve, is 8% sodium sulfite solution adjust pH 7.5 with mass volume ratio concentration;
C, the feed liquid that the b step is prepared are heated to 60 ℃; be incubated 10 minutes; and then add 0.05% injection active carbon (according to material liquid volume and quality of activated carbon than meter) and EDTA-2Na; after stirring, dissolving, the decarburization; use the 0.2um double filter to filter, after feed temperature is down to below 40 ℃, under hundred grades of environment, is distributed into 2ml/ and props up; filling and sealing (nitrogen protection), leak detection, lamp inspection, packing obtain the Citicoline sodium injection that specification is 2ml: 100mg.
Comparison example 1 (according to the prior art preparation)
Take by weighing C14H25N4NaO11P2 1.0kg, sodium chloride 0.45kg adds the suitable quantity of water dissolving, add again the suitable quantity of water dilution, add 0.05% active carbon, stir evenly, static 15 minutes, decarburization is filtered, and adds 5 times of amount waters for injection again and is diluted to 50～500kg, and surveying pH is 7.0, filter with the titanium rod, through 0.22 μ m microporous filter membrane fine straining, by every bottle of 500ml fill, roll lid, sealing, sterilization again.
Embodiment 4:
The Citicoline sodium injection of the present invention's preparation compares with the Citicoline sodium injection product quality effect for preparing according to prior art.The results are shown in Table 1
Table 1
| Content | PH | The rate of qualifiid of the lamp inspection | Product microbiological contamination rate | |
| Embodiment 1 | Up to specification | Up to specification | 98.9％ | 0 |
| Embodiment 2 | Up to specification | Up to specification | 98.5％ | 0 |
| Embodiment 3 | Up to specification | Up to specification | 98.9％ | 0 |
| Comparison example | Up to specification | Up to specification | 94.3％ | 6.5％ |
Annotate: quality standard is according to Chinese Pharmacopoeia version standard in 2005.
Embodiment 5 study on the stability:
Preparing the Citicoline sodium injection specification according to the preparation method of embodiment 1 is: 2ml: 0.25g, under the condition of 40 ± 2 ℃ of temperature, humidity 75% ± 5%, placed 6 months, take a sample respectively 1 time 1st month, the 2nd month, the 3rd month, the 6th the end of month at duration of test, press the study on the stability project and detect, the results are shown in Table 2:
Table 2 accelerated test testing result
Annotate: quality standard is according to Chinese Pharmacopoeia version standard in 2005.
Show from above result: the Citicoline sodium injection that the present invention makes is stable at 3 years effect phase intensive amounts, not too large variation, and the related substance rate of climb is slower, and it is all qualified that other indices detect, and illustrates that the product stability that this preparation method makes is high.
Claims (2)
1. the preparation method of a Citicoline sodium injection is characterized in that it may further comprise the steps:
A, take by weighing each component according to following prescription:
C14H25N4NaO11P2 2500g, disodium edetate 5g water for injection 20000ml;
B, under ten thousand grades of environment, prepare, at first water for injection is heated to 28～30 ℃, add 0.02～0.05% injection-use activated carbon, adsorb after 20～30 minutes, filter, then adding C14H25N4NaO11P2, stir, dissolve, is 5～10% sodium sulfite solution adjust pH 6.0-8.0 with mass volume ratio concentration;
C, the feed liquid for preparing is heated to 60-65 ℃; be incubated 8～10 minutes; and then add 0.02% injection-use activated carbon and disodium edetate; after stirring, dissolving, take off charcoal; use 0.2 μ m double filter to filter; after feed temperature is down to below 40 ℃, packing under hundred grades of environment, minute process of assembling nitrogen protection.
2. the preparation method of Citicoline sodium injection according to claim 1 is characterized in that said is 5～10% sodium sulfite solution adjust pH 6.5-7.5 with mass volume ratio concentration.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103006550A (en) * | 2012-12-11 | 2013-04-03 | 哈药集团三精制药股份有限公司 | Citicoline sodium injection and preparation method thereof |
| CN104490771A (en) * | 2014-12-19 | 2015-04-08 | 成都天台山制药有限公司 | Citicoline Sodium injection pharmaceutical composition and preparation method thereof |
| CN104523739A (en) * | 2014-12-30 | 2015-04-22 | 山东新时代药业有限公司 | Citicoline sodium lyophilized preparation for injection and preparation method of cticoline sodium lyophilized preparation |
| CN110934825A (en) * | 2019-12-31 | 2020-03-31 | 江西润泽药业有限公司 | Citicoline injection and preparation method thereof |
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| CN1559613A (en) * | 2004-03-10 | 2005-01-05 | 杨喜鸿 | Medicinal invert sugar injection |
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| CN1663569A (en) * | 2004-03-06 | 2005-09-07 | 杨喜鸿 | Fructose injection for cardiovascular medicine |
| CN1559613A (en) * | 2004-03-10 | 2005-01-05 | 杨喜鸿 | Medicinal invert sugar injection |
| CN101829134A (en) * | 2009-03-09 | 2010-09-15 | 北京利乐生制药科技有限公司 | New clinical application of medical composition |
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