CN114224831A - Citicoline sodium injection and preparation process thereof - Google Patents
Citicoline sodium injection and preparation process thereof Download PDFInfo
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- CN114224831A CN114224831A CN202111655346.1A CN202111655346A CN114224831A CN 114224831 A CN114224831 A CN 114224831A CN 202111655346 A CN202111655346 A CN 202111655346A CN 114224831 A CN114224831 A CN 114224831A
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- 229960004774 citicoline sodium Drugs 0.000 title claims abstract description 48
- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
- YWAFNFGRBBBSPD-OCMLZEEQSA-M sodium;[[(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 YWAFNFGRBBBSPD-OCMLZEEQSA-M 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 36
- 238000001914 filtration Methods 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000011780 sodium chloride Substances 0.000 claims abstract description 18
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000008215 water for injection Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000001514 detection method Methods 0.000 claims abstract description 7
- 239000000706 filtrate Substances 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000012528 membrane Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 12
- 238000007865 diluting Methods 0.000 claims description 8
- 230000001954 sterilising effect Effects 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000004695 Polyether sulfone Substances 0.000 claims description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 7
- 229920006393 polyether sulfone Polymers 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 238000009826 distribution Methods 0.000 claims description 4
- 238000007689 inspection Methods 0.000 claims description 4
- 238000004806 packaging method and process Methods 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- 238000007639 printing Methods 0.000 claims description 4
- 238000007792 addition Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 239000003610 charcoal Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940105082 medicinal charcoal Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 238000005070 sampling Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 238000004088 simulation Methods 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 4
- 229960002668 sodium chloride Drugs 0.000 abstract description 3
- 230000006866 deterioration Effects 0.000 abstract description 2
- 238000004140 cleaning Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000003708 ampul Substances 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000007789 sealing Methods 0.000 description 3
- 230000003727 cerebral blood flow Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 208000022540 Consciousness disease Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 210000002804 pyramidal tract Anatomy 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YIVJSMIYMAOVSJ-UHFFFAOYSA-M sodium;hydron;phosphonato phosphate Chemical compound [Na+].OP(O)(=O)OP(O)([O-])=O YIVJSMIYMAOVSJ-UHFFFAOYSA-M 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D36/00—Filter circuits or combinations of filters with other separating devices
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- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
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Abstract
The invention relates to citicoline sodium injection and a preparation process thereof, belonging to the technical field of injection preparation. The raw materials of the injection comprise citicoline sodium, sodium chloride, edetate disodium and water for injection, and the main procedures comprise: material preparation, thick preparation rough filtration, thin preparation fine filtration, detection and post treatment; the injection prepared by the invention has low impurity content and reduces the storage deterioration of the injection by two steps of concentrated preparation rough filtration and diluted preparation fine filtration matched with reasonable process parameter setting, and the injection prepared by the invention shows excellent stability in strong light accelerated simulation experiments at 40 +/-2 ℃ and 4000 lx.
Description
Technical Field
The invention belongs to the technical field of injection preparation, and particularly relates to a citicoline sodium injection and a preparation process thereof.
Background
Citicoline sodium, the chemical name of which is choline cytosine nucleoside diphosphate monosodium salt, is a nucleoside derivative, is a coenzyme necessary for lecithin synthesis, can reduce cerebrovascular resistance, increase cerebral blood flow, promote brain substance metabolism, improve brain circulation, enhance brain stem reticular structure function related to consciousness, play a role in stimulating pyramidal tract, promote recovery of damaged cells, enhance tension of cerebral vessels, enhance cerebral blood flow, enhance cell membrane function, improve brain metabolism, and are clinically used for treating consciousness disorder caused by acute craniocerebral trauma and brain surgery, intravenous injection is generally adopted, so citicoline sodium injection is usually prepared, and in the prior art, the most common dosage is 2 mL: 0.25g and 5 mL: the two specifications of 0.5g are most widely used in the past.
Chinese patent CN1395935 discloses citicoline sodium injection and a preparation method thereof, the injection is prepared by a one-step preparation method, and the prepared injection has low stability, contains more impurities which can not be detected by naked eyes and is easy to deteriorate in the storage process.
Disclosure of Invention
In order to solve the technical problems mentioned in the background art, the invention aims to provide a citicoline sodium injection and a preparation process thereof.
The purpose of the invention can be realized by the following technical scheme:
the citicoline sodium injection comprises the following raw materials: citicoline sodium, sodium chloride, edetate disodium and water for injection.
A preparation process of citicoline sodium injection comprises the following steps:
step S1, batching: according to the dosage ratio of citicoline sodium to water for injection of 0.25 g: 2mL of citicoline sodium and water for injection, wherein sodium chloride is taken according to 6.8% of the weight of citicoline sodium, and edetate disodium is taken according to 0.08% of the weight of citicoline sodium;
further, the medium-efficiency pressure difference of the negative pressure weighing cover in the material preparing process is kept at 50-60Pa, and the high-efficiency pressure difference is kept at 100-200 Pa.
Step S2, concentration and rough filtration: adding 50% of injection water into a concentration preparation tank, adding the full amount of sodium chloride and edetate disodium, stirring until the sodium chloride and the edetate disodium are completely dissolved, adding the full amount of citicoline sodium, stirring until the sodium citicoline sodium is completely dissolved, adding 1mol/L sodium hydroxide solution to adjust the pH value of a dissolved solution to 6.5-7.5, adding medicinal carbon, stirring and adsorbing for 15-30min, and finally performing reflux filtration by using a 0.45 mu m titanium rod until a filtrate is clear to obtain a crude preparation solution;
further, the addition amount of the medicinal charcoal is 0.02% of the total mass of the raw materials.
Step S3, diluted distribution and fine filtration: conveying the crude preparation liquid to a diluting preparation tank, adding injection water to full volume, stirring and mixing, and finely filtering the diluted liquid through a series filter membrane until the filtrate is clear to obtain a fine filtrate;
furthermore, the filter membranes are connected in series to form three layers of polyethersulfone filter membranes, and the pore diameters of the filter membranes are 0.45 mu m, 0.22 mu m and 0.22 mu m in sequence.
Furthermore, the bubble point pressure of the three polyether sulfone filter membranes is more than or equal to 0.3 MPa.
Furthermore, the fine filtration pressure is less than or equal to 0.2 MPa.
Step S4, detection: sampling the fine filtrate, and detecting that the pH value is 6.5-7.5 and the content of the main drug is 95.0% -105.0%, thus obtaining the qualified product;
step S5, post-processing: and (3) filling and sealing the qualified fine filtrate by using an ampoule bottle, then sterilizing in water bath at 100 ℃ for 30min, and finally sequentially performing lamp inspection, printing and packaging to obtain the citicoline sodium injection.
The invention has the beneficial effects that:
1. the injection prepared by the invention is low in impurity content and reduces the storage deterioration of the injection by two-step liquid preparation of concentrated coarse filtration and diluted fine filtration in combination with reasonable process parameter setting, and the injection prepared by the invention shows excellent stability in strong light accelerated simulation experiments at 40 +/-2 ℃ and 4000 lx.
2. The invention provides a set of mature preparation process through long-term experimental research, and is suitable for the mass production of citicoline sodium injection.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
In this embodiment, 98 ten thousand ml of citicoline sodium injection is prepared, and the specific implementation process is as follows:
step S1, batching: checking that the temperature of a negative pressure weighing chamber is 18-26 ℃, the humidity is 45-65%, the relative pressure difference is more than or equal to-5 Pa, opening a negative pressure weighing cover for 20 minutes in advance for self-cleaning, keeping the middle effect pressure difference at 50-60Pa and the high effect pressure difference at 100-200Pa, then weighing 122.5kg of citicoline sodium (meeting the standard of QC-STP-160-01), 8.33kg of sodium chloride (meeting the standard of QC-STP-223-01) and 98g of edetate disodium (meeting the standard of QC-STP-245-01), measuring 980L of water for injection (meeting the standard of QC-STP-215-01), and taking the above raw materials for later use;
step S2, concentration and rough filtration: checking all equipment containers, various pipelines, filters and liquid medicine pumps which are contacted with liquid medicine, cleaning the equipment containers, the various pipelines, the filters and the liquid medicine pumps, connecting a 0.45 mu m titanium rod filter within a cleaning period, then adding 50% of injection water into a concentration tank, adding the full amount of sodium chloride and the full amount of edetate disodium, starting a stirrer in the concentration tank, stirring until the sodium chloride and the edetate disodium are completely dissolved, keeping stirring, slowly adding the full amount of citicoline sodium until the sodium chloride and the edetate disodium are completely dissolved, then dropwise adding the prepared 1mol/L sodium hydroxide solution into the concentration tank until the pH value of a dissolved solution is 6.5, adding medicinal carbon accounting for 0.02% of the weight of each prepared raw material, adsorbing for 15min under a stirring state, then filtering the mixed solution through the 0.45 mu m titanium rod filter in a backflow mode for 10min, and clarifying the filtrate at the moment, wherein no visible impurities exist, so as to obtain a crude prepared solution;
step S3, diluted distribution and fine filtration: mounting a fine filter on a diluting preparation tank, wherein the fine filter comprises three layers of polyethersulfone filter membranes of 0.45 mu m, 0.22 mu m and 0.22 mu m in sequence, the bubble point pressure of the filter membranes is more than or equal to 0.3MPa, sterilizing the diluting preparation tank at 121 ℃ for 30 minutes, then conveying a crude preparation liquid into the diluting preparation tank, adding water for injection to full volume, stirring for 15min, then performing reflux filtration through the fine filter, and controlling the fine filter pressure to be less than or equal to 0.2MPa until the filtrate is clarified to obtain a fine filter liquid;
step S4, detection: taking about 300mL of the fine filtrate from a liquid outlet reflux pipeline of the fine filter, placing the fine filtrate in a conical flask with a plug, sending the sample to QC for intermediate test, and determining that the pH value is 6.5-7.5 and the content of the main drug is 95.0-105.0 percent, namely the sample is qualified;
step S5, post-processing: filling and sealing qualified fine filtrate by adopting a clean and dry ampoule bottle, controlling the filling amount difference to be 2.08-2.15mL, then loading the ampoule bottle into a vacuum sterilization cabinet, setting the vacuum pressure to be 50kPa, sterilizing for 30min by water bath at 100 ℃, and finally sequentially performing lamp inspection, printing and packaging to obtain the citicoline sodium injection.
Example 2
In this embodiment, a batch of 98 ten thousand ml citicoline sodium injection is prepared, and the specific implementation process is as follows:
step S1, batching: checking that the temperature of a negative pressure weighing chamber is 18-26 ℃, the humidity is 45-65%, the relative pressure difference is more than or equal to-5 Pa, opening a negative pressure weighing cover for 20 minutes in advance for self-cleaning, keeping the middle effect pressure difference at 50-60Pa and the high effect pressure difference at 100-200Pa, then weighing 122.5kg of citicoline sodium (meeting the standard of QC-STP-160-01), 8.33kg of sodium chloride (meeting the standard of QC-STP-223-01) and 98g of edetate disodium (meeting the standard of QC-STP-245-01), measuring 980L of water for injection (meeting the standard of QC-STP-215-01), and taking the above raw materials for later use;
step S2, concentration and rough filtration: checking all equipment containers, various pipelines, filters and liquid medicine pumps which are contacted with liquid medicine, cleaning the equipment containers, the various pipelines, the filters and the liquid medicine pumps, connecting a 0.45 mu m titanium rod filter within a cleaning period, then adding 50% of injection water into a concentration tank, adding the full amount of sodium chloride and the full amount of edetate disodium, starting a stirrer in the concentration tank, stirring until the sodium chloride and the edetate disodium are completely dissolved, keeping stirring, slowly adding the full amount of citicoline sodium until the sodium chloride and the edetate disodium are completely dissolved, then dropwise adding the prepared 1mol/L sodium hydroxide solution into the concentration tank until the pH value of a dissolved solution is 7.5, adding medicinal carbon accounting for 0.02% of the weight of each prepared raw material, adsorbing for 30min under the stirring state, then filtering the mixed solution through the 0.45 mu m titanium rod filter in a backflow mode for 10min, and clarifying the filtrate at the moment, wherein no visible impurities exist, so as to obtain a crude prepared solution;
step S3, diluted distribution and fine filtration: mounting a fine filter on a diluting preparation tank, wherein the fine filter comprises three layers of polyethersulfone filter membranes of 0.45 mu m, 0.22 mu m and 0.22 mu m in sequence, the bubble point pressure of the filter membranes is more than or equal to 0.3MPa, sterilizing the diluting preparation tank at 121 ℃ for 30 minutes, then conveying a crude preparation liquid into the diluting preparation tank, adding water for injection to full volume, stirring for 15min, then performing reflux filtration through the fine filter, and controlling the fine filter pressure to be less than or equal to 0.2MPa until the filtrate is clarified to obtain a fine filter liquid;
step S4, detection: taking about 300mL of the fine filtrate from a liquid outlet reflux pipeline of the fine filter, placing the fine filtrate in a conical flask with a plug, sending the sample to QC for intermediate test, and determining that the pH value is 6.5-7.5 and the content of the main drug is 95.0-105.0 percent, namely the sample is qualified;
step S5, post-processing: filling and sealing qualified fine filtrate by adopting a clean and dry ampoule bottle, controlling the filling amount difference to be 2.08-2.15mL, then loading the ampoule bottle into a vacuum sterilization cabinet, setting the vacuum pressure to be 50kPa, sterilizing for 30min by water bath at 100 ℃, and finally sequentially performing lamp inspection, printing and packaging to obtain the citicoline sodium injection.
Example 3
In this example, a batch of 98 ten thousand milliliters of citicoline sodium injection is prepared by repeating the example 2, and the specific formula and the process control are completely the same as those in the example 2.
Comparative example 1
In the comparative example, 98 ten thousand milliliters of citicoline sodium injection is prepared by adopting the existing one-step preparation method, the used raw materials and the control standard are the same as those in the example 2, and the specific implementation process is as follows:
the method comprises the following steps: adding the total amount of water for injection into a concentration tank, sequentially adding the total amount of sodium chloride, edetate disodium and citicoline sodium, stirring until the sodium chloride, the edetate disodium and the citicoline sodium are completely dissolved, adding 0.02% of medicinal carbon, stirring and adsorbing for 30min, and then dropwise adding 1mol/L sodium hydroxide solution to adjust the pH value of the mixed solution to 6.8-7.2 to obtain a stock solution;
step two: and (3) carrying out reflux filtration on the stock solution by adopting a 0.45-micron titanium rod filter until the mixed solution is clear, filtering the mixed solution by adopting a 0.2-micron polyethersulfone filter membrane until the mixed solution is clear, and finally carrying out treatment by adopting the post-treatment process the same as that of the example 2 to obtain the citicoline sodium injection.
The citicoline sodium injection prepared in examples 1-3 and comparative example 1 was subjected to property detection, and specific data are shown in table 1:
TABLE 1
| Traits | Visible foreign body | pH value | Content of principal drug | |
| Example 1 | Colorless clear liquid | Compliance with regulations | 6.95 | 99.8％ |
| Example 2 | Colorless clear liquid | Compliance with regulations | 7.08 | 100.2％ |
| Example 3 | Colorless clear liquid | Compliance with regulations | 7.05 | 100.3％ |
| Comparative example 1 | Colorless clear liquid | Compliance with regulations | 7.15 | 98.4％ |
Note: the quality standard is based on the standard of the 2020 edition of Chinese pharmacopoeia.
As can be seen from the data in Table 1, the citicoline sodium injections prepared in examples 1-3 and comparative example 1 all meet the specification, the pH values of the injections prepared in examples 1-3 are stable, and the content of the main drug is closer to the labeled amount.
Long-term storage simulation experiments were performed on the citicoline sodium injection prepared in examples 1-3 and comparative example 1, as follows:
placing a sample in a water-proof electric heating constant temperature incubator at 40 +/-2 ℃, irradiating for 6 months under 4000lx strong light, and detecting the shape of the injection, wherein the specific data are shown in table 2:
TABLE 2
As can be seen from the data in Table 2, the injection prepared by the invention has good stability in strong light accelerated simulation experiments at 40 +/-2 ℃ and 4000 lx.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is illustrative and explanatory only and is not intended to be exhaustive or to limit the invention to the precise embodiments described, and various modifications, additions, and substitutions may be made by those skilled in the art without departing from the scope of the invention or exceeding the scope of the claims.
Claims (8)
1. A preparation process of citicoline sodium injection is characterized by comprising the following steps:
step S1, batching: the weight ratio of 0.25 g: 2mL of citicoline sodium and water for injection, wherein sodium chloride is taken according to 6.8% of the weight of citicoline sodium, and edetate disodium is taken according to 0.08% of the weight of citicoline sodium;
step S2, concentration and rough filtration: taking 50% of injection water, adding the total amount of sodium chloride and disodium edetate, stirring until the sodium chloride and the disodium edetate are completely dissolved, adding the total amount of citicoline sodium, stirring until the sodium citicoline sodium is completely dissolved, then adding a sodium hydroxide solution to adjust the pH value of a dissolved solution to be 6.5-7.5, adding medicinal carbon, stirring and adsorbing for 15-30min, and finally performing reflux filtration by using a 0.45-micrometer titanium rod until a filtrate is clear to obtain a crude preparation solution;
step S3, diluted distribution and fine filtration: conveying the crude preparation liquid to a diluting preparation tank, adding injection water to full volume, stirring and mixing, and finely filtering the diluted liquid through a series filter membrane until the filtrate is clear to obtain a fine filtrate;
step S4, detection: sampling the fine filtrate, and detecting that the pH value is 6.5-7.5 and the content of the main drug is 95.0% -105.0%, thus obtaining the qualified product;
step S5, post-processing: and (3) encapsulating the fine filtrate which is qualified by detection, sterilizing the fine filtrate in water bath at 100 ℃ for 30min, and finally sequentially performing lamp inspection, printing and packaging to obtain the citicoline sodium injection.
2. The preparation process of citicoline sodium injection as claimed in claim 1, wherein the intermediate pressure difference of the negative pressure weighing cover is maintained at 50-60Pa, and the high-efficiency pressure difference is maintained at 100-200 Pa.
3. The preparation process of the citicoline sodium injection as claimed in claim 1, wherein the addition amount of the medicinal charcoal is 0.02% of the total mass of the raw materials.
4. The process for preparing citicoline sodium injection as claimed in claim 1, wherein the concentration of sodium hydroxide solution is 1 mol/L.
5. The process according to claim 1, wherein the filter membranes are connected in series to form three polyethersulfone filter membranes, and the diameters of the filter membranes are 0.45 μm, 0.22 μm, and 0.22 μm.
6. The preparation process of the citicoline sodium injection as claimed in claim 5, wherein the bubble point pressure of the three layers of polyethersulfone filter membranes is not less than 0.3 MPa.
7. The process of claim 6, wherein the pressure of fine filtration is less than or equal to 0.2 MPa.
8. Citicoline sodium injection, which is prepared by the formulation process according to any one of claims 1 to 7.
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| 医学教育网: "《药学考点速记蓝宝书》", 31 May 2020, 云南科技出版社，第1版 * |
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