CN104490771A - Citicoline Sodium injection pharmaceutical composition and preparation method thereof - Google Patents
Citicoline Sodium injection pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a citicoline sodium injection pharmaceutical composition and a preparation method thereof. Particularly, the invention belongs to the technical field of medicines, relates to a pharmaceutical composition for treating consciousness disturbance caused by acute craniocerebral trauma and brain surgery and particularly relates to an injection pharmaceutical composition for treating consciousness disturbance caused by acute craniocerebral trauma and brain surgery. More particularly, the invention relates to the citicoline sodium injection pharmaceutical composition and a preparation method of citicoline sodium injection. The citicoline sodium injection comprises citicoline sodium and injection water, wherein the injection water serves as a solvent, and the concentration of citicoline sodium is 0.01g/ml-1g/ml. The citicoline sodium injection has excellent pharmaceutical properties explained in the specification.
Description
Technical field
The invention belongs to medical art, relate to a kind of pharmaceutical composition being used for the treatment of the disturbance of consciousness that Acute Brain Injury and brain Post operation cause, particularly relate to a kind of injection pharmaceutical composition being used for the treatment of the disturbance of consciousness that Acute Brain Injury and brain Post operation cause, more especially relate to a kind of Citicoline sodium injection pharmaceutical composition, the invention still further relates to the preparation method of this injection.
Background technology
Single sodium salt that C14H25N4NaO11P2 (Citicoline Sodium) is choline cytidine diphosphate ester, its molecular formula is C14H25N4NaO11P2, and molecular weight is 510.31, and chemical structural formula is as follows:
C14H25N4NaO11P2 is white crystals or crystalline powder; Odorless.C14H25N4NaO11P2 is easily molten in water, insoluble in ethanol, acetone, chloroform.
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 promote metabolism of brain, improves cerebral circulation, is used for the treatment of the disturbance of consciousness that Acute Brain Injury and brain Post operation cause clinically.C14H25N4NaO11P2 is the derivant of karyon thuja acid, it is coenzyme necessary in lecithin synthesis, have and strengthen the reticular formation of brain stem function relevant with consciousness, excitation is risen to tractus pyramidalis, impel damaged cell to recover, cerebrovascular tension force can also be strengthened, and strengthen cerebral blood flow, strengthen the function of cell membrane, improve brain metabolism.Be mainly used in function that central nervous system's acute injury causes and disturbance of consciousness clinically.The nerve injury caused Acute Stroke, surgical site infections, disturbance of consciousness, have obvious therapeutical effect to parkinsonism, dementia, glaucoma etc.
Current Citicoline sodium injection has the several formulations such as intravenous fluid, lyophilized injectable powder.China's biochemical drug magazine 2002 the 23rd volume the 4th interim " study on the stability of injection C14H25N4NaO11P2 and Citicoline sodium injection " is studied and is reported that the stability of citicoline sodium freeze-dried powder injection is better than Citicoline sodium injection.But someone actual investigation result is contrary with it.Also may be that after making lyophilized preparation, its moisture can not ensure because C14H25N4NaO11P2 water absorption is strong, thus cause it oxidized, rotten.CN1395935A (02135377.8, Li great Peng) provides a kind of citicoline sodium injection for intravenous injection, and it comprises following component (with parts by weight): C14H25N4NaO11P2 0.25 ~ 1.0, sodium chloride 0.45 ~ 4.5, water for injection 50 ~ 500; Its preparation method: get C14H25N4NaO11P2 0.25 ~ 1.0kg, sodium chloride 0.45 ~ 4.5kg, adds suitable quantity of water and dissolves, add suitable quantity of water dilution again, add proper amount of active carbon, stir evenly, static 15 minutes, decarburization is filtered, then adds 5 times amount waters for injection and be diluted to 50 ~ 500kg, and surveying solution ph is 5.0 ~ 7.0, filter with titanium rod or core, again through 0.22 μm of microporous filter membrane fine straining, by every bottle of 50 ~ 500ml fill, roll lid, sealing, sterilizing.It is believed that this invention product is easy to use, not easily incompatibility occur, can not pollute to medicine.But injection products quality prepared by the method is unstable, and its loading amount is large, and the bad control of production process, easily introduces visible foreign matters in medicinal liquid, and the undetected probability of lamp inspection is large.After undetected microgranule injects human body, larger can block blood capillary, if invade the position such as brain, eye will cause the encirclement and propagation of organizing thromboembolism and macrophage, forms the harm such as granuloma.In addition, because loading amount is large, the filling time is long, medicinal liquid in atmosphere open-assembly time long, aseptic bad control, needs high temperature sterilize.But some bacterium colonies as actinomycetes need to go out more than 140 DEG C 15-20 minute just can deactivation, traditional sterilization process has certain risk concerning the production of infusion solutions.And high temperature can cause the related substance of product to increase, particulate matter increases, thus increases the untoward reaction of Citicoline sodium injection.Consider from production cost, bottle utilization rate, the rate of qualifiid of the lamp inspection of infusion solutions all will well below small-volume injections.China's biochemical medical magazine the 25th volume the 6th phase in 2004 is mentioned in " improvement of preparation of citicoline sodium injection ": second adsorption technique is to control the thermal source of Citicoline sodium injection, the preparing process boiled during dosing, and it is all qualified to make study on the stability outward appearance, content, pH value, clarity.But in fact boiling water batching causes the instability of product, and increases related substance; Second adsorption technology theory is set up, from inadvisable actual fabrication, because without any adjuvant in prescription, the active carbon second adsorption of 0.1% can make medicinal liquid content lower 6-10%, if for making content up to standard, must dosage be strengthened, because this increasing production cost.
Prior art also discloses the preparation method of many citicoline sodium pharmaceutical compositions particularly its injection.Such as, CN104027304A (201410244261.8, echo must) provide a kind of citicoline sodium glucose injection, it is made up of C14H25N4NaO11P2, glucose, glycine, citric acid, and wherein C14H25N4NaO11P2 is 3g, and glucose is 40g, glycine is 1.8g, citric acid is 1.3g, uses sodium hydroxide adjust ph to be 5.5-5.6, injects water to 1000ml.CN102144963A (201010106623.9, Cologne) discloses a kind of citicoline sodium glucose injection and preparation technology thereof, primarily of active component C14H25N4NaO11P2, and isotonic agent glucose, stabilizing agent and pH adjusting agent and water for injection composition; Stabilizing agent is selected from one or both of malic acid and salt compounds and sulphite compounds; PH adjusting agent is one or more of sodium hydroxide, hydrochloric acid, malic acid and natrium malicum; The weight ratio of active component C14H25N4NaO11P2 and isotonic agent glucose is 1: 20 ~ 100, and the weight ratio of active component C14H25N4NaO11P2 and stabilizing agent is 1: 0.02 ~ 2.It is believed that this invention is by adding stabilizing agent, solving injection in the problem of producing and exceed standard by thermally labile and related substance in storage, improve quality stability and the safety and effectiveness of medicine.
CN103006550A (201210529664.8, breathe out medicine) provides a kind of Citicoline sodium injection and preparation method thereof.The Citicoline sodium injection of this invention is prepared into by C14H25N4NaO11P2 1125 ~ 1375g, medicinal carbon 5 ~ 15g, water for injection 10000ml.Get the water for injection of the volume 30 ~ 50% that about always makes up a prescription, be cooled to less than 20 DEG C, logical noble gas is to saturated, add C14H25N4NaO11P2 1125 ~ 1375g, be stirred to abundant dissolving, then lead to noble gas 15 ~ 20 minutes in solution, be cooled to 20 DEG C ~ 25 DEG C, airtight placement is for subsequent use after 8 hours.And before dosing, in concentrated solution, drop into medicinal charcoal 5 ~ 15g, stirring and adsorbing 20 ~ 30 minutes, coarse filtration, filtrate is diluted to dosing full dose to saturated water for injection in 15 ~ 20 minutes with filling with inert gas.It is believed that this invention controls the related substance such as pyrogen, microorganism, intracellular toxin in medicinal liquid effectively, improve the stability of product, adapt to suitability for industrialized production.
CN102462659A (201010546637.2, North China) discloses the Citicoline sodium injection that a kind of quality is good, cost is low, provides a kind of method preparing this injection simultaneously.The Citicoline sodium injection that this invention provides, is made up of following formula: C14H25N4NaO11P2 1000 ~ 5000g, and disodium edetate 5g water for injection 20000ml, often props up 2 ~ 5ml.Its preparation method comprises the following steps: take each component; First water for injection is heated to 28 ~ 30 DEG C, adds 0.02 ~ 0.05% injection active carbon, adsorb after 20 ~ 30 minutes, filter; Feed liquid is heated to 60-65 DEG C, is incubated 8 ~ 10 minutes, and then after adding 0.02% injection active carbon stirring, dissolving, decarburization, filter, feed temperature is down to after below 40 DEG C, subpackage.It is believed that this inventive method effectively controls the related substance of product and the level of pollution of microorganism and level of endotoxin.Improve stability and the rate of qualifiid of the lamp inspection of product.
Within 2010, version " Chinese Pharmacopoeia " two has recorded injection with small volume " Citicoline sodium injection ", every bottle of 2ml, and drug level is 0.05 ~ 0.25g/ml.Relatively strict in quality control to existing Citicoline sodium injection clinically, such as need to control wherein certain/some specific impurities is within the scope of certain limit.Therefore, those skilled in the art still expect there is new method to prepare the Citicoline sodium injection pharmaceutical composition with excellent pharmaceutical property.
Summary of the invention
The object of the present invention is to provide a kind of Citicoline sodium injection, expect that this Citicoline sodium injection has excellent pharmaceutical properties and such as has excellent quality stability.Have been surprisingly found that, the Citicoline sodium injection prepared by the present invention at least obtains the pharmaceutical properties that this area is expected with regard to this product.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides a kind of Citicoline sodium injection, wherein comprises C14H25N4NaO11P2 and the water for injection as solvent.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, wherein the concentration of C14H25N4NaO11P2 is 0.01 ~ 1g/ml.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, wherein the concentration of C14H25N4NaO11P2 is 0.025 ~ 0.3g/ml.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, wherein the concentration of C14H25N4NaO11P2 is 0.05 ~ 0.25g/ml.
According to the present invention, the amount of the wherein said water for injection as solvent in injection need not be particularly limited, and as everyone knows, water for injection is used for standardize solution as main body solvent wherein and is diluted to normal concentration to prescribed volume or by principal agent.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 100%:
formula I
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 75%.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 50%.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 40%.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 35%.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 30%.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, it prepares according to the method comprised the steps:
(1) get appropriate water for injection (60 ~ 80% of such as formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, wherein in step (3), active carbon dilute acid pretreatment used is crossed.
The Citicoline sodium injection of arbitrary embodiment according to a first aspect of the present invention, wherein in step (3), active carbon diluted acid used processed as follows: be dipped in by active carbon at 40-45 DEG C of temperature in 0.1mol/L hydrochloric acid solution and stir 30 minutes, leaching active carbon; 2 times are embathed again, leaching active carbon, and at 90 DEG C of dry 30-60 minute with water for injection, then at 120 DEG C dry 30 minutes.Have been surprisingly found that, use by the charcoal treatment of said method process injection of the present invention, the gained injection formula I impurity content that not only impurity is wherein particularly special is low, and this injection in Long-term Storage process this special impurities growth rate significantly lower than the injection that alternate manner prepares.Contribute to reducing the impurity (static effects) in product although those skilled in the art can conjesture charcoal treatment in some cases, after but can not predicting such charcoal treatment completely, contribute to the stability (dynamic effect) improving injection.
Further with, second aspect present invention provides the method preparing Citicoline sodium injection (described in the arbitrary embodiment of such as first aspect present invention Citicoline sodium injection), and it comprises the steps:
(1) get appropriate water for injection (60 ~ 80% of such as formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
The method of arbitrary embodiment according to a second aspect of the present invention, comprises C14H25N4NaO11P2 and the water for injection as solvent in wherein said Citicoline sodium injection.
The method of arbitrary embodiment according to a second aspect of the present invention, the concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.01 ~ 1g/ml.
The method of arbitrary embodiment according to a second aspect of the present invention, the concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.025 ~ 0.3g/ml.
The method of arbitrary embodiment according to a second aspect of the present invention, the concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.05 ~ 0.25g/ml.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said Citicoline sodium injection its place 5 months at 40 DEG C of temperature places, the increase percent wherein as the formula I of impurity is less than 100%:
formula I
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 75%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 50%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 40%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 35%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 30%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein in step (3), active carbon dilute acid pretreatment used is crossed.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein in step (3), active carbon diluted acid used processed as follows: be dipped in by active carbon at 40-45 DEG C of temperature in 0.1mol/L hydrochloric acid solution and stir 30 minutes, leaching active carbon; 2 times are embathed again, leaching active carbon, and at 90 DEG C of dry 30-60 minute with water for injection, then at 120 DEG C dry 30 minutes.
Further, third aspect present invention provides and suppresses in Citicoline sodium injection as the method that the formula I of impurity increases
formula I.
The method of arbitrary embodiment according to a third aspect of the present invention, comprises C14H25N4NaO11P2 and the water for injection as solvent in wherein said Citicoline sodium injection.
The method of arbitrary embodiment according to a third aspect of the present invention, comprises C14H25N4NaO11P2 and the water for injection as solvent in wherein said Citicoline sodium injection.
The method of arbitrary embodiment according to a third aspect of the present invention, the concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.01 ~ 1g/ml.
The method of arbitrary embodiment according to a third aspect of the present invention, the concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.025 ~ 0.3g/ml.
The method of arbitrary embodiment according to a third aspect of the present invention, the concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.05 ~ 0.25g/ml.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said Citicoline sodium injection its place 5 months at 40 DEG C of temperature places, the increase percent wherein as the formula I of impurity is less than 100%:
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 75%.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 50%.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 40%.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 35%.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 30%.
The method of arbitrary embodiment according to a third aspect of the present invention, the method comprises prepares described Citicoline sodium injection by the method comprised the steps:
(1) get appropriate water for injection (60 ~ 80% of such as formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein in step (3), active carbon dilute acid pretreatment used is crossed.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein in step (3), active carbon diluted acid used processed as follows: be dipped in by active carbon at 40-45 DEG C of temperature in 0.1mol/L hydrochloric acid solution and stir 30 minutes, leaching active carbon; 2 times are embathed again, leaching active carbon, and at 90 DEG C of dry 30-60 minute with water for injection, then at 120 DEG C dry 30 minutes.
Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
In the present invention, formula I also can be described as 5'-CMP usually.
Citicoline sodium injection is that cellular metabolism improves medicine, be mainly used in Acute Brain Injury and the postoperative disturbance of consciousness of brain clinically, the function of extremity can be recovered gradually to the hemiplegia caused by apoplexy, also can be used for function that other central nervous system's acute injuries cause and disturbance of consciousness, also for ischemic cerebrovascular and vascular dementia.C14H25N4NaO11P2 is nucleoside derivates, can strengthen reticular formation of brain stem, especially with the function realizing closely-related up network structure activating system; Strengthen the function of pyramidal system, improve paralysis motorica; Improve brain circulation, by reducing cerebral blood flow resistance, increase brain and promote brain function recovery and promotion to revive etc. has certain effect.C14H25N4NaO11P2, by reducing cerebral vascular resistance, increases cerebral blood flow and promotes metabolism of brain, improve cerebral circulation.Also can strengthen the function of brain stem ARAS (ascending reticular activating system), strengthen the function of pyramidal system, improve paralysis motorica, therefore the recovery and promotion that promote brain function are revived have certain effect.Can enter blood rapidly after injecting Citicoline sodium injection, have part to enter cerebral tissue by blood brain barrier, choline portion becomes the good donor that methylates in vivo, can have transmethylated effect to multiple compounds, and the choline of about 1% is discharged from urine.After Citicoline sodium injection injection, haemoconcentration declines rapidly, and during near injection in 30 minutes 1/3.1-2 hour basicly stable, distribution is to account for 10% at most in liver, major part entered in urine in 2 hours, this product is more difficult passes through blood brain barrier, the medicine entered in brain is little: only account for 0.1%, but medicine time of staying in brain is very long, injects drug level peaking in latter 3 hours, and remains unchanged in 24 hours; And damage brain is than normal brain activity, impaired hemisphere obviously raises than the citicoline content for impaired hemisphere.
The content assaying method of the related substance of injection of the present invention particularly impurity formula I wherein, if not otherwise indicated, can carry out according to following [related substance] assay method.
[related substance]:
It is appropriate that precision measures injection, quantitatively dilutes the solution made containing 2.5mg in every 1ml, as need testing solution with water;
Precision measures need testing solution 1ml, puts in 100ml measuring bottle, is diluted with water to scale, shake up, in contrast solution;
It is appropriate that another precision takes formula I, is dissolved in water and quantitatively dilutes the solution made about containing 7.5 μ g in every 1ml, as formula I reference substance solution;
According to the chromatographic condition under this paper [assay] item, get contrast solution 10 μ l, injection liquid chromatography, regulate detection sensitivity, the peak height of main constituent chromatographic peak is made to be about 25% of full scale, precision measures each 10 μ l ， Fen Do injection liquid chromatographies of need testing solution, contrast solution and formula I reference substance solution respectively again, and record chromatogram is to 2.5 times of main peak retention time; By external standard method, with the amount of calculated by peak area need testing solution chromatogram compounds of formula I, (that is, formula I is relative to the percentage composition of C14H25N4NaO11P2, referred to as formula I content; For Citicoline sodium injection, this area requires that the content of impurity formula I should be less than 0.3% usually).
The content of active component in injection of the present invention, if not otherwise indicated, can carry out according to following [assay] method.
[assay]:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD);
Chromatographic condition and system suitability: be filler with 18 protective embankment base silane bonded silica gels; Phosphate buffer [potassium dihydrogen phosphate of 0.1mol/L and TBuA solution (getting 0.01mol/L TBAH solution phosphoric acid adjust ph to 4.5) mixed in equal amounts]-methanol (95:5) is mobile phase; Determined wavelength is 276nm; Modus ponens I is appropriate, is dissolved in water and makes the solution about containing 0.25mg in every 1ml, getting above-mentioned solution appropriate, with C14H25N4NaO11P2 reference substance solution mixed in equal amounts, shake up, get injection liquid chromatography, record chromatogram, the separating degree at C14H25N4NaO11P2 peak and formula I peak should meet the requirements;
Algoscopy: precision measures injection in right amount, and quantitatively dilute the solution made about containing 0.25mg in every 1ml with water, precision measures 10 μ l injection liquid chromatographies, record chromatogram; Separately get C14H25N4NaO11P2 reference substance appropriate, be measured in the same method, by external standard method with calculated by peak area, obtain final product.
Citicoline sodium injection provided by the invention has the excellent properties as illustrated in the context of the invention.
Detailed description of the invention
The following examples provided only for task of explanation instead of for, should not be interpreted as limiting the present invention by any way yet.Those skilled in the art will recognize that can make routine to following examples when not surmounting the spirit or scope of the present invention changes and amendment.
Below prepare in the example of compositions, if not otherwise indicated, the material used in each embodiment is the material of same batch.Hereinafter, if not otherwise indicated, needle-use activated carbon used is all processed as follows with diluted acid in advance: be dipped in by active carbon at 40-45 DEG C of temperature in 0.1mol/L hydrochloric acid solution and stir 30 minutes, leaching active carbon; 2 times are embathed again, leaching active carbon, and at 90 DEG C of dry 30-60 minute with water for injection, then at 120 DEG C dry 30 minutes.If needle-use activated carbon is without above-mentioned dilute acid pretreatment in advance, be then marked as common needle-use activated carbon.If not otherwise indicated, with the preparation of the amount of 10,000 ml that feed intake, during liquid drug in every bottle in subpackage medicinal liquid 2ml ampoule bottle, but when indicating formula ratio, be all calculate with the gauge of 2ml injection.
Embodiment 1: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.25g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 2: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.1g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (60% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 3: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.5g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (80% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 4: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.05g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 5: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.6g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 6: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.2g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 7: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.3g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 8: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.4g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 9: prepare Citicoline sodium injection
Respectively with reference to formula and the method for making of embodiment 19-23, different is only common needle-use activated carbon is wherein replaced with of the present invention in advance with the needle-use activated carbon that dilute acid pretreatment is crossed, prepare five kinds of injection, they can be labeled as E91, E92, E93, E94, E95 respectively.
Embodiment 11: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.25g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 12: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.1g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (60% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 13: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.5g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (80% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 14: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.05g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 15: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.6g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 16: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.2g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 17: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.3g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 18: prepare Citicoline sodium injection
Formula:
| c14H25N4NaO11P2 | 0.4g, |
| water for injection | in right amount, 2mL is added to. |
Method for making:
(1) get appropriate water for injection (70% of formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the common needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
Embodiment 19: prepare Citicoline sodium injection
Get C14H25N4NaO11P2 1kg, sodium chloride 2.25kg is dissolved in 50kg water, add appropriate common needle-use activated carbon, stir, leave standstill 15 minutes, decarburization is filtered, and adds water to 250kg.Survey solution ph and should be 5.0-7.0, qualified rear titanium rod filters, then through 0.22um microporous filter membrane fine straining, by every bottle of 250ml fill, roll lid, sealing, 115 DEG C of pressure sterilizings 30 minutes, obtain citicoline sodium injection for intravenous injection (this sample can represent with numbering #935E1).
Embodiment 20: prepare Citicoline sodium injection
Prescription: C14H25N4NaO11P2 2.5g, glucose 50g, malic acid 0.5g, sodium sulfite 0.5g, 10% Sodium hydroxide q. s, water for injection add to 1000ml in right amount.
Method for making: add appropriate water for injection in dense preparing tank, heating, drop into glucose, malic acid, the sodium sulfite of recipe quantity, stirring and dissolving, adds the common needle-use activated carbon of recipe quantity, boils 15 minutes, and solution takes off charcoal through titanium rod filter, and filtrate pumps in dilute preparing tank; In dilute preparing tank, drop into the C14H25N4NaO11P2 of recipe quantity and 10% appropriate sodium hydroxide solution, add to the full amount of water for injection, stir; Detect medicinal liquid content and pH value (middle control scope 5.7 ~ 6.3) qualified after, medicinal liquid through titanium rod filter ,≤0.22 μm of microporous filter membrane fine straining to visible foreign matters passed examination, fill in glass infusion bottle, upper butyl rubber plug, add a cover, roll lid after send sterilizing; Sample, through 115 DEG C of 30min pressure sterilizings, is cooled to after below 60 DEG C and offers for sale.Lamp inspection, namely product inspection obtains (this sample can represent with numbering #963E1).
Embodiment 21: prepare Citicoline sodium injection
A () takes C14H25N4NaO11P2 2.5Kg, EDTA-2Na5g, water for injection 20000ml; B () prepares under ten thousand grades of environment, first water for injection is heated to 30 DEG C, adds 0.05% common needle-use activated carbon, adsorb after 20 minutes, filter, then add C14H25N4NaO11P2, stirring, dissolve, is the sodium sulfite solution adjust pH 6.5 of 10% by mass volume ratio concentration; C b is walked the feed liquid prepared and is heated to 65 DEG C by (); be incubated 10 minutes; and then add 0.05% common needle-use activated carbon (according to material liquid volume with quality of activated carbon than counting) and EDTA-2Na; after stirring, dissolving, decarburization; 0.2um double filter is used to filter; feed temperature is down to after below 40 DEG C; under hundred grades of environment, be distributed into 2ml/ prop up; filling and sealing (nitrogen protection), leak detection, lamp inspection, packaging, obtain the Citicoline sodium injection (this sample can represent with numbering #659E1) that specification is 2ml: 0.25g.
Embodiment 22: prepare Citicoline sodium injection
Get the water for injection of 3000ml, be cooled to 15 DEG C, logical nitrogen adds C14H25N4NaO11P2 1125g to saturated, be stirred to abundant dissolving for 15 minutes, then leads to nitrogen 15 minutes in solution, and be cooled to 20 DEG C, airtight placement is for subsequent use after 8 hours, in concentrated solution, common needle-use activated carbon 5g is dropped into before dosing, stirring and adsorbing 20 minutes, with 3 μm of titanium rod coarse filtration de-carbons, filtrate is diluted to dosing full dose to saturated water for injection in 15 minutes with inflated with nitrogen, stir 20 minutes, measuring citicoline sodium content is 94% of labelled amount, pH=6.4, nitrogen is led to medicinal liquid liquid level, after qualified to medicinal liquid visible foreign matters with 0.22 μm of folded membrane fine straining, embedding is in ampoule, ampoule space leads to nitrogen, through 100 DEG C, sterilizing in 15 minutes, lamp inspection, packaging, obtain the Citicoline sodium injection (this sample can represent with numbering #550E1) that specification is 2ml:0.25g.
Embodiment 23: prepare Citicoline sodium injection
Glucose 40g is dissolved in water for injection, filters after then adding the absorption of common needle-use activated carbon, filtrate is diluted to isotonic concentration with water for injection, thus obtains the isotonic aqueous solution of glucose; C14H25N4NaO11P2 3g, glycine 1.8g and citric acid 1.3g is added in isotonic aqueous solution, stirring makes it dissolve, then filter after adding the absorption of common needle-use activated carbon, 0.1N sodium hydroxide is used to regulate adjust ph to be 5.5-5.6, inject water to 1000ml, filtering with microporous membrane, aseptic subpackaged, obtain Citicoline sodium injection (this sample can represent with numbering #304E1).
Test example 1: injection Performance
Whole Citicoline sodium injections above-described embodiment 1-9, embodiment 11-23 prepared are placed 5 months under 40 DEG C of conditions, measure each injection sample respectively 0 month time and in up-to-date style I content in May (%), pressing examination calculating formula I content increases percent (%):
Formula I content increase percent (%)=
[(formula I content in May-0 month formula I content) ÷ 0 month formula I content] × 100%
Above-mentioned " formula I content increases percent " value is larger then represents that injection is more unstable.
The formula I content of whole Citicoline sodium injections that result: embodiment 1-9 prepares increases percent all in 18 ~ 37% scopes, and the overwhelming majority is in 18 ~ 34% scopes, great majority are in 18 ~ 29% scopes, and it is 23% that the formula I content of such as embodiment 1 Citicoline sodium injection increases percent; The formula I content of whole Citicoline sodium injections of embodiment 11-23 increases percent all in 165 ~ 232% scopes, and it is 183% that the formula I content of such as embodiment 11 Citicoline sodium injection increases percent;
Test example 2: injection Performance
The formula I content of whole Citicoline sodium injections prepared by mensuration above-described embodiment 1-9, embodiment 11-23 and the content of active component C14H25N4NaO11P2.
Result shows whole sample in above-mentioned two parameters without significant difference, the formula I content of whole Citicoline sodium injection is all in 0.07 ~ 0.14% scope, and the content of active component C14H25N4NaO11P2 is all in 98 ~ 102% scopes of injection labelled amount.For whole injection sample, these two parameters all drop on this area within the scope of the required standard of this kind, show that various diverse ways can prepare qualified product, but different process products obtained therefrom in stability, particularly increase sign with formula I stability in present obvious difference.
Industrial applicability
The present invention relates to a kind of pharmaceutical composition being used for the treatment of the disturbance of consciousness that Acute Brain Injury and brain Post operation cause, particularly relate to a kind of injection pharmaceutical composition being used for the treatment of the disturbance of consciousness that Acute Brain Injury and brain Post operation cause, more especially relate to a kind of Citicoline sodium injection pharmaceutical composition, the invention still further relates to the preparation method of this injection.Citicoline sodium injection of the present invention has excellent pharmaceutical properties.
Claims (10)
1. a Citicoline sodium injection, wherein comprises C14H25N4NaO11P2 and the water for injection as solvent.
2. Citicoline sodium injection according to claim 1, is characterized in that:
Wherein the concentration of C14H25N4NaO11P2 is 0.01 ~ 1g/ml;
Wherein the concentration of C14H25N4NaO11P2 is 0.025 ~ 0.3g/ml;
Wherein the concentration of C14H25N4NaO11P2 is 0.05 ~ 0.25g/ml;
It places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 100%;
It places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 75%;
It places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 50%;
It places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 40%;
It places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 35%; And/or
It places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 30%.
3. Citicoline sodium injection according to claim 1, it prepares according to the method comprised the steps:
(1) get appropriate water for injection (60 ~ 80% of such as formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
4. prepare the method for Citicoline sodium injection, it comprises the steps:
(1) get appropriate water for injection (60 ~ 80% of such as formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
5. method according to claim 4, is characterized in that:
C14H25N4NaO11P2 and the water for injection as solvent is comprised in wherein said Citicoline sodium injection;
The concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.01 ~ 1g/ml;
The concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.025 ~ 0.3g/ml; And/or
The concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.05 ~ 0.25g/ml.
6. method according to claim 4, is characterized in that:
Wherein said Citicoline sodium injection its place 5 months at 40 DEG C of temperature places, the increase percent wherein as the formula I of impurity is less than 100%;
Wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 75%;
Wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 50%;
Wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 40%;
Wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 35%; And/or
Wherein said Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 30%.
7. method according to claim 4, is characterized in that:
Wherein in step (3), active carbon dilute acid pretreatment used is crossed;
Wherein in step (3), active carbon diluted acid used processed as follows: be dipped in by active carbon at 40-45 DEG C of temperature in 0.1mol/L hydrochloric acid solution and stir 30 minutes, leaching active carbon; 2 times are embathed again, leaching active carbon, and at 90 DEG C of dry 30-60 minute with water for injection, then at 120 DEG C dry 30 minutes.
8. to suppress in Citicoline sodium injection, as the method that the formula I of impurity increases, in described Citicoline sodium injection, to comprise C14H25N4NaO11P2 and the water for injection as solvent.
9. method according to claim 8, is characterized in that:
C14H25N4NaO11P2 and the water for injection as solvent is comprised in wherein said Citicoline sodium injection;
The concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.01 ~ 1g/ml;
The concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.025 ~ 0.3g/ml;
The concentration of wherein said Citicoline Sodium in Citicoline Sodium Injection is 0.05 ~ 0.25g/ml;
Described Citicoline sodium injection its place 5 months at 40 DEG C of temperature places, the increase percent wherein as the formula I of impurity is less than 100%;
Described Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 75%;
Described Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 50%;
Described Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 40%;
Described Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 35%; And/or
Described Citicoline sodium injection places 5 months at 40 DEG C of temperature places, and the increase percent wherein as the formula I of impurity is less than 30%.
10. method according to claim 8, the method comprises prepares described Citicoline sodium injection by the method comprised the steps:
(1) get appropriate water for injection (60 ~ 80% of such as formula ratio) C14H25N4NaO11P2 is dissolved;
(2) regulate between pH value to 6.5 ~ 7.0 of solution with 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution;
(3) solution is heated to 60 DEG C ~ 70 DEG C, adds the needle-use activated carbon of 1 ‰ of existing liquor capacity in solution, absorption 20 ~ 30min, de-charcoal, circulating filtration, mends and injects water to formula full dose;
(4) by the medicinal liquid of preparation by 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in ampoule bottle, inflated with nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111840220A (en) * | 2020-08-19 | 2020-10-30 | 开封康诺药业有限公司 | Citicoline sodium injection and preparation method thereof |
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| CN102462659A (en) * | 2010-11-17 | 2012-05-23 | 华北制药股份有限公司 | Citicoline sodium injection and preparation method thereof |
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| CN111840220A (en) * | 2020-08-19 | 2020-10-30 | 开封康诺药业有限公司 | Citicoline sodium injection and preparation method thereof |
| CN111840220B (en) * | 2020-08-19 | 2022-09-30 | 开封康诺药业有限公司 | Citicoline sodium injection and preparation method thereof |
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