CN110314146A - A kind of pharmaceutical composition containing active constituent Calcium Levofolinate - Google Patents
A kind of pharmaceutical composition containing active constituent Calcium Levofolinate Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention belongs to biomedicine technical fields, and in particular to and a kind of l-leucovorin calcium medicine compound, the pharmaceutical composition are made of following parts by weight of component, and 54 parts of Calcium Levofolinate, 10-20 parts of sodium alginate, -10 parts of arginase 12；Pharmaceutical composition solves the problems, such as that traditional l-leucovorin calcium stability is bad, it is poor to place safety for a long time.The purpose of the present invention is to provide a kind of l-leucovorin calcium medicine compound, which has good stability using Calcium Levofolinate as main active.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of using Calcium Levofolinate as main active component
Pharmaceutical composition and preparation method thereof is mainly used for anti-anemia action and the removing toxic substances antagonist in tumour medicine etc..
Background technique
Calcium Levofolinate is otherwise known as (6S)-Calciumlevofolinate, and medical value is increasingly valued by the people, especially uses
Removing toxic substances antagonist etc. in treatment anaemia and tumor pharmacother.The pharmacological action of l-leucovorin and folinic acid phase
Seemingly, but its dosage is the 1/2 of folinic acid.L-leucovorin does not need to be restored to participate in by dihyrofolate reductase to utilize folic acid
Reaction of the salt as one carbon unit source, and l-leucovorin can actively or passively pass through cell membrane, l-leucovorin is made substantially
With identical with folic acid, but effect is better than folic acid, because folic acid first becomes folinic acid in liver and marrow and can just work, and Zuo Ya
Folic acid is the active form of folinic acid, it may have the effect of stimulation Leukocyte Growth maturation can improve megaloblastic anemia.It is left
Calciumlevofolinate is succeeded in developing first by U.S.'s Hui Shi drug company, is listed first in Britain within 94 years, and in Italy plus take
Greatly, more than 10 country's listings such as Japan, South Africa, Finland, Iceland, preparation have tablet, liquid drugs injection and lyophilized injection.L-leucovorin
Calcium has the advantage in terms of drug effect and safety, has exact effect, the data carcinoma of the rectum, in terms of there is a constant current modulation
Effect.
Calcium Levofolinate is that the drug of various medicaments is made in active constituent and related pharmaceutical technology has much relevant
It is disclosed on medical journal.But since the formula of current medicament is incomplete, production method is complicated, and the selection of auxiliary material does not conform in addition
Reason, causes the higher cost of this medicament, and the therapeutic effect of obtained medicament is undesirable, and the kind of medicament is more single, difficult
In high volume to promote the use of.
Summary of the invention
In order to overcome a series of problems existing in the prior art, the present invention creatively has found a feature formula
Pharmaceutical composition solves the problems, such as that traditional l-leucovorin calcium stability is bad, it is poor to place safety for a long time.Mesh of the invention
Be a kind of l-leucovorin calcium medicine compound is provided, the pharmaceutical composition using Calcium Levofolinate as main active, tool
There is good stability.
The purpose of the present invention is what is be achieved through the following technical solutions.
A kind of l-leucovorin calcium medicine compound, composed of the following components:
A kind of l-leucovorin calcium medicine compound, the pharmaceutical composition are made of following parts by weight of component, Calcium Levofolinate
54 parts by weight, 10-20 parts of sodium alginate, -10 parts of arginase 12.
A kind of l-leucovorin calcium medicine compound as described in claim 1, the pharmaceutical composition is by following parts by weight group
It is grouped as, 54 parts of Calcium Levofolinate, 15 parts of sodium alginate, 6 parts of arginine.
The pharmaceutical composition is prepared into freeze drying powder injection.
The preparation method of the l-leucovorin calcium medicine compound dissolves all components with water for injection, solution warp
Heat preservation adsorption filtration in 40-50 DEG C of medicinal carbon, 15-20 minutes, then through 0.22 μm of filtering with microporous membrane, it is made sterile molten
Liquid, then powder-injection is made through drying.
The drying is that sterile solution is sub-packed in the cillin bottle of dry sterilization, in -20 to -40 DEG C of precooling 2.5-3
Hour, -22 to -35 DEG C lyophilization 20-30 minutes, 35 DEG C of re-dries 10-15 hours to get.
A kind of application of l-leucovorin calcium medicine compound as described in claim 1, can be used as and resist huge juvenile cell
The medication of property anaemia and chemotherapy of tumors.
A kind of Calcium Levofolinate freeze drying powder injection, the powder-injection are grouped as by following parts by weight supplementary material group:
54 parts by weight of Calcium Levofolinate, 10-20 parts of sodium alginate, -10 parts of arginase 12.
The wherein parts by weight composition of preferred supplementary material are as follows:
54 parts of Calciumlevofolinate, 15 parts of sodium alginate, 6 parts of arginine.
The powder-injection the preparation method comprises the following steps:
All components are dissolved with water for injection, solution is adsorbed through 40-50 DEG C of medicinal carbon, heat preservation in 15-20 minutes
Filtering, then through 0.22 μm of filtering with microporous membrane, sterile solution is made, then powder-injection is made through drying；The drying is will be sterile
Solution is sub-packed in the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 2.5-3 hours, in -22 to -35 DEG C of lyophilizations
20-30 minutes, 35 DEG C of re-dries 10-15 hours to get.
The inventor of the present application discovered that the stability in storage of the pharmaceutical composition containing Calcium Levofolinate is poor, is easy to produce
More impurity, to affect the safety in utilization of drug.Therefore, in order to improve Drug safety, present inventor is passed through
Test of many times is crossed, the creative reasonable formula having found suitable for l-leucovorin calcium medicine compound is solved with storage
Deposit the time growth, drug safety reduce the problem of.
L-leucovorin calcium medicine compound of the present invention is the dosage forms such as freeze drying powder injection.For example all components are infused
It penetrates and is dissolved with water, solution is absorbed and filter through 40-50 DEG C of medicinal carbon, heat preservation in 15-20 minutes, then through 0.22 μm of miillpore filter
Filtering with microporous membrane is made sterile solution, then powder-injection is made through drying.The drying is by sterile solution by predetermined weight point
In cillin bottle loaded on dry sterilization, -20 to -40 DEG C precooling 2.5-3 hours, in -22 to -35 DEG C of lyophilization 20-30
Minute, 35 DEG C of re-dries 10-15 hours to get.Alternatively, the drying is to be sub-packed in XiLin again by sterilizing freeze-drying, crushing
Bottle or first dress are with cillin bottle, and after freeze-dried, Zha Gai sealing packs two layers.The drying can also be using spray drying
Method, it is sterile solution low-temperature reduced-pressure is dry, crushing, and by regulation quantitative separating and cillin bottle, Zha Gai sealing is packed.
Freeze-drying of the present invention controls vacuum degree 20-30Pa.
In addition, can be used as the invention also includes a kind of application of l-leucovorin calcium medicine compound and resist huge juvenile cell
The medication of property anaemia and chemotherapy of tumors.
The pharmaceutical composition of Calcium Levofolinate of the invention, is formulated simple and easy to get, and preparation process is simple, easy to use, can
It leans on, practical safety, is able to achieve industrialized production, work, production efficiency greatly improve.Most of all, with inventive formulation
Medicament, have many advantages, such as drug storage time increase, the safety is improved, substantially increase Calcium Levofolinate medicament use the longevity
Life.
Preparation of the present invention is obtained in Conformance Assessment research；
Supplementary material of the present invention is provided by grand reputation wing Yao (Beijing) Science and Technology Ltd..
Calcium Levofolinate raw material of the present invention, content 101.1%, total impurities 0.27%, impurity A: (2S) -2-
[(4- aminobenzoyl) amino] glutaric acid content 0.04%；Impurity C:(2S) 2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae-two
Hydrogen -6- pteridyl) methyl] amino] benzoyl] amino] glutaric acid content 0.05%；Impurity D:(2S) -2- [[4- [[(2- ammonia
Base -4- oxo-Isosorbide-5-Nitrae-dihydro -6- pteridyl) methyl] formamido group] benzoyl] amino] glutaric acid content is not detected；Impurity
G:2S) -2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae, 7,8- tetrahydro -6- pteridyls) methyl] amino] benzoyl] amino] penta
Two acid contents are not detected.
Specific embodiment
A specific embodiment of the invention is only limitted to make further explanation the content of present invention, not to this hair
It is bright to be construed as limiting.
Supplementary material of the present invention is provided by grand reputation wing Yao (Beijing) Science and Technology Ltd..
Calcium Levofolinate raw material of the present invention, content 101.1%, total impurities 0.27%, impurity A: (2S) -2-
[(4- aminobenzoyl) amino] glutaric acid content 0.04%；Impurity C:(2S) 2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae-two
Hydrogen -6- pteridyl) methyl] amino] benzoyl] amino] glutaric acid content 0.05%；Impurity D:(2S) -2- [[4- [[(2- ammonia
Base -4- oxo-Isosorbide-5-Nitrae-dihydro -6- pteridyl) methyl] formamido group] benzoyl] amino] glutaric acid content is not detected；Impurity
G:2S) -2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae, 7,8- tetrahydro -6- pteridyls) methyl] amino] benzoyl] amino] penta
Two acid contents are not detected.
Embodiment 1
Calcium Levofolinate 54g, sodium alginate 10g, arginase 12 g.
Calcium Levofolinate and other components are weighed, are dissolved in 3000ml water for injection, solution is through medicinal carbon
40 DEG C, the adsorption filtration of heat preservation in 20 minutes, then through 0.22 μm of filtering with microporous membrane, sterile solution is made, sterile solution is dispensed
In the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 2.5 hours, -22 to -35 DEG C lyophilization 20 minutes, 35
DEG C re-dry 10 hours, Zha Gai sealing was packed.
Embodiment 2
Calcium Levofolinate 54g, sodium alginate 20g, arginine 10g.
Calcium Levofolinate and other components are weighed, are dissolved in 4000ml water for injection, solution is through medicinal carbon
50 DEG C, the adsorption filtration of heat preservation in 15 minutes, then through 0.22 μm of filtering with microporous membrane, sterile solution is made, sterile solution is dispensed
In the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 3 hours, -22 to -35 DEG C lyophilization 30 minutes, 35 DEG C
Re-dry 15 hours, Zha Gai sealing was packed.
Apply example 3
Calcium Levofolinate 54g, sodium alginate 10g, arginine 6g.
Calcium Levofolinate and other components are weighed, are dissolved in 3500ml water for injection, solution is through medicinal carbon
45 DEG C, the adsorption filtration of heat preservation in 18 minutes, then through 0.22 μm of filtering with microporous membrane, sterile solution is made, sterile solution is dispensed
In the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 2.8 hours, -22 to -35 DEG C lyophilization 25 minutes, 35
DEG C re-dry 12.5 hours, Zha Gai sealing was packed.
Embodiment 4
Calcium Levofolinate 54g, sodium alginate 18g, arginine 9g.
Calcium Levofolinate and other components are weighed, are dissolved in 3800ml water for injection, solution is through medicinal carbon
45 DEG C, the adsorption filtration of heat preservation in 16 minutes, then through 0.22 μm of filtering with microporous membrane, sterile solution is made, sterile solution is dispensed
In the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 2.6 hours, -22 to -35 DEG C lyophilization 24 minutes, 35
DEG C re-dry 12 hours, Zha Gai sealing was packed.
Embodiment 5
Calcium Levofolinate 54g, sodium alginate 15g, arginine 6g.
Calcium Levofolinate and other components are weighed, are dissolved in 3600ml water for injection, solution is through medicinal carbon
45 DEG C, the adsorption filtration of heat preservation in 18 minutes, then through 0.22 μm of filtering with microporous membrane, sterile solution is made, sterile solution is dispensed
In the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 2.8 hours, -22 to -35 DEG C lyophilization 28 minutes, 35
DEG C re-dry 14 hours, Zha Gai sealing was packed.
Calcium Levofolinate raw material of the present invention, content 101.1%, total impurities 0.27%, impurity A: (2S) -2-
[(4- aminobenzoyl) amino] glutaric acid content 0.04%；Impurity C:(2S) 2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae-two
Hydrogen -6- pteridyl) methyl] amino] benzoyl] amino] glutaric acid content 0.05%；Impurity D:(2S) -2- [[4- [[(2- ammonia
Base -4- oxo-Isosorbide-5-Nitrae-dihydro -6- pteridyl) methyl] formamido group] benzoyl] amino] glutaric acid content is not detected；Impurity
G:(2S) -2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae, 7,8- tetrahydro -6- pteridyls) methyl] amino] benzoyl] amino]
Glutaric acid content is not detected.
Assay:
It is measured according to high performance liquid chromatography (general rule 0512).
Chromatographic condition and system suitability: being filler with octadecylsilane chemically bonded silica.Mobile phase: to contain
The disodium hydrogen phosphate buffer of 0.1% tetrabutylammonium hydroxide-methanol (90:10) is mobile phase A, to contain 0.1% tetrabutylammonium hydrogen
The disodium hydrogen phosphate buffer of amine-oxides-methanol (50:50) is Mobile phase B；According to 1 gradient elution of table；Column temperature is 40 DEG C；Detection
Wavelength is 280nm；Flow velocity is 1ml per minute；Sample volume is 10 μ l.
Test solution preparation: taking injection Calcium Levofolinate 5, and water is added to make contents melting and shift to set 250ml amount
Bottle adds water to scale, then the accurate 10ml that measures sets 100ml measuring bottle, adds water that the solution containing about l-leucovorin 0.1mg/ml is made, makees
For test solution.Prepare 6 parts of test solutions.
Reference substance solution preparation: taking Calciumlevofolinate reference substance about 11.6mg, accurately weighed, sets in 100ml measuring bottle, adds water-soluble
Scale is solved and be diluted to, is shaken up；The solution in every 1ml containing about 0.1mg is made, as reference substance solution.Measuring method: precision measures
10 μ l inject liquid chromatograph, record chromatogram；By external standard method with calculated by peak area to get.
1 mobile phase of table and elution time
Related substance:
It is measured according to high performance liquid chromatography (general rule 0512).
Chromatographic condition and system suitability: being filler with octadecylsilane chemically bonded silica.With phosphate-buffered
Liquid (0.01mol/L disodium hydrogen phosphate, 0.08% tetrabutylammonium hydroxide, with phosphoric acid tune pH value to be 7.8) mobile phase A, with phosphorus
(0.01mol/L disodium hydrogen phosphate, 0.08% tetrabutylammonium hydroxide are 7.8)-methanol with phosphoric acid tune pH value to phthalate buffer
(40:60) is Mobile phase B, carries out gradient elution according to table 2, column temperature is 40 DEG C, flow velocity 1.0ml/min, and Detection wavelength is
280nm.Number of theoretical plate is calculated by Calcium Levofolinate peak should be not less than 5000, and the separating degree of main peak and other impurities peak should be greater than
1.5。
It takes injection Calcium Levofolinate appropriate, mixes, precision weighs appropriate (being approximately equivalent to l-leucovorin 25mg), adds water system
The solution for being 1mg/ml at concentration, as test solution.Precision measures in right amount, and being diluted with water and concentration is made is 0.01mg/
The solution of ml, as contrast solution.Precision measures 10 μ l of contrast solution and injects liquid chromatograph, adjusts detection sensitivity, makes to lead
Ingredient chromatography peak height is about the 10-20% of full scale, then the accurate 10 μ l of test solution that measures injects liquid chromatograph, records color
Spectrogram is to 2.5 times of Calcium Levofolinate main peak retention time, if any impurity peaks, maximum single impurity in test solution chromatogram
It is not greater than 0.1%, measures the sum of each impurity peak area, is not greater than 1 times (1%) of contrast solution main peak area.
2 mobile phase of table and elution time
The freeze drying powder injection of comparative example 1:CN108392470A embodiment 1.
Test method: embodiment 1-5 and comparative example 1 are respectively placed in 70 DEG C of high temperature, relative humidity 95% and illumination are shone
Under the conditions of 6000Lx, indices are investigated respectively at the 10th day, sampling in 30 days, as a result see the table below 3, table 4:
Calcium Levofolinate raw material of the present invention, content 101.1%, total impurities 0.27%, impurity A: (2S) -2-
[(4- aminobenzoyl) amino] glutaric acid content 0.04%；Impurity C:(2S) 2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae-two
Hydrogen -6- pteridyl) methyl] amino] benzoyl] amino] glutaric acid content 0.05%；Impurity D:(2S) -2- [[4- [[(2- ammonia
Base -4- oxo-Isosorbide-5-Nitrae-dihydro -6- pteridyl) methyl] formamido group] benzoyl] amino] glutaric acid content is not detected；Impurity
G:(2S) -2- [[4- [[(2- amino -4- oxo-Isosorbide-5-Nitrae, 7,8- tetrahydro -6- pteridyls) methyl] amino] benzoyl] amino]
Glutaric acid content is not detected.
Table 3 10 days each group contents and related substance compare
Table 4 30 days each group contents and related substance compare
Conclusion (of pressure testing): it is above-mentioned experiments have shown that, the preparation of comparative example passes through 70 DEG C of high temperature, and relative humidity 95% and illumination are shone
Under the conditions of 6000Lx, after 10 days and 30 days, preparation has not met the requirement of quality standard, absolutely proves that invention formulation has
Better stability.
Claims (9)
1. a kind of l-leucovorin calcium medicine compound, it is characterised in that: the pharmaceutical composition is made of following parts by weight of component, left
54 parts of Calciumlevofolinate, 10-20 parts of sodium alginate, -10 parts of arginase 12.
2. a kind of l-leucovorin calcium medicine compound as described in claim 1, it is characterised in that: the pharmaceutical composition is by following
Parts by weight of component composition, 54 parts of Calcium Levofolinate, 15 parts of sodium alginate, 6 parts of arginine.
3. a kind of l-leucovorin calcium medicine compound as described in claim 1, it is characterised in that: the pharmaceutical composition is prepared into
For freeze drying powder injection.
4. a kind of preparation method of l-leucovorin calcium medicine compound as described in claim 1, it is characterised in that: by all groups
Divide and dissolved with water for injection, solution is absorbed and filter through 40-50 DEG C of medicinal carbon, heat preservation in 15-20 minutes, then micro- through 0.22 μm
Hole membrane filtration is made sterile solution, then powder-injection is made through drying.
5. a kind of preparation method of l-leucovorin calcium medicine compound as claimed in claim 4, it is characterised in that: the drying
That sterile solution is sub-packed in the cillin bottle of dry sterilization, -20 to -40 DEG C precooling 2.5-3 hours, at -22 to -35 DEG C
Lyophilization 20-30 minutes, 35 DEG C of re-dries 10-15 hours to get.
6. a kind of application of l-leucovorin calcium medicine compound as described in claim 1, it is characterised in that: it can be used as anti-
The medication of megaloblastic anemia and chemotherapy of tumors.
7. a kind of Calcium Levofolinate freeze drying powder injection, it is characterised in that: the powder-injection is grouped as by following parts by weight supplementary material group:
54 parts by weight of Calcium Levofolinate, 10-20 parts of sodium alginate, -10 parts of arginase 12.
8. a kind of Calcium Levofolinate freeze drying powder injection according to claim 7, wherein the parts by weight of supplementary material form are as follows:
54 parts of Calciumlevofolinate, 15 parts of sodium alginate, 6 parts of arginine.
9. a kind of Calcium Levofolinate freeze drying powder injection according to claim 7, it is characterised in that: the preparation side of the powder-injection
Method are as follows:
All components are dissolved with water for injection, solution is absorbed and filter through 40-50 DEG C of medicinal carbon, heat preservation in 15-20 minutes,
Again through 0.22 μm of filtering with microporous membrane, sterile solution is made, then powder-injection is made through drying；The drying is by sterile solution point
In cillin bottle loaded on dry sterilization, -20 to -40 DEG C precooling 2.5-3 hours, in -22 to -35 DEG C of lyophilization 20-30
Minute, 35 DEG C of re-dries 10-15 hours to get.
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| CN201910737165.XA CN110314146A (en) | 2019-08-11 | 2019-08-11 | A kind of pharmaceutical composition containing active constituent Calcium Levofolinate |
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| CN201910737165.XA CN110314146A (en) | 2019-08-11 | 2019-08-11 | A kind of pharmaceutical composition containing active constituent Calcium Levofolinate |
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| CN108392470A (en) * | 2018-04-13 | 2018-08-14 | 健进制药有限公司 | A kind of production technology of injection Calcium Levofolinate freeze-dried powder |
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| CN1456162A (en) * | 2003-04-01 | 2003-11-19 | 杭州华卫制药技术开发有限公司 | Injection of leucovorin calcium and its preparing method |
| CN102178681A (en) * | 2011-03-25 | 2011-09-14 | 江苏奥赛康药业有限公司 | Injection calcium folinate composite and preparation method thereof |
| WO2018029699A1 (en) * | 2016-08-11 | 2018-02-15 | Msn Research & Development Center | Solid state forms of (2e)-n-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide and process for preparation thereof |
| CN108392470A (en) * | 2018-04-13 | 2018-08-14 | 健进制药有限公司 | A kind of production technology of injection Calcium Levofolinate freeze-dried powder |
| CN110101670A (en) * | 2019-05-20 | 2019-08-09 | 天津乾丰瑞科技有限公司 | A kind of aztreonam ejection preparation and preparation method thereof |
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