CN1799546A - Sodium folinate injection and preparation method thereof - Google Patents
Sodium folinate injection and preparation method thereof Download PDFInfo
- Publication number
- CN1799546A CN1799546A CN 200510076773 CN200510076773A CN1799546A CN 1799546 A CN1799546 A CN 1799546A CN 200510076773 CN200510076773 CN 200510076773 CN 200510076773 A CN200510076773 A CN 200510076773A CN 1799546 A CN1799546 A CN 1799546A
- Authority
- CN
- China
- Prior art keywords
- injection
- sodium
- semi
- folinate
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 235000008190 sodium folinate Nutrition 0.000 title claims abstract description 37
- 239000011673 sodium folinate Substances 0.000 title claims abstract description 37
- UDDUKFYJPZYIPC-ZEDZUCNESA-M sodium folinate Chemical compound [Na+].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 UDDUKFYJPZYIPC-ZEDZUCNESA-M 0.000 title claims abstract description 37
- 238000002347 injection Methods 0.000 title claims abstract description 29
- 239000007924 injection Substances 0.000 title claims abstract description 29
- 229940055334 sodium folinate Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000000243 solution Substances 0.000 claims abstract description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 23
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims abstract description 16
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims abstract description 15
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 claims abstract description 15
- 235000008191 folinic acid Nutrition 0.000 claims abstract description 15
- 239000011672 folinic acid Substances 0.000 claims abstract description 15
- 229960001691 leucovorin Drugs 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000008215 water for injection Substances 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000011049 filling Methods 0.000 claims abstract description 4
- 239000011265 semifinished product Substances 0.000 claims description 17
- 230000001954 sterilising effect Effects 0.000 claims description 13
- 238000004659 sterilization and disinfection Methods 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000012982 microporous membrane Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 230000010412 perfusion Effects 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 238000003860 storage Methods 0.000 abstract description 7
- 238000007789 sealing Methods 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 239000012528 membrane Substances 0.000 abstract description 2
- 239000007864 aqueous solution Substances 0.000 abstract 2
- 239000013618 particulate matter Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- 239000004411 aluminium Substances 0.000 description 7
- 235000008207 calcium folinate Nutrition 0.000 description 7
- 239000011687 calcium folinate Substances 0.000 description 7
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 7
- 239000011575 calcium Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- JOAQINSXLLMRCV-UHFFFAOYSA-N 4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}benzoic acid Chemical compound C1=NC2=NC(N)=NC(O)=C2N=C1CNC1=CC=C(C(O)=O)C=C1 JOAQINSXLLMRCV-UHFFFAOYSA-N 0.000 description 5
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 5
- NRGONRDRXCPMIC-GDKBPFBDSA-N N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 Chemical class N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 NRGONRDRXCPMIC-GDKBPFBDSA-N 0.000 description 5
- 235000019152 folic acid Nutrition 0.000 description 5
- 239000011724 folic acid Substances 0.000 description 5
- 229960000304 folic acid Drugs 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012859 sterile filling Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010020741 Hyperpyrexia Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229940003871 calcium ion Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000005308 flint glass Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及亚叶酸钠注射液及其制备方法。亚叶酸钠注射液中含有亚叶酸钠和注射用水。制备方法是使亚叶酸与氢氧化钠水溶液反应生成亚叶酸钠水溶液，用氢氧化钠或盐酸调节pH值为7.8～8.1，制得半成品溶液，半成品溶液经过双层微孔滤膜(0.22μm)过滤，装入瓶中，最后用橡胶塞密封，整个制备过程在充氮气环境中进行。本发明的亚叶酸钠性能稳定，有利于长期贮存，微粒物质少，污染机会少，临床应用效果好。The present invention relates to sodium folinate injection and a preparation method thereof. The sodium folinate injection contains sodium folinate and water for injection. The preparation method comprises reacting folinic acid with a sodium hydroxide aqueous solution to generate a sodium folinate aqueous solution, adjusting the pH value to 7.8-8.1 with sodium hydroxide or hydrochloric acid, and obtaining a semi-finished solution, filtering the semi-finished solution through a double-layer microporous filter membrane (0.22 μm), filling the bottle, and finally sealing the bottle with a rubber stopper. The entire preparation process is carried out in a nitrogen-filled environment. The sodium folinate of the present invention has stable performance, is conducive to long-term storage, has less particulate matter, has less pollution opportunities, and has good clinical application effects.
Description
Technical field
The present invention relates to a kind of sodium folinate injection and preparation method thereof.
Background technology
The chemical formula of folinic acid (FA) is N-[4-(2-amino-5-formoxyl-5,6,7, a 8-tetrahydrochysene-4-hydroxyl-pteridine-6-methylamino) benzoyl]-L (+)-glutamic acid, have another name called 5-formyl tetrahydrofolic acid or folinic acid.Calcium folinate at home and abroad goes on the market for many years, and clinical being mainly used in and the 5-fluorouracil drug combination increases the effect of its treatment colorectal cancer, also can be used as the excessive cure of separating of methotrexate.Calcium folinate is owing to there is the existence of calcium ion, and poor solubility has certain limitation in clinical treatment.Show as: during (1) clinical application, need 1% calcium folinate solution is dissolved in 0.9% the sodium chloride isosmotic solution, increased the medication total amount and with the incoherent ionic weight of treatment; (2) calcium folinate must slowly instil, otherwise the increase meeting health risk of plasma calcium ion concentration; (3) calcium easily stops up tube for transfusion treatment can't be carried out.
Because the active component of calcium folinate is a folinic acid, calcium ion and drug action are irrelevant, so replace calcium folinate with leucovorin sodium, not only uncorrelated impurity is few in consumption minimizing and the preparation, and clinical application effect is better than calcium folinate.Because leucovorin sodium is to factor sensitivities such as temperature, pH value, oxygen, stability is poor, therefore, still needs to develop new sodium folinate injection product, meets clinical needs.
Summary of the invention
The present invention is directed to above-mentioned present situation, aim to provide simple sodium folinate injection of a kind of prescription and preparation method thereof, avoided leucovorin sodium because of the existence of hyperpyrexia, low pH value and oxygen causes decomposing, help long term store, impurity content is low, clinical practice safety.
In the injection of the present invention, leucovorin sodium accounts for 4～6% of injection gross weight, with hydrochloric acid or sodium hydroxide the pH value of injection is adjusted to 7.8 to 8.1, and all the other are water for injection.
The preparation method of sodium folinate injection may further comprise the steps:
1) under aseptic condition, with water for injection and nitrogen perfusion washing mixer;
2) keep the inflated with nitrogen state to add folinic acid down, add sodium hydroxide solution under stirring, make it dissolve salify fully, adjusting pH value with NaOH or HCL is 7.8 to 8.1, adds water for injection to ormal weight, obtains semi-finished product solution;
3) content of oxygen in the detection semi-finished product solution is controlled at below the 1ppm;
4) under aseptic and inflated with nitrogen state, semi-finished product solution in the bottle of packing into, adds the sealing of plug and aluminium lid through the double-deck filtering with microporous membrane of 0.22 μ m at last.
Be no more than 8 hours from the filtration sterilization that begins to produce semi-finished product solution, finishing to finish to fill from the filtration sterilization of semi-finished product solution also is no more than 8 hours.
Sodium folinate injection of the present invention has the following advantages: prescription is simple, saves cost; Avoid the degraded of the leucovorin sodium that Yin Gaowen, pH value and oxygen causes, improved stability.
The long-term stable experiment result shows, after all loading amount specification samples stored 36 months, it is original 5% that the decline of content is no more than, in the 95-105% scope; The enhancing of the reduction of pH value and solution absorption degree is all in prescribed limit; Related substances 5-Calcium Folinate-SF pteroic acid, 5, the content of 10-two formyl tetrahydrofolic acids and folic acid is very stable, and other impurity does not all go beyond the limit.
According to experimental result, determine that the shelf-life is 36 months (condition of storage: 2-8 ℃ keeps in Dark Place).
Sodium folinate injection of the present invention is under room temperature (20-23 ℃) sunshine condition, and is stable in 72 hours with the sample of 0.9% sodium chloride dilution.In addition, (sample PP) is tested in room temperature (25 ± 2 ℃) and refrigerator-freezer (5 ± 2 ℃) for PE, PVC, and the result proves that various transfusion bag are to the not influence of leucovorin sodium solution to depositing in different transfusion bag.
Description of drawings:
Fig. 1 is the technological process of production figure of sodium folinate injection of the present invention
The specific embodiment:
The preparation method of sodium folinate injection of the present invention is: with the mixer steam sterilization, add down at 20 ℃ then and be equivalent to the water for injection of final preparation amount 80% in sterilized mixer, keep vacuum state beginning in 10 minutes inflated with nitrogen at least 10 minutes, and in whole mixed process, keep the inflated with nitrogen state; Stirring down, (150 rev/mins) add folinic acid in the mixer, stirred (150-200 rev/min) suspension 10 minutes, the NaOH solution of adding 20% makes folinic acid dissolve salify fully, regulating pH value with 20% NaOH simultaneously is 7.8-8.1, each add mix 2 minutes even to guarantee solution, if necessary, it is 7.8-8.1 that the hydrochloric acid of adding 3.7% is regulated pH value, add remaining water for injection and reach ormal weight, if desired, the osmotic pressure that adds the sodium chloride regulator solution continued mixed solution 9-12 minute, guaranteed that solution is even, draw 2 portions of 20ml mixed liquors with pipet or flask through sterilization, carry out microbial check,, promptly obtain semi-finished product solution at nitrogen current lower seal mixing reactor; Detect the content of oxygen in the semi-finished product solution, be controlled at below the 1ppm; Under aseptic and inflated with nitrogen state, semi-finished product solution in the bottle of packing into, adds the sealing of plug and aluminium lid through the double-deck filtering with microporous membrane of 0.22 μ m at last; Be no more than 8 hours from the filtration sterilization that begins to produce semi-finished product solution, finishing to finish to fill from the filtration sterilization of semi-finished product solution also is no more than 8 hours.Sterile filling, add the sealing of plug and aluminium lid and adopt automatic loading production line, fill, add plug and the aluminium lid water-tight equipment is in the horizontal laminar flow state fully, make fill liquid from mixer, transfer to filling machine by adding nitrogen pressure.
Further explain content of the present invention in the mode of embodiment below, but should not be construed as limitation of the present invention.
Embodiment 1:
With the mixer steam sterilization, add 32.5-35.8L water for injection down in sterilized mixer at 20 ℃ then, keep vacuum state beginning in 10 minutes inflated with nitrogen at least 10 minutes, and in whole mixed process, keep the inflated with nitrogen state; Stirring down, (150 rev/mins) add the 2239g folinic acid in the mixer, stirred (150-200 rev/min) suspension 10 minutes, the NaOH solution of adding 20% makes folinic acid dissolve salify fully, regulating pH value with 20% NaOH simultaneously is 7.8-8.1, each add mix 2 minutes even to guarantee solution, if necessary, it is 7.8-8.1 that the hydrochloric acid of adding 3.7% is regulated pH value, add remaining water for injection and reach ormal weight 45.5kg, if desired, the osmotic pressure that adds the sodium chloride regulator solution continued mixed solution 9-12 minute, guaranteed that solution is even, draw 2 portions of 20ml mixed liquors with pipet or flask through sterilization, carry out microbial check,, promptly obtain semi-finished product solution at nitrogen current lower seal mixing reactor; Detect the content of oxygen in the semi-finished product solution, be controlled at below the 1ppm; Under aseptic and inflated with nitrogen state, semi-finished product solution in the bottle of packing into, adds the sealing of plug and aluminium lid through the double-deck filtering with microporous membrane of 0.22 μ m at last; Be divided into 100mg during fill, 200mg, three specifications of 300mg (in leucovorin sodium).Be no more than 8 hours from the filtration sterilization that begins to produce semi-finished product solution, finishing to finish to fill from the filtration sterilization of semi-finished product solution also is no more than 8 hours.Sterile filling, add the sealing of plug and aluminium lid and adopt automatic loading production line, fill, add plug and the aluminium lid water-tight equipment is in the horizontal laminar flow state fully, make fill liquid from mixer, transfer to filling machine by adding nitrogen pressure.
Stability study:
In order to assess the influence of pH value (6.0-8.5), higher temperature and oxygen, carried out the research of Journal of Sex Research steady in a long-term and accelerated stability to the leucovorin sodium stability of solution.The result shows: the existence of high temperature, oxygen and be lower than PH6, can quicken the degraded of folinic acid.Avoid high temperature sterilize, add protective gas and make pH value greater than 7.3, the trend that content is reduced slows down.Therefore the pH value of finished product is limited between the 7.5-8.0, and sterilization method adopts double-deck microporous filter membrane (0.22 μ m) to filter, and the fill of semi-finished product solution and storage need the inflated with nitrogen protection.
1, accelerated stability research
Leucovorin sodium 50mg/ml injection: specification: 100mg/ bottle
Condition of storage: 25 ± 2 ℃, relative humidity 60% ± 5%
Not (n.c.=no change) (n.d.=can not detect) (n.t.=does not detect)
| Test item | Beginning | 3 months | 6 months |
| Outward appearance | Consistent | Consistent | Consistent |
| Trap (420nm dilution in 1: 10) | 0.04 | 0.307 | 0.547 |
| Microgranule: granule 〉=10 μ m granules 〉=25 μ m | 8.8 0.0 | 25.2 0.4 | 19.6 0.4 |
| pH | 7.8 | 7.0 | 6.9 |
| Content (labelled amount %) | 96.6 | 88.0 | 84.8 |
| The reduction of content (%) | 8.90 | 12.22 | |
| Impurity 5-Calcium Folinate-SF pteroic acid | ＜0.1 | ＜0.1 | 0.2 |
| PABG | ＜0.1 | 0.7 | 1.1 |
| 10-formyl dihydrofoilic acid | 0.4 | 1.9 | 1.4 |
| 5,10-two formyl tetrahydrofolic acids | n.d. | n.d. | n.d. |
| The 10-formylpropionic acid | 0.1 | 1.4 | 2.7 |
| Folic acid | ＜0.1 | ＜0.1 | 0.3 |
| Indivedual unknown impurities | ＜0.1 | 0.5 | 0.4 |
| The unknown impuritie total amount | ＜0.1 | 1.4 | 0.4 |
| Aseptic | Aseptic | (n.t.) | Aseptic |
| Bacterial endotoxin | ＜6.0 | (n.t.) | ＜6.0 |
2, long-term stable experiment:
Experimental condition:
Storage requirement: 5 ± 2 ℃ of temperature
Packing: flint glass is bottled, upright or inversion.
Minute: 0,3,6,9,12,18,24,36 months respectively sampling press stability test quality standard watch test.
High, normal, basic three specifications are deposited testing result scope table after 36 months under 5 ± 2 ℃
| Parameter | 100mg | 200mg | 300mg |
| Outward appearance | Consistent | Consistent | Consistent |
| Color | ＜GY2 | n.t. | n.t. |
| Trap (420nm) | 0.177-0.182 | 0.197 | 0.183 |
| Microgranule: |
| Granule 〉=10 μ m granules 〉=25 μ m | 4.4-21.2 0 | 50.4 4.8 | 92.4 3.6 |
| pH | 7.3 | 7.3 | 7.2 |
| Content (labelled amount %) | 97.0-100.1 | 91.4 | 94.6 |
| The reduction of content (%) | 2.31-4.79 | 4.81 | 4.94 |
| Impurity 5-Calcium Folinate-SF pteroic acid | ＜0.1 | ＜0.1 | ＜0.1 |
| PABG | 0.4-0.5 | 0.4 | 0.3 |
| 10-formyl dihydrofoilic acid | 0.6-0.7 | 0.2 | 0.2 |
| 5,10-two formyl tetrahydrofolic acids | n.d. | n.d. | n.d. |
| The 10-formylpropionic acid | 0.6-0.7 | 0.3 | 0.4 |
| Folic acid | 0.2 | 0.1 | 0.1 |
| Indivedual unknown impurities | 0.2-0.3 | 0.3 | 0.2 |
| The unknown impuritie total amount | 0.6-0.9 | 0.8 | 0.8 |
| Aseptic | Aseptic | Aseptic | Aseptic |
| Bacterial endotoxin | ＜6.0 | ＜6.0 | ＜6.0 |
4, instil with the stability test of cut-back product
Before instiling, sodium folinate injection needs in diluting rearmounted transfusion bag, therefore, to have studied the stability of its cut-back product.
Result of the test shows, leucovorin sodium solution is through 0.9% NaCl dilution back (folinic acid is diluted to 4-9mg/ml), in room temperature (20-23 ℃), not under the condition of lucifuge, stablizes in 72 hours.
Because plastics do not adsorb folinic acid, so diluent not only can leave in the vial, also can leave in PVC, PP or the PE transfusion bag.
25 ℃, under relative humidity 60% condition, 5-FU and 50mg/ml sodium folinate injection leave not significantly degraded in each test chamber in.Its impurity content is consistent with 0 o'clock in the research process; Consistent in impurity content and the vial in the different vessels, as seen, the 50mg/ml sodium folinate injection can be with 0.9% sodium chloride dilution, and is compatible with 5-FU solution.
5, protective gas is to the stability study of injection
Whole preparation sodium folinate injection process is all carried out in the inflated with nitrogen environment; we have carried out inflated with nitrogen and the not comparative study of inflated with nitrogen; and carried out accelerated tests; the result proves that the adding of protective gas nitrogen avoided the degraded of the leucovorin sodium that Yin Gaowen, pH value and oxygen causes, has improved stability.
The inflated with nitrogen environment:
Leucovorin sodium 50mg/ml injection: specification: 100mg/ bottle
Condition of storage: 25 ± 2 ℃, relative humidity 60% ± 5%
Not (n.c.=no change) (n.d.=can not detect) (n.t.=does not detect)
| Test item | Beginning | 3 months | 6 months |
| Outward appearance | Consistent | Consistent | Consistent |
| pH | 7.8 | 7.0 | 6.9 |
| Content (labelled amount %) | 96.6 | 88.0 | 84.8 |
| Impurity 5-Calcium Folinate-SF pteroic acid | ＜0.1 | ＜0.1 | 0.2 |
| PABG | ＜0.1 | 0.7 | 1.1 |
| 10-formyl dihydrofoilic acid | 0.4 | 1.9 | 1.4 |
| 5,10-two formyl tetrahydrofolic acids | n.d. | n.d. | n.d. |
| The 10-formylpropionic acid | 0.1 | 1.4 | 2.7 |
| Folic acid | ＜0.1 | ＜0.1 | 0.3 |
| Indivedual unknown impurities | ＜0.1 | 0.5 | 0.4 |
| The unknown impuritie total amount | ＜0.1 | 1.4 | 0.4 |
| Aseptic | Aseptic | (n.t.) | Aseptic |
| Bacterial endotoxin | ＜6.0 | (n.t.) | ＜6.0 |
Inflated with nitrogen environment not:
Leucovorin sodium 50mg/ml injection: specification: 100mg/ bottle
Condition of storage: 25 ± 2 ℃, relative humidity 60% ± 5%
Not (n.c.=no change) (n.d.=can not detect) (n.t.=does not detect)
| Test item | Beginning | 3 months | 6 months |
| Outward appearance | Consistent | Consistent | Consistent |
| pH | 7.0 | 6.3 | 5.9 |
| Content (labelled amount %) | 90.1 | 82.6 | 81.0 |
| Impurity 5-Calcium Folinate-SF pteroic acid | ＞0.1 | ＞0.2 | ＞0.2 |
| PABG | ＞0.1 | 0.9 | 1.4 |
| 10-formyl dihydrofoilic acid | 0.8 | 2.3 | 2.6 |
| 5,10-two formyl tetrahydrofolic acids | 0.05 | 0.07 | 0.11 |
| The 10-formylpropionic acid | 0.6 | 1.9 | 2.8 |
| Folic acid | ＞0.1 | 0.2 | 0.4 |
| Indivedual unknown impurities | ＜0.1 | 0.7 | 0.8 |
| The unknown impuritie total amount | ＜0.1 | 1.1 | 0.7 |
| Aseptic | Aseptic | (n.t.) | Aseptic |
| Bacterial endotoxin | ＜6.0 | (n.t.) | ＜6.0 |
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510076773 CN1799546A (en) | 2005-06-14 | 2005-06-14 | Sodium folinate injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510076773 CN1799546A (en) | 2005-06-14 | 2005-06-14 | Sodium folinate injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1799546A true CN1799546A (en) | 2006-07-12 |
Family
ID=36809907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510076773 Pending CN1799546A (en) | 2005-06-14 | 2005-06-14 | Sodium folinate injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1799546A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068435A (en) * | 2011-01-10 | 2011-05-25 | 齐建新 | Composite fluorouracil anti-tumor medicament |
| CN102125558A (en) * | 2011-01-10 | 2011-07-20 | 齐建新 | Compound sodium levofolinate fluorouracil antineoplastic medicament |
| CN101229167B (en) * | 2008-02-21 | 2011-08-24 | 齐建新 | Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines |
| CN102258463A (en) * | 2011-07-18 | 2011-11-30 | 重庆煜澍丰医药有限公司 | Stable sodium folinate injection |
| CN112472673A (en) * | 2020-12-07 | 2021-03-12 | 南京海纳医药科技股份有限公司 | Freeze dried levofolinic acid powder for injection and its production process |
| CN118059042A (en) * | 2024-04-17 | 2024-05-24 | 成都瑞尔医药科技有限公司 | Calcium folinate injection and preparation method thereof |
-
2005
- 2005-06-14 CN CN 200510076773 patent/CN1799546A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229167B (en) * | 2008-02-21 | 2011-08-24 | 齐建新 | Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines |
| CN102068435A (en) * | 2011-01-10 | 2011-05-25 | 齐建新 | Composite fluorouracil anti-tumor medicament |
| CN102125558A (en) * | 2011-01-10 | 2011-07-20 | 齐建新 | Compound sodium levofolinate fluorouracil antineoplastic medicament |
| CN102258463A (en) * | 2011-07-18 | 2011-11-30 | 重庆煜澍丰医药有限公司 | Stable sodium folinate injection |
| CN112472673A (en) * | 2020-12-07 | 2021-03-12 | 南京海纳医药科技股份有限公司 | Freeze dried levofolinic acid powder for injection and its production process |
| CN118059042A (en) * | 2024-04-17 | 2024-05-24 | 成都瑞尔医药科技有限公司 | Calcium folinate injection and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101439031B (en) | Pharmaceutical composition containing 18 kinds of amino acid | |
| CN1799546A (en) | Sodium folinate injection and preparation method thereof | |
| CN105106110A (en) | Injectable medicine composition capable of improving stability of puerarin medicine injection preparation and preparation method of injectable medicine composition | |
| CN106822175A (en) | A kind of sodium acid carbonate ringer's injection and preparation method thereof | |
| WO2022206090A1 (en) | Pentoxifylline injection, and preparation method therefor | |
| JP6957233B2 (en) | Stable injectable solution of pemetrexed | |
| CN114288385B (en) | Preparation method of octreotide acetate preparation | |
| CN104666241A (en) | Preparation method of high-stability linezolid injection liquid | |
| CN112842991B (en) | Preparation method of granisetron hydrochloride injection | |
| CN113521244A (en) | Argatroban injection and preparation method thereof | |
| CN105125485A (en) | Preparation method of injecting drug improving stability of puerarin drug injection preparation | |
| CN105708852A (en) | Fluconazole and sodium chloride injection and preparation method thereof | |
| CN101933922A (en) | Amino acid composition containing new antioxidant | |
| WO2022222630A1 (en) | Multiple electrolytes injection and preparation method therefor | |
| CN104840418A (en) | Fasudil hydrochloride injection composition and preparation method thereof | |
| CN108743527B (en) | Tirofiban hydrochloride injection and preparation method thereof | |
| CN113171340B (en) | Alanyl glutamine injection and production process thereof | |
| CN116440158A (en) | Iron sucrose composition, and preparation method and application thereof | |
| CN111643521A (en) | Injection containing 10 trace elements and preparation process thereof | |
| CN101664385B (en) | Ibutilide fumarate injection and preparation method thereof | |
| CN109381457A (en) | A kind of pharmaceutical composition and preparation method thereof containing 14 kinds of amino acid | |
| CN119385943B (en) | Phenylephrine hydrochloride injection and its preparation process | |
| CN116509799B (en) | Naloxone hydrochloride injection and preparation method thereof | |
| CN113252589B (en) | Detection method for content of sodium carboxymethylcellulose in wine | |
| CN110755373A (en) | Fasudil hydrochloride injection pharmaceutical composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |