CN103142512B - High-quality composition containing oxaliplatin and preparation method of composition - Google Patents
High-quality composition containing oxaliplatin and preparation method of composition Download PDFInfo
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- CN103142512B CN103142512B CN201310093074.XA CN201310093074A CN103142512B CN 103142512 B CN103142512 B CN 103142512B CN 201310093074 A CN201310093074 A CN 201310093074A CN 103142512 B CN103142512 B CN 103142512B
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- oxaliplatin
- lactose
- weight
- aqueous solution
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 49
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 49
- 239000000203 mixture Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002158 endotoxin Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000002347 injection Methods 0.000 claims abstract description 15
- 239000007924 injection Substances 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000000843 powder Substances 0.000 claims abstract 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 39
- 239000008101 lactose Substances 0.000 claims description 39
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 11
- 239000003610 charcoal Substances 0.000 claims description 8
- 238000007796 conventional method Methods 0.000 claims description 8
- 230000008676 import Effects 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 4
- 239000002510 pyrogen Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 231100000337 synergistic cytotoxicity Toxicity 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a high-quality composition containing oxaliplatin. The bacterial endotoxin of the composition is detected by the method specified by standards on registration of imported drug of oxaliplatin for injection; and the composition contains the bacterial endotoxin less than 0.5EU per 1mg. The invention also discloses a method for preparing high-quality oxaliplatin freeze-dried powder. The oxaliplatin composition disclosed by the invention is high in quality and high in safety. The preparation method disclosed by the invention is easy for industrialization.
Description
Technical field
Herein disclosed is a kind of compositions that contains oxaliplatin, with and preparation method thereof.
Technical background
Oxaliplatin is a kind of platinum series antineoplastic medicament that all has in vivo and in vitro broad-spectrum anti-tumor activity, and the tumor cell of resistance to cisplatin is also had to cytotoxicity.In vivo with in vitro study in, all can be observed the synergistic cytotoxicity of oxaliplatin and 5-fluorouracil use in conjunction.
At present, oxaliplatin as the first-line treatment medicinal application of metastatic colorectal carcinoma in clinical.When as treatment, oxaliplatin is with intravenous form administration.Intravenous injection is that one absorbs without human gastrointestinal tract, directly by the administering mode of infusion of medicine blood of human body, if contain harmful antibacterial or pyrogen in the preparation of injection, these harmful materials will directly enter blood circulation of human body without gastrointestinal tract barrier, and these harmful substances also can cause great infringement to human body even quantity is extremely small.Therefore drug control department in various countries' all requires the aseptic safeguard level of preparation of injection can guarantee the safety of human body medication in drug quality.
The pyrogen that Oxaliplatin for Injection may contain is mainly bacterial endotoxin.Bacterial endotoxin is brought into by gram negative bacteria.Antibacterial does not discharge in the time of animation, when only having when the dead self-dissolving of antibacterial or sticking to other cell, just shows its toxicity, and the main chemical compositions of bacterial endotoxin is the lipoid A composition in lipopolysaccharide.It has the multiple serious effect such as pyrogenicity, lethal toxicity.Therefore, in " Chinese Pharmacopoeia ", there is pair general provision of injection Bacterial endotoxin limit, in drug standard, the bacterial endotoxin to Oxaliplatin for Injection has clear and definite requirement, such as, in the import drugs registered standard JX20020117 of Oxaliplatin for Injection, stipulate, the amount containing bacterial endotoxin in every 1mg is less than 1EU.
Although be qualified products by the product of the standard control bacterial endotoxin of this import drugs standard or " Chinese Pharmacopoeia ", if the standard of bacterial endotoxin is promoted, patient's the safety of drug safety and product life-time service will more be contributed to.
Summary of the invention
The invention provides the compositions that contain oxaliplatin of a kind of quality standard far above the high-quality of existing national standard.
The compositions that contains oxaliplatin of high-quality provided by the invention, its bacterial endotoxin, detects its bacterial endotoxin by the method for Oxaliplatin for Injection import drugs registered standard regulation, and the content in every 1mg is less than 0.5EU.
The compositions that contains oxaliplatin of the present invention is Oxaliplatin for Injection, is preferably the Oxaliplatin for Injection using lactose as carrier.
The present invention also provides a kind of method that contains oxaliplatin compositions of preparing, and comprises the following steps:
1) prepare according to a conventional method lactose aqueous solution;
2) add charcoal treatment lactose aqueous solution, the weight of wherein said active carbon is the 0.5%-2% of lactose aqueous solution weight;
3) compositions that preparation contains oxaliplatin according to a conventional method.
The addition of wherein said active carbon, is preferably 1% of lactose solution weight.
Lactose is the cryodesiccated carrier of oxaliplatin, large usage quantity.And all deriving from animal as the lactose of pharmaceutic adjuvant, the risk that polluted by bacterial endotoxin is higher.In order to reduce the risk that contains bacterial endotoxin in final products, the present invention is preparing after lactose aqueous solution, first uses a large amount of charcoal treatment lactose aqueous solutions, the burden that greatly reduces subsequent technique and remove bacterial endotoxin.If but addition is excessive, after will increase difficulty in the filter progress that fills.From being beneficial to industrialization, can remove the bacterial endotoxin in lactose and to facilitate post-order process as benchmark, after test, the addition of active carbon is at the 0.5-2% of lactose aqueous solution weight, and particularly 1% left and right is comparatively suitable.
For more effectively removing the bacterial endotoxin in product, the method that the present invention also provides another preparation to contain oxaliplatin, is to be briefly dissolved in after lactose aqueous solution at oxaliplatin, has carried out again once except bacterial endotoxin processing.Be exactly specifically,
1) prepare according to a conventional method lactose aqueous solution;
2) add charcoal treatment lactose aqueous solution, the weight of wherein said active carbon is the 0.5%-2% of lactose solution weight;
3) oxaliplatin is dissolved in after lactose aqueous solution, adds charcoal treatment oxaliplatin lactose aqueous solution, and the weight of wherein said active carbon is the 0.05%-0.09% of the weight of oxaliplatin lactose aqueous solution;
4) carry out according to a conventional method lyophilization.
Wherein said step 2) in the weight of active carbon be 1% of lactose solution weight; In step 3) the weight of active carbon be oxaliplatin lactose aqueous solution weight 0.05%.
In the method for preparing injection of routine, generally there is a step to remove pyrogen or bacterial endotoxin, before fill, use activated carbon adsorption.The general consumption of active carbon is amount of liquid medicine 0.1%～0.5%.In the present invention, the amounts of activated carbon adopting in this technique is very little, only has 0.05%-0.09%, and preferably 0.05%.
Because active carbon has obvious absorption to oxaliplatin, activated carbon dosage is larger, more to the absorption of oxaliplatin.With the charcoal treatment medicinal liquid of small amount, effectively reduce the absorption of active carbon to oxaliplatin, improve the accuracy of loading amount, guarantee the accuracy of using dosage.
Oxaliplatin for Injection provided by the invention, has the more bacterial endotoxin of low content, thereby has higher safety; Because adopted meticulousr preparation technology, make the content of product more accurate simultaneously.Simultaneously very simple of technique of the present invention, is suitable for suitability for industrialized production.
The specific embodiment
Embodiment 1
A, batch prescription
Specification: 50 mg
B, preparation method
1) preparation of lactose solution
Getting lactose, to make concentration be 20% lactose solution, adds lactose solution amount 1%(W/W) needle-use activated carbon, use the filter pressure filtration after pressure sterilizing sterilization, remove active carbon, collect filtrate, inject dilute with water and make 4% lactose solution.
2), the preparation of medicinal liquid
Get recipe quantity oxaliplatin, add 4% lactose solution of recipe quantity, stir and make its dissolving.
Add amount of liquid medicine 0.05%(W/W) needle-use activated carbon, under room temperature, stir after 30 minutes, coarse filtration is removed active carbon.
3), technique is carried out the operations such as aseptic filtration, the inspection of semifinished product, fill, lyophilizing routinely, makes finished product.
C, (identical with the algoscopy essence of 2000 editions by the gel method mensuration in " Chinese Pharmacopoeia " 2010 bacterial endotoxins tests, operate more rigorous compared with 2000 editions) edition method bacterial detection endotoxin stipulating, record bacteria endotoxin content and be less than 0.25EU/mg; Survey content by the method for import drugs registered standard JX20020117 regulation, recording content is 49.89mg/ bottle.
Embodiment 2-7
The active carbon of following examples 2-7 feeds intake as shown in the table, and preparation technology is as embodiment 1.
And survey bacterial endotoxin and content according to the method for embodiment 1, survey the bacterial endotoxin of each embodiment and content as following table.
Claims (4)
1. a method that contains oxaliplatin compositions of preparing high-quality, comprises the following steps:
1), prepare according to a conventional method lactose aqueous solution;
2), adding charcoal treatment lactose aqueous solution, the weight of wherein said active carbon is the 0.5%-2% of lactose solution weight;
3), post-order process according to a conventional method, obtain contain oxaliplatin compositions;
The wherein said compositions that contains oxaliplatin, detect its bacterial endotoxin by the method for Oxaliplatin for Injection import drugs registered standard regulation, amount containing bacterial endotoxin in every 1mg is less than 0.5EU, and the wherein said compositions that contains oxaliplatin is freeze-dried powder;
The wherein said compositions that contains oxaliplatin, take lactose as carrier.
2. the preparation method of Oxaliplatin for Injection as claimed in claim 1, is characterized in that the weight of described active carbon is 1% of lactose solution weight.
3. preparation method as claimed in claim 1 or 2, comprises the following steps:
1) prepare according to a conventional method lactose aqueous solution;
2) add charcoal treatment lactose aqueous solution, the weight of wherein said active carbon is the 0.5%-2% of lactose solution weight;
3) oxaliplatin is dissolved in after lactose aqueous solution, adds charcoal treatment oxaliplatin lactose aqueous solution, and the weight of wherein said active carbon is the 0.05%-0.09% of oxaliplatin lactose aqueous solution weight;
4) carry out according to a conventional method lyophilization;
The wherein said compositions that contains oxaliplatin, detect its bacterial endotoxin by the method for Oxaliplatin for Injection import drugs registered standard regulation, amount containing bacterial endotoxin in every 1mg is less than 0.5EU, and the wherein said compositions that contains oxaliplatin is freeze-dried powder;
The wherein said compositions that contains oxaliplatin, take lactose as carrier.
4. preparation method as claimed in claim 3, the weight that it is characterized in that the active carbon of described step 3) be oxaliplatin lactose aqueous solution weight 0.05%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310093074.XA CN103142512B (en) | 2013-03-21 | 2013-03-21 | High-quality composition containing oxaliplatin and preparation method of composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310093074.XA CN103142512B (en) | 2013-03-21 | 2013-03-21 | High-quality composition containing oxaliplatin and preparation method of composition |
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| Publication Number | Publication Date |
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| CN103142512A CN103142512A (en) | 2013-06-12 |
| CN103142512B true CN103142512B (en) | 2014-06-11 |
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| CN201310093074.XA Active CN103142512B (en) | 2013-03-21 | 2013-03-21 | High-quality composition containing oxaliplatin and preparation method of composition |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525957A (en) * | 2011-12-15 | 2012-07-04 | 苏州二叶制药有限公司 | Preparation method of Oxaliplatin for injection |
-
2013
- 2013-03-21 CN CN201310093074.XA patent/CN103142512B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525957A (en) * | 2011-12-15 | 2012-07-04 | 苏州二叶制药有限公司 | Preparation method of Oxaliplatin for injection |
Non-Patent Citations (2)
| Title |
|---|
| 权莹、杨国军.注射用奥沙利铂细菌内毒素检查法研究.《内江师范学院学报》.2007,第22卷(第2期),57-59. |
| 注射用奥沙利铂细菌内毒素检查法研究;权莹、杨国军;《内江师范学院学报》;20070430;第22卷(第2期);57-59 * |
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| CN103142512A (en) | 2013-06-12 |
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| CB02 | Change of applicant information |
Address after: 310012 West Lake international science and technology building, No. 391 Wen two road, Hangzhou, Zhejiang, C910, Xihu District Applicant after: HANGZHOU HUADONG MEDICINE GROUP NEW MEDICINE RESEARCH INSTITUTE CO., LTD. Address before: 310012 West Lake international science and technology building, No. 391 Wen two road, Hangzhou, Zhejiang, C910, Xihu District Applicant before: Hangzhou Huadong Medicine Group Biological Engineering Research Institute Co., Ltd. |
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Free format text: CORRECT: APPLICANT; FROM: HUADONG MEDICINE BIOLOGICAL ENGINEERING RESEARCH INSTITUTE CO., LTD. TO: NEW DRUG RESEARCH INSTITUTE CO., LTD. OF HANGZHOU HUADONG MEDICINE GROUP |
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Application publication date: 20130612 Assignee: Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou Assignor: HANGZHOU HUADONG MEDICINE GROUP NEW MEDICINE RESEARCH INSTITUTE CO., LTD. Contract record no.: 2015330000275 Denomination of invention: High-quality composition containing oxaliplatin and preparation method of composition Granted publication date: 20140611 License type: Exclusive License Record date: 20151211 |
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Effective date of registration: 20160418 Address after: 310012 West Lake international science and technology building, No. 391 Wen two road, Hangzhou, Zhejiang, C910, Xihu District Patentee after: HANGZHOU HUADONG MEDICINE GROUP NEW MEDICINE RESEARCH INSTITUTE CO., LTD. Patentee after: Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou Address before: 310012 West Lake international science and technology building, No. 391 Wen two road, Hangzhou, Zhejiang, C910, Xihu District Patentee before: HANGZHOU HUADONG MEDICINE GROUP NEW MEDICINE RESEARCH INSTITUTE CO., LTD. |