CN103142511B - High-purity and high-stability composition containing oxaliplatin and preparation method of composition - Google Patents
High-purity and high-stability composition containing oxaliplatin and preparation method of composition Download PDFInfo
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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 45
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 45
- 239000000203 mixture Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 28
- 239000012535 impurity Substances 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000002347 injection Methods 0.000 claims abstract description 13
- 239000007924 injection Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 238000000859 sublimation Methods 0.000 claims description 23
- 230000008022 sublimation Effects 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 15
- 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 14
- 239000008101 lactose Substances 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 230000000630 rising effect Effects 0.000 claims description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 230000008676 import Effects 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000001914 filtration Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 229920002307 Dextran Polymers 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000012423 maintenance Methods 0.000 description 5
- 239000011265 semifinished product Substances 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000004108 freeze drying 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
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000004071 biological 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
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 231100000337 synergistic cytotoxicity Toxicity 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a high-purity and high-stability composition containing oxaliplatin. The total amount of impurities in the composition are detected by the method specified by standards on registration of imported drug of oxaliplatin for injection, and the total amount of the impurities is less than 0.5%, which is far above the value specified in the standard. The invention also discloses a method for preparing high-purity oxaliplatin lyophilized powder. The oxaliplatin composition disclosed by the invention is high in quality, high in safety and excellent in stability, and can be used for effectively prolonging the expiration date of a product to four years or more. The preparation method disclosed by the invention is easy for industrialization.
Description
Technical field
Herein disclosed is a kind of preparation method of the freeze-dried powder for the compositions that contains oxaliplatin of injecting.
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 the impurity producing from raw material or production process in the preparation of injection, these impurity will directly enter blood circulation of human body without gastrointestinal tract barrier, and these impurity also may cause great infringement to human body even quantity is extremely small.Because compound chemical change can occur in storage process as oxidation, decompose etc., impurity will be accumulated along with the prolongation of medicine storage time.The principal element that determines Oxaliplatin for Injection effect duration is also the growth of total impurities in storage process.
In the quality standard of existing product, total impurities is an important index, therefore, in drug quality, total impurities is had to strict requirement, such as the national drug standards (the WS1-(X-090)-2003Z of State Food and Drug Administration) in related substance is limited to " summation of each impurity peak area, must not be greater than reference substance solution main constituent peak peak area 1.0% ".(standard No.: JX20020117) regulation " total amount of impurity must not cross oxaliplatin labelled amount 1.0% " in import drugs registered standard.
If therefore can control the amount of oxaliplatin impurity well, will effectively improve the quality of product, reduce the generation of side effect, make medication safer; Also will improve the stability of medicine simultaneously, extend the effect duration of product, thereby reduce selling cost.
Summary of the invention
The invention provides a kind of quality standard far above the high-purity of existing drug standard and the compositions that contains oxaliplatin of high stability.
Highly purified Oxaliplatin for Injection provided by the invention, detects its total impurities by the method for Oxaliplatin for Injection import drugs registered standard JX20020117 regulation, and its total impurities is lower than 0.5%.
The impurity of known chemical constitution comprises oxalic acid, two water diamino cyclohexane extraction platinum, two hydroxo oxaliplatins, also has the impurity of chemical constitution the unknown.Total impurities refers to the summation of above-mentioned all impurity.
The compositions that contains oxaliplatin of the present invention is Oxaliplatin for Injection.Its excipient is selected from one or more in lactose, mannitol, glucose sugar, cyclodextrin, sucrose, trehalose, glycine, histidine, dextran, Polyethylene Glycol.Excipient and oxaliplatin routinely mass ratio carry out proportioning.
In order to obtain total impurities lower than 0.5% high-purity Oxaliplatin for Injection, the present invention also provides preparation method:
1) prepare according to a conventional method the aqueous solution containing excipient,
2) oxaliplatin is dissolved in to excipient aqueous solution, the temperature of excipient aqueous solution maintains 35 ℃ ± 1 ℃;
3) in the time of lyophilizing, dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 6～8 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within about 45-55 hour, temperature is risen to 0 ℃, sublimation stage vacuum 0.1-0.2mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in about 5-9 hour, and baffle temperature keeps 4-15 hour at 35 ℃
Wherein step 2) described in dissolving oxaliplatin time, the temperature of excipient aqueous solution is preferably 35 ℃.
Wherein shelf temperature is down to-45 ℃, pre-freeze 7 hours when the pre-freeze described in step 3).
Wherein the duration of sublimation stage described in step 3) is 50 hours; Vacuum maintains 0.2mbar.
In the quality standard of injection, impurity content is an important Index for examination.In preparation, impurity produces and mainly contains three kinds of approach, and the one, in raw material, bring into; The 2nd, in the production process of preparation, produce; The 3rd, preparation deposit process in produce.And the main source of impurity is exactly the chemical change of medicine itself in latter two approach.Temperature and reaction medium are the key factors that chemical change is occurred.In the preparation process of Oxaliplatin for Injection, need to carry out dosing, be dissolved in the water and make solution by oxaliplatin, this process need carries out at a certain temperature, water is a kind of reaction medium, and dissolve and will continue for some time, therefore, the height of solution temperature and the length of persistent period can be brought the difference of the initial impurity content of product.And temperature is relevant to dissolution time, temperature is higher, and dissolution time is shorter, and temperature is lower, and dissolution time is longer.Temperature is high, and impurity increases fast.Temperature is low, and impurity increases slow, but the persistent period is long, and impurity accumulation is many, and the persistent period is short, and impurity accumulation is few.
Production technology of the present invention has been controlled the solution temperature of oxaliplatin subtly, and solution temperature is 35 ℃ ± 1 ℃, can under speed, dissolve faster, can not produce more impurity because of excess Temperature again.Effectively control the growth of impurity in preparation process.The present invention has investigated the relation of solution temperature and total impurities by test, thereby determines optimum temperature of solubilization temperature of the present invention.
The oxaliplatin (0.15g) of equal in quality is dissolved in the water (25ml) of same volume, after dissolving, measure total impurities (pressing the relevant regulations of 2010 editions high performance liquid chromatography of Chinese Pharmacopoeia and import drugs registered standard JX20020117) with identical method, related data is as following table:
| Solution temperature | Total impurities after dissolving | Dissolution time completely |
| 60℃ | 0.7% | 8 minutes |
| 50℃ | 0.6% | 12 minutes |
| 40℃ | 0.5% | 18 minutes |
| 37℃ | 0.3% | 19 minutes |
| 36℃ | 0.2% | 20 minutes |
| 35℃ | 0.2% | 20 minutes |
| 34℃ | 0.2% | 22 minutes |
| 33℃ | 0.3% | 24 minutes |
| 25℃ | 0.5% | 40 minutes |
As can be seen from the above table, in the time that solution temperature is high, although dissolution time is short, after dissolving, total impurities is very high, and this is by the difficulty of the quality control of increase postorder product; In the time that solution temperature is lower, can reduce the growth rate of impurity, but dissolution time prolongation, the cumulative rises of impurity.And solution temperature is while maintaining 35 ℃ ± 1 ℃, its total impurities is well controlled.
Technical scheme provided by the invention is except controlling well impurity in the link of preparation, also considers fully that preparation is depositing issuable impurity in process.Because medicine may be deposited the longer time before use, therefore, in finished product, the minute differences of moisture also can produce significant impact to the effect duration of product.What the residual moisture in finished product was chemical change provides reaction medium.
Therefore the present invention will remove the moisture in product as much as possible in freezing dry process, and the setting of freeze drying process parameter is related to the final moisture of product.Freeze drying process of the present invention, has been controlled at extremely low level by the moisture in product, has got rid of to greatest extent the factor that impurity is increased.Effectively reduce the generation that preparation is deposited impurity in process.
As the medicine for people, require it to there is certain stability, namely within a period of time, keep the stable of physics and chemistry character, to guarantee its biological activity and safety, this time range is exactly the effect duration of medicine.According to the explanation of nouns of " drug research technological guidance principle " (2005), effect duration meant in a period of time, and commercially available back medicine is placed under the storage requirement of regulation, and the quality of medicine still meets registration quality standard.At present, the effect duration of commercially available Oxaliplatin for Injection is 3 years.And adopt the Oxaliplatin for Injection of explained hereafter of the present invention, and to place after 4 years, its impurity still meets registration quality standard.Therefore, adopt the stability of the Oxaliplatin for Injection of explained hereafter of the present invention will significantly be better than current existing product.The effect duration of the product of producing with the present invention can be extended for 4 years from 3 years to such an extent as to be longer, thereby has reduced the selling cost of product.
The specific embodiment
Embodiment 1 A, batch prescription
Specification: 50 mg
B, preparation method
1) preparation of lactose solution
Get lactose, add stirring and dissolving in hot water (water for injection), making concentration is 4%(W/W) lactose solution.
2) preparation of medicinal liquid
Get recipe quantity oxaliplatin, add 35 ℃ of lactose solutions of recipe quantity, stir and make its dissolving.
3) needle-use activated carbon absorption, coarse filtration is removed active carbon, aseptic filtration, the inspection of semifinished product, fill
4) lyophilizing
Use freeze dryer by sample lyophilizing.Dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 7 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within 50 hours, temperature is risen to 0 ℃, sublimation stage vacuum 0.2mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in 9 hours, and baffle temperature is resolved the period 35 ℃ of maintenances for 7 hours, removes moisture remaining in goods.
5) roll lid, check acquisition finished product.
Embodiment 2
A, batch prescription
Specification: 50 mg
B, preparation method
1) preparation of mannitol solution
Get mannitol, add stirring and dissolving in hot water (water for injection), making concentration is 4%(W/W) mannitol solution.
2) preparation of medicinal liquid
Get recipe quantity oxaliplatin, add the mannitol solution of 36 ℃ of recipe quantity, stir and make its dissolving.
3) needle-use activated carbon absorption, coarse filtration is removed active carbon, aseptic filtration, the inspection of semifinished product, fill
4) lyophilizing
Use freeze dryer by sample lyophilizing.Dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 6 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within 45 hours, temperature is risen to 0 ℃, sublimation stage vacuum 0.2mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in 5 hours, and baffle temperature is resolved the period 35 ℃ of maintenances for 15 hours, removes moisture remaining in goods.
5) roll lid, check acquisition finished product.
Embodiment 3
A, batch prescription
Specification: 50 mg
B, preparation method
1) preparation of dextran solution
Get dextran, add stirring and dissolving in hot water (water for injection), making concentration is 4%(W/W) dextran solution.
2) preparation of medicinal liquid
Get recipe quantity oxaliplatin, add the dextran solution of 34 ℃ of recipe quantity, stir and make its dissolving.
3) needle-use activated carbon absorption, coarse filtration is removed active carbon, aseptic filtration, the inspection of semifinished product, fill
4) lyophilizing
Use freeze dryer by sample lyophilizing.Dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 8 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within 55 hours, temperature is risen to 0 ℃, sublimation stage vacuum 0.1mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in 7 hours, and baffle temperature is resolved the period 35 ℃ of maintenances for 4 hours, removes moisture remaining in goods.
5) roll lid, check acquisition finished product.
Embodiment 4
A, batch prescription
Specification: 50 mg
B, preparation method
1) preparation of lactose solution
Get lactose appropriate, add stirring and dissolving in hot water (water for injection), making concentration is 4%(W/W) lactose solution.
2) preparation of medicinal liquid
Get recipe quantity oxaliplatin, add the lactose solution of 46 ℃ of recipe quantity, stir and make its dissolving.
3) needle-use activated carbon absorption, coarse filtration is removed active carbon, aseptic filtration, the inspection of semifinished product, fill
4) lyophilizing
Use freeze dryer by sample lyophilizing.Dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 7 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within 50 hours, temperature is risen to 0 ℃, sublimation stage vacuum 0.2mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in 9 hours, and baffle temperature is resolved the period 35 ℃ of maintenances for 6 hours, removes moisture remaining in goods.
5) roll lid, check acquisition finished product.
Embodiment 5
A, batch prescription
Specification: 50 mg
B, preparation method
1) preparation of lactose solution
Get lactose appropriate, add stirring and dissolving in hot water (water for injection), making concentration is 4%(W/W) lactose solution.
2) preparation of medicinal liquid
Get recipe quantity oxaliplatin, add the lactose solution of 35 ℃ of recipe quantity, stir and make its dissolving.
3) needle-use activated carbon absorption, coarse filtration is removed active carbon, aseptic filtration, the inspection of semifinished product, fill
4) lyophilizing
Use freeze dryer by sample lyophilizing.Dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 4 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within 30 hours, temperature is risen to 0 ℃, sublimation stage vacuum 0.08mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in 4 hours, and baffle temperature is resolved the period 35 ℃ of maintenances for 10 hours, removes moisture remaining in goods.
5) roll lid, check acquisition finished product.
Embodiment 6
The impurity and the moisture that detect embodiment 1, embodiment 4,5 three batches of finished products of embodiment, result is as following table.
Table 1 three batch sample assays
Embodiment 7
In embodiment 1, embodiment 4, embodiment 5, finished product was placed after 4 years, checked for impurities and moisture, and result is as following table.
Table 2 is three batch sample assays after 4 years
Claims (5)
1. a method of preparing high-purity high stability oxaliplatin compositions, comprises the following steps:
1) prepare according to a conventional method the aqueous solution containing excipient,
2) oxaliplatin is dissolved in to excipient aqueous solution, the temperature of excipient aqueous solution maintains 35 ℃ ± 1 ℃;
3) in the time of lyophilizing, dividing plate cooling is final to-45 ℃, and pre-freeze is finished for 6～8 hours; The sublimation drying stage, open vacuum pump, dividing plate starts to heat up simultaneously, within about 45-55 hour, temperature is risen to 0 ℃, sublimation stage vacuum 0.1-0.2mbar; In the parsing-desiccation stage, sublimation drying finishes follow-up temperature of continuing rising, temperature is risen to 35 ℃ in about 5-9 hour, and baffle temperature keeps 4-15 hour at 35 ℃;
Wherein said oxaliplatin compositions, detects its total impurities by the method for Oxaliplatin for Injection import drugs registered standard regulation, and its total impurities is lower than 0.5%, and the wherein said compositions that contains oxaliplatin is freeze-dried powder;
Wherein said freeze-dried powder excipient used is selected from one or more in lactose, mannitol, glucose sugar.
2. the method for preparing high-purity high stability oxaliplatin compositions as claimed in claim 1, is characterized in that step 2) described in dissolving oxaliplatin time, the temperature of excipient aqueous solution maintains 35 ℃.
3. the method for preparing high-purity high stability oxaliplatin compositions as claimed in claim 1, while it is characterized in that the pre-freeze described in step 3), shelf temperature is down to-45 ℃, pre-freeze 7 hours.
4. the method for preparing high-purity high stability oxaliplatin compositions as claimed in claim 1, is characterized in that the duration of sublimation stage described in step 3) is 50 hours; Vacuum maintains 0.2mbar.
5. the method for preparing high-purity high stability oxaliplatin compositions as claimed in claim 1, it is characterized by freeze-dried powder effect duration and be 4 years or more than.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092274.3A CN103142511B (en) | 2013-03-21 | 2013-03-21 | High-purity and high-stability composition containing oxaliplatin and preparation method of composition |
Applications Claiming Priority (1)
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| CN105343018A (en) * | 2015-12-03 | 2016-02-24 | 南京多宝生物科技有限公司 | Anti-cancer oxaliplatin freeze-dried powder for injection |
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| CN102657624A (en) * | 2012-06-01 | 2012-09-12 | 齐鲁制药有限公司 | High optical purity trans-dextro oxaliplatin lyophilized powder injection and preparation method thereof |
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