CN102525957A - Preparation method of Oxaliplatin for injection - Google Patents
Preparation method of Oxaliplatin for injection Download PDFInfo
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- CN102525957A CN102525957A CN2011104206298A CN201110420629A CN102525957A CN 102525957 A CN102525957 A CN 102525957A CN 2011104206298 A CN2011104206298 A CN 2011104206298A CN 201110420629 A CN201110420629 A CN 201110420629A CN 102525957 A CN102525957 A CN 102525957A
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Abstract
The invention provides a preparation method of Oxaliplatin for injection. The preparation method of the invention comprises the steps of cleaning rubber plugs and sterilizing; cleaning vials and sterilizing; disinfecting aluminum-plastic covers; preparing a solution; filling the inspection qualified solution into vials and partially inserting the plugs; lyophilizing; pressing the rubber slugs, unboxing, capping and visually inspecting; and packaging. The final products are stored after product quality inspection.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of method for preparing of injection oxaliplatin.
Background technology
Oxaliplatin is by Switzerland Debiopharm company research and development, the production and sales of French Sanofi company, and on Europe, South America and other places go on the market subsequently in France's listing that takes the lead in October, 1996.China is in approval of import oxaliplatin injection in 1999, and 15 tame hospitals have carried out clinical trial in the whole nation, and is respond well.Homemade medication effect is suitable with imported medicine, but price is merely about 1/4 of imported medicine.After the homemade medicine listing, the market share enlarges rapidly, also forces imported medicine to reduce price.In recent years, oxaliplatin market growing way is powerful.
Oxaliplatin is included in people's colorectal cancer model in the kinds of tumors model system, all shows broad-spectrum vitro cytotoxicity and anti-tumor in vivo active function.The injection oxaliplatin belongs to new platinum analog derivative, and the injection oxaliplatin acts on DNA through producing the alkanisation conjugate, forms in the chain and interchain linkage, thereby suppresses the synthetic of DNA and duplicate.The injection oxaliplatin combines with DNA rapidly, needs 15 minutes at most, and cisplatin when being divided into two with the combination of DNA mutually, comprising a delay phase after 48 hours.In human body, after the administration one hour,, can show its existence through measuring leukocytic adduct.DNA in the reproduction process is synthetic, and the synthetic of the separation of DNA, RNA and cell protein all is suppressed thereafter, and some is to the cell line of cisplatin resistance, and the injection oxaliplatin treatment is effective.
Oxaliplatin 130mg/m
2Venoclysis 2 hours, per 3 weeks repeat 1 time, during with 1-5 cycle, and oxaliplatin 85mg/m
2Venoclysis 2 hours, per 2 weeks repeat 1 time, during with 1-3 cycle, its ultrafiltration platinum, the unconjugated platinum class of various forms pharmacokinetic parameter is following:
When transfusion finished in 2 hours, 15% platinum was present in the body circulation.Remaining 85% is diffused into rapidly in the tissue or with urine and discharges.Because oxaliplatin can carry out irreversible the combination with erythrocyte and plasma protein, causes the natural life-span of the half-life of conjugate near erythrocyte and plasma albumin.85 mg/m
2Per 2 all 1 time or 130 mg/m
2Per 3 weeks 1 time, not seeing in the blood plasma ultrafiltrate has the phenomenon of accumulating, and can keep steady statue in the 1st cycle.It is lower usually to reach individual interior difference between individuality.
Oxaliplatin will carry out sufficient biotransformation in the patient body.After infusion finished in 2 hours, detect less than complete medicine in the blood plasma ultrafiltration thing.Several kinds of cytotoxicity bioconversion products comprise monochloride, dichloride and two hydration DACH base platinum constituents etc., all can in peripheral circulation system, detect, and after a while, also can find many inactive conjugates.
The platinum class is main discharges through urine, how after medication, to remove in 48 hours.In the time of the 5th day, nearly 54% with the urine discharge, only discharges with feces less than 3%.
Work as renal insufficiency, clearance rate obviously descends, and as when 17.6 ± 2.18 l/h drop to 9.95 ± 1.91 l/h, its volume of distribution also significantly descends, and drops to 241 ± 36.1L from 330 ± 40.9L, and there were significant differences on the statistics.During the severe renal functional defect, the influence of platinum class clearance rate is assessed as yet.
Summary of the invention
Key technology of the present invention shows craft screening and optimization; We according to the rule of pharmaceutics freeze-dried powder preparation, serve as to detect index with content, related substance etc. according to the character of these article; Preferred this preparation process is finally confirmed its prescription and technological process.
The invention provides a kind of technology for preparing the injection oxaliplatin, it comprises the steps:
(1) plug cleans, sterilizes:
Plug is sent into rubber plug cleaning machine clean, rinsing to visible foreign matters is qualified, puts into the sterilization of vacuum sterilization baking oven, the special stainless steel bucket of packing into, sealing;
(2) cillin bottle washing and sterilizing:
Import cillin bottle into bottle washer and clean, the cillin bottle after cleaning is sent into tunnel baking oven sterilization, and is subsequent use;
(3) aluminium-plastic cap sterilization:
The plastic-aluminum composite cover is carried out disinfection,, take out the plastic-aluminum composite cover and pour in the dedicated storage bucket, seal subsequent use;
(4) dosing:
The lactose of recipe quantity is dissolved in the water for injection, and stirring and dissolving adds the oxaliplatin stirring and dissolving again, measures pH value; Supply the injection water yield; Add active carbon, stir decarbonization filtering,, need filter element is carried out the bubble experimental tests before filtering through filter element filtering, and should be up to specification, the filtered liquid medicine sampling is carried out intermediate and is detected, and surveys pH, content;
(5) with the liquid medicine filling that is up to the standards in glass tube vial, and false add plug;
(6) vacuum lyophilization:
Pre-freeze: put into pre-freeze on the freeze drying box shelf to the medicine that branch installs;
Sublimation drying: pre-freeze begins the sublimation drying that heats up after finishing;
Dry again;
(7) moulding plug, outlet rolls lid, visual inspection;
(8) packing stores after product inspection is qualified.
Comprise oxaliplatin, lactose and water for injection in the injection oxaliplatin prescription provided by the invention.
The specification of preparation of the present invention can be 50mg.Usage: oxaliplatin is used for intravenous drip.Oxaliplatin need not aquation when using.Oxaliplatin is dissolved in 5% glucose solution 250-500ml (so that reaching the above concentration of 0.2Mg/ml), and through periphery or central vein instillation 2-6 hour, oxaliplatin must instil before 5-fluorouracil.If leak outside blood vessel, must stop administration immediately.Instruction: oxaliplatin must be prepared and further dilution before use, must dissolve and dilute lyophilized injectable powder with the solution of regulation.Use operating instruction:, use and dispose oxaliplatin and must abide by points for attention and carry out carefully as other cytotoxic drugs.The preparation of solution: should use injection 5% glucose solution during obtain solution.The 50mg packing needs to add the 10ml solvent, makes oxaliplatin concentration reach 5.0mg/ml.The 100mg packing needs to add the 20ml solvent, makes oxaliplatin concentration reach 5.0mg/ml.From microbiology and chemical terms, the solution of preparation must dilute with 5% glucose solution immediately.Should check its transparency before using, having only does not clarifyingly have sedimentary solution to use.
The specific embodiment
Below in conjunction with concrete embodiment scheme of the present invention is further described.For explaining conveniently, the chemical compound of addressing is represented with its common name.
Prescription
| Supplementary material | Specification 50mg/ bottle |
| Oxaliplatin | 50g |
| Lactose | 450g |
| Water for injection adds to | 10000ml |
| Process | 1000 |
2. preparation technology
(1) plug cleans, sterilizes:
Plug is sent into rubber plug cleaning machine clean, rinsing to visible foreign matters is qualified, puts into the vacuum sterilization baking oven, sterilization in 121 ℃, 30 minutes, the special stainless steel bucket of packing into, sealing.
(2) cillin bottle washing and sterilizing:
Import 30ml control cillin bottle into bottle washer and clean, the cillin bottle after cleaning is sent into tunnel baking oven sterilization, guarantees sterilising temp >=350 ℃, and is 5 minutes, subsequent use.
(3) aluminium-plastic cap sterilization:
The plastic-aluminum composite cover carried out disinfection 120 ℃ is incubated 1.5 hours, and insulation finishes to be cooled to below 40 ℃, takes out the plastic-aluminum composite cover and pours in the dedicated storage bucket, seals subsequent use.
(4) dosing:
The lactose of recipe quantity is dissolved in 40 ℃ of waters for injection of recipe quantity 90%, and stirring and dissolving adds the oxaliplatin stirring and dissolving again, measures pH value 4.0-6.0; Supply the injection water yield; Add the active carbon of 0.05% (w/v), stirred 15 minutes, decarbonization filtering is through 0.45 μ m filter element coarse filtration, through 0.22 μ m filter element aseptic filtration.Need before filtering filter element is carried out the bubble experimental tests, and should be up to specification.The filtered liquid medicine sampling is carried out intermediate and is detected, and surveys pH, content.
(5) with the liquid medicine filling that is up to the standards in glass tube vial, and false add plug;
(6) vacuum lyophilization:
Pre-freeze: the medicine that installs branch is put on the freeze drying box shelf pre-freeze to goods-40 ℃, is incubated about 8 hours;
Sublimation drying: after pre-freeze is finished, begin the sublimation drying that heats up, when goods carry out drying program again from-40 ℃ to 0 ℃ during the left and right sides, this stage took time 38 hours approximately;
Dry again: products temperature rises to 25 ℃ for 0 ℃, about 1 hour; About about 4 hours of 25 ℃ of heat preservation and drynesses need about 5 hours altogether;
(7) moulding plug, outlet rolls lid, visual inspection;
(8) packing stores after product inspection is qualified.
Should be noted that; The above is merely preferred embodiment of the present invention; Be not limited to scope of the present invention, all any modifications of within spirit of the present invention and principle, having done, the replacement that is equal to and improvement etc. all should be included within protection scope of the present invention.
Claims (1)
1. the method for preparing of an injection oxaliplatin comprises: (1) plug cleans, sterilization: plug is sent into rubber plug cleaning machine clean, rinsing to visible foreign matters is qualified; Put into the vacuum sterilization baking oven; Sterilization in 121 ℃, 30 minutes, the special stainless steel bucket of packing into, sealing; (2) cillin bottle washing and sterilizing: import 30ml control cillin bottle into bottle washer and clean, the cillin bottle after cleaning is sent into tunnel baking oven sterilization, guarantees sterilising temp >=350 ℃, and is 5 minutes, subsequent use; (3) aluminium-plastic cap is sterilized: the plastic-aluminum composite cover is carried out disinfection 120 ℃ is incubated 1.5 hours, and insulation finishes to be cooled to below 40 ℃, takes out the plastic-aluminum composite cover and pours in the dedicated storage bucket, seals subsequent use; (4) dosing: the lactose of recipe quantity is dissolved in 40 ℃ of waters for injection of recipe quantity 90%, and stirring and dissolving adds the oxaliplatin stirring and dissolving again, measures pH value 4.0-6.0; Supply the injection water yield; Add the active carbon of 0.05% (w/v), stirred 15 minutes, decarbonization filtering, through 0.45 μ m filter element coarse filtration, through 0.22 μ m filter element aseptic filtration, the filtered liquid medicine sampling is carried out intermediate and is detected, and surveys pH, content; (5) with the liquid medicine filling that is up to the standards in glass tube vial, and false add plug; (6) vacuum lyophilization:
Pre-freeze: the medicine that installs branch is put on the freeze drying box shelf pre-freeze to goods-40 ℃, is incubated about 8 hours; Sublimation drying: after pre-freeze is finished, begin the sublimation drying that heats up, when goods carry out drying program again from-40 ℃ to 0 ℃ during the left and right sides, this stage took time 38 hours approximately; Dry again: products temperature rises to 25 ℃ for 0 ℃, about 1 hour; About about 4 hours of 25 ℃ of heat preservation and drynesses need about 5 hours altogether; (7) moulding plug, outlet rolls lid, visual inspection; (8) packing stores after product inspection is qualified.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104206298A CN102525957A (en) | 2011-12-15 | 2011-12-15 | Preparation method of Oxaliplatin for injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104206298A CN102525957A (en) | 2011-12-15 | 2011-12-15 | Preparation method of Oxaliplatin for injection |
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| Publication Number | Publication Date |
|---|---|
| CN102525957A true CN102525957A (en) | 2012-07-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104206298A Pending CN102525957A (en) | 2011-12-15 | 2011-12-15 | Preparation method of Oxaliplatin for injection |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670526A (en) * | 2012-05-10 | 2012-09-19 | 南京臣功制药股份有限公司 | Oxaliplatin freeze-dried powder injection and preparation method thereof |
| CN103142512A (en) * | 2013-03-21 | 2013-06-12 | 杭州华东医药集团生物工程研究所有限公司 | High-quality composition containing oxaliplatin and preparation method of composition |
| CN103705383A (en) * | 2013-12-18 | 2014-04-09 | 山东新时代药业有限公司 | Oxaliplatin lyophilized powder injection |
| CN104940151A (en) * | 2015-07-23 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Oxaliplatin freeze-dried powder injection composition as anti-cancer drug |
| JP5963156B1 (en) * | 2016-03-23 | 2016-08-03 | テバ製薬株式会社 | Method for producing and stabilizing aqueous pharmaceutical composition comprising oxaliplatin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1868455A (en) * | 2006-05-20 | 2006-11-29 | 沈阳药科大学 | Intravenous nanometer suspension injection contg. oxaliplatin platinum phospholipid compound |
| CN1954811A (en) * | 2005-10-26 | 2007-05-02 | 四川美大康佳乐药业有限公司 | Oxaliplatin intravenous injection and its preparation method |
-
2011
- 2011-12-15 CN CN2011104206298A patent/CN102525957A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1954811A (en) * | 2005-10-26 | 2007-05-02 | 四川美大康佳乐药业有限公司 | Oxaliplatin intravenous injection and its preparation method |
| CN1868455A (en) * | 2006-05-20 | 2006-11-29 | 沈阳药科大学 | Intravenous nanometer suspension injection contg. oxaliplatin platinum phospholipid compound |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670526A (en) * | 2012-05-10 | 2012-09-19 | 南京臣功制药股份有限公司 | Oxaliplatin freeze-dried powder injection and preparation method thereof |
| CN102670526B (en) * | 2012-05-10 | 2013-12-04 | 南京臣功制药股份有限公司 | Oxaliplatin freeze-dried powder injection and preparation method thereof |
| CN103142512A (en) * | 2013-03-21 | 2013-06-12 | 杭州华东医药集团生物工程研究所有限公司 | High-quality composition containing oxaliplatin and preparation method of composition |
| CN103142512B (en) * | 2013-03-21 | 2014-06-11 | 杭州华东医药集团新药研究院有限公司 | High-quality composition containing oxaliplatin and preparation method of composition |
| CN103705383A (en) * | 2013-12-18 | 2014-04-09 | 山东新时代药业有限公司 | Oxaliplatin lyophilized powder injection |
| CN104940151A (en) * | 2015-07-23 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Oxaliplatin freeze-dried powder injection composition as anti-cancer drug |
| JP5963156B1 (en) * | 2016-03-23 | 2016-08-03 | テバ製薬株式会社 | Method for producing and stabilizing aqueous pharmaceutical composition comprising oxaliplatin |
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Application publication date: 20120704 |