CN101461801B - Oxaliplatin medicament composition and preparation method thereof - Google Patents
Oxaliplatin medicament composition and preparation method thereof Download PDFInfo
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- CN101461801B CN101461801B CN 200810249853 CN200810249853A CN101461801B CN 101461801 B CN101461801 B CN 101461801B CN 200810249853 CN200810249853 CN 200810249853 CN 200810249853 A CN200810249853 A CN 200810249853A CN 101461801 B CN101461801 B CN 101461801B
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Abstract
The invention belongs to the technical field of medicine and particularly relates to an oxaliplatin medicine composition and a preparation method thereof. The invention aims to provide the oxaliplatin medicine composition, the pH value of the product is closer to that of a body fluid of a human body, and the product has smaller irritation to blood vessels of patients and has steadier quality. The invention provides the preparation method for the oxaliplatin medicine composition, which overcomes the defect that: in the prior art, the quality of the product is seriously affected due to the fact that oxaliplatin reacts with a metal pipe or a container during the preparation of an oxaliplatin water solution.
Description
1. technical field
The present invention relates to a kind of oxaliplatin pharmaceutical formulations, belong to medical technical field, the invention still further relates to the preparation method of this pharmaceutical preparation.
2. background technology
Oxaliplatin is take diamino-cyclohexane as carrying a platinum complexes of platinum part, not only improved the toxic and side effects of cisplatin and carboplatin, and enlarged their activity profile, cell strain or tumor strain to many anti-cisplatin or carboplatin have activity, show obvious advantage in many-sides such as active anticancer and toxic and side effects.This product is a kind of platinum series antineoplastic medicament that broad-spectrum anti-tumor activity is all arranged in vivo and in vitro, and the tumor cell of anti-cisplatin is also had cytotoxicity.Its mechanism of action is that DNA is formed in interchain and chain is crosslinked, thereby interrupts synthetic and final cytotoxicity and the antitumor curative effect of producing of DNA.WO96/04904 has related to a kind of oxaliplatin aqueous solution preparation, and said preparation does not only contain and is comprised of oxaliplatin and water, and concentration is 1～5mg/ml, and the product pH value is between 4.5～6.CN1954811A discloses a kind of oxaliplatin intravenous fluid, and it is active ingredient that this injection contains oxaliplatin, and adding mannitol is that osmotic pressure regulator is prepared from, and it is 3.0～4.5 that the document provides the pH value of this product simultaneously.
Under existing pharmaceutical production condition, the pipeline that process of producing product is used and the preparation container overwhelming majority are the stainless steel metal goods, when preparation oxaliplatin aqueous solution injection, the active ingredient oxaliplatin is easy to react with metallic conduit or container inner wall, cause product colour to change, content descends and related substance increases, and has a strong impact on product quality.Human body fluid pH is alkalescence in 7.4 left and right, and the product pH value that document is mentioned is 3.0～4.5, and solution acidic is stronger, and is larger to patient vessel's zest of using this product, has clinical drug safety hidden danger.
Not yet find to overcome at present the report of above-mentioned preparation and preparation technology's defective.
3. summary of the invention
The object of the present invention is to provide a kind of oxaliplatin medicament composition, this product pH value is more near human body fluid pH, and product is less to patient vessel's zest, and product quality is more stable.
The invention provides a kind of preparation method of oxaliplatin medicament composition, solved in prior art in preparation oxaliplatin aqueous solution process, because oxaliplatin and metallic conduit or container react, have a strong impact on the defective of product quality.
The present invention can be prepared from by the component of following ratio range, and following umber is weight portion, but the present invention never only limits to following ratio range
Oxaliplatin 40-60 part mannitol 4500-5500 part
Oxaliplatin medicament composition product pH value of the present invention is 5.1～5.9.
Oxaliplatin medicament composition pH value preferred 5.5 of the present invention.
Oxaliplatin medicament composition preparation method of the present invention comprises following preparation process:
A, the passivation of producing pipeline and producing container:
A, be 50 ℃ with temperature, the salpeter solution of concentration 20%, circulation flushing rustless steel are produced pipeline and are produced with container 60 minutes;
B, rinse rustless steel with water for injection and produce pipeline and produce and use container, to the flushing water pH value be 5.1～5.9;
C, produce pipeline and produce with container 5 minutes with 1%～5% sodium carbonate liquor circulation flushing rustless steel:
D, rinse rustless steel with the EDTA-2Na solution circulation of 1 ‰ (g/ml) and produce pipeline and produce with container 5 minutes;
E, water for injection rinse rustless steel and produce pipeline and produce and use container, to the flushing water pH value be 5.1～5.9;
B, make up a prescription
A, get mannitol, join in appropriate water for injection, calculate the active carbon that adds 0.1%～0.3% (g/ml) by liquid volume, be heated to boiling, boiled 10 minutes, cool to below 70 ℃, filter out active carbon, get solution I;
B, get oxaliplatin, join temperature and be in the appropriate water for injection of 55 ℃～60 ℃, be stirred to dissolving, get solution II;
C, will get solution I and solution II and mix, the supplementary injection water is regulated the mixed liquor pH value to 5.1-5.9 to full dose with hydrochloric acid or sodium hydroxide, and in mixed process, solution temperature must not surpass 60 ℃, get solution III;
C, fill, gland and sterilization
According to common process, with solution III fill, gland and sterilization, namely get oxaliplatin medicament composition of the present invention.
The preparation method of above-mentioned oxaliplatin medicament composition, the c in the passivation of steps A production pipeline and production container preferably produces pipeline with 3% sodium carbonate liquor circulation flushing rustless steel and produces and use container 5 minutes.
The preparation method of above-mentioned oxaliplatin medicament composition, the c during step B makes up a prescription preferably will get solution I and solution II and mix, and regulate pH value to 5.5 with hydrochloric acid or sodium hydroxide, get solution III.
The preparation method of above-mentioned oxaliplatin medicament composition during step B makes up a prescription, can be selected to regulate pH value to 5.1～5.9 with the mixture of any or they in carboxylic acid, dicarboxylic acids, oxalic acid or malonic acid.
In order to illustrate that oxaliplatin pharmaceutical formulations of the present invention has good stability and safety, according to embodiment 1 preparation oxaliplatin formula mannitol injection liquid of the present invention, sterilising conditions is selected 115 ℃ of pressure sterilizing 30min, gets product one of the present invention.Place it in room temperature environment, during respectively at firm placement, place sample thief check in 1,6,12,24 month, observe its outward appearance and measure oxaliplatin content and its related substances.Assay adopts high performance liquid chromatography, is filler with octadecylsilane chemically bonded silica; Take methanol-water (7: 93) as mobile phase; The detection wavelength is 249nm.Number of theoretical plate should be not less than 2000 by oxaliplatin peak calculating, carries out according to two appendix detection methods of Chinese Pharmacopoeia version in 2000.
Table 1 oxaliplatin pharmaceutical formulations room temperature is investigated the stability test result
As can be seen from Table 1, oxaliplatin pharmaceutical formulations of the present invention is after room temperature is deposited 24 months, and the content of outward appearance and principal agent oxaliplatin does not change than basic with depositing preliminary phase, illustrates that quality stability of the present invention is good.
Other steps all are same as embodiment 1, the passivation of only remove steps A in embodiment 1, producing pipeline and producing container, and preparation test specimen one is observed this sample appearance, measures oxaliplatin content, and result is as follows:
Table 2 oxaliplatin pharmaceutical formulations engineer testing result
Illustrate that production technology of the present invention can effectively control the oxaliplatin pharmaceutical formulations minimizing of content in process of production, and the increase of controlling the product its related substances.
In order to illustrate that this product by adjusting suitable pH value, has not only improved the quality stability of product, the safety that has more improved product prepares test specimen two, carries out zoology test research.
Get mannitol 51g, join in 45 ℃ of water for injection 600ml, stir and to make entirely moltenly, add the 0.6g active carbon, after stirring 15min, sucking filtration, decarburization; Get oxaliplatin 1.0g, join in 45 ℃ of water for injection 300ml, stirring makes entirely molten, and above-mentioned mannitol solution is added wherein, after mixing, adds water for injection to 950ml, regulates pH4 with 5% oxalic acid solution; Add water for injection to 1000ml; Fine straining, embedding, 115 ℃ of pressure sterilizing 30min, test specimen two.
Get 9 of body weight 2.1～2.3kg healthy rabbits, the male and female dual-purpose is divided into three groups at random, and 3 every group, minute medicine group I, medicine group II and matched group.Rabbit is placed in holder.the left auricular vein instillation of medicine group I rabbit product one 15ml/kg of the present invention, the left auricular vein instillation of medicine group II rabbit test specimen two 15ml/kg, the left auricular vein instillation of matched group rabbit formula mannitol injection liquid 15ml/kg, drip velocity is 20 (1ml) min, every morning instils once, be equivalent to 3.6 times of the each consumption of 60kg adult (100ml), for three days on end, observe the left auricular vein reaction of rabbit, 24h is with the animal sacrificed by exsanguination after the last administration, take off left ear, carry out tissue slice inspection (routine paraffin wax section, dyeing, light microscopy checking is also taken pictures), the position of drawing materials is that the centripetal end at inserting needle position is apart from inserting needle position 1～4cm, divide 1～2.5cm and 2.5～4cm two-stage nitration to draw materials.Observe the obvious irritant reaction in rabbit ear position during each the instillation and after administration.
Table 3, oxaliplatin pharmaceutical formulations animal test results
| Phenomenon | Red and swollen | Congested | Downright bad |
| Matched group | Nothing | Nothing | Nothing |
| Product one of the present invention | Nothing | Nothing | Nothing |
| Test specimen two | 1 example | 1 example | Nothing |
Result of the test shows, intravenous drip oxaliplatin formula mannitol injection liquid of the present invention to the rabbit auricular vein without obvious irritation.
4. the specific embodiment
In order to understand better and to implement the present invention, the specific embodiment of the invention is explained, but the present invention never only limits to embodiment
Embodiment 1
Oxaliplatin 50g mannitol 5100g water for injection adds to 100L
A, the passivation of producing pipeline and producing container:
A, be 50 ℃ with temperature, the salpeter solution of concentration 20%, circulation flushing rustless steel are produced pipeline and are produced with container 60 minutes;
B, rinse rustless steel with water for injection and produce pipeline and produce and use container, to the flushing water pH value be 5.5;
C, produce pipeline and produce with container 5 minutes with 3% sodium carbonate liquor circulation flushing rustless steel;
D, rinse rustless steel with the EDTA-2Na solution circulation of 1 ‰ (g/ml) and produce pipeline and produce with container 5 minutes;
E, water for injection rinse rustless steel and produce pipeline and produce and use container, to the flushing water pH value be 5.5;
B, make up a prescription
A, get mannitol 5100g, all add in 50L water for injection, calculate the active carbon that adds 0.1%～0.3% (g/ml) by liquid volume, be heated to boiling, boiled 10 minutes, cool to below 70 ℃, filter out active carbon, get solution I;
B, get oxaliplatin, join temperature and be in the 20L water for injection of 55 ℃～60 ℃, be stirred to dissolving, get solution II;
C, will get solution I and solution II and mix, and add water for injection to volume 100L, and regulate the mixed liquor pH value to 5.1-5.9 with hydrochloric acid or sodium hydroxide, in mixed process, solution temperature must not surpass 60 ℃, get solution III;
C, fill, gland and sterilization
According to common process, with solution III fill, gland and sterilization, namely get oxaliplatin medicament composition of the present invention.
Embodiment 2
Oxaliplatin 40g mannitol 5500g water for injection adds to 100L
Other steps are with embodiment 1
Embodiment 3
Oxaliplatin 60g mannitol 4500g water for injection adds to 100L
Other steps are with embodiment 1
Embodiment 4
Oxaliplatin 60g mannitol 5500g water for injection adds to 100L
Other steps are with embodiment 1
Embodiment 5
Oxaliplatin 50g mannitol 5100g water for injection adds to 100L
A, the passivation of producing pipeline and producing container:
A, be 50 ℃ with temperature, the salpeter solution of concentration 20%, circulation flushing rustless steel are produced pipeline and are produced with container 60 minutes;
B, rinse rustless steel with water for injection and produce pipeline and produce and use container, to the flushing water pH value be 5.1;
C, produce pipeline and produce with container 5 minutes with 5% sodium carbonate liquor circulation flushing rustless steel;
D, rinse rustless steel with the EDTA-2Na solution circulation of 1 ‰ (g/ml) and produce pipeline and produce with container 5 minutes;
E, water for injection rinse rustless steel and produce pipeline and produce and use container, to the flushing water pH value be 5.1;
B, make up a prescription
A, get mannitol 5100g, all add in 50L water for injection, calculate the active carbon that adds 0.3% (g/ml) by liquid volume, be heated to boiling, boiled 10 minutes, cool to below 70 ℃, filter out active carbon, get solution I;
B, get oxaliplatin, join temperature and be in the 20L water for injection of 55 ℃, be stirred to dissolving, get solution II;
C, will get solution I and solution II and mix, and add water for injection to volume 100L, and regulate mixed liquor pH value to 5.1 with hydrochloric acid or sodium hydroxide, in mixed process, solution temperature must not surpass 60 ℃, get solution III;
C, fill, gland and sterilization
According to common process, with solution III fill, gland and sterilization, namely get oxaliplatin medicament composition of the present invention.
Embodiment 6
Oxaliplatin 60g mannitol 5100g water for injection adds to 100L
A, the passivation of producing pipeline and producing container:
A, be 50 ℃ with temperature, the salpeter solution of concentration 20%, circulation flushing rustless steel are produced pipeline and are produced with container 60 minutes;
B, rinse rustless steel with water for injection and produce pipeline and produce and use container, to the flushing water pH value be 5.9;
C, produce pipeline and produce with container 5 minutes with 1% sodium carbonate liquor circulation flushing rustless steel;
D, rinse rustless steel with the EDTA-2Na solution circulation of 1 ‰ (g/ml) and produce pipeline and produce with container 5 minutes;
E, water for injection rinse rustless steel and produce pipeline and produce and use container, to the flushing water pH value be 5.9;
B, make up a prescription
A, get mannitol 5100g, all add in 50L water for injection, calculate the active carbon that adds 0.1% (g/ml) by liquid volume, be heated to boiling, boiled 10 minutes, cool to below 70 ℃, filter out active carbon, get solution I;
B, get oxaliplatin, join temperature and be in the 20L water for injection of 60 ℃, be stirred to dissolving, get solution II;
C, will get solution I and solution II and mix, and add water for injection to volume 100L, and regulate mixed liquor pH value to 5.9 with hydrochloric acid or sodium hydroxide, in mixed process, solution temperature must not surpass 60 ℃, get solution III;
C, fill, gland and sterilization
According to common process, with solution III fill, gland and sterilization, namely get oxaliplatin medicament composition of the present invention.
Embodiment 7
Oxaliplatin 60g mannitol 5500g water for injection adds to 100L
A, the passivation of producing pipeline and producing container:
A, be 50 ℃ with temperature, the salpeter solution of concentration 20%, circulation flushing rustless steel are produced pipeline and are produced with container 60 minutes;
B, rinse rustless steel with water for injection and produce pipeline and produce and use container, to the flushing water pH value be 5.9;
C, produce pipeline and produce with container 5 minutes with 3% sodium carbonate liquor circulation flushing rustless steel;
D, rinse rustless steel with the EDTA-2Na solution circulation of 1% (g/ml) and produce pipeline and produce with container 5 minutes;
E, water for injection rinse rustless steel and produce pipeline and produce and use container, to the flushing water pH value be 5.9;
B, make up a prescription
A, get mannitol 5100g, all add in 50L water for injection, calculate the active carbon that adds 0.3% (g/ml) by liquid volume, be heated to boiling, boiled 10 minutes, cool to below 70 ℃, filter out active carbon, get solution I;
B, get oxaliplatin, join temperature and be in the 20L water for injection of 58 ℃, be stirred to dissolving, get solution II;
C, will get solution I and solution II and mix, and add water for injection to volume 100L, and regulate mixed liquor pH value to 5.9 with hydrochloric acid or sodium hydroxide, in mixed process, solution temperature must not surpass 60 ℃, get solution III;
C, fill, gland and sterilization
According to common process, with solution III fill, gland and sterilization, namely get oxaliplatin medicament composition of the present invention.
Claims (2)
1. the preparation method of an oxaliplatin medicament composition is characterized in that comprising following preparation process:
A, the passivation of producing pipeline and producing container:
A, be 50 ℃ with temperature, the salpeter solution of concentration 20%, circulation flushing rustless steel are produced pipeline and are produced with container 60 minutes;
B, rinse rustless steel with water for injection and produce pipeline and produce and use container, to the flushing water pH value be 5.1～5.9;
C, produce pipeline and produce with container 5 minutes with 1%～5% sodium carbonate liquor circulation flushing rustless steel;
D, rinse rustless steel with the EDTA-2Na solution circulation of 1 ‰ (g/ml) and produce pipeline and produce with container 5 minutes;
E, water for injection rinse rustless steel and produce pipeline and produce and use container, to the flushing water pH value be 5.1～5.9;
B, make up a prescription:
A, get mannitol, join in appropriate water for injection, be stirred to dissolving, calculate the active carbon that adds 0.1%～0.3% (g/ml) by liquid volume, be heated to boiling, boiled 10 minutes, cool to below 70 ℃, filter out active carbon, get solution I;
B, get oxaliplatin, join temperature and be in the appropriate water for injection of 55 ℃～60 ℃, be stirred to dissolving, get solution II;
C, solution I and solution II are mixed, the supplementary injection water is regulated the mixed liquor pH value to 5.1-5.9 to full dose with hydrochloric acid or sodium hydroxide, and in mixed process, solution temperature must not surpass 60 ℃, get solution III;
C, fill, gland and sterilization:
According to common process, with solution III fill, gland and sterilization, namely get oxaliplatin medicament composition;
The proportioning of described oxaliplatin medicament composition is: oxaliplatin 40-60 weight portion, mannitol 4500-5500 weight portion.
2. the preparation method of oxaliplatin medicament composition as claimed in claim 1 is characterized in that steps A produces pipeline and produce c in the passivation of container, produces pipeline and produces and use container 5 minutes with 3% sodium carbonate liquor circulation flushing rustless steel.
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| CN106265497A (en) * | 2016-08-31 | 2017-01-04 | 辰欣药业股份有限公司 | A kind of oxaliplatin formula mannitol injection liquid and preparation method |
| CN106176594A (en) * | 2016-08-31 | 2016-12-07 | 辰欣药业股份有限公司 | A kind of oxaliplatin formula mannitol injection liquid and preparation technology thereof |
| CN108078918B (en) * | 2017-12-28 | 2020-01-21 | 石药银湖制药有限公司 | Treatment method for improving stability of terbutaline sulfate injection |
| BR112022001365A2 (en) * | 2019-08-29 | 2022-06-07 | Lilly Co Eli | Crystalline forms of a cd73 inhibitor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1291886A (en) * | 1998-02-25 | 2001-04-18 | 圣诺菲-合成实验室公司 | Formulations |
| CN101022790A (en) * | 2003-08-28 | 2007-08-22 | 梅恩医药有限公司 | Acid containing oxaliplatin formulations |
| CN101199506A (en) * | 2007-12-20 | 2008-06-18 | 江苏奥赛康药业有限公司 | Oxaliplatin lyophilized powder injection and preparing method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1291886A (en) * | 1998-02-25 | 2001-04-18 | 圣诺菲-合成实验室公司 | Formulations |
| CN101022790A (en) * | 2003-08-28 | 2007-08-22 | 梅恩医药有限公司 | Acid containing oxaliplatin formulations |
| CN101199506A (en) * | 2007-12-20 | 2008-06-18 | 江苏奥赛康药业有限公司 | Oxaliplatin lyophilized powder injection and preparing method thereof |
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