CN102274171A - Oxaliplatin injection - Google Patents
Oxaliplatin injection Download PDFInfo
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- CN102274171A CN102274171A CN2011102230625A CN201110223062A CN102274171A CN 102274171 A CN102274171 A CN 102274171A CN 2011102230625 A CN2011102230625 A CN 2011102230625A CN 201110223062 A CN201110223062 A CN 201110223062A CN 102274171 A CN102274171 A CN 102274171A
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- oxaliplatin
- injection
- acetic acid
- pharmaceutically acceptable
- sodium acetate
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Abstract
The invention discloses an oxaliplatin injection which comprises oxaliplatin, effective and stable quantity of buffer solution formed by acetic acid and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. The oxaliplatin injection prepared by using the buffer solution formed by acetic acid and pharmaceutically acceptable salts thereof has good quality and superior stability, and does not additionally introduce impurities which need to be controlled and can cause side effect; compared with a freeze-dried powder oxaliplatin preparation, the injection disclosed by the invention has the advantages of low manufacturing cost and simple production process, and can be used instantly; and the oxaliplatin injection can be sterilized by heating without having a negative influence on the quality, thereby satisfying industrial preparation requirements and pharmaceutical preparation quality requirements of the oxaliplatin injection.
Description
Technical field
The present invention relates to a kind of oxaliplatin injection, belong to technical field of medicine.
Background technology
(oxaliplatin is to be developed by Switzerland Debiopharm company L-OHP) to oxaliplatin, the production and sales of French Sanofi company, the third generation platinum-containing anticancer drug that take the lead in going on the market in France in October, 1996.The molecular structure of oxaliplatin has 3 optical isomers, promptly trans-l (1R, 2R-dach, oxaliplatin), trans-d (1S, 2S-dach) and cis meso-(1R, 2S-dach) isomer.In general, their relative mole of size order of tiring is: anti--l＞anti--d＞suitable-isomer, promptly oxaliplatin is active maximum.The chemical constitution of oxaliplatin and cisplatin and carboplatin have marked difference, and this medicine not only makes the toxic and side effects of cisplatin and carboplatin have preferably to improve, and has enlarged their activity profile, and the tumor of some anti-cisplatin or carboplatin is also had activity.This medicine is that especially knot, the rectal cancer to anti-5-FU has better curative effect, and has synergism with 5-FU to knot, rectum metastatic carcinoma.
At present, oxaliplatin is used for preclinical test and clinical trial with the freeze-dried powder form, and it just just using injection water or 5% glucose solution to come assembly again before giving patient's administration, dilutes with 5% glucose solution then.But such freeze-drying prods has some shortcomings: at first, lyophilization process relative complex and operation are expensive; In addition, the use of freeze-drying prods needs in use with the product reprovision, and this is for providing the chance that mistake takes place when selecting suitable assembly solution.For example, if when the reprovision of oxaliplatin freeze-drying prods, misapplied 0.9%NaCl solution, the solution of very using always when the latter is reprovision freeze-drying prods or diluent liquid preparation, then will be harmful to active component, this is fast reaction will take place, not only cause the loss of oxaliplatin, also can cause the sample precipitation to produce.Other shortcoming of freeze-drying prods has: (a) for the sterile product that does not need reprovision, the reprovision of freeze-drying prods has increased the risk of microbial contamination; (b) solution product with sterilization or heating (last) sterilization after filtration compares, and freeze-drying prods has the risk of bigger sterilization failure; And (c) freeze-drying prods has incomplete dissolved potentiality when reprovision, causes not conforming with the granule of injection product demand.
Defective in view of the above, people begin one's study how to prepare a kind of instant available through stable oxaliplatin aqueous liquid preparation.Because can degrading as time passes, the aqueous solution that studies show that oxaliplatin produces not commensurability two water DACH platinum, two water DACH platinum dimers and platinum class impurity, because the impurity level that exists in any pharmaceutical preparation is passable, and in many cases, influence the toxicology characteristic of preparation, therefore, the key of exploitation oxaliplatin injection is to solve the stability problem of oxaliplatin in solution.
WO 9943355 discloses the oxaliplatin solution compositions that a kind of buffer (based on oxalic acid or its alkali metal salt) that adds effective stable quantity constitutes to the aqueous solution of oxaliplatin.Because the decomposition of oxaliplatin discharges oxalic acid, think that this interpolation can suppress to decompose in equilibrium system.Yet oxalic acid is deleterious, and can damage kidney and other organ.The stable suitability of the oxaliplatin solution by oxalic acid and/or its salt is also doubtful, because it does not consider the situation of the chelate bonds of part in complex.
WO 03047587 discloses a kind of lactic acid with effective dose, its salt or lactate buffer and has been added into the oxaliplatin solution compositions that constitutes in the aqueous solution of oxaliplatin as stabilizing agent.But stability test has shown that this liquid composite after storing for 5 weeks under 40 ℃, can be settled out a spot of black particle, is evident as reductive metal platinum.
Patent application WO 2006/048194 discloses a kind of sodium acetate or acetate of adding to the aqueous solution of oxaliplatin and the oxaliplatin solution compositions that constitutes, and point out to exist, and o'clock can obtain best stabilization result in pH=4～6 with very little concentration.But the inventor tests and finds that described oxaliplatin solution compositions significantly increases at sterilization rear impurity content, and the pH value before and after the sterilization changes greatly.
As mentioned above, prior art has been carried out multiple trial to the stability of oxaliplatin in water, and it uses many auxiliary materials that have astonishing opposite chemical property sometimes, organic or inorganic acid, monosaccharide, disaccharide and oligosaccharide or polymerizable compound.Carry out these researchs, its purpose is to reach mainly stablizes active compound-oxaliplatin, and does not consider to follow the negative interaction of impurity.Apparently, accidentally selected the chemical compound of stabilisation, and do not understood it is reason owing to the decomposition of reactive compound.This also is the self-contradictory reason of why describing in the patent application of being quoted of result.In one piece of document claimed compounds as powerful stabilizing agent in, show there is not stabilizing active according to other author.This result's discordance is different with the amount that non-reproduction may be interpreted as the effective impurity of catalytic in the reactive compound.This type of impurity exists with trace usually, and it can not detect by the analytical method of current use, and therefore can not find this impurity in the quality testing of oxaliplatin.
The fluid composition of the oxaliplatin that is made of the solution of reactive compound in aqueous carrier only seems simple.In fact, the system that their representatives are very complicated interacts between its composition, and their interaction influences the performance and the character of this system.The decomposition of oxaliplatin in water-based system is subjected to the influence of many physics and chemical factor, and may provide the product that multiple or non-activity or worse situation have serious side effects.Therefore, a kind of real oxaliplatin injection that solves the stability problem of oxaliplatin in solution of exploitation is badly in need of in this area.
Summary of the invention
At existing in prior technology the problems referred to above, the purpose of this invention is to provide a kind of real oxaliplatin injection that solves the stability problem of oxaliplatin in solution, require and as the prescription of pharmaceutical preparation with the industrial preparation that satisfies the oxaliplatin injection.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of oxaliplatin injection comprises the buffer solution and the pharmaceutically acceptable carrier of oxaliplatin, effectively acetic acid and the pharmaceutically acceptable salt formation of acetic acid of stable quantity.
The pharmaceutically acceptable salt of described acetic acid is recommended as water solublity acetic acid alkali metal salt, for example sodium acetate, potassium acetate etc., preferably sodium acetate.
Described pharmaceutically acceptable carrier is meant pharmaceutically acceptable injection carrier, be recommended as any one or the mixed solution that forms more than two kinds in water for injection or water for injection and ethanol, Polyethylene Glycol, polypropylene glycol, pharmaceutically acceptable lactose, glucose, the mannitol, be preferably water for injection.
The preferred plan of oxaliplatin injection of the present invention is: be made up of buffer solution and water for injection that oxaliplatin, acetic acid and sodium acetate form.
The acetic acid in the described buffer solution and the mol ratio of sodium acetate be recommended as 1: 1～and 5: 1; Be preferably 3: 1～5: 1; The best is 3: 1～4: 1.
The acetic acid in the described oxaliplatin injection and the molar concentration of sodium acetate all are recommended as 5 * 10
-6～5 * 10
-2M; Be preferably 5 * 10
-5～5 * 10
-3M.
The mass concentration of the oxaliplatin in the described oxaliplatin injection is recommended as 1～7mg/ml; Be optimized for 2～5mg/ml; The best is 5mg/ml.
The pH value of described oxaliplatin injection is recommended as 3～7; Be preferably 3～5, the best is 3.7～4.7.
The preparation method of described oxaliplatin injection comprises the steps:
A) with the oxaliplatin heating for dissolving in pharmaceutically suitable carrier, the dissolving postcooling to room temperature;
B) add the buffer solution of acetic acid and the pharmaceutically acceptable salt formation of acetic acid, and complement to final volume, filtration, fill, sterilization with pharmaceutically suitable carrier.
Solution temperature in the step a) is recommended as 40～60 ℃, is preferably 50 ℃.
The buffer solution that the present invention forms with the pharmaceutically acceptable salt of acetic acid and acetic acid is as the oxaliplatin injection of stabilizing agent preparation, compare with present known oxaliplatin solution compositions, have better quality and more superior stability, and do not introduce the impurity that needs to control, can cause side effect in addition; Different with the oxaliplatin formulations of freeze-dried powder form, the cheap for manufacturing cost and production process of injection of the present invention is simple, can use immediately; And can be by heat sterilization can the negative effect preparation quality, thereby the industrial preparation that has satisfied the oxaliplatin injection requires and as the prescription of pharmaceutical preparation.
The specific embodiment
The present invention is described in further detail and completely below in conjunction with embodiment, but do not limit content of the present invention.
Embodiment 1
Precision weighing oxaliplatin 5g adds 50 ℃ water for injection 900ml again to container, be stirred to oxaliplatin and dissolve fully, is cooled to room temperature; Add 10ml acetic acid-sodium acetate buffer solution, wherein: the acetic acid in the buffer solution and the mol ratio of sodium acetate are 4: 1, and the molar concentration of acetic acid and sodium acetate is respectively 0.2M and 0.05M; Complement to 1000ml with water for injection then; Filtration, fill, jump a queue, Zha Gai, in 121 ℃ of moist heat sterilizations 15 minutes, promptly get oxaliplatin injection of the present invention at last, be designated as preparation 1.
Comparative Examples 1
Precision weighing oxaliplatin 5g adds 50 ℃ water for injection 900ml again to container, be stirred to oxaliplatin and dissolve fully, is cooled to room temperature; Add 10ml lactic acid-sodium lactate buffer solution, wherein: the lactic acid in the buffer solution and the mol ratio of sodium lactate are 4: 1, and the molar concentration of lactic acid and sodium lactate is respectively 0.2M and 0.05M; Complement to 1000ml with water for injection then; Filtration, fill, jump a queue, Zha Gai, in 121 ℃ of moist heat sterilizations 15 minutes, the liquid composite of prepared oxaliplatin was designated as preparation 2 at last.
Comparative Examples 2
Precision weighing oxaliplatin 5g adds 50 ℃ water for injection 900ml again to container, be stirred to oxaliplatin and dissolve fully, is cooled to room temperature; Adding the 10ml molar concentration is the oxalic acid aqueous solution of 0.02M; Complement to 1000ml with water for injection then; Filtration, fill, jump a queue, Zha Gai, in 121 ℃ of moist heat sterilizations 15 minutes, prepared oxaliplatin solution compositions was designated as preparation 3 at last.
With reference to the above-mentioned 3 kinds of preparations of the detection content detection about the oxaliplatin injection among the American Pharmacopeia USP 33 editions and at present commercially available oxaliplatin injection (produce by Sanofi-Aventis South Africa company, specification is 10ml: 50mg, injection consist of oxaliplatin and water) the amount (testing result is shown in Table 1) of content, pH value and related substance.Described related substance comprises maximum down single assorted other total impurities under the B item that reaches of impurity A (oxalic acid), impurity B (two water diamino cyclohexane extraction platinum), impurity E (dimers of two water diamino cyclohexane extraction platinum), B item.
Table 1
By table 1 as seen: the oxaliplatin injection of the present invention's preparation is compared with present known oxaliplatin solution compositions, has better quality, and the pH value before and after the sterilization is stable, the impurity content minimum.
Above-mentioned 3 kinds of preparations and at present commercially available oxaliplatin injection are carried out accelerated stability test, promptly, above 4 kinds of preparations were placed 6 months under 40 ℃, 75% relative humidity condition, respectively at 1,2,3, the sampling in June detects the amount of its content, pH value and related substance, testing result is shown in Table 2.
Table 2
By table 2 as seen: the oxaliplatin injection of the present invention's preparation is compared with present known oxaliplatin solution compositions, has better storage stability.
Embodiment 2
Prepare preparation 4, preparation 5 and preparation 6 by embodiment 1 described preparation technology, concrete prescription is shown in Table 3.
Table 3
The testing result of the amount of the content of above-mentioned 3 kinds of preparations, pH value and related substance is shown in Table 4.
Table 4
By table 4 as seen: use acetic acid or sodium acetate as stabilizing agent separately, the pH value before and after the sterilization changes greatly, and the related substance after the sterilization is bigger; Especially separately with acetic acid during as stabilizing agent, the growth of the related substance after sterilization is particularly evident; And the buffer solution that the present invention uses acetic acid-sodium acetate is as steady quality before and after sterilization of the oxaliplatin injection of stabilizing agent preparation and superior.
Above-mentioned 3 kinds of preparations are carried out accelerated stability test, that is, above 3 kinds of preparations were placed 6 months under 40 ℃, 75% relative humidity condition, respectively at 1,2,3, the sampling in June detects the amount of its content, pH value and related substance, testing result is shown in Table 5.
Table 5
By table 5 as seen: use acetic acid or sodium acetate as stabilizing agent separately, can not play real Stabilization; And the buffer solution that the present invention uses acetic acid-sodium acetate has extraordinary storage stability as the oxaliplatin injection of stabilizing agent preparation, and the quality place 6 months under 40 ℃, 75% relative humidity condition after does not change substantially.
Embodiment 3
Prepare preparation 7, preparation 8, preparation 9, preparation 10 and preparation 11 by embodiment 1 described preparation technology, concrete prescription is shown in Table 6.
Table 6
The testing result of the amount of the content of above-mentioned 5 kinds of preparations, pH value and related substance is shown in Table 7.
Table 7
By table 7 as seen: be the oxaliplatin injection of the buffer solution preparation that formed in 1: 1～5: 1 with the mol ratio of acetic acid and sodium acetate, all have stabilised quality; Especially it is more high quality to be with the mol ratio of acetic acid and sodium acetate that the oxaliplatin injection of the buffer solution preparation that formed in 3: 1～5: 1 has, and is that the oxaliplatin injection that the buffer solution that formed in 3: 1～4: 1 prepares has optimum quality with the mol ratio of acetic acid and sodium acetate.
Above-mentioned 5 kinds of preparations are carried out accelerated stability test, that is, placed 6 months under 40 ℃, 75% relative humidity condition, respectively at 1,2,3, the sampling in June detects the amount of its content, pH value and related substance, testing result is shown in Table 8.
Table 8
By table 8 as seen: be the oxaliplatin injection of the buffer solution preparation that formed in 1: 1～5: 1 with the mol ratio of acetic acid and sodium acetate, all have storage stability; Especially being that the oxaliplatin injection of the buffer solution preparation that formed in 3: 1～5: 1 has more excellent stability with the mol ratio of acetic acid and sodium acetate, is that the oxaliplatin injection that the buffer solution that formed in 3: 1～4: 1 prepares has optimal stability with the mol ratio of acetic acid and sodium acetate.
Should be noted that at last: above embodiment only is used for purpose that technical scheme of the present invention is further illustrated; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (15)
1. oxaliplatin injection is characterized in that: the buffer solution and the pharmaceutically acceptable carrier that comprise oxaliplatin, effectively acetic acid and the pharmaceutically acceptable salt formation of acetic acid of stable quantity.
2. oxaliplatin injection according to claim 1 is characterized in that: the pharmaceutically acceptable salt of described acetic acid is a water solublity acetic acid alkali metal salt.
3. oxaliplatin injection according to claim 2 is characterized in that: the pharmaceutically acceptable salt of described acetic acid is a sodium acetate.
4. oxaliplatin injection according to claim 1 is characterized in that: described pharmaceutically acceptable carrier is any one or the mixed solution that forms more than two kinds in water for injection or water for injection and ethanol, Polyethylene Glycol, polypropylene glycol, pharmaceutically acceptable lactose, glucose, the mannitol.
5. oxaliplatin injection according to claim 4 is characterized in that: described pharmaceutically acceptable carrier is a water for injection.
6. according to each described oxaliplatin injection in the claim 1 to 5, it is characterized in that: described injection is made up of buffer solution and water for injection that oxaliplatin, acetic acid and sodium acetate form.
7. oxaliplatin injection according to claim 6 is characterized in that: the acetic acid in the described injection and the molar concentration of sodium acetate are 5 * 10
-6～5 * 10
-2M.
8. oxaliplatin injection according to claim 7 is characterized in that: the acetic acid in the described injection and the molar concentration of sodium acetate are 5 * 10
-5～5 * 10
-3M.
9. oxaliplatin injection according to claim 6 is characterized in that: the acetic acid in the described buffer solution and the mol ratio of sodium acetate are 1: 1～5: 1.
10. oxaliplatin injection according to claim 9 is characterized in that: the acetic acid in the described buffer solution and the mol ratio of sodium acetate are 3: 1～5: 1.
11. oxaliplatin injection according to claim 6 is characterized in that: the mass concentration of the oxaliplatin in the described injection is 1～7mg/ml.
12. oxaliplatin injection according to claim 11 is characterized in that: the mass concentration of the oxaliplatin in the described injection is 2～5mg/ml.
13. oxaliplatin injection according to claim 6 is characterized in that: the pH value of described injection is 3～7.
14. oxaliplatin injection according to claim 13 is characterized in that: the pH value of described injection is 3～5.
15. oxaliplatin injection according to claim 14 is characterized in that: the pH value of described injection is 3.7～4.7.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102230625A CN102274171A (en) | 2011-08-04 | 2011-08-04 | Oxaliplatin injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102230625A CN102274171A (en) | 2011-08-04 | 2011-08-04 | Oxaliplatin injection |
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|---|---|
| CN102274171A true CN102274171A (en) | 2011-12-14 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523674A (en) * | 2014-12-11 | 2015-04-22 | 杨玉廷 | Injection composition with oxaliplatin as main medicine component |
| CN105726474A (en) * | 2016-04-12 | 2016-07-06 | 夏建明 | Injection for treating advanced ovarian cancer and preparation method thereof |
| CN105726475A (en) * | 2016-04-12 | 2016-07-06 | 夏建明 | Injection for treating advanced ovarian carcinoma and preparation method thereof |
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|---|---|---|---|---|
| WO1999043355A2 (en) * | 1998-02-25 | 1999-09-02 | Sanofi-Synthelabo | Formulations containing oxaliplatin |
| CN1612737A (en) * | 2001-12-06 | 2005-05-04 | 法玛西雅意大利公司 | Platinum derivative pharmaceutical formulations |
| US20070299132A1 (en) * | 2004-11-02 | 2007-12-27 | Reinhard Rametsteiner | Stable Aqueous Formulation of a Platin Derivative |
| 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 |
| CN101612146A (en) * | 2009-07-22 | 2009-12-30 | 山东罗欣药业股份有限公司 | A kind of oxaliplatin medicament composition and preparation method thereof, and the synthetic method of crude drug oxaliplatin |
-
2011
- 2011-08-04 CN CN2011102230625A patent/CN102274171A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043355A2 (en) * | 1998-02-25 | 1999-09-02 | Sanofi-Synthelabo | Formulations containing oxaliplatin |
| CN1612737A (en) * | 2001-12-06 | 2005-05-04 | 法玛西雅意大利公司 | Platinum derivative pharmaceutical formulations |
| US20070299132A1 (en) * | 2004-11-02 | 2007-12-27 | Reinhard Rametsteiner | Stable Aqueous Formulation of a Platin Derivative |
| 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 |
| CN101612146A (en) * | 2009-07-22 | 2009-12-30 | 山东罗欣药业股份有限公司 | A kind of oxaliplatin medicament composition and preparation method thereof, and the synthetic method of crude drug oxaliplatin |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523674A (en) * | 2014-12-11 | 2015-04-22 | 杨玉廷 | Injection composition with oxaliplatin as main medicine component |
| CN104523674B (en) * | 2014-12-11 | 2017-10-24 | 广州市上为医药科技有限公司 | A kind of composition for injection using oxaliplatin as main ingredient composition |
| CN105726474A (en) * | 2016-04-12 | 2016-07-06 | 夏建明 | Injection for treating advanced ovarian cancer and preparation method thereof |
| CN105726475A (en) * | 2016-04-12 | 2016-07-06 | 夏建明 | Injection for treating advanced ovarian carcinoma and preparation method thereof |
| CN105726474B (en) * | 2016-04-12 | 2018-04-13 | 周英杰 | It is a kind of to be used to treat parenteral solution of advanced ovarian cancer and preparation method thereof |
| CN105726475B (en) * | 2016-04-12 | 2018-05-04 | 青岛市妇女儿童医院 | A kind of parenteral solution for treating advanced ovarian cancer and preparation method thereof |
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Application publication date: 20111214 |