CN101081301A - Medicinal composition containing pemetrexed - Google Patents
Medicinal composition containing pemetrexed Download PDFInfo
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- CN101081301A CN101081301A CN 200610044324 CN200610044324A CN101081301A CN 101081301 A CN101081301 A CN 101081301A CN 200610044324 CN200610044324 CN 200610044324 CN 200610044324 A CN200610044324 A CN 200610044324A CN 101081301 A CN101081301 A CN 101081301A
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Abstract
The present invention provides one kind of medicine composition, which contains Pemetrexed, at least one kind of antioxidant selected from L-arginine, L-glutathione, L-methionine and L-tryptophan, and pharmaceutically acceptable excipient. The medicine composition has high stability and acceptable storing period, and is suitable for liquid administration through no gastrointestinal tract.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains chemical compound pemetrexed (PEMETREXED), specifically, the present invention relates to a kind of liquid preparation that contains pemetrexed and antioxidant.
Background technology
Pemetrexed is an antifolate class antitumor agent, can suppress to relate to the enzymatic conversion of the metabolic derivative of folic acid.It with the lyophilized injectable powder listing, is used for the treatment of mesothelioma and nonsmall-cell lung cancer the earliest by the exploitation of Li Lai company.
People wish it is mixed with concentrated liquid as the administration of infusion dosage form very much, to reduce the infection that might cause in the lyophilized injectable powder dilution.A kind of standby, stablize, be easy to reconstruct and the solution that can at room temperature preserve is desirable especially for pemetrexed, wherein this standby preparation provides simpler and easy, safer operation, storage and distribution, and described stabilization formulations need not to use freeze drying technology to prepare.Desirable liquid preparation can provide high security for the treatment of cytotoxic substance operation, and in addition, stable, wieldy liquid preparation more can be accepted by the medical personnel clinically.
Simple, the normal isotonic saline solution of discovering pemetrexed said so pharmaceutically unacceptable from commercial object, form the unacceptable related substances of human body because this solution is degraded easily.Find at present when preparation contains some antioxidant, can prepare pemetrexed in pharmaceutically acceptable, spissated, standby liquid solution.It is L-cysteine, monothioglycerol and mercapto acetic acid that Li Lai company discloses qualified antioxidant at CN1396828A, and other antioxidant can't provide ideal formulation characteristics.Be meant colour stability and acceptable storage life in the formulation characteristics described in this patent.Yet we find under study for action, and disclosed three kinds of antioxidant are not best to the protective effect of pemetrexed in the CN1396828A patent of Li Lai company.
Summary of the invention
At the deficiencies in the prior art, the invention provides a kind of pharmaceutical composition that contains pemetrexed.
Pharmaceutical composition of the present invention comprises pemetrexed, antioxidant and pharmaceutical acceptable excipient, and it is following at least a to it is characterized in that antioxidant is selected from:
1. L-arginine
2. L-glutathion
3. L-methionine
4. L-tryptophan.
Four kinds of above-mentioned antioxidant have unique effect for described preparation.Astoundingly, these antioxidant not only are better than conventional antioxidant, as sodium metabisulfite, ascorbic acid, EDTA sodium, monoethanolamine gentisate, sodium sulfoxylate formaldehyde, sodium bisulfate, and be better than three kinds of antioxidant L-cysteine, monothioglycerol and mercapto acetic acid disclosed in the CN1396828A patent, make the preparation stability of preparation be higher than the preparation of three kinds of antioxidant preparations of the employing among the CN1396828A.
Preferably, aforementioned pharmaceutical compositions is the liquid preparation that is fit to parenterai administration.
Especially preferred, antioxidant is the L-arginine.
The first-selected 0.02mg/ml-5mg/ml of the arginic concentration of L-(mg/ml is meant the arginic amount of L-in every ml of formulation liquid, down with) can be based on the oxygen concentration of contact said preparation and optimization for this concentration of specified preparation.The arginic concentration of L-can be preferably 0.2mg/ml at least, more preferably 0.5mg/ml at least, especially preferably 1.0mg/ml at least.The arginic concentration of L-can be preferably 3mg/ml at the most, especially preferably 2mg/ml at the most.Preferably the arginic concentration of L-is 0.2mg/ml-3mg/ml, and more preferably the arginic concentration of L-is the about 2.5mg/ml of about 0.5mg/ml-, and the especially preferred arginic concentration of L-is the about 2mg/ml of about 1mg/ml-.
The concentration of L-glutathion is preferably greater than 0.5mg/ml, more preferably greater than 1mg/ml and first-selected greater than 1.5mg/ml.The concentration of L-glutathion is more preferably less than 20mg/ml and first-selected less than 8mg/ml preferably less than 40mg/ml.
Preferably the concentration of L-methionine is 0.5mg/ml-60mg/ml, and more preferably, the concentration of L-methionine is 1mg/ml-40mg/ml.Especially the L-methionine concentration of Xi Wanging is 2mg/ml-20mg/ml.
The concentration of L-tryptophan is preferably greater than 0.1mg/ml, more preferably greater than 0.5mg/ml and first-selected greater than 1mg/ml.The concentration of L-tryptophan is more preferably less than 20mg/ml and first-selected less than 8mg/ml preferably less than 40mg/ml.
The concentration of pemetrexed is 20mg/ml-100mg/ml.The concentration of preferred pemetrexed is 30mg/ml-70mg/ml.Further preferred embodiment is that the concentration of pemetrexed is 35mg/ml-50mg/ml.Further preferred embodiment be that pemetrexed concentration is 38mg/ml-44mg/ml.
Be meant its stable salt, acid and free alkali form at this used term " pemetrexed ", referring to patent CN1396828A.
Be meant the additive of the acceptable preparations carrier of pharmacy, solution or reinforcement preparation characteristic at this used term " pharmaceutical acceptable excipient ".Examples of such additives is well-known to one skilled in the art.Suit although any pharmacy can be accepted diluent, the excipient of preferred especially parenterai administration is a saline solution.For example, sodium chloride, mannitol etc.
The disodium salt of pemetrexed is particularly preferred in the preparation of the present invention.The pH of described preparation is 6.0-10.0.Especially ideal, the pH7.0-9.0 of preparation, further preferred pH7.5-8.5.Described those skilled in the art should be understood that the cooperative programs of these antioxidant can provide new preferred pH scope.The standard of said composition is improved the compositions that different pH of the present invention can be provided.In order to keep the pH value scope of solution, can use buffer salt, wait as phosphate, acetate, citrate and regulate, this is that those skilled in the art person is known.
The method of general preferred for preparation preparation comprises uses the noble gas that cleans.This type of noble gas can be nitrogen, argon etc.It is desirable using isolator to keep hypoxia condition, but is not that storage preparation of the present invention is necessary.
Though the acceptable stopper of any pharmacy can be used for sealing the bottle that contains described preparation, preferably use the plug seal bottle of silication.Require to come the sealed storage bottle with the stopper of sterilization polytetrafluorethylecoatings coatings.
Pharmaceutically the most acceptable liquid preparation bottle or container can be used for the described preparation of packing.Wish that container makes the concentration minimum of the oxygen of the described preparation of contact.So bottle or ampoule are especially desirable for described preparation.
One of ordinary skill in the art should be understood that and wish to use the pre-wash bottle that removes thermal source the storage of the sterilized liquid preparation of using for non-intestinal.Bottle can have color; Yet clear vial is a preparation storage acceptable.Any pharmacy can be accepted the container that material can be used for preparing preparation; Yet glass is particularly preferred container material.Vial is preferred container.Packaging material such as plastic bottle that other non-intestinals use also are the selections that suits.For example, can use plastic bottle.
In the process of preparation preparation, wish protection this product solution lucifuge; Yet this protective effect is not that preparation of the present invention is necessary.
The preparation of gained can utilize well-known to one skilled in the art method sterilization.
This sterilizing methods can comprise, for example, and sterilising filtration or heating.Especially the sterilizing methods of Xi Wanging is that preparation of the present invention keeps stablizing in the heat sterilization process.
The headroom of preferred bottle contains the oxygen less than 8%V./V; Yet if suitably adjusted other condition of said preparation, the headroom of bottle can contain greater than 8% oxygen.More preferably the headroom of bottle contains the oxygen less than about 5%.The headroom of especially preferred described bottle contains the oxygen of having an appointment less than 3%.
The headroom that can adjust bottle makes the minimum oxygen of described preparation contact.Wish that generally this headroom is no more than the about 1/3 of this container total capacity, fill simultaneously account for this container total capacity at least about 2/3.For example, can preferably fill 5ml for the bottle of 7.5ml.If wish the large percentage of headroom and filling, then can adjust the concentration of antioxidant as required.
Pharmaceutical preparation provided by the invention is suitable for human clinical's application simultaneously and the veterinary is used for animal.
Pemetrexed compositions of the present invention can effectively be treated cancer.
In addition, L-arginine (alkali) (CAS:74-79-3), L-arginine monohydrochloride (CAS:1119-34-2), L-methionine (CAS:63-68-3), L-tryptophan (CAS:73-22-3), L-glutathion (CAS:70-18-8) be easy to obtain from the supplier of fine chemistry.
The preparation stability of antioxidant preparation is better than the antioxidant in the CN1396828A of the Yu Lilai company patent described in employing the present invention, and the concrete outcome data see Table 1.
With respectively with the preparation of the L-cysteine of reporting among the preparation of different antioxidant L-arginine, L-glutathion, L-methionine, the preparation of L-tryptophan and the patent CN1396828A, monothioglycerol, the preparation of mercapto acetic acid, adopt identical technology and packing, the investigation result who places 10 days stability respectively under 60 ℃ and 4500LX illumination condition is as follows:
Four kinds of the antioxidant preparation for preparing respectively and the preparations that adopt the antioxidant preparation among the CN1396828A under same process and terms of packing are placed 10 days study on the stability results under the same conditions among table 1 the present invention
Annotate: Y represents yellow
Above result shows: the preparation that L-cysteine, monothioglycerol, the mercapto acetic acid that the preparation stability that L-arginine, L-glutathion, L-methionine, L-tryptophan prepare respectively all is better than reporting among the patent CN1396828A prepares.
Preparation of the present invention has acceptable stability, has kept pharmaceutically desirable outward appearance, has kept required mapping stability, and meets requirement stable, the reserve liquid body preparation.In addition, be fit to parenterai administration, can leave in clear vial or the brown bottle, and can preserve with highly enriched state more than 4 ℃ at this preparation that provides.
The present invention has reached the requirement to the liquid pemetrexed preparation of pharmaceutically stable, has colour stability and acceptable storage life simultaneously, thereby makes this solution dosage keep the stable unacceptable Degradation of human body of having avoided.In addition, described preparation can be diluted to required administration concentration.At last, preparation provided by the present invention need not add any antiseptic except antioxidant, thereby keeps the stability of expection concentration and Geng Gao.
The specific embodiment
Following examples will further specify the present invention, but not limit the present invention.
Embodiment 1.
Liquid preparation comprises pemetrexed, antioxidant and pharmaceutical acceptable excipient, and wherein antioxidant is the L-arginine.Pemetrexed is selected pemetrexed disodium for use.
L-arginine 10mg adds injection water 8ml dissolving, transfers pH to 8.0 with hydrochloric acid, adds then to add the injection water after pemetrexed disodium 400mg (in pemetrexed) dissolves to 10ml.
Protection this product solution avoids illumination.In this solution, feed nitrogen, aseptic filtration subsequently in 20 minutes.Described preparation is divided in removing in the thermal source bottle of prewashing, clogs with prewashing, pre-sterilized polytetrafluorethylecoatings coatings stopper subsequently.Lid is installed with beading machine.Sterilising filtration and packing step utilize nitrogen isolation gas (5%V/V oxygen) to carry out.
With the solution heat sterilization that is filled in the bottle.
Embodiment 2. is as different is that antioxidant is the 0.02mg/mlL-arginine as described in the embodiment 1.
Embodiment 3. is as different is that antioxidant is the 5mg/mlL-arginine as described in the embodiment 1.
Embodiment 4. is as different is that water for injection changes normal saline into as described in the embodiment 1.
Embodiment 5. is as different is the phosphate-buffered salt that adds 0.05M in the solution as described in the embodiment 4.
Embodiment 7. is as different is that pH value of solution transfers to 7.0 as described in the embodiment 2.
Embodiment 8. is 20mg/ml as the concentration of different is as described in the embodiment 4 pemetrexed.
Embodiment 9. is as different is that pemetrexed substitutes pemetrexed disodium as described in the embodiment 1.
Embodiment 10 is as described in the embodiment 1, and different is that antioxidant is 2.0mg/ml L-glutathion, and the concentration of pemetrexed is 40mg/ml.
Embodiment 11 is as described in the embodiment 5, and different is that antioxidant is 0.25mg/ml L-glutathion, and the concentration of pemetrexed is 50mg/ml.
Embodiment 12 is as described in the embodiment 1, and different is that antioxidant is 40mg/ml L-glutathion, and the concentration of pemetrexed is 10mg/ml.
Embodiment 13 is as described in the embodiment 9, and different is that antioxidant is 2.0mg/ml L-glutathion, and the concentration of pemetrexed is 80mg/ml.
Embodiment 14. is as described in the embodiment 1, and different is that antioxidant is 10.0mg/ml L-methionine, and the concentration of pemetrexed is 40mg/ml.
Embodiment 15. is as described in the embodiment 4, and different is that antioxidant is 20.0mg/ml L-methionine, and the concentration of pemetrexed is 60mg/ml.
Embodiment 16. is as described in the embodiment 1, and different is that antioxidant is 0.5mg/ml L-methionine, and the concentration of pemetrexed is 40mg/ml.
Embodiment 17. is as described in the embodiment 1, and different is that antioxidant is 5.0mg/ml L-tryptophan, and the concentration of pemetrexed is outside the 40mg/mL, basically according to embodiment 1 described method pharmaceutical compositions.
Claims (10)
1, pharmaceutical composition comprises pemetrexed, antioxidant and pharmaceutical acceptable excipient, and it is following at least a to it is characterized in that antioxidant is selected from:
1. L-arginine,
2. L-glutathion,
3. L-methionine,
4. L-tryptophan.
2, pharmaceutical composition as claimed in claim 1 is characterized in that said composition is the liquid preparation that is fit to parenterai administration.
3, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that pemetrexed is the disodium salt of pemetrexed.
4, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that its pH scope 6.0-10.0, preferred pH7.0-9.0, most preferably pH7.5-8.5.
5, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that described antioxidant is that concentration is the L-arginine of 0.02mg/ml-5mg/ml.
6, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that the arginic concentration of described L-is 0.2mg/ml-3mg/ml.
7, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that the arginic concentration of described L-is 0.5mg/ml-2.5mg/ml, is good with 1mg/ml-2mg/ml.
8, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that described antioxidant is the L-glutathion, and concentration is 0.25mg/ml at least, is good with 1mg/ml-40mg/ml.
9, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that described antioxidant is the L-methionine, and concentration is that 0.5mg/ml-60mg/ml is good with 2mg/ml-10mg/ml.
10, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that described antioxidant is the L-tryptophan, and concentration 0.1mg/ml at least is good with 1mg/ml-8mg/ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610044324 CN101081301A (en) | 2006-05-29 | 2006-05-29 | Medicinal composition containing pemetrexed |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610044324 CN101081301A (en) | 2006-05-29 | 2006-05-29 | Medicinal composition containing pemetrexed |
Publications (1)
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| CN101081301A true CN101081301A (en) | 2007-12-05 |
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| CN 200610044324 Pending CN101081301A (en) | 2006-05-29 | 2006-05-29 | Medicinal composition containing pemetrexed |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040834A (en) * | 2012-12-25 | 2013-04-17 | 山西普德药业股份有限公司 | Pemetrexed disodium for injection and preparation method thereof |
| WO2013165130A1 (en) * | 2012-04-30 | 2013-11-07 | 씨제이제일제당(주) | Stabilized liquid preparation for injection containing pemetrexed |
| WO2013179248A1 (en) | 2012-05-30 | 2013-12-05 | Fresenius Kabi Oncology Ltd. | Pharmaceutical compositions of pemetrexed |
| CN104098573A (en) * | 2013-04-10 | 2014-10-15 | 重庆医药工业研究院有限责任公司 | Pemetrexed salt and preparation method thereof |
| WO2014198338A1 (en) * | 2013-06-14 | 2014-12-18 | Synthon B.V. | Stable pemetrexed arginine salt and compositions comprising it |
| CN105726501A (en) * | 2016-02-29 | 2016-07-06 | 北京颐诺赛医药科技有限公司 | Pemetrexed oral preparation |
| US9789113B2 (en) | 2014-06-30 | 2017-10-17 | Shilpa Medicare Limited | Pemetrexed dipotassium formulations |
| US20180271872A1 (en) * | 2014-10-16 | 2018-09-27 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
| EP3470045A1 (en) | 2017-10-10 | 2019-04-17 | Sun Pharmaceutical Industries Ltd | Intravenous infusion dosage form for pemetrexed |
| EP3962453A4 (en) * | 2019-05-01 | 2023-01-25 | Intas Pharmaceuticals Ltd. | A stable, ready to use aqueous pharmaceutical composition of pemetrexed |
| WO2023237093A1 (en) * | 2022-06-09 | 2023-12-14 | 上海云晟研新生物科技有限公司 | Pemetrexed disodium liquid composition, preparation method therefor and use thereof |
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2006
- 2006-05-29 CN CN 200610044324 patent/CN101081301A/en active Pending
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013165130A1 (en) * | 2012-04-30 | 2013-11-07 | 씨제이제일제당(주) | Stabilized liquid preparation for injection containing pemetrexed |
| US9421207B2 (en) | 2012-05-30 | 2016-08-23 | Fresenius Kabi Oncology Limited | Pharmaceutical compositions comprising pemetrexed and tromethamine |
| WO2013179248A1 (en) | 2012-05-30 | 2013-12-05 | Fresenius Kabi Oncology Ltd. | Pharmaceutical compositions of pemetrexed |
| US9968608B2 (en) | 2012-05-30 | 2018-05-15 | Fresenius Kabi Oncology Limited | Pharmaceutical compositions comprising pemetrexed and tromethamine |
| EP3210629A1 (en) | 2012-05-30 | 2017-08-30 | Fresenius Kabi Oncology Ltd | Pharmaceutical composition of pemetrexed |
| EP2854768B1 (en) | 2012-05-30 | 2017-03-22 | Fresenius Kabi Oncology Limited | Pharmaceutical compositions of pemetrexed |
| CN103040834A (en) * | 2012-12-25 | 2013-04-17 | 山西普德药业股份有限公司 | Pemetrexed disodium for injection and preparation method thereof |
| CN104098573A (en) * | 2013-04-10 | 2014-10-15 | 重庆医药工业研究院有限责任公司 | Pemetrexed salt and preparation method thereof |
| JP2016521732A (en) * | 2013-06-14 | 2016-07-25 | シントン・ベスローテン・フェンノートシャップ | Arginine salt of stable anticancer agent and composition containing the same |
| WO2014198338A1 (en) * | 2013-06-14 | 2014-12-18 | Synthon B.V. | Stable pemetrexed arginine salt and compositions comprising it |
| US9789113B2 (en) | 2014-06-30 | 2017-10-17 | Shilpa Medicare Limited | Pemetrexed dipotassium formulations |
| US10188655B2 (en) * | 2014-10-16 | 2019-01-29 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
| US10272090B1 (en) | 2014-10-16 | 2019-04-30 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
| US20180271872A1 (en) * | 2014-10-16 | 2018-09-27 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
| CN105726501A (en) * | 2016-02-29 | 2016-07-06 | 北京颐诺赛医药科技有限公司 | Pemetrexed oral preparation |
| CN105726501B (en) * | 2016-02-29 | 2018-08-28 | 长乐智睿恒创节能科技有限责任公司 | A kind of pemetrexed oral preparation |
| EP3470045A1 (en) | 2017-10-10 | 2019-04-17 | Sun Pharmaceutical Industries Ltd | Intravenous infusion dosage form for pemetrexed |
| EP3804686A1 (en) | 2017-10-10 | 2021-04-14 | Sun Pharmaceutical Industries Ltd | Intravenous infusion dosage form for pemetrexed |
| EP3962453A4 (en) * | 2019-05-01 | 2023-01-25 | Intas Pharmaceuticals Ltd. | A stable, ready to use aqueous pharmaceutical composition of pemetrexed |
| WO2023237093A1 (en) * | 2022-06-09 | 2023-12-14 | 上海云晟研新生物科技有限公司 | Pemetrexed disodium liquid composition, preparation method therefor and use thereof |
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Open date: 20071205 |