CN100522173C - Pharmaceutical composition containing pemetrexed - Google Patents
Pharmaceutical composition containing pemetrexed Download PDFInfo
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- CN100522173C CN100522173C CNB2006100408285A CN200610040828A CN100522173C CN 100522173 C CN100522173 C CN 100522173C CN B2006100408285 A CNB2006100408285 A CN B2006100408285A CN 200610040828 A CN200610040828 A CN 200610040828A CN 100522173 C CN100522173 C CN 100522173C
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- pemetrexed
- pharmaceutical composition
- glycine
- methionine
- weight ratio
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Abstract
The invention discloses a drug composition with Peimeiqusai and stabilizer at 5: 2-7, wherein the weight rate of Peimeiqusai and shaping agent is 0.5-1: 1. The invention is stable for light and heat, which can be reserved at normal temperature.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, relate in particular to a kind of pharmaceutical composition that contains pemetrexed.
Background technology
Pemetrexed is a kind of novel antifolate matter based on pyrroles [2,3-d] pyrimidine.Chemistry N-[4[2 (amino 3 by name; 4 dihydros-4 ketone-1H-pyrroles [2; 3-d] pyrimidine-5-hydroxyl) ethyl]-benzoyl group]-L-disodium glutamate salt, with the pyrazine ring in the pyrrole ring replacement folic acid pteridine part, the benzyl nitrogen of bridging part is then substituted by methyl group.Its anhydride be off-white color to the unformed powder of light gray green, tool draws moist, easily suction forms stable heptahydrate, outward appearance is that light green is to green crystalloid powder.
Known some anti-folic acid metabolism medicine has antitumor action at present, and these chemical compounds reach the antitumor purpose by the enzymatic conversion that suppresses to rely in the folic acid metabolism process.Pemetrexed belongs to this class medicine, by the parenterai administration mode can useful effect in diseased region, carry out clinical research in the U.S. at present.
Pemetrexed can suppress the activity of a plurality of folic acid dependent enzymes, comprise TS, dihydrofolate reductase (Dihydrofolate Reductase, DHFR), formyl glycyl nucleotidyl transferase (GlycinamideRibonicleotide Formytransferase, GARFT) and 5-aminoimidazole-4-carbozamide transferring enzyme (AICARFT), thereby suppress the de novo synthesis of purine and pyrimidine, and then influence the synthetic performance antitumaous effect of DNA.
Preclinical study finds that pemetrexed has active anticancer to malignant mesothe, nonsmall-cell lung cancer, cancer of pancreas, colorectal cancer, bladder cancer, head and neck cancer and breast carcinoma.In the research of TEICHER etc., adopt the associating of pemetrexed and other drug, treat human transplantation tumor, the result shows that the Graft Versus Tumor that pemetrexed is increased prior to the FU use in conjunction is better than MTX associating FU, in the nonsmall-cell lung cancer transplantation tumor, the associating of pemetrexed and platinum-like compounds is as cisplatin or oxaliplatin, and the synergism of uniting generation than pemetrexed and cyclophosphamide, gemcitabine, doxorubicin is more obvious, and combines with radiotherapy and can play sensitization.Pemetrexed list usefulness can be used for treating local late period and transitivity nonsmall-cell lung cancer after the early stage chemotherapy.Adding 0.9% sodium chloride injection dilution posterior vein when using clinically instils.
Discover pemetrexed now to light, heat and humidity sensitive, dissolubility is relatively poor.Simple pemetrexed is separated out crystal or degraded formation to the disadvantageous related substances of human body easily in the normal isotonic saline solution instability, increases the generation of little good reaction.A kind of stable preparation that can at room temperature preserve is more satisfactory for pemetrexed, and this preparation preferably do not contain organic solvent, and water solublity is better, and operation, storage and the distribution of walk away safety can be provided, and can provide high security for treatment.Stable in addition, that the organic solvent use is few, wieldy preparation is also accepted by doctor and patient easily.
Find at present when the pemetrexed preparation contains some stabilizing agents, can prepare pharmaceutically acceptable stable formulation, improve the dissolubility of pemetrexed water.CN01804441.7 introduced a kind of pemetrexed liquid preparation that contains in the hope of solving the oxidative phenomena of pemetrexed, is easy to get but the adjuvant of its use is non-at home, and used a large amount of organic solvents.In addition, this antioxidant does not have positive effect for the water solublity that improves pemetrexed.
Summary of the invention
The objective of the invention is to overcome the instability of above pemetrexed, easily degraded, to light, heat and humidity sensitive, the relatively poor shortcoming of dissolubility, but a kind of place and pharmaceutical composition that adjuvant is easy to get of stable room temperature that contains pemetrexed is provided.
Purpose of the present invention can reach by following measure:
A kind of pharmaceutical composition that contains pemetrexed contains pemetrexed and stabilizing agent in the compositions, its weight ratio is 5:2～7.
Purpose of the present invention specifically can reach by following measure:
A kind of pharmaceutical composition that contains pemetrexed contains pemetrexed and stabilizing agent in the compositions, its weight ratio is preferably 5:4～6, most preferably is 5:5.
The pemetrexed that contains in the compositions is stable salt, acid or free alkali form, the disodium salt of preferred pemetrexed.
Stabilizing agent is one or more in pyrosulfurous acid hydrogen sodium, VC, EDTA sodium, sodium bisulfate, arginine, cysteine, methionine or the glycine.
Preferred stabilizer is one or more in arginine, methionine or the glycine.
These three kinds of antioxidant have effect unique for preparation of the present invention, and the cysteine that uses among conventional antioxidant and the patent CN0180441.7 etc. can't reach ideal antioxidation in this product preparation.
Usually use wherein arbitrary antioxidant can obtain pharmaceutically acceptable qualified products, most preferred antioxidant is methionine or glycine, and especially preferred antioxidant is glycine.
In addition, the cooperative programs of these three kinds of antioxidant also can be used and the present invention.The combination of preferred methionine and glycine, consumption preferred weight ratio 1:4～4:1, especially preferred weight ratio 2:2.
Also can add pharmaceutically acceptable excipient among the present invention, as dextran, mannitol or lecithin etc., preferred excipient is a mannitol, and its consumption is 0.5～1:1 for the weight ratio with the beautiful Qu Sai of training, preferred 0.7:1.
Compositions can be made lyophilized injectable powder with conventional method, before the vacuum lyophilization solution pH value of preparation be 5.5～8.5, two preparation of sodium more preferably PH be about 6～8.
Pharmaceutical preparation provided by the invention is applicable to that the human clinical uses with the veterinary and is used for animal.With the unresectable or invalid malignant pleural mesothelioma of performing the operation of cisplatin coupling treatment; Single medicine can be treated local late period and transitivity nonsmall-cell lung cancer after the early stage chemotherapy.
Lyophilized formulations adjuvant provided by the present invention is easy to get, and does not contain other organic solvents, can place at normal temperatures, can obtain with the isotonic saline solution dilution with preceding, can be used for parenterai administration.Described antioxidant comprises one or more the combination in arginine, methionine or the glycine.The lyophilized formulations of the one or more combination preparation in pemetrexed and these antioxidant just can have required preparation characteristic described herein.
The present invention has reached the requirement to the pemetrexed preparation of the be prepared into parenterai administration of pharmaceutically stable, and has colour stable, long shelf-life simultaneously, has avoided pemetrexed to produce the Degradation of unfavorable related substances to greatest extent.At last, preparation provided by the present invention need not to add any antiseptic except antioxidant.
The specific embodiment
Embodiment 1
Pemetrexed disodium 500g, arginine 100g, mannitol 350g and water for injection are made 5.0L solution, regulate pH value and are about 5.5, remove pyrogen, packing, lyophilization, promptly.
Embodiment 2
Pemetrexed disodium 500g, methionine 100g, glycine 300g, mannitol 250g and water for injection are made 5.0L solution, regulate pH value and are about 8.5, remove pyrogen, packing, lyophilization, promptly.
Embodiment 3
Pemetrexed disodium 500g, glycine 150g, mannitol 350g and water for injection are made 5.0L solution, regulate pH value and are about 6, remove pyrogen, packing, lyophilization, promptly.
Embodiment 4
Pemetrexed disodium 500g, methionine 300g, glycine 100g, mannitol 250g and water for injection are made 5.0L solution, regulate pH value and are about 8, remove pyrogen, packing, lyophilization, promptly.
Embodiment 5
Pemetrexed disodium 500g, methionine 100g, glycine 400g, mannitol 200g and water for injection are made 5.0L solution, regulate pH value and are about 8, remove pyrogen, packing, lyophilization, promptly.
Embodiment 6
Pemetrexed disodium 500g, methionine 400g, glycine 100g, dextran 350g and water for injection are made 5.0L solution, regulate pH value and are about 8, remove pyrogen, packing, lyophilization, promptly.
Embodiment 7
Pemetrexed disodium 500g, methionine 350g, glycine 350g, mannitol 500g and water for injection are made 5.0L solution, regulate pH value and are about 8, remove pyrogen, packing, lyophilization, promptly.
Embodiment 8
Pemetrexed disodium 500g, methionine 400g, mannitol 250g and water for injection are made 5.0L solution, regulate pH value and are about 7, remove pyrogen, packing, lyophilization, promptly.
One, the mixed water solublity experiment of pemetrexed and stabilizing agent
Table 1
Two, the stable comparative experiments of this pharmaceutical composition
Prepare sample respectively by following composition proportion (table 2), the every batch of formulation samples be positioned over respectively 60 ℃ of following 10 days and illumination (4500 ± 500LX) 10 days, pemetrexed content and impurity content in the comparative formulations sample.Experimental result table (table 3) by the back as can be seen, three kinds of stabilizing agents involved in the present invention have positive effect to principal agent stable.
Table 2
The experimental result table
Table 3
Claims (9)
1, a kind of pharmaceutical composition that contains pemetrexed is characterized in that containing in the compositions pemetrexed and stabilizing agent, and its weight ratio is 5:2～7, and wherein stabilizing agent is one or more in arginine, methionine or the glycine.
2, according to the right 1 described pharmaceutical composition that contains pemetrexed, it is characterized in that compositions also contains pharmaceutically acceptable excipient, the weight ratio of itself and pemetrexed is 0.5～1:1.
3, according to the right 2 described pharmaceutical compositions that contain pemetrexed, the weight ratio that it is characterized in that excipient and pemetrexed is 0.7:1.
4, according to the right 1 described pharmaceutical composition that contains pemetrexed, it is characterized in that pemetrexed and stabilizing agent, its weight ratio is 5:4～6.
5,, it is characterized in that described stabilizing agent is methionine or glycine according to the right 1 described pharmaceutical composition that contains pemetrexed.
6, according to the right 1 described pharmaceutical composition that contains pemetrexed, it is characterized in that described stabilizing agent is the combination of methionine and glycine, the weight ratio of the two is 1:4～4:1.
7, according to the right 6 described pharmaceutical compositions that contain pemetrexed, the weight ratio that it is characterized in that methionine and glycine is 2:2.
8,, it is characterized in that described excipient is mannitol, lecithin or dextran according to right 2 or the 3 described pharmaceutical compositions that contain pemetrexed.
9, the pharmaceutical composition that pemetrexed is arranged according to claim 1 and 2 is characterized in that compositions is made injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100408285A CN100522173C (en) | 2006-07-28 | 2006-07-28 | Pharmaceutical composition containing pemetrexed |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100408285A CN100522173C (en) | 2006-07-28 | 2006-07-28 | Pharmaceutical composition containing pemetrexed |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1907284A CN1907284A (en) | 2007-02-07 |
| CN100522173C true CN100522173C (en) | 2009-08-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100408285A Expired - Fee Related CN100522173C (en) | 2006-07-28 | 2006-07-28 | Pharmaceutical composition containing pemetrexed |
Country Status (1)
| Country | Link |
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| CN (1) | CN100522173C (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040834B (en) * | 2012-12-25 | 2014-07-02 | 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 |
| JP6248189B2 (en) | 2013-06-14 | 2017-12-13 | 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 |
| NZ630299A (en) | 2014-06-30 | 2014-11-28 | Shilpa Medicare Ltd | Pemetrexed dipotassium formulations |
| HUE048357T2 (en) | 2014-10-16 | 2020-08-28 | Synthon Bv | Liquid pharmaceutical composition comprising pemetrexed |
| CN107837237B (en) * | 2016-09-18 | 2019-11-05 | 南京先声东元制药有限公司 | A kind of pemetrexed disodium pharmaceutical composition and preparation method thereof |
| CN106421082A (en) * | 2016-12-27 | 2017-02-22 | 郑州莉迪亚医药科技有限公司 | Medicine composition for treating gastric ulcer |
| CA3137265A1 (en) * | 2019-05-01 | 2020-11-05 | Intas Pharmaceuticals Ltd. | A stable, ready to use aqueous pharmaceutical composition of pemetrexed |
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2006
- 2006-07-28 CN CNB2006100408285A patent/CN100522173C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1907284A (en) | 2007-02-07 |
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