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Pemetrexed disodium freeze-dried powder injection and preparation method thereof

A technology of pemetrexed disodium and freeze-dried powder injection, applied in the field of medicine, can solve the problems of rough freeze-drying process, low economic benefit, slow heating rate and the like, and achieve the effect of avoiding adverse effects

Active Publication Date: 2012-05-02
HAINAN JINRUI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The stability of pemetrexed disodium is relatively poor, and it is easy to degrade under high temperature and oxidative conditions, and produces impurities that may cause toxic and side effects. It is not suitable for making injections that require high-temperature sterilization. However, in the process of transportation and storage of the existing pemetrexed disodium freeze-dried powder injection, the impurity content in the freeze-dried powder injection often increases significantly because of the lax temperature control. Suggestions for improving the above-mentioned defects have not been disclosed with technology and common knowledge
[0008] CN200810234188.0 discloses a pemetrexed disodium freeze-dried powder injection and a preparation method thereof. The pemetrexed disodium freeze-dried powder injection is composed of pemetrexed disodium, mannitol and sodium sulfite, and sodium sulfite is commonly used Antioxidant, with strong chemical activity, can undergo addition reaction with some aldehydes and ketones, and will have a certain impact on the efficacy of the main drug. In addition, because the human body has extremely high requirements for freeze-dried powder injection, However, there are many types of excipients in the freeze-dried powder, which not only increases the types and contents of impurities in the freeze-dried powder, but also increases the risk of impurities in the excipients. The impurity content of the freeze-dried powder is 0.72%. ~0.85%; Moreover, during the freeze-drying process of the freeze-dried powder, first cool the product to -40°C, continue to freeze for 2-4 hours, vacuumize, and then raise the temperature at a rate of 2-4°C per hour to 35°C, the freeze-drying process is rough, and the moisture content of the finished product after freeze-drying is high. The moisture content of the freeze-dried powder is 4.8% to 5.8%. In addition, during the drying process, the heating rate is too slow, which is required for production. Excessive energy consumption and low economic benefits

Method used

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  • Pemetrexed disodium freeze-dried powder injection and preparation method thereof
  • Pemetrexed disodium freeze-dried powder injection and preparation method thereof
  • Pemetrexed disodium freeze-dried powder injection and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Add 2244ml of water for injection into the liquid preparation tank, the temperature of the liquid preparation tank is 5°C, then add 80g of pemetrexed disodium, and stir to dissolve. Then add 96g of mannitol, stir to make the liquid into a clear solution; use 0.1mol / L hydrochloric acid solution and / or 0.1mol / L sodium hydroxide solution to adjust the pH value of the liquid to 7.3, add 396ml of water for injection, and mix well .

[0048] Add 0.20% (g / ml) of medicinal activated carbon to the clear solution, stir and absorb for 30 minutes, filter with a 0.45 μm microporous membrane for decarburization, filter with a 0.2 μm primary sterile filter and 0.2 μm secondary Terminal sterilization and filtration, the obtained filtrate is put into the liquid medicine bottle for filling.

[0049] The filtrate is subpackaged, half-stoppered, and put into a freeze dryer for freeze-drying. The freeze-drying is divided into three stages: pre-freezing, primary drying and secondary drying;...

Embodiment 2

[0055] Add 3060ml of water for injection into the liquid preparation tank, the temperature of the liquid preparation tank is 0°C, then add 80g of pemetrexed disodium, stir to dissolve. Then add 160g of mannitol, stir to make the liquid into a clear solution; use 0.1mol / L hydrochloric acid solution and / or 0.1mol / L sodium hydroxide solution to adjust the pH value of the liquid to 7.0, add 540ml of water for injection, and mix well .

[0056] Add 0.20% (g / ml) of medicinal activated carbon to the clear solution, stir and absorb for 30 minutes, filter with a 0.45 μm microporous membrane for decarburization, filter with a 0.2 μm primary sterile filter and 0.2 μm secondary Terminal sterilization and filtration, the obtained filtrate is put into the liquid medicine bottle for filling.

[0057] The filtrate is subpackaged, half-stoppered, and put into a freeze dryer for freeze-drying. The freeze-drying is divided into three stages: pre-freezing, primary drying and secondary drying;

...

Embodiment 3

[0063] Add 2652ml of water for injection into the liquid preparation tank, the temperature of the liquid preparation tank is 10°C, then add 80g of pemetrexed disodium, stir to dissolve. Then add 128g of mannitol, stir to make the liquid into a clear solution; use 0.1mol / L hydrochloric acid solution and / or 0.1mol / L sodium hydroxide solution to adjust the pH value of the liquid to 7.54, add 468ml of water for injection, and mix well .

[0064] Add 0.20% (g / ml) of medicinal activated carbon to the clear solution, stir and absorb for 30 minutes, filter with a 0.45 μm microporous membrane for decarburization, filter with a 0.2 μm primary sterile filter and 0.2 μm secondary Terminal sterilization and filtration, the obtained filtrate is put into the liquid medicine bottle for filling.

[0065] The filtrate is subpackaged, half-stoppered, and put into a freeze dryer for freeze-drying. The freeze-drying is divided into three stages: pre-freezing, primary drying and secondary drying; ...

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Abstract

The invention belongs to the technical field of medication, and in particular relates to a pemetrexed disodium freeze-dried powder injection and a preparation method thereof. The pemetrexed disodium freeze-dried powder injection consists of pemetrexed disodium and mannitol, wherein the mass ratio of the mannitol to the pemetrexed disodium is (0.6-2.0):1. The preparation method comprises the following steps: adding injecting water into a liquid preparation tank; adding the pemetrexed disodium weighted according to the formula; stirring until the pemetrexed disodium completely dissolved; addingthe mannitol; regulating the pH by utilizing a hydrochloric acid solution or a sodium hydroxide solution; adding activated carbon for decoloration; filtering to remove the carbon; finely filtering with a filter membrane; subpackaging; and freezing and drying. The pemetrexed disodium freeze-dried powder injection has excellent moldability; the appearance of the solution before freezing is clear; the frozen and dry product has good re-dissolubility; and the re-dissolved product has the advantages of good clarity, low impurity content, low moisture content, good stability and controllable quality.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a pemetrexed disodium freeze-dried powder injection and a preparation method thereof. Background technique [0002] Pemetrexed disodium, its chemical name is: N-[4-[2-(2-amino-4,7-dihydro-4-carbonyl-1H-pyrrole[2,3-d]-pyrimidine-5 -yl)ethyl]benzoyl]-L glutamate disodium salt 2.5 hydrate. The molecular formula is: C 20 h 19 N 5 Na 2 o 6 2.5H 2 O, molecular weight is 516.38, its chemical structure formula: [0003] [0004] Pemetrexed is an antifolate preparation with a pyrrolic pyrimidine group in its structure. It can inhibit the growth of tumors by destroying the normal metabolic process dependent on folic acid in cells and inhibiting cell replication. In vitro studies have shown that pemetrexed can inhibit the activities of thymidylate synthase, dihydrofolate reductase and glycinamide nucleotide formyltransferase, which are all enzymes necessary for the synthesis of fo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/19A61K31/519A61K47/10A61P35/00
Inventor 马鹰军钟正明
Owner HAINAN JINRUI PHARMA CO LTD
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