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A stabilized pemetrexed formulation

A pemetrexed preparation technology, applied in the field of stable pemetrexed preparations, can solve problems such as insufficient stability, achieve the effects of preventing microbial contamination, and improving convenience and stability

Active Publication Date: 2015-07-29
CJ HEALTHCARE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the present inventors prepared liquid formulations containing pemetrexed using about 60 kinds of stabilizers including ascorbic acid, sodium thiosulfate, butylated hydroxyanisole, propyl gallate, EDTA, L-methionine acid and acetylcysteine, but these formulations have insufficient stability

Method used

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  • A stabilized pemetrexed formulation
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  • A stabilized pemetrexed formulation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 to 14

[0049] Examples 1 to 14: Containing different amounts of acetylcysteine ​​as Preparation of Injectable Solution Containing Pemetrexed with Antioxidant and Sodium Citrate as Buffer

[0050] 2.5 g of D-mannitol was dissolved in 100 ml of WFI (Water for Injection), and then acetylcysteine ​​and sodium citrate were continuously added thereto at the concentrations shown in Table 1 below and completely dissolved therein. 2.5 g of pemetrexed was slowly added to the solution (in Example 14 3.0 g of pemetrexed was added slowly) and the solutions were stirred until they became clear. Then, the solution was adjusted to the pH shown in Table 1 with aqueous hydrochloric acid or sodium hydroxide. The solution was sterile filtered through a sterile 0.22-μm membrane filter in a clean room. The obtained solution was poured into previously washed / sterilized sealable containers purged with nitrogen.

[0051] The composition and pH of the obtained injectable solution containing pemetrexed a...

Embodiment 15 and 16

[0054] Examples 15 and 16: Preparation of injectable solutions containing pemetrexed with different pH

[0055] 2.5 g of D-mannitol was dissolved in 100 ml of WFI (Water for Injection), and then acetylcysteine ​​and sodium citrate were continuously added thereto at the concentrations shown in Table 2 below and completely dissolved therein. 2.5 g of pemetrexed was slowly added to the solution and the solutions were stirred until they became clear. Then, the solution was adjusted to the pH shown in Table 2 with aqueous hydrochloric acid or sodium hydroxide. The solution was sterile filtered through a sterile 0.22-μm membrane filter in a clean room. The obtained solution was poured into previously washed / sterilized sealable containers purged with nitrogen.

[0056] The composition and pH of the obtained injectable solution containing pemetrexed are shown in Table 2 below.

[0057] Table 2

[0058]

experiment Embodiment 1

[0075] Experimental Example 1: Stress stability test (60°C / 80%, 4-week evaluation)

[0076] The stress stability test was performed as described above and the test results are shown in Tables 7 to 11 below.

[0077] and also, figure 1 The injectable liquid formulation containing pemetrexed according to the present invention (Example 11) and the state of the art containing pemetrexed were shown during the 4-week stability test period under stress test conditions (60°C and 80%) Comparison of appearance between the injectable liquid formulations (Comparative Examples 1, 12 and 14) of . For comparison, the appearance of WFI (Water for Injection) is also shown in figure 1 middle.

[0078] Table 7

[0079]

[0080]

[0081]

[0082] As can be seen from the results in Table 7, formulations containing 1.5 mg / mL acetylcysteine ​​as an antioxidant and 1-15 mg / mL sodium citrate as a buffer showed 0.2% or less The individual impurity content and the total impurity content ...

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Abstract

The present invention relates to a stabilized pemetrexed formulation, and more particularly to a stabilized pemetrexed formulation comprising acetylcysteine as antioxidant and a citrate salt as buffer.

Description

technical field [0001] The present invention relates to stable pemetrexed formulations, more particularly to stable pemetrexed formulations comprising acetylcysteine ​​as an antioxidant and citrate as a buffer. Background technique [0002] Certain compounds known to have antifolate activity are well known as chemotherapeutic agents for cancer treatment. U.S. Patent No. 5,344,932 discloses methods for preparing certain substituted pyrrolo[2,3-d]pyrimidinyl antifolate derivatives, including pemetrexed, and European Patent Publication No. 0434426 discloses a series of 4-hydroxy Pyrrolo[2,3-d]pyrimidine-L-glutamate derivatives. [0003] Pemetrexed, a 5-substituted pyrrolo[2,3-d]pyrimidine, is a multi-targeted antifolate agent shown to target a variety of cancers—including non-small Cell Lung Cancer—Anticancer Effects. [0004] Pemetrexed is known to enter cells via the reduced folate carrier (RFC), which is the major folate transport system, and is then activated by folylpol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K31/517A61P35/00
CPCA61K31/519A61K31/198A61K9/0019A61K47/183A61K47/20A61P35/00A61K2300/00A61K31/517A61J1/05A61K9/08A61K47/12A61K2121/00
Inventor 朴映准申明珍秦宏澈崔河龙崔洛铉
Owner CJ HEALTHCARE CORP
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