A method for preparing a pharmaceutical preparation in the form of an antioxidant-free solution containing pemetrexed or a salt thereof for injection

The technology of a pharmaceutical preparation and pemetrexed is applied in the field of pharmaceutical preparations in the form of an antioxidant-free solution containing pemetrexed or a salt thereof for injection, and can solve the problems of low stability and the like

Inactive Publication Date: 2016-03-30
KUHNIL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, pemetrexed is less stable in the medium used for injection (e.g., water for injection), resulting in various degradation products

Method used

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  • A method for preparing a pharmaceutical preparation in the form of an antioxidant-free solution containing pemetrexed or a salt thereof for injection
  • A method for preparing a pharmaceutical preparation in the form of an antioxidant-free solution containing pemetrexed or a salt thereof for injection
  • A method for preparing a pharmaceutical preparation in the form of an antioxidant-free solution containing pemetrexed or a salt thereof for injection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of a solution for injection by distillation degassing

[0034]700 ml of water for injection was distilled by heating under a nitrogen atmosphere by heating, and then cooled under a nitrogen atmosphere to remove dissolved oxygen therein. The obtained dissolved oxygen concentration in the water for injection (deaerated water) was 0.5 ppm. Disodium pemetrexed (equivalent to 1.25 g pemetrexed) and 0.45 g sodium chloride were placed in a 100 ml glass container which was then placed in a glove bag. Also place the glass vial, rubber stopper, and sterile filter into the glove bag. Calibrate the electrode of the pH meter, wash it, and place it in the glove bag. Nitrogen gas was injected into the glove pocket under reduced pressure in order to adjust the partial pressure of oxygen to 0.1% v / v. Take 50ml of degassed water with a syringe and add it to a 100ml glass container in the glove bag to dissolve the components. The pH in the glove pocket was measu...

Embodiment 2

[0035] Example 2: Preparation of a solution for injection by vacuum degassing

[0036] Add pemetrexed disodium (equivalent to 2.5 g of pemetrexed) and 0.9 g of sodium chloride into a 250 ml glass bottle equipped with an air inlet and a vacuum exhaust port on its cap, and then add the 100ml of water to dissolve the components. The dissolved oxygen concentration in the water used for injection was 6.5 ppm. Connect nitrogen to the gas inlet, and connect a diaphragm vacuum pump to the vacuum exhaust. Repeated vacuum degassing operation and nitrogen purging. An aliquot of the resulting solution was used to measure the dissolved oxygen concentration and pH therein. As a result of the measurement, the dissolved oxygen concentration was 0.8 ppm, and the pH was 7.68.

[0037] Take the resulting solution by syringe and place it in the glove bag. Also place the glass vial, rubber stopper, and sterile filter into the glove bag. Nitrogen gas was injected into the glove belt under red...

experiment example

[0042] Experimental example: Stability test

[0043] Under pressure conditions (75±2° C., relative humidity 85±5%), the stability of the solutions for injection prepared according to Examples and Comparative Examples was evaluated. The content of pemetrexed and degradation products was analyzed by high performance liquid chromatography (HPLC) under pressure conditions according to known methods published in Chromatography (Chromatographia, 2007, 66, pp. The results of the 7-day stability test are shown in Table 2 below.

[0044]

[0045]

[0046]

[0047] As can be seen from Table 2, in the solution for injection (prepared by using water for injection not adjusted for dissolved oxygen) according to the comparative example, even if it was not sterilized in an autoclave, when in When the solution for injection was stored under pressure for 1 week, a change in appearance and an increase in degradation products were clearly observed. In contrast, in the solutions for inj...

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PUM

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Abstract

The present invention provides a method for preparing a pharmaceutical preparation in the form of an antioxidant-free solution for injection, the method comprising: (a) adding the dissolved oxygen concentration in the solution containing pemetrexed or a salt thereof controlled at 1 ppm or less; and (b) filling a container for injection with the solution obtained in step (a) in a closed system with an oxygen partial pressure of 0.2% v / v or less.

Description

technical field [0001] The present invention relates to a method for preparing a pharmaceutical preparation for injection containing pemetrexed or a salt thereof as an active ingredient in the form of an antioxidant-free solution. Background technique [0002] Pemetrexed (pemetrexed) or its salt (such as disodium salt) is an anti-folate antineoplastic drug, its chemical name is: N-[4-[2-(2-amino-4,7-dihydro -4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid, represented by the following formula (US Pat. No. 5,344,932): [0003] [0004] Currently, pemetrexed or its salts are available for injection in the form of lyophilized powder. The lyophilized powder is reconstituted with, for example, physiological saline and administered to patients. However, preparing such lyophilized powders through a complicated freezing process increases manufacturing costs. Furthermore, in order to administer the lyophilized powder to clinical or hospital patients, a reco...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/08A61K31/519A61K31/505
CPCA61K9/0019A61K31/519A61K47/02A61K9/08A61K31/505
Inventor 宋泰昊徐城基李磨世
Owner KUHNIL PHARMA CO LTD
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