Liquid pharmaceutical composition comprising pemetrexed

a technology of pemetrexed and pharmaceutical composition, which is applied in the direction of drug compositions, pharmaceutical delivery mechanisms, organic active ingredients, etc., can solve the problems of insufficient long-term stability of the disclosed composition, difficult to achieve, and simple pemetrexed isotonic saline solution, etc., to achieve excellent long-term stability

Inactive Publication Date: 2018-08-23
SYNTHON BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]Thus, in view of the prior art cited above, there is still a need for a ready to use reconstituted solution comprising pemetrexed, which is safe and exhibits excellent long term stability.

Problems solved by technology

It is known that a simple, isotonic saline solution of pemetrexed is not pharmaceutically acceptable for commercial purposes due to degradation into unacceptable related substances.
Although in theory degradation could be prevented by controlling the oxygen content, in practice this is not easy to achieve.
Repetition of the examples cited in the prior art show that the long term stability of the disclosed compositions is insufficient.
Moreover, some of the compositions are not desirable from a toxicological point of view.

Method used

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  • Liquid pharmaceutical composition comprising pemetrexed

Examples

Experimental program
Comparison scheme
Effect test

example 1

Stability Results

A) Without Steam Sterilization

[0056]

NameZero1 m / 25° C.3 m / 25° C.6 m / 25° C.AppearancePale yellowPale yellowPale yellowYellowsolutionsolutionsolutionsolutionpH8.998.908.928.85ColorGY4-GY5GY2-GY3ClarityPXD (mg / ml)53.05 50.04 50.52 49.64 ΣIMP (% IN)0.340.580.370.41

B) Sterilized by Steam 121° C. / 15 min

[0057]

NameZero1 m / 25° C.6 m / 25° C.AppearancePale yellowPale yellowDark yellowsolutionsolutionsolutionpH8.978.928.86ColorGY4-GY5out of scaleClarityPXD (mg / ml)53.74 49.97 50.26 ΣIMP (% IN)0.520.400.94

example 2

Stability Results

A) Without Steam Sterilization

[0058]

NameZero1 m / 25° C.3 m / 25° C.6 m / 25° C.AppearancePale yellowPale yellowPale yellowPale yellowsolutionsolutionsolutionsolutionpH8.988.918.888.86ColorGY4-GY5ClarityPXD (mg / ml)52.82 50.59 51.91 50.51 ΣIMP (% IN)0.340.370.300.26

B) Sterilized by Steam 121° C. / 15 min

[0059]

NameZero1 m / 25° C.6 m / 25° C.AppearancePale yellowPale yellowColorlesssolutionsolutionsolutionpH8.968.908.84ColorGY4-GY5ClarityPXD (mg / ml)54.32 50.63 51.13 ΣIMP (% IN)0.470.380.27

Inert Atmosphere of Nitrogen

[0060]

CompositionPropyl-Tar-Argi-eneCyste-taricPXDnineGlycolineAcidNITRO-mg / mlmg / mlmg / mlmg / mlmg / mlGENExample 3253010011YESExample 4253010011NO

example 3

Stability Results

Without Steam Sterilization

[0061]

NameZero1 m / 40° C.2 m / 40° C.AppearanceColorlessColorlessColorlesssolutionsolutionsolutionpH8.998.93not measuredColorClarityPXD (mg / ml)25.85 25.87 25.09ΣIMP (% IN)0.180.30 0.26

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PUM

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Abstract

The present invention relates to a liquid pharmaceutical composition suitable for parenteral administration comprising: a) pemetrexed diacid; b) at least one organic amine; c) at least one antioxidant; d) 10-200 mg/ml of propylene glycol; and e) one or more parenteral solvents, wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1 The invention further relates to the use of said liquid pharmaceutical composition as medicament in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.

Description

BACKGROUND OF THE PRESENT INVENTION[0001]Pemetrexed, chemically N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid of formula (I),[0002]is a pharmaceutically active compound used for the treatment of malignant pleural mesothelioma and for second-line treatment of non-small cell lung cancer. The compound has been first disclosed in EP432677.[0003]The disodium heptahydrate salt of pemetrexed is marketed by Eli Lilly under the brand name ALIMTA® and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The lyophilized product is available in the strengths of 100 mg and 500 mg per vial and is reconstituted with 0.9% saline solution at a concentration of 25 mg / ml. After further dilution with 0.9% saline solution to 100 ml it is then administered intravenously over 10 minutes.[0004]It would be an advantage to have a stable, ready to use reconstituted solution that only has to be further diluted b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61K47/18A61K47/10A61K31/198A61K9/00A61P35/00
CPCA61K31/519A61K47/183A61K47/10A61K31/198A61K9/0019A61P35/00A61K47/18A61K47/20
Inventor ZALUDEK, BOREK
Owner SYNTHON BV
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