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Publication Number
US-9603930-B2
Publication Date
2017-03-28
Expiration Date
Abstract
The present invention provides stable bendamustine-containing pharmaceutical compositions suitable for long term storage. The compositions include bendamustine, a pharmaceutically acceptable salt, and/or a hydrate form thereof, a solvent mixture of N,N-dimethylacetamide and glycerin, and an antioxidant. The bendamustine-containing compositions have less than about 2% of total impurities after two month storage at 25° C./60% RH. The pharmaceutical compositions may be used for treating neoplastic diseases.
Core Innovation
The invention relates to a stable liquid bendamustine pharmaceutical composition for neoplastic diseases. The composition comprises bendamustine in a pharmaceutically acceptable salt and/or hydrate form in a pharmaceutically acceptable solvent system comprising N,N-dimethylacetamide and glycerin.
The solvent system includes glycerin in a defined volume fraction range in combination with N,N-dimethylacetamide. The disclosed formulation is associated with stability performance measured as total impurities after storage for a defined time at 25°C and 60% relative humidity, where the total impurities remain below a specified threshold.
The stability behavior is described as being attributed to glycerin–DMA co-solvent interactions and an increased dielectric constant of the mixture. The disclosure contrasts with prior approaches that required rapid use of reconstituted aqueous Treanda® and describes limitations and impurity concerns of existing liquid and lyophilized approaches.
Claims Coverage
The document provides two independent claims directed to stable liquid bendamustine pharmaceutical compositions. Across the independent claims, the core inventive structure is defined by bendamustine in salt/hydrate form and a solvent system of N,N-dimethylacetamide with glycerin at constrained volume fractions.
Stable liquid bendamustine composition with N,N-dimethylacetamide and glycerin
A stable liquid bendamustine pharmaceutical composition comprising bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, and a pharmaceutically acceptable solvent system comprising N,N-dimethylacetamide and glycerin, wherein the pharmaceutically acceptable solvent system comprises about 5% v/v of glycerin to about 15% v/v of glycerin.
Stable liquid bendamustine composition including hydrate form with expanded glycerin range
A stable liquid bendamustine pharmaceutical composition comprising a hydrate form of bendamustine or a hydrate form of bendamustine salt, and a pharmaceutically acceptable solvent system comprising N,N-dimethylacetamide and glycerin, wherein the pharmaceutically acceptable solvent system comprises about 5% v/v of glycerin to about 60% v/v of glycerin.
Overall, claim coverage centers on stable liquid compositions of bendamustine salt and hydrate forms in a defined N,N-dimethylacetamide/glycerin solvent system, with glycerin constrained to specified v/v ranges.
Stated Advantages
Total impurities remain less than 2.0% after two months of storage at 25°C and 60% relative humidity.
Improved long-term stability for a liquid bendamustine formulation relative to prior need for rapid use of reconstituted aqueous Treanda® and limitations and impurity concerns of existing liquid and lyophilized approaches.
Documented Applications
Use of the stable liquid bendamustine pharmaceutical composition for neoplastic diseases.
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