Formulations of bendamustine

Patent No. US9572796 (titled "Formulations of bendamustine") on Feb 2, 2016. The application was issued on Feb 21, 2017.

'796 is related to the field of pharmaceutical formulations, specifically addressing the problem of long-term storage stability of bendamustine, a drug used to treat various cancers. Bendamustine is known to degrade rapidly in aqueous solutions, making it unsuitable for ready-to-use liquid formulations. Existing formulations often require inconvenient and time-consuming reconstitution from a lyophilized powder, which also introduces instability concerns.

The underlying idea behind '796 is to create a stable, ready-to-use liquid formulation of bendamustine by using a non-aqueous solvent system combined with specific stabilizing agents. The key insight is that a mixture of polyethylene glycol (PEG) and propylene glycol (PG), along with an antioxidant, can significantly reduce the degradation of bendamustine over extended storage periods.

The claims of '796 focus on a non-aqueous liquid composition containing bendamustine or its salt, a pharmaceutically acceptable fluid comprising a mixture of PEG and PG (with a ratio between 95:5 and 50:50), and a stabilizing amount of an antioxidant. The independent claims specify that the resulting composition maintains less than 5% total impurities after 15 months of storage at about 5°C or after 15 days at 25°C, as measured by HPLC.

In practice, the invention involves dissolving bendamustine in a mixture of PEG and PG, adding an antioxidant like thioglycerol or lipoic acid, and then storing the resulting solution in a sealed container. The ratio of PEG to PG is crucial, with higher PEG concentrations generally leading to better stability. The antioxidant further inhibits degradation by scavenging free radicals or otherwise interfering with the degradation pathways of bendamustine.

This approach differs from prior art by avoiding aqueous solutions, which are known to promote bendamustine degradation. While lyophilized formulations exist, they require reconstitution, which introduces instability and inconvenience. The specific combination of a non-aqueous PEG/PG solvent system with an antioxidant provides a synergistic effect, resulting in a ready-to-use liquid formulation with significantly improved long-term stability compared to previous attempts.

How does this patent fit in bigger picture?

Technical Landscape

In the early 2010s when ’796 was filed, the formulation of nitrogen mustard derivatives for oncology was typically implemented using lyophilized powders that required reconstitution immediately before clinical use. At a time when systems commonly relied on aqueous reconstitution, the rapid hydrolytic degradation of the active pharmaceutical ingredient made long-term storage in liquid form non-trivial due to the high reactivity of aliphatic chlorine atoms. Consequently, engineering constraints in the pharmaceutical field often forced a trade-off between the clinical convenience of ready-to-use liquids and the chemical stability required for a viable shelf life.

Prosecution Position

The examiner permitted the application because the prior art specifically focused on using water-based or water-and-alcohol solutions to stabilize the drug. While earlier studies suggested that certain alcohols could reduce impurity formation in these aqueous mixtures, the examiner found no logical reason, other than hindsight, to completely remove water from the formulation. Therefore, the examiner concluded that the applicant’s specific non-aqueous liquid composition—utilizing an antioxidant combined with polyethylene glycol and propylene glycol—was a distinct and patentable departure from the water-containing solutions described in previous technical records.

Claims

This patent contains 26 claims, with claims 1 and 14 being independent. The independent claims are directed to a non-aqueous liquid composition comprising bendamustine, a mixture of polyethylene glycol and propylene glycol, and an antioxidant. The dependent claims generally specify particular concentrations, formulations, or uses of the composition described in the independent claims.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)	Support for Specification	Interpretation
Non-aqueous liquid composition (Claim 1, Claim 14)	In several embodiments of the invention, pharmaceutically acceptable fluid is non-aqueous and may be, but is not necessarily, a solvent for the bendamustine or salt thereof. Within this aspect, the pharmaceutically acceptable fluid is propylene glycol (PG) or polyethylene glycol (PEG).	A liquid formulation that does not contain water.
Normalized peak area response (Claim 1, Claim 14)	For purposes of the present invention, “substantially free of impurities” shall be understood to include bendamustine-containing compositions in which the amount of total impurities is less than about 5%, as calculated on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after a period of about 15 months at a temperature of from about 5° C. to about 25° C.	A method of calculating the amount of total impurities as determined by high performance liquid chromatography at a wavelength of 223 nm.
Pharmaceutically acceptable fluid (Claim 1, Claim 14)	For purposes of the present invention, a pharmaceutically acceptable fluid is a fluid which is suitable for pharmaceutical use. In other embodiments of the invention however, the pharmaceutically acceptable fluid is a mixture of PEG and PG. For example, the pharmaceutically acceptable fluid can include about 50% PEG and about 50% PG.	A fluid suitable for pharmaceutical use, comprising a mixture of polyethylene glycol and propylene glycol.
Stabilizing amount of an antioxidant (Claim 1, Claim 14)	The bendamustine-containing compositions according to several preferred aspects of the invention include a stabilizing amount of an antioxidant. For purposes of the present invention, “stabilizing amount” shall be understood to include those amounts which increase or enhance the stability of the bendamustine in the compositions described herein. The presence of one or more antioxidants described herein thus contributes, at least in part to the long term stability of the composition.	An amount of antioxidant that increases or enhances the stability of bendamustine in the composition.
Total impurities (Claim 1, Claim 14)	The total impurities in the inventive compositions resulting from the degradation of the bendamustine in the compositions is less than about 5% PAR as determined by HPLC at a wavelength of 223 nm after at least about 15 months at a temperature of from about 5° C. to about 25° C., and thus have long term stability for at least the same period of time or longer.	Degradants resulting from the degradation of bendamustine in the compositions.

Litigation Cases New

US Latest litigation cases involving this patent.

Case Number	Filing Date	Title
1:25-cv-00075	Jan 17, 2025	Eagle Pharmaceuticals, Inc. V. Slayback Pharma Llc

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US9572796

Application Number: US15013424A
Filing Date: Feb 2, 2016
Publication Date: Feb 21, 2017
External Links: Slate, USPTO, Google Patents

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