IP Verse

Formulations Of Bendamustine

Patent No. US12138248 (titled "Formulations Of Bendamustine") was filed by Lsi Financing Llc on Apr 25, 2024.

What is this patent about?

’248 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 ’248 is to create a stable, ready-to-use liquid formulation of bendamustine by using a non-aqueous solvent system in combination with specific stabilizing agents. The key insight is that certain combinations of pharmaceutically acceptable fluids, such as polyethylene glycol (PEG) and propylene glycol (PG), along with antioxidants or chloride salts, can significantly inhibit the degradation of bendamustine over extended periods.

The claims of ’248 focus on a liquid bendamustine composition comprising bendamustine (or a salt thereof) at a concentration of about 25 mg/mL, a pharmaceutically acceptable fluid consisting of polyethylene glycol and optionally one or more of propylene glycol, ethanol, benzyl alcohol and glycofurol, and a stabilizing amount of an antioxidant. The independent claims require that the total impurities resulting from bendamustine degradation remain below 5% as measured by HPLC after at least 15 months of storage between 5°C and 25°C.

In practice, the invention involves dissolving bendamustine in a mixture of PEG and optionally PG, ethanol, benzyl alcohol and glycofurol, and adding a stabilizing amount of an antioxidant like thioglycerol or lipoic acid. The resulting solution can then be stored in a sterile container, ready for use without reconstitution. The ratio of PEG to PG can be varied to optimize stability, with higher PEG concentrations generally preferred. The antioxidant concentration is also carefully controlled to provide the necessary stabilization without introducing unwanted side effects.

This approach differs from prior art by avoiding aqueous solutions, which are known to promote bendamustine degradation. The use of PEG as a primary solvent, combined with specific antioxidants or chloride salts, provides a synergistic effect that significantly extends the shelf life of the bendamustine formulation. The resulting ready-to-use liquid formulation offers improved convenience and stability compared to existing lyophilized products, addressing a critical need in the administration of this important cancer drug. The combination of PEG and an antioxidant is key.

How does this patent fit in bigger picture?

Technical landscape at the time

In the early 2010s when ’248 was filed, at a time when sterile pharmaceutical products were commonly manufactured using well-established aseptic techniques, the long-term storage of bendamustine in liquid form presented a non-trivial challenge due to its inherent instability and degradation pathways. At that time, analytical techniques such as HPLC were routinely used to quantify drug concentrations and identify degradation products, when hardware or software constraints made achieving long-term stability of bendamustine formulations non-trivial.

Novelty and Inventive Step

The examiner rejected claims 1-12 for obviousness under 35 U.S.C. 103(a) and for indefiniteness under 35 U.S.C. 112(b). The examiner also rejected claims 1-12 for nonstatutory double patenting over multiple U.S. patents. The examiner stated that the claimed subject matter did not find support in the provisional application. The information disclosure statements submitted were considered.

Claims

There are 22 claims in total. Claims 1 and 8 are independent. The independent claims are directed to a sterile container and a liquid composition, respectively, both containing bendamustine, an antioxidant, and a pharmaceutically acceptable fluid comprising polyethylene glycol. The dependent claims generally specify particular antioxidants, concentrations, stability conditions, fluid compositions, and amounts of bendamustine.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
Pharmaceutically acceptable fluid
(Claim 1, Claim 8)		“For purposes of the present invention, a pharmaceutically acceptable fluid is a fluid which is suitable for pharmaceutical use. Within this aspect, the pharmaceutically acceptable fluid is propylene glycol (PG) or polyethylene glycol (PEG). 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, consisting of polyethylene glycol and optionally one or more of propylene glycol, ethanol, benzyl alcohol and glycofurol.
Stabilizing amount of an antioxidant
(Claim 1, Claim 8)		“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. Within this guideline, suitable antioxidant concentrations in the compositions can range from about 2.5 mg/mL to about 35 mg/mL, and preferably from about 5 mg/mL to about 20 mg/mL or from about 10 mg/mL to about 15 mg/mL.”An amount of antioxidant that increases or enhances the stability of bendamustine in the composition.
Total impurities resulting from the degradation of the bendamustine
(Claim 1, Claim 8)		“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. The amount of impurities is further calculated as being based upon the original amount bendamustine (or salt thereof) being present in the composition or formulation.”The total amount of impurities in the bendamustine-containing compositions, calculated on a normalized peak area response basis as determined by high performance liquid chromatography 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.

Litigation Cases New

US Latest litigation cases involving this patent.

Case NumberFiling DateTitle
1:25-cv-00079Jan 17, 2025Eagle Pharmaceuticals, Inc. V. Baxter Healthcare Corporation
1:25-cv-00075Jan 17, 2025Eagle Pharmaceuticals, Inc. V. Slayback Pharma Llc

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US12138248

LSI FINANCING LLC
Application Number
US18646171
Filing Date
Apr 25, 2024
Status
Granted
Expiry Date
Jan 28, 2031
External Links
Slate, USPTO, Google Patents