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Injectable formulations of Bendamustine Hydrochloride

IP.com Disclosure Number: IPCOM000242163D
Publication Date: 2015-Jun-22
Document File: 2 page(s) / 19K

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Abstract

Bendamustine rapidly hydrolyzes in aqueous solutions to yield three main degradation impurities, a monohydroxy compound (the main degradant), a dihydroxy compound, and rarely, a dimer compound. Therefore, the aqueous solution of bendamustine is not suitable for long-term storage and is formulated as lyophilized formulation. Further, when ethanol is used for lyophilisation, bendamustine ethyl ester is also known to be formed as bendamustine reacts with ethyl alcohol. Described herein are stable, lyophilized pharmaceutical compositions of bendamustine hydrochloride.

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Injectable formulations of Bendamustine Hydrochloride

The chemical entity, 1H-Benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1-methyl-, monohydrochloride, generically known as Bendamustine hydrochloride is marketed worldwide by M/s Cephalon under the brand of 'Treanda®'. TREANDA for Injection is indicated for treatment of patients with Chronic Lymphocytic Leukemia (CLL) and Indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Bendamustine is a white to off-white, water soluble microcrystalline powder with amphoteric properties. The active pharmaceutical ingredient is not stable in water and in aqueous solutions, bendamustine rapidly hydrolyzes by direct substitution, leading to three main degradation impurities: a monohydroxy compound (the main degradant), a dihydroxy compound, and sometimes as a dimer compound. Therefore, an aqueous solution of bendamustine is not suitable for long-term storage and is formulated as lyophilized formulation.

The marketed Treanda formulation is lyophilized by using 30% t-butyl alcohol and requires 3-5 minutes for reconstitution. Reconstitution of the lyophilisate prepared with other solvent systems is reported to be difficult and may take more than 45 minutes. Further, when ethanol is used for lyophilisation, Bendamustine ethyl ester is also known to be formed as bendamustine reacts with ethyl alcohol. Therefore, selection of lyophilisation solvent and lyophilisation process is very critical for preparing the lyophilized formulation of bendamustine, as degradation products that may occur during manufacturing of the drug substance and/or during the lyophilization process to make the finished drug product, may render such products unsafe for...