Formulations of bendamustine

A bendamustine and antioxidant technology, applied in the field of bendamustine preparations, can solve the problems of stability differences of excipients, etc., and achieve the effect of overcoming stability differences and improving long-term stability

Active Publication Date: 2014-12-10
SCIDOSE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Excipient stability has been found to vary significantly depending on supplier, storage and handling conditions, etc.

Method used

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  • Formulations of bendamustine
  • Formulations of bendamustine
  • Formulations of bendamustine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0143]A mixture of PEG400 treated with sodium hydroxide was prepared by combining 200 μl of 1 N sodium hydroxide with PEG qs to 200 ml such that the NaOH concentration was 0.001 molar and mixing well. The pH of the PEG400 and NaOH mixture was determined according to the USP official monograph. A mixture of 5 g of PEG400 and sodium hydroxide was added to 100 ml of carbon dioxide-free water, and 0.3 ml of saturated potassium chloride solution was added. The pH was then measured to be 7.30, which is within the preferred range. A mixture of PEG:PG (90:10) was prepared by combining 20ml of a mixture of PG with PEG400 and sodium hydroxide qs to 200ml. Thioglycerol at a concentration of 5 mg / ml was added to 60 ml of a mixture of PEG:PG (90:10) and mixed well. Then bendamustine hydrochloride at a concentration of 25 mg / ml was added to 40 ml of a mixture of PEG:PG (90:10) and thioglycerol and mixed well. Additional PEG:PG (90:10) solution was added to bring the volume of the bendamu...

Embodiment 3

[0146] A mixture of PEG:PG (90:10) was prepared by combining 10ml of PG and PEG400 qs to 100ml. Add thioglycerol at a concentration of 5 mg / ml to 80 ml of PEG:PG (90:10) mixture and mix well. Then bendamustine hydrochloride at a concentration of 25 mg / ml was added to 40 ml of a mixture of PEG:PG (90:10) and thioglycerol and mixed well. Except for one sample where no sodium hydroxide was added (sample 1), the other two samples were prepared by adding 1 N sodium hydroxide solution to a PEG:PG (90:10) mixture to a concentration of 0.01 or 0.03 molar and mixing (for samples 2 and 3, respectively), such as image 3 (Table 3). The 0.01 and 0.03 molar samples were different from the samples in Examples 1 and 2 where the sodium hydroxide concentration was 0.001 molar. Additional PEG:PG (90:10) mixture was added to bring the volume of the bendamustine-containing solution to 50 ml. Formulations containing bendamustine were filtered and transferred to 5cc vials containing 4ml each. ...

Embodiment 4

[0150] A mixture of PEG400 with sodium hydroxide was prepared by combining 0.1 ml, 0.2 ml or 0.3 ml (samples 5, 6 and 7 respectively) of 1 N sodium hydroxide and PEG qs to 200 ml. The pH of the mixture of PEG400 and sodium hydroxide was determined according to the official monograph of USP. A mixture of 5 g of PEG400 and sodium hydroxide was added to 100 ml of carbon dioxide-free water, and 0.3 ml of saturated potassium chloride solution was added. The pH was then measured and the pH of the mixture of PEG400 and sodium hydroxide of sample 5 was 6.32. The pH of the mixture of PEG400 and sodium hydroxide for sample 6 was 7.30. The pH of the mixture of PEG400 and sodium hydroxide for sample 7 was 7.89. The pH of each PEG400 and NaOH mixture of Samples 5, 6 and 7 was within the preferred range. A mixture of PEG:PG (90:10) was prepared by combining 20 ml of PG with PEG400 qs to 200 ml, without sodium hydroxide (sample 4) or with sodium hydroxide at a concentration of 0.0005, 0.0...

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Abstract

Long term storage stable bendamustine-containing compositions are disclosed. The compositions can include bendamustine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable fluid contains a mixture of PEG and PG; an organic or inorganic compound in an amount sufficient to obtain a pH of from about 6.0 to about 11 for the polyethylene glycol, as measured using USP monograph for polyethylene glycol; and optionally an antioxidant. The bendamustine-containing compositions have less than about 5% total esters, on a normalized peak area response ("PAR") basis as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.

Description

[0001] Related Application Cross Reference [0002] This patent application claims priority to U.S. Provisional Patent Application No. 61 / 598,729, filed February 14, 2012, entitled "Formulations of Bendamustine," under 35 U.S.C § 119(e), which states Incorporated herein by reference in its entirety. technical field [0003] Bendamustine free base is represented by the following structural formula (I): [0004] [0005] Bendamustine is used to treat a variety of cancers, including leukemia, Hodgkin's disease, and multiple myeloma. Bendamustine is a commodity Treanda TM The active ingredient in this product is a lyophilized powder for reconstitution. Background technique [0006] Once the lyophilized product is reconstituted, bendamustine exhibits rapid degradation. Due to the presence of highly unstable aliphatic chlorine atoms, bendamustine undergoes hydrolysis by direct substitution rather than addition elimination. Some major degradation products of bendamustine ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4184A61P35/00
CPCA61K47/10A61K47/02A61K47/12A61K31/4184A61P35/00A61P35/02A61P7/00
Inventor 纳格什·R·帕利普菲利普·克里斯托夫·巴克斯顿斯瑞坎斯·孙达拉姆
Owner SCIDOSE
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