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Solid Dosage Forms Of Bendamustine

a technology of bendamustine and solid dosage forms, which is applied in the direction of drug compositions, immunological disorders, microcapsules, etc., can solve the problems of time-consuming, burdensome, and difficult reconstitution for healthcare professionals, and achieve the effect of improving the dissolution profil

Inactive Publication Date: 2012-01-05
ASTELLAS DEUTLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present inventors have developed stable pharmaceutical compositions that can be taken as an oral medicine. These compositions contain bendamustine or a similar substance as the main ingredient, along with other acceptable ingredients. These compositions have improved dissolution, which means they can be better absorbed by the body."

Problems solved by technology

Furthermore, reconstitution has been reported to be difficult.
Further, it is burdensome and time-consuming for the healthcare professionals responsible for reconstituting the product in the 2 step process.

Method used

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  • Solid Dosage Forms Of Bendamustine
  • Solid Dosage Forms Of Bendamustine
  • Solid Dosage Forms Of Bendamustine

Examples

Experimental program
Comparison scheme
Effect test

example 1a

[0059]For compatibility testing mixtures containing bendamustine hydrochloride and an excipient at a ratio of 1:1 (m / m) were prepared. The excipients were selected from mannitol and lactose. After preparation the mixtures were packed in clear glass HPLC-Vials (6 ml) Agilent and stored at different storage conditions as shown in Table 1 below. At defined time points samples were removed from storage and tested for purity (HPLC; column: Zorbax Bonus-RP, 5 μm; temperature of column oven: 30° C.; temperature of autosampler: 5° C.; detector: 254 nm) and appearance.

TABLE 1Storage ConditionsBendamustine hydrochloride and excipients for oral formulationTested time pointsStorage conditionT = 0T = 1 month(1) 50° C., Vials closedn = 2n = 1(2) 70° C., Vials closed*n = 2n = 2(3) 40° C. / 75% r.h., Vials open**n = 2n = 2*stored at 50° C. for one month before storage at 70° C.**stored at 25° C. / 60% r.h. for one month before storage at 40° C. / 75%

[0060]In all these mixtures, the bendamustine hydrochlo...

example 1b

[0062]For further compatibility testing in accordance with the methods of example 1a, mixtures containing bendamustine hydrochloride and an excipient at a ratio of 1:1 (m / m) were prepared. The excipients were selected from Opadry®, Eudragit® E PO, sodium carboxymethylcellulose (Avicel® RC 591) and cross-linked polyvinylpyrrolidone (Crospovidone).

[0063]In the case of Eudragit® E PO the initial amounts of the impurities HP1 (hydrolysis product) and BM1DIMER were significantly increased (HP1: 1.5%, BM1DIMER: 1%) but during storage a decrease of these impurities could be detected at all storage conditions independent of the influence of humidity. In the case of cross-linked polyvinylpyrrolidone a significant increase of HP1 from 0.1% to 0.4% could be detected at the storage condition 40° / 75% R.H. / vials open. At all other storage conditions (vials closed) no increase of HP1 could be detected.

[0064]The appearance of the mixtures containing Eudragit® E PO and cross-linked polyvinylpyrrolid...

example 2

[0067]253 g of a mixture comprising mannitol as the main excipient and microcrystalline cellulose, Ac-Di-Sol®, colloidal silicon dioxide, talc and stearic acid in the relative quantities mentioned in the following table 2a was prepared by mixing in a 1 liter cube blender (Erweka) for 15 minutes. Thereafter 10.612 g of the mixture and 3.0 g of bendamustine hydrochloride were sieved through a 0.425 mm sieve and then transferred into a Turbula mixer T2A, equipped with a glass vial of 50 ml and subsequently mixed for 10 minutes at 60 rpm.

[0068]From this mixture round tablets were compressed having the following characteristics:

[0069]Mean value diameter: 9.1 mm; mean value mass: 247.7 mg; mean value hardness: 81N.

TABLE 2aTabletmg / RelativeComponentdosage-formContent %bendamustine hydrochloride55.122.04Mannitol141.456.56Microcrystalline cellulose (Avicel ® PH112)25.010.00Ac-Di-Sol ®12.55.00Colloidal silicon dioxide (Aerosil ® 200)1.00.40Talc12.55.00Stearic acid2.51.00

[0070]Tablets were sto...

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Abstract

In the present invention there is provided a pharmaceutical composition in a solid dosage form suitable for oral administration, the composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, which is a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1:1-5.

Description

BACKGROUND OF THE INVENTION[0001]Bendamustine(4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazo-2-yl]butanoic acid, a nitrogen mustard) is an alkylating agent with bifunctional alkylating activity. It corresponds to the following formula I:[0002]Bendamustine appears to be free of any cross-resistance with other alkylating agents, which offers advantages in terms of chemotherapy for patients who have already received treatment with an alkylating agent.[0003]Bendamustine was initially synthesized in the German Democratic Republic (GDR). The hydrochloric acid of bendamustine was the active ingredient in a commercial product available from 1971 to 1992 under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin® and has been widely used to treat chronic lymphocytic leukemia, non-Hodgkin's lymphoma and multiple myeloma.[0004]The marketed product contains a lyophilized powder of bendamustine hydrochloride which is reconstituted with ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/28A61K9/16A61K39/395A61P35/02A61K31/437A61K33/24A61K31/573A61P35/00A61K31/4184A61K31/704A61K33/243
CPCA61K9/2018A61K9/2846A61K9/2866A61K9/48A61K31/4184A61K47/30A61K39/395A61K45/06A61K47/36A61K33/24A61K31/704A61K31/573A61K31/437A61K47/26A61K9/1623A61K9/1652A61K9/2054A61K9/2059A61K33/243A61K2300/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P43/00A61K9/0053A61K9/2853A61K9/4866A61K9/2009A61K9/2013A61K9/2813A61K9/282A61K9/284
Inventor COLLEDGE, JEFFREYPROFITLICH, THOMAS ALFREDPATZAK, ULRICHOUATAS, TAOUFIKOLTHOFF, MARGARETHA
Owner ASTELLAS DEUTLAND
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