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Oral Dosage Forms of Bendamustine

a bendamustine and oral technology, applied in the field of oral dosage forms of bendamustine, can solve the problems of poor bioavailability, burdensome and time-consuming for healthcare professionals, and difficult reconstitution, and achieve the effect of improving the dissolution profile and good stability

Inactive Publication Date: 2015-11-26
ASTELLAS DEUTLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new pharmaceutical composition that solves issues with existing treatments for certain diseases. The composition is made up of bendamustine or a safe version of it, along with other ingredients that make it stable and easy to dissolve in the body. This invention provides a more effective and reliable treatment for certain diseases.

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.
Therefore it is not surprising that the oral bendamustine compositions, as investigated by Preiss et al. and Weber gave rise to relatively poor bioavailability results and a large inter-individual variability.

Method used

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  • Oral Dosage Forms of Bendamustine
  • Oral Dosage Forms of Bendamustine
  • Oral Dosage Forms of Bendamustine

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Bendamustine Capsule Formulation (Prior art)

[0058]20.0±1 mg of bendamustine hydrochloride were weighed into the body of an empty hard gelatine capsule, and put into a clear glass HPLC vial (6 ml) of Agilent. Capsules were closed by placing the cap on top of the body and slight pushing.

[0059]Capsules were stored at 40° C. / 75% RH (glass vial open) or 50° C. (glass vial closed). The amount of bendamustine hydrochloride and of related substances was measured with HPLC (column: Zorbax Bonus-RP, 5 μm; temperature of column oven: 30° C.; temperature of autosampler: 5° C.; detector: 254 nm). The results are shown in Table 1:

TABLE 1Related substances and assay of bendamustine HCl (residual content) inbendamustine capsulesBendamustineHCl [% area]StorageRelatedT = 1T = 1conditionsubstancesT = 0monthT = 0month40° C. / 75% RHHP10.100.4599.6498.83(open vial)NP1*10.020.02BM1Dimer*10.060.42BM1EE*10.130.11HP2n.d.*2n.d.HP3n.d.n.d.50° C. (closedHP10.101.4699.6497.51vial)NP10.020.02BM1Dimer0.060.24BM1EE0...

reference example 2

[0060]

TABLE 2aBendamustine powder mixture for capsulesComponentmg / dosage-formRelative Content %bendamustine hydrochloride55.121.09Mannitol141.454.11Microcrystalline cellulose25.09.57(Avicel ® PH101)Crosscarmellose sodium12.54.78(Ac-Di-Sol ®)Colloidal silicon dioxide1.00.38(Aerosil ® 200)Talc18.87.19Stearic acid7.52.87Sum261.3100

[0061]For a batch size of 1000 capsules all excipients except for colloidal silicon dioxide and stearic acid were loaded into a Somakon vessel (5 L). Bendamustine was added and blending was conducted for 4 minutes at 1000 rpm (wiper 10 rpm). The resulting blend was sieved through a 0.5 mm sieve. The vessel was reloaded with the blend and colloidal silicon dioxide was added. Blending was conducted for 2 minutes at the afore-mentioned conditions. Thereafter stearic acid was added and blending was continued for 1 minute. The blend was subsequently sieved through a 0.5 mm sieve, reloaded into the vessel and blended for another 30 seconds, all at the same conditio...

reference example 3

[0063]

TABLE 3aBendamustine powder mixture for capsulesComponentmg / dosage-formRelative Content %bendamustine hydrochloride55.121.09Lactose anhydrous141.454.11Microcrystalline cellulose25.09.57(Avicel ® PH112)Crosscarmellose sodium12.54.78(Ac-Di-Sol ®)Colloidal silicon dioxide1.00.38(Aerosil ® 200)Talc18.87.19Stearic acid7.52.87Sum261.3100

[0064]For 1000 capsules all excipients except for colloidal silicon dioxide and stearic acid were loaded into a Somakon vessel (5 L). Bendamustine was added and blending was conducted for 4 minutes at 1000 rpm (wiper 10 rpm). The resulting blend was sieved through a 0.5 mm sieve. The vessel was reloaded with the blend and colloidal silicon dioxide was added. Blending was conducted for 2 minutes at the afore-mentioned conditions. Thereafter stearic acid was added and blending was continued for 1 minute. The blend was subsequently sieved through a 0.5 mm sieve, reloaded into the vessel and blended for another 30 seconds, all at the same conditions.

[006...

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PUM

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Abstract

In the present invention there is provided an oral pharmaceutical composition, comprising bendamustine or a pharmaceutically acceptable, ester, salt or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient, which is a pharmaceutically acceptable non-ionic surfactant, selected from the group consisting of polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide and propylene oxide.

Description

[0001]The present invention relates to oral dosage forms comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof.BACKGROUND OF THE INVENTION[0002]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):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 lym...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/48A61K31/4184A61K9/00A61K45/06
CPCA61K9/4875A61K45/06A61K31/4184A61K9/4858A61K9/4825A61K9/4866A61K9/485A61K9/0053A61K9/145A61K31/573A61P35/00A61P35/02A61P37/02A61P43/00Y02A50/30A61K9/14A61K9/20A61K9/48
Inventor COLLEDGE, JEFFREYOLTHOFF, MARGARETHA
Owner ASTELLAS DEUTLAND
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