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

AI Technical Summary

Benefits of technology

[0011]In order to solve the above problems the present inventors have carried out detailed investigations. They finally succeeded in obtaining the stable pharmaceutical compositions according to the invention. These compositions are suitable for oral administration and comprise bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, which compositions apart from having a good stability also have an improved dissolution profile.

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)

[0059]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.

[0060]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) in bendamustine capsulesBendamustine HCl[% area]StorageRelatedT = 1T = 1conditionsubstancesT = 0monthT = 0month40° C. / HP10.100.4599.6498.8375% RHNP1*10.020.02(open vial)BM1Dimer*10.060.42BM1EE*10.130.11HP2 n.d.*2n.d.HP3n.d.n.d.50° C.HP10.101.4699.6497.51(closed vial)NP10.020.02BM1Dimer0.060.24BM1EE...

reference example 2

[0061]

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

[0062]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

[0064]

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

[0065]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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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): A61K9/48A61K39/395A61K31/704A61P35/02A61K33/24A61K31/573A61P35/00A61K31/4184A61K31/437
CPCA61K9/145A61K31/573A61K31/4184A61K9/4858A61P35/00A61P35/02A61P37/02A61P43/00Y02A50/30A61K9/14A61K9/20A61K9/48A61K9/4875A61K45/06A61K9/0053A61K9/4825A61K9/4866A61K9/485
Inventor COLLEDGE, JEFFREYOLTHOFF, MARGARETHA
Owner ASTELLAS DEUTLAND
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