Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof

Abstract

In the present invention there is provided a pharmaceutical composition for oral administration which comprises bendamustine or a pharmaceutically acceptable, ester, salt or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient and which shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes, as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5, and wherein the pharmaceutically acceptable excipient is either a pharmaceutically acceptable non-ionic surfactant, selected from the group consisting of a polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide and propylene oxide or 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. The invention further relates to the above pharmaceutical composition for use for the oral treatment of a medical condition which is selected from chronic lymphocytic leukemia, acute lymphocytic leukaemia, chronic myelocytic leukaemia, acute myelocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer and non-small cell lung cancer. The invention moreover relates to the above pharmaceutical composition for the above use wherein the dosage regimen comprises at least the administration of a dose of 100 to 600 mg / m2 / per person of bendamustine on day 1 and day 2, optionally a dose of 50 to 150 mg / m2 i.v. or orally of a corticosteroid on days 1 to 5, and optionally a suitable dose of a further active agent selected from the group consisting of an antibody specific for CD20, an anthracyclin derivative, a vinca alkaloid or a platin derivative; and the repetition of said dosage regimen 4 to 15 times after intervals of two to four weeks.

Description

[0001]The present invention relates to oral dosage forms comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof and therapeutic use 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...

AI Technical Summary

Benefits of technology

The present invention provides stable pharmaceutical compositions of bendamustine or a pharmaceutically acceptable composition thereof for oral administration. These compositions have good stability, dissolution profile in acidic media, bioavailability, and therapeutically acceptable inter- and intraindividual variability. This informs the development of a stable and effective pharmaceutical product for the treatment of certain medical conditions.

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.

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