Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof

a technology of bendamustine and oral dosage, which is applied in the direction of powder delivery, microcapsules, drug compositions, etc., can solve the problems of poor bioavailability, burdensome and time-consuming for healthcare professionals, and difficult reconstitution, and achieve good stability, good bioavailability, and good dissolution profil

Inactive Publication Date: 2013-08-15
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 acc...

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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  • Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof
  • Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof
  • Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof

Examples

Experimental program
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Effect test

reference example 1

Bendamustine Capsule Formulation (Prior Art)

[0119]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.

[0120]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 capsulesBendamustine HClStorageRelatedT = 1[% area]conditionsubstancesT = 0monthT = 0T = 1 month40° C. / HP10.100.4599.6498.8375% RHNP1*10.020.02(open vial)BM1Dimer*10.060.42BM1EE*10.130.11HP2n.d.*2n.d.HP3n.d.n.d.50° C. (closedHP10.101.4699.6497.51vial)NP10.020.02BM1Dimer0.060.24BM1EE...

reference example 2

[0121]

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

[0122]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

[0124]

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

[0125]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.

[012...

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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...

Claims

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Application Information

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IPC IPC(8): A61K31/4184A61K45/06
CPCA61K9/145A61K9/1623A61K9/2018A61K9/2846A61K9/4808A61K45/06A61K9/4858A61K9/4866A61K31/4184A61K47/10A61K9/485A61K31/475A61K31/573A61P35/00A61P35/02A61K9/14A61K9/16A61K9/20A61K9/28A61K9/48A61K9/2072A61K9/4825A61K39/39558
Inventor PATZAK, ULRICHOUATAS, TAOUFIK
Owner ASTELLAS DEUTLAND
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