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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: 2014-01-02
ASTELLAS DEUTLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]FIG. 1 shows the mean plasma concentration (tablets versus capsule) vs. time curve obtained after administering bendamustine hydrochloride in the form of prior art capsules and the tablet formulations of Examples 6 to 8 (Tablets 1-3) and example 9 (formulation 3) (Tablet 4) to dogs. It is apparent from FIG. 1 that the tablet formulations provide for higher maximum concentrations of bendamustine, as compared to the prior art capsule.
[0013]FIG. 2 shows a flow sheet of wet granulation manufacturing trials.

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

[0060]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 pointsT = 1Storage conditionT = 0month(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%

[0061]In all these mixtures, the bendamustine hydrochlor...

example 1b

[0063]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).

[0064]In the case of Eudragit® E PO the initial amounts of the impurities HP1 (hydrolysis product) and BM1DIMER were significantly increased (HP 1: 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 HP 1 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.

[0065]The appearance of the mixtures containing Eudragit® E PO and cross-linked polyvinylpyrrol...

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 2aTabletComponentmg / dosage-formRelative Content %bendamustine hydrochloride55.122.04Mannitol141.456.56Microcrystalline cellulose25.010.00(Avicel ® PH112)Ac-Di-Sol ®12.55.00Colloidal silicon dioxide1.00.40(Aerosil ® 200)Talc12.55.00Stearic acid2.51.00

[0070]Tablets were stor...

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PUM

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Abstract

In the present invention there is provided a pharmaceutical composition in a solid dosage form suitable or 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

[0001]The present invention relates to solid dosage forms for oral administration 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:[0003]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.[0004]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 lymphocyti...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/36A61K39/395A61K31/704A61K47/26A61K33/24A61K31/573A61K45/06A61K47/30A61K31/4184A61K31/437A61K33/243
CPCA61K47/36A61K31/4184A61K39/395A61K31/704A61K31/437A61K33/24A61K31/573A61K45/06A61K47/30A61K47/26A61K9/1623A61K9/1652A61K9/2018A61K9/2054A61K9/2059A61K33/243A61K2300/00A61K9/2846A61K9/2866A61K9/48A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P43/00A61K9/0053A61K9/2853A61K9/4866A61K9/2009A61K9/2013A61K9/2813A61K9/282A61K9/284
Inventor COLLEDGE, JEFFREYPROFITLICH, THOMAS ALFREDPATZAK, ULRICHOUATAS, TAOUFIKOLTHOFF, MARGARETHA
Owner ASTELLAS DEUTLAND
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