Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-y1)-1H-benzimidazol-2-y1]-1H-quinolin-2-one lactate monohydrate

• US 20130090344A1
• Filed: 06/29/2011
• Published: 04/11/2013
• Est. Priority Date: 06/30/2010
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Thakur, Jeewan, Qiu, Zhihui
• Granted Patent: US 9,545,402 B2
• Time in Patent Office: Days
• US Class Current: 514/253.07
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia

Abstract

A pharmaceutical composition for oral administration comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monolactate monohydrate, a filler in an amount of 15 to 70% by weight, a disintegrant in an amount of less than 15% by weight, a glidant and/or a lubricant in an amount of 0.1 to 10% by weight wherein the amounts by weight are based on the total weight of the composition.

Claims

1. A pharmaceutical composition for oral administration comprising

4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monolactate monohydrate in an amount of 40 to 65% by weight,

one or more filler in an amount of 30 to 60% by weight,

a disintegrant in an amount of 5 to 15% by weight,

a glidant and/or a lubricant in an amount of 0.1 to 10% by weight wherein the amounts by weight are based on the total weight of the composition.

2. The pharmaceutical composition according to claim 1 wherein the filler is not microcrystalline cellulose 101.

3. The pharmaceutical composition according to claim 1 wherein one or more filler is selected from the list comprising MCC102, MCC105, MCC112, MCC200, mannitol or combinations thereof.

4. The pharmaceutical composition according to claim 1 wherein the disintegrant is not croscarmellose sodium.

5. The pharmaceutical composition according to claim 1 wherein said pharmaceutical formulation is a capsule and wherein one filler is mannitol.

6. The pharmaceutical composition according to claim 1 wherein one or more filler is selected from the list comprising MCC102, MCC105, MCC200, or combinations thereof.

7. The pharmaceutical composition according to claim 1 wherein 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monolactate monohydrate in an amount of 40 to 65% by weight,

one or more filler selected from microcrystalline cellulose 102, 105, 112, 200 in an amount of 30 to 60% by weight

disintegrant in an amount of 5 to 15% by weight

silicon dioxide and/or magnesium stearate in an amount of 0.1 to 10% by weight wherein the amounts by weight are based on the total weight of the composition.

8. The pharmaceutical composition according to claim 1 wherein the disintegrant is Crospovidone XL.

9. The pharmaceutical composition according to claim 1 wherein the disintegrant is present in an amount above 4% to 8% by weight, for example 5% to 8% by weight.

10. The pharmaceutical composition according to claim 1 wherein glidant, e.g. silicon dioxide, is in the amount of 0.5 to 2% by weight and lubricant, magnesium stearate, is in the amount of 1 to 4% by weight.

11. A process for the production of a composition as claimed in claim 1 which process is carried out under substantially dry conditions using granulation, for example by roller compaction.

12. A process for the production of a composition as claimed in claim 1 which process comprises:

i) Preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate, one or more filler, e.g. a filler, and an additional filler, disintegrant and glidant

ii) Sieving the mixture of step (i)

iii) Lubricating the mixture of step (ii) with a lubricant

iv) Processing the mixture of step (iii) by roller compaction

v) Blending milled granulate of step (iv) disintegrant and glidant

vi) Lubricating with a lubricant

vii) Encapsulation of the mixture of step (vi)

13. A process for the production of a composition as claimed in claim 1 which process comprises:

i) Preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate, filler, disintegrant and lubricant

ii) Sieving the mixture

iii) Adding lubricant

iv) Processing the mixture of step iii) by roller compaction

v) Blending milled granulate from step (iv) with glidant, filler and disintegrant and mixing

vi) Lubricating with a lubricant

vii) Forming tablets by compression

14. The composition according to claim 1 or process of claim 11, 12 or 13, wherein the lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one is Form H_A.