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

1. A pharmaceutical composition for oral administration, the composition being a tablet not including microcrystalline cellulose 101 and having:

an intragranular phase comprising:

at least 250 mg of active agent 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,

a filler selected from the group consisting of MCC102, MCC105, MCC200, and combinations thereof, wherein the filler is in an amount of 30 to 60% by weight,

one or more disintegrants in an amount of 1 to 15% by weight, and

silicon dioxide and magnesium stearate in an amount of 0.1 to 10% by weight; and,

an extragranular phase comprising 0.2 to 1% silicon dioxide, 1 to 3% magnesium stearate, and lacking microcrystalline cellulose,

wherein:

the composition exhibits bioequivalence at a 90% confidence interval to a capsule composition comprising 34% of a lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one, 4% w/w crospovidone, 1% silicon dioxide, 60% microcrystalline cellulose, and 1% magnesium stearate;

at least 90% of the active agent is released from the composition within 10 minutes as determined using USP apparatus 2 (Rotary Paddle) at a stirring rate of 50 rpm at 37° C. in 0.04 M HCl, 2 g/L NaCl, pH 1.5; and,

at least 80% of the active agent is released from the composition within 10 minutes as determined using USP apparatus 2 (Rotary Paddle) at a stirring rate of 50 rpm at 37° C. in pH 4.5 acetate buffer.

2. The pharmaceutical composition of claim 1 wherein the disintegrant is not croscarmellose sodium.

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

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

5. The pharmaceutical composition according to claim 1 wherein the silicon dioxide is present in the intragranular phase in the amount of 0.5 to 2% by weight and the magnesium stearate is present in the intragranular phase in the amount of 1 to 4% by weight.

6. A process for the production of a composition as claimed in claim 1 which process is carried out under substantially dry conditions using granulation.

7. A process for the production of a composition as claimed in any one of the preceding claim 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 monolactate monohydrate, one or more filler, disintegrant and glidant;

ii) sieving the mixture;

iii) adding lubricant;

iv) processing the mixture of step (iii) by roller compaction;

v) blending milled granulate of step (iv) with glidant, filler and disintegrant and mixing

vi) lubricating with a lubricant; and,

vii) forming tablets by compression.

8. The composition of claim 1 or process of claim 7 , wherein the lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-IH-benzimidazol-2-yl]-IH-quinolin-2-one is Form H A .