PHARMACEUTICAL COMPOSITIONS COMPRISING AZD9291

Abstract

The present invention relates to pharmaceutical compositions suitable for oral administration, and more particularly to pharmaceutical compositions, including pharmaceutical tablet compositions, containing N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide (“AZD9291”) or a pharmaceutically acceptable salt thereof, wherein such compositions comprise a certain amount of microcrystalline cellulose and at least one other pharmaceutical diluent.

Claims

1. A pharmaceutical composition comprising: (a) from 2 to 70 parts of the Agent; (b) from 5 to 96 parts of two or more pharmaceutical diluents; (c) from 0 to 15 parts of one or more pharmaceutical disintegrants; (d) from 0 to 1.5 parts of one or more pharmaceutical solubilising agents; and (c) from 0 to 3 parts of one or more pharmaceutical lubricants; wherein all parts are by weight and the sum of the parts (a)±(b)+(c)±(d)+(e)=100; wherein one of the two or more pharmaceutical diluents is microcrystalline cellulose wherein the microcrystalline cellulose makes up from 7 to 30 wt % of the two or more pharmaceutical diluents (b); and wherein the Agent is N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition comprises from 0.5 to 3 parts of the one or more pharmaceutical lubricants (e).

3. The pharmaceutical composition according to claim 2 wherein the one or more pharmaceutical lubricants (e) comprises sodium stearyl fumarate and/or one or more behenate esters of glycerine.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises from 2 to 15 parts of the one or more pharmaceutical disintegrants (c).

5. The pharmaceutical composition according to claim 4 wherein the one or more pharmaceutical disintegrants (c) comprises low-substituted hydroxypropyl cellulose.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition comprises from 0 to 0.75 parts of one or more pharmaceutical solubilising agents (d).

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition comprises from 5 to 50 parts of the Agent (a).

8. The pharmaceutical composition according to any one of claims 1 to 7 wherein the Agent is the mesylate salt of N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

9. Use of the pharmaceutical composition, as claimed in any one of claims 1 to 8, for the manufacture of a medicament.

10. A pharmaceutical composition, as claimed in any one of claims 1 to 8, for use as a medicament.

11. A method of treating cancer in a patient in need thereof, which method comprises the oral administration to the patient of an effective amount of the pharmaceutical composition as claimed in any one of claims 1 to 8.

12. A pharmaceutical tablet comprising the pharmaceutical composition as claimed in any one of claims 1 to 8.

13. A pharmaceutical tablet comprising a tablet core wherein the tablet core comprises the pharmaceutical composition as claimed in any one of claims 1 to 8, wherein the tablet core has a coating.

14. A method of treating cancer in a patient in need thereof, which method comprises the oral administration of an effective number of the pharmaceutical tablet(s), as claimed in claim 12 or claim 13, to the patient.

Description

LIST OF FIGURES

[0351] FIGS. 1 to 6 show dissolution data that was obtained using the United States Pharmacopoeia methodology that is described hereinafter in the experimental section.

[0352] FIG. 1: Dissolution profile for Examples 1 to 5 (pH 6.8)

[0353] FIG. 2: Dissolution profile for Examples 6A, 6B, 6C and 6D (pH 6.8)

[0354] FIG. 3: Expanded dissolution profile for Examples 6A, 6B, 6C and 6D (pH 6.8)

[0355] FIG. 4: Dissolution profile for Examples 7A, 7B, 8A and 8B (pH 6.8)

[0356] FIG. 5: Dissolution profile for Example 9 (80 mg, pH 6.8)

[0357] FIG. 6: Dissolution profile for Example 9 (pH 1.3)

Experimental Details

Dissolution Tests

[0358] The dissolution described herein were performed according to the general procedure of the United States Pharmacopoeia using Apparatus II (paddle), with either 900 mL of pH 6.8 phosphate buffer (50 mM NaH.sub.2PO.sub.4) or pH 1.3 media (2 g/L of NaCl adjusted to pH 1.3 with either HCl or NaOH) at a temperature of 37° C. 10 mL samples of the dissolution media were withdrawn at 7.5, 15, 20, 30, 45 and 60 minutes, filtered through a glass fibre syringe filter (Acrodisc glass fibre GxF part number 4529 or equivalent), discarding the first 4 mL. The concentration of drug substance in the remaining solution was quantified by UV analysis at a wavelength of 335 nm (pH 6.8) or 270 nm (pH 1.3) versus a standard solution. Generally, the dissolution results disclosed in this specification are based on an average of three repeated tests.

Materials Used in Examples

[0359] The materials used in the Examples described hereinafter are shown in the table below:

TABLE-US-00006 Material Grade Supplier Cellulose, Avicel ™ PH-102 FMC Biopolymer microcrystalline (Ireland) Behenate esters Compitrol 888 ATO.sup.# Gattefosse S.A. of glycerine (France) Lactose monohydrate Pharmatose 450M DFE Pharma (Germany) Low-substituted LH-31 Shin Etsu hydroxypropyl cellulose Chemical Co. Ltd. (Japan) Magnesium stearate NF Non Bovine Mallinckrodt (USA) Mannitol Pearlitol 200SD Roquette Freres S.A. (France) Sodium lauryl sulphate Kolliphor BASF/Cognis (Sodium dodecyl sulfate) (Germany) Sodium starch glycolate Glycolys LV Roquette Freres S.A. (France) Sodium stearyl fumarate Pruv JRS Pharma (Germany) .sup.#Compitrol 888 ATO is described as a mixture of glycerol esters including glyceryl dibehenate, tribehenin and glyceryl behenate.

Comparative Example 1— ‘Blend in Capsule’ Formulation

[0360] AZD9291 mesylate was blended with microcrystalline cellulose in the ratio 1:2 by weight and filled into opaque, white, size 0 HPMC capsules such that each capsule contained the equivalent of 20 mg AZD9291 free base. The quantitative composition of this ‘blend in capsule’ formulation is shown in the table below:

TABLE-US-00007 Quantities Components (g per batch) (mg/capsule) (wt %) AZD9291 26.20 23.80.sup.a 29.75 mesylate Microcrystalline 61.80 56.20 70.25 cellulose Total 88.00 80.00 100.00 .sup.aEquivalent to 20 mg of AZD9291 free base

Example 2

[0361] This tablet formulation was manufactured using a dry mixing/direct compression process. AZD9291 mesylate was dry mixed with the excipients listed in the table below (excluding the magnesium stearate) using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. The magnesium stearate was added to the mix and blending continued for a further 5 minutes at 28 rpm. The dry mix was compressed to form 200 mg tablets using a Riva single station mini-press equipped with 8 mm round concave punches. The quantitative composition of this tablet formulation is shown in the table below:

TABLE-US-00008 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 8.93 23.80.sup.a 11.90 Drug mesylate substance Lactose 45.50 121.28 60.64 Diluent monohydrate Microcrystalline 15.00 39.98 19.99 Diluent cellulose Sodium starch 3.75 10.00 5.00 Disintegrant glycolate Magnesium 0.75 2.00 1.00 Lubricant stearate Sodium lauryl 1.13 2.94 1.47 Solubilising sulphate Agent Total 75.06 200.00 100.00 .sup.aEquivalent to 20 mg of AZD9291 free base

Example 3

[0362] This tablet formulation was manufactured using the process described above for Example 2. The quantitative composition of this tablet formulation is shown in the table below:

TABLE-US-00009 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 11.90 23.80.sup.a 11.90 Drug mesylate substance Mannitol 62.10 124.20 62.10 Diluent Microcrystalline 20.00 40.00 20.00 Diluent cellulose Sodium starch 5.00 10.00 5.00 Disintegrant glycolate Magnesium 1.00 2.00 1.00 Lubricant stearate Total 100.00 200.00 100.00 .sup.aEquivalent to 20 mg of AZD9291 free base

Example 4

[0363] This tablet formulation was manufactured using the process described above for Example 2. The quantitative composition of this tablet formulation is shown in the table below:

TABLE-US-00010 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 11.90 23.80.sup.a 11.90 Drug mesylate substance Mannitol 62.10 124.20 62.10 Diluent Microcrystalline 20.00 40.00 20.00 Diluent cellulose Low-substituted 5.00 10.00 5.00 Disintegrant hydroxypropyl cellulose Magnesium 1.00 2.00 1.00 Lubricant stearate Total 100.00 200.00 100.00 .sup.aEquivalent to 20 mg of AZD9291 free base

Example 5

[0364] This tablet formulation was manufactured using the process described above for Example 2. The quantitative composition of this tablet formulation is shown in the table below:

TABLE-US-00011 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 11.90 23.80.sup.a 11.90 Drug mesylate substance Mannitol 62.10 124.20 62.10 Diluent Microcrystalline 20.00 40.00 20.00 Diluent cellulose Low-substituted 5.00 10.00 5.00 Disintegrant hydroxypropyl cellulose Sodium stearyl 1.00 2.00 1.00 Lubricant fumarate Total 100.00 200.00 100.00 .sup.aEquivalent to 20 mg of AZD9291 free base

Example 6A

[0365] This tablet formulation was manufactured using a dry mixing/roller compaction process using the materials listed in the table below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. A portion of the sodium stearyl fumarate (0.5% of the batch weight) was added and mixing continued using the same parameters for a further 5 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1-10.2 rpm (25 mm rollers) and a screw speed of 22.4-22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. The resulting granules were returned to the Turbula T2 blender, the remaining sodium stearyl fumarate added, and mixing continued at 28 rpm for 5 minutes. This dry mix was compressed to form 500 mg tablets using a Riva classic rotary press equipped with 14.5×7.25 mm punches.

TABLE-US-00012 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 9.52 95.36 19.07 Drug mesylate substance Mannitol 32.48 324.64 64.93 Diluent Microcrystalline 5.00 50.00 10.00 Diluent cellulose Low-substituted 2.50 25.00 5.00 Disintegrant hydroxypropyl cellulose Sodium stearyl 0.50 5.00 1.00 Lubricant fumarate Total 50.00 500.00 100.00

Example 6B

[0366] This tablet formulation was manufactured using a dry mixing/roller compaction process using the materials listed in the table below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. A portion of the behenate esters of glycerine (0.5% of the batch weight) was added and mixing continued using the same parameters for a further 5 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1-10.2 rpm (25 mm rollers) and a screw speed of 22.4.sup.—22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. The resulting granules were returned to the Turbula T2 blender, the remaining behenate esters of glycerine added, and mixing continued at 28 rpm for 5 minutes. This dry mix was compressed to form 200 mg tablets using a Riva single station press equipped with 7 mm concave punches.

TABLE-US-00013 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 9.52 38.08 19.04 Drug mesylate substance Mannitol 32.48 129.92 64.96 Diluent Microcrystalline 5.00 20.00 10.00 Diluent cellulose Low substituted 2.50 10.00 5.00 Disintegrant hydroxypropyl cellulose Behenate esters 0.50 2.00 1.00 Lubricant of glycerine Total 50.00 200.00 100.00

Example 6C

[0367] This tablet formulation was manufactured using a dry mixing/roller compaction process using the materials listed in the table below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1-10.2 rpm (25 mm rollers) and a screw speed of 22.4.sup.—22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. This dry mix was compressed to form 200 mg tablets using a Riva single station press equipped with 7 mm concave punches.

TABLE-US-00014 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 9.52 38.08 19.04 Drug mesylate substance Mannitol 32.98 131.92 65.96 Diluent Microcrystalline 5.00 20.00 10.00 Diluent cellulose Low substituted 2.50 10.00 5.00 Disintegrant hydroxypropyl cellulose Total 50.00 200.00 100.00

Example 6D

[0368] This tablet formulation was manufactured using a dry mixing/roller compaction process using the materials listed in the table below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. A portion of the sodium stearyl fumarate (0.5% of the batch weight) was added and mixing continued using the same parameters for a further 5 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1—10.2 rpm (25 mm rollers) and a screw speed of 22.4—22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. The resulting granules were returned to the Turbula T2 blender, the remaining sodium stearyl fumarate added, and mixing continued at 28 rpm for 5 minutes. This dry mix was compressed to form 500 mg tablets using a Riva classic rotary press equipped with 14.5×7.25 mm punches.

TABLE-US-00015 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 26.20 94.25 18.85 Drug mesylate substance Mannitol 90.77 326.50 65.30 Diluent Microcrystalline 13.76 49.50 9.90 Diluent cellulose Low-substituted 5.50 19.80 3.96 Disintegrant hydroxypropyl cellulose Sodium stearyl 2.77 9.95 1.99 Lubricant fumarate Total 139.00 500.00 100.00

Example 7A

[0369] This tablet formulation was manufactured using a dry mixing/roller compaction process using the materials listed in the table below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. A portion of the sodium stearyl fumarate (0.5% of the batch weight) was added and mixing continued using the same parameters for a further 5 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1—10.2 rpm (25 mm rollers) and a screw speed of 22.4-22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. The resulting granules were returned to the Turbula T2 blender, the remaining sodium stearyl fumarate added, and mixing continued at 28 rpm for 5 minutes. This dry mix was compressed to form 500 mg tablets using a Riva classic rotary press equipped with 14.5×7.25 mm punches.

TABLE-US-00016 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 9.53 95.36.sup.a 19.07 Drug mesylate substance Mannitol 29.84 298.39 59.68 Diluent Microcrystalline 7.50 75.00 15.00 Diluent cellulose Low-substituted 2.50 25.00 5.00 Disintegrant hydroxypropyl cellulose Sodium stearyl 0.63 6.25 1.25 Lubricant fumarate Total 50.00 500.00 100.00 .sup.aEquivalent to 80 mg of AZD9291 free base

Example 7B

[0370] This tablet formulation was manufactured using a dry mixing/roller compaction process using the materials listed in the table below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Turbula T2 blender at a speed of 28 rpm for 30 minutes. A portion of the sodium stearyl fumarate (0.5% of the batch weight) was added and mixing continued using the same parameters for a further 5 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1—10.2 rpm (25 mm rollers) and a screw speed of 22.4-22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. The resulting granules were returned to the Turbula T2 blender, the remaining sodium stearyl fumarate added, and mixing continued at 28 rpm for 5 minutes. This dry mix was compressed to form 500 mg tablets using a Riva classic rotary press equipped with 14.5×7.25 mm punches.

TABLE-US-00017 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 9.54 95.36.sup.a 19.07 Drug mesylate substance Mannitol 32.34 323.39 64.68 Diluent Microcrystalline 7.50 75.00 15.00 Diluent cellulose Sodium stearyl 0.63 6.25 1.25 Lubricant fumarate Total 50.00 500.00 100.00 .sup.aEquivalent to 80 mg of AZD9291 free base

Example 8A and 8B

[0371] These tablet formulations were manufactured using a dry mixing/roller compaction process using the materials listed in the tables below. The AZD9291 mesylate, mannitol, microcrystalline cellulose and hydroxypropyl cellulose were first mixed using a Muller Blender (25 litre drum) at 15 rpm for 58 minutes. A portion of the sodium stearyl fumarate (0.5% of the batch weight) was added and mixing continued using the same parameters for a further 9.5 minutes. The mixture was roller compacted using an Alexanderwerk bench top roller compactor with a roller pressure of 40 bar, a gap size of 2 mm, a roller speed of 10.1-10.2 rpm (25 mm rollers) and a screw speed of 22.4-22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a screen size of 1.27 mm. The resulting granules were returned to the Muller Blender, the remaining sodium stearyl fumarate added, and mixing continued at 15 rpm for 5 minutes. Tablet cores were compressed using a Riva Picolla rotary press equipped with 7 mm (20 mg strength) or 14.5×7.25 mm (80 mg strength) punches with a turret speed of 20 rpm.

[0372] The resulting tablet cores were coated with a proprietary film coat (Opadry II beige, supplied by Colorcon UK Ltd) at a level of 4% of the core weight, to give coated tablets with a nominal weight of 130 mg (20 mg strength) and 520 mg (80 mg strength) for Examples 8A and 8B respectively. The quantitative composition of the tablet core (prior to coating) of Example 8A is shown in the table below:

TABLE-US-00018 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 448.19 23.84.sup.a 19.07 Drug mesylate substance Mannitol 1402.43 74.60 59.68 Diluent Microcrystalline 352.50 18.75 15.00 Diluent cellulose Low-substituted 117.50 6.25 5.00 Disintegrant hydroxypropyl cellulose Sodium stearyl 29.38 1.56 1.25 Lubricant fumarate Total 2350.00 125.00 100.00 .sup.aEquivalent to 20 mg of AZD9291 free base
The quantitative composition of the tablet core (prior to coating) of Example 8B is shown in the table below:

TABLE-US-00019 Quantities Components (g per batch) (mg/tablet) (wt %) Function AZD9291 448.19 95.36.sup.a 19.07 Drug mesylate substance Mannitol 1402.43 298.39 59.68 Diluent Microcrystalline 352.50 75.00 15.00 Diluent cellulose Low-substituted 117.50 25.00 5.000 Disintegrant hydroxypropyl cellulose Sodium stearyl 29.38 6.25 1.25 Lubricant fumarate Total 2350.00 500.00 100.00 .sup.aEquivalent to 80 mg of AZD9291 free base

Example 9

[0373] This tablet formulation was manufactured using a dry mixing/roller compaction process as described in Example 8A and 8B using the materials listed in the tables below. Tablet cores were compressed using a Riva Classic rotary press equipped with 9 mm (40 mg strength) or 14.5×7.25 mm (80 mg strength) punches with a turret speed of 20 rpm. The resulting tablet cores were coated with a proprietary film coat (Opadry II beige, supplied by Colorcon UK Ltd) at a level of 4% of the core weight, to give coated tablets with a nominal weight of 520 mg (80 mg strength) and at a level of 5% of the core weight, to give coated tablets with a nominal weight of 262.5 mg (40 mg strength). The quantitative composition of the tablet core (prior to coating) of Example 9 is shown in the table below:

TABLE-US-00020 Quantities Components (mg/tablet) (mg/tablet) (wt %) Function AZD9291 47.68.sup.a 95.36.sup.b 19.07 Drug mesylate substance Mannitol 147.32 294.65 58.93 Diluent Microcrystalline 37.50 75.00 15.00 Diluent cellulose Low-substituted 12.50 25.00 5.000 Disintegrant hydroxypropyl cellulose Sodium stearyl 5.00 10.00 2.00 Lubricant fumarate Total 250.00 500.00 100.00 .sup.aEquivalent to 40 mg of AZD9291 free base .sup.bEquivalent to 80 mg of AZD9291 free base