PHARMACEUTICAL COMPOSITION COMPRISING GEFITINIB

Abstract

The present invention relates to pharmaceutical tablet compositions comprising the compound gefitinib as the active pharmaceutical ingredient and a PVA-based coating, suitable for oral administration as well as to processes for their preparation. The compositions exhibit good long-term stability and dissolution properties.

Claims

1. A pharmaceutical tablet composition comprising from 45-60% of gefitinib; from 10-50% of a water soluble or water insoluble diluent or combinations thereof; from 0.5-5% of a binding agent; from 0.1-5% of a wetting agent; from 2-6% of a disintegrant; and from 0.4-4% of a lubricant; wherein the pharmaceutical tablet composition comprises a PVA-based coating.

2. The pharmaceutical tablet composition of claim 1 comprising from 45-55% of gefitinib; from 25-40% of lactose; from 5-15% of microcrystalline cellulose; from 1-3% of povidone; from 0.1-1% of sodium lauryl sulphate; from 3-5% of croscarmellose sodium; and from 0.5-2% of magnesium stearate.

3. The pharmaceutical tablet composition according to claim 1 prepared by an aqueous wet granulation process, an organic granulation process or a dry granulation process.

4. The pharmaceutical tablet composition according to claim 1 prepared by an aqueous wet granulation process.

5. The pharmaceutical tablet composition according to claim 1 wherein the PVA-based coating is selected from Opadry® II and Kollicoat®.

6. The pharmaceutical tablet composition according to claim 1, wherein the amount of coating is 2-7 wt % of the tablet core weight.

7. The pharmaceutical tablet composition according to claim 1, wherein the gefitinib has a particle size distribution characterised by a D.sub.90 of less than 40 μm.

8. The pharmaceutical tablet composition according to claim 1, packed in Triplex/Alu or Alu/Alu blister pack material.

9. The pharmaceutical tablet composition according to claim 1, comprising from 50 to 500 mg of gefitinib, calculated as the free base.

10. (canceled)

11. The pharmaceutical tablet composition according to claim 9, comprising from 250 mg of gefitinib, calculated as the free base.

12. The pharmaceutical tablet composition according to claim 1, wherein said PVA-based coating comprises a polymer selected from polyvinyl alcohol polymers and polyvinyl alcohol-polyethyleneglycol graft copolymers.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention relates to a pharmaceutical tablet composition, suitable for oral use, comprising gefitinib. “Gefitinib” is a generically used name for4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy] quinazoline and will be so used throughout this specification, unless expressly stated differently.

[0025] Solid state gefitinib may exist as a crystalline or an amorphous material. Crystalline materials may exist in different polymorphic modifications. In addition, they may be substantially anhydrous (e.g., form 1) or may exist in the form of a hydrate (e.g., monohydrate form 6 or trihydrate form 5) and/or a solvate (e.g., methanol solvate form 2 or DMSO solvate form 3). Any such modifications are included within the terms “gefitinib” throughout this specification.

[0026] Gefitinib is either commercially available or may be obtained by processes known in the art.

[0027] The essential features of the pharmaceutical tablet compositions of the present invention are from 45-60% of gefitinib, from 10-50% of a water soluble or water insoluble diluent or combinations thereof, from 0.5-5% of a binding agent, from 0.1-5% of a wetting agent, from 2-6% of a disintegrant, and from 0.4-4% of a lubricant, wherein the pharmaceutical tablet composition comprises a polyvinyl alcohol (PVA)-based coating.

[0028] EP1480679 teaches that in order to enhance the bioavailability of gefitinib either a water-soluble cellulose ether or an ester of a water-soluble cellulose ether is needed in the formulation. According to EP1651233 and CN102631347A, preferably a water-soluble acid is also present, either in the composition or in the production process. Furthermore, to prevent the gefitinib base from polymorphic conversion, it may be necessary to prepare a complex with a tecton before preparing the tablet composition as described in WO2010/081443.

[0029] Surprisingly, it was found that simple tablet compositions of gefitinib may be prepared without the addition of water soluble cellulose ethers or esters thereof through either a process of aqueous wet granulation, organic granulation or dry granulation. In addition, the tablets of the present invention do not have to be prepared in an acidic environment. Surprisingly, it was found that the tablet compositions of the present invention, comprising a PVA-based coating, show no increase in the rate of precipitation of gefitinib from solutions with pHs similar to either that of the stomach or the upper gastro-intestinal tract when compared with the marketed 250 mg Iressa® tablets with HPMC coating. Furthermore, the compositions of the present invention exhibit excellent long-term stability without polymorphic conversion of the gefitinib base.

[0030] Accordingly, the present invention provides for a pharmaceutical tablet composition for oral administration comprising gefitinib.

[0031] Water-soluble diluents advantageously comprise polyols and sugars such as mannitol, sorbitol, lactose, etc., but are not limited thereto. The preferred water-soluble diluents is lactose.

[0032] Water-insoluble diluents advantageously comprise a cellulose, a cellulose derivative and a starch, but are not limited thereto. Preferably the water insoluble diluent is microcrystalline cellulose or starch or a combination thereof.

[0033] Binding agents advantageously comprise povidone and polyethylene glycol, but are not limited thereto. Preferred binder is povidone.

[0034] Wetting agents advantageously comprise sodium lauryl sulphate and polysorbate 80, but are not limited thereto. Preferred wetting agent is sodium lauryl sulphate.

[0035] Disintegrants advantageously comprise croscarmellose sodium, crospovidone, starches, sodium starch glycolate, and clays, but are not limited thereto. Preferred disintegrant is croscarmellose sodium.

[0036] Lubricants advantageously comprise magnesium stearate and sodium stearyl fumarate, but are not limited thereto. Preferred lubricant is magnesium stearate.

[0037] In one advantageous embodiment, the pharmaceutical tablet composition comprising a PVA-based coating comprises from 45-55% of gefitinib, from 25-40% of lactose, from 5-15% of microcrystalline cellulose, from 1-3% of povidone, from 0.1-1% of sodium lauryl sulphate, from 3-5% of croscarmellose sodium, and from 0.5-2% of magnesium stearate.

[0038] The pharmaceutical tablet composition of the invention is preferably a swallowable tablet. The dosage form advantageously comprises a unit dose of gefitinib, which may be from 50 to 500 mg of gefitinib, preferably 250 mg of gefitinib, calculated as the free base.

[0039] The tablet compositions of the present invention display dissolution behavior typical for immediate-release formulations, exhibiting a dissolution rate of at least 85% in 10 minutes when tested in 1000 ml 0.01 N aqueous HCl pH 1.0, 0.01 N aqueous HCl pH 2.0, acetate buffer pH 4.5 or 5% Tween in water in a USP apparatus II at 50 rpm. The dissolution profiles of the tablets are similar to the profiles of Iressa®.

[0040] The pharmaceutical tablet composition of the present invention may be prepared by

[0041] (a) An aqueous wet granulation process;

[0042] (b) An organic granulation process; or

[0043] (c) A dry granulation process.

[0044] Preferably, the gefitinib has a particle size distribution characterised by a D.sub.90 of less than about 40 μm. The known particle size analysis methods can be used for determining the particle size, for example particle size measurement using the Malvern Mastersizer aqueous dispersion method with a low amount of a suitable surfactant and moderate sonication.

[0045] Gefitinib may optionally be milled and/or pre-screened before mixing in order to remove lumps. Advantageously, the particles of the treated product pass a screen with 400-800 μm (0.4-0.8 mm) mesh size. Accordingly, the various excipients may be treated in the same manner.

[0046] Sub a)

[0047] Gefitinib, the water soluble and/or water insoluble diluent(s) and the disintegrant (complete or partial quantity) are blended and sieved through a sieve of a suitable mesh size. The binder and wetting agent are dissolved in a sufficient amount of purified water to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated. The mix is compressed using suitable punches.

[0048] Sub b)

[0049] Organic granulation avoids water and is therefore effective in solving polymorphic issues arising due to water (e.g., formation of dihydrates, trihydrates, etc.).

[0050] Gefitinib, the water soluble and/or water insoluble diluent(s) and the disintegrant (complete or partial quantity) are blended and sieved through a sieve of a suitable mesh size. The binder and wetting agent are dissolved in a sufficient amount of ethanol or isopropyl alcohol (IPA) to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated. The mix is compressed using suitable punches.

[0051] Sub c)

[0052] Dry granulation is effective in solving polymorphic conversion as the granulation occurs without any aqueous or organic solvent.

[0053] Gefitinib, the water soluble and/or water insoluble diluent(s), the binder, the wetting agent and the disintegrant (complete or partial quantity) are blended and sieved through a sieve of a suitable mesh size. The blend is mixed with a partial quantity of the lubricant. The blend is then compacted in a roller compactor or slugged using suitable slug punches, followed by milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with the remaining quantity of lubricant. The mix is compressed using suitable punches.

[0054] The preferred process to prepare the tablets of the present invention is by an aqueous wet granulation process.

[0055] The tablet compositions are coated with a PVA-based coating. Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating. Preferably, the pharmaceutical composition of the current invention is coated with a PVA-based coating selected from Opadry® II, wherein polyvinyl alcohol (PVA) is the base polymer and Kollicoat®, which is a polyvinyl alcohol-polyethylene glycol graft copolymer.

[0056] Preferably the tablet compositions of the present invention comprise 2-7 wt % of the tablet core weight.

[0057] Based on laboratory experiments, prior art and non-conventional packaging of the marketed 250 mg Iressa® tablets (PVC-blisters packed within aluminium pouch pack), it is clear that gefitinib and its tablet formulation are sensitive to chemical, physical and/or polymorphic stability. Gefitinib base is reported to exist in various hydrated forms, i.e., anhydrous form 1, monohydrate form 6 and trihydrate form 5.

[0058] The pharmaceutical compositions of the present invention are packaged in blister pack material. The blister pack materials to be used in accordance with the present invention may be any blister pack material known to a person of ordinary skill in the art. Suitable blister pack materials to be used in accordance with the present invention are selected from the group of PVC/Alu, Duplex/Alu, Triplex/Alu and Alu/Alu. To ensure protection of the compositions of the present invention from e.g. moisture and thereby preventing polymorphic conversions, Triplex/Alu and Alu/Alu are particularly preferred blister pack materials.

[0059] The pharmaceutical tablet compositions of the present invention are useful, for treating a disease or condition treatable by gefitinib. Thus, in a second particular aspect, the present invention relates to a pharmaceutical tablet composition comprising gefitinib according to the present invention for use as a medicament, preferably for treating various cancer indications, more preferable for treating NSCLC.

[0060] The invention will be further illustrated by the following non-limiting examples.

EXAMPLES

Examples with Aqueous Wet Granulation

Example 1

Aqueous Wet Granulation with Water Soluble and Insoluble Fillers

[0061]

TABLE-US-00001 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Lactose (anhydrous or 72.5-90   Water soluble monohydrate diluent Microcrystalline 72.5-90   Water insoluble cellulose (MCC) diluent Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) or polysorbate 80 surfactant Purified water q.s. For binder solution Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0062] Process:

[0063] Gefitinib, lactose, MCC and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS or povidone and polysorbate 80 are dissolved in a sufficient amount of purified water to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with magnesium stearate. The mix is compressed using suitable punches.

Example 2

Aqueous Wet Granulation with Water Insoluble Fillers

[0064]

TABLE-US-00002 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Microcrystalline cellulose 145-180 Water insoluble (MCC) or starch, or a diluent combination thereof Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) or polysorbate 80 surfactant Purified water q.s. For binder solution Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0065] Process:

[0066] Gefitinib, lactose, MCC and/or starch and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS or povidone and polysorbate 80 are dissolved in a sufficient amount of purified water to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with magnesium stearate. The mix is compressed using suitable punches.

Example 3

Aqueous Wet Granulation with Water Soluble Fillers

[0067]

TABLE-US-00003 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Lactose (anhydrous or 145-180 Water soluble monohydrate or mannitol diluent Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) or polysorbate 80 surfactant Purified water q.s. For binder solution Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0068] Process:

[0069] Gefitinib, lactose or mannitol and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS or povidone and polysorbate 80 are dissolved in a sufficient amount of purified water to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with magnesium stearate. The mix is compressed using suitable punches.

Examples with Organic Granulation

[0070] Organic granulation avoids water and is therefore effective in solving polymorphic issues arising due to water (e.g., formation of dihydrates, trihydrates, etc.).

Example 4

Organic Granulation with Water Soluble and Insoluble Fillers

[0071]

TABLE-US-00004 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Lactose (anhydrous or 72.5-90   Water soluble monohydrate diluent Microcrystalline 72.5-90   Water insoluble cellulose (MCC) diluent Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) or polysorbate 80 surfactant Ethanol or isopropyl q.s. For binder To avoid alcohol ((IPA) solution polymorphic conversion of the active ingredient Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0072] Process:

[0073] Gefitinib, lactose, MCC and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS or povidone and polysorbate 80 are dissolved in a sufficient amount of ethanol or IPA to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with magnesium stearate. The mix is compressed using suitable punches.

Example 5

Organic Granulation with Water Insoluble Fillers

[0074]

TABLE-US-00005 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Microcrystalline 145-180 Water insoluble cellulose (MCC) or diluent starch Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) or polysorbate 80 surfactant Ethanol or isopropyl q.s. For binder To avoid alcohol ((IPA) solution polymorphic conversion of the active ingredient Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0075] Process:

[0076] Gefitinib, lactose, MCC or starch and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS or povidone and polysorbate 80 are dissolved in a sufficient amount of ethanol or IPA to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with magnesium stearate. The mix is compressed using suitable punches.

Example 6

Organic Granulation with Water Soluble Fillers

[0077]

TABLE-US-00006 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Lactose (anhydrous or 145-180 Water soluble monohydrate or mannitol diluent Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) or polysorbate 80 surfactant Ethanol or isopropyl q.s. For binder To avoid alcohol ((IPA) solution polymorphic conversion of the active ingredient Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0078] Process:

[0079] Gefitinib, lactose or mannitol and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS or povidone and polysorbate 80 are dissolved in a sufficient amount of ethanol or IPA to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with magnesium stearate. The mix is compressed using suitable punches.

Examples with Dry Granulation (Roller Compaction/Slugging)

[0080] Dry granulation is effective in solving polymorphic conversion as the granulation occurs without any aqueous or organic solvent.

Example 7

Dry Granulation with Water Soluble and Insoluble Fillers

[0081]

TABLE-US-00007 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Lactose (anhydrous or 72.5-90   Water soluble monohydrate diluent Microcrystalline 72.5-90   Water insoluble cellulose (MCC) diluent Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) surfactant Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0082] Process:

[0083] Gefitinib, lactose, MCC, povidone, SLS and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Mix the blend with a partial quantity of magnesium stearate. The blend is then compacted in a roller compactor or slugged using suitable slug punches, followed by milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with the remaining quantity of magnesium stearate. The mix is compressed using suitable punches.

Example 8

Dry Granulation with Water Insoluble Fillers

[0084]

TABLE-US-00008 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Microcrystalline 145-180 Water insoluble cellulose (MCC) or diluent starch Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) surfactant Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0085] Process:

[0086] Gefitinib, MCC, povidone, SLS and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Mix the blend with a partial quantity of magnesium stearate. The blend is then compacted in a roller compactor or slugged using suitable slug punches, followed by milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with the remaining quantity of magnesium stearate. The mix is compressed using suitable punches.

Example 9

Dry Granulation with Water Soluble Fillers

[0087]

TABLE-US-00009 Per tablet Ingredient (mg) Function Remark Gefitinib (form 1 or 250 Active D.sub.90 below monohydrate form 6) ingredient 40 μm D.sub.50 below 20 μm Lactose (anhydrous or 145-180 Water soluble monohydrate or mannitol diluent Povidone (K-30) 4.5-9.0 Binder Sodium lauryl sulphate 5.0-15  Wetting agent/ (SLS) surfactant Croscarmellose sodium/ 11.0-22.0 Disintegrant crospovidone/sodium starch glycolate Magnesium stearate 4.5-9.0 Lubricant Core tablet weight 420-480

[0088] Process:

[0089] Gefitinib, lactose, povidone, SLS and a partial quantity of disintegrant (e.g. 50%) are blended and sieved through a sieve of a suitable mesh size. Mix the blend with a partial quantity of magnesium stearate. The blend is then compacted in a roller compactor or slugged using suitable slug punches, followed by milling to a suitable size. The obtained granules are mixed with the remaining quantity of disintegrant and lubricated with the remaining quantity of magnesium stearate. The mix is compressed using suitable punches.

Example 10 to 18

[0090] Tablet cores of examples 1 to 9 were coated with 2-7% of a PVA-based coating.

Example 19

Aqueous Wet Granulation with Water Soluble and Insoluble Fillers and Opadry II Coating

[0091]

TABLE-US-00010 Per tablet Ingredient % (mg) Function Tablet core Gefitinib (form 1), 50.0 250.0 Active ingredient D.sub.90 below 40 μm Lactose monohydrate 32.7 163.5 Water soluble diluent Microcrystalline 10.0 50.0 Water insoluble cellulose (MCC) diluent Croscarmellose sodium 4.0 20.0 Disintegrant Povidone 2.0 10.0 Binder Sodium lauryl sulphate 0.3 1.5 Wetting agent/ (SLS) surfactant Magnesium stearate 1.0 5.0 Lubricant Core tablet weight 500 Coating Opadry ® II 2.5 12.5 Coating

[0092] Process:

[0093] Gefitinib, lactose, MCC and croscarmellose sodium are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS are dissolved in a sufficient amount of purified water to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed magnesium stearate. The mix is compressed using suitable punches. The tablets are coated with an Opadry® II coating.

[0094] The tablets obtained, exhibited a dissolution rate of at least 85% in 10 minutes when tested in 1000 ml 0.01 N HCl pH 1.0, 0.01 N HCl pH 2.0, acetate buffer pH 4.5 or 5% Tween in water in a USP apparatus II at 50 rpm. The dissolution profiles of the tablets were similar to the profiles of Iressa®.

Example 20

Aqueous Wet Granulation with Water Soluble and Insoluble Fillers and Kollicoat® Coating

[0095]

TABLE-US-00011 Per tablet Ingredient % (mg) Function Tablet core Gefitinib (form 1), 50.0 250.0 Active ingredient D.sub.90 below 40 μm Lactose monohydrate 32.7 163.5 Water soluble diluent Microcrystalline 10.0 50.0 Water insoluble cellulose (MCC) diluent Croscarmellose sodium 4.0 20.0 Disintegrant Povidone 2.0 10.0 Binder Sodium lauryl sulphate 0.3 1.5 Wetting agent/ (SLS) surfactant Magnesium stearate 1.0 5.0 Lubricant Core tablet weight 500 Coating Kollicoat ® 2.5 12.5 Coating

[0096] Process:

[0097] Gefitinib, lactose, MCC and croscarmellose sodium are blended and sieved through a sieve of a suitable mesh size. Povidone and SLS are dissolved in a sufficient amount of purified water to make a binder solution. The binder solution is added to the blend and a granulate is formed in a high shear granulator, followed by drying and milling to a suitable size. The obtained granules are mixed magnesium stearate. The mix is compressed using suitable punches. The tablets are coating with an Opadry® II coating.

[0098] The tablets obtained, exhibited a dissolution rate of at least 85% in 10 minutes when tested in 1000 ml 0.01 N HCl pH 1.0, 0.01 N HCl pH 2.0, acetate buffer pH 4.5 or 5% Tween in water in a USP apparatus II at 50 rpm. The dissolution profiles of the tablets were similar to the profiles of Iressa®.