DESC:PHARMACEUTICAL COMPOSITIONS OF GEFITINIB

FIELD OF THE INVENTION

The present invention relates to a tablet containing 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3- morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof.

BACKGROUND OF THE INVENTION

The compound Gefitinib is disclosed in International Patent Application WO 96/33980 (Example 1) and is a potent inhibitor of the epidermal growth factor receptor (EGFR) family of tyrosine kinase enzymes such as erbB 1. The compound has the structure of Formula I


Formula-I

and has the Chemical Abstracts Registry Number 184475-35-2.

The compound possesses anti-proliferative activity such as anti-cancer activity and accordingly, is useful in methods for treatment of proliferative disease such as cancer in the human or animal body. The compound is expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by EGF (particularly erbB 1) receptor tyrosine kinases, particularly cancers such as lung, breast, prostate, ovarian, colorectal, gastric, brain, head and neck, bladder, pancreas, oesophageal, stomach, renal, skin, gynaecological and thyroid cancers and in the treatment of a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas.

Gefitinib is currently marketed as a film coated tablet under the brand name Iressa®, wherein the tablet core comprises Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate and magnesium stearate and the film coating comprises a water-soluble cellulose ether viz. hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide. This film coated tablet composition is described in European Patent EP 1 480 679.

Hence, as seen above, the marketed formulation of Gefitinib (Iressa®) contains in addition to the active ingredient, diluent, binding agent, disintegrant, lubricant and glidant in the core and the coating contains a film forming agent which is a water-soluble cellulose ether along with a plasticiser, opacifier and coloring agents.

Till date, few compositions of Gefitinib are known in the prior art which are discussed below:

European Patent EP 1 480 679, as discussed above discloses solid oral compositions of Gefitinib in the form of film coated tablets. The patent discloses that the rate at which the compound is precipitated from solution upon pH increase from stomach to GI tract is significantly reduced when Gefitinib is formulated or administered together with certain excipients. This is described as providing improved pharmacokinetic properties for example, increased absorption and/or bioavailability and thus reducing inter-patient variability. The excipients disclosed in the patent are water soluble cellulose ethers and the esters of such water soluble cellulose ethers and their salts, the preferred one being hydroxypropylmethylcellulose/ hypromellose (HPMC).

United States Patent Publication Number 20070141141 discloses an immediate release pharmaceutical composition comprising 4-(3'-chloro-4'-fluoroanilino)-7- methoxy-6-(3- mor-pholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof (the Agent), a water-soluble acid, and a water-soluble cellulose ether or an ester of a water- soluble cellulose ether. The preferred cellulose ether is HPMC.

Hence, as seen above in both the reported pharmaceutical compositions comprising Gefitinib, water-soluble cellulose ether or an ester of water-soluble cellulose ether is used for coating of the tablets.

However, the problem with this prior art is that HPMC solutions are viscous in nature and hence only low amounts of solids can be incorporated in the coating solution. The problem of viscosity may result in higher process time, less efficient atomization, more buildup of the spraying solution on the spraying guns and less ease of pumping, as a result of which it may be difficult to obtain a smooth and uniform coating on the tablets.

It is thus one object of the present invention to provide a stable oral formulation of Gefitinib which can be produced more rapidly and efficiently.

It is another object of the present invention to provide a stable oral formulation of Gefitinib with a smoother and more uniform tablet coating.

It is another object of the present invention to provide a stable oral formulation of Gefitinib which is more cost-efficient.

SUMMARY OF THE INVENTION

The inventors of the present application have surprisingly found that using a film coating comprising a vinyl polymer provides a solution to one or more of the above-mentioned objects.

Accordingly, in one aspect the present invention relates to a tablet comprising (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline (Gefitinib) or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer.

In another aspect, the present invention relates to a method of preparing the tablet according to the invention by wet granulation.

In another aspect, the present invention relates to a method of preparing the tablet comprising a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline (Gefitinib) or a pharmaceutically-acceptable salt thereof and a film coating comprising vinyl polymer, wherein a coating solution is applied on the said core.

DETAILS OF THE INVENTION

One aspect of the present invention is a tablet comprising (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline (Gefitinib) or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer. The tablet core contains a pharmacologically effective amount of Gefitinib. The tablet will typically contain at least one pharmaceutically acceptable excipient suitable for the preparation of tablets.

In a preferred embodiment the amount of Gefitinib or pharmaceutically acceptable salts thereof is 250 mg per tablet.

In another aspect, the present invention is a tablet comprising (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline (Gefitinib) or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer in the range of 30 to 50% by weight of the film coating.

In yet another aspect, tablet of the present invention does not contain any water soluble cellulose ether or an ester thereof such as hydroxypropyl methylcellulose, in the core as well as in the film coating.

One or more pharmaceutically acceptable excipients may be present in the tablet core, e. g. those conventionally used, such as a filler, e. g. lactose monohydrate, microcrystalline cellulose, binder e.g. povidine etc., at least one disintegrant, e. g. croscarmellose sodium, sodium lauryl sulphate etc., one glidant, e. g. colloidal silicon dioxide and one lubricant, e. g. magnesium stearate . The film coating comprises a suitable film-forming vinyl polymer such as polyvinyl alcohol, plasticiser such as polyethylene glycol 300, opacifier such as titanium dioxide, dispersion aid such as talc and colorants such as iron oxide.

The term "pharmaceutically acceptable" refers to an ingredient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.

Suitable fillers include, for example, lactose (which may be in an anhydrous or hydrated form, for example lactose monohydrate), sugar, starches (for example corn, wheat, maize, potato), modified starches (for example as starch hydrolysates or pregelatinized starch which may be thermally, mechanically or chemically modified), microcrystalline starches, mannitol, sorbitol, trehalose, maltose, inorganic salts (e.g. calcium carbonate, magnesium carbonate, dibasic calcium phosphate (anhydrous/dihydrate), tribasic calcium phosphate), cellulose, cellulose derivatives (e.g. microcrystalline cellulose), calcium sulphate, xylitol and lactitol. Of these the preferred ones are lactose monohydrate and microcrystalline cellulose.

Suitable binders include, for example, polyvinylpyrrolidone (for example povidone K25-32, particularly K29-32, wherein the "K value" is an indication of the average molecular weight range obtained from the Fikentscher equation described in the Handbook of Pharmaceutical Excipients, 3.sup.rd Edition 2000 American Pharmaceutical Association p 433), lactose (which may be in an anhydrous or hydrated form, for example lactose monohydrate), starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and salts thereof (for example sodium carboxymethylcellulose), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and alginates (for example sodium alginate). Of these the preferred ones are lactose monohydrate, microcrystalline cellulose and povidone.

Suitable disintegrants include, for example, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, starches, microcrystalline cellulose. Of these the preferred one is croscarmellose sodium.

Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, sodium lauryl sulphate and sodium stearyl fumarate. Of these magnesium stearate is the most preferred one.

In addition to these excipients, glidants such as colloidal silicon dioxide and wetting agents such as sodium lauryl sulphate may also be used in the tablet core.

According to the present invention, the fillers may be present in an amount of from 10 to 90% by weight, preferably in the range from about 30 to 50% in weight based on the total weight of the tablet.

According to the present invention, the amount of binder may vary within a range of from about 1 to 40%, preferably 1 to 30%, in particular 0.5 to 25% in weight based on the total weight of the tablet.

The amount of disintegrant may vary within a range of from to 5 to 40%, e. g. 1 to 10% in weight based on the total weight of the tablet.

The amount of glidant may vary within ranges of from 0.1 to 10%, in particular 0.1 to 5%, e. g. 0.5 to 3% in weight based on the total weight of the tablet or 2 to 4 % in weight based on the total weight of the tablet.

The amount of lubricant may vary within a range of from 0.1 to 5%, e. g. 0.5 to 2% in weight based on the total weight of the tablet.

In another embodiment, the tablet core is coated with the film coating solution comprising vinyl polymer together with plasticiser, opacifier, dispersion aid and colorants. Advantageously, the vinyl polymer will be present in an amount of 30 to 50% by weight of the film coating. Suitable vinyl polymers include, for example polyvinyl alcohols or polyvinyl acetate phthalate.

In a particularly preferred embodiment, the vinyl polymer is polyvinyl alcohol (PVA). PVA has several advantages over water soluble cellulose ethers such as hypromellose (HPMC). The polyvinyl alcohol based coatings may be applied on the tablet core at the recommended 20% solid concentration, which is much higher than the concentration of HPMC that may be used for the coating. This is primarily due to the fact that the PVA-based coating system also exhibited very low viscosity compared to the HPMC-based system. The low viscosity of this system enables a higher solid concentration of coating to be delivered to the tablets resulting in faster protection of the tablets and shorter process times. Lower viscosity coating formulations can also be beneficial in terms of more efficient atomization, less build-up of material on the spray guns and ease in pumping. Additionally, the PVA-based coating also exhibited three-fold higher film adhesion compared to the HPMC based system. Another advantage of the PVA based coating is that increased pan speed resulted in a significant increase in defects for the tablets coated with the HPMC-based system. However, the defect rate was lower overall for the PVA-based film coated tablets. Hence, these are the advantages of using PVA based coatings over HPMC based coatings.

In a preferred embodiment of the present invention, the tablet comprises (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer, wherein the tablet does not contain any water soluble cellulose ether or any ester thereof.

In yet another embodiment of the present invention, the tablet comprises (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer, wherein the tablet does not contain any water soluble cellulose ether or an ester thereof such as hydroxypropyl methylcellulose in the core as well as in the film coating.

Concentration of PVA is critical to the formation of uniform coating on the tablet. Inventors of the present invention have surprisingly found that concentration in the range of 30 to 50%, particularly 35 to 45% produces tablet with advantages as mentioned above. This optimal concentration helps to achieve good dissolution and bioavailability of Gefitinib in plasma. Also, vinyl polymer is specifically used for increasing the film adhesion of a composition for film coating a tablet comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof.

Additionally, the film coating may contain additional components such as plasticiser, colorants, dispersion aid and opacifier. Plasticiser may be used to improve film flexibility and durability and adhesion properties of the film coating. Suitable plasticisers include, for example glycerin, acetylated monoglycerides, citrate esters (for example triethyl citrate), propylene glycols, polyethylene glycols (for example polyethylene glycols with a molecular weight of from 200 to 500, particularly 300), triacetin (glycerol tri-acetate), triglycerides (for example castor oil), or phthalate esters (for example diethylphthalate). Suitable opacifier and colorants include for example titanium dioxide and ferric oxides (for example iron oxide red and iron oxide yellow). Suitable dispersion aids include, for example talc.

In another preferred embodiment of the present invention the film coating may comprises:
vinyl polymer in an amount of from 30 to 50% by weight of the film coating, particularly from 35 to 45%;
plasticiser in an amount of from 10 to 30% by weight of the film coating, particularly from 15 to 25%,
dispersion aid in amount of from 5 to 20% by weight of the film coating, particularly from 11 to 20%,
opacifier in amount of from 0 to 10% by weight of the film coating, particularly from 3 to 7%,
colorants in amount of from 0 to 30% by weight of the film coating, particularly from 10 to 20%.

In yet another embodiment of the present invention the pharmaceutical composition of the present invention is prepared by using standard techniques and manufacturing processes generally known in the art, for example by dry blending the components or, particularly, wet granulation techniques followed by compression to form a tablet. The wet granulation technique comprises for example, mixing Gefitinib, one or more fillers and a portion of the disintegrant. The binder solution is prepared by dispersing the binder in purified water in presence of the wetting agent. The above-mentioned dry mixture of Gefitinib is then wet granulated with the binder solution containing wetting agent. The granulate is then passed through a screen, to break up large aggregates, dried and passed though a mill. Any remaining disintegrant and a lubricant are then added to the milled granulation and after blending the resultant homogeneous mixture is then compressed into tablets.

In another embodiment, the present invention relates to a method of preparing the tablet comprising a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline (Gefitinib) or a pharmaceutically-acceptable salt thereof and a film coating comprising vinyl polymer, wherein a coating solution is applied on the said core. Film coating may comprises a vinyl polymer in the range of 30 to 50% by weight of the film coating.

The film coating aqueous solution further comprises a plasticiser, an opacifier, a dispersion aid and colorants, wherein the plasticiser is present in an amount of 10 to 30%, the opacifier in amount of 0 to 10%, dispersion aid in amount of 5 to 20% and colorants in amount of 0 to 30% by weight of the film coating.

Film coating is applied using conventional methods, for example by coating with a film coating formulation, particularly a water-based film coating formulation. The film-coating formulation may be applied to the composition according to the present invention by, for example, spray coating or fluidized bed coating. Film coating may be present in the range of 2% to 4% by weight based on the core tablet weight. The film coated tablets thus prepared are then advantageously packaged in blister packs.

In another aspect, the present invention relates to a tablet according to the invention for use in the treatment of cancer, preferably non-small cell lung cancer or to the treatment of cancer, preferably non-small cell lung cancer using a tablet according to the invention.

EXAMPLES

Various embodiments of the pharmaceutical compositions of Gefitinib according to the present invention were prepared and studied for their stability and impurity profile when stored under accelerated stability conditions, which are illustrated below:

Example 01 (Representative formulation I)
Pharmaceutical composition of Gefitinib using polyvinyl alcohol in the coating.

Ingredients Mg/Tablet
Intragranular
Gefitinib 250.00 mg
Lactose monohydrate 163.50 mg
Microcrystalline Cellulose 50.00 mg
Croscarmellose Sodium (Ac-di-sol) 20.00 mg
Binder
Povidone (K29-32) 10.00 mg
Sodium Lauryl sulphate 1.50 mg
Purified Water q.s
Extragranular
Magnesium stearate 5.00 mg
Core Tablet Weight 500.00 mg
Aqueous Film Coating@ 2 – 4% of core tablet weight
@ Coating comprises Polyvinyl Alcohol, Macrogol, Talc, Iron Oxide Red, Iron Oxide Yellow and Titanium Dioxide

The pharmaceutical composition according to Example 01 was prepared by below mentioned process:

Gefitinib, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium mixed together in a high shear granulator to produce a homogeneous mix. Binder solution was prepared by dissolving povidone and sodium lauryl sulphate in purified water. Wet granulated the mixture of Gefitinib, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium with the binder solution. Dried the granules obtained by the wet granulation process. Dried granules were then milled to obtain suitable sized granules. Lubricated the sized/milled granules using magnesium stearate. Tablets were compressed using the blends of granules. Film coating was done on the tablets using polyvinyl alcohol as the film forming polymer along with Polyethylene glycol, titanium dioxide and the colorants in aqueous solution. Finally the film coated tablets were packed in blister packs containing of 10’s tablets and the blisters were further combined with an Aluminum foil laminate over-wrap in a carton.

Example 02 (Representative formulation II )
Pharmaceutical composition of Gefitinib using polyvinyl alcohol in the coating.

Ingredients Mg/Tablet
Intragranular
Gefitinib 250.00 mg
Lactose monohydrate 163.50 mg
Microcrystalline Cellulose 50.00 mg
Croscarmellose Sodium (Ac-di-sol) 10.00 mg
Binder
Povidone (K29-32) 10.00 mg
Sodium Lauryl sulphate 1.50 mg
Purified Water q.s
Extragranular
Croscarmellose sodium (Ac-di-sol) 10.00 mg
Magnesium stearate 5.00 mg
Core Tablet Weight 500.00 mg
Aqueous Film Coating@ 2 – 4% of core tablet weight

@ Coating comprises Polyvinyl Alcohol, Macrogol, Talc, Iron Oxide Red, Iron Oxide Yellow and Titanium Dioxide.

The pharmaceutical composition according to Example 02 was prepared by below mentioned process:
Gefitinib, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium mixed together in a high shear granulator to produce a homogeneous mix. Binder solution was prepared by dissolving povidone and sodium lauryI sulphate in purified water. Wet granulated the mixture of Gefitinib, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium with the binder solution. Dried the granules obtained by the wet granulation process. Dried granules were then milled to obtain suitable sized granules. Added the disintegrant and lubricated the sized/milled granules using magnesium stearate. Tablets were compressed using the blends of granules. Film coating was done on the tablets using polyvinyl alcohol as the film forming polymer along with Polyethylene glycol, titanium dioxide and the colorants in aqueous solution. Finally the film coated tablets were packed in blister packs containing of 10’s tablets and the blisters were further combined with an aluminum foil laminate over-wrap in a carton.

Table 01. Stability data of Representative formulation I
Stability of the pharmaceutical composition of the present invention was tested at initial stage and by subjecting the samples under various storage conditions: 400C/75%RH for 1 month, 2 months, 3 months and 6 months; 25°C/60%RH for 3 months, 6 months and 12 months. Impurity analysis of formulation was done during initial stage and after storage under various conditions at various time periods.

Stability condition Time Period Water Content (%) Related Substances (%w/w)
GEF-1 N-Oxide GEF-2 Dimer GEF-3 Total RS
Initial Initial 2.07 ND ND ND 0.01 ND 0.05
40°C/75%RH 1M 2.3 0 0 0 0.01 0 0.05
40°C/75%RH 2M 3.50 0 0 0 0.01 0 0.04
40°C/75%RH 3M 3.41 0 0 0 0.01 0 0.04
40°C/75%RH 6M 3.83 ND ND ND 0.01 0.01 0.07
25°C/60%RH 3M 3.31 0 0 0 0 0 0.06
25°C/60%RH 6M 3.29 ND ND ND 0.01 ND 0.05
25°C/60%RH 12M 3.94 0.01 ND ND 0.01 ND 0.07
ND - Not detected

Table 02. Stability data of commercially available Iressa® Tablet 250 mg
Samples of commercially available Iressa® tablet 250 mg were also analyzed at initial stage, 40°C/75%RH for 1 month 3 months, 6 month and 12 months.

Stability condition Time Period Water Content (%) Related Substances (%w/w)
GEF-1 N-Oxide GEF-2 Dimer GEF-3 Total RS
Initial Initial 2.55 ND ND ND 0.03 ND 0.09
40°C/75%RH 1M 2.53 ND ND ND 0.03 ND 0.09
40°C/75%RH 2M 3.02 ND ND ND 0.03 0.03 0.08
40°C/75%RH 3M 3.28 ND ND ND 0.03 0.03 0.08
40°C/75%RH 6M 3.54 ND ND ND 0.03 0.04 0.09
ND – Not detected

From Table 01 and 02, it is apparent that the tablet formulation of the present invention is having better stability profile with the marketed Iressa® tablets. Thus the results show that the tablet composition of the present invention is stable.

Table 03. Dissolution Data: (comparative evaluation of representative formulation II and Iressa® tablet)
Comparative evaluation of dissolution of representative formulation and commercially marketed Iressa® tablet was done using Tween 80 (5% v/v) in water, 1000 ml, USP apparatus type II at 50 RPM. Samples were taken at regular interval and amount of % drug dissolved was determined, which is represented as below.

Formulation details Dissolution
Media* Dissolution Profile (min)
%age drug dissolved
10 20 30 45 60
Representative formulation II Tween 80 (5% v/v) in water, 1000 ml, using USP apparatus type II at 50 RPM 30 46 58 69 76
Iressa® 34 70 84 89 92

From Table 03, it is apparent that the tablet formulation of the present invention is having comparable dissolution profile with the marketed Iressa® tablets.
,CLAIMS:We claim:

1. A tablet comprising (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer, wherein the tablet does not contain any water soluble cellulose ether or any ester thereof.

2. The tablet according to claim 1, wherein the vinyl polymer is present in the range of 30 to 50% per dry weight of the film coating.

3. The tablet according to any of the preceding claims, wherein the vinyl polymer is selected from polyvinyl alcohol or polyvinyl acetate phthalate, preferably polyvinyl alcohol.

4. The tablet according to any of the preceding claims, wherein the film coating further comprises a plasticiser, an opacifier, a dispersion aid, and at least one colorant.

5. The tablet according to any of the preceding claims, wherein the plasticiser is present in an amount of 10 to 30%, the opacifier in amount of 0 to 10%, dispersion aid in amount of 5 to 20% and colorants in amount of 0 to 30% by weight of the film coating.

6. The tablet according to any of the preceding claims, wherein the film coating further comprises talc.

7. The tablet according to claim 6, wherein talc is present at 5-20%, preferably 11-20% per dry weight of the film coating

8. The tablet according to any of the preceding claims, wherein the film coating comprises polyethylene glycol, titanium dioxide and iron oxide.

9. The tablet according to any of the preceding claims, wherein the film coating is present in an amount of 2 to 4% by weight based on the core weight.

10. A method of preparing a tablet comprising (a) a core comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof and (b) a film coating comprising a vinyl polymer in the range of 30 to 50% by weight of the film coating wherein a coating solution is applied on the said core.

11. The method according to claim 10 wherein the tablet does not contain any water soluble cellulose ether or an ester thereof such as hydroxypropyl methylcellulose in the core as well as in the film coating.

12. The method according to claim 10 or 11 comprises depositing on the surface of said tablet the coating solution applied by spray coating or fluidized bed coating.

13. The method according to any of the preceding claims 10 to 12, wherein the coating solution further comprises a plasticiser, a dispersion aid, an opacifier and colorants.

14. The method according to any of the preceding claims 10 to 13, wherein the plasticizer is present in an amount of 10 to 30%, the opacifier in amount of 0 to 10%, dispersion aid in amount of 5 to 20% and colorants in amount of 0 to 30% by weight of the film coating.

15. The tablet according to any of the preceding claims, wherein the core comprises at least one filler, at least one binder, at least one disintegrant, at least one lubricant and at least one glidant.

16. Use of a vinyl polymer for increasing the film adhesion of a composition for film coating a tablet comprising 4- (3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy) quinazoline or a pharmaceutically-acceptable salt thereof.

17. Use according to claim 16, wherein the vinyl polymer is polyvinyl alcohol.