WO2010099150A1 - Pharmaceutical tablet and process - Google Patents

Abstract

Oral pharmaceutical tablet formulations containing a 4-quιnazolιneamιne or a salt thereof are described as well as methods of using the same in the treatment of disorders characterized by aberrant erbB family PTK activity The tablets have the advantages of smaller size while retaining good dissolution characteristics

Description

PHARMACEUTICAL TABLET AND PROCESS

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions containing, as an active ingredient, 4-quιnazolιnamιnes as well as use of the compositions in the treatment of proliferative diseases such as cancer In particular, the pharmaceutical compositions contain at least one 4-quιnazolιnamιne active ingredient that is an inhibitor of EGFR and/or erbB2 protein tyrosine kinase BACKGROUND OF THE INVENTION

Pharmaceutically active compounds may be formulated for administration by numerous routes Typically, the appropriate route will depend on the disease being treated, the chemical and physical properties of the pharmaceutically active substance as well as the subjects to be treated Suitable pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal, sub-lingual, and transdermal), vaginal or parenteral (including intramuscular, sub-cutaneous, intravenous, and directly into the affected tissue) administration or in a form suitable for administration by inhalation or insufflation Pharmaceutical compositions for the treatment of cancer typically have been injectible, parenteral formulations for intravenous infusion of the pharmaceutically active compound Generally, use of intravenous formulation has been indicated because of the cytotoxic nature of the anticancer formulation and/or the weakened condition of the patient Anti-cancer solid dosage forms have been available in tablet form, for example Alkeran®, Leukeran®, Myleran®, Purmethol®, Tabloid®, and recently Xeloda®, but these have been the exception rather than the norm

Tablets offer several advantages to both the manufacturer and to the patient

Tablets may be manufactured economically and are conveniently shipped, stored and dispensed The patient can take advantage of a dosage form, which can be produced with an accurate dosage and has ease of administration and portability 4-Quιnazolιnamιnes as dual inhibitors of the protein tyrosine kinases EGFR

(Epithelial Growth Factor Receptor - also known as erbB-1 ) and erbB-2 have been disclosed in International Patent Application PCT/EP99/00048 filed January 8, 1999, and published as WO 99/35146 on July 15, 1999 The anhydrous and monohydrate ditosylate forms of specific 4-quιnazolιnamιnes were disclosed in International Patent Application PCT/US01 /20706 filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002 Of particular interest is N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2- (methanesulphonyl)ethyl] amιno}methyl)-2-furyl]-4-quιnazolιnamιne ditosylate monohydrate This compound is now available to the public in various countries as Tykerb® or Tyverb® brand of lapatinib ditosylate monohydrate or in development as GW572016F in the treatment of various cancers, including breast, lung, bladder, head and neck, and gastric cancers GW572016F has poor flow characteristics and is poorly soluble in aqueous media over the physiologically relevant pH range Typically, for a pharmaceutical composition containing a drug having poor solubility in water and a high drug load, it is difficult to maintain high dissolution properties and the good flow characteristics needed for typical pharmaceutical manufacturing processes. Due to the poorly soluble active ingredient, rapid tablet disintegration, and high drug dissolution is required to achieve acceptable bioavailability A suitable oral tablet on the market in the United States is generally set forth in WO 2006/113649 and has achieved acceptance Such a tablet has the disadvantage, however, of a weight of about 900mg and a size of about 19mm by 10mm

SUMMARY OF THE INVENTION

The present invention provides a smaller tablet than the commercially available Tykerb® brand tablet with, however, a similar dissolution profile such that bioequivalence is achieved

In a first aspect of the present invention, there is provided a pharmaceutical tablet core comprising N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2- (methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend, and MI) pressing the granular blend produced in step ιι) in the form of a tablet

In a second aspect of the present invention, there is provided a film-coated pharmaceutical tablet comprising N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2- (methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend,

MI) pressing the granular blend produced in step ιι) in the form of a tablet, and iv) coating said tablet produced in step in) with a tablet coating

In a third aspect of the present invention, there is provided a process for producing a pharmaceutical tablet core comprising N-{3-chloro-4-[(3- fluoro benzyl )oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazolinamine or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture,

II) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend, and

MI) pressing the granular blend produced in step ιι) in the form of a tablet

In a fourth aspect of the present invention, there is provided a process for producing a film-coated pharmaceutical tablet comprising N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, II) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend,

MI) pressing the granular blend produced in step ιι) in the form of a tablet, and iv) coating said tablet produced in step in) with a tablet coating DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder The term also includes within its scope amounts effective to enhance normal physiological function

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent Such solvents for the purpose of the invention may not interfere with the biological activity of the solute Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid Preferably the solvent used is a pharmaceutically acceptable solvent Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid Most preferably the solvent used is water As used herein the term "core tablet" is defined as a tablet without a film coating Accordingly, as used herein the term "tablet" is defined as the core tablet with a film coating

As used herein the term "PTK" means protein tyrosine kinase

As used herein the term "EP" means European Pharmacopeia, the term "USP" means United States Pharmacopeia, the term "NF" means National Formulary, the term "JP" means Japanese Pharmacopeia, and the term "JPE" Japanese Pharmaceutical Excipients

Oral Pharmaceutical Composition Active Ingredient

The oral pharmaceutical composition of the present invention includes an active ingredient, which is selected from a compound of formula (I) or salts, including solvates, thereof

name N-{3-Chloro-4-[(3- fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine In one embodiment, the compound is the ditosylate salt of the compound of formula Il In another embodiment, the compound is the monohydrate form of the ditosylate salt of formula (I) and is designated GW572016F In another embodiment, the compound is the anhydrate form of the ditosylate salt of the compound of formula

(I) GW572016F is lapatanib ditosylate monohydrate whose chemical name is N-

{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno} methyl)-2-furyl]-4-quιnazolιnamιne ditosylate monohydrate

The anhydrous and monohydrate ditosylate forms of N-{3-Chloro-4-[(3- fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno} methyl)-2-furyl]-4- quinazolinamine may be prepared according to the procedures disclosed in International Patent Application PCT/US01/20706 filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002

The active ingredient is present in a range of about 50 to 65 percent by weight of the film-coated tablet oral pharmaceutical composition of the invention In one embodiment, the active ingredient is present in the tablet at about 405mg and the tablet weight is about 700mg In particular, the film-coated tablet of the invention will have dimensions of about 16mm by 8mm, which the patient may find preferable to the commercial tablets having dimensions of 19mm by 10mm, both being of generally oval or "caplet" shape Typically, the salts of the present invention are pharmaceutically acceptable salts Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent of the compound of formula (I). Representative salts include the following salts acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention

The free base and HCI salts of the compounds of Formula (I) may be prepared according to the procedures of International Patent Application No PCT/EP99/00048, filed January 8, 1999, and published as WO 99/35146 on July 15, 1999, referred to above

Step i): Granulation

The tablet forming process of the present invention includes admixing the active ingredient and at least one diluent to form a granulation mixture The admixing is done, for instance, in a fluid bed granulator by placing the active ingredient and the at least one diluent in the bowl of a GLATT® GPCG30 fluid bed granulator available from Glatt Air Technologies of Ramsey, New Jersey or a GLATT® WSTCD 160/200 fluid bed granulator available from the Glatt Group of Companies of Binzen, Germany The at least one diluent may optionally be sieved prior to admixing with the active If sieved, the at least one diluent is sieved using a US Mesh sized 16, 20, or 24, preferably a 20 sieve The admixed active and at least one diluent are then fluidized in the GLATT® GPCG30 or GLATT® WSTCD 160/200 to form a fluidized mixture using standard process parameters known in the art After preparation, the fluidized mixture is granulated using a granulating solution The granulating solution may be an aqueous, non-aqueous or a aqueous/non-aqueous solution The solution may or may not include at least one binder That is, the granulating solution may be an aqueous non-aqueous, or an aqueous/non-aqueous solution including the at least one binder or in another embodiment, the at least one binder is included in the fluidized mixture and the granulating solution is water, a non-aqueous liquid, or an aqueous/non-aqueous liquid The aqueous solution is of course water or a water solution with the at least one binder The non-aqueous solution includes, but is not limited to, alcohols such as ethanol, or isopropanol, other organics such as acetone, or mixtures of alcohols or other organics such as an acetone/ethanol mixture, or acetone/isopropanol mixture, and the like with or without the at least one binder The aqueous/non-aqueous solution is, but is not limited to, water/ethanol, water/acetone, or water/isopropanol mixtures with or without the at least one binder

In one embodiment, the aqueous solution may be a 5 to 25% solution of at least one binder in purified water (USP) In particular, the aqueous solution may be a 5 to 25, percent solution of povidone in purified water (USP) The aqueous solution is prepared for instance in a suitable tank with a propeller type mixer such as a Lightnin' Mixer with suitable bowl The aqueous mixture is sprayed onto the fluidized mixture after formation of the fluidized mixture at a rate adequate to insure proper granule formation As is known in the art, the specific combination of batch size, inlet air temperature, inlet air dewpoint, and inlet air volume will determine acceptable binder solution spray rates An additional amount of water may be added as needed to provide proper granulation wetness At the end of granulation the inlet air temperature, may be raised to facilitate the drying process until an acceptable moisture content (such as Loss On Drying - LOD) is reached The dried granules may be passed through, for instance, a cone mill, such as a Comil® available from Quadro Engineering Incorporated of Waterloo, Ontario, using an appropriate combination of screen size and impeller speed to produce the desired active granule product

Granulating step ι) of the present invention may be carried out by top spray fluid bed granulation or high shear granulation, both as known in the art Generally, a high shear process may be better for a smaller tablet, although poor dissolution may result In one embodiment, the oral pharmaceutical composition of the present invention is a tablet that is prepared using a fluid bed granulation process

The granules produced by step ι) are particularly those having a size of about 100-150mιcrons Smaller sizes such as 15-75 microns have been found to poorly flow for processing into the tablet or poorly dissolve once the tablet is formed in many cases

Binder The oral pharmaceutical tablet core of the present invention includes at least one binder A binder is used to impart cohesiveness qualities to powdered materials so that tablets or granules formed will remain together and not fall apart Any suitable binder that is compatible with the active ingredient and to good flow properties and dissolution may be utilized Exemplary binders include, but are not limited to gelatin, starch, sucrose, polyvinyl pyrrohdone (povidone), natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, polyethylene glycol, waxes and the like

In one embodiment, the at least one binder is polyvinyl pyrrohdone polymer or povidone, which is available from International Specialty Products of Wayne , New Jersey as the Plasdone® line of products including Plasdone K-29/32® In one embodiment, povidone is the only binder In another embodiment, no lactose is used The at least one binder is present in a range of about 2 to 11%, particularly about 4 to 9 per cent, by weight of the weight of the granulation produced in step ι) The solution itself to be used would be from about 5 to 20% by weight binder in aqueous solution Diluent/Filler

The oral pharmaceutical tablet core of the present invention may further comprise at least one diluent A diluent or filler is used to increase the bulk of the composition granulated in step ι) so that the final product has a practical size or volume, for instance for a tablet a practical size for proper compression A suitable diluent that is compatible with the active ingredient and to good flow properties and dissolution may be utilized Exemplary diluents include, but are not limited to lactose, sucrose or powdered sugar, manmtol, sorbitol, xylitol, inositol, calcium phosphate, calcium carbonate, calcium sulfate or dry starch In one embodiments, a starch such as Starch 1500 (maize starch) is used in the present invention Other suitable starches include commercially available wheat, potato, or rice starch, or mixtures thereof A particular aspect of this invention is that the known diluents of cellulose such as Avicel PH105, including microcrystalline cellulose or silicified microcrystalline cellulose and the like are not used during granulation Povidone, which may also be characterized as a binder in the tablets of this invention, may also be functioning as a diluent

The starch diluent is present in the granulation mixture of step ι) in a range of about 10 to 50 per cent by weight of the granulation mixture produced in step ι) In one embodiment, the diluent Starch 1500 is used in an amount of about 15-30% by weight

Flowing Aid The granulation mixture used in step ι) may also have a flowing aid such as a starch (as defined above) or silicon dioxide The amount used may be about up to about 5%, particularly about 1 % by weight of the granulation mixture used in step ι)

In an embodiment of the invention, a granule prepared according to step ι) comprises 55 to 80 wt% active ingredient, 15 to 35 wt% diluent, 0 1 to 5 0 wt% flowing aid, and 2 to 11 wt% binder, each by weight of granule The granule of this embodiment optionally further comprises 1 to 10 wt% of disintegrant by weight of granule

In another embodiment of the invention, a granule prepared according to step i) comprises 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule The granule of this embodiment optionally further comprises 1 to 10 wt% of sodium starch glycolate by weight of granule Optionally, the granule of this embodiment comprises 4 0 to 5 0 wt% sodium starch glycolate by weight of granule In another embodiment of the invention, a granule prepared according to step ι) consists essentially of 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule

In another embodiment of the invention, a granule prepared according to step i) consists of 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule

Step H): Blending

Step ii) comprises the blending of the granules from step ι) with extra- granular excipients so as to produce a blend which can be compressed into a tablet Various method knows in the art can be used After preparation the active granules are blended in step ιι) with at least one disintegrant and at least one lubricant to form a compression blend The active granules may be first blended with the at least one disintegrant and then the active granules/dismtegrant mixture blended with the at least one lubricant to form a compression blend Alternatively, the active granules, the at least one disintegrant, and the at least one lubricant are blended together to form the compression mixture

The ingredients are blended, using for instance a V-Blender available from Granulair Technologies of Lausanne, Switzerland or BULS cube blender available from Matcon, Incorporated of Sewell, New Jersey, at low rpm until blend uniformity is achieved As is recognized in the art, the time needed to achieve such uniformity will vary according to the amount and character of the ingredients and specific process equipment

Disintegrant The oral pharmaceutical core tablet of the present invention also includes at least one disintegrant A disintegrant functions to ensure or facilitate the breakup or disintegration of the granules made in step ι) after administration thereby facilitating dissolution of the active substance Any suitable disintegrant which is compatible with the active ingredient and to good flow properties and dissolution may be utilized Exemplary disintegrants include, but are not limited to starch, cellulose and cellulose derivatives such as methyl cellulose, hydroxylpropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, and crosslinked sodium carboxymethyl cellulose, crosslinked polyvinyl pyrrohdone, sodium starch glycolate, agar, bentonite, and xanthan gum Preferably, the at least one disintegrant is sodium starch glycolate, which is available from DMV International of Veghel, The Netherlands as Primojel® Primojel® is a purified sodium starch glycolate, Ph Eur,, USP/NF, JPE, produced by cross-linking and carboxymethylation of potato starch with subsequent purification Sodium starch glycolate is also available from JRS Pharma of Patterson, New York as the Explotab® or VivaStar® line of products including Explotab®, VivaStarP®, and Explotab CLV® The disintegrant may be used in an amount of about 1 to 10%, e g 4%, by weight of the granules produced in step ι)

It is understood by those skilled in the art that the disintegrant described above may be added into a tablet making process at two stages Disintegrant can be added to the granulation mixture before granulation This disintegrant is termed intra- granular disintegrant in that it becomes part of the granules formed Disintegrant may also be added to the formed granules to form a compression mixture before compression This disintegrant is termed extra-granular disintegrant in that it is not part of the granules, but rather is in mixture with the granules Preferably, in this invention, the disintegrant is used only in step ιι), i e , the step of blending the granules produced in step ι) to produce a granular blend

Lubricant

The oral pharmaceutical composition of the present invention may further comprise at least one lubricant A lubricant is used to prevent adhesion of material to the surface of dies and punches in tablet formation, reduce inter-particle friction, facilitate ejection of tablets from the die cavity, and may improve the flow characteristics of a powder or granules Any suitable lubricant that is compatible with the active ingredient and to good flow properties and dissolution profile may be utilized Exemplary lubricants include, but are not limited to talc, magnesium 5 stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oils, and polyethylene glycol

In one embodiment, the at least one lubricant is magnesium stearate, which is available from Mallincrodkt Corporation of St Louis, Missouri

The at least one lubricant is present in a range of 0 1 to 2%, particularly 0 6 to 10 1 3 more particularly 0 8 to 1 2 per cent by weight of the oral pharmaceutical composition

Compression Aid

A compression aid, sometimes referred to as a filler for purposes of tablet

15 compression, may be used in step ιι) for the purpose of aiding the subsequent pressing of the granular blend into a tablet Aides which may be used include cellulose, such as Avicel PH102 The compression aid may be used in an amount of about 8-15% by weight of the tablet core, eg about 10% by weight

20 Step iii):Compression

Pressing the granular blend produced in step ιι) into the form of a tablet can be carried out as known in the art Core tablets are formed from the compression blend (step ιι)) by compressing the blend into tablet form Any suitable means for tablet compression may be used, including, but not limited to, a single punch

25 machine, rotary tablet machines and instrumented tablet machines In one embodiment, the tableting is done by a rotary tablet machine, for instance a Hata model HT-AP18SSU rotary tablet press available from Ehzabeth-Hata International of North Huntingdon, Pennsylvania or a Fette 1200 available from William Fette GmbH of Schwarzenbek, Germany The Hata press, for example, is fitted with a 16 33 x

30 8 17 mm standard concave tooling In-process controls for uniformity of weight, average weight, hardness, friability, and disintegration time are applied during the compression run and adjustments to the tablet press are made if necessary The composition of the core tablets are as described above

In an embodiment of the invention, a tablet prepared according to steps ιι)

35 and in) comprises 45 to 70 wt% active ingredient, 10 to 30 wt% diluent, 0 1 to 5 0 wt% flowing aid, and 2 0 to 8 0 wt% binder, 1 to 10 wt% of disintegrant, 0 1 to 2 0 wt% lubricant, and 8 0 to 15 0 wt% compression aid, by weight of tablet

In another embodiment of the invention, a tablet prepared according to steps ii) and in) comprises 45 to 70 wt% active ingredient, 10 to 30 wt% starch, 0 1 to 5 0

5 wt% silicon dioxide, and 2 0 to 8 0 wt% povidone, 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

In another embodiment of the invention, a tablet prepared according to steps

II) and in) consists essentially of 45 to 70 wt% active ingredient, 10 to 30 wt% starch,

10 0 1 to 5 0 wt% silicon dioxide, and 2 0 to 8 0 wt% povidone, 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

In another embodiment of the invention, a tablet prepared according to steps

II) and in) consists of 45 to 70 wt% active ingredient, 10 to 30 wt% starch, 0 1 to 5 0

15 wt% silicon dioxide, and 2 0 to 8 0 wt% povidone, 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

In another embodiment of the invention, there is provided a pharmaceutical tablet core comprising N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2- 20 (methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule, essentially in the absence of a cellulose, thereby producing granules of 25 said mixture,

II) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend, and

MI) pressing the granular blend produced in step ιι) in the form of a tablet In another embodiment of the invention, there is provided the tablet core of 30 the embodiment immediately above, wherein the extra-granular excipients comprise 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

In another embodiment of the invention, there is provided the tablet core of either of the two embodiments immediately above, wherein the process further 35 comprises the step of iv) coating said tablet produced in step in) with a tablet coating In another embodiment of the present invention, there is provided a process for producing a pharmaceutical tablet core comprising N-{3-chloro-4-[(3- fluoro benzyl )oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazolinamine or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend, and

MI) pressing the granular blend produced in step ιι) in the form of a tablet In another embodiment of the invention, there is provided the process of the embodiment immediately above, wherein the extra-granular excipients comprise 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

In another embodiment of the invention, there is provided the process of either of the two embodiments immediately above, wherein the process further comprises the step of iv) coating said tablet produced in step in) with a tablet coating

Step iv): Coating The tablets may optionally be film coated (step iv)) by any suitable means In one embodiment, the tablets are film coated using a coater such as a Compulab Accela Cota available from Thomas Engineering, lnc of Hoffman Estates, Illinois or a GC coater available from the Glatt Group of Companies of Binzen, Germany Coating of the tablets will enhance patient acceptance and control dust In one embodiment, the tablets are coated with about 3% dry weight of a coating, such as by using a 12 per cent by weight aqueous suspension of Orange Opadry® YS-1- 13065A aqueous suspension available from Colorcon, Incorporated of Westpoint, Pennsylvania Thus, the tablets produced in step in) may be coated for ease of storage, to prevent the patient from tasting the tablet core components and for stablihty Coating can be with commercially available coatings such as the Opadry coatings

The final tablet of the invention has a weight of no more than about 800mg, particularly about 700mg

In one embodiment, the granulation mixture produced in step ι) of the present invention includes an active ingredient that is N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine ditosylate monohydrate, povidone, silicon dioxide, and a starch The active ingredients disclosed herein have been shown to be effective inhibitors of EGFR and/or erbB2 kinases as well as having anti-tumour efficacy versus various cancer cell lines whose cells express EGFR and/or erbB2 See for instance the aforementioned International Patent Application No PCT/EP99/00048, filed January 8, 1999, and published as WO 99/35146 on July 15, 1999, International Patent Application No PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002, and International Patent Application No PCT/US03/10747, filed on April 8, 2003 and published as WO 03/086467 on October 23, 2003, which applications are incorporated herein by reference to the extent that they disclose the biological activity of the active ingredients recited herein Accordingly, also provided in the present invention, is a method for treating a disorder in a mammal characterized by aberrant activity of at least one erbB family PTK which includes administering an oral pharmaceutical composition as described herein

The aberrant PTK activity referred to herein is any erbB family PTK activity that deviates from the normal erbB family protein kinase activity expected in a particular mammalian subject Aberrant erbB family PTK activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of PTK activity Such aberrant activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation Furthermore, it is also understood that unwanted PTK activity may reside in an abnormal source, such as a malignancy That is, the level of PTK activity does not have to be abnormal to be considered aberrant, rather the activity derives from an abnormal source

The oral pharmaceutical compositions of the present invention contain compounds of formula (I) or anhydrate or hydrated salt forms thereof that are inhibitors of one or more erbB family PTKs and as such have utility in the treatment of disorders in mammals which are characterized by aberrant PTK activity, particularly humans In one embodiment of the present invention, the disorder treated is characterized by at least one erbB family PTK, selected from EGFR, c-erb- B2 and c-erb-B4, exhibiting aberrant activity In another embodiment, the disorder treated is characterized by at least two erbB family PTKs, selected from EGFR, c- erb-B2 and c-erb-B4, exhibiting aberrant activity In one embodiment of the treatment method, the compounds of formula (I) or anhydrate or hydrate forms thereof inhibit at least one erbB family PTK, selected from EGFR, c-erb-B2 and c- erb-B4 In another embodiment of the treatment method, the compounds of formula I or anhydrate or hydrate forms thereof inhibit at least two erbB family PTKs selected from EGFR, c-erb-B2 and c-erb-B4

The disorders referred to may be any disorder which is characterized by aberrant PTK activity As recited above such disorders include, but are not limited to, cancer and psoriasis In a preferred embodiment, the disorder is cancer In a more preferred embodiment, the cancer is non-small cell lung, bladder, prostate, brain, head and neck, breast, ovarian, gastric, colorectal, or pancreatic cancer

A therapeutically effective amount of a compound of formula (I) and anhydrate or hydrate forms thereof will depend on a number of factors including, but not limited to, the age and weight of the mammal, the precise disorder requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian Typically, the compounds of formula (I) and anhydrate or hydrate forms thereof will be given for treatment in the range of 0 1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 50 mg/kg body weight per day Acceptable daily dosages, may be from about 0 1 to about 2000 mg/day, and preferably from about 10 to about 1800 mg/day

The oral pharmaceutical compositions containing compounds of formula (I) or anhydrate or hydrated salt forms thereof, described above, are useful in therapy. At least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies. The additional anti-cancer therapy is typically selected from one or more of surgical, radiological, or chemotherapeutic therapies. In one embodiment, the additional anti-cancer therapy is at least one surgical therapy. In another embodiment, the additional anti-cancer therapy is at least one radiological therapy. In one embodiment, the additional anti-cancer therapy is at least one of surgical, radiological, or chemotherapeutic therapy. In one embodiment, the additional anti-cancer therapy is at least one chemotherapeutic therapy including administration of at least one anti-neoplastic agent. The administration in combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds, or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i e , are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i e , are non-cell cycle specific and operate by other mechanisms

Anti-neoplastic agents useful in combination with the compounds or salts, solvates or physiologically functional derivatives thereof of formula I include the following

(1) cell cycle specific anti-neoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel, vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine, epipodophyllotoxins such as etoposide and teniposide, gemcitabine, fluoropyrimidines such as 5-fluorouracιl, capecitabine, and fluorodeoxyuridine , antimetabolites such as allopuπnol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine and thioguanine, and camptothecins such as 9-amιno camptothecin, irinotecan, topotecan, CPT-11 and the various optical forms of 7-(4-methylpιperazιno-methylene)-10,11- ethylenedιoxy-20-camptothecιn ,

(2) cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine, anti-tumour antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin and mithramycin, and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin, and

(3) other chemotherapeutic agents including, but not limited to, anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene, progestrogens such as megestrol acetate, aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane, antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate, LHRH agonists and antagagonists such as goserelm acetate and luprolide, testosterone 5α-dιhydroreductase inhibitors such as finasteride, metalloproteinase inhibitors such as marimastat, antiprogestogens, urokinase plasminogen activator receptor function inhibitors, growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor, erb-B2, erb-

B4, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor

(PDGFR), insulin growth factor receptor (IGF-R1 ), vascular endothelial growth factor receptor (VEGFR, and TIE-2 (other than those VEGFR and TIE-2 inhibitors described in the present invention), and other tyrosine kinase inhibitors such as inhibitors of CDK2 and CDK4, Akt inhibitors, and b-raf inhibitors

Additional description of these and additional anti-cancer therapies can be found in published US Application 2004/0053946A1 published March 18, 2004 The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry Standard single-letter or three-letter abbreviations are generally used to designate ammo acid residues, which are assumed to be in the L- configuration unless otherwise noted Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification Specifically, the following abbreviations may be used in the examples and throughout the specification g (grams), mg (milligrams),

L (liters), mL (milliliters), μL (microliters), psi (pounds per square inch), mm (millimeters), kN (kiloNewton) cfm (cubic feet per minute) kP (kilopond)

M (molar), mM (millimolar),

N (Normal) Kg (kilogram) mol (moles), mmol (millimoles),

RT (room temperature), min (minutes),

(hours), RSD (relative standard deviation) rpm (revolutions per minute) mp (melting point),

Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade) All reactions conducted under an inert atmosphere at room temperature unless otherwise noted

Reference Example A

Preparation of N-(3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methane sulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne Tablets, 250 mg

Table 1 contains a description of the components used in the preparation of a granulation mixture and Table 2 contains a description of the components used in the preparation of a compression blend for one embodiment of N-{3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine Tablets, 250 mg for a batch size of 20,000 tablets

¹ N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne dιtosylate monohydrate (GW572016F) Prepared according to the procedure of Scheme B of WO 2006/113649 The actual amount of drug substance may be adjusted based on the purity of the specific lot of drug substance included in the batch The amount of diluent (microcrystalline cellulose) may then be adjusted to maintain a core tablet weight of 900mg

² Plasdone K29/32

³ Removed during drying process

* Based on theoretical drug substance factor of 1 62 = 1 00 ** Quantities for a 20,000 tablet granulation

Table 2

¹ Granules prepared from Granular Mix similar to that of Table 1

² Primojel NF, Pharm Eur, JPE

³ Removed during drying process

^■ 120000 Tablets

For this example all ingredients were weighed to amounts which were consistent with the weight percents recited in Tables 1 and 2

(ι) Formation of active granules (Batch size - 120,000 Tablets) N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιn amine ditosylate monohydrate and microcrystalline cellulose NF, PH Eur , JP were added to the bowl of a Glatt 30 granulator A 10% solution of povidone in water was prepared using a Lightnin' mixer with a suitable tank The N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2- (methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιn amine ditosylate monohydrate and microcrystalline cellulose were fluidized in the Glat 30 bowl and spraying of the 10% povidone solution began immediately at approximately 220g/mιnute with an inlet air temperature of 54°C The inlet air dewpoint was maintained between 10 to 15 ⁰C After the povidone solution was applied purified water was added as needed to obtain a proper granulation wetness At the end of granulation the inlet air temperature was raised to 60°C and drying was continued until an LOD of approximately 2 5% was reached The dried active granules were passed through a Comil Model 197S cone mill fitted with a 0 075 inch round holed screen at approximately 1720 RPM (28 6 Hz)

Sieve analysis was performed and tapped density profiles established Sieve analysis was performed using a Retsch sieve shaker, Model AS200 Digit Approximately 20 g of active dried granules was placed on the top of a nest of tared sieves of 20, 30, 40, 60, 100, and 200 mesh Shaking was done for 5 minutes at an amplitude setting of 60 with the pulse on This sieve analysis revealed little batch to batch variation in particle size of the active granules The granules were also characterized for Bulk Density (BD) and Tapped Density (TD) BD and TD of the granules was measured by adding a weighed amount of granules into a 100 ml graduated cylinder and measuring the volume initially and after 25, 50, 200, 500, and 1250 taps respectively

BD and TD showed minimal variation between batches (n) Tablet Formation

A compression blend was formed by combining the prepared active granules and sodium starch glycolate in a bin which was transferred to a tumble blender where the ingredients were blended for 15 minutes @ 12 RPM The bin was then removed from the tumble blender and magnesium stearate added to the blend of active granules and sodium starch glycolate The bin was sealed and transferred back to the tumble blender and blended for 3 minutes @ 12 RPM to obtain the compression mix Tablets were compressed from the compression blend using a Hata model HT- AP18SSU rotary tablet press fitted with 19 05 x 1041 mm standard concave tooling The tablet press was adjusted to provide tablets with the following specifications Weight of 10 tablets 9 0O g

Weight Range of 10 tablets 8 80-9 2O g

Individual Tablet Weight 900 0 mg

5 Individual Weight Range 855 0 - 945 0 mg

Target Average Tablet Hardness 18 kp

Individual Hardness Range 9 - 27 kp

Individual Thickness Range 5 00 - 8 00 mm

Compression Speed Range 15 - 45 RPM

10

Uncoated tablets were characterized for weight, hardness, disintegration and dissolution Tablets were weighed and hardness determined using, for example, a Dr Schleuniger® Pharmatron Testlink Instrument available from Dr Schleuniger® Pharmatron of Solothurn, Switzerland. Disintegration was determined in 1L of water 15 at 37°C and drug dissolution was evaluated using a USP Type Il apparatus at 55 rpm paddle speed in 900 ml of 0 1N HCI/2% w/w Tween 80 at 37°C Results for three groups of tablets follow

Average Weight #1 = 900 2 ± 1 23 mg, n = 120 20 #2 = 902 6± 1 28 mg, n = 90

#3 = 901 8 ± 0 99, n = 60

Average Hardness #1 = 18 6 kp

#2 = 19 1 kp

25 #3 = 18 6 kp

Disintegration #1 = 2 mm 2 seconds

#2 = 1 minute 59 seconds #3 = 1 minute 57 seconds 30

The produced tablets were coated in a Thomas Engineering lnc , Compu-Lab coater using 12% w/w Orange Opadry®/YS-1-13065-A aqueous suspension at a pan speed of 6-8 rpm Two spray nozzles (orifice opening - 1 2 mm) were used to deliver coating solution at a total rate of 90-120 g/min The airflow was maintained at 500 to

35 700 cfm with the outlet air temperature ranging from 50 to 63°C The gun to bed distance was kept at 8 5 to 9 inches Sufficient film coating was applied to achieve a 3 percent by weight gam assuming 100% coating efficiency

Coated tablets were characterized for drug dissolution using a USP Type Il apparatus at 55 rpm paddle speed in 900 ml of 0 1N HCI/2% w/w Tween 80 at 37°C The results follow

% Dissolution (45 mm) Range = 81-95 %

Average = #1 = 87

#2 = 93

#3 = 94

Table 3 recites the tablet composition

Table 3

1 N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne ditosylate monohydrate (GW572016F), equivalent to 250 mg ¹ N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6- [5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne 2 Theoretical core tablet weight is 900 mg 3 Removed during drying

Reference Example B Preparation of N-(3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methane sulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne Tablets, 250 mg

Table 4 contains a description of the components used in the preparation of a granulation mixture and Table 5 contains a description of the components used in the preparation of a compression blend for one embodiment of N-{3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine Tablets, 250 mg for a batch size of 120,000 tablets

Table 4

¹ N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne ditosylate monohydrate(GW572016F) Prepared according to the procedure of Scheme B The actual amount of drug substance may be adjusted based on the purity of the specific lot of drug substance included in the batch The amount of diluent (microcrystalline cellulose) may then adjusted to maintain a core tablet weight of 900mg

² Removed during drying process

* Based on theoretical drug substance factor of 1 62 = 1 00 ** Quantities for a 120,000 tablet granulation

¹ Granules prepared from Granular Mix similar to that of Table 4

² Removed during drying process * 360,000 Tablets

For this example all ingredients were weighed to amounts which were consistent with the weight percents recited in Tables 4 and 5

(ι) Formation of active granules (Batch size - 120,000 Tablets)

N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιn amine ditosylate monohydrate and microcrystalline cellulose NF, PH Eur , JP were added to the bowl of a Glatt WSTCD 160/200 granulator A 20% solution of povidone in water was prepared using a Lightnin' mixer with a suitable tank The N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}- 6-[5-({[2-(methanesulphonyl) ethyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate monohydrate and microcrystalline cellulose were fluidized in the Glatt WSTCD 160/200 bowl and spraying of the 20% povidone solution began immediately at approximately 2000 g/minute with an inlet air temperature of 58⁰C The inlet air humidity was maintained below 10 g/kg After the povidone solution was applied purified water was added as needed to obtain a proper granulation wetness At the end of granulation the inlet air temperature was raised to 60°C and drying was continued until an LOD of approximately 2 5% was reached The dried active granules were passed through a Comil Model 196S cone mill fitted with a 0 075 inch round holed screen at approximately 1000 RPM

Sieve analysis was performed and tapped density profiles established Sieve analysis was performed using, for example, a Retsch sieve shaker, Model AS200 Digit Approximately 20 g of active dried granules was placed on the top of a nest of tared sieves of 20, 30, 40, 60, 100, and 200 mesh Shaking was done for 5 minutes at an amplitude setting of 60 with the pulse on This sieve analysis revealed little batch to batch variation in particle size of the active granules The granules were also characterized for Bulk Density (BD) and Tapped Density (TD) BD and TD of the granules was measured by adding a weighed amount of granules into a 100 ml graduated cylinder and measuring the volume initially and after 25, 50, 100, 200,

300, 500, and 1250 taps respectively

(ιι) Tablet Formation A compression blend was formed by combining the prepared active granules and sodium starch glycolate in a bin which was transferred to a Bin blender where the ingredients were blended for 15 minutes @ 17 RPM The bin was then removed from the tumble blender and magnesium stearate added to the blend of active granules and sodium starch glycolate The bin was sealed and transferred back to the tumble blender and blended for 3 minutes @ 17 RPM to obtain the compression mix Tablets were compressed from the compression blend using a Fette model 2090 rotary tablet press fitted with 19 05 x 1041 mm standard concave tooling The tablet press was adjusted to provide tablets with the following specifications Weight of 10 tablets 9 0O g

Weight Range of 10 tablets 8 80-9 2O g

Individual Tablet Weight 900 0 mg

Individual Weight Range 855 0 - 945 0 mg

Target Average Tablet Hardness 18 kp Individual Hardness Range 9 - 27 kp

Individual Thickness Range 5 00 - 8 00 mm

Compression Speed Range 40,000 - 100,000 tpm

Uncoated tablets were characterized for weight, hardness, disintegration and dissolution Tablets were weighed and hardness determined using, for example, a

Dr Schleuniger® Pharmatron Testlink Instrument available from Dr Schleuniger® Pharmatron of Solothurn, Switzerland. Disintegration was determined in 900 mL of water at 37⁰C and drug dissolution was evaluated using a USP Type Il apparatus at 55 rpm paddle speed in 900 ml of 0 1N HCI containing 2% w/w Tween 80 at 37⁰C

The produced tablets were coated in a GLATT® 1500 coater using 12% w/w Orange Opadry®/YS-1-13065-A aqueous suspension at a pan speed of 5 - 7 rpm Five spray nozzles (orifice opening - 1 2 mm) were used to deliver coating solution at a total rate of 450-550 g/min The airflow was maintained at 3800 - 4200 cmh with the outlet air temperature ranging from 50 to 70⁰C The gun to bed distance was kept at 18 - 30 cm Sufficient film coating was applied to achieve a 3 percent by weight gain assuming 100% coating efficiency

Coated tablets were characterized for drug dissolution using a USP Type Il apparatus at 55 rpm paddle speed in 900 ml of 0 1 N HCI containing 2% w/w Tween 80 at 37⁰C

Table 6 recites the tablet composition

Table 6

¹ N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne ditosylate monohydrate (GW572016F), equivalent to 250 mg ¹ N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6- [5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne

² Theoretical core tablet weight is 900 mg

³ Removed during drying Examples

In Examples 1-9, Tables 7, 8 and 9 depict target weights of ingredients A target weight in Example 1 for the active ingredient is 2223 6g and so an acceptable actual amount may weigh an amount which is insignificantly different, for example 2223 9g This target protocol is consistent with industry practice Regarding equipment used in the Examples of the invention, the fluid bed processor may be a Glatt GPCG-5, the peristaltic pump may be a Masterflex, the conical mill may be a Quadro Comil 197, the blender may be Patterson-Kelly Twin Shell Blender and the rotary tablet press may be a Korsch XL-100

In Examples 1-9, the Povidone was applied as an aqueous solution and was generally prepared as a solution for multiple granulations Atomization air pressure for Examples 1-9 for the granulation was about 1 5 bar or about 22 psi For Examples 1-9, the inlet air temperature was about 50-65°C Tablet coatings may be carried out with the amount of materials set forth in Tables 7, 8 and 9 according to conventional procedures Thus an aqueous suspension is sprayed onto tablets in a rotating coating pan such as a Vector LDCS-5

Examples 1 -3

The following amounts set forth in Table 7 were utilized The following procedure was followed Weighing

1 Weighed the materials, 2 Prepared the granulating solution by combining Povidone and water and mixing until dissolved

3 Weighed target batch amount of Povidone solution

4 Combined Starch 1500 and colloidal silicon dioxide and pass the mixture through a No 20 mesh screen for de-lumping Fluid Bed Granulation

1 Preheated the GPCG-5 to target inlet temperature

2 Charged the GPCG-5 product bowl with GW572016f (the ditosylate monohydrate) and Starch 1500-colloιdal silicon dioxide mixture

3 Began the granulation process with the Povidone solution 4 After completion of the Povidone solution, continue spraying with the rinse water

5 Dried the granulation via fluid bed drying Milling

1 Passed the granulation through the Comil 197 to obtain particles about 150 microns in size

2 Collected in-process samples for characterization Blending

1 Weighed out materials as in the Table

2 Charged the blender with the granulation, Avicel PH102 and sodium starch glycolate and mix for about 10 minutes 3 Added magnesium stearate to the blender and mix for about 3 minutes Compression

1 Charged the tablet press with the final blend and adjust parameters to achieve the target tablet weight 2 Produced tablet cores with the press to a target hardness of 15kp for dissolution testing 3 Collected in-process samples for characterization

A Film Coating may be included 1 The core tablets produced may be film coated according to conventional practices so as to allow ease of administration to patients

Example 1 The following writeup was used to prepare the granules and uncoated tablet core of Example 1 Granules and uncoated tablet cores of Examples 2-9 were produced by an analogous process

(ι) Formation of active granules (Batch size - 5,490Tablets)

2223 6 g of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2- (methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4-quιnazolιn amine ditosylate monohydrate, 5134 g of pregelatmized starch NF, PH Eur , JP and 5 5 g of colloidal silicon dioxide NF, PH Eur , JP were added to the bowl of a Glatt 5 fluid bed granulator A 10% solution of povidone in water (about 1153 g total solution) was prepared using a Lightnin' mixer with a suitable tank The N-{3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amιno}methyl)-2-furyl]-4- quinazohn amine ditosylate monohydrate, pregelatmized starch, and colloidal silicon dioxide were fluidized in the Glat 5 bowl and spraying of the 10% povidone solution began after approximately 5 minutes at approximately 85 g/minute with an inlet air temperature of about 5O⁰C After the povidone solution was applied, purified water was added as needed to obtain a proper granulation wetness At the end of granulation (after about 25 minutes), the inlet air temperature was set to 60°C and drying was continued until an LOD (loss on drying) of approximately 1 5% was reached The dried active granules were passed through a Comil Model 197 cone mill fitted with a 0 075 inch round holed screen at approximately 2660 RPM (44 3 Hz)

(n) Tablet Formation

A compression blend was formed by combining the 2000 0 g of prepared active granules, 236 3 g of microcrystalline cellulose and 103 8 g of sodium starch glycolate in a V-blender where the ingredients were blended for 10 minutes at approximately 25 RPM 17 3 g of magnesium stearate was then added to the blend of active granules, microcrystalline cellulose and sodium starch glycolate and the V- blender was operated for 3 minutes at approximately 25 RPM to obtain the compression blend Tablets were compressed from the compression blend using a Korsch XL-100 rotary tablet press fitted with 19 05 x 10 41 mm standard concave tooling The tablet press was adjusted to provide tablets with the following specifications

Weight of 10 tablets 6 135 g

Individual Tablet Weight 613 5 mg (average)

Individual Weight Range 583 0 - 644 0 mg

Target Average Tablet Hardness 15 kp

Table 7

Example 1 2 3

Item mg/Tablet (% w/w) g/batch mg/Tablet mg/Tab

Granulatio n

GW572016 405 0 77 81 2223 6 405 0 405 0

Starch 1500 93 5 17 96 513 4 99 0 94 5

Colloidal silicon dioxide 1 0 0 19 5 5 1 0 5 5

Povidone,

K29-32 21 0 4 03 115 3 44 0 21 0

Water Qs ... 1037 7 qs qs

Rinse water Qs — 518 9 qs qs

Sub-total 520 5 100 00 2857 8 549 0 526 0

Sub-total

(without

PVP) 499 5 — 2742 5 505 0 505 0

Tablet Core

Granulation 520 5 84 84 2000 0 549 0 526 0

Avicel

PH102 61 5 10 02 236 3 64 5 62 0

Sodium starch glycolate 27 0 4 40 103 8 28 5 27 5

Magnesium stearate 4 5 0 73 17 3 5 0 4 5

Total 100 00 23574

Core Tablet

Weight, mg 613 5 647 0 620 0

Film- coated Tablet

Tablet cores 613 5 97 07 6₄7 0 620 0

Opadry, orange 18 5 2 93 19 5 18 5

Total Batch

Weight

Total

Tablet

Weight 632.0 666.5 638.5

Examples 4-6

In a manner similar to Examples 1-3, the following formulations may be produced according to the invention:

Table 8

Example 4 5 6

Item mg/Tablet mg/Tablet mg/Tablet

Granulatio n

GW572016 405 0 405 0 405 0

Starch 1500 100 0 184 5 196 5

Colloidal silicon dioxide 5 5 1 0 1 5

Povidone,

K29-32 44 5 24 5 52 5

Water Qs qs qs

Rinse water Qs qs qs

Sub-total 555 0 615 0 655 5

Sub-total

(without

PVP) 510 5 590 5 603 0

Tablet Core

Granulation 555 0 615 0 655 5

Avicel

PH102 65 5 72 5 77 0

Sodium starch glycolate 29 0 32 0 34 0

Magnesium stearate 5 0 5 5 6 0

Core Tablet

Weight, mg 654 5 725 0 772 5

Film- coated

Tablet

Tablet cores 654 5 725 0 772 5

Opadry, 19 5 21 5 23 0 orange

Total

Tablet

Weight 674.0 746.5 795.5

Examples 7-9

In a manner similar to Examples 1-3, the following formulations may be produced according to the invention:

Table 9

Example 7 8 9

Item mg/Tablet mg/Tablet mg/Tablet

Granulatio n

GW572016 ₄05 0 ₄05 0 ₄05 0

Starch 1500 187 0 199 0 I₄O O

Colloidal silicon dioxide 6 0 6 5 3 5

Povidone,

K29-32 25 0 53 0 35 0

Water Qs qs qs

Rinse water Qs qs qs

Sub-total 623 0 663 5 583 5

Sub-total

(without

PVP) 598 0 610 5 5₄8 5

Tablet Core

Granulation 623 0 663 5 583 5

Avicel

PH102 73 5 78 0 69 0

Sodium starch glycolate 32 5 3₄ 5 30 5

Magnesium stearate 5 5 6 0 5 0

Core Tablet

Weight, mg 73₄ 5 782 0 688 0

Film- coated

Tablet

Tablet cores 73₄ 5 782 0 688 0

Opadry, orange 22.0 23.5 20.5

Total

Tablet

Weight 756.5 805.5 708.5

Example 10

Comparison of Components in Commercial Product and Present Invention One can compare these different tablets in terms of the amount of cellulose and starch in the granules and the extra-granular excipients as follows below Note that the extra granular excipient wt % of cellulose and starch may vary based on the total amount of extragranular excipients used

I-Microcrystalline Cellulose

Present Commercial Product Invention

Granules 45% by weight 0%

Extra-granular excipients 0% 5-15%

Coating 0% 0%

Il-Starch

Granules 0% 10-50% Extra-granular excipients 4 5% 4 5%

Coating 0% 0%

Claims

What is claimed is

1 A pharmaceutical tablet core comprising N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend, and

MI) pressing the granular blend produced in step ιι) in the form of a tablet

2 The tablet core of claim 1 , wherein step ι) comprises ι) granulating a mixture comprising 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule, essentially in the absence of a cellulose, thereby producing granules of said mixture

3 The tablet core of claims 1 or 2, wherein the extra-granular excipients comprise 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

4 A film-coated pharmaceutical tablet comprising N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4- quinazohnamine or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture,

II) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend,

MI) pressing the granular blend produced in step ιι) in the form of a tablet, and iv) coating said tablet produced in step in) with a tablet coating

5 The tablet core of claim 4, wherein step ι) comprises ι) granulating a mixture comprising 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule, essentially in the absence of a cellulose, thereby producing granules of said mixture 6 The tablet core of claims 4 or 5, wherein the extra-granular excipients comprise 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

7 A process for producing a pharmaceutical tablet core comprising N-{3- chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-

(methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend, and

MI) pressing the granular blend produced in step ιι) in the form of a tablet

8 The process of claim 1 , wherein step ι) comprises ι) granulating a mixture comprising 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule, essentially in the absence of a cellulose, thereby producing granules of said mixture

9 The process of claims 7 or 8, wherein the extra-granular excipients comprise 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet

10 A process for producing a film-coated pharmaceutical tablet comprising N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2- (methanesulphonyl)ethyl]amιno}methyl)-2-furyl]-4-quιnazolιnamιne or a salt thereof as an active ingredient, produced by a process which comprises the steps of ι) granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture,

II) blending the granules produced in step ι) with one or more extra-granular excipients to produce a granular blend,

MI) pressing the granular blend produced in step ιι) in the form of a tablet, and iv) coating said tablet produced in step in) with a tablet coating

11 The process of claim 10, wherein step ι) comprises i) granulating a mixture comprising 55 to 80 wt% active ingredient, 15 to 35 wt% starch, 0 1 to 5 0 wt% silicon dioxide, and 2 to 11 wt% povidone, each by weight of granule, essentially in the absence of a cellulose, thereby producing granules of said mixture

12 The process of claims 10 or 11 , wherein the extra-granular excipients comprise 1 0 to 10 wt% of sodium starch glycolate, 0 1 to 2 0 wt% magnesium stearate, and 8 0 to 15 0 wt% cellulose, by weight of tablet