WO2013008253A2

WO2013008253A2 - Imatinib formulations

Info

Publication number: WO2013008253A2
Application number: PCT/IN2012/000488
Authority: WO
Inventors: Suresh KONATHAM; Madhusudan MALLADI; Prasad Vure; Moumita BISWAS; Rahul BHISE; Ramesh KOTA
Original assignee: Dr. Reddys Laboratories Limited
Priority date: 2011-07-11
Filing date: 2012-07-11
Publication date: 2013-01-17
Also published as: WO2013008253A3

Abstract

Aspects of the present application relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects relate to processes for preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient.

Description

IMATINIB FORMULATIONS

INTRODUCTION

The drug having the adopted name "imatinib mesylate" has a chemical name 4-[(4-Methyl1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- phenyl]benzamide methanesulfonate, and its structural formula is shown below.

Imatinib mesylate has the empirical formula C₂9H₃iN70^«CH₄S03 and its molecular weight is 589.7. Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. It is soluble in aqueous buffers at pH <5.5, but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. Imatinib is a small molecule kinase inhibitor, used for the treatment of chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia, myelodysplastic/ myeloproliferative diseases (MDS/MPD), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), dermatofibrosarcoma protuberans (DFSP), and gastrointestinal stromal tumors (GIST).

Imatinib mesylate is the active ingredient in products sold as GLEEVEC™ for oral administration, in film-coated tablets containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base, in US. In European countries, imatinib mesylate is sold as GLIVEC™ for oral administration, which is available as tablet dosage forms containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib is also available as GLIVEC™ hard gelatin capsules in some European countries, each capsule containing 50 mg or 100 mg imatinib mesylate. As per the approved dosage regimen, doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

U.S. Patent No. 5,521 ,184 discloses imatinib and the use thereof, especially as an anti-tumor agent. U.S. Patent No. 6,894,051 , U.S. Patent No. 7,300,938, U.S. Patent No. 7,544,799, U.S. Patent No. 7,977,348, and U.S. Patent No. 8,067,421 disclose various polymorphic forms of imatinib or its salts. International Application Publication Nos. WO 2007/136510, WO 2011/023146 and WO 2011/157450 disclose polymorphic forms of imatinib or its salts, amorphous form and processes for their preparation.

Two different crystalline forms of anhydrous imatinib mesylate, form a and form β, are known in the art. Form a has a lower melting enthalpy than form β, which indicates an enantiotropic relationship between both forms. Form β is the more stable polymorph at 25°C and 50°C, but at high temperatures Form β is converted to Form a. Both polymorphs show similar aqueous solubility characteristics. The β form is thermodynamically stable and shows a suitable morphology with respect to flow properties. Form β is not hygroscopic in an environment with a relative humidity up to 90% and is very soluble in water (pH=5.8). Apart from Polymorph a and β, other polymorphic forms of imatinib mesylate are also known in the art, such as, a2, F, G, H, I, K, Delta, Epsilon, and H1. Two amorphous forms of imatinib mesylate are also known in the art.

International Application Publication No. WO 2003/090720 discloses high drug load tablets comprising imatinib or a pharmaceutically acceptable salt thereof in an amount from about 30% to 80% in weight of the active moiety based on the total weight of the tablet, but they are all produced by conventional wet granulation technique. According to said disclosure, the preferable hardness and abrasion resistance of the tablet and a sufficient bioavailability of the active ingredient can only be achieved by wet granulation, wherein imatinib mesylate preferably being used in the beta crystalline form.

U.S. Patent No. 7,943,172 discloses dry granulation processes of preparation of film-coated tablets comprising imatinib mesylate in alpha crystalline form wherein tablet cores and granule cores contain the active ingredient in proportions of 25% by weight to 80% by weight, based on the total weight of the tablet cores or granule cores, together with at least one filler-binder. International Application Publication No. 2011/161689 discloses

pharmaceutical tablet, comprising Imatinib in an amount of 50-75%w/w of the total tablet weight and comprising at least one pharmaceutically acceptable excipient without a binding agent. International Application Publication No. 2011/160798 discloses pharmaceutical tablet comprising at least one pharmaceutically acceptable excipient without a binding agent.

U.S. Patent Application Nos. 20080226731 and 20100240672 disclose sustained release pharmaceutical compositions of Imatinib Mesylate, melt granulated with a release retardant using an extruder.

Imatinib free base has very low solubility in water and in aqueous solutions that are slightly alkaline. The solubility of imatinib mesylate in aqueous solutions depends on pH; at pH 5.8, it is very soluble but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.

The aim of the present invention is to develop a new oral tablet comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient that can be produced in a simple manner. Additionally, to afford patient compliance, the tablet according to the invention should preferably have the active ingredient present in a high amount in the tablet in order to obtain smaller tablets which are more suitable especially for patients who have problems with swallowing. Surprisingly, it was found that tablets comprising imatinib or a pharmaceutically acceptable salt thereof in an amount from more than about 80% in weight of the active moiety based on the total weight of the tablet, can be prepared using conventional techniques, ensuring good storage stability throughout the shelf-life, wherein, such compositions may be prepared using any polymorphic form of imatinib mesylate. Furthermore, the present invention provides sustained release formulations of imatinib or a pharmaceutically acceptable salt thereof for once daily administration instead of currently available twice daily administration, to further improve patient compliance.

SUMMARY

Aspects of the present application relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects of the present application relate to processes of preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient. In embodiments, the application includes pharmaceutical formulations comprising imatinib mesylate in an amount from more than about 80% in weight of the active moiety based on the total weight of the tablet.

In embodiments, the application includes pharmaceutical formulations comprising imatinib mesylate, such that drug release characteristics of such formulations are maintained during storage for commercially relevant times.

In embodiments, the application includes pharmaceutical formulations comprising imatinib mesylate, wherein such formulations ensure good bioavailability by exhibiting desirable dissolution profile.

In embodiments, the application includes once daily sustained release formulations comprising imatinib mesylate and at least one release rate controlling material.

DETAILED DESCRIPTION

As used herein, the term "imatinib" includes the compound imatinib, pharmaceutically acceptable salts, esters and prodrugs thereof, the active

metabolites of imatinib, and any of their polymorphs, solvates, hydrates, and combinations thereof such as hydrated salts of imatinib. Formulations can contain imatinib in the range of 5 to 1000 mg per dosage unit.

The term "pharmaceutically acceptable salt" as used herein refers to salts that are known to be non-toxic and are commonly used in pharmaceutical practice. Acid salts include, for example, mineral acid salts, such as a hydrochloride,

hydrobromide, sulfate, etc. Salts with organic acids include, for example, a succinate, maleate, fumarate, malate, tartrate, etc. Sulfonate salts include, for example, a methanesulfonate (mesylate), benzenesulfonate, toluenesulfonate, etc. Basic salts include alkali metal salts, for example a sodium salt, potassium salt, and alkaline earth metal salt, for example a calcium salt, etc.

In the present application, imatinib and its salts can be used in any crystalline form, amorphous form, or combinations thereof. In the present application, imatinib or its salt can be anhydrous or in the form of hydrates, solvates, etc.

In embodiments, the application provides pharmaceutical dosage forms containing imatinib mesylate, wherein imatinib mesylate is in non-needle shaped alpha crystalline form. In embodiments, imatinib mesylate is in micronized non- needle shaped alpha crystalline form which can be prepared using spiral jet mill for example Hosokawa Micronizer. The material after fist milling can be further milled for second and third time following the same procedure, in order to get desired particle size distribution. Alternatively, needle shaped alpha crystalline form of imatinib mesylate can be slugged using compression machine known in the art and the obtained slugs can be milled through Qudroco mill. Material collected from Qudroco mill can be further processed using spiral jet mill to obtain non-needle shaped alpha crystalline form. Various processing parameters may be manipulated to obtain desired particle size distribution.

The mean particle size distribution of at least 80% of the imatinib mesylate is in the range from about 1pm to about 10pm, preferably in the range from about 2 pm to about 9 pm.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc.

The term "formulation" as used herein refers to dosage forms for

administration to a patient, comprising imatinib and one or more excipients, wherein dosage forms may be solid oral dosage forms such as tablets, capsules, pills, granules, sachets, etc.

The term "content uniformity," as used herein refers to an assessment of how uniformly a micronized or submicron active ingredient is dispersed in a formulation. Content uniformity can be measured according to USP test method 905 "Uniformity of Dosage Units."

The term "disintegration", as used herein, refers to the breakdown of unit dosage forms into smaller granules or particles. Disintegration can be evaluated according to USP test method 701 "Disintegration".

The term "stability" for purposes of the present application relates to physical stability, chemical stability, and thermodynamic stability. The term "physical stability" refers to maintenance of the polymorphic form of the drug, such as crystalline or amorphous, and the term "chemical stability" relates to formation of drug-related impurities. For pharmaceutical products, stability is required for commercially relevant times after manufacturing, such as for about 6, 12, 18, or 24 months, during which a product is kept in its original packaging under normal ambient conditions.

Stability testing frequently is conducted using storage conditions such as room temperature, e.g., 25°C and 60% relative humidity ("RH"), intermediate conditions (e.g., 30°C and 65% RH), and accelerated conditions (e.g., 40°C and 75% RH).

In embodiments, the present application provides imatinib mesylate tablets wherein the content of Impurity 1 is not greater than about 0.15%. In embodiments, the content of Impurity 2 is not greater than about 0. 5%. In embodiments, the content of the other individual impurity is not greater than about 0.1%. In

embodiments, the content of total drug-related impurities is not greater than about 0.5%. All of these impurity contents are expressed as weight percentages of the label drug content. Solid compositions of imatinib mesylate can be analyzed by common techniques, such as high performance liquid chromatography, to determine their drug content and the concentrations of drug-related impurities.

Details for known impurities Relative Retention Time (RRT) and Relative Response Factor (RRF);

In embodiments, the application provides pharmaceutical dosage forms of imatinib having content uniformities (CU) from about 90% to about 110% by weight, with relative standard deviations (RSD) of not more than about 5%. In embodiment, the invention relates to pharmaceutical formulations having a disintigration time of about 15 minutes.

In embodiments, pharmaceutically acceptable excipients for preparing dosage forms include, but are not limited to, any one or more of diluents, disintegrants, binders, glidants, lubricants, colouring agents, coating materials, and the like.

Alternatively, such pharmaceutically acceptable excipients may include Co- processed excipients. Disintegrants may be incorporated into intragranular or extragranular blends, or both. Various useful disintegrants include, but are not limited to, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium (e.g., Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KOLLIDON™ CL from BASF (Germany), POLYPLASDONE™ XL, XL10, and INF-10 from ISP Inc. (USA), and low-substituted hydroxypropylcelluloses ("L- HPC"). Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, starches, and any combinations thereof.

Solvents that are useful in processing include, but are not limited to, water, ^' methanol, ethanol, isopropanol, butanols, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,

dimethylsulphoxide, Ν,Ν-dimethylformamide, tetrahydrofuran, and any combinations thereof.

Glidants or anti-sticking agents can be used, including but not limited to talc, silica derivatives, colloidal silicon dioxide, and the like, and any mixtures thereof, and lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, glyceryl monostearates, calcium stearate, zinc stearate, polyoxyethylene monostearates, fumed silicas (e.g., Aerosil® products), sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats castor oils, waxes, and any combinations thereof.

Various useful acidifiers include, but are not limited to, organic acids such as citric acid, acetic acid, lactic acid, malic acid, fumaric acid, or succinic acid and combinations of organic acids such as malic acid, fumaric acid, and pyruvic acid. Inorganic acids, such as phosphoric acid, may also be used.

Various co-processed excipients may include Pharmaburst™, F-Melt®, PROSOLV® SMCC or suitable combinations thereof. Pharmaburst™, available as three different grades like Pharmaburst B1, Pharmaburst B2, and Pharmaburst C1 , is described as "delivery system" products used by pharmaceutical industry in the production of "quick dissolve" tablets. Pharmaburst B1 is composed of 85 percent mannitol (a sweetenter), 7.5 percent starch (a tabletting aid), 4.5 percent

polyplasdone, 3 percent sodium croscarmellose (disintegrants), and less than one percent each of colloidal silica and syloid (anti-adherents). Pharmaburst B2 consists of 85 percent mannitol, 10 percent polyplasdone, 5 percent sorbitol (a sweetener), and less than one percent syloid. Pharmaburst CT is made of 84 percent mannitol, 16 percent polyplasdone, and less than one percent syloid. F-MELT® is a co-spray dried excipient system containing 5 pharmaceutical excipients such as

carbohydrates, disintegrants and inorganic ingredients.

Various filler-binders are sugars, sugar alcohols, polymeric glycosides and inorganic compounds (salts). Examples of sugars are sucrose and lactose as the monohydrate or in anhydrous form. Examples of sugar alcohols are mannitol, xylitol and sorbitol. Examples of polymeric glycosides are maltodextrin, microcrystalline cellulose and starches of different origins, e.g. maize starch. Examples of suitable salts are calcium hydrogen phosphate, calcium silicates and sodium carbonate. Preferred filler-binders are calcium silicates, cellulose and starch.

Various useful colourants include, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, iron oxides, and any combinations thereof.

If desired, an outer continuous phase in the form of a film coating may be used, optionally containing additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, the like, including any combinations thereof.

Film-forming agents include, but are not limited to: soluble alkyl- or hydroalkyl- cellulose derivatives, for example and not limited to methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, and hydroxypropyl celluloses.

Various plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycol, triacetin, triethyl citrate and mixtures thereof. A plasticizer is frequently present in an amount ranging from 5% to 30%, based on the total weight of the film coating. An opacifier like titianium dioxide may also be present, in amounts ranging from about 0% to about 20%, based on the total weight of the coating. Anti-adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc. The anti-adhesive typically is present in the film coating in an amount of about 5% to 5%, based upon the total weight of the .coating.

As alternatives for the above coating ingredients, sometimes pre-formulated coating products such as those sold as OPADRY™ (supplied by Colorcon) will be used, for example Opadry Blue 13B50579 or Opadry White OY 59800 or Opadry AMB or Opadry Orange. The products sold in a solid form require only mixing with a liquid before use. Alternatively, film-forming agents may be applied as powders, using suitable powder coating equipment known in the art.

Pharmaceutical formulations such as tablets may be prepared using any of techniques such as dry granulation technique involving slugging or roller compaction etc., direct compression. Alternatively, granules prepared by dry granulation techniques may be filled into capsules or sachets.

Equipment suitable for processing pharmaceutical formulations of the present application include any one or a combination of mechanical sifters, blenders, roller compactors, granulators (rapid mixers or fluid bed granulators), fluid bed dryers, compression machines, rotating bowls or coating pans, etc.

Tablets prepared as above can be subjected to in vitro drug dissolution evaluations according to USP test 711 "Dissolution" to determine the rate at which the active substance is released from the dosage forms, and the content of active ingredient can conveniently be determined in solutions using techniques such as high performance liquid chromatography.

In embodiments, the application relates to sustained release formulations comprising imatinib or its salts, wherein the formulations, following dosing, can result in a reduced incidence of adverse effects and/or enhanced efficacy, when compared to an equivalent dose in an immediate release formulation. Such sustained release dosage forms contain imatinib in the range of 5 to 1000 mg, or 20 to 800 mg, or 30 to 600 mg, or 50 to 400 mg, per dosage unit.

In embodiments, solid dosage forms may be multi-unit particulate systems comprising one portion having delayed release particles and another portion having immediate release, extended release, or combinations of immediate and extended release particles, filled into capsules or sachets or tableted into finished dosage forms. In embodiments, sustained release formulations of the present application may be prepared by coating powders, granules, pellets, tablets, or cores with one or more functional coatings and then filling into capsules.

A sustained-release dosage form comprises a release rate-controlling material. The rate-controlling material can be associated with the formulation either in the form of a matrix or a coating. The rate-controlling material is a material that permits release of the active agent at a sustained rate into an aqueous medium.

In embodiments, the application relates to sustained-release formulations comprising imatinib or its salts and at least one release rate-controlling material, wherein a rate-controlling component is hydrophilic, hydrophobic, enteric, or combinations thereof. Suitable hydrophilic materials comprise water-soluble or water swellable materials. Examples of such materials include hydroxyalkyl celluloses, hydroxyalkyl alkylcelluloses, and carboxyalkyl cellulose esters, for example, hydroxypropyl methylcelluloses (hypromelloses or HPMC), hydroxypropylcelluloses (HPC), and combinations comprising one or more of the foregoing materials. For the purposes of this application, the release modifying agent may be present in a matrix, or in a coating covering the matrix. For the purposes of this application, the concentration of hydrophilic material ranges from about 5% to about 50% by weight of the formulation. Suitable "hydrophobic" materials include water-insoluble neutral or synthetic waxes, fatty alcohols such as lauryl, myristyl, stearyl, cetyl, and cetostearyl alcohols, fatty acids and derivatives thereof, including fatty acid esters such as glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, stearin, palmitin, laurin, myristin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oils, cottonseed oils, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, materials having hydrocarbon backbones, and combinations comprising one or more of the foregoing materials. Suitable waxes include, but are not limited to, beeswax, Glycowax® (a Ν,Ν'-distearoylethyelenediamine, from

Lonza), castor wax, carnauba wax, and wax-like substances.

Certain specific aspects and embodiments of the application will be further described in the following examples, which are provided solely for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. EXAMPLE 1-5: Imatinib mesylate tablets prepared using dry granulation.

*Evaporates during processing.

^**Opadry Orange is a formulated coating product of Colorcon, containing hypromellose 6 cP, triacetin/glycerol triacetate, titanium dioxide, and

pharmaceutically acceptable pigment.

Manufacturing Process:

1. Imatinib Mesylate and crospovidone or mannitol or croscarmellose sodium or sodium starch glycolate or L-HPC are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.

2. Sieved imatinib mesylate and crospovidone or mannitol or

croscarmellose sodium or sodium starch glycolate or L-HPC are made in to slugs with 25 mm round punches with desirable hardness.

3. The obtained slugs are milled though a Quadro™ Comil™ to obtain desirable granule size.

4. The granules from step 3 are made in to slugs second time with 25 mm round punches with desirable hardness and the slugs are milled though a Quadro™ Comil™ to obtain desirable granule size. 5. Sodium stearyl fumarate, previously passed through a #60 mesh sieve, is mixed with the blend from step 4, and then the mixture is compressed using desired oval shaped punches on rotary tablet press.

Coating

1. Opadry Orange is dispersed in I PA and DCM.

2. Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, and then dried.

Tablets prepared of Examples 1 and 2 are packaged in closed HDPE containers, together with desiccant canister, and stored at three different conditions: 25°C and 60% relative humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and 75% RH (Condition 3) for one month. Dissolution testing results of initial and stored samples are shown in Table 1 and Table 2 respectively. The dissolution study is conducted in 1000 mL of 0.1 N HCI medium, using USP type 2 apparatus, while stirred at 50 rpm for 30 minutes.

Table 1

Table 2

30 102 2.4 101 1.6 101 1.3 101 1.6

Measurement of drug content and concentrations of impurities: 5 Tablets of Examples 1 and 2 are transferred in to 250 mL of volumetric flask and 20mL diluent (Methanol: Water = 55: 45) was added and sonicated until complete tablet disintegration takes place. 120 mL of diluent was added and kept on rotary shaker at 150 rpm for 20 minutes and then sonicated for 15 minutes at room temperature. Volume was made up with desired quantity of diluent. Obtained solution was centrifuged at 4000 rpm for 10 minutes. 2.0 mL of supernatant solution was diluted to 20.0mL with diluent. Drug content or individual impurity content was measured using HPLC analysis. Results are shown in Table 3, where drug content and impurity values are expressed as percentages of the label drug content.

Table 3

ND = not detected.

* Oil = other individual impurity

EXAMPLES 6-9: Imatinib tablets prepared using direct compression

Crospovidone — — — 50

Colloidal silicon dioxide 5 5 5 5

Sodium stearyl fumarate 6 6 6 6

Coating

Opadry AMB 20 20 20 20

Isopropyl alcohol (IPA)* q.s. q.s. q.s. q.s.

Dichloromethane (DCM)* q.s. q.s. q.s. q.s.

Total Weight 559 559 559 559

*Evaporates during processing.

*^*Opadry AMB is a formulated coating product of Colorcon, containing polyvinyl alcohol, lecithin, soy, xanthan gum, polyethylene glycol (PEG 3350), titanium dioxide, talc, and pharmaceutically acceptable pigment.

Manufacturing process:

1. Non-coating ingredients, except for colloidal silicon dioxide and sodium stearyl fumarate, are sifted through a #30 mesh sieve and blended.

2. Colloidal silicon dioxide and sodium stearyl fumarate, previously passed through a #60 mesh sieve, is mixed with the blend from step 1 , and then the mixture is compressed into tablets.

Coating

1. Opadry AMB is dispersed in IPA and DCM.

2. Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, then dried.

EXAMPLE 10: Imatinib mesylate capsules

Instead of compressing into tablets, lubricated granules prepared in Examples 1-5 or a lubricated blends prepared in Example 6-9, are filled into capsules of suitable size.

EXAMPLE 11-12: Imatinib mesylate tablets

Sodium Stearyl Fumarate 3 0.75

Extragranular

Sodium Stearyl Fumarate 3 0.75

Total weight 484 121

Manufacturing process:

1. Imatinib mesylate is sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.

2. Sifted imatinib mesylate and Sodium Stearyl fumarate are transferred into the blender and blended for 3 minutes.

3. The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.

4. The obtained slugs are milled though a Quadro™ Comil™ to obtain desirable granule size.

5. The granules are blended with extra granular material (Sifted sodⁱum stearyl fumarate) for 3 minutes.

6. The lubricated blend is compressed with the suitable size punches^.

EXAMPLE 13-14: Imatinib mesylate tablets

Manufacturing process:

1. Imatinib mesylate and crospovidone are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sⁱeve.

2. Sifted imatinib mesylate and Sodium Stearyl fumarate are transferred into the blender and blended for 3 minutes. 3. The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.

5. Sifted crosspovidone is added to above milled granules and blended for 5 minutes.

6. Sifted sodium stearyl fumarate is added to above preluricated blend and blended for 3 minutes.

7. The lubricated blend is compressed with the suitable size punches.

Manufacturing process:

. imatinib mesylate, sodium starch glycolate, colloidal silicon dioxide and citric acid are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate ⁱs sifted through a #60 mesh sieve.

2. Sifted imatinib mesylate and colloidal silicon dioxide are transferred into a blender and blended for 5 minutes.

4. The obtained slugs are milled though a Quadro™ Comil™ to obtain desirable granule size. 5. Sifted sodium starch glycolate, colloidal silicon dioxide and citric acid are added to above milled granules and blended for 5 minutes.

7. The lubricated blend is compressed with the suitable size punches.

Dissolution testing results of tablets of Examples 11 , 13 and 15 are shown in Table 3. The dissolution study is conducted in 900 mL of 6.8 pH phosphate buffer medium, using (JSP type 2 apparatus, while stirred at 50 rpm for 30 minutes.

Table 3

EXAMPLE 17-24: Imatinib mesylate tablets

Manufacturing process:

1. Imatinib mesylate, crosspovidone and colloidal silicon dioxide are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve. 2. Sifted imatinib mesylate is slugged using round flat punches 25mm using tablet compression machine with desired hardness.

4. Sifted crosspovidone is added to above milled granules and blended for 5 minutes.

5. Sifted colloidal silicon dioxide and sodium stearyl fumarate are added to above blend and blended for 3 minutes.

6. The lubricated blend is compressed with the suitable size punches.

EXAMPLE 25-27: Imatinib mesylate sustained release tablets

*Evaporates during processing.

Manufacturing process:

1. Imatinib mesylate, Kollidon SR, ethyl cellulose and sodium stearyl fumarate were shifted.

2. Imatinib mesylate and Kollidon SR were blended for 5 min at 20 rpm in a double cone blender.

3. Ethyl cellulose was added and blended for 5 min at 20 rpm, with the blend prepared in step 2.

4. Obtained blend was made in to slugs with 25 mm round punches with desired hardness.

5. Obtained slugs were milled though a Quadro™ Comil™ to obtain , desirable size granules. 6. Obtained granules were again made into slugs with 25 mm Round punches with desired hardness.

7. Obtained slugs were milled though a Quadro™ Comil™ to obtain desirable size granules.

8. Obtained granules were taken in a double cone blender and blended with Sodium stearyl fumarate for 3 min at 20 rpm.

9. Obtained lubricated blend was made into tablets using 8- station rotary tablet press.

Coating

1. Opadry AMB is dispersed in IPA and DCM.

EXAMPLES 28: Imatinib mesylate sustained release tablets

*Evaporates during processing.

Manufacturing process:

1. Imatinib mesylate, hypromellose K 100M and sodium stearyl fumarate were shifted.

2. Imatinib mesylate and hypromellose K 100M were blended for 5 min at 20 rpm in a double cone blender.

3. Obtained blend was made in to slugs with 25 mm round punches with desired hardness.

4. Obtained slugs were milled though a Quadro™ Comil™ to obtain desirable size granules. 5. Obtained granules were again made into slugs with 25 mm Round punches with a hardness of 8-10 KP.

6. Obtained slugs were milled though a Quadro™ Comil™ to obtain desirable size granules.

7. Obtained granules were taken in a double cone blender and blended with Sodium stearyl fumarate for 3 min at 20 rpm.

8. Obtained lubricated blend was made into tablets using 8- station rotary tablet press.

Coating

1. Opadry AMB is dispersed in IPA and DCM.

Dissolution testing results of tablets of Examples 25-28 are shown in Table 4. The dissolution study is conducted in 900 mL of 0.1 N HCI medium, using USP type 2 apparatus, while stirred at 00 rpm for 2 hours.

Claims

I. A stable pharmaceutical formulation comprising imatinib or

pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable excipients.

2. A stable pharmaceutical formulation of claim 1 , wherein such formulation comprises imatinib or pharmaceutically acceptable salt in an amount of at least about 81% in weight of the active moiety based on the total weight of the formulation.

3. A stable pharmaceutical formulation of claim 2, wherein such formulation is tablet or capsule.

4. A stable pharmaceutical formulation of claim , wherein such formulation comprises monomesylate salt of imatinib.

5. A stable pharmaceutical formulation of claim 1 , wherein such formulation comprises monomesylate salt of imatinib having mean particle size distribution in the range from about 1 μητι to about 10 μιη.

6. A stable pharmaceutical formulation of claim 1 , wherein atleast 70 % imatinib monomesylate has a mean particle size distribution in the range from about 1 m to about 0 m.

7. A stable pharmaceutical formulation of claim , wherein such pharmaceutically acceptable excipients comprises at least one disintegrant, at least one glidant.

8. A stable pharmaceutical formulation of claim 1 , wherein such disintegrant comprises crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose or mixtures thereof.

9. A stable pharmaceutical formulation of claim 1 , wherein such pharmaceutically acceptable excipients do not comprise crospovidone.

10. A stable pharmaceutical formulation comprising imatinib or

pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable excipients, wherein such pharmaceutically acceptable excipients do not comprise any filler-binder.

I I. A stable pharmaceutical formulation of claim 7, wherein the formulation is tablet or capsule.

12. A process of preparation of a solid oral pharmaceutical formulation of imatinib mesylate of claim 1, wherein such process involves dry granulation or direct compression technique.

3. An once daily sustained release formulation comprising imatinib or pharmaceutically acceptable salt thereof wherein such formulation comprises at least one release rate controlling material.

14. An once daily sustained release formulation of claim 9, wherein preparation of such formulation does not involve melt processing.

5. An once daily sustained release formulation of claim 9, wherein such release rate controlling material includes hydrophilic material, hydrophobic material or suitable combination thereof.