WO2012080703A1

WO2012080703A1 - Pharmaceutical composition comprising imatinib

Info

Publication number: WO2012080703A1
Application number: PCT/GB2011/001726
Authority: WO
Inventors: Geena Malhotra; Shrinivas Madhukar Purandare
Original assignee: Cipla Limited; Turner, Craig Robert
Priority date: 2010-12-15
Filing date: 2011-12-15
Publication date: 2012-06-21

Abstract

A solid oral pharmaceutical composition comprises greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients. A process for preparing a pharmaceutical composition comprising than greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients comprises manufacturing a solid oral pharmaceutical composition by granulating imatimib with one or more pharmaceutically acceptable excipients. A solid oral pharmaceutical composition for use in medicine comprises greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients.

Description

PHARMACEUTICAL COMPOSITION COMPRISING IMATINIB

FIELD OF INVENTION:

The present invention relates to a solid oral pharmaceutical composition comprising imatinib, a process for preparing such pharmaceutical composition, therapeutic uses thereof and methods of treatment employing the same.

BACKGROUND AND PRIOR ART

Imatinib is used to treat certain types of cancer. The mesylate salt, imatinib mesylate is chemically named as 4-[(4-Methyl-l-piperazinyl) methyl]-N-[4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl] amino] -phenyl] benzamide methanesulfonate, and has the following chemical structure.

It is a protein-tyrosine kinase inhibitor that inhibits Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines, as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.

Imatinib, its salts and various compositions have been described extensively in patent and non patent literature.

U.S.5, 521,184 discloses imatinib, its structural analogs and their salts. It also specifically discloses capsules of imat iib arid its salts and their use in the treatment of tumors. However, the amount of active ingredient (imatinib) present in these capsules is 1 Omg. WO2009/100176 discloses the solid dispersion product of tyrosine kinase inhibitors including imatinib, for the treatment of proliferative disorders. The dispersion shows resistance against recrystallization or decomposition of the active ingredient(s). However, the active ingredient is present in an amount of 0.5-40% by weight (0.1 mg to 100 mg) of the said tyrosine kinase inhibitor.

EP1888040 discloses oral sustained release pharmaceutical composition comprising melt granules of imatinib and a release retardant polymer, wherein the amount of the drug in the composition is at least 50% by weight of the composition.

US2011206827 discloses film-coated tablets or granules comprising imatinib mono- methanesulfonate in the crystalline alpha form, wherein the tablet cores and the granules are prepared by pressing the starting materials i.e. by pressing of the active ingredient (imatinib) together with the additives in the mixture, and, prior to pressing of the starting materials, at least one of them is dry-granulated, preferably compressed or compacted.

Imatinib is currently marketed in the form of imatinib mesylate by Novartis under the trade name Gleevec. The recommended dosage of Gleevac is 400 mg/day for patients in chronic phase chronic myelogenous leukemia (CML) and 600 mg day for patients in accelerated phase or blast crisis. Dose increase from 400 mg to 600 mg in patients with chronic phase disease, or from 600 mg to 800 mg (administered as 400 mg twice daily) in patients with accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in circumstances such as disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of treatment and loss of a previously achieved hematologic response.

It is a well known fact that continuous and adequate dosing of imatinib is essential to achieve therapeutic outcomes.

In a study carried out on patient behaviors of non adherence to imatinib therapy, it was observed that the association of non-adherence with imatinib dosing of 600 mg/day or higher may be due to the various dosage regimens that are employed in the therapy. Currently, for a dose of 600 mg/day, one tablet of 400 mg has to be administered in the morning followed by two capsules of 100 mg in the evening. Alternatively three capsules of 100 mg are administered in the morning and evening. Because of this multiple dosing therapy of imatinib, there is a potential negative impact on treatment adherence (Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study, Ivo Abraham et al; Blood, April 6, 2009).

Currently imatinib mesylate capsules of 50 and 100 mg have been approved by European Medicines Agency (EMEA) and 100 mg capsules are available commercially. Therefore, a patient may have to ingest around four to eight capsules of imatinib per day to achieve the therapeutically effective dose. Further, they may even have to ingest eight capsules at a time in case an initial dose of 800 mg is to be administered.

The requirement of such large amount of imatinib to treat certain diseases and conditions makes it patient non-compliant. Some patients may not take it in its currently available oral dosage form regularly or in the large amounts necessary to effectively treat their disease.

Low compliance to prescribed medical interventions is an ever present and complex problem, especially for patients with a chronic illness such as cancer. Many factors, such as lack of knowledge about pain management, misunderstanding instructions about how to take drugs, complex treatment regimens, anxiety about adverse effects, inadequate understanding by health professionals of drug dependence and long distance from the treatment setting, among many others, have been shown to be significant barriers to adherence, and should be taken into account when developing interventions.

Several interventions have been designed to improve adherence to medications such as patient cooperation, therapeutic relationship, simplification of regimens and adaptation to prescribed medication.

Failure to address these barriers may lead to therapeutic failure and poor quality of life for the patient.

Hence, there is a need to develop pharmaceutical compositions having a high dose content of imatinib and which would also be convenient for patient administration. OBJECT OF THE INVENTION

The object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of imatinib, or any of its salts, solvates, enantiomers, derivatives, esters, hydrates, complexes, polymorphs or prodrugs with one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of imatinib mesylate.

Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of alpha form of imatinib mesylate.

Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of beta form of imatinib mesylate.

A further object of the present invention is to provide solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to up to 1000 mg of imatinib free base.

Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to 800 mg of imatinib free base.

Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to 600 mg of imatinib free base. Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to 400 mg of imatinib free base.

Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to not less than 100 mg of imatinib free base.

Another object of the present invention is to provide a process for preparing the solid oral pharmaceutical compositions comprising imatinib mesylate.

Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

SUMMARY OF THE INVENTION:

According to an aspect of the invention, there is provided a solid oral pharmaceutical composition comprising greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a capsule.

According to another aspect of the invention, there is provided a solid oral pharmaceutical composition preferably in the form of a capsule comprising greater than 100 mg of imatinib, and from 40% or less by weight of the composition of pharmaceutically acceptable excipients, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.

Imatinib is present in an amount of greater than lOOmg, 200 mg or more, 400 mg or more, 600 or more, or 800 mg or more. Preferably, imatinib is present in an amount of 1000 mg or less. Most preferably, imatinib is present in an amount of from 100 mg to 400 mg, 400 mg to 600 mg, or from 600 mg to 800 mg or from 800 mg to 1000 mg. Preferably, these defined weights of imatinib correspond to weights of imatinib free base. Preferably, the pharmaceutically acceptable excipients are present in an amount of from 40% or less or from 35% or less by weight of the pharmaceutical composition. However, the pharmaceutically acceptable excipients may be present in lower amounts, such as 30% or less, 25% or less, 20% or less, 15% or less, or 10% or less by weight of the composition. By weight of the pharmaceutical composition refers to the weight of the pharmaceutical composition not including the weight of the capsule if present. Imatinib is preferably in the form of a pharmaceutically acceptable salt, most preferably in the form of the salt imatinib mesylate. The term mesylate refers to the methanesulphonate salt of imatinib. The mesylate anion has structural formula CH3SO3^". Preferably, the amount of imatinib mesylate present in the pharmaceutical composition is equivalent to from 100 mg to 400 mg, 400 mg to 1000 mg, from 400 mg to 600 mg, or from 600 mg to 800 mg. or from 800 mg to 1000 mg of imatinib free base. The amount of imatinib mesylate present in the compositions can be an amount equivalent to 100 mg, 400mg, 600mg, 800 mg or 1000 mg of imatinib free base. The term "free base" is used to refer to molecular imatinib as an uncharged molecule, as opposed to imatinib as a salt where it may exist as a cation, with a corresponding anion such as mesylate, tartrate, citrate etc. These terms are understood clearly by persons having skill in the art.

According to another aspect of the invention there is provided a pharmaceutical composition according to the present invention for use in medicine. Preferably, this use is in the treatment of chronic myeloid leukemia. Preferably, the myeloid leukemia is in blast phase, accelerated phase, or chronic phase after failure of interferon-alpha therapy. Preferably the use comprises administration of one or two capsules per day to a patient.

In yet another aspect of the present invention there is provided a process for preparing a solid oral pharmaceutical composition according to the invention, comprising preparing a pharmaceutical composition by granulating imatimib with one or more pharmaceutically acceptable excipients, and preferably filling a capsule with said pharmaceutical composition to form a capsule of the invention.

In a further aspect of the present invention there is provided a solid oral pharmaceutical composition according to the invention for use in medicine. Preferably, the use is for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Preferably, the pharmaceutical composition is in the form of a capsule.

According to another aspect of the invention there is provided the use of a solid oral pharmaceutical composition according to the invention for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

According to another aspect of the invention, there is provided a method of treating chronic myeloid leukemia in a human or other mammal, which method comprises administering to a patient in need thereof a solid oral pharmaceutical composition according to the present invention. Preferably, the method is for the treatment of chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

According to another aspect of the invention, there is provided use of a solid oral pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of chronic myeloid leukaemia, preferably chronic myeloid leukemia in blast phase, accelerated phase, or chronic phase after failure of interferon-alpha therapy.

DETAILED DESCRIPTION OF THE INVENTION:

Imatinib is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It is used for the treatment of various types of cancers .The recommended dose of imatinib is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. Also higher initial dosage (600 mg and 800 mg) can induce better results than a standard dosage (400 mg).

Imatinib capsules are only commercially available in lOOmg strength. As per the recommended dosage regimen of imatinib, a patient may have to ingest 4, 6 or even 8 capsules at a time to achieve the therapeutically effective dose. This can lead to patient inconvenience especially for geriatric patients and children. Elderly patients may even forget to keep a count of the number of capsules that have been consumed by them during the day in the course of the treatment.

Hence, there exists a need to develop a pharmaceutical composition of imatinib that can deliver a higher dose of imatinib as well as provides patient compliance.

The inventors of the present invention have developed a solid oral pharmaceutical composition preferably in the form of a capsule that can deliver higher dosage of imatinib. The pharmaceutical composition of the present invention preferably delivers up to 800 mg of imatinib.

The inventors of the present invention have found that higher dose strength of imatinib, such as greater than 100 mg, i. e 400mg, 600 mg, 800 mg or 1000 mg can be administered, preferably in the form of a capsule dosage form. .

The solid oral pharmaceutical composition according to the present invention can be formulated in such a way that the capsule size is not too large, so as to be convenient for patient administration and yet can deliver higher dose of imatinib

The solid oral pharmaceutical composition according to the present invention may be particularly useful in patients who are unable or unwilling to consume multiple doses of imatinib mesylate regularly or in the large amounts necessary for the treatment of patients with chronic myeloid leukemia (CML).

The term 'Imatinib' is used in a broad sense to include not only "Imatinib" per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable hydrates, pharmaceutically acceptable complexes, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

"Pharmaceutically acceptable salts of imatinib free base" include, but are not limited to, pharmaceutically acceptable acid addition salts. Such acid addition salts include, but are not limited to, inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di- carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2- hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. Other examples of acid addition salts include, but are not limited to, tartrate salt, such as a (£⁾)(-) tartrate salt or a (L)(+) tartrate salt, a hydrochloride salt, a citrate salt, a malate salt, particularly a £>-malate salt, a fumarate salt, a succinate salt, a benzoate salt, a benzenesulfonate salt, a pamoate salt, a formate salt, a malonate salt, a 1,5- naphthalenedisulfonate salt, a salicylate salt, a cyclohexanesulfamate salt, a lactate salt, particularly a (5)-lactate salt, a mandelate salt, particularly an (i?)(-) mandelate salt, a glutarate salt, an adipate salt, a squarate salt, a vanillate salt, an oxaloacetate salt, an ascorbate salt, particularly an (Z)-ascorbate salt and a sulfate salt.

The term "free base" is used to refer to molecular imatinib as an uncharged molecule, as opposed to imatinib as a salt where it may exist as a cation, with a corresponding anion such as mesylate, tartrate, citrate etc. These terms are understood clearly by persons having a skill in the art.

Preferably, the imatinib salt in the capsule of the present invention is imatinib mesylate.

The term mesylate refers to the methanesulphonate salt of imatinib. The mesylate anion has structural formula CH₃S0₃ ^".

Preferably, the amount of imatinib mesylate in the pharmaceutical composition of the present invention is equivalent to greater than 100 mg, but up to 400 mg, 400 mg to 1000 mg, from 400 mg to 600 mg, or from 600 mg to 800 mg of imatinib free base. The amount of imatinib mesylate present in the pharmaceutical compositions can be m an amount equivalent to greater than 100 mg, or in an amount equivalent to 400 mg, 600 mg, or 800 mg of imatinib free base. Preferably, the solid oral pharmaceutical composition of the present invention when in the form of a capsule is administered as one or two capsules per day to a patient in need thereof.

Imatinib, according to the present invention may be in different polymorphic form such as alpha (a, a2 etc), beta (β), gamma (δ), epsilon (ε), HI, I, II, F, G, H, I, K and the like.

Preferably, imatinib is present in the a form. Preferably, imatinib is substantially free of genotoxic impurity. Preferably, imatinib mesylate is present in the a form and is also free of genotoxic impurity.

Imatinib is preferably present in an amount of greater than 100 mg; or 200 mg or more, 400 mg or more, 600 mg or more. Preferably, imatinib is present in an amount of 1000 mg or less. Most preferably, imatinib is present in an amount of greater than 100 mg and up to 400 mg, or 400 mg to 600 mg, from 600 mg to 800 mg, or from 800 mg to 1000 mg. Preferably, these defined weights of imatinib correspond to weight of imatinib free base.

The solid oral pharmaceutical composition of the present invention further comprises pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipients that may be used in the compositions of the present invention comprise disintegrating agents, binders, fillers, lubricants, glidants, diluents, stabilizers and any other suitable excipients that are employed in the formulation of a conventional capsule dosage form. The pharmaceutical compositions of the present invention are also preferably free of a release retardant.

Preferably, the pharmaceutically acceptable excipients are present in an amount, of 40% or less or from 35% or less, by weight of the pharmaceutical composition comprising imatinib. The pharmaceutically acceptable excipients can also be present in an amount of 30% or less, 25% or less, 20% or less, 15% or less, or 10% or less, 5% or less by weight of the pharmaceutical composition present in the capsule. In this paragraph, the definition "by weight of the composition" refers to by weight of the pharmaceutical composition in the absence of the capsule shell, i. e. the total weight of the pharmaceutical composition that is to be placed in the capsule. The excipients may be present in an amount of 40% or less by weight of the total capsule weight. Preferably, the excipients are present in an amount of 30% or less by weight of the total capsule weight. The excipients may also be present in an amount of 20% or less by weight of the total weight of the filled capsule. Suitable stabilizers include, but are not limited to, amino acids and carboxylic acid. The stabilizer (s) is added in the capsule formulation to prevent cross linking of gelatin shell. Stabilizer acts as scavenger and stabilizes pH and prevents the reaction that occurs between the composition in the capsule and capsule shell thereby preventing cross linking.

Preferable amino acids are selected form the group comprising glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, phenylalanine, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ornithine, p-aminobenzoic acid, nicotinic acid or mixtures thereof. The amino acid stabilizer preferably is in a quantity ranging from 1 to 5 % if present.

Preferably, if present, the amino acid is glycine.

Preferable carboxylic acids are selected form the group comprising benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid, and gluconic acid, or a salt and mixtures thereof. The carboxylic acid stabilizer is preferably in a quantity ranging from 0.1 to 1 %, if present.

Preferably, if present the carboxylic acid is citric acid.

Suitable diluents include, but are not limited to, one or more of calcium phosphate- dibasic, calcium sulfate, cellulose-microcrystalline, calcium carbonate, calcium phosphate-tribasic, copovidone, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, equivalents and mixtures thereof . The diluents may be preferably present in a quantity ranging from 10 to 40 %.

Suitable binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, other cellulose derivatives, equivalents and mixtures thereof. The binders may be preferably present in a quantity ranging from 1 tol5%

Suitable disintegrating agents include, but are not limited to, hydroxypropyl cellulose, carboxymethylcellulose, calciumcarboxymethylcellulose, sodiumcarboxymethylcellulose, croscarmellose sodium, starch, crystalline cellulose, sodium starch glycollate, hydroxypropyl starch, partly pregelatinized starch, crospovidone, equivalents and mixtures thereof. The disintegrating agents may be preferably present in a quantity ranging from 1 to 10%

Suitable lubricants and glidants include, but are not limited to, stearic acid, fumaric acid, adipic acid, hydrogenated castor oil, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose and mixtures thereof. The lubricants may be preferably present in a quantity ranging from 0.5 to 5%.

The solid oral pharmaceutical composition, according to the present invention, may be encapsulated in capsules of suitable size so as to ensure that the size is not too large yet can incorporate higher dose of imatinib. For example, capsules of size 000, OOel, 00, Oel, 0, 1, 2el, 2, 3, 4, 5 can be used. These capsule sizes are standard sizes known to the person having skill in the art of medicament formulation.

Preferably, the size of the empty capsule shell is 00, OOel Oel or 0.

The capsules may be made of different material such as, but not limited to gelatin, polyethylene glycol (PEG), hydroxypropyl methyl cellulose (HPMC) and may be filled with the fill material such as, but not limited to powder, beads or granules.

The solid oral pharmaceutical composition may be manufactured by conventional techniques such as, but not limited to, dry granulation, wet granulation or direct compression. The solid oral pharmaceutical composition of the present may be manufactured by hydro alcoholic granulation. The drug (Imatinib mesylate) is sifted with one or more pharmaceutically acceptable excipients and then sieved to form a premix. This premix is then loaded in fluidized bed processor and a granulating solvent (s) is sprayed to form granules that are subsequently dried. These dried granules are then blended with other pharmaceutically acceptable excipients such as lubricants and then filled into empty capsule shells.

Alternatively, other processes of preparing the capsules of the present invention may also be used wherein the drug (Imatinib mesylate) is sifted with one or more pharmaceutically acceptable and then sieved to form a premix. The premix is then roll compacted and sifted to obtain granules. The granules are then lubricated with pharmaceutically acceptable excipients such as lubricant and then filled into empty capsule shells.

The solid oral pharmaceutical composition, preferably in the form of capsules, of the present invention may also be manufactured by a slugging method where the drug (Imatinib mesylate) is sifted with one or more pharmaceutically acceptable and then sieved to form a premix. The premix is than slugged and broken into granules .The granules are lubricated with pharmaceutically acceptable excipients such lubricant and then filled into empty capsule shells.

The present invention also provides the use of a solid oral pharmaceutical composition according to the invention for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon- alpha therapy.

The present invention further provides a method for the treatment in a mammal, such as a human, of chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy, which method comprises administering to a patient in need thereof a solid oral pharmaceutical composition according to the present invention . Preferably, the solid oral pharmaceutical composition is administered as one or two capsules per day to a patient in need thereof. EXAMPLES:

The present invention is now illustrated by the following examples, which does not limit the scope of the invention in any way.

Example 1

Process:

1) Imatinib mesylate and crospovidone were co-sifted through a sieve to form a premix.

2) The premix obtained in step (1) was loaded in a fluid bed processor.

3) A mixture of isopropyl alcohol and purified water was sprayed on to the powder bed in fluid bed processor to form granules to produce granules.

4) The granules obtained in step (3) were dried and sifted through sieves.

5) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells.

Example 2:

3. Magnesium Stearate 6.0

4. Isopropyl alcohol q.s

5. Purified water q.s.

Capsule size 000

Process:

1) Imatinib mesylate and crospovidone were co-sifted through a sieve to form premix.

2) The premix obtained in step (1) was loaded in a fluid bed processor.

4) The granules obtained in step (3) were dried and sifted through sieves.

Example 3:

Process:

2) The premix obtained in step (1) was loaded in a fluid bed processor. 3) A mixture of isopropyl alcohol and purified water was sprayed on to the powder bed in fluid bed processor to form granules to produce granules.

4) The granules obtained in step (3) were dried and sifted through sieves.

Example 4:

Process:

2) The premix obtained in step (1) was loaded in a fluid bed processor.

4) The granules obtained in step (3) were dried and sifted through sieves.

5) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants; reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

Claims

1. A solid oral pharmaceutical composition comprising greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients.

2. A solid oral pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a capsule.

3. A solid oral pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients are present in an amount of 40% or less by weight of the pharmaceutical composition, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.

4. A solid oral pharmaceutical composition according to any preceding claim comprising 200 mg or more of imatinib.

5. A solid oral pharmaceutical composition according to any preceding claim comprising 400 mg or more of imatinib.

6. A solid oral pharmaceutical composition according to any preceding claim comprising 600 mg or more of imatinib.

7. A solid oral pharmaceutical composition according to any preceding claim comprising 800 mg or more of imatinib.

8. A solid oral pharmaceutical composition according to any preceding claim comprising 1000 mg or less of imatinib.

wherein the pharmaceutical composition comprises from 400 mg to 600 mg of imatinib.

10. A solid oral pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition comprises from 600 mg to 1000 mg of imatinib.l 1. A solid oral pharmaceutical composition according to any preceding claim wherein the defined weights of imatinib correspond to weights of imatinib free base.

12. A solid oral pharmaceutical composition according to any preceding claim, wherein the imatinib is imatinib mesylate.

13. A solid oral pharmaceutical composition according to claim 12, wherein the amount of imatinib mesylate in the pharmaceutical composition is equivalent to from 400 to 1000 mg of imatinib free base, 400 mg to 600 mg of imatinib free base, 600mg to 800 mg of imatinib free base, or 800 mg to 1000 mg of imatinib free base.

14. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises the pharmaceutically acceptable excipients in an amount of from 35% or less by weight of the composition, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.

15. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises the pharmaceutically acceptable excipients in an amount of from 30% or less by weight of the composition, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.

16. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises the pharmaceutically acceptable excipients in an amount of from 20% or less by weight of the composition, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.

17. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises the pharmaceutically acceptable excipients in an amount of from 15% or less by weight of the composition, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.

18. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutically acceptable excipients are present in an amount of less than 40% by weight, preferably less than 30% by weight of the total weight of the filled capsule if present.

19. A solid oral pharmaceutical composition according to any preceding claim, wherein the imatinib is present as the a polymorphic form, and preferably is free of genotoxic impurities.

20. A solid oral pharmaceutical composition according to any one of claims 1 to 19, wherein the imatinib is present as the β polymorphic form.

21. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutically acceptable excipients comprise one or more of a disintegrating agent , a binder, a filler, a lubricant, a glidant, a diluent, or a stabiliser.

22. A solid oral pharmaceutical composition according to claim 21, comprising one or more disintegrating agents comprising one or more of hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, starch, crystalline cellulose, sodium starch glycollate, hydroxypropyl starch, partly pregelatinized starch, crospovidone, equivalents and mixtures thereof.

23. A solid oral pharmaceutical composition in the form of a capsule according to any one of claims 2 to 22, wherein the capsule is of capsule size 000, OOel, 00. Oel, 0, 1, 2el, 2, 3, 4, or 5, preferably 00, OOel, Oel, or 0.

24. A solid oral pharmaceutical composition according to any one of claims 2 to 23, wherein the capsule is made of one or more of gelatine, polyethylene glycol (PEG), or hydroxypropyl methylcellulose (HPMC).

25. A solid oral pharmaceutical composition according to anyone of claims 2 to 24, wherein the pharmaceutical composition is present in the capsule in the form of powder, beads, or granules.

26. A solid oral pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition is free of a release retardant.

27. A capsule comprising a pharmaceutical composition comprising greater than 100 mg of Imatinib, and one or more pharmaceutically acceptable excipients.

28. A capsule according to claim 27, wherein the composition is as defined in any one of claims 2 to 26.

29. A process for preparing a pharmaceutical composition according to any one of claims 1 to 26, comprising manufacturing a solid oral pharmaceutical composition as defined in any one of claims 1 to 26, by granulating imatimib with one or more pharmaceutically acceptable excipients.

30. A process according to claim 29, further comprising filling a capsule with the pharmaceutical composition.

31. A process according to claim 29 or 30, wherein the granulation comprises dry granulation, wet granulation or direct compression.

32. A solid oral pharmaceutical composition according to any one of claims 1 to 26, or a capsule according to claim 27 or 28, for use in medicine.

33. A solid oral pharmaceutical composition according to claim 32, for use in the treatment of chronic myeloid leukemia.

34. A solid oral pharmaceutical composition according to claim 31 or 32, for use in the treatment of chronic myeloid leukemia in blast phase, accelerated phase, or chronic phase after failure of interferon-alpha therapy.

34. A solid oral pharmaceutical composition according to any one of claims 32 to 34, wherein the treatment comprises administration of one or two capsules per day to a patient in need thereof.

35. Use of a solid oral pharmaceutical composition as defined in any one of claims 1 to 26 for the manufacture of a medicament for the treatment of chronic myeloid leukaemia, preferably chronic myeloid leukemia in blast phase, accelerated phase, or chronic phase after failure of interferon-alpha therapy.

36. A method of treatment of chronic myeloid leukemia in a human or other mammal, which method comprises administering to a patient in need thereof a solid oral pharmaceutical composition according to any one of claims 1 to 26.

37. A solid oral pharmaceutical composition in the form of a capsule substantially as herein described with reference to the examples.