DESC:FIELD OF THE INVENTION
The invention relates to pharmaceutical composition comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2 %w/w of binder and 1-6% w/w of disintegrant.
The invention also relates to pharmaceutical compositions comprising an oral composition of Imatinib mesylate and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Imatinib mesylate (I) is chemically known as 4-[(4-Methyl-1-piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate.

Imatinib mesylate is a tyrosine-kinase inhibitor used in the treatment of multiple cancers and is sold under the trade name GLEEVEC®/GLIVEC®. Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. The U.S. Food and Drug Administration (FDA) have approved Imatinib as firstline treatment for Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML), both in adults and children. The drug is approved in multiple Ph+ cases CML, including after stem cell transplant, in blast crisis, and newly diagnosed. The FDA first granted approval for advanced GIST patients in 2002. Later in 2012, Imatinib was approved also for use after the surgical removal of KIT-positive tumors to help prevent recurrence. The drug is also approved in unresectable KIT-positive GISTs.
USFDA has approved imatinib for use in adult patients with relapsed or refractory Ph positive Acute lymphoblastic leukemia (ALL), myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, aggressive systemic mastocytosis (ASM) without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1Ll-PDGFRa fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRa fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Recently on 25 January 2013, Gleevec has been approved for use in children with Ph+ ALL.
Imatinib and its salts have been disclosed in EP0564409B1 (US5521184). Specifically, imatinib mesylate and its crystalline polymorphic Forms a and ß are disclosed in WO99/003854A1.
Furthermore, EP0564409B1 and WO/99003854A1 disclose generically many possible formulations, which are prepared in a manner known per se, for example by means of conventional mixing, granulating, dissolving or lyophilizing processes, and comprise approximately from 1% to 100%, especially from approximately 1% to approximately 20%, active ingredient. In the examples, direct compression, gelatinizing and mixing techniques are disclosed.
In one of the anonymously published literature in IP.com (on February 19, 2008 of IP.com number: IPCOM000167554D) discloses stable tablet formulation containing more than 80% of Imatinib mesylate.
Wet granulation process for making imatinib pharmaceutical compositions has been disclosed by Luftensteiner et al in patent application EP1501485B1 (WO03/090720A1). Imatinib mesylate (Form a and ß disclosed) and binder are mixed together with water and the mixture is processed for granulation, e.g., using a high-shear granulator to form wet granulates containing 30% to 80% imatinib mesylate and binder.
Malhotra et al in WO2012080703A1 disclose a solid oral pharmaceutical composition and its granulate comprises greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients.
Adhibatla et al in WO2012176014A1 disclose an oral pharmaceutical composition comprising greater than 80% Imatinib by weight based on the total weight of the composition.
Konatham et al in WO2013008253A2 disclose a stable pharmaceutical formulation comprising imatinib or pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable excipients.
Van Den et al in WO2012019633Al disclose a wet granulation process for making imatinib pharmaceutical compositions which comprise a process without the use of additional excipients, such as binders, except for the granulation liquid.
Bilgic et al in WO2012087255A2 covers a pharmaceutical formulation comprising imatinib characterized in that said formulation comprises a pharmaceutically acceptable disintegrant in the range of 0.1% to 05% by weight and at least one other excipient.
Bilgic et al in WO2012087256A2 covers pharmaceutical formulations comprising imatinib characterized in that said formulations comprise a pharmaceutically acceptable lubricant, a glidant and at least one other excipient; and the ratio of the lubricant and the glidant comprised in the formulations to each other is minimum 5 by weight.
Zimmermann et al in EP564409 B1 initially disclosed the preparation of Imatinib in free form (not as a salt). Further, Zimmermann et al in US 6,894,051 B1 described a and ß crystal forms of Imatinib Mesylate.
Zimmermann et al in US ‘051 disclosed that the a-crystal form of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl] benzamide methane sulfonate i.e. Imatinib mesylate is characterized by needle-shaped crystals and is hygroscopic. It has also mentioned that in this form, the crystals are not particularly well-suited to pharmaceutical formulation as solid dosage forms, because of their physical properties, including their flow characteristics, which are found unfavorable and unsuitable.
Under certain conditions, it is possible to obtain 4-( 4-methylpiperazin-1-ylmethyl)-N-[4-methyl3-( 4-pyridin-3-yl) pyrimidin-2-yl amino) phenyl] benzamide methane sulfonate in a crystal form which is not needle-shaped, which is described as ß-crystal form. The ß-crystal form of Imatinib mesylate is detailed as having the advantage of its flow properties being substantially more favorable than those of the a-crystal form. This crystal form has the further advantage of being thermodynamically more stable at temperatures below 140°C. Also applicant of US ‘051 describes that the ß-crystal form is less hygroscopic than the a-crystal form and thus also stores better and is easier to process.
Besides a and ß crystal forms various other polymorphic forms of Imatinib mesylate and the process for preparation thereof have been described in patent publications WO2004106326, WO2005077933, WO2005095379, W02006054314, W020060223816, W02006048890, W02007/023182, W02007059963 and W02011108953.
Gerber et al in US8414918 disclosed a pharmaceutical composition in the form of a coated tablet comprising polymorphic form X of imatinib mesylate, wherein less than 10% of the polymorphic form of imatinib mesylate is converted to form a or form ß after storage at 40°C at 75% relative humidity for 1 month, and wherein the coated tablet is prepared by coating a tablet using a C1-4 alcohol solvent with less than 20% w/v water. In Gerber et al, the uncoated pharmaceutical composition, such as a tablet, is prepared by dry granulation or direct compression.
Despite several granulation processes reported in the prior art however, due to unsuitable tableting properties of crystalline imatinib mesylate and its reported formulations itself, still there remains need for the composition/formulation, which are scalable on industrial scale and results in stable pharmaceutical composition.
SUMMARY OF INVENTION
Provided herein are simple and easily scalable oral unit solid pharmaceutical compositions of imatinib mesylate with improved granulating, tabletting or encapsulation properties, and the process of preparing such composition. The present invention provides a tablet containing imatinib mesylate, which provides high stability of imatinib mesylate within the compositions.
In one aspects of the present invention, it relates to a pharmaceutical composition of imatinib mesylate comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2% w/w of binder and 1-6% w/w of disintegrant.
In another aspects of the present invention, it relates to a pharmaceutical composition of imatinib mesylate comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2% w/w of binder and 1-6% w/w of disintegrant, wherein the granulate composition is prepared using binder in isopropyl alcohol solvent.
In yet another aspects of the present invention, it relates to a process of preparing pharmaceutical composition of imatinib mesylate wherein the process comprising the steps of:
a) sifting Imatinib mesylate and disintegrant followed by premixing for 5-15 min.
b) preparing binding solution using binder in isopropyl alcohol.
c) perform granulation using premixed material of step a) and step b) solution.
d) drying and sifting the granules.
e) adding extragranular composition comprising pharmaceutical acceptable excipients, followed by blending.
In yet another aspects of the present invention, it relates to preparing pharmaceutical compositions for oral administration comprising a step of admixing the imatinib mesylate granulate with pharmaceutically acceptable excipients, optionally, comprising a step of compressing the composition into tablets, and optionally followed by a film-coating or directly encapsulating in desired capsule size.
In further another aspects of the present invention, it relates to process of preparing pharmaceutical composition, wherein the coating materials are used not exceeding 3% of the overall weight of composition.
The aspects of present invention also relate to process of preparing pharmaceutical composition, wherein the coating materials containing solvent selected from C1-4 alcohol or water, mixtures thereof.
The solid oral pharmaceutical composition of imatinib mesylate according to present invention may be useful in for the treatment of various types of cancer.
Various other specific aspects of the invention are further detailed in the description part of the specification, wherever appropriate.
DETAILED DESCRIPTION
The present invention provides novel pharmaceutical composition of imatinib mesylate which are useful in the treatment of cancer.
In one embodiment according to present invention, it provides a pharmaceutical composition of imatinib mesylate comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2% w/w of binder and 1-6% w/w of disintegrant.
Imatinib mesylate as active substance is typically prescribed in high doses, e.g., 400 mg to 800 mg daily as a treatment of leukemia in adults. It is generally known to be as hygroscopic material and is having the characteristic of high solubility and high permeability. Imatinib mesylate itself is having the higher affinity towards the binding sites and pharmaceutically compatible with most of the reported adjuvants/excipients. Thus, in view of the high dosage desired for the therapy and the nature of the active ingredient, there is a further need to optimize the pharmaceutical dosage forms comprising imatinib mesylate so that it is convenient to manufacture, administer, and simultaneously provide the requisite daily dosage of imatinib.
It is also required that the said pharmaceutical dosage forms exhibit stability upon storage, as this is essential to ensure an adequate shelf life of the final dosage form. Further there is an apparent need to develop an optimized stable pharmaceutical dosage form that contains a high dosage amount of imatinib mesylate and also exhibits stability throughout the shelf life with acceptable dissolution profile.
The present invention particularly provides a pharmaceutical composition of imatinib mesylate wherein imatinib mesylate dose is equivalent to imatinib base. The active pharmaceutical ingredient (API) in the composition of imatinib mesylate according to present invention may be crystalline needle or non-needle shape material.
In one of the specific embodiment, non-needle shape crystalline material was utilized.
The invention provides that the pharmaceutical composition of imatinib mesylate comprising binder wherein binder is selected from cellulose derivatives e.g. ethyl cellulose, methyl cellulose, guar gum, blende guar gum and other cellulose e.g. cellulose gums (carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose), polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pregelatinized starch, acacia, alginic acid, carbomer, dextrin, maltodextrin.
In a specific embodiment according to present invention the binder used in the pharmaceutical composition was ethyl cellulose.
The present invention also provides the pharmaceutical composition of imatinib mesylate comprising disintegrant wherein disintegrant is selected from mannitol, alginic acid, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, magnesium aluminum silicate, methylcellulose, sodium alginate, starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch.
The pharmaceutical composition of imatinib mesylate comprising the addition of disintegrant in intragranular or extragranular part of composition.
Inventors of present invention successfully optimized the addition of disintegrant in intragranular or extragranular part of the composition or both.
It is required that the pharmaceutical composition of the present invention provide adequate compaction with desired disintegration time. Inventors of the present invention surprisingly found that disintegrant play a major role and impact on pharmaceutical composition when disintegrant is distributed as intragranular or extragranular or both.
Present invention also provides the pharmaceutical composition of imatinib mesylate comprising disintegrant as alginic acid wherein the total weight of disintegrant is to distribute as intragranular or extragranular or both.
In one embodiment according to present invention, it provides a pharmaceutical composition of imatinib mesylate comprising 86.0-96.0 %w/w of imatinib mesaylate, 0.05-0.2 %w/w of binder and 1-6 %w/w of disintegrant wherein the composition is prepared using binder in isopropyl alcohol solvent.
The invention, provides a process for preparing pharmaceutical composition comprising imatinib mesylate, the process particularly comprises wetting extragranular part with a granulation liquid, which is isopropyl alcohol containing binder, and granulating the mixture in a suitable granulator, e.g. high shear (Rapid mixer granulator/RMG) or fluid bed granulator (FBG or FBP), followed by drying, and optionally, sieving and/or milling, slugging.
Present invention also provides a process for preparing pharmaceutical composition comprising imatinib mesylate whereas the granules further followed by drying, and optionally, sieving and/or milling.
Further step of present invention involves addition of extragranular part of excipients and blending to make final blend for tablet compression, or filling into hard gelatin capsules.
In yet another embodiment of the present invention, it provides to a process of preparing pharmaceutical composition of imatinib mesylate wherein the process comprising the steps of:
a) sifting Imatinib mesylate and disintegrant followed by premixing for 5-15 min.
b) preparing binding solution using binder in isopropyl alcohol.
c) perform granulation using premixed material of step a) and step b) solution.
d) drying and sifting the granules.
e) adding extragranular composition comprising pharmaceutical acceptable excipients, followed by blending.
The step a) of sifting according to the present invention, carried out in a shifter by conventional method however it was found that sifting carried out using mesh size of ranging between 20#-30# at temperature ranging between 15-30° C.
Premixing of both sifted material is carried out for 5-15 min using fluidized bed processor. However, it is preferred that a time of 5-8 min premixing is necessary.
The step b) of preparing the binder solution according to the present invention, carried out with isopropyl alcohol and ethyl cellulose as binder. Binder solution prepared as granulating fluid at the temperature ranging between 15-35° C by using conventional stirrer for 5-20 min by gradually mixing.
Fluidization step c) carried out using premixed material and granulating fluid in fluidized bed processor with proper spraying of fluid material. The flow of premix material is upward, downward or tangible. However, it was found that downward flow gives proper entrapment of granulating fluid with premix material at the 35-40° C.
Drying of granules in further step d) is carried out at the temperature of 25-35° C. Granules are dried using tray drier to achieve the acceptable LOD.
Further process carried out in step d) is sifting followed by drying to maintain the uniformity of granules. Sifting of coated material varied out using sieve with mesh ranging between 20#-30# at temperature ranging between 15-30° C. As advantage of sifting inventors of the present application found that this kind of step has satisfactory outcome and betterment of further step.
The step e) of addition extragranular part of the composition which comprises sifting of alginic acid and magnesium stearate and/or separately or in combination by using sieve 30#-60#. However, inventors found that separate addition of alginic at blending stage and followed by addition of magnesium stearate gives optimized particle size and avoid of agglomerates and bulking.
The blend mixture prepared in step e) of present invention further processed for compression and/or encapsulating in capsules shell.
In yet another embodiment of the present invention, it provide to preparing pharmaceutical compositions for oral administration comprising a step of admixing the imatinib mesylate granulate with pharmaceutically acceptable excipients, optionally, comprising a step of compressing the composition into tablets, and optionally followed by a film-coating or directly encapsulating in desired capsule size.
The granulate composition according to the present invention may be use for direct compression for making the solid oral composition which may be further film coated. However, inventors of the present application have surprisingly found the advantages of admixing extragranular component more particularly a combination of disintegrant and lubricant. This extragranular component addition in granulate composition provides improved dissolution profile. Besides additional advantages in trouble from compression and subsequent coating process.
The pharmaceutical composition of imatinib mesylate according to present invention involves necessarily use of lubricant, wherein lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, vegetable oil, mineral oil.
Inventors of the present application additionally found the advantage of addition of lubricant as magnesium stearate which upon addition as extragranular component give the improved flow of granules in hopper while performing the compression or filling in capsule shells.
It has been observed by present inventors that various composition discussed in prior art suffer a disadvantage of either not meeting dissolution profile parameters or making coating process non-uniform and difficult which may results as blistering, chipping, picking, blushing, cracking (splitting) or the like.
The inventors of the present invention of pharmaceutical composition of imatinib mesylate gives the advantages over aforementioned difficulties while preparing for coating of pharmaceutical composition by admixing an optimized coating solution contains polymer, iron oxide, PEG and titanium di-oxide as opacifier.
Present invention, provides a process for making the pharmaceutical composition for oral administration comprising a step of admixing the imatinib mesylate granulate with pharmaceutically acceptable excipients, optionally, comprising a step of compressing the composition into tablets, followed by a non-aqueous film-coating, containing an organic solvent with an amount of less than about 5% v/v which was found capable to provide adequate coating with gloss surface appearance of solid oral composition.
The coating step according to the present invention is carried using commercially available ethylene glycol and or with other coating materials in combination for eg. polyethylene glycol and polymer as HPMC. The coating solution can be prepared with at least 90%v/v of C1-4 organic solvents like isopropanol, ethanol etc, and <10%v/v of water. The coating of core tablets can be carried out in conventional pan coating apparatus.
The preparation of coating material according to the present invention comprising prepare the liquid solution of PEG in aqueous at the temperature of 25-30° C. In further step it involves preparing titanium di oxide solution using IPA as solvent in colloidal mill at temperature of 25-30° C.
The inventors of present application utilized colloidal process, which gives an advantage of uniformity of solution before adding the cellulosic polymer material viz. HPMC.
In step of preparing coating solution add HPMC in aforementioned IPA solution and allowed to soak for 05-10 min. Inventors of present application also found that this process is necessary to overcome from any possible agglomerates formation. Coloring agent as iron oxide is added in the final step for preparing the coating solution which may be used for coating of oral solid composition.
The coating material prepare from aforementioned process spread through nozzles of pan coater at the rate of 2-5 rpm having the temperature not exceeding 40° C.
The term "oral solid composition" or "oral pharmaceutical composition" comprises capsule, tablet (film coated tablet, controlled release tablet, modified release tablet, delayed release etc.), micro tablet, powder, granule and pellets. Capsules used as oral dosage form can be soft or hard capsules, though oral dosage form of the present invention is tablet or capsule.
The term "about" is a value that can be considered ±5% of the given value.
Based on context of discussion, the term "% w/w" refers to the relative value to total weight of granules or to total weight of pharmaceutical composition and “% v/v” refer to volume by total volume percentage.
In one of embodiments, the application provides pharmaceutical dosage forms of imatinib mesylate having content uniformities (CU) from about 90% to about 110% by weight, with relative standard deviations (RSD) of not more than about 5%. In embodiments, the invention relates to pharmaceutical formulations having a disintegration time of less than about 15 minutes. In embodiments, the invention relates to pharmaceutical formulations having friability not more than about 1 % w/w.
Usage of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The term wt % refers to percent by weight. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those particular embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in best possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
Example 01: Tablet Composition of imatinib mesylate-

INGREDIENTS Quantity (mg/ tablet) %w/w
of coated tablet
Granulate for 400 mg/tab
Intragranular
Imatinib Mesylate
(equivalent to Imatinib) 478.00 91.92
Alginic acid 15.01 2.89
Granulating fluid
Ethyl cellulose 5.2 1.0
Isopropyl alcohol q.s -
Extragranular
Alginic Acid 5.25 1.01
Magnesium Stearate 1.10 0.21
Core tablet weight 504.6 97.03
Coating composition
HPMC E-15 10.94 2.1
PEG 4000 1.5 0.288
Titanium Dioxide (E171) 1.5 0.288
Iron oxide brown (E172) 1.5 0.288
Water/Organic q.s. q.s
Coated tablet weight 520.0 100.00

Manufacturing process of coated tablet composition using wet granulation:
1. Imatinib Mesylate and Alginic Acid are sifted through sieve #20.
2. Ethyl cellulose is dissolved in required quantity of lsopropyl alcohol.
3. Step -1 material is loaded into FBP and pre-mix step carried for 5 min and the granulating fluid of step-2 is sprayed onto the pre-mix material of FBP with proper fluidisation, and if required an additional amount of IPA is added.
4. The wet granules are dried at 30°C until desired LOD got achieved.
5. The dried granules are passed through sieve #20.
6. The dried granulate of Step 05 is taken for final blend preparation.
7. The weighed quantity of Alginic Acid and Magnesium stearate are sifted separately through sieve # 40 and sifted Alginic Acid is added to the step-6 material and blended for 5 min, followed with lubrication stage blending with sifted Magnesium stearate for 5 min.
8. The final blend of step-7 is compressed with appropriate oval shape standard concave punches for 400mg tablets respectively.
9. The Core tablets of step-7 are coated with organic or aqueous dispersion of coating material.
Tablets prepared of Examples 1 is packaged in closed HOPE 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 (paddle) apparatus, while stirred at 50 rpm for 30 minutes.
Table 01:
Time
(Minutes) Cumulative% of Drug Dissolved (Example 1)
Initial (T1) Condition (T1) Condition (T2) Condition (T3)
Avg. % RSD Avg. % RSD Avg. % RSD Avg. % RSD
05 28 4.9 29 4.3 28 4.2 28 4.1
10 55 3.3 54 2.5 59 3.3 57 2.3
15 71 3.1 72 3.6 71 3.4 69 3.5
20 89 2.7 88 3.4 85 1.4 86 2.9
30 99 1.8 101 2.0 99 1.2 99 1.9

Examples 02-06: Imatinib mesylate Film Coated Tablet prepare using Slugging:
INGREDIENTS Quantity (mg/ tablet)

Example 2 Example 3 Example 4 Example 5 Example 6
Intragranular Alginic acid 3.5% Alginic acid 3.0% Alginic acid 2.5% Alginic acid 2.0% Alginic acid 1.5%
Imatinib Mesylate
(equivalent to Imatinib) 478.00 478.00 478.00
478.00
478.00

Alginic acid 18.2 15.6 13.0
10.4 7.8
Granulating fluid
Ethyl cellulose
5.2 5.2 5.2 5.2 5.2
Isopropyl alcohol
q.s q.s q.s q.s q.s
Extragranular Alginic acid 0.4% Alginic acid 0.9% Alginic acid 1.4% Alginic acid 1.9% Alginic acid 2.4%
Alginic Acid 2.08 4.68 7.28
9.88 12.48
Magnesium Stearate 1.10 1.10 1.10 1.10 1.10
Core tablet weight 504.6 504.6 504.6 504.6 504.6
Coating composition
Up to 3%
HPMC E-15 10.94 10.94 10.94 10.94 10.94
PEG 4000 1.5 1.5 1.5 1.5 1.5
Titanium Dioxide (E171) 1.5 1.5 1.5 1.5 1.5
Iron oxide brown (E172) 1.5 1.5 1.5 1.5 1.5
Water/Organic q.s. q.s. q.s. q.s. q.s.
Coated tablet weight 520.0 520.0 520.0 520.0 520.0

Manufacturing process of film coated imatinib mesylate composition using slugging process:
1. Imatinib Mesylate, ethyl cellulose and alginic acid are sifted together through sieve #20.
2. Magnesium Stearate is sifted separately through sieve #40.
3. Step 1 & 2 material is blended in blender for 10 min.
4. Step 3 material is subjected to slugging on a compression machine using appropriate punches.
5. The slugs obtained in step 4 are milled with 1.5 mm screen.
6. The granules of step 5 are sifted through sieve # 20.
7. The granules and fines of step 6 material are separated by sifting the blend of step 6 through sieve# 60.
8. Repeat the steps 5, 6 & 7 till granules to fines ratio obtained are 75:25.
9. The blend of step 8 is charged into blender.
10. The weighed quantity of alginic acid is added to blend of step 9 and blended for 10 min.
11. Magnesium stearate is sifted through sieve # 40 and added to the step 10 and blended for lubrication for 5 min.
12. The final blend of step 11 is compressed with appropriate punch size.
13. The Core tablets of are coated with coating solution prepared form material as described in table using organic and or aqueous as solvent.
Examples 07: Imatinib mesylate Film Coated Tablet
Ingredients Quantity (mg/ tablet) Percentage
Imatinib Mesylate 478.00 88.85
Povidone k30 0.55 0.10
Isopropyl alcohol QS QS
Micro crystalline cellulose 40.20 7.47
Sodium Starch glycolate 11.00 2.04
Sodium Stearyl fumarate 2.75 0.51
Talc 5.50 1.02
Core weight 538.00 100.00
Coating formula
HPMC E-15 11.43 70.81
PEG 4000 1.57 9.72
Titanium dioxide (E171) 1.57 9.72
Iron oxide brown (E172) 1.57 9.72
Purified water/Organic solvent q.s q.s
Coated tablet weight 554.14 --

Manufacturing process of film coated imatinib mesylate composition in Example 07:
1. Imatinib Mesylate is sifted through #20 mesh.
2. Povidone k 30 is dissolved in required quantity of Isopropyl alcohol.
3. Imatinib is transferred into the RMG and add the binder solution slowly for 2-3 minutes with impeller slow speed 55 RPM.
4. Run RMG blade with 90-100 RPM for 2-3 minutes and chopper about 2000 RPM for 30 seconds.
5. Dried the granules prepared as step 4 initially by air dying and dried granules are milled through #8 mesh.
6. Dried the blend at temperature between 35°C-40°C, until achieves the LOD 1-2 %.
7. Final dried granules are milled or sifted through sieve number #20 and blended.
8. Micro crystalline cellulose and sodium starch glycolate are passed through #40 mesh and transfer the both into the octagonal blender and mix the blend for 20 minutes.
9. Sift the Sodium Stearyl fumarate and talc together through #60 mesh, add the sifted materials to the step 8 and lubricate.
10. The final blend of step 09 is compressed with appropriate punch size.
11. The core tablets are coated with coating solution prepared from material as described in example using organic or aqueous solvent.
Dissolution testing results of tablets of Examples 02-07 are shown in Table 02
Table 02:
Dissolution in 0.1 N HCl phosphate buffer, 1000 ml, Paddle II 50 rpm
Time
(Minutes) Cumulative% of Drug Dissolved
02 03 04 05 06
Avg. % RSD Avg. % RSD Avg. % RSD Avg. % RSD Avg. % RSD
05 49 12.8 32 5.2 31 9.2 58 8.1 49 11
10 87 4.9 57 4.2 79 6.1 87 2.3 80 1.6
15 92 1.1 81 2.2 88 3.4 91 3.5 92 2.1
20 93 1.6 94 1.1 93 1.1 93 2.9 94 1.1
30 96 2.7 98 1.1 94 1.2 95 1.9 95 1.4

The abovementioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.
,CLAIMS:1. A pharmaceutical composition of imatinib mesylate comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2% w/w of binder and 1-6% w/w of disintegrant, wherein binder is selected from ethylcellulose and disintegrant is alginic acid.
2. A pharmaceutical composition of imatinib mesylate according to claim 1, comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2% w/w of binder and 1-6% w/w of disintegrant, wherein the granulate composition is prepared using binder in isopropyl alcohol solvent.
3. A pharmaceutical composition of imatinib mesylate comprising 86.0-96.0 %w/w of imatinib mesylate, 0.05-0.2% w/w of binder and 1-6% w/w of disintegrant, wherein binder is selected from povidone and disintegrant is sodium starch glycolate.
4. A process for preparing the pharmaceutical composition according to the claim 3 wherein solid oral composition is tablet or capsule.
5. A process of preparing pharmaceutical composition of imatinib mesylate wherein the process comprising the steps of:
a) sifting Imatinib mesylate and disintegrant followed by premixing for 5-15 min.
b) preparing binding solution using binder in isopropyl alcohol.
c) performing granulation using premixed material of step a) and step b) solution.
d) drying and sifting the granules.
e) adding extragranular composition comprising pharmaceutical acceptable excipients, followed by blending.
6. A process for preparing the pharmaceutical composition according to the claim 5 where step e) of adding extragranular composition comprising pharmaceutical acceptable excipients selected from a combination of alginic acid or sodium starch glycolate and magnesium stearate or magnesium stearate alone.
7. A process for preparing the pharmaceutical composition according to the claim 6, where the ratio of alginic acid or sodium starch glycolate and magnesium stearate is 1-5:1.
8. A process of preparing pharmaceutical composition according to claim 7, wherein the coating materials are used not exceeding 3% of the overall weight of composition.
9. A process of preparing pharmaceutical composition according to claim 8, wherein the coating materials comprising of HPMC, PEG 4000, titanium dioxide and iron oxide.