WO2006040779A2

WO2006040779A2 - Controlled release gastric floating matrix formulation containing imatinib

Info

Publication number: WO2006040779A2
Application number: PCT/IN2005/000333
Authority: WO
Inventors: Durga Maheswari Parvataneni; Appala Swamy Naidu Rongala; Khadgapathi Podile; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2004-10-11
Filing date: 2005-10-06
Publication date: 2006-04-20
Also published as: WO2006040779A3

Abstract

A pharmaceutical formulation and its process for the preparation of controlled release gastric floating matrix solid oral dosage form of Imatinib or its pharmaceutically acceptable salts and its polymorphs such as β, α2, Form I and Form 2 thereof for once daily administration in the form of coated tablet or minitablets and / or pellets filled in hard gelatin capsules.

Description

CONTROLLED RELEASE GASTRIC FLOATING MATRIX FORMULATION CONTAINING IMATINIB

INTRODUCTION

The present invention relates to formulation and its process for the preparation of controlled release gastric floating matrix pharmaceutical formulation for once daily administration containing Imatinib or its pharmaceutically acceptable salts, and its polymorphs such as β, α2, Form 1& Form 2 thereof.

\0 Imatinib mesylate is designated chemically as 4-[(4-Methyl-l-piperazinyl) methyl] -N- [4- methyl-3- [[4-(3-pyridinyl)-2-pyrimidmyl] amino] -phenyl] benzamide methanesulfonate and its structural formula is

Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline to

15 amorphous powder. Its molecular formula is C2₉H₃iN₇O*CH₄Sθ₃ and its relative molecular mass is 589.7. Imatinib mesylate is very soluble in water and soluble in aqueous buffer < pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol and ethanol, but is insoluble in n-octanol,

20 acetone and acetonitrile. BACKGROUND AND PRIOR ART OF THE INVENTION:

Imatinib mesylate is a protein-tyrosine kinase inhibitor; it inhibits the abnormally functioning Bcr-Abl tyrosine kinase, which is produced by the Philadelphia chromosome abnormality found in chronic myeloid leukemia (CML). Imatinib inhibits cell proliferation and induces apoptosis (programmed cell death) in the Bcr-Abl cell lines and in the leukemic cells generated by CML. Imatinib also inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation. More recently, the drug has been approved for the treatment of mesenchymal cell neoplasms of the intestinal tract.

It has now been discovered that Imatinib mesylate can be used as a treatment for patients suffering from hepatic fibrosis based on its ability to down regulate stellate cell activation in culture and in vivo.

Imatinib is well absorbed after oral administration with C_max achieved within 2-4 hours post-dose. It was also reported that mean absolute bioavailability from capsule formulation is 98%. Biotransformation of Imatinib is via hepatic metabolism and cytochrome P450 enzymes (especially CYP3A4). Imatinib is converted to its main circulating active metabolite, a N-demethylated piperazine derivative. This derivative, in vitro, has potency similar to Imatinib and comprises about 15% of the AUC ("area under the curve") for Imatinib.

When imatinib is orally administered, the elimination half-lives of Imatinib and its major active metabolite, the N-desmethyl derivative, are approximately 18 and 40 hours, respectively and the time to reach peak concentration is 2 to 4 hours.

Imatinib mesylate is presently administered in compressed tablet form of lOOmg and 400mg and hard gelatin capsule form of 100 mg of Imatinib.

The approved dosage range for imatinib in the treatment of CML is 400 mg to 800 mg (400 mg twice a day) and 600 mg per day for gastrointestinal stromal tumors (GIST). It was reported that amounts of imatinib mesylate effective to treat hepatic fibrosis would broadly range between about 50 mg and about 600 mg per day and preferably between about 50 mg and about 200 mg per day administered orally. The usual oral recommended dose of Imatinib for humans is between 50 and about 1600 mg/day, in two or four doses.

Prior art

EP 0564409 patent discloses the preparation of [(4-(4-memylpiperazin-l-ylmethyl)-N-4- [methyl-3-(4-pyridin-3-yl) pyrimidin-2-yl amino)phenyl]benzarnide (Imatinib) and the use thereof especially as an antitumor agent

US patent no 5521184 disclosed 'Pyrimidine derivatives and process for the preparation thereof ' and in equivalent applications in other countries. The above patent provides method of preparation of formulation of conventional tablets comprising active ingredient, wheat starch, lactose, and colloidal silicic acid, talc and magnesium stearate.

WO 99 / 03854, WO 02/22597 and related Australian patent no. 740713 or US 20020115858 or EP 0998473 titled 'Crystal modification of a N-phenyl-2- pyrimidineamine derivative, processes for its manufacture and its use' discloses a process for the preparation of β -crystal form of 4-(4-methylpiperazm-l-ylmethyl) - N- (4-methyl - 3- (4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl] -benzamide methanesulfonate, and one of the examples specifies process for manufacture of conventional tablets containing 100 mg of the active substance, crystalline lactose and avicel, PVPPXL, aerosil, and magnesium stearate. Also one of the examples specifies preparation of hard gelatin capsules with lOOmg of the above compound as active ingredient, avicel, PVPPXL, aerosil, magnesium stearate.

The US Patent application 20050143389 disclosed a method of treating of hepatic fibrosis with imatinib mesylate. In the above patents, the formulations provide rapid dissolution of the active ingredient that results in a rapid increase in blood plasma levels of the active compound above the therapeutic steady state levels, immediately after administration followed by approaching a decrease in blood plasma levels upto subtherapeutic plasma levels after about twelve hours following oral administration, thus requiring additional dosing with the drug in accelerated or blast crisis phase of CML.

Also, with the above conventional formulations of the prior arts, the pharmacokinetics of imatinib shows a large inter-patient variability (coefficient of variation 66 and 51%, respectively for C_max and AUC), which might, for a part, be attributable to variations in gastrointestinal absorption and metabolism.

Imatinib therapy in CML is referred as a targetted therapy, but the disease progression warrants dosage escalation which leads to dose-related side effects such as myelosuppresion, nausea, edema, fatigue, head aches, muscle cramps, arthralgias, myalgias, diarrhea, and skin rashes with conventional dosage forms of the above patents during treatment over a longer period.

As Imatinib mesylate is very slightly soluble to insoluble in neutral/alkaline region of intestine where its absorption is maximum, it is not absorbed to the same extent once it passes the upper small intestine especially with the conventional dosage forms described above. Imatinib must be continuously released in the stomach before it reaches the absorption window, thus ensuring optimal bioavailability.

Hence, there is a need to develop a new formulation and its process for imatinib that maintains 24 hour optimum therapeutic steady state plasma concentrations to avoid inter- patient variability and side effects by maintaining dosage form for 12 hours in the gastric region by designing controlled release gastric floating drug delivery system, and therefore, research efforts have been focused on development of gastric retention platforms. Various systems can be used as platforms to retain the dosage form in the stomach as a way of increasing the retention time. These systems include introducing floating dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying drugs.

Among these, the floating dosage forms have been used most commonly since floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time.

Gastric floating systems would provide the best results for drugs that are poorly soluble in alkaline pH and absorbed rapidly from the proximal small intestine.

Due to low solubility in intestine and fast GI transit, drug released in the stomach will be available below its saturation solubility at the absorption site i.e. intestine and hence gastric retention is suitable.

Since imatinib is insoluble in neutral/alkaline aqueous buffers but absorbed in the intestine, it is required to make the drug soluble before entering into the intestine where the drug gets absorbed. Hence there is a requirement to develop imatinib gastric floating matrix formulations for consistent and uniform blood levels of medication over an extended period of time.

None of the above said prior arts discloses and / or envisages a continuous and uniform controlled release of drug in gastric region, hence the above drawback was considered in our invention.

Since Imatinib is having all the above favorable features suitable to formulate controlled release gastric floating matrix formulations, the work on present invention was taken up. The present invention, relates to design and development of 'controlled release gastric floating matrix formulation containing Imatinib and a process for its preparation', indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase, accelerated phase and blast crisis and GIST

Objectives of the Invention:

Accordingly, the main objective of the present invention is to design and develop controlled release gastric floating matrix tablet dosage form containing Imatinib or its pharmaceutically acceptable salts, and its polymorphs such as β, oc2, Form 1& Form 2, thereof for once daily administration for the treatment of CML, GIST and other diseases.

Another objective of this invention is to retain the drug in the stomach for prolonged duration and to achieve therapeutic levels over a period of 24 hours by floating technology.

A further objective of the invention is to provide controlled release gastric floating matrix formulation containing hydroxypropylmethylcellulose KlOOM, hydroxypropyl methyl - cellulose K4M and sodium bicarbonate that reacts with acid present in the stomach and generates gas allowing the dosage form to float for a period of 12 hours.

Yet another objective of the present invention is to reduce the fluctuations in blood plasma concentration by reducing the number of doses and enhancing patient compliance.

Still another objective of the present invention is to reduce the risk of toxicity both in liver and other organs due to higher concentration of drug in the liver that can be avoided by controlling the release of drug in the stomach. More especially, the present invention is to develop a controlled release gastric floating matrix formulation with a simple and cost effective manufacturing process for the design of a hydrodynamically balanced formulation containing a gel forming hydrophilic polymers that provides a floating property to the dosage form with lower density and achieve controlled release floating matrix formulation.

Yet another objective of the present invention is to provide controlled release gastric floating matrix tablet formulation, prepared by wet and/or dry granulation processes and direct compression.

Yet another objective of the present invention is to provide controlled release gastric floating matrix minitablets prepared by wet and/or dry granulation processes and filled into capsules of suitable size.

Statement of Invention: -

Accordingly, the present invention provides a pharmaceutical oral once daily controlled release gastric floating matrix formulation containing Imatinib or its polymorphs such as β, α2, form 1, form 2 and a process for its preparation to retain the dosage form in the stomach for prolonged duration and to achieve steady state therapeutic levels over a period of 24 hours and reduces the risk of toxicity both in liver and other organs.

Detailed description of the invention:

The present invention has been developed based on our finding that when tablets made with hydroxypropyl methylcellulose, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline cellulose, talc, magnesium stearate and other conventional excipients along with imatinib, and studied dissolution profile in 0.1N HCl, the tablet was found to be floating more than 12 hours and providing the drug release at a controlled level such that when administered orally, the drug will be available at site of absorption i.e., proximal portion of the intestine below its saturation level. Sodium bicarbonate induced carbon dioxide generation in the presence of dissolution medium (0.1N HCl) is trapped and protected within the gel, formed by hydration of polymer, thus decreasing the density of the tablet. As the density of the tablet falls below 1, the tablet becomes buoyant.

The composition of the present invention in the dosage form comprises of a solid stable controlled release pharmaceutical formulation and its process provide imatinib in the form of floating tablets and/or minitablets in capsules which release imatinib in the stomach for a period of 12 hours for maintaining constant therapeutic plasma levels for 24 hours useful for the treatment of CML, GIST, and live fibrosis comprises: The core tablet contains i) A therapeutically effective pharmaceutical ingredient, Imatinib or its pharmaceutically acceptable salts, and its polymorph such as β, α2, form 1, form 2, and thereof. ii) A gas generating alkaline material such as sodium bicarbonate and the like iii) Hydroxypropylmethylcellulose K4M and Hydroxypropylmethylcellulose KlOOM as gelling polymers in a preferred matrix tablet. iv) Higher viscosity grades of cellulose ethers as tablet binders at various concentrations. v) A coating on the core tablet with a film coating layer comprising a mixture of a polymer, plastisizer and other processing agents that were removed during coating operation. vi) Gastric floating matrix tablets prepared by direct compression method, vii) Gastric floating matrix tablets prepared by wet granulation method, viii) Gastric floating matrix tablets and/or minitablets prepared by hot-melt granulation ix) Gastric floating matrix mini tablets prepared by direct compression or by wet granulation method and 2 to 10 smaller tablets filled into hard gelatin capsules, x) Encapsulated pellets made by extrusion and spheronization or by fluid bed coating.

The pharmaceutical composition and process of the present invention comprises hydrophilic non-erosion gelling amount in the range of about 1% to about 80 % and preferably about 5% to about 60%, of the total weight of the composition. According to one preferred embodiment of the composition according to the invention, the hydroxypropylmethylcellulose is having viscosity ranging from 3cps to 120,000 cps and preferably from 4,000cρs to 100,000 cps.

The pharmaceutical composition of the present invention comprises gelling agents in the core tablet may be selected from other excipients such as methylcellulose, ethylcelmlose, hydroxyethylcellulose, hydroxypropylcellulose, acrylic acid or acrylic acid derivatives, or a combination thereof. The hydrogel-forming polymer may be a blend of polymers (for example, a blend of polycarbophil and Eudragit.RTM. RL- 100), sodium alginate and other salts of alginic acid, carrageenan, agar, agarose, guar gum, konjac gum, locust bean gum, gum arabic, xanthan gum, karaya. TM, tragacanth, microcrystalline cellulose, starch, dextran, calcium pectinate, polyvinyl acetate, carbopol 934P, carboxylmethylcellulose, sodium carboxylmethylcellulose, polyethyleneoxide, polycarbonates and the like, as well as modified natural products such as certain water- swellable cellulose derivatives and synthetic products such as polyacrylic acid and the like may be used.

The pharmaceutical composition of the present invention comprises sodium bicarbonate, which is employed individually, or in combination of with acids such as citric acid as a gas-generating component in the controlled release gastric floating matrix tablets when in contact with water or gastric fluid. The gas, which forms, is incorporated into the hydrated gel layer and thus contributes to the buoyancy of the tablet. The amount of gas- generating component used is preferably about 0.5 % to about 20 % and more preferably about 1% to about 10%, of the total weight of the composition.

Optionally other gas generating component such as and potassium bicarbonate, tartaric acid and mixtures thereof may be used.

The pharmaceutical composition of the present invention comprises polyvinylpyrrolidone (a synthetic polymer consisting essentially of linear 1- vinyl-2-pyrrolidinone groups), as binder. The molecular weight of povidone is in the range of about 2,500 daltons to about 3,000,000 dalton, preferably about 50,000 daltons to about 1,000,000 dalton. The amount of binder used in the present invention is in the range of about 0.75% to about 25%, and preferably about 1% to about 20%, of the total weight of the composition.

The pharmaceutical composition of the present invention may also contain other conventional pharmaceutical excipients such as diluents, processing agents, disintegrants, lubricants, anti adherents and the like thereof.

The pharmaceutical compositions of the present invention comprise, Eudragit E, (a gastric soluble cationic polymer based on diemethylaminoethyl methacrylate and other neutral methacrylic acid esters) as a protective coating material as a thin layer for controlled release gastric floating matrix tablets. The present pharmaceutical compositions comprise the coating polymer in the range of from 0.1% to about 25%, and preferably from 0.75% to about 10%, of the total weight of the composition.

Optionally the other protective coating material may be selected from, hyrpomellose, hydroxypropylcellulose, hydroxypropylethylcellulose, ethyl cellulose, hydroxyethyl cellulose, methylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl acetate (Kollidon SR) polyvinyl alcohol, carbopol 934P, Lustreclear LC 103, polymethacrylates like Eudragit NE 30D, Eudragit RS, Eudragit RL, Eudragit RD, Eudragit E PO, Eudragit L, cellulose acetate butyrate, cellulose acetate, or other pharmaceutically acceptable polymers.

The pharmaceutical composition of the present invention may also contain other conventional pharmaceutical excipients such as organoleptic materials, plasticizers, colouring agents and the like thereof.

The controlled release gastric floating matrix formulation of the present invention containing Imatinib mesylate and other polymorphs of Imatinib mesylate as beta or alpha crystal or delta or epsilon or α2, Form 1 & Form 2 equivalent to 50mg, lOOmg, 200mg, 400mg, 600mg and 800mg of Imatinib, may be prepared with the above mentioned excipients using different proportions.

The controlled release floating formulation of the present invention optionally comprises imatinib mesylate in an encapsulated pellets made by extrusion and spheronization technique.

Optionally, higher doses of drug may be loaded on uniform, spherical non-pareil seeds for making capsules containing pellets by using fluid bed processor.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

The details of the process of the invention are provided in the Examples given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. The preparation of controlled release gastric floating matrix formulation containing Imatinib tablets that can be administered by the oral route is carried out according to the following process:

EXAMPLE 1

Composition of one tablet

TABLE 1

* Equivalent to 200mg Imatinib as freebase.

Imatinib mesylate was mixed with hydroxypropyl methylcellulose K4M (available from Dow chemicals), hydroxypropyl methylcellulose KlOOM (Methocel KlOOM available from Colourcon), microcrystalline cellulose and sodium bicarbonate for five minutes. The mixture was sifted through 60# S. S sieve and then blended in a mixing bowl of Kalweka apparatus for 5 minutes.

Binding solution was prepared by dissolving polyvinylpyrrolidone (K-30) in isopropyl alcohol under stirring for a period of 10 minutes.

The dry powder mixture was wet granulated with the above binding solution using Kalweka apparatus. The wet mass was passed through 12# S.S sieve and the granules were air dried initially and dried finally in a laboratory oven at 50 to 55°C for 45 minutes to reduce the moisture content to between 0.5 and 5.0% w/w and the dried granules were sifted through 18# S.S sieve.

The dried granules were lubricated with magnesium stearate (previously sifted through 60# S.S sieve) by blending for 2 minutes in a double cone blender. The lubricated granules were compressed using 16.5 mm x 8 mm, oblong punches, on a 16 stationary compression machine (Cadmach), at a tablet core weight of 420 mg. The above granules were also compressed using 18 mm x 9 mm, oblong punches at a tablet core weight of 840 mg to get Imatinib 400mg.

Coating: Eudragit ElOO (available from Degussa), is dissolved while stirring in a mixture of isopropyl alcohol and acetone in the ratio of 6:4 and then added homogenized suspension of triethyl citrate, titanium dioxide, ferric oxide red, ferric oxide yellow and talc (materials previously sieved through 200 mesh) in isopropyl alcohol. Prepared suspension was sprayed on to the cores employing conventional coating equipment till achieving film coating weight gain of about 1.85% w/w.

The release rate of Imatinib from floating tablets was determined using dissolution testing apparatus 2 (paddle method). The dissolution test was performed using 900 ml of 0.1N HCl, at 37 ± 0.5°C and 50 rpm. A sample of the solution was withdrawn from the dissolution apparatus hourly for 12 hours and at each time the sample withdrawn was replaced with fresh dissolution medium. The samples were filtered through a 0.45-μ- membrane filter and diluted to a suitable concentration with 0.1N HCl. Absorbance of these solutions was measured at 240nm using a Shimadzu UV-2201 UV/Visible spectrophotometer.

Table 2: Dissolution time vs. percentage of released Imatinib.

EXAMPLE 2

Controlled release gastric floating matrix tablets with a core weight of 350mg containing Imatinib 200mg and with a core weight of 700mg containing Imatinib 400mg were prepared according to the procedure given in Example 1, using hydroxypropyl methylcellulose KlOOM as the gelling agent, in the following formulation:

Composition of one tablet

TABLE 3

* Equivalent to 200mg Imatinib as freebase.

Coating: Eudragit ElOO is dissolved while stirring in a mixture of isopropyl alcohol and acetone in the ratio of 6:4 and then added homogenized suspension of triacetin, titanium dioxide and talc (materials previously sieved through 200 mesh) in isopropyl alcohol. Prepared suspension was sprayed on to cores employing conventional coating equipment till achieving film coating weight gain of about 2.14% w/w. Table 4: Dissolution time vs. percentage of released Imatinib

EXAMPLE 3

Controlled release gastric floating matrix tablets with a core weight of 370mg containing Imatinib 200mg and with a core weight of 740mg containing Imatinib 400mg were prepared according to the procedure given in Example 1, using hydroxypropyl methylcellulose K4M as the gelling agent, in the following formulation:

Composition of one tablet

TABLE 5

* Equivalent to 200mg Imatinib as free base.

Coating: Eudragit ElOO is dissolved while stirring in a mixture of isopropyl alcohol and acetone in the ratio of 6:4 and then added homogenized suspension of microcrystalline cellulose, and magnesium stearate (materials previously sieved through 200 mesh) in isopropyl alcohol. Prepared suspension was sprayed on to cores employing conventional coating equipment till achieving film coating weight gain of about 2.03% w/w.

Table 6: Dissolution time vs. percentage of released Imatinib

EXAMPLE 4

Controlled release gastric floating matrix tablets with a core weight of 350mg containing Imatinib 200mg and with a core weight of 700mg containing Imatinib 400mg were prepared according to the procedure given in Example 1, using hydroxypropyl methylcellulose KlOOM as the gelling agent.

Citric acid anhydrous was passed through 100# S. S sieve and added prior to the addition of purified talc and magnesium stearate during lubrication stage in the following formulation:

Composition of one tablet

TABLE 7

* Equivalent to 200mg Imatinib as free base. Coating: Eudragit ElOO is dissolved while stirring in a mixture of isopropyl alcohol and acetone in the ratio of 6:4. Prepared solution was sprayed on to cores employing conventional coating equipment till achieving film coating weight gain of about 1.43% w/w.

Table 8: Dissolution time vs. percentage of released Imatinib

EXAMPLE 5

Controlled release gastric floating matrix tablets with a core weight of 380mg containing Imatinib 200mg and with a core weight of 760mg containing Imatinib 400mg were prepared according to the procedure given in Example 4, using hydroxypropyl methylcellulose K4M as the gelling agent.

Composition of one tablet

TABLE 9

* Equivalent to 200mg Imatinib as free base.

Coating: Eudragit ElOO is dissolved while stirring in a mixture of isopropyl alcohol and acetone in the ratio of 6:4 and then added homogenized suspension of triacetin, titanium dioxide, ferric oxide red and talc (materials previously sieved through 200 mesh) in isopropyl alcohol. Prepared suspension was sprayed on to cores employing conventional coating equipment till achieving film coating weight gain of about 1.92% w/w. Table 10: Dissolution time vs. percentage of released Imatinib

EXAMPLE 6

Controlled release gastric floating matrix tablets with a core weight of 768mg (punch size: 18 mm x 9 mm) containing Imatinib 400mg and with a core weight of 1152mg (19 mm x 9 mm) containing Imatinib 600mg were prepared according to the procedure given in Example I₅ using hydroxypropyl methylcellulose K4M and hydroxypropyl methylcellulose KlOOM as gelling agents, in the following formulation:

Composition of one tablet

TABLE 11

* Equivalent to 400mg Imatinib as free base.

Coating: Hydroxypropyl methylcellulose E5 is dissolved while stirring in a mixture of purified water and isopropyl alcohol and then added homogenized suspension of polyethylene glycol 6000, titanium dioxide, ferric oxide red, ferric oxide yellow and talc (materials previously sieved through 200 mesh) in purified water. Prepared suspension was sprayed on to cores employing conventional coating equipment till achieving film coating weight gain of about 2.03%^* w/w.

Table 12: Dissolution time vs. percentage of released Imatinib

EXAMPLE 7

Controlled release gastric floating matrix tablets with a core weight of 680mg containing Imatinib 400mg were prepared according to the procedure given in Example I₅ using hydroxypropyl methylcellulose K4M as the gelling agent and purified water as granulating agent in the following formulation:

Composition of one tablet

TABLE 13

* Equivalent to 400mg Imatinib as free base.

Coating: Hydroxypropyl methylcellulose E5 is dissolved while stirring in purified water and then added homogenized suspension of polyethylene glycol 6000, titanium dioxide and talc (materials previously sieved through 200 mesh) in purified water. Prepared suspension was sprayed on to cores employing conventional coating equipment till achieving film coating weight gain of about 2.21% w/w.

Table 14: Dissolution time vs. percentage of released Imatinib

The controlled release gastric floating matrix formulation of examples 1 to 7 were also compressed into mini-tablets by using 2mm, round shallow concave multi-tip punctures. 2 to 10 smaller mini tablets of Imatinib mesylate equvalent to imatinib 200mg, 400mg, and 600mg were filled into hard gelatin capsules of suitable size.

Advantages of the Present Invention:

1. Patient compliance can be improved by reducing frequency of once daily.

2. Risk of toxicity both in liver and other organs due to higher concentration of drug in the liver can be avoided by controlling the release of drug in the stomach.

3. Improve efficiency in treatment and reduce fluctuation in blood levels.

Claims

We Claim

1. A once daily formulation useful for oral administration in humans for the controlled release of imatinib comprising of pharmaceutically effective amount of imatinib mesylate and its pharmaceutical acceptable salts and its polymorphs such as β, α2, Form 1 and Form 2, hydroxy propyl methyl cellulose of different viscosity grades as water soluble gel polymer, sodium bicarbonate and citric acid as gas generating components and Polyvinyl pyrrolidine K30 as binder in a preferred matrix tablet/ mini tablets / pellets coated with film coating layer consisting of Eurdagit E lOO polymer.

2. A formulation as claimed in claim 1 wherein the composition is in the form of tablet / mini tablets prepared by direct compression or by wet granulation or hot melt granulation method and 2 to 10 smaller tablets filled into hard gelatin capsules.

3. A formulation as claimed in claim 1 wherein the composition is encapsulated pellets filled in hard gelatin capsules.

4. A formulation claimed in claim 1 to 3 wherein the active pharmaceutical agent used is selected from pharmaceutically acceptable Imatinib or its pharmaceutically acceptable salts, and its polymorph such as β, α2, Form 1, Form 2 wherein the amount used is in the range of 10% to about 80%, and more preferably about 15% to about 60%, of the total weight of the composition.

5. A formulation as claimed in claims 1 to 4 wherein hydrophilic gelling agent used is hydroxy propyl methyl cellulose K 100 M or hydroxy propyl methyl cellulose K4M alone or in combination, present in the range of about 1% to about 80 % and preferably about 5% to about 60%, of the total weight of the composition.

6. A formulation as claimed in claims 1 to 5 wherein the various grades of hydroxypropylmethylcellulose used in the formulation is having viscosity ranging from 3cps to 12O₅OOO cps and preferably from 4,000cρs to 100,000 cps.

7. A formulation as claimed in claims 1 to 6 wherein the gas-generating component used comprises sodium bicarbonate, which is employed individually, or in combination of with acids such as citric acid wherein the amount used is in the range of 0.5 % to about 20 % and more preferably about 1% to 10%, of the total weight of the composition.

8. A formulation as claimed in claim 1 to 7 wherein optionally the other gas- generating component such as potassium bicarbonate, tartaric acid and mixtures thereof may also be used.

9. A formulation as claimed in claims 1 to 8 wherein the binder used in the formulation comprises polyvinylpyrrolidone of molecular weight 2,500 daltons to 3,000,000 dalton, in the range of 0.75% to 25%, and preferably 1% to 20%, of the total weight of the composition.

10. A formulation once daily dosage form as claimed in claims 1 to 9 for oral administration in humans for the controlled release of Imatinib and its pharmaceutical acceptable salts and its polymorphs such as β, α2, Form 1 and Form 2 in the stomach containing hydroxypropylmethyl cellulose of different viscosity grades, sodiumbicarbonate, citric acid, Polyvinylpyrrolidine K30, and optionally other pharmaceucial excipients such as microcrystalline cellulose, purified talc, magnesium stearate, lactose, starch, and the like.

11. A formulation as claimed in claims 1 to 10 wherein the protective coating material as a thin layer used in the formulation comprising of Eudragit ElOO wherein the amount is in the range of 0.1% to 25%, and preferably from 0.75% to 10%, of the total weight of the composition, and optionally contains other conventional, plasticizers, colorants and the like.

12. A formulation as claimed in claims 1 to 11 wherein the dosage form containing Imatinib mesylate and other polymorphs such as β, α2, Form 1 & Form 2 equivalent to 50mg, lOOmg, 200mg, 400mg, 600mg and 800 mg of Imatinib

13. A formulation as claimed in the claims 1 to 12 wherein the controlled release floating formulation of imatinib mesylate in an encapsulated pellet made by extrusion and spheronization or by fluid bed coating techniques.

14. The formulation as claimed in claims 1 to 13 in the form of a tablet or mini- tablets or pellets in hard gelatin capsules.