DESC:FIELD OF THE INVENTION

The present invention relates to extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours. Further, the present invention discloses process for the preparation of the said tablets.

BACKGROUND OF THE INVENTION

Capecitabine is a fluoropyrimidine carbamate having antineoplastic activity. It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to fluorouracil. Molecular formula of Capecitabine is C15H22FN3O6 and the molecular weight is 359.35 and has following chemical structure:

(Capecitabine)

US4966891 and US5472949 discloses Fluorocytidine derivatives and N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds respectively which cover Capecitabine and methods of using same. Capecitabine is marketed as immediate release tablet comprising 150 or 500 mg Capecitabine for oral administration under trade name XELODA® by Roche. The inactive ingredients in XELODA® include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. Capecitabine is indicated for colon cancer, metastatic colorectal cancer and metastatic breast cancer as monotherapy or combination therapy.
Recommended standard starting dose of Capecitabine is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles. In combination with docetaxel, the recommended dose of Capecitabine is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Capecitabine Tablets should be swallowed with water within 30 minutes after the end of a meal.

Currently available immediate release (IR) composition of Capecitabine has Tmax of approximately 1.5 hours and T1/2 of 0.75 hours. Further the available composition does not maintain constant plasma concentration i.e difficult to achieve steady state concentration.

After administration of currently available IR composition of Capecitabine, the plasma concentration of a Capecitabine reaches below minimum effective concentration after approximately 6 hours, which result in no therapeutic effect between 6 to 12 hours after administration of the dose (figure 1).

Capecitabine has high therapeutic value for the treatment of cancer. IR tablet of Capecitabine may lead to severe gastrointestinal side effects. Till date, several approaches are reported to overcome the problem associated with IR composition.

WO2013030602 discloses extended release pharmaceutical composition for oral administration comprising substantially amorphous Capecitabine or an analog thereof and optionally extended release component, wherein the extended release component is present in an amount of less than 200% w/w, relative to the total weight of the Capecitabine or analog thereof.

WO2006110800 discloses a multiparticulate modified release composition comprising Capecitabine, wherein, following oral delivery, the composition delivers Capecitabine in a pulsatile manner.

US20070122481 discloses a multiparticulate modified release composition comprising a Capecitabine, wherein, following oral delivery, the composition delivers the Capecitabine in a pulsatile manner.

However, still there is need to develop Capecitabine composition which overcomes problems associated with currently available IR tablet, and releases the drug from the composition up to at least 12 hours after administration, which in-turn shall provide and maintain effective plasma concentration of Capecitabine approximately for 12 hours.

OBJECT OF THE INVENTION

It is therefore, object of the invention is to provide extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

Another object of the present invention is to provide process for the preparation of extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

Another object of the present invention is to provide extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and not less than (NLT) 85% of the total amount of Capecitabine released after 12 hours.

Another object of the present invention is to provide process for the preparation of the extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and not less than (NLT) 85% of the total amount of Capecitabine released after 12 hours.

Another object of the present invention is to provide extended release tablets comprising Capecitabine, wherein the release is controlled by modified release matrix material.

Another object of the present invention is to provide extended release tablets comprising Capecitabine, wherein the release is controlled by modified release coating material.

Another object of the present invention is to provide extended release tablets comprising Capecitabine, wherein the release is controlled by modified release coating on multi-particulates comprising Capecitabine.

Another object of the present invention is to provide extended release tablets comprising Capecitabine suitable for twice daily dosage regime, wherein dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

Another object of the present invention is to provide extended release tablets comprising Capecitabine which would release the drug from the said tablets up to at least 12 hours after administration.

Another object of the present invention is to provide extended release tablets comprising Capecitabine, which shall provide and maintain effective plasma concentration of Capecitabine approximately for 12 hours after administration.

Another object of the present invention is to provide extended release tablets comprising Capecitabine wherein the tablets comprises Capecitabine ranging from 150 to 750 mg, wherein dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

Another object of the present invention is to provide extended release tablets comprising a) Capecitabine in an amount of 55 to 80 % w/w of the total weight of the tablet b) diluent in an amount of 1 to 15 % w/w of the total weight of the tablet c) modified release matrix material in an amount of 5 to 40 % w/w of the total weight of the tablet d) binder in an amount of 2 to 4 % w/w of the total weight of the tablet e) lubricant in an amount of 0.5 to 2 % w/w of the total weight of the tablet.

Another object of the present invention is to provide extended release tablets comprising Capecitabine, wherein the release is controlled by modified release matrix material or modified release coating material or modified release coating on multi-particulates which would release the drug from the said tablets up to 24 hours after administration.

SUMMARY OF THE INVENTION

Present invention provides extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours. Further the present invention provides extended release tablets comprising Capecitabine, wherein the release from the tablets is controlled by modified release matrix material, modified release coating material or modified release coating on multi-particulates. Further the present invention provides extended release tablets comprising Capecitabine suitable for twice daily dosage regime which releases the drug from the said tablets up to at least 12 hours after administration. Further the present invention provides extended release tablets comprising Capecitabine ranging from 150 to 750 mg.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows plasma conc. of Capecitabine immediate release tablet.
Figure 2 shows dissolution profile of Capecitabine extended release tablets 500 mg prepared according to example 2.
Figure 3 shows dissolution profile of Capecitabine extended release tablets 150 mg prepared according to example 3.
Figure 4 shows dissolution profile of Capecitabine extended release tablets 500 mg prepared according to example 5.
Figure 5 shows dissolution profile of Capecitabine extended release tablets 500 mg prepared according to example 7.

DETAILED DESCRIPTION OF THE INVENTION

Present invention provides extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

In another embodiment, the present invention provides process for the preparation of extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and NLT 85% of the total amount of Capecitabine is released after 12 hours.

In another embodiment, the present invention provides process for the preparation of the extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and NLT 85% of the total amount of Capecitabine is released after 12 hours.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine which would release the drug from the said tablets up to at least 12 hours after administration.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine suitable for twice daily administration which shall provide and maintain effective plasma concentration of Capecitabine approximately for 12 hours after administration.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the said tablets is extended up to at least 12 hours, wherein the release is controlled by modified release matrix material or modified release coating material or modified release coating on multi-particulates and process for preparation thereof.

In another embodiment, the present invention provides extended release tablets comprising a) Capecitabine in an amount of 55 to 80 % w/w of the total weight of the tablet b) diluent in an amount of 1 to 15 % w/w of the total weight of the tablet c) modified release matrix material in an amount of 5 to 40 % w/w of the total weight of the tablet d) binder in an amount of 2 to 4 % w/w of the total weight of the tablet e) lubricant in an amount of 0.5 to 2 % w/w of the total weight of the tablet.

For the purpose of this specification, the term "extended release" means a release of drug for a longer duration of time i.e. not immediate release.

For the purpose of this specification, the term “modified release coating material" means coating material applied onto the core tablet comprising Capecitabine which controls the release of Capecitabine form the tablet. Modified release coating material is interchangeable with functional coat used in the examples.

For the purpose of this specification, the term "multi-particulates" means a plurality of spheres, granules or pellets, wherein Capecitabine is present into the core of the spheres, granules or pellets or wherein inert core of the spheres, granules or pellets are coated with a layer comprising Capecitabine.

According to the present invention, extended release tablets comprising Capecitabine, wherein the release of Capecitabine is controlled by modified release matrix material or modified release coating material or modified release coating on multi-particulates which further comprises suitable excipients.

According to the present invention, suitable excipients may include, but not limited to binder, diluent, lubricant, glidant, and like thereof.

According to the present invention, binder may include, but not limited to acacia, carbomer, carboxymethylcellulose, cellulose microcrystalline, copovidone, gelatin, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, methyl cellulose, ethyl cellulose, polyethylene oxide, povidone, starch, pregelatinized starch, ammonio methacrylate copolymer and the like, or mixtures thereof.

According to the present invention, diluent may include, but not limited to lactose anhydrous, lactose monohydrate, spray dried lactose, dicalcium phosphate, calcium phosphate tribasic, calcium carbonate, calcium sulfate, starch, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose microcrystalline powdered and the like, or mixtures thereof.

According to the present invention, lubricant may include, but not limited to calcium stearate, glyceryl behenate, magnesium stearate, mineral oil light, polyethylene glycol, castor oil, sodium stearyl fumarate, starch, stearic acid, talc, hydrogenated vegetable oil, zinc stearate, sodium benzoate and the like, or mixtures thereof.

According to the present invention, glidant may include, but not limited to calcium silicate, magnesium silicate, colloidal silicon dioxide, talc and the like, or mixtures thereof.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein dissolution of Capecitabine from the said tablets is extended up to at least 12 hours.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the release is controlled by modified release matrix material or modified release coating material or modified release coating on multi-particulates which further comprises suitable excipients, wherein the dissolution of Capecitabine from the said tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and NLT 85% of the total amount of Capecitabine is released after 12 hours.

In another embodiment, the present invention provides extended release tablets comprising: a) Capecitabine in an amount of 150 to 750 mg per tablet, b) lactose in an amount of 5 to 35 mg per tablet, c) microcrystalline cellulose in an amount of 5 to 50 mg per tablet, d) Hydroxypropyl methylcellulose in an amount of 15 to 100 mg per tablet, e) binder in an amount of 5 to 30 mg per tablet and f) lubricant in an amount of 2 to 15 mg per tablet; wherein, the dissolution of Capecitabine from the tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and not less than (NLT) 85% of the total amount of Capecitabine released after 12 hours.

Method of dissolution study is well known in the art. Preferably dissolution study can be carried out in type II or type I dissolution apparatus USP, using suitable buffer or purified water as dissolution medium at 37°C and 50/75/100 RPM.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein dissolution of Capecitabine from the said tablets is extended up to at least 12 hours after administration, wherein the tablets comprises Capecitabine ranging from 150 to 750 mg.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein dissolution of Capecitabine from the said tablets is extended up to at least 12 hours after administration, wherein the tablets comprises crystalline or amorphous form of Capecitabine.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the release is controlled by modified release matrix material.

According to the present invention modified release matrix material may include hydrophilic matrix material or hydrophobic matrix material or mixture thereof.

According to the present invention modified release matrix material may include, but not limited to hydroxypropyl methylcellulose (HPMC) with different viscosity grade; for example, HPMC K4M, HPMC K100M, HPMC K100LV, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl ethylcellulose, methylcellulose, ethylcellulose, carboxyethylcellulose, carboxymethyl hydroxyethylcellulose, carbomer, sodium carboxymethylcellulose, polyvinylpyrrolidone, hydrophobic polymers, waxes, fats, long-chained fatty acids, fatty alcohols or corresponding esters or ethers or their mixtures, and the like, or mixtures thereof.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the release is controlled by modified release coating material.

According to the present invention modified release coating material may include pH-dependent coating material or pH-independent coating material or mixture thereof.

According to the present invention modified release coating material may include, but not limited to alkyl celluloses such as, e.g. ethyl cellulose, or cellulose esters, such as, e.g. cellulose acetate, cellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate, poly vinyl acetate phthalate, polymethacrylate, copolymer of ethyl acrylate and methyl methacrylate, ammonio methacrylate copolymers, polyacrylic acid and polyacrylate and methacrylate copolymers, shellac, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and the like, or mixtures thereof.

In another embodiment, the present invention provides process for the preparation of extended release tablets comprising Capecitabine, wherein the release is controlled by modified release matrix material comprises steps of: a) mixing Capecitabine, diluent(s) and modified release matrix material to form blend, b) Preparing binder solution by dissolving binder into purified water, c) granulating the blend obtained in step a) using binder solution, d) mixing lubricant and / or glidant and optionally modified release matrix materials with granules obtained in step c), e) compressing the blended granules obtained in step d) to form tablets and f) optionally, film coating the tablets obtained in step e.

According to the present invention modified release coating on multi-particulates, wherein the modified release coating material may include, but not limited to alkyl celluloses such as, e.g. ethyl cellulose, or cellulose esters, such as, e.g. cellulose acetate, cellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate, poly vinyl acetate phthalate, polymethacrylate, copolymer of ethyl acrylate and methyl methacrylate, ammonio methacrylate copolymers, polyacrylic acid and polyacrylate and methacrylate copolymers, shellac, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and the like, or mixtures thereof.

In another embodiment, the present invention provides process for the preparation of extended release tablets comprising Capecitabine, wherein the release is controlled by modified release coating material comprises steps of: a) mixing Capecitabine and diluent(s), b) granulating the blend obtained in step a) using binder solution, c) mixing lubricant with granules obtained in step b), d) compressing the blended granules obtained in step c) to form tablets and e) applying modified release coat on to the tablet obtained in step d).

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the release is controlled by modified release coating on multi-particulates.

In another embodiment, the present invention provides extended release tablets comprising Capecitabine, wherein the release is controlled by modified release matrix material or modified release coating material or modified release coating on multi-particulates which would release the drug from the said tablets up to 24 hours after administration.

EXAMPLES
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.

EXAMPLE 1: Extended release tablets comprising Capecitabine wherein release is controlled by hydrophilic modified release matrix material

Sr.No. Ingredients %w/w of Tablet
1 Capecitabine 55% to 80%
2 Diluent(s) 0% to 15%
3 Hydrophilic modified release matrix material(s) 5% to 40%
4 Binder 2% to 4%
5 Granulating fluid q.s.
6 Glidant (s) 0.5% to 1.5%
7 Lubricant(s) 0.5% to 1.5%
8 Film coat 2% to 4%

Process:
1. Capecitabine, diluent(s) and modified release matrix material(s) were admixed together to form uniform blend.
2. The blended material of step 1 was granulated using binder solution.
3. Modified release matrix material(s), glidant(s) and / or lubricant(s) were mixed with granules obtained in step 2.
4. Blended granules of step 3 were compressed to form tablets.
5. Optionally film coating the tablets obtained in step 4.
EXAMPLE 2: Extended release tablets comprising Capecitabine wherein release is controlled by hydrophilic modified release matrix material

Sr.No. Ingredients Mg/tablet
Core Tablets
1 Capecitabine 500.00
2 Microcrystalline cellulose 26.00
3 Hydroxypropyl Methylcellulose
(HPMC K4M ) 70.00
4 Hydroxypropyl Methylcellulose 6 cps 20.00
5 Purified water q.s
6 Hydroxypropyl Methylcellulose
(HPMC K4M) 70.00
7 Talc 7.00
8 Magnesium stearate 7.00
9 Film coat 20
Total weight of coated tablet 720

Process:
1. Capecitabine, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC K4M) were admixed properly to obtain uniform blend.
2. Hydroxypropyl methylcellulose 6 cps was dissolved in purified water and used to granulate the blend of step 1 to obtain granule, optionally sifting the granules.
3. Hydroxypropyl methylcellulose (HPMC K4M) and Talc were sifted and mixed properly with granules of step 2.
4. Magnesium stearate was mixed properly with materials of step 3.
5. Lubricated blend of step 4 was compressed to form tablet.
6. Film coat was applied on compressed tablets of step 5.

EXAMPLE 3: Extended release tablets comprising Capecitabine wherein release is controlled by hydrophilic modified release matrix material

Sr.No. Ingredients Mg/tablet
Core Tablets
1 Capecitabine 150.00
2 Lactose anhydrous 7.500
3 Microcrystalline cellulose 10.50
4 Hydroxypropyl Methylcellulose 6 cps 7.50
5 Purified water q.s
6 Hydroxypropyl Methylcellulose
(HPMC K4M CR) 22.50
7 Magnesium stearate 3.00
8 Film coat 6.00
Total weight of coated tablet 207

Process:
1. Capecitabine, lactose anhydrous, microcrystalline cellulose and part of Hydroxypropyl methylcellulose 6 cps were admixed properly to obtain uniform blend.
2. Remaining part of hydroxypropyl methylcellulose 6 cps was dissolved in purified water and was used to granulate the blend of step 1 to obtain granules.
3. Hydroxypropyl methylcellulose (HPMC K4M CR) and magnesium stearate were sifted and mixed properly with granules of step 2.
4. Lubricated blend of step 3 was compressed to form tablet.
5. Film coat was applied on compressed tablets of step 4.

EXAMPLE 4: Extended release tablets comprising Capecitabine wherein release is controlled by Hydrophobic modified release matrix material

Sr.No. Ingredients %w/w of Tablet
1 Capecitabine 55% to 80%
2 Diluent(s) 0% to 15%
3 Hydrophobic modified release matrix material(s) 5% to 15%
4 Granulating fluid q.s.
5 Glidant (s) 0.5% to 1.5%
6 Lubricant(s) 0.5% to 1.5%
7 Film coat 2% to 4%

Process:
1. Capecitabine and diluent(s) were admixed together to form uniform blend.
2. Hydrophobic modified release matrix material(s) was dissolved in Granulating fluid.
3. The blended material of step 1 was granulated using solution obtained in step 2.
4. Glidant(s) and / or lubricant(s) were mixed with granules obtained in step 3.
5. Blended granules of step 4 were compressed to form tablets.
6. Optionally film coating the tablets obtained in step 4.

EXAMPLE 5: Extended release tablets comprising Capecitabine wherein release is controlled by Hydrophobic modified release matrix material

Sr.No. Ingredients Mg/tablet
Core Tablet
1 Capecitabine 500.00
2 Microcrystalline cellulose 66.00
3 Ethyl cellulose 80.00
4 Ethanol q.s
5 Talc 7.00
6 Magnesium stearate 7.00
7 Film coat 20
Total weight of coated tablet 680

Process:
1. Capecitabine and microcrystalline cellulose were admixed together to form uniform blend.
2. Ethyl cellulose was dissolved in ethanol and used to granulate the materials of step 1.
3. The blended material of step 1 was granulated using solution obtained in step 2.
4. Talc and magnesium stearate were sifted through appropriate sieve and mixed properly with sized granules.
5. Blended granules of step 4 were compressed to form tablets.
6. Film coat was applied on compressed tablets of step 5.

EXAMPLE 6: Extended release tablets comprising Capecitabine wherein release is controlled by modified release coating material

Sr.No. Ingredients %w/w of Tablet
Core
1 Capecitabine 50% to80%
2 Diluent(s) 15% to 50%
3 Binder(s) 1% to 3%
4 Granulating fluid q.s.
5 lubricant(s) 0.5 % to 2%
Functional coat
7 Ethyl cellulose 3% to 7%
8 Hydroxypropyl Methylcellulose E6 0.1% to 1%
9 Talc 0.1% to 1%
10 Purified water q.s

Process:
1. Capecitabine and diluent(s) were sifted and mixed.
2. Binder(s) was dissolved in granulating fluid.
3. The blended material of step 1 was granulated using solution of step 2.
4. The granules of step 3 were dried.
5. Lubricant(s) was mixed with granules of step 4.
6. Lubricated blend of step 5 was compressed to form tablet.
7. Functional film coat was applied on tablets of step 6.

EXAMPLE 7: Extended release tablets comprising Capecitabine wherein release is controlled by modified release coating material

Sr.No. Ingredients Mg/tab
Core
1 Capecitabine 500.00
2 Lactose monohydrate 130.00
3 Microcrystalline cellulose 50.00
4 Hydroxypropyl Methylcellulose E5 14.00
5 Purified water q.s
6 Magnesium stearate 6.00
Functional coat
7 Ethyl cellulose 35.00
8 Hydroxypropyl Methylcellulose E6 3.00
9 Talc 2.00
10 Purified water q.s

Process:
1. Capecitabine, lactose monohydrate, microcrystalline cellulose were sifted through appropriate sieve.
2. Materials of step 1 were placed in granulator and dry mixed properly.
3. Hydroxypropyl methylcellulose (HPMC E5) was dissolved in Purified water and used to granulate the materials of step 2.
4. Wet mass was dried in rapid dryer.
5. Dried granules were passed through appropriate sieve.
6. Magnesium stearate was passed through appropriate sieve and mixed with sized granules for 5 minutes.
7. Lubricated blend was compressed using appropriate tooling.
8. Tablets obtained of step 7 were coated using coating solution prepared from ethyl cellulose, hydroxypropyl methylcellulose E6, talc and purified water.

EXAMPLE 8: Extended release tablets comprising Capecitabine wherein release is controlled by hydrophilic modified release matrix material

Sr.No. Ingredients Mg/tablet
Core Tablets
1 Capecitabine 500.00
2 Lactose anhydrous 25.00
3 Microcrystalline cellulose 35.00
4 Hydroxypropyl Methylcellulose 6 cps 25.00
5 Purified water q.s
6 Hydroxypropyl Methylcellulose
(HPMC K4M CR) 75.00
7 Magnesium stearate 10.00
8 Film coat 20.00
Total weight of coated tablet 690

Process:
1. Capecitabine, lactose anhydrous, microcrystalline cellulose and part of Hydroxypropyl methylcellulose 6 cps were admixed properly to obtain uniform blend.
2. Remaining part of hydroxypropyl methylcellulose 6 cps was dissolved in purified water and was used to granulate the blend of step 1 to obtain granules.
3. Hydroxypropyl methylcellulose (HPMC K4M CR) and magnesium stearate were sifted and mixed properly with granules of step 2.
4. Lubricated blend of step 3 was compressed to form tablet.
5. Film coat was applied on compressed tablets of step 4.

Dissolution study results: The dissolution study of the tablets prepared according to examples 2, 3, 5, and 7 were carried by in type II dissolution apparatus USP, using 900 ml purified water as dissolution medium at 37°C and 50 RPM.

The obtained dissolution study results are tabulated below:

% Drug release
Time (Hours) Example 2 Example 3 Example 5 Example 7
0 0 0 0 0
1 22 20 25 19
4 53 45 48 46
8 71 77 68 69
12 95 97 90 92

Thus, extended release tablets comprising Capecitabine suitable for twice daily administration can be prepared according to the present invention wherein dissolution of Capecitabine from the said tablets is extended up to at least 12 hours. ,CLAIMS:1. Extended release tablets comprising Capecitabine, wherein the dissolution of Capecitabine from the tablets is extended up to at least 12 hours.

2. The extended release tablets according to claim 1, wherein the dissolution of Capecitabine from the tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and not less than (NLT) 85% of the total amount of Capecitabine released after 12 hours.

3. The extended release tablets according to claim 1, wherein the release is controlled by modified release matrix material.

4. The extended release tablets according to claim 3, wherein modified release matrix material comprises hydrophilic matrix material or hydrophobic matrix material or mixture thereof.

5. The extended release tablets according to claim 1, wherein the release is controlled by modified release coating material.

6. The extended release tablets according to claim 1, wherein the tablets comprises Capecitabine ranging from 150 to 750 mg.

7. Process for the preparation of extended release tablets according to claim 3, wherein the process comprises steps of:
a) Mixing Capecitabine, diluent(s) and modified release matrix material to form blend.
b) Preparing binder solution by dissolving binder into purified water.
c) Granulating the blend obtained in step a) using binder solution.
d) Mixing lubricant and / or glidant and optionally modified release matrix materials with granules obtained in step c).
e) Compressing the blended granules obtained in step d) to form tablets.
f) Optionally, film coating the tablets obtained in step e.

8. Process for the preparation of extended release tablets according to claim 5, wherein the process comprises steps of:
a) Mixing Capecitabine and diluent.
b) Granulating the blend obtained in step a) using binder solution.
c) Mixing lubricant with granules obtained in step b).
d) Compressing the blended granules obtained in step c) to form tablets.
e) Applying modified release coat on to the tablet obtained in step d).

9. Extended release tablets comprising
a) Capecitabine in an amount of 55 to 80 % w/w of the total weight of the tablet
b) Diluent in an amount of 1 to 15 % w/w of the total weight of the tablet
c) Modified release matrix material in an amount of 5 to 40 % w/w of the total weight of the tablet
d) Binder in an amount of 2 to 4 % w/w of the total weight of the tablet
e) Lubricant in an amount of 0.5 to 2 % w/w of the total weight of the tablet.

10. Extended release tablets comprising
a) Capecitabine in an amount of 150 to 750 mg per tablet
b) Lactose in an amount of 5 to 35 mg per tablet
c) Microcrystalline cellulose in an amount of 5 to 50 mg per tablet
d) Hydroxypropyl methylcellulose in an amount of 15 to 100 mg per tablet
e) Binder in an amount of 5 to 30 mg per tablet
f) Lubricant in an amount of 2 to 15 mg per tablet
wherein, the dissolution of Capecitabine from the tablets is 15 to 35% after 1 hour, 40 to 60% after 4 hours, 60 to 80% after 8 hours and not less than (NLT) 85% of the total amount of Capecitabine released after 12 hours.