DESC:Technical field of the invention:
The present invention relates to a process for preparing a pharmaceutical composition comprising Topiramate ER capsules.

Background of the invention:
A seizure is a sudden surge of electrical activity in the brain. The electrical activity is caused by complex chemical changes that occur in nerve cells. Brain cells either excite or inhibit (stop) other brain cells from sending messages. However, when there is too much or too little activity, causing an imbalance between exciting and stopping activity, seizure occurs. Seizures are not a disease in themselves. Instead, they are a symptom of many different disorders that can affect the brain. Some seizures can hardly be noticed, while others are totally disabling.

Tonic–clonic seizures (formerly known as grand mal seizures) are a type of generalized seizure that affects the entire brain. A partial onset seizure is a seizure which occurs only in one area of the brain. The Lennox-Gastaut Syndrome (LGS) is a type of epilepsy with multiple different types of seizures, particularly tonic (stiffening) and atonic (drop) seizures. The cause of the disorder is unknown in 1 out of 4 children. Children with Lennox-Gastaut syndrome experience delays in their development and up to dozens of different, mixed types of seizures a day.

Treatment for tonic-clonic seizures includes medications, changes in lifestyle for adults and children, such as activity and diet, and sometimes surgery. Medicines to prevent seizures, called anticonvulsants, may reduce the number of future seizures. Topiramate is an anti-epileptic or anti-seizure drug that is used to prevent the seizures of epilepsy. It is used primarily among patients who are not controlled by other anti-epileptic drugs. Topiramate is used alone or in combination with other anti-seizure drugs to treat individuals 2 years old or older with partial seizures or generalized tonic- clonic seizures (in which there is prolonged contraction of the muscles of the body that causes rigidity as well as jerking motions). Topiramate also is used in patients 2 years of age and older with seizures associated with the Lennox-Gastaut syndrome, a severe form of epilepsy which accounts for up to 10% of all cases of childhood epilepsy.

Topiramate is a sulfamate-substituted monosaccharide. Chemically it is designated as 2,3:4,5-Di-O-isopropylidene-ß-D-fructopyranose sulfamate and its empirical formula is C12H21NO8S.

Topiramate is available as Trokendi XR® 25 mg, 50 mg, 100 mg and 200 mg extended-release capsules in the US market. Trokendi XR® contains the following inactive ingredients: Sugar Spheres, Hypromellose, Mannitol, Docusate Sodium, Sodium Benzoate, Ethyl cellulose, Oleic Acid, Medium Chain Triglycerides, Polyethylene Glycol, Polyvinyl Alcohol, Titanium Dioxide, Talc, Lecithin and Xanthan Gum. The capsule shells contain gelatin, USP; Titanium Dioxide, USP; and Colorants. The colorants are: FD&C Blue #1 (all strength capsules) Yellow Iron Oxide, USP (25 mg and 50 mg capsules) FD&C Red #3 (50 mg, 100 mg and 200 mg capsules) FD&C Yellow #6 (50 mg, 100 mg and 200 mg capsules) Riboflavin, USP (25 mg capsules). All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF.

US 8298576 discloses sustained release formulation of topiramate comprising an immediate release bead population, a first extended release bead population and a second extended release bead population.

US 8298580 disclose sustained release formulation of topiramate comprising at least two different extended release topiramate-containing components and an immediate release topiramate containing component.

US 8663683 discloses sustained release formulation of topiramate comprising an extended release component, wherein greater than or equal to 80% of the topiramate contained therein is released in vitro in less than or equal to about 4 hours and an immediate release component, wherein 80% of the topiramate contained therein is released in vitro in not more than 1 hour.

US 8877248 discloses sustained release formulation comprising topiramate, an extended release (XR) topiramate-containing component and an immediate release (IR) topiramate-containing component comprising complexing agent.
US 20150024055 discloses enhanced immediate release formulation comprising topiramate, wherein at least 30% of the total topiramate in the formulation is dissolved in a time period of not more than 5 minutes.

US 8652527 discloses extended-release topiramate capsule comprising single population of coated particles wherein core comprises a homogeneous mixture with a coating thereon in an amount sufficient to provide 8 to 14% of weight gain.

WO 2014167439 discloses modified release pharmaceutical composition comprising two different components comprising immediate release component of topiramate and extended release component of topiramate.

US 20150099003 disclose sustained-release pharmaceutical composition of topiramate, in which drug layer is free of binding agent.

US 20140348931 discloses sustained release formulation of topiramate comprising two extended release components or one immediate release and one extended release component, both the components containing topiramate and at least one of the components is present in a matrix form.

US 20070224281 discloses sustained-release topiramate preparation produced using double granules comprising granulating topiramate or a pharmaceutically acceptable salt thereof using a solid dispersant by a solid dispersion method and further granulating the resultant granules using a release-sustaining material by a dry or a wet granulation process.
US 20070087976 disclose non hygroscopic topiramate in highly pure form and in which at least 90% of the particles have a particle size of ?250 µm.

475/MUM/2012 discloses bead composition comprising an inert carrier, a first gradient topiramate layering, an extended release component surrounding the first gradient topiramate layering, a second gradient topiramate layering, a delayed release component surrounding the second gradient topiramate layering, and an optional immediate release component surrounding the delayed release component.

3069/MUM/2013 discloses modified release formulation comprising topiramate, hydroxy propyl methyl cellulose, dicalcium phosphate, povidone, and ethyl cellulose and magnesium stearate.

The present inventors have developed a pharmaceutical composition comprising topiramate or its salts in an extended release form which provides a daily single dose effectively improving patient compliance.

Summary of the invention
The present invention provides an extended release pharmaceutical composition comprising topiramate and its pharmaceutically acceptable excipients.

In an embodiment, the present invention provides an extended release pharmaceutical composition comprising topiramate in three different portions in varying percentages.
In an aspect of the embodiment, the present invention provides an extended release pharmaceutical composition comprising topiramate and antioxidant in the ratio of 450:1 to 550:1 in all the three portions.

In another aspect of the embodiment, the extended release pharmaceutical composition of topiramate comprises an immediate release portion in addition to extended release portions.

In yet another aspect of the embodiment, the three portions containing topiramate are first extended release portion, second delayed extended release portion and third immediate release portion.

In yet another aspect of the embodiment, the pharmaceutically acceptable excipients comprise diluents, disintegrants, binders, solubilizers, lubricants, glidants, extended release polymers, plasticizers and enteric polymers.

In yet another aspect of the embodiment, the present invention provides a process for preparation of extended release composition comprising topiramate.

In yet another aspect of the embodiment, the present invention provides a process for preparation of topiramate extended release composition comprising the steps:
(a) granulating 30%-60% of topiramate and one or more pharmaceutically acceptable excipients;
(b) coating the granules obtained in step (a) with solution/suspension comprising extended release polymer;
(c) layering the particles obtained in step (b) with solution/suspension comprising 30%-50% of topiramate;
(d) coating the particles obtained in step (c) with solution/suspension comprising extended release polymer;
(e) coating the particles obtained in step (d) with solution/suspension comprising enteric polymer;
(f) layering the particles obtained in step (e) with solution/suspension comprising 10%-20% of topiramate;
(g) optionally coating the particles obtained in step (f) with solution/suspension comprising Opadry.

Detailed description of the invention
The present invention provides an extended release pharmaceutical composition comprising topiramate and its pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a pharmaceutical composition comprising topiramate in three different portions in varying percentages.

In an aspect of the embodiment, the present invention provides an extended release pharmaceutical composition comprising topiramate and antioxidant in the ratio of 450:1 to 550:1 in all the three portions.

In another aspect of the embodiment, the extended release pharmaceutical composition of topiramate comprises an immediate release portion in addition to extended release portions.

In yet another aspect of the embodiment, the three portions containing topiramate are first extended release portion, second delayed extended release portion and third immediate release portion.

In another aspect of the embodiment, the pharmaceutically acceptable excipients comprise diluents, disintegrants, binders, solubilizers, lubricants, glidants, extended release polymers, plasticizers and enteric polymers.
In yet another aspect of the embodiment, the present invention provides a process for preparation of extended release composition comprising topiramate.
In yet another aspect of the embodiment, the present invention provides a process for preparation of topiramate extended release composition comprising the steps:
(a) granulating 30%-60% of topiramate and one or more pharmaceutically acceptable excipients;
(b) coating the granules obtained in step (a) with solution/suspension comprising extended release polymer;
(c) layering the particles obtained in step (b) with solution/suspension comprising 30%-50% of topiramate;
(d) coating the particles obtained in step (c) with solution/suspension comprising extended release polymer;
(e) coating the particles obtained in step (d) with solution/suspension comprising enteric polymer;
(f) layering the particles obtained in step (e) with solution/suspension comprising 10%-20% of topiramate;
(g) optionally coating the particles obtained in step (f) with solution/suspension comprising opadry.

The term ‘pharmaceutical composition’ denotes a composition which shows extended release.

The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes topiramate or its pharmaceutically acceptable salts or polymorphic forms (amorphous or crystalline).

The term "pharmaceutically acceptable excipients", denotes any of the components of a pharmaceutical composition other than the active and which are approved by regulatory authorities or are generally ‘regarded as safe’ for human or animal use.

Examples of pharmaceutically acceptable excipients include, but are not limited to diluents, disintegrants, lubricants, binders, solubilizers, solvents and plasticizers. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch (maize starch); microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyl propyl methylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and other materials known to one ordinarily skilled in the art and mixtures thereof. Low viscosity grades of Hydroxypropyl methyl cellulose are used as binders in order to facilitate granulation. They can thicken, bind and suspend particulates to form stable granules.

A 2% solution of Hydroxypropyl methyl cellulose in water at 20°C produces a solution of 4- 6 mPa.S. Hydroxypropyl methyl cellulose is odorless and tasteless, white or creamy-white fibrous or granular powder.

Diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate and other materials known to one ordinarily skilled in the art and mixtures thereof.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and other materials known to one ordinarily skilled in the art and mixtures thereof.

Anti-tacking agents include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.

Solvents include, but are not limited to purified water, acetone, ethyl alcohol, isopropyl alcohol dichloromethane and other materials known to one ordinarily skilled in the art and mixtures thereof.

Plasticizers include, but are not limited to propylene glycol, liquid polyethylene glycol, glycerin, hexylene glycol, 1,2,6-trihydroxyhexane, triethyl citrate, acetyl tributyl citrate and diethyl phthalate and other materials known to one ordinarily skilled in the art and mixtures thereof.

Pore formers include, but are not limited to calcium carbonate, calcium phosphate, calcium saccharide, hydroxy propyl methyl cellulose, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate and other materials known to one ordinarily skilled in the art and mixtures thereof.

Antioxidants include but are not limited to butylhydroxytoluene, ascorbic acid, propyl gallate, butylhydroxyanisole and sodium benzoate and other materials known to one ordinarily skilled in the art and mixtures thereof.
Release controlling polymers include, but are not limited to cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose, starch or its derivatives, alginates, acrylic and methacrylic acid derivatives, polyethylene oxide, gums and other materials known to one ordinarily skilled in the art and mixtures thereof.

Enteric polymers include, but are not limited to cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose phthalate, hydroxypropyl-methyl cellulose acetate succinate, ethylacrylate methacrylic acid copolymer, methyl methacrylate methacrylic acid copolymer, shellac and other materials known to one ordinarily skilled in the art and mixtures thereof.

In an aspect of the embodiment, the weight ratio of topiramate to antioxidant is 450:1 to 550:1, preferably 480:1 to 520:1 and more preferably 500:1 in all the three portions.

It should be appreciated that there is considerable overlap between the above-listed excipients in common usage, since a given excipient is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed excipients should be taken as merely exemplary, and not limiting, of the types of excipients that can be included in compositions of the present invention. One or more of these excipients can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden.

The amount of each type of excipients employed may vary within ranges conventional in the art.

In an aspect of the embodiment, the three portions containing topiramate may or may not be coated with polymers. The first portion is coated with extended release polymer and second portion is coated with extended release polymer followed by enteric polymer and the third portion may be optionally coated with opadry.

In an aspect of the embodiment, the extended release composition comprising topiramate may be in the form of tablet, mini tablet, beads or pellets filled in capsules and mini tablets filled in the capsules.

Preparation of drug loading solution: Hydroxy propyl methyl cellulose was added to water under continuous stirring for 30 minutes to get clear solution. Mannitol was added to water followed by addition of topiramate under stirring until homogeneous dispersion was formed. Dissolve butylated hydroxy anisole in isopropyl alcohol under stirring to get clear solution. Both the solutions were added to topiramate dispersion under continuous stirring for 1 hour to get clear solution.

Preparation of extended release coating solution: Ethyl cellulose was added to isopropyl alcohol and methylene chloride under stirring for 15 minutes to get clear solution. Hydroxy propyl methyl cellulose was added to the above solution under continuous stirring for 15 minutes followed by the addition of triethyl citrate under stirring for 15 minutes.

Preparation of enteric coating solution: Hydroxy propyl methyl cellulose phthalate was added to water under continuous stirring for 15 minutes to get clear solution. Hydroxy propyl methyl cellulose was added to the solution under continuous stirring for 15 minutes and then triethyl citrate was added under stirring. Talc was added to the above solution under stirring for 15 minutes.

In yet another embodiment, the present invention provides a process for preparation of extended release composition of topiramate comprising steps of:
(a) granulating 30%-60% of topiramate and one or more pharmaceutically acceptable excipients with binder solution;
(b) coating the granules obtained in step (a) with solution/suspension comprising extended release polymer and one or more pharmaceutically acceptable excipients;
(c) loading the particles obtained in step (b) with solution/suspension comprising 30%-50% of topiramate and one or more pharmaceutically acceptable excipients;
(d) coating the particles obtained in step (c) with solution/suspension comprising extended release polymer and one or more pharmaceutically acceptable excipients;
(e) coating the particles obtained in step (d) with solution/suspension comprising enteric polymer and one or more pharmaceutically acceptable excipients;
(f) loading the particles obtained in step (e) with solution/suspension comprising 10%-20% of topiramate and one or more pharmaceutically acceptable excipients;
(g) optionally coating the particles obtained in step (f) with solution/suspension comprising opadry.

Topiramate in amount of 30%-60% and diluent are sifted in ASTM #20 sieve and mixed for 20 minutes in rapid mixer granulator.

Granulation is carried out in rapid mixer granulator. The granules so obtained are transferred into suitable equipment to enable drying. Drying of granules can be carried out using Fluidized Bed Dryers, Tray Dryers, Belt Dryers, Vacuum Tray Dryers, Rotary Dryers and the like. The preferable equipment used for drying is Fluid Bed Dryer.

Fluid bed dryer is designed to introduce the hot air stream at the base of the product container which is filled with the material. Fluidization causes agitation of solid particles and since each particle gets surrounded by hot air, heat transfer is extremely high and hence uniformity of temperature is maintained. The product is dried fast without appreciable loss of heat. The equipment also has filter bags which prevents particles escaping from the dryer.

The granules transferred to fluidized bed dryer are dried for about 5 minutes at 80° C. Drying is continued till desired moisture loss is achieved i.e., loss on drying should be not more than 2%.
The use of fluidized bed dryer offers several advantages, including rapid heat and mass transfer, large capacity, and relatively low capital cost. Also, due to the continuous movements of product during drying, lump formation, case hardening etc. are minimized.

Granules obtained are passed through extruder and spheronized and dried till loss on drying of not more than 2% is achieved.

Coating may be performed by applying the coating composition as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or in glatt particle coating granulator. The coating may be functional or non-functional.

The granules obtained are coated with the extended release coating solution. Extended release coating is carried out in glatt particle coating granulator and dried at 80° C for 5 minutes till loss on drying limit of not more than 2% is achieved.

Drug loading is done over the extended release particles containing 30%-50% of topiramate using glatt particle coating granulator until the desired weight gain is achieved at 80° c for 5 minutes, till loss on drying of not more than 2% is achieved.

Extended release coating is done over the drug loaded particles in glatt particle coating granulator and dried at 80° C for 5 minutes till loss on drying limit of not more than 2% is achieved.

Enteric coating is done over the extended release particles obtained above in glatt particle coating granulator and dried at 80° C for 5 minutes till loss on drying limit of not more than 2% is achieved.

Drug loading is done over the enteric coated particles containing 10%-20% of topiramate in glatt particle coating granulator at 80° C for 5 minutes, till loss on drying of not more than 2% is achieved. This outer portion of drug layer acts as immediate release portion releasing the drug instantly.

In some embodiments, the outer immediate release portion may be optionally coated with opadry coating materials such as cellulosic polymers including but not limited to hydroxy propyl methylcellulose and hydroxy propyl cellulose. Opadry coating is carried out in glatt particle coating granulator and dried at 80° C for 5 minutes till loss on drying limit of not more than 2% is achieved.

Examples
The foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.
Example 1: Pharmaceutical composition comprising Topiramate ER capsules

SN Name of Pharmaceutical Ingredient 200 mg
1. Topiramate 200.00
2. Micro crystalline cellulose 153.00
3. Hydroxy propyl methyl cellulose 94.00
4. Butylated hydroxy anisole (BHA) 0.50
5. Purified water q.s.
6. Isopropyl alcohol q.s.
7. Ethyl Cellulose (Ethocel) 50.00
8. Triethyl citrate 16.00
9. Methylene dichloride q.s.
10. Mannitol 30.00
11. Hydroxy propyl methyl cellulose phthalate (HPMC phthalate) 25.00
12. Talc 7.00
13. Opadry 23.00
Theoretical Weight 598.5
14. Lubricated pellets 598.5
15. Capsule size Size ‘00’
q.s. = quantity sufficient

Manufacturing Process:
1. Topiramate & microcrystalline cellulose were mixed in Rapid Mixer Granulator (RMG) and granulated using mixture of aq. solution of HPMC and alcoholic solution of Butylated hydroxy anisole. The collected wet mass was further extruded and then spheronoized. Dried pellets were collected and further used for coating.
2. The dried pellets of step 1 were coated with coating solution which is prepared by dissolving ethyl cellulose, HPMC and triethyl citrate in mixture of Isopropyl alcohol and methylene chloride.
3. The coated pellets of step 2 were further sprayed with drug solution. The drug solution was prepared by adding aq. solution of HPMC and alcoholic solution (IPA) of butylated hydroxy anisole to an. aq. dispersion containing topiramate and mannitol.
4. The drug loaded pellets of step 3 were further coated with coating solution which is prepared by dissolving ethyl cellulose, HPMC and triethyl citrate in mixture of Isopropyl alcohol and methylene chloride.
5. The coated pellets of step 4 were further coated with coating solution which is prepared by dissolving HPMC Phthalate, HPMC and triethyl citrate in mixture of Isopropyl alcohol and methylene chloride.
6. The enteric coated pellets of step 5 were further sprayed with drug solution. The drug solution was prepared by adding aq. solution of HPMC and alcoholic solution (IPA) of butylated hydroxy anisole to an. aq. dispersion containing topiramate and mannitol.
7. The drug pellets of step 6 were film coated using aq. Opadry solution.
8. The coated pellets of step 7 were further lubricated with talc and filled in suitable capsules.
,CLAIMS:We Claims,
1. An extended release composition of topiramate comprising topiramate in at least two portions in varying percentage and one or more pharmaceutically acceptable excipients.
2. The extended release composition of topiramate as claimed in claim 1, wherein the composition comprising topiramate in an immediate release portion and an extended release portion.
3. The extended release composition of topiramate as claimed in claim 1, wherein the composition comprising topiramate in first extended release portion, second delayed extended release portion and third immediate release portion.
4. The extended release composition of topiramate as claimed in claim 1, wherein the composition comprising 40%-60% of topiramate in first extended release portion, 30%-50% of topiramate in second delayed extended release portion and 10%-20% of topiramate in third immediate release portion.
5. The extended release composition of topiramate as claimed in claim 1, wherein the pharmaceutically acceptable excipients comprises diluent, disintegrant, binder, lubricant, glidant, extended release polymer, plasticizer and enteric polymer and combinations thereof.
6. The extended release composition of topiramate as claimed in claim 5, wherein the extended release polymer is selected from cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose, starch or its derivatives, alginates, acrylic and methacrylic acid derivatives, polyethylene oxide and gums and mixtures thereof.
7. The extended release composition of topiramate as claimed in claim 5, wherein enteric polymer is selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose phthalate, hydroxypropyl-methyl cellulose acetate succinate, ethyl acrylate methacrylic acid copolymer, methyl methacrylate methacrylic acid copolymer and shellac and mixtures thereof.
8. The extended release composition of topiramate as claimed in claim 1, wherein the composition comprising topiramate and an antioxidant in the ratio of 450:1 to 550:1 in all portions.
9. An extended release composition of topiramate comprising 50% of topiramate in first extended release portion, 40% of topiramate in second delayed extended release portion 10% of topiramate in third immediate release portion; wherein, extended release portion comprises ethyl cellulose and delayed extended release portion comprises ethyl cellulose and hydroxy propyl methyl cellulose phthalate.
10. A process for the preparation of extended release composition of topiramate comprising of;
(a) granulating the topiramate and one or more pharmaceutically acceptable excipients,
(b) coating the granules obtained in step (a) with solution/suspension comprising extended release polymer,
(c) layering the particles obtained in step (b) with solution/suspension comprising topiramate,
(d) coating the particles obtained in step (c) with solution/suspension comprising extended release polymer,
(e) coating the particles obtained in step (d) with solution/suspension comprising enteric polymer,
(f) layering the particles obtained in step (e) with solution/suspension comprising topiramate,
(g) optionally coating the particles obtained in step (f) with solution/suspension comprising Opadry.