Claims:Claims:
1. A sustained release solid oral dosage formulation of topiramate which comprises single population of pellets consisting essentially of polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material present in the formulation.

2. The formulation according to claim 1, wherein said pellets comprises:
a) an inert sphere
b) optionally a seal coating
c) an inner layer comprising topiramate and
d) an outer layer consisting essentially of polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.
e) optionally an additional outermost layer comprising Topiramate

3. The formulation according to claim 2, wherein said inert sphere is a sugar sphere which forms about 10% to about 70%, preferably about 20% to about 60% or most preferably about 30 to about 60% by total weight of pellets.

4. The formulation according to claim 2, wherein said inner layer further comprises one or more pharmaceutically acceptable excipients selected from binders, pore formers, surfactants, plasticizers, anti-sticking agents, lubricants, glidants, or mixtures thereof.

5. The formulation according to claim 2, wherein polyvinyl acetate polymer further comprises polyvinylpyrrolidone and sodium lauryl sulphate in 30% aqueous dispersion.

6. The formulation according to claim 2, wherein said outer layer consists essentially of polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material, which forms about 40 to about 95%, more preferably about 50 to about 90% or most preferably about 60 to about 90% by weight of the outer layer and which forms about 2 to about 40%, more preferably about 5 to about 30 % by total weight of pellets.

7. The formulation according to claim 2, wherein said outer layer further comprises one or more other pharmaceutically acceptable excipients selected from binders, pore formers, release modifying agents, wetting agents, surfactants, plasticizers, anti-sticking agents, lubricants, glidants, or mixtures thereof.

8. The formulation according to claim 2, wherein outer layer of pellets is devoid of alkalizers.

9. The formulation according to any of preceding claims, wherein topiramate is present in an amount of from about 0.5mg to about 1000mg in the formulation.

Dated this 08th day of May, 2017

-----------------------------------------
Dr. Rajiv G. Shah,
Torrent Pharmaceuticals Limited,
Torrent Research Centre
P.O. Bhat – 382428, Gandhinagar
Gujarat, India
Torrent Pharmaceuticals Ltd. , Description:SUSTAINED RELEASE TOPIRAMATE FORMULATION

FIELD OF THE INVENTION:
The present invention relates to a sustained release solid oral dosage formulation of topiramate and more specifically to a stable sustained release formulation of topiramate which comprises polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.

BACKGROUND OF THE INVENTION:
Topiramate is chemically known as: 2,3:4,5 Di-O-isopropylidene- beta.-D-fructopyranose sulfamate and has structural formula:

Topiramate is a sulfamate substituted monosaccharide which has been approved, under the tradename TOPAMAX.RTM, as an antiepileptic agent, as an adjuvant therapy for patients with partial onset seizures or primary generalized tonic-clonic seizures, and for the prevention of migraine [Physician's Desk Reference, 60th ed., 2538-2447 (2006); U.S. Pat. No. 4,513,006)]

The approved product Topamax.RTM is an immediate release composition and the recommended dose for TOPAMAX.RTM. for the treatment of epilepsy is 400 mg/day in one or multiple doses. The treatment of epilepsy in adults is initiated with a dose of 25-50 mg/day, with the dose being titrated in increments of 25-50 mg at weekly intervals to the recommended or effective dose.

Topiramate has a relatively long half-life of 21 hours in vivo and when taken in higher doses, it usually results in severe side-effects. Therefore, to avoid these side effects due to higher doses, Topamax.RTM is generally prescribed in multiple, "divided" doses, usually twice-daily ("BID").

However, administration of topiramate medicament in multiple doses does not provide patient compliance. Further, each administration of dose is associated with a peak in plasma concentrations of the drug, and the fluctuations associated with the peaks and valleys of blood plasma levels of the drug is not desirable.

Likely solution to this problem could be the once-a-day administration as it would be advantageous over multiple-dose administration in terms of patient compliance and reduced adverse events, thus providing better treatment of the conditions for which the topiramate is indicated.

WO2008061226 discloses a once-daily sustained-release dosage form of topiramate or salts thereof wherein the composition comprises an enhanced immediate release coated bead population in addition to two extended release (XR) coated bead populations, wherein each XR population comprises a release controlling coating which is specific for every population of beads and determines the rate of release of topiramate from the given bead population.

US20140348931 discloses a sustained release formulation of topiramate comprising either two extended release populations, a first extended release population (XR1) and a second extended release population (XR2) or a combination of one immediate release population (IR1) and other extended release population wherein topiramate is present in both the populations and at least one of the populations is present in a matrix form. As per the disclosure made, IR1 population is generally an Immediate Release matrix tablet, XR1 population is matrix tablet or pellets prepared by extrusion/spheronization method and XR2 population is always an extended release pellet loaded with drug solution and then coated with extended release layer. Population of any of these two populations is filled in a Capsule.

However, the said compositions so obtained are complex with several components and result from an elaborate manufacturing process. This increases the cost and leads to exercise of additional precautions during manufacturing which ultimately makes composition production cumbersome and less cost efficient.

WO2014143380 discloses an extended-release topiramate capsule that includes a capsule shell containing single population of coated particles; wherein each coated particle includes a core and a coating thereon; wherein each particle core includes a homogeneous mixture comprising topiramate throughout its core prepared by Extrusion process; and wherein the coating includes one or more release controlling agent(s). Further specification discloses the use of a stabilizer selected from the group of calcium hydroxide, calcium carbonate, sodium bicarbonate, magnesium carbonate and combinations thereof in the core which can be used in an amount of at least 1% to at least 2% and up to 10% by weight of the sustained release core. Extrusion spheronization is a costly process and requires specific equipment and excipients for manufacturing of spheres.

US20160235776 discloses a sustained release topiramate composition comprising a single population of beads, wherein each bead comprises a) an inert carrier b) an inner layer comprising topiramate, c) an outer layer comprising at least one sustained release material and at least one alkalizer, wherein amount of beads sufficient to deliver the desired dose may be for example compressed into a tablet, filled into pouches, encapsulated into a capsule of any desirable size. The specification also discloses the use of a specific amount of alkalizer in the coating.

As topiramate is an acid-labile drug and degradation of topiramate in the acidic environment of the stomach is the likely cause of its reduced bioavailability in the available dosage forms. The inventions as disclosed in above mentioned applications address this problem by incorporating a specific amount of alkalizer in the compositions, thus stabilizing the drug in the acidic environment.

Thus, there is still need for a simplified once-a-day sustained release topiramate formulation which is stable and could ease or simplify the overall manufacturing process and composition.

OBJECTS OF THE INVENTION:
Therefore, the principal object of the present invention is to provide a sustained release solid oral dosage formulation of topiramate for once-a-day administration which can address one or more of drawbacks associated with the prior art.

Other object of the present invention is to provide a simplified process and composition for sustained release solid oral dosage formulation of topiramate for once-a-day administration.

Another object of the present invention is to provide a sustained release solid oral dosage formulation of topiramate for once-a-day administration which may avoid the need for more than one type of topiramate populations in the formulation.

Another object of the present invention is to provide a sustained release solid oral dosage formulation of topiramate for once-a-day administration which may avoid the need for alkalizers in the formulation.

Yet another object of the present invention is to provide an alternative once-a-day sustained release solid oral dosage formulation of topiramate which is stable and provides a simplified process and a composition for preparation of formulation.

SUMMARY OF THE INVENTION:
In one aspect, there is provided a sustained release solid oral dosage formulation of topiramate for once-a-day administration which consists essentially of polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.

In another aspect, there is provided a sustained release solid oral dosage formulation of topiramate for once-a-day administration which comprises single population of pellets.

In another aspect, there is provided a sustained release solid oral dosage formulation of topiramate for once-a-day administration which comprises single population of pellets prepared by using polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.

In another aspect, there is provided a stable sustained release solid oral dosage formulation of topiramate for once-a-day administration which is devoid of alkalizers.

In other aspect, there is provided a process for preparing sustained release solid oral dosage formulation of topiramate for once-a-day administration comprising the following steps:
? providing inert spheres
? optionally, seal coating of inert spheres
? coating of inert spheres with an inner layer comprising topiramate
? optionally, barrier coating of drug loaded spheres
? coating of drug loaded spheres with an outer layer consisting essentially of polyvinyl acetate polymer or derivative thereof as sustained release material to provide pellets
? optionally, coating an additional outermost layer comprising topiramate
? lubricating and filling of said pellets into a capsule shell.

In further aspect, there is provided a process for preparing sustained release solid oral dosage formulation of topiramate for once-a-day administration which comprise the steps of;
? mixing and/or granulating topiramate with polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material and one or more pharmaceutically acceptable excipients to form a wet mass;
? extruding the wet mass of step (i);
? spheronizing the product of step (ii) to form pellets; and
? processing of pellets and filling into a capsule shell.

Figures:
FIG-01 is a graphical representation of release profile of present formulation comparative to Trokendi® formulation.

DETAILED DESCRIPTION OF THE INVENTION:
The inventors of present invention have found that sustained release solid oral dosage formulation of topiramate for once a day administration can be provided using polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.

Thus, in one embodiment, present invention provides a sustained release solid oral dosage formulation of topiramate which consists essentially of polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.

The inventors of present invention have further found that, through present invention, need for more than one type of population of topiramate components in composition to provide sustained release formulation of topiramate can be avoided.

Thus, in another embodiment, sustained release solid oral dosage formulation of topiramate for once-a-day administration comprises single population of pellets prepared by using polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material in the formulation.

Additionally, the inventors of present invention found that a stable sustained release solid oral dosage formulation of topiramate for once-a-day administration is possible without adding alkalizers in the formulation.

Thus, in another preferred embodiment, a stable sustained release solid oral dosage formulation of topiramate for once-a-day administration comprising single population of pellets and one or more pharmaceutically acceptable excipients, which is devoid of alkalizers.

For the present invention, as far as meaning and scope of usage of different terms in the specification is concerned, these may be defined as follows;

The term “topiramate” includes topiramate or any pharmaceutically acceptable salts or derivative thereof, including polymorphs, hydrates, solvates or amorphous forms.

The term "about" has been recited here and throughout the specification to account for variations, which can arise from inaccuracies in measurement inherent and understood by those of ordinary skill in the chemical and pharmaceutical arts.

The term “pellets”, as used herein, includes, without any limitations on the nature and size thereof, any substantially spherical shaped particle or any substantially spherical structural units that may be incorporated into any oral solid dosage form, preferably the tablets or capsules.

The term “sustained release” is defined herein as release of a pharmaceutically active agent in a continuous manner over a prolonged period of time wherein “prolonged period of time” is a continuous period of time of greater than about 1 hour, preferably greater than about 4 hours, more preferably greater than about 8 hours, even more preferably greater than about 12 hours and most preferably greater than about 16 hours up to more than about 24 hours.

The term “pharmaceutically acceptable excipient(s)” used in pharmaceutical formulation of invention comprise, but not limited to, diluents or fillers, binders, disintegrants, lubricants, glidants, wetting agents, pore forming agents, release modifying agents, surfactants, plasticizers, anti-sticking agents, or mixtures thereof.

The term "solid oral dosage formulation” as used herein includes solid dosage forms for oral administration, preferably as tablet or capsule.

The term "inert spheres", as used herein, includes, without any limitations on the nature and size thereof, any particle or any structural units which are devoid of active pharmaceutical ingredient/s. The inert spheres useful in the present invention may be selected from, but are not limited to, a group of cellulose spheres, silicon dioxide, starch or sugar spheres, preferably sugar sphere.

The term “polyvinyl acetate polymer or derivative thereof” (PVAc) as used herein, includes, without any limitations, polyvinyl acetate polymer in pure form, its copolymers, blend or dispersions, preferably aqueous dispersion of polyvinyl acetate which may additionally comprises polyvinyl pyrrolidone or/and surfactants such as sodium lauryl sulphate, or mixtures thereof.

The term “single population” as used herein means single type of pellets used for preparation of final dosage form such as tablet or capsules. It excludes combination of separate units of immediate release pellets and sustained release pellets.

Thus, in another embodiment, present invention provides sustained release solid oral dosage formulation of topiramate for once-a-day administration which comprises single population of pellets.

For the purpose of this invention, a person skilled in the art can replace pellets with any particles or structural units like microgranules, granules, compacts, spheres, beads, spheroids or microcapsule particles. Thus, any structural units that may be formulated into any solid dosage sustained release form such as tablet or filled into capsule can form the part of this invention.

In specific embodiment, pellet comprises;
a) an inert sphere,
b) optionally a seal coat,
c) an inner layer comprising Topiramate,
d) an outer layer consisting essentially of polyvinyl acetate polymer or derivatives thereof as atleast one of sustained release material in the formulation and
e) optionally an additional outermost layer comprising Topiramate.

Such inert sphere may be generally present in an amount of from about 10% to about 70% by weight, preferably in an amount of about 20% to about 60% by weight and more preferably in an amount of about 30% to about 60% by weight of pellet.

The seal coating material may include a binder, film forming polymer, a plasticizer, anti-sticking agent and like, which is commonly known to the person of ordinary skill in the art.

The inner layer may comprise topiramate, salt or any derivative thereof and one or more other pharmaceutically acceptable excipients selected from binders, pore formers, surfactants, plasticizers, anti-sticking agents, lubricants, glidants, or mixtures thereof.

Such inner layer may form about 20 to about 70%, more preferably about 30 to about 60 and even more preferably about 40 to about 55% by weight of the pellet.

The outer layer may consist essentially of polyvinyl acetate polymer or derivative thereof as atleast one of sustained release material and one or more other pharmaceutically acceptable additives known in the art selected from binders, pore formers, release modifying agents, surfactants, plasticizers, anti-sticking agents, lubricants, glidants, or mixtures thereof.

Thus, in an embodiment, said outer layer consists essentially of polyvinyl acetate polymer or derivative thereof as atleast one sustained release material to control the release of the drug in formulation.

Generally, the PVAc may be used in either substantially pure form or as a blend, later is preferred. If a substantially pure form of PVAc is used, it can be dissolved in a suitable non-aqueous solvent to provide a coating solution.

A commercial blend contains primarily a polyvinyl acetate polymer, polyvinylpyrrolidone and minor amounts of sodium lauryl sulphate.

More specifically, the preferred aqueous based coating solution is KOLLICOAT SR 30 D (BASF Corporation) and whose composition is about 27% PVAc polymer, about 2.7% polyvinylpyrrolidone (PVP), about 0.3% sodium lauryl sulphate (solid content 30%w/w).

It is a low-viscosity, non-sticky aqueous dispersion of polyvinyl acetate which is available with brand name such as Kollicoat® SR, Kollicoat® SR 30D from BASF.

In an embodiment of present invention, Kollicoat® SR 30 D may form about 40 to about 95%, more preferably about 50 to about 90% or even more preferably about 60 to about 90% by weight of the outer layer.

Alternatively, Kollicoat® SR 30 D may form about 2 to about 40%, more preferably about 5 to about 30 % by weight of pellet.

The coating composition of the present invention is preferably applied in the form of a polyvinyl acetate (PVAc) polymer based aqueous coating dispersion.

It was observed that use of PVAc in the formulation of present invention not just facilitated in providing robust and cost effective process but also minimized dose-dumping effect or batch-wise variations of the release profile of topiramate.

Further, additional release controlling material of the present invention may include, but not limited to, any material of nature hydrophilic, hydrophobic or mixtures thereof.

Such hydrophilic materials may include, without limitation, one or more of cellulose derivatives, polysaccharides, a polyacrylate, polyvinyl alcohol or polyvinyl pyrrolidone, carbopols, polyethylene oxides, magnesium aluminium silicate, modified starch derivatives or a derivative of such hydrophilic polymers or combinations thereof.

Suitable cellulose derivatives may include one or more of methylcellulose, ethyl cellulose, hydroxymethyl cellulose, different viscosity grades of hydroxypropyl methylcellulose, hydroxy propyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose or a combination thereof.

Such hydrophobic material may include, without limitation, one or more of waxes, ethylcellulose, copolymer of acrylic acid and methacrylic acid esters, polyethylene, polyamide, polyvinyl acetate copolymers, glycerol monostearate, stearylalcohol, glyceryl behenate or mixtures thereof. Copolymer may include ethylene-vinyl acetate copolymer, Isooctyl acrylate/acrylamide/vinyl acetate copolymer, polyester/ethylene-vinyl acetate, polyvinyl acetate phthalate, polyvinyl chloride-polyvinyl acetate copolymer, vinyl acetate - crotonic acid copolymer, PVP-VA copolymer, Polyvinyl Alcohol Graft Polyethylene Glycol Copolymer and like. Polyvinyl acetate copolymers are available with brand names such as Kollicoat EMM 30D, Kollicoat MAE with different grades.

Thus, total sustained release material used in formulation may form about 2 to about 40% or more preferably about 5 to about 30% weight of pellet.

For obtaining optimum sustained release functionality, depending on the solubility of the active ingredient and the required dissolution profile, pore formers may be added to adjust the release of drug from core of formulation.

Suitable pore former may be selected, without limitation, from the group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropyl methyl cellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone, polyethylene oxide, carbomer, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(a-?)alkylenediols, or mixtures thereof, preferably polyvinylpyrrolidones.

An additional outermost layer comprising Topiramate can be coated optionally over the outer layer. Said outermost layer may comprise topiramate, salt or any derivative thereof and one or more other pharmaceutically acceptable excipients selected from release controlling agents, binders, pore formers, surfactants, plasticizers, anti-sticking agents, lubricants, glidants, or mixtures thereof. Outermost layer comprises about 10% of total topiramate of the composition.

Said outermost layer over the outer layer forms about 2-20%, preferable 5-15% of the total weight of pellet.

Suitable wetting agents may include non-ionic surfactants, ionic surfactants, or mixtures thereof.

Suitable plasticizers useful for the purposes of the present invention may include, without limitation, such as triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, acetylated monoglycerides, glycerin, triacetin, polyethylene glycol, propylene glycol, phthalate esters, castor oil, sorbitol and dibutyl sebacate; anti-tackiness agents like talc and glyceryl monostearate; pigments like titanium dioxide or ferric oxides, polishing agents like glyceryl monostearate, carnauba wax, candellila wax, or mixtures thereof, preferably triethyl citrate.

Suitable lubricants, glidants, anti-adherents or antitacking agents may include, without limitations, one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin, or mixtures thereof, preferably ultramicronized talc.

In another preferred embodiment, a stable sustained release formulation of topiramate for once-a-day administration is devoid of alkalizers.

Such alkalizers may include any of those pH regulating agents that are employed in prior art related to topiramate compositions to improve stability of the product.

In one of further embodiment, the total amount of topiramate in the composition varies from 0.5 mg to about 1000 mg, preferably selected from 25mg, 50mg, 100mg, 150mg and 200 mg.

In another embodiment, topiramate or a pharmaceutically acceptable salt is present in the composition in an amount of from about 0.5% to about 85% by weight, preferably from about 20% to about 70% by weight, more preferably from about 20% to about 60% by weight of the formulation.

In another embodiment, said pellets of the present invention, along with one or more other suitable pharmaceutically acceptable excipients, can be processed, preferably, into a final formulation such as a tablet or capsule.

The pellets can further be coated with one or more additional coating layer/s to provide further protection from moisture, static charge reduction, taste masking and coloring attributes to the particulates.

In a preferred embodiment pellets, optionally, are mixed with one or more other pharmaceutically acceptable excipients to be filled into capsule shell.

A suitable capsule shell can comprise of, but is not limited to, hydroxypropyl methylcellulose and gelatin, preferably hard gelatin capsule.

The pharmaceutical formulations as described herein may be prepared by the processes known to the person having ordinary skill in the art of pharmaceutical technology.

Topiramate is introduced to the inert sphere by techniques known to one skilled in the art, such as drug layering, powder coating, extrusion/spheronization, roller compaction or granulation.

Preferably, the introduction method is drug layering by spraying a suspension of topiramate and a binder onto the inert sphere.

Thus, in one of another embodiment, a sustained release solid oral dosage formulation of topiramate is prepared by a process comprising the steps of:
? providing inert spheres
? optionally, seal coating of inert spheres
? coating of inert spheres with an inner layer comprising topiramate
? optionally, barrier coating of drug loaded spheres
? coating of drug loaded spheres with an outer layer consisting essentially of polyvinyl acetate polymer or derivatives thereof
? optionally, an additional outermost layer coating comprising topiramate
? lubricating and filling of said pellets into a capsule shell.

Similarly, the sustained release solid oral dosage formulation of topiramate may be prepared by a process comprising the steps of:
? mixing and/or granulating topiramate with sustained release material such as polyvinyl acetate polymer derivatives thereof and one or more pharmaceutically acceptable excipients to form a wet mass;
? extruding the wet mass of step (i);
? spheronizing the product of step (ii) to form pellets; and
? processing the pellets to form solid oral dosage formulation.

The invention is further illustrated by the following example which is exemplary in nature and does not limit the scope of the invention.

Example 1

S. No Ingredients Function Mg/Cap
Seal Coating
1 Sugar Spheres Carrier 200.00
2 Povidone K-30 Binder 4.30
3 Triethyl Citrate Plasticizer 0.70
4 Talc Antitacking agent 1.00
5 Purified Water Vehicle QS
Total 206.00
Total Solid Content 6.00
Drug Loading
6 Seal Coated spheres Carrier 206.00
7 Topiramate Active 200.00
8 Povidone K-30 Binder 20.00
9 Talc Antitacking agent 55.00
10 Methanol Solvent QS
Total 481.00
Total solid content 275.00
11 Drug loaded spheres Carrier 481.00
12 Kollicoat SR 30 D Rate controlling agent 51.00
12 Povidone K-30 Binder 10.50
14 Talc Antitacking agent 5.25
15 Triethyl Citrate Plasticizer 5.25
16 Purified Water Vehicle QS
Total 553.00

Process of Manufacturing:
Seal coating on sugar spheres:
1. Polyvinylpyrrolidone, Talc and Triethyl citrate were added in Purified Water to get
homogeneous dispersion.
2. Sugar spheres were loaded in Fluidised Bed Processor (FBP) and coated with prepared dispersion of step 1.
3. Coated spheres were dried.
Drug coating on seal coated spheres:
4. Topiramate, Polyvinylpyrrolidone and Talc were added in Methanol to get homogeneous dispersion.
5. Seal coated spheres were loaded in FBP and coated with prepared dispersion of step 4.
6. Coated spheres were dried.
Release controlling coating:
7. Kollicoat SR 30 D, Polyvinylpyrrolidone, Triethyl Citrate and Talc were added in Purified Water to get homogeneous dispersion.
8. Drug coated spheres were loaded in Wurster coater and coated with prepared dispersion of step 7 up to desired weight gain.
9. Coated pellets were dried and filled in empty hard gelatin capsule.

Example 2

S. No Ingredients Function Mg/Cap
Seal Coating
1 Sugar Spheres Carrier 200.00
2 Povidone K-30 Binder 4.30
3 Triethyl Citrate Plasticizer 0.70
4 Talc Antitacking agent 1.00
5 Purified Water Vehicle QS
Total 206.00
Drug Coating
6 Seal Coated spheres Carrier 206.00
7 Topiramate Active 180.00
8 Povidone K-30 Binder 18.00
9 Talc Antitacking agent 49.50
10 Methanol Solvent QS
Total 453.50
Polymer Coating
11 Drug loaded spheres Carrier 453.50
12 Kollicoat SR 30 D Rate controlling agent 32.14
12 Povidone K-30 Binder 6.67
14 Talc Antitacking agent 3.65
15 Triethyl Citrate Plasticizer 3.14
16 Purified Water Vehicle QS
Total 449.10
Drug Coating
17 Polymer coated pellets Carrier 449.10
18 Topiramate Active 20.00
19 Povidone K-30 Binder 2.00
20 Talc Antitacking agent 5.90
21 Methanol Solvent QS
Total 527.00

Process of Manufacturing:
Seal coating on sugar spheres:
1. Polyvinylpyrrolidone, Talc and Triethyl citrate were added in Purified Water to get
homogeneous dispersion.
2. Sugar spheres were loaded in Fluidised Bed Processor (FBP) and coated with prepared dispersion of step 1.
3. Coated spheres were dried.
Drug coating on seal coated spheres:
4. Topiramate, Polyvinylpyrrolidone and Talc were added in Methanol to get homogeneous dispersion.
5. Seal coated spheres were loaded in FBP and coated with prepared dispersion of step 4.
6. Coated spheres were dried.
Release controlling coating:
7. Kollicoat SR 30 D, Polyvinylpyrrolidone, Triethyl Citrate and Talc were added in Purified Water to get homogeneous dispersion.
8. Drug coated spheres were loaded in Wurster coater and coated with prepared dispersion of step 7 up to desired weight gain.
9. Coated pellets were dried.
Additional outermost Drug Coating on Polymer coated pellets:
10. Topiramate, Polyvinylpyrrolidone and Talc were added in Methanol to get homogeneous dispersion.
11. Polymer coated pellets were loaded in FBP and coated with prepared dispersion of step 10.
12. Coated pellets were dried and filled in empty hard gelatin capsule.

The dissolution performance for the topiramate composition of the invention was measured using a USP dissolution apparatus Type III (Bio-disc) and the amount of drug released was analyzed via UV analysis. Release times were measured by allowing the composition to sink in the dissolution vessel and operating the apparatus at 15 Dips Per Minute (dpm). To mimic the in-vivo condition dissolution medium was selected with gradient increase in pH as tabulated below.

Dissolution performance for the composition of Example 1 in USP type III (Bio disc) apparatus at 15 dpm using 250 ml of dissolution medium of different pH. Time (Hr) % drug release 1,2,4,6,8,10,12,14,16,24 hr is presented in table 1 below.

Table 1: Dissolution data
Time Intervals 0 1 2 4 6 8 10 12 14 16 24
Dissolution Media 0.1 N HCl pH 4.5 pH 6.8 pH 7.5 phosphate buffer, App-III, 15 DPM, 250 ml
Trokendi XR B.
No. 474296 0 15 22 33 45 55 64 71 77 80 99
Example 1 0 10 19 35 46 56 65 73 80 86 99

Thus it is observed that composition, when subjected to in vitro dissolution testing, releases at least about 20% and not more than about 70% of topiramate within 2 hours in vitro, more preferably at least about 20% and not more than about 60% of topiramate within 2 hours in vitro; at least about 20% and not more than about 80% of topiramate within 4 hours in vitro, more preferably at least about 30% and not more than about 80% of topiramate within 4 hours in vitro; at least about 50% of topiramate within 8 hours in vitro and at least about 90% of topiramate within 24 hours in vitro.

Table 2: Stability Data
S. No. Tests Storage Period
(In Months)
Initial 1 Month
1 Topiramate Related compound A impurity 0.01% 0.01%
2 Maximum single unknown impuritiy 0.02% 0.04%
3 Total
impurities 0.03% 0.06%

Thus, it is observed that product is stable up to 1 Month at 40°C/75%RH.

Hence, while specific embodiments have been illustrated and described, those skilled in the art will recognize that, various modifications and changes may be made without departing from the spirit and scope of the invention, and thus will be considered to be within the scope of this invention as defined by the appended claims.