DESC:FIELD OF THE INVENTION:
The present invention relates to topiramate extended-release composition. The present invention specifically relates to extended-release composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is in the form of tablet or capsule. The present invention specifically relates to extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is devoid of immediate release component, cellulosic polymer or acrylic polymer.

BACKGROUND OF THE INVENTION:
Topiramate is 2,3:4,5-Di-O-isopropylidine-ß-D-fructopyranose sulfamate, and has the following chemical structure:

Topiramate is a white crystalline powder with a bitter taste. Topiramate is a sulfamate-substituted monosaccharide. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3.
Topiramate formulations commercially available in the United States of America under the brand name of Topamax Capsule, 15 & 25MG; Topamax Tablet, 25, 50, 100 & 100MG; Qudexy XR Capsules, 25, 50, 100, 150 & 200MG; Trokendi XR Capsules, 25, 50, 100 & 200MG & Eprontia Oral solution 25MG/ML and are indicated for treatment of Epilepsy: Initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older; adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older and Preventive treatment of migraine in patients 12 years of age and older.
PCT application No. WO 2008070670 describes a novel enhanced immediate release formulation of topiramate for oral administration to a mammalian subject, wherein at least 80% of the active compound is dissolved in a time period of not more than 30 minutes. The formulation comprises topiramate as an active ingredient and at least one complexing agent. The application describes a highly soluble complex of topiramate with a cyclodextrin which is selected from a group consisting of hydroxypropyl-ß-cyclodextrin, ß-cyclodextrin, .gamma.-cyclodextrin, and a-cyclodextrin, or its derivative.
PCT application No. WO 2008061226 describes more soluble and bioavailable form of topiramate for once-daily sustained-release dosage form of topiramate or salts thereof wherein the formulation comprises an enhanced immediate release coated bead population in addition to two extended release (XR) coated bead populations, wherein each XR component 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.
US Patent application no. 20140348931 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.
PCT Appl. No. WO2014143380 is directed to extended-release topiramate capsule that includes a capsule shell containing a 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; and wherein the coating includes one or more release controlling agent(s).
US Patent application no. 20160235776 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.
U.S. Pat. No. 4,513,006 discloses topiramate and its use for treating epilepsy and glaucoma.
PCT application No. WO2005048981 discloses a controlled release formulation of topiramate in a liquid dosage form.
PCT application No. WO2014167439 discloses modified release pharmaceutical compositions comprising at least two types of components, wherein at least one type of the component comprises a matrix of topiramate or salts thereof and one or more release modifying substances.
US Pat. No. 10,363,224 discloses an extended-release topiramate capsule that includes a capsule shell containing a 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; and wherein the coating includes one or more release controlling agent(s).
Despite the above mentioned prior art, there still exists a need for a pharmaceutical composition of topiramate and process for the preparation thereof which is able to overcome the problems associated with the existing formulation such as solubility, stability and impurity.
SUMMARY OF THE INVENTION:
The present invention relates to an extended-release composition comprising topiramate and pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is devoid of immediate release component.
Another embodiment of the present invention relates to an extended-release capsule composition, wherein said composition is devoid of uncoated active ingredient, cellulosic polymer or acrylic polymer.
Another embodiment of the present invention relates to an extended-release capsule composition comprising one or more coatings on extended release coating comprising topiramate and polyvinyl acetate polymer.
Another embodiment of the present invention relates to an extended-release capsule composition comprising one or more coatings on extended release coating comprising topiramate and polyvinyl acetate polymer, wherein said coating comprises pH dependent polymers such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimelliate or like.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof and delayed release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof and delayed release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with about 0.1% w/w to about 2% w/w polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 20% w/w to about 40 % w/w topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof in an amount of about 1% w/w to about 20% w/w and delayed release component comprises (a) sugar spheres coated with 0.01% w/w to about 2% w/w polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 5% w/w to about 20 % w/w topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate in amount of about 1% w/w to about 10% w/w; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.

DESCRIPTION OF THE INVENTION:
The present invention relates to an extended-release composition comprising topiramate and pharmaceutically acceptable excipients
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
The term "topiramate" used throughout the specification refers to not only topiramate per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
The term "modified release" used throughout the specification shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. Types of modified release include controlled, prolonged, sustained, extended, delayed, and the likes.
The term "component" used throughout the specification refers to mini-tablet, tablet, pellet, bead or granule prepared by standard methods known to the person skilled in the art, including but not limited to compression, granulation, spray coating, and extrusion/spheronization.
The term "pellets" used throughout the specification refers, but not limited to a carrier for pharmacologically active ingredients. Methods of manufacturing pellets for pharmaceutical use in both conventional (immediate release) and extended release single dosage forms include, but not limited to, extrusion/spheronization.
The concentration of topiramate used in the extended release composition is from 0.5% to 50% (w/w) of total weight of the composition.
In one embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein topiramate is present in an amount of about 25 mg or about 50 mg or about 100 mg or about 200 mg.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is two components in the form of extended release component and delayed release component.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is devoid of immediate release component.
Another embodiment of the present invention relates to an extended-release capsule composition, wherein said composition is devoid of uncoated active ingredient, cellulosic polymer or acrylic polymer.
Another embodiment of the present invention relates to an extended-release capsule composition comprising one or more coatings on extended release coating comprising topiramate and polyvinyl acetate polymer.
The polymers used herein may be water soluble polymers, water insoluble polymers, water permeable polymers and pH dependent polymers.
Another embodiment of the present invention relates to an extended-release capsule composition comprising one or more coatings on extended release coating comprising topiramate and polyvinyl acetate polymer, wherein said coating comprises pH dependent polymers such as phthalate or like.
The pharmaceutical composition of the present invention may be developed in the form a capsule, a tablet, a caplet and a mini-tablet. Preferably, the dosage form is in the form of a capsule.
In another embodiment, the extended-release pharmaceutical composition in accordance with the present invention retains at least 90% w/w of the potency of topiramate or salt thereof, when stored at 25°C and 60% relative humidity or at 40°C and 75% relative humidity for at least 1 month.
In another embodiment, the extended-release pharmaceutical composition in accordance with the present invention, wherein the composition remains stable when stored at 25°C and 60% relative humidity or at 40°C and 75% relative humidity for at least 1 month.
In another embodiment, the extended-release pharmaceutical composition in accordance with the present invention, wherein increase in the total impurity is not more than (NMT) 0.5 %, when stored at 25°C and 60% relative humidity or at 40°C and 75% relative humidity for at least 1 month.
In another embodiment, the extended-release pharmaceutical composition in accordance with the present invention, there is no major change in dissolution profile measured using pH 7.5 phosphate buffer using USP type II (paddle) with sinker with volume of 750 mL, when stored at 25°C and 60% relative humidity or at 40°C and 75% relative humidity for at least 1 month.
The topiramate extended release compositions can be any kind of pharmaceutical bead, pellet, or other pharmaceutical particulate that contains topiramate and releases the topiramate in an extended manner. This sustained or extended release characteristic is in contrast to an immediate release profile which generally requires release of 90% of the topiramate in 30 minutes as measured in a suitable in vitro dissolution test. For purposes of the present invention, a sustained or extended release topiramate does not release 90% of the topiramate in less than 2 hours in a USP Type I apparatus (Basket) using 0.1 N HCl as the dissolution media.
The delayed release topiramate composition comprises a topiramate, such as those having the preferred in vitro dissolution release profile described above, having an outer coating layer that causes a delay in the start of the release. Generally, the delay coating is designed to achieve a release delay in vivo of at least 3 hours, often within the range of 4-8 hours, before significant release starts. Delay coatings are generally known in the art and are usually based on pH, solubility, or a combination. A pH-dependent coating, also known as an enteric coating, changes solubility based on pH. At low pH such as found in the stomach, the coating is insoluble and prevents the body fluids from reaching and releasing the drug from the beads. At higher pH such as found in the intestines, the coating becomes soluble and is removed and/or becomes permeable thereby permitting the body fluids to reach and release the drug from the beads. The delay is controlled by the pH at which the coating becomes soluble and by the coating thickness/amount. A solubility-based coating uses a low water-soluble coating that slowly dissolves or erodes to reveal the underlying bead and thereby permit drug release to start. The solubility and thickness/amount of the coating control the time of the delay (e.g., how long until the coating is gone). Both kinds of coating can be used together in a hybrid fashion.
Though delay coatings of various constructions can achieve the same effect in vivo, they may provide different results in an in vitro dissolution test, depending upon the conditions, because of their design principles. For example, using the two media in vitro dissolution test described above, a pH-dependent delay coating will start to permit drug release shortly after the changeover to the pH 7.4 media. A solubility-based delay coating that is not pH-dependent will not be as affected by the media changeover.
The pharmaceutical composition containing the two kinds of components or beads is typically a unit dosage form for oral administration. The beads are frequently filled into a capsule but can also be mixed with excipients and compressed into tablets. If desired, the tablets could be bi-layer tablets having the sustained release topiramate in one layer and the delayed sustained release topiramate beads in the other layer, but such is not required. Other compositions including sachets containing the beads are also possible. The sachet composition, which may additionally include excipients such as a sweetener or taste masking agent, etc., can be swallowed directly from the package or it can be sprinkled onto food or deposited into a drink such as water or juice and then immediately consumed with the food or drink, respectively. Usually the composition contains only the two populations of beads: the sustained release topiramate beads and the delayed sustained release topiramate. It is possible, however, that additional topiramate types or populations are contained.
The enteric coating can prevent release of the drug in the stomach and/or intestine until the enteric coating is sufficiently soluble to permit diffusion, erosion, and/or is dissolved away. By selecting the kind of polymer(s) and the amount of coating, the enteric coating can provide any desired level of pH protection; e.g. release/soluble at pH 6, 6.8, 7, etc. Generally, the present invention prefers an enteric coating that is designed to release at pH 7 or greater, especially about pH 7.4. Commercially available enteric coatings are often designated by the manufacturer as having a release at specified pH. Those designated as having a release at pH 7 are thus deemed to be designed to release at pH 7 and are sometimes described as providing colon release. In the GI tract, the pH gradually increases in the small intestine from pH 6 to about pH 7.4 in the terminal ileum. In preferred embodiments of the present invention, the delayed sustained release topiramate are targeted to begin releasing in or near the terminal ileum. Even if designed to release at pH 7.4, for instance, enteric coatings are generally not perfect and often begin permitting appreciable release of the drug before pH 7. For purposes of the present invention, an enteric coating "designed to release at pH 7 or higher" includes those that have a significant reduction in release during hours 2-6 when the two media dissolution test is modified by replacing the pH 7.4 phosphate buffer media with pH 6.8 phosphate buffer media. A significant reduction is at least 50%. For example, if the delayed sustained release bead released 30% of the topiramate at hour 4 (second hour in the pH 7.4 buffer media), the same component would only release 15% or less at hour 4 when tested using the lower pH 6.8 buffer media. This 50% reduction would also apply at hour 6. Often the reduction is more significant, achieving only 35% or less, sometimes only 25% or less, of the release in pH 7.4 buffer when tested using the pH 6.8 buffer. As shown in the examples below, polyvinyl acetate phthalate is suitable for providing an enteric coating “designed to release at pH 7 or higher.”
Alternatively, the delay coating can be a time delay coating based on thickness and water solubility rather than sensitivity to pH. Generally, film formers for time-delayed release can be water soluble, dissolving during GI transit, or water insoluble which swell under physiological conditions whereupon drug release is controlled by diffusion through the swollen coating. The duration of time delay is influenced by the hydrophilic and swelling properties of the polymer and coat thickness. Examples of such polymers are cellulose acetates, ethylcellulose, glycerides, substituted methacrylates, polyvinyl acetate (such as Kollicoat® SR 30D which a polyvinyl acetate dispersion stabilized with povidone and sodium lauryl sulfate), hydroxypropyl methyl cellulose (HPMC), and carboxymethylcelluloses (CMC). In some embodiments, the coating contains polymers having low water solubility which slowly dissolve away. In other embodiments, the coating contains a mixture of water soluble and water insoluble polymers (or higher and lower water soluble polymers). By controlling the ratios of the polymers and the thickness/amount, the desired time delay can be achieved. Examples of water-soluble polymers include cellulose ethers such as HPMC, methylcellulose, hydroxyethylcellulose, Na CMC, polyvinyl acetate (such as Kollicoat® SR 30D which a polyvinyl acetate dispersion stabilized with povidone and sodium lauryl sulfate), and polyvinylpyrrolidone (PVP). Less soluble or insoluble polymers include ethylcellulose and polymethacrylates.
In an embodiment, the process of preparing the extended release pharmaceutical composition comprises steps of: (a) coating sugar sphere with polymers such as polyvinyl pyrrolidone optionally one or more pharmaceutical excipients (b) coating topiramate and optionally with one or more pharmaceutical excipients on the sugar spheres coated with seal coating (c) applying extended release coating comprising polymers with one or more pharmaceutical excipients on the topiramate containing layer (d) optionally, lubricating the topiramate extended release components; following similar steps (a)-(d) for the preparation of delayed release composition (e) filling the topiramate extended and delayed release components in capsule.
In certain embodiments, the coating also includes a pore former and/or a plasticizer.
The composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from, but not limited to, diluent, binder, disintegrant, glidant, lubricant, stabilizing agent, and flavoring agents.
The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.
The inert carrier used in the present invention includes, but are not limited to, a group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres. The amount of the inert carrier in the composition ranges from about 20% to about 95% w/w, and preferably from about 30% to about 90% w/w of the composition.
Topiramate is introduced to the inert carrier by techniques known to one skilled in the art such as drug layering, powder coating, extrusion/spheronization, roller compaction or dry/wet granulation. Preferably, the introduction method is drug layering by spraying a suspension of topiramate and a binder onto the inert carrier.
Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compressed may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, polyvinylpyrrolidone (PVP K30 or PVP K 90) and starch.
Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include, but not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Pore formers that are suitable for use in the coating formulation include, but are not limited to, hypromellose, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum, sodium alginate, povidone (i.e., polyvinylpyrrolidone), crospovidone, sodium starch glycolate, croscarmellose sodium, starch (e.g., pregelatinized starch), carbohydrates (e.g., mannitol, glucose, sucrose, fructose, mannose, galactose, sorbitol, and dextran), sodium chloride, potassium chloride, and calcium chloride. Preferred pore formers for use in the coating on the particle core include, but are not limited to, hydroxypropyl methylcellulose ("HPMC" such as hypromellose 2910 USP available under the trade name METHOCEL E5 Premium, METHOCEL E15 Premium), carboxymethylcellulose, methylcellulose, croscarmellose sodium, povidone, sodium starch glycolate, starch (e.g., pregelatinized starch), alginic acid, guar gum, and polyethylene glycol. Combinations of pore formers can be used if desired. Preferably, hydroxypropyl methylcellulose (hypromellose 2910) is used as a pore former (such as that available from The Dow Chemical Company under the trade designation METHOCEL E5 Premium).
One or more pore formers can be used in an amount of at least 5 %w/w, or at least 10 %w/w, or at least 15 %w/w, or at least 20 %w/w, or at least 22 %w/w, based on the total weight of the coating. One or more pore formers can be used in an amount of up to 30 %w/w, or up to 26 %w/w, or up to 25 %w/w, or up to 24 %w/w, based on the total weight of the coating. In certain embodiments, the particle coatings include 20 %w/w to 25 %w/w pore former(s), based on the total weight of the coating. In certain embodiments, the particle coatings include 22 %w/w to 24 %w/w pore former(s), based on the total weight of the coating.
Suitable plasticizers for use in the coating on the particle core include, but are not limited to, diethyl phthalate, triethyl citrate, dibutyl sebacate, polyethylene glycol, triacetin, tributyl citrate, glycerol, and propylene glycol. Combinations of plasticizers can be used if desired. Preferably, diethyl phthalate is used as a plasticizer.
One or more plasticizers can be used in an amount of at least 5 %w/w, or at least 10 %w/w, or at least 15 %w/w, based on the total weight of the coating. One or more plasticizers can be used in an amount of up to 30 %w/w, or up to 20 %w/w, or up to 18 %w/w, based on the total weight of the coating. In certain embodiments, the particle coatings include 10 %w/w to 20 %w/w plasticizer(s), based on the total weight of the coating. In certain embodiments, the particle coatings include 15 %w/w to 18 %w/w plasticizer(s), based on the total weight of the coating.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein the extended release component comprises one or more polymer selected from group comprising cellulose acetate, ethylcellulose, glyceride, substituted methacrylate, polyvinyl acetate, hydroxypropyl methyl cellulose, and carboxymethylcelluloses and polyvinylpyrrolidone.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein the extended release component comprises polyvinyl acetate, polyvinylpyrrolidone or mixture thereof.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein the extended release component comprises about 0.2 % w/w to about 10 % w/w of polyvinyl acetate, polyvinylpyrrolidone (povidone) or mixture thereof.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein the delayed release component comprises one or more polymer selected from group comprising cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimelliate.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein the delayed release component comprises polyvinyl acetate phthalate.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein the delayed release component comprises about 1 % w/w to about 10 % w/w of polyvinyl acetate phthalate.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof; and delayed release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof; and delayed release component comprises (a) sugar spheres coated with polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with about 0.1% w/w to about 2% w/w polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 20% w/w to about 40 % w/w topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof in an amount of about 1% w/w to about 20% w/w; and delayed release component comprises (a) sugar spheres coated with 0.01% w/w to about 2% w/w polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 5% w/w to about 20 % w/w topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate in amount of about 1% w/w to about 10% w/w; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with about 0.2% w/w to about 1% w/w polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 25% w/w to about 35 % w/w topiramate (c) extended release layer onto drug coating layer comprising polymers such as polyvinyl acetate or povidone or combination thereof in an amount of about 0.2% w/w to about 10% w/w ; and delayed release component comprises (a) sugar spheres coated with 0.1% w/w to about 1.5% w/w polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 7% w/w to about 15 % w/w topiramate (c) delayed release layer onto drug coating layer comprising enteric polymers such as polyvinyl acetate phthalate in amount of about 2% w/w to about 5% w/w; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) sugar spheres coated with about 0.49% w/w of polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 25.68% w/w of topiramate (c) extended release layer onto drug coating layer comprising about 6.11 % w/w of mixture of polyvinyl acetate and povidone (such as polyvinyl acetate dispersion 30% (Kollicoat SR 30 D)) (d) about 0.99 % w/w of povidone; and delayed release component comprises (a) sugar spheres coated with about 0.51% w/w of polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 8.56% w/w of topiramate (c) delayed release layer onto drug coating layer comprising about 3.58 % w/w of polyvinyl acetate phthalate; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Still another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component wherein extended release component comprises (a) sugar spheres coated with about 0.57% w/w of polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 30.24% w/w of topiramate (c) extended release layer onto drug coating layer comprising about 7.19 % w/w of mixture of polyvinyl acetate and povidone (such as polyvinyl acetate dispersion 30% (Kollicoat SR 30 D)) (d) about 1.17 % w/w of povidone; and delayed release component comprises (a) sugar spheres coated with about 0.19% w/w of polyvinylpyrrolidone (b) drug coating layer onto coated sugar spheres containing about 10.08% w/w of topiramate (c) delayed release layer onto drug coating layer comprising about 2.93 % w/w of polyvinyl acetate phthalate; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Still another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component wherein extended release component comprises (a) about 13.39 mg sugar spheres coated with about 0.35 mg of polyvinylpyrrolidone and about 0.05 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 18.75 mg of topiramate, about 4.68 mg of polyvinylpyrrolidone, about 0.50 mg of polyethylene glycol 400 and about 0.84 mg of micronized talc (c) extended release layer onto drug coating layer comprising about 4.46 mg of polyvinyl acetate, about 0.72 mg of povidone, about 0.49 mg of propylene glycol and about 2.26 mg of micronized talc; and delayed release component comprises (a) about 13.9 mg of sugar spheres coated with about 0.37 mg of polyvinylpyrrolidone and about 0.05 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 6.25 mg of topiramate, about 1.80 mg of polyvinylpyrrolidone, about 0.19 mg of polyethylene glycol 400 and about 0.33 mg of micronized talc (c) delayed release layer onto drug coating layer comprising about 2.61 mg of polyvinyl acetate phthalate and about 0.25 mg of micronized talc; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Still another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component wherein extended release component comprises (a) about 26.78 mg sugar spheres coated with about 0.71 mg of polyvinylpyrrolidone and about 0.09 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 37.50 mg of topiramate, about 9.36 mg of polyvinylpyrrolidone, about 0.99 mg of polyethylene glycol 400 and about 1.69 mg of micronized talc (c) extended release layer onto drug coating layer comprising about 8.92 mg of polyvinyl acetate, about 1.45 mg of povidone, about 0.98 mg of propylene glycol and about 4.51 mg of micronized talc; and delayed release component comprises (a) about 27.80 mg of sugar spheres coated with about 0.74 mg of polyvinylpyrrolidone and about 0.10 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 12.5 mg of topiramate, about 3.60 mg of polyvinylpyrrolidone, about 0.380 mg of polyethylene glycol 400 and about 0.65 mg of micronized talc (c) delayed release layer onto drug coating layer comprising about 5.22 mg of polyvinyl acetate phthalate and about 0.49 mg of micronized talc; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Still another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component, wherein extended release component comprises (a) about 53.55 mg sugar spheres coated with about 1.42 mg of polyvinylpyrrolidone and about 0.19 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 75.00 mg of topiramate, about 18.71 mg of polyvinylpyrrolidone, about 1.98 mg of polyethylene glycol 400 and about 3.38 mg of micronized talc (c) extended release layer onto drug coating layer comprising about 17.84 mg of polyvinyl acetate, about 2.89 mg of povidone, about 1.97 mg of propylene glycol and about 9.02 mg of micronized talc; and delayed release component comprises (a) about 17.85 mg of sugar spheres coated with about 0.47 mg of polyvinylpyrrolidone and about 0.06 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 25.00 mg of topiramate, about 6.24 mg of polyvinylpyrrolidone, about 0.66 mg of polyethylene glycol 400 and about 1.13 mg of micronized talc (c) delayed release layer onto drug coating layer comprising about 7.26 mg of polyvinyl acetate phthalate and about 0.73 mg of micronized talc; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Still another embodiment of the present invention relates to an extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component wherein extended release component comprises (a) about 107.11 mg sugar spheres coated with about 2.84 mg of polyvinylpyrrolidone and about 0.37 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 150 mg of topiramate, about 37.42 mg of polyvinylpyrrolidone, about 3.97 mg of polyethylene glycol 400 and about 6.75 mg of micronized talc (c) extended release layer onto drug coating layer comprising about 35.68 mg of polyvinyl acetate, about 5.78 mg of povidone, about 3.94 mg of propylene glycol and about 18.04 mg of micronized talc; and delayed release component comprises (a) about 35.70 mg of sugar spheres coated with about 0.95 mg of polyvinylpyrrolidone and about 0.12 mg of micronized talc (b) drug coating layer onto coated sugar spheres containing about 50.00 mg of topiramate, about 12.47 mg of polyvinylpyrrolidone, about 1.32 mg of polyethylene glycol 400 and about 2.25 mg of micronized talc (c) delayed release layer onto drug coating layer comprising about 14.53 mg of polyvinyl acetate phthalate and about 1.46 mg of micronized talc; wherein extended release and delayed release components are mixed or sifted together and filled into the capsules.
Bioequivalence is established by comparing pharmacokinetic parameters, for example mean AUC and Cmax of the present invention with Trokendi® extended release capsules in healthy human subjects.
The term “AUC” refers to the area under the time/plasma concentration curve after the administration of composition of topiramate extended release to healthy human subjects.
The term “Cmax” refers to the maximum concentration of topiramate in the blood following the administration of composition of topiramate extended release to healthy human subjects.
The term “Tmax” refers to the time at which the peak plasma level concentration of topiramate is attained in a healthy human subjects following administration of composition of topiramate extended release.
Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
The present invention is further illustrated by reference to the following examples disclosing various dosage forms which is for illustrative purpose only and does not limit the scope of the invention in any way.
Example 1: Topiramate Extended Release Capsule
Table 1a: Topiramate extended release component composition
S. No Topiramate ER capsule 1A 1B 1C 1D
Ingredients mg/cap mg/cap mg/cap mg/cap
Stage Seal coat
1 Sugar Spheres 106 107 108.2 107.7
2 PVP K 30 3.00 2.80 2.90 2.95
3 Micronized Talc 0.35 0.30 0.38 0.29
4 Isopropyl Alcohol q. s. q. s. q. s. q. s.
5 Purified water q. s. q. s. q. s. q. s.
Stage Drug coat
1 Topiramate 150 150 150 150
2 PVP K 90 38.10 37.50 37.65 37.95
3 Polyethylene glycol 400 4.5 4.0 4.3 4.45
4 Micronized Talc 6.60 6.50 6.65 6.45
5 Purified water q. s. q. s. q. s. q. s.
Stage Extended release coat
1 Polyvinyl acetate dispersion 30% (Kollicoat SR 30 D) 36.10 35.75 35.70 35.80
2 PVP K 30 5.90 5.80 5.95 5.85
3 Propylene glycol 3.85 3.90 3.88 3.95
4 Micronized Talc 16.40 16.35 16.45 16.50
5 Purified water q. s. q. s. q. s. q. s.
6 Micronized Talc 1.80 1.75 1.80 1.85
Stage Lubrication
1 Micronized Talc 4.10 4.00 4.15 3.95

Table 1b: Topiramate delayed release component composition
S. No Topiramate ER capsule 1A 1B 1 C 1D
Ingredients mg/cap mg/cap mg/cap mg/cap
Stage Seal coat
1 Sugar Spheres 35.75 35.80 35.90 35.85
2 PVP K 30 0.85 0.90 0.85 0.93
3 Micronized Talc 0.20 0.10 0.15 0.18
4 Isopropyl Alcohol q. s. q. s. q. s. q. s.
5 Purified water q. s. q. s. q. s. q. s.
Stage Drug coat
1 Topiramate 50.00 50.00 50.00 50.00
2 PVP K 90 13.20 13.15 13.22 13.18
3 Polyethylene glycol 400 1.30 1.25 1.26 1.32
4 Micronized Talc 2.30 2.25 2.35 2.40
5 Purified water q. s. q. s. q. s. q. s.
Stage delayed release coat
1 Polyvinyl acetate phthalate 14.45 14.50 14.55 14.75
2 Micronized Talc 0.80 0.90 0.95 0.75
3 Isopropyl Alcohol q. s. q. s. q. s. q. s.
4 Purified water q. s. q. s. q. s. q. s.
5 Micronized Talc 0.55 0.50 0.55 0.60
Stage Lubrication
1 Micronized Talc 1.20 1.00 1.10 1.20

Manufacturing process for example 1a-1d
A. Seal Coat
1. PVP K30 in IPA was dissolved, purified water was added and mixed well to obtain clear solution.
2. Micronized Talc was added to step 1 and stirred to mix well.
3. Sugar spheres were coated with the seal dispersion using bottom spray technique in fluid bed processer.
4. Dried coated pellets were sifted and collected through appropriate sieves.
B. Drug coat
1. PVP K 90 was dissolved in Purified water PEG 400 was added in it.
2. Topiramate was added in step and stirred to mix well.
3. Micronized Talc was added to step 1 and stirred to mix well.
4. Seal coated sugar spheres were coated with the drug dispersion using bottom spray technique in fluid bed processer to obtain target weight gain.
5. Dried coated pellets were sifted through appropriate sieves.
C. Extended Release Coating
1. PVP K 30 was dissolved in half Purified water then propylene glycol was added in it.
2. Polyvinyl acetate dispersion 30% (Kollicoat SR 30 D) was added in step 1 and stirred to mix well.
3. Micronized Talc was dispersed in remaining half of purified water then added to step 1 and stirred to mix well.
4. Drug coated spheres were coated with the extended release coating dispersion using bottom spray technique in fluid bed processer.
5. Micronized Talc was sprinkled over the coated pellets to start the curing process.
6. Dried coated pellets were sifted through appropriate sieves.
7. Sifted pellets were lubricated with talc and store.
D. Delayed release coating
1. Opadry enteric (PVAP) was dispersed in IPA and purified water was added to mixed thereafter.
2. Micronized Talc was dispersed in step 1 and stirred to mix well.
3. Drug coated spheres were coated with the delayed release coating dispersion using bottom spray technique in fluid bed processer.
4. Micronized Talc was sprinkled over the coated pellets to start the curing process.
5. Dried coated pellets were sifted through appropriate sieves.
6. Sifted pellets were lubricated with talc and store.
E: Capsule Filing:
Lubricated extended release component and delayed release component were filled in to capsules.
Table 2: Dissolution profile:
Medium: pH 7.5 Phosphate buffer; Apparatus: USP Type II (Paddle) with sinker; Volume: 750 mL
Time (hrs) Trokendi® XR 200 mg Example 1 A Example 1 B Example 1 C Example 1 D
Cumulative Amount of Drug Released (%)
1 21 19 20 19 22
2 42 23 25 24 28
3 61 29 31 29 34
4 76 35 35 33 40
6 94 40 45 41 51
8 97 45 54 47 62
10 97 55 62 52 71
12 98 58 69 56 78
16 98 60 83 70 85
18 98 70 94 79 88
20 NA 89 98 84 91

Based on the above results, topiramate extended release formulation as per example 1B were found to be satisfactory.
Pharmacokinetic Studies under Fasting and Fed conditions:
Topiramate extended release 200 mg in Example 1 B was compared with Trokendi XR under fasting and fed condition in healthy adult human subjects.
Values for various pharmacokinetic parameters, including observed mean Cmax, AUC0-t and AUC0-8 were calculated for Example 1 B and are provided in Table 3 below.
Table 3: Pharmacokinetic parameters
Pharmacokinetic parameters Fasting Fed
Mean Cmax (ng/mL/mg) 2158.09 2392.65
Mean AUC0-t (ng · hr/mL/mg) 136316.4 141492.9
Mean AUC0-8 (ng · hr/mL/mg) 149212.7 154579.3

Example 2: Topiramate Extended Release Capsule of 25 mg and 50 mg
Table 4a: Topiramate extended release component composition
S. No Topiramate ER capsule 2A 2B 2C
Ingredients % w/w % w/w % w/w
Stage Seal coat
1 Sugar Spheres 18.34 18.34 18.34
2 PVP K 30 0.49 0.40 0.52
3 Micronized Talc 0.06 0.15 0.03
4 Isopropyl Alcohol q.s. q.s. q.s.
5 Purified water q.s. q.s. q.s.
Stage Drug coat
1 Topiramate 25.68 25.68 25.68
2 PVP K 90 6.41 6.10 7.20
3 Polyethylene glycol 400 0.68 0.80 0.40
4 Micronized Talc 1.16 1.35 0.65
5 Purified water q.s. q.s. q.s.
Stage Extended release coat
1 Polyvinyl acetate dispersion 30% (Kollicoat SR 30 D) 6.11 5.60 7.20
2 PVP K 30 0.99 1.62 0.40
3 Propylene glycol 0.67 0.71 0.59
4 Micronized Talc 2.79 2.73 2.27
5 Purified water q.s. q.s. q.s.
6 Micronized Talc 0.300 0.200 0.400
Stage Lubrication
1 Micronized Talc 0.70 0.70 0.70
Table 4b: Topiramate delayed release component composition
S. No Topiramate ER capsule 2A 2B 2C
Ingredients % w/w % w/w % w/w
Stage Seal coat
1 Sugar Spheres 19.04 19.04 19.04
2 PVP K 30 0.51 0.53 0.49
3 Micronized Talc 0.07 0.05 0.09
4 Isopropyl Alcohol q.s. q.s. q.s.
5 Purified water q.s. q.s. q.s.
Stage Drug coat
1 Topiramate 8.56 8.56 8.56
2 PVP K 90 2.47 2.42 2.53
3 Polyethylene glycol 400 0.26 0.23 0.29
4 Micronized Talc 0.45 0.53 0.36
5 Purified water q.s. q.s. q.s.
Stage delayed release coat
1 Polyvinyl acetate phthalate 3.58 3.47 3.62
2 Micronized Talc 0.23 0.37 0.15
3 Isopropyl Alcohol q.s. q.s. q.s.
4 Purified water q.s. q.s. q.s.
5 Micronized Talc 0.10 0.07 0.14
Stage Lubrication
1 Micronized Talc 0.36 0.36 0.36
Compositions of example 2 were prepared using same manufacturing process as used in example 1.
Example 3: Topiramate Extended Release Capsule of 100 mg and 200 mg
Table 5a: Topiramate extended release component composition
S. No Topiramate ER capsule 3A 3B 3C
Ingredients % w/w % w/w % w/w
Stage Seal coat
1 Sugar Spheres 21.59 21.59 21.59
2 PVP K 30 0.57 0.59 0.55
3 Micronized Talc 0.08 0.06 0.10
4 Isopropyl Alcohol q.s. q.s. q.s.
5 Purified water q.s. q.s. q.s.
Stage Drug coat
1 Topiramate 30.24 30.24 30.24
2 PVP K 90 7.54 6.89 8.02
3 Polyethylene glycol 400 0.80 0.93 0.68
4 Micronized Talc 1.36 1.78 1.00
5 Purified water q.s. q.s. q.s.
Stage Extended release coat
1 Polyvinyl acetate dispersion 30% (Kollicoat SR 30 D) 7.19 6.78 7.59
2 PVP K 30 1.17 1.64 1.09
3 Propylene glycol 0.79 0.68 0.92
4 Micronized Talc 3.28 3.38 2.81
5 Purified water q.s. q.s. q.s.
6 Micronized Talc 0.35 0.30 0.37
Stage Lubrication
1 Micronized Talc 0.83 0.83 0.83

Table 5b: Topiramate delayed release component composition
S. No Topiramate ER capsule 3A 3B 3C
Ingredients % w/w % w/w % w/w
Stage Seal coat
1 Sugar Spheres 7.20 7.20 7.20
2 PVP K 30 0.19 0.20 0.17
3 Micronized Talc 0.03 0.02 0.05
4 Isopropyl Alcohol q.s. q.s. q.s.
5 Purified water q.s. q.s. q.s.
Stage Drug coat
1 Topiramate 10.08 10.08 10.08
2 PVP K 90 2.51 2.39 2.58
3 Polyethylene glycol 400 0.27 0.32 0.24
4 Micronized Talc 0.45 0.52 0.41
5 Purified water q.s. q.s. q.s.
Stage delayed release coat
1 Polyvinyl acetate phthalate 2.93 2.76 3.04
2 Micronized Talc 0.18 0.39 0.05
3 Isopropyl Alcohol q.s. q.s. q.s.
4 Purified water q.s. q.s. q.s.
5 Micronized Talc 0.11 0.07 0.13
Stage Lubrication
1 Micronized Talc 0.24 0.24 0.24

Composition of example 3 was prepared using same manufacturing process as used in example 1.

Example 4: Dissolution profile of Topiramate Extended Release Capsule of examples 2 and 3; Medium: pH 7.5 Phosphate buffer; Apparatus: USP Type II (Paddle) with sinker; Volume: 750 mL
Table 6: Dissolution profile of Topiramate Extended Release Capsule of examples 2 and 3
Time (hrs) Trokendi® XR 200 mg Example 2A
(25 mg) Example 2A
(50 mg) Example 3A
(100 mg) Example 3A
(200 mg)
Cumulative Amount of Drug Released (%)
1 21 26 22 22 22
2 42 32 30 29 28
3 61 36 36 35 34
4 76 40 41 42 40
6 94 49 44 53 51
8 97 57 59 63 62
10 97 64 69 72 71
12 98 69 76 80 78
16 98 81 87 91 90
18 98 86 91 95 93
20 NA 90 95 98 96
Based on the above results, compositions of example 2 and 3 were found satisfactory.
Example 5: Stability study of compositions of Topiramate Extended Release Capsule of examples 2 and 3 based on impurity data
Table 7a: Impurity profile of Topiramate Extended Release Capsule of examples 2 during stability condition
Parameter Specification Initial 6M - 25/60* 6M - 40/75* 12M - 25/60 6M - 25/60 6M - 40/75 12M - 25/60
Example 2A (25 mg) Example 2A (50 mg)
Assay 90-110 103.7 104.3 103.9 105.4 104.2 103.3 106.2
Organic Impurity
Topiramate related compound A NMT 0.3 % ND* ND ND ND ND ND ND
Individual unspecified degradation products NMT 0.2 % ND ND ND ND ND ND ND
Total degradation product NMT 0.5 % ND ND ND ND ND ND ND
Limit of Sulfate and Sulfamate
Sulfate NMT 0.25 % 0.08 0.08 0.08 0.07 0.08 0.08 0.08
Sulfamate NMT 0.25 % 0.04 0.03 0.03 0.03 0.03 0.03 0.03
Water Content NMT 5.5 % 1.1 1.7 1.6 1.2 0.8 1 1.4
*ND: Not detected
*25/60: 25°C and 60% relative humidity
* 40/75: 40°C and 75% relative humidity
Table 7b: Impurity profile of Topiramate Extended Release Capsule of examples 3 during stability condition
Parameter Specification Initial 6M - 25/60 6M - 40/75 12M - 25/60 6M - 25/60 6M - 40/75 12M - 25/60
Example 3A (100 mg) Example 3A (200 mg)
Assay 90-110 103.7 99.2 102.1 101.9 102 101.1 101.6
Organic Impurity
Topiramate related compound A NMT 0.3 % ND ND ND ND ND ND ND
Individual unspecified degradation products NMT 0.2 % ND ND ND ND ND ND ND
Total degradation product NMT 0.5 % ND ND ND ND ND ND ND
Limit of Sulfate and Sulfamate
Sulfate NMT 0.25 % 0.08 0.07 0.08 0.07 0.07 0.08 0.07
Sulfamate NMT 0.25 % 0.04 0.03 0.03 0.05 0.03 0.04 0.02
Water Content NMT 5.5 % 1.1 1 0.6 1 1 1.4 1.1
*ND: Not detected
*25/60: 25°C and 60% relative humidity
* 40/75: 40°C and 75% relative humidity
Based on the above results, compositions of example 2 and 3 were found satisfactory after 6 months as stability condition of 40°C and 75% relative humidity and 12 months as stability condition of 25°C and 60% relative humidity.
Example 6: Stability study of compositions of Topiramate Extended Release Capsule of examples 2 and 3 based on dissolution data
Table 8a: Dissolution profile of Topiramate Extended Release Capsule of examples 2 during stability condition
Time (hrs) Example 2A (25 mg) Example 2A (50 mg)
12M - 25/60 6M - 40/75 12M - 25/60 6M - 40/75
Cumulative Amount of Drug Released (%)
1 26 26 22 25
6 49 48 47 49
18 91 86 85 90

Table 8b: Dissolution profile of Topiramate Extended Release Capsule of examples 3 during stability condition
Time (hrs) Example 3A (100 mg) Example 3A (200 mg)
12M - 25/60 6M - 40/75 12M - 25/60 6M - 40/75
Cumulative Amount of Drug Released (%)
1 21 22 22 23
6 47 49 48 49
18 87 90 89 88

Based on the above results, compositions of example 2 and 3 were found satisfactory after 6 months as stability condition of 40°C and 75% relative humidity and 12 months as stability condition of 25°C and 60% relative humidity.
Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. ,CLAIMS:We claim:
1. An extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component.
2. The extended-release capsule composition as claimed in claim 1, wherein the extended release component comprises one or more polymer selected from group comprising cellulose acetate, ethylcellulose, glyceride, substituted methacrylate, polyvinyl acetate, hydroxypropyl methyl cellulose, carboxymethylcelluloses and polyvinylpyrrolidone.
3. The extended-release capsule composition as claimed in claim 2, wherein the extended release component comprises polyvinyl acetate, polyvinylpyrrolidone or mixture thereof.
4. The extended-release capsule composition as claimed in claims 1-3, wherein the extended release component comprises about 0.2 % w/w to about 10 % w/w of polyvinyl acetate, polyvinylpyrrolidone or mixture thereof.
5. The extended-release capsule composition as claimed in claim 1, wherein the delayed release component comprises one or more polymer selected from group comprising cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, and cellulose acetate trimelliate.
6. The extended-release capsule composition as claimed in claim 5, wherein the delayed release component comprises polyvinyl acetate phthalate.
7. The extended-release capsule composition as claimed in claims 5-6, wherein the delayed release component comprises about 1 % w/w to about 10 % w/w of polyvinyl acetate phthalate.
8. An extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed release component,
wherein extended release component comprises
(a) sugar spheres coated with about 0.49% w/w of polyvinylpyrrolidone;
(b) Drug coating layer onto coated sugar spheres containing about 25.68% w/w of topiramate;
(c) extended release layer onto drug coating layer comprising about 6.11 % w/w of mixture of polyvinyl acetate and povidone;
(d) about 0.99 % w/w of povidone;
and delayed release component comprises
(a) sugar spheres coated with about 0.51% w/w of polyvinylpyrrolidone;
(b) drug coating layer onto coated sugar spheres containing about 8.56% w/w of topiramate;
(c) delayed release layer onto drug coating layer comprising about 3.58 % w/w of polyvinyl acetate phthalate.
9. An extended-release capsule composition comprising topiramate and pharmaceutically acceptable excipients, wherein said composition is having two components in the form of extended release component and delayed component,
wherein extended release component comprises
(a) sugar spheres coated with about 0.57% w/w of polyvinylpyrrolidone;
(b) drug coating layer onto coated sugar spheres containing about 30.24% w/w of topiramate;
(c) extended release layer onto drug coating layer comprising about 7.19 % w/w of mixture of polyvinyl acetate and povidone;
(d) about 1.17 % w/w of povidone;
and delayed release component comprises
(a) sugar spheres coated with about 0.19% w/w of polyvinylpyrrolidone;
(b) drug coating layer onto coated sugar spheres containing about 10.08% w/w of topiramate;
(c) delayed release layer onto drug coating layer comprising about 2.93 % w/w of polyvinyl acetate phthalate.
10. The extended-release capsule composition as claimed in any of the preceding claims, wherein the composition remains stable for at least 1 month when stored at 25°C and 60% relative humidity or at 40°C and 75% relative humidity.