An orodispersible tablet of topiramate and its process of preparation

Abstract

The present invention relates to an orodispersible tablet manufactured by a direct compression method comprising Topiramate or pharmaceutically acceptable salts thereof, at least one or more diluents, at least two or more disintegrant, at least one lubricant, at least one glidant, and at least one flavoring agents. The orodispersible tablet prepared using these excipients exhibits desirable properties such as facilitating disintegration, and dissolution of the drug for oral administration. Further, the present invention also relates to the process for preparing the said Orodispersible tablet.

Description

[0001] Title: - An Orodispersible Tablet of Topiramate and its Process of Preparation

[0002] Field of the Invention

[0003] The present invention relates to the pharmaceutical compositions of Topiramate. More particularly, the present invention provides orodispersible tablets of topiramate or pharmaceutically acceptable salts thereof for oral administration. The present invention provides orodispersible tablets of Topiramate comprising Topiramate or pharmaceutically acceptable salts thereof, diluents, disintegrants, lubricants, glidants, and flavoring agents. The present invention also provides an orodispersible tablet of Topiramate for the treatment of epilepsy and migraine headaches and the process for preparing the same.

[0004] Background of the Invention

[0005] Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures resulting from abnormal electrical activity in the brain. These seizures can vary in severity and manifestation, ranging from brief lapses in attention or muscle jerks to severe and prolonged convulsions. The disorder affects individuals of all ages, with a notable prevalence in pediatric and geriatric populations, and can significantly impact the quality of life, cognitive function, and psychosocial wellbeing.

[0006] Topiramate (TPM) is a widely used drug for the treatment of epilepsy. It is useful for several types of partial-onset and generalized-onset seizures and is therefore considered a broad-spectrum agent. TPM was first approved for prescription use in 1996.

[0007] Topiramate was first disclosed in the U.S. Pat. No. 4513006 with the process of preparing the same. Topiramate is an antiepileptic drug with a unique and multifaceted mechanism of action, contributing to its effectiveness in the treatment of epilepsy and migraine prevention. It primarily functions by blocking voltagedependent sodium channels, which stabilizes neuronal membranes and prevents the initiation and propagation of abnormal electrical discharges. Additionally, topiramate enhances the activity of gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the central nervous system, through modulation of GABA-A receptors, leading to increased neuronal inhibition. It also antagonizes the kainate subtype of glutamate receptors, thereby reducing excitatory neurotransmission, and inhibits carbonic anhydrase isoenzymes, which may contribute to its anticonvulsant effects. These combined actions make topiramate a broad-spectrum antiepileptic agent, capable of addressing various seizure types and providing prophylactic benefits in migraine management.

[0008] Topiramate is well absorbed from the gastrointestinal tract, with peak plasma levels being usually attained in 2-3 h. Topiramate is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine. Topiramate belongs to BCS class II having low solubility and high permeability. Topiramate is metabolized by hydroxylation, hydrolysis, and glucuronidation.

[0009] The IUPAC name of Topiramate is [(lR,2S,6S,9R)-4,4,l l,l l-tetramethyl- 3,5,7,10,12-pentaoxatricyclo[7.3.0.02,6]dodecan-6-yl]methyl sulfamate and the chemical structure is as follows:

[0010] The oral route of administration is the most widely used method for delivering medications due to its numerous advantages, including ease of administration, patient convenience, and cost-effectiveness. Additionally, it does not require specialized equipment or professional assistance, enabling patients to selfadminister their medications effortlessly. Topiramate is marketed as an oral tablet, capsule, extended-release capsule, and solution. The commercially marketed products of Topiramate in tablet form are available in dosage strengths: 25mg, 50mg, lOOmg, 200mg, 300mg, and 400mg. The capsule comes in strengths of 15mg, 25mg, and 50 mg. The extended capsules are available in dosage strengths: 25mg, 50mg, 100 mg, 200 mg. Additionally, the oral solution comes in a strength of 25 mg / ml. However, there are some drawbacks in marketed formulations. Capsules must be swallowed whole, which can pose significant difficulties for pediatric, geriatric, and dysphagic patients who have trouble swallowing pills. Capsules also typically require water for ingestion, limiting their convenience and portability, especially in situations where water is not readily available.

[0011] Liquid dosage forms present challenges such as bulkiness, difficulty in transport, and significant space occupation. They are more prone to spillage or leakage during transport or storage compared to solid dosage forms. Accurate measuring devices are required for dosing liquids, which can lead to errors if not used properly, particularly with medications requiring precise dosing. Some liquid formulations are less stable than solid forms, requiring refrigeration or having shorter shelf lives due to factors like light exposure, temperature changes, or container-material interactions. Liquids are also more susceptible to microbial contamination if not stored or handled correctly. These challenges associated with liquid dosage forms and capsules contribute to decreased patient compliance. To overcome these challenges, there is a need to develop an oral solid dosage form that provides fast disintegration in the oral cavity without the need for water, leading to increased patient compliance.

[0012] Orally disintegrating tablet formulations that dissolve rapidly in the mouth without needing water are highly beneficial due to the advantages they offer to patients who have difficulty swallowing, such as elderly individuals, infants, patients with mental health disorders, and non-cooperative patients, as well as the general population. Furthermore, because the formulation disintegrates in the mouth, the drug can be absorbed in the oral, pharyngeal, and gastrointestinal regions.

[0013] There are some documents that disclose the formulations for Topiramate for the treatment of epilepsy and migraine.

[0014] WO2012029348A1 discloses an oral disintegrating tablet of cinacalcet, topiramate or olopatadine containing bitter-drug-containing powdered medicine or granular medicine and an orally disintegrating tablet that achieves both suppression of bitterness in the oral cavity and superior dissolution in the stomach. The drugcontaining granules, which comprise (a) core particles containing the bitter drug and (b) a masking coating fdm that coats the core particles, are characterized by the masking coating fdm.

[0015] JP2012056948A discloses topiramate granules include (a) the core particles containing topiramate and (b) a masking-coating membrane to coat the core particles. The masking-coating membrane includes 15-70 wt.% of a polymer such as an ethyl acrylate / methyl methacrylate copolymer, 15-60 wt.% of an excipient such as D-mannitol based on the weight of the membrane, and a coating substrate so that the weight ratio of the coating substrate and the polymer is 0: 1 to 4: 1, wherein the total amount of the polymer and the excipient is 50-95 wt.% based on the weight of the masking -coating membrane.

[0016] US20170368087A1 discloses a solid pharmaceutical composition comprising topiramate, glyceryl behenate, hydroxypropylmethylcellulose, microcrystalline cellulose, starch, PVP K30, and magnesium stearate. The process of this invention involves sieving all the excipients through a 60-mesh sieve, then mixing topiramate, hydroxypropylmethylcellulose, and glyceryl behenate into the blender. The microcrystalline cellulose with starch was added and mixed evenly. The mixed powder is wet granulated with a PVP K30 solution which was prepared by using ethanol. Lastly, the above blend was compressed into tablet using an appropriate punch.

[0017] US8298576B2 discloses sustained release bead formulation of topiramate for oral administration to a mammalian subject comprising an extended release component, and an optional immediate release component, wherein topiramate is released from the formulation at the sustained rate along the pre-determined release profile. The beads useful in the formulation of the present invention comprise an inert carrier, topiramate, a binder, an afore-mentioned release controlling coating

[0018] EP2968181B1 discloses a taste-masked rapidly dispersing solid oral dosage form comprising wax-coated particles of topiramate, a binder, a disintegrant, and a surfactant. It is prepared using a three-dimensional printing process to ensure sufficient hardness and low friability, making it suitable for storage and handling. The rapidly dispersing nature and taste masking make it ideal for patients who have difficulty swallowing conventional tablets, ensuring better compliance and therapeutic efficacy.

[0019] US8889190B2 discloses an extended-release capsule comprising topiramate, microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate, dehydrated alcohol, and purified water. The capsule shell contains a single population of coated particles; wherein each coated particle includes a core of homogeneous mixture throughout its core, the mixture comprising topiramate, filler, and binder, and the coating components are release controlling agents, pore former, and plasticizer.

[0020] Therefore, the inventors of this invention have developed an orodispersible tablet of Topiramate that disintegrates rapidly in saliva when placed in the mouth, without the need for water, making administration easier for patients. This formulation is the best-suited dosage form due to its numerous benefits: it allows for precise dosing, rapid disintegration, fast dissolution, and enhanced patient adherence. It is particularly suitable for patients who struggle with swallowing, including pediatric and geriatric populations with dysphagia.

[0021] Summary of the Invention

[0022] The main aspect of the present invention is to provide an orodispersible tablet of Topiramate for oral administration with its bitter taste masked by a flavoring agent.

[0023] Another main aspect of the present invention is to provide an orodispersible tablet of Topiramate for oral administration comprising topiramate or pharmaceutically acceptable salts thereof, at least one or more diluents, at least two or more disintegrant, at least one lubricant, at least one glidant, and at least one flavoring agent.

[0024] The other aspect of the present invention is to provide an orodispersible tablet of Topiramate for oral administration and a process for preparing the same.

[0025] Objects of the Invention

[0026] The main object of the present invention is to provide an orodispersible tablet of Topiramate or pharmaceutically acceptable salts thereof.

[0027] Another object of the present invention is to provide an orodispersible tablet of Topiramate that disintegrates rapidly in the mouth, leading to increased disintegration and dissolution.

[0028] Another object of the present invention is to provide an orodispersible tablet of Topiramate with taste-masking properties and pleasant palatability, making the administration of the tablet more acceptable for pediatric, geriatric, and unconscious patients.

[0029] Another object of the present invention is to provide a stable orodispersible tablet of Topiramate or pharmaceutically acceptable salts thereof. A further object of the present invention is to provide an orodispersible tablet of Topiramate that can be administered without the need for water, which is convenient and effective for individuals with swallowing difficulties, particularly children, the elderly, and patients with dysphagia, thereby increasing patient compliance.

[0030] Yet another object of the present invention is to provide an orodispersible tablet of Topiramate for use as monotherapy in the treatment of epilepsy, specifically for partial -onset or primary generalized tonic-clonic seizures in patients 2 years of age and older, as adjunctive therapy for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older, and for the preventive treatment of migraine in patients 12 years of age and older.

[0031] Detailed description of the Invention

[0032] The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and / or utilized. The description sets forth the functions and the sequence of steps for constructing and / or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences that may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the invention.

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

[0034] As stated herein, that it follows in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components.

[0035] The term “Orodispersible tablet” refers to a solid dosage form that quickly dissolves and disintegrates in the mouth, releasing its active ingredients promptly without the need for chewing or swallowing with water.

[0036] The terms 'Orodispersible tablet,' 'Orally disintegrating tablet,' and 'Fast dissolving tablet' used herein are interchangeable and convey the same meaning.

[0037] As used herein, the term "formulation" or “composition” unless otherwise defined as Topiramate orodispersible tablet formulation of the invention.

[0038] As used herein, the term “about” means an approximate, close-to, or rough estimation. When used alongside a numerical range, it expands the boundaries to include values slightly above and below the specified range. Generally, "about" indicates a range that extends approximately ±10% from the mentioned value.

[0039] The term “% w / w” refers to the weight percentage of an ingredient relative to the total weight of the composition, which is considered to be 100%. This calculation of % w / w is based on the complete weight of the composition. In other words, the percentage by weight is determined by comparing the weight of the individual ingredient to the total weight of all components in the formulation.

[0040] The main embodiment of the present invention is to provide an orodispersible tablet of Topiramate.

[0041] Another main embodiment of the present invention is to provide an orodispersible tablet formulation of Topiramate comprising Topiramate or pharmaceutically acceptable salts thereof, at least one or more diluents, at least two or more disintegrant, at least one lubricant, at least one glidant, and at least one flavoring agent.

[0042] The term "pharmaceutically acceptable salts," as used herein, encompasses salts commonly employed to form alkali metal salts and addition salts of free acids or bases. Suitable pharmaceutically acceptable acid addition salts of Topiramate may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p- hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzene sulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, malonic, galactaric and galacturonic acid. Preferably Topiramate as used herein is in the form of the free base.

[0043] As per one embodiment of the present invention, the DIO particle size of Topiramate or pharmaceutically acceptable salts thereof, is less than 20 microns, more preferably less than 10 microns. The D50 particle size of Topiramate or a pharmaceutically acceptable salt thereof is about 10 to 60 microns, more preferably about 20 to 50 microns. The D90 particle size of Topiramate or a pharmaceutically acceptable salt thereof is about 110 to 190 microns, more preferably 120 to 180 microns.

[0044] In one embodiment of the present invention, the composition comprises Topiramate or its pharmaceutically acceptable salts in an amount ranging from about 20% w / w to about 40% w / w, preferably from about 25% w / w to about 35% w / w.

[0045] In one embodiment of the present invention, a suitable diluent is selected from the group consisting of calcium carbonate, cellulose derivatives, microcrystalline cellulose, microfine cellulose, sugar alcohols such as maltitol, spray dried mannitol, sorbitol, com starch, potato starch, hydroxypropyl methylcellulose (HPMC), dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, lactose, starch, pregelatinized starch, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous or any combination thereof.

[0046] In the preferred embodiment of the present invention, the combination of spray- dried mannitol and microcrystalline cellulose is used as diluents. Mannitol is preferred for its high flowability, non-hygroscopicity, chemical inertness, and excellent compressibility, which enhance mechanical properties and ensure uniform compression. Spray-dried mannitol also promotes rapid disintegration upon contact with saliva, leading to quick dissolution and a faster onset of action. Microcrystalline Cellulose facilitates efficient dry blending and tablet compression, and its water-imbibing action promotes quick wetting and drying. Therefore, the combination of microcrystalline cellulose and spray-dried mannitol ensures the production of stable, uniform tablets with consistent quality and rapid disintegration, making it the preferred choice of diluents in the present invention.

[0047] In another preferred embodiment of the present invention, the combination of diluents is included in an amount ranging from about 35 % w / w to about 80% w / w, preferably from about 45 % w / w to about 70 % w / w.

[0048] In one another preferred of the present invention, spray-dried mannitol is present in an amount ranging from about 25% w / w to about 50% w / w, preferably from about 30% w / w to about 45% w / w. Microcrystalline Cellulose is present in an amount ranging from about 10% w / w to about 30% w / w, more preferably from about 15% w / w to about 25% w / w.

[0049] In one embodiment of the present invention, a suitable disintegrant is selected from the group consisting of alginic acid, guar gum, croscarmellose sodium, carmellose calcium, crospovidone, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sodium carboxymethylcellulose (CMC), carboxy methyl cellulose, cross-linked sodium carboxy methylcellulose (Ac-di-sol), poloxamer, magnesium aluminum silicate, pregelatinized starch, sodium starch glycolate, microcrystalline cellulose, or any combination thereof.

[0050] In the preferred embodiment of the present invention, the combination of croscarmellose sodium and pregelatinized starch is used as the disintegrant.

[0051] In another preferred embodiment of the present invention, the combination of disintegrant is included in an amount ranging from about 3 % w / w to about 25 % w / w, preferably from about 6 % w / w to about 20 % w / w.

[0052] In one embodiment of the present invention, croscarmellose sodium is included in an amount ranging from about 0.5% w / w to about 10% w / w, preferably from about 1% w / w to about 5% w / w. Pregelatinized Starch is included in an amount ranging from about 1% w / w to about 20% w / w, more preferably from about 5% w / w to about 15% w / w.

[0053] In one embodiment of the present invention, a suitable glidant is selected from the group consisting of com starch, calcium phosphate tribasic, calcium palmitate, polyethylene glycol (PEG), stearic acid, calcium silicate, magnesium stearate, colloidal silica anhydrous, starch, and talc, or combinations thereof.

[0054] In the preferred embodiment of the present invention, colloidal silica anhydrous is used as the glidant.

[0055] In one embodiment of the present invention, the glidant is included in an amount ranging from about 0.05% w / w to about 2% w / w, preferably from about 0.1% w / w to about 1% w / w. In one embodiment of the present invention, a suitable lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, micronized polyoxyethylene glycol, Colloidal Silicon Dioxide, Glyceryl Behenate, hydrogenated vegetable oils, sodium benzoate, beeswax, polyethylene glycol (PEG), sodium lauryl sulfate, stearic acid, talc, sodium stearate, sodium starch glycolate, calcium stearate, or combinations thereof.

[0056] In the preferred embodiment of the present invention, magnesium stearate is used as the lubricant.

[0057] In one embodiment of the present invention, the lubricant is included in an amount ranging from about 0.1% w / w to about 3% w / w, preferably from about 0.5% w / w to about 2% w / w.

[0058] In one embodiment of the present invention, a suitable flavoring agent is selected from the group consisting of raspberry flavor, strawberry flavor, blueberry flavor, caramel flavor, butterscotch flavor, floral fennel flavor, mint powder, vanillin, mint flavor, orange flavor, peppermint oil, spearmint oil or combinations thereof. The flavoring agent is masked the bitter taste of Topiramte.

[0059] In the preferred embodiment of the present invention, Mint flavor is used as a flavoring agent.

[0060] In one embodiment of the present invention, the flavoring agent is included in an amount ranging from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w.

[0061] In one embodiment of the present invention, the orodispersible tablet comprising Topiramate or pharmaceutically acceptable salts thereof is present in an amount ranging from about 20 %w / w to about 40 %w / w, preferably in the range from about 25 %w / w to about 35 %w / w, diluent combinations are present in the range from about 35 % w / w to about 80% w / w, preferably from about 45 % w / w to about 70 % w / w, disintegrant combination is present in the range from about 3 % w / w to about 25 % w / w, preferably from about 6 % w / w to about 20 % w / w, lubricant is present in the range from about 0. 1 %w / w to about 3 %w / w, preferably in the range from about 0.5 %w / w to about 2 %w / w, glidant is present in the range from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w, flavoring agent is present in the range from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w.

[0062] In the preferred embodiment of the present invention, the orodispersible tablet comprising Topiramate or pharmaceutically acceptable salts thereof, is present in an amount ranging from about 20 %w / w to about 40 %w / w, preferably in the range from about 25 %w / w to about 35 %w / w, a combination of spray-dried mannitol and microcrystalline cellulose present in the range from about 35 % w / w to about 80% w / w, preferably from about 45 % w / w to about 70 % w / w, spray-dried mannitol is present in the range from about 25 %w / w to about 50 %w / w, preferably in the range from about 30 %w / w to about 45 %w / w, microcrystalline cellulose is present in the range from about 10 %w / w to about 30 %w / w, more preferably in the range from about 15 %w / w to about 25 %w / w, a combination of pregelatinized starch and croscarmellose sodium present in the range from about 3 % w / w to about 25 % w / w, preferably from about 6 % w / w to about 20 % w / w, Pregelatinized starch is present in the range from about 1 %w / w to about 20 %w / w, more preferably in the range from about 5 %w / w to about 15 %w / w, croscarmellose sodium is present in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range from about

[0063] 1 %w / w to about 5 %w / w, magnesium stearate is present in the range from about 0.1 %w / w to about 3 %w / w, preferably in the range from about 0.5 %w / w to about

[0064] 2 %w / w, colloidal silica anhydrous is present in the range from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0. 1 %w / w to about 1 %w / w, mint flavour is present in the range from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w. In another preferred embodiment of the present invention, the orodispersible tablet comprising 27.77 % w / w of Topiramate or pharmaceutical-acceptable salts thereof, 37.84% w / w of spray-dried mannitol, and 20% w / w of microcrystalline cellulose as a combination of diluents, 3 % w / w of croscarmellose sodium and 9% w / w of pregelatinized starch as a combination of disintegrant, 0.50 % w / w of colloidal silica anhydrous, 0.37 % w / w of mint flavor and 1.50 % w / w ofmagnesium stearate.

[0065] In one embodiment of the present invention, an orodispersible tablet of Topiramate is manufactured by using the direct compression method.

[0066] In one embodiment of the present invention, the disintegrating time of the Topiramate orodispersible tablet is less than 3 minutes, preferably less than 60 seconds.

[0067] In one embodiment of the present invention, more than 80% of the Topiramate is released within 15 minutes, preferably 85% is released within 15 minutes.

[0068] In one embodiment of the present invention, the packaging material for an orodispersible tablet of Topiramate is selected from the group consisting of an aluminum foil blister, PVC / aluminum combinations blister, polypropylene bottle with a silica canister, PP bottle with an oxygen scavenger, HDPE bottle, an HDPE bottle with SAF, an HDPE bottle with a CR cap canister, HDPE bottle with silica canister, HDPE bottle with an oxygen scavenger, Alu-Alu blister, PVC / PVDC-alu fdm, aluminum foil strip, polyethylene (pe) strip and polypropylene (pp) strip.

[0069] In the preferred embodiment of the present invention, an HDPE bottle with a CR cap canister is used as packaging material.

[0070] In one embodiment of the present invention, the orodispersible tablet of Topiramate is effective in the treatment of epilepsy and migraine headaches. It is also used off- label for conditions such as bipolar disorder, weight loss, and certain types of pain management.

[0071] In one embodiment of the present invention, the process for preparing the orodispersible tablet of Topiramate by the direct compression method comprises the following steps: a) Weighing all raw materials individually; b) Sieving Topiramate, spray-dried mannitol, microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, pregelatinized starch, and mint flavor separately through a 40# sieve, and sieving Magnesium Stearate separately through a 60# sieve; c) Adding Topiramate, spray-dried mannitol, and microcrystalline cellulose into a blender; d) Dry mixing the ingredients of step (c) for 15 minutes at 12 RPM in the blender; e) Mixing the previously sifted colloidal anhydrous silica, croscarmellose sodium, pregelatinized starch, and mint flavor from step (b) into the blender and blend for about 15 minutes at 12 RPM; f) Transferring the previously sifted Magnesium Stearate from step (b) into the blender and blend for about 5 minutes at 12 RPM; and g) Compressing the lubricated blend into a tablet dosage form.

[0072] The invention is exemplified by the following examples, which are provided to illustrate the invention and are not intended to restrict its scope. While specific embodiments of the present invention have been described, modifications and equivalents that would be apparent to those skilled in the art are considered to fall within the scope of the present invention.

[0073] EXAMPLES

[0074] Example 1: The orodispersible tablet was prepared according to the method described below, using the composition having the ingredients shown in Table I, for a dose strength of 25 mg.

[0075] Table 1: Composition of Topiramate tablet

[0076] Manufacturing process:

[0077] (a) All raw materials were weighed individually.

[0078] (b) The ingredients were sieved separately from step (a), including Topiramate, Lactose, Microcrystalline Cellulose, Croscarmellose Sodium, Pregelatinized Starch, and Mint Flavor through a 40# sieve, and sieved Magnesium Stearate separately through a 60# sieve.

[0079] (c) Topiramate, lactose, and Microcrystalline Cellulose were transferred into a blender.

[0080] (d) The ingredients from step (c) were dry-mixed for 15 minutes at 12 RPM in the blender.

[0081] (e) The previously sifted Croscarmellose Sodium, Pregelatinized Starch, and Mint Flavor from step (b) were transferred into the blender and blended for about 15 minutes at 12 RPM.

[0082] (f) The previously sifted Magnesium Stearate from step (b) was transferred into the blender and blended for about 5 minutes at 12 RPM.

[0083] (g) The lubricated blend was compressed into a tablet dosage form. Result

[0084] Table 2: Result of example 1 tablet formulation

[0085] As shown in the above table, it was concluded that the physical parameters of the blend were unsatisfactory, and poor blend flow was observed. To optimize blend flow, the diluent was changed from lactose to spray-dried mannitol in Example 2.

[0086] Example 2:

[0087] The 25 mg orodispersible tablet was prepared using the direct compression method by changing the diluent to improve the physical parameters of the blend. Table 3: Composition of Topiramate tab et

[0088] Manufacturing process:

[0089] (a) All raw materials were weighed individually.

[0090] (b) The ingredients were sieved separately from step (a), including topiramate, spray-dried mannitol, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch, and mint flavor through a 40# sieve, and sieved magnesium Stearate separately through a 60# sieve. (c) Topiramate, spray-dried mannitol, and Microcrystalline Cellulose 102 were transferred into a blender.

[0091] (d) The ingredients from step (c) were dry-mixed for 15 minutes at 12 RPM in the blender.

[0092] (e) The previously sifted Croscarmellose Sodium, Pregelatinized Starch, and Mint Flavor from step (b) were transferred into the blender and blended for about 15 minutes at 12 RPM.

[0093] (f) The previously sifted Magnesium Stearate from step (b) was transferred into the blender and blended for about 5 minutes at 12 RPM.

[0094] (g) The lubricated blend was compressed into a tablet dosage form.

[0095] Result

[0096] Table 4: Results of the tablet formulation from Example 2

[0097] As shown in the above table, it was found that hardness, average weight, and thickness were within the specifications range; however, hardness was not satisfied. To optimize hardness, the glidant colloidal silicon anhydrous was added in further batches.

[0098] Example 3:

[0099] The 25 mg orodispersible tablet was prepared using the direct compression method to achieve acceptable physical properties.

[0100] Table 5: Composition of Topiramate tablet

[0101] Manufacturing process:

[0102] (a) All raw materials were weighed individually.

[0103] (b) The ingredients were sieved separately from step (a), including topiramate, spray-dried mannitol, microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, pregelatinized starch, and mint flavor through a 40# sieve, and sieved magnesium stearate separately through a 60# sieve.

[0104] (c) Topiramate, spray-dried mannitol, and microcrystalline cellulose were added into a rapid mixer granulator. (d) The ingredients from step (c) were dry-mixed for 15 minutes at 12 RPM in the blender.

[0105] (e) The previously sifted colloidal anhydrous silica, croscarmellose sodium, pregelatinized starch, and mint flavor from step (b) were mixed into the blender and blended for about 15 minutes at 12 RPM. (f) The previously sifted Magnesium Stearate from step (b) was transferred into the blender and blended for about 5 minutes at 12 RPM.

[0106] (g) The lubricated blend was compressed into a tablet dosage form.

[0107] Result

[0108] Table 6: Results of the tablet formulation from Example 3

[0109] As shown in the above results, it was found that all parameters such as hardness, average weight, thickness, friability, and disintegration meet the specified ranges and provide satisfactory results. Therefore, Example 3 was considered an optimized batch. Further studies, such as stability studies, and dissolution studies were performed on the optimized batch.

[0110] Example 4: Dissolution data of optimized batch (Example 3)

[0111] The dissolution study of an orally disintegrating tablet of 25 mg was conducted with the following dissolution condition. The reference product batch number is

[0112] NAS 1400 (Topamac 25 mg) and the test product batch number is ORB / S / TOP / 04.

[0113] Product Name: Topiramate 25 mg orally disintegrating tablet

[0114] Dissolution Media: Water, 0. 1 N HC1, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer Apparatus: Apparatus II (Paddle)

[0115] Rate of rotation: 50 RPM

[0116] Volume: 500 ml

[0117] Temperature: 37±5°C

[0118] Detection: RI detector

[0119] Table 8: Dissolution data of reference and test product

[0120] As shown in the dissolution data, the test product provided more than 85% drug release in 15 minutes and more than 95% drug release in 60 minutes in water, 0. 1 N HC1, pH 4.5 Acetate Buffer, and pH 6.8 Phosphate Buffer. The F2 value of 68 indicates a high degree of similarity between dissolution profiles. In dissolution testing, F2 values above 50 generally indicate greater similarity between two profiles. The final dissolution media is water.

[0121] Example 5: Stability study

[0122] The orally disintegrating tablets prepared according to example 3 were subjected to a stability study of 25°C / 60%RH and 40°C / 75%RH for 1, 3 and 6 months. The stability study was performed for the 25 mg dose strength of Topiramate. Results are tabulated below.

[0123]

[0124] ND* - Not detect

[0125] Table 9: Stability study of Topiramate ODT

[0126] As shown in the above stability data, there was not much difference observed in disintegration, assay, and dissolution results before, after one month, and after three 5 months and six months of the study, indicating that the topiramate ODT formulation is stable. No impurities were detected.

Claims

Claims:

1. An orodispersible tablet of topiramate for oral administration with masked bitter taste by a flavoring agent, comprising: a) Topiramate or pharmaceutically acceptable salts thereof, present in an amount ranging from about 20 %w / w to about 40 %w / w, preferably in the range from about 25 %w / w to about 35 %w / w; b) at least one or more diluents present in the range from about 35 % w / w to about 80% w / w, preferably from about 45 % w / w to about 70 % w / w; c) at least two or more disintegrates present in the range from about 3 % w / w to about 25 % w / w, preferably from about 6 % w / w to about 20 % w / w; d) at least one lubricant present in the range from about 0.1 %w / w to about 3 %w / w, preferably in the range from about 0.5 %w / w to about 2 %w / w; e) at least one glidant present in the range from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w; and f) at least one flavoring agent present in the range from about 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w; wherein the orodispersible tablet is uncoated and packaged in an HDPE bottle with a CR cap canister.

2. The orodispersible tablet according to claim 1 , wherein the diluent is selected from the group consisting of a calcium carbonate, cellulose derivatives, microcrystalline cellulose, microfine cellulose, sugar alcohols such as maltitol, spray-dried mannitol, sorbitol, corn starch, potato starch, hydroxypropyl methylcellulose (HPMC), dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, lactose, starch, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous or any combination thereof.

3. The orodispersible tablet according to claim 2, wherein the diluents comprise a combination of spray-dried mannitol and microcrystalline cellulose.

4. The orodispersible tablet according to claim 3, wherein diluent spray-dried mannitol presents in the range from about 25 %w / w to about 50 %w / w, preferably in the range from about 30 %w / w to about 45 %w / w.

5. The orodispersible tablet according to claim 3, wherein diluent microcrystalline cellulose presents in the range from about 10 %w / w to about 30 %w / w, more preferably in the range from about 15 %w / w to about 25 %w / w.

6. The orodispersible tablet according to claim 1 , wherein the disintegrant is selected from the group consisting of alginic acid, guar gum, croscarmellose sodium, carmellose calcium, crospovidone, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sodium carboxymethylcellulose (CMC), carboxy methyl cellulose, cross-linked sodium carboxy methylcellulose (Ac-Di-Sol), poloxamer, magnesium aluminum silicate, pregelatinized starch, sodium starch glycolate, microcrystalline cellulose, or any combination thereof.

7. The orodispersible tablet according to claim 6, wherein the disintegrants comprise combination of croscarmellose sodium and pregelatinized starch.

8. The orodispersible tablet according to claim 7, wherein disintegrant croscarmellose sodium presents in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w.

9. The orodispersible tablet according to claim 7, wherein disintegrant pregelatinized starch presents in the range from about 1 %w / w to about 20 %w / w, more preferably in the range from about 5 %w / w to about 15 %w / w.

10. The orodispersible tablet according to claim 1, wherein the glidant is selected from the group consisting of corn starch, calcium phosphate tribasic, calcium palmitate,polyethylene glycol (PEG), stearic acid, calcium silicate, magnesium stearate, colloidal silica anhydrous, starch, and talc, or combinations thereof.

11. The orodispersible tablet according to claim 10, wherein the glidant is colloidal silica anhydrous.

12. The orodispersible tablet according to claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, micronized polyoxyethylene glycol, colloidal silicon dioxide, glyceryl behenate, hydrogenated vegetable oils, sodium benzoate, beeswax, polyethylene glycol (PEG), sodium lauryl sulfate, stearic acid, talc, sodium stearate, sodium starch glycolate, calcium stearate, or combinations thereof.

13. The orodispersible tablet according to claim 12, wherein the lubricant is magnesium stearate.

14. The orodispersible tablet according to claim 1, wherein the flavoring agent is selected from the group consisting of raspberry flavor, strawberry flavour, blueberry flavour, caramel flavor, butterscotch flavor, floral fennel flavor, mint powder, vanillin, mint flavor, orange flavor, peppermint oil, spearmint oil or combinations thereof.

15. The orodispersible tablet according to claim 14, wherein the flavoring agent is mint flavor.

16. The process for preparing an orodispersible tablet by the direct compression method according to claim 1, comprising the steps of:(a) Weighing all raw materials individually;(b) Sieving topiramate or pharmaceutically acceptable salts thereof, spray-dried mannitol, microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, pregelatinized starch, and mint flavor separately through a 40# sieve, and sieving magnesium stearate separately through a 60# sieve;(c) Adding topiramate, spray-dried mannitol, and microcrystalline cellulose into a blender;(d) Dry mixing the ingredients of step (c) for 15 minutes at 12 RPM in the blender;(e) Mixing the previously sifted colloidal anhydrous silica, croscarmellose sodium, pregelatinized starch, and mint flavor from step (b) into the blender and blend for about 15 minutes at 12 RPM;(f) Transferring the previously sifted magnesium stearate from step (b) into the blender and blend for about 5 minutes at 12 RPM; and(g) Compressing the lubricated blend into a tablet dosage form.

17. The orodispersible tablet according to claim 1, wherein the orally disintegrating tablet is disintegrated in the buccal cavity upon contact with saliva in not more than 3 minutes, preferably less than 90 seconds.

18. The use of orodispersible tablets according to claim 1, for the treatment of epilepsy and migraine headaches.

19. The orodispersible tablet according to claim 1, wherein the hardness of the orally disintegrating tablet is between about 20 N to about 50 N, preferably between 30 N to 40 N.

20. The orodispersible tablet according to claim 1, wherein the packaging material of the container is selected from the group consisting of an aluminum foil blister, PVC / aluminum combinations blister, polypropylene bottle with a silica canister, PP bottle with an oxygen scavenger, HDPE Bottle, an HDPE bottle with SAF, an HDPE bottle with a CR cap canister, HDPE bottle with silica canister, HDPE bottle with an oxygen scavenger, Alu-Alu blister, PVC / PVDC-alu film, aluminum foil strip, polyethylene (pe) strip and polypropylene (pp) strip.

21. The orodispersible tablet according to claim 1, wherein the DIO particle size of topiramate or pharmaceutically acceptable salts thereof, is less than 20 microns, more preferably less than 10 microns; the D50 particle size of topiramate or a pharmaceutically acceptable salt thereof is about 10 to 60 microns, more preferably about 20 to 50 microns; the D90 particle size of topiramate or a pharmaceutically acceptable salt thereof is about 110 to 190 microns, more preferably 120 to 180 microns.

22. The orodispersible tablet according to claim 1, wherein said tablet composition comprises: a) 20 %w / w to about 40 %w / w, preferably in the range from about 25 %w / w to about 35 %w / w of topiramate or pharmaceutically acceptable salts thereof; b) combination of spray-dried mannitol, and microcrystalline cellulose present in the range from about 35 % w / w to about 80% w / w, preferably from about 45 % w / w to about 70 % w / w; c) 25 %w / w to about 50 %w / w, preferably in the range from about 30 %w / w to about 45 %w / w of spray-dried mannitol; d) 10 %w / w to about 30 %w / w, more preferably in the range from about 15 %w / w to about 25 %w / w of microcrystalline cellulose; e) combination of croscarmellose sodium and pregelatinized starch present in the range from about 3 % w / w to about 25 % w / w, preferably from about 6 % w / w to about 20 % w / w; f) 1 %w / w to about 20 %w / w, more preferably in the range from about 5 %w / w to about 15 %w / w of pregelatinized starch; g) 0.5 %w / w to about 10 %w / w, preferably in the range from about 1 %w / w to abouth) 0.1 %w / w to about 3 %w / w, preferably in the range from about 0.5 %w / w to about 2 %w / w of magnesium stearate; i) 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w of colloidal silica anhydrous; and j) 0.05 %w / w to about 2 %w / w, preferably in the range from about 0.1 %w / w to about 1 %w / w of mint flavour.

23. The orodispersible tablet according to claim 1, wherein said tablet composition comprises: a) 27.77 % w / w of topiramate or pharmaceutical-acceptable salts thereof; b) 37.84% w / w of spray-dried mannitol, and 20% w / w of microcrystalline cellulose as a combination of diluents; c) 3 % w / w of croscarmellose sodium and 9% w / w of pregelatinized starch as a combination of disintegrates; d) 0.50 % w / w of colloidal silica anhydrous; e) 0.37 % w / w of mint flavor; and f) 1.50 % w / w of magnesium stearate.

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