An orodispersible tablet of levetiracetam and its process of preparation

Abstract

An orodispersible tablet of levetiracetam, comprising: 55-85 %w / w levetiracetam or pharmaceutically acceptable salts thereof; a diluent at 2-35 %w / w (e.g. microcrystalline cellulose (MCC) (1-20 %w / w),

Description

The present invention relates to the pharmaceutical compositions of levetiracetam. The present invention more particularly relates to orodispersible tablets of levetiracetam or pharmaceutically acceptable salts thereof for oral administration. The present invention also provides an orodispersible tablet of levetiracetam for the treatment of epilepsy and the process for preparing the same. Background of the Invention Levetiracetam was first disclosed in the U.S. Pat. No. 4943639 with the process of preparing the same. Levetiracetam is a drug within the pyrrolidine class that is used to treat various types of seizures stemming from epileptic disorders. Levetiracetam’s binding to synaptic vesicle protein 2A (SV2A) is a key driver of its action. SV2A is a membrane-bound protein that is found on synaptic vesicles and is ubiquitous throughout the CNS it appears to play a role in vesicle exocytosis, and in the modulation of synaptic transmission by increasing the available amount of secretory vesicles available for neurotransmission. Stimulation of pre-synaptic SV2A by levetiracetam may inhibit neurotransmitter release, but this action does not appear to affect normal neurotransmission. This has led to the suggestion that levetiracetam exclusively modulates the function of (SV2A) only under pathophysiological conditions. Levetiracetam and related analogues showed a correlation between affinity for SV2A and anti-epileptic potency, further suggesting that action at this site contributes to the anti-epileptic activity of the drug. Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. It is also indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary' generalisation in 1 adults, adolescents, children, and infants from 1 month of age with epilepsy, in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy and in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy. Levetiracetam is an antiepileptic drug that is chemically unrelated to existing antiepileptic drugs It is a single enantiomer, the S-form of the pyrrolidone etiracetam, chemically known as (-)-(S)- a-ethyl-2-o\o-l-pyrrolidine acetamide and the chemical structure is as follows: Levetiracetam is marketed as an oral tablet, extended-release tablet, tablet for suspension, oral solution, and injection. The commercially marketed products of levetiracetam in oral tablet, extended-release tablet, and oral tablet for suspension are available in dosage strengths of 250mg, 500mg, 750mg, and Igm. The injection comes in strengths of 500mg / 5ml, 500mg / 100ml, Igm / lOOml, 1.5gm / 100ml, and 250mg / 50ml. Additionally, the oral solution is available in lOOmg / ml. Levetiracetam belongs to BCS class 1 drug (high solubility, high permeability). It is completely absorbed orally, partly hydrolysed, but mainly excreted unchanged in the urine with a 1½ of 6 S hours. It is neither oxidized by CYP enzymes nor induces or inhibits them. There are some documents that disclose the formulations for Levetiracetam for the treatment of epilepsy. US 2008 / 0045583 Al discloses stable, liquid compositions of levetiracetam that are substantially or entirely free of preservatives, particularly parabens, and / or sugars, such as natural sugars and sugar alcohols. The liquid compositions preferably include oral solutions or suspensions and may include pharmaceutically acceptable excipients. EP2563340A2 discloses a water-soluble pharmaceutical composition comprising levetiracetam, diluent, binder, lubricant, sweetener, flavoring agent, and optionally effervescent couple, and use of said composition in the treatment of partial seizures, myoclonic seizures, and tonic-clonic seizures of patients diagnosed with epilepsy. US20090263481A1 discloses an oral extended-release tablet containing levetiracetam and having an inner solid phase and outer continuous phase, wherein one or both of the phases comprise at least one hydrophobic material, lipophilic material, or a combination thereof. WO / 2007 / 012439 relates to solid dosage forms with improved stability as compared to tire conventional immediate-release levetiracetam compositions, wherein tire composition has disintegrant, gliding agent, binder, and lubricant. It also teaches that such formulations are preferably not prepared by conventional wet granulation process which may cause degradation of levetiracetam upon contact with the liquid phase. The currently available solid dosage form of levetiracetam poses challenges for patients who struggle with swallowing, resulting in poor patient compliance. The fear of swallowing or choking on such solid formulation is still a concern in certain populations, especially in geriatrics. Solid dosage forms become sticky when wetted by saliva, and if the patient experiences difficulty in swallowing on the first attempt, then the tablet must often be discarded. Furthermore, if solid dosage forms partially dissolve in the patient's mouth due to unsuccessful swallowing or the solid dosage form gets stuck in an orthodontic appliance, the resulting unpleasant taste can discourage the patient from taking another dose. These challenges associated with solid dosage forms contribute to decreased patient compliance. Liquid dosage forms, on the other hand, present challenges such as bulkiness, difficulty in transport, and significant space occupation. Due to their inherent instability, liquid dosage forms often have shorter shelf lives. The accurate measurement of the exact volume by the patient determines whether the dose is administered appropriately, introducing a potential for variability. Therefore, alternative dosage forms that are easier to swallow and have a faster onset time need to be explored. An orodispersible tablet of the present invention is a pharmaceutical formulation specifically designed in such a way that the entire tablet disintegrates with saliva within a short time when put in the mouth, facilitating easy administration to patients. Hie orodispersible tablet of levetiracetam is the best-suited dosage form to formulate, as it offers several benefits, including precise dosing, fast disintegration in the oral cavity without the need for water, fast dissolution, and improved patient adherence who have difficulty swallowing, such as pediatrics and geriatrics suffering from dysphagia. The present invention solves all prior art problems and provides a pharmaceutical composition for oral administration comprising levetiracetam. Summary of the Invention The main aspect of the present invention is to provide the stable pharmaceutical compositions of levetiracetam. Another main aspect of the present invention is to provide an orodispersible tablet of levetiracetam for oral administration comprising levetiracetam or pharmaceutically acceptable salts thereof, at least one disintegrant, at least one diluent, at least one binder, and one or more pharmaceutically acceptable excipient selected from a glidant, sweetener, flavoring agent, and lubricant. The other aspect of the present invention is to provide an orodispersible tablet of levetiracetam and a process of preparation thereof. Objects of the Invention The mam object of the present invention is to provide an orodispersible tablet of levetiracetam or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide an orodispersible tablet of levetiracetam which enhances the disintegration and dissolution of the drug for oral administration. Another object of the present invention is to provide an orodispersible tablet of levetiracetam which has taste-masking properties and presents pleasant palatability such that the administration of the orodispersible tablet is not unpleasant for pediatrics, geriatrics, or unconscious patients. Another further object of the present invention is to provide a treatment that is effective and very convenient for administration without the need for water or swallowing difficulties, which will improve patient compliance. A further object of the present invention is to provide a stable orodispersible tablet of levetiracetam or pharmaceutically acceptable salts thereof. Yet another object of the present invention is to provide an orodispersible tablet of levetiracetam which can effectively be treated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. It is also indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children, and infants from 1 month of age with epilepsy, in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy and in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy. Detailed description of the Invention 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 exemplan- methods are also intended to be encompassed within the spirit and scope of the invention. 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. 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, tire 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. Tire term "Orodispersible tablet” as used herein means solid dosage form that disintegrates rapidly in the oral cavity of a patient after administration, without chewing. The term “excipient” as used herein refers to any pharmaceutical additive material that is used in the pharmaceutical dosage form other than the one or more pharmaceutically active substances. The term ‘‘about" is used herein to mean approximately, in the region of, roughly, or around. When the term ‘‘about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about", as and when used in this specification, means ±10 % of the mentioned value. The term “% w / w” is intended to mean the percentage of an ingredient(s) / the total percentage by weight of the composition (100%). Here the % w / w is to be calculated against the total weight of the composition. The main embodiment of the present invention is to provide an orodispersible tablet formulation of levetiracetam. Another main embodiment of the present invention is to provide an orodispersible tablet formulation of levetiracetam comprising levetiracetam or pharmaceutically acceptable salts thereof, at least one disintegrant, at least one diluent, and at least one binder and one or more pharmaceutically acceptable excipient selected from a glidant, sweetener, flavoring agent, and lubricant. In the present invention, an orodispersible tablet may contain other pharmaceutically acceptable excipients as needed, insofar as they do not reduce the effect of the present invention. The term pharmaceutically-acceptable salts can be used herein includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Suitable pharmaceutically acceptable acid addition salts of levetiracetam 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 (parnoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, malonic, galactaric and galacturonic acid. Preferably levetiracetam as used herein is in the form of the free base. In the one embodiment of the present invention, levetiracetam or pharmaceutically acceptable salts thereof, is present in the range of about 55 %w / w to about 85 %w / w, preferably in the range of about 60 %w / w to about 80 %w / w. In the one embodiment of the present invention, a suitable diluent for the present invention can be selected from the group consisting of a calcium carbonate, cellulose derivative, microcrystalline cellulose, microfine cellulose, sugar alcohols such as maltitol, xylitol, mannitol, sorbitol, erythritol, dextrates, dextrose, lactose, starch, pregelatinized starch, and dextrin, or any combinations thereof. In the preferred embodiment of the present invention, the combination of cellulose derivative, and sugar alcohol is preferred as a diluent in the range of about 2 %w / w to about 35 %w / w, preferably in the range from about 10 %w / w to about 25 %w / w. Microcrystalline cellulose 1000 is present in the range from about 1 %w / w to about 20 %w / w, preferably from about 5 %w / w to about 15 %w / w, mannitol is present in the range from about 1 %w / w to about 15 %w / w, preferably from about 5 %w / w to about 10 %w / w. The use of mannitol as a diluent in tablets is preferred due to its various physicochemical properties, including high flowability, nonhygroscopicity, chemical inertness, and advantageous compatibility during tableting. By incorporating mannitol into the tablet formulation, both the mechanical properties of the tablet and the flow of the powder can be improved, ensuring uniform compression. Mannitol is a crystalline material with excellent compressibility, capable of forming a strong bond with other tablet components. This feature helps to prevent tablet defects by ensuring that the tablets are uniformly compressed and have adequate binding between their components. Furthermore, granulations containing mannitol are easy to dry’. Apart from these benefits, mannitol's negative heat of solution, sweetness, and mouthfeel not only enhances the perception of flavors but also helps with optimizing taste-masked formulations. Firstly, its ability to promote rapid disintegration upon contact with saliva ensures quick dissolution and absorption of active ingredients, leading to a faster onset of action and improved patient compliance. On the other hand, microcrystalline cellulose is a type of fdler that facilitates efficient dry blending of ingredients and enables excellent tablet compression. Its swelling tendencies and exceptional water imbibing or wicking action encourage rapid wetting of the powder mixture, reduce sensitivity to over-wetting, and accelerate the drying process, resulting in faster tablet disintegration. Thus, the combination of microcrystalline cellulose and mannitol is preferred over other diluents in the present invention. In the one another embodiment of the present invention, a suitable disintegrant is selected from tine group consisting of methylcellulose, alginic acid, guar gum, carboxymethylcellulose calcium, polacrilin potassium, croscarmellose sodium, carmellose calcium, crospovidone, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, poloxamer, magnesium aluminum silicate, sodium starch glycolate, and sodium alginate or any combination thereof. In the preferred embodiment of the present invention, the combination of croscarmellose sodium and crospovidone is preferred as a disintegrant in the range of about 1 %w / w to about 15 %w / w, preferably in the range from about 3 %w / w to about 10 %w / w. Croscarmellose sodium is present in the range from about 0.5 %w / w to about 6 %w / w, preferably in the range from about 1 %w / w to about 4 %w / w, Crospovidone is present in the range from about 0.5 %w / w to about 9 %w / w, preferably in the range of about 2 %w / w to about 6 %w / w. Croscarmellose sodium is a cross-linked sodium salt of carboxymethyl cellulose, highly hydrophilic, and has a large swelling capacity. Croscarmellose sodium speeds up the disintegration process (wicking) through the mechanisms of swelling, recovering elastic energy, and capillary action resulting in rapid and uniform disintegration. Crospovidone is a water-msolubie noniomc polymer consisting of 9 cross-lmked 1-vinyl-2-pyrrolidone monomers. Crospovidone, used in solid dosage form manufacturing as a disintegrant, acts via a different mechanism than the swelling starches. When compaction force is applied, the polymer deforms. Upon contact with water, it adsorbs water via capillary action and regains its normal structure releasing an amount of energy capable of breaking the tablet. Crospovidone is considered an excellent excipient leading to fast disintegration without compromising dissolution due to its inability to form a gel. This property makes it useful as a disintegrant m tablets. Thus, the combination of disintegrants is preferred in the present invention. In one more embodiment of the present invention, a suitable binder can be selected from the group consisting of starch, polyethylene glycol, polyvinylpyrrolidone, povidone gelatin, sugars such as sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol, polymethacrylates, acrylates such as Eudragits, natural and synthetic gums such as acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, irish moss extract, panwar gum, ghatti gum, guar gum, zein, cellulose derivatives such as carboxymethyl cellulose and salts thereof, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose and ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, waxes, magnesium aluminum silicate, bentonites or any combinations thereof. In the preferred embodiment of the present invention, polyvinylpyrrolidone K30 is preferred as tire binder in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 3 %w / w. In one embodiment of the present invention, the glidant can be selected from the group consisting of ascorbyl palmitate, calcium phosphate tribasic calcium palmitate, calcium silicate, magnesium stearate, colloidal anhydrous silica, starch and talc, or combinations thereof. In the preferred embodiment of the present invention, colloidal anhydrous silica is preferred as a glidant in the range of about 0.05 %w / w to about 0.5 %w / w, preferably in the range of about 0.08 %w / w to about 0.3 %w / w. In one embodiment of the present invention, a suitable lubricant can be selected from the group consisting of boric acid, magnesium stearate, sodium stearyl fumarate, micronized polyoxy ethylene glycol, leucine, sodium benzoate, sodium acetate, sodium lauryl sulfate, stearic acid, sodium stearate, sodium oleate, calcium stearate, waxes or any combination thereof. In the preferred embodiment of the present invention, magnesium stearate is preferred as a lubricant for the present invention and is present in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 2 %w / w. In one more embodiment of the present invention, a sweetener can be selected from the group consisting of cyclamate, acesulfame potassium, neo hesperidin dihydrochalcone, monoammonium glycyrrhizinate, saccharin sodium, sucralose, saccharin, aspartame or any combination thereof. In the preferred embodiment of the present invention, acesulfame potassium is preferred as a sweetener for the present invention and is present in the range of about 0.05 %w / w to about 0.8 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w. In one another embodiment of the present invention, a flavoring agent can be selected from a group consisting of menthol, floral fennel flavor, mint powder, vanillin, raspberry flavor, orange flavor, or any combinations thereof. In the preferred embodiment of the present invention, raspberry’ flavor is preferred as a flavoring agent present in the range from about 0.1 %w / w to about l%w / w, preferably in the range of about 0.5 %w / w to about 0.9 %w / w. In the preferred embodiment, the present invention has been made to solve the above-mentioned problems, and its object is to use levetiracetam or a pharmaceutically acceptable salt thereof as an active ingredient, which provides a faster disintegration time and faster dissolution rate. Levetiracetam can effectively be treated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. It is also indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children, and infants from 1 month of age with epilepsy, in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy and in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy. In one embodiment of the present invention, the orodispersible tablet comprising levetiracetam or pharmaceutically acceptable salts thereof, present in an amount from about 55 %w / w to about 85 %w / w, preferably in the range of about 60 %w / w to about 80 %w / w, a combination of diluents is present in the range of about 2 %w / w to about 35 %w / w, preferably in the range of about 10 %w / w to about 25 %w / w, a combination of disintegrants is present in the range from about 1 %w / w to about 15 %w / w, preferably in the range of about 3 %w / w to about 10 %w / w, binder is present in the range from about 0.5 %w / w to about 5 %w / w, preferably m the range of about 0.8 %w / w to about 3 %w / w, glidant is present in the range from about 0.05 %w / w to about 0.5 %w / w, preferably in the range of about 0.08 %w / w to about 0.3 %w / w, lubricant is present in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 2 %w / w, the sweetener is present in the range of about 0.05 %w / w to about 0.8 %w / w, preferably in the 12 range of about 0.1 %w / w to about 0.5 %w / w and the flavoring agent is present in the range from about 0.1 %w / w to about l%w / w, preferably in the range of about 0.5 %w / w to about 0.9%w / w. In the preferred embodiment of the present invention, the orodispersible tablet comprising levetiracetam or pharmaceutically acceptable salts thereof, present in an amount from about 55 %w / w to about 85 %w / w, preferably in the range of about 60 %w / w to about 80 %w / w, the combination of microcrystalline cellulose 1000 and mannitol is present in the range of about 2 %w / w to about 35 %w / w, preferably in die range of about 10 %w / w to about 25 %w / w, the combination of croscarmellose Sodium and crospovidone is present in the range from about 1 %w / w to about 15 %w / w, preferably in the range of about 3 %w / w to about 10 %w / w, Polyvinylpyrrolidone K30 is present in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 3 %w / w, Colloidal anhydrous silica is present in the range from about 0.05 %w / w to about 0.5 %w / w, preferably in the range of about 0.08 %w / w to about 0.3 %w / w, Magnesium stearate is present in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 2 %w / w, the acesulfame potassium is present in the range of about 0.05 %w / w to about 0.8 %w / w, preferably in die range of about 0.1 %w / w to about 0.5 %w / w and the raspberry flavor is present in the range from about 0.1 %w / w to about l%w / w, preferably in the range of about 0.5 %w / w to about 0.9%w / w. In one embodiment of the present invention is to manufacture an orodispersible tablet containing levetiracetam by wet granulation process, which is one of the most economical methods. Wet granulation enhances the flow properties of powders, making them easier to handle and ensuring a more uniform distribution during the tableting process. As per one another embodiment of the present invention, the disintegrating time of the levetiracetam orodispersible tablet is less than 3 minutes, preferably less than 2 minutes. As per another embodiment of the present invention, 95 % of the levetiracetam is released in 30 minutes, preferably more than 95 % is released within 10 minutes. As per one embodiment of the present invention, packaging material for an orodispersible tablet of levetiracetam is selected from the polypropylene bottle with silica canister, PP Bottle with an Oxygen scavenger, HDPE Bottle, HDPE Bottle with SAF, HDPE Bottle with CR cap, HDPE Bottle with Silica canister, HDPE Bottle with an Oxygen scavenger, Alu-Alu Blister and PVC / PVDC-Alu Film. In the present invention, the HDPE Bottle with a CR cap containing silica gel is preferred as packaging material to deliver the desired physicochemical parameters. As per one more embodiment, the wet granulation method is used to manufacture the orodispersible tablet. Levetiracetam, microcrystalline cellulose 1000, mannitol, croscarmellose sodium, crospovidone, colloidal silica anhydrous, raspberry flavor, and acesulfame potassium are sieved separately through a 40# sieve, and magnesium stearate, are sieved separately through a 60# sieve. In a rapid mixer granulator previously sifted levetiracetam and mannitol are blended and mixed for 5 minutes. Povidone k30 is then dissolved in Isopropyl Alcohol with continuous stirring until a clear and viscous solution is obtained to prepare a binder solution. Subsequently, the binder solution obtained earlier is gradually added to the rapid mixer granulator at the slow speed of the impeller and chopper off, ensuring a homogeneous mixture with continuous mixing for 10 minutes with intermittent addition of the remaining quantity of Isopropyl alcohol. The granulated blend is then dried in a dryer at 50°C ± 5°C and the dry granules are passed through a 24# sieve and retained granules are milled through a 1.5 mm screen, and the entire blend is subsequently passed through a 24# sieve. Further, the granules are mixed with previously sifted microcrystalline Cellulose-1000, Colloidal anhydrous silica, Croscarmellose Sodium, Crospovidone, Acesulfame potassium, and Raspberry Flavor are added to the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate is added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture is compressed to form tablets. The prepared tablets were packed in HDPE bottles with CR cap containing silica gel preferred as packaging materials to deliver the desired physicochemical parameters. Embodiments of the present disclosure are now further illustrated on the basis of examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustrating and description only, they are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed. EXAMPLES Example 1: The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table I for a dose strength of 500mg: TABLE-I Ingredients Levetiracetam 71.43 Lactose 24.22 Colloidal silica anhydrous 0.17 Croscarmellose sodium 2.00 Acesulfame potassium 0.43 Raspberry Flavor 0.75 Magnesium Stearate 1.00 Total 100 Manufacturing process: Levetiracetam, lactose, colloidal silica anhydrous, croscarmellose sodium, acesulfame potassium, and raspberry flavor were sieved separately through a 40# sieve. Magnesium stearate was sieved separately through a 60# sieve. In a blender previously sifted levetiracetam and lactose were blended and mixed for 20 minutes. The previously sifted colloidal silica anhydrous, croscarmellose sodium, acesulfame potassium, and raspberry flavor were added to the blender and blended for 10 minutes. At last, previously sifted magnesium stearate was added to the above blend and mixed for 5 minutes. The blend flow was not good so, further compression activity was not performed. To optimize blend flow, the diluent and manufacturing process was changed from dry mixing to wet granulation. Test Parameters of blend Result Bulk Density' (gm / ml) 0.285 Tap Density (gm / ml) 0.355 Carr’s Index (%) 19.71 Hausner’s Ratio 1.24 Example 2: The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table II for a dose strength of 500 mg: TABLE-II Ingredients Levetiracetam 71.43 Mannitol 22.65 Polyvinylpyrrolidone K 30 1.57 Isopropyl alcohol QS Colloidal silica anhydrous 0.17 Croscarmellose sodium 2.00 Acesulfame potassium 0.43 Raspberry Flavor 0.75 Magnesium Stearate 1.00 Total 100 Manufacturing process: Levetiracetam, Mannitol, colloidal silica anhydrous, Croscarmellose sodium. Acesulfame potassium, Raspberry flavor, and Polyvinylpyrrolidone K30 were sieved separately through a 40# sieve, and magnesium stearate was sieved separately through a 60# sieve. In a rapid mixer granulator previously sifted levetiracetam and mannitol were blended and mixed for 5 minutes. Povidone k30 was then dissolved in Isopropyl Alcohol with continuous stirring until a clear and viscous solution was obtained to prepare a binder solution. Subsequently, the binder solution obtained earlier is gradually added to the rapid mixer granulator at the slow speed of the impeller and chopper off, ensuring a homogeneous mixture with continuous mixing for 10 minutes with intermittent addition of the remaining quantity of Isopropyl alcohol. The granulated blend was then dried in a dryer at 50°C ± 5°C and the dry granules were passed through a 24# sieve retained granules were milled through a 1.5 mm screen, and the entire blend was subsequently passed through a 24# sieve. Further, the granules were mixed with previously sifted colloidal anhydrous silica, croscarmellose sodium, acesulfame potassium, and raspberry flavor added to the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate was added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture was compressed to form tablets The hardness and physical parameters of the blend were found not satisfactory. To optimize the hardness, microcn. stallinc Cellulose-1000 was added into the above formulation. The tablets present the characteristics mentioned in the table below: Test Parameters Result Hardness 45N - 125N 40N Average weight 700 mg ± 5% 700.2 Thickness 4.40 ±0.30 mm 4.41 5 Example 3: The orodispersible tablet was made according to the method defined below using tire formulation having the ingredients shown in Table III for a dose strength of 500 mg: TABLE-m Ingredients Levetiracetam 71.43 Mannitol 11.03 Polyvinylpyrrolidone K 30 1.57 Isopropyl alcohol Q.S Colloidal silica anhydrous 0.17 Croscarmellose sodium 2.00 Microcrystalline Cellulose-1000 11.61 Acesulfame potassium 0.43 Raspberry Flavor 0.75 Magnesium Stearate 1.00 Total 100.00 Manufacturing process: Levetiracetam, microcrystalline cellulose 1000, mannitol, croscarmellose sodium, colloidal silica anhydrous, raspberry flavor, and acesulfame potassium were sieved separately through a 40# sieve, and magnesium stearate was sieved separately through a 60# sieve. In a rapid mixer granulator previously sifted levetiracetam and mannitol were blended and mixed for 5 minutes. Povidone k30 was then dissolved in Isopropyl Alcohol with continuous stirring until a clear and viscous solution was obtained to prepare a binder solution. Subsequently, the binder solution obtained earlier was gradually added to the rapid mixer granulator at the slow speed of the impeller and chopper off, ensuring a homogeneous mixture with continuous mixing for 10 minutes with intermittent addition of the remaining quantity of Isopropyl alcohol. The granulated blend was then dried in a dryer at 50°C ± 5°C and the dry granules were passed through a 24# sieve retained granules were milled through a 1.5 mm screen, and the entire blend was subsequently passed through a 24# sieve. Further, the granules were mixed with previously sifted microcrystalline Celhilose-1000, Colloidal anhydrous silica, Croscarmellose Sodium, Acesulfame potassium, and raspberry flavor were added to the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate was added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture was compressed to form tablets. The physical parameters of the tablets were not found satisfactory. To optimize the disintegration time add another disintegrant into the above formulation. The tablets present the characteristics mentioned in the table below: Test Parameters Test Parameters Result Hardness 45N - 125N 63N Average weight 700 mg ± 5% 700.1 Thickness 4.40 ±0.30 mm 4.42 Disintegration time Not more than 3 minutes 1 minute 20sec Example 4: The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table IV for a dose strength of 500 mg: 5 TABLE-IV Ingredients Levetiracetam 71.43 Mannitol 7.04 Polyvinylpyrrolidone K-30 1.57 Isopropyl Alcohol Q.S Microcrystalline cellulose-1000 11.61 Colloidal silica anhydrous 0.17 Croscarmellose sodium 2.00 Crospovidone 4.00 Acesulfame potassium 0.43 Raspberry Flavor 0.75 Magnesium Stearate 1.00 Total 100.00 Manufacturing process: Levetiracetam, microcrystalline cellulose 1000, mannitol, croscarmellose sodium, crospovidone, colloidal silica anhydrous, raspberry flavor, and acesulfame 10 potassium were sieved separately through a 40# sieve, and magnesium stearate were sieved separately through a 60# sieve. In a rapid mixer granulator previously sifted levetiracetam and mannitol were blended and mixed for 5 minutes. Povidone k30 was then dissolved in Isopropyl Alcohol with continuous stirring until a clear and viscous solution was obtained to prepare a binder solution. Subsequently, the 15 binder solution obtained earlier was gradually added to the rapid mixer granulator at the slow speed of the impeller and chopper off, ensuring a homogeneous mixture with continuous mixing for 10 minutes with intermittent addition of the remaining quantity of Isopropyl alcohol. The granulated blend was then dried in a dryer at 50°C ± 5°C and the dry granules were passed through a 24# sieve retained granules were milled through a 1.5 mm screen, and the entire blend was subsequently passed through a 24# sieve. Further, the granules were mixed with previously sifted 5 microcrystalline Cellulose-1000, Colloidal anhydrous silica, Croscarmellose Sodium, Crospovidone, Acesulfame potassium, and Raspberry Flavor were added to the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate was added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture was compressed to form tablets. The 10 prepared tablets were packed in HDPE Bottle with CR cap containing silica gel preferred as packaging materials to deliver the desired physicochemical parameters. All the physical and chemical parameters of the tablets were found satisfactory. Test Parameters of blend Result Bulk Density (gm / ml) 0.356 Tap Density (gm / ml) 0.499 Carr’s Index (%) 28.65 Hausner’s Ratio 1.40 Levetiracetam ODT 500 mg Test Parameters Specification Result Hardness 45N - 125N 62N Average weight 700 mg ± 5% 700.2 Thickness 4.40 ± 0.30 mm 4.41 Friability Not more than 1.0% 0.23 Disintegration Not more than 3 minutes 21 sec Example 5: The Dissolution profile of the tablet prepared according to Example 4 The conditions of dissolution are the following: Apparatus: USP type II (paddle) Rate of rotation: 50 Volume: 900ml 5 Temperature: 37°C ± 0.5°C Detection: High-performance liquid chromatography equipped with UV / PDA at 210 nm. Dissolution medium: water Levetiracetam 500 mg Orodispersible tablet Time (Min) % Drug Release % RSD 10 101.3 0.6 15 101.2 0.6 20 100.9 0.5 30 100.6 0.7 45 100.3 0.6 60 100.4 0.4 10 Result: The Orodispersible Tablet of levetiracetam was tested for its dissolution profile measured in 900 mL of water, at 50 RPM in USP II (Paddle) apparatus and the active ingredient of the tablet was released at more than 95 % in 10 minutes. Example 6: Hie tablets prepared according to example 4 were subjected to a 15 stability study of 25°C / 60% RH and 40°C / 75% RH for 3 months and 6 months. Results are tabulated below. Levetiracetam 500 mg Orodispersible Tablets Test Specification Exp 4 (initial) Exp 4 (After 3 months) Exp 4 ( After 6 months) iliili liii RH ■ili Iiiii RH iiiii liii iiiii 40°C7 75% RH Hardness 45N - 125N 62N 63N 65N 62N 64N Disintegration time Not more than 3 minutes 21 sec 19sec 24sec 26sec 2 3 sec Assay (%) 95.0% - 105.0% of the labeled amount of Levetiracetam. 99.7 103.4 103.5 99.2 99.9 Dissolution NLT 75% (Q) labeled amount of Levetiracetam should be dissolved in 15 minutes. 99.9 99.6 100.1 100.1 100.0

Claims

1. An orodispersible tablet of levetiracetam for oral administration, comprising:a) levetiracetam or pharmaceutically acceptable salts thereof, present in an amount ranging from about 55 %w / w to about 85 %w / w, preferably in the range of about 60 %w / w to about 80 %w / w;b) at least one or more diluents present in the range from about 2 %w w to about 35 %w / w, preferably in the range of about 10 %w / w to about 25 %w / w;c) at least one or more disintegrants present in the range of about 1 %w / w to about 15 %w / w, preferably in the range of about 3 %w / w to about 10 %w / w;d) at least one lubricant present in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 2 %w / w;(e) at least one binder presents in the range from about 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 3 %w / w;(f) at least one glidant presents in the range from about 0.05 %w / w to about 0.5 %w / w, preferably in the range of about 0.08 %w / w to about 0.3 %w / w; and(g) at least one or more pharmaceutically acceptable excipients.

2. The orodispersible tablet according to claim 1, wherein the diluent is selected from the group consisting of a calcium carbonate, cellulose derivative, microcrystalline cellulose, microfine cellulose, sugar alcohols such as maltitol, xylitol, mannitol, sorbitol, erythritol, dextrates, dextrose, natural polymers, lactose, starch, pregelatmized starch, and dextrin, or any combinations thereof.

3. The orodispersible tablet according to claim 2, wherein the diluent comprises combination of microcrystalline cellulose and mannitol.

4. The orodispersible tablet according to claim 3, wherein the diluent mannitol present in the range from about 1 %w / w to about 15 %w / w, preferably in the range of about 5 %w / w to about 10 %w / w.

5. The orodispersible tablet according to claim 3, wherein the diluent microcrystalline cellulose present in the range from about 1 %w / w to about 20 %w / w, preferably in the range of about 5 %w / w to about 15 %w / w.

6. The orodispersible tablet according to claim 1, wherein the disintegrant is selected from the group consisting of methylcellulose, alginic acid, guar gum, carboxymethylcellulose calcium, polacrilin potassium, croscarmellose sodium, carmellose calcium, crospovidone, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, poloxamer, magnesium aluminum silicate, sodium starch glycolate, and sodium alginate or any combination thereof.

7. The orodispersible tablet according to claim 6, wherein the disintegrant comprises combination of croscarmellose sodium and crospovidone.

8. The orodispersible tablet according to claim 7, wherein the disintegrantcroscarmellose sodium present in the range from 0.5 %w / w to about 6 %w / w,preferably in the range of about I %w / w to about 4 %w / w.

9. The orodispersible tablet according to claim 7, wherein the disintegrantcrospovidone present in the range from 0.5 %w / w to about 9 %w / w, preferably in therange of about 2 %w / w to about 6 %w / w.

10. The orodispersible tablet according to claim 1, wherein the binder is selected from the group consisting of starch, gelatin, sugars such as sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol, polymethacrylates, natural and synthetic gums such as acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, Irish moss extract, panwar gum, ghatti gum, guar gum, zein, cellulose derivatives such as carboxymethyl cellulose and salts thereof, methylcellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose and ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, waxes, magnesium aluminum silicate, bentonites or any combinations thereof.

11. The orodispersible tablet according to claim 10, wherein the binder is povidone K30.

12. The orodispersible tablet according to claim 1, wherein the glidant is selected from the group consisting of ascorbyl palmitate, calcium phosphate tribasic calcium palmitate, calcium silicate, magnesium stearate, colloidal anhydrous silica, starch and talc or combinations thereof.

13. The orodispersible tablet according to claim 12, wherein the glidant is colloidal anhydrous silica.

14. The orodispersible tablet according to claim 1, wherein the lubricant is selected from the group consisting of boric acid, magnesium stearate, sodium stearyl fumarate, micronized polyoxyethylene glycol, leucine, sodium benzoate, sodium acetate, sodium lauryl sulfate, stearic acid, sodium stearate, sodium oleate, calcium stearate, waxes or combinations thereof.

15. The orodispersible tablet according to claim 14, wherein the lubricant is magnesium stearate.

16. The orodispersible tablet according to claim 1, wherein the sweetener is selected from the group consisting of cyclamate, acesulfame potassium, neo hesperidin dihydrochalcone, monoammonium glycyrrhizinate, saccharin sodium, sucralose, saccharin, aspartame or combinations thereof.

17. The orodispersible tablet according to claim 1, wherein the flavoring agent is selected from the group consisting of menthol, raspberry flavor, floral fennel flavor, mint powder, vanillin, or orange flavor or combinations thereof.

18. The orodispersible tablet according to claim 1, further comprises acesulfame potassium as sweetener present in the range from about 0.05 %w / w to about 0.8 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w and raspberry flavor as flavoring agent present in the range from about 0.1 %w / w to about l%w / w, preferably in the range of about 0.5 %w / w to about 0.9 %w / w.

19. The process for preparing an orodispersible tablet by the wet granulation method according to claim 1, comprising the steps of:(a) Sieving levetiracetam or pharmaceutically acceptable salts thereof, microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal anhydrous silica, crospovidone, acesulfame potassium, raspberry flavor separately through a 40# sieve and magnesium stearate sieve separately through a 60# sieve;(b) Dissolving povidone K30 in isopropyl alcohol with continuous stirring until it gets a clear viscous binder solution;(c) Dry mixing of levetiracetam or pharmaceutically acceptable salts thereof and mannitol in the rapid mixer granulator;(d) Adding binder solution gradually in step (c) dry mixed blend in rapid mixer granulator with continuance mixing;(e) Drying the granulated blend of step (d) in a dryer at 50°C ± 5°C;(f) Passing the dry granules of step (e) through a 24# sieve and retained granules milled through a 1.5 mm screen and pass all blend through a 24# sieve;(g) Mixing of granules with previously shifted microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, crospovidone, acesulfame potassium, and raspberry flavor in the blender;(h) Mixing of the blend prepared in step (g) with magnesium stearate in a blender;(i) Compressing the resulting mixture into tablet dosage form; and(j) Packing of the tablet into an HDPE Bottle with CR cap containing silica gel.

20. The orodispersible tablet according to claim 1, wherein 95 % of the levetiracetam or pharmaceutically acceptable salts thereof, is released within 30 minutes, preferably more than 95 % is released within 10 minutes.

21. The orodispersible tablet according to claim 1, wherein the hardness of the orally disintegrating tablet is between about 45 N to about 125 N, preferably between 50 N to 75 N.

22. 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.

23. The use of orodispersible tablets according to claim 1, for the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy; it is also indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents, children, and infants from 1 month of age with epilepsy, in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy and in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.

24. The orodispersible tablet according to claim 1, wherein said tablet composition comprises:a) 55 %w / w to about 85 %w / w, preferably in the range of about 60 %w / w to about 80 %w / w levetiracetam or pharmaceutically acceptable salts thereof;b) a combination of microcrystalline cellulose and mannitol present in the range from about 2 %w / w to about 35 %w / w, preferably in the range of about 10 %w / w to about 25 %w / w;c) 1 %w / w to about 15 %w / w, preferably in the range of about 5 %w / w to about 10 %w / w of mannitol;d) 1 %w / w to about 20 %w / w, preferably in the range of about 5 %w w to about 15 %w / w of microcrystalline cellulose;e) a combination of croscarmellose sodium and crospovidone present in the range of about 1 %w / w to about 15 %w / w, preferably in the range of about 3 %w / w to about 10 %w / w;f) 0.5 %w / w to about 6 %w / w, preferably in the range of about 1 %w / w to about 4 %w / w of croscarmellose sodium;g) 0.5 %w / w to about 9 %w / w, preferably in the range of about 2 %w / w to about 6 %w / w of crospovidone;h) 0.05 %w / w to about 0.5 %w / w, preferably in the range from about 0.08 %w / w to about 0.3 %w / w of colloidal anhydrous silica;i) 0.5 %w / w to about 5 %w / w, preferably in the range from about 0.8 %w / w to about 2 %w / w of magnesium stearate;j) 0.05 %w / w to about 0.8 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 % w / w of acesulfame potassium;k) 0.1 %w / w to about 1 %w / w, preferably in the range from about 0.5 % w / w to about 0.9 % w / w of raspberry flavor; and1) 0.5 %w / w to about 5 %w / w, preferably in the range of about 0.8 %w / w to about 3 %w / w of Povidone K30.

25. The orodispersible tablet according to claim 1, wherein said orodispersible tablet composition comprises:a) 71.42 %w / w of levetiracetam or pharmaceutically acceptable salts thereof;b) 7.03 % w / w of mannitol, and 11.61 % w / w of microcrystalline Cellulose as a 5 combination of diluents;c) 2 % w / w of croscarmellose sodium and 4 % w / w of crospovidone as a combination of disintegrates;d) 0.171 % w / w of colloidal Silica Anhydrous;e) 0.43 %w / w of acesulfame potassium;10 f) 1.57% w / w of povidone K30;g) 0.37 % w / w of raspberry Flavor; andh) 1.0 % w / w of magnesium stearate.31