An orodispersible tablet of lamotrigine and its process of preparation

Abstract

The present invention relates to an orodispersible tablet manufactured by a wet granulation method comprising lamotrigine or pharmaceutically acceptable salts thereof, at least one disintegrant, at least one diluent, at least one binder, at least one glidant, at least one solubilizer, at least one lubricant, and one or more pharmaceutically acceptable excipients. 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 solid pharmaceutical composition.

Description

[0001] Title: - An orodispersible tablet of Lamotrigine and its process of preparation

[0002] Field of the Invention

[0003] The present invention relates to the pharmaceutical compositions of lamotrigine. The present invention more particularly relates to orodispersible tablet of lamotrigine or pharmaceutically acceptable salts thereof for oral administration. The present invention also relates to the process of the preparation of the same. of the Invention

[0004] Lamotrigine was first disclosed in the U.S. Pat. No. 4602017 with the process of preparing the same. It is a triazine derivate that inhibits voltage-sensitive sodium channels, leading to the stabilization of neuronal membranes. Lamotrigine modifies maximal electroshock responses and reduces the duration of electrically evoked and photic after-discharges but also prolongs Na+ channel inactivation and suppresses high-frequency firing. Furthermore, it may directly inhibit voltage-sensitive Na+ channels, thereby stabilizing presynaptic membranes and preventing the release of excitatory neurotransmitters, particularly glutamate and aspartate. This broader spectrum of antiseizure efficacy may contribute to its effectiveness. However, it does not antagonize pentylenetetrazole (PTZ) seizures or block N-methyl-D- aspartate (NMD A) type glutamate receptors. Lamotrigine blocks L-, N-, and P-type calcium channels and weakly inhibits the serotonin 5-HT3 receptor. These actions inhibit the release of glutamate at cortical projections in the ventral striatum limbic areas, and its neuroprotective and antiglutamatergic effects are considered promising factors contributing to its mood-stabilizing activity.

[0005] Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients >2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to Lennox-Gastaut syndrome. It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy.

[0006] The IUPAC name of Lamotrigine is 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5- diamine and the chemical structure is as follows:

[0007] Lamotrigine is marketed as an oral tablet, extended-release tablet, and suspension. The commercially marketed products of Lamotrigine in extended-release tablet form are available in dosage strengths: 25mg, 50mg, lOOmg, 200mg, 250mg, and 300mg. The tablet comes in strengths of 25mg, lOOmg, 150mg, and 200mg. Additionally, the oral suspension comes in strengths of 5mg / ml, lOmg / ml, and 20mg / ml. Lamotrigine is well absorbed orally and metabolized completely in the liver. Lamotrigine belongs to BCS-class II (Low solubility and High permeability) and is rapidly and entirely absorbed with minimal first-pass metabolism effects. Lamotrigine is excreted in both the urine and faeces. The average elimination halflife of lamotrigine ranges from approximately 14-59 hours.

[0008] W02009063484A2 discloses an oral tablet containing Lamotrigine, the process of this invention involves sieving lamotrigine, lactose monohydrate, microcrystalline cellulose 102, and starch were sifted through # 40 mesh, and sodium starch glycolate & yellow oxide of iron were sifted through 200# mesh and mixed for 10 minutes at slow speed. This blend was granulated at a slow speed by a solution of sodium lauryl sulphate made in the required quantity of purified water. The wet mass was dried and the dried granules were rasped through 30# mesh. Sodium starch glycolate and avicel 102 were sifted through 60# mesh and magnesium stearate was sifted through 60# mesh separately. The rasped granules and sifted sodium starch glycolate, avicel 102 were mixed in a blender for 20 minutes. The sifted magnesium stearate was added for 5 minutes in the same blender. Lastly, the above blend was compressed using an appropriate punch.

[0009] US10653626B2 discloses a powder formulation for reconstitution with a pharmaceutically acceptable carrier to form a suspension of lamotrigine. The process of this invention involves dihydrate dihydrogen phosphate, polyethylene glycol, sucralose, strawberry essence, potassium sorbate, and maltitol were added successively into purified water with a stirring and then carrageenan was added into a pre-mixed solution with constant stirring. Thus, to the final solution mixture, lamotrigine was added slowly with stirring to form a suspension.

[0010] US20210069109A1 discloses an oral liquid suspension formulated with lamotrigine as the active ingredient, alongside inactive ingredients such as water, glycerin, propylene glycol, polyethylene glycol, methylparaben, sodium benzoate, sorbitol, saccharin sodium, sucralose, xanthan gum, sodium carboxymethyl cellulose, sodium phosphate dibasic, MCC, colloidal silicon dioxide, coloring agent, and flavoring agent.

[0011] WO92 / 13527 describes water dispersible tablet comprising lamotrigine and a dispersing agent where the dispersing agent is a swellable clay such as smectite and is present within the granules of the tablet to provide a tablet that is capable of dispersing in water within 3 minutes to provide a dispersion which will pass through a 710 mm sieve. The tablet can be optionally film-coated. These are generally administered to paediatric patients.

[0012] US 5,942,510 discloses a lyophilized injectable formulation of lamotrigine mesylate. A process for preparing a lyophilized formulation of lamotrigine wherein the bulking agent, mannitol is included in the aqueous solution allowing reconstitution with a liquid carrier up to a concentration of 60 mg / ml of lamotrigine before lyophilization.

[0013] The currently available solid dosage form of lamotrigine 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.

[0014] 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. The orodispersible tablet of lamotrigine 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 lamotrigine. Summary of the Invention

[0015] The present invention relates to stabilized pharmaceutical compositions of lamotrigine. The present invention provides compositions of lamotrigine or pharmaceutically acceptable salts thereof, comprising at least one disintegrant, at least one diluent, at least one binder, at least one solubilizer, and one or more pharmaceutically acceptable excipient selected from a glidant, sweetener, flavoring agent, and lubricant. The present invention also relates to a process of preparation of such stabilized compositions.

[0016] Objects of the Invention

[0017] The main object of the present invention is to provide an orodispersible tablet of lamotrigine or pharmaceutically acceptable salts thereof.

[0018] Another object of the present invention is to provide a process for preparing the solid pharmaceutical composition of lamotrigine or pharmaceutically acceptable salts thereof for oral administration.

[0019] Another object of the present invention is to provide an onset of action within a short time after administration.

[0020] Another object of the present invention is to enhance the disintegration and dissolution of the drug for oral administration.

[0021] Another further object of the present invention is to provide taste-masking properties and present pleasant palatability such that the administration of the orodispersible tablet is not unpleasant for pediatrics, geriatrics, or unconscious patients. A 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.

[0022] Another object of the present invention is to provide a stable orodispersible tablet of lamotrigine or pharmaceutically acceptable salts thereof.

[0023] Yet another object of the present invention can effectively be treated as adjunctive therapy for the following seizure types in patients 5=2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to Lennox- Gastaut syndrome. It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). In addition to the above, it is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, and mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy.

[0024] Detailed description of the Invention

[0025] The invention is further illustrated by the following examples, which are by no means intended to limit the scope of the invention but are given by way of illustration.

[0026] 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.

[0027] The term "Orodispersible tablet” refers to a solid dosage form of the present invention, which disintegrates rapidly in the oral cavity of a patient after administration, without chewing.

[0028] 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.

[0029] 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.

[0030] The main embodiment of the present invention is to provide an orodispersible tablet formulation of lamotrigine.

[0031] Another main embodiment of the present invention is to provide an orodispersible tablet formulation of lamotrigine comprising lamotrigine or pharmaceutically acceptable salts thereof, at least one disintegrant, at least one diluent, and at least one binder. In addition, the orodispersible tablet further comprises one or more pharmaceutically acceptable excipients selected from a glidant, solubilizer, sweetener, flavoring agent, and lubricant.

[0032] 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 lamotrigine 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, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, malonic, galactaric and galacturonic acid. Preferably lamotrigine as used herein is in the form of the free base.

[0033] As per one embodiment of the present invention lamotrigine or pharmaceutically acceptable salts thereof, is present in the range of about 25 %w / w to about 40 %w / w, preferably in the range of about 30 %w / w to about 35 %w / w.

[0034] As per 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, natural polymers, lactose, starch, pregelatinized starch, and dextrin, or any combinations thereof. In the present invention, the combination of calcium carbonate, cellulose derivative, and sugar alcohol is preferred as a diluent in the range of about 40 %w / w to about 70 %w / w, preferably in the range from about 45 %w / w to about 65 %w / w. Microcrystalline cellulose is present in the range from about 5 %w / w to about 20 %w / w, preferably from about 11 %w / w to about 15 %w / w, mannitol is present in the range from about 30 %w / w to about 45 %w / w, preferably from about 35 %w / w to about 40 %w / w, and calcium carbonate is present in the range from about 5 %w / w to about 20 %w / w, preferably from about 11 %w / w to about 15 %w / w. The use of mannitol as a diluent in tablets is preferred due to its various physicochemical properties, including high flowability, non-hygroscopicity, 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. Calcium carbonate contributes to the stability of orodispersible tabletss by maintaining their integrity throughout storage, and its compatibility with a wide range of pharmaceutical ingredients and excipients ensures smooth integration into formulations. On the other hand, microcrystalline cellulose is a type of filler 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 overwetting, and accelerate the drying process, resulting in faster tablet disintegration. Thus, the combination of calcium carbonate, microcrystalline cellulose, and mannitol is preferred over other diluents in the present invention.

[0035] As per one another embodiment of the present invention, a suitable disintegrant for the present invention can be selected from a 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. Croscarmellose sodium is the preferred disintegrant for the present invention 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. 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. Therefore, Croscarmellose is the disintegrant of choice for orodispersible tablets.

[0036] As per 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, 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 aluminium silicate, bentonites or any combinations thereof. In the present invention, Povidone K30 is preferred as the binder in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range from about 0.5 %w / w to about 1 %w / w.

[0037] As per another 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 present invention, colloidal anhydrous silica is preferred as a glidant in the range of about 0.5 %w / w to about 8 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w.

[0038] As per one another 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. Sodium stearyl fumarate is preferred as a lubricant for the present invention and is present in the range from about 0.5 %w / w to about 3 %w / w, preferably in the range from about 0.9 %w / w to about 2.5 %w / w, wherein the ratio of sodium stearyl fumarate to a combination of calcium carbonate, microcrystalline cellulose and mannitol is 1 :50 to 1 :70 preferably in the range of about 1 :55 to 1 :65.

[0039] As per one embodiment of the present invention, a solubilizing agent can be selected from the group consisting of cyclodextrins, poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polysorbates, which further includes a-cyclodextrin, P-cyclodextrin, 2-hydroxypropyl-8-cyclodextrin, y- cyclodextrin and 2-hydroxypropyl-y-cyclodextrin, poloxamer 124, poloxamer 18, poloxamer 23, poloxamer 338, poloxamer 407, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sorbitan tristearate or any combinations thereof. In the present invention, polysorbate 80 is preferred as a solubilizing agent present in the range from about 0.005 %w / w to about 0.1 %w / w, preferably in the range from about 0.01 %w / w to about 0.05 %w / w.

[0040] As per 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. Saccharin sodium is preferred as a sweetener for the present invention and is present in the range of about 0.05 %w / w to about 0.7 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w.

[0041] As per 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. The raspberry flavor is preferred as a flavoring agent present in the range from about 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. In the preferred embodiment, the present invention has been made to solve the above-mentioned problems, and its object is to use lamotrigine or a pharmaceutically acceptable salt thereof as an active ingredient, which provides a faster disintegration time and faster dissolution rate. Lamotrigine can effectively be treated as adjunctive therapy for the following seizure types in patients 5=2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to lennox-gastaut syndrome. It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy.

[0042] As per one embodiment of the present invention, the orodispersible tablet comprising lamotrigine or pharmaceutically acceptable salts thereof, present in an amount from about 25 %w / w to about 40 %w / w, preferably in the range of about 30 %w / w to about 35 %w / w, a diluent is present in the range of about 40 %w / w to about 70 %w / w, preferably in the range from about 45 %w / w to about 65 %w / w, a disintegrant is present 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, binder is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range from about 0.5 %w / w to about 1 %w / w, glidant is present in the range from about 0.5 %w / w to about 8 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w, solublizer is present in the range from about 0.005 %w / w to about 0.1 %w / w, preferably in the range from about 0.01 %w / w to about 0.05 %w / w, lubricant is present in the range from about 0.5 %w / w to about 3 %w / w, preferably in the range from about 0.9 %w / w to about 2.5 %w / w, the sweetener is present in the range of about 0.05 %w / w to about 0.7 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w and the flavoring agent is present in the range from about 0.05 %w / w to about 0.5 %w / w, preferably in the range from about 0.08 %w / w to about 0.3 %w / w.

[0043] As per one preferred embodiment of the present invention comprising lamotrigine or pharmaceutically acceptable salts thereof, present in an amount from about 25 %w / w to about 40 %w / w, preferably in the range of about 30 %w / w to about 35 %w / w, the combination of calcium carbonate, microcrystalline cellulose and mannitol is present in the range of about 40 %w / w to about 70 %w / w, preferably in the range from about 45 %w / w to about 65 %w / w, croscarmellose is present 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, povidone K30 is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range from about 0.5 %w / w to about 1 %w / w, colloidal anhydrous silica is present in the range from about 0.5 %w / w to about 8 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w, polysorbate 80 is present in the range from about 0.005 %w / w to about 0.1 %w / w, preferably in the range from about 0.01 %w / w to about 0.05 %w / w, sodium stearyl fumarate is present in the range from about 0.5 %w / w to about 3 %w / w, preferably in the range from about 0.9 %w / w to about 2.5 %w / w, the sodium saccharin is present in the range of about 0.05 %w / w to about 0.7 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w and the raspberry is present in the range from about 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.

[0044] As per one more embodiment of the present invention, the ratio of lubricant to diluent is 1 :50 to 1 :70 preferably in the range of about 1 :55 to 1 :65. The ratio of Sodium stearyl fumarate to a combination of calcium carbonate, microcrystalline cellulose and mannitol is 1 :50 to 1 :70 preferably in the range of about 1 :55 to 1 :65.

[0045] Another embodiment of the present invention is to manufacture an orodispersible tablet containing lamotrigine 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.

[0046] As per one another embodiment of the present invention, the disintegrating time of the Lamotrigine orodispersible tablet is less than 3 minutes, preferably less than 2 minutes.

[0047] As per another embodiment of the present invention, 95 % of the Lamotrigine is released in 80 minutes, preferably more than 95 % is released within 60 minutes.

[0048] As per one embodiment of the present invention, packaging material for an orodispersible tablet of lamotrigine 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 is preferred as packaging material to deliver the desired physicochemical parameters.

[0049] As per one more embodiment, the wet granulation method is used to manufacture the orodispersible tablet. Lamotrigine, microcrystalline cellulose 101, mannitol, croscarmellose sodium, calcium carbonate, colloidal silica anhydrous, and sodium saccharin are Sieved separately through a 40# sieve. Raspberry flavor, and sodium stearyl fumarate, are sieved separately through a 60# sieve. Povidone k30 and polysorbate 80 are then dissolved in purified water with continuous stirring until a clear and viscous solution is obtained to prepare a binder solution. In a rapid mixer granulator previously sifted lamotrigine, mannitol, microcrystalline cellulose 101, and croscarmellose sodium are blended and mixed for 10 minutes. Subsequently, the binder solution obtained earlier is gradually added to the dry mixed blend in the rapid mixer granulator, ensuring a homogeneous mixture with continuous mixing for 10 minutes. 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 mannitol, colloidal silica anhydrous, croscarmellose sodium, calcium carbonate, sodium saccharin, and raspberry flavor are added to the above blend and mixed for 15 minutes. At last, the previously sifted sodium stearyl fumarate 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 Bottle with CR Closure preferred as packaging materials to deliver the desired physicochemical parameters.

[0050] The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0051] EXAMPLES

[0052] Example 1:

[0053] 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 5mg, 25mg, and 100 mg:

[0054] TABLE-I

[0055] Manufacturing process:

[0056] Lamotrigine, Mannitol, Microcrystalline cellulose 102, colloidal silica anhydrous, Povidone K30, calcium carbonate, and croscarmellose sodium are sieved separately through a 40# sieve. Sodium saccharin, raspberry flavor, and sodium stearyl fumarate are sieved separately through a 60# sieve. In a blender previously sifted lamotrigine, microcrystalline cellulose 102, mannitol, colloidal silica anhydrous, croscarmellose Sodium, Sucralose, Povidone k30, calcium carbonate, colloidal silica anhydrous, sodium saccharin, and raspberry flavor are blended and mixed for 20 minutes. At last, the previously sifted sodium stearyl fumarate is added to the above mixture and blended for 5 minutes.

[0057] The blend flow was not good so, further compression activity was not performed. To optimize blend flow, the manufacturing process changed from dry mixing to wet granulation.

[0058] Example 2:

[0059] 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 5mg, 25mg, and 100 mg: TABLE-II

[0060] Manufacturing process:

[0061] Lamotrigine, microcrystalline cellulose 101, mannitol, croscarmellose sodium, calcium carbonate, sodium saccharin and colloidal silica anhydrous, are sieved separately through a 40# sieve. Raspberry flavor and magnesium stearate are sieved separately through a 60# sieve. Povidone K30 is then dissolved in purified water with continuous stirring until a clear and viscous solution is obtained to prepare a binder solution. In a rapid mixer granulator previously sifted Lamotrigine, mannitol, microcrystalline cellulose 101, and croscarmellose sodium are blended and mixed for 10 minutes. Subsequently, the binder solution obtained earlier is gradually added to the dry mixed blend in the rapid mixer granulator, ensuring a homogeneous mixture with continuous mixing for 10 minutes. 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 mannitol, colloidal silica anhydrous, croscarmellose sodium, calcium carbonate, sodium saccharin, and raspberry flavor are added to the above blend and mixed for 15 minutes. At last, the previously sifted sodium stearyl fumarate is added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture is compressed to form tablets. The Disintegration time was observed Higher.

[0062] To optimize the Disintegration Time, it was necessary to change the concentration of disintegrant.

[0063] Example 3:

[0064] The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table III for a dose strength of 5mg, 25mg, and 100 mg:

[0065] TABLE-III Manufacturing process:

[0066] Lamotrigine, microcrystalline cellulose 101, mannitol, croscarmellose sodium, calcium carbonate, colloidal silica anhydrous, and sodium saccharin are sieved separately through a 40# sieve. Raspberry flavor, and Sodium stearyl fumarate, are sieved separately through a 60# sieve. Povidone k30 is then dissolved in purified water with continuous stirring until a clear and viscous solution is obtained to prepare a binder solution. In a rapid mixer granulator previously sifted lamotrigine, mannitol, microcrystalline cellulose 101, and croscarmellose sodium are blended and mixed for 10 minutes. Subsequently, the binder solution obtained earlier is gradually added to the dry mixed blend in the rapid mixer granulator, ensuring a homogeneous mixture with continuous mixing for 10 minutes. 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 mannitol, colloidal silica anhydrous, croscarmellose sodium, calcium carbonate, sodium saccharin, and raspberry flavor are added to the above blend and mixed for 15 minutes. At last, the previously sifted sodium stearyl fumarate is added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture is compressed to form tablets.

[0067] The physical parameters of the tablets were found satisfactory.

[0068] However, incomplete dissolution was observed. To increase dissolution solubilizers were added in the next trials. The conditions of dissolution are the following:

[0069] Apparatus: USP type II (paddle)

[0070] Rate of rotation: 50

[0071] Volume: 900ml Temperature: 37°C ± 0.5°C

[0072] Detection: High-performance liquid chromatography equipped with UV / PDA at 275 nm.

[0073] Dissolution medium: 0.1 N HC1

[0074] The tablets present the characteristics mentioned in the table below:

[0075] Example 4:

[0076] 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 5mg, 25mg, and 100 mg: TABLE-IV

[0077] Manufacturing process:

[0078] Lamotrigine, microcrystalline cellulose 101, mannitol, croscarmellose sodium, calcium carbonate, colloidal silica anhydrous, and sodium saccharin are Sieved separately through a 40# sieve. Raspberry flavor, and Sodium stearyl fumarate, are sieved separately through a 60# sieve. Povidone k30 and polysorbate 80 are then dissolved in purified water with continuous stirring until a clear and viscous solution is obtained to prepare a binder solution. In a rapid mixer granulator previously sifted Lamotrigine, mannitol, microcrystalline cellulose 101, and croscarmellose sodium are blended and mixed for 10 minutes. Subsequently, the binder solution obtained earlier is gradually added to the dry mixed blend in the rapid mixer granulator, ensuring a homogeneous mixture with continuous mixing for 10 minutes. 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 mannitol, colloidal silica anhydrous, croscarmellose sodium, calcium carbonate, sodium saccharin, and raspberry flavor are added to the above blend and mixed for 15 minutes. At last, the previously sifted sodium stearyl fumarate 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 Bottle with CR Closure preferred as packaging materials to deliver the desired physicochemical parameters.

[0079] All the physical and chemical parameters of the tablets were found satisfactory.

[0080] Lamotrigine ODT 5 mg

[0081] Lamotrigine ODT 25 mg

[0082] Lamotrigine ODT 100 mg

[0083] Example 5: The Dissolution profile of the tablet prepared according to Example 4

[0084] The conditions of dissolution are the following:

[0085] Apparatus: USP type II (paddle)

[0086] Rate of rotation: 50

[0087] Volume: 900ml Temperature: 37°C ± 0.5°C

[0088] Detection: High-performance liquid chromatography equipped with UV / PDA at 275 nm.

[0089] Dissolution medium: 0.1 N HC1 Result: The Orodispersible Tablet of Lamotrigine was tested for its dissolution profile measured in 900 mL of 0. IN HCL, at 50 RPM in USP II (Paddle) apparatus and the active ingredient of the tablet was released at more than 95 % in 60 minutes. Example 6: The tablets prepared according to example 4 were subjected to a stability study of 25°C / 60% RH and 40°C / 75% RH for 3 months and 6 months. Results are tabulated below. Lamotrigine 5mg Orodispersible Tablets

[0090] Lamotrigine 25mg Orodispersible Tablets

[0091] Lamotrigine 100 mg Orodispersible Tablets

Claims

Claims:

1. An orodispersible tablet of lamotrigine for oral administration comprising: a) lamotrigine or pharmaceutically acceptable salts thereof, is present in an amount ranging from about 25 %w / w to about 40 %w / w, preferably in the range from about 30 %w / w to about 35 %w / w; b) at least one diluent; c) at least one disintegrant is present in the range of about 0.5 %w / w to about 10 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w; d) at least one lubricant is present in the range from about 0.5 %w / w to about 3 %w / w, preferably in the range from about 0.9 %w / w to about 2.5 %w / w;(e) at least one binder is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range from about 0.5 %w / w to about 1 %w / w;(f) at least one glidant is present in the range from about 0.5 %w / w to about 8 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w;(g) at least one solubilizer is present in the range from about 0.005 %w / w to about 0.1 %w / w, preferably in the range from about 0.01 %w / w to about 0.05 %w / w; and(h) at least one or more pharmaceutically acceptable excipients, wherein the orodispersible tablet is disintegrated upon contact with saliva in less than 3 minutes, preferably less than 2 minutes,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, pregelatinized starch, and dextrin, or any combinations thereof.

3. The orodispersible tablet according to claim 2, wherein the diluent is the combination of calcium carbonate, microcrystalline cellulose, and mannitol present in the range from about 40 %w / w to about 70 %w / w, preferably in the range from about 45 %w / w to about 65 %w / w.

4. The orodispersible tablet according to claim 2, wherein the diluent is mannitol present in the range from about 30 %w / w to about 45 %w / w, preferably in the range from about 35 %w / w to about 40 %w / w.

5. The orodispersible tablet according to claim 2, wherein the diluent is microcrystalline cellulose present in the range from about 5 %w / w to about 20 %w / w, preferably in the range from about 11 %w / w to about 15 %w / w.

6. The orodispersible tablet according to claim 2, wherein the diluent is calcium carbonate present in the range from about 5 %w / w to about 20 %w / w, preferably in the range from about 11 %w / w to about 15 %w / w.

7. 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.

8. The orodispersible tablet according to claim 7, wherein the disintegrant is Croscarmellose sodium.

9. 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 syntheticgums 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.

10. The orodispersible tablet according to claim 9, wherein the binder is povidone K30.

11. 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.

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

13. The orodispersible tablet according to claim 1, wherein the solubilizing agent is selected from the group consisting of cyclodextrins, poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polysorbates, which further includes a-cyclodextrin, P-cyclodextrin, 2-hydroxypropyl-8-cyclodextrin, y-cyclodextrin and 2- hydroxypropyl-y-cyclodextrin, poloxamer 124, poloxamer 18, poloxamer 23, poloxamer 338, poloxamer 407, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sorbitan tristearate or any combinations thereof.

14. The orodispersible tablet according to claim 13, wherein the solubilizing agent is polysorbate 80.

15. 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, sodiumlauryl sulfate, stearic acid, sodium stearate, sodium oleate, calcium stearate, waxes or combinations thereof.

16. The orodispersible tablet according to claim 15, wherein the lubricant is sodium stearyl fumarate.

17. The orodispersible tablet according to claim 1, wherein the ratio of a lubricant to the diluent is in the range of 1:50 to 1:70 preferably in the range of about 1:55 to 1 :65.

18. The orodispersible tablet according to claim 17, wherein the ratio of sodium stearyl fumarate to a combination of calcium carbonate, microcrystalline cellulose, and mannitol is 1:50 to 1:70 preferably in the range of about 1 :55 to 1:65.

19. 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.

20. 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.

21. The orodispersible tablet according to claim 1, further comprises sodium saccharin present in the range from about 0.05 %w / w to about 0.7 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w and raspberry flavor present in the range from about 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.

22. The orodispersible tablet according to claim 1 , wherein the Orodispersible tablet is manufactured by the wet granulation method comprising the steps:(a) Sieving lamotrigine or pharmaceutically acceptable salts thereof, microcrystalline cellulose 101, mannitol, croscarmellose sodium, calcium carbonate, colloidalanhydrous silica, sodium saccharin, raspberry flavor separately through a 40# sieve and sodium stearyl fumarate sieve separately through a 60# sieve;(b) Dissolving polysorbate 80 and povidone K30 in purified water with continuous stirring until it gets a clear viscous binder solution;(c) Dry mixing of lamotrigine or pharmaceutically acceptable salts thereof, mannitol, microcry stalline cellulose 101, and croscarmellose sodium in the rapid mixer granulator;(d) Adding binder solution gradually in dry mixed blend in rapid mixer granulator with continuance mixing;(e) Drying the above granulated blend in a dryer at 50°C ± 5°C;(f) Passing the dry granules 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 croscarmellose sodium, calcium carbonate, colloidal anhydrous silica, sodium saccharin, and raspberry flavor in the blender;(h) Mixing of the blend prepared in step (g) with sodium stearyl fumarate in a blender;(i) Compressing the resulting mixture into tablet dosage form; and(j) Packing of the tablet into a HDPE Bottle with CR Closure.

23. The Orodispersible tablet according to claim 1, wherein 95 % of the lamotrigine or pharmaceutically acceptable salts thereof, is released within 80 minutes, preferably more than 95 % is released within 60 minutes.

24. The Orodispersible tablet according to claim 1, is used as adjunctive therapy for the treatment of partial seizures primary generalized tonic-clonic seizures, and generalized seizures due to Lennox-Gastaut syndrome in patients >2 years of age. It isalso indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy.

25. The Orodispersible tablet according to claim 1, wherein: a) 25 %w / w to about 40 %w / w, preferably in the range from about 30 %w / w to about 35 %w / w of lamotrigine or pharmaceutically acceptable salts thereof; b) a combination of calcium carbonate, microcrystalline cellulose, and mannitol present in the range from about 40 %w / w to about 70 %w / w, preferably in the range from about 45 %w / w to about 65 %w / w; c) 30 %w / w to about 45 %w / w, preferably in the range from about 35 %w / w to about 40 %w / w of mannitol; d) 5 %w / w to about 20 %w / w, preferably in the range from about 11 %w / w to about 15 %w / w of microcrystalline cellulose; e) 5 %w / w to about 20 %w / w, preferably in the range from about 11 %w / w to about 15 %w / w of calcium carbonate; f) 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w of croscarmellose sodium; g) 0.1 %w / w to about 5 %w / w, preferably in the range from about 0.5 %w / w to about 1 %w / w of povidone K30;h) 0.005 %w / w to about 0.1 %w / w, preferably in the range from about 0.01 %w / w to about 0.05 %w / w of polysorbate 80 i) 0.5 %w / w to about 8 %w / w, preferably in the range from about 1 %w / w to about 5 %w / w of colloidal anhydrous silica; j) 0.5 %w / w to about 3 %w / w, preferably in the range from about 0.9 %w / w to about 2.5 %w / w of sodium stearyl fumarate; k) 0.05 %w / w to about 0.7 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 % w / w of sodium saccharin; and1) 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 raspberry flavor.

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