An orodispersible tablet of pregabalin and its process of preparation

Abstract

An orodispersible tablet of pregabalin for oral administration comprising 15-60%w / w pregabalin or a pharmaceutically acceptable salt thereof; at least one diluent; a least one disintegrant comprising 0.1-10 %w / w; at least one lubricant comprising 0.1-5 %w / w; at least one binder comprising 0.1-10 %w / w; at least one glidant comprising 0.1-10 %w / w; and at least one or more pharmaceutically acceptable excipients; wherein the orodispersible table is disintegrated upon contact with saliva in less than 3 minutes. The diluent is preferably a combination of microcrystalline cellulose and mannitol; the disintegrant is preferably croscarmellose sodium; the binder is preferably low substituted hydroxypropyl cellulose; the glidant is preferably a combination of talc and colloidal anhydrous silica; and the lubricant is preferably magnesium stearate. The ratio of the lubricant to the diluent may be in the range of 1:70 to 1:90, preferably 1:75 to 1:85. The tablet may further comprise a sweetener, flavouring agent and / or sucralose. Methods of manufacturing the tablet via wet granulation are also provided. The tablet may release 85% of the pregabalin within 80 minutes, preferably within 60 minutes.

Description

The present invention relates to the pharmaceutical compositions of pregabalin. The present invention more particularly relates to orodispersible tablet of pregabalin or pharmaceutically acceptable salts thereof for oral administration. The present invention also relates to the process of the preparation of the same. Background of the Invention Pregabalin was first disclosed in the U.S. Pat. No. 6,197,819. Pregabalin is also called P-isobutyl-y-aminobutyric acid or isobutyl-GABA. Pregabalin is a structural derivative of the inhibitory neurotransmitter GABA, however, it does not bind to GABAA, GABAB, or benzodiazepine receptors and does not enhance GABAA responses in cultured neurons. Pregabalin, however, enhances the density of GABA transporter protein and increases the rate of functional GABA transport in cultured neurons when it is administered for a prolonged period of time. When the concentration of GABA diminishes below a threshold level appears to terminate seizures. Pregabalin inhibits the calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by interfering with the movement of calcium channels that contain alpha2-delta and reducing calcium currents. The antinociceptive effects of pregabalin may interact with descending noradrenergic and serotonergic pathways, which originate in the brainstem and influence spinal cord pain transmission, pregabalin is indicated for the treatment of postherpetic neuralgia, fibromyalgia, and as adjunctive therapy for the treatment of partial-onset seizures in adults. It is also indicated for the management of neuropathic pain related to spinal cord injury and diabetic peripheral neuropathy or generalized anxiety disorder. The IUPAC name of pregabalin is (35)-3-(aminomethyl)-5-m ethyl hexanoic acid and the chemical structure is as follows: Pregabalin is marketed as an oral tablet, capsule, solution, and powder. The commercially marketed products of pregabalin in extended-release tablet form are available in three dosage strengths: 82.5 mg, 165 mg, and 330 mg for oral administration. The dosage strength of the powder is available in 500 g, 1 kg, and 5 kg. The dosage strength of the capsule is available in 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg capsules, as well as in an oral solution containing 20 mg / ml. Pregabalin belongs to BCS-class I and its oral bioavailability is reported to be >90% regardless of the dose. The elimination half-life of pregabalin is 6.3 hours. The mean renal clearance is estimated to be 67.0 to 80.9 mL / min. US 8,945,620 B2 discloses an oral tablet containing pregabalin, matrix forming agent, and a swelling agent. The matrix-forming agent includes mixtures of polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent includes crosslinked polyvinylpyrrolidone and polyethylene oxide. The Pregabalin was dry blended with matrix-forming agents, followed by the addition of other excipients. To prepare the final drug product, the compressed dosage forms may undergo further processing such as polishing and coating. WO 2010 / 115612A2 discloses an oral capsule that comprises pregabalin and pregelatinized starch, wherein the blend is free of lactose, mannitol, or microcrystalline cellulose. The process comprises sieving and blending the pregabalin with pregelatinized starch to a homogenous blend. To the blend, talc and other excipients were added and the mixture was blended again. The final mixture was filled in a size 0 capsule in an amount of 400 mg of the blend per capsule. WO 2013 / 100874 Al discloses an effervescent powder, tablet, and granule comprising of pregabalin and at least one pharmaceutically acceptable excipient selected from the effervescent couple, flavoring agent, binder, lubricant, sweetener, and taste regulating agent. The effervescent formulation was prepared by the wet granulation method. The process of this invention involves mixing a binder, solvent, and active agent to prepare a granulation solution. Mix pregabalin with another pharmaceutically acceptable excipient. Wet granulating the mixture with the granulation solution and then granules are dried and sieved. The granules are compressed into a tablet, bottle-filled, or sachet-filled to produce the specified dosage form. US 2005 / 0171203A1 discloses the oral liquid pharmaceutical composition of pregabalin contains at least one preservative, a taste-masking agent, and a viscositycontrolling agent. The process involves adding sterile water to a vessel and then the contents of the vessel are heated to 80° C. Methylparaben and ethyl paraben are stirred into the hot water. After a clear solution is obtained, Sodium Saccharin and hydroxyethyl cellulose are added. The resulting liquid mixture is cooled to 30°C. The pregabalin and flavoring agent are added in small portions with Stirring. The solution is filtered using a Millipore (R) membrane filter and stored in Sealed containers. WO 2009 / 087682A2 discloses an injectable formulation of pregabalin which is stable between pH 4.0 to 8.0. The process involves taking water for injection into an SS container and sparge with 0.2p filtered nitrogen until the level of dissolved oxygen falls below 1 ppm. Dissolve sodium chloride, citric acid monohydrate, and pregabalin with continuous nitrogen sparging. Make up the volume with nitrogen-sparged water for injection. Filter the bulk solution through a 0.2 p polyvinylfluoridine filter by using nitrogen gas. Fill the filtered bulk solution into 5ml clear glass USP type 1 ampoules. The currently available solid dosage form of pregabalin has relatively long onset times, leading to delayed therapeutic effects. It also poses challenges for patients who struggle with swallowing tablets and capsules, 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 capsule or 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. Moreover, the solid dosage form available in the market takes more time to disintegrate, thereby delaying the onset of action. 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. The orodispersible tablet of pregabalin 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 pregabalin. Summary of the Invention The present invention relates to stabilized pharmaceutical compositions of pregabalin. The present invention provides compositions of pregabalin or pharmaceutically acceptable salts thereof, comprising 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 present invention also relates to a process of preparation of such stabilized compositions. Further, The present invention is directed to a method of preparing composition comprising: (a) Weighing all raw materials individually as per the batch formula; (b) Sieving Pregabalin or pharmaceutically acceptable salts thereof, microcrystalline cellulose 101, mannitol, microcrystalline cellulose-1000, colloidal silica anhydrous, croscarmellose sodium separately through 40# sieve and talc, sucralose, orange flavor, magnesium stearate separately through 60# sieve; (c) Dissolving L-HPC in purified water with continuous stirring until it gets clear viscous solution; (d) Dry mixing of Pregabalin or pharmaceutically acceptable salts thereof, mannitol, and microcrystalline cellulose 101 in the rapid mixer granulator; (e) Adding binder solution gradually in dry mixed blend in rapid mixer granulator with continuance mixing; (f) Drying the above granulated blend in a dryer at 50°C ± 5°C; (g) Passing the dry granules through 24# sieve and retained granules milled through 1.5 mm screen and pass all blend through 24# sieve; (h) Mixing of granules with previously shifted microcrystalline cellulose -1000, colloidal silica anhydrous, croscarmellose sodium, talc, sucralose, orange flavor in the blender; (i) Mixing of the blend prepared in step (h) with magnesium stearate in a blender; and (j) Compressing the resulted mixture into tablet dosage form. Objects of the Invention The primary object of the present invention is to provide an orodispersible tablet of Pregabalin or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a therapeutically effective amount of Pregabalin or pharmaceutically acceptable salts thereof, mannitol, microcrystalline cellulose, Low-Substituted Hydroxypropyl Cellulose (L-HPC), croscarmellose sodium, colloidal silica anhydrous, and one or more pharmaceutically acceptable excipients. Another object of the present invention is to provide a process for the preparation of an orodispersible tablet of pregabalin preferably a wet granulation method. Another further object of the present invention is to enhance the disintegration and dissolution of the drug for oral administration. Another object of the present invention relates to an orodispersible tablet which consists essentially of 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w croscarmellose sodium, wherein the tablet exhibits disintegration within less than 3 minutes, preferably less than 2 minutes. Another object of the present invention is to provide a pharmaceutical composition comprising pregabalin or pharmaceutically acceptable salts thereof, wherein the composition releases not less than about 95% of the dose in 15 min when tested for dissolution using United States Pharmacopoeia Apparatus 2, paddles @ 50 rpm in 900 mLofO.l NHC1. 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. Another object of the present invention is to provide a stable orodispersible tablet of Pregabalin or pharmaceutically acceptable salts thereof. Yet another object of the present invention can effectively treat postherpetic neuralgia, fibromyalgia, and as adjunctive therapy for the treatment of partial-onset seizures in adults. It is also indicated for the management of neuropathic pain related to spinal cord injury and diabetic peripheral neuropathy or generalized anxiety disorder. Detailed description of the Invention 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. The term "Orally disintegrating 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. 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 an orodispersible tablet comprised of Pregabalin 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, sweetener, flavoring agent, and lubricant. As per one embodiment of the present invention Pregabalin or pharmaceutically acceptable salts thereof, is present in the range of about 15 %w / w to about 60 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w. As per one embodiment of the present invention, a suitable diluent for the present invention is selected from the group consisting of a 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 cellulose derivative and sugar alcohol is preferred as a diluent in the range of about 45 %w / w to about 75 %w / w, preferably in the range from about 55 %w / w to about 65 %w / w. Microcrystalline cellulose is present in the range from about 10 %w / w to about 55 %w / w, preferably from about 15 %w / w to about 45 %w / w, and comprises coarser particles and fine particles and mannitol is present in the range from about 0.5 %w / w to about 20 %w / w, preferably from about 1 %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. 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 make it an ideal filler for the wet granulation process. Moreover, its wicking action encourages rapid wetting of the powder mixture, reduces sensitivity to overwetting, and accelerates 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. As per one another embodiment of the present invention, a suitable disintegrant for the present invention is 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 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %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. As per one more embodiment of the present invention, a suitable 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 aluminium silicate, bentonites or any combinations thereof. In the present invention, Low-Substituted Hydroxypropyl Cellulose is preferred as the binder in the range from about 0.1%w / w to about 10 %w / w, preferably in the range from about 0.5%w / w to about 5 %w / w. As per another embodiment of the present invention, 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. In the present invention combination of the talc and colloidal anhydrous silica is preferred as a glidant in the range of about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w. colloidal anhydrous silica is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w and talc is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w. As per one another embodiment of the present invention, a suitable lubricant is 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. Magnesium stearate is preferred as a lubricant for the present invention and 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, wherein the ratio of magnesium stearate to a combination of microcrystalline cellulose and mannitol is 1:70 to 1:90 preferably in the range of about 1:75 to 1:85. As per one more embodiment of the present invention, at least one further pharmaceutically acceptable excipient is a sweetener selected from the group consisting of cyclamate, acesulfame potassium, neo hesperidin dihydrochalcone, monoammonium glycyrrhizinate, saccharin sodium, sucralose, saccharin, aspartame or any combination thereof. Sucralose is preferred as a sweetener for the present invention and is present in the range of about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 2 %w / w. As per one another embodiment of the present invention, a flavoring agent is selected from a group consisting of menthol, floral fennel flavor, mint powder, vanillin, orange flavor, or any combinations thereof. The orange flavor is preferred as a flavoring agent present in the range from about 0.05 %w / w to about 1 %w / w, preferably in the range from about 0.1 %w / w to about 0.8 %w / w. In the preferred embodiment, the present invention has been made to solve the above-mentioned problems, and its object is to use pregabalin or a pharmaceutically acceptable salt thereof as an active ingredient, which provides a faster disintegration time and faster dissolution rate. Pregabalin is used for the treatment or prevention of postherpetic neuralgia, fibromyalgia, and as adjunctive therapy for the treatment of partial-onset seizures in adults. It is also indicated for the management of neuropathic pain related to spinal cord injury and diabetic peripheral neuropathy or generalized anxiety disorder. As per one embodiment of the present invention, the orodispersible tablet comprising pregabalin or pharmaceutically acceptable salts thereof, present in an amount from about 15 %w / w to about 60 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w, a diluent is present in the range of about 45 %w / w to about 75 %w / w, preferably in the range from about 55 %w / w to about 65 %w / w, a disintegrant is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w, binder is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w, glidant is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w, lubricant 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, the sweetener is present in the range of about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 2 %w / w and the flavoring agent is present in the range from about 0.05 %w / w to about 1 %w / w, preferably in the range from about 0.1 %w / w to about 0.8 %w / w. As per one preferred embodiment of the present invention comprising pregabalin or pharmaceutically acceptable salts thereof, present in an amount from about 15 %w / w to about 60 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w, the combination of microcrystalline cellulose and mannitol is present in the range of about 45 %w / w to about 75 %w / w, preferably in the range from about 55 %w / w to about 65 %w / w, croscarmellose sodium is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w, L-HPC is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w, the combination of talc and colloidal silica anhydrous is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w, Magnesium stearate 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, the sucralose is present in the range of about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 2 %w / w and the orange flavour is present in the range from about 0.05 %w / w to about 1 %w / w, preferably in the range from about 0. l%w / w to about 0.8 %w / w. As per one more embodiment of the present invention, the ratio of lubricant to diluent is 1:70 to 1:90 preferably in the range of about 1:75 to 1:85. The ratio of magnesium stearate to a combination of microcrystalline cellulose and mannitol is 1:70 to 1:90 preferably in the range of about 1:75 to 1:85. Another embodiment of the present invention is to manufacture an orodispersible tablet containing pregabalin 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 Pregabalin orodispersible tablet is less than 3 minutes, preferably less than 2 minutes. As per another embodiment of the present invention, 95 % of the Pregabalin is released in 80 minutes, preferably more than 95 % is released within 60 minutes. As per one embodiment of the present invention, packaging material for an orally disintegrating tablet of Paroxetine 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 PVDC-coated PVC film or HDPE Bottle with a CR cap 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. Pregabalin, microcrystalline cellulose 101, mannitol, croscarmellose sodium, Microcrystalline cellulose-1000, and Colloidal silica anhydrous, are Sieved separately through a 40# sieve. Talc, sucralose, orange flavor, and magnesium stearate, are sieved separately through 60# sieve. L-HPC 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 Pregabalin, mannitol, and microcrystalline cellulose 101 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 microcrystalline cellulose -1000, colloidal silica anhydrous, croscarmellose sodium, talc, sucralose, and orange flavor are added to the above blend and mixed for 15 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 PVDC-coated PVC FILM and HDPE Bottle with CR Closure preferred as packaging materials to deliver the desired physicochemical parameters. 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. 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 150 mg: TABLE-I Ingredients %w / w Pregabalin 34.88 Microcrystalline cellulose 101 32.07 Mannitol 6.98 L-HPC 1.40 Croscarmellose Sodium 2.09 Talc 1.00 Microcrystalline cellulose-1000 18.60 Colloidal silica anhydrous 1.00 Sucralose 0.81 Orange Flavor 0.47 Magnesium Stearate 0.70 Total 100 Manufacturing process: Pregabalin, Mannitol, Microcrystalline cellulose 101, HPC-L, Microcrystalline cellulose-1000, colloidal silica anhydrous, and Croscarmellose Sodium are sieved separately through a 40# sieve. Sucralose, orange flavor, Talc, and magnesium stearate are sieved separately through a 60# sieve. In a blender Previously sifted pregabalin, Microcrystalline cellulose 101, Mannitol, and L-HPC are blended and mixed for 15 minutes. After that, previously sifted Microcrystalline cellulose-1000, colloidal silica anhydrous, Croscarmellose Sodium, Sucralose, orange flavor &and Talc are blended with the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate is added to the above mixture and blended for 5 minutes. 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. 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 150 mg: TABLE-II Ingredients %w / w Pregabalin 34.88 Microcrystalline cellulose 101 32.54 Mannitol 6.98 L-HPC 1.40 Purified Water QS Microcrystalline Cellulose-1000 18.60 Croscarmellose Sodium 2.09 Talc 1.00 Colloidal Silica anhydrous 1.00 Sucralose 0.81 Orange Flavor 0.47 Magnesium Stearate 0.23 Total 100 Manufacturing process: Pregabalin, microcrystalline cellulose 101, mannitol, croscarmellose sodium, Microcrystalline cellulose-1000, and Colloidal silica anhydrous, are Sieved separately through a 40# sieve. Talc, sucralose, orange flavor, and magnesium stearate, are sieved separately through 60# sieve. Hydroxypropyl cellulose low viscosity (HPC-L) 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 Pregabalin, mannitol, and microcrystalline cellulose 101 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 microcrystalline cellulose -1000, colloidal silica anhydrous, croscarmellose sodium, talc, sucralose, and orange flavor are added to the above blend and mixed for 15 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 blend flow was proper but a Capping problem was observed during compression. To optimize the Capping problem, it was necessary to change the concentration of Lubricant. 5 Example 3: 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 150 mg: TABLE-III Ingredients %w / w Pregabalin 34.88 Microcrystalline cellulose 101 32.07 Mannitol 6.98 L-HPC 21 1.40 Purified Water QS Croscarmellose Sodium 2.09 Microcrystalline Cellulose-1000 18.60 Colloidal Silica anhydrous 1.00 Talc 1.00 Sucralose 0.81 Orange flavor 0.47 Magnesium Stearate 0.70 Total 100 10 Manufacturing process: Pregabalin, microcrystalline cellulose 101, mannitol, croscarmellose sodium, Microcrystalline cellulose-1000, and Colloidal silica anhydrous, are Sieved separately through a 40# sieve. Talc, sucralose, orange flavor, and magnesium 15 stearate, are sieved separately through 60# sieve. L-HPC 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 Pregabalin, mannitol, and microcrystalline cellulose 101 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 microcrystalline cellulose -1000, colloidal silica anhydrous, croscarmellose sodium, talc, sucralose, and orange flavor are added to the above blend and mixed for 15 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 Disintegration time was observed Higher. To optimize the Disintegration Time, it was necessary to change in concentration of HPC-L in further trials. Test Parameters of blend Result Bulk Density (gm / ml) 0.498 Tap Density (gm / ml) 0.618 Carr’s Index (%) 24.09 Hausner’s Ratio 1.24 The tablets present the characteristics mentioned in the table below: Test Parameters Test Parameters Result Hardness 25N - 85N (Target 65N) 68N Average weight 430.0 mg ± 5% (408.5 mg - 451.5 mg) 431.5 Thickness 4.2± 0.30 mm (3.90mm to 4.50mm) 4.18mm Friability NMT 1.0% 0.16% Disintegration time NMT 3 Minute 2 min 50sec 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 150 5 mg: TABLE-IV Ingredients %w / w Pregabalin 34.88 Microcrystalline cellulose 101 32.47 Mannitol 6.98 L-HPC 1.00 Purified Water QS Croscarmellose Sodium 2.09 Microcrystalline Cellulose-1000 18.60 Colloidal Silica anhydrous 1.00 Talc 1.00 Sucralose 0.81 Orange flavor 0.47 Magnesium Stearate 0.70 Total 100.00 Manufacturing process: Pregabalin, microcrystalline cellulose 101, mannitol, croscarmellose sodium, 10 Microcrystalline cellulose-1000, and Colloidal silica anhydrous, are Sieved separately through a 40# sieve. Talc, sucralose, orange flavor, and magnesium stearate, are sieved separately through a 60# sieve. L-HPC 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 Pregabalin, mannitol, and microcrystalline cellulose 101 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 microcrystalline cellulose -1000, colloidal silica anhydrous, croscarmellose sodium, talc, sucralose, and orange flavor are added to the above blend and mixed for 15 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 PVDC-coated PVC FILM and HDPE Bottle with CR Closure preferred as packaging materials to deliver the desired physicochemical parameters. All the physical and chemical parameters of the tablets were found satisfactory. l est Parameters of blend Result Bulk Density (gm / ml) 0.509 Tap Density (gm / ml) 0.678 Carr’s Index (%) 25.10 Hausner’s Ratio 1.33 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 Temperature: 37°C ± 0.5°C Dissolution medium: 0.1 NHC1 Result: The Orodispersible Tablet of pregabalin was tested for its dissolution profile measured in 900mL of 0. IN HCL, at 50 RPM in USP II (Paddle) apparatus 5 and the active ingredient of the tablet was released at more than 95% in 15 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 1 month. Results are tabulated below. 10 Pregabalin 150mg Orodispersible Tablets Test Specification (Initial) Exp 4 (After 1 month) 40°C / 75% RH Hardness 25N - 85N (Target 65N) 68N 66N Disintegration NMT 3 min 16 sec 18 sec Assay (%) 95.0% - 105.0% 101.5 100.2 Dissolution NLT 75% (Q) labelled amount of Pregabalin should dissolve in 15 minutes. 95.5 94.9 15

Claims

1. An orodispersible tablet of pregabalin for oral administration comprising:a) pregabalin or pharmaceutically acceptable salts thereof, is present in an amount ranging from about 15 %w / w to about 60 %w / w, preferably in the range from about 25 %w / w to about 45 %w / w;b) at least one diluent;c) at least one disintegrant is present in the range of about 0.1 %w / w to about 10 %w / w, preferably in the range of about 0.5 %w / w to about 5 %w / w;d) at least one lubricant 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;(e) at least one binder is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w;(f) at least one glidant is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w; andg) 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 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 microcrystalline cellulose and mannitol present in the range fromabout 45 %w / w to about 75 %w / w, preferably in the range from about 55 %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 0.5 %w / w to about 20 %w / w, preferably in the range from about 1 %w / w to about 15 %w / w.

5. The orodispersible tablet according to claim 2, wherein the diluent is microcrystalline cellulose present in the range from about 10 %w / w to about 55 %w / w, preferably in the range from about 15 %w / w to about 45 %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 is Croscarmellose sodium.

8. 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 thereof9. The orodispersible tablet according to claim 8, wherein the binder is Low-Substituted Hydroxypropyl Cellulose.

10. 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.

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

12. The orodispersible tablet according to claim 11, wherein the glidant is colloidal anhydrous silica present in the range from about 0.1%w / w to about 10%w / w, preferably in the range from about 0.5%w / w to about 5%w / w.

13. The orodispersible tablet according to claim 11, wherein the glidant is talc present in the range from about 0.1 %w / w to about 10% w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w.

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 ratio of a lubricant to the diluent is in the range of 1:70 to 1:90 preferably in the range of about 1:75 to 1:85.

17. The Orodispersible tablet according to claim 16, wherein the ratio of magnesium stearate to a combination of microcrystalline cellulose and mannitol is in the range of 1:70 to 1:90 preferably in the range of about 1:75 to 1:85.

18. 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.

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

20. The orodispersible tablet according to claim 1, further comprises sucralose present in the range from about 0.1 %w / w to about 5%w / w, preferably in the range of about 0.5 %w / w to about 2 %w / w and orange flavor present in the range from about 0.05 %w / w to about 1 %w / w, preferably in the range from about 0.1 %w / w to about 0.8 %w / w.

21. The orodispersible tablet according to claim 1, wherein the Orodispersible tablet is manufactured by the wet granulation method comprising the steps of:(a) Sieving pregabalin or pharmaceutically acceptable salts thereof, microcrystalline cellulose 101, mannitol, microcrystalline cellulose 1000, colloidal silica anhydrous, croscarmellose sodium separately through 40# sieve and talc, sucralose, orange flavor, magnesium stearate separately through 60# sieve;(b) Dissolving L-HPC in purified water with continuous stirring until it gets a clear viscous solution;(c) Dry mixing of pregabalin or pharmaceutically acceptable salts thereof, mannitol, and microcrystalline cellulose 101 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 microcrystalline cellulose 1000, colloidal silica anhydrous, croscarmellose sodium, talc, sucralose, orange flavor in the blender;(h) Mixing of the blend prepared in step (g) with magnesium stearate in a blender;(i) Compressing the resulted mixture into tablet dosage form; and(j) Packing of the tablet into a PVDC-coated PVC FILM and HDPE Bottle with CR Closure22. The Orodispersible tablet according to claim 1, wherein 95 % of the pregabalin or pharmaceutically acceptable salts thereof, is released within 80 minutes, preferably more than 95 % is released within 60 minutes.

23. The Orodispersible tablet according to claim 1, is used for the treatment of postherpetic neuralgia, fibromyalgia, neuropathic pain related to spinal cord injury, diabetic peripheral neuropathy, generalized anxiety disorder, and adjunctive therapy for the treatment of partial-onset seizures in adults.

24. The Orodispersible tablet according to claim 1, wherein:a) 15 %w / w to about 60 %w / w, preferably in the range from about 25 %w / w to about 45 %w / w of pregabalin or pharmaceutically acceptable salts thereof;b) a combination of microcrystalline cellulose and mannitol present in the range from about 45%w / w to about 75%w / w, preferably in the range from about 55%w / w to about 65%w / w;c) 0.5 %w / w to about 20 %w / w, preferably in the range from about 1 %w / w to about 15 %w / w of mannitol;d) 10 %w / w to about 55 %w / w, preferably in the range from about 15 %w / w to about 45 %w / w of microcrystalline cellulose;e) 0.1 %w / w to about 10 %w / w, preferably in the range of about 0.5 %w / w to about 5 %w / w of croscarmellose sodium;f) 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w of low substituted hydroxypropyl cellulose;g) a combination of glidant is present in the range from about 0.1 %w / w to about 10 %w / w, preferably in the range from about 0.5 %w / w to about 5 %w / w;h) 0.1%w / w to about 10%w / w, preferably in the range from about 0.5%w / w to about 5 %w / w of colloidal anhydrous silica;i) 0.1%w / w to about 10 %w / w, preferably in the range from about 0.5%w / w to about 5 %w / w of talc;j) 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 magnesium stearate;k) 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 2 % w / w of sucralose; and1) 0.05 %w / w to about 1 %w / w, preferably in the range from about 0.1 % w / w to about 0.8 % w / w of orange flavor.Application No: GB2403888.7Examiner: Mr Aaron ButtClaims searched: 1-24Date of search: 12 July 2024Patents Act 1977: Search Report under Section 17Documents considered to be relevant:Category Relevant to claims Identity of document and passage or figure of particular relevance X 124 CN 112107550 A (BEIJING VENTUREPHARM BIOTECH CORP) See whole document, esp. Examples. X 1-24 JP 2019052147 A (OHARA YAKUHIN KOGYO KK) See whole document. X 1-24 CN 103271888 A (SHANGHAI AUCTA PHARMACEUTICALS CO LTD) See whole document. X 1-24 WO 2019 / 098327 Al (OHARA PHARMACEUTICAL CO LTD) See hole document. X 1-24 WO 2024 / 047352 Al (NOVUMGEN LTD) See whole document. X 1-24 GB 2619970 A (NOVUMGEN LTD) See whole document.Categories:X Document indicating lack of novelty or inventive step A Document indicating technological background and / or state of the art. Y Document indicating lack of inventive step if P Document published on or after the declared priority date but combined with one or more other documents of same category. before the filing date of this invention. & Member of the same patent family E Patent document published on or after, but with priority date earlier than, the filing date of this application.Field of Search:International Classification:Subclass Subgroup Valid From A61K 0009 / 00 01 / 01 / 2006 A61K 0009 / 20 01 / 01 / 2006 A61K 0031 / 197 01 / 01 / 2006 A61P 0025 / 02 01 / 01 / 2006 A61P 0029 / 00 01 / 01 / 2006