An orally disintegrating tablet containing amlodipine or pharmaceutically acceptable salts thereof and the process of preparing the same

Abstract

An orally disintegrating tablet of amlodipine for oral administration comprising: a) amlodipine or pharmaceutically acceptable salts thereof, is present in an amount ranging from 2 to 10% w / w; b) at least one diluent; c) at least one disintegrant is present in the range from 1 to 10% w / w; d) at least one lubricant is present in the range from 0.2 to 7% w / w; e) at least one non-nutritive sweetener is present in the range from 0.1 to 7% w / w; f) at least one or more pharmaceutically acceptable excipients; wherein the ratio of combination of diluents to disintegrant is in the range from 15:1 to 40:1; and wherein orally disintegrating tablet is stable for at least three months under storage conditions of 25°C / 60% RH and 40°C / 75% RH.

Description

Field of the Invention The present invention relates to a pharmaceutical composition of Amlodipine. The present invention relates to an orally disintegrating tablet of amlodipine 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 Amlodipine was first disclosed in US4572909. Amlodipine is an oral dihydropyridine calcium channel blocker. Amlodipine works by blocking the voltage-dependent L-type calcium channels, thereby inhibiting the initial influx of calcium. Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements. Amlodipine is used alone or in combination with other antihypertensive and antianginal agents for the treatment of the following conditions: hypertension, coronary artery disease, chronic stable angina, vasospastic angina, coronary artery disease in patients without heart failure or an ejection fraction < 40% and also to reduce the risk of hospitalization from angina and to mitigate the risk of a coronary revascularization procedure. The IUPAC name of amlodipine is 3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-l,4-dihydropyridine-3,5 dicarboxylate. The plasma half-life of amlodipine is 56 hours. Amlodipine has high permeability and high solubility which belongs to biopharmaceutics classification system BCS class I. Amlodipine is commercially available in oral tablets, capsules, orally disintegrating tablets, suspension, solution, and in combination with other active ingredients in solid oral dosage forms. The orally disintegrating tablets of amlodipine are available in three dose strengths: 2.5mg, 5mg, and lOmg. The oral capsules and tablets are available in three dose strengths: 2.5mg, 5 mg, and lOmg. The solution and suspension form is available in dose strength 1 mg / ml. US8778392B2 discloses an oral disintegrating tablet comprising D-mannitol, amlodipine besylate, crospovidone, carmellose, sodium stearyl fumarate, hydroxypropyl cellulose, a pregelatinized starch, or a combination thereof. The surface of the active ingredient is coated with a coating agent such as a water-insoluble polymer or a water-soluble polymer. US8715730B2 discloses a stable orally disintegrating coated tablet of amlodipine, wherein said tablet is coated with a coating layer that contains a light shading agent, a water-soluble substance and a polyvinyl alcohol resin. The stable orally disintegrating coated tablet with coating layer which does not cause a crack by high humidity with rapid disintegration properties in an oral cavity is formulated. JP5820951B2 discloses an oral solid composition containing amlodipine besylate, iron oxide, mannitol, crosscarmellose sodium, titanium oxide, sodium stearyl fumarate, yellow ferric oxide and starch. The dissolution or disintegration time for said orally disintegrating tablet is usually within few minutes to seconds. There are many challenges being faced by paediatric and geriatric patients who often experience difficulty in swallowing (Dysphagia), ingestion issues, bitter taste over use of currently available marketed tablets of amlodipine. Therefore, to resolve the aforementioned problems, the orally disintegrating tablet of amlodipine disclosed herein is formulated, in order to achieve good patient compliance, improved palatability, and taste-masking of bitter drug and it is also beneficial in providing accurate dosing over liquid dosage forms. Summary of the Invention In accordance with the present invention, an orally disintegrating tablet of Amlodipine is prepared. The orally disintegrating tablet comprising amlodipine or pharmaceutically acceptable salts thereof, at least one diluent, at least one disintegrant, at least one lubricant, and one or more pharmaceutically acceptable excipients. Another embodiment of the present invention is to provide an orally disintegrating tablet that comprises amlodipine or pharmaceutically acceptable salts thereof, which achieves acceptable palatability and taste-masking of bitter drug. Another embodiment of the present invention involves a process for obtaining said orally disintegrating tablet by direct compression method where the direct compression method is a process that involves sieving, mixing, and compression operations. Further, another embodiment of the present invention which effectively treats hypertension, coronary artery disease, chronic stable angina, vasospastic angina, and coronary artery disease in patients without heart failure or an ejection fraction < 40%, to reduce the risk of hospitalization from angina and reduce the risk of a coronary revascularization procedure. Objects of the Invention The principal object of the present invention is to provide an orally disintegrating tablet of Amlodipine or pharmaceutically acceptable salts thereof. It is an object of the present invention to provide an orally disintegrating tablet, which is particularly convenient for administration for paediatric and geriatric patients and presents pleasant palatability for patients with dysphagia. It is further object of the present invention to provide a process of preparation of an orally disintegrating tablet of amlodipine or its pharmaceutically acceptable salts thereof. A further object of the present invention is to enhance the disintegration and dissolution of the drug for oral administration. Detailed description of the Invention The present invention is understood more readily by reading the following detailed description of the invention and by studying the included examples. The term "orally disintegrating tablet” refers to a solid unit dosage forms, of the present invention, which disintegrates rapidly in the oral cavity of a patient after administration, without chewing. The term "about", as and when used in this specification, means ±10 % of the mentioned value. As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. The main embodiment of the present invention is an orally disintegrating tablet comprised of amlodipine or pharmaceutically acceptable salts thereof, at least one diluent and disintegrant. In addition, the orally disintegrating tablet further comprises at least one pharmaceutically acceptable excipient selected from a lubricant, glidant, sweetener and a flavour. As per one embodiment of the present invention, amlodipine or pharmaceutically acceptable salts thereof, is present in the range from about 2%w / w to about 10%w / w, preferably in the range from about 4%w / w to about 8%w / w. The D90 particle size of amlodipine or a pharmaceutically acceptable salt thereof is less than 50pm, more preferably less than 40pm.The D50 particle size distribution of amlodipine or pharmaceutically acceptable salts thereof is less than 35 pm, more preferably less than 25pm. As per one another embodiment of the present invention, a suitable diluent is selected from group consisting of spray-dried lactose, dicalcium phosphate, dextrates, microcrystalline cellulose, dextrose, maize starch, fructose, Sorbitol, pre-gelatinized starch, starch, xylitol, sucrose, sorbitol, maltodextrin, maltose, mannitol or combinations thereof. In the present invention, a combination of sugar alcohol and cellulose derivative is preferred as diluent in the range from about 65%w / w to about 95%w / w, preferably in the range from about 75%w / w to about 90%w / w. As per preferred embodiment of the present invention, the cellulose derivative is with mean particle size of 100 micrometres is preferred. The cellulose derivative with coarser particle size of 100pm provide adequate flow properties and commonly used as diluent in wet granulation due to its wicking action and its ability to retain water which promotes rapid wetting of powder mixture for successful tablet compression. As per one embodiment of the present invention, microcrystalline cellulose is preferred as cellulose derivative in the range from about l%w / w to about 35%w / w, preferably in the range from about 5%w / w to about 25%w / w. Mannitol is present in the range from about 45%w / w to about 95%w / w, preferably in the range from about 55%w / w to about 85%w / w. The combinations of mannitol and microcrystalline cellulose are commonly used in orally disintegrating tablets. As per one embodiment of the present invention, the D10 particle size of microcrystalline cellulose is in the range from about 10pm to about 70pm, preferably in the range from about 20pm to about 50pm, the D50 particle size of microcrystalline cellulose is in the range from about 50pm to about 170pm, preferably in the range from about 80pm to 150pm, the D90 particle size of microcrystalline cellulose is in the range from about 200pm to 300pm, preferably in the range from about 225pm to about 285pm. As per, one more embodiment of the present invention, the coarser particles of mannitol are present in the range from about 280pm to about 350pm, preferably in the range from about 300pm to about 325pm, median particles of mannitol are present in the range from about 100pm to about 200pm, preferably in the range from about 125pm to about 175pm, finer particles of mannitol are present in the range from about 35 pm to 95 pm, preferably in the range from about 20pm to about 80pm. As per another embodiment of the present invention, a disintegrant is selected from the group consisting of crosslinked polymers, crospovidone, croscarmellose sodium, modified starch sodium starch glycolate, calcium silicate, or any combinations thereof. Crospovidone is preferred as a disintegrant due to its action by a wicking mechanism, drawing water into the tablet through capillary action due to its porous particle morphology, resulting in secondary swelling and rupture of inter-particulate bonds and in tablet disintegration. In the present invention, Crospovidone is preferred as disintegrant in the range from about l%w / w to about 10%w / w, preferably in the range from about 2%w / w to about 7%w / w. As per one more embodiment of the present invention, the ratio of sugar alcohol to disintegrant is in the range from about 10:1 to about 30:1, preferably in the range from about 15:1 to about 25:1. As per one preferred embodiment of the present invention, the ratio of mannitol to Crospovidone is in the range from about 10:1 to about 30:1, preferably in the range from about 15:1 to about 25:1. As per one embodiment of the present invention, the ratio of combination of diluents to disintegrant is in the range from about 15:1 to about 40:1 and preferably it is in the range from about 18:1 to about 30:1. As per preferred embodiment of the present invention, the ratio of combination of mannitol and microcrystalline cellulose to Crospovidone is in the range from about 15:1 to about 40:1 and preferably it is in the range from about 18:1 to about 30:1. As per one embodiment of the present invention, lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium stearate, stearic acid, talc, hydrogenated vegetable oil, silicon dioxide, or any combinations thereof. In the present invention, magnesium stearate is preferred as a lubricant in the range from about 0.2%w / w to about 7%w / w, preferably in the range from about 0.5%w / w to about 5%w / w. As per one more embodiment of the present invention, a suitable glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, colloidal silicon dioxide, starch and talc or combinations thereof. In the present invention, colloidal anhydrous silica is preferred as glidant in the range from about 0.05%w / w to about 5%w / w, preferably in the range from about 0.1%w / w to about 1.5%w / w. As per another embodiment of the present invention, sweetener is selected from the group consisting of acesulfame potassium, aspartame, glucose, dextrate, dextrose, fructose, mannitol, maltose, alitame, isomalt, saccharin, sorbitol, sucralose, xylitol or any combinations thereof. In the present invention, sucralose is preferred as non-nutritive sweetener in the range from about 0.1%w / w to about 7%w / w, preferably in the range from about 0.7%w / w to about 5%w / w. As per one embodiment of the present invention, flavour is selected from the group consisting of Peppermint flavor, cooling flavor, flavor oils and flavoring aromatic oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, oil of bitter almonds, vanilla, citrus oils, fruit essences or any combinations thereof. In the present invention, peppermint flavour is preferred as flavour in the range from about 0.015%w / w to about 7%w / w, preferably in the range from about 0.05%w / w to about 5%w / w. As per the preferred embodiment, the orally disintegrating tablet of Amlodipine is used in the treatment of hypertension, coronary artery disease, chronic stable angina, vasospastic angina, coronary artery disease in patients without heart failure or an ejection fraction < 40%, to reduce the risk of hospitalization from angina and risk of a coronary revascularization procedure. As per one another embodiment of the present invention, the orally disintegrating tablet comprising calcium channel blocker or pharmaceutically acceptable salts thereof, present in an amount from about 2%w / w to about 10%w / w, preferably in the range from about 4%w / w to about 8%w / w, a combination of sugar alcohol and cellulose derivative is present in the range from about 65%w / w to about 95%w / w preferably in the range from about 75%w / w to about 90%w / w, a disintegrant is present in the range from about l%w / w to about 10%w / w, preferably in the range from about 2%w / w to about 7%w / w, a lubricant is present in the range from about 0.2%w / w to about 7%w / w, preferably in the range from about 0.5%w / w to about 5%w / w, a glidant is present in the range from about 0.05%w / w to about 5%w / w, preferably in the range from about 0.1%w / w to about 1.5%w / w, a sweetener is present in the range from about 0.1%w / w to about 7%w / w, preferably in the range from about 0.7%w / w to about 5%w / w, a flavour is present in the range from 0.015%w / w to about 7%w / w, preferably in the range from about 0.05%w / w to about 5%w / w. As per preferred embodiment of the present invention, the orally disintegrating tablet comprising amlodipine or pharmaceutically acceptable salts thereof, present in an amount from about 2%w / w to about 10%w / w, preferably in the range from about 4%w / w to about 8%w / w, a combination of mannitol and microcrystalline cellulose is present in the range from about 65%w / w to about 95%w / w preferably in the range from about 75%w / w to about 90%w / w, Crospovidone is present in the range from about l%w / w to about 10%w / w, preferably in the range from about 2%w / w to about 7%w / w, magnesium stearate is present in the range from about 0.2%w / w to about 7%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 0.05%w / w to about 5%w / w, preferably in the range from about 0.1%w / w to about 1.5%w / w, sucralose is present in the range from about 0.1%w / w to about 7%w / w, preferably in the range from about 0.7%w / w to about 5%w / w, peppermint flavour is present in the range from 0.015%w / w to about 7%w / w, preferably in the range from about 0.05%w / w to about 5%w / w. Another embodiment of the present invention is to manufacture Orally disintegrating tablets containing amlodipine by direct compression method, which is one of the most economical methods. As per one another embodiment, the disintegrating time of Amlodipine oral disintegrating tablet is less than 3 minutes, preferably less than 2 minutes. As per another embodiment of the present invention, 90% of the Amlodipine is released from said tablets in 30 minutes, preferably more than 90% is released within 15 minutes. As per one embodiment of the present invention, the stability study of an orally disintegrating tablet of Amlodipine was carried out by placing tablets in blister strip and HDPE bottle with SAF cap containing canister holding silica gel and stored at 25°C / 60% RH and 40°C / 75% RH for 3 months. The orally disintegrating tablets of Amlodipine were stable in blister and bottle as the said packaging conditions delivered good physicochemical parameters in stability studies. As per one more embodiment of the present invention, the direct compression method is used to manufacture the orally disintegrating tablet of amlodipine. Amlodipine besylate, mannitol, microcrystalline cellulose, Crospovidone and colloidal anhydrous silica, sucralose, peppermint flavour was sieved separately through 40# sieve. Magnesium stearate was sieved separately through 60# sieve. In the blender, mannitol, microcrystalline cellulose, amlodipine besylate, were mixed. To this resulting mixture, previously sifted Crospovidone, colloidal Anhydrous silica, sucralose and peppermint flavour were added and mixed in blender for 10 minutes. To this final mixture, previously sifted magnesium stearate was added and mixed in blender. This lubricated mixture was finally compressed into tablets. The said tablets of amlodipine were packed in blister strip and HDPE bottle with SAF cap containing canister holding silica gel and stored at 25°C / 60%RH and 40°C / 75% RH for 3 months to deliver the desired physicochemical parameters in said packaging conditions. 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-I The Orally disintegrating tablet of Amlodipine was manufactured according to the method defined below with ingredients shown in table I for different dose strengths 5mg and lOmg: Table -I Ingredients %w / w Amlodipine Besylate is equivalent to Amlodipine 6.935 Lactose 72.815 Microcrystalline cellulose 15.00 Crosspovidone 2.00 Sucralose 2.00 Peppermint Flavour 0.75 Magnesium stearate 0.5 Total 100.00 Manufacturing process: Amlodipine Besylate, lactose, microcrystalline cellulose, cross-povidone, sucralose and peppermint flavour were sieved separately through 40# sieve. Magnesium stearate was separately sieved through 60# sieve. In the blender, lactose, microcrystalline cellulose, amlodipine besilate, were mixed. To this resulting mixture, previously sifted crospovidone, sucralose, peppermint flavour was added in blender for about 10 minutes. To this final mixture, magnesium stearate was added and mixed in blender for about 5 minutes. Blend flow was found to be poor, therefore further compression activity was not performed. In order to optimize blend flow, it was necessary to change the formulation. Example-II The Orally disintegrating tablet of Amlodipine was manufactured according to the method defined below with ingredients shown in table II for different dose strengths 5mg and lOmg: Table-II Ingredients %w / w Amlodipine Besylate is equivalent to Amlodipine 6.935 Mannitol 72.815 Microcrystalline cellulose 15.00 Crospovidone 2.00 Sucralose 2.00 Peppermint Flavor 0.75 Magnesium stearate 0.5 Total 100.00 Manufacturing process: Amlodipine Besylate, Mannitol, Microcrystalline cellulose, Crospovidone and Sucralose, Peppermint Flavour were sieved separately through 40# sieve. Magnesium stearate was sieved separately through 60# sieve. In the blender, mannitol, Microcrystalline cellulose, Amlodipine Besilate were mixed. To this resulting mixture, previously sifted Crospovidone and sucralose and peppermint flavour were added and mixed in blender for about 10 minutes. To this final mixture, previously sifted magnesium stearate was added in the blender and mixed for 5 minutes. Blend compressibility was poor. Hence, glidant was added to improve compressibility. Example -III The Orally disintegrating tablet of Amlodipine was manufactured according to the method defined below with ingredients shown in table III for different dose strengths of 5 mg and lOmg: Table-Ill Ingredients %w / w Amlodipine Besylate is equivalent to Amlodipine 6.935 Mannitol 72.015 Microcrystalline cellulose 15.00 Colloidal Anhydrous Silica 0.30 Crospovidone 2.00 Sucralose 2.00 Peppermint Flavor 0.75 Magnesium stearate 1.00 Total 100.00 Manufacturing Process: Amlodipine Besylate, mannitol, microcrystalline cellulose, Crospovidone and colloidal 5 anhydrous silica, sucralose, peppermint flavour was sieved separately through 40# sieve. Magnesium Stearate was sieved through 60# sieve. In the blender mannitol and microcrystalline cellulose, amlodipine besylate were mixed. To the resulting mixture, previously sifted Crospovidone, colloidal anhydrous silica, sucralose and peppermint flavour were mixed in blender. To the final mixture, magnesium stearate was added and 10 mixed in blender. Disintegration time of tablets was found to be 2 minutes 30 sec. In order to optimize the disintegration time, it was necessary to increase the concentration of disintegrant. J est Parameters Result Bulk Density (gm / ml) 0.420 Tap Density (gm / ml) 0.540 Carr Index (%) 22.22 Hausner Ratio 1.28 Test Parameters Specification Result Hardness 15N-65N 43N Average weight 200.0 mg ± 7.5% 200.6 Thickness 2.90 ± 0.3 mm 2.92mm Friability NMT 1.0% 0.19% Disintegration Not more than 3 minutes 2 min 30 sec Example -IV The Orally disintegrating tablet of Amlodipine was manufactured according to the method defined below with ingredients shown in table IV for different dose strengths of 5 mg and lOmg: 10 Table-IV Ingredients %w / w Amlodipine Besylate is equivalent to Amlodipine 6.935 Mannitol 70.015 Microcrystalline cellulose 15.00 Colloidal Anhydrous Silica 0.30 Crospovidone 4.00 Sucralose 2.00 Peppermint Flavor 0.75 Magnesium stearate 1.00 Total 100.00 Manufacturing Process: Amlodipine Besylate, mannitol, microcrystalline cellulose, cross-povidone and colloidal anhydrous silica, sucralose, peppermint flavour were sieved separately through 40# sieve. Magnesium stearate was sieved separately through 60# sieve. In the blender, mannitol and microcrystalline cellulose, amlodipine besylate were mixed. To this resulting mixture, previously sifted Crospovidone, colloidal anhydrous silica, sucralose, peppermint flavour was added and mixed in blender. To this final mixture, previously sifted magnesium stearate was added and mixed in blender. This lubricated mixture was finally compressed into tablets. The said tablets of amlodipine were packed in blister strip and HDPE bottle with SAF cap containing canister holding silica gel and was stored at 25°C / 60%RH and 40°C / 75%RH for 3 months to deliver desired physicochemical parameters. All the physical and chemical parameters of tablets were found satisfactory. Test Parameters Result Bulk Density (gm / ml) 0.429 Tap Density (gm / ml) 0.545 Carr Index (%) 21.43 Hausner Ratio 1.27 Example 5: The Dissolution profile of the tablet prepared according the Example -4 The conditions of dissolution are the following: Product Name: Amlodipine orally disintegrating tablets Apparatus: Apparatus II (Paddle) Rate of rotation: 50 RPM Volume: 900 ml Temperature: 37°C Dissolution medium: 0.1 HCL The orally disintegrating tablet of amlodipine was analysed for its dissolution profile measured in 500 ml of 0.1N HCL at 50 RPM in USP II (Paddle) apparatus and the active ingredient of the tablet is released is more than 90% in 15 minutes. Example 6: The tablet prepared according to example 4 were subjected to stability study of 25°C / 60%RH and 40°C / 75%RH and results are tabulated below for dose strengths 5mg and lOmg in blister and bottle: Stability Data: Amlodipine 5 mg Orally disintegrating tablet(Blister) 3M Example-4            . Parameters     Specification                   25°C / 60   40°C / 75% (Blistcr)Initial % RI I       RI I Hardness 20N - 100N 60N 62N 61N Average weight 100.0 mg ±7.5% (92.5 mg - 107.5 mg) 100.4 100.2 99.5 Thickness 2.30 ± 0.3 mm 2.21mm 2.25mm 2.31mm Friability NMT 1.0% 0.16% 0.19% 0.18% Disintegratio n Not more than 3 minutes. 13 sec 17 sec 14 sec Assay (%) 95.0% - 105.0% of the labelled amount of Amlodipine. 99.0 98.8 99.3 Dissolution NLT 75% (Q) labelled amount of Amlodipine should be dissolve in 20 minutes. 98.4 93.7 92.7 Stability Data: Amlodipine 5 mg Orally disintegrating tablets (Bottle) 3M Example-4 Parameters      Specification                   25°C / 60% 40°C / 75 (Bottle) Initial Hardness 20N - WON 60N 62N 59N Average weight 100.0 mg ±7.5% (92.5 mg -107.5mg) 100.4 99.8 99.9 Thickness 2.30 ± 0.3 mm 2.21mm 2.27mm 2.26mm Friability NMT 1.0% 0.16% 0.16% 0.15% Disintegration Not more than 3 minutes. 13Sec 15sec 12sec Assay (%) 95.0% - 105.0% of the labelled amount of Amlodipine. 99.0 98.8 95.0 Dissolution NLT 75% (Q) labelled amount of Amlodipine should be dissolve in 20 minutes. 98.4 92.3 93.4 Stability Data: Amlodipine 10 mg Orally disintegrating tablet Example-4 (Blister) Example-4          3M Parameters      Specification        (Blister)    25°C / 60% 40°C / 75% Initial          Rll          Rll Hardness 15N- 65N 42N 40N 43N Average weight 200.0 mg ± 7.5% (185.Omg - 215.0 mg) 200.1 200.6 199.91 Thickness 2.90 ± 0.3 mm 2.86mm 2.91mm 2.87mm Friability NMT 1.0% 0.17% 0.19% 0.16% Disintegration Not more than 3 minutes. 14Sec 18sec 16sec Assay (%) 95.0% - 105.0% of the labelled amount of Amlodipine. 102.6% 99.1 99.4 Dissolution NLT 75% (Q) labelled amount of Amlodipine should be dissolve in 20 minutes. 98.3 95.3 92.2 Stability Data: Amlodipine 10 mg Orally disintegrating tablet of Example-4 (Bottle) Examplc-4          3M Parameters      Specification       (Bottle) 25°C / 60% 40°C / 75% Initial          Rll          Rll Hardness 15N- 65N 42N 40N 43N Average weight 200.0 mg ± 7.5% 200.1 200.6 199.91 Thickness 2.90 ± 0.3 mm 2.86mm 2.91mm 2.87mm Friability NMT 1.0% 0.12% 0.18% 0.13% Disintegration Not more than 3 minutes. 14 sec 13sec 16sec Assay (%) 95.0% - 105.0% of the labelled amount of Amlodipine. 102.6% 100.8% 98.5 Dissolution NLT 75% (Q) labelled amount of Amlodipine should be dissolve in 20 minutes. 98.3 95.9% 91.3%

Claims

1. An orally disintegrating tablet of amlodipine for oral administration comprising:a) amlodipine or pharmaceutically acceptable salts thereof, is present in an amount ranging from about 2%w / w to about 10%w / w, preferably in the range from about 4%w / w to about 8%w / w;b) at least one diluent;c) at least one disintegrant is present in the range from about l%w / w to about 10%w / w, preferably in the range from about 2%w / w to about 7%w / w;d) at least one lubricant is present in the range from about 0.2%w / w to about 7%w / w, preferably in the range from about 0.5%w / w to about 5%w / w;e) at least one non-nutritive sweetener is present in the range from about 0.1%w / w to about 7%w / w, preferably in the range from about 0.7%w / w to about 5%w / w;f) at least one or more pharmaceutically acceptable excipients;wherein the ratio of combination of diluents to disintegrant is in the range from about 15:1 to about 40:1 and preferably it is in the range from about 18:1 to about 30:1; andwherein orally disintegrating tablet is stable for at least three months under storage conditions of 25°C / 60% RH and 40°C / 75% RH.

2. The orally disintegrating tablet according to Claim 1, wherein the diluent is selected from the group consisting of sugars, sugar alcohols, cellulose derivatives, inorganic chemicals, starches, modified starches, or combinations thereof.

3. The orally disintegrating tablet according to Claim 2, wherein the diluent is a combination of sugar alcohol and cellulose derivative present in the range from about 65%w / w to about 95%w / w, preferably in the range from about 75%w / w to about 90%w / w.

4. The orally disintegrating tablet according to Claim 3, wherein the cellulose derivative is having mean particle size of about 100 micrometers.

5. The orally disintegrating tablet according to Claim 3, wherein the cellulose derivative is microcrystalline cellulose present in the range from about l%w / w to about 35%w / w, preferably in the range from about 5%w / w to about 25%w / w.

6. The orally disintegrating tablet according to Claim 5, wherein the microcrystalline cellulose has D10 particle size in the range from about 10pm to about 70pm, preferably in the range from about 20pm to about 50pm, the D50 particle size of micro crystalline cellulose is in the range from about 50pm to about 170pm, preferably in the range from about 80pm to 150pm, the D90 particle size of micro crystalline cellulose is in the range from about 200pm to 300pm, preferably in the range from about 225pm to about 285pm.

7. The orally disintegrating tablet according to Claim 3, wherein the sugar alcohol ismannitol present in the range from about 45%w / w to about 95%w / w, preferably in the range from about 55%w / w to about 85%w / w.

8. The orally disintegrating tablet according to Claim 3, wherein the coarser particlesof mannitol are present in the range from about 280pm to about 350pm, preferably in the range from about 300pm to about 325pm, median particles of mannitol are present in the range from about 100pm to about 200pm, preferably in the range from about 125 pm to about 175 pm, finer particles of mannitol are present in the range from about 35pm to 95pm, preferably in the range from about 20pm to about 80 pm.

9. The orally disintegrating tablet according to Claim 1, wherein the disintegrant is selected from the group consisting of cross-linked polymers, crospovidone, croscarmellose sodium, modified starch, sodium starch glycolate, calcium silicate or any combinations thereof.

10. The orally disintegrating tablet according to claim 9, wherein the disintegrant is crospovidone.

11. The orally disintegrating tablet according to claim 10, wherein the ratio of sugar alcohol to disintegrant is in the range from about 10:1 to about 30:1, preferably in the range from about 15:1 to about 25:1.

12. The orally disintegrating tablet according to claim 11, wherein the ratio of mannitol to Crospovidone is in the range from about 10:1 to about 30:1, preferably in the range from about 15:1 to about 25:1.

13. The orally disintegrating tablet according to claim 1, wherein the ratio of combination of mannitol and microcrystalline cellulose to Crospovidone is in the range from about 15:1 to about 40:1 and preferably it is in the range from about 18:1 to about 30:1.

14. The orally disintegrating tablet according to claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium stearate, stearic acid, talc, hydrogenated vegetable oil, silicon dioxide, or any combinations thereof.

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

16. The orally disintegrating tablet according to claim 1, wherein the glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, colloidal silicon dioxide, starch and talc or combinations thereof.

17. The orally disintegrating tablet according to claim 16, wherein the glidant is colloidal anhydrous silica present in the range from about 0.05%w / w to about 5%w / w, preferably in the range from about 0.1%w / w to about 1.5%w / w.

18. The orally disintegrating tablet according to claim 1, wherein the non-nutritive sweetener is sucralose.

19. The orally disintegrating tablet according to claim 1, wherein the D90 particle size of amlodipine or a pharmaceutically acceptable salt thereof is less than 50pm,more preferably less than 40pm, D50 particle size of amlodipine or pharmaceutically acceptable salt thereof is less than 35 pm, more preferably less than 25 pm.

20. The orally disintegrating tablet according to claim 1, wherein the orally disintegrating tablet is manufactured by direct compression method comprising the steps of:(a) Sieving amlodipine besylate or pharmaceutically acceptable salts thereof, mannitol, microcrystalline cellulose, Crosspovidone and Colloidal Anhydrous silica, Sucralose, Peppermint Flavour through 40# sieve, and magnesium stearate separately through 60# sieve;(b) Blending of Mannitol and Microcrystalline cellulose, Amlodipine besylate, in a blender;(c) Mixing of previously sifted Crosspovidone and Colloidal Anhydrous silica, Sucralose, and Peppermint Flavour to the above blend;(d) Adding previously sifted magnesium stearate to the above mixture of step (c) and mix in blender;(e) Compressing the lubricated mixture into the tablet dosage form; and(d) Packing of the tablets in blister strip and HDPE bottle with SAF cap containing canister holding silica gel.

21. The orally disintegrating tablet according to claim 1, wherein the orally disintegrating tablet is disintegrated upon contact with saliva in less than 3 minutes, preferably less than 2 minutes.

22. The orally disintegrating tablet according to claim 1, wherein 90% of the amlodipine or pharmaceutically acceptable salts thereof, is released from said tablets in 30 minutes, preferably more than 90% is released within 15 minutes.

23. The orally disintegrating tablet according to claim 1, is for the treatment of hypertension, coronary artery disease, chronic stable angina, vasospastic angina and coronary artery disease.

24. The orally disintegrating tablet according to Claim 1, wherein:a) 2%w / w to about 10%w / w, preferably in the range from about 4%w / w to about 8%w / w of amlodipine or pharmaceutically acceptable salt thereof;b) a combination of mannitol and microcrystalline cellulose present in the range from about 65%w / w to about 95%w / w preferably in the range from about 75%w / w to about 90%w / w;c) 45%w / w to about 95%w / w, preferably in the range from about 55%w / w to about 85%w / w of mannitol;d) l%w / w to about 35%w / w, preferably in the range from about 5%w / w to about 25%w / w of microcrystalline cellulose;e) l%w / w to about 10%w / w, preferably in the range from about 2%w / w to about 7%w / w of Crospovidone;f) 0.2%w / w to about 7%w / w, preferably in the range from about 0.5%w / w to about 5%w / w of magnesium stearate;g) 0.05%w / w to about 5%w / w, preferably in the range from about 0.1%w / w to about 1.5%w / w of colloidal Anhydrous Silica;h) 0.1%w / w to about 7%w / w, preferably in the range from about 0.7%w / w to about 5%w / w of sucralose; andi) 0.015%w / w to about 7%w / w, preferably in the range from about 0.05%w / w to about 5%w / w of peppermint flavour.