Orally disintegrating tablet compositions of lamotrigine

Abstract

The compositions of the present invention composition comprise a therapeutically effective amount of particles comprising lamotrigine, in combination with granules comprising a disintegrant, and a sugar alcohol and/or a saccharide. These compositions are useful in treating epilepsy and bipolar disorder, particularly for patients with dysphagia, and to improve compliance with bipolar patients.

What is claimed is: 
     
         1 . An orally dissolving or disintegrating (ODT) composition comprising a therapeutically effective amount of lamotrigine, wherein after administration said composition substantially disintegrates in the oral cavity of a patient and provides a lamotrigine release profile which is substantially the same as the lamotrigine release profile of an immediate release lamotrigine composition. 
     
     
         2 . The ODT composition of  claim 1 , wherein the composition substantially disintegrates within about 60 seconds after administration in the oral cavity of the patient. 
     
     
         3 . The ODT composition of  claim 2 , wherein the composition substantially disintegrates within about 30 seconds after administration in the oral cavity of the patient. 
     
     
         4 . The ODT composition of  claim 1 , wherein the composition disintegrates within about 30 seconds when tested by the <USP 701> Disintegration Test. 
     
     
         5 . The ODT composition of  claim 1 , wherein the composition releases about 70% or more of the lamotrigine in 30 min when tested for dissolution using United States Pharmacopoeia Apparatus 2 (paddles @ 75 rpm in 900 ml of 0.01N HCl buffer). 
     
     
         6 . The ODT composition of  claim 1 , further comprising additional pharmaceutically acceptable ingredients selected from the group consisting of a filler, a flavor, a sweetener, a colorant, a disintegrant, and combinations thereof. 
     
     
         7 . The ODT composition of  claim 6 , comprising lamotrigine in the form of lamotrigine-containing particles coated wish a taste-masking layer; and
 rapidly dispersing granules comprising a disintegrant and a sugar alcohol and/or a saccharide.   
     
     
         8 . The ODT composition of  claim 6 , comprising lamotrigine which is not coated with a taste-masking layer; and
 rapidly dispersing granules comprising a disintegrant and a sugar alcohol and/or a saccharide.   
     
     
         9 . The ODT composition of  claim 7 , wherein the lamotrigine-containing particles are in fee form of a lamotrigine crystalline material, granules, or drug-layered beads comprising lamotrigine, and the lamotrigine-containing particles are coated with a taste-masking layer. 
     
     
         10 . The ODT composition of  claim 7 , wherein secondary lamotrigine-containing particles have an average particle size of about 400 μm or less, and primary particles of lamotrigine have an average particle size of about 1-300 μm. 
     
     
         11 . The ODT composition of  claim 10 , wherein secondary lamotrigine-containing particles have an average particle size of about 300 μm or less and primary particles of lamotrigine have an average particle size of about 1-100 μm. 
     
     
         12 . The ODT composition of  claim 10 , wherein secondary lamotrigine-containing particles have an average particle size of about 100 μm or less and primary particles of lamotrigine have an average particle size of about 1-50 μm. 
     
     
         13 . The ODT composition of  claim 7 , wherein secondary lamotrigine-containing particles have an average particle size of about 400 μm or less, primary particles of the lamotrigine have an average particle size of about 1-50 μm; and
 the rapidly dispersing granules have an average particle size of about 400 μm or less, and primary particles of the sugar alcohol and/or saccharide have an average particle size of about 1-30 μm. 
 
     
     
         14 . The ODT composition of  claim 1 , wherein the taste-masking layer comprises a water-insoluble taste-masking polymer or a water-insoluble taste-masking polymer in combination with a water-soluble or gastrosoluble pore former. 
     
     
         15 . The ODT composition of  claim 1 , wherein after the composition disintegrates in the oral cavity, the disintegrated composition has a mouthfeel rating of 5 or higher on a mouthfeel/aftertaste scale of: 1 (very bitter)-5 (further taste-masking needed)-10 (pleasant taste). 
     
     
         16 . The ODT composition of  claim 9 , wherein the lamotrigine particles are drug-layered beads comprising an inert core and a drag layer coated with a taste-masking layer, and the core is a sugar sphere or a cellulose sphere. 
     
     
         17 . The ODT composition of  claim 9 , wherein the taste-masking layer composes a water-insoluble taste masking polymer. 
     
     
         18 . The ODT composition of  claim 17 , comprising about 5% to about 30% by weight of lamotrigine particles. 
     
     
         19 . The ODT composition of  claim 17 , wherein the water-insoluble taste-masking polymer is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic ester copolymer, ammonio methacrylate copolymers and mixtures thereof. 
     
     
         20 . The ODT composition of  claim 17 , wherein the lamotrigine-containing particles comprise a water-insoluble taste-masking polymer in combination with a water-soluble pore former, and the water-soluble pore former is selected from the group consisting of sucrose, sodium chloride, povidone, and mixtures thereof. 
     
     
         21 . The ODT composition of  claim 17 , wherein the lamotrigine-containing particles comprise a water-insoluble taste-masking polymer in combination with a gastrosoluble pore former, and the gastrosoluble pore former is selected from the group consisting of calcium carbonate, magnesium hydroxide, and mixtures thereof. 
     
     
         22 . The ODT composition of  claim 20 , wherein the ratio of water-insoluble polymer/water-soluble pore former ranges from about 90/10 to about 50/50. 
     
     
         23 . The ODT composition of  claim 21 , wherein the ratio of a water-insoluble taste-masking polymer/gastrosoluble pore former ranges from about 90/10 to about 50/50. 
     
     
         24 . The ODT composition of  claim 17 , wherein the water-insoluble taste-masking polymer is ethylcellulose having a viscosity of about 90-110 cps when tested in an Ubbelohde viscometer as a 5 weight % 80:20 toluene/ethanol solution at 25° C. 
     
     
         25 . The ODT composition of  claim 7 , wherein the disintegrant and the sugar alcohol and/or saccharide are present at a ratio of sugar alcohol and/or saccharide to disintegrate of from about 90/10 to about 99/1. 
     
     
         26 . The ODT composition of  claim 6 , wherein the composition comprises a disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, crosslinked carboxymethyl cellulose of sodium, low-substituted hydroxypropylcellulose and mixtures thereof. 
     
     
         27 . The ODT composition of  claim 6 , wherein the composition comprises a sugar alcohol selected from the group consisting of mannitol, xylitol, sorbitol, maltitol, maltitol and mixtures thereof. 
     
     
         28 . The ODT composition of  claim 6 , wherein the composition comprises a saccharide selected from the group consisting of lactose, sucrose, and maltose and mixtures thereof. 
     
     
         29 . A method of preparing the ODT composition of  claim 1 , comprising granulation comprising lamotrigine, a filler, a polymer binder and/or a disintegrant, and forming an ODT composition. 
     
     
         30 . The method of  claim 29 , wherein the composition comprises one or more pharmaceutically acceptable Ingredients selected from the group consisting of a filler, a flavor, a sweetener, a colorant, a disintegrant, and combinations thereof. 
     
     
         31 . The method of  claim 1 , comprising:
 (a) coating particles comprising lamotrigine with a taste-masking layer;   (b) preparing granules comprising a disintegrant and a sugar alcohol and/or a saccharide;   (c) mixing the coated particles of step (a) with the granules of step (b) and optionally other pharmaceutically acceptable ingredients; and   (d) compressing the blend of step (c) into tablets.   
     
     
         32 . The method of  claim 31 , wherein the particles comprising lamotrigine have an average particle size of not more than about 400 μm and the rapidly dispersing granules have an average particle size of not more than about 400 μm. 
     
     
         33 . The method of  claim 31 , wherein the particles' comprising lamotrigine are in the form of lamotrigine crystalline material having an average particle size of about 1-200 μm. 
     
     
         34 . The method of  claim 33 , wherein the lamotrigine crystalline material has an average particle size of about 1-50 μm. 
     
     
         35 . The method of  claim 31 , wherein the particles comprising lamotrigine are microgranules of lamotrigine in combination with a polymeric binder, a disintegrant, and a hydrophilic filler/diluent. 
     
     
         36 . The method of  claim 31 , wherein the particles comprising lamotrigine are drug-layered beads comprising lamotrigine and a polymeric binder, layered onto an inert core. 
     
     
         37 . The method of  claim 31 , wherein said coating step is coacervation. 
     
     
         38 . The method of  claim 31 , wherein said coating step is carried out in a fluid bed coating equipment. 
     
     
         39 . The method of  claim 31 , wherein the taste-masking layer comprises a water-insoluble taste-masking polymer selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic ester copolymer, ammonio-methacrylate copolymers and mixtures thereof. 
     
     
         40 . The method of  claim 39  wherein the taste-masking layer further comprises a water-soluble or gastrosoluble pore-former selected from the group consisting of sucrose, sodium chloride, povidone, and calcium carbonate. 
     
     
         41 . The method of  claim 31 , wherein said compressing is carried out with tablet press equipped with an external lubrication system to pre-lubricate the dies and punches. 
     
     
         42 . The method of  claim 41 , wherein step (a) further comprises blending the particles comprising lamotrigine with a lubricant; and
 said compression is carried out using a rotary tablet press.   
     
     
         43 . A method of treating a mood disorder, or treating or preventing seizures comprising administering to a patient in need thereof a therapeutically effective amount of the ODT composition of  claim 1 , wherein said administration of the ODT composition provides a lamotrigine release profile in the patient which is substantially the same as the lamotrigine release profile of an immediate re lease lamotrigine composition. 
     
     
         44 . The method of  claim 43 , wherein die mood disorder is a bipolar disorder. 
     
     
         45 . A method of increasing patient compliance with a method of treating a bipolar disorder comprising administering the ODT composition of  claim 1 , wherein the increase in patient compliance is compared to a non-ODT lamotrigine composition. 
     
     
         46 . The method of  claim 45 , wherein the ODT composition dissolves or disintegrates in the patient's oral cavity before the patient can expel the composition. 
     
     
         47 . The method of  claim 46 , wherein the ODT composition substantially disintegrates in the patient's oral cavity within about 60 seconds. 
     
     
         48 . The method of  claim 46 , wherein the ODT composition substantially disintegrates in the patient's oral cavity within about 30 seconds. 
     
     
         49 . The method of  claim 47 , wherein the ODT composition substantially disintegrates in the patient's oral cavity within about 30 seconds. 
     
     
         50 . The method of  claim 49 , wherein the ODT composition delivers at least about 70% of the total dose of lamotrigine upon entering the stomach of the patient. 
     
     
         51 . The method of  claim 49 , wherein the ODT composition delivers at least about 90% of the total dose of lamotrigine upon entering the stomach of the patient. 
     
     
         52 . The method of  claim 49 , wherein the ODT composition delivers at least about 95% of the total dose of lamotrigine upon entering the stomach of the patient.