Taste-masked pharmaceutical compositions with gastrosoluble pore-formers

Abstract

There is provided a method for preparing an orally disintegrating tablet (ODT) composition comprising microparticles of one or more taste-masked active pharmaceutical ingredient(s), rapidly-dispersing microgranules, and other optional, pharmaceutically acceptable excipients wherein the ODT disintegrates on contact with saliva in the buccal cavity forming a smooth, easy-to-swallow suspension. Furthermore, the microparticles (crystals, granules, beads or pellets containing the active), coated with a taste-masking membrane comprising a water-insoluble polymer and one or more gastrosoluble inorganic or organic pore-formers (practically insoluble in water and saliva, but soluble in an acidic buffer), exhibit acceptable taste-masking when placed in the oral cavity and provide rapid, substantially-complete release of the dose on entry into the stomach.

1 . A pharmaceutical composition comprising a plurality of taste-masked particles, wherein the task-masked particles comprise: 
 (a) a drug-containing core particle; and    (b) a taste-masking membrane on said drug-containing core particle comprising a combination of a water-insoluble polymer and a gastrosoluble inorganic or organic pore-former at a ratio ranging from about 95/5 to about 50/50 having a thickness of from about 5% to about 50% based on the weight of the coated particle and an average particle size of not more than about 400 μm wherein the composition exhibits acceptable taste-masking when the composition is placed in the oral cavity for 60 seconds and the composition releases not less than about 60% of the dose in 30 min when tested for dissolution using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm in 900 mL of pH 1.2 buffer).    
     
     
         2 . A pharmaceutical composition in accordance with  claim 1  further comprising: 
 (c) a plurality of rapidly-dispersing microgranules with an average particle size of not more than about 300 μm comprising (i) a disintegrant and (ii) a sugar alcohol or a saccharide or a combination thereof, each having an average particle diameter of not more than about 30 μm; and    (d) one or more pharmaceutically acceptable excipients,    wherein said composition as a tablet exhibits at least one of the following properties: 
 (1) a tablet friability of not more than about 1% in order to be suitable in order to be suitable for packaging in blisters and bottles for storage, transportation and commercial distribution; and  
 (2) disintegrates on contact with the saliva in the oral cavity within approximately 60 seconds.  
   
     
     
         3 . The pharmaceutical composition of  claim 2  in the form of an orally disintegrating tablet (ODT).  
     
     
         4 . The pharmaceutical composition of  claim 2  wherein said taste-masked microparticles release not more than about 10% in about 3 minutes when dissolution tested in a simulated saliva fluid (pH ˜6.8).  
     
     
         5 . The pharmaceutical composition of  claim 1  comprising one or more active pharmaceutical ingredient(s) in sufficient quantities to be administered orally to a patient at prescribed dosing regimen to provide therapeutic efficacy.  
     
     
         6 . The pharmaceutical composition of  claim 1  wherein the drug is selected from the group consisting of ranitidine, famotidine, cetirizine, fexofenadine, sumatriptan, electriptan, zolmitriptan, ondansetron, granisetron, tiagabine, tizanidine, zolpidem, zaleplon, zafirlukast, montelukast, sildenafil, tadalafil and combinations thereof.  
     
     
         7 . The pharmaceutical composition of  claim 1  wherein the drug-containing particle comprises a drug-layered bead comprising an inert particle coated with one or more pharmaceutically acceptable actives from a polymer binder solution.  
     
     
         8 . The pharmaceutical composition of  claim 1  wherein the drug-containing particle comprises a microgranule or an extruded/spheronized pellet comprising one or more pharmaceutically acceptable active ingredient(s), a polymeric binder and a hydrophilic filler/diluent.  
     
     
         9 . The pharmaceutical composition of  claim 1  wherein said drug is a pharmaceutically acceptable active ingredient requiring taste-masking.  
     
     
         10 . The pharmaceutical composition of  claim 1  wherein the water-insoluble polymer and the gastrosoluble pore-former are present at a weight ratio of from about 95/5 to 50/50 and the membrane thickness is from about 5% to 50% by weight.  
     
     
         11 . The pharmaceutical composition of  claim 1  wherein the water-insoluble polymer is selected from the group consisting of ethycellulose, polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, methacrylate copolymers and combinations thereof.  
     
     
         12 . The pharmaceutical composition of  claim 1  wherein the gastrosoluble organic or inorganic pore-former is selected from the group consisting of calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate and mixtures thereof.  
     
     
         13 . The pharmaceutical composition of  claim 1  wherein the water-insoluble polymer comprises ethyl cellulose and the gastrosoluble pore former comprises calcium carbonate.  
     
     
         14 . The pharmaceutical composition of  claim 2  wherein the sugar alcohol or saccharide to disintegrant ratio is from about 90/10 to about 99/1.  
     
     
         15 . The pharmaceutical composition of  claim 2  wherein the rapidly-dispersing microgranules and taste-masked microparticles are present in a ratio of about 6/1 to 2/1.  
     
     
         16 . The pharmaceutical composition of  claim 3  wherein the rapidly-dispersing microgranules comprise a disintegrant selected from the group consisting of crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked carboxymethylcellulose of sodium, low-substituted hydroxypropylcellulose and mixtures thereof, and a sugar alcohol or a saccharide selected from the group consisting of mannitol, xylitol, sorbitol, maltol, maltitol, lactose, sucrose, maltose, and combinations thereof.  
     
     
         17 . A method of manufacturing a pharmaceutical composition comprising: 
 a) preparing core particles comprising an active pharmaceutical ingredient; and    b) coating the core particles by applying a membrane comprising a mixture of water-insoluble polymer and a gastrosoluble organic or inorganic pore former present at a ratio of from about 95/5 to about 50/50, the membrane coating comprising from about 5% to about 50% based on the total weight of the coated particles, wherein the composition exhibits the following properties:    1) acceptable taste-masking when the composition is placed in the oral cavity for 60 seconds; and    2) releases not less than about 60% of the active in 30 min when tested for dissolution using United States Pharmacopoeia Apparatus  2  (paddles @ 50 rpm in 900 mL of pH 1.2 buffer).    
     
     
         18 . The method of  claim 17  wherein the water-insoluble polymer is selected from the group consisting of ethycellulose, polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, methacrylate copolymers and combinations thereof.  
     
     
         19 . The method of  claim 17  wherein the gastrosoluble pore former is selected from a group consisting of calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate and mixtures thereof.  
     
     
         20 . The method of  claim 17  wherein the water-insoluble polymer comprises ethyl cellulose and the gastrosoluble pore former comprises calcium carbonate.  
     
     
         21 . The method of  claim 17  wherein the water-insoluble polymer and the gastrosoluble inorganic pore-former are present at a weight ratio of from about 95/5 to 50/50 and the membrane thickness is from about 5% to 50% by weight.  
     
     
         22 . The method of  claim 17  further comprising: 
 c) granulating a sugar alcohol or a saccharide, or a combination thereof, each having an average particle diameter of not more than 30 μm, with a disintegrant to produce rapidly disintegrating microgranules with an average particle size not more than about 400 μm;    d) blending membrane coated microparticles of step (b) with rapidly disintegrating microgranules of step (c) at a ratio of about 1:6 to about 1:2; and    e) compressing the blend of step (d) into tablets.    
     
     
         23 . The method of  claim 22  wherein said step of compressing comprises utilizing a conventional rotary tablet press equipped with an external lubrication system to pre-lubricate the dies and punches.  
     
     
         24 . The method of  claim 22  wherein the tablet, when tested for dissolution using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL buffer, releases not more than about 10% of the dose in about 3 minutes in a simulated saliva buffer at pH 6.8 and not less than about 60% of the dose in about 30 minutes in an acidic buffer at pH 1.2.  
     
     
         25 . The method of  claim 22  wherein said rapidly dispersing microgranules have an average particle size of not more than about 300 μm.