Coated Tablets Of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-Oxo-6,7-Dihydro-5H-Pyrrolo[3,4-b]Pyrazine And Methods For Measuring Effectiveness Of Coating

Abstract

Coated tablets of (6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) are provided. The tablets minimize the perceived bitterness of the medicament. A method for analyzing instantaneous dissolution of sub-microgram quantities of core material is also disclosed.

1 . A pharmaceutical composition for oral administration as a solid dose comprising a therapeutically effective amount of (6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) or (S)-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), or a salt thereof, coated with a water-soluble polymeric coating, said polymeric coating representing about 2% to about 10% by weight of said composition. 
     
     
         2 . The composition of  claim 1 , wherein the coating comprises at least one cellulose derivative. 
     
     
         3 . The composition of  claim 2  wherein said cellulose derivative is selected from the group consisting of a cellulose ether and a cellulose ester. 
     
     
         4 . The composition of  claim 1 , wherein said coating comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose or mixtures thereof. 
     
     
         5 . The composition of  claim 1 , wherein said coating comprises a mixture of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose and hydroxyethyl cellulose. 
     
     
         6 . The composition of  claim 1 , wherein said coating additionally comprises a taste modifying agent. 
     
     
         7 . The composition according to  claim 1 , wherein said solid dose is a tablet. 
     
     
         8 . The composition of  claim 1 , wherein the composition is capable of masking the taste of (6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) or (S)-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), or a salt thereof, for about 20 seconds. 
     
     
         9 . The composition of  claim 1 , wherein the composition is capable of masking the taste of (6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) or (S)-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), or a salt thereof, for about 30 seconds. 
     
     
         10 . The composition according to  claim 1  wherein said coating comprises an amount between about 3% to about 8% by weight of the composition. 
     
     
         11 . The composition according to  claim 1  wherein said coating comprises an amount between about 4% to about 7% by weight of the composition. 
     
     
         12 . The composition according to  claim 1  wherein said coating comprises an amount between about 4% to 6% by weight of the composition. 
     
     
         13 . The composition according to  claim 1  wherein said coating comprises at least a cellulose ether, an emulsifier and a plasticizer. 
     
     
         14 . The composition according to  claim 1  wherein said coating comprises about 5-25% titanium dioxide, about 25-70% hydroxypropyl methylcellulose, and about 0-10% polyethylene glycol, respective weight to weight. 
     
     
         15 . A method for treating a sleep disorder in a subject comprising administering to a subject in need thereof a composition of  claim 1 , such that administration of the composition treats the sleep disorder. 
     
     
         16 . A method for treating anxiety in a subject comprising administering to a subject in need thereof a composition of  claim 1 , such that administration of the composition treats the anxiety. 
     
     
         17 . A process for preparing the pharmaceutical composition of  claim 1  comprising:
 (a) providing from 0.5 to 5 mg of (6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) or (S)-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) or a salt thereof in the from of a tablet;   (b) spray-coating said tablet with an aqueous dispersion comprising a cellulose derivative to provide a coating comprising about 2% to about 10% by weight of said composition.   
     
     
         18 . A method for determining the presence of exposed core material in a coated solid oral dosage form comprising a core and a coating, said method comprising the following steps: (a) providing ex vivo a dissolution medium; (b) bringing the coated solid oral dosage form into contact with the dissolution medium; and (c) measuring a concentration of the core material dissolved in the dissolution medium within 5 minutes of bringing the coated solid oral dosage form into contact with the dissolution medium. 
     
     
         19 . A method according to  claim 18  for determining the presence of exposed core material in a coated solid oral dosage form comprising a core and a coating, said method comprising the following steps: (a) providing ex vivo a dissolution medium; (b) bringing the coated solid oral dosage form into contact with the dissolution medium; and (c) measuring a concentration of the core material dissolved in the dissolution medium within 60 seconds of bringing the coated solid oral dosage form into contact with the dissolution medium. 
     
     
         20 . A method according to  claim 18  wherein a coated tablet is brought into contact with the dissolution medium in a vessel and a concentration of active ingredient is measured by LC-MS/MS. 
     
     
         21 . A method according to  claim 18  additionally comprising at least one repetition of steps (a) to (c) whereby a relationship between time and the concentration of core material is obtained.