Modified release ibuprofen dosage form

Abstract

The present invention is a solid dosage form for oral administration of ibuprofen comprising a modified release formulation of ibuprofen which provides an immediate burst effect and thereafter a sustained release of sufficient ibuprofen to maintain blood levels at least 6.4 μg/ml over an extended period of at least 8 hours following administering of a single dose.

1 . A solid dosage form for modified oral administration of ibuprofen comprising: 
 a hydrophilic polymer;    300. to 800 mg of ibuprofen in the solid dosage form uniformly dispersed in said polymer;    a dissolution additive dispersed in said hydrophilic polymer in an amount in the range of 10% to 35% by weight of the ibuprofen, said dissolution additive comprising an alkali metal salt, an amino acid having a neutral to alkaline side chain, croscarmellose or a salt thereof, or a combination of any two of such dissolution additives; and    an inert formulation additive dispersed in said hydrophilic polymer in an amount in the range of 15% to 75% by weight of the ibuprofen, said formulation additive comprising binders, flow agents, lubricants and other conventional tableting additives,    wherein at least 20% of the ibuprofen is released within 2 hours following oral administration or exposure to an agitated aqueous medium of a single dosage unit, then thereafter ibuprofen is released at a relatively constant rate over a period of at least 8 hours, at least 70% of the ibuprofen being released over a period of not more than 14 hours following such administration or exposure.    
     
     
         2 . The solid dosage form of  claim 1 , wherein ibuprofen is present in each dosage form in an amount of about 300 mg, 400 mg or 600 mg.  
     
     
         3 . The solid dosage form of  claim 1 , wherein said polymer comprises polyethylene oxide, hydroxypropyl methylcellulose or a combination thereof.  
     
     
         4 . The solid dosage form of  claim 1 , wherein said polymer comprises hydroxypropyl methylcellulose with a viscosity of at least 100 cps and is present at a concentration of about 25% to about 40% by weight of the ibuprofen.  
     
     
         5 . The solid dosage form of  claim 4 , in which said polymer comprises a first and second hydroxypropyl methylcellulose each having a different viscosity in the range of about 100 cps to about 100,000 cps.  
     
     
         6 . The solid dosage form of  claim 5 , in which the first hydroxypropyl methylcellulose has a viscosity of about 100 cps, and the second hydroxypropyl methylcellulose has a viscosity of about 4,000 or about 15,000 cps.  
     
     
         7 . The solid dosage form of  claim 6 , in which the first hydroxypropyl methylcellulose is present at a concentration in the range of 5% to 20% by weight of the ibuprofen and the second hydroxypropyl methylcellulose has a viscosity of about 4000 cps and is present at a concentration in the range of about 10% to about 30% by weight of the ibuprofen.  
     
     
         8 . The solid dosage form of  claim 1 , wherein said dissolution additive is sodium carbonate, glycine, arginine, croscarmellose sodium or a combination thereof.  
     
     
         9 . The solid dosage form of  claim 8 , in which said dissolution additive is sodium carbonate present at a concentration in the range of about 15% to about 30% by weight of the ibuprofen.  
     
     
         10 . The solid dosage form of  claim 8 , in which said dissolution additive is a combination of croscarmellose sodium and glycine each at a concentration in the range of about 5% to about 10% by weight of the ibuprofen, the combination of which is present at about 10% to about 20% by weight of the ibuprofen.  
     
     
         11 . The solid dosage form of  claim 7 , in which said dissolution additive is a combination of croscarmellose sodium and glycine, each at a concentration in the range of about 5% to about 10% by weight of the ibuprofen, the combination of which is present at about 10% to about 20% by weight of the ibuprofen.  
     
     
         12 . The solid dosage form of  claim 1 , in which said formulation additive comprises one or more of microcrystalline cellulose, including silicified microcrystalline cellulose, silica, magnesium stearate, stearic acid, lactose, pre-gelatinized starch, or dicalcium phosphate.  
     
     
         13 . The solid dosage form of  claim 12 , in which at least one formulation additive comprises silica, microcrystalline cellulose or a combination thereof, in which the solid dosage form is prepared by an improved manufacturing process which comprises the steps of: 
 a) dry pre-blending ibuprofen with silica or a combination of silica and microcrystalline cellulose to form a pre-blend,    b) blending said pre-blend with other excipients to provide a tableting formulation,    c) compressing said tableting formulation to form a tableted dosage form.    
     
     
         14 . The solid dosage form of  claim 12 , in which said inert formulation additive comprises a first microcrystalline cellulose having a first particle size and a second microcrystalline cellulose having a second particle size, each of which is present at a concentration in the range of about 15% to about 35% by weight of the ibuprofen.  
     
     
         15 . The solid dosage form of  claim 12 , in which said inert formulation additive comprises a first silicified microcrystalline cellulose having a first particle size and a second silicified microcrystalline cellulose having a second particle size, each of which is present at a concentration in the range of about 15% to about 35% by weight of the ibuprofen, the combination of which comprises from about 40% to about 60% by weight of the ibuprofen.  
     
     
         16 . The solid dosage form of  claim 11 , in which said inert formulation additive comprises silica, a first silicified microcrystalline cellulose having a first particle size and a second silicified microcrystalline cellulose having a second particle size, each such microcrystalline cellulose being present at a concentration in the range of about 15% to about 35% by weight of the ibuprofen, the combination of which comprises from about 40% to about 60% by weight of the ibuprofen.  
     
     
         17 . The solid dosage form of  claim 16 , formed by an improved manufacturing process which comprises the steps of: 
 a) dry pre-blending ibuprofen with silica or a combination of silica and silicified microcrystalline cellulose to form a pre-blend,    b) blending said pre-blend with other excipients to provide a tableting formulation,    c) compressing said tableting formulation to form a tableted dosage form.    
     
     
         18 . The solid dosage form of  claim 16 , in which the formulation additive comprises silicified microcrystalline cellulose having a particle size ranging from about 60 μm up to a particle size of 110 μm.  
     
     
         19 . The solid dosage form of  claim 1 , wherein said solid dosage form demonstrates a mean serum ibuprofen concentration in a subject greater than or equal to 6.4 μg/ml within two hours of administration, and wherein said solid dosage form also demonstrates a mean serum ibuprofen concentration in a subject greater than or equal to 6.4 μg/ml for at least 8 hours after administration.  
     
     
         20 . A method of maintaining a mean plasma ibuprofen concentration of at least 6.4 μg/ml over a time period of 2 to 8 hours in a patient, comprising: 
 administering a single dosage of the solid dosage form according to  claim 1 .    
     
     
         21 . The method for providing immediate and extended release of ibuprofen to a subject, comprising: 
 administering to a subject in a single dose of a modified release tablet comprising,    ibuprofen in an amount in the range of 300 mg to 800 mg per tablet;    a hydrophilic polymer;    a dissolution additive at a concentration of from 10% to 35% by weight of the ibuprofen comprising alkali metal salts, an amino acid possessing neutral-to-alkaline side chain, croscarmellose or a salt thereof or a combination thereof; and    an inert formulation additive comprising microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, lactose, pre-gelatinized starch or mixtures thereof, said inert formulation additive being present in said dosage in an amount of 15% to about 75% by weight of the ibuprofen,    wherein said tablet demonstrates a mean serum ibuprofen concentration in a subject greater than or equal to 6.4 μg/ml within two hours of administration, and wherein said tablet also demonstrates a mean serum ibuprofen concentration in a subject greater than or equal to 6.4 μg/ml for at least 8 hours after administration.    
     
     
         22 . The method according to  claim 21 , 
 wherein said hydrophilic polymer comprises hydroxypropyl methylcellulose having two differing viscosities, selected from the group consisting of HPMC 100 cps, HPMC 4000 cps, HPMC 15000 cps, and HPMC 100000 cps, at a combined concentration of 17% to 42% by weight of ibuprofen;    wherein 300 mg to 800 mg ibuprofen dispersed uniformly in said polymer;    wherein the dissolution additives comprises sodium carbonate uniformly dispersed in said polymer at a concentration of 5% to 35% by weight of the ibuprofen, glycine uniformly dispersed in said polymer at a concentration of 5% to 35% by weight of the ibuprofen, and croscarmellose sodium uniformly dispersed in said polymer at a concentration of 1% to 15% by weight of the ibuprofen or a combination thereof;    wherein the formulation additive is two differing particle sizes of microcrystalline cellulose dispersed in said polymer, each at 15% to 50% by weight of the ibuprofen.    
     
     
         23 . The method according to  claim 21 , 
 wherein said hydrophilic polymer comprises hydroxypropyl methylcellulose having two differing viscosities, selected from the group consisting of HPMC 100 cps, HPMC 4000 cps, HPMC 15000 cps, and HPMC 100000 cps, at a combined concentration of 17% to 42% by weight of ibuprofen;    wherein 300 mg to 800 mg ibuprofen dispersed uniformly in said polymer;    wherein the dissolution additive comprises glycine uniformly dispersed in said polymer at a concentration of 5% to 20% by weight of the ibuprofen, and croscarmellose sodium uniformly dispersed in said polymer at a concentration of 1% to 15% by weight of the ibuprofen;    wherein the formulation additive is two differing particle sizes of microcrystalline cellulose dispersed in said polymer, each at 15% to 50% by weight of the ibuprofen.    
     
     
         24 . The method according  claim 21 , 
 wherein said hydrophilic polymer comprises hydroxypropyl methylcellulose having two differing viscosities, selected from the group consisting of HPMC 100 cps, HPMC 4000 cps, HPMC 15000 cps, and HPMC 100000 cps, at a combined concentration of 17% to 42% by weight of ibuprofen;    wherein 600 mg ibuprofen is dispersed uniformly in said polymer; and    wherein the dissolution additive comprises sodium carbonate uniformly dispersed in said polymer at a concentration of 10% to 35% by weight of the ibuprofen, and glycine uniformly dispersed in said polymer at a concentration of 1% to 15% by weight of the ibuprofen;    wherein said tablet demonstrates a mean serum ibuprofen concentration in a subject greater than or equal to 6.4 μg/ml within two hours of administration, and wherein said tablet also demonstrates a mean serum ibuprofen concentration in a subject greater than or equal to 6.4 μg/ml for at least 8 hours after administration.