Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient

Abstract

Dosage forms for oral administration of a PDE4 inhibitor whose solubility is slight are described. They contain PVP as a binder.

1 .- 11 . (canceled)  
     
     
         12 . A solid dosage form in tablet or pellet form for oral administration of a PDE 4 inhibitor, comprising a PDE 4 inhibitor together with polyvinylpyrrolidone as binder, and one or more other suitable pharmaceutical excipients, wherein the PDE 4 inhibitor is a compound of the formula I  
       
         
           
           
               
               
           
         
       
       in which 
 R1 is difluoromethoxy,  
 R2 is cyclopropylmethoxy and  
 R3 is 3,5-dichloropyrid-4-yl,  
 or a salt of this compound, an N-oxide of the pyridine of this compound or a salt thereof, wherein said dosage form has immediate release of the PDE 4 inhibitor.  
 
     
     
         13 . The dosage form as claimed in  claim 12 , wherein the PDE 4 inhibitor is N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (roflumilast).  
     
     
         14 . The dosage form as claimed in  claim 12 , wherein the PDE 4 inhibitor is the N-oxide of the pyridine of the compound of formula I.  
     
     
         15 . The dosage form according to  claim 13 , containing from 0.01 mg to 5 mg of roflumilast per dosage unit.  
     
     
         16 . The dosage form according to  claim 12 , wherein the proportion of polyvinylpyrrolidone is from 1 to 5% by weight.  
     
     
         17 . The dosage form according to  claim 12 , wherein the proportion of polyvinylpyrrolidone is from 2 to 3% by weight.  
     
     
         18 . The dosage form as claimed in  claim 12 , where the pharmaceutical excipients are excipients selected from the group consisting of fillers, additional binders, tablet disintegrants, lubricants, release agents, flavouring substances, buffer substances, preservatives, coloring substances and emulsifiers.  
     
     
         19 . The dosage form according to  claim 12 , wherein the proportion of all binders present is from 0.5 to 20% by weight.  
     
     
         20 . The dosage form according to  claim 18 , which is a tablet and wherein the proportion of filler is from 40 to 99% by weight.  
     
     
         21 . The dosage form as claimed in  claim 18 , wherein the filler is selected from the group consisting of sugar alcohols, starches, saccharides and mixtures thereof.  
     
     
         22 . The dosage form as claimed in  claim 21 , wherein the filler is selected from the group consisting of corn starch, microcrystalline cellulose, lactose and mixtures thereof.  
     
     
         23 . The dosage form according to  claim 18 , wherein the lubricant or release agent is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, talc and colloidal anhydrous silica.  
     
     
         24 . The dosage form as claimed in  claim 12 , which is a tablet.  
     
     
         25 . The dosage form as claimed in  claim 24 , wherein the pharmaceutical excipients are at least one filler and at least one lubricant or release agent.  
     
     
         26 . The dosage form as claimed in  claim 24 , comprising  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                   1. 
                   Roflumilast 
                   0.125 mg 
                 
                   2. 
                   Lactose monohydrate 
                   49.660 mg  
                 
                   3. 
                   Corn starch 
                   13.390 mg  
                 
                   4. 
                   Polyvidone K90 
                   1.300 mg 
                 
                   5. 
                   Magnesium stearate (vegetable) 
                    0.650 mg. 
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         27 . The dosage form as claimed in  claim 24 , comprising  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                   1. 
                   Roflumilast 
                   0.250 mg 
                 
                   2. 
                   Lactose monohydrate 
                   49.660 mg  
                 
                   3. 
                   Corn starch 
                   13.390 mg  
                 
                   4. 
                   Polyvidone K90 
                   1.300 mg 
                 
                   5. 
                   Magnesium stearate (vegetable) 
                    0.650 mg. 
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         28 . The dosage form as claimed in  claim 24 , comprising  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                   1. 
                   Roflumilast 
                   0.500 mg 
                 
                   2. 
                   Lactose monohydrate 
                   49.660 mg  
                 
                   3. 
                   Corn starch 
                   13.390 mg  
                 
                   4. 
                   Polyvidone K90 
                   1.300 mg 
                 
                   5. 
                   Magnesium stearate (vegetable) 
                    0.650 mg. 
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         29 . The dosage form according to  claim 12 , comprising a solid solution of the PDE 4 inhibitor in the binder PVP as carrier.  
     
     
         30 . The dosage form according to  claim 29 , wherein the solid solution is a solid solution with amorphous structure, in which the PDE 4 inhibitor is in the form of a molecular dispersion in the carrier material.  
     
     
         31 . The process for producing a dosage form as claimed in  claim 12 , comprising the steps: (a) producing a mixture of PDE 4 inhibitor of formula I and one or more pharmaceutical excipients and (b) granulating the mixture obtained in (a) with an aqueous solution of polyvinylpyrrolidone.  
     
     
         32 . The process according to  claim 31 , further comprising: 
 (a) drying the granules,    (b) optionally admixing other pharmaceutical excipients,    (c) mixing with a release agent and    (d) compressing in a tablet press.    
     
     
         33 . The process according to  claim 31 , further comprising processing wet preparations obtained after granulating to pellets.  
     
     
         34 . The process according to  claim 31 , wherein the granulating takes place in a fluidized bed granulator.  
     
     
         35 . The process according to  claim 31 , wherein in step (a) the PDE 4 inhibitor is admixed with other pharmaceutical excipients in the form of a trituration with a pharmaceutical excipient.  
     
     
         36 . The process according to  claim 35 , which trituration is obtained by grinding the PDE 4 inhibitor with a pharmaceutical excipient.  
     
     
         37 . The process according to  claim 35 , wherein the pharmaceutical excipient is a filler.  
     
     
         38 . The process according to  claim 31 , comprising granulating a mixture of (a) a PDE 4 inhibitor of formula I, or a trituration of a PDE 4 of formula I with corn starch, (b) corn starch and (c) lactose monohydrate with an aqueous polyvinylpyrrolidone solution to form granules, drying the granules, mixing the granules with a release agent and compressing the granules in a tablet press.  
     
     
         39 . The process according to  claim 31 , comprising granulating a mixture of (a) a PDE 4 inhibitor of formula I, or a trituration of a PDE 4 of formula I with corn starch, (b) corn starch, (c) microcrystalline cellulose and (d) sodium carboxymethylstarch with an aqueous polyvinylpyrrolidone solution to form granules, drying the granules, mixing the granules with a release agent and compressing the granules in a tablet press.  
     
     
         40 . A process for producing a dosage form as claimed in  claim 12 , comprising the steps: 
 (a) producing a mixture of pharmaceutical excipients, and    (b) granulating the mixture obtained in (a) with a suspension of the PDE 4 inhibitor of formula I in an aqueous solution of PVP.    
     
     
         41 . The process according to  claim 40 , comprising granulating a mixture of corn starch and lactose monohydrate with a suspension of a PDE 4 inhibitor of formula I in an aqueous solution of PVP to form granules, drying the granules, mixing the granules with a release agent and compressing the granules in a tablet press.  
     
     
         42 . A process for producing a dosage form as claimed in  claim 12 , comprising producing a solid solution of polyvinylpyrrolidone and a PDE 4 inhibitor of formula I, comprising the following steps: 
 (a) dissolving PVP and a PDE 4 inhibitor of formula I in a solvent, and    (b) removing the solvent from the solution of PVP and PDE 4 inhibitor.    
     
     
         43 . The process according to  claim 42 , wherein the solid solution is a solid solution with amorphous structure in which the PDE 4 inhibitor of formula I is in the form of a molecular dispersion in polyvinylpyrrolidone.  
     
     
         44 . The process according to  claim 42 , wherein the solid solution is produced by a solvent method in which polyvinylpyrrolidone, the PDE 4 inhibitor and optionally other pharmaceutical excipients are dissolved in a solvent, and wherein the solvent is subsequently removed again by spray drying, normal drying, vacuum drying or freeze-drying.  
     
     
         45 . The process according to  claim 42 , wherein the solid solution is produced by a mixing method in which the PDE 4 inhibitor and where appropriate other pharmaceutical excipients are vigorously mixed together with polyvinylpyrrolidone.  
     
     
         46 . A process for producing a dosage form according to  claim 12 , comprising the steps: (a) producing an active ingredient preparation in the form of a solid solution in polyvinylpyrrolidone of a PDE 4 inhibitor of formula I, (b) producing a mixture of an active ingredient preparation and pharmaceutical excipients and (c) granulating the mixture obtained in (b) with an aqueous solution of polyvinylpyrrolidone.  
     
     
         47 . The process according to  claim 46  for producing a dosage form in the form of a tablet, wherein the granules obtained in step (c) are dried, mixed with lubricants or release agents and compressed in a tablet press.  
     
     
         48 . The process according to  claim 46  for producing a dosage form in the form of pellets, wherein the wet granules obtained in step (c) are produced by an extruder/spheronizer process to suitable pellets.  
     
     
         49 . A process for producing a dosage form according to  claim 12  in the form of pellets, wherein dispersions/suspensions of an active ingredient preparation are applied in the form of a solid solution in polyvinylpyrrolidone of a PDE 4 inhibitor in a solvent to pellet-like carriers.  
     
     
         50 . The process according to  claim 49 , wherein the pellet-like carriers are nonpareils or HPMC-containing pellets.  
     
     
         51 . A method for the treatment of a disease regarded as treatable by PDE 4 inhibitors, wherein a dosage form according to  claim 12  is administered.  
     
     
         52 . The method of treatment according to  claim 51 , wherein the disease is selected from the group consisting of asthma and airway obstructions.  
     
     
         53 . The method of treatment according to  claim 52 , wherein the disease is COPD (chronic obstructive pulmonary disease).  
     
     
         54 . The dosage form according to  claim 13 , containing from 0.05 mg to 2.5 mg roflumilast per dosage unit.  
     
     
         55 . The dosage for according to  claim 13  containing from 0.1 mg to 0.5 mg of roflumilast per dosage unit.  
     
     
         56 . The dosage form according to  claim 18 , which is a tablet and wherein the proportion of filler is from 60 to 97% by weight.  
     
     
         57 . The dosage form as claimed in  claim 18 , wherein the filler is selected from the group consisting of calcium carbonate, sodium carbonate, mannitol, sorbitol, xylitol, maltitol, corn starch, potato starch and wheat starch, microcrystalline cellulose, glucose, lactose, lactose monohydrate, levulose, sucrose, dextrose and mixtures thereof.  
     
     
         58 . The process according to  claim 36 , wherein the pharmaceutical excipient is a filler.  
     
     
         59 . A solid dosage form in tablet or pellet form for oral administration of a PDE 4 inhibitor, comprising a PDE 4 inhibitor together with polyvinylpyrrolidone as binder, and one or more other suitable pharmaceutical excipients, wherein the PDE 4 inhibitor is a compound of the formula I  
       
         
           
           
               
               
           
         
       
       in which 
 R1 is difluoromethoxy,  
 R2 is cyclopropylmethoxy and  
 R3 is 3,5-dichloropyrid-4-yl,  
 or a salt of this compound, an N-oxide of the pyridine of this compound or a salt thereof, wherein said dosage form has immediate release of the PDE 4 inhibitor, and wherein the polyvinylpyrrolidone has an average molecular weight of above 2000.  
 
     
     
         60 . The dosage form as claimed in  claim 59 , wherein the PDE 4 inhibitor is N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(roflumilast).  
     
     
         61 . A solid dosage form in tablet or pellet form for oral administration of a PDE 4 inhibitor, comprising a PDE 4 inhibitor together with polyvinylpyrrolidone as binder, and one or more other suitable pharmaceutical excipients, wherein the PDE 4 inhibitor is a compound of the formula I  
       
         
           
           
               
               
           
         
       
       in which 
 R1 is difluoromethoxy,  
 R2 is cyclopropylmethoxy and  
 R3 is 3,5-dichloropyrid-4-yl,  
 or a salt of this compound, an N-oxide of the pyridine of this compound or a salt thereof, wherein said dosage form has immediate release of the PDE 4 inhibitor, and wherein the polyvinylpyrrolidone has an average molecular weight of above 20,000.  
 
     
     
         62 . The dosage form as claimed in  claim 61 , wherein the PDE 4 inhibitor is N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(roflumilast).