Controlled release dosage form of [R-(Z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride

Abstract

A controlled release formulation of an acetonitrile compound and its use in the treatment and/or prophylaxis of certain disorders.

1 . A controlled release oral dosage form containing [R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X), its parent free base or any other pharmaceutically acceptable salt thereof.  
     
     
         2 . A dosage form according to  claim 1  which provides an in vitro release profile selected to provide an area under the in vivo plasma profile curve that is similar to that obtained following conventional oral administration of a fast release tablet 5 to 75 μg (calculated as free base) compound X twice a day.  
     
     
         3  A dosage form according to  claim 1  or  2  which provides an in vitro release profile of 25-70% over 4 hours and 70-100% over 8 hours.  
     
     
         4 . A dosage form according to any of  claims 1  to  3  selected from wax matrices, swellable and/or gellable matrices, tablets coated with release controlling polymers or waxes, and pellets, granules or beads comprising matrices or coated with release controlling polymers or waxes and then formulated as capsules, compressed tablets or suspensions.  
     
     
         5 . A dosage form according to any preceding claim comprising a swellable and/or gellable matrix selected from alkyl celluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, polymethylmethacrylates, methacrylate/divinylbenzene copolymers, carboxymethylamide, polyoxyalkylene glycols, polyvinyl pyrrolidone and carboxymethyl cellulose.  
     
     
         6 . A dosage form according to  claim 5  wherein the matrix is selected from alkyl celluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, cross-linked polyvinylpyrrolidone and sodium carboxymethyl cellulose.  
     
     
         7 . A dosage form according to  claim 5  or  6  comprising a hydrogel matrix tablet coated with a hydrophobic release controlling polymer coating selected from alkyl celluloses and methacrylic acid derivatives.  
     
     
         8 . A dosage form according to  claim 7  wherein the polymer matrix comprises 10-50% and the hydrophobic release controlling polymer comprises 4-10% by weight of the tablet.  
     
     
         9 . A dosage form according to  claim 7  or  8  comprising a tablet of the following composition (mg/tablet):  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Compound X 
                   0.005-0.1 pfb 
                 
                     
                   Hydroxpropyl Methcellulose E4M CR 
                   75.0 
                 
                     
                   Sodium Dihydrogen Citrate 
                      0-3.00 
                 
                     
                   Lactose, Fast Flo 
                   70.38-73.38 
                 
                     
                   Magnesium Stearate 
                    1.50 
                 
                     
                   Opadry ® White 
                    2.25 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
               
            
           
         
       
       seal coated with a solution of Opadry® Clear (YS-1-7006) in purified water at 10% solids concentrations and polymer coated with a 60% w/w (25% as solids) dispersion containing Ethylcellulose (Surelease®) at 10% weight gain, formed into core tablets, coated with the Opadry® Clear seal coating solution and polymer coated to 4% weight gain using 60% w/w (25% as solids) dispersion containing Ethylcellulose (Surelease®). -  
     
     
         10 . A dosage form according to any of  claims 1  to  4  which comprises drug-layered beads coated with a release controlling polymer either alone or in combination with drug-layered beads not coated with a release controlling polymer (immediate release beads) and optionally, inert excipients and/or retardants and/or one or more binders.  
     
     
         11 . A dosage form according to  claim 10  wherein the layered beads are seal coated with a film-forming polymer.  
     
     
         12 . A dosage form according to  claim 10  or  11  wherein the release controlling polymer coating is selected from from alkyl celluloses, hydroxyalkylcelluloses, sodium carboxymethyl cellulose and methacrylic acid derivatives.  
     
     
         13 . A dosage form according to any of  claims 10  to  12  wherein the polymer(s) make up 10 to 30% by weight of the total dosage form.  
     
     
         14 . A dosage form according to  claim 10  in capsule form comprising non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size, coated to a drug loading of 100 microgrammes (calculated as free base) per 200 mg beads, with a medicated aqueous layer solution of the following composition (%w/w):  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Compound X 
                   0.003-0.06 pfb 
                 
                     
                   Opadry ® Clear 
                   3 
                 
                     
                   Sodium dihydride citrate 
                      0-1.5 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
               
            
           
         
       
       seal coated with a solution of Opadry® Clear (YS-1-7006) in purified water at 10% solids concentrations to a weight gain of 3%, and a portion of the beads further polymer coated to a weight gain of 10-25% with a 60%w/w (25% as solids) dispersion containing ethylcellulose (Surelease®) and then seal coated to a weight gain of 2% with the above seal coat.  
     
     
         15 . A method of treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals by administering an effective amount of a controlled release oral dosage form according to  claim 1 , to a sufferer in need thereof.  
     
     
         16 . A method for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease by administering an effective amount of a controlled release oral dosage form according to  claim 1 , to a sufferer in need thereof.  
     
     
         17 . The use of a controlled release oral dosage form according to  claim 1  in the manufacture of a medicament for treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals.  
     
     
         18 . The use of a controlled release oral dosage form according to  claim 1 , in the manufacture of a medicament for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease.  
     
     
         19 . A pharmaceutical composition for treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals which comprises a controlled release oral dosage form according to  claim 1 .  
     
     
         20 . A pharmaceutical composition for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease which comprises a controlled release oral dosage form according to  claim 1 .  
     
     
         21 . A dosage form, method, use or composition according to any preceding claim in which release in the gastro-intestinal tract takes place predominantly over the first-eight to twelve hours following ingestion.  
     
     
         22 . A dosage form, method, use or composition according to any preceding claim containing [R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride.  
     
     
         23 . A dosage form, method, use or composition according to any of  claims 1  to  22  containing 5 μg compound X (calculated as free base).  
     
     
         24 . A dosage form, method, use or composition according to any of  claims 1  to  22  containing 12.5 μg compound X (calculated as free base).  
     
     
         25 . A dosage form, method, use or composition according to any of  claims 1  to  22  containing 25 μg compound X (calculated as free base).  
     
     
         26 . A dosage form, method, use or composition according to any of  claims 1  to  22  containing 50 μg compound X (calculated as free base).  
     
     
         27 . A dosage form, method, use or composition according to any of  claims 1  to  22  containing 75 μg compound X (calculated as free base).  
     
     
         28 . A dosage form, method, use or composition according to any of  claims 1  to  22  containing 100 μg compound X (calculated as free base).