Methods and Compositions Particularly for Treatment of Attention Deficit Disorder

Abstract

There is described, inter alia, a coated bead comprising: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of an active pharmaceutical ingredient comprising a central nervous system stimulant; and (c) a second layer coated over the first layer, the second layer being present in an amount sufficient to substantially delay release of the active pharmaceutical ingredient in the first layer until after the coated bead reaches a distal intestine portion of a subject to whom the coated bead is administered; and (d) the third layer coated over the second layer, the third layer comprising a second amount of the active pharmaceutical ingredient, the third layer being configured to permit substantially immediate release of the active pharmaceutical ingredient comprised therein. Embodiments related to a solid oral pharmaceutical composition are also described.

1 .- 29 . (canceled) 
     
     
         30 . A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a pediatric subject from 6 to 11 years of age, the method comprising administering to a pediatric subject from 6 to 11 years of age in need thereof, an oral solid pharmaceutical composition comprising 35, 55, or 85 mg of methylphenidate hydrochloride, wherein the oral solid pharmaceutical composition, when administered to pediatric subjects from 6 to 11 years of age in a fasted state, provides a methylphenidate AUC 0-4 , a methylphenidate AUC 8-14 , and a methylphenidate AUC 14-24  in the following ranges: 
       
         
           
                 
                 
                 
                 
               
                     
                 
                   Oral Methylphenidate 
                   Methylphenidate 
                   Methylphenidate 
                   Methylphenidate 
                 
                   HCl dosage (mg) 
                   AUC 0-4   
                   AUC 8-14   
                   AUC 14-24   
                 
                     
                 
                   35 
                   from 18010 pg · hr/mL 
                   from 40610 pg · hr/mL 
                   from 23070 pg · hr/mL 
                 
                     
                   to 26470 pg · hr/mL 
                   to 80390 pg · hr/mL 
                   to 81850 pg · hr/mL 
                 
                   55 
                   from 23270 pg · hr/mL 
                   from 64370 pg · hr/mL 
                   from 23230 pg · hr/mL 
                 
                     
                   to 43880 pg · hr/mL 
                   to 109080 pg · hr/mL 
                   to 80910 pg · hr/mL 
                 
                   85 
                   from 54790 pg · hr/mL 
                   from 100550 pg · hr/mL 
                   from 76600 pg · hr/mL 
                 
                     
                   to 65660 pg · hr/mL 
                   to 200860 pg · hr/mL 
                   to 161310 pg · hr/mL 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         31 . The method of  claim 30 , wherein the oral solid pharmaceutical composition of a 35, 55, or 85 mg dosage of the methylphenidate hydrochloride, when administered to pediatric subjects from 6 to 11 years of age in a fasted state, provides an average methylphenidate AUC 0-4 , an average methylphenidate AUC 8-14 , and an average methylphenidate AUC 14-24  as specified below: 
       
         
           
                 
                 
                 
                 
               
                     
                 
                     
                   Average 
                   Average 
                   Average 
                 
                   Oral 
                   methylphenidate 
                   methylphenidate 
                   methylphenidate 
                 
                   Methylphenidate 
                   AUC 0-4   
                   AUC 8-14   
                   AUC 14- 24   
                 
                   HCl dosage 
                   (±1 standard 
                   (±1 standard 
                   (±1 standard 
                 
                   (mg) 
                   deviation) 
                   deviation) 
                   deviation) 
                 
                     
                 
                   35 
                   20715 ± 3029.2 
                   55762 ± 13851.3 
                   42158 ± 21622.5 
                 
                     
                   pg · hr/mL 
                   pg · hr/mL 
                   pg · hr/mL 
                 
                   55 
                   32658 ± 7738.5 
                   81205 ± 15048.9 
                   62880 ± 20288.9 
                 
                     
                   pg · hr/mL 
                   pg · hr/mL 
                   pg · hr/mL 
                 
                   85 
                   60418 ± 4000.2 
                   134007 ± 35930.2  
                   110877 ± 27695.7  
                 
                     
                   pg · hr/mL 
                   pg · hr/mL 
                   pg · hr/mL 
                 
                     
                 
             
                
                
                
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         32 . The method of  claim 30 , wherein the oral solid pharmaceutical composition in the 35, 55, or 85 mg dosage, when administered to pediatric subjects from 6 to 11 years of age in a fasted state, provides a methylphenidate Cmax 0-4 , a methylphenidate Cmax 4-8 , and a methylphenidate Cmax 8-14  for in the ranges as specified below: 
       
         
           
                 
                 
                 
                 
               
                     
                 
                   Oral Methylphenidate 
                   Methylphenidate 
                   Methylphenidate 
                   Methylphenidate 
                 
                   HCl dosage (mg) 
                   Cmax 0-4   
                   Cmax 4-8   
                   Cmax 8-14   
                 
                     
                 
                   35 
                   from 6020 pg/mL 
                   from 6820 pg/mL 
                   from 9160 pg/mL 
                 
                     
                   to 8570 pg/mL 
                   to 14000 pg/mL 
                   to 15350 pg/mL 
                 
                   55 
                   from 7930 pg/mL 
                   from 10750 pg/mL 
                   from 13820 pg/mL 
                 
                     
                   to 14950 pg/mL 
                   to 20790 pg/mL 
                   to 22540 pg/mL 
                 
                   85 
                   from 19550 pg/mL 
                   from 14810 pg/mL 
                   from 18820 pg/mL 
                 
                     
                   to 23290 pg/mL 
                   to 37120 pg/mL 
                   to 39420 pg/mL 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         33 . The method of  claim 30 , wherein the oral solid pharmaceutical composition of a 35, 55, or 85 mg dosage of the methylphenidate hydrochloride, when administered to pediatric subjects from 6 to 11 years of age in a fasted state, provides an average methylphenidate Cmax 0-4 , an average methylphenidate Cmax 4-8 , and an average methylphenidate Cmax 8-14  as specified below: 
       
         
           
                 
                 
                 
                 
               
                     
                 
                     
                   Average 
                   Average 
                   Average 
                 
                   Oral 
                   methylphenidate 
                   methylphenidate 
                   methylphenidate 
                 
                   Methylphenidate 
                   Cmax 0-4   
                   Cmax 4-8   
                   Cmax 8-14   
                 
                   HCl dosage 
                   (±1 standard 
                   (±1 standard 
                   (±1 standard 
                 
                   (mg) 
                   deviation) 
                   deviation) 
                   deviation) 
                 
                     
                 
                   35 
                   7055 ± 939.3 
                   10038 ± 2428.5 
                   11127 ± 2283.1 
                 
                     
                   pg/mL 
                   pg/mL 
                   pg/mL 
                 
                   55 
                   11198 ± 2633.2 
                   13035 ± 3850.3 
                   15933 ± 3347.6 
                 
                     
                   pg/mL 
                   pg/mL 
                   pg/mL 
                 
                   85 
                   21235 ± 1539.9 
                   23782 ± 7908.8 
                   27045 ± 6730.4 
                 
                     
                   pg/mL 
                   pg/mL 
                   pg/mL 
                 
                     
                 
             
                
                
                
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         34 . The method of  claim 30 , wherein the oral solid pharmaceutical composition of a 35, 55, or 85 mg dosage of the methylphenidate hydrochloride, when administered to pediatric subjects from 6 to 11 years of age in a fasted state, provides a methylphenidate Tmax 0-4  and a methylphenidate Tmax 8-14  in the ranges as specified below: 
       
         
           
                 
                 
                 
               
                     
                 
                   Oral Methylphenidate 
                   Methylphenidate 
                   Methylphenidate 
                 
                   HCl dosage (mg) 
                   Tmax 0-4   
                   Tmax 8-14   
                 
                     
                 
                   35 
                   from 1.0 hours 
                   from 8.0 hours 
                 
                     
                   to 4.0 hours 
                   to 11.0 hours 
                 
                   55 
                   from 1.0 hours 
                   from 9.0 hours 
                 
                     
                   to 2.0 hours 
                   to 14.0 hours 
                 
                   85 
                   from 1.0 hours 
                   from 8.0 hours 
                 
                     
                   to 2.0 hours 
                   to 14.0 hours 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         35 . The method of  claim 30 , wherein the oral solid pharmaceutical composition of a 35, 55, or 85 mg dosage of the methylphenidate hydrochloride, provides, when administered to pediatric subjects from 6 to 11 years of age in a fasted state, an average methylphenidate Tmax 0-4  and an average methylphenidate Tmax 8-14  as specified below: 
       
         
           
                 
                 
                 
               
                     
                 
                     
                   Average 
                   Average 
                 
                     
                   methylphenidate 
                   methylphenidate 
                 
                   Oral dosage 
                   Tmax 0-4   
                   Tmax 8-14   
                 
                   Methylphenidate 
                   (±1 standard 
                   (±1 standard 
                 
                   HCl (mg) 
                   deviation) 
                   deviation) 
                 
                     
                 
                   35 
                   1.833 ± 1.1690 hours 
                   9.167 ± 1.1690 hours 
                 
                   55 
                   1.667 ± 0.5164 hours 
                   11.167 ± 2.0412 hours  
                 
                   85 
                   1.667 ± 0.5164 hours 
                    11.0 ± 2.1909 hours 
                 
                     
                 
             
                
                
                
                
                
                
                
               
               
                
                
                
                
               
            
           
         
       
     
     
         36 . The method of  claim 30 , wherein the oral solid pharmaceutical composition provides the following in vitro methylphenidate dissolution profile: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                   Methylphenidate 
                 
                     
                   Time (hours) 
                   (% dissolved) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   1 
                   NLT 15% 
                 
                     
                   4 
                   18-38% 
                 
                     
                   8 
                   35-55% 
                 
                     
                   12 
                   68-98     
                 
                     
                   16 
                   NLT 68 
                 
                     
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
               
            
           
         
         when tested according to the USP paddle method, 100 rpm, at 37° C.; (i) starting with 900 mL simulated gastric fluid for 2 hours, (ii) followed by 900 mL phosphate buffer pH 6.0 for 4 hours, and (iii) for the 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP <711> Acceptance Table 2. 
       
     
     
         37 . The method of  claim 30 , wherein the pharmaceutical composition is efficacious for at least 13 hours. 
     
     
         38 . A method of treating ADHD in a pediatric subject aged at least 6 years old to 17 years of age, the method comprising administering to the pediatric subject in need thereof an oral solid pharmaceutical composition comprising 25 mg of methylphenidate hydrochloride once daily with or without food in the morning and optionally titrating to 35 mg, 45 mg, 55 mg, 70 mg, or 85 mg methylphenidate hydrochloride using an oral solid pharmaceutical composition comprising 35 mg, 45 mg, 55 mg, 70 mg, or 85 mg methylphenidate hydrochloride, in intervals of no less than five days.