Orally effective methylphenidate extended release powder and aqueous suspension product

Abstract

An oral methylphenidate powder which is reconstitutable into a final oral aqueous sustained release formulation containing at least about 50%, or at least about 80% by weight water based on the total weight of the suspension, is provided. The powder is a blend containing a combination of an uncoated methylphenidate-ion exchange resin complex, a barrier coated methylphenidate-ion exchange resin complex-matrix, and a water soluble buffering agent such that upon formed into an aqueous liquid formulation, the formulation has a pH in the range of about 3.5 to about 5, or about 4 to about 4.5. Following administration of a single dose of the oral aqueous methylphenidate suspension, a therapeutically effective amount of methylphenidate is reached in less than one hour and the composition provides a twelve-hour extended release profile.

What is claimed is: 
     
         1 . A methylphenidate aqueous oral suspension, wherein said suspension has a pH of about 4.2;
 (i) an immediate release methylphenidate component;   (ii) a sustained release methylphenidate component comprising a water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex-optional matrix, and   (iii) water;   wherein the aqueous oral suspension provides a pharmacokinetic profile in which d-methylphenidate has an area under the curve (AUC) 0-∞  of about 114 ng-hr/mL to about 180 ng-hr/mL following a single oral administration of the aqueous oral suspension to adult subjects under fasted conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.   
     
     
         2 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein said suspension comprises at least about 80% w/w water based on the total weight of the suspension. 
     
     
         3 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein the immediate release methylphenidate component and the sustained release methylphenidate component in said suspension provides a dose equivalent to about 25 mg racemic methylphenidate HCl per 5 mL suspension. 
     
     
         4 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein the therapeutic effect of the suspension is observed and has an onset at least as early as 45-minutes and throughout an extended release profile in the subject following a single oral administration. 
     
     
         5 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein the barrier coated methylphenidate-ion exchange resin complex of the sustained release component-optional matrix comprises a matrix forming component, wherein said coating is over the methylphenidate-ion exchange resin complex-matrix. 
     
     
         6 . The methylphenidate aqueous oral suspension according to  claim 5 , wherein the methylphenidate-ion exchange resin complex-matrix comprises a hydrophilic polymer or co-polymer matrix forming component. 
     
     
         7 . The methylphenidate aqueous oral suspension according to  claim 6 , wherein the methylphenidate-ion exchange resin complex-matrix comprises a hydrophilic polymer in an amount of about 5 to about 20% by weight, based on the weight of the methylphenidate-ion exchange resin complex-matrix. 
     
     
         8 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein the methylphenidate in the immediate release methylphenidate component comprises about 20% w/w of the total methylphenidate in said suspension. 
     
     
         9 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein the immediate release methylphenidate component comprises an uncoated methylphenidate-ion exchange resin complex. 
     
     
         10 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein the immediate release methylphenidate component comprises a methylphenidate-ion exchange resin complex having a coating that provides immediate release. 
     
     
         11 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein in the water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex of the sustained release component, the barrier coat is pH-independent and comprises a polyvinyl acetate polymer and a plasticizer. 
     
     
         12 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein in the barrier coating of the water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex of the sustained release component, the barrier coat is pH-independent and comprises ethylcellulose. 
     
     
         13 . The methylphenidate aqueous oral suspension according to  claim 1 , wherein in the water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex of the sustained release component, the barrier coat is pH-independent and comprises a methyl methacrylate polymer or co-polymer. 
     
     
         14 . The methylphenidate aqueous oral suspension according to  claim 1  wherein the suspension further comprises a buffering agent selected from the group consisting of one or more of a pharmaceutically acceptable acid consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, and mixtures thereof. 
     
     
         15 . A method of treating a patient having a disorder selected from Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), postural orthostatic tachycardia syndrome, and narcolepsy, said method comprising delivering an effective amount of a methylphenidate aqueous oral suspension according to  claim 1  to the patient. 
     
     
         16 . The method according to  claim 15 , wherein the immediate release methylphenidate component and the sustained release methylphenidate component in the suspension provides a methylphenidate dose equivalent to about 25 mg racemic methylphenidate HCl per 5 mL. 
     
     
         17 . The method according to  claim 15 , wherein the suspension has an onset of action for methylphenidate of about 45 minutes and a continuous extended release profile of up to about 12 hours post-dosing. 
     
     
         18 . A methylphenidate aqueous oral suspension, wherein said methylphenidate aqueous oral suspension has a pH of about 4.2,
 (i) an immediate release methylphenidate component,   (ii) a sustained release methylphenidate component comprising a water-insoluble, water-permeable, pH-independent sustained release barrier coated methylphenidate-ion exchange resin complex, and   (iii) water,
 wherein said methylphenidate aqueous oral suspension provides a pharmacokinetic profile in which d-methylphenidate has an area under the curve (AUC) 0-∞  of 114 ng-hr/mL to 180 ng-hr/mL in adult subjects following a single oral dose of said methylphenidate aqueous oral suspension under fasted conditions and a reduced T max  in adults fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to said single oral dose, and 
 wherein following a single oral dose said methylphenidate aqueous oral suspension at a dose equivalent to 60 mg racemic methylphenidate HCl has a therapeutic effect which has an onset at least as early as 45-minutes and which is maintained for at least about 12 hours post-dosing.