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.

1 . A methylphenidate aqueous oral suspension, wherein said suspension has a pH of about 4.2, an immediate release methylphenidate component and a sustained release methylphenidate component comprising a water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex, and wherein following a single oral administration of the aqueous oral suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults subjects under fasted conditions said suspension has an area under the curve (AUC) 0-∞  for d-methylphenidate of about 114 ng-hr/mL to about 180 ng-hr/mL. 
     
     
         2 . The 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 suspension according to  claim 1 , wherein the suspension contains a total methylphenidate concentration equivalent to about 25 mg racemic methylphenidate HCl per 5 mL suspension. 
     
     
         4 . The suspension according to  claim 1 , wherein the therapeutic effect of the suspension is observed at 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 suspension according to  claim 1 , wherein the coated methylphenidate-ion exchange resin complex of the sustained release component is in a methylphenidate-ion exchange resin complex-matrix with a matrix forming component, wherein said coating is over the methylphenidate-ion exchange resin complex-matrix. 
     
     
         6 . The 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 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 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 suspension according to  claim 1 , wherein the immediate release methylphenidate component comprises an uncoated methylphenidate-ion exchange resin complex. 
     
     
         10 . The 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 suspension according to  claim 1 , wherein the barrier coating of the sustained release component is a water-insoluble, water-permeable, pH-independent cured barrier coat over the methylphenidate-ion exchange resin complex, said barrier coat comprising a polyvinyl acetate polymer and a plasticizer. 
     
     
         12 . The suspension according to  claim 1 , wherein the barrier coating of the sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex comprises ethylcellulose. 
     
     
         13 . The suspension according to  claim 1 , wherein the barrier coating of the sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex comprises a methyl methyacrylate polymer or co-polymer. 
     
     
         14 . The 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, Attention Deficit Hyperactivity Disorder (ADHD), postural orthostatic tachycardia syndrome, and narcolepsy, said method comprising delivering an effective amount of a methylphenidate aqueous suspension according to  claim 1  to the patient. 
     
     
         16 . The method according to  claim 15 , wherein the suspension contains a total methylphenidate concentration equivalent to about 25 mg racemic methylphenidate HCl per 5 mL suspension. 
     
     
         17 . The method according to  claim 15 , wherein the composition has an onset of efficacy for methylphenidate of about 45 minutes and a continuous extended release profile. 
     
     
         18 . The method according to  claim 17 , wherein the suspension contains a total methylphenidate concentration equivalent to about 25 mg racemic methylphenidate HCl per 5 mL suspension. 
     
     
         19 . A methylphenidate aqueous oral suspension,
 wherein said suspension has a pH of about 4.2, an immediate release methylphenidate component and a sustained release methylphenidate component comprising a water-insoluble, water-permeable, pH-independent sustained release barrier coated methylphenidate-ion exchange resin complex,   wherein following a single oral administration of said suspension at a dose equivalent to 60 mg racemic methylphenidate HCl said suspension has a pharmacokinetic profile in which the d-methylphenidate has an area under the curve (AUC) 0-∞  of 114 ng-hr/mL to 180 ng-hr/mL for d-methylphenidate in adult subjects 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 administration, and   wherein following a single oral administration said suspension 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.   
     
     
         20 . The suspension according to  claim 1 , wherein the suspension has a pharmacokinetic curve for d-methylphenidate bioequivalent to  FIG. 4B  following a single dose of the suspension in adult subjects under fasted conditions. 
     
     
         21 . The suspension according to  claim 1 , wherein the suspension has a pharmacokinetic curve for d-methylphenidate bioequivalent to  FIG. 4A  following a single dose of the suspension in subjects under fed conditions. 
     
     
         22 . The suspension according to  claim 1 , wherein following a single dose of the suspension in adult subjects under fasted conditions, the pharmacokinetic profile for d-methylphenidate is bioequivalent to one or more of the parameters selected from (AUC) 0-3 , (AUC) 3-7 , or (AUC) 7-12  for the d-methylphenidate in the pharmacokinetic curve of  FIG. 4B . 
     
     
         23 . The suspension according to  claim 21 , wherein the (AUC) 0-3  is about 20 ng-hr/mL, about 48 ng-hr/mL for (AUC) 3-7 , and about 36 ng-hr/mL for (AUC) 7-12 . 
     
     
         24 . The suspension according to  claim 1 , wherein following a single dose of the suspension in adult subjects under fed conditions, the pharmacokinetic profile for d-methylphenidate is bioequivalent to one or more of the parameters selected from (AUC) 0-3 , (AUC) 3-7 , (AUC) 7-12 , (AUC) 0-4 , (AUC) 4-8 , and/or (AUC) 8-12  for the d-methylphenidate in the pharmacokinetic curve of  FIG. 4A . 
     
     
         25 . The suspension according to  claim 24 , wherein the (AUC) 0-3 , is about 26 ng-hr/mL, the (AUC) 3-7  is about 55 ng-hr/mL, the (AUC) 7-12  is about 43 ng-hr/mL following a single dose of the suspension in adult subjects under fed conditions. 
     
     
         26 . The suspension according to  claim 24 , wherein the (AUC) 0-4  is about 40 ng-hr/mL, the (AUC) 4-8  is about 52 ng-hr/mL, and (AUC) 8-12  is about 31 ng-hr/mL following a single dose of the suspension in adult subjects under fed conditions. 
     
     
         27 . The method according to  claim 15 , wherein the suspension has a pharmacokinetic curve for d-methylphenidate bioequivalent to  FIG. 4B  following a single dose of the suspension in adult subjects under fasted conditions. 
     
     
         28 . The method according to  claim 15 , wherein the suspension has a pharmacokinetic curve for d-methylphenidate bioequivalent to  FIG. 4A  following a single dose of the suspension in subjects under fed conditions. 
     
     
         29 . The method according to  claim 15 , wherein following a single dose of the suspension in adult subjects under fasted conditions, the pharmacokinetic profile for d-methylphenidate is bioequivalent to one or more of the parameters selected from (AUC) 0-3 , (AUC) 3-7 , or (AUC) 7-12  for the d-methylphenidate in the pharmacokinetic curve of  FIG. 4B  or one or more of the parameters selected from (AUC) 0-3 , (AUC) 3-7 , (AUC) 7-12 , (AUC) 0-4 , (AUC) 4-8 , and/or (AUC) 8-12  for the d-methylphenidate in the pharmacokinetic curve of  FIG. 4A . 
     
     
         30 . The method according to  claim 29 , wherein the (AUC) 0-3  is about 20 ng-hr/mL, the (AUC) 3-7  is about 48 ng-hr/mL, and the (AUC) 7-12  is about 36 ng-hr/mL under fasted conditions, wherein the (AUC) 0-3  is about 26 ng-hr/mL, the (AUC) 3-7  is about 55 ng-hr/mL, and the (AUC) 7-12  is about 43 ng-hr/mL under fed conditions, the (AUC) 0-4  is about 40 ng-hr/mL, the (AUC) 4-8  is about 52 ng-hr/mL, and (AUC) 8-12  is about 31 ng-hr/mL under fed conditions.