Extended release amphetamine compositions

Abstract

An oral amphetamine extended release liquid suspension is described. The compositions contain a combination of an uncoated amphetamine-cation exchange resin complex, a barrier coated amphetamine-cation exchange resin complex-matrix, and an uncomplexed amphetamine, wherein one or more of these components contains blends of different forms of amphetamines. Either the modified release coated and/or the uncoated amphetamine-cation exchange resin complex may have two forms of amphetamine in a complex with a single cation exchange resin. Following administration of a single dose of the composition, a therapeutically effective amount of amphetamine is reached by about one hour and the composition provides at least a thirteen hour effect post-dose.

1 . (canceled) 
     
     
         2 . A method for treating a patient having attention deficit hyperactivity disorder, said method comprising delivering to the patient an orally administrable extended release once-daily amphetamine liquid suspension comprising amphetamine components (A), (B) and (C):
 (A) 50% w/w to about 75% w/w of total amphetamines in the suspension being in a modified release form as determined based on the weight of free amphetamines, wherein at least one modified release amphetamine component is a modified release coated amphetamine-cation exchange resin complex-optional matrix multiparticulate, wherein the modified release amphetamine-cation exchange resin complex comprises (i) two or more amphetamines both bound to the same cation exchange resin or each bound to a different cation exchange resins, wherein when the optional matrix is present, the amphetamine-cation exchange resin complex-matrix comprises the complex and further comprises a hydrophilic polymer or copolymer or a hydrophobic polymer and (ii) a water-insoluble, water-permeable, modified release barrier coating which provides a modified release to the two or more amphetamines, wherein the two or more amphetamines are at least a d-amphetamine and an l-amphetamine, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine;   (B) a first immediate release amphetamine component which is d-amphetamine or a pharmaceutically acceptable salt thereof, and l-amphetamine or a pharmaceutically acceptable salt thereof, or mixtures thereof, wherein the d- and l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine; and   (C) a second immediate release amphetamine component which comprises an amphetamine-cation exchange resin complex in an optional matrix, wherein the amphetamine-cation exchange resin complex-optional matrix comprises at least a d-amphetamine and an l-amphetamine both bound to the same cation exchange resin or each bound to different cation exchange resins, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine or l-amphetamine;   wherein the suspension comprises a ratio of about 3 parts by weight d-amphetamine to about 1 part by weight l-amphetamine.   
     
     
         3 . The method of  claim 2 , wherein the suspension provides a therapeutic effect for the amphetamines through at least about thirteen hours post-dose administration to a patient. 
     
     
         4 . The method of  claim 2 , wherein following a single dose of the suspension in a pediatric patient 6 to 12 years of age, the suspension provides a pharmacokinetic profile for d-amphetamine and l-amphetamine of: geometric mean plasma AUC0-∞ of about 910 h*ng/mL to about 1115 h*ng/mL for d-amphetamine and about 245 h*ng/mL to about 400 h*ng/mL for l-amphetamine and a geometric mean plasma C max  of about 45 ng/mL to about 60 ng/mL for d-amphetamine and about 14 ng/mL to about 18 ng/mL for l-amphetamine. 
     
     
         5 . The method of  claim 2 , wherein following a single dose of the suspension in a pediatric patient 6 to 12 years of age, the suspension provides a pharmacokinetic profile for d-amphetamine and l-amphetamine of: (a) geometric mean plasma AUC0-∞ for d-amphetamine is about 950 h*ng/mL to about 1050 h*ng/mL for d-amphetamine and about 300 h*ng/mL to about 375 h*ng/mL for l-amphetamine and a geometric mean plasma C max  of about 50 ng/mL to about 55 ng/mL for d-amphetamine and about 15 ng/mL to about 17 ng/mL for l-amphetamine, and/or (b) geometric mean plasma AUC0-∞ for d-amphetamine is about 1013 h*ng/mL for d-amphetamine and for l-amphetamine is about 363 h*ng/mL and the geometric mean plasma C max  for d-amphetamine is about 53 ng/mL and for l-amphetamine is about 16 ng/mL. 
     
     
         6 . The method of  claim 2 , wherein the (d,l)-amphetamine and the d-amphetamine of modified release component (A) are each bound to separate cation exchange resins and/or the (d,l)-amphetamine and the d-amphetamine of immediate release component (C) are each bound to separate cation exchange resins. 
     
     
         7 . The method of  claim 2 , wherein the (d,l)-amphetamine and the d-amphetamine of modified release component (A) are both bound to the same cation exchange resins and/or the (d,l)-amphetamine and the d-amphetamine of immediate release component (C) are both bound to the same cation exchange resin. 
     
     
         8 . The method of  claim 2 , wherein the suspension contains two different amphetamine counterions. 
     
     
         9 . The method of  claim 8 , wherein the two different counterions are aspartate and sulfate. 
     
     
         10 . The method of  claim 9 , wherein the aspartate counterions are present in a concentration of about 0.01% w/v to up to 0.05% w/v. 
     
     
         11 . The method of  claim 9 , wherein the sulfate counterions are present in a concentration of about 0.01% w/v to up to 0.05% w/v. 
     
     
         12 . The method of  claim 2 , wherein the water-insoluble, water-permeable, barrier coating of (A) is an ionic, pH-independent, acrylic based coating comprising a polymer or copolymer comprising ethyl acrylate and methyl methacrylate applied as an aqueous dispersion; or a solvent-based ethylcellulose, optionally with a plasticizer. 
     
     
         13 . The method of  claim 2 , wherein the matrix is present and the barrier coating is a cured, water-insoluble, water-permeable, non-ionic, pH-independent barrier coating which comprises about 70 to about 90% w/w polyvinylacetate, a stabilizer, and about 2% w/w to about 20% w/w of a plasticizer, based on the weight of the barrier coating layer. 
     
     
         14 . The method of  claim 2 , which comprises 2.5 mg total amphetamines base equivalents per mL, wherein the weight of total amphetamines is determined on the basis of amphetamine base in the amphetamine components. 
     
     
         15 . The method of  claim 2 , wherein the patient is dosed with 2.5 mg, 5 mg, 10 mg, 15 mg or 20 mg per day. 
     
     
         16 . The method of  claim 2 , wherein the modified release component (A) comprises at least 55% of the total amphetamines and the immediate release component (C) comprises at least 35% of the total amphetamines, wherein the weight of total amphetamines is determined on the basis of amphetamine base in the amphetamine components. 
     
     
         17 . The method of  claim 2 , wherein the modified release component (A) comprises at least 60% w/w of the total amphetamines, wherein the weight of total amphetamines is determined on the basis of amphetamine base in the amphetamine components. 
     
     
         18 . An orally administrable extended release aqueous liquid suspension useful for treating attention deficit hyperactivity disorder comprising amphetamines, wherein the amphetamine components are:
 (A) a modified release, barrier coated amphetamine-cation exchange resin complex-matrix comprising (i) two or more amphetamines both bound to the same cation exchange resin or each bound to a different cation exchange resin to afford at least one amphetamine-cation exchange resin, wherein the amphetamine-cation exchange resin complex is in a matrix which further comprises a hydrophilic polymer or copolymer or a hydrophobic polymer and (ii) a water-insoluble, water-permeable, non-ionic modified release barrier coating which provides a modified release to the two or more amphetamines, wherein the two or more amphetamines are at least a d-amphetamine and an l-amphetamine, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine,   wherein 50% w/w to about 80% w/w of total amphetamines in the suspension are provided by (A), as determined based on the weight of free amphetamine base;   (B) an immediate release amphetamine-cation exchange resin complex in an optional matrix, wherein the amphetamine-cation exchange resin complex-optional matrix comprises at least a d-amphetamine and an l-amphetamine both bound to the same cation exchange resin or each bound to different cation exchange resins, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine or l-amphetamine;   (C) about 5% w/w to about 25% w/w of total amphetamines in the suspension is a (dl)-amphetamine aspartate and a (d)-amphetamine sulfate, each being uncomplexed to a cation exchange resin; and   (E) an aqueous suspension base.   
     
     
         19 . The orally administrable extended release amphetamine liquid suspension of  claim 18 , wherein the therapeutic effect lasts up to about 18 hours following post-dose administration to a patient. 
     
     
         20 . The orally administrable extended release amphetamine liquid suspension of  claim 18 , wherein the immediate release amphetamine-cation exchange resin of (B) contains about 5% w/w to about 40% w/w of the total amphetamines in the suspension, as determined based on the weight of free amphetamine base.