Controlled dose drug delivery system

Abstract

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising a pharmaceutically active amphetamine salt covered with an immediate-release coating and a pharmaceutically active amphetamine salt covered with an enteric coating wherein the immediate release coating and the enteric coating provide for multiple pulsed dose delivery of the pharmaceutically active amphetamine salt. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.

1 . A pharmaceutical composition comprising:
 (a) an immediate release bead comprising at least one amphetamine salt;   (b) a first delayed release bead comprising at least one amphetamine salt; and   (c) a second delayed release bead comprising at least one amphetamine salt;   wherein the first delayed release bead provides pulsed release of the at least one amphetamine salt and the second delayed release bead provides sustained release of the at least one amphetamine salt.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the first delayed release bead and the second delayed release bead comprise an enteric coating. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the enteric coating is pH dependent. 
     
     
         4 . The pharmaceutical composition of  claim 2 , wherein the first delayed release bead and the second delayed release bead comprise different enteric coatings. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the first delayed release bead and the second delayed release bead comprise the same enteric coating. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is bioequivalent to ADDERALL® XR followed by an immediate release amphetamine formulation administered 8 hours after the ADDERALL® XR;
 wherein the combined dosage of the ADDERALL® XR and the immediate release formulation is equal to the dosage of the pharmaceutical composition. 
 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein administration of a 37.5 mg dose of the pharmaceutical composition to a human patient results in a d-amphetamine C max  of about 50 ng/ml. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the d-amphetamine area under the curve from time 0 to the last measured time (AUC 0-last ) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 1058 ng·hr/ml. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the d-amphetamine area under the curve from time 0 to time infinity (AUC 0-inf ) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 1085 ng·hr/ml. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the d-amphetamine T max  is about 8.2 hours after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the l-amphetamine C max  after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 15 ng/ml. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the l-amphetamine area under the curve from time 0 to the last measured time (AUC 0-last ) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 354 ng·hr/ml. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the l-amphetamine area under the curve from time 0 to time infinity (AUC 0-inf ) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 373 ng·hr/ml. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the l-amphetamine T max  is about 8.4 hours after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the immediate release bead and at least one delayed release bead are present on a single core. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the immediate release bead and at least one delayed release bead are present on different cores. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the at least one amphetamine salt is coated onto a core. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the at least one amphetamine salt is incorporated into a core. 
     
     
         19 . The pharmaceutical composition of  claim 2 , which further comprises a protective layer over at least one enteric coating. 
     
     
         20 . The pharmaceutical composition of  claim 2 , which further comprises a protective layer between the amphetamine salt and at least one enteric coating. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the at least one amphetamine salt is selected from the group consisting of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine sulfate, and mixtures thereof. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the at least one amphetamine salt is a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate. 
     
     
         23 . The pharmaceutical composition of  claim 1 , wherein the composition does not exhibit a food effect. 
     
     
         24 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 12.5 mg. 
     
     
         25 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 18.75 mg. 
     
     
         26 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 25 mg. 
     
     
         27 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 31.25 mg. 
     
     
         28 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 37.5 mg. 
     
     
         29 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 43.75 mg. 
     
     
         30 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 50 mg. 
     
     
         31 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 62.5 mg. 
     
     
         32 . The composition of  claim 6 , wherein the amount of at least one amphetamine salt is about 75 mg. 
     
     
         33 . A pharmaceutical composition comprising:
 at least one amphetamine salt and a pharmaceutically acceptable carrier;   wherein the composition provides an about bioequivalent plasma level of amphetamine in a patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL® and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®.   
     
     
         34 . The composition of  claim 33 , wherein the composition provides an about bioequivalent plasma level of d-amphetamine in the patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL® and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®. 
     
     
         35 . The composition of  claim 33 , wherein the composition provides an about bioequivalent plasma level of l-amphetamine in the patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL® and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®. 
     
     
         36 . A method for treating ADHD, which comprises administering the pharmaceutical composition of  claim 1  to a patient suffering from ADHD. 
     
     
         37 . A sustained release pharmaceutical composition comprising:
 (a) at least one amphetamine salt,   (b) a sustained release coating, and   (c) a delayed release coating,   wherein the at least one amphetamine salt is released about 4 to about 6 hours after oral administration to a patient.   
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the sustained release coating is external to the delayed release coating. 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein about 50% of the at least one amphetamine salt is released at about six hours at a pH of about 7.5. 
     
     
         40 . The pharmaceutical composition of  claim 37 , comprising:
 (a) at least one amphetamine salt layered onto a core,   (b) a delayed release coating layered onto the at least one amphetamine salt;   (c) a sustained release coating layered onto the delayed release coating, and   (d) a protective coating layered onto the sustained release coating.   
     
     
         41 . The pharmaceutical composition of  claim 37 , wherein the at least one amphetamine salt comprises dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine sulfate, and mixtures thereof. 
     
     
         42 . The pharmaceutical composition of  claim 37 , wherein the delayed release coating is selected from the group consisting of: cellulose acetate phthalate; cellulose acetate trimellitate; hydroxypropyl methylcellulose phthalate; polyvinyl acetate phthalate; carboxymethylethylcellulose; co-polymerized methacrylic acid/methacrylic acid methyl esters, EUDRAGIT® L12.5, L100; EUDRAGIT® S12.5, S100; and EUDRAGIT® FS30 D. 
     
     
         43 . The pharmaceutical composition of  claim 37 , wherein the sustained release coating is selected from the group consisting of: polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and esters thereof, alkyl alcohols, waxes, zein (prolamine from corn), EUDRAGIT® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®, SURELEASE®, KOLLICOAT® SR30D, and cellulose acetate latex. 
     
     
         44 . The pharmaceutical composition of  claim 42 , wherein the delayed release coating is EUDRAGIT® FS-30D. 
     
     
         45 . The pharmaceutical composition of  claim 43 , wherein the sustained release coating is SURELEASE®. 
     
     
         46 . The pharmaceutical composition of  claim 37 , comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an d-amphetamine AUC (0-inf) of about 367 ng·hr/mL. 
     
     
         47 . The pharmaceutical composition of  claim 37 , comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an l-amphetamine AUC (0-inf) of about 125 ng·hr/mL. 
     
     
         48 . The pharmaceutical composition of  claim 37 , wherein the composition comprises 18.75 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of at least one amphetamine salt and has an AUC (0-inf) that is linearly proportional to the AUC (0-inf) for a 12.5 mg at least one amphetamine salt composition. 
     
     
         49 . The pharmaceutical composition of  claim 37 , comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an d-amphetamine Cmax of about 18.67 ng/mL. 
     
     
         50 . The pharmaceutical composition of  claim 37 , comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an l-amphetamine Cmax of about 5.64 ng/mL. 
     
     
         51 . The pharmaceutical composition of  claim 37 , wherein the composition comprises 18.75 mg, 25 mg, 37.5 mg, or 50 mg of at least one amphetamine salt and has a Cmax that is linearly proportional to the Cmax for a 12.5 mg at least one amphetamine salt composition. 
     
     
         52 . The pharmaceutical composition of  claim 37 , comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an d-amphetamine Tmax of about 8.83 hours. 
     
     
         53 . The pharmaceutical composition of  claim 37 , comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an l-amphetamine Tmax of about 9.33 hours. 
     
     
         54 . The pharmaceutical composition of  claim 37 , wherein the composition comprises 18.75 mg, 25 mg, 37.5 mg, or 50 mg of at least one amphetamine salt and has a Tmax that is linearly proportional to the Tmax for a 12.5 mg at least one amphetamine salt composition. 
     
     
         55 . A method of treating ADHD comprising administering the pharmaceutical composition of  claim 37  in combination with an immediate release mixed amphetamine salt composition and/or an extended release mixed amphetamine salt composition to a patient in need of such treatment. 
     
     
         56 . The method of  claim 55 , wherein the pharmaceutical composition of  claim 37  and the immediate release mixed amphetamine salt composition and/or the extended release mixed amphetamine salt composition are administered simultaneously. 
     
     
         57 . The method of  claim 55 , wherein the sustained release pharmaceutical composition comprises about 10% to about 150% of the amphetamine dosage of the immediate release mixed amphetamine salt composition and/or an extended release mixed amphetamine salt composition. 
     
     
         58 . The method of  claim 55 , wherein the immediate release mixed amphetamine salt composition and/or an extended release mixed amphetamine salt composition is ADDERALL XR®.