Prevention of accumulated tolerance to stimulant medication for the treatment of adhd

Abstract

It is proposed that dissipation of relative benefit during long-term treatment is due to long-term tolerance to stimulant medications. To improve adherence and persistence of medication use, it is advantageous to develop medications that are not undermined by long-term tolerance. Disclosed herein in certain implementations are formulations and methods relating to an alternative formulation of medication for the treatment of ADHD based on two principles: (a) retaining the initial immediate-release component of controlled-release formulations that targets a neural mechanism, which elicits acute tolerance, and (b) replacing the subsequent sustained-release component with a medication that maintains the initial benefit by targeting a different neural mechanism does not elicit tolerance, thus allowing more time for acute tolerance elicited by the initial bolus dose of stimulant medication to dissipate completely each day and avoid carry-over and accumulation that results in long-term tolerance.

1 . A pharmaceutical composition for treating ADHD, comprising:
 a first component comprising a first unit dose of a first drug formulated for immediate release, wherein the first drug is a stimulant drug having effectiveness against ADHD and which causes tachyphylaxis; and   a second component comprising an extended-release formulation of a second drug having effectiveness against ADHD and configured to be delivered over a time period beginning about 2-4 hours following administration of the composition and ending about 6 to 14 hours following administration of the composition, wherein the second drug does not cause tachyphylaxis;   wherein the composition is in a single unit dosage form; and   wherein the composition treats ADHD without accumulating tolerance for the first drug when administered on a once-daily basis.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein second component is a solid dosage form and the first component is in the form of a coating applied upon some or all of an outer surface of the second component. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the composition is in the form of a capsule containing therein one or more first beads comprising the first component for immediate release and two or more second beads comprising the second component for extended release. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the first drug is selected from the group consisting of: dextroamphetamine, amphetamine, dexmethylphenidate, methylphenidate, lisdexamfetamine, and combinations thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the second drug is selected from the group consisting of: mazindol, modafinil, atomoxetine, clonidine, guanfacine, viloxazine, bupropion, desipramine, imipramine, nortriptyline, and combinations thereof. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the composition is effective for a period of about 10 to 16 hours following administration. 
     
     
         7 . A pharmaceutical composition for treating ADHD, comprising:
 a first component comprising a first unit dose of a first drug formulated for immediate release, wherein the first drug is a stimulant drug having effectiveness against ADHD and which causes tachyphylaxis; and   a second component comprising an extended-release formulation of a second drug having effectiveness against ADHD and configured to be delivered over a total period of about 6 to 10 hours, such period beginning about one hour before the pharmacodynamic half-life of the first drug and ending about one hour after the pharmacodynamic half-life of the first drug, wherein the second drug does not cause tachyphylaxis;   wherein the composition is in a single unit dosage form; and   wherein the composition treats ADHD without accumulating tolerance for the first drug when administered on a once-daily basis.   
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein second component is a solid dosage form and the first component is in the form of a coating applied upon some or all of an outer surface of the second component. 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the composition is in the form of a capsule containing therein one or more first beads comprising the first component for immediate release and two or more second beads comprising the second component for extended release. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the first drug is selected from the group consisting of: dextroamphetamine, amphetamine, dexmethylphenidate, methylphenidate, lisdexamfetamine, and combinations thereof. 
     
     
         11 . The pharmaceutical composition of  claim 7 , wherein the second drug is selected from the group consisting of: mazindol, modafinil, atomoxetine, clonidine, guanfacine, viloxazine, bupropion, desipramine, imipramine, nortriptyline, and combinations thereof. 
     
     
         12 . The pharmaceutical composition of  claim 7 , wherein the composition is effective for a period of about 10 to 16 hours following administration. 
     
     
         13 . A method of treating ADHD or symptoms thereof, comprising:
 administering a first unit dose of a first drug formulated for immediate release wherein the first drug is a stimulant drug having effectiveness against ADHD and which causes tachyphylaxis to a patient in need thereof; and   administering an extended-release formulation of a second drug having effectiveness against ADHD and configured to be delivered over a time period lasting about 6 to 12 hours, wherein the second drug does not cause tachyphylaxis;   wherein the extended-release formulation of the second drug is administered such that the delivery of the second drug is initiated within a period beginning one hour before the pharmacodynamic half-life of the first drug and ending one hour after the pharmacodynamic half-life of the first drug; and   wherein the composition treats ADHD or symptoms thereof without accumulating tolerance for the first drug when administered on a once-daily basis.   
     
     
         14 . The method of  claim 13 , wherein the first and second drug are administered simultaneously, and the first drug is delivered before the second drug is delivered. 
     
     
         15 . The method of  claim 13 , wherein the first and second drug are administered at different times and the first drug is delivered before the second drug is delivered. 
     
     
         16 . The method of  claim 13 , wherein second drug is a solid dosage form and the first drug is in the form of a coating applied upon some or all of an outer surface of the second drug. 
     
     
         17 . The method of  claim 13 , wherein the first and second drugs are contained in a capsule containing therein one or more first beads comprising the first drug for immediate release and two or more second beads comprising the second drug for extended release. 
     
     
         18 . The method of  claim 1 , wherein the first drug is selected from the group consisting of: dextroamphetamine, amphetamine, dexmethylphenidate, methylphenidate, lisdexamfetamine, and combinations thereof. 
     
     
         19 . The method of  claim 13 , wherein the second drug is selected from the group consisting of: mazindol, modafinil, atomoxetine, clonidine, guanfacine, viloxazine, bupropion, desipramine, imipramine, nortriptyline, and combinations thereof. 
     
     
         20 . A method of treating ADHD, comprising:
 administering a first unit dose of a first drug formulated for immediate release wherein the first drug is a stimulant drug having effectiveness against ADHD and which causes tachyphylaxis to a patient in need thereof; and   administering an extended-release formulation of a second drug having effectiveness against ADHD and configured to be delivered over a time period lasting 6 to 10 hours, wherein the second drug does not cause tachyphylaxis;   wherein the extended-release formulation of the second drug is administered such that the second drug is delivered beginning about 2-4 hours following administration of the first drug; and   wherein the composition treats ADHD without accumulating tolerance for the first drug over time.   
     
     
         21 . The method of  claim 20 , wherein the first and second drug are administered simultaneously, and the first drug is delivered before the second drug is delivered. 
     
     
         22 . The method of  claim 20 , wherein the first and second drug are administered at different times and the first drug is delivered before the second drug is delivered. 
     
     
         23 . The method of  claim 20 , wherein second drug is a solid dosage form and the first drug is in the form of a coating applied upon some or all of an outer surface of the second drug. 
     
     
         24 . The method of  claim 20 , wherein the first and second drugs are contained in a capsule containing therein one or more first beads comprising the first drug for immediate release and two or more second beads comprising the second drug for extended release. 
     
     
         25 . The method of  claim 20 , wherein the first drug is selected from the group consisting of: dextroamphetamine, amphetamine, dexmethylphenidate, methylphenidate, lisdexamfetamine, and combinations thereof. 
     
     
         26 . The method of  claim 20 , wherein the second drug is selected from the group consisting of: mazindol, modafinil, atomoxetine, clonidine, guanfacine, viloxazine, bupropion, desipramine, imipramine, nortriptyline, and combinations thereof.