Methods of treatment using amphetamine controlled release, prodrug, and abuse-deterrent dosage forms

Abstract

The invention also relates to pharmaceutical compositions comprising highly pure amphetamine and amphetamine-class compounds resulting from the synthesis of chiral and racemic amphetamine derivatives by stereospecific, regioselective cuprate addition reaction with aziridine phosphoramidate compounds, and to methods of manufacturing, delivering, and using the amphetamine compounds resulting from the synthesis of chiral and racemic amphetamine derivatives by stereospecific, regioselective cuprate addition reaction with aziridine phosphoramidate compounds.

1 . A method of treating a disorder which comprises administering to a patient in need thereof an effective amount of pharmaceutical composition which comprises a drug product prepared by the process of 
       synthesis of an amphetamine derivative comprising the step of performing a organo-cuprate addition reaction upon an aziridine phosphoramidate compound to obtain an aryl or aryl-alkyl phosphoramidate amphetamine precursor and deprotecting under acidic conditions to obtain an amphetamine product having a regioisomeric purity >98%. 
     
     
         2 . The method of  claim 1 , wherein the organo cuprate addition reaction is stereospecific regioselective cuprate addition reaction upon an aziridine phosphoramidate compound to obtain a chiral aryl or aryl-alkyl phosphoramidate amphetamine precursor and deprotecting under acidic conditions to obtain a chiral amphetamine product having a regioisomeric purity >98%. 
     
     
         3 . The method of  claim 2 , wherein the patient is a mammal. 
     
     
         4 . The method of  claim 2 , wherein the disorder is selected from the group consisting of diseases involving behavior, metabolism, drug absorption, drug excretion, and drug distribution in the body. 
     
     
         5 . The method of  claim 2 , wherein said administering of said pharmaceutical composition results in an improvement of patient's condition, a change in behavior, reduction of symptoms, an improvement in patient's appearance, or a combination thereof. 
     
     
         6 . The method of  claim 4  wherein the disorder is selected from the group consisting of attention deficit hyperactivity disorder (ADHD), diet control, binge eating disorder, obesity and narcolepsy. 
     
     
         7 . The method of  claim 5  wherein said improvement of patient's condition, a change in behavior, reduction of symptoms, an improvement in patient's appearance, or a combination thereof can be measured. 
     
     
         8 . The method of  claim 2  wherein the symptoms improved are selected from the group consisting of inattentiveness, hyperactivity, and impulsivity. 
     
     
         9 . The method of  claim 2  wherein the amphetamine employed is at least about 85% pure. 
     
     
         10 . The method of  claim 9  wherein the impurity concentration is not more than about 0.015% 
     
     
         11 . The method of  claim 9  wherein the impurity is selected from the group consisting of an aziridinyl impurity, an amine impurity (such as but not limited to betamethylphenethyl amine), an organic impurity with potential pharmacologic effects. 
     
     
         12 . The method of  claim 11  wherein the concentration of the impurity is less than 0.01% on a weight basis. 
     
     
         13 . The method of  claim 5  wherein the symptoms are selected from the group consisting of inattentiveness, hyperactivity, and impulsivity. 
     
     
         14 . The method of  claim 7  wherein the drug affects a receptor in an organ of the patient. 
     
     
         15 . The method of  claim 13  wherein the drug affects a receptor in the brain of the patient. 
     
     
         16 . The method of  claim 13  wherein the receptor is involved in the patient's neuropathic pathway. 
     
     
         17 . The method of  claim 2  wherein the delivery of therapeutic or sub-therapeutic quantities of the above ingredient compositions may be accomplished through administration of single or multiple units given at one time or multiple times throughout the day. 
     
     
         18 . The method of  claim 2  where in the composition is a pharmaceutically acceptable dosage form. 
     
     
         19 . The method of  claim 2  wherein the composition is a dosage form selected from the group consisting of capsules, caplets, tablets, pills, powders, dissolving tablet or strip, a gum, wafer, cookie, solid in a gelatin capsule, soft gelatin capsule, liquid filled gelatin capsule, an aerosol, granules, inhaler, and enteric coated dosage forms. 
     
     
         20 . The method of  claim 2  where the effective amount of the pharmaceutical composition is combined with one or more of a pharmaceutically acceptable excipient. 
     
     
         21 . The method of  claim 2  where the dosage form employs a soft mass comprised of pharmaceutically acceptable thickener selected from the group consisting of gelatin, natural gums, carbomer, glycols including polyethylene, propylene and glycerin, natural and synthetic oils. 
     
     
         22 . The method of  claim 17  wherein solid compositions are employed as fillers in soft and hard-filled gelatin capsules. 
     
     
         23 . The method of  claim 2  wherein pharmaceutical composition is included in a dosage form for consumption by a mammal wherein the release the active ingredient(s), occurs in a certain part of the intestinal tract. 
     
     
         24 . The method of  claim 2  wherein the release of the pharmaceutical composition is immediate, delayed, sustained, or combinations thereof. 
     
     
         25 . The method of  claim 2  wherein the solid dosage form can be coated to mask or improve the taste, improve appearance or to alter the release rate. 
     
     
         26 . The method of  claim 2  wherein one or more of the actives are in a microencapsulated form. 
     
     
         27 . The method of  claim 2  wherein the dosage form is in a flowable state. 
     
     
         28 . The method of  claim 27  wherein the flowable state is selected from the group consisting of a liquid, a pharmaceutically acceptable emulsion, a pharmaceutically acceptable solution, a pharmaceutically acceptable suspension, a pharmaceutically acceptable syrup, pharmaceutically acceptable aerosolized preparation, and a pharmaceutically acceptable elixir. 
     
     
         29 . The method of  claim 2  wherein the composition employs an abuse deterrent technology, 
     
     
         30 . The method of  claim 28  wherein the abuse deterrent technology is selected from the group of physical barriers, chemical barriers, agonist/antagonist combinations, aversive compounds, prodrugs, depot injections, a surface applied device, an implantable device, an aerosol, or combinations thereof. 
     
     
         31 . The method of  claim 2  where the patient is given storage stable, composition for treating a disorder in  claim 6 . 
     
     
         32 . The method of  claim 1 , wherein the pharmaceutical composition comprises a storage stable amphetamine composition wherein the amount of degradation of said amphetamine or amphetamine derivative produced after storage at 1, 3 or 24 months at a temperature of approximately 25 or 30 deg. C. is less than 1, 3, 5, or 10% of the amount of amphetamine derivative in said storage stable amphetamine composition present at the time of manufacture of the dosage form. 
     
     
         33 . The method of  claim 29 , wherein the dosage form is storage stable. 
     
     
         34 . The method of  claim 30 , wherein the pharmaceutical composition comprises a storage stable amphetamine composition wherein the amount of degradation of said amphetamine or amphetamine derivative produced after storage at 3 months at a temperature of approximately 38-32 deg. C. is less than 10% of the amount of amphetamine derivative in said storage stable amphetamine composition present at the time of manufacture of the dosage form. 
     
     
         35 . The method of  claim 3  where in the mammal is between the ages of about 2 and 75 years of age. 
     
     
         36 . The method of  claim 2 , wherein said pharmacologically active agent has a purity of at least 93% and not more than 100% at time of manufacture. 
     
     
         37 . The method of  claim 2 , wherein said administered dosage form is prepared using concentration of the present invention contains degradation product(s) less than about 7% of the starting concentration of said pharmacologically active agent. 
     
     
         38 . The method of  claim 2 , wherein said administered dosage form is prepared using concentration of the present invention contains degradation product(s) less than about 5% of the starting concentration of said pharmacologically active agent. 
     
     
         39 . The method of  claim 2  wherein the composition of the present invention is administered to a patient as a component of a therapeutic treatment regimen along with at least one additional therapeutic agent. 
     
     
         40 . The method of  claim 2  wherein the composition of the present invention is packaged in a container suitable for storage and delivery of pharmaceutical composition. 
     
     
         41 . The method of  claim 2  wherein the amphetamine product contains less than 10 ppm of an organic solvent. 
     
     
         42 . The method of  claim 41  where the organic solvent is selected from the group consisting of isopropanol and methyl tertiary butyl ether. 
     
     
         43 . The method of  claim 2  contains an inorganic impurity from 0% to not more than 0.002% on a weight basis.