Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and Processes for Making and Using the Same

Abstract

Disclosed are polar, hydrophilic stimulant prodrug compositions comprising at least one stimulant chemically attached to a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.

1 . A composition for stimulating the central nervous system of a human or animal, comprising amphetamine chemically attached to a polar hydrophilic ligand selected from the group consisting of citrulline, homocitrulline, salts thereof, and combinations thereof. 
     
     
         2 . The composition of  claim 1 , wherein the amphetamine is d-amphetamine. 
     
     
         3 . The composition of  claim 1 , wherein the amphetamine is l-amphetamine. 
     
     
         4 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the amphetamine is an l-citrulline, l-homocitrulline, a salt thereof, or a combination thereof. 
     
     
         5 . The composition of  claim 1 , having a reduced or prevented pharmacological activity when administered by parenteral routes. 
     
     
         6 . The composition of  claim 1 , wherein the composition is in the form comprising a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral film, a transdermal patch, or a suspension. 
     
     
         7 . The composition of  claim 6 , wherein the tablet, thin strip, troche, or lozenge is chewable. 
     
     
         8 . The composition of  claim 1 , wherein the amphetamine chemically attached to the polar hydrophilic ligand is present in an amount of about 1 mg or greater. 
     
     
         9 . The composition of  claim 1 , wherein the amphetamine chemically attached to the polar hydrophilic ligand is present in an amount of from about 5 mg to about 250 mg. 
     
     
         10 . The composition of  claim 1 , wherein the amphetamine chemically attached to the polar hydrophilic ligand is present in the amount of from about 10 mg to about 100 mg. 
     
     
         11 . The composition of  claim 1 , wherein the amphetamine chemically attached to the polar hydrophilic ligand is provided to the human or animal in an amount sufficient to provide therapeutic effectiveness when compared to amphetamine alone, but provides no or substantially lessened rebound effect. 
     
     
         12 . The composition of  claim 1 , wherein the amphetamine chemically attached to the polar hydrophilic ligand is provided to the human or animal in an amount sufficient to provide therapeutic effectiveness when compared to amphetamine alone, but does not provide an equivalent C max . 
     
     
         13 . The composition of  claim 1 , wherein the salt thereof is an acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adipate, aminosalicylate, ammonium, ascorbate, l-aspartate, benzoate, besylate, bicarbonate, borate, butyrate, calcium, camphocarbonate, camphorate, d-camsylate, l-camsylate, camsylate, carbonate, cholate, citrate, cypionate, decanoate, dichloroacetate, edentate, edisylate, estolate, esylate, ethyl sulfate, fumarate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate (enanthate), hexanoate, hippurate, hybenzate, hydrobromide/bromide, hydrochloride/chloride, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d,l-lactate, lactobionate, laurate, lithium, magnesium, malate, d,l-malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylsulfate, myristate, napadisilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamoate, phenylpropionate, phosphate, picrate, pivalate, potassium, propionate, pyrophosphate, salicylate, salicylsulfate, sodium, stearate, succinate, sulfate, sulfosalicylate, tannate, d-tartrate, l-tartrate, d,l-tartrate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triflate, undecylenate, valerate, valproate, xinafoate, zinc, and mixtures thereof. 
     
     
         14 . The composition of  claim 1 , wherein the salt thereof is a mesylate, a hydrochloride salt, a sulfate, an oxalate, a triflate, a citrate, a malate, a tartrate, a phosphate, a nitrate, a benzoate, or a mixture thereof. 
     
     
         15 . A composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperactivity disorder, comprising at least one conjugate, a salt of the conjugate, or a combination thereof;
 wherein the conjugate comprises amphetamine and a polar hydrophilic ligand selected from the group consisting of citrulline, homocitrulline, salts thereof, and combinations thereof.   
     
     
         16 . The composition of  claim 15 , wherein the amphetamine is d-amphetamine. 
     
     
         17 . The composition of  claim 15 , wherein the amphetamine is l-amphetamine. 
     
     
         18 . The composition of  claim 15 , wherein the composition has reduced pharmacological activity when administered by parenteral routes. 
     
     
         19 . The composition of  claim 15 , wherein the salt of the conjugate is an acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adipate, aminosalicylate, ammonium, ascorbate, l-aspartate, benzoate, besylate, bicarbonate, borate, butyrate, calcium, camphocarbonate, camphorate, d-camsylate, l-camsylate, camsylate, carbonate, cholate, citrate, cypionate, decanoate, dichloroacetate, edentate, edisylate, estolate, esylate, ethyl sulfate, fumarate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate(enanthate), hexanoate, hippurate, hybenzate, hydrobromide/bromide, hydrochloride/chloride, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d,l-lactate, lactobionate, laurate, lithium, magnesium, malate, d,l-malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylsulfate, myristate, napadisilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamoate, phenylpropionate, phosphate, picrate, pivalate, potassium, propionate, pyrophosphate, salicylate, salicylsulfate, sodium, stearate, succinate, sulfate, sulfosalicylate, tannate, d-tartrate, l-tartrate, d,l-tartrate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triflate, undecylenate, valerate, valproate, xinafoate, zinc, and mixtures thereof. 
     
     
         20 . A method for treating a patient having a disorder or condition requiring the stimulation of the central nervous system, comprising the step of orally administering to the patient a pharmaceutically effective amount of the composition of  claim 1  or  15 .