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 at least one stimulant chemically attached to a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. 
   
   
       2 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant comprises one or more functional groups consisting essentially of hydroxyl, carboxylic acid, primary amine, secondary amine, ketone, aldehyde, acetyl halide, phosphate, phosphono, sulfate, sulfonyl, sulfonamide, or thiol. 
   
   
       3 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a non-standard amino acid, a synthetic amino acid, an amino acid derivative, an amino acid precursor, or a mixture thereof. 
   
   
       4 . The composition of  claim 3 , wherein the non-standard amino acid is selected from the group consisting of homoarginine, citrulline, homocitrulline, hydroxyproline, 2-hydroxy-4-(methylthio) butanoic acid (HMB), homoserine, γ-aminobutyric acid, β-alanine, taurine, glutathione, statine, homocysteine, selenomethionine, derivatives thereof, and combinations thereof. 
   
   
       5 . The composition of  claim 3 , wherein the synthetic amino acid is selected from the group consisting of 2-amino-3-guanidinopropionic acid, 2-amino-3-ureidopropioninc acid, 2-amino benzoic acid, 3-amino benzoic acid, 4-amino benzoic acid, 2-aminomethyl benzoic acid, 3-aminomethyl benzoic acid, 4-aminomethyl benzoic acid, 5-acetamido-2-aminobenzoic acid, (3,4)-diamino benzoic acid, (3,5)-diamino benzoic acid, 2-amino-3-methoxy benzoic acid, 4-nitroanthranillic acid, derivatives thereof, and combinations thereof. 
   
   
       6 . The composition of  claim 3 , wherein the amino acid derivative or precursor is selected from the group consisting of isoserine, N-ω-nitro-arginine, N-ε,ε-dimethyl-lysine, buthionine, cysteic acid, ethionine, (2-amino ethyl) cysteine, cystathion, 2-amino-3-ethyoxybutanoic acid, methylserine, saccharopine, ethoxytheorine, derivatives thereof, and combinations thereof. 
   
   
       7 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is an amino alcohol selected from the group consisting of alaminol, indano, norephedrine, asparaginol, aspartimol, glutamol, leucinol, methioninol, phenylalaminol, prolinol, tryptophanol, valinol, isoleucinol, argininol, serinol, tyrosinol, threoninol, cysteinol, lysinol, histidinol, derivatives thereof, and combinations thereof. 
   
   
       8 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a phosphorylated carbohydrate. 
   
   
       9 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a sugar alcohol. 
   
   
       10 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a phospholipid. 
   
   
       11 . The composition of  claim 1 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is selected from the group consisting of carnitine, benzoic acid, tartaric acid, biotin, citric acid, pantothenic acid and salts, choline, cystine dimer, lactic acid, niacin, riboflavin, thiamine, Vitamin A, Vitamin B12, Vitamin D2, Vitamin D3, ascorbic acid, ethylene diamine tetraacetic acid (EDTA), t-butylated hydroxyanisole (BHA), propionic acid, sorbic acid, erythorbic acid, methyl paraben, propyl gallate, propyl paraben, thiodipropionic acid, propylene glycol, pyridoxine, adipic acid, succinic acid, malic acid, acetoin, N-butyric acid, vanillin, geraniol, methyl anthranilate, benzoin, benzyl alcohol, derivatives thereof, and combinations thereof. 
   
   
       12 . The composition of  claim 1 , wherein the at least one stimulant comprises amphetamine, adrafinil, modafinil, a minorex, benzylpiperazine, cathinone, chlorphentermine, chlobenzorex, cyclopentamine, diethylpropion, ephedrine, fenfluramine, 4-methyl-aminorex, methylone, methylphenidate, pemoline, phentermine, phenylephrine, propylhexadrine, pseudoephedrine, synephrine, a metabolite thereof, a derivative thereof, or a combination thereof. 
   
   
       13 . The composition of  claim 1 , wherein the at least one stimulant is amphetamine, a metabolite thereof, a derivative thereof, or a mixture thereof. 
   
   
       14 . The composition of  claim 13 , wherein the amphetamine is d-amphetamine. 
   
   
       15 . The composition of  claim 14 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant comprises a non-standard amino acid, l-carnitine, l-sarcosine, l-lysinol, benzoic acid, citric acid, choline, EDTA, or succinic acid. 
   
   
       16 . The composition of  claim 13 , wherein the metabolite is p-hydroxyamphetamine, p-hydroxyephedrine, or a mixture thereof. 
   
   
       17 . The composition of  claim 1 , having a reduced or prevented pharmacological activity when administered by parenteral routes. 
   
   
       18 . The composition of  claim 1 , wherein the salt comprises a mesylate, a hydrochloride salt, a sulfate, an oxalate, a triflate, a citrate, a malate, a tartrate, a phosphate, a nitrate, a benzoate, an acetate, a carbonate, a hydroxide, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, an ammonium salt, or a mixture thereof. 
   
   
       19 . 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. 
   
   
       20 . The composition of  claim 19 , wherein the tablet, thin strip, troche, or lozenge is chewable. 
   
   
       21 . The composition of  claim 1 , wherein the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, the derivative thereof, or the combination thereof is present in an amount of about 1 mg or greater. 
   
   
       22 . The composition of  claim 1 , wherein the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, derivatives thereof, or the combination thereof is present in an amount of from about 5 mg to about 250 mg. 
   
   
       23 . The composition of  claim 1 , wherein the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, derivatives thereof, or the combination thereof is present in the amount of from about 10 mg to about 100 mg. 
   
   
       24 . The composition of  claim 1 , wherein the at least one stimulant chemically attached to a polar hydrophilic ligand, the salt thereof, the derivative thereof, or the combination thereof is provided to the human or animal in an amount sufficient to provide therapeutic effectiveness when compared to the at least one stimulant alone, but provide no or substantially lessened rebound effect. 
   
   
       25 . The composition of  claim 1 , wherein the at least one stimulant chemically attached to a polar hydrophilic ligand, the salt thereof, the derivative thereof, or the combination thereof is provided to the human or animal in an amount sufficient to provide therapeutic effectiveness when compared to the at least one stimulant alone, but does not provide an equivalent C max . 
   
   
       26 . 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 at least one stimulant chemically attached to a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. 
   
   
       27 . The method of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant comprises one or more functional groups consisting essentially of hydroxyl, carboxylic acid, primary amine, secondary amine, ketone, aldehyde, acetyl halide, phosphate, phosphono, sulfate, sulfonyl, sulfonamide, or thiol. 
   
   
       28 . The method of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a non-standard amino acid, a synthetic amino acid, an amino acid derivative, an amino acid precursor, or a mixture thereof. 
   
   
       29 . The method of  claim 28 , wherein the non-standard amino acid is selected from the group consisting of homoarginine, citrulline, homocitrulline, hydroxyproline, 2-hydroxy-4-(methylthio) butanoic acid (HMB), homoserine, γ-aminobutyric acid, β-alanine, taurine, glutathione, statine, homocysteine, selenomethionine, derivatives thereof, and combinations thereof. 
   
   
       30 . The method of  claim 28 , wherein the synthetic amino acid is selected from the group consisting of 2-amino-3-guanidinopropionic acid, 2-amino-3-ureidopropioninc acid, 2-amino benzoic acid, 3-amino benzoic acid, 4-amino benzoic acid, 2-aminomethyl benzoic acid, 3-aminomethyl benzoic acid, 4-aminomethyl benzoic acid, 5-acetamido-2-aminobenzoic acid, (3,4)-diamino benzoic acid, (3,5)-diamino benzoic acid, 2-amino-3-methoxy benzoic acid, 4-nitroanthranillic acid, derivatives thereof, and combinations thereof. 
   
   
       31 . The method of  claim 28 , wherein the amino acid derivative or precursor is selected from the group consisting of isoserine, N-ω-nitro-arginine, N-ε,ε-dimethyl-lysine, buthionine, cysteic acid, ethionine, (2-amino ethyl) cysteine, cystathion, 2-amino-3-ethyoxybutanoic acid, methylserine, saccharopine, ethoxytheorine, derivatives thereof, and combinations thereof. 
   
   
       32 . The method of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is an amino alcohol selected from the group consisting of alaminol, indano, norephedrine, asparaginol, aspartimol, glutamol, leucinol, methioninol, phenylalaminol, prolinol, tryptophanol, valinol, isoleucinol, argininol, serinol, tyrosinol, threoninol, cysteinol, lysinol, histidinol, derivatives thereof, and combinations thereof. 
   
   
       33 . The method of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a phosphorylated carbohydrate. 
   
   
       34 . The composition of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a sugar alcohol. 
   
   
       35 . The method of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is a phospholipid. 
   
   
       36 . The method of  claim 26 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant is selected from the group consisting of carnitine, benzoic acid, tartaric acid, biotin, citric acid, pantothenic acid and salts, choline, cystine dimer, lactic acid, niacin, riboflavin, thiamine, Vitamin A, Vitamin B12, Vitamin D2, Vitamin D3, ascorbic acid, ethylene diamine tetraacetic acid (EDTA), t-butylated hydroxyanisole (BHA), propionic acid, sorbic acid, erythorbic acid, methyl paraben, propyl gallate, propyl paraben, thiodipropionic acid, propylene glycol, pyridoxine, adipic acid, succinic acid, malic acid, acetoin, N-butyric acid, vanillin, geraniol, methyl anthranilate, benzoin, benzyl alcohol, derivatives thereof, and combinations thereof. 
   
   
       37 . The method of  claim 26 , wherein the at least one stimulant comprises amphetamine, adrafinil, modafinil, a minorex, benzylpiperazine, cathinone, chlorphentermine, chlobenzorex, cyclopentamine, diethylpropion, ephedrine, fenfluramine, 4-methyl-aminorex, methylone, methylphenidate, pemoline, phentermine, phenylephrine, propylhexadrine, pseudoephedrine, synephrine, a metabolite thereof, a derivative thereof, or a combination thereof. 
   
   
       38 . The method of  claim 26 , wherein the stimulant comprises amphetamine, a metabolite thereof, a derivative thereof, or a mixture thereof. 
   
   
       39 . The method of  claim 38 , wherein the amphetamine is d-amphetamine. 
   
   
       40 . The method of  claim 39 , wherein the polar hydrophilic ligand prior to chemical attachment to the at least one stimulant comprises a non-standard amino acid, l-carnitine, l-saccharopine, l-lysinol, benzoic acid, citric acid, choline, EDTA, or succinic acid. 
   
   
       41 . The method of  claim 38 , therein the metabolite is p-hydroxyamphetamine, p-hydroxyephedrine, or a mixture thereof. 
   
   
       42 . The method of  claim 26 , wherein said oral administration step comprises administering at least one a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, an oral solution, a thin strip, an oral film, or an oral suspension. 
   
   
       43 . The method of  claim 26 , wherein the at least one stimulant chemically attached to the polar hydrophilic ligand is administered in the form of a salt. 
   
   
       44 . The method of  43 , wherein the salt is a mesylate, a hydrochloride salt, a sulfate, an oxalate, a triflate, a citrate, a malate, a tartrate, a phosphate, a nitrate, a benzoate, an acetate, a carbonate, a hydroxide, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, an ammonium salt, or a mixture thereof. 
   
   
       45 . The method of  claim 26 , comprising the step of administering a dosage form containing about 1 mg or greater of the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, the derivative thereof, or the combination thereof. 
   
   
       46 . The method of  claim 26 , comprising the step of administering a dosage form containing from about 5 mg to about 250 mg of the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, or the combination thereof. 
   
   
       47 . The method of  claim 26 , comprising the step of administering a dosage form containing from about 10 mg to about 100 mg of the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, or the combination thereof. 
   
   
       48 . The method of  claim 26 , wherein the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, or the combination thereof is provided in an amount sufficient to provide therapeutic effectiveness when compared to the at least one stimulant alone, but does not provide a C max  which results in euphoria. 
   
   
       49 . The method of  claim 26 , wherein the at least one stimulant chemically attached to the polar hydrophilic ligand, the salt thereof, or the combination thereof is provided in an amount sufficient to provide therapeutic effectiveness when compared to amphetamine alone, but does not provide an equivalent C max . 
   
   
       50 . The method of  claim 26 , wherein the disorder or condition is attention deficit hyperactivity disorder, attention deficit disorder, obesity, narcolepsy, appetite suppression, depression, anxiety, wakefulness, withdrawal, or a combination thereof. 
   
   
       51 . The method of  claim 26 , wherein the disorder or condition is attention deficit hyperactivity disorder. 
   
   
       52 . The method of  claim 26 , wherein the disorder or condition is attention deficit disorder. 
   
   
       53 . The method of  claim 26 , wherein the disorder or condition is obesity. 
   
   
       54 . The method of  claim 26 , wherein the disorder or condition is appetite suppression. 
   
   
       55 . The method of  claim 26 , wherein the disorder or condition is depression. 
   
   
       56 . The method of  claim 26 , wherein the disorder or condition is narcolepsy.