Polar hydrophilic prodrugs and non-standard amino acid conjugates of amphetamine and other stimulants and processes for making and using the same
View Patent ↗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. Also disclosed are non-standard amino acid conjugates of amphetamine. Methods of making and using the same are also disclosed.
1. A composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperactivity disorder, comprising at least one salt of a conjugate comprising amphetamine chemically attached to homoarginine, wherein the salt is selected from an acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adipate, aminosalicylate, ammonium, ascorbate, l-aspartate, besylate, bicarbonate, borate, butyrate, calcium, camphocarbonate, camphorate, d-camsylate, l-camsylate, camsylate, carbonate, cholate, 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, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d,l-lactate, lactobionate, laurate, lithium, magnesium, maleate, malonate, mandelate, meso-tartrate, methanesulfonate, methylsulfate, myristate, napadisilate, 2-napsylate, nicotinate, octanoate, oleate, orotate, palmitate, pamoate, phenylpropionate, picrate, pivalate, potassium, propionate, pyrophosphate, salicylate, salicylsulfate, sodium, stearate, succinate, sulfosalicylate, tannate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, undecylenate, valerate, valproate, xinafoate, zinc, and mixtures thereof.
2. The composition of claim 1 , wherein the homoarginine is l-homoarginine.
3. The composition of claim 1 , wherein the amphetamine is d-amphetamine.
4. A composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperactivity disorder, comprising a derivative of amphetamine chemically attached to homoarginine, a salt thereof, or a combination thereof, wherein the derivative of amphetamine is selected from l-amphetamine, methamphetamine, p-methoxyamphetamine, 3,4-methylenedioxyamphetamine, 2,3-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, 2,5-dimethoxy-4-methylamphetamine, 3,4,5-trimethoxyamphetamine, 2,4,5-trimethoxyamphetamine, 2,3,4-trimethoxyamphetamine, 2,3,5-trimethoxyamphetamine, 2,3,6-trimethoxyamphetamine, and 2,4,6-trimethoxyamphetamine.
5. The composition of claim 4 , wherein the homoarginine is l-homoarginine.
6. The composition of claim 4 , wherein the derivative of amphetamine is l-amphetamine.
7. The composition of claim 4 , 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, kartrate, d,l-tartrate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triflate, undecylenate, valerate, valproate, xinafoate, zinc, and mixtures thereof.
8. The composition of claim 1 , wherein the conjugate is l-homoarginine-d-amphetamine.
9. The composition of claim 1 , wherein the composition has a reduced pharmacological activity when administered by parenteral routes.
10. The composition of claim 1 , wherein the composition is in the form of a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a oral film, a thin strip, or a suspension.
11. The composition of claim 10 , wherein the tablet, troche, or lozenge is chewable.
12. The composition of claim 1 , wherein the salt of the conjugate is present in the amount of from about 1 mg to about 500 mg.
13. The composition of claim 12 , wherein the salt of the conjugate is present in the amount of from about 5 mg to about 250 mg.
14. The composition of claim 13 , wherein the salt of the conjugate is present in the amount of from about 10 mg to about 100 mg.
15. The composition of claim 1 , wherein the salt of the conjugate is in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to amphetamine alone, but does not provide a C max spike.
16. The composition of claim 1 , wherein the salt of the conjugate is in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to amphetamine alone, but does not provide an equivalent C max .