Abuse resistant lysine amphetamine compounds

• US 20050038121A1
• Filed: 06/01/2004
• Published: 02/17/2005
• Est. Priority Date: 05/29/2003
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: New River Pharmaceuticals Inc. (Shire plc)
• Inventors: Piccariello, Thomas, Bishop, Barney, Krishnan, Suma, Mickle, Travis, Moncrief, James Scott, Lauderback, Christopher, Oberlender, Rob
• Granted Patent: US 7,223,735 B2
• Time in Patent Office: Days
• US Class Current: 514/563
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 237/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10S 436/901 Drugs of abuse, e.g. narcotics, amphetamine
• CPC Class Codes: Y10T 436/173845 Amine and quaternary ammonium

Abstract

The present invention describes compounds, compositions and methods of using the same comprising lysine covalently attached to amphetamine. These compounds and compositions are useful for reducing or preventing abuse and overdose of amphetamine. These compounds and compositions find particular use in providing an abuse-resistant alternative treatment for certain disorders, such as attention deficit hyperactivity disorder (ADHD), ADD, narcolepsy, and obesity. Oral bioavailability of amphetamine is maintained at therapeutically useful doses. At higher doses bioavailability is substantially reduced, thereby providing a method of reducing oral abuse liability. Further, compounds and compositions of the invention decrease the bioavailability of amphetamine by parenteral routes, such as intravenous or intranasal administration, further limiting their abuse liability.

Claims

1. A compound comprising amphetamine covalently attached to a lysine.

2. A compound comprising amphetamine covalently attached to a single lysine.

3. A compound consisting essentially of amphetamine covalently attached to a lysine.

4. A compound consisting of amphetamine covalently attached to a lysine.

5. A composition comprising amphetamine covalently attached to a lysine and a pharmaceutically acceptable excipient.

7. The composition of claim 5, in an oral dosage form.

8. The composition of claim 7, wherein said oral dosage form is selected from a tablet, a capsule, a caplet, an oral solution, or an oral suspension.

9. The composition of claim 5, wherein said amphetamine is pharmacologically inactive or has diminished pharmacological activity when administered via a route other than oral.

10. The composition of claim 5, wherein peak concentrations of released amphetamine are extended when compared to unbound amphetamine given in a similar oral dosage and formulation in equimolar amounts.

11. The composition of claim 5, that is resistant to release of amphetamine in a pharmacologically active form when administered intranasally.

12. The composition of claim 5, that is resistant to release of amphetamine in a pharmacologically active form when administered by inhalation.

13. The composition of claim 5, that is resistant to release of amphetamine in a pharmacologically active form when administered by parenteral injection.

14. The composition of claim 5, wherein release of amphetamine in a pharmacologically active form is further diminished by the addition of specific excipients.

15. The composition of claim 14 wherein said excipient is an ionically charged compound.

16. The composition of claim 15 wherein the said ionically charged compound is carboxymethyl cellulose.

17. The composition of claim 5, wherein said amphetamine is selected from amphetamine, methamphetamine, methylphenidate, or mixtures thereof.

21. A method of treating attention deficit hyperactivity disorder comprising providing a patient with the composition according to claim 5.

24. A method for preventing abuse of amphetamine through intravenous administration comprising administering the composition of claim 5 wherein the intravenous bioavailability of amphetamine is reduced as compared to non-conjugated amphetamine at doses containing equimolar amounts of amphetamine.

25. A method for preventing abuse of amphetamine through intranasal administration comprising administering the composition of claim 5 wherein the intranasal bioavailability of amphetamine is reduced as compared to non-conjugated amphetamine at doses containing equimolar amounts of amphetamine.

26. A method for reducing or preventing abuse of amphetamine, comprising providing the composition of claim 5 to a human in need thereof, wherein the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

27. A method for reducing or preventing abuse of amphetamine, comprising administering the composition of claim 5 to a human in need thereof, wherein the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

28. A method for reducing or preventing abuse of amphetamine, comprising prescribing the composition of claim 5 to a human in need thereof, wherein the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

29. A method of preventing overdose of amphetamine, comprising providing the composition of claim 5 to a human in need thereof.

30. A method for reducing or preventing the euphoric effect of amphetamine, comprising providing the composition of claim 5 to a human in need thereof, wherein the pharmacological activity of amphetamine is substantially decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

31. A method for reducing or preventing the euphoric effect of amphetamine, comprising administering the composition of claim 5 to a human in need thereof, wherein the pharmacological activity of amphetamine is substantially decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

32. A method for reducing or preventing the euphoric effect of amphetamine, comprising prescribing the composition of claim 5 to a human in need thereof, wherein the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

33. A method for reducing or preventing the euphoric effect of amphetamine, comprising consuming the composition of claim 5, wherein the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer'"'"'s instructions.

34. A method of providing a tamper proof amphetamine formulation comprising providing the composition of claim 5, wherein said pharmaceutical composition is adapted for oral administration and wherein said amphetamine is resistant to release from said lysine when the composition is administered parenterally.

6. A composition consisting essentially of amphetamine covalently attached to a lysine and a pharmaceutically acceptable excipient.

18. A method for delivering amphetamine which prevents or diminishes euphoria, comprising administering to a patient in need thereof a composition formulated for oral dosage comprising amphetamine covalently attached to a single lysine wherein blood levels of amphetamine maintain a therapeutically effective level but do not result in a euphoric effect.

19. A method for treating a patient in need of amphetamine comprising providing to a patient a composition comprising amphetamine covalently bound to a lysine.

20. The method of claim 19, wherein said patient suffers from attention deficit hyperactivity disorder, attention deficit disorder, narcolepsy or obesity.

35. The method of claim 19, wherein said active agent provides a therapeutically bioequivalent AUC when compared to active agent alone but does provide a C_max which results in euphoria.

22. A method for delivering amphetamine comprising providing a patient with a therapeutically effective amount of amphetamine covalently attached to a single lysine which provides a therapeutically bioequivalent AUC when compared to amphetamine administered alone.

23. A method for delivering amphetamine comprising administering amphetamine covalently bound to a single lysine wherein the oral bioavailability of amphetamine is reduced at doses above those intended for therapeutic effect as compared to non-conjugated amphetamine at doses containing equimolar amounts of amphetamine.