Abuse-resistant amphetamine prodrugs

• US 7,678,770 B2
• Filed: 08/29/2008
• Issued: 03/16/2010
• Est. Priority Date: 02/22/2002
• Status: Expired due to Term

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Piccariello, Thomas, Bishop, Barney, Krishnan, Suma, Verbicky, Christopher A., Oberlender, Robert, Mickle, Travis, Moncrief, James Scott, Lauderback, Christopher, Paul, Bernhard J.
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US12/201,739
• Publication Number:
  US 20090124696A1
• Time in Patent Office: 564 Days
• Field of Search: None
• US Class Current: 514/17.5
• 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 invention describes compounds, compositions, and methods of using the same comprising a chemical moiety 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 method of treating a subject six to twelve years of age having attention deficit hyperactivity disorder, said method comprising orally administering to said subject a pharmaceutically effective amount of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof.

2. A method as defined in claim 1, wherein said attention deficit hyperactivity disorder is of the combined type.

3. A method as defined in claim 1, wherein said attention deficit hyperactivity disorder is of the hyperactive-impulsive type.

4. A method as defined in claim 1, wherein said subject is administered a mesylate salt of L-lysine-d-amphetamine.

5. A method as defined in claim 1, wherein said subject is administered L-lysine-d-amphetamine dimesylate.

6. A method as defined in claim 1, wherein said subject is administered 30 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof once daily.

7. A method as defined in claim 1, wherein said subject is administered 50 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof once daily.

8. A method as defined in claim 1, wherein said subject is administered 70 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof once daily.

9. A method as defined in claim 1, wherein said L-lysine-d-amphetamine is administered in a pharmaceutical composition comprising said L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive suitable for oral administration.

10. A method as defined in claim 9, wherein therapeutic effects of L-lysine-d-amphetamine occur within two hours post administration and continue through twelve hours post administration.

11. A method as defined in claim 9, wherein said administration provides a T_MAX of d-amphetamine approximately 3.5 hours following administration of L-lysine-d-amphetamine to said subject and a T_MAX of approximately 1 hour of L-lysine-d-amphetamine after administration of L-lysine-d-amphetamine to said subject.

12. A method as defined in claim 9, wherein said d-amphetamine exhibits linear pharmacokinetics after administration.

13. A method of treating symptoms of attention deficit hyperactivity disorder in a subject six to twelve years of age in need thereof, said method comprising orally administering to said subject a pharmaceutically effective amount of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof;

whereby one or more of said symptoms diminish in said subject in a statistically significant amount as compared to a subject not receiving treatment of symptoms of attention deficit hyperactivity disorder.

14. A method as defined in claim 13, wherein said attention deficit hyperactivity disorder is of the combined type.

15. A method as defined in claim 13, wherein said attention deficit hyperactivity disorder is of the hyperactive-impulsive type.

16. A method as defined in claim 13, wherein said symptoms are included in the DSM-IV criteria for attention deficit hyperactivity disorder.

17. A method as defined in claim 13, wherein said diminished symptom is deportment.

18. A method as defined in claim 13, wherein said diminished symptom is inattention.

19. A method as defined in claim 13, wherein said diminishment is measured using the ADHD ratings scale.

20. A method as defined in claim 19, wherein said diminishment is measured at a study end point.

21. A method as defined in claim 13, wherein said diminishment is measured using the Connor'"'"'s Parents Rating Scale.

22. A method as defined in claim 21, wherein said diminishment is measured at a study end point.

23. A method as defined in claim 13, wherein said diminishment is measured using the SKAMP Deportment Rating Scale.

24. A method as defined in claim 23, where said diminishment is measured at a study end point.

25. A method as defined in claim 13, wherein said subject is administered 30 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof once daily.

26. A method as defined in claim 13, wherein said subject is administered 50 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof once daily.

27. A method as defined in claim 13, wherein said subject is administered 70 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof once daily.