Abuse resistant lysine amphetamine compounds

• US 7,223,735 B2
• Filed: 06/01/2004
• Issued: 05/29/2007
• 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, Lauderback, Christopher, Oberlender, Rob, Moncrief, James Scott
• Primary Examiner(s): Tsang; Cecilia J.
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US10/857,619
• Publication Number:
  US 20050038121A1
• Time in Patent Office: 1,092 Days
• Field of Search: 514/18
• US Class Current: 514/1.3
• 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 pharmaceutical composition comprising an unprotected prodrug and one or more pharmaceutically acceptable additives;

wherein said prodrug consists of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof;

wherein said composition is in a form suitable for oral administration;

wherein said composition provides release of amphetamine as an active from said prodrug following oral administration; and

wherein said prodrug has limited bioavailability of amphetamine when administered through alternative routes of administration.

2. The composition of claim 1 wherein said L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof provides a therapeutically effective amount of amphetamine, but a reduced C_max of amphetamine as compared to unbound amphetamine.

3. The composition of claim 1 or 2 wherein said L-lysine-d-amphetamine salt is L-lysine-d-amphetamine mesylate.

4. The composition of claim 1 or 2 wherein said L-lysine-d-amphetamine salt is L-lysine-d-amphetamine hydrochloride.

5. The composition of claim 1 or 2, wherein said form suitable for oral administration is a tablet, a capsule, a caplet, an oral solution, or an oral suspension.

6. The composition of claim 3, wherein said form suitable for oral administration is a tablet, a capsule, a caplet, an oral solution, or an oral suspension.

7. The composition of claim 4, wherein said form suitable for oral administration is a tablet, a capsule, a caplet, an oral solution, or an oral suspension.

8. The composition of claim 2, wherein the pharmaceutically acceptable additive comprises diluents, binders and adhesives, lubricants, plasticizers, distintegrants, colorants, bulking substances, flavorings, sweeteners, buffers or adsorbents.

9. The composition of claim 1, wherein said L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof is in an amount sufficient to provide a pharmacologically effective amount to treat a patient in need of amphetamine.

10. The composition of claim 9, wherein said L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof is in an amount sufficient to provide a therapeutically bioequivalent area under the curve (AUC) of amphetamine when compared to amphetamine alone, but in an amount insufficient to provide a C_max which results in euphoria.

11. The pharmaceutical composition of claim 1, wherein said L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof is in an amount sufficient to maintain a steady-state serum release curve of amphetamine which provides a therapeutically effective bioavailability of amphetamine but prevents spiking or increased blood serum concentrations compared to unbound amphetamine.

12. The pharmaceutical composition of claim 1, wherein said L-lysine-d-amphetamine or salt thereof provides sustained release characteristics.

13. The pharmaceutical composition of claim 1, wherein said L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof is in an amount sufficient to provide a therapeutically effective amount of amphetamine, but at a reduced rate of absorption of the amphetamine as compared to unbound amphetamine.

14. The pharmaceutical composition of claim 1, wherein the L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof is in an amount exceeding those within the therapeutic range for unbound amphetamine.

15. A pharmaceutical composition comprising an oral dosage form of an unprotected prodrug consisting of L-lysine-d-amphetamine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives.

16. The pharmaceutical composition of claim 15 wherein said prodrug provides an increased rate of clearance of amphetamine when given at doses exceeding those within the therapeutic range of unbound amphetamine.

17. The pharmaceutical composition of claim 15 wherein said prodrug exhibits a reduced rate of absorption of amphetamine as compared to unbound amphetamine when administered at doses exceeding those within the therapeutic range of unbound amphetamine.

18. An oral pharmaceutical dosage form for the administration of amphetamine comprising an unprotected prodrug and one or more pharmaceutically acceptable additives;

wherein said prodrug consists of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof;

wherein said composition provides limited release of amphetamine as an active from said prodrug following oral administration; and

wherein said prodrug has limited bioavailability of amphetamine when administered through alternative routes of administration.