Abuse-resistant amphetamine prodrugs

• US 7,700,561 B2
• Filed: 04/10/2006
• Issued: 04/20/2010
• 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:
  US11/400,304
• Publication Number:
  US 20070042955A1
• Time in Patent Office: 1,471 Days
• Field of Search: None
• US Class Current: 514/17.7
• 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 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• 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: 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 pharmaceutical composition comprising:

a. about 10 mg to about 250 mg of L-lysine-d-amphetamine or a pharmaceutically acceptable salt thereof;

b. about 40% to about 90% by weight percent of microcrystalline cellulose;

c. about 1% to about 10% by weight percent of croscarmellose sodium; and

d. less than about 5% by weight percent of magnesium stearate.

2. The pharmaceutical composition of claim 1, consisting essentially of:

a. about 30 mg L-lysine-d-amphetamine dimesylate;

b. about 151 mg microcrystalline cellulose;

c. about 4.69 mg croscarmellose sodium;

d. about 1.88 mg magnesium stearate.

3. The pharmaceutical composition of claim 1, consisting essentially of:

a. about 50 mg L-lysine-d-amphetamine dimesylate;

b. about 70 mg microcrystalline cellulose;

c. about 3.12 mg croscarmellose sodium;

d. about 1.88 mg magnesium stearate.

4. The pharmaceutical composition of claim 1, consisting essentially of:

a. about 70 mg L-lysine-d-amphetamine dimesylate;

b. about 98 mg microcrystalline cellulose;

c. about 4.37 mg croscarmellose sodium;

d. about 2.63 mg magnesium stearate.

5. The pharmaceutical composition of claim 1, wherein the C_max of released amphetamine is within about 80% to about 120% of a value selected wherein said value is 53.2±

9.62 ng/mL, 93.3±

18.2 ng/mL, or 134±

26.1 ng/mL.

6. The pharmaceutical composition of claim 1, wherein the T_max of released amphetamine is within about 80% to about 120% of a value selected wherein said value is 3.41±

1.09 hours 3.58±

1.18 hours, or 3.46±

1.34 hours.

7. The pharmaceutical composition of claim 1, wherein the area under the curve (AUC) of released amphetamine is within about 80% to about 120% of a value selected wherein said value is 845±

117 ngh/mL 1510±

242 ngh/mL, or 2157±

383 ngh/mL.

8. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the oral bioavailability of amphetamine released from the prodrug following administration is at least about 60% of the area under the curve (AUC) of that following administration of an equivalent amount of unbound d-amphetamine.

9. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the oral bioavailability of amphetamine released from the prodrug following administration is at least about 95% of the area under the curve (AUC) of that following administration of an equivalent amount of unbound d-amphetamine.

10. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the parenteral bioavailability of amphetamine released from the prodrug following administration is less than about 50% of the area under the curve (AUC) of that following administration of an equivalent amount of unbound d-amphetamine.

11. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the parenteral bioavailability of amphetamine released from the prodrug following administration is less than about 1% of the area under the curve (AUC) of that following administration of an equivalent amount of unbound d-amphetamine.