Abuse-resistant amphetamine prodrugs

• US 7,659,253 B2
• Filed: 06/02/2008
• Issued: 02/09/2010
• 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:
  US12/131,923
• Publication Number:
  US 20090234002A1
• Time in Patent Office: 617 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• 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. Crystalline lisdexamphetamine dimesylate.

2. The crystalline lisdexamphetamine dimesylate of claim 1, wherein the crystalline lisdexamphetamine dimesylate exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 77.

3. The crystalline lisdexamphetamine dimesylate of claim 1, wherein the crystalline lisdexamphetamine dimesylate exhibits an X-ray powder diffraction pattern having at least one peak in degrees 2Θ

±

0.2 2Θ

selected from 4.5, 9.0, 12.0, 15.7, and 16.3.

4. The crystalline lisdexamphetamine dimesylate of claim 3, wherein the dimesylate exhibits an X-ray powder diffraction pattern having at least two peaks in degrees 2Θ

±

0.2 2Θ

selected from 4.5, 9.0, 12.0, 15.7, and 16.3.

5. The crystalline lisdexamphetamine dimesylate of claim 4, wherein the dimesylate exhibits an X-ray powder diffraction pattern having peaks in degrees 2Θ

±

0.2 2Θ

at 4.5, 9.0, 12.0 and 15.7.

6. The crystalline lisdexamphetamine dimesylate of claim 1, wherein the crystalline lisdexamphetamine dimesylate has a melting point onset as determined by differential scanning calorimetry at about 194.7°

C.

7. The crystalline lisdexamphetamine dimesylate of claim 1, wherein the crystalline lisdexamphetamine dimesylate exhibits a single crystal X-ray crystallographic analysis at 150 K with crystal parameters that are approximately equal to the following:

11. A pharmaceutical composition comprising crystalline lisdexamphetamine dimesylate of claim 1 and a pharmaceutically acceptable additive.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises at least about 95% by weight of crystalline lisdexamphetamine dimesylate, based upon 100% total weight of lisdexamphetamine dimesylate in the pharmaceutical composition.

8. Crystalline lisdexamphetamine dimesylate particles having at least one of:

(a) a d₁₀ ranging from about 1 to about 10 μ

m;

(b) a d₅₀ ranging from about 8 to about 40 μ

m; and

(c) a d₅₀ particle size ranging from about 25 to about 90 μ

m.

9. The crystalline lisdexamphetamine dimesylate particles of claim 8, wherein the crystalline lisdexamphetamine dimesylate has a d₉₀ particle size ranging from about 25 to about 90 μ

m.

10. The crystalline lisdexamphetamine dimesylate particles of claim 8, wherein the crystalline lisdexamphetamine dimesylate has a d₅₀ ranging from about 8 to about 40 μ

m.

13. A method of treating attention deficit hyperactivity disorder in a patient in need thereof, comprising the step of orally administering crystalline lisdexamphetamine dimesylate.