Compounds and compositions for prevention of overdose of oxycodone

• US 8,106,016 B2
• Filed: 12/08/2006
• Issued: 01/31/2012
• Est. Priority Date: 09/30/2003
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Moncrief, James Scott, Krishnan, Suma, Mickle, Travis, Lauderback, Christopher, Bera, Sanjib, Guenther, Sven, Hirschelman, Wendy
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US11/635,788
• Publication Number:
  US 20070203055A1
• Time in Patent Office: 1,880 Days
• Field of Search: None
• US Class Current: 514/18.4
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence

Abstract

The invention relates to pharmaceutical compounds and compositions comprised of a chemical moiety attached to an opioid such as oxycodone in a manner that substantially decreases the potential of the opioid to cause overdose. When delivered at the proper dosage the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent. Further the compounds and compositions of the invention are useful in preventing addiction and susceptibility to addiction.

Claims

1. A pharmaceutical composition comprising oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to the C- or N-terminus of an amino acid, or to the C- or N-terminus of an amino acid in an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone and one or more pharmaceutically acceptable additives, wherein said composition is in a dosage form suitable for oral delivery.

2. The pharmaceutical composition of claim 1, wherein the amino acid or oligopeptide bound to the 6′

position and the 14′

position of the oxycodone are the same.

3. The pharmaceutical composition of claim 1, wherein the amino acid or oligopeptide bound to the 6′

position of the oxycodone is not the same as the amino acid or oligopeptide bound to the 14′

position of the oxycodone.

4. The pharmaceutical composition of claim 1, wherein said oxycodone is bound to an oligopeptide of 12 or fewer amino acids selected from a dipeptide, a tripeptide, a pentapeptide, and a hexapeptide.

5. The pharmaceutical composition of claim 1 wherein said amino acid or oligopeptide consists essentially of naturally occurring amino acids.

6. The pharmaceutical composition of claim 1 wherein the oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to provide a therapeutically effective amount of oxycodone for treating pain, but a reduced or delayed C_max of oxycodone as compared to unbound oxycodone.

7. The pharmaceutical composition of claim 1 wherein said oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to provide a therapeutically effective amount of oxycodone for treating pain, but has limited bioavailability of oxycodone when administered by routes of administration other than an oral route of administration.

8. The pharmaceutical composition of claim 1 wherein said oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to provide an area under the curve (AUC) of oxycodone that is therapeutically effective for treating pain when compared to oxycodone alone, but in an amount insufficient to provide a C_max which results in euphoria.

9. The pharmaceutical composition of claim 1 wherein said oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to maintain a steady-state serum release curve of oxycodone which provides a bioavailability of oxycodone that is therapeutically effective for treating pain, but prevents spiking or increased blood serum concentrations compared to unbound oxycodone.

10. The pharmaceutical composition of claim 1 wherein the oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to provide a therapeutically effective amount of oxycodone for treating pain, and wherein said composition provides sustained release characteristics of said oxycodone.

11. The pharmaceutical composition of claim 1 wherein the oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to provide a therapeutically effective amount of oxycodone for treating pain, but at a reduced rate of absorption of oxycodone as compared to unbound oxycodone.

12. The pharmaceutical composition of claim 1 wherein the oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount exceeding those within the therapeutic range of unbound oxycodone for treating pain.

13. The pharmaceutical composition of claim 1, wherein the oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone is in an amount sufficient to provide a therapeutically effective amount of oxycodone for treating pain, with an increased rate of clearance of oxycodone when given at doses exceeding those within the therapeutic range of unbound oxycodone for treating pain.

14. The pharmaceutical composition of claim 1, wherein the oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to an amino acid, or to an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone exhibits a reduced rate of absorption of oxycodone is in an amount sufficient to provide a therapeutically effective amount of oxycodone for treating pain, and as compared to unbound oxycodone when administered at doses exceeding those within the therapeutic range of unbound oxycodone for treating pain.

15. The pharmaceutical composition of claim 1, wherein the dosage form is selected from a tablet, a capsule, an oral solution, and an oral suspension.

16. The pharmaceutical composition of claim 2, wherein said oxycodone is bound to an oligopeptide selected from the group consisting of Phe-Phe-Lys-Phe-Phe [SEQ ID NO:

5]Tyr-Tyr-Lys-Tyr-Tyr [SEQ ID NO;

4], Glu-Glu-Phe-Phe-Ile [SEQ ID NO;

1], Asp-Asp-Ile, Gly-Tyr-Ile, Phe-Phe-Val, Tyr-Tyr-Ile, Asp-Asp-Val, Gly-Tyr-Leu, Phe-Val-Val, Tyr-Tyr-Phe, Glu-Asp-Val, Gly-Tyr-Val, Pro-Glu-Val, Tyr-Tyr-Val, Glu-Glu-Val, Ile-Tyr-Val, Pro-Pro-Ile, Val-Glu-Gly, Glu-Leu-Val, Leu-Tyr-Val, Pro-Pro-Leu, Glu-Pro-Val, Lys-Lys-Leu, Pro-Pro-Vat, Glu-Tyr-Val, Lys-Lys-Val, Ser-Gly-Val, Gly-Glu-Val, Lys-Ser-Val, Ser-Thr-Val, Gly-Gly-Ile, Phe-Phe-Ile, Thr-Thr-Val, Gly-Leu-Val, Phe-Phe-Leu, and Tyr-Pro-Val.

17. The pharmaceutical composition of claim 3, wherein said oxycodone is bound to an oligopeptide selected from the group consisting of Phe-Phe-Lys-Phe-Phe [SEQ ID NO:

5]Tyr-Tyr-Lys-Tyr-Tyr [SEQ ID NO;

4], Glu-Glu-Phe-Phe-Ile [SEQ ID NO;

1], Asp-Asp-Ile, Gly-Tyr-Ile, Phe-Phe-Val, Tyr-Tyr-Ile, Asp-Asp-Val, Gly-Tyr-Leu, Phe-Val-Val, Tyr-Tyr-Phe, Glu-Asp-Val, Gly-Tyr-Val, Pro-Glu-Val, Tyr-Tyr-Val, Glu-Glu-Val, Ile-Tyr-Val, Pro-Pro-Ile, Val-Glu-Gly, Glu-Leu-Val, Leu-Tyr-Val, Pro-Pro-Leu, Glu-Pro-Val, Lys-Lys-Leu, Pro-Pro-Vat, Glu-Tyr-Val, Lys-Lys-Val, Ser-Gly-Val, Gly-Glu-Val, Lys-Ser-Val, Ser-Thr-Val, Gly-Gly-Ile, Phe-Phe-Ile, Thr-Thr-Val, Gly-Leu-Val, Phe-Phe-Leu, and Tyr-Pro-Val.

18. A pharmaceutical composition comprising oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to the C- or N-terminus of an amino acid, or to the C- or N-terminus of an amino acid in an oligopeptide of 12 or fewer amino acids, at the 6′

position of said oxycodone, and one or more pharmaceutically acceptable additives, wherein said composition is in a dosage form suitable for oral delivery.

19. A method of treating pain, comprising administering to a subject in need thereof an effective amount of a composition comprising oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to the C- or N-terminus of an amino acid, or to the C- or N-terminus of an amino acid in an oligopeptide of 12 or fewer amino acids, at the 6′

position and the 14′

position of said oxycodone and one or more pharmaceutically acceptable additives, wherein said composition is in a dosage form suitable for oral delivery.

20. A method of treating pain, comprising administering to a subject in need thereof an effective amount of a composition comprising oxycodone, or a pharmaceutically acceptable salt thereof, covalently bound to the C- or N-terminus of an amino acid, or to the C- or N-terminus of an amino acid in an oligopeptide of 12 or fewer amino acids, at the 6′

position of said oxycodone, and one or more pharmaceutically acceptable additives, wherein said composition is in a dosage form suitable for oral delivery.