Pharmaceutical compositions for prevention of overdose or abuse

• US 7,375,083 B2
• Filed: 09/30/2004
• Issued: 05/20/2008
• Est. Priority Date: 09/30/2003
• Status: Active Grant

• Current Assignee: Shire LLC (Shire plc)
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Mickle, Christal, Krishnan, Suma, Mickle, Travis, Moncrief, James Scott, Lauderback, Christopher
• Primary Examiner(s): Tsang; Cecilia J.
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US10/953,119
• Publication Number:
  US 20050176646A1
• Time in Patent Office: 1,328 Days
• Field of Search: 514/9
• US Class Current: 514/1.3
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 31/18 for HIV

Abstract

The invention relates to pharmaceutical compositions comprised of a chemical moiety attached to an active agent in a manner that substantially decreases the potential of the active agent to cause overdose or to be abused. When delivered at the proper dosage the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

Claims

1. A method for altering the short term bioavailability of an oral dosage form of a hydromorphone composition comprising:

covalently bonding hydromorphone or a pharmaceutically acceptable salt thereof through the 2′

or 6′

position to the C-terminus of a single amino acid or an oligopeptide of 15 or fewer amino acids such that the hydromorphone does not release into a patient'"'"'s bloodstream at levels that give rise to a euphoric or overdose level.

3. The method of claim 1 or 2 wherein the oligopeptide is selected from a single amino acid, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide and a hexapeptide.

4. The method of claim 1 or 2 wherein hydromorphone is bound to a single amino acid and the single amino acid is selected from Ala, Glu, lie, Leu, Lys, Phe, Ser, or Val.

5. The method of claim 3 wherein said oligopeptide is a dipeptide selected from Val-Val, Val-Gly, Ser-Amp, Phe-Amp, Lys-Lys, Gly-Gly, Glu-Glu, Glu-Amp, or Ala-Pro.

6. The method of claim 3 wherein said oiigopeptide is a tripeptide selected from Tyr-Tyr-Val, Tyr-Tyr-Phe, Tyr-Tyr-Ile, Thr-Thr-Val, Pro-Glu-Val, Pro2-Leu, Pro2-Ile, Phe-Phe-Leu, Phe-Phe-Ile, Lys-Lys-Val, Lys-Lys-Ile, Leu-Pro-Leu, Leu-Leu-Leu, Gly-Gly-Leu, Gly-Gly-Ile, Glu-Tyr-Val, Glu-Leu-Val, Glu-Glu-Val, Glu-Glu-Ile, Glu-Glu-Glu, Glu-Glu-Phe, Asp-Asp-Val, Asp-Asp-Ile, His-Gly-Gly, Ile-Tyr-Val, Gly-Gly-Gly, Val-Glu-Gly, Leu-Tyr-Val, Gly-Tyr-Leu, Gly-Tyr-Ile, Lys-Ser-Val, Ser-Gly-Val, Gly-Tyr-Val, Gly-Glu-Val, Glu-Pro-Val, Tyr-Pro-Val, Ser-Thr-Val, Phe-Val-Val, Gly-Leu-Val, Glu-Asp-Val, or Gly-Lys-Gly.

7. The method of claim 3 wherein said oligopeptide is a pentapeptide selected from Tyr-Tyr-Phe-Phe-Ile [SEQ ID NO:

8], Tyr-Tyr-Lys-Tyr-Tyr [SEQ ID NO;

9], Tyr-Tyr-Phe-Pro-Ile [SEQ ID NO;

12], Tyr-Tyr-Gly-Gly-Ile [SEQ ID NO;

19], Tyr-Tyr-Glu-Glu-Ile [SEQ ID NO;

24], Phe-Phe-Lys-Phe-Phe [SEQ ID NO;

10], Lys-Lys-Gly-Gly-Ile [SEQ ID NO;

17], Lys-Lys-Glu-Glu-Ile [SEQ ID NO;

26], Lys-Lys-Asp-Asp-Ile [SEQ ID NO;

23], Gly-Gly-Gly-Gly-Leu [SEQ ID NO;

1], Gly-Gly-Gly-Gly-Ile [SEQ ID NO;

16], Gly-Gly-Pro-Pro-Ile [SEQ ID NO;

20], Glu-Glu-Phe-Phe-Phe [SEQ ID NO;

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

5], Glu-Glu-Glu-Glu-Glu [SEQ ID NO;

13], Glu-Glu-Gly-Gly-Leu [SEQ ID NO;

15], Glu-Glu-Gly-Gly-Ile [SEQ ID NO;

14], Glu-Glu-Asp-Asp-Ile[SEQ ID NO;

22], Asp-Asp-Asp-Asp-Ile [SEQ ID NO;

25], Asp-Asp-Phe-Phe-Ile [SEQ ID NO;

21], or Lys-Lys-Pro-Pro-Ile [SEQ ID NO;

18].

8. The method of claim 3 wherein said oligopeptide is a hexapeptide that is Glu-Glu-Phe-Phe-Phe-Ile [SEQ ID NO:

2].

9. The method of claim 3 wherein said oligopeptide is a tetrapeptide that is Lys-Lys-Gly-Gly [SEQ ID NO:

11].

10. The method of claim 1 or 2, wherein said oral dosage form is a tablet, a capsule, an oral solution, or an oral suspension.

2. A method for altering the short term bioavailability of an oral dosage form of a hydromorphone composition in a patient comprising providing to said patient hydromorphone, or a pharmaceutically acceptable salt thereof, covalently bound through the 2′

or 6′

position to the C-terminus of a single amino acid or an oligopeptide of 15 or fewer amino acids wherein said bound hydromorphone maintains a serum release curve which provides therapeutically effective bioavailability but prevents spiking or an increase in blood serum concentrations compared to unbound hydromorphone when taken at doses exceeding the therapeutically effective range.