Pharmaceutical compositions for prevention of overdose or abuse

• US 20060014697A1
• Filed: 03/25/2005
• Published: 01/19/2006
• Est. Priority Date: 08/22/2001
• Status: Abandoned Application

• Current Assignee: Shire LLC (Shire plc)
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Krishnan, Suma, Mickle, Travis, Moncrief, James Scott, Lauderback, Christopher
• Application Number:
  US11/089,056
• Publication Number:
  US 20060014697A1
• Time in Patent Office: Days
• US Class Current: 514/18.300
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• 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: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07K 5/06086 with the first amino acid being basic
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

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 compound of the formula:

A-X_m-Z_n

wherein

A is an active agent;

X is a linker covalently bound to A; and

Z is an amino acid, peptide, or oligopeptide covalently bound to x,

wherein m and n range from 1 to 50.

2. The compound of claim 1, wherein X comprises a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups.

3. The compound of claim 2, wherein the functional groups are selected from amines, amides, alcohols or acids.

4. The compound of claim 1, wherein A is oxycodone or hydrocodone.

5. The compound of claim 1, wherein X an enolate.

6. The compound of claim 1, wherein X is an amino acid.

7. The compound of claim 6, wherein Z is bonded to X through a side chain of the amino acid.

8. The compound of claim 6, wherein Z is bonded to Z through a peptide bond.

9. The compound of claim 1, wherein X is an amino acid or dipeptide and Z is bonded to X through a peptide bond.

10. The compound of claim 1, wherein X comprises Ser, Lys, Glu, Asp, Ala, Leu, Phe, Val, Gly, Tyr, Pro, or Thr.

11. The compound of claim 1, wherein -X-Z comprises Lys-Lys, Lys-Lys-Val, (Lys-Lys-Gly-Gly)₂, [(l)-Lys-(d)-Lys-Leu]₂, Glu-Glu, Glu-Glu-Phe-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Glu-Glu-Phe-Phe-Ile, Glu-Glu-Val, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Asp-Asp-Val, Ala-Ser, Ala-Cys, Leu-Glu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, Val-Val, Gly-Gly-Leu, Gly-Gly-Gly-Gly-Leu, Gly-Gly-Ile, Asp-Asp-Ile, Pro-Pro-Leu, Pro-Pro-Ile, or Thr-Thr-Val.

12. The compound of claim 1, wherein -X-Z comprises Ser-Ser, PolySer, Lys, Glu-Glu, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Ala-Glu, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gin, Ala-Tyr, LeuGlu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, PheGlu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg, Phe-Cys, Phe-Gln, Phe-Tyr, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, or Val-Tyr.

13. The compound of claim 1, wherein -X-Z comprises Pro-Pro-Leu, Pro-Pro-Ile, Val-Val, Lys-Lys, Gly-Gly-Ile, Phe-Phe-Ile, Phe-Phe-Leu, Thr-Thr-Val, Tyr-Tyr-Val, Tyr-Tyr-Phe, Glu-Glu-Val, Asp-Asp-Val, Lys-Lys-Val, Glu-Glu-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Tyr-Tyr-Ile, Asp-Asp-Ile, Tyr-Tyr-Phe-Phe-Ile, Tyr-Tyr-Lys-Tyr-Tyr, Phe-Phe-Lys-Phe-Phe, Glu-Glu-Phe-Phe-Ile, (Lys-Lys-Gly-Gly)₂, or [(1)-Lys-(d)-Lys-Leu]₂.

14. The compound of claim 1, wherein -X-Z comprises Ser-Ser, PolySer, Glu-Glu, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Ala-Glu, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gln, Ala-Tyr, Leu-Glu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, Phe-Glu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg, Phe-Cys, Phe-Gin, Phe-Tyr, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, Ala-Pro, Gly-Gly-Leu, Gly-Gly-Gly-Gly-Leu, Glu-Glu-Phe-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Tyr-Tyr-Ile, Asp-Asp-Ile, Tyr-Tyr-Phe-Phe-Ile, or Glu-Glu-Phe-Phe-Ile.

15. The compound of claim 1, wherein -X-Z comprises Ser-Ser, PolySer, Lys-Lys, Lys-Lys-Val, (Lys-Lys-Gly-Gly)₂, [(1)-Lys-(d)-Lys-Leu]₂, Glu-Glu, Glu-Glu-Phe-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Glu-Glu-Phe-Phe-Ile, Glu-Glu-Val, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Asp-Asp-Val, Ala-Glu, Ala-Pro, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gln, Ala-Tyr, Leu-Glu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, Phe-Glu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg, Phe-Cys, Phe-Gln, Phe-Tyr, Phe-Phe-Ile, Phe-Phe-Leu, Phe-Phe-Lys-Phe-Phe, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, Val-Val, Gly-Gly-Leu, Gly-Gly-Gly-Gly-Leu, Gly-Gly-Ile, Tyr-Tyr-Ile, Tyr-Tyr-Phe-Phe-Ile, Tyr-Tyr-Val, Tyr-Tyr-Phe, Tyr-Tyr-Lys-Tyr-Tyr, Asp-Asp-Ile, Pro-Pro-Leu, Pro-Pro-Ile, or Thr-Thr-Val.

16. The compound of claim 1, wherein X is lysine.

17. The compound of claim 16, wherein Z is bonded to lysine through the side chain of the lysine.

18. The compound of claim 1, wherein the active agent is alphacetylmethadol hydrochloride, anileridine, apomorphine, bemidone, betacetylmethadol hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, codeine, dezocine, dihydrocodeine, dihydromorphine, dipanone hydrochloride, eptazocine hydrobromide, ethylmorphine, etorphine hydrochloride, hydromorphone, ketobemidone, levorphanol tartrate, loperamide, meptazinol hydrochloride, methyldihydromorphinone, nalbuphine hydrochloride, nalbuphine hydrochloride, normorphine, oxycodone, oxymorphone, pentazocine, piminodine, tramadol, allobarbitone, alprazolan, amylobarbitone, barbitone sodium, butobarbitone, captodiame hydrochloride, chloral betaine, chloral hydrate, chloralose, chlorhexadol, chlormethiazole edisylate, cinolazepam, potassium clorazepate, cyclobarbitone calcium, delorzepam, difebarbamate, enciprazine hydrochloride, flunitrazepam, hexobarbitone sodium, ibomal, lorazepam, lormetazepam, meprobamate, methylpentynol, midazolam maleate, oxazepam, pentabarbitone calcium, phenprobamate, proxibarbal, quinalbaritone, quinalbarbitone sodium, secbutobarbitone sodium, temazepam, triclofos sodium, zalepan, or zolazepam hydrochloride.

19. The compound of claim 1, wherein A is a radical of a pain relief drug.

20. The compound of claim 1, wherein A is a radical of oxycodone or hydrocodone.

22. A method of treating pain, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 1.

21. (canceled)

23-24. -24. (canceled)

25. A compound of the formula:

A-X_m-Z_n

wherein

A is a drug radical;

X is a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups, wherein X is bonded to A through a carboxyl group; and

Z is an amino acid, peptide, or oligopeptide covalently bound to X,

wherein m and n range between 1 and 50.

26-45. -45. (canceled)

46. A compound comprising a drug radical covalently bonded to a first amino acid selected from the group consisting of Ser, Lys, Glu, Asp, Ala, Leu, Phe, Val, Gly, Tyr, Pro, and Thr, and a second amino acid or peptide covalently bonded to the first amino acid, wherein an optional linker attaches the first amino acid to the drug radical.

47-61. -61. (canceled)