MONO AND DI-SUBSTITUTED OXYCODONE COMPOUNDS AND COMPOSITIONS

• US 20110040072A1
• Filed: 03/11/2010
• Published: 02/17/2011
• Est. Priority Date: 04/10/2006
• 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, Bera, Sanjib
• Application Number:
  US12/722,495
• Publication Number:
  US 20110040072A1
• Time in Patent Office: Days
• US Class Current: 530/330
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

The invention relates to pharmaceutical compounds and compositions comprised of a chemical moiety attached to oxycodone in a manner that substantially decreases the potential for overdose. When delivered at the proper dosage the pharmaceutical composition provides therapeutic activity similar to that of oxycodone and may also provide sustained release characteristics and/or reduced side-effects. Further the compounds and compositions of the invention are useful in preventing addiction and susceptibility to addiction of oxycodone.

Claims

1-23. -23. (canceled)

24. A composition comprising an oxycodone covalently bound to at least one chemical moiety through a ketone, hydroxyl, or both in a pharmaceutically acceptable oral dosage form.

25. The composition of claim 24, wherein said chemical moiety is a polypeptide of two or more amino acids.

26. The composition of claim 25, wherein the amino acid adjacent to the said oxycodone is a nonpolar amino acid.

27. The composition of claim 26, wherein the amino acid adjacent to the said oxycodone is a branched nonpolar amino acid.

28. The composition of claim 27, wherein the amino acid adjacent to the said oxycodone is a branched nonpolar amino acid chosen from the naturally occurring amino acids valine, leucine, or isoleucine.

29. The composition of claim 25, wherein said polypeptide is comprised of one or more of the naturally occurring amino acids.

30. The composition of claim 25, wherein said chemical moiety is comprised of one or more of the D-isomers of the naturally occurring amino acids.

31. The composition of claim 25, wherein said chemical moiety is comprised of one or more of the L-isomers of the naturally occurring amino acids.

32. The composition of claim 25, wherein said chemical moiety is comprised of a mixture of one or more of the D- or L-isomers of the naturally occurring amino acids.

36. The composition of claim 25, wherein said polypeptide comprises the amino acid sequence selected from the group 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 (SEQ ID NO:

34), Glu-Glu-Phe-Phe-Phe [SEQ ID NO;

151, Tyr-Tyr-Ile, Asp-Asp-Ile, Tyr-Tyr-Phe-Phe-Phe-Ile (SEQ ID NO;

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

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

31], Glu-Glu-Phe-Phe-Leu (SEQ ID NO;

10], {Lys-Lys-Gly-Gly (SEQ ID NO;

     35), and [(1)-Lys-(d)-Lys-Leu]₂.

37. The composition of claim 25, wherein the dosage form is a tablet, a capsule, oral solution, an oral suspension, or a controlled release formulation.

39. The composition of claim 24, wherein said chemical moiety is a polypeptide of fewer than eight amino acids.

33-35. -35. (canceled)

38. (canceled)

40-85. -85. (canceled)

86. A compound comprising oxycodone covalently attached to one or more peptide.

87. The compound of claim 86 comprising oxycodone covalently attached to one or more peptide comprising the amino acid sequence selected from the group consisting of Pro-Pro-Ile. Phe-Phe-Lys-Phe-Phe [SEQ ID NO:

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

33], Tyr-Tyr-Phe, Phe-Phe-Leu, Phe-Phe-Val, Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe-Ile [SEQ ID NO;

34]. Tyr-Tyr-Ile, Lys-Lys-Val, Asp-Asp-Val, Tyr-Tyr-Val, Pro-Pro-Val, Glu-Glu-Val, and Thr-Thr-Val.

88. The compound of claim 87, wherein said one or more peptide comprises the amino acid sequence Pro-Pro-Ile.

89. A composition comprising a compound of claim 86.

209. A composition comprising the compound from claim 87.

90-93. -93. (canceled)

94. A compound comprising oxycodone covalently bound to a single amino acid a dipeptide, a tripeptide, a tetrapeptide, or a pentapeptide.

222. A composition comprising the compound from claim 94.

95-99. -99. (canceled)

100. A compound selected from:

(Bio-Gly₂-Ile)₂-oxycodone,

(Bio-Gly₂-Leu)₂-oxycodone,

(Gal-Gly₂-Ile)₂-oxycodone

(Gal-Gly₂-Leu)₂-oxycodone,

(Gal-Prθ

2-Ile)₂-oxycodone,

(Gal-Prθ

2-Leu)₂-oxycodone,

(Glu)₂-oxycodone,

(Glu-Asp-Val)₂-oxycodone,

(Gly-Leu-Val)₂-oxycodone,

(Ile)₂-oxycodone,

(Ile-Tyr-Val)₂-oxycodone,

(Ile-Tyr-Val)-oxycodone-(Gly-Tyr-Ile),

(He-Tyr-Val)-oxycodone-(Val-Glu-Gly),

(Leu)₂-oxycodone,

(Leu-Tyr-Val)-oxycodone-(Gly-Tyr-Leu),

(Leu-Tyr-Val)-oxycodone-(Val-Glu-Gly),

(Lvs)₂-oxycodone,

(Lys-Lys-Gly-Gly)₂-oxycodone [SEQ ID NO;

35],

(Lys-Ser-Val)₂-oxycodone,

(Nia-Gly₉-Ile)₂-oxycodone,

(Nia-Gly₂-Leu)₂-oxycodone,

(Phe)₂-oxycodone,

(Phe-Val-Val)₂-oxycodone,

(Ser-Thr-Val)₂-oxycodone,

(Tyr-Pro-Val)₂-oxycodone,

(Val)₂-oxycodone,

[(1)-Lys-(d)-Lys-Leu]₂-oxycodone,

[Glu-Pro-Val]₂-oxycodone,

[Glu-Tyr-Val]₂-oxycodone,

[Gly₂-Lys(-Gly₂)]2-oxycodone [SEQ ID NO;

36],

[Gly-Glu-Val]₂-oxycodone,

[Gly-Tyr-Valj₂-oxycodone,

[Ile-Tyr-Val]₂-oxycodone,

[Leu-Tyr-Val]₂-oxycodone,

[Pro-Glu-Val]₂-oxycodone,

[Ser-Gly-Val]₂-oxycodone,

[Tyr-Tyr-Val]₂-oxycodone,

[Val-Glu-Val]₂-oxycodone,

Ala-Ala-Val-oxycodone,

Asp-Asp-Ile-oxycodone,

Asp-Asp-Val-oxycodone,

Glu-Glu-Ala-oxycodone,

Glu-Glu-Ile-oxycodone,

Glu-Glu-Leu-oxycodone,

Glu-Glu-Phe-oxycodone,

Glu-Glu-Phe-Phe-Ile-oxycodone [SEQ ID NO;

34],

Glu-Glu-Phe-Phe-Phe-oxycodone [SEQ ID NO;

15],

Glu-Glu-Pro-oxycodone,

Glu-Glu-β

-Ala-oxycodone,

Glu-Glu-Val-oxycodone,

Glu-Leu-Val-oxycodone,

Glu-Tyr-Val-oxycodone,

Gly-Gly-Ile-oxycodone,

Gly-Gly-Leu-oxycodone,

Gly-Gly-Phe-oxycodone,

Gly-Gly-β

-Ala-oxycodone,

Gly-Gly-Val-oxycodone,

Ile-Ile-Ile-oxycodone,

Ile-oxycodone,

Ile-Tyr-Val-oxycodone,

Leu-Leu-Ala-oxycodone,

Leu-Leu-Leu-oxycodone,

Leu-Leu-Val-oxycodone,

Leu-Leu-β

-Ala-oxycodone,

Leu-oxycodone,

Lys-Lys-Ala-oxycodone,

Lys-Lys-Ile-oxycodone,

Lys-Lys-Leu-oxycodone,

Lys-Lys-oxycodone,

Lys-Lys-Phe-oxycodone,

Lys-Lys-Val-oxycodone,

Lys-Lys-β

-Ala-oxycodone,

oxycodone-succinate,

oxycodone-β

-alanine,

Phe-oxycodone,

Phe-Phe-Ile-oxycodone,

Phe-Phe-Leu-oxycodone,

Phe-Phe-Lys-Phe-Phe-oxycodone [SEQ ID NO;

31],

Phe-Phe-Val-oxycodone,

Pro₂-Ile-oxycodone,

Pro₂-Leu-oxycodone,

Pro-Glu-Val-oxycodone,

Pro-Pro-Ala-oxycodone,

Pro-Pro-Ile-oxycodone,

Pro-Pro-Leu-oxycodone,

Pro-Pro-Val-oxycodone,

Thr-Thr-Val-oxycodone,

Tyr-Tyr-Ala-oxycodone,

Tyr-Tyr-Ile-oxycodone,

Tyr-Tyr-Leu-oxycodone,

Tyr-Tyr-Lys-Tyr-Tyr-oxycodone [SEQ ID NO;

33],

Tyr-Tyr-Phe-oxycodone,

Tyr-Tyr-Phe-Phe-Ile-oxycodone [SEQ ID NO;

27],

Tyr-Tyr-β

-Ala-oxycodone,

Tyr-Tyr-Val-oxycodone,

Val-oxycodone,

Val-oxycodone-Gly,

Val-Val-Leu-oxycodone,

Val-Val-oxycodone,

Val-Val-Phe-oxycodone, or

Val-Val-Val-oxycodone.

223. A composition comprising the compound from claim 100.

101-208. -208. (canceled)

210-221. -221. (canceled)