Pharmaceutical compositions for prevention of overdose or abuse
View Patent ↗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.
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.
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.
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.