Opioid compositions resistant to overdose and abuse

1. A composition comprising a macromolecule of Formula (I):

and a therapeutically-effective amount of a macromolecule of Formula (II):

or pharmaceutically acceptable salts thereof, wherein:

PD is a gastrointestinal enzyme-labile opioid agonist prodrug and the gastrointestinal enzyme-labile opioid agonist prodrug is:

wherein:

Y is H or OH;

AA is a natural or unnatural amino acid side chain that is recognized by the gastrointestinal enzyme; and

R is independently hydrogen, methyl, ethyl, substituted alkyl, acyl, a natural or unnatural amino acid, or a polypeptide comprising up to 10 natural and/or unnatural amino acids;

I is a gastrointestinal enzyme inhibitor and the gastrointestinal enzyme inhibitor is:

X 2 is independently at each occurrence absent or

that joins I to a polymer P 2 wherein: k and m are independently at each occurrence an integer from 0 to 10;

X 1 is independently at each occurrence absent or an ether, an ester, a thioester, an amide, an amine, a carbamate, a carbonate, a thioether, or a urea, wherein the nitrogen atom of the amide, amine, or carbamate, is substituted or unsubstituted and the nitrogen atoms of the urea are each independently substituted or unsubstituted, that joins PD to a polymer P 1 ;

each P 1 and P 2 is independently a polyalkylene glycol; and

n is independently an integer from 1 to 2.

2. The composition of claim 1 , wherein P 1 and P 2 are identical.

3. The composition of claim 1 , wherein P 1 and P 2 have equal molecular weights.

4. The composition of claim 1 , wherein the macromolecules of Formula (I) and Formula (II) are each independently formulated in an immediate release matrix or in an extended release matrix.

5. The composition of claim 1 , wherein some or all of the macromolecule of Formula (I) is formulated in an extended release matrix and the macromolecule of Formula (II) is formulated in an immediate release matrix.

6. The composition of claim 1 , wherein the polymers P 1 and P 2 are each polyethylene glycol.

7. The composition of claim 1 , wherein the gastrointestinal enzyme is trypsin.

8. The composition of claim 1 , wherein the gastrointestinal enzyme releases an opioid agonist from the PD.

9. The composition of claim 1 , wherein the gastrointestinal enzyme-labile opioid agonist prodrug is:

wherein:

Y is H or OH;

AA is a side chain of lysine or arginine; and

R is independently hydrogen, methyl, ethyl, or a natural or unnatural amino acid.

10. The composition of claim 3 , wherein the molecular weights are from about 1,500 to about 50,000 Da.

11. The composition of claim 1 , wherein P 1 and P 2 have molecular weights, independently, from about 1,500 to about 50,000 Da.

12. The composition of claim 6 , wherein the macromolecule of Formula (I) is:

wherein:

k and m are each independently an integer from 0 to 3;

p is independently an integer from 2 to 1,000; and

R 1 is hydrogen, methyl or ethyl; or

pharmaceutically acceptable salts thereof.

13. The composition of claim 12 , wherein the macromolecule of Formula (I) is:

herein p is an integer from 10 to 200; or

pharmaceutically acceptable salts thereof.

14. The composition of claim 9 , wherein the macromolecule of Formula (I) is:

the macromolecule of Formula (II) is:

wherein Y is H or OH, and AA is a side chain of lysine or arginine; and

wherein p is independently at each occurrence an integer from 10 to 200; or

pharmaceutically acceptable salts thereof.

15. The composition of claim 14 , wherein the macromolecule of Formula (I) is:

and the macromolecule of Formula (II) is:

or pharmaceutically acceptable salts thereof.