Compositions of buprenorphine and μ antagonists

1. A composition comprising buprenorphine and a μ opioid receptor antagonist, wherein the composition is characterized by an Agonist Antagonist Activity Index (AAnAI) of between about 0.7 and about 2.2; wherein;

AAnAI

=

[

C

max

⁡

(

BUP

)

/

EC

50

]

[

C

max

⁡

(

ANTAGONIST

)

/

IC

50

]

wherein, EC 50 represents the half maximal effective serum concentration of buprenorphine, expressed as nM;

IC 50 represents the half maximal inhibitory concentration of the μ opioid antagonist in humans, expressed as nM;

C max(BUP) represents the peak serum or plasma concentration of buprenorphine and/or a μ opioid receptor agonist metabolite of buprenorphine, expressed as nM; and

C max(ANTAGONIST) represents the peak serum concentration of the μ opioid antagonist and/or a μ opioid receptor antagonist metabolite of said μ opioid antagonist, expressed as nM.

2. The composition according to claim 1 , wherein said AAnAI is between about 0.8 and about 2.1, or between about 0.9 and about 2.0, or between about 1.0 and about 1.8, or between about 1.1 and about 1.6, or between about 1.2 and about 1.4.

3. The composition according to claim 1 , wherein said antagonist is a compound of Formula I:

or a pharmaceutically acceptable salt, ester or prodrug thereof wherein;

s is 0, 1 or 2;

t is 0, 1, 2, 3, 4, 5, 6, or 7;

X is S or O;

R 1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently selected from absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl;

each R 9 and R 10 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

alternatively, two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 together with the atoms they are attached to form an optionally substituted ring; alternatively R 2 and R 3 together with the carbon they are attached to form a C═X group; wherein each R 20 and R 21 is independently selected from absent, hydrogen, halogen, —OH, —SH, —NH 2 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OH, —C(O)NH 2 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; and

alternatively R 9 and R 10 together with the atom they are attached to form an optionally substituted ring; alternatively two R 5 groups, or an R 5 and an R 6 group, together with the carbon they are attached to form a C═X group.

4. The composition according to claim 3 , wherein said antagonist is a compound of Formula II:

or a pharmaceutically acceptable salt, ester or prodrug thereof wherein;

R 1 is —(CH 2 ) n -c-C 3 H 5 , —(CH 2 ) n -c-C 4 H 7 , —(CH 2 ) n -c-C 5 H 9 , —(CH 2 ) n —CH═CH 2 or —(CH 2 ) n —CH═C(CH 3 ) 2 wherein n and m are independently 0, 1, 2 or 3;

R 6 and R 7 are independently H, —OH or together R 6 and R 7 form an —O— or —S— group; and

R 5 and R 11 are independently H, —OH, OCH 3 or together R 5 and R 1 form a ═O or ═CH 2 group.

5. The composition according to claim 4 , wherein said antagonist is selected from:

6. A composition comprising buprenorphine and a compound of Formula I:

or a pharmaceutically acceptable salt, ester or prodrug thereof wherein;

s is 0, 1 or 2;

t is 0, 1, 2, 3, 4, 5, 6, or 7;

X is S or O;

R 1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently selected from absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl;

Each R 9 and R 10 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

alternatively, two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 together with the atoms they are attached to form an optionally substituted ring; alternatively R 2 and R 3 together with the carbon they are attached to form a C═X group; wherein each R 20 and R 21 is independently selected from absent, hydrogen, halogen, —OH, —SH, —NH 2 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OH, —C(O)NH 2 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; and

alternatively R 9 and R 10 together with the atom they are attached to form an optionally substituted ring; alternatively two R 5 groups, or an R 5 and an R 6 group, together with the carbon they are attached to form a C═X group.

7. The composition according to claim 6 , wherein said compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt, ester or prodrug thereof wherein;

R 1 is —(CH 2 ) n -c-C 3 H 5 , —(CH 2 ) n -c-C 4 H 7 , —(CH 2 ) n -c-C 5 H 9 , —(CH 2 ) n —CH═CH 2 or —(CH 2 ) n —CH═C(CH 3 ) 2 wherein n and m are independently 0, 1, 2 or 3;

R 6 and R 7 are independently H, —OH or together R 6 and R 7 form an —O— or —S— group; and

R 5 and R 11 are independently H, —OH, OCH 3 or together R 5 and R 1 form a ═O or ═CH 2 group.

8. The composition according to claim 6 , wherein said compound of Formula I is selected from:

9. A composition according to claim 3 , wherein said compound of Formula I is:

or its pharmaceutically acceptable salt, ester or prodrug.

10. A composition comprising about 1 mg to about 100 mg of buprenorphine and about 0.25 to about 100 mg of a compound of Formula I.

11. The composition of claim 10 comprising about 2 mg to about 50 mg of buprenorphine.

12. The composition of claim 10 comprising about 3 to about 25 mg of buprenorphine.

13. The composition of claim 10 comprising about 3 to about 10 mg of buprenorphine.

14. The composition according to claim 11 comprising about 0.25 to about 50 mg of a compound of Formula I.

15. The composition according to claim 10 comprising about 0.5 to about 25 mg of a compound of Formula I.

16. The composition according to claim 10 comprising about 1.0 to about 20 mg of a compound of Formula I.

17. The composition according to claim 10 comprising about 2.0 to about 10 mg of a compound of Formula I.

18. The composition according to claim 10 wherein said compound of Formula I is a compound of Formula II.

19. The composition according to claim 10 wherein said compound of Formula I is selected from:

20. The composition according to claim 10 , wherein said compound of Formula I is:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

21. A composition according to claim 1 , wherein said composition has an AAnAI of about 1.3.