Compositions comprising enzyme-cleavable oxycodone prodrug

1. N-1-[(S)-2-(oxycodone-6-enol-carbonyl-methyl-amino)-2-carbonyl-sarcosine-ethyl amine]-arginine-glycine-acetate, Compound KC-7, shown below:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. A composition comprising N-1-[(S)-2-(oxycodone-6-enol-carbonyl-methyl-amino)-2-carbonyl-sarcosine-ethyl amine]-arginine-glycine-acetate, Compound KC-7, shown below:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. A method of treating or preventing pain in a patient in need thereof, which comprises administering a therapeutically effective amount of a compound of claim 1 to the patient.

4. A composition comprising a trypsin inhibitor and N-1-[(S)-2-(oxycodone-6-enol-carbonyl-methyl-amino)-2-carbonyl-sarcosine-ethyl amine]-arginine-glycine-acetate, Compound KC-7, shown below:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

5. The composition of claim 4 , wherein the trypsin inhibitor is an arginine mimic or a lysine mimic.

6. The composition of claim 5 , wherein the arginine mimic or lysine mimic is a synthetic compound.

7. The composition of claim 4 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 1 is selected from —O-Q 4 or -Q 4 -COOH, where Q 4 is C 1 -C 4 alkyl;

Q 2 is N or CH; and

Q 3 is aryl or substituted aryl.

8. The composition of claim 4 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 5 is —C(O)—COOH or —NH-Q 6 -Q 7 -SO 2 —C 6 H 5 , where

Q 6 is —(CH 2 ) p —COOH;

Q 7 is —(CH 2 ) r —C 6 H 5 ;

Q 8 is NH;

n is a number from zero to two;

o is zero or one;

p is an integer from one to three; and

r is an integer from one to three.

9. The composition of claim 4 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 5 is —C(O)—COOH or —NH-Q 6 -Q 7 -SO 2 —C 6 H 5 , where

Q 6 is —(CH 2 ) p —COOH;

Q 7 is —(CH 2 ) r —C 6 H 5 ; and

p is an integer from one to three; and

r is an integer from one to three.

10. The composition of claim 4 , wherein the trypsin inhibitor is a compound of formula:

wherein

X is NH;

n is zero or one; and

R t1 is selected from hydrogen, halogen, nitro, alkyl, substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, aminoacyl, guanidine, amidino, carbamide, amino, substituted amino, hydroxyl, cyano and —(CH 2 ) m —C—(O)—O—(CH 2 ) m —C(O)—N—R n1 R n2 , wherein each m is independently zero to 2; and R n1 and R n2 are independently selected from hydrogen and C 1-4 alkyl.

11. The composition of claim 4 , wherein the trypsin inhibitor is a compound of formula:

wherein

X is NH;

n is zero or one;

L t1 is selected from —C(O)—O—; —O—C(O)—; —O—(CH 2 ) m —O—; —OCH 2 —Ar t2 —CH 2 O—; —C(O)—Nr t3 —; and —NR t3 —C(O)—;

R t3 is selected from hydrogen, C 1-6 alkyl, and substituted C 1-6 alkyl;

Ar t1 and Ar t2 are independently a substituted or unsubstituted aryl group;

m is a number from 1 to 3; and

R t2 is selected from hydrogen, halogen, nitro, alkyl, substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, aminoacyl, guanidine, amidino, carbamide, amino, substituted amino, hydroxyl, cyano and —(CH 2 ) m —C(O)—O—(CH 2 ) m —C(O)—N—R n1 R n2 , wherein each m is independently zero to 2; and R n1 and R n2 are independently selected from hydrogen and C 1-4 alkyl.

12. The composition of claim 4 , wherein the trypsin inhibitor is a compound of formula:

wherein

each X is NH;

each n is independently zero or one;

L t1 is selected from —C(O)—O—; —O—C(O)—; —O—(CH 2 ) m —O—; —OCH 2 —Ar t2 —CH 2 O—; —C(O)—NR t3 —; and —NR t3 —C(O)—;

R t3 is selected from hydrogen, C 1-6 alkyl, and substituted C 1-6 alkyl;

Ar t1 and Ar t2 are independently a substituted or unsubstituted aryl group; and

m is a number from 1 to 3.

13. The composition of claim 4 , wherein the trypsin inhibitor is selected from

(S)-ethyl 4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazine-1-carboxylate;

(S)-ethyl 4-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperazine-1-carboxylate;

(S)-ethyl 1-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperidine-4-carboxylate;

(S)-ethyl 1-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperidine-4-carboxylate;

(S)-6-(4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazin-1-yl)-6-oxohexanoic acid;

4-aminobenzimidamide;

3-(4-carbamimidoylphenyl)-2-oxopropanoic acid;

(S)-5-(4-carbamimidoylbenzylamino)-5-oxo-4-((R)-4-phenyl-2-(phenylmethylsulfonamido)butanamido)pentanoic acid;

6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate; and

4,4′-(pentane-1,5-diylbis(oxy))dibenzimidamide.

14. The composition of claim 4 , wherein the trypsin inhibitor is 6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate (Compound 109).

15. A method of treating or preventing pain in a patient in need thereof, which comprises administering a therapeutically effective amount of a compound of claim 4 to the patient.

16. A method for reducing drug abuse potential of a composition containing a compound of claim 1 , the method comprising: combining Compound KC-7 with a trypsin inhibitor, wherein the trypsin inhibitor reduces the ability of a user to release oxycodone from Compound KC-7 by addition of trypsin.

17. A composition comprising:

a prodrug comprising oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-7: (N-1-[(S)-2-(oxycodone-6-enol-carbonyl-methyl-amino)-2-carbonyl-sarcosine-ethyl amine]-arginine-glycine-acetate), Compound KC-7, shown below:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and

a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of oxycodone from the prodrug following ingestion of the composition.

18. A method to treat a patient comprising administering a composition of claim 17 to a patient in need thereof.

19. A method of making a dose unit, the method comprising: combining in a dose unit:

a prodrug comprising oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-7; and

a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of oxycodone from the prodrug;

wherein the prodrug and trypsin inhibitor are present in the dose unit in an amount effective to attenuate release of oxycodone from the prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of oxycodone.

20. A method of claim 19 , wherein said release of oxycodone is decreased compared to release of oxycodone by an equivalent dosage of prodrug in the absence of inhibitor.

21. A method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:

combining a prodrug, a trypsin inhibitor, and trypsin in a reaction mixture, wherein the prodrug comprises oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-7; and

detecting prodrug conversion,

wherein a decrease in prodrug conversion in the presence of the trypsin inhibitor as compared to prodrug conversion in the absence of the trypsin inhibitor indicates the prodrug and trypsin inhibitor are suitable for formulation in a dose unit.

22. A method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:

administering to an animal a prodrug and a trypsin inhibitor, wherein the prodrug comprises oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-7; and

detecting prodrug conversion, wherein a decrease in oxycodone conversion in the presence of the trypsin inhibitor as compared to oxycodone conversion in the absence of the trypsin inhibitor indicates the prodrug and trypsin inhibitor are suitable for formulation in a dose unit.

23. The method of claim 22 , wherein said administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of prodrug.

24. The method of claim 22 , wherein said detecting facilitates identification of a dose of inhibitor and a dose of prodrug that provides for a pre-selected pharmacokinetic (PK) profile.

25. The method of claim 22 , wherein said method comprises an in vivo assay.

26. The method of claim 22 , wherein said method comprises an ex vivo assay.

27. A method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:

administering to an animal tissue a prodrug and a trypsin inhibitor, wherein the prodrug comprises oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-7; and

detecting prodrug conversion, wherein a decrease in prodrug conversion in the presence of the trypsin inhibitor as compared to prodrug conversion in the absence of the trypsin inhibitor indicates the prodrug and trypsin inhibitor are suitable for formulation in a dose unit.

28. A compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. A composition of claim 2 , wherein the composition comprises N-1-[(S)-2-(oxycodone-6-enol-carbonyl-methyl-amino)-2-carbonyl-sarcosine-ethyl amine]-arginine-glycine-acetate, Compound KC-7, shown below:

or a pharmaceutically acceptable salt thereof.

30. A method of treating or preventing pain in a patient in need thereof, which comprises administering a therapeutically effective amount of a composition of claim 2 to the patient.

31. A method of treating or preventing pain in a patient in need thereof, which comprises administering a therapeutically effective amount of a composition of claim 17 to the patient.