Compositions comprising enzyme-cleavable oxycodone prodrug

1. A composition comprising a trypsin inhibitor and N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, shown below:

or acceptable salts thereof.

2. The composition of claim 1 , wherein the trypsin inhibitor is an arginine mimic or a lysine mimic.

3. The composition of claim 2 , wherein the arginine mimic or lysine mimic is a synthetic compound.

4. The composition of claim 1 , 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.

5. The composition of claim 1 , 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.

6. The composition of claim 1 , 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.

7. The composition of claim 1 , 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.

8. The composition of claim 1 , 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.

9. The composition of claim 1 , 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.

10. The composition of claim 1 , 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.

11. The composition of claim 1 , wherein the trypsin inhibitor is 6-carbamimidoylnaphthalen-2-yl-4-(diaminomethyleneamino)benzoate (Compound 109).

12. A method of treating or preventing pain in a patient in need thereof, which comprises administering an effective amount of a composition of claim 1 to the patient.