Pharmaceutical formulation of nitrooxyderivatives of NSAIDs

1. A gelatin capsule comprising a filling, the filling consisting essentially of:

a) one or more NO-releasing NSAID(s) of formula (I)

b) one or more surfactants wherein the ratio of surfactant to NO-releasing NSAID is from 0.1:1 to 10:1;

c) a carbonyl scavenger compound selected from the group consisting of: free acid forms, salts, and carboxylic acid esters derivatives of a compound of formula (II)

H 2 N—(CH 2 ) m —(C 6 H 4 )—COOH  (II)

 wherein m=0-10, wherein the amount of the compound of formula (II) is from about 0.01% to about 5% by weight of the total weight of the composition;

wherein in formula (I)

M is selected from the group consisting of:

 X is a spacer selected from the group consisting of:

i) straight or branched C 1 -C 20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO 2 and T, wherein T is —OC(O)(C 1 -C 10 alkyl)-ONO 2 or —O(C 1 -C 10 alkyl)-ONO 2 ;

ii) C 5 -C 7 cycloalkylene group optionally substituted with linear or branched C 1 -C 10 alkyl group;

iii)

wherein n is an integer from 0 to 20; and

n 1 is an integer from 1 to 20; wherein the —ONO 2 group of formula (I) is bound to —(CH 2 ) n 1 ; and

iv)

wherein

X 2 is —O— or —S—;

n 3 is an integer from 1 to 6, and R 2 is H or CH 3 .

2. The pharmaceutical formulation according to claim 1 wherein the amount of the compound of formula (II) is from about 0.01% to about 2% by weight of the total weight of the composition.

3. The pharmaceutical formulation according to claim 1 wherein the amount of the compound of formula (II) is from about 0.01% to about 1% by weight of the total weight of the composition.

4. The pharmaceutical formulation according to claim 1 , wherein the ratio of surfactant to NO-releasing NSAID is from 0.3:1 to 3:1.

5. The pharmaceutical formulation according to claim 1 , wherein the surfactant is non-ionic.

6. The pharmaceutical formulation according to claim 5 , wherein the surfactant is a poloxamer.

7. The pharmaceutical formulation according to claim 1 , wherein the compound of formula (II) is p-aminobenzoic acid.

8. The pharmaceutical formulation according to claim 1 wherein the NO-releasing NSAID of formula (I) is selected from the group consisting of:

9. The pharmaceutical formulation according to claim 1 wherein the NO-releasing NSAID of formula (I) is the compound of formula (IA)

10. The pharmaceutical formulation according to claim 9 wherein

b) the surfactant is poloxamer 407 and the ratio of surfactant to compound (Ia) is 0.6; and

c) the compound of formula (II) is p-aminobenzoic acid and the amount of p-aminobenzoic acid is about the 0.1% by weight of the total weight of the composition.

11. The pharmaceutical formulation according to claim 9 wherein

b) the surfactant is poloxamer 407 and the ratio of surfactant to compound (Ia) is 0.6; and

c) the compound of formula (II) is p-aminobenzoic acid and the amount of p-aminobenzoic acid is about the 0.5% by weight of the total weight of the composition.

12. The pharmaceutical formulation according to claim 1 , wherein X is a straight or branched C 1 -C 10 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO 2 and T, wherein T is —OC(O)(C 1 -C 10 alkyl)-ONO 2 or —O(C 1 -C 10 alkyl) —ONO 2 .

13. The pharmaceutical formulation according to claim 1 , wherein X is a C 5 -C 7 cycloalkylene group optionally substituted with CH 3 .

14. The pharmaceutical formulation according to claim 1 , wherein n is an integer from 0 to 5.

15. The pharmaceutical formulation according to claim 1 , wherein n 1 is an integer from 1 to 5.

16. The pharmaceutical formulation according to claim 1 , wherein n 3 is an integer from 1 to 4.