Formulations of Factor VIIa inhibitors and utility

1. A method for treating a subject having a vascular disorder, said method comprising administering a therapeutic effective amount of a nanoparticle to the subject to treat the disorder, wherein the vascular disorder is selected from the group consisting of sickle cell disease, an angiogenesis-mediated disorder, pulmonary hypertension, and combinations thereof, and wherein the nanoparticle comprises a poly L-arginine polymer and a Factor VIIa inhibitor conjugated to or encapsulated in the poly L-arginine polymer, wherein the Factor VIIa inhibitor is selected from the group consisting of:

Factor VIIa inhibitor I

in which R 1 is independently selected from the group consisting of hydrogen and a NO donor at positions 3, 4, 5, and 6;

Factor VIIa inhibitor II

in which R 1 is independently selected from the group consisting of hydrogen and a NO donor at positions 3, 4, and 6 and in which R 2 is independently selected from the group consisting of hydrogen and a NO donor at positions 2, 4, 5, and 6,

wherein for each position at which R 2 is independently selected as the NO donor, the NO donor is selected independently from the group consisting of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 ;

Factor VIIa inhibitor III

in which R 1 is independently selected from the group consisting of hydrogen and a NO donor at positions 3, 4, 5, and 6; and

Factor VIIa inhibitor IV

in which R 1 is independently selected from the group consisting of hydrogen and a NO donor at positions 3, 4, and 5;

wherein the Factor VIIa inhibitor includes at least one NO donor, and

wherein for each position in each Factor VIIa inhibitor of Factor VIIa inhibitors I, II, III, and IV at which R 1 is independently selected as the NO donor, the NO donor is selected independently from the group consisting of

O═N—S—  (R 11 ),

—ONO 2   (R 12 ),

—CH 2 ONO 2   (R 13 ),

—CH 2 CH 2 ONO 2   (R 14 ),

—C(═NOH)(CH 2 ) 3 ONO 2   (R 15 ),

—CH 2 CH(ONH 2 )CH 2 ONO 2   (R 16 ),

2. The method of claim 1 , wherein the Factor VIIa inhibitor is encapsulated in the poly L-arginine polymer and is not covalently bonded to the poly L-arginine polymer.

3. The method of claim 1 , wherein the Factor VIIa inhibitor is conjugated to the poly L-arginine polymer by being covalently bonded to the poly L-arginine polymer.

4. The method of claim 1 , wherein the poly L-arginine polymer is cross-linked with at least one substance selected from the group consisting of chitosan, poly(lactic-co-glycolic) acid (PLGA), fatty acids, bile acids, amino acids, hyaluronic acid, and combinations thereof.

5. The method of claim 1 , wherein the poly L-arginine polymer is cross-linked to chitosan.

6. The method of claim 1 , wherein the therapeutic effective amount is in a range of 0.1-10 mg per kilogram of body weight of the subject.

7. The method of claim 1 , wherein the vascular disorder is the angiogenesis-mediated disorder.

8. The method of claim 7 , wherein the angiogenesis-mediated disorder comprises breast cancer, pancreatic cancer, prostate cancer, or combinations thereof.

9. The method of claim 7 , wherein the angiogenesis-mediated disorder comprises tumor angiogenesis, tumor growth, or a combination thereof.

10. The method of claim 7 , wherein the angiogenesis-mediated disorder comprises an ocular angiogenesis-mediated disorder.

11. The method of claim 10 , wherein the ocular angiogenesis-mediated disorder is selected from the group consisting of diabetic retinopathy and macular degeneration.

12. The method of claim 1 , wherein the vascular disorder comprises pulmonary hypertension.

13. The method of claim 1 , wherein the vascular disorder comprises sickle cell disease.

14. A method for treating a subject having a vascular disorder, said method comprising administering a therapeutic effective amount of a chemical structure to the subject to treat the disorder, wherein the vascular disorder is selected from the group consisting of sickle cell disease, an angiogenesis-mediated, pulmonary hypertension, and combinations thereof, and wherein the chemical structure comprises Factor VIIa inhibitor that includes at least one nitric oxide (NO) donor, wherein the Factor VIIa inhibitor is selected from the group consisting of:

Factor VIIa inhibitor I

in which R 1 is a NO donor at positions 3, 4, 5, and 6;

Factor VIIa inhibitor II

in which R 1 is a NO donor at position 3, 4, and 6 and in which R 2 is a NO donor at position 2, 4, 5, and 6,

wherein for each position of R 2 , the NO donor is selected independently from the group consisting of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 ;

which is Factor VIIa inhibitor III

in which R 1 is a NO donor at positions 3, 4, 5, and 6; and

Factor VIIa inhibitor IV

in which R 1 is a NO donor at positions 3, 4, and 5;

wherein for each position in each Factor VIIa inhibitor of Factor VIIa inhibitors I, II, III, and IV at which R 1 exists as the NO donor, the NO donor is selected independently from the group consisting of

O═N—S—  (R 11 ),

—ONO 2   (R 12 ),

—CH 2 ONO 2   (R 13 ),

—CH 2 CH 2 ONO 2   (R 14 ),

—C(═NOH)(CH 2 ) 3 ONO 2   (R 15 ),

—CH 2 CH(ONH 2 )CH 2 ONO 2   (R 16 ),

15. The method of claim 14 , wherein the therapeutic effective amount is in a range of 0.1-10 mg per kilogram of body weight of the subject.

16. The method of claim 14 , wherein the vascular disorder is the angiogenesis-mediated disorder.

17. The method of claim 16 , wherein the angiogenesis-mediated disorder comprises breast cancer, pancreatic cancer, prostate cancer, or combinations thereof.

18. The method of claim 16 , wherein the angiogenesis-mediated disorder comprises tumor angiogenesis, tumor growth, or a combination thereof.

19. The method of claim 16 , wherein the angiogenesis-mediated disorder comprises an ocular angiogenesis-mediated disorder.

20. The method of claim 19 , wherein the ocular angiogenesis-mediated disorder is selected from the group consisting of diabetic retinopathy and macular degeneration.

21. The method of claim 14 , wherein the vascular disorder comprises pulmonary hypertension.

22. The method of claim 14 , wherein the vascular disorder comprises sickle cell disease.