Nanoparticulate compositions and formulations of piperazine compounds
The present invention relates to storage stable nanoparticulate compositions of piperazine compounds. The pharmaceutical compositions comprising the nanoparticulate compositions that are useful for the treatment and prevention of proliferative diseases including cancer are also described.
1. A method for treating a tumor, comprising administering to an animal in need thereof a stable composition comprising nanoparticles, wherein the nanoparticles comprise:
(a) a compound of formula (1),
or a pharmaceutically acceptable salt thereof,
wherein
X and Y are independently N or C—R 7 ;
R 1 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl or halogen and R 2 is F; or
R 1 is F and R 2 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl or halogen;
R 3 is C 1 -C 3 alkyl; and
R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylcarbonyl, cyano, nitro or halogen; and
(b) at least one surface stabilizer comprising a poloxamer selected from poloxamer 407 or poloxamer 338, wherein the nanoparticles have an effective median particle size (D50) of less than about 1,000 nm.
2. The method of claim 1 , wherein the compound of formula (1) is 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl]piperazine or its pharmaceutically acceptable salt.
3. The method of claim 1 , wherein the composition is in the form of a liquid suspension or a dry powder.
4. The method of claim 1 , wherein the composition is stable after storage for at least about four weeks.
5. The method of claim 1 , wherein the effective median particle size of the nanoparticles is less than about 500 nm.
6. The method of claim 1 , wherein the composition has a ratio (wt/wt) of the compound of formula (1) to the surface stabilizer of from about 100:1 to about 5:1.
7. The method of claim 1 , wherein said tumor is selected from the group consisting of breast cancer, lung cancer, esophageal cancer, gastric cancer, small bowel cancer, large bowel cancer, rectal cancer, glioma, sarcoma involving bone, cartilage, soft tissue, muscle, blood or lymph vessels, ovarian cancer, myeloma, lymphoma, leukemia, cervical cancer, endometrial cancer, head and neck cancer, mesothelioma, renal cancer, ureter cancer, bladder cancer, urethral cancer, colon cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, and melanoma.
8. The method of claim 1 , wherein said tumor is selected from the group consisting of ovary tumors, breast tumors, prostate tumors, liver tumors, lung tumors, kidney tumors, colon tumors, pancreatic tumors, stomach tumors, and endothelial cancers.
9. The method of claim 1 , further comprising administering at least one additional chemotherapeutic agent.
10. The method of claim 1 , wherein the composition is administered orally.
11. A method of treating a tumor that is refractory to treatment, comprising administering to an animal in need thereof a stable composition comprising a mixture of (a) nanoparticles of a compound of formula (1),
or a pharmaceutically acceptable salt thereof,
wherein
X and Y are independently N or C—R 7 ;
R 1 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl or halogen and R 2 is F; or
R 1 is F and R 2 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl or halogen;
R 3 is C 1 -C 3 alkyl; and
R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylcarbonyl, cyano, nitro or halogen; and
(b) at least one surface stabilizer comprising a poloxamer selected from poloxamer 407 or poloxamer 338, wherein the nanoparticles have an effective median particle size of less than about 1,000 nm.
12. The method of claim 11 , wherein the refractory to treatment is due to multidrug resistance.
13. The method of claim 11 , further comprising administering at least one additional chemotherapeutic agent.
14. The method of claim 11 , wherein the mixture comprises from about 5% to about 50% by weight of the compound of formula (1) or pharmaceutically acceptable salt thereof, and from about 0.1% to about 5% by weight of the surface stabilizer.
15. The method of claim 11 , wherein the mixture comprises from about 75% to about 90% by weight of the compound of formula (1) or pharmaceutically acceptable salt thereof, and from about 10% to about 25% by weight of the surface stabilizer.
16. The method of claim 11 , wherein the composition has a ratio (wt/wt) of the compound of formula (1) to the surface stabilizer of from about 100:1 to about 5:1.
17. The method of claim 11 , wherein the compound of formula (1) is 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl]piperazine or its pharmaceutically acceptable salt.
18. The method of claim 11 , wherein said tumor is selected from the group consisting of breast cancer, lung cancer, esophageal cancer, gastric cancer, small bowel cancer, large bowel cancer, rectal cancer, glioma, sarcoma involving bone, cartilage, soft tissue, muscle, blood or lymph vessels, ovarian cancer, myeloma, lymphoma, leukemia, cervical cancer, endometrial cancer, head and neck cancer, mesothelioma, renal cancer, ureter cancer, bladder cancer, urethral cancer, colon cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, and melanoma.
19. The method of claim 11 , wherein said tumor is selected from the group consisting of ovary tumors, breast tumors, prostate tumors, liver tumors, lung tumors, kidney tumors, colon tumors, pancreatic tumors, stomach tumors, and endothelial cancers.
20. The method of claim 11 , wherein the composition is in the form of a liquid suspension or a dry powder.
21. The method of claim 11 , wherein the composition is administered orally.
22. The method of claim 1 , wherein said tumor is selected from the group consisting of gastrointestinal cancer, sarcoma, and skin cancer.
23. The method of claim 11 , wherein said tumor is selected from the group consisting of gastrointestinal cancer, sarcoma, and skin cancer.