Nanoparticulate compositions and formulations of piperazine compounds

1. A stable composition comprising nanoparticles; wherein the nanoparticles comprise:

(a) the compound of formula (1),

or pharmaceutically acceptable salts 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 H, 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 composition of claim 1 , wherein the compound of formula 1 is 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl]piperazine.

3. The composition of claim 1 , in the form of a liquid suspension or a dry powder.

4. The composition of claim 1 , wherein the composition is stable after storage for at least four weeks.

5. The composition of claim 1 , wherein the effective median particle size is of less than about 500 nm.

6. The composition of claim 1 , wherein the ratio (wt/wt) of the compound of formula (1) to surface stabilizer is from about 100:1 to about 5:1.

7. A method of making a storage stable composition comprising preparing a mixture of

(a) particles of a compound of formula (1),

or pharmaceutically acceptable salts thereof,

wherein

X and Y are independently N or C—R 7 ;

for the combination of variables R 1 and R 2 :

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 H, 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, and

reducing the size of the particles of a compound of the formula (1) under conditions sufficient to provide a nanoparticulate suspension having an effective median particle size of less than about 1,000 nm, thereby producing a stable composition.

8. The method of claim 7 , further comprising drying the nanoparticulate suspension, by lyophilization, to form a powder.

9. The method of claim 7 , wherein the mixture comprises from about 5% to about 50% of the compound of formula 1 and from about 0.1% to about 5% of the surface stabilizer.

10. The method of claim 7 , wherein the powder comprises from about 75% to about 90% of the compound formula 1 and from about 10% to about 25% of the surface stabilizer.

11. The method of claim 7 , wherein the ratio of the compound of formula (1) to surface stabilizer is from about 100:1 to about 5:1.

12. The method of claim 7 , wherein the reducing comprises grinding, homogenizing or precipitating.

13. The method of claim 12 , wherein the reducing comprises grinding from about 360 to about 600 minutes.

14. The method of claim 7 , wherein the compound of formula 1 is 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl]piperazine.

15. The method of claim 7 , further comprising adding water to the mixture after reducing the size of the particles.

16. A pharmaceutical composition comprising the composition of claim 1 and at least one pharmaceutically acceptable excipient.

17. The pharmaceutical composition of claim 16 , wherein the at least one pharmaceutically acceptable excipient comprises water or hydroxypropyl methylcellulose.

18. The pharmaceutical composition of claim 16 , wherein the composition is an oral dosage form or a parenteral dosage form.

19. The pharmaceutical composition of claim 16 , comprising about 0.01 to about 250 mg of the compound of formula (1).