Pharmaceutical formulations of antineoplastic agents and processes of making and using the same

1. A pharmaceutical formulation comprising Temozolomide or a pharmaceutically acceptable salt thereof, at least one aqueous diluent, and at least one dissolution enhancing agent sufficient to substantially dissolve said Temozolomide, wherein said dissolution enhancing agent is selected from the group consisting of urea, L-histidine, L-threonine, L-asparagine, L-serine, and L-glutamine.

2. The pharmaceutical formulation according to claim 1 , further comprising an excipient selected from the group consisting of polysorbate, polyethylene glycol, propylene glycol, polypropylene glycol, and mixtures thereof.

3. The pharmaceutical formulation according to claim 2 , wherein said excipient is selected from the group consisting of polysorbate 20, polysorbate 80, and mixtures thereof.

4. The pharmaceutical formulation according to claim 1 , further comprising at least one bulking agent.

5. The pharmaceutical formulation according to claim 4 , wherein said bulking agent is selected from the group consisting of mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hetastarch, cellulose, cyclodextrins, glycine, and mixtures thereof.

6. The pharmaceutical formulation according to claim 1 , wherein said bulking agent is mannitol.

7. The pharmaceutical formulation according to claim 1 , further comprising at least one buffer.

8. The pharmaceutical formulation according to claim 7 , wherein said buffer is selected from the group consisting of lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium citrate heptahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, calcium citrate heptahydrate, lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium maleate, sodium maleate, potassium maleate, calcium maleate, lithium tartarate, sodium tartarate, potassium tartarate, calcium tartarate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate. sodium acetate, potassium acetate, calcium acetate, and mixtures thereof.

9. The pharmaceutical formulation according to claim 8 , wherein said buffer is selected from the group consisting of lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium citrate heptahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, calcium citrate heptahydrate and mixtures thereof.

10. The pharmaceutical formulation according to claim 1 , further comprising a pH adjuster.

11. The pharmaceutical formulation according to claim 10 , wherein said pH adjuster is selected from the group consisting of hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid, and mixtures thereof.

12. The pharmaceutical formulation according to claim 11 , wherein said pH adjuster is hydrochloric acid.

13. The pharmaceutical formulation according to claim 1 , wherein the pH of said formulation ranges from about 2.5 to about 6.0.

14. The pharmaceutical formulation according to claim 13 , wherein the pH of said formulation ranges from about 3.0 to about 4.5.

15. The pharmaceutical formulation according to claim 14 , wherein the pH of said formulation ranges from about 3.8 to about 4.2.

16. The pharmaceutical formulation according to claim 1 wherein said aqueous diluent is selected from the group consisting of water, normal saline, 5% dextrose solution, and mixtures thereof.

17. The pharmaceutical formulation according to claim 1 , wherein said dissolution enhancing agent is urea and wherein said pharmaceutical formulation further comprises hydrochloric acid, at least one citrate buffer, and mannitol.

18. The pharmaceutical formulation according to claim 16 , wherein said Temozolomide is present in an amount ranging from about 1 wt % to about 50 wt %, said hydrochloric acid is present in an amount ranging from about 1 wt % to about 20 wt %, said citrate buffer(s) is present in an amount ranging from about 5 wt % to about 60 wt %, said urea is present in an amount ranging from about 4 wt % to about 60 wt %, and said mannitol is present in an amount ranging from about 10 wt % to about 85 wt %.

19. The pharmaceutical formulation according to claim 1 , wherein said dissolution enhancing agent is selected from the group consisting of L-histidine, L-threonine, L-asparagine, L-serine, and L-glutamine, and wherein said pharmaceutical formulation further comprises polysorbate, hydrochloric acid, at least one citrate buffer, mannitol, and water.

20. The pharmaceutical formulation according to claim 19 , wherein said Temozolomide is present in an amount ranging from about 1 wt % to about 50 wt %, said hydrochloric acid is present in an amount ranging from about 1 wt % to about 20 wt %, said citrate buffer(s) is present in an amount ranging from about 5 wt % to about 60 wt %, said polysorbate is present in an amount ranging from about 1 wt % to about 50 wt %, said dissolution enhancing agent is present in an amount ranging from about 2 wt % to about 60 wt %, and said mannitol is present in an amount ranging from about 15 wt % to about 85 wt %.