Claims for Patent: 8,722,700

Summary for Patent: 8,722,700

Title:	CCI-779 formulations for parenteral administration
Abstract:	This invention provides CCI-779 cosolvent concentrates which are useful in preparing a parenteral formulation of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) following admixture with a diluent.
Inventor(s):	Rubino; Joseph T. (Towaco, NJ), Siskavich; Victoria (Lyon Mountain, NY), Harrison; Maureen M. (Sugar Loaf, NY), Gandhi; Pooja (Highland Mills, NY)
Assignee:	Wyeth LLC (Madison, NJ)
Application Number:	13/892,389
Patent Claims:	1. A method for administering a parenteral CCI-779 formulation to a subject in need thereof, said method comprising: (i) mixing CCI-779 with about 15 to about 60% w/v of dehydrated ethanol, about 0.01 to about 0.1% of d,1-.alpha.-tocopherol, about 0.001 to about 0.005% w/v of citric acid, and about 15 to about 60% w/v of propylene glycol to provide a cosolvent concentrate comprising about 1 to about 25 mg/mL of CCI-779; (ii) mixing about 15 to about 60% w/v of polysorbate 80, about 15 to 60% w/v of polyethylene glycol 400, and about 15 to about 60% w/v of dehydrated ethanol to provide a diluent; (iii) mixing said cosolvent concentrate and said diluent; and (iv) administering the product of step (iii) to said subject. 2. The method according to claim 1, wherein the ratio of said cosolvent concentrate to diluent is about 1:1.5 to about 1:2. 3. The method according to claim 1, wherein said parenteral CCI-779 formulation is administered by direct injection. 4. The method according to claim 1, further comprising: (v) mixing the product of step (iii) with water. 5. The method according to claim 4, wherein said water is a sterile infusion fluid. 6. The method according to claim 5, wherein said parenteral CCI-779 formulation is administered by intravenous infusion. 7. The method according to claim 1, wherein said cosolvent concentrate comprises about 25 mg/mL CCI-779, about 40% w/v of dehydrated ethanol, about 0.075% w/v of d,1-.alpha.-tocopherol, 0.0025% w/v of citric acid, and about 35% w/v propylene glycol. 8. The method according to claim 1, wherein said diluent comprises 20% w/v of dehydrated ethanol, about 40% w/v of polysorbate 80, and about 40% w/v of polyethylene glycol 400. 9. A CCI-779 direct injection fluid, said fluid comprising: (i) about 1 to about 25 mg/mL of CCI-779; (ii) about 0.01 to about 0.1% w/v of d,1-.alpha.-tocopherol; (iii) about 0.001 to about 0.005% w/v of citric acid; (iv) about 15 to about 60% w/v of a combination of dehydrated ethanol and propylene glycol; and (v) about 15 to about 60% w/v of a combination of polysorbate 80 and polyethylene glycol 400. 10. The CCI-779 direct injection fluid according to claim 9, wherein the ratio of dehydrated ethanol to propylene glycol in component (vi) is about 1.4:1. 11. The CCI-779 direct injection fluid according to claim 9, wherein the ratio of polysorbate 80 to polyethylene glycol 400 in component (v) is about 1:1. 12. The CCI-779 direct injection fluid according to claim 9, wherein the ratio of mixture (iv) to mixture (i) is about 50:1. 13. The CCI-779 direct injection fluid according to claim 9, wherein the ratio of mixture (vi) to component (i) is about 50:1. 14. The CCI-779 direct injection fluid according to claim 9, comprising about 1% w/v of CCI-779, about 0.03% w/v of d,1-.alpha.-tocopherol, about 0.001% w/v of citric acid, about 28% w/v of dehydrated ethanol, about 20% w/v of propylene glycol, about 24% w/v of polysorbate 80, and about 25% w/v of polyethylene glycol 400. 15. A CCI-779 intravenous infusion solution comprising: (i) about 1 to about 25 mg/mL of CCI-779, about 0.01 to about 0.1% w/v of d,1-.alpha.-tocopherol, about 0.001 to about 0.005% w/v of citric acid, about 15 to about 60% w/v of a combination of dehydrated ethanol and propylene glycol, and about 15 to about 60% w/v of a combination of polysorbate 80 and polyethylene glycol 400; and (ii) a sterile infusion fluid. 16. The CCI-779 intravenous infusion solution according to claim 15, wherein the ratio of dehydrated ethanol to propylene glycol is about 1.4:1. 17. The CCI-779 intravenous infusion solution according to claim 15, wherein the ratio of polysorbate 80 to polyethylene glycol 400 is about 1:1. 18. The CCI-779 intravenous infusion solution according to claim 15, wherein the ratio of the combination of dehydrated ethanol and propylene glycol to CCI-779 is about 50:1. 19. The CCI-779 intravenous infusion solution according to claim 15, wherein the ratio of the combination of polysorbate 80 and polyethylene glycol 400 to CCI-779 is about 50:1. 20. The CCI-779 intravenous infusion solution according to claim 15, wherein said component (i) comprises about 1% w/v of CCI-779, about 0.03% w/v of d,1-.alpha.-tocopherol, about 0.001% w/v of citric acid, about 28% w/v of dehydrated ethanol, about 20% w/v of propylene glycol, about 24% w/v of polysorbate 80, and about 25% w/v of polyethylene glycol 400. 21. A method of solubilizing CCI-779 in a solution, said method comprising mixing about 1 to about 25 mg/mL of CCI-779, about 0.01 to about 0.1% w/v of d,1-.alpha.-tocopherol, about 0.001 to about 0.005% w/v of citric acid, about 15 to about 60% w/v of a combination of dehydrated ethanol and propylene glycol, and about 15 to about 60% w/v of a combination of polysorbate 80 and polyethylene glycol 400. 22. A method of stabilizing a solution comprising CCI-779, said method comprising mixing about 1 to about 25 mg/mL of said CCI-779 with about 15 to about 60% w/v of dehydrated ethanol, about 0.01 to about 0.1% of of d,1-.alpha.-tocopherol, about 0.001 to about 0.005% w/v of critic acid, and about 15 to about 60% w/v of propylene glycol. 23. A method of stabilizing a solution comprising CCI-779, said method comprising mixing about 1 to about 25 mg/mL of said CCI-779 with about 0.01 to about 0.1% w/v of d,1-.alpha.-tocopherol, about 0.001 to about 0.005% w/v of citric acid, about 15 to about 60% w/v of a combination of dehydrated ethanol and propylene glycol, and about 15 to about 60% w/v of a combination of polysorbate 80 and polyethylene glycol 400. 24. A method of preventing precipitation of CCI-779 in an aqueous infusion solution or blood, said method comprising: (i) mixing CCI-779 with about 15 to about 60% w/v of dehydrated ethanol, about 0.01 to about 0.1% of d,1-.alpha.-tocopherol, about 0.001 to about 0.005% w/v of citric acid, and about 15 to about 60% w/v of propylene glycol to provide a cosolvent concentrate comprising about 1 to about 25 mg/mL of CCI-779; (ii) mixing about 15 to about 60% w/v of polysorbate 80, about 15 to 60% w/v of polyethylene glycol 400, and about 15 to about 60% w/v of dehydrated ethanol to provide a diluent; (iii) mixing said cosolvent concentrate and said diluent; and (iv) adding the product of step (iii) to said aqueous infusion solution or blood.