Parenteral CCI-779 formulations containing cosolvents, an antioxidant, and a surfactant
View Patent ↗Parenteral formulations of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl) -2-methylpropionic acid (CCI-779) are provided. One parenteral formulation contains CCI-779, an alcoholic co-solvent, and an antioxidant. Another parenteral formulation contains CCI-779, an alcoholic solvent, an antioxidant, a diluent solvent, and a surfactant. Processes for preparing parenteral CCI-779 formulations using a co-solvent concentrate are also provided.
1. A parenteral composition comprising:
(i) a first mixture of about 1 to about 25 mg/mL of CCI-779, about 15 to about 60% w/v of dehydrated ethanol, about 0.01 to about 0.1% w/v of d,1-α-tocopherol, about 0.001 to about 0.005% w/v of citric acid, and about 15 to about 60% w/v of propylene glycol, and
(ii) a second mixture of about 15 to about 60% w/v of polysorbate 80, 15 to 60% w/v of polyethylene glycol 400, and about 15 to about 60% w/v of dehydrated ethanol.
2. The parenteral composition according to claim 1 , wherein (i) and (ii) are present in a ratio of about 1:1.5 to 1:2.
3. The parenteral composition according to claim 1 , comprising about 10 mg/mL of CCI-779.
4. The parenteral composition according to claim 1 , comprising about 0.0025 to about 0.005% w/v of citric acid.
5. The parenteral composition according to claim 1 , comprising:
(i) a first mixture of about 25 mg/mL CCI-779, about 40% w/v of dehydrated ethanol, about 0.075% w/v of d,1-a-tocopherol, about 0.0025% w/v of citric acid, and 35% w/v propylene glycol, and
(ii) a second mixture of about 20% w/v of dehydrated ethanol, about 40% w/v of polysorbate 80, and about 40% w/v of polyethylene glycol 400.
6. The parenteral composition according to claim 5 , wherein (i) and (ii) are present in a ratio of about 1:1.5.
7. The parenteral composition according to claim 1 , comprising:
(i) a first mixture of about 1 to about 25 mg/mL of CCI-779, about 40% w/v of dehydrated ethanol, about 0.075% w/v of d,1-α-tocopherol, about 0.0025% w/v of citric acid, and q.s. of propylene glycol, and
(ii) a second mixture of about 40% w/v of polysorbate 80, about 20% w/v of polyethylene glycol 400, and about 40% w/v of dehydrated ethanol.
8. A parenteral composition comprising:
(i) a first mixture of about 1 to about 25 mg/mL of CCI-779, about 15 to about 60% w/v of dehydrated ethanol, about 0.01 to about 0.1% w/v of d,1-α-tocopherol, and about 15 to about 60% w/v of propylene glycol, and
(ii) a second mixture of about 15 to about 60% w/v of polysorbate 80, 15 to 60% w/v of polyethylene glycol 400, and about 15 to about 60% w/v of dehydrated ethanol.
9. A parenteral composition consisting of:
(i) a concentrate of about 1 to about 25 mg/mL of CCI-779, about 0.01 to 0.1% w/v of d,1-α-tocopherol, about 0.001 to about 0.005% w/v of citric acid, and about 15 to about 60% w/v of dehydrated ethanol and propylene glycol, and
(ii) a diluent of about 15 to about 60% w/v of polysorbate 80, 15 to 60% w/v of polyethylene glycol 400, and about 15 to about 60% w/v of dehydrated ethanol.
10. The parenteral composition according to claim 9 , wherein (i) and (ii) are present in a ratio of about 1:1.5 to 1:2 of concentrate to diluent.
11. The parenteral composition according to claim 9 , consisting of about 10 mg/mL of CCI-779.
12. A parenteral composition consisting of
(i) a concentrate of about 1 to about 25 mg/mL of CCI-779, about 0.01 to 0.1% w/v of d,1-α-tocopherol, and about 15 to about 60% w/v of dehydrated ethanol and propylene glycol, and
(ii) a diluent of about 15 to about 60% w/v of polysorbate 80, 15 to 60% w/v of polyethylene glycol 400, and about 15 to about 60% w/v of dehydrated ethanol.
13. A parenteral composition comprising:
(i) about 1 to about 25 mg/mL of CCI-779,
(ii) about 0.01 to 0.1% w/v of d,1-α-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.
14. The parenteral composition according to claim 13 , wherein the ratio of polysorbate 80 to polyethylene glycol 400 is about 1:1.
15. The parenteral composition according to claim 13 , wherein the ratio of dehydrated ethanol to propylene glycol in (iv) is about 1.4:1.
16. The parenteral composition according to claim 13 , wherein the ratio of component (iv) to (i) is about 50:1.
17. The parenteral composition according to claim 13 , wherein the ratio of component (v) to (i) is about 50:1.
18. A parenteral composition comprising:
(i) about 1 to about 25 mg/mL of CCI-779,
(ii) about 0.01 to 0.1% w/v of d,1-α-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, wherein the ratio of dehydrated ethanol to propylene glycol is about 1.4:1, and
(v) about 15 to about 60% w/v of a combination of polysorbate 80 and polyethylene glycol 400, wherein the ratio of polysorbate 80 to polyethylene glycol 400 is about 1:1;
wherein:
the ratio of mixture (iv) to (i) is about 50:1; and
the ratio of mixture (v) to (i) is about 50:1.
19. A parenteral composition comprising:
(i) about 1 to about 25 mg/mL of CCI-779,
(ii) about 0.01 to 0.1% w/v of d,1-α-tocopherol,
(iii) about 15 to about 60% w/v of a combination of dehydrated ethanol and propylene glycol, wherein the ratio of dehydrated ethanol to propylene glycol is about 1.4:1, and
(iv) about 15 to about 60% w/v of a combination of polysorbate 80 and polyethylene glycol 400, wherein the ratio of polysorbate 80 to polyethylene glycol 400 is about 1:1;
wherein:
the ratio of mixture (iii) to (i) is about 50:1; and
the ratio of mixture (iv) to (i) is about 50:1.
20. A parenteral composition comprising:
(i) about 2.5% w/v of CCI-779, about 0.075% w/v of d,1-α-tocopherol, about 0.0025% w/v of citric acid, about 40% w/v of dehydrated ethanol, and about 50% w/v of propylene glycol, and
(ii) about 40% w/v of polysorbate 80, about 20% w/v of dehydrated ethanol, and about 43% w/v of polyethylene glycol 400.
21. The parenteral composition according to claim 20 , wherein (i) and (ii) are present in a ratio of about 1:1.5 to 1:2.
22. A parenteral composition comprising:
(i) about 1% w/v of CCI-779,
(ii) about 0.03% w/v of d,1-α-tocopherol,
(iii) about 0.001% w/v of citric acid,
(iv) about 28% w/v of dehydrated ethanol,
(v) about 20% w/v propylene glycol,
(vi) about 24% w/v of polysorbate 80 and
(vii) about 26% w/v of polyethylene glycol 400.
23. A process for preparing a parenteral composition of claim 1 , said process comprising combining mixtures (i) and (ii).
24. The process according to claim 23 , further comprising combining mixtures (i) and (ii) with water.