Fulvestrant formulations
The invention provides a fulvestrant composition comprising a pharmaceutically acceptable alcohol, polysorbate 80 , an antioxidant, and castor oil, which is substantially or completely free of a non-aqueous ester solvent and which demonstrates excellent storage stability. The composition may be used to treat hormone receptor positive metastatic breast cancer in a subject.
1. A composition, comprising:
fulvestrant,
a pharmaceutically acceptable alcohol,
polysorbate 80 ,
an antioxidant, and
castor oil,
wherein the composition is substantially free of a non-aqueous ester solvent.
2. The composition of claim 1 , wherein the composition is completely free of a non-aqueous ester solvent.
3. The composition of claim 1 , wherein the antioxidant is a vitamin E compound.
4. The composition of claim 3 , wherein the vitamin E compound is α-tocopherol.
5. The composition of claim 1 , wherein the pharmaceutically acceptable alcohol comprises a mixture of ethanol and benzyl alcohol.
6. The composition of claim 5 , wherein the ethanol and benzyl alcohol are present in approximately equivalent w/v amounts.
7. The composition of claim 6 , comprising 10% w/v ethanol and 10% w/v benzyl alcohol.
8. The composition of claim 1 , wherein the castor oil is characterized by a carbonyl value of 0.5 micromole/gram or less, a peroxide value of 5.0 meq O 2 /kg or less, an iodine value of 85 g iodine/100 g castor oil or less, and/or a Gardner 1933 value of 1.5 or less.
9. The composition of claim 1 , wherein following storage of the composition at 25° C. for a period of 3 months, the amount of total impurities present in the composition is not more than 1%.
10. The composition of claim 1 , wherein following storage of the composition at 25° C. for a period of 3 months, the amount of fulvestrant sulfone present in the composition is not more than 0.5%.
11. The composition of claim 1 , comprising 5-10% w/v fulvestrant, 10-30% w/v pharmaceutically acceptable alcohol, and 0.05-0.2% w/v polysorbate 80 .
12. A syringe comprising 2.5 mL-5 mL of the composition of claim 1 .
13. A vial comprising 2.5 mL-5 mL of the composition of claim 1 .
14. A composition, comprising:
5% w/v fulvestrant,
10% ethanol,
10% benzyl alcohol,
0.12% w/v polysorbate 80 ,
0.06% a-tocopherol, and
castor oil,
wherein the composition is substantially free of a non-aqueous ester solvent.
15. A method of stabilizing a fulvestrant composition, comprising forming a mixture comprising:
5-10% w/v fulvestrant,
10-30% w/v pharmaceutically acceptable alcohol,
0.05-0.2% w/v polysorbate 80 ,
an antioxidant, and
castor oil,
thereby stabilizing a fulvestrant composition,
wherein the mixture is substantially free of a non-aqueous ester solvent.
16. The method of claim 15 , wherein following storage of the composition at 25° C. for a period of 3 months, the amount of total impurities present in the composition is not more than 1%.
17. A method of treating hormone receptor positive metastatic breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the composition of claim 1 to the subject, thereby treating the hormone receptor positive metastatic breast cancer in the subject.