Stable bortezomib formulations
Multi-dose formulations for bortezomib are presented in which bortezomib has significantly improved stability. Especially preferred formulations include those in which bortezomib is in a liquid form suitable for injection, wherein the solvent system predominantly comprises propylene glycol. In other preferred aspects, bortezomib is present as a Lewis donor-acceptor complex with a hetero-bifunctional Lewis base.
1. A storage-stable liquid pharmaceutical composition that includes bortezomib in a therapeutically effective amount, the composition comprising:
a single-phase liquid formulation comprising a substantially non-aqueous solvent system suitable for injection, an aqueous acetate buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration;
wherein the solvent system comprises as a predominant component propylene glycol, and wherein the buffer has a pH of 3; and
wherein the solvent system, the buffer, and the pH are selected such as to be effective to suppress formation of at least one of an amide degradation product, a first carbinolamide degradation product, and a second carbinolamide degradation product when the liquid formulation is stored under storage conditions.
2. The composition of claim 1 wherein the substantially non-aqueous solvent system consists essentially of propylene glycol.
3. The composition of claim 1 wherein the formulation comprises at least 70 vol % propylene glycol.
4. The composition of claim 1 wherein the formulation comprises at least 90 vol % propylene glycol.
5. The composition of claim 1 wherein the liquid formulation is stored for at least 15 days under storage conditions.
6. The composition of claim 5 wherein the storage conditions comprises storage at 50° C.
7. The composition of claim 1 wherein the bortezomib is present at a concentration of between 1 mg/ml and 5 mg/ml.
8. The composition of claim 7 wherein the buffer is an aqueous acetate buffer at a concentration of between 0.05 and 0.25M.
9. The pharmaceutical composition of claim 1 in a container, wherein the container is a vial, an ampoule, an intravenous bag, or a syringe, and wherein the container is optionally configured as a multi-use container.
10. The container of claim 9 comprising a quantity of the liquid formulation that is suitable for independent multiple administrations.
11. A method of suppressing formation of a plurality of degradation products of bortezomib in solution, comprising:
compounding a single-phase liquid formulation from a substantially non-aqueous solvent system suitable for injection, an aqueous acetate buffer, and bortezomib, wherein the bortezomib is present in the formulation at a pharmaceutically effective concentration;
wherein the solvent system comprises as a predominant component propylene glycol and wherein the buffer has a pH of 3; and
wherein the solvent system, the buffer, and the pH are selected such as to be effective to suppress formation of at least one of an amide degradation product, a first carbinolamide degradation product, and a second carbinolamide degradation product when the liquid formulation is stored under storage conditions.
12. The method of claim 11 wherein the substantially non-aqueous solvent system consists essentially of propylene glycol.
13. The method of claim 12 wherein the buffer is an acetate buffer at a concentration of between 0.05 and 0.25M.
14. The method of claim 11 wherein the bortezomib is present at a concentration of between 1 mg/ml and 5 mg/ml.
15. The method of claim 11 wherein the storage conditions comprise storage at 50° C. over 15 days.