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 method of manufacturing a ready to inject bortezomib-containing pharmaceutical article comprising:
formulating a liquid parenteral formulation that contains bortezomib such that the formulation exhibits equal or less than 10% degradation of the bortezomib at accelerated conditions after 3 months;
wherein the liquid parenteral formulation is prepared as a single-phase liquid formulation that comprises a substantially non-aqueous solvent system suitable for injection and including at least 50 vol % propylene glycol, an aqueous buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration; and
packaging the liquid parenteral formulation in an amount sufficient for at least two distinct uses into a container, wherein the container is configured to allow providing multiple independent dosages of the liquid formulation.
2. The method of claim 1 wherein the liquid parenteral formulation is formulated such as to exhibit equal or less than 6% degradation of the bortezomib at ambient conditions after 3 months.
3. The method of claim 1 wherein the substantially non-aqueous solvent system includes at least 75 vol % propylene glycol.
4. The method of claim 1 wherein the liquid parenteral formulation has a pH that is equal or less than 4.0.
5. The method of claim 1 wherein the aqueous buffer has a buffer strength of between 0.05 and 0.25M.
6. The method of claim 1 wherein the bortezomib is present in the liquid parenteral formulation in an amount of between 0.5 mg/ml and 5.0 mg/ml.
7. The method of claim 1 wherein the amount is sufficient for at least ten distinct uses.
8. The method of claim 1 wherein the liquid parenteral formulation is formulated to allow storage at accelerated conditions over at least 1 month after first use without significant degradation of the bortezomib.
9. A bortezomib-containing pharmaceutical article, comprising:
a liquid parenteral formulation contained in a container suitable for providing multiple independent dosages of the liquid formulation;
wherein the liquid parenteral formulation is a single-phase liquid formulation and comprises a substantially non-aqueous solvent system suitable for injection that includes at least 50 vol % propylene glycol, an aqueous buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration;
wherein the liquid parenteral formulation is present in an amount sufficient for at least two distinct uses; and
wherein the liquid parenteral formulation is formulated such as to exhibit equal or less than 10% degradation of bortezomib at accelerated storage conditions after 3 months.
10. The pharmaceutical article of claim 9 wherein the container is a vial or a bag and contains the liquid formulation in an amount sufficient for at least five distinct uses.
11. The pharmaceutical article of claim 9 wherein the liquid parenteral formulation is sterile, and wherein the liquid formulation has not undergone lyophilization before accelerated storage for 3 months.
12. The pharmaceutical article of claim 9 wherein the substantially non-aqueous solvent system includes at least 75 vol % propylene glycol.
13. The pharmaceutical article of claim 12 wherein the liquid parenteral formulation has a pH that is equal or less than 4.0.
14. The pharmaceutical article of claim 13 wherein the aqueous buffer has a buffer strength of between 0.05 and 0.25M.
15. The pharmaceutical article of claim 13 wherein the aqueous buffer is an acetate buffer.
16. A method of using the bortezomib-containing parenteral formulation of claim 9 , comprising:
withdrawing from a container a first dosage of a liquid bortezomib-containing pharmaceutical parenteral formulation for a first administration, wherein the container contains at least a second dosage of the liquid bortezomib-containing pharmaceutical parenteral formulation for a second administration;
storing the at least second dosage for at least one week;
withdrawing from the container the at least second dosage for the second administration.
17. The method of claim 16 further comprising a step of withdrawing from the container at least a third dosage.
18. The method of claim 16 wherein the step of storing comprises storage at 4° C. or ambient condition.
19. The method of claim 16 wherein the container is configured to include the liquid bortezomib-containing pharmaceutical formulation in an amount sufficient for at least ten distinct uses.
20. The method of claim 16 wherein the substantially non-aqueous solvent system includes at least 75 vol % propylene glycol, a buffer having a pH of equal or less than 4.0, and bortezomib at a concentration of between 0.5 mg/ml and 5.0 mg/ml.