Isoproterenol compositions and methods
Storage stable aqueous ready-to-administer formulations comprising isoproterenol are presented with desirable stability characteristics. In preferred aspects, formulations are terminally sterilized and packaged in a suitable format, such as a polymeric bag with metalized overwrap and include a non-contact oxygen scavenger.
1. A storage stable sterile ready-to-administer pharmaceutical composition, comprising:
a buffered aqueous solution comprising isoproterenol at a concentration of between 1-10 mcg/mL;
wherein the buffered aqueous solution has a pH range of between 3.0 and 4.5 and wherein the buffer is a tartrate buffer and has a concentration of equal to or less than 10 mM;
wherein the solution further comprises ethylenediamine tetraacetic acid (EDTA) as a chelating agent at a concentration of about 5 mcg/mL and a tonicity agent;
wherein the ready-to-administer composition contains, after storage over at least three weeks at 60° C. in a container having a headspace that has not been flushed with an inert gas, equal to or less than 2.0% of total impurities formed from degradation of the isoproterenol, and
wherein the composition is formulated for intravenous administration and is antioxidant free.
2. The composition of claim 1 wherein the isoproterenol is present at a concentration of 4.0±0.2 mcg/mL.
3. The composition of claim 1 wherein the buffered aqueous solution has a pH range of between 3.5 and 4.2.
4. The composition of claim 1 wherein the buffered aqueous solution has a pH of 4.0±0.2.
5. The composition of claim 1 wherein the buffer has a concentration of equal to or less than 1 mM.
6. The composition of claim 1 wherein the buffer has a concentration of 1 mM or 0.25 mM.
7. The composition of claim 1 wherein the tonicity agent is NaCl and is present in an amount of equal to or less than 9 mg/mL.
8. The composition of claim 1 wherein the tonicity agent is present in an amount that generates a tonicity between 260 and 320 mOsm.
9. The composition of claim 1 wherein the ready-to-administer composition contains, after storage over at least three weeks at 60° C., equal to or less than 1.5% of total impurities formed from degradation of the isoproterenol.
10. The composition of claim 1 wherein the ready-to-administer composition is an autoclaved composition or filter sterilized composition.
11. A kit comprising a primary container and a pharmaceutical composition disposed in the primary container, wherein the pharmaceutical composition is the storage stable sterile ready-to-administer pharmaceutical composition of claim 1 , and wherein the pharmaceutical composition is present in the primary container at a volume of between 10 mL and 150 mL.
12. The kit of claim 11 wherein the primary container is disposed in a secondary container, and wherein the secondary container comprises a metal or is light impermeable.
13. The kit of claim 12 further comprising a non-contact oxygen absorber disposed in a space between the primary container and the secondary container.
14. The kit of claim 11 wherein the volume is 100 mL.
15. A method of preparing a storage stable liquid sterile ready-to administer pharmaceutical composition, comprising:
formulating a liquid parenteral composition for intravenous administration that contains in a buffered aqueous acidic solution isoproterenol, a chelating agent, and a tonicity agent;
wherein the buffered aqueous acidic solution has a pH range of between 3.0 and 4.5, wherein the buffer is a tartrate buffer, and wherein the buffer has a concentration of equal to or less than 10 mM;
wherein the isoproterenol is present in the composition at a concentration of between 1 and 10 mcg/mL;
wherein the chelating agent is ethylenediamine tetraacetic acid (EDTA) and is present at a concentration of equal to or less than 10 mcg/mL; and
sterilizing the liquid parenteral composition via thermal sterilization to obtain the storage stable liquid sterile ready-to-administer pharmaceutical composition,
wherein the liquid sterile ready-to-administer pharmaceutical composition contains, after storage over at least three weeks at 60° C. in a container having a headspace that has not been flushed with an inert gas, equal to or less than 2.0% of total impurities formed from degradation of the isoproterenol.
16. The method of claim 15 wherein the isoproterenol is present at a concentration of 4.0±0.2 mcg/mL, and/or wherein the buffered aqueous solution has a pH of 4.0±0.2.
17. The method of claim 15 wherein the buffer has a concentration of 1 mM or 0.25 mM, and/or wherein the chelating agent is present at a concentration of 5±2 mcg/mL.
18. The method of claim 15 further comprising a step of packaging the composition into a primary container, packaging the primary container into a secondary container, and placing a non-contact oxygen absorber in a space between the primary container and the secondary container.