PACKAGED, SEALED CONTAINER SYSTEM FOR STABLE STORAGE OF AN OXYGEN SENSITIVE PHARMACEUTICAL FORMULATION
A packaged, sealed container system for stable storage of a formulation of an oxygen-sensitive pharmaceutical compound, the packaged, sealed container system comprising a primary container including therein a formulation of an oxygen-sensitive pharmaceutical compound, a secondary outer container comprising a first flexible sheet layer, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers, such that the primary container is disposed between and enclosed by the first and second flexible sheet layers of the secondary outer container. An oxygen scavenger is also disposed between and enclosed by the first and second flexible sheet layers of the secondary outer container. The oxygen scavenger is in fluid communication with the contents of the primary container.
1 .- 29 . (canceled)
30 . A packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation, the packaged, sealed container system comprising:
a primary container comprising a ready-to-use, stable norepinephrine formulation therein, the ready-to-use, stable norepinephrine formulation comprising:
about 0.015 mg/ml to about 0.035 mg/ml norepinephrine; a tonicity agent; and
a pH between 3.4 and 4.0;
wherein the ready-to-use, stable norepinephrine formulation is free of an antioxidant;
a secondary container comprising a first flexible sheet, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers, wherein the primary container is disposed between and enclosed by the first and second flexible sheet layers of the secondary container; and
an oxygen scavenger disposed between and enclosed by the first and second flexible sheet layers of the secondary container, the oxygen scavenger being in fluid communication with the contents of the primary container,
wherein the primary container is an intravenous (IV) bag; and
wherein the ready-to-use, stable norepinephrine formulation does not comprise sodium chloride,
wherein the norepinephrine is in the form of norepinephrine bitartrate monohydrate,
wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.5 ppm after storage for at least 150 days at 25° C., and
wherein the ready-to-use, stable norepinephrine formulation retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25° C.
31 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 30 , wherein the second flexible sheet layer has a water transmission rate less than 3.0 g/m 2 /day.
32 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 30 , wherein the oxygen scavenger comprises iron powder, iron oxide powder, or a mixture thereof.
33 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 30 , wherein the concentration of norepinephrine is between about 0.015 mg/ml and about 0.020 mg/ml.
34 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 30 , wherein the concentration of norepinephrine is between about 0.030 mg/ml and about 0.035 mg/ml.
35 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 30 , wherein the pH is between about 3.5 and about 3.9.
36 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 30 , wherein the pH is between about 3.6 and about 3.8.
37 . The packaged, sealed container system according to claim 30 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.1 ppm after storage for at least 150 days at 25° C.
38 . The packaged, sealed container system according to claim 30 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.5 ppm after storage for at least 180 days at 25° C.
39 . The packaged, sealed container system according to claim 30 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.1 ppm after storage for at least 180 days at 25° C.
40 . A packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation, the packaged, sealed container system comprising:
a primary container comprising a ready-to-use, stable norepinephrine formulation therein, wherein the primary container is an intravenous (IV) bag;
a secondary container comprising a first flexible sheet layer, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers, wherein the primary container is disposed between and enclosed by the first and second flexible sheet layers of the secondary container; and
an oxygen scavenger disposed between and enclosed by the first and second flexible sheet layers of the secondary container, the oxygen scavenger being in fluid communication with the contents of the primary container,
wherein the ready-to-use, stable norepinephrine formulation consists essentially of about 0.015 mg/ml to about 0.035 mg/ml norepinephrine; a tonicity agent;
water; and
optionally, hydrochloric acid and/or sodium hydroxide as pH adjusters,
wherein the ready-to-use, stable norepinephrine formulation has a pH between 3.4 and 4.0, and has a dissolved oxygen level of less than 0.5 ppm after storage for at least 150 days at 25° C.,
wherein the ready-to-use, stable norepinephrine formulation retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25° C., and
wherein the norepinephrine is in the form of norepinephrine bitartrate monohydrate.
41 . The packaged, sealed container system according to claim 40 , wherein the norepinephrine is present at a concentration of 0.015 mg/ml to 0.020 mg/ml or 0.030 to 0.035 mg/ml.
42 . The packaged, sealed container system according to claim 40 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.1 ppm after storage for at least 150 days at 25° C.
43 . The packaged, sealed container system according to claim 40 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.5 ppm or less than 0.1 ppm_after storage for at least 180 days at 25° C.
44 . A packaged, sealed container system comprising:
a ready-to-use, stable norepinephrine formulation consisting of 0.015 mg/ml to 0.035 mg/ml norepinephrine and a tonicity agent, wherein the ready-to-use, stable norepinephrine formulation has a pH of 3.4-4.0 and has a dissolved oxygen level of less than 0.5 ppm after storage for at least 150 days at 25° C., wherein the ready-to-use, stable norepinephrine formulation retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25° C., and wherein the norepinephrine is in the form of norepinephrine bitartrate monohydrate;
a primary container comprising the ready-to-use, stable norepinephrine formulation therein, wherein the primary container is an intravenous (IV) bag;
a secondary container comprising a first flexible sheet layer, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers, wherein the primary container is disposed between and enclosed by the first and second flexible sheet layers of the secondary container; and
an oxygen scavenger disposed between and enclosed by the first and second flexible sheet layers of the secondary container, the oxygen scavenger being in fluid communication with the contents of the primary container.
45 . The packaged, sealed container system according to claim 44 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.1 ppm after storage for at least 150 days at 25° C.
46 . The packaged, sealed container system according to claim 44 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.5 ppm or less than 0.1 ppm after storage for at least 180 days at 25° C.
47 . A method of treating hypotension in a subject in need thereof, the method comprising:
obtaining a packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation; and
administering to the subject by intravenous infusion, a therapeutically effective amount of the ready-to-use, stable norepinephrine formulation, wherein the ready-to-use, stable norepinephrine formulation is not diluted prior to infusion, and wherein the subject has hypotension,
wherein the packaged, sealed container system comprises:
a ready-to-use, stable norepinephrine formulation consisting of 0.015 mg/ml to 0.035 mg/ml norepinephrine, dextrose, and hydrochloric acid and/or sodium hydroxide as pH adjusters, wherein the ready-to-use, stable norepinephrine formulation has a pH of 3.4-4.0 and has a dissolved oxygen level of less than 0.5 ppm after storage for at least 150 days at 25° C., and wherein the norepinephrine is in the form of norepinephrine bitartrate monohydrate, and wherein the ready-to-use, stable norepinephrine formulation retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25° C.;
a primary container comprising the ready-to-use, stable norepinephrine formulation therein, wherein the primary container is an intravenous (IV) bag;
a secondary container comprising a first flexible sheet layer, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers, wherein the primary container is disposed between and enclosed by the first and second flexible sheet layers of the secondary container; and
an oxygen scavenger disposed between and enclosed by the first and second flexible sheet layers of the secondary container, the oxygen scavenger being in fluid communication with the contents of the primary container.
48 . The method according to claim 47 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.1 ppm after storage for at least 150 days at 25° C.
49 . The method according to claim 47 , wherein the ready-to-use, stable norepinephrine formulation has a dissolved oxygen level of less than 0.5 ppm or less than 0.1 ppm after storage for at least 180 days at 25° C.
50 . The method according to claim 47 , wherein the formulation consists of 0.015 mg/ml to 0.020 mg/ml or 0.030 to 0.035 mg/ml norepinephrine.