US-20260124162-A1 - PACKAGED, SEALED CONTAINER SYSTEM FOR STABLE STORAGE OF AN OXYGEN SENSITIVE PHARMACEUTICAL FORMULATION

US20260124162A1US 20260124162 A1US20260124162 A1US 20260124162A1US-20260124162-A1

Abstract

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.

Inventors

Steven M Cope
Allan E. Titus

Assignees

BAXTER INTERNATIONAL INC.
BAXTER HEALTHCARE SA

Dates

Publication Date: 20260507
Application Date: 20251229

Claims (20)

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; dextrose; 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, 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 . 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; dextrose; 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, 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.
38 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 37 , wherein the oxygen scavenger comprises iron powder, iron oxide powder, or a mixture thereof.
39 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 37 , wherein the concentration of norepinephrine is between about 0.015 mg/ml and about 0.020 mg/ml.
40 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 37 , wherein the concentration of norepinephrine is between about 0.030 mg/ml and about 0.035 mg/ml.
41 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 37 , wherein the pH is between about 3.5 and about 3.9.
42 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 37 , wherein the pH is between about 3.6 and about 3.8.
43 . 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 dextrose, wherein the ready-to-use, stable norepinephrine formulation has a pH of 3.4-4.0, 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.
44 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 43 , wherein the oxygen scavenger comprises iron powder, iron oxide powder, or a mixture thereof.
45 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 43 , wherein the concentration of norepinephrine is between about 0.015 mg/ml and about 0.020 mg/ml.
46 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 43 , wherein the concentration of norepinephrine is between about 0.030 mg/ml and about 0.035 mg/ml.
47 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 43 , wherein the pH is between about 3.5 and about 3.9.
48 . The packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation according to claim 43 , wherein the pH is between about 3.6 and about 3.8.

Description

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional patent application Ser. No. 62/986,606, filed Mar. 6, 2020, the entire disclosure of which is incorporated herein by reference. FIELD OF THE DISCLOSURE The disclosure relates generally to a packaged, sealed container system for stable storage of a formulation of an oxygen-sensitive pharmaceutical compound. More particularly, the disclosure relates to a packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation. BACKGROUND Numerous pharmaceutical compounds are known to be sensitive to oxygen. Degradation of pharmaceutically active compounds by oxidation is particularly undesirable, as it leads to loss in activity of the active ingredient and potentially also to various degradation products, which can make the pharmaceutical composition including the same to be unmarketable and/or cause undesirable physiological effects. Norepinephrine, also known as noradrenaline, is a hormone and a neurotransmitter and an example of a pharmaceutical compound that is known to be sensitive to oxygen. Norepinephrine directly stimulates adrenergic receptors to cause vasoconstriction of the radial smooth muscle of arteries and veins, and an increase in myocardial contractility and heart rate. It is given intravenously as a vasopressor medication for patients with critical hypotension. It is also known as 1-arterenol, levarterenol and 1-norepinephrine. Norepinephrine is a catecholamine with a structure similar to that of a catechol. A catecholamine is an organic compound containing a benzene with two hydroxyl side groups on carbons 1 and 2, and a side chain amine. Norepinephrine bitartrate monohydrate, a pharmaceutically accepted salt form of norepinephrine, has the following chemical structure: Norepinephrine has two stereoisomers, the R-isomer and the S-isomer. The norepinephrine bitartrate monohydrate salt shown above is a salt of the R-isomer and has the following IUPAC name: (−)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate monohydrate. The R-isomer is known to have a higher affinity to various receptors and is more potent than the S-isomer, which has negligible pharmaceutical activity. As a result, pharmaceutical compositions including substantially only the R-isomer of norepinephrine are typically administered to a patient, instead of a racemic mixture of the two isomers. Norepinephrine is sparingly soluble in water, slightly soluble in alcohols and ethers, and readily soluble in acidic solutions. It is known to be light and oxygen sensitive, particularly in aqueous solutions. Degradation by oxidation is undesirable, as it leads to particulate formation and loss in activity of the active ingredient and also to various degradation products, namely noradrenalone and noradrenochrome, which cause undesirable physiological effects, and the latter of which renders the formulation a dark color, making the solution unmarketable. Norepinephrine is administered by intravenous infusion for blood pressure control in certain acute hypotensive states (e.g. pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion), as well as an adjunct in treatment of cardiac arrest and profound hypotension. It is commercially available, for example under the brand LEVOPHED® (Hospira, Inc.) in the United States, which uses sodium metabisulfite as an antioxidant in order to reduce degradation of norepinephrine by oxidation. LEVOPHED®'s label warns that the antioxidant present in the formulation, sodium metabisulfite, may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. While the prevalence of sulfite sensitivity is unknown, it is seen more frequently in asthmatic than in nonasthmatic people. Due to the frequent use of norepinephrine in emergency situations, the risk and potential of further compromising a patient due to an allergic reaction to the antioxidant in the formulation is undesirable and disadvantageous. On the other hand, the oxygen sensitivity of the drug strongly suggests removing the antioxidant(s) from the formulation is problematic. Furthermore, LEVOPHED® is not ready-to-use. Instead, it is generally sold in concentrated form, i.e. 4 mg/4 mL, that must be diluted immediately prior to administration to the patient. Typically, dilute and ready-to-use formulations of norepinephrine have poor long-term stability and generally expire twenty-four hours after dilution at room temperature. (See, e.g., Walker et al., Can. J. Hosp. Pharm, 63(2):113-8, 2010). Therefore, these commercial concentrates, containing norepinephrine and antioxidant, are diluted in various tonicity adjusted fluids in order to prepare a composition suitable for parenteral administration. The need for manual dilution introduces the risk of contaminat