Compositions comprising ephedrine or ephedrine salt and methods of making and using those compositions

Abstract

To provide compositions comprising ephedrine or an ephedrine salt and methods of making and using the compositions.SOLUTION: The present disclosure provides compositions comprising ephedrine sulfate ready for immediate use in a clinical setting, and methods of making and using the compositions. The present disclosure is based in part on an inventor's discovery that pharmaceutical compositions consistent with those disclosed herein and comprising an ephedrine salt (e.g., ephedrine sulfate) in a premixed (e.g., ready-to-use) formulation that does not require reconstitution or dilution prior to administration to a subject remains stable and active after prolonged storage.SELECTED DRAWING: None

Description

[Technical field]

[0001] Claiming priority This application claims priority to U.S. Provisional Patent Application No. 62 / 849,125, filed May 16, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Ephedrine sulfate ((1R,2S)-(-)-2-methylamine-1-phenylpropan-1-ol sulfate) is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent approved by the FDA for the treatment of clinically significant hypotension occurring in the setting of anesthesia. However, all FDA-approved formulations must be diluted 10-fold before administration to patients. The required dilution step is inconvenient, delays administration of necessary therapeutic interventions, and introduces a significant and dangerous source of potential error into the clinical setting. Dilution immediately prior to administration also introduces a significant contamination risk into compositions that are otherwise sterile. For example, a recent study by the Institute for Safe Medicine Practices found that roughly 1 in 10 drug products is incorrectly prepared prior to administration to patients. A 2009 survey reported that 30% of hospitals reported a patient event involving a compounding error in the past 5 years.

[0003] Shelf-stable ready-to-use formulations generally contain excipients, such as preservatives and / or chelating agents. While the use of such agents is advantageous from the standpoint of stability, the risk of allergic reactions, patient sensitivity, and undesirable cross-reactivity with other medicines prevents widespread use of pre-diluted compositions. These risks are significant in certain situations, such as emergency rooms, where rapid action is required and complete patient records are often not available.

[0004] Typically, ephedrine sulfate compositions are prepared using sterile compounding techniques, whether by compounding laboratories or on-site by medical professionals. Sterile compounding is generally considered safe, but still results in frequent (approximately 1 / 1,000) contamination with biological materials. For example, Sandoz, US Compounding, Pharmakon Pharmaceuticals, Allergy Laboratories, Cantrell Drug Company, SCA Pharmaceuticals, Banner Pharmaceuticals and PherMEDium have recalled countless compounded ephedrine sulfates, equivalent to millions of doses, since 2012 due to lack of sterility assurance. Therefore, the current method of administering ephedrine sulfate compositions involves serious infection risks for patients.

[0005] Ephedrine sulfate compositions are known to be sensitive to light, pH changes, and humidity. FDA approved formulations have a short shelf life, typically about 24 months. Ready-to-use (e.g., pre-diluted) preparations of ephedrine sulfate are not known to be stable for more than 60 days, and ready-to-use preparations of other ephedrine salts are not known to be stable for more than 12 months. Summary of the Invention [Means for solving the problem]

[0006] In view of these clinically relevant drawbacks, there remains a need for improved formulations of ephedrine sulfate.

[0007] The present disclosure provides formulations comprising ephedrine sulfate.

[0008] In some embodiments, the disclosure provides a composition comprising ephedrine sulfate in water, where the ephedrine sulfate is present in a concentration of about 1 mg / mL to about 10 mg / mL.

[0009] In other embodiments, the present disclosure provides a pre-diluted sterile pharmaceutical product comprising about 3.8 mg / mL ephedrine or an equimolar amount of an ephedrine salt, about 9 mg / mL sodium chloride, and water.

[0010] In other embodiments, the disclosure provides a packaged pharmaceutical product comprising a vial and a solution contained in the vial, where the solution comprises, consists essentially of, or consists of about 5 mg / mL ephedrine sulfate, about 9 mg / mL sodium chloride, and water.

[0011] In other embodiments, the disclosure provides a method of administering ephedrine sulfate to a subject in need thereof, comprising drawing a composition comprising ephedrine sulfate from a sterile premixed pharmaceutical product into a syringe and injecting the composition into the subject using the syringe, wherein the ephedrine sulfate is present in the composition in an amount of about 5 mg / mL.

[0012] In other embodiments, the disclosure provides a method of making a ready-to-use pharmaceutical composition comprising ephedrine or an ephedrine salt, comprising combining ephedrine or an ephedrine salt, sodium chloride, and water to provide a solution comprising about 3.8 mg / mL ephedrine or an equimolar amount of an ephedrine salt, and about 9 mg / mL sodium chloride, and then sterilizing the solution to provide a ready-to-use pharmaceutical composition comprising ephedrine or an ephedrine salt.

[0013] These and other embodiments are described in further detail herein below.

[0014] The detailed description and examples provided herein illustrate various embodiments of the present disclosure for illustrative purposes only. Those skilled in the art will readily recognize from the following discussion that alternative embodiments of the structures and methods illustrated herein may be used without departing from the principles of the embodiments described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description The present disclosure provides compositions comprising ephedrine or ephedrine salts (e.g., ready-to-use premixed pharmaceutical compositions) that are ready for use in a clinical setting.

[0016] The present disclosure is based in part on the inventors' discovery that pharmaceutical compositions consistent with those disclosed herein that include ephedrine salts (e.g., ephedrine sulfate) in a premixed (e.g., ready-to-use) formulation that does not require reconstitution or dilution prior to administration to a subject remain stable and active after extended storage.

[0017] Ephedrine and ephedrine salts The compositions of the present disclosure include ephedrine or a biologically active salt thereof. Ephedrine has the empirical formula C 10 H 15 NO, with a molecular weight of 165.2 g / mol, and the structural formula of its clinically important 1R,2S enantiomer as shown below [ka] has.

[0018] Ephedrine sulfate has the empirical formula C 20 H 32 N2O6S, with a molecular weight of 428.5 g / mol, and the structural formula of its clinically important 1R,2S enantiomer as shown below [ka] has.

[0019] Ephedrine hydrochloride has the empirical formula C 10 H 16 NOCl, with a molecular weight of 201.7 g / mol, and the structural formula of its clinically important 1R,2S enantiomer as shown below [ka] has.

[0020] Ephedrine and its salts are characterized by at least two chemical reactive centers: a secondary amine at C-2 and a secondary alcohol at C-1. In addition, ephedrine compositions are known to degrade during storage in transparent containers, including when exposed to light.

[0021] In some embodiments, the compositions of the present disclosure include ephedrine. In some embodiments, the ephedrine is enantiopure (-)-ephedrine or substantially enantiopure (-)-ephedrine.

[0022] In some embodiments, after a composition comprising enantiopure (-)-ephedrine or substantially enantiopure (-)-ephedrine is stored at about 20° C. for at least 12 months, the composition contains about 30 wt% or less of (+)-ephedrine, e.g., about 30 wt% or less, about 29 wt% or less, about 28 wt% or less, about 27 wt% or less, about 26 wt% or less, about 25 wt% or less, or about 30 wt% or less of (+)-ephedrine. wt% or less, about 24wt% or less, about 23wt% or less, about 22wt% or less, about 21wt% or less, about 20wt% or less, about 19wt% or less, about 18wt% or less, about 17wt% or less, about 1 6wt% or less, about 15wt% or less, about 14wt% or less, about 13wt% or less, about 12wt% or less, about 11wt% or less, about 10wt% or less, about 9wt% or less, about 8wt% or less, about 7w t% or less, about 6 wt% or less, about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2 wt% or less, or about 1 wt% or less of (+)-ephedrine.

[0023] In some embodiments, after a composition comprising enantiopure (-)-ephedrine or substantially enantiopure (-)-ephedrine is stored at about 20° C. for at least 24 months, the composition contains about 30 wt% or less of (+)-ephedrine, e.g., about 30 wt% or less, about 29 wt% or less, about 28 wt% or less, about 27 wt% or less, about 26 wt% or less, about 25 wt% or less, about 24 wt% or less, about 23 wt% or less, about 22 wt% or less, about Contains 21 wt% or less, about 20 wt% or less, about 19 wt% or less, about 18 wt% or less, about 17 wt% or less, about 16 wt% or less, about 15 wt% or less, about 14 wt% or less, about 13 wt% or less, about 12 wt% or less, about 11 wt% or less, about 10 wt% or less, about 9 wt% or less, about 8 wt% or less, about 7 wt% or less, about 6 wt% or less, about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2 wt% or less, or about 1 wt% or less of (+)-ephedrine.

[0024] In some embodiments, the compositions of the present disclosure include ephedrine sulfate, hi some embodiments, the ephedrine sulfate is enantiopure (-)-ephedrine sulfate or substantially enantiopure (-)-ephedrine sulfate.

[0025] In some embodiments, after a composition comprising enantiopure (-)-ephedrine sulfate or substantially enantiopure (-)-ephedrine sulfate is stored at about 20° C. for at least 12 months, the composition contains about 30 wt.% or less of (+)-ephedrine or a salt thereof, e.g., about 30 wt.% or less, about 29 wt.% or less, about 28 wt.% or less, about 27 wt.% or less, about 26 wt.% or less, about 25 wt.% or less, about 24 wt.% or less, about 23 wt.% or less, about 22 wt.% or less. about 21 wt% or less, about 20 wt% or less, about 19 wt% or less, about 18 wt% or less, about 17 wt% or less, about 16 wt% or less, about 15 wt% or less, about 14 wt% or less, about 13 wt% or less, about 12 wt% or less, about 11 wt% or less, about 10 wt% or less, about 9 wt% or less, about 8 wt% or less, about 7 wt% or less, about 6 wt% or less, about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2 wt% or less, or about 1 wt% or less of (+)-ephedrine or a salt thereof.

[0026] In some embodiments, after a composition comprising enantiopure (-)-ephedrine sulfate or substantially enantiopure (-)-ephedrine sulfate is stored at about 20° C. for at least 24 months, the composition contains about 30 wt.% or less of (+)-ephedrine or a salt thereof, e.g., about 30 wt.% or less, about 29 wt.% or less, about 28 wt.% or less, about 27 wt.% or less, about 26 wt.% or less, about 25 wt.% or less, about 24 wt.% or less, about 23 wt.% or less, about 22 wt.% or less. about 21 wt% or less, about 20 wt% or less, about 19 wt% or less, about 18 wt% or less, about 17 wt% or less, about 16 wt% or less, about 15 wt% or less, about 14 wt% or less, about 13 wt% or less, about 12 wt% or less, about 11 wt% or less, about 10 wt% or less, about 9 wt% or less, about 8 wt% or less, about 7 wt% or less, about 6 wt% or less, about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2 wt% or less, or about 1 wt% or less of (+)-ephedrine or a salt thereof.

[0027] In some embodiments, the compositions of the present disclosure include ephedrine hydrochloride, hi some embodiments, the ephedrine hydrochloride is enantiopure (-)-ephedrine hydrochloride or substantially enantiopure (-)-ephedrine hydrochloride.

[0028] In some embodiments, after storage of a composition comprising enantiopure (-)-ephedrine hydrochloride or substantially enantiopure (-)-ephedrine hydrochloride at about 20° C. for at least 12 months, the composition contains about 30 wt.% or less of (+)-ephedrine or a salt thereof, e.g., about 30 wt.% or less, about 29 wt.% or less, about 28 wt.% or less, about 27 wt.% or less, Contains about 26 wt% or less, about 25 wt% or less, about 24 wt% or less, about 23 wt% or less, about 22 wt% or less, about 21 wt% or less, about 20 wt% or less, about 19 wt% or less, about 18 wt% or less, about 17 wt% or less, about 16 wt% or less, about 15 wt% or less, about 14 wt% or less, about 13 wt% or less, about 12 wt% or less, about 11 wt% or less, about 10 wt% or less, about 9 wt% or less, about 8 wt% or less, about 7 wt% or less, about 6 wt% or less, about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2 wt% or less, or about 1 wt% or less of (+)-ephedrine or a salt thereof.

[0029] In some embodiments, after a composition comprising enantiopure (-)-ephedrine hydrochloride or substantially enantiopure (-)-ephedrine hydrochloride is stored at about 20° C. for at least 24 months, the composition contains about 30 wt.% or less of (+)-ephedrine or a salt thereof, e.g., about 30 wt.% or less, about 29 wt.% or less, about 28 wt.% or less, about 27 wt.% or less, about 26 wt.% or less, about 25 wt.% or less, about 24 wt.% or less, about 23 wt.% or less, about 22 wt.% or less. about 21 wt% or less, about 20 wt% or less, about 19 wt% or less, about 18 wt% or less, about 17 wt% or less, about 16 wt% or less, about 15 wt% or less, about 14 wt% or less, about 13 wt% or less, about 12 wt% or less, about 11 wt% or less, about 10 wt% or less, about 9 wt% or less, about 8 wt% or less, about 7 wt% or less, about 6 wt% or less, about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2 wt% or less, or about 1 wt% or less of (+)-ephedrine or a salt thereof.

[0030] In some embodiments, the compositions of the present disclosure contain at least about 70% of the initial amount of (-)-ephedrine after being stored at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0031] In some embodiments, the compositions of the present disclosure contain at least about 80% of the initial amount of (-)-ephedrine after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0032] In some embodiments, the compositions of the present disclosure contain at least about 90% of the initial amount of (-)-ephedrine after being stored at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0033] In some embodiments, the compositions of the present disclosure have a shelf life of at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 39 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months, at least about 49 months, at least about 50 months, at least about 51 months, at least about 52 months, at least about 53 months, at least about 54 months, at least about 55 months, at least about 56 months, at least about 57 months, at least about contains at least about 95% of the initial amount of (-)-ephedrine after storage for about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, or at least about 48 months.

[0034] In some embodiments, the compositions of the present disclosure contain at least about 70% of the initial amount of (-)-ephedrine sulfate after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0035] In some embodiments, the compositions of the present disclosure contain at least about 80% of the initial amount of (-)-ephedrine sulfate after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0036] In some embodiments, the compositions of the present disclosure contain at least about 90% of the initial amount of (-)-ephedrine sulfate after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0037] In some embodiments, the compositions of the present disclosure contain at least about 95% of the initial amount of (-)-ephedrine sulfate after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0038] In some embodiments, the compositions of the present disclosure contain at least about 70% of the initial amount of (-)-ephedrine hydrochloride after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0039] In some embodiments, the compositions of the present disclosure contain at least about 80% of the initial amount of (-)-ephedrine hydrochloride after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0040] In some embodiments, the compositions of the present disclosure contain at least about 90% of the initial amount of (-)-ephedrine hydrochloride after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0041] In some embodiments, the compositions of the present disclosure contain at least about 95% of the initial amount of (-)-ephedrine hydrochloride after storage at about 20° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0042] In some embodiments, the compositions of the present disclosure contain at least about 70% of the initial amount of (-)-ephedrine after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0043] In some embodiments, the compositions of the present disclosure contain at least about 80% of the initial amount of (-)-ephedrine after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0044] In some embodiments, the compositions of the present disclosure have a shelf life of at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about Contains at least about 90% of the initial amount of (-)-ephedrine after storage for 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, or at least about 48 months.

[0045] In some embodiments, the compositions of the present disclosure contain at least about 95% of the initial amount of (-)-ephedrine after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0046] In some embodiments, the compositions of the present disclosure contain at least about 70% of the initial amount of (-)-ephedrine sulfate after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0047] In some embodiments, the compositions of the present disclosure contain at least about 80% of the initial amount of (-)-ephedrine sulfate after storage at about 40° C.+ / -2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0048] In some embodiments, the compositions of the present disclosure contain at least about 90% of the initial amount of (-)-ephedrine sulfate after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0049] In some embodiments, the compositions of the present disclosure contain at least about 95% of the initial amount of (-)-ephedrine sulfate after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0050] In some embodiments, the compositions of the present disclosure contain at least about 70% of the initial amount of (-)-ephedrine hydrochloride after storage at about 40° C.+ / -2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0051] In some embodiments, the compositions of the present disclosure contain at least about 80% of the initial amount of (-)-ephedrine hydrochloride after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0052] In some embodiments, the compositions of the present disclosure contain at least about 90% of the initial amount of (-)-ephedrine hydrochloride after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0053] In some embodiments, the compositions of the present disclosure contain at least about 95% of the initial amount of (-)-ephedrine hydrochloride after storage at about 40° C. + / - 2° C. for at least about 12 months, e.g., at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, at least about 36 months, at least about 38 months, at least about 40 months, at least about 42 months, at least about 44 months, at least about 46 months, at least about 48 months.

[0054] In some embodiments, the compositions of the disclosure comprise about 2 μg / mL or less of dichlorobenzoic acid, e.g., about 2 μg / mL or less, about 1.9 μg / mL or less, about 1.8 μg / mL or less, about 1.7 μg / mL or less, about 1.6 μg / mL or less, about 1.5 μg / mL or less, about 1.4 μg / mL or less, about 1.3 μg / mL or less, about 1.2 μg / mL or less, about 1.1 μg / mL or less, about 1 μg / mL or less, about 0.9 μg / mL or less, about 0.8 μg / mL or less, about 0.7 μg / mL or less, about 0.6 μg / mL or less, about 0.5 μg / mL or less, about 0.4 μg / mL or less, about 0.3 μg / mL or less, about 0.2 μg / mL or less, or about 0.1 μg / mL or less of dichlorobenzoic acid, after storage at about 25° C. + / - 2° C. for at least about 12 months.

[0055] In some embodiments, the compositions of the present disclosure have a dichlorobenzoic acid concentration of about 2 μg / mL or less, e.g., about 2 μg / mL or less, about 1.9 μg / mL or less, about 1.8 μg / mL or less, about 1.7 μg / mL or less, about 1.6 μg / mL or less, about 1.5 μg / mL or less, about 1.4 μg / mL or less, about 1.3 μg / mL or less, after storage at about 25° C. + / - 2° C. for at least about 24 months. L or less, about 1.2 μg / mL or less, about 1.1 μg / mL or less, about 1 μg / mL or less, about 0.9 μg / mL or less, about 0.8 μg / mL or less, about 0.7 μg / mL or less, about 0.6 μg / mL or less, about 0.5 μg / mL or less, about 0.4 μg / mL or less, about 0.3 μg / mL or less, about 0.2 μg / mL or less, or about 0.1 μg / mL or less of dichlorobenzoic acid.

[0056] Ready-to-use ephedrine preparations In some embodiments, the compositions of the present disclosure include ephedrine or an ephedrine salt, an isotonic agent, and water.

[0057] In some embodiments, the composition of the present disclosure does not contain preservative.Non-limiting examples of preservative include (e.g., benzyl alcohol, chlorobutanol, phenylethyl alcohol), paraben (e.g., methylparaben, ethylparaben, propylparaben, butylparaben), phenol (e.g., phenol, chlorocresol, o-phenylphenol), mercury compounds (e.g., thiomersal, nitromersol, phenylmercuric nitrate, phenylmercuric acetate), and quaternary ammonium compounds (e.g., benzalkonium chloride, cetylpyridinium chloride).In some embodiments, the composition does not contain benzyl alcohol.

[0058] In some embodiments, the composition of the present disclosure does not include chelating agent.Non-limiting examples of chelating agent include EDTA, edetate calcium disodium, and edetate disodium.In some embodiments, the composition does not include EDTA.

[0059] In some embodiments, the composition does not include a preservative or a chelating agent. In some embodiments, the composition does not include benzyl alcohol or EDTA.

[0060] In some embodiments, ephedrine or an ephedrine salt is present in an amount equivalent to about 3.8 mg / mL of ephedrine free base. For example, but not by way of limitation, in embodiments in which ephedrine or an ephedrine salt comprises ephedrine free base, ephedrine free base may be present in an amount of about 3.8 mg / mL. In embodiments in which ephedrine or an ephedrine salt comprises ephedrine sulfate, ephedrine sulfate may be present in an amount of about 5 mg / mL. In embodiments in which ephedrine or an ephedrine salt comprises ephedrine hydrochloride, ephedrine hydrochloride may be present in an amount of about 4.6 mg / mL.

[0061] In some embodiments, the isotonic agent is sodium chloride. In other embodiments, the isotonic agent is dextrose. In embodiments where the isotonic agent is sodium chloride, the sodium chloride may be present in an isotonic amount, for example, about 9 mg / mL. In dextrose embodiments, sodium chloride may be present in an amount to render it isotonic, for example about 5%.

[0062] In some embodiments, the compositions of the present disclosure include ephedrine (e.g., (-)-ephedrine), sodium chloride, and water (e.g., water for injection). In some embodiments, the ephedrine is present in an amount of about 3.8 mg / mL, and the sodium chloride is present in an amount of about 9 mg / mL.

[0063] In some embodiments, the compositions of the present disclosure include ephedrine sulfate (e.g., (-)-ephedrine sulfate), sodium chloride, and water (e.g., water for injection). In some embodiments, the ephedrine sulfate is present in an amount of about 5 mg / mL and the sodium chloride is present in an amount of about 9 mg / mL.

[0064] In some embodiments, the compositions of the present disclosure include ephedrine hydrochloride (e.g., (-)-ephedrine hydrochloride), sodium chloride, and water (e.g., water for injection). In some embodiments, the ephedrine hydrochloride is present in an amount of about 4.6 mg / mL, and the sodium chloride is present in an amount of about 9 mg / mL.

[0065] In some embodiments, the compositions of the present disclosure include ephedrine (e.g., (-)-ephedrine), dextrose, and water (e.g., water for injection). In some embodiments, the ephedrine is present in an amount of about 3.8 mg / mL and the dextrose is present in an amount of about 5%.

[0066] In some embodiments, the compositions of the present disclosure include ephedrine sulfate (e.g., (-)-ephedrine sulfate), dextrose, and water (e.g., water for injection). In some embodiments, the ephedrine sulfate is present in an amount of about 5 mg / mL and the dextrose is present in an amount of about 5%.

[0067] In some embodiments, the compositions of the present disclosure include ephedrine hydrochloride (e.g., (-)-ephedrine hydrochloride), dextrose, and water (e.g., water for injection). In some embodiments, the ephedrine hydrochloride is present in an amount of about 4.6 mg / mL and the dextrose is present in an amount of about 5%.

[0068] In any embodiment disclosed herein, the composition can have a total volume sufficient to provide an effective dose of ephedrine to a subject. In some embodiments, the total volume is about 5 mL to about 25 mL, such as about 5 mL, about 10 mL, about 15 mL, about 20 mL, or about 25 mL. In some embodiments, the total volume is about 10 mL.

[0069] In any embodiment disclosed herein, the composition can be contained in a container, for example, a disposable container. In some embodiments, the disposable container is a vial, for example, a glass vial. In other embodiments, the disposable container is a syringe, for example, a polypropylene syringe.

[0070] In some embodiments, the present disclosure provides a disposable container comprising about 10 mL of a composition comprising about 38 mg of ephedrine (e.g., (-)-ephedrine), about 90 mg of sodium chloride, and water (e.g., water for injection). In some embodiments, the disposable container is a glass vial. In some embodiments, the disposable container is a syringe.

[0071] In some embodiments, the present disclosure provides a disposable container comprising about 10 mL of a composition comprising about 50 mg of ephedrine sulfate (e.g., (-)-ephedrine sulfate), about 90 mg of sodium chloride, and water (e.g., water for injection). In some embodiments, the disposable container is a glass vial. In some embodiments, the disposable container is a syringe.

[0072] In some embodiments, the present disclosure provides a disposable container comprising about 10 mL of a composition comprising about 46 mg of ephedrine hydrochloride (e.g., (-)-ephedrine hydrochloride), about 90 mg of sodium chloride, and water (e.g., water for injection). In some embodiments, the disposable container is a glass vial. In some embodiments, the disposable container is a syringe.

[0073] In some embodiments, the present disclosure provides a storage stable composition comprising ephedrine or an ephedrine salt (e.g., ephedrine sulfate) without a preservative, such as benzyl alcohol. In some embodiments, the storage stable composition comprises ephedrine or an ephedrine salt (e.g., ephedrine sulfate), an isotonicity agent (e.g., sodium chloride) and water, but without a preservative (e.g., benzyl alcohol). In some embodiments, the storage stable composition comprises ephedrine sulfate (e.g., (-)-ephedrine sulfate), sodium chloride and water, but without benzyl alcohol.

[0074] In some embodiments, the present disclosure provides a storage stable composition comprising ephedrine or an ephedrine salt (e.g., ephedrine sulfate) without a chelating agent, such as EDTA. In some embodiments, the storage stable composition comprises ephedrine or an ephedrine salt (e.g., ephedrine sulfate), an isotonicity agent (e.g., sodium chloride) and water, but without a chelating agent (e.g., EDTA). In some embodiments, the storage stable composition comprises ephedrine sulfate (e.g., (-)-ephedrine sulfate), sodium chloride and water, but without EDTA.

[0075] In some embodiments, the present disclosure provides a storage stable composition comprising ephedrine or an ephedrine salt (e.g., ephedrine sulfate) that does not include a preservative (e.g., benzyl alcohol) or a chelating agent (e.g., EDTA). In some embodiments, the storage stable composition comprises ephedrine or an ephedrine salt (e.g., ephedrine sulfate), an isotonicity agent (e.g., sodium chloride), and water, but does not include a preservative (e.g., benzyl alcohol) or a chelating agent (e.g., EDTA). In some embodiments, the storage stable composition comprises ephedrine sulfate (e.g., (-)-ephedrine sulfate), sodium chloride, and water, but does not include benzyl alcohol or EDTA.

[0076] In some embodiments, the compositions of the present disclosure have a pH value of 4.5 to 7.0. In some embodiments, the compositions have a pH value of 5.5 to 6.5. In some embodiments, the compositions have a pH value of about 5.6 to 6.2. In some embodiments, the compositions have a pH value of about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0.

[0077] In some embodiments, compositions of the disclosure contain 10 colony forming units ("CFU") or less per mL, e.g., 10 CFU / mL or less, 9 CFU / mL or less, 8 CFU / mL or less, 7 CFU / mL or less, 6 CFU / mL or less, 5 CFU / mL or less, 4 CFU / mL or less, 3 CFU / mL or less, 2 CFU / mL or less, 1 CFU / mL or less, 0.5 CFU / mL or less, 0.4 CFU / mL or less, 0.3 CFU / mL or less, 0.2 CFU / mL or less, or 0.1 CFU / mL or less.

[0078] In some embodiments, compositions of the present disclosure comprise endotoxin in an amount of 1.7 Eu / mg or less, 1.6 Eu / mg or less, 1.5 Eu / mg or less, 1.4 Eu / mg or less, 1.3 Eu / mg or less, 1.2 Eu / mg or less, 1.1 Eu / mg or less, 1.0 Eu / mg or less, 0.9 Eu / mg or less, 0.8 Eu / mg or less, 0.7 Eu / mg or less, 0.6 Eu / mg or less, 0.5 Eu / mg or less, 0.4 Eu / mg or less, 0.3 Eu / mg or less, 0.2 Eu / mg or less, or 0.1 Eu / mg or less.

[0079] In some embodiments, the disclosure provides a composition comprising ephedrine sulfate in water, wherein the ephedrine sulfate is present at a concentration of about 1 mg / mL to about 10 mg / mL. In some embodiments, the ephedrine sulfate is present at a concentration of about 2 mg / mL to about 8 mg / mL. In some embodiments, the ephedrine sulfate is present at a concentration of about 3 mg / mL to about 7 mg / mL. In some embodiments, the ephedrine sulfate is present at a concentration of about 4 mg / mL to about 6 mg / mL. In some embodiments, the ephedrine sulfate is present at a concentration of about 5 mg / mL. In some embodiments, the composition further comprises sodium chloride. In some embodiments, the sodium chloride is present in an amount of about 9 mg / mL. In some embodiments, the composition is stable when stored at 20° C. for at least 12 months. In some embodiments, the composition does not include dextrose. In some embodiments, the composition does not include a preservative, such as benzyl alcohol. In some embodiments, the composition does not include a chelating agent, such as EDTA. In some embodiments, the composition consists essentially of ephedrine sulfate, sodium chloride, and water. In some embodiments, the composition consists of ephedrine sulfate, sodium chloride, and water. In some embodiments, the ephedrine sulfate is (-)-ephedrine sulfate.

[0080] In some embodiments, the disclosure provides a pre-diluted sterile pharmaceutical product comprising about 3.8 mg / mL ephedrine or an equimolar amount of ephedrine salt, about 9 mg / mL sodium chloride, and water. In some embodiments, the pharmaceutical product does not contain dextrose. In some embodiments, the pharmaceutical product does not contain benzyl alcohol. In some embodiments, the total volume of the pharmaceutical product is about 10 mL. In some embodiments, the pharmaceutical product is packaged in a vial. In some embodiments, after storage at about 20° C., the pharmaceutical product comprises at least 3 mg / mL ephedrine or a molar equivalent amount of ephedrine salt. In some embodiments, the ephedrine or ephedrine salt is ephedrine sulfate. In some embodiments, the ephedrine sulfate is (−)-ephedrine sulfate.

[0081] In some embodiments, the disclosure provides a ready-to-use unit dose form comprising about 3.8 mg / mL ephedrine or an equimolar amount of ephedrine salt (e.g., about 5 mg / mL ephedrine sulfate), about 9 mg / mL sodium chloride, and water. In some embodiments, the ready-to-use unit dose form is contained in a vial. In some embodiments, the ready-to-use unit dose form has a total volume of about 10 mL. In some embodiments, the ready-to-use unit dose form does not contain dextrose. In some embodiments, the ready-to-use unit dose form does not contain benzyl alcohol. In some embodiments, after storage at about 20° C., the ready-to-use unit dose form comprises at least 3 mg / mL ephedrine or an equimolar amount of ephedrine salt (e.g., at least 4 mg / mL ephedrine sulfate).

[0082] In some embodiments, the disclosure provides a packaged pharmaceutical product comprising a vial and a solution contained in the vial, wherein the solution comprises, consists essentially of, or consists of about 5 mg / mL ephedrine sulfate, about 9 mg / mL sodium chloride, and water. In some embodiments, the solution has a total volume of about 10 mL. In some embodiments, the solution does not comprise dextrose. In some embodiments, the vial comprises, consists essentially of, or consists of glass. In some embodiments, the vial comprises, consists essentially of, or consists of polypropylene. In some embodiments, the solution is stable when stored at about 20° C. for at least 12 months. In some embodiments, after storage at about 20° C. for at least 12 months, the solution comprises ephedrine sulfate at a concentration of about 4 mg / mL to about 6 mg / mL. In some embodiments, after storage at about 20° C. for at least 12 months, the solution comprises at least 4 mg / mL ephedrine sulfate. In some embodiments, the solution contains at least 4.5 mg / mL of ephedrine sulfate after being stored for at least 12 months at about 20° C. In some embodiments, the ephedrine sulfate is (−)-ephedrine sulfate.

[0083] Methods of Using Ready-to-Use Ephedrine Compositions The present disclosure provides methods of using ready-to-use compositions comprising ephedrine or ephedrine salts. Generally, the methods disclosed herein do not require a clinician to dilute the ready-to-use composition before administering it to a subject. In some embodiments, the risk of microbial contamination to a subject administered a ready-to-use ephedrine composition consistent with the present disclosure is lower, e.g., substantially lower, compared to the risk of microbial contamination to a subject (e.g., a similarly situated subject) administered an ephedrine composition that requires dilution of a packaged concentrated ephedrine pharmaceutical composition.

[0084] In some embodiments, the disclosure provides methods of reducing the risk of microbial infection associated with administration of ephedrine or an ephedrine salt (e.g., ephedrine sulfate) to a subject in need thereof.

[0085] In some embodiments, the risk of microbial contamination to a subject administered a ready-to-use composition comprising ephedrine or an ephedrine salt (e.g., ephedrine sulfate) consistent with the present disclosure is less, or substantially less, than the risk of microbial contamination to a second subject administered ephedrine sulfate diluted (e.g., diluted by a clinician) to a concentration of 5 mg / mL. In some such embodiments, the second subject receives ephedrine sulfate prepared by mixing (e.g., diluting) a concentrated ephedrine sulfate composition from a packaged sterile pharmaceutical product comprising 50 mg / mL ephedrine sulfate with (e.g., diluting with) a diluent, e.g., saline, to form a diluted ephedrine sulfate composition.

[0086] In some embodiments, the disclosure provides a method of administering ephedrine sulfate to a subject in need thereof, comprising drawing a composition comprising ephedrine sulfate from a sterile premixed pharmaceutical product into a syringe and injecting the composition into the subject using the syringe, wherein the ephedrine sulfate is present in the composition in an amount of about 5 mg / mL. In some embodiments, the composition further comprises sodium chloride in an amount of about 9 mg / mL. In some embodiments, the composition further comprises water. In some embodiments, the composition does not comprise dextrose. In some embodiments, the method does not include diluting the sterile premixed pharmaceutical product prior to injecting the composition into the subject using the syringe. In some embodiments, the composition contained in a vial of the sterile premixed pharmaceutical product is stable when stored at about 20° C. for at least 12 months. In some embodiments, after being stored at about 20° C. for at least 12 months, the composition comprises ephedrine sulfate in an amount of about 4 mg / mL to about 6 mg / mL. In some embodiments, the ephedrine sulfate is (-)-ephedrine sulfate.

[0087] In some embodiments, the disclosure provides a method of treating hypotension in a subject in need thereof, comprising drawing an effective amount of a packaged composition comprising ephedrine or an ephedrine salt into a syringe and injecting the effective amount of the packaged composition into a subject in need thereof. In some embodiments, the packaged composition comprises ephedrine or an ephedrine salt in an amount equivalent to about 3.8 mg / mL of ephedrine. In some embodiments, the packaged composition further comprises sodium chloride in an amount of about 9 mg / mL. In some embodiments, the packaged composition further comprises water. In some embodiments, the packaged composition does not comprise dextrose. In some embodiments, the method does not comprise diluting the packaged composition prior to injecting the effective amount of the packaged composition into a subject in need thereof. In some embodiments, the packaged composition is stable when stored at about 20° C. for at least 12 months. In some embodiments, after storage at about 20° C. for at least 12 months, the packaged composition comprises ephedrine sulfate in an amount of about 4 mg / mL to about 6 mg / mL. In some embodiments, the ephedrine or ephedrine salt is (-)-ephedrine sulfate. In some embodiments, the method further comprises determining a hypotension reading in the subject prior to drawing an effective amount of a packaged composition comprising ephedrine or an ephedrine salt into a syringe. In some embodiments, the hypotension is clinically significant hypotension. In some embodiments, the clinically significant hypotension is clinically significant hypotension in the context of anesthesia. In some embodiments, the method further comprises detecting a hypotensive condition associated with the subject (e.g., a clinically significant hypotensive condition) prior to injecting an effective amount of the packaged composition into the subject.

[0088] In some embodiments, the disclosure provides a method of increasing blood pressure in a subject in need thereof, comprising: determining a hypotensive reading associated with the subject; drawing about 1 mL to about 10 mL of a packaged composition comprising about 5.0 mg / mL ephedrine sulfate into a syringe; and injecting about 1 mL to about 10 mL of the packaged composition into the subject in need thereof, wherein the blood pressure reading associated with the subject is increased after injecting the packaged composition into the subject in need thereof, and the method does not include diluting the packaged composition prior to injecting the packaged composition into the subject in need thereof. In some embodiments, the packaged composition further comprises sodium chloride in an amount of about 9 mg / mL. In some embodiments, the packaged composition further comprises water. In some embodiments, the packaged composition does not comprise dextrose. In some embodiments, the method further comprises determining a second blood pressure reading associated with the subject after injecting the packaged composition into the subject, wherein the second blood pressure reading is hypotensive. In some embodiments, the method further comprises injecting about 1 mL to about 10 mL of the packaged composition into the subject after determining a second hypotensive blood pressure reading associated with the subject. In some embodiments, the packaged composition is stable when stored at about 20° C. for at least 12 months. In some embodiments, after storage at about 20° C. for at least 12 months, the packaged composition comprises ephedrine sulfate in an amount of at least about 4 mg / mL. In some embodiments, after storage at about 20° C. for at least 12 months, the packaged composition comprises ephedrine sulfate in an amount of at least about 4.5 mg / mL. In some embodiments, the ephedrine sulfate is (-)-ephedrine sulfate.

[0089] Method for making ready-to-use ephedrine compositions The present disclosure further provides methods of making ready-to-use compositions containing ephedrine or ephedrine salts.

[0090] Typically, ephedrine or an ephedrine salt (e.g., ephedrine sulfate) is combined with sodium chloride or dextrose in water for injection and mixed to form a clear, colorless solution. In some embodiments, the pH of the solution is adjusted to 4.5-7.0 using an acid (e.g., glacial acetic acid) or a base (e.g., sodium hydroxide). The final concentration of ephedrine or an ephedrine salt in the optionally pH-adjusted solution is equivalent to about 3.8 mg / mL of ephedrine free base. Thus, in embodiments where the ephedrine or ephedrine salt is ephedrine sulfate, the final concentration of ephedrine sulfate in the optionally pH-adjusted solution is about 5.0 mg / mL. In embodiments where the ephedrine or ephedrine salt is ephedrine hydrochloride, the final concentration of ephedrine hydrochloride in the optionally pH-adjusted solution is about 4.6 mg / mL. The concentration of sodium chloride or dextrose in the solution, pH adjusted as necessary, should be made isotonic with human serum (e.g., about 9 mg / mL sodium chloride or about 5% dextrose).

[0091] The ephedrine or ephedrine salt solution must be sterilized prior to use by the clinician. In some embodiments, the ephedrine or ephedrine salt solution is placed in a vial (e.g., a glass or plastic disposable vial) and then sterilized by any suitable method known in the art.

[0092] In some embodiments, the disclosure provides a method of making a ready-to-use pharmaceutical composition comprising ephedrine or an ephedrine salt, comprising combining ephedrine or an ephedrine salt, sodium chloride, and water to provide a solution comprising about 3.8 mg / mL ephedrine or an equimolar amount of ephedrine salt, and about 9 mg / mL sodium chloride, and then sterilizing the solution to provide a ready-to-use pharmaceutical composition comprising ephedrine or an ephedrine salt. In some embodiments, the method further comprises placing the solution in one or more vials prior to the sterilization step. In some embodiments, the solution does not contain dextrose. In some embodiments, the pharmaceutical composition is stable when stored at about 20° C. for at least 12 months. In some embodiments, after storage at about 20° C. for at least 12 months, the pharmaceutical composition comprises an amount of ephedrine or an ephedrine salt that is at least 80% of about 3.8 mg / mL ephedrine or an equimolar amount of ephedrine salt. In some embodiments, the ephedrine or ephedrine salt is ephedrine sulfate. In some embodiments, the ephedrine salt is (-)-ephedrine sulfate. In some embodiments, the equimolar amount of the ephedrine salt is about 5 mg / mL of ephedrine sulfate. In some embodiments, the ephedrine or ephedrine salt is ephedrine hydrochloride. In some embodiments, the ephedrine hydrochloride is (-)-ephedrine hydrochloride. In some embodiments, the equimolar amount of the ephedrine salt is about 4.6 mg / mL of ephedrine hydrochloride. EXAMPLES

[0093] Aspects of the embodiments may be further understood in light of the following examples, which should not be construed as limiting in any way.

[0094] Example 1: Ready-to-use ephedrine sulfate composition

[0095] A ready-to-use injectable composition of ephedrine sulfate was prepared at a 50 L scale by combining ephedrine sulfate USP / EP powder (Lot No. 18130597, Siegfried PharmaChemikalien, Minden Germany), sodium chloride USP / EP (Lot No. 18804697, Merck & Co., Kenilworth, NJ), and water for injection in the amounts shown in Table 1 below in a 200 L stainless steel vessel.

[0096] [Table 1]

[0097] Sampling of two 20 mL vials of the mixed solution at this stage indicated that ephedrine sulfate was present in the solution at 100.2%-102.2% of the desired amount of 5 mg / mL. Also at this stage, bioburden testing of 200 mL of the mixed solution revealed acceptable levels of biological content (0-0.1 CFU / mL).

[0098] After mixing, the solution was filtered through an Opticap XL4 capsule Durapore membrane (Lot #18131597, Merck Millipore, Burlington, MA) and then filled into washed and depyrogenized 10 cc clear glass Type I vials (Lot #18500797, Gerresheimer / Bormioli, Duesseldorf, Germany). The vials were capped with chlorobutyl fluorotic coated stoppers (Lot #18803297, West Pharma, Exton, PA) and flip-off caps (Lot #18700897, Capsulit SpA, Roncello, Italy).

[0099] The pH levels of the solutions in the vials ranged from 5.6 to 6.2, well within the acceptable range of 4.5 to 7.0. Ephedrine sulfate was present in the solutions in the vials in amounts ranging from 100.8% to 102.5% of the desired 5 mg / mL concentration. Bioburden testing of the solutions in the vials revealed 0 CFU / mL.

[0100] The capped vials were crimped and sterilized by overkill technique in a steel cassette at 122.1° C. for 15 minutes in an A601A autoclave.

[0101] Visual inspection of the terminally sterilized vials revealed no foreign material, low product volume, or cosmetic defects. Sterilized vials were sterilized according to USP method <71> Passed sterility testing in accordance with USP method <87> The endotoxin level was ≦1.7Eu / mg.

[0102] Bioburden testing on 20 stoppers pooled after filling showed a range of 0 to 0.5 CFU / mL. Analysis of three lots of ready-to-use 10 mL vials of ephedrine sulfate prepared by this method is shown below in Table 2. [Table 2]

[0103] Example 2. Real-time stability of ready-to-use ephedrine sulfate compositions. A 10 mL batch of ephedrine sulfate injection, 5 mg / mL, was prepared in each of 510 10 mL Type I flint glass vials (Gerresheimer / Bormioli), closed with a 20 mm chlorobutyl flurotec coated stopper (West), and sealed with a 20 mm flip-off aluminum crimp seal (Capsult) in a production facility using standard production equipment, processes, personnel, and procedures all consistent with the method disclosed in Example 1. Ephedrine sulfate API was sourced from Siegfried PharmaChemikalien Minden GmbH (Germany).

[0104] Vials were stored in a restricted access safety cabinet or security chamber at 25 + / - 2°C and 60 + / - 5% relative humidity (RH) for 24 months and removed only for testing. Some vials were stored upright and others upside down (e.g., liquid in contact with the vial closure). Samples were identified and records maintained in a stability study log. Vials were tested according to the parameters shown in Table 3 below, at the time points shown in Table 4, and with the upright / upside down vial designation shown in Table 5. [Table 3] [Table 4] [Table 5]

[0105] The number of vials withdrawn for testing at each time point is summarized in Table 6 below. [Table 6]

[0106] Quantitative analyses were plotted as average values ​​as a function of time, while qualitative analyses were recorded and compiled to allow profile changes to be examined and conclusions drawn.

[0107] Real-time stability study results 1. Physical Appearance specification: A) 10cc flint glass vial with seal and stopper and aluminum seal B) Transparent C) No visible particulates D) colorless [Table 7]

[0108] 2. Mass osmolarity Specifications: 270~330mOsm / kg [Table 8]

[0109] 3. pH Specification: Between 4.5 and 7.0 [Table 9]

[0110] 4. Ephedrine Sulfate Assay (5 mg / mL) Specifications: 95.0% to 105.0% of the indicated amount [Table 10]

[0111] 5.Enantiomeric purity Specification: (+)-1S,2R-ephedrine, NMT 0.5% by chiral HPLC [Table 11]

[0112] 6. Related Substances: Any unknown individual impurities Specification: Any unknown individual impurities, ≤0.2% by HPLC [Table 12-1]

[0113] 7. Related substances: Total impurities specification: Total impurities ≤0.75% by HPLC [Table 12-2]

[0114] 8. Particulate matter specification: A) For particles ≧10 μm, NMT6000 by HIAC per container B) For particles ≧25μm, NMT600 by HIAC per container [Table 13]

[0115] 9. Sterility Specification: Sterile [Table 14]

[0116] 10.Bacterial toxins Specification: NMT7.0EU / mg [Table 15]

[0117] 11. Elemental Impurities Specification: USP <232> Meet the requirements of [Table 16]

[0118] 12. Container / Closure Integrity Testing (CCIT) Specification: integral [Table 17]

[0119] Example 3 Accelerated Stability Study of Ready-to-Use Ephedrine Sulfate Compositions A 10 mL batch of ephedrine sulfate injection, 5 mg / mL, was prepared in each of 510 10 mL Type I flint glass vials (Gerresheimer / Bormioli), closed with a 20 mm chlorobutyl flurotec coated stopper (West), and sealed with a 20 mm flip-off aluminum crimp seal (Capsult) in a production facility using standard production equipment, processes, personnel, and procedures all consistent with the method disclosed in Example 1. Ephedrine sulfate API was sourced from Siegfried PharmaChemikalien Minden GmbH (Germany).

[0120] Vials were stored in a secure, restricted access stability chamber at 40 + / - 2°C and 75 + / - 5% relative humidity (RH) for 6 months and removed only for testing. Some vials were stored upright and others upside down (e.g., with liquid in contact with the vial closure). Samples were identified and records maintained in a stability study log. The vials were tested according to the parameters set forth in Table 18 below, at the time points set forth in Table 19, and with the upright / upside down vial designation set forth in Table 20. [Table 18] [Table 19] [Table 20]

[0121] The numbers of vials withdrawn for testing at each time point are summarized in Table 21 below. [Table 21]

[0122] Quantitative analyses were plotted as average values ​​as a function of time, while qualitative analyses were recorded and compiled to allow profile changes to be examined and conclusions drawn.

[0123] Accelerated stability study results 1. Physical Appearance specification: A) 10cc flint glass vial with seal and stopper and aluminum seal B) Transparent C) No visible particulates D) colorless [Table 22]

[0124] 2. Mass osmolarity Specifications: 270~330mOsm / kg [Table 23]

[0125] 3. pH Specification: Between 4.5 and 7.0 [Table 24]

[0126] 4. Ephedrine Sulfate Assay (5 mg / mL) Specifications: 95.0% to 105.0% of the indicated amount [Table 25]

[0127] 5.Enantiomeric purity Specification: (+)-1S,2R-ephedrine, NMT 0.5% by chiral HPLC [Table 26]

[0128] 6. Related substances specification: A) unknown individual impurity, ≤ 0.2% B) Total impurities, ≦0.75% [Table 27]

[0129] 7. Particulate matter specification: A) For particles ≧10 μm, NMT6000 by HIAC per container B) For particles ≧25μm, NMT600 by HIAC per container [Table 28]

[0130] Example 4 Extractables and Leachables Study Ephedrine sulfate, 50 mg / 10 mL (5 mg / mL) in 0.9% sodium chloride injection was packaged in 10 cc Type I glass vials (20 mm 4110 / 40, B2-40 manufactured by Gray, West) with Flurotec coated chlorobutyl rubber stoppers. The extractables and leachables (E and L) study was performed according to USP <1663> , <1664> The design was based on the guidelines provided in.

[0131] Whole stoppers were immersed in extraction solvents and refluxed overnight for a minimum of 12 hours in three solvents: water at pH 3.4, water at pH 9.4, and IPA / water (50 / 50) (uncoated surfaces were exposed as well) to provide higher extraction power than the ready-to-use ephedrine composition consistent with the present disclosure. Additionally, leachables analysis was performed on three exhibit batches of ready-to-use ephedrine sulfate composition samples of Example 2 stored upside down for 24 months at 25° C.±2° C. and 60%±5% relative humidity (RH). The results were analyzed by QTOF GC-MS, QTOF LC-MS and HPLC. Extractables studies were performed on stoppers and vials using 2% HNO3 to extract metal impurities, and the extracts were screened using ICP-MS analysis. Additionally, three submitted batches of ready-to-use ephedrine sulfate composition samples of Example 2 stored upside down at 25°C±2°C and 60%±5% RH for 24 months were analyzed for class 1 and 2A elements.

[0132] Result summary Extracts from the extractables study conducted on the stoppers were analyzed by GC-MS for volatile and semi-volatile compounds and by LC-MS for non-volatile compounds. Control samples were also prepared and analyzed along with all exposed extractables samples and stability samples of the drug product. MS studies were conducted by an independent laboratory using LC-MS and GC-MS to identify and relatively quantify the extractables and leachables in the extracts or ready-to-use ephedrine sulfate compositions. Leachables studies were then also conducted by a validated method (EPH-006) based on high pressure liquid chromatography (HPLC).

[0133] Most of the extractables identified appeared to originate from the uncoated surface of the stoppers. Extractables included siloxane oligomers, nonionic surfactants (laureth-9 and related), sulfur compounds, butylated hydroxytoluene (BHT), and fatty acids (inorganic fillers) commonly used in the production of elastomeric components. Another extractable found in the LC-MS analysis was triethylene glycol, a common plasticizer used in the production of vinyl polymers. During the analysis of leachables, a compound consistent with bis(2-ethylhexyl) isophthalate was detected in the ready-to-use ephedrine sulfate composition samples at concentrations at or below 0.15 μg / mL by QTOF-GCMS. Another compound consistent with dichlorobenzoic acid (DCBA) was also detected in the ready-to-use ephedrine sulfate composition samples at levels at or below 1.4 μg / mL by QTOF-LCMS-UV-CAD. Dichlorobenzoic acid was also detected during the HPLC analysis at concentrations at or below 0.7 μg / mL using test method EPH-006. Note that DCBA, detected by both the MS study and the HPLC analysis, was also previously detected during the analysis of leachables of the 18-month sample of the ready-to-use ephedrine sulfate composition.

[0134] The maximum amount of dichlorobenzoic acid (DCBA) found based on MS studies and HPLC analysis was about 1.4 ppm (about 0.02% with respect to ephedrine sulfate) in one sample of ready-to-use ephedrine sulfate composition stored in an upside-down position for 24 months. As per ICH guidelines (Impurities in New Drug Products Q3B R2), the discrimination threshold for any impurity that may be present in ephedrine sulfate is 0.2% and the qualification threshold is 0.5%. The DCBA found in this upside-down stored sample was about 1.4 ppm (about 0.02% with respect to ephedrine sulfate). The amount of A was below the limit of quantification (LOQ), i.e., <0.1 ppm.

[0135] Extracts from stoppers and vials were analyzed by ICP-MS for elemental impurity evaluation. Results from ICPMS analysis of the extract solutions indicate that classes 1, 2A, and 3 were found to be below the established PDEs, respectively. Additionally, three submitted batches of ready-to-use ephedrine sulfate composition of Example 2 stored in an upside-down position at 25°C ± 2°C and 60% ± 5% RH for 24 months were analyzed for class 1 and 2A elements by ICP-MS. All elemental impurities tested were found to be significantly lower than their established acceptable daily exposure (PDE) values. Thus, based on the data from this extractables and leachables study, the safety risks associated with leachables or metallic impurities in ready-to-use ephedrine sulfate compositions consistent with the present disclosure appear to be low.

[0136] Research into extractables The stoppers were extracted using three extraction solvents mentioned below: a) water adjusted to pH 3.4 using 1N HCl, b) water adjusted to pH 9.4 using 1N NaOH, c) IPA / water 50% / 50% (v / v). Three sets of 10 stoppers (each weighing approximately 16.8 g) were transferred to three separate 250 mL round bottom flasks. 100 mL each of the pH 3.4 aqueous solution, pH 9.4 aqueous solution and IPA / water (50:50 v / v) mixture were transferred to the three separate round bottom flasks mentioned above. Each solvent containing the 10 stoppers was refluxed and boiled overnight (minimum 12 hours). Refluxing was performed for 12 hours for the IPA / water mixture and pH 3.4 solution, respectively, and 20 hours for the pH 9.4 solution. The solutions obtained from each reflux solvent were analyzed for extractables using QTOF LC-MS and GC-MS.

[0137] Extractables studies intended to extract metals were conducted with rubber stoppers and glass vials. Ten stoppers were weighed (approximately 17 g weight) and transferred to a 1 L plastic container. Approximately 200 mL of 2% HNO3 solution (a suitable volume for immersing the stoppers) was transferred to the container with the stoppers and placed in an oven maintained at 60°C for approximately 24 hours. Similarly, five vials (approximately 20 g weight each) were transferred to a 1 L plastic container. Approximately 300 mL of 2% HNO3 solution (a suitable volume for immersing the vials) was transferred to the container with the vials and placed in an oven maintained at 60°C for approximately 24 hours. Additionally, the refluxed aqueous solution (pH 3.4, from the extractables study above) was also analyzed for metal impurities, since metals tend to be extracted in more acidic solutions. Ten elements (classes 1, 2A, and 3) were investigated. Extractables were analyzed according to USP <233> The compounds were analyzed by ICP-MS based on the ICH Q3D daily permitted exposure (PDE) limits.

[0138] The extracts from each reflux solvent were analyzed for extractables using QTOF LC-MS and GC-MS. Extractables included siloxane oligomers, non-ionic surfactants (laureth-9 and related), sulfur compounds, butylated hydroxytoluene (BHT) and fatty acids (inorganic fillers) commonly used in the production of elastomeric components. Another extractable found in the LC-MS analysis was triethylene glycol, a common plasticizer used in vinyl polymers. The extractable compounds detected in the extracts along with relative quantification are provided in Tables 29-32. According to the manufacturer, bisphenol A (BPA), melamine, 2-mercaptobenzothiazole, nitrosamines, phthalates and polyvinyl chloride (PVC) are not intentionally added to the stoppers. [Table 29] [Table 30] [Table 31] [Table 32-1] [Table 32-2]

[0139] To evaluate metal impurities, 2% nitric acid stopper extracts and pH 3.4 reflux extracts were prepared according to USP <233> The extractables were screened according to a base ICP-MS analysis and the results compared to the established PDEs for each element. Ten elements (Classes 1, 2A and 3) were selected. Results from the ICPMS analysis of the extract solutions indicate that Classes 1, 2A and 3 elements were found to be below their respective established PDEs. The ICP-MS results from the extractables study are summarized in Table 33. [Table 33]

[0140] Leachables Study Three submitted batches of ready-to-use ephedrine sulfate composition of Example 2 stored in an upside down position at 25°C ± 2°C and 60% ± 5% RH for 24 months were subjected to leachables study by QTOF GC-MS and LC-MS. A control sample was also prepared by dissolving 5 g of ephedrine sulfate API and 9 g of NaCl in 1 L of purified water in a volumetric flask. The pH of the resulting solution was about 5.6.

[0141] In the MS study, identification and relative quantification of leachables was achieved by GCMS QTOF and LC-MS QTOF analysis. The analytical evaluation threshold (AET) was calculated to be 0.15 μg / mL based on the proposed maximum daily dose of the drug product and was set at 0.2 μg / mL for GC-MS analysis and 0.1 μg / mL for LC-MS analysis. Drug product samples from the three lots described in Example 2 were extracted as is, as well as at lower and higher pH to prepare extracts for GC-MS analysis. Drug product samples were analyzed by LCMS analysis without further preparation. A summary of the leachables data for ephedrine sulfate injection samples is provided in Table 34 below. Reference standards of various structures and chromophores were used in the MS study, and quantification of extractables and leachables was performed based on the calibration curves of closely matched reference standards.

[0142] MS / MS studies were also performed where necessary to aid in identification from fragmentation patterns. It should be noted that the same test methods (GC-MS and LC-MS) were used for identification and quantification of extractables in the stopper extracts. The extensive list of extractables of various structures detected by these methods demonstrates the versatility of these methods. From the MS data, it is evident that numerous extractables were detected due to the stringent conditions used in the extractables study, however, the only compounds detected during the leachables analysis were dichlorobenzoic acid (1.4 μg / mL or less) and trace amounts of bis(2-ethylhexyl)isophthalate (0.15 μg / mL or less). The results from the leachables identification and relative quantification values ​​are summarized below in Table 34. [Table 34-1] [Table 34-2]

[0143] The aforementioned drug product samples were also analyzed for leachables by a validated HPLC method, EPH-006. EPH-006 was previously validated for accuracy, precision, linearity and LOQ using dichlorobenzoic acid, diethyl phthalate (same functional class as bis(2-ethylhexyl)isophthalate), BPA and Irganox related leachables. Dichlorobenzoic acid was also detected during the HPLC analysis using test method EPH-006 and the results are summarized in Table 35. [Table 35]

[0144] The LOQ of the method was determined to be 0.1 ppm, which is lower than the AET, i.e., 0.15 ppm. The only compounds detected above the LOQ level in the drug product samples were 2,4-dichlorobenzoic acid or its possible isomers, which were not detected by LC - is consistent with the MS data. It should be noted that dichlorobenzoic acid detected by both MS studies and HPLC analysis was also already detected during the analysis of leachables of the 18M sample. The formation of DCBA may be due to a possible interaction of benzoic acid with chloride ions in the drug product formulation. The amount of DCBA in drug product lots 1 and 2 (manufactured using the same API Siegfried lot number 16152015) is relatively higher than that of lot 3 (manufactured using a different API Siegfried lot number 16152017). These results are consistent with the previous results and further support our hypothesis that the formation of DCBA may be due to the interaction of benzoic acid with chloride ions during the formulation of ready-to-use ephedrine sulfate compositions consistent with the present disclosure.

[0145] To assess elemental impurities, the three submitted batches of Lots 1-3 of Example 2 stored in an inverted position at 25° C.±2° C. and 60%±5% RH for 24 M were analyzed for class 1 and 2A elements. The ICP-MS data is summarized in Table 36 below. [Table 36]

[0146] conclusion Extractables and leachables were identified using a combination of QTOF-GCMS and QTOF-LCMS-UV-CAD. Most of the identified extractables were likely derived from elastomer components or additives. The same test method was used for identification and relative quantification of extractables and leachables, and the instrumental analytical evaluation threshold (AET) was set at 0.1 μg / mL for LC-MS analysis and 0.2 μg / mL for GC-MS analysis. During the analysis of leachables, a compound consistent with bis(2-ethylhexyl) isophthalate was detected at concentrations of 0.15 μg / mL or less by QTOF-GCMS in the ephedrine sulfate injection sample. A compound consistent with dichlorobenzoic acid was detected at concentrations of 1.43 μg / mL or less by QTOF-LCMS-UV-CAD in the ephedrine sulfate injection sample. Dichlorobenzoic acid was also found by EPH-006 in HPLC analysis, and the amount was found to be 0.7 μg / mL or less. The formation of DCBA may be due to the possible interaction of benzoic acid and chloride ions present in the API in the drug product formulation. Therefore, based on the data from this extractables and leachables study, the safety risk associated with leachables or elemental impurities in ready-to-use ephedrine compositions consistent with the present disclosure appears to be low.

[0147] Further Examples Further Examples 1. A composition comprising ephedrine sulfate in water, wherein the ephedrine sulfate is present in a concentration of about 1 mg / mL to about 10 mg / mL.

[0148] Further Example 2. The composition of Further Example 1, wherein ephedrine sulfate is present in a concentration of about 2 mg / mL to about 8 mg / mL.

[0149] Further Example 3. The composition of Further Example 1, wherein ephedrine sulfate is present in a concentration of about 3 mg / mL to about 7 mg / mL.

[0150] Further Example 4. The composition of Further Example 1, wherein ephedrine sulfate is present in a concentration of about 4 mg / mL to about 6 mg / mL.

[0151] Further Example 5. The composition of Further Example 1, wherein ephedrine sulfate is present in a concentration of about 5 mg / mL.

[0152] Further Example 6 The composition of any further example above, further comprising sodium chloride.

[0153] Further Example 7. The composition of Further Example 6, wherein the sodium chloride is present in an amount of about 9 mg / mL.

[0154] Further Example 8. The composition of any further example above, which is stable when stored at 20° C. under light for at least 12 months.

[0155] Further Example 9. The composition of any further example above, which does not include dextrose.

[0156] Further Example 10. The composition of any further example above, which does not include benzyl alcohol.

[0157] Further Example 11 The composition of any further example above, consisting essentially of ephedrine sulfate, sodium chloride and water.

[0158] Further Example 12 The composition of any further example above consisting of ephedrine sulfate, sodium chloride and water.

[0159] Further Example 13. The composition of any further example above, wherein the ephedrine sulfate is (-)-ephedrine sulfate.

[0160] Further Example 14. About 3.8 mg / mL of ephedrine or an equimolar amount of an ephedrine salt; Approximately 9 mg / mL sodium chloride, and water Pre-diluted sterile pharmaceutical products, including:

[0161] Further Example 15. The pre-diluted sterile pharmaceutical product of Further Example 14, which does not contain dextrose.

[0162] Further Example 16. The pre-diluted sterile pharmaceutical of Further Example 14 or Further Example 15, which does not contain benzyl alcohol.

[0163] Further Example 17. The pre-diluted sterile pharmaceutical product of any one of further Examples 14-16, wherein the total volume of the pharmaceutical product is about 10 mL.

[0164] Further Example 18. The pre-diluted sterile pharmaceutical of any one of Further Examples 14-17, contained in a vial.

[0165] Further Example 19. The pre-diluted sterile pharmaceutical product of any one of further Examples 14-18, comprising at least 3 mg / mL ephedrine or a molar equivalent ephedrine salt after storage under light at about 20° C.

[0166] Further Example 20. The pre-diluted sterile pharmaceutical product of any one of further Examples 14-19, wherein the ephedrine or ephedrine salt is ephedrine sulfate.

[0167] Further Example 21. The pre-diluted sterile pharmaceutical of further Example 20, wherein the ephedrine sulfate is (-)-ephedrine sulfate.

[0168] Further Example 22. ephedrine sulfate at approximately 5 mg / mL; Approximately 9 mg / mL sodium chloride, and water A ready-to-use unit dosage form comprising:

[0169] Further Example 23. A ready-to-use unit dose form of Further Example 22, contained in a vial.

[0170] Further Example 24. A ready-to-use unit dose form of Further Example 22 or Further Example 23 having a total volume of about 10 mL.

[0171] Further Example 25. The ready-to-use unit dosage form of any one of Further Examples 22-24, which does not contain dextrose.

[0172] Further Example 26. The ready-to-use unit dosage form of any one of Further Examples 22-25, which does not contain benzyl alcohol.

[0173] Further Example 27. The ready-to-use unit dosage form of any one of further Examples 22-26, comprising at least 4 mg / mL of ephedrine sulfate after storage under light at about 20° C.

[0174] Further Example 28. Vials, and Solution in a vial 1. A packaged pharmaceutical product comprising: The solution is ephedrine sulfate at approximately 5 mg / mL; Approximately 9 mg / mL sodium chloride, and water A packaged pharmaceutical product comprising, consisting essentially of, or consisting of.

[0175] Further Example 29 The packaged pharmaceutical product of Further Example 28, wherein the solution has a total volume of about 10 mL.

[0176] Further Example 30. The packaged pharmaceutical product of Further Example 28 or Further Example 29, wherein the solution does not contain dextrose.

[0177] Further Example 31 The packaged pharmaceutical product of any one of further Examples 28-30, wherein the vial comprises, consists essentially of, or consists of glass.

[0178] Further Example 32. The packaged pharmaceutical product of any one of further Examples 28-31, wherein the vial comprises, consists essentially of, or consists of polypropylene.

[0179] Further Example 33. The packaged pharmaceutical product of any one of Further Examples 28-32, wherein the solution is stable when stored at about 20° C. under light for at least 12 months.

[0180] Further Example 34. The packaged pharmaceutical product of Further Example 33, wherein after storage under light at about 20° C. for at least 12 months, the solution comprises ephedrine sulfate in a concentration of about 4 mg / mL to about 6 mg / mL.

[0181] Further Example 35. The packaged pharmaceutical product of Further Example 33, wherein after storage at about 20° C. under light for at least 12 months, the solution contains at least 4 mg / mL of ephedrine sulfate.

[0182] Further Example 36. The packaged pharmaceutical product of Further Example 33, wherein after storage at about 20° C. under light for at least 12 months, the solution contains at least 4.5 mg / mL of ephedrine sulfate.

[0183] Further Example 37. The packaged pharmaceutical product of any one of Further Examples 28-36, wherein the ephedrine sulfate is (-)-ephedrine sulfate.

[0184] Further Example 38. A method of administering ephedrine sulfate to a subject in need thereof, comprising: drawing a composition comprising ephedrine sulfate from a sterile premixed pharmaceutical product into a syringe; injecting the composition into the subject using a syringe; Including, ephedrine sulfate is present in the composition in an amount of about 5 mg / mL; method.

[0185] Further Example 39. The method of further Example 38, wherein the composition further comprises sodium chloride in an amount of about 9 mg / mL.

[0186] Further Example 40 The method of Further Example 38 or Further Example 39, wherein the composition further comprises water.

[0187] Further Example 41. The method of any one of further Examples 38-40, wherein the composition does not include dextrose.

[0188] Further Example 42. The method of any one of further Examples 38-41, which does not include diluting a sterile premixed pharmaceutical product prior to the step of injecting the composition into the subject using a syringe.

[0189] Further Example 43. The method of any one of further Examples 38-42, wherein the composition contained in a vial of sterile premixed pharmaceutical product is stable when stored under light at about 20° C. for at least 12 months.

[0190] Further Example 44. The method of further Example 43, wherein after storage at about 20° C. under light for at least 12 months, the composition comprises ephedrine sulfate in an amount of about 4 mg / mL to about 6 mg / mL.

[0191] Further Example 45. The method of any one of further Examples 38-44, wherein the ephedrine sulfate is (-)-ephedrine sulfate.

[0192] Further Example 46. A method for making a ready-to-use pharmaceutical composition comprising ephedrine or an ephedrine salt, comprising: Combine ephedrine or an ephedrine salt, sodium chloride, and water. About 3.8 mg / mL of ephedrine or an equimolar amount of an ephedrine salt, and Approximately 9 mg / mL sodium chloride providing a solution comprising: Thereafter, sterilizing the solution to provide a ready-to-use pharmaceutical composition comprising ephedrine or an ephedrine salt. A method comprising:

[0193] Further Example 47. The method of further example 46, further comprising the step of placing the solution in one or more vials prior to the sterilization step.

[0194] Further Example 48. The method of Further Example 46 or Further Example 47, wherein the solution does not contain dextrose.

[0195] Further Example 49. The method of any one of Further Examples 46-48, wherein the pharmaceutical composition is stable when stored at about 20° C. under light for at least 12 months.

[0196] Further Example 50. The method of further Example 49, wherein after storage under light at about 20° C. for at least 12 months, the pharmaceutical composition comprises ephedrine or an ephedrine salt in an amount that is at least 80% of about 3.8 mg / mL of ephedrine or an equimolar amount of ephedrine salt.

[0197] Further Example 51. The method of any one of further Examples 46-50, wherein the ephedrine or ephedrine salt is ephedrine sulfate.

[0198] Further Example 52. The method of further Example 51, wherein the ephedrine salt is (-)-ephedrine sulfate.

[0199] Further Example 53. The method of Further Example 51 or Further Example 52, wherein the equimolar amount of ephedrine salt is about 5 mg / mL of ephedrine sulfate.

[0200] Further Example 54. The method of any one of further Examples 46-50, wherein the ephedrine or ephedrine salt is ephedrine hydrochloride.

[0201] Further Example 55. The method of further Example 54, wherein the ephedrine hydrochloride is (-)-ephedrine hydrochloride.

[0202] Further Example 56. The method of Further Example 54 or Further Example 55, wherein the equimolar amount of ephedrine salt is about 4.6 mg / mL of ephedrine hydrochloride.

[0203] Further Example 57. A method of treating hypotension in a subject in need thereof, comprising: drawing an effective amount of a packaged composition comprising ephedrine or an ephedrine salt into a syringe; injecting an effective amount of the packaged composition to a subject in need thereof; A method comprising:

[0204] Further Example 58. The method of further Example 57, wherein the packaged composition comprises ephedrine or an ephedrine salt in an amount equivalent to about 3.8 mg / mL of ephedrine.

[0205] Further Example 59. The method of Further Example 57 or Further Example 58, wherein the packaged composition further comprises sodium chloride in an amount of about 9 mg / mL.

[0206] Further Example 60. The method of any one of further Examples 57-59, wherein the packaged composition further comprises water.

[0207] Further Example 61. The method of any one of further Examples 57-60, wherein the packaged composition does not contain dextrose.

[0208] Further Example 62. The method of any one of further Examples 57-61, wherein the method does not include diluting the packaged composition prior to the step of injecting an effective amount of the packaged composition to a subject in need thereof.

[0209] Further Example 63. The method of any one of Further Examples 57-62, wherein the packaged composition is stable when stored at about 20° C. under light for at least 12 months.

[0210] Further Example 64. The method of further Example 63, wherein after storage under light at about 20° C. for at least 12 months, the packaged composition comprises ephedrine sulfate in an amount of about 4 mg / mL to about 6 mg / mL.

[0211] Further Example 65. The method of any one of further Examples 57-64, wherein the ephedrine or ephedrine salt is (-)-ephedrine sulfate.

[0212] Further Example 66. The method of any one of further Examples 57-65, further comprising the step of determining a hypotension reading of the subject prior to the step of drawing an effective amount of a packaged composition comprising ephedrine or an ephedrine salt into a syringe.

[0213] Further Example 67. A method of increasing blood pressure in a subject in need thereof, comprising: determining a hypotension reading associated with the subject; drawing about 1 mL to about 10 mL of a packaged composition containing about 5.0 mg / mL of ephedrine sulfate into a syringe; injecting about 1 mL to about 10 mL of the packaged composition into a subject in need thereof; Including, A method, wherein a blood pressure reading associated with the subject is elevated following a step of injecting the packaged composition into the subject in need thereof, the method not including diluting the packaged composition prior to the step of injecting the packaged composition into the subject in need thereof.

[0214] Further Example 68 The method of further Example 67, wherein the packaged composition further comprises sodium chloride in an amount of about 9 mg / mL.

[0215] Further Example 69 The method of Further Example 67 or Further Example 68, wherein the packaged composition further comprises water.

[0216] Further Example 70. The method of any one of further Examples 67-69, wherein the packaged composition does not contain dextrose.

[0217] Further Example 71. The method of any one of further Examples 67-70, further comprising, after the step of injecting the packaged composition into the subject, determining a second blood pressure reading associated with the subject, wherein the second blood pressure reading is hypotensive.

[0218] Further Example 72. The method of further Example 71, further comprising injecting about 1 mL to about 10 mL of the packaged composition into the subject after the step of determining a second hypotensive blood pressure reading associated with the subject.

[0219] Further Example 73. The method of any one of Further Examples 67-72, wherein the packaged composition is stable when stored at about 20° C. under light for at least 12 months.

[0220] Further Example 74. The method of further Example 73, wherein after storage at about 20° C. under light for at least 12 months, the packaged composition comprises ephedrine sulfate in an amount of at least about 4 mg / mL.

[0221] Further Example 75. The method of further Example 73, wherein after storage at about 20° C. under light for at least 12 months, the packaged composition comprises ephedrine sulfate in an amount of at least about 4.5 mg / mL.

[0222] Further Example 76. The method of any one of further Examples 67-75, wherein the ephedrine sulfate is (-)-ephedrine sulfate.

[0223] Further Example 77. A ready-to-use packaged pharmaceutical composition comprising ephedrine or a pharma- ceutically acceptable salt thereof, the ready-to-use packaged pharmaceutical composition exhibiting no more than about 5% decrease in concentration of ephedrine or a pharma- ceutically acceptable salt thereof when stored for at least 24 months.

[0224] Further Example 78 The ready-to-use packaged pharmaceutical composition of Further Example 77, further comprising sodium chloride.

[0225] Further Example 79. The ready-to-use packaged pharmaceutical composition of Further Examples 77 or 78, stored in a sealed glass container.

[0226] Further Example 80. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-79, which does not contain dextrose.

[0227] Further Example 81. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-80, which does not contain benzyl alcohol.

[0228] Further Example 82. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-81, consisting essentially of ephedrine or a pharma-ceutically acceptable salt thereof, sodium chloride and water.

[0229] Further Example 83. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-82, comprising about 5 mg / mL ephedrine sulfate.

[0230] Further Example 84. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-82, comprising about 3.8 mg / mL of ephedrine base.

[0231] Further Example 85. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-84, wherein the ephedrine sulfate is (-)-ephedrine sulfate.

[0232] Further Example 86. The ready-to-use packaged pharmaceutical composition of any one of Further Examples 77-85, formulated in a total volume of about 10 mL.

[0233] conclusion Unless otherwise specified or required by context, the term "ephedrine," as used herein, refers to (-)-ephedrine (i.e., (1R,2S)-2-methylamino-1-phenylpropan-1-ol sulfate).

[0234] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teachings. The embodiments have been chosen and described to best explain the principles of the invention and its practical application, and thereby enable others skilled in the art to best utilize the invention and its various embodiments, with various modifications, as suited to the particular uses intended. It is intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

[0235] It should be understood that both the foregoing descriptions are merely exemplary and explanatory and are not limiting of the methods and devices described herein. In this application, the use of the singular includes the plural unless specifically stated otherwise. Also, the use of "or" means "and / or" unless specifically stated otherwise. Similarly, "comprises," "including," "compounds ... "Comprising," "include," "includes," and "including" are not intended to be limiting.

[0236] All patent documents, patent applications, publications, and references cited in this specification are expressly incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The present invention provides, for example, the following items. (Item 1) 1. A method of administering ephedrine sulfate to a subject in need thereof, comprising: drawing a composition comprising ephedrine sulfate from a sterile premixed pharmaceutical product into a syringe; injecting the composition into the subject using the syringe; Including, The ephedrine sulfate is present in the sterile premixed pharmaceutical product in an amount of about 5 mg / mL. method. (Item 2) 13. The method of claim 1, wherein the composition further comprises sodium chloride in an amount of about 9 mg / mL. (Item 3) 3. The method of claim 1 or 2, wherein the composition further comprises water. (Item 4) The method according to any one of items 1 to 3, wherein the composition does not contain dextrose. The method according to any one of items 1 to 4, which does not include diluting the sterile premixed pharmaceutical product prior to the step of injecting the composition into the subject using the syringe. 6. The method according to any one of items 1 to 5, wherein the composition in the sterile premixed pharmaceutical product is stable when stored at about 20° C. for at least 12 months. (Item 7) 7. The method of claim 6, wherein after storage at about 20° C. for at least 12 months, the composition comprises ephedrine sulfate in an amount of about 4 mg / mL to about 6 mg / mL. (Item 8) 8. The method according to any one of items 1 to 7, wherein the ephedrine sulfate is (-)-ephedrine sulfate. (Item 9) 9. The method of any one of items 1 to 8, further comprising the step of determining a hypotensive blood pressure reading associated with the subject prior to the step of injecting the composition into the subject. (Item 10) 10. The method of any one of items 1 to 9, wherein the risk of microbial contamination to the second subject is lower or substantially lower than the risk of microbial contamination to a second subject requiring administration of ephedrine sulfate at a concentration of 5 mg / mL, and the second subject receives ephedrine sulfate prepared by diluting a concentrated ephedrine sulfate composition with a diluent. (Item 11) 1. A ready-to-use packaged pharmaceutical composition comprising ephedrine or a pharma- ceutically acceptable salt thereof, the ready-to-use packaged pharmaceutical composition exhibiting no more than about 5% decrease in concentration of said ephedrine or a pharma- ceutically acceptable salt thereof when stored for at least 12 months. (Item 12) 12. The ready-to-use packaged pharmaceutical composition according to item 11, further comprising sodium chloride. (Item 13) 13. The ready-to-use packaged pharmaceutical composition according to item 11 or item 12, stored in a sealed glass container. (Item 14) 14. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 13, which does not contain dextrose. (Item 15) 15. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 14, which does not contain benzyl alcohol. (Item 16) 16. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 15, consisting essentially of ephedrine or a pharma- ceutically acceptable salt thereof, sodium chloride and water. (Item 17) 17. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 16, comprising about 5 mg / mL ephedrine sulfate. (Item 18) 17. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 16, comprising about 3.8 mg / mL of ephedrine base. (Item 19) 19. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 18, wherein the ephedrine sulfate is (-)-ephedrine sulfate. (Item 20) 20. The ready-to-use packaged pharmaceutical composition according to any one of items 11 to 19, formulated in a total volume of about 10 mL.

Claims

[Claim 1] The invention described in the present specification.

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