WO2024254522A2 - Epinephrine liquid formulations - Google Patents

Abstract

The invention provides a liquid formulation comprising epinephrine or a pharmaceutically acceptable salt thereof. The formulation invention includes ascorbic acid and/or a pharmaceutically acceptable salt thereof, an isotonicity agent, and has a pH of about 3.0-5.0. The liquid formulation according to the invention is stable and ready-to-administer.

Description

EPINEPHRINE LIQUID FORMULATIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/506,780, filed June 7, 2023, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Epinephrine is a phenylethamine and catecholamine that functions in the body as a neurotransmitter and a hormone. In the brain, epinephrine increases arousal, enhances memory, and focuses attention while also increasing restlessness and anxiety. Elsewhere in the body, epinephrine increases heart rate and blood pressure, triggers glucose release from energy stores, increases blood flow to skeletal muscle, relaxes bronchial smooth muscle and dilates the bronchi.

[0003] Epinephrine also is referred to as adrenalin, adrenaline, L-adrenaline, (-)- adrenaline, L-epinephrine, R-epinephrine, (-)-epinephrine, (-)-(L)-epinephrine, (-)-(R)- epinephrine, 4-[(17?)-I-hydroxy-2-(methylamino)ethyl]benzene-l,2-diol, and L-l-(3,4- dihydroxyphenyl)-2-methylaminoethanol. Epinephrine has a molecular weight of approximately 183.20 and the following chemical structure:

[0004] In medicine, injections of epinephrine, or a pharmaceutically acceptable salt thereof, are used for the treatment of critically low blood pressure, or hypotension, anaphylaxis, and induction and maintenance of mydriasis. ADRENALIN™ (epinephrine) injection was approved in the United States in December 2012 under New Drug Application (ND A) 204200 packaged as a 1 mL sterile aqueous solution in a 3 mL clear glass vial containing 1 mg/mL of epinephrine base, 9.0 mg/mL sodium chloride for isotonicity, 1.0 mg/mL sodium metabisulfite as an antioxidant, and having a pH of 2.2 to 5.0. The prescribing information for ADRENALIN™ (epinephrine) injection states that the product is administered undiluted for treatment of anaphylaxis. For induction and maintenance of mydriasis it must be diluted before use, as follows. Dilute 1 mL of ADRENALIN™ 1 mg/mL (1 : 1000) in 100 to 1000 mL of an ophthalmic irrigation fluid to create an epinephrine concentration of 1 : 100,000 to 1 : 1,000,000 (10 mcg/mL to 1 mcg/mL). The approval letter for NDA 204200 states that a shelf life period of 15 months is granted for the 1 mg/mL product when stored at 20°C - 25°C (68°F - 77°F).

[0005] In September 2016, the FDA approved a supplemental NDA 204200/S-004 for ADRENALIN™ as a 1 mL sterile aqueous solution containing 1 mg/mL of epinephrine base, 7.3 mg/mL sodium chloride, 0.457 mg/mL sodium metabisulfite, 1 mg/mL sodium hydroxide, 2.25 mg/mL tartaric acid, 0.20 mg/mL disodium edetate dihydrate, hydrochloric acid to adjust pH, and water for injection, and having a pH range of 2.2-5.0. The approval letter for NDA 204200/S-004 states that the shelf life of the 1 mg/mL product is extended to 24 months and that the mydriasis indication is removed from the labeling.

[0006] ADRENALIN™ also is available in the US under NDA 204640 packaged as 30 mL of solution in a multiple dose amber glass vial. In the 30 mL vial, each 1 mL of solution contains 1 mg epinephrine, 6.15 mg sodium chloride, 0.457 mg sodium metabisulfite, 0.920 mg sodium hydroxide, 2.25 mg tartaric acid, 0.20 mg disodium edetate dihydrate, hydrochloric acid to adjust pH, 5.25 mg chlorobutanol as a preservative and water for injection. The pH range is 2.2-5.0. The prescribing information states that the vial and contents must be discarded 30 days after initial use.

[0007] U.S. Patent Nos. 9,119,876 and 9,295,657 disclose ready -to-inject epinephrine compositions that contain about 0.5 to 1.5 mg/mL of epinephrine and/or salts thereof, about 6 to 8 mg/mL of a tonicity regulating agent, about 2.8 to 3.8 mg/mL of a pH raising agent, about 0.1 to 1.1 mg/mL of an antioxidant, about 0.001 to 0.010 mL/mL of a pH lowering agent, and about 0.01 to 0.4 mg/mL of a transition metal complexing agent that is sodium bisulfite and/or sodium metabisulfite.

[0008] A pharmaceutical product containing 1 mg/mL epinephrine in a 2 mL clear glass ampule was approved for use in the United States in July 2014 under NDA 205029. The prescribing information states that the product is supplied as a sterile solution containing 1 mg/1 mL epinephrine as the hydrochloride in a preservative and sulfite free solution. Each mL contains 1 microgram epinephrine base (as the hydrochloride), sodium chloride (9 mg/mL), and may contain hydrochloric acid for pH adjustment. The prescribing information also states that it must be diluted prior to infusion by adding 1 mL (1 mg) of epinephrine to 1,000 mL of a 5% dextrose or a 5% dextrose and sodium chloride solution. In February 2022, the FDA approved a supplemental ND A 205029/S-009 for a 10 mL solution in a multiple dose amber vial. In the 10 mL vial, each 1 mL contains 1 mg epinephrine, 5.0 mg chlorobutanol as preservative, 7.5 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid for pH adjustment and water for injection. The pH range is 2.2-5.0. In May

2023, the FDA approved a supplemental NDA 205029/S-010 for a 1 mL solution in a 1 mL single-dose prefilled clear glass syringe. In the 1 mL syringe, each mL contains 1 mg epinephrine, 8.6 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid for pH adjustment and water for injection. The pH range is 2.2-5.0.

[0009] U.S. Patent Nos. 9,283,197, 10,004,700, and 10,039,728 and U.S. Patent Application Publication No. 2018/0333374 disclose liquid pharmaceutical formulations of a preservative free and sulfite-free, 1 mg/mL L-epinephrine sterile solution for injection having a pH between 2.8 and 3.3. The solution has no more than 6.5% total impurities at release, including no more than 6% d-epinephrine and no more than 0.5% adrenalone, and no more than 12.5% total impurities over a shelf-life of at least 12 months, including no more than 12% d-epinephrine and no more than 0.5% adrenalone. The formulations are stored in a container with an inert gas.

[0010] A pharmaceutical product containing 8-40 mcg/mL epinephrine in 0.9% sodium chloride in a premixed, ready-to-use 250 mL infusion bag was approved for use in the United States in April 2023 under NDA 215875. The prescribing information states that the product is supplied as a clear, colorless, sterile solution administered by intravenous infusion. Each mL contains the equivalent of 8, 16, 20, 32, or 40 micrograms of epinephrine base along with a corresponding 6.6, 13.1, 16.4, 26.2, and 32.8 micrograms of L(+) tartaric acid. The product contains sodium chloride (9 mg/mL), disodium edetate dihydrate (10 mcg/mL), and may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. It has a pH of 3.7 - 4.3, and the headspace of the bags has been displaced with nitrogen gas. The prescribing information also states that no further dilution prior to infusion is required. The product has an expiration date 24 months from the date of manufacture when stored at 20°C - 25°C (68°F - 77°F).

[0011] U.S. Patent Nos. 10,653,646, 11,083,698, and 11,207,280 and U.S. Patent Publication No. 2022/0110891 disclose ready to administer epinephrine compositions that comprise an aqueous pharmaceutically acceptable carrier containing epinephrine, a tonicity agent, and a metal ion chelator. The epinephrine is present at a concentration of equal or less than 0.07 mg/ml, and substantially all of the epinephrine is an R-isomer. The compositions have a pH of between 3.0-4 and the metal ion chelator is present at a concentration of between about 1 and 50 pg/ml. The compositions have storage stability such that after storage of at least one month, the epinephrine composition comprises total impurities of equal or less than 0.7% and equal or less than 4.5% S-isomer content. The epinephrine compositions are administered by injection without prior dilution from the container. [0012] International PCT Publication No. 2014/127015 discloses a pharmaceutical formulation comprising epinephrine or its salt thereof, sulfobutyl ether P-cyclodextrin, and a tonicity modifier in an aqueous solution.

[0013] International PCT Publication No. 2017/218918 describes a pharmaceutical composition comprising epinephrine, an antioxidant in an amount of about 0.07 wt. % or less, a buffering agent, a chelating agent, and a tonicity modifier in an aqueous medium.

[0014] There remains a need in the art for improved ready -to-administer, injectable formulations of epinephrine which are storage stable, preferably for longer durations at room temperature.

BRIEF SUMMARY OF THE INVENTION

[0015] The invention provides a ready -to-administer, liquid formulation comprising a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to 5.0.

[0016] The invention provides a ready -to-administer, liquid formulation comprising a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to 5.0 and is substantially free of sodium chloride.

[0017] The invention provides a ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine, from about 10 pg/mL to about 1 mg/mL ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2.

[0018] The invention also provides a ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine, from about 10 pg/mL to about 1 mg/mL ascorbic acid and/or a pharmaceutically acceptable salt thereof , a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2 and is substantially free of sodium chloride.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The invention provides a ready -to-administer, liquid formulation comprising a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to 5.0. The liquid formulation according to the invention is ready -to-administer and has a shelf life of at least about 12 months.

[0020] As used herein, a “ready -to-administer” formulation refers to a sterile, injectable formulation that need not be reconstituted from a solid or diluted from a concentrated solution by a healthcare provider prior to use. Rather, in the context of epinephrine formulations of the invention, a ready -to-administer formulation is supplied by a pharmaceutical manufacturer as a liquid having a pharmaceutically effective amount of epinephrine dissolved therein and contained within a suitable container (e.g., a bag or bottle) along with instructions indicating that no further dilution prior to injection or infusion is required. The ready -to-administer formulation of the invention also may be referred to as “premix”, “premixed”, or “premixture”, which distinguishes the formulation of the invention from other ready -to-administer formulations that are prepared by sterile-to-sterile compounding or active pharmaceutical ingredient (API)-to-sterile compounding and typically have a shelf life of 180 days or less, e.g., 90 days or less, 45 days or less, or 30 days or less. [0021] The formulation according to the present invention is stable. As used herein, the terms “stable” and “stability” encompass any characteristic of the formulation which may change or be affected by storage conditions including, without limitation, potency, total impurities, epinephrine degradation products, specific optical rotation, optical purity, appearance, viscosity, sterility, particulates (visible and subvisible), color, and/or clarity. The storage conditions which may affect stability may include, for example, duration, temperature, humidity, and/or light exposure.

[0022] For example, a stable epinephrine formulation may refer to a formulation that contains at least about 90%, e.g., at least about 92%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the labeled concentration of epinephrine or pharmaceutically acceptable salt thereof after storage under room temperature (e.g., 25° C ±2° C / 60% relative humidity (RH) ±5% RH) and/or accelerated (e.g., at 40° C ±2° C / 75% RH ±5% RH) conditions. A stable epinephrine formulation also may refer to a formulation that contains less than about 110%, e.g., less than about 108%, less than about 106%, less than about 105%, less than about 104%, less than about 103%, less than about 102%, or less than about 101% of the of the labeled concentration of epinephrine or pharmaceutically acceptable salt thereof after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation additionally may refer to a formulation that contains an amount of epinephrine bounded by any two of the foregoing endpoints. For example, a stable epinephrine formulation may contain from about 95% to about 105%, from about 97% to about 103%, from about 98% to about 102%, or from about 99% to about 101%, of the labeled concentration of epinephrine or pharmaceutically acceptable salt thereof after storage under room temperature and/or accelerated conditions.

[0023] A stable epinephrine formulation also may refer to a formulation that contains less than about 10% (area percent), e.g., less than about 8.0%, less than about 6.0%, less than about 5.0%, less than about 4.0%, less than about 3.0%, less than about 2.0%, or less than about 1.0%, of total epinephrine-related impurities present in the formulation after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation additionally may refer to a formulation that contains total epinephrine-related impurities present in an amount of about 0.5% or more, e.g., about 1.0% or more, about 1.5% or more, about 2.0% or more, about 2.5% or more, about 3.0% or more, about 3.5% or more, or about 4.0% or more, after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation also may refer to a formulation that contains total epinephrine- related impurities present in an amount bounded by any two of the aforementioned endpoints. For example, a stable epinephrine formulation also may refer to a formulation that contains from about 1.0% to about 10%, e.g., from about 1.0% to about 8.0%, from about 2.0% to about 6.0%, from about 0.5% to about 5.0%, from about 1.5% to about 4.0%, from about 1.0% to about 2.5%, or from about 0.5% to about 2.0%, of total epinephrine-related impurities present in the formulation after storage under room temperature and/or accelerated conditions.

[0024] A stable epinephrine formulation also may refer to a formulation that contains less than about 5.0% (area percent), e.g., less than about 4.0%, less than about 3.0%, less than about 2.0%, less than about 1.5%, less than about 1.0%, less than about 0.8%, less than about 0.4%, or less than about 0.2%, of any individual epinephrine-related impurity present in the formulation after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation additionally may refer to a formulation that contains any individual epinephrine-related impurity present in an amount of about 0.1% or more, e.g., about 0.2% or more, about 0.3% or more, about 0.4% or more, about 0.5% or more, about 0.6% or more, about 0.7% or more, or about 0.8% or more, after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation also may refer to a formulation that contains any individual epinephrine-related impurity present in an amount bounded by any two of the aforementioned endpoints. For example, a stable epinephrine formulation additionally may refer to a formulation that contains from about 0.1% to about 5.0%, from about 0.2% to about 4.0%, from about 0.4% to about 3.0%, from about 0.4% to about 1.5%, from about 0.5% to about 2%, or from about 0.3% to about 3.0% of any individual epinephrine-related impurity present in the formulation after storage under room temperature and/or accelerated conditions.

[0025] A stable epinephrine formulation also may refer to a formulation that contains less than about 10% (area percent), e.g., less than about 8.0%, less than about 6.0%, less than about 5.0%, less than about 4.0%, less than about 3.0%, less than about 2.0%, less than about 1.0%, less than about 0.8%, less than about 0.4%, or less than about 0.2%, of S-isomer of ephinephrine present in the formulation after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation additionally may refer to a formulation that contains S-isomer present in an amount of about 0.1% or more, e.g., about 0.3% or more, about 0.5% or more, about 0.7% or more, about 0.9% or more, about 1.2% or more, about 1.5% or more, about 2.0% or more, about 3.0% or more, or about 4.0% or more, after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation also may refer to a formulation that contains S-isomer present in an amount bounded by any two of the aforementioned endpoints. For example, a stable epinephrine formulation additionally may refer to a formulation that contains about 0.1% to about 5.0%, about 0.3% to about 4.0%, about 0.5% to about 3.0%, about 0.3% to about 1.5%, about 0.5% to about 2.0%, or about 0.9% to about 3.0% of S-isomer of ephinephrine present in the formulation after storage under room temperature and/or accelerated conditions.

[0026] A stable epinephrine formulation also may refer to a formulation that contains nitrosamines in an amount of about 5000 parts per billion (ppb) or less, e.g., about 4000 ppb or less, about 3000 ppb or less, about 2000 ppb or less, about 1000 ppb or less, about 800 ppb or less, about 600 ppb or less, about 500 ppb or less, about 400 ppb or less, about 300 ppb or less, about 200 ppb or less, or about 100 ppb or less, after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation additionally may refer to a formulation that contains nitrosamines in an amount of about 50 ppb or more, e.g., about 75 ppb or more, about 100 ppb or more, about 125 ppb or more, about 150 ppb or more, about 200 ppb or more, about 250 ppb or more, about 300 ppb or more, or about 350 ppb or more, after storage under room temperature and/or accelerated conditions. A stable epinephrine formulation also may refer to a formulation that contains nitrosamines in an amount bounded by any two of the aforementioned endpoints. For example, a stable epinephrine formulation may contain nitrosamines in an amount of from about 50 ppb to about 5000 ppb, from about 50 ppb to about 2000 ppb, from about 75 ppb to about 3000 ppb, from about 125 ppb to about 2000 ppb, from about 100 ppb to about 1000 ppb, from about 150 ppb to about 800 ppb, or from about 200 ppb to about 600 ppb, after storage under room temperature and/or accelerated conditions.

[0027] In some embodiments, the epinephrine formulation of the invention is stable for at least about 9 months, e.g., at least about 12 months, at least about 18 months, at least about 24 months, or at least about 36 months at room temperature (e.g., at 25 ±2° C / 60% RH ±5% RH) or at refrigerated temperature (e.g., at 5 ±3° C). The invention also includes embodiments in which the epinephrine formulation of the invention is stable for at least about 1 month, e.g., at least about 3 months, at least about 6 months, or at least about 12 months under accelerated conditions (e.g., at 40° C ±2° C / 75% RH ±5% RH).

[0028] Methods for determining the stability of a formulation of the invention with respect to a given parameter are well-known in the art. For example, individual impurities and total impurities may be assessed by high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Unless indicated otherwise, a percentage amount epinephrine, any individual impurity, or total impurities reported herein in the formulation is determined by a peak area percent method using HPLC, and nitrosamines are determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Non-limiting methods of analyzing the formulation of the invention are described, for example, in US Patent 10,653,646.

[0029] In some embodiments, a stable epinephrine formulation may refer to a formulation that is colorless after storage under room temperature and/or accelerated conditions. The color of the formulation may be determined, for example, by a United States Pharmacopoeia (USP) or European Pharmacopoeia (Ph. Eur.) color method. [0030] The formulation may include a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, such as, e.g., epinephrine bitartrate, epinephrine tartrate, or epinephrine HC1. Preferably, the epinephrine is of high enantiomeric purity or enantiomerically pure, e.g., at least about 95% R-isomer relative to all possible (R and S) enantiomers combined, at least about 97% R-isomer relative to all possible enantiomers, or at least about 99% R-isomer relative to all possible enantiomers. In some embodiments, the formulation includes a therapeutically effective amount of epinephrine bitartrate, which is preferably of high enantiomeric purity or enantiomerically pure. The epinephrine or pharmaceutically acceptable salt thereof in the formulation of the invention may be at a concentration of from about 0.5 pg/mL to about 200 pg/mL, e.g., from about 1 pg/mL to about 100 pg/mL, from about 5 pg/mL to about 50 pg/mL, from about 8 pg/mL to about 40 pg/mL, or from about 30 pg/mL to about 70 pg/mL. In some embodiments, the formulation includes about 8 pg/mL, about 16 pg/mL, about 20 pg/mL, about 32 pg/mL, or about 40 pg/mL epinephrine (as free base).

[0031] The formulation may be provided in any suitable volume. In some embodiments, the volume of the formulation is about 5 mL or more, e.g., about 10 mL or more, about 50 mL or more, about 100 mL or more, about 150 mL or more, about 200 mL or more, or about 250 mL or more. In other embodiments, the volume of the formulation is about 1 L or less, e.g., about 750 mL or less, about 500 mL or less, about 400 mL or less, about 300 mL or less, about 250 mL or less, or about 200 mL or less. The formulation also may be provided in a volume bounded by any two of the aforementioned endpoints. For example, the formulation may be provided in a volume of from about 10 mL to about 200 mL, from about 50 mL to about 500 mL, from about 100 mL to about 400 mL, from about 150 mL to about 300 mL, or from about 200 mL to about 300 mL. In certain embodiments, the volume of the formulation is about 250 mL. One of ordinary skill in the art may readily select an appropriate container based upon the volume of the formulation.

[0032] The formulation of the invention may include at least one antioxidant. In some embodiments, the antioxidant comprises ascorbic acid and/or a pharmaceutically acceptable salt thereof, each of which may be added to the formulation in anhydrous or hydrated form. In certain embodiments, the antioxidant comprises ascorbic acid and sodium ascorbate. In other embodiments, the antioxidant comprises a derivative of ascorbic acid and/or a pharmaceutically acceptable salt thereof, each of which may be added to the formulation in anhydrous or hydrated form. Non-limiting examples of a derivative of ascorbic acid include ascorbyl phosphates, ascorbyl sulfates, ascorbyl glycosides, and ascorbyl fatty acid esters. [0033] In some embodiments, the antioxidant may include an amino acid or a pharmaceutically acceptable salt thereof. The amino acid may include an L-stereoisomer, a D-stereoisomer, or a combination thereof. In some embodiments, the amino acid is naturally occurring. For example, the amino acid may include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, selenocysteine, pyrrolysine, or a combination thereof. In some embodiments, the amino acid may include tryptophan, methionine, histidine, lysine, arginine, or tyrosine. The invention also includes embodiments in which the amino acid comprises at least two primary or secondary amine groups, such as arginine, asparagine, lysine, methyl lysine, or ornithine. In certain embodiments, the antioxidant includes arginine.

[0034] In certain embodiments, the formulation comprises two or more antioxidants. In some embodiments, the formulation comprises ascorbic acid and an amino acid, or pharmaceutically acceptable salts thereof. In certain embodiments, the formulation comprises ascorbic acid, sodium ascorbate, and arginine.

[0035] The antioxidant may be present in the formulation in any suitable concentration. For example, the antioxidant may be present in the formulation at a concentration of about 10 pg/mL or more, e.g., about 25 pg/mL or more, about 50 pg/mL or more, about 62.5 pg/mL or more, about 100 pg/mL or more, about 250 pg/mL or more, about 400 pg/mL or more, about 500 pg/mL or more, about 600 pg/mL or more, about 1 mg/mL or more, about 5 mg/mL or more, about 7.5 mg/mL or more, or about 10 mg/mL or more. Alternatively, the antioxidant may be present in the formulation at a concentration of about 50 mg/mL or less, for example, about 25 mg/mL or less, about 10 mg/mL or less, about 7.5 mg/mL or less, about 5 mg/mL or less, about 2.5 mg/mL or less, about 2 mg/mL or less, about 1 mg/mL or less, about 750 pg/mL or less, about 500 pg/mL or less, or about 100 pg/mL or less. The antioxidant also may be present in the formulation in a concentration bounded by any two of the aforementioned endpoints. For example, the antioxidant can be present in the formulation in a concentration of from about 25 pg/mL to about 25 mg/mL, e.g., from about 50 pg/mL to about 5 mg/mL, from about 50 pg/mL to about 500 pg/mL, from about 100 pg/mL to about 10 mg/mL, from about 100 pg/mL to about 1 mg/mL, from about 250 pg/mL to about 5 mg/mL, from about 400 pg/mL to about 7.5 mg/mL, from about 500 pg/mL to about 2.5 mg/mL, from about 1 mg/mL to about 2.5 mg/mL, or from about 1 mg/mL to about 2 mg/mL.

[0036] In some embodiments, the antioxidant includes ascorbic acid present at a concentration of about 62.5 pg/mL. In other embodiments, the antioxidant includes sodium ascorbate present at a concentration of about 50 pg/mL. In certain embodiments, the antioxidant includes about 62.5 pg/mL ascorbic acid and about 50 pg/mL sodium ascorbate. In some embodiments, the antioxidant includes arginine present at a concentration of about 1.7 mg/mL. In other embodiments, the antioxidant includes arginine present at a concentration of about 600 pg/mL. In yet other embodiments, the antioxidant includes about 62.5 pg/mL ascorbic acid, about 50 pg/mL sodium ascorbate, and about 600 pg/mL arginine. [0037] The present invention is based, at least in part, on the surprising and unexpected discovery that certain metal ion chelators and/or antioxidants that are commonly used in liquid pharmaceutical formulations intended for parenteral administration are not necessary to stabilize a liquid epinephrine formulation. The invention accordingly includes embodiments in which the formulation is substantially free of a metal ion chelator and/or antioxidant other than ascorbic acid, an amino acid, and/or pharmaceutically acceptable salts thereof, thereby advantageously avoiding the need to include and administer such additives by injection. The invention accordingly includes embodiments in which the formulation is substantially free of, for example, a sulfite or a bisulfite. The invention also includes embodiments in which the formulation is substantially free of, e.g., an aminopolycarboxylic acid such as, for example, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(P-aminoethyl ether)-N,N,N',N'- tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid (DTP A), or a salt thereof. The invention further includes embodiments in which the formulation is substantially free of, e.g., butylated hydroxyl anisole (BHA), butylated hydroxyl toluene (BHT), alpha-tocopherol, or propyl gallate. The term “substantially free” as used herein with respect to an excipient means that no amount of the excipient is added during manufacture of the formulation and, if present, only may be present as an impurity.

[0038] The invention also includes embodiments wherein an amino acid or pharmaceutically acceptable salt thereof and another antioxidant are included in the formulation. In some embodiments, the formulation comprises arginine, asparagine, lysine, methyl lysine, or ornithine, and a sulfite, bisulfite, BHA, BHT, ascorbic acid, alphatocopherol, or propyl gallate. In certain embodiments, the formulation comprises arginine and a sulfite, such as, for example, sodium metabisulfite. The amino acid and additional antioxidant may be present in the formulation in any suitable concentration as described herein with respect to antioxidants. In some embodiments, the formulation comprises from about 100 pg/mL to about 10 mg/mL of an amino acid, and from about 0.5 pg/mL to about 200 pg/mL of another antioxidant. In certain embodiments, the formulation comprises from about 0.5 mg/mL to about 5 mg/mL of arginine, and from about 1 pg/mL to about 50 pg/mL of sodium metabisulfite.

[0039] The formulation of the invention also may include at least one tonicity agent.

Suitable tonicity agents may include, without limitation, sodium chloride, dextrose, mannitol, trehalose, potassium chloride, glycerol, or a combination thereof. In some embodiments, the tonicity agent includes sodium chloride. In other embodiments, the tonicity agent includes dextrose. In certain embodiments, the tonicity agent includes dextrose and the formulation is substantially free of sodium chloride. The tonicity agent is preferably present in an amount that renders the formulation isotonic. For example, the tonicity agent may present in an amount sufficient to provide the formulation with an osmolality of about 250-350 mOsm/kg, e.g., about 270-330 mOsm/kg, about 260-320 mOsm/kg, about 300-340 mOsm/kg, or about 310-330 mOsm/kg. In some embodiments, the tonicity agent is present in an amount that provides the formulation with an osmolality of 290 mOsm/kg ± 10%. The invention also includes embodiments in which the formulation includes about 50 mg/mL dextrose.

[0040] In certain embodiments the invention provides a ready -to-administer, liquid formulation comprising a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, arginine, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to 3.8 and is substantially free of sodium chloride. [0041] In other embodiments, invention provides a ready -to-administer, liquid formulation comprising a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to 5.0 and is substantially free of sodium chloride.

[0042] The formulation additionally may include at least one buffer other than ascorbic acid, which may have buffering capacity depending upon, e.g., concentration, presence of conjugate base, and/or pH. In some embodiments, however, the formulation is free of a buffer, or substantially free of a buffer other than ascorbic acid. If present, the type and amount of buffer present in the formulation may be selected based on several considerations, including but not limited to, for example, a target pH, pH stabilization, impurity formation, coloration, and/or patient tolerance upon administration. In some embodiments, the buffer may include a weak acid and a conjugate base of the weak acid. The weak acid and conjugate base may be added to the formulation in an anhydrous or hydrated form. In some embodiments, the conjugate base may be present in salt form. The invention also includes embodiments in which the acid or weak acid component may be a dicarboxylic acid or a tricarboxylic acid. For example, the acid includes citric acid, isocitric acid, aconitic acid, trimesic acid, propane-1, 2, 3 -tricarboxylic acid, fumaric acid, oxalic acid, maleic acid, malonic acid, glutaric acid, succinic acid, tartaric acid, or a combination thereof. In some embodiments, the buffer includes citric acid and a salt thereof (i.e., a citrate salt). [0043] In other embodiments, the formulation is free of a dicarboxylic acid, a tricarboxylic acid, and salts thereof, or substantially free of a dicarboxylic acid, a tricarboxylic acid, and salts thereof. The invention accordingly includes embodiments in which the formulation is free of citric acid and a citrate salt, or substantially free of citric acid and a citrate salt. The invention also includes embodiments in which the formulation is free of tartaric acid and a tartrate salt, or substantially free of tartaric acid and a tartrate salt. [0044] One of ordinary skill in the art may readily determine the amount of buffer required to achieve or maintain the desired pH, for example, based upon a weak acid and conjugate base included in the formulation. In some embodiments, the buffer may be present at a concentration of about 50 mM or less, e.g., about 40 mM or less, about 30 mM or less, about 20 mM or less, about 10 mM or less, or about 5 mM or less. In some embodiments, the buffer may be present at a concentration of about 0.5 mM or more, e.g., about 1 mM or more, about 2 mM or more, about 5 mM or more, about 10 mM, or about 20 mM or more. The invention also includes embodiments in which the buffer is present at a concentration of about 0.5-40 mM, e.g., about 1-20 mM, about 2-12 mM, about 7-11 mM, or about 8-10 mM. In some embodiments, the buffer includes a citrate buffer present at a concentration of about 5-15 mM, and preferably at a concentration of about 7-11 mM, for example, about 9 mM of a citrate buffer.

[0045] The formulation of the invention may further include a pH adjuster. The pH adjuster may include any suitable pH adjuster. A suitable pH adjuster may include, for example, sodium hydroxide, potassium hydroxide, hydrochloric acid, or a combination thereof. In some embodiments, the pH adjuster includes sodium hydroxide, hydrochloric acid, or a combination thereof.

[0046] The formulation of the invention may have any suitable pH. In some embodiments, the formulation may have a pH of about 3.0 or more, e.g., about 3.1 or more, about 3.2 or more, about 3.3 or more, about 3.4 or more, about 3.5 or more, about 3.6 or more, about 3.7 or more, about 3.8 or more, about 3.9 or more, or about 4.0 or more. In some embodiments, the formulation may have a pH of about 5.0 or less, e.g., about 4.8 or less, about 4.6 or less, from about 4.5 or less, from about 4.4 or less, about 4.3 or less, about 4.2 or less, about 4.1 or less, about 4.0 or less, about 3.9 or less, about 3.8 or less, about 3.7 or less, about 3.6 or less, or about 3.5 or less. The invention also includes embodiments in which the formulation may have a pH bounded by any two of the foregoing endpoints for the formulation. For example, the formulation may have a pH of from about 3.0 to about 5.0, from about 3.0 to about 4.5, from about 3.0 to about 4.0, from about 3.0 to about 3.8, from about 3.5 to about 4.5, from about 3.8 to about 4.2, from about 3.0 to about 3.4, from about 3.1 to about 3.7, from about 3.2 to about 3.6, from about 3.3 to about 3.7, or from about 3.4 to about 3.6. In some embodiments, the formulation has a pH of about 4.9, about 4.8, about 4.7, about 4.6, about 4.5, about 4.4, about 4.3, about 4.2, or about 4.1, about 4.0, about 3.9, about 3.8, about 3.7, or about 3.6, about 3.5, about 3.4, about 3.3, about 3.2, or about 3.1.

[0047] The formulation of the invention may be formulated to exhibit a stable pH following storage under room temperature and/or accelerated conditions. In some embodiments, the pH drift of the formulation is less than about 0.4 pH units, e.g., less than about 0.3 pH units, less than about 0.25 pH units, less than about 0.2 pH units, less than about 0.15 pH units, less than about 0.1 pH units, or less than about 0.05 pH units, following storage for at least about 6 months at room temperature. The invention also includes embodiments in which the pH drift of the formulation is less than about 0.4 pH units, e.g., less than about 0.3 pH units, less than about 0.25 pH units, less than about 0.2 pH units, less than about 0.15 pH units, less than about 0.1 pH units, or less than about 0.05 pH units, following storage for at least about 12 months at room temperature. In some embodiments, the pH drift of the formulation is less than about 0.4 pH units, e.g., less than about 0.3 pH units, less than about 0.25 pH units, less than about 0.2 pH units, less than about 0.15 pH units, less than about 0.1 pH units, or less than about 0.05 pH units, following storage for at least about 24 months at room temperature.

[0048] In some embodiments, the invention provides a ready -to-administer, liquid formulation which includes a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, an antioxidant, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 5.0, and wherein the formulation is substantially free of a sulfite. The tonicity agent may include dextrose, and the formulation also may be substantially free of sodium chloride. The formulation further may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0049] The invention also provides a ready -to-administer, liquid formulation which includes a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 5.0, and wherein the formulation is substantially free of a sulfite. The tonicity agent may include dextrose, and the formulation also may be substantially free of sodium chloride. The formulation may further include an amino acid that has at least two primary or secondary amine or amino groups. For example, the amino acid may be arginine, asparagine, lysine, methyl lysine, ornithine, or a combination thereof. The formulation also may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0050] The invention additionally provides a ready -to-administer, liquid formulation consisting essentially of a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 5.0. The tonicity agent may include dextrose. The formulation may further include an amino acid that has at least two primary or secondary amine groups. For instance, the amino acid may be arginine, asparagine, lysine, methyl lysine, or ornithine, or a combination of two of more of such amino acids.

[0051] The invention further provides a ready -to-administer, liquid formulation which includes a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 5.0, and wherein the formulation is substantially free of a sulfite. The tonicity agent may include about 50 mg/mL dextrose, and the formulation also may be substantially free of sodium chloride. The formulation additionally may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0052] The invention moreover provides a ready -to-administer, liquid formulation consisting essentially of a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 5.0. The tonicity agent may include about 50 mg/mL dextrose, and the formulation also may be substantially free of sodium chloride.

[0053] The invention furthermore provides a ready -to-administer, liquid formulation that includes from about 5 pg/mL to about 50 pg/mL epinephrine base, from about 10 pg/mL to about 1.0 mg/mL ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2. The formulation may also be substantially free of a sulfite. The tonicity agent may include about 50 mg/mL dextrose, and the formulation also may be substantially free of sodium chloride. The formulation further may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0054] In certain embodiments the invention provides a ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine, from about 10 pg/mL to about 1.0 mg/mL ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2 and is substantially free of sodium chloride.

[0055] The invention also provides a ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine base, from about 10 pg/mL to about 1.0 mg/mL ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2. The tonicity agent may include about 50 mg/mL dextrose. In some embodiments, the formulation has an osmolality of about 260-320 mOsm/kg.

[0056] The invention also provides a ready -to-administer, liquid formulation which includes a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, an amino acid, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8, and wherein the formulation is substantially free of a sulfite. The tonicity agent may include dextrose, and the formulation also may be substantially free of sodium chloride. The amino acid may include at least two primary or secondary amine or amino groups. For example, the amino acid may include arginine, asparagine, lysine, methyl lysine, ornithine, or a combination thereof. The formulation also may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0057] The invention additionally provides a ready -to-administer, liquid formulation consisting essentially of a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, an amino acid, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8. The tonicity agent may include dextrose. The amino acid may include at least two primary or secondary amine groups. For instance, the amino acid may include arginine, asparagine, lysine, methyl lysine, or ornithine, or a combination of two of more of such amino acids.

[0058] The invention further provides a ready -to-administer, liquid formulation which includes a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, arginine, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8, and wherein the formulation is substantially free of a sulfite. The tonicity agent may include about 50 mg/mL dextrose, and the formulation also may be substantially free of sodium chloride. The formulation additionally may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0059] The invention moreover provides a ready -to-administer, liquid formulation consisting essentially of a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, arginine, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8. The tonicity agent may include about 50 mg/mL dextrose, and the formulation also may be substantially free of sodium chloride. [0060] The invention furthermore provides a ready -to-administer, liquid formulation that includes from about 5 pg/mL to about 50 pg/mL epinephrine base, from about 400 pg/mL to about 7.5 mg/mL arginine, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8. The formulation may also be substantially free of a sulfite. The tonicity agent may include about 50 mg/mL dextrose, and the formulation also may be substantially free of sodium chloride. The formulation further may be substantially free of a metal ion chelator, such as an aminopolycarboxylic acid.

[0061] In certain embodiments the invention provides a ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine, from about 400 pg/mL to about 7.5 mg/mL arginine, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8 and is substantially free of sodium chloride.

[0062] The invention also provides a ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine base, from about 400 pg/mL to about 7.5 mg/mL arginine, a tonicity agent, and water, wherein the formulation has a pH of from about 3.0 to about 3.8. The tonicity agent may include about 50 mg/mL dextrose. In some embodiments, the formulation has an osmolality of about 260-320 mOsm/kg.

[0063] The invention further provides a pharmaceutical product which includes a primary container with the ready -to-administer, liquid epinephrine formulation of the invention contained therein, and a sealed secondary container which houses the primary container. The liquid formulation component of the pharmaceutical product may include formulations having the same composition and characteristics (e.g., stability) as described herein with respect to the formulation of the invention. The primary container may include, for example, a syringe, a cartridge, a vial, an ampoule, a bag, or a bottle. In some embodiments, the primary container includes a bag or a bottle.

[0064] The primary container may include, for example, a flexible, multi-layered bag. The bag may include a material which is chemically inert to the formulation, sterilizable, and weldable. Such materials include, without limitation, polyolefin polymers (e.g., a polyethylene or polypropylene), cycloolefin polymers or cycloolefin copolymers, polycarbonates, styrene polymers, and block co-polymers thereof. In some embodiments, a polyolefin may be combined with an elastomeric polymer, such as, e.g., a styrene- ethylene/butylene-styrene-triblock polymer (SEBS), a styrene-ethylene/propylene-styrene- triblock polymer (SEPS), a styrene-butadiene-styrene-triblock polymer (SBS), and/or a styrene-isoprene-styrene triblock polymer (SIS). In certain embodiments, the innermost layer of the multi-layered bag comprises polypropylene and SEBS. In other embodiments, the innermost layer of the multi-layered bag comprises a polymer of cyclic olefin such as cycloolefin homopolymer or cycloolefin copolymer or mixture thereof. In yet other embodiments, the innermost layer of the multi-layered bag comprises ethylene-vinyl acetate copolymer. Suitable flexible bags are described in US Patent Nos. 5,783,269, 7,875,016, 8,162,915, 7,828,787, and/or 8,118,802, which are incorporated herein by reference in their entireties, and marketed under the tradename, FREEFLEX™. Other flexible polymeric containers suitable for use with a formulation according to the invention include, without limitation, GALAXY™, VIAFLO™, INTRAVIA™, and EXCEL™ containers.

[0065] In some embodiments, the primary container is disposed within and enclosed by a secondary container, such as a blister package or an overwrap. The secondary container may include an overwrap with, e.g., a first foil, a second foil, and a seal disposed along a common peripheral edge of the first and second foils. The first and second foils of the secondary container overwrap may include multilayer films. In some embodiments, the secondary container is fully transparent to enable visual inspection of the primary container, labeling, and any other contents within the secondary container (e.g., oxygen absorber). The invention also includes embodiments in which the secondary container is fully intransparent, for example, an aluminum overpouch. The invention additionally includes embodiments in which the secondary container includes a completely or partially intransparent first foil and a completely or partially transparent second foil. Examples of secondary containers suitable for use in the present invention are described in US Patent Application Publication Nos. 2006/0240204 and 2019/0151202, which are incorporated herein by reference in their entireties.

[0066] The pharmaceutical product may further include an oxygen absorber that absorbs and removes or decreases the level of oxygen that may be present in the liquid epinephrine formulation, in the headspace of the primary container, and/or within the secondary container after initial packaging, as well as oxygen that may permeate through the secondary container during the shelf life of the pharmaceutical product. The oxygen absorber may be provided in any suitable size, form, or shape including, for example, a sachet, pouch, capsule, label, strip, patch, canister, cartridge, lining, or sticker, etc. The oxygen absorber may be placed inside of the secondary container or adhered or integrated into the primary container and/or the secondary container. In some embodiments, the oxygen absorber may be in the form of a sachet or in the form of a canister. The pharmaceutical product of the invention also includes embodiments in which the oxygen absorber may be in the form of a label or in the form of a strip. The pharmaceutical product of the invention additionally includes embodiments in which the oxygen absorber may be in the form of a sticker or label that adheres to the secondary container or to the primary container. The pharmaceutical product of the invention further includes embodiments in which the oxygen absorber may be incorporated as part of the secondary container itself such as, for example, as part of a lid, film, or seal of the secondary container.

[0067] Suitable materials for oxygen absorbers may include, for example, metal-based substances that remove oxygen by reacting with it by chemical bonding, generally forming a metal oxide component. Metal-based substances may include, e.g., elemental iron as well as iron oxide, iron hydroxide, iron carbide, and the like, and combinations thereof. Other metals for use as oxygen absorbers may include, e.g., nickel, tin, copper, zinc, and combinations thereof. Metal-based oxygen absorbers may be provided in the form of a powder, e.g., to increase active surface area. Powder forms of suitable metal-based oxygen absorbers may be obtained by any known method including, but not limited to, atomization, milling, pulverization, and electrolysis. Additional materials for oxygen absorbers may include, e.g., low molecular weight organic compounds such as, e.g., ascorbic acid, sodium ascorbate, catechol and phenol, activated carbon, polymeric materials incorporating a resin and a catalyst, and combinations thereof. In some embodiments, the oxygen absorber includes a metal-based oxygen absorber, such as an iron-based oxygen absorber.

[0068] A formulation of the invention that includes a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, an antioxidant, and a tonicity agent may be prepared by any suitable technique, many of which are known in the art. The formulation also may be prepared, e.g., in a batch or continuous process. In some embodiments, the formulation may be prepared by combining the components thereof in any order. The term “component” as used herein includes individual ingredients (e.g., epinephrine bitartrate, antioxidant, tonicity agent, pH adjuster, optional buffer, etc.) as well as any combination of two or more individual ingredients. In some embodiments, the formulation may be formed by combining the components together in a vessel. Such components may be combined in any order.

[0069] Thus, the invention provides a method for making a ready -to-administer, liquid epinephrine formulation that is stable for at least 9 months at room temperature. In some embodiments, the method includes (1) dissolving a tonicity agent and an antioxidant in water to form a first solution, (2) adjusting the first solution to pH of from about 3.0 to about 5.0 to form a second solution, (3) dissolving a pharmaceutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof in the second solution to form a epinephrine solution, and (4) sterilizing the epinephrine solution to provide the ready -to-administer, liquid epinephrine formulation.

[0070] In some embodiments, the method of the invention includes adding water to a suitable vessel, adding the antioxidant and tonicity agent, either sequentially or together, and stirring the mixture until dissolution is complete. Next, the pH may be adjusted to the desired value by adding one or more pH adjusters. Subsequently, the epinephrine or pharmaceutically acceptable salt thereof may be added, and the mixture stirred until dissolution is complete or substantially complete. Next, the volume of the formulation may adjusted to a desired volume with water, filtered through one or more sterilizing filters, and filled into primary containers. Then, the primary container may be sealed and placed into a secondary container, which may then be sealed. In some embodiments, an oxygen absorber may be placed into the secondary container before it is sealed. Preferably, dissolved oxygen is removed, e.g., by nitrogen sparging, at one or more steps of the compounding, filling, and/or packaging processes.

[0071] In some embodiments, the sealed, pharmaceutical product is sterilized by terminal sterilization, e.g., autoclaving. In certain embodiments, a formulation according to the present invention is autoclaved at a temperature of 120 °C - 122 °C and a pressure of 0.5 bar to 2.5 bar for 5-20 minutes, e.g., 1.0-1.5 bar for 5-15 minutes. In some embodiments, the thermal sterilization is carried out at a temperature of about 122 °C and a pressure of about 1.2 bar for 5 minutes. In other embodiments, the thermal sterilization is carried out at a temperature of about 122 °C and a pressure of about 1.2 bar for 15 minutes. The pharmaceutical product also may be manufactured using aseptic processing techniques, such that terminal sterilization is not required.

[0072] The invention also provides a method of stabilizing a epinephrine formulation by forming a mixture which includes epinephrine or a pharmaceutically acceptable salt thereof, an antioxidant, a tonicity agent, and water, thereby stabilizing the formulation. The type/form and amounts of epinephrine or pharmaceutically acceptable salt thereof, antioxidant, and tonicity agent present in the mixture, as well as the pH, may include the same types/forms and amounts of these components and the pH described herein with respect to a formulation of the invention. The formulation produced by the inventive method of stabilizing a epinephrine formulation may have the same stability characteristics as the stability characteristics described herein with respect to a formulation of the invention, particularly with regard to API assay, total impurities, individual impurities, and/or S-isomer content.

[0073] The formulation according to the invention is suitable for administration to a subject to treat or prevent a disease or condition, including a disease or condition that is treatable with epinephrine or a pharmaceutically acceptable salt thereof. Preferably, the subject is a mammal such as, for example, a human. The disease or condition that is treatable by the administration of epinephrine or a pharmaceutically acceptable salt thereof may include, for example, low blood pressure. In some embodiments, the condition may include severe, acute hypotension.

[0074] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLE 1

[0075] This example may demonstrate the stability of exemplary formulations comprising epinephrine, a tonicity agent, and an antioxidant.

[0076] Samples containing epinephrine or a pharmaceutically acceptable salt thereof, a tonicity agent, such as dextrose, an antioxidant selected from arginine, sodium metabisulfite, cysteine, and glutathione, optionally a citrate buffer composed of citric acid (anhydrous) and trisodium citrate dihydrate, and water may be adjusted to pH 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, or 4.4, filled into IV bags and sealed using aseptic technique, optionally placed into aluminum overwraps optionally containing an oxygen absorberand sealed, and optionally terminally sterilized by autoclaving. To analyze the samples for epinephrine content and impurities they may be placed into stability chambers under room temperature (25° C ±2° C / 60% RH ±5% RH) or accelerated temperature (e.g., at 40° C ±2° C / 75% RH ±5% RH) storage conditions for 1-9 months, and then analyzed by HPLC.

[0077] The results for epinephrine content (API assay) and total impurities may be determined by a peak area percent method.

[0078] To demonstrate stability, the API assay, individual impurities eluting at relative response times (RRT), total impurities, and/or S-isomer content may be compared among the exemplary epinephrine formulations.

EXAMPLE 2

[0079] This example may demonstrate the stability of exemplary formulations comprising epinephrine, a tonicity agent, and an antioxidant.

[0080] Samples containing epinephrine or a pharmaceutically acceptable salt thereof, the antioxidant arginine, and a tonicity agent selected from sodium chloride or dextrose, and water may be adjusted to pH 3.0, 3.4, or 3.8, filled into IV bags and sealed using aseptic technique, optionally placed into aluminum overwraps optionally containing an oxygen absorber and sealed, and optionally terminally sterilized by autoclaving. The samples may additionally contain a citrate buffer composed of citric acid (anhydrous) and trisodium citrate dehydrate. To analyze the samples for epinephrine content and impurities the samples may be placed into stability chambers under room temperature (25° C ±2° C / 60% RH ±5% RH) or accelerated temperature (e.g., at 40° C ±2° C / 75% RH ±5% RH) storage conditions for 1- 9 months, and then analyzed by HPLC. [0081] The results for epinephrine content (API assay), individual impurities eluting at RRTs, total impurities, and/or S-isomer content may be determined by a peak area percent method.

[0082] To demonstrate stability the API assay, individual impurities, and total impurities may be compared among the exemplary epinephrine formulations comprising arginine and dextrose and epinephrine formulations comprising arginine, sodium chloride, and citrate buffer.

EXAMPLE 3

[0083] This example demonstrates the stability of exemplary formulations comprising epinephrine, a tonicity agent, and an optional antioxidant.

[0084] Samples containing 20 pg/mL epinephrine, a tonicity agent selected from 9 mg/mL sodium chloride (NaCl) or 50 mg/mL dextrose (Dex), an optional antioxidant selected from 0.6 mg/mL arginine (Arg), 0.15 mg/mL glycine (Gly), and/or ascorbate buffer (Asc, 62.5 pg/mL ascorbic acid and 50 pg/mL sodium ascorbate), and water were adjusted to pH 4.0 using hydrochloric acid and/or sodium hydroxide, filled into IV bags, and sealed. A subset of each sample group was subjected to terminal sterilization (TS) by autoclaving at 122 °C for 5 minutes or 15 minutes. The samples were analyzed by HPLC for content of epinephrine, S-isomer, individual impurities, total impurities, and by LC-MS/MS for content of nitrosamines (N-Nitroso-epinephrine or NNE).

[0085] For assay, S-isomer, and impurities, the HPLC conditions were as follows: Column: Phenomenex Luna Hexyl-Phenyl 3 pm, 4.6 x 250 mm

Mobile Phase A: 52.5 mM monobasic potassium phosphate in water, pH 2.9

Mobile Phase B: acetonitrile:water (69:31)

Column temperature: 13° C

Flow rate: 0.8 mL/min

Injection volume: 50 pL

Autosampler temperature: 5° C

Detection UV: 225 nm

Separation mode: Gradient

Run time: 40 minutes

[0086] The results for content of epinephrine, S-isomer, individual impurities, and total impurities by peak area percent method as compared to placebo samples containing the same components except epinephrine are summarized in Table 1.

Table 1

[0087] These results demonstrate that the exemplary epinephrine formulations comprising ascorbic acid had more stable API assay, lower S-isomer content, and lower degradation products as compared with epinephrine formulations comprising lacking ascorbic acid. The results also demonstrate that exemplary formulations comprising dextrose had more stable API assay, lower S-isomer content, and lower degradation products as compared with epinephrine formulations comprising sodium chloride.

[0088] For nitrosamines, the HPLC and MS parameters were as follows.

Column: Zorbax Eclipse Plus C18 Rapid Resolution, 2.1 x 50 mm, 1.8 pm

Mobile Phase A: 0.1% Formic Acid in Water

Mobile Phase B: 0.1% Formic Acid in Methanol

Column temperature: 28° C

Flow rate: 0.35 mL/min

Injection volume: 20 pL

Autosampler temperature: 5° C

Run time: 10 minutes

Separation mode: Gradient

Detection: MS/MS

Mass Spectrometer: Agilent 6495D Triple Quadrupole

Polarity: Positive

Scan Type: MRM

[0089] The results for N-Nitroso-epinephrine in each sample against a calibration curve prepared from 0.004 ng/mL to 0.02 ng/mL N-Nitroso-epinephrine (corresponding to 200 ppb to 1000 ppb NNE) are summarized in Table 2.

Table 2

[0090] These results demonstrate that the exemplary epinephrine formulations comprising sodium chloride and ascorbic acid had lower nitrosamines as compared with epinephrine formulations comprising sodium chloride and arginine or glycine, but lacking ascorbic acid. The results also demonstrate that exemplary formulations comprising sodium chloride had lower nitrosamines as compared with epinephrine formulations comprising dextrose in the absence of antioxidant.

[0091] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0092] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0093] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S):

1. A ready -to-administer formulation comprising: a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof; ascorbic acid and/or a pharmaceutically acceptable salt thereof; a tonicity agent; and water; wherein the formulation has a pH of from about 3.0 to about 5.0.

2. The formulation of claim 1, wherein the epinephrine or pharmaceutically acceptable salt thereof is present at a concentration of from about 5 pg/mL to about 50 pg/mL.

3. The formulation of claim 1 or claim 2, wherein the formulation is substantially free of an aminopolycarboxylic acid and/or a sulfite.

4. The formulation of any one of claims 1-3, wherein the ascorbic acid and/or salt thereof is present at a concentration of from about 10 pg/mL to about 10 mg/mL.

5. The formulation of any one of claims 1-4, wherein the formulation has an osmolality of about 260-320 mOsm/kg.

6. The formulation of any one of claims 1-5, wherein the tonicity agent comprises dextrose and the formulation is substantially free of sodium chloride.

7. The formulation of any one of claims 1-6, wherein the formulation comprises ascorbic acid and sodium ascorbate.

8. The formulation of any one of claims 1-7, wherein the formulation comprises an amino acid or a pharmaceutically acceptable salt thereof.

9. The formulation of claim 8, wherein the amino acid comprises arginine.

10. The formulation of any one of claims 1-9, wherein the formulation has a pH of about 3.8 to about 4.2.

11. The formulation of any one of claims 1-10, wherein the formulation has a pH drift of less than about 0.3 pH units following storage for at least about 6 months at room temperature.

12. The formulation of any one of claims 1-11, wherein the formulation contains not more than about 3% total impurities as determined by a peak area percent method by high-performance liquid chromatography (HPLC) after storage for at least about 3 months at 40° C ±2° C / 75% RH ±5% RH.

13. A ready -to-administer formulation comprising: a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof; ascorbic acid and/or a pharmaceutically acceptable salt thereof; a tonicity agent; and water; wherein the formulation has a pH of from about 3.0 to about 5.0 and is substantially free of sodium chloride.

14. The formulation of claim 13, wherein the epinephrine or pharmaceutically acceptable salt thereof is present at a concentration of at a concentration of from about 5 pg/mL to about 50 pg/mL.

15. The formulation of claim 13 or claim 14, wherein the formulation is substantially free of an aminopolycarboxylic acid and/or a sulfite.

16. The formulation of any one of claims 13-15, wherein the ascorbic acid and/or salt thereof is present at a concentration of from about 10 pg/mL to about 10 mg/mL.

17. The formulation of any one of claims 13-16, wherein the formulation has an osmolality of about 260-320 mOsm/kg.

18. The formulation of any one of claims 13-17, wherein the formulation comprises ascorbic acid and sodium ascorbate.

19. The formulation of any one of claims 13-18, wherein the formulation comprises an amino acid or a pharmaceutically acceptable salt thereof.

20. The formulation of claim 19, wherein the amino acid comprises arginine.

21. The formulation of any one of claims 13-20, wherein the formulation has a pH of about 3.8 to about 4.2.

22. The formulation of any one of claims 13-21, wherein the formulation has a pH drift of less than about 0.3 pH units following storage for at least about 6 months at room temperature.

23. The formulation of any one of claims 13-22, wherein the formulation contains not more than about 3% total impurities as determined by a peak area percent method by high-performance liquid chromatography (HPLC) after storage for at least about 3 months at 40° C ±2° C / 75% RH ±5% RH.

24. A pharmaceutical product comprising a primary container comprising the ready -to-administer formulation according to claim 1, and a sealed secondary container which houses the primary container.

25. The pharmaceutical product according to claim 24, wherein the primary container comprises a flexible, multi-layer bag comprising a polyolefin.

26. The pharmaceutical product according to claim 24 or claim 25, wherein the secondary container comprises an aluminum overwrap.

27. The pharmaceutical product according to any one of claims 24-26, further comprising an oxygen absorber.

28. A pharmaceutical product comprising a primary container comprising the ready -to-administer formulation according to claim 13, and a sealed secondary container which houses the primary container.

29. The pharmaceutical product according to claim 28, wherein the primary container comprises a flexible, multi-layer bag comprising a polyolefin.

30. The pharmaceutical product according to claim 28 or claim 29, wherein the secondary container comprises an aluminum overwrap.

31. The pharmaceutical product according to any one of claims 28-30, further comprising an oxygen absorber.

32. A ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine, from about 10 pg/mL to about 1 mg/mL ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2.

33. The formulation of claim 32, wherein the formulation has an osmolality of about 260-320 mOsm/kg.

34. The formulation of claim 32 or claim 33, wherein the tonicity agent comprises dextrose and the formulation is substantially free of sodium chloride.

35. The formulation of any one of claims 32-34, wherein the formulation comprises ascorbic acid and sodium ascorbate.

36. The formulation of any one of claims 32-35, wherein the formulation comprises an amino acid or a pharmaceutically acceptable salt thereof.

37. The formulation of claim 36, wherein the amino acid comprises arginine.

38. The formulation of any one of claims 32-37, wherein the formulation has a pH of about 4.0.

39. The formulation of any one of claims 32-38, wherein the formulation has a pH drift of less than about 0.3 pH units following storage for at least about 6 months at room temperature.

40. The formulation of any one of claims 32-39, wherein the formulation contains not more than not more than about 3% total impurities as determined by a peak area percent method by high-performance liquid chromatography (HPLC) after storage for at least about 3 months at 40° C ±2° C / 75% RH ±5% RH.

41. A ready -to-administer, liquid formulation consisting essentially of from about 5 pg/mL to about 50 pg/mL epinephrine, from about 10 pg/mL to about 1 mg/mL of ascorbic acid and/or a pharmaceutically acceptable salt thereof, a tonicity agent, and water, wherein the formulation has a pH of from about 3.8 to about 4.2 and is substantially free of sodium chloride.

42. The formulation of claim 41, wherein the formulation has an osmolality of about 260-320 mOsm/kg.

43. The formulation of claim 41 or 42, wherein the formulation comprises ascorbic acid and sodium ascorbate.

44. The formulation of any one of claims 41-43, wherein the formulation has a pH of about 4.0.

45. The formulation of any one of claims 41-44, wherein the formulation has a pH drift of less than about 0.3 pH units following storage for at least about 6 months at room temperature.

46. The formulation of any one of claims 41-45, wherein the formulation contains not more than not more than about 3% total impurities as determined by a peak area percent method by high-performance liquid chromatography (HPLC) after storage for at least about 3 months at 40° C ±2° C / 75% RH ±5% RH.

47. A pharmaceutical product comprising a primary container comprising the ready -to-administer formulation according to claim 32, and a sealed secondary container which houses the primary container.

48. A pharmaceutical product comprising a primary container comprising the ready -to-administer formulation according to claim 41, and a sealed secondary container which houses the primary container.