FIELD OF INVENTION

The present invention relates to stable injectable pharmaceutical compositions comprising Epinephrine or its pharmaceutically acceptable salts with low level of degradants.

The present invention specifically relates to stable injectable pharmaceutical compositions comprising Epinephrine or its pharmaceutically acceptable salts which is not having sulfite anti- oxidants, amino-acid antioxidants, complexing agents and preservatives.

BACKGROUND OF INVENTION

Epinephrine, also known as 4-[(lR)-l-Hydroxy-2-(methylamino)ethyl]-l,2- benzenediol, is an endogenous adrenergic neurotransmitter synthesized and stored in the adrenal medulla that acts on both alpha and beta adrenergic receptors. Epinephrine generates an inotropic effect, wherein it increases the heart rate, the force of contraction of the heart, narrows the blood vessels thus increasing blood pressure, reduces airway resistance to make it easier to breath, and raises blood glucose and blood fatty acids to supply the body energy during stress. Epinephrine remains the first-line inotrope/vasopressor in many parts of the world and is recognized by the World Health Organization as an essential medicine with many medical uses and forms of administration.

Epinephrine is available in a variety of formulations suited for different clinical indications and routes of administration, for example by injection, by inhalation, or topically. It used to treat the different clinical indications like allergic reactions (Type 1) including anaphylaxis, induction and maintenance of mydriasis during intraocular surgery, treatment of bronchospasm, reducing nasal congestion, sensitivity reactions, cardiac arrhythmias, GI and renal hemorrhage, superficial bleeding, premature labor, hypoglycemia, and cardiogenic, hemorrhagic, and traumatic shock. Epinephrine can also be used to increase blood flow in ACLS during CPR, as an adjunct to local anesthesia, and for radiographic uses.

These days allergic emergencies such as anaphylaxis are a growing concern. Anaphylaxis is a systemic allergic reaction that can be fatal, if left untreated. Anaphylaxis can involve various areas of the body, such as the skin, respiratory tract, gastrointestinal tract, and cardiovascular system. Acute symptoms occur from within minutes to two hours after contact with the allergy-causing substance, but in rare instances onset may be delayed by as much as four hours.

According to the Merck Manual, immediate treatment with epinephrine is imperative for the successful treatment of anaphylaxis (Merck Manual, l7.sup.th Ed., 1053-1054 (1999)). The recommended dose is about 0.01 mL/Kg in adults: usually about 0.3 to 0.5 mL of a 1: 1000 dilution of epinephrine in a suitable carrier. While the dose may be given manually, such as either subcutaneously or intramuscularly. Recently, automatic injectors have become an accepted first aid means of delivering epinephrine. It is recommended that persons at risk of anaphylaxis, and persons responsible for children at risk for anaphylaxis, maintain one or more automatic epinephrine injectors in a convenient place at all times. It is further recommended that, if the symptoms of anaphylaxis persist after the first dose of epinephrine is injected, the patient should be treated with a second dose of epinephrine (about 0.3 mL of the 1: 1000 dilution).

Epinephrine Injection is administered by intravenous injection, in cardiac arrest by intracardiac injection into the left ventricular chamber, through endotracheal tube directly into the bronchial tree. The adult intravenous dose for hypersensitivity reactions or to relieve bronchospasm is ranges from 0.1 to 0.25 mg (1 to 2.5 mL of 1: 10,000 solution) injected slowly. Neonates may be given a dose of 0.01 mg per kg of body weight; for the infant 0.05 mg is an adequate initial dose and this may be repeated at 20 to 30 minute intervals in the management of asthma attacks. While in case of cardiac arrest, 0.5 to 1.0 mg (5 to 10 mL of 1: 10,000 solution) may be given. During a resuscitation effort, 0.5 mg (5 mL) should be administered intravenously every five minutes. Intracardiac injection may be administered, if there has not been sufficient time to establish an intravenous route. The intracardiac dose usually ranges from 0.3 to 0.5 mg (3 to 5 mL of 1: 10,000 solution).

Epinephrine is destroyed readily in alkaline solutions by aldehydes, weak oxidizing agents and oxygen of the air. Dilute solutions are partially stabilized by the addition of chlorobutanol and by reducing agents, such as sodium metabisulfite or sodium bisulfite. The primary determinant of catecholamine stability in intravenous admixtures is the pH of the solution. Epinephrine hydrochloride is unstable in dextrose (5% in water) at a pH above 5.5. The pH of optimum stability is from about 3 to about 4. In one study, the decomposition rate increased two-fold (from 5 to 10% in 200 days at 30° C.) when the pH was increased from 2.5 to 4.5. Epinephrine hydrochloride is rapidly destroyed by alkali or by oxidizing agents including halogens, permanganates, chromate, nitrates, nitrites and salts of easily reducible metals such as iron, copper, and zinc. In alkaline solution and when exposed to air or light, it turns pink from oxidation to adenochrome and then brown from the formation of polymers. Epinephrine should not be mixed with aminophylline containing solutions because of the alkalinity of these solutions. In one evaluation with aminophylline stored at 25°C, a colour change was noted after about 8 hours and only 40% of the initial drug was still present in the admixture at 24 hours.

Though epinephrine is useful in treatment of many clinical conditions, existing epinephrine formulations are associated with many problems such as low stability, reduced potency, high impurity level, less desirable effects.

U.S. Patent No. 3,966,905 discloses catecholamine solutions at mild pH are suitable for physiological use. U.S. Patent No. 9,119,876 Bl discloses a pharmaceutical compositions comprising epinephrine, where the composition may comprise at least one of an active agent, a pH raising agent, an sulfite antioxidant, a transition metal complexing agent, a pH lowering agent, a tonicity regulating agent, optionally a preservative, and optionally a solvent.

WO 2017/218918 discloses a formulation comprises epinephrine or a salt thereof, a complexing agent, and a "non-sulfite" antioxidant. The epinephrine formulations substantially demonstrated the superior physicochemical stabilities to conventional sulfite formulation of commercial medications currently available. In some instances, sulfite-free formulations further provide further benefit (e.g., safety benefits) to sulfite- sensitive patients.

Currently approved epinephrine products are Adrenalin® 1 mL and Adrenalin® 30 mL. FDA approved for an 18 month shelf life for Adrenalin® 1 mL, while 14 months for Adrenalin® 30 mL. Shelf life of these products is limited by the formation of degradants i.e. epinephrine sulfonic acid (ESA) and D-epinephrine that has insignificant therapeutic activity. The currently approved Adrenalin® 1 mL and Adrenalin® 30 mL products have a total impurity limit of £20%. Adrenalin® 1 mL has a concentration limit of £ 13.5% ESA and £9.5% D-epinephrine while Adrenalin®30 mL has a concentration limit of £l4.5% ESA and £9.5% D- epinephrine.

Existing epinephrine formulations has many deficiencies due to which quality, purity, potency and safety of the drug product cannot be assured adequately. There is a need for improved epinephrine-containing pharmaceuticals which is stable, having minimal levels of degradants including d-epinephrine, sulfite-free and with minimal overage. It is an objective of the present invention to fulfil this unmet medical need by providing an epinephrine-containing pharmaceutical composition that addresses some of the limitations of existing epinephrine formulations along with method of preparation for safer medicinal use to achieve an improved standard of patient care.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide stable aqueous pharmaceutical preparations comprising Epinephrine or its pharmaceutically acceptable salts.

Another objective of the present invention is to provide stable aqueous compositions of Epinephrine or its pharmaceutically acceptable salts with low to nil levels of epinephrine sulfonic acid (ESA) impurity, wherein the compositions are free of sulfite antioxidants, amino-acid antioxidants, preservatives and complexing agents.

Another objective of the present invention is to provide stable aqueous compositions of Epinephrine or its pharmaceutically acceptable salts with low levels of d- epinephrine, wherein the compositions are free of sulfite antioxidants, amino- acid antioxidants, preservatives and complexing agents.

SUMMARY OF INVENTION

Accordingly, the present invention provides a stable aqueous composition of

Epinephrine or its pharmaceutically acceptable salts comprising trometh amine which is completely free of sulfite anti-oxidants, amino acid antioxidants, preservatives and complexing agents. Another embodiment of the present invention provides a stable aqueous composition of Epinephrine or its pharmaceutically acceptable salts comprising trometh amine with low to nil levels of epinephrine sulfonic acid (ESA) impurity, wherein the composition is free of sulfite anti-oxidants, amino acid antioxidants, preservatives and complexing agents. Another embodiment of the present invention provides a stable aqueous composition of Epinephrine or its pharmaceutically acceptable salts comprising tromethamine with low levels of d- epinephrine impurity, wherein the composition is free of sulfite anti- oxidants, amino acid antioxidants, preservatives and complexing agents.

Another embodiment of the present invention provides a stable aqueous composition of Epinephrine or its pharmaceutically acceptable salts comprising one or more excipients selected from pH modifying agents, antioxidants, chelating agents, tonicity regulating agents and a vehicle.

Yet another embodiment of the present invention provides a process for preparing stable aqueous composition of Epinephrine or its pharmaceutically acceptable salts comprising the steps of:

a) preparing an aqueous solution of chelating agent,

b) adding the Epinephrine or its pharmaceutical acceptable salts to the above solution by mixing under inert atmosphere,

c) adding pH modifying agent to the above solution with continuous stirring,

d) adding specified amount of antioxidants to the above solution, e) adding specified amount of tonicity agent by mixing the solution, f) adding the tromethamine to the solution to adjusting the pH in the range of 2.2 to 5.0,

g) optionally adding pH modifying agent to adjust the pH, and

h) sterilizing the above solution and filling into suitable containers.

DETAILED DESCRIPTION OF THE INVENTION

Existing formulations of epinephrine uses antioxidant such as Sulfites were able to counter the oxidation of epinephrine by reacting with residual oxygen in its container instead of reacting with epinephrine. When epinephrine dissolution was carried out by means of addition of diluted hydrochloric acid, HC1, some excess of acid could maintain a low pH near 2.2 and causes racemization of epinephrine. Epinephrine racemizes at an appreciable rate even at near ambient temperature and the process is acid catalyzed. At pH 3.5 or less, racemization occurs by an SN type reaction. This acid catalyzed reaction is thought to occur by rapid protonation of the secondary alcoholic oxygen atom followed by rate determining elimination of this hydroxyl as water. Attack of a second molecule of water on the shielded incipient carbonium ion then results in production of the optical isomer. Since the same reaction occurs on d-isomer, a racemic mixture results. The d-isomer of epinephrine has little pharmacological activity as compared to the 1- isomer. At pH 3.5 or less there is low level of other epinephrine degradants.

Closely allied with epinephrine's racemization reaction is its reaction with anions of sulfurous acid. Bisulfite or metabisulfite salts are frequently used as antioxidants in aqueous formulations of epinephrine where they function to retard colour formation. Further, it was shown that at pH 4.7 or higher, epinephrine was lost more rapidly in the presence of bisulfite than in its absence. Anions of sulfurous acid generated from bisulfite or metabisulfite salts actually react with epinephrine to produce l-(3,4-dihydroxyphenyl)-2-methylaminoethane sulfonic acid (ESA). Although the optical activity of the solution of the catecholamine is lost progressively in the presence of bisulfite, the loss has been shown by chemical analysis to be due to formation of the optically inactive sulfonate. The increase of ESA in the epinephrine formulation containing sodium metabisulfite or sodium bisulfite could be greater than 15% at the end of product life. The safety and/or toxicity of ESA in commercial epinephrine products for anaphylactic treatment are still not well understood. In addition, the potency of epinephrine also could be substantially degraded to nearly l0%> due to such reaction at the end of product life.

The present invention provides sulfite free, amino acid free, preservative free and complexing agent free composition comprising epinephrine and its salts, pH modifying agents, antioxidants, chelating agents, tonicity regulating agents and water as vehicle.

The active agent is present at a concentration sufficient for any of the uses described herein. In some embodiments, the active agent is present at a concentration of about 0.1 to 2 mg/mL, preferably about 0.5 to 1.5 mg/mL, more preferably about 0.75 to 1.25 mg/mL and most preferably about 1 mg/mL.

According to the present invention, it is also possible to adjust the pH with at least one physiologically-pH modifying agents. In some embodiments, the pH modifying agent may have a pH range from 2 to 5, pH of said composition is between 2.2 to 5.0, preferably about 3.5 to about 4.5, preferably about 3.7 to about 4.2. pH of formulation plays important role in generation of degradants and racemization of epinephrine. pH should be adjusted to such a value so that there will be balance between epinephrine impurities and d-isomer level of epinephrine.

Suitable pH modifying agents used in the compositions of the present invention include, but are not limited to acids, bases or salt form of one or more, such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, phosphorous acid, carbonic acid, sulfurous acid, nitrous acid, ascorbic acid, propionic acid, lactic acid, citric acid, formic acid, oxalic acid, benzoic acid, acetic acid, tartaric acid, malonic acid, maleic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tromethamine, sodium hydroxide, calcium hydroxide, potassium hydroxide and magnesium hydroxide, sodium dihydrogen phosphate and its hydrates, sodium phosphate and its hydrates, disodium hydrogen phosphate and its hydrates, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, sodium nitrite, sodium nitrate, magnesium nitrate, calcium nitrite and magnesium nitrite; Tris hydrochloride or combinations thereof. Preferably, the pH modifying agent comprises at least one of tromethamine, citric acid, ascorbic acid, hydrochloric acid and sodium hydroxide, and more preferably mixture of these compounds. The present invention provides for a composition that comprise of at least one antioxidant that prevent the formation of oxidative degradants in the composition during the period of shelf life. The term“antioxidant” refers to the component that may react with oxygen that might otherwise compromise the composition by producing oxidative impurities in the composition responsible for unacceptable colour of formulation. Oxygen may originate from the composition's environment or the composition itself e.g. oxygen present in headspace of vials. The oxidative impurities comprise one or more of adrenochrome, adrenolutin, and melanins.

Antioxidant used in the compositions of the present invention include, but are not limited to butylhydroxytoluene (BHT), benzotriazol, butylhydroxyanisole (BHA), ascorbyl palmitate, disodium calcium ethylenediaminetetraacetate, DL-alpha- tocopherol, disodium ethylenediaminetetraacetate, erythorbic acid, dithiothreitol, monothioglycerol, thioglycerol, propyl gallate, erythorbate, sodium thioglycolate, vitamin E and derivatives thereof, a-thioglycerin, and/or salts thereof. Sulfite containing antioxidants generate anions of sulfurus acid which react with epinephrine to produce l-(3,4-dihydroxyphenyl)-2-methylaminoethane sulfonic acid (ESA). Also generation of sulfurus acid anions reduce pH of formulation which promote the racemization of epinephrine results in formation of d-isomer of epinephrine which has little pharmacological activity as compared to the 1- isomer. Preferably, the antioxidant comprises monothioglycerol. In some embodiments, the antioxidant may be monothioglycerol.

Monothioglycerol may be present at a concentration in the range of about 0.0001 mg/mL and 0.045 mg/mL, preferably in the range of about 0.0005 mg/mL and 0.045 mg/mL, preferably in the range of about 0.001 mg/mL and 0.045 mg/mL, and most preferably in the range of about 0.01 mg/mL and 0.045 mg/mL. Chelating agents used in the compositions of the present invention include, but are not limited to ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly (aspartic acid), citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof, and the like or a combination thereof may be employed. Preferably, the chelating agent comprises EDTA. The chelating agent may be present at the at a concentration of about 0.12 and 2 mg/mL, preferably in the range of about 0.12 and 1.5 mg/mL, more preferably in the range of about 0.12 and 1 mg/mL, and most preferably about 1 mg/mL.

Tonicity agents used in the compositions of the present invention include, but are not limited to sodium chloride, calcium chloride, magnesium chloride, sodium lactate; glucose, fructose, sorbitol, mannitol, galactose, inositol, maltitol, lactose, trehalose, maltose, sucrose, dextran, glycerin, sorbitol, propylene glycol, etc., or a combination thereof. Preferably, the tonicity regulating agent comprises sodium chloride, mannitol or a combination thereof may be employed. The amount of tonicity agent in a given formulation can be selected based on the nature of the tonicity agent and the tonicity of the composition without the tonicity agent.

The present invention provides for a pharmaceutical composition that can acceptable for administration by various routes include, but are not limited to, subcutaneous, intracameral, intravenous, and intramuscular injection, infusion, intraarterial administration, intracardiac injection, endotracheal administration, intraosseous administration, oral inhalation, topical administration, and as ophthalmic irrigation. The present invention provides for a pharmaceutical composition to a final volume which is suitable for administration. In some embodiments, the final volume may be 1 mL. In some embodiments, the final volume may be 10 mL. The present invention provides for a pharmaceutical composition that may have a low level of impurities during period of shelf life. The term“impurity” refers to an undesired substance formed due to the degradation of one or more components of the composition. Sources of degradation include, but are not limited to, racemization, oxidation, ultraviolet light, visible light, heat, sulfite addition, changes in pH, and composition component interactions.

The present invention provides for a pharmaceutical composition that may have a low level of noradrenaline, adrenalone, d- epinephrine as well as epinephrine sulfonic acid (ESA). The present invention provides for a pharmaceutical composition that have a low level of oxidative degradants generated due to an oxidation reaction involving one or more components of the composition. Examples of oxidative degradants include, but are not limited to, adrenochrome, adrenolutin, melanins, and analogues thereof.

The present invention provides for compositions in single-dose formulations. In some embodiments, the composition may be contained in vials. In some embodiments, the vials may comprise clear glass, amber glass, or plastic. In some embodiments, the vials may be in the range of about 0.1 to 10 mL in volume, preferably in the range of about 0.5 to 5 mL, more preferably in the range of about 0.5 to 2 mL, and most preferably in the range of about 0.5 to 1 mL. In some embodiments, the composition may be contained in ampoule. In some embodiments, the ampoule may comprise clear glass and/or amber glass. In some embodiments, the ampoule may be in the range of about 0.5 mL to 5 mL, more preferably in the range of about 0.5 mL to 2 mL, and most preferably in the range of about 0.5 mL to 1 mL. In some embodiments, the composition may be contained in cartridge. In some embodiments, the ampoule may comprise clear glass. In some embodiments, the cartridge may be in the range of about 1 mL to 3 mL. In some embodiments, the composition may be contained in prefilled syringe.

In some embodiments, the prefilled syringe may comprise clear glass, amber glass, or plastic. In some embodiments, the prefilled syringe may be in the range of about 0.5 to 10 mL in volume, more preferably in the range of about 1 to 10 mL. In some embodiments, the composition may exist in a 1 mL prefilled syringe. In some embodiments, the composition may exist in a 10 mL prefilled syringe.

The present invention provides a pharmaceutical composition that may be housed in the injection apparatus or housed separately from the injection apparatus. The injection apparatus may be further defined as an autoinjector.

The injection apparatus may be provided with a secondary packaging system. The secondary packaging provides a barrier to light and oxygen. In one embodiment, the secondary packaging is of an aluminium over-pouch. It can protect the solution from photolytic degradation. Additionally oxygen scavengers may be added to the secondary packaging system to protect composition from oxidative degradation.

The present invention also provides for methods of making pharmaceutical compositions of the present invention. A stable solution of epinephrine or its pharmaceutically acceptable salts of the present invention can be prepared by a following process. 100% of batch size water for injection to be collected in vessel and nitrogen purging was started to achieve Dissolved oxygen level below 1.0 ppm. 80% of batch size water for injection (Dissolved oxygen level Controlled) to be transferred into separate manufacturing vessel and was maintained at a temperature of 20°C to 25°C. Then specified amount of a chelating agent added to the solution while mixing. Then Epinephrine or its pharmaceutical acceptable salts thereof added to the solution while mixing. Then pH modifying agent added to the solution while mixing. Continue stirring till dissolution of Epinephrine or its pharmaceutical acceptable salts thereof. Complete solubilization of Epinephrine or its pharmaceutical acceptable salts thereof and clarity of solution was visually checked. Then specified amount of antioxidant added to the solution while mixing. Then specified amount of tonicity agent added and mixed. Then Tromethamine was added to the solution to adjust the pH of bulk solution in range of 2.2 to 5.0. Then make up final volume of formulation using water for injection (Dissolved oxygen level Controlled). The process is carried under the constant nitrogen purging to replace the level to minimum amount of the oxygen. Then bulk solution may be sterilized by filtration.

The present invention also relates to the formulation having at least 90 wt. % of the epinephrine in the composition and the composition is substantially colorless after a 6 months of stability period at accelerated condition and the composition is substantially colorless through a shelf life of at least 18 months controlled room temperature.

The present invention also relates to the use of the injectable pharmaceutical composition comprising epinephrine or its pharmaceutically acceptable salts in the treatment of an adrenaline-requiring condition such as for example allergic reactions (Type 1), including anaphylaxis, cardiac arrest, sensitivity reactions, induction and maintenance of mydriasis during intraocular surgery, cardiac arrhythmias, treatment of bronchospasm, superficial bleeding, premature labor, GI and renal hemorrhage, hypoglycemia, and hemorrhagic, cardiogenic, and traumatic shock. The composition may also be used to increase blood flow in ACLS during CPR, as an adjunct to local anesthesia, and for radiographic uses. The composition can be administrable via intravenous, intramuscular, subcutaneous, intracameral, injection, infusion, intracardiac injection, intra-arterial administration, intraosseous administration, endotracheal administration, topical administration, oral inhalation, and as ophthalmic irrigation. The present invention is illustrated in detail but not limiting to, the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention

Examples 1 - 4

Examples 5 - 9

Example 39-40

Finished product was stored at different stability conditions as per ICH guideline. For example, shelf life may be determined for long term, accelerated, and, where appropriate, intermediate storage conditions by measuring the concentration of impurities after storage in the following conditions, wherein the composition is packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. The initial sample of ready to use solution and samples stored at different stability conditions were analyzed for assay, related substance (%), d-epinephrine content (%), pH, and osmolality. Results are as follow.

The improved Epinephrine formulation has assay in range of 90 to 110 %, pH in range of 2.2 to 5.0 and osmolality in range of 270 to 330 mOsmol/kg through a shelf life of at least 18 months. The improved Epinephrine formulation has no more than 2.5 % total impurities including d-epinepbrine, preferably not more than about 2%, more preferably not more than about 1 %, and most preferably not more than about 0.75% at the time of release. While the concentration of total impurities including d-epinephrine in the improved Epinephrine formulation is less than or not more than about 14%, and most preferably not more than about 12% through a shelf life of at least 18 months.

The improved Epinephrine formulation has not more than 2.5 % d-epinephrine, preferably not more than about 2%, more preferably not more than about 1 %, more preferably not more than about 0.75%, more preferably not more than about 0.6%, and most preferably not more than about 0.5% at the time of release. While the concentration of d-Epinephrine in the improved Epinephrine formulation is less than or not more than about 3%, more preferably not more than about 2%, and most preferably not more than about 1.75% through a shelf life of at least 18 months.

The improved Epinephrine formulation has not more than 0.5 % Noradrenaline, more preferably not more than about 0.3%, more preferably not more than about 0.2%, more preferably not more than about 0.1%, and most preferably not more than about 0.05% at the time of release. While the concentration of Noradrenaline in the improved Epinephrine formulation is less than or not more than about 0.5%, more preferably not more than about 0.3%, more preferably not more than about 0.2%, and most preferably not more than about 0.1% through a shelf life of at least 18 months.

The improved Epinephrine formulation has not more than 0.5 % adrenalone, more preferably not more than about 0.4%, more preferably not more than about 0.3%, more preferably not more than about 0.2%, more preferably not more than about 0.1%, and most preferably not more than about 0.05% at the time of release. While the concentration of adrenalone in the improved Epinephrine formulation is less than or not more than about 0.5%, more preferably not more than about 0.4%, and most preferably not more than about 0.3% through a shelf life of at least 18 months. The improved Epinephrine formulation has not more than 1 % epinephrine sulfonic acid (ESA), more preferably not more than about 0.75%, more preferably not more than about 0.5%, more preferably not more than about 0.3%, and most preferably not more than about 0.2% at the time of release. While the concentration of epinephrine sulfonic acid (ESA) in the improved Epinephrine formulation less than or not more than about 5 %, more preferably not more than about 4%, more preferably not more than about 3 %, more preferably not more than about 2.5%, more preferably not more than about 2%, and most preferably not more than about 1.5% through a shelf life of at least 18 months.

The present invention therefore provides improved, stable composition along with the methods of formulating safer and more reliable pharmaceutical preparations of epinephrine for medicinal use.

Unlike other epinephrine formulations, these improved formulations are free of sulfite antioxidants, amino-acid antioxidants, preservatives and complexing agents so that there are no safety issues for anaphylaxis and no toxic epinephrine sulfonate by products. Also, unlike other epinephrine formulations, these improved formulations have very low level of d-epinephrine. The d-isomer of epinephrine has little pharmacological activity as compared to the 1- isomer. Thus the invention provide more potent and less toxic pharmaceutical preparations of epinephrine can acceptable for administration by various routes include, but are not limited to, subcutaneous, intracameral, intravenous, and intramuscular injection, infusion, intra-arterial administration, intracardiac injection, endotracheal administration, intraosseous administration, oral inhalation, topical administration, and as ophthalmic irrigation.

These improved epinephrine formulations have no need for high overages, and use minimal overages, if any to assure reliable dosage. The present methods of this invention provides a composition in, but not limited to, clear or amber glass ampules, clear or amber glass vials with caps, prefilled syringes (clear glass, amber glass, or plastic), cartridges. The present invention provides a pharmaceutical composition that may be housed in the injection apparatus or housed separately from the injection apparatus i.e. an autoinjector.

The injection apparatus may be provided with a secondary packaging system like an aluminium over-pouch with or without oxygen scavengers. The present invention provides more potent and less toxic pharmaceutical composition comprising epinephrine or its pharmaceutically acceptable salts in the treatment of an adrenaline-requiring condition such as for example allergic reactions (Type 1), including anaphylaxis, cardiac arrest, sensitivity reactions, induction and maintenance of mydriasis during intraocular surgery, cardiac arrhythmias, treatment of bronchospasm, superficial bleeding, premature labor, GI and renal hemorrhage, hypoglycemia, and hemorrhagic, cardiogenic, and traumatic shock. The composition may also be used to increase blood flow in ACLS during CPR, as an adjunct to local anesthesia, and for radiographic uses. The composition can be administrable via intravenous, intramuscular, subcutaneous, intracameral, injection, infusion, intracardiac injection, intra-arterial administration, intraosseous administration, endotracheal administration, topical administration, oral inhalation, and as ophthalmic irrigation.

Other variations and embodiments of the invention described herein will now be apparent to those of skill in the art without departing from the disclosure of the invention or the coverage of the claims to follow.