WO2019162892A1 - Compositions injectables stables d'épinéphrine - Google Patents

Compositions injectables stables d'épinéphrine Download PDF

Info

Publication number
WO2019162892A1
WO2019162892A1 PCT/IB2019/051452 IB2019051452W WO2019162892A1 WO 2019162892 A1 WO2019162892 A1 WO 2019162892A1 IB 2019051452 W IB2019051452 W IB 2019051452W WO 2019162892 A1 WO2019162892 A1 WO 2019162892A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
epinephrine
composition
sodium
stable aqueous
Prior art date
Application number
PCT/IB2019/051452
Other languages
English (en)
Inventor
Srinivas Reddy MALE
Atul KOLTE
Shashidhar Bagam
Shantaram Laxman PAWAR
Original Assignee
Hetero Healthcare Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Healthcare Limited filed Critical Hetero Healthcare Limited
Publication of WO2019162892A1 publication Critical patent/WO2019162892A1/fr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions

Definitions

  • 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.
  • 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.
  • Type 1 allergic reactions
  • Epinephrine can also be used to increase blood flow in ACLS during CPR, as an adjunct to local anesthesia, and for radiographic uses.
  • 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.
  • 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.
  • 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.
  • 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.
  • sulfite-free formulations further provide further benefit (e.g., safety benefits) to sulfite- sensitive patients.
  • Adrenalin® 1 mL and Adrenalin® 30 mL 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.
  • ESA epinephrine sulfonic acid
  • 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.
  • 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.
  • ESA epinephrine sulfonic acid
  • 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.
  • 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.
  • ESA epinephrine sulfonic acid
  • 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.
  • the present invention provides sulfite free, amino acid free, preservative free and complexing agent free composition
  • 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.
  • 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
  • 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.
  • 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.
  • BHT butylhydroxytoluene
  • BHA butylhydroxyanisole
  • ascorbyl palmitate disodium calcium ethylenediaminetetraacetate
  • DL-alpha- tocopherol disodium ethylenediaminetetraacetate
  • erythorbic acid dithio
  • 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.
  • 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.
  • EDTA
  • 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.
  • 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.
  • 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.
  • oxidative degradants include, but are not limited to, adrenochrome, adrenolutin, melanins, and analogues thereof.
  • the composition may be contained in vials.
  • the vials may comprise clear glass, amber glass, or plastic.
  • 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.
  • the composition may be contained in ampoule.
  • the ampoule may comprise clear glass and/or amber glass.
  • 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.
  • the composition may be contained in cartridge.
  • the ampoule may comprise clear glass.
  • the cartridge may be in the range of about 1 mL to 3 mL.
  • the composition may be contained in prefilled syringe.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ESA epinephrine sulfonic acid
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, hypog
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques injectables stables comprenant de l'épinéphrine ou ses sels pharmaceutiquement acceptables avec un faible taux d'agents de dégradation. La présente invention concerne spécifiquement des compositions pharmaceutiques injectables stables comprenant de l'épinéphrine ou ses sels pharmaceutiquement acceptables qui ne contient pas d'antioxydants au sulfite, d'antioxydants à base d'acides aminés, d'agents complexants ou des conservateurs.
PCT/IB2019/051452 2018-02-23 2019-02-22 Compositions injectables stables d'épinéphrine WO2019162892A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201841006959 2018-02-23
IN201841006959 2018-02-23

Publications (1)

Publication Number Publication Date
WO2019162892A1 true WO2019162892A1 (fr) 2019-08-29

Family

ID=67687534

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2019/051452 WO2019162892A1 (fr) 2018-02-23 2019-02-22 Compositions injectables stables d'épinéphrine

Country Status (1)

Country Link
WO (1) WO2019162892A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112569181A (zh) * 2019-09-27 2021-03-30 中国科学院上海高等研究院 一种快速增溶肾上腺素的方法
CN113384521A (zh) * 2020-03-12 2021-09-14 中国科学院上海高等研究院 一种快速增溶去甲肾上腺素水溶液且有效抑制样品氧化的方法
WO2022046976A1 (fr) * 2020-08-26 2022-03-03 Amphastar Pharmaceuticals, Inc. Formulation d'injection d'épinéphrine ayant une très faible concentration d'épinéphrine et une faible quantité d'impuretés pendant sa durée de conservation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016149028A2 (fr) * 2015-03-13 2016-09-22 Par Pharmaceutical, Inc. Formulations d'épinéphrine
WO2017218918A1 (fr) * 2016-06-17 2017-12-21 Ys Pharmtech Stabilisation de formulations d'épinéphrine
US20170368000A1 (en) * 2012-06-27 2017-12-28 G2B Pharma Inc. Intranasal Formulation of Epinephrine for the Treatment of Anaphylaxis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170368000A1 (en) * 2012-06-27 2017-12-28 G2B Pharma Inc. Intranasal Formulation of Epinephrine for the Treatment of Anaphylaxis
WO2016149028A2 (fr) * 2015-03-13 2016-09-22 Par Pharmaceutical, Inc. Formulations d'épinéphrine
WO2017218918A1 (fr) * 2016-06-17 2017-12-21 Ys Pharmtech Stabilisation de formulations d'épinéphrine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112569181A (zh) * 2019-09-27 2021-03-30 中国科学院上海高等研究院 一种快速增溶肾上腺素的方法
CN113384521A (zh) * 2020-03-12 2021-09-14 中国科学院上海高等研究院 一种快速增溶去甲肾上腺素水溶液且有效抑制样品氧化的方法
WO2022046976A1 (fr) * 2020-08-26 2022-03-03 Amphastar Pharmaceuticals, Inc. Formulation d'injection d'épinéphrine ayant une très faible concentration d'épinéphrine et une faible quantité d'impuretés pendant sa durée de conservation

Similar Documents

Publication Publication Date Title
RU2527337C9 (ru) Стабилизированная композиция, включающая по крайней мере одно адренергическое соединение
US20190240337A1 (en) Epinephrine formulations for medicinal products
US20230355551A1 (en) Stabilization of epinephrine formulations
EP2683361B1 (fr) Méthode de manufacture d'une solution de lévothyroxine
WO2019162892A1 (fr) Compositions injectables stables d'épinéphrine
US9283197B1 (en) More potent and less toxic formulations of epinephrine and methods of medical use
EP3675837A1 (fr) Solutions d'antagoniste d'opioïde stables à basse température
JP2003506416A (ja) モキシフロキサシン/塩化ナトリウム製剤
AU2015289035B2 (en) Aqueous formulation comprising paracetamol and ibuprofen
US11925608B2 (en) Stabilization of epinephrine formulations
US20210205238A1 (en) Stabilized injectable pharmaceutical composition of l-epinephrine
US20080261939A1 (en) Stannsoporfin compositions and administration
CN108324683A (zh) 一种稳定的大输液依达拉奉注射液及其制备工艺
US10004700B1 (en) More potent and less toxic formulations of epinephrine and methods of medical use
US10039728B1 (en) More potent and less toxic formulations of epinephrine and methods of medical use
WO2023072714A1 (fr) Phytonadione pour administration parentérale
US20220151956A1 (en) More potent and less toxic formulations of epinephrine and methods of medical use
US11786512B2 (en) Stable pharmaceutical compositions of dihydroergotamine mesylate
WO2022256545A1 (fr) Formulations de prégabaline injectables
CN115518035A (zh) 一种酮咯酸液体组合物、其制备方法及应用
JP2008255115A (ja) エルゴリン化合物の安定化された水溶液
US20090239894A1 (en) Stabilized aqueous solutions of ergoline compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19756506

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19756506

Country of ref document: EP

Kind code of ref document: A1