Compositions of epinephrine

Abstract

The present invention discloses an injectable composition of epinephrine, their processes, and methods of treating hypotension.

Description

[0001] COMPOSITIONS OF EPINEPHRINE

[0002] This application claims priority of previously filed provisional patent applications 202441041032 filed on May 27, 2024 and 202541033722 filed on April 7, 2025. The disclosure of both these applications is combined in the present complete specification.

[0003] Field of Invention

[0004] The present invention relates to an injectable composition of epinephrine, their processes, and methods of treating hypotension.

[0005] Background of the Invention

[0006] Epinephrine is a non-selective alpha- and beta- adrenergic agonist approved for emergency treatment of allergic reactions including anaphylaxis or hypotension associated with septic shock. Although it is a prescription only drug, its being stored at homes by subjects having fatal allergies to foods, insect bites or such other substances. Therefore, it is necessary that the epinephrine drug product is stable at variable temperatures, easy to transport and user friendly. To address these needs epinephrine products in autoinjector, pre-filled syringes (PFS), single and multiple dose vials have been developed with several different strength.

[0007] Further epinephrine is sensitive to light and air and its solution usually degrades with such exposures. Therefore, preparation of an epinephrine injectable that is stable at temperature as high as 30°C to 40°C has also been a challenge. The pH of the formulation, presence of metals or even the temperature at which it is stored also plays critical role in the stability of the product. Some of the solutions suggested in the prior references to address the stability issue of epinephrine are use of antioxidant such as sodium bisulfite and / or sodium metabisulfite (US9119876), addition of preservatives (US10130592), specific ratios of epinephrine to antioxidants such as bisulfite, a meta bisulfite and a sulfite compound (US9155694), unique mixture of a sulfite containing antioxidant and butylated hydroxyl anisole (US 11234925), addition of tromethamine and monothioglycerol (WO2019162892). These references are related to the epinephrine formulations with very high concentrations. Many a times, it is necessary to dilute these formulations for practical use. The dilution usually is time consuming making such formulations useless for emergency use. Also, there is a risk of contamination during dilution.

[0008] US9433589 discloses highly diluted composition of epinephrine. This composition comprises 0.2-50 pg / ml of epinephrine and citric acid. The invention specifies that the absence or very low concentrations of sulfite and lower amount of sodium chloride as tonicity agent results in a stable highly diluted composition of epinephrine. The patent further discloses that the presence of about 9 mg / ml Sodium Chloride (NaCl) may have a negative influence on storage stability at 40°C, whereas traces of NaCl seem to have no effect on the stability.

[0009] Recently USFDA approved epinephrine diluted composition comprising from 8 pg / ml to 40 pg / ml of epinephrine. US10653646 claims an antioxidant free composition comprising epinephrine equal or less than 0.07 mg / mL and between about 1 and 50 pg / mL of metal ion chelator selected from the group consisting of EDTA (edetic acid), EGTA, and diethylenetriaminepentaacetic acid. According to US10653646, desired effect of chelators was observed at relatively low concentrations of them with preferred concentration of less than about 10 pg / ml. The patent further states that a) at higher pH, the stability of ready-to-administer formulation decreases, b) the stability of epinephrine in the low concentration formulations is in part attributable to the low concentration of a chelator (for e.g. equal or less than about 30 mcg / mL) at relatively low quantities of dissolved oxygen (for e.g. equal or less than about 1.8 ppm). It appears that there are too many criteria to be full filled for preparation of highly diluted, sterile and stable composition of epinephrine, and there is need of an hour to develop a simplified, easily scalable composition of epinephrine. Accordingly, the object of the present invention is to provide and develop an epinephrine formulation that is highly dilute, easy to handle, stable at temperature as high as 40°C and which can be cost effective for manufacturing on industrial scale. Also, it is an object of the present invention to develop a process to prepare highly diluted composition of epinephrine wherein the process is reproducible and cost effective. Further, it is an object of the present invention to provide a product comprising highly diluted composition, wherein the product is easy to store, handle, transport and provides a patient with ready-to-use, sterile epinephrine composition. The method of use of composition and product of present invention is also one of the objects of present invention.

[0010] Summary of the Invention

[0011] According to an embodiment, the present invention provides a composition comprising epinephrine.

[0012] According to another embodiment, the present invention provides an injectable composition comprising Epinephrine.

[0013] According to yet another embodiment, the present invention provides injectable composition comprising less than about 0.1 mg / mL of epinephrine.

[0014] According to yet another embodiment, the present invention provides injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL.

[0015] According to a further embodiment, the present invention provides injectable composition comprising epinephrine more preferably in the range of 5 mcg / mL to 70 mcg / mL and most preferably in the range of 5 mcg / mL to 50 mcg / mL.

[0016] The present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof. According to an embodiment, the present invention provides an injectable composition comprising epinephrine with buffer. According to another embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer.

[0017] According to an embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0018] According to another embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0019] According to yet another embodiment the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises not less than about 0.1 mg / mL of antioxidant.

[0020] According to an embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof. According to another embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof. According to yet another embodiment the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises not less than about 0.1 mg / ml of antioxidant.

[0021] According to an embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and not less than about 0.1 mg / ml of antioxidant.

[0022] According to an embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL and antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL.

[0023] According to another embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine and not less than about 0.1 mg / ml of antioxidant, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0024] According to another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL and antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0025] According to any of the previous embodiment the composition may further comprise tonicity agent and a carrier.

[0026] According to any of the previous embodiment, the composition may optionally comprise a pH adjuster, wherein the pH of the composition is between 2 and 5. According to an embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of a buffer, and a tonicity agent.

[0027] According to another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least O.OOl mg / mL of abuffer, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL and a tonicity agent.

[0028] According to yet another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of a buffer, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, a tonicity agent, a carrier and a pH adjuster, wherein the pH of the composition is between 2 and 5.

[0029] According to another embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL epinephrine, at least about 0.001 mg / mL of a buffer, not less than about 0.1 mg / mL antioxidant, a tonicity agent, a carrier and a pH adjuster, wherein the pH of the composition is between 2 and 5 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0030] According to another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least about 0.001 mg / mL of a buffer, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, a tonicity agent, a carrier and a pH adjuster, wherein the pH of the composition is between 2 and 5 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0031] According to an embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, and a tonicity agent.

[0032] According to another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL and a tonicity agent.

[0033] According to yet another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, a tonicity agent, a carrier and a pH adjuster, wherein the pH of the composition is between about 2 and 5.

[0034] According to another embodiment, the present invention provides an injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, a tonicity agent, a carrier and a pH adjuster, wherein the pH of the composition is between 2 and 5 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0035] According to any of the previous embodiment, the composition of the present invention is stable.

[0036] According to an embodiment, the present invention provides a stable, injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of a buffer, wherein the composition comprises dissolved oxygen of not more than 5 ppm. According to another embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of a buffer, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0037] According to another embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of a buffer, not less than about 0.1 mg / mL of antioxidant, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0038] According to another embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of a buffer, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0039] According to an embodiment, the present invention provides a stable, injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0040] According to another embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, wherein the composition comprises dissolved oxygen of not more than 5 ppm. According to another embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, not less than about 0.1 mg / mL of antioxidant, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0041] According to one preferred embodiment, the present invention provides a stable, injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of a citrate buffer, not less than about 0.12 mg / mL sodium metabisulfite, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0042] According to another preferred embodiment, the present invention provides a stable, injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of a citrate buffer, sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0043] According to yet another preferred embodiment, the present invention provides a stable, injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0044] According to another preferred embodiment, the present invention provides a stable, injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of a citrate buffer, sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and also wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0045] According to another preferred embodiment, the present invention provides a stable, injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and also wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0046] In another specific embodiment, the present invention provides a stable, injectable composition comprising: a) less than about 0.1 mg / mL epinephrine; b) at least 0.001 mg / mL of a citrate buffer; c) NaCl in the range of 6 mg / mL to 9 mg / mL; d) sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL wherein the composition is free of an aminopolycarboxylic acid or salt thereof, and the composition comprises dissolved oxygen of not more than 5 ppm.

[0047] In another specific embodiment, the present invention provides a stable, injectable composition comprising: a) epinephrine in the range of 5 mcg / mL to 100 mcg / mL; b) at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof; c) NaCl in the range of 6 mg / mL to 9 mg / mL; d) sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL wherein the composition is free of an aminopolycarboxylic acid or salt thereof, and the composition comprises dissolved oxygen of not more than 5 ppm.

[0048] According to an embodiment, the present invention provides a pharmaceutical product comprising a seal bag or a bottle containing an injectable composition of the present invention.

[0049] According to an embodiment, the present invention provides a process for the preparation of compositions of the present invention.

[0050] According to yet another embodiment, the present invention provides a method of treatment of hypotension associated with septic shock using an epinephrine injectable composition comprising less than about 0.1 mg / mL epinephrine and at least 0.001 mg / mL buffer.

[0051] According to yet another embodiment, the present invention provides a method of treatment of hypotension associated with septic shock using an epinephrine injectable composition comprising less than about 0.1 mg / mL epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof.

[0052] According to an embodiment, the present invention provides a method of treatment of condition requiring epinephrine, wherein the method comprises administering to the subject requiring such treatment using compositions of present invention.

[0053] Detailed Description of the Invention

[0054] Epinephrine is a neurotransmitter that plays a vital role in the body’s acute stress response by stimulating the sympathetic nervous system. Chemically it is 4-(l- Hydroxy-2-(methylamino)ethyl)-l,2-benzenediol.

[0055] The present invention relates to the compositions of epinephrine, their processes and method of use.

[0056] Epinephrine, according to present invention encompasses epinephrine or its pharmaceutically acceptable salts. Such salts may include organic or inorganic acid salts. For example, organic salt may be tartrate, acetate or citrate salt and inorganic salt may be hydrochloride, hydrofluoride, nitrate, phosphate, or sulphate salt. In a preferred embodiment the present invention comprises epinephrine.

[0057] According to an embodiment, the present invention provides a composition comprising epinephrine.

[0058] The terms ‘composition’ and ‘formulation’ are used interchangeably.

[0059] According to another embodiment, the present invention provides an injectable composition comprising epinephrine.

[0060] The skilled person would understand that an injectable composition may be in different forms. For example, the composition may be in powder form which can be diluted using diluent before administration, it may be solution supplied in vial or in a ready to use device such as pen or syringe or it may be in the diluted form supplied in infusion bottles or bags.

[0061] In a preferred embodiment, the present invention relates to an injectable composition comprising epinephrine in highly diluted form. A term ‘highly diluted form of epinephrine’ has a meaning that the concentration of epinephrine in the composition is less than 1 mg / mL and the volume of the composition is not less than 50 mL. According to an embodiment, the composition comprises less than 1 mg / mL, less than 0.5 mg / mL, less than 0.1 mg / mL of epinephrine.

[0062] In another preferred embodiment, the composition comprises about 8 mcg / mL, about 16 mcg / mL, about 20 mcg / mL, about 32 mcg / mL, about 40 mcg / mL of epinephrine.

[0063] Herein ‘mcg’ and pg are used interchangeably and mean micro grams.

[0064] The composition of present invention may further comprise one or more excipients.

[0065] Excipients are the inactive ingredients present in the composition that may not play an active role in the treatment of disease or reduction of symptoms of the disease. However, they may be formulated along with active ingredient for reasons such as to improve solubility or stability of the active ingredient, to reduce viscosity or increase flowability, make the formulation easy to handle or increase its absorption. Suitable excipients may be selected from those known in the prior art or those listed in the standard reference books such as The Handbook of Pharmaceutical Excipients or those which are listed in Inactive Ingredient Database of US FDA web site ( nactive Ingredients Database Download i FD . )

[0066] According to an embodiment, the composition of the present invention may further comprise at least one excipient selected from diluent, tonicity agent, buffer, pH adjusters, stabilizer, antioxidant, metal ion chelator or any other such excipient known to the person skilled in the art.

[0067] It will be appreciated by the skilled person that highly diluted epinephrine composition of the present invention can be diluted using water for injection or a suitable diluent known in the art. Some of the non-limiting examples of diluents are saline (NaCl), dextrose solution and Ringer's lactate solution.

[0068] According to an embodiment, the diluent in the present invention is water for injection.

[0069] Injectable formulations need to be isotonic with human plasma to avoid osmotic shock and damage to the tissues.

[0070] In some aspects, a tonicity adjusting agent may be used in the compositions of the present invention.

[0071] Some of the non-limiting examples for tonicity agents are glycerin, mannitol, glycerol, NaCl and dextrose.

[0072] According to an embodiment, the tonicity agent may be NaCl.

[0073] The concentration of the tonicity agent can be from 2 mg / mL to 10 mg / mL.

[0074] The tonicity agent when present along with other excipients may affect both tonicity as well as the stability of the composition, thus making the concentration of the tonicity agent highly significant in composition.

[0075] In some aspects of the present invention the concentration of the tonicity agent may be from 5 mg / mL to 10 mg / mL.

[0076] In some other aspects, the concentration may be from 8 mg / mL to 9.5 mg / mL.

[0077] In some aspect, the concentration may be about 9 mg / mL.

[0078] In some aspects the composition of the present invention may be devoid of tonicity agent. According to an embodiment, the composition of the present invention may further comprise at least one of antioxidant, preservative and metal ion chelator.

[0079] An antioxidant prevents oxidation of the active ingredient and avoids formation of unacceptable impurities.

[0080] Some of the non-limiting examples of antioxidant are sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, tocopherol polyethylene glycol succinate, butylated hydroxyl anisole, glutathione, thiourea.

[0081] According to an embodiment, epinephrine injectable composition of the present invention comprises at least one antioxidant selected from the group of sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite.

[0082] In an aspect, the present invention comprises 0.5 wt% of antioxidant.

[0083] In an aspect, the present invention comprises 0.2 wt% of antioxidant.

[0084] In an aspect, the present invention comprises 0.1 wt% of antioxidant.

[0085] In another aspect, the present invention comprises 0.05 wt% of antioxidant.

[0086] In an aspect, the present invention comprises 0.01 wt% of antioxidant.

[0087] In an aspect, the present invention comprises not less than 0.01 wt% of an antioxidant.

[0088] In another aspect, the present invention comprises not less than 0.012 wt% of an antioxidant.

[0089] In an aspect, the present invention comprises 1 mg / mL of antioxidant. In another aspect, the present invention comprises 0.5 mg / mL of antioxidant.

[0090] In an aspect, the present invention comprises 0.2 mg / mL of antioxidant.

[0091] In an aspect, the present invention comprises not less than 0.1 mg / mL of an antioxidant.

[0092] In another aspect, the present invention comprises not less than 0.12 mg / mL of an antioxidant.

[0093] In an aspect, the present invention comprises an antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL.

[0094] In an aspect, the present invention comprises an antioxidant in the range of 0.12 mg / mL to 0.2 mg / mL.

[0095] Herein, the term weight percent (wt%) is used interchangeably with percentage weight by weight (here after - % w / w) and mean the percentage of solute present in total amount of solution, wherein both the amounts of solute and solution are measured as per their weights (mass) and not volumes.

[0096] The skilled person is well aware of the methods of calculating wt%. All such methods are incorporated herein by way of reference.

[0097] In one of the main aspects, of the invention, the composition is free of aminopolycarboxylic acid derivatives or salts thereof such as, for example, disodium calcium ethylenediaminetetraacetate and disodium ethylenediaminetetraacetate.

[0098] According to yet another main aspect the composition of the present invention is not free of antioxidant. According to an embodiment, the composition of present invention optionally comprises preservative.

[0099] Preservative alone or in combination with antioxidant stabilizes a formulation both physically and chemically, prevents or reduces decomposition and improves its shelf life.

[0100] For the purpose of present invention, the preservative may be selected as per knowledge and understanding of the skilled person or as disclosed in the handbook of pharmaceutical excipients.

[0101] Some of the non-limiting examples of preservatives are benzalkonium chloride, benzyl paraben or chlorbutanol.

[0102] In an aspect, the present invention comprises at least one preservative.

[0103] In another aspect, the present invention is free of preservative.

[0104] According to an embodiment, the composition of the present invention optionally comprises metal ion chelator.

[0105] Metal ion chelators are metal complexing agent that form coordinate bonds with trace metals present in the composition. Trace metals may have the capacity to catalyze the decomposition reactions thereby accelerate the formation of impurities and reduce the stability of the composition. Metal ion chelator complex with such trace metals making them ineffective catalyst. It will be appreciated by the skilled person that the metal ion chelator alone or in combination with antioxidant and / or preservative may improve stability of the composition and extend shelf life.

[0106] For the purpose of present invention non-limiting examples of metal ion chelators are aminopolycarboxylic acid derivatives such as ethylene diamine tetraacetic acid (EDTA), Pentetic acid (DTP A), ethylene glycol (bis) aminoethyl ether tetra acetic acid (EGTA), O,O'-bis(2-aminophenyl ethylene glycol) ethylenediamine- N,N,N',N'-tetraacetic acid (BAPTA), trans- 1,2-diamino cyclohexane- ethylenediamine-N,N,N',N'-tetraacetic acid (CyDTA), l,3-diamino-2-hydroxy- propane-ethylenediamine-N,N,N',N'-tetraacetic acid (DPTA-OH), ethylene- diamine-N,N'-dipropionic acid dihydrochloride (EDDP), 1,6- hexamethylenediamine-N,N,N',N'-tetraacetic acid (HDTA), triethylenetetramine- N,N,N',N",N"-hexaacetic acid (TTHA), derivatives or salts thereof, or acids such as citric acid, malic acid or salicylic acid.

[0107] In some aspects, the composition of present invention comprises metal ion chelator.

[0108] In some other aspects, the composition of present invention is free of metal ion chelator.

[0109] In some aspect, the composition of present invention is free of aminopolycarboxylic acid derivatives of their salts as metal ion chelator.

[0110] In an embodiment, the composition of the present invention may further comprise pH adjusters and buffer. pH of the composition plays a significant role in its stability. Epinephrine compositions are stable at pH of around 3 to 5.

[0111] The methods of adjusting pH of injectable compositions are well known to the skilled person. For the purpose of the present invention, pH adjusters known in the art may be used. It would be appreciated by the skilled person that the quantities of the pH adjusters would vary and may be necessarily adjusted.

[0112] The composition of the present invention comprises a buffer. A buffer may be added to the composition to avoid significant change in pH of the composition.

[0113] Phosphates, acetates, citrates, titrates are some of the non-limiting examples of buffer systems that are used in prior art. For the purpose of present invention, to maintain the pH and for stabilization of the composition the pH adjuster and buffer may be used in combination. pH adjuster may be selected from acid or bases known to the skilled person. According to an embodiment, the pH adjuster may be an organic acid or base or an inorganic acid or base. According to an embodiment a pH adjuster may be a mineral acid. According to an embodiment the pH adjuster may be a dicarboxylic acid or a tricarboxylic acid. According to an embodiment the pH adjuster may be a base. According to an aspect pH adjusting agent may be selected from hydrochloric acid, tartaric acid or citric acid, acetic acid, nitric acid, sulfuric acid, ascorbic acid, lactic acid, malic acid, maleic acid, fumaric acid, phosphoric acid, succinic acid, sodium hydroxide alone or in combination may be used as buffer. According to another aspect pH adjusters may be used to stabilize the composition.

[0114] According to an aspect, the pH adjuster may be a dicarboxylic acid or a tricarboxylic acid or a combination thereof in an amount not less than 0.001 mg / mL or not less than 0.01 mg / mL, or not less than 0.05 mg / mL, or not less than 0.1 mg / mL.

[0115] According to an aspect, the pH adjuster may be a buffer or a combination of buffer system and an acid, wherein the concentration of pH adjuster is not less 0.001 mg / mL or not less than 0.01 mg / mL, or not less than 0.05 mg / mL, or not less than 0.1 mg / mL, or not less than 0.12 mg / mL, or not less than 0.15 mg / mL, or not less than 0.17 mg / mL, or not less than 0.18 mg / mL, or not less than 0.2 mg / mL.

[0116] According to an embodiment the composition of the present invention is stable.

[0117] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer. According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof.

[0118] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0119] According to an embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0120] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition comprises not less than about 0.1 mg / mL of antioxidant.

[0121] According to an embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, wherein the composition comprises antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL.

[0122] According to an embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0123] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof. According to an embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL and at least 0.001 mg / mL buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0124] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0125] According to an embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0126] According to an embodiment, the present invention provides a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL and at least 0.001 mg / mL buffer, wherein the composition comprises not less than about 0.1 mg / mL of antioxidant.

[0127] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least about 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition comprises not less than about 0.1 mg / mL of antioxidant.

[0128] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition comprises dissolved oxygen of not more than 5 ppm. According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least about 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0129] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises not less than about 0.1 mg / mL of antioxidant.

[0130] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0131] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine, wherein the composition comprises not less than about 0.1 mg / mL of antioxidant and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0132] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises not less than about 0.1 mg / mL of antioxidant.

[0133] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein the composition comprises not less than about 0.1 mg / mL of antioxidant. According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0134] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0135] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL buffer, wherein the composition comprises not less than about 0.1 mg / mL of antioxidant and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0136] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least about 0.001 mg / mL buffer, not less than about 0.1 mg / mL of antioxidant wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0137] According to an embodiment, the present invention provides a stable injectable composition comprising less than about 0.1 mg / mL of epinephrine and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, not less than about 0.1 mg / mL of antioxidant wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0138] The term ‘ stable’ as used herein means that the composition of the present invention remains unchanged or changes within the acceptable limits both physically and chemically when stored under stability conditions over a period of stability. It will be within the knowledge of the skilled person that the physical stability relates to the state of the physical condition of the composition and can be detected by observations by the analyst. If the composition after stability period appears same as that of before initiation of stability period upon observation, it is said to be physically stable. Chemical stability relates to the presence of known or unknown impurities and can be detected by chemical assays or other known analytical techniques.

[0139] The composition is said to be chemically stable if the total impurities formed after said stability period are less than 6%. The composition may be said to be chemically stable if the total impurities formed after said stability period are less than 5%. The composition may be said to be chemically stable if the total impurities formed after said stability period are less than 4%. The composition may be said to be chemically stable if the total impurities formed after said stability period are less than 3%. The composition may be said to be chemically stable if the total impurities formed after said stability period are less than 2%. The composition may be said to be chemically stable if the total impurities formed after said stability period are less than 1%. The composition may be said to be chemically stable if the total impurities formed after said stability period are less than 0.5%.

[0140] Known impurities that may form in the composition of epinephrine are Impurity F [( I / )-! -(3, 4-di hydroxyphenyl )-2-(methyl ami nojethanesulfonic acid] and Impurity C [l-(3, 4-Dihydroxyphenyl)-2-(methylamino)ethenone], The unknown impurities may be monitored based on the peaks detected during analysis using high performance liquid chromatography (HPLC), which is a well-known method to the skilled person for the analysis of pharmaceutical compositions such as epinephrine.

[0141] The stability conditions may include temperature from 2°C to 40°C, 25% to 75% relative humidity (RH), presence or absence of oxygen and an opaque or transparent container.

[0142] In an embodiment the temperatures for stability conditions are from 2°C to 8°C or from 25°C to 30°C or from 30°C to 35°C or from 35°C to 40°C.

[0143] The composition of the present invention is stable when the amount of dissolved oxygen in the composition is less than 10 ppm.

[0144] In an embodiment the composition of the present invention is stable when the amount of dissolved oxygen is less than 5 ppm.

[0145] In a preferred embodiment the composition of the present invention is stable when the amount of dissolved oxygen is less than 3 ppm.

[0146] A period of stability is the time period for which the composition is maintained under above conditions to test the stability. The stability period may be at least 14 days or may be 1 month.

[0147] In certain embodiments the stability period may be at least 3 months. In certain embodiments the stability period may be at least 6 months.

[0148] In certain embodiments the stability period may be at least 12 months. In certain embodiment the stability period may be at least 18 months.

[0149] In a preferred embodiment the composition of the present invention is said to be stable if it is physically stable and the impurities formed are less than 6% when stored at 2°C to 8°C in the absence of oxygen in an opaque container for at least 14 days.

[0150] In another preferred embodiment the composition of the present invention is said to be stable if it is physically stable and the impurities formed are less than 4% when stored at 25°C / 60% relative humidity (RH) in the absence of oxygen in an opaque container for at least 1 month.

[0151] In a preferred embodiment the composition of the present invention is said to be stable if it is physically stable and the impurities formed are less than 6% when stored at 2°C to 8°C in the absence of oxygen in an opaque container for at least 14 days.

[0152] In another preferred embodiment the composition of the present invention is said to be stable if it is physically stable and the impurities formed are less than 4% when stored at 25°C / 60% RH in the absence of oxygen in an opaque container for at least 1 month.

[0153] In a preferred embodiment the composition of the present invention is said to be stable if it is physically stable and the impurities formed are less than 6% when stored at 40°C / 75% RH in the absence of oxygen in an opaque container for at least 14 days.

[0154] In another preferred embodiment the composition of the present invention is said to be stable if it is physically stable and the impurities formed are less than 4% when stored at 40°C / 75% RH in the absence of oxygen in an opaque container for at least 1 month.

[0155] The phrase ‘absence of oxygen’ mean the amount of oxygen present in the closed container around the composition is less than 10%. According to an embodiment, the composition of the present invention is free of aminopolycarboxylic acid derivatives or salts thereof.

[0156] Non-limiting examples of aminopolycarboxylic acid are ethylene diamine tetraacetic acid (EDTA), Pentetic acid (DTP A), ethylene glycol (bis) aminoethyl ether tetra acetic acid (EGTA), O,O'-bis(2-aminophenyl ethylene glycol) ethyl enediamine-N,N,N',N'-tetraacetic acid (BAPTA), trans- 1,2-diamino cyclohexane-ethylenediamine-N,N,N',N'-tetraacetic acid (CyDTA), 1,3-diamino- 2-hydroxy-propane-ethylenediamine-N,N,N',N'-tetraacetic acid (DPTA-OH), ethyl ene-diamine-N,N'-dipropionic acid dihydrochloride (EDDP), 1,6- hexamethylenediamine-N,N,N',N'-tetraacetic acid (HDTA), triethylenetetramine- N,N,N',N",N"-hexaacetic acid (TTHA).

[0157] According to a preferred embodiment, the composition of the present invention is free of EDTA, DTP A, EGTA, their derivatives and / or salts thereof.

[0158] In some aspects, the composition of present invention does not comprise aminopolycarboxylic acid derivatives or salts thereof.

[0159] In some aspects, the composition of present invention comprises aminopolycarboxylic acid derivatives or salts thereof in less than 0.01 mg / mL.

[0160] In some aspects, the composition of present invention comprises aminopolycarboxylic acid derivatives or salts thereof in less than 0.001 mg / mL.

[0161] In some aspects, the composition of the present invention comprises aminopolycarboxylic acid derivatives or salts thereof from 0 to 0.001 mg / mL.

[0162] In a preferred embodiment, the present invention provides an injectable composition comprising less than 0.1 mg / mL of epinephrine wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof. In a more preferred embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL epinephrine and a buffer, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0163] In a most preferred embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL epinephrine not less than 0.1 mg / mL of an antioxidant, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0164] In a preferred embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL of epinephrine wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0165] In a more preferred embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL epinephrine and a dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0166] In a most preferred embodiment, the present invention provides an injectable composition comprising less than about 0.1 mg / mL epinephrine not less than 0.1 mg / mL of an antioxidant, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0167] According to one preferred embodiment, the present invention provides a stable, injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of a citrate buffer, not less than about 0.12 mg / mL sodium metabisulfite, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof. According to one preferred embodiment, the present invention provides a stable, injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, not less than about 0.12 mg / mL sodium metabisulfite, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0168] According to another preferred embodiment, the present invention provides a stable, injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of a citrate buffer, not less than about 0.12 mg / mL sodium metabisulfite, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and also wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0169] According to another preferred embodiment, the present invention provides a stable, injectable composition comprising less than about 0.1 mg / mL epinephrine, at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, not less than about 0.12 mg / mL sodium metabisulfite, sodium chloride (NaCl), sodium hydroxide (NaOH), and water, wherein the pH of the composition is about 4 and wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and also wherein the composition comprises dissolved oxygen of not more than 5 ppm.

[0170] In another specific embodiment, the present invention provides a stable, injectable composition comprising: a) epinephrine in the range of 5 mcg / mL to 100 mcg / mL; b) at least 0.001 mg / mL of a citrate buffer; c) NaCl in the range of 6 mg / mL to 9 mg / mL; d) sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL wherein the composition is free of an aminopolycarboxylic acid or salt thereof, and the composition comprises dissolved oxygen of not more than 5 ppm.

[0171] In another specific embodiment, the present invention provides a stable, injectable composition comprising: a) epinephrine in the range of 5 mcg / mL to 100 mcg / mL; b) at least about 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof; c) NaCl in the range of 6 mg / mL to 9 mg / mL; d) sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL wherein the composition is free of an aminopolycarboxylic acid or salt thereof, and the composition comprises dissolved oxygen of not more than 5 ppm.

[0172] In an aspect, the present invention provides a process for the preparation of compositions of the present invention. In another aspect, the present invention provides a process for the preparation of stable composition of epinephrine, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

[0173] The method of preparation of the composition can vary as per understanding and the knowledge of the skilled person. For example, necessity of filtrations and the required filters, temperatures during the processes or the sequence of addition of excipients are within the ambit of knowledge of the skilled person and therefore can prepare a composition of present invention based on the information provide in the present specification.

[0174] In an embodiment the composition of the present invention may be prepared by adding and dissolving each of the excipient one after other to water for injection, wherein water for injection is purged with an inert gas to reduce dissolved oxygen to less than 10 ppm. pH of the excipient solution is adjusted to 3 to 5 using pH adjusters and / or buffer. Epinephrine is finally added to the pH adjusted solution and homogenized. The composition is terminally sterilized at 121°C. for at least 15 minutes.

[0175] Accordingly in another embodiment, the present invention provides a process of preparing a composition comprising: a) epinephrine in the range of 5 mcg / mL to 100 mcg / mL, b) at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, c) antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof, and wherein the process comprises a step of aseptic sterilization of the composition.

[0176] According to an embodiment, the present invention relates to a process of preparation of a ready to administer composition comprising: a) epinephrine in the range of 5 mcg / mL to 100 mcg / mL; b) at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof; c) NaCl in the range of 6 mg / mL to 9 mg / mL; d) sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL, wherein the composition is free of an aminopolycarboxylic acid or salt thereof, and wherein the composition is sterilized before filling in a sterilized primary package.

[0177] According to previous embodiment, the process further comprises the steps of: a) combining one or more excipients in a solvent having oxygen content less than 3 ppm to obtain excipient solution, wherein solvent is a carrier or tonicity agent or combination thereof; b) adjusting the pH of excipient solution obtained in step a) between 2 and 5; and c) adding epinephrine to the solution of step b). According to one specific embodiment, the present invention relates to a process of preparation of ready to administer composition, wherein the process comprises the steps of a) combining one or more excipients in a solvent having oxygen content less than 3 ppm to obtain excipient solution, wherein solvent is a carrier or tonicity agent or combination thereof; b) adjusting the pH of excipient solution obtained in step a) between 2 and 5 to prepared pH adjusted solution; c) adding epinephrine to the pH adjusted solution of step b) under inert conditions to obtain the composition; d) sterilizing the composition prepared in step c) to obtain sterilized composition; e) filling the sterilized composition of step d) in a sterilized primary packaging material to obtain product; f) optionally packing the product obtained in step e) in a sterilized secondary packing material, and wherein the ready to administer composition comprises epinephrine in the range of 5 mcg / mL to 100 mcg / mL; dicarboxylic acid or a tricarboxylic acid or combination thereof and the composition is free of an aminopolycarboxylic acid or salt thereof.

[0178] According to an embodiment, the present invention provides a stable, ready to administer injectable composition, wherein the composition is prepared by the process comprising aseptic sterilization step, and wherein the composition comprises epinephrine in the range of 5 mcg / mL to 100 mcg / mL; di carboxylic acid or a tricarboxylic acid or combination thereof and the composition is free of an aminopolycarboxylic acid or salt thereof.

[0179] The present invention relates to the process of preparation of preparation of epinephrine composition. The present invention specifically relates to the process of preparation of epinephrine composition by aseptic sterilization. Most important criteria for injectable composition is that it must be sterile and should be free of any visible and non-visible impurities including microbial impurities. The sterilization of injectables is carried out either terminally or non- terminally. Terminal sterilization involves filling and sealing product containers under highly sterile environmental conditions to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful.

[0180] In most cases, the product, container, and closure have low bioburden, but they are not sterile. The product in its final container is then subjected to a sterilization process such as heat or irradiation. Terminal sterilization is mostly carried at high temperature and pressure.

[0181] The non-terminal sterilization is a process in which the composition, container, and closure are individually subjected to sterilization by appropriate methods and the sterilized components are brought together in a sterile environment.

[0182] The methods of sterilization of each component may include filtration, radiation, and chemical sterilization. As opposed to terminal sterilization non-terminal sterilization usually takes place at room or lower temperatures and is more often carried out for the products that cannot withstand high temperatures. However, to ensure complete sterile product it is necessary to carry out the process under meticulous control and validation.

[0183] Epinephrine is sensitive to light and air (oxygen) and there are reports of use of nonterminal sterilization process to prepare its injectable. However, terminal sterilization of Epinephrine compositions is preferred process that has been successful and yields highly sterile and stable products. Terminal sterilization is an easy process and ensures product free of microbial impurities, therefore it may be the preferred process. US10653646 discloses the diluted composition of epinephrine that is prepared by terminal and non-terminal sterilization. However, the present inventors surprisingly found that the terminal sterilization process did not yield the desired results of sterile product for diluted epinephrine composition. This may be due to the difference in the components of composition reported in US10653646 and the present invention.

[0184] According to an aspect, the present invention relates to the process of preparing stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL and at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, wherein the process comprises a step of aseptic sterilization of the composition.

[0185] According to another aspect, the present invention relates to the process of preparing stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mLwherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof, and wherein the process comprises a step of aseptic sterilization of the composition.

[0186] According to yet another embodiment, the present invention relates to the process of preparing a stable injectable composition comprising epinephrine in the range of 5 mcg / mL to 100 mcg / mL, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof and wherein composition comprises dissolved oxygen of not more than 5 ppm.

[0187] According to an aspect, the process according to present invention comprises the step of aseptic sterilization.

[0188] According to another aspect, the process comprises step of aseptic filtration of the composition. According to yet another aspect, the process comprises step of aseptic filtration using microfilters of suitable grades. The microfilter of suitable grade may be of 0.22 microns.

[0189] In an embodiment, the process may comprise a step of high temperature sterilization.

[0190] In an embodiment, the process may be devoid of the step comprising high temperature sterilization.

[0191] In an embodiment, the sterilization step in the present invention may be carried out at temperature equal to or less than 30°C.

[0192] In another embodiment, the sterilization step in the present invention is carried out at room temperature.

[0193] In an aspect, the process of the present invention may further comprise a step of adding and dissolving each of the excipient one after other to water for injection.

[0194] In another aspect, the process may further comprise a step of purging of water for injection using an inert gas to reduce the dissolved oxygen to less than 10 ppm or less than 7 ppm or less than 5 ppm.

[0195] In a preferred embodiment the purging of water for injection using inert gas is continued till the dissolved oxygen is less than 5 ppm.

[0196] In yet another aspect, the pH of the water for injection comprising excipients is adjusted to between 3 and 5 using pH adjusters and / or buffer. The non-limiting examples of pH adjusters and / or buffers are hydrochloric acid, tartaric acid or citric acid, acetic acid, nitric acid, sulfuric acid, ascorbic acid, lactic acid, malic acid, maleic acid, fumaric acid, phosphoric acid, succinic acid, sodium hydroxide or combination thereof. Epinephrine is finally added to the pH adjusted solution and homogenized. Every step in the process of the present invention is carried out under inert and aseptic conditions.

[0197] The methods of packaging and storage of the compositions of present invention, which are highly sensitive to light and oxygen are known to the skilled person.

[0198] According to an aspect, the primary packaging material may be a high-volume polymeric container such as bottles or bags or any other container that would be acceptable for the packaging of an injectable useful for intravenous administration such as blow-fill-seal (BFS) container. Volume of such container may be between 100 mL and 1000 mL.

[0199] The bottles or bags may be further covered using light air, or oxygen barrier material such as metal film including but not limited to aluminum wrap or an oxygen absorber.

[0200] In an embodiment of present invention, the headspace of the container is filled with inert gas. It would be appreciated by the skilled person that the headspace is the space in the container apart from the composition. It will also be appreciated by the skilled person that the dissolved oxygen in the composition and the amount of oxygen in the headspace needs to be controlled for stability of the composition. The headspace of the container may be preferably filled with inert gas such as nitrogen.

[0201] The containers bottle or bag are made of polymeric materials such as polyvinyl chloride (PVC), polyethylene, low-density polyethylene (LDPE), polyethylene terephthalate (PET), polypropylene or their copolymers. The container could be any other container that would be acceptable for the packaging of an injectable useful for intravenous administration. Based on the discussion herein before it would be appreciated by the person skilled in the art that the composition of the present invention is highly diluted composition and has total volume of not less than 50 mL.

[0202] In an embodiment the total volume of the composition is between 100 mL and 1000 mL.

[0203] In preferred embodiment the volume of the composition is between 150 mL and 500 mL.

[0204] The process of the present invention gives sterile and stable product. The sterile product is the product free of any chemical impurities and biological contaminations such as bacteria, viruses or other microorganisms. It is ready for infusing a human as per USFDA and EMA standards.

[0205] In an aspect, the present invention relates to the epinephrine product obtained by the process of the present invention.

[0206] In another aspect, the present invention relates to method of treating a condition treatable using the product of present invention.

[0207] According to an embodiment, the present invention provides a method of treatment of hypotension associated with septic shock using an epinephrine injectable composition of the present invention.

[0208] According to another embodiment, the present invention provides a method of treatment of condition requiring epinephrine, wherein the method comprises administering to the subject requiring such treatment the compositions of present invention. The aminopolycarboxylic acid derivatives such as EDTA, EGTA or diethylenetriaminepentaacetic acid or their salts are the commonly used metal ion chelators for epinephrine compositions. The compositions with different buffers such as tartaric acid or citric acid, unique antioxidants or varying concentrations of antioxidants are disclosed. The report of stability issues due to high concentrations of tonicity agents are also mentioned in the prior art. However, there are no reports of compositions without aminopolycarboxylic acid or its salt. It may be mentioned generally in the description or specification that metal ion chelators are optional or aminopolycarboxylic acid derivatives may be replaced by other metal ion chelators, but there are no reports or practical examples of stable epinephrine compositions that are devoid of aminopolycarboxylic acid derivatives. Therefore, the inventive aspect of the present invention lies in the development of highly diluted formulation of epinephrine that is stable at temperature as high as 40°C even in the presence of antioxidant such as sodium metabisulfite and high concentrations of tonicity agent and in the absence of aminopolycarboxylic acid derivatives, both of which according to the prior references are responsible for epinephrine formulations to be unstable.

[0209] Examples

[0210] The examples provided below are for the purpose of demonstration of the present invention. Any variation within the scope of the invention is well known to the skilled person. Therefore, the examples do not limit the invention in any manner.

[0211] Example la: Epinephrine compositions with amount of Epinephrine of 8 mcg / mL or 40 mcg / mL

[0212] Process: a) About 90% of the batch size quantity of water was collected, nitrogen gas was purged for about 30 minutes to reduce the dissolved oxygen of water to 3 ppm; b) excipients solution was prepared by adding sodium chloride, citrate buffer and sodium metabisulfite to the water in ‘step a)’ one at a time and stirred to dissolve; c) epinephrine was added to the solution of ‘step b)’ and mixed until dissolved to prepared composition; d) pH of the solution in ‘step c)’ was adjusted to around 4.0 using sodium hydroxide to prepared pH adjusted solution; e) volume of the composition of ‘step d)’ was made 100% with water and mixed until a homogenous solution was obtained; f) the homogeneous solution of ‘ step e)’ is aseptically filtered using 0.2 micron (or suitable grade) of filter to obtain filtered composition; g) the filtered composition of ‘step f)’ is aseptically packed in polymeric bag enclosed in a metallized over-container that optionally further comprises an oxygen scavenger or absorber disposed between the polymeric container and the metallized over-container.

[0213] Stability data for Example la:

[0214] Stability conditions: Temperature 25°C and 60% RH

[0215] Acceptable pH Limit: 3.7-4.3

[0216] RRT: Relative Retention Time (HPLC)

[0217] Example lb: Epinephrine compositions with amount of Epinephrine of 8 mcg / mL or 40 mcg / mL

[0218] Stability data for Example lb:

[0219] Stability conditions: Temperature 25°C and 60%RH Example 1c: Epinephrine compositions with amount of Epinephrine of 8 mcg / mL or 40 mcg / mL

[0220] Process: a) About 90% of the batch size quantity of water was collected, nitrogen gas was purged for about 30 minutes to reduce the dissolved oxygen of water to 4 ppm; b) excipients solution was prepared by adding sodium chloride, succinic acid sodium metabisulfite to the water in ‘step a)’ one at a time and stirred to dissolve; c) pH of the solution in ‘step b)’ was adjusted to around 4.0 using sodium hydroxide to prepared pH adjusted solution. d) epinephrine was added to the pH adjusted solution of ‘step c)’ and mixed until dissolved to prepared composition. e) volume of the composition of ‘step d)’ was made 100% with water and mixed until a homogenous solution was obtained; f) the homogeneous solution of ‘ step e)’ is aseptically filtered using 0.2 micron (or suitable grade) of filter to obtain filtered composition; g) the filtered composition of ‘step f)’ is aseptically packed in polymeric bag.

Claims

We Claim,1. An injectable composition comprising epinephrine or pharmaceutically acceptable salt thereof and a dicarboxylic acid and / or a tricarboxylic acid, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

2. The injectable composition as claimed in claim 1, wherein composition comprises epinephrine or pharmaceutically acceptable salt thereof in the range of 5 mcg / mL to 100 mcg / mL.

3. The injectable composition as claimed in claim 2, wherein the composition comprises epinephrine or pharmaceutically acceptable salt thereof in the range of 5 mcg / mL to 50 mcg / mL.

4. The injectable composition as claimed in claim 1, wherein the composition comprises at least 0.001 mg / mL of a dicarboxylic acid or a tricarboxylic acid or combination thereof.

5. The injectable composition as claimed in claim 4, wherein the dicarboxylic acid and tricarboxylic acid is selected from succinic acid, citric acid, malic acid, maleic acid, fumaric acid, tartaric acid.

6. The injectable composition as claimed in claim 1, wherein the composition further comprises excipients selected from buffer, pH adjuster, tonicity agent, carrier and antioxidant.

7. The injectable composition as claimed in claim 6, wherein the composition comprises at least 0.001 mg / mL buffer.

8. The injectable composition as claimed in claim 7, wherein the buffer is selected from phosphate buffer, acetate buffer, citrate buffer, titrate buffer, hydrochloric acid, tartaric acid, citric acid, acetic acid, nitric acid, sulfuric acid, lactic acid, malic acid, maleic acid, fumaric acid, phosphoric acid, succinic acid, sodium hydroxide or combination thereof.

9. The injectable composition as claimed in claim 6, wherein the composition comprises not less than about 0.1 mg / ml of antioxidant.

10. The injectable composition as claimed in claim 9, wherein the composition comprises antioxidant in the range of 0.1 mg / mL to 0.5 mg / mL.

11. The injectable composition as claimed in claim 10, wherein the composition comprises antioxidant in the range of 0.12 mg / mL to 0.2 mg / mL.

12. The injectable composition as claimed in claim 9, wherein the antioxidant is selected from sodium sulfite, sodium hydrogen sulfite or sodium metabisulfite.

13. The injectable composition as claimed in claim 6, wherein the composition comprises sodium chloride as a tonicity agent.

14. The injectable composition as claimed in claim 9, wherein the composition comprises sodium chloride in the range of 6 mg / mL to 9 mg / mL.

15. The injectable composition as claimed in claim 6, wherein the pH adjuster is hydrochloric acid, tartaric acid, citric acid, acetic acid, nitric acid, sulfuric acid, lactic acid, malic acid, maleic acid, fumaric acid, phosphoric acid, succinic acid, sodium hydroxide alone or combination thereof.

16. The injectable composition as claimed in claim 15, wherein the pH of the composition is between 2 and 5.

17. The injectable composition as claimed in claim 1, wherein the composition comprises dissolved oxygen of not more than 5 ppm.

18. The injectable composition as claimed in claim 1, wherein the composition comprises less than 6% total impurities after storage for 6 months at 25°C.

19. An injectable composition comprising epinephrine or pharmaceutically acceptable salt thereof, a dicarboxylic acid and / or a tricarboxylic acid and antioxidant in the range of 0.1 mg / mL to 0.5 mg / mL.

20. An injectable composition comprising epinephrine or pharmaceutically acceptable salt thereof, a dicarboxylic acid and / or a tricarboxylic acid, sodium chloride as tonicity agent and antioxidant in the range of 0.1 mg / mL to 0.5 mg / mL.

21. An injectable composition comprising: a. epinephrine in the range of 5 mcg / mL to 100 mcg / mL,b. at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, and c. sodium chloride in the range of 6 mg / mL to 9 mg / mL, wherein the composition is free of aminopolycarboxylic acid derivatives or salts thereof.

22. An injectable composition comprising: a. epinephrine in the range of 5 mcg / mL to 100 mcg / mL, b. at least 0.001 mg / mL of dicarboxylic acid or a tricarboxylic acid or combination thereof, c. sodium chloride, and d. antioxidant in the range of 0.12 mg / mL to 0.5 mg / mL.

23. An injectable composition comprising: a. epinephrine in the range of 5 mcg / mL to 100 mcg / mL, b. at least 0.001 mg / mL of a citrate buffer, c. sodium chloride in the range of 6 mg / mL to 9 mg / mL, and d. sodium metabisulfite in the range of 0.12 mg / mL to 0.2 mg / mL wherein the composition is free of an aminopolycarboxylic acid or salt thereof, and the composition comprises dissolved oxygen of not more than 5 ppm.

24. A pharmaceutical product comprising composition as claimed in any of the preceding claims, wherein the pharmaceutical product is a polymeric bag or bottle with volume not less than 50 mL.

25. A process for the preparation of the composition as claimed in claim in any of the preceding claims.

26. The process as claimed in claim 25, wherein the process comprises a step of aseptic sterilization.

27. The process as claimed in claim 25, wherein the process comprises the steps of: a) combining one or more excipients in a solvent having oxygen content less than 3 ppm to obtain excipient solution, wherein solvent is a carrier or tonicity agent or combination thereof;b) adjusting the pH of excipient solution obtained in step a) between 2 and 5 to prepared pH adjusted solution; c) adding epinephrine to the pH adjusted solution of step b) under inert conditions to obtain the composition; d) sterilizing the composition prepared in step c) to obtain sterilized composition; e) filling the sterilized composition of step d) in a sterilized primary packaging material to obtain product; f) optionally packing the product obtained in step e) in a sterilized secondary packing material, and wherein the sterilization in step c) is carried out by aseptic sterilization.

28. A method of treatment of hypotension associated with septic shock using the composition as claimed in claim 1.

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