DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

INJECTABLE PHARMACEUTICAL COMPOSITION COMPRISING EPINEPHRINE AND PROCESS FOR PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to an injectable pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and its preparation process and method of using the same.

BACKGROUND OF THE INVENTION

Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Anaphylaxis may result from allergic reactions to insect stings, biting insects, foods, drugs, sera, diagnostic testing substances and other allergens. Among those people who go to a hospital with anaphylaxis in the United States about 0.3% die due to this allergic reaction. During an anaphylactic attack, one might receive cardiopulmonary resuscitation (CPR) if it stop breathing or if heart stops beating. Such medications can be given, including epinephrine (adrenalin) to reduce your body's allergic response or oxygen to help you breathe or intravenous (IV) antihistamines and cortisone to reduce inflammation of air passages and improve breathing and a beta-agonist (such as albuterol) to relieve breathing symptoms.

Epinephrine acts directly on both alpha and beta adrenergic receptors. Alpha and beta adrenergic receptor belongs to a class of sympathomimetic agents. In general, a-adrenergic agonists and ß-adrenergic agonists have the opposite function of alpha and beta blockers respectively. The chemical name of Epinephrine is 1, 2-Benzenediol, 4-[(1R)-1-hydroxy-2-(methylamino) ethyl]-, or (-)-3, 4-Dihydroxy-a-[2- (methylamino) ethyl] benzyl alcohol having chemical formula C9H13NO3, a molecular weight of 183.2 and having the following chemical formula:

Epinephrine is currently available in the market as a clear, colorless, sterile solution form with dose EQ 1mg base/ml (EQ 1mg base/ml) and EQ 30mg base/30ml (EQ 1mg base/ml) approved by USFDA on Dec 7, 2012 and Dec 18, 2013 respectively under the brand name ADRENALIN® for intramuscular, intravenous and subcutaneous administration and indicated for the emergency treatment of allergic reactions (Type I), including anaphylaxis and to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin.

The following patents or patent publications pertain to various formulations of Epinephrine:
U.S. Patent No. 9,119,876 discloses a pharmaceutical composition comprising epinephrine and/or salts thereof. The composition comprises active agent, tonicity regulating agent, pH raising agent, antioxidant, pH lowering agent and transition metal complexing agent at a certain range.

U.S. Patent No. 9,295,657 discloses a pharmaceutical composition comprising epinephrine, sodium metabisulfite as an antioxidant along with tonicity regulating agent, pH adjusting agent and metal complexing agent at a certain range.

U.S. Patent No. 10,130,592 discloses a pharmaceutical composition comprising epinephrine and its salts thereof, an antioxidant, tartaric acid, sodium chloride, preservatives and disodium edetate dihydrate.

U.S. Patent publication No. 20170165206 discloses deoxygenation process containing epinephrine and/or salts thereof with sodium chloride as tonicity regulating agent.

U.S. Patent publication No. 20150246009 discloses a stabilized injectable pharmaceutical composition comprising epinephrine and its salts thereof, along with sodium metabisulfite in the range of about 1:0.005 to about 1:1.5 by weight.

U.S. Patent publication Nos. 20190105288 and 20190151261 discloses epinephrine formulations that comprises tonicity regulating agent, buffering agent etc.

PCT publication Nos. WO2017/218918; WO2019/067505 and WO2019/072723 discloses epinephrine formulations that comprises suitable antioxidant.

It is well known in the prior art that epinephrine in admixture with anti-oxidants, particularly sulfite containing antioxidants i.e., sodium metabisulfite or sodium bisulfite which are used in conventional epinephrine formulations has been associated with some other severe allergic reactions. In addition, sodium bisulfite can directly react with epinephrine to produce a degradation product i.e. Epinephrine sulfonic acid (ESA). Hence, there is need to design alternative pharmaceutical compositions of epinephrine or its pharmaceutically acceptable salts thereof to avoid such degradation.

Innovator of the present invention surprisingly found that pharmaceutical composition of epinephrine using combination of antioxidants exhibits excellent storage stability and it is comparable to marketed reference product ADRENALIN®. The present invention further provides a simple, economical and industrially feasible process for preparing pharmaceutical composition of epinephrine.

SUMMARY OF THE INVENTION

In one aspect, an invention provides an injectable pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In another aspect, an invention provides an injectable pharmaceutical composition comprising:
a) epinephrine;
b) an antioxidant;
c) a buffering agent; and
d) other suitable pharmaceutically acceptable excipients,
wherein said composition is in the form of solution.

In another aspect, an invention provides an injectable pharmaceutical composition comprising:
a) 0.05 to 0.15 % w/v of epinephrine;
b) 0.005 to 0.3 % w/v of antioxidant;
c) 0.25 to 0.50 % w/v of lactic acid; and
d) other suitable pharmaceutically acceptable excipients,
wherein one or more antioxidant is selected from the group consisting of ascorbic acid, cysteine hydrochloride, sodium metabisulfite, L-methionine, vitamin E polyethylene glycol succinate, monothioglycerol, propyl gallate, thioglycolate sodium or combination thereof.

In another aspect, an invention provides an injectable pharmaceutical composition comprising:
a) 0.5 to 1.5 mg/ml of epinephrine;
b) 0.05 to 3 mg/ml of antioxidant;
c) 0.8 to 6 mg/ml of a buffering agent;
d) 4 to 9 mg/ml of tonicity regulating agent;
e) 0.1 to 0.4 mg/ml of chelating agent; and
f) optionally 3 to 8 mg/ml of preservative;
wherein said composition provides pH value of in the range of 2.2-5.0.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.0045-0.0055 % w/v of sodium metabisulfite;
c) 0.005-0.3 % w/v of L-methionine;
d) 0.018-0.022 % w/v of disodium edetate dihydrate;
e) 0.407-0.498 % w/v of lactic acid;
f) 0.0828-0.11% w/v of sodium hydroxide;
g) 0.5535-0.803 % w/v of sodium chloride;
h) optionally 0.45-0.58 % w/v of chlorobutanol;
wherein said composition exhibits stability when stored at 40°C/75% relative humidity for at least 3 months.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.045-0.055 mg/ml of sodium metabisulfite;
c) 0.05-3 mg/ml of L-methionine;
d) 0.18-0.22 mg/ml of disodium edetate dihydrate;
e) 4-5 mg/ml of lactic acid;
f) 0.82-1.1 mg/ml of sodium hydroxide;
g) 5.5-8.1 mg/ml of sodium chloride;
h) optionally 4-6 mg/ml of chlorobutanol;
wherein said composition provides pH value of in the range of 2.2-5.0.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.005 % w/v of sodium metabisulfite;
c) 0.2 % w/v of L-methionine;
d) 0.02 % w/v of disodium edetate dihydrate;
e) 0.453 % w/v of lactic acid;
f) 0.09-0.1 % w/v of sodium hydroxide;
g) 0.615-0.73 % w/v of sodium chloride;
wherein said composition comprises buffering agent which contains lactic acid and sodium hydroxide in weight ratio is in the range of 5:1 to 4:1.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.005 % w/v of sodium metabisulfite;
c) 0.2 % w/v of L-methionine;
d) 0.02 % w/v of disodium edetate dihydrate;
e) 0.453 % w/v of lactic acid;
f) 0.09-0.1 % w/v of sodium hydroxide;
g) 0.615-0.73 % w/v of sodium chloride;
wherein said composition comprises antioxidants which contains L-methionine and sodium metabisulfite in the weight ratio is in the range of of 1:0.020 to 1:0.030.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.05 mg/ml of sodium metabisulfite;
c) 2 mg/ml of L-methionine;
d) 0.2 mg/ml of disodium edetate dihydrate;
e) 4.53 mg/ml of lactic acid;
f) 0.9-1 mg/ml of sodium hydroxide;
g) 6.15-7.3 mg/ml of sodium chloride;
h) optionally 4-6 mg/ml of chlorobutanol;
wherein the weight ratio of epinephrine to L-methionine is in the range of 1:2.5 to 1:1.5 and weight ratio of epinephrine to sodium metabisulfite is in the range of 1:0.1 to 1:0.01.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 2.72-8.18 mM of epinephrine;
b) 0.230-0.290 mM of sodium metabisulfite;
c) 0.33-20.1 mM of L-methionine;
d) 0.483-0.591 mM of disodium edetate dihydrate;
e) 45.30-55.33 mM of lactic acid;
f) 23-25 mM of sodium hydroxide;
g) 105-125 mM of sodium chloride;
h) optionally 21-34 mM of chlorobutanol;
wherein the molar ratio of epinephrine to sodium metabisulfite is in the range of 1:0.08 to 1:0.03 and molar ratio of epinephrine to L-methionine is in the range of 1:0.12 to 1:2.46 and molar ratio of epinephrine to lactic acid is in the range of 1:16.5 to 1:6.8.

In another aspect, an invention provides a stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.045-0.055 mg/ml of sodium metabisulfite;
c) 0.05-3 mg/ml of L-methionine;
d) 0.18-0.22 mg/ml of disodium edetate dihydrate;
e) 4-5 mg/ml of lactic acid;
f) 0.82-1.1 mg/ml of sodium hydroxide;
g) 5.5-8.1 mg/ml of sodium chloride;
wherein said composition contains sodium metabisulfite in the weight ratio is in the range of 0.045:1 to 0.055:1 with epinephrine and optionally said composition contains chlorobutanol as a preservative when composition packed in multiple dose vials.

In another aspect, an invention provides a process for the preparation of an injectable pharmaceutical composition wherein the process comprising:
a) mixing of sodium chloride, sodium hydroxide, lactic acid, EDTA, L-methionine and sodium metabisulfite with WFI to get clear solution;
b) adding hydrochloric acid and suitable quantity of epinephrine to solution obtained in step (a) and stirring to get clear solution;
c) optionally adding suitable quantity of chlorobutanol to solution obtained in step(b);
d) adjusting pH of solution obtained in step (c) to 2.2 to 5.0 and make up the volume to 100% with water for injection;
e) dissolved oxygen [DO] level should be maintained in the range of 0.2 to 2ppm in all the above steps (a – d);
f) packing solution of step (d) in a single dose vials or multiple dose vials, with head space oxygen in the range of 0.2 to 2%.

In preferred aspects of each embodiment of the invention, the pharmaceutical composition is found to be sterile and stable.

DETAILED DESCRIPTION OF THE INVENTION

The term “composition” or “pharmaceutical composition” or “dosage form” or “injectable pharmaceutical composition” as used herein synonymously include dosage forms such as emulsion, solution, lyophilized powder and the like.

The term “Epinephrine” (1, 2-Benzenediol, 4-[(1R)-1-hydroxy-2-(methylamino) ethyl]-, or (-)-3, 4-Dihydroxy-a-[2- (methylamino) ethyl] benzyl alcohol). Further the term ‘‘Epinephrine’’ as used herein, refers to free acid form, its salts, solvates, polymorphs, enantiomers or mixtures thereof.

The term “Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient epinephrine.

The term “excipient” includes inactive components such as a solvent, diluent, disintegrant, isotonicity agents, buffering agents, antioxidants, chelating agents, preservatives, carrier, or the like.

The term ‘‘stable’’ refers to formulations that substantially retain the label amount of the active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term ‘‘w/v’’ refers to the amount by weight (mass) of a solid substance dissolved in a measured quantity of liquid.
The term “about” is used herein to mean approximately, roughly, around, or in the regions of. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The term ‘‘Antioxidant’’ refers to a component in a composition that may prevent and/or inhibit the formation of unacceptable amounts of oxidative degradants in the composition after a certain period of shelf life. Examples of antioxidants include, but are not limited to group comprising of ascorbic acid, citric acid, cysteine hydrochloride, vitamin E polyethylene glycol succinate, isopropyl citrate, sodium hydrogen sulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, monothioglycerol, methionine or L-methionine, thioglycolate sodium, thioglycerol, vitamin E PEG succinate (tocopherol PEG succinate) and/or salts thereof. Preferably, the antioxidant is selected from group consisting of methionine or L-methionine, sodium hydrogen sulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, cysteine hydrochloride, monothioglycerol and thioglycolate sodium. More preferably the antioxidants are selected from L-methionine, sodium metabisulfite or combination thereof. The antioxidants according to the invention may be present at a concentration of from about 0.55 to 3.05 mg/ml, and preferably from about 1 to 2.8 mg/ml, specifically 1.8 to 2.4 mg/ml or 2 to 2.3 mg/ml or 2.01 to 2.1 mg/ml or 2.05 mg/ml.

The combination of antioxidants are used which are selected from L-methionine and sodium metabisulfite, the weight ratio of L-methionine and sodium metabisulfite is about 1:0.020 to 1:0.030, more preferably from 1:0.020 to 1:0.0.28, specifically 1:0.023 to 1:0.026 or 1:0.024 to 1:0.025 or 1:0.025. Further antioxidants according to the invention may be present at a concentration of 0.50 mM to 20.40 mM, preferably 5 to 18 mM, specifically 12 mM, 13 mM, 13.5 mM, 13.6 mM, 13.67 mM or 13.7 mM or 14 mM in combination.

The weight ratio of epinephrine to L-methionine is in the range of 1:0.05 to 1:3, and preferably from about 1:0.5 to 1:2.8, more preferably 1:1.8 to 1:2.5, most preferably 1:1.5 to 1:2.2 or 1:1.3 to 1:2.1 or 1:2 and the weight ratio of epinephrine to sodium metabisulfite is in the range of 1:0.1 to 1:0.01 or 1:0.05 and the molar ratio of epinephrine to L-methionine is in the range of 1:0.06 to 1:3.70, preferably 1:0.1 to 1:3.5, more preferably 1:0.5 to 1:3.2, most preferably 1:1.5 to 1:3 or 1:2 to 1:2.6 or 1:2.45 or 1:2.46 or 1:2.50 or 1:2.55, molar ratio of epinephrine to sodium metabisulfite is in the range of 1:0.035 to 1:0.08, preferably 1:0.04 to 1:0.05, specifically 1:0.041 or 1:0.042 or 1:045 or 1:0.046 or 1:0.047 or 1:0.048.

The term ‘‘Buffering agent’’ refers to a component present in a composition or solution which may provide a resistance to significant change in pH caused by a strong acid or base.

Examples of buffering agents include, but are not limited to group comprising of lactic acid, citric acid, acetic acid, tartaric acid, glutamic acid, succinic acid or salt forms of one or more of lactate, tartarate and sodium hydroxide. Preferably, the buffering agent is selected from the group consisting of tartaric acid, citric acid, acetic acid, succinic acid, lactic acid and sodium hydroxide. More preferably the buffering agents are selected from lactic acid, sodium hydroxide or combination thereof.

The buffering agents according to the invention may be present at a concentration of from about 3 to 8 mg/ml, and preferably from about 4 to 7.5 mg/ml and more particularly from about 4.5 to 6.5 mg/ml. The combination of buffering agents are used which are selected from lactic acid and sodium hydroxide, the weight ratio of lactic acid and sodium hydroxide is about 5:1 to 4:1, more preferably from 4.5:1 to 4.9:1. Further buffering agents according to the invention may be present at a concentration of 60 mM to 85 mM, specifically 60 mM, 65 mM, 70 mM, 75 mM, 80 mM or 85 mM in combination.

The weight ratio of epinephrine and L-methionine and lactic acid is in the range of 1:0.05:4.25 to 1:3:4.75, preferably 1:0.1:4.30 to 1:2.8:4.70 and more preferably 1:1:4.4 to 1:2.5:4.65, most preferably 1:1.5:4.45 to 1:2.3:4.60 or 1:1.6:4.50 to 1:2.2:4.56 or 1:1.8:4.55 or 1:1.9:4.54 or 1:2:4.53 or 1:2:4.52 and the molar ratio of epinephrine to lactic acid is in the range of 1:8.30 to 1:10.15.

The term ‘‘Tonicity’’ refers to the effective osmotic pressure equivalent of a solution or composition. Examples of tonicity regulating agent include, but are not limited to group comprising of glucose, glycerin, hydroxypropyl methyl cellulose, sodium chloride, sodium iodide, sorbitol, urea, xylitol, and/or combinations thereof. Preferably, the tonicity regulating agent is sodium chloride. The tonicity regulating agent according to the invention may be present at a concentration of from about 2 to 10 mg/ml, and preferably from about 3.5 to 9.5 mg/ml and more particularly from about 5.0 to 8.5 mg/ml or 5.5 to 7.5 mg/ml. Further tonicity regulating agent according to the invention may be present at a concentration of 100 mM to 130 mM, specifically 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM or 130 mM.

The term ‘‘Chelating agent’’ refers to a substance capable of chelation, i.e., the formation or presence of two or more separate coordinate bonds between a polydentate ligand and a single central atom. They are also known as chelants, chelators, or sequestering agents. Examples of chelating agents, but are not limited to group comprising of disodium edetate dihydrate (EDTA), citric acid, salicylic acid, and/or malic acid, including analogues, derivatives. Preferably, the chelating agent is EDTA. The chelating agent according to the invention may be present at a concentration of from about 0.01 to 1.0 mg/ml, and preferably from about 0.1 to 0.5 mg/ml and more particularly from about 0.18 to 0.22 mg/ml or 0.19 to 0.21 or 0.20 mg/ml. Further chelating agent according to the invention may be present at a concentration of 0.48 mM to 0.55mM, specifically 0.48 mM, 0.50 mM, 0.52 mM, 0.54 mM or 0.55 mM.

The term ‘‘Preservative’’ refers to a substance or a chemical that is added to products such as food, beverages, pharmaceutical products and many other products to prevent decomposition by microbial growth or by undesirable chemical changes. Examples of preservative include, but are not limited to group comprising of benzoic acid, benzyl alcohol, chlorobutanol, ethyl alcohol, sodium benzoate and sodium propionate. Preferably, the preservative is chlorobutanol. The preservative according to the invention may be present at a concentration of from about 3 to 9 mg/ml, and preferably from about 4 to 6 mg/ml and more particularly from about 4.5 to 5.8 mg/ml or 5 to 5.3 mg/ml or 5.25 mg/ml.

The term ‘‘pH adjusting agent’’ refers to an excipient that reduces sticking by a solid formulation to the equipment used for production of a unit dose form. Examples of pH adjusting agent include, but are not limited to group comprising of acetic acid, ascorbic acid, citric acid, hydrochloric acid, lactic acid, succinic acid, sulfuric acid, and/or tartaric acid. Preferably, the pH adjusting agent is hydrochloric acid.

In the present invention hydrochloric acid is used in sufficient quantity (0.2 mg/ml) to get desired pH value and also used to convert the epinephrine into salt form to get soluble in the composition. The preferred pH value of said composition is from about 2.2 to 5.0, more preferably the pH value of said composition is in the range of 3.5 to 4.5 and most preferably 3.6, 3.7, 3.8, 3.9, 4.0 or 4.1 or 4.2 or 4.3.

The term ‘‘Solvent/vehicle’’ refers to a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a solution. Examples of solvents include but not limited to group comprising of acetone, glycerin, propylene glycol and/or water for injection (WFI). Preferably, the solvent used is water for injection.

The aqueous solution is deoxygenated by bubbling through an inert gas, such as nitrogen. The bubbling process can be continued until a dissolved oxygen (DO) level of less than 2 ppm (parts per million) is obtained. The deoxygenated solution thus obtained can then be conveyed, safe from the air, into a filling machine, to be distributed into containers such as flasks, ampoules or bottles.

The head space oxygen of the solution obtained according to the present invention is in the range of 0.2 to 2%.
The term “optionally” with respect to any element of a claim is intended to mean that the subject element is required, or alternatively, is not required. Both alternatives are intended to be within the scope of the claim.

In the present invention, the solvent is present in an amount that brings the composition to a final volume, the final volume may be 1 ml for packing in single dose vials (SDV) and in some embodiments, the final volume may be 30 ml for packing in multiple dose vials (MDV).

In one embodiment, an invention provides an injectable pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In another embodiment, an invention provides an injectable pharmaceutical composition comprising:
a) 0.5 to 1.5 mg/ml of epinephrine;
b) 0.05 to 3.07 mg/ml of antioxidant;
c) a buffering agent; and
d) other suitable pharmaceutically acceptable excipients,
wherein one or more antioxidant is selected from the group consisting of ascorbic acid, cysteine hydrochloride, sodium metabisulfite, L-methionine, vitamin E polyethylene glycol succinate, monothioglycerol, propyl gallate, thioglycolate sodium or combination thereof.

In another embodiment, an invention provides an injectable pharmaceutical composition comprising:
a) 0.05 to 0.15 % w/v of epinephrine;
b) 0.005 to 0.3 % w/v of antioxidant;
c) 0.25 to 0.50 % w/v of lactic acid; and
d) other suitable pharmaceutically acceptable excipients,
wherein one or more antioxidant is selected from the group consisting of ascorbic acid, cysteine hydrochloride, sodium metabisulfite, L-methionine, vitamin E polyethylene glycol succinate, monothioglycerol, propyl gallate, thioglycolate sodium or combination thereof.

In another embodiment, an invention provides an injectable pharmaceutical composition comprising:
a) 0.5 to 1.5 mg/ml of epinephrine;
b) 0.05 to 3 mg/ml of antioxidant;
c) 0.8 to 6 mg/ml of a buffering agent;
d) 4 to 9 mg/ml of tonicity regulating agent;
e) 0.1 to 0.4 mg/ml of chelating agent; and
f) optionally 3 to 8 mg/ml of preservative;
wherein said composition provides pH value of in the range of 2.2-5.0.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.0045-0.0055 % w/v of sodium metabisulfite;
c) 0.005-0.3 % w/v of L-methionine;
d) 0.018-0.022 % w/v of disodium edetate dihydrate;
e) 0.407-0.498 % w/v of lactic acid;
f) 0.0828-0.11% w/v of sodium hydroxide;
g) 0.5535-0.803 % w/v of sodium chloride;
h) optionally 0.45-0.58 % w/v of chlorobutanol;
wherein said composition exhibits stability when stored at 40°C/75% relative humidity for at least 3 months.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.045-0.055 mg/ml of sodium metabisulfite;
c) 0.05-3 mg/ml of L-methionine;
d) 0.18-0.22 mg/ml of disodium edetate dihydrate;
e) 4-5 mg/ml of lactic acid;
f) 0.82-1.1 mg/ml of sodium hydroxide;
g) 5.5-8.1 mg/ml of sodium chloride;
h) optionally 4-6 mg/ml of chlorobutanol;
wherein said composition provides pH value of in the range of 2.2-5.0.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.005 % w/v of sodium metabisulfite;
c) 0.2 % w/v of L-methionine;
d) 0.02 % w/v of disodium edetate dihydrate;
e) 0.453 % w/v of lactic acid;
f) 0.09-0.1 % w/v of sodium hydroxide;
g) 0.615-0.73 % w/v of sodium chloride;
wherein said composition comprises buffering agent which contains lactic acid and sodium hydroxide in weight ratio is in the range of 5:1 to 4:1.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.005 % w/v of sodium metabisulfite;
c) 0.2 % w/v of L-methionine;
d) 0.02 % w/v of disodium edetate dihydrate;
e) 0.453 % w/v of lactic acid;
f) 0.09-0.1 % w/v of sodium hydroxide;
g) 0.615-0.73 % w/v of sodium chloride;
wherein said composition comprises antioxidants which contains L-methionine and sodium metabisulfite in weight ratio is in the range of 1:0.020 to 1:0.030.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.05 mg/ml of sodium metabisulfite;
c) 2 mg/ml of L-methionine;
d) 0.2 mg/ml of disodium edetate dihydrate;
e) 4.53 mg/ml of lactic acid;
f) 0.9-1 mg/ml of sodium hydroxide;
g) 6.15-7.3 mg/ml of sodium chloride;
h) optionally 4-6 mg/ml of chlorobutanol;
wherein the weight ratio of epinephrine to L-methionine is in the range of 1:2.5 to 1:1.5 and weight ratio of epinephrine to sodium metabisulfite is in the range of 1:0.1 to 1:0.01.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 5.45 mM of epinephrine;
b) 0.230-0.290 mM of sodium metabisulfite;
c) 0.33-20.1 mM of L-methionine;
d) 0.537 mM of disodium edetate dihydrate;
e) 45.30-55.33 mM of lactic acid;
f) 23-25 mM of sodium hydroxide;
g) 105-125 mM of sodium chloride;
h) optionally 21-34 mM of chlorobutanol;
wherein the molar ratio of epinephrine to sodium metabisulfite is in the range of 1:0.042 to 1:0.053 and molar ratio of epinephrine to antioxidant L-methionine is in the range of 1:0.06 to 1:3.70 and molar ratio of epinephrine to lactic acid is in the range of 1:8.30 to 1:10.15.

In another embodiment, an invention provides a stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.045-0.055 mg/ml of sodium metabisulfite;
c) 0.05-3 mg/ml of L-methionine;
d) 0.18-0.22 mg/ml of disodium edetate dihydrate;
e) 4-5 mg/ml of lactic acid;
f) 0.82-1.1 mg/ml of sodium hydroxide;
g) 5.5-8.1 mg/ml of sodium chloride;
wherein said composition contains sodium metabisulfite in the weight ratio of 0.045:1 to 0.055:1 with epinephrine and optionally said composition contains chlorobutanol as a preservative when composition packed in multiple dose vials.

In another embodiment, an invention provides a process for the preparation of an injectable pharmaceutical composition wherein the process comprising:
a) mixing of sodium chloride, sodium hydroxide, lactic acid, disodium edetate dihydrate, L-methionine and sodium metabisulfite with WFI to get clear solution;
b) adding hydrochloric acid and suitable quantity of epinephrine to solution obtained in step (a) and stirring to get clear solution;
c) optionally adding suitable quantity of chlorobutanol to solution obtained in step(b);
d) adjusting pH of solution obtained in step (c) to 2.2 to 5.0 and make up the volume to 100% with water for injection;
e) dissolved oxygen [DO] level should be maintained in the range of 0.2 to 2ppm in all the above steps (a – d) and packing solution of step (d) in a single dose vials or multiple dose vials, with head space oxygen in the range of 0.2 to 2%.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention.

Examples 1 – 7 represents Epinephrine compositions according to the present invention:

Example - 1:

S. No. Ingredients Qty (mg/ml)
SDV MDV
1 Epinephrine 1 1
2 Sodium chloride 7.3 6.15
3 Ascorbic acid or Cysteine HCl or Methionine or Vitamin E PEG Succinate 1 - 10
4 Sodium hydroxide 1 0.92
5 Citric acid or Acetic acid or Lactic acid or Succinic acid 1 - 5
6 Disodium edetate dihydrate 0.20 0.2
7 Chlorobutanol - 5.25
8 Hydrochloric acid (Q.s to adjust pH) 2.2 to 5.0. 2.2 to 5.0.
9 Water for injection Q.s to 1ml Q.s to 1ml
* Qs – Quantity sufficient

Manufacturing process:
a) Mixing of sodium chloride, sodium hydroxide, EDTA, buffering agent, antioxidants and optionally chlorobutanol with WFI to get a clear solution;
b) Hydrochloric acid (to adjust pH) and a suitable quantity of epinephrine was added to solution obtained in step (a) and stirred to get clear solution;
c) Finally volume of the solution obtained in step (b) was maintained with water for injection and the bulk solution was filtered through 0.2 µ filter.

Example - 2:

S. No. Ingredients Qty (mg/ml)
SDV MDV
1 Epinephrine 1 1
2 Sodium chloride 7.3 6.15
3 Ascorbic acid or Cysteine HCl or Methionine or Monothioglycerol or Propyl gallate or Thioglycolate sodium 1 - 10
4 Sodium hydroxide 1 0.92
5 Tartaric acid 2.25 2.25
6 Disodium edetate dihydrate 0.20 0.20
7 Chlorobutanol - 5.25
8 Hydrochloric acid (Q.s to adjust pH) 2.2 to 5.0 2.2 to 5.0
9 Water for injection Q.s to 1 ml Q.s to 1 ml

Manufacturing process: Same as per Example 1.
Example - 3:
S. No. Ingredients SDV MDV
mg/ml % w/v mg/ml % w/v
1 Epinephrine 1 0.1 1 0.1
2 Sodium chloride 7.3 0.73 6.15 0.615
3 Sodium metabisulfite 0.05 0.005 0.05 0.005
4 L-Methionine 2 0.2 2 0.2
5 Sodium hydroxide 1 0.1 0.92 0.092
6 Lactic acid 4.53 0.453 4.53 0.453
7 Disodium edetate dihydrate 0.2 0.02 0.2 0.02
8 Chlorobutanol NA NA 5.25 0.525
9 Hydrochloric acid Q.s to adjust pH
10 Water for injection Q.s to 1mL Q.s to 1mL Q.s to 1mL Q.s to 1mL

Manufacturing process:
Brief manufacturing process for single dose vial (SDV):
a) Mixing of sodium chloride, sodium hydroxide, lactic acid, disodium edetate dihydrate, sodium metabisulfite and L-methionine with WFI to get a clear solution;
b) Hydrochloric acid and a suitable quantity of epinephrine was added to solution obtained in step (a) and stirred to get clear solution and pH of solution was adjusted to 2.2 to 5.0 using hydrochloric acid;
c) Finally make up the volume of the solution obtained in step (b) to 100% of batch size with water for injection;
d) Dissolved oxygen [DO] level should be maintained in the range of 0.2 to 2ppm in all the above steps (a – c);
e) Packing solution of step (d) in a single dose vials or multiple dose vials, with head space oxygen in the range of 0.2 to 2%.

Brief manufacturing process for multiple dose vial (MDV):
a) Mixing of sodium chloride, sodium hydroxide, lactic acid, disodium edetate dihydrate, sodium metabisulfite, L-methionine and chlorobutanol with WFI to get a clear solution;
b) Hydrochloric acid and a suitable quantity of epinephrine was added to solution obtained in step (a) and stirred to get clear solution; and pH of solution was adjusted to 2.2 to 5.0 using hydrochloric acid;
c) Finally make up the volume of the solution obtained in step (b) to 100% of batch size with WFI;
d) Dissolved oxygen [DO] level should be maintained in the range of 0.2 to 2ppm in all the above steps (a – c);
e) Packing solution of step (c) in a single dose vials or multiple dose vials, with head space oxygen in the range of 0.2 to 2%.

Example - 4 & 5: (SDV)
S. No Ingredients (mg/ml) % w/v
Example - 4 Example - 5
1 Epinephrine 1.00 1.00 0.1
2 Sodium chloride 8.03 6.57 0.657 – 0.803
3 Sodium metabisulfite 0.045 0.055 0.0045 – 0.0055
4 L-Methionine 1.80 2.20 0.18 – 0.22
5 Sodium hydroxide 0.90 1.10 0.09 – 0.11
6 Lactic acid 4.077 4.983 0.4077 – 0.4983
7 Disodium edetate dihydrate 0.18 0.22 0.018 – 0.022
8 Hydrochloric acid Q.s to adjust pH NA
9 Water for injection Q.s to 1mL NA
Manufacturing process: Same as per Example 3 (SDV).

Example - 6 & 7: (MDV)

S. No Ingredients (mg/ml) % w/v
Example - 6 Example - 7
1 Epinephrine 1.00 1.00 0.1
2 Sodium chloride 6.765 5.535 0.5535 – 0.6765
3 Sodium metabisulfite 0.045 0.055 0.0045 – 0.0055
4 L-Methionine 1.80 2.20 0.18 – 0.22
5 Sodium hydroxide 0.828 1.012 0.0828 – 0.1012
6 Lactic acid 4.077 4.983 0.4077 – 0.4983
7 Disodium edetate dihydrate 0.18 0.22 0.018 – 0.022
8 Chlorobutanol 4.725 5.775 0.4725 – 0.5775
9 Hydrochloric acid Q.s to adjust pH NA
10 Water for injection Q.s to 1mL NA

Manufacturing process: Same as per Example 3 (MDV).

Stability studies: Epinephrine Injection was subjected to accelerated stability testing as per the ICH guidelines at temperature 40°C & relative humidity of 75% and 25°C & relative humidity of 60% for 3 months. The Epinephrine Injection was placed in a single dose vials and multiple dose vials exposed to above mentioned condition and then evaluated for impurity profile which is shown in Table 1 & 2:
Table 1: Stability study data of Epinephrine Injection (Examples 3 - 5) in a single dose vial:
Conditions Initial 40°C/75% RH 25°C/60% RH
1 month 3 month 3 month
Description Clear colorless solution
pH (2.2-5.0) 3.896 3.84 3.834 3.91
Assay (90.0 - 115.0) 101.2 101.5 98.0 103.0
Related substances (with Specifications)
Impurity F (NMT 10.0) 0.2 1.3 2.9 0.8
Specified Impurity at -0.16 RRT (NMT* 1.0%) 0.03 0.17 0.62 0.23
Any other individual
Unknown impurity (NMT 0.5%) 0.05 0.04 0.05 0.04
Total Impurities (NMT 12.0%) 0.33 1.54 3.65 1.1
*: NMT – Not more than
Table 2: Stability study data of Epinephrine Injection (Examples 3, 6 - 7) in a multiple dose vial:

Conditions Initial 40°C/75% RH 25°C/60% RH
1 month 3 month 3 month
Description Clear colorless solution
pH (2.2-5.0) 3.701 3.586 3.45 3.721
Assay (90.0 - 115.0) 101.9 101.2 99.8 101.7
Related substances (with Specifications)
Impurity F (NMT 10.0) 0.2 1.4 2.5 0.6
Specified Impurity at -0.16 RRT (NMT 1.0%) 0.04 0.18 0.46 0.1
Any other individual
Unknown impurity (NMT 0.5%) 0.01 Not Detected 0.03 0.03
Total Impurities (NMT 12.0%) 0.26 1.58 3.00 0.75

The present formulation clearly indicates excellent chemical stability upon storage at accelerated stability conditions at 40°C & 75% relative humidity and 25°C & 60% relative humidity for three months showed no evidence of any major change in color, pH, degradation products and no significant reduction in the content of active substance.
,CLAIMS:We Claim:

1. A stable injectable pharmaceutical composition comprising:
a) 0.1 % w/v of epinephrine;
b) 0.0045-0.0055 % w/v of sodium metabisulfite;
c) 0.005-0.3 % w/v of L-methionine;
d) 0.018-0.022 % w/v of disodium edetate dihydrate;
e) 0.407-0.498 % w/v of lactic acid;
f) 0.0828-0.11% w/v of sodium hydroxide;
g) 0.5535-0.803 % w/v of sodium chloride;
h) optionally 0.45-0.58 % w/v of chlorobutanol;
wherein said composition exhibits stability when stored at 40°C/75% relative humidity for at least 3 months.

2. A stable injectable pharmaceutical composition comprising:
a) 1 mg/ml of epinephrine;
b) 0.045-0.055 mg/ml of sodium metabisulfite;
c) 0.05-3 mg/ml of L-methionine;
d) 0.18-0.22 mg/ml of disodium edetate dihydrate;
e) 4-5 mg/ml of lactic acid;
f) 0.82-1.1 mg/ml of sodium hydroxide;
g) 5.5-8.1 mg/ml of sodium chloride;
h) optionally 4-6 mg/ml of chlorobutanol;
wherein said composition provides pH value of in the range of 2.2-5.0.

3. A stable injectable pharmaceutical composition comprising:
a) 5.45 mM of epinephrine;
b) 0.230-0.290 mM of sodium metabisulfite;
c) 0.33-20.1 mM of L-methionine;
d) 0.537 mM of disodium edetate dihydrate;
e) 45.30-55.33 mM of lactic acid;
f) 23-25 mM of sodium hydroxide;
g) 105-125 mM of sodium chloride;
h) optionally 21-34 mM of chlorobutanol;
wherein the molar ratio of epinephrine to sodium metabisulfite is in the range of 1:0.042 to 1:0.053 and molar ratio of epinephrine to L-methionine is in the range of 1:0.06 to 1:3.70 and molar ratio of epinephrine to lactic acid is in the range of 1:8.30 to 1:10.15.

4. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein said composition comprises buffering agent which contains lactic acid and sodium hydroxide in weight ratio is in the range of 5:1 to 4:1, preferably 4.53.

5. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein said composition comprises antioxidant which contains L-methionine and sodium metabisulfite in weight ratio is in the range of 1:0.020 to 1:0.030, preferably 0.025.

6. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein the weight ratio of epinephrine to L-methionine is in the range of 1:0.05 to 1:3, preferably 1:0.5 to 1:2.5 and most preferably 1:1.5 to 1:2.2 or 1:2.

7. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein composition contains less than 5% of total impurities by weight relative to epinephrine when measured by HPLC after storage for 3 months at 40oC/75% or 25oC/60% relative humidity.

8. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein the weight ratio of epinephrine and L-methionine and lactic acid is in the range of 1:0.05:4.25 to 1:3:4.75, preferably 1:0.5:4.3 to 1:2.5:4.60, most preferably 1:2:4.53.

9. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein said composition contains sodium metabisulfite in the weight ratio of 0.045:1 to 0.055:1 with epinephrine.

10. The stable injectable pharmaceutical composition comprising according to claim 1-3, wherein said composition optionally contains chlorobutanol as a preservative when composition packed in multiple dose vials.