DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“Stable injectable pharmaceutical composition of epinephrine”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003,
Gujarat, India.

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION

The present subject matter relates to a stable injectable pharmaceutical composition comprising epinephrine, a non-sulfite antioxidant and a chelating agent. Further, the subject matter provides a process of preparing such composition and use thereof.

BACKGROUND OF THE INVENTION

Epinephrine, also known as adrenaline, is a sympathomimetic catecholamine. Chemically, epinephrine is (-)-3,4- Dihydroxy-a-[(methylamino)methyl]benzyl alcohol with the following structure:

Epinephrine is available in a variety of formulations suited for different clinical indications and routes of administration, for example by injection, by inhalation, or topically. Its uses include at least the following: combating low blood pressure during hemorrhagic or allergic shock, opening the airways during asthmatic attack, restricting the distribution of locally administered drugs such as local anesthetics, reducing nasal congestion and/or performance aid in emergency situations.

US 2008/0269347 discloses epinephrine formulations comprising epinephrine, EDTA, and at least one antioxidant, wherein the antioxidant is selected from the group consisting of cysteine, citric acid, thioglycerol, acetylcysteine, and a combination thereof.

US 2016/113891 discloses stable epinephrine formulations with citric acid as antioxidant but with only very low epinephrine concentrations.

US FDA approved and commercially available epinephrine auto-injectors for treatment of allergic reactions are Epipen®, Adrenaclick® and Auvi-Q®.

The Epipen® formulation contains 1.0 mg/mL epinephrine (Epipen® Jr formulation 0.5 mg/mL epinephrine), 6.0 mg/mL sodium chloride, 1.67 mg/mL sodium metabisulfite (Na2S205), hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2–5.0. The EpiPen® Auto-Injector products contains more than about 10% of the epinephrine overages. This is in order to compensate the amount of epinephrine degraded during manufacture or over storage. Such overages however, may either lead to undesirable side effects due to dose inaccuracy or generate more degradants in the product. The Epipen® has shelf-life of 20 months.

Adrenaclick® has a similar composition to Epipen®, but uses sodium bisulfite instead of sodium metabisulfite and includes chlorobutanol as a preservative. Auvi-Q® has a similar composition to Adrenaclick® but does not contain chlorobutanol.

Epinephrine is destroyed readily in alkaline solutions by aldehydes, weak oxidizing agents, oxygen of the air and by auto-oxidation involving the formation of adrenaline-o-quinone, which in turn converts to adrenochrome. In alkaline solution and when exposed to air, light or elevated temperature epinephrine turns pink from oxidation to adrenochrome which is further degraded to adrenolutin and melanin or oxidation leads to the formation of polymers both with brown color.

In order to prevent oxidative degradation commercially available epinephrine formulations such as EpiPen®, Adrenaclick® and Auvi-Q® uses sodium metabisulfite or sodium bisulfite as antioxidant, but sodium metabisulfite or sodium bisulfite have been associated with some severe allergic reactions.

In addition, sodium bisulfite can directly react with epinephrine to form a biologically inactive sulfonic acid derivative, epinephrine sulfonic acid (ESA). The safety and/or toxicity of ESA in commercial epinephrine products for anaphylactic treatment are still not well understood. In addition, the potency of epinephrine formulations also can be substantially degraded due to such reaction over product shelf-life.

It is recommended that persons at risk of anaphylaxis, and persons responsible for children at risk for anaphylaxis, always maintain one or more automatic epinephrine injectors. Commercially available epinephrine auto injectors have a shelf –life of about 20 months. Thus an objective of the present subject matter was to develop stable epinephrine injection with longer shelf-life.

Another objective of the present subject matter was to develop a sulfite free stable injectable pharmaceutical composition of epinephrine that exhibits improved storage stability and may not require addition of epinephrine overages.

The inventors of present subject matter, surprisingly found that a stable injectable pharmaceutical composition of epinephrine devoid of sulfite antioxidant can be obtained by using citric acid as antioxidant and such composition is characterized by significantly low level of impurities and longer shelf-life compared to other marketed epinephrine auto-injectors.

SUMMARY OF THE INVENTION:

The present subject matter relates to a stable injectable pharmaceutical composition comprising epinephrine, a non-sulfite antioxidant and a chelating agent. Further, the subject matter provides a process of preparing such composition and use thereof.

In one aspect, there is provided a sulfite free stable injectable pharmaceutical composition of epinephrine or a pharmaceutically acceptable salt thereof.

In an embodiment, the stable injectable pharmaceutical composition comprises a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof, an antioxidant which is not a sulfite antioxidant, a chelating agent, a tonicity-adjusting agent, a pH adjusting agent, water for injection, and optionally other pharmaceutically acceptable excipients.

In another embodiment, the stable injectable pharmaceutical composition comprises an aqueous solution comprising a therapeutically effective amount of epinephrine, citric acid as antioxidant, EDTA disodium as chelating agent, sodium chloride as tonicity agent and a hydrochloric acid to adjust the pH.

In an embodiment, the stable injectable pharmaceutical composition of epinephrine have a pH in the range of about 2.2 to about 5.0.

In another aspect, the present subject matter provides a stable injectable pharmaceutical composition of epinephrine, characterized in that the composition is substantially free of epinephrine overages.

In another aspect, there is provided a stable injectable pharmaceutical composition of epinephrine, which may retain at least about 90 % potency, for example, at least about 95 % potency or at least about 99 % potency of the drug when stored at 25°C/60 % RH for more than 1 month, for example, for 3 months, for 6 months, for 12 months, for 18 months, for 24 months or for 36 months.

In another aspect, there is provided a stable injectable pharmaceutical composition of epinephrine, which does not contain more than 3 % total impurities, for example, the composition does not contain more than 2 %, does not contain more than 1 % or does not contain more than 0.5 % of the total impurities when stored at 25°C/60 % RH for more than 1 month , for example , for 3 months, for 6 months, for 12 months, for 18 months, for 24 months or for 36 months as determined by high performance liquid chromatography (HPLC).

In another aspect, there is provided a stable injectable pharmaceutical composition of epinephrine, which remains stable for commercially relevant time period after manufacturing, such as for about 1, 3, 6, 12, 18, 24 or 36 months , when it is kept in its original packaging under the specified storage conditions.

In another aspect, the present subject matter provides a process for preparation of stable injectable pharmaceutical composition comprising epinephrine or salt thereof, which process comprises of mixing epinephrine or salt thereof, citric acid, EDTA disodium, water for injection, and optionally one or more other pharmaceutically acceptable excipients.

In another aspect the compositions described herein are administered by using any suitable method and/or device. The composition provided herein is loaded into an administrative device that delivers an effective amount of medication. The administrative device is, by way of non-limiting example, a syringe or a cartridge suitable for delivering injectable medications via a manual and/or auto injector.

In another aspect, the present subject matter provides use of stable injectable pharmaceutical composition of epinephrine for the preparation of medicaments useful for treating allergic reactions (Type I) including anaphylaxis to stinging insects and biting insects, allergen immunotherapy, foods, drugs, diagnostic testing substances and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis, comprising administering to human patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION:

The present subject matter relates to a stable injectable pharmaceutical composition comprising epinephrine, a non-sulfite antioxidant and a chelating agent. Further, the subject matter provides a process of preparing such composition and use thereof.

The term “epinephrine”, as used herein includes epinephrine and a pharmaceutically acceptable salt thereof such as epinephrine bitartrate or epinephrine hydrochloride.

The term "therapeutically effective amount" is defined as the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, medical doctor or other clinician. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like.

The term “sulfite anti-oxidant” as used herein means any anti-oxidant capable of providing sulfite, bisulfite, or metabisulfite anions in water. For instance, sodium sulphite, sodium bisulfite, sodium metabisulphite, sodium pyrosulphite and the like.

The term “stable” refers to any preparation of epinephrine or pharmaceutically acceptable salts thereof having sufficient physical and chemical stability to allow storage at a convenient temperature, such as between about 15°C to about 30° C, for a commercially reasonable period of time. The term “physical stability” refers to maintenance of color and absence of particulate matter and the term “chemical stability” relates to no or acceptable level of drug-related impurities in terms of total impurity, maximum individual unknown impurity and single maximum individual impurity. Further, a pharmaceutical composition of the invention is “stable” or “stabilized” if one or more of the active agents therein exhibit good stability as determined by a standard potency test. More specifically, such compositions exhibit a potency loss of less than about 10%, preferably less than about 8%, more preferably less than about 5% as determined by the test. Potency can be evaluated by one or a combination of strategies known in the field.

Epinephrine is destroyed readily in alkaline solutions by aldehydes, weak oxidizing agents, oxygen of the air and by auto-oxidation involving the formation of adrenaline-o-quinone, which in turn converts to adrenochrome. In alkaline solution and when exposed to air, light or elevated temperature epinephrine turns pink from oxidation to adrenochrome which is further degraded to adrenolutin and melanin or oxidation leads to the formation of polymers both with brown color.

In order to prevent the thermal and/or oxidative degradations of epinephrine, commercial formulations available on the market are currently using a common conventional antioxidant of sulfite related compounds such as sodium metabisulfite and/or sodium bisulfite. The sulfite related compounds can directly react with epinephrine, resulting in a substantial loss of epinephrine potency and generating degradation products, such as epinephrine sulfonic acid (ESA), which rapidly increases with time and becomes a major limiting factor to the product shelf life.

In some instances, sulfite related compounds in foods and/or medications cause a severe allergy or asthma reaction. For instance, some people have experienced severe reactions from sulfite-containing medications including intravenous drugs and inhaled medications, these reactions including flushing, hives, and a drop in lung function. The present subject matter provides sulfite free formulations of epinephrine, which significantly improves the product stability and eliminates the patient's risk of a potential exposure to a severe allergy or asthma reaction from the aforementioned antioxidant of sulfite related compounds.

In one aspect, the present subject matter provides composition and methods of using a novel composition to enhance the physicochemical stability of epinephrine in an aqueous solution and subsequently extend the product shelf life.

In another aspect, there is provided a safer medication for patients by reducing and/or eliminating additives, such as a conventional "sulfite" antioxidant, in the formulation that degrade the epinephrine potency, generates degradation products, and potentially causes the subsequent severe asthma and/or allergy reactions.

In another embodiment, compositions provided herein reduce a patient's risk of exposure to unwanted degradation products (e.g., high ESA levels and unnecessary asthma and/or allergy reactions associated therewith), a patient's risk of exposure to drastic dosage overages and/or underages depending on the manufacture date of the product, a patient's exposure to unnecessary additives and agents, etc.

In another embodiment, the stable injectable pharmaceutical composition comprises epinephrine, wherein the composition is devoid of sulfite antioxidant.

In an embodiment provided herein are pharmaceutically acceptable compositions comprising epinephrine and one or more excipients. In another embodiment, compositions provided herein comprise epinephrine, a non-sulfite antioxidant, a chelating agent, a pH adjusting agent, a tonicity modifier, or any combination thereof. In another embodiment, provided herein are compositions comprising epinephrine and an antioxidant which is citric acid. In more another embodiment, provided herein are compositions comprising epinephrine, citric acid and a chelating agent. In one embodiment, the pharmaceutical formulation comprises of epinephrine (e.g., formulated as a free base or a pharmaceutically acceptable salt thereof), an antioxidant, a chelating agent, a pH adjusting agent, and a tonicity modifier in water for injection.

In an embodiment, compositions provided herein are formulated with any suitable epinephrine, such as the free base, conjugate acid, or a pharmaceutically acceptable salt thereof. In another embodiment, the epinephrine utilized to formulate a composition provided herein is selected from epinephrine (free base), epinephrine bitartrate, and epinephrine hydrochloride and/or a combination thereof. Generally, compositions described herein as comprising epinephrine refer to a dissolved epinephrine, whether dissolved free base, conjugate acid, or a salt thereof. Compositions provided herein optionally comprise epinephrine in the free base form and/or in a protonated cation (conjugate acid) or salt form. In an embodiment, the epinephrine is provided in a composition herein and/or formulated into a composition herein in a free base equivalent amount of about 0.01 wt. % to about 2 wt. % . In some instances, concentrations vary with varying subject age, therapeutic treatments and/or administration routes. In another embodiment, compositions provided herein comprise about 0.03 wt. % to about 1 wt. % epinephrine, more specifically about 0.05 wt. %.

In an embodiment, the composition provided herein comprises citric acid as a non-sulfite antioxidant. The inventors of the present subject matter surprisingly found that use of citric acid as an antioxidant in the present subject matter efficiently inhibits drug oxidation and minimize the cross reaction with drug. Further low concentrations of citric acid inhibited the drug oxidation. Indeed, the use of citric acid as an antioxidant at low concentration demonstrated herein to provide dramatically improved physiochemical stability (improved potency, reduced degradation products, and improved color profile) over time, as compared to compositions having an antioxidant other than citric acid (e.g., sodium metabisulfite and/or sodium bisulfite, cysteine, ascorbic acid).

In an embodiment, citric acid is present in an amount of about 0.05 wt. % to about 2.0 wt. %, e.g., about 0.01 wt. % to about 1.0 wt %, about 0.01 wt. % to about 0.5 wt. %, about 0.5 wt. % to about 0.2 wt. %, about 0.1 wt. %.

In an embodiment, citric acid is provided in the composition in an amount of about 0.05 mg/mL to less than 4 mg/mL, about 0.05 mg/mL to about 3 mg/mL, about 0.05 to about 2 mg/mL, about 0.05 mg/mL to about 1 mg/mL, more specifically about 1 mg/mL.

In another embodiment, the composition provided herein comprises suitable chelating agents Chelating agents are chemical compounds that react with metal ions to form a stable, water-soluble complex. They are also known as chelants, chelators, or sequestering agents. Suitable chelating agents which may be used in the present invention include, but not limited to edetate disodium (EDTA), edetate disodium anhydrous, edetate sodium, edetate disodium dehydrate, edetate tetrasodium, and/or a combination thereof preferably EDTA disodium. The amount of the chelating agent present in the aqueous pharmaceutical composition may range from about 0.001-0.1% w/v preferably 0.01%.

In an embodiment, the composition provided herein comprises suitable a tonicity modifier. Tonicity modifer is utilized to adjust the solution osmolality within body physiological range of about 200-400 mOsm/kg. Suitable tonicity modifier which may be used in the present invention include, but not limited to sodium chloride, dextrose or a combination thereof, preferably sodium chloride

In an embodiment, the composition provided herein comprises suitable pH adjusting agents Suitable pH adjusting agents which may be used in the present invention include, but not limited to sodium hydroxide, hydrochloric acid, acetic acid, fumaric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or combinations thereof, preferably hydrochloric acid to about pH 2.2 to about pH 5.0

In one embodiment, there is provided a stable injectable dosage form comprising an aqueous solution comprising
a) a therapeutically effective amount of epinephrine in an amount ranging from about 0.05 mg/ml to about 1.0 mg/ml,
b) citric acid
c) EDTA disodium
d) sodium chloride
e) hydrochloric acid to adjust the pH of solution in a range of 2.2 to 5.0.

Currently, marketed products of epinephrine i.e. the Epipen Auto-Injector products contains more than about 10% of the epinephrine overages. This is in order to compensate the amount of epinephrine degraded during manufacture or over storage. Such overages however, may either lead to undesirable side effects due to dose inaccuracy or generate more degradation products in the product. Therefore another aspect, of the present subject matter is to provide a stable injectable pharmaceutical composition of epinephrine, characterized in that the composition is substantially free of epinephrine overages.

The present subject matter provides for a composition that may have a low level of impurities. The term "impurity" refers to an undesired substance in a composition. In an embodiment, an amount of impurities may be present in an initial composition and/or may be formed after a certain period of shelf life of a composition. In another embodiment, impurities may be formed via degradation of one or more components of the composition. Sources of degradation include, but are not limited to, oxidation, racemization, visible light, ultraviolet light, moisture, heat, changes in pH, and composition component interactions. Unless indicated otherwise, the percentages of impurities expressed herein are expressed as % w/w of the active agent.

Various methods of analyzing (characterization and quantification) the impurities are well established in the art. Various spectoroscopic techniques, such as NMR, MS, IR etc. and chromatographic techniques, such as HPLC, HPLC-TLC, HPLC-CE and hyphenated methods, such as LC-MS-MS, HPLC-DAD-MS, HPLC-NMR, GC-MS & LCMS can be used for analyzing impurities.

In another aspect, there is provided a stable injectable pharmaceutical composition of epinephrine, which may retain at least about 90 % potency, for example, at least about 95 % potency or at least about 99 % potency of the drug when stored at 25°C/60 % RH, for more than 1 month, for example, for 3 months, for 6 months, for 12 months, for 18 months, for 24 months or for 36 months.
In another aspect, there is provided a stable injectable pharmaceutical composition of epinephrine, which does not contain more than 3 %, for example , does not contain more than 2 % , does not contain more than 1 % or does not contain more than 0 .5 % of the total impurities when stored at 25°C/60 % RH, for more than 1 month, for example, for 3 months, for 6 months, for 12 months, for 18 months, for 24 months or for 36 months as determined by high performance liquid chromatography.

In another aspect, there is provided a stable injectable pharmaceutical composition of epinephrine, which remains stable for commercially relevant time period after manufacturing , such as for about 1 , 3 , 6 , 12 , 18 , 24 or 36 months , when it is kept in its original packaging under the specified storage conditions.

Further there is provided a stable injectable pharmaceutical composition of epinephrine, which remains stable and compliant as per ICH guideline for impurities for respective product, for more than 2 months , for example, for 3 months, for 6 months, for 12 months, for 24 months or for 36 months, when stored at 15° to 30°C° C temperature.

The present subject matter also provides a process of manufacturing stable injectable pharmaceutical composition of epinephrine. The process involves adding citric acid, EDTA disodium and sodium chloride to water for injection (WFI) under continuous nitrogen purging. Epinephrine was sequentially added to the solution under stirring to get clear solution.1N HCI solution was added to adjust the pH to 2.2 to 5.0. Final volume of the solution was made with water for injection. pH of the final solution can be adjusted using HCI solution if required. The solution was then subjected to filtration through 0.22µm membrane filter and loaded into cartridge.

In another embodiment, the present epinephrine compositions is used in a conjunction with an administrative device for administration into body. Any suitable device is utilized. In another embodiment, the device is, by way of non-limiting example, a pre-filled syringe or cartridge with or without the auto injector for both manual and auto injections. In some instances, such devices are calibrated and/or configured to precisely and accurately deliver effective amount of epinephrine medication.

In another embodiment, the epinephrine compositions can be used for treating anaphylactic shock by administrating epinephrine formulation to patients via intramuscular injection or subcutaneous injection or intravenous injection.

Examples:

The present subject matter is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present subject matter.

Example 1: Composition of Epinephrine injection 0.5 mg/mL & 1 mg/mL.

Table -1
Name of Ingredients Pharmaceutical function Ex-1a Ex-1b
0.5mg/mL 1.0 mg/mL
Qty. (mg/mL) Qty. (%w/v) Qty. (mg/mL) Qty. (%w/v)
Epinephrine API 0.5 0.05 1.0 0.1
Sodium chloride Isotonicity agent 6.0 0.6 6.0 0.6
EDTA Chelating agent 0.1 0.01 0.1 0.01
Citric acid Anti-oxidant 1.0 0.1 1.0 0.1
Hydrochloric acid pH adjusting agent q.s. to pH 2.2 to 5.0 q.s. to pH 2.2 to 5.0 q.s. to pH 2.2 to 5.0 q.s. to pH 2.2 to 5.0
Water for injection Diluent q.s to mL q.s. to 100% q.s to mL q.s. to 100%

Manufacturing Process: Citric acid, EDTA disodium and sodium chloride was dissolved in water for injection (WFI) under continuous nitrogen purging to maintain dissolved oxygen content less than 1%. Epinephrine was sequentially added to the solution under stirring to get clear solution.1N HCI solution was added to adjust the pH to 2.2 to 5.0. Final volume of the solution was made with water for injection.The solution was then subjected to filtration through 0.22µm membrane filter. The above manufacturing process was performed under the light intensity of not more than 400 lux. The solution was then filled in a sterile cartridge.

Example 2: Comparative examples:

Table -2

Ingredients Ex-2a
(Cysteine) Ex-2b(Ascorbic acid) Ex-2c
(Sodium metabisulfite
/Epipen®-RLD) Ex-2d
(Citric acid + Cysteine)
Epinephrine 0.5 0.5 0.5 0.5
Sodium chloride 6.0 6.0 6.0 6.0
Sodium metabisulfite - - 1.67 -
Edetate disodium 0.1 0.1 - 0.1
Citric acid - - - 0.2
Cysteine 1 - - 1.0
Ascorbic acid - 1 - -
Hydrochloric acid q.s. to adjust pH q.s. to adjust pH q.s. to adjust pH q.s. to adjust pH
Water for injection q.s to mL q.s to mL q.s to mL q.s to mL
Nitrogen q.s. q.s. q.s. q.s.

Manufacturing Process: The above comparative examples i.e. Ex-2a, 2b & 2d are prepared similar to process given in example-1; Ex-2c is manufactured using the same composition as that of Epipen.

The epinephrine compositions Ex-1 & Ex2a -2d were tested for appearance of coloration precipitation, pH, drug potency and related substances. The drug potency and related substances of drug were analyzed. The results are presented in Table 3 and 4 below

Table 3: Long term Stability data (25ºC±2ºC/60%±5%RH)

Test Ex-1
(Citric acid) Ex-2a
(Cysteine) Ex-2b
(Ascorbic acid) Ex-2c
(RLD) Ex-2d
(Citric acid + Cysteine)
Initial 3M Initial 3M Initial 3M Initial 3M Initial

Description # # # # # # # # #
pH 2.58 2.86 2.23 2.48 3.11 3.40 4.09 4.67 3.69
Assay 100 100 100 100 102 100 96 98 102
Adrenalone (EP-C) 0.01 0.015 0.25 1.626 0.06 0.323 0.02 0.0 0.171
Norepinephrine 0.01 0.012 0.01 0.042 0.16 0.367 0.08 0.051 ND
HUI 0.11 0.118 0.26 1.696 0.14 0.248 0.07 3.995 0.269
Total impurities 0.15 0.262 0.61 3.746 0.56 3.210 0.28 4.364 0.651
# Clear colorless solution
Result of the stability study conducted on the above compositions i.e. Ex-1a & Ex 2a-2d indicates that epinephrine composition containing citric acid (Ex-1a) exhibits excellent storage stability relative to epinephrine composition containing cysteine, ascorbic acid, sodium metabisulfite, cysteine + citric acid over the storage period. Further there is significant increase in level of impurities over stability in cysteine, ascorbic acid, sodium metabisulfite and cysteine + citric acid composition formulation, whereas level of impurities in citric acid formulation is significantly less.

Table 4: Accelerated Stability data (40ºC±2ºC/75%±5%RH)

Test Ex-1a
(Citric acid) Ex-2a
(Cysteine) Ex-2b
(Ascorbic acid) Ex-2c
(Sodium metabisulfite- RLD) Ex-2d
(Citric acid + Cysteine)
Initial 3M Initial 3M Initial 3M Initial 3M Initial
Description # Clear light tan colored solution # # # Clear pale yellow solution # # #
pH 2.58 2.89 2.23 2.49 3.11 3.40 4.09 4.37 3.69
Assay 100 98.0 100 94.0 102 94.0 96 78.0 102
Adrenalone (EP-C) 0.01 0.087 0.25 9.365 0.06 0.591 0.02 0.050 0.171
Norepinephrine 0.01 0.047 0.01 0.057 0.16 0.096 0.08 0.019 ND
HUI 0.11 0.413 0.26 9.694 0.14 4.864 0.07 24.364 0.269
Total impurities 0.15 1.042 0.61 21.534 0.56 9.669 0.28 25.529 0.651
# Clear colorless solution
Result of the stability study conducted on the above compositions i.e. Ex-1a & comparative example Ex 2a-2d indicates that epinephrine composition containing citric acid (Ex-1) exhibits improved storage stability as compared to epinephrine composition containing either cysteine, ascorbic acid, sodium metabisulfite, cysteine + citric acid over the storage period. Further there is significant increase in level of impurities over stability in cysteine, ascorbic acid and cysteine + citric acid composition formulation, whereas level of impurities in citric acid formulation is significantly less.

,CLAIMS:We claim:
1. A stable injectable pharmaceutical composition comprising:
a. a therapeutically effective amount of epinephrine or its pharmaceutically acceptable salt thereof;
b. a non-sulfite antioxidant; and
c. a chelating agent;
wherein the pH of the composition is 2.2 to 5.0

2. The composition as claimed in claim 1, wherein said non-sulfite antioxidant is selected from the group consisting of cysteine, citric acid, thioglycerol, acetylcysteine, and a combination thereof.

3. The composition as claimed in claim 2, wherein said non-sulfite antioxidant is citric acid, wherein the citric is present in an amount ranging from about of about 0.05 mg/mL to less than 4 mg/mL.

4. The composition as claimed in claim 1, wherein said chelating agent is selected from edetate disodium (EDTA), edetate disodium anhydrous, edetate sodium, edetate disodium dehydrate, edetate tetrasodium, and/or a combination thereof.

5. The composition as claimed in claim 4, wherein chelating agent said is edetate disodium (EDTA).

6. The composition as claimed in claim 1, further comprising one or more pharmaceutically acceptable excipients such as tonicity modifiers and pH adjusting agents.

7. The composition as claimed in claim 1, wherein said composition has one or more of the following:

a. a total impurities in the aqueous solution of not more than 2.0% by weight after storage at 40oC /75 % RH for at least 3 months,
b. total impurities in the aqueous solution is not more than 4.0% by weight after storage at 40oC /75 % RH for at least 3 months,
c. no single impurity of greater than 1%,
d. less than 1 ppm of dissolved oxygen, and/or
e. retains at least 95% w/w of total potency of epinephrine after storage at 40°C and 75% relative humidity for at least 3 months.

8. The composition as claimed in claim 1, wherein said composition remains stable for at least about 1, 3, 6, 12, 18, 24 or 36 months, and/or has an longer shelf-life compared to other marketed epinephrine auto-injectors.

9. A stable injectable pharmaceutical composition consisting of :
a. a therapeutically effective amount of epinephrine or its pharmaceutically acceptable salt thereof;
b. citric acid;
c. EDTA disodium;
d. sodium chloride, and
e. water for injection, and
f. pH adjusting agent to adjust the pH of solution in a range of 2.2 to 5.0.

10. The composition as claimed in claim 9, wherein said composition has one or more of the following:
a. a total impurities in the aqueous solution of not more than 2.0% by weight after storage at 40oC /75 % RH for at least 3 months,
b. total impurities in the aqueous solution is not more than 4.0% by weight after storage at 40oC /75 % RH for at least 3 months,
c. no single impurity of greater than 1%,
d. less than 1 ppm of dissolved oxygen, and/or
e. retains at least 95% w/w of total potency of epinephrine after storage at 40°C and 75% RH for at least 3 months.