Description

There is provided a stabilized injectable pharmaceutical composition of epinephrine or salts thereof comprising sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight. It has been observed that stable injectable epinephrine compositions with excellent storage stability and substantially free of overages can be prepared using sodium metabisulfite in said ratios. Particularly  it was found that using sodium metabisulfite in said ratios controls levels of adrenaline sulfonate impurity in said pharmaceutical compositions.

Epinephrine  also known as adrenaline  is a sympathomimetic catecholamine. Chemically  epinephrine is B-(3  4dihydroxyphenyl)-a-methyl-amino ethanol.

Epinephrine is the drug of choice for the initial treatment of anaphylaxis. Many epinephrine products are commerically available currently. For instance  epinephrine is marketed in the United States in the form of intramuscular and subcutaneous injection under trade name Twinject®  Auvi-Q®  EpiPen® Auto-Injector  which contains 0.3 mg epinephrine  and EpiPen®Jr Auto-Injector  which contains 0.15mg epinephrine.

It is well known in the art that there is an issue with potency of epinephrine (both in free base form and ionic form) when used in presence of oxygen and free radicals i.e degradation of epinephrine is accelerated in the presence of oxygen and free radicals.

Numerous studies have been conducted to address the effect of formulation variables on the epinephrine degradation kinetics  and attempts have been made to improve the formulation stability.

U.S. Patent No. 3 149 035 discloses use of bisulphite and boric acid to enhance stability of the catechol amines.

U.S. Patent No. 3 966 905 discloses catecholamine solutions at mild pH are suitable for physiological use.

Several literatures suggests that there is an increase in stability of epinephrine when stored in gas-tight containers with an inert gas (e.g. nitrogen) purging  and/or limiting or protecting the epinephrine formulation from direct light exposure or storing in a secondary opaque package. Inspite of using sodium metabisulfite controlling the degradation of epinephrine however continues to be an issue. In addition  interaction of sodium metabisulfite with epinephrine further leads to complications.

Currently marketed products of epinephrine as discussed above includes sodium metabisulfite as an antioxidant as it prevents degradation of the product due to oxidation that may take place during manufacturing  filling  storage  and environmental influence on the formulation.
Currently marketed products of epinephrine i.e EpiPen® Auto-Injector containing 0.3 mg epinephrine and EpiPen® Jr Auto-Injector containing 0.15 mg of epinephrine comprises of same amount of sodium metabisulfite i.e. 0.5 mg. It is also observed that EpiPen® Jr Auto-Injector product generally degrades relatively faster than that in EpiPen® Auto-Injector  presumably due to exposure of the product to substantial vacant space left in the cartridge.

Moreover  Currently marketed products of epinephrine i.e the EpiPen® Auto-Injector products contains more than about 20% 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.

Further  currently marketed products contain 0.3mg or 0.15mg in 2.0ml solution  of which only 0.3ml is injected and rest 1.7ml is discarded  which leads to lots of wastage.

Since said product is used in severe anaphylactic reactions  so controlling impurities and improvement of stability is critical. Hence  there exists an enduring need for improved and stable pharmaceutical composition of epinephrine  which exhibits excellent storage stability and does not require addition of epinephrine overages.

The inventors of the present invention have surprisingly found that while making an injectable composition of epinephrine  amount of sodium metabisulfite plays a critical role in order to control degradation due to oxidation as well as in controlling impurities. It was surprisingly found that epinephrine reacts with sodium metabisulfite  thereby leading to formation of adrenaline sulfonate impurity. In particular  the inventors have found that judicial amount of sodium metabisulfite can effectively curb the oxidation of epinephrine and eventually control generation of sulfonate impurity along with a wide range of several other epinephrine impurities. As a result  inventors of the present invention have found a novel way of preparing the injectable pharmaceutical composition of epinephrine which can exhibit excellent storage stability.

The inventors of the present invention further surprisingly found that judicial amount of sodium metabisulfite can retain epinephrine potency in the composition during the manufacture as well as over the storage period  thus may eliminate the need of adding epinephrine overages.

The present invention relates to novel and stabilized injectable pharmaceutical compositions of epinephrine and process of preparing such compositions.

In one general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5by weight.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains epinephrine having purity equal to or greater than 98%.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains total impurity of 4% or less.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains no single impurity of greater than 3%.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains adrenaline sulfonate impurity of about 3.0% or less at RRT 0.15.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains noradrenaline impurity of about 0.1% or less.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains adrenalone impurity of about 0.5% or less.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains N-benzyl adrenalone impurity of about 0.1% or less.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains impurity observed at RRT 0.17  RRT 0.2  or RRT 0.73 of about 0.5% or less.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight characterized in that said composition contains retains at least 90% w/w of total potency of epinephrine after storage at 25°C and 60% relative humidity for at least 3 months.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof  sodium metabisulfite  one or more tonicity-adjusting agents  one or more pH adjusting agents  aqueous vehicle  and optionally one or more other pharmaceutically acceptable excipients  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight.

In another general aspect  there is provided a process for preparation of stable injectable pharmaceutical composition comprising epinephrine or salt thereof  which process comprises of mixing epinephrine or salt thereof  sodium metabisulfite  aqueous vehicle  and optionally one or more other pharmaceutically acceptable excipients  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight.

In another general aspect  there is provided use of a stable injectable pharmaceutical composition comprising epinephrine or salt thereof and sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight 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.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising 0.3mg of epinephrine or salt thereof and 0.3mg of sodium metabisulfite in 0.3ml of solution  wherein the said 0.3ml of solution is delivered completely in single injection.

In another general aspect  there is provided a stabilized injectable pharmaceutical composition comprising 0.15mg of epinephrine or salt thereof and 0.3mg of sodium metabisulfite in 0.3ml of solution  wherein the said 0.3ml of solution is delivered completely in single injection.

The stabilized injectable pharmaceutical composition of the present invention comprises epinephrine or salt thereof and sodium metabisulfite  characterized in that the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight.

The stabilized injectable pharmaceutical composition of the present invention comprises epinephrine or salt thereof and sodium metabisulfite  characterized in that the composition is substantially free of epinephrine overages.

The term "epinephrine" used throughout the specification refers to not only epinephrine per se  but also its pharmaceutically acceptable salts  pharmaceutically acceptable solvates  pharmaceutically acceptable hydrates  pharmaceutically acceptable enantiomers  pharmaceutically acceptable derivatives  pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term "substantially free" used throughout the specification refers to pharmaceutical compositions of epinephrine comprising less than about 10% by weight of epinephrine overages.

The “stabilized injectable pharmaceutical composition” of the present invention refers to injectable compositions characterized by epinephrine having purity equal to or greater than 98% by weight or total impurity of 4% or less or no single impurity of greater than 3% or adrenaline sulfonate impurity of about 3.0% or less at RRT 0.15 or noradrenaline impurity of about 0.1% or less or adrenalone impurity of about 0.5% or less or N-benzyl adrenalone impurity of about 0.1% or less.

In an embodiment  the stabilized injectable pharmaceutical composition of the present invention retains at least 90% w/w of total potency of epinephrine after storage at 25°C and 60% relative humidity for at least 3 months.

Extent of the stability have been observed to be more pronounced on four specific impurities (RRT 0.15  RRT 0.17  RRT 0.20  and RRT 0.73) out of a large number of impurities that affect the stability not only in the presence or absence of sodium metabisulfite but also under normal atmospheric condition  or inert atmosphere  or the exposure to oxygen. Some of the specific impurities formed which had a significant influence on the stability are as given below.

.

In an embodiment  the stabilized injectable pharmaceutical composition comprises total impurity of about 4% or less when stored at 25°C and 60% relative humidity for at least 3 months.

In another embodiment  the stabilized injectable pharmaceutical composition comprises adrenaline sulfonate impurity of about 3% or less when stored at 25°C and 60% relative humidity for at least 3 months.

In a further embodiment  the stabilized injectable pharmaceutical composition comprises noradrenaline impurity of about 0.05% or less when stored at 25°C and 60% relative humidity for at least 3 months.

In a further embodiment  the stabilized injectable pharmaceutical composition comprises adrenalone impurity of about 0.3% or less when stored at 25°C and 60% relative humidity for at least 3 months.

In a further embodiment  the stabilized injectable pharmaceutical composition comprises N-benzyl adrenalone impurity of about 0.05% or less when stored at 25°C and 60% relative humidity for at least 3 months.

In a further embodiment  the stabilized injectable pharmaceutical composition comprises impurity observed at RRT 0.17  RRT 0.20  or RRT 0.73 of about 0.5% or less when stored at 25°C and 60% relative humidity for at least 3 months.

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 & LC-MS can be used for analyzing impurities.

Related substances of Epinephrine were performed by reverse phase chromatography using Cosmosil AR-II  C-18  (250 x 4.6) mm  5 µm columns. All impurities were separated in gradient mode with resolution more than 3.0. The detection was carried out at optimum wavelength 210 nm

The pharmaceutical composition of the present invention may be developed in the form of a dosage form suitable of parenteral administration. The parenteral route of administration of the compositions comprises subcutaneous  intramuscular  intravenous  transdermal  intradermal  intranasal  intraarterial and intraperitoneal injection or infusion. In an embodiment the injection includes aqueous vehicle based injection and oil based injection (e.g. depot injection).

The pharmaceutical composition of the present invention further comprises various pharmaceutically acceptable excipients suitable for parenteral administration. Such excipient includes  but not limited to pH adjusting agents or buffers  co-solvents  chelating agents  isotonicity adjusting agents  preservatives  and aqueous vehicle.

Examples of suitable pH adjusting agents includes  but not limited to hydrochloric acid  citric acid  ascorbic acid  acetic acid  tartaric acid  phosphoric acid  metaphosphoric acid  polymetaphosphoric acid  carbonic acid  sodium hydroxide  potassium hydroxide  sodium citrate  potassium citrate  sodium bicarbonate  potassium bicarbonate  ammonium carbonate  sodium hydrogen phosphate  potassium hydrogen phosphate  ethanolamine  diethanolamine  triethanolamine  hexane-1 2-diamine  sodium carbonate  sodium potassium tartrate  potassium metaphosphate  potassium polymetaphosphate  and sodium metaphosphate. The pH of the pharmaceutical composition preferably ranges from 2.2 to 5.0.

Examples of suitable buffers includes  but not limited to pharmaceutically acceptable salts and acids of acetate  glutamate  citrate  tartrate  benzoate  lactate  histidine or other amino acids  gluconate  phosphate  malate  succinate  formate  propionate  and carbonate.

Examples of suitable co-solvents includes  but not limited to ethanol  glycerol  propylene glycol  polyethylene glycol  and different oils.

Examples of suitable chelating agents includes  but not limited to calcium ethylenediaminetetraacetic acid (EDTA)  calcium diethylenetriaminepentaacetic acid (DTPA)  calcium hydroxyethylenediaminetriacetic acid (HEDTA)  calcium ethylene glycol-bis-(2-aminoethyl)-N N N"" N""-tetraacetic acid (EGTA)  calcium nitrilotriacetic acid (NTA)  calcium citrate  and calcium salt derivatives thereof.

Examples of suitable isotonicity adjusting agents includes  but not limited to anhydrous or hydrous forms of sodium chloride  dextrose  sucrose  xylitol  fructose  glycerol  sorbitol  mannitol  potassium chloride  mannose  calcium chloride  magnesium chloride and other inorganic salts.

The pharmaceutical composition of the present invention may be hypotonic  isotonic or hypertonic. In an embodiment  the pharmaceutical composition have a tonicity from about 250 to about 350 mOsm/kg.

Examples of suitable preservative include  but not limited to benzyl alcohol  propyl and methyl paraben.

The present invention also provides for a process of manufacturing aqueous epinephrine compositions. The process involves mixing epinephrine  sodium metabisulfite  water  and optionally other pharmaceutically acceptable excipients together.

The composition may be rendered non-pyrogenic  if required  by passing through Tangential Flow Filtration System (TFF) before sterilization. The composition may be sterilized by membrane filter of 0.22 μm pore size.

The process of manufacturing the aqueous epinephrine compositions of the present invention further may comprises sterilization of the composition. The compositions may be sterilized by known and acceptable methods. In an embodiment  the composition is sterilized by filtering through a sterilizing grade filter. Preferably  the solution is filtered through 0.2 μm sterilizing grade filters.

After sterilization  it may be desirable to aseptically place the filtered solutions into sterile containers such as vials  ampoules  or cartridges of the pre-filled syringes. In an embodiment  after aseptically placing the filtered solution into the cartridge of prefilled syringes  the air in the cartridge is purged with an inert gas  such as nitrogen  and then the filled cartridge is sealed in the pre-filled syringe.

The present invention further refers to the use of the above defined composition for the preparation of medicaments useful for treating allergic reactions (Type I) including anaphylaxis to stinging insects (e.g.  order Hymenoptera  which include bees  wasps  hornets  yellow jackets and fire ants) and biting insects (e.g.  triatoma  mosquitos)  allergen immunotherapy  foods  drugs  diagnostic testing substances (e.g.  radiocontrast media) and other allergens  as well as idiopathic anaphylaxis or exercise-induced anaphylaxis.

The present invention 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 invention.

Example 1: Epinephrine Injection 0.3mg/0.3mL

Table 1

Sr.No. Ingredient Composition AQty. (% w/v) Composition BQty. (% w/v)
1. Epinephrine 0.3 0.3
2. Sodium chloride 1.8 1.8
3. Sodium metabisulfite 0.3 0.2
4. 1N HCl Solution q.s. to pH 2.2-5.0 q.s. to pH 2.2-5.0
5. Water for Injection q.s. to 0.3 mL q.s. to 0.3 mL

Example 2: Epinephrine Injection 0.15mg/0.3mL

Table 2

Sr.No. Ingredient Composition CQty. (% w/v) Composition DQty. (% w/v)
1. Epinephrine 0.15 0.15
2. Sodium chloride 1.8 1.8
3. Sodium metabisulfite 0.15 0.10
4. 1N HCl Solution q.s. to pH 2.2-5.0 q.s. to pH 2.2-5.0
5. Water for Injection q.s. to 0.3 mL q.s. to 0.3 mL

Process: Sodium chloride was dissolved in water for injection under continuous nitrogen sparging. 1N HCl solution was added to adjust the pH. Epinephrine and sodium metabisulfite were sequentially added to the solution under stirring to get clear solution. Final volume of the solution was made with water for injection. pH of the final solution can be adjusted using HCl solution if required. The solution was then subjected to filtration through 0.22m membrane filter. The solution was then filled in sterile 1mL pre-filled syringes.

Example 3: Comparative Stability Study of effect of Sodium metabisulfite concentration on stability of Epipen/Epipen Jr. v Epinephrine composition of the invention
Table 3
Composition 1 (Epipen Jr)0.15 mg Epinephrine  0.5 mg Sodium metabisulfite Composition 2 (Invention)0.15 mg Epinephrine  0.3 mg Sodium metabisulfite Composition 3 (Epipen)0.3 mg Epinephrine  0.5 mg Sodium metabisulfite Composition 4 (Invention)0.3 mg Epinephrine  0.3 mg Sodium metabisulfite
Description Clear colorless Solution Clear colorless Solution Clear colorless Solution Clear colorless Solution
Storage Conditions 25°C  60% RH for 3 months 25°C  60% RH for 3 months 25°C  60% RH for 3 months 25°C  60% RH for 3 months
Assay 107.8 112 108.8 115.5
Adrenaline sulfonate impurity (%) 4.983 0.415 3.893 2.721
Noradrenaline impurity (%) 0.0 0.0 0.0 0.0
Adrenalone impurity (%) 0.128 0.023 0.071 0.083
N-Benzyl adrenalone impurity (%) 0.0 0.0 0.0 0.0
Total impurity (%) 6.288 0.935 4.65 3.633

Result of the stability study conducted on the composition of the present invention (Composition 2 & 4) indicates that epinephrine composition containing 0.3 mg sodium metabolite exhibits excellent storage stability relative to epinephrine composition containing 0.5 mg sodium metabolite over the storage period.
We claim:

1. A stabilized injectable pharmaceutical composition of epinephrine or salt thereof comprising sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight  characterized in that said composition contains epinephrine having purity equal to or greater than 98% by weight.

2. A stabilized injectable pharmaceutical composition of epinephrine comprising sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight  characterized in that said composition contains total impurity of less than 4%.

3. A stabilized injectable pharmaceutical composition of epinephrine comprising sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight  characterized in that said composition contains no single impurity of greater than 3%.

4. A stabilized injectable pharmaceutical composition of epinephrine or salt thereof comprising sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight  characterized in that said composition is substantially free of epinephrine overages.

5. The stabilized injectable pharmaceutical composition of claim 1  wherein the composition comprises adrenaline sulfonate less than about 3.0% or less at RRT 0.15.

6. The stabilized injectable pharmaceutical composition of claim 1  wherein the composition comprises less than about 0.5% impurity observed at RRT 0.17  RRT 0.2  or RRT 0.73.

7. A stabilized injectable pharmaceutical composition comprising epinephrine  sodium metabisulfite  wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight  characterized in that said composition retains at least 90% w/w of total potency of epinephrine after storage at 25°C and 60% relative humidity for at least 3 months.

8. A stabilized injectable pharmaceutical composition comprising 0.3mg of epinephrine or salt thereof and 0.3mg of sodium metabisulfite in 0.3ml of solution  wherein the said 0.3ml of solution is delivered completely in single injection.

9. A stabilized injectable pharmaceutical composition comprising 0.15mg of epinephrine or salt thereof and 0.3mg of sodium metabisulfite in 0.3ml of solution  wherein the said 0.3ml of solution is delivered completely in single injection.

Dated 5th day of October 2012 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory