A STABLE PHARMACEUTICAL COMPOSITION COMPRISING EDARAVONE PROVIDED IN A POLYMERIC CONTAINER
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising edaravone, wherein the composition is provided in a sealed container comprises three layered film. The three layered film container of the present invention reduces sorption and thereby reduces a reduction in the content of edaravone in the injectable composition and is excellent in shock resistance and handling ability.
BACKGROUND OF THE INVENTION
Edaravone (3-methyl-l-phenyl-2-pyrazolin-5-one) is commercially available in a solution form of injection in glass ampule and plastic bag presentations. The PCT publication WO 2007/055312 discloses a plastic container filled with aqueous solution containing a pyrazolone derivative (e.g., edaravone).
The PCT publication WO 2009/066752 discloses a plastic container comprising multilayered film for storing an aqueous solution of pyrazolone derivative including edaravone. The multilayered film described herein preferably comprises five or more layers. The multilayered plastic container disclosed herein comprises at least a cyclic polyolefin layer and a resin composition layer between an outermost layer and a seal layer.
There exists a need in the prior art to provide a pharmaceutical composition of edaravone provided in a container system which reduces a reduction in the content of edaravone during manufacturing and storage for a longer period of time.
SUMMARY OF THE INVENTION
In one embodiment, the present invention relates to a pharmaceutical composition of edaravone provided in a polymeric container that comprises three layered film. In a

further embodiment, the present invention provides storage stable solution of edaravone provided in a sealed container that comprises a contact layer containing cycloolefin polymers.
The sealed container comprises a cycloolefin polymer in at least one contact layer, wherein the contact layer is in direct contact with the pharmaceutical composition. For example, the sealed container may be selected from the group consisting of bags, vials, bottles and pre-filled syringes and may be made from a cycloolefin polymer, or comprise a cycloolefin polymer as a contact layer.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention relates to a pharmaceutical composition of edaravone provided in a polymeric container that comprises three layered film. In one aspect, the pharmaceutical composition comprises an aqueous solution of edaravone and pharmaceutically acceptable excipients. In another aspect, a pharmaceutical composition of edaravone provided in a polymeric container that contains cycloolefin polymers as a contact layer.
In another embodiment, the polymeric container according to the present invention comprises three layered film. In one aspect, the contact layer comprises cycloolefin polymer. The contact layer is in direct contact with the pharmaceutical composition comprising edaravone and pharmaceutically acceptable excipients. In an aspect, the outer layer comprises polypropylene. In an aspect, the middle layer comprises polyethylene; preferably linear low density polyethylene.
In another embodiment, the polymeric container is sealed and in the form of vials, bags and pre-filled syringes. In an aspect, the cycloolefin polymer of the sealed container is in direct contact with the pharmaceutical composition.
The pharmaceutical composition of the present invention comprises edaravone and pharmaceutically acceptable excipients and is provided in three layered container

comprising cycloolefin polymer. Specifically, the pharmaceutical composition is mentioned below:
As mentioned herein, the term "storage" refers to the holding of a composition under controlled or uncontrolled conditions for a period ranging from a few minutes to several months or longer. Storage conditions that can be controlled include, for example, temperature, humidity and the level of light. In many cases, storage of a pharmaceutical formulation is under industry acceptable standards and/or standards that are mandated by regulatory agencies, such as US FDA.
The term "stable" refers to both the physical and chemical stability of a composition comprising edaravone in any form, such as a solution. A composition is said to be stable if it exhibits minimal change over time relative to when it is manufactured. Stability is measured at various time points through a planned product expiration date with evaluation criteria including such items as therapeutic activity, appearance, levels of particulate matter, pH, content of active ingredient(s), and levels of degradation products, impurities or related substances.
In aspect, the polymeric container contains three layered film comprising cycloolefin polymer. The polymeric container reduces sorption and oxidation thereby reduces a reduction in the content of edaravone in the injectable composition and is excellent in

shock resistance and handling ability during the filling, further storage of the composition in the container and transportation.
In an aspect, the pharmaceutical composition comprising edaravone and pharmaceutically acceptable excipients provided in a polymeric container according to the present invention is stable during sterilization and storage for a longer time. The three layered film container according to the present invention suppresses a reduction of content of edaravone due to the degradation mechanisms such as oxidation, sorption or any other means of degradation.
In another embodiment, a pharmaceutical composition comprising edaravone where the composition is provided in a sealed container comprises three layered film that is selected from an outer layer comprising polypropylene, the middle layer comprising linear low density polyethylene and a contact layer comprising cycloolefin polymers wherein the pharmaceutical composition is in direct contact with the contact layer.
As mentioned herein, the term "cycloolefin polymer" or "COP" includes polymers that are made from at least one cyclic monomer. The term "cycloolefin polymer" also includes cyclo olefin copolymers ("COC"). Suitable cycloolefin polymers and copolymers may be used, including commercially-available cycloolefin copolymers based on a variety of different types of cyclic monomers and polymerization methods. In certain embodiments, the polymeric container includes cycloolefin copolymer container, more specifically polymeric container comprises of laminated bags having an inner layer comprising a cycloolefin copolymer selected from POLYELITE® PHC available from Hosokawa Yoko Co., Ltd, Japan. In an embodiment, the polymeric container is also selected from INERTA® (Source: TECHNOFLEX) and Polyolefine bag (Source: SIPPEX).
In certain embodiments, the polymeric container is a vial, bag (for example: an infusion bag or a pouch), bottle, or pre-filled syringe. In certain non-limiting

embodiments, the polymeric container includes flexible polymeric containers such as bags, e.g., infusion bags or pouches.
The pharmaceutical composition comprising edaravone and pharmaceutically acceptable excipients provided in a three layered container according to the present invention may be sterilized using methods known to the skilled artisan. Non-limiting examples of sterilization techniques include filtration through a bacterial-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating.
Sterilization may be accomplished by any of the conventional methods including aseptic filling, irradiation and heat sterilization. Heat sterilization is normally performed using steam, preferably moist heat to allow for the use of pressure as a means of temperature control. The time period for the sterilization must be long enough to meet the sterility requirements required of an injectable product. When steam is used, the period may be from about 5 to 30 minutes at temperatures of about 110° C. to 130° C, or from about 10 to 30 minutes at temperatures of about 110° C. to 130° C, preferably at 120° C. to 125° C. for 15 to 30 minutes. In another embodiment, the sterilization can be at 121° C. for 5 to 15 minutes.
The pharmaceutical composition comprising edaravone and pharmaceutically acceptable excipients provided in a polymeric container wherein the container may be overwrapped with secondary packaging. In an aspect, the secondary packaging is selected from polypropylene, polyvinyl alcohol, etc. The overwrapped package also contains an oxygen absorber to minimize oxidation. Further, the overwrapped package contains an oxygen indicator. In an aspect, the primary container containing the pharmaceutical composition overwrapped with the secondary packaging is further overwrapped with another container like aluminum pouch.
The following examples further describe certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof It

is to be understood that the examples are provided only for purposes of illustration and are not intended to limit the scope of the invention in any manner.
General Manufacturing Process:
About 80% of batch size of water for injection was added into the manufacturing vessel under nitrogen purging at 20-25°C and the temperature was maintained between 50°C and 65°C. Edaravone was added into the water under stirring until complete dissolution. The solution was cooled to room temperature followed by addition and dissolution of L-Cysteine Hydrochloride hydrate USP, Sodium bisulfite and sodium chloride and mixed until to get a clear solution. pH of the solution was

adjusted to 4 using sodium hydroxide solution or phosphoric acid or appropriate pH adjusting agent. A sufficient quantity of water for injection was added to make up the final volume.
The final solution was passed through 0.2 um filter and then filled into 100 mL POLYELITE® PHC bag. The bags were sterilized at 12TC for a validated duration to achieve a SAL of 10"6. The sterilized bags were observed for stability and the results are provided in Table-I and II.
In view of the above stability data from Table I & II, the pharmaceutical composition I and II provided in a three layered polymeric container [POLYELITE® PHC bag] shows less than 5% reduction in content of edaravone when stored at the conditions as mentioned herein.

Claims:
1. A pharmaceutical composition comprising edaravone and pharmaceutically acceptable ingredients provided in a polymeric container comprises cycloolefin polymer.
2. The pharmaceutical composition according to claim 1, wherein the composition is provided in a polymeric container consists of three layered film.
3. The pharmaceutical composition according to claim 2, wherein the three layered film is selected from an outer layer comprises polypropylene, a middle layer comprising of linear low density polyethylene and a contact layer comprises cycloolefin polymer.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is in direct contact with the contact layer comprising of cycloolefin polymer.
5. The pharmaceutical composition according to claim 1, wherein the polymeric container is selected from vials, bags and pre-filled syringes.
6. The pharmaceutical composition according to claim 5, wherein the polymeric container is an infusion bag.
7. The pharmaceutical composition according to claim 6, wherein the polymeric container is POLYELITE® PHC bag, DSfERTA® (TECHNOFLEX) and polyolefine bag (SIPPEX).
8. The pharmaceutical composition according to claim 7, wherein the polymeric container is POLYELITE® PHC bag.

9. The pharmaceutical composition according to claim 1, wherein the composition shows less than 2% reduction in content of edaravone when stored at 25°C±2°C for a period of three months.