FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10 and Rule 13]
TITLE OF THE INVENTION
STABLE PARENTERAL DOSAGE FORM OF PYRAZOLONE DERIVATIVE
APPLICANT(S)
FTF PHARMA PRIVATE LIMITED
An Indian Company of,
Block No. 193(Part) + 211(Part), Xcelon Industrial Park,
Chak-de India Weigh Bridge Road,
Vasna Chacharwadi, Tal: Sanand,
Ahmedabad, Gujarat-382 213
The following specification particularly describes the invention and the manner in which it is
to be performed.
2
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical dosage form preferably in the form of a
parenteral dosage form which involves use of a packaging system which is stable during storage
and transportation. The pharmaceutical dosage form of the present invention is convenient in
5 use and involves use of less expensive packaging materials as compared to known packaging
materials. The present invention also relates to a packaging system and packaging materials for
packaging a parenteral dosage form of a drug which comprises use of bottles or vials, preferably
made of glass and stoppers, preferably rubber stoppers which are uncoated rubber stoppers and
optionally capping on said rubber stoppers.
10
BACKGROUND OF THE INVENTION
The present invention is related to the field of pharmaceutical formulation technology. More
particularly, the present invention is directed to the injectable pharmaceutical formulations of
a drug suitable for parenteral administration. The drug which is used in the present invention
15 is a pyrazolone derivative, viz. 3-methyl-1-phenyl-2-pyrazoline-5-one or its pharmaceutically
acceptable salt.
The compound 3-methyl-1-phenyl-2-pyrazoline-5-one is a member of the substituted 2-
pyrazoline-5-one class and is generically known as edaravone. The molecular formula of
20 edaravone is C10H10N2O and the molecular weight of edaravone is 174.20. The structural
formula of edaravone is shown below.
Edaravone is an active ingredient of the drug product RADICAVA, approved in the United
States in May 2017 for the treatment of amyotrophic lateral sclerosis (ALS). Edaravone is a
25 free radical scavenger that acts to scavenge various types of free radicals including active
oxygen as a typical example, so as to prevent cell injury.
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) is a disease
that causes the death of neurons controlling voluntary muscles. Some also use the term motor
3
neuron disease for a group of conditions of which ALS is the most common. ALS is
characterized by stiff muscles, muscle twitching, and gradually worsening weakness due
to muscles decreasing in size. It may begin with weakness in the arms or legs, or with
difficulty speaking or swallowing. About half of the people affected develop at least mild
5 difficulties with thinking and behavior and most people experience pain. Most eventually lose
the ability to walk, use their hands, speak, swallow, and breathe. United States Patent Number
6933310 (assigned to Mitsubishi Tanabe Pharma Corporation) discloses and claims use of
edaravone for the treatment of amyotrophic lateral sclerosis.
10 Edaravone was first approved in Japan as RADICUT. RADICUT has been commercially
available as an injection 30 mg in the form of a 20 ml of solution containing 30 mg of edaravone
filled into a glass ampoule.
RADICAVA injection is supplied for intravenous infusion in a polypropylene bag containing
15 30 mg/60 mg edaravone in 100 mL isotonic, sterile, aqueous solution, which is further
overwrapped with polyvinyl alcohol (PVA) secondary packaging. The overwrapped package
also contains an oxygen absorber and oxygen indicator to minimize oxidation, which should
be pink to reflect appropriate oxygen levels. Each bag contains the following inactive
ingredients: L-cysteine hydrochloride hydrate (20 mg), sodium bisulfite (40 mg). Sodium
20 chloride is added for isotonicity and phosphoric acid and sodium hydroxide are added to adjust
to pH 4.0.
The RADICAVA injection should be stored in overwrapped package to protect from oxygen
degradation until time of use. The oxygen indicator will turn blue or purple if the oxygen has
25 exceeded acceptable levels. Once the overwrap package is opened, RADICAVA injection
should be used within 24 hours.
International Publication Number WO 2007/055312 (filed by Mitsubishi Tanabe Pharma
Corporation) discloses a plastic container filled with an aqueous solution containing edaravone,
30 coloration of which is suppressed. The ‘312 publication tested a bag
using polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polypropylene, or a
combination of polyethylene and cyclic olefin polymer as the material, and ethylene. It is
disclosed that the bag of vinyl acetate copolymer or polyvinyl chloride is colored. It is known
that the use of cyclic polyolefin in the inner layer can prevent coloring of the formulation
4
container by the active ingredient. However, a plastic container capable of suppressing a
reduction in the content of edaravone due to adhesion of edaravone to the plastic container was
not disclosed.
5 International Publication Number WO 2009/066752 (filed by Mitsubishi Tanabe Pharma
Corporation) discloses a multilayered film and a plastic container each of which comprises a
heat-sealable seal layer, a cyclic polyolefin layer and an outermost layer, wherein the seal layer
comprises a polypropylene, the cyclic polyolefin layer comprises a cyclic polyolefin polymer
or a cyclic polyolefin copolymer and the outermost layer comprises a layer comprising a
10 polypropylene, and wherein each of the multilayered film and the plastic container further
comprises a resin composition layer comprising a blend of a propylene polymer and a styrenetype elastomer. The plastic container enables to prevent the reduction in the content of a
medicinal agent in a liquid pharmaceutical preparation, and has excellent impact resistance,
excellent handling properties during filling a material into the container, excellent moldability,
15 and excellent transparency.
The problem identified in the Japanese Patent Publication Number JP 2009084203 (Filed by
Temuro Corp) is provision of a bottle, a bag or a prefilled syringe formulation made of a plastic
stably housing an edaravone-containing aqueous formulation and to provide the bag
20 formulation stably housing a premix formulation of the edaravone-containing aqueous
formulation. To which, the ‘203 publication provides solution as a stable edaravone-containing
aqueous formulation in which at least a part of a container housing the edaravone-containing
aqueous formulation is a container made of a plastic composed of a cyclic polyolefin resin.
25 Japanese Patent Publication Number JP 2010162344 (filed by Fujimori Kogyo Co Ltd)
discloses the package constituted by introducing the aqueous solution agent into a plastic
container and sealing the container, thereafter packaging the container with a gas-barrier outer
packaging material having a resin layer consisting essentially of a cyclic polyolefin-based resin,
as an innermost layer or a layer adjacent to the innermost layer.
30
Chinese Patent Publication Number CN 101933899 (filed by Nanjing Simcere Dongyuan
Pharmaceutical Co Ltd) discloses edaravone injection and a preparation method thereof. The
injection contains edaravone serving as an active material, sodium pyrosulfite serving as
antioxygen and propylene glycol serving as cosolvent. In the invention, in an edaravone
5
injection production process, the sodium pyrosulfite antioxygen is added and high-purity
nitrogen is charged into an ampoule bottle before and after liquid medicine canning and sealing
to ensure the residual oxygen in the air above the liquid medicine in the ampoule bottle is less
than 3 percent, so the edaravone is kept in a low-oxygen environment all the time. However,
5 the ampoule packaging has several disadvantages. A small fixed volume of the drug does not
allow to use the solution continuously (for example, with drip) in the desired volume. There is
also a risk that small particles of glass getting into the infusion solution when the ampoule is
opened.
10 When plastic is used, there is a problem of tightness, namely, oxygen from the air enters the
solution of edaravone. Due to the high affinity edaravone combines with oxygen and changes
the properties of the drug. To overcome this problem, antioxidants and double packaging are
used to stabilize the edaravone solution, as described in the Japanese Patent Publication
Number JP 2011136973 (Filed by Keiki Imoto et al.). That makes the process of obtaining a
15 stable drug more complicate. The container is made of polypropylene, polyethylene or other
flexible plastic. It has a rubber stopper of elastomer coated with a fluorine coating. The
container is packed into another container having reduced oxygen permeability and made of a
film based on aluminum oxide or silicon oxide or other similar material.
20 Japanese Patent Publication Number JP 2016022092 (filed by Nipro Corp) discloses a plastic
container that is an alternative plastic container storing an aqueous solution containing
edaravone, the plastic container showing sufficient stability. The plastic container disclosed in
‘092 publication is the plastic container having a polypropylene layer as an outer layer, a
polypropylene layer as an intermediate layer, and a cyclic polyolefin layer as an inner layer.
25 International Publication WO 2019159967 (filed by Fujimori Kogyo Co Ltd) discloses a plastic
container having superior storage stability of a pharmaceutical product, and in particular, a
pharmaceutical formulation having a high affinity with plastics. The ‘967 publication more
specifically discloses a plastic container in which an innermost layer of a sheet member forming
a bag body of a bag is formed from an amorphous polymer, as a main component, by
30 polymerizing at least one type or two or more types of olefin monomers, in which at least one
type among the olefin monomers is a monomer having a cyclic hydrocarbon skeleton, and a
port member forming an opening part is formed from a crystalline polyolefin having no cyclic
hydrocarbon skeleton, as a main component.
6
International Publication Number WO 2020/044106 (filed by Sia Emteko Holding) discloses a
method for producing a liquid dosage form of the drug Edaravone for parenteral use which is
stable in storage and transportation and convenient for use, which involves: preparing a
solution comprising Edaravone or pharmaceutically acceptable salts thereof as the active
5 ingredient, and excipients (an acidic component, an alkaline component, an antioxidant, an
osmolar agent and/or a stabilizer); packaging said dosage form in a pre-sterilized glass bottle
having a cap at least partially coated with an anti-adhesive coating; sealing the bottle with said
cap at least partially coated with an anti-adhesive coating, and sterilizing the bottle containing
a solution comprising Edaravone or pharmaceutically acceptable salts thereof as the active
10 ingredient, and excipients. The ‘106 publication further discloses a method for packaging a
liquid dosage form of the drug Edaravone for parenteral use which is stable in storage and
transportation and convenient for use, which involves: sterilizing a glass bottle having a cap;
pouring a solution comprising Edaravone or pharmaceutically acceptable salts thereof as the
active ingredient, and excipients (an acidic component, an alkaline component, an antioxidant,
15 an osmolar agent and/or a stabilizer) into said sterilized glass bottle; closing (sealing) the bottle
containing the solution using said cap, which is at least partially coated with an anti-adhesive
coating; and sterilizing the sealed bottle containing the liquid dosage form. The ‘106
publication further discloses a bottle filled with a liquid dosage form of a drug for parenteral
use comprising Edaravone or pharmaceutically acceptable salts thereof as the active ingredient,
20 and excipients (an acidic component, an alkaline component, an antioxidant, an osmolar agent
and/or a stabilizer), said bottle being made of glass and being closed with a cap which is made
of a material based on flexible polymers and which is at least partially coated with an antiadhesive coating.
25 It is evident from the prior art documents that storage of a drug solution containing pyrazolone
derivative, i.e. edaravone and stability of edaravone in the solution during storage has always
been prime concern of the researchers and for that various efforts have been put in. Discovery
of plastic containers having multiple layers and different types of polymers and is one of them.
Researchers have also found out that use of glass bottles or vials is also advantageous for the
30 storage of edaravone solution during stability studies and shelf life. It is also convenient from
the transportation view point. However, this research specifically talks about use of cap made
of an elastic polymer and is coated, at least in part, with an anti-adhesive coating of
polychlorotrifluoroethylene (PCTFE), perfluoroalkoxyalkane (PFA), ethylene
7
tetrafluoroethylene (ETFE), fluoroethylene), polypropylene (FEP) or polyvinylidene fluoride
(PVDF).
Therefore, the need still exists in the art, for more economic packaging system for storing
5 edaravone drug solution which fulfills the purposes of stability of a drug in the solution during
stability, shelf life and during transportation and ease and convenient in use.
The present inventors have, therefore, through their extensive research efforts, identified that
when edaravone drug solution is filled in glass bottles or vials using simple and commonly
10 available stoppers or caps which are not coated with anti-adhesive coating, still the above
mentioned purposes can be achieved. It is well known in the industry that expensive packaging
materials used for packaging the drug product ultimately increases the price of the drug and the
whole burden is on the patient who has to pay such higher prices. Use of such uncoated stoppers
or caps with glass bottles/vials make the present invention significantly economic without
15 compromising with the quality of the drug product. With the packaging materials used in the
present invention the price of the drug product may significantly be brought down.
OBJECTS OF THE INVENTION
It is therefore one of the objects of the present invention to provide a drug solution containing
20 a pyrazolone derivative, i.e. 3-methyl-1-phenyl-2-pyrazoline-5-one (edaravone) filled in the
glass bottle or vials with the use of stoppers or caps without anti-adhesive coating.
A yet another object of the present invention is to use borosilicate glass bottles or vials and use
of commonly available rubber stoppers (which, for example, without limitation include natural
25 rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrolbutadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or
halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber,
chloroprene rubber and the like) or stoppers/caps made of elastic polymer. However, the
stoppers/caps used in the present invention are uncoated which means they are without anti30 adhesive coating.
A yet another object of the present invention is to pack the bottle or vial filled with edaravone
drug solution with an aluminium cap over the stoppers (which, for example, without limitation
include natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural
8
rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane)
rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile
rubber, chloroprene rubber and the like) which crimps the bottle cap in order to seal the
container with the solution. The glass bottle or vial may further be packaged in simple and
5 commonly available cartoon as secondary or outer packaging.
A yet another object of the present invention is to provide a container-closure system for
packaging edaravone drug solution. A yet another object of the present invention is to provide
a method for obtaining a parenteral dosage form of edaravone in the form of intravenous
10 solution for infusion or drip, that is stable during storage, transportation and convenient in use.
A yet another object of the present invention is to provide a packaging method for a parenteral
dosage form of edaravone in the form of intravenous solution for infusion or drip, that is stable
during storage, transportation and convenient in use.
15 A yet another object of the present invention is to prepare edaravone drug solution which
comprises use of edaravone as an active ingredient, and a pharmaceutically acceptable
excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying
agent, a vehicle and a combination thereof. The edaravone drug solution according to the
present invention is in the form of ready-to-use parenteral dosage form for intravenous infusion.
20
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the field of pharmaceutical formulation technology, in particular to a
method for producing a drug product comprising a pyrazolone derivative 3-methyl-1-phenyl2-pyrazoline-5-one, i.e. edaravone. The drug product of the present invention is stable during
25 storage (stability and/or shelf life), transportation and use.
Edaravone has the ability to scavenge free radicals and this is why it is used as a scavenger of
free radicals in cerebral infarction. Edaravone is administered by intravenous infusion or drip.
30 However, there is a significant problem when using edaravone, in particular, its instability in
solution, adhesion of the molecules of the drug substance on the surface of the bottle cap. In
addition, when using packaging with insufficient tightness, the concentration of edaravone in
the solution increases due to the evaporation of the liquid.
9
In the prior art, the abovementioned problem has been tried to overcome by packing edaravone
drug solution in glass ampoules to ensure hermetic storage of a solution with a constant
concentration.
5 In order to get rid of residual oxygen in the space above the edaravone solution and to ensure
the stability of the drug, nitrogen is added before sealing the ampoules with edaravone solution.
However, ampoule packaging has also numbers of disadvantages, including a small-fixed
volume of the drug, which does not allow the solution to be used continuously in the required
10 volume (for example, when the drug is used in infusion or drip). There is also a risk of small
glass particles getting into the infusion solution when opening the ampoule. If proper
precaution and care is not taken the opener or the health care professional opening the ampoule
may also get injured.
15 An attempt has therefore been also made to solve above problem existing in the prior art by
replacing the glass ampoule with a plastic container. However, such packaging usually has a
complex structure. The plastic container is formed by an outer polypropylene layer, an
intermediate polypropylene layer and an inner cyclic polyolefin layer.
20 A bottle, bag, or syringe pre-filled with the edaravone solution is also used. These packages
are at least partially made of plastic, in particular of a cyclic polyolefin resin. A rubber stopper
made of elastomer, isoprene rubber or butyl rubber is provided in the said plastic container,
and the surface that contacts the edaravone solution is coated with a fluorine or parylene resin
having anti-adhesive properties.
25
However, when using plastic, the problem of the tightness arises, namely, oxygen from the air
enters into the edaravone solution. Due to the high affinity, when edaravone combines with
atmospheric oxygen, the properties of the drug change. In order to overcome this problem,
antioxidants and double packaging are used to stabilize the edaravone in the solution, which
30 complicates the process of obtaining a stable finished dosage form. So, the container is made
of polypropylene, polyethylene or other flexible plastic; it has a rubber stopper made of
elastomer coated with a fluorine-based coating. The container is packaged in another container
that has a reduced oxygen permeability and is made of a film based on alumina or silica or
other similar material.
10
Although this package provides stability to the drug into the solution, it is not convenient for
use, because after opening or damaging the seal of the outer container, it loses its protective
property. In addition, such packaging does not provide containers of different sizes (volumes),
which can lead to irrational use of the drug.
5
From the prior art documents, edaravone or its pharmaceutically acceptable salt in liquid form
which is ready-to-use packaged in different packaging materials is known. Packaging in the
form of ampoules is hermetically sealed, however, the disadvantage of this form of preparation
is the impossibility of multiple use of one ampoule and the high probability of glass particles
10 getting into the infusion solution. Also, the drug is produced in large volume plastic packaging,
which, however, is not tight enough and, as a result, allows oxygen to pass from the
environment, which negatively affects the quality of the drug.
A multilayer plastic container performs its function of ensuring the stability of the drug during
15 storage and transportation only until it is opened. After opening the container, the drug must
be used immediately, since the tightness is broken and the degradation of edaravone starts
occurring. As a result, the drug increases the permissible level of impurities/degradants that
can cause undesirable side effects and/or less therapeutic effect when used in patients. In
addition, this form of packaging is complex both for the production of the drug itself (the plastic
20 must withstand double high heat treatment with the drug), and for the production of packaging
as such (a double container is made of a triple layer of plastic).
Thus, there is a problem of obtaining the edaravone in the solution packaged in such a package
which would allow maintaining its stability during storage, transportation, and use.
25
Accordingly, the object of the present invention is to provide a ready-to-use, stable (during
storage-stability/shelf life), easy and convenient to transport and use edaravone parenteral
dosage form. The edaravone finished dosage form according to the present invention is in the
form of intravenous solution for infusion or drip.
30
Accordingly, the present invention provides a method for obtaining a parenteral dosage form
of edaravone in the form of intravenous solution for infusion or drip, that is stable during
storage, transportation and convenient in use. The method comprises:
11
(a) preparing a solution containing edaravone or its pharmaceutically acceptable salt as
an active ingredient and a pharmaceutically acceptable excipient selected from an
antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle
and a combination thereof;
5 (b) packaging the edaravone dosage form in a glass bottle or vial, preferably presterilized, with a lid covered on said glass bottle or vial, wherein said lid is without
an anti-adhesive coating; and
(c) closing the bottle or vial with a lid covered on said bottle or vial and sterilizing said
bottle or vial containing edaravone solution.
10
In an alternative embodiment, the present invention provides a method for obtaining a
parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip.
The method comprises:
(a) preparing a solution containing edaravone or its pharmaceutically acceptable salt as
15 an active ingredient and a pharmaceutically acceptable excipient selected from an
antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle
and a combination thereof;
(b) packaging the edaravone dosage form in a glass bottle or vial, that is optionally presterilized, with a lid covered on said glass bottle or vial, wherein said lid is without
20 an anti-adhesive coating; and
(c) closing the bottle or vial with a lid covered on said bottle or vial and optionally
sterilizing said bottle or vial containing edaravone solution.
In the above method, the glass bottle or vial is made of borosilicate glass and the lid or cap or
25 stopper is made of an elastic polymer or rubber (which, for example, without limitation include
natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber),
styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber,
butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber,
chloroprene rubber and the like) which is uncoated, i.e. without anti-adhesive coating.
30
The present invention also provides a packaging method for a parenteral dosage form of
edaravone in the form of intravenous solution for infusion or drip, that is stable during storage,
transportation and convenient in use. The method comprises:
(a) sterilization of a glass bottle or vial with a lid or cap over it;
12
(b) filling a solution containing edaravone or its pharmaceutically acceptable salt as an
active ingredient and a pharmaceutically acceptable excipient selected from an
antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle
and a combination thereof into said pre-sterilized glass bottle or vial;
5 (c) closing (sealing) the bottle or vial containing edaravone solution with a lid or cap
covered on it; and
(d) sterilizing the closed bottle or vial.
In an alternative embodiment, the present invention provides a packaging method for a
10 parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip.
The method comprises:
(a) optionally sterilization of a glass bottle or vial with a lid or cap over it;
(b) filling a solution containing edaravone or its pharmaceutically acceptable salt as an
active ingredient and a pharmaceutically acceptable excipient selected from an
15 antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle
and a combination thereof into said optionally pre-sterilized glass bottle or vial;
(c) closing (sealing) the bottle or vial containing edaravone solution with a lid or cap
covered on it; and
(d) optionally sterilizing the closed bottle or vial.
20
In the above method, the glass bottle or vial is made of borosilicate glass and the lid or cap or
stopper is made of an elastic polymer or rubber (which, for example, without limitation include
natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber),
styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber,
25 butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber,
chloroprene rubber and the like) which is uncoated, i.e. without anti-adhesive coating.
The present invention further provides a bottle or vial filled with a parenteral dosage form of
edaravone in the form of intravenous solution for infusion or drip, containing edaravone or its
30 pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable
excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying
agent, a vehicle and a combination thereof, the bottle or vial made of glass, closed with a lid or
cap or stopper made of a material based on an elastic polymer, rubber (which, for example,
without limitation include natural rubber (latex), synthetic rubber, isoprene rubber (a chemical
13
copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone
(polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and
the like, nitrile rubber, chloroprene rubber and the like) the lid or cap is not coated with an antiadhesive coating.
5
According to the present invention, the bottle or vial is made of borosilicate glass, the lid or
cap or stopper is made of a derivative of rubber or thermoplastic polymer and on the inside or
is completely uncoated with a release coating known in the art. When packing, an aluminum
cap may also be used, which crimps the bottle cap in order to seal the container with the solution
10 containing edaravone.
A pharmaceutically acceptable excipient:
The edaravone formulation as described in the present invention comprises a pharmaceutically
acceptable excipient, which comprises an antioxidant, a stabilizer, a pH adjusting agent, a
15 tonicity modifying agent, a vehicle and a combination thereof. Non-limiting embodiments on
the pharmaceutically acceptable excipients which may be used in the present invention are
described below.
Antioxidants can be compounds that can reduce a drug that has been oxidized, or compounds
20 that are more readily oxidized than the agents they are to protect (oxygen scavengers). Mixtures
of chelating agents and antioxidants are often used because there appears to be a synergistic
effect. This occurs because many of the agents act at differing steps in the oxidative process.
The antioxidants when used in the compositions of the present invention include, but are not
limited to, butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-
25 hydroxymethyl-2, 6-di-tert-butylphenol, 2, 4, 5- trihydroxybutyrophenone, alkylgallates,
propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid,
glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl
stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic
acid, L-carnitine, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine,
30 cysteine, glutathione, methionine, tartaric acid, citric acid, fumaric acid, glycolic acid, oxalic
acid, succinic acid, ellagic acid, malic acid, maleic acid, tocopherols such as, but not limited
to, delta tocopherol, alpha tocopherol; lipoic acid, thiolated polymers such as, but not limited
to, polymethacrylic-SH, carboxy methylcellulose-cysteine, polycarbophil-cysteine, betacarotene, carotenoids, flavonoids, flavones, isoflavones, flavanones, catechins, anthocyanidins,
14
chalcones, sulfites, including but not limited to potassium sulfite, sodium metabisulfite, sodium
sulfite, sodium thiosulfate and sodium bisulfite or a combination thereof may be employed.
The use of an antioxidant in the form of sodium bisulfite (about 0.005 mg/mL to about 1.0
mg/mL) has been found effectively prevents oxidation of edaravone in the solution at elevated
5 temperature in pre-fillable syringes, ampoules and bottles/vials.
Typically, tonicity adjusting agents are used to adjust the osmolality of the pharmaceutical
compositions to bring it closer to the osmotic pressure of body fluids, such as blood or plasma.
In some embodiments the tonicity of the formulation can be modified by adjusting the
10 concentration of buffer and/or other components present in the formulation.
Provided that the compositions are physiologically compatible, the compositions do not require
any particular osmolality. Thus, the compositions can be hypotonic, isotonic or hypertonic.
Typically, the pharmaceutical compositions have a tonicity between about 250 to about 350
15 mOsm/kg. In some of the alternative embodiments, the formulations of the present invention
are isotonic, i.e., in the range of 260-320 mOsm/kg. In some of the alternative embodiments,
the formulations of the present invention are isotonic, i.e., in the range of 270-328 mOsm/kg.
However, the formulations may have a tonicity in the range of 250-350 mOsm/kg. Therefore,
the formulations may be either slightly hypotonic, 250-269 mOsm/kg, or slightly hypertonic,
20 329-350 mOsm/kg.
Suitable tonicity adjusting agents for use in the pharmaceutical compositions include, but are
not limited to, anhydrous or hydrous forms of sodium chloride, dextrose, sucrose, xylitol,
fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride,
25 magnesium chloride and other inorganic salts. The quantity of the tonicity adjusting agent in
the formulation can be expressed in mg/ml or in g/L. In typical embodiments, the tonicity
adjusting agent(s) is present from about 1 mg/ml to about 90 mg/ml. Thus, the pharmaceutical
compositions can comprise one or more tonicity adjusting agents at about 1-5 mg/ml, at about
5-10 mg/ml, at about 10-15 mg/ml, at about 15-25 mg/ml, at about 25-50 mg/ml, at about 50-
30 60 mg/ml, at about 60-70 mg/ml, at about 70-80 mg/ml, and at about 80 to 90 mg/ml, as well
as combinations of the above ranges.
Alternatively, the tonicity adjusting agent concentration is measured in weight/volume percent.
In typical embodiments, the tonicity adjusting agent(s) is present from about 0.1% to about
15
10%. For example, suitable tonicity adjusting agent concentrations include, but are not limited
to, from about 0.1% to about 0.2%, from about 0.2% to about 0.3%, from about 0.3% to about
0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, from about 0.6% to
about 0.7%, from about 0.7% to about 0.8%, from about 0.8% to about 0.9%, from about 0.9%
5 to about 1%, from about 1% to about 2%, from about 2% to about 3%, from about 3% to about
4%, from about 4% to about 5%, from about 5% to about 6%, from about 6% to about 7%,
from about 7% to about 8%, from about 8% to about 9%, and from about 9% to about 10%, as
well as combinations of the above ranges.
10 In some embodiments, the tonicity adjusting agent is sodium chloride. Typically, the
concentration of sodium chloride suitable for use in the pharmaceutical compositions is
between about 0.1% (w/v) to about 1.8%. By way of example, suitable sodium chloride
concentrations include, but are not limited to, from about 0.1% to about 0.2%, from about 0.2%
to about 0.3%, from about 0.3% to about 0.4%, from about 0.4% to about 0.5%, from about
15 0.5% to about 0.6%, from about 0.6% to about 0.7%, from about 0.7% to about 0.8% (which
is equivalent to 8 mg/ml), from out 0.8% to about 0.9% (which is equivalent to 9 mg/ml), from
about 0.9% to about 1.0%, from about 1% to about 1.2%, from 1.2% (which is equivalent to
12 mg/ml) to about 1.4%, from about 1.4% to about 1.6%, and from about 1.6% to about 1.8%.
20 In some embodiments, the pharmaceutical composition comprises two, three, or more tonicity
adjusting agents. In these embodiments, the concentration of each tonicity adjusting agent is
typically less than the concentration that is used when only a single agent is present in the
formulation.
25 Buffers/Buffering agent(s) if and when used in the formulation of the present invention include,
but are not limited to, pharmaceutically acceptable salts and acids of acetate, glutamate, citrate,
tartrate, benzoate, lactate, histidine or other amino acids such as arginine, alanine, glycine and
lysine, gluconate, phosphate, malate, succinate, formate, propionate, and carbonate.
“Pharmaceutically acceptable” is used herein in the sense of being compatible with the other
30 ingredients of the formulation and not deleterious to the recipient thereof. Accordingly, the
term “pharmaceutically acceptable salt” references salt forms of the active compounds which
are prepared with counter ions which are non-toxic under the conditions of use and are
compatible with a stable formulation. Buffers suitable for use in the formulations of the present
16
invention also include, but are not limited to tris (hydroxymethyl)aminomethane (TRIS),
triethanolamine, trolamine, diethanolamine, meglumine etc.
The concentration of the buffer/buffering agent in the formulation can be expressed in mg/ml,
5 g/l or as a molar concentration. Typically, from about 0.0001 mg/ml to about 100 mg/ml of a
suitable buffer is present in the formulations of the present invention. Thus, the formulations
can comprise from about 0.0001 to about 0.001 mg/ml of a suitable buffer, from about 0.001
to about 0.01 mg/ml of a suitable buffer, from about 0.01 to about 0.1 mg/ml of a suitable
buffer, from about 0.1 to 1 mg/ml of a suitable buffer, from about 1 to about 5 mg/ml of a
10 suitable buffer, from about 5 to about 10 mg/ml of a suitable buffer, from about 10 to about 15
mg/ml of a suitable buffer, from about 15 to about 20 mg/ml of a suitable buffer, from about
20 to about 25 mg/ml of a suitable buffer, from about 25 to about 50 mg/ml of a suitable buffer,
from about 50 to about 75 mg/ml of a suitable buffer, and from about 75 to about 100 mg/ml
of a suitable buffer.
15
Alternatively, the buffer concentration can be expressed as molar concentrations. In typical
embodiments, from about 0.1 to 100 mM of a suitable buffer is present in the pharmaceutical
compositions. Thus, the pharmaceutical compositions can comprise a suitable buffer having a
concentration from about 0.1 to about 100 mM, from about 0.1 to about 0.5 mM, from about
20 0.5 to about 1.0 mM, from about 1.0 to about 5 mM, from about 5 to about 10 mM, from about
10 to about 15 mM, from about 15 to about 25 mM, from about 25 to about 50 mM, from about
50 to about 75 mM, and from about 75 to about 100 mM.
In some embodiments, the formulation of the present invention comprises a pH adjusting agent.
25 Suitable pH adjusting agents typically include at least an acid or a salt thereof, and/or a base or
a salt thereof. Acids and bases can be added on an as needed basis in order to achieve the
desired pH. For example, if the pH is greater than the desired pH, an acid can be used to lower
the pH to the desired pH. Acids suitable for use in formulations include, but are not limited to,
hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, sulphuric acid,
30 carbonic acid, nitric acid and the like. By way of another example, if the pH is less than the
desired pH, a base can be used to adjust the pH to the desired pH. Bases suitable for use in
formulations include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium
hydroxide, sodium carbonate, sodium citrate, sodium acetate, magnesium hydroxide and the
like.
17
A “Buffer/Buffering agent” or a “pH adjusting agent” as used herein is a system which is used
for the purposes and is capable of maintaining the desired/required pH of the formulations
throughout desired/required time period, e.g. stability studies and/or shelf life of the drug
product. The desired pH of the formulation according to the present invention is about 4.0.
5
In some of the embodiments of the invention, both buffering agent and pH adjusting agent is
used. In some of the embodiments of the invention, only a buffering agent is used. In some of
the embodiments of the invention, only a pH adjusting agent is used.
10 In some of the preferred embodiments, phosphoric acid and/or sodium hydroxide are used as
pH adjusting agent(s) which adjusts and/or maintains the desired/required pH, i.e. about 4.0.
However, in the non-limiting embodiments of the present invention, the pH of the edaravone
formulation is between about 3.0 and about 5.0. In some of the non-limiting embodiments, the
15 pH of the edaravone solution of the present invention is about 3.0, about 3.1, about 3.2, about
3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about
4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, and about 5.0.
In some of the further non-limiting embodiments, the pH of the edaravone solution of the
present invention is any value between the ranges about 3.0 to about 5.0.
20
Stabilizing agents when used in the formulation of the present invention without limitation
include ethylene diamine tetraacetic acid (EDTA) or salts thereof, ascorbic acid, cysteine or
salt thereof, L-cysteine or salt thereof, sorbitol, sorbitol solution, glycols such as propylene
glycol and the like and a combination thereof. The use of a stabilizing agent in the form of L25 cysteine hydrochloride hydrate (about 0.005 mg/mL to about 1.0 mg/mL) has been found
effectively stabilizes edaravone in the solution at elevated temperature in pre-fillable syringes,
ampoules and bottles/vials.
Since, the edarvone formulation of the present invention is in the form of aqueous solution,
30 water or water for injection is used as a vehicle.
Further, during the packaging of the drug product of the present invention and also during its
preparation, the drug product may have to undergo sterilization process for multiple times, for
18
example, twice. Therefore, the materials from which the container which contains ready-to-use
edaravone injection solution is made, must have appropriate characteristics.
If above mentioned conditions are fulfilled then prolonged stability of the drug (i.e. edaravone)
5 may be ensured during its storage under various conditions and may make the edaravone
solution prepared according to the present invention safer for use, storage for prolonged time
and even during transport.
The packaging material according to the present invention, which should ensure the stability
10 of the drug into the solution without changing pH, density, heat resistance and other
characteristics, is borosilicate glass, which can easily withstand temperatures above 200°C and
does not change the chemical composition of the edaravone. Thus, it is advantageous to fill or
store the edaravone solution in a borosilicate glass container.
15 The closure of the glass bottle or vial with the edaravone drug product must be carried out in
such a way that the lid or cap or stopper, firstly, seals the vial hermetically, and secondly, the
lid or cap or stopper must be heat-resistant, and thirdly, made of a material that prevents the
adhesion of the active substance on its surface.
20 According to the present invention, the lid or cap or stopper is made of an elastic polymer based
on a rubber or thermoplastic derivative, which has high impermeable properties, high heat
resistance, strength and at the same time good flexible properties, which prevents the lid from
breaking. Other similar materials may also be used which meet the specified characteristics,
for example, in the class of unnatural synthetic elastomers. It is pertinent to note that the lid or
25 cap or stopper used in the present invention are uncoated and does not contain anti-adhesive
coating.
It is also not required that at least that part of the surface of the lid or cap or stopper, partially
or completely, which is in contact with the drug solution, be covered with a layer of a substance
30 with anti-adhesive properties. The lid or cap or stopper should not affect the chemical
composition of the mixture and it should be heat-resistant.
During transportation and storage, additional stability of the drug in the package of the present
invention is due to the use of an aluminum cap, which crimps the bottle or vial cap to seal the
container containing edaravone solution.
19
As primary packaging materials, the present invention uses glass vials, rubber closures and
aluminum tear off seals. The glass vials used in the present invention are USP/EP Type-I clear
100 mL ISO-Molded glass vials (manufactured by SGD Pharma India Ltd.). However, other
glass vials of similar quality and having different size (capacity) may also be used for the
5 purposes of the present invention. Similarly, Type II and Type III glass containers may also be
used if found suitable for parenteral use. The glass vials of the present invention are made of
borosilicate glass. However, vials made of other glass material (which, for example, without
limitation include lime soda glass, neutral glass, lead free glass sulphured containers, silicone
treated containers and the like) may also be used if found suitable for parenteral use. The lids
10 or caps or stoppers used in the present invention to close the vials containing edaravone solution
are 20 mm chlorobutyl rubber stoppers (S-127 4432/50/Grey Westar RS SIL 1; manufactured
by West Pharmaceutical Services Singapore Pte. Ltd.). However, 20 mm-35 mm size rubber
closures which, for example, without limitation include natural rubber (latex), synthetic rubber,
isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene
15 dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as
bromobutyl, chlorobutyl and the like, nitrile rubber, chloroprene rubber or any other suitable
closures made of suitable material and the like may also be used for the purposes of the present
invention. The formulation of the rubber closures used in the present invention complies with
the chemical requirements in the corresponding monograph 3.2.9 for “rubber closures” Type 1
20 in the valid version of the European Pharmacopoeia. The formulation also complies with the
physicochemical tests, as described in the current USP General Chapter [381] “Elastomeric
Closures for Injections”. The rubber closures used in the present invention are uncoated which
means they do not contain any anti-adhesive coatings. The present invention also uses 20 mm
size Aluminum tear off seal to pack the vial containing edaravone solution. These Aluminum
25 seal crimps the vial cap to seal the containers. However, Aluminum seals of any suitable size
may also be used depending upon the size of the stopper used.
As secondary packaging materials, the present invention uses white folded cartoon. However,
any packaging material made of suitable material which fulfills the requirements of the present
30 invention (i.e. stability during storage and transportation, easy and convenient use etc.) may
also be used.
Definitions:
20
The use of the terms “a” and “an” and “the” and similar referents in the context of describing
the invention are to be construed to cover both the singular and the plural, unless otherwise
indicated herein or clearly contradicted by context.
5 As used herein, the term “about” is synonymous with “approximately” and is used to provide
flexibility to a numerical value or range endpoint by providing that a given value may be “a
little above” or “a little below” the value stated. “About” can mean, for example, within 3 or
more than 3 standard deviations. “About” can mean within a percentage range of a given value.
For example, the range can be ±1 %, ±5%, ±10%, ±20%, ±30%, ±40% or ±50% of a given
10 value. “About” can mean with an order of magnitude of a given value, for example, within 2-
fold, 3-fold, 4-fold or 5-fold of a value. However, it is to be understood that even when a
numerical value is accompanied by the term “about” in this specification, that express support
shall be provided at least for the exact numerical value as well as though the term “about” were
not present.
15
As used herein, the terms “stable” or “stability” encompass any characteristic of the
formulations which may be affected by storage conditions including, without limitation,
potency, total impurities, degradation products, specific optical rotation, optical purity, water
content, appearance, viscosity, sterility, and colour and clarity. The storage conditions which
20 may affect stability include, for example, duration of storage, temperature, humidity, and/or
light exposure.
The term “degradant”, “impurity”, “degradation impurity” and “related substance” as used
herein represents the same meaning and can be used interchangeably.
25
In some embodiments, the formulations of the present invention are stable for prolonged time
when stored under storage conditions. The term “storage conditions” as used herein without
limitation include typical storage conditions such as 2°C-8°C. The compositions of the present
invention may also be stored at 40°C±2°C/75±5% RH, 30°C±2°C/65±5% RH,
30 25°C±2°C/40±5% RH, 25°C±2°C/60±5% RH, 40°C±2°C/NMT 25% RH (NMT = not more
than) and accelerated conditions such as 40°C±2°C/75±5% RH. The term “prolonged time” as
used herein indicates that the formulations of the present invention are stable for at least 1
month or more, at least 3 months or more, at least 6 months or more or at least 12 months or
more when stored under storage conditions.
21
In some of the embodiments of the present invention, “stable” or “storage stable”, or “stability”
when used with reference to the formulations of the present invention or when used “stable or
storage stable formulations” or “stability of the formulations” all these terms/phrases refer to
formulations of the present invention which retain at least about 90%, or at least about 95%, or
5 at least about 96%, or at least about 98%, of the labelled concentration of edaravone or salt
thereof contained in the said formulation after storage under typical and/or accelerated
conditions. In further embodiments, stable formulations or stability of the formulations refer to
less than about 15% (area percent), or less than about 10% (area percent), or less than about
7% (area percent), or less than about 5% (area percent), or less than about 2% (area percent) of
10 edaravone-related impurities are present after storage under typical and/or accelerated
conditions.
In some of the embodiments, formulations of the present invention contain no more than about
15% (area percent), or no more than about 10% (area percent), or no more than about 7% (area
15 percent), or no more than about 5% (area percent), or no more than about 2% (area percent), or
no more than about 1% (area percent), or no more than about 0.5% (area percent), or no more
than about 0.2% (area percent), or no more than about 0.1% (area percent) any known or
unknown single edaravone-related impurity or other impurity after storage under typical and/or
accelerated conditions.
20
In some of the embodiments, formulations of the present invention contain no more than about
15% (area percent), or no more than about 10% (area percent), or no more than about 7% (area
percent), or no more than about 5% (area percent), or no more than about 2% (area percent), or
no more than about 1% (area percent), or no more than about 0.5% (area percent), or no more
25 than about 0.2% (area percent), or no more than about 0.1% (area percent) total edaravonerelated impurities or other impurities after storage under typical and/or accelerated conditions.
Methods for determining the stability of the formulations of the present invention with respect
to a given parameter are well-known to those of skill in the art. For example, individual
30 impurities and total impurities can be assessed by high-performance liquid chromatography
(HPLC) or thin layer chromatography (TLC). Unless otherwise indicated to the contrary, a
percentage amount of any individual impurities (known/unknown), or total impurities reported
herein in the formulations are determined by a peak area percent method using HPLC.
22
The term “compatible” as used herein refers to those added excipients or ingredients or
additives those are not substantially antagonistic to the other excipients or ingredients or
additives or pharmaceutically active ingredients.
5 As used herein an “effective amount” of a compound or composition for treating a particular
disease is an amount that is sufficient to ameliorate, or in some manner reduce symptoms to
achieve the desired physiological effect. Such amount can be administered as a single dosage
or can be administered according to a regimen, whereby it is effective. The effective amount is
readily determined by one of skill in the art following routine procedures.
10
As used herein, “optional” or “optionally” means that the subsequently described event or
circumstance does or does not occur, and that the description includes instances where said
event or circumstance occurs and instances where it does not. For example, an optionally
substituted group means that the group is un-substituted or is substituted.
15
As used herein, “comprises”, “comprising”, “containing” and “having” and the like can have
the meaning ascribed to them in patent law and can mean “includes”, “including” and the like,
and are generally interpreted to be open ended terms. The terms “consisting of” or “consists
of” are closed terms, and include only the components, structures, steps, or the like specifically
20 listed in conjunction with such terms, as well as that which is in accordance with patent law.
“Consisting essentially of” or “consists essentially of” have the meaning generally ascribed to
them by patent law. In particular, such terms are generally closed terms, with the exception of
allowing inclusion of additional items, materials, components, steps, or elements, that do not
materially affect the basic and novel characteristics or function of the item(s) used in
25 connection therewith. For example, trace elements present in a composition, but not affecting
the composition’s nature or characteristics would be permissible if present under the
“consisting essentially of” language, even though not expressly recited in a list of items
following such terminology. When using an open ended term, like “comprising” or “including”
it is understood that direct support should be afforded also to “consisting essentially of”
30 language as well as “consisting of” language as if stated explicitly and vice versa. In essence,
use of one of these terms in the specification provides support for all of the others. The term
“comprise/comprises/comprising” as used herein mean that other ingredients, steps, etc. are
optionally present. When reference is made herein to a method comprising two or more defined
steps, the steps can be carried in any order or simultaneously (except where the context
23
excludes that possibility), and the method can include one or more steps which are carried out
before any of the defined steps, between two of the defined steps, or after all of the defined
steps (except where the context excludes that possibility).
5 As used herein, “rubber” without limitation includes natural rubber (latex), synthetic rubber,
isoprene rubber (a chemical copy of natural rubber), styrene-butadiene rubber, neoprene (poly-
(2-chloro-1,3-butadiene), styrol-butadine rubber, ethylene propylene dyes monomers, silicone
(polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and
the like, nitrile rubber, and chloroprene rubber. Thus, the rubber stoppers include all stoppers
10 made of above mentioned rubbers.
As used herein, “glass vials” or “glass bottles” without limitation include vials or bottles made
of borosilicate glass, lime-soda glass, neutral glass, lead free glass, sulphured treated glass, and
silicone treated glass. The glass vials according to the present invention without limitation
15 include tubing glass vials and molded glass vials.
The term “easy and convenient to transport and use”, as used herein, means that the bottles or
vials containing edaravone formulation of the present invention when packaged as described
in the present invention are not adversely affected or damaged during transportation from one
20 place to another and even during use, e.g., use by pharmacies, healthcare providers etc. In other
words, the transportation and use of the edaravone formulation of the present invention when
packaged as described in the present invention does not require any special handling techniques
and/or care.
25 Further, as used herein, the term “stable during storage, transportation and convenient in use”
means that the bottles or vials containing edaravone formulation of the present invention when
packaged as described in the present invention, the quality of the product is not adversely
affected or diminished during storage period or during transportation during one place to
another and also during shelf life and that it is convenient to use by the healthcare providers or
30 in pharmacies that no special handling techniques or care is required.
As used herein, “USP” is an abbreviated form of United States Pharmacopeia and “EP” is an
abbreviated form of European Pharmacopeia.
24
All percentages mentioned herein, unless otherwise indicated, are on a w/v basis, i.e.
percentage ingredient (active/inactive) present by weight in the total volume of the
composition.
5 BEST MODE OF CARRYING OUT THE INVENTION
EXAMPLE(S)
The edaravone parenteral dosage form of the present invention is prepared as ready-to-use
intravenous solution for infusion. Said edaravone dosage form contains edaravone or its
pharmaceutically acceptable salt as active ingredient and an antioxidant, a stabilizer, a pH
10 adjusting agent and a tonicity modifying agent as inactive ingredients. The edaravone dosage
form of the present invention is in the form of aqueous solution having pH about 4.0.
Table 1: Edaravone aqueous solution of the present invention
Sr Name of ingredient Role of ingredient Strength(s)
0.3 mg/mL 0.6 mg/mL
1 Edaravone Active 30mg/100mL 60mg/100mL
2
L-cysteine
hydrochloride hydrate Stabilizer 10mg/100mL 20mg/100mL
3 Sodium bisulfite Antioxidant 20mg/100mL 40mg/100mL
4 Sodium chloride Tonicity modifying
agent 860mg/100mL 855mg/100mL
5
Phosphoric
acid/sodium hydroxide
pH adjusting
agent(s)
Q.S. to
adjust/maintain
pH about 4.0
Q.S. to
adjust/maintain
pH about 4.0
6 Water for injection Vehicle Q.S. to 100 mL Q.S. to 100 mL
Q.S. = quantity sufficient
15 The edaravone solution of the present invention, in the qualitative and quantitative composition
as mentioned above, was prepared by dissolving required quantity of L-cysteine hydrochloride
in the required quantity of the water for injection (having dissolved oxygen below 1ppm).
Required quantity of edaravone was dissolved in above solution. The mixture was heated, if
required. Required quantity of sodium chloride was dissolved in the above drug solution. The
20 pH was adjusted to about 4.0 using suitable pH adjusting agent (phosphoric acid/sodium
hydroxide). For example, if pH of the solution is higher than 4.0 then pH is adjusted using
phosphoric acid and if pH of the solution is lower than 4.0 then pH is adjusted using sodium
hydroxide. Finally, required quantity of sodium bisulfite is dissolved in above pH adjusted drug
solution. The pH of the final drug solution is checked and adjusted to about 4.0, if required, as
25 mentioned above. The above method of preparation is for illustrative purpose only and the
25
edaravone solution of the present invention can be prepared by following alternative methods
also where the order of addition of drug and excipients is altered. The edaravone solution can
also be prepared in two or more parts preparation process where some excipients with or
without drug are dissolved in one part and some excipients with or without drug is dissolved
5 in another part followed by mixing of both the parts to finally prepare edaravone solution. It
should be noted that the order to addition of drug and excipients and the two-part preparation
does not negatively affect the quality of the product.
The fact that sodium chloride used in the edaravone formulations of the present invention is
10 8.6 mg/mL (for 0.3 mg/mL strength) and 8.55 mg/mL (for 0.6 mg/mL strength) does not
necessarily mean it can only be used in the edaravone formulations in these amounts only.
Sodium chloride can be used in any quantity that is sufficient to bring the osmolality of the
solution between about 260 mOsmol/kg and about 320 mOsmol/kg, e.g., sodium chloride may
be used from 710mg/100mL to 860mg/100mL for both the strengths.
15
The edaravone drug formulation obtained by above method is filled in USP/EP Type-I clear
100 mL ISO-Molded glass vial (manufactured by SGD Pharma India Ltd.). The glass vial was
closed using 20 mm chlorobutyl uncoated rubber stopper (S-127 4432/50/Grey Westar RS SIL
1; manufactured by West Pharmaceutical Services Singapore Pte. Ltd.). The glass vial closed
20 with above said rubber stopper was finally clogged with 20 mm Aluminum tear off seal to pack
the vial. The Aluminum seal crimps the vial cap to seal the container. The sealed vial was
finally packed in white folded cartoon.
The stability of the edaravone in the solution using above mentioned primary and secondary
25 packaging was tested at various temperatures and under different humidity conditions at
various end points (for example after 1 month, 2 months, 3 months, 6 months, 9 months etc.).
The results of these stability studies show that the edaravone was not susceptible to oxidation
and other degradation even after using above mentioned simple and economic packaging
materials. The concentration of edaravone in the solution was not increased due to evaporation
30 of the liquid of the solution. Also, the concentration of edaravone was not decreased due to
adhesion of the drug molecule with the rubber closure used even after using uncoated rubber
stopper (rubber stopper without anti-adhesive coating). These surprising findings are not
envisaged from the disclosure of any of the prior art documents, then, when the prior art
26
documents specifically teaches advantages of the coated stoppers/lids with anti-adhesive
polymers.
Thermal Stability Study Results of Edaravone injection 30mg/100mL:
Test
parameters Initial
40°C/75% RH 30°C/65% RH 25°C/60%RH
1M
I
3M
I
6M
I
1M
I
3M
I
6M
I
12M
I
1M
I
3M
I
6M
I
12M
I
Description C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S.
pH 4.25 4.21 3.93 3.68 4.30 4.09 3.64 3.63 4.02 4.02 3.67 3.65
Osmolality 280 283 287 282 280 288 280 282 284 288 281 283
Assay of
Edaravone
(in %)
100.1 99.7 98.7 98.0 99.8 99.3 98.8 99.3 99.9 100.1 99.4 100.2
Content of LCysteine HCl
Monohydrate
(in %)
103.6 97.6 82.9 83.6 97.8 84.9 78.9 70.2 101.0 90.4 80.1 67.2
Content of
Sodium
Bisulfite
(in %)
89.1 82.4 73.6 66.9 84.8 77.4 70.0 64.8 86.9 81.2 70.3 65.7
Head Space
Oxygen
(in %v/v)
2.73 2.09 1.49 1.11 2.43 1.53 0.95 1.66 1.88 1.45 2.01 1.11
Single
maximum
unspecified
impurity
0.02 0.03 0.07 0.13 0.02 0.02 0.05 0.09 0.02 0.02 0.03 0.05
Total
impurities 0.06 0.12 0.23 0.44 0.07 0.07 0.17 0.38 0.06 0.06 0.12 0.20
5 C.S. = colorless solution; NMT = not more than; NLT = not less than; RH = relative humidity; M = month(s); I =
inverted
Thermal Stability Study Results of Edaravone injection 60mg/100mL:
Test parameters Initial
40°C/75% RH 30°C/65% RH 25°C/60%RH
1M
I
3M
I
6M
I
1M
I
3M
I
6M
I
1M
I
3M
I
6M
I
Description C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S.
pH 4.24 3.59 3.78 3.54 3.85 3.59 3.57 3.95 3.67 3.60
Osmolality 286 287 293 289 287 293 288 288 292 288
Assay of Edaravone
(in %) 99.8 99.2 99.1 97.9 99.5 99.6 98.9 99.6 99.8 99.0
Content of L-Cysteine
HCl Monohydrate (in %) 102.3 96.3 88.0 81.5 98.3 77.9 82.7 101.1 83.3 83.5
Content of Sodium
Bisulfite (in %) 80.9 76.6 68.9 64.9 78.7 64.5 67.2 80.5 66.8 68.4
Head space Oxygen
(in %v/v) 3.59 1.54 0.89 3.66 2.07 1.34 NP 2.01 1.7 NP
27
Single maximum
unspecified impurity 0.02 0.04 0.07 0.14 0.03 0.04 0.07 0.03 0.05 0.03
Total impurities 0.04 0.11 0.18 0.38 0.07 0.11 0.17 0.07 0.11 0.09
C.S. = colorless solution; NMT = not more than; NLT = not less than; RH = relative humidity; M = month(s); NP
= not performed; I = inverted
From above data it can be concluded that the edaravone formulation of the present invention
5 when packaged in the packaging materials described herein is stable at 25°C temperature and
60% relative humidity. Further, based on the above data it can be concluded that the shelf life
of the edaravone solution when packaged in the packaging materials of the present invention
can be at least 2 years (or 24 months) at 25°C.
10 It is pertinent to note that, the quality and stability of the drug product is not affected even after
using uncoated stoppers/caps (that does not contain anti-adhesive coatings/polymers as
described in the prior art). In other words, all the test parameters were within the specification
even after using the uncoated stoppers/vials and keeping the containers containing edaravone
solution in inverted position for above said time periods and stability conditions. These studies
15 suggest that for packaging edaravone solution expensive packaging system (coated
stoppers/caps having anti-adhesive polymers) is not required and the edaravone solution can
be packaged in less expensive and easily available packaging materials which makes the drug
product more economically viable and affordable by the patients.
20 The compositions and the packaging materials in which they are packaged as described in the
present invention are suitable for use in the industry.
It should be understood that various changes and modifications to the embodiments described
herein will be apparent to those skilled in the art. Such changes and modifications can be made
25 without departing from the spirit and scope of the subject matter of the present invention and
without diminishing its intended advantages. It is therefore intended that such changes and
modifications be covered within the scope of the present invention.
28
We claim,
1. A bottle or vial filled with a parenteral dosage form of edaravone in the form of an
intravenous solution for infusion or drip comprising edaravone or its pharmaceutically
acceptable salt and a pharmaceutically acceptable excipient selected from an antioxidant, a
stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination
thereof, the bottle or vial, closed with a lid or cap or stopper, wherein the lid or cap or
stopper is not coated with an anti-adhesive coating.
2. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 1,
wherein the bottle or vial is made of borosilicate glass.
3. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 1,
wherein the lid or cap or stopper is made of a material based on an elastic polymer or rubber.
4. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 3,
wherein the rubber is natural rubber (latex), synthetic rubber, isoprene rubber (a chemical
copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers,
silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl,
chlorobutyl and the like, nitrile rubber, or chloroprene rubber and the like.
5. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 1,
wherein said parenteral dosage form is stable at 25°C at least for 6 months or more or 12
months or more.
6. A method for obtaining a parenteral dosage form of edaravone in the form of an intravenous
solution for infusion or drip, said method comprises:
(a) preparing a solution comprising edaravone or its pharmaceutically acceptable salt
and a pharmaceutically acceptable excipient selected from an antioxidant, a
stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a
combination thereof;
(b) packaging the edaravone dosage form in a glass bottle or vial, that is optionally presterilized, with a lid or cap or stopper covered on said glass bottle or vial, wherein
said lid or cap or stopper is without an anti-adhesive coating; and
(c) closing the bottle or vial with a lid or cap or stopper covered on said bottle or vial
and optionally sterilizing said bottle or vial containing said edaravone solution.
7. The method for obtaining a parenteral dosage form of edaravone as claimed in claim 6,
wherein the glass bottle or vial is made of borosilicate glass.
29
8. The method for obtaining a parenteral dosage form of edaravone as claimed in claim 6,
wherein the lid or cap or stopper is made of rubber selected from natural rubber (latex),
synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine
rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or
halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, or
chloroprene rubber and the like.
9. A packaging method for a parenteral dosage form of edaravone in the form of an
intravenous solution for infusion or drip, said method comprises:
(a) optionally sterilization of a glass bottle or vial with a lid or cap or stopper over it;
(b) filling a solution comprising edaravone or its pharmaceutically acceptable salt and
a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer,
a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination
thereof into said optionally pre-sterilized glass bottle or vial;
(c) closing (sealing) the bottle or vial containing edaravone solution with a lid or cap
or stopper covered on it; and
(d) optionally sterilizing the closed bottle or vial,
wherein said lid or cap or stopper is not coated with an anti-adhesive coating.
10. The packaging method for a parenteral dosage form of edaravone as claimed in claim 9,
wherein the glass bottle or vial is made of borosilicate glass and the lid or cap or stopper is
made of rubber selected from natural rubber (latex), synthetic rubber, isoprene rubber (a
chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes
monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as
bromobutyl, chlorobutyl and the like, nitrile rubber, or chloroprene rubber and the like.