Page 1 of 7
`
`SENJU EXHIBIT 2030
`LUPIN v. SENJU
`IPR2015-01105
`
`

`
`1
`METHOD FOR STABILIZING
`PRANOPROFEN AND STABLE LIQUID
`PREPARATION OF PRANOPROFEN
`
`5,856,345
`
`2
`
`This is a divisional application of Ser. No. 08/404,102,
`filed Mar. 14, 1995.
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention relates to a method for stabilizing
`pranoprofen having anti-inflammatory activity, in an aque-
`ous solution of pranoprofen, and to a liquid preparation
`comprising, as an active ingredient, pranoprofen which is
`stabilized by adding an antioxidant.
`2. Description of Related Art
`Pranoprofen having a chemical name of ot-methyl-5H-[1]
`benzopyrano[2,3-b]pyridine-7-acetic acid exhibits promi-
`nent anti-inflammatory action, analgesic action and anti-
`pyretic action. It is a non-steroidal anti-inflammatory drug
`having a wider safety margin, and is commercially available
`by the product name of Niflan (trademark). The properties
`and production method thereof are described in U.S. Pat.
`No. 3,931,295.
`There has also been proposed an eye drop containing
`pranoprofen as an anti-inflammatory active ingredient and
`boric acid as an isotonizing agent, as being useful for, in
`particular, herpesvirus eye diseases (U.S. Pat. No. 4,607,
`038).
`However, pranoprofen is unstable in an aqueous solution
`state, particularly to light and is gradually decomposed
`during long-term preservation.
`It is therefore an object of the present invention to provide
`a method for stabilizing pranoprofen in an aqueous solution
`state.
`
`Another object of the present invention is to provide an
`aqueous solution of pranoprofen, wherein decomposition of
`pranoprofen is suppressed.
`SUMMARY OF THE INVENTION
`
`According to the present invention, it has now been found
`that decomposition of pranoprofen can be markedly sup-
`pressed by placing an aqueous solution of pranoprofen in
`coexistence with an antioxidant, or placing an aqueous
`solution of pranoprofen under the conditions of limited
`supply of oxygen.
`That
`is,
`the present
`thereof are as follows.
`
`invention and preferable modes
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`(1) A method for stabilizing pranoprofen, comprising plac-
`ing an aqueous solution of pranoprofen in coexistence
`with an antioxidant.
`
`50
`
`(2) A method for stabilizing pranoprofen according to (1),
`comprising adding an antioxidant to an aqueous solution
`of pranoprofen.
`(3) A method for stabilizing pranoprofen according to (2),
`comprising adding an antioxidant at a ratio to pranoprofen
`of 0.0002—5.0 by weight.
`(4) A method for stabilizing pranoprofen according to (1),
`comprising sealing an aqueous solution of pranoprofen in
`a container formed from a material comprising an anti-
`oxidant.
`
`(5) A method for stabilizing pranoprofen according to (4),
`comprising adding an antioxidant to a material of the
`container at a ratio to the material of 0.0001—0.005 by
`weight.
`(6) A method for stabilizing pranoprofen according to (4),
`wherein the container is made of polypropylene.
`
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`Page 2 of 7
`
`(7) A method for stabilizing pranoprofen according to (2),
`wherein the antioxidant is at least one compound selected
`from the group consisting of alkylphenols, benzopyran
`derivatives, sodium thiosulfate and amino acids.
`(8) A method for stabilizing pranoprofen according to (7),
`wherein the alkylphenol is at least one compound selected
`from the group consisting of dibutylhydroxytoluene and
`butylhydroxyanisole.
`(9) A method for stabilizing pranoprofen according to (7),
`wherein the benzopyran derivative is at least one member
`selected from the group consisting of L-ascorbic acid
`2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-
`trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen
`phosphate] and salts thereof.
`(10) A method for stabilizing pranoprofen according to (7),
`wherein the amino acid is at least one member selected
`from the group consisting of methionine, tryptophan and
`histidine.
`
`(11) A method for stabilizing pranoprofen according to any
`one of (4)—(6), wherein the antioxidant is at least one
`alkylphenol.
`(12) A method for stabilizing pranoprofen according to (11),
`wherein the alkylphenol is at least one member selected
`from the group consisting of dibutylhydroxytoluene and
`butylhydroxyanisole.
`(13) A method for stabilizing pranoprofen, comprising plac-
`ing an aqueous solution of pranoprofen under the condi-
`tions of limited supply of oxygen.
`(14) A method for stabilizing pranoprofen according to (13),
`comprising sealing a container,
`in which an aqueous
`solution of pranoprofen has been sealed, in a container or
`enclosing the container with a sheet,
`together with a
`deoxygenating agent.
`(15) A method for stabilizing pranoprofen according to (13),
`comprising sealing an aqueous solution of pranoprofen in
`a container having a low oxygen permeability or enclos-
`ing the solution with a sheet having a low oxygen per-
`meability.
`(16) A stabilizing method according to (1), wherein the
`aqueous solution of pranoprofen is an eye drop or a
`collunarium.
`
`(17) A stabilizing method according to (13), wherein the
`aqueous solution of pranoprofen is an eye drop or a
`collunarium.
`
`(18) A stable liquid preparation of pranoprofen, comprising
`pranoprofen and an antioxidant.
`(19) The liquid preparation of (18), wherein the antioxidant
`is at least one compound selected from the group con-
`sisting of alkylphenols, benzopyran derivatives, sodium
`thiosulfate and amino acids.
`
`(20) The liquid preparation of (19), wherein the alkylphenol
`is at least one member selected from the group consisting
`of dibutylhydroxytoluene and butylhydroxyanisole.
`(21) The liquid preparation of (19), wherein the benzopyran
`derivative is at least one compound selected from the
`group consisting of L-ascorbic acid 2-[3,4-dihydro-2,5,7,
`8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-
`benzopyran-6-yl-hydrogen phosphate] and salts thereof.
`(22) The liquid preparation of (19), wherein the amino acid
`is at least one member selected from the group consisting
`of methionine, tryptophan and histidine.
`(23) The liquid preparation of (18), comprising an antioxi-
`dant at a ratio to pranoprofen of 0.0002—5 .0 by weight.
`(24) The liquid preparation of (18), which is an eye drop.
`(25) The liquid preparation of (18), which is a collunarium.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The first mode of the stabilizing method of the present
`invention is placing an aqueous solution of pranoprofen in
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`5,856,345
`
`3
`coexistence with an antioxidant, which is realized by, for
`example,
`adding an antioxidant to an aqueous solution of
`pranoprofen (Mode I) or (ii) sealing an aqueous solution of
`pranoprofen in a container formed from a material compris-
`ing an antioxidant (Mode II). The Modes I and II may be
`used in combination.
`
`for
`includes,
`to be used in Mode I
`The antioxidant
`example, alkylphenols, benzopyran derivatives, sodium
`thiosulfate and amino acids.
`
`Examples of alkylphenol include dibutylhydroxytoluene
`(BHT), butylhydroxyanisole (BHA), n-propyl gallate and
`catechol, with preference given to BHT and BHA.
`Examples of benzopyran derivative include tocopherol,
`tocol, L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-
`(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen
`phosphate] and salts thereof, with preference given to
`L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,
`12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen
`phosphate] potassium salt (EPC-K1).
`Amino acid is, for example, methionine, tryptophan or
`histidine, with preference given to methionine and tryp-
`tophan.
`When an antioxidant is added to an aqueous solution of
`pranoprofen according to Mode I, the antioxidant is gener-
`ally added at a ratio to pranoprofen of 0.0002—5 .0 by weight,
`preferably 0.002—2.5 by weight.
`When an aqueous solution of pranoprofen is sealed in a
`container formed from a material comprising an antioxidant,
`according to Mode II, the container is, for example, gener-
`ally a plastic container such as the one composed of poly-
`olefin [e.g. polyethylene (PE) and polypropylene (PP)], with
`preference given to the one composed of PP.
`An antioxidant is added to the material of the container at
`
`a ratio to the material of, for example, 0.0001—0.005 by
`weight, preferably 0.0005—0.005 by weight.
`In the Mode II, the antioxidant to be used is, for example,
`a phenol such as alkylphenol, alkyldiphenol or thiobisalky-
`lphenol.
`Examples of alkylphenol include dibutylhydroxytoluene
`(BHT), butylhydroxyanisole (BHA), n-propyl gallate,
`stearyl
`[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate,
`tetrakis[3 -(3,5 -di-tert-butyl-4-hydroxyphenyl)
`propionyloxymethyl]methane, 1,3,5-tris(3,5-di-tert-butyl-4-
`hydroxybenzyl)-1H,2H,3H-triazine-2,4,6-trione, 1,3,5-tris[
`(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethyl]
`benzene and 3,9-bis[2-(3-(3-tert-butyl-4-hydroxy-5-
`methylphenyl)propionyloxy)-1,1-dimethylethyl]-2,4,8,10-
`tetraoxaspiro[5 .5]undecane, with preference given to BHT
`and BHA.
`
`Examples of alkyldiphenol include 2,2‘-methylenebis(4-
`methyl-6-tert-butylphenol), 4,4‘-butylidenebis(2-tert-butyl-
`5-methylphenol) and 2-tert-butyl-6-(3-tert-butyl-2-hydroxy-
`5-methylbenzyl)-4-methylphenyl acrylate.
`Examples of thiobisalkylphenol
`include 4,4‘-thiobis(2-
`tert-butyl-5-methylphenol).
`The second mode of the stabilizing method of the present
`invention is placing an aqueous solution of pranoprofen
`under the conditions of limited oxygen supply. For example,
`a container containing an aqueous solution of pranoprofen
`sealed therein is sealed in another container or enclosed with
`
`a sheet in coexistence with a deoxygenating agent (Mode
`III), or an aqueous solution of pranoprofen is sealed in a
`container having a low oxygen permeability, or enclosed
`with a sheet having a low oxygen permeability (Mode IV).
`In the Mode III, the container for sealing an aqueous
`solution of pranoprofen is subject to no particular limitation
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`as long as it can seal an aqueous solution of pranoprofen, and
`is preferably exemplified by a container formed from a
`material containing an antioxidant, such as those exempli-
`fied for the above-mentioned Mode II, and a container
`having a low oxygen permeability to be mentioned below.
`The deoxygenating agent
`to be used in Mode III is
`exemplified by iron powder, iron oxide, ascorbic acid and
`catechol, with preference given to iron oxide. The deoxy-
`genating agent is preferably packed in a bag etc. made of an
`oxygen-permeable material and put to use.
`The container and the sheet to enclose a container, in
`which an aqueous solution of pranoprofen has been sealed,
`together with a deoxygenating agent according to Mode III,
`are not subject to any particular limitation as long as they
`can enclose both the container, in which an aqueous solution
`of pranoprofen has been sealed, and a deoxygenating agent
`in such a manner that the outside air is shut off from them.
`Examples of the container include plastic containers and
`glass containers, and examples of the sheet include plastic
`sheets and aluminum sheets. The materials for such con-
`
`tainers and sheets may contain an antioxidant, as exempli-
`fied in the above-mentioned Mode II, or may have a low
`oxygen permeability as discussed below. Also, an antioxi-
`dant may be added to an aqueous solution of pranoprofen in
`Mode III.
`
`The container and the sheet having low oxygen
`permeability, which are to be used in Mode IV, are prefer-
`ably made from a material having an oxygen permeability of
`not more than 120 cc/m2-24 hr-atom [20° C.-90% relative
`humidity (RH), thickness of material 25 gm], preferably not
`more than 70 cc/m2-24 hr-atom (20° C.-90% RH, thickness
`of material 25 gm), such as those made from acrylonitrile
`resins [e.g. acrylonitrile styrene (AS) and acrylonitrile buta-
`diene styrene
`and polyethylene terephthalate (PET),
`with particular preference given to those made from PET.
`The solvent to be used to prepare a liquid preparation and
`an aqueous solution of pranoprofen of the present invention
`is exemplified by sterile purified water, in particular, dis-
`tilled water for injection. The concentration of the active
`ingredient pranoprofen is generally 0.01—2.0 w/v %, pref-
`erably 0.05—1.0 w/v %, which is increased or decreased as
`appropriate according to the object of use.
`The antioxidant to be used for the liquid preparation of
`pranoprofen of the present invention is exemplified by those
`mentioned for Mode I.
`
`invention may
`The liquid preparation of the present
`further contain various additives on demand, such as buffers,
`isotonizing agents, solubilizing agents, preservatives,
`thickeners, chelating agents, pH adjusting agents and aro-
`matic agents.
`Examples of buffer include phosphate buffer (e.g. sodium
`dihydrogenphosphate-disodium hydrogenphosphate and
`potassium dihydrogenphosphate-potassium hydroxide),
`borate buffer (e.g. boric acid-sodium tetraborate), citrate
`buffer (e.g. sodium citrate-sodium hydroxide), tartrate buffer
`(e.g. tartaric acid-sodium tartrate), acetate buffer (e.g. acetic
`acid-sodium acetate), carbonate buffer
`(e.g. sodium
`carbonate-citric acid and sodium carbonate-boric acid) and
`amino acid (e.g. sodium glutamate and e-aminocaproic
`acid).
`When the liquid preparation of pranoprofen is used as an
`eye drop, it is preferable that borate buffer, acetate buffer or
`carbonate buffer be used to decrease irritation.
`
`Examples of isotonizing agent include saccharides such as
`sorbitol, glucose and mannitol, polyhydric alcohols such as
`glycerol and propylene glycol, salts such as sodium chloride
`and sodium tetraborate, and boric acid.
`
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`5,856,345
`
`5
`Examples of solubilizing agent include non-ionic surfac-
`tants such as polyoxyethylenesorbitan monooleate
`(polysorbate 80), polyoxyethylenemonostearate, polyethyl-
`ene glycol and polyoxyethylene hydrogenated castor oil.
`Examples of preservative include quaternary ammonium
`salts such as benzalkonium chloride, benzethonium chloride
`and cetylpyridinium chloride, p-hydroxybenzoates such as
`methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, pro-
`pyl p-hydroxybenzoate and butyl p-hydroxybenzoate, ben-
`zyl alcohol, phenetyl alcohol, sorbic acid and salts thereof,
`thimerosal, chlorobutanol and sodium dehydroacetate.
`Examples of thickener include polyvinylpyrrolidone,
`hydroxyethylcellulose , hydroxypropylcellulose ,
`methylcellulose, hydroxypropylmethylcellulose, carboxym-
`ethylcellulose and salts thereof.
`Examples of chelating agent include disodium edetate and
`citric acid.
`
`include hydrochloric
`Examples of pH-adjusting agent
`acid, citric acid, phosphoric acid, acetic acid, tartaric acid,
`sodium hydroxide, potassium hydroxide, sodium carbonate
`and sodium hydrogencarbonate.
`Examples of aromatic agent include 1-menthol, borneol,
`camphor (e.g. dl-camphor) and eucalyptus oil.
`The liquid preparation of the present invention is used as
`an eye drop, collunarium and the like. When used as an eye
`drop, its pH is generally adjusted to about 6.0-8.5, prefer-
`ably about 7.0-8.0, and when used as a collunarium, its pH
`is generally adjusted to about 6.0-8.5, preferably about
`7.0-8.0.
`
`While the method for producing the liquid preparation of
`the present invention varies depending on the kind of liquid
`preparation, a known method for each liquid preparation can
`be used.
`
`The dose of the liquid preparation of the present
`invention, when used, for example, as an eye drop, is an
`amount sufficient
`to effectively resolve ophthalmic
`inflammation, and varies depending on symptoms and the
`kind of inflammation. The dose is generally 5.0-1,000
`yg/administration, preferably 25-500 yg/administration,
`which is administered 2 to 5 times a day as appropriate.
`The present invention is described in more detail in the
`following by referring to Experimental Examples and
`Examples.
`
`6
`profen in the containers was determined with time by high
`performance liquid chromatography. The results are shown
`in Table 1.
`
`TABLE 1
`
`Residual content of pranoprofen %
`
`Container
`
`PP (control)
`PP—05
`PP—01
`PP—005
`PET
`
`On prepa-
`ration
`
`36
`24
`12
`6
`3
`months months months months months
`
`100.0
`100.0
`100.0
`100.0
`100.0
`
`95.6
`100.4
`100.4
`100.4
`99.5
`
`93.9
`99.3
`98.3
`98.3
`101.0
`
`—
`99.0
`98.1
`97.0
`100.3
`
`81.9
`98.5
`95.4
`93.2
`100.8
`
`78.5
`100.2
`96.0
`93.3
`99.4
`
`PP: polypropylene container without BHT oxygen permeability, 3800 cc/m2
`- 24 hr - atom (20° C.
`- 90% RH, 25 ,um)
`PP-05: polypropylene container containing 0.5% BHT
`PP-01: polypropylene container containing 0.1% BHT
`PP-005: polypropylene container containing 0.05% BHT
`PET: polyethylene terephthalate container without BHT oxygen permeability,
`63 cc/m2 - 24 hr - atom (20° C.
`- 90% RH, 25 ,um)
`
`As is evident from Table 1, superior suppression of
`decomposition of pranoprofen was achieved by preserving
`pranoprofen in the containers (PP) formed from a material
`containing BHT and in the container (PET) having a low
`oxygen permeability.
`
`EXPERIMENTAL EXAMPLE 2
`
`[Stability Test—No. 2]
`BHT or sodium thiosulfate was added to a basic formu-
`
`lation solution [pranoprofen, 0.1 w/v %; boric acid, 1.6 w/v
`%; sodium tetraborate, appropriate amount; disodium
`edetate, 0.01 w/v %; benzalkonium chloride, 0.005 w/v %;
`polysorbate 80, 0.1 w/v %; sterile purified water, appropriate
`amount], and the mixture was filled in 5 ml polypropylene
`containers. The containers were left standing in the dark at
`room temperature for 39 months. The residual content of
`pranoprofen in the containers was determined by high
`performance liquid chromatography. The results are shown
`in Table 2.
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`TABLE 2
`
`Compound
`
`45
`
`Concentration
`
`Residual content of pranoprofen %
`
`EXPERIMENTAL EXAMPLE 1
`
`[Stability Test—No. 1]
`
`A solution of 0.1 w/v % pranoprofen [boric acid, 1.6 w/v
`%; sodium tetraborate, appropriate amount; disodium
`edetate, 0.01 w/v %; benzalkonium chloride, 0.005 w/v %;
`polysorbate 80, 0.1 w/v %; sterile purified water, appropriate
`amount] was filled in 5 ml polypropylene containers manu-
`factured by adding BHT to 0.05, 0.1 or 0.5 w/v % [oxygen
`permeability of 25 pm thick test sample, 3,800 cc/m2~24
`hr-atom (20° C.-90% RH); Gas Permeation Test Method of
`Plastic Film and Sheet of Japanese Industrial Standards, the
`equal pressure method [Japanese Standards Association, JIS
`Handbook, p 400, Tokyo (1991)]] and 15 ml polyethylene
`terephthalate containers [oxygen permeability of 25 gm
`thick test samples, 63 cc/m2~24 hr~atom (20° C.~90% RH);
`Gas Permeation Test Method of Plastic Film and Sheet of
`
`Japanese Industrial Standards, the equal pressure method
`[Japanese Standards Association, JIS Handbook, p 400,
`Tokyo (1991)]], and left standing in the dark at room
`temperature for 36 months. The residual content of prano-
`
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`added
`Control
`(not added)
`BHT
`"
`sodium
`thiosulfate
`
`(%)
`
`0
`
`0.0004
`0.0001
`0.1
`
`On preparation
`100.0
`
`after 39 months
`77.0
`
`100.0
`100.0
`100.0
`
`99.6
`94.7
`93.0
`
`As is evident from Table 2, superior suppression of
`decomposition of pranoprofen was achieved by the addition
`of respective antioxidants.
`EXPERIMENTAL EXAMPLE 3
`
`[Stability Test—No. 3]
`
`BHT, BHA, L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-
`tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-
`6-yl-hydrogen phosphate] potassium salt
`(EPC-K1),
`methionine, tryptophan or histidine was added to a basic
`formulation solution [pranoprofen, 0.05 w/v %; boric acid,
`1.6 w/v %; sodium tetraborate, appropriate amount; diso-
`dium edetate, 0.01 w/v %; benzalkonium chloride, 0.005
`
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`5,856,345
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`7
`W/V %; polysorbate 80, 0.1 W/v %; sterile purified Water,
`appropriate amount], and the mixture was filled in colorless
`15 ml polyethylene terephthalate containers. The containers
`were left standing under a fluorescent lamp (20
`When
`the total irradiation reached 100,000 lux~hr,
`the residual
`content of pranoprofen in the containers was determined by
`high performance liquid chromatography. The results are
`shown in Table 3.
`
`TABLE 3
`
`Resicual content of pranoprofen %
`
`Concentration
`(%)
`0
`
`On
`preoaration
`00.0
`
`after irradiation of
`100,000 lux - hr
`52.5
`
`0.005
`0.002
`0.0002
`0.002
`0.05
`0.01
`0.001
`0.24
`0.06
`0.13
`
`00.0
`00.0
`00.0
`00.0
`00.0
`00.0
`00.0
`00.0
`00.0
`00.0
`
`98.0
`96.6
`70.8
`92.8
`79.1
`70.5
`68.2
`95.2
`96.9
`75.9
`
`Compound
`added
`Control
`(not added)
`BHT
`"
`"
`BHA
`EPC-K1
`"
`"
`methionine
`tryptophan
`histidine
`
`As is evident from Table 3, the decomposition of prano-
`profen caused by the exposure to the light was markedly
`suppressed by the addition of respective antioxidants.
`EXPERIMENTAL EXAMPLE 4
`
`[Stability Test—No. 4]
`
`A solution of 0.1 W/v % pranoprofen [boric acid, 1.6 W/v
`%; sodium tetraborate, appropriate amount; disodium
`edetate, 0.01 W/v %; benzalkonium chloride, 0.005 W/V %;
`polysorbate 80, 0.1 W/v %; sterile purified Water, appropriate
`amount] was filled in 5 ml polypropylene containers and the
`containers were tightly sealed. The containers were enclosed
`together with iron oxide (Ageless Z-30, manufactured by
`Mitsubishi Gas Chemical Company, Inc.) as a deoxygenat-
`ing agent, with the use of a multi-layer
`film of
`polypropylene/poly(vinyl alcohol)/polyethylene and left
`standing at room temperature for 30 months. The residual
`content of pranoprofen in the containers was determined
`with time by high performance liquid chromatography. The
`results are shown in Table 4.
`
`TABLE 4
`
`Residual content of pranoprofen %
`30
`On
`2
`6
`9
`preparation months months months months
`100.0
`95.1
`89.4
`92.0
`80.3
`100.0
`98.1
`97.6
`97.2
`101.0
`
`100.0
`
`95.0
`
`93.4
`
`89.5
`
`88.5
`
`Enclosing
`Unenclosed
`Film—enclosed
`(deoxygenator)
`Film—enclosed
`(N2 substitution)
`
`Containers used: polypropylene containers Without BHT
`Film: multi-layer film of polypropylene/poly(vinyl alcohol)
`/polyethylene
`deoxygenating agent: iron oxide (Ageless Z-30, manufac-
`tured by Mitsubishi Gas Chemical Company, Inc.)
`As is evident from Table 4, marked suppression of decom-
`position of pranoprofen was achieved by sealing a container,
`in which an aqueous solution of pranoprofen had been
`
`5
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`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`sealed, together with a deoxygenating agent.
`
`Example 1 [Eye drop]
`
`Pranoprofen
`(1)
`(2) Disodium hydrogenphosphate
`(3)
`Sodium dihydrogenphosphate
`(4)
`Polyoxyethylene hydrogenated castor oil 60
`(5)
`Poly(vinyl alcohol)
`(6)
`Sodium chloride
`(7)
`Benzethonium chloride
`(8)
`BHT
`(9)
`Sodium hydroxide
`(10)
`Sterile purified Water
`
`0.2 g
`0.5 g
`0.1 g
`0.1 g
`0.2 g
`0.8 g
`0.007 g
`0.01 g
`appropriate amount
`appropriate amount
`
`Total
`
`100 ml
`
`(5) was added to about 70 ml of (10) and the mixture was
`stirred with heating to about 70° C. for dissolution. (4) and
`(8) were added to this solution and the mixture was admixed
`until
`it became a uniform dispersion. The mixture was
`cooled to room temperature. (1), (2), (3), (6) and (7) were
`dissolved in this solution and pH was adjusted to 7.2 with
`(9). (10) was added to make the total amount 100 ml and the
`mixture was filled in a 5 ml PE container for an eye drop.
`
`Example 2 [Eye drop]
`
`(1)
`(2)
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`
`Pranoprofen
`Sodium chloride
`Polysorbate 80
`Polyethylene glycol
`Citric acid
`Benzalknoium chloride
`Sodium thiosulfate
`Sodium carbonate
`Sterile purified Water
`Total
`
`0.4 g
`0.5 g
`0.15 g
`0.5 g
`0.2 g
`0.009 g
`0.01 g
`appropriate amount
`appropriate amount
`100 ml
`
`(1), (2), (3), (4), (5), (6) and (7) were dissolved in about
`70 ml of (9) and pH was adjusted to 8.0 with
`(9) was
`added to make the total amount 100 ml and the mixture was
`
`filled in a 5 ml PP container for an eye drop.
`
`Example 3 [Eye drop]
`
`(1)
`(2)
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`
`Pranoprofen
`Potassium dihydrogenphosphate
`Cone. glycerol
`Potassium hydroxide
`Disodium edetate
`EPC—K1
`Methyl p-hydroxybenzoate
`Propyl p-hydroxybenzoate
`Sterile purified Water
`
`Total
`
`0.1 g
`0.3 g
`2.6 g
`appropriate amount
`0.01 g
`0.05 g
`0.026 g
`0.014 g
`appropriate amount
`100 ml
`
`About 80 ml of (9) was heated to about 90° C. and (7) and
`(8) were dissolved. The mixture was cooled to room tem-
`perature. An appropriate amount of (4) was dissolved and
`then, (1), (2), (3), (5) and (6) were dissolved. Its pH was
`adjusted to 6.5 with
`(9) was added to make the total
`amount 100 ml and the mixture was filled in a 10 ml
`
`polycarbonate container for an eye drop.
`
`Page 5 of 7
`
`Page 5 of 7
`
`

`
`5,856,345
`
`10
`-continued
`
`Example 4 [Eye drop]
`
`(1)
`(2)
`(3)
`(4)
`(5)
`(6)
`(7)
`
`Pranoprofen
`Boric acid
`Sodium tetraborate
`Disodium edetate
`Polysorbate 80
`Benzalkonium chloride
`Sterile purified water
`Total
`
`0.1 g
`1.6 g
`appropriate amount
`0.01 g
`0.15 g
`0.007 g
`appropriate amount
`100 ml
`
`10
`
`(1), (2), (3), (4), (5) and (6) were dissolved in about 80 ml
`of (7), and pH was adjusted to 7.0 with
`(7) was added
`to make the total amount 100 ml and the mixture was filled
`
`15
`
`in a 5 ml PP container for an eye drop, which comprised
`0.5% BHT.
`
`Example 5 [Eye drop]
`
`(1)
`(2)
`(3)
`(4)
`(5)
`(6)
`(7)
`
`Pranoprofen
`Boric acid
`Sodium tetraborate
`Disodium edetate
`Polysorbate 80
`Benzalkonium chloride
`Sterile purified water
`Total
`
`0.1 g
`1.6 g
`appropriate amount
`0.01 g
`0.15 g
`0.007 g
`appropriate amount
`100 ml
`
`(1), (2), (3), (4), (5) and (6) were dissolved in about 80 ml
`of (7), and pH was adjusted to 7.0 with
`(7) was added
`to make the total amount 100 ml and the mixture was filled
`
`in a 5 ml PP container for an eye drop. The container and
`iron oxide (Ageless Z-30; manufactured by Mitsubishi Gas
`Chemical Company, Inc.) were enclosed with a multi-layer
`film of polypropylene/poly(vinyl alcohol)/polyethylene.
`
`Example 6 [Eye drop]
`
`(1)
`(2)
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`
`Pranoprofen
`Boric acid
`Sodium tetraborate
`Disodium edetate
`Benzalkonium chloride
`1-menthol
`d1-camphor
`Polysorbate 80
`Sterile purified water
`Total
`
`0.05 g
`1.6 g
`appropriate amount
`0.01 g
`0.005 g
`0.002 g
`0.0005 g
`0.1 g
`appropriate amount
`100 ml
`
`(1), (2), (3), (4) and (5) were dissolved in about 70 ml of
`(9). (6), (7) and (8) were admixed and uniformly dispersed
`in about 20 ml of (9) heated to about 60° C. This dispersion
`was added to the above-mentioned solution. The pH of the
`mixture was adjusted to 7.5 with (3) and (9) was added to
`make the total amount 100 ml. The mixture was filled in a
`
`15 ml PET container for an eye drop and enclosed to avoid
`light.
`
`Example 7 [Collunarium]
`
`(1)
`(2)
`(3)
`(4)
`(5)
`
`Pranoprofen
`Sodium citrate
`Polysorbate 80
`Glycerol
`Benzethonium chloride
`
`0.4 g
`0.2 g
`0.1 g
`2.6 g
`0.007 g
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Example 7 [Collunarium]
`
`(6)
`(7)
`(8)
`
`Methionine
`Sodium hydroxide
`Sterile purified water
`Total
`
`0.24 g
`appropriate amount
`appropriate amount
`100 ml
`
`(1), (2), (3), (4), (5) and (6) were dissolved in about 70 ml
`of (8), and pH was adjusted to 7.5 with
`(8) was added
`to make the total amount 100 ml and the mixture was filled
`in a 5 ml PP container for a collunarium.
`
`Example 8 [Collunarium]
`
`Pranoprofen
`(1)
`Boric acid
`(2)
`Sodium tetraborate
`(3)
`Disodium edetate
`(4)
`Polysorbate 80
`(5)
`Benzalkonium chloride
`(6)
`(7) Sodium hydroxide
`(8) Sterile purified water
`Total
`
`1.0 g
`1.2 g
`0.8 g
`0.01 g
`0.15 g
`0.007 g
`appropriate amount
`appropriate amount
`100 ml
`
`(1), (2), (3), (4), (5) and (6) were dissolved in about 80 ml
`of (8), and pH was adjusted to 7.0 with
`(8) was added
`to make the total amount 100 ml and the mixture was filled
`in a 8 ml PE container for a collunarium. The container and
`
`iron oxide (Ageless Z-30; manufactured by Mitsubishi Gas
`Chemical Company, Inc.) were enclosed with a multi-layer
`film of polypropylene/poly(vinyl alcohol)/polyethylene.
`According to the present invention, the decomposition of
`the active ingredient pranoprofen is remarkably suppressed.
`In particular, pranoprofen becomes stable to light,
`thus
`permitting long-term preservation of an aqueous solution
`(preparation) of pranoprofen.
`What is claimed is:
`1. A method for stabilizing pranoprofen, comprising add-
`ing an antioxidant which is at least one member selected
`from the group consisting of an alkyl phenol, a benzopyran
`derivative, sodium thiosulfate and an amino acid,
`to an
`aqueous solution of pranoprofen.
`2. The method for stabilizing pranoprofen according to
`claim 1, wherein the weight ratio of the antioxidant
`to
`pranoprofen is 0.0002—5.0:1.
`3. The method for stabilizing pranoprofen according to
`claim 1, wherein the alkyl phenol is at least one member
`selected from the group consisting of dibutylhydroxytoluene
`and butylhydroxyanisole.
`4. The method for stabilizing pranoprofen according to
`claim 1, wherein the benzopyran derivative is at least one
`member selected from the group consisting of L-ascorbic
`acid 2-(3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-
`trimethyltridecyl)-2H-1 -benzopyran-6-yl-
`hydrogenphosphate) and a salt thereof.
`5. The method for stabilizing pranoprofen according to
`claim 1, wherein the amino acid is at least one member
`selected from the group consisting of methionine,
`tryp-
`tophan and histidine.
`6. The method for stabilizing pranoprofen according to
`claim 1, wherein the aqueous solution of pranoprofen is an
`eye drop or a collunarium.
`7. A stable liquid preparation of pranoprofen comprising
`pranoprofen and an antioxidant which is at least one member
`selected from the group consisting of an alkyl phenol, a
`benzopyran derivative, sodium thiosulfate and an amino
`acid.
`
`Page 6 of 7
`
`Page 6 of 7
`
`

`
`5,856,345
`
`11
`8. The stable liquid preparation of pranoprofen of claim 7,
`wherein the alkyl phenol is at least one member selected
`from the group consisting of dibutylhydroxytoluene and
`butylhydroxyanisole
`9. The Stable liquid pr€pafati0I1 Of praI10pr0f€I1 Of Claim 7,
`wherein the benzopyran derivative is at least one member
`selected from the group consisting of L-ascorbic acid 2-(3,
`4'dihydr0'2’5’7’8'tetramethy1'2'(4’8’12'mmethy1trideCy1)'
`2H-1-benzopyran-6-yl-hydrogenphosphate) and a salt
`thereof.
`
`5
`
`12
`10. The stable liquid preparation of pranoprofen of claim
`7» wherein the amine. aeid is at leasl 0¥1e member Selected
`Ehogldlhe group Conslstmg of methlomne’ tryptophan and
`1S111.1"Il1“l:1ie stable liquid preparation of pranoprofen of claim
`7, wherein the weight ratio of the antioxidant to pranoprofen
`is 00002-5011.
`.
`.
`.
`.
`.
`.
`12' The Stable hquld preparatlon of Clalm 7> Whlch 15 an
`eyflglrgllhe stable liquid preparation of claim 7 which is a
`10 Couuilarium.
`’
`*
`*
`*
`*
`*
`
`Page 7 of 7
`
`Page 7 of 7