`Doi et al.
`
`[54]
`
`[75]
`
`[73]
`
`METHOD FOR STABILIZING
`PRANOPROFEN AND STABLE LIQUID
`PREPARATION OF PRANOPROFEN
`
`Inventors: Koji Doi, Kobe; Hisako Sawa, Otsu;
`Yoshie Ozaki, Kobe; Yoshiyuki
`Kimura, Kakogawa, all of Japan
`
`Assignees: Senju Pharmaceutical Co., Ltd.;
`Yoshitomi Pharmaceutical Industries,
`Ltd., both of Osaka, Japan
`
`[21]
`
`Appl. No.: 779,604
`
`[22]
`
`Filed:
`
`Jan. 7, 1997
`
`Related U.S. Application Data
`
`[62]
`
`[30]
`
`Division of Ser. No. 404,102, Mar. 14, 1995.
`
`Foreign Application Priority Data
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005856345A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,856,345
`Jan. 5, 1999
`
`FOREIGN PATENT DOCUMENTS
`
`0 258 865
`0 471 084 A1
`2 839 752
`2 007 091
`86/06629
`92/20376
`
`3/1988
`2/1992
`5/1979
`5/1979
`11/1986
`11/1992
`
`European Pat. Off ..
`European Pat. Off ..
`Germany.
`United Kingdom .
`WIPO.
`WIPO.
`
`OTHER PUBLICATIONS
`
`Patent Abstracts of Japan, unexamined applications, C field,
`vol. 10, No. 318, Oct. 29, 1986, p. 140 C 381 of JP-A-61
`130 222.
`Chemical Abstracts, vol. 118, 1993 No. 118:66887f
`(Abstract of Reference AD).
`Chemical Abstracts, vol. 105, 1986, No. 105: 158837z.
`
`Primary Examiner-Jose G. Dees
`Assistant Examiner-Michael A Williamson
`Attorney, Agent, or Firm-Wenderoth, Lind & Ponack,
`L.L.P.
`
`Mar. 15, 1994
`
`[JP]
`
`Japan .................................... 6-044184
`
`[57]
`
`ABSTRACT
`
`[51]
`[52]
`
`[58]
`
`[56]
`
`Int. Cl.6
`..................................................... A61K 31/44
`U.S. Cl. .......................... 514/350; 514/912; 514/913;
`514/914; 514/915
`Field of Search ..................................... 514/350, 912,
`514/913, 914, 915
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,525,348
`4,607,038
`5,110,493
`5,414,011
`5,693,337
`
`6/1985 Arizono et a!. ........................... 424/81
`8/1986 Ogata et a!.
`... ... ... ... ... .... ... ... ... 514/291
`5/1992 Cherng-Chyi eta!. ................. 514/413
`5/1995 Fu eta!. .................................. 514/413
`12/1997 Suzuki et a!. ........................... 424/450
`
`A method for stabilizing pranoprofen, comprising 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, and a
`stable aqueous preparation of pranoprofen, comprising pra(cid:173)
`noprofen and an antioxidant. According to the present
`invention, the decomposition of pranoprofen in an aqueous
`solution of pranoprofen is remarkably suppressed. In
`particular, pranoprofen becomes stable to light, thus permit(cid:173)
`ting long -term preservation of an aqueous solution, specifi(cid:173)
`cally a liquid preparation, of pranoprofen.
`
`13 Claims, No Drawings
`
`Page 1 of 7
`
`SENJU EXHIBIT 2030
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`5,856,345
`
`1
`METHOD FOR STABILIZING
`PRANOPROFEN AND STABLE LIQUID
`PREPARATION OF PRANOPROFEN
`
`This is a divisional application of Ser. No. 08/404,102, 5
`filed Mar. 14, 1995.
`
`20
`
`2
`(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-te trame thyl-2-( 4,8,12-
`trimethy 1 tridecy 1 )- 2H -1-benzopyran -6-y 1-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.
`25 (13) A method for stabilizing pranoprofen, comprising plac(cid:173)
`ing an aqueous solution of pranoprofen under the condi(cid:173)
`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(cid:173)
`ing the solution with a sheet having a low oxygen per(cid:173)
`meability.
`(16) A stabilizing method according to (1), wherein the
`aqueous solution of pranoprofen is an eye drop or a
`collunarium.
`40 (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.
`45 (19) The liquid preparation of (18), wherein the antioxidant
`is at least one compound selected from the group con(cid:173)
`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- te trame thy 1-2-( 4,8,12- trime thy ltridecy l)-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(cid:173)
`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.
`
`15
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to a method for stabilizing 10
`pranoprofen having anti-inflammatory activity, in an aque(cid:173)
`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 a-methyl-5H-[1]
`benzopyrano[2,3-b ]pyridine-7 -acetic acid exhibits promi(cid:173)
`nent anti-inflammatory action, analgesic action and anti(cid:173)
`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 30
`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.
`
`35
`
`SUMMARY OF THE INVENTION
`According to the present invention, it has now been found
`that decomposition of pranoprofen can be markedly sup(cid:173)
`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 invention and preferable modes
`thereof are as follows.
`(1) A method for stabilizing pranoprofen, comprising plac(cid:173)
`ing an aqueous solution of pranoprofen in coexistence 50
`with an antioxidant.
`(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), 55
`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- 60
`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.
`
`65
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The first mode of the stabilizing method of the present
`invention is placing an aqueous solution of pranoprofen in
`
`Page 2 of 7
`
`
`
`5,856,345
`
`3
`coexistence with an antioxidant, which is realized by, for
`example, (i) 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(cid:173)
`ing an antioxidant (Mode II). The Modes I and II may be 5
`used in combination.
`The antioxidant to be used in Mode I includes, for
`example, alkylphenols, benzopyran derivatives, sodium
`thiosulfate and amino acids.
`Examples of alkylphenol include dibutylhydroxytoluene 10
`(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 15
`phosphate] and salts thereof, with preference given to
`L-ascorbic acid 2-[3,4-dihydro-2,5,7 ,8-tetramethyl-2-( 4,8,
`12-trimethy ltridecy 1)-2H -1-benzopyran -6-y 1-hydrogen
`phosphate] potassium salt (EPC-K1).
`Amino acid is, for example, methionine, tryptophan or 20
`histidine, with preference given to methionine and tryp(cid:173)
`tophan.
`When an antioxidant is added to an aqueous solution of
`pranoprofen according to Mode I, the antioxidant is gener(cid:173)
`ally added at a ratio to pranoprofen of0.0002-5.0 by weight, 25
`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(cid:173)
`ally a plastic container such as the one composed of poly(cid:173)
`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(cid:173)
`lphenol.
`Examples of alkylphenol include dibutylhydroxytoluene
`(BHT), butylhydroxyanisole (BHA), n-propyl gallate,
`steary 1 ~ -(3,5 -di-t-buty 1-4-hydroxypheny !)propionate,
`te tr akis[ 3 -(3 ,5 -di-te rt- bu tyl-4- hydroxyphe nyl)
`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- bu ty 1-4-h ydroxybenzy 1)-2,4,6- trime thy 1]
`benzene and 3,9-bis[2-(3-(3- tert-buty 1-4-hydroxy-5-
`methylphenyl)propionyloxy)-1 ,1-dimethy lethyl ]-2,4,8,10-
`tetraoxaspiro[5.5]undecane, with preference given to BHT
`and BHA.
`Examples of alkyldiphenol include 2,2'-methylenebis(4-
`methy 1-6-tert -buty lphenol), 4,4'-buty lidenebis(2-tert -buty 1-
`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
`
`4
`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(cid:173)
`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(cid:173)
`tainers and sheets may contain an antioxidant, as exempli(cid:173)
`fied in the above-mentioned Mode II, or may have a low
`oxygen permeability as discussed below. Also, an antioxi(cid:173)
`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(cid:173)
`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 ,urn], preferably not
`30 more than 70 cc/m2 ·24 hr·atom (20° C. ·90% RH, thickness
`of material 25 ,urn), such as those made from acrylonitrile
`resins [e.g. acrylonitrile styrene (AS) and acrylonitrile buta(cid:173)
`diene styrene (ABS)] 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(cid:173)
`tilled water for injection. The concentration of the active
`ingredient pranoprofen is generally 0.01-2.0 w/v %, pref(cid:173)
`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
`45 mentioned for Mode I.
`The liquid preparation of the present invention may
`further contain various additives on demand, such as buffers,
`isotonizing agents, solubilizing agents, preservatives,
`thickeners, chelating agents, pH adjusting agents and aro-
`50 matic agents.
`Examples of buffer include phosphate buffer (e.g. sodium
`dihydrogenphosphate-disodium hydrogenphosphate and
`po tassi urn dih ydro ge np hasp hate-potassium hydroxide),
`borate buffer (e.g. boric acid-sodium tetraborate ), citrate
`55 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
`60 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
`65 sorbitol, glucose and mannitol, polyhydric alcohols such as
`glycerol and propylene glycol, salts such as sodium chloride
`and sodium tetraborate, and boric acid.
`
`35
`
`40
`
`Page 3 of 7
`
`
`
`5
`Examples of solubilizing agent include non-ionic surfac(cid:173)
`tants such as polyoxyethylenesorbitan monooleate
`(polysorbate 80), polyoxyethylenemonostearate, polyethyl(cid:173)
`ene glycol and polyoxyethylene hydrogenated castor oil.
`Examples of preservative include quaternary ammonium 5
`salts such as benzalkonium chloride, benzethonium chloride
`and cetylpyridinium chloride, p-hydroxybenzoates such as
`methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, pro(cid:173)
`pyl p-hydroxybenzoate and butyl p-hydroxybenzoate, ben(cid:173)
`zyl alcohol, phenetyl alcohol, sorbic acid and salts thereof, 10
`thimerosal, chlorobutanol and sodium dehydroacetate.
`Examples of thickener include polyvinylpyrrolidone,
`h ydroxye thy lcell ulo se, hydro xypropy lee 11 ulose,
`methylcellulose, hydroxypropylmethylcellulose, carboxym-
`ethylcellulose and salts thereof.
`Examples of chelating agent include disodium edetate and
`citric acid.
`Examples of pH-adjusting agent include hydrochloric
`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(cid:173)
`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
`,ug/administration, preferably 25-500 ,ug/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.
`
`5,856,345
`
`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 12rano12rofen (%)
`
`Container
`
`PP (control)
`PP-05
`PP-01
`PP-005
`PET
`
`On prepa-
`ration
`
`12
`36
`24
`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
`
`15
`
`PP: polypropylene container without BHr oxygen permeability, 3800 cc/m2
`· 24 hr · atom (20° C. · 90% RH, 25 .urn)
`PP-05: polypropylene container containing 0.5% BHr
`PP-01: polypropylene container containing 0.1% BHr
`PP-005: polypropylene container containing 0.05% BHr
`PET: polyethylene terephthalate container without BHr oxygen permeability,
`20 63 cc/m2
`· 24 hr · atom (20° C. · 90% RH, 25 .urn)
`
`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
`25 containing BHT and in the container (PET) having a low
`oxygen permeability.
`
`30
`
`BHT or sodium thiosulfate was added to a basic formu(cid:173)
`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 %;
`35 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
`40 performance liquid chromatography. The results are shown
`in Table 2.
`
`EXPERIMENTAL EXAMPLE 2
`
`[Stability Test-No. 2]
`
`TABLE 2
`
`Compound
`
`Concentration
`
`Residual content of 12rano12rofen (%)
`
`added
`
`Control
`(not added)
`BHr
`
`sodium
`thiosulfate
`
`(%)
`
`0
`
`0.0004
`0.0001
`0.1
`
`On preparation
`
`after 39 months
`
`100.0
`
`100.0
`100.0
`100.0
`
`77.0
`
`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
`
`45
`
`EXPERIMENTAL EXAMPLE 1
`
`[Stability Test-No. 1]
`
`50
`
`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(cid:173)
`factured by adding BHT to 0.05, 0.1 or 0.5 w/v% [oxygen 55
`permeability of 25 ,urn 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 60
`terephthalate containers [oxygen permeability of 25 ,urn
`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-
`
`[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
`65 formulation solution [pranoprofen, 0.05 w/v %; boric acid,
`1.6 w/v %; sodium tetraborate, appropriate amount; diso(cid:173)
`dium edetate, 0.01 w/v %; benzalkonium chloride, 0.005
`
`Page 4 of 7
`
`
`
`5,856,345
`
`8
`sealed, together with a deoxygenating agent.
`
`Example 1 [Eye drop]
`
`(1)
`Pranoprofen
`(2) Disodium hydrogenphosphate
`(3)
`Sodium dihydrogenphosphate
`( 4)
`Polyoxyethylene hydrogenated castor oil 60
`(5)
`Poly(vinyl alcohol)
`( 6)
`Sodium chloride
`(7) Benzethonium chloride
`(8) BHr
`(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.
`
`30
`
`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
`
`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
`
`Total
`
`100 ml
`
`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 W). When
`the total irradiation reached 100,000 lux·hr, the residual 5
`content of pranoprofen in the containers was determined by
`high performance liquid chromatography. The results are
`shown in Table 3.
`
`TABLE 3
`
`Residual content of pranoprofen (%)
`
`Concentration
`(%)
`
`On
`preparation
`
`after irradiation of
`100,000 lux · hr
`
`0
`
`0.005
`0.002
`0.0002
`0.002
`0.05
`0.01
`0.001
`0.24
`0.06
`0.13
`
`100.0
`
`100.0
`100.0
`100.0
`100.0
`100.0
`100.0
`100.0
`100.0
`100.0
`100.0
`
`52.5
`
`98.0
`96.6
`70.8
`92.8
`79.1
`70.5
`68.2
`95.2
`96.9
`75.9
`
`10
`
`15
`
`20
`
`25
`
`Compound
`added
`
`Control
`(not added)
`BHr
`
`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 35
`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 40
`Mitsubishi Gas Chemical Company, Inc.) as a deoxygenat(cid:173)
`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.
`
`(1), (2), (3), ( 4), (5), (6) and (7) were dissolved in about
`70 ml of (9) and pH was adjusted to 8.0 with (8). (9) was
`added to make the total amount 100 ml and the mixture was
`45 filled in a 5 ml PP container for an eye drop.
`
`TABLE 4
`
`Residual content of pranoprofen (%)
`
`50
`
`30
`9
`2
`On
`preparation months months months months
`
`100.0
`100.0
`
`95.1
`98.1
`
`89.4
`97.6
`
`92.0
`97.2
`
`80.3
`101.0
`
`55
`
`100.0
`
`95.0
`
`93.4
`
`89.5
`
`88.5
`
`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
`
`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
`
`Total
`
`100 ml
`
`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(cid:173)
`tured by Mitsubishi Gas Chemical Company, Inc.)
`As is evident from Table 4, marked suppression of decom- 65
`position of pranoprofen was achieved by sealing a container,
`in which an aqueous solution of pranoprofen had been
`
`60
`
`About 80 ml of (9) was heated to about 90° C. and (7) and
`(8) were dissolved. The mixture was cooled to room tem(cid:173)
`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 (4). (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
`
`
`
`9
`
`5,856,345
`
`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
`
`0.1 g
`1.6 g
`appropriate amount
`0.01 g
`0.15 g
`0.007 g
`appropriate amount
`
`Total
`
`100 ml
`
`5
`
`10
`
`(1), (2), (3), (4), (5) and (6) were dissolved in about 80 ml
`of (7), and pH was adjusted to 7.0 with (3). (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.
`
`10
`-continued
`
`Example 7 [Collunarium]
`
`(6)
`(7)
`(8)
`
`Methionine
`Sodium hydroxide
`Sterile purified water
`
`0.24 g
`appropriate amount
`appropriate amount
`
`Total
`
`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 (7). (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]
`
`(1)
`Pranoprofen
`(2)
`Boric acid
`(3)
`Sodium tetraborate
`(4)
`Disodium edetate
`(5)
`Polysorbate 80
`(6)
`Benzalkonium chloride
`(7) Sodium hydroxide
`(8) Sterile purified water
`
`1.0 g
`1.2 g
`0.8 g
`0.01 g
`0.15 g
`0.007 g
`appropriate amount
`appropriate amount
`
`Total
`
`100 ml
`
`20
`
`25
`
`(1), (2), (3), (4), (5) and (6) were dissolved in about 80 ml
`of (8), and pH was adjusted to 7.0 with (7). (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
`30 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.
`35 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-
`40 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- te tramethy 1-2-( 4,8,12-
`t rime thy lt ride c y 1)- 2 H- 1 -benz o p y ran- 6- y 1-
`ss 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(cid:173)
`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.
`
`45
`
`50
`
`60
`
`65
`
`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
`
`0.1 g
`1.6 g
`appropriate amount
`0.01 g
`0.15 g
`0.007 g
`appropriate amount
`
`Total
`
`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 (3). (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
`
`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
`
`Total
`
`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. Th