JPH07304670A - Method for stabilizing pranoprofen and stable aqueous pranoprofen solution - Google Patents

Abstract

(57) [Summary] [Structure] Planoprofen is prepared by coexisting an aqueous solution of pranoprofen with an antioxidant or by placing the aqueous solution of pranoprofen under conditions in which oxygen supply to the aqueous solution of pranoprofen is suppressed. A method for stabilizing prophen, and a stable aqueous pranoprofen formulation comprising pranoprofen and an antioxidant. [Effects] In the aqueous solution of pranoprofen, the decomposition of pranoprofen is remarkably suppressed, and it becomes particularly stable to light, which enables long-term storage of the aqueous solution of pranoprofen, especially the aqueous solution of pranoprofen.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for stabilizing pranoprofen in an aqueous solution of pranoprofen having an anti-inflammatory effect, and stabilizing by using pranoprofen as an active ingredient and an antioxidant. Relates to an aqueous solution of pranoprofen.

[0002]

BACKGROUND OF THE INVENTION Planoprofen, chemical name α-methyl-
5H- [1] benzopyrano [2,3-b] pyridine-7
-Acetic acid is a non-steroidal anti-inflammatory drug that has significant anti-inflammatory, analgesic and antipyretic properties and has a wide safety margin, and is commercially available under the trade name of Niflan (registered trademark). The characteristics and manufacturing method of pranoprofen are described in US Pat. No. 3,9312.
95. In addition, an eye drop containing pranoprofen as an anti-inflammatory active ingredient and boric acid as an isotonicity agent has been proposed as being particularly useful as an eye drop for herpesvirus eye diseases (Japanese Patent Publication No. 2). -16728). However, there is a problem that pranoprofen is unstable (particularly unstable to light) in an aqueous solution state and is gradually decomposed during long-term storage.

[0003]

An object of the present invention is to provide a method for stabilizing pranoprofen in an aqueous solution of pranoprofen. Another object of the present invention is to provide an aqueous solution of pranoprofen in which decomposition of pranoprofen is suppressed.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that the aqueous solution of pranoprofen is allowed to coexist with an antioxidant to decompose pranoprofen. Have been found to be significantly improved. Further, the present inventors have found that the decomposition of pranoprofen is remarkably improved by subjecting the aqueous solution of pranoprofen to conditions in which oxygen supply is suppressed.

That is, the gist of the present invention and its preferred embodiments are as follows. (1) A method for stabilizing pranoprofen, which comprises placing an aqueous solution of pranoprofen in the presence of an antioxidant. (2) The method for stabilizing pranoprofen according to (1), which comprises adding an antioxidant to the aqueous solution of pranoprofen. (3) The blending ratio of pranoprofen and the antioxidant is such that pranoprofen: antioxidant = 1: 0.0002 to 5.0.
(2) The method for stabilizing pranoprofen according to (2), which is (weight ratio). (4) It is characterized in that the aqueous solution of pranoprofen is enclosed in a container molded from a material containing an antioxidant.
(1) The method for stabilizing pranoprofen as described above. (5) The method for stabilizing pranoprofen according to (4), wherein the mixing ratio of the container material and the antioxidant is container material: antioxidant = 1: 0.0001 to 0.005 (weight ratio). (6) The method for stabilizing pranoprofen according to (4), wherein the container material is polypropylene. (7) The method for stabilizing pranoprofen according to (2), wherein the antioxidant is at least one compound selected from alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. (8) The method for stabilizing pranoprofen according to (7), wherein the alkylphenol is at least one selected from dibutylhydroxytoluene and butylhydroxyanisole. (9) The benzopyran derivative is 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.
(7) The method for stabilizing pranoprofen as described above. (10) The method for stabilizing pranoprofen according to (7), wherein the amino acid is at least one selected from methionine, tryptophan and histidine. (11) The method for stabilizing pranoprofen according to any one of (4) to (6), wherein the antioxidant is at least one compound selected from alkylphenols. (12) The method for stabilizing pranoprofen according to (11), wherein the alkylphenol is at least one selected from dibutylhydroxytoluene and butylhydroxyanisole. (13) A method for stabilizing pranoprofen, which comprises subjecting the pranoprofen aqueous solution to conditions in which oxygen supply to the pranoprofen aqueous solution is suppressed. (14) The method for stabilizing pranoprofen according to (13), characterized in that the vessel in which the aqueous solution of pranoprofen is enclosed is enclosed in a vessel or a sheet in the presence of an oxygen scavenger. (15) The method for stabilizing pranoprofen according to (13), wherein the aqueous solution of pranoprofen is sealed in a container or sheet having low oxygen permeability. (16) The stabilization method according to (1), wherein the aqueous pranoprofen solution is an eye drop or a nasal drop. (17) The stabilization method according to (13), wherein the aqueous pranoprofen solution is an eye drop or a nasal drop. (18) A stable aqueous pranoprofen solution comprising pranoprofen and an antioxidant. (19) The aqueous liquid preparation according to (18), wherein the antioxidant is at least one compound selected from alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. (20) The aqueous liquid preparation according to (19), wherein the alkylphenol is at least one selected from dibutylhydroxytoluene and butylhydroxyanisole. (21) The benzopyran derivative is 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 at least one compound selected from the salts thereof, (19). (22) The aqueous liquid preparation according to (19), wherein the amino acid is at least one selected from methionine, tryptophan and histidine. (23) The compounding ratio of pranoprofen and antioxidant is such that pranoprofen: antioxidant = 1: 0.0002 to 5.
The aqueous liquid preparation according to (18), which is 0 (weight ratio). (24) The aqueous liquid preparation according to (18), which is an eye drop. (25) The aqueous liquid preparation according to (18), which is a nasal drop.

The stabilizing method of the present invention is carried out by first placing an aqueous solution of pranoprofen in the presence of an antioxidant. As an embodiment, for example, (i) an aqueous solution of pranoprofen is mixed with an antioxidant (aspect I), and (ii) an aqueous solution of pranoprofen is enclosed in a container molded from a material containing an antioxidant. That (Aspect I
I) etc. Of course, aspect I and aspect II may be combined.

The antioxidants used in aspect I include:
Examples thereof include alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. Alkylphenols include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA),
Examples thereof include n-propyl gallate and catechol, with BHT and BHA being particularly preferably used.

Examples of the benzopyran derivative are tocopherol, tocol, and 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, and particularly L-ascorbic acid 2-
[3,4-dihydro-2,5,7,8-tetramethyl-
2- (4,8,12-trimethyltridecyl) -2H-
Benzopyran-6-yl - hydrogensulfate phosphate] potassium salt (EPC-K ₁₎ is preferably used.

Examples of amino acids include methionine, tryptophan, histidine and the like, and particularly methionine,
Tryptophan is preferably used.

In aspect I, that is, when an antioxidant is added to an aqueous solution of pranoprofen, the mixing ratio is usually pranoprofen: antioxidant = 1: 0.0002 to 5.0.
(Weight ratio), preferably about 1: 0.002-2.5 (weight ratio).

In the case of mode II, that is, when the aqueous solution of pranoprofen is enclosed in a container molded from a material containing an antioxidant, the container is usually a plastic container such as polyethylene (PE) or polypropylene (PP). Examples thereof include those made of polyolefin and the like, and those made of PP are particularly preferably used.

The amount of the antioxidant mixed in the container is usually as follows: container material (without antioxidant):
Antioxidant = 1: 0.0001 to 0.005 (weight ratio), preferably about 1: 0.0005 to 0.005 (weight ratio).

In Embodiment II, the antioxidants include, for example, phenols (eg, alkylphenols, alkyldiphenols, thiobisalkylphenols).
Etc. are used.

Alkylphenols include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), n-propyl gallate, stearyl β- (3,5-di-t-butyl-4-hydroxyphenyl) propionate and tetrakis. [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionyloxymethyl] methane, 1,3,5-tris (3,5-
Di-t-butyl-4-hydroxybenzyl) -1H, 2
H, 3H-triazine-2,4,6-trione, 1,
3,5-tris (3,5-di-t-butyl-4-hydroxybenzyl) -2,4,6-trimethylbenzene,
3,9-bis [2- (3- (3-t-butyl-4-hydroxy-5-methylphenyl) propionyloxy)-
Examples thereof include 1,1-dimethylethyl] -2,4,8,10-tetraoxaspiro [5.5] undecane, and BHT and BHA are particularly preferably used.

Alkyl diphenols include 2,
2'-methylenebis (4-methyl-6-t-butylphenol), 4,4'-butylidenebis (2-t-butyl-5-methylphenol), 2-t-butyl-6- (3
-T-butyl-2-hydroxy-5-methylbenzyl)
Examples include diphenol compounds such as -4-methylphenyl acrylate. Examples of thiobisalkylphenols include 4,4′-thiobis (2-t-butyl-5-
Methylphenol) and the like.

The second stabilizing method of the present invention is carried out by subjecting the pranoprofen aqueous solution to a condition in which oxygen supply is suppressed. As an aspect thereof, a container enclosing the aqueous solution of pranoprofen is enclosed in a container or a sheet in the coexistence of an oxygen scavenger (Aspect III), and the aqueous solution of pranoprofen is enclosed in a container or a sheet having low oxygen permeability. (Aspect IV).

In aspect III, the container for enclosing the aqueous solution of pranoprofen is not particularly limited as long as it can enclose the aqueous solution of pranoprofen, and the antioxidants exemplified in the above-mentioned aspect II are used. A preferable example is a container formed from the compounded materials, a container having low oxygen permeability described later, or the like. As the oxygen scavenger used in the embodiment III, iron powder, iron oxide, ascorbic acid,
Examples thereof include catechol, and iron oxide is particularly preferable. The oxygen scavenger is preferably used by filling it in a bag or the like made of an oxygen permeable material. As the container or sheet for enclosing the container containing the pranoprofen aqueous solution and the oxygen scavenger in aspect III, both the container enclosing the aqueous solution of pranoprofen and the oxygen scavenger are covered with air blocking. There is no particular limitation as long as it can be obtained, and examples of the container include a plastic container and a glass container, and examples of the sheet include a plastic sheet and an aluminum sheet. The container or sheet material may be blended with an antioxidant as exemplified in the above-mentioned aspect II, or one having a low oxygen permeability may be used as described later. Further, also in the aspect III, an antioxidant may be added to the aqueous pranoprofen solution.

The container or sheet having low oxygen permeability used in the embodiment IV has an oxygen permeability of 120 cc.
/ M ² · 24 hours (hr) · atmospheric pressure (atm) [20 ° C ·
90% relative humidity (RH), material thickness 25 μm or less, preferably 70 cc / m ² · 24 hr · atm (20 ° C ·
90% RH, material having a thickness of 25 μm) or less is preferable, and examples thereof include those made of acrylonitrile resin [acrylonitrile styrene (AS), acrylonitrile butadiene styrene (ABS)] and polyethylene terephthalate (PET). Especially PE
Those consisting of T are preferred.

The solvent used in the aqueous solution or aqueous solution of pranoprofen of the present invention includes sterilized purified water, especially distilled water for injection. The concentration of pranoprofen as an active ingredient is usually 0.01 to 2.0 (w / v)%, preferably 0.05 to 1.0 (w / v)% as a standard, depending on the purpose of use. Increase or decrease as appropriate.

As the antioxidant used in the aqueous solution of pranoprofen of the present invention, the same antioxidants as those in the above-mentioned embodiment I are used.

The aqueous liquid preparation of the present invention further comprises a buffer, a tonicity agent, a solubilizing agent, a preservative, a thickener, a chelating agent, and a pH.
Various additives such as regulators and fragrances may be appropriately added.

As the buffer, for example, a phosphate buffer (sodium dihydrogen phosphate-disodium hydrogen phosphate,
Potassium dihydrogen phosphate-potassium hydroxide), boric acid buffer (boric acid-borax), citrate buffer (sodium citrate-sodium hydroxide), tartrate buffer (tartaric acid-sodium tartrate), acetic acid Examples thereof include salt buffers (acetic acid-sodium acetate), carbonate buffers (sodium carbonate-citric acid, sodium carbonate-boric acid), amino acids (sodium glutamate, epsilon aminocaproic acid), and the like. When used as an eye drop, it is preferable to use a borate buffer, an acetate buffer, or a carbonate buffer in order to reduce irritation.

Examples of the tonicity agent include sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, salts such as sodium chloride and borax, and boric acid.

Examples of the solubilizing agent include nonionic surfactants such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monostearate, polyethylene glycol, and polyoxyethylene hydrogenated castor oil.

Examples of preservatives include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and paraoxy butyl such as butyl paraoxybenzoate. Examples thereof include benzoic acid esters, benzyl alcohol, phenethyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, sodium dehydroacetate and the like.

Examples of the thickener include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof.

Examples of the chelating agent include sodium edetate and citric acid. As a pH adjuster,
Examples thereof include hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogen carbonate. Examples of the fragrance include l-menthol, borneol, camphor (dl-camphor and the like), eucalyptus oil and the like.

The aqueous liquid preparation of the present invention is used as eye drops, nasal drops and the like. When used as an eye drop, the pH is usually about 6.0 to 8.5, preferably about 7.0 to 8.0,
When used as a nasal drop, the pH is usually about 6.0-6.0.
It is adjusted to 8.5, preferably about 7.0 to 8.0.

Although the method for producing the aqueous liquid preparation of the present invention varies depending on the type of the liquid preparation, a means known per se for each liquid preparation can be adopted.

When the aqueous liquid preparation of the present invention is used, for example, in the form of eye drops, it may be used in an amount sufficient to effectively extinguish eye inflammation, and may vary depending on the symptoms, type of inflammation, etc. 0 to 1,000 μg / time, preferably 25 to 500 μg / time can be appropriately selected within the range of 2 to 5 times a day.

[0031]

EXAMPLES The present invention will be described in more detail below with reference to experimental examples and examples.

Experimental Example 1 [Stability Test (1)] Pranoprofen 0.1 w / v% solution [boric acid (1.6
w / v%), borax (appropriate amount), sodium edetate (0.01 w / v%), benzalkonium chloride (0.0
05 w / v%), polysorbate 80 (0.1 w / v)
%), Sterile purified water (appropriate amount)], BHT of 0.05,
A polypropylene container with a capacity of 5 ml prepared by blending so as to be 0.1 and 0.5 w / v% [thickness of test piece 2
Oxygen permeability of 5μm is 3,800cc / m ² · 24hr
・ Atm (20 ° C ・ 90% RH); Japanese Industrial Standards Gas Permeability Test Method for Plastic Films and Sheets, Isobaric Method (Japan Standards Association, JIS Handbook,
400 pages, Tokyo; 1991)] and a polyethylene terephthalate container with a capacity of 15 ml [thickness of test piece 25 μ
Oxygen permeability of m is 63cc / m ² · 24hr · atm
(20 ° C, 90% RH); Japanese Industrial Standard Plastic Film and Sheet Gas Permeability Test Method, Isobaric Method (Japan Standards Association, JIS Handbook, 400
P., Tokyo; 1991)] and left for 36 months in the dark at room temperature. The residual rate of pranoprofen in the container was measured over time by high performance liquid chromatography. The results are shown in Table 1.

[0033]

[Table 1]

As is clear from the results shown in Table 1, B
By storing the aqueous solution of pranoprofen in a container containing HT (PP) and a container having low oxygen permeability (PET), an excellent inhibitory effect on the decomposition of pranoprofen was observed.

Experimental Example 2 [Stability test (Part 2)] Basic formulation [Pranoprofen (0.1 w / v%), boric acid (1.6 w / v%), borax (appropriate amount), sodium edetate (0.01 w / v%), benzalkonium chloride (0.005 w / v%), polysorbate 80 (0.1
(w / v%), sterile purified water (appropriate amount)], BHT or sodium thiosulfate was added, and this solution was filled in a polypropylene container having a capacity of 5 ml. The container was left at room temperature in the dark for 39 months. The residual rate of pranoprofen in the container was measured by high performance liquid chromatography. The results are shown in Table 2.

[0036]

[Table 2]

As is clear from the results shown in Table 2, the addition of each antioxidant was confirmed to have an excellent inhibitory effect on the decomposition of pranoprofen.

Experimental Example 3 [Stability test (3)] Basic formulation [Pranoprofen (0.05 w / v%), boric acid (1.6 w / v%), borax (appropriate amount), sodium edetate (0.01 w / v%), benzalkonium chloride (0.005 w / v%), polysorbate 80 (0.1
w / v%), sterile purified water (appropriate amount)], BHT, BH
A, 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
-K _1), methionine, was added tryptophan or histidine was filled each of these liquid colorless polyethylene terephthalate container 15ml capacity. The container was left under a fluorescent lamp (20 W), and when the total irradiation amount reached 100,000 lux · hour, the residual rate of pranoprofen in the container was measured by a high performance liquid chromatography method. The results are shown in Table 3.

[0039]

[Table 3]

As is clear from the results shown in Table 3, the effect of suppressing the decomposition of planoprofen by light was remarkably recognized by adding each antioxidant.

Experimental Example 4 [Stability Test (Part 4)] 0.1 w / v% solution of pranoprofen [boric acid (1.6
w / v%), borax (appropriate amount), sodium edetate (0.01 w / v%), benzalkonium chloride (0.0
05 w / v%), polysorbate 80 (0.1 w / v)
%), Sterilized purified water (appropriate amount)] and prepare a volume of 5 m
1 polypropylene container was filled and tightly closed. This container was packed with a polypropylene / polyvinyl alcohol / polyethylene multilayer film together with iron oxide [Ageless Z-30, manufactured by Mitsubishi Gas Chemical Industry Co., Ltd.] as an oxygen scavenger and left at room temperature for 30 months. The residual rate of pranoprofen in the container was measured over time by high performance liquid chromatography. The results are shown in Table 4.

[0042]

[Table 4]

As is clear from the results shown in Table 4, the inhibitory effect on the decomposition of pranoprofen was remarkably recognized by encapsulating with the oxygen absorber.

Example 1 [Eye drops] (1) Pranoprofen 0.2 g (2) Disodium hydrogen phosphate 0.5 g (3) Sodium dihydrogen phosphate 0.1 g (4) Polyoxyethylene Hydrogenated castor oil 60 0.1 g (5) polyvinyl alcohol 0.2 g (6) sodium chloride 0.8 g (7) benzethonium chloride 0.007 g (8) BHT 0.01 g (9) sodium hydroxide suitable amount (10) Appropriate amount of sterilized purified water 100 ml (10) Add (5) to about 70 ml, and heat to about 70 ° C. with stirring to dissolve. After mixing (4) and (8) with this solution and uniformly dispersing it, the mixture is cooled to room temperature. (1), (2), (3), (6) and (7) are dissolved in this solution, and the pH of the resulting solution is adjusted to 7.2 with (9). To this liquid (10)
Is added to bring the total volume to 100 ml, and the container is filled in a 5 ml PE eye drop container.

Example 2 [Eye drops] (1) Pranoprofen 0.4 g (2) Sodium chloride 0.5 g (3) Polysorbate 80 0.15 g (4) Polyethylene glycol 0.5 g (5) Citric acid 0.2 g (6) Benzalkonium chloride 0.009 g (7) Sodium thiosulfate 0.01 g (8) Sodium carbonate proper amount (9) Sterilized purified water proper amount total amount 100 ml (9) to about 70 ml, (1), (2), (3), (4), (5), (6) and
After dissolving (7), the pH of the obtained solution was adjusted to 8.0 by (8).
Adjust to. (9) is added to this solution to make the total volume 100 ml, and the solution is filled in a PP eye drop container having a volume of 5 ml.

Example 3 [Eye drops] (1) Pranoprofen 0.1 g (2) Potassium dihydrogen phosphate 0.3 g (3) Concentrated glycerin 2.6 g (4) Potassium hydroxide suitable amount (5 ) Sodium edetate 0.01 g (6) EPC-K ₁ 0.05 g (7) Methyl paraoxybenzoate 0.026 g (8) Propyl paraoxybenzoate 0.014 g (9) Sterile purified water Suitable amount Total 100 About 80 ml of ml (9) is heated to about 90 ° C. to dissolve (7) and (8) and cooled to room temperature. After dissolving an appropriate amount of (4) in this solution, dissolve (1), (2), (3), (5) and (6) and adjust the pH of the resulting solution to 6.5 with (4). To do. To this liquid (9)
Is added to bring the total volume to 100 ml, and the container is filled with a polycarbonate eye drop container having a volume of 10 ml.

Example 4 [Eye drops] (1) Pranoprofen 0.1 g (2) Boric acid 1.6 g (3) Borax suitable amount (4) Sodium edetate 0.01 g (5) Polysorbate 80 0.15 g (6) Benzalkonium chloride 0.007 g (7) Sterilized purified water Appropriate amount 100 ml (7) About 80 ml (1), (2), (3), (4), (5) And (6) are dissolved and the pH of the resulting solution is adjusted to 7.0 with (3). (7) was added to this solution to make the total volume 100 ml, and
It is filled in a 5 ml capacity PP eye drop container containing 5% BHT.

Example 5 [Eye drops] (1) Pranoprofen 0.1 g (2) Boric acid 1.6 g (3) Borax suitable amount (4) Sodium edetate 0.01 g (5) Polysorbate 80 0.15 g (6) Benzalkonium chloride 0.007 g (7) Sterilized purified water Appropriate amount 100 ml (7) About 80 ml (1), (2), (3), (4), (5) And (6) are dissolved and the pH of the resulting solution is adjusted to 7.0 with (3). Add (7) to this solution to make the total volume 100 ml, and
Fill a 1-volume PP eye-drop container. This container is made of iron oxide [Ageless Z-30, manufactured by Mitsubishi Gas Chemical Industry Co., Ltd.]
Along with it, it is hermetically sealed with a polypropylene / polyvinyl alcohol / polyethylene multilayer film.

Example 6 [Eye drops] (1) Pranoprofen 0.05 g (2) Boric acid 1.6 g (3) Borax suitable amount (4) Sodium edetate 0.01 g (5) Chlorinated benza Ruconium 0.005 g (6) 1-menthol 0.002 g (7) d1-camphor 0.0005 g (8) Polysorbate 80 0.1 g (9) Sterilized purified water Appropriate amount 100 ml (9) To about 70 ml Dissolve (1), (2), (3), (4) and (5). (6), (7) and (8) were mixed and heated to about 60 ° C.
(9) Add about 20 ml of the uniformly dispersed solution to the above solution, and adjust the pH of this solution to 7.5 by (3). (9) is added to this solution to make a total volume of 100 ml, and the solution is filled in a PET eye drop container having a capacity of 15 ml and light-shielded.

Example 7 [Nasal Drop] (1) Pranoprofen 0.4 g (2) Sodium Citrate 0.2 g (3) Polysorbate 80 0.1 g (4) Glycerin 2.6 g (5 ) Benzethonium chloride 0.007 g (6) Methionine 0.24 g (7) Sodium hydroxide proper amount (8) Sterilized purified water proper amount total amount 100 ml (8) About 70 ml (1), (2), (3), After dissolving (4), (5) and (6), the pH of the obtained solution is adjusted to 7.5 with (7). Add (8) to this liquid to make the total volume 100 ml, and
Fill a 1-volume PP nasal drop container.

Example 8 [Nasal drops] (1) Pranoprofen 1.0 g (2) Boric acid 1.2 g (3) Borax 0.8 g (4) Sodium edetate 0.01 g ( 5) Polysorbate 80 0.15 g (6) Benzalkonium chloride 0.007 g (7) Sodium hydroxide proper amount (8) Sterilized purified water proper amount total amount 100 ml (8) About 80 ml (1), (2), Dissolve (3), (4), (5) and (6). The pH of the resulting liquid is adjusted to 7.0 with (7). Add (8) to this solution to make the total volume 100 ml.
Fill a PE volume nasal drop container of ml capacity. Use iron oxide [Ageless Z-30, Mitsubishi Gas Chemical Industry Co., Ltd.]
And a multi-layer film made of polypropylene / polyvinyl alcohol / polyethylene.

[0052]

INDUSTRIAL APPLICABILITY In the present invention, decomposition of pranoprofen as an active ingredient is remarkably suppressed, and an aqueous solution (formulation) of pranoprofen which is particularly stable to light is obtained, which can be stored for a long period of time. Becomes

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/10 K 47/16 K 47/18 K 47/20 K 47/22 K // C07D 491 / 052 7019-4C (72) Yoshie Ozaki Inventor Yoshie Ozaki 2-12410 Uzumoridai, Higashinada-ku, Kobe-shi, Hyogo Prefecture (72) Yoshiyuki Kimura 527 Kitano, Noguchi-cho, Kakogawa-shi, Hyogo Prefecture

Claims (25)

[Claims] 1. A method for stabilizing pranoprofen, which comprises placing an aqueous solution of pranoprofen in the presence of an antioxidant. 2. The method for stabilizing pranoprofen according to claim 1, which comprises adding an antioxidant to the aqueous solution of pranoprofen. 3. The blending ratio of pranoprofen and antioxidant is such that pranoprofen: antioxidant = 1: 0.000.
The method for stabilizing pranoprofen according to claim 2, wherein the weight ratio is 2 to 5.0. 4. The method for stabilizing pranoprofen according to claim 1, wherein the aqueous solution of pranoprofen is enclosed in a container formed of a material containing an antioxidant. 5. The mixing ratio of the container material and the antioxidant is such that container material: antioxidant = 1: 0.0001 to 0.005.
(Weight ratio) The method for stabilizing pranoprofen according to claim 4, wherein 6. The method for stabilizing pranoprofen according to claim 4, wherein the container material is polypropylene. 7. The method for stabilizing pranoprofen according to claim 2, wherein the antioxidant is at least one compound selected from alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. 8. The method for stabilizing pranoprofen according to claim 7, wherein the alkylphenol is at least one selected from dibutylhydroxytoluene and butylhydroxyanisole. 9. The benzopyran derivative is 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, and the method for stabilizing pranoprofen according to claim 7. 10. The method for stabilizing pranoprofen according to claim 7, wherein the amino acid is at least one selected from methionine, tryptophan and histidine. 11. The antioxidant is at least one compound selected from alkylphenols.
The method for stabilizing pranoprofen according to any one of 1. 12. The method for stabilizing pranoprofen according to claim 11, wherein the alkylphenol is at least one selected from dibutylhydroxytoluene and butylhydroxyanisole. 13. A method for stabilizing planoprofen, which comprises subjecting the planoprofen aqueous solution to conditions in which oxygen supply to the planoprofen aqueous solution is suppressed. 14. The method for stabilizing planoprofen according to claim 13, wherein the container in which the aqueous solution of pranoprofen is sealed is sealed in a container or a sheet in the coexistence of an oxygen scavenger. 15. The method for stabilizing pranoprofen according to claim 13, wherein the pranoprofen aqueous solution is sealed in a container or sheet having low oxygen permeability. 16. The stabilizing method according to claim 1, wherein the aqueous pranoprofen solution is an eye drop or a nasal drop. 17. The stabilizing method according to claim 13, wherein the aqueous pranoprofen solution is an eye drop or a nasal drop. 18. A stable aqueous solution of pranoprofen, which comprises pranoprofen and an antioxidant. 19. The antioxidant is an alkylphenol,
2. At least one compound selected from a benzopyran derivative, sodium thiosulfate and an amino acid.
8. The aqueous liquid preparation according to 8. 20. The aqueous liquid preparation according to claim 19, wherein the alkylphenol is at least one selected from dibutylhydroxytoluene and butylhydroxyanisole. 21. The benzopyran derivative is 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 at least 1
The aqueous liquid preparation according to claim 19, which is a compound of a kind. 22. The aqueous liquid preparation according to claim 19, wherein the amino acid is at least one selected from methionine, tryptophan and histidine. 23. The blending ratio of pranoprofen and the antioxidant is pranoprofen: antioxidant = 1: 0.00.
The aqueous liquid preparation according to claim 18, which has a weight ratio of 02 to 5.0. 24. The aqueous liquid preparation according to claim 18, which is an eye drop. 25. The aqueous liquid preparation according to claim 18, which is a nasal drop.