JP3021312B2 - Method for stabilizing pranoprofen and stable aqueous solution of pranoprofen - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for stabilizing pranoprofen in an aqueous solution of pranoprofen having an anti-inflammatory action, and a method for stabilizing pranoprofen by using pranoprofen as an active ingredient and containing an antioxidant. Aqueous solution of pranoprofen.

[0002]

2. Description of the Related Art Pranoprofen, chemical name α-methyl-
5H- [1] benzopyrano [2,3-b] pyridine-7
Acetic acid is a non-steroidal anti-inflammatory agent with a pronounced anti-inflammatory, analgesic and antipyretic effect and with a wide safety margin and is marketed under the trade name Nifuran®. The properties of pranoprofen, the production method, etc. are described in US Pat.
No. 95 discloses this. Further, an eye drop containing pranoprofen as an anti-inflammatory active ingredient and boric acid as an isotonic agent has been proposed as being particularly useful as an eye drop for herpes virus eye diseases (Japanese Patent Publication No. Hei 2 (1994)). No. 16728). However, there is a problem that pranoprofen is unstable (especially unstable to light) in an aqueous solution state and is gradually decomposed during long-term storage.

[0003]

SUMMARY OF THE INVENTION 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 the 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 decomposition of pranoprofen can be achieved by placing an aqueous solution of pranoprofen in the presence of an antioxidant. Was found to be significantly improved. The present inventors have also found that the degradation of pranoprofen is significantly improved by keeping the aqueous solution of pranoprofen under conditions where the supply of oxygen is suppressed.

That is, the gist of the present invention and preferred embodiments thereof are as follows. (1) A method for stabilizing pranoprofen, comprising placing an aqueous solution of pranoprofen together with an antioxidant. (2) The method for stabilizing pranoprofen according to (1), by adding an antioxidant to the aqueous pranoprofen solution. (3) The mixing ratio of pranoprofen and antioxidant is such that pranoprofen: antioxidant = 1: 0.0002-5.0.
(2) The method for stabilizing pranoprofen according to (2), wherein (4) The pranoprofen aqueous solution is sealed in a container molded from a material containing an antioxidant.
(1) The method for stabilizing pranoprofen according to the above. (5) The method for stabilizing pranoprofen according to (4), wherein the mixing ratio of the container material and the antioxidant is 1: 0.0001 to 0.005 (weight ratio): container material: antioxidant. (6) The method for stabilizing pranoprofen according to (4), wherein the container material is made of 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 according to the 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 placing the pranoprofen aqueous solution under conditions where the supply of oxygen to the pranoprofen aqueous solution is suppressed. (14) The method for stabilizing pranoprofen according to (13), wherein the container enclosing the aqueous solution of pranoprofen is sealed in a container or a sheet in the presence of an oxygen scavenger. (15) The method for stabilizing pranoprofen according to (13), wherein the pranoprofen aqueous solution is sealed in a container or a sheet having low oxygen permeability. (16) The method according to (1), wherein the aqueous pranoprofen solution is an eye drop or a nasal drop. (17) The stabilizing method according to (13), wherein the aqueous pranoprofen solution is an eye drop or a nasal drop. (18) A stable aqueous solution of pranoprofen 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 salts thereof, the aqueous liquid preparation according to (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 mixing 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.

[0006] The stabilization method of the present invention is first carried out by placing an aqueous solution of pranoprofen in the presence of an antioxidant. For example, (i) mixing an antioxidant with an aqueous solution of pranoprofen (aspect I), and (ii) enclosing the aqueous solution of pranoprofen in a container molded from a material containing the antioxidant. (Aspect I
I). Of course, the embodiments I and II may be combined.

The antioxidants used in the embodiment I include:
Examples include alkylphenols, benzopyran derivatives, sodium thiosulfate, amino acids and the like. As alkylphenols, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA),
Examples thereof include n-propyl gallate and catechol, and BHT and BHA are particularly preferably used.

[0008] Benzopyran derivatives include 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-hydrogenphosphate] and its salts, especially 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 the amino acid include methionine, tryptophan, histidine and the like.
Tryptophan is preferably used.

[0010] In the embodiment I, ie, when an antioxidant is added to the aqueous solution of pranoprofen, the compounding ratio is usually pranoprofen: antioxidant = 1: 0.0002 to 5.0.
(Weight ratio), preferably about 1: 0.002 to 2.5 (weight ratio).

In the embodiment II, that is, when the aqueous solution of pranoprofen is sealed in a container molded from a material containing an antioxidant, the container is usually a plastic container, for example, polyethylene (PE), 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 to be added to the container is usually determined by the material of the container (containing no antioxidant):
Antioxidant = 1: 0.0001 to 0.005 (weight ratio), preferably about 1: 0.0005 to 0.005 (weight ratio).

In the embodiment II, examples of the antioxidant include phenols (eg, alkylphenols, alkyldiphenols, thiobisalkylphenols)
Are used.

Examples of the alkylphenols include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), n-propyl gallate, stearyl β- (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, 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)-
1,1-dimethylethyl] -2,4,8,10-tetraoxaspiro [5.5] undecane and the like, and BHT and BHA are particularly preferably used.

As the alkyl diphenols, 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)
And diphenol compounds such as -4-methylphenyl acrylate. As thiobisalkylphenols, 4,4′-thiobis (2-t-butyl-5-
Methylphenol) and the like.

The second stabilization method of the present invention is carried out by placing an aqueous solution of pranoprofen under conditions where the supply of oxygen is suppressed. As an embodiment, the container enclosing the aqueous solution of pranoprofen is sealed in a container or a sheet in the presence of an oxygen scavenger (Embodiment III), and the aqueous solution of pranoprofen is sealed in a container or a sheet having low oxygen permeability. (Embodiment IV).

In the embodiment III, the container for enclosing the aqueous solution of pranoprofen is not particularly limited as long as it can seal the aqueous solution of pranoprofen, and the antioxidant exemplified in the above-mentioned embodiment II can be used. A container molded from the compounded material, a container having a low oxygen permeability described later, and the like are exemplified as suitable ones. The oxygen scavenger used in Embodiment III includes iron powder, iron oxide, ascorbic acid,
Catechol and the like are exemplified, and iron oxide is particularly preferable. The oxygen scavenger is preferably used after being filled in a bag made of an oxygen-permeable material. As the container or sheet for enclosing the container enclosing the aqueous solution of pranoprofen and the oxygen absorber in Embodiment III, both the container enclosing the aqueous solution of pranoprofen and the oxygen absorber are air-blocked. There is no particular limitation as long as it can be obtained. 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 and the sheet material may be mixed with an antioxidant as exemplified in the above-described embodiment II, and may be a material having low oxygen permeability as described later. Also, in Embodiment III, an antioxidant may be added to the aqueous solution of pranoprofen.

The low oxygen permeable container or sheet used in Embodiment IV may have 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.
Suitable are those made of a material having 90% RH and a material thickness of 25 μm or less, such as 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 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 antioxidant as in the above embodiment I is used.

The aqueous solution of the present invention may further contain a buffer, an isotonic agent, a solubilizer, a preservative, a thickener, a chelating agent,
Various additives such as a regulator and a fragrance may be appropriately added.

As the buffer, for example, a phosphate buffer (sodium dihydrogen phosphate-disodium hydrogen phosphate,
Potassium dihydrogen phosphate-potassium hydroxide), borate buffer (boric acid-borax), citrate buffer (sodium citrate-sodium hydroxide), tartrate buffer (tartaric acid-sodium tartrate), acetic acid 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 eye drops, to reduce irritation, use of a borate buffer, an acetate buffer, or a carbonate buffer is preferred.

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 the preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride; Benzoic acid esters, benzyl alcohol, phenethyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, sodium dehydroacetate and the like can be mentioned.

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,
Hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. Examples of the fragrance include 1-menthol, borneol, camphor (such as dl-camphor), and eucalyptus oil.

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

The method for producing the aqueous liquid preparation of the present invention varies depending on the type of the liquid preparation, but any means known per se for each liquid preparation can be employed.

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

[0031]

The present invention will be described below in more detail 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 0.05,
0.1 ml and 0.5 w / v% blended and manufactured 5 ml polypropylene container [specimen thickness 2
5 μm oxygen permeability of 3,800 cc / m ² · 24 hr
Atm (20 ° C./90% RH); gas permeability test method for Japanese Industrial Standard plastic films and sheets, isobar method (Japan Standards Association, JIS Handbook,
400, Tokyo; 1991)] and a polyethylene terephthalate container having a capacity of 15 ml [test piece thickness 25 μm.
oxygen permeability of m is 63cc / m ² · 24hr · atm
(20 ° C./90% RH); Gas permeability test method for plastic films and sheets according to Japanese Industrial Standards, Isobaric method (Japan Standards Association, JIS Handbook, 400
, Tokyo; 1991)], and allowed to stand at room temperature in a dark place for 36 months. Over time, the residual ratio of pranoprofen in the container was measured by high performance liquid chromatography. The results are as shown in Table 1.

[0033]

[Table 1]

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

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

[0036]

[Table 2]

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

Experimental Example 3 [Stability test (part 3)] Basic formulation [pranoprofen (0.05 w / v%), boric acid (1.6 w / v%), borax (suitable amount), sodium edetate (0.01 w / v%), benzalkonium chloride (0.005 w / v%), polysorbate 80 (0.1
w / v%), sterilized 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-hydrogenphosphate] potassium salt (EPC
-K ₁ ), methionine, tryptophan or histidine were added, and these solutions were filled into colorless polyethylene terephthalate containers each having a capacity of 15 ml. The container was left under a fluorescent lamp (20 W), and when the total irradiation amount reached 100,000 lux-hour, the residual ratio of pranoprofen in the container was measured by a high-performance liquid chromatography. The results are as shown in Table 3.

[0039]

[Table 3]

As is evident from the results shown in Table 3, the effect of adding each antioxidant on the decomposition of pranoprofen by light was remarkably observed.

Experimental Example 4 [Stability Test (Part 4)] 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)
%), Sterilized purified water (appropriate amount)] and a volume of 5 m
l polypropylene container was filled and sealed. This container was packaged with a multilayer film made of polypropylene / polyvinyl alcohol / polyethylene together with iron oxide (Ageless Z-30, manufactured by Mitsubishi Gas Chemical Industry Co., Ltd.) as an oxygen scavenger, and allowed to stand at room temperature for 30 months. Over time, the residual ratio of pranoprofen in the container was measured by high performance liquid chromatography. The results are as shown in Table 4.

[0042]

[Table 4]

As is evident from the results shown in Table 4, the effect of suppressing the degradation of pranoprofen was remarkably recognized by encapsulation with a deoxidizer.

Example 1 [Ophthalmic solution] (1) Pranoprofen 0.2 g (2) Disodium hydrogen phosphate 0.5 g (3) Sodium dihydrogen phosphate 0.1 g (4) Polyoxyethylene Hardened 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 (10) Suitable 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 the liquid and uniformly dispersing the mixture, 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 by (9). (10)
To make the total amount 100 ml, and filled into a 5 ml PE ophthalmic container.

Example 2 [Ophthalmic solution] (1) Pranoprofen 0.4 g (2) Sodium chloride 0.5 g (3) Polysorbate 80 0.15 g (4) Polyethylene glycol 0.5 g (5) 0.2 g of citric acid (6) 0.009 g of benzalkonium chloride (7) 0.01 g of sodium thiosulfate (8) Suitable amount of sodium carbonate (9) Suitable amount of sterilized purified water 100 ml (9) About 70 ml (1), (2), (3), (4), (5), (6) and
After dissolving (7), the pH of the resulting solution was adjusted to 8.0 according to (8).
Adjust to (9) is added to this solution to make the total amount 100 ml, and the solution is filled into a 5 ml PP ophthalmic container.

Example 3 [Ophthalmic Solution] (1) Pranoprofen 0.1 g (2) Potassium dihydrogen phosphate 0.3 g (3) Concentrated glycerin 2.6 g (4) Potassium hydroxide (5) ) sodium edetate 0.01 g (6) EPC-K 1 0.05 g (7) methyl parahydroxybenzoate 0.026 g (8) propyl parahydroxybenzoate 0.014 g (9) sterile purified water qs Total 100 Heat about 80 ml to about 90 ° C. to dissolve (7) and (8) and cool 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 by (4). I do. (9)
To make the total volume 100 ml, and filled into a 10 ml polycarbonate ophthalmic container.

Example 4 [Ophthalmic solution] (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) Appropriate amount of sterilized purified water 100 ml (7) (1), (2), (3), (4), (5) And (6) are dissolved, and the pH of the resulting solution is adjusted to 7.0 by (3). (7) was added to this solution to make the total volume 100 ml.
Fill a 5 ml PP ophthalmic container containing 5% BHT.

Example 5 [Ophthalmic solution] (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) Appropriate amount of sterilized purified water 100 ml (7) (1), (2), (3), (4), (5) And (6) are dissolved, and the pH of the resulting solution is adjusted to 7.0 by (3). (7) was added to this solution to make the total amount 100 ml, and 5 m
Fill into 1 volume PP ophthalmic container. This container is made of iron oxide [Ageless Z-30, manufactured by Mitsubishi Gas Chemical Industry Co., Ltd.].
Together 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) Benza chloride 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 qs 100 ml (9) approx. 70 ml Dissolve (1), (2), (3), (4) and (5). (6), (7) and (8) were mixed and heated to about 60 ° C.
(9) A solution uniformly dispersed in about 20 ml is added to the above solution, and the pH of this solution is adjusted to 7.5 by (3). (9) is added to this solution to make the total volume 100 ml, and the solution is filled into a PET eye drop container having a capacity of 15 ml, and light-shielded and packaged.

Example 7 [Nasal drops] (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) Appropriate amount of sodium hydroxide (8) Appropriate amount of sterilized purified water 100 ml (8) About 70 ml of (1), (2), (3), After dissolving (4), (5) and (6), the pH of the resulting solution is adjusted to 7.5 by (7). (8) was added to this solution to make the total amount 100 ml, and 5 m
Fill 1 volume of 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) Appropriate amount of sodium hydroxide (8) Appropriate amount of sterilized purified water 100 ml (8) About 80 ml (1), (2), Dissolve (3), (4), (5) and (6). The pH of the resulting solution is adjusted to 7.0 by (7). (8) was added to this solution to make the total volume 100 ml.
Fill a PE nasal container of ml volume. This container is made of iron oxide [Ageless Z-30, Mitsubishi Gas Chemical Industry Co., Ltd.
And hermetic packaging with a polypropylene / polyvinyl alcohol / polyethylene multilayer film.

[0052]

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

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 47/20 A61K 47/20 47/22 47/22 47/32 47/32 // C07D 491/052 C07D 491/052 (72 ) Inventor Yoshie Ozaki 2--12 410 Uzumoridai, Higashinada-ku, Kobe City, Hyogo Prefecture (72) Inventor Yoshiyuki Kimura 527 Kitano, Noguchi-cho, Kakogawa City, Hyogo Prefecture 3 (56) References A) JP-A-60-184013 (JP, A) JP-A-3-287535 (JP, A) JP-A-5-186349 (JP, A) JP-A-62-1221352 (JP, A) JP-A-62 -194861 (JP, A) Jikai Sho 56-125876 (JP, U) JP-B-59-18066 (JP, B1) Pharmaceutical Excipients Study Group, “Practical Pharmaceutical Additives” (1974) Chemical Industries, p. . 11-12, 99-101, 217-220 Junichi Miyazaki, Masahiko Takano, “Ophthalmic preparations and their applications” (1962) Nanzando, p. 87−88 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/436 A61K 9/08 A61K 47/10 A61K 47/16 A61K 47/18 A61K 47/20 A61K 47/22 A61K 47 / 32 C07D 491/052 CA (STN)

Claims (21)

(57) [Claims] 1. An aqueous solution of pranoprofen which is non-ionic
In the presence of a surfactant, alkylphenols, benzo
From pyran derivatives, sodium thiosulfate and amino acids
A method for stabilizing pranoprofen , comprising blending at least one selected antioxidant . 2. Composition ratio of pranoprofen and antioxidant
In the case of pranoprofen: antioxidant = 1: 0.000
The method for stabilizing pranoprofen according to claim 1, wherein the ratio is 2 to 5.0 (weight ratio) . 3. At least one alkylphenol
Formed from materials containing antioxidants selected from
Characterized by enclosing an aqueous solution of pranoprofen in a container
Method for stabilizing pranoprofen to be. 4. The mixing ratio between the container material and the antioxidant is
Container material: antioxidant = 1: 0.0001 to 0.005
The method for stabilizing pranoprofen according to claim 3, which is (weight ratio) . 5. The method according to claim 1, wherein the container material is made of polypropylene.
Item 3. The method for stabilizing pranoprofen according to Item 3 . 6. The method of claim 1 , wherein the alkylphenol is dibutyl hydride.
From roxytoluene and butylhydroxyanisole
The method for stabilizing pranoprofen according to claim 1, which is at least one selected from the group consisting of: 7. The benzopyran derivative is L-ascorbin.
Acid 2- [3,4-dihydro-2,5,7,8-tetrame
Tyl-2- (4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-yl-hydrogenpho
Sulfate] and salts thereof.
The method for stabilizing pranoprofen according to claim 1 , wherein 8. The method according to claim 1, wherein the amino acid is methionine or tryptophan.
And at least one selected from histidine and
The method for stabilizing pranoprofen according to claim 1 . 9. An alkyl phenol comprising dibutyl hydride
From roxytoluene and butylhydroxyanisole
The method for stabilizing pranoprofen according to claim 3, which is at least one selected from the group consisting of: 10. Planoprofen and a nonionic interface
Activators, alkylphenols and benzopyran derivatives
Body, sodium thiosulfate and amino acids
Stable pranoprof consisting of at least one antioxidant
An aqueous solution. 11. The method according to claim 11 , wherein the alkylphenol is dibutylhydrazine.
Doxytoluene and butylhydroxyanisole?
The aqueous solution according to claim 10, which is at least one member selected from the group consisting of:
Liquid. 12. The benzopyran derivative is L-ascorbi.
Acid 2- [3,4-dihydro-2,5,7,8-tetra
Methyl-2- (4,8,12-trimethyltridecyl)
-2H-1-benzopyran-6-yl-hydrogenf
At least one selected from phosphates and salts thereof.
The aqueous liquid preparation according to claim 10, which is a seed. 13. amino acid methionine, 10. The aqueous liquid preparation according at least one selected from tryptophan and arsenate scan cytidine. 14. A combination of pranoprofen and an antioxidant.
The ratio is pranoprofen: antioxidant = 1: 0.00
The aqueous liquid according to claim 10, wherein the aqueous liquid is 02 to 5.0 (weight ratio).
Agent. 15. The aqueous liquid according to claim 10, which is an eye drop.
Agent. 16. The aqueous liquid according to claim 10, which is a nasal drop.
Agent. 17. An aqueous solution of pranoprofen , which is treated with acrylo
Nitrile styrene, acrylonitrile butadiene styrene
Selected from polyethylene and polyethylene terephthalate
Characterized by being enclosed in a container or sheet consisting of
How to stabilize pranoprofen . 18. The container or sheet is made of polyethylene.
18. Planoprof according to claim 17, which is terephthalate.
How to stabilize the chain. 19. An aqueous solution of pranoprofen comprising an antioxidant
18. Planoprof according to claim 17, which is an aqueous solution containing
How to stabilize the chain. 20. The method according to claim 20, wherein the nonionic surfactant is polyoxyethylene.
Tylenesorbitan monooleate, polyoxyethylene
Nostearate, polyoxyethylene glycol and
At least selected from polyoxyethylene hydrogenated castor oil
2. The stabilization of pranoprofen according to claim 1, wherein
Method. 21. The method according to claim 20, wherein the nonionic surfactant is polyoxyethylene.
Tylenesorbitan monooleate, polyoxyethylene
Nostearate, polyoxyethylene glycol and
At least selected from polyoxyethylene hydrogenated castor oil
The aqueous liquid preparation according to claim 10, wherein at least one is also used.