Method for stabilizing pranoprofen and stable liquid preparation of pranoprofen

Abstract: 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 pranoprofen 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 permitting long-term preservation of an aqueous solution, specifically a liquid preparation, of pranoprofen.

Description: FIELD OF THE INVENTION The present invention relates to a method for stabilizing pranoprofen having anti-inflammatory activity, in an aqueous solution of pranoprofen, and to a liquid preparation comprising, as an active ingredient, pranoprofen which is stabilized by adding an antioxidant. BACKGROUND OF THE INVENTION Pranoprofen having a chemical name of α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid exhibits prominent anti-inflammatory action, analgesic action and antipyretic 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 United States Patent No. 3931295. 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 (US Patent No. 4,607,038). US Patent No 4 525 348 discloses gelled ountments comprising pranoprofen as an active ingredient. However, pranoprofen is unstable in an aqueous solution state (particularly to light) and is gradually decomposed during long-term preservations. It is therefore an object of the present invention to provide a method for stabilizing pranoprofen in an aqueous solution state. Another object of the present invention is to provide an aqueous solution of pranoprofen, wherein decomposition of pranoprofen is suppressed. SUMMARY OF THE INVENTION According to the present invention, it has now been found that decomposition of pranoprofen can be markedly suppressed by placing an aqueous solution of pranoprofen in coexistence with an antioxidant wherein the antioxidant is at least one compound selected from the group consisting of alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. That is, the present invention and preferable modes thereof are as follows. (1) A method for stabilizing pranoprofen, comprising placing an aqueous solution of pranoprofen in coexistence with an antioxidant wherein the antioxidant is at least one compound selected from the group consisting of alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. (2) A method for stabilizing pranoprofen according to (1), comprising adding an antioxidant wherein the antioxidant is at least one compound selected from the group consisting of alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids to an aqueous solution of pranoprofen. (3) A method for stabilizing pranoprofen according to (2), wherein the weight ratio of the antioxidant to pranoprofen is 0.0002-5.0:1. (4) A method for stabilizing pranoprofen according to (2), wherein the alkylphenol is at least one compound selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole. (5) A method for stabilizing pranoprofen according to (2), wherein the benzopyran derivative is at least one member selected from the group consisting of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] and salts thereof. (6) A method for stabilizing pranoprofen according to (2), wherein the amino acid is at least one member selected from the group consisting of methionine, tryptophan and histidine. (7) A method for stabilizing pranoprofen according to (2), wherein the antioxidant is at least one alkylphenol. (8) A method for stabilizing pranoprofen according to (7), wherein the alkylphenol is at least one member selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole. (16) A stabilizing method according to (1), wherein the aqueous solution of pranoprofen is an eye drop or a collunarium. (9) A stable liquid preparation of pranoprofen, comprising pranoprofen and an antioxidant wherein the antioxidant is at least one compound selected from the group consisting of alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. (10) The liquid preparation of (9), wherein the alkylphenol is at least one member selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole. (11) The liquid preparation of (9), wherein the benzopyran derivative is at least one compound selected from the group consisting of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] and salts thereof. (12) The liquid preparation of (9), wherein the amino acid is at least one member selected from the group consisting of methionine, tryptophan and histidine. (13) The liquid preparation of (9), wherein the weight ratio of the antioxidant to pranoprofen is 0.0002-5.0:1. (14) The liquid preparation of (9), which is an eye drop. (15) The liquid preparation of (9), which is a collunarium. DETAILED DESCRIPTION OF THE INVENTION The first mode of the stabilizing method of the present invention is placing an aqueous solution of pranoprofen in coexistence with an antioxidant wherein the antioxidant is at least one compound selected from the group consisting of alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids , which is realized by, for example, adding an antioxidant to an aqueous solution of pranoprofen Examples of alkylphenol include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), n-propyl gallate and catechol, with preference given to BHT and BHA. Examples of benzopyran derivative include tocopherol, tocol, L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] and salts thereof, with preference given to L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] potassium salt (EPC-K 1 ). Amino acid is, for example, methionine, tryptophan or histidine, with preference given to methionine and tryptophan. When an antioxidant is added to an aqueous solution of pranoprofen , the weight ratio of the antioxidant to pranoprofen is generally 0.0002-5.0:1, preferably 0.002-2.5:1. 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 aromatic agents. Examples of buffer include phosphate buffer (e.g. sodium dihydrogenphosphate-disodium hydrogenphosphate and potassium dihydrogenphosphate-potassium hydroxide), borate buffer (e.g. boric acid-sodium tetraborate), citrate buffer (e.g. sodium citrate-sodium hydroxide), tartrate buffer (e.g. tartaric acid-sodium tartrate), acetate buffer (e.g. acetic acid-sodium acetate), carbonate buffer (e.g. sodium carbonate-citric acid and sodium carbonate-boric acid) and amino acid (e.g. sodium glutamate and ε-aminocaproic acid). When the liquid preparation of pranoprofen is used as an eye drop, it is preferable that borate buffer, acetate buffer or carbonate buffer be used to decrease irritation. Examples of isotonizing agent include saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerol and propylene glycol, salts such as sodium chloride and sodium tetraborate, and boric acid. Examples of solubilizing agent include non-ionic surfactants such as polyoxyethylenesorbitan monooleate (polysorbate 80), polyoxyethylenemonostearate, polyethylene glycol and polyoxyethylene hydrogenated castor oil. Examples of preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, p-hydroxybenzoates such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and butyl p-hydroxybenzoate, benzyl alcohol, phenetyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol and sodium dehydroacetate. Examples of thickener include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose 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, preferably 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 µg/administration, preferably 25-500 µg/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. Experimental Example 1 [Stability test - No. 1] A solution of 0.1 w/v% pranoprofen [boric acid, 1.6 w/v%; sodium tetraborate, appropriate amount; disodium edetate, 0.01 w/v%; benzalkonium chloride, 0.005 w/v%; polysorbate 80, 0.1 w/v%; sterile purified water, appropriate amount] was filled in 5 ml polypropylene containers manufactured by adding BHT to 0.05, 0.1 or 0.5 w/v% [oxygen permeability of 25 µm thick test sample, 3,800 cc/m 2 · 24 hr · atm (20°C · 90% RH); Gas Permeation Test Method of Plastic Film and Sheet of Japanese Industrial Standards, the equal pressure method [Japanese Standards Association, JIS Handbook, p 400, Tokyo (1991)]] and 15 ml polyethylene terephthalate containers [oxygen permeability of 25 µm thick test samples, 63 cc/m 2 · 24 hr · atm (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 pranoprofen in the containers was determined with time by high performance liquid chromatography. The results are shown in Table 1. Container Residual content of pranoprofen (%) On preparation 3 months 6 months 12 months 24 months 36 months PP (control) 100.0 95.6 93.9 - 81.9 78.5 PP-05 100.0 100.4 99.3 99.0 98.5 100.2 PP-01 100.0 100.4 98.3 98.1 95.4 96.0 PP-005 100.0 100.4 98.3 97.0 93.2 93.3 PET 100.0 99.5 101.0 100.3 100.8 99.4 PP : polypropylene container without BHT oxygen permeability, 3800 cc/m 2 · 24 hr · atm (20°C · 90% RH, 25 µm) PP-05 : polypropylene container containing 0.5% BHT PP-01 : polypropylene container containing 0.1% BHT PP-005: polypropylene container containing 0.05% BHT PET : polyethylene terephthalate container without BHT oxygen permeability, 63 cc/m 2 · 24 hr · atm (20°C · 90% RH, 25 µm) As is evident from Table 1, superior suppression of decomposition of pranoprofen was achieved by preserving pranoprofen in the containers (PP) formed from a mixture containing BHT and in the container (PET) having a low oxygen permeability. Experimental Example 2 [Stability test - No. 2] BHT or sodium thiosulfate was added to a basic formulation solution [pranoprofen, 0.1 w/v%; boric acid, 1.6 w/v%; sodium tetraborate, appropriate amount; disodium edetate, 0.01 w/v%; benzalkonium chloride, 0.005 w/v%; polysorbate 80, 0.1 w/v%; sterile purified water, appropriate amount], and the mixture was filled in 5 ml polypropylene containers. The containers were left standing in the dark at room temperature for 39 months. The residual content of pranoprofen in the containers was determined by high performance liquid chromatography. The results are shown in Table 2. Compound added Concentration (%) Residual content of pranoprofen (%) On preparation after 39 months Control (not added) 0 100.0 77.0 BHT 0.0004 100.0 99.6 " 0.0001 100.0 94.7 sodium thiosulfate 0.1 100.0 93.0 As is evident from Table 2, superior suppression of decomposition of pranoprofen was achieved by the addition of respective antioxidants. Experimental Example 3 [Stability test - No. 3] BHT, BHA, L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] potassium salt (EPC-K 1 ), methionine, tryptophan or histidine was added to a basic formulation solution [pranoprofen, 0.05 w/v%; boric acid, 1.6 w/v%; sodium tetraborate, appropriate amount; disodium edetate, 0.01 w/v%; benzalkonium chloride, 0.005 w/v%; polysorbate 80, 0.1 w/v%; sterile purified water, appropriate amount], and the mixture was filled in 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 content of pranoprofen in the containers was determined by high performance liquid chromatography. The results are shown in Table 3. Compound added Concentration (%) Residual content of pranoprofen (%) On preparation after irradiation of 100,000 lux · hr Control (not added) 0 100.0 52.5 BHT 0.005 100.0 98.0 " 0.002 100.0 96.6 " 0.0002 100.0 70.8 BHA 0.002 100.0 92.8 EPC-K 1 0.05 100.0 79.1 " 0.01 100.0 70.5 " 0.001 100.0 68.2 methionine 0.24 100.0 95.2 tryptophan 0.06 100.0 96.9 histidine 0.13 100.0 75.9 As is evident from Table 3, the decomposition of pranoprofen caused by the exposure to the light was markedly suppressed by the addition of respective antioxidants. Experimental Example 4 [Stability test - No. 4] A solution of 0.1 w/v% pranoprofen [boric acid, 1.6 w/v%; sodium tetraborate, appropriate amount; disodium edetate, 0.01 w/v%; benzalkonium chloride, 0.005 w/v%; polysorbate 80, 0.1 w/v%; sterile purified water, appropriate amount] was filled in 5 ml polypropylene containers and the containers were tightly sealed. The containers were enclosed together with iron oxide (Ageless Z-30, manufactured by Mitsubishi Gas Chemical Company, Inc.) as a deoxygenating 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. Enclosing Residual content of pranoprofen (%) On preparation 2 months 6 months 9 months 30 months Unenclosed 100.0 95.1 89.4 92.0 80.3 Film-enclosed (deoxygenator) 100.0 98.1 97.6 97.2 101.0 Film-enclosed (N 2 substitution) 100.0 95.0 93.4 89.5 88.5 Containers used: polypropylene containers without BHT Film: multi-layer film of polypropylene/poly(vinyl alcohol)/polyethylene deoxygenating agent: iron oxide (Ageless Z-30, manufactured by Mitsubishi Gas Chemical Company, Inc.) As is evident from Table 4, marked suppression of decomposition of pranoprofen was achieved by sealing a container, in which an aqueous solution of pranoprofen had been sealed, together with a deoxygenating agent. Example 1 [Eye drop] (1) Pranoprofen 0.2 g (2) Disodium hydrogenphosphate 0.5 g (3) Sodium dihydrogenphosphate 0.1 g (4) Polyoxyethylene hydrogenated castor oil 60 0.1 g (5) Poly(vinyl alcohol) 0.2 g (6) Sodium chloride 0.8 g (7) Benzethonium chloride 0.007 g (8) BHT 0.01 g (9) Sodium hydroxide appropriate amount (10) Sterile purified water appropriate amount Total 100 ml (5) was added to about 70 ml of (10) and the mixture was stirred with heating to about 70°C for dissolution. (4) and (8) were added to this solution and the mixture was admixed until it became a uniform dispersion. The mixture was cooled to room temperature. (1), (2), (3), (6) and (7) were dissolved in this solution and pH was adjusted to 7.2 with (9). (10) was added to make the total amount 100 ml and the mixture was filled in a 5 ml PE container for an eye drop. Example 2 [Eye drop] (1) 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 appropriate amount (9) Sterile purified water appropriate amount Total 100 ml (1), (2), (3), (4), (5), (6) and (7) were dissolved in about 70 ml of (9) and pH was adjusted to 8.0 with (8). (9) was added to make the total amount 100 ml and the mixture was filled in a 5 ml PP container for an eye drop. Example 3 [Eye drop] (1) Pranoprofen 0.1 g (2) Potassium dihydrogenphosphate 0.3 g (3) Conc. glycerol 2.6 g (4) Potassium hydroxide appropriate amount (5) Disodium edetate 0.01 g (6) EPC-K 1 0.05 g (7) Methyl p-hydroxybenzoate 0.026 g (8) Propyl p-hydroxybenzoate 0.014 g (9) Sterile purified water appropriate amount Total 100 ml About 80 ml of (9) was heated to about 90°C and (7) and (8) were dissolved. The mixture was cooled to room temperature. 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. Example 4 [Eye drop] (1) Pranoprofen 0.1 g (2) Boric acid 1.6 g (3) Sodium tetraborate appropriate amount (4) Disodium edetate 0.01 g (5) Polysorbate 80 0.15 g (6) Benzalkonium chloride 0.007 g (7) Sterile purified water 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, which comprised 0.5% BHT. Example 5 [Eye drop] (1) Pranoprofen 0.1 g (2) Boric acid 1.6 g (3) Sodium tetraborate appropriate amount (4) Disodium edetate 0.01 g (5) Polysorbate 80 0.15 g (6) Benzalkonium chloride 0.007 g (7) Sterile purified water 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) Pranoprofen 0.05 g (2) Boric acid 1.6 g (3) Sodium tetraborate appropriate amount (4) Disodium edetate 0.01 g (5) Benzalkonium chloride 0.005 g (6) 1-menthol 0.002 g (7) dl-camphor 0.0005 g (8) Polysorbate 80 0.1 g (9) Sterile purified water 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. The pH of the mixture was adjusted to 7.5 with (3) and (9) was added to make the total amount 100 ml. The mixture was filled in a 15 ml PET container for an eye drop and enclosed to avoid light. Example 7 [Collunarium] (1) Pranoprofen 0.4 g (2) Sodium citrate 0.2 g (3) Polysorbate 80 0.1 g (4) Glycerol 2.6 g (5) Benzethonium chloride 0.007 g (6) Methionine 0.24 g (7) Sodium hydroxide appropriate amount (8) Sterile purified water 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 1.0 g (2) Boric acid 1.2 g (3) Sodium tetraborate 0.8 g (4) Disodium edetate 0.01 g (5) Polysorbate 80 0.15 g (6) Benzalkonium chloride 0.007 g (7) Sodium hydroxide appropriate amount (8) Sterile purified water appropriate amount Total 100 ml (1), (2), (3), (4), (5) and (6) were dissolved in about 80 ml of (8), and pH was adjusted to 7.0 with (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 iron oxide (Ageless Z-30; manufactured by Mitsubishi Gas Chemical Company, Inc.) were enclosed with a multi-layer film of polypropylene/poly(vinyl alcohol)/polyethylene. According to the present invention, the decomposition of the active ingredient pranoprofen is remarkably suppressed. In particular, pranoprofen becomes stable to light, thus permitting long-term preservation of an aqueous solution (preparation) of pranoprofen.

Claims: Use of an antioxidant for stabilizing pranoprofen in an aqueous solution of pranoprofen in the presence of a non-ionic surfactant, wherein the antioxidant is at least one compound selected from the group consisting of alkylphenols, benzopyran derivatives, sodium thiosulfate and amino acids. The use of claim 1, wherein the weight ratio of the antioxidant to pranoprofen is 0.0002-5.0:1. The use of claim 1, wherein the alkylphenol is at least one compound selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole. The use of claim 1, wherein the benzopyran derivative is at least one member selected from the group consisting of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] and salts thereof. The use of claim 1, wherein the amino acid is at least one member selected from the group consisting of methionine, tryptophan and histidine. The use of claim 1, wherein the aqueous solution of pranoprofen is an eye drop or a collunarium. A stable liquid preparation of pranoprofen, comprising pranoprofen and dibutylhydroxytoluene in the presence of polyoxyethylenesorbitan monooleate. The liquid preparation of claim 7, wherein the weight ratio of dibutylhydroxytoluene to pranoprofen is 0.0002-5.0:1. The liquid preparation of claim 7, which is an eye drop. The liquid preparation of claim 7, wherein which is a collunarium.

Inventors: DOI KOJI, KIMURA YOSHIYUKI, OZAKI YOSHIE, SAWA HISAKO, DOI, KOJI, KIMURA, YOSHIYUKI, OZAKI, YOSHIE, SAWA, HISAKO
Applicants: MITSUBISHI PHARMA CORP, SENJU PHARMA CO, MITSUBISHI PHARMA CORPORATION, SENJU PHARMACEUTICAL CO., LTD.
Application year: 1995
Main classification: A61K31
IPC codes: A61K47, A61K9, A61K31, A61P29