JP2005015368A - Method for stabilizing pranoprofen-containing aqueous liquid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pranoprofen-containing aqueous liquid preparation which is stable under the irradiation of light. <P>SOLUTION: The pranoprofen-containing aqueous liquid preparation stable against light comprises pranoprofen and at least one stabilizer selected from the group consisting of hydrogensulfites, berberine compounds, cyanocobalamin and sodium azulenesulfonate. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【００６１】
プラノプロフェンの光に対する安定性において、亜硫酸水素ナトリウムの効果を観察した。表１に示す結果から明らかなように、いずれも露光によるプラノプロフェンの分解に対して長時間の優れた抑制効果が認められた。
【００６２】
【表２】

【００６３】
緩衝剤、防腐剤、等張化剤等の添加物の種類及び量を同一のものとし、亜硫酸水素ナトリウムの添加量を変化させ、光照射下におけるプラノプロフェンの安定化に必要な添加量を見出すべく検討した。表２に示す結果から明らかなように、プラノプロフェンに対する亜硫酸水素ナトリウムの配合の割合が０．２５以上添加した場合に、十分な効果がみられた。
【００６４】
参考例４
医療用点眼剤であるニフラン点眼液（プラノプロフェン１ｗ／ｖ％製剤。添加剤としてホウ酸、ホウ砂、ポリソルベート８０、エデト酸ナトリウム、塩化ベンザルコニウムを含有。製造：千寿製薬（株）、販売：武田薬品工業（株））を露光条件が同じになるようにその他の参考例・実施例と同じ無色の１０ｍＬ合成樹脂容器に移し、試料とした。
【００６５】
参考例５〜１３及び実施例１５〜１８（点眼剤）
ホウ酸 ３５０ ｍｇ
ホウ砂 ９０ ｍｇ
イプシロン−アミノカプロン酸 ５００ ｍｇ
グリセリン １５００ ｍｇ
パラオキシ安息香酸メチル ３０ ｍｇ
パラオキシ安息香酸プロピル １０ ｍｇ
プラノプロフェン ５０ ｍｇ
参考例（又は実施例）添加化合物（表３参照） 表３記載の量
滅菌精製水 適 量
全量 １００ ｍＬ
【００６６】
調製方法
滅菌精製水約９０ｍＬにホウ酸、ホウ砂、イプシロン−アミノカプロン酸及びグリセリンを溶解し、約５０℃に温め、攪拌しながらパラオキシ安息香酸メチル、パラオキシ安息香酸プロピル及びプラノプロフェンを添加した後、溶解する。表３に示す添加化合物を表記の濃度になるように添加し、溶解し、冷却した後、全量１００ｍＬとする。メンブランフィルターでろ過した後、無色の１０ｍＬ合成樹脂容器に充てんし、試料とする。
【００６７】
参考例１４及び実施例１９〜４６（点眼剤）
クエン酸 １００ ｍｇ
ホウ砂 ３５０ ｍｇ
イプシロン−アミノカプロン酸 ５００ ｍｇ
エデト酸ナトリウム ５ ｍｇ
グリセリン １５００ ｍｇ
パラオキシ安息香酸メチル ３０ ｍｇ
パラオキシ安息香酸プロピル １０ ｍｇ
ｌ−メントール ５ ｍｇ
ｄ−カンフル ５ ｍｇ
プラノプロフェン ５０ ｍｇ
参考例（又は実施例）添加化合物（表３参照） 表３記載の量
滅菌精製水 適 量
全量 １００ ｍＬ
【００６８】
｛製造法｝
滅菌精製水約９０ｍＬにクエン酸、ホウ砂、イプシロン−アミノカプロン酸、エデト酸ナトリウム及びグリセリンを溶解し、約５０℃に温め、攪拌しながらパラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、ｌ−メントール、ｄ−カンフル及びプラノプロフェンを添加し、溶解する。更に表３に示す添加化合物を表記の濃度になるように添加し、溶解し、冷却した後、全量１００ｍＬとする。メンブランフィルターでろ過した後、無色の１０ｍＬ合成樹脂容器に充てんし、試料とする。
【００６９】
【表３】

【００７０】
表３において、ベルベリン類（塩化ベルベリン又は硫酸ベルベリン）、シアノコバラミン又はアズレンスルホン酸ナトリウムを添加しない参考例（表３の参考例４〜１４）とベルベリン類、シアノコバラミン又はアズレンスルホン酸ナトリウムを添加する実施例（表３の実施例１６〜１８、２０〜２７、３２〜３５及び４０〜４３）との比較から明らかなように、ベルベリン類、シアノコバラミン又はアズレンスルホン酸ナトリウムは、濃度依存的に、プラノプロフェンの光照射による含有量減少及びにごりを抑制した。
【００７１】
また、クロモグリク酸ナトリウム添加の実施例（表３の実施例１５及び１９）においては、分解の抑制に関して目立った効果は見られないものの、にごりを抑制する効果は顕著に見られた。また、実施例１６〜１８、２０〜２７、３２〜３５及び４０〜４３とベルベリン類、シアノコバラミン又はアズレンスルホン酸ナトリウム添加に加え、さらにクロモグリク酸ナトリウムを添加した実施例（表３の実施例２８〜３１、３６〜３９及び４４〜４６）を比較すると、クロモグリク酸ナトリウムを添加した実施例において、特に低濃度域かつ総光照射量が増大するにつれ、プラノプロフェンの光分解およびにごりが効果的に抑制されていた。
【００７２】
【発明の効果】
本発明において、水性液剤中の有効成分であるプラノプロフェンの光による含有量減少又はにごりは顕著に抑制され、光照射下における長期保存が可能となった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an aqueous planoprofen solution obtained by stabilizing pranoprofen which is unstable to light.
[0002]
[Prior art]
Planoprofen is a drug developed as a powerful propionic acid non-steroidal anti-inflammatory drug having a tricyclic structure, and its characteristics, production method, and the like have already been disclosed (for example, see Patent Document 1). . In addition, pranoprofen is widely used in the form of tablets, capsules, syrups, liquids, eye drops, etc. (see, for example, Non-Patent Document 1), and other stimulating substances using boric acid as a buffer. An eye drop containing pranoprofen having a small anti-inflammatory action has also been disclosed (see, for example, Patent Document 2).
[0003]
However, pranoprofen is unstable to light, especially when used as an aqueous solution. In order to stabilize pranoprofen in an aqueous solution, for example, at least one antioxidant selected from alkylphenols, benzofuran derivatives, sodium thiosulfate and amino acids has been incorporated in the presence of a nonionic surfactant. Method for stabilizing an aqueous liquid preparation, a method for stabilizing pranoprofen by enclosing a pranoprofen aqueous solution in a container formed of a material containing at least one of alkylphenols, and an aqueous solution containing pranoprofen It is disclosed that acrylonitrile styrene, acrylonitrile butadiene styrene, or polyethylene terephthalate is used as a material for a container or sheet for enclosing a liquid agent (for example, see Patent Document 3).
[0004]
In addition, eye drops containing organic amines have been proposed as a method for stabilizing and reducing irritation of pranoprofen-containing eye drops (see, for example, Patent Document 4). In addition, an ophthalmic solution containing pranoprofen and carbonate, which is less irritating (see, for example, Patent Document 5), and an ophthalmic solution in which acetate ion is added to try to reduce irritation of pranoprofen (For example, refer patent document 6) There exist reports, such as an ophthalmic solution excellent in stability (for example, refer patent document 7) etc. which added propylene glycol and polysorbate 80, and lost the irritation of pranoprofen. The above prior arts all relate to pronoprofen stability and reduced irritation.
[0005]
Here, in an aqueous liquid preparation containing pranoprofen as a main drug, the content of pranoprofen is reduced or garlic is generated by light irradiation, but a stabilizer for the purpose of reducing the content and preventing gargle As a result, there is no report on a preparation containing bisulfite, berberine, cyanocobalamin, sodium azulenesulfonate or sodium cromoglycate.
[0006]
[Patent Document 1]
US Pat. No. 3,931,205
[Patent Document 2]
Japanese Patent Publication No. 2-16728
[Patent Document 3]
Japanese Patent No. 3021312
[Patent Document 4]
Japanese Patent No. 3170619
[Patent Document 5]
JP-A-5-186349
[Patent Document 6]
JP 7-017863 A
[Patent Document 7]
Japanese Patent Laid-Open No. 10-236951
[Non-Patent Document 1]
Japanese Pharmacopoeia (14 stations)
[0007]
[Problems to be solved by the invention]
As a method of protecting the main component of an aqueous liquid unstable to light, a method of blocking light by storing it in an opaque / translucent container or a colored container such as brown can be considered, but foreign matter is mixed in. In this case, it is difficult to detect and there is a risk of using the contaminated product as it is. On the other hand, in the case of transparent containers, light shielding bags are not used in the course of the manufacturing process, or light shielding bags are not used at the stage of the consumer until light-wrapping is performed. In some cases, photolysis is unavoidable.
[0008]
The objective of this invention is providing the stabilization method of the planoprofen which does not depend on external packaging of the aqueous liquid agent containing pranoprofen itself. The object of the present invention also relates to the type and amount of ingredients formulated for the stabilization of pranoprofen, and the ingredients formulated to reduce the irritation at the time of instillation of the ophthalmic solution that is an aqueous solution. .
[0009]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above object, the inventors of the present invention obtained a planoprofen-containing aqueous solution by combining bisulfite, berberine, cyanocobalamin, sodium azulenesulfonate or sodium cromoglycate, or a combination thereof. It has been found that the decrease in the content of pranoprofen or turbidity under light irradiation is markedly improved by the coexistence. In addition, the types and amounts within the range permitted by the current regulations as additives to be added to pharmaceutical preparations are appropriately mixed in consideration of liquidity, isotonicity, buffering properties, etc. An aqueous solution containing pranoprofen that was stable against heat, particularly light, could be obtained.
[0010]
As an effect of the present invention, in these pranoprofen-containing aqueous liquid preparations, even when irradiated with light such as sunlight while being stored in a transparent synthetic resin or glass container, the decrease in pranoprofen content and fogging are prevented. Can be mentioned. In addition to the above effects, 1. In the case of using bisulfite and / or berberine, antiseptic / antibacterial effect by bisulfite and / or berberine; 2. Anti-allergic action when using berberine and / or sodium azulene sulfonate, anti-inflammatory and astringent action, and when using cromoglycate sodium, When using berberine, sodium cyanocobalamin, or sodium azulene sulfonate, it produces a bright yellow, red, or purple color, so it can be used happily by using as eye drops for children and syrup for children. There are effects other than the effect of a mere stabilizer, such as enhancing compliance.
[0011]
The present invention relates to an aqueous solution of pranoprofen in which bisulfite, berberine, cyanocobalamin, sodium azulenesulfonate or sodium cromoglycate is blended alone or in combination as a stabilizer for pranoprofen.
[0012]
The aqueous liquid preparation of the present invention can be widely used regardless of the dosage form as long as it is an aqueous liquid preparation such as eye drops, nasal drops, eyewashes, syrups and the like.
[0013]
In the aqueous liquid preparation of the present invention, the concentration of pranoprofen as an active ingredient is preferably 0.01 to 0.2 (w / v)%, more preferably 0.05 as an eye drop or nasal drop. To 0.1 (w / v)%, and as an eye wash, preferably 0.001 to 0.02 (w / v)%, more preferably 0.005 to 0.01 (w / v)%. As an internal use liquid medicine (including syrup), it is 0.75 to 3 (w / v)%, more preferably 1.0 to 2 (w / v)%.
[0014]
Examples of the bisulfites that can be used in the aqueous liquid preparation of the present invention include sodium bisulfite, potassium bisulfite, and its components sodium pyrosulfite and potassium pyrosulfite. Of these, preferred bisulfites are sodium bisulfite and potassium bisulfite, and more preferred bisulfites are sodium bisulfite. The above bisulfites may be used alone or in combination of two or more. The concentration of the bisulfites can be appropriately selected, but is preferably 0.0025 to 2 (w / v)%, and more preferably 0.0125 to 1 (w / v)%. In addition, the blending ratio of pranoprofen and bisulfite at this time is preferably 1: 0.25 to 10 (weight ratio). In addition, the said density | concentration and a mixture ratio are the total density | concentrations or a weight, when using the said bisulfite in combination.
[0015]
Examples of the berberine that can be used in the aqueous liquid preparation of the present invention include berberine chloride, berberine sulfate, plant extracts containing berberine such as a buckwheat extract and abalone extract. Of these, berberine sulfate and berberine chloride are preferred. The said berberines may be used independently and may be used in combination of 2 or more type.
[0016]
The concentration of berberine, cyanocobalamin or sodium azulenesulfonate can be selected as appropriate, but is preferably 0.0002 to 0.1 (w / v)%, particularly preferably 0.001 to 0.05 (w / v)%. . Moreover, it is preferable that the compounding ratio of pranoprofen and berberine, cyanocobalamin, or sodium azulenesulfonate at this time is 1: 0.02-0.5 (weight ratio). In addition, when the said berberine is used in combination, the said use density | concentration and a mixture ratio are the density | concentration or weight of the sum total.
[0017]
The concentration of cromoglycate sodium can be appropriately selected, but is preferably 0.04 to 8 (w / v)%, particularly preferably 0.05 to 4 (w / v)%. The blending ratio of pranoprofen and sodium cromoglycate at this time is preferably 1: 0.5 to 40 (weight ratio), more preferably 1: 1 to 10, most preferably 1: 1 to 3. is there.
[0018]
When blending at least one selected from pranoprofen and berberine, cyanocobalamin or sodium azulene sulfonate and sodium cromoglycate, the concentration is preferably the above-mentioned component concentrations, and the ratio of prey is preferably 1: 0.02-0.5: 0.5-40, more preferably 1: 0.02-0.5: 1-10, most preferably 1: 0.02-0.5: 1-3 (weight ratio) ).
[0019]
In addition to adding bisulfite, berberine, cyanocobalamin, sodium azulenesulfonate or sodium cromoglycate to pranoprofen alone or in combination, the aqueous liquid preparation of the present invention is a buffer, isotonic agent, pH adjuster Additives such as solubilizing agents and preservatives and other pharmaceutically active ingredients may be added as appropriate.
[0020]
Examples of the buffer include boric acid or a salt thereof (such as borax), phosphoric acid or a salt thereof (such as sodium hydrogen phosphate), citric acid or a salt thereof (such as sodium citrate), acetic acid or a salt thereof (such as sodium acetate) ), Tartaric acid or salts thereof (sodium tartrate, etc.), sodium gluconate, sodium L-glutamate, sodium carbonate, sodium bicarbonate, sodium chloride, potassium chloride, calcium chloride, aminoethylsulfonic acid, epsilon-aminocaproic acid, monoethanolamine , Creatinine, tomometamol, glucose and glycerin or combinations thereof.
[0021]
The concentration of the buffering agent can be appropriately selected within a pharmaceutically acceptable range depending on the use of the aqueous liquid preparation.
[0022]
Examples of tonicity agents include polyhydric alcohols such as glycerin and propylene glycol, saccharides such as sorbitol, xylitol, mannitol, and glucose, sodium hydroxide, sodium chloride, potassium chloride, magnesium chloride, boric acid or salts thereof, and phosphoric acid. Or a salt thereof, citric acid or a salt thereof, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen sulfite and the like.
[0023]
The concentration of the tonicity agent can be appropriately selected within a pharmaceutically acceptable range depending on the use of the aqueous liquid preparation.
[0024]
Examples of the pH adjuster include boric acid or a salt thereof, phosphoric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, tartaric acid or a salt thereof, sodium carbonate, sodium bicarbonate, hydrochloric acid, sodium hydroxide, hydroxide Examples include potassium and monoethanolamine.
[0025]
These pH adjusters can be added in an appropriate amount in order to adjust the pH according to the use of the aqueous liquid preparation.
[0026]
Examples of solubilizers include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monofatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene monostearate, polyoxyethylene Hydrophilic nonionic such as polyoxyethylene mono fatty acid esters such as monooleate and polyoxyethylene monopalmitate, polyoxyethylene alcohol ether such as polyoxyethylene lauryl ether, polyethylene glycol and polyoxyethylene hydrogenated castor oil Surfactant, polyethylene glycol, propylene glycol, trometamol, polyvinylpyrrolidone, macrogol, glycerin and the like can be mentioned.
[0027]
Examples of preservatives include bisulfite, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, dehydroacetic acid or its salts (such as sodium dehydroacetate), benzoic acid and its salts (such as sodium benzoate), paraoxybenzoic acid Examples include esters (methyl paraben, ethyl paraben, propyl paraben, butyl paraben, etc.), sorbic acid or salts thereof (potassium sorbate, etc.), chlorobutanol, phenylethyl alcohol, boric acid or salts thereof.
[0028]
However, when the aqueous liquid preparation of the present invention contains sodium cromoglycate, turbidity of the liquid preparation is remarkably generated, and therefore quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate are not included.
[0029]
Examples of other additives other than those described in the claims include sodium edetate, cyclodextrin, sodium thiosulfate, sodium pyrosulfite, ethanol, glycerin, trometamol, creatinine, dibutylhydroxytoluene, L-cysteine, Examples thereof include L-methionine, citric acid or a salt thereof.
[0030]
Examples of the thickening agent include polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, chondroitin sulfate, hyaluronic acid salt, alginic acid salt, and fucoidans.
[0031]
Examples of the refreshing agent or fragrance include menthol, 3-l-menthoxypropane-1,2-diol, borneol, camphor, geraniol, limonene, mint water, mint oil, agate, eucalyptus oil, bergamot oil, fennel oil, And thymol.
[0032]
Examples of the corrigent include saccharin, sugar and glucose.
[0033]
Other pharmaceutically active ingredients are not particularly limited, but for example, decongestants (naphazoline hydrochloride, tetrahydrozoline hydrochloride, etc.), anti-inflammatory / astringents (neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, dipotassium glycyrrhizinate, zinc sulfate , Zinc lactate, lysozyme chloride, etc.), antihistamines (diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), vitamins (sodium flavin adenine dinucleotide, retinol acetate and retinol palmitate, pyridoxine hydrochloride, panthenol and pantothenate, tocopherol acetate Etc.), amino acids (L-aspartate, aminoethylsulfonic acid, chondroitin sodium sulfate, etc.), sulfa drugs, inorganic salts such as sodium chloride, bactericides (isopropyl Butylphenol, hinokitiol, etc.), local anesthetics (lidocaine, lidocaine hydrochloride, procaine hydrochloride, can be appropriately compounded like dibucaine hydrochloride, etc.).
[0034]
Examples of the container filled with the aqueous liquid preparation include glass containers as well as synthetic resin containers such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, and polyarylate.
[0035]
Examples of the film for sealing the container filled with the aqueous liquid agent include synthetic resin films such as polyethylene, polypropylene, polyurethane, polyamide, and polyethylene terephthalate, films obtained by laminating those resins, and aluminum foil.
[0036]
The aqueous liquid preparation of the present invention is used as eye drops, nasal drops and internal liquids. The pH when used as eye drops is usually 6.5 to 8.5, preferably 7.0 to 8.0, and the pH when used as nasal drops is usually 6.0 to 8.5, preferably 7.0. Adjust to ~ 8.0.
[0037]
The method for producing the aqueous liquid preparation of the present invention varies depending on the type of the liquid preparation, but pranoprofen is poorly soluble in acidic liquids, and when bisulfite is used as a stabilizer, bisulfite is weak. In consideration of the acidity, each can be produced by employing a conventional production method.
[0038]
Although the formulation example of the aqueous liquid preparation of this invention is shown below, these examples are for demonstrating this invention better and do not limit the scope of the present invention.
[0039]
【Example】
experimental method
The container shown in the reference examples and examples is left under irradiation of a light source having a wavelength spectrum approximate to sunlight in a dark room (the light amount at this time is 1600 lux on average), and the total light irradiation amount (lux × light irradiation) The remaining amount (%) of pranoprofen over time was measured over time. The results are as shown in Tables 1-3.
[0040]
Effect of bisulfite on photostability
Reference Example 1 (eye drops)
Sodium hydrogen phosphate 12-hydrate 3000 mg
Sodium dihydrogen phosphate dihydrate 350 mg
Sodium chloride 300 mg
Methyl paraoxybenzoate 25 mg
Propyl paraoxybenzoate 10 mg
Planoprofen 50 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0041]
Preparation method
Dissolve sodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride in about 90 mL of sterile purified water, warm to about 50 ° C., add methyl paraoxybenzoate, propyl paraoxybenzoate and pranoprofen with stirring, Dissolve. After cooling to room temperature, 1 mol / L sodium hydroxide is added to adjust the solution to pH 7.3, and then the total volume is 100 mL. After filtration with a membrane filter, fill a colorless 10 mL synthetic resin container. The same applies to Examples 1 to 3, but the pH is adjusted after adding the stabilizer.
[0042]
Example 1 (eye drops)
Sodium hydrogen phosphate 12-hydrate 3000 mg
Sodium dihydrogen phosphate dihydrate 350 mg
Sodium chloride 300 mg
Methyl paraoxybenzoate 25 mg
Propyl paraoxybenzoate 10 mg
Planoprofen 50 mg
Sodium bisulfite 200 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0043]
Example 2 (eye drops)
Sodium hydrogen phosphate 12-hydrate 3000 mg
Sodium dihydrogen phosphate dihydrate 350 mg
Glycerin 1000 mg
Methyl paraoxybenzoate 25 mg
Propyl paraoxybenzoate 10 mg
Planoprofen 50 mg
Sodium bisulfite 200 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0044]
Example 3 (eye drops)
Sodium hydrogen phosphate 12-hydrate 3000 mg
Sodium dihydrogen phosphate dihydrate 350 mg
Propylene glycol 1000 mg
Methyl paraoxybenzoate 25 mg
Propyl paraoxybenzoate 10 mg
Planoprofen 50 mg
Sodium bisulfite 200 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0045]
Reference Example 2 (eye drops)
Boric acid 1600 mg
Borax 400 mg
Polysorbate 80 100 mg
Planoprafen 50 mg
1% benzalkonium chloride solution 0.5 mL
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.5
[0046]
Preparation method
Boric acid and borax are dissolved in about 80 mL of sterilized purified water while stirring, and then polysorbate 80 is poured into water. After dissolving pronoprofen, adding 1% benzalkonium chloride solution and adding 1 mol / L sodium hydroxide solution, the pH of the solution was adjusted to 7.5, and then water was added to the total amount Set to 100 mL. After filtering with a membrane filter, fill a colorless 10 mL synthetic resin container. The same applies to Examples 4 to 13, but the pH is adjusted after adding the stabilizer.
[0047]
Example 4 (eye drops)
Boric acid 1600 mg
Borax 400 mg
Sodium citrate 800 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 100 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.5
[0048]
Example 5 (eye drops)
Boric acid 1600 mg
Borax 400 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 100 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.5
[0049]
Reference Example 3 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 350 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0050]
Preparation method
It was prepared in the same manner as in Reference Example 2.
[0051]
Example 6 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 12.5 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0052]
Example 7 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 25 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0053]
Example 8 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 50 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0054]
Example 9 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 100 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0055]
Example 10 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 200 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0056]
Example 11 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 300 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0057]
Example 12 (eye drops)
Citric acid 100 mg
Sodium citrate 800 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 10 mg
Borax 360 mg
Glycerin 1000 mg
Polysorbate 80 100 mg
Planoprofen 50 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 400 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.3
[0058]
Example 13 (nasal drops)
Boric acid 800 mg
Borax 260 mg
Glycerol 2000 mg
Polysorbate 80 100 mg
Tetrahydrozoline hydrochloride 100 mg
Planoprofen 200 mg
1% benzalkonium chloride solution 0.5 mL
Sodium bisulfite 200 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.5
[0059]
Example 14 (Liquid preparation for internal use)
Saccharin sodium 10 mg
Sodium benzoate 70 mg
Sodium edetate 50 mg
Polysorbate 80 1000 mg
Planoprofen 1500 mg
Sodium bisulfite 1500 mg
1 mol / L sodium hydroxide solution
Sterilized purified water
Total volume 100 mL
pH 7.5
[0060]
[Table 1]

[0061]
The effect of sodium bisulfite on the light stability of pranoprofen was observed. As is clear from the results shown in Table 1, all of them exhibited an excellent inhibitory effect for a long time against the decomposition of pranoprofen by exposure.
[0062]
[Table 2]

[0063]
The same type and amount of additives such as buffering agent, preservative, tonicity agent, etc., the amount of sodium bisulfite added can be changed, and the amount added to stabilize pranoprofen under light irradiation. We examined to find out. As is clear from the results shown in Table 2, a sufficient effect was observed when the ratio of sodium bisulfite to pranoprofen was added at 0.25 or more.
[0064]
Reference example 4
Niflan ophthalmic solution (planoprofen 1 w / v% formulation) containing boric acid, borax, polysorbate 80, sodium edetate, and benzalkonium chloride as additives. Manufactured by: Senju Pharmaceutical Co., Ltd. Sale: Takeda Pharmaceutical Co., Ltd.) was transferred to the same colorless 10 mL synthetic resin container as the other Reference Examples and Examples so that the exposure conditions were the same, and used as a sample.
[0065]
Reference Examples 5 to 13 and Examples 15 to 18 (eye drops)
Boric acid 350 mg
Borax 90 mg
Epsilon-aminocaproic acid 500 mg
Glycerin 1500 mg
Methyl paraoxybenzoate 30 mg
Propyl paraoxybenzoate 10 mg
Planoprofen 50 mg
Reference Example (or Example) Addition Compound (See Table 3) Amounts listed in Table 3
Sterilized purified water
Total volume 100 mL
[0066]
Preparation method
Dissolve boric acid, borax, epsilon-aminocaproic acid and glycerin in about 90 mL of sterile purified water, warm to about 50 ° C., add methyl paraoxybenzoate, propyl paraoxybenzoate and pranoprofen with stirring and dissolve To do. The additive compounds shown in Table 3 are added so as to have the indicated concentrations, dissolved, cooled, and then made up to a total volume of 100 mL. After filtering with a membrane filter, fill a colorless 10 mL synthetic resin container to make a sample.
[0067]
Reference Example 14 and Examples 19 to 46 (eye drops)
Citric acid 100 mg
Borax 350 mg
Epsilon-aminocaproic acid 500 mg
Sodium edetate 5 mg
Glycerin 1500 mg
Methyl paraoxybenzoate 30 mg
Propyl paraoxybenzoate 10 mg
l-Menthol 5 mg
d-Camphor 5 mg
Planoprofen 50 mg
Reference Example (or Example) Addition Compound (See Table 3) Amounts listed in Table 3
Sterilized purified water
Total volume 100 mL
[0068]
{Production method}
Dissolve citric acid, borax, epsilon-aminocaproic acid, sodium edetate and glycerin in about 90 mL of sterilized purified water, warm to about 50 ° C., stir with stirring, methyl paraoxybenzoate, propyl paraoxybenzoate, l-menthol, d Add and dissolve camphor and pranoprofen. Further, the additive compounds shown in Table 3 are added so as to have the indicated concentrations, dissolved, cooled, and made up to a total volume of 100 mL. After filtering with a membrane filter, fill a colorless 10 mL synthetic resin container to make a sample.
[0069]
[Table 3]

[0070]
In Table 3, Reference Examples (Reference Examples 4 to 14 in Table 3) to which berberines (berberine chloride or berberine chloride), cyanocobalamin or sodium azulenesulfonate are not added, and examples in which berberines, cyanocobalamin or sodium azulenesulfonate are added As is clear from the comparison with (Examples 16 to 18, 20 to 27, 32 to 35 and 40 to 43 in Table 3), berberine, cyanocobalamin or sodium azulenesulfonate is in a concentration-dependent manner, pranoprofen. The content reduction and the dust caused by light irradiation were suppressed.
[0071]
Moreover, in the example of addition of sodium cromoglycate (Examples 15 and 19 in Table 3), although no remarkable effect was observed regarding the suppression of decomposition, the effect of suppressing turbidity was noticeable. Moreover, in addition to Examples 16-18, 20-27, 32-35 and 40-43 and addition of berberine, sodium cyanocobalamin or azulene sulfonate, examples in which cromoglycate sodium was further added (Examples 28 to 28 in Table 3) 31, 36-39 and 44-46), in the examples where sodium cromoglycate was added, the photodecomposition and turbidity of pranoprofen were more effective especially in the low concentration range and as the total light irradiation increased. It was suppressed.
[0072]
【The invention's effect】
In the present invention, the decrease in content or dust of pranoprofen, which is an active ingredient in the aqueous liquid preparation, is significantly suppressed, and long-term storage under light irradiation is possible.

Claims (5)

A planoprofen aqueous solution that is stable to light, comprising pranoprofen and at least one stabilizer selected from the group consisting of bisulfites, berberines, cyanocobalamin, and sodium azulenesulfonate. The aqueous liquid preparation according to claim 1, wherein the bisulfites are at least one selected from sodium bisulfite and potassium bisulfite, or sodium pyrosulfite and potassium pyrosulfite which are constituents thereof. The aqueous solution according to claim 1, wherein the berberine is at least one selected from plant extracts containing berberine chloride, berberine sulfate and berberine. The aqueous liquid preparation according to any one of claims 1 to 3, further comprising sodium cromoglycate as a stabilizer. An aqueous solution of pranoprofen which is stable to light and contains pranoprofen and sodium cromoglycate, and does not contain quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate.