JPWO2020017571A1 - Flurbiprofen axetyl-containing fat emulsion and its production method - Google Patents

Flurbiprofen axetyl-containing fat emulsion and its production method Download PDF

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JPWO2020017571A1
JPWO2020017571A1 JP2020531351A JP2020531351A JPWO2020017571A1 JP WO2020017571 A1 JPWO2020017571 A1 JP WO2020017571A1 JP 2020531351 A JP2020531351 A JP 2020531351A JP 2020531351 A JP2020531351 A JP 2020531351A JP WO2020017571 A1 JPWO2020017571 A1 JP WO2020017571A1
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axetyl
flurbiprofen
lecithin
fat emulsion
oils
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喜一郎 鍋田
喜一郎 鍋田
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Techno Guard Co Ltd
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Abstract

本発明の課題は、脂肪乳剤が多くの量のフルルビプロフェンアキセチルを担持することができるように油脂の含量が多いにもかかわらず、透明性を有するとともに安定性に優れ、加えて乳化剤としてレシチンを用いることで安全性に優れるフルルビプロフェンアキセチル含有脂肪乳剤およびその製造方法を提供することである。その解決手段としての本発明のフルルビプロフェンアキセチル含有脂肪乳剤は、フルルビプロフェンアキセチル、油脂、乳化剤、水性媒体を少なくとも構成成分とするフルルビプロフェンアキセチル含有脂肪乳剤であって、油脂の含量が３〜５０ｍｇ／ｍＬ、油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）が０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）、乳化剤としてのレシチンの含量が２０〜１５０ｍｇ／ｍＬ（用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよい）であり、濁度が０．５以下であることを特徴とする。The subject of the present invention is that despite the high content of fats and oils so that the fat emulsion can carry a large amount of flurbiprofen axetyl, it is transparent and stable, and in addition, it is an emulsifier. It is an object of the present invention to provide a flurbiprofen axetyl-containing fat emulsion having excellent safety by using lecithin and a method for producing the same. The flurubiprofene axetyl-containing fat emulsion of the present invention as a solution thereof is a flurubiprofen axetyl-containing fat emulsion containing at least flurubiprofen axetyl, a fat, an emulsifier, and an aqueous medium as constituents. , The content of fats and oils is 3 to 50 mg / mL, and the weight ratio of flurubiprofen axetyl to fats and oils (flurubiprofen axetyl / fats and oils) is 0.1 to 5 (however, the total of flurubiprofen axetyl and fats and oils). The maximum content is 100 mg / mL), the content of lecithin as an emulsifier is 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin), and the turbidity is 0.5 or less. It is characterized by being.

Description

本発明は、透明性を有するとともに安定性と安全性に優れるフルルビプロフェンアキセチル含有脂肪乳剤およびその製造方法に関する。 The present invention relates to a flurbiprofen axetyl-containing fat emulsion having transparency and excellent stability and safety, and a method for producing the same.

下記の化学構造式で示されるフルルビプロフェンアキセチル（Ｆｌｕｒｂｉｐｒｏｆｅｎ ａｘｅｔｉｌ）は、優れた抗炎症作用を有するが、油状物質であって水難溶性であることから（日本薬局方・通則に規定の水への溶解性が「ほとんど溶けない」（溶質１ｇまたは１ｍＬを溶かすために要する溶媒量が１００００ｍＬ以上：溶質が薬物に相当し溶媒が水に相当））、脂肪乳剤化して上市され、汎用されていることは当業者によく知られた事実である。しかしながら、こうしたフルルビプロフェンアキセチル含有脂肪乳剤は、フルルビプロフェンアキセチルの含量に比較して大量の油脂（その含量は少なく見積もっても例えば１００ｍｇ／ｍＬ以上である）が用いられた乳白状の製剤であり、変質や異物混入の有無、配合変化を目視で容易に確認できないことから使用の可否判断が困難であるといった制約を有している。そこで、このような制約が緩和された、透明性を有するとともに安定性に優れるフルルビプロフェンアキセチル含有脂肪乳剤が求められており、その解決手段として、本発明者は、特許文献１において、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を提案している。 Flurbiprofen axetil, which is represented by the following chemical structural formula, has an excellent anti-inflammatory effect, but is an oily substance and sparingly soluble in water. Solubility in "almost insoluble" (10000 mL or more of solvent required to dissolve 1 g or 1 mL of solute: solute corresponds to drug and solvent corresponds to water), fat emulsion was put on the market and widely used. It is a well-known fact to those in the art. However, such a flurbiprofen axetyl-containing fat emulsion is a milky white containing a large amount of fat (the content of which is at least 100 mg / mL or more) compared to the content of flurbiprofen axetil. It is a state-like preparation, and has restrictions that it is difficult to judge whether or not it can be used because it is not possible to easily visually confirm the presence or absence of alteration or contamination with foreign substances and the change in formulation. Therefore, there is a demand for a flurbiprofen axetyl-containing fat emulsion in which such restrictions are relaxed, which is transparent and has excellent stability. We are proposing a drug-containing fat emulsion that is transparent and has excellent stability.

Figure 2020017571
Figure 2020017571

特許文献１において本発明者が提案した薬物含有脂肪乳剤は、油脂の含量を最大で２ｍｇ／ｍＬにすることで製造することができるものであり、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤として評価されている。しかしながら、この薬物含有脂肪乳剤は、油脂の含量が最大で２ｍｇ／ｍＬと少ないため、脂肪乳剤が担持することができる薬物の量に制限があることから、脂肪乳剤がより多くの量の薬物を担持することができるようにより多くの量の油脂が用いられ、それでいて透明性を有するとともに安定性に優れる薬物含有脂肪乳剤が要望されている。加えて、その製造に際しては、脂肪乳剤を製造するための乳化剤として知られているものの中でも、レシチンを用いることが、乳化力が弱く、また、高濃度において粘度が高いことから取り扱いが必ずしも容易でないものの、安全性が高いことから期待されており、こうした要求に応えるべく、本発明者はその開発を試みてきたが、これまで有効な解決手段を見出すには至らなかった。 The drug-containing fat emulsion proposed by the present inventor in Patent Document 1 can be produced by setting the fat content to a maximum of 2 mg / mL, and is a drug-containing fat having transparency and excellent stability. It is evaluated as an emulsion. However, since this drug-containing fat emulsion has a low fat content of 2 mg / mL at the maximum, the amount of the drug that the fat emulsion can carry is limited, so that the fat emulsion can carry a larger amount of the drug. A larger amount of fats and oils are used so that they can be carried, and there is a demand for a drug-containing fat emulsion that is transparent and has excellent stability. In addition, in the production thereof, it is not always easy to use lecithin among those known as emulsifiers for producing a fat emulsion because the emulsifying power is weak and the viscosity is high at a high concentration. However, it is expected because of its high safety, and the present inventor has tried to develop it in order to meet such a demand, but has not found an effective solution so far.

特許第５３４０９５４号公報Japanese Patent No. 5340954

そこで本発明は、脂肪乳剤が多くの量のフルルビプロフェンアキセチルを担持することができるように油脂の含量が多いにもかかわらず、透明性を有するとともに安定性に優れ、加えて乳化剤としてレシチンを用いることで安全性に優れるフルルビプロフェンアキセチル含有脂肪乳剤およびその製造方法を提供することを目的とする。 Therefore, the present invention has transparency and excellent stability, and also as an emulsifier, despite having a high content of fats and oils so that the fat emulsion can carry a large amount of flurbiprofen axetyl. It is an object of the present invention to provide a flurbiprofen axetyl-containing fat emulsion having excellent safety by using lecithin and a method for producing the same.

本発明者は上記の点に鑑みて鋭意研究を行った結果、油脂の含量、油脂に対するフルルビプロフェンアキセチルの重量比率、フルルビプロフェンアキセチルと油脂の合計含量、乳化剤としてのレシチンの含量を好適な数値範囲とすることにより、２ｍｇ／ｍＬを超える量の油脂を用いたフルルビプロフェンアキセチル含有脂肪乳剤であるにもかかわらず、透明性を有するとともに安定性に優れ、加えて乳化剤としてレシチンを用いていることで安全性に優れるフルルビプロフェンアキセチル含有脂肪乳剤を製造することができることを知見した。 As a result of diligent research in view of the above points, the present inventor has conducted intensive studies on the content of fats and oils, the weight ratio of flurbiprofen axetil to fats and oils, the total content of flurbiprofen axetil and fats and oils, and lecithin as an emulsifier. By setting the content in a suitable numerical range, although it is a flurbiprofen axetyl-containing fat emulsion using an amount of fat and oil exceeding 2 mg / mL, it has transparency and excellent stability, and in addition. It was found that by using lecithin as an emulsifier, a fat emulsion containing flurbiprofen axetyl, which is excellent in safety, can be produced.

以上の知見に基づいてなされた本発明は、請求項１記載の通り、フルルビプロフェンアキセチル、油脂、乳化剤、水性媒体を少なくとも構成成分とするフルルビプロフェンアキセチル含有脂肪乳剤であって、油脂の含量が３〜５０ｍｇ／ｍＬ、油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）が０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）、乳化剤としてのレシチンの含量が２０〜１５０ｍｇ／ｍＬ（用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよい）であり、濁度が０．５以下であることを特徴とする。
また、請求項２記載のフルルビプロフェンアキセチル含有脂肪乳剤は、請求項１記載のフルルビプロフェンアキセチル含有脂肪乳剤において、脂肪粒子の平均粒子径が１〜１５０ｎｍであることを特徴とする。
また、請求項３記載のフルルビプロフェンアキセチル含有脂肪乳剤は、請求項１記載のフルルビプロフェンアキセチル含有脂肪乳剤において、プロピレングリコール、グリセリン、マクロゴール、乳酸、Ｎ，Ｎ−ジメチルアセトアミド、ポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、コンドロイチン硫酸またはその塩、ヒアルロン酸またはその塩、グリチルリチン酸またはその塩から選ばれる少なくとも１つをさらに構成成分とすることを特徴とする。
また、請求項４記載のフルルビプロフェンアキセチル含有脂肪乳剤は、請求項１記載のフルルビプロフェンアキセチル含有脂肪乳剤において、糖類をさらに構成成分とすることを特徴とする。
また、本発明は、請求項５記載の通り、フルルビプロフェンアキセチル、油脂、乳化剤、水性媒体を少なくとも構成成分とする、濁度が０．５以下であるフルルビプロフェンアキセチル含有脂肪乳剤の製造方法であって、油脂の含量を３〜５０ｍｇ／ｍＬ、油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）を０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）、乳化剤としてのレシチンの含量を２０〜１５０ｍｇ／ｍＬ（用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよい）として構成成分を乳化することを特徴とする。
また、請求項６記載の製造方法は、請求項５記載の製造方法において、乳化を３５０〜１５００バールの圧力で行うことを特徴とする。As described in claim 1, the present invention made based on the above findings is a flurbiprofen axetyl-containing fat emulsion containing at least a flurbiprofen axetyl, a fat, an emulsifier, and an aqueous medium as constituents. , The content of fats and oils is 3 to 50 mg / mL, and the weight ratio of flurbiprofen axetyl to fats and oils (flurbiprofen axetyl / fats and oils) is 0.1 to 5 (however, the total of flurbiprofen axetyl and fats and oils). The maximum content is 100 mg / mL), the content of lecithin as an emulsifier is 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin), and the turbidity is 0.5 or less. It is characterized by being.
The flurbiprofen axetyl-containing fat emulsion according to claim 2 is characterized in that the average particle size of fat particles is 1 to 150 nm in the flurbiprofen axetil-containing fat emulsion according to claim 1. do.
The flurbiprofen axetyl-containing fat emulsion according to claim 3 is the flurbiprofen axetyl-containing fat emulsion according to claim 1, wherein propylene glycol, glycerin, macrogol, lactic acid, N, N-dimethylacetamide. , Polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, chondroitin sulfate or a salt thereof, hyaluronic acid or a salt thereof, glycyrrhizic acid or a salt thereof, and at least one of them is further contained as a constituent component.
Further, the flurbiprofen axetyl-containing fat emulsion according to claim 4 is characterized in that the flurbiprofen axetil-containing fat emulsion according to claim 1 further contains a saccharide as a constituent component.
Further, as described in claim 5, the present invention comprises a flurbiprofen axetyl-containing fat having a turbidity of 0.5 or less, which comprises at least a flurbiprofen axetyl, an oil or fat, an emulsifier, and an aqueous medium as constituents. An emulsion production method in which the content of fats and oils is 3 to 50 mg / mL, and the weight ratio of flurbiprofen axetyl to fats and oils (flurbiprofen axetyl / fats and oils) is 0.1 to 5 (however, flurbiprofen). The total content of fenaxetyl and fats and oils is 100 mg / mL at maximum), and the content of lecithin as an emulsifier is 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin). It is characterized by emulsifying.
The production method according to claim 6 is characterized in that the production method according to claim 5 is emulsified at a pressure of 350 to 1500 bar.

本発明によれば、脂肪乳剤が多くの量のフルルビプロフェンアキセチルを担持することができるように油脂の含量が多いにもかかわらず、透明性を有するとともに安定性に優れ、加えて乳化剤としてレシチンを用いることで安全性に優れるフルルビプロフェンアキセチル含有脂肪乳剤およびその製造方法を提供することができる。 According to the present invention, despite the high content of fats and oils so that the fat emulsion can carry a large amount of flurbiprofen axetyl, it is transparent and stable, and in addition, it is an emulsifier. By using lecithin as an emulsion, it is possible to provide a flurbiprofen axetyl-containing fat emulsion having excellent safety and a method for producing the same.

本発明は、フルルビプロフェンアキセチル、油脂、乳化剤、水性媒体を少なくとも構成成分とするフルルビプロフェンアキセチル含有脂肪乳剤であって、油脂の含量が３〜５０ｍｇ／ｍＬ、油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）が０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）、乳化剤としてのレシチンの含量が２０〜１５０ｍｇ／ｍＬ（用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよい）であり、濁度が０．５以下であることを特徴とするものである。 The present invention is a flurbiprofen axetyl-containing fat emulsion containing flurbiprofen axetyl, fats and oils, an emulsifier, and an aqueous medium as at least components, and has a fat content of 3 to 50 mg / mL and flurbi with respect to fats and oils. The weight ratio of profen axetil (flurbiprofen axetyl / fat) is 0.1 to 5 (however, the total content of flurbiprofen axetil and fat is 100 mg / mL at maximum), and the content of lecithin as an emulsifier. Is 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin), and the turbidity is 0.5 or less.

本発明において、油脂としては、大豆油、トウモロコシ油、ヤシ油、サフラワー油、エゴマ油、オリーブ油、ヒマシ油、綿実油などの植物油の他、ラノリンなどの動物油、卵黄油、魚油、流動パラフィンなどの鉱物油、中鎖脂肪酸トリグリセリド、化学合成トリグリセリド、ゲル化炭化水素など、油脂として用いることができる公知の油脂が挙げられる。 In the present invention, the fats and oils include vegetable oils such as soybean oil, corn oil, palm oil, saflower oil, egoma oil, olive oil, castor oil and cottonseed oil, animal oils such as lanolin, egg yolk oil, fish oil, liquid paraffin and the like. Examples thereof include known fats and oils that can be used as fats and oils, such as mineral oils, medium-chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons.

本発明において、乳化剤として用いるのはレシチンである。具体的には、卵黄レシチン、大豆レシチン、水素添加卵黄レシチン、水素添加大豆レシチンなど、乳化剤として用いることができる公知のレシチンであってよい。なお、レシチンの乳化力を補ったり、高濃度でレシチンを用いた場合の粘度の高まりを抑制しつつ、レシチンが有する安全性が発揮されるように、用いるレシチンの５０重量％以下を乳化剤として用いることができる他の物質、例えば、ポリソルベート２０，４０，６０，６５，８０などのポリソルベート（ポリオキシエチレンソルビタン脂肪酸エステル）、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油などに置き換えてもよい（置き換えた他の乳化剤に効果を十分に発揮させるためには用いるレシチンの１０重量％以上を置き換えることが望ましい）。 In the present invention, lecithin is used as an emulsifier. Specifically, it may be a known lecithin that can be used as an emulsifier, such as egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin. In addition, 50% by weight or less of the lecithin used is used as an emulsifier so that the safety of lecithin can be exhibited while supplementing the emulsifying power of lecithin and suppressing the increase in viscosity when lecithin is used at a high concentration. It may be replaced with other substances that can be used, such as polysolvates (polyoxyethylene sorbitan fatty acid esters) such as polysolvates 20, 40, 60, 65, 80, polyoxyethylene lecithin oil, polyoxyethylene hardened lecithin oil, etc. ( It is desirable to replace 10% by weight or more of the lecithin used in order for the other emulsifiers that have been replaced to exert their effects sufficiently).

本発明において、水性媒体としては、水（純水や精製水や注射用水など）の他、酢酸−酢酸ナトリウム、ホウ酸−炭酸ナトリウム、ホウ酸−四ホウ酸ナトリウム、塩酸−四ホウ酸ナトリウム、リン酸−リン酸ナトリウム、リン酸二水素ナトリウム−リン酸水素二ナトリウム、クエン酸−水酸化ナトリウム、塩酸−フタル酸水素カリウム、水酸化ナトリウム−フタル酸水素カリウム、クエン酸−リン酸水素二ナトリウム、コハク酸−四ホウ酸ナトリウム、アンモニア−塩化アンモニウム、リン酸二水素カリウム−リン酸水素二ナトリウム−リン酸、リン酸二水素カリウム−リン酸水素二ナトリウム−水酸化ナトリウム、リン酸二水素カリウム−リン酸水素二ナトリウム、リン酸二水素カリウム−水酸化ナトリウム、リン酸水素二ナトリウム−水酸化ナトリウムなどを水に添加することで所定のｐＨ、例えば３．５〜９．０、望ましくは４．０〜８．０、より望ましくは４．５〜７．０の範囲のｐＨに調整した緩衝液が挙げられる。 In the present invention, the aqueous medium includes water (pure water, purified water, water for injection, etc.), acetic acid-sodium acetate, borate-sodium carbonate, borate-sodium tetraborate, hydrochloric acid-sodium tetraborate, and the like. Disodium Phosphate-Sodium Phosphate, Sodium Dihydrogen Phosphate-Disodium Hydrogen Phosphate, Citrate-Sodium Hydroxide, Hydrochloric Acid-Potato Hydrogen Phosphate, Sodium Hydroxide-Potassium Hydrophthalate, Disodium Citrate-Disodium Hydrogen Phosphate , Succinic acid-sodium tetraborate, ammonia-ammonium chloride, potassium dihydrogen phosphate-disodium hydrogen phosphate-phosphate, potassium dihydrogen phosphate-disodium hydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate By adding disodium hydrogen phosphate, potassium dihydrogen phosphate-sodium hydroxide, disodium hydrogen phosphate-sodium hydroxide, etc. to water, a predetermined pH, for example 3.5 to 9.0, preferably 4 Examples thereof include a buffer solution adjusted to a pH in the range of 9.0 to 8.0, more preferably 4.5 to 7.0.

本発明において、油脂の含量を３〜５０ｍｇ／ｍＬと規定するのは、３ｍｇ／ｍＬよりも少ないと脂肪乳剤が担持できるフルルビプロフェンアキセチルの量が少なくなってしまう一方、５０ｍｇ／ｍＬよりも多いと油脂の量が多すぎることで乳化が困難になって透明性を有する脂肪乳剤が得にくくなるからである。油脂の含量は５〜４０ｍｇ／ｍＬが望ましく、７〜３５ｍｇ／ｍＬがより望ましく、１０〜３０ｍｇ／ｍＬがさらに望ましい。油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）を０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）と規定するのは、０．１よりも小さいとフルルビプロフェンアキセチルに対して油脂が過多となり、患者に対して無用な油脂を投与することになってしまう一方、５よりも大きいと油脂に対してフルルビプロフェンアキセチルが過多となり、フルルビプロフェンアキセチルの安定性が損なわれ、フルルビプロフェンアキセチルが凝集や析出しやすくなるからである。油脂に対するフルルビプロフェンアキセチルの重量比率は０．２〜３が望ましく、０．３〜２がより望ましい。フルルビプロフェンアキセチルと油脂の合計含量を最大で１００ｍｇ／ｍＬと規定するのは、１００ｍｇ／ｍＬよりも多いと透明性を有する脂肪乳剤を得るための乳化が困難になるからである。フルルビプロフェンアキセチルと油脂の合計含量は３〜９０ｍｇ／ｍＬが望ましい。乳化剤としてのレシチンの含量を２０〜１５０ｍｇ／ｍＬと規定するのは、２０ｍｇ／ｍＬよりも少ないとレシチンの量に対する油脂の量が多すぎることで乳化が困難になる一方、１５０ｍｇ／ｍＬよりも多いとレシチンの粘度が高くなることで乳化が困難になるからである。用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよいことは、前述の通りである。この場合、レシチンとレシチン以外の乳化剤の合計含量が２０〜１５０ｍｇ／ｍＬであり、５０重量％以上のレシチンと５０重量％以下のレシチン以外の乳化剤からなる。レシチンの含量は３０〜１４０ｍｇ／ｍＬが望ましく、５０〜１３０ｍｇ／ｍＬがより望ましい。フルルビプロフェンアキセチルと油脂に対するレシチンの重量比率（レシチン／（フルルビプロフェンアキセチル＋油脂））を１〜３０、望ましくは２〜２０、より望ましくは３〜１０とすることで、透明性を有するとともに安定性に優れる脂肪乳剤が得やすくなる（フルルビプロフェンアキセチルと油脂に対するレシチンの重量比率が３０を超えるとレシチンが凝集や析出する恐れが強くなる）。なお、フルルビプロフェンアキセチルの含量は例えば１〜３０ｍｇ／ｍＬであってよい。３ｍｇ／ｍＬ以上の量の油脂を用いることで、脂溶性を有するフルルビプロフェンアキセチルは油脂に溶解することにより、また、油脂に溶解しきれないフルルビプロフェンアキセチルは水と油脂の界面においてレシチンと共存することにより、より多くの量が脂肪乳剤に担持される。 In the present invention, the content of fats and oils is defined as 3 to 50 mg / mL. This is because if the amount is too large, the amount of fat and oil is too large, which makes emulsification difficult and makes it difficult to obtain a transparent fat emulsion. The content of fats and oils is preferably 5 to 40 mg / mL, more preferably 7 to 35 mg / mL, and even more preferably 10 to 30 mg / mL. The weight ratio of flurbiprofen axetil to fats and oils (flurbiprofen axetil / fats and oils) is specified as 0.1 to 5 (however, the total content of flurbiprofen axetil and fats and oils is 100 mg / mL at maximum). If it is less than 0.1, the amount of fat and oil will be excessive for flurbiprofen axetil, and unnecessary fat and oil will be administered to the patient, while if it is larger than 5, it will be for fat and oil. This is because the excess of flurbiprofen axetil impairs the stability of flurbiprofen axetil, and flurbiprofen axetil tends to aggregate and precipitate. The weight ratio of flurbiprofen axetil to fats and oils is preferably 0.2 to 3, more preferably 0.3 to 2. The maximum total content of flurbiprofen axetil and fats and oils is defined as 100 mg / mL because if it is more than 100 mg / mL, emulsification to obtain a transparent fat emulsion becomes difficult. The total content of flurbiprofen axetil and fats and oils is preferably 3 to 90 mg / mL. The content of lecithin as an emulsifier is defined as 20 to 150 mg / mL because if it is less than 20 mg / mL, the amount of fat and oil is too large for the amount of lecithin, which makes emulsification difficult, while it is more than 150 mg / mL. This is because the increase in the viscosity of lecithin makes emulsification difficult. As described above, 50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin. In this case, the total content of lecithin and the emulsifier other than lecithin is 20 to 150 mg / mL, and it is composed of 50% by weight or more of lecithin and 50% by weight or less of the emulsifier other than lecithin. The lecithin content is preferably 30-140 mg / mL, more preferably 50-130 mg / mL. Transparent by setting the weight ratio of lecithin to flurbiprofen axetil and fats and oils (lecithin / (flurbiprofen axetil + fats and oils)) to 1 to 30, preferably 2 to 20, and more preferably 3 to 10. It becomes easy to obtain a fat emulsion having properties and excellent stability (when the weight ratio of flurbiprofen axetil and lecithin to fats and oils exceeds 30, the risk of lecithin aggregation and precipitation increases). The content of flurbiprofen axetyl may be, for example, 1 to 30 mg / mL. Flurbiprofen axetil, which has fat solubility, can be dissolved in fats and oils by using an amount of 3 mg / mL or more, and flurbiprofen axetyl, which cannot be completely dissolved in fats and oils, can be used in water and fats and oils. By coexisting with lecithin at the interface, a larger amount is carried on the fat emulsion.

本発明のフルルビプロフェンアキセチル含有脂肪乳剤は、油脂の含量、油脂に対するフルルビプロフェンアキセチルの重量比率、フルルビプロフェンアキセチルと油脂の合計含量、乳化剤としてのレシチンの含量を上記の数値範囲に設定し、自体公知の手順、例えば、フルルビプロフェンアキセチル、油脂、レシチンをいったん均一に混合して溶解させて油相とし、これに水性媒体を加えた後、あるいは水性媒体を加えながら、超音波乳化機を用いて乳化したり、また、強力に撹拌して粗乳化液を調製し（例えば回転数が１００００〜１５０００ｒｐｍで５〜３０分間の攪拌による）、次いで粗乳化液をマントンゴーリンホモジナイザーなどの高圧乳化機を用いて乳化したりすることにより製造することができる。乳化機の運転条件や乳化時間を調節すれば、脂肪粒子の粒子径分布を狭くすることができる。また、脂肪粒子の粒子径分布を狭くするために、乳化は複数回行ってもよい（例えば３〜５０回）。特筆すべきは、油脂の含量、油脂に対するフルルビプロフェンアキセチルの重量比率、フルルビプロフェンアキセチルと油脂の合計含量、レシチンの含量を上記の数値範囲に設定することで、超音波乳化機を用いて乳化することによって、また、高圧乳化機を用いて例えば１５００バール以下、望ましくは３５０〜１０００バールの圧力で乳化することによって、脂肪粒子の平均粒子径が１５０ｎｍ以下、好適には１４０ｎｍ以下、より好適には１２０ｎｍ以下、さらに好適には１００ｎｍ以下であり（下限は例えば１ｎｍ）、濁度が０．５以下、好適には０．４以下、より好適には０．３以下、さらに好適には０．２以下の、透明性を有するとともに安定性に優れるフルルビプロフェンアキセチル含有脂肪乳剤が得やすくなる点にある。 The flurubiprofene axetyl-containing fat emulsion of the present invention has the above-mentioned contents of fats and oils, weight ratio of flurubiprofen axetyl to fats and oils, total content of flurubiprofen axetyl and fats and oils, and content of lecithin as an emulsifier. Set in the numerical range of, and the procedure known per se, for example, flurubiprofene axetyl, fat, and lecithin are once uniformly mixed and dissolved to form an oil phase, to which an aqueous medium is added, or an aqueous medium. While adding, emulsify using an ultrasonic emulsifier, or stir vigorously to prepare a crude emulsion (for example, by stirring at a rotation speed of 1000 to 15000 rpm for 5 to 30 minutes), and then the crude emulsion. Can be produced by emulsifying using a high-pressure emulsifier such as a manton gorin homogenizer. By adjusting the operating conditions of the emulsifier and the emulsification time, the particle size distribution of the fat particles can be narrowed. Further, in order to narrow the particle size distribution of the fat particles, emulsification may be performed a plurality of times (for example, 3 to 50 times). Of particular note is the ultrasonic emulsification by setting the content of fats and oils, the weight ratio of flurubiprofen axetil to fats and oils, the total content of flurubiprofen axetil and fats and oils, and the content of lecithin within the above numerical ranges. The average particle size of the fat particles is 150 nm or less, preferably 140 nm, by emulsifying with a machine, or by emulsifying with a high pressure emulsifier, for example at a pressure of 1500 bar or less, preferably 350 to 1000 bar or less. Hereinafter, it is more preferably 120 nm or less, further preferably 100 nm or less (the lower limit is, for example, 1 nm), and the turbidity is 0.5 or less, preferably 0.4 or less, more preferably 0.3 or less, and further. A fat emulsion containing flurubiprofene axetyl, which is preferably 0.2 or less and has transparency and excellent stability, can be easily obtained.

なお、本発明のフルルビプロフェンアキセチル含有脂肪乳剤の構成成分としてプロピレングリコール、グリセリン、マクロゴール、乳酸、Ｎ，Ｎ−ジメチルアセトアミド、ポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、コンドロイチン硫酸またはその塩（ナトリウム塩など）、ヒアルロン酸またはその塩（ナトリウム塩など）、グリチルリチン酸またはその塩（ナトリウム塩やアンモニウム塩など）などをさらに用いることで、フルルビプロフェンアキセチルの溶解性の向上、脂肪乳剤やフルルビプロフェンアキセチルの安定性の向上、脂肪乳剤の等張化などを図ってもよい。これらの含量は１〜１００ｍｇ／ｍＬが望ましく、１０〜５０ｍｇ／ｍＬがより望ましい。１ｍｇ／ｍＬよりも少ないと効果が発揮されにくくなる一方、１００ｍｇ／ｍＬよりも多いと粘度の上昇によって乳化が困難になったり、脂肪乳剤が酸性化されて不安定になったりしやすくなる。 The components of the flurbiprofen axetyl-containing fat emulsion of the present invention include propylene glycol, glycerin, macrogol, lactic acid, N, N-dimethylacetamide, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, chondroitin sulfate or a salt thereof (sodium). Further use of (salts, etc.), hyaluronic acid or its salts (sodium salt, etc.), glycyrrhizinic acid or its salts (sodium salt, ammonium salt, etc.), etc., to improve the solubility of flurbiprofen axetyl, fat emulsions, etc. The stability of flurbiprofen axetil may be improved, the fat emulsion may be isotonic, and the like. These contents are preferably 1 to 100 mg / mL, more preferably 10 to 50 mg / mL. If it is less than 1 mg / mL, the effect is less likely to be exhibited, while if it is more than 100 mg / mL, emulsification becomes difficult due to an increase in viscosity, or the fat emulsion tends to be acidified and become unstable.

また、本発明のフルルビプロフェンアキセチル含有脂肪乳剤の構成成分としてオレイン酸、ステアリン酸、リノール酸、リノレン酸、パルミチン酸、パルミトレイン酸、ミリスチン酸などの高級脂肪酸をさらに用いることで、脂肪乳剤の安定化を図ってもよい。高級脂肪酸の含量は０．００１〜１０ｍｇ／ｍＬが望ましく、０．０１〜５ｍｇ／ｍＬがより望ましい。０．００１ｍｇ／ｍＬよりも少ないと効果が発揮されにくくなる一方、１０ｍｇ／ｍＬよりも多いとフルルビプロフェンアキセチルに対して劣化を招く危険性が生じる。 Further, by further using higher fatty acids such as oleic acid, stearic acid, linoleic acid, linolenic acid, palmitic acid, palmitoleic acid, and myristic acid as constituents of the flurubiprofene axetyl-containing fat emulsion of the present invention, the fat emulsion is used. You may try to stabilize. The content of the higher fatty acid is preferably 0.001 to 10 mg / mL, more preferably 0.01 to 5 mg / mL. If it is less than 0.001 mg / mL, the effect will be less likely to be exhibited, while if it is more than 10 mg / mL, there is a risk of causing deterioration for flurbiprofen axetil.

また、本発明のフルルビプロフェンアキセチル含有脂肪乳剤の構成成分として糖類をさらに用いることで、時として発生しうる析出浮遊物の発生を効果的に抑制することができる。好適な糖類としては、イノシトール、グルコース、ソルビトール、フルクトース、マンニトールなどの単糖類、トレハロース、ラクトース、スクロース、マルトースなどの二糖類の他、デキストリン、シクロデキストリン、デキストラン、キシリトールなどが挙げられる。糖類の含量は１０〜６００ｍｇ／ｍＬが望ましい。 Further, by further using a saccharide as a constituent component of the flurbiprofen axetyl-containing fat emulsion of the present invention, it is possible to effectively suppress the generation of precipitated suspended matter that may sometimes occur. Suitable saccharides include monosaccharides such as inositol, glucose, sorbitol, fructose and mannitol, disaccharides such as trehalose, lactose, sucrose and maltose, as well as dextran, cyclodextran, dextran and xylitol. The sugar content is preferably 10-600 mg / mL.

また、本発明のフルルビプロフェンアキセチル含有脂肪乳剤の構成成分として自体公知のｐＨ調整剤や浸透圧調整剤をさらに用い、ｐＨを調整したり（例えば３．５〜９．０）、浸透圧を調整したりすることで、脂肪乳剤の安定化を図ってもよい。なお、必要に応じて防腐剤や抗酸化剤や安定化剤などとして機能する物質（例えばトコフェロールやエチレンジアミン四酢酸の金属塩）を構成成分としてもよいことは言うまでもない。また、本発明のフルルビプロフェンアキセチル含有脂肪乳剤は、フルルビプロフェンアキセチルに加えてその他の薬物を構成成分とすることを妨げるものではない。 Further, a pH adjusting agent or an osmotic pressure adjusting agent known per se as a constituent component of the flurubiprofene axetyl-containing fat emulsion of the present invention is further used to adjust the pH (for example, 3.5 to 9.0) or permeate. The fat emulsion may be stabilized by adjusting the pressure. Needless to say, a substance (for example, a metal salt of tocopherol or ethylenediaminetetraacetic acid) that functions as a preservative, an antioxidant, a stabilizer, or the like may be used as a constituent component, if necessary. In addition, the flurbiprofen axetyl-containing fat emulsion of the present invention does not prevent the inclusion of other drugs in addition to flurbiprofen axetil.

本発明のフルルビプロフェンアキセチル含有脂肪乳剤は、例えば平均粒子径を１５０ｎｍ以下に設定することで、ろ過滅菌を容易に行うことができる他、高圧蒸気滅菌を行うこともできる。高圧蒸気滅菌は、本発明のフルルビプロフェンアキセチル含有脂肪乳剤をガラス製アンプルや合成樹脂製容器などに充填した後、一般的な条件（例えば１２０〜１２２℃×１０〜１５分）で行えばよい。 The flurbiprofen axetyl-containing fat emulsion of the present invention can be easily sterilized by filtration by setting the average particle size to 150 nm or less, and can also be sterilized by high-pressure steam. High-pressure steam sterilization is performed under general conditions (for example, 120 to 122 ° C. × 10 to 15 minutes) after filling the flurbiprofen axetyl-containing fat emulsion of the present invention in a glass ampoule or a synthetic resin container. Just do it.

本発明のフルルビプロフェンアキセチル含有脂肪乳剤は、安定性に優れるので、室温（例えば５〜３０℃）で保存することができる。また、透明性を有することは、変質や異物混入の有無、配合変化の目視での確認を容易にする他、投与される患者に対して安心感を与える。これらの作用は、とりわけ本発明のフルルビプロフェンアキセチル含有脂肪乳剤を、注射剤、点眼剤、点鼻剤、点耳剤、吸入剤などとして用いる場合に有効に機能する。 The flurbiprofen axetyl-containing fat emulsion of the present invention has excellent stability and can be stored at room temperature (for example, 5 to 30 ° C.). In addition, having transparency makes it easy to visually confirm the presence or absence of alteration or contamination with foreign substances, and the change in composition, and also gives a sense of security to the patient to be administered. These actions function particularly effectively when the flurbiprofen axetyl-containing fat emulsion of the present invention is used as an injection, an eye drop, a nasal drop, an ear drop, an inhalant, or the like.

以下、本発明を実施例によって詳細に説明するが、本発明は以下の記載に限定して解釈されるものではない。 Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not construed as being limited to the following description.

実施例１：
フルルビプロフェンアキセチル１００ｍｇ、市販の中鎖脂肪酸トリグリセライド２００ｍｇ、精製卵黄レシチン（ＰＣ−９８：キユーピー社製、以下同じ）５００ｍｇ、ポリソルベート８０（ＧＳ：日油社製、以下同じ）５００ｍｇ、プロピレングリコール５００ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、フルクトース５００ｍｇを添加し、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その７ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機（ＳＭＴ社製、以下同じ）で１５分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１０ｍＬとしてから、０．２２μｍφのセルロースアセテート膜（ＣＡ膜、以下同じ）でろ過滅菌を行い、目的とする薄濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 1:
Flurbiprofen axetyl 100 mg, commercially available medium-chain fatty acid triglyceride 200 mg, purified egg yolk lecithin (PC-98: manufactured by QP, the same below) 500 mg, polysorbate 80 (GS: manufactured by Nichiyu Co., the same below) 500 mg, propylene glycol 500 mg was weighed, and 500 mg of fructose was added thereto under heating and stirring at about 50 ° C. using a hot stirrer, and the mixture was uniformly mixed to prepare an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer (0.18 mol / L, pH 6.0) was prepared, and 7 mL of the buffer was added to the oil phase under stirring using a stirrer while adding an ultrasonic emulsifier (SMT). Emulsified for 15 minutes (under water cooling). The above buffer solution is added to the emulsion thus obtained to make the total volume 10 mL, and then filtration sterilization is performed with a 0.22 μmφ cellulose acetate membrane (CA membrane, the same applies hereinafter) to obtain the desired turbid flurbiprofen. An axetyl-containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例２：
精製卵黄レシチンの使用量を８００ｍｇに変更し、ポリソルベート８０の使用量を２００ｍｇに変更すること以外は実施例１と同様にして、目的とする薄濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 2:
The desired turbid flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 1 except that the amount of purified egg yolk lecithin used was changed to 800 mg and the amount of polysorbate 80 used was changed to 200 mg. rice field. The physical characteristics are shown in Table 1.

実施例３：
フルルビプロフェンアキセチル１００ｍｇ、市販の中鎖脂肪酸トリグリセライド２００ｍｇ、精製卵黄レシチン（ＰＣ−９８）５００ｍｇ、ポリソルベート８０ ５００ｍｇ、プロピレングリコール２００ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、トレハロース５００ｍｇを添加し、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その８ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で２０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１０ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 3:
Flurbiprofen axetyl 100 mg, commercially available medium-chain fatty acid triglyceride 200 mg, purified egg yolk lecithin (PC-98) 500 mg, polysorbate 80 500 mg, propylene glycol 200 mg were weighed and measured at about 50 ° C. using a hot stirrer. Under warming and stirring, 500 mg of trehalose was added and mixed uniformly to prepare an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.18 mol / L, pH 6.0) was prepared, and 8 mL of the buffer solution was added to the oil phase under stirring using a stirrer and 20 by an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to make the total volume 10 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl-containing fat emulsion. .. The physical characteristics are shown in Table 1.

実施例４：
クエン酸−リン酸水素二ナトリウム緩衝液（０．１８ｍｏｌ／Ｌ、ｐＨ６．０）をクエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）に変更すること以外は実施例３と同様にして、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 4:
Except for changing the citrate-disodium hydrogen phosphate buffer (0.18 mol / L, pH 6.0) to the citrate-disodium hydrogen phosphate buffer (0.018 mol / L, pH 6.0) In the same manner as in Example 3, the desired transparent flurbiprofen axetyl-containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例５：
フルルビプロフェンアキセチル２００ｍｇ、市販の中鎖脂肪酸トリグリセライド４００ｍｇ、精製卵黄レシチン（ＰＣ−９８）１ｇ、ポリソルベート８０ １ｇ、プロピレングリコール１ｇ、トコフェロール２０ｍｇ、エチレンジアミン四酢酸二ナトリウム２ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、フルクトース１ｇを添加し、均一に混合して油相とした。この油相に、スターラーを用いた撹拌下、純水１５ｍＬを添加しながら超音波乳化機で２０分間乳化した。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．０に調整し、さらに超音波乳化機で５分間乳化した後、純水を添加して全量を２０ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌し、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 5:
Weigh 200 mg of fructose phenaxetyl, 400 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin (PC-98), 1 g of polysorbate, 1 g of propylene glycol, 20 mg of tocopherol, and 2 mg of disodium ethylenediaminetetraacetate. Under warming and stirring at about 50 ° C. using a hot stirrer, 1 g of fructose was added and mixed uniformly to prepare an oil phase. The oil phase was emulsified with an ultrasonic emulsifier for 20 minutes while adding 15 mL of pure water under stirring using a stirrer. A 1N aqueous sodium hydroxide solution was added to the emulsion thus obtained to adjust the pH to 6.0, and after emulsifying with an ultrasonic emulsifier for 5 minutes, pure water was added to make the total volume 20 mL, and then 0. The film was sterilized by filtration through a 22 μmφ CA membrane to obtain the desired transparent flurubiprofene axetyl-containing fat emulsion. The physical characteristics are shown in Table 1.

実施例６：
フルクトースをトレハロースに変更すること以外は実施例５と同様にして、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 6:
The desired transparent flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 5 except that fructose was changed to trehalose. The physical characteristics are shown in Table 1.

実施例７：
フルルビプロフェンアキセチル２００ｍｇ、市販の中鎖脂肪酸トリグリセライド４００ｍｇ、精製卵黄レシチン（ＰＣ−９８）１ｇ、ポリソルベート８０ １ｇ、グリセリン４００ｍｇ、トコフェロール２０ｍｇ、エチレンジアミン四酢酸二ナトリウム２ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃の加温撹拌下、フルクトース１ｇを添加し、均一に混合して油相とした。この油相に、スターラーを用いた撹拌下、純水１５ｍＬを添加しながら超音波乳化機で２５分間乳化した。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．０に調整し、さらに超音波乳化機で５分間乳化した後、純水を添加して全量を２０ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌し、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 7:
Weigh 200 mg of flurubiprofen axetyl, 400 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin (PC-98), 1 g of polysorbate, 400 mg of glycerin, 20 mg of tocopherol, and 2 mg of disodium ethylenediamine tetraacetate. Under warming and stirring at about 50 ° C. using a stirrer, 1 g of fructose was added and mixed uniformly to prepare an oil phase. The oil phase was emulsified with an ultrasonic emulsifier for 25 minutes while adding 15 mL of pure water under stirring using a stirrer. A 1N aqueous sodium hydroxide solution was added to the emulsion thus obtained to adjust the pH to 6.0, and after emulsifying with an ultrasonic emulsifier for 5 minutes, pure water was added to make the total volume 20 mL, and then 0. The film was sterilized by filtration through a 22 μmφ CA membrane to obtain the desired transparent flurubiprofene axetyl-containing fat emulsion. The physical characteristics are shown in Table 1.

実施例８：
グリセリンをプロピレングリコールに変更し、フルクトースをトレハロースに変更すること以外は実施例７と同様にして、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 8:
A desired turbid flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 7 except that glycerin was changed to propylene glycol and fructose was changed to trehalose. The physical characteristics are shown in Table 1.

実施例９：
フルルビプロフェンアキセチル４００ｍｇ、市販の中鎖脂肪酸トリグリセライド８００ｍｇ、精製卵黄レシチン（ＰＣ−９８）２ｇ、ポリソルベート８０ ２ｇ、プロピレングリコール２ｇを量り採り、ホットスターラーを用いた約５０℃の加温撹拌下、均一に混合して油相とした。この油相に、スターラーを用いた撹拌下、純水２８ｍＬを添加しながら超音波乳化機で４０分間乳化した。その後、フルクトース２ｇを添加し、スターラーを用いて撹拌して溶解した。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．０に調整した後、純水を添加して全量を４０ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌し、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 9:
Weigh 400 mg of flurbiprofen axetyl, 800 mg of commercially available medium-chain fatty acid triglyceride, 2 g of purified egg yolk lecithin (PC-98), 802 g of polysorbate, and 2 g of propylene glycol, and use a hot stirrer to heat and stir at about 50 ° C. , Uniformly mixed to obtain an oil phase. The oil phase was emulsified with an ultrasonic emulsifier for 40 minutes while adding 28 mL of pure water under stirring using a stirrer. Then, 2 g of fructose was added, and the mixture was dissolved by stirring with a stirrer. A 1N aqueous sodium hydroxide solution was added to the emulsion thus obtained to adjust the pH to 6.0, pure water was added to make the total volume 40 mL, and then filtration sterilized with a 0.22 μmφ CA membrane for the purpose. A transparent flurbiprofen axetyl-containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例１０：
プロピレングリコールをマクロゴール４００に変更し、フルクトースをマンニトールに変更すること以外は実施例９と同様にして、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 10:
The desired transparent flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 9 except that propylene glycol was changed to macrogol 400 and fructose was changed to mannitol. The physical characteristics are shown in Table 1.

実施例１１：
精製卵黄レシチンの使用量を３ｇに変更し、ポリソルベート８０の使用量を１ｇに変更し、フルクトースをマンニトールに変更すること以外は実施例９と同様にして、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 11:
Similar to Example 9, except that the amount of purified egg yolk lecithin used was changed to 3 g, the amount of polysorbate 80 used was changed to 1 g, and fructose was changed to mannitol, the target slightly turbid flurbiprofen was used. An axetyl-containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例１２：
フルルビプロフェンアキセチル１ｇ、市販の中鎖脂肪酸トリグリセライド２ｇ、精製卵黄レシチン（ＰＣ−９８）１０ｇ、プロピレングリコール１０ｇを量り採り、ホットスターラーを用いた約６０℃の加温撹拌下、均一に混合して油相とした。この油相に、ハイフレックスディスパーサー（ＳＭＴ社製、以下同じ）を用いた攪拌下、純水７５ｍＬを少しずつ添加し、添加終了後、１２０００ｒｐｍで１０分間粗乳化した。純水をさらに添加して全量を１００ｍＬとした後、高圧ホモジナイザー（ＬＡＢ２０００：ＳＭＴ社製、以下同じ）を用いて精密乳化した。乳化圧力は１４００バールとし、乳化回数は１５回とした（循環乳化）。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．０に調整してから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする薄濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 12:
Weigh 1 g of flurbiprofen axetyl, 2 g of commercially available medium-chain fatty acid triglyceride, 10 g of purified egg yolk lecithin (PC-98), and 10 g of propylene glycol, and mix them uniformly under warm stirring at about 60 ° C. using a hot stirrer. And made it an oil phase. To this oil phase, 75 mL of pure water was added little by little under stirring using a high flex disperser (manufactured by SMT, the same applies hereinafter), and after the addition was completed, the oil was roughly emulsified at 12000 rpm for 10 minutes. After further adding pure water to make the total volume 100 mL, precision emulsification was performed using a high-pressure homogenizer (LAB2000: manufactured by SMT, the same applies hereinafter). The emulsification pressure was 1400 bar and the number of emulsifications was 15 (circular emulsification). A 1N aqueous sodium hydroxide solution is added to the emulsion thus obtained to adjust the pH to 6.0, and then filtration sterilization is performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl. A containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例１３：
フルルビプロフェンアキセチル４０ｍｇ、市販の中鎖脂肪酸トリグリセライド８０ｍｇを量り採り、超音波洗浄器を用いた約５０℃の加温撹拌下、均一に混合した。一方、精製卵黄レシチン（ＰＣ−９８）２００ｍｇ、ポリソルベート８０ ２００ｍｇ、マクロゴール４００ ２００ｍｇを量り採り、超音波洗浄器を用いた約５０℃の加温撹拌下、均一に混合した。両者を混合して油相とした後、純水２．５ｍＬを添加しながら、超音波乳化機で１０分間乳化した。その後、トレハロース４００ｍｇを添加し、ミキサーを用いて撹拌して溶解した。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．０に調整した後、純水を添加して全量を４ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌し、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 13:
40 mg of flurbiprofen axetyl and 80 mg of commercially available medium-chain fatty acid triglyceride were weighed and mixed uniformly under warm stirring at about 50 ° C. using an ultrasonic cleaner. On the other hand, 200 mg of purified egg yolk lecithin (PC-98), 200 mg of polysorbate 80, and 200 mg of macrogol 400 were weighed and mixed uniformly under warm stirring at about 50 ° C. using an ultrasonic cleaner. After mixing the two to obtain an oil phase, the mixture was emulsified with an ultrasonic emulsifier for 10 minutes while adding 2.5 mL of pure water. Then, 400 mg of trehalose was added, and the mixture was stirred and dissolved using a mixer. A 1N aqueous sodium hydroxide solution was added to the emulsion thus obtained to adjust the pH to 6.0, pure water was added to make the total volume 4 mL, and then filtration sterilized with a 0.22 μmφ CA membrane for the purpose. A transparent flurbiprofen axetyl-containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例１４：
フルルビプロフェンアキセチル１ｇ、市販の精製大豆油１ｇ、精製卵黄レシチン（ＰＣ−９８）１２ｇ、プロピレングリコール５ｇを量り採り、ホットスターラーを用いた約６０℃の加温撹拌下、均一に混合して油相とした。この油相に、ハイフレックスディスパーサーを用いた攪拌下、純水７０ｍＬを少しずつ添加し、添加終了後、１２０００ｒｐｍで１０分間粗乳化した。純水をさらに添加して全量を１００ｍＬとした後、高圧ホモジナイザーを用いて精密乳化した。乳化圧力は１４００バールとし、乳化回数は１５回とした（循環乳化）。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．０に調整してから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする薄濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 14:
Weigh 1 g of flurbiprofen axetil, 1 g of commercially available refined soybean oil, 12 g of refined egg yolk lecithin (PC-98), and 5 g of propylene glycol, and mix them uniformly under heating and stirring at about 60 ° C. using a hot stirrer. The oil phase was used. To this oil phase, 70 mL of pure water was added little by little under stirring using a high flex disperser, and after the addition was completed, the oil was coarsely emulsified at 12000 rpm for 10 minutes. After further adding pure water to make the total volume 100 mL, precision emulsification was performed using a high-pressure homogenizer. The emulsification pressure was 1400 bar and the number of emulsifications was 15 (circular emulsification). A 1N aqueous sodium hydroxide solution is added to the emulsion thus obtained to adjust the pH to 6.0, and then filtration sterilization is performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl. A containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例１５：
中鎖脂肪酸トリグリセライドの使用量を４０ｍｇに変更し、マクロゴール４００をプロピレングリコールに変更すること以外は実施例１３と同様にして、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 15:
The target transparent flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 13 except that the amount of the medium-chain fatty acid triglyceride used was changed to 40 mg and macrogol 400 was changed to propylene glycol. .. The physical characteristics are shown in Table 1.

実施例１６：
フルルビプロフェンアキセチル１ｇ、中鎖脂肪酸トリグリセライド２ｇ、精製卵黄レシチン（ＰＬ−１００Ｍ：キユーピー社製）５ｇ、プロピレングリコール５ｇを量り採り、ホットスターラーを用いた約６０℃の加温撹拌下、均一に混合して油相とした。この油相に、ハイフレックスディスパーサーを用いた攪拌下、純水８０ｍＬを少しずつ添加し、添加終了後、１２０００ｒｐｍで１０分間粗乳化した。純水をさらに添加して全量を１００ｍＬとした後、高圧ホモジナイザーを用いて精密乳化した。乳化圧力は１４００バールとし、乳化回数は１５回とした（循環乳化）。こうして得た乳化液に１Ｎ水酸化ナトリウム水溶液を添加してｐＨを６．４に調整してから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 16:
Weigh 1 g of flurbiprofen axetyl, 2 g of medium-chain fatty acid triglyceride, 5 g of purified egg yolk lecithin (PL-100M: manufactured by QP), and 5 g of propylene glycol, and uniformly under heating and stirring at about 60 ° C. using a hot stirrer. To make an oil phase. To this oil phase, 80 mL of pure water was added little by little under stirring using a high flex disperser, and after the addition was completed, the oil was coarsely emulsified at 12000 rpm for 10 minutes. After further adding pure water to make the total volume 100 mL, precision emulsification was performed using a high-pressure homogenizer. The emulsification pressure was 1400 bar and the number of emulsifications was 15 (circular emulsification). A 1N aqueous sodium hydroxide solution was added to the emulsion thus obtained to adjust the pH to 6.4, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl. A containing fat emulsion was obtained. The physical characteristics are shown in Table 1.

実施例１７：
プロピレングリコールをマクロゴール４００に変更すること以外は実施例４と同様にして、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 17:
A desired slightly turbid flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 4 except that propylene glycol was changed to macrogol 400. The physical characteristics are shown in Table 1.

実施例１８：
プロピレングリコールをグリセリンに変更すること以外は実施例４と同様にして、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 18:
The desired transparent flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 4 except that propylene glycol was changed to glycerin. The physical characteristics are shown in Table 1.

実施例１９：
プロピレングリコールをグリセリンに変更すること以外は実施例３と同様にして、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 19:
The desired slightly turbid flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 3 except that propylene glycol was changed to glycerin. The physical characteristics are shown in Table 1.

実施例２０：
フルルビプロフェンアキセチル２００ｍｇ、市販の中鎖脂肪酸トリグリセライド２００ｍｇ、精製卵黄レシチン（ＰＣ−９８）１ｇ、ポリソルベート８０ ５００ｍｇ、プロピレングリコール３００ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、トレハロース１ｇを添加し、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その１６ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で２０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を２０ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 20:
Flurbiprofen axetyl 200 mg, commercially available medium-chain fatty acid triglyceride 200 mg, purified egg yolk lecithin (PC-98) 1 g, polysorbate 80 500 mg, propylene glycol 300 mg were weighed and measured at about 50 ° C. using a hot stirrer. Under warming and stirring, 1 g of trehalose was added and mixed uniformly to prepare an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 16 mL thereof was added to the oil phase under stirring using a stirrer and 20 using an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to bring the total volume to 20 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl-containing fat emulsion. .. The physical characteristics are shown in Table 1.

実施例２１：
プロピレングリコールをグリセリンに変更すること以外は実施例２０と同様にして、目的とする薄濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 21:
The desired turbid flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 20 except that propylene glycol was changed to glycerin. The physical characteristics are shown in Table 1.

実施例２２：
中鎖脂肪酸トリグリセライドの使用量を１００ｍｇに変更し、ポリソルベート８０の使用量を６００ｍｇに変更すること以外は実施例２０と同様にして、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 22:
In the same manner as in Example 20 except that the amount of the medium-chain fatty acid triglyceride used was changed to 100 mg and the amount of polysorbate 80 used was changed to 600 mg, the desired turbid flurbiprofen axetyl-containing fat emulsion was prepared. Obtained. The physical characteristics are shown in Table 1.

実施例２３：
フルルビプロフェンアキセチル１５０ｍｇ、市販の中鎖脂肪酸トリグリセライド７５ｍｇ、精製卵黄レシチン（ＰＣ−９８）７５０ｍｇ、ポリソルベート８０ ３７５ｍｇ、マクロゴール４００ ７５０ｍｇを量り採り、ホットスターラーを用いた約５０℃での加温撹拌下、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その１２ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で３０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１５ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 23:
Flurbiprofen axetyl 150 mg, commercially available medium-chain fatty acid triglyceride 75 mg, purified egg yolk lecithin (PC-98) 750 mg, polysorbate 80 375 mg, macrogol 400 750 mg were weighed and heated at about 50 ° C. using a hot stirrer. Under stirring, the mixture was uniformly mixed to obtain an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL thereof was added to the oil phase under stirring using a stirrer while using an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to bring the total volume to 15 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl-containing fat emulsion. .. The physical characteristics are shown in Table 1.

実施例２４：
フルルビプロフェンアキセチル１５０ｍｇ、市販の中鎖脂肪酸トリグリセライド７５ｍｇ、精製卵黄レシチン（ＰＣ−９８）７５０ｍｇ、ポリソルベート８０ ３７５ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、トレハロース７５０ｍｇを添加し、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その１２ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で３０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１５ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 24:
Weigh 150 mg of flurbiprofen axetyl, 75 mg of commercially available medium-chain fatty acid triglyceride, 750 mg of purified egg yolk lecithin (PC-98), and 375 mg of polysorbate 80, and use a hot stirrer to heat and stir at about 50 ° C. , 750 mg of trehalose was added and mixed uniformly to prepare an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL thereof was added to the oil phase under stirring using a stirrer while using an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to bring the total volume to 15 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl-containing fat emulsion. .. The physical characteristics are shown in Table 1.

実施例２５：
フルルビプロフェンアキセチル１５０ｍｇ、市販の中鎖脂肪酸トリグリセライド７５ｍｇ、精製卵黄レシチン（ＰＣ−９８）４５０ｍｇ、ポリソルベート８０ ３００ｍｇ、プロピレングリコール２２５ｍｇを量り採り、ホットスターラーを用いた約５０℃での加温撹拌下、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その１２ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で３０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１５ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする薄濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 25:
Flurbiprofen axetyl 150 mg, commercially available medium-chain fatty acid triglyceride 75 mg, purified egg yolk lecithin (PC-98) 450 mg, polysorbate 80 300 mg, propylene glycol 225 mg were weighed and heated and stirred at about 50 ° C. using a hot stirrer. Below, the mixture was uniformly mixed to obtain an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL thereof was added to the oil phase under stirring using a stirrer while using an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to make the total volume 15 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl-containing fat emulsion. .. The physical characteristics are shown in Table 1.

実施例２６：
フルルビプロフェンアキセチル１５０ｍｇ、市販の中鎖脂肪酸トリグリセライド４５０ｍｇ、精製卵黄レシチン（ＰＣ−９８）７５０ｍｇ、ポリソルベート８０ ７５０ｍｇ、プロピレングリコール３００ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、トレハロース４５０ｍｇを添加し、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その１２ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で３０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１５ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする微濁のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 26:
Flurbiprofen axetyl 150 mg, commercially available medium-chain fatty acid triglyceride 450 mg, purified egg yolk lecithin (PC-98) 750 mg, polysorbate 80 750 mg, and propylene glycol 300 mg were weighed and measured at about 50 ° C. using a hot stirrer. Under warm stirring, 450 mg of trehalose was added and mixed uniformly to prepare an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL thereof was added to the oil phase under stirring using a stirrer while using an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to bring the total volume to 15 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired turbid flurbiprofen axetyl-containing fat emulsion. .. The physical characteristics are shown in Table 1.

実施例２７：
ポリソルベート８０の使用量を４８０ｍｇに変更すること以外は実施例２６と同様にして、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 27:
The target transparent flurbiprofen axetyl-containing fat emulsion was obtained in the same manner as in Example 26 except that the amount of polysorbate 80 used was changed to 480 mg. The physical characteristics are shown in Table 1.

実施例２８：
フルルビプロフェンアキセチル１５０ｍｇ、市販の中鎖脂肪酸トリグリセライド４５０ｍｇ、精製卵黄レシチン（ＰＣ−９８）７５０ｍｇ、ポリソルベート８０ ７５０ｍｇ、プロピレングリコール２００ｍｇ、マクロゴール４００ ３００ｍｇを量り採り、そこに、ホットスターラーを用いた約５０℃での加温撹拌下、トレハロース４５０ｍｇを添加し、均一に混合して油相とした。一方、クエン酸−リン酸水素二ナトリウム緩衝液（０．０１８ｍｏｌ／Ｌ、ｐＨ６．０）を作製し、その１２ｍＬを、スターラーを用いた撹拌下、油相に添加しながら超音波乳化機で３０分間乳化した（水冷下にて）。こうして得た乳化液に上記の緩衝液を添加して全量を１５ｍＬとしてから、０．２２μｍφのＣＡ膜でろ過滅菌を行い、目的とする透明のフルルビプロフェンアキセチル含有脂肪乳剤を得た。その物性値を表１に示す。Example 28:
Flurbiprofen axetyl 150 mg, commercially available medium-chain fatty acid triglyceride 450 mg, purified egg yolk lecithin (PC-98) 750 mg, polysorbate 80 750 mg, propylene glycol 200 mg, and macrogol 400 300 mg were weighed and used with a hot stirrer. Under warming and stirring at about 50 ° C., 450 mg of trehalose was added and mixed uniformly to prepare an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL thereof was added to the oil phase under stirring using a stirrer while using an ultrasonic emulsifier. Emulsified for minutes (under water cooling). The above buffer solution was added to the emulsion thus obtained to bring the total volume to 15 mL, and then filtration sterilization was performed with a 0.22 μmφ CA membrane to obtain the desired transparent flurbiprofen axetyl-containing fat emulsion. The physical characteristics are shown in Table 1.

Figure 2020017571
Figure 2020017571

なお、濁度の測定は、紫外分光光度計（ＵＶ１８００：島津製作所社製）を用い、サンプルをセル幅が１ｃｍの測定セルに入れて波長λ＝６２０ｎｍで行った（ブランクは水）。サンプルが透けて見え、凝集や沈殿などの変質や異物混入の有無、配合変化を目視で容易に確認できる透明〜半透明領域はＡｂｓ（吸光度）＝０．５以下であるので、この濁度を合否の境界とした。平均粒子径の測定は、光子相関法を用いた粒子径測定装置（ゼータサイザー ナノＺＳ：マルバーン社製）を用いて行った。 The turbidity was measured using an ultraviolet spectrophotometer (UV1800: manufactured by Shimadzu Corporation), and the sample was placed in a measurement cell having a cell width of 1 cm and measured at a wavelength of λ = 620 nm (blank is water). The transparent to translucent region where the sample can be seen through and the presence or absence of deterioration such as agglutination and precipitation, the presence or absence of foreign matter mixed in, and the change in composition can be easily confirmed is Abs (absorbance) = 0.5 or less. It was used as a pass / fail boundary. The average particle size was measured using a particle size measuring device (Zetasizer Nano ZS: manufactured by Malvern) using a photon correlation method.

表１から明らかなように、実施例１〜２８のいずれのフルルビプロフェンアキセチル含有脂肪乳剤も、平均粒子径が１００ｎｍ以下であって透明性が極めて高いものであり（濁度が０．５以下）、４０℃で１ヶ月間保存した後も、実用上において支障となるような変化が認められない保存安定性に優れるものであった（相分離、沈殿、析出、相変化の有無などの目視観察とフルルビプロフェンアキセチルの残存含量が製造当初の９０％以上であることの確認による）。 As is clear from Table 1, all of the flurbiprofen axetyl-containing fat emulsions of Examples 1 to 28 have an average particle size of 100 nm or less and are extremely transparent (turbidity is 0. Even after storage at 40 ° C. for 1 month (5 or less), it was excellent in storage stability with no change that would hinder practical use (phase separation, precipitation, precipitation, presence or absence of phase change, etc.). (By visual observation and confirmation that the residual content of flurbiprofen axetyl is 90% or more at the beginning of production).

実施例２９：
フルルビプロフェンアキセチルの使用量を５０ｍｇに変更すること以外は実施例４と同様にして、実施例４で得たフルルビプロフェンアキセチル含有脂肪乳剤と同等の物性値を有するフルルビプロフェンアキセチル含有脂肪乳剤を得た。Example 29:
Flurbiprofen has the same physical characteristics as the fat emulsion containing flurbiprofen axetyl obtained in Example 4 in the same manner as in Example 4 except that the amount of flurbiprofen axetil used is changed to 50 mg. A fat emulsion containing phenaxetyl was obtained.

実施例３０：
フルルビプロフェンアキセチルの使用量を２００ｍｇに変更し、中鎖脂肪酸トリグリセライドの使用量を４００ｍｇに変更すること以外は実施例４と同様にして、実施例４で得たフルルビプロフェンアキセチル含有脂肪乳剤と同等の物性値を有するフルルビプロフェンアキセチル含有脂肪乳剤を得た。Example 30:
Flurbiprofen axetyl obtained in Example 4 in the same manner as in Example 4 except that the amount of flurbiprofen axetil used was changed to 200 mg and the amount of medium-chain fatty acid triglyceride used was changed to 400 mg. A flurbiprofen axetyl-containing fat emulsion having the same physical properties as the contained fat emulsion was obtained.

実施例３１：
クエン酸−リン酸水素二ナトリウム緩衝液を酢酸−酢酸ナトリウム緩衝液に変更すること以外は実施例４と同様にして、実施例４で得たフルルビプロフェンアキセチル含有脂肪乳剤と同等の物性値を有するフルルビプロフェンアキセチル含有脂肪乳剤を得た。Example 31:
Similar to Example 4 except that the citric acid-disodium hydrogen phosphate buffer solution is changed to the acetic acid-sodium acetate buffer solution, and the same physical properties as the flurbiprofen axetyl-containing fat emulsion obtained in Example 4. A fat emulsion containing flurbiprofen axetyl having a value was obtained.

実施例３２：
クエン酸−リン酸水素二ナトリウム緩衝液をリン酸二水素カリウム−水酸化ナトリウム緩衝液に変更すること以外は実施例４と同様にして、実施例４で得たフルルビプロフェンアキセチル含有脂肪乳剤と同等の物性値を有するフルルビプロフェンアキセチル含有脂肪乳剤を得た。Example 32:
Flurbiprofen axetyl-containing fat obtained in Example 4 in the same manner as in Example 4 except that the citric acid-disodium hydrogen phosphate buffer was changed to the potassium dihydrogen phosphate-sodium hydroxide buffer. A flurbiprofen axetyl-containing fat emulsion having the same physical properties as the emulsion was obtained.

本発明は、脂肪乳剤が多くの量のフルルビプロフェンアキセチルを担持することができるように油脂の含量が多いにもかかわらず、透明性を有するとともに安定性に優れ、加えて乳化剤としてレシチンを用いることで安全性に優れるフルルビプロフェンアキセチル含有脂肪乳剤およびその製造方法を提供することができる点において産業上の利用可能性を有する。 The present invention has a high content of fats and oils so that a fat emulsion can carry a large amount of flurbiprofen axetyl, yet has transparency and excellent stability, and lecithin as an emulsifier. It has industrial applicability in that it is possible to provide a flurbiprofen axetyl-containing fat emulsion having excellent safety and a method for producing the same.

Claims (6)

フルルビプロフェンアキセチル、油脂、乳化剤、水性媒体を少なくとも構成成分とするフルルビプロフェンアキセチル含有脂肪乳剤であって、油脂の含量が３〜５０ｍｇ／ｍＬ、油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）が０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）、乳化剤としてのレシチンの含量が２０〜１５０ｍｇ／ｍＬ（用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよい）であり、濁度が０．５以下であることを特徴とするフルルビプロフェンアキセチル含有脂肪乳剤。 Flurubiprofen Axetyl-containing fat emulsion containing at least components of flurubiprofene axetyl, fats and oils, emulsifiers, and aqueous media, with a fat content of 3 to 50 mg / mL and flurubiprofen axetyl relative to fats and oils. Weight ratio (flurubiprofen axetyl / fat) is 0.1 to 5 (however, the total content of flurubiprofen axetil and fat is 100 mg / mL at maximum), and the content of lecithin as an emulsifier is 20 to 150 mg. A flurubiprofene axetyl-containing fat emulsion characterized in that it is / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin) and the turbidity is 0.5 or less. 脂肪粒子の平均粒子径が１〜１５０ｎｍであることを特徴とする請求項１記載のフルルビプロフェンアキセチル含有脂肪乳剤。 The flurbiprofen axetyl-containing fat emulsion according to claim 1, wherein the average particle size of the fat particles is 1 to 150 nm. プロピレングリコール、グリセリン、マクロゴール、乳酸、Ｎ，Ｎ−ジメチルアセトアミド、ポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、コンドロイチン硫酸またはその塩、ヒアルロン酸またはその塩、グリチルリチン酸またはその塩から選ばれる少なくとも１つをさらに構成成分とすることを特徴とする請求項１記載のフルルビプロフェンアキセチル含有脂肪乳剤。 Further at least one selected from propylene glycol, glycerin, macrogol, lactic acid, N, N-dimethylacetamide, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, chondroitin sulfate or a salt thereof, hyaluronic acid or a salt thereof, glycyrrhizinic acid or a salt thereof. The flurbiprofen axetyl-containing fat emulsion according to claim 1, which comprises a constituent component. 糖類をさらに構成成分とすることを特徴とする請求項１記載のフルルビプロフェンアキセチル含有脂肪乳剤。 The flurbiprofen axetyl-containing fat emulsion according to claim 1, further comprising a saccharide as a constituent component. フルルビプロフェンアキセチル、油脂、乳化剤、水性媒体を少なくとも構成成分とする、濁度が０．５以下であるフルルビプロフェンアキセチル含有脂肪乳剤の製造方法であって、油脂の含量を３〜５０ｍｇ／ｍＬ、油脂に対するフルルビプロフェンアキセチルの重量比率（フルルビプロフェンアキセチル／油脂）を０．１〜５（但しフルルビプロフェンアキセチルと油脂の合計含量は最大で１００ｍｇ／ｍＬ）、乳化剤としてのレシチンの含量を２０〜１５０ｍｇ／ｍＬ（用いるレシチンの５０重量％以下をレシチン以外の乳化剤に置き換えてもよい）として構成成分を乳化することを特徴とする製造方法。 A method for producing a flurbiprofen axetyl-containing fat emulsion having at least a component of flurbiprofen axetyl, fat, emulsifier, and aqueous medium and having a turbidity of 0.5 or less, wherein the content of fat and oil is 3. ~ 50 mg / mL, weight ratio of flurbiprofen axetyl to fats and oils (flurbiprofen axetyl / fats and oils) 0.1 to 5 (however, the total content of flurbiprofen axetyl and fats and oils is 100 mg / fat at maximum / mL), a production method characterized by emulsifying the constituents with a content of lecithin as an emulsifier of 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin). 乳化を３５０〜１５００バールの圧力で行うことを特徴とする請求項５記載の製造方法。 The production method according to claim 5, wherein the emulsification is carried out at a pressure of 350 to 1500 bar.
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