JP3410364B2 - Difluprednate-containing composition - Google Patents
Difluprednate-containing compositionInfo
- Publication number
- JP3410364B2 JP3410364B2 JP12990898A JP12990898A JP3410364B2 JP 3410364 B2 JP3410364 B2 JP 3410364B2 JP 12990898 A JP12990898 A JP 12990898A JP 12990898 A JP12990898 A JP 12990898A JP 3410364 B2 JP3410364 B2 JP 3410364B2
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- oil
- difluprednate
- weight
- composition
- parts
- Prior art date
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、ジフルプレドナー
ト、油、水、および乳化剤を含有することを特徴とする
液状組成物に関する。詳細には、本発明はジフルプレド
ナートの患部への移行性が良好で、薬物分布が均一で違
和感、異物感の少ないジフルプレドナート液状組成物に
関する。TECHNICAL FIELD The present invention relates to a liquid composition containing difluprednate, oil, water, and an emulsifier. More specifically, the present invention relates to a liquid composition of difluprednate having good transferability of difluprednate to an affected area, uniform drug distribution, and less discomfort or foreign body sensation.
【０００２】[0002]
【従来の技術】ジフルプレドナート（６α，９α−ジフ
ルオロプレドニゾロン １７−ブチレート ２１−アセ
テート）は、ステロイド性抗炎症薬であり、経皮投与に
より優れた抗炎症作用を示すことが知られている（特公
昭４５−２８３７０号公報、特公昭４５−２８３７１号
公報）。また、ジフルプレドナートは経皮投与および皮
下投与により優れた抗炎症作用および抗アレルギー作用
を示すことが報告されている（応用薬理 (1985) 29 (3)
343-353、応用薬理 (1985) 29 (3) 355-362）。このた
め、ジフルプレドナートは主に軟膏、クリーム等の形態
で皮膚疾患の治療薬として使用されている。一方、ジフ
ルプレドナートを眼、鼻、耳等の局所に投与する場合に
は、点眼液、点鼻液、点耳液等の液状形態とすることが
望まれる。しかしジフルプレドナートは水に対する溶解
度がきわめて低いため、治療有効濃度を含有する安定な
点眼液、点鼻液、点耳液等を調製することは困難であ
り、上記のような局所に投与する際には懸濁水性製剤の
形態が提案されている（特開平８−２１７６７８号公
報）。2. Description of the Related Art Difluprednate (6α, 9α-difluoroprednisolone 17-butyrate 21-acetate) is a steroidal anti-inflammatory drug and is known to exhibit an excellent anti-inflammatory effect by transdermal administration ( JP-B-45-28370 and JP-B-45-28371). Difluprednate has also been reported to show superior anti-inflammatory and anti-allergic effects by transdermal and subcutaneous administration (Applied Pharmacology (1985) 29 (3).
343-353, Applied Pharmacology (1985) 29 (3) 355-362). Therefore, difluprednate is mainly used as a therapeutic agent for skin diseases in the form of ointments, creams and the like. On the other hand, when the difluprednate is administered locally to the eye, nose, ear, etc., it is desired to be in a liquid form such as eye drops, nasal drops, ear drops. However, since difluprednate has a very low solubility in water, it is difficult to prepare stable eye drops, nasal drops, ear drops, etc. containing a therapeutically effective concentration. Has proposed a form of a suspension aqueous preparation (JP-A-8-217678).
【０００３】しかし、例えばジフルプレドナート懸濁水
性製剤を点眼液として使用する場合、懸濁水性点眼液の
持つ共通の問題点、すなわち、点眼時の薬物分布の均一
性の維持が困難であることや、固体が目に入る違和感、
異物感が完全に除去できないという点が指摘され続けて
きた。さらに、ジフルプレドナートはステロイド性抗炎
症薬であるため、炎症性疾患やアレルギー性疾患等の治
療に対して効果が充分ある反面、副作用もあるという問
題点が指摘された。従って、点眼部位（外眼部）より離
れた部位（内眼部）に炎症がある場合などを考慮し、有
効量が速やかかつ均一に患部に移行し、副作用を抑える
ことのできる投与形態の開発が望まれている。However, for example, when a difluprednate suspension aqueous solution is used as an eye drop, a common problem with the suspension aqueous eye drop, that is, it is difficult to maintain uniform drug distribution at the time of instillation Or, a sense of discomfort that a solid gets into your eyes,
It has been pointed out that the feeling of foreign matter cannot be completely removed. Further, since difluprednate is a steroidal anti-inflammatory drug, it has been pointed out that it has sufficient side effects for the treatment of inflammatory diseases and allergic diseases, but also has side effects. Therefore, in consideration of the case where there is inflammation in the part (inner part of the eye) away from the instilled part (outer part of the eye), an effective dosage will be rapidly and uniformly transferred to the affected part, and development of a dosage form that can suppress side effects Is desired.
【０００４】上述したように、ジフルプレドナートは優
れた抗炎症作用および抗アレルギー作用を有するため、
種々の炎症性疾患やアレルギー性疾患の予防・治療に有
用である。眼、鼻、耳等の局所における疾患の治療に対
しては点眼、点鼻、点耳等が可能な投与形態に製剤化す
る必要があるが、これらの局所疾患の治療にジフルプレ
ドナートを懸濁水性製剤の形態で使用すると、上記のよ
うに薬物の患部への移行性、薬物分布の均一性、および
違和感、異物感といった使用感の面で問題がある。As mentioned above, since difluprednate has excellent anti-inflammatory and antiallergic effects,
It is useful for the prevention and treatment of various inflammatory diseases and allergic diseases. For the treatment of local diseases such as eyes, nose, and ears, it is necessary to formulate into a dosage form capable of instillation, nose, ear, etc., but difluprednate is required for the treatment of these local diseases. When used in the form of a turbid aqueous formulation, there are problems in terms of transferability of the drug to the affected area, uniformity of drug distribution, and feeling of use such as discomfort and foreign body sensation as described above.
【０００５】[0005]
【発明が解決しようとする課題】従って、本発明の目的
は、患部への移行性が良好で、投与時の薬物分布が均一
であり、さらに投与時の違和感、異物感が少なく、副作
用が抑制されたジフルプレドナート含有組成物を提供す
ることである。Therefore, the object of the present invention is to have good transferability to the affected area, uniform drug distribution during administration, less discomfort during administration, less foreign body sensation, and reduced side effects. To provide a difluprednate-containing composition.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、上記の課
題を解決すべく鋭意研究を重ねた結果、ジフルプレドナ
ート、油、水、および乳化剤を含有する液状組成物の形
態に調製して使用することにより、眼、鼻、耳等の局所
に投与する際にもジフルプレドナートの移行が速やかで
移行量が多く、分布量が均一であり、さらに使用時の違
和感、異物感が極めて少ないことを見出した。また、ジ
フルプレドナートの移行性が良好であるため、低用量の
投与で薬効が十分発揮され、副作用を抑制することが可
能であることを見い出し、本発明を完成した。As a result of intensive studies to solve the above problems, the present inventors have prepared a liquid composition containing difluprednate, oil, water, and an emulsifier. When used topically, the transfer of difluprednate is rapid even when administered locally to the eyes, nose, ears, etc., the transfer amount is large, the distribution amount is uniform, and discomfort and foreign body sensation during use are extremely high. I found that there are few. Further, they have found that, because difluprednate has a good migration property, the drug effect is sufficiently exerted even at a low dose, and side effects can be suppressed, and the present invention was completed.
【０００７】すなわち、本発明は、（１）ジフルプレド
ナート、油、水、および乳化剤を含有することを特徴と
するジフルプレドナート液状組成物、（２）ジフルプレ
ドナート１重量部に対して、油１０〜１０００００重量
部、水１００〜１０００００重量部および乳化剤１０〜
１０００００重量部を含有する上記（１）の組成物、
（３）ジフルプレドナート１重量部に対して、油１０〜
１００００重量部、水１００〜５００００重量部および
乳化剤１０〜１００００重量部を含有する上記（１）の
組成物、（４）ジフルプレドナート１重量部に対して、
油１０〜５０００重量部、水５００〜５００００重量部
および乳化剤１０〜５０００重量部を含有する上記
（１）の組成物、（５）油がグリセリンの脂肪酸エステ
ルを含有する油である上記（１）の組成物、（６）グリ
セリンの脂肪酸エステルがヒマシ油、落花生油、綿実
油、大豆油、オリーブ油および中鎖脂肪酸トリグリセリ
ドからなる群より選ばれる上記（５）の組成物、（７）
乳化剤が界面活性剤を含有する上記（１）の組成物、
（８）界面活性剤が非イオン界面活性剤である上記
（７）の組成物、（９）非イオン界面活性剤がポリオキ
シエチレン硬化ヒマシ油およびポリオキシエチレンソル
ビタン脂肪酸エステルからなる群より選ばれる上記
（８）の組成物、（１０）ポリオキシエチレンソルビタ
ン脂肪酸エステルがポリオキシエチレンソルビタンモノ
オレエート、ポリオキシエチレンソルビタンモノラウレ
ート、ポリオキシエチレンソルビタンモノパルミテート
およびポリオキシエチレンソルビタンモノステアレート
からなる群より選ばれる上記（９）の組成物、（１１）
水中油滴型エマルジョンである上記（１）、（２）、
（３）または（４）の組成物、および（１２）点眼液、
点鼻液または点耳液の形態である上記（１）、（２）、
（３）または（４）の組成物に関する。That is, the present invention relates to (1) difluprednate liquid composition characterized by containing difluprednate, oil, water, and an emulsifier, and (2) 1 part by weight of difluprednate, Oil 10-100,000 parts by weight, water 100-100,000 parts by weight and emulsifier 10
The composition of (1) above, containing 100,000 parts by weight,
(3) Oil 10 to 10 parts by weight of difluprednate
10000 parts by weight of water, 100 to 50000 parts by weight of water, and 10 to 10000 parts by weight of an emulsifier, (4) 1 part by weight of difluprednate,
The composition of the above (1) containing 10 to 5,000 parts by weight of oil, 500 to 50,000 parts by weight of water and 10 to 5,000 parts by weight of an emulsifier, (5) The above (1) wherein the oil is an oil containing a fatty acid ester of glycerin. (6) The composition of (5) above, wherein the fatty acid ester of glycerin is selected from the group consisting of castor oil, peanut oil, cottonseed oil, soybean oil, olive oil, and medium chain fatty acid triglyceride, (7)
The composition according to (1) above, wherein the emulsifier contains a surfactant,
(8) The composition according to (7) above, wherein the surfactant is a nonionic surfactant, and (9) the nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester. The composition (8), wherein the polyoxyethylene sorbitan fatty acid ester (10) is selected from polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate. The composition of (9) above selected from the group consisting of: (11)
The above (1), (2), which is an oil-in-water emulsion,
(3) or (4) composition, and (12) eye drops,
The above (1), (2) in the form of nasal drops or ear drops,
It relates to the composition of (3) or (4).
【０００８】[0008]
【発明の実施の形態】本発明の組成物は、ジフルプレド
ナート、油、水、および乳化剤を含有する。本発明で用
いることのできる油の種類としては、低毒性、低刺激性
の眼に適用可能なものであればよく、好ましくはグリセ
リンの脂肪酸エステルを含有するもの、例えばヒマシ
油、落花生油、綿実油、大豆油、オリーブ油、中鎖脂肪
酸トリグリセリド［例えば、ミグリオール（商品名、ミ
ツバ貿易）］等が挙げられる。さらに好ましくはジフル
プレドナートの溶解性が高いヒマシ油および中鎖脂肪酸
トリグリセリド（例えば、ミグリオール）等が挙げられ
る。BEST MODE FOR CARRYING OUT THE INVENTION The composition of the present invention contains difluprednate, oil, water, and an emulsifier. The type of oil that can be used in the present invention may be one that can be applied to the eyes of low toxicity and low irritation, and preferably those containing a fatty acid ester of glycerin, such as castor oil, peanut oil, and cottonseed oil. , Soybean oil, olive oil, medium-chain fatty acid triglyceride [eg, Miglyol (trade name, Mitsuba Trading Co., Ltd.)] and the like. More preferred are castor oil and medium-chain fatty acid triglyceride (for example, migliol) having high solubility of difluprednate, and the like.
【０００９】本発明においては、乳化剤として、界面活
性剤、例えば界面活性能のある非イオン界面活性剤等を
配合することができる。非イオン界面活性剤の例として
は、ポリオキシエチレン硬化ヒマシ油類またはポリオキ
シエチレンソルビタン脂肪酸エステル、好ましくはポリ
オキシエチレンソルビタンモノオレエート類、ポリオキ
シエチレンソルビタンモノラウレート類、ポリオキシエ
チレンソルビタンモノパルミテート類、ポリオキシエチ
レンソルビタンモノステアレート類等が挙げられる。In the present invention, as an emulsifier, a surfactant, for example, a nonionic surfactant having surface active ability can be blended. Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, preferably polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoester. Examples thereof include palmitates and polyoxyethylene sorbitan monostearates.
【００１０】本発明の組成物における上記各成分の配合
割合は特に限定されないが、例えばジフルプレドナート
１重量部に対し、油１０〜１０００００重量部、水１０
０〜１０００００重量部、乳化剤１０〜１０００００重
量部、好ましくはジフルプレドナート１重量部に対し、
油１０〜１００００重量部、水１００〜５００００重量
部、乳化剤１０〜１００００重量部の割合で配合され
る。特に好ましくはジフルプレドナート１重量部に対
し、油１０〜５０００重量部、水５００〜５００００重
量部、乳化剤１０〜５０００重量部の割合で配合され
る。特に、油と媒体である水の重量比率が１：４〜１：
９９であることが好ましい。The blending ratio of each of the above components in the composition of the present invention is not particularly limited, but for example, 10 parts by weight to 100,000 parts by weight of oil and 10 parts by weight of water to 1 part by weight of difluprednate.
0 to 100,000 parts by weight, emulsifier 10 to 100,000 parts by weight, preferably 1 part by weight of difluprednate,
The oil is mixed in an amount of 10 to 10000 parts by weight, water 100 to 50000 parts by weight, and an emulsifier 10 to 10000 parts by weight. Particularly preferably, the oil is mixed in an amount of 10 to 5000 parts by weight, water in an amount of 500 to 50,000 parts by weight, and an emulsifier in an amount of 10 to 5,000 parts by weight with respect to 1 part by weight of difluprednate. In particular, the weight ratio of oil to water as the medium is 1: 4 to 1:
It is preferably 99.
【００１１】本発明の組成物には、乳化安定性を高める
ために、水溶性高分子を配合することができる。水溶性
高分子の例としては、ポビドン（ポリビニルピロリド
ン）、ポリビニルアルコール、ヒドロキシエチルセルロ
ース、ヒドロキシプロピルセルロース、メチルセルロー
ス、ヒドロキシプロピルメチルセルロース、カルボキシ
メチルセルロース、およびそれらの塩等が挙げられる。A water-soluble polymer can be added to the composition of the present invention in order to improve the emulsion stability. Examples of the water-soluble polymer include povidone (polyvinylpyrrolidone), polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof.
【００１２】本発明の組成物には緩衝剤を配合すること
ができる。緩衝剤の例としては、酢酸ナトリウム等の酢
酸塩、リン酸二水素一ナトリウム、リン酸一水素二ナト
リウム、リン酸二水素一カリウム、リン酸一水素二カリ
ウム等のリン酸塩、イプシロンアミノカプロン酸、グル
タミン酸ナトリウム等のアミノ酸塩、ホウ酸およびその
塩、クエン酸およびその塩等が挙げられる。A buffer may be added to the composition of the present invention. Examples of the buffer include acetate such as sodium acetate, monosodium dihydrogen phosphate, disodium monohydrogen phosphate, monopotassium dihydrogen phosphate, phosphate such as dipotassium monohydrogen phosphate, epsilon aminocaproic acid. Amino acid salts such as sodium glutamate, boric acid and its salts, citric acid and its salts, and the like.
【００１３】本発明の組成物には保存剤を配合すること
ができる。保存剤の例としては、塩化ベンザルコニウ
ム、塩化ベンゼトニウム等の第四級アンモニウム塩、グ
ルコン酸クロルヘキシジン等の陽イオン化合物、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等の
パラオキシ安息香酸エステル、クロロブタノール、ベン
ジルアルコール等のアルコール化合物、デヒドロ酢酸ナ
トリウム、チメロサール、ソルビン酸等が挙げられる。A preservative can be added to the composition of the present invention. Examples of preservatives include benzalkonium chloride, quaternary ammonium salts such as benzethonium chloride, cationic compounds such as chlorhexidine gluconate, methyl paraoxybenzoate, paraoxybenzoic acid esters such as propyl paraoxybenzoate, chlorobutanol, and the like. Examples thereof include alcohol compounds such as benzyl alcohol, sodium dehydroacetate, thimerosal, sorbic acid and the like.
【００１４】本発明の組成物には、等張化剤を配合する
ことができる。等張化剤の例としては、塩化ナトリウ
ム、グリセリン、ブドウ糖、マンニトール、ソルビトー
ル等が挙げられる。A tonicity agent may be added to the composition of the present invention. Examples of the tonicity agent include sodium chloride, glycerin, glucose, mannitol, sorbitol and the like.
【００１５】本発明の組成物には他に安定化剤、抗酸化
剤、キレート化剤、ｐＨ調整剤、増粘剤等の各種添加剤
を配合することができる。抗酸化剤の例としては、アス
コルビン酸およびその塩、トコフェロール、チオ硫酸ナ
トリウム、亜硫酸水素ナトリウム、ピルビン酸およびそ
の塩等が挙げられる。キレート化剤の例としては、エデ
ト酸ナトリウム、クエン酸およびその塩等が挙げられ
る。ｐＨ調整剤の例としては、塩酸、リン酸、酢酸、硫
酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウ
ム、炭酸水素ナトリウム、アンモニア水等が挙げられ
る。In addition to the composition of the present invention, various additives such as stabilizers, antioxidants, chelating agents, pH adjusters and thickeners can be added. Examples of antioxidants include ascorbic acid and salts thereof, tocopherol, sodium thiosulfate, sodium bisulfite, pyruvic acid and salts thereof, and the like. Examples of chelating agents include sodium edetate, citric acid and salts thereof. Examples of pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, aqueous ammonia and the like.
【００１６】本発明の組成物は、水中油滴型（Ｏ／Ｗ
型）のエマルジョン、マイクロエマルジョン等の水性製
剤として提供できる。The composition of the present invention is an oil-in-water type (O / W
Type) emulsions, microemulsions, and other aqueous preparations.
【００１７】本発明の組成物の油滴のメディアン径とし
ては５〜０．０００１μｍが好ましく、さらに１〜０．
００１μｍがより好ましく、１〜０．０１μｍが特に好
ましい。メディアン径の測定は粒度分布測定装置を用い
て行うことができる。The median diameter of oil droplets of the composition of the present invention is preferably 5 to 0.0001 μm, and more preferably 1 to 0.
001 μm is more preferable, and 1 to 0.01 μm is particularly preferable. The median diameter can be measured using a particle size distribution measuring device.
【００１８】本発明の組成物のｐＨは３〜８が好まし
い。さらに好ましいｐＨはジフルプレドナートの安定性
がより向上する４〜７である。The pH of the composition of the present invention is preferably 3-8. A more preferable pH is 4 to 7, which further improves the stability of difluprednate.
【００１９】本発明の組成物は、公知の手法を用いて、
ジフルプレドナートを溶解させた油と水を、乳化剤を用
いて乳化することにより調製する。例えば、水に、乳化
剤および必要に応じて上記の添加剤を添加し、ｐＨ調整
剤を用いてｐＨ３〜８に調整した後、ジフルプレドナー
トを溶解した油を添加して乳化物とすることができる。
均一に乳化を行うために、ホモミキサー、ホモジナイザ
ー、マイクロフルイダイザー、高圧ホモジナイザー等の
公知の手段を使用することができる。The composition of the present invention is prepared by a known method.
It is prepared by emulsifying oil and water in which difluprednate is dissolved with an emulsifier. For example, an emulsifier may be prepared by adding an emulsifier and, if necessary, the above-mentioned additive to water and adjusting the pH to 3 to 8 using a pH adjuster, and then adding an oil in which difluprednate is dissolved. it can.
Known means such as a homomixer, a homogenizer, a microfluidizer, and a high-pressure homogenizer can be used for uniform emulsification.
【００２０】本発明の組成物は、眼、鼻、または耳に対
する局所投与用の製剤として用いることが好ましく、さ
らに点眼液、点鼻液、点耳液として用いることが好まし
い。The composition of the present invention is preferably used as a preparation for topical administration to the eye, nose or ear, and further preferably used as eye drops, nasal drops and ear drops.
【００２１】本発明の組成物は、優れた抗炎症作用およ
び抗アレルギー作用を有する。また、ジフルプレドナー
トの移行性が良好で移行量が多く、分布量が均一であ
り、投与した際の違和感、異物感が極めて少ない。さら
に、低用量の投与で薬効が十分発揮されるので、副作用
を抑制することができる。このため、アレルギー性結膜
炎、春季カタル、眼瞼縁炎、カタル性結膜炎、ぶどう膜
炎等の種々の炎症性疾患およびアレルギー性疾患の予防
・治療に有用であり、また、眼、鼻、耳等の局所に投与
する際にも有利に使用することができる。The composition of the present invention has excellent anti-inflammatory and anti-allergic effects. In addition, the migration of difluprednate is good, the migration is large, the distribution is uniform, and the discomfort and foreign body sensation upon administration are extremely small. Furthermore, since the drug effect is sufficiently exerted at the administration of a low dose, side effects can be suppressed. Therefore, it is useful for the prevention and treatment of various inflammatory diseases and allergic diseases such as allergic conjunctivitis, spring catarrhal, blepharitis, catarrhal conjunctivitis, uveitis, and also for the eyes, nose, ears, etc. It can also be used advantageously when administered topically.
【００２２】本発明の組成物は、哺乳動物（ヒト、イ
ヌ、ウサギ、ウシ、ウマ、サル、ネコ、ヒツジ等）に安
全に投与することができる。The composition of the present invention can be safely administered to mammals (humans, dogs, rabbits, cows, horses, monkeys, cats, sheep, etc.).
【００２３】本発明の組成物の投与量は、疾病の種類、
症状、患者の年齢、体重などにより異なるが、例えば成
人に点眼液として用いる場合、患者１人に対し、１眼に
つき、ジフルプレドナートを０．００５〜０．１％程度
含有する点眼液として、症状に応じて１回量１〜２滴を
１日２〜４回程度点眼投与することが望ましい。The dose of the composition of the present invention depends on the type of disease,
Although it varies depending on symptoms, age of the patient, weight, etc., when used as an eye drop for adults, for example, as an eye drop containing about 0.005 to 0.1% of difluprednate per eye per patient, Depending on the symptom, it is desirable to administer a single dose of 1 to 2 drops to the eye drop about 2 to 4 times a day.
【００２４】[0024]
【実施例】以下に、実施例および試験例を挙げて本発明
をさらに詳細に説明するが、本発明はこれらに限定され
るわけではない。以下の実施例および試験例において、
メディアン径は、島津レーザ回折式粒度分布測定装置Ｓ
ＡＬＤ−２０００（分散媒：水、屈折率：１．７０−
０．２０ｉ）に、測定する組成物約２ｍＬを添加し、測
定した。EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. In the following examples and test examples,
The median diameter is Shimadzu laser diffraction type particle size distribution measuring device S
ALD-2000 (dispersion medium: water, refractive index: 1.70-
To 0.20i), about 2 mL of the composition to be measured was added and measured.
【００２５】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、酢酸ナトリウム、ホウ酸、エ
デト酸ナトリウム、ソルビン酸を加えて溶かし、水酸化
ナトリウムでｐＨを６．０に調整し水相とした。別にヒ
マシ油を約７０℃に加温し、ジフルプレドナートを加え
て溶かし、油相とした。水相をホモミキサーで攪拌しな
がら油相を加えて粗乳化物を得た。この粗乳化物をマイ
クロフルイダイザーで微粒子化し、ろ過滅菌し、本発明
の組成物を得た。本発明組成物中の油滴のメディアン径
は０．０６μｍであった。[0025] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, boric acid, sodium edetate, and sorbic acid are added and dissolved, and the pH is adjusted to 6.0 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.
【００２６】
実施例２
ジフルプレドナート ０．００５ｇ
ヒマシ油 １．０ ｇ
ポリソルベート８０ ０．５ ｇ
濃グリセリン ２．２ ｇ
ヒドロキシプロピルメチルセルロース ０．１ ｇ
酢酸ナトリウム ０．０５ｇ
クロロブタノール ０．３ ｇ
塩酸 適量
滅菌精製水 全量１００ｍＬ
（ｐＨ４．０）
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、ヒドロキシプロピルメチルセ
ルロース、酢酸ナトリウム、クロロブタノールを加えて
溶かし、塩酸でｐＨを４．０に調整し水相とした。別に
ヒマシ油を約７０℃に加温し、ジフルプレドナートを加
えて溶かし、油相とした。水相をホモミキサーで攪拌し
ながら油相を加えて粗乳化物を得た。この粗乳化物をマ
イクロフルイダイザーで微粒子化し、ろ過滅菌し、本発
明の組成物を得た。本発明組成物中の油滴のメディアン
径は０．１２μｍであった。Example 2 Difluprednate 0.005 g Castor oil 1.0 g Polysorbate 80 0.5 g Concentrated glycerin 2.2 g Hydroxypropylmethylcellulose 0.1 g Sodium acetate 0.05 g Chlorobutanol 0.3 g Hydrochloric acid qs Sterile purified water Total volume 100 mL (pH 4.0) Sterile purified water is heated to about 70 ° C., polysorbate 80, concentrated glycerin, hydroxypropylmethylcellulose, sodium acetate and chlorobutanol of the above formulation are added and dissolved, and pH is adjusted to 4 with hydrochloric acid. The water phase was adjusted to 0.0. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.12 μm.
【００２７】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、ε−アミノカプロン酸、グル
コン酸クロルヘキシジンを加えて溶かし、水酸化ナトリ
ウムでｐＨを５．５に調整し水相とした。別にミグリオ
ールを約７０℃に加温し、ジフルプレドナートを加えて
溶かし、油相とした。水相をホモミキサーで攪拌しなが
ら油相を加えて粗乳化物を得た。この粗乳化物をマイク
ロフルイダイザーで微粒子化し、ろ過滅菌し、本発明の
組成物を得た。本発明組成物中の油滴のメディアン径は
０．２１μｍであった。[0027] Sterile purified water was heated to about 70 ° C., polysorbate 80, concentrated glycerin, ε-aminocaproic acid, and chlorhexidine gluconate of the above formulation were added and dissolved, and the pH was adjusted to 5.5 with sodium hydroxide to obtain an aqueous phase. . Separately, Miglyol was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.21 μm.
【００２８】
滅菌精製水を約７０℃に加温し、上記処方のポリオキシ
エチレン硬化ヒマシ油６０、濃グリセリン、グルタミン
酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ
安息香酸プロピルを加えて溶かし、水酸化ナトリウムで
ｐＨを５．０に調整し水相とした。別にヒマシ油を約７
０℃に加温し、ジフルプレドナートを加えて溶かし、油
相とした。水相をホモミキサーで攪拌しながら油相を加
えて粗乳化物を得た。この粗乳化物をマイクロフルイダ
イザーで微粒子化し、ろ過滅菌し、本発明の組成物を得
た。本発明組成物中の油滴のメディアン径は０．０６μ
ｍであった。[0028] Sterile purified water is heated to about 70 ° C., polyoxyethylene hydrogenated castor oil 60, concentrated glycerin, sodium glutamate, methyl paraoxybenzoate and propyl paraoxybenzoate of the above formulation are added and dissolved, and the pH is adjusted to 5 with sodium hydroxide. The water phase was adjusted to 0.0. Castor oil about 7
The mixture was heated to 0 ° C., difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention is 0.06μ.
It was m.
【００２９】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、ポリビニルアルコール、濃グリセリン、酢酸
ナトリウム、塩化ベンザルコニウムを加えて溶かし、塩
酸でｐＨを５．０に調整し水相とした。別にヒマシ油を
約７０℃に加温し、ジフルプレドナートを加えて溶か
し、油相とした。水相をホモミキサーで攪拌しながら油
相を加えて粗乳化物を得た。この粗乳化物をマイクロフ
ルイダイザーで微粒子化し、ろ過滅菌し、本発明の組成
物を得た。本発明組成物中の油滴のメディアン径は０．
０６μｍであった。[0029] Sterile purified water was heated to about 70 ° C., polysorbate 80, polyvinyl alcohol, concentrated glycerin, sodium acetate and benzalkonium chloride of the above formulation were added and dissolved, and the pH was adjusted to 5.0 with hydrochloric acid to form an aqueous phase. . Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention is 0.
It was 06 μm.
【００３０】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、リン酸水素ナトリウム、エデ
ト酸ナトリウム、塩化ベンザルコニウムを加えて溶か
し、水酸化ナトリウムでｐＨを７．０に調整し水相とし
た。別にミグリオールを約７０℃に加温し、ジフルプレ
ドナートを加えて溶かし、油相とした。水相をホモミキ
サーで攪拌しながら油相を加えて粗乳化物を得た。この
粗乳化物をマイクロフルイダイザーで微粒子化し、ろ過
滅菌し、本発明の組成物を得た。本発明組成物中の油滴
のメディアン径は０．０６μｍであった。[0030] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium hydrogen phosphate, sodium edetate, and benzalkonium chloride are added and dissolved, and the pH is adjusted to 7.0 with sodium hydroxide. The water phase was used. Separately, Miglyol was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.
【００３１】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、酢酸ナトリウム、エデト酸ナ
トリウム、ホウ酸、ソルビン酸を加えて溶かし、水酸化
ナトリウムでｐＨを５．５に調整し水相とした。別にヒ
マシ油を約７０℃に加温し、ジフルプレドナートを加え
て溶かし、油相とした。水相をホモミキサーで攪拌しな
がら油相を加えて粗乳化物を得た。この粗乳化物をマイ
クロフルイダイザーで微粒子化し、ろ過滅菌し、本発明
の組成物を得た。本発明組成物中の油滴のメディアン径
は０．０６μｍであった。[0031] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, sodium edetate, boric acid and sorbic acid are added and dissolved, and the pH is adjusted to 5.5 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.
【００３２】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、酢酸ナトリウム、エデト酸ナ
トリウム、ホウ酸、ソルビン酸を加えて溶かし、水酸化
ナトリウムでｐＨを５．５に調整し水相とした。別にヒ
マシ油を約７０℃に加温し、ジフルプレドナートを加え
て溶かし、油相とした。水相をホモミキサーで攪拌しな
がら油相を加えて粗乳化物を得た。この粗乳化物をマイ
クロフルイダイザーで微粒子化し、ろ過滅菌し、本発明
の組成物を得た。本発明組成物中の油滴のメディアン径
は０．０６μｍであった。[0032] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, sodium edetate, boric acid and sorbic acid are added and dissolved, and the pH is adjusted to 5.5 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.
【００３３】
滅菌精製水を約７０℃に加温し、上記処方のポリソルベ
ート８０、濃グリセリン、酢酸ナトリウム、エデト酸ナ
トリウム、ホウ酸、ソルビン酸を加えて溶かし、水酸化
ナトリウムでｐＨを５．５に調整し水相とした。別にヒ
マシ油を約７０℃に加温し、ジフルプレドナートを加え
て溶かし、油相とした。水相をホモミキサーで攪拌しな
がら油相を加えて粗乳化物を得た。この粗乳化物をマイ
クロフルイダイザーで微粒子化し、ろ過滅菌し、本発明
の組成物を得た。本発明組成物中の油滴のメディアン径
は０．０６μｍであった。[0033] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, sodium edetate, boric acid and sorbic acid are added and dissolved, and the pH is adjusted to 5.5 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.
【００３４】試験例１
ジフルプレドナート懸濁点眼液と本発明の組成物の１回
点眼後のウサギ前房内移行性（眼内移行性）を比較検討
した。ステロイド剤であるジフルプレドナート懸濁点眼
液はすでにウサギ実験的ぶどう膜炎に対して有意な抑制
効果が報告されている。本試験ではジフルプレドナート
の眼内移行性の向上を目的として、ジフルプレドナート
の前房内移行性（眼内移行性）について、本発明の組成
物とジフルプレドナート懸濁点眼液を比較検討した。
(1) 被験組成物
表１に記載の処方の本発明組成物、および懸濁点眼液を
以下のようにして調製した。
〔本発明組成物〕滅菌精製水８００ｍＬを約７０℃に加
温し、ポリソルベート８０ ４０ｇ及び濃グリセリン２
６ｇを加えて溶かし、水相とした。別に、ヒマシ油５０
ｇを約７０℃に加温し、ジフルプレドナート０．５ｇを
加えて溶かし、油相とした。水相をホモミキサーで攪拌
しながら油相を加えて粗乳化物とし、滅菌精製水を加え
て１０００ｍＬとした。この粗乳化物をマイクロフルイ
ダイザーで微粒子化し、その後、濾過滅菌し、本発明の
組成物を得た。
〔懸濁点眼液〕滅菌精製水８００ｍＬを約７０℃に加温
し、ヒドロキシプロピルメチルセルロース２ｇを加え、
十分分散させた後、約３０℃まで冷却させ、ヒドロキシ
プロピルメチルセルロースを溶かした。この液に酢酸ナ
トリウム１ｇ、塩化ナトリウム８ｇ及び塩化ベンザルコ
ニウム液（１０W/V%）０．５ｍＬを加えて溶かした。塩
酸でｐＨを５．０に調整した後、濾過滅菌し、ジフルプ
レドナート１ｇを加え、十分懸濁させ、滅菌精製水を加
えて１０００ｍＬとし、懸濁点眼液を得た。Test Example 1 Difluprednate suspension ophthalmic solution and the composition of the present invention were compared and examined for the transferability in rabbit anterior chamber (intraocular transferability) after a single instillation. The steroid drug difluprednate suspension ophthalmic solution has already been reported to have a significant inhibitory effect on experimental uveitis in rabbits. In this study, for the purpose of improving the intraocular translocation of difluprednate, the composition of the present invention and difluprednate suspension ophthalmic solution were compared and examined for the intracameral translocation of difluprednate (intraocular translocation). did. (1) Test composition The composition of the present invention having the formulation shown in Table 1 and a suspension ophthalmic solution were prepared as follows. [Inventive Composition] 800 mL of sterile purified water is heated to about 70 ° C., 40 g of polysorbate 80 and concentrated glycerin 2 are added.
6 g was added and dissolved to obtain an aqueous phase. Separately, castor oil 50
g was heated to about 70 ° C., 0.5 g of difluprednate was added and dissolved to obtain an oil phase. While stirring the aqueous phase with a homomixer, the oil phase was added to make a crude emulsion, and sterilized purified water was added to make 1000 mL. This crude emulsion was made into fine particles using a microfluidizer and then sterilized by filtration to obtain the composition of the present invention. [Suspension eye drop] 800 mL of sterilized purified water is heated to about 70 ° C., 2 g of hydroxypropylmethyl cellulose is added,
After being sufficiently dispersed, the mixture was cooled to about 30 ° C. to dissolve hydroxypropylmethyl cellulose. To this solution, 1 g of sodium acetate, 8 g of sodium chloride and 0.5 mL of a benzalkonium chloride solution (10 W / V%) were added and dissolved. After adjusting the pH to 5.0 with hydrochloric acid, the solution was sterilized by filtration, 1 g of difluprednate was added and sufficiently suspended, and sterile purified water was added to 1000 mL to obtain a suspension ophthalmic solution.
【００３５】[0035]
【表１】 [Table 1]
【００３６】(2) 試験動物
眼に異常の認められない体重約２ｋｇの日本白色種雄性
ウサギを使用した。これらのウサギは室温２３±３℃、
相対湿度５５±１０％に設定した飼育室で１匹ずつ飼育
し、固型飼料（ラボＲＧ−ＲＯ、日本農産）を１日１０
０ｇ与え、水道水を自由に摂取させた。(2) Test Animal A Japanese White Male Rabbit having a body weight of about 2 kg with no abnormalities in the eyes was used. These rabbits have a room temperature of 23 ± 3 ° C,
The animals were bred one by one in a breeding room set at a relative humidity of 55 ± 10%, and were fed solid feed (Lab RG-RO, Japanese agricultural products) 10 times a day.
0 g was given and tap water was freely taken.
【００３７】(3) 試験方法
被験組成物５０μＬをウサギに点眼し、１時間後にペン
トバルビタールで屠殺した。屠殺後直ちに前眼部を生理
食塩水で洗浄し、前房水を採取した。ジフルプレドナー
トは房水中等で２１位の脱エステル化をうけＤＦＢ（６
α，９α−difluoroprednisolone １７−butyrate）に
代謝されることから、前房内ジフルプレドナート濃度の
指標としてＤＦＢを高速液体クロマトグラフ法により測
定した。高速液体クロマトグラフ条件は以下の通りであ
る。(3) Test method Rabbits were instilled with 50 μL of the test composition, and 1 hour later, the animals were sacrificed with pentobarbital. Immediately after the sacrifice, the anterior ocular segment was washed with physiological saline, and the anterior chamber water was collected. Difluprednate was deesterified at the 21st position in aqueous humor etc.
Since it is metabolized to α, 9α-difluoroprednisolone 17-butyrate), DFB was measured by high performance liquid chromatography as an index of the concentration of difluprednate in the anterior chamber. The high performance liquid chromatographic conditions are as follows.
【００３８】 高速液体クロマトグラフ条件 カ ラ ム：TSK gel ODS-80Ts 移 動 相：10mM NaH2 PO4 ・2H2 O(pH7)/CH 3 CN = 55/45 カラム温度：40℃ 流 速：1.3 ｍＬ/min 波 長：240nm 注 入 量：50μＬHigh-performance liquid chromatographic conditions Column: TSK gel ODS-80Ts Mobile phase: 10 mM NaH 2 PO 4 .2H 2 O (pH 7) / CH 3 CN = 55/45 Column temperature: 40 ° C Flow rate: 1.3 mL / min Wavelength: 240 nm Injection volume: 50 μL
【００３９】被験組成物１回点眼１時間後のウサギ前房
内ＤＦＢ濃度を表２に示す。Table 2 shows the DFB concentration in the rabbit anterior chamber 1 hour after the first instillation of the test composition.
【００４０】[0040]
【表２】 [Table 2]
【００４１】ジフルプレドナートを本発明の組成物に調
製することにより、含有薬物濃度が懸濁剤の半量である
にもかかわらず、眼内移行量は４２．９５ｎｇ／ｍＬの
値を示した。この値は懸濁剤の眼内移行量の約２．２倍
であり、有意な差が認められた。以上の結果から、本発
明の組成物は、懸濁剤より低用量であっても、懸濁剤以
上の薬効を発揮することが判明した。By preparing difluprednate in the composition of the present invention, the amount transferred into the eye showed a value of 42.95 ng / mL, even though the concentration of the drug contained was half that of the suspension. This value was about 2.2 times the intraocular amount of the suspension, and a significant difference was observed. From the above results, it was revealed that the composition of the present invention exerts the drug effect more than that of the suspension even if the dose is lower than that of the suspension.
【００４２】[0042]
【発明の効果】本発明の組成物は、優れた抗炎症作用お
よび抗アレルギー作用を有する。また、本発明の組成物
は、従来のジフルプレドナート含有製剤に比べると、患
部への移行性が良好であり、投与時の薬物分布が均一で
あるため低用量の投与で薬効が十分発揮される。さら
に、従来のジフルプレドナート含有製剤に比して投与時
の違和感、異物感が極めて少なく、眼、鼻、耳等の局所
にも容易に投与することができる。The composition of the present invention has excellent anti-inflammatory and anti-allergic effects. Further, the composition of the present invention, compared to the conventional difluprednate-containing formulation, has good transferability to the affected area, and since the drug distribution during administration is uniform, the drug effect is sufficiently exerted at low dose administration. It Further, compared to the conventional preparation containing difluprednate, the discomfort and foreign body sensation during administration are extremely small, and the preparation can be easily administered locally to the eyes, nose, ears and the like.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ Ａ６１Ｐ 37/08 Ａ６１Ｐ 37/08 (72)発明者 山口 正純 兵庫県神戸市西区南別府４丁目366番地 の１ ＫＣＣハウス101号 (72)発明者 稲田 勝弘 兵庫県神戸市西区井吹台東町１丁目２番 地の１ ３−401号 (56)参考文献 特開 平５−43465（ＪＰ，Ａ) 特開 平８−217678（ＪＰ，Ａ) 特公 昭45−28370（ＪＰ，Ｂ１) 特公 昭45−28371（ＪＰ，Ｂ１) 米国特許3780177（ＵＳ，Ａ) 米国特許4427670（ＵＳ，Ａ) 国際公開98／30221（ＷＯ，Ａ１) (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/575 A61K 9/107 A61P 11/02 A61P 27/14 A61P 27/16 A61P 37/08 ＣＡ（ＳＴＮ)─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI A61P 37/08 A61P 37/08 (72) Inventor Masazumi Yamaguchi 1 KCC House No. 101, 4-366, Minamibeppu, Nishi-ku, Kobe City, Hyogo Prefecture (72) Inventor Katsuhiro Inada, No. 1-3401, 1-2-2, Ibukidaihigashi-cho, Nishi-ku, Kobe-shi, Hyogo (56) References JP-A-5-43465 (JP, A) JP-A-8-217678 (JP, A) Japanese Patent Publication No. 45-28370 (JP, B1) Japanese Patent Publication No. 45-28371 (JP, B1) US Patent 3780177 (US, A) US Patent 4427670 (US, A) International Publication 98/30221 (WO, A1) (58) Fields surveyed (Int.Cl. 7 , DB name) A61K 31/575 A61K 9/107 A61P 11/02 A61P 27/14 A61P 27/16 A61P 37/08 CA (STN)
Claims (10)
シ油、落花生油、綿実油、大豆油、オリーブ油および中
鎖脂肪酸トリグリセリドからなる群より選ばれる油、
（ｃ）水、および（ｄ）乳化剤を含有する、点眼液、点
鼻液または点耳液であるジフルプレドナート含有エマル
ジョン組成物。1. (a) Difluprednate, (b) Castor
Oil, peanut oil, cottonseed oil, soybean oil, olive oil and medium
An oil selected from the group consisting of chain fatty acid triglycerides ,
(C) Water and (d) Emulsifier-containing eye drops, spots
Emul containing difluprednate which is nasal or ear drops
John composition.
油１０〜１０００００重量部、水１００〜１０００００
重量部および乳化剤１０〜１０００００重量部を含有す
る請求項１記載の組成物。2. With respect to 1 part by weight of difluprednate,
Oil 10-100,000 parts by weight, water 100-100,000
A composition according to claim 1 which comprises parts by weight and 10 to 100,000 parts by weight of emulsifier.
油１０〜１００００重量部、水１００〜５００００重量
部および乳化剤１０〜１００００重量部を含有する請求
項１記載の組成物。3. With respect to 1 part by weight of difluprednate,
The composition according to claim 1, which comprises 10 to 10000 parts by weight of oil, 100 to 50000 parts by weight of water, and 10 to 10000 parts by weight of an emulsifier.
油１０〜５０００重量部、水５００〜５００００重量部
および乳化剤１０〜５０００重量部を含有する請求項１
記載の組成物。4. With respect to 1 part by weight of difluprednate,
An oil containing 10 to 5000 parts by weight, 500 to 50000 parts by weight of water and 10 to 5000 parts by weight of an emulsifier.
The composition as described.
記載の組成物。5. The emulsifier contains a surfactant.
The composition as described.
請求項５記載の組成物。6. The composition according to claim 5 , wherein the surfactant is a nonionic surfactant.
ン硬化ヒマシ油およびポリオキシエチレンソルビタン脂
肪酸エステルからなる群より選ばれる請求項６記載の組
成物。7. The composition according to claim 6, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester.
ステルがポリオキシエチレンソルビタンモノオレエー
ト、ポリオキシエチレンソルビタンモノラウレート、ポ
リオキシエチレンソルビタンモノパルミテートおよびポ
リオキシエチレンソルビタンモノステアレートからなる
群より選ばれる請求項７記載の組成物。8. The polyoxyethylene sorbitan fatty acid ester is selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate. Item 7. The composition according to Item 7 .
１、２、３または４記載の組成物。9. The composition according to claim 1, which is an oil-in-water emulsion.
およびポリオキシエチレン（２０）ソルビタンモノオレ
エートを含有する、点眼液、点鼻液また は点耳液である
ジフルプレドナート含有エマルジョン組成物。 10. Difluprednate, castor oil, water,
And polyoxyethylene (20) sorbitan monoole
Containing benzoate, eye drops, nasal solutions or are ear drops
An emulsion composition containing difluprednate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12990898A JP3410364B2 (en) | 1997-05-14 | 1998-05-13 | Difluprednate-containing composition |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12441597 | 1997-05-14 | ||
| JP9-124415 | 1997-05-14 | ||
| JP12990898A JP3410364B2 (en) | 1997-05-14 | 1998-05-13 | Difluprednate-containing composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1129483A JPH1129483A (en) | 1999-02-02 |
| JP3410364B2 true JP3410364B2 (en) | 2003-05-26 |
Family
ID=26461097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12990898A Expired - Lifetime JP3410364B2 (en) | 1997-05-14 | 1998-05-13 | Difluprednate-containing composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3410364B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011007893A1 (en) | 2009-07-14 | 2011-01-20 | Yamagata University | Eye drop with difluprednate for macular edema treatment |
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| AU2005304035B2 (en) * | 2004-11-09 | 2010-07-22 | Santen Sas | Ophthalmic oil-in-water type emulsion with stable positive zeta potential |
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| US8476319B2 (en) * | 2005-03-10 | 2013-07-02 | 3M Innovative Properties Company | Methods of treating ear infections |
| JP2009526064A (en) * | 2006-02-09 | 2009-07-16 | シェーリング コーポレイション | Pharmaceutical formulation |
| ES2399976T3 (en) | 2006-06-01 | 2013-04-04 | Novagali Pharma S.A. | Use of prodrugs for ocular intravitreal administration |
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| BR112013001508A2 (en) * | 2010-07-21 | 2016-06-07 | Alcon Res Ltd | pharmaceutical composition with enhanced solubility characteristics |
| CN103228283A (en) * | 2010-11-29 | 2013-07-31 | 千寿制药株式会社 | Oil-in-water emulsion composition containing difluprednate and tobramycin |
| US20150374820A1 (en) * | 2013-02-15 | 2015-12-31 | Senju Pharmaceutical Co., Ltd. | Difluprednate emulsion composition containing zinc |
| CN105228630A (en) | 2013-02-15 | 2016-01-06 | 千寿制药株式会社 | Containing the difluprednate emulsion compositions of antimicrobial metal |
| JP6993231B2 (en) * | 2015-02-06 | 2022-02-04 | アールピー シーラー テクノロジーズ リミテッド ライアビリティ カンパニー | Preparation of polymer-stabilized oil-in-water emulsion for pharmaceuticals |
| PT3266446T (en) * | 2016-07-07 | 2019-01-30 | Salvat Lab Sa | Ophthalmic composition comprising castor oil and medium chain triglyceride |
| CN109963556A (en) | 2016-11-17 | 2019-07-02 | 千寿制药株式会社 | Emulsion eye drops |
-
1998
- 1998-05-13 JP JP12990898A patent/JP3410364B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011007893A1 (en) | 2009-07-14 | 2011-01-20 | Yamagata University | Eye drop with difluprednate for macular edema treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH1129483A (en) | 1999-02-02 |
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