JP3701693B2

JP3701693B2 - Sustained release fat emulsion for injection containing analgesics

Info

Publication number: JP3701693B2
Application number: JP35226093A
Authority: JP
Inventors: 苑起洪; 宇人松尾; 洋介片岡; 健二金子
Original assignee: Nihon Pharmaceutical Co Ltd
Current assignee: Nihon Pharmaceutical Co Ltd
Priority date: 1993-12-28
Filing date: 1993-12-28
Publication date: 2005-10-05
Anticipated expiration: 2020-10-05
Also published as: JPH07196510A

Description

【０００１】
【産業上の利用分野】
本発明は鎮痛薬の徐放性製剤に関する。更に詳しくは、非経口投与、特に皮下、筋肉内投与することによる鎮痛効果の持続性向上を図ったオピオイド系鎮痛薬を含有する脂肪乳剤に関する。
【０００２】
【従来の技術】
モルヒネ、ブプレノルフィン、ペンタゾシン等のオピオイド系鎮痛薬は、優れた鎮痛効果を有することから、激しい痛みを伴う癌性疼痛、術後疼痛等の緩和を目的として臨床の場で広く用いられている。しかし、その鎮痛効果の持続性は投与後数時間であり、頻回投与を余儀なくされ、患者の精神的負担を大きくしている。
【０００３】
一方、徐放性製剤は薬物の投与回数を削減し、治療効果を高め副作用を軽減させ、また経口投与剤の場合は患者のコンプライアンスを向上させるなど医療上多くの利点を有している。そのため徐放性製剤開発のために多くの剤型上の工夫がなされている。オピオイド系鎮痛薬としてはモルヒネの経口徐放性製剤が現在市販されているが持続時間は１２時間が限度であり、又、経口製剤であるが故に消化器系障害のある患者には投与できない欠点がある。またこのように経口投与が困難な場合には注射剤が有用であるが、現在、注射型の徐放性鎮痛剤は実用化されていない。
【０００４】
また近年、脂肪乳剤のドラックキャリヤー及び薬物担体としての有用性が注目されており、プロスタグランジン類（特開平４−３００８３３、特開平４−３３８３３３、特開平４−３３８３３４、特開平４−３６０８２４等）、抗癌剤（特開平４−３６０８２４、特公平５−１８８０６等）、抗炎症剤（特開昭６０−１１２２、特開平４−３６０８２４）、ビタミンＫ_２（特公平４−２２８８６）等の脂溶性薬物を含有した脂肪乳剤において、薬物の安定性の向上、目的部位への集積、薬効の延長等の効果が報告されている。しかしながら、脂肪乳剤を徐放性製剤の担体として用いることで、明確な徐放効果を記載した例は未だなされていない。更にブプレノルフィン、ペンタゾシン、モルヒネ等のオピオイド系鎮痛薬を脂肪乳剤に含有せしめた報告は皆無である。
【０００５】
【発明が解決しようとする課題】
薬物徐放性製剤の担体は生体内での適合性、分解性、安全性などの多面的な要因を全て満足できる条件が求められている。
一方、脂肪乳剤は既に栄養供給輸液として頻繁に用いられ、その安全性、分解性、適合性について保証されているにも関わらず、徐放性製剤の担体として用いている例は非常に少ないのが現状である。
上記の点から、本発明の目的は徐放性を持ちかつ徐放性をコントロールできるオピオイド系鎮痛薬含有注射用脂肪乳剤を得ることにある。
【０００６】
【課題を解決するための手段】
このような事情に鑑み、本発明者らは水中油型脂肪乳剤を用いた徐放性製剤を開発するために鋭意研究を行い、徐放性を有した鎮痛薬含有脂肪乳剤を製造する方法を見いだし、これに基づいて更に研究した結果、本発明を完成した。
【０００７】
すなわち、本発明はオピオイド系鎮痛薬を脂肪乳剤に含有せしめることにより徐放性を持たせ、更に目的に応じて徐放化能を調整するために脂肪乳剤の水相画分に生体適合性、生体分解性を有する高分子物質を添加してなることを特徴とする注射用徐放性鎮痛剤である。
【０００８】
本発明において脂肪乳剤に含有せしめるオピオイド系鎮痛薬は特に限定されないが、ブプレノルフィン、モルヒネ、ペンタゾシン及びその塩が特に好ましい。また、その配合量は脂肪乳剤の形態及び用途によって適宜増減できるが、一般には当該乳剤または乳剤組成物中に有効量添加すればよい。
【０００９】
本発明の脂肪乳剤の製造において用いる油基剤としては、注射剤として使用可能なグリセライドであれば限定はなく、例えば、大豆油、ゴマ油、綿実油、サフラワー油、コーン油のような植物油、魚油（特にエイコサペンタエン酸、ドコサヘキサエン酸含有油脂）、馬油、鯨油のような動物油及びこれらの精製物、更にはトリカプリリン（中鎖脂肪酸トリグリセライド）のごとく各種合成油脂、水素、ヨウ素等を添加した硬化ヒマシ油、硬化芥子油等が挙げられる。これらの油基剤はそれぞれ単独または数種の混合で用いられるが、更にこれらの油基剤にポリエチレングリコール等の合成高分子、ミツロウ等の脂肪酸エステルを添加することができる。さらに前述の植物油または動物油は、高純度精製油であることが好ましい。
【００１０】
本発明で用いる乳化剤は乳化作用を有するものであれば特に限定はなく、例えば、イオン系、非イオン系界面活性剤、卵黄レシチン、大豆レシチン、水素添加レシチン、精製リン脂質、合成リン脂質、脂肪酸のアルカリ金属塩等が挙げられる。これらの乳化剤は単独または数種の混合で用いてもよいが、好適には精製卵黄レシチンが単独で用いられる。
【００１１】
乳化補助剤としては炭素数６〜２２の脂肪酸類及びそのアルカリ金属塩を使用することができる。これらの脂肪酸は医薬品に添加可能なものであれば使用でき、直鎖、分岐のいずれでもよいが、直鎖のステアリン酸、オレイン酸、リノール酸、パルミチン酸、ミリスチン酸を用いるのが特に好ましい。また、これらの塩としては生理的に受け入れられる塩、例えばアルカリ金属塩（ナトリウム、カリウム塩）、アルカリ土類金属塩（カルシウム塩等）を用いることができる。
乳化安定剤としてはコレステロールやホスファチジン酸を用いることができ、医薬品として使用が可能であれば特に制限はない。
【００１２】
本発明の脂肪乳剤に添加される生体適合性高分子物質は、医薬品として添加可能なものであればよく、例えば、ヒアルロン酸、アルギン酸、コンドロイチン硫酸、もしくはその塩、キトサン、デキストラン等の多糖類及びその誘導体、アルブミン、ゼラチン、コラーゲン等のタンパク質及びその分解物であるペプチド、またはカルボキシメチルセルロース、ポリビニルアルコール、エチルセルロース、メチルセルロース、ポリエチレングリコール、ポリビニルピロリドン等の各種合成高分子が挙げられるが、特にゼラチン及びヒアルロン酸、アルギン酸もしくはその塩が好ましい。
【００１３】
これらの生体適合性高分子物質の添加剤は単独或いは数種を混合して用いられる。至適濃度は添加剤の種類によって異なるが、通常０．１〜３０％位が好ましい。
【００１４】
本発明の脂肪乳剤は例えば、以下のような方法により製造される。
オピオイド系鎮痛薬を含有した油基剤に乳化剤、グリセリン等の等張化剤、乳化補助剤、更に安定化剤を含有した水溶液を加えて、４０℃〜９０℃に加温しながら通常のホモジナイザー（例えば高圧噴射型ホモジナイザー、超音波ホモジナイザー等）を用いて均質化処理することにより油中水型分散液を作り、次いでこれに必要量の蒸留水を加え、再び前記ホモジナイザーで均質化を行って水中油型乳剤に転相することで製造することができる。
更に徐放化能を調節させる手段として、調製したオピオイド系鎮痛薬含有脂肪乳剤の水相に生体適合性高分子物質を添加することができる。
【００１５】
また、オピオイド系鎮痛薬を含有した油基剤と乳化剤、等張化剤、乳化安定剤及び蒸留水を同時に加え、加温下でホモジナイザーを用い均質化処理をすることによって一挙に水中油型乳剤を製造することも可能である。この場合も水相に生体適合性高分子物質を添加することによって徐放化能を調節できる。
【００１６】
本発明の脂肪乳剤を非経口投与、特に皮下、筋肉に投与するとき、市販のオピオイド系鎮痛剤より薬物が徐々に放出されるため長期間薬効が持続する。かかる徐放性は、乳剤の水相に生体適合性高分子物質を添加することによって更に長くすることが可能である。
【００１７】
例えば、ブプレノルフィンを薬剤として用いた場合のマウスによる薬効試験では、市販の塩酸ブプレノルフィン製剤の薬効持続時間が８時間であったのに対して、脂肪乳剤に含有せしめたものは、２４時間まで薬効の延長が認められた。更に当該乳剤の水相にゼラチンを添加することで投与後４８時間まで薬効が延長し、従来の塩酸ブプレノルフィン製剤の６倍の作用時間を有するに至ったのである。つまり、本発明により、初めてオピオイド系鎮痛薬としての徐放性製剤の製造が可能となったのである。
【００１８】
【実施例】
以下、実施例及び実験例により本発明を具体的に説明するが、本発明はこれらに何ら限定されるものではない。
【００１９】
参考例１
塩酸ブプレノルフィン２００ｍｇを蒸留水１００ｍｌに溶解後、ｐＨ８．０に調製し、精製大豆油１００ｇを加え、振とう抽出後、遠心分離にてブプレノルフィン抽出大豆油を分取した。このブプレノルフィン抽出大豆油１００ｇに精製卵黄レシチン（旭化成製）１２ｇ、濃グリセリン（和光純薬製、試薬特級）２５ｇを加え、更に蒸留水を加え１０００ｇとした。これを８０℃でオートホモミキサーを用い、粗乳化した後、加圧噴射型ホモジナイザー（商品名：マントンゴウリン）にて７０℃、３５０ｋｇ／ｃｍ^２の乳化条件にて乳化を行い、平均粒子径２３０ｎｍのブプレノルフィン含有脂肪乳剤約１０００ｍｌを得た。
【００２０】
実施例１
参考例１の脂肪乳剤１０ｍｌにゼラチン（新田ゼラチン製、注射用）５００ｍｇを添加し、４０℃にて水相に溶解し、ゼラチン添加ブプレノルフィン含有脂肪乳剤を得た。
【００２１】
実施例２
参考例１の脂肪乳剤１０ｍｌにヒアルロン酸ナトリウム（和光純薬製、生化学用）８０ｍｇを添加し、４０℃にて水相に溶解し、ヒアルロン酸添加ブプレノルフィン含有脂肪乳剤を得た。
【００２２】
実施例３
参考例１の脂肪乳剤１０ｍｌにアルギン酸ナトリウム（和光純薬製、試薬特級）１２０ｍｇを添加し、４０℃にて水相に溶解し、アルギン酸添加ブプレノルフィン含有脂肪乳剤を得た。
【００２３】
参考例２
大豆油１００ｇに塩酸ブプレノルフィン２００ｍｇ、精製卵黄レシチン（旭化成製）１２ｇ、濃グリセリン（和光純薬製、試薬特級）２５ｇおよび蒸留水を加えた後、ｐＨ８．０に調整し、さらに蒸留水にて１０００ｇとした。これを８０℃でオートホモミキサーを用い、粗乳化した後、加圧噴射型ホモジナイザー（商品名：マントンゴウリン）にて８０℃、４００ｋｇ／ｃｍ^２の乳化条件にて乳化を行い、平均粒子径２１０ｎｍのブプレノルフィン含有脂肪乳剤約１０００ｍｌを得た。
【００２４】
実施例４
参考例２の脂肪乳剤１０ｍｌにゼラチン（新田ゼラチン製、注射用）５００ｍｇを添加し、４０℃にて水相に溶解し、ゼラチン添加ブプレノルフィン含有脂肪乳剤を得た。
【００２５】
実施例５
参考例２の脂肪乳剤１０ｍｌにヒアルロン酸ナトリウム（和光純薬製、生化学用）８０ｍｇを添加し、４０℃にて水相に溶解し、ヒアルロン酸添加ブプレノルフィン含有脂肪乳剤を得た。
【００２６】
実施例６
参考例２の脂肪乳剤１０ｍｌにアルギン酸ナトリウム（和光純薬製、試薬特級）１２０ｍｇを添加し、４０℃にて水相に溶解し、アルギン酸添加ブプレノルフィン含有脂肪乳剤を得た。
【００２７】
参考例３
大豆油１００ｇにブプレノルフィン２００ｍｇ、精製卵黄レシチン（旭化成製）１２ｇ、濃グリセリン（和光純薬製、試薬特級）２５ｇを加え、更に蒸留水を加え１０００ｇとした。これを８０℃でオートホモミキサーを用い、粗乳化した後、加圧噴射型ホモジナイザー（商品名：マントンゴウリン）にて８０℃、４６０ｋｇ／ｃｍ^２の乳化条件にて乳化を行い、平均粒子径２００ｎｍのブプレノルフィン含有脂肪乳剤約１０００ｍｌを得た。
【００２８】
実施例７
参考例３の脂肪乳剤１０ｍｌにゼラチン（新田ゼラチン製、注射用）５００ｍｇを添加し、４０℃にて水相に溶解し、ゼラチン添加ブプレノルフィン含有脂肪乳剤を得た。
【００２９】
実施例８
参考例３の脂肪乳剤１０ｍｌにヒアルロン酸ナトリウム（和光純薬製、生化学用）８０ｍｇを添加し、４０℃にて水相に溶解し、ヒアルロン酸添加ブプレノルフィン含有脂肪乳剤を得た。
【００３０】
実施例９
参考例３の脂肪乳剤１０ｍｌにアルギン酸ナトリウム（和光純薬製、試薬特級）１２０ｍｇを添加し、４０℃にて水相に溶解し、アルギン酸添加ブプレノルフィン含有脂肪乳剤を得た。
【００３１】
参考例４
ペンタゾシン３ｇをトリカプリリン２００ｇに加熱溶解し、精製卵黄レシチン（旭化成製）１２ｇ、濃グリセリン（和光純薬製、試薬特級）２５ｇを加え、更に蒸留水を加え１０００ｇとした。これを８０℃でオートホモミキサーを用い、粗乳化した後、加圧噴射型ホモジナイザー（商品名：マントンゴウリン）にて８０℃、４６０ｋｇ／ｃｍ^２の乳化条件にて乳化を行い、平均粒子径２２０ｎｍのペンタゾシン含有脂肪乳剤約１０００ｍｌを得た。
【００３２】
実施例１０
参考例４の脂肪乳剤１０ｍｌにゼラチン（新田ゼラチン製、注射用）５００ｍｇを添加し、４０℃にて水相に溶解し、ゼラチン添加ペンタゾシン含有脂肪乳剤を得た。
【００３３】
実験例１
ブプレノルフィン乳剤血中動態
参考例１、実施例１，２，３の脂肪乳剤について、ブプレノルフィン量として４ｍｇ／ｋｇをマウスの皮下に投与後、経時的に採血し、その血漿中濃度を測定し、市販の塩酸ブプレノルフィン製剤（レペタン注、大塚製薬）と比較した。また、測定方法は公知の方法を用い、以下の条件による高速液体クロマトグラフィーにて測定した。
その結果を図１に示した。
【００３４】
〈ブプレノルフィン測定条件〉
検出波長：励起波長２８５ｎｍ測定波長３５５ｎｍ
カラム：ウォーターズ（株）マイクロポラシル１０μｍ（３．９×３００ｍｍ）
移動相：５ｍＭ酢酸緩衝液（ｐＨ３．７５）：アセトニトリル＝２０：８０混液
溶出速度：１ｍｌ／ｍｉｎ
【００３５】
図１から明らかなように、市販の塩酸ブプレノルフィン製剤と参考例１、実施例１，２，３によって製造された製剤とではブプレノルフィンの血中濃度推移に違いがみられた。すなわち、参考例１、実施例１，２，３による本発明の脂肪乳剤は薬物の血中放出速度がコントロールされ、徐放性製剤特有のパターンを示した。
【００３６】
実験例２
ブプレノルフィン含有脂肪乳剤の薬理効果試験
参考例１、実施例１，２，３の脂肪乳剤について、ブプレノルフィン量として４ｍｇ／ｋｇを各試験毎１０例のマウスに皮下投与後、経時的にハフナー法により鎮痛効果を測定し、市販の塩酸ブプレノルフィン製剤（レペタン注：大塚製薬）と比較した。その結果を図２に示した。
【００３７】
試験に用いるマウスは、試験液投与前にハフナー法により以下に示すスコアー（Ｓｃｏｒｅ）が０のものを選択した（クレンメのはさみ圧は約５００ｇ）。なお、クレンメではさむ部位は、尾根部より約１０ｍｍの部位とし、クレンメにかみつく動作を痛みの指標とした。
【００３８】
Ｓｃｏｒｅ
Ｓｃｏｒｅ０：クレンメ適用後２秒以内で噛み付く動作を示す
Ｓｃｏｒｅ１：クレンメ適用後２秒を超え６秒未満で噛み付く動作を示す
Ｓｃｏｒｅ２：クレンメ適用後６秒以上で噛み付く動作を示す
【００３９】
図２の試験結果からわかるように、市販の塩酸ブプレノルフィン注射剤では薬効の持続時間が８時間であったのに対し、ブプレノルフィン含有脂肪乳剤（参考例１）では、投与後、２４時間まで薬効持続が認められた。更に、当該脂肪乳剤に０．８％ヒアルロン酸添加試料（実施例２）、５％ゼラチン添加試料（実施例１）では４８時間まで、１．２％アルギン酸添加試料（実施例３）では３０時間まで薬効の持続が認められた。
【００４０】
実験例３
ブプレノルフィン含有脂肪乳剤の薬理効果試験
参考例２、実施例４，５，６の脂肪乳剤について実験例２と同様に、ブプレノルフィン量として４ｍｇ／ｋｇを各試験毎１０例のマウスに皮下投与後、経時的にハフナー法により鎮痛効果を測定し、市販の塩酸ブプレノルフィン製剤と比較した。その結果を表１に示した。
【００４１】

【００４２】
表１の試験結果からわかるように、市販の塩酸ブプレノルフィン注射剤では薬効の持続時間が８時間であったのに対し、ブプレノルフィン含有脂肪乳剤（参考例２）では、投与後、２４時間まで薬効持続が認められた。更に、当該脂肪乳剤に０．８％ヒアルロン酸添加試料（実施例５）、５％ゼラチン添加試料（実施例４）では４８時間まで、１．２％アルギン酸添加試料（実施例６）では３０時間まで薬効の持続が認められた。
【００４３】
実験例４
ブプレノルフィン含有脂肪乳剤の薬理効果試験
参考例３、実施例７，８，９の脂肪乳剤について実験例２と同様に、ブプレノルフィン量として４ｍｇ／ｋｇを各試験毎１０例のマウスに皮下投与後、経時的にハフナー法により鎮痛効果を測定し、市販の塩酸ブプレノルフィン製剤と比較した。その結果を表２に示した。
【００４４】

【００４５】
表２の試験結果からわかるように、市販の塩酸ブプレノルフィン注射剤では薬効の持続時間が８時間であったのに対し、ブプレノルフィン含有脂肪乳剤（参考例３）では、投与後、２４時間まで薬効持続が認められた。更に、当該脂肪乳剤に０．８％ヒアルロン酸添加試料（実施例８）、５％ゼラチン添加試料（実施例７）では４８時間まで、１．２％アルギン酸添加試料（実施例９）では３０時間まで薬効の持続が認められた。
【００４６】
実験例５
ペンタゾシン含有脂肪乳剤血中動態
参考例４、実施例１０の脂肪乳剤について、ペンタゾシン量として２ｍｇ／ｋｇをウサギ（雌性、約３ｋｇ）に皮下投与後、経時的に採血し、その血漿中濃度を測定し、市販のペンタゾシン製剤（ペルタゾン注：グレラン製薬）と比較した。また、測定法は公知の方法を用い、下記条件による高速液体クロマトグラフィーにて測定した。その結果を図３に示した。
【００４７】
〈ペンタゾシン測定条件〉
検出波長：励起波長２７９ｎｍ測定波長３１０ｎｍ
カラム：東ソー（株）ＯＤＳカラム（４．６×１５０ｍｍ）
移動相：５０ｍＭクエン酸（ｐＨ４．７５）：アセトニトリル＝３：１混液
溶出速度：１ｍｌ／ｍｉｎ
【００４８】
図３から明らかなように、市販のペンタゾシン製剤と参考例４、実施例１０によって製造された製剤とではペンタゾシンの血中濃度推移に違いがみられた。即ち、参考例４、実施例１０の本発明の脂肪乳剤は薬物の血中放出速度がコントロールされ、徐放性製剤特有のパターンを示した。
【００４９】
【発明の効果】
本発明の鎮痛薬含有注射用脂肪乳剤は、従来の鎮痛薬と比較して優れた薬効の持続性を有し、投与回数及び投与量を軽減する効果を有する。
なお、参考までに本発明の脂肪乳剤の効果が優れていることを明確にしたものとして文献値（ファーマシー，プラクティス，ニュース，．４月（１９９３）から引用）及び本発明の薬理効果試験値を図４に示す。
【図面の簡単な説明】
【図１】図１はブプレノルフィン皮下投与時の血中濃度を示すグラフである。
図中白三角印は市販の塩酸ブプレノルフィン注射剤、白ひし形印はブプレノルフィン含有脂肪乳剤（参考例１）、黒ひし形印は当該脂肪乳剤に１．２％アルギン酸ナトリウムを添加した試料（実施例３）、黒四角印は当該脂肪乳剤に５％ゼラチンを添加した試料（実施例１）、黒丸印は当該脂肪乳剤に０．８％ヒアルロン酸ナトリウムを添加した試料（実施例２）を示す。
【図２】図２は、ハフナー法による本発明製剤の鎮痛効果持続時間を示すグラフである。
図中バツ印は、生理食塩水投与群、白三角印は市販の塩酸ブプレノルフィン注射剤、白ひし形印はブプレノルフィン含有脂肪乳剤（参考例１）、黒ひし形印は当該脂肪乳剤に１．２％アルギン酸ナトリウムを添加した試料（実施例３）、黒四角印は当該脂肪乳剤に５％ゼラチンを添加した試料（実施例１）、黒丸印は当該脂肪乳剤に０．８％ヒアルロン酸ナトリウムを添加した試料（実施例２）を示す。
【図３】図３は、ペンタゾシン皮下投与時の血中濃度を示すグラフである。
図中白三角印は市販のペンタゾシン製剤、白ひし形印はペンタゾシン含有脂肪乳剤（参考例４）、黒四角印は当該乳剤に５％ゼラチンを添加した試料（実施例１０）を示す。
【図４】図４は、各鎮痛薬の薬理効果持続時間の比較により本発明の脂肪乳剤の効果が優れていることを示すグラフである。[0001]
[Industrial application fields]
The present invention relates to sustained-release preparations of analgesics. More particularly, the present invention relates to a fat emulsion containing an opioid analgesic that is intended to improve the persistence of analgesic effect by parenteral administration, particularly subcutaneous or intramuscular administration.
[0002]
[Prior art]
Opioid analgesics such as morphine, buprenorphine, and pentazocine have excellent analgesic effects, and are therefore widely used in clinical settings for the purpose of alleviating cancer pain accompanied by severe pain, postoperative pain, and the like. However, the persistence of the analgesic effect is several hours after administration, and frequent administration is forced, increasing the mental burden of the patient.
[0003]
On the other hand, sustained-release preparations have many medical advantages such as reducing the number of administrations of drugs, increasing therapeutic effects and reducing side effects, and oral administrations improving patient compliance. Therefore, many devices have been devised for the development of sustained-release preparations. As an opioid analgesic, an oral sustained-release preparation of morphine is currently marketed, but the duration is limited to 12 hours, and it is an oral preparation, so it cannot be administered to patients with digestive disorders There is. In addition, an injection is useful when oral administration is difficult in this way, but an injection-type sustained-release analgesic has not been put into practical use at present.
[0004]
In recent years, the usefulness of fat emulsions as a drug carrier and drug carrier has attracted attention, and prostaglandins (Japanese Patent Laid-Open Nos. 4-300343, 4-338333, 4-338334, 4-360824, etc.) ), Anticancer agents (JP-A-4-360824, JP-B-5-18806, etc.), anti-inflammatory agents (JP-A-60-1122, JP-A-4-360824), vitamin K ₂ (JP-B-4-22886), etc. In fat emulsions containing a drug, effects such as improvement of drug stability, accumulation at a target site, and extension of drug efficacy have been reported. However, there has not yet been described an example of a clear sustained release effect by using a fat emulsion as a carrier for a sustained release preparation. Furthermore, there are no reports of opioid analgesics such as buprenorphine, pentazocine, morphine and the like incorporated in fat emulsions.
[0005]
[Problems to be solved by the invention]
A carrier for a sustained-release drug preparation is required to satisfy all the various factors such as in vivo compatibility, degradability, and safety.
On the other hand, fat emulsions are already frequently used as nutrient-feeding infusions, and even though their safety, degradability, and compatibility are guaranteed, there are very few examples of using them as carriers for sustained-release preparations. Is the current situation.
In view of the above, an object of the present invention is to obtain a fat emulsion for injection containing an opioid analgesic agent having sustained release properties and capable of controlling the sustained release properties.
[0006]
[Means for Solving the Problems]
In view of such circumstances, the present inventors have conducted intensive research to develop a sustained-release preparation using an oil-in-water type fat emulsion, and have developed a method for producing an analgesic-containing fat emulsion having sustained release. As a result of finding and further research based on this, the present invention was completed.
[0007]
That is, the present invention has a sustained release property by incorporating an opioid analgesic into a fat emulsion, and is further biocompatible with the aqueous phase fraction of the fat emulsion in order to adjust the sustained release ability according to the purpose. A sustained-release analgesic for injection characterized by adding a biodegradable polymer substance.
[0008]
In the present invention, the opioid analgesic contained in the fat emulsion is not particularly limited, but buprenorphine, morphine, pentazocine and salts thereof are particularly preferable. The blending amount can be appropriately increased or decreased depending on the form and use of the fat emulsion, but in general, an effective amount may be added to the emulsion or emulsion composition.
[0009]
The oil base used in the production of the fat emulsion of the present invention is not limited as long as it is a glyceride that can be used as an injection. For example, vegetable oil such as soybean oil, sesame oil, cottonseed oil, safflower oil, corn oil, fish oil (Especially eicosapentaenoic acid, docosahexaenoic acid-containing fats and oils), horse oil, animal oils such as whale oil and their refined products, as well as hardened with various synthetic oils such as tricaprylin (medium chain fatty acid triglyceride), hydrogen, iodine, etc. Castor oil, hydrogenated coconut oil and the like can be mentioned. These oil bases are used singly or in combination of several kinds, and further, synthetic polymers such as polyethylene glycol and fatty acid esters such as beeswax can be added to these oil bases. Furthermore, the aforementioned vegetable oil or animal oil is preferably a high-purity refined oil.
[0010]
The emulsifier used in the present invention is not particularly limited as long as it has an emulsifying action. For example, ionic, nonionic surfactant, egg yolk lecithin, soybean lecithin, hydrogenated lecithin, purified phospholipid, synthetic phospholipid, fatty acid And alkali metal salts of the above. These emulsifiers may be used alone or in combination of several kinds, but preferably purified egg yolk lecithin is used alone.
[0011]
As the emulsification aid, fatty acids having 6 to 22 carbon atoms and alkali metal salts thereof can be used. These fatty acids can be used as long as they can be added to pharmaceuticals, and may be either linear or branched, but it is particularly preferable to use linear stearic acid, oleic acid, linoleic acid, palmitic acid, or myristic acid. As these salts, physiologically acceptable salts such as alkali metal salts (sodium, potassium salts) and alkaline earth metal salts (calcium salts, etc.) can be used.
As the emulsion stabilizer, cholesterol or phosphatidic acid can be used, and there is no particular limitation as long as it can be used as a medicine.
[0012]
The biocompatible polymer substance added to the fat emulsion of the present invention may be any substance that can be added as a pharmaceutical, for example, hyaluronic acid, alginic acid, chondroitin sulfate, or salts thereof, polysaccharides such as chitosan, dextran, and the like. Derivatives thereof, albumin, gelatin, collagen and other proteins such as peptides and degradation products thereof, or various synthetic polymers such as carboxymethyl cellulose, polyvinyl alcohol, ethyl cellulose, methyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, etc., especially gelatin and hyaluron Acid, alginic acid or a salt thereof is preferred.
[0013]
These additives for biocompatible polymer substances may be used alone or in combination of several kinds. The optimum concentration varies depending on the type of additive, but is usually preferably about 0.1 to 30%.
[0014]
The fat emulsion of the present invention is produced, for example, by the following method.
An ordinary homogenizer while adding an aqueous solution containing an emulsifier, an isotonic agent such as glycerin, an emulsifying aid, and a stabilizer to an oil base containing an opioid-based analgesic and heating to 40 ° C to 90 ° C Make a water-in-oil dispersion by homogenizing using a high-pressure jet homogenizer (for example, a high-pressure jet homogenizer, an ultrasonic homogenizer, etc.), then add the required amount of distilled water and homogenize again with the homogenizer. It can be produced by phase inversion into an oil-in-water emulsion.
Furthermore, as a means for adjusting the sustained release ability, a biocompatible polymer substance can be added to the aqueous phase of the prepared opioid analgesic fat emulsion.
[0015]
In addition, an oil base containing an opioid-based analgesic, an emulsifier, an isotonic agent, an emulsion stabilizer and distilled water are added simultaneously, and the mixture is homogenized using a homogenizer under heating. Can also be manufactured. Also in this case, the sustained release ability can be adjusted by adding a biocompatible polymer substance to the aqueous phase.
[0016]
When the fat emulsion of the present invention is administered parenterally, particularly subcutaneously or intramuscularly, since the drug is gradually released from a commercially available opioid analgesic agent, the drug efficacy lasts for a long time. Such sustained release can be further prolonged by adding a biocompatible polymer substance to the aqueous phase of the emulsion.
[0017]
For example, in a pharmacological test with mice using buprenorphine as a drug, the duration of drug efficacy of a commercially available buprenorphine hydrochloride preparation was 8 hours, whereas that contained in a fat emulsion was effective for up to 24 hours. Extension was allowed. Furthermore, by adding gelatin to the aqueous phase of the emulsion, the efficacy was extended up to 48 hours after administration, and the action time was 6 times that of the conventional buprenorphine hydrochloride preparation. That is, according to the present invention, a sustained-release preparation as an opioid analgesic can be produced for the first time.
[0018]
【Example】
EXAMPLES Hereinafter, although an Example and an experiment example demonstrate this invention concretely, this invention is not limited to these at all.
[0019]
Reference example 1
200 mg of buprenorphine hydrochloride was dissolved in 100 ml of distilled water, adjusted to pH 8.0, 100 g of purified soybean oil was added, and after extraction with shaking, buprenorphine-extracted soybean oil was collected by centrifugation. To 100 g of this buprenorphine-extracted soybean oil, 12 g of purified egg yolk lecithin (manufactured by Asahi Kasei) and 25 g of concentrated glycerin (manufactured by Wako Pure Chemicals, reagent special grade) were added, and distilled water was further added to make 1000 g. This was roughly emulsified using an auto homomixer at 80 ° C., and then emulsified with a pressure injection type homogenizer (trade name: Manton Gourin) under emulsification conditions of 70 ° C. and 350 kg / cm ² , and the average particle size About 1000 ml of 230 nm buprenorphine-containing fat emulsion was obtained.
[0020]
Example 1
Gelatin (Nitta Gelatin, for injection) 500 mg was added to 10 ml of the fat emulsion of Reference Example 1, and dissolved in an aqueous phase at 40 ° C. to obtain a gelatin-added buprenorphine-containing fat emulsion.
[0021]
Example 2
80 mg of sodium hyaluronate (manufactured by Wako Pure Chemicals, for biochemistry) was added to 10 ml of the fat emulsion of Reference Example 1 and dissolved in the aqueous phase at 40 ° C. to obtain a buprenorphine-containing fat emulsion containing hyaluronic acid.
[0022]
Example 3
120 mg of sodium alginate (manufactured by Wako Pure Chemicals, reagent grade) 120 mg was added to 10 ml of the fat emulsion of Reference Example 1 and dissolved in the aqueous phase at 40 ° C. to obtain a buprenorphine-containing fat emulsion containing alginate.
[0023]
Reference example 2
To 100 g of soybean oil, 200 mg of buprenorphine hydrochloride, 12 g of purified egg yolk lecithin (manufactured by Asahi Kasei), 25 g of concentrated glycerin (manufactured by Wako Pure Chemicals, reagent special grade) and distilled water were added, and the pH was adjusted to 8.0, and 1000 g with distilled water. It was. This was roughly emulsified at 80 ° C. using an auto homomixer, and then emulsified with a pressure injection type homogenizer (trade name: Manton Gourin) under the emulsification conditions of 80 ° C. and 400 kg / cm ² to obtain an average particle size. About 1000 ml of 210 nm buprenorphine-containing fat emulsion was obtained.
[0024]
Example 4
Gelatin (Nitta Gelatin, for injection) 500 mg was added to 10 ml of the fat emulsion of Reference Example 2 and dissolved in the aqueous phase at 40 ° C. to obtain a gelatin-added buprenorphine-containing fat emulsion.
[0025]
Example 5
To 10 ml of the fat emulsion of Reference Example 80, 80 mg of sodium hyaluronate (manufactured by Wako Pure Chemicals, for biochemistry) was added and dissolved in an aqueous phase at 40 ° C. to obtain a hyaluronic acid-added buprenorphine-containing fat emulsion.
[0026]
Example 6
120 mg of sodium alginate (manufactured by Wako Pure Chemicals, reagent grade) 120 mg was added to 10 ml of the fat emulsion of Reference Example 2 and dissolved in the aqueous phase at 40 ° C. to obtain a buprenorphine-containing fat emulsion containing alginate.
[0027]
Reference example 3
To 100 g of soybean oil, 200 mg of buprenorphine, 12 g of purified egg yolk lecithin (manufactured by Asahi Kasei) and 25 g of concentrated glycerin (manufactured by Wako Pure Chemical Industries, reagent special grade) were added, and distilled water was further added to make 1000 g. This was roughly emulsified at 80 ° C. using an auto homomixer, and then emulsified with a pressure injection type homogenizer (trade name: Manton Goulin) at 80 ° C. and 460 kg / cm ^{2 to} obtain an average particle size. About 1000 ml of a 200 nm buprenorphine-containing fat emulsion was obtained.
[0028]
Example 7
Gelatin (Nitta Gelatin, for injection) 500 mg was added to 10 ml of the fat emulsion of Reference Example 3, and dissolved in an aqueous phase at 40 ° C. to obtain a gelatin-added buprenorphine-containing fat emulsion.
[0029]
Example 8
To 10 ml of the fat emulsion of Reference Example 80, 80 mg of sodium hyaluronate (manufactured by Wako Pure Chemicals, for biochemistry) was added and dissolved in the aqueous phase at 40 ° C. to obtain a hyaluronic acid-added buprenorphine-containing fat emulsion.
[0030]
Example 9
To 10 ml of the fat emulsion of Reference Example 120 mg of sodium alginate (manufactured by Wako Pure Chemicals, reagent grade) was added and dissolved in the aqueous phase at 40 ° C. to obtain an alginate-added buprenorphine-containing fat emulsion.
[0031]
Reference example 4
3 g of pentazocine was dissolved by heating in 200 g of tricaprylin, 12 g of purified egg yolk lecithin (manufactured by Asahi Kasei) and 25 g of concentrated glycerin (manufactured by Wako Pure Chemicals, reagent special grade) were added, and distilled water was further added to make 1000 g. This was roughly emulsified at 80 ° C. using an auto homomixer, and then emulsified with a pressure injection type homogenizer (trade name: Manton Goulin) at 80 ° C. and 460 kg / cm ^{2 to} obtain an average particle size. About 1000 ml of a 220 nm pentazocine-containing fat emulsion was obtained.
[0032]
Example 10
Gelatin (Nitta Gelatin, for injection) 500 mg was added to 10 ml of the fat emulsion of Reference Example 4, and dissolved in the aqueous phase at 40 ° C. to obtain a gelatin-added pentazocine-containing fat emulsion.
[0033]
Experimental example 1
Buprenorphine emulsion blood kinetics For the fat emulsions of Reference Example 1 and Examples 1, 2 and 3, 4 mg / kg of buprenorphine was administered subcutaneously to mice, and blood was collected over time, and the plasma concentration was measured. Compared with the buprenorphine hydrochloride preparation (Repetan Injection, Otsuka Pharmaceutical). Moreover, the measuring method used the well-known method, and measured by the high performance liquid chromatography on the following conditions.
The results are shown in FIG.
[0034]
<Buprenorphin measurement conditions>
Detection wavelength: excitation wavelength 285 nm, measurement wavelength 355 nm
Column: Waters Co., Ltd. Microporacil 10 μm (3.9 × 300 mm)
Mobile phase: 5 mM acetate buffer (pH 3.75): acetonitrile = 20: 80 mixed solution Elution rate: 1 ml / min
[0035]
As is clear from FIG. 1, there was a difference in the transition of blood concentration of buprenorphine between the commercially available buprenorphine hydrochloride preparation and the preparation produced in Reference Example 1 and Examples 1, 2 and 3. That is, the fat emulsions of the present invention according to Reference Example 1 and Examples 1, 2 and 3 controlled the release rate of the drug in the blood and exhibited a pattern specific to sustained-release preparations.
[0036]
Experimental example 2
Pharmacological effect test of buprenorphine-containing fat emulsion For the fat emulsions of Reference Example 1 and Examples 1, 2, and 3, 4 mg / kg of buprenorphine was subcutaneously administered to 10 mice for each test, and then analgesic was carried out by the Huffner method over time. The effect was measured and compared with a commercially available buprenorphine hydrochloride preparation (Repetan injection: Otsuka Pharmaceutical). The results are shown in FIG.
[0037]
The mice used in the test were selected to have the following score (Score) of 0 by the Huffner method before administration of the test solution (Clemme's scissors pressure was about 500 g). In addition, the site | part pinched by a clamp is a site | part of about 10 mm from a ridge part, The operation | movement which bites into a clamp is used as the parameter | index of pain.
[0038]
Score
Score 0: Indicates an operation of biting within 2 seconds after applying the clamp. Score 1: Indicates an operation of biting after 2 seconds after applying the clamp and less than 6 seconds. Score 2: Indicates an operation of biting after 6 seconds after applying the clamp.
As can be seen from the test results in FIG. 2, the buprenorphine hydrochloride injection in the market had a duration of efficacy of 8 hours, whereas the buprenorphine-containing fat emulsion (Reference Example 1) lasted for up to 24 hours after administration. Was recognized. Furthermore, 0.8% hyaluronic acid-added sample (Example 2), 5% gelatin-added sample (Example 1) up to 48 hours, and 1.2% alginate-added sample (Example 3) to the fat emulsion. Until then, the medicinal effects were sustained.
[0040]
Experimental example 3
Pharmacological effect test of fat emulsion containing buprenorphine The fat emulsions of Reference Example 2, Examples 4, 5 and 6 were administered subcutaneously to 10 mice in each test at 4 mg / kg as the amount of buprenorphine as in Experimental Example 2, Specifically, the analgesic effect was measured by the Huffner method and compared with a commercially available buprenorphine hydrochloride preparation. The results are shown in Table 1.
[0041]

[0042]
As can be seen from the test results in Table 1, the commercially available buprenorphine hydrochloride injection had a duration of 8 hours, whereas the buprenorphine-containing fat emulsion (Reference Example 2) lasted for up to 24 hours after administration. Was recognized. Furthermore, 0.8% hyaluronic acid added sample (Example 5) and 5% gelatin added sample (Example 4) were added to the fat emulsion up to 48 hours, and 1.2% alginate added sample (Example 6) was 30 hours. Until then, the medicinal effects were sustained.
[0043]
Experimental example 4
Pharmacological effect test of fat emulsion containing buprenorphine As in Experimental Example 2, fat emulsions of Reference Example 3 and Examples 7, 8, and 9 were subcutaneously administered to 10 mice in each test at 4 mg / kg as the amount of buprenorphine. Specifically, the analgesic effect was measured by the Huffner method and compared with a commercially available buprenorphine hydrochloride preparation. The results are shown in Table 2.
[0044]

[0045]
As can be seen from the test results in Table 2, with the buprenorphine hydrochloride injection in the market, the duration of the drug effect was 8 hours, whereas with the buprenorphine-containing fat emulsion (Reference Example 3), the drug effect lasted up to 24 hours after administration. Was recognized. Furthermore, 0.8% hyaluronic acid-added sample (Example 8) and 5% gelatin-added sample (Example 7) were added to the fat emulsion up to 48 hours, and 1.2% alginate-added sample (Example 9) was 30 hours. Until then, the medicinal effects were sustained.
[0046]
Experimental example 5
Blood kinetics of pentazocine-containing fat emulsion In the fat emulsions of Reference Example 4 and Example 10, 2 mg / kg as the amount of pentazocine was subcutaneously administered to rabbits (female, about 3 kg), blood was collected over time, and the plasma concentration was measured. And compared with a commercially available pentazocine preparation (Pertazone Injection: Grelan Pharmaceutical). Moreover, the measuring method used the well-known method and measured by the high performance liquid chromatography on the following conditions. The results are shown in FIG.
[0047]
<Pentazocine measurement conditions>
Detection wavelength: excitation wavelength 279 nm, measurement wavelength 310 nm
Column: Tosoh Corporation ODS column (4.6 x 150 mm)
Mobile phase: 50 mM citric acid (pH 4.75): acetonitrile = 3: 1 mixture elution rate: 1 ml / min
[0048]
As is clear from FIG. 3, there was a difference in the transition of pentazocine in blood between the commercially available pentazocine preparation and the preparations produced in Reference Example 4 and Example 10. That is, the fat emulsions of the present invention of Reference Example 4 and Example 10 controlled the drug release rate in the blood, and showed a pattern specific to sustained-release preparations.
[0049]
【The invention's effect】
The analgesic-containing fat emulsion for injection according to the present invention has a long lasting medicinal effect as compared with conventional analgesics, and has the effect of reducing the number of administrations and the dose.
For reference, the literature values (quoted from Pharmacy, Practice, News, April (1993)) and the pharmacological effect test values of the present invention are used to clarify that the effect of the fat emulsion of the present invention is excellent for reference. As shown in FIG.
[Brief description of the drawings]
FIG. 1 is a graph showing blood concentration at the time of subcutaneous administration of buprenorphine.
In the figure, the white triangle mark indicates a commercially available buprenorphine hydrochloride injection, the white diamond mark indicates a buprenorphine-containing fat emulsion (Reference Example 1), and the black diamond mark indicates a sample obtained by adding 1.2% sodium alginate to the fat emulsion (Example 3). The black square mark shows a sample (Example 1) in which 5% gelatin is added to the fat emulsion, and the black circle mark shows a sample (Example 2) in which 0.8% sodium hyaluronate is added to the fat emulsion.
FIG. 2 is a graph showing the analgesic effect duration of the preparation of the present invention by the Huffner method.
In the figure, the cross indicates a physiological saline administration group, the white triangle indicates a commercially available buprenorphine hydrochloride injection, the white diamond indicates a fat emulsion containing buprenorphine (Reference Example 1), and the black diamond indicates 1.2% alginate in the fat emulsion. A sample to which sodium was added (Example 3), a black square symbol was a sample in which 5% gelatin was added to the fat emulsion (Example 1), and a black circle symbol was a sample in which 0.8% sodium hyaluronate was added to the fat emulsion (Example 2) is shown.
FIG. 3 is a graph showing the blood concentration at the time of subcutaneous administration of pentazocine.
In the figure, a white triangle mark indicates a commercially available pentazocine preparation, a white diamond mark indicates a pentazocine-containing fat emulsion (Reference Example 4), and a black square mark indicates a sample (Example 10) in which 5% gelatin is added to the emulsion.
FIG. 4 is a graph showing that the effect of the fat emulsion of the present invention is superior by comparing the pharmacological effect duration of each analgesic.

Claims

An oil-in-water type sustained-release fat emulsion for injection comprising an opioid analgesic, wherein one or more biocompatible polymer substances are added to the aqueous phase fraction of the fat emulsion. Sustained release fat emulsion.

The fat emulsion according to claim 1, wherein the opioid analgesic is buprenorphine, pentazocine, or morphine.

2. The fat emulsion according to claim 1, wherein the biocompatible polymer substance is hyaluronic acid, alginic acid or a salt thereof, or gelatin.