JP6964312B2 - 生体吸収性のシート又はフィルム - Google Patents
生体吸収性のシート又はフィルム Download PDFInfo
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- JP6964312B2 JP6964312B2 JP2019207022A JP2019207022A JP6964312B2 JP 6964312 B2 JP6964312 B2 JP 6964312B2 JP 2019207022 A JP2019207022 A JP 2019207022A JP 2019207022 A JP2019207022 A JP 2019207022A JP 6964312 B2 JP6964312 B2 JP 6964312B2
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- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
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Description
また、本発明の他の課題は、溶解性が制御され、あるいは、生物活性薬剤を含有する場合には該薬剤の徐放性が制御された生体吸収性のシート又はフィルムを提供することである。
また、生物活性薬剤を含有する本発明のシート又はフィルムにおいて、化学修飾したリン酸化プルランを使用することで、あるいは他の層を設けることで、リン酸化プルランの溶解性が制御でき、薬剤の徐放性も制御することができる。
[リン酸化プルラン]
リン酸化プルランは、生体組織に対して親和性が高いだけでなく、そのリン酸基が生体組織に対してキレート結合を形成して吸着性を示し、その後、生体吸収性も示す。また、リン酸化プルランそのものや、その構成単位であるオリゴ糖、単糖は、生体安全性が高いものであり、生体内での酵素による代謝を受けにくいことから、異物反応が軽微である。本発明では、かかる特性を有するリン酸化プルランを生体内に適用すると、生体内の組織や臓器表面に存在する体液(組織液ともいう)がリン酸化プルランに浸潤することで、組織液内の陽イオンがリン酸化プルランのリン酸基とキレート結合を形成して架橋構造を形成するため、プルランによる増粘作用に加えて長期に亘って粘性を発揮することが可能になり、ひいては、適用箇所での自己治癒力を向上することになると考えられる。但し、これらの推測は、本発明を限定するものではない。
本発明のシート又はフィルムは、リン酸化プルラン以外の成分としては、例えば、成形時の収縮などを抑制し、シート又はフィルムの柔軟性を向上させる観点から、可塑剤を含有することができる。
本発明のシート又はフィルムは、生体内に埋め込んで使用することから薬効を付与して用いてもよく、生物活性薬剤を含有することができる。生物活性薬剤を含有する場合には、リン酸化プルランに由来するリン酸基などのイオン性基と生物活性薬剤との相互作用により、前記シート又はフィルムが生体に吸収される際に生物活性薬剤も逐次放出されて吸収されることになる。よって、本発明のシート又はフィルムが、前記生物活性薬剤の徐放用基材として機能することができる。
抗菌薬(以下の系に含まれる薬剤:β-ラクタム系(ペニシリン系、複合ペニシリン系、βラクタマーゼ阻害剤配合ペニシリン系、セフェム系、βラクタマーゼ阻害剤配合セフェム系、カルバペネム系、モノバクタム系、ペネム系)、アミノグリコシド系、リンコマイシン系、ホスホマイシン系、テトラサイクリン系、クロラムフェニコール系、マクロライド系、ケトライド系、ポリペプチド系、グリコペプチド系、ストレプトグラミン系、キノロン系、ニューキノロン系、サルファ剤系、オキサゾリジノン系);
抗真菌薬(以下の系に含まれる薬剤:ポリエン系、アゾール系、アリルアミン系、キャンディン系);
抗ウイルス薬(例えば、インターフェロン、抗ヘルペス剤、抗インフルエンザ薬、抗HIV薬(各種核酸系逆転写酵素阻害薬、核酸複製阻害薬含む)、ビダフラビン、ガンシクロビル、バルガンシクロビル、バラシクロビル、シドフォビル、ホスカルネット、アシクロビル、免疫調整剤);
抗寄生虫薬(線虫薬(メベンダゾール、パモ酸ピランデル、チアベンダゾール、ジエチルカルバマジン、イベルメクチン)、条虫薬(ニクロサミド、プラジカンテル、アルベンダゾール)、吸虫薬(プラジカンテル)、原虫薬(メラルソプロール、エフロルニチン、メトロニダゾール、チニダゾール、ミルテホシン)、アメーバ薬(リファンピン、アンホテリシンB);
抗原虫薬(たとえば、抗マラリア剤(キニーネ、クロロキン、メフロキン、ファンシダール、プリマキン)、エフロルニチン、フラゾリドン、メラルソプロール、メトロニダゾール、オルニダゾール、パロモマイシン硫酸、ペンタミジン、ピリメタミン、チニダゾール);
非ステロイド性抗炎症薬(以下の系に含まれる各薬剤:サルチル酸系、プロピオン系、酢酸系、オキシカム系、塩基性、ピリン系、非ピリン系、総合感冒薬、COX-2阻害剤、COX-3阻害剤);
ステロイド性抗炎症薬(例えば、コルチゾール、プレドニゾロン、トリアムシノロン、デキサメタゾン、ベタメタゾン);
抗ヒスタミン薬(以下の系に含まれる各薬剤:エタノールアミン系、プロピルアミン系、フェノチアジン系、ピペラジン系、第二世代(エピナスチン、ロラタジン、フェキソフェナジン、セチリジン));
プロスタグランジン及び細胞毒性薬;
肥満細胞安定化剤(例えば、クロモリンナトリウム);
受容体拮抗剤(たとえば、ヒスタミンH2受容体拮抗剤、ロイコトルエン受容体拮抗薬、交感神経β受容体拮抗薬、アンジオテンシンII受容体拮抗薬、セロトニン5-HT(3)受容体拮抗薬、NMDA受容体拮抗薬、オレキシン受容体拮抗薬、アデノシンa2a受容体拮抗薬、バソプレシン受容体拮抗薬、ADP受容体拮抗薬、ニューロキニン1受容体拮抗薬、抗コリン薬、サイトカイン受容体拮抗薬);
抗腫瘍薬(以下の系に含まれる各薬剤:DNA架橋剤およびアルキル化剤、ニトロソウレア、白金錯体、代謝拮抗薬(葉酸拮抗薬、プリン拮抗薬、ピリミジン拮抗薬)、リボヌクレオチド還元酵素阻害薬、防錘体毒(ビンカアルカロイド類、タキサン)、トポイソメラーズ阻害剤(ポドフィトトキシン、アントラサイクリン系、カンプトテシン、チロシンキナーゼ阻害剤、ブレオマイシン類、マイトマイシン、生物学的反応修飾物質(インターフェロンα)、酵素、ホルモン製剤、アンドロゲン受容体遮断薬、アロマターゼ阻害薬、モノクローナル抗体);
免疫原性薬剤(immunogenic agents);
免疫抑制剤(例えば、シクロスポリン、アザチオプリン、ミゾリビン、及びFK506(タクロリムス));
心臓血管薬(例えば、冠状血管拡張薬及びニトログリセリン);
抗狭心症薬(例えば、β−アドレナリン遮断薬;カルシウムチャネル遮断薬(例えば、ニフェジピン及びジルチアゼム)及び;ニトレート(例えば、ニトログリセリン、イソソルビドジニトレート、ペンタエリトリトールテトラニトレート、及びエリトリチルテトラニトレート);
抗不整脈薬(例えば、ブレチリウムトシレート、エスモロール、ベラパミル、アミオダロン、エンカイニド、ジゴキシン、ジギトキシン、メキシレチン、リン酸ジソピラミド、プロカインアミド、硫酸キニジン、キニジングルコネート(quinidine gluconate)、キニジンポリガラクツロネート(quinidine polygalacturonate)、酢酸フレカイニド、トカイニド、及びリドカイン);
抗高血圧薬(例えば、プロプラノロール(propanolol)、プロパフェノン、オキシプレノロール(oxyprenolol)、ニフェジピン、レセルピン、トリメタファン、フェノキシベンザミン、塩酸パルジリン、デセルピジン、ジアゾキシド、硫酸グアネチジン(guanethidine monosulfate)、ミノキシジル、レシンナミン、ニトロプルシドナトリウム、インドジャボク(rauwolfia serpentina)、アルセロキシロン、及びフェントラミン);
脈管形成剤(例えば、アンジオクライン);
抗脈管形成剤;
抗血液凝固薬(例えば、ヘパリン、ヘパリンナトリウム、及びワルファリンナトリウム)抗うつ薬(例えば、ネオパム、オキシペルチン、ドキセピン、アモキサピン、トラゾドン、アミトリプチリン、マプロチリン、フェニルジン(phenylzine)、デシプラミン、ノルトリプチリン、トラニルシプロミン、フルオキセチン、ドキセピン、イミプラミン、イミプラミンパモエート、イソカルボキサジド(isocarboxazid)、トリミプラミン、及びプロトリプチリン);
鎮静催眠薬(例えば、バルビツール酸類(例えば、ペントバルビタール及びセコバルビタール);ベンゾジアゼピン(benzodiazapine)類(例えば、塩酸フルラゼパム、トリアゾラム、及びミダゾラム));
抗不安薬(例えば、ロラゼパム、ブスピロン、プラゼパム、クロルジアゼポキシド、オキサゼパム、クロラゼプ酸二カリウム、ジアゼパム、ヒドロキシジンパモエート、塩酸ヒドロキシジン、アルプラゾラム、ドロペリドール、ハラゼパム、クロルメザノン、及びダントロレン);
抗精神病薬(例えば、ハロペリドール、コハク酸ロクサピン、塩酸ロクサピン、チオリダジン、塩酸チオリダジン、チオチキセン、フルフェナジン、デカン酸フルフェナジン、エナント酸フルフェナジン、トリフルオペラジン、クロルプロマジン、パーフェナジン、クエン酸リチウム、及びプロクロルペラジン);
抗痙攣薬(例えば、バルプロ酸、ジバルプロックスナトリウム、フェニトイン(phenyloin)、フェニトインナトリウム(phenyloin sodium)、クロナゼパム、プリミドン、フェノバルビタール(phenobarbitol)、カルバマゼピン、アモバルビタールナトリウム、メトスクシミド、メタルビタール、メフォバルビタール、メフェニトイン(mephenyloin)、フェンスクシミド、パラメタジオン、エトトイン、フェナセミド、セコバルビタールナトリウム(secobarbitol sodium)、クロラゼプ酸二カリウム、及びトリメタジオン);
抗躁病薬(例えば、炭酸リチウム、カルバマゼピン、バルプロ酸ナトリウム、クロナゼパム、バルプロ酸ナトリウム);
精神活性剤(精神に作用する薬剤は全て向精神薬、精神活性剤とする);
精神安定剤(例えば、ベンゾジアゼピン系抗不安薬、エチゾラム、クロチアゼパム、アルプラゾラム、オキサゾラム、プラゼパム、ヒドロキシジン塩酸塩、タンドスピロンクエン酸塩);
抗片頭痛剤(例えば、エルゴタミン、プロプラノロール(propanolol)、ムチン酸イソメテプテン、及びジクロラルフェナゾン、トリプタン系);
抗パーキンソン剤(例えば、L−ドパ及びエトスクシミド、塩酸プロフェナミン、レボドパ);
鎮咳薬(例えば、中枢性鎮咳薬(ジヒドロコデイン)、アドレナリン作動薬(トリメトキノール)、キサンチン誘導体(テオフィルン));
気管支拡張薬(例えば、交感神経作用薬(例えば、塩酸エピネフリン、硫酸メタプロテレノール、硫酸テルブタリン、イソエタリン、メシル酸イソエタリン、塩酸イソエタリン、硫酸アルブテロール、アルブテロール、ビトルテロルメシレート、塩酸イソプレテレノール、硫酸テルブタリン、酒石酸水素エピネフリン、硫酸メタプロテレノール、エピネフリン、及び酒石酸水素エピネフリン);
ぜん息治療薬(例えば、ケトチフェン及びトラキサノクス);
抗ムスカリン薬(例えば、ブチルスコポラミン臭化物、ピレンゼピン塩酸塩);
麻酔薬(例えば、コデイン、ジヒドロコデイノン、メペリジン、モルヒネなど);
オピオイドレセプターアンタゴニスト(例えば、ナルトレキソン及びナロキソン);
鎮吐剤(例えば、塩酸メクリジン、ナビロン、プロクロルペラジン、ジメンヒドリネート、塩酸プロメタジン、チエチルペラジン、及びスコポラミン);
血糖降下薬(例えば、ヒトインスリン、精製ウシインスリン、精製ブタインスリン、グリブリド、クロルプロパミド、グリピジド、トルブタミド、及びトラザミド);
抗糖尿病薬(例えば、ビグアナイド類及びスルホニル尿素誘導体類);
高脂質血症薬剤(hypolipidemic agents)(例えば、クロフィブレート、デキストロサイロキシンナトリウム、プロブコール、プラバスタチン(pravastitin)、アトルバスタチン、ロバスタチン、及びナイアシン);
血栓溶解薬(例えば、ウロキナーゼ、ストレプトキナーゼ、及びアルテプラーゼ);
抗線維素溶解薬(例えば、アミノカプロン酸);
血液レオロジー剤(例えば、ペントキシフィリン);
抗血小板薬(例えば、アスピリン);
カルシウム調節に有用な薬剤(例えば、カルシトニン及び副甲状腺ホルモン);
赤血球生成刺激に有用な薬剤(例えば、エリトロポイエチン);及び
抗関節炎薬(例えば、フェニルブタゾン、スリンダク、ペニシラミン(penicillanine)、サルサラート、ピロキシカム、アザチオプリン、インドメタシン、メクロフェナメート(meclofenamate)、金チオリンゴ酸ナトリウム、ケトプロフェン、オーラノフィン、金チオグルコース、及びトルメチンナトリウム);
抗痛風薬(例えば、コルヒチン及びアロプリノール);
筋弛緩薬(例えば、アフロクアロン、エペリゾン塩酸塩);
アドレナリン作用性ニューロン遮断薬(例えば、タムスロシン);
副交感神経様作用剤(例えば、ピロカルピン、ムスカリン);
神経伝達物質(例えば、アドレナリン、ガンマアミノ酪酸、グリシン);
抗体;
胃腸薬(例えば、アズレンスルホン酸ナトリウム、ウルソ、塩酸カルニチン);
抗潰瘍/抗逆流剤(例えば、ファモチジン、シメチジン、及び塩酸ラニチジン)
利尿薬(例えば、トリクロルメチアジド、メチクラン、フロセミド);
脂質;
リポ多糖類;
多糖類;
酵素;
うっ血除去薬(例えば、プソイドエフェドリン、フェニレフリン);
スルホンアミド;
ビタミン;
キサンチン類(例えば、アミノフィリン、ジフィリン、硫酸メタプロテレノール、及びアミノフィリン);
アルカロイド(例えば、モルヒネ、キニーネ、エフェドリン);
診断薬;
が挙げられる。
また、本発明のシート又はフィルムは、前記以外に乳化剤を含有することができる。乳化剤によって、油溶性成分を含有する事が出来る。またシート又はフィルムの可塑性を制御することができる。生物活性薬剤と併用する場合には、乳化剤によって生物活性薬剤の体内への吸収を促進させるなど、体内への吸収性を制御することができる。
表面処理としては、リン酸化プルランの水酸基の部分の化学修飾などが挙げられる。例えば、表面を疎水化したり、架橋構造を導入するなどが例示でき、前記化学修飾は公知の方法に従って行うことができ、また、水酸基と反応するものであれば何でも良いが、エーテル化剤、エステル化剤、アセタール化剤、イソシアネート、イソチオシアネート、カルバモイルクロリド、チオカルバモイルクロリド、シランカップリング剤、塩化スルホニル、スルホン酸無水物、ポリマー、その他高分子用架橋剤等を用いて化学修飾することなどが考えられる。これらの化学修飾によりリン酸化プルランの溶解性を制御することができ、本発明のシート又はフィルムに含まれる薬剤に徐放性を付与するなど、徐放性の制御が可能となる。したがって、リン酸化プルランの溶解性、薬剤の徐放性が制御されたリン酸化プルラン含有の生体吸収性シート又はフィルムを提供することも、本発明の一つの態様である。
本発明のシート又はフィルム以外の他の層を設ける態様、即ち、他の層を積層した複層構造とすることも本発明の一つの態様であり、貼付側の反対側に他の層を設ける態様が挙げられる。このような態様とすることで、生体内で使用する場合には生物活性薬剤が体液中に漏洩することを抑制でき、皮膚等に使用する場合には生物活性薬剤の揮発を抑制できる。
内容積2Lのセパラブルフラスコを用いて、プルラン(林原商事社製)40.0gを蒸留水200mLに室温で溶解させた。この溶液を攪拌しながら、1Mのリン酸水溶液(水酸化ナトリウムでpHを5.5に調整したもの)1000gを10分かけて添加し、添加後さらに1時間攪拌を継続した。その後、100℃から103℃の間で蒸留水約1100mLを留去し、続いて、170℃で3時間攪拌を継続した後、反応物を室温まで冷却した。反応物を取り出し、乳鉢で粉砕することで茶色固体98.4gを得た。
生分解性ポリマーの種類による、フィルムの湿潤下での強度を調べた。
フィルムを30×100mmに切り取り、片面10μLの水を用いて、両面それぞれを湿潤させたその両端を長辺方向に引っ張り荷重をかけ値を測定する。試料は4枚用い、その平均値を評価に用いる。
乳化剤は有効成分の体内への吸収促進が期待できる成分であるが、有効成分の溶解又は分散の他、フィルムの強度などの物性にも影響することから、その添加量について検討を行った。
フィルムを30×100mmに切り取り、その両端を長辺方向にデジタルフォースゲージに挟んで牽引し、フィルムが破断した時点での強さを引張強度とする。試料は4枚用い、その平均値を評価に用いる。引張強度が大きい程フィルム強度は高いことを示し、2MPa以上であれば貼付使用に問題ないものである。
水を入れたシャーレに16.5×22mmに切り取ったフィルムを浮かべ、静止状態で溶解する様子を観察し、完全に溶解した時間を計測する。試料は4枚用い、その平均値を評価に用いる。溶解時間が長い程フィルムの溶解性が高いことを示すが、30〜45秒程度であれば生体使用に問題ないものである。
フィルムが生物活性薬剤を含有する場合について、フィルム化が可能であるかを検討した。
フェノール樹脂を生理食塩水で濡らし、1.5cm幅(長さ10cm)にカットしたフィルムの下半分を貼り付けて乾燥させる。フェノール樹脂をデジタルフォースゲージに挟み、接着していない側のフィルムを180度方向に牽引し、フィルムがフェノール樹脂から完全に剥離した時点での強さを接着強度とする。試料は4枚用い、その平均値を評価に用いる。接着強度が大きい程フィルムの粘着力は高いことを示し、2.0N/15mm幅程度であれば貼付使用に問題ないものである。
フィルムが生物活性薬剤を含有する場合に、生物活性薬剤の乳化による影響を検討した。
マウス(C57BL/6)の背部皮下、腰背筋上に実施例10のフィルム(10×10mm)を埋植し、24時間後にマウスを屠殺し、埋植部の組織を抽出した。組織中のゲンタマイシン薬剤濃度をELISA法で測定した(埋植一日後)。なお、参考のために、実施例10のフィルムをPBS 1mL中に一晩放置し、翌日上清を回収し同様にしてゲンタマイシン薬剤濃度を測定した(フィルム含有量)。結果を図2に示す。なお、フィルム埋植時に、フィルムは組織に直ぐ馴染み、また、ピンセットでつまむと粘着性を示していることを確認した。
実施例9で得られたアルギニンフィルムについて、その止血効果を検討した(図3)。マウスの肝臓表面をこすって傷をつけ、そこにアルギニンフィルムを静置した。フィルム静置により、肉眼的に出血が軽減した傾向があった。直後にフィルムを剥がしても、肝臓表面からの出血は確認できなかった。
30L反応缶に超純水26L,食品添加物プルラン(プルラン/林原社製)350g(仕込み基準)を仕込んだ。50w/v%水酸化ナトリウム水溶液581mLを内温20〜25℃で追加し、同温度範囲で19時間撹拌した。内温を0℃まで冷却し、0〜10℃で塩化ホスホリル229gを追加した。同温度範囲で1時間撹拌した後、内温を20〜25℃に調整し15時間撹拌した。UF膜を用いて膜ろ過濃縮を行い、留去液が少なくなるまで濃縮した後、超純水を追加し、リン酸化プルラン水溶液とした。得られたリン酸化プルラン水溶液をスプレードライヤーにて粉末化し、リン酸化プルラン280gを得た。但し、水へ完全に溶解しないため、重量平均分子量は測定出来なかった。
1000LGL反応缶にイオン交換水508L,食品添加物プルラン7kg(プルラン/林原社製)(仕込み基準)を仕込んだ。予め調製した水酸化ナトリウム水溶液(水酸化ナトリウム5.81 kg、イオン交換水18kg使用)を内温20〜25℃で追加し、同温度範囲で5時間撹拌後、内温0〜10℃で塩化ホスホリル4.56kgを滴下した。同温度範囲で1時間撹拌した後、内温を20〜25℃に調整した。水酸化ナトリウム水溶液を更に添加し、終夜攪拌した。UF膜を用いて膜ろ過濃縮を行い、留去液が少なくなるまで濃縮した後、超純水を追加し、リン酸化プルラン水溶液とした。得られたリン酸化プルラン水溶液をスプレードライヤーにて粉末化し、リン酸化プルラン3.5kg(重量平均分子量210110)を得た。
<測定条件>
測定機器: 高速液体クロマトグラフ
カラム: TSKgel GMPWXL(7.8mmID×390mm)×2本連結
移動相: 200mM硝酸ナトリウム水溶液
流速: 1mL/min
検出器: 示唆屈折検出器
カラム温度: 40℃
注入量: 100μL
試料溶液: 2mg/mL
(試料10mgに移動相5mLを加えた後,振り混ぜて溶解)
測定: プルラン標準品にて較正曲線を作成し、重量平均分子量を計算
実施例6で調製したリン酸化プルランフィルム0.0236gを120℃に加熱した無水酢酸の蒸気で5分間処理を行った。未処理のリン酸化プルランフィルムは2時間、超純水に浸漬させると膨潤し、溶解した。一方、無水酢酸処理したリン酸化プルランは0.0916gに膨潤し、乾燥させると0.0176gとなった。これを水中に浸漬させると、乳化剤等は溶出してしまったが、リン酸化プルランフィルムとして、柔軟性はやや失われたが、フィルム状の形態を維持した。以上より、無水酢酸処理によりリン酸化プルランフィルムを難溶化できることがわかった。なお、無水酢酸に代えて塩化ホスホリルを使用して処理しても、同様に難溶化することができる。
リン酸化プルランの粉末についてエチレンオキサイドガス滅菌を行った。ガスに対する暴露時間を変えることにより、エチレンオキサイドガスとの反応量を変えて、その変化を観察した。その結果、エチレンオキサイドガス暴露時間が進むほど、リン酸化プルランが変性することがわかり、得られたリン酸化プルランは水に対して難溶性となったことから、エチレンオキサイドガスによる処理により、リン酸化プルランを水に対して難溶化できることがわかった。結果を図4に示す。図中の5%、10%、20%は、エチレンオキサイドガスの濃度を示す。
公知のウェットラミネート法により、実施例5と同様にして調製したリン酸化プルランフィルムにポリグリコール酸不織布(製品名:ネオベール 0.3mm厚)を貼り合せ、リン酸化プルラン層とポリグリコール酸不織布の2層構造シートを調製した。結果を図5、6に示す。
ラット脊椎横突起をドリルで削り、同部位に、BMP−2を1μg/cm2配合する点を除くと同様にして調製したBMP−2を含有するリン酸化プルランフィルム(5mm角)を図7の位置に静置した。フィルムは直ちに組織に吸着し、はがす事は困難であった。図8中の丸で囲んだ部位に骨形成を期待できる。
2 ポリグリコール酸不織布
Claims (10)
- リン酸化プルランおよび乳化剤を含有する組成物から成り、リン酸化プルランの含有量が30質量%を超える、生体吸収性のシート又はフィルム。
- 乳化剤が、グリセリン脂肪酸エステル、ラウリル硫酸ナトリウム、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリエチレングリコール脂肪酸エステル、ポリグリセリン脂肪酸エステル、アルキルスルホン酸、アルキルベンゼンスルホン酸、ポリオキシエチレンアルキルエーテルスルホン酸、大豆由来レシチン、及びこれらの塩からなる群より選択される1種以上の乳化剤である、請求項1記載のシート又はフィルム。
- 乳化剤の含有量が、リン酸化プルラン100質量部に対して2〜60質量部である、請求項1又は2記載のシート又はフィルム。
- 組成物が更に可塑剤を含んでなる、請求項1〜3いずれか記載のシート又はフィルム。
- 可塑剤がグリセリン及びポリエチレングリコールから選ばれる少なくとも一種を含む、請求項4に記載のシート又はフィルム。
- 組成物が更に生物活性薬剤を含有してなる、請求項1〜5いずれか記載のシート又はフィルム。
- 支持体シートに支持されている、請求項1〜6いずれか記載のシート又はフィルム。
- 生体内の臓器又は組織における創傷部、欠損部、又は脆弱部の被覆材である、請求項1〜7いずれか記載のシート又はフィルム。
- 生体内組織の再生又は再建材料の漏洩又は拡散防止材あるいは固定材である、請求項1〜7いずれか記載のシート又はフィルム。
- 生物活性薬剤の漏洩又は拡散防止材である、請求項1〜7いずれか記載のシート又はフィルム。
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KR100888219B1 (ko) * | 2007-06-01 | 2009-03-12 | (주) 태웅메디칼 | 약물 방출 스텐트용 코팅제, 그의 제조방법 및 이 코팅제로코팅된 약물 방출 스텐트 |
JP5487410B2 (ja) * | 2010-02-22 | 2014-05-07 | 国立大学法人 岡山大学 | 生体硬組織接着用キット |
US9636362B2 (en) * | 2010-03-04 | 2017-05-02 | The Board Of Trustees Of The Leland Stanford Junior University | Pullulan regenerative matrix |
CN102600493B (zh) * | 2012-03-06 | 2013-12-18 | 四川大学 | 天然普鲁兰多糖水凝胶伤口敷料及其制备方法 |
CN105121163B (zh) * | 2013-03-15 | 2017-07-18 | 东丽株式会社 | 使用了聚乳酸系树脂的层叠膜 |
JP6211680B2 (ja) * | 2014-03-07 | 2017-10-11 | 日本全薬工業株式会社 | プルランゲルならびにその製造方法および利用 |
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2017
- 2017-03-08 CN CN201780028979.5A patent/CN109310795A/zh active Pending
- 2017-03-08 US US16/083,071 patent/US20190091166A1/en not_active Abandoned
- 2017-03-08 JP JP2018504565A patent/JP6619870B2/ja active Active
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JP2020022861A (ja) | 2020-02-13 |
US20190091166A1 (en) | 2019-03-28 |
CN109310795A (zh) | 2019-02-05 |
EP3427762A1 (en) | 2019-01-16 |
EP3427762A4 (en) | 2019-10-30 |
JP6619870B2 (ja) | 2019-12-11 |
WO2017154998A1 (ja) | 2017-09-14 |
JPWO2017154998A1 (ja) | 2019-02-21 |
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