JP4012928B2 - 接合安定化されたポリペプチド組成物 - Google Patents
接合安定化されたポリペプチド組成物 Download PDFInfo
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Description
特定の病気の系統的な治癒ためにポリペプチドおよびタンパク質を使用することは、今や医療分野における一般的なこととなっている。ペプチドが置換治療において果たす役割は、非常に重要であり、このため、DNA組換え技術により大量に合成することを目的として多数の研究が行われている。こうしたポリペプチドの多くは、その生物学的作用を発揮させる可能性を秘めかつ特定的である内在性分子である。
接合体2は以下の式で表される。
残りの第1のアルコール基は、トリチル基により保護される一方、第2のアルコール基は、ポリエチレングリコールにより所望の重合体が変換される。
[接合体1]
ポリソルベート・トリオレート・p−ニトロフェニル・カーボネート 50mlの無水アセトニトリル中のp−ニトロフェニルクロロフォルメート溶液(0.8g、4モル)に乾燥ポリソルベート・トリオレート(7g、4モル)を添加し、次に、ジメチルラミノピリジン(0.5g、4モル)を添加する。この反応混合体は、室温で24時間攪拌する。低圧下にて溶剤を除去し、形成される析出物は、乾燥ベンゼンで希釈し、セルーテを通じてろ過する。残留物は、乾燥ベンゼン中で一昼夜、冷蔵し、更なる析出物は、ろ過により除去する。溶剤は低圧下にて除去し、残留ベンゼンは低圧にて排出することにより除去し、6.4gのポリソルベート・トリオレー卜p−ニトロフェニル・カーボネートが得られるようにする。
[接合体2]
ポリエチレングリコール・モノスチアレートの端末ヒドロキシル基を上述のように、p−ニトロフェニル・クロロフォルメートと反応させることにより、活性化させる。蒸留水中の活性重合体(1g)の溶液に、pH8.8にて0.1MpHリン酸塩緩衝液中に溶融させたウシインシュリン(80mg)を添加する。
[接合体3]
テトラヒドロ−2−(12-bromododecanoxy)−2Hピロン ピリジニウムp−トルエンスルホン酸塩(P−TSA)を含むジクロロメタン中の12−ブロモ−1−ドデカノール(1モル)の溶液に、ジヒドロピラン(2モル)を添加する。反応混合体は、24時間攪拌し、次に水で2回洗浄し、無水MgSO4により乾燥させる。ジクロロメタンを低圧下で除去する。必要であれば、形成される生成物は、シリカゲルによりクロマトグラフィにより精製する。
重合体−インシュリン接合体、および自然のインシュリンについてウシインシュリンを使用して比較試験を行い、動物におけるその相対的安定性およびその活性を判断した。動物について研究した場合、重合体−インシュリンの血圧降下の効果を自然のインシュリンの効果と比較した。平均体重25gの雌および雄の白子鼠を一昼夜断食させ、2日間に亘り各種の段階で行った各治療に対し、5匹を1つの群として使用した。
非接合形態のインシュリンおよび接合体1を試験材料として使用して、雄および雌白子鼠についてインシュリンの効果実験を行った。この実験の1つの目的は、接合体1の形態によるインシュリンを皮下注射したときに、インシュリンと同様の方法で血糖値に対する効果があるか否かを判断することである。第2の目的は、自由インシュリンと異なり、接合体1のインシュリン複合体が経口投与したとき、血液の血糖値を低下させる作用があるかどうかを判断することである。その結果は図2に掲げてあり、この場合「インシュリン複合体」は、接合体1を意味する。
[ポリソルベート・モノパルミテートのパラーニトロフェニル・カルボネートの調合]
最初に乾燥ベンゼンを使用する共沸により、ポリソルベート・モノパルミテートを乾燥させる。
[インシュリンとのポリソルベート・モノパルミテート接合体の調合]
上述した実験例1の接合反応手順に従い、1gの量のポリソルベート・モノパルミテートおよび80mgのインシュリンを使用し、反応生成物をHPLCで分離すると、インシュリン−ポリソルベート・モノパルミテートの共有結合した接合体が得られる。
[酵素−重合体接合体の調合]
実験例1の接合体1に関して説明した方法と同一の方法を使用して、アルカリフォスファターゼ(AP)を重合体に結合させた、更に、重合体対タンパク質の比率を高くするかまたは低くする何れかが有利かを判断するため、140モルの重合体/酸素モルと、14モルの重合体/酵素モルを使用して接合体を調合した。接合体APの分子当りの重合体群の数は、重合体の高および低比率に対し、それぞれ30および5である。
A.ボーラー(voller)その他の者の文献WHO、53、55(1976)方法に従い、フォスファターゼ分析を行った。マイクロウェルのアリコット(50μl)を添加し、200μlの基礎溶液(20%のエタノラミン緩衝液内の4−ニトロフェニルリン酸塩、10g/l、pH9.3)と混合させ、室温にて45時間、保温した。50μlの3M・NaOHにより反応を停止させた。この吸収率は、マイクロプレート読取り装置内で405nmにて測定した。
[接合体1]
A.pH9.2の0.05Mナトリウム・バイカーボネート緩衝液中のインシュリン溶液(50mg)に水−ジメチルスルホキシド中の活性重合体溶液(1g)を添加し、室温にて3時間、攪拌した。この混合体のpHは、1N・NaOHにより慎重に調整することにより維持する。次に、この反応混合体を0.1M−pH7.0のリン酸塩緩衝液で透析する。精製された生成物を凍結乾燥する。ビューレット検定法により、タンパク質含有量(48mg)を測定する。インシュリンに結合された重合体鎖の数は、TNBS検定により求め、重合対2モル対インシュリン1モルの比率となるようにする。
次の方法にて、糖尿病(BB)鼠モデルにて、重合体−インシュリンを評価する。BB鼠は、人間のインシュリン依存性糖尿病の信頼性の高いモデルである。
Claims (12)
- 前記ペプチドが生理的に活性な治療用ペプチドである請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、インビボあるいはインビトロで、ある症状あるいはある成分の有無を反応により決定するために用いられる診断用ペプチドである請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、植物またはその成分中で活性である請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、生理的に活性なペプチドであって、該生理的に活性なペプチドが、生理的に活性なペプチド単独の場合と比較して、前記ポリマーペプチド接合体中で、増強されたインビボにおける酵素分解耐性を有するように、前記親油性の部分と前記親水性の部分とのコンフォメーションが決定されている請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、500〜10000ダルトンの分子量である請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、インシュリン、カルシトニン、ACTH、グルカゴン、ソマトスタチン、ソマトトロピン、ソマトメジン、副甲状腺ホルモン、エリスロポエチン、視床下部放出因子、プロラクチン、甲状腺剌激ホルモン、エンドルフィン、エンケファリン、バソプレシン、天然に存在しないオピオイド、スーパーオキシドジムスターゼ、リボヌクレアーゼ、並びにパパインからなる群より選択される請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、インシュリンである請求項1に記載のポリマーペプチド接合体。
- 前記ペプチドが、カルシトニンである請求項1に記載のポリマーペプチド接合体。
- 生理的に活性なペプチドが、(i)親水性の線状ポリアルキレングリコール部分と、(ii)親油性部分とを含むポリソルベート複合体に共有結合的に結合されたポリマーペプチド接合体であって、該ポリソルベート複合体が、以下の化学式、
で表される重合体であり、
前記生理的に活性なペプチドと、前記線状ポリアルキレングリコール部分と、前記親油性部分とが、(a)該線状ポリアルキレングリコール部分が、外側から利用できるように、また(b)該生理的に活性なペプチドが、インビボにおいて、生理的に活性な治療用ペプチド単独のときと比べて増強された酵素分解耐性を有するように、相互のコンフォメーションが決定されている生理的活性ポリマーペプチド接合体。 - 請求項1〜10に記載の接合体のインシュリン欠乏症治療用経口製剤であって、前記ペプチドがインシュリンである製剤の製造のための使用方法。
- 請求項1〜10に記載の接合体と、担体または希釈剤とを含み、前記ペプチドがインシュリンである、インシュリン欠乏症治療用経口製剤。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/059,701 US5359030A (en) | 1993-05-10 | 1993-05-10 | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002260460A Division JP4482267B2 (ja) | 1993-05-10 | 2002-09-05 | 接合安定化されたポリペプチド組成物 |
Publications (3)
Publication Number | Publication Date |
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JP2006348039A JP2006348039A (ja) | 2006-12-28 |
JP2006348039A5 JP2006348039A5 (ja) | 2007-02-22 |
JP4012928B2 true JP4012928B2 (ja) | 2007-11-28 |
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Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6525657A Withdrawn JPH08510255A (ja) | 1993-05-10 | 1994-05-10 | 接合−安定化ポリペプチド組成物 |
JP2002260459A Pending JP2003160598A (ja) | 1993-05-10 | 2002-09-05 | 接合安定化されたポリペプチド組成物 |
JP2002260460A Expired - Lifetime JP4482267B2 (ja) | 1993-05-10 | 2002-09-05 | 接合安定化されたポリペプチド組成物 |
JP2006202440A Expired - Lifetime JP4012928B2 (ja) | 1993-05-10 | 2006-07-25 | 接合安定化されたポリペプチド組成物 |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
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JP6525657A Withdrawn JPH08510255A (ja) | 1993-05-10 | 1994-05-10 | 接合−安定化ポリペプチド組成物 |
JP2002260459A Pending JP2003160598A (ja) | 1993-05-10 | 2002-09-05 | 接合安定化されたポリペプチド組成物 |
JP2002260460A Expired - Lifetime JP4482267B2 (ja) | 1993-05-10 | 2002-09-05 | 接合安定化されたポリペプチド組成物 |
Country Status (12)
Country | Link |
---|---|
US (2) | US5359030A (ja) |
EP (2) | EP0707596B1 (ja) |
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DK0707596T3 (da) | 2005-12-12 |
JP2006348039A (ja) | 2006-12-28 |
EP0707596B1 (en) | 2005-08-03 |
WO1994026778A1 (en) | 1994-11-24 |
ATE301134T1 (de) | 2005-08-15 |
EP1264837A1 (en) | 2002-12-11 |
EP0707596A4 (en) | 1997-11-12 |
JP2003206236A (ja) | 2003-07-22 |
JP4482267B2 (ja) | 2010-06-16 |
IL109619A (en) | 2000-12-06 |
JPH08510255A (ja) | 1996-10-29 |
JP2003160598A (ja) | 2003-06-03 |
HK1049488A1 (zh) | 2003-05-16 |
CA2162366A1 (en) | 1994-11-24 |
IL109619A0 (en) | 1994-08-26 |
DE69434448D1 (de) | 2005-09-08 |
EP0707596A1 (en) | 1996-04-24 |
ES2247586T3 (es) | 2006-03-01 |
DE69434448T2 (de) | 2006-06-08 |
AU694919B2 (en) | 1998-08-06 |
CA2162366C (en) | 2009-10-27 |
US5359030A (en) | 1994-10-25 |
AU6946694A (en) | 1994-12-12 |
US5438040A (en) | 1995-08-01 |
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