JP2010533687A - 活性成分の徐放システムおよび調製方法 - Google Patents
活性成分の徐放システムおよび調製方法 Download PDFInfo
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- JP2010533687A JP2010533687A JP2010516541A JP2010516541A JP2010533687A JP 2010533687 A JP2010533687 A JP 2010533687A JP 2010516541 A JP2010516541 A JP 2010516541A JP 2010516541 A JP2010516541 A JP 2010516541A JP 2010533687 A JP2010533687 A JP 2010533687A
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Abstract
Description
(実施例1から5)
Arg-Lys-Arg-Ser-Arg-Lys-Glu(7P)およびポリリシン(PLL)の徐放システムの調製
1)使用試薬:
錯形成剤:
- PMLA,Na(Mw=30000g/mol)
- PLCA,Na(Mw=40000g/mol、Mn=20000g/mol)
マトリックス:
- 実施例1から4について、PLA(37.5)GA(25)(Mw=30000g/mol、Mn=9000g/mol)
- 実施例5について、PLA50(Mw=50000g/mol)
活性成分、すなわち高分子電解質のテンプレート:
- 上記のヘプタペプチド(7P)、タンパク質キナーゼ阻害剤は、959g/molの分子量を有し、全部で5価の正電荷を含有する。
- ポリリシン(PLL)は、12000g/molの分子量Mwを有し、1構造単位あたり1価の正電荷を含有する。
例1:一般に、PLL,HBr25mgを含有する水溶液500μlを、PMLA,Na16.7mgを含有する水溶液1mlに加えた。この混合物を遠心分離し、沈殿物を乾燥させた後に、PMLA-PLL固体錯塩26mg(収率=88%)を回収した。
一般に、実施例1から4におけるシステムについて、PLA(37.5)GA(25)1gを、50℃でプレス機(CARVER4120CE)により圧縮し、厚さ数百ミクロンのフィルムを得た。
イオン性活性成分の放出
実施例1から4におけるそれぞれの錯塩について、以下の3つのシステムを検討した。すなわち、2成分の固体高分子電解質/活性成分の錯塩のシステム(曲線上の▲)、2成分のマトリックス/活性成分のシステム(曲線上の■)、および3成分のマトリックス/固体高分子電解質-活性成分錯塩のシステム(曲線上の●)である。
マトリックスの分解により、高分子電解質パートナーを選択的に分解することにより高分子電解質-活性成分の錯塩の分解を触媒する酸生成物が供給される。マトリックスの分解速度により、生理活性イオン性物質の放出速度が直接決定される。
実施例5におけるものと同じ条件下で調製された、3成分のPLA50/PMLA/7Pシステムも検討した。3ヶ月後の放出も示されている。
同様の放出特性が、実施例1、3および4におけるシステムと同様のものにより得られ、重量比率は、マトリックス中に4%から8%の比率に増加した。最終的に得られたマトリックスは、1.3mmの厚さを有する。
安定な沈殿物の錯塩を、実施例1および2における方法と同様な方法で調製し、PLL相中のロイプロリドを、PMLAと、およびPLCAと錯形成した。
実施例1から4におけるように沈殿ではなく、凍結乾燥し、PMLA-ブルシンおよびPLCA-ブルシンの錯塩も調製し、凍結乾燥された生成物を、PLAGAのシート中に組み入れた。
実施例2において上記のように、PLCA,Na錯形成剤およびPLL活性成分(高分子電解質テンプレート)により、PLCA-PLL錯塩を調製し、ポリ(ε-カプロラクトン)マトリックス(PCL)をマトリックス中に組み入れた。マトリックス中への錯塩の組み入れ重量比4重量%で組み入れを行い、70℃で圧縮後の最終的なマトリックスの厚さは0.5mmであった。
非酸感応性錯形成剤ポリ(メタクリル酸)(PMA,Na)および活性成分(高分子電解質テンプレート)PLLで、PMA-PLL錯塩を、PLL,HBr25mgを含有する水溶液500μlをPMA,Na12.9mgを含有する水溶液1mlに加えることにより調製した。混合物を遠心分離し、沈殿物を乾燥した後に、固体PMA-PLL錯塩18mg(収率=71%)を回収した。実施例1から4において上記のように、PMA-PLL錯塩を、マトリックスPLA(37.5)GA(25)中に組み入れた。マトリックス中への錯塩の組み入れ重量比率5重量%で組み入れを行い、60℃で圧縮後の最終的なマトリックスの厚さは0.15mmであった。
ポリ(α-アミノセリネート)(PSA)および活性成分(高分子電解質テンプレート)ポリアクリル酸(PAA,Na)で、PPA-PSa錯塩を、PSA,HBr10.5mgを含有する水溶液500μlをPPA,Na5.5mgを含有する水溶液1mlに加えることにより調製した。混合物を遠心分離し、沈殿物を乾燥させた後に、固体PAA-PSA錯塩6.8mg(収率=68%)を回収した。実施例1から4と同じ方法で、PAA-PSA錯塩を、PLA(37.5)GA(25)マトリックス中に組み入れた。マトリックス中への錯塩の組み入れ重量比率4.5重量%で組み入れを行い、60℃で圧縮後の最終的なマトリックスの厚さは0.22mmであった。
Claims (14)
- 酸化合物を形成する少なくとも(a)1種の分解性ポリマーマトリックスと、(b)少なくとも1価の静電荷を有する活性成分、および反対の電荷の前記活性成分と錯形成する高分子電解質パートナーの少なくとも1種の錯塩とを含み、前記錯形成剤が酸感応性である、活性成分の徐放システム。
- 前記ポリマーマトリックスが、ポリ(α-ヒドロキシ酸)またはポリ酸無水物またはポリカプロラクトンの型であることを特徴とする、請求項1に記載のシステム。
- 前記ポリマーマトリックスが、ポリ(ラクチド-co-グリコリド)共重合体型であることを特徴とする、請求項1または2に記載のシステム。
- 前記錯形成剤が、ポリ(リンゴ酸)(PMLA)、ポリ(リシンシトルアミド)(PLCAまたはPLCAI)およびポリ(アミノセリネート)(PSA)の型の高分子電解質錯形成剤から選択されることを特徴とする、請求項1から3のいずれかに記載のシステム。
- 前記錯塩が、塩基性活性成分と、ポリ(リンゴ酸)またはポリ(リシンシトルアミド)の型の多価アニオン錯形成剤との間のイオン対形成により形成されることを特徴とする、請求項1から4のいずれかに記載のシステム。
- 前記塩基性活性成分が、多価アミン型であることを特徴とする、請求項1から5のいずれかに記載のシステム。
- 前記酸感応性錯塩が、酸性活性成分と、酸感応性ポリ(アミノセリネート)(PSA)型ポリカチオン錯形成剤との間のイオン対形成により形成されることを特徴とする、請求項1から4のいずれかに記載のシステム。
- 前記錯塩が、水性媒体に不溶性であることを特徴とする、請求項1から7のいずれかに記載のシステム。
- 前記活性成分が、高分子電解質であることを特徴とする、請求項1から8のいずれかに記載のシステム。
- 前記システム中の錯塩の比率が、0.1から60重量%、好ましくは1から40重量%の範囲内であることを特徴とする、請求項1から9のいずれかに記載のシステム。
- 少なくとも1価の静電荷を有する活性成分、および反対の電荷の酸感応性錯形成高分子電解質パートナーの間の錯塩を形成し、前記錯塩が、生理的媒体のpH、塩分および温度の条件下で安定であり、次いで、前記錯塩を、酸の加水分解生成物を形成する生体吸収性ポリマーマトリックス中に組み入れることからなるステップを少なくとも含む、請求項1から10のいずれかに記載の徐放システムの調製方法。
- 酸化合物を形成する少なくとも1種の分解性ポリマーマトリックスと、少なくとも1価の静電荷を有する活性成分、および反対の電荷の前記活性成分と錯形成する高分子電解質パートナーの間の少なくとも1種の錯塩とを含む、活性成分の徐放システムにおける、錯形成剤としての酸感応性高分子電解質の使用。
- 前記ポリマーマトリックスが、ポリ(α-ヒドロキシ酸)またはポリ酸無水物またはポリカプロラクトンの型、好ましくは、PLAまたはPLAGAであることを特徴とする、請求項12に記載の使用。
- 前記錯形成剤が、PMLA、PLCA、PLCAIまたはPSAから選択されることを特徴とする、請求項12または13に記載の使用。
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US20050118718A1 (en) * | 2003-09-22 | 2005-06-02 | University Of Utah Research Foundation | Stabilization and controlled delivery of ionic biopharmaceuticals |
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