JP2014177490A - 制御放出系の調製方法 - Google Patents
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Abstract
【解決手段】この方法により、活性成分の制御放出、特に制御された薬物送達のための系がもたらされる。本発明によると、用語「制御放出」は、徐放出、持続放出および遅延放出を含むあらゆる種類の制御放出を包含する。特に、本発明は、制御放出のための、ミセル、ナノ粒子、ミクロスフェアなどのポリマー担体または高分子デバイスおよび他の種類のポリマーデバイスに封入された、または他の方法で組み入れられた、またはそれらに結合した活性成分をもたらす。活性成分は、ポリマー担体または高分子デバイスに共有結合している。
【選択図】図1
Description
(i)反応性部分を含む活性成分を、活性成分の反応性部分と反応可能な少なくとも1つの反応性部分を含むポリマー鎖を含む水溶液またはディスパージョンと混合するステップであり、ポリマー鎖がさらに分子内または分子間で架橋可能である、ステップと;
(ii)ポリマーマトリックスの形成と同時に、活性成分がこのポリマーマトリックス、すなわち形成された高分子ネットワークに封入されるような条件下で、この混合物を架橋に供して、ポリマーマトリックスを形成させるステップ
を含む、方法が見いだされた。ステップ(i)において、ポリマー鎖は、好ましくは互いに相互作用して(本明細書の下記参照のこと)水相にポリマー部分相を形成する。すなわち、比較的ポリマー鎖に富んだ相と比較的にポリマー鎖に乏しい相とが作り出される。最良の形態では、活性成分は、富ポリマー鎖相に存在するのが好まれる。富ポリマー鎖部分相における活性成分の部分局在(sub-location)は、活性成分とポリマー鎖との間の物理的な相互作用によって生じる。ステップ(i)では、活性成分はポリマー鎖と共有結合を形成しない。架橋ステップ(ii)においてのみ、活性成分とポリマー鎖が一緒になり3D-ネットワークを形成する。
(生物)活性化合物は、溶媒中に含めても、または上記ポリマーを溶解した後に添加してもよく、この(生物)活性化合物は、ポリマー溶液中全体に分布されることになる;
次に、この系は、特定の環境(例えば、温度、pH、溶媒)変化を受けることもあり、これにより少なくともポリマーの一部がポリマーの他の部分と異なる挙動を示す状態がもたらされ、クラスター化が起こる;
(生物)活性薬剤の物理的特性により、こうした薬剤は新たに形成されたクラスター化したポリマーの溶液の特定の領域に局在化する;
この局在化の後、架橋が起こって、その好適な領域に(生物)活性化合物が固定される。
(a)in vivoにおける投与の際の、例えば、経口適用、血流への注入または器官もしくは腫瘍への直接注入による、架橋したミセルに封入された(薬物)分子の制御放出;
(b)局所投与の際の、架橋した高分子ミクロスフェアまたはヒドロゲルに封入された薬物および/またはタンパク質の制御放出;および
(c) 封入された薬物分子によるデバイスのコーティングの際の、(薬物)分子の制御放出。これは、感熱性ポリマーの相転移温度を超える温度に保たれている医療用デバイスに氷冷のポリマー水溶液および(有機溶媒の)薬物溶液を二重にスプレーすることなどにより、次いで起こる架橋および溶媒の蒸発の後、架橋したコーティングが形成される。
Claims (20)
- 活性成分を組み入れたポリマーマトリックスを含む制御放出系の調製方法であって、
(i)反応性部分を含む活性成分を、前記活性成分の前記反応性部分と反応可能な少なくとも1つの反応性部分を含むポリマー鎖を含む水溶液またはディスパージョンと混合するステップであり、前記ポリマー鎖がさらに分子内または分子間で架橋可能である、ステップと;
(ii)ポリマーマトリックスの形成と同時に、前記活性成分がこのポリマーマトリックスに共有結合的に封入されるような条件下で、この混合物を架橋に供して、前記ポリマーマトリックスを形成させるステップと
を含む、方法。 - ステップ(i)における前記ポリマー鎖が、連続水相中に富ポリマー鎖相を形成する、請求項1に記載の方法。
- 前記活性成分が、前記水相と比較して前記ポリマー相により高濃度に存在し、好ましくは前記ポリマー相に本質的に存在する、請求項2に記載の方法。
- 前記ポリマー鎖が感熱性ポリマー鎖である、請求項1から3のいずれか一項に記載の方法。
- 前記活性成分が水性環境で混合され、未架橋のポリマー鎖も、最初は下限臨界溶液温度(LCST)未満の温度で存在し、その後、前記LCSTよりも高い温度でステップ(ii)が行われる;または最初は臨界ミセル形成温度(CMT)未満の温度で存在し、その後、前記CMTよりも高い温度でステップ(ii)が行われる、請求項4に記載の方法。
- 前記感熱性ポリマー鎖が、N-ヒドロキシアルキル-(メタ)アクリルアミドまたはN-(メタ)アクリロイルアミノ酸の疎水性修飾エステルをベースとする(コ)ポリマーから選択される、請求項4または5に記載の方法。
- 前記ポリマー鎖が、メタクリル化されている官能基を含み、HPMAm(ヒドロキシプロピルメタクリルアミド)またはHEMAm(ヒドロキシエチルメタクリルアミド)の(オリゴ)乳酸エステルを含む、N-ヒドロキシアルキルメタクリルアミド-オリゴラクテートの(コ)ポリマーなどである、請求項4、5または6のいずれか一項に記載の方法。
- 感熱性ポリマー鎖が、N-イソプロピルアクリルアミドおよび/またはアルキル-2-オキサゾリン由来のモノマーも含む、請求項4から7のいずれか一項に記載の方法。
- 前記感熱性ポリマーをベースとするポリマーを形成するミセル、ヒドロゲル、微粒子および/またはコーティングを用いる、請求項4から8のいずれか一項に記載の方法。
- 前記ポリマーがPEGとのジ-またはトリブロックコポリマーである、請求項9に記載の方法。
- 前記活性成分が、薬物分子、ペプチド、タンパク質、造影剤、遺伝物質またはこれらの化合物の組合せである、請求項1から10のいずれか一項に記載の方法。
- 前記ポリマー鎖および前記活性成分が、重合可能な、特にフリーラジカル重合可能な部分を含む、請求項1から11のいずれか一項に記載の方法。
- 前記重合可能な、特にフリーラジカル重合可能な部分が、末端二重結合、好ましくはビニル基、(メタ)アクリレート基、(メタ)アクリルアミド基を含む;または不飽和化合物、好ましくは炭素-炭素二重結合を含む直鎖である、請求項12に記載の方法。
- 前記重合可能な部分が、分解可能な結合を介して前記活性成分に結合される、請求項13に記載の方法。
- 請求項1から14のいずれか一項に記載の方法により得られるポリマー担体。
- ミセル、ナノ粒子、ミクロスフェア、またはヒドロゲルの形態である、請求項15に記載のポリマー担体。
- 好ましくは親水性ブロックに連結している、疎水性修飾ポリ(N-ヒドロキシアルキル(メタ)アクリルアミド)からなる請求項15または16に記載のポリマー担体。
- 部分的にメタクリル化されたオリゴラクテート単位を有するPEG-b-ポリ(N-ヒドロキシアルキルメタクリルアミド-オリゴラクテート)を含む、請求項17に記載のポリマー担体。
- 活性成分の制御放出のための、請求項15から18のいずれか一項に記載のポリマー担体の使用。
- 薬物送達のための、請求項19に記載の使用。
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