JP2020530865A - 生分解性高分子微粒子の製造方法及びそれにより製造される生分解性高分子微粒子 - Google Patents
生分解性高分子微粒子の製造方法及びそれにより製造される生分解性高分子微粒子 Download PDFInfo
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Abstract
Description
本発明の第2の目的は、前記微粒子製造方法によって製造される生分解性高分子微粒子を提供することである。
本発明の第3の目的は、前記微粒子を用いて高分子フィラーを製造する方法を提供することである。
本発明の第4の目的は、前記微粒子を含む高分子フィラーを提供することである。
1)生分解性高分子を有機溶媒に溶解して、分散相を形成する工程;
2)工程1)で形成された分散相に圧力を加え、分散相にSPG膜(シラス多孔質ガラス膜)の気孔を通過させ、界面活性剤を含む連続相内でエマルションを形成する工程;及び、
3)工程2)で形成されたエマルションから有機溶媒を除去して、微粒子を形成する工程;
を含む生分解性高分子微粒子の製造方法に関するものである。
前記方法によって生分解性高分子微粒子を製造する工程;及び
生分解性高分子微粒子を一つ以上の生体適合性キャリアと混合する工程;
を含む高分子フィラーの製造方法に関する。
前記生分解性高分子微粒子;及び、
一つ以上の生体適合性キャリア;
を含む、高分子フィラーに関する。
本発明の一実施形態では、生分解性高分子微粒子は、以下の特性i)及びii)を満たすことができる:
i)球状(spherical);
ii)粒径10〜200μm。
i)球状(spherical);
ii)粒径10〜200μm;
iii)気孔径0.1〜20μm;
iv)多孔率10〜50%。
スパン値=(D90−D10)/D50
[D10、D50、D90の定義:粒子の累積分布で最大値のそれぞれ10%、50%、90%に対応する値であり、サイズに応じて相対的に累積される粒子の量を曲線で表す粒度分布曲線を測定及び図式化し、10個のフラクションに分割したとき、それぞれ1/10、5/10、9/10に対応する粒子のサイズを求めて表したもの]
多孔率=(多孔性高分子微粒子のボリューム−非多孔性高分子微粒子のボリューム)/多孔性高分子微粒子のボリューム×100
分散相として、数平均分子量45,000のポリ(カプロラクトン)(PCL)5gとテトラデカン1gを塩化メチレン100gに溶解した。15μmの気孔を持つSPG膜(図6参照)をSPG膜乳化装置に結合した。製造された分散相を、SPG膜を通して2kPaの窒素圧下で連続相(2重量%のポリビニルアルコール水溶液)に注入した。この時点で、ポリビニルアルコール水溶液を250rpmの速度で撹拌し、注入完了後、混合物を24時間連続して撹拌した(図5参照)。製造された多孔性PCL微粒子を500mLの蒸溜水中で2時間撹拌して、残留ポリビニルアルコールを洗い流し、微粒子を遠心分離機で回収し、エチルアルコール500mLで2時間洗浄して、残留テトラデカンと塩化メチレンを除去した。洗浄後、多孔性PCL微粒子を真空乾燥機で48時間乾燥して、残留エチルアルコールを除去した。
分散相として、数平均分子量50,000のポリ(カプロラクトン)(PCL)1gとテトラデカン0.2gを塩化メチレン20gに溶解した。15μmの気孔を持つSPG膜(図6参照)をSPG膜乳化装置に結合した。製造された分散相を、SPG膜を通して2kPaの窒素圧下で連続相(2重量%ポリビニルアルコール水溶液)に注入した。この時点で、ポリビニルアルコール水溶液を250rpmの速度で撹拌し、注入完了後、混合物を24時間連続して撹拌した(図5参照)。製造された多孔性PCL微粒子(多孔率:10%)を500mLの蒸溜水中で2時間撹拌して、残留ポリビニルアルコールを洗い流し、微粒子を遠心分離機で回収し、エチルアルコール500mLで2時間洗浄して、残留テトラデカンと塩化メチレンを除去した。洗浄後、多孔性PCL微粒子を真空乾燥機で48時間乾燥して、残留エチルアルコールを除去した。
分散相として、数平均分子量50,000のポリ(カプロラクトン)(PCL)1gとテトラデカン0.3gを塩化メチレン20gに溶解した。15μmの気孔を持つSPG膜(図6参照)をSPG膜乳化装置に結合した。製造された分散相を、SPG膜を通して2kPaの窒素圧下で連続相(2重量%ポリビニルアルコール水溶液)に注入した。この時点で、ポリビニルアルコール水溶液を250rpmの速度で撹拌し、注入完了後、混合物を24時間連続して撹拌した(図5参照)。製造された多孔性PCL微粒子(多孔率:20%)を500mLの蒸溜水中で2時間撹拌して、残留ポリビニルアルコールを洗い流し、微粒子を遠心分離機で回収し、エチルアルコール500mLで2時間洗浄して、残留テトラデカンと塩化メチレンを除去した。洗浄後、多孔性PCL微粒子を真空乾燥機で48時間乾燥して、残留エチルアルコールを除去した。
分散相を2重量%ポリビニルアルコール水溶液にホモジナイザー(Homogenizer)を使用して4000rpmの速度で撹拌しながら迅速に供給し、1分間撹拌した後、250rpmの速度で24時間撹拌したことを除いて、実施例1と実質的に同じ手順に従って多孔性PCL微粒子を製造した。
実施例1で得られた多孔性PCL微粒子と比較例1により得られた多孔性PCL微粒子を走査型電子顕微鏡(SEM)で観察した。その結果をそれぞれ図1及び図2に示した。これらの図から確認できるように、SPG膜乳化法を使用する本発明により、ホモジナイザーを使用する場合と比較して、より小さなサイズ及び狭い粒度分布、即ち、均一な粒径を有する多孔性微粒子を得ることができた。
実施例1で得られた多孔性PCL微粒子と比較例1で得られた多孔性PCL微粒子の粒度分布を粒度分析器で観察した。その結果をそれぞれ図3及び図4に示した。これらの図から確認できるように、実施例1で得られた多孔性PCL微粒子は、比較例1で得られた多孔性PCL微粒子と比較して、著しく狭い粒度分布、即ち、均一な粒径を有していた。粒度分布分析の結果を表1に示した。
前記実施例1〜3でそれぞれ製造された生分解性高分子の多孔性微粒子を、カルボキシメチルセルロース3重量%とグリセリン27重量%及びリン酸緩衝液70重量%から製造されたキャリアと混合することにより、実施例4〜6の高分子フィラー製剤をそれぞれ製造した。このとき、混合比は混合物100重量%基準として、多孔性微粒子30重量%、キャリア70重量%であった。
比較例2としては、PCL原料として使用する市販の顔面用フィラー(Ellanse(登録商標))を購入して使用した。比較例3としては、ポリ(乳酸)(PLA)を原料として使用する市販の顔面用フィラー(Sculptra(登録商標))を購入して使用した。
実施例4〜6及び比較例2及び3の各製剤をシリンジに充填後、無毛マウスの背中に200μLを注射した。注射部位のサイズを測定し、一定の時間で継続的にサイズの変化を測定した。その結果を表2に示した。また、実施例4の高分子フィラーと比較例2の高分子フィラーをマウスに注入した。2週間、注入部位をDSLR(Digital Single Lens Reflex)カメラで撮影した写真を図7に示し、注入部位を3次元撮影した写真を図8に示した。
下記表2に示すように、本発明による生分解性高分子の多孔性微粒子を含むフィラー製剤は、処置後の初期ボリューム減少が一時留守区改善されたことを確認することができる。
Claims (16)
- 1)生分解性高分子を有機溶媒に溶解して、分散相を形成する工程;
2)工程1)で形成された分散相に圧力を加え、分散相にSPG膜(シラス多孔質ガラス膜)の気孔を通過させ、界面活性剤を含む連続相内でエマルションを形成する工程;及び、
3)工程2)で形成されたエマルションから有機溶媒を除去して、微粒子を形成する工程;
を含む生分解性高分子微粒子の製造方法。 - 微粒子が、以下の特性i)及びii)を満たす請求項1に記載の生分解性高分子微粒子の製造方法:
i)球状(spherical);
ii)粒径10〜200μm。 - 分散相が、多孔性微粒子を形成するポロゲン(porogen)をさらに含む請求項1に記載の生分解性高分子微粒子の製造方法。
- 多孔性微粒子が、以下の特性i)〜iv)を満たす請求項3に記載の生分解性高分子微粒子の製造方法:
i)球状(spherical);
ii)粒径10〜200μm;
iii)気孔径0.1〜20μm;
iv)多孔率10〜50%。 - 前記微粒子が、20μmより大きいd10、100μmより小さいd90を有する請求項1に記載の生分解性高分子微粒子の製造方法。
- 微粒子が、1より小さいスパン値を有する請求項1に記載の生分解性高分子微粒子の製造方法。
- SPG膜が、10〜30μm範囲の気孔を有する請求項1に記載の生分解性高分子微粒子の製造方法。
- 分散相に加えられる圧力が、0.1〜10kPa範囲である請求項1に記載の生分解性高分子微粒子の製造方法。
- 界面活性剤の濃度が、0.5〜5重量%範囲である請求項1に記載の生分解性高分子微粒子の製造方法。
- 分散相に溶解する生分解性高分子の濃度が、5〜20重量%範囲である請求項1に記載の生分解性高分子微粒子の製造方法。
- 連続相が100〜500rpm範囲の速度で撹拌される請求項1に記載の生分解性高分子微粒子の製造方法。
- 生分解性高分子が、ポリ(乳酸)、ポリ(グリコール酸)、ポリ(ジオキサノン)、ポリ(カプロラクトン)、乳酸−グリコール酸共重合体、ジオキサノン−カプロラクトン共重合体、乳酸−カプロラクトン共重合体、これらの誘導体及びこれらの共重合体からなる群から選ばれる1種以上である請求項1に記載の生分解性高分子微粒子の製造方法。
- 生分解性高分子が、10,000〜1,000,000g/molの範囲の数平均分子量(Mn)を有する請求項1に記載の生分解性高分子微粒子の製造方法。
- 請求項1〜13のいずれか1項に記載の方法により製造された生分解性高分子微粒子。
- 請求項1〜13のいずれか1項に記載の方法により生分解性高分子微粒子を製造する工程;及び
生分解性高分子微粒子を一つ以上の生体適合性キャリアと混合する工程;
を含む高分子フィラーの製造方法。 - 請求項14に記載の生分解性高分子微粒子;及び
一つ以上の生体適合性キャリア;
を含む高分子フィラー。
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