JP2021532911A - 薬物送達システムとしてのビーズ不織布膜 - Google Patents
薬物送達システムとしてのビーズ不織布膜 Download PDFInfo
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- JP2021532911A JP2021532911A JP2021505852A JP2021505852A JP2021532911A JP 2021532911 A JP2021532911 A JP 2021532911A JP 2021505852 A JP2021505852 A JP 2021505852A JP 2021505852 A JP2021505852 A JP 2021505852A JP 2021532911 A JP2021532911 A JP 2021532911A
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Abstract
Description
本出願は、2018年8月3日に提出された欧州特許出願第18382589.2号の利益を主張する。
−ナノファイバは、ナノファイバの長さに沿って分布し且つナノファイバの平均直径の1.5〜20倍の平均直径を有するビーズを含み、
−活性剤は、33mg/mL以下の水溶性を有し、
−活性剤の全量は、膜内に物理的に閉じ込められているが、膜のポリマーナノファイバの外部に配置されている、ビーズ不織布膜に関する。
a)適切な溶媒系中の1つまたは複数のポリマーの溶液を調製するステップと、
b)特にステップa)からのポリマー(複数可)が不溶性である適切な溶媒系中の活性剤の溶液または懸濁液を調製するステップと、
c)ステップa)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ステップb)の溶液または懸濁液をポリマーナノファイバ上に堆積させるステップと、
d)任意選択で、ステップc)から得られた不織布膜を乾燥させるステップと、
を含む製造方法に関する。
a)適切な溶媒系中の1つまたは複数のポリマーの溶液を調製するステップと、
b)特にステップa)からのポリマー(複数可)が不溶性である適切な溶媒系中の活性剤の溶液または懸濁液を調製するステップと、
c)ステップa)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ステップb)の溶液または懸濁液をポリマーナノファイバ上に堆積させるステップと;
d)任意選択で、ステップc)から得られた不織布膜を乾燥させるステップと、
を含む方法によって調製され得る。
a)界面活性剤を任意選択で含む適切な溶媒系中の1つまたは複数のポリマーの溶液を調製するステップと;
b)界面活性剤を任意選択で含む適切な溶媒系中の活性剤の溶液または懸濁液を調製するステップであって、特にステップa)からのポリマー(複数可)が不溶性である、ステップと;
c)ステップa)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ステップb)の溶液または懸濁液をポリマーナノファイバ上に堆積させるステップと;
d)任意選択で、ステップc)から得られた不織布膜を乾燥させるステップと、
を含む。
A)界面活性剤を任意選択で含む適切な溶媒系中の1つまたは複数のポリマーの第1の溶液を調製するステップと;
B)ステップa)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバの第1の層を生成するステップと;
C)適切な溶媒系中に界面活性剤を任意選択で含む1つまたは複数のポリマーの第2の溶液を調製するステップと;
D)界面活性剤を任意選択で含む適切な溶媒系、特に工程a)からの1つまたは複数のポリマーが不溶性である適切な溶媒系中の活性剤の溶液または懸濁液を調製するステップと;
E)ステップC)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ポリマーナノファイバおよび活性剤の第2の層が第1の層上に堆積されるように、ポリマーナノファイバ上にステップD)の溶液または懸濁液を堆積させるステップと;
F)界面活性剤を任意選択で含む適切な溶媒系中の1つまたは複数のポリマーの第3の溶液を調製するステップと;
G)ステップF)からの溶液のエレクトロスピニングを実行して、第2の層の上に堆積されるビーズポリマーナノファイバの第3の層を生成するステップと;
E)任意選択で、ステップG)から得られたビーズ不織布膜を乾燥させるステップと、
を含む。
a)適切な溶媒系中の1つまたは複数のポリマーの溶液を調製するステップと;
b)特にステップa)からのポリマー(複数可)が不溶性である適切な溶媒系中の活性剤の溶液または懸濁液を調製するステップと;
c)ステップa)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ステップb)の溶液または懸濁液をポリマーナノファイバ上に堆積させるステップと;
d)任意選択で、ステップc)から得られた不織布膜を乾燥させるステップと、
を含む方法により得ることができるビーズ不織布膜も本発明の一部を形成する。
SN−38(4mg)を、酢酸緩衝液、pH5、15mLに撹拌しながら懸濁させた。
エレクトロスピニングされたPLGAナノファイバの3つの層(連続して堆積された第1の薬物不含層、第2の薬物担持層、および第3の薬物不含層)を含むビーズ不織布膜を調製した。
PLGAを溶解するために使用された溶媒がジオキサン/アセトン(40%/60%w/w)の混合物であり、ポリマー濃度が16%w/wであったことを除いて、実施例1で説明されたのと同じ手順に従ってビーズ不織布膜を調製した。
PLGAの代わりにPLA(高分子量)が使用され、PLAの溶解に使用された溶媒がジクロロメタンであり、ポリマー濃度が10%w/wであったことを除いて、実施例1で説明されたのと同じ手順に従ってビーズ不織布膜を調製した。
比較例のビーズ不含不織布膜を、PCT出願WO2013144206に従って調製した。簡単に説明すると、HFIP中のPLGAの濃度が実施例1で使用された7%ではなく8.4%w/wであったことを除いて、実施例1で説明されたのと同じ手順に従ってビーズ不含不織布膜を調製した。濃度の増加により、非ビーズ膜が生成された。
本発明による実施例1のビーズ不織布膜および比較例4のビーズ不含不織布膜の収縮挙動を比較した。
異なる収縮度を有するSN−38が担持された不織布膜1〜3の活性剤のインビトロ薬物放出を比較した。溶出試験装置SOTAX、モデル:AT 7Smartを使用して、リン酸緩衝生理食塩水(Phosphate Buffered Saline:PBS)バッファーpH7.4、37℃中で75rpmで撹拌しながら放出を評価した。媒体の体積は200mLであり、薬物の溶解度が低いため、1、2、3、4および7日目に交換した。
溶出試験装置SOTAX、モデル:AT 7Smartを使用して、リン酸緩衝生理食塩水(PBS)バッファーpH7.4、37℃中で75rpmで撹拌しながら、実施例1で得られたビーズ膜のインビトロ放出を評価した。媒体の体積は200mLであり、薬物の溶解度が低いため、1、2、3、4および7日目に交換した。その上、約10%の収縮を示すビーズ膜(表1の膜3に類似した膜)および約30%の収縮を示す非ビーズ膜(表1の膜2に類似した膜)に対しても、上記条件での比較放出アッセイを行った。
−WO2013144206
−US2018000744
−Seeram Ramakrishnaら:「Advances in drug delivery via electrospun and electrosprayed nanomaterials」、International Journal of Nanomedicine 2013、2997ページ
−CN105386155
−CN107675364
−CN106727447
a)適切な溶媒系中の1つまたは複数のポリマーの溶液を調製するステップと、
b)ステップa)からのポリマー(複数可)が不溶性である適切な溶媒系中の活性剤の溶液または懸濁液を調製するステップと、
c)ステップa)からの溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ステップb)の溶液または懸濁液をポリマーナノファイバ上に堆積させるステップと;
d)任意選択で、ステップc)から得られた不織布膜を乾燥させるステップと、
を含む製造方法。
Claims (15)
- ポリマーナノファイバおよび少なくとも1種の活性剤を含むビーズ不織布膜であって、
−前記ナノファイバは、前記ナノファイバの長さに沿って分布し且つ前記ナノファイバの平均直径の1.5〜20倍の平均直径を有するビーズを含み、
−前記活性剤は、33mg/mL以下の水溶性を有し、
−前記活性剤の全量は、前記膜内に物理的に閉じ込められているが、前記膜のポリマーナノファイバの外部に配置されている、
ビーズ不織布膜。 - 前記ビーズは、2〜25μmの平均直径を有する、請求項1に記載のビーズ不織布膜。
- 前記ビーズの量は、500〜5000ビーズ/mm2である、請求項1または2に記載のビーズ不織布膜。
- 界面活性剤をさらに含む、請求項1から3のいずれか一項に記載のビーズ不織布膜。
- 本発明の前記不織布膜に含まれる活性剤は、0.1〜20μmの平均粒子サイズを有する粒子の形態で存在する、請求項1から4のいずれか一項に記載のビーズ不織布膜。
- 治療薬の量は、前記不織布膜の総重量に対して0.01〜20重量%である、請求項1から5のいずれか一項に記載のビーズ不織布膜。
- 前記活性剤が可溶化される適切な量の媒体と前記膜を接触させたときに、37℃の水中で72時間において、20%以下の線形収縮度を有する、請求項1から6のいずれか一項に記載のビーズ不織布膜。
- 前記膜を前記活性剤が可溶化される適切な量の媒体と接触させた後、前記膜は、前記ポリマーナノファイバの分解時間の50%以下の期間に、前記活性剤の総重量の80%以上の量を放出することができる、請求項7に記載のビーズ不織布膜。
- 前記膜のポリマーナノファイバは、50〜2000nmの平均直径を有する、請求項1から8のいずれか一項に記載のビーズ不織布膜。
- 前記ポリマーナノファイバは、ポリグリコール酸(PGA)、ポリD,L−乳酸(PLA)、ポリ−L−乳酸(PLLA)、ポリ−D,L−ラクチド−co−グリコリド(PLGA)、ポリカプロラクトン(PCL)、ポリエチレングリコール(PEG)、ポリジオキサノン(PDO)、ポリビニルアルコール(PVA)、コラーゲン、セルロース、ヒアルロン酸、ポリアミド、ポリエステル、ポリウレタン、ポリプロピレン、エラスタン、シルク、およびそれらの組み合わせからなる群から選択される1つまたは複数のポリマーで作製される、請求項1から9のいずれか一項に記載のビーズ不織布膜。
- 前記ポリマーナノファイバは、ポリグリコール酸(PGA)、ポリD,L−乳酸(PLA)、ポリ−L−乳酸(PLLA)、ポリ−D,L−ラクチド−co−グリコリド(PLGA)、ポリカプロラクトン(PCL)、ポリエチレングリコール(PEG)、シルク、およびそれらの組み合わせからなる群から選択される1つまたは複数のポリマーで作製される、請求項10に記載のビーズ不織布膜。
- ポリマーナノファイバを含む第1の層と、ポリマーナノファイバおよび少なくとも1種の活性剤を含む第2の層と、ポリマーナノファイバを含む第3の層と、を少なくとも含む、請求項1から11のいずれか一項に記載のビーズ不織布膜。
- 前記活性剤は、化学療法剤;栄養補助食品;抗生物質または抗真菌剤;タンパク質;細胞、免疫療法剤、抗感染剤、内分泌剤および心臓血管剤からなる群から選択される治療剤である、請求項1から12のいずれか一項に記載のビーズ不織布膜。
- 請求項1から13のいずれか一項に記載のビーズ不織布膜の製造方法であって、
a)適切な溶媒系中の1つまたは複数のポリマーの溶液を調製するステップと、
b)適切な溶媒系中の前記活性剤の溶液または懸濁液を調製するステップと、
c)ステップa)からの前記溶液のエレクトロスピニングを実行して、ビーズポリマーナノファイバを生成し、同時に、ステップb)の前記溶液または懸濁液を前記ポリマーナノファイバ上に堆積させるステップと;
d)任意選択で、ステップc)から得られた前記不織布膜を乾燥させるステップと、
を含む製造方法。 - バイタル血管を有する切除不能な領域を含む腫瘍の処置;腫瘍の残留物が残っている外科的境界の処置;腫瘍浸潤もしくは陽性骨スキャンを伴う骨組織の処置;または組織再生;に使用するための、請求項1から13のいずれか一項に記載のビーズ不織布膜であって、前記活性剤は化学療法剤である、ビーズ不織布膜。
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CN105386155A (zh) * | 2015-12-10 | 2016-03-09 | 华侨大学 | 一种担载紫杉醇的串珠状纳米纤维及其制备方法 |
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CN112512514A (zh) | 2021-03-16 |
FI3829549T3 (fi) | 2023-01-13 |
PT3829549T (pt) | 2022-12-27 |
US20210154151A1 (en) | 2021-05-27 |
EP3829549B1 (en) | 2022-10-12 |
JP7389105B2 (ja) | 2023-11-29 |
HRP20221534T1 (hr) | 2023-03-17 |
ES2935179T3 (es) | 2023-03-02 |
EP3829549A1 (en) | 2021-06-09 |
CN112512514B (zh) | 2024-04-23 |
WO2020025793A1 (en) | 2020-02-06 |
PL3829549T3 (pl) | 2023-03-20 |
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