JP7391978B2 - 塞栓マイクロスフェア及び方法 - Google Patents
塞栓マイクロスフェア及び方法 Download PDFInfo
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- JP7391978B2 JP7391978B2 JP2021544429A JP2021544429A JP7391978B2 JP 7391978 B2 JP7391978 B2 JP 7391978B2 JP 2021544429 A JP2021544429 A JP 2021544429A JP 2021544429 A JP2021544429 A JP 2021544429A JP 7391978 B2 JP7391978 B2 JP 7391978B2
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Description
上記態様と組み合わせて使用できるいくつかの実施形態では、ミクロスフェアは、ビーズブロック(Bead Block)(登録商標)300-500の平均圧縮弾性率の少なくとも5倍の平均圧縮弾性率を有する。
上記態様と組み合わせて使用できるいくつかの実施形態では、300μmを超える浸透値を有するミクロスフェアは10%以下である。
上記態様と組み合わせて使用できるいくつかの実施形態では、80μm未満の浸透値を有するミクロスフェアは5%以下であり、300μmを超える浸透値を有するミクロスフェアは5%以下である。
上記態様と組み合わせて使用できるいくつかの実施形態では、ミクロスフェアは、ビーズブロック(登録商標)300-500の平均圧縮弾性率の少なくとも10倍の平均圧縮弾性率を有する。
上記態様と組み合わせて使用できるいくつかの実施形態では、ポリマーは、ポリビニルアルコールを含有する。
上記態様と組み合わせて使用できるいくつかの実施形態では、ポリマーは放射線不透過性である。
本発明の別の態様は、体重の減少、又は体重の増加の遅延を要する患者において、体重の減少を誘発、又は体重の増加を遅延させる方法に関し、方法は、有効量の上記態様及び実施形態にかかるミクロスフェアの集団、又は有効量の上記態様及び実施形態の任意の1つに係る薬学的組成物を患者の胃底の毛細血管床に送達する工程を含む。
本発明の他の態様は、体重の減少を誘発、又は体重の増加を遅延させる必要のある患者に、体重の減少を誘発、又は体重の増加を遅延させる方法で使用するための上記態様及び実施形態のいずれか1つにかかる組成物に関する。
治療塞栓術は、血管を閉塞して、血流を減速又は停止させて供給された組織の虚血を引き起こすために、経カテーテル経路によって材料を血管に導入する低侵襲的方法である。このアプローチは、肝細胞癌などの血管過多腫瘍の治療や、子宮筋腫などの良性腫瘍の治療に従前より使用されている。
ミクロスフェアの圧縮率(圧縮弾性率)は、血管床の中への浸透の深さに影響を及ぼす。ミクロスフェアの圧縮性が高ければ高いいほど、所定のサイズで血管床内により深く浸透する。ミクロスフェアの圧縮弾性率の測定については、Caine et al(2017)、及びDuran et al(2016)に記載されている。本明細書に記載の測定方法が上記方法から逸脱する範囲については、本明細書に記載の方法に従うものとする。本明細書の例2を参照。
したがって、好ましい態様では、組成物は、100μm未満の直径を有するミクロスフェアが10%以下であり、かつ、200μmを超える直径を有するミクロスフェアが10%以下であるような固有のサイズ分布を有するポリマーミクロスフェアの集団を含有し、ミクロスフェアは、少なくとも1000kPaの平均圧縮弾性率を有する。
第2の態様では、本発明は、ブタ腎臓モデルにおいて、80μm未満の浸透値を有するミクロスフェアが10%以下である、ポリマーミクロスフェアの集団を含有する組成物も提供する。
そのような集団は、第1の態様に関して上記したように、固有のサイズ分布及び圧縮性特性を有する。
親水性ポリマーは、アクリルポリマー、アクリルアミド、アセタール、アリル、ポリアミド、ポリカーボネート、ポリエステル、ポリエーテル、ポリイミド、ポリオレフィン、ポリホスフェート、ポリウレタン、スチレン系、ビニル、多糖類、又はそれらの組み合わせ、及び/又はコポリマーからなる群から選択されてもよい。好ましくは、ポリマーは、ビニルアルコール、エチレン又はプロピレングリコール、アクリレート、メタクリレート、アクリルアミド又はメタクリルアミドから選択されるモノマーを含有する。
(実施例1)ミクロスフェアの調製
架橋したヒドロゲルミクロスフェアは、国際公開第2004/071495号明細書の実施例1(高AMPSの場合)に従って調製した。工程は、生成物を真空乾燥して残留溶媒を除去したあと、ミクロスフェアをふるいにかけて適切なサイズ範囲を形成した後に終了させた。500μm、425μm、355μm、323μm、250μm、212μm及び160μmのふるいを順次使用し、ふるいからミクロスフェアを回収して、使用するサンプル、つまり355~425μm(「304」)、250~323μm(「203」)、及び160~212μm(「102」)を形成した。ビーズは、乾燥状態で保存し、必要に応じて、国際公開第2015/033093号明細書に記載の方法に従って、2,3,5-トリヨードベンズアルデヒドでアセタール化して、放射線不透過性のヨウ素化ミクロスフェアを形成した。
ミクロスフェアの弾性圧縮弾性率(ECM)は、Cain et al(2018)、及びDuran et al(2016)に概説されたプロトコルに従って測定してもよい。Caine et al(2018)は、さまざまな市販のミクロスフェアの圧縮弾性率の値の表も開示している。簡潔に説明すると、ECMは、独自のインデンテーションソフトウェアによって操作されるUNHTバイオインデンターシステム(UNHT Bioindentor system)(アントンパール社(Anton Paar)、スイス)を使用して、0.01~20mNの力範囲と、1nm~100μmの変位範囲で決定した。ミクロスフェアのサンプルは、皿に分散させて、通常の生理食塩水に沈めた。機器の光学顕微鏡を用いて個々のミクロスフェアを選択し、それらの直径を最も近い1μmまで測定した(5倍の倍率で)。個々のミクロスフェアを50μm/minで圧縮し、5秒間休止した後、サンプルを50μm/minで脱負荷(unloaded)させた。取得(Acquisition)は20Hzに設定した。各ビーズの弾性率は、2つの平坦な表面間で圧縮された球の場合に線形弾性ヘルツ接触力学(Hertzian contact mechanics)を適用することによって、荷重曲線から計算し、10~15%の個々のビーズ直径圧縮範囲でn=5の反復の算術平均として得た。
以下の手順に従って、体重約30kgの雌ヨークシャーブタの腎動脈に塞栓を形成した。
放射線不透過性の102ミクロスフェア(95mg/mL ヨウ素)を、健康で発育中のブタ(~32kg)の左胃大網動脈と、右胃動脈とに注入した。これらの2つの動脈は胃底に供給する。ミクロスフェアは、非イオン性造影剤で1:10に希釈して送達した。3匹の比較ブタに生理食塩水を注入して偽の処置を行った。
市販の放射線不透過性ミクロスフェア(ディーシービーズルミ(登録商標)公称サイズ40-90μm及び公称サイズ100-300μm-バイオコンパチブルズUK社)を使用して実施例4を行った。これらの製品のそれぞれでは、100μm未満のミクロスフェアは10%以上であった。
(参照文献)
Arepally et al(2007)Radiology、244:138 -143
Bawudun et al(2012)Cardiovasc. Intervent. Radiol. 35:1460-1466。
Duran et al(2016)Theranostics 6(1): 28-39
Fu et al(2018)Radiology 289(1):83-89。
McGavin et al(2015)International Journal of Obesity volume 39、pages 447-455。
Paxton et al(2014). Vasc. Interv. Radiol. 25: 455-461。
Saad et al(2002)JJ. Clin. Endocrinol. Metab.87: 3997-4000。
Weiss et al(2014)Presented at the 30th Annual Scientific Meeting of the European Society of Interventional Radiology; Glasgow, UK. 9月13-17日。
Claims (24)
- 胃底部における治療塞栓術に用いられる組成物であって、ポリマーからなるポリマーミクロスフェアの集団を含み、前記ポリマーミクロスフェアの集団は120μm未満の直径を有するミクロスフェアが10%以下であり、かつ、200μmを超える直径を有するミクロスフェアが10%以下である、固有のサイズ分布を有しており、前記ミクロスフェアは1000kPaを超える平均圧縮弾性率を有し、前記ポリマーはポリヒドロキシル化ポリマーを含み、且つ前記ポリマーに共有結合した、沈降ミクロスフェア1mLあたり70~150mgのヨウ素を含有する、治療塞栓術に用いられる組成物。
- 前記ミクロスフェアは、100μm未満の直径を有するミクロスフェアが5%以下であり、かつ、200μmを超える直径を有するミクロスフェアが5%以下である、固有のサイズ分布を有する、請求項1に記載の組成物。
- 前記ミクロスフェアは、120μm未満の直径を有するミクロスフェアが5%以下であり、かつ、185μmを超える直径を有するミクロスフェアが10%以下であるような固有のサイズ分布を有する、請求項1に記載の組成物。
- ブタ腎臓モデルにおいて、前記ミクロスフェアの10%以下は、80μm未満の浸透値を有する、請求項1~3のいずれか一項に記載の組成物。
- 前記ミクロスフェアの10%以下は、ブタ腎臓モデルにおいて、300μmを超える浸透値を有する、請求項1~3のいずれか一項に記載の組成物。
- 前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、80μm未満の浸透値を有し、かつ、前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、300μmを超える浸透値を有する、請求項1~3のいずれか一項に記載の組成物。
- 前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、90μm未満の浸透値を有し、かつ、前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、250μmを超える浸透値を有する、請求項1~3のいずれか一項に記載の組成物。
- 胃底部における治療塞栓術に用いられる組成物であって、ポリマーからなるポリマーミクロスフェアの集団を含有し、ブタ腎臓モデルでは、前記ミクロスフェアの10%以下は、80μm未満の浸透値を有し、前記ポリマーミクロスフェアの集団は、120μm未満の直径を有するミクロスフェアが10%以下であり且つ200μmを超える直径を有するミクロスフェアが10%以下である、固有のサイズ分布を有し、前記ミクロスフェアは1000kPaを超える平均圧縮弾性率を有し、前記ポリマーはヒドロゲルであり且つポリヒドロキシル化ポリマーを含有する、治療塞栓術に用いられる組成物。
- 前記ミクロスフェアの10%以下は、ブタ腎臓モデルにおいて、300μmを超える浸透値を有する、請求項8に記載の組成物。
- 前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、80μm未満の浸透値を有し、前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、300μmを超える浸透値を有する、請求項8に記載の組成物。
- 前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、90μm未満の浸透値を有し、前記ミクロスフェアの5%以下は、ブタ腎臓モデルにおいて、250μmを超える浸透値を有する、請求項8に記載の組成物。
- 前記ミクロスフェアは、120μm未満の直径を有するミクロスフェアが5%以下であり、かつ、185μmを超える直径を有するミクロスフェアが10%以下であるような固有のサイズ分布を有する、請求項8~11のいずれか一項に記載の組成物。
- 前記ポリマーは、ポリビニルアルコールを含有する、請求項1~12のいずれか一項に記載の組成物。
- 前記ポリマーは、画像化可能である、請求項1~13のいずれか一項に記載の組成物。
- 前記ポリマーは、放射線不透過性である、請求項1~14のいずれか一項に記載の組成物。
- 前記ポリマーは、ポリマーに共有結合した、沈降ミクロスフェア1mLあたり85~120mgのヨウ素を含む、請求項1~15のいずれか一項に記載の組成物。
- 前記ポリマーは、ポリマーに共有結合した、沈降ミクロスフェア1mLあたり90~110mgのヨウ素を含む、請求項1~16のいずれか一項に記載の組成物。
- 前記ポリマーは、共有結合したペンダント型ヨウ素化芳香族基を含む、請求項1~17のいずれか一項に記載の組成物。
- 前記ポリマーは、共有結合したペンダント型ヨウ素化フェニル基を含む、請求項1~18のいずれか一項に記載の組成物。
- 請求項1~19のいずれか一項に記載の組成物、及び薬学的に許容される希釈剤を含む、胃底部における治療塞栓術に用いられる医薬組成物。
- 体重の減少の誘発、又は体重の増加の遅延を必要とする患者に体重の減少を誘発、又は体重の増加を遅延させる方法で用いられる、請求項1~19のいずれか一項に記載の組成物。
- 体重の減少の誘発、又は体重の増加の遅延を必要とする患者に体重の減少を誘発、又は体重の増加の遅延させる方法で用いられる、請求項20に記載の医薬組成物。
- 肥満治療用の方法で用いられる、請求項1~19のいずれか一項に記載の組成物。
- 肥満治療用の方法で用いられる、請求項20に記載の医薬組成物。
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