JP6900416B2 - コア−シェル生分解性粒子の製造方法 - Google Patents
コア−シェル生分解性粒子の製造方法 Download PDFInfo
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- JP6900416B2 JP6900416B2 JP2019062736A JP2019062736A JP6900416B2 JP 6900416 B2 JP6900416 B2 JP 6900416B2 JP 2019062736 A JP2019062736 A JP 2019062736A JP 2019062736 A JP2019062736 A JP 2019062736A JP 6900416 B2 JP6900416 B2 JP 6900416B2
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
粒子は、対象体の体内管腔(例えば、動脈等の血管、リンパ管等)に投与されると、投与の時点から、投与の約1週間後から投与の約4週間後までの任意の範囲にある、治療剤の放出が停止する時点である第1の時点まで、治療剤が放出されるように構成されている。例えば、治療剤の放出が停止する第1の時点は、投与の1週間後から、2週間後まで、3週間後まで、最大4週間後までの任意の範囲であってよい。
本明細書中に定義されているように、完全に分解した時点とは、粒子の初期重量(つまり、注入時点での重量)に比べて、少なくとも95重量%の粒子の分解が生じた時点である。
α−アミノ酸部分の例には、式(I)
ある実施形態では、本明細書で使用するためのAA−PEAは、1つ又は複数の式(VIII)
「治療剤」、「生物活性剤」、「薬物」、「薬学的活性剤」、「薬学的活性材料」、及び他の関連用語は、本明細書では同義的に使用することができ、遺伝子治療剤、非遺伝子治療剤、及び細胞を含む場合がある。多種多様な疾患及び症状を治療(つまり、疾患若しくは症状の予防、疾患若しくは症状に関連する症候の軽減若しくは解消、又は疾患若しくは症状の実質的な若しくは完全な解消)するために使用されるものを含む多数の治療剤を、本開示と共に使用することができる。多数の治療剤が、本明細書に記載されている。
更なる治療剤には、浸透圧ストレスを生成する作用剤(例えば、塩等)を含む、化学アブレーション剤(本開示の製剤に有効量で含有させると、注入の際に近くの組織のネクローシス又は退縮をもたらす物質)が含まれる。化学アブレーション剤の具体的な例には、数ある作用剤の中でも特に以下のものが含まれ、好適な作用剤をそれらから選択することができる:塩基性作用剤(例えば、水酸化ナトリウム、水酸化カリウム等)、酸性作用剤(例えば、酢酸、ギ酸等)、酵素(例えば、コラゲナーゼ、ヒアルロニダーゼ、プロナーゼ、パパイン等)、フリーラジカル生成剤(例えば、過酸化水素、過酸化カリウム等)、他の酸化剤(例えば、次亜塩素酸ナトリウム等)、組織固定剤(例えば、ホルムアルデヒド、アセトアルデヒド、グルタルアルデヒド等)、血液凝固剤(例えば、ゲングピン(gengpin)等)、非ステロイド系抗炎症薬、避妊薬(例えば、デソゲストレル、エチニルエストラジオール、エチノジオール、二酢酸エチノジオール、ゲストデン、リネストレノール、レボノルゲストレル、メストラノール、メドロキシプロゲステロン、ノルエチンドロン、ノルエチノドレル、ノルゲスチメート、ノルゲストレル等)、GnRHアゴニスト(例えば、ブセレリン、セトレリクス、デカペプチル、デスロレリン、ジオキサラン誘導体、ユーレキシン(eulexin)、ガニレリクス、ゴナドレリン塩酸塩、ゴセレリン、酢酸ゴセレリン、ヒストレリン、酢酸ヒストレリン、ロイプロリド、酢酸ロイプロリド、リュープロレリン、ルトレリン、ナファレリン、メテレリン、トリプトレリン等)、抗プロゲストゲン(例えば、ミフェプリストン等)、選択的プロゲステロン受容体修飾因子(SPRM)(例えば、アソプリスニル等)、上述のものの種々の薬学的に許容される塩及び誘導体、並びに上述のものの組み合わせ。
そのような構造は、例えば以下の文献で説明されている技術の1つを使用して達成することができる:K.K.Kim及びD.W.Pack(2006年)“Microspheres for Drug Delivery”、BioMEMS、及びBiomedical Nanotechnology 第1巻:Biological and Biomedical Nanotechnology、(M.Ferrari、A.P.Lee、及びL.J.Lee編)、19〜50頁、Springer、New York。
本開示の粒子組成物は、例えば水性懸濁液として、湿潤形態で保管及び輸送することができる(例えば、酵素的に分解可能であるが、酵素の非存在下では加水分解安定性を示すAA−PEAが知られている)。また、本開示の粒子組成物は、無菌乾燥形態で保管及び輸送することができる。また、上述のポリマー、治療剤、及び任意の造影剤、及び任意の磁性/常磁性/強磁性材料に加えて、湿潤又は乾燥組成物は、例えば、下記の1つ又は複数から選択される追加の作用剤を任意に含んでいてもよい:(a)特に、糖(例えば、デキストロース、ラクトース等)、多価アルコール(例えば、グリセロール、プロピレングリコール、マンニトール、ソルビトール等)、及び無機塩(例えば、塩化カリウム、塩化ナトリウム等)等の等張化剤、(b)特に、種々の界面活性剤、湿潤剤、及びポリマー(例えば、アルブミン、PEO、ポリビニルアルコール、ブロックコポリマー等)を含む懸濁剤、及び(c)特に、種々の緩衝液溶質を含むpH調節剤。
実施例1:マイクロ流体システムを使用したコア−シェル粒子の調製。
マイクロ流体二重Tチャネルデバイスを、Brian N.Johnson、“Creation and Application of PDMS Microfluidic Devices”、National Nanotechnology Infrastructure Network(NNIN)Lurie Nanofabrication Facility(LNF)、University of Michigan、2009年6月11日、23頁の記載に従った方法により、ポリジメチルシロキサン(PDMS、SYLGARD(登録商標)184 シリコーンエラストマーキット、ダウコーニング社、米国ミシガン州ミッドランド)を使用して製造する。デバイスは、直径10μmの中央入口チャネル及びT字状分岐部での直径が10μmである第1の複数のサイドチャネル、並びに出口直径が40μmである出口チャネルを備える第1のT字状分岐構造を含む。この出口チャネルは、二次T字状分岐部での直径が10μmである第2の複数のサイドチャネル及び130μmの出口直径を備える二次T字状分岐構造に供給される。硬化させ、取り出したPDMS構造を、両表面にプラズマ酸化工程を施した後、アクリル板に密着させる。密着させたマイクロ流体デバイスを、テフロン(登録商標)チューブにより、2つのデュアルデジタル制御シリンジポンプ(Fusion 100 Touch、デュアルシリンジ点滴専用ポンプ、KRアナリティカル(KR Analytical)社、英国チェシャー サンドバック)に接続する。水溶性ポリ(エステル−アミド)(Hybrane H/S80 1700、ポリマーファクトリースウェーデン社(Polymer Factory Sweden AB)、スウェーデン ストックホルム)の第1の溶液を、40mg/mlの濃度で調製する。第2の溶液については、ポリ(エステル−アミド)(Hybrane D2800、ポリマーファクトリースウェーデン社、スウェーデン ストックホルム)を、窒素雰囲気下で少なくとも4時間ジクロロメタンに溶解して、およそ40mg/mlのポリエステルアミド溶液を得る。この溶液に、10%w/wの量のパクリタキセル(溶解PEAの重量に対して)を添加する。図6に模式的に示されているように、Hybrane H/S80 1700溶液を、一次T字状分岐部の中央チャネル610から、1ml/時間の速度で注入する。第2の溶液(Hybrane D−パクリタキセル)を、一次T字状分岐部の2つのサイドチャネル620に、2ml/時間の速度で注入する。ポリビニルアルコール(PVA;1.0%w/w、MW=6000、ポリサイエンシーズ・ヨーロッパ社(Polysciences Europe GmbH)、独国)を含有するTris緩衝液(pH=8.5、0.2M、シグマ・アルドリッチ社、米国)の水溶液(Millipore、脱イオン化)を、二次T字状分岐部の2つのサイドチャネル625に、4ml/時間の速度で導入する。PVAは、粒子の凝集を回避するための界面活性剤として作用する。PEA液滴を含む液体を、サイドチャネル625に導入したのと同じ水溶液の10mlの初期量を含有するフラスコに収集する。30分後、プロセスを停止させ、フラスコを回転減圧蒸発器(ハイドルフインスツルメンツ社(Heidolph Instruments GmbH)、独国シュヴァーバッハ)に導入して、減圧(9.3Pa(70mTorr))下で室温にて30分間ジクロロメタン溶媒を除去する。ジクロロメタンを除去した後、固化微粒子(PEAコア及びPEA/パクリタキセルシェルを有する)を、50mL円錐管(ベクトン・ディッキンソン アンド カンパニー社、米国ニュージャージー州フランクリンレイクス)に収集し、遠心分離にかけ(1500rpm、5分間)、脱イオン水(30mL)で3回すすいで、過剰PVAを除去する。その後、粒子懸濁液を液体窒素中で急速凍結し、減圧下で凍結乾燥して水相を除去する。およそ15cm/sの平均速度で出口チャネルを通過し、およそ43マイクロメートルのサイズを有する粒子が毎時約80mg得られ、これはおよそ毎秒600個のビーズを含有する。
二重液体供給スプレーノズル(ソノテックコーポレーション、米国ニューヨーク州ミルトン)を、円形フラスコ(ハイドルフインスツルメンツ社、独国シュヴァーバッハ)内部の入口から垂直に5cmのところに取り付ける。フラスコには、ポリビニルアルコール(PVA;1.0%w/w、MW=6000、ポリサイエンシーズ社、独国)を含有するTris緩衝液(pH=8.5、0.2M、シグマ社)の20ml水溶液(Millipore、脱イオン化)を、事前に入れておく。二重供給スプレーノズルを、2つのシリンジポンプ(ソノテック、997型シリンジポンプ)に接続し、ノズルは、35kHzの周波数に設定した精密超音波発生器(Precision Ultrasonic Generator)(ソノテック)に接続されている。ポリ(エステル−アミド)(Hybrane D2800、ポリマーファクトリースウェーデン社、スウェーデン ストックホルム)の第1の溶液(溶液A)を、窒素雰囲気下で少なくとも4時間ジクロロメタンに溶解して、およそ10重量%のポリエステルアミド溶液を得る。この溶液に、10%w/wの量のパクリタキセル(溶解PEAの重量に対して)を添加する。ポリ(エステル−アミド)(Hybrane D1500、ポリマーファクトリースウェーデン社、スウェーデン ストックホルム)の第2の溶液(溶液B)を、窒素雰囲気下で少なくとも4時間ジクロロメタンに溶解して、およそ10重量%の溶液を得る。溶液Aを1ml/分の速度でスプレーノズルの外側オリフィスに、溶液Bを0.8ml/分の速度で内側入口に供給する。得られる液滴サイズは、およそ80μmである。10分後、プロセスを停止させ、フラスコを、回転減圧蒸発器(ハイドルフインスツルメンツ社、独国シュヴァーバッハ)に導入して、減圧(9.3Pa(70mTorr))下で室温にて30分間ジクロロメタン溶媒を除去する。ジクロロメタンを除去した後、PEAコア及びPEA−パクリタキセルシェルを有する固化微粒子を、50mL円錐管(ベクトン・ディッキンソン アンド カンパニー社、米国ニュージャージー州フランクリンレイクス)に収集し、遠心分離にかけ(1500rpm、5分間)、脱イオン水(30mL)で3回すすいで、過剰PVAを除去した。その後、粒子懸濁液を液体窒素中で急速凍結し、減圧下で凍結乾燥して連続水相を除去する。
実施例2の装置を使用するが、ただし、溶液A(PEA+薬物)のシリンジを、SonicSyringe(商標)超音波式分散シリンジ(Ultrasonic Dispersion Syringe)(ソノテック)と取り替える。PEGでコーティングされた水中磁性酸化鉄ナノ結晶(20nm)(MKN−IOW−PEG−020)を、MKナノ(MKnano)社、カナダ ミシサガから入手する。ナノ粒子溶液を、60℃で3日間乾燥する。乾燥試料を、音波槽中で15分間超音波処理し、その後ジクロロメタンに再分散して、0.1mg/mlの濃度にする。この溶液を、実施例2で使用した溶液Aに、1:1の比率で添加した。プロセスの設定は、実施例2と同様である。
Claims (15)
- コア−シェル生分解性粒子の製造方法であって、
(a)共軸三重ノズルを用いて、内側から順にコア溶液、シェル溶液、及び非溶媒担体を同時に射出することによりコア−シェル生分解性粒子を形成するか、又は
(b)共軸三重ノズルを用いて、内側から順にコア溶液、シェル溶液、及び非溶媒担体を同時に射出するか、又は、共軸二重ノズルを用いてコア溶液及びシェル溶液を非溶媒担体中に射出することにより、コア−シェル生分解性粒子を形成し、さらにレーザードリルにより、コア−シェル生分解性粒子に開口部を形成することを含み、
前記コア溶液は、溶解した生分解性ポリマー及び適切な溶媒を含み、前記シェル溶液は、溶解した生分解性ポリマー及び適切な溶媒を含み、前記コア溶液又は前記シェル溶液のいずれか一方が治療剤を更に含む、方法。 - コア−シェル生分解性粒子は、共軸三重ノズルを用いて、内側から順にコア溶液、シェル溶液、及び非溶媒担体を同時に射出することにより形成される、請求項1に記載の方法。
- コア−シェル生分解性粒子は、共軸二重ノズルを用いてコア溶液及びシェル溶液を非溶媒担体中に射出することにより形成される、請求項1に記載の方法。
- 前記コア溶液が造影剤を更に含む、請求項1〜3のいずれか一項に記載の方法。
- 前記コア溶液が磁性材料、常磁性材料、又は強磁性材料を更に含む、請求項1〜4のいずれか一項に記載の方法。
- 前記コア溶液が、クロロホルム、ジクロロメタン、及びテトラヒドロフランのうちから選択される溶媒を含む、請求項1〜5のいずれか一項に記載の方法。
- 前記シェル溶液が造影剤を更に含む、請求項1〜6のいずれか一項に記載の方法。
- 前記シェル溶液が、磁性材料、常磁性材料、又は強磁性材料を更に含む、請求項1〜7のいずれか一項に記載の方法。
- 前記シェル溶液が、クロロホルム、ジクロロメタン、及びテトラヒドロフランのうちから選択される溶媒を含む、請求項1〜8のいずれか一項に記載の方法。
- 前記コア溶液は前記シェル溶液よりも粘性が高いか、又はその逆である、請求項1〜9のいずれか一項に記載の方法。
- 前記シェル溶液は前記コア溶液よりも粘性が高い、請求項1〜9のいずれか一項に記載の方法。
- コア及びシェルは不混和性溶媒を用いて形成される、請求項1〜11のいずれか一項に記載の方法。
- 前記治療剤がパクリタキセルである、請求項1〜12のいずれか一項に記載の方法。
- レーザードリルにより、コア−シェル生分解性粒子に開口部を形成する工程を含む、請求項1〜13のいずれか一項に記載の方法。
- コア−シェル生分解性粒子を凍結乾燥させる工程を更に含む、請求項1〜14のいずれか一項に記載の方法。
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JP2019062736A Active JP6900416B2 (ja) | 2012-05-30 | 2019-03-28 | コア−シェル生分解性粒子の製造方法 |
JP2021100226A Pending JP2021138767A (ja) | 2012-05-30 | 2021-06-16 | コア−シェル生分解性粒子の製造方法 |
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JP2017247698A Pending JP2018044016A (ja) | 2012-05-30 | 2017-12-25 | 治療剤制御放出用の注射可能な生分解性の塞栓粒子 |
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EP (1) | EP2854890B1 (ja) |
JP (4) | JP2015512422A (ja) |
CN (1) | CN104271171A (ja) |
CA (1) | CA2866330A1 (ja) |
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---|---|---|---|---|
BR112016005770B1 (pt) | 2013-09-19 | 2021-07-27 | Terumo Corporation | Partículas de polímero |
EP3046956B1 (en) | 2013-09-19 | 2019-08-28 | Microvention, Inc. | Polymer films |
KR102287781B1 (ko) | 2013-11-08 | 2021-08-06 | 테루모 가부시키가이샤 | 중합체 입자 |
JP6280996B2 (ja) * | 2014-02-14 | 2018-02-14 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | 治療剤の放出を伴う急速分解性塞栓粒子および同塞栓粒子を含む医療用組成物 |
CA2969171C (en) * | 2014-12-18 | 2023-12-12 | Dsm Ip Assets B.V. | Drug delivery system for delivery of acid sensitive drugs |
WO2016154592A1 (en) | 2015-03-26 | 2016-09-29 | Microvention, Inc. | Embiolic particles |
GB201506381D0 (en) | 2015-04-15 | 2015-05-27 | Isis Innovation | Embolization particle |
AU2017336786B2 (en) | 2016-09-28 | 2020-04-09 | Terumo Corporation | Polymer particles |
US10841083B2 (en) * | 2018-03-15 | 2020-11-17 | Arm Ltd. | Systems, devices, and/or processes for OMIC content processing and/or communication |
US10841299B2 (en) * | 2018-03-15 | 2020-11-17 | Arm Ltd. | Systems, devices, and/or processes for omic content processing and/or partitioning |
IL309211A (en) * | 2018-05-18 | 2024-02-01 | Bard Peripheral Vascular Inc | Microspheres containing radioactive isotopes and other markers and related methods |
CN109821056A (zh) * | 2019-02-21 | 2019-05-31 | 南方科技大学 | 栓塞剂及其制备方法和应用 |
CN111939311B (zh) * | 2020-07-15 | 2022-08-05 | 中南大学 | 一种基于微流控芯片的磁响应性载药栓塞微球的制备方法 |
CN114601964A (zh) * | 2022-03-14 | 2022-06-10 | 珠海麦得发生物科技股份有限公司 | 一种可注射pha微球及其制备方法和应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4063064A (en) * | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
US5783793A (en) * | 1996-02-29 | 1998-07-21 | Merck & Co., Inc. | Process for producing a plurality of holes in dosage forms using a laser beam deflected by an acousto-optic deflector |
US7304122B2 (en) * | 2001-08-30 | 2007-12-04 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
US6503538B1 (en) * | 2000-08-30 | 2003-01-07 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
JP2006521366A (ja) * | 2003-03-28 | 2006-09-21 | シグモイド・バイオテクノロジーズ・リミテッド | シームレスマイクロカプセルを含む固形経口剤形 |
US7976823B2 (en) * | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
KR100453273B1 (ko) * | 2003-09-04 | 2004-10-15 | 주식회사 펩트론 | 초음파 이중공급노즐을 이용한 서방성 미립구의 제조 방법 |
RU2373958C2 (ru) * | 2003-09-25 | 2009-11-27 | Рутгерс, Дзе Стейт Юниверсити | Полимерные по существу рентгеноконтрастные продукты для эмболотерапии |
EP1696822B1 (en) * | 2003-11-13 | 2010-03-17 | PSivida US Inc. | Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin |
US20050175709A1 (en) * | 2003-12-11 | 2005-08-11 | Baty Ace M.Iii | Therapeutic microparticles |
US8685431B2 (en) * | 2004-03-16 | 2014-04-01 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on copolymers having ester bonds and methods for fabricating the same |
EP1958622A1 (en) * | 2006-11-07 | 2008-08-20 | Royal College of Surgeons in Ireland | Method of producing microcapsules |
ES2963291T3 (es) * | 2007-04-26 | 2024-03-26 | Sublimity Therapeutics Ltd | Fabricación de múltiples minicápsulas |
US20090117039A1 (en) * | 2007-11-02 | 2009-05-07 | Boston Scientific Scimed, Inc. | Charged biodegradable polymers for medical applications |
DE102008002395A1 (de) * | 2008-06-12 | 2009-12-17 | Biotronik Vi Patent Ag | Wirkstoffbeladenes Implantat |
WO2011045443A1 (en) * | 2009-10-16 | 2011-04-21 | Dsm Ip Assets B.V. | Coatings comprising bis-(alpha-amino-diol-diester) containing polyesteramide |
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- 2013-05-21 EP EP13729833.7A patent/EP2854890B1/en not_active Not-in-force
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- 2013-05-21 CA CA2866330A patent/CA2866330A1/en not_active Abandoned
- 2013-05-21 CN CN201380022676.4A patent/CN104271171A/zh active Pending
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2019
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2021
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WO2013181022A1 (en) | 2013-12-05 |
JP2018044016A (ja) | 2018-03-22 |
CN104271171A (zh) | 2015-01-07 |
JP2015512422A (ja) | 2015-04-27 |
EP2854890B1 (en) | 2019-02-06 |
US20130323306A1 (en) | 2013-12-05 |
JP2019123733A (ja) | 2019-07-25 |
CA2866330A1 (en) | 2013-12-05 |
JP2021138767A (ja) | 2021-09-16 |
EP2854890A1 (en) | 2015-04-08 |
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