JP2012505882A - 高濃度薬物粒子、製剤、懸濁液、及びこれらの使用 - Google Patents
高濃度薬物粒子、製剤、懸濁液、及びこれらの使用 Download PDFInfo
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Abstract
Description
本出願は、2008年10月15日付けで出願された米国仮出願第61/196,277号(現在係属中)、及び2009年1月9日付けで出願された米国仮出願第61/204,714号(現在係属中)の優先権を主張し、これらの出願の全体を参考のため本明細書中に引用する。
言うまでもなく、本明細書中に使用される用語は、特定の実施態様を説明する目的に使用されるにすぎず、限定を意図するものではない。本明細書及び添付の特許請求の範囲に使用される単数形「a」、「an」及び「the」は、文脈が他のことを明示するのではない限り、複数の言及対象を含む。このように、例えば「溶媒」に言及したときには、これは1つ又は2つ以上のこのような溶媒を含み、「タンパク質」に言及したときには、これは1つ又は2つ以上のこのようなタンパク質、タンパク質の混合物、及び同様のものを含む。
ここでF/Aは剪断応力(単位面積当たりの力)、
μ=比例定数(粘度)、及び
V/L=層厚当たりの速度(剪断速度)。
本発明を詳細に説明する前に理解するべきことは、本発明が特定の薬物送達タイプ、特定の薬物送達装置タイプ、特定の薬物源、特定の溶媒、及び特定のポリマーなどに限定されないことである。それというのも、このような具体的な事項は、本明細書の教示内容に照らして選択して使用することができるからである。また、本明細書中に使用される用語は、本発明の特定の実施態様を説明することを目的としているにすぎず、限定的であることを意図してはいない。
3.1.0 高濃度薬物粒子製剤
1つの態様において、本発明は、製薬用途のために高濃度薬物粒子製剤を提供する。粒子製剤は典型的には約20wt%〜約75wt%の薬物を含み、そして1又は複数の追加成分(例えば安定剤)を含んでいる。安定化成分である追加成分の一例としては、炭水化物、抗酸化剤、アミノ酸、緩衝剤、無機化合物、及び界面活性剤が挙げられる。
高濃度薬物粒子製剤は、1又は複数の薬物を含んでいてよい。薬物は生理的又は薬理的に活性の任意の物質、具体的には、ヒト又は動物の身体に送達されることが知られている物質、例えば薬剤、ビタミン、又は栄養素などであってよい。本発明の高濃度薬物粒子製剤は典型的には医薬製剤であり、そして例えば乾燥形態又は懸濁製剤としてパッケージングすることができる。
が挙げられる。
本発明の1態様において、懸濁ビヒクルは、高濃度薬物粒子製剤が分散される安定な環境を提供する。高濃度薬物粒子製剤は、(上記のように)懸濁ビヒクル中で化学的物理的に安定である。懸濁ビヒクルは典型的には、1又は複数のポリマーと1又は複数の溶媒とを含み、これらは薬物を含む粒子を均一に懸濁させるのに十分な粘度の溶液を形成する。懸濁ビヒクルは、例えば界面活性剤、抗酸化剤、及び/又はビヒクル中に可溶性のその他の化合物を含む更なる成分を含んでいてよい。
本明細書中に記載された懸濁製剤を植え込み型薬物送達装置内に使用することにより、長期にわたって、例えば数週間、数か月、又は最大約1年、例えば少なくとも約1か月、少なくとも約1.5か月、好ましくは少なくとも約3か月、好ましくは少なくとも約6か月、より好ましくは少なくとも約9か月、より好ましくは少なくとも約12か月にわたって化合物の持続的な送達を可能にすることができる。このような植え込み型薬物送達装置は典型的には、所望の期間にわたって所望の流量で化合物を送達することができる。懸濁製剤はコンベンショナルな技術によって、植え込み型薬物送達装置内にローディングされてよい。
本明細書中に記載された懸濁製剤は、選択された薬物の連日投与を必要とする数多くの治療に対する有望な代替手段を提供する。例えば、高濃度インクレチン模倣体粒子製剤を含む本発明の懸濁製剤は、糖尿病(例えば真性糖尿病、及び妊娠糖尿病)、及び糖尿病関連障害(例えば糖尿病性心筋症、インスリン耐性、糖尿病性神経障害、糖尿病性腎症、網膜症、白内障、高血糖、高コレステロール血、高血圧、高インスリン血、高脂血、アテローム性動脈硬化、及び組織虚血、特に心筋虚血)、並びに、高血糖(例えば、ベータ・ブロッカー、チアジド系利尿薬、コルチコステロイド、ナイアシン、ペンタミジン、プロテアーゼ阻害薬、L−アスパラギナーゼ、及びいくつかの抗精神病薬を含む、高血糖のリスクを高くする薬剤による治療に関連する)、食物摂取量の低減(例えば肥満治療、食欲制御、又は減量)、卒中、血漿中脂質低下、急性冠状症候群、冬眠心筋、胃腸運動性の調節、尿流の増大、の治療に有用である場合がある。
本発明の高濃度薬物粒子製剤は、例えば浸透圧送達装置を使用して送達されてよい。1実施態様の場合、本発明は、現在使用されている浸透圧送達装置と比較して小型化された浸透圧送達装置の使用に関する。図6Bは、長さ約45mm及び直径約3.8mmの寸法を有する浸透圧送達装置を概略的に示している。このサイズの浸透圧送達装置は、例えばオメガ・インターフェロン粒子懸濁製剤及びエキセナチド粒子懸濁製剤の送達のために使用されている(“Continuous Delivery of Stabilized Proteins and Peptides at Consistent Rates for at least Three Months from the DUROR Device”, 2008 American Association of Pharmaceutical Sciences, Annual Meeting and Exposition, Poster No. T3150, Nov. 18, 2008, Yang, B.他; “A Phase 1b Study of ITCA 650: Continuous Subcutaneous Delivery of Exenatide via DUR R Device Lowers Fasting and Postprandial Plasma Glucose”, American Diabetes Association 69th Scientific Sessions, June 5-9, 2009, Luskey, K.他; 及び“A Phase 1b Study of ITCA 650:Continuous Subcutaneous Delivery of Exenatide via DUROR Device Lowers Fasting and Postprandial Plasma Glucose”, European Association for the Study of Diabetes 45th Annual Meeting, September 29 to October 3, 2009, Luskey, K.他)。本発明の高濃度薬物粒子製剤は、より小さな寸法の浸透圧送達装置の使用を容易にする一方、所定の時間にわたって制御された量の薬物を連続的に長期送達する能力を依然として提供する。例えば、図6Cは、長さ約30mm及び直径約3.8mmの寸法を有する浸透圧送達装置を概略的に示している。薬物粒子製剤中の薬物濃度を高くすることによって、浸透圧送達装置内にローディングされるべき薬物粒子懸濁製剤の量を低減することができ、薬物粒子懸濁製剤の流量を低減することができ、そして所定の時間にわたって予め決められた量の薬物を連続的に長期送達する能力を維持しつつ、浸透圧送達装置を小型化することもできる。
活性薬物が高濃縮された粒子は、容易に植え込まれ患者に受け入れられ続けるのに十分に小さな全体の装置サイズを維持しながら、高投与量の薬物を送達できる浸透圧送達装置を調製するのに有用である。高濃度薬物粒子製剤は、疾患又は状態の効果的な治療のために、高投与量の選択された薬物が必要とされるときに特に有用であり得る。具体的には、高濃度薬物粒子製剤は、浸透圧送達装置の有用性及び用途を、このような装置にとっては余りにも高いと典型的には考えられている投与量を必要する低効能の薬物、例えばタンパク質、例えばGLP−1、エキセナチド、PYY、オキシントモジュリン、GIP、インターフェロン(例えばアルファ、ベータ、ガンマ、ラムダ、オメガ、タウ、コンセンサス、変異インターフェロン)、抗体、又は小分子、例えばテストステロン又はその他のステロイドにまで広げる。高濃度粒子はまた、動物毒物学研究及びヒトにおける初期投与量決定研究の両方に関する投与量範囲決定研究に必要とされる高投与量浸透圧送達装置の調製を容易にする。
下記例は、本発明の装置、方法、及び製法をどのように形成して使用するかに関する完全な開示及び説明を当業者に提供するために示すものであって、発明者が発明と見なすものの範囲を限定しようと意図するものではない。使用した数値(例えば量、温度など)に関して正確さを確保しようと努めてはいるが、しかし或る程度の試験誤差及び偏差は考慮に入れるべきである。他のことを示すのでなければ、部は重量部であり、分子量は重量平均分子量であり、温度は℃であり、そして圧力は大気圧又は近大気圧である。
高濃度薬物粒子製剤
この例では、高濃度の活性医薬成分(すなわち薬物)を含む噴霧乾燥粒子製剤の製造を記述する。本発明の製剤は、噴霧乾燥粉末製剤における薬物ローディングを行う。
凍結したバルク・オメガ・インターフェロン溶液5g/Lを、2〜8℃で解凍し、次いでpH5.9の22mMのクエン酸ナトリウム緩衝剤にこれを添加した。溶液をクエン酸ナトリウム緩衝剤で透析することにより、14mg/mlのオメガ・インターフェロンを含む最終溶液を形成した。次いで、溶液をスクロース及びメチオニンとともに製剤し、そして0.5L捕集容器を備えたNiro SD Micro噴霧乾燥器を使用して噴霧乾燥させた。ポンプ・フィード量は400g/hであり、噴霧器ガスは2.3kg/hであり、噴霧器ガスは周囲温度であり、プロセスガス入口温度は140℃であり、プロセスガスは30kg/hであった。乾燥粉末は35%のオメガ・インターフェロンであり、残留水分は3.0%であった。この粒子製剤中の成分の比は次の通りである。2:1:2:1(オメガ・インターフェロン:メチオニン:スクロース:クエン酸緩衝剤)。
エキセナチド溶液を下記のように調製した。2.5gのエキセナチドをpH5.8〜6.0のクエン酸ナトリウム緩衝剤中に溶解した。溶液を、クエン酸ナトリウム緩衝剤、スクロース、及びメチオニンを含有する製剤溶液で透析した。次いで、0.7mmのノズルを備えたBuchi 290を使用して、製剤された溶液を噴霧乾燥させた。出口温度85℃、噴霧圧力100Psi、固形分2%、及び流量2.8ml/minであった。乾燥粉末は44.82%のエキセナチドを含有し、残留水分は3.8%であり、密度は0.2329g/mlであった。この粒子製剤中の成分の比は次の通りである。5:1:1:3.5(エキセナチド:メチオニン:スクロース:クエン酸緩衝剤)。
エキセナチド溶液を下記のように調製した。13.7gのエキセナチドをpH6.0の50mMクエン酸ナトリウム緩衝剤中に溶解した。溶液を、クエン酸ナトリウム緩衝剤、スクロース、及びメチオニンを含有する製剤溶液で透析した。次いで、製剤された溶液を、0.5L捕集容器を備えたNiro SD Micro噴霧乾燥器を使用して噴霧乾燥させた。ポンプ・フィード量は400g/hであり、噴霧器ガスは2.3kg/hであり、噴霧器ガスは周囲温度であり、プロセスガス入口温度は140℃であり、プロセスガスは30kg/hであった。乾燥粉末は41.24%のエキセナチドであり、残留水分は4.13%であった。この粒子製剤中の成分の比は次の通りである。5:1:1:3.4(エキセナチド:メチオニン:スクロース:クエン酸緩衝剤)。
オメガ・インターフェロン濃度5mg/mLの凍結したバルク・オメガ・インターフェロン溶液を、2〜8℃で解凍し、次いでpH6.0のクエン酸ナトリウム緩衝剤で透析することにより、14mg/mlのオメガ・インターフェロンを含む溶液を形成した。次いで、溶液をスクロース及びメチオニンとともに製剤した。次いで、0.7mmのノズルを備えたBuchi 290を使用して、製剤された溶液を噴霧乾燥させた。出口温度80℃、噴霧圧力100Psi、固形分2%、及び流量2.8ml/minであった。乾燥粉末は69%のオメガ・インターフェロンを含有し、残留水分は4%であった。この粒子製剤中の成分の比は次の通りである。6.8:1:1:1(オメガ・インターフェロン:メチオニン:スクロース:クエン酸緩衝剤)。
PYY溶液を下記のように調製した。1gのPYYをpH5.0の25mMクエン酸ナトリウム緩衝剤中に溶解した。溶液を、クエン酸ナトリウム緩衝剤、スクロース、及びメチオニンを含有する製剤溶液で透析した。次いで、0.7mmのノズルを備えたBuchi 290 Micro 噴霧乾燥器を使用して、製剤された溶液を噴霧乾燥させた。出口温度100℃、噴霧圧力100Psi、固形分2%、及び流量2.8ml/minであった。乾燥粉末は27.6%のPYYを含有した。この粒子製剤中の成分の比は次の通りである。1.8:1.0:2.2:1.5(PYY:メチオニン:スクロース:クエン酸緩衝剤)。
オキシントモジュリン溶液を下記のように調製した。1gのオキシントモジュリンをpH4.0の25mMクエン酸ナトリウム緩衝剤中に溶解した。溶液を、クエン酸ナトリウム緩衝剤、スクロース、及びメチオニンを含有する製剤溶液で透析した。次いで、0.7mmのノズルを備えたBuchi 290 Micro 噴霧乾燥器を使用して、製剤された溶液を噴霧乾燥させた。出口温度100℃、噴霧圧力100Psi、固形分2%、及び流量2.8ml/minであった。乾燥粉末は43.3%のオキシントモジュリンを含有した。この粒子製剤中の成分の比は次の通りである。4.1:1.8:1:2.6(オキシントモジュリン:メチオニン:スクロース:クエン酸緩衝剤)。
懸濁製剤
この例では、懸濁ビヒクルと本発明の粒子製剤とを含む懸濁製剤の製造を記述する。
粒子製剤を例1(製剤1)に記載したように調製した。
粒子製剤を例1(製剤2)に記載したように調製した。
粒子製剤を例1(製剤3)に記載したように調製した。
粒子製剤を例1(製剤3)に記載したように調製した。エキセナチド粒子製剤は例1(製剤3)に記載されている。
粒子製剤及び懸濁製剤における薬物安定性
A. 粒子製剤安定性
噴霧乾燥粉末としての粒子製剤の安定性を評価するための研究を行った。サイズ排除クロマトグラフィ(SEC)及び逆相高性能液体クロマトグラフィ(RP−HPLC)によって試料を分析した。結果を表8に示す。
生体適合性であり単一相であり、そして非水性であるビヒクル中に懸濁された薬物粒子製剤の安定性を評価するための研究を行った。分析試験のために、オメガ・インターフェロン又はエキセナチドを懸濁液から抽出溶媒で抽出し、そしてサイズ排除クロマトグラフィ(SEC)、逆相高性能液体クロマトグラフィ(RP−HPLC)、及びバイオアッセイを用いて試料を分析した。
放出速度
植え込み型浸透圧送達装置を使用して本発明の実施態様に従って懸濁製剤の放出速度を評価するための研究を行った。各研究に対して、植え込み型浸透圧送達装置の薬物リザーバに、例2に記載された懸濁製剤のうちの1つを160ul充填した。浸透圧ポンプの膜端部を、3mlのリン酸緩衝溶液(PBS)で充填されたストッパ付きガラスバイアル内に入れ、そして浸透圧ポンプの拡散モデレータ端部を、2.5〜3mlの放出速度媒体(0.14M NaCl及び0.2%のアジ化ナトリウムを含むpH6.0のクエン酸緩衝溶液)で充填されたガラスバイアル内に入れた。
薬物送達速度、量、及び使用期間
表10に示されたデータは、高濃度粒子が、規定された送達速度で長期間にわたって薬物投与量を送達できる植え込み型浸透圧送達装置を調製するのに有用であることを実証した。
Claims (43)
- 粒子製剤であって、
約25wt%〜約80wt%の薬物と;
約75wt%〜約20wt%の1又は複数の追加成分とを
含み、
薬物:追加成分の比が約1:1〜約5:1である、
粒子製剤。 - 該薬物が約40wt%〜約75wt%を占め、そして該1又は複数の追加成分が約60wt%〜約25wt%を占める、請求項1に記載の粒子製剤。
- 該1又は複数の追加成分が、抗酸化剤、炭水化物、及び緩衝剤から成る群から選択される、請求項1又は2に記載の粒子製剤。
- 該1又は複数の追加成分が抗酸化剤を含み、該抗酸化剤が、システイン、メチオニン、及びトリプトファンから成る群から選択される、請求項1から3までのいずれか1項に記載の粒子製剤。
- 該抗酸化剤がメチオニンである、請求項4に記載の粒子製剤。
- 該1又は複数の追加成分が緩衝剤を含み、そして該緩衝剤が、クエン酸塩、ヒスチジン、琥珀酸塩、及びこれらの混合物から成る群から選択される、請求項1から5までのいずれか1項に記載の粒子製剤。
- 該緩衝剤がクエン酸塩である、請求項6に記載の粒子製剤。
- 該1又は複数の追加成分が炭水化物を含み、そして該炭水化物が二糖類である、請求項1から7までのいずれか1項に記載の粒子製剤。
- 該二糖類が、ラクトース、スクロース、トレハロース、セロビオース、又はこれらの混合物から成る群から選択される、請求項8に記載の粒子製剤。
- 該二糖類がスクロースである、請求項9に記載の粒子製剤。
- 該1又は複数の追加成分が、抗酸化剤、炭水化物、及び緩衝剤を含み、そして薬物:抗酸化剤:炭水化物:緩衝剤の比が約2〜20:1〜5:1〜5:1〜10である、請求項1から10までのいずれか1項に記載の粒子製剤。
- 該粒子製剤が、粒子の噴霧乾燥調製物である、請求項1から11までのいずれか1項に記載の粒子製剤。
- 該薬物がタンパク質である、請求項1から12までのいずれか1項に記載の粒子製剤。
- 該タンパク質がインターフェロンである、請求項13に記載の粒子製剤。
- 該タンパク質が、コンセンサス・インターフェロン、アルファ・インターフェロン、ベータ・インターフェロン、ガンマ・インターフェロン、タウ・インターフェロン、オメガ・インターフェロン、及びこれらの混合物から成る群から選択される、請求項14に記載の粒子製剤。
- 該タンパク質が、インクレチン模倣体である、請求項13に記載の粒子製剤。
- 該インクレチン模倣体が、グルカゴン様ペプチド−1(GLP−1)、GLP−1の誘導体、又はGLP−1の類似体である、請求項16に記載の粒子製剤。
- 該インクレチン模倣体がGLP−1(7−36)アミドである、請求項17に記載の粒子製剤。
- 該インクレチン模倣体がエキセナチド、エキセナチドの誘導体、又はエキセナチドの類似体である、請求項16に記載の粒子製剤。
- 該インクレチン模倣体がエキセナチドである、請求項19に記載の粒子製剤。
- 該タンパク質が、エキセナチド、PYY、GLP−1(7−36)アミド、オキシントモデュリン、GIP、及びレプチンから成る群から選択される、請求項13に記載の粒子製剤。
- 該タンパク質が、組み換え抗体、抗体フラグメント、ヒト化抗体、単鎖抗体、モノクローナル抗体、及びアヴィマーから成る群から選択される、請求項13に記載の粒子製剤。
- 該タンパク質が、ヒト成長ホルモン、上皮成長因子、線維芽細胞成長因子、血小板由来成長因子、形質転換成長因子、及び神経成長細胞から成る群から選択される、請求項13に記載の粒子製剤。
- 該タンパク質がサイトカインである、請求項13に記載の粒子製剤。
- 該粒子製剤の粒子が、約2ミクロン〜約10ミクロンの粒子である、請求項1から24までのいずれか1項に記載の粒子製剤。
- 懸濁製剤であって、
請求項1から25までのいずれか1項に記載の粒子製剤と、
1又は複数のポリマー及び1又は複数の溶媒を含む、非水性単一相懸濁ビヒクルと
を含み;
該懸濁ビヒクルが粘性流体特性を示し、そして該粒子製剤が該ビヒクル中に均質に分散されている、
懸濁製剤。 - 該1又は複数のポリマーが、ピロリドンを含むポリマーである、請求項26に記載の懸濁製剤。
- 該1又は複数のポリマーが、ポリビニルピロリドンである、請求項27に記載の懸濁製剤。
- 該1又は複数の溶媒が、乳酸ラウリル、ラウリルアルコール、安息香酸ベンジル、及びこれらの混合物から成る群から選択される、請求項26から28までのいずれか1項に記載の懸濁製剤。
- 該懸濁ビヒクルが本質的に、1又は複数のポリマーと、1又は複数の溶媒とから成っている、請求項26に記載の懸濁製剤。
- 該1又は複数の溶媒が本質的に、安息香酸ベンジルから成っている、請求項30に記載の懸濁製剤。
- 該1又は複数のポリマーが本質的に、ポリビニルピロリドンから成っている、請求項30又は31に記載の懸濁製剤。
- 該懸濁ビヒクルが本質的に、安息香酸ベンジルと、ピロリドンを含むポリマーとから成っている、請求項30に記載の懸濁製剤。
- 該懸濁ビヒクルが約50%の溶媒、及び約50%のポリマーである、請求項26から33までのいずれか1項に記載の懸濁製剤。
- 該懸濁ビヒクルの粘度が、約15,000ポアズ±約3,000ポアズである、請求項26から34までのいずれか1項に記載の懸濁製剤。
- 請求項26から35までのいずれか1項に記載の懸濁製剤を含む、浸透圧送達装置。
- 該浸透圧送達装置が、長さ約35mm〜約20mm及び直径約8mm〜約3mmの寸法を有するリザーバを含む、請求項36に記載の浸透圧送達装置。
- 該リザーバが、長さ約30mm〜約25mm及び直径約4mm〜約3.8mmの寸法を有している、請求項37に記載の浸透圧送達装置。
- 浸透圧送達装置の製造方法であって、
該浸透圧送達装置のリザーバ内に、請求項26から35までのいずれか1項に記載の懸濁製剤を充填する
ことを含む、浸透圧送達装置の製造方法。 - 該浸透圧送達装置が、長さ約35mm〜約20mm及び直径約8mm〜約3mmの寸法を有するリザーバを含む、請求項39に記載の方法。
- 該リザーバが、長さ約30mm〜約25mm及び直径約4mm〜約3.8mmの寸法を有している、請求項40に記載の方法。
- 請求項1から25までのいずれか1項に記載の粒子製剤を含む、医薬製剤。
- 請求項26から35までのいずれか1項に記載の懸濁製剤を含む、医薬製剤。
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EP2240155B1 (en) * | 2008-02-13 | 2012-06-06 | Intarcia Therapeutics, Inc | Devices, formulations, and methods for delivery of multiple beneficial agents |
NZ592113A (en) * | 2008-10-15 | 2012-04-27 | Intarcia Therapeutics Inc | Highly concentrated drug particles, formulations, suspensions and uses thereof |
JP5464610B2 (ja) * | 2009-06-05 | 2014-04-09 | ジェ ファ チン | パーマ液第1剤 |
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JP2017119709A (ja) * | 2008-10-15 | 2017-07-06 | インターシア セラピューティクス,インコーポレイティド | 高濃度薬物粒子、製剤、懸濁液、及びこれらの使用 |
JP2018196401A (ja) * | 2017-05-19 | 2018-12-13 | ロレアル | マイクロニードルシート |
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CN102281865A (zh) | 2011-12-14 |
JP2015143286A (ja) | 2015-08-06 |
US20100092566A1 (en) | 2010-04-15 |
CN102281865B (zh) | 2017-04-05 |
US20120289944A1 (en) | 2012-11-15 |
US20170119854A1 (en) | 2017-05-04 |
KR101419583B1 (ko) | 2014-07-25 |
MX2011003833A (es) | 2011-06-20 |
IL211948A0 (en) | 2011-06-30 |
AU2009303905A1 (en) | 2010-04-22 |
KR20110069054A (ko) | 2011-06-22 |
US20160022582A1 (en) | 2016-01-28 |
AU2009303905B2 (en) | 2015-01-22 |
JP2017119709A (ja) | 2017-07-06 |
WO2010044867A1 (en) | 2010-04-22 |
HK1200332A1 (en) | 2015-08-07 |
CA2738715A1 (en) | 2010-04-22 |
JP2015017143A (ja) | 2015-01-29 |
NZ592113A (en) | 2012-04-27 |
CA2738715C (en) | 2013-07-16 |
EP2349200A1 (en) | 2011-08-03 |
CN106880596A (zh) | 2017-06-23 |
JP5643762B2 (ja) | 2014-12-17 |
CN104013569A (zh) | 2014-09-03 |
CN106539756A (zh) | 2017-03-29 |
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