JP2016501867A - Dtpaジエチルエステル、その組成物、およびそれを使用する方法 - Google Patents
Dtpaジエチルエステル、その組成物、およびそれを使用する方法 Download PDFInfo
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- JP2016501867A JP2016501867A JP2015544175A JP2015544175A JP2016501867A JP 2016501867 A JP2016501867 A JP 2016501867A JP 2015544175 A JP2015544175 A JP 2015544175A JP 2015544175 A JP2015544175 A JP 2015544175A JP 2016501867 A JP2016501867 A JP 2016501867A
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 150000003751 zinc Chemical class 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- UVJDUBUJJFBKLD-UHFFFAOYSA-L zinc;2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;hydron Chemical compound [H+].[H+].[H+].[Zn+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC(=O)[O-])CCN(CC([O-])=O)CC([O-])=O UVJDUBUJJFBKLD-UHFFFAOYSA-L 0.000 description 1
Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/225—Polycarboxylic acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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Abstract
Description
本出願は、2012年11月26日に出願された米国仮特許出願第61/729,780号の利益およびそれからの優先権を主張し、その開示はその全体が参照により本明細書に組み込まれる。
本発明は、米国国立衛生研究所により与えられた助成金番号HHSN272201000030Cの下で政府の支援を受けて行われた。米国政府は、本発明に対して一定の権利を有する。
本発明は、ジエチレントリアミン五酢酸三ナトリウム(DTPA)ジエチルエステルに関する。本発明はさらに、DTPAジエチルエステルを含む組成物およびそれを使用する方法に関する。
(a)DTPAビス無水物、エタノール、およびピリジンを混ぜ合わせて、反応混合物を形成する工程と、
(b)反応混合物を窒素下で約24時間撹拌する工程と、
(c)反応混合物をジクロロメタンに添加して、ジクロロメタン溶液を形成する工程と、
(d)ジクロロメタン溶液を約−20℃の温度に冷却して、6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体の沈殿物を形成する工程と、
(e)ジクロロメタン溶液を濾過して、沈殿物を得る工程と、
(f)任意選択的に、濾過する工程の間に沈殿物をジクロロメタンで洗浄する工程と、
(g)任意選択的に、沈殿物を乾燥させ、それにより、多形体を得る工程と
を含む方法である。
(a)DTPAビス無水物および無水エタノールを混ぜ合わせて、反応混合物を形成する工程と、
(b)反応混合物を加熱して、撹拌しながら約1.5時間還流させる工程と、
(c)反応混合物を濾過して、濾液を形成する工程と、
(d)濾液を約20℃未満の温度に冷却して、6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体の沈殿物を形成する工程と、
(e)濾液を濾過して、沈殿物を得る工程と、
(f)任意選択的に、沈殿物を冷エタノールで洗浄する工程と、
(g)任意選択的に、沈殿物をメチルtert−ブチルエーテルで洗浄して、濾過ケーキを形成する工程と、
(h)任意選択的に、濾過ケーキをエタノールと混合して、第2のスラリーを形成する工程と、
(i)任意選択的に、第2のスラリーを約70℃の温度に加熱する工程と、
(j)任意選択的に、第2のスラリーを濾過して、第2の濾液を形成する工程と、
(k)任意選択的に、第2の濾液を約20℃未満の温度に冷却して、第2の沈殿物を形成する工程と、
(l)任意選択的に、第2の濾液を濾過して、第2の沈殿物を得る工程と、
(m)任意選択的に、沈殿物を乾燥させ、それにより、多形体を得る工程と
を含む方法である。
C2E2(6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸としても知られている)を調製するための方法1における第1の工程は、DTPAビス無水物を準備する工程を含む。DTPAビス無水物は、市販されており、商業的供給業者、例えば、TCI America of Portland、Oregonから入手されてもよいか、または以下の通りに調製されてもよい。
[工程1]DTPA(3.93g、10mmol)および無水酢酸(5.72g、56.9mmol)を6.2mLのピリジンに添加し、65〜70℃に14時間加熱還流した。この材料をブヒナー漏斗に通して濾過し、ジエチルエーテルですすぎ洗いした。オフホワイトの粉末(DTPA−BA、1)を集め、デシケータ中で乾燥させた。1HNMR (400MHz, DMSO) δ 3.65 (8H, s), 3.44 (2H, d), 2.74 (4H, t), 2.59 (4H, t).
[工程2]DTPA−BA(1)を用いて、DTPA−BA(1)をエタノールと反応させることによってC2E2(2)を生成させる。DTPA−BA(1.02g、2.8mmol)、エタノール(0.38g、8.2mmol)およびピリジン(0.67g、8.4mmol)を窒素下で24時間撹拌した。生成物をジクロロメタン(DCM)(200mL)中−20℃で沈殿させ、DCMで洗浄しながら濾過し、真空オーブン中で乾燥させて、オフホワイトの粉末を得た(収率−81.3±13.3、n=4)。1HNMR (400MHz, DMSO) δ 4.07 (4H, q), 3.53 (4H, s), 3.45 (2H, s), 3.43 (4H, s), 2.89 (4H, d), 2.84 (4H, d), 1.19 (6H, t). 元素分析: 予測値- C, 48.10; H, 6.95; N, 9.35; O, 35.60; 実測値- C, 47.59; H, 7.22; N, 8.67; O, 36.29.C2E2の合成も、2gスケールで首尾よく調製された。
C2E2を調製するための方法2によって、図1の合成スキームに従って1.5kgスケールでC2E2を製造した。DTPA(1)からのビス無水物2の合成は、欧州出願第EP136134A1号(2003)、国際公開第WO2007/142804A2号、およびChemistry,A European Journal,2004,10,3252−3260に記載されており、これらのそれぞれの内容は、それらの全体が、この段落に関連した教示について、参照により本明細書に組み込まれる。それぞれの場合、五酢酸を無水酢酸およびピリジンでMeCNの存在下で又は非存在下で処理し、実測された収率範囲は95〜97%であった。次いで、ビス無水物をエタノールとの反応によりC2E2に変換する。この変換を用いて、800gおよび1.5kgのC2E2を調製した。
構造:
ロット番号: 020WJL050
バッチサイズ: 1.72kg
外観: 白色固体
同一性: 1H NMRにより決定。データは構造と一致している。
クロマトグラフィー純度: 逆相HPLC−ELSDにより97.5%(面積%)
未確定個別不純物(面積%、二重の平均):
RRT0.33 0.33%
RRT1.08 1.39%
RRT1.28 0.77%
合計不純物: 2.49%
KFによる水分: 0.17%
DSC: 実測141.6℃を中心とした単一吸熱
複数のC2E2多形体の可能性が、C2E2投与溶液の分析の間に生じた。C2E2投与溶液は、方法2を用いて得られたロット050のC2E2で調製した。多形体の調査は、バルク粉末の物理化学的特性に影響を与えるので重要である。準安定結晶性固体は、高い化学ポテンシャルを有し、不安定である。物理化学的特性、粒径および表面積の差は、溶解速度の変化のために薬剤の生物学的利用能を変更し得る。以下の研究の目標は、最も安定な多形形態を同定することであったが、他のいずれの多形体も準安定であり、保存の間に変化し得るからである。この相変化は、溶液からの沈殿または保存の間の不安定性をもたらし得る。
予備試験:C2E2の少量の試料(0.1g、JH012B)を量り分け、25mLのメスシリンダーに入れた。増加する容量の蒸留水を以下のチャートに従って添加した。
代謝安定性:Caco−2細胞は、輸送体、排出タンパク質および第II相酵素を発現するヒト結腸上皮癌細胞株であり、細胞透過性を薬剤吸収と相関させるために用いることができる。見掛け透過係数の決定に加えて、輸送の間のC2E2代謝の推定を得ることができる。これらの予備研究の目的は、さらなる研究を行うことができる線形濃度範囲を決定するために、C2E2濃度(25、50および100μM)の範囲を評価することであった。
ラットにおけるC2E2単回用量体外除去の要約:この研究は、241Am汚染ラットにおけるC2E2の単回強制経口投与用量の効力を評価することであった。200μLのアリコートを硝酸241Amの原液(5mLの1M HNO3中0.1mCi)から抜き取り、蒸発乾固させ、濃HNO3(15M、5mL)に溶解させ、次いで、蒸発乾固させ、希HNO3(0.1M、8mL)に溶解させて、注射液を形成した。IM注射(0.1μL)により250nCiの硝酸241Amで4匹の雌スプレーグドーリーラットの群を汚染し、次いで、滅菌水中10%w/w溶液を用いて自由給餌条件下で200、600、または1000mg/kg(用量体積は、それぞれ、200、600、および1000mg/kg用量について2、6、および10mL/kgであった)で強制経口投与によりC2E2の単回用量を投与した。研究の断食要素については、動物を、処置24時間前、次いで薬剤投与後2時間断食させた。餌および水を自由摂取とした対照群は、未処置であったか、または14mg/kg(標的用量体積0.7mL/kgおよび濃度20mg/mL)でDTPAのカルシウム塩(Ca−DTPA)のIV用量を投与した。処置は、汚染1日後に投与した。すべての動物を汚染7日後に安楽死させ、以下の組織、すなわち、同側および反対側後肢筋組織ならびに注射部位からの生皮(pelt)に加えて、肝臓、両腎臓、両大腿骨を集めた。尿および糞を、汚染時から安楽死を通して集めた。ケージ洗浄物も研究の最後に集め、総尿収集の一部とみなした。注射液の2つのアリコート(100μL)を取り出し、放射能自動検出を用いて241Amガンマ放射能を決定した。これらの標準の平均が、すべての動物に用いた注射用量である。組織および試料のすべてを同様に計数した。アメリシウム含有量は、注射用量のパーセントとして表した。この研究におけるすべての群にわたる放射能の全体回収は、およそ90%であった。表4は、未処置対照の安楽死の時点における、およびCa−DTPAまたはC2E2の単回用量後の総体外除去および残留肝臓負荷量を示す。DTPAおよびC2E2の両方により増強された241Amの排泄が生じた主要経路は、尿クリアランスによっていた。結果は、給餌状態が総241Amクリラランスに影響を与えなかったことを示唆する。241Amの糞クリアランスは、給餌状態によって変更されず、研究の最後での2群間の同様の肝臓負荷量と一致する観察結果であった。この研究は、C2E2が雌ラットにおける総体外除去を増加させ、用量依存的に241Am肝臓負荷量を減少させることを実証した。DTPAと同様に、C2E2による体外除去増強が、尿クリアランスの増強によって生じた。
動物:雄および雌のラットの汚染およびその後の処置は、6月9日から8月24日の間に9つのコホートで行われた。8月2日に開始したコホートの3匹の雄ラットは、強制経口投与処置の間に実験者の誤りの結果として死に、これらの失われた動物を置き換えるために追加の動物を8月24日のコホートに加えた。いくつかの困難を雌ラットに投与する際に経験した。具体的には、5匹の雌ラットで強制経口投与の間に投与液を口内に認めた。投与液が口に含まれたままの2例では、実測体積を問題にはならないとみなし、副作用が認められず、これらのラットを分析に維持した。しかしながら、3匹のラットにおいて口からの用量のいくらかの損失が生じ、短時間の呼吸困難を認めたので用量の部分吸引が行われた場合がある。これらの動物における投与の副作用は投与1時間後に認められず、それらは研究の生存中の部分を終了したが、これらの動物はデータ分析から除いた。
イヌにおける10日間の反復用量研究:10日間の1日強制経口投与用量を介してイヌに投与した場合、試験品C2E2の毒性を評価し、トキシコキネティクスを決定するために、探索的研究を行った。2匹のビーグル犬/性別の群に、0、60、200、400、または600mg/kgの用量レベルで強制経口投与を介してC2E2を投与した。ビヒクルは逆浸透水であり、用量体積は8mL/kgであった。毒性の評価は、死亡率、臨床観察、体重、餌消費、臨床病理学、肉眼的病理学、臓器重量、選択組織の組織病理学、および血漿必須微量元素分析に基づいた。C2E2、C2E1、DTPAおよびC2E3のトキシコキネティクス評価のために、血液試料を1日目および10日目に集めた。C2E3は、用いたC2E2ロット中の不純物であると考えられる。
沈着放射能=エアロゾル濃度(AC)*毎分呼吸量(RMV)*沈着率(DF)*暴露期間(ED)
(ここで、AC=イヌのエアロゾル濃度(nCi/L);RMV=0.499*体重∧(0.809);DF=10%;ED=8分)
により与えられる。
Claims (24)
- 図6Aに示されるものと実質的に同じ粉末x線回折パターン、ならびに/または約7.6、12.4,13.5、14.0、15.3、18.1、18.7、18.8、21.0、22.5、23.4、24.5,28.7、および35.7±0.2度の2シータにピークを有する粉末x線回折パターンにより特徴付けられる、6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体。
- 約110℃から約121℃の融点を有するとさらに特徴付けられる、請求項1に記載の多形体。
- 6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体を調製する方法であって、
(a)DTPAビス無水物、エタノール、およびピリジンを混ぜ合わせて、反応混合物を形成する工程と、
(b)前記反応混合物を窒素下で約24時間撹拌する工程と、
(c)前記反応混合物をジクロロメタンに添加して、ジクロロメタン溶液を形成する工程と、
(d)前記ジクロロメタン溶液を約−20℃の温度に冷却して、6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体の沈殿物を形成する工程と、
(e)前記ジクロロメタン溶液を濾過して、前記沈殿物を得る工程と、
(f)任意選択的に、前記濾過する工程の間に前記沈殿物をジクロロメタンで洗浄する工程と、
(g)任意選択的に、前記沈殿物を乾燥させて、前記多形体を得る工程と
を含む方法。 - 対象を、前記対象から放射性元素を除去するために処置する方法であって、
治療有効量の請求項1〜3のいずれか1項に記載の多形体を対象に投与する工程を含む、方法。 - 前記投与する工程が、前記対象の全体重の1キログラム当たり約1mgから約2,000mgの多形体を前記対象に送達する、請求項4に記載の方法。
- 前記投与する工程が、前記対象の放射性元素への暴露前に行われる、請求項4または5に記載の方法。
- 前記投与する工程が、前記対象の組織、臓器、骨、またはそれらの任意の組合せ中への放射性元素の取り込みを予防するために行われる、請求項6に記載の方法。
- 前記投与する工程が、前記対象の放射性元素への暴露後に行われる、請求項4から7のいずれか1項に記載の方法。
- 前記投与する工程が、前記対象から放射性元素を除去するために行われる、請求項4から8のいずれか1項に記載の方法。
- 前記放射性元素が、プルトニウム(Pu)、アメリシウム(Am)、キュリウム(Cm)、またはそれらの任意の組合せの同位元素を含む、請求項4から9のいずれか1項に記載の方法。
- 前記対象が哺乳類である、請求項4から10のいずれか1項に記載の方法。
- 前記対象がヒトである、請求項4から11のいずれか1項に記載の方法。
- 図6Dに示されるものと実質的に同じ粉末x線回折パターン、ならびに/または約8.1、12.0、13.8、15.4、16.0、16.6、18.3、19.3、21.4、22.1、24.0、26.5、および29.2±0.2度の2シータにピークを有する粉末x線回折パターンにより特徴付けられる、6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体。
- 約133℃から約141℃の範囲で融点を有するとさらに特徴付けられる、請求項13に記載の多形体。
- 6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体を調製する方法であって、
(a)DTPAビス無水物および無水エタノールを混ぜ合わせて、反応混合物を形成する工程と、
(b)前記反応混合物を加熱して、撹拌しながら約1.5時間還流させる工程と、
(c)前記反応混合物を濾過して、濾液を形成する工程と、
(d)前記濾液を約20℃未満の温度に冷却して、6,9−ビス(カルボキシメチル)−3−(2−エトキシ−2−オキソエチル)−11−オキソ−12−オキサ−3,6,9−トリアザテトラデカン−1−オイック酸の多形体の沈殿物を形成する工程と、
(e)前記濾液を濾過して、前記沈殿物を得る工程と、
(f)任意選択的に、前記沈殿物を冷エタノールで洗浄する工程と、
(g)任意選択的に、前記沈殿物をメチルtert−ブチルエーテルで洗浄して、濾過ケーキを形成する工程と、
(h)任意選択的に、前記濾過ケーキをエタノールと混合して、第2のスラリーを形成する工程と、
(i)任意選択的に、前記第2のスラリーを約70℃の温度に加熱する工程と、
(j)任意選択的に、前記第2のスラリーを濾過して、第2の濾液を形成する工程と、
(k)任意選択的に、前記第2の濾液を約20℃未満の温度に冷却して、第2の沈殿物を形成する工程と、
(l)任意選択的に、前記第2の濾液を濾過して、前記第2の沈殿物を得る工程と、
(m)任意選択的に、前記沈殿物を乾燥させて、前記多形体を得る工程と
を含む方法。 - 対象を、前記対象から放射性元素を除去するために処置する方法であって、
治療有効量の請求項13から15のいずれか1項に記載の多形体を対象に投与する工程
を含む、方法。 - 前記投与する工程が、前記対象の全体重の1キログラム当たり約1mgから約2,000mgの多形体を前記対象に送達する、請求項16に記載の方法。
- 前記投与する工程が、前記対象の放射性元素への暴露前に行われる、請求項16または17に記載の方法。
- 前記投与する工程が、前記対象の組織、臓器、骨、またはそれらの任意の組合せ中への放射性元素の取り込みを予防するために行われる、請求項18に記載の方法。
- 前記投与する工程が、前記対象の放射性元素への暴露後に行われる、請求項16から19のいずれか1項に記載の方法。
- 前記投与する工程が、前記対象から放射性元素を除去するために行われる、請求項16から20のいずれか1項に記載の方法。
- 前記放射性元素が、プルトニウム(Pu)、アメリシウム(Am)、キュリウム(Cm)、またはそれらの任意の組合せの同位元素を含む、請求項16から21のいずれか1項に記載の方法。
- 前記対象が哺乳類である、請求項16から22のいずれか1項に記載の方法。
- 前記対象がヒトである、請求項16から23のいずれか1項に記載の方法。
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EP2922816A4 (en) | 2016-07-13 |
WO2014082046A1 (en) | 2014-05-30 |
US20180305297A1 (en) | 2018-10-25 |
JP2018188459A (ja) | 2018-11-29 |
EP2922816B1 (en) | 2021-06-23 |
US20150251991A1 (en) | 2015-09-10 |
JP6660735B2 (ja) | 2020-03-11 |
US9546129B2 (en) | 2017-01-17 |
ES2890650T3 (es) | 2022-01-21 |
US9969681B2 (en) | 2018-05-15 |
EP2922816A1 (en) | 2015-09-30 |
US20170088506A1 (en) | 2017-03-30 |
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