JP6827429B2 - 共結晶 - Google Patents
共結晶 Download PDFInfo
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- JP6827429B2 JP6827429B2 JP2017565565A JP2017565565A JP6827429B2 JP 6827429 B2 JP6827429 B2 JP 6827429B2 JP 2017565565 A JP2017565565 A JP 2017565565A JP 2017565565 A JP2017565565 A JP 2017565565A JP 6827429 B2 JP6827429 B2 JP 6827429B2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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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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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
薬物の腸管からの吸収は、溶解過程あるいは膜透過過程が律速段階となる(非特許文献1)。難溶性薬物の場合、溶解過程が律速段階になることが多く、溶解性を向上させることにより薬物の生物学的利用能を増加させることが期待できる。
水和物を含む溶媒和物あるいは結晶多形はそれぞれ、溶解性をはじめとした結晶の物理化学的特性が異なることが知られている。単一の結晶形に制御することは、医薬品の品質を一定に保つ上で重要である(非特許文献2)。
「共結晶」とは、一般に、該共結晶を構成する成分が、イオン結合以外で結びつく分子間相互作用を含む多成分結晶を意味する(非特許文献3)。
6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドは、Smo阻害作用を有し、癌の予防または治療剤として有用であることが知られている(特許文献1)。
本薬物の膜透過性は良好であることが示唆されていることから(非特許文献4)、生物学的利用能を増加させるためには、薬物の溶解性を向上させる必要がある。また、本薬物は多くの有機溶媒と溶媒和物を形成し、さらにその溶媒和物から多種の結晶多形が誘導されるため(非特許文献5)、結晶形を制御した製造は難しい。
〔2〕(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶である〔1〕記載の共結晶;
〔3〕粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2および8.6±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する〔2〕記載の共結晶;
〔4〕(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶である〔1〕記載の共結晶;
〔5〕粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2および8.7±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する〔4〕記載の共結晶;
〔6〕〔1〕記載の共結晶を含有してなる医薬;
〔7〕Smo阻害剤である〔6〕記載の医薬;
〔8〕癌の予防および/または治療剤である〔6〕記載の医薬;
〔9〕哺乳動物に対し、〔1〕記載の共結晶の有効量を投与することを特徴とする、該哺乳動物におけるSmoの阻害方法;
〔10〕哺乳動物に対し、〔1〕記載の共結晶の有効量を投与することを特徴とする、該哺乳動物における癌の予防および/または治療方法;
〔11〕癌の予防および/または治療に使用するための、〔1〕記載の共結晶;および
〔12〕癌の予防および/または治療剤を製造するための、〔1〕記載の共結晶の使用。
本発明は、(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸またはL-酒石酸との共結晶(以下、「本発明の共結晶」とする)を提供する。
(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶としては、粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2および8.6±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
また、(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶としては、粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2、8.6±0.2、5.8±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
さらに、上記共結晶としては、粉末X線回折の格子面間隔(d)が11.7±0.2、10.7±0.2、10.0±0.2、8.6±0.2、8.4±0.2、5.8±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、11.7±0.2、10.7±0.2、10.0±0.2、8.6±0.2、8.4±0.2、7.5±0.2、7.2±0.2、5.8±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、または11.7±0.2、10.7±0.2、10.0±0.2、8.6±0.2、8.4±0.2、7.5±0.2、7.2±0.2、5.8±0.2、4.9±0.2、4.5±0.2および4.2±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶としては、粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2および8.7±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
また、(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶としては、粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2、8.7±0.2、5.9±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
さらに、上記共結晶としては、粉末X線回折の格子面間隔(d)が12.0±0.2、11.0±0.2、10.1±0.2、8.4±0.2、8.7±0.2、5.9±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、12.0±0.2、11.0±0.2、10.1±0.2、8.4±0.2、8.7±0.2、7.6±0.2、7.3±0.2、5.9±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、または12.0±0.2、11.0±0.2、10.1±0.2、8.4±0.2、8.7±0.2、7.6±0.2、7.3±0.2、5.9±0.2、4.9±0.2、4.7±0.2および4.5±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
本発明の共結晶を経口投与する場合の剤形としては、例えば、錠剤(糖衣錠、フィルムコーティング錠を含む)、丸剤、顆粒剤、散剤、カプセル剤(ソフトカプセル剤、マイクロカプセル剤を含む)、シロップ剤、乳剤、懸濁剤等が挙げられ、また、非経口投与する場合の剤形としては、例えば、注射剤、注入剤、点滴剤、坐剤等が挙げられる。また、適当な基剤(例、酪酸の重合体、グリコール酸の重合体、酪酸−グリコール酸の共重合体、酪酸の重合体とグリコール酸の重合体との混合物、ポリグリセロール脂肪酸エステル等)と組み合わせ徐放性製剤とすることも有効である。
結合剤の例としては、5ないし10重量%デンプンのり液、10ないし20重量%アラビアゴム液またはゼラチン液、1ないし5重量%トラガント液、カルボキシメチルセルロース液、アルギン酸ナトリウム液、グリセリン等が挙げられる。
崩壊剤の例としては、でんぷん、炭酸カルシウム等が挙げられる。
滑沢剤の例としては、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、精製タルク等が挙げられる。
甘味剤の例としては、ブドウ糖、果糖、転化糖、ソルビトール、キシリトール、グリセリン、単シロップ等が挙げられる。
界面活性剤の例としては、ラウリル硫酸ナトリウム、ポリソルベート80、ソルビタンモノ脂肪酸エステル、ステアリン酸ポリオキシル40等が挙げられる。
懸濁化剤の例としては、アラビアゴム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、メチルセルロース、ベントナイト等が挙げられる。
乳化剤の例としては、アラビアゴム、トラガント、ゼラチン、ポリソルベート80等が挙げられる。
実施例において、室温は、約15〜30℃を意味する。
粉末X線回折測定は、Cu−Kα線を用い、株式会社リガク社製試料水平型多目的X線回折装置Ultima IVにより測定した。示差走査熱量測定あるいは熱重量測定は、メトラー・トレド社製DSC1/700/903−2あるいはメトラー・トレド社製TGA/DSC1/LF/629−2を用いて、昇温速度5℃/分で測定した。赤外分光スペクトルは、島津製作所社製フーリエ変換赤外分光光度計Shimadzu IR Prestige−21にSmiths Detection社製Dura Sample IR IIを装着して、全反射法吸収測定法にて分解能4cm−1で測定した。ラマン分光測定は、Kaiser Optical Systems社製RXN2に励起波長1064nmのレーザー光源を用いて測定した。単結晶X線回折は、Cu−Kα線を用い、株式会社リガク社製湾曲イメージングプレート単結晶自動X線構造解析装置R−AXIS RAPID IIにより測定した。直接法で初期位相を決定し、SHELXL−97で構造を精密化した。溶解度は、各結晶を37℃で24時間振とうした蒸留水、日本薬局方溶出試験第1液、空腹時人工腸液(FaSSIF)あるいは飽食時人工腸液(FeSSIF)中の6−エチル−N−[1−(ヒドロキシアセチル)ピペリジン−4−イル]−1−メチル−4−オキソ−5−(2−オキソ−2−フェニルエチル)−3−(2,2,2−トリフルオロエトキシ)−4,5−ジヒドロ−1H−ピロロ[3,2−c]ピリジン−2−カルボキサミドの濃度とした。固有溶解速度測定は、結晶粉末のみを圧縮成型したディスクを用いて、0.2%(w/v)のラウリル硫酸ナトリウムを含む20mmoL/Lのリン酸ナトリウム緩衝液(pH6.8)中で回転ディスク法(回転数:100rpm)により評価した。溶出試験は、結晶粉末と同重量の乳糖を物理的に混合した粉末を用いて、37℃の空腹時人工腸液中(FaSSIF)において回転パドル法(パドル回転数:50rpm)で評価した。溶液中の薬物濃度はWaters社製Alliance HPLCシステムe2695と検出器2789を用いた液体クロマトグラフ法(分離カラムは:YMCPackPro C18 4.6mmφ×150mm、温度:40℃、移動相:20mmol/Lリン酸ナトリウム緩衝液(pH6.8)/アセトニトリル=60/40(v/v)、流速:1mL/分、紫外吸収検出波長:240nm)で決定した。スラリー実験は、結晶粉末に試験溶媒を添加して約25℃で24時間懸濁攪拌して得られた残渣をろ取して、結晶形を粉末X線回折測定あるいはラマン分光法で確認した。再結晶実験では、結晶をエタノール、アセトン、2−プロパノール、テトラヒドロフラン、メチルエチルケトン、酢酸エチル、酢酸イソプロピル、アニソールあるいは酢酸イソブチルに55℃で溶解させてフィルターろ過したのち、5℃まで徐冷あるいは、溶液にn−ヘプタンを添加して同じく5℃まで徐冷して得られた析出物の結晶形を粉末X線回折測定あるいはラマン分光法で確認した。
その他の本明細書中の記号は以下の意味を示す。
JP1:日本薬局方溶出試験第1液
FaSSIF:空腹時人工腸液
FeSSIF:飽食時人工腸液
API:6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミド
APIとL−リンゴ酸との共結晶
約1gのAPIの無水物結晶を10mLのアセトンに、約130mgのL−リンゴ酸を約1mLのエタノールにそれぞれ50℃で溶解して、混和させた。得られた溶液を50℃に保ちながら熱時ろ過して約17mLのn−ヘプタンをゆっくり加えた。得られた溶液を室温で放冷することにより得られた析出物をろ取して、80℃で減圧乾燥して結晶を得た。
APIとL−酒石酸との共結晶
約1gのAPIの無水物結晶を約10mLのメチルエチルケトンに、約146mgのL−酒石酸を約1mLのエタノールにそれぞれ75℃で溶解して、混和させた。得られた溶液を75℃に保ちながら熱時ろ過して、約9.5mLのn−ヘプタンをゆっくり加えた。得られた溶液を室温で放冷することにより得られた析出物をろ取して、80℃で減圧乾燥して結晶を得た。
本発明の共結晶を有効成分として含有する医薬は、例えば、次のような処方によって製造することができる。
1.カプセル剤
(1)実施例1で得られた共結晶 40mg
(2)ラクトース 70mg
(3)微結晶セルロース 9mg
(4)ステアリン酸マグネシウム 1mg
1カプセル 120mg
(1)、(2)、(3)および(4)の1/2を混和した後、顆粒化する。これに残りの(4)を加えて全体をゼラチンカプセルに封入する。
(1)実施例1で得られた共結晶 40mg
(2)ラクトース 58mg
(3)コーンスターチ 18mg
(4)微結晶セルロース 3.5mg
(5)ステアリン酸マグネシウム 0.5mg
1錠 120mg
(1)、(2)、(3)、(4)の2/3および(5)の1/2を混和した後、顆粒化する。残りの(4)および(5)をこの顆粒に加えて錠剤に加圧成型する。
日局注射用蒸留水50mlに実施例1で得られた共結晶50mgを溶解した後、日局注射用蒸留水を加えて100mlとする。この溶液を滅菌条件下でろ過し、次にこの溶液1mlずつを取り、滅菌条件下、注射用バイアルに充填し、凍結乾燥して密閉する。
Claims (12)
- (1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸またはL-酒石酸との共結晶。
- (1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶である請求項1記載の共結晶。
- 粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2および8.6±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する請求項2記載の共結晶。
- (1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶である請求項1記載の共結晶。
- 粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2および8.7±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する請求項4記載の共結晶。
- 請求項1記載の共結晶を含有してなる医薬。
- Smo阻害剤である請求項6記載の医薬。
- 癌の予防および/または治療剤である請求項6記載の医薬。
- 哺乳動物における癌の治療のための医薬の製造のための、請求項1記載の共結晶の使用。
- 医薬がSmo阻害剤である、請求項9記載の使用。
- 癌が、大腸癌、肺癌、中皮腫、膵癌、咽頭癌、喉頭癌、食道癌、胃癌、十二指腸癌、小腸癌、乳癌、卵巣癌、精巣腫瘍、前立腺癌、肝臓癌、甲状腺癌、腎臓癌、子宮癌、脳腫瘍、網膜芽細胞腫、皮膚がん、肉腫、悪性骨腫瘍、膀胱癌、および血液癌の1以上から選ばれる、請求項10記載の使用。
- 癌が、神経膠腫、髄芽細胞腫、基底細胞腫、小細胞肺癌、膵癌、胆管癌、前立腺癌、食道癌、胃癌、大腸癌、横紋筋肉腫および乳癌の1以上から選ばれる、請求項10記載の使用。
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WO2017135259A1 (ja) | 2017-08-10 |
US12024512B2 (en) | 2024-07-02 |
EP3412667A4 (en) | 2019-09-18 |
EP3412667A1 (en) | 2018-12-12 |
CN113788826A (zh) | 2021-12-14 |
EA035376B1 (ru) | 2020-06-03 |
EP3954372A1 (en) | 2022-02-16 |
US20210115039A1 (en) | 2021-04-22 |
JPWO2017135259A1 (ja) | 2018-11-22 |
EP3412667B1 (en) | 2021-11-03 |
HUE057240T2 (hu) | 2022-04-28 |
EA201891736A1 (ru) | 2019-02-28 |
CN108884094A (zh) | 2018-11-23 |
CN108884094B (zh) | 2021-09-21 |
DK3412667T3 (da) | 2022-01-10 |
ES2902513T3 (es) | 2022-03-28 |
US20200048245A1 (en) | 2020-02-13 |
CA3013183A1 (en) | 2017-08-10 |
PT3412667T (pt) | 2022-01-20 |
US10906898B2 (en) | 2021-02-02 |
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