JP2017534673A - 精神病性障害を治療するための方法および組成物 - Google Patents
精神病性障害を治療するための方法および組成物 Download PDFInfo
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Abstract
Description
本出願は、2014年9月15日に出願された米国特許仮出願第62/050,635号の恩典を主張し、これは参照によりその全体が本明細書に組み入れられる。
本発明は、GPx媒介障害を治療する組成物および方法に関する。特に、組成物は、グルタチオンペルオキシダーゼモジュレーターと抗精神病薬との組み合わせを含む。
数十年間にわたって、ドーパミンは、統合失調症(SZ)についての病態生理学的視点および療法の中心であり、GABAおよびグルタミン酸神経伝達理論が続いた。最近になって、SZの病態生理は酸化ストレスと強く関連付けられた(Do et al., 2009; Kano et al., 2013)。中枢神経系のニューロンなどの活性細胞において、自然抗酸化防御は、グルタチオンの還元形態、即ち単量体グルタチオン(GSH)の、グルタチオンペルオキシダーゼ(GPx)による、グルタチオンの酸化形態、即ちグルタチオンジスルフィド(GSSG)への変換を介しての、グルタチオンによるフリーラジカルの隔離を含む。GPxの主な機能および酸化還元機構のGSH→GPx→GSSG方向は、フリーラジカル、例えば、過酸化水素(H2O2)、ペルオキシ亜硝酸(ONOO-)、および脂質ヒドロペルオキシド(LOOH)をそれらの対応の酸化還元不活性相当物、例えば水およびアルコールへ還元し、細胞膜、タンパク質および他の構造体を酸化的損傷から保護することである。
その多くの態様において、本開示は、例えば、グルタチオンペルオキシダーゼ(GPx)モジュレーターとして有用な化合物の新規の組み合わせ、そのような組み合わせを調製する方法、1つまたは複数のそのような組み合わせを含む薬学的組成物、1つまたは複数のそのような組み合わせを含む薬学的組成物を調製する方法、およびそのような組み合わせまたは薬学的組成物を使用して、GPx媒介障害と関連する1つまたは複数の疾患を治療、予防、抑制、または改善する方法を提供する。
の式を有する(2-フェニル-1,2-ベンゾイソセレナゾール-3(2H)-オン)である、エブセレンを含む。
の化合物を含み、
式中、
R1は、H、メチル、エチル、またはイソプロピルであり;
R2は、H、またはエチルであり;かつ
R3は、H、アセチル、フェニルアセチル、
である。
の化合物を含み、
式中、
R1は、H、オキソ、メチル、エチル、n-プロピル、n-ペンチル、フェニル、-(CHOH)nCH2OH、ここでnは1〜5である、または
であり;かつ
R2は、Hまたは-COOHである。
本発明のこれらおよび他の特徴、局面、および利点は、以下の説明、および添付の図面に関してよりよく理解されるだろう。
本開示における態様は、GPx媒介障害、酸化ストレス亢進、統合失調症、双極性障害、うつ病、躁病、不安症または関連精神病性障害、遅発性ジスキネジア、およびそれらの随伴症状または合併症を含むがこれらに限定されない、多数の状態の治療、改善、予防、または抑制のための、少なくとも2つの化合物の新規の組み合わせに関し、第1の化合物はグルタチオンペルオキシダーゼモジュレーターを含み、第2の化合物は抗精神病薬である。
の式を有する(2-フェニル-1,2-ベンゾイソセレナゾール-3(2H)-オン)である、エブセレンを含む。
の化合物を含み、
式中、
R1は、H、メチル、エチル、またはイソプロピルであり;
R2は、H、またはエチルであり;かつ
R3は、H、アセチル、フェニルアセチル、
である。
の化合物を含み、
式中、
R1は、H、オキソ、メチル、エチル、n-プロピル、n-ペンチル、フェニル、-(CHOH)nCH2OH、ここでnは1〜5である、または
であり;かつ
R2は、Hまたは-COOHである。
一般に、特許請求の範囲および明細書において使用される用語は、当業者によって理解される普通の意味を有すると解釈されるように意図される。追加の明確さを提供するために、ある用語を下記に定義する。普通の意味と提供される定義との間に矛盾がある場合、提供される定義が使用される。特許請求の範囲および明細書において使用される用語は、特に指定のない限り以下に記載されるとおりに、または本開示の全体にわたるそれらの使用によって、定義される。
・ACC:前帯状皮質
・AEC:有害事象チェックリスト
・BPRS:簡便精神医学的評価尺度
・CAT:カタラーゼ
・CDSS:統合失調症に関するカルガリーうつ病尺度
・C-SSRS:コロンビア自殺重症度評価尺度
・EOS:試験終了
・GSH:グルタチオンの還元形態
・GSSG:グルタチオンの酸化形態
・GPx:グルタチオンペルオキシダーゼ
・GR:グルタチオンレダクターゼ
・MCCB:MATRICSコンセンサス認知機能評価バッテリー
・MMN:ミスマッチ陰性電位
・MRS:磁気共鳴分光法
・NAC:N-アセチル-システイン
・NC:正常対照
・NMDAR:N-メチル-D-アスパラギン酸受容体
・POC:概念実証
・Redox:還元/酸化
・RNS:活性窒素種
・ROS:活性酸素種
・SOD:スーパーオキシドジスムターゼ
・SPI:サウンド・ファーマシューティカル・インコーポレイテッド
・SZ:統合失調症患者または統合失調症
・UPSA:カリフォルニア日常生活技能簡易評価尺度
・hまたはhr (時間)
・LCMS (高圧液体クロマトグラフィー質量分析計)
・Me (メチル)
・Mg (ミリグラム)
・rtまたはRT (室温)
・TLC (薄層クロマトグラフィー)
本発明の代表的な化合物を本明細書および特許請求の範囲の全体にわたって記載する。
を有する(2-フェニル-1,2-ベンゾイソセレナゾール-3(2H)-オン)である、エブセレンを含む。
本化合物はGPxモジュレーターであり、従って、統合失調症、双極性障害、精神病性障害、およびそれに関連する他の障害、疾患または状態を含むがこれらに限定されないGPx媒介状態の治療、予防、または進行抑制に有用である。
GPxによって媒介される障害、疾患、または状態の治療における当業者は、本明細書以下に提示される試験結果および他の情報から、有効な一日量を決定することができる。厳密な投与量および投与頻度は、当業者には周知であるように、使用される本発明の特定の化合物、治療される特定の状態、治療される状態の重症度、特定の患者の年齢、体重、および全身的な健康状態、ならびに患者が服用中であってもよい他の医薬に依存する。さらに、前記有効な一日量が、治療される患者の応答に応じて、および/または本発明の化合物を処方する医師の評価に応じて、減少または増加されてもよいことは明白である。本明細書に記載される有効な一日量の範囲は、従って、本発明の実施における、単なるガイドラインである。
本明細書に開示される薬学的組成物を調製するために、有効成分としての本明細書に開示される1つまたは複数の化合物またはその塩を、従来の薬学的配合技術に従って、薬学的担体と完全に混合し、この担体は、投与(例えば、経口または非経口)に望ましい調製物の形態に応じて様々な形態をとることができる。好適な薬学的に許容される担体は、当技術分野において周知である。これらの薬学的に許容される担体のいくつかの説明は、American Pharmaceutical AssociationおよびPharmaceutical Society of Great Britain出版のThe Handbook of Pharmaceutical Excipientsに見出すことができる。
さらに、新生仔期腹側海馬傷害(neonatal ventral hippocampal lesion)(NVHL)ラットを使用する方法、ならびに、酸化ストレス、統合失調症、双極性障害、および他の精神病性障害を含むがこれらに限定されない、GPx媒介障害を代表する動物モデルの分析/診断に関する方法を本明細書に開示する。本明細書に開示されるこれらの方法の用途は、研究適用、治療的目的、医学的診断、および/または1人または複数の患者もしくは対象の階層化を含み得る。GPx媒介障害の予防または治療に有用である組成物を同定する方法を開示する。
幼若NVHLラットのPFC中の酸化ストレス免疫標識のレベルの増加が、PV細胞カウントの減少、PPI不足、局所PFC回路の変更されたドーパミン調節、および成体NVHLラットのEEGにおける誘発関連電位の不足と共に観察された。これらの不足の全てが、P5からP50までのN-アセチルシステイン(NAC)処置で予防された。NAC処置が青年期の間(P35)にかつ2つの他の酸化還元モジュレーター(エブセレン、アポシニン)によって開始された場合、PPI不足はまた予防された。データは、前前頭皮質における酸化ストレスが、NVHLによって誘導された変更を媒介するコアな特徴であり、抗酸化処置がこれらの変更を予防することを示した。従って、PVI中に高度に存在しかつ錐体ニューロン中にも観察される発症前酸化ストレスは、酸化還元経路の直接操作を伴わない神経発達モデルにおける多様な統合失調症関連現象を担う。
この実施例は、エブセレン単独でまたは別の抗精神病剤と組み合わせて治療された患者に対する生理学的効果を記載する。前臨床試験におけるエブセレンの主要転帰の一つは、統合失調症(SZ)患者について減少することが以前に示された(Do et al., 2000; Wood et al. 2009)、神経GSHレベルの増大を示した。磁気共鳴分光法(MRS)を改良し、エブセレンによる脳ターゲットエンゲージメントの間、GSHをモニタリングした。磁気共鳴断層撮影装置を使用して効果の大きさを評価するために、非常に短いエコー時間1H-MRSシーケンスを使用して、11人の統合失調症患者および11人の正常対照患者におけるGSHレベルを評価した。図2Aおよび2Bに示されるように前帯状皮質(ACC)でのGSHは、正常対照患者と比較してSZ患者において減少した(平均値±sd=2.4±0.3 vs. 2.6±0.4、F=2.0、p=0.17; d=0.65)。この方法を使用して、スペクトル定量化は、GSHおよび他の成分について素晴らしいフィッティングをもたらし、クラメール・ラオの下限(CRLB)は10未満であった。
この実施例は、酸化還元調節部位中に含有される酸化還元感受性タンパク質であるN-メチル-D-アスパラギン酸受容体についてのミスマッチ陰性電位(MMN)を記載する(Do et al., 2009, Gonzalez-Burgos et al., 2012, Choi et al., 2012, Kohr, et al., 1994, Nakazawa, et al., 2012)。エブセレンは、この酸化還元調節部位を調節し、ニューロン生存可能性を増大させる(Herin, et al., 2001)。統合失調症(SZ)は、ミスマッチ陰性電位によって指標を付けられると考えられる、N-メチル-D-アスパラギン酸受容体機能不全と関連する(Javitt, et al., 1993, Javitt, et al., 1998, Javitt, et al., 1996)。n-アセチルシステインの投与は、SZにおけるミスマッチ陰性電位を改善した(Berk, et al., 2008, Lavoie, et al., 2008)。MMNおよび末梢GSHは、図3に示されるように対照において有意に相関した。もっともらしくは調節不全関係に起因して、相関性はSZにおいて有意ではなく、何故ならば、図3A〜3Cに示されるように、MMNおよびGSHの両方がSZにおいて減少するためである。MMNは、エブセレン効果が、存在する場合、NMDAR関連機構を通して媒介されるかどうかを試験するためのバイオマーカーとして役立ち得る。
エブセレンはGPxの小分子模倣物であり、これは、ヒトにおいて、同様のペルオキシダーゼ機能を有する8個のアイソザイムのファミリーを伴う。大部分のGPxアイソザイムは、そのセレン(Se)部分へのフリーラジカルの結合によって活性酸素/窒素種(ROS/RNS)を還元する。GSHと反応することによって、GPxは、過酸化水素(H2O2)(図5A、Wendel, et al., 1984, Reiter, et al., 1984, Muller, et al., 1984)、2つのフリーラジカルであるスーパーオキシドアニオンおよび一酸化窒素によって形成されるRNSラジカルである、ペルオキシ亜硝酸(ONOO-)(図5B、Noguchi, et al., 1992, Daiber, et al., 2000)、および酸化還元不活性アルコールへ脂質ヒドロペルオキシド(LOOH)(図5C、Sies, 1994)を還元することを通して、フリーラジカル毒性を制限することにより細胞保護的である。エブセレンはまた、図5Dに示されるようにテオレドキシン(theoredoxin)(Trx)の基質である(Zhao, et al., 2002)。しかしながら、GPx酵素自体の投与は、その大きなサイズおよび不安定性に起因して実用的ではない。
エブセレンは、素晴らしい経口利用可能性を有する(Fisher et al., 1988)。脳レベルは血漿中レベルの約20%であった(Imai, et al., 2001, Ullrich, et al., 1996)。その神経保護効果は10 uMの血漿中レベルで観察される(Zhao, et al., 2002)。Ph-1試験が、プラセボ対照、無作為化、単一漸増用量設計で、32人のヒトにおいて行われた。エブセレンは製剤中200 mg〜1600 mgの範囲であった。(1)薬物動態:エブセレンおよびその3つの代謝産物のPKパラメータが公表された(Lynch, et al., 2009)。簡潔には、平均エブセレンCmaxは30.3 ng/mL〜83.4 ng/mLの範囲であり;平均AUC0-tは117.4 ng*hr/mL〜880.6 ng*hr/mLの範囲であり;Tmax中央値は1.5〜2.3時間の範囲であり;平均t1/2は6.4〜16.7時間の範囲であった。2-グルクロニルセレノベンズアニリドが主要な代謝産物であった。(2)安全性:重篤な有害事象(AE)またはAEに起因する中止はなかった。全てのAEは、軽度または中程度であり、後遺症なしに消散した。いかなる臨床検査およびECG所見においても治療または用量関連傾向は観察されなかった。表にされた副作用がLynch, et al., 2009において公表された。1600 mgまでの単回経口用量でのエブセレンカプセル剤が、安全であり、健康な男性および女性によって十分に許容されるようであった。
この実施例は、エブセレンの処置によるプレパルス抑制の逆転を記載する。統合失調症研究における最も反復された実験による知見の一つは、皮質抑制性介在ニューロンと関連するマーカーの減少である(Lewis et al., 2012)。成体の新生仔期腹側海馬傷害(NVHL)ラットは、ドーパミンによる異常な調節を特徴とする、変更された皮質介在ニューロン成熟によって引き起こされる電気生理学的異常を示す(Tseng et al., 2008)。背側縁前方および前帯状皮質(ACC)を含む、PFC中のパルブアルブミン(PV)陽性介在ニューロンがNVHLラットにおいて変更されるかどうかを、不偏立体解析学的カウンティング(unbiased stereological counting)技術を使用して、評価した。出生後日数(P)21およびP61の間に、PV免疫反応性介在ニューロン(PVI)の数は、図7Aおよび1Bに示されるように、シャム手術ラットにおいて増加したが、NVHLラットにおいては増加しなかった。幼若ラット(P21)において、NVHLラットとシャムラットとの間でPVIカウントの有意差はなかったが、成体(P61)NVHLラットは、シャムラットと比較して前前頭皮質(PFC)における有意により少ないPVIを示した。PVI減少は、P5(即ち、海馬傷害の2日前)で始まりかつ青年期まで継続する(P50;図7A〜Cに示される)、N-アセチルシステイン(NAC)処置で予防され、このことは、新生仔期傷害によって誘導された幼若酸化ストレスはPVI成熟を損なうことを示唆している。カスパーゼ3標識は、NVHLラットのPFCにおけるアポトーシス活性化を明らかにせず(データを示さず)、このことは、PVI免疫反応性の減少が細胞消失よりも介在ニューロン活性の減少を反映している可能性が高いことを示唆している。
エブセレンは、グルタチオンペルオキシダーゼ(GPx)模倣物(Muller et al., 1984)であり、これは、GPx発現を誘導し(Kil et al., 2007)、ニューロンにおいてGSHレベルを高め、神経毒性機構によって消耗されたGSHを補充する(Pawlas and Malecki, 2007)。成体ビヒクル処置シャム(n=10)、エブセレン処置シャム(n=7)、ビヒクル処置NVHL(n=8)、およびエブセレン処置NVHLラット(n=9)においてPPIを試験し、青年期の間のエブセレン処置は、NVHLラットにおけるPPI不足を逆転した(図15Dに示される通り)。
動物:時期調節して妊娠させたSprague-Dawleyラットを、Charles River (Wilmington, MA)から妊娠日齢13〜15日で得、12:12時間の明/暗サイクル(7:00 AMに点灯)で温度および湿度制御環境において食物および水を自由に与えながら個々に収容した。仔がP5に達すると、雌親の半分は飲料水中のNACを受けた。健康な子孫が無作為に分離されかつNVHLまたはシャム手術のいずれかを受けたP7〜9まで仔を平静にしておいた。P21において、雄性および雌性の仔は、免疫細胞化学のために4%パラホルムアルデヒドを経心腔的に灌流されたか、または、離乳され、かつ傷害状態全体にわたって釣り合いを取った2〜3匹の群で収容された。P50までの青年期の間中NAC処置を継続した。成年期(>P60)に達した後、動物は、免疫細胞化学のために4%パラホルムアルデヒドで灌流されたか、スライス電気生理学のために人工脳脊髄液(aCSF)で灌流されたか、インビボ細胞内記録のために用いられたか、またはPPIもしくはMMNについて試験された。
Claims (21)
- 治療有効量のグルタチオンペルオキシダーゼモジュレーター化合物を同時投与する工程を含む、精神病性障害を治療するための投与される抗精神病薬の用量を減らす方法であって、同時投与される該グルタチオンペルオキシダーゼモジュレーター化合物の存在下での抗精神病化合物の有効投与量が、該グルタチオンペルオキシダーゼモジュレーター化合物の非存在下での該抗精神病化合物の有効用量よりも少ない、方法。
- 前記グルタチオンペルオキシダーゼモジュレーター化合物が、エブセレン、2,2’-ジセレノ-ビス-β-シクロデキストリン、6A,6B-ジセレニン酸-6A’,6B’-セレン架橋β-シクロデキストリン、グルタチオン、グルタチオンプロドラッグ、およびシステインプロドラッグからなる群より選択される、請求項1に記載の方法。
- 前記抗精神病薬が、クロルプロマジン(トラジン)、ハロペリドール(ハルドール)、ペルフェナジン、フルフェナジン、リスペリドン(リスパダール)、オランザピン(ジプレキサ)、クエチアピン(セロクエル)、ジプラシドン(ゲオドン)、アリピプラゾール(エビリファイ)、パリペリドン(インヴェガ)、ルラシドン(ラツーダ)、およびそれらの組み合わせからなる群より選択される、請求項1に記載の方法。
- 前記精神病性障害がGPx媒介障害である、請求項1に記載の方法。
- 前記精神病性障害が、酸化ストレス亢進、統合失調症、双極性障害、うつ病、躁病、不安症、関連精神病性障害、遅発性ジスキネジア、それらの随伴症状または合併症を含む、請求項1に記載の方法。
- 治療有効量のグルタチオンペルオキシダーゼモジュレーター化合物と抗精神病薬とを含む薬物組み合わせを投与する、精神病性障害を治療する方法。
- 前記グルタチオンペルオキシダーゼモジュレーター化合物が、エブセレン、2,2’-ジセレノ-ビス-β-シクロデキストリン、6A,6B-ジセレニン酸-6A’,6B’-セレン架橋β-シクロデキストリン、グルタチオン、グルタチオンプロドラッグ、およびシステインプロドラッグからなる群より選択される、請求項6に記載の方法。
- 前記抗精神病薬が、クロルプロマジン(トラジン)、ハロペリドール(ハルドール)、ペルフェナジン、フルフェナジン、リスペリドン(リスパダール)、オランザピン(ジプレキサ)、クエチアピン(セロクエル)、ジプラシドン(ゲオドン)、アリピプラゾール(エビリファイ)、パリペリドン(インヴェガ)、ルラシドン(ラツーダ)、およびそれらの組み合わせからなる群より選択される、請求項6に記載の方法。
- 前記精神病性障害がGPx媒介障害である、請求項6に記載の方法。
- 前記精神病性障害が、酸化ストレス亢進、統合失調症、双極性障害、うつ病、躁病、不安症、関連精神病性障害、遅発性ジスキネジア、それらの随伴症状または合併症を含む、請求項6に記載の方法。
- 治療有効量のグルタチオンペルオキシダーゼモジュレーター化合物を同時投与する工程を含む、精神病性障害を治療するための抗精神病薬を投与することによる副作用を軽減する方法。
- 前記グルタチオンペルオキシダーゼモジュレーター化合物が、エブセレン、2,2’-ジセレノ-ビス-β-シクロデキストリン、6A,6B-ジセレニン酸-6A’,6B’-セレン架橋β-シクロデキストリン、グルタチオン、グルタチオンプロドラッグ、およびシステインプロドラッグからなる群より選択される、請求項11に記載の方法。
- 前記抗精神病薬が、クロルプロマジン(トラジン)、ハロペリドール(ハルドール)、ペルフェナジン、フルフェナジン、リスペリドン(リスパダール)、オランザピン(ジプレキサ)、クエチアピン(セロクエル)、ジプラシドン(ゲオドン)、アリピプラゾール(エビリファイ)、パリペリドン(インヴェガ)、ルラシドン(ラツーダ)、およびそれらの組み合わせからなる群より選択される、請求項11に記載の方法。
- 前記副作用が遅発性ジスキネジアである、請求項11に記載の方法。
- 治療剤の組み合わせを含み、該組み合わせが、
(i)グルタチオンペルオキシダーゼモジュレーター化合物またはその薬学的に許容される塩;および
(ii)抗精神病薬またはその薬学的に許容される塩
からなる、薬学的組成物。 - 前記グルタチオンペルオキシダーゼモジュレーター化合物が、エブセレン、2,2’-ジセレノ-ビス-β-シクロデキストリン、6A,6B-ジセレニン酸-6A’,6B’-セレン架橋β-シクロデキストリン、グルタチオン、グルタチオンプロドラッグ、およびシステインプロドラッグからなる群より選択される、請求項15に記載の薬学的組成物。
- 前記抗精神病薬が、クロルプロマジン(トラジン)、ハロペリドール(ハルドール)、ペルフェナジン、フルフェナジン、リスペリドン(リスパダール)、オランザピン(ジプレキサ)、クエチアピン(セロクエル)、ジプラシドン(ゲオドン)、アリピプラゾール(エビリファイ)、パリペリドン(インヴェガ)、ルラシドン(ラツーダ)、およびそれらの組み合わせからなる群より選択される、請求項15に記載の薬学的組成物。
- 前記システインプロドラッグが2置換チアゾリジン-4-カルボン酸を含み、チアゾリジン-4-カルボン酸の2置換がアルドース単糖類である、請求項16に記載の薬学的組成物。
- 前記アルドース単糖類が、グリセルアルデヒド、アラビノース、リキソース、リボース、キシロース、ガラクトース、グルコース、およびマンノースからなる群より選択される、請求項20に記載の薬学的組成物。
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JP2005508333A (ja) * | 2001-09-27 | 2005-03-31 | ザ メンタル ヘルス リサーチ インスティチュート オブ ビクトリア | 生理学的過程の調節およびこれに有用な薬剤 |
JP2008538586A (ja) * | 2005-04-21 | 2008-10-30 | グレン エー. ゴールドスタイン, | 酸化ストレスに関連する疾患および病気の処置のためのn−アセチルシステインアミド(nacアミド) |
JP2009513672A (ja) * | 2005-10-31 | 2009-04-02 | ブレインセルス,インコーポレイティド | 神経発生のgaba受容体媒介調節 |
JP2010507572A (ja) * | 2006-10-23 | 2010-03-11 | ザ メンタル ヘルス リサーチ インスティチュート オブ ビクトリア | 併用療法 |
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US20110046090A1 (en) * | 2005-10-31 | 2011-02-24 | Braincells Inc. | Modulation of neurogenesis with gaba agents and gaba analogs |
JP2014524936A (ja) * | 2011-07-28 | 2014-09-25 | プロメンテイス・フアーマシユーテイカルズ・インコーポレイテツド | システインプロドラッグ |
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WO2016044314A1 (en) | 2016-03-24 |
CA2961380A1 (en) | 2016-03-24 |
AU2023200727A1 (en) | 2023-03-09 |
EP3194027A4 (en) | 2018-04-18 |
JP2021181473A (ja) | 2021-11-25 |
KR20230107890A (ko) | 2023-07-18 |
US20210379017A1 (en) | 2021-12-09 |
EP3194027A1 (en) | 2017-07-26 |
AU2021200583A1 (en) | 2021-03-04 |
US20170246148A1 (en) | 2017-08-31 |
US20240050409A1 (en) | 2024-02-15 |
JP2023169413A (ja) | 2023-11-29 |
KR20170066432A (ko) | 2017-06-14 |
AU2015317877A1 (en) | 2017-05-04 |
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