JP6463333B2 - オキシカルバゼピンの急速分散性の剤形 - Google Patents
オキシカルバゼピンの急速分散性の剤形 Download PDFInfo
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- JP6463333B2 JP6463333B2 JP2016502709A JP2016502709A JP6463333B2 JP 6463333 B2 JP6463333 B2 JP 6463333B2 JP 2016502709 A JP2016502709 A JP 2016502709A JP 2016502709 A JP2016502709 A JP 2016502709A JP 6463333 B2 JP6463333 B2 JP 6463333B2
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- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
- B29K2105/0005—Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
- B29K2105/0035—Medical or pharmaceutical agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
- B29K2105/0058—Liquid or visquous
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
- B29K2105/25—Solid
- B29K2105/251—Particles, powder or granules
Description
号、第6,213,168号、第6,336,480号、第6,363,606号、第6,375,874号、第6,508,971号、第6,530,958号、第6,547,994号、第6,596,224号、第6,772,026号、第6,850,334号、第6,905,645号、第6,945,638号、第6,989,115号、第7,220,380号、第7,291,002号、第7,365,129号、第7,435,368号、第7,455,804号、第7,828,022号、第8,017,055号;PCT国際公開第WO00/26026号、第WO98/043762号、第WO95/034468号、第WO95/011007号;および、その構築のため円柱状の(放射状または対極の)座標に基づく(coordinate−based)システムを使用する欧州特許第1,631,440号に開示されている。これら参考の各々の開示全体が本明細書に組み入れられる。
以下のプロセスを用いて、オキシカルバゼピンの薬物含有粒子を作製した。指摘する量の以下の成分を用いた。
示差走査熱量測定を用いて、材料をコーティングされている粒子に含める前および後の結晶化度のレベルを決定した。温度傾斜プロファイルに以下のプロセスを用いた。
1.−10℃で平衡化;
2.10℃/分で70℃まで傾斜;
3.5分間等温;
4.10℃/分で−20℃まで傾斜;
5.−20℃で平衡化;
6.60秒ごとに±0.8℃調整;
7.2分間等温;
8.5℃/分で250℃まで傾斜;
9.5℃/分で−10℃まで傾斜.
以下のプロセスを用いて、オキシカルバゼピンの結合型薬物コーティング粒子を含むマトリクスを含む、味覚マスキングした3次元印刷された口内分散性の剤形を調製した。以下に指摘する量の印刷液およびバルク粉末用の成分を用いた:
上記に記載した3DPプロセスに従うが;増加性の層の硬さおよび組成が多様である、異なる構造の剤形を調製するために、これをいくつかの異なる方法において行うことができた。以下のプロセスは、剤形の内部ポーションの硬さに比べて、上部および下部表面の硬さが硬い剤形を提供するものであった。この戦術は、機械的性質の異なる剤形内にセクションを作製する手助けとなった。この取組みを用いて、頂部および底部の層の組成が中間の層と異なる剤形をデザインした。このデザインにより、剤形はより強力な頂部および底部の層を有することができ、それにより硬さは増大し、摩損性は低下し、硬さの低い大型の中央ポーションにより剤形が急速に分散できるようになった。
このプロセスでは、異なる増加性の層、または同じ増加性の層内の異なる予め規定された領域内に堆積する結合剤の量が変化した。実施例3のプロセスに従いこれらの剤形を調製したが、結合剤の濃度が異なる印刷液を用いることにより、印刷液によって粉末上に堆積する結合剤の量は、増加性の粉末層間で異なった。
実施例3のプロセスに従いこれらの剤形を調製したが、粉末上に堆積する印刷液の量は増加性の粉末層間で異なった。上部および下部の増加性の層は、より大量の印刷液を受け取り、中央ポーションの増加性の層は、より少量の印刷液を受け取った。
このプロセスでは、剤形の上部および下部の増加性の層に用いる印刷パターンはソリッドパターンである(図3A)。増加性の層の中央ポーションに対する印刷パターンはグレースケールである(図3B)。
このプロセスでは、剤形の増加性の層の上部および下部の増加性の層に用いる印刷パターンはソリッドパターンである(図3A)。増加性の層の中央ポーションに対する印刷パターンは、環によって取り囲まれるエリアに印刷のない、環状/中空の高飽和印刷である(図3C)。
このプロセスでは、剤形の増加性の層の上部および下部の増加性の層に用いる印刷パターンはソリッドパターンである(図3A)。増加性の層の中央ポーションに対する印刷パターンは、外部の高飽和印刷によって取り囲まれる内部のグレースケール印刷の組合せである(図3D)。
以下の手順を用いて、3次元印刷された固体の多孔性口内分散性のマトリクスをキャラクタリゼーションした。
錠剤摩損度試験(tablet friability test)(USPプロトコール<1216>)を用いて、破壊に対するマトリクスの抵抗性を分析した。試験では、25rpmで100回回転する、直径285mm、深さ39mmの寸法を有するドラムを装着したVanKel摩損性測定装置(friabilator)(モデル45−2000、Varian、USA)を用いた。最小数10個の剤形を、ドラムの中央から外部壁に延びる歪曲した突出によって、各回転時に転倒した。よって、各回転時に、錠剤は回転または滑走を引き起こされ、ドラム上または相互に約130mm落下させられた。ゆるい粉末を全て錠剤から取り除き、100回転の前および後にこれらをまとめて重量を測った。
マトリクスを、顕微鏡の助けで、またはそれなしで目視点検した。表面の質感を分析して、ラフであるか、またはスムーズであるか、ならびに上部表面上の証印の縁、および剤形の周囲の縁が清浄で鋭利であるか、または粗く尖っているかを決定した。
マトリクスを、VK200錠剤硬度試験機(Varian、US)を用いて、USP<127>(第31改定)に従って錠剤破壊力アッセイによって決定される全体の硬さについて分析した。剤形の強度または硬さは破砕試験によって測定した。剤形を試験機のジョーの間の中央に置き、剤形が破砕するまで力を適用した。破砕時の負荷をキロポンド(kp)で返した。キロポンドは、力の測定の測量単位で、1kpは9.807ニュートンに等しい。最小数6個の剤形を試験した。
マトリクスを、5kgのロードセルおよび直径1.0インチのアクリル製プローブ(Stable Micro Systems)を装着したTexture Analyzer(TA HP、Texture Technologies、US)を用いて、以下の通り、水性液体中の分散時間に対して分析した。剤形を、両面接着テープでプローブに接着させた。50gの一定の力の下で(Dorら、Pharm.Dev.Technol.(2000年)、5巻(4)、575〜577頁;およびEl−Ariniら、Pharm.Dev.Technol.(2002年)、7巻(3)、361〜371頁)、平底アルミニウム製秤量ボート(weigh boat)中、室温で、剤形を水3ml中に浸漬した。分散時間試験は、以下のパラメータを用いて行った。最小5個の剤形を試験した。
マトリクスのかさ密度を、剤形の重量を測定し、その値を剤形の計算体積によって除すことにより決定した。剤形の体積を、その寸法を測定し、剤形の形状に従って適切な数式を用いることにより計算した。例えば、円柱状剤形では、その体積を、π*r2*Hの式を用いて計算する(式中、rはウエハーの半径であり、Hはウエハーの高さである)。重量0.5g、高さ0.6cm、および直径1.1cmの剤形の体積は約0.57cm3であり、かさ密度は約0.877g/cm3であり、これは約877mg/mlに等しい。
溶解試験を、産業向け指針(Guidance for Industry)(セクション3.3.2;Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate−Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.、2000年8月、セクションIIIc、7頁)に従って行った。USP<711>の方法に従った。溶解を、以下の脱気した溶解媒体900mL:(1)0.1N HCl;(2)pH4.5の0.05M酢酸ナトリウムバッファー;および(3)37℃でpH6.8の0.05M KH2PO4バッファー、を用いて、50rpmのUSP Apparatus II(パドル)を用いて行った。
この方法を用いて、剤形の効能を確立した。オキシカルバゼピンを含む単一剤形を、12時間間隔で1日2回対象に投与した。剤形を対象の口中に配置し、場合により一口(5〜20ml)の液体を対象に投与することによって、投与を行った。短時間内に剤形は対象の口中で分散した。あるいは、剤形を最小量の液体中に分散し、次いで対象に経口投与した。オキシカルバゼピンの1日量の合計は、約300mgから約1200mgの範囲が典型的であった。対象の薬物動態学的プロファイルを、当技術分野では知られている方法を用いて決定した。剤形に対する治療応答の対象のレベルを、当技術分野では知られている方法を用いて決定した。
上記に記載した3DPプロセスを用いて、オキシカルバゼピンの結合型薬物含有粒子を含むマトリクスを含む、3次元印刷された急速分散性の剤形を調製した。以下に指摘する量の印刷液およびバルク粉末用の成分を用いた。
Claims (16)
- 多孔性の非圧縮の3次元印刷された結合型マトリクスを含む急速分散性の固体剤形であって:
第1のオキシカルバゼピン(OXC)粒子径を有する第1のOXC粒子、第2のOXC粒子径を有する第2のOXC粒子、少なくとも1つの第1の崩壊剤、少なくとも1つの界面活性剤、および薬物含有凝集体内で第1のOXC粒子と第2のOXC粒子とを結合させるための少なくとも1つの第1の結合剤を含む、複数の操作された薬物含有凝集体;
少なくとも1つの第2の崩壊剤;および
3次元印刷された結合型マトリクス内で薬物含有凝集体を結合させるための少なくとも1つの第2の結合剤を含み;
該剤形は、水性液体15ml中に配置した場合、15秒以下で分散し;
該凝集体のサイズと第1のOXC粒子のサイズとの比は1:1から5:1であり;
該凝集体のサイズと第2のOXC粒子のサイズとの比は20:1から50:1であり;
第2のOXC粒子は、薬物含有凝集体内の全OXCの約75重量%から約100重量%を構成する、前記剤形。 - 急速分散性の3次元印刷された多孔性の非圧縮の結合型マトリクスであって:
第1のOXC粒子径を有する第1のOXC粒子、第2のOXC粒子径を有する第2のOXC粒子、および薬物含有凝集体内で第1のOXC粒子と第2のOXC粒子とを結合させるための少なくとも1つの第1の結合剤を含む、複数の操作された薬物含有凝集体;
少なくとも1つの甘味剤;
少なくとも1つの崩壊剤;
少なくとも1つの界面活性剤;
少なくとも1つの流動促進剤;および
3次元印刷された結合型マトリクス内で薬物含有凝集体を結合させるための少なくとも1つの第2の結合剤を含み;
該マトリクスは、15mlの体積の水性液体中、15秒未満で分散し;
該凝集体のサイズと第1のOXC粒子のサイズとの比は1:1から5:1であり;
該凝集体のサイズと第2のOXC粒子のサイズとの比は、20:1から50:1であり
;
第2のOXC粒子は、薬物含有凝集体内の全OXC粒子の約75重量%から約100重量%を構成し;
OXCは、マトリクスの合計重量ベースでマトリクスの約35重量%から約60重量%を構成する、前記マトリクス。 - a)第1のOXC粒子または第2のOXC粒子の少なくとも1つは、二峰性、もしくは多峰性の粒子径分布を有し;b)薬物含有凝集体は、一峰性、二峰性、もしくは多峰性の粒子径分布を有し;またはc)上記の1つまたはそれ以上の組合せである、請求項1に記載の剤形または請求項2に記載のマトリクス。
- a)少なくとも1つの界面活性剤が、マトリクスの合計重量の約0.5重量%から約7.0重量%を構成し;b)少なくとも1つの甘味剤が、マトリクスの合計重量の約0.01重量%から約2.0重量%を構成し;c)少なくとも1つの第1の結合剤および少なくとも1つの第2の結合剤が、合わせてマトリクスの合計重量の約5重量%から約15重量%を構成し;d)少なくとも1つの第1の崩壊剤および少なくとも1つの第2の崩壊剤が、合わせてマトリクスの合計重量の約10重量%から約30重量%を構成し;および/またはe)少なくとも1つの流動促進剤が、マトリクスの合計重量の最大約2%を構成する、請求項1に記載の剤形または請求項2に記載のマトリクス。
- a)マトリクスの硬さは約1キロポンドから約7キロポンド、または約1キロポンドから約3キロポンドの範囲であり;b)マトリクスは、水または唾液15ml中に配置した場合10秒以下で分散し;c)少なくとも1つの第2の結合剤は、マトリクスを形成するのに用いられる印刷液によってマトリクス中に導入され;d)少なくとも1つの第2の結合剤は、マトリクスを形成するのに用いられるバルク粉末によってマトリクス中に導入され;e)マトリクスは、OXC約150mgから約600mgを含み;ならびに/またはf)マトリクスは、3次元印刷された増加性の層を10から40含む、請求項1に記載の剤形または請求項2に記載のマトリクス。
- 薬物含有凝集体は、少なくとも1つの甘味剤および/または少なくとも1つの香味剤をさらに含む、請求項1に記載の剤形または請求項2に記載のマトリクス。
- a)薬物含有凝集体は、マトリクスの合計重量の約55重量%から約85重量%、約60重量%から約80重量%、もしくは約65重量%から約70重量%を構成し;b)第1のOXC粒子および第2のOXC粒子は、合わせて薬物含有凝集体の合計重量の約55重量%から約85重量%、約60重量%から約80重量%、もしくは約65重量%から約70重量%を構成し;c)第1の崩壊剤は、薬物含有凝集体の合計重量の0重量%から約30重量%、約1重量%から約15重量%、もしくは約2重量%から約5重量%を構成し;d)第1の結合剤は、薬物含有凝集体の合計重量の0重量%から約10重量%、約1重量%から約7重量%、もしくは約2重量%から約5重量%を構成し;e)界面活性剤は、薬物含有凝集体の合計重量の0重量%から約10重量%、約1重量%から約5重量%、もしくは約1.4重量%から約4.2重量%を構成し;および/またはf)薬物含有凝集体は湿式造粒法により製造された顆粒である、請求項1に記載の剤形または請求項2に記載のマトリクス。
- マトリクスは、OXCを、約150mgから約1200mg、約150mg、約300mg、約450mg、約600mg、約750mg、約900mg、約1050mg、または約1200mg含む、請求項1に記載の剤形または請求項2に記載のマトリクス。
- 剤形は、ウエハー、円柱、環、ドーナツ、チューブ、立方体、球状体、楕円体、または長方形の箱として成形される、請求項1に記載の剤形。
- a)第1の結合剤および第2の結合剤は、ポリビニルピロリドン(ポビドン)、マンニトール、ヒドロキシプロピルセルロース、およびこれらの組合せからなる群から選択され;b)第1の崩壊剤および第2の崩壊剤は、微結晶性セルロース、2つのグレードの微結晶性セルロースの組合せ、クロスカルメロース、およびこれらの組合せからなる群から選択され;またはb)上記の組合せである、請求項1に記載の剤形または請求項2に記載のマトリクス。
- オキシカルバゼピンに治療的に応答性である疾患、状態、または障害を処置するための医薬を製造するための、請求項1に記載の剤形または請求項2に記載のマトリクスの使用であって、ここで該医薬は処置期間を通して、1日1回から3回、それを必要とする対象に投与される、上記使用。
- 増加性の層の厚さは、約0.006インチから約0.014インチ、または約0.008インチから約0.012インチの範囲である、請求項5に記載の剤形またはマトリクス。
- 第1の結合剤および第2の結合剤の少なくとも1つは、水性液体可溶性または部分的に水性液体可溶性である、請求項1に記載の剤形。
- 第1の結合剤および第2の結合剤の少なくとも1つは、水性液体可溶性または部分的に水性液体可溶性である、請求項2に記載のマトリクス。
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US201361791726P | 2013-03-15 | 2013-03-15 | |
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PCT/US2014/028125 WO2014143935A1 (en) | 2013-03-15 | 2014-03-14 | Rapidly dispersible dosage form of oxcarbazepine |
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JP2016502709A Active JP6463333B2 (ja) | 2013-03-15 | 2014-03-14 | オキシカルバゼピンの急速分散性の剤形 |
JP2018172088A Abandoned JP2019006812A (ja) | 2013-03-15 | 2018-09-14 | オキシカルバゼピンの急速分散性の剤形 |
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JP2018172088A Abandoned JP2019006812A (ja) | 2013-03-15 | 2018-09-14 | オキシカルバゼピンの急速分散性の剤形 |
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US (4) | US9314429B2 (ja) |
EP (1) | EP2968354B1 (ja) |
JP (2) | JP6463333B2 (ja) |
CN (1) | CN105050604B (ja) |
AU (2) | AU2014228063B2 (ja) |
CA (1) | CA2906107C (ja) |
ES (1) | ES2761265T3 (ja) |
HK (2) | HK1213472A1 (ja) |
MX (1) | MX364381B (ja) |
WO (1) | WO2014143935A1 (ja) |
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CN105770899A (zh) * | 2016-03-07 | 2016-07-20 | 北京诺康达医药科技有限公司 | 一种大剂量药物的速释制剂及其制备方法 |
AU2017235598A1 (en) * | 2016-03-18 | 2018-08-09 | Grünenthal GmbH | Floating pharmaceutical dosage form |
US10765658B2 (en) | 2016-06-22 | 2020-09-08 | Mastix LLC | Oral compositions delivering therapeutically effective amounts of cannabinoids |
GB201612853D0 (en) | 2016-07-25 | 2016-09-07 | Univ Central Lancashire | Solid dosage form production |
US10703549B2 (en) * | 2017-06-30 | 2020-07-07 | The Procter And Gamble Company | Water soluble containers and methods of making them |
WO2019081540A1 (en) * | 2017-10-26 | 2019-05-02 | Merck Patent Gmbh | METHODS FOR ACHIEVING CELL CULTURE |
CN116270513A (zh) | 2018-01-09 | 2023-06-23 | 南京三迭纪医药科技有限公司 | 一种包含固定剂量adhd非兴奋剂和adhd兴奋剂的复方口服药物剂型 |
CN112867482B (zh) | 2018-10-15 | 2023-04-25 | 阿普雷奇亚制药有限责任公司 | 在包装内形成剂型的方法和系统 |
EP3662898A1 (en) * | 2018-12-07 | 2020-06-10 | Tillotts Pharma AG | Solid composition comprising mesalazine |
EP3913243A4 (en) | 2019-01-18 | 2022-10-19 | IHI Corporation | PRINT FOIL STORE |
EP3789015A1 (en) * | 2019-09-05 | 2021-03-10 | Universität Innsbruck | Fast consolidating compounds |
ES2828509B2 (es) | 2019-11-26 | 2022-03-09 | Fund Idonial | Composicion para la impresion 3d de farmacos semisolidos |
CA3183295A1 (en) | 2020-06-26 | 2021-12-30 | Jaedeok Yoo | Rapidly-orodispersible tablets having an interior cavity |
WO2024038000A1 (en) * | 2022-08-18 | 2024-02-22 | Merck Patent Gmbh | Process for the manufacture of a solid pharmaceutical administration form |
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2014
- 2014-03-14 CA CA2906107A patent/CA2906107C/en active Active
- 2014-03-14 ES ES14763545T patent/ES2761265T3/es active Active
- 2014-03-14 JP JP2016502709A patent/JP6463333B2/ja active Active
- 2014-03-14 CN CN201480014727.3A patent/CN105050604B/zh active Active
- 2014-03-14 MX MX2015012136A patent/MX364381B/es active IP Right Grant
- 2014-03-14 WO PCT/US2014/028125 patent/WO2014143935A1/en active Application Filing
- 2014-03-14 EP EP14763545.2A patent/EP2968354B1/en active Active
- 2014-03-14 AU AU2014228063A patent/AU2014228063B2/en active Active
-
2015
- 2015-08-27 US US14/837,493 patent/US9314429B2/en active Active
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2016
- 2016-02-04 HK HK16101293.4A patent/HK1213472A1/zh unknown
- 2016-02-17 US US15/045,711 patent/US9616018B2/en active Active
- 2016-03-02 HK HK16102379.9A patent/HK1214173A1/zh unknown
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2017
- 2017-02-21 US US15/437,966 patent/US10028909B2/en active Active
- 2017-05-19 AU AU2017203365A patent/AU2017203365B2/en active Active
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2018
- 2018-06-22 US US16/015,552 patent/US20180296479A1/en not_active Abandoned
- 2018-09-14 JP JP2018172088A patent/JP2019006812A/ja not_active Abandoned
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MX364381B (es) | 2019-04-25 |
AU2014228063B2 (en) | 2017-04-20 |
US20150366802A1 (en) | 2015-12-24 |
CN105050604B (zh) | 2021-10-26 |
CA2906107A1 (en) | 2014-09-18 |
AU2014228063A1 (en) | 2015-10-08 |
HK1213472A1 (zh) | 2016-07-08 |
US10028909B2 (en) | 2018-07-24 |
JP2016513724A (ja) | 2016-05-16 |
JP2019006812A (ja) | 2019-01-17 |
US20160250145A1 (en) | 2016-09-01 |
HK1214173A1 (zh) | 2016-07-22 |
US20180296479A1 (en) | 2018-10-18 |
CA2906107C (en) | 2021-08-24 |
CN105050604A (zh) | 2015-11-11 |
AU2017203365A1 (en) | 2017-06-08 |
EP2968354A1 (en) | 2016-01-20 |
ES2761265T3 (es) | 2020-05-19 |
EP2968354B1 (en) | 2019-11-13 |
AU2017203365B2 (en) | 2019-07-25 |
WO2014143935A1 (en) | 2014-09-18 |
MX2015012136A (es) | 2015-11-25 |
US9314429B2 (en) | 2016-04-19 |
US20170172919A1 (en) | 2017-06-22 |
WO2014143935A4 (en) | 2014-11-20 |
EP2968354A4 (en) | 2016-01-20 |
US9616018B2 (en) | 2017-04-11 |
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