TWI556817B - 藥劑製品之製法 - Google Patents
藥劑製品之製法 Download PDFInfo
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Description
本申請案依美國專利法第119(e)條之規定,主張以2010年11月22日提出申請之第61/416,150號美國臨時專利申請案「附有藥劑製品之可吞式裝置」之申請日為優先權日,該申請案之內容以引用之方式併入本文。
本申請案與下列申請案有關,在此將該等申請案以引用之方式併入本文:2007年10月25日提出申請之第12/447,172號美國專利申請案「受控啟動之可吞式標示器」、2006年10月25日提出申請之第60/862,925號美國臨時專利申請案「受控啟動之藥物資訊學系統」,以及2007年10月25日提出申請之第US2007/82563號PCT國際專利申請案「受控啟動之可吞式標示器」。
本發明係關於電子裝置;詳言之,本發明係關於具有一部分電源且固著於一藥劑製品之電子裝置。
膠囊係由一種一旦接觸流體即變為凝膠狀之材料製成。若膠囊內裝有一可吞式裝置,且該裝置具有可溶性構件及電子元件,則此凝膠狀材料有可能干擾該裝置之運作。例如,由於凝膠狀材料之導電性偏低,若該裝置之運作須藉助流體導電,則該裝置恐將無法正常運作。因此,務須防止膠囊之凝膠狀材料於溶解時接觸該裝置之構件。
此外,膠囊內之藥物在長期儲存之過程中,有可能與該裝置產生交互作用,甚至使該裝置受損。例如,膠囊內之製品可能為酸性,且對電子元件有害;膠囊內容物若鹼性過強,同樣對電子元件有害。此外,膠囊一經吞入並開始分解後,膠囊內之物質或製品便與周圍之流體產生交互作用。膠囊之內容物可包括藥物、賦形劑或化合物等物質,此等物質若以高濃度溶解,將對同一膠囊內之可吞式裝置之運作造成干擾。上述物質於膠囊溶解處進入溶液時,該裝置周圍局部區域之濃度升高。透過胃部運動及擴散作用,膠囊內容物將分散至整個胃部,而濃度亦隨之降低。在此期間,該裝置若於出現局部高濃度之區域內啟動,恐無法正常運作。因此,必須延遲該裝置之啟動時間,且應使該裝置不受膠囊溶解或分解之影響。
承上,該裝置應受到保護,以免受到周圍環境之影響,所謂周圍環境包括膠囊之內容物及濕氣。此外,吾人需要一種用以製造上述裝置且可將此裝置置放於一膠囊內而不使該裝置受損之製程解決方案。因此,須有一種可保護上述裝置之適當系統及製造方法。
本發明所揭示之內容包括一種可保護上述裝置且可將其置放或結合於一藥劑製品或膠囊內之系統及製造方法。此系統包括可置放於某些環境中之電路及構件。該裝置則包括一組件,此組件包括一電子單元、一固著於該單元之撓性膜,以及一保護性包覆層。
除後附之申請專利範圍外,本發明亦由下列條款加以界定:
條款1:一種製造一藥劑製品之方法,該方法包含下列步驟:製造一裝置片體,此裝置片體包括複數個裝置;將一上層片體固著於該裝置片體之一面,以製成一局部包覆之裝置片體;將一下層片體固著於該局部包覆之裝置片體之另一面,以製成一受保護之裝置片體,其中該上層片體與該下層片體形成一保護層;從該受保護之裝置片體分離出一受保護裝置;及將該受保護裝置與一藥劑結合,以製成該藥劑製品。
條款2:如條款1之方法,其中該裝置片體界定包圍各該裝置之複數個孔洞。
條款3:如條款2之方法,其中將該下層片體固著於該局部包覆之裝置片體之另一面之步驟包括下列步驟:加熱該下層片體及該上層片體,致使該下層片體透過該等孔洞接觸該上層片體,該下層片體包圍各該裝置,且該上層片體與該下層片體於接觸點相互固著。
條款4:如條款1至3中任一條款之方法,其中該分離步驟包括下列步驟:令該受保護之裝置片體對準一模具內所界定之一開口,致使該受保護裝置對準該模具之該開口;及利用一衝頭衝壓該受保護裝置,使其穿過該開口並進入置放於一膠囊承座內之一膠囊中。
條款5:如上列任一條款之方法,其中該分離步驟包括下列步驟:令該受保護之裝置片體對準一盤體所界定之一開口,致使該受保護之裝置片體之該受保護裝置對準該盤體之該開口;利用一衝頭使該受保護裝置自該受保護之裝置片體分離;及將該受保護裝置置放於該盤體之該開口中。
條款6:如條款5之方法,進一步包含下列步驟:令包含該受保護裝置之該盤體之該開口對準界定複數個凹穴之一膠囊承座,該等凹穴固持一膠囊之一第一端,其中該膠囊包括該第一端及一第二端。
條款7:如條款6之方法,進一步包含下列步驟:將該受保護裝置從該盤體之該開口中推出,並推入該膠囊承座之該凹穴內所置放之該膠囊之該第一端。
條款8:如條款7之方法,其中該結合步驟包括下列步驟:將一藥劑製品填入包括該受保護裝置之該膠囊之該第一端;及將該膠囊之該第二端固著於該膠囊之該第一端。
條款9:一種可置放於一膠囊內之裝置,該裝置包含:一組件,該組件包括:一單元,其可以一電流特徵編碼資訊,該單元包含一部分電源;及一固著於該單元之撓性膜,其中該膜係與該膠囊之壁面接合,並將該裝置固定於該膠囊內。
條款10:如條款9之裝置,進一步包含包圍該組件之一保護性包覆層。
條款11:如條款9或10之裝置,進一步包含一第一保護片體,其係固著於該組件之一上表面;及一第二保護片體,其係固著於該組件之一下表面。
條款12:如條款11之裝置,其中該第一保護片體與該第二保護片體係透過該撓性膜所界定之複數個孔洞而相互固著。
條款13:如條款11或12之裝置,其中該第一保護片體與該第二保護片體係於該組件之邊緣相互固著,且延伸至該組件之周緣外,致使將該組件封閉於該等保護片體內。
條款14:如條款9至13中任一條款之裝置,其中該單元包括:一第一材料,其係固著於一支撐結構;及一第二材料,其係固著於該支撐結構且與該第一材料電性隔離,致使該第一材料與該第二材料在接觸一導電流體時呈現一化學電位(chemical voltage potential)。
條款15:如條款14之裝置,其中該支撐結構包含一控制模組,該控制模組係電性連接至該第一材料與該第二材料以控制該第一材料與該第二材料間之電導,其中該控制模組藉由改變該電導而以該電流特徵編碼該資訊。
條款16:如條款9至15中任一條款之裝置,其中該撓性膜包括複數個支腳;當該組件被壓入該膠囊時,該等支腳係與該膠囊之壁面接合。
條款17:如條款9至16中任一條款之裝置,其中該撓性膜包括複數個延伸部,該等延伸部之形狀適可卡入該膠囊內並將該組件固定。
條款18:一種藥劑製品,包含:一膠囊,其具有一上端及一下端,其中該上端與該下端接合以形成一外殼,該外殼界定一空腔,且其中該空腔內填有一藥物,該膠囊可在接觸一周圍流體時分解;及與該膠囊相關之一可攝取裝置,最好係如條款9至17中任一條款之裝置,其可以一電流特徵編碼資訊,其中該可攝取裝置係置放於該外殼內,其中該可攝取裝置包括由一保護層包圍之電子元件,其中在該膠囊分解後並使該膠囊之內容物曝露於該周圍流體後,該保護層即開始分解。
條款19:如條款18之製品,進一步包含一撓性膜,其係固著於該可攝取裝置以製成一組件,其中該撓性膜將該組件定位於該膠囊內。
條款20:如條款19之製品,進一步包含一第一保護片體,其係固著於該組件之一上表面;及一第二保護片體,其係固著於該組件之一下表面,其中該第一保護片體與該第二保護片體係相互固著且包圍該組件。
為保護一置放於一膠囊內之裝置,本發明揭示多種適用之方法,期使該裝置免受該膠囊及該膠囊內容物之有害影響。本發明亦揭示多種可將該裝置固著於該膠囊內之方法,其中該膠囊內另裝有一製品。本發明之範圍並不受該膠囊內製品種類之限制。例如,該製品可為膠囊、長效型口服劑、粉劑、凝膠、舌下含片或任何口服劑製品。根據本發明之一態樣,該裝置係定位於該膠囊內,或固著於該膠囊之內部。在一替選配置方案中,該裝置係固著於該膠囊之外部,或為該膠囊囊壁之一部分。
根據本發明之教示,在若干實施例中,該裝置係置放於該膠囊內。根據本發明之其他態樣,該裝置係固著於該膠囊。在此揭示多種可將該裝置固著於該膠囊之方法。例如,可利用可攝取之黏膠、壓感黏著劑、熱熔膠或以機械連附方式將該裝置固著於該膠囊,或者先將該裝置固著於一帶狀物,再將該帶狀物置放於該製品周圍。
除了多種用以將該裝置固著於該製品之方法外,本發明亦提供多種用以包覆或壓合該裝置、包圍該裝置或使該裝置與該膠囊內之藥物或製品分離或隔離以免該裝置與該藥物或製品產生反應之方法。例如,某些製品含有可能損害該裝置之酸,如酒石酸。此外,若過早啟動該裝置,該裝置亦可能與該製品或藥物產生反應。為避免上述問題,該裝置可搭配選用多種壓合及封裝方式,詳見下文之說明。
參見第1圖,一可攝取裝置20具有一層體20a,而該層體20a則包圍電子元件20b。層體20a為可溶性,且為電子元件20b周圍之一層可分解材料。層體20a可延遲電子元件20b曝露於周圍流體之時間。裝置20係置放於膠囊22內,該膠囊22中另裝有一藥劑製品或藥物。膠囊22具有一底端22a及一頂端22b。膠囊22係由一可溶解之材料製成,例如明膠。膠囊22一經吞下,其囊壁因與流體接觸而成為一凝膠狀材料。層體20a可防止膠囊22之凝膠狀材料接觸電子元件20b,直到該凝膠狀材料溶解且不再干擾裝置20之運作為止。在膠囊22之溶解過程中,層體20a亦緩慢分解,使電子元件20b得以接觸上述流體並因而啟動。裝置20內之電子元件類型範例可參見2009年9月21日提出申請之第12/564,017號美國專利申請案「具有部分電源之通訊系統」,該申請案已於2011年7月12日取得第7,978,064號美國專利,在此將該美國專利之全文以引用之方式併入本文。在本文所說明之所有實施例中,膠囊22之用途均為盛裝一藥物;換言之,膠囊22除裝置外尚包括一藥物製品。
參見第2A與2B圖,根據本發明之另一態樣,膠囊22內設有一裝置24。此裝置24包括一可分解之薄膜或材料24a、電子元件24b及其他構件。根據本發明之一實施例,裝置24具有如第2A圖所示之一壓合包覆層。根據本發明之另一實施例,裝置24係由材料24a所包圍,如第2B圖所示。當膠囊22被吞入時,膠囊之兩端22a與22b便開始分解或溶解,致使膠囊22之內容物接觸周圍之流體。材料24a將與此流體產生反應,以防止膠囊22之凝膠狀材料接觸電子元件24b,一如前文針對第2A及2B圖所做之說明。
現請參閱第3圖,根據本發明之另一態樣,膠囊22內設有一裝置26,此裝置26係定位於膠囊末端22b內。裝置26係以摩擦或一機械手段固持於膠囊末端22b內,下文將分別參照第4A與4B圖加以說明。根據本發明之多種態樣,裝置26可分別以類似第1圖及第2A與2B圖中裝置20或裝置24之方式覆蓋。例如,裝置26可包括一層體或壓合材料,或者裝置26可包括一可分解之材料。一如前述,裝置26係透過摩擦或以機械連附之方式固持於定位。
參見第4A圖,根據本發明之一態樣,裝置26包括電子元件26b及凸片或支腳28。支腳28具有可撓性,當裝置26被推入膠囊末端22b時,支腳28與膠囊末端22b壁面間之摩擦可將裝置26固定。當膠囊22溶解時,膠囊末端22b之壁面將變形或塌陷,導致支腳28與膠囊末端22b壁面間之摩擦減弱,如此一來,裝置26便可從膠囊末端22b內釋出。
參見第4B圖,根據本發明之另一態樣,裝置26a包括電子元件26b及凸片或支腳30。支腳30係用以將裝置26a固著於一膠囊末端22c內。在此以膠囊末端22c取代第3圖之膠囊末端22b。膠囊末端22c包括凹槽或凹痕32,其數量係與裝置26a之支腳30相匹配。在本發明之一替選態樣中,支腳30之數量可與凹槽32之數量不同。在將裝置26a壓入膠囊末端22c之過程中,凸片30將與凹槽32相互接合,因而以機械方式將裝置26a鎖固於定位。而當膠囊末端22c溶解時,膠囊末端22c之壁面將變形或塌陷,因而將裝置26a從膠囊末端22c中釋出。
參見第5圖,根據本發明之另一態樣,膠囊22內設有一裝置34。此裝置34包括一材料34a,以及固著於該材料之電子元件34b(類似於電子元件24b)與一層體或覆蓋物34c。
第6圖與第7圖繪示本發明之一態樣中一種製造一裝置之方法,其中該裝置具有一覆蓋物或一壓合層。圖中之裝置40係置放於一片體41上,而片體41則位於一上壓合片體42a與一下壓合片體42b之間。壓合片體42a與42b可以多種材料或薄膜製成,例如聚乙烯氧化物、羥丙纖維素及檸檬酸三乙酯等聚合物薄膜。其他適用之薄膜包括任何可溶解之聚合物、塑化劑。此薄膜可阻擋濕氣,且可在適當條件下溶解以延遲裝置之啟動時間。該薄膜層之設計可使該裝置曝露於周圍流體之時間充分晚於膠囊材料之分解及膠囊內容物之擴散。該薄膜層可包括可溶性材料、阻隔材料(如脂質、聚乙烯醇)、加工助劑(如塑化劑、黏著促進劑)及安定劑。此外,該薄膜層之製造可採用壓合法,或先塗佈一包覆溶液或漿料再固化此溶液或漿料。根據本發明之其他態樣,該薄膜或層體可與第2圖所示者類似,並以乾壓縮法形成,例如使用一平板壓床。
可置放於一膠囊內之活性劑或藥劑製品種類眾多。例如,經FDA核准之藥物、在專利申請案或已核准之專利案中以化學方式揭示之藥物、橘皮書(Orange Book)所揭示之藥物(其為核准藥物製品之一部分),以及一般藥物。根據本發明之教示,上列藥物中之任一者或其組合均可與該裝置一同置放於膠囊內。上列藥物之化學組成各不相同,因此,無論對該裝置之運作或對所用薄膜之分解,均具有某些且獨特之影響。也因此,該薄膜層之材料種類可有所變化,俾與所用製品之化學組成相容。是以,本發明之範圍既不受限於膠囊內容物之種類,亦不受限於該裝置電子元件周圍之薄膜或包覆層之類別。
根據本發明之另一態樣及優點,該薄膜或包覆層亦可防止該裝置之構件與膠囊內之藥物產生交互作用。因此,該裝置並不會改變或影響該藥物之效力。
如第7圖所示,裝置40之一範例包括電子元件40b及具有複數個孔洞44之一裙部40a。片體42a及42b受熱或受壓時,便透過孔洞44相互固著,因而將裝置40穩固固持於片體42a與42b之間。如第7圖所示,裝置40係壓合於片體42a與42b之間。根據本發明之另一態樣,片體42a及42b供各裝置40使用之部分可先行衝孔、切下或移除,然後分別置放於裝置40之上、下方。切下之部分較裝置40為大,因此,當片體42a及42b之該等部分受熱或受壓時,該等過大部分便在邊緣處相互固著,因而形成一包圍裝置40之囊袋,該等過大部分也透過孔洞44相互固著,一如前述。根據本發明之又一態樣,若裝置40係置放於上述過大部分之間,並且固著於包圍該裝置40之一囊袋內,則可不設孔洞44。
參見第8圖與第9圖,根據本發明之一態樣,一壓合裝置片體50係定位於一模具52上方,其中該模具52具有一孔洞52a。雖然圖中僅繪示單一孔洞52a,但熟習此項技藝之人士應可瞭解,該模具亦可包括複數孔洞,且此處所討論之單孔範例可於該模具設有多孔之情況下重覆施作。模具52之孔洞52a係定位於一膠囊承座54之上方,而膠囊承座54內則裝有一膠囊末端56。在將片體50定位於孔洞52a上方後,可利用一衝頭58將裝置50a從片體50中切下,同時將裝置50a插入膠囊末端56。一如前文有關本發明多種態樣之說明,裝置50a可具有多種形狀,且該等形狀可以衝頭58製成。
參見第10至14圖,根據本發明之一態樣,第6圖之裝置40可以衝孔方式切下,然後置放於一傳送盤62之一孔洞62a內。盤體62在第10圖中具有複數孔洞。如第11圖所示,盤體62係定位於一包含複數裝置之片體(如第8圖所示之片體50)下方。衝頭刀刃64將一裝置66從該包含複數裝置之片體中切下,並將該裝置66插入孔洞62a中。裝置66係以摩擦方式固定於孔洞62a內,如第12圖所示。然後將盤體62移至製程之下一步驟,利用一壓孔機70將裝置66推入固持於一膠囊承座74中之一膠囊末端72,如第13與14圖所示。
一如前述,可用以包圍電子元件之可分解材料種類眾多。例如,適用之分解劑包括羧甲基澱粉鈉,或諸如羥丙纖維素之水溶性賦形劑。此外,本文所揭示之各層體可相互壓合或結合,端視所用之材料及其性質而定。
如本文所述,本發明之一系統可搭配一導電流體使用,俾在該導電流體與該系統接觸時,指出此一接觸事件。例如,本發明之系統可與一藥劑製品搭配使用,而所須指出之事件係該製品於何時被服用或吞入(或攝取)。「吞入」或「吞服」(或攝取)一詞泛指任何可將該系統導入活體內之動作。例如,「吞入」包括將該系統置放於口中,使其一路抵達降結腸,因此,「吞入」一詞係指任何一個將該系統導入內含導電流體之一環境之時間點。又例如,在一非導電流體須與一導電流體混合之情況下,可將該系統設置於該非導電流體中;當該兩種流體相互混合時,該系統即接觸該導電流體並因而啟動。再舉一例,若需偵測某種導電流體是否存在,可偵測該系統是否出現在該導電流體中(若出現則將被啟動),進而偵測出該導電流體是否存在。
請注意,在本文及後附之申請專利範圍中,除非上下文另有清楚說明,否則單數型態之「一」與「該」均包括複數個指涉對象。此外亦請注意,申請項之內容可能不包含任何非必要元件。以上聲明旨在為「僅」、「唯一」等用以在申請專利範圍中描述元件之排他性用語提供前置基礎,或為「負面」限制提供前置基礎。
凡熟習此項技藝者在閱讀本文後即可明瞭,本文所描述及繪示之各種實施例之個別構件及特徵,可輕易與其他實施例之特徵分離或結合而不脫離本發明之範圍或精神。前述之任一方法可依本文所說明之事件順序進行,或依任何符合邏輯之順序進行。
為使讀者清楚瞭解發明內容,本發明已搭配圖式及範例詳述如上。然而,具備發明所屬領域一般技藝者在參閱本發明之教示後當可輕易瞭解,本發明可以若干方式加以變化及修改而不脫離後附申請專利範圍之精神或範疇。
因此,以上說明僅例示本發明之原理。熟習此項技藝者可設計出多種配置方式以實現本發明之原理;該等配置方式在本文中雖無明確之描述或圖式,但均涵蓋在本發明之精神與範圍之中。再者,本文中所有範例及條件式用語旨在協助讀者瞭解本發明之原理以及發明人為精進此項技藝所提出之構想,惟本發明並不受限於該等明確描述之範例及條件。此外,本文中有關本發明原理、態樣、實施例及某些範例之所有敘述,應包含其結構與功能等同物。所述等同物包括目前已知之等同物以及尚未開發之等同物;換言之,所述等同物包括任何可執行相同功能之元件,此與其結構無涉。是以,本發明之範圍並不限於本文所繪示及描述之示範用實施例。本發明之範圍與精神係由後附之申請專利範圍加以界定。
20...可攝取裝置
20a...層體
20b...電子元件
22...膠囊
22a...底端
22b...頂端
22c...膠囊末端
24...裝置
24a...可分解之薄膜或材料
24b...電子元件
26...裝置
26a...裝置
26b...電子元件
28...凸片或支腳
30...凸片或支腳
32...凹槽或凹痕
34...裝置
34a...材料
34b...電子元件
34c...層體或覆蓋物
40...裝置
40a...裙部
40b...電子元件
41...片體
42a...上壓合片體
42b...下壓合片體
44...孔洞
50...壓合裝置片體
50a...裝置
52...模具
52a...孔洞
54...膠囊承座
56...膠囊末端
58...衝頭
62...傳送盤
62a...孔洞
64...衝頭刀刃
66...裝置
70...壓孔機
72...膠囊末端
74...膠囊承座
第1圖繪示一膠囊,該膠囊內設有一疊層裝置。
第2A圖繪示一膠囊,該膠囊內設有一板體,且該板體包括一包覆式裝置。
第2B圖繪示一膠囊,該膠囊內設有一板體,且該板體包括一裝置。
第3圖繪示一膠囊,該膠囊之一部分內設有一包覆式裝置。
第4A圖繪示一可用於第3圖所示膠囊之裝置範例。
第4B圖繪示另一種可用於第3圖所示膠囊之裝置範例,其經過設計之一某些膠囊末端可將該裝置以機械方式固定。
第5圖繪示一具有覆蓋物之裝置,該裝置係固著於一板體,而該板體則係置放於一膠囊內。
第6圖繪示壓合或覆蓋上述裝置之方法。
第7圖係第6圖中一組件之近視圖。
第8圖繪示本發明之一態樣中用以將一裝置插入一膠囊末端之方法。
第9圖繪示第8圖所示方法之下一階段。
第10圖係一傳送盤之立體圖式。
第11圖繪示本發明另一態樣中用以將一裝置插入一膠囊末端之方法之初始階段。
第12圖繪示第11圖之裝置位於第10圖之傳送盤內。
第13圖繪示第11圖所示方法之下一階段。
第14圖繪示第13圖所示階段之再下一階段。
20...可攝取裝置
20a...層體
20b...電子元件
22...膠囊
22a...底端
22b...頂端
Claims (6)
- 一種藥劑製品之製法,該製法包含下列步驟:製造一裝置片體,該裝置片體包括複數個裝置;將一上層片體固著於該裝置片體之一面,以製成一局部包覆之裝置片體;將一下層片體固著於該局部包覆之裝置片體之另一面,以製成一受保護之裝置片體,其中該上層片體與該下層片體形成一保護層;從該受保護之裝置片體分離出一受保護裝置;及將該受保護裝置與一藥劑結合,以製成該藥劑製品;其中該裝置片體界定包圍各該裝置之複數個孔洞;且其中將該下層片體固著於該局部包覆之裝置片體之另一面之步驟包括下列步驟:加熱該下層片體及該上層片體,直到該下層片體透過該等孔洞接觸該上層片體,該下層片體包圍各該裝置,且該上層片體與該下層片體於接觸點相互固著。
- 如申請專利範圍第1項之製法,其中該分離步驟包括下列步驟:令該受保護之裝置片體對準一模具內所界定之一開口,致使該受保護裝置對準該模具之該開口;及利用一衝頭衝壓該受保護裝置,使其穿過該開口並進入置放於一膠囊承座內之一膠囊中。
- 如申請專利範圍第1項之製法,其中該分離步驟包括下列步驟: 令該受保護之裝置片體對準一盤體所界定之一開口,致使該受保護之裝置片體的該受保護裝置對準該盤體之該開口;利用一衝頭使該受保護裝置自該受保護之裝置片體分離;及將該受保護裝置置放於該盤體之該開口中。
- 如申請專利範圍第3項之製法,尚包含下列步驟:令包括該受保護裝置之該盤體之該開口對準界定複數個凹穴之一膠囊承座,該等凹穴固持一膠囊之一第一端,其中該膠囊包含該第一端及一第二端。
- 如申請專利範圍第4項之製法,尚包含下列步驟:將該受保護裝置從該盤體之該開口中推出,並推入該膠囊承座之該凹穴內所置放之該膠囊之該第一端。
- 如申請專利範圍第5項之製法,其中該結合步驟包括下列步驟:將一藥劑製品填入含有該受保護裝置之該膠囊之該第一端;及將該膠囊之該第二端固著於該膠囊之該第一端。
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EP2642983A2 (en) | 2013-10-02 |
TW201225949A (en) | 2012-07-01 |
US20120302999A1 (en) | 2012-11-29 |
WO2012071280A2 (en) | 2012-05-31 |
US10653875B2 (en) | 2020-05-19 |
EP2642983A4 (en) | 2014-03-12 |
JP2014504902A (ja) | 2014-02-27 |
US20170216569A1 (en) | 2017-08-03 |
US20150352343A1 (en) | 2015-12-10 |
US20230034761A1 (en) | 2023-02-02 |
WO2012071280A3 (en) | 2012-07-26 |
US20210060319A1 (en) | 2021-03-04 |
US9107806B2 (en) | 2015-08-18 |
US11504511B2 (en) | 2022-11-22 |
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