JP2008517899A - 治療適用および/または診断適用のための充填可能なポリホスファゼン含有粒子、ならびにその調製方法および使用方法 - Google Patents
治療適用および/または診断適用のための充填可能なポリホスファゼン含有粒子、ならびにその調製方法および使用方法 Download PDFInfo
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- JP2008517899A JP2008517899A JP2007537420A JP2007537420A JP2008517899A JP 2008517899 A JP2008517899 A JP 2008517899A JP 2007537420 A JP2007537420 A JP 2007537420A JP 2007537420 A JP2007537420 A JP 2007537420A JP 2008517899 A JP2008517899 A JP 2008517899A
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- phosphazene
- barium sulfate
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Abstract
Description
Jayakrishnan et al.,Bull.Mat.Sci.,(1989)Vol.12,No.1,pp.17−25
100μm±25μm
250μm±50μm
400μm±50μm
500μm±50μm
700μm±50μm
900μm±50μm。
また、前述のような種々の範囲、例えば500〜700μmの範囲の粒子も、配合用途のために調製および混合できる可能性があることも、本発明の範囲に含まれる。
直径約500〜600μmの微粒子を調製した。最初に、分子量が3×106g/モルのPTFEPポリマーを、ポリマー溶媒である酢酸エチルに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下し、上記分散液を150mLのペンタンの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。
直径約350〜450μmの微粒子を調製した。最初に、分子量が3×106g/モルのPTFEPポリマーを、酢酸エチルに溶解することによってポリマー溶液を調製し、1%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を150mLのペンタンの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。
直径約500〜600μmの微粒子を調製した。最初に、分子量が12×106g/モルのPTFEPポリマーを、メチルイソブチルケトンに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を、エタノール/ペンタン比1:9(v/v)の混合物150mLの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。
直径約500〜600μmの微粒子を調製した。最初に、分子量が9×106g/モルのPTFEPポリマーを、イソアミルケトンに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を150mLのペンタンの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。
直径約500〜600μmの微粒子を調製した。最初に、分子量が16×106g/モルのPTFEPポリマーを、シクロヘキサノンに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を、エタノール/ジエチルエーテル比1:1(v/v)の混合物150mLの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。
直径約500〜600μmの微粒子を調製した。最初に、分子量が3×106g/モルのPTFEPポリマーを、酢酸エチルに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を150mLのヘキサンの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。
直径約500〜600μmの微粒子を調製した。最初に、分子量が3×106g/モルのPTFEPポリマーを、酢酸エチルに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を150mLのエタノールの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。粒子は著しくゲル状になっており、乾燥後は楕円形になっていた。
直径約500〜600μmの微粒子を調製した。最初に、分子量が3×106g/モルのPTFEPポリマーを、酢酸エチルに溶解することによってポリマー溶液を調製し、2%(wt/v)のポリマー溶液を得た。上記ポリマー溶液4mLを、5mLのシリンジを使用して液体窒素に手動で滴下した。上記分散液を150mLのジエチルエーテルの凍結層の上に分注した(図2を参照)。凍結濃縮には3日間を要した。その後、ポリマー粒子を反応容器から取り出し、21℃で風乾した。乾燥後に得られた粒子は緻密で均一な球形であった。
図6に示すような2Lの凍結容器に、非溶媒としてジエチルエーテル100mLを充填した。上記凍結容器は、以下の表1に示すような特徴および標準寸法を有していた。
上記容器を絶縁蓋で閉じ、テフロン(登録商標)チューブを介してシリンジポンプに連結されたシリンジ針を、上記蓋の小さな開口部に差し込んだ。
実施例1の方法によって調製された微粒子の形状および表面形状を、光学顕微鏡、走査型電子顕微鏡(SEM)および原子間力顕微鏡によって調べた。当該解析の結果を図3Aおよび3Bに示す。図3Aには、倍率4倍の光学顕微鏡を使用して観察された微粒子を示す。図3Bには、倍率100倍の走査型電子顕微鏡を使用して観察された微粒子を示す。
好ましいコア粒子を得るため、PMMAと3種類の異なる架橋性モノマー(EDGMA、DEGDMAおよびTEGDMA)、異なるラジカル開始剤(ベンゾイルペルオキシド(BPO)およびラウロイルペルオキシド(LPO))、錯化剤であるEDTA、種々の分散剤(Cyanamer 370M、ポリアクリル酸(PAA))および種々のポリビニルアルコールの組み合わせを変えて使用し、いくつかの重合を行った。いくつかの重合においては、リン酸ナトリウムバッファー溶液(Na2HPO4/NaH2PO4)を使用した。選択した分散剤のタイプおよび濃度により、反応手順によっては失敗に終わったものも認められた。当該分散剤の失敗は、発熱反応の早期の発生、水相および有機相の融合、およびガラス相の早すぎる開始の形で示された。実施例は成功したもののみ示す。以下の表2には、成功した実験を、当該試料(1〜6)の成分、濃度および反応条件を含めて示す。
本明細書に開示される手順によって形成されたヒドロゲル微小粒子を、塞栓形成用途に使用するため、浮力および懸濁特性について評価した。上記微小粒子には、修飾されていないポリメタクリル酸カリウム塩ヒドロゲル粒子を使用した試料(試料A);トリフルオロエチルエステル化ポリメタクリル酸カリウム塩ヒドロゲルを使用した試料(試料B);および粒子がPTFEPでコーティングされていることを除いて試料Bと同じヒドロゲルを使用した試料(試料C)が含まれた。そして、5個のリン酸バッファー生理食塩錠剤(Fluka(登録商標))をミリQ超純水999.5mlに溶解することによって、0.05容量%のTween(登録商標)20を含むpH 7.4の等張リン酸バッファー生理食塩溶液を調製した。上記溶液にTween(登録商標)20界面活性物質0.5mlが加えられ、続いて評価のため、上記等張バッファー生理食塩水中にImeron300(登録商標)造影剤を20〜50容量%含む溶液を調製した。
続いて、かかる時間の遅れを考慮に入れ、さらに好ましい密度を達成し、上記粒子の蛍光透視可視性を向上させるため、実施例12の試料Bおよび試料Cで使用されたタイプの微小粒子についてセシウム処理を作用させた。
さらなる圧縮率および機械特性の試験を、実施例12の試料Bおよび/または試料Cの微粒子で実施した。さらなる評価に使用された圧力試験台を図8に示す。0〜250mm/時の可変送り速度を提供するモーター4、およびギヤボックス6を有する自動化シリンジプランジャー2には、さらに0〜500Nの力を測定することができるLorenz社の圧力変換器が装備されていた。上記シリンジプランジャー2は、図示の通りシリンジ本体10と結合していた。変換器のデジタル出力は、パーソナルコンピュータを使用して記録された。上記シリンジ本体10には、造影剤濃度約30〜32容量%の等張リン酸バッファー/界面活性物質(Tween(登録商標)20)溶液5mLが充填されていた。微小粒子を56mgの乾燥質量でシリンジに入れた後、上記シリンジ内容物を、シリンジの遠心端14に取り付けられたマイクロカテーテル12に注入した。上記マイクロカテーテルは、管腔直径が533μmであった。そして、上記カテーテルからシャーレ16(微小粒子溶液を入れるために表示)に微小粒子を押し出す際に必要な力を、圧力として測定し、記録した。
ρ=VEmb/VTot=2mL/18mL=0.111塞栓形成剤/容量画分。
微小粒子は本明細書の好ましい実施態様に従って形成され、重量平均分子量が約85,000〜124,000であり、約87〜89%で加水分解されているPVA約23g、並びに水1000gを使用して、ポリビニルアルコール(PVA)の脱イオン水溶液を調製した。そして、脱イオン水900g、リン酸水素二ナトリウム4.53g、リン酸二水素ナトリウム0.26g、およびエチレンジアミン四酢酸(EDTA)0.056gを使用して、リン酸バッファー溶液を調製した。メタクリル酸メチル(MMA)モノマーは、使用前に減圧蒸留した。
本実施例では、実施例15に従って形成された微小粒子をエステル化した。まず、エステル化表面処理を行うため、実施例15の乾燥微小粒子800gを、還流凝縮器を備えた2Lの反応容器に秤量した。そして、ジエチルエーテル1.5L中に250gの塩化チオニルを含む溶液を撹拌しながら加えた。撹拌は室温で20時間続けた。その後、溶媒および揮発性の反応物を、ろ過とそれに続く減圧乾燥によって除去した。次に、エーテル1.5mL中に500gのトリフルオロエタノールを含む溶液を導入し、懸濁液を室温でさらに20時間撹拌した。最後に、上記粒子を減圧下で乾燥させた。
本実施例では、実施例16とは別の表面処理において、実施例15の乾燥微粒子800gを1140gのトリフルオロエタノールと反応させ、44gの硫酸を触媒として加えた。上記混合物を室温で20時間撹拌して、ろ過した後、減圧下で乾燥させた。
上述の実施例15および実施例16で開示したように、トリフルオロエタノールで部分的にエステル化された乾燥PMMAカリウム塩微小粒子800gを、MP−1 Precision Coater(登録商標)流動層コーティング装置(Aeromatic−Fidler AG[スイス ブーベンドルフ]製)にて、PTFEPによりスプレーコーティングした。上記粒子を気流(40〜60m3/時、入力温度55℃)によって捕らえ、空気−流体同軸ノズルからのPTFEP溶液の微小液滴を使用してスプレーコーティングした。上記溶液の組成物は、PTFEP0.835g、酢酸エチル550gおよび酢酸イソペンチル450gであり、これを10〜30g/分の速度で1.3mm幅の内側の孔を通って提供した。ノズルヘッドでは、加圧空気(2.5バール)によって微粒化された。噴霧溶液の全量(3kg)は、厚さ150nmのPTFEPフィルムにて粒子をコーティングするために算出された。
前述の通りトリフルオロエタノールで部分的にエステル化された、実施例15および実施例16の乾燥カリウム塩微小粒子を、市販される流動層コーティング装置(実施例16を参照)にて、酢酸エチル中で希釈したPTFEP溶液によりスプレーコーティングした。このようにコーティングした100mgの乾燥微小粒子を、トリフルオロエタノールで部分的にエステル化された、コーティングされていない乾燥PMAカリウム塩微小粒子と共に、脱イオン水100mLに塩化セシウム30.0gを溶解することによって調製した、約30%の塩化セシウム水溶液中に浸漬した。10分間の平衡時間の後、上清液体を捨て、微小粒子を脱イオン水で洗浄し、さらに10分間平衡化させて、上清を捨て、界面活性物質を含まないpH 7.4のリン酸バッファー溶液3mLに懸濁した。次に、溶液中の造影剤の密度を整合させるため、溶液中の粒子の密度を測定した。各タイプの微小粒子には、Imeron(登録商標)300造影剤(密度1.335g/mL)3.5mLとリン酸バッファー生理食塩水(密度1.009g/mL)4mLの比率で含有される造影剤溶液を加えた。いずれのヒドロゲルも、溶液中における45〜50%の造影剤濃度で浮力に達した。これは、1.16g/mLという増加した微小粒子の密度に相当する。
本実施例では、実施例15の方法に従って微小粒子が形成されたが、但し、粒子の中和後に外側の硫酸バリウムコーティングを微小粒子上に調製し、硫酸バリウムコーティング手順の前の中和後に粒子を乾燥させなかった。硫酸バリウムコーティングを調製するため、0.5M硫酸ナトリウム(Na2SO4)溶液2000mLに水和粒子2500mLを入れ、4〜12時間の間飽和させた。続いて、上記粒子懸濁液に0.5M塩化バリウム(BaCl2)溶液1950mLを、室温で撹拌しながらゆっくりと加えた。過剰な脱イオン水で洗浄した後に得られる、膨張した状態にある粒子には、硫酸バリウム粉末でコーティングされた表面を含んでいた。続いて、実施例16に記載した方法で粒子を乾燥させ、エステル化した。続いて、以下の実施例21の流動層法を使用して粒子をコーティングした。得られた微小粒子は、非付着性硫酸バリウム粉末により外側がコーティングされていた。本発明および手順に従って調製された硫酸バリウムコーティングは、乾燥時の粒子の凝塊形成が防止され、密度が増加する。硫酸バリウムの濃度および比率は異なる結果を得るために変更させることができ、過剰な硫酸バリウムを使用することで、残る塩化バリウムを最小限にすることができる。ガラス瓶を汚染している過剰な硫酸バリウム粉末を最小限にするため、本実施例に従って形成された粒子は熱水で効果的に洗浄した。硫酸バリウムは、水和された微小粒子の流動化の補助として乾燥させる前に、粒子の付着を防止する作用が効果的に働く。
硫酸バリウム粉末ビーズの流動層コーティングは、実施例20に従って形成された硫酸バリウムの表面層を有するポリメタクリレートビーズを使用して行ったが、バリウムイオンがコア中に拡散し、ヒドロゲルコア内で沈殿が形成されるように、過剰な塩化バリウムが使用された。
本実施例では、実施例15に従って形成された微小粒子にて、有機染料の吸収を試験した。まず、1mLの水和ビーズを含むリン酸バッファー生理食塩水2mLに、5〜10μLのそれぞれの色素を、10ミリモルのエタノール溶液として加えた。そして、ガラス瓶を穏やかに振盪しながら、上記試料を室温で30〜60分間インキュベーションした後、上清液体を捨て、粒子を2mLの脱イオン水、生理食塩水またはPBSバッファー溶液のいずれかで2回洗浄し、光学および蛍光顕微鏡で可視化した。試験した色素には、DiI等のカルボシアニンをベースした色素と共に評価される、フルオレセイン二酢酸およびローダミン6G等のトリフェニルメタン誘導体が含まれた。また、トリフェニルメタンをベースしたフルオレセインおよびローダミン色素は、イオン相互作用を通じて、親水性PMMAヒドロゲルコアに対する特異的な親和性を呈し、当該色素は、実質的な浸出なく洗浄と蒸気滅菌を繰り返す厳しい条件に容易に耐えることができた。
Claims (31)
- 治療手順および/または診断手順において使用するための粒子であって、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、粒子。
- 前記粒子が多孔性粒子である、請求項1に記載の粒子。
- 前記粒子がコアおよび外部コーティングを含み、該コアは、アクリルベースのポリマーから形成されるヒドロゲルを含み、該外部コーティングはポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、請求項1に記載の粒子。
- 前記コアがさらに硫酸バリウムを含む、請求項3に記載の粒子。
- 前記コアが硫酸バリウムの内部コーティングに囲まれており、前記外部コーティングが該硫酸バリウムの内部コーティングを包囲する、請求項4に記載の粒子。
- 前記硫酸バリウムが前記コアに吸収されている、請求項4に記載の粒子。
- 前記粒子がさらに、該粒子の密度を増加させる物質を含む、請求項3に記載の粒子。
- 前記物質が、酸化ジューテリウム、セシウム、少なくとも1種類の有機染料、硫酸バリウム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7に記載の粒子。
- 哺乳動物中の組織への血流を最小限にする方法であって、
少なくとも1種類の粒子を用いて該哺乳動物中の血管の少なくとも一部を閉塞する工程;
を包含し、該粒子は、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、方法。 - 前記粒子がコアおよび外部コーティングを含み、該コアは、アクリルベースのポリマーから形成されるヒドロゲルを含み、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、請求項9に記載の方法。
- 前記粒子コアがさらに、コーティングとして、かつ/または該コア内に吸収された、硫酸バリウムを含む、請求項10に記載の方法。
- 哺乳動物の体内の局所領域に活性物質を送達する方法であって、
ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体と、活性物質とを含む少なくとも1種類の粒子を、該局所領域に接触させて、有効量の該活性物質が該局所領域に曝露されるようにする工程;
を包含する、方法。 - 前記粒子がコアおよび外部コーティングを含み、前記活性物質が前記外部コーティングを通って送達され、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、請求項12に記載の方法。
- 前記粒子コアがさらに、コーティングとして、かつ/または該コア内に吸収された、硫酸バリウムを含む、請求項13に記載の方法。
- 前記粒子が、アクリルベースのポリマーコアから形成されるヒドロゲル、および外部コーティングを含み、前記活性物質が該コア中にある状態で送達されて該外部コーティングを通って拡散し、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、請求項12に記載の方法。
- 経口投与用の活性物質の徐放処方物であって、該処方物は、ポリマーカプセルおよび活性物質を含み、該ポリマーカプセルは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む、処方物。
- 前記ポリマーカプセルが、コアと、前記コアを囲む外部コーティングとを含み、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含み、該コアは、アクリルベースのポリマーのヒドロゲルを含む、請求項16に記載の徐放処方物。
- 前記粒子コアがさらに、コーティングとして、かつ/または該コア内に吸収された、硫酸バリウムを含む、請求項17に記載の方法。
- 哺乳動物中の血管を通る粒子の通過を追跡する方法であって、
ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体と、造影剤とを含む、少なくとも一種類のトレーサー粒子を哺乳動物の血流に注入する工程;および
該粒子の経路を画像化する工程;
を包含する、方法。 - 前記トレーサー粒子が、コアと、該コアを囲む外部コーティングとを含み、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含み、該コアは、アクリルベースのポリマーのヒドロゲルを含む、請求項19に記載の方法。
- 前記粒子コアがさらに、コーティングとして、かつ/または該コア内に吸収された、硫酸バリウムを含む、請求項20に記載の方法。
- 前記造影剤が、硫酸バリウム、タンタル化合物、ガドリニウム化合物およびヨウ素含有化合物からなる群より選択される、請求項19に記載の方法。
- 向上した超音波画像化方法であって、
ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含む少なくとも1種類の中空マイクロカプセルを、超音波被験体の領域に投与する工程;および
超音波を使用して該被験体の領域を画像化することを含む、方法。 - 哺乳動物の体内の局所領域に活性物質を送達する方法であって、
ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体と、活性物質とを含む少なくとも1種類の粒子を、該局所領域に接触させて、有効量の該活性物質が該局所領域に曝露されるようにする工程;
を包含し、該粒子は、密度を増加させる物質を含む、方法。 - 前記密度を増加させる物質が、酸化ジューテリウム、セシウム、少なくとも1種類の有機染料、硫酸バリウム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24に記載の方法。
- 前記粒子が外部コーティングおよびコアを含み、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含み、該コアは、アクリルベースのポリマーのヒドロゲルを含み、該粒子は、該粒子にセシウムを提供するために塩化セシウムで前処理されている、請求項24に記載の方法。
- 前記粒子が外部コーティングおよびコアを含み、該外部コーティングは、ポリ[ビス(トリフルオロエトキシ)ホスファゼン〕および/またはその誘導体を含み、該コアは、アクリルベースのポリマーのヒドロゲル、および硫酸バリウムを含む、請求項24に記載の方法。
- 前記硫酸バリウムが、前記コアのコーティングとして存在する、請求項27に記載の方法。
- 前記硫酸バリウムが、前記コア内で拡散される、請求項27に記載の方法。
- アクリルベースのポリマーから形成された粒子の凝塊形成および/または凝集を最小限にする方法であって、
該粒子のコアおよび/または表面に硫酸バリウムを提供する工程;
を包含する、方法。 - 請求項30に記載の方法であって、前記粒子は、ポリ[ビス(トリフルオロエトキシ)ホスファゼン]および/またはその誘導体の外部コーティングを含み、
該方法は、
該外部コーティングに対する損傷を最小限にする工程;
をさらに包含する、方法。
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JP2010090104A (ja) * | 2008-10-08 | 2010-04-22 | Postech Academy-Industry Foundation | X線を利用した流動情報測定用カプセル及びこれを利用した流動情報測定方法 |
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JP2013535506A (ja) * | 2010-08-12 | 2013-09-12 | マイクロビオン コーポレーション | 農業用、工業用およびその他の使用のための消毒薬としてのビスマス−チオール |
JP2018008971A (ja) * | 2010-08-12 | 2018-01-18 | マイクロビオン コーポレーション | 農業用、工業用およびその他の使用のための消毒薬としてのビスマス−チオール |
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US11464749B2 (en) | 2018-07-31 | 2022-10-11 | Microbion Corporation | Bismuth-thiol compositions and methods of use |
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TW200626178A (en) | 2006-08-01 |
US11052050B2 (en) | 2021-07-06 |
EP1804773B1 (en) | 2011-03-30 |
US20130052142A1 (en) | 2013-02-28 |
JP4885866B2 (ja) | 2012-02-29 |
KR101153785B1 (ko) | 2012-07-09 |
CA2584122C (en) | 2013-04-30 |
US20060088476A1 (en) | 2006-04-27 |
US8318209B2 (en) | 2012-11-27 |
HK1116058A1 (en) | 2008-12-19 |
WO2006046155A2 (en) | 2006-05-04 |
ATE503465T1 (de) | 2011-04-15 |
EP1804773A2 (en) | 2007-07-11 |
MY147841A (en) | 2013-01-31 |
KR20070084341A (ko) | 2007-08-24 |
US20170172933A1 (en) | 2017-06-22 |
US20210290555A1 (en) | 2021-09-23 |
AU2005298344B2 (en) | 2011-02-10 |
DE602005027229D1 (de) | 2011-05-12 |
BRPI0518383A2 (pt) | 2008-11-18 |
IL182650A0 (en) | 2007-07-24 |
WO2006046155A3 (en) | 2006-08-17 |
IL182650A (en) | 2013-01-31 |
CA2584122A1 (en) | 2006-05-04 |
AU2005298344A1 (en) | 2006-05-04 |
US9511153B2 (en) | 2016-12-06 |
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