JP2010516759A - N,n−ジメチルイミドジカルボンイミド酸ジアミドの酢酸塩、その製造方法、及びそれを含む薬剤学的組成物 - Google Patents
N,n−ジメチルイミドジカルボンイミド酸ジアミドの酢酸塩、その製造方法、及びそれを含む薬剤学的組成物 Download PDFInfo
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- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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Abstract
Description
1. Ogawa N, Satsu H, Watanabe H, et al. Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of caco-2 cells. J Nutr. 2000 Mar;130(3):507-13 (非特許文献5)
2. Carol S. Johnston, PhD, RD; Cindy A. Gaas, BS. Vinegar: Medicinal Uses and Antiglycemic Effect,Medscape General Medicine. 2006;8(2):61. (非特許文献4)
3. Ostman E, Granfeldt Y, Persson L, Bjorck I. Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr. 2005 Sep;59(9),983-8. (非特許文献6)
4. Johnston CS, Kim CM, Buller AJ. Vinegar improves insulin sensitivity to a high carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care. 2004 Jan;27(1):281-2. (非特許文献7)
5. Leeman M, Ostman E, Bjorck I. Vinegar dressing and cold storage of potatoes lowers postprandial glycaemic and insulinaemic responses in healthy subjects. Eur J Clin Nutr. 2005 Nov;59(11):1266-71. (非特許文献8)
6. Ebihara K, Nakajima A. Effect of acetic acid and vinegar on blood glucose and insulin responses to orally administered sucrose and starch. Agric Biol Chem. 1988;52:1311-1312. (非特許文献9)
7. Brighenti F, Castellani G, Benini L, et al. Effect of neutralized and native vinegar on blood glucose and acetate responses to a mixed meal in healthy subjects. Eur J Clin Nutr. 1995 Apr;49(4):242-7 (非特許文献10)
技術的課題
本発明では適切な制御放出基剤の選択による製剤設計としてメトホルミン塩酸塩の問題点を克服しなければならないというパラダイムから外れ、有効活性成分の溶解度を低くすると速放出性製剤の服用時にも過度な血糖降下や胃腸管障害のような副作用が改善され、徐放型製剤化時により効率的な制御放出を表すことができると判断し、水に対する溶解度が相対的に低いメトホルミン付加塩について研究した。しかし、溶解度が低いメトホルミン誘導体を合成しても新たなメトホルミン誘導体が、メトホルミン塩酸塩に比べて分子量が大きすぎると、メトホルミンの投与容量は増加することになり、実用性に劣るという問題点がある。これはメトホルミンの単位投与量が大きいという点を考慮すると、非常に重要な問題である。分子量が大きすぎず錠剤に打錠できる投与容量を有し、溶解度を低くして制御放出が容易で、下部胃腸管及び結腸での透過性が相対的に優れ、メトホルミン塩酸塩に比べて相対的に吸収範囲が広いメトホルミン付加塩を開発すれば、薬剤学的や薬物動力学的に優れた波及効果を有すると考えられる。
本発明者等は、メトホルミン酢酸塩、その製造方法及びそれを含む糖尿病治療剤として有用な組成物を製造して本発明を完成した。
(1) 下記の式1で表されるメトホルミン酢酸塩。
[化1]
(2) 上記(1)において、無水物、半水和物、又は一水和物の状態のメトホルミン酢酸塩。
(3) 水又は有機溶媒中で、下記の式4のメトホルミン塩酸塩1当量と無機塩類1〜2当量を水や有機溶媒上で反応させてメトホルミン遊離塩基を生成した後に無機塩を除去したり除去していない状態で、式2の1当量〜2当量の酢酸と反応させて製造する、下記の式1で表されるメトホルミン酢酸塩の製造方法。
[化2]
[化3]
[化4]
(4) 上記の式4のメトホルミン塩酸塩1当量と有機アルカリ1〜2当量を水で反応させ、無機塩類を除去していない状態で上記の式2の酢酸と反応させて上記の式1で表したメトホルミン酢酸塩を製造する方法。
(5) 水溶液中で上記の式4のメトホルミン塩酸塩1当量と、無機塩類又は有機アルカリ1〜2当量と式2の酢酸1当量〜2当量と反応させて無機塩を除去していない状態で製造する、上記の式1で表されるメトホルミン酢酸塩の製造方法。
(6) 前記(3)又は(4)において、メトホルミン遊離塩基1当量と酢酸1当量を反応させる、メトホルミン(1:1)酢酸塩の製造方法。
(7) 前記(3)において、有機溶媒が、メタノール、エタノール、イソプロパノール、アセトン、及びアセトニトリルからなる群より選ばれる、製造方法。
(8) 前記(3)において、1当量のメトホルミン塩酸塩と1〜2当量の無機塩類を水又は有機溶媒上で反応してメトホルミン遊離塩基を合成する、製造方法。
(9) 前記(1)のメトホルミン酢酸塩を有効成分とする、糖尿及び糖尿病、肥満症、高脂血症、冠動脈心疾患等が複合的に表れる代謝症候群患者の糖尿病治療及び合併症予防用の薬剤学的組成物。
(10) 前記(9)において、錠剤又はカプセル剤に剤形化されたものである、糖尿及び糖尿病、肥満症、高脂血症、冠動脈心疾患等が複合的に表れる代謝症候群患者の糖尿病治療及び合併症予防用の薬剤学的組成物。
(11) 前記(10)において、薬学的に許容可能な担体、希釈剤、又は賦型剤を更に含む薬剤学的組成物。
(12) 前記(9)、(10)、又は(11)において、メトホルミン遊離塩基として一日1〜3回に亘り50〜3,000mgが経口投与される、2型糖尿病の予防と治療、体重調節、高脂血症脂質の低下、脂肪肝の治療、動脈硬化の予防、多嚢性卵巣症候群治療用、P53遺伝子が欠如した癌治療、並びに筋肉痛、筋肉細胞毒性、及び横紋筋融解等の予防のための薬剤学的組成物。
本発明にかかるメトホルミン酢酸塩は、既存に糖尿病治療剤として用いられていたメトホルミン塩酸塩より優れた血糖降下効果、特に空腹時だけでなく食後の血糖降下に非常に効果的で、インシュリン感受性を増加させる効果を表す。より詳しくは、本発明にかかるメトホルミン酢酸塩は、メトホルミン塩酸塩に比べて溶解度を低くし、薬物の効果的な制御放出を表す薬剤学的、薬物動力学的に優れた効果を表す。また、本発明にかかるメトホルミン酢酸塩は、分子量の面でも適切で、薬物学的、薬剤学的、且つ臨床学的な面で塩酸塩より優れている。本発明のメトホルミン酢酸塩は、経口服用時に小腸で徐々に溶出されながらメトホルミンと酢酸に分離され、メトホルミンは吸収され、酢酸は小腸で二炭糖の分解を抑制し血糖上昇を抑制する。メトホルミン酢酸塩は、最適な生体利用率を表すため薬剤学的にも非常に優れた化合物である。
本発明は、溶解度、安定性、非吸湿性、及び錠剤剤形への加工性等の物理化学的特性がより優れるだけでなく、糖尿病及びその合併症の治療や予防により有効な式1の新規なメトホルミン酢酸塩に関するものである。
1) 式4のメトホルミン塩酸塩の付加塩を除去する段階;
2) 式2の酢酸を上記の式3のメトホルミン反応液に添加して混合物を製造する段階;及び
3) 前記混合物を攪拌して得た固体を、ろ過、洗浄及び乾燥させて式1の新規な結晶性酸付加塩を形成する段階から構成される。
メトホルミン塩酸塩2Kg(1当量)と水酸化ナトリウム483g(1当量)をメタノール10Lで2時間室温で攪拌した後、残っている固形物をろ過し、残ったろ液を減圧濃縮した。減圧濃縮後、生成された固形物にアセトン15Lを加えて攪拌した後、不溶物をろ過し、ろ液を減圧濃縮して1,230gのメトホルミン遊離塩基を得た。メトホルミン遊離塩基をアセトン33Lに溶解後、酢酸2.8L(4当量)を加え2時間室温で攪拌した。生成された結晶をろ過し、水とアセトンで再結晶して1,089gのメトホルミン酢酸塩(得量収率:47.7%)を得た。
10L反応器に、水5L、メトホルミン塩酸塩2Kg(1当量)、水酸化ナトリウム578g(1.2当量)を入れ、室温で2時間攪拌した。1時間酢酸1L(1.45当量)を加え、一晩室温で攪拌した。生成された結晶をアセトン−水(12:1)混合液で洗浄した後、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩1,112g(得量収率:48.7%)を得た。
反応器にメトホルミン塩酸塩1Kg(1当量)、水2Lを入れ、酢酸0.5L(1.45当量)を加えた後、30℃で2時間攪拌して完全に溶解した。この反応溶液に水酸化ナトリウム289.8g(1.2当量)水溶液を1時間小分け投与した。生成された結晶をろ過し、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩601g(得量収率:52.7%)を得た。
反応器にメトホルミン塩酸塩20g(1当量)、水30mLを入れ、酢酸10mL(1.45当量)を加えた後、30℃で2時間攪拌して完全に溶解した。この反応溶液に水酸化ナトリウム1.23g(1.5当量)を溶解した水溶液を投与した。生成された結晶をろ過し、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩16.7g(得量収率:73.0%)を得た。
反応器にメトホルミン塩酸塩20.0g(1当量)、水50mL、酢酸ナトリウム三水和物19.72g(1.2当量)を入れ攪拌した。生成された結晶をろ過し、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩11.72g(得量収率:51.3%)を得た。
20L反応器に水0.4L、水酸化ナトリウム241.50g、アセトン9L、メトホルミン塩酸塩1Kgを反応液に投入し、室温で2時間40分攪拌した。生成された結晶をろ過し、ろ過物をアセトンで洗浄した。ろ過液に水0.2Lと酢酸1Lを加え、攪拌した。生成された結晶をろ過し、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩1,056g(得量収率:92.4%)を得た。
反応器にメトホルミン遊離塩基78g(1当量)、イソプロパノール234mL、水234mL、酢酸57mL(1.65当量)を入れ攪拌した。生成された結晶をろ過し、イソプロパノールで洗浄し60℃で乾燥してメトホルミン酢酸塩54.6g(得量収率:47.8%)を得た。
メトホルミン塩酸塩20.00g(1当量)と水酸化ナトリウム4.84g(1当量)をエタノール200mLで2時間室温で攪拌した後、残っている固形物をろ過し、残ったろ液を減圧濃縮した。減圧濃縮後、生成された固形物にアセトン300mlを加えて攪拌した後、不溶物をろ過し、ろ液を減圧濃縮して12.0gのメトホルミン塩基を得た。遊離塩基にアセトン500mLと氷酢酸10mL(1.45当量)を加え攪拌した。生成された結晶をろ過し、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩13.6g(得量収率:59.5%)を得た。
反応器にメトホルミン塩酸塩20g(1当量)、水50mLを入れ、氷酢酸10mL(1.45当量)を加えた後、30℃で2時間攪拌して完全に溶解した。この反応溶液に水酸化カリウム10.2g(1.5当量)を溶解した水溶液を投与した。生成された結晶をろ過し、アセトンで洗浄し60℃で乾燥してメトホルミン酢酸塩13.3g(得量収率:58.2%)を得た。
次の表2に示した含量の通りメトホルミン酢酸塩とヒドロキシプロピルメチルセルロース及び硬質無水ケイ酸を入れて混合し、16〜17Mpaの圧力条件でローラーコンパクティングしてスラグ化した。これを14号篩で整粒した後、ステアリン酸マグネシウムを入れて混合し、打錠して錠剤層を製造し、ハイコーター(SFC-30N, セジョン機械, 韓国)でオパドライOY-C-7000Aをコーティング基剤にしてフィルムコーティング層を形成し、メトホルミン酢酸塩が500mg含有されたメトホルミン徐放錠を製造した。
次の表2に示した含量の通りメトホルミン酢酸塩とカルボキシメチルセルロースナトリウム、微結晶セルロース及び硬質無水ケイ酸を入れて混合し、16〜17Mpaの圧力条件でローラーコンパクティングしてスラグ化した。これを14号篩で整粒した後、ステアリン酸マグネシウムを入れて混合し、打錠して錠剤層を製造し、ハイコーター(SFC-30N, セジョン機械, 韓国)でオパドライOY-C-7000Aをコーティング基剤にしてフィルムコーティング層を形成し、メトホルミン酢酸塩が500mg含有されたメトホルミン徐放錠を製造した。
次の表2に示した含量の通りメトホルミン酢酸塩とポリビニルピロリドン、ヒドロキシプロピルメチルセルロース及びグリセリルジベヘネートを20号篩で篩過して混合し、硬質無水ケイ酸を35号篩で整粒した後、ステアリン酸マグネシウムと一緒に入れて混合し、打錠して錠剤層を製造し、ハイコーター(SFC-30N, セジョン機械, 韓国)でオパドライOY-C-7000Aをコーティング基剤にしてフィルムコーティング層を形成し、メトホルミン酢酸塩が750mg含有されたメトホルミン徐放錠を製造した。
メトホルミン遊離塩基500mgをアセトン30mLに溶解後、濃塩酸280mLを加え、2時間室温で攪拌した。生成された結晶をろ過し、アセトンで洗浄し70℃で熱風乾燥してメトホルミン塩酸塩490mg(得量収率:76.4%)を得た。
次の表2に示した含量の通りメトホルミン塩酸塩とヒドロキシプロピルメチルセルロース及び硬質無水ケイ酸を入れて混合し、16〜17Mpaの圧力条件でローラーコンパクティングしてスラグ化した。これを14号篩で整粒した後、ステアリン酸マグネシウムを入れて混合し、打錠して錠剤層を製造し、ハイコーター(SFC-30N, セジョン機械, 韓国)でオパドライOY-C-7000Aをコーティング基剤にしてフィルムコーティング層を形成し、メトホルミン塩酸塩が500mg含有されたメトホルミン徐放錠を製造した。
次の表2に示した含量の通りメトホルミン塩酸塩とカルボキシメチルセルロースナトリウム、微結晶セルロース及び硬質無水ケイ酸を入れて混合し、16〜17Mpaの圧力条件でローラーコンパクティングしてスラグ化した。これを14号篩で整粒した後、ステアリン酸マグネシウムを入れて混合し、打錠して錠剤層を製造し、ハイコーター(SFC-30N, セジョン機械, 韓国)でオパドライOY-C-7000Aをコーティング基剤にしてフィルムコーティング層を形成し、メトホルミン塩酸塩が500mg含有されたメトホルミン徐放錠500mgを製造した。
次の表2に示した含量の通りメトホルミン塩酸塩とポリビニルピロリドン、ヒドロキシプロピルメチルセルロース及びグリセリルジベヘネートを20号篩で篩過して混合し、硬質無水ケイ酸を35meshに整粒した後、ステアリン酸マグネシウムと併せて入れて混合し、打錠して錠剤層を製造し、ハイコーター(SFC-30N, セジョン機械, 韓国)でオパドライOY-C-7000Aをコーティング基剤にしてフィルムコーティング層を形成し、メトホルミン塩酸塩が750mg含有されたメトホルミン徐放錠を製造した。
前記実施例1によって製造された式1のメトホルミン酢酸塩のX−線回析分光度、核磁気共鳴分光データ、赤外線分光データ及び溶融点から本発明にかかるメトホルミン酢酸塩は比較例1によって製造された式4のメトホルミン塩酸塩と相違する結晶形態と構造を有することを確認した。
図1の粉末X−線回析分析図スペクトルに示されたメトホルミン酢酸塩の特徴的なピーク(peak)を下記の表3に示し、ここで“2θ”は回折角を、“d”は結晶面間の距離を、“I/Iο”はピークの相対強度を意味する。下記の分析はRigaku社D/MAX-2200V X-ray Diffractometer(XRD)で分析した。図1のメトホルミン酢酸塩と図2のメトホルミン塩酸塩を比較して相違する結晶が得られたことを確認した。
前記実施例1で製造された式1のメトホルミン酢酸塩は227.3〜228.0℃の溶融点を有し、前記比較例1のメトホルミン塩酸塩は222.8〜224.0℃の溶融点を有することを確認した。
前記実施例1で製造された式1のメトホルミン酢酸塩を元素分析(Elemental Analysis)した結果、実際の測定値と1価塩と2価塩の理論値を比較して酢酸が1当量結合されていることを確認した。表4に示された結果から、下記の分析は、C, H, NはFISONS EA-1108 Elemental Analyzerに依って、OはThermo Finnigan FLASH EA-1112 Elemental Analyzerで分析した。
前記実施例1で製造された式1のメトホルミン酢酸塩の核磁気共鳴(1H-NMR)ピーク(図3)と前記比較例1のメトホルミン塩酸塩のピーク(図4)を確認すると、酢酸のメチル基がδ=1.885ppmで生成されたことが確認できるため、メトホルミン遊離塩基に酢酸が結合されたことが分かった。
前記実施例1で製造された式1のメトホルミン酢酸塩の赤外線分光(FT-IR)ピーク(図5)と前記比較例1のメトホルミン塩酸塩のピーク(図6)を確認すると、全体的にピークが変わっており、特に酢酸のカルボニル基が1622cm-1で生成されたことから、メトホルミン遊離塩基に酢酸が結合されたことを確認した。
前記実施例1で製造された式1のメトホルミン酢酸塩と、現在までメトホルミンの薬学組成物の活性成分として利用されている市販のメトホルミン塩酸塩の水に対する溶解度を比較した。
1) 振盪恒温水槽に水を満たして温度を30℃に設定した。
2) 100mLの三角フラスコに水20mLを入れ、10gのメトホルミン塩酸塩とメトホルミン酢酸塩をそれぞれ入れた。
3) メトホルミン酢酸塩とメトホルミン塩酸塩がそれぞれ入っている三角フラスコを水槽のrackに固定させた後、温度30℃、振盪速度は1分当り60回に機器を作動させた。
4) 24時間間隔でサンプルを採取してろ過した後、紫外部吸光光度計(λ=233nm)を利用して定量し濃度を計算した。
前記実施例1で製造された式1のメトホルミン酢酸塩と、現在までメトホルミンの薬学組成物の活性成分として利用されている市販のメトホルミン塩酸塩の吸湿性を比較した。
1) メトホルミン塩酸塩とメトホルミン酢酸塩をそれぞれ40℃で24時間乾燥して恒量になるようにした。
2) KH2PO4飽和溶液(22g/100g)をデシケーター下段部に入れて内部の湿度を95%に合わせ、デシケーターが位置した空間の室内温度は25℃を維持させた。
3) メトホルミン塩酸塩とメトホルミン酢酸塩をそれぞれ100mgを精密に取って容器と共に重量を測定した。
4) メトホルミン塩酸塩とメトホルミン酢酸塩を容器と共にデシケーター内に入れ、24時間間隔で容器と共に取り出して重量を測定し重量の増加分だけ水分を吸収したものと計算した。
前記の実施例1で製造された式1のイオン化されるメトホルミン酢酸塩は、pHによって酸、遊離塩基又は両性化合物として作用することから、各適正点でpHの変化が生じることになるため、計算されたpH値と実際に測定されたpH値の差から得られたpKa値は下記の通りであり、その結果を添付図面の図9のように示した。
前記実施例10によって製造された本発明のメトホルミン酢酸塩徐放錠と、比較例2によって製造されたメトホルミン塩酸塩徐放錠を使用して大韓薬典一般試験法中の溶出試験項のパドル法で溶出特性を測定し、その結果を添付図面の図10のように示した。
1. 血糖降下効果
本試験は発明の効果を裏付ける実験であり、実施例1のメトホルミン酢酸塩と市販のメトホルミン塩酸塩を実験動物に投与して、その効果を比較するために表8のように実施した。
本試験は発明の効果を裏付ける実験であり、実施例1のメトホルミン酢酸塩と市販のメトホルミン塩酸塩を実験動物に投与してその効果を比較するために表10のように実施した。
2) 120分にはG3で、240分にはG2及びG3で血糖降下効果を観察できた。
3) スクロース投与後、20〜60分の時間帯に試験物質200、400mg/k g容量群でメトホルミン酢酸塩がメトホルミン塩酸塩より高い血糖降下効果を示したことが確認できた。
4) 前記結果から類推すると、メトホルミン酢酸塩の食後血糖降下効果がメトホルミン塩酸塩より優れることを確認した。
上述の通り、本発明にかかるメトホルミン酢酸塩は既存のメトホルミン塩酸塩に比べて血糖降下効果に優れ、特にメトホルミン塩酸塩の短所が食後血糖調節能力が弱いのに比べ、本発明の酢酸塩は食後血糖降下効果がはるかに優れている。また、生産方法が困難だったり、過酷な条件で生産されなければならなかった既存の製造方法に対し、本発明では特別な設備がなくても一般的な生産設備で合成ができるように単純に工程を改善してより低い単価でメトホルミンの新規塩を合成できるように産業の利用可能性を高めた。また、溶解度がメトホルミン塩酸塩より低いため、急激な放出による過度な血糖降下と薬物の早い消失を防止できるため、酢酸塩は塩酸塩に比べて速放出性で、又は1日24時間徐放型に製剤化して均等な血中濃度の維持が容易だという等、薬学組成物の活性成分として非常に有用である。
Claims (16)
- 無水物、半水和物、又は一水和物の状態にある、請求項1記載の式1のメトホルミン酢酸塩。
- 1価塩である、請求項1記載の式1のメトホルミン酢酸塩。
- 糖尿病を治療又は予防するための、請求項1記載の式1のメトホルミン酢酸塩。
- 無機塩類が水酸化ナトリウム又は水酸化カリウムである、請求項5又は6記載の式1のメトホルミン酢酸塩の製造方法。
- 1モルのメトホルミン塩酸塩と反応する無機塩類の分子比率が1〜2である、請求項5又は6記載の式1のメトホルミン酢酸塩の製造方法。
- 1モルのメトホルミン遊離塩基と反応する酢酸の分子比率が1〜2である、請求項5記載の式1のメトホルミン酢酸塩の製造方法。
- 有機アルカリが、炭酸水素ナトリウム、炭酸カリウム、酢酸ナトリウム、又は酢酸ナトリウム3水和物である、請求項10記載の式1のメトホルミン酢酸塩の製造方法。
- 1モルのメトホルミン塩酸塩と反応する有機アルカリの分子比率が1〜2である、請求項10記載の式1のメトホルミン酢酸塩の製造方法。
- 反応が−10〜50℃の温度範囲で行われる、請求項5、6、及び10のいずれか一項記載の式1のメトホルミン酢酸塩の製造方法。
- 有機溶媒が、水、メタノール、エタノール、イソプロパノール、アセトン、及びアセトニトリルからなる群より選ばれる、請求項5又は6記載の式1のメトホルミン酢酸塩の製造方法。
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JP4592818B2 (ja) | 2010-12-08 |
US8058312B2 (en) | 2011-11-15 |
US8541474B2 (en) | 2013-09-24 |
WO2008093984A1 (en) | 2008-08-07 |
EP2109447A1 (en) | 2009-10-21 |
CN105152983A (zh) | 2015-12-16 |
KR20080071095A (ko) | 2008-08-01 |
EP2109447A4 (en) | 2011-08-17 |
KR100926417B1 (ko) | 2009-11-12 |
US20120010287A1 (en) | 2012-01-12 |
CN101652131A (zh) | 2010-02-17 |
US20100087544A1 (en) | 2010-04-08 |
EP2109447B1 (en) | 2015-06-10 |
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