TW201032798A - Antitumor combination combining AVE8062 and docetaxel - Google Patents
Antitumor combination combining AVE8062 and docetaxel Download PDFInfo
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- TW201032798A TW201032798A TW098142340A TW98142340A TW201032798A TW 201032798 A TW201032798 A TW 201032798A TW 098142340 A TW098142340 A TW 098142340A TW 98142340 A TW98142340 A TW 98142340A TW 201032798 A TW201032798 A TW 201032798A
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- IXWNTLSTOZFSCM-YVACAVLKSA-N ombrabulin Chemical compound C1=C(NC(=O)[C@@H](N)CO)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 IXWNTLSTOZFSCM-YVACAVLKSA-N 0.000 title claims abstract description 79
- 229950003600 ombrabulin Drugs 0.000 title claims abstract description 57
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 title claims abstract description 44
- 229960003668 docetaxel Drugs 0.000 title claims abstract description 42
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- RDTRHBCZFDCUPW-KWICJJCGSA-N 2-[(4r,7s,10s,13s,19s,22s,25s,28s,31s,34r)-4-[[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-34-[[(2s,3s)-2-amino-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10,13-bis(1h-imidazol-5-ylmethyl)-19-(1h-indol Chemical compound C([C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CSSC[C@@H](C(N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)NCC(=O)N[C@@H](CC=2NC=NC=2)C(=O)N1)C(C)C)C(C)C)=O)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)C1=CN=CN1 RDTRHBCZFDCUPW-KWICJJCGSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
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- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
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- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 108010027437 compstatin Proteins 0.000 description 1
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- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
201032798 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種用於治療實體腫瘤之結合AVE8062或 AVE8062之鹽及多烯紫杉醇之抗腫瘤組合。 【先前技術】
Clinical Cancer Research 2004，10，415-427比較用於治 療實體腫瘤之血管靶向劑（或VTA)。其中，AVE8062A (AVE8062鹽酸鹽）係以每週劑量4.3-30 mg/m2單獨投與。
Proc. Am. Soc. Clin. Oncol. 2003, 22, 834, abstract 834 敍述以每週劑量 4.5、6.0、8.0、11.5、15.5、22 及 30 mg/m2單獨投與AVE8062A。當以過高劑量投與AVE8062A 時，觀察到心臟毒性。 J. Clin. One. 2006, ASCO meeting, 2006:13074, Vol.24, No. 18S以摘要形式敍述AVE8062A與奥沙利始（oxaliplatin) 之組合。該組合亦敍述於Jpn. J Cancer Res. 1999, 90, 1016-1025中。 WO 02/056692敍述康普瑞汀（Combretastatin)A-4與兩種 抗癌劑之組合。在所示之實例中，由劑量1-100 mg/m2之 康普瑞汀A-4與劑量40_250 mg/m2之紫杉醇組合。WO 2006/078422亦敍述劑量1-100 mg/m2之康普瑞汀與劑量40-250 mg/m2之紫杉醇之組合。 WO 02/074229敍述AVE8062與選自紫杉烷類（尤其太平 洋紫杉醇或多烯紫杉醇）、長春花生物鹼、烷化劑及抗代 謝劑之抗癌劑之組合。該組合可包括同時或依序投與兩種 144963.doc 201032798 化合物。不指定投與順序。此等化合物可經口、靜脈内、 皮下或肌内注射投與。 就紫杉烧而言，其係以介於1及10 mg/kg之間之劑量藉 由腹膜内注射或以介於1及3 mg/kg之間之劑量藉由靜脈内 注射而投與。所示之實例係對小鼠投與150 mg/kg劑量之 AVE8062及109.6 mg/kg劑量之多烯紫杉醇的組合 (AVE8062A/多烯紫杉醇之比例：1.37)。以小鼠為例，以 小氣。人之換算因數為3(參見Freireich, EJ 「Quantitative comparison of toxicity of anticancer agents in mouse, rat, dog, monkey and man」，Cancer Chemother Rep. 1966, 50(4), 219-244)，此產生用於人之450 mg/m2劑量之 AVE8062及330 mg/m2劑量之多烯紫杉醇。
Cancer Res. 2007，67(19)，9337-9345敍述用於治療小鼠 SKOV3ipl、HeyA8或HeyA8-MDR型（卵巢癌細胞）腫瘤細 胞之組合。AVE8062A係以 10、30、50及 100 mg/kg(30-300 mg/m2)之劑量投與小鼠及多稀紫杉醇係以2或1.4 mg/kg(6 或4.2 mg/m2)之劑量投與小鼠。針對AVE8062，建議使用 3 0 mg/kg之劑量。 在網址 www.clinicaltrials.gov 上，顯示 AVE8062+順銘 (D1)/多烯紫杉醇（D2)組合用於治療患有晚期實體腫瘤之患 者之階段I研究（代號NCT00719524)。未指定劑量。
Proc. Amer. Assoc. Cancer Res. 2005, Vol.46, abstract# 3425(In vivo synergy between docetaxel and AVE8062A, a tumor vasculature targeting agent)敍述投與患有 MA13/C乳 144963.doc 201032798 房腫瘤之小鼠之AVE8062A及多烯紫杉醇之組合。已發現 針對該組合之最高無毒劑量（HNTD)為37.5 mg/kg/注射之 AVE8062A及54.8 mg/kg/注射之多烯紫杉醇（亦即多烯紫杉 醇/AVE8062A之比例為1.461)。本發明敍述一種欲投與人 類患者之組合。 【發明内容】
本發明係關於一種AVE8062或AVE8062鹽及多烯紫杉醇 之抗腫瘤及依序使用的組合，其特徵在於AVE8062係以介 於10及50 mg/m2之間之劑量投與患者，然後於該周之另一 天中，較佳係於間隔24小時後，以介於50及120 mg/m2之 間之劑量投與多烯紫杉醇。 AVE8062或AVE8062鹽之劑量較佳係20-40 mg/m2，較佳 係30-40 mg/m2。多浠紫杉醇之劑量較佳係50-100 mg/m2， 較佳係60-80 mg/m2。AVE8062或AVE8062鹽之劑量可為35 mg/m2及多烯紫杉醇之劑量可為75 mg/m2。 AVE8062或AVE8062鹽及多烯紫杉醇可經灌注投與。 本發明亦係關於一種計畫在一個週期期間投與患者之組 合，該週期包含投與代表該週期開始之AVE8062或 AVE8062鹽，然後投與多烯紫杉醇，其特徵在於首先投與 AVE8062或AVE8062鹽，然後於該周之另一天中，較佳係 於間隔24小時後，投與多烯紫杉醇，AVE8062及多烯紫杉 醇之劑量係如技術方案1至4中任一項所定義。可重複該週 期，介於AVE8062或AVE8062鹽之兩次投與間之間隔範圍 為1至4週，較佳係3週。 144963.doc 201032798 本發明亦關於以AVE8062或AVE8062鹽及多烯紫杉醇於 製備如技術方案1至1〇中任一項所定義之抗腫瘤組合之用 途。本發明亦關於以AVE8062或AVE8062鹽於製備如技術 方案1至10中任一項所定義之抗腫瘤組合之用途。 該組合可治療實體腫瘤。其可治療乳癌、卵巢癌、食道 癌、胰臟癌、肌肉組織癌或軟組織癌、頭/頸癌、膀胱 癌、肝癌、前列腺癌、卵巢癌或皮膚癌。 【實施方式】 關於AVE8062，其具有結構式： OMe
及具有化學名稱（Z)-N-[2-甲氧基-5-[2-(3,4,5-三甲氧基苯 基）乙烯基]苯基]-L-絲胺醯胺。AVE8062A表示AVE8062之 鹽酸鹽。 AVE8062可根據敍述於WO 03/084919中之方法製備。所 採用方案之内容係使用AVE8062A ;該化合物係呈包含有 效成分水溶液之小瓶的形式封裝。在投與患者之前，從小 瓶抽出大約25 mg含量之AVE8062A，然後在灌注袋中稀 釋。袋中AVE8062A之濃度係在0.012 mg/ml及 1.62 mg/ml 之間。給予每位患者之灌注體積取決於該患者。 關於多稀紫杉醇，其係由Sanofi-Aventis在商標 Taxotere®下銷售。其具有化學式： 144963.doc 201032798
其可呈具有CAS號114977-28-5或148408-66-6(三水合物）之
形式。多烯紫杉醇之製備敍述於例如EP 0253738、EP 0253739及 WO 92/09589 中。 0 在所採用方案之内容中，多烯紫杉酵係呈包含40 mg/ml 濃度之含於聚山梨酸酯8〇之無水多烯紫杉酵的小瓶形式封 裝。有可能使用包含20 mg多烯紫杉醇（0.5 ml)之小瓶，其 接著使用含有13% w/w之乙醇水溶液小瓶（1.98 ml)的内容 物稀釋，以獲得具有10 mg/ml之最終多烯紫杉醇濃度的預 混溶液。亦可能使用包含80 mg多烯紫杉醇（2 ml)之小瓶， 其接著用含有13% w/w之乙醇水溶液小瓶（7·33 ml)的内容 物稀釋，以獲得具有1〇 mg/ml之最終多烯紫杉醇濃度的預 φ 混溶液。 該預混溶液本身繼而在包含葡萄糖或氯化鈉之灌注袋中 再次稀釋。給予每位患者之灌注體積係取決於該患者。 關於該抗腫瘤組合，其包括較佳藉由灌注法依序投與介 •於10及50 mg/m2之間之劑量之AVE8〇62*AVE8〇62鹽，然 後於該周之另-天中，較佳係於間隔24小時後，投與介於 5〇及12〇 mg/〆之間劑量的多烯紫杉醇。較佳係依該次序 依序結合該兩種化合物，亦即首先使用ave8〇62或 144963.doc 201032798 AVE8062鹽，然後使用多烯紫杉醇。 較佳地，AVE8062或AVE8062鹽之劑量為20-40 mg/m2， 較佳係30-40 mg/m2及/或多烯紫杉醇之劑量為50-100 mg/m2，較佳係60-80 mg/m2。一種組合可為例如35 mg/m2 之AVE8062或AVE8062鹽及75 mg/m2之多烯紫杉醇。 [結果] 該方案包括將AVE8062A及多烯紫杉醇之組合投與患有 晚期實體腫瘤之患者。AVE8062A之投藥法係灌注約30分 鐘，而多烯紫杉醇係於隔天經灌注投與約1小時。然後每 三周重複該AVE8062A/多烯紫杉醇週期。 患者：年齡中間值：53歲（範圍28-71歲）；39位患者，14 位男性/25位女性；主要腫瘤：乳房腫瘤（12位患者）及食道 腫瘤（8位患者）。 144963.doc 201032798 表i 治療患者之人數 39 性別 男性 14 (35.9%) 女性 25 (64.1%) 年齡中間值(歲)範圍 53 [28-71] ECOGPS 0 15 (38.5%) 1 24(61.5%) 腫瘤類型 乳房 12 (30.8%) 食道 8 (20.5%) 肌肉/軟組織 5 (12.8%) 胰臟 5 (12.8%) 其他a 9(23.1%) 先前化學療法 先前化學療法(CT) 36 (92.3%) 針對晚期腫瘤之CT療程之人 數中間值[範圍] 1 [0-7] 針對晚期腫瘤及頑固性腫瘤b 以紫杉烷類之先前治療 18 (46.1%) 3 (7.7%) 3包括頭/頸癌或未明原因之癌症(各2位患者），及膀胱癌、肝癌、前列腺 癌、卵巢癌及皮膚癌(各1位患者）。 G b在紫杉烷治療期間進展之腫瘤。 144963.doc 201032798 表II 劑量1 AVE8062A [mg/m2】 多烯紫杉醇 [mg/m2】 N患者 在第一週期 出現DLT之 患者人數 在下一週期 出現DLT之 患者人數 I 11.5 75 3 無 益 II 15.5 75 5 無 1位第4級> 5 天（C2) 嗜中性白血 球減少症 III 20 75 3 無 具有第3級 呼吸衰竭 (C4)之嗜中 性白血球減 少性敗血症 IV 25 75 6 1位嗜中性 白血球減少 性感染 1位第3級 (C10, 11, 12)指曱毒 性 1位第3級 (C6)瘻 V 30 75 3 無 V 35 75 13 無 1位第3級 (C2)ALAT VI 42 75 6 -第3級頭痛 -1位第3級 疲勞 1位第3級 (C2)疲勞 1.週期數目中間值：3(1-14) 此等組合不導致任何嚴重的心臟中毒效果。 144963.doc 10· 201032798
表III 劑量 AVE8062A [mg/m2] 11.5 N=3 15.5 N=5 20 N=3 25 N=6 30 N=3 35 N=13 42 N=6 總數 N=39 可評估人 數(N) 3 5 3 6 2 11 6 36 (92.3%) 部分反應 0 la 0 2a 0 0 0 3 (7.7%) 穩定疾病 1 1 3 2 2 7b 2 18 (50%) 腫瘤進展 2 3 0 2 0 4 4 15 (46.2%) 關於該腫瘤，其可為實體腫瘤，尤其成年人或兒童之實 體腫瘤。該組合可治療乳癌、卵巢癌、食道癌、胰臟癌、 肌肉組織癌或軟組織癌、頭/頸癌、膀胱癌、肝癌、前列 腺癌、卵巢癌或皮膚癌。
144963.doc • 11 ·
Claims (1)
- 201032798 七、申請專利範圍： 1· 一種AVE8062或AVE8062鹽及多烯紫杉醇之抗腫瘤及依 序使用的組合，其特徵在於該AVE8062係以介於1〇及50 mg/m2之間之劑量投與患者，然後於該周之另一天中， 較佳係於間隔24小時後，以介於50及120 mg/m2之間之劑 量投與多烯紫杉醇。 2.如請求項1之組合，其中該AVE8062或AVE8062鹽之劑量 為 20-40 mg/m2，較佳係 30-40 mg/m2。 © 3.如請求項1或2之組合，其中該多稀紫杉醇之劑量為50- 100 mg/m2，較佳係 60-80 mg/m2。 4. 如請求項1之組合，其中該AVE8062或AVE8062鹽之劑量 為3 5 mg/m2及該多浠紫杉醇之劑量為75 mg/m2。 5. 如請求項1至4中任一項之組合，其中該AVE8062或 AVE8062鹽及多烯紫杉醇係經灌注投與。 6. —種計畫在一個週期期間投與患者之組合，該週期包括投與代表該週期開始之AVE8062或AVE8062鹽，然後投 與多烯紫杉醇，其特徵在於首先投與該AVE8062或 AVE8062鹽，然後於該周之另一天中，較佳係於間隔24 小時後，投與多烯紫杉醇，AVE8062及多烯紫杉酵之劑 量係如請求項1至4中任一項所定義。 7.如請求項6之組合，其特徵在於重複該週期，介於 AVE8062或AVE8062鹽之兩次投與間之間隔範圍係1至4 週，較佳係3週。 8-如請求項1至7中任一項之組合，其係用於治療實體腫 144963.doc 201032798 瘤。 •» _ 9. 如請求項名之組合，其中該實體腫瘤不是乳房實體腫 瘤。 10. 如請求項1至7中任一項之組合，其係用於治療乳癌、卵 巢癌、食道癌、胰臟癌、肌肉組織癌或軟組織癌、頭/頸 癌、膀脱癌、肝癌、前列腺癌、卵巢癌或皮膚癌。 11. 一種以AVE8062或AVE8062鹽及多烯紫杉醇於製備如請 求項1至1 0中任一項所定義之抗腫瘤組合之用途。 12· —種以AVE8062或AVE8062鹽於製備如請求項1至10中任 一項所定義之抗腫瘤組合之用途。 144963.doc 201032798 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：ococ6h5144963.doc -2-
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| FR0806979A FR2939665B1 (fr) | 2008-12-12 | 2008-12-12 | Combinaison antitumorale associant l'ave8062a et le docetaxel |
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| FR2601675B1 (fr) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent |
| FR2601676B1 (fr) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Procede de preparation du taxol et du desacetyl-10 taxol |
| MX9102128A (es) | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | Derivados de taxano,procedimiento para su preparacion y composicion farmaceutica que los contiene |
| US20050209310A1 (en) | 2000-12-22 | 2005-09-22 | Chaplin David J | Methods for modulating tumor growth and metastasis |
| CA2432792C (en) | 2000-12-22 | 2012-04-03 | Bristol-Myers Squibb Company | Methods for modulating tumor growth and metastasis |
| US20020183266A1 (en) * | 2001-03-15 | 2002-12-05 | Aventis Pharma, S.A. | Combination comprising combretastatin and anticancer agents |
| FR2838437B1 (fr) | 2002-04-11 | 2004-06-04 | Aventis Pharma Sa | Procedes de preparation de combretastatines |
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Also Published As
| Publication number | Publication date |
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| CL2011001316A1 (es) | 2011-10-28 |
| EA201170803A1 (ru) | 2011-12-30 |
| TN2011000268A1 (fr) | 2012-12-17 |
| BRPI0923349A2 (pt) | 2015-07-21 |
| ZA201104358B (en) | 2012-09-26 |
| FR2939665B1 (fr) | 2011-10-07 |
| CN102245175A (zh) | 2011-11-16 |
| PA8853301A1 (es) | 2010-07-27 |
| MX2011006253A (es) | 2011-11-04 |
| CR20110319A (es) | 2011-09-20 |
| IL213458A0 (en) | 2011-07-31 |
| FR2939665A1 (fr) | 2010-06-18 |
| US20120004294A1 (en) | 2012-01-05 |
| CO6390037A2 (es) | 2012-02-29 |
| JP2012511554A (ja) | 2012-05-24 |
| PE20120125A1 (es) | 2012-02-23 |
| MA32955B1 (fr) | 2012-01-02 |
| WO2010067027A1 (fr) | 2010-06-17 |
| NI201100114A (es) | 2011-12-13 |
| KR20110104932A (ko) | 2011-09-23 |
| CA2746475A1 (fr) | 2010-06-17 |
| AR074599A1 (es) | 2011-01-26 |
| UY32318A (es) | 2010-07-30 |
| EP2376076A1 (fr) | 2011-10-19 |
| AU2009326220A1 (en) | 2011-07-07 |
| ECSP11011112A (es) | 2011-07-29 |
| SG172071A1 (en) | 2011-07-28 |
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