TWI536997B - 穿心蓮萃取物 - Google Patents
穿心蓮萃取物 Download PDFInfo
- Publication number
- TWI536997B TWI536997B TW097125255A TW97125255A TWI536997B TW I536997 B TWI536997 B TW I536997B TW 097125255 A TW097125255 A TW 097125255A TW 97125255 A TW97125255 A TW 97125255A TW I536997 B TWI536997 B TW I536997B
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- TW
- Taiwan
- Prior art keywords
- extract
- dry weight
- dosage form
- andrographolide
- solid dosage
- Prior art date
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- 244000118350 Andrographis paniculata Species 0.000 title claims description 26
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- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims description 21
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Description
本發明係關於一種穿心蓮萃取物以及一種以穿心蓮萃取物治療炎性腸病的方法。
“炎性腸病”(inflammatory bowel disease)包括慢性胃腸道疾病，其病理特徵為炎性細胞滲透到消化道黏膜。克隆氏病(Crohn’s disease)和潰瘍性結腸炎(ulcerative colitis)是其中兩種比較常見的疾病。
潰瘍性結腸炎(ulcerative colitis)發生在大腸(如結腸)。由於腸內的病變導致發炎以至潰瘍。
克隆氏病(Crohn’s disease)主要發生在小腸末端(如回腸末端)和大腸的一部分。它的發炎情況比潰瘍性結腸炎更深入腸壁內。
以上兩種疾病均與前體炎症細胞激素TNFα和IL－1 β的不正常有關。(e.g.,McClane S.J.et al.,Journal of Parenteral and Enteral Nutrition 23,1999.)下調前體炎症細胞激素的藥物已經被開發。如，5－氨基水楊酸－一種TNFα抑制劑已經用於治療潰瘍性結腸炎(Therapeutic Immunology Ed.Austen,K F.,Blackwell Publishing,2001,159－167)然而目前的藥物均存在治療效果不明顯和副作用大的缺點。
因此很有必要開發更有效的治療炎性腸病的藥物。
本發明主要是基於一令人驚喜的發現，一種穿心蓮萃取物可以對炎性腸病產生有效的治療效果。
該穿心蓮萃取物包含總穿心蓮內酯、多糖和黃酮類化合物，其中總穿心蓮內酯、多糖和黃酮類化合物在穿心蓮萃取物乾粉中的重量百分比含量分別為10－22%(優選為13－17%)、18－28%(優選為20－25%)和10－15%(優選為12－14%)；其中總穿心蓮內酯包括穿心蓮內酯、14－去氧穿心蓮內酯、14－去氧－11,12去氫－穿心蓮內酯和新穿心蓮內酯，其在穿心蓮萃取物乾粉中的重量百分比含量分別為2－20%(優選為3－10%，更優選為6－10%)、0.01－6%(優選為0.01－2%，更優選為0.01－1%)、1－6%(優選為2－5%，更優選為2－4%)和1－5%(優選為2－4%)。
本發明另一方面是關於一種治療炎性腸病(包括克隆氏病和潰瘍性結腸炎)的方法，包括給予需要治療的個體以一有效劑量的上述穿心蓮萃取物。
另外在本發明範圍內的是一種藥學組合物，包含上述穿心蓮萃取物和一種藥學上可接受的載體，以及應用該藥學組合物治療炎性腸病，及應用該組合物生產治療炎性腸病的製劑。
關於本發明之一個或更多實施例的內容，將揭示於以下的說明書中。本發明之其他特點、目的以及優點將可明
顯見於說明書及權利要求書中。
為了製備本發明的穿心蓮萃取物，可以將穿心蓮的地上部分浸入80－95%的乙醇中，然後收集乙醇部分，最後去掉乙醇。下面會給出一個具體的例子。如此得到的萃取物可以進一步通過薄層層析、快速柱層析、高壓液相色譜或其他合適的方法純化。
本發明包括的治療炎性腸病的方法，包括給予需要治療的個體有效劑量的本發明的萃取物。“有效劑量”一詞指的是，能夠使個體產生上述治療效果所需要的萃取物的量。依據給藥途徑、賦形劑的用法、與其他治療用藥物一起使用的可能性，有效劑量可以改變，可由熟悉本領域之通常知識者所推知。優選地，萃取物乾粉的有效劑量為1－100mg/kg/天。“治療”一詞，系指將上述萃取物給予一具有炎性腸病、具有疾病的症狀、或易患病體制之機體施用或服用，從而治癒、治療、緩和、抒解、修改、醫治、改善、改良或是影響疾病、疾病的症狀、或是易患病的體質之目的。
為了實施上述治療方法，可以通過如下方式給予個體萃取物：口服、直腸給藥、注射、吸入、或植入上述萃取物、萃取物與藥學上可接受載體的組合物。“注射”指的是經皮下，皮內，靜脈，肌內，顱內等給藥技術。
可接受的口服製劑包括，但不限於以下幾種：片劑，
膠囊劑，脂肪乳劑和水混懸劑，分散劑和溶液劑。片劑中常使用的稀釋介質包括乳糖和澱粉，也常加入潤滑劑如硬脂酸鎂等。或為了藥物釋放傳輸或美觀而將片劑進行包衣。口服膠囊劑常用的稀釋劑包括乳糖和乾澱粉。當水混懸劑和脂肪乳劑用於口服時，活性成分常混懸於或溶於油相中，再進行乳化或加入混懸劑。如果需要，可加入適量的甜味劑，矯味劑或著色劑。
直腸給藥製劑包括但不限於以下直腸可以接受的製劑形式：霜劑、凝膠劑、脂肪乳劑、混懸劑、栓劑和片劑。首選的直腸給藥劑型是形狀和大小都符合人體直腸特點的栓劑。栓劑在人體溫度下通常會軟化、熔融或溶出。栓劑輔料包括但不限於可可油、甘油白凝膠、氫化植物油、各種分子量的聚乙二醇混合物和聚乙二醇脂肪酸酯。
無菌注射劑(如水針、油性混懸液)可通過已有的製劑技術使用適當的分散劑、潤濕劑(如吐溫－80)和混懸劑製成。無菌注射製劑也可以是使用無毒且人體可接受的稀釋劑或溶劑製成的無菌注射溶液或混懸液，例如1，3－丁二醇溶液。在常用的溶液或溶劑中可使用的有：甘露醇、水、Ringer溶液和等滲氯化鈉溶液。另外，無菌的(組分確定)的不揮發的油類也可作為溶劑或混懸介質(如合成的單、或二甘油酸酯)。脂肪酸，如油酸及其甘油酯衍生物、一些天然的可藥用的油類，如橄欖油等，特別是他們的聚氧乙烯化衍生物，也常用於注射劑。這些油性溶液或混懸液常含有長鏈醇類作為稀釋劑或分散劑，或羧甲基纖維素或類似的物質作為
稀釋劑。
吸入製劑的製備技術有很多種，這種劑型可以是藥物的鹽溶液，並使用苯甲醇等作為防腐劑，使用吸收促進劑提高生物利用度，使用的碳氟化合物以及促溶促分散成份在文獻中都可以找到。
局部給藥的製劑可以是油劑，乳膏劑，洗液，油膏等，所用的基質可以是蔬菜油，礦物油，白色礦物脂(例如白色軟體石蠟)，支鏈脂肪或者油，動物脂肪，高分子量的醇(大於12個碳)。最好的基質是藥物能夠在裏面溶解。乳化劑，穩定劑，保濕劑，抗氧化劑以及顏色味道調節劑等都可以根據需要進行添加。而且，透皮吸收促進劑可以用於局部給藥製劑，在美國專利3,989,816和4,444,762中給出了一些促進劑的例子。霜劑是非常合適的局部給藥製劑，它由礦物油，自乳化蜂蠟和水混合含有活性藥用成份的油(例如杏仁油)形成。一個霜劑的處方是含有40份的水，20份的蜂蠟，40份的礦物油和一份的杏仁油。油膏可以通過將活性藥物成份溶液與蔬菜油混合而成，例如杏仁油和熱的軟體石蠟，然後冷卻。一個例子是處方中含有30%的杏仁油和70%的白色軟體石蠟(重量百分比)。
在藥物製劑成份中，基質(藥物載體)應該是與藥物相容的(互相之間是惰性的，沒有相互作用)，而且不應該對患者產生危害。例如，助溶劑，像環糊精(與活性成份形成高溶解度的複合物)，可以被做為藥物輔料用於藥物的傳輸。其他藥物傳輸載體包括膠質二氧化矽，硬脂酸鎂，纖維素，
十二烷基硫酸鈉和D&C Yellow # 10等。
一合適的體外實驗可用於初步評價上述萃取物抑制TNF α或IL－1 β的活性。萃取物還可以進一步用炎性腸病的體內實驗來檢驗。比如，把穿心蓮萃取物給與動物模型(如小鼠模型)或有炎性腸病的患者，從而評價其治療效果。根據這些結果來評定給藥的劑量和方式。
無須進一步說明，相信上述已經充分表達，本發明能據以實施。因此，以下的實施例僅為本發明之例示，而非用以限定其他以任何形式結露本發明者。本文中任何文獻包括專利，其內容在此皆並入本文以供參考。
穿心蓮枝葉粉末(350kg)用90%乙醇(2100kg)浸泡，在75－80℃回流2小時，萃取乙醇液，殘渣供再次浸取，混合乙醇液，經過濾、濃縮得密度為1.00－1.10g/ml的流浸膏。
取少量流浸膏乾燥後使用高效液相色譜分析，結果乾燥萃取物含總穿心蓮內酯(14.8%占乾燥萃取物比)，總多糖(24.6%)及總黃酮(12.8%)。在總穿心蓮內酯中含穿心蓮內酯占乾燥萃取物的9.2%，14－去氧穿心蓮內酯<0.1%，14－去氧－11,12－脫水穿心蓮內酯2.6%，及新穿心蓮內酯3.0%。糊精(0.03kg)加入流浸膏後噴霧乾燥(進風：185－195℃；排風：90－100℃)，經粉碎、過篩後包裝得穿心蓮萃取物用於製備片劑和膠囊。
片劑的製備為：澱粉(10g)、蔗糖(10g)及水(80.0g)製備粘合劑，另取穿心蓮萃取物(500.0g)，澱粉(140.0g)，微晶
纖維素(337.5g)，混合，經濕法制粒，在55℃乾燥得乾顆粒。取乾顆粒(957.6g)和硬脂酸鎂(2.4g)混合5分鐘。將最終混合物壓片(片重400mg，相當於200mg穿心蓮萃取物)。另製備包衣液，含羥丙甲基纖維素(7.5g)，丙二醇(1.6g)，二氧化鈦(3.0g)，鋁色澱(0.4g)，純水(87.5g)，片劑經薄膜包衣得穿心蓮萃取物薄膜包衣片。
膠囊劑的製備為：穿心蓮萃取物(340.0g)，乾燥澱粉(221.0g)，二氧化矽(2.125g)，和微晶纖維素(34.0g)混合，使用膠囊填充板填充於#0硬膠囊，得穿心蓮萃取物膠囊(每粒裝量351.25mg，相當於200mg穿心蓮萃取物)。
實驗材料：
1.細胞：正常人外周血單核細胞(PBMC)
2.受試藥物：穿心蓮浸膏(按實施例1方法製備)
3.陽性對照：地塞米松(美國Sigma公司產品)
4.試劑：Ficoll－Paque Plus(Amersham Bioscience)；內毒素(LPS，lipopolysaccharide)和地塞米松(CalBiochem.)；TNFa ELISA Kit及IL－1 β ELISA Kit(晶美生物工程公司)；二甲基亞碸(DMSO)為美國Sigma公司產品；細胞培養基及胎牛血清Gibco公司為產品
方法與結果：
新鮮血液以EDTA為抗凝劑，Ficoll分離血細胞，重懸細胞於含有10%胎牛血清的RIMP 1640培養基中。在96孔板中加入100μl密度為1×105細胞/ml新分離的細胞，每孔細胞
總數為104個，每個樣品作3個孔。
在細胞中加入指定濃度的(終濃度分別為1，3，10，30，100ug/ml，加樣量為1)加樣量為10ul)供試藥物和陽性對照(地塞米松，10uM)。置於37℃含5%CO2的培養箱中保溫15分鐘；2)加入10ul濃度為100ug/ml的LPS，置於37℃含5%CO2的培養箱中保溫16小時；3)與1000rpm離心15分鐘，將上清轉移入新的培養板中，測定TNFa及IL－1 β濃度；或凍藏於－20℃，避免反復凍融。
實驗方法
1.模型製作
5%TNBS用雙蒸水稀釋與50%乙醇等體積混合成1.5%TNBS。小鼠用1%戊巴比妥0.05mg/10g麻醉，麻醉後，用灌胃器由肛門輕緩插入深約3cm，生理鹽水組以0.1ml/只的50%生理鹽水溶液，模型組以1.5%含(150mg/kg)TNBS的50%乙醇溶液0.1ml/只緩緩推入結腸，誘導克隆病形成，正常對照組僅單獨接受50%乙醇，每只0.1ml。
2.給藥方式
造模前24，2小時及造模後每天給藥一次，連續7天服用，末次給藥一小時取材。
3.評價指標
(1)體重
造模後，每一天測體重1次，並記錄
(2)炎症評價
A稱重：末次給藥後24小時，打開腹腔，觀察結腸與其他器官的粘連程度，取出每段結腸，對每段結腸稱重，計算結腸與體重比率。
減少百分率＝(對照組比率/正常組比率－給藥組比率/正常組比率)/(對照組比率/正常組比率)*100。
B組織切片
對結腸取一部分結腸做病理切片，病理評分標準：0分無炎症症狀；1分低水平炎症。無結構改變；2分低水平白細胞浸潤；3分高水平白細胞浸潤，高血管密度，腺窩延伸，結腸壁增厚，淺表潰瘍；4分高水準白細胞浸潤超過粘膜層，腺窩延伸，杯狀細胞減少，高血管密度，腸壁增厚，廣泛潰瘍。
實驗結果
1.對小鼠體重的影響
從穿心蓮浸膏對克隆病模型引起的小鼠體重減輕有明顯的改善作用，與模型組比較有顯著性差異。
2.對小鼠結腸重量、死亡率及結腸組織病變的影響
小鼠誘導克隆病後，模型組存活鼠結腸占體重比重明顯增加，死亡率達到了50%直腸端結腸均有明顯潰瘍，與周圍組織重度粘連。病理組織檢查表現高水平白細胞浸潤超過粘膜層，腺窩延伸，杯狀細胞減少，高血管密度，腸
壁增厚，廣泛潰瘍，而穿心蓮浸膏500mg/kg口服可明顯減輕小鼠結腸比重，減輕率達到了88%，死亡率也明顯降低，腸組織無粘連現象，粘膜壁大部分光滑，未見明顯病變。陽性藥也可明顯減輕結腸比重，減輕率達到了66%。
在中國上海5家醫院進行了一項隨機、雙盲、安慰劑8周對照的臨床試驗，研究穿心蓮萃取物治療潰瘍性結腸炎的有效性，該研究符合國際協調會議GCP(ICH－GCP)規範。120位經結腸鏡檢查證實為輕~中度活動性潰瘍性結腸炎病人被分成2組(每組60名病人)。一組用上述穿心蓮萃取物片劑治療(一天3次，一次2片)，另一組用5－氨基－2－羥基苯甲酸(艾迪莎，Etiasa)治療(一天3次，一次500mg)。未給予其他藥物治療。每2周採用類似部分Mayo評分系統和臨床症狀打分下降(症狀下降>50%)來評價治療效果。再採用標準部分Mayo評分(PMS)，臨床反應(改善>2點或最終得分為0)和疾病症狀消退(8周時<1PMS)等計算得分。在治療開始和結束時結腸鏡結果修飾Baron評分，結腸鏡活組織檢查採用0－3等級打分。
2組病人具有相似的人口情況。每組平均發病時間在3.5－3.7年，PMS平均基線3.8，53名意向治療病人採用萃取物治療，臨床症狀評分2周時改善27%，8周時改善56%。55名意向治療病人採用艾迪莎治療，顯示相同的改善。8周時，萃取物治療病人的有效率是58%，給予艾迪莎治療的有效率是58%；8周時，疾病症狀消退率，萃取物治療的病
人為43%，艾迪莎治療的為58%。8周2組治療的PMS結果具有統計學意義(p<0.0002)。
8周時，內窺鏡檢查顯示，28%的萃取物治療病人和24%的艾迪莎治療病人的症狀完全消退(Baron評分為0)；至少2周時47%的萃取物治療病人和42%的艾迪莎治療病人評分降低。
病理檢查上，對19個用萃取物治療的病人以及15個用Etiasa治療的病人進行評估。19個用萃取物治療的病人中有10個在第8周顯示出25－ 0%的炎症降低，在15個用Etiasa治療的病人中有6個也有相同反應。在萃取物治療組裏，12/15原先有C反應蛋白升高的病人在第8周回到了正常水平，在Etiasa治療組裏，4/6有該變化。兩組的結果都十分令人滿意。(p<0.0001)
結果表明，萃取物對於治療潰瘍性結腸炎有效。令人驚喜的是，它的功效可以與Etiasa堪比，甚至優於後者。
一系列的實施例已經在本發明中做了描述。但是，可以理解的是，在不脫離本發明之精神和範圍內，可做不同改動。相應的，其他的實施例也在本發明專利權利範圍之內。
本發明的一個或幾個實施例的細節通過相應的附圖和說明書進行闡述清楚。其他的特徵、物體和本發明的優點，通過說明、附圖和權利要求書可以很清楚的理解。
Claims (9)
- 一種穿心蓮萃取物於製造供用以經由口服給藥來有效治療一需要治療之人之炎性腸病之選自片劑和膠囊之固體劑量形式的用途，其中該穿心蓮萃取物是由包含用90%乙醇回流穿心蓮之地上部分之方法製得且包含總穿心蓮內酯，其中於該萃取物中的該總穿心蓮內酯包括：穿心蓮內酯，其含量範圍係從該萃取物乾重量之2%至20%；14-去氧穿心蓮內酯，其含量範圍係從大於0至該萃取物乾重量之2%；14-去氧-11,12去氫-穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至6%；和新穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至5%；又其中該固體劑量形式進一步包含糊精與至少一藥學上可接受的載體，且該劑量形式之口服給藥係要以至少1200mg該萃取物之每日劑量進行達8周。
- 一種穿心蓮萃取物於製造供用以經由口服給藥來有效治療一需要治療之人之潰瘍性結腸炎之選自片劑和膠囊之固體劑量形式的用途，其中該穿心蓮萃取物是由包含用90%乙醇回流穿心蓮之地上部分之方法製得且包含總穿心蓮內酯，其中於該萃取物中的該總穿心蓮內酯包括： 穿心蓮內酯，其含量範圍係從該萃取物乾重量之2%至20%；14-去氧穿心蓮內酯，其含量範圍係從該萃取物乾重量之0.01%至2%；14-去氧-11,12去氫-穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至6%；和新穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至5%；又其中該固體劑量形式進一步包含糊精與至少一藥學上可接受的載體，且該劑量形式之口服給藥係要以該固體劑量形式之每日劑量進行達8周；以及甚至又其中該每日劑量在該口服給藥予人後在治療人之潰瘍性結腸炎上顯示有效。
- 一種穿心蓮萃取物於製造供用以經由口服給藥來有效治療一需要治療之人之潰瘍性結腸炎之選自片劑和膠囊之固體劑量形式的用途，其中該穿心蓮萃取物是由包含用90%乙醇回流穿心蓮之地上部分之方法製得且包含總穿心蓮內酯，其中於該萃取物中的該總穿心蓮內酯包括：穿心蓮內酯，其含量範圍係從該萃取物乾重量之2%至20%；14-去氧穿心蓮內酯，其含量範圍係從該萃取物乾重量之0.01%至2%；14-去氧-11,12去氫-穿心蓮內酯，其含量範圍係從該 萃取物乾重量之1%至6%；和新穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至5%；又其中該固體劑量形式進一步包含至少一藥學上可接受的載體，且該劑量形式之口服給藥係要以在治療人之潰瘍性結腸炎上有效之劑量進行達8周；以及甚至又其中該固體劑量形式在該口服給藥予人後在治療潰瘍性結腸炎上顯示有效。
- 一種穿心蓮萃取物於製造供用以經由口服給藥來有效治療一需要治療之人之炎性腸病之選自片劑和膠囊之固體劑量形式的用途，其中該穿心蓮萃取物是由包含用90%乙醇回流穿心蓮之地上部分之方法製得且包含總穿心蓮內酯，其中於該萃取物中的該總穿心蓮內酯包括：穿心蓮內酯，其含量範圍係從該萃取物乾重量之2%至20%；14-去氧穿心蓮內酯，其含量範圍係從該萃取物乾重量之0.01%至2%；14-去氧-11,12去氫-穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至6%；和新穿心蓮內酯，其含量範圍係從該萃取物乾重量之1%至5%；又其中該固體劑量形式進一步包含至少一藥學上可接受的載體，且該劑量形式之口服給藥係要以在治療人之 炎性腸病上有效之劑量進行達8周。
- 如申請專利範圍第1-4項中任一項之用途，其中該萃取物進一步包含多糖和黃酮類化合物。
- 如申請專利範圍第1-4項中任一項之用途，其中於該萃取物中之14-去氧穿心蓮內酯係少於該萃取物乾重量的1%。
- 如申請專利範圍第6項之用途，其中於該萃取物中之14-去氧穿心蓮內酯係少於該萃取物乾重量的0.1%。
- 一種穿心蓮萃取物於製造供用以治療炎性腸病之選自片劑和膠囊之固體劑量形式的用途，其中該萃取物是由包含下列步驟之方法製備：用90%乙醇回流穿心蓮之地上部分；收集乙醇相，以提供一混合物；以及噴霧乾燥該混合物，以提供該萃取物。
- 一種穿心蓮萃取物於製造供用以治療炎性腸病之選自片劑和膠囊之固體劑量形式的用途，其中該萃取物是由包含下列步驟之方法製備：用90%乙醇在75-80℃回流穿心蓮之地上部分2小時；收集乙醇相；濃縮該乙醇相以提供一第一混合物；將糊精加入該第一混合物，以提供一第二混合物；以及噴霧乾燥該第二混合物，以提供該萃取物。
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| US20090117209A1 (en) | 2007-11-02 | 2009-05-07 | Hutchison Medipharma Enterprises Limited | Andrographis paniculata extract |
-
2007
- 2007-11-02 US US11/934,143 patent/US20090117209A1/en not_active Abandoned
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2008
- 2008-07-04 TW TW097125255A patent/TWI536997B/zh not_active IP Right Cessation
- 2008-10-31 KR KR1020107011798A patent/KR101545366B1/ko not_active Expired - Fee Related
- 2008-10-31 EP EP08845832A patent/EP2217254A4/en not_active Withdrawn
- 2008-10-31 BR BRPI0817138A patent/BRPI0817138A2/pt not_active IP Right Cessation
- 2008-10-31 AU AU2008318487A patent/AU2008318487B2/en not_active Ceased
- 2008-10-31 WO PCT/US2008/082022 patent/WO2009059158A1/en active Application Filing
- 2008-10-31 MX MX2010004773A patent/MX2010004773A/es active IP Right Grant
- 2008-10-31 KR KR20157002001A patent/KR20150021126A/ko not_active Ceased
- 2008-10-31 RU RU2010122317/15A patent/RU2468809C2/ru active
- 2008-10-31 CA CA2704773A patent/CA2704773A1/en not_active Abandoned
- 2008-10-31 JP JP2010532287A patent/JP2011502995A/ja active Pending
- 2008-11-04 US US12/264,646 patent/US8557302B2/en active Active
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2012
- 2012-09-11 US US13/609,318 patent/US8557308B2/en active Active
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2013
- 2013-09-06 US US14/019,613 patent/US20140004212A1/en not_active Abandoned
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2014
- 2014-07-01 US US14/321,394 patent/US20140315846A1/en not_active Abandoned
- 2014-08-27 PH PH12014501926A patent/PH12014501926A1/en unknown
- 2014-11-07 JP JP2014227140A patent/JP2015025024A/ja active Pending
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2016
- 2016-01-07 US US14/990,749 patent/US20160193268A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US8557302B2 (en) | 2013-10-15 |
| AU2008318487A1 (en) | 2009-05-07 |
| BRPI0817138A2 (pt) | 2018-09-11 |
| EP2217254A1 (en) | 2010-08-18 |
| US20140315846A1 (en) | 2014-10-23 |
| TW201002334A (en) | 2010-01-16 |
| AU2008318487B2 (en) | 2013-08-01 |
| CA2704773A1 (en) | 2009-05-07 |
| MX2010004773A (es) | 2010-06-23 |
| PH12014501926A1 (en) | 2015-09-07 |
| RU2468809C2 (ru) | 2012-12-10 |
| KR20150021126A (ko) | 2015-02-27 |
| RU2010122317A (ru) | 2011-12-10 |
| JP2011502995A (ja) | 2011-01-27 |
| US20140004212A1 (en) | 2014-01-02 |
| JP2015025024A (ja) | 2015-02-05 |
| US20160193268A1 (en) | 2016-07-07 |
| US8557308B2 (en) | 2013-10-15 |
| US20090117210A1 (en) | 2009-05-07 |
| WO2009059158A1 (en) | 2009-05-07 |
| US20130023493A1 (en) | 2013-01-24 |
| EP2217254A4 (en) | 2012-04-18 |
| KR101545366B1 (ko) | 2015-08-18 |
| US20090117209A1 (en) | 2009-05-07 |
| KR20100095425A (ko) | 2010-08-30 |
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