CN103228296B - 苯达莫司汀阴离子-阳离子型环聚糖组合物 - Google Patents
苯达莫司汀阴离子-阳离子型环聚糖组合物 Download PDFInfo
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明是针对药学组合物,其包括:(a)苯达莫司汀,(b)第一带电环聚糖以及(c)稳定剂,该稳定剂为具有与该第一带电环聚糖的电荷相反的电荷的第二带电环聚糖。该组合物提供在反应环境(例如血浆)中意外理想的稳定性,加上意外理想的抗癌活性。该组合物适合伴随苯达莫司汀注射或输注至需要治疗的病患。
Description
技术领域
此申请主张于2010年7月19日提出的美国临时专利申请号61/399,855的优先权,藉此其全文是以引用的方式并入此申请中。
本发明是针对组合物,其包含:
(a)苯达莫司汀;
(b)包含至少一带电基团的第一带电环聚糖;以及
(c)稳定剂,其为具有至少一带电基团的第二带电环聚糖,该带电基团具有与第一带电环聚糖的电荷相反的电荷。
背景技术
苯达莫司汀,4-[5-[双(2-氯乙基)胺基]-1-甲基苯并咪唑-2-基]丁酸被用于白血病以及某些淋巴瘤的治疗。然而,在血浆中此化合物具有有限的化学稳定性,为达成治疗效果从而需要高或重复剂量。因此对于会表现增加稳定性的此药物配方有需求。
已尝试经由将此类分子与聚合材料复合而增加苯达莫司汀的稳定性。然而,采取的方法仅达到微小的成功。因此,Pencheva et al;"HPLC study onthe stability of bendamustine hydrochloride immobilized ontopolyphosphoesters;J.Pharma.Biomed.Anal;(2008)尝试经由将此类化合物与聚磷酸酯复合而改善苯达莫司汀的稳定性。然而,此文章的第2图显示,即使最稳定的复合物于pH7中约45分钟减少了一个数量级。
Evjen;"Development of Improved Bendamustin-Liposomes";MastersThesis;University of Tromso(2007)采用双不对称离心(dual asymmetriccentrifugation)以将苯达莫司汀纳入脂质体中。根据表格18(于第79页),这些配方相对于游离苯达莫司汀仅提供稳定性的轻微增加(20分钟半衰期与散布于细胞培养基中的游离苯达莫司汀的14分钟半衰期相比)。
于2010年2月24日提出,标题为「苯达莫司汀环聚糖组合物」的美国专利申请号12/711,979描述苯达莫司汀组合物,其包含:(a)苯达莫司汀,(b)带电环聚糖,以及(c)具有与环聚糖的电荷相反的电荷的稳定剂。此类组合物提供意外理想的稳定性加上意外理想的抗癌活性,其益处被认为是由苯达莫司汀受保护而免于反应环境的影响的结构形成而提供。
本发明的组合物提供在反应环境(例如血浆)中意外理想的稳定性,加上意外理想的抗癌活性。该组合物适合以注射或输注至需要以苯达莫司汀治疗的病患。
发明内容
本发明是针对组合物,其包含:
(a)苯达莫司汀;
(b)包含至少一带电基团的第一带电环聚糖;以及
(c)稳定剂,其为具有至少一带电基团的第二带电环聚糖,该带电基团具有与第一带电环聚糖的电荷相反的电荷。
据认为描述于美国专利申请号12/711,979('979申请案)的结构涉及类桶形结构的生成,其中伴随扮演为「盖子」的稳定剂,将苯达莫司汀分子***至环聚糖的孔洞,以隔离该分子的凸出部分。'979申请案揭露各种有用的稳定剂,但是它没有揭露作为稳定剂的带电环聚糖的用途。鉴于此类分子的甜甜圈形状,意外的是此类分子可有效地作为由第一带电环聚糖造成的桶形的有效的盖子。
对于提供可有效率地与第一带电环聚糖作用的稳定剂有需求。
发明详述
本发明是针对组合物,其包含:
(a)苯达莫司汀;
(b)包含至少一带电基团的第一带电环聚糖;以及
(c)稳定剂,其为具有至少一带电基团的第二带电环聚糖,该带电基团具有与第一带电环聚糖的电荷相反的电荷。
如同本文中所采用的,该用语「苯达莫司汀」意指化合物4-[5-[双(2-氯乙基)胺基]-1-甲基苯并咪唑-2-基]丁酸,以及其药学上可接受的盐类,包括苯达莫司汀盐酸盐。
优选地,苯达莫司汀对第一带电环聚糖的比例,以重量计,是介于大约1:5000及大约1:5之间;更优选地为介于大约1:1000及大约1:8之间;甚至更优选地为介于大约1:500及大约1:10之间,以及最优选地介于大约1:100及大约1:10之间。
稳定剂典型地以对第一带电环聚糖的重量比率介于大约5:1及大约1:1000之间;优选地介于大约1:4及大约1:100之间而存在。
环聚糖
可被采用于本发明的实践的环聚糖包括环糊精、环甘露聚糖(cyclomannin)、环阿卓糖(cycloaltrin)、环果聚糖(cyclofructan)以及诸如此类。一般而言,优选包含介于6与8之间的糖单元的环聚糖。
其中首选的环聚糖为环糊精。环糊精为由至少6糖单元所组成的环状寡聚-1-4-α-D-吡喃葡萄糖。最广为人知的是包含六、七或八个糖单元的环糊精。包含六个糖单元的环糊精被称为α-环糊精,包含七个糖单元的那些被称为β-环糊精,以及包含八个糖单元的那些被称为γ-环糊精。特别优选的环聚糖为β-环糊精。
不论作为第一环聚糖或作为稳定剂,被采用于本发明的实践的环聚糖为带电环聚糖。该用语「带电环聚糖」意指具有其羟基基团中的一或更多个被带电基团取代的环聚糖。此类基团本身可以为带电基团或它可包含被一或更多带电基团取代的有机基团(例如C1-C6烷基或C1-C6烷基醚基团)。
在第一带电环聚糖被阴离子基团取代的情况中,稳定剂为阳离子环聚糖。相反地,在第一带电环聚糖被阳离子基团取代的情况中,稳定剂为阴离子环聚糖。
虽然阴离子环聚糖可包含阴离子基团的任一个或混合物,阴离子环聚糖包含羧基、磺酰基或硫酸盐基团是优选的。优选的阴离子环聚糖包括磺丁基醚β-环糊精、羧甲基-β-环糊精钠、O-磷酸-β-环糊精钠、琥珀酰基-(2-羟基)丙-β-环糊精、磺丙基-β-环糊精钠以及O-硫酸-β-环糊精钠。磺丁基醚β-环糊精为特别优选的。
虽然阳离子环聚糖可包含阳离子基团的任一个或混合物,阳离子环聚糖包含胺、胍或季铵基团是优选的。可被采用的适合胺基-环糊精为胺基-α-环糊精、胺基-β-环糊精以及胺基-γ-环糊精,其优选地具有介于大约4与大约10间的取代程度。此类型优选的胺基-环糊精包括六(6-胺基-6-脱氧)α-环糊精、七(6-胺基-6-脱氧)β-环糊精、八(6-胺基-6-脱氧)γ-环糊精。可被采用的其它阳离子环聚糖包括胍-环糊精,其优选地具有介于大约4与大约10间的取代程度,例如七(6-胍-6-脱氧)β-环糊精;烷基胺-环糊精,其优选地具有介于大约4与大约10间的取代程度,例如6-脱氧-6-(3-羟基)丙基胺β-环糊精;以及烷基铵-环糊精,其优选地具有介于4与9间的取代程度,例如2-羟基-N,N,N-三甲基丙烷基铵-环糊精。
特别优选的阳离子聚糖包括六(6-胺基-6-脱氧)α-环糊精、七(6-胺基-6-脱氧)β-环糊精、八(6-胺基-6-脱氧)γ-环糊精、七(6-胍-6-脱氧)β-环糊精、八(6-胍-6-脱氧)-γ-环糊精、2-羟基-N,N,N-三甲基丙烷基铵-环糊精以及6-脱氧-6-(3-羟基)丙基胺β-环糊精。
在本发明的特别优选的具体实施例中,第一带电环聚糖包含磺丁基醚β-环糊精,并且稳定剂包含七(6-胺基-6-脱氧)β-环糊精。
赋形剂
本发明的组合物可进一步地包含药学上可接受的赋形剂,例如糖、多元醇、水溶性聚合物、盐类与脂类。
可被采用的糖与多元醇包括但不限于乳糖、蔗糖、甘露糖醇以及山梨糖醇。
可被采用的水溶性聚合物的例子为聚氧乙烯、泊洛沙姆、聚乙烯吡咯烷酮与葡聚糖。
有用的盐类包括但不限于,氯化钠、氯化镁以及氯化钙。
可被采用的脂类包括但不限于,脂肪酸酯、糖脂、磷脂。
制备
本发明的组合物可经由固态苯达莫司汀溶解于第一带电环聚糖的水溶液而制备;或经由将第一带电环聚糖的水溶液与苯达莫司汀的原液水溶液混合而制备。混合所生成的混合物并且随选地进行超音波的动作,以获得均质且平衡的水溶液。当环聚糖为环糊精时,优选的是用于组合物制备的环糊***溶液包含至少4%环糊精;更优选地是此类溶液包含至少10%环糊精。
优选地将稳定剂与赋形剂(若存在)经由其加入至预先制备的苯达莫司汀与第一带电环聚糖的均质且平衡的水溶液而引入至组合物中。可以固体或以水溶液添加此剂。
优选地,在用于注射前过滤最终组合物。
可随选地冷冻干燥组合物,以产生适合在其使用前溶解于注射媒介的固体材料。将含有胺类作为稳定剂的组合物在此类稳定剂加入之前冷冻干燥,伴随在使用前不久将此剂引入还原后的组合物中是优选的。
在一具体实施例中,经由将成分混合以及培养以制备本发明的组合物。
在另一具体实施例中,经由将成分混合并且对混合物施加超音波以制备本发明的组合物。
在另一具体实施例中,经由将成分混合、培养并且将产物冷冻干燥以制备本发明的组合物。
在优选的具体实施例中,经由将成分混合、对混合物施加超音波并且将产物冷冻干燥以制备本发明的组合物。
在体外以及在体内两者条件下,当引入血浆时,本发明的组合物表现增强的稳定性。因此,相较于未调配的苯达莫司汀的半衰期,在血浆中此配方表现更优的半衰期;其半衰期可延长至少约10%、约25%、约50%或约100%或更多。
此外,本发明的组合物相对于包含苯达莫司汀与环聚糖的组合物以及相对于仅有苯达莫司汀而言表现了不可预期的改良的抗肿瘤活性。
可以其下列实施例进一步地说明此发明,虽然将理解到,除非另外具体说明,本案包含这些实施例仅供说明的目的并且不意图限制本发明的范围。除非另有说明,本文的说明书、实施例与权利要求中的所有百分比、比率与份数为以重量计且为约略值。
具体实施方式
实施例1
包含磺丁基醚β-环糊精钠(SBECD)与七(6-胺基-6-脱氧)-β-环糊精盐酸盐(H6A)的苯达莫司汀组合物的制备
包含2.5mg/g苯达莫司汀HCl、20%SBECD与1%H6A的组合物
所有操作均于室温下进行。将3917mg的水加至1000mg的磺丁基醚β-环糊精钠,并将混合物混合直到固体完全溶解。将12.5mg的苯达莫司汀盐酸盐与21mg甘露糖醇加至溶液中并且混合2小时。将50mg的H6A加至溶液并混合15分钟。将产物溶液经由0.2微米尼龙过滤器过滤。
包含2.5mg/g苯达莫司汀HCl、20%SBECD与2%H6A的组合物
所有操作均于室温下进行。将3867mg的水加至1000mg的磺丁基醚β-环糊精钠,并将混合物混合直到固体完全溶解。将12.5mg的苯达莫司汀盐酸盐与21mg甘露糖醇加至溶液中并且混合2小时。将100mg的H6A加至溶液并混合15分钟。将产物溶液经由0.2微米尼龙过滤器过滤。
包含13mg/g苯达莫司汀HCl、20%SBECD与1%H6A的组合物
所有操作均于室温下进行。将400mg的水加至200mg的磺丁基醚β-环糊精钠,并将混合物混合直到固体完全溶解。将13mg的苯达莫司汀盐酸盐与22.1mg甘露糖醇加至溶液中并且混合2小时。将10mg的H6A溶解于355mg的水中,并将H6A溶液加至先前制备的SBECD、苯达莫司汀与甘露糖醇的溶液并且混合15分钟。将产物溶液经由0.2微米尼龙过滤器过滤。
实施例2
分剂予大鼠的包含磺丁基醚β-环糊精钠与七(6-胺基-6-脱氧-β-环糊精)的组合物中的苯达莫司汀的药物动力学。
测试组合物:
控制组:2.5mg/g苯达莫司汀盐酸盐、在0.9%NaCl中的4.25mg/g甘露糖醇;剂量10mg/kg。
组合物1:2.5mg/g苯达莫司汀盐酸盐、20%w/w磺丁基醚β-环糊精钠、1%七(6-胺基-6-脱氧-β-环糊精)、在水中的4.3mg/g甘露糖醇(根据实施例1中所述的步骤制备);剂量10mg/kg。
组合物2:2.5mg/g苯达莫司汀盐酸盐、20%w/w磺丁基醚β-环糊精钠、2%七(6-胺基-6-脱氧-β-环糊精)、在水中的4.3mg/g甘露糖醇(根据实施例1中所述的步骤制备);剂量10mg/kg。
组合物A:5mg/mL苯达莫司汀盐酸盐、20%w/w磺丁基醚β-环糊精钠、在水中的10.2mg/g甘露糖醇;剂量10mg/kg。
动物:
雌性Sprague-Dawley大鼠(250–350g)。将动物以每笼三只饲养在光照(12h亮/暗周期,于06h00灯亮)且具有空气过滤器盖子的笼中并且控制温度为22°C+/-1°C。对动物的所有操作均于无菌抽风柜(laminar hood)中进行。动物可随意进食Purina鼠饲料及饮水。在给药前让动物空腹隔夜并麻醉。
分剂与取样:
将苯达莫司汀组合物与控制组以在尾巴静脉的静脉注射给药予大鼠。在注射后5、15、30、45分钟、1、1.5、2、3与4小时的时间区间之后收集血液样本。将大鼠以异氟醚的一般吸入麻醉。以肝素管从颈静脉收集血液样本并保持于冰上。将血液立即离心,并且分离血浆。立即萃取血浆样本。
样品萃取与分析:
将血浆样品0.100mL转移至塑料管中。以0.400mL在乙腈中的100mM HCl激烈震荡30秒以萃取样品。将样品于10000RPM下离心5分钟。分离上清液。将样品在干冰中冷冻并且保持在-80°C直到HPLC分析。将20微升的等分样品注入HPLC以供分析。
HPLC条件:
C18逆相管柱50x4.6mm,对称/屏蔽(Symmetry/Shield)3.5微米
管柱温度30°C
流速1.5mL/min
注入体积20微升
荧光侦测波长:激发327nm,发射420nm
移动相:缓冲液A:5%乙腈0.1%TFA
缓冲液B:90%乙腈0.1%TFA
运行时间:10min
相对于控制组,测试组合物的苯达莫司汀的改善的药物动力学概况显示于下列表格1。
表格1.老鼠血浆中的苯达莫司汀浓度对注射后时间
SEM–标准误差均值
上述数据显示若将药物以本发明的组合物给个体服药,苯达莫司汀的药物动力学被大为延长。上述数据进一步显示通过H6A的加入亦大为增加药物动力学。
实施例3
在包含磺丁基醚β-环糊精钠与七(6-胺基-6-脱氧-β-环糊精)的组合物中苯达莫司汀对Balb/c小鼠中的人类乳腺癌细胞MDA-MB-231的皮下实质肿瘤生长的影响。
动物:
从Charles River Canada Inc购买5至6周大的Balb/c小鼠。将动物以每笼5只饲养在光照(12h亮/暗周期,于6H00灯亮)具有空气过滤器盖、的笼中并且控制温度(22°C+/-1°C)。对动物的所有操作均于无菌抽风柜中进行。动物可随意进食Purina鼠饲料(Pro Lab PMH4018,Trademark ofAgway,Syracuse,New York)及饮水。根据「实验动物护理和使用指南」(Guidelines for Care and Use of Experimental Animals)进行这些动物研究。
肿瘤细胞培养:
将人类乳腺癌细胞MDA-MB231在适当的培养基中培养。在细胞的对数生长期将其收获,以供肿瘤植入的准备。
肿瘤细胞植入:
将带有30%基质膜(Matrigel)的培养基中的MDA-MB-231细胞(每次注射5.0x105细胞)皮下注射于每只动物的侧腹两侧。在植入后九至十日,当肿瘤尺寸达到直径0.5至0.8cm时,将动物随机分组,每组5只动物。于第1、2、13及14日进行皮下注射的治疗。以等渗盐水处理控制组。以35mg/kg剂量的在水中的苯达莫司汀HCl(7mg/mL)处理参考组。以60mg/kg剂量(与参考组的治疗等毒性)的本发明的组合物处理测试组,该组合物包含13mg/g苯达莫司汀HCl、20%SBECD与1%H6A以及甘露糖醇,其根据实施例1中所述的步骤制备。
功效评估:
在第一次注射之日以及于其后的3至4日区间进行皮下实质肿瘤测量。用测径器测量每个肿瘤最大的两个垂直直径,并且使用公式估算肿瘤尺寸:
TV=L x W x/2,其中TV:肿瘤体积;L:长度;W:宽度。
亦注意动物的体重。
结果呈现于下列表格2。
表格2.在裸鼠中的人类乳腺癌MDA-MB231s.c.实体肿瘤在治疗后的肿瘤重量
SEM–标准误差均值
相较于非调配的苯达莫司汀的等毒性剂量,此结果显示包含SBECD与H6A的本发明的组合物的卓越功效。
要了解上述的具体实施方式仅为说明性的,为许多可能的特定具体实施例中的少数个,其可代表本发明原理的应用。本领域的技术人员可以在不脱离本发明的精神与范围下,根据这些原理很轻易地设计众多不同的其它安排。
Claims (4)
1.一种组合物,其包含:
(a)苯达莫司汀;
(b)第一带电环聚糖,其包含至少一带电基团;以及
(c)稳定剂,其为具有至少一带电基团的第二带电环聚糖,所述第二带电环聚糖具有与该第一带电环聚糖的电荷相反的电荷;
其中,所述第一带电环聚糖为磺丁基醚β-环糊精或七(6-胺基-6-脱氧)β-环糊精,且当所述第一带电环聚糖为磺丁基醚β-环糊精时,所述第二带电环聚糖为七(6-胺基-6-脱氧)β-环糊精;当所述第一带电环聚糖为七(6-胺基-6-脱氧)β-环糊精时,所述第二带电环聚糖为磺丁基醚β-环糊精。
2.根据权利要求1所述的组合物,其中成分(b)为磺丁基醚β-环糊精。
3.根据权利要求1所述的组合物,其中成分(b)为七(6-胺基-6-脱氧)β-环糊精。
4.根据权利要求1所述的组合物,其中该苯达莫司汀为苯达莫司汀盐酸盐的形式。
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US13/032,168 US8383663B2 (en) | 2010-07-19 | 2011-02-22 | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
US13/032,168 | 2011-02-22 | ||
PCT/IB2011/003367 WO2012127277A2 (en) | 2010-07-19 | 2011-02-23 | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
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CN108997514B (zh) * | 2017-06-06 | 2021-06-08 | 首都医科大学 | 单-6-(苯达莫司汀酰胺基)-6-脱氧-β-环糊精的制备和应用 |
KR102450975B1 (ko) | 2017-10-05 | 2022-10-07 | 튜브 파마수티칼스 게엠베하 | 경구 벤다무스틴 제형 |
WO2021203377A1 (zh) * | 2020-04-09 | 2021-10-14 | 比卡生物科技(广州)有限公司 | 苯达莫司汀组合物及其用途 |
CN111557904A (zh) * | 2020-04-09 | 2020-08-21 | 比卡生物科技(广州)有限公司 | 苯达莫司汀组合物及其用途 |
US11970977B2 (en) | 2022-08-26 | 2024-04-30 | Hamilton Sundstrand Corporation | Variable restriction of a secondary circuit of a fuel injector |
US20240148696A1 (en) | 2022-10-25 | 2024-05-09 | Softkemo Pharma Inc. | Lyophilized bendamustine-cyclodextrin composition |
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WO2012127277A3 (en) | 2013-03-14 |
MX341356B (es) | 2016-07-07 |
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BR112013001462A2 (pt) | 2016-05-31 |
CA2805805A1 (en) | 2012-09-27 |
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AU2011363446B2 (en) | 2017-05-18 |
BR112013001462B1 (pt) | 2022-04-19 |
RU2647368C2 (ru) | 2018-03-15 |
BR112013001462B8 (pt) | 2022-08-02 |
AU2019219792B2 (en) | 2023-03-02 |
AU2011363446A1 (en) | 2013-02-21 |
WO2012127277A2 (en) | 2012-09-27 |
AU2017216568A1 (en) | 2017-09-14 |
KR101874764B1 (ko) | 2018-07-04 |
US8383663B2 (en) | 2013-02-26 |
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JP5788982B2 (ja) | 2015-10-07 |
CN103228296A (zh) | 2013-07-31 |
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