CN102526006B - 单羧酸和二羧酸的酰胺化物在肾病治疗中的应用 - Google Patents
单羧酸和二羧酸的酰胺化物在肾病治疗中的应用 Download PDFInfo
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- CN102526006B CN102526006B CN201110306328.2A CN201110306328A CN102526006B CN 102526006 B CN102526006 B CN 102526006B CN 201110306328 A CN201110306328 A CN 201110306328A CN 102526006 B CN102526006 B CN 102526006B
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Abstract
本发明涉及单羧酸和二羧酸的酰胺化物在肾病治疗中的应用。肾病、特别是在糖尿病患者或已经历使用例如铂衍生物的抗肿瘤化疗以及更广义来说在肾水平上治疗肿瘤疾病的细胞毒性药物进行治疗的患者中发生的肾病的治疗。具体来说,本发明涉及棕榈酰乙醇酰胺和富马酸的二乙醇酰胺,在肾病、特别是由代谢异常疾病或毒性剂或化疗剂例如铂衍生物引起的肾病的治疗中的应用。棕榈酰乙醇酰胺优选以微粉化或超微粉化形式使用。富马酸的二乙醇酰胺优选在水溶液中使用。
Description
技术领域
本发明涉及肾病以及随之发生的肾功能改变的治疗,特别是,即使不是排他性的,涉及在糖尿病患者或已经历使用铂衍生物进行抗肿瘤化疗的患者中发生的肾病的治疗。
背景技术
慢性肾病以及源于其的肾衰,即使未达到诊断标准,也是极其常见的疾病;事实上,据估计17%的成年人群受到这种疾病的影响。
最常见的肾病以肾小球受损为特征。
肾病可能是先天性或获得性的;具体来说,获得性肾病可能具有各种病因:
●免疫性的,例如古德帕斯丘综合征、狼疮肾炎和免疫球蛋白A肾病。在由免疫介导的肾病的情况下,病因在于存在引发免疫反应的强抗原性刺激物;
●代谢异常的,特别是糖尿病性肾病,其是慢性肾病的最常见病因之一。其发病率在患有1型糖尿病的患者中为20-30%,在患有2型糖尿病的患者中为约10%。这是一种隐伏的疾病,因为其特征在于发病特别缓慢(从发生糖尿病开始算,最长20-30年),并且事实上在很长时期内无症状;它最初通过微量白蛋白尿发生(尿液中白蛋白的量在30至300mg/l之间),其慢慢发展成表现出明显肾病的巨量白蛋白尿(24小时内尿液中的白蛋白量超过300mg/l,最高达到3g的值);
●血液动力学的,由动脉高血压引起。随着时间过去,肾血流的压力机制的改变引起肾脏过滤能力的降低;
●缺血性的,在自体肾和移植肾两者中,肾脏缺血是与急性肾病和随之发生的肾小管坏死相关的最常见的病理事件;
●毒性的,大多数临床上重要的药物(细胞毒性剂、化疗剂、非甾类抗炎药、皮质甾族化合物治疗等)和各种化学产品(例如放射造影介质、溶剂等)产生肾毒性,其能够非常频繁地引起肾实质水平的炎症和短期和长期的机能不全。
甚至在兽医学中,势必会发展成的慢性肾病的肾病构成了重要的临床类别,在狗中成为仅次于源于肿瘤死亡的第二大死因,在衰老的猫中是第一大死因。从病因学观点来说,在小型动物中决定肾单位功能的渐进性和不可逆丧失的原因,在(Squires等,1998)中被精确分类为:
-退行性:慢性间质性肾炎;肾梗塞
-自体免疫性:抗GBM肾小球肾炎
-代谢性:糖尿病;甲状腺机能亢进(猫);高钙血症
-肿瘤性:肾淋巴瘤和肾癌
-特发性:淀粉样变性;特发性肾小球肾炎
-感染性:细菌性肾盂肾炎;莱姆肾病(疏螺旋体病)
-免疫介导性:免疫复合物肾小球肾炎
-毒性:肾毒性药物(例如顺铂、氨基糖苷类、非甾体抗炎药)
-创伤性:膀胱和尿道破裂。
在人类和动物两者中的、不论何种病因的所有获得性肾病的任何情况中,存在着炎性过程的活化,其首要目的在于对抗有害事件,但是其可能变成肾小球硬化和肾小管间质纤维化的原因,后者能够决定慢性肾病发展到其中大多数肾单位被破坏的末期前期(末期肾病前期)。肾病学的两个主要目标之一,首先以及最主要的是理解从急性肾损伤到慢性纤维化肾病的过程的调控机制,因为一旦纤维发生已经开始,介入纤维化过程在当前可能是非常困难的;在任何情况下,考虑到慢性肾病也构成了心血管疾病的重要风险因子,因此阻止或至少减缓这些疾病的进展仍然是极为重要的。就此而言,目前存在着几项旨在准确理解最重要的发病机制的研究,目的在于阻止决定疾病的不可逆性的现象。在这些现象中,最重要的是诱导了被认为是慢性肾病的主要原因的肾小管间质纤维化的现象;纤维化引起主要由胶原蛋白构成的细胞外类型的过度积聚,并且当正常组织被瘢痕组织代替时,它通常伴有肾功能的进行性丧失。目前研究的最多的现象之一是控制肌成纤维细胞发生的过程以及这些细胞在纤维化瘢痕组织的形成中所发挥的作用。具体来说,这些研究试图理解通常由连续经历大量病因的组织、例如肾脏组织提供的修复现象,为什么可能一度决定细胞外基质的过量增加,并因此决定肾小管间质纤维化的原因。目前,对于从肾小管上皮细胞和内皮细胞两者开始,通过受到TGF-1β(转化生长因子)强有力刺激的从上皮至间质的表型转化过程的肌成纤维细胞的发生,给予了特殊的关注。事实上,在纤维发生的活跃过程中,肾小管上皮中TGF-1β的表达恒定地增加。在肾损伤的动物模型中,肾小管上皮中TGF-1β的剂量被当做纤维发生的活化状态、因此也是由肾病诱导的功能改变状态的重要指示。
尽管获得了与涉及肾病发展的致病机制相关的大量新信息,但用于控制这些病症的令人满意的治疗解决方案仍有待发现。
棕榈酰乙醇酰胺(PEA)是被称为Aliamide的N-酰基酰胺家族的母体化合物,所述Aliamide是一类能够通过局部拮抗机制使得免疫细胞活性正常化的内源性脂类分子。相反,止痛效应与营养因子例如NGF的受控释放的正常化相关,所述NGF如果在组织中过量存在,使神经元结构过度敏感和过度兴奋,发生痛觉过敏和痛觉异常。从临床观点来看,口服摄入含有PEA的产品能够改善与外周神经病相关的神经病症状学(neuropathicsymptomatology),也促进运动传导速度的功能恢复。在实验水平下,PEA在代谢异常的神经病中也有效,特别是将其向用链脲佐菌素(streptozootocin)制造成糖尿病的动物给药,消除了痛觉异常并诱导体重的部分恢复和血液胰岛素水平的增加。这些动物也显示出低的血液自由基的过量生产和低的坐骨神经中NGF水平。
与PEA类似,尽管通常从单乙醇胺和饱和或不饱和脂肪二羧酸形成的N-酰基酰胺本身是非生理性的,但是在分解代谢过程中同样能够形成在哺乳动物生物体中以生理性存在的物质,因此不产生任何种类的积聚和/或毒性,并被证明能够产生与母体PEA类似的药理效应。
发明内容
现在,我们令人吃惊地发现,某些属于氨基醇与单羧酸或二羧酸之间的酰胺化物类型的分子在肾病治疗中具有活性。具体来说,观察到棕榈酰乙醇酰胺(PEA),和富马酸(在哺乳动物生物体中正常存在的一种单不饱和二羧酸)的二乙醇酰胺,对所述疾病显示相当高的活性。
因此,本发明的第一个目的是饱和或单不饱和C12-C20单羧酸或饱和或单不饱和C4-C14二羧酸分别与选自单乙醇胺和丝氨酸的胺形成的单酰胺或二酰胺或其混合物,其用于肾病、特别但不专指由代谢异常疾病或毒性剂引起的肾病的治疗。
本发明的另一个目的是用于肾病治疗的棕榈酰乙醇酰胺(PEA),其中PEA优选是微粉化形式或超微粉化形式。
本发明的另一个目的是用于肾病治疗的PEA,其中所述PEA经口给药。
本发明的另一个目的是用于肾病治疗的在水溶液中的富马酸的二乙醇酰胺。
发明详述
本发明是基于下述令人吃惊的发现,即饱和或单不饱和C12-C20单羧酸或饱和或单不饱和C4-C14二羧酸分别与选自单乙醇胺和丝氨酸的胺形成的单酰胺或二酰胺的外源性给药,特别是优选微粉化形式(PEAm)或超微粉化形式(PEAum)的棕榈酰乙醇酰胺和/或优选在适合的水性介质中的溶解形式的富马酸的二乙醇酰胺的经口给药,能够在受肾病、特别是受糖尿病性肾病和源自于抗肿瘤剂的肾病影响的哺乳动物中显著改善肾功能。本发明人还发现,肾功能的改善与被认为是正在进行的纤维发生的重要指示的TGF-1β的较低表达相关。在受到炎性肾病和糖尿病性肾病影响的患者中也证实了肾功能的改善。
在本发明的实施方案中,所述饱和或单不饱和C12-C20单羧酸选自棕榈酸、硬脂酸和油酸。
在本发明的实施方案中,所述饱和或单不饱和C4-C14二羧酸选自富马酸、壬二酸和反式愈伤酸。
棕榈酰乙醇酰胺是商业化产品,其可以通过本技术领域的专业人员公知的常规方法来制备,例如在适合的缩合条件下提供可能采取受保护形式的乙醇胺或丝氨酸与所述单羧酸或二羧酸之间的反应的方法,所述缩合条件也可以使用缩合剂来提供。
术语“微粉化形式的PEA”或“PEAm”用于指称棕榈酰乙醇酰胺,其中至少94%或至少95%或约96%的粒子具有小于10微米的尺寸,并且优选至少77%或至少78%或约80%的粒子具有小于6微米的尺寸。PEAm可以按照欧洲专利EP 1 207 870 B1的公开内容来制备。
术语“超微粉化形式的PEA”或“PEAum”用于指称棕榈酰乙醇酰胺,其中至少97%或至少98%或至少99%或约99.9%的粒子具有小于6微米的尺寸,并且优选至少57%或至少58%或至少59%或约59.6%的粒子具有小于2微米的尺寸。PEAum可以按照专利申请PCT/IT2009/000399的公开内容来制备。
富马酸的二乙醇酰胺可以通过按照专利号US 5,618,842的实施例10的公开内容进行合成来制备。
因此,本发明涉及由饱和或单不饱和C12-C20单羧酸或饱和或单不饱和C4-C14二羧酸分别与选自单乙醇胺和丝氨酸的胺形成的单酰胺或二酰胺或其混合物,用于肾病、特别但不专指由代谢异常疾病或毒性剂引起的肾病的治疗。
在实施方案中,所述饱和或单不饱和C12-C20单羧酸或饱和或单不饱和C4-C14二羧酸的单酰胺或二酰胺是PEA、或是富马酸的二乙醇酰胺。
在实施方案中,PEA以微粉化形式(PEAm)使用。
在不同实施方案中,PEA以超微粉化形式(PEAum)单独使用,或与PEAm混合使用。
在实施方案中,富马酸的二乙醇酰胺以在适合的水性溶剂中的溶解形式使用。
本发明化合物的药理活性
在向小鼠给药链脲佐菌素后肾损伤的发生
小鼠中的链脲佐菌素模型代表了经典的已知高血糖模型,其能够在动物中诱导进行性肾损伤,引起特征性参数明显改变的肾病。
采用的模型如下所示:将雄性C57BL6/J小鼠保持在标准护理条件下。通过连续5天腹膜内注射在柠檬酸缓冲液中的链脲佐菌素(55mg/Kg体重/天),在8周龄并且平均体重约为22g的小鼠中诱导糖尿病。对照小鼠在同样条件下使用单独的柠檬酸缓冲液进行处理。
使用悬浮在载体中的微粉化棕榈酰乙醇酰胺-PEAm(10.0mg/Kg)和悬浮在载体中的超微粉化棕榈酰乙醇酰胺PEAum(10.0mg/Kg)两者,利用管子进行经口给药治疗;将结果与只用载体处理的对照小鼠进行比较。使用0.5%羧甲基纤维素作为载体。
富马酸的二乙醇酰胺在无菌盐水溶液中通过腹膜内注射(10.0mg/Kg)进行给药;将结果与只用无菌盐水溶液处理的动物进行比较。
载体和含有棕榈酰乙醇酰胺的两种不同悬液或含有富马酸的二乙醇酰胺的注射液的给药,从最后一次给药链脲佐菌素的当天起每日进行一次。在处死之前,使用微量注射器从隐静脉收集血液,通过常规方法测定血糖、糖化血红蛋白和血清肌酸酐水平。
肾组织上TGF-1β的评估通过下述方法进行:
将仔细分离并称重的小片肾皮质,在含有2M NaCl、1mM PMSF(苯甲基磺酰氟,作为蛋白酶抑制剂)、1mM EDTA和0.01%土温80的pH7.4的10mM Tris-HCl缓冲液中匀浆。将样品以19,000rpm离心30分钟,收集上清液,测量并保存在-80℃下。TGF-1β的评估使用商业化ELISA试剂盒(Quantikine KitTM,Res&Diagn Systems,Minneapolis,USA)进行,数值以pg/mg总蛋白为单位表示。总蛋白浓度使用Bio-Rad商业化检测试剂(Hercules,Ca,USA)来测量。
获得的结果总结在表1中。
表1
在向小鼠给药顺铂后肾损伤的发生
顺铂是已知并广泛使用的化疗剂,其公知在经历治疗的50%患者中产生严重肾损伤。在实验中使用了小鼠动物模型,顺铂在其中诱导了严重肾毒性以及随之而来的肾病。采用的模型如下所示:将雄性C57BL6/J小鼠保持在标准护理条件下。通过腹膜内注射在盐水溶液中的顺铂二盐酸盐(一次给药20mg/Kg),在8周龄并且平均体重约为23g的小鼠中诱导了肾毒性。对照动物在相同条件下使用单独的盐水溶液进行处理。在用顺铂处理后72小时将动物处死。
使用悬浮在载体中的微粉化棕榈酰乙醇酰胺-PEAm(10.0mg/Kg)和悬浮在载体中的超微粉化棕榈酰乙醇酰胺PEAum(10.0mg/Kg)两者,利用管子进行了6次经口给药治疗,每12小时一次;第一次治疗在给药顺铂之前12小时进行。将结果与只用载体处理的对照动物进行比较。使用0.5%羧甲基纤维素溶液作为载体。
富马酸的二乙醇酰胺以与PEA类似的剂量学在无菌盐水溶液中通过腹膜内注射(10.0mg/Kg)进行给药;将结果与只用无菌盐水溶液处理的动物进行比较。
在处死之前,使用微量注射器从隐静脉收集血液,通过常规方法测定血清肌酸酐水平。
肾组织上TGF-1β的水平通过下述方法来测量:
将仔细分离并称重的小片肾皮质,在含有2M NaCl、1mM PMSF(苯甲基磺酰氟,作为蛋白酶抑制剂)、1mM EDTA和0.01%土温80的pH7.4的10mM Tris-HCl缓冲液中匀浆。将样品以19,000rpm离心30分钟,收集上清液,测量并保存在-80℃下。TGF-1β的量使用商业化ELISA试剂盒(Quantikine KitTM,Res & Diagn Systems,Minneapolis,USA)进行测量,数值以pg/mg总蛋白为单位表示。总蛋白浓度使用Bio-Rad商业化检测试剂(Hercules,Ca,USA)来测量。
获得的结果总结在表2中。
表2
超微粉化棕榈酰乙醇酰胺-PEAum在肾病患者中的效果
将棕榈酰乙醇酰胺以每片含有600mg超微粉化形式的活性成分的片剂形式给药于患者;连续60天每天给药2片(每12小时一片,饭后服用)。
根据美国国家肾脏基金会标准(US National Renal Foundation criteria)(K/DOQI用于慢性肾脏疾病的临床实践准则,2002),使用Cockcroft-Gault方程(CockcroftD.W.等,1976)通过肌酸酐内源标志物确定GRF(肾小球滤过率)。
结果显示在表3中。
表3
上面显示的结果清楚地显示,PEA、特别是当以微粉化或超微粉化形式经口给药时,可以成功地用于在哺乳动物中治疗肾病。此外,揭示出富马酸的二乙醇酰胺通过腹膜内注射时有活性。
因此,本发明的化合物在肾病的治疗中,可用于人类和兽医两种目的。
这样的疾病优选选自:
-糖尿病性肾病
-肾动脉硬化
-肾盂肾炎
-多囊肾病(多囊肾)
-奥尔波特综合征
-莱-尼综合征
-古德帕斯丘综合征
-狼疮肾炎
-免疫球蛋白A肾病
-肾小管坏死
-肾小球肾炎
-尿道狭窄
-医源性肾病(源自非甾体抗炎药、细胞毒性药、锂、抗生素、环孢素等)
-源自治疗性辐射的肾病
-老年肾病。
因此,本发明的化合物可以配制成用于经口、经颊、非肠道、直肠或透皮给药。
PEA优选可被配制成用于经口给药。
考虑到富马酸的二乙醇酰胺这种合成分子在水中的高溶解性,其优选可被配制成用于经口或注射给药。
对于经口给药来说,药物组合物可被提供成例如片剂或胶囊形式,其可以使用可药用赋形剂按惯例制备,所述可药用赋形剂例如合剂(例如预胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素)、增量剂(例如乳糖、微晶纤维素或磷酸氢钙)、润滑剂(例如硬脂酸镁、滑石粉或二氧化硅)、崩解剂(例如马铃薯淀粉或淀粉乙醇酸钠)或抑制剂(例如月桂基硫酸钠)。片剂可以通过本技术领域公知的手段进行包衣。用于经口给药的液体制剂可以采取例如溶液剂、糖浆剂或混悬剂的形式,或者它们可以采取在使用前用水或其他适合载体重构的冻干产品的形式。这样的液体制剂可以通过常规方法使用可药用添加剂来制备,所述添加剂例如助悬剂(例如山梨糖醇浆、纤维素衍生物或可食用氢化脂肪)、乳化剂(例如卵磷脂或阿拉伯胶)、非水性载体(例如杏仁油、油性酯、乙醇或分馏植物油)以及防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)。制剂也可以适合地包含芳香剂、着色剂和甜味剂。
用于经口给药的制剂可经过适合地配制,以允许活性成分的受控释放。
对于经颊给药来说,组合物可以采取常规配制的、适合于在颊粘膜水平上吸收的片剂形式。典型的颊剂型是用于舌下给药的片剂。
本发明的化合物可被配制成用于通过注射的非肠道给药。注射用剂型可以采取例如一小瓶中一份剂量的形式,并含有添加的防腐剂。组合物可以采取例如在油性或水性载体中的混悬剂、溶液剂或乳剂的形式,并且它们可以含有配制用试剂例如助悬剂、稳定剂和/或分散剂。可选地,活性成分可以采取粉末形式,其在使用前用适合的载体例如无菌水进行重构。
富马酸的二乙醇酰胺可以按照制药工业的传统文献,容易地配制在无菌无热原的水溶液中。
根据本发明,本发明的化合物也可以按照直肠组合物例如栓剂或渚留灌肠剂进行配制,其含有例如常规栓剂的基本组分例如可可脂或其他甘油酯。
除了前面描述的组合物之外,本发明的化合物也可被配制成储库型制剂。这样的长期剂型可以通过植入(例如皮下、透皮或肌肉内)或通过肌肉内注射来给药。因此,例如,本发明的化合物可以用适合的聚合物或疏水性材料(例如采取在适合的油中的乳液的形式)或离子交换树脂来配制。
根据本发明,建议用于给药到人类(体重约为70Kg)的本发明的化合物或其混合物的剂量,在每剂量单位1mg至2g、优选100mg至1g活性成分的范围内。剂量单位可以每天给药例如1至4次。剂量应该由所选的给药方法来决定。应该考虑到,取决于患者的年龄和体重以及待治疗临床病症的严重性,可能需要频繁改变剂量。最后,给药的具体剂量和方法应该由具体的医生或兽医斟酌决定。
本发明的药物组合物可以使用常规方法来制备,例如在《Remington药物学手册》(Remington′s Pharmaceutical Sciences Handbook),Mack Pub.Co.,N.Y.,USA,第17版,1985中所描述的方法。
具体事实方式
下面是本发明的药物组合物的非穷举的实施例。
制剂实施例
实施例1
每片片剂含:
实施例2
每片片剂含:
实施例3
每片片剂含:
实施例4
每片片剂含:
实施例5
儿科用的5g剂量的口溶解型微颗粒剂,其含有:
-PEAum mg 50.00
-非致龋性糖 mg 200,00
-可药用赋形剂适量,达 g 5.00
实施例6
儿科用的5ml剂量的无菌混悬剂,其含有:
-PEAum mg 80,00
-羧甲基纤维素 mg 25.00
-双蒸水适量,达 ml 5.00
实施例7
5g剂量的口溶解型微颗粒剂,其含有:
-PEAum mg 600.00
-非致龋性糖 mg 200.00
-可药用赋形剂适量,达 g 5.00
实施例8
每个无菌单剂5ml双层容器,其含有:
在水性凝胶中:
-透明质酸钠盐 mg 80.00
-双蒸水适量,达 ml 2.50
在油性凝胶中:
-PEAum mg 600.00
-单硬脂酸甘油酯(Geleol) mg 40.00
-植物油适量,达 ml 2,50
实施例9
每粒兽医用(狗和猫)软明胶胶囊,其含有:
-PEAum mg 100.00
-可药用油性赋形剂 mg 300.00
实施例10
2ml玻璃小瓶,其含有:
-富马酸的二乙醇酰胺 mg 100.00
-无菌盐水溶液适量,达 ml 2.0
实施例11
4ml冻干玻璃小管,其含有:
-富马酸的二乙醇酰胺 mg 200.00
-甘氨酸 mg 85.00
4ml溶剂小瓶,其含有:
无菌盐水溶液 ml 4.0ml
Claims (14)
1.全部或部分微粉化形式的棕榈酰乙醇酰胺单独在制备用于治疗肾病的药物中的应用。
2.权利要求1的应用,其中所述微粉化棕榈酰乙醇酰胺的粒子的至少94%具有小于10微米的尺寸。
3.权利要求1的应用,其中所述微粉化棕榈酰乙醇酰胺的粒子的至少77%具有小于6微米的尺寸。
4.权利要求1的应用,其中所述棕榈酰乙醇酰胺全部或部分是超微粉化形式。
5.权利要求4的应用,其中所述超微粉化棕榈酰乙醇酰胺的粒子的至少97%具有小于6微米的尺寸。
6.权利要求4的应用,其中所述超微粉化棕榈酰乙醇酰胺的粒子的至少57%具有小于2微米的尺寸。
7.权利要求1至6任一项的应用,其用于治疗由代谢异常疾病或毒性剂引起的肾病。
8.权利要求1至6任一项的应用,其中所述肾病选自:
‐糖尿病性肾病
‐肾动脉硬化
‐肾盂肾炎
‐多囊肾病
‐奥尔波特综合征
‐莱-尼综合征
‐古德帕斯丘综合征
‐狼疮肾炎
‐免疫球蛋白A肾病
‐肾小管坏死
‐肾小球肾炎
‐尿道狭窄
‐源自非甾体抗炎药、细胞毒性药、锂、抗生素或环孢素的医源性肾病
‐源自治疗性辐射的肾病
‐老年肾病。
9.权利要求1至6任一项的应用,其中所述治疗经口进行。
10.权利要求1至6任一项的应用,其中所述棕榈酰乙醇酰胺以每剂量单位1mg至2g活性成分范围内的量被包含在药物组合物中。
11.权利要求10的应用,其中所述棕榈酰乙醇酰胺以每剂量单位100mg至1g活性成分范围内的量被包含在药物组合物中。
12.权利要求1至6任一项的应用,其中所述棕榈酰乙醇酰胺被包含在选自下列的药物组合物中:用于经口给药的受控释放类型或非受控释放类型的片剂、胶囊、溶液剂、糖浆剂、混悬剂;经颊或舌下给药的片剂;用于注射给药的、在油性或水性载体中的混悬剂、溶液剂或乳剂;用于直肠给药的栓剂或渚留灌肠剂;用于皮下、透皮或肌肉内给药的储库型制剂。
13.权利要求1至6任一项的应用,其用于人类治疗。
14.权利要求1至6任一项的应用,其用于兽医治疗。
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EP1844784A1 (en) * | 2006-03-28 | 2007-10-17 | Epitech Group S.r.l. | A pharmaceutical composition for the treatment of pathologies caused by the general response of the immune system |
CN101641089A (zh) * | 2006-12-20 | 2010-02-03 | 新西兰适华利营养有限公司 | 提取物 |
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Publication number | Publication date |
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BRPI1107261A2 (pt) | 2013-07-30 |
JP6462198B2 (ja) | 2019-01-30 |
US20120083533A1 (en) | 2012-04-05 |
JP2012077084A (ja) | 2012-04-19 |
CN102526006A (zh) | 2012-07-04 |
US9402818B2 (en) | 2016-08-02 |
PT2444078T (pt) | 2017-11-15 |
ES2648051T3 (es) | 2017-12-28 |
US20150065576A1 (en) | 2015-03-05 |
JP2017128578A (ja) | 2017-07-27 |
EP2444078A1 (en) | 2012-04-25 |
EP2444078B1 (en) | 2017-09-13 |
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