CN101668542A - 肺病治疗药 - Google Patents
肺病治疗药 Download PDFInfo
- Publication number
- CN101668542A CN101668542A CN200880013780A CN200880013780A CN101668542A CN 101668542 A CN101668542 A CN 101668542A CN 200880013780 A CN200880013780 A CN 200880013780A CN 200880013780 A CN200880013780 A CN 200880013780A CN 101668542 A CN101668542 A CN 101668542A
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- Prior art keywords
- hmg
- coa reductase
- reductase inhibitor
- polymer
- treatment
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明在于提供一种有效性高并且副作用小的肺病治疗药,提供一种气管内给药用肺病治疗药,含有生物体适应性聚合物纳米颗粒,该生物体适应性聚合物纳米颗粒含有HMG-CoA还原酶抑制剂。
Description
技术领域
本发明涉及对肺病显示优异的改善作用的肺病治疗药。
背景技术
难治性肺病(慢性阻塞性肺病(COPD)、肺纤维症、急性呼吸窘迫综合征(ARDS)、肺高血压病等)是导致QOL恶化并且预后也恶化的难治性疾病,肺高血压病等的5年生存率在50%以下。最近,针对重症肺高血压病的前列环素持续静脉注射法、波生坦(Bosentan)、西地那非(Sildenafil)等作为新的治疗方法而使用,但是,其效果并不充分。另外,对慢性阻塞性肺病、肺纤维症等的治疗方法也是有限的。因此,期望对重症肺病的根本性以及低侵袭性的治疗法进一步研究开发。
另外,支气管哮喘、COPD、肺纤维症(间质性肺炎)等急性或慢性呼吸器官疾病大多伴随气管炎症的病状。
作为一般的炎症的病状形成,首先,在初期阶段中,被释放的称为趋化因子的信息传递分子促进嗜中性粒细胞、嗜碱性粒细胞、嗜酸性粒细胞、巨噬细胞等的炎症性细胞的区域性游走,游走后的炎症细胞释放损伤性的酶或者自由基,对组织造成损伤,同时通过放出细胞因子等导致炎症细胞的游走以及活化。这样的炎症在气管中发病时,浸润后的炎症细胞对支气管和肺的组织造成损伤,最终引起各种疾病特征性的呼吸量和氧气交换能力的降低,即引起呼吸机能的障碍。
从这样的见解可知在炎症性呼吸器官疾病的治疗中,可以使用具有抗炎症作用的药剂,已知肾上腺皮质类固醇在轻度~中度的支气管哮喘中具有显著效果(非专利文献1)。另外,有报告称,肾上腺皮质类固醇能够预防COPD的恶化,但是对COPD的病症的效果是有限的(非专利文献2),在肺纤维症中,目前还没有获得能够积极支持肾上腺皮质类固醇的有效性的结果(非专利文献3)。另一方面,肾上腺皮质类固醇不仅能够非特异性地抑制免疫机能,也具有引起电解质异常、消化性溃疡、肌肉疾病、行动异常、白内障、骨质疏松症、骨坏死以及发育障碍等各种各样的副作用的可能性(非专利文献4)。
另外,在支气管哮喘的治疗中,通过以类固醇吸入剂为主流的治疗的渗透,发病导致急诊患者数量、入院患者数量减少,门诊中能够控制病情的患者数量增加。
即使在这样的状况下,也不能减少患者数量,另外,依然存在致死性发作导致的哮喘死亡,因此,在目前的以类固醇吸入剂为中心的哮喘治疗剂的组合疗法中,仍不能达到充分的治疗,期望能够开发一种新的治疗剂,其具有良好的效果以及能够减轻副作用。
近年来,对具有强烈的LDL-胆固醇降低作用从而被作为高血脂症治疗的第一选择使用的HMG-CoA还原酶抑制剂相关的回顾性临床研究(流行病学研究),报道了HMG-CoA还原酶抑制剂的使用能够提高COPD患者的生存率(非专利文献5、6)。另一方面,也报道了HMG-CoA还原酶抑制剂中,还具有独立于LDL-胆固醇降低作用的多效性作用(Pleiotropic Effects)之一的抗炎症作用,提示在上述的炎症性肺病中具有其应用的可能性(非专利文献7)。
但是,口服给药HMG-CoA还原酶抑制剂时,吸收后的HMG-CoA还原酶抑制剂通过药物转运蛋白的参与,在肝脏特异性聚积,因此为了使HMG-CoA还原酶抑制剂在肺中聚积,发挥对肺病的作用,必须以高用量给药,但是在以特别高用量给药时,担心其存在导致横纹肌溶解症等的严重副作用。
非专利文献1:GINA Guideline,2006
非专利文献2:GOLD Guideline,2006
非专利文献3:Walter N,et al.,Proc Am Thorac Soc,Vol3,330-338,2006
非专利文献4:Goodman & Gilman,Pharmacological Basis ofTherapeutics,10th ed,McGraw hill 2001
非专利文献5:Soyseth V,et al.,Eur Respir J,29,279-283,2007
非专利文献6:Mancini GBJ et al,J Am Coll Cardiol,47,2554-2560,2006
非专利文献7:Hothersall E,et al.,Thorax 61,729-734,2006
发明内容
本发明的目的在于提供一种有效性高并且副作用小的优异肺病治疗药。
本发明的发明者为了将HMG-CoA还原酶抑制剂应用于肺病治疗药进行了各种研究,发现通过使HMG-CoA还原酶抑制剂含在生物体适应性聚合物纳米颗粒中,向作为肺病的主要病变部位的细支气管~肺胞进行直接给药,能够以低用量得到良好的肺病治疗效果,从而完成了本发明。
即,本发明提供一种气管内给药用肺病治疗药,含有生物体适应性聚合物纳米颗粒,该生物体适应性聚合物纳米颗粒含有HMG-CoA还原酶抑制剂。
另外,本发明提供含有HMG-CoA还原酶抑制剂的生物体适应性聚合物颗粒在制造气管内给药用肺病治疗药中的使用。
另外,本发明提供一种气管内给药用肺病治疗用的含有HMG-CoA还原酶抑制剂的生物体适应性聚合物纳米颗粒。
另外,本发明提供一种肺病治疗方法,其特征在于,向气管内给药有效量的含有HMG-CoA还原酶抑制剂的生物体适应性聚合物纳米颗粒。
发明的效果
根据本发明,能够提供一种肺病治疗药,肺病治疗药通过例如吸入等的简便操作,向肺直接给药,含有HMG-CoA还原酶抑制剂的生物体适应性聚合物纳米颗粒向肺病的病变部位进行良好的移动,并且在病变部位的贮留性高,因此与以治疗高血压病为目的的HMG-CoA还原酶抑制剂的口服给药相比,用量低,有效性高并且副作用少。
附图说明
图1是在LPS诱发急性肺障碍小鼠中,通过封入匹伐他汀钙的PLGA纳米颗粒的气管内给药,对支气管肺胞洗净液中的细胞数的效果。
图2是野百合碱诱发重症肺高血压大鼠中,封入匹伐他汀钙的PLGA纳米颗粒的气管内给药的生存率。
具体实施方式
本发明的气管内给药用肺病治疗药含有生物体适应性聚合物纳米颗粒,该生物体适应性聚合物纳米颗粒含有HMG-CoA还原酶抑制剂,有效成分为HMG-CoA还原酶抑制剂。
本发明中使用的HMG-CoA还原酶抑制剂具有胆固醇合成抑制活性,包括全部的作为高血脂症治疗剂被公知的所谓斯他汀(Statin)类化合物。也包括这些的内酯体和开环体或其盐中的任一种。包括这些化合物及其盐的水合物和作为医药所允许的溶剂化物。
作为优选的HMG-CoA还原酶抑制剂,例如可以列举洛伐他汀(日本特开昭57-163374号公报、美国专利第4231938号公报)、辛伐他汀(日本特开昭56-122375号公报、美国专利第4444784号公报)、普伐他汀(日本特开昭57-2240号公报、美国专利第4346227号公报)、氟伐他汀(日本特表昭60-500015号公报、美国专利第4739073号公报)、阿托伐他汀(日本特开平3-58967号公报、美国专利第4681893号公报、第5273995号公报)、罗苏伐他汀(日本特开平5-178841号公报、美国专利第5260440号公报)、匹伐他汀(日本专利第2569746号公报、美国专利第5102888号公报、美国专利第5856336号公报、欧洲专利304063号公报)及这些的盐等。作为HMG-CoA还原酶抑制剂的盐,可以列举碱金属盐、碱土金属盐、铵盐、烷基铵盐等。
作为最合适的HMG-CoA还原酶抑制剂,优选阿托伐他汀、匹伐他汀或这些的盐,特别优选匹伐他汀或其盐。作为盐,优选钙盐、钠盐。
本发明的肺病治疗药的纳米颗粒中的HMG-CoA还原酶抑制剂的含量,从到达肺病变部位的效率的角度出发,优选为0.001~20重量%,进一步优选为0.005~20重量%,更优选为0.01~20重量%,特别优选为0.05~15重量%。这里,HMG-CoA还原酶抑制剂包括被吸附在纳米颗粒的内部和表面的情况。
作为形成纳米颗粒的生物体适应性聚合物,可以列举聚乳酸、聚乙醇酸、聚天冬氨酸、乳酸-乙醇酸共聚物、天冬氨酸-乳酸-乙醇酸共聚物、聚酰胺、聚碳酸酯、聚乙烯这样的聚烯、聚丙烯、聚乙二醇、聚氧化乙烯、聚对苯二甲酸乙二醇酯、聚乙烯醇、聚乙烯醚和聚乙烯酯这样的聚乙烯基化合物、丙烯酸和甲基丙烯酸的聚合物、纤维素及其它的多糖类、以及肽或蛋白质、或者这些的共聚物或混合物。其中,更优选聚乳酸、聚乙醇酸、乳酸-乙醇酸共聚物(PLGA)以及这些与聚乙二醇(PEG)的嵌段共聚物,特别优选乳酸-乙醇酸共聚物(PLGA)与聚乙二醇(PEG)的嵌段共聚物(PEG修饰PLGA:peg-PLGA)。上述生物体适应性聚合物能够内包HMG-CoA还原酶抑制剂,能够原样保持该药物的效力进行长期保存。另外,通过生物体内的酶将生物体适应性聚合物分解,能够在肺中进行数小时到数十小时单位的HMG-CoA还原酶抑制剂的缓缓释放。
生物体适应性聚合物的分子量优选为5000~200000,特别优选为15000~25000。乳酸-乙醇酸共聚物(PLGA)中乳酸和乙醇酸的组成比(摩尔比)可以为1∶99~99∶1,但是优选相对于乳酸1,乙醇酸为0.333。另外,乳酸和乙醇酸的含量在25重量%~65重量%的范围内的PLGA是非晶质,并且可溶于丙酮等有机溶剂,因此可以适当地使用。
另外,本发明中使用的纳米颗粒的粒径,从有效到达肺病变部位以及HMG-CoA还原酶抑制剂的含有效率的角度出发,优选为30nm~10μm,特别优选为100nm~5μm。该纳米颗粒的粒径可以通过CoulterCounter N4PLUS(Beckman Coulter社制)进行测定。
本发明使用的纳米颗粒可以通过例如粉体工学会志42(11)、765-772(2005)、日本特开2003-275281号公报、日本特开2004-262810号公报、日本特开2006-321763号公报等中记载的方法进行制造。
使用水中乳液溶剂扩散法的本发明纳米颗粒制造例如下所示。
将PLGA溶解在丙酮等有机溶剂中,作为聚合物溶液,在其中混合HMG-CoA还原酶抑制剂或其水溶液。搅拌下将其滴入聚乙烯醇(PVA)水溶液、精制水等中,调制成乳液。除去丙酮等有机溶剂而得到的PLGA纳米颗粒悬浊液,通过离心分离法回收PLGA纳米颗粒的沉淀,在精制水中再悬浊,通过洗净除去不能吸附在PLGA表面上的剩余PVA,冷冻干燥、粉末化。另外,也可以直接将PLGA纳米颗粒悬浊液冷冻干燥、并粉末化。
本发明的纳米颗粒能够复合(composite)化高级结构,也包括被复合化后的纳米颗粒。复合化可以通过在以上述方法等制造的纳米颗粒含有液中添加糖醇,均匀混合、并冷冻干燥而进行制造。作为糖醇,可以列举甘露醇、海藻糖、山梨糖醇、赤藓醇、麦芽糖醇、木糖醇等。糖醇的添加量相对于纳米颗粒含有液整体,优选为0.001~1重量%,特别优选为0.01~0.1重量%。
本发明的纳米颗粒优选使之含在日本药典生理盐水(pH=6.0)、精制水(pH=6.8)等的水溶液中使用。另外,该含有液优选使用聚乙烯醇、聚乙二醇等的分散剂。该含有液中的纳米颗粒的浓度,从防止颗粒彼此的凝聚的角度出发,优选为0.1~20重量%,特别优选为1~10重量%。另外,分散剂的浓度,从将纳米颗粒有效分散的角度出发,优选为0.1~20重量%,特别优选为1~10重量%。
本发明的纳米颗粒的给药量根据疾病、症状进行适当选择,作为HMG-CoA还原酶抑制剂,每天为0.001~100mg,优选为0.01~50mg,更优选为0.01~30mg,进一步优选为0.1~10mg。特别是匹伐他汀或其盐的情况下,每天优选为0.001~50mg,更优选为0.01~30mg。
对肺的给药,优选使用吸入器、雾化器等进行。给药次数,多时为1天1~3次,少时为2、3天、1周左右1次。
本发明的药剂通过直接对肺、例如细支气管~肺胞给药,到达肺的病变部位,经过长时间,放出HMG-CoA还原酶抑制剂,因此,能够以低用量进行安全的肺病治疗。作为对象的肺病,可以列举肺高血压病、慢性阻塞性肺病、肺纤维症、急性呼吸窘迫综合症、支气管哮喘、炎症性肺病、肺炎、支气管炎等,对肺高血压病的治疗特别有效。
另外,在肺病的治疗中使用肾上腺皮质类固醇时,可以通过与本发明的治疗药并用从而减少其用量,并减轻类固醇的副作用。
实施例
下面列举实施例对本发明进行更详细的说明,但是,本发明不受其限定。
实施例1
封入匹伐他汀的钙盐的PLGA纳米颗粒的调制方法
PLGA纳米颗粒中的匹伐他汀的钙盐(匹伐他汀钙)(日本专利2569746号公报、美国专利第5102888号公报、美国专利第5856336号公报、欧洲专利304063号公报)的封入,参考已经报道的在精制水中的乳液溶剂扩散法而进行调制(粉体工学会志,42,765-772(2005))。
将乳酸-乙醇酸共聚物(PLGA,分子量20000,乳酸/乙醇酸的比:75/25)(1g)和匹伐他汀钙(0.025g)溶解于丙酮(40mL)中,在其中添加乙醇(20mL),作为聚合物溶液。将该聚合物溶液滴加到使用搅拌机以400rpm搅拌的PVA水溶液(含有PVA(0.5g)的水溶液(100mL))中,进行乳液化。减压下,在40℃下进行1小时搅拌,除去有机溶剂后使用滤膜进行过滤,然后将滤液进行冷冻干燥,得到目的的PLGA纳米颗粒粉末。
在PLGA纳米颗粒中含有1.3重量%的匹伐他汀钙。
另外,对照组的没有封入匹伐他汀钙的PLGA纳米颗粒,不添加匹伐他汀钙,与上述方法同样进行调制。
实施例2
封入匹伐他汀的钙盐的PEG修饰PLGA纳米颗粒的调制方法
将PEG修饰PLGA(peg-PLGA)(2g)、匹伐他汀钙(0.1g)溶解于丙酮(20mL)中,添加乙醇(10mL),制作聚合物溶液。
将该溶液滴加到40℃下以400rpm的速度搅拌的精制水(50mL)中。
减压下,在40℃下利用2小时除去有机溶剂后,为了除去形成块状的纳米颗粒,使用孔尺寸为32μm的滤膜过滤得到的悬浊液。
原样将滤液用于下述的试验例2。本纳米颗粒含有液中含有0.0998重量%的匹伐他汀钙。
试验例1
在LPS诱发急性肺损伤模型中,封入匹伐他汀钙的PLGA纳米颗粒的气管内给药对炎症性细胞的效果
试验方法:
将由日本Charles River购入的雄性BALB/c小鼠(使用时为8周龄),在设定为室温21±2℃、湿度50±20%、光亮期:7:00-19:00的饲养室中,以食料和水可以自由摄取的条件进行预备饲养后使用。
将小鼠分为3组进行实验:LPS(Lipopolysaccharide,脂多糖)非吸入暴露组(Control(-);n=7);给药没有封入匹伐他汀钙的PLGA纳米颗粒后、LPS吸入暴露的组(Control(+);n=14);给药封入匹伐他汀钙的PLGA纳米颗粒后、LPS吸入暴露的组(Pitava;n=13)。
将腹腔内给药戊巴比妥钠(50mg/10mL/kg)并麻醉后的小鼠的颈部切开,使气管露出,分别将没有封入匹伐他汀钙的PLGA纳米颗粒和封入匹伐他汀钙的PLGA纳米颗粒,在目视下悬浊于生理盐水中,将各自的悬浊液50μL与200μL空气一起用27G注射针向气管内给药。给药后缝合颈部,从麻醉中清醒后的小鼠顺次回到饲养笼。
给药量以PLGA纳米颗粒的重量计,为15μg/body(匹伐他汀钙的含量:0.2μg/body)。
另外,纳米颗粒的给药液在使用时悬浊于生理盐水中,使用超声波均化器进行超声波降解30秒。
气管内给药24小时后,将小鼠移至内部尺寸为26cm×26cm×10cm(W×D×H)的丙烯酸制的笼子中,向该笼子中,将用超声波雾化器(Omron)雾化后的30μg/mL的LPS(Sigma)进行送气,进行吸入暴露。吸入暴露持续进行30分钟,暴露结束后小鼠再次返回饲养笼。
从LPS的吸入暴露开始4小时后,将腹腔内给药戊巴比妥钠(50mg/10mL/kg)并麻醉后的小鼠的腹部大动脉切断,放血致死。然后切开颈部,在支气管固定外径1.2mm的聚乙烯管(SP55,夏目制作所),通过反复进行3次1mL的磷酸缓冲生理盐水(PBS)的注入·回收操作,进行支气管肺胞的洗净。回收后的支气管肺胞洗净液(BALF)以1000rpm,4℃离心10分钟,收集到的游走细胞在200μL的PBS中再悬浊,使用多项目自动血球分析装置(XT-2000i,Sysmex)对总细胞数和嗜中性粒细胞数进行计数。
实验结果:
得到的结果以相对于Control(+)组的百分率表示,其平均值±标准误差,表示于表1和图1中。
[表1]
通过封入匹伐他汀钙的PLGA纳米颗粒的气管内给药,能够显著抑制炎症性细胞的游走(p<0.05)。可以确认,对炎症性细胞的游走抑制,不是单独的PLGA纳米颗粒的效果,而是封入匹伐他汀钙的纳米颗粒的效果。
另外,以原体的匹伐他汀钙的3个用量(0.2μg/body、2μg/body、20μg/body),分别将其溶解于生理盐水(50μL)中,与上述相同进行实验,但是,任何一个用量中都没有发现对炎症性细胞的游走抑制作用(匹伐他汀钙非给药组:n=8;匹伐他汀钙给药组(各自用量中):n=8)。
从这次的试验,可以得到通过封入匹伐他汀钙的PLGA纳米颗粒对肺的局部给药,能够抑制LPS引起的炎症性反应,另外,该匹伐他汀钙的用量,与以给药原体本身的情况相比,能够以极低用量抑制炎症性反应。由此得到,封入匹伐他汀钙的PLGA纳米颗粒对伴随炎症的各种肺病的治疗有效。
试验例2
通过封入匹伐他汀钙的PLGA纳米颗粒的气管内给药的肺高血压病治疗实验
试验方法:
对雄性SD大鼠(7周龄:250-300g)以野百合碱(MCT)进行皮下注射(60mg/kg body weight),制作MCT诱发肺高血压病大鼠(MCT给药3周后确立重症肺高血压病)。
将大鼠分为两组:(1)第1组(封入匹伐他汀钙的PEG修饰PLGA纳米颗粒的组(纳米颗粒给药组,n=26))、(2)第2组(作为对照给药PBS的组(对照组;n=41))。
MCT给药后,第21天,切开前颈部,在第1组中将封入匹伐他汀钙的PEG修饰PLGA纳米颗粒含有液(上述实施例2中制造)(100μL)与100μL的空气一起向气管内给药,在第2组中将PBS(100μL)与100μL的空气一起向气管内给药。封入匹伐他汀钙的PEG修饰PLGA纳米颗粒中含有的匹伐他汀钙的量为100μg/body。
纳米颗粒给药后14天期间,进行大鼠的生存确认。
试验结果:
如表2和图2所示,对照组中14天后生存率降低至37%,但是纳米颗粒给药组中14天后生存率为69%,可以确认与对照组相比,具有显著意义的生存率的改善(p<0.01)。
[表2]
使用大鼠数 | 14天后生存大鼠数 | 生存率 | |
对照组 | 41 | 15 | 37% |
纳米颗粒给药组 | 26 | 18 | 69% |
这次的结果是在肺高血压病的治疗中,匹伐他汀钙的给药量为一次给药100μg的极低用量而得到的结果。由此可以得到,封入匹伐他汀钙的PLGA纳米颗粒的气管内给药非常有效。
通过HMG-CoA还原酶抑制剂的口服给药进行高血脂症的治疗时,用量大时,阿托伐他汀的钙盐为10~80mg/天,用量小时,匹伐他汀的钙盐为1~4mg/天。从试验例1和2,可以确认与此相比,在封入HMG-CoA还原酶抑制剂的生物体适应性聚合物颗粒的气管内给药时,可以以低剂量的HMG-CoA还原酶抑制剂表现对肺疾病的抑制效果。
Claims (15)
1.一种气管内给药用肺病治疗药,其特征在于:
含有生物体适应性聚合物纳米颗粒,该生物体适应性聚合物纳米颗粒含有HMG-CoA还原酶抑制剂。
2.如权利要求1所述的肺病治疗药,其特征在于:
HMG-CoA还原酶抑制剂为洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀或其盐。
3.如权利要求1所述的肺病治疗药,其特征在于:
HMG-CoA还原酶抑制剂为匹伐他汀或其盐。
4.如权利要求1~3中任一项所述的肺病治疗药,其特征在于:
肺病为肺高血压病、慢性阻塞性肺病、肺纤维症、急性呼吸窘迫综合症、支气管哮喘、炎症性肺病、肺炎或支气管炎。
5.如权利要求1~4中任一项所述的肺病治疗药,其特征在于:
生物体适应性聚合物为聚乳酸、聚乙醇酸、乳酸-乙醇酸共聚物或这些聚合物与聚乙二醇的嵌段共聚物。
6.含有HMG-CoA还原酶抑制剂的生物体适应性聚合物纳米颗粒在制造气管内给药用肺病治疗药中的使用。
7.如权利要求6所述的使用,其特征在于:
HMG-CoA还原酶抑制剂为洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀或其盐。
8.如权利要求6所述的使用,其特征在于:
HMG-CoA还原酶抑制剂为匹伐他汀或其盐。
9.如权利要求6~8中任一项所述的使用,其特征在于:
肺病为肺高血压病、慢性阻塞性肺病、肺纤维症、急性呼吸窘迫综合症、支气管哮喘、炎症性肺病、肺炎或支气管炎。
10.如权利要求6~9中任一项所述的使用,其特征在于:
生物体适应性聚合物为聚乳酸、聚乙醇酸、乳酸-乙醇酸共聚物或这些聚合物与聚乙二醇的嵌段共聚物。
11.一种肺病治疗方法,其特征在于:
向气管内给药有效量的含有HMG-CoA还原酶抑制剂的生物体适应性聚合物纳米颗粒。
12.如权利要求11所述的治疗方法,其特征在于:
HMG-CoA还原酶抑制剂为洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀或其盐。
13.如权利要求11所述的治疗方法,其特征在于:
HMG-CoA还原酶抑制剂为匹伐他汀或其盐。
14.如权利要求11所述的治疗方法,其特征在于:
肺病为肺高血压病、慢性阻塞性肺病、肺纤维症、急性呼吸窘迫综合症、支气管哮喘、炎症性肺病、肺炎或支气管炎。
15.如权利要求11所述的治疗方法,其特征在于:
生物体适应性聚合物为聚乳酸、聚乙醇酸、乳酸-乙醇酸共聚物或这些聚合物与聚乙二醇的嵌段共聚物。
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-
2008
- 2008-04-25 WO PCT/JP2008/001081 patent/WO2008139703A1/ja active Application Filing
- 2008-04-25 KR KR1020097021959A patent/KR101530393B1/ko active IP Right Grant
- 2008-04-25 ES ES08751606T patent/ES2425969T3/es active Active
- 2008-04-25 EP EP08751606.8A patent/EP2140882B1/en active Active
- 2008-04-25 PT PT87516068T patent/PT2140882E/pt unknown
- 2008-04-25 US US12/596,996 patent/US20100086615A1/en not_active Abandoned
- 2008-04-25 CN CN2008800137806A patent/CN101668542B/zh not_active Expired - Fee Related
- 2008-04-25 JP JP2009513998A patent/JP4896220B2/ja not_active Expired - Fee Related
- 2008-04-25 CA CA2685054A patent/CA2685054C/en not_active Expired - Fee Related
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107206084A (zh) * | 2014-11-10 | 2017-09-26 | 伊井正明 | 用于增强干细胞功能的内含抑制素纳米粒子制剂、以及含有其的功能增强干细胞及其制备方法 |
CN107206084B (zh) * | 2014-11-10 | 2021-05-14 | 伊井正明 | 用于增强干细胞功能的内含抑制素纳米粒子制剂以及含有其的功能增强干细胞及其制备方法 |
CN109152764A (zh) * | 2016-05-06 | 2019-01-04 | 学校法人大阪医科药科大学 | 用于增强炎性疾病治疗用干细胞的功能的包封抑制素的纳米粒子制剂、以及含有其的炎性疾病治疗用功能增强干细胞 |
CN112004524A (zh) * | 2018-02-26 | 2020-11-27 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | 药物递送系统 |
CN112912068A (zh) * | 2018-05-10 | 2021-06-04 | 伊井正明 | 包封有抑制素的纳米颗粒制剂、含有其的牙髓源性干细胞和含有该干细胞的细胞制剂 |
Also Published As
Publication number | Publication date |
---|---|
PT2140882E (pt) | 2013-09-30 |
US20100086615A1 (en) | 2010-04-08 |
WO2008139703A1 (ja) | 2008-11-20 |
KR101530393B1 (ko) | 2015-06-19 |
CA2685054A1 (en) | 2008-11-20 |
KR20100015758A (ko) | 2010-02-12 |
HK1141708A1 (en) | 2010-11-19 |
JPWO2008139703A1 (ja) | 2010-07-29 |
ES2425969T3 (es) | 2013-10-18 |
CN101668542B (zh) | 2012-06-27 |
EP2140882A4 (en) | 2010-05-26 |
JP4896220B2 (ja) | 2012-03-14 |
CA2685054C (en) | 2014-11-04 |
EP2140882A1 (en) | 2010-01-06 |
EP2140882B1 (en) | 2013-08-14 |
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