CN110269841A - 用于腹膜透析的脂质体组合物 - Google Patents
用于腹膜透析的脂质体组合物 Download PDFInfo
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- CN110269841A CN110269841A CN201910232676.6A CN201910232676A CN110269841A CN 110269841 A CN110269841 A CN 110269841A CN 201910232676 A CN201910232676 A CN 201910232676A CN 110269841 A CN110269841 A CN 110269841A
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- liposome
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- lipid
- disease
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Abstract
本发明涉及一种用于患有内源性或外源性中毒病的患者的腹膜透析的脂质体组合物，其中所述脂质体内的pH与腹膜腔内的pH不同，和其中所述脂质体内的pH导致产生脂质体包囊的带电荷的毒素。本发明也涉及包含所述脂质体的药物组合物。本发明的另一方面涉及治疗患有内源性或外源性中毒病的患者的方法，所述中毒病优选选自药物、代谢物、农药、杀虫剂、毒素和化学战剂中毒病、更优选高氨血症，所述方法包括将本发明的脂质体以治疗有效量给予有其需要的患者的腹腔内的步骤。仅次于人，本发明特别适合于兽药方面。
Description
本申请是申请日为2013年8月6日、申请号为201380042294.8(PCT/EP2013/002352)、发明名称为“用于腹膜透析的脂质体组合物”的发明专利申请的分案申请。
本发明涉及一种用于患有内源性或外源性中毒病的患者的腹膜透析的脂质体组合物，其中所述脂质体内的pH与腹膜腔内的pH不同，和其中所述脂质体内的pH导致产生脂质体包囊的带电荷的毒素。本发明也涉及包含所述脂质体的药物组合物。本发明的另一方面涉及治疗患有内源性或外源性中毒病的患者的方法，所述中毒病优选选自药物、代谢物、农药、杀虫剂、毒素和化学战剂中毒病、更优选高氨血症，所述方法包括将本发明的脂质体以治疗有效量给予有其需要的患者的腹腔内的步骤。仅次于人，本发明特别适合于兽药方面。
发明背景
为了改变药物的药代动力学和生物分布特性，已经开发出多种多样的基于脂质-和聚合物的颗粒并且进行了表征，包括脂质体，即直径在纳米到微米大小范围内的小的脂质双层颗粒，其中脂质双层将内部的水环境包裹住。脂质体目前用于药物递送的医药和用于药物解毒的研究。
药物可采用多种技术例如通过被动方法和pH-梯度技术被包封在脂质体中。有关综述参见Fenske和Cullis, Encapsulation of Drugs within Liposomes by pH-Gradient Techniques, Liposome Technology, 第II卷, Gregory Gregoriadis编著,Informa Healthcare September 2006, 27-50。跨越脂质双层的pH梯度的优势在于一旦药物是在里面，它就可以根据药物和pH通过质子化或去质子化而带电荷，致使其通过亲脂性膜向外的反向传递(back transfer)被阻碍。参见例如Mayer等, Biochimica etBiophysica Acta, 857:123-126, 1986和Madden等, Chemistry and Physics ofLipids, 53:37-46, 1990。因此，脂质体载体系统通过将药物包封在它们的内腔里面而显著地缓冲了药物的毒性。脂质体药物经常静脉内给予或者在预计的药物作用部位给予(例如腹膜内)。有关腹膜内脂质体药物递送请参考例如Verschraegen等, J. Cancer Res.Clin. Oncol., 129:549-555, 2003和Parker等, Cancer Res. 41: 1311-1317, 1981。腹膜内给予的脂质体包封的药物的腹膜保留取决于制剂的组成，例如脂质双层的脂质组成、所包括的胆固醇量、脂质体的大小、脂质体的电荷和/或脂质体的涂层(例如涂覆PEG (聚乙二醇))。腹膜内给予的脂质体药物经过血液和淋巴运输并且可以在血液、淋巴结以及在多种器官中被检测到。具体地说，脂质体的大小对腹膜保留有影响。对于静脉内注射的脂质体，约100 nm的直径通常被认为对于延长的血液循环是最佳的，而增加脂质体大小当腹膜内注射时会产生较高的腹膜保留。大小为约1000 nm或更大的脂质体具有最高的腹膜腔保留。有关影响腹膜内给予的脂质体的腹膜保留的因素的更多信息请参考例如，Sadzuka等,Toxicology Letters 116:51-59, 2000; Dadashzadeh等, Journal of ControlledRelease, 148:177-186, 2010; Mirahmadhi等, International Journal ofPharmaceutics, 383:7-13, 2010; Hirano和Hunt, Journal of PharmaceuticalSciences, 74 (9), 915-921, 1985。
此外，脂质体以及脂质的乳剂在药物解毒中具有实用性。
Jamaty等, Clinical Toxicology 48:1-27, 2010综述了静脉内用脂肪乳剂(intravenous fat emulsions, IFE)即脂质乳剂(lipid emulsions)在治疗急性药物中毒中的应用的文献资料。Intralipid®是一种临床相关商品脂肪乳剂的品牌名称，该脂肪乳剂包含10%、20%或30% (重量)的纯化大豆油以及纯化卵磷脂、甘油和水，在营养不良的情况下，用作静脉内或胃肠外给予的营养药。此外，它用作麻醉药物丙泊酚和依托咪酯的溶媒以及用于治疗由过量的局部麻醉药物例如布比卡因引起的严重心脏毒性以挽救在其它情况下对普通复苏方法无反应的患者。对于营养疗法和解毒疗法，Intralipid®是静脉内给予的。Cave和Harvey (Academic Emergency Medicine, 16:151-156, 2009)综述了IFE在解毒疗法中的应用的文献资料。而且在氯米帕明输注治疗的兔的动物模型中，静脉内和同时通过腹膜给药给予的Intralipid®显示与Intralipid®单独的静脉内给药相比，氯米帕明萃取提高(参见Harvey等, Academic Emergency Medicine, 16:815-824, 2009)。以IFE为基础的解毒机制是脂质制剂通过脂质萃取清除了有毒药物并因此将其掩盖。当然，这种机制仅仅对于具有足够亲脂性的药物可利用并且取决于药物在脂质组合物中的萃取系数。
像IFE一样，对静脉内给予的脂质体治疗心血管药物中毒进行了调查。J.-C.Leroux, Nature Biotechnology, 2:679-864, 2007综述了可注射的纳米载体、特别是脂质体的可注射的纳米载体在药物解毒中的应用。Bertrand等, ACS Nano, 4 (12), 7552-7558, 2010证明了在接受静脉内大量剂(bolus)的地尔硫(一种心血管药物)和用地尔硫(一种心血管药物)灌注的大鼠中，使用静脉内给予的跨膜pH-梯度脂质体的解毒作用。与用IFE的脂质萃取不一样，脂质体的作用机制是脂质体摄取和药物因为pH梯度而带电荷，从而使摄取成为不可逆的。与IFE相比，清除药物的脂质体在捕获药物、特别是钙通道阻滞药中更加有效，参见例如Forster等, Biomaterials 33, 3578-3585, 2012。
高氨血症是指与血氨水平升高相关的临床病症，表现为多种症状，包括中枢神经系统(CNS)异常。当以高浓度存在时，氨是有毒的。当身体排泄含氮废物的能力削弱时，内源性氨中毒就可以发生，就好像患先天性酶缺乏症所见到的一样。多种环境原因和用药也可能导致氨毒性。有关氨血症的综述请参考Auron和Brophy, Pediatr. Nephrol., 27:207-222, 2012; 和Clay和Hainline, CHEST, Official journal of the American Collegeof Chest Physicians, (132), 1368-1378, 2007。通常，高氨血症与脑水肿、脑代谢减少和脑血流增加相关。仅次于治疗颅内高压、防止蛋白质分解代谢的营养支持和停止蛋白质的营养摄入的疗法，通过主动除氨而降低血氨水平可能是必需的。除了通过药理学操作的氮消除(例如给予苯乙酸钠和苯甲酸钠以通过“替代的”代谢途径促进氨的清除)之外，腹膜透析、血液透析、连续性静脉血液滤过、连续性静脉血液渗滤和连续性动脉血液渗滤都是除氨的有效方式并且已经辅助用于治疗与儿童和成人的尿素循环障碍相关的高氨血症。特别是对于患有先天性代谢缺陷的儿童，静脉血液透析和连续性腹膜透析都是高氨血症的紧急处理的治疗选择，例如参见Arbeiter等, Nephrol. Dial. Transplant., 25:1257-1265,2010和Pela等; Pediatr. Nephrol., 23:163-168, 2008。
本发明的目的是提供脂质体组合物的新的医药用途。另一个目的是提供内源性和外源性中毒病、特别是药物、代谢物、农药、杀虫剂、毒素和化学战剂中毒病的新的疗法。本发明还有一个目的是提供高氨血症的新的治疗方法。
以上目的通过将脂质体组合物用于患有内源性或外源性中毒病的患者的腹膜透析中而得到解决，其中所述脂质体内的pH与腹膜腔内的pH不同，和其中所述脂质体内的pH导致产生脂质体包囊的带电荷的毒素。
术语“腹膜透析用脂质体组合物”意味着是指这样的脂质体组合物：(i)适用于腹膜内给药，即该脂质体组合物由生理上可接受的脂质和其它成分组成；(ii)在生理条件、特别是腹膜腔和血液的生理条件下在适用于药物和代谢物的摄取和延长保留的时间内是稳定的；和(iii)显示出跨膜转移能力。
为了实施本发明，脂质体内的pH与腹膜腔内的pH不同并且脂质体内的pH导致产生脂质体包囊的带电荷的毒素是必需的。
鉴于以上所述，本发明的脂质体组合物是生理上可接受的、稳定的、跨膜、pH-梯度脂质体组合物，适用于腹膜给药，即相适应的pH使得所述脂质体内的特定毒素带电荷。
如本文所用的术语“腹膜透析”意味着像腹膜透析治疗领域的技术人员通常理解的一样理解。为了实施本发明，将药学上有效量的本发明的脂质体组合物给予腹膜腔内，例如通过作为单次大剂量(single bolus)注射或通过连续输注或灌注。腹膜腔和附近组织和器官内的脂质体将会摄取目标毒素。所述脂质体内的pH适应于使得毒素在膜转移时被带电荷，即质子化或去质子化，导致产生带正电荷或负电荷的毒素化合物，这样的毒素化合物不能通过疏水性脂质体双层进行反向转移。
包封药物的脂质体螯合毒素达延长的时间周期并且降低游离化合物的毒性浓度。如果由所述脂质体的最终生物降解和毒素的释放所致的毒性浓度对于患者不是病理性的，那么所述脂质体可以留在腹膜腔和机体组织内。另一方面，优选所述脂质体的组成和/或大小与延长腹膜定位相适应。在这种情况下，优选将腹腔内荷载毒素的脂质体从腹膜腔中抽吸出来。腹膜内给药和抽吸可以随后和/或同时进行。
适用于实施本发明的生理上可接受的、跨膜、pH-梯度脂质体组合物可以按照现有技术中大量描述的方法(例如在以上提及的文件中)来制备。所述脂质体制剂可包含不同的性质(单层的，多层的)、组成、大小和特征的囊泡，将多种组成、pH和渗透强度的含水介质包裹住。在优选的实施方案中，所述脂质体脂质层膜的主要成分选自天然磷脂或合成磷脂，例如以下列出的那些：
- 1,2-二月桂酰基-sn-甘油基-3-磷酸胆碱(DLPC)
- 1,2-二肉豆蔻酰基-sn-甘油基-3-磷酸胆碱(DMPC)
- 1,2-二棕榈酰基-sn-甘油基-3-磷酸胆碱(DPPC)
- 1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)
- 1,2-二油酰基-sn-甘油基-3-磷酸胆碱(DOPC)
- 1,2-二肉豆蔻酰基-sn-甘油基-3-磷酸乙醇胺(DMPE)
- 1,2-二棕榈酰基-sn-甘油基-3-磷酸乙醇胺(DPPE)
- 1,2-二硬脂酰基-sn-甘油基-3-磷酸乙醇胺(DSPE)
- 1,2-二油酰基-sn-甘油基-3-磷酸乙醇胺(DOPE)
- 1-肉豆蔻酰基-2-棕榈酰基-sn-甘油基-3-磷酸胆碱(MPPC)
- 1-棕榈酰基-2-肉豆蔻酰基-sn-甘油基-3-磷酸胆碱(PMPC)
- 1-硬脂酰基-2-棕榈酰基-sn-甘油基-3-磷酸胆碱(SPPC)
- 1-棕榈酰基-2-硬脂酰基-sn-甘油基-3-磷酸胆碱(PSPC)
- 1,2-二肉豆蔻酰基-sn-甘油基-3-[磷酸-rac-(1-甘油)] (DMPG)
- 1,2-二棕榈酰基-sn-甘油基-3-[磷酸-rac-(1-甘油)] (DPPG)
- 1,2-二硬脂酰基-sn-甘油基-3-[磷酸-rac-(1-甘油)] (DSPG)
- 1,2-二油酰基-sn-甘油基-3-[磷酸-rac-(1-甘油)] (DOPG)
- 1,2-二肉豆蔻酰基-sn-甘油基-3-磷酸酯(DMPA)
- 1,2-二棕榈酰基-sn-甘油基-3-磷酸酯(DPPA)
- 1,2-二棕榈酰基-sn-甘油基-3-[磷酸-L-丝氨酸] (DPPS)
- 天然的L-α-磷脂酰胆碱(来自鸡蛋，EPC；或来自大豆，SPC)。
优选的磷脂是长的饱和磷脂，例如具有超过12个、优选超过14个、更优选超过16个、最优选超过18个碳原子的烷基链的那些。
优选的按照本发明使用的脂质体组合物优选地为其中所述脂质体是单层的和/或多层的并且包含以下成分的那些：
(i)1-100 mol%、优选40-70 mol%生理上可接受的磷脂，优选选自DLPC、DMPC、DPPC、DSPC、DOPC、DMPE、DPPE、DSPE、DOPE、MPPC、PMPC、SPPC、PSPC、DMPG、DPPG、DSPG、DOPG、DMPA、DPPA、DPPS、EPC和/或SPC；
(ii)1-100 mol%、优选40-70 mol%鞘脂、优选鞘磷脂；
(iii)1-100 mol%、优选40-70 mol%表面活性剂、优选特征为疏水性烷基醚(例如Brij)、烷基酯、聚山梨醇酯、山梨醇酐酯和/或烷基酰胺；
(iv)5-100 mol%、优选50-100 mol%两亲聚合物和/或共聚物、优选包含至少一个嵌段的亲水性聚合物或共聚物例如聚乙二醇和至少一个嵌段的疏水性聚合物或共聚物例如聚(丙交酯)、聚(己内酯)、聚(环氧丁烷)、聚(氧化苯乙烯)、聚(苯乙烯)、聚(乙基乙烯)或聚二甲基硅氧烷的嵌段共聚物，
(v)0-60 mol%、优选20-50 mol%毒素保留-增强化合物、优选甾醇衍生物、优选胆固醇，
(vi)0-30 mol%、优选1-5 mol%空间稳定剂、优选PEG化化合物、优选PEG化脂质、更优选DSPE-PEG。
在优选的实施方案中，脂质体样囊泡由聚合物制成并且不包含脂质，为此，它们在形式上被认为不是脂质体而被称作聚合物囊泡(polymeromes)。然而，对于本发明的目的，聚合物囊泡意味着被用于限定本发明和权利要求的术语脂质体所涵盖。
同样，由合成表面活性剂制成的并且不包含脂质的脂质体样囊泡被称作非离子表面活性剂囊泡(niosomes)。然而，对于本发明的目的，非离子表面活性剂囊泡意味着被用于限定本发明和权利要求的术语脂质体所涵盖。
在一个优选的实施方案中，用于本发明的脂质体包含10-100 mol%、更优选30-80mol%、更优选40-70 mol%、最优选50-60 mol%的生理上可接受的磷脂。
在一个优选的实施方案中，用于本发明的脂质体包含10-100 mol%、更优选25-75mol%、更优选40-70 mol%、最优选50-60 mol%的鞘脂、优选鞘磷脂。
在一个优选的实施方案中，用于本发明的脂质体包含30-100 mol%、更优选40-95mol%、最优选45-60 mol%的表面活性剂。
在一个优选的实施方案中，用于本发明的脂质体包含5-100 mol%、更优选30-100mol%、更优选60-100 mol%、最优选95-100 mol%的两亲聚合物和/或共聚物。
在优选的实施方案中，所述脂质体组合物中的甾醇的浓度在0和60 mol %、优选20mol %和50 mol %、更优选30 mol %至45 mol %之间变动，以使代谢物或药物的保留提高。
在一个进一步优选的实施方案中，所述脂质体组合物中的空间稳定剂、优选PEG化脂质的浓度在0和30 mol %、优选0.5 mol %和20 mol %、更优选1 mol %至5 mol %之间变动。
在另一个优选的实施方案中，所述脂质体的直径大小为大于600 nm、优选大于700nm、最优选大于800 nm，即，直径大小为600 nm至10 µm、优选700 nm至10 µm、更优选800 nm至5 µm，以避免从腹腔中的引流速度太快。
本发明的脂质体的脂质双层内的水溶液优选为等渗的，优选在低pH下具有高缓冲能力(例如柠檬酸盐、硫酸盐、乙酸盐、苯甲酸盐、甲酸盐、羟乙酸盐、苹果酸盐缓冲液)用于高保留碱性化合物和在高pH下具有高缓冲能力(例如乙酸钙、1,3-双(三羟基甲氨基)丙烷(bis-tris propane)、磺酸盐(CAPS、CABS、TABS、CHES)、N-二(羟乙基)甘氨酸、曲辛(tricin)、乙醇胺缓冲液)用于高保留酸性化合物。pH和缓冲化合物必须与目标毒素相适应。例如，硫酸铵(即，一种弱碱)将不适合于清除强碱氨(即，治疗高氨血症)，因为它会把氨引入身体内，氨是计划被清除的化合物。为了螯合弱酸，内部水溶液应该是碱性缓冲液(例如乙酸钙)。
优选地，本发明的脂质体组合物的特征是所述脂质体组合物内的pH为1-6.5、优选1.5-5、更优选1.5-4。
还优选的是用于本发明的脂质体组合物的特征是所述脂质体组合物内的pH为8.5-12、优选9-11、更优选9-10。
在一个最优选的实施方案中，用于本发明的脂质体组合物是其中所述脂质体双层包含以下成的脂质体组合物：
(i)50-60 mol %、优选约54 mol % DPPC，
(ii)40-50 mol%、优选45 mol%胆固醇(CHOL)，
和0.5-2 mol%、优选1 mol% 1,2-二硬脂酰基-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-2000] (DSPE-PEG)，
和所述脂质体内的水溶液包含缓冲在pH 1.5-3、优选pH 2的250 mM柠檬酸盐溶液，
和其中所述脂质体的直径为800 nm或更大、优选900 nm或更大、更优选1000 nm或更大。
以上脂质体组合物优选用于治疗高氨血症。适用于实施本发明的脂质体的更多实例是(以摩尔比计)：DMPC/CHOL，2:1; DPPC/CHOL，2:1; DSPC:CHOL，2:1；DSPC/CHOL/PEG2000-DSPE，2:1:0,2；DSPC/DSPG/CHOL，60:10:30；DSPC/DSPG/CHOL/PEG2000-DSPE，55.83:10:27.92:6.25，EPC/CHOL/DESP-PEG，50:45:5，鞘磷脂/DPPC/CHOL/DSPE-PEG，25:25:45:5，包含和内部缓冲液为柠檬酸盐110 mM pH 4，或200 mM pH 3，或250 mM pH 3，或250 mM pH 2，或300 mM pH 2。
术语外源性和内源性中毒病是指由身体产生的毒素即内源性毒素或由外部引到身体内的毒素即外源性毒素的受累情况。
优选地，本发明的脂质体组合物用于治疗选自代谢物、药物、农药、杀虫剂、毒素和化学战剂中毒病的外源性中毒病。优选的除草剂中毒来自植物生长素或莠去津(atrazine)，一种优选的农药中毒来自新烟碱类(neonicotinoid)。
在一个优选的实施方案中，本发明涉及治疗代谢物中毒病(metabolitetoxicopathy)。如本文所用的术语“代谢物中毒病”意味着是指导致病理病症的内源性化合物例如氨、精氨基琥珀酸、尿酸、异戊酸、丙酸的有毒浓度。该术语不包括基于外源性代谢物(例如药物代谢物)的病理。
优选的代谢物中毒病选自高氨血症、精氨基琥珀酸血症、高尿酸血症、异戊酸血症和丙酸血症。
在一个进一步优选的实施方案中，本发明涉及治疗药物中毒病，优选选自酸性药物和碱性药物的药物中毒病。
适用于根据本发明所述的腹膜内脂质体包封的药物优选地选自：
(1) 抗肿瘤药，优选选自米托蒽醌、表柔比星、柔红霉素、多柔比星、环丙沙星、长春新碱、长春瑞滨或长春碱；
(2) 局部麻醉药，优选选自普鲁卡因、利多卡因、布比卡因、氯丙嗪、咪达唑仑或地布卡因；
(3) 肾上腺素能拮抗药，优选普萘洛尔、去氧肾上腺素、阿普洛尔、阿替洛尔、克仑特罗、沙丁胺醇或噻吗洛尔；
(4) 抗心律失常药，优选奎尼丁；
(5) 胆碱能药，优选毛果芸香碱或毒扁豆碱；
(6) 抗抑郁药，优选丙米嗪、去甲替林、阿米替林、安非他酮、多塞平或文拉法辛；
(7) 抗组胺药，优选苯海拉明或氯苯那敏；
(8) 抗疟疾药，优选伯氨喹、奎宁、氯喹、阿莫地喹或乙胺嘧啶；
(9) 抗原虫药，优选奎纳克林；
(10) 镇痛药，优选可待因、对乙酰氨基酚、阿司匹林、芬太尼、美沙酮或哌替啶；
(11) 心血管药，优选地尔硫、维拉帕米或双嘧达莫；
(12) 抗惊厥药，优选丙戊酸或苯巴比妥；
(13) 抗精神病药，优选喹硫平、氯丙嗪或氟哌啶醇；
(14) 抗焦虑药，优选阿普唑仑或地西泮；
(15) 抗炎药，优选双氯芬酸或布洛芬；
(16) 勃起功能障碍药，优选西地那非或他达拉非；
(17) 抗结核药，优选乙胺丁醇、异烟肼或吡嗪酰胺；
(18) 神经递质类药，优选肾上腺素或去甲肾上腺素；
(19) 精神兴奋剂，优选苯丙胺、MDMA、哌甲酯、可卡因或海洛因。
涉及可用本发明的腹膜透析用脂质体组合物治疗的中毒的最优选药物是：
乙酰水杨酸、阿普唑仑、阿米替林、氨氯地平、苯丙胺、阿替洛尔、阿托品、布比卡因、安非他酮、卡托普利、氯喹、氯非尼拉敏、氯丙嗪、氯磺丙脲、克仑特罗、可卡因、可待因、地西泮、地尔硫、苯海拉明、双嘧达莫、丙吡胺、多塞平、乙胺丁醇、芬太尼、芬太尼、氟哌啶醇、海洛因、布洛芬、丙米嗪、异烟肼、酮洛芬、利多卡因、劳拉西泮、MDMA、二甲双胍、美沙酮、美沙酮、哌甲酯、硝苯地平、去甲替林、哌替啶、苯巴比妥、苯丙香豆醇、普鲁卡因酰胺、普萘洛尔、乙胺嘧啶、喹硫平、奎纳克林、奎尼丁、奎宁、罗哌卡因、西地那非、丙戊酸、文拉法辛、维拉帕米、华法林。
本发明的脂质体组合物优选地用于治疗患有内源性或外源性中毒病的人患者。还优选的是应用脂质体组合物治疗患有内源性或外源性中毒病的哺乳动物和鸟类，优选选自猪、牛、狗、猫、绵羊、山羊和马等的哺乳动物。
本发明的另一方面涉及包含至少一种本发明的脂质体组合物和任选的一种或多种药学上可接受的赋形剂的药物组合物。本发明的药物组合物典型地包含治疗有效量的根据本发明所述的脂质体组合物和任选的辅助物质(例如药学上可接受的赋形剂)。所述药物组合物采用制药领域中众所周知的方式来制备。载体或赋形剂可以是液体材料，该液体材料可以充当活性成分的溶媒或介质使用。合适的载体或赋形剂是本领域众所周知的并且包括例如稳定剂、助悬剂、渗透剂(例如葡萄糖溶液、明胶、木糖醇、山梨糖醇、甘露糖醇、葡萄糖聚合物(例如，艾考糊精(icodextrin))或氨基酸)、抗微生物防腐剂、抗氧化剂、pH-调节物质(例如乳酸钠和乳酸钾)、着色剂等。本发明的药物制剂必须适合于腹膜内给药并且可以以溶液剂、混悬剂等的形式给予患者、优选人。
本发明的另一方面涉及治疗方法，即治疗患有内源性或外源性中毒病的患者的方法，包括将根据本发明所述的脂质体组合物以治疗有效量给予有其需要的患者的腹腔内的步骤。
优选地，待治疗的外源性中毒病选自药物、农药、杀虫剂、毒素和化学战剂中毒病。还优选的是，待治疗的代谢物中毒病选自高氨血症、精氨基琥珀酸血症、高尿酸血症、异戊酸血症和丙酸血症。
优选地，根据本发明治疗的患者是人类。
在本发明的方法的一个替代实施方案中，患有内源性或外源性中毒病的患者选自哺乳动物和鸟类，优选选自猪、牛、狗、猫、绵羊、山羊和马等的哺乳动物。
在实施对患有如上所述的内源性或外源性中毒病的患者的治疗时，本发明的脂质体组合物可以以使所述脂质体或脂质体样囊泡(例如聚合物囊泡(polymeromes)或非离子表面活性剂囊泡(niosomes))在腹膜腔内以有效量生物可利用的任何形式或方式给予。优选地，腹膜内脂质体给药是通过推注(bolus injection)、输注和/或灌注。在腹膜内制剂的制备领域中，本领域的技术人员可以根据所要螯合和/或去除的毒素的具体特征容易地选择出正确的给药形式和方式。
在一个优选的实施方案中，本发明的方法还包括在给药步骤之后和/或同时，从腹腔中抽吸所述脂质体的步骤。
下面，本发明参考具体的实验实施方案和附图说明予以说明，但是它们都不会计划将本发明限制在超出所附权利要求书的范围之外。
附图说明
图1说明腹腔中的有毒物质(例如药物或氨，NH3)被跨膜pH-梯度脂质体螯合(弱碱的情况)。未电离的化合物从毛细血管扩散到腹腔，在腹腔中以离子化形式(NH4 +)被俘获在囊泡中。扩散继续直到脂质体内部缓冲能力全部丧失。
图2是说明脂质体在腹膜内给药后从腹腔排进血液中的曲线图。在脂质体膜中掺入不可交换的甾醇染料(Cholesteryl BODIPY® FL-C12, Invitrogen) (0.05 mol%) (在脂质薄膜生产过程中)。在脂质体的腹膜内给药之后，测量血浆等分样品中的染料荧光值(λex=470 nm, λem=520 nm)，并将其与校准曲线进行比较以获得脂质体的脂质浓度。在腹腔中，脂质体越大，保持时间越长(8 h)；然而在4 h后在重要的浓度下，在血液中发现了小的脂质体。平均值± SD (n = 3)。
图3是显示于37°C在50%胎牛血清中pH-梯度脂质体的体外氨摄取的曲线图。脂质体表现出对氨的快速和有效摄取。初始氨和脂质体浓度设定为1.7 mM和3.8 mM，潜在耐受最大捕获能力为0.45 µmol氨/µmol脂质。感兴趣的是，所述囊泡能螯合比该系统中荷载的氨的总量还要多(虚线)。过剩的来自血清中存在的天然氨。脂质体的直径为840 nm。平均值± SD (n = 6)。
图4是显示在脂质体不存在(实心三角)和存在(空心三角)时腹膜透析液中氨(NH3)的浓度的曲线图。在健康大鼠中，在t = 0时，腹膜内注射透析液。注射的脂质体剂量为180 mg/kg，透析液中的脂质浓度为15 mM。脂质体的直径为850 nm。
图5是显示在脂质体不存在(实心三角)和存在(空心三角)时腹膜透析液中维拉帕米(VP)的浓度。VP在t=0 h时通过经口管饲法给予(50 mg/kg,)，然后在t = 1 h时腹膜内注射透析液()。注射的脂质体剂量为180 mg/kg，透析液中的脂质浓度为15 mM。脂质体的直径为850 nm。
实施例
在以下实施例中，证明了说明性的脂质体组合物(实施例1)可以在腹膜内(intraperoneal)给药后在腹腔内保留一段延长的时间周期，这取决于脂质体的大小(实施例2)。这些脂质体表现出在50%胎牛血清中对氨的快速和有效摄取(实施例3)。此外，这些脂质体能够将腹腔内的氨(实施例4)和口服给予的药物维拉帕米(实施例5)捕获并浓缩，因此证明了这类脂质体经腹膜内给药在代谢物和药物的解毒中的实用性。
实施例1 - 脂质体组合物与制备
在以下体内实验中测试的制剂由DPPC加上45 mol%的CHOL和5 mol%的DSPE-PEG组成，脂质体内的水溶液是缓冲在pH 2的250 mM柠檬酸钠溶液。该制剂通过脂质薄膜水合/挤出方法制备(Hope M, Bally M, Webb G, Cullis PR. Production of large unilamellarvesicles by a rapid extrusion procedure. Characterization of sizedistribution, trapped volume and ability to maintain a membrane potential (用快速挤出法生产大单层囊泡。大小分布、包封体积和维持膜电位的能力的表征). BiochimBiophys Acta 1985, 55-65)。将脂质、CHOL，和最终的来自Invitrogen公司的CholesterylBODIPY® FL-C12染料(0.05 mol%)溶解于氯仿中，氯仿随后在连续氮气流和高真空下>12h而除去。脂质薄膜用柠檬酸盐缓冲液(250 mM, pH 2)水合。通过5 µm的2张叠在一起的膜，用挤压法获得了大囊泡。通过在生理盐水中透析>12 h (膜截留：1000 kDa)，建立了跨膜pH-梯度。
实施例2 - 在腹膜内给药后脂质体从腹腔排进血液中
Sprague-dawley大鼠(雄性，300 g)通过异氟烷吸入(2%)被轻微麻醉，通过无菌穿刺将20 mL 7.5%含有脂质体(直径250 nm或850 nm)并在其膜中带有不可交换的甾醇染料(Cholesteryl BODIPY® FL-C12, Invitrogen, 0.05 mol%)的艾考糊精(icodextrin)溶液慢慢地注入腹腔内。然后，在腹膜内(i.p.)注射后，在15 min、1、2、4、6、8、10、12、14、16 h时，通过尾静脉抽取250 uL的血液等分样品。通过离心(6000 g 10 min)从这些血液等分样品中分离出血浆，然后测量血浆中在λem=520 nm (λex=470 nm)下的染料荧光值。
实施例3 - pH-梯度脂质体在50%胎牛血清中的体外氨摄取
在37°C，氨(NH3)摄取动力学在50% FBS中在并排扩散小室(PermGear, Hellertown,PA)中进行监测。本实验中使用的脂质体的直径为850 nm并含有54 mol% DPPC、45 mol%的胆固醇和1 mol%的DSPE-PEG，以及缓冲在pH 2的内部柠檬酸盐溶液(250 mM)。用带有多个100 nm小孔的聚碳酸酯膜把供体区室(无脂质体)与接收区室(含有脂质体)分隔开。NH3与脂质的摩尔比设定为0.45，在两个小室中初始NH3浓度均为1.7 mM以达到平衡。在接收区室中囊泡的NH3摄取值与供体小室中的毒素浓度降低直接相关。在pH-梯度脂质体注入接收区室后3、30 min、1、2、4、8和24 h，从供体区室中取出100 µL的等分样品。NH3用比色测定法进行定量(Berthelot MPE, Violet d'aniline. Repert Chim Appl 1859, 1:284)。
实施例4 - 在不存在和存在脂质体时腹膜透析液中的氨的浓度
Sprague-Dawley大鼠(300 g)用异氟烷(2.5%, 0.6 L/min O2)轻微麻醉，在保温毯上保持，通过无菌腹部穿刺用22G 硅导管(Venflon; Becton Dickinson)将20 mL 7.5%含有(或不含有)脂质体(3 mg/mL)的艾考糊精溶液慢慢地灌进腹腔内。本实验中使用的脂质体的直径为850 nm并含有54 mol% DPPC、45 mol%的胆固醇和1 mol%的DSPE-PEG，以及缓冲在pH 2的内部柠檬酸盐溶液(250 mM)。在透析开始后0.5、1、1.5、2、3和4 h，采集腹膜透析液的等分样品。腹膜液样品中的氨含量用比色测定法进行测定(Berthelot MPE, Violet d'aniline. Repert Chim Appl 1859, 1:284)。
实施例5 - 在不存在和存在脂质体时腹膜透析液中的维拉帕米的浓度
将维拉帕米(50 mg/kg, p.o.)给予Sprague-Dawley大鼠(300 g)后1小时，动物用异氟烷(2.5%, 0.6 L/min O2)轻微麻醉，在保温毯上保持，通过无菌腹部穿刺用22G硅导管(Venflon; Becton Dickinson)将20 mL 7.5%含有(或不含有)脂质体(3 mg/mL)的艾考糊精溶液慢慢地灌进腹腔内。本实验中使用的脂质体的直径为850 nm并含有54 mol% DPPC、45 mol%的胆固醇和1 mol%的DSPE-PEG，以及缓冲在pH 2的内部柠檬酸盐溶液(250 mM)。在经口管饲法给予维拉帕米后2、4、6、8、10和12 h，采集腹膜透析液的等分样品。腹膜液中的药物含量通过HPLC进行测定，像在例如Forster等, Biomaterials 33, 3578-3585, 2012)中所描述的一样。
Claims (17)
1.脂质体组合物制备用于通过受试者的腹膜透析治疗内源性中毒病的药物的用途，其中所述脂质体内的pH与腹膜腔内的pH不同且导致产生脂质体包囊的带电荷的内源性毒素，其中所述内源性中毒病是高氨血症、精氨基琥珀酸血症、高尿酸血症、异戊酸血症和丙酸血症，其中所述脂质体是单层的或多层的，并且包含：
(i) 1-100 mol%生理上可接受的磷脂、鞘脂或二者，
(ii) 0-60 mol%毒素保留-增强化合物，
(iii) 0-30 mol%空间稳定剂；
且其中所述脂质体的直径大于700 nm。
2.根据权利要求1所述的用途，其中所述脂质体的直径为700 nm至10 µm。
3.根据权利要求1或2所述的用途，其中所述生理上可接受的磷脂是DLPC、DMPC、DPPC、DSPC、DOPC、DMPE、DPPE、DSPE、DOPE、MPPC、PMPC、SPPC、PSPC、DMPG、DPPG、DSPG、DOPG、DMPA、DPPA、DPPS、EPC、SPC或其任意组合。
4.根据权利要求3所述的用途，其中所述生理上可接受的磷脂为DPPC。
5.根据权利要求1-4中任一项所述的用途，其中所述毒素保留-增强化合物为甾醇衍生物。
6.根据权利要求5所述的用途，其中所述甾醇衍生物为胆固醇(CHOL)。
7.根据权利要求1-6中任一项所述的用途，其中所述空间稳定剂为PEG化化合物。
8.根据权利要求7所述的用途，其中所述PEG化化合物为PEG化脂质。
9.根据权利要求8所述的用途，其中所述PEG化脂质为DSPE-PEG。
10.根据权利要求1-9中任一项所述的用途，其中所述脂质体包含 0.5-20 mol%空间稳定剂。
11.根据权利要求10所述的用途，其中所述脂质体包含 0.5-2 mol%DSPE-PEG。
12.根据权利要求1-11中任一项所述的用途，其中所述脂质体内的pH为8.5-12。
13.根据权利要求1-11中任一项所述的用途，其中所述脂质体内的pH为(i)1.5-4；或(ii)1.5-3。
14.根据权利要求13所述的用途，其中所述脂质体包含柠檬酸盐缓冲液。
15.根据权利要求14所述的用途，其中所述柠檬酸盐缓冲液的浓度在110 mM、200 mM、250 mM或300 mM。
16.根据权利要求13-15中任一项所述的用途，其中所述内源性中毒病是高氨血症。
17.根据权利要求1-16中任一项所述的用途，其中所述受试者是人受试者。
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| EP2695606A1 (en) * | 2012-08-09 | 2014-02-12 | ETH Zürich | Liposome composition for peritoneal dialysis |
| US20170246175A1 (en) * | 2014-09-24 | 2017-08-31 | Nanyang Technological University | Sustained timolol maleate delivery from liposomes for glaucoma therapy and occular hypertension |
| CN107735170A (zh) * | 2015-04-02 | 2018-02-23 | 南洋理工大学 | 聚合物‑脂质共混物形成的管状和囊泡结构及其形成方法 |
| AU2016256979B2 (en) | 2015-05-04 | 2021-01-28 | Versantis AG | Method for preparing transmembrane pH-gradient vesicles |
| EP3120842A1 (en) * | 2015-07-20 | 2017-01-25 | Opterion Health AG | Peritoneal therapeutic fluid |
| WO2017187426A1 (en) * | 2016-04-29 | 2017-11-02 | Aptamir Therapeutics, Inc. | Inhibition of mir-22 mirna by apt-110 |
| CN106220562B (zh) * | 2016-07-29 | 2019-10-01 | 上海璃道医药科技有限公司 | 两种喹啉环类药物的新用途 |
| JP7178090B2 (ja) * | 2016-08-16 | 2022-11-25 | イーティーエイチ チューリッヒ | 膜貫通ｐＨ勾配ポリマーソーム並びにアンモニア及びそのメチル化類似体の除去におけるそのポリマーソームの使用 |
| AU2018333099B2 (en) | 2017-09-12 | 2023-11-23 | Eth Zurich | Transmembrane pH-gradient polymersomes for the quantification of ammonia in body fluids |
| KR20190085734A (ko) | 2018-01-11 | 2019-07-19 | 이광영 | 말뚝의 결합장치 |
| US20210015844A1 (en) * | 2018-03-14 | 2021-01-21 | Beacon Medcare (Hk) Limited | Composition for purification of biofluids |
| CN111939126A (zh) * | 2019-05-15 | 2020-11-17 | 上海交通大学医学院附属第九人民医院 | 一种阳离子脂质体、包含所述脂质体的分散液及它们的制备方法和用途 |
| CN109966277B (zh) * | 2019-05-23 | 2021-04-30 | 济宁医学院附属医院 | 一种治疗难治性癫痫的药物组合物及其应用 |
| CN112294763A (zh) * | 2019-07-30 | 2021-02-02 | 上海交通大学医学院附属第九人民医院 | 一种腹膜透析用脂质体分散液及其制备方法和用途 |
| KR20210128169A (ko) | 2020-04-16 | 2021-10-26 | 이광영 | 파일 결합 장치 |
| MX2023005797A (es) | 2020-11-17 | 2023-05-29 | Genfit | Metodos de tratamiento de la insuficiencia hepatica. |
| CN112933045B (zh) * | 2021-04-09 | 2022-04-12 | 贵州医科大学 | 共载双氢青蒿素/磷酸氯喹双敏感纳米制剂及其制备方法 |
| WO2024105101A1 (en) | 2022-11-16 | 2024-05-23 | Genfit | Use of transmembrane ph gradient liposomes for treating hyperammonemic crisis associated with inborn errors of metabolism |
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- 2013-08-06 ES ES13745798T patent/ES2922278T3/es active Active
- 2013-08-06 WO PCT/EP2013/002352 patent/WO2014023421A1/en active Application Filing
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- 2013-08-06 BR BR112015002584-6A patent/BR112015002584B1/pt active IP Right Grant
- 2013-08-06 PT PT137457982T patent/PT2882421T/pt unknown
- 2013-08-06 EP EP22172208.5A patent/EP4062905A1/en active Pending
- 2013-08-06 CN CN201380042294.8A patent/CN104519873A/zh active Pending
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