CN108026131B - 聚合物-环糊精-脂质的缀合物 - Google Patents
聚合物-环糊精-脂质的缀合物 Download PDFInfo
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- CN108026131B CN108026131B CN201680036637.3A CN201680036637A CN108026131B CN 108026131 B CN108026131 B CN 108026131B CN 201680036637 A CN201680036637 A CN 201680036637A CN 108026131 B CN108026131 B CN 108026131B
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- cyclodextrin
- acid
- lipid
- backbone
- polymer
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Abstract
本发明包括一类化合物及其制备方法和使用方法。公开了一组具有中心主链骨架和三个或四个附加官能团的聚合物‑环糊精‑脂质缀合物,其中亲水组分之一是环糊精。该化合物具有中心主链及其三个或四个附加官能团组成:其中含有一种或两种亲脂性化合物包括甾醇或“脂溶性”维生素或脂肪酸,以及一种或两种亲水性聚合物和一种环糊精。可以在配制药物,化妆品,营养品等中的具体应用中选择特定的官能团。该缀合物的典型偶联反应可以包括一种或多种或组合或串联烷基化,包括N‑烷基化或O‑烷基化,醚化,酯化和酰胺化学过程。还可以选择中心骨架和官能团之间的各种链来修饰耦合反应的载体或中心骨架,并优化缀合物的性能。
Description
优先权的要求
本申请要求对由吴念于2015年6月23号提交的申请号为:62/183,400、名称为“Polymer-Cyclodextrin-Lipid Conjugates”(聚合物、环糊精和脂质的缀合物)的美国临时专利申请和2016年6月16号由吴念提交的申请号为:15/184,014、名称为:“Polymer-Cyclodextrin-LipidConjugates”(聚合物、环糊精和脂质的缀合物)的美国专利申请享有优先权。
发明领域
本发明涉及聚合物-环糊精-脂质缀合物,详细而具体的公开了合成聚乙二醇-环糊精脂质-缀合物,其中采用脂肪酸、甾醇或被称为“脂溶性”维生素(脂类维生素)作为亲脂性载体,如果用于静脉药物给药。优选具有基本单分散的PEG链。更具体地说,本发明涉及一类聚合物-碳水化合物缀合物含有与脂肪酸、甾醇或甾醇类或亲脂性维生素结构成分,尤其是,本发明涉及使用环状的聚糖取代我们以前的发明中的线性碳水化合物的糖基部分而产生的新型聚合物-环糊精-脂质缀合物。这种组合将所含脂质的亲脂性和环糊精的内含包裹作用同时形成一个增溶的核心。它能最大化地提供非水溶性药物或亲脂性物质的水溶性并减少药物毒性的作用,同时也可以用于化妆品,食品和其他用途。
发明的背景
在过去的三十年中,一些有临床使用价值的药物载体在给药***方面的研究,包括脂质体、聚合物纳米颗粒、聚合物胶束、陶瓷纳米粉体颗粒、粒树突状聚合物纳米结构的多聚体[Cherian et al.Drug.Dev.Ind.Pharm,26:(2000)459━463;Lian andHo.J.Pharm.Sci,90(2001)667-680;Adams et al.Pharm.Sci,92(2003)1343-1355;Na etal.Eur.J.Med.Chem,41(2006)670-674;Kaur et al.J.Control.Rel,127(2008),97-109]。全身给药可通过静脉注射或非静脉注射,因此对人体为非创伤性的、可根据需要反复给药。然而,为了在目标部位达到所需的治疗浓度,大剂量的全身给药,则需要使用相对较高含量的辅料。这可能会引起副作用,比如过敏反应["Cremophor-based paclitaxel‘chemo’drugtriggers fatal allergic reactions,”The Medical News.9June 2009]。
在安全和生物相容性的药物传递***的设计中,几个重要因素可以考虑,包括载体的高溶解性,保持力(retainning power)以及允许与潜在的靶向组织部位相互作用或细胞膜渗透的适当的表面特征。
环糊精(CDs)环状单聚糖(化学结构1),作为美国FDA(食品和药物管理局)批准临床使用的药用辅料已经被研究了几十年,是广泛使用在数十种上市医药产品中的主要辅料之一。他们仍然是增加药物水溶性的重要手段。与高分子聚合物辅料不同,环糊精具有生物活性的、它能通过与多种疏水剂形成水溶性络合物而达到增溶的能力。
化学结构1:本发明中使用的单聚糖化学结构包括6(α),7(β)和8(γ)元环的环糊精
脂类是一类天然产物分子,包括脂肪酸、甾醇、脂溶性维生素(维生素A,D和E)、单甘酯、双甘酯、甘油三酯、磷脂和其他脂类。脂的主要生物功能包括储存能量,生物信号传递,以及作为细胞膜结构的组份[Fahy E,Subramaniam S,Brown HA,et al.(2005)."Acomprehensive classification system for lipids".J.Lipid Res.46(5):839–61]。脂质分类方法是综合化学和脂质中不同的疏水和亲水组分构成而定。固醇和相关化合物在真核生物的胜利发挥重要作用的是类固醇的子群。甾醇及相关化合物在真核生物的生理发挥重要作用的类固醇的子群。它们在植物、动物和真菌自然成在,最熟悉的一类动物甾醇是胆固醇。胆固醇对动物细胞膜的结构和功能非常重要包括在动物细胞膜形成的组份同时会影响到细胞膜的流动性并作为的细胞发育信号的第二信使[Alberts B,Johnson A,Lewis J,Raff M,Roberts K,and Walter P(2002).Molecular biology of the cell.4thEdition,New York:Garland Science.p.1874]。
本发明的缀合物组成的三个载体之一的脂质,其包括但不限于脂肪酸、甾醇类,特别是包括但不限于胆固醇、豆甾醇、麦角甾醇、藿烷类化合物(hopanoids)、植物甾醇、谷甾醇、菜油甾醇、菜籽甾醇、燕麦甾醇(avenastero)、碘甲氧胆固醇(adosterol)和甾醇(饱和类固醇醇或氢化甾醇)。甾醇作为具有高度生物兼容性的重要的药物传递工具,例如胆固醇约占天然细胞膜脂质的总和的10-50%,含有甾醇或脂溶性维生素缀合物可能会增加细胞靶向传递的药物渗透地作用。
人体有保持稳定平衡状态的自然趋势,并且可以从现有食物中,有选择性地摄取维生素,矿物质,必需的氨基酸和必需的脂肪酸包括多不饱和脂肪酸其在预防人类心血管疾病有显著的作用。维生素E包括所有生育酚和生育三烯酚,其中α-生育酚是天然的和最具有生物活性形式的总称。维生素E的抗氧化功能被认为是用于预防组织的氧化的关键。既然这些分子是人体必需的,它们作为更安全的成分可用来设计的一种理想的聚合物-环糊精-脂质的缀合物的安全组份。
本发明的缀合物的含有包括甾醇或的脂溶性维生素组成三个载体。其中一个载体是含有从六到八个葡萄糖单体的环糊精。第三载体为水溶性高分子聚合物如聚乙二醇。三个载体通过共链接到中心骨架其含有至少三个可供键合的位置或基团。该共轭反应可通过一个或多个类型的反应或系列反应包括N-烷基化反应或O-烷基化、醚化、酯化、酰胺化的烷基化反应。
有机化合物的溶解性通常可以阐述为“相似相溶”。这意味着多数含有极性基团的化合物(或非极性分子)更易溶于极性溶剂,而含有非极性基团的化合物(或非极性分子)将更易溶于非极性溶剂[R.Casiday and R.Frey,“Maintaining the Body's Chemistry:Dialysis in the Kidneys,”http://www.chemistry.wustl.edu/~edudev/LabTutorials/Dialysis/Kidneys.html,Department of Chemistry,WashingtonUniversity,St.Louis,MO,accessed on December 3,2013]。
根据其分子的结构,维生素可分为水溶性或脂溶性二类:溶于非极性溶剂的脂溶性维生素和溶于极性溶剂如水的水溶性维生素。水溶性维生素一般含有多个极性基团,与此相反脂溶性维生素则主要为非极性结构,因此仅溶于非极性溶剂,如其可溶身体中的脂肪(非极性)组织内。
溶解性是一个复杂的现象,取决于自由能(ΔG)的量变过程。对于一个可以自发溶解地过程,如维生素溶解在溶剂中,自由能的变化可为负值(即ΔG<0)[M.Traverso,“Vitamin Solubility,”http://www.chemistry.wustl.edu/~edudev/LabTutorials/Course Tutorials/Tutorials/Vitamins/molecularbasis.htm,Washington University,St.Louis,MO,accessed on December 3,2013)]。
具有狭窄的分子量分布范围的高分子聚合物在生物医学中药物传递的应用中相当重要,尤其是用于静脉注射剂方面。例如,聚乙二醇-8辛酸/癸甘油酯(PEG-8CCG)为一个含有平均相对分子质量200到400之间的聚乙二醇双酯和单酯的混合物。由于观察到动物过敏反应的原因,PEG-8CCG在用于许多水不溶性药物时受到限制,因此在临床药物配方上可应用范围是有限地。
本发明的简短摘要
本发明包括的化合物是由一个中枢骨架与三或四个附加的官能团组成的聚合物-脂质共轭化合物,如图1所示:先由一或两个脂溶性维生素或类似甾醇的脂溶性化合物以及一或两个亲水聚合物通过中枢骨架接合成为聚合物脂质共轭化合物,然后再进一步连接到环糊精上。可链接到环糊精上的聚合物-脂质共轭化合物数目要取决于可供键合的伯醇数目。如化学结构2所示,具有最高的反应活性羟基基团主要为C-6(由开放箭头表示),尤其是在使用较大体积的基团进行地替代反应时。如C-2、C-3上的伯醇(由实线箭头表示)的反应活性较低。这要由于在相邻的吡喃葡萄糖单糖之间,C-3上的羟基质子和C-2羟基上的氧原子的形成氢键的相互作用[F.M.Menger and M.A.Dulany(1985).Tetrahedron Lett.26:267]。所以,一个吡喃葡萄糖单糖的C-2羟基可以与相邻的吡喃葡萄糖单糖的C-3羟基形成氢键[B.Gillet,D.J.Nicole and J.J.Delpuech,Tetrahedron Lett.,1982,23,65]和α-环糊精、β-环糊精和γ-环糊精二羟基氢-氘交换表明,最强的氢键***形成β-环糊精[B.Casu,G.G.Gallo,M.Reggiani and A.Vigevani,J.Chem.Soc.Spec.publ.,1968,23,217]。而由这些氢键在β-环糊精形成了完整的二级氢环辅助带,α-环糊精的刚性结构从而使其吡喃葡萄糖单糖是处在一个扭曲的位置,只有四个可以形成而不是六个可能氢键,因此无法形成一个完整的氢键环[D.A.Rees,J.Chem.Soc.(B),1970,877;B.P.Schonberger,A.C.A.Jansen and L.H.M.Janssen,in‘Proceedings of the 4th InternationalSymposium on Cyclodextrins,Munich,1988’,eds.O.Huber and J.Szejtli,Kluwer,Dordrecht,1988,p.61]。在化学结构2中,(a)和(b)象征着具有相同的环糊精的基本结构和“n”表示吡喃葡萄糖单位数目其在(a)中表示为一截断的圆线。为了简化图示,在本发明申请中仅使用(b)作为环糊精分子结构的完整表达。
化学结构2:环糊精中可能活泼的羟基点(n=6到8)
]在本发明的特点之一正如一般性结构1所显示,环糊精具的有多个可供聚合物脂质所取代的位置,最常用方法为环糊精中碳6位置的通过如甲苯磺酰等适合的亲核的取代反应,单取代的6-磺酰基环糊精环糊精衍生物的合成是通过p-甲苯磺酰氯与环糊精在吡啶或碱性的二甲基甲酰胺等摩尔当量反应[R.C.Petter,J.S.Salek,C.T.Sikorsky,G.Kumaravel and F.T.Lin,J.Am.Chem.Soc.,1990,112,3860;X.M.Gao,L.H.Tong,Y.Inoue,and A.Tai,Synth.Commun.,1995,25,703;K.A.Martin and A.W.Czarnik,Tetrahedron Lett.,1994,35,6781]。单取代的6-甲苯磺基环糊精和单取代的甲磺基环糊精是用于各种修饰环糊精的重要前体。亲核取代通过甲苯磺酰基或甲磺酰基与合适的亲核化合物,如碘化物、叠氮化物、硫代乙酸酯、烷基、羟胺或烷基多胺反应而产生单元的碘、叠氮、硫基、羟氨基-或二烷氨基环糊精[L.E.Fikes,D.T.Winn,R.W.Sweger,M.P.Johnson andA.W.Crarnik,J.Am.Chem.Soc.,1992,114,1493;A.Ueno,F.Moriwaki T.Osa,F.Hamada andK.Murai,Tetrahedron,1987,43,1571;K.Tsujihara,H.Kurita and M.Kawazu(1977).Bull.Chem.Soc.Jpn.,50,1567;D.W.Griffiths and M.L.Bender,Adv.Catal.,1973,54,625;B.Siegel(1979).J.Inorg.Nucl.Chem.41,609]。进一步纯化可以采用在混合的甲醇和水中重结晶方法[M.Popr(2014).Beilstein J.Org.Chem.,10,1390-1396]。
一般结构1
其中“n”是环糊精中吡喃葡萄糖环的从6到8的数目,“i”是每个吡喃葡萄糖上PEG-脂质基的取代数(摩尔比)的平均值,它可以从0.5到3。特定的聚合物或含亲脂基团可能被选择以用于特定的药物制剂,化妆品,营养品或相关方面的应用。聚合物的中心骨架和功能团之间的也会选择不同的链以优化作用。聚合物的偶联反应可以是一个、不同或一系列的烷基化、酯化、醚化和酰胺化化学过程。
附图说明
图1显示本发明中聚合物-环糊精-脂质缀合物的一个例子:PEG-β-环糊精-胆甾烯基-丙二胺。缀合物每个部分的长度是使用软件Ultra 10估算的。(CambridgeSoft,Waltham,MS,USA)
图2是结果对比图。其中(a)显示1%丙泊酚的溶解度比较:(1)溶于3.5%的胆固醇-乳糖酸-mPEG12:(2)溶于35%的2-羟丙基-β-CD;(3)溶于混合的2%胆固醇-乳糖酸-mPEG12和15%2-羟丙基-β-CD以及(4)溶于2%mPEG12-β-环糊精-胆固醇;(b)显示了相同的样品溶液在5天后的结果。
详细说明
为明确保障权益起见,本发明的实施方案仅就在与各种聚合物-环糊精-脂质缀合物相关的化合物以及用于药物传递的运用范围内进行描述。本发明的公开发表,并不是对所有的实施例常规特征都进行了描述。在这样的实际实施的发展中,众多特定的实施细节必须被确定以便实现开发者的特定目标,且这些特定目标将改变。本领域的普通技术人员将认识到本发明的以下详述部分仅是说明性的且没有以任何方式进行限制。其它实施方案对从该项公开中受益的技术人员来说不言自明。本发明实施的详细阐述将仅作为参考。
为清楚起见,并不是所有常规操作特征会在此介绍。可以理解在这种实际执行工作的发展中,有些特定的详细操作信息,可能需要进行许多实现特定的细节以便实现开发者的具体目标,并且这些具体目标可能不同。
已公开发表的美国专利20150157721和20120202890,在此引用并作为参考文献,这些已发表地文献演示了通如何采用某些高分子碳水化合物脂类(PCL)缀合物用于水溶性差的化合物的水溶性制剂。该专利中描述了如何制备高分子碳水化合物脂质缀合物及其应用;通过简单地添加缀合物而制成的水溶液以及它证明PCLs可以增溶疏水性药物的水溶性而无需通过形成脂质体或微乳化的制剂过程。
为区别与已在美国发表的在US20150157721和US20120202890,虽然本发明的缀合物仍具以下的基本结构,由一个中心骨架和三或四个链接的功能基团:一个或两个脂溶性维生素或甾醇或脂肪酸,一种或两种亲水性聚合物以及环糊精。而环糊精作为环聚糖其化学和物理特征明显有别于以前的发明中使用的线性寡糖。非水溶剂可能与环糊精内腔部分形成包合物达到增溶的效果,它们也能通过中心骨架与PEG-脂质部分形成微乳或被包裹而被溶解。同时具备本发明中具有的两项功能(脂溶性和包裹性)的缀合物能达到更好的溶解疏水性药物的效果。PEG-环糊精-脂质缀合物结合了环糊精的包裹功能和PEG脂质脂溶性的增溶性功能从而可以实现对很多疏水性药物的制剂和配方进行改进。通用结构(1)中显示了这一类化合物的基本结构框架,“B”表示为中心骨干,“Polymer”或“PEG”为聚合物,“Lipid”为脂类化合物包括脂溶性维生素或甾醇或脂肪酸。在水溶液中,新的缀合物用作疏水性溶剂的溶解度增强剂,能形成真实溶液或与活性药物形成非常稳定的乳化悬浮液。当环糊精具有6或7或8个成员环时,环状寡糖的取代度可以为0.53。
另外一个区别或不同与我们以前的发表在美国专利发明申请US20150157721和US20120202890的内容是,本发明的缀合物包含有的环糊精[Brigandi,RA.,et al(2014).Clinical Pharm in Drug Dev.4(2),130-136]可能会减少脂肪酸本身诱导地溶血性作用。相应地,可能还显著减少脂肪酸类潜在的溶血活性[Mimura,T."Fatty acids andsterols of the tunicate,Salpa thompsoni,from the Antarctic Ocean:chemicalcomposition and hemolytic activity".Chemical&pharmaceutical bulletin,34(1986)4562]。与甾醇不同的是,水溶性类固醇酸(胆汁酸类)更有可能诱导溶血性贫血[[Ilani,A."The pH dependence of the hemolytic potency of bile salts".Biochimica etbiophysica acta,1027(1990)199]。鉴于这个特殊的原因,非水溶性甾醇是最佳的亲脂性载体并作为缀合物的主要成分。若同时选用两个亲脂性的载体,其一个可用胆固醇或非溶血性的甾醇或“脂溶性”维生素。
在另一个方面的本发明,本发明含有的环糊精显著减少脂肪酸潜在的溶血活性。与市场上的聚乙二醇脂类相比,包括聚乙二醇山梨糖、聚氧乙烯蓖麻油(蓖麻)甘油中辛酸/癸酸的单/二甘醇二酯聚乙二醇甘油酯PEG-6甘油单油酸酯或PEG-6甘油基亚油酸酯聚乙二醇-8甘油辛酸/癸酸酯虽然这些基于脂肪酸的脂质聚合物可能增加疏水性溶剂的水溶性,但在更高的脂质-药物比例下诱导溶血[G.D.Noudeh,P.Khazaeli and P.Rahmani.“Study of the Effects of PolyethyleneGlycol Sorbitan Esters Surfactants Group on Biological Membranes.”International Journal of Pharmacology,4(2008)27-33;A.O.Nornooa,D.W.Osborneb,D.S.L.Chow(2008).“Cremophor-free intravenous microemulsions for paclitaxel:I:Formulation,cytotoxicity and hemolysis.”International Journal ofPharmaceutics.349,108–116]。
本发明与US20150157721和US20120202890中公开的我们先前发明的进一步区别在于,本发明包含大量的环状寡糖环,它是共轭结构中的刚性组分,不具有与线性寡糖共轭物具有相同的移动自由度。这在缀合物中产生两个不同的空间,如果环糊精的相邻聚合物-脂质替代物即PEG-胆固醇,则两个“空间”都是刚性的。如果聚合物-脂质是PEG-油酸酯,那么第二空间比环糊精有更高的自由度。如图1所示,环糊精的大小约为PEG-脂质取代基的三分之一(1/3),这样溶质在两个空间之间“穿行”更容易。在单个缀合物中具有两相/空间结构对溶解作用是特别有用的。可能存在两个递增的过程:基于环糊精的“主客”内包含机制和基于胶束溶解的PEG-脂质的微胶囊化机制。虽然两个过程在物理上是不同的,但这种独特的组合将导致比单独的过程有更高的溶解度,因为环糊精的容量使得它作为“主体”分子的络合效率(CE)是非常有限;理想情况下,药物在环糊精存在下的溶解度可以通过1:1包合物来实现。很重要的一点需要认识的是环糊精的水溶性增强是有限的,通常需要更高的浓度或摩尔比的环糊精来溶解疏水化合物(表1)。聚合物-脂质与环糊精的缀合能够补偿或提供额外的“主体”分子的溶解力。
表1.销售的药品的溶解度
1对数的分配系数=油性或疏水性的测量
2http://www.rxlist.com
3http://aac.asm.org/content/early/2014/04/08/AAC.02686-13.full.pdf
4http://www.jurox.com
5http://www.sigmaaldrich.com/life-science/cell-culture/learning-center/cyclodextrin.html
不同于其他已知线性环糊精衍生物或共聚物[Y.Ping,et al(2011)Biomaterials.32(32):8328–8341;ME.Davis et al.US 7091192],在本发明中的聚合物-环糊精-脂质缀合物公开了一种新颖的含有两个非极性中心或核心的分子。这些很大程度上增加了聚合物-环糊精-脂质缀合物与亲脂性的溶质之间的非极性相互作用,因而亲脂性溶质的水溶性显著增强。对于那些环糊精衍生物如磺烷基环糊精或羟丙基环糊精和环糊精共聚物,增加成分或聚合物大小可能只会增加其本身的水溶性,而不具有与溶质间的非极性相互作用。虽然共聚合物可能改变环糊精包含效率,但其“主-客”增溶过程仍然不变。而在本发明中聚合物-环糊精-脂质缀合物不仅有“主-客体”增溶过程,还有一个不同的微胶囊化溶解过程。
在一个方面,本发明大大改善了环糊精的增溶效果。在水溶液中环糊精与许多药物形成配合物,在这个过程中位于环糊精中心内腔的水分子要么被整个药物分子要么更可能的是药物的亲脂性部分取代。药物-环糊精配合物的形成是药物与环糊精之间的一种动态均衡[R.Arun,et al(2008).Scientia Pharmaceutica.76(4),567-598;M.E.Brewsterand T.Loftsson(2007).Advanced Drug Delivery Review.59(7):645-666;M.Jug andM.B.(2008).Rad.Medical Sciences,32(499),9-26]。环糊精的包含效率在很大程度上受溶质分子形状和疏水性的影响(如表1所示)。疏水性可由的油/水相分配系数(LogP)估算,LogP可通过计算软件Marvin Sketch(ChemAxon Kft,Budapest,Hungary)计算。正值表明更溶于油而负值表明更溶于水。环糊精-药物络合物的稳定是建立在暂时性物理性包裹上。这也许可以解释为什么在环糊精溶解药物的过程中需要高浓度(或摩尔比)的环糊精,简单的1/1或2/1(环糊精/药物比例)不足以保持溶质在水溶液中。因此PEG-脂质的取代(通过中心骨架)提供一个更具亲脂性的核心和将药物胶囊化包裹而提高环糊精-药物的稳定性,从而使药物在室温下完全溶于水。
在本发明的一个方面,环糊精与PEG-脂质相联的位置可能并不关键。在合成聚合物-环糊精-脂质缀合物的过程中可能会产生位置异构体,而这些异构体可能功能相当。异构体的选择可能会在传递药物过程中有些应用,比如细胞内转运各种亲脂性分子,以及运输药物的载体。例如,不同的异构体在溶解和储存药物时稳定化合物的能力可能是不同的。
虽然环糊精(CD)可以提高药物生物利用度。但如表1所示,对于LogP值大的溶质,高浓度的环糊精是必需的。与聚合物-环糊精-脂质缀合物相比,即使环糊精有很大的负LogP值(表2),它们在水中的溶解度的增强是微弱的,这可能主要是由于其缺乏脂溶性。被环糊精内包含后,药物的理化和生物属性可能会改变,从而影响其治疗功能。当需要高浓度的环糊精来改善药物在水中的溶解度,药物的代谢和药代动力学也可能会改变。在动物模型中非肠道给药,发现了α-环糊精和β-环糊精的肾毒性[Frank DW,et al(1976).Cyclodextrin nephrosis in the rat.Am J Pathol 83:367–82],还有报道改进后的环糊精也存在一些问题[Irie T,et al(1997).J Pharm Sci.86:147–62;Thompson DO(1997).Crit Rev Ther Drug Carrier Syst.14:1–104;Gould S,et al(2005).Food ChemToxicol.43:1451–9]。此外,高浓度的环糊精会延长它的消除时间从而造成严重肾损伤。
在本发明的一个方面,聚合物-脂质中纳入环糊精显著增加疏水相互作用。亲脂性分子包含在缀合物的疏水中心空腔中胶囊化而得到改进,因而其水溶性增强。不同于先前描述的线性脂质-糖缀合物,发明提供了与亲脂性溶质具有更强的疏水相互作用的双功能增强作用。由于其微弱的亲水性(表2),单独的环糊精可能无法达到同样的疏水相互作用。或者单独聚乙二醇-直链糖-脂质也不能达到,因为两个溶解进程可能互相补偿。环糊精与聚合物-脂质的结合能支持非内含药物的溶解比如溶胶效应和分子聚集等。
在本发明的一个方面是包括环糊精分子与聚合物-脂质,非极性的溶质在环糊精的非极性内腔和脂质之间形成平衡,而不是环糊精的非极性内腔或疏水性的聚乙二醇-脂类与水相之间形成平衡。后者可能会产生沉淀。
在水溶液的环境中,聚合物-脂质缀合物内部或环糊精的内腔很大程度上是非极性的。而决定烃类溶解时的原则是“相似相溶”除了笼式包裹,环糊精或聚合物-脂质与亲脂性溶质间的非内含相互作用聚集在一起形成“相似相溶”。在聚合物-脂质或环糊精的外层大部分是极性基团,能够与极性水分子相互作用,从而纳入亲脂性的溶质与整个聚合物-环糊精-脂质缀合物是可溶于水的。
本发明新颖的聚合物-环糊精-脂质缀合物在内部有两个非极性点,而在外层有很多羟基和能增强溶解度的聚合物链。他们可能有助于形成稳定的溶液、乳液、或水与亲油性化合物的混合液。这些缀合物提供扩展的非极性中心,通过最大化保留力和减少在液-液界面的界面能量来稳定水中的疏水性分子。
疏水作用定义为疏水性溶质打破了液态水分子之间的高度动态的氢键而产生的熵效应[T.P.Silverstein,"The Real Reason Why Oil and Water Don't Mix".Journalof Chemical Education.75(1998)116–346]。水分子与疏水性溶质是不发生反应的,当疏水性溶质混合在水介质中时,水分子之间的氢键将断开为疏水性溶质腾出空间。这种疏水效应可以通过测量非极性分子在非极性溶剂与水分配系数而量化。分配系数可能换算成包括焓(δH)和熵(δ)的自由能源(δG)的转换。由于非极性溶质周围溶剂层中的水分子流动性减少,在室温下疏水效应已被认定为熵驱动。***的热焓的变化(δH)可能为零、负值或正值,因为新的氢键的形成可能部份地、完全地、或过度补偿由疏水性溶质的加入打破的氢键。热焓的变化在确定混合疏水性的分子和水时可能并不重要,因为熵(δ)的变化是非常大。根据吉布斯自由能方程,δG=δH-TδS,较小的未知值的焓δH和较大负值的熵δS,δG的值是正值。正值的δG表明,疏水性物质与水分子的混合不是自发的结果从而造成分层或沉淀。
在本发明的另一个方面,亲水-亲脂性的相互作用在聚合物-环糊精-脂质缀合物是均衡的[Griffin WC."Calculation of HLB Values of Non-Ionic Surfactants,"Journal of the Society of Cosmetic Chemists.5(1954)259]。例如,由于本缀合物中大的极性部分能自发地形成半透明微乳液(表2),亲水亲油平衡值仍然大于15。不同于由表面活性剂或脂质聚合物、共同表面活性剂及共同溶剂的混合物形成的微乳液,这些混合物中表面活性剂或脂质-聚合物浓度要高出数倍,大大超过分散相的浓度,或者需要专门的设备来机械地产生半透明微乳液。如表2所示,在本发明中聚合物-环糊精-脂质缀合物优化了logP值,仅仅聚合物-环糊精-脂质缀合物本身就能够自发形成透明溶液或纳米级乳液,而不需要其他共同溶剂和额外输入能量[Mason TG,Wilking JN,Meleson K,Chang CB,Graves SM."Nanoemulsions:formation,structure,and physical properties",Journalof Physics:Condensed Matter,18(2006)R635-R666]。
表2
在本发明的一个方面,可以用较小的聚合物-环糊精-脂质缀合物形成稳定的水溶液。这是优于传统的环糊精、环糊精衍生物、表面活性剂、其他脂质-聚合物。因为环糊精、表面活性剂或其他脂质-聚合物会引起许多不需要的副作用。高浓度的环糊精或环糊精衍生物在许多应用中是不利的或禁止的。此外,由表面活性剂或环糊精微乳液或纳米乳液的稳定性通常在稀释、加热、pH变化的时候受到破坏。如图2所示,简单地混合聚乙二醇-糖-脂质缀合物(cholestoryllactobionate-mPEG-12)和HP-β-CD(2-羟丙基-β-环糊精)只形成一种不透明的乳液。因此通过化学键联接是必要的,以便实现增溶稳定性而不是简单地物理地混合环糊精和聚乙二醇-脂类。
虽然在本发明中可以使用不同的亲水聚合物,聚乙二醇(PEG)是首选因为其有效性历史久,而且其通常视为安全(GRAS)的地位。加入聚乙二醇后,新的聚合物-环糊精-脂质缀合物的通用结构2如下式所示:
通用结构2
在通用结构2中,“i”是通过中心骨架联接到环糊精的包括聚合物-脂质的取代数目,“i”可能相当于环糊精上的可用羟基数,可以是从1到7和更好的从1到5,最好是从1到3。R1和R2可能是相同或者不同的。R1和R2可能是氢、羧基或烷基醚,包括但不局限于-CH2CHOHCH3或-(CH2)4SO3-Na+或-CH3。骨架“B”选择的化合物至少包括三个位置可用于联接第一、第二和第三载体。每个联接位点可以是用于反应的氨基、羟基、或羧酸基团。中心骨架可能选自甘油或甘油类似物、多胺、二胺、三胺、四胺、氨二醇、氨三醇、氨醇与有三个联接位点的氨基酸、三元醇、四元醇、赤藓糖醇、三元酸、四元酸、四元乙酸、葡庚糖酸和酒石酸,包括但不是限于乙二胺、丙二胺、丁二胺、戊二胺、己二胺、二乙烯三胺、1,2-乙二胺、1,3-丙二胺(丙烷-1,3-二胺)4-氨基-3-羟基酸、N-(2-羟乙基)乙二胺、4-氨基-2-羟基丁酸、2-羟基-4-氨基丁酸、l-β-高丝氨酸、l-苏氨酸、N-β-氨乙基甘氨酸、腐胺(丁烷-1,4-二胺)、尸胺(戊烷-1,5-二胺)、己二胺(正己烷-1,6-二胺)、1,2-丙二胺、二苯基乙二胺、二氨基环己烷、二乙烯三胺、二(3-氨基丙基)胺、三乙烯四胺、三(2-氨乙基)胺、精胺、亚精胺、二(3-氨丙基)胺、二(3-氨丙基)-1,3-丙二胺、1,2-二(3-氨丙基氨)乙烷、N,N′-二(3-氨丙基)-1,3-丙二胺、三羟氨氨基-甲烷、二氨基联苯胺、N-乙基-N′-(3-二甲胺基)碳二亚胺、内消旋赤藓糖醇、1,4,7-三氮杂环壬烷、四氮杂环、苏糖醇、二硫苏糖醇、三甲基环己烷-1,3,5-三羧酸、三甲基二己烯基三胺、二己烯三胺、精氨酸、氧二氨丙酸、3-氨基-1,2-丙二醇3-溴-1,2-丙二醇、3-氯-1,2-丙二醇、3-氟-1,2-丙二醇、甘油酸、丙酸、葡庚糖酸、1,2,4-丁三醇、2,2-二羟甲基丁酸、1,3-二氨基-2-丙醇和2-(3-氨丙氨基)乙醇和3-((3-氨丙基)氨基)丙醇;天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、赖氨酸、鸟氨酸、丝氨酸和苏氨酸或苄基三元醇或氨基羟基苯甲酸或苯三酚、二羟基苯甲酸、苯甲酸、二氨基苯酚、氨基苯甲酸、氨基水杨酸、羟基间苯二甲酸、氨基间苯二甲酸、4-(羟甲基)环戊烷-1,3-二醇、脱氧复合吉非霉素、脱氧野尻霉素、***素、羟甲基哌啶醇、二羟基(羟甲基)胺、二氨基苯酚、甲酸、苯三甲酸、氨基苯三酚、二羟基苯甲酸、氨基羟基苯甲酸、三羟基甲苯、苯三酚、二甲氧基苯二胺、三羟基苯酚、(二苯氧基)苯二胺和氨基溴代苯酚。环糊精由(n=)六、七、八个吡喃葡萄糖组成或支链葡萄糖或麦芽糖组成。“脂”是一种亲脂性化合物或其双酯,包括但不限于脂肪酸或类固醇或甾醇类化合物或脂维生素。尽管环糊精是一个大的载体,它仍是连接到中心骨架的三大载体之一。载体和中心骨架的联接可以是相同或不同,包括烷基化、酯化、醚化或酰胺化。每个联接可能是简单氧、氮、硫或其他单个的原子,在载体和骨架之间形成酯、醚、酰胺或巯键。另外,每个联接可能是单一或重复的联接,选择的是:氨基、琥珀酰氨基、乙酰氨基、氨基戊酰胺基、氨乙酰、丙烯酰基、硫丙酰基、N-(巯)丙酰胺基、硫丙基硫丙酰胺基、(1,2-二羟基-3-巯基-丙硫基)丙酰基、特戊酰基、丁二酸、乙酰基、氧丙酰基、氨基甲酰基、氨基烃基、谷酰氨基、氨基乙硫醇、硫丙醇、羟丙基硫丙酰胺基、3-((2-丙酰胺乙基)-二硫基)丙酰胺基、(((乙酰胺基-乙基)-二硫基)丙氧基)谷酰胺、氨乙基硫酯、2-羟基丙酸酸酐、甘油或甘油类似物、多胺、二胺、三胺、四胺、氨基三醇、氨基醇和有三个联接点的氨基酸、三元醇、四元醇、赤藓糖醇、三元酸、四元酸、四元乙酸、葡庚糖酸和酒石酸,包括但不是限于乙二胺、丙二胺、丁二胺、戊二胺、己二胺、二乙烯三胺、1,2-乙二胺、1,3-丙二胺(丙烷-1,3-二胺)、4-氨基-3-羟基酸、N-(2-羟乙基)乙二胺、4-氨基-2-羟基丁酸、2-羟基-4-氨基丁酸、l-β-高丝氨酸、l-苏氨酸、腐胺(丁烷-1,4-二胺)N-β氨乙基甘氨酸、尸胺(戊烷-1,5-二胺)、己二胺(正己烷-1,6-二胺)、1,2-丙二胺、二苯基乙二胺、二氨基环己烷、二乙烯三胺、二(3-氨基丙基)胺、三乙烯四胺、三(2-氨乙基)胺、精胺、亚精胺、去甲精胺、双(3-氨丙基)-1,3-丙二胺、1,2-双(3-氨基丙氨基)乙烷、N,N′-双(3-氨丙基)-1,3-丙二胺、三(羟甲基)氨基甲烷、二氨基联苯胺、N-乙基-N′-(3-二甲氨基丙基)碳二亚胺、内消旋赤藓糖醇、1,4,7-三氮杂环壬烷、四氮杂环-十二烷、苏糖醇、二硫苏糖醇、三甲基环己烷-1,3,5-三羧酸、三甲基二己烯基三胺、二己烯三胺、精氨酸、氧二氨丙丙酸、3-氨基-1,2-丙二醇3-溴-1、2-丙二醇、3-氯-1,2-丙二醇、3-氟-1,2-丙二醇、甘油酸、丙酸、葡庚糖酸、1,2,4-丁三醇、2,2-二羟甲基丁酸、1,3-二氨基-2-丙醇和2-(3-氨基丙基-氨基)乙醇和3-((3-氨丙基)-氨基)丙醇;天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、赖氨酸、鸟氨酸、丝氨酸和苏氨酸或苄基三元醇或氨基羟基苯甲酸或苯三酚、氨基水杨酸。在某些情况下,联接链可能延伸到中心骨架或其部分或用于合成缀合物的官能团。
缀合物的典型耦合反应涉及与一个或多或组合或一系列的烷基化反应包括N-烷基化反应或O-烷基化、醚化、酯化、酰胺化反应的化学过程。通用结构是包括了所有消旋异构体或结构异构体的结构,因为它们的功能可能是等同。PEG链的组成倾向于约5至115亚基之间,最好是单分散体。Ri是PEG链的终端基团,可能选择于众多化学基团。羟基或甲氧基通常是被选择的终端基团。Ri分子量最好少于约650。市场上的PEG-脂质单酯可通过直接链接中心骨架上用于形成许多化合物。
在本发明的一个方面,没有任何药品或肽或生物分子选作为中心骨架。不同于其他修改生物活性药物后的前体药物,本发明的主要应用之一是药物传递,因此缀合物本身作为载体化学性稳定,对身体较少毒性或无毒。
PEG链的终端基团可能选择于众多的化学基团。这种化学组分的分子量最好是小于650。这些基团包括-OH,-OCH3,-NH2,-COOH,-OCH2CH3,-OCH2CH2OH,-COCH=CH2,-OCH2CH2NH2,-OSO2CH3,-OCH2C6H6,-OCH2COCH2CH2COONC4H4O2,-CH2CH2=CH2,C10H16N2O3S和-OC6H6。终端化学基团可能是有利于链接用于治疗或目标化合物到脂质囊泡聚合物的表面的官能团。氨基酸、氨基烷基酯、生物素、马来酰亚胺、二缩水甘油醚、马来酰亚胺丙酸、甲基氨基甲酸酯、甲苯磺酰肼、叠氮、丙炔、丙炔醇、琥珀酰亚胺(NHS)酯(例如,炔丙基琥珀酰亚胺酯、NHS-生物素磺酸-琥珀酰亚胺-LC-生物素或NHS碳酸盐)、酰肼、琥珀酰亚胺酯、琥珀酰亚胺酒石酸、琥珀酰亚胺丁二酸、对甲苯磺酸盐等可用于此类链接。链接的治疗和靶向剂可能包括Fab片段、细胞表面粘结剂等相关的分子。此外,终端基团可能包括功能化的细胞靶向分子,如叶酸、转铁蛋白和单克隆抗体等分子,细胞受体的配体或可能会加到脂质体表面的特定的肽序列来提供特异结合位点。终端基团可能是中性的或者是带正,负电荷的基团,包括癸醇氨、十八醇氨基、辛醇氨、丁醇氨、十二醇氨、己醇氨、季癸醇氨、十六醇氨、油氨、癸醇三甲氨盐、十八烷氧三甲氨盐、辛醇三甲氨盐、丁醇三甲氨盐、十二醇三甲氨盐、己醇三甲氨盐、十四醇三甲氨盐、十六醇三甲氨盐、油醇三甲氨盐。其他有用的R基团包括脂肪酸或烷基比如烷氧基基团、氨基酸、糖类包括单糖、双糖、三糖和含1、2、3和4个或更多的单糖单元的寡糖。此外,靶向成分包括抗体片段和维生素等基团也可以是R基团。R基团的分子量最好是小于650,对于大多数应用来说,R基团最好是很容易极化,以增加与靶点蛋白质的结合与相互作用。然而,离子平衡好的R基团也有利于用于某些特定给药方式,比如外用凝胶和针对口腔和喉咙的口服溶液。
本发明包括可能优化和提高聚乙二醇-环糊精-脂质基础配方的联接化学基团。选择适当的链来联接脂质部分或聚乙二醇或环糊精和中心骨架之间可能是重要的,原因如下所述。
三个联接起来的成分中,亲脂性成分或脂溶性维生素是可以被消化的,环糊精是部分消化而PEG是不能被消化。打破的三个组成部分之间的联系可能会增加它们的消除。因此,本发明的一个目的是使用不同的可生物降解链来优化用于药物递送的脂质囊泡和脂质的清除率。
当联接到聚合物后,分子本身的特点可能会处于非活性状态。故本发明的目标之一是使用较少的可生物降解的链来稳定中心骨架和载体成分之间的键,特别是缀合物的某一部分本身是有相对的毒性的。
在本发明的一个方面,缀合物的典型耦合反应涉及与一个、多个、组合或一系列的烷基化反应包括N-烷基化反应或O-烷基化、醚化、酯化、酰胺化反应的化学过程。出于实用和经济的原因,尽可能选择低成本,简单的过程来制备那些缀合物。
溶解增强剂的保留力可能对药物制剂和防止药物在稀释或体液循环中沉淀是很重要的。通过引进更多的疏水性的载体基团到聚合物-环糊精-脂质缀合物,本发明提供了提高保留力的手段。此外,缀合物保留力的增加,可以取消肠外给药产品中防腐剂的使用,这是因为给药剂量中缀合物的浓度相对较低,通常形成真正的溶液,可以无菌过滤。
本发明的缀合物中的环糊精比聚合物链或亲脂性载体的表面极性更大。例如,那些PEG-环糊精-脂质缀合物在应用纳米悬浮液或纳米颗粒时能提供更好的药物分散,特别是对一些两性药物或其他化合物;这为药物或其他化合物进入非极性内腔或缀合物的亲脂性中心提供了一种更好的平衡。
本发明的聚乙二醇-环糊精-脂质缀合物可能被制备成注射剂而不需要糖。糖通常用于稳定冻干的蛋白质和多肽注射剂。用聚乙二醇-环糊精-脂质缀合物制备的注射剂即使在高温或高湿度条件下是非常稳定的。减少或消除糖在药物制剂中的使用对于糖尿病患者尤其有益。
在本发明中缀合物的聚合物链最好是单分散或窄分散聚乙二醇。合成这种单分散PEG链的材料和方法已经在美国专利12/802,197公开,在此作为整体引用。特定的缀合物中PEG链有30%以上有相同的分子量较好。有50%以上相同的分子量更好。最好是有80%以上有相同的分子量。
在本发明的一个方面,通用结构是包括了所有消旋异构体或结构异构体的结构,因为它们的功能可能是等同。PEG链的组成倾向于约5至115亚基之间,最好是单分散体。R是PEG链的终端基团,可能会选择于众多的化学基团。R优选分子量小于650的基团。
总而言之,本发明包括合成聚乙二醇-环糊精-脂质缀合物的组成和方法:一个PEG链与一个亲脂性成分联接到中心骨架上,然后PEG-脂质连接到环糊精的一个活化的羟基上;同样,激活的环糊精也可能和其他的载体一样以同样的过程连接到中心骨架上。耦合过程是通过烷基化反应包括N-烷基化反应或O-烷基化、醚化、酯化、酰胺化反应的化学过程。选定的链可能用于形成酯或醚或酰胺键。这些键位于中心骨架和PEG链或环糊精或亲脂性成分之间或耦合到中心骨架之前。中心骨架包括甘油或其类似物,有三个可结合的位置或二胺、三胺、四胺和多胺或二氨醇或有三个可用结合的位点的氨基酸。亲脂性的载体包括脂肪酸、甾醇、胆固醇、单羟基胆固醇类似物、生育酚或生育三烯酚或胆钙化醇或视黄醇、视黄醛、视黄酸。
本发明的变化包括各种化合物作为中心的骨干,至少有三个可以结合的位置。分子具有两个可以成键的位置,如二胺、氨基醇或氨基酸可能是化学扩展到三个结合位点。
在合成聚合物-环糊精-脂质缀合物的过程中可能会产生位置异构体,而这些异构体可能功能相当。异构体的选择可能会在传递药物过程中有些应用,比如细胞内转运各种亲脂性分子,以及运输药物的载体。例如,不同的异构体在溶解和储存药物时稳定化合物的能力是不同的。
虽然可以使用各种中心骨架来制备聚合物-环糊精-脂质缀合物,在本发明实践中引入直链或环状分子被证明是非常有用的。在一方面是因为甾醇或生育酚或胆钙化醇可以在很大程度上增强“相似相溶”。在另一方面,环糊精的非极性空腔作为“主体”为“客体”分子提供了进驻的空间。如图2通用结构所示,主链可以从甘油或甘油类似物中选择,多胺(二-或三-或四-或五-胺),具有三个可用的结合位点的氨基酸,和三醇和三酸如葡庚糖酸和酒石酸。亲脂性组分可以从一组化合物中选择,包括但不限于胆固醇、豆甾醇、麦角甾醇、藿烷类、植物甾醇、谷甾醇、菜油甾醇、菜籽甾醇、燕麦甾醇、碘甲氧胆固醇、烷醇(饱和甾醇或氢化的甾醇)、类视黄醇、视黄醛、视黄酸、维生素A酸、类胡萝卜素、β-胡萝卜素、α生育酚、生育三烯酚、胆钙化醇、麦角钙化醇、虾青素、金黄素、辣椒红、辣椒玉红素、菊黄素、隐黄素、岩藻黄素、叶黄素、新黄素、红宝黄素、紫黄素、玉米黄素。环糊精可以是α环糊精、β环糊精或γ环糊精。载体和中心骨架之间相同或不同的链可以通过烷基化、醚化、酯化或酰胺化形成。每个链可以是例如简单的氧、硫或其它单个原子。或者,每个链可以是单个或重复的基团比如:氨基、琥珀酰胺基、乙酰胺基、氨基戊酰胺基、氨基乙酰基、丙烯酰基、硫丙酰基、N-(巯基甲基)-丙酰胺基、硫丙硫丙酰基、(1,2-二羟基-3-硫基丙硫基)丙酰基、琥珀酰基、乙酰基、氧代戊酰基、氨基甲酰基、氨基烷基、戊二酰胺、氨基乙硫醇、巯基丙醇、(羟基丙硫基)丙酰基、3-((2-丙酰乙氨基)二硫基)丙酰基、(((乙酰氨基-乙基)二硫基)丙酰氧基)-谷酰胺基、氨基乙硫酯基和2-羟基乙酸丙酸酐。
在某些情况下,链可能是中心骨架或其部分或者用于合成缀合物的官能团的延伸。虽然没有显示,本发明包括了碳水化合物处于中心骨架的中间位置的例子。然而,从合成路线上看,更实际的是碳水化合物处于中心骨架的终端而不是中间位置。总结构包括了所有光旋异构或结构异构体的结构,因为它们可能是等同。PEG链倾向于由约5至115个亚基组成,最好主要是单分散的。R是PEG链的终端基团,可能选择于从众多的化学基团。R分子量大约小于650。
在本发明的另一个方面,各种脂肪酸可用于制备的聚合物-环糊精-脂质缀合物、肉豆蔻酸、棕榈酸、油酸、月桂酸、肉豆蔻酸、棕榈酸和硬脂酸可能更常用。肉豆蔻酸、棕榈酸、油酸棕榈酸和硬脂酸可能更为可取。
在本发明的一个方面适用的、可取的氨基酸链有脯氨酸、甘氨酸、丙氨酸、赖氨酸、半胱氨酸、缬氨酸、异亮氨酸、亮氨酸、蛋氨酸、苯丙氨酸、组氨酸、色氨酸、酪氨酸、硒代半胱氨酸和精氨酸,更可取的是脯氨酸、甘氨酸、丙氨酸、赖氨酸、半胱氨酸、缬氨酸、异亮氨酸、亮氨酸、蛋氨酸,最优选的脯氨酸、甘氨酸和丙氨酸。
本发明总结构2中,即使没有在图中画出,链可能比联接载体和中心骨架的N-烷基化反应或O-烷基化反应、酯或醚酰胺链多一个或更多个碳原子。只要合适,应该选择一个简单、低成本的耦合反应而避免选择多个链比如多肽。链的形成是最好是有方向的,以便于中心骨架和载体的联接。
本发明可以使用各种非药物的中心骨架。优选的骨架具有至少三个可用的或两个可扩展的位点用于碳水化合物或脂质或PEG附通过烷基化、酯化、醚化或酰胺化的联接。合适的可以用作骨架的分子,包括但不限于乙二胺(1,2-二氨基乙烷、1,3-二氨基丙烷(丙-1,3-二胺)、腐胺(丁烷-1,4-二胺)二胺)、尸胺(戊烷-1,5-二胺)、六亚甲基二胺(己烷-1,6-二胺)、乙二胺、1,3-二氨基丙烷、1,2-二氨基丙烷、1,4-二氨基丁烷、二苯乙二胺、二氨基环己烷、3-氨基-1,2-丙二醇、3-溴-1,2-丙二醇、3-氯-1,2-丙二醇、3-氟-1,2-丙二醇、DL-甘油酸、二氨基丙酸、酒石酸酸、葡庚糖酸和1,2,4-丁三醇、2,2-双(羟甲基)丁酸、1,3-二氨基-2-丙醇、2-(3-氨基丙基氨基)乙醇、3-((3-氨基丙基)氨基)丙醇、二亚乙基三胺、亚精胺、三亚乙基四胺、精胺、亚精胺、双(3-氨基丙基)-1,3-丙二胺和双(六亚甲基)三胺、天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、鸟氨酸、丝氨酸、苏氨酸、苄基三醇或氨基羟基苯甲酸或苯酚类似物、具有羧基或胺的苯基二醇和具有羟基或羧基的二胺、二氨基苯甲酸、氨基羟基苯甲酸、氨基水杨酸、羟基间苯二甲酸、羟基间苯二甲酸、氨基间苯二甲酸。例如,合适的中心骨架可以选自4-(羟甲基)环戊烷-1,3-二醇、脱氧复合吉非霉素、脱氧野尻霉素、***素、羟甲基哌啶醇、二羟基(羟甲基)氨基环戊烷、二氨基苯酚、苯四甲酸、苯三甲酸、氨基苯二酚、二羟基苯甲酸、氨基羟基苯甲酸、三羟基苯胺、苯三醇、二甲氧基苯二胺、三羟基苯酚、(二氨基苯氧基)-苯二胺或氨基溴苯酚。
本发明的聚合物-环糊精-脂质缀合物可用于许多应用。已经介绍了化妆品和药物的制剂和传递。此外,本发明的聚合物-环糊精-脂质缀合物可能用于水溶性载体是优点的情况,例如工业和食品加工。
PEG链的终端基团可能选择于众多的化学基团。这种化学组分的分子量最好是小于650。这些基团包括–OH,-OCH3,–NH2,-COOH,-OCH2CH3,-OCH2CH2OH,-COCH=CH2,-OCH2CH2NH2,-OSO2CH3,-OCH2C6H6,-OCH2COCH2CH2COONC4H4O2,-CH2CH2=CH2,C10H16N2O3S和-OC6H6。终端化学基团可能是有利于链接用于治疗或目标化合物到脂质囊泡聚合物的表面的官能团。氨基酸、氨基烷基酯、生物素、马来酰亚胺、二缩水甘油醚、马来酰亚胺丙酸、甲基氨基甲酸酯、甲苯磺酰肼、叠氮、丙炔、丙炔醇、琥珀酰亚胺(NHS)酯(例如,炔丙基琥珀酰亚胺酯、NHS-生物素磺酸-琥珀酰亚胺-LC-生物素或NHS碳酸盐)、酰肼、琥珀酰亚胺酯、琥珀酰亚胺酒石酸、琥珀酰亚胺丁二酸、对甲苯磺酸盐等可用于此类链接。链接的治疗和靶向剂可能包括Fab片段、细胞表面粘结剂等相关的分子。此外,终端基团可能包括功能化的细胞靶向分子,如叶酸、转铁蛋白和单克隆抗体等分子,细胞受体的配体或可能会加到脂质体表面的特定的肽序列来提供特异结合位点。终端基团可能是中性的或者是带正、负电荷的基团,包括癸醇氨、十八醇氨基、辛醇氨、丁醇氨、十二醇氨、己醇氨、季癸醇氨、十六醇氨、油氨、癸醇三甲氨盐、十八烷氧三甲氨盐、辛醇三甲氨盐、丁醇三甲氨盐、十二醇三甲氨盐、己醇三甲氨盐、十四醇三甲氨盐、十六醇三甲氨盐、油醇三甲氨盐。其他有用的R基团包括脂肪酸或烷基比如烷氧基基团、氨基酸、糖类包括单糖、双糖、三糖和含1、2、3或4个或更多的单糖单元的寡糖。此外,靶向成分包括抗体片段和维生素等基团也可以是R基团。R基团的分子量最好是小于650,对于大多数应用来说,R基团最好是很容易极化,以增加与靶点蛋白质的结合与相互作用。然而,离子平衡好的R基团也有利于用于某些特定给药方式,比如外用凝胶和针对口腔和喉咙的口服溶液。
根据选择的中心骨架、官能成分和链,本发明的化合物可分为下列几类:这些类别包括但并不限于(a)甾醇和“脂肪可溶性”维生素基础的:胆固醇-甘油-环糊精-聚乙二醇(CGC-PEGs);生育酚-甘油-环糊精-聚乙二醇(TGC-PEGs)、胆固醇-二亚乙基四胺-环糊精-聚乙二醇(CDC-PEGs)、生育酚-二亚乙基-环糊精-聚乙二醇(TDC-PEGs)、胆固醇-三亚乙基四胺-环糊精-聚乙二醇(CTC-PEGs)、生育酚-三亚乙基四胺-环糊精-聚乙二醇(TTC-PEGs);(b)脂肪酸基础:油酸-甘油-环糊精-聚乙二醇(OGC-PEGs);油酸-二亚乙基四胺-环糊精-聚乙二醇(ODC-PEGs)、油酸-三亚乙基四胺-环糊精-聚乙二醇(OTC-PEGs)和肉豆蔻酸-甘油-环糊精-聚乙二醇(MGC-PEGs);肉豆蔻酸-二亚乙基四胺-环糊精-聚乙二醇(MDC-PEGs);肉豆蔻酸-三亚乙基四胺-环糊精-聚乙二醇(MTC-PEGs钉)。
在本发明中,聚合物-环糊精-脂质缀合物的构成包括中心骨架、聚合物和脂质。其分类如表3中所示。
表3典型组成的聚合物-CD-脂质共轭
聚合物-环糊精-脂质缀合物包括但不限于油酰基-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰环糊精,硬脂酰-甲氧基聚乙二醇醚-(氨基丙氧基)-乙酰环糊精,棕榈酰-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰环糊精,肉豆蔻酰基-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰环糊精,胆固醇-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰环糊精,胆固醇-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰环糊精,生育酚-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰-环糊精,视黄酰基-甲氧基聚乙二醇醚-(氨基丙氧基)乙酰环糊精,视黄酰基-甲氧基聚乙二醇醚-(氨基丙氧基)-乙酰环糊精,胆钙化甾醇-甲氧基聚乙二醇醚(氨基丙氧基)乙酰环糊精,油酰丙烷-二氨基环糊精-甲氧基聚乙二醇醚,α-环糊精-N,N-油酰基-甲氧基聚乙二醇醚-赖氨酸酯,ε-环糊精-N-肉豆蔻酰-甲氧基聚乙二醇醚-赖氨酸酯,ε-环糊精-α-硬脂酰-甲氧基聚乙二醇醚-赖氨酸酯,硬脂酰丙二胺-环糊精-甲氧基聚乙二醇醚,油酰二亚乙基三胺-双甲氧基聚乙二醇醚-环糊精,棕榈酰二乙基三胺-甲氧基聚乙二醇醚-环糊精,油酰三亚甲基四胺-β-环糊精-双甲氧基聚乙二醇醚,棕榈酰丙二胺-环糊精-双甲氧基聚乙二醇醚,肉豆蔻酰丙二胺-环糊精-甲氧基聚乙二醇醚,棕榈酰丙烷-二胺-环糊精-甲氧基聚乙二醇醚,胆固醇丙二胺-环糊精-甲氧基聚乙二醇醚,Nε-环糊精-Nα-胆固醇-甲氧基聚乙二醇醚-赖氨酸酯,胆固醇二亚乙基三胺-环糊精-甲氧基聚乙二醇醚,α-生育酚三亚乙基-四胺-双甲氧基聚乙二醇醚-环糊精,胆甾醇-三乙基-乙胺四甲基-β-PEG-环糊精,胆固醇三亚乙基四胺-环糊精-双甲氧基聚乙二醇醚,胆固醇三亚甲基四胺-β-环糊精-甲氧基聚乙二醇醚,生育酚丙二胺-环糊精-甲氧基聚乙二醇醚,视黄酰基丙二胺-环糊精-甲氧基聚乙二醇醚,视黄酰二亚乙基三胺-环糊精-甲氧基聚乙二醇醚,胆钙化二亚乙基三胺-环糊精-甲氧基聚乙二醇醚,胆钙化二亚乙基三胺-双甲氧基聚乙二醇醚-环糊精,环糊精-生育酸乙烯-双甲氧基聚乙二醇醚-氨基水杨酸酯,胆固醇-二磷酸二亚乙基三胺双甲氧基聚乙二醇醚-β-环糊精,胆固醇对-二乙烯基二亚乙基三胺-色氨酰基-双甲氧基聚乙二醇醚-环糊精,胆固醇-马来酰基-甲氧基聚乙二醇醚-丙二胺环糊精,胆固醇天冬氨酸-甲氧基聚乙二醇醚-环糊精,胆甾烯酰基抗坏血酸-二亚乙基三胺-甲氧基聚乙二醇醚-环糊精,胆固醇-视黄酰基二亚乙基三胺-甲氧基聚乙二醇醚-环糊精,胆固醇对-三亚乙基四胺-双甲氧基聚乙二醇醚-环糊精,环糊精-生育酚-甲氧基聚乙二醇醚-赖氨酸酯,胆固醇三亚乙基四胺-双甲氧基聚乙二醇醚-环糊精,胆固醇酚酰-环糊精二亚乙基三胺-甲氧基聚乙二醇醚,双甲氧基聚乙二醇醚-丙二胺-N-环糊精,环糊精二氨基-2-丙醇胆固醇抗坏血酸酯,胆钙化甾体抗坏血酸乙酰二乙烯-三胺-环糊精-甲氧基聚乙二醇醚,ε-环糊精-ε-胆固醇基-α-乙酰基-甲氧基聚乙二醇醚-赖氨酸酯,胆酸-二茂铁-二亚丙基三胺-甲氧基聚乙二醇醚-环糊精,胆固醇二亚乙基三胺四乙酰基-甲氧基聚乙二醇醚-环糊精胆固醇酰视黄酰三亚乙基四胺-甲氧基聚乙二醇醚-环糊精,胆固醇三亚乙基四胺双-甲氧基聚乙二醇醚环糊精,ε-环糊精-εN-α-生育酚-α-乙酰基-单甲氧基-PEG-醚-赖氨酸酯,α-生育酚-三亚乙基四胺-双甲氧基聚乙二醇醚-环糊精,胆固醇-二乙烯基亚乙基三胺-甲氧基聚乙二醇醚-环糊精,胆钙化芳酰基玻璃酰胆碱二亚乙基三胺-甲氧基聚乙二醇醚-环糊精和胆甾烯酰基抗坏血酸二亚乙基三胺-甲氧基聚乙二醇醚-环糊精。
在本发明的另一个方面,可能选择中的多元不饱和脂肪酸或多元不饱和脂肪醇,包括但不限于硬脂酸、二十碳三烯酸、二十碳四烯酸、二十碳五烯酸、二十一碳五烯酸、二十二碳五烯酸、二十二碳六烯酸,二十四碳五烯酸、二十四碳六烯酸、二十二碳二烯酸、肾上腺酸、鲁梅尼奇酸、鲁梅尼奇酸、α-十八碳四烯酸(α-Parinaric acid)、β-十八碳四烯酸(β-Parinaric acid)、柠檬酸、α-十一酸、β-十一酸、梓酸、石榴酸、月桂酸、α-对白酸、β-对白酸、十八碳五烯酸(Bosseopentaenoic acid)和天然多不饱和醇如法尼醇(farnesol)、茄尼醇(solanesol)、十二异戊二烯醇(dodecaprenol)、十六碳三烯酸(Hexadecatrienoicacid)等。
在另一个方面,本发明包括由下列化合物分子所示的通用结构3:
通用结构3
其中bPEG官能是带有2或更多的PEG分枝链的PEG,每个PEG子链可能包括约5至115亚基。其中Ri是终端基团,可能会选择于众多的化学基团。Ri分子量最好少于约650。除了脂质体,聚乙二醇-糖缀合物可用于其他方面,例如,在水溶液中的溶解度增强剂。所有缀合物的其他组成部分可能如通用结构1和2所述保持不变。
在本发明的一个方面,载体和中心骨架之间的偶联反应如烷基化反应、醚化、酯化或酰胺化反应,根据如通用结构4所示的特定中心骨架和载体结构,可以在加或不加链接的基础上实现。
一般结构4
其中D是第四个载体,是重复的亲脂性载体或聚乙二醇。中心骨架是不是药物的部分的一个分子,包括甘油或有三个可联接的位点的类似物,或二胺、三胺、四胺、二氨基醇、氨基醇、氨基二醇、氨基三醇或有三个可联接的位点的氨基酸、至少有三个可联接的位点的多胺。所有其他组成部分可能是如通用结构1和2所述。
本发明更进一步,聚乙二醇-糖糊精-脂质缀合物的第三和第四个载体如通用结构5所示,可能是通过另一个链联接形成。
通用结构5
其中D是第二个的亲脂性载体或聚乙二醇;L是从一组化合物中选择的联接物,包括甘油或有三个可联接的位点的类似物,或二胺、三胺、四胺、二氨基醇、氨基醇、氨基二醇、氨基三醇或有三个联接位点的氨基酸、至少有三个联接位点的多胺。如化学结构3所示,N-二-单甲氧基-聚乙二醇-丝氨酸-N-胆固醇-N'-α-环糊精-丙二胺。联接物是3-氨基-1,2-丙二醇(丝氨酸),“D”是第二个mPEG。
化学结构3
本发明的另一个方面包括给药方法,这个方法包括制备聚乙二醇-环糊精-脂质缀合物基础上的药物的制剂。这个制剂包括的聚乙二醇-环糊精-脂质缀合物含有氨基酸链和可能的第二链选自于不同的基团,包括氨基、琥珀酰胺基、乙酰胺、氨基戊胺基、氨基乙酰基、丙烯基、巯基丙酰胺基、巯基丙基硫丙酰基、1,2-二羟基-3-巯基丙基硫丙酰基、琥珀酰基、乙酰基、氧戊酰基、氨基甲酰基、氨基烃基、谷酰胺基、氨基乙硫醇、巯基丙醇、羟丙基硫丙酰基、3-((2-丙酰胺基乙基)二硫)丙酰基、(((乙酰胺基乙基)二硫)丙氧基)谷酰胺基、氨基乙硫酯和2-羟基丙酸酐;并提供释放剂,它能造成链的降解。这个释放剂可能是一种酸、光、缺氧环境或一种催化剂。
本发明在一个方面,是将中心骨架通过氨基酸连接(烷基化或酰胺化过程)联接到三个载体的之一的一种方法。载体中的羟基可能与二琥珀酰亚胺基碳酸酯(disuccimidylcarbonate(DCS))或甲磺酸或对甲苯磺酸盐或丙烯酸或强碱(醚或酯化反应)反应而激活。
聚乙二醇-环糊精-脂质缀合物的合成例子如下式(反应方案1)所示,是单氨基丙烯基-6-脱氧--β-环糊精与PEG-二乙基二胺之间的反应。
反应方案1
烯丙基-环糊精的制备可以从已发表的文章中的方法改进而来。[Jindrich J.,etal(19950.Carbohydr Res.266(1):75-80;LI YingJie,et al(2010).Scientia SinicaChimica,40(11):1682-1687]PEG-脂质部分的制备可能根据我们以前公开发表的方法合成[US20120202979或US20120202890]。此反应计划适用于与环糊精联接的所有各种亲脂性化合物或PEG链的载体。本申请中的通用结构包括所有的旋光异构体和结构异构体的结构,因为它们可能功能等同。
本发明还使用了支链-聚乙二醇作为聚合物载体。市场上已有支链聚乙二醇,而且分子量相对较大。因此单个短链的支链PEG的制备可能与按顺序依次增长的单链PEG制备相同。如通用结构3所示,活化的支链PEG被用于制备支链PEG-碳水化合物聚合物。如反应计划1所示,有多个化学过程如烷基化反应、醚化、酯化或酰胺化可能参与制备每个最终产品,相应地设计了每个耦合反应的步骤。
另一个方面,本发明包括PEG-糖缀合物含有三个载体,有三个联接位点的中心骨架,一个载体和中心骨架之间的一个或多个链。这种聚乙二醇-糖缀合物是由通用结构1到5所示,链是选自于不同的基团,包括氨基、琥珀酰胺基、乙酰胺基、氨基戊胺基、氨基乙酰基、丙烯基、巯基丙酰胺基、巯基丙基硫丙酰基、1,2-二羟基-3-巯基丙基硫丙酰基、琥珀酰基、乙酰基、氧戊酰基、氨基甲酰基、氨基烃基、谷酰胺基、氨基乙硫醇、巯基丙醇、羟丙基硫丙酰基、3((2-丙酰胺基乙基)二硫)丙酰基、(((乙酰胺基乙基)二硫)丙氧基)谷酰胺基、氨基乙硫酯、2-羟基丙酸酐。表4显示某些样品的聚乙二醇-环糊精-脂质缀合物。如果化学名称有不同时,所示的结构注定作为标准。
表4:每个样品的聚乙二醇-环糊精-脂质缀合物
表4中的载体和中心骨架之间的偶联反应,以及耦合之前环糊精,载体或中心骨架上的化学修饰反应的类型是烷基化反应包括N-烷基化反应或O-烷基化反应、酯化、醚化和酰胺化。例如,环糊精可能与丙烯酰氯反应,然后与中心骨架反应,因此可能涉及到两种类型的反应:酯化、N-烷基化反应(迈克尔加成)。作为制备缀合物的的关键中间体,如反应方案2所示,环糊精的单甲苯磺酰化(monotosylation)可能是从对甲苯磺酰-咪唑开始的[T.Tan,et al(2011).Protocol Exchange.doi:10.1038/protex.2011.214]。
反应方案2:6-甲苯磺酰基-环糊精的制备
如反应方案3所示,CD缀合物可以从单-6-对甲苯磺酰基-环糊精制备。得到的产品可能用甲醇和乙腈的混合溶剂进一步纯化。
反应方案3(R为中心骨架含有或不含有聚乙二醇或脂质)
单-6-对甲苯磺酰-环糊精转换成单-6-氨基丙烯基-环糊精的制备,可以通过反应方案4中步骤实现[W.Zhang,et al(2010).Applied Surface Science.256:3000–3005]。
反应方案4.单-N-氨丙烯基-6-脱氧-环糊精
反应方案5所示,用较少的步骤,类似丙烯酰化可能也适用于聚乙二醇或脂质载体。
反应方案5(R为中心骨架)
在本发明的一个方面,单取代的环糊精可能更为可取,而多取代的环糊精已经商用,从简单性和节约成本考虑,天然或没有取代的环糊精可以作为合成的起始原料。由于聚合物-环糊精-脂质缀合物最终产品是增溶剂,使用昂贵的修饰过或已取代环糊精可能不必要。
本发明的实例介绍包括聚合物-环糊精-脂质缀和物的制备以及聚合物-环糊精-脂质缀和物能增加溶解度,增强药物的传递。药物制剂的接近最好的组合配方在此作一般介绍,虽然不同的药物通常有不同的最佳配方。
实施例
用化学品和试剂:N,N'-二环己脲、N,N′-二环己基碳二亚胺(DCC)、油酸、抗坏血酸维生素C、α-环糊精、β-环糊精、γ-环糊精、胆钙化醇、胆固醇甲酰氯、胆固醇、葡萄糖醛酸、聚乙二醇(PEG)、视黄酸、α-生育酚和其他化学品取自Sigma-Aldrich(St.Louis,MO,USA),Alfa Aesar(Ward Hill,MA,USA),TCI America(Portland,OR,USA)。活化的PEGs来自于Quanta BioDesign(Powell,Ohio,USA)或Thermo Fisher Scientific(Rockford,IL)或由LipoSeutics LLC(North Brunswick,New Jersey,USA)提供。
示例1:制备Boc保护的氨基基团
一种不需要催化剂,室温条件下的高产率和有效的合成方法已经报道过[Chankeshwara SV and Chakraborti,AK.Org.Lett.,(2006);8,3259],在此作略有修改。向含有起始原料胺的甲醇溶液中,加入1:1摩尔比的二叔丁醇二碳酸酯。产生的混合物在室温搅拌过夜。反应结束后,真空除去溶剂。残留物溶解于乙酸乙酯,饱和NH4Cl水溶液洗过一次,然后用硫酸钠干燥,浓缩有机相得到产品(>90%)。这个反应的例子如反应方案6所示,其中R是中心骨架的主要结构。用这种方法选择性的得到Boc保护的胺,而没有得到其他的副产品(如异氰酸酯、尿素,N,N-二叔丁氧羰酰胺)。
反应方案6
示例2叔丁基氨基甲酸酯(Boc)保护的氨基的制备
叔丁醇氨基碳酸酯和叔丁醇酯的有效脱保护剂有磷酸和三氟醋酸。这些反应产率高,反应方便。[Li,B.Berliner,M.etc,J.Org.Chem.,2006;71,9045]叔丁氧醇氨基碳酸酯甲酯的二氯甲烷(10%的初产品)的溶液中,加入同等体积的的三氟乙酸。在室温下搅拌过夜,溶剂蒸发后,残留物重新溶入二氯甲烷,饱和碳酸氢钠水溶液洗,有机相用硫酸钠干燥。溶剂蒸发后,得到的产品不用进一步纯化,直接用到下一步反应中。
示例3:N-叔丁氧碳酸-胆固醇-丝氨酸酯的制备
0.03摩尔的N-叔丁氧羰基-丝氨酸溶于在100毫升的氯仿,在氮气下不断搅动。0.03摩尔的胆固醇氨基甲酸酯溶于100毫升的氯仿,加入上述溶液中。在此混合溶液中加入10毫升的无水吡啶。室温下不断搅拌30分钟直至混合溶液变成均相溶液。反应完毕,没有检出原料胆固醇氨基甲酸酯。真空除去溶剂,得到的初产品直接用于下一步反应,无需进一步提纯。最终产品(产量70-80%)如化学结构5所示。
化学结构5
示例4:N-叔丁氧羰基-胆固醇-m聚乙二醇-丝氨酸酯的制备
m聚乙二醇(0.01摩尔)溶于50毫升的无水CH2Cl2,加入0.01摩尔的DCC和胆固醇丝氨酸酯。在0℃下搅拌2小时,升温到室温下和额外48小时。反应结束后,硅藻土过滤掉白色沉淀。滤液用少量的CH2Cl2冲洗两次,合并有机相。有机相用饱和NH4Cl洗,然后用硫酸钠干燥。蒸干溶剂后得到淡黄色的油状物,其结构如化学结构6所示。粗产物纯度测定是用1HNMR和UPLC-MS,ESI MS(>70%)。
化学结构6
示例5:胆固醇基丝氨酸单甲氧基十二甘醇-聚乙二醇-β-环糊精的制备
根据在示例2中描述的方法,脱掉氨基上的Boc保护基团。0.01摩尔的从示例4得到的N-叔丁氧羰基-胆固醇丝氨酸-m-聚乙二醇溶于50毫升的无水四氢呋喃(THF),然后加入0.01摩尔的单-N-氨丙烯基-6-脱氧-环糊精和3%的三乙胺。50-60℃下搅拌过夜,然后冷却至室温。反应液在异丙醇(IPA)乙腈(ACN,1/4,v/v)中析出沉淀,加入甲基叔丁基醚(MTBE)最大限度地得到产品的沉淀。粗产品是用20/80(v/v)IPA/ACN洗涤,30-40℃真空干燥。最终产品(化学结构7)(>95%)的纯度是用1H NMR和UPLC-MS测定。
化学结构7
例6:环糊精二亚乙基三胺的制备
二亚乙基三胺(0.01mol)溶于50毫升的干燥(分子筛处理过)四氢呋喃,然后加入单-6-磺酰基-α-环糊精(0.005mol)。50-60℃下搅拌6小时后,冷却到室温,反应完毕。反应液在异丙醇(IPA)-乙腈(ACN,1/4,v/v)中析出沉淀,加入甲基叔丁基醚(MTBE)最大限度地得到产品的沉淀。粗产品是用20/80(v/v)IPA/ACN洗涤,30-40℃真空干燥。初产品(化学结构8)没有进一步纯化,将直接应用于下一步。
化学结构8
示例7:环糊精-油酸-二亚乙基三胺-mPEG的制备
0.01摩尔从示例6得到的起始物α-环糊精-二亚乙基三胺溶于200毫升的四氢呋喃。稍过量的活化油酸N-羟基琥珀酰亚胺酯(0.011mol)溶于20毫升的四氢呋喃(THF),加入上述得到的溶液中,再加入三乙胺(3%,v/v),室温下搅拌2小时。检测反应产率,直接用于下一步反应。活化的mPEG24NHS(0.01mol)溶于四氢呋喃,然后与上述反应产物混合均匀,室温下搅拌过夜。反应结束,真空除去溶剂,加入50毫升的丙酮,过滤,用丙酮(30毫升)洗三次。得到的初品在IPA和ACN混合溶剂中沉淀,沉淀物用20/80(v/v)IPA/ACN洗,然后30-40℃真空干燥,得到的最终产品(化学结构9)其纯度(>95%)用1H NMR和UPLC-MS测定。
例8:α-环糊精三亚乙基四胺的制备
三亚乙基四胺(0.02mol)溶于50毫升的干燥(分子筛处理)四氢呋喃,加入单-6-磺酰基-α-环糊精(0.01mol)。50-60℃下搅拌6小时,然后冷却到室温,反应完毕。反应液在异丙醇中析出沉淀,加入ACN最大限度地得到能分离的沉淀。沉淀用丙酮洗,然后用20/80(v/v)IPA/ACN洗,30-40℃下真空干燥。得到的初产品(化学结构10)用于下一步反应,没有进一步纯化。
示例9:α-环糊精-胆固醇-三亚乙基四胺的制备
0.01摩尔的α-环糊精三亚乙基四胺(示例8)溶于50毫升的无水四氢呋喃,加入0.01摩尔的胆固醇酯甲酰氯。在45-50℃下搅拌过夜,冷却至室温。反应液在异丙醇中析出沉淀,加入ACN最大限度地得到能分离的沉淀。粗产品用20/80(v/v)IPA/ACN洗,30-40℃下真空干燥。得到纯度>80%的最终产品(化学Structure11)1H NMR和UPLC-MS测定其结构和纯度。
化学结构9
化学结构10
化学结构11
例10:α-环糊精三亚乙基四胺胆固醇基-mPEG的制备
0.01摩尔的起始原料α-环糊精-胆固醇-三亚乙基四胺(例9),溶于无水四氢呋喃。室温下加入略有过剩的活化mPEG24NHS 20毫升(0.021mol在10毫升四氢呋喃),室温下搅拌过夜。反应结束,加入300毫升的丙酮,真空除去溶剂。粗产品用丙酮清洗和过滤。得到的湿的产品(60-65%)进一步冻干到蜡状物,如化学结构12所示。
化学结构12
例11:胆固醇乙二醇醚的制备
在配有机械搅拌和加热套的圆底烧瓶中,胆固醇对甲苯磺酸酯(0.1mol)溶于四氢呋喃(500毫升),然后加入与乙二醇(1mol)混合。在氮气保护下搅拌回流12小时,真空除去溶剂,剩余物再溶解在200毫升的二氯甲烷,用200毫升的水清洗三次。蒸除二氯甲烷,真空干燥得到粗产品固体(90-105%)结构如化学结构13所示。
化学结构13
示例12:胆固醇乙二醇乙酸的制备
在配有机械搅拌和加热套的圆底烧瓶中,加入胆固醇乙二醇(例11)(0.02mol)溶在四氢呋喃(100毫升)中,得到的溶液氮气下干燥(50-100磅/平方英寸)。在室温下,缓慢添加钠块(0.05g)。加完后,加热至60℃,下不断搅拌6小时,加入氯乙酸钠(0.03mol)和碘化钠(0.005mol)。继续在55-60℃下搅拌过夜。反应液用氢氧化钠溶液(100毫升的5%,w/v)处理,真空下蒸除四氢呋喃,然后用二氯甲烷(50毫升)萃取。水层用盐酸酸化(36%)pH至3-4。水相再用二氯甲烷(25毫升)萃取两次。合并有机层,硫酸钠干燥1小时。过滤,真空除去溶剂得到产生油状产品(45-73%),结构如如化学结构14所示。
化学结构14
示例13:γ-环糊精丙二胺的制备
1,3-氨基丙烷(0.01mol)溶于50毫升的无水加四氢呋喃,加入单-6-对甲苯磺酰-γ-环糊精(0.005mol),50-60℃下搅拌6小时,冷却到室温,反应完毕。反应液在异丙醇中析出沉淀,加入ACN最大程度地得到能分离的沉淀。粗产品用20/80(v/v)IPA/ACN洗,30-40℃下真空干燥。得到的初产品(化学结构15)直接用于下一步反应。
化学结构15
例14:γ-环糊精-丙二胺-mPEG的制备
0.01摩尔的起始物质(例14)γ-环糊精丙二胺溶于200毫升的四氢呋喃,室温下加入活化的mPEG24-对甲苯磺酸盐(0.01mol)四氢呋喃溶液,室温下搅拌过夜。反应结束,加入50毫升的丙酮,过滤,真空除去溶剂。粗产品用30毫升丙酮洗三次。得到的湿的产品(60-65%)进一步冻干到蜡状物,如化学结构16所示。
化学结构16
示例15:γ-环糊精-胆固醇-丙二胺-mPEG的制备
0.01摩尔的γ-环糊精-丙二胺-mPEG(例14)溶于50毫升的无水N-甲基-2-吡咯烷酮,加入胆固醇基乙二醇乙酸(0.01mol)(例12)的四氢呋喃(50毫升)溶液和略有过剩的活化N-羟基琥珀酰亚胺酯(0.011mol)的四氢呋喃(20毫升)混合溶液,加入三乙胺(3%,v/v),室温搅拌2小时。加热至45-50℃,搅拌过夜,冷却至室温。反应液沉淀在异丙醇(IPA)和添加甲基叔丁基醚(MTBE)是为了最大限度地孤立的产量的沉淀。反应液在异丙醇中析出沉淀,加入MTBE最大程度地得到能分离的沉淀。粗产品用20/80(v/v)IPA/MTBE洗,30-40℃下真空干燥。得到纯度>93%的最终产品(化学结构17),1H NMR和UPLC-MS测定。
例16:Boc-甘氨酸-丝氨酸的制备
Boc甘氨酸(0.1mol)和DCC(0.1mol)混溶在二氯甲烷(50毫升),搅拌30分钟,混合液慢慢加入(0.1mol)丝氨酸的二氯甲烷(50毫升)溶液。将混合物搅拌2个小时。过滤,真空除去溶剂,得到Boc-甘氨酸-丝氨酸初产品,直接用到到下一步,没有进一步纯化。
化学结构17
示例17:胆固醇甲磺酯的制备
冰浴下,甲磺酰氯(0.1mol)滴加到到胆固醇(0.1mol)和三乙胺(0.1mol)在二氯甲烷(100毫升)的混合溶液中。加完后,继续搅拌1小时。反应液用饱和盐水洗,硫酸钠干燥,过滤,真空除去溶剂,得到的初产品用与Boc-甘氨酸-丝氨酸(例16)反应。
示例18:叔丁氧羰基-甘氨酸-丝氨酸-胆固醇的制备
叔丁氧羰基-甘氨酸-丝氨酸-胆固醇(例17)的四氢呋喃溶液(100毫升)中,加入叔丁醇钾(0.1mol)。65℃下搅拌约6小时。冷却至室温,真空蒸除溶剂,得到的混合物溶于二氯甲烷,用饱和盐水洗,硫酸钠干燥有机相,真空除去溶剂,得到的中间产物叔丁氧羰基-甘氨酸-丝氨酸-胆固醇,直接用于下一步反应。
示例19:叔丁氧羰基-甘氨酸-丝氨酸-胆固醇-PEG-的制备
甲醚聚乙二醇17(0.1mol)和叔丁氧羰基-甘氨酸-丝氨酸-胆固醇(0.1mol)(例18)与DCC(0.1mol)混溶在四氢呋喃(100毫升)。室温下搅拌过夜(约16小时),薄层色谱法或高效液相色谱法检测反应完成。过滤,真空除去溶剂,粗品经硅胶柱纯化(流动相:己烷:乙基乙酸酯(1:1,v/v)。得到叔丁氧羰基-甘氨酸-丝氨酸-胆固醇-PEG中间产品。
示例20:PEG17-胆固醇-甘氨酸-丝氨酸-6-β-环糊精的制备
得到叔丁氧羰基-甘氨酸-丝氨酸-胆固醇-PEG17(0.1mol)(例19)的二氯甲烷(500毫升)溶液中加入三氟乙酸(1mol)。室温搅拌2小时,脱掉氨基保护基Boc。反应液加入饱和的碳酸氢钠溶液(~10%),硫酸钠干燥有机相,真空除去溶剂,得到的中间体氨基-甘氨酸-丝氨酸-胆固醇-聚乙二醇17直接用于下一步反应,而没有进一步纯化。氨基-甘氨酸-丝氨酸-胆固醇-聚乙二醇17(0.1mol)和干燥单-6-氨基丙烯酰-6-脱氧-β-环糊精(0.1mol)溶于THF(500毫升),并加入三乙胺3%(v/v)。60-65℃下回流16小时下连续搅拌,真空除去溶剂,产生的蜡状初产品用己烷洗,真空干燥,得到苍白至淡黄色固体(80至95%),如化学结构18所示。
示例21:Nε叔丁氧羰基-Nα-胆固醇-赖氨酸的制备
在配有机械搅拌和加热套的圆底烧瓶中,Nε-叔丁氧羰基-赖氨酸(0.2mol)溶于150毫升的二氯甲烷溶液,加入三乙胺(0.4mol),反应混合物冷却至0和10℃的冰水浴中搅拌。滴加入胆固醇乙二醇乙酰氯(0.18mol)的二氯甲烷(100毫升)溶液。加完后,继续搅拌2小时,直接用于下一步反应。
化学结构18
示例22:Nε-叔丁氧羰基-赖氨酸-胆固醇-mPEG的制备
等量的mPEG与制备的Nε-叔丁氧羰基Nα-胆固醇-赖氨酸溶于200毫升四氢呋喃/二氯甲烷(1/1.v/v)的混合溶液,加入等量的DCC,常温下搅拌过夜。薄层色谱法或高效液相色谱法检测反应。反应结束后,过滤,真空浓缩过滤液。粗品经硅胶柱层析纯化(洗脱剂:乙酸乙酯/hexanes:1/1)得到的产品(产量≥50%)用于下一步反应。
示例23:Nε-赖氨酸-Nα-胆固醇-mPEG的制备
三氟醋酸(10当量)添加到Nε-叔丁氧羰基-赖氨酸-胆固醇-mPEG中间体(1当量)(例22)的二氯甲烷溶液,室温下搅拌2个小时。缓慢加入饱和碳酸氢钠溶液,静止分层,硫酸钠干燥有机相,过滤,真空干燥得到100%产率的中间体Nε-赖氨酸-胆固醇-mPEG。
示例24:Nεβ-环糊精-Nα-胆固醇-mPEG-赖氨酸的制备
等当量的单-6-氨基丙烯基-6-脱氧-β-环糊精与Nε-赖氨酸-Nα-胆固醇-mPEG混溶于四氢呋喃,加入3%(v/v)三乙胺,60-65℃下反应过夜,得到Nεβ-环糊精-Nα-胆固醇-mPEG-赖氨酸初产品(化学结构19)。反应混合物装在一层硅胶上,空气中挥发干燥。约1L的硅胶填在过滤漏斗中,预先干燥的样品硅胶放置在硅胶柱的顶部,依次用洗脱剂洗脱:丙酮/己烷(1/1)200毫升,丙酮/异丙醇(1/5)500毫升,和500毫升的100%丙酮。含有产品的洗脱剂部分真空干燥,得到Nεβ-环糊精-Nα-胆固醇-mPEG-赖氨酸(产率~80%)。
与例1到24类似的合成方法可用于其他聚乙二醇-环糊精-脂质缀合物的制备。同时也表明有些分子可以延伸和修饰含有3或4个的结合位点,这些相关的分子包括并不仅限于氨基醇与二元胺包括乙二胺、丙二胺、乙醇胺和氨基丙醇、丁醇、氨基戊醇、氨基己醇。
在本发明中,虽然在表4所示的聚乙二醇-环糊精-脂质缀合物是单取代的,由于环糊精结构的复杂性,可能存在不同取代的聚乙二醇-环糊精-脂质缀合物的混合物。为了质量控制和药学应用的方便,每个吡喃葡萄糖上的取代基越少越好。然而多个取代基吡喃葡萄糖并不影响的溶解度提高或牵连到任何安全问题,因为这些改进的环糊精的主要优点是与非环糊精辅料相比,它显著减少了每单位剂量的辅料用量。
化学结构19
在另一方面,聚合物链可以被其它聚合物例如聚甲二醇或聚丙二醇或者甲二醇,乙二醇和丙二醇的混合物代替。可用于形成本发明的聚合物-碳水化合物缀合物的亲水性聚合物包括聚乙二醇(PEG)和其它聚烯氧聚合物,聚氧乙基烷基醚,聚乙烯吡咯烷酮,聚(烯丙胺),聚(1-甲基丙烯酸甘油酯),聚(2-乙基–2-唑啉),聚(2-羟乙基甲基丙烯酯/甲基丙烯酸/聚2-羟乙基甲基丙烯酯)聚(2-乙烯基基吡啶),聚(丙烯酰胺/丙烯酸),聚(丙烯酸),聚(丁二烯/马来酸),聚(丙烯酸乙酯/丙烯酸),聚(氧乙基-b-氧丙基),聚(乙烯/丙烯酸),聚(甲基丙烯酸),聚(马来酸),聚(N-异丙烯酰胺),聚(N-乙烯基吡咯烷酮/乙酸乙烯酯),聚(苯乙烯磺酸),聚(苯乙烯磺酸/马来酸),聚乙酸乙烯酯,聚(乙烯基磷酸),聚(乙烯基胺),聚丙烯酰胺,聚丙烯酸,聚苯胺,聚乙烯亚胺,支链淀粉,聚甲基丙烯酰胺。也可以使用基于上述列举的共聚物和嵌段共聚物。游离聚合物在室温下是水溶性的,并且是无毒的。它们在哺乳动物中不会引起明显的免疫原性反应。具有窄分子量分布的亲水聚合物是优选的。由于制药业已经接受,PEG是优选的亲水性聚合物。
示例25:药用溶液的制备
如下制备适于药物递送的聚乙二醇-环糊精-脂质缀合物的溶液:4%(w/v)的聚乙二醇-环糊精-脂质缀合物加入装有搅拌器的容器中,并将2%(w/v)的活性药物成分(API)预先溶解于乙醇(1%的总体积,v/v),室温恒速搅拌下加入。继续搅拌,直到肉眼看见均匀澄清的溶液。等体积的生理盐水加入到容器中,充分搅拌。继续混合30分钟或直至达到均匀溶液。得到的溶液放置真空过夜,除去乙醇。示例配方如表5所述。
表5
成分 | 毫克/毫升 |
活性药物成分 | 10 |
聚乙二醇-环糊精-脂质缀合物 | 20.0 |
氯化钠 | 9.0 |
氢氧化钠 | 请参阅以下所述 |
盐酸 | 请参阅以下所述 |
纯化的水 | qs 1毫升 |
聚乙二醇-糖缀合物可能是本发明所述任何一种聚乙二醇-环糊精-脂质缀合物。PEG链是由6至45组成。活性药物成分依托咪酯、丙泊酚、阿伐他汀、多西紫杉醇、伏立康唑、波沙星、吉西他滨、铂类药、他克莫司、阿糖胞苷、异环磷酰胺、链球菌素、普卡霉素、紫杉醇、奥美拉唑、前列地尔、丝裂霉素、齐拉西酮、吡喹酮、奥美拉唑、地高辛、阿苯达唑、盐酸依维莫胺、磺胺甲噻酮、酮洛芬、灰黄霉素、伊曲康唑、卡马西平唑吡旦、苯妥英、芦丁、喜树碱、苯妥英、达那唑、氟西酮、螺内酯、雷帕霉素。氢氧化钠用于制备10%w/w的纯水溶液。pH的值在4.0至7.5范围。如有必要,稀碱或盐酸可用于调整pH值。
示例26:丙泊酚溶解度研究。
在具有不同PEG-碳水化合物缀合物的盐水溶液中制备1%(w/v)异丙酚。表6列出了将丙泊酚溶解度为溶解度试验参考所需的缀合物的最小浓度。虽然PEG-碳水化合物-脂质缀合物只需要较低的摩尔浓度用于溶解丙泊酚,但羟丙基-β-环糊精需要高得多的浓度,而PEG-环糊精-脂质缀合物仅需要约2%。混合2%胆固醇-丙二氨基乳糖苷-mPEG12和2-羟丙基-β-环糊精得到乳状液(图2)。
表6
在另一方面,本发明包括增溶不溶于水的药物的方法,即药物制剂,由于其在水中的低溶解度,通常需要与药学上可接受的载体配制以有效地递送到预期的部位。这种药物传递可以是静脉内、口服、局部、皮下、舌下或任何其它给药方式。本发明还包括用于这种给药的成分。与不溶于水性的药物的给药方式有关的方法和成分都使用本发明的PEG-环糊精-脂质缀合物和上述方法和材料。
示例27伏立康唑:溶解度研究
在具有不同PEG-脂质缀合物和改进环糊精的盐水溶液中制备1%(w/v)的伏立康唑。表7列出了将伏立康唑溶解为溶解度试验参考所需的缀合物的最低浓度。虽然N,N,N-油酰丙二胺-β-环糊精-MPEG(12)只需最低的聚合物与药物浓度比为用于溶解伏立康唑,但是需要高浓度的磺丁基醚-β-环糊精钠来溶解伏立康唑。这主要是由于当将非极性空腔和疏水中心与改进的环糊精或PEG-碳水化合物-脂质相结合时,会造成相对较强的疏水相互作用。该实例进一步证明了使用PEG-脂质-改进的环糊精缀合物溶解疏水化合物的是显著增强。尽管磺丁基醚-β-环糊精钠具有更多的负值LogP或水溶性,然而,亲脂性化合物的增溶效力也取决于增溶剂的保留功效。
表7
1亲水亲油平衡值
与天然的脂质如磷脂不同,本发明的缀合物不具有临界胶束浓度(CMC)。当表面活性剂的浓度大于CMC时,仅形成胶束,并且***的温度大于临界胶束温度。本发明的聚合物-环糊精-脂质缀合物可以以任何给定的浓度自发形成聚集体。
本发明公开了一种新的聚合物-环糊精-脂质缀合物,其具有可用作药物或分子传递的安全和生物相容性载体的聚合物-脂质取代基(通过中心骨架结构)中的至少一种。用于治疗,诊断或美容的化合物可以溶解或包封在那些聚合物-环糊精-脂质缀合物中以形成溶液或微悬浮液。
实施方案的另一特征或方面是在本专利申请提交时被证明可能广泛地存在化合物或制备化合物的方法,其中PEG-环糊精-脂质缀合物的结构如通用结构1到5所示。
通常,本发明包括用于合成聚合物-环糊精-脂质缀合物的成份和方法。缀合物包含甘油骨架、多胺、氨基酸与聚合物(PEG)链、环糊精和脂肪酸或胆固醇或“脂溶性”维生素或类似基团与中心骨架结合。可以在骨架和PEG链,环糊精或亲脂基团之间包括间隔物或连接基团,比如氨基酸。此外,PEG链的末端可以是带电荷或极性部分。例如,在本发明公开的至少一个方面,公开了用于改善治疗药物的生物相容性,并提高疏水性或亲脂性化合物在水中的溶解度的载体化合物。载体可以包含由下式表示的分子结构:
其中:脂质(Lipid)是包括类固醇酸和脂肪酸、甾醇和脂溶性维生素的亲脂性载体。
"CD"是包含α-,β-,γ-的环糊精。“mPEG”是聚乙二醇的聚合物;D是第二个脂肪酸、甾醇或亲脂性维生素或PEG;中心骨架(Backbone)是具有三个或四个可结合的位置但不是药物的分子,所述骨干包含甘油、甘油类似物、二胺、三胺、四胺、二氨基醇、氨基醇、氨基二醇、氨基三醇、氨基酸和多胺;L是包含具有三个可结合位置的甘油或甘油样类似物中的至少一种的偶联剂,二胺、三胺、二氨基醇、氨基醇、氨基二醇、氨基三醇和具有三个可用结合位置的氨基酸。
本发明的化合物是有效配制活性药物的配方成份,比如吉西他滨或铂类药物,由此减少与治疗相关的副作用和毒性。
在本发明中,PEG-环糊精-脂质缀合物的渗透增强性质可以增加药物的体内靶向传送,降低毒性并提高各种药物的口服生物利用度。
实施方案的另一特征或方面是在本专利申请提交时被证明可能广泛地存在化合物或制备化合物的方法,其中制备具有确定载体的聚合物-CD-脂质缀合物的方法通过包括以下步骤:
a.选择具有至少三个可用位点的无药物中心骨架部分用于三个载体和中心骨架之间的偶联;
b.选择聚合物作为第一个载体;
c.选择聚合物载体上的终端基团;
d.选择脂质作为第二载体;
e.选择环糊精作为第三个载体;
f.选择聚合物或脂质作为第四个载体;
g.或者选择非甾醇或脂溶性维生素的疏水性化合物作为第四个载体;
h.选择用于耦合载体和中心骨架的链的烷基化反应包括N-烷基化反应、O-烷基化、酯化或醚化或酰胺化。
本申请的另一个特征或方面是在本专利申请提交时被证明可能广泛地存在于化合物中,或者制备化合物的方法,其中每个缀合步骤的顺序不受限制,并且可以进一步包括烷基化、醚化、酯化或酰胺化:
a.保护羟基或氨基;
b.联接第一载体到中心骨架;
c.联接第二载体到中心骨架;
d.脱去羟基或氨基的保护基团;和
e.联接第三个载体到中心骨架。
实施方案的另一个特征或方面在本专利申请提交时被证明可能广泛地存在于化合物中,或者制备其中合适的分子可以用作主链的方法,包括甘油或甘油样类似物或二胺,三胺或多胺或具有羧基或胺的三元醇或二元醇或具有羟基或羧基的二胺和可延伸的胺或醇的多胺或三醇或二醇,其中疏水性载体是胆固醇或亲脂性维生素。
实施例的另一特征或方面在本专利申请提交时被证明可能广泛地存在于化合物中或制备聚合物是具有5至115个亚基的PEG的化合物的方法中。PEG链可以由约5到115个亚基组成。更倾向于PEG链由约8个和115个亚基组成。最好是PEG链由约8个和45个亚基组成。
本申请的另一个特征或方面在本专利申请提交时被证明可能广泛地存在于化合物中或制备聚合物是具有2个或更多个亚链的支链PEG的化合物的方法,每个亚链具有5至115个的PEG亚基。
在本专利申请的提交时可以广泛地描述化学化合物或制备具有无环载体基团的化合物的方法中证明了一个实施方案的另一特征或方面,其中疏水基团选自脂肪酸,包括月桂酸,肉豆蔻酸,棕榈酸,油酸和硬脂酸或甾醇,包括胆固醇,豆甾醇,麦角固醇,类胡椒甾醇,植物甾醇,谷甾醇,菜油甾醇,菜子甾醇,燕麦甾醇(avenasterol),阿多甾醇(adosterol),不含类固醇酸,甾醇(饱和类固醇或氢化固醇)或亲脂维生素:维生素E,包括但不限于生育酚和生育三烯酚,维生素D,包括但不限于胆钙化醇和麦角钙化醇,以及维生素A,包括但不限于类维生素A,视黄醇,视黄醛,视黄酸和类胡萝卜素。
实施例的另一特征或方面在本专利申请提交时被证明可能宽泛地存在于化合物中,或者制备具有非甾体或非“脂溶性”维生素的化合物的方法为第四载体基团,其中疏水基团可以选自饱和脂肪酸和不饱和脂肪酸或叶黄素、虾青素、黄体素、辣椒红色素(Capsanthin)、辣椒玉红素(capsorubin)、菊花黄素、番红花素、番红花素、隐黄素、岩藻黄素、隐黄质、叶黄素、新黄素、红宝石素、紫黄素、玉米黄素和多不饱和脂肪酸或多不饱和脂肪醇,包括天然多不饱和醇,如法呢醇、茄尼醇和十二烷酚。优选将胆固醇作为主要亲脂性载体,其可以降低或抑制脂肪酸的溶血活性。
实施例的进一步特征或方面在本专利申请提交时被证明可能广泛地存在于化合物中,或制备其中CD是环糊精的化合物的方法,其中包括α-环糊精、β-环糊精和γ-环糊精。
本申请的另一个特征或方面在本专利申请提交时被证明可能广泛地存在于化合物中或制备化合物的方法中,其中链选自于-S-,-O-,-N-,-OCOO-等基团,并在载体和中心主链之间形成酯、醚、酰胺的共价键。尽管烷基化、醚化、酯化或酰胺化的共轭反应优选在添加或不加入连接基团的情况下,载体或中心主链可以在最终偶联反应之前进行化学修饰。化学修饰的那些可以用一个或多个连接基团进行。
本申请的另一个特征或方面在本专利申请提交时被证明可能广泛地存在于化合物中,或者制备化合物的方法,其中PEG链于选自下列的聚合物:聚亚甲基二醇、聚丙二醇和由至少两种选自亚甲基二醇、乙二醇和丙二醇的单体组成的共聚物。
本申请的另一个特征或方面在本专利申请提交时可能广泛地存在于化合物或其中终端(R)基团优选易于极化的化合物或其制备方法中,负电荷或带正电荷的头基如烷氧基部分、胺、氨基酸和寡糖。
在提交本专利申请时,可以广泛地描述化学化合物或制备聚合物-环糊精-脂质缀合物的方法,其中用于缀合物的实施方案的另一特征或方面被证明能传递活性药物,特别是用于生物药物分类II或IV的难溶性水溶性化合物,包括但不限于阿法福康、异丙酚、多西紫杉醇、紫杉醇、伏立康唑和泊沙康唑。
实施方案的另一特征或方面在本专利申请提交时被证明可能广泛地存在于传递化合物的方法中,该方法包括制备基于聚合物-环糊精-脂质缀合物的制剂的化合物,其中PEG-环糊精-脂质包括PEG、脂质、环糊精和中心骨架,中心骨架选自乙二胺、二氨基丙烷、乙醇胺、氨基丙醇、氨基丁醇、氨基戊醇、氨基-1-己醇,中心骨架可以是化学上扩展和修改以提供所述第三或第四个可用的结合位置或位点。
说明性实施例的一个特征或方面被认为在提交本专利申请时可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中以改善治疗药物的生物相容性并提高疏水性或亲脂性药物在水中的溶解度这些缀合物包括如下的分子结构:
其中:脂质是脂肪酸、甾醇、甾烷醇、胆钙化醇、麦角钙化醇、类视色素、类胡萝卜素、生育酚或生育三烯酚的亲脂性载体;环糊精CD是包含α-环糊精、β-环糊精或γ-环糊精的环糊精;“mPEG”是聚乙二醇;D是重复的脂质或聚乙二醇;中心骨架是具有具有三个或四个可利用的结合位置或位点并且不含药物组分的主链中心骨架,该主链中心骨架包含甘油、具有三个结合位置的甘油样类似物、二胺、三胺、四胺、多胺、二氨基醇、氨基醇、氨基二醇、氨基三醇、具有三个或四个可用结合位置的氨基酸、三醇、四醇、三酸、四酸、含卤素的二醇、含卤素的胺和含羧基的二醇中的至少一种。
说明性实施例的另一特征或方面在本专利申请的提交时被认为可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中,其中中心骨架具有至少三个可用于偶合第一载体、第二载体和第三载体的可利用的结合位置或结合位点,每个所述可利用的结合位置或结合位点含有可扩展的氨基、羟基、丙烯酰基或羧基;第一载体包括可扩展的氨基、羟基、丙烯酰基或羧基基团,以及与之结合的脂质;第二载体包括可扩展的氨基、羟基、丙烯酰基或羧基基团,以及与之结合的mPEG;第三载体包括可扩展的氨基、羟基、丙烯酰基或羧基基团,以及与之结合的环糊精。
说明性实施例的另一个特征或方面被认为在提交本专利申请时可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中,其中主链包含至少四个可用的结合位置或用于联接第一载体、第二载体、第三载体和第四载体,每个可用的结合位置或位点包含可扩展的氨基、羟基、丙烯酰基或羧基。
相信在提交本专利申请时可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中的说明性实施例的另一个特征或方面,其中主链包含三个用于联接第一载体、第二载体和第三载体的可用的结合位置或位点,每个可用结合位置或位点包含可扩展的氨基、羟基、丙烯酰基或羧基,其中:第一载体具有可与主链结合的脂质;第二载体具有可与主链结合的mPEG,所述mPEG包含末端(R)基团;并且第三载体具有可与主链联接的环糊精。
说明性实施例的另一特征或方面被认为在提交本专利申请时可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中,其中中心骨架是(a)到(d)中的一个:(a)选自由甘油、甘油样类似物、多胺、二胺、三胺、四胺、氨基二醇、氨基三醇、氨基醇、具有三个可结合位置或位点的氨基酸、三醇、四醇、赤藓糖醇、三酸、四酸、四乙酸和酒石酸组成的组;(b)选自乙二胺、丙二胺、丁二胺、戊二胺、己二胺、二亚乙基三胺、二亚乙基三胺、双(3-氨基丙基)-胺、双(3-氨基丙基)-1,3-丙二胺或N,N'-双(3-氨基丙基)-1,3-丙二胺、三亚乙基四胺、1,2-双(3-氨基丙基氨基)乙烷、精胺、三(2-氨基乙基)胺、亚精胺、去甲精眯、双(六亚甲基)三胺、三(羟甲基)氨基甲烷、二氨基联苯胺、三氮杂环壬烷、四氮杂环十二烷、苏糖醇、内消旋赤藓糖醇、二硫苏糖醇、三甲基环己烷-1,3,5-三羧酸、1,3,5-环己烷三甲酸、三甲基双(六亚甲基)三胺、精氨酸、含氧二氨基丙酸、具有三个或四个可利用的结合位置或位点的草酰基二氨基丙酸、三元醇、三元酸、葡庚糖酸和酒石酸;(c)选自3-氨基-1,2-丙二醇、3-溴-1,2-丙二醇、3-氯-1,2-丙二醇、3-氟-1,2-丙二醇、DL-甘油酸、二氨基丙酸、酒石酸、葡庚糖酸、2,4-丁三醇、2,2-双(羟甲基)丁酸、1,3-二氨基-2-丙醇、2-(3-氨基丙基氨基)乙醇和3-((3-氨基丙基)-氨基)丙醇;以及(d)选自天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、赖氨酸、鸟氨酸、丝氨酸和苏氨酸。
说明性实施例的另一特征或方面被认为是在提交本专利申请时可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中,其中两个可接近的结合位置或位点选自氨基醇、二胺、乙二胺、二氨基丙烷、乙醇胺、氨基丙醇、氨基丁醇、氨基戊醇和氨基-1-己醇;化合物经化学扩展和改性以提供第三或第四个可用的结合位置或位点。
在提交本专利申请时,可能广泛地存在聚乙二醇-环糊精-脂质缀合物中的说明性实施例的另一个特征或方面,其中中心骨架的三个可结合位置或位点选自由甘油或甘油样类似物、二胺、三胺、四胺、多胺、三醇、异恶唑醇、三酸、氨基酸;并且中心骨干被化学扩展和修改以提供第四个可结合位置或位点。
在提交本专利申请时可能广泛存在于聚乙二醇-环糊精-脂质缀合物中的说明性实施例的另一个特征或方面,其中mPEG包含具有5至115个亚单位的单个PEG链或支链PEG具有2个或更多个子链,其中每个子链具有5至115个亚基,以及包含甲氧基,羟基或生物素的末端基团(R)。
说明性实施例的另一特征或方面在本专利申请提交时被认为可能广泛地存在于化合物载体聚乙二醇-环糊精-脂质缀合物中,其中脂质选自具有5至22个碳原子的脂肪酸。
说明性实施例的另一个特征或方面被认为在提交本专利申请时可能广泛地存在于聚乙二醇-环糊精-脂质缀合物中,其中中心骨架选自甘油、多胺、二胺、三胺、四胺、氨基二醇、氨基三醇、氨基醇、三醇、四醇、赤藓醇、三酸、四酸、四乙酸、葡庚糖酸、酒石酸和具有三个可结合位置或位点的氨基酸,CD选自α-环糊精、β-环糊精或γ-环糊精,其平均数量为每个吡喃葡萄糖重复单元的范围为0.6至3,脂质选自肉豆蔻酸、棕榈酸、硬脂酸肉豆蔻酸、棕榈油酸、苯乙酸、反油酸、异烯酸、亚油酸、生育酚、生育三烯酚、类维生素A、类胡萝卜素、胆钙化醇、类固醇和甾醇;mPEG是mPEGn,其中n代表乙二醇亚基的数目在5到115之间。
说明性实施例的另一个特征或方面被认为是在提交本专利申请时可能广泛地存在于如上所述的具有化合物载体的哺乳动物中治疗疾病或健康状况的方法中,该方法包括的应用于全身麻醉或***的镇静作用。
实施方案的另一特征或方面是将化学和物理方面的本发明与先前公开的专利发明申请US2012/202,979和US2012/202,890进行区分;在本发明中,加入了环糊精。如表4所示,在先前的发明中没有提到或使用这种结构可能增加这种类型缀合物的亲脂性。例如,PEG-环糊精-脂肪酸缀合物,PEG-环糊精-胆固醇缀合物和PEG-环糊精-脂溶性维生素缀合物的功能均为首次被证实。
虽然已经描述了本发明的优选实施方案,但本领域技术人员将能认识到,可以进行其他和另外的改变和修改,而不偏离本发明的精神,且所有这些变化和修改应当被理解为属于本发明的范畴。
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CA2988587C (en) | 2021-07-27 |
EP3313857A4 (en) | 2019-02-06 |
US10064954B2 (en) | 2018-09-04 |
US20160375150A1 (en) | 2016-12-29 |
EP3313857B1 (en) | 2021-01-06 |
JP7196378B2 (ja) | 2022-12-27 |
EP3313857A1 (en) | 2018-05-02 |
JP2018521152A (ja) | 2018-08-02 |
CA2988587A1 (en) | 2016-12-29 |
CN108026131A (zh) | 2018-05-11 |
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