CN111518285B - 可成像聚合物 - Google Patents
可成像聚合物 Download PDFInfo
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- CN111518285B CN111518285B CN202010385369.4A CN202010385369A CN111518285B CN 111518285 B CN111518285 B CN 111518285B CN 202010385369 A CN202010385369 A CN 202010385369A CN 111518285 B CN111518285 B CN 111518285B
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Abstract
本发明涉及可成像聚合物,尤其包含聚乙烯醇的那些,以及涉及用于制备所述聚合物的方法以及包含所述聚合物的栓子微球。所述微球在栓塞程序期间可成像并且可负载药物或其它治疗剂以提供可成像药物递送系统。
Description
本发明涉及不透射线聚合物和用于制造所述不透射线聚合物的方法。本发明提供不透射线水凝胶且具体说来不透射线水凝胶微球,其可在栓塞程序期间成像。所述微球可负载有药物或其它治疗剂以提供可成像药物递送系统。
射线不透性是指阻塞电磁辐射、尤其x射线的通道或使所述通道渐狭的特性。不透射线材料因此在X射线放射照片中或在X射线成像期间且在荧光检查下可见。不透射线材料因而在如计算机断层扫描(CT)和荧光检查的放射学和医学成像技术中发现多种用途。
血管栓塞(阻断血流)为肿瘤、纤维瘤和血管畸形的治疗中的重要医学程序,其中栓子或阻断引入血管中以减慢血流且诱导肿瘤和畸形的萎缩。多种栓子材料在临床使用中需要输导管递送至栓塞位点。近来,微球(本文中还称作“珠粒”)作为可注射栓子材料的用途变得普遍,因为其形状和尺寸可加以控制,使其用途比先前微粒材料更可预测。
栓塞程序的成像是重要的,因为其向临床医师提供监测栓子材料的精确位置且确保其施用于且保留于血管中的正确位置中,因此改进程序结果且降低程序风险的能力。目前仅在使用固有不透射线栓子材料时或通过混合非不透射线栓子粒子与不透射线材料才可能成像。
碘化聚乙烯醇(I-PVA)为在体内遭遇的水性条件中沉淀的呈粘性液体形式的不透射线栓子材料。然而,形成栓子的精确位置可为不一致的,有在脱靶位置中出现沉淀的风险。
然而,如和/>的造影剂按惯例与栓子粒子混合以向可注射组合物赋予射线不透性。尽管所述组合物为适用的,但栓子粒子的水性悬浮液和造影剂的不同物理特性导致不同体内定位。在施用后,造影剂为可见的,而非栓子粒子,且造影剂和栓子粒子不可停留于组织中的相同位置处。
因此,需要组合栓子微球的可预测性和可再现性益处与造影剂的射线不透性。
EP1810698描述了一种用于形成稳定不透射线栓子珠粒(本文中还称作RO珠粒或RO微球)的方法,其中PVA水凝胶栓子珠粒负载有碘化油以使其为不透射线的。使所述油保留于珠粒内的机制尚不清楚。此外,由于所述油为乙碘脂肪酸的混合物,所以最终产物未严密地定义且这种方法不提供对于造影剂从珠粒洗脱的控制,其也不涵盖造影剂对药物的负载和洗脱的影响。
WO2011/110589描述了通过将碘苯甲酰氯经由酯键联接枝至聚(乙烯醇)来合成碘化聚(乙烯醇)。虽然证明这种聚合物为不透射线的,但所述方法产生水不溶性聚合物,所述聚合物无法接着通过油包水聚合方法形成微球,所述油包水聚合方法通常用于产生具有所需栓塞特性的水凝胶微球。同一公布提及微球,但不含关于如何获得这种微球的公开内容。
Mawad等人(Biomacromolecules 2008,9,263-268)描述了基于PVA的可降解水凝胶的化学修饰,其中共价结合的碘被引入聚合物主链中以使所述聚合物为不透射线的。碘通过使PVA上的0.5%侧接醇基与4-碘苯甲酰氯反应而引入。所得聚合物为生物可降解的,经由沉淀栓塞且未形成微球。
因此,清楚地需要在单一产品中组合栓子珠粒的栓塞效率和可再现性与如乙碘油的造影剂的射线不透性的不透射线栓子材料。理想的栓子粒子是固有地不透射线且在大小和物理特性方面稳定且可再现的粒子,使得临床医师可执行栓塞程序且成像,从而更确定由栓子粒子产生可见造影。可能监测这些珠粒注射和沉积于血管位点中,但在临床追踪期间进行监测也将可能监测栓塞的效应,确保栓子保留于所需位置中且鉴定处于风险中的区域以用于进一步处理。其中可获得追踪成像的时间窗相对于现有方法显著增加。
射线不透性(削弱X射线的能力)可根据亨氏等级(Hounsfield scale)定量。亨氏单位基于体积(体素)量度射线不透性。X射线计算机断层扫描(CT)中的典型体素大约为1mm3且因此约100um直径的个别微球必须具有高射线不透性,以便其或其在容器中的集合(例如)将增加所述体素的射线不透性且因此目测。大于100HU且优选地大于500HU的射线不透性将为适当的。
除了良好的射线不透性,理想的栓子珠粒还将具有使有效药物负载和洗脱成为可能的特性,使得可以有把握监测化学栓塞程序。
本申请人已经确定,通过利用相对简单化学,有可能修饰聚合物以使其为不透射线的。包含一个或多个共价连接的不透射线卤素(如溴或碘)的低分子量醛通过与所述聚合物的1,3二醇基反应而偶合于所述聚合物。也有可能与1,2二醇反应。这形成与卤代基团共价偶合的环状缩醛(在与1,3二醇反应的情况下为二噁烷环)。所述卤代基团具有小于1000道尔顿且典型地小于750道尔顿的分子量。典型地,最小值为156道尔顿。
所述卤代基团典型地具有6个与18个之间的碳,但优选地6个与10个之间;和任选地一个氧原子;并且包含一个或多个共价连接的不透射线卤素的芳环。所述芳环优选地为苯基。
所述化学以可预测且可控制的方式产生聚合物,所述聚合物具有共价连接于所述聚合物的规定的不透射线基团。其可对任何含二醇聚合物执行且其尤其适合于水凝胶聚合物和预形成的微球,使得可使非不透射线微球固有地且永久地不透射线,而不会不利地影响微球的物理特性(即,大小、球形形状、高含水量、可溶胀性和可压缩性)。所述不透射线微球具有类似于和/或优于形成所述微球的非不透射线珠粒的药物负载能力和/或洗脱特性。所述微球的射线不透性为永久的或充分长寿命以允许在临床追踪期间进行监测。
后加工预形成的珠粒的能力提供在制造方面的灵活性程度,因为相同制造过程可用于不透射线和非不透射线珠粒和大小选择或筛分可在后加工之前进行,使得仅特定大小或大小范围的珠粒可制为不透射线的或必要时可在后加工之后进行,使得定大小(sizing)会考虑到归因于射线不透过程的珠粒大小的任何变化。
因此,在第一方面,本发明提供包含用不透射线物质缩醛化的1,2-二醇或1,3-二醇基团的聚合物。用不透射线物质缩醛化会产生通过环状缩醛基团(在1,3二醇聚合物的情况下为二噁烷)偶合于聚合物的不透射线物质。所述聚合物的射线不透性因此来源于具有经由环状缩醛键联共价并入聚合物中的不透射线材料。
如本文所用,“不透射线物质”和“不透射线材料”是指化学实体或通过所述化学实体修饰的物质,其在X射线放射照片中可见并且其可使用如计算机断层扫描的常规技术从围绕所述不透射线材料或物质的介质解析。
术语微球或珠粒是指微米大小的球形或接近球形栓子材料。术语粒子或微米粒子是指形状不规则并且一般来源于例如使较大单块破裂的栓子粒子。
其中除非另外规定,否则本文指出“卤素”或“卤代”碘为优选的。
对以HU为单位的射线不透性水平的提及是指通过X射线微计算机断层扫描,并且优选地当使用0.5mm铝制滤板和65kV的源电压,优选地在如本文所述的琼脂糖体模(实施例12)中,优选地使用本文所述的仪器和条件(实施例12)测量时进行的测量。对在灰度单位方面的射线不透性的提及也指通过X射线微计算机断层扫描在这些条件下进行的测量。
对“湿珠粒”或“完全水合珠粒”的提及意指在生理盐水(0.9%NaCl1mM磷酸盐缓冲液pH7.2至7.4,作为填充体积(例如,如在量筒中所定量)中充分水合的珠粒。
在这方面和其它方面,所述聚合物可为包含1,2-二醇或1,3二醇基团或其混合物的任一聚合物。优选地,所述聚合物在聚合物主链中包含高程度的二醇基,如聚羟基聚合物。所述聚合物适合地为水凝胶或其它交联聚合物网络。尤其适合的聚合物为包含聚乙烯醇(PVA)或PVA的共聚物的那些。基于PVA的水凝胶为尤其优选的,因为其为所属领域中众所周知的并且广泛地用于栓塞程序。
在一个特定实施方案中,所述聚合物包含具有携带可交联基团的侧链的PVA骨架,所述可交联基团交联以形成水凝胶。所述PVA骨架具有至少两个含有可交联的基团的侧链,所述基团如乙酸酯基和丙烯酸酯基。所述交联剂宜以每克骨架约0.01至10毫当量的交联剂(meq/g)、更宜约0.05至1.5meq/g的量存在。所述PVA聚合物可含有超过一种类型的可交联基团。所述侧链宜经由所述聚合物骨架的羟基连接,经由环状缩醛键联连接于所述PVA的1,3-二醇羟基。
经修饰PVA的交联可经由多种方式中的任一种,如物理交联或化学交联。物理交联包括但不限于络合、氢键结、去溶剂化、范德华相互作用和离子键结。化学交联可通过多种方式实现,所述方式包括但不限于链反应(加成)聚合、逐步反应(缩合)聚合和如对于聚合物化学家来说将为惯常的其它方法。
PVA聚合物骨架上的交联基团适合地为烯系不饱和官能团,如乙酸酯基,其可经由自由基引发聚合交联而无需添加醛交联剂。优选地,所述PVA聚合物包含用N-丙烯酰基-氨基乙醛二甲基缩醛(NAADA)使PVA缩醛化所形成的侧接乙酸酯基团。PVA的所述修饰描述于美国专利号5,583,163中。这种类型的经修饰PVA的实例为Nelfilcon A。
可交联PVA适合地与额外乙烯系共聚单体并且适合地亲水性乙烯系共聚单体,如羟基取代的低碳烷基丙烯酸酯和甲基丙烯酸酯、丙烯酰胺和甲基丙烯酰胺交联。在一个特定实施方案中,如上文所述的经修饰PVA与2-丙烯酰胺基-2-甲基丙烷磺酸(来自LubrizolCorporation的单体)交联以提供丙烯酰胺基聚乙烯醇-共-丙烯酰胺基-2-甲基丙烷磺酸酯水凝胶。在一个优选实施方案中,所述交联反应作为反相乳液聚合反应执行以产生呈微球形式的丙烯酰胺基聚乙烯醇-共-丙烯酰胺基-2-甲基丙烷磺酸酯水凝胶。
本发明的聚合物或水凝胶由于通过呈环状缩醛形式的聚合物共价连接的不透射线材料而为不透射线的。用于环状缩醛的形成的反应为有机化学中众所周知的并且因此,任何能够形成环状缩醛的不透射线物质均预计在本发明的范围内。已知多种材料为不透射线的,如碘、铋、钽、钆、金、钡和铁。如卤素的电子致密元素为尤其适用的。溴、氯、氟和碘可容易地并入能够形成环状缩醛键联的有机分子中并且提供高程度的射线不透性。因而,在一个特定实施方案中,所述不透射线聚合物包含共价连接的卤素,优选为碘。所述不透射线卤素可共价连接于芳族基团以形成通过环状缩醛连接于聚合物的不透射线物质。所述芳族基团可包含1、2、3或4个共价连接的不透射线卤素,如溴或碘。所述基团优选地包含共价连接1、2、3或4个所述不透射线卤素的苯基。因此,所述聚合物便利地包含卤代基团(下式中的X),其包含经由环状缩醛连接于所述聚合物的共价结合的不透射线卤素,如碘。
用不透射线物质缩醛化会产生通过如下文说明的环状缩醛基团偶合于聚合物的不透射线物质。所述不透射线聚合物具有或包含根据通式I(在PVA中,J为-CH2-)或II(其说明具有1,2或1,3二醇的其它聚合物)的结构:对所述聚合物中缩醛化的所述基团的数目(n)的控制会控制所存在的碘的量并且因此控制射线不透性。每gm材料中二醇的数目讨论如下。
其中X为由一个或多个卤素且优选地一个或多个溴或碘部分取代的基团并且n至少为1。
J为基团-CH2-或为键。
X优选地为下式的基团
其中Z为键结于所述环状缩醛的连接基团或不存在,使得所述苯基键结于环状缩醛;
如果Z存在,那么Z为C1-6亚烷基、C1-6亚烷氧基或C1-6烷氧基亚烷基;
Hal为1、2、3或4个共价连接的不透射线卤素
优选地,如果Z存在,那么Z为亚甲基或亚乙基或基团–(CH2)p-O-(CH2)q-,其中q为0、1或2且p为1或2;更优选地,选自-CH2O-、-CH2OCH2-和-(CH2)2O-的基团,
具体说来,Z为-CH2OCH2-或-CH2O-或不存在
Hal具体说来为3或4个溴或碘并且优选地为碘,如2,3,5或2,4,6三碘或2,3,4,6四碘
J优选地为-CH2-。
因此,优选地,不透射线碘以碘化苯基的形式并入聚合物中。如上文,碘化苯基通过环状缩醛键联并入聚合物中。
如上文所述的那些和尤其卤代(例如碘化)苯基的基团为适用的,因为其可经单、二、三或甚至四取代以便控制并入不透射线聚合物中的卤素(如碘)的量,并且因此控制射线不透性的水平。
卤代的潜在水平也受聚合物起始材料中1,3或1,2二醇基团的水平影响。所述水平可基于所述聚合物的结构和-OH基团的任何取代的存在或不存在,例如通过交联剂或其它侧基估算。具有至少0.1mmol/g干燥聚合物的-OH基团水平的聚合物为优选的。具有至少1mmol/g的水平的聚合物为更优选的。卓越的射线不透性水平已经由具有大于5mmol/g-OH基团(2.5mmol/g二醇)的聚合物实现。
所属领域的技术人员应了解,聚合物中的碘或其它不透射线卤素的量也可通过控制聚合物中的缩醛化程度来控制。在本发明中,所述聚合物包含多达50%的缩醛化二醇基团。优选地,所述聚合物中的至少10%的二醇基团缩醛化并且更优选地至少20%的二醇基团缩醛化。无论所述聚合物中的卤素(例如碘)的量是通过增加例如苯环上的取代还是通过控制所述聚合物的缩醛化程度来控制,所得聚合物均含有以干重计至少10%卤素(卤素重量/总重量)。优选地,所述聚合物含有以干重计至少20%卤素并且优选地以干重计大于30%、40%、50%或60%卤素。适用的照影由具有以干重计在30与50%之间的卤素的聚合物获得。
卤素含量也可表述为卤素的量(以mg为单位)/ml珠粒。这是指卤素的量/ml在作为填充体积(例如,如在量筒中所定量)的生理盐水中充分水合的珠粒。本发明提供具有例如大于15mg/ml湿珠粒的卤素(尤其为碘)水平的珠粒。大于25或50mg、优选地大于100mg/ml珠粒的卤素(尤其为碘)含量已经提供良好结果。
本发明尤其适合于水凝胶和尤其呈微粒或微球形式的水凝胶。微球尤其适用于栓塞,因为微球的大小可控制(例如通过筛分)并且栓子的不必要聚集由于球形形状而避免。微球可通过所属领域的技术人员已知的多种技术,如单一和双重乳液、悬浮聚合、溶剂蒸发、喷雾干燥和溶剂提取来制备。
包含聚乙烯醇或乙烯醇共聚物的微球描述于例如Thanoo等人Journal ofApplied Biomaterials,第2卷,67-72(1991);WO0168720、WO03084582;WO06119968和WO04071495(其以引用的方式并入本文)中。在一个特定实施方案中,所述水凝胶微球由如上文所述(并且公开于US5,583,163中)用N-丙烯酰基-氨基乙醛二甲基缩醛(NAADA)修饰并且如上文所述与2-丙烯酰胺基-2-甲基丙烷磺酸交联的PVA制备。这种类型的水凝胶微球描述于US 6,676,971和US 7,070,809中。
微球可以介于约10微米(μm)至2000μm范围内的大小制备。较小的大小可通过微脉管系统且堆积于别处。在大多数应用中,其将需要具有小的大小范围的微球以便减少团集且提供可预测的栓塞。可控制用于制备微球的方法以实现特定所需的大小范围的微球。如筛分的其它方法可用于甚至更严密地控制微球的大小范围。
在一个特定实施方案中,根据本发明的水凝胶或非水凝胶微球具有10至2000μm、更优选地20至1500μm且甚至更优选地40至900μm的平均直径大小范围。微球的制剂典型地提供在适合所计划的处理的大小范围内的粒子,例如100-300、300-500、500-700或700-900微米。较小粒子倾向于更深地进入血管床中且因此对于某些程序,在范围40-75、40-90和70-150微米内的粒子为尤其适用的。
在一个特定实施方案中,所述聚合物为在生理pH(7.4)下具有净负电荷的水凝胶微球。
射线不透性可根据亨氏等级定量,在亨氏等级下蒸馏水具有0亨氏单位(HU)的值,并且空气具有-1000HU的值。便利地,栓子微球将具有大于100HU且甚至更优选地大于500HU的射线不透性。使用本文所述的方法,已经有可能制备具有大于10000HU的射线不透性的不透射线微球。优选的微球具有大于2000、3000、4000或5000HU的射线不透性。这些水平的射线不透性允许所述微球与例如血液(30-45HU)、肝(40-60HU)、脑(20-45HU)和软组织(100-300HU)区分。
射线不透性也可根据American Society for Testing and Materials(ASTM)F-640在背景减除后以在0与255之间的灰度单位表述。
本发明的另一方面因此提供如本文中在第一方面所述的不透射线微球,其具有至少500HU的射线不透性。
这个实施方案的水凝胶微球可与适合的赋形剂或稀释剂,如注射用水一起用于组合物中,并且直接用于使血管栓塞。因此,本发明的另一方面提供一种药物组合物,其包含如本文所述的水凝胶微球和药学上可接受的载剂或稀释剂。
因而,包含由包含用如本文所述的不透射线物质缩醛化的1,2-二醇或1,3-二醇基团的聚合物形成的不透射线水凝胶微球的药物组合物形成本发明的另一方面。优选所述聚合物包含通过如上文所述的环状缩醛键联共价结合于所述聚合物的碘化芳族基团。
包含所述不透射线微球的药物组合物也可包含额外不透射线材料,如造影剂(离子的或非离子的,包括油性照影剂,如乙碘罂粟籽油适合的非离子照影剂包括碘异酞醇、碘克沙醇、碘海醇、碘普胺、碘比醇、碘美普尔、碘喷托、碘必乐、碘昔兰、碘曲仑、碘酞胺醇和碘佛醇。
也可使用离子照影剂,但其不优选与负载药物的离子交换微球组合,因为高离子浓度有利于离子药物从基质离解。离子照影剂包括泛影葡胺、甲基三元影酸和碘克酸。
所述微球可通过所属领域中认可的任何方法干燥,然而在真空下干燥,如通过冷冻干燥(冻干)是有利的,因为其允许微球干燥并且在减压下存储。这种方法引起改进的再水合,如WO07147902(其以引用的方式并入本文)中所讨论。典型地,存储干燥微球时所处的压力小于1毫巴(线径)。
或者或另外,有效量的一种或多种生物活性剂可包括于栓子组合物中。可需要递送来自所形成的不透射线水凝胶或来自微球的活性剂。可需要递送的生物活性剂包括预防剂、治疗剂和诊断剂,其包括有机和无机分子和细胞(本文中统称为“活性剂”、“治疗剂”或“药物”)。多种活性剂可并入所述不透射线水凝胶和微球中。从所述水凝胶释放所并入的活性剂是通过使所述试剂与如体液的水性介质接触从水凝胶扩散、使所述水凝胶降解和/或使偶合所述试剂至所述聚合物的化学键降解来实现。在这方面,“有效量”是指获得所需效应所需的活性剂的量。
因此,另一方面,本发明提供一种药物组合物,其包含如上文所述的不透射线水凝胶微球和治疗剂,其中所述治疗剂吸附至水凝胶基质中。本发明的另一方面提供一种包含一种或多种如本文所述的不透射线水凝胶微球的组合物,所述微球另外包含一种或多种治疗剂,如药物活性剂。可并入的活性剂或药物活性剂的实例包括但不限于抗血管生成剂、细胞毒性剂和化学治疗剂,从而使所述微球尤其适用于化学栓塞程序。
在一个尤其有利的实施方案中,本发明的不透射线水凝胶微球具有净电荷,使得带电药物可例如通过离子交换机制负载至所述微球中。结果,治疗剂通过静电保持于水凝胶中并且在如生理盐水的电解介质中或体内,例如在血液或组织中从水凝胶洗脱,以提供药物在数小时、数天或甚至数周内的持续释放。在这个实施方案中,尤其适用的是本发明的不透射线水凝胶微球在包括生理条件(7.4)的pH范围内具有净负电荷,使得带正电药物可控制地并且可再现地负载至所述微球中,并且通过静电保留于其中,用于随后在体内从水凝胶延长洗脱。所述电荷可来源于连接于聚合物基质的离子交换基团,如羧基或磺酸酯基。应了解,在生理pH下无电荷的药物可仍负载至本发明的微球中并且这在需要快速洗脱或“突释效应”时,例如在栓塞后即刻可为尤其有利的或简单地用于在不需要或不必要栓塞或其在生理条件下的低溶解性而非离子相互作用决定其释放概况的情况下快速药物递送至组织。
可以这种方式负载的药物的尤其优选的实例包括但不限于喜树碱(如依立替康和拓扑替康)和蒽环霉素(如阿霉素、柔红霉素、伊达比星和表柔比星)、抗血管生成剂(如血管内皮生长因子受体(VEGFR)抑制剂,如阿西替尼、硼替佐米、伯舒替尼、卡奈替尼、多韦替尼、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、来他替尼、麻舒替尼、莫立替尼(mubitinib)、帕唑帕尼、帕唑帕尼司马沙尼、索拉非尼、坦度替尼、凡德他尼、瓦他拉尼和维莫德吉)、微管组装抑制剂(如长春花碱、长春瑞滨和长春新碱)、芳香酶抑制剂(如阿那曲唑)、铂药物(如顺铂、奥克赛铂、卡波铂和米铂)、核苷类似物(如5-FU、阿糖胞苷、氟达拉滨和吉西他滨)和。其它优选药物包括紫杉醇、多西紫杉醇、丝裂霉素、米托蒽醌、博来霉素、平阳霉素、阿比特龙、阿米福汀、布舍瑞林、地加瑞克、亚叶酸、戈舍瑞林、兰瑞肽、来拉度胺、来曲唑、亮丙瑞林、奥曲肽、他莫昔芬、曲普瑞林、苯达莫司汀、苯丁酸氮芥、达卡巴嗪、美法仑、甲基苄肼、替莫唑胺、雷帕霉素(和类似物,如佐他莫司、依维莫斯、佐他莫司和西罗莫司)、甲氨蝶呤、培美曲塞和雷替曲塞。
所述不透射线水凝胶微球优选地为水可溶胀的,但为水不可溶的。
在一个实施方案中,所述珠粒为水可溶胀的,但在水中具有一些溶解性。在这个实施方案中,溶胀程度可通过使用水性盐溶液或适合的溶剂来控制,如可通过常规实验来确定。这可尤其应用于非共价交联的PVA聚合物。
在另一实施方案中,所述珠粒为水和溶剂可溶胀的,但也为生物可降解的。在这个实施方案中,所述珠粒在介于4周至24个月范围内的一段时间内体内生物降解。包含PVA的生物可降解聚合物公开于例如WO2004/071495、WO 2012/101455和Frauke-Pistel等人J.Control Release 2001年5月18日;73(1):7-20中。
如上文所讨论,本发明的不透射线聚合物可通过使用简单化学直接修饰预形成的微球以使其固有地不透射线来制备。因此,另一方面,本发明提供一种制备不透射线聚合物的方法,所述方法包括使包含1,2-二醇或1,3-二醇基团的聚合物与能够与所述1,2-二醇或1,3二醇优选地在酸性条件下形成环状缩醛的不透射线物质反应。
尤其,所述能够形成环状缩醛的不透射线物质包含共价结合的不透射线卤素,如本文所述的碘。尤其,卤素共价结合于如苯基的芳族基团。
所述化学尤其适合具有具有1,2-二醇或1,3-二醇结构的单元的主链的聚合物,如聚羟基聚合物。例如,聚乙烯醇(PVA)或含有1,3-二醇骨架的乙烯醇的共聚物。所述主链也可含有呈1,2-二醇形式的羟基,如1,2-二羟基乙烯的共聚物单元。这些单元可例如通过乙酸乙烯酯-碳酸亚乙烯酯共聚物的碱性水解获得。
可使用其它聚合物二醇,如糖。在一个特定实施方案中,所述聚合物发生交联,如交联PVA或PVA的共聚物。
可如本文所述衍生化的聚乙烯醇优选地具有至少约2,000的分子量。作为上限,PVA可具有多达1,000,000的分子量。优选地,PVA具有多达300,000、尤其多达约130,000且尤其优选多达约60,000的分子量。
在一个优选实施方案中,所述PVA为交联PVA水凝胶,其中用N-丙烯酰基-氨基乙醛二甲基缩醛(NAADA)修饰的PVA如上文所述与2-丙烯酰胺基-2-甲基丙烷磺酸交联,优选地呈微球的形式,如US6,676,971和US 7,070,809中所述。
所述不透射线物质经缩醛化,并且通过二醇基团共价连接于所述聚合物。优选的不透射线物质为电子致密化学部分,如提供大于+1HU的射线不透性的简单有机分子或有机金属复合物,并且其包含使得能够在所述聚合物上与二醇基团形成环状缩醛的反应性部分。特定反应性部分包括醛、缩醛、半缩醛、硫缩醛和二硫缩醛。
在一个特定实施方案中,所述不透射线物质包含溴或碘。这是便利的,因为其中溴或碘已经被取代的小有机分子可在市面上购得或可使用所属领域中众所周知的化学制备。例如,碘化或溴化醛为不透射线的并且容易使用本发明的方法并入含二醇聚合物中。尤其适用的不透射线物质包括碘化或溴化苄基醛、碘化苯基醛和碘化苯氧基醛。
不透射线醛与含二醇聚合物的反应与已经预形成为例如微球(不过预期其它预形成的水凝胶结构,如涂层)的水凝胶聚合物一起令人意外地良好工作。因此,另一方面,本发明提供一种制备不透射线水凝胶微球的方法,所述方法包括以下步骤:
(a)使包含具有1,2-二醇或1,3-二醇基团的聚合物的预形成的水凝胶微球在能够使所述微球溶胀的溶剂中溶胀;和(b)使溶胀的微球与能够与所述1,2或1,3二醇在酸性条件下形成环状缩醛的不透射线物质的溶液混合或接触;以及(c)提取或分离所述微球。
所述提取或分离的微球可接着直接使用、调配成如上文所述的药物组合物或干燥用于长期存储。
在一个优选实施方案中,所述反应在丙烯酰胺基聚乙烯醇-共-丙烯酰胺基-2-甲基丙烷磺酸酯水凝胶微球上执行。所述微球的实例描述于US 6,676,971和US 7,070,809中。
所述反应便利地在极性有机溶剂并且更特定地如四氢呋喃(THF)、乙酸乙酯、丙酮、二甲基甲酰胺(DMF)、乙腈(MeCN)和二甲亚砜(DMSO)的极性质子惰性溶剂中进行,不过适合的溶剂将由熟练人员通过常规实验和/或考虑如沸点、密度等的溶剂特性来确定。
所述反应为快速地并且可在室温下或在高温下进行以改进产率并且减少反应时间。在一个优选实施方案中,所述反应在大于25℃并且适合地大于40℃但小于135℃并且优选地小于80℃的温度下进行。在50与75℃之间的反应温度为尤其适用的。在高温下,水凝胶珠粒转化为不透射线水凝胶珠粒可在仅仅2-3小时内实现。
如上文,所述不透射线物质包含选自由醛、缩醛、半缩醛、硫缩醛和二硫缩醛组成的群组的官能团,并且包含碘或其它不透射线卤素。在这方面,如缩醛和硫缩醛的基团可被视为被保护的醛。如碘化苄基醛、碘化苯基醛或碘化苯氧基醛的碘化醛为尤其适用的并且其广泛可得且产生良好反应产率。
因此,优选地所述不透射线物质为式IV化合物:
其中
A为能够与1,2二醇或1,3二醇形成环状缩醛的基团。
优选地,A为醛、缩醛、半缩醛、硫缩醛或二硫缩醛基团;
优选地,A为–CHO、-CHOR1OR2、–CHOR1OH、–CHSR1OH或–CHSR1SR2,其中R1和R2独立地选自C1-4烷基,优选为甲基或乙基。
已经显示产生不透射线PVA水凝胶微球的不透射线物质的特定实例包括2,3,5-三碘苯甲醛、2,3,4,6-四碘苯甲醛和2-(2,4,6-三碘苯氧基)乙醛。
另一方面,本发明提供通过包含1,2-二醇或1,3-二醇基团的聚合物与卤代醛、卤代缩醛或卤代半缩醛、卤代硫缩醛或卤代二硫缩醛的反应获得或可获得的不透射线水凝胶微球。
在这一方面的一个优选实施方案中,所述不透射线水凝胶微球通过丙烯酰胺基聚乙烯醇-共-丙烯酰胺基-2-甲基丙烷磺酸酯水凝胶微球的反应获得。这些微球的实例公开于US 6,676,971、US 7,070,809和WO 2004/071495中,已经发现这些微球快速地与碘化醛、碘化缩醛和碘化硫缩醛反应以生成具有高碘含量的不透射线微球并且提供良好体内照影。物理特征(大小、形状、电荷、药物负载能力等)不会受碘化作用不利地影响并且在一些情况下有所改进。处置看来也在很大程度上不受影响。机械坚固性得以保留并且所述珠粒不会在照影剂和其它递送媒剂中充分聚集和悬浮,使得通过导管的递送可相对简易实现。已经观察到递送平滑并且均匀,而无所述导管的任何阻塞。此外,所述珠粒对蒸汽和高压釜灭菌方法稳定。
尤其适合的碘化醛包括但不限于2,3,5-三碘苯甲醛、2,3,4,6-四碘苯甲醛和2-(2,4,6-三碘苯氧基)乙醛。
上文所述的不透射线微球和组合物可用于其中本文所述的微球或包含所述微球的组合物施用于患者的血管中以使所述血管栓塞的处理方法中。所述血管可能为与实体肿瘤有关的血管,所述实体肿瘤如富血管肝肿瘤(包括肝细胞癌(HCC))和一些其它肝转移(包括转移性结肠直肠癌(mCRC))以及神经内分泌肿瘤(NET)。所述处理方法为可成像的并且向临床医师提供实时或接近实时的对所述程序的良好视觉反馈。所述方法尤其适用于药物活性剂负载于微球中的情况,并且所述处理将治疗有效量的所述活性剂提供至有需要的患者。
不透射线微球也可用于其中所述微球通过注射递送至作用位点的程序中。进行这种程序的一种方法是将包含药物活性剂的微球通过注射直接递送至肿瘤。
本发明还提供用于上文所述的处理方法中的本发明的组合物和微球。
本文所述的微球意外地在负载和洗脱药物方面有效。所述微球容易负载带正电药物,如尤其阿霉素、表柔比星、柔红霉素、伊达比星和依立替康。实验研究已经显示所述微球负载和洗脱药物的能力在使用本发明的化学使珠粒不透射线之前与其在反应后相同。在一些情况下,药物负载效率或能力意外地改进超过50%。在一些情况下,已经测量出药物负载的100%增加。在多种情况下,药物洗脱的程度如与所述珠粒的非不透射线型式相比不受影响,在一些情况下实质上所有药物均在一段持续时期内从珠粒洗脱。在多种情况下,药物洗脱概况有所改进,因为药物从不透射线微球洗脱经历的时间如与相等非不透射线微球相比有所增加。本发明的微球因此意外地提供相对于其非不透射线相等物增加的药物负载效率和改进的(即,延长的)药物洗脱。
本发明的上述方面和实施方案中的任一者的聚合物或微球均可用于其中提供一种使栓塞程序成像的方法的本发明的另一方面中。另一方面,提供一种在程序完成后监测栓塞的方法。视本发明的不透射线聚合物的生物降解的永久性或速率而定,其中可监测栓塞的程序后窗可在数天、数周或甚至数月的范围内。
本发明现将经由以下非限制性实施例参考图式进一步描述。这些实施例仅为了说明目的而提供并且所属领域的技术人员根据这些实施例将想起属于权利要求书的范围内的其它实施例。本文所引用的所有参考文献书目均以引用的方式并入。
图式
图1为根据实施例制备的不透射线水凝胶珠粒的显微照片。所示的珠粒在不同照明条件下在碘化后筛分为75-300μm。
图2为根据本发明制备的不透射线珠粒的微CT图像。图2A为不透射线珠粒的3D放射照片。图2B显示2D微CT图像。线剖面(图2C)显示:x轴(μm)为所绘线的长度(在放射照片的截面中以红色显示;并且y轴使用介于0(黑色)至255(白色)范围内的灰度值指示强度水平。
图3显示根据本发明制备的灭菌不透射线珠粒在负载有阿霉素之前和之后的光学显微照片。图3A显示负载之前的不透射线珠粒并且图3B显示负载药物的珠粒。
图4显示负载有阿霉素的RO和非RO珠粒的洗脱概况。所述珠粒的直径为70-150um。RO珠粒为158mg I/ml湿珠粒。两种珠粒类型均负载有50mg阿霉素/ml湿珠粒。
图5显示负载有舒尼替尼的RO珠粒的洗脱概况。
图6显示负载有索拉非尼的RO和非RO珠粒的洗脱概况。RO珠粒为70-150um大小并且具有碘含量134mg I/ml湿珠粒。
图7显示负载有凡德他尼的RO和非RO珠粒的洗脱概况。所述珠粒的直径为70-150um。RO珠粒为158mg I/ml湿珠粒。
图8显示负载有米铂的RO和非RO珠粒的洗脱概况。珠粒为70-150um大小并且RO珠粒具有碘含量134mg I/ml湿珠粒。
图9显示负载有拓扑替康的RO和非RO珠粒的洗脱概况。RO和非RO珠粒具有70-150um大小并且RO珠粒具有碘含量146mg I/ml湿珠粒。
图10显示根据本发明制备的10种RO珠粒与水和空气空白相比的样品横截面微CT图像。
图11显示在使用本发明的RO珠粒栓塞后由单一猪拍摄的CT扫描。
(a)栓塞前;(b)栓塞后1小时;(c)栓塞后7天;(d)栓塞后14天。箭头指示血管中的RO珠粒。
在这些实施例中,包含1,2-二醇或1,3-二醇基团的聚合物的结构由以下结构表示:
实施例
实施例1:由2,3,5-三碘苄醇制备2,3,5-三碘苯甲醛
在配备有温度计、氮气泡和气密密封的50ml三颈圆底烧瓶中,10.2g所述醇在氮气层和搅拌条件下溶解于100ml无水DMSO中。接着,在22℃至25℃下经5分钟逐滴添加1.0摩尔当量的丙烷膦酸酐(T3P)(乙酸乙酯中的50%溶液)。反应溶液在室温下搅拌并且通过高效液相色谱(柱:Phenominex Lunar 3um C18:流动梯度:相A水0.05%TFA,相B ACN 0.05%TFA,经10min线性梯度A至B:柱温度40℃:流动速率1ml/min:在240nm下UV检测)监测。转化在240分钟后完成。所述黄色溶液在搅拌下倒入100ml去离子水中,生成白色沉淀,所述沉淀过滤,用母液和50ml去离子水洗涤。滤饼在50ml乙酸乙酯中成浆,过滤并且再用50ml水洗涤,在40℃下在亚真空下干燥20小时以生成7.7g白色固体。结构和纯度通过NMR分析和高效液相色谱确认。
实施例2:制备2-(2,3,5-三碘苯氧基)乙醛
a)由2,4,6-三碘苯酚合成2-(2,4,6-三碘苯氧基)乙醇
在配备有温度计、氮气泡和顶置式搅拌器的500ml三颈平底烧瓶中,10g苯酚在氮气层和剧烈搅拌条件下在室温下溶解于100ml乙醇中。添加1.25摩尔当量的氢氧化钠小球并且在氮气层下搅拌所述浆液30分钟直至所述小球完全溶解。接着,添加1.1摩尔当量的2-碘乙醇,维持温度在25℃下并且搅拌15分钟。所述溶液加热至乙醇回流。通过HPLC(按照实施例1的条件)监测所述苯酚的消耗和2-(2,4,6-三碘苯氧基)乙醇的形成。25小时后,再添加0.27摩尔当量的2-碘乙醇并且所述溶液再在回流下搅拌2小时。在冷却所述溶液至室温后,在剧烈搅拌条件下快速添加150ml去离子水。所得浆液在真空下过滤,用母液洗涤,用30ml去离子水洗涤三次并且最终用5ml乙醇洗涤。所得粉色滤饼溶解于100ml乙酸乙酯中并且有机层用大量的氢氧化钠溶液(pH 14)提取,经硫酸镁干燥并且在旋转蒸发器上浓缩以生成5.9g灰粉色固体,所述固体通过用来自sigma-aldrich的商业分析标准物进行比较分析而鉴定为2-(2,4,6-三碘苯氧基)乙醇。
(b)氧化2-(2,4,6-三碘苯氧基)乙醇为2-(2,3,5-三碘苯氧基)乙醛:
在配备有温度计、氮气泡和顶置式搅拌器的500ml三颈平底烧瓶中,5.9g所述醇在氮气层下溶解于150ml无水DMSO中。所述溶液搅拌且加热至40℃,并且缓慢添加1.6摩尔当量的T3P(EtOAc中的50%w/w溶液),同时维持温度在40℃至41℃下。通过高效液相色谱随时间(按照实施例1的条件)监测醇的消耗和醛的产生。24小时后,使用注射泵经2小时将150ml水缓慢地添加至反应混合物中。灰粉色固体从所述溶液中沉淀出并且在真空下过滤以生成粉色滤饼,所述滤饼用水洗涤。所得不纯的絮凝物溶解于乙酸乙酯和己烷中,接着在真空下在40℃下浓缩以生成油状物,所述油状物通过1H NMR分析鉴定为2-(2,3,5-三碘苯氧基)乙醛。
实施例3:由2,3,5-三碘苄基醇和2-溴-1,1-二甲氧基-乙烷制备1-(2,2-二甲氧基乙氧基甲基)-2,3,5-三碘-苯(不透射线缩醛/被保护的醛的实例)
在配备有顶置式搅拌器、温度计、氮气泡和气密隔片的50ml三颈平底烧瓶中,5.07g所述醇在氮气层和搅拌条件下溶解于55ml无水2-甲基四氢呋喃中。接着,添加2.11g缩醛,随后添加0.540g氢化钠(矿物油中的60%分散液)。所述浆液在氮气层下加热至回流持续1010分钟并且通过高效液相色谱(按照实施例1的条件)监测。反应混合物溶解于50ml二氯甲烷中并且用25ml水洗涤四次。有机层在亚真空下浓缩以生成棕色油状物,所述油状物通过1H NMR鉴定为1-(2,2-二甲氧基乙氧基甲基)-2,3,5-三碘-苯。
实施例4:制备交联的水凝胶微球。
根据WO 2004/071495的实施例1制备交联的水凝胶微球。所述方法在其中产物经真空干燥以去除残留溶剂的步骤之后终止。制备所述聚合物的高AMPS和低AMPS形式并且筛分珠粒以提供适当大小范围。珠粒干式或在生理盐水中存储并且高压灭菌。所述聚合物的高AMPS和低AMPS形式均可以良好射线不透性结果使用。
实施例5:由2,3,5-三碘苯甲醛和预形成的交联PVA水凝胶微球一般性制备不透射线微球
在配备有顶置式搅拌器、温度计和氮气泡的50ml三颈圆底烧瓶中,1.0g干燥的基于PVA的珠粒(参见实施例4-高AMPS型式)在氮气层和搅拌条件下在适当溶剂(例如DMSO)中溶胀。接着,0.20至1.5摩尔当量的醛(根据实施例1制备)添加至浆液中,随后立即添加1.0至10摩尔当量的酸(例如硫酸、盐酸、甲烷磺酸或三氟乙酸-典型地使用甲烷磺酸)。基于所用PVA的特征和交联程度估算可用–OH基团的理论水平(关于高AMPS珠粒的典型值=0.0125mol/gm干珠粒)。反应浆液在50℃至130℃下搅拌持续12小时与48小时之间,同时通过高效液相色谱(HPLC)监测醛的消耗。需要时,添加如硫酸镁或硫酸钠的干燥剂以进一步驱动所述反应。以这种方式,可能获得具有碘并入的不同水平的不透射线微球的批料。当充足的醛已经在基于PVA的水凝胶的1,3-二醇上反应以使其充分地不透射线时(参见下文),将反应浆液冷却至室温并且过滤。珠粒的滤饼用大量DMSO和水洗涤,直至不含任何未反应的醛,如通过高效液相色谱所确定。
实施例6:由2,3,5-三碘苯甲醛和交联的PVA水凝胶微球制备不透射线微球
5.0g干燥的基于PVA的珠粒(参见实施例4-高AMPS型式105-150um)和0.26当量的醛(7.27g)(根据实施例1制备)放置于用氮气净化的500ml容器中。在氮气层下添加175ml无水DMSO并且搅拌以使珠粒保持悬浮。所述悬浮液温至50C并且缓慢地添加11ml甲烷磺酸。反应浆液在50℃下搅拌27小时,同时通过HPLC监测醛的消耗。反应浆液接着用大量DMSO/1%NaCl,随后用生理盐水洗涤。所得珠粒具有141mg I/ml湿珠粒的碘浓度并且具有4908HU的射线不透性。
实施例7:由2-(2,4,6-三碘苯氧基)乙醛制备不透射线PVA水凝胶珠粒。
2-(2,4,6-三碘苯氧基)乙醛根据实施例2制备并且根据与实施例5相同的方法与基于PVA的水凝胶珠粒(参见实施例4高AMPS型式)反应,但反应的温度维持在20℃与50℃之间。反应时间也减少至不足一小时。碘含量确定为18mg I/ml湿珠粒。
实施例8:由1-(2,2-二甲氧基乙氧基甲基)-2,3,5-三碘-苯制备不透射线PVA水凝胶微球
在配备有顶置式搅拌器、温度计和氮气泡的50ml三颈平底烧瓶中,1.0g干燥的基于PVA的珠粒(参见实施例4高AMPS型式)在氮气层和搅拌条件下在适当溶剂(例如DMSO)中溶胀。接着,0.5摩尔当量的醛(1-(2,2-二甲氧基乙氧基甲基)-2,3,5-三碘-苯,根据实施例3制备)添加至浆液中,随后立即添加163μl甲烷磺酸。反应浆液在40℃下搅拌80分钟,并且接着加热至80℃持续200分钟,同时通过高效液相色谱监测醛的消耗。当充足的醛已经在基于PVA的水凝胶的1,3-二醇上反应以使其此后充分地不透射线时,将反应浆液冷却至室温并且过滤。珠粒的滤饼用大量DMSO和水洗涤,直至不含任何未反应的缩醛和醛,如通过高效液相色谱所确定。珠粒的碘含量确定为31mg/ml湿珠粒。
实施例9:由2,3,4,6四碘苯甲醛制备不透射线PVA水凝胶微球
2,3,4,6-四碘苄基醇(ACES Pharma;USA)使用如实施例1所述的T3P和DMSO转化为2,3,4,6四碘苯甲醛。0.6摩尔当量的2,3,4,6四碘苯甲醛(8.8g)接着在氮气层下添加至具有DMSO的2.05g PVA水凝胶微球(参见实施例4-150-250μm大小的高AMPS型式)中。反应混合物加热至50℃并且搅拌数小时。反应用HPLC监测并且当完成时,珠粒过滤并且用DMSO、水和接着0.9%生理盐水洗涤。所述不透射线珠粒接着存储于0.9%生理盐水溶液中用于分析。碘含量确定为30mg/ml湿珠粒。
实施例10:不透射线珠粒的表征
所述珠粒、典型地通过实施例(5和6)制造的那些的光学显微照片显示于图1中。珠粒的干重通过去除填充生理盐水并且用组织带走剩余的生理盐水来测量。所述珠粒接着在50℃下真空干燥过夜以去除水,并且由此获得干珠粒重量和聚合物的固体含量(w/w%)。
干珠粒中的碘含量(w/w%)通过根据烧瓶方法进行元素分析来测量。关于湿珠粒中的碘含量,计算为:
珠粒固体含量(%)x干珠粒中的碘含量(%)
根据实施例5在0.9%生理盐水中制备的不透射线水凝胶珠粒的固体含量经测量在5%与16%w/w之间,而重量/重量干碘含量经测量在5%与56%之间,视所述化学和所用的反应条件而定。
表述碘含量的替代方法为mg I/mL湿珠粒(湿填充珠粒体积),其与用于照影剂的单位相同。使用根据实施例5的方案,实现在范围26mg I/ml珠粒至214mg I/ml珠粒内的碘含量。
使用类似方案但基于低AMPS聚合物的微球(实施例4),可能实现较高碘含量(高达250mg I/ml珠粒)。
实施例11–不透射线珠粒的微CT分析
使用微CT来评估根据上文实施例5制备的不透射线栓子珠粒的样品的射线不透性。
所述样品在Nunc冻存管小瓶(Sigma-Aldrich产品代码V7634,48mm×12.5mm)中制备。所述珠粒悬浮于0.5%琼脂糖凝胶(用Sigma-Aldrich产品代码A9539制备)中。所得悬浮液一般称作“珠粒体模”。为了制备这些珠粒体模,首先将琼脂糖溶液(1%)提高至大约50℃的温度。接着添加已知浓度的所述珠粒,并且两者轻柔地混合在一起直至所述溶液开始凝固或胶凝。当所述溶液冷却时,其胶凝并且所述珠粒保持均匀地分散并且悬浮于所述琼脂糖凝胶中。
使用微计算机断层扫描(μCT)使用RSSL Laboratories,Reading,Berkshire,UK的配备有钨阳极的Bruker Skyscan 1172μCT扫描仪测试珠粒体模的射线不透性。使用具有在64kv电压和155μA电流下操作的钨阳极的相同仪器配置分析各体模。使用铝制滤板(500μm)。
采集参数:
软件:SkyScan1172版本1.5(build 14)
NRecon版本1.6.9.6
CT分析仪版本1.13.1.1
光源类型:10Mp Hamamatsu 100/250
照相机分辨率(像素):4000x 2096
照相机帧率(Binning):1x 1
光源电压kV:65
光源电流uA:153
图像像素大小(um):3.96
滤板:Al 0.5mm
旋转步进(度):0.280
输出格式:8比特BMP
动态范围:0.000–0.140
平滑:0
射束硬化:0
后对准:经校正
环状伪影:16
少量纯化的MilliQ水小心地倾析至各样品管中。各样品接着通过X射线微计算机断层扫描使用单次扫描来分析,以包括水参考物和所述珠粒。所述样品接着使用NRecon重建并且针对纯化的水参考物的目标体积(VOI)进行校准。在校准后分析空气和水的研究区(ROI)以检验亨氏校准。
射线不透性以跨珠粒的线扫描投影的灰度单位和亨氏单位报告。在NRecon中用于所有样品的动态范围的值(阈值):-0.005、0.13(最小和最大衰减系数)。典型图像和线扫描显示于图2中。
表1给出在时间和醛的当量的变化条件下根据实施例4制备的微球的以灰度和亨氏单位表示的射线不透性。射线不透性数据为大约150微米的珠粒的十次线扫描的平均值。
表1
图10显示具有153um的平均大小和4908HU的平均射线不透性的10种珠粒的横截面图像的样品。
实施例12不透射线珠粒的药物负载:
实施例12(a)阿霉素
通过使用量筒来测量根据实施例5制备的1mL RO珠粒浆液(大小100-300um,碘47mg I/ml湿珠粒),并且移出所述液体。4mL阿霉素溶液(25mg/mL)在环境温度下与所述不透射线珠粒在恒定振荡下混合。在20h负载后,移出所述废弃溶液,并且负载药物的珠粒用去离子水(10mL)冲洗4-5次。通过在Varian UV分光光度计上在483nm下测量合并的废弃负载溶液和冲洗溶液的阿霉素浓度,所负载的阿霉素经计算为80mg/mL珠粒。所述不透射线珠粒的阿霉素盐酸盐药物负载能力经确定为所述珠粒中的碘含量的非线性函数。
在一个独立实验中,如上文使用3ml阿霉素溶液(25mg/ml)负载1.5ml具有158mg/ml湿珠粒的碘含量的70-150um的RO珠粒。对照物,即相同大小的非RO珠粒也以相同方式进行负载。所述RO珠粒负载50mg/ml的阿霉素,而对照珠粒负载37.5mg/ml。
在一个独立实验中,RO珠粒(大小70-150um;碘含量150mg I/ml)的负载基本上在3h后完成。
根据上文实施例5制备的不透射线珠粒根据以上方法负载37.5mg/ml的阿霉素溶液。图3A显示负载之前的不透射线珠粒并且图3B显示负载药物的珠粒。在药物负载之前,观察到所述珠粒呈球形微球,具有苍白至暗棕色色调。当阿霉素负载至所述珠粒中时,其变为鲜红色。在这个实施例中,所述珠粒经高压灭菌以证明在灭菌期间所述珠粒的稳定性。珠粒完整性在高压灭菌期间得以保持;在高压灭菌期间平均珠粒大小从177μm降至130μm。当珠粒负载阿霉素时,观察到珠粒大小分布的进一步转变,其与由非不透射线珠粒观察到的药物负载一致。在另一实施例中,在以51mg/ml进行药物负载时,平均珠粒大小从130μm降至102μm。所得珠粒保持在所述范围内,所述范围甚至在改质、灭菌和药物负载之后仍临床上适用。
实施例12(b)表柔比星
表柔比星以与阿霉素相同的方式负载至RO珠粒(根据实施例5制备)和非RO珠粒(大小70-150um高AMPS,根据实施例4制备)中。使用1.5ml负载溶液(25mg/ml的表柔比星)负载1ml珠粒。在90min后,所述不透射线珠粒中的最终负载为37.49mg(99.97%负载效率)且关于非RO珠粒为36.43(97.43%负载效率)。
实施例12(c)舒尼替尼
通过将400mg舒尼替尼粉末溶解于10mL容量瓶中的无水DMSO中来制备舒尼替尼DMSO溶液。1ml RO珠粒浆液(70-150um,134.4mg I/ml根据实施例5制备的湿珠粒)用10mlDMSO预洗涤3次以去除水残留物。2.5mL舒尼替尼-DMSO溶液(40mg/mL)与RO珠粒浆液混合并且使其混合1-2h。随后,在去除所述负载溶液后,10mL生理盐水添加至珠粒浆液中以使舒尼替尼在所述珠粒内部沉淀。所述洗涤溶液和药物离子通过细胞过滤器过滤,并且所述洗涤重复3至4次。非RO珠粒(100-300um,根据实施例4制备)以相同方式进行处理。
实施例12(d)索拉非尼
1ml RO PVA微球(大小70至150um,碘含量134mg碘/ml珠粒,根据实施例5制备)或非RO PVA微球(DC BeadTM 100-300,Biocompatibles;UK)用10ml DMSO预洗涤3次以去除水残留物。索拉非尼/DMSO溶液(无水DMSO中39.8mg/mL)与1mL珠粒浆液混合1h(关于所述不透射线珠粒为2.5mL并且关于所述非不透射线珠粒为2mL)。在去除所述负载溶液后,20mL生理盐水添加至珠粒浆液中。所述珠粒悬浮液通过细胞过滤器过滤,并且所述洗涤重复3或4次。最终负载水平通过对一小部分水合珠粒进行DMSO提取并且通过HPLC(柱:Kinetex 2.6uXB-C18 100A 75x4.60 mm;流动相水:乙腈:甲醇:三氟乙酸290:340:370:2(v/v);检测254nm;柱温40℃;流动速率:1mL/min)确定药物浓度来确定。
49.9mg索拉非尼负载至1ml RO珠粒中并且34.7mg负载至1ml非RO(DC BeadTM)珠粒中。
实施例12(e)凡德他尼。
通过将500mg凡德他尼溶解于在声波处理下的25ml琥珀色容量瓶中的14ml 0.1MHCl中,并且用去离子水补足25ml来制备20mg/ml凡德他尼溶液。凡德他尼接着根据以下方案负载于RO PVA水凝胶微球(根据实施例5制备:大小70至150um;碘含量147mg/ml珠粒)和非RO微球(DC Bead 100-300;Biocompatibles UK Ltd)中:
通过量筒等分1毫升包括填充溶液的微球并且转移至10mL小瓶中。所述填充溶液接着使用移液管去除。3毫升的所述20mg/ml药物溶液接着添加至所述非RO珠粒中或1.5mL的所述溶液添加至RO珠粒中。在不透射线珠粒负载实验中,所述溶液的pH在4.6与4.8之间;在DC珠粒负载实验中,pH在大约4.2下。在2h负载后,去除残留溶液,并且所述珠粒用5mL去离子水洗涤3次。合并废弃负载和洗涤溶液并且通过C18反相HPLC在254nm下检测来分析以确定负载产率。关于灭菌,需要时,1ml去离子水中的负载珠粒在121℃下高压灭菌持续30min,或冻干持续24h并且接着在25kGy下进行γ灭菌。
不透射线珠粒负载凡德他尼至29.98mg/ml湿珠粒的水平。
非不透射线珠粒负载凡德他尼至26.4mg/ml的水平。
实施例12(f)米铂
各小瓶中1mL的水合RO微球(大小70-150um,碘含量134mg碘/ml珠粒,根据实施例5制备)和非RO PVA微球(DC Bead 100-300,Biocompatibles;UK)用5mL 1-甲基-2-吡咯烷酮洗涤4次。接着去除溶剂。0.147g米铂与25mL 1-甲基-2-吡咯烷酮混合,并且所述悬浮液在水浴中加热至75℃以溶解米铂。2mL所述药物溶液添加至经过洗涤的珠粒中并且所述混合物放置于75℃水浴中持续1h。所述珠粒悬浮液通过细胞过滤器过滤以去除所述负载溶液,随后用约100mL生理盐水洗涤。
已知体积的珠粒用去离子水洗涤并且冷冻干燥。总的铂通过使用感应耦合等离子体-光学发射光谱(ICP-OES;Inductively Coupled Plasma-Optical EmissionSpectroscopy)进行元素分析来确定并且转化为米铂水平。
重复所述实验,以相同方式负载冻干的珠粒。表2显示负载米铂至湿和冻干的RO珠粒中的结果。
表2:米铂负载数据。
实施例12(g)依立替康
非RO珠粒(100-300um-根据实施例4制备,高AMPS型式)和RO珠粒(100-300um,163mg I/mL,根据实施例5制备)的2mL珠粒样品与10ml依立替康水溶液(10mg/mL)混合。通过由UV光谱法在384nm下确定废弃负载溶液中的依立替康水平来测量负载。非RO和RO珠粒在90min内负载大约100%的所述药物。
实施例12(h)拓扑替康
非RO珠粒(70-150um-根据实施例4制备,高AMPS型式)和RO珠粒(70-150um,146mgI/mL,根据实施例5制备)的1mL珠粒样品与拓扑替康水溶液(15.08mg/mL)在搅拌下混合以负载40mg(2.5ml)或80mg(5ml)的剂量。在约1.5h后,通过由UV光谱法在384nm下确定如上文所述的废弃负载溶液中的拓扑替康水平来测量拓扑替康的负载。表3显示最多80mg拓扑替康负载于RO珠粒样品中。非RO和RO珠粒均负载>98%的40mg拓扑替康。
表3.RO和非RO珠粒中的拓扑替康负载
时间(h) | 负载的药物(mg) | %负载的药物 | |
RO珠粒,1mL | 1.5 | 40 | 100 |
RO珠粒,1mL | 1.5 | 80 | 100 |
非RO珠粒,1mL | 1.5 | 39 | 98 |
实施例13不透射线珠粒的药物洗脱
实施例13(a)阿霉素。
根据实施例13(a)制备的负载阿霉素的珠粒(70-150um,158mg I/ml,50mg/ml的阿霉素)在室温下添加至棕色罐中的1000ml PBS中。所述珠粒悬浮液用磁力搅拌器以低速搅拌。在取样时间点处,通过5um滤针取出1mL洗脱介质并且通过UV在483nm下针对标准物进行分析。洗脱概况显示于图4中。
实施例13(b)舒尼替尼
根据实施例13(c)制备的负载舒尼替尼的珠粒添加至在37℃水浴中在棕色罐中的400ml PBS、0.5g/L Tween 80中。所述珠粒悬浮液用磁力搅拌器以低速搅拌。在1、2、3和4小时的取样时间点处,通过5um滤针取出10mL洗脱介质用于HPLC分析(按照实施例13(c)的条件)并且添加10mL新鲜PBS溶液以补足体积。在5、25、48和73小时的取样时间点处,用相等体积的新鲜PBS溶液替换100mL洗脱介质。样品通过HPLC分析。洗脱概况说明并显示于图6中。
实施例13(c)索拉非尼
根据实施例13(d)制备的负载索拉非尼的珠粒添加至在37℃水浴中在棕色罐中的具有0.5g/L Tween 80的400mL PBS中。所述珠粒悬浮液用磁力搅拌器以低速搅拌。在1、2、4和6小时的取样时间点处,通过5um滤针取出10mL洗脱介质用于HPLC分析并且添加10mL新鲜PBS溶液以补足400mL体积。在取样时间点8、24.5和31h处,用相等体积的新鲜PBS溶液替换100mL洗脱介质。针对各类型的珠粒进行两次平行测定。RO珠粒和非RO珠粒的索拉非尼洗脱概况显示于图6中。
实施例13(d)凡德他尼。
根据实施例13(e)制备的负载凡德他尼的RO和非RO珠粒(2ml在30mg凡德他尼/ml珠粒下的珠粒、珠粒70-150um和具有141mg I/ml湿珠粒的RO珠粒)在环境温度下放置于具有磁蚤的含有500mL PBS的琥珀色罐中。在各取样时间点处,通过套管过滤器由蠕动泵从所述罐中取出完全PBS洗脱介质,并且用相等体积的新鲜PBS替换。通过C18反相HPLC由在254nm下的检测分析5ul所述洗脱介质。洗脱概况说明于图7中。
实施例13(e)米铂
根据实施例13(f)制备的负载米铂的珠粒添加至100mL瓶中具有1%Tween 80的50mL PBS中。所述瓶悬浮于37℃水浴中并且在75rpm下旋转以搅拌所述珠粒。在1、5、11、15和22天的取样时间点处,取出20mL洗脱介质用于ICP分析并且添加20mL新鲜PBS/Tween溶液以补足50mL体积。RO珠粒和非RO珠粒的米铂洗脱概况显示于图8中。
实施例13(f)依立替康
在实施例13(g)中制备的珠粒样品(163m I/ml)在37℃下添加至棕色罐中的500mlPBS中并且用磁力搅拌器以低速搅拌。在取样时间点处,通过5um滤针取出1ml洗脱介质并且通过UV在369nm下针对标准物进行分析。洗脱概况显示于图9中。
实施例14负载药物的不透射线珠粒的射线不透性
根据实施例13制备的负载阿霉素的珠粒的等分试样以如实施例12中所述的相同方式经历微CT分析。发现所述负载药物的珠粒为不透射线的。平均珠粒射线不透性(灰度)经确定为139(n=3)。
实施例15-冷冻干燥方案。
本发明的微球(无论负载药物或非负载药物)均可根据WO07/147902(第15页)中所述的方案使用具有Lyo Screen Control(LSC)面板和Pfeiffer DUO 10Rotary Vane真空泵并且通过Lyolog LL-1文档软件控制的Epsilon 1-6D冷冻干燥器(Martin ChristGefriertrocknungsanlagen GmbH,Osterode am Harz,Germany)冷冻干燥,如下文简要描述。
所述微球通过在约-30℃而无真空下冷冻至少1h,接着在约半小时的时期内逐渐地降低压力至范围0.35-0.40毫巴内的压力,同时使温度升至约-20℃而冻干。所述温度和压力条件保持过夜,随后在相同时间、压力下升高温度至室温持续约1-2小时的时期,随后一段时期在室温下将压力降低至约0.05毫巴,直至24小时的总循环时间。
如果需要制剂维持在减压下,那么在循环结束时并且实质上在不允许空气进入的情况下,在真空下通过转动小瓶闭合机构来塞住小瓶,所述小瓶闭合机构降低搁板以塞住下面的搁板上的小瓶。接着对腔室充气以使腔室到达环境压力。接着使所述搁板恢复其最初位置并且打开腔室。如果所述样品不维持在减压下,那么压力在塞住之前逐渐地恢复至环境。
实施例16:体内栓塞研究
雄性家养Yorkshire杂交猪(大约14周龄)用于所述研究中。
在引起麻醉后,将套管放置于股动脉中并且在透视导向下,导线通过导引器并且移动通过至主动脉。接着将越过导线的引导导管放置于腹腔动脉的入口处。移出导线,并且使用照影剂来目测腹腔动脉的分支。
微线/微导管组合通过所述引导导管并且用于选择肝总动脉,从而分离肝体积的25至50%。微导管越过导线进入肝叶中,移出所述导线并且使用照影剂来捕捉所述叶片的血管造影照片。执行数字式减影血管造影以确认导管位置。
根据实施例5制备的2ml RO珠粒(大小75-150um,碘含量141mg I/ml)转移至20-30mL注射器中并且弃去填充溶液。容纳5mL非离子照影剂(320)的较小注射器经由三路旋塞连接于较大注射器并且所述珠粒通过经过所述旋塞的通道与所述照影剂混合。通过添加照影剂将总体积调节至20mL。在透视导向下缓慢地施用这一悬浮液,直至实现几乎静态平衡。递送至实现静态平衡的悬浮液的体积在2与6ml之间。
在给药前、给药后1和24小时并且在第7天和第14天拍摄腹部CT图像。在第14天,拍摄基线CT图像并且注射75cc照影剂材料。在照影剂材料注射后,拍摄第二张CT图像。关于肝中珠粒的可见性的程度分析所述图像。
所述RO珠粒在所述程序期间在X射线中可见并且在CT上可见。这在无需IV照影而获得的第7天和第14天的CT扫描中最佳显示(参见图11)。所述珠粒容易在肝动脉的多个分支中可见。所述珠粒比IV照影衰减更多并且可与其区别。
Claims (18)
1.一种水凝胶聚合物微球,该水凝胶聚合物包含含有1,3-二醇基团的聚乙烯醇(PVA)骨架,还包含至少两个侧链,所述侧链含有可交联的乙烯系不饱和官能团,其通过乙烯系共聚单体交联;
其中所述PVA骨架的1,3-二醇基团至少一些用不透射线物质缩醛化,所述不透射线物质通过环状缩醛基团连接至所述水凝胶聚合物,所述不透射线物质包含一个或多个共价结合的碘;且
其中所述水凝胶聚合物微球,以填充体积计,每毫升完全水合的微球包含至少50mg的碘。
2.根据权利要求1的水凝胶聚合物微球,其中含有可交联的乙烯系不饱和官能团的所述侧链通过环状缩醛键联连接到PVA骨架的1,3-二醇基团。
3.根据权利要求1的水凝胶聚合物微球,其中乙烯系共聚单体是2-丙烯酰胺基-2-甲基丙磺酸。
4.根据权利要求1的水凝胶聚合物微球,其中所述乙烯系不饱和官能团是丙烯酸酯基。
5.根据权利要求1的水凝胶聚合物微球,其中所述不透射线物质包括碘化苯基。
6.根据权利要求1的水凝胶聚合物微球,其中不透射线物质通过环状缩醛基团连接至所述水凝胶聚合物,从而使所述水凝胶聚合物包括符合通式I的结构:
其中X为下式的基团:
其中,
Z为键结于所述环状缩醛的连接基团或不存在,使得所述苯基键结于所述环状缩醛;如果Z存在,那么Z为C1-6亚烷基、C1-6亚烷氧基或C1-6烷氧基亚烷基;
Hal为1、2、3或4个共价连接的碘。
7.根据权利要求6的水凝胶聚合物微球,其中,Z为(i)亚甲基或乙烯基,或者是(ii)基团-(CH2)p-O-(CH2)q-,其中q是0、1或2,p是1或2,或者(iii)不存在。
8.根据权利要求6的水凝胶聚合物微球,其中,Z是-CH2O-、-(CH2)2O-、-CH2OCH2-、-(CH2)2O(CH2)2-或不存在。
9.根据权利要求6的水凝胶聚合物微球,其中Hal是3或4个碘。
10.根据权利要求6的水凝胶聚合物微球,其中Hal是2,3,5三碘、2,4,6三碘或2,3,4,6四碘。
11.根据权利要求1的水凝胶聚合物微球,其中所述不透射线物质通过环状缩醛基团连接至所述水凝胶聚合物,使得所述水凝胶聚合物包括根据通式Ia至Ie中任何一个的结构
12.根据权利要求1的水凝胶聚合物微球,其中所述水凝胶聚合物在pH 7.4时具有净电荷。
13.根据权利要求12的水凝胶聚合物微球,其中所述水凝胶聚合物在pH 7.4时具有净负电荷。
14.根据权利要求1的水凝胶聚合物微球,其平均直径大小范围为10至2000μm。
15.一种包括根据权利要求1的水凝胶聚合物微球以及治疗剂的组合物,其中治疗剂通过静电保持在水凝胶基质内。
16.根据权利要求15的组合物,其中所述治疗剂选自喜树碱、蒽环霉素、抗血管生成剂、微管组装抑制剂、芳香酶抑制剂、铂类药物和核苷类似物。
17.根据权利要求15的组合物,其中治疗剂选自依立替康、拓扑替康、阿霉素、柔红霉素、伊达柔比星、表柔比星、阿西替尼、硼替佐米、伯舒替尼、卡奈替尼、多韦替尼、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、莱他替尼、麻舒替尼,莫比替尼、帕唑帕尼、帕佐帕尼、司马沙尼、索拉非尼、舒尼替尼、坦杜替尼、凡德他尼、瓦他拉尼、维莫德吉、长春花碱、长春瑞滨、长春新碱、阿那曲唑、顺铂、奥克赛铂、卡波铂、米铂、5-FU、阿糖胞苷、氟达拉滨、吉西他滨、紫杉醇、多西紫杉醇、丝裂霉素、米托蒽醌、博来霉素、平阳霉素、阿比特龙、阿米福汀、布舍瑞林、地加瑞克、亚叶酸、戈舍瑞林、兰瑞肽、来那度胺、来曲唑、亮丙瑞林、奥曲肽、他莫昔芬、曲普瑞林、苯达莫司汀、苯丁酸氮芥、达卡巴嗪、美法仑、甲基苄肼、替莫唑胺、雷帕霉素、佐他莫司、依维莫斯、西罗莫司、甲氨蝶呤、培美曲塞和雷替曲塞。
18.根据权利要求15的组合物,其中治疗剂选自伊立替康、拓扑替康、阿霉素、表柔比星、索拉非尼、舒尼替尼、凡德他尼和米铂。
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GB201315936D0 (en) | 2013-10-23 |
CA2922961C (en) | 2022-07-19 |
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