CN102639670B - 具有改进的释放特性的bab三嵌段聚合物 - Google Patents
具有改进的释放特性的bab三嵌段聚合物 Download PDFInfo
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Abstract
本发明提供显示逆向热胶凝性质的改进的生物可降解和生物可吸收BAB-嵌段共聚物和包括所述BAB-嵌段共聚物的含水聚合物组合物。本发明还提供制造所述改进的BAB-嵌段共聚物和包括所述改进的BAB-嵌段共聚物的组合物的方法。
Description
发明背景
(a)发明领域
本发明涉及刚好在施用之前或施用时暴露于高温(如暴露于体温)就显示逆向热胶凝性质的生物可降解和生物可吸收BAB-嵌段共聚物。该公开的聚合物有利于(例如)用于药物的肠胃外施用。
(b)相关技术的描述
显示逆向热胶凝的生物可降解嵌段共聚物公开于Rathi等人的美国专利第6,201,072号、第6,117,949号和第6,004,573号以及Cha等人的美国专利第5,702,717号，各个专利均以引用方式并入本文。这些聚合物组合物在低温作为液体溶液存在，随后在生理学适当的温度可逆地形成凝胶，并且提供良好的药物释放特性。这些组合物包括具有介于约2000和4990之间的重均分子量的生物可降解ABA或BAB型嵌段共聚物，并且包括约51至83重量％的含生物可降解聚酯的疏水性A聚合物嵌段和约17至49重量％的含聚乙二醇的亲水性B聚合物嵌段。Piao等人的美国专利第7,018,645号和第7,135,190号公开了显示相似的逆向热胶凝性质的三嵌段共聚物的混合物。
Rathi的专利公开具有逆向热胶凝性质的BAB-嵌段共聚物。根据′949专利，BAB三嵌段共聚物使用相同PEGB-嵌段在任一末端(Mw＝550)合成，但使用的聚(丙交酯)和/或聚(乙交酯)的含量不同。PEG和PLGA经由酯、尿烷或酯和尿烷键的组合相互偶合。在Rathi的专利中描述的先前的BAB-嵌段共聚物具有从2000至4990的重均分子量Mw。下表列出在Rathi的专利中公开的BAB三嵌段共聚物的特性：
在上表中列出的所有PEG-PLGA-PEG三嵌段共聚物均具有逆向热胶凝性质。上述三嵌段聚合物的溶胶/凝胶转变温度分别是36、34、30和26℃。虽然Rathi的专利证明了具有在2000-4990道尔顿范围内的重均分子量Mw的ABA-三嵌段共聚物的良好药物释放特性，但是Rathi的专利没有表征公开的BAB-三嵌段共聚物的释放特性。此外，没有研究对于亲水性化合物的释放特性。已经发现，先前的三嵌段共聚物组合物对于亲水性活性剂的释放特性不适于许多控释应用。
发明概述
已经开发出显示逆向热胶凝性质并且具有改进的药物释放特性(特别是对于亲水性活性剂)的新型的可复水BAB-三嵌段共聚物。已经意外地发现，对于提供控释热可逆聚合物组合物(特别是与亲水性活性剂使用时显示希望的释放特性的那些)而言，本发明的BAB-三嵌段共聚物相对于ABA-三嵌段共聚物是有利的。本发明人还发现，相对于已知的BAB-嵌段共聚物组合物，增加PLG/PEG的比例和增加BAB-嵌段共聚物的分子量对所述BAB-嵌段共聚物的药物释放特性具有显著的影响，特别是在亲水性活性剂的情况下。先前对于ABA和BAB三嵌段的研究显示两种聚合物的释放特性是相似的，并且相同范围的三嵌段分子量适合BAB以及ABA三嵌段共聚物。然而，本发明人意外地发现，用于控释热可逆BAB-三嵌段组合物的三嵌段分子量范围不同于对于ABA-三嵌段共聚物有效的分子量范围。
本发明的一个目的是提供生物可降解、显示逆向热胶凝性质(即在低温作为液体溶液存在，在生理学适当的温度可逆地形成凝胶)的低分子量三嵌段共聚物药物递送系统，以及提供相对于先前的BAB和ABA-三嵌段共聚物改进的药物释放特性。
本发明的又一个目的是提供一种肠胃外施用生物可降解聚合物基质中的药物导致在体内形成凝胶储库(药物从其中释放)的方法，以使所述聚合物相对于先前的BAB和ABA-三嵌段共聚物显示改进的药物释放特性。
本发明的再一个目的是提供用于肠胃外或瘤内施用亲水性和疏水性药物、肽和蛋白质药物、激素、基因/核酸、寡核苷酸和抗癌剂的药物递送系统。抗癌剂的种类包括(例如)烷化剂、抗代谢剂、抗生素、激素剂、抗血管形成剂或亚硝基脲。
这些和其它目的可通过BAB-嵌段共聚物实现，所述嵌段共聚物包含：i)约60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和ii)约15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间，其中所述BAB-嵌段共聚物具有从5000至8000的Mw，并且在聚合物水溶液中形成时能够显示逆向热胶凝性质。优选地，所述嵌段共聚物具有从65至80％的A-嵌段含量且所述共聚物的B-嵌段含量为从20至35％，并且更优选地，所述嵌段共聚物具有从67至75％的A-嵌段含量和从25至33％的B-嵌段含量。所述嵌段共聚物的数均分子量Mn优选为从3800至5000道尔顿，并且更优选为4000至4600道尔顿。
这些和其它目的可通过含水BAB-嵌段共聚物组合物实现，所述组合物包含：i)约60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和ii)约15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间；其中所述BAB-嵌段共聚物组合物具有从5000至8000的Mw，并且显示逆向热胶凝性质。优选地，所述嵌段共聚物具有从65至80％的A-嵌段含量且所述共聚物的B-嵌段含量为从20至35％，并且更优选地，所述嵌段共聚物具有从67至75％的A-嵌段含量和从25至33％的B-嵌段含量。所述嵌段共聚物的数均分子量Mn优选为从3800至5000道尔顿，并且更优选为4000至4600道尔顿。
这些和其它目的可通过以控释形式对温血动物施用至少一种药物的方法实现，所述方法包含：(1)提供一种含水BAB-嵌段共聚物组合物，其包含：i)约60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和ii)约15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间；其中所述BAB-嵌段共聚物组合物具有从5000至8000的Mw，并且显示逆向热胶凝性质；和(2)对温血动物施用所述组合物。优选地，所述嵌段共聚物具有从65至80％的A-嵌段含量且所述共聚物的B-嵌段含量为从20至35％，并且更优选地，所述嵌段共聚物具有从67至75％的A-嵌段含量和从25至33％的B-嵌段含量。所述嵌段共聚物的数均分子量Mn优选为从3800至5000道尔顿，并且更优选为4000至4600道尔顿。
这些和其它目的可通过制造BAB-嵌段共聚物组合物的方法实现，所述方法包括：(1)提供一种BAB-嵌段共聚物组合物，其包含：i)约60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和ii)约15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间；其中所述BAB-嵌段共聚物组合物具有从5000至8000的Mw，并且在聚合物水溶液中形成时能够显示逆向热胶凝性质；和(2)冷冻干燥所述嵌段共聚物，其中当所述嵌段共聚物作为聚合物水溶液形成时能够显示参比热胶凝(referencethermalgellation)。优选地，所述嵌段共聚物具有从65至80％的A-嵌段含量且所述共聚物的B-嵌段含量为从20至35％，并且更优选地，所述嵌段共聚物具有从67至75％的A-嵌段含量和从25至33％的B-嵌段含量。所述嵌段共聚物的数均分子量Mn优选为从3800至5000道尔顿，并且更优选为4000至4600道尔顿。
附图简述
图1比较所述实施例的聚合物组合物与ABA-嵌段共聚物ReGel的释放曲线。
图2比较通过所述实施例的BAB-嵌段共聚物组合物的亲水性高分子的释放。
优选实施方案详述
通过以下概述和本发明的各种实施方案的详细描述，本发明的其它目的和优点将变得显而易见。如本文所用，以下术语应具有指定的含义：
“肠胃外”应包括肌内、腹膜内、腹内、皮下、瘤内、颅内(或进入切除的肿瘤腔)、关节内、鞘内、髓内、眼和(在可行的范围内)静脉内和动脉内。
“胶凝温度”表示生物可降解嵌段共聚物进行逆向热胶凝的温度，即低于所述温度嵌段共聚物溶于水且高于所述温度嵌段共聚物进行相变以增加粘度或形成半固体凝胶的温度。
术语“胶凝温度”和“逆向热胶凝温度”等在指胶凝温度时应可互换使用。
“聚合物溶液”、“水溶液”等，当用于指包含于此溶液中的生物可降解嵌段共聚物时，应表示其中溶解有一定功能性浓度的此嵌段共聚物并且保持在低于所述嵌段共聚物的胶凝温度的温度的水基溶液。
聚乙二醇(PEG)有时也称为聚(环氧乙烷)(PEO)或聚(氧乙烯)并且为了本发明的目的所述术语可互换使用。
“逆向热胶凝”是当溶液的温度升高至高于共聚物的胶凝温度时，嵌段共聚物的溶液粘度自发地增加，并且在许多情况下转变成半固体凝胶的现象。为了本发明的目的，术语“凝胶”包括半固体凝胶状态和高于胶凝温度时存在的高粘度状态。当冷却至低于胶凝温度时，凝胶自发地可逆重新形成低粘度溶液。在溶液和凝胶之间的这种循环可无限地重复，因为溶液/凝胶转变不涉及聚合物体系的任何化学组成的变化。生成凝胶的所有的相互作用实质上都是物理的并且不涉及共价键的形成或断裂。
“药物递送液体”或“具有逆向热胶凝性质的药物递送液体”应表示含有适于对温血动物施用的药物(所述药物本身可以是溶解或胶态的)的聚合物溶液，其在温度升到嵌段共聚物的胶凝温度或更高时形成凝胶药物储库。
“储库”表示对温血动物施用后在温度升到胶凝温度或更高时形成凝胶的药物递送液体。
“凝胶”表示当“聚合物溶液”或“药物递送液体”的温度升到嵌段共聚物的胶凝温度或更高时自发出现的半固体状态。在某些情况下，形成的凝胶可能自周围环境失去或吸收水以变得更致密或溶胀，这些凝胶也属于本发明的范围。
“含水聚合物组合物”表示由水相组成的药物递送液体或凝胶，所述水相具有均匀地含在其中的药物和生物可降解嵌段共聚物。在低于胶凝温度的温度时共聚物可溶于水相并且组合物将是溶液。在胶凝温度或更高的温度时共聚物将固化以与水相形成凝胶，并且组合物将是凝胶或半固体。
“生物可降解”表示嵌段共聚物可在体内化学分解或降解以形成无毒成分。降解速率可与药物释放速率相同或不同。
“药物”应表示具有生物活性并且适于或用于治疗目的的任何有机或无机化合物或物质。蛋白质、激素、抗癌剂、寡核苷酸、DNA、RNA和基因治疗均包括在药物的广泛定义内。
当指肽或蛋白质药物时，“肽”、“多肽”、“寡肽”和“蛋白质”应可互换使用，并且除非明确说明，否则不应限于任何特定的分子量、肽序列或长度、生物活性领域或治疗用途。这些治疗用途可包括(例如)烷化剂、抗代谢剂、抗生素、激素剂、抗血管形成剂或亚硝基脲。
“生物可降解聚酯”是指任何生物可降解聚酯，其优选从以下的至少一种合成：D，L-丙交酯、D-丙交酯、L-丙交酯、D，L-乳酸、D-乳酸、L-乳酸、乙交酯、乙醇酸、ε-己内酯、ε-羟基己酸、γ-丁内酯、γ-羟基丁酸、δ-戊内酯、δ-羟基戊酸、羟基丁酸、苹果酸或其共聚物。
可根据公开于美国专利第5,702,717号、第6,004,573号和第6,117,949号(在此以引用方式全部并入本文)的反应方案通过开环聚合或缩合聚合以形成单官能二嵌段(MeO-PEG-PLG)随后通过偶合使用的相同或不同分子量的两个二嵌段共聚物来合成BAB型嵌段共聚物。例如，酯或尿烷键合以得到BAB三嵌段(MeO-PEG-PLG-PEG-OMe)共聚物。在其它情况下，单官能B(PEG)嵌段可通过酯或尿烷键等偶合到A嵌段(聚酯)的各末端。或者，还可通过使双官能疏水性A嵌段在任一末端与环氧乙烷反应来制备BAB型嵌段共聚物。可使用的缩合聚合和开环聚合方法可以是在偶合剂(如异氰酸酯)存在下使单官能亲水性B嵌段在双官能疏水性A嵌段的任一末端偶合。此外，偶合反应可在用活化剂(如羰基二咪唑、琥珀酸酐、N-羟基琥珀酰亚胺和氯甲酸对硝基苯酯等)活化官能团后进行。
亲水性B-嵌段由适当分子量的PEG形成。由于其独特的生物相容性、无毒性、亲水性、增溶性质和迅速从患者体内清除，选择PEG作为亲水性、水溶性嵌段。在一个优选实施方案中，PEG成分可选自具有不同平均分子量的PEG混合物。使用疏水性A-嵌段是因为其生物可降解、生物相容和增溶性质。这些疏水性、生物可降解聚酯A-嵌段的体外和体内降解被充分理解并且降解产物是容易被患者身体代谢和/或消除的天然的(或具有等同于天然产物的性质)或生物相容的化合物。
嵌段共聚物在低于胶凝温度的温度下可溶的浓度可被认为是功能性浓度。一般来讲，可使用低至3％和最多约50重量％的嵌段共聚物浓度并且仍然是功能性的。然而，在约5至40％范围内的浓度是优选的并且在约10-35重量％范围内的浓度是最优选的。为了获得共聚物的可用凝胶相变，需要某种最低浓度(例如3重量％)。在较低的功能性浓度范围，形成的凝胶可能是弱的并且可能引起相分离。聚合物浓度较高时，可形成更强的凝胶网络。
生物可降解共聚物和肽/蛋白质药物和/或其它类型的药物的混合物可在低于胶凝温度下制备成所述共聚物的水溶液以形成药物递送液体，药物可在药物递送液体中部分或完全溶解。当药物部分溶解时，或当药物基本上不可溶时，所述药物以胶态状态(如混悬液或乳状液)存在。所公开的聚合物有利的是用于肠胃外施用(如肌内或皮下给药、瘤内给药、颅内(或进入切除的肿瘤腔)给药、关节内给药、鞘内给药、髓内给药、眼部给药、局部给药、经皮给药、阴道给药、口腔给药、透粘膜(transmucosal)给药、肺部给药、经尿道给药、直肠给药、鼻腔给药、口服给药或耳部给药)，所述聚合物将在此进行可逆热胶凝，这是因为体温将高于胶凝温度。
由于材料的生物相容性、凝胶的柔软性和在生理区域(溶胀可在此对周围组织引起损伤)中的溶胀特性的精确控制，这个体系将对周围组织产生极小的毒性和极小的机械刺激。在所述体系中的聚酯嵌段会在特定的时间间隔内进一步被完全生物降解成乳酸、乙醇酸和其它相应单体。聚乙二醇嵌段通过排泄从体内除去。可通过各种共聚物嵌段的适当设计和制备来控制，即通过改变A-嵌段和B-嵌段的重量百分数、乳酸酯和乙醇酸酯的摩尔百分数和BAB嵌段共聚物的分子量和多分散性来控制药物释放、凝胶强度、胶凝温度和降解速率。还可通过调节药物递送液体中的聚合物浓度来控制药物释放。
对身体施用由含有溶解的药物或呈混悬液或乳状液的药物的嵌段共聚物溶液组成的剂型。由于嵌段共聚物的逆向热胶凝性质，随着制剂的温度升高到体温，这个制剂随后自发地胶凝以形成药物储库。所述制剂可装载多少药物的唯一限制就是功能性。即装载的药物可增加直到所述共聚物的热胶凝性质被不利地影响至不可接受的程度(药物释放性质被不利地改变)，或直到所述制剂的性质被不利地影响至制剂的施用达到不可接受的困难程度。一般来讲，希望在大多数情况下药物占制剂约0.01至20重量％，很常用的范围为介于约0.01至10％之间。这些药物装载范围不限制本发明。只要保持功能性，在这些范围外的药物装载仍属于本发明的范围。
本文中所述的组合物的一个突出优点在于所述嵌段共聚物提高许多药物物质溶解度的能力。疏水性A-嵌段和亲水性B-嵌段的组合使两亲嵌段共聚物具有稳定和增溶疏水性药物的独特的亲水性和疏水性功能域。在那方面，它的作用更像同时具有亲水性和疏水性性质的肥皂或表面活性剂。虽然发现先前的ABA三嵌段共聚物在增溶疏水性或水溶性差的药物(如紫杉醇)时特别有利，但是已经发现这些ABA三嵌段共聚物对于亲水性化合物的释放特性不适于许多控释应用。
已经意外地发现，相对于ABA-三嵌段共聚物，本发明的BAB-三嵌段共聚物对于提供控释热可逆聚合物组合物(特别是对于亲水性活性剂)是有利的。研究了本发明的BAB-三嵌段共聚物对于牛血清白蛋白(BSA)的释放特性，BSA是用于预测众多亲水性蛋白质和其它亲水性活性剂的控释性质的模型蛋白质。如图1所示，现有技术的ABA-三嵌段共聚物(ReGel)在最初五天内释放大约95％的BSA。相比之下，BAB-三嵌段(表1，第4个组合物)显示经过超过二十五天时间的BSA的缓释。图1中的数据证明BAB-三嵌段共聚物对于亲水性分子(包括蛋白质如BSA)经延长时间的控释是有利的。
本发明人还发现，相对于已知的BAB-嵌段共聚物组合物，增加PLG/PEG的比例和增加BAB-嵌段共聚物的分子量对BAB-嵌段共聚物的药物释放特性具有显著的影响，特别是在亲水性活性剂的情况下。先前对于ABA和BAB三嵌段的研究显示两种聚合物的释放特性是相似的，并且相同范围的三嵌段分子量适于BAB以及ABA三嵌段共聚物。研究了BAB-三嵌段共聚物对于示例性亲水性高分子葡聚糖(M.W.70,000道尔顿)的释放特性。本发明人意外地发现，当在BAB-三嵌段中的PLG/PEG比例和总分子量增加至高于先前所述的合适水平时，获得了对于亲水性活性剂的希望的控释特性。
根据本发明的一个特别优选的方面，根据其亲水性特性，预期以下亲水性生物活性剂特别适于与本发明的BAB-嵌段共聚物组合使用：催产素、加压素、促肾上腺皮质激素、表皮生长因子、血小板衍生生长因子(PDGF)、色素上皮衍生因子(PEDF)、催乳素、促黄体素释放素、黄体生成素释放激素(LHRH)、LHRH激动剂、LHRH拮抗剂、生长激素(人、猪、牛等)、生长激素释放因子、胰岛素、促红细胞生成素、促生长素抑制素、胰高血糖素、白细胞介素[白细胞介素-2(IL-2)、白细胞介素-11(IL-11)]、干扰素(干扰素-α、β或γ)、胃泌素(四肽胃泌素、五肽胃泌素、尿抑胃素)、胰泌素、降钙素、脑啡肽、免疫球蛋白、内啡肽、血管紧张素、促甲状腺素释放激素(TRH)、肿瘤坏死因子(TNF)、神经生长因子(NGF)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、巨噬细胞-集落刺激因子(M-CSF)、肝素酶、hANP、胰高血糖素样肽(GLP-1)、骨形态发生蛋白(BMP)、抗体和其片段、酶、细胞因子、疫苗、戈舍瑞林、雷帕霉素、利妥昔单抗、肾素、缓激肽、杆菌肽、多粘菌素、粘杆菌素、短杆菌酪肽、短杆菌肽、环孢菌素和其合成类似物、修饰物和药理学活性片段。
在某些情况下，可以凝胶状态施用装载药物的聚合物而不是作为溶液施用。胶凝可能是在施用之前使装载药物的聚合物溶液的温度升高至高于聚合物的胶凝温度的结果，或可能由在施用温度下使溶液中聚合物的浓度增加至高于饱和浓度引起，或可能由向聚合物溶液中添加使溶液胶凝的添加剂引起。无论如何，由此形成的凝胶可以肠胃外施用方式来施用，如通过肌内或皮下给药、瘤内给药、颅内(或进入切除的肿瘤腔)给药、关节内给药、鞘内给药、髓内给药、眼部给药、局部给药、经皮给药、阴道给药、口腔给药、透粘膜给药、肺部给药、经尿道给药、直肠给药、鼻腔给药、口服给药或耳部给药。
本发明适用于所有类型的生物活性剂和药物，包括核酸、激素、抗癌剂，并且其提供递送多肽和蛋白质的非常有效的方法。许多不稳定的肽和蛋白质药物能够配制到本发明的嵌段共聚物中并且可受益于本文中所述的逆向热胶凝过程。虽然不特定限于以下多肽和蛋白质，但是可药用的多肽和蛋白质的实例可以是促红细胞生成素、催产素、加压素、促肾上腺皮质激素、表皮生长因子、血小板衍生生长因子(PDGF)、催乳素、促黄体素释放素、黄体生成素释放激素(LHRH)、LHRH激动剂、LHRH拮抗剂、生长激素(人、猪、牛等)、生长激素释放因子、胰岛素、促生长素抑制素、胰高血糖素、白细胞介素-2(IL-2)、干扰素-α、β或γ、胃泌素、四肽胃泌素、五肽胃泌素、尿抑胃素、胰泌素、降钙素、脑啡肽、内啡肽、血管紧张素、促甲状腺素释放激素(TRH)、肿瘤坏死因子(TNF)、神经生长因子(NGF)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、巨噬细胞-集落刺激因子(M-CSF)、肝素酶、骨形态发生蛋白(BMP)、hANP、胰高血糖素样肽(GLP-1)、白细胞介素-11(IL-11)、肾素、缓激肽、杆菌肽、多粘菌素、粘杆菌素、短杆菌酪肽、短杆菌肽、环孢菌素或其合成类似物、修饰物和药理学活性片段、酶、细胞因子、抗体或疫苗。
对可以使用的多肽或蛋白质药物的唯一限制是功能性。在一些情况下，还可通过在形成聚合物药物组合物之前或之后向本发明的BAB嵌段共聚物添加各种添加剂来增加多肽和蛋白质的功能性或物理稳定性。也可将添加剂加入多肽或蛋白质药物的水溶液或混悬液中。添加剂(如多元醇(包括糖)、氨基酸、表面活性剂、聚合物、其它蛋白质)和某些盐可以结合使用，使药物本身稳定而不改变药物递送组合物的性质。这些添加剂可容易地并入嵌段共聚物，所述嵌段共聚物将保持功能性并具有逆向热胶凝性质。
蛋白质工程的开发可提供增加肽或蛋白质的固有稳定性的可能性。虽然这些所得的设计的蛋白质或修饰的蛋白质根据法规的含义可以被认为是新的实体，但其并不改变用于本发明的适应性。一个典型修饰的实例是PEG化，其中多肽药物的稳定性可通过水溶性聚合物(如聚乙二醇)与多肽的共价结合而显著改善。另一个实例是通过末端和/或内部添加、删除或替换就一个或多个氨基酸残基的识别或定位对氨基酸序列进行修饰。任何稳定性的改善均能在对患者单次施用药物递送液体之后使治疗上有效的多肽或蛋白质经延长的时间持续释放。
除了先前列出的基于肽或蛋白质的药物之外，还可使用所有治疗上和医学上有用种类的其它药物。这些药物描述于众所周知的参考文献中，如MerckIndex、PhysiciansDeskReference和ThePharmacologicalBasisofTherapeutics。提供特定药剂的简单列表仅是用于说明目的，而不应认为是限制：抗癌剂，如放线菌素D、阿那曲唑、阿扎胞苷、贝伐珠单抗、比卡鲁胺、博莱霉素、BCNU、硼替佐米、喜树碱、卡培他滨、卡铂、西妥昔单抗、柔红霉素、达沙替尼、多西他赛、多柔比星、表柔比星、埃罗替尼、依西美坦、吉非替尼、吉西他滨、戈舍瑞林、伊马替尼、STI-571、伊立替康、拉帕替尼、来曲唑、亮丙瑞林、甲氨蝶呤、丝裂霉素、奥沙利铂、紫杉醇、培美曲塞、利妥昔单抗、索拉非尼、舒尼替尼、他莫昔芬、泰索帝、替加氟-尿嘧啶、替莫唑胺、曲妥珠单抗、曲普瑞林、长春瑞滨；抗精神病药，如奥氮平(olanzapine)和齐拉西酮(ziprasidone)；抗菌药，如头孢噻吩；驱虫药，如伊佛霉素；抗病毒药，如阿昔洛韦；免疫抑制剂，如环孢菌素A(环多肽型剂)、类固醇和前列腺素。其它抗癌剂包括丙卡巴肼、达卡巴嗪、六甲蜜胺、顺铂、巯嘌呤、硫乌嘌呤、氟达拉滨磷酸酯、克拉屈滨、喷司他丁、氟尿嘧啶、阿糖胞苷、阿扎胞苷、长春花碱、长春新碱、依托泊苷、替尼泊苷、拓扑替康、更生霉素、伊达比星、普卡霉素、氟他胺、亮丙瑞林、戈舍瑞林、氨格鲁米特、安吖啶、羟基脲、天冬酰胺酶、米托蒽醌、米托坦、视黄酸衍生物、骨髓生长因子氨磷汀、亚硝脲氮芥、洛莫司汀、司莫司汀、抗VEGF等。
如上所述，本发明涉及相对于已知的BAB-三嵌段共聚物显示改进的药物释放特性的BAB-三嵌段共聚物。意外地发现，对于BAB-嵌段共聚物，提高PLG/PEG的比例和提高BAB-嵌段共聚物的分子量对嵌段共聚物的药物释放特性具有显著的影响，特别是对于亲水性化合物。为了说明本发明的优选实施方案，完成了各种BAB-三嵌段共聚物的合成。以下是说明本发明的优选实施方案的实施例，但是仅希望作为代表性实施例。
实施例1
MeO-PEG-PLG-PEG-OMe聚合物(PLG/PEG＝2.6，L/G＝72/28)的合成
将单甲氧基聚乙二醇(MeO-PEG，Mw550；50g)加入350mL甲苯中并通过共沸蒸馏除去残留的水。反应混合物中甲苯的最终体积大约是200mL。将反应烧瓶冷却至90℃，并添加DL-丙交酯(98.99g)，随后添加乙交酯(31.01g)。DL-丙交酯和乙交酯溶解之后，逐滴滴加辛酸亚锡(～126mg)以引发聚合。将反应混合物在130℃下回流20-22小时。将反应烧瓶冷却至60℃并添加六甲基二异氰酸酯HMDI(7.65g)，并且将反应混合物在60℃下加热18-20小时，随后在130℃再加热6小时。将甲苯(～100mL)蒸出并使反应混合物在1400mL无水二乙醚中析出。将二乙醚倾析掉，将残留物溶于二氯甲烷(60mL)，并且使聚合物在1000mL无水二乙醚中析出。将二乙醚倾析掉并在80-90℃下使用旋转蒸发器在真空下除去残留溶剂。最后，将产品在140℃下真空(＜1mm汞柱)干燥5小时，以得到162gMeO-PEG-PLG-PEG-OMe聚合物。
BAB聚合物的纯化
通过以大约20％(w/w)的浓度溶于水随后在70-80℃析出来进一步纯化BAB聚合物。将上清液倾析掉并向析出的聚合物混合物中加入等量的水。将聚合物溶解并在70-80℃再次析出。最后，将析出的聚合物溶于最小量的水中并冻干，以得到纯聚合物。
分析方法
重均分子量和数均分子量分别通过GPC(凝胶渗透色谱法)和NMR测定。丙交酯/乙交酯的比例由NMR数据计算。在Phenogel(混合床)和Phenogel，500Angstrom柱(用PEG标准物校准)的联合装置上使用RI检测器和四氢呋喃作为洗脱剂进行GPC分析。在CDCl3中用Bruker200MHz仪器获得NMR波谱。
实施例2
按照实施例1中列出的一般操作，合成具有不同疏水性/亲水性比例的BAB型嵌段共聚物(表I)。表I中示出了各种BAB聚合物的组合物。所有合成的嵌段共聚物(MeO-PEG-PLG-PEG-OMe)均具有可逆的热胶凝性质。
表I
*RTG＝逆向热胶凝。
实施例3
此实施例说明牛血清白蛋白(一种模型蛋白质)从BAB三嵌段[MeO-PEG-(DL-丙交酯-共聚-乙交酯)-PEG-OMe]聚合物凝胶的体外释放曲线。将FITC标记的牛血清白蛋白以5mg/mL的浓度溶于BAB三嵌段共聚物(表1的实施例4)水溶液。最终混合物中的BAB聚合物浓度是30％(w/w)。为了进行体外释放测试，将此混合物的0.25gm样品放入小瓶中并在37℃平衡。因为温度大于共聚物的胶凝温度，所以在小瓶的底部形成凝胶。一旦形成凝胶，就将5mLPBS(磷酸盐缓冲盐水，pH7.4)加入小瓶。将小瓶封闭并放入37℃温育箱。在相同条件下重复三次进行释放研究。在释放研究期间定期性地收集样品。在各时间点用新鲜缓冲液替换释放缓冲液。通过荧光微板分析仪分析样品中释放的蛋白质含量。结果在图1中呈现。
图1比较根据本发明的BAB-三嵌段(表1的第4个组合物)与已知的ABA-三嵌段对于牛血清白蛋白(BSA，一种用于预测亲水性蛋白质和其它亲水性活性剂的释放特性的模型蛋白质)的释放曲线。用于比较目的的ABA-三嵌段是ReGel(由Rathi等人在美国专利第6,201,072号、第6,117,949号和第6,004,573号中公开)。如图1所示，现有技术的ABA-三嵌段共聚物ReGel在最初五天内释放大约95％的BSA。相比之下，本发明的BAB-三嵌段共聚物(表1的第4个组合物)显示经过超过二十五天时间的BSA的缓释。图1中的数据证明BAB-三嵌段共聚物对于亲水性分子(包括蛋白质如BSA)经延长时间的控释是有利的。
实施例4
此实施例说明BAB三嵌段共聚物组合物对葡聚糖(70kDa，一种模型高分子)的释放曲线的影响。将FITC标记的葡聚糖以5mg/mL的浓度溶于各种BAB三嵌段共聚物(表1的实施例1、2和4)水溶液。最终混合物中的BAB聚合物浓度是30％(w/w)。在37℃下进行如实施例3所述的释放研究并且通过荧光微板分析仪分析样品。结果在图2中提供。
图2比较具有不同PLG/PEG比例的BAB-三嵌段共聚物对于示例性亲水性高分子葡聚糖(M.W.70,000道尔顿)的释放曲线。本发明人出乎意料地发现，相对于已知的BAB-嵌段共聚物组合物，增加PLG/PEG的比例和增加BAB-嵌段共聚物的分子量对BAB-嵌段共聚物的药物释放特性具有显著的影响，特别是在亲水性活性剂的情况下。如图2所示，具有PLG/PEG比例为2.36的BAB-三嵌段共聚物在十天时间内释放了超过90％的葡聚糖，而具有PLG/PEG比例为2.45和2.60的BAB-三嵌段共聚物在相同时间内分别释放了小于45％和小于25％。因此，图2中的数据证明根据本发明的BAB-三嵌段共聚物具有改进的释放特性，特别是对于亲水性药剂。
以上描述将会使本领域技术人员能够制造形成具有逆向热胶凝性质的水溶液的BAB型嵌段共聚物以及在药物递送领域使用所述BAB型嵌段共聚物。虽然在实施例中说明了蛋白质的受控递送以展示由嵌段共聚物的水溶液形成的水凝胶的功能性，但是不希望这些描述作为可以使用和装载到生物可降解嵌段共聚物的所有药物的全面叙述。毋庸置疑，来自各种类治疗剂的众多其它药物很适于由本文所述的嵌段共聚物的含水组合物来递送。也没有特定地展示所有的可制备的嵌段共聚物，且这些嵌段共聚物可显示临界逆向热胶凝性质。然而，对本领域技术人员来说很快就会显而易见的是，可以进行各种修改而不脱离本发明的范围，本发明的范围仅由以上权利要求书和其功能等价物限制。
Claims (15)
1.一种BAB-嵌段共聚物，包含：
i)60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和
ii)15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间；
其中所述BAB-嵌段共聚物具有从5000至8000道尔顿的Mw，其中A-嵌段与B-嵌段的重量比为2.45至2.70，其中所述BAB-嵌段共聚物在聚合物水溶液中形成时能够显示逆向热胶凝性质。
2.根据权利要求1所述的BAB-嵌段共聚物，其中所述共聚物的A-嵌段含量为从65至80％并且所述共聚物的B-嵌段含量为从20至35％。
3.根据权利要求1所述的BAB-嵌段共聚物，其中所述共聚物的A-嵌段含量为从67至75％并且所述共聚物的B-嵌段含量为从25至33％。
4.根据权利要求1所述的BAB-嵌段共聚物，其中所述嵌段共聚物的数均分子量为从3800至5000道尔顿。
5.根据权利要求1所述的BAB-嵌段共聚物，其中所述聚酯单体包含来自以下至少一种的残基：D,L-丙交酯、D-丙交酯、L-丙交酯、D,L-乳酸、D-乳酸、L-乳酸、乙交酯、乙醇酸、ε-己内酯、ε-羟基己酸、γ-丁内酯、γ-羟基丁酸、δ-戊内酯、δ-羟基戊酸、羟基丁酸、苹果酸或其共聚物。
6.一种BAB-嵌段共聚物组合物，其包含根据权利要求1所述的BAB-嵌段共聚物和药物。
7.根据权利要求6所述的BAB-嵌段共聚物组合物，其中所述药物是多肽或蛋白质、核酸或基因、激素、抗癌剂或抗细胞增殖剂。
8.根据权利要求6所述的BAB-嵌段共聚物组合物，其中所述组合物的药物含量介于0.01和20重量％之间。
9.一种含水BAB-嵌段共聚物组合物，所述组合物包含根据权利要求1所述的BAB-嵌段共聚物。
10.根据权利要求9所述的含水BAB-嵌段共聚物组合物，其中所述共聚物的A-嵌段含量为从65至80％并且所述共聚物的B-嵌段含量为从20至35％。
11.根据权利要求9所述的含水BAB-嵌段共聚物组合物，其中所述共聚物的A-嵌段含量为从67至75％并且所述共聚物的B-嵌段含量为从25至33％。
12.根据权利要求9所述的含水BAB-嵌段共聚物组合物，其中所述嵌段共聚物的数均分子量为从3800至5000道尔顿。
13.根据权利要求9所述的含水BAB-嵌段共聚物组合物，其进一步包含药物。
14.一种含水BAB-嵌段共聚物组合物在制备以控释形式对温血动物施用的至少一种药物中的用途，其中所述含水BAB-嵌段共聚物组合物包含：
i)60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和
ii)15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间；
其中所述BAB-嵌段共聚物组合物具有从5000至8000道尔顿的Mw且A-嵌段与B-嵌段的重量比为2.45至2.70，并且所述BAB-嵌段共聚物显示逆向热胶凝性质。
15.一种制造BAB-嵌段共聚物组合物的方法，所述方法包括：
(1)提供BAB-嵌段共聚物组合物，其包含：
i)60至85重量％的含生物可降解聚酯的生物可降解的疏水性A-嵌段；和
ii)15至40重量％的含聚乙二醇的生物可降解的亲水性B-嵌段，其中每个B-嵌段的重均分子量介于300和1000道尔顿之间；
其中所述BAB-嵌段共聚物组合物具有从5000至8000道尔顿的Mw，且A-嵌段与B-嵌段的重量比为2.45至2.70，并且在聚合物水溶液中形成时能够显示逆向热胶凝性质；和
(2)冷冻干燥所述嵌段共聚物，其中当所述嵌段共聚物作为聚合物水溶液形成时能够显示逆向热胶凝。
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| US617949A (en) | 1899-01-17 | Machine for manufacturing glassware | ||
| US5702717A (en) * | 1995-10-25 | 1997-12-30 | Macromed, Inc. | Thermosensitive biodegradable polymers based on poly(ether-ester)block copolymers |
| US6201072B1 (en) * | 1997-10-03 | 2001-03-13 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| US6004573A (en) | 1997-10-03 | 1999-12-21 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| ES2239408T3 (es) * | 1997-10-03 | 2005-09-16 | Macromed Inc. | Copolimeros tribloque de poli(lactido-co-glicolido) polietilenglicol de bajo peso molecular biodegradables con propiedades de gelificacion termica inversa. |
| US6117949A (en) | 1998-10-01 | 2000-09-12 | Macromed, Inc. | Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| US6841617B2 (en) * | 2000-09-28 | 2005-01-11 | Battelle Memorial Institute | Thermogelling biodegradable aqueous polymer solution |
| JP4548623B2 (ja) * | 1999-02-24 | 2010-09-22 | 多木化学株式会社 | 生体材料 |
| US7018645B1 (en) | 2000-04-27 | 2006-03-28 | Macromed, Inc. | Mixtures of various triblock polyester polyethylene glycol copolymers having improved gel properties |
| US20040185101A1 (en) * | 2001-03-27 | 2004-09-23 | Macromed, Incorporated. | Biodegradable triblock copolymers as solubilizing agents for drugs and method of use thereof |
| EP1555278A1 (en) * | 2004-01-15 | 2005-07-20 | Innocore Technologies B.V. | Biodegradable multi-block co-polymers |
| CN1958074B (zh) | 2006-08-21 | 2010-11-03 | 中国科学院成都有机化学有限公司 | 可注射温敏性聚(ε-己内酯-对二氧六环酮)-聚乙二醇嵌段共聚物水凝胶 |
| CN1916050B (zh) | 2006-08-21 | 2010-05-26 | 中国科学院成都有机化学有限公司 | 可注射温敏性聚(丙交酯-乙交酯-对二氧六环酮)-聚乙二醇嵌段共聚物水凝胶 |
| CN101333294A (zh) | 2007-06-28 | 2008-12-31 | 信谊药厂 | 具有可逆热胶凝性质的可生物降解三嵌段共聚物 |
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| JP5643824B2 (ja) | 2014-12-17 |
| CA2774526C (en) | 2018-04-24 |
| MX2012003361A (es) | 2012-07-03 |
| CN102639670A (zh) | 2012-08-15 |
| ES2626929T3 (es) | 2017-07-26 |
| KR20120082425A (ko) | 2012-07-23 |
| BR112012005859A2 (pt) | 2017-02-21 |
| EP2478066A4 (en) | 2014-10-01 |
| JP2013505337A (ja) | 2013-02-14 |
| BR112012005859B1 (pt) | 2021-08-31 |
| RU2012111985A (ru) | 2013-10-27 |
| AU2010295314B2 (en) | 2014-08-28 |
| AU2010295314A1 (en) | 2012-04-19 |
| EP2478066A1 (en) | 2012-07-25 |
| KR101838304B1 (ko) | 2018-03-13 |
| EP2478066B1 (en) | 2017-04-26 |
| KR101894200B1 (ko) | 2018-08-31 |
| CA2774526A1 (en) | 2011-03-24 |
| WO2011035264A1 (en) | 2011-03-24 |
| KR20170123353A (ko) | 2017-11-07 |
| MX343980B (es) | 2016-12-01 |
| DK2478066T3 (en) | 2017-06-19 |
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