CN117440977A - 高分子化丙戊酸及其用途 - Google Patents

高分子化丙戊酸及其用途 Download PDF

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CN117440977A
CN117440977A CN202280041000.9A CN202280041000A CN117440977A CN 117440977 A CN117440977 A CN 117440977A CN 202280041000 A CN202280041000 A CN 202280041000A CN 117440977 A CN117440977 A CN 117440977A
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vpa
block copolymer
valproic acid
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长崎幸夫
池田丰
田鹿裕也
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University of Tsukuba NUC
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Abstract

[课题]提供丙戊酸衍生物，以改善将丙戊酸本身用作药物时伴随的短处或缺点。[解决手段]提供丙戊酸的高分子化物，其是包含聚(乙二醇)链段和聚(丙戊酸乙烯酯)链段的嵌段共聚物。

Description

高分子化丙戊酸及其用途
技术领域
本发明涉及高分子化丙戊酸及其用途，更具体而言，涉及聚(乙二醇)-b-聚(丙戊酸乙烯酯)共聚物及其在医疗领域的用途。
背景技术
目前，丙戊酸(或2-丙基戊酸)(以下，有时也简写为VPA)的钠盐被广泛用作抗癫痫药、针对双相情感障碍的躁狂状态的治疗药、偏头痛发作的发病抑制剂。另外，由于VPA抑制组蛋白去乙酰化酶(HDAC)的异常活化而具有抗肿瘤效果，因此还进行了几个临床试验。而且，还报道了对癌症恶病质(cancer cachexia)有效(参照Am J Physiol Cell Physiol311:C101-C115,2016)。
丙戊酸钠(VPA钠)虽然被用作抗癫痫药的首选药物，但存在下述应解决的课题：例如，需要保持血中浓度恒定，一天必须服用1次或多次而不遗忘，出于自残目的等大量服药，存在肝损伤·致畸性等副作用等。为了解决这样的课题，提供了如下的制剂：在临床上使用的丙戊酸钠的缓释制剂中，掺混有相关技术领域中常用的载体或添加剂等、例如偏硅酸铝酸镁、羟丙基纤维素、硬脂酸镁、乙基纤维素、羟丙甲纤维素、甘油脂肪酸酯、滑石、白糖、沉降碳酸钙、聚氧乙烯(105)聚氧丙烯(5)二醇、阿拉伯树胶粉末、氧化钛等。另外，作为改变活性物质本身的制剂，以前对作为活性物质的丙戊酸没有具体记载，但提出了具有游离羧基的酸性活性物质与具有叔氨基的聚合物结合而成的口服给药形态物(参照日本特表平9-511488号公报)。
发明内容
发明所要解决的课题
为了解决上述问题中的一部分，提出了特定的薄膜包衣剂、包含如上所述的各种载体或添加剂的缓释制剂等，但还希望提供可采取更加多样的形态的手段。
用于解决课题的手段
为了解决这样的课题，本发明人在对VPA的化学衍生化进行研究时发现了：包含在聚合物主链上经由酯键共价键合有VPA的聚合物(有时也简写为聚VPA)的链段和聚(乙二醇)(有时也简写为PEG)链段的嵌段共聚物在以人为代表的动物的体内缓慢释放VPA，发挥VPA本来具有的作用、效果。
因此，作为本说明书中公开的技术事项的主要特征或方案，可列举如下。
方案1：包含下述式I所表示的高分子化丙戊酸链段的嵌段共聚物。
式中，A表示未取代或取代的C1-C12烷基，在被取代的情况下的取代基表示甲酰基或式R1R2CH-的基团，这里，R1和R2独立地表示C1-C4烷氧基，或者R1和R2一起表示-OCH2CH2O-、-O(CH2)3O-或-O(CH2)4O-，
L表示连接基团，
X表示H或C1-C6烷基、或者H或C1-C3烷基、或者H或甲基，
Y表示H、SH或S(C＝S)-Ph或S(C＝S)-OC1-C6烷基，
m表示3～100、或5～60、或5～40、或8～40的整数，
n表示5～10000、或10～1000、或20～500的整数。
方案2：方案1的嵌段共聚物酸，其中，L选自下式
和-(CH2)bS-所表示的基团，各b独立地为1～5的整数。这里，在连接基团L用-(CH2)bS-表示的情况下，该基团沿式I的记载方向连接。具体而言，该基团的末端亚甲基的碳原子与式I的m个重复单元即PEG链的末端氧原子(O)键合，另一末端S原子与式I的n个重复单元即含VPA的聚合物链的α末端碳原子键合。
方案3：纳米颗粒，其包含方案1或2所述的嵌段共聚物。
方案4：一种药学制剂，其包含作为有效成分的方案1或2的嵌段共聚物和生理盐水或其他的相关技术领域中常用的添加剂或稀释剂，所述药学制剂例如用于用作抗癫痫药、针对双相情感障碍的躁狂状态的治疗药、偏头痛发作的发病抑制剂、由组蛋白去乙酰化酶(HDAC)的异常活性引起的疾病的抑制剂、抗肿瘤药。
发明效果
包含上述式I所表示的高分子化丙戊酸链段的嵌段共聚物本身在以人为代表的动物的体内缓慢释放游离的丙戊酸。另外，尽管不受理论的约束，但上述嵌段共聚物在水性介质(不受限定，为根据需要缓冲化的生理盐水等)中能以纳米尺寸的颗粒的形式存在，该纳米尺寸的颗粒由主要包含聚VPA链段的核和主要包含PEG链段的壳构成。这样的颗粒中，由于在水性介质中可动性高的PEG链的存在，可能抑制例如体内的蛋白(包括各种酶)等向聚VPA链段的附着或靠近等，从而可能抑制或调节由上述颗粒释放游离的VPA或其他的体内作用物质的作用。如此，上述嵌段共聚物可能起到VPA本身的作用效果，同时作为不同于VPA的药品发挥优异的作用、效果，可改变乃至增强VPA的化学或生物学特性。因此，可有助于医药或制药领域的VPA技术的丰富化，而不受限定。
附图说明
[图1]是制造例4中得到的目标物质(PEG-b-聚VPA)的1H NMR谱。
[图2]是显示制造例5中得到的纳米颗粒(NanoVPA)的动态散射光测定结果的粒径分布图。
[图3]是试验例1中通过给予受试药剂而引起的小鼠的行为模式的评分的图形表示。
[图4]是对试验例2中通过给予受试药剂对来自脑的神经营养因子(BDNF)的表达量的影响进行汇总的图形表示。
[图5]是关于试验例3中通过给予受试药剂对C26荷瘤恶病质模型小鼠产生的治疗效果(存活率)的图形表示。
[图6]是显示试验例4中通过给予受试药剂而引起的模型小鼠的体重变化的图形表示。
[图7]是显示试验例5中VPA和NanoVPA在小鼠中的体内动力学的图形表示。
具体实施方式
关于本说明书中公开的技术事项或本申请发明而阐述的术语等，只要没有特别说明，则作为具有相关技术领域中常用的含义或内容的术语使用。关于该技术事项，可进一步追加以下的说明。
上述式I所表示的嵌段共聚物的L所表示的连接基团通常是指含有最多34个、或最多18个、或最多10个碳原子、以及任选的氧和氮原子的基团。作为其具体例子，可列举：上述方案2中所示的连接基团。关于该技术事项或本发明，例如，C1-C12烷基是指碳原子数为1～12个的未分支或分支的烷基，不受限定，表示甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、己基、辛基、癸基、十二烷基等，例如C1-C6烷基或C1-C3烷基表示上述烷基中碳原子分别为6或3以下的烷基，OC1-C6烷基中的C1-C6烷基也与上述同样，C1-C4烷氧基具有与OC1-C4烷基相同的含义。
上述嵌段共聚物可在水性介质(水或根据需要缓冲化的生理盐水等)中以主要包含聚VPA链段的核和主要包含PEG链段的纳米尺寸的颗粒的形式存在。纳米尺寸的颗粒不受限定，但颗粒在水溶液中通过动态光散射法测定的流体力学平均直径可处于10nm～500nm、或20nm～180nm、或40nm～150nm的范围内。
上述嵌段共聚物可方便地通过如下来制备：在需要的情况下用相关技术领域中公知的保护基事先保护PEG的任一末端的OH，并将另一末端的OH事先修饰或改变成可延长丙戊酸烷基乙烯酯的重复单元的相关技术领域中公知的基团或部分(例如，包括末端SH或S(＝S)烷基)(制备大分子引发剂)，对该末端使用丙戊酸烷基酯，实施其本身公知的延长(聚合)反应。
由上述嵌段共聚物得到的纳米尺寸的颗粒可通过溶解于可溶解该共聚物的水混溶性有机溶剂，并将所得溶液经由透析膜、例如具备1kDa～50kDa的截留细孔的透析膜相对于水进行透析来提供。
如此操作而得到的纳米颗粒(NanoVPA)例如通过冷冻干燥、离心分离等可从它们的溶液或分散液中分离，因此根据需要可重新溶解或悬浮于生理盐水中，制成口服或胃肠外给药用制剂。在制成口服给药用制剂时，根据需要，利用相关技术领域中常用的添加剂、稀释剂等，可以以口服用片剂、颗粒剂的形式提供。口服用制剂的添加剂或稀释剂不受限定，可列举：丙戊酸钠的缓释制剂中使用的上述偏硅酸铝酸镁、羟丙基纤维素、硬脂酸镁、乙基纤维素、羟丙甲纤维素、甘油脂肪酸酯、滑石、白糖、沉降碳酸钙、聚氧乙烯(105)聚氧丙烯(5)二醇、阿拉伯树胶粉末、氧化钛等，还可列举：氯代羧甲纤维素(chlorocarmellose)钠、十二烷基硫酸钠等。另外，上述纳米颗粒在水中可增溶或分散，因此例如还可制成在根据需要缓冲化的生理盐水中增溶或分散的胃肠外制剂。
包含这样的嵌段共聚物或纳米颗粒作为有效成分的组合物，其最适的用量可根据处置对象的疾病的严重度、给药对象的患者的年龄、性别、体重而变化，因此不能一概而论，但专科医生可参照目前临床上使用的VPA钠盐的用法、用量等，在需要的情况下基于通过小规模的临床试验等得到的有效数据等来确定。
以下，为了避免说明变得繁琐，根据本说明书的公开事项或本发明的典型示例，进一步具体地说明该公开事项或本发明，但该公开事项或本发明并不限定于这些例子。
制造例1：丙戊酸乙烯酯的合成
在25mL乙酸乙烯酯(富士胶片和光)和17mL丙戊酸(东京化成)中加入5.6mg乙酸钯(II)(富士胶片和光)和17mg氢氧化钾(富士胶片和光)，在室温下反应3天。使用蒸发仪去除副产物乙酸后，再次加入25ml乙酸乙烯酯反应3天。通过硅藻土过滤去除钯后，通过减压蒸馏得到了20mL丙戊酸乙烯酯。
制造例2：CH3O-(CH2CH2O)n-CH2PhCH2Cl(T59)的合成
在50g(10mmol)市售的CH3O-(CH2CH2O)n-H(MW＝5,000)中加入100mL四氢呋喃(THF)和7.2mL(11.5mmol)丁基锂(1.6M-己烷)，之后加入17.5g(0.1mmol)α,α’-二氯对二甲苯，在50℃下反应两天。在2-丙醇(IPA)中沉淀后，向沉淀物加入甲醇使其溶解，再次于IPA中沉淀。重复该操作3次，之后将得到的淡黄色沉淀物减压干燥，得到了47.2g目标物质。
制造例3：CH3O-(CH2CH2O)n-CH2PhCH2S(＝S)OCH2CH3(T64)的合成
将制造例1中得到的30g CH3O-(CH2CH2O)n-CH2PhCH2Cl(T59)溶解于150mL甲醇，加入0.96g乙基黄原酸钾(CH3CH2OC(＝S)SK)，在室温下反应10分钟。通过离心分离排除沉淀物后，将甲醇减压干燥。将残余物溶解于氯仿，用水洗涤，分离出氯仿层，经无水硫酸钠脱水并过滤后于IPA中沉淀，离心分离后进行减压干燥，得到了27.4g目标物质。
制造例4：CH3O-(CH2CH2O)n-CH2PhCH2(CH2CH(OC(＝O)CH(CH2CH2CH3)2))mS(＝S)OCH2CH3(T71)的合成
将制造例2中合成的5.3g CH3O-(CH2CH2O)n-CH2PhCH2S(＝S)OCH2CH3(T64)、57mg偶氮二异丁腈、8.6g丙戊酸乙烯酯装入烧瓶中，氮气鼓泡5分钟后，在60℃下反应2天。将所得的目标物质溶解于THF，进行IPA沉淀、减压干燥，得到了5.4g目标物。目标物的1H NMR谱见图1。由图1所示的各质子峰值(参照下表的数据)导出丙戊酸乙烯酯的重复数m为36.0。
c d e f g h
质子 2m m m 4m 4m 6m
实测值 69.3 31.1 36.3 164.9 143.2 221
计算值 34.65 31.1 36.3 41.2 35.8 36.8
制造例5：自组装颗粒的制备
采集4.46g上述合成的共聚物(T71)，溶解于44.6mL的二甲基甲酰胺(DMF)，装入透析膜(截留分子量(MWCO)＝3.5KDa)中，相对于2L的水进行透析。每8小时更换6次透析水，之后进行动态光散射测定，确认形成了69nm的颗粒。动态光散射测定的结果见图2。
试验例1：使用戊四唑诱发癫痫点燃(epilepsy kindling)模型小鼠的抗癫痫效果
将戊四唑(PTZ)进行腹腔给药(30mg/kg)(第1、3、5、8、10、12天)，制作PTZ点燃模型小鼠。将给药量增加至33mg/kg(第15天)，之后每次增加2％的给药量。
用丙戊酸或制造例5中制作的丙戊酸颗粒(NanoVPA)对点燃模型小鼠进行腹腔给药(100mg/kg(按VPA量换算))，通过行为观察分析其效果。在第0、2、4、7、9、11、14和21天给予VPA或NanoVPA。
根据小鼠的行为模式的评分确认到：通过给予NanoVPA，痉挛得到抑制。结果见图3。
需要说明的是，评分是依据如下所示的打分标准：
评分1：运动不能、探索行为、理毛；评分2：点头行为、短肌阵挛；评分3：长肌阵挛、反复性的头部运动、反复性的身体颤抖行为、尾部硬直；评分4：阵挛性痉挛、前肢旋转发作、后肢外翻、持续性站立行为、跌倒、斯特劳布举尾(Straub tail)、袋鼠样姿势；评分5：强直痉挛、无法维持正向姿势的强直阵挛性痉挛。
试验例2：来自脑的神经营养因子(BDNF)的定量
据报道，在PTZ诱发癫痫点燃模型小鼠中BDNF上升。回收来自试验例1的小鼠的海马，通过RT-PCR法分析给予药剂对BDNF的表达量产生了怎样的影响。结果见图4。由该图可以确认：BDNF的表达量因PTZ而上升，但上述表达量通过给予NanoVPA而下降。
试验例3
据报道，由于丙戊酸具有组蛋白去乙酰化酶抑制活性，所以在C26荷瘤恶病质模型小鼠中具有治疗效果。关于通过给予NanoVPA是否可确认到同样的效果，使用癌症恶病质模型小鼠分析其效果。对Balb/c小鼠皮下移植在癌症恶病质模型中使用的C26细胞，制作了荷瘤小鼠。对荷瘤小鼠进行VPA或NanoVPA的口服或腹腔给药，观察给药后的存活率。结果见图5。根据该图，在NanoVPA给药组中可见存活率的改善。
试验例4：毒性评价
为了评价VPA和NanoVPA的毒性，持续5天将VPA和NanoVPA以500mg/kg进行腹腔给药，观察小鼠的体重变化。结果见图6。由该图可知：虽然VPA给药组的体重减少，但NanoVPA给药组未见体重减少。试验例5：VPA和NanoVPA的体内动力学
对于6周龄的ICR小鼠(雄)，将丙戊酸钠(VPA)或丙戊酸纳米颗粒(NanoVPA)以按丙戊酸浓度计为400mg/kg的浓度对小鼠进行腹腔内给药。经过规定的时间后，解剖小鼠，将血液回收到实施过肝素处理的管中，离心后得到了血浆。利用Nanopia TDM Valproic Acid(积水医疗)分析血浆中的丙戊酸浓度。结果见图7。由图可知：VPA的纳米颗粒化使作为有效成分的丙戊酸在血中长时间滞留，可使效果持续。
产业实用性
根据本发明，丙戊酸的改变或修饰物无需使用各种载体或添加剂的特定组合物，即可在例如医疗和制药业中应用以发挥丙戊酸本身的作用效果。

Claims (5)

1.嵌段共聚物，其包含下述式I所表示的高分子化丙戊酸链段：
式中，A表示未取代或取代的C1-C12烷基，在被取代的情况下的取代基表示甲酰基或式R1R2CH-的基团，这里，R1和R2独立地表示C1-C4烷氧基，或者R1和R2一起表示-OCH2CH2O-、-O(CH2)3O-或-O(CH2)4O-，
L表示连接基团，
X表示H或C1-C6烷基，
Y表示H、SH或S(C＝S)-Ph或S(C＝S)-OC1-C6烷基，
m表示3～100的整数，
n表示5～10000的整数。
2.根据权利要求1所述的嵌段共聚物，其中，L选自下式
和-(CH2)bS-所表示的基团，
各b独立地为1～5的整数。
3.纳米颗粒，其包含权利要求1所述的嵌段共聚物。
4.药学制剂，其包含作为有效成分的权利要求1所述的嵌段共聚物和生理盐水或相关技术领域中常用的添加剂或稀释剂。
5.根据权利要求4所述的药学制剂，所述药学制剂用于用作选自如下的药剂：抗癫痫药、针对双相情感障碍的躁狂状态的治疗药、偏头痛发作的发病抑制剂、由组蛋白去乙酰化酶(HDAC)的异常活性引起的疾病的抑制剂和抗肿瘤药。
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