CN101160354B - 高分子型癌症治疗用药及其制造方法 - Google Patents
高分子型癌症治疗用药及其制造方法 Download PDFInfo
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- CN101160354B CN101160354B CN2006800123378A CN200680012337A CN101160354B CN 101160354 B CN101160354 B CN 101160354B CN 2006800123378 A CN2006800123378 A CN 2006800123378A CN 200680012337 A CN200680012337 A CN 200680012337A CN 101160354 B CN101160354 B CN 101160354B
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Abstract
本发明在于提供一种药剂含量多、肿瘤集聚性高、大于肾排泄的分子大小的高分子型药剂。通过由金属卟啉衍生物(锌原卟啉等)与苯乙烯·马来酸共聚物(SMA)经非共价键结合形成SMA胶束复合物,可得到药剂含量多的高分子型癌症治疗用药。此SMA胶束复合物是通过以下方法制得,即,使金属卟啉衍生物与苯乙烯·马来酸共聚物在不存在缩合剂、碱性条件下进行反应,可溶化后将pH调节为6~8,经高分子成分分离操作回收高分子药剂胶束复合物成份的方法。
Description
技术领域
本发明涉及通过将癌症治疗用药制成高分子胶束复合物,可使其选择性集聚于肿瘤部位等病变部位(以下称为肿瘤部位),进一步延长在肿瘤部位的滞留时间,而可减少给药次数,此外,可藉此增大抗肿瘤效果,减轻对正常器官组织的副作用的高分子型癌症治疗用药及其改良制造方法。更详细地讲,涉及金属原卟啉(以下称为MePP)与苯乙烯·马来酸共聚物(以下称为SMA)结合、进行配位使其变成大于肾排泄的分子大小的高分子胶束复合物的胶束复合物,将其作为有效成分的高分子型癌症治疗用药,以及使上述金属原卟啉与SMA直接以特定的pH条件、不存在缩合剂下为特定的立体构型的高分子型癌症治疗用药的制造方法。
背景技术
一般而言即使通过经口给药,或注射等给予癌症治疗药等药剂,其效果对于症灶并无特异性,因此即使为强效药剂,也无法充分发挥效果,同时对于症灶以外的正常器官·组织也产生作用,引起严重的副作用。这样的强效药剂因为其副作用,而给药量的增加受到限制,此为所谓的药物传递系统(DDS)的病灶靶向型的药剂开发在现今世界中持续竞相研究开发的理由。DDS研究在副作用影响大的癌症治疗剂领域中特别重要。
本发明人着眼于通过抗肿瘤剂的高分子化,形成病灶靶向型及缓释型药,首先发现40Kda以上的高分子型药剂系选择性地集聚在肿瘤组织,更长时间滞留的独特现象,将此命名为EPR(enhanced permeability and retention,通透性增强及停滞)效果(非专利文献1)。在高分子型药剂及脂质微粒等中观察到该现象。
发明人等基于此见解,迄今制造了使药剂与各种高分子反应后得到的多个高分子型药剂,这些高分子化药剂因为上述EPR效果而被赋予高的肿瘤集聚性及对发炎部位的集聚性,结果发现了,与低分子量的抗肿瘤剂相比不仅抗肿瘤 效果显著优异、而且对正常器官的副作用少的优异的高分子型抗肿瘤剂(专利文献1、专利文献2、专利文献3、非专利文献2)。
这些高分子型抗肿瘤剂中,也发现了专利文献3所记载的,低分子抗肿瘤剂与苯乙烯·马来酸共聚物(SMA)通过非共价键结合而形成高分子胶束复合物结构的高分子型抗肿瘤剂(以下称为SMA胶束复合物)是抗肿瘤效果特别优异、而且对正常器官的副作用少的优异的抗肿瘤剂。
【专利文献1】日本专利特开平11-60499
【专利文献2】日本专利特开2003-73273
【专利文献3】WO2004/10349A1
【非专利文献1】Cancer Res.,44,2115-2121,1984;ibid,46,6387-92,1986;Anticancer Res.,13,1287-1292,1993
【非专利文献2】J.Controll.Release,74,47-61,2001;Adv.EnzymeRegul.,41,189-207,2001
【非专利文献3】Cancer Res.,63,3567-3574,2003;
【非专利文献4】Bioconj.Chem.13,1031-1038,2002;
另一方面,本发明人之前在上述专利文献2中,提出了可使对发炎部位及肿瘤部位所衍生的hemoxygenase(HO-1)为抑制剂的具有hemoxygenase阻碍活性的金属卟啉衍生物,例如式(1)所示的锌-原卟啉(以下称为ZnPP),与聚乙二醇(PEG)键结而成为高分子型抗肿瘤剂。
ZnPP原本不溶于水,到目前为止为了使其可溶于水中,本发明人使两性的聚乙二醇(PEG)的平均分子量100~20000(较佳为5000左右)结合,制造出可溶于水的衍生物(专利文献2),该PEG-ZnPP结合物显示出约68000的分子量,所以此高分子在机体内的动向,在表现上述所示EPR效果上很重要。
发明内容
然而,PEG虽本身的分子量巨大,但对于与药剂结合的高分子(此时1.1万)而言ZnPP仅为1分子,为了给予一定量以上的有效成分,将被高分子化的药剂的总有效给药量换算为人为数g以上,该剂量过多。这简直是增加对患者的给药量,实际上为了获得人有效血中浓度,必须给予数g~250g,很难具实用性。
此外,专利文献2中作为两性或水溶性的聚合物,最适合者为聚乙二醇 (PEG),但因为通过直接结合将PEG加成于ZnPP的方法很难,因此必须采用通过二胺结构使PEG加成的方法。专利文献2中虽提及除PEG以外使用SMA作为高分子化合物,但并未具体揭示,此外叙述使用SMA时也与PEG加成时同样,通过使导入氨基的卟啉与SMA发生脱水缩合反应,而进行高分子化反应。
此外,上述专利文献3中揭示了各种低分子抗肿瘤剂-SMA胶束复合物的制造方法,虽没有SMA-金属PP衍生物的记载,但作为SMA胶束复合物的制造方法,公开了使用SMA的半丁酯等SMA的衍生物,在酸性条件下,于溶解性碳化二亚胺等、脱水缩合剂的存在下使其反应,接着pH升高至8以上后调节至中性,通过高分子成分的分离精制操作例如交联葡聚糖等凝胶色谱法、超滤膜等,回收高分子成分的方法。
依据此方法,不用使用一般所用的胶束化剂及脂质体制剂中的作为必须构成成分的乳化剂(例如糖酯、磷酯酰胆碱、鞘氨醇、胆固醇等),而可制造胶束化药剂。
但是,此反应中,需要水溶解性碳化二亚胺这类昂贵的脱水缩合剂。此外使用该缩合剂时,难以完全去除缩合剂,期望其完全去除会伴随药剂的活性降低等,产生很难实用化等的问题。另外,关于依据此方法所得到的SMA-ZnPP胶束,其分子量也有意义地小于肾排泄的界限分子量,此为问题所在。
因此发明人此次对通过在MePP加成SMA来得到药剂含量多的高分子型药剂进行了研究,发现了通过调节反应各阶段的pH,进行金属卟啉的可溶化与进到胶束中,可得到金属卟啉衍生物与苯乙烯·马来酸共聚物的胶束复合物。
此胶束复合物是金属卟啉衍生物与苯乙烯·马来酸共聚物通过非共价键进行结合,形成高分子胶束复合物结构的复合物,因此在胶束复合物中可含有10~60%的大量的药剂,藉此可以更简略化的方法得到以更少量(换算成人为0.1~6g)的给药量而显现出有效性的胶束。
发现如此所得的高分子型癌症治疗用药(以下称为SMA胶束复合物)是抗肿瘤效果特别优异、而且对正常器官的副作用少的优异的癌症治疗用药。此处的癌症治疗用药除了直接使肿瘤坏死的抗肿瘤剂之外,还包括进行放射线及激光治疗时,预先给药的光增感剂,或细胞内信号传递控制等在癌症治疗中使用的药剂。
此外癌症治疗用药,不仅对实体癌,还包括对淋巴肿瘤、白血病(包括成人T细胞白血病、艾滋相关T细胞白血病)等所有癌症的治疗药。
另外,本发明人研究了以更简单且廉价的可以得到该癌症治疗用药的制造方法,结果发现,通过使用特定的pH条件直接使SMA与药剂反应,即使在缩合剂不存在下反应也进行,可得到效率佳、高纯度的药剂。
此外依据此方法,不需要如专利文献2中所揭示的在原卟啉中加成二胺基乙烷、加成氨基的反应操作。
亦即本发明为金属卟啉衍生物与苯乙烯·马来酸共聚物通过非共价键进行结合而成的SMA胶束复合物及其作为有效成分的高分子型癌症治疗用药。
此外本发明是使金属卟啉衍生物与苯乙烯·马来酸共聚物在不存在缩合剂下、碱性条件下进行反应,将可溶化后的pH调节为6~8,通过高分子成分分离操作(去除低分子级分)回收高分子药剂胶束复合物成分的上述SMA胶束复合物的制造方法。
本发明的SMA胶束复合物是使金属卟啉衍生物与SMA通过非共价键结合的胶束复合物,与上述的非专利文献2差异极大,分子量增大至13万附近或16万以上,因此可更选择性地集聚于肿瘤部位,在肿瘤内的滞留时间也长。因此组我诶抗肿瘤效果优异、且对于正常器官的副作用少等的制癌性药剂可用性更高。
另外通过本发明的SMA胶束复合物的制造方法,不使用缩合剂而可由金属卟啉衍生物与SMA用单纯方法合成,而且纯化步骤简单,可得到纯度高的制品。
具体实施方式
金属卟啉衍生物是在具有卟啉环的化合物上配位金属的络合物,作为具有卟啉环的化合物的原卟啉容易取得,适合使用。
被配位的金属,只要是除了如汞的有毒金属、如1价金属的难以配位的金属以外的均可,并没有特别的限制,但依用途而有所不同。作为抗肿瘤剂使用时,不具有hemoxygenase抑制活性的铁并不适合,可使用锌、锡、钴、镍、铜等,特别优选锌。原卟啉上配位锌的Zn-原卟啉(ZnPP)如下式(1)所示。
此外,配位了铁的亚铁原卟啉类并不适合作为抗肿瘤剂,但可作为放射线治疗时的放射线增感剂使用,将其制成SMA胶束后事先给药,则集聚在肿瘤局部,因此可进行选择性的放射线治疗。或可使用于自由基分子(R,ROO,R)等的生成的催化剂功能为必须的情况。作为亚铁原卟啉类可使用卟啉的铁错合物的亚铁原卟啉、3价的铁卟啉中配位了氯离子的氯化亚铁原卟啉(haminchloride)等。作为放射线增感剂可使用ZnPP等,也可使用作为上述抗肿瘤剂所使用的各种金属PP。
本发明中作为高分子化剂使用的SMA由苯乙烯与马来酸酐共聚合而得到,是具有下述式(2)或式(3)所示的重复单元的共聚物,具有苯乙烯与马来酸酐作为必须成分。
但是,R为H或其它的烃、氨基酸、醇类。
本发明中,SMA可直接使用苯乙烯·马来酸酐共聚物的无水物,也可使用专利文献3所公开的经完全开环的苯乙烯·马来酸(或其半烷酯物)。直接使用酸酐者不需要水解等的操作,由从可简便实施的观点考虑为佳,另一方面使用经开环的苯乙烯·马来酸的方法,即使未极度的升高至高pH(12以上),也可在短时间结束胶束形成,具有可防止因强碱性而使药剂成分分解等的优点。
SMA因聚合度而存在各种分子量,本发明中作为高分子化剂使用的SMA优选三聚物(约660Da)而得具有约40KDa的大小,更严密而言分子量800~2500由不会集聚于体内、容易排泄出体外而言为佳。
通过使MePP与SMA反应的高分子胶束复合物的制造为,以ZnPP为例,将SMA(酸酐或水解物等)与ZnPP混合,加入如碳酸苏打这类碱性液使其成碱性,搅拌加温。加入适当的碳酸苏打使其维持于碱性。整体可溶化后用酸中和。藉此产物沉淀,有效率地使药剂被包含于胶束中。进而将pH值调节于中性而可溶化后,使用超滤、柱色谱法等高分子成分的分离纯化操作来回收高分子成分。通过上述的操作,经SMA的立体结构变化和分子间作用,使低分子药剂包含于SMA胶束,这样产生胶束结构。
MePP与SMA的反应也可以使MePP及/或SMA酸酐溶解于有机溶剂后反应,对于水为不溶性的化合物也可使其溶解于四氢呋喃、二甲基亚砜等有机溶剂后反应。作为SMA的溶剂,可使用丙酮、四氢呋喃、二甲基甲酰胺、二甲基亚砜、甲基溶纤剂、乙腈、乙醇、丙三醇等,特别优选丙酮、乙腈等。有机溶剂溶液的浓度优选为1~30%,此时可添加吡啶、二氨基乙烷等作为催化剂。
也可以一边照射超声波一边进行MePP与SMA的反应,通过照射超声波,可在于更短时间内高效形成胶束,照射条件例如照射1分钟、暂停1分钟,持续5分钟~60分钟,至少持续5~10分钟。
高分子成分分离操作优选由分子量3000~50000的超滤膜进行。优选的截断(cut off)分子量为3万~5万。依据本方法所产生的SMA-ZnPP的分子量为4万以上。更优选的表观中心分子量为13万~18万。
该本发明的高分子型癌症治疗用药是,为了形成胶束复合物,不需要表面活性剂等辅助成分的存在,此外也不使用脱水缩合剂,仅使用作为原料的MePP与SMA而制得,可简单制备仅由SMA与MePP所成的稳定的胶束复合物结构的药剂。
另外,根据需要可在作为稳定化剂的乳糖、甘露醇、氨基酸、丙三醇、卵磷脂等与药剂等量至100倍量存在下制备该胶束。
本发明的高分子型胶束复合物癌症治疗用药是由MePP与SMA的反应,形成高分子胶束复合物结构,使MePP包覆于胶束内而被含有的药,MePP与SMA的结合状态为氢键、疏水键或离子键,不存在酰胺键、酯键等共价键。此可经后述实施例所得的图1的红外吸收光谱来证明。
如此制得的胶束型SMA-MePP复合物如目前为止于高分子药剂中所见,与原本的低分子量药剂比较,可赋予有用的药理学的性质这一点不用多说,而且与专利文献3的方法所制物比较,也具有作为药剂的如下优异性质。
相对于按照以往方法而得的SMA~药剂胶束复合物的分子大小为4万以下,通过按照本发明所得的SMA胶束复合物为分子大小为10万以上约13~18万的大幅度的高分子化物,此超过了作为肾排泄界限的分子量4万,因此大幅提高了血中浓度、血中滞留性,藉此表现出更佳的EPR效果,对于改善作为肿瘤选择性药剂的各种癌症治疗剂有极大的贡献。
此外,胶束内的药物含量较一般的脂质体(w/w10~20%)比较大幅增加(w/w40~60%),而且使用碳化二亚胺等作为脱水缩合剂时,极难以将其去除,既使纯化5次仍被确认出其残留氮,本发明因为不混入缩合剂、催化剂成分等,故可期待来由此带来的副作用减少的效果。
接着,此物是经静脉给药由EPR效果而更集聚于肿瘤组织,通过ZnPP(或其它的金属PP)具有的放射线增感作用,即使照射同一线量的电磁线(γ线、x线、紫外线、α线),也仅使含有该ZnPP的组织受到更多的抑制,可达到抗 肿瘤效果更提高一层的癌症治疗。即本发明的高分子型癌症治疗用药不仅本身作为抗肿瘤剂使用,也可作为光增感剂使用。
[实施例1]
(SMA-ZnPP胶束复合物的制造方法)
向平均分子量约1500的苯乙烯与马来酸酐共聚物(SMA)1.5g中加入200ml的0.1M NaOH,使其pH成为13,用磁力搅拌器搅拌,搅拌下加入微粉末化的锌(Zn)-原卟啉(PP)的粉末1.5g,接着持续搅拌。随着时间的经过混浊液逐渐在数小时内变成深红酒色的透明溶液。离心(3000rpm)除去不溶性的ZnPP、其它的残渣,接着将pH降至7附近,加入约3倍量的10mM Na2CO3/NaHCO3溶液后持续搅拌该溶液,接着2小时后加入适量的0.1M HCl,使pH约为7,再持续搅拌2小时。接着使用超滤膜的分子界限大小(分子量3000阿米控公司制)于加压下浓缩至50ml。藉此除去游离的ZnPP或非胶束化SMA或其衍生物及其分解物。而且对于含有该被浓缩的SMA-ZnPP胶束的级分,加入约20倍量的纯水稀释,与上述同样使用超滤膜(分子量5000)于加压下浓缩·洗净。ZnPP的SMA胶束物没有从该膜漏出,而仅有各游离的低分子成分漏出。这样可进行胶束的洗净。最后3次以上使用蒸馏水进行,同样的操作总计重复3~5次后将其冷冻干燥,成为注射用原物的粉末。
图2表示了SMA-ZnPP使用交联葡聚糖G-150的分子量的解析结果,结果推定,其分子量为13万~15万,与IgG(免疫球蛋白、16万)同等。
得知本发明的SMA-ZnPP胶束在SMA与ZnPP之间没有共价键,而是以非共价键的结合物。为了证明这一点而表示出与PEG-ZnPP对比的红外吸收光谱。图1-B是PEG-ZnPP的红外吸收光谱,其中具有因共价键而产生的典型的酰胺I、II的吸收。另一方面,图1-A是按照本发明的方法而得的SMA-ZnPP的光谱,其中显示出图1-B所示的酰胺键样式等新键的吸收峰。
此纯化物未通过分子量10万的超膜,比较均匀的分布,将其紫外·可见光吸收光谱与PEG-ZnPP、未修饰的ZnPP一并示于图3。与PEG-ZnPP(图3B)、未修饰的ZnPP(图3C)比较,得知本发明的SMA-ZnPP胶束复合物(图3A)是吸收极大向短波长移动,350nm附近具有小的吸收波肩。
(治疗效果)
此外将使用实施例1所得的SMA-ZnPP胶束复合物对兔子的VX-2肿瘤的治疗效果示于表3。
[表1]
肿瘤移植部位:肝脏皮膜下
如上,本发明的SMA-ZnPP胶束复合物显示出强大的抗肿瘤效果,其效价优于PEG-MePP。
(通过激光分解的光增感效果)
通过对通常的细胞培养条件下的Jurkat细胞的闪光分解法,与PEG-ZnPP比较下评估SMA-ZnPP的光增感剂效果。将激光照射开始后的时间(微秒)与相对吸收发光度的关系示于图4。相对吸收发光度表示ZnPP的三重态(激发状态)的寿命,比较寿命(相对吸收发光度的半衰期)可知,相对于SMA-ZnPP为2.4μs,PEG-ZnPP为27μs,SMA-ZnPP的光增感效果的效果好且高速进行,产生一重态氧。
图4的结果,系Jurkat细胞中于一般的空气环境下的结果,也一并进行水中的结果的通过氮气鼓泡使溶存空气(氧气)释放的在脱氧下的试验。将该结果示于表2。SMA-ZnPP在Jurkat细胞中较在空气中显现出特别显著的效果。此外低氧环境几乎没有效果,推测抗肿瘤效果基于经由光照射所生成的一重态氧的生成。
(SMA-ZnPP及PEG-ZnPP的光照射下的细胞毒性)
将淋巴球Jurkat细胞于Dulbecco MEM培养基、加入了5%CO2的空气中,以37℃进行培养,通过MTT法对经光照射第24小时的Jurkat细胞的生存率进行分光学定量。结果示于图5。本发明的SMA-ZnPP胶束复合物为5.0μM的浓度时,Jurkat细胞几乎全部死亡,可知优于给予同浓度的PEG-ZnPP。
[表2]
试样 | τt[μs](一般状态) | τt[μs](40分钟N<sub>2</sub>闪光脱氧后) |
PEG-ZnPP在H<sub>2</sub>O | 2.5(±0.2)μs | 406(±40)μs |
PEG-ZnPP在JCS | 27(±3)μs | 325(±30)μs |
SMA-ZnPP在H<sub>2</sub>O | 1.4(±0.2)μs | 484(±11)μs |
SMA-ZnPP在JCS | 2.4(±0.2)μs | 92(±40)μs1.2ms(±0.1) |
[实施例2]
(SMA-氯化亚铁原卟啉胶束的制造)
于200ml的烧杯中,加入SMA的完全碱水解物300mg,加入50ml的脱离子水,用磁力搅拌器搅拌下溶解,接着滴入0.1M NaOH,使pH为10。在20ml的玻璃管形瓶中将氯化亚铁原卟啉(sigma公司制)100mg溶解于4ml的DMSO(二甲基亚砜),于上述的烧杯中于搅拌下滴入此溶液,进行混合,接着滴入1M NaOH,使pH为12,搅拌15分钟,接着继续滴定1M HCl,当pH降至2成为暗褐色的悬浮液,直接持续溶解搅拌30分钟~60分钟。接着离心(3000~6000rpm)除去沉淀物与上清液,再加入30ml的0.02M乙酸溶液,再次搅拌(30分钟)悬浮液,接着向该SMA-胶束的水悬浮液中滴入0.1M NaOH,将pH提高至10,进行30分钟的搅拌后,再次使用0.1M HCl使pH降至7.4,成为完全变成暗褐色的透明溶液。以上的操作在室温下进行。将其用阿米控的截断分子量为10KDa的分子筛膜,与上述的实施例同样重复浓缩、洗净,接着变成冷冻干燥物(粉末)。取出这样所得的胶束的一部份(0.5mg/ml),使用此水溶液所测量的光散射数据图为图6,由图6可知此胶束显示出平均直径为25.5nm的均匀分布的标准品。其紫外线可见光部的吸收光谱示于图7。显著显示出来自亚铁原卟啉的吸收特征的在约386附近的强的吸收、在500nm与612nm的弱吸收,同时显示出来自SMA的在260nm附近的弱吸收。(浓度0.01mg/ml,蒸馏水中)
产业上利用的可能性
大多数的低分子量的治疗癌症药虽然抗肿瘤效果强大,但没有对肿瘤部位的选择集聚性,因此对正常器官·组织的副作用极大。所以它们的给药量受到限制。通过使该药剂与SMA形成胶束复合物,形成分子量在5万以上的高分子型癌症治疗用药,可以发挥EPR效果,提高抗肿瘤效果,显著减轻对正常器官·组织的副作用。
本发明通过使作为抗肿瘤剂的ZnPP、作为放射线增感剂的如亚铁原卟啉的MePP与SMA经非共价键而结合成胶束复合物,可使胶束内含入大量药剂,此外因为为肾排泄界限的分子量4万以上的高分子量,故大大提高了血中浓度、血中滞留性,发挥了EPR效果,细胞摄取也优良,所以生物活性也大,故作为癌症治疗用药具有优异的药效。
此外本发明通过在特定的pH条件下使该药剂与SMA的胶束复合物反应,不需要一般难以分离的脱水缩合剂及其它的乳化剂等,可省略纯化从而简化工序,同时由于不使用脱水缩合剂,因此可以得到高纯度的制品。
附图说明
[图1]图1-A是由本发明方法(实施例1)所得SMA-ZnPP胶束复合物的红外线吸收光谱。图1-B是PEG-ZnPP胶束复合物的红外线吸收光谱。
[图2]是由本发明方法所得SMA-ZnPP胶束复合物及各种标准品的分子量的比较示图。
[图3]SMA-ZnPP(A)、PEG-ZnPP(B)及未修饰ZnPP(C)的紫外·可见部吸收光谱。
[图4]为SMA-ZnPP及PEG-ZnPP在激光闪光分解的光增感剂效果的示图。
[图5]为由SMA-ZnPP及PEG-ZnPP产生的光照射下的细胞毒性的示图。
[图6]SMA-氯化亚铁原卟啉胶束复合物的光散射图。
[图7]SMA-氯化亚铁原卟啉胶束复合物的紫外可见光部的吸收光谱。
Claims (8)
1.一种SMA-金属卟啉胶束复合物,其特征在于,由金属卟啉衍生物与苯乙烯·马来酸共聚物经非共价键结合而成,使金属卟啉衍生物与苯乙烯·马来酸共聚物于不存在缩合剂的碱性条件下进行反应,可溶化后将pH调节为6~8,通过高分子成分分离操作回收高分子药剂胶束复合物成分。
2.如权利要求1所述的SMA-金属卟啉胶束复合物,其特征在于,金属卟啉衍生物为锌原卟啉。
3.一种高分子型癌症治疗用药,其特征在于,以权利要求1或2所述的SMA-金属卟啉胶束复合物作为有效成分。
4.权利要求1或2所述的SMA-金属卟啉胶束复合物的制造方法,其特征在于,使金属卟啉衍生物与苯乙烯·马来酸共聚物于不存在缩合剂的碱性条件下进行反应,可溶化后将pH调节为6~8,通过高分子成分分离操作回收高分子药剂胶束复合物成分。
5.如权利要求4所述的SMA-金属卟啉胶束复合物的制造方法,其特征在于,使苯乙烯·马来酸共聚物或金属卟啉衍生物的有机溶剂溶液在碱性条件下进行反应。
6.如权利要求4或5所述的SMA-金属卟啉胶束复合物的制造方法,其特征在于,进行超声波处理使其反应。
7.如权利要求4或5所述的SMA-金属卟啉胶束复合物的制造方法,其特征在于,高分子成分分离操作为利用分子量3000~50000的超滤膜的操作。
8.如权利要求6所述的SMA-金属卟啉胶束复合物的制造方法,其特征在于,高分子成分分离操作为利用分子量3000~50000的超滤膜的操作。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6017206B2 (ja) * | 1977-03-24 | 1985-05-01 | 浩 前田 | ネオカルチノスタチン誘導体の製造法 |
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JPH07330773A (ja) | 1994-06-07 | 1995-12-19 | Toyo Hatsuka Kogyo Kk | ポルフィリン誘導体とその用途 |
JPH1160499A (ja) * | 1997-08-22 | 1999-03-02 | Hiroshi Maeda | 抗腫瘍剤 |
JPH11335267A (ja) * | 1998-05-27 | 1999-12-07 | Nano Career Kk | 水難溶性薬物を含有するポリマーミセル系 |
JP4291973B2 (ja) | 2001-02-08 | 2009-07-08 | 大阪瓦斯株式会社 | 光電変換材料および光電池 |
JP3615721B2 (ja) * | 2001-07-13 | 2005-02-02 | ナノキャリア株式会社 | 薬物含有高分子ミセルの製造方法 |
JP5000050B2 (ja) * | 2001-08-31 | 2012-08-15 | 浩 前田 | 抗腫瘍剤及びその製造方法 |
US7670627B2 (en) * | 2002-12-09 | 2010-03-02 | Salvona Ip Llc | pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients |
HUE035003T2 (en) * | 2003-05-26 | 2018-05-02 | Hiroshi Maeda | To produce anticancer agent and procedure |
JP2005029480A (ja) * | 2003-07-08 | 2005-02-03 | Nano Career Kk | ピルビニウムを内包した高分子ミセルを含有する抗癌剤 |
GB0415663D0 (en) * | 2004-07-13 | 2004-08-18 | Psimei Pharmaceuticals Plc | Compound |
-
2006
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Non-Patent Citations (1)
Title |
---|
Khaled Greish et al..Copoly(styrene-maleic acid)-Pirarubicin Micelles:High Tumor-Targeting Efficiency with Little Toxicity.《Bioconjugate Chem.》.2004,第16卷(第1期),230-236. * |
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AU2006238072A1 (en) | 2006-10-26 |
EP1873204B1 (en) | 2011-09-21 |
US20090062476A1 (en) | 2009-03-05 |
TW200719904A (en) | 2007-06-01 |
WO2006112362A1 (ja) | 2006-10-26 |
JP4522452B2 (ja) | 2010-08-11 |
JPWO2006112361A1 (ja) | 2008-12-11 |
JPWO2006112362A1 (ja) | 2008-12-11 |
EP1873204A4 (en) | 2009-03-25 |
TWI374742B (zh) | 2012-10-21 |
KR20080002814A (ko) | 2008-01-04 |
KR101165760B1 (ko) | 2012-07-18 |
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CA2605205A1 (en) | 2006-10-26 |
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