CN103127521B - 具有螯合型复合微胞的药物载体及其应用 - Google Patents
具有螯合型复合微胞的药物载体及其应用 Download PDFInfo
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Abstract
本发明提供一种螯合型复合微胞应用于药物载体上,本发明的螯合型复合微胞能键结而不破坏或改变药物结构,并延长药物在人体内的半衰期。
Description
技术领域
本发明是关于一种药物载体,特别是关于一种具有螯合型复合微胞的药物载体及其配方与形成方法。
背景技术
癌症病患接受放射线治疗与化学治疗时所引发的副作用众人皆知,抗癌治疗药物的毒性也一向为病患所诟病,因为严重副作用会造成许多癌症病患的二度伤害与更大的梦靥;如果病患因为放射线治疗与化学治疗时所引发的严重副作用而不能完成预定的疗程,不仅未能达到疗效也造成医疗资源的浪费。放射线治疗与化学治疗不论对正常细胞或癌细胞都无选择性,因此在癌细胞被消灭的同时,正常细胞也遭受池鱼之殃,病人常见治疗后有口腔溃疡、食欲不振、腹泻、落发及白血球、血小板下降等副作用,甚至引发其它可致命的并发症。副作用往往也限制了治疗剂量的给予,影响了疗效;部分副作用可以靠改变给药方法予以减轻,如分散或长时间给药,或以局部给药方式,像腹膜内或动脉化疗,让高浓度的药物只局限于病灶所在,不致引发全身性的副作用;或待药物作用时间过后,马上给予某种拮抗药物(解毒剂),减除抗癌药部分细胞杀伤力。然而上述方法并无选择性,只能稍减对正常细胞的毒性,相对于癌细胞的疗效也被打折扣,他法即是迅速治疗发生的副作用,尽量降低伤害的程度,如白血球生成素及强效止吐剂的注射,但此法也仅部分减轻已形成的副作用,并无预防功效,因此疗效与零副作用犹同鱼与熊掌,不可兼得。又肿瘤形成后,癌细胞不断滋生,经由淋巴管及血管蔓延各处,族群越来越复杂,最后生出有抗药性的细胞群,此时肿瘤即到达无法根治的地步,任何治疗皆告无效;故抗癌治疗药物的毒性与放射线治疗无法有效控制肿瘤滋生蔓延,是目前治癌无法奏全功的绊脚石。据此,为令癌症病患免除或减少副作用,并能完成放射线治疗与化学治疗的疗程以增加疗效,重点即在于如何能在攻击癌细胞时同时保护正常细胞。部分的化学治疗与放射线治疗作用机转来自于自由基伤害,如果能够选择性的利用具抗氧化与自由基物质,可以降低这些治疗对正常细胞的伤害。
氨磷汀Amifostine(Ethyol;WR-2721)是一种含磷酸硫(thiophosphate)的抗辐射细胞保护剂,其为phosphorylatedaminothiol的前驱物,此药物须经由存在生物体内的细胞、体液和血液的碱性磷酸酶(alkaline phosphatase)的去磷酸化作用(dephosphorylated),此为一种碱性磷酸酵素作用,之后才能转换成有保护细胞作用的活性代谢物free thiol,其通称为WR-1065,可使细胞不受辐射及化学药物的伤害,进而使癌症病患免于放射线治疗与化学治疗时所引发的严重副作用。由于癌细胞的碱性磷酸酵素含量较正常细胞低得多,癌细胞内的血流状况及较酸环境也不利碱性磷酸酵素作用,Amifostine的组织保护作用机转可与alkylating agents、platinum analogs的活性物质结合成thioether conjugates,防止其与正常组织的DNA或RNA结合;另外WR-1065可部分逆转已形成DNA-platinum的内转产物;协助移除DNA-platinum,让正常的DNA继续进行作用;也可提供H基给DNA的游离子修补DNA的损伤。WR-1065同时也是一个强力的ROS(Reactive oxygen species)净化剂,可清除放射线治疗及特定化学治疗药物所产生的ROS,预防细胞损伤。在体外也可有效清除-OH基相关的spin-trap信号、过氧化阴离子及Doxorubincin衍生的过氧化阴离子,另外WR-1065对AOS的清除作用,可预防Bleomycin所诱发的肺脏发炎及纤维化。
氨磷汀Amifostine可减少癌症化学治疗引起的毒性作用、保护正常的组织、提高化疗及电疗的有效治疗剂量、增加反应率,此外,氨磷汀Amifostine更可配合其它生长因子,细胞素共同使用,具有加成保护造血干细胞效果。氨磷汀Amifostine注射5-10分钟后即开始产生细胞保护作用,具短暂的血中半衰期(βt1/2=8.8min),在血浆中快速的清除,约90%会在6分钟内清除。迅速分布于各组织,在正常组织中经由酵素相关的去磷酸化作用,快速利用,滞留时间长,达到稳定状态约10分钟。相反的,此作用在肿瘤组织中则利用缓慢或分布极少。氨磷汀Amifostine注射后,在正常细胞内的浓度较癌细胞高十倍,包括肾脏、肺脏、肝脏、皮肤、骨髓、肠道及脾脏等,较少存于脑组织、横纹肌及肿瘤细胞,因此氨磷汀Amifostine对正常细胞有选择性的保护作用,但须在化疗或放射治疗前15~30分钟给予。然而,一般的治疗期间需有几个小时的疗程,因此,如何能延长氨磷汀Amifostine在人体内的半衰期即为当前产业亟需发展的重要标的。
除上述氨磷汀Amifostine外,一般药物剂型在体内代谢半衰期都很短,经服用或以针剂方式进入人体后,会广泛的散布至全身各组织,为了维持长时间的药效和有效的药物分布,须用比实际药物浓度需求量更多的剂量或以多次投药方式,方能达到预期疗效。但其也因此毒害正常组织,且引起不必要的副作用。为了改善传统药剂重复多次投药的缺点,避免药物过量和浪费,提出药物传释系统(drug delivery system;DDS)的概念,以增加药物的疗效并减少用药次数。其中一种商业用的载体如脂质体(或称微脂囊;Liposome),其为一种球形载体,主由单层或多层的卵磷脂(Phosphatidylcholin;PC)所构成,由于结构限制只能携带亲水性的药物(包覆于内层),尤其容易累积在肝脏内,其对于温度相当敏感,因而保存困难,也不易以干粉的型态运输,参考C.Chen,D.Han,et al.(2010).″An overview of liposomelyophilization and its future potential.″Journal ofControlled Release 142:299-311。
高分子纳米微胞是极具潜力的药物载体之一,其优点包括提高药物效率、降低细胞毒性、保护与安定药物、提供标的效果等,而纳米尺寸的微胞具有延长体内循环时间、躲避巨噬细胞(mononuclear phagocyte system,MPS)与内质网(reticularepithelial system,RES)的功能,因此是目前最受瞩目的药物控制释放系统。一般的纳米微胞由两性团联共聚物(amphiphiliccopolymer)构成。在水相环境下,高分子链段因亲疏水性的不同会排列形成核壳结构(core-shell structure)微胞,因此提供了疏水性药物(如:indomethacin、adriamycin、amphotericin B)绝佳的保护环境,以高分子微胞携带抗癌药物也可有效提高药物的安定性与效率。高分子微胞可借由物理性包覆、化学键结或静电作用力来包覆药物。物理性包覆的驱动力主要是疏水性链段与药物间的疏水性作用力。化学键结方式即利用共价键键结药物,如酰胺键(amide bond),此类键结非常安定,不易被酵素分解或水解,因此须在药物与高分子之间导入一特定环境下会断裂的隔离基(spacer)以利药物释放。以物理作用力在包覆疏水性药物时往往会造成较多的损耗;而以化学作用力包覆药物则因合成步骤较繁复,载药量会较低。
除上述两性质包覆药物的方法外,目前也有用静电作用力的高分子微胞。通常这种高分子微胞会设计成一端的不带电性的高分子形成壳(shell),而另一端则具有电荷链段,其在经过相反电荷的基因或是药物中和电性后会变成较疏水性的核(core),借此可形成具有壳核(core-shell)结构的聚离子错合型微胞(Polyion Complex micelles;PIC micelles)。然而,利用静电吸附药物也有其限制,分子量太小或水溶性药物很容易被取代置换,如同离子交换树脂般,无法形成微胞的核。另一种方式则在于直接键结药物,尤其是含金属的药物,如Cisplatin(顺铂)、Carboplatin(卡铂)、Oxaliplatin(奥沙利铂)等等,然而,由于这些含金属的药物在此用以当成路易斯酸,配位子与铂Pt键结后药物的官能基已被取代,不是原本药物结构,因此必须重新验证药物的安全性与有效性等,恐将导致成本大幅增加。据此,更是需要发展一种新的药物释放的载体即为当前产业亟欲发展的重要标的。
发明内容
鉴于上述的发明背景中,为了符合产业上特别的需求,本发明提供一种具有配位键的螯合型药物载体可用以解决上述传统技术未能达成的标的。
本发明的一目的是提供一种具有金属离子核心的载体结构,本发明以至少一金属离子(包含过渡金属)为中心,并与具有螯合端的高分子(包含莰段共聚物;block copolymer)形成具有配位键的药物载体,以使得可提供电子对的药物(包含具有官能基如羧酸carboxylic acids,醇alcohols,酮ketones,呋喃furans,胺amines,苯胺anilines,吡咯pyrroles,硫醇thiols,酯esters,酰胺amides,亚胺imines,吡啶pyridines,嘧啶pyrimidins,咪唑imidazoles,比唑pyrazols,磺胺sulfonamides,膦酸phosphonic acids等)与金属离子借由配位键键结,借此可与具有螯合端的高分子同时形成螯合型复合微胞(Chelating Complex Micelles;CCM)。众所周知,配位键(又称配位共价键,或简称配键;Coordinate bond)是一种特殊的共价键,当共价键中共享的电子对由其中一原子独自供应时,即称的为配位键。配位键的形成需要两个条件:一是中心原子或离子,它必须有能接受电子对的空轨道;二是配位体,组成配位体的原子必须能提供配对的孤对电子。当一路易斯碱供应电子对给路易斯酸而形成化合物时,配位键就形成了。在配位化合物中,由电负性小的元素原子向电负性大的元素原子提供孤对电子形成配位键时,每个有一对孤对电子的前者(电负性小的原子)显示正价,后者显示负价。反之,由电负性大的元素原子提供孤对电子与电负性小的元素原子之间形成配位键时,两种元素都无价态变化。
本发明的螯合型复合微胞(CCM)在制备上比一般物理/化学作用力包覆药物简单。使用物理或是化学性包覆药物往往受到链段设计上的限制,通常仅能包覆疏水性药物,而这些药物与高分子进行包覆时由于溶解度不佳,造成在水溶液中会有很多损耗。因此,本发明架构仅需药物具有可提供电子对官能基,且能与金属形成配位键者,即可混成具有多牙配位子(polydentateligands)的螯合型复合微胞。不仅可以包覆疏水性药物也能够包覆亲水性药物,所以能更加广泛在其它类型的药物传输系统上;而且配位键与药物间的吸引力较亲疏水作用力强进而能提高包覆效率以及增加药物溶解度。
再者,本发明的金属离子核心除可提供作为高分子与药物连结中心外,也可提供如使用钆Gd可作为MRI磁振造影、鎝99mTc(SPECT单光子计算机断层)、镓68Ga(PET/CT正子计算机断层)、铼188Re(体内放射疗法)以及铟111In(白血球造影)等显影功能,本发明借此应用而提供一实时监控造影与治疗(Real-timemonitoring and therapy)的技术手段,若再加上可提供标靶效果的标的分子(targeting moiety),如叶酸(folic acid),等,能累积至肿瘤组织以达到攻击癌细胞的目的。
本发明的另一目的是提供一种细胞保护剂载体,其以一具有配位基的金属(包含过渡金属)离子为核心(Core),其分别与一细胞保护剂(包含氨磷汀Amifostine、WR-1065)以及至少一嵌段共聚物(包含聚乙二醇-聚麸胺酸嵌段共聚物;PEG-b-PGA,聚乙二醇-聚乳酸莰段共聚物)以配位方式键结形成细胞保护剂载体,此外,本发明的莰段共聚物中不具螯合能力的高分子链段会延伸在螯合型复合微胞外侧,以稳定微胞结构与强化分散性。
据此,本发明的螯合型复合微胞同时具有多牙配位子以及金属离子,其具备可包覆亲、疏水性药物、生物可分解、流体分散性好、可显影、延展药物等特质,故其可广泛地应用于医药的商业与工业中以达成产业亟需发展的重要标的。
根据本发明上述的目的,本发明提供一种螯合型复合微胞,该螯合型复合微胞包含一金属离子核心,该金属离子核心为路易斯酸;与至少一配位子,该配位子是与该金属离子核心借由配位键彼此键结。上述的金属离子核心选自下列族群中的一者或其任意组合或其衍生物:铁Fe,铜Cu,镍Ni,铟In,钙Ca,钴Co,铬Cr,钆Gd,铝Al,锡Sn,锌Zn,钨W,钪Sc,钛Ti,锰Mn,钒V,镁Mg,铍Be,镧La,金Au,银Ag,镉Cd,汞Hg,钯Pd,铼Re,鎝Tc,铯Cs,镭Ra,铱Ir,镓Ga,及其组合。其中该配位子选自下列族群中的一者或其任意组合或其衍生物:羧酸carboxylic acids,醇alcohols,酮ketones,呋喃furans,胺amines,苯胺anilines,吡咯pyrroles,硫醇thiols,酯esters,酰胺amides,亚胺imines,吡啶pyridines,嘧啶pyrimidins,咪唑imidazoles,比唑pyrazols,磺胺sulfonamides,膦酸phosphonic acids。
上述的螯合型复合微胞更包含一药物,该药物为路易斯碱,且该药物是与该金属离子核心借由配位键彼此键结。上述的药物包含一或多个官能基,该官能基其选自下列族群中的一者或其任意组合或其衍生物:羧酸carboxylic acids,醇alcohols,酮ketones,呋喃furans,胺amines,苯胺anilines,吡咯pyrroles,硫醇thiols,酯esters,酰胺amides,亚胺imines,吡啶pyridines,嘧啶pyrimidins,咪唑imidazoles,比唑pyrazols,磺胺sulfonamides,膦酸phosphonic acids,其中上述的药物选自下列族群中的一者或其任意组合或其衍生物:Amifostine(氨磷汀),WR-1065,Doxorubicin(阿霉素),Pemetrexed(培美曲塞),Gemcitabine(吉西他滨),Methotrexate(灭杀除癌锭),Docetaxel(多西紫杉醇),Vinblastine(长春碱),Epirubicin(表柔比星),Topotecan(拓扑替康),Irinotecan(抗癌妥),Ifosfamide(异环磷酰胺),Gefitinib(吉非替尼),Erlotinib(埃罗替尼),Penicillin class(青霉素类),cloxacillin(邻氯青霉素),dicloxacillin(双氯青霉素),Gentamicin(庆大霉素),Vancomycin(万古霉素),Amphotericin(两性霉素),Quinolones(喹诺酮类),Piperazine(哌嗪),fluoroquinolone(氟化奎林酮类),Nalidixic acid(萘啶酸),Ciprofloxacin(环丙氟哌酸),Levofloxacin(左氧氟沙星),Trovafloxacin(曲氟沙星),Oseltamivir(奥塞米韦),Metformin(二甲双胍),Trastuzumab(曲妥珠单抗),Imatinib(依麦替尼布),Rituximab(利妥昔单抗),Bevacizumab(贝伐珠单抗),Celecoxib(塞来昔布),Etodolac(依托度酸),Ibuprofen(布洛芬),Cyclosporine(环孢菌素),Morphine(吗啡),Erythropoietin(红血球生成素),Granulocytecolony-stimulating factor(粒细胞集落刺激因子),Curcumin(姜黄素)(Enol,Keto Form),Resveratrol(白藜芦醇),Glutathione(榖胱甘肽),VitamineC(维生素C),Acetylcysteine(乙酰半胱氨酸),Carnitine(肉碱),Galantamine(加兰他敏),insulin(胰岛素),Imipenem(亚胺培南),Cilastatin(西司他丁),Ertapenem(厄他培南),Meropenem(美罗培南),Entecavir(恩替卡韦),Telbivudine(替比夫定),Lamivudine(拉米夫定)。
根据本发明上述的目的,本发明提供一种具有螯合型复合微胞的药物载体,该具有螯合型复合微胞的药物载体包含至少一高分子聚合物,该高分子聚合物为路易斯碱;与一金属离子核心,该金属离子核心为路易斯酸,且该金属离子核心是与该高分子聚合物形成配位键,且该具有螯合型复合微胞的药物载体用以搭载一为路易斯碱的药物,其中上述的金属离子核心、药物的选择是相同于本发明的螯合型复合微胞的内容。此外,上述的高分子聚合物为下列之一:unidentate ligands(单牙配位子),bidentateligands(双牙配位子),tridentate ligands(三牙配位子),hexadentate ligands(六牙配位子),polydentate ligands(多牙配位子),且该高分子聚合物的分子量(Molecular weight)范围约为1,000-100,000道尔顿(Dalton),其中上述的高分子聚合物选自下列族群中之一者或其任意组合或其衍生物:聚乙二醇Poly(ethylene glycol),聚天门冬氨酸Poly(aspartic acid),聚麸胺酸Poly(glutamic acid),聚赖氨酸Polylysine,聚丙烯酸Poly(acrylic acid),几丁聚醣chitosan,聚乙烯亚胺Polyethyleneimine,聚甲基丙烯酸Poly(methacrylic acid),透明质酸hyaluronic acid,胶原蛋白collagen,聚(氮-异丙基丙烯酰胺)Poly(N-isopropyl acrylamide),直链淀粉amylose,纤维素cellulose,聚羟基丁酸酯poly(hydroxybutyrate),聚乳酸poly(lactic acid),聚琥珀酸丁酯poly(butylenesuccinate),聚己内酯poly(caprolactone),羧甲基纤维素carboxymethylcellulose,糊精dextran,环糊精cyclodextrin。
根据本发明上述的目的,本发明提供一种具有螯合型复合微胞的医药组合物,该具有螯合型复合微胞的医药组合物包含一嵌段共聚物,该嵌段共聚物为路易斯碱,其中,该嵌段共聚物更包含一螯合端以进行配位键结,与一分散端以使该医药组合物能稳定而良好地分散于生物流体中;一药物,该药物包含路易斯碱的官能基;与一金属离子核心,该金属离子核心为路易斯酸,且该金属离子核心分别与该嵌段共聚物以及该药物形成配位键。上述的金属离子核心为一二价铁离子、三价铁离子或三价钆离子,且上述的药物为一氨磷汀(Amifostine)或WR-1065,而上述的嵌段共聚物为一聚乙二醇-聚麸胺酸嵌段共聚物(Poly(ethyleneglycol)-b-Poly(glutamic acid);PEG-b-PGA),其中,聚麸胺酸为该螯合端,且聚乙二醇为该分散端。
根据本发明上述的目的,本发明提供一种具有螯合型复合微胞的医药组合物的制造方法,该具有螯合型复合微胞的医药组合物的制造方法包含提供一原料,该原料包含一氨磷汀(Amifostine)、一聚乙二醇-聚麸胺酸嵌段共聚物(PEG-b-PGA)与一氯化亚铁(FeCl2);与将该原料置入缓冲液中进行一匀相扰动程序,借此,该氨磷汀(Amifostine)经由该亚铁离子(Fe2+)与该聚乙二醇-聚麸胺酸嵌段共聚物借由配位键直接进行自组装(self-assembly)反应,上述的氨磷汀(Amifo stine)的重量为0.1-10mg、该聚乙二醇-聚麸胺酸嵌段共聚物(PEG-b-PGA)的重量为0.1-100mg,及该氯化亚铁(FeCl2)的重量为0.01-50mg。上述的氨磷汀(Amifostine)浓度约为0.01-10mg/mL,且上述的缓冲液可为HEPES[4-(2-hydroxyethyl)-1-piperazinee-thanesulfonic acid),4-羟乙基哌嗪乙磺酸],其中,上述的缓冲液的pH值约为6.5-7.5之间,此外,上述的匀相扰动程序是在4-40℃下进行。
附图说明
图1所示为根据本发明的第三实施例形成的具有螯合型复合微胞的医药组合物的制作方法示意图。
图2A与图2B所示为本发明的氨磷汀及其衍生物的结构式示意图。
图3所示为本发明的聚乙二醇-聚麸胺酸嵌段共聚物的结构式示意图。
图4所示为本发明的具有螯合型复合微胞的细胞保护剂的结构式示意图。
图5所示为PEG与PEG-b-PGA的凝胶渗透层析仪分析图。
图5所示为以聚乙二醇PEG为巨起始剂合成聚乙二醇-聚麸胺酸莰段共聚物。
图6所示为PEG-b-PGA的氢核磁共振光谱与相对应官能基的化学位移(chemical shift)。
图7所示为粒径分析仪分析螯合型复合微胞(CCM)的粒径示意图。
图8所示为透析膜模拟本发明的药物释放分析示意图。
9图所示为根据本发明的透析膜模拟药物释放分析示意图。
100:具有螯合型复合微胞的医药组合物
110:细胞保护剂氨磷汀
120:聚乙二醇-聚麸胺酸莰段共聚物
130:氯化亚铁
具体实施方式
本发明在此所探讨的方向为药物载体,为了能彻底地了解本发明,将在下列的描述中提出详尽的结构及其元件与方法步骤。显然地,本发明的施行并未限定于药物载体的技术者所熟习的特殊细节。另一方面,众所周知的结构及其元件并未描述于细节中,以避免造成本发明不必要的限制。此外,为提供更清楚的描述及使熟悉该项技术者能理解本发明的发明内容,图示内各部分并没有依照其相对的尺寸而绘图,某些尺寸与其它相关尺度的比例会被突显而显得夸张,且不相关的细节部分也未完全绘出,以求图示的简洁。本发明的较佳实施例会详细描述如下,然而除了这些详细描述之外,本发明还可以广泛地施行在其它的实施例中,且本发明范围不受限定,其以之后的专利范围为准。
根据本发明的一第一实施例,本发明提供一种螯合型复合微胞当成药物载体,螯合型复合微胞更包含一金属离子核心与至少一配位子(ligands),金属离子核心用以当成路易斯酸(Lewisacid)并借由配位键键结配位子(ligands),其选自下列族群中之一者或其任意组合或其衍生物:铁Fe,铜Cu,镍Ni,铟In,钙Ca,钴Co,铬Cr,钆Gd,铝Al,锡S n,锌Zn,钨W,钪Sc,钛Ti,锰Mn,钒V,镁Mg,铍Be,镧La,金Au,银Ag,镉Cd,汞Hg,钯Pd,铼Re,鎝Tc,铯Cs,镭Ra,铱Ir,镓Ga,且配位子(ligands)120的组成选自下列族群中之一者或其任意组合或其衍生物:羧酸carboxylic acids,醇alcohols,酮ketones,呋喃furans,胺amines,苯胺anilines,吡咯pyrroles,硫醇thiols,酯esters,酰胺amides,亚胺imines,吡啶pyridines,嘧啶pyrimidins,咪唑imidazoles,比唑pyrazols,磺胺sulfonamides,膦酸phosphonic acids。
螯合型复合微胞可借由金属离子核心与能当成路易斯碱(Lewis base)的药物(drug)形成配位键,当成路易斯碱(Lewisbase)的药物(drug)用以贡献电子对者(electron pairs),且其组成选自下列族群中的一者或其任意组合或其衍生物:Amifostine(氨磷汀),WR-1065,Doxorubicin(阿霉素),Pemetrexed(培美曲塞),Gemcitabine(吉西他滨),Methotrexate(灭杀除癌锭),Docetaxel(多西紫杉醇),Vinblastine(长春碱),Epirubicin(表柔比星),Topotecan(拓扑替康),Irinotecan(抗癌妥),Ifosfamide(异环磷酰胺),Gefitinib(吉非替尼),Erlotinib(埃罗替尼),Penicillinclass(青霉素类),cloxacillin(邻氯青霉素),dicloxacillin(双氯青霉素),Gentamicin(庆大霉素),Vancomycin(万古霉素),Amphotericin(两性霉素),Quinolones(喹诺酮类),Piperazine(哌嗪),fluoroquinolone(氟化奎林酮类),Nalidixic acid(萘啶酸),Ciprofloxacin(环丙氟哌酸),Levofloxacin(左氧氟沙星),Trovafloxacin(曲氟沙星),Oseltamivir(奥塞米韦),Metformin(二甲双胍),Trastuzumab(曲妥珠单抗),Imatinib(依麦替尼布),Rituximab(利妥昔单抗),Bevacizumab(贝伐珠单抗),Celecoxib(塞来昔布),Etodolac(依托度酸),Ibuprofen(布洛芬),Cyclosporine(环孢菌素),Morphine(吗啡),Erythropoietin(红血球生成素),Granulocyte colony-stimulating factor(粒细胞集落刺激因子),Curcumin(姜黄素)(Enol,Keto Form),Resveratrol(白藜芦醇),Glutathione(榖胱甘肽),Vitamine C(维生素C),Acetylcysteine(乙酰半胱氨酸),Carnitine(肉碱),Galantamine(加兰他敏),insulin(胰岛素),Imipenem(亚胺培南),Cilastatin(西司他丁),Ertapenem(厄他培南),Meropenem(美罗培南),Entecavir(恩替卡韦),Telbivudine(替比夫定),Lamivudine(拉米夫定)。
根据本发明的一第二实施例,本发明提供一种具有螯合型复合微胞的药物载体,具有螯合型复合微胞的药物载体更包含一金属离子核心、至少一高分子聚合物(polymer)与一药物(drug),其中,金属离子核心用以当成路易斯酸(Lewis acid),且至少一高分子聚合物(polymer)与一药物(drug)皆当成路易斯碱(Lewis base),并借由路易斯碱(Lewis base)提供电子对而使得金属离子核心能与高分子聚合物与药物形成配位键。
上述的高分子聚合物可为Monodentate(单牙配位团簇)orunidentate ligands(单牙配位子),bidentate ligands(双牙配位子),tridentate ligands(三牙配位子),hexadentateligands(六牙配位子),polydentate ligands(多牙配位子),其分子量(Molecular weight)范围约为1,000-50,000道尔顿(Dalton),且其组成选自下列族群中之一者或其任意组合或其衍生物:聚乙二醇Poly(ethylene glycol),聚天门冬氨酸Poly(aspartic acid),聚麸胺酸Poly(glutamic acid),聚赖氨酸Polylysine,聚丙烯酸Poly(acrylic acid),几丁聚醣chitosan,聚乙烯亚胺Polyethyleneimine,聚甲基丙烯酸Poly(methacrylic acid),透明质酸hyaluronic acid,胶原蛋白collagen,聚(氮-异丙基丙烯酰胺)Poly(N-isopropylacrylamide),直链淀粉amylose,纤维素cellulose,聚羟基丁酸酯poly(hydroxybutyrate),聚乳酸poly(lactic acid),聚琥珀酸丁酯poly(butylenesuccinate),聚己内酯poly(caprolactone),羧甲基纤维素carboxymethylcellutose,糊精dextran,环糊精cyclodextrin。
此外,当成路易斯碱(Lewis base)的药物(drug)用以贡献电子对者,且其组成如同第一实施例所述者。再者,当成路易斯酸(Lewis acid)的金属离子核心的组成也如同第一实施例所述者。
根据本发明的一第三实施例,本发明提供一种具有螯合型复合微胞的医药组合物,如:细胞保护剂,具有螯合型复合微胞的医药组合物更包含一金属离子核心、至少一嵌段共聚物(blockcopolymer)与药物,其中,金属离子核心用以当成路易斯酸(Lewis acid),且至少一嵌段共聚物(block copolymer)与药物皆当成路易斯碱(Lewis base),并借由路易斯碱(Lewis base)提供电子对而使得金属离子核心能与嵌段共聚物(blockcopolymer)与药物形成配位键。
上述的金属离子核心更包含一Fe铁离子或Gd钆离子,且上述的药物更包含氨磷汀Amifostine、WR-1065,而上述的嵌段共聚物更包含一端为螯合端可与铁离子进行键结,另一端为分散端以便使具有螯合型复合微胞的医药组合物能稳定而良好地分散于生物流体中,例如,聚乙二醇-聚麸胺酸嵌段共聚物(Poly(ethylene glycol)-b-Poly(glutamic acid);PEG-b-PGA)。上述的聚乙二醇-聚麸胺酸莰段共聚物是以具有高生物适应性的聚麸胺酸提供螯合端(-COO-)以便与铁离子产生配位键,同时借由具水溶性的聚乙二醇的高分散性使得整体药剂能稳定而良好地分散于生物流体中,其中值得注意的是,聚乙二醇本身并无可提供任何具配位的官能基,聚乙二醇必须经由适当地改质始得与金属形成配位键,本实施例所使用的聚麸胺酸的目的的一也在于连结分散度高的聚乙二醇与铁离子,且聚麸胺酸为一种生物可分解性高分子天然物质。
上述的药物更包含氨磷汀Amifostine、WR-1065,Amifostine具有五个提供电子对之处,其分别位于两个-OH、-P=O、NH与-NH2;WR-1065则具有三个提供电子对之处,其分别位于-SH、-NH与-NH2。
根据本实施例,参阅图1所示,具有螯合型复合微胞的医药组合物100的制作方法如下,取0.1-10mg细胞保护剂氨磷汀(Amifostine)110,0.1-100mg聚乙二醇-聚麸胺酸崁段共聚物(PEG-b-PGA)120与0.01-50mg氯化亚铁(FeCl2)130。然后,将上述混合原料置入1-10mL缓冲液中在4-40℃下进行0至48小时的匀相扰动程序,借由前述的键结原理,氨磷汀Amifostine 110可经由Fe离子130与PEG-b-PGA 120直接进行自组装(self-assembly)反应而形成粒径约为l0-300nm之间的具有螯合型复合微胞的细胞保护剂300,其中上述的缓冲液可为0.05M的HEPES(4-(2-hydroxyethyl)-1-piperazineethane-sulfonic acid),其pH值约为6.5-7.5之间。
根据上述实施例,上述的氨磷汀(Amifostine)及其衍生物的结构如图2A与图2B所示,而聚乙二醇-聚麸胺酸莰段共聚物(PEG-b-PGA)的结构式如图3所示,且具有螯合型复合微胞的细胞保护剂的结构式如图4所示。根据本实施例,图5所示为以聚乙二醇PEG为巨起始剂(macroinitiator)合成聚乙二醇-聚麸胺酸嵌段共聚物PEG-b-PGA,其重量平均分子量Mw 5700,数目平均分子量Mn4900,分布系数PdI 1.16,其中,图6所示则为PEG-b-PGA的氢核磁共振光谱(Proton Nuclear Magnetic Resonance,1H-NMR)与相对应官能基(functional groups)的化学位移(chemical shift)。图7所示则为以粒径分析仪分析螯合型复合微胞(Chelating Complex Micelles;CCM),平均粒径为31.61nm。
图8所示,取5mg氨磷汀(Amifostine)、20mg PEG-b-PGA(分子量5700 Dalton)与1.25-10mg FeCl2,重量比为(1∶4∶0.25至1∶4∶2)。然后,将上述原料置入5mL缓冲液中在25℃下进行24小时的均匀扰动程序,并置入分子量3500的透析膜模拟药物释放。结果显示FeCl2 10mg时,多数药物已与铁离子与PEG-b-PGA自组装(self-assembly)反应而形成螯合型复合微胞,因此停留在透析膜内未释放。其中上述的缓冲液为0.05M的HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonicacid),其pH值约为7.0。
图9所示,取5mg氨磷汀(Amifostine)、20mg PEG-b-PGA(分子量5700 Dalton)与10mg FeCl2。然后,将上述原料置入5mL缓冲液中在25℃下进行不同时间的均匀扰动程序,并置入分子量3500的透析膜模拟药物释放。结果显示均匀扰动24小时药物氨磷汀(Amifostine)释放到透析膜外的比例较低,多数已与铁离子与PEG-b-PGA自组装(self-assembly)反应而形成螯合型复合微胞。其中上述的缓冲液为0.05M的HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonicacid),其pH值约为7.0。
一般的药剂上通常无法直接与高分子连接改质,因此,借由本发明的配位共价的概念,利用金属离子当作路易式酸来自行同时结合药剂与高分子,所形成的具有螯合型复合微胞不但具有如同螯合剂(EDTA)的结构,同时适度地延长了药物在人体内半衰期(可在人体内循环更久而不衰退),而且不会造成人体毒性(EDTA会攫取人体内的金属元素)。此外,配位共价键也可弥补以电荷相吸的键结强度不足的问题。再者,金属离子本身多易沉淀,而PEG本身虽然具有很好的流体分散度,但并无官能基可接其它物质,因此,必须通过PGA的改质以便与金属离子键结,以便于整体载体能均匀分散于流体中而不致因金属离子造成沉淀阻塞的现象。值得注意的是,本发明的载体能适用各种亲水(hydrophilic)或亲油(hydrophobic)的药物,而提升了相当高的应用价值。此外,对于已经符合FDA或相关医药检验规范的药物而言,若是破坏原药物的结构,即使仅占极小比例,都很可能被视为新药而需重新进行安全性与有效性的验证,耗费成本极高,相对而言,本发明完全不会破坏药物本身结构,不会造成重新验证的问题,对于工艺兼容性而言,具有极高的成本价值。
显然地,依照上面实施例中的描述,本发明可能有许多的修正与差异。因此需在其附加的权利要求的范围内加以理解,除上述详细描述外,本发明还可以广泛地在其它的实施例中施行。上述仅为本发明的较佳实施例而已,并非用以限定本发明的申请专利范围;凡其它未脱离本发明所揭示的精神下所完成的等效改变或修饰,均应包含在下述申请专利范围内。
Claims (5)
1.一种螯合型复合微胞,其特征在于该螯合型复合微胞包含:
金属离子核心,该金属离子核心为路易斯酸,上述路易斯酸是铁;
至少一配位子,该配位子是与该金属离子核心借由配位键彼此键结,上述配位子是聚乙二醇-聚麸胺酸嵌段共聚物;与
药物,该药物为路易斯碱,且该药物是与该金属离子核心借由配位键彼此键结,上述路易斯碱是氨磷汀。
2.一种具有螯合型复合微胞的药物载体,其特征在于该具有螯合型复合微胞的药物载体包含:
至少一高分子聚合物,该高分子聚合物为路易斯碱,上述路易斯碱是聚乙二醇-聚麸胺酸嵌段共聚物;与
金属离子核心,该金属离子核心为路易斯酸,且该金属离子核心是与该高分子聚合物形成配位键,上述路易斯酸是铁;
其中该具有螯合型复合微胞的药物载体用以搭载路易斯碱药物,上述路易斯碱药物是氨磷汀。
3.如权利要求2所述的具有螯合型复合微胞的药物载体,其特征在于该高分子聚合物的分子量范围为1,000-100,000道尔顿。
4.一种具有螯合型复合微胞的医药组合物,其特征在于该具有螯合型复合微胞的医药组合物包含:
嵌段共聚物,该嵌段共聚物为路易斯碱,其中,该嵌段共聚物更包含一螯合端以进行配位键结,与一分散端以使该医药组合物能稳定而良好地分散于生物流体中,上述嵌段共聚物是聚乙二醇-聚麸胺酸嵌段共聚物,其中上述嵌段共聚物之螯合端是聚麸胺酸,上述嵌段共聚物之分散端是聚乙二醇;
药物,该药物包含路易斯碱的官能基,上述药物是氨磷汀;与
金属离子核心,该金属离子核心为路易斯酸,且该金属离子核心分别与该嵌段共聚物以及该药物形成配位键。
5.如权利要求4所述的具有螯合型复合微胞的医药组合物,其特征在于上述的金属离子核心为二价铁离子、或三价铁离子。
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JP6445648B2 (ja) | 2018-12-26 |
TWI568453B (zh) | 2017-02-01 |
KR101885677B1 (ko) | 2018-08-06 |
JP2015507605A (ja) | 2015-03-12 |
KR20170004044A (ko) | 2017-01-10 |
CN103127521A (zh) | 2013-06-05 |
EP2783679A4 (en) | 2015-08-26 |
JP6224776B2 (ja) | 2017-11-01 |
CA2856501C (en) | 2017-01-03 |
JP2018021070A (ja) | 2018-02-08 |
KR101815030B1 (ko) | 2018-01-08 |
AU2012343239B2 (en) | 2016-04-28 |
CA2856501A1 (en) | 2013-05-30 |
TW201321027A (zh) | 2013-06-01 |
AU2012343239A1 (en) | 2014-06-05 |
IN2014MN00936A (zh) | 2015-04-24 |
IL232729A0 (en) | 2014-07-31 |
IL232729B (en) | 2019-06-30 |
EP2783679A1 (en) | 2014-10-01 |
JP2016188236A (ja) | 2016-11-04 |
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