CN112933250A - 一种碘油乳剂或载药碘油乳剂及其制备方法和应用 - Google Patents
一种碘油乳剂或载药碘油乳剂及其制备方法和应用 Download PDFInfo
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- CN112933250A CN112933250A CN202011493617.3A CN202011493617A CN112933250A CN 112933250 A CN112933250 A CN 112933250A CN 202011493617 A CN202011493617 A CN 202011493617A CN 112933250 A CN112933250 A CN 112933250A
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Abstract
本发明所述的碘油乳剂,包括碘油、及乳化剂载体,所述乳化剂载体包括脂微球、细胞膜成分、磷脂和胆固醇类、固体脂质和液体脂质类、助乳化剂中的一种或几种;所述碘油乳剂还可以携带药物,方式为药物均匀分散于碘油中,再将载药的碘油制成水包油型乳剂;或将药物水溶液与碘油制成水包油包水型乳剂。通过将碘油乳化,将只能通过自然腔道造影和肝动脉注射的碘油转化为可经全身动脉、静脉、淋巴管注射或直接组织注射使用的安全的碘油乳剂,扩大了碘油适应症,同时可以载带药物,增强治疗效果,减轻了药物的全身副作用。
Description
技术领域
本发明涉及肿瘤诊断和治疗药剂技术领域,更具体地,涉及一种碘油乳剂或载药碘油乳剂及其制备方法和应用。
背景技术
经导管动脉化疗栓塞术(TACE)是治疗中晚期肝癌的主要手段之一。传统的TACE治疗使用的栓塞剂为碘油,一般是将碘油与一到两种化疗药物做成临时乳剂,通过导管注射到肝动脉内。碘油及碘油所携带的化疗药物会停留在肿瘤血管或组织内发挥杀伤肿瘤细胞作用。通常情况下,碘油可以长时间保留在肝癌病灶,但在正常肝组织或肝硬化肝组织中很快被清除。
目前临床中,碘油多用于肝恶性肿瘤的经肝动脉介入治疗,主要是由于肝脏有肝动脉和门静脉两条供血系统,栓塞了肝动脉,还有门静脉供血系统,不会影响非肿瘤部分肝脏供血。肺虽然有支气管动脉和肺动脉两套供血系统,使用碘油栓塞支气管动脉虽然不至于引起肺组织坏死,但容易异位栓塞脊髓动脉,导致截瘫。其他的脏器组织只有一条供血系统,一旦使用碘油栓塞,组织器官就会缺血坏死。如果在使用碘油治疗肿瘤过程中,既治疗了肿瘤又不会引起正常组织的缺血坏死,临床意义重大。
中国发明专利CN 109663145 A碘油靶向药物复合物,采用油包水型乳剂或水包油包水型复合乳剂的碘油乳剂具有靶向性,提高了使用碘油的安全性和扩大了使用碘油的适应症。但是,该技术方案中油包水剂型虽然可以携带靶向药物,但也只能通过肝动脉注射使用,如果在其他组织器官使用仍然会导致该组织的缺血坏死或异位栓塞,所以有必要使其可以更加安全的使用。
发明内容
本发明的首要目的在于针对上述缺陷和不足,解决现有技术中碘油仅能用于肝癌的造影和治疗、使用范围窄的技术问题,提供了一种可在全身动脉、静脉、淋巴管和直接组织注射使用的安全的碘油乳剂或载药碘油乳剂。本发明的另一个目的在于,提供一种碘油乳剂的制备方法。
本发明的再一个目的在于,提供一种可载药物的碘油乳剂。
本发明的再一个目的在于,提供一种载药碘油乳剂的制备方法。
本发明的再一个目的在于,提供一种碘油乳剂和载药碘油乳剂的应用。
为了实现上述目的,本发明采用的具体技术方案为:
本发明所述的剂型有:(1)碘油乳剂:将碘油和生理盐水、葡萄糖水、糖盐水、平衡盐溶液、水溶性造影剂做成乳剂。(2)载带药物的碘油乳剂:其中载药方式有以下两种:①药物均匀分散于碘油中,碘油为连续相,药物为分散项,在此基础上做成水包油乳剂;②将药物溶解在水溶液中,然后将碘油和药物水溶液直接制成水包油包水剂型。
本发明所述的碘油乳剂,包括碘油、乳化剂载体以及生理盐水、葡萄糖水、糖盐水、平衡盐溶液;其中,乳化剂载体与总体系的质量体积比为0.05g-2g:10ml;碘油占比为0.1ml-5ml。
优选的,所述乳化剂载体包括脂微球、细胞膜成分、磷脂和胆固醇类、固体脂质类如硬脂酸酯及其衍生物和液体脂质类如辛酸/癸酸甘油三酯及其衍生物、助乳化剂如泊洛沙姆和山梨醇酯、肉豆蔻酸异丙酯及其衍生物中的一种或几种。
优选的,所述磷脂与胆固醇类的质量比为1-7:0-3。
优选的,所述碘油乳剂的含碘量为4.8-240mg/ml。
本发明所述的碘油乳剂的制备方法,包括步骤,将碘油与乳化剂载体加入有机溶剂中使其充分溶解,然后利用挥发度差异、溶解度差异、或膜挤压装置、减压旋转蒸发装置、静电喷雾装置去除有机溶剂,得到分散均匀的碘油乳剂。
优选地,还包括搅拌振荡、微流控法、超声法、超临界流体法或机械吹打、高压经典喷雾法常压和高压均质中的一种或多种用于乳化的方法。
本发明所述的载药碘油乳剂,包括碘油乳剂,还包括可分散在碘油中或结合于碘油上或分散于碘油乳剂的药物。
优选的,载药方式有以下两种:
(1)药物结合于碘油分子上或均匀分散于碘油中,再将载药的碘油制成水包油型乳剂,其中水相为生理盐水、葡萄糖溶液或平衡盐溶液;
(2)将药物溶液与碘油制成水包油包水型乳剂,其中药物溶液为内水相,生理盐水、葡萄糖溶液或平衡盐溶液为外水相。
优选的,所述药物包括小分子化合物药物和蛋白药物;
小分子化合物药物包括抗炎类药物、化疗药物、抗肿瘤靶向药物、抗肿瘤血管靶向药物;蛋白药物包括抗体药物、疫苗及多肽类药物;
所述抗炎药包括甾体抗炎药和/或非甾体抗炎药;
所述化疗药包括尼莫司汀、卡莫司汀、洛莫司汀、环磷酰胺、异环磷酰胺、甘磷酰芥、司莫司汀、去氧氟鸟苷、氟尿嘧啶、巯嘌呤、硫鸟嘌呤、阿糖胞苷、氟鸟苷、替加氟、吉西他滨、卡莫氟、羟基脲、甲氨蝶呤、优福定、安西他滨、放线菌素D、多柔比星、柔红霉素、表柔比星、丝裂霉素、培洛霉素、平阳霉素、吡柔比星、伊立替康、三尖杉酯碱、羟基喜树碱、长春瑞宾、紫杉醇、泰索帝、拓扑替康、长春新碱、长春地辛、长春碱、替尼泊苷、依托泊苷、阿他美坦、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酶、卡铂、顺铂、达卡巴嗪、奥沙利铂、米托蒽醌、丙卡巴肼以及上述药物的衍生物中至少一种;
所述抗肿瘤靶向药物包括吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、色瑞替尼、Alunbrig、brigatinib、艾乐替尼、克唑替尼、曲美替尼、达拉替尼、帕博西林、瑞博西林、玻玛西林、来那替尼、拉帕替尼、依维莫司、奥拉帕尼、阿柏西普、伊马替尼、舒尼替尼、尼拉帕尼、依维莫司、替西罗莫司、普纳替尼、达沙替尼、伯舒替尼、Midostaurin、依鲁替尼、Idelalisib、Venetoclax、贝利司他、罗米地辛、伏立诺他、硼替佐米、卡菲司米托、ixazomib、泛诺他宁、狄诺塞麦、卡比替尼、阿利维A酸、维莫德、索尼德吉以及上述药物的衍生物中的至少一种;
所述抗肿瘤血管药物包括索拉菲尼、阿帕替尼、阿昔替尼、舒尼替尼、乐伐替尼、瑞格菲尼、帕唑帕尼、凡德他尼、尼达尼布、卡博替尼、西地尼布、安罗替尼、呋喹替尼、替沃扎尼、莫沙替尼以及上述药物的衍生物中的至少一种;
所述蛋白药物包括帕博丽珠单抗、耐昔妥珠单抗、纳武单抗、派姆单抗、阿特珠单抗、durvalumab、雷莫芦单抗、贝伐珠单抗、肺癌疫苗-CimaVax、Ado-trastuzumab、帕妥珠单抗、曲妥珠单抗、西妥西单抗、帕尼单抗、伊匹单抗、emtanisine、Lanreotide acetate、avelumab、Lu 177dotatate、前列腺癌治疗疫苗、重组人白介素-2、阿特珠单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、Blinatumomab、替伊莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、olaratumab、重组人血管内皮抑制素中至少一种。
本发明所述的载药碘油乳剂的制备方法,包括化学方法、或物理方法;
其中,化学方法采用催化剂在保持药物和碘油原有性能不变的情况下使药物和碘油通过化学键结合;
其中,物理方法包括膜高压挤压法、微流体高压反应法、超临界流体高压法、或亚临界流体高压法、常压均质或高压均质中的一种或几种的组合,以实现将药物颗粒在高压下以纳米或微米粒子的形式均匀分散在碘油中。
本发明所述的碘油乳剂或载药碘油乳剂的应用为:作为静脉注射、动脉注射、淋巴及淋巴管注射、或通过自然腔道的造影进行恶性肿瘤及一些良性疾病的诊断和治疗的药物。
本发明与现有技术相比,具有以下有益效果:
本发明通过将碘油乳化,将只能通过自然腔道造影和肝动脉注射的碘油转化为可经全身动脉、静脉、淋巴管注射或直接组织注射使用的安全的碘油乳剂,扩大了碘油适应症。
本发明提供的碘油乳剂可以载带药物,所载药物随着碘油富集在肿瘤组织,并在肿瘤组织内停留,使肿瘤区域内药物浓度高,其他组织器官药物低,在保证治疗效果的同时使药物总剂量减少;碘油和药物结合增强了治疗效果,并减轻了药物的全身副作用。增强治疗效果,减轻了药物的全身副作用。
本发明中乳化剂载体主要成分包括脂微球、细胞膜成分、磷脂和胆固醇类、脂质类载体如聚乙二醇羟基硬脂酸酯、助乳化剂如泊洛沙姆和聚山梨酸酯、肉豆蔻酸异丙酯中的一种,利用这个结构特征,例如磷脂和胆固醇作为脂质体的成膜材料,使乳剂对于肿瘤细胞有特异的亲和性,使碘油更易通过细胞膜进入肿瘤细胞。
本发明还改变了很多药物的给药方式,例如阿帕替尼/索拉菲尼等药物,目前主要采用片剂的形式肠胃吸收转运到全身,本发明可以使其进行静脉或动脉注射,安全性增强。
安全性的说明:对ICR小鼠做了安全性的测试,给小鼠尾静脉注射0.5ml的纯碘油,小鼠立即死亡;但给小鼠注射本发明的含有0.5ml的碘油乳剂1.25ml,小鼠与正常小鼠无异,生长和活动在观察期一个月内都很正常。
本发明的碘油乳剂和载药碘油乳剂非常安全,本身稳定性良好,另外,将其稀释于水或者PBS溶液中,稍作震荡,也非常稳定,没有出现分层或分散不均的情况。
下面结合附图对本发明作进一步的说明。
附图说明
图1:实施例1制得的碘油乳剂的外观图。
图2:实施例1中碘油乳剂的透射电镜图。
图3:实施例1中碘油乳剂的粒径图。
图4:实施例1中碘化油乳剂注射于肿瘤组织HE染色结果图。
图5:实施例1中碘化油乳剂注射于肿瘤组织治疗前后肿瘤大小对比。
图6:实施例2中载甲磺酸阿帕替尼的碘油乳剂的外观图。
图7:实施例2中载甲磺酸阿帕替尼的碘油乳剂的透射电镜图。
图8:实施例2中载甲磺酸阿帕替尼的碘油乳剂的粒径图。
图9:实施例2中载甲磺酸阿帕替尼的碘油乳剂注射于肿瘤组织治疗前后肿瘤大小对比。
图10:实施例3中载阿霉素的碘油乳剂的外观图。
图11:实施例3中载阿霉素的碘油乳剂的透射电镜图。
图12:实施例3中载阿霉素的碘油乳剂的碘油乳剂注射于肿瘤组织治疗前后肿瘤大小对比。
图13:实施例5中不同时间点乳剂的粒径分布(乳剂的稳定性检测)。
图14:实施例6中载贝伐单抗的碘油乳剂的透射电镜图。
图15:实施例6中载贝伐单抗的碘油乳剂注入肿瘤部位的HE染色图。
图16:实施例7中治疗前后肿瘤大小对比。
图17:实施例7中载索拉菲尼的碘油乳剂裸鼠CT结果。
图18:实施例1中不同时间点乳剂的粒径分布(乳剂的稳定性检测)。
具体实施方式
下面通过具体实施方式对本发明做进一步的解释及说明,应当理解下面的实施方式的目的是为了使本发明的技术方案更加清楚、易于理解,并不限制权利要求的保护范围。
实施例1采用乙醚注入-超声乳化法制备碘油乳剂
称取大豆磷脂1320mg与胆固醇220mg于烧杯中,加入碘油(国药准字H37022398)200μL,以及4ml无水乙醇,置于50℃,使其充分溶解。将溶解好的脂质溶液吹打均匀后注入到6ml磷酸盐缓冲液pH6.0中,然后将其转移到茄形瓶中,置于50-60℃水浴中真空旋转蒸发除去乙醚,真空度为-0.08MPa,处理时间20min,转移到含有200mg吐温-80的离心管或烧杯中,再在240W超声24min,直至形成均匀乳液。见图1。得到碘含量为9.6mg/ml的乳液,电镜图和粒径分布分别见图2和图3。乳剂在4℃冰箱储存12个月,性状依然稳定。不同时间的粒径比较见图18。乳剂制备后放置一年,依然稳定,流动性良好,粒径分布几乎没有变化。
本实施例1通过原位注射上述碘化油乳液注射液进入实体瘤组织,14天后处死裸鼠,取出实体瘤进行HE染色,观察碘化油注射液在肿瘤组织中的分布,取材时我们发现与没有注射碘化油乳剂注射液的肿瘤组织相比,碘油乳剂注射液均匀分布于细胞间隙、细胞质及细胞核周围,取材时还有部分没有被吸收,少量残留于肿瘤间隙,肿瘤内部结构有破坏迹象,拿捏易碎。从HE染色的结果看到,乳剂甚至破坏细胞形态,使细胞破裂,HE染色结果中看到,乳剂治疗过后的肿瘤组织在取材时就发现有破裂,切片时很难成型,染色结果也可以看到治疗后的组织几乎看不到细胞核,说明切片部分的组织细胞部分破裂破坏。见图4。治疗前后的肿瘤大小对比见图5。
实施例2采用乙醇注入-超声法制备碘油-甲磺酸阿帕替尼纳米脂质体
称取大豆磷脂660mg与胆固醇55mg于烧杯中,加入超液化碘油500μL,以及5ml无水乙醇置于45℃,使其充分溶解。将溶解好的脂质溶液注入到含有500mg甲磺酸阿帕替尼的50ml磷酸盐缓冲液(浓盐酸调至pH2)中,然后将其转移到茄形瓶中,置于45℃水浴中真空旋转蒸发除去乙醇,真空度为-0.08MPa,处理时间20min,转移到含有5mg吐温-80的离心管或烧杯中,再在141W超声24min,直至形成均匀乳液。检测pH,用10%的NaOH调节pH值,使达到7。得到碘含量为4.8mg/ml、阿帕替尼含量10mg/ml的均匀乳液。见图6。得到碘含量为9.6mg/ml的乳液,电镜图和粒径分布分别见图7和图8。
动物实验采用H22细胞为ICR小鼠皮下种植肿瘤,记录为day 0,之后尾静脉注射以上载甲磺酸阿帕替尼的碘油乳剂,记录肿瘤大小,见图9。
实施例3采用乙醇-二甲基亚砜注入-超声法制备碘油-阿霉素脂质体
称取大豆磷脂660mg与胆固醇220mg于烧杯中,盐酸阿霉素20mg,加入超液化碘油1ml和200mg吐温-80,以及5ml无水乙醇,置于50℃,使其充分溶解。将溶解好的脂质溶液注入到9ml磷酸盐缓冲液pH6.6(0.05mol/L)中,然后将其转移到茄形瓶中,置于79℃水浴中真空旋转蒸发除去乙醇和二甲基亚砜,真空度为-0.1MPa,处理时间20min,转移到50ml的离心管或烧杯中,再在141W超声20min,直至形成均匀乳液。见图10,透射电镜观察图见图11。
动物实验如权利要求1,采用h22细胞为ICR小鼠皮下种植肿瘤,记录为day 0,之后尾静脉注射以上载甲磺酸阿帕替尼的碘油乳剂,记录肿瘤大小,见图12。
实施例4采用乙醇-二甲基亚砜注入-超声法制备碘油-索拉菲尼脂质体。
准确称取卵磷脂1000mg、胆固醇200mg、20mg吐温-80和400mg索拉菲尼于烧杯中,加入碘油3ml,以及3ml无水乙醇和2ml二甲基亚砜,置于50℃,使其充分溶解。将溶解好的脂质溶液逐滴缓慢注入到,边加边沿着一个方向震荡然后将其转移到茄形瓶中,置于50-60℃水浴中真空旋转蒸发出去乙醇和二甲基亚砜,真空度为-0.08MPa,处理时间20min,转移到离心管或烧杯中,再在248W超声30min,直至形成均匀乳液。
实施例5微流控法和超声乳化法结合制备载地塞米松碘油乳剂
准确称取20mg的span-80于烧杯中,加入碘油5ml,再加入5ml乙醇,通过微流控管道(第一层中的各通道结构的高度为1-5微米,高度为5-10微米,第一混合部的宽度为1-10微米),含有400mg地塞米松的6ml 5%PF-127磷酸盐缓冲液pH6.6(0.05mol/L)中(第二层中各通道的高度为1-10微米,W/O(油包水)乳剂形成腔道的高度为1-10微米),水相注入到油相中,水油相初步混合,进入第三层通道(第三层中各通道的高度为1-10微米,W/O乳剂形成腔道的高度为1-10微米),再在248W超声30min,直至形成均匀乳液。乳剂在4℃冰箱储存6个月,性状依然稳定。不同时间的粒径比较见图13。
实施例6超临界流体法制备载贝伐单抗碘油乳剂
准确称取卵磷脂900mg、胆固醇160mg、25mg吐温-80和400mg贝伐单抗于烧杯中,加入碘油3ml,以及3ml无水乙醇,置于50℃,使其充分溶解。将溶解好的脂质溶液逐滴缓慢注入到6ml磷酸盐缓冲液pH6.6(0.05mol/L)中,沿着一个方向震荡,震荡均匀,在超临界流体的作用下置于高压装置中,压力为50个大气压,作用8-16h,除去乙醇,即可得到载有贝伐单抗的均匀乳液。
我们通过皮下注射碘化油注射液进入实体瘤组织,14天后处死裸鼠,取出实体瘤进行HE染色,观察碘化油注射液在肿瘤组织中的分布,我们发现与没有注射碘化油乳剂注射液的肿瘤组织相比,碘油乳剂注射液均匀分布于细胞间隙、细胞质及细胞核周围,甚至破坏细胞形态,使细胞破裂,HE染色结果中看到,乳剂治疗过后的肿瘤组织在取材时就发现有破裂,切片时很难成型,染色结果也可以看到治疗后的组织几乎看不到细胞核,说明细胞部分破裂破坏。见图15。
实施例7机械法结合挤压法制备碘油乳剂
准确称取卵磷脂600mg、胆固醇100mg、和15mg吐温-60于烧瓶中,置于50℃,使其充分溶解,加入碘油2ml,混合均匀,再5ml无水乙醇助溶。将溶解好的脂质溶液逐滴缓慢注入到5ml磷酸盐缓冲液pH6.6(0.05mol/L)中,沿着一个方向机械搅拌,转速为1000rpm/min,搅拌30min,通过膜挤压装置(制备脂质体微球的常用装置),挤出至10ml磷酸盐缓冲液中,分散均匀,形成稳定的乳液。
裸鼠皮下未注射碘化油注射液时,我们进行了CT拍摄,然后将碘化油注射液注入裸鼠皮下肿瘤15天后再进行了CT拍摄,对比发现肿瘤内仍有碘化油注射液的沉积。说明碘化油注射液可以进入肿瘤组织中和肿瘤组织结合在一起,不易被机体清除。红色圆圈为肿瘤,注射碘化油注射液的肿瘤呈现高密度影,见图17。治疗前后肿瘤大小对比结果见图16。
实施例8超临界CO2流体法制备载阿帕替尼的碘油
(1)将甲磺酸阿帕替尼100mg分散在二甲基亚砜-乙醇(1:4)5ml中,搅拌震荡使其溶解,得到甲磺酸阿帕替尼的澄清透明无色溶液;
(2)将碘油注射液和甲磺酸阿帕替尼的溶液在超临界CO2的帮助下加入到高压釜中;
(3)加压至20Mpa,温度控制在室温,待温度压力稳定后,搅拌反应4h;
(4)反应完全后减压,超临界流体带走甲磺酸阿帕替尼溶液的溶剂,从高压釜中收集到,甲磺酸阿帕替尼均匀分散在碘油中的制剂。
实施例9微流控流体法制备乳剂
微流控芯片,第一层中的各通道结构的高度为5-10微米,因此,第一混合部的高度为5-10微米,第一混合部的宽度为10-50微米。第二层中各通道的高度为20-50微米,W/O乳剂形成腔道的高度为10-50微米。
三相溶液的配置:
(1)内水相:10-50mg/ml的PF-127溶于PBS缓冲液中;
(2)中间相:将磷脂和胆固醇(摩尔比为1-3:1)溶于乙醇制备50mg/ml储备液;
(3)外水相:10-50mg/ml的PF-127,10-15%无水乙醇,2-15%甘油或tween80/6020/40溶于蒸馏水中。
分别将外水相、中间相、内水相液体用1ml注射器固定在泵上,设定内水相流速为10-50nl/s,总体积为500μl,中间相的流速为1μl/s,总体积为1000μl,外水相的流速为1-10μl/s,总体积为10000μl,在外界注射泵的压力推动作用下,三相流体分别从进样口流入,在流经过滤结构时,尺寸大于微柱间隔的杂质被过滤掉,过滤后的液体分别流入外水相管道、内水相管道、中间相管道,待三相液体流满整个各自管道时,内水相与中间相在第一混合部混合,形成W/O初乳,之后再继续流入更深的管道于外水相混合,形成W/O/W复乳,经复乳收集部流出,即可收集所制备的W/O/W复乳。将收集的W/O/W复乳透析去除有机溶剂,即得到脂质体乳液。之后进行超声,通过光学显微镜对其粒径进行测量,得到粒径为150~300纳米大小的脂质体,并且粒径均一。
实施例10超临界流体法制备载药碘化油
根据药物溶解性(药物不溶于水的情况):选择溶剂二甲基亚砜、乙酸乙酯、乙醚、乙醇、甲醇、三氯甲烷,溶解温度为40-60℃,药物溶液滴加到超临界流体下搅拌中的碘化油溶液中,碘化油的搅拌速度1000-10000rpm/min,药物溶液和碘化油溶液的体积比例为1:1-9,药物溶液滴注柱头直径为0.1mm-1mm,滴注的速度为每10s-50s滴1滴,滴加完成后,继续搅拌反应,搅拌速度1000-10000rpm/min,反应温度为常温,高压为10-80MPa,反应的时间为2-24h。
载药碘化油乳剂(药物水溶的情况):大致与上述方法类似,不同之处是加入卵磷脂和胆固醇类于油中,比例为3-6:1,占油的质量比为0.1-20%,山梨醇类助溶剂的质量比为0.2-5%;之后按照以上的方式进行反应,之后将其加入水中进行快速旋转混合,制备出水包油包水的乳液。
本发明是通过实施例来描述的,但并不对本发明构成限制,参照本发明的描述,所公开的实施例的其他变化,如对于本领域的专业人士是容易想到的,这样的变化应该属于本发明权利要求限定的范围之内。
Claims (9)
1.一种碘油乳剂,其特征在于:
包括碘油、及乳化剂载体;所述乳化剂载体包括脂微球、细胞膜成分、磷脂和胆固醇类、固体脂质和液体脂质类、助乳化剂中的一种或几种。
2.根据权利要求1所述的碘油乳剂,其特征在于:乳化剂载体与总体系的质量体积比为0.05g-2g:10ml;碘油体积为0.1ml-5ml。
3.根据权利要求1所述的碘油乳剂,其特征在于:所述磷脂与胆固醇类的质量比为1-7:0-3。
4.根据权利要求1所述的碘油乳剂,其特征在于:所述碘油乳剂的含碘量为4.8-240mg/ml。
5.一种根据权利要求1~4任一项所述的碘油乳剂的制备方法,其特征在于:步骤包括将碘油与乳化剂载体加入有机溶剂中使其溶解后注入到水相,然后利用挥发度差异、溶解度差异,去除有机溶剂,得到分散均匀的碘油乳剂。
6.一种载药碘油乳剂,其特征在于:包括根据权利要求1~5任一项所述的碘油乳剂,还包括可结合于碘油分子上或分散在碘油中或分散于碘油乳剂中的药物;
载药方式为药物结合于碘油分子上或均匀分散于碘油中,再将载药的碘油制成水包油型乳剂;
或将药物溶液与碘油制成水包油包水型乳剂,其中药物溶液为内水相。
7.根据权利要求6所述的载药碘油乳剂,其特征在于:所述药物包括小分子化合物药物和蛋白药物;
小分子化合物药物包括抗炎类药物、化疗药物、抗肿瘤靶向药物、抗肿瘤血管靶向药物;蛋白药物包括抗体药物、疫苗及多肽类药物;
所述抗炎药包括甾体抗炎药和/或非甾体抗炎药;
所述化疗药包括尼莫司汀、卡莫司汀、洛莫司汀、环磷酰胺、异环磷酰胺、甘磷酰芥、司莫司汀、去氧氟鸟苷、氟尿嘧啶、巯嘌呤、硫鸟嘌呤、阿糖胞苷、氟鸟苷、替加氟、吉西他滨、卡莫氟、羟基脲、甲氨蝶呤、优福定、安西他滨、放线菌素D、多柔比星、柔红霉素、表柔比星、丝裂霉素、培洛霉素、平阳霉素、吡柔比星、伊立替康、三尖杉酯碱、羟基喜树碱、长春瑞宾、紫杉醇、泰索帝、拓扑替康、长春新碱、长春地辛、长春碱、替尼泊苷、依托泊苷、阿他美坦、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酶、卡铂、顺铂、达卡巴嗪、奥沙利铂、米托蒽醌、丙卡巴肼以及上述药物的衍生物中至少一种;
所述抗肿瘤靶向药物包括吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、色瑞替尼、Alunbrig、brigatinib、艾乐替尼、克唑替尼、曲美替尼、达拉替尼、帕博西林、瑞博西林、玻玛西林、来那替尼、拉帕替尼、依维莫司、奥拉帕尼、阿柏西普、伊马替尼、舒尼替尼、尼拉帕尼、依维莫司、替西罗莫司、普纳替尼、达沙替尼、伯舒替尼、Midostaurin、依鲁替尼、Idelalisib、Venetoclax、贝利司他、罗米地辛、伏立诺他、硼替佐米、卡菲司米托、ixazomib、泛诺他宁、狄诺塞麦、卡比替尼、阿利维A酸、维莫德、索尼德吉以及上述药物的衍生物中的至少一种;
所述抗肿瘤血管药物包括索拉菲尼、阿帕替尼、阿昔替尼、舒尼替尼、乐伐替尼、瑞格菲尼、帕唑帕尼、凡德他尼、尼达尼布、卡博替尼、西地尼布、安罗替尼、呋喹替尼、替沃扎尼、莫沙替尼以及上述药物的衍生物中的至少一种;
所述蛋白药物包括帕博丽珠单抗、耐昔妥珠单抗、纳武单抗、派姆单抗、阿特珠单抗、durvalumab、雷莫芦单抗、贝伐珠单抗、肺癌疫苗-CimaVax、Ado-trastuzumab、帕妥珠单抗、曲妥珠单抗、西妥西单抗、帕尼单抗、伊匹单抗、emtanisine、Lanreotide acetate、avelumab、Lu 177dotatate、前列腺癌治疗疫苗、重组人白介素-2、阿特珠单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、Blinatumomab、替伊莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、olaratumab、重组人血管内皮抑制素中至少一种。
8.一种根据权利要求6或7所述的载药碘油乳剂的制备方法,其特征在于:
包括通过超声法、膜高压挤压法、微流体高压反应法、高压均质法、超临界流体高压法、高压静电喷雾法或亚临界流体高压法中的一种或几种的组合,以实现将药物颗粒在高压下以纳米或微米粒子的形式均匀分散在碘油中;
还包括通过化学反应法将药物与碘油以稳定化学键结合或中间连接体连接。
9.一种根据权利要求1~5任一项所述的碘油乳剂或根据权利要求6~8任一项所述的载药碘油乳剂的应用,其特征在于:作为静脉注射、动脉注射、淋巴及淋巴管注射、直接组织注射或通过自然腔道的造影进行恶性肿瘤及一些良性疾病的诊断和治疗的药物。
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