CN112933044A - 一种用于恶性肿瘤治疗的载药油制剂及制备方法和应用 - Google Patents
一种用于恶性肿瘤治疗的载药油制剂及制备方法和应用 Download PDFInfo
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Abstract
本发明所述的用于恶性肿瘤治疗的载药油制剂,包括可靶向进入肿瘤组织的油载体、及抗肿瘤药物;所述的油载体包括植物油和/或动物油、或植物油和/或动物油的成分及其衍生物,所述抗肿瘤药物包括小分子化合物药物或蛋白药物。本发明中药物均匀分散在油相中,油为连续相,也可以制成水包油型或水包油包水型乳剂。本发明中油作为药物的载体,使药物具有靶向性,同时油本身也有治疗作用;药物可以随着油富集并停留在肿瘤组织内,保证治疗效果的同时减少使用的总剂量;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。
Description
技术领域
本发明涉及恶性肿瘤治疗药剂技术领域,更具体地,涉及一种用于恶性肿瘤治疗的载药油制剂及制备方法和应用。
背景技术
目前恶性肿瘤的治疗有以下几个基本的治疗方法:1、手术治疗,60%的实体瘤早期通过手术可以完全达到治愈,在手术治疗过程中有一些是根治性手术,有一些是姑息性手术。姑息性手术能够缓解患者目前的不适症状,达到提高生活质量的目的;2、放射线治疗,即放疗,通过放射线对肿瘤细胞进行局部的消杀,肿瘤细胞得到局部的控制。3、化学治疗,即化疗,主要是通过口服和静脉给一些药物这两种途径治疗,通过药物对全身的肿瘤细胞进行治疗,也是肿瘤治疗中比较主要的治疗手段;4、免疫治疗,包括非特异性免疫刺激和免疫检验点阻断,以及各种肿瘤疫苗和过继性免疫细胞治疗。
化疗药物是治疗恶性肿瘤的主要药物,给药方式通常是静脉注射或口服给药,是进行全身治疗。给药后药物分布于各组织,肿瘤所在局部药物浓度低,为达到治疗效果使用较大剂量,全身的毒性反应和副作用相对较大,对实体肿瘤作用有限。常见毒副反应包括骨髓抑制、胃肠道反应、脱发、心脏毒性、肝肾损害、呼吸系统毒性、神经毒性等。
分子靶向药物是依据已知肿瘤发生中涉及的异常分子和基因,设计针对这些特定分子和基因靶点的药物,选择性杀伤肿瘤细胞。选择的靶点多为肿瘤生长和转移的一些关键因子,例如增殖靶点EGFR、Raf、mTOR,血管源性靶点VEGF/VEGFR、PDGFR,通过抑制信号转导通路或直接拮抗靶点因子或受体,从而达到促进凋亡、遏制增殖、抗肿瘤血管生成等抑制肿瘤的作用。分子靶向药物包括小分子靶向药物以及抗体类蛋白多肽药物,给药方式也是通过口服或静脉注射进行全身治疗。靶向治疗药物较传统化疗药物副作用显著降低,但还是存在一些不良反应和安全性方面的问题,使患者的生活质量下降,一些患者因严重的不良反应而停止了治疗,影响了抗肿瘤临床疗效,降低患者治疗信心。常见不良反应包括皮肤毒性、血栓、高血压、心脏毒性、出血、伤口愈合延迟、手足综合征、粘膜炎、腹泻等。
免疫检查点抑制能够特异地激活针对肿瘤细胞的免疫反应,从而达到灭杀肿瘤细胞的作用。但这个过程中,难免会激活一些不针对肿瘤细胞的免疫反应,对正常细胞造成伤害。常见不良反应包括皮肤毒性、消化道毒性、肝毒性、肺毒性等。
发明内容
本发明的目的在于克服现有技术缺陷,提供一种负载抗肿瘤药物的油制剂,将肿瘤治疗药物靶向递送至肿瘤所在区域,并停留在肿瘤组织内,使肿瘤局部药物浓度高,而其他组织器官中药物浓度低,在保证治疗效果的同时使药物总剂量减少,减轻了药物的全身副作用。
本发明的另一个目的在于,提供一种载药油制剂的制备方法。
本发明的另一个目的在于,提供一种载药油制剂的应用途径。
为了实现上述目的,本发明采用的具体技术方案为:
本发明所述的用于恶性肿瘤治疗的载药油制剂,包括可靶向进入肿瘤组织的油载体、及抗肿瘤药物;
所述油载体与药物的结合有三种方式:
(1)药物均匀分散在油相中,油为连续相;
(2)药物均匀分散在油相中,再制成油包水型乳剂,其中水相为生理盐水、葡萄糖溶液或平衡盐溶液;
(3)油和药物溶液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或蛋白药物;所述小分子化合物药物包括甾体抗炎药、非甾体抗炎药、化疗药物、抗肿瘤靶向药物、或抗肿瘤血管靶向药物中的一种或多种。
优选的,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、或丙卡巴肼以及上述药物的衍生物中至少一种。
优选的,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、德瓦鲁单抗、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、Lanreotideacetate、avelumab、Lu177dotatate、Sipueucel-T、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、或重组人血管内皮抑制素中至少一种。
优选的,所述抗肿瘤血管药物包括酪氨酸激酶抑制剂、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、或莫沙替尼以及上述药物的衍生物中的至少一种。
优选的,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、或索尼德吉以及上述药物的衍生物中的至少一种。
优选的,所述油载体包括植物油和/或动物油,或植物油和/或动物油的成分及其衍生物。
优选的,所述植物油包括粟米油、菜籽油、花生油、火麻油、玉米油、橄榄油、茶树油如山茶油、茶籽油、棕榈液油、芥花子油、葵花子油、大豆油、蓖麻油、芝麻油、亚麻籽油(胡麻油)、葡萄籽油、核桃油、棉籽油、米糠油、小麦胚芽油、杏仁油、南瓜籽油、石榴籽油、橘子籽油、樱桃籽油、沙棘油、花椒油、青刺果仁油、松子油、大蒜油、洋葱油、生姜油、苹果油、罂粟籽油、薏苡仁油、紫苏籽油、迷迭香油、木香子油、滇牡丹油、芸香草油、罗勒油、红花籽油、牡丹籽油或霍霍巴油中的一种或多种。优选的,所述植物油的成分包括构成植物油的脂肪酸以及脂肪酸与甘油形成的酯及其衍生物;所述脂肪酸包括软脂酸、硬脂酸、油酸、芥酸、桐油酸、蓖麻油酸、亚油酸、或α-亚麻酸中的一种或多种。
优选的,所述动物油包括鱼油和/或海豹油;
优选的,所述动物油成分包括构成动物油的脂肪酸以及脂肪酸与甘油形成的酯及其衍生物;所述脂肪酸包括二十碳五烯酸和/或二十二碳六烯酸。
本发明中油制剂中的油也可为植物油和动物油的混合物。
本发明中所述水包油型乳剂或水包油包水型乳剂中还包括一种助剂,所述的助剂,与油载体的质量体积比为4~300mg:1ml;所述助剂包括质量比为1.5~12mg:1mg的磷脂和胆固醇;或,质量体积质量比为10~20mg:1~10ml:50~100mg的碳二亚胺、甘油、和N-羟基琥珀酰亚胺。
本发明所述的水包油型乳剂或水包油包水型乳剂的制备方法,包括步骤:将油载体、药物、及助剂混合,加入生理盐水或葡萄糖溶液或平衡盐溶液,经反应或乳化后形成制剂;所述反应的方式包括高压反应、超临界反应、亚临界反应、或微流控反应中的一种或多种;所述乳化的方式包括机械搅拌乳化、减压悬转蒸发、超声乳化、微流体乳化、超临界流体法或亚临界流体中的一种或几种。
本发明所述的载药油制剂中油为连续相的剂型可经肝动脉注射,水包油型乳剂或水包油包水型乳剂可经全身静脉、动脉、淋巴管注射或直接注入肿瘤组织的应用。
本发明与现有技术相比,具有以下有益效果:
本发明所述油载体在治疗恶性肿瘤的同时可以作为抗肿瘤药物的载体,使药物具有靶向性;药物可以随着油富集在肿瘤组织,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;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。
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中载紫杉醇的大豆油乳剂的外观图。
图2:实施例1中载紫杉醇的大豆油乳剂粒径分布图。
图3:实施例1中载紫杉醇的大豆油乳剂透射电镜下观察图。
图4:实施例1中载紫杉醇的大豆油乳剂对于小鼠肿瘤大小的影响。
图5:实施例2中载顺铂的罂粟籽油乳剂的外观图。
图6:实施例2中载顺铂的罂粟籽油乳剂的粒径分布图。
图7:实施例2中载顺铂的罂粟籽油乳剂的透射电镜下观察图。
图8:实施例2中载顺铂的罂粟籽油乳剂治疗下的小鼠肿瘤组织HE图。
图9:实施例4中载贝伐单抗-油酸乳剂的粒径分布图。
图10:实施例4中载贝伐单抗-油酸乳剂的透射电镜下观察图。
图11:实施例4中载贝伐单抗-油酸乳剂对于小鼠肿瘤大小的影响。
图12:实施例4中载贝伐单抗-油酸乳剂治疗下的小鼠肿瘤组织HE图。
图13:实施例5中本妥昔单抗-碘油乳剂的粒径分布图。
图14:实施例5中本妥昔单抗-碘油乳剂的透射电镜下观察图。
图15:实施例8中贝伐单抗-葵花籽油乳剂的粒径分布图。
图16:实施例8中贝伐单抗-葵花籽油乳剂的电镜图。
图17:实施例8中贝伐单抗-葵花籽油乳剂对于小鼠肿瘤大小的影响。
图18:实施例8中贝伐单抗-葵花籽油乳剂治疗下的小鼠肿瘤组织HE图。
图19:实施例8中贝伐单抗-葵花籽油乳剂治疗下的小鼠肿瘤组织HA(透明质酸)成分的染色图。
图20:实施例9中索拉菲尼-核桃油乳剂的粒径分布图。
图21:实施例9中索拉菲尼-核桃油乳剂的透射电镜下观察图。
图22:实施例9中索拉菲尼-核桃油乳剂对于小鼠肿瘤大小的影响。
图23:实施例9中索拉菲尼-核桃油乳剂治疗下的小鼠肿瘤组织HE图。
图24:实施例9中索拉菲尼-核桃油乳剂治疗下的小鼠肿瘤组织HA(透明质酸)成分的染色图。
图25:实施例10中阿帕替尼-油酸乳剂的粒径分布图。
图26:实施例10中阿帕替尼-油酸乳剂的透射电镜下观察图。
图27:实施例10中阿帕替尼-油酸乳剂对于小鼠肿瘤大小的影响。
图28:实施例10中阿帕替尼-油酸乳剂治疗下的小鼠肿瘤组织HE图。
图29:实施例12中吉非替尼-碘油乳剂粒径分布图。
图30:实施例12中吉非替尼-碘油乳剂透射电镜下观察图。
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:载紫杉醇的大豆油乳剂制备方法
称取大豆磷脂660mg与胆固醇220mg于烧杯中,紫杉醇200mg,加入大豆油4ml和20mg吐温-80,以及5ml无水乙醇,置于40℃,使其充分溶解。将溶解好的脂质溶液注入到46ml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40℃水浴中真空旋转蒸发除去乙醇,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。得到载紫杉醇的大豆油乳剂,乳剂外观图见图1,粒径分布和透射电镜下观察图分别见图2和3。以ICR小鼠作为实验动物,以h22细胞作为肿瘤细胞,100万打入小鼠腹腔注射,一周后取腹腔腹水,数细胞300万于小鼠后腿部,造肿瘤模型,两周后模型形成,每个一天尾静脉注射以上乳剂,每次100ul,每周测一次肿瘤大小,见图4,分为了一周、两周、三周,与自身对照,可以看到对于肿瘤的生长有抑制作用,期间肿瘤没有继续长大,虽然没有显著性的差异但有逐渐变小的趋势。
实施例2:载顺铂的罂粟籽油乳剂制备方法
称取大豆磷脂300mg与胆固醇200mg于烧杯中,顺铂10mg,加入罂粟籽油4ml和20mg吐温-80,以及5ml无水乙醇,置于40℃,使其充分溶解。将溶解好的脂质溶液注入到6ml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40℃水浴中真空旋转蒸发除去乙醇和二甲基亚砜,真空度为-0.01MPa,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。得到载顺铂的罂粟籽油乳剂,乳剂外观图见图5,粒径分布和透射电镜下观察图分别见图6和7。
如实施例1进行动物模型构建,实体瘤原位注射以上乳剂,每次10ul,隔天注射,连续两周后处死小鼠肿瘤部位作HE染色,观察与未注射乳剂组的肿瘤组织变化,见图8,A为对照组(即为没有注射乳剂的肿瘤组织)B为注射药物的乳剂组,注射药物后肿瘤组织内部有明显坏死,内部大部分组织没有细胞形态,组织易碎易散,细胞间连接断裂,有助于治疗肿瘤。
实施例3:载阿霉素的花生油制剂的制备方法
准确称取100mg阿霉素、10mgEDC(碳二亚胺)、1ml甘油和50mgNHS(N-羟基琥珀酰亚胺)于烧杯中,加入花生油3ml,以及5ml无水乙醇,使其充分溶解后混合均匀。将溶解好的阿霉素花生油混合乙醇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,10MPa,作用8-16h,除去乙醇,即可得到载有阿霉素的花生油制剂。
实施例4:载贝伐单抗-油酸乳剂
称取大豆磷脂500mg与胆固醇100mg于烧杯中,置于40℃,使其充分溶解,再加贝伐单抗200μg,加入油酸4ml和20mg吐温-80,以及5ml无水乙醇,混合均匀。将溶解好的脂质溶液注入到16ml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40℃水浴中真空旋转蒸发除去乙醇,真空度为-0.1MPa,处理时间40min,除去乙醇,转移到50ml的离心管或烧杯中,再在241W超声30min,直至形成均匀乳液。得到载贝伐单抗-油酸乳剂,粒径分布和透射电镜下观察图分别见图9和10。
如实施例1进行动物模型构建,实体瘤原位注射以上乳剂,每次10ul,隔天注射,每周测量肿瘤组织大小,见图11;连续三周后处死小鼠肿瘤部位作HE染色,观察与未注射乳剂组的肿瘤组织变化,见图12,A为对照组(即为没有注射乳剂的肿瘤组织)B为注射药物的乳剂组,注射药物后肿瘤组织内部有明显坏死,内部大部分组织没有细胞形态,组织易碎易散,细胞间连接断裂,有助于治疗肿瘤。
实施例5:本妥昔单抗-碘油乳剂
称取大豆磷脂500mg与胆固醇100mg于烧杯中,置于40℃,使其充分溶解,再加贝伐单抗200μg,加入油酸4ml和20mg吐温-80,以及5ml无水乙醇,混合均匀。将溶解好的脂质溶液注入到16ml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40℃水浴中真空旋转蒸发除去乙醇,真空度为-0.1MPa,处理时间40min,除去乙醇,转移到50ml的离心管或烧杯中,再在241W超声30min,直至形成均匀乳液。得到载贝伐单抗-油酸乳剂,粒径分布和透射电镜下观察图分别见图13和14。
实施例6:Aldesleukin(重组人白介素-2)-玉米油乳剂
准确称取20mg的span-80于烧杯中,加入玉米油5ml,通过内径为5μm的微流控管道,注入含有400μgAldesleukin(重组人白介素-2)的5ml磷酸盐缓冲液pH6.6(0.05mol/L)中,水油相初步混合,再在200W超声30min,直至形成均匀乳液。
实施例7:伊匹单抗-大豆油
准确称取100μg伊匹单抗、20mgEDC(碳二亚胺)、1ml甘油和100mgNHS(N-羟基琥珀酰亚胺)于烧杯中,加入大豆油3ml,以及5ml无水乙醇,使其充分溶解后混合均匀。将溶解好的伊匹单抗-大豆油混合乙醇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导入置于高压装置中,7.28MPa,作用8-12h,萃取分离除去乙醇,即可得到载有伊匹单抗的大豆油制剂。
实施例8:贝伐单抗-葵花籽油乳剂
称取大豆磷脂660mg与胆固醇220mg于烧杯中,置于40℃,使其充分溶解,再加贝伐单抗200μg,加入葵花籽油3ml和40mg吐温-80,以及5ml无水乙醇,混合均匀。将溶解好的脂质溶液注入到16ml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35℃水浴中真空旋转蒸发除去乙醇,真空度为-0.1MPa,处理时间30min,除去乙醇,转移到50ml的离心管或烧杯中,再在240W超声30min,直至形成均匀乳液。得到载贝伐单抗-葵花籽油乳剂,粒径分布和透射电镜下观察图分别见图15和16。
如实施例1进行动物模型构建,实体瘤原位注射以上乳剂,每次10ul,隔天注射,每周测量肿瘤组织大小,见图17;连续三周后处死小鼠肿瘤部位作HE染色,观察与未注射乳剂组的肿瘤组织变化,见图18,A为对照组(即为没有注射乳剂的肿瘤组织)B为注射药物的乳剂组,注射药物后肿瘤组织内部有明显坏死,内部大部分组织没有细胞形态,组织易碎易散,细胞间连接断裂,有助于治疗肿瘤。图19为各自肿瘤组织HA染色的对比,治疗后肿瘤组织破坏,显示HA成分的蓝色减少甚至消失。
实施例9:索拉菲尼-核桃油乳剂
称取大豆磷脂330mg与胆固醇110mg于烧杯中,置于45℃,使其充分溶解,再加索拉菲尼240mg,加入核桃油2ml和20mg吐温-80,以及2.5ml无水乙醇,2.5ml二甲基亚砜,混合均匀。将溶解好的脂质溶液注入到8ml磷酸盐缓冲液(pH=7)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-0.1MPa,处理时间30min,除去乙醇,转移到50ml的离心管或烧杯中,再在240W超声30min,直至形成均匀乳液。得到载索拉菲尼-核桃油乳剂,粒径分布和透射电镜下观察图分别见图20和21。
以ICR小鼠作为实验动物,以h22细胞作为肿瘤细胞,100万打入小鼠腹腔注射,一周后取腹腔腹水,数细胞300万于小鼠后腿部,造肿瘤模型,两周后模型形成,后腿部皮下形成7.65mm×8.22mm×1.32mm大小的瘤块,开始注射负载索拉菲尼的核桃油乳剂,每次250ul,隔天尾静脉注射一次,两周后再测肿瘤大小,为5.03mm×4.22mm×1.12mm,正常肿瘤(未有注射乳剂的肿瘤)大小为12.06mm×15.22mm×2.32mm,HE染色的结果见图23,图中可见注射乳剂的肿瘤组织内部细胞有坏死。透明质酸的染色见图24。
实施例10:阿帕替尼-油酸乳剂
称取大豆磷脂660mg与胆固醇55mg于烧杯中,加入超液化碘油4ml,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6ml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10mg吐温-80的离心管或烧杯中,再在250W超声25min,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,阿帕替尼含量10mg/ml的均匀乳液。粒径分布和透射电镜下观察图分别见图25和26。
以ICR小鼠作为实验动物,以h22细胞作为肿瘤细胞,100万打入小鼠腹腔注射,一周后取腹腔腹水,数细胞100万于小鼠后腿部,造肿瘤模型,两周后模型形成,后腿部皮下形成8.65mm×9.22mm×3.32mm大小的瘤块,开始注射负载索拉菲尼的核桃油乳剂,每次250ul,隔天尾静脉注射一次,每周量一次肿瘤大小,见图27,HE染色的结果见图28,图中可见注射乳剂的肿瘤组织内部细胞有坏死,肿瘤组织破碎。
实施例11:贝伐单抗-罂粟籽油
准确称取卵磷脂600mg、胆固醇100mg和20mgEDC(碳二亚胺)、100mgNHS(N-羟基琥珀酰亚胺)于烧杯中,加入罂粟籽油10ml,以及10ml无水乙醇,置于35℃,使其充分溶解。将溶解好的脂质溶液逐滴缓慢注入到6ml含有400μg贝伐单抗的磷酸盐缓冲液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,5MPa,作用8h,分离除去乙醇,即可得到10ml载有贝伐单抗的罂粟籽油。
实施例12吉非替尼-碘油乳剂
称取大豆磷脂660mg与胆固醇220mg于烧杯中,吉非替尼100mg,加入碘油4ml和20mg吐温-80,以及5ml无水乙醇,置于40℃,使其充分溶解。将溶解好的脂质溶液注入到6ml磷酸盐缓冲液pH6.6(0.05mol/L)中,然后将其转移到烧瓶中,室温置于真空旋转蒸发除去乙醇,真空度为-0.1MPa,处理时间30min,转移到50ml的离心管中,再在141W超声24min,直至形成均匀乳液。得到载吉非替尼的碘油乳剂,粒径分布和透射电镜下观察图分别见图29和30。
实施例13舒尼替尼–油酸-亚油酸混合脂微球
称取磷脂100mg与胆固醇48mg于烧杯中,舒尼替尼10mg,加入亚油酸2.8g,油酸1.2ml,再加入20mg司盘-85,以及3ml无水乙醇和2ml乙醚,置于40℃,使其充分溶解。将溶解好的脂质溶液注入到6ml磷酸盐缓冲液pH6.6(0.05mol/L)中,然后将其转移到烧瓶中,室温置于真空旋转蒸发除去溶剂,真空度为-0.09MPa,处理时间30min,转移到50ml的离心管中,再在141W超声24min,直至形成均匀乳液。得到载舒尼替尼的油酸-亚油酸混合脂微球。
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 (10)
1.一种用于恶性肿瘤治疗的载药油制剂,其特征在于:
包括可靶向进入肿瘤组织的油载体、及抗肿瘤药物,所述油载体包括植物油和/或动物油、或植物油和/或动物油的成分及其衍生物;所述抗肿瘤药物包括小分子化合物药物和/或蛋白药物。
2.根据权利要求1所述的用于恶性肿瘤治疗的载药油制剂,其特征在于:
抗肿瘤药物均匀分散在油相中,油为连续相,或制成水包油型或水包油包水型乳剂;所述水包油型乳剂或水包油包水型乳剂中还包括一种助剂,所述助剂包括磷脂和胆固醇;或碳二亚胺、甘油、和N-羟基琥珀酰亚胺。
3.根据权利要求2所述的用于恶性肿瘤治疗的载药油制剂,其特征在于:
所述助剂与油载体的质量体积比为4~300mg:1ml。
4.根据权利要求3所述的用于恶性肿瘤治疗的载药油制剂,其特征在于:
所述助剂包括质量比为1.5~12mg:1mg的磷脂和胆固醇;或,质量体积质量比为5~20mg:1~10ml:5~100mg的碳二亚胺、甘油、和N-羟基琥珀酰亚胺。
5.根据权利要求1所述的用于恶性肿瘤治疗的载药油制剂,其特征在于:所述植物油包括粟米油、菜籽油、花生油、火麻油、玉米油、橄榄油、茶树油如山茶油、茶籽油、棕榈液油、芥花子油、葵花子油、大豆油、蓖麻油、芝麻油、亚麻籽油、葡萄籽油、核桃油、棉籽油、米糠油、小麦胚芽油、杏仁油、南瓜籽油、石榴籽油、橘子籽油、樱桃籽油、沙棘油、花椒油、青刺果仁油、松子油、大蒜油、洋葱油、生姜油、苹果油、罂粟籽油、薏苡仁油、紫苏籽油、迷迭香油、木香子油、滇牡丹油、芸香草油、罗勒油、红花籽油、牡丹籽油或霍霍巴油中的一种或多种;
所述植物油的成分包括构成植物油的脂肪酸以及脂肪酸与甘油形成的酯及其衍生物;所述脂肪酸包括软脂酸、硬脂酸、油酸、芥酸、桐油酸、蓖麻油酸、亚油酸、或α-亚麻酸中的一种或一种以上。
6.根据权利要求1所述的用于恶性肿瘤治疗的载药油制剂,其特征在于:
所述动物油包括鱼油和/或海豹油;
所述动物油成分包括构成动物油的脂肪酸以及脂肪酸与甘油形成的酯及其衍生物;所述脂肪酸包括二十碳五烯酸和/或二十二碳六烯酸。
7.根据权利要求1所述的用于恶性肿瘤治疗的载药油制剂,其特征在于:
所述药物包括化疗药,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、或丙卡巴肼以及上述药物的衍生物中至少一种;
所述药物包括蛋白药,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、德瓦鲁单抗、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、Lanreotideacetate、avelumab、Lu177dotatate、Sipueucel-T、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、或重组人血管内皮抑制素中至少一种;
所述药物包括抗肿瘤血管药,所述抗肿瘤血管药物包括酪氨酸激酶抑制剂、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、或莫沙替尼以及上述药物的衍生物中的至少一种;
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、或索尼德吉以及上述药物的衍生物中的至少一种。
8.一种用于恶性肿瘤治疗的载药油制剂的制备方法,其特征在于:
所述水包油型乳剂或水包油包水型乳剂的制备方法包括步骤:将油载体、药物、及助剂混合,加入生理盐水或葡萄糖溶液或平衡盐溶液,经反应或乳化后形成制剂。
9.根据权利要求8所述的用于恶性肿瘤治疗的载药油制剂的制备方法,其特征在于:
所述反应的方式包括高压反应、低压反应、超临界反应、亚临界反应、或微流控反应中的一种或多种;
所述乳化的方式包括机械搅拌乳化、减压悬转蒸发、超声乳化、微流体乳化、超临界流体法或亚临界流体中的一种或几种。
10.一种根据权利要求1~7任一项所述的用于恶性肿瘤治疗的载药油制剂的应用,其特征在于:所述油制剂中,油为连续相的剂型用于经肝动脉注射,水包油型乳剂或水包油包水型乳剂用于经全身静脉、动脉、淋巴管注射或直接注入肿瘤组织。
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