CN116407548A - 一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物及其制备方法 - Google Patents
一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物及其制备方法 Download PDFInfo
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- CN116407548A CN116407548A CN202111680831.4A CN202111680831A CN116407548A CN 116407548 A CN116407548 A CN 116407548A CN 202111680831 A CN202111680831 A CN 202111680831A CN 116407548 A CN116407548 A CN 116407548A
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Abstract
本发明提供一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物及其制备方法,将EP、OXP限定在固定的比例中,可以提高药效,或者将两药为代表的两类药物以固定的协同比共同包载入纳米粒载体中,如脂质体,能突破传统化疗的限制,实现两药在体内长时间维持协同比载药、递药、释药,靶向蓄积于肿瘤,可以显著提高药效,达成协同增效减毒的目标,使患者获益,为临床提供一种疗效、安全性及用药依从性更好的治疗药物。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种蒽环类抗肿瘤药和铂类抗肿瘤药共载于纳米制剂中复方比例,还涉及提供一种适于产业化生产的蒽环类抗肿瘤药和铂类抗肿瘤药复方脂质体的处方制备工艺。
背景技术
EP(盐酸表柔比星)为第三代蒽环类抗肿瘤药,与二代的DOX(盐酸多柔比星)同属阿霉素类,且两药为同分异构体,作用与功效一致,其主要作用部位均是细胞核。抗癌机制是直接嵌入DNA相邻的碱基对之间,与DNA双螺旋形成可逆的结合,干扰转录过程,从而抑制RNA和DNA的合成,达到治疗肿瘤的目的。此外,它们对拓扑异构酶II也有抑制作用,还可作用于细胞核,影响肿瘤细胞的细胞膜及其转运系统,为细胞周期非特异性药物。对多种移植性肿瘤均有效,适应症为淋巴瘤、乳腺癌、肺癌、软组织肉瘤、食道癌、胃癌、肝癌、胰腺癌、黑色素瘤、结肠直肠癌、卵巢癌、多发性骨髓瘤、白血病;膀胱内给药有助于浅表性膀胱癌、原位癌的治疗和预防其经尿道切除术后的复发。临床疗效EP与DOX相等或比DOX略高,不良反应EP与DOX相似,但程度较低,尤其是心肌毒性和骨髓抑制毒性。
OXP(奥沙利铂)属于铂类抗癌药,与其它铂类药物相似均以DNA为靶点。它通过产生烷化结合物作用于DNA,形成链内和链间交联,从而抑制DNA的合成及复制,发挥抗肿瘤活性和细胞毒性的作用,达到治疗疾病的目的。目前被广泛应用于胃肠道恶性肿瘤疾病的治疗,是迄今为止唯一对结直肠癌具有显著活性的络铂类药物,一线应用治疗转移性结直肠癌;也用于不适合手术切除或局部治疗的局部晚期和转移的肝细胞癌(HCC)的治疗。
而EP与OXP联合常用于胃癌、食管癌、原发性肝癌的治疗,但因存在毒副反应大,主要为血液毒性(III级以上中心粒细胞减少症为30-40%)、胃肠道毒性、神经毒性、心脏毒性等,较之于FOLFIRI方案(伊立替康加5-FU),虽临床疗效相当,但FOLFIRI的毒性更小且耐受性更好,致使两药联合应用受到极大限制,逐步被其它化疗方案所取代而列入低级别的2B类推荐。
发明内容
本发明为克服现有技术中EP和OXP普通制剂联合用药时存在毒性大、疗效差的问题,提供一种蒽环类抗肿瘤药和铂类的制剂组合物。
本发明提供的一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物,蒽环类抗肿瘤药和铂类抗肿瘤药的摩尔比为10∶1~1∶3,,优选的7∶1~1∶3,在一些优选的实施例中,蒽环类抗肿瘤药和铂类抗肿瘤药摩尔比为6∶1~1∶2;优选的5∶1~1∶2。
本发明所述的蒽环类抗肿瘤药可以选自:表柔比星、多柔比星、吡柔比星、柔红霉素、阿柔比星、伊达比星、戊柔比星或米托蒽醌。
本发明所述的铂类抗肿瘤药可以选自:奥沙利铂、顺铂、卡铂或奈达铂。
在一种具体的实例中,本发明提供的一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物,具体为表柔比星(或多柔比星)和奥沙利铂的组合,其中表柔比星(或多柔比星)和奥沙利铂的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,在一些优选的实施例中,表柔比星(或多柔比星)和奥沙利铂摩尔比为5∶1~1∶2。
本发明还提供一种蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,蒽环类抗肿瘤药和铂类抗肿瘤药包裹在复方纳米制剂的水相中,蒽环类抗肿瘤药和铂类抗肿瘤药的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,在一些更优选的实施例中,蒽环类抗肿瘤药和铂类抗肿瘤药摩尔比为6∶1~1∶2;进一步优选的5∶1~1∶2。
本发明所述的蒽环类抗肿瘤药和铂类抗肿瘤药可以如前所述。
在一种具体的实例中,本发明还提供的蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,具体为蒽环类抗肿瘤药和奥沙利铂包裹在复方纳米制剂的水相中,其中蒽环类抗肿瘤药为表柔比星或多柔比星;蒽环类抗肿瘤药和奥沙利铂的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,优选的,蒽环类抗肿瘤药和奥沙利铂摩尔比为6∶1~1∶2;进一步5∶1~1∶2。
本发明所述的复方纳米制剂可以是脂质体、乳剂、胶束或聚合物纳米粒子等本领域常见的复方纳米制剂的形式。所述的制剂形式可以按照本领域常规的方法制备而成。
在一种具体的实例中,所述蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂为脂质体;更具体的为蒽环类抗肿瘤药和铂类抗肿瘤药包裹在脂质体薄膜中,所述脂质体薄膜包括中性磷脂和其他原料,其他原料为带电荷磷脂、胆固醇或培化磷脂酰乙醇胺中的一种或几种。
本发明所述的中性磷脂可以为本领域常用的中性磷脂,例如包括但不限于:大豆磷脂、蛋黄磷脂、氢化大豆磷脂(HSPC)、二油酰磷脂酰胆碱(DOPC)、二棕榈酰磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰胆碱(DSPC)、二肉豆蔻磷脂酰胆碱(DMPC)中的一种或多种。
本发明所述的带电荷磷脂可以为本领域常用的带电荷磷脂,可以为带负电荷磷脂或带正电荷磷脂,其中带负电荷磷脂为:磷脂酰甘油(PG)、二棕榈酰磷脂酰甘油(DPPG)、磷脂酰肌醇(PI)、磷脂酸(PA)、磷脂酰丝氨酸(PS)中的一种或多种;带正电荷磷脂为:二油酰基丙基三甲基氯化铵(DOTAP)、二油醇二甲基氨基丙烷(DODMA)中的一种或多种。
本发明所述的胆固醇可以为本领域常用的胆固醇,例如包括但不限于:胆固醇、胆固醇硫酸酯。
本发明所述的培化磷脂酰乙醇胺可以为本领域常用的培化磷脂酰乙醇胺,例如包括但不限于:DSPE-mPEG2000、DPPE-mPEG5000中的一种或两种。
在一些实施例中,抗肿瘤药的总质量与脂质体总的质量比为1∶5~1∶50,优选1∶7~1∶40。
在一些实施中,带电荷磷脂与中性磷脂质量比为(0~0.3)∶1,优选(0~0.2)∶1。
在一些实施例中,胆固醇与中性磷脂质量比为(0~0.3)∶1,优选(0~0.2)∶1。
在一些实施例中,培化磷脂酰乙醇胺与中性磷脂质量比为(0~0.3)∶1,优选(0.02~0.2)∶1。
在一些实施例中,带电荷磷脂、胆固醇和培化磷脂酰乙醇胺三者不同时为零。
在一些实施例中,所述脂质体内的水相溶液为pH为2.5-5.0的硫酸铵-甘露醇溶液,硫酸铵-甘露醇溶液的浓度和比例可以按照本领域常规选择,例如,溶液中硫酸铵的浓度为0.15mol/L-0.35mol/L,甘露醇的重量百分浓度为0.5-5%。
在一些实施例中,所述脂质体外的水相溶液为pH为4.5-7.5的蔗糖溶液、葡萄糖溶液、甘露醇溶液、蔗糖/氨基酸混合溶液、葡萄糖/氨基酸混合溶液或者是甘露醇/氨基酸混合溶液。混合溶液的比例可以按照本领域常规进行选择,例如,蔗糖/氨基酸混合溶液中蔗糖的重量百分浓度为5-20%,氨基酸的浓度为5-30mmol/L;葡萄糖/氨基酸混合溶液中葡萄糖的重量百分浓度为5-20%,氨基酸的浓度为5-30mmol/L;甘露醇/氨基酸混合溶液中甘露醇的重量百分浓度为5-10%,氨基酸的浓度为5-30mmol/L。
本发明所述的脂质体可以按照本领域的常规方法进行制备,在本发明的一种具体实例中,提供一种具体的制备方法,包括如下步骤:
(1)按处方量将中性磷脂、带电荷磷脂、胆固醇和培化磷脂酰乙醇胺溶于乙醇或二氯甲烷中,置旋转蒸发仪上减压旋蒸除去乙醇或二氯甲烷形成脂质薄膜;
(2)将处方量的铂类抗肿瘤药加入至pH为2.5-5.0的硫酸铵-甘露醇溶液中,于25-65℃超声或搅拌溶解完全后,加入脂质薄膜中洗膜水化,温度为40℃-65℃,水化完全后,得铂类抗肿瘤药脂质体初液;
(3)均质整粒:采用高压均质机或挤压整粒设备将铂类抗肿瘤药脂质体初液均质整粒至所需的粒径和均匀度;
(4)超滤浓缩:采用切线流超滤系统或透析装置去除铂类抗肿瘤药脂质纳米粒外水相体系中的硫酸铵-甘露醇溶液,置换溶液可为注射用水;待外水相体系中的硫酸铵-甘露醇溶液去除至终点后再改用脂质体外的水相溶液置换去水并浓缩至规定体积;或直接采用脂质体外的水相溶液进行洗脱并置换浓缩至规定体积,得铂类抗肿瘤药脂质体;所述的脂质体外的水相溶液为蔗糖溶液、葡萄糖溶液、甘露醇溶液、蔗糖/氨基酸混合溶液、葡萄糖/氨基酸混合溶液或者是甘露醇/氨基酸混合溶液;
(5)将处方量蒽环类抗肿瘤药溶于蔗糖溶液、葡萄糖溶液或甘露醇溶液中的一种溶液中室温搅拌溶解完全后,缓缓加入至铂类抗肿瘤药脂质体中,于45-65℃下孵育5-30min,冷却至室温,加或不加入氨基酸调节渗透压,即得蒽环类抗肿瘤药和铂类抗肿瘤药共载的脂质体。
本发明所述方法制得的脂质体,两药包封率均不低于90%,平均粒径80-300nm,可以于2-8℃下密封保存至使用。
本发明所述的表柔比星为表柔比星盐形式,如盐酸表柔比星。
本发明所述的多柔比星为多柔比星盐形式,如盐酸多柔比星。
相对于现有技术,本申请具有如下优势:
(1)临床EP+OXP联用的常规用法用量是:EP 50mg/m2 ivd1,奥沙利铂130mg/m2 ivd1,摩尔比为1∶3.8。而本申请所述的不同于临床用药比例的协同配比范围,相对于临床摩尔比具有更好的治疗效果。
(2)将EP、OXP两药为代表的两类药物以固定的协同比共同包载入纳米粒载体中,如脂质体,能突破传统化疗的限制,实现两药在体内长时间维持协同比载药、递药、释药,靶向蓄积于肿瘤,可以显著提高药效,达成协同增效减毒的目标,使患者获益,为临床提供一种疗效、安全性及用药依从性更好的治疗药物。
附图说明
图1为实施例1的粒径分布图;
图2为实施例2的粒径分布图;
图3为实施例3的粒径分布图;
图4为实施例4的粒径分布图;
图5为人胃癌NUGC-4第28天各组肿瘤体积图;
图6为H22肝癌第21天各组肿瘤体积图。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。
实施例1一种EP+OXP复方脂质体
取DSPC(二硬脂酰基磷脂酰胆碱)1.0g、Chol(胆固醇)0.1g和0.2g DSPE-mPEG2000溶解于乙醇中,置旋转蒸发仪上于40-60℃减压旋蒸除去乙醇形成脂质薄膜;将140mg OXP加入至16mL pH为2.8(草酸调pH)的0.25M硫酸铵-5%甘露醇溶液中,于55℃超声/搅拌溶解完全后,加入至脂质薄膜于60℃洗膜水化40min,得OXP脂质体初液;采用高压均质机将OXP脂质体初液均质整粒,得平均粒径150±50nm OXP脂质纳米粒;以10%蔗糖溶液为置换溶液,采用透析装置去除OXP脂质纳米粒外水相体系中的硫酸铵-甘露醇溶液,置换完成后,得到30mL浓度为2.33mg/mL OXP脂质体;将51.1mg EP溶解于4.0mL10%蔗糖溶液中,并缓缓加入至OXP脂质体中混合均匀,于60±2℃孵育15min,冷却至室温,再加入适量组氨酸,使其在药液中的浓度为10mM,混合均匀,加10%蔗糖溶液稀释至总体积为35mL,除菌过滤,分装,充N2压塞,即得EP+OXP复方脂质体,于2-8℃下密封保存至使用。粒径分布如图1所示。
实施例2一种EP+OXP复方脂质体
取DOPC(二油酰磷脂酰胆碱)2.5g、DPPG(二棕榈酰磷脂酰甘油)0.5g和0.1g DPPE-mPEG5000溶解于二氯甲烷中,置旋转蒸发仪上于50±5℃减压旋蒸除去二氯甲烷形成脂质薄膜;将80mg OXP加入至20mL pH为4.0(枸橼酸调pH)的0.2M硫酸铵=1%甘露醇溶液中,于室温超声/搅拌溶解完全后,加入至脂质薄膜于50±2℃洗膜水化10min,得OXP脂质体初液;采用挤压整粒设备将OXP脂质体初液均质整粒,得平均粒径100±20nm OXP脂质纳米粒;以注射用水为置换溶液,采用切线流超滤系统超滤去除OXP脂质纳米粒外水相体系中的硫酸铵=甘露醇溶液,置换完成后,再加入20mL 10%甘露醇溶液混合并超滤浓缩至20mL,得到浓度为1.02mg/mL OXP脂质体;将60mg EP溶解于10mL5%甘露醇溶液中,并加入至OXP脂质体中混合均匀,于50℃孵育10min,冷却至室温,除菌过滤,分装,充N2压塞,即得EP+OXP复方脂质体,于2-8℃下密封保存至使用。粒径分布如图2所示。
实施例3一种EP+OXP复方脂质体
取HSPC(氢化大豆卵磷脂)1.2g、DOTAP 0.1g、Chol(胆固醇)0.2g和0.15gDSPE-mPEG2000溶解于乙醇中,置旋转蒸发仪上于55±5℃减压旋蒸除去乙醇形成脂质薄膜;将60mg OXP加入至12mL pH为3.2(草酸调pH)的0.25M硫酸铵-3%甘露醇溶液中,于室温超声/搅拌溶解完全后,加入至脂质薄膜于60±2℃洗膜水化10min,得OXP脂质体初液;采用高压均质整粒设备将OXP脂质体初液均质整粒,得平均粒径150±20nm OXP脂质纳米粒;以10%蔗糖溶液为置换溶液,采用切线流超滤系统去除OXP脂质纳米粒外水相体系中的硫酸铵=甘露醇溶液,置换完成后,得到20mL浓度为0.41mg/mL OXP脂质体;将60mg EP溶解于10mL10%蔗糖溶液中,并加入至OXP脂质体中混合均匀,于60℃孵育10min,冷却至室温,除菌过滤,分装,充N2压塞,即得EP+OXP复方脂质体,于2-8℃下密封保存至使用。粒径分布如图3所示。
实施例4一种DOX+OXP复方脂质体
取HSPC 1.8g、胆固醇硫酸酯0.1g和0.36g DSPE-mPEG2000溶解于二氯甲烷中,置旋转蒸发仪上于55±5℃减压旋蒸除去乙醇形成脂质薄膜;将120mg OXP加入至20mL pH为4.5(苹果酸调pH)的0.3M硫酸铵-3%甘露醇溶液中,于50℃超声/搅拌溶解完全后,加入至脂质薄膜于60±2℃洗膜水化20min,得OXP脂质体初液;采用高压均质整粒设备将OXP脂质体初液均质整粒,得平均粒径150±20nm OXP脂质纳米粒;以10%葡萄糖溶液为置换溶液,采用切线流超滤系统去除OXP脂质纳米粒外水相体系中的硫酸铵-甘露醇溶液,置换完成后,得到20mL浓度为2.06mg/mL OXP脂质体;将60mg DOX溶解于5mL 10%葡萄糖溶液中,并加入至OXP脂质体中混合均匀,于60±2℃孵育20min,冷却至室温,再加入适量苏氨酸,使其在药液中的浓度为5mM,混合均匀,加10%葡萄糖溶液稀释至总体积为30mL后,除菌过滤,分装,充N2压塞,即得DOX+OXP复方脂质体,于2-8℃下密封保存至使用。粒径分布如图4所示。
对实施例1-4的制剂的检测结果如表1所示:
【表1】
药效试验:
1、人胃癌NUGC-4细胞移植瘤Balb/c裸鼠药效数据
方法:取冻存于液氮的NUGC-4人胃癌肿瘤细胞复苏并扩增,于90%RPMI 1640培养基加10%胎牛血清,37℃5%CO2培养箱中培养。一周两次用胰酶-EDTA进行常规消化处理传代,扩增传代比例为1∶2,当细胞饱和度为80%-90%,数量达到要求时,选用6-8W的雄性Balb/c裸鼠,于右侧腋下接种,接种细胞量为1*107cells/只;在接种后待肿瘤体积均值达到100mm3后,选择肿瘤大小合适,形状规则,体重差异较小的裸鼠入组,采用随机法分组,经尾静脉给药。每7天给药1次,共给药3次。
结果:实施例1、2、3的EP+OXP复方脂质体、以及EP联合OXP摩尔比分别为1∶3.8(临床使用配方)、1∶2、2∶1、5∶1时,在人胃癌NUGC-4裸鼠药效数据如表2和图5所示:
【表2】
依据《细胞毒类抗肿瘤药物非临床研究技术指导原则》有效性研究中明确指出:针对人癌异体移植瘤模型,推荐采用相对肿瘤增殖率T/C(%)作为试验评价指标。原则上,评价标准为:T/C(%)>40%为无效;T/C(%)≤40%,并经统计学处理P<0.05为有效。本实验结果发现,当EP联合OXP以摩尔比1∶3.8时,T/C为50%,未达到有效的抑瘤活性;而当EP联合OXP以本发明所述范围的摩尔比5∶1、2∶1、1∶2时,其抑瘤活性较1∶3.8时显著增强,可达60%以上,表示临床具有显著的效果提升;而实施例1、2、3分别以EP∶OXP为5∶1、2∶1、1∶2制备成复方脂质体后,其抑瘤率进一步获得显著提高(与EP∶OXP=1∶3.8比较,*P<0.05,**P<0.01)。
2、肝癌H22荷瘤鼠药效数据
方法:取冻存于液氮的H22小鼠肝癌肿瘤细胞复苏并扩增,于90%RPMI 1640培养基加10%胎牛血清,37℃5%CO2培养箱中培养,一周三次离心更换培养基进行常规传代,扩增传代比例为1∶3。当细胞饱和度为80%-90%,数量达到要求时,稀释到细胞量为1*107cells/1ml,选用6-8W的雄性Balb/c小鼠,于右侧腋下接种,细胞量为1*106cells/只。接种后5天,肿瘤体积均值达到100mm3,选择肿瘤大小合适,形状规则,体重差异较小的小鼠入组进行试验,采用随机法分组,经尾静脉给药。每7天给药1次,共给药2次。
结果:实施例3制备的EP+OXP复方脂质体对比于临床使用的EP单剂联合OXP单剂(摩尔比约为1∶3.8),肝癌H22荷瘤鼠药效试验数据见表3和图6。
【表3】
结果发现,实施例3显著优效于EP联合OXP 1∶3.8组(与EP∶OXP=1∶3.8比较,**P<0.01)。
3、小鼠重复试验毒性
ICR小鼠按表4分组静脉注射给药,每周给药一次,共计3次,末次给药后观察28天。在本实验条件下,实施例2、实施例3中EP的最高非严重毒性剂量(HNSTD)为12mg/kg,而EP联合OXP摩尔比2∶1、5∶1组中EP的HNSTD为8mg/kg,说明EP+OXP复方脂质体可显著降低联合用药的毒性,提高用药剂量。
【表4】
Claims (10)
1.一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物,其特征在于,蒽环类抗肿瘤药和铂类抗肿瘤药的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,蒽环类抗肿瘤药和铂类抗肿瘤药摩尔比为6∶1~1∶2;优选的5∶1~1∶2,所述的蒽环类抗肿瘤药选自表柔比星、多柔比星、吡柔比星、柔红霉素、阿柔比星、伊达比星、戊柔比星或米托蒽醌;所述的铂类抗肿瘤药选自奥沙利铂、顺铂、卡铂或奈达铂。
2.一种蒽环类抗肿瘤药和铂类抗肿瘤药的组合物,其特征在于,具体为表柔比星和奥沙利铂的组合,其中表柔比星和奥沙利铂的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,更优选的表柔比星和奥沙利铂摩尔比为5∶1~1∶2。
3.一种蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,蒽环类抗肿瘤药和铂类抗肿瘤药包裹在复方纳米制剂的水相中,蒽环类抗肿瘤药和铂类抗肿瘤药的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,更优选的蒽环类抗肿瘤药和铂类抗肿瘤药摩尔比为6∶1~1∶2;进一步优选的5∶1~1∶2,所述的蒽环类抗肿瘤药选自表柔比星、多柔比星、吡柔比星、柔红霉素、阿柔比星、伊达比星、戊柔比星或米托蒽醌;所述的铂类抗肿瘤药选自奥沙利铂、顺铂、卡铂或奈达铂。
4.一种蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,具体为蒽环类抗肿瘤药和奥沙利铂包裹在复方纳米制剂的水相中,其中蒽环类抗肿瘤药为表柔比星或多柔比星;蒽环类抗肿瘤药和奥沙利铂的摩尔比为10∶1~1∶3,优选的7∶1~1∶3,优选的,蒽环类抗肿瘤药和奥沙利铂摩尔比为6∶1~1∶2;进一步5∶1~1∶2。
5.根据权利要求3或4所述的蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,所述的复方纳米制剂为脂质体、乳剂、胶束或聚合物纳米粒子。
6.根据权利要求5所述的蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,所述蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂为脂质体,优选的,所述脂质体薄膜包括中性磷脂和其他原料,其他原料为带电荷磷脂、胆固醇或培化磷脂酰乙醇胺中的一种或几种。
7.根据权利要求6所述的蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,所述的中性磷脂为大豆磷脂、蛋黄磷脂、氢化大豆磷脂、二油酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻磷脂酰胆碱中的一种或多种;所述的带电荷磷脂为带负电荷磷脂或带正电荷磷脂,其中带负电荷磷脂为:磷脂酰甘油、二棕榈酰磷脂酰甘油、磷脂酰肌醇、磷脂酸、磷脂酰丝氨酸中的一种或多种;带正电荷磷脂为:二油酰基丙基三甲基氯化铵、二油醇二甲基氨基丙烷中的一种或多种;所述的胆固醇为胆固醇或胆固醇硫酸酯;所述的培化磷脂酰乙醇胺为DSPE-mPEG2000、DPPE-mPEG5000中的一种或两种。
8.根据权利要求6所述的蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,抗肿瘤药的总质量与脂质体的总质量比为1∶5~1∶50;优选的1∶7~1∶40,带电荷磷脂与中性磷脂质量比为(0~0.3)∶1,优选(0~0.2)∶1;胆固醇与中性磷脂质量比为(0~0.3)∶1,优选(0~0.2)∶1;培化磷脂酰乙醇胺与中性磷脂质量比为(0~0.3)∶1,优选(0.02~0.2)∶1,优选的,带电荷磷脂、胆固醇和培化磷脂酰乙醇胺三者不同时为零。
9.根据权利要求6所述的蒽环类抗肿瘤药和铂类抗肿瘤药共载的复方纳米制剂,其特征在于,所述脂质体内的水相溶液为pH为2.5-5.0的硫酸铵-甘露醇溶液,脂质体外的水相溶液为pH为4.5-7.5的蔗糖溶液、葡萄糖溶液、甘露醇溶液、蔗糖/氨基酸混合溶液、葡萄糖/氨基酸混合溶液或者是甘露醇/氨基酸混合溶液。
10.一种权利要求6所述的复方纳米制剂的制备方法,其特征在于,包括如下步骤:
(1)按处方量将中性磷脂、带电荷磷脂、胆固醇和培化磷脂酰乙醇胺溶于乙醇或二氯甲烷中,置旋转蒸发仪上减压旋蒸除去乙醇或二氯甲烷形成脂质薄膜;
(2)将处方量的铂类抗肿瘤药加入至pH为2.5-5.0的硫酸铵-甘露醇溶液中,于25-65℃超声或搅拌溶解完全后,加入脂质薄膜中洗膜水化,温度为40℃-65℃,水化完全后,得铂类抗肿瘤药脂质体初液;
(3)均质整粒:将铂类抗肿瘤药脂质体初液均质整粒至所需的粒径和均匀度;
(4)超滤浓缩:采用切线流超滤系统或透析装置去除铂类抗肿瘤药脂质纳米粒外水相体系中的硫酸铵-甘露醇溶液,置换溶液可为注射用水,待外水相体系中的硫酸铵-甘露醇溶液去除至终点后再改用脂质体外的水相溶液置换去水并浓缩至规定体积;或直接采用脂质体外的水相溶液进行洗脱置换并浓缩至规定体积,得铂类抗肿瘤药脂质体;
(5)将处方量蒽环类抗肿瘤药溶于蔗糖溶液、葡萄糖溶液或甘露醇溶液中的一种溶液中室温搅拌溶解完全后,缓缓加入至铂类抗肿瘤药脂质体中,于45-65℃下孵育5-30min,冷却至室温,加或不加入氨基酸调节渗透压,即得蒽环类抗肿瘤药和铂类抗肿瘤药共载的脂质体;
优选的,所述的脂质体外的水相溶液为蔗糖溶液、葡萄糖溶液、甘露醇、蔗糖/氨基酸混合溶液、葡萄糖/氨基酸混合溶液或者是甘露醇/氨基酸混合溶液。
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