CN117338721A - 一种瑞德西韦改性脂质体组合物及其制备方法 - Google Patents
一种瑞德西韦改性脂质体组合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种瑞德西韦改性脂质体组合物。具体地,所述的瑞德西韦改性脂质体组合物中包括:瑞德西韦或其药学上可接受的盐、脂质体材料、稳定剂、pH调节剂和载体,其中,所述的稳定剂选自下组:维生素E聚乙二醇琥珀酸酯、聚氧乙烯蓖麻油、15‑羟基硬脂酸聚乙二醇酯,或其组合。
Description
技术领域
本发明属于药物制备领域,具体地,本申请涉及一种瑞德西韦改性脂质体组合物及其制备方法。
背景技术
新型冠状病毒肺炎(新冠肺炎,COVID-19)为新发急性呼吸道传染病,该病作为急性呼吸道传染病已纳入《中华人民共和国传染病防治法》规定的乙类传染病,按甲类传染病管理。目前,仍未发现经严格“随机、双盲、安慰剂对照研究”证明有效的抗病毒药物,推荐试用α-干扰素、利巴韦林(联用α-干扰素或者洛匹那韦/利托那韦)、磷酸氯喹和阿比多尔。针对COVID-19感染引起的肺炎疫情,寻找疗效确切药物是重中之重。
瑞德西韦(remdesivir,GS-5734)是由美国吉利德科学公司(Gilead Science)研制的一种新型腺苷类似物的单磷酸酰胺前药,其三磷酸活性代谢物(GS-443902)能够干扰病毒RNA依赖性RNA聚合酶(RdRp)的活性,通过抑制病毒核酸合成而发挥抗病毒作用。瑞德西韦前期研发的适应症为抗埃博拉病毒(丝状病毒),相关研究表明其抗丝状病毒效果良好。经体外细胞实验和动物模型实验证实,瑞德西韦对非典型性肺炎冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)均具有抗病毒作用。依据文献报道,新型冠状病毒COVID-19是导致2002-2003年爆发严重急性呼吸综合征(SARS)冠状病毒(SARS-CoV)的变种,两者同源性>85%。
瑞德西韦在成人和青少年(体重≥40kg)中的推荐给药方案为:治疗第1天首次静脉输注瑞德西韦200mg(静脉输注30min以上),之后静脉输注瑞德西韦100mg×1次/天(每次30min以上)维持9~13天。瑞德西韦给药剂量相对较大,但是其在水中溶解度较低,约5.3μg/mL,在水性介质中溶解性较差且化学不稳定。因此目前批准上市的瑞德西韦注射剂采用环糊精包合技术增加瑞德西韦的溶解度和稳定性。但该方式环糊精用量极大,环糊精与瑞德西韦质量比达到30∶1才能保证药物完全包合,大剂量的辅料直接进入体循环存在潜在的安全隐患。根据文献,肾是瑞德西韦多次给药毒性靶器官,以50mg/kg/天计量给大鼠和猴分别给药2周会导致肾小管细胞空泡化,大鼠和猴以10mg/kg/天计量给药4周也导致肾小管细胞空泡化,并且随着给药周期延长空泡化分布更广(肝、淋巴管、肾上腺、脾),空泡化归因于瑞德西韦载体磺丁基倍他环糊精钠。依据文献,瑞德西韦在静脉给药后4小时内分布到睾丸、附睾、眼睛和脑组织。相对于其他组织,第4小时脑内药物浓度水平较低,但在给药168小时后仍可检测到瑞德西韦浓度高于血浆水平。因此,已上市的注射用瑞德西韦存在诱发全身性毒副作用的潜在风险。
脂质体是由单层或多层脂质双分子膜以同心圆的形式包封而成,类似细胞膜的微球体,其主要成分为磷脂和胆固醇,其作为药物载体有制备简单、对人体无害、无免疫原性反应、延长药效、降低药物毒性、提高疗效、避免耐受性等优点;但其通常载药浓度低、易渗漏,粒度分布直接会影响其包载药物的体内行为。因此,脂质体的技术难点在于包封率、粒度分布和稳定性的控制和保证。
发明内容
本发明的一个目的是提供一种包封率高、粒度分布均匀、稳定性高的瑞德西韦改性脂质体组合物及其制备方法。
在本发明的第一方面,提供了一种瑞德西韦改性脂质体组合物,所述的组合物包括:
(i)活性成分,所述活性成分为式I所示的瑞德西韦或其药学上可接受的盐;
(ii)脂质体材料;和
(iii)稳定剂,所述的稳定剂选自下组:维生素E聚乙二醇琥珀酸酯、聚氧乙烯(35)蓖麻油、15-羟基硬脂酸聚乙二醇酯,或其组合;
其中,所述的活性成分与脂质体材料的质量比为(1±0.2):5~(1±0.2):20;
所述的活性成分与稳定剂的质量比为(1±0.2):0.5~(1±0.2):20;
按重量比计,所述的活性成分0.5%~10%;脂质体材料30%~74%;稳定剂为18%~65%。
在另一优选例中,所述的活性成分与脂质体材料的重量比(1±0.2):5~(1±0.2):15。
在另一优选例中,所述的活性成分与稳定剂的质量比为(1±0.2):0.5~(1±0.2):15。
在另一优选例中,所述的活性成分与稳定剂的质量比为(1±0.2):2~(1±0.2):12。
在另一优选例中,所述的稳定剂和脂质体材料的质量比为(1±0.2):0.5~(1±0.2):20;较佳地为(1±0.2):0.5~(1±0.2):15。
在另一优选例中,所述的组合物中,所述的瑞德西韦或其药学上可接受的盐的包封率为85%~100%;较佳为90%~100%。
在另一优选例中,所述的瑞德西韦改性脂质体的粒度分布为90~300nm;多分散系数为0.01~0.50。
在另一优选例中,所述的瑞德西韦改性脂质体的粒度分布为100~250nm;多分散系数为0.05~0.45。
在另一优选例中,所述的组合物中,所述的瑞德西韦或其药学上可接受的盐的载药量为0.5~10wt%;较佳地为3~8wt%。
在另一优选例中,所述的组合物的pH为4~9。
在另一优选例中,所述的组合物中还含有pH调节剂,且所述的pH调节剂选自下组:盐酸、磷酸、醋酸、枸橼酸、氢氧化钠、磷酸氢二钠、磷酸二氢钠、醋酸钠、枸橼酸钠,或其组合。
在另一优选例中,所述的脂质体材料选自下组:蛋黄卵磷脂、大豆磷脂、氢化磷脂酰胆碱、二棕榈酰磷脂酰胆碱、胆固醇,或其组合。
在另一优选例中,当所述的组合物还含有冻干支撑剂时,则所述组合物的剂型为冻干制剂,所述冻干制剂中,瑞德西韦的浓度为0.5~10wt%;较佳地为3~8wt%。
在另一优选例中,当所述的组合物为冻干制剂时,所述的稳定剂还包括吐温80。
在另一优选例中,所述的冻干支撑剂选自下组:甘露醇、蔗糖、海藻糖,或其组合。
在另一优选例中,所述的冻干制剂在使用前需要载体复溶,形成脂质体组合物混悬液B给药;其中,所述的混悬液B中瑞德西韦的浓度为0.1~2.0wt%;较佳地为0.3~1.0wt%。
在另一优选例中,所述的冻干制剂复溶后保持混悬状态,混悬状态保持24h,复溶后,瑞德西韦改性脂质体以游离状态存在,复溶后瑞德西韦的浓度为0.1~10mg/ml。
在本发明的第二方面,提供了一种本发明第一方面所述的组合物的制备方法,包括如下步骤:
a)提供第一混合物,所述的第一混合物中含有本发明第一方面所述的(i)、(ii)、(iii)、惰性溶剂以及任选地pH调节剂;
b)对所述的第一混合物进行处理,形成含有脂质体组合物的第二混合物;
c)对所述的第二混合物进行后处理,得到含有本发明第一方面所述的组合物的混悬液。
在另一优选例中,当所述的组合物制备成冻干制剂时,所述的第一混合物中还含有冻干支撑剂。
在另一优选例中,在步骤(b)中,所述的处理包括:
(Z1)减压蒸发去除所述第一混合物中的惰性溶剂,加入载体水化后,经超声分散形成含有脂质体组合物的第二混合物;和/或
(Z2)对所述的第一混合物进行高速剪切,形成含有脂质体组合物的第二混合物。
在另一优选例中,所述的载体选自下组:注射用水、氯化钠注射液、葡萄糖注射液,或其组合。
在另一优选例中,在冻干制剂时,向步骤(b)得到的所述的第二混合物中加入冻干支撑剂,溶解均匀后,进行步骤(c)的操作。
另一优选例中,所述的惰性溶剂选自下组:从C1-C6醇类溶剂、C1-C6烃类溶剂、C2-C6醚类溶剂、C1-C6酮类溶剂、C1-C6卤代烃类溶剂、水,或其组合。
在另一优选例中,所述的惰性溶剂选自下组:乙醇、氯仿、乙醚、二氯甲烷、丙酮,或其组合。
在另一优选例中,当处理过程为Z2时,第一混合物中的惰性溶剂为水。
在另一优选例中,所述的后处理包括:
Y1)将所述的第二混合物通过薄膜挤出机挤出,得到瑞德西韦改性脂质体组合物混悬液;和/或
Y2)将所述的第二混合物经高压匀质,过滤,得到瑞德西韦改性脂质体组合物混悬液;和/或
Y3)将所述的第二混合物经过0.2μm聚醚砜滤器过滤,得到瑞德西韦改性脂质体组合物混悬液。
在本发明的第三方面,提供了一种如本发明第一方面所述的瑞德西韦改性脂质体组合物的冻干制剂的制备方法,冻干过程包括以下步骤:
(d)预冻阶段:将本发明第二方面获得的所述瑞德西韦改性脂质体组合物混悬液分装于制剂瓶置于-55~-30℃,保温2~12h;
(e)升华阶段:在1h内逐渐升温至-50~-25℃,真空度为50~200mTor,保温4~20h;
(f)解析干燥:在6h内逐渐升温至-20~5℃,真空度为50~200mTor,保温1~6h,即得到所述瑞德西韦改性脂质体组合物的冻干制剂。
在另一优选例中,所述的冻干过程在冷冻干燥机中进行。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本申请人经过广泛而深入的研究,经过大量筛选,首次开发了一种瑞德西韦改性脂质体组合物及其制备方法。本发明通过将瑞德西韦包覆脂质体中,得到粒径分布为100-300nm,载药量为0.5-10wt%的瑞德西韦改性脂质体组合物。在此基础上,完成了本发明。
术语
如本文所用,术语“稳定剂”是指能够增加脂质体变形性有助于粒径减小和粒度分布变窄、并提高其渗透性和稳定性的表面活性剂,其包括但不限于:维生素E聚乙二醇琥珀酸酯、聚氧乙烯蓖麻油、15-羟基硬脂酸聚乙二醇酯,或其组合。
其中,维生素E琥珀酸聚乙二醇酯(Vitamin E Polyethylene Glycol Succinate,TPGS),已被美国药典USP43-NF38收载,为d-α-生育酚琥珀酸酯和聚乙二醇酯化形成的混合物。酯混合物主要由单酯化聚乙二醇和少量二酯化聚乙二醇组成。含d-α-生育酚(d-alphatocopherol,C29H50O2)不少于25.0%。
商品如PMC Isochem和Sigma的d-α-生育酚聚乙二醇1000琥珀酸酯,CAS号:9002-96-4。结构式如下所示:
聚氧乙烯(35)蓖麻油(Polyoxyl 35Castor Oil,Polyethylene glycol 35castoroil,Polyoxyethylene 35castor oil),CAS号:61791-12-6。收录于《中国药典》2020年版四部和美国药典USP43-NF38。本品为聚氧乙烯甘油三蓖麻酸酯,其中还含少量聚乙二醇蓖麻酸酯、游离乙二醇,本品为1mol甘油蓖麻酸酯与35mol环氧乙烷反应得到。
商品如BASF的EL,结构式如下所示:
15-羟基硬脂酸聚乙二醇酯(Polyoxyl 15Hydroxystearate,12-Hydroxyoctadecanoic acid polymer withα-hydro-ω-hydroxypoly(oxy-1,2-ethanediyl),Polyethylene glycol 15hydroxystearate),CAS号:70142-34-6。收录于美国药典USP43-NF38。本品为约15mol环氧乙烷与1mol的12-羟基硬脂酸反应得到。本品主要由聚乙二醇在12-羟基硬脂酸的羧基和羟基上聚乙氧基化组成。它含有游离的聚乙二醇。
商品如BASF的HS 15,结构式如下所示:
施用方法
本发明的药物组合物包含安全有效量范围内的本发明脂质体组合物及药学上可接受的赋形剂或载体。其中,“安全有效量”指的是化合物的量足以明显改变病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的式:一种或多种相容性固体或液体填料或凝胶物质,他们适合于人使用,而且必须有足够的的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其亚生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热源水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物(例如其他抗病毒制剂)联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于治疗相关疾病。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明的主要优点:
1.本发明的瑞德西韦改性脂质体组合物,摒弃了磺丁基倍他环糊精钠,采用的主要辅料为生物相容性良好的脂质材料,更有利于药物的跨膜转运并加快药物起效时间,同时避免了大剂量的辅料直接进入体循环,降低了辅料的毒副作用。
2.本发明解决了瑞德西韦溶解性极差的问题(水溶解度约5.3μg/mL),采用基于改性脂质体材料的包载技术,制备得到的瑞德西韦改性脂质体组合物,最终制剂包封率达到85%以上,载药量达4%及以上,有利于提高患者依从性。
3.本发明的瑞德西韦改性脂质体冻干制剂复溶后在24h内冷藏/室温保持混悬状态不发生明显沉降,可以满足临床使用需求。
4.本发明在传统脂质体材料的基础上添加了稳定剂,使其不易渗漏,且具有超塑性和柔性,更易穿过生物膜,还可进一步增加其渗透性以及溶解度。
5.本发明可用于口服给药增加药物胃肠道吸收,眼局部给药时易于透过眼生理屏障,雾化吸入或注射给药进入体内后更易于到达组织深部,有利于提高药物的生物利用度从而提高其抗病毒效果。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、TPGS于茄形瓶中,加入5mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL进行水化,然后超声分散,形成含有脂质体组合物的混合物,经0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径127nm,多分散系数0.19,超滤法(分子量50K,20000×g,10min)测定包封率98.5%;高效液相色谱(HPLC)法测定药物浓度为3.5mg/ml。
实施例2
一种瑞德西韦改性脂质体组合物混悬液,其原料组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、TPGS于茄形瓶中,加入30mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液100mL进行水化,然后超声分散,形成含有脂质体组合物的混合物。经高压匀质800bar 3次,再经0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径195nm,多分散系数0.35,超滤法(分子量50K,20000×g,10min)测定包封率93.8%;HPLC法测定药物浓度为3.8mg/ml。
实施例3
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、聚氧乙烯(35)蓖麻油于茄形瓶中,加入3.2mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液7.3mL进行水化,然后超声分散,形成含有脂质体组合物的混合物。经0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体混悬液。激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径241nm,多分散系数0.11,超滤法(分子量50K,20000×g,10min)测定包封率88.9%;HPLC法测定药物浓度为3.5mg/ml。
实施例4
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、HS-15于茄形瓶中,加入2.2mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在45℃进行水化,然后通超声分散,形成含有脂质体组合物的混合物。经0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径159nm,多分散系数0.05,超滤法(分子量50K,20000×g,10min)测定包封率93.1%;HPLC法测定药物浓度为3.7mg/ml。
实施例5
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、胆固醇、聚氧乙烯(35)蓖麻油于茄形瓶中,加入2mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在45℃进行水化,然后超声分散,形成含有脂质体组合物的混合物。经100nm薄膜挤出机挤出,即得瑞德西韦改性脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径168nm,多分散系数0.20,超滤法(分子量50K,20000×g,10min)测定包封率91.5%;HPLC法测定药物浓度为3.7mg/ml。
实施例6
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、Lipoid S PC-3、聚氧乙烯(35)蓖麻油于茄形瓶中,加入3mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在55℃进行水化,然后超声分散,形成含有脂质体组合物的混合物,经200nm薄膜挤出机挤出,即得瑞德西韦改性脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径259nm,多分散系数0.28,超滤法(分子量50K,20000×g,10min)测定包封率86.0%;HPLC法测定药物浓度为3.5mg/ml。
实施例7
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、PC-98T、聚氧乙烯(35)蓖麻油于茄形瓶中,加入2mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在45℃进行水化,然后超声分散,形成含有脂质体组合物的混合物。经200nm薄膜挤出机挤出,即得瑞德西韦改性脂质体组合物混悬液。激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径247nm,多分散系数0.32,超滤法(分子量50K,20000×g,10min)测定包封率90.0%;HPLC法测定药物浓度为3.6mg/ml。
实施例8
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、聚氧乙烯(35)蓖麻油溶于茄形瓶中,加入30mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液100mL在45℃进行水化,然后超声分散,形成含有脂质体组合物的水合物。经高压匀质900bar 3次,再经0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体混悬液。激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径96nm,多分散系数0.29,超滤法(分子量50K,20000×g,10min)测定包封率93.0%;HPLC法测定药物浓度为3.7mg/ml。
实施例9
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、聚氧乙烯(35)蓖麻油于茄形瓶中,加入1.5mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在45℃进行水化,然后超声分散,形成脂质体,经0.45μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径167nm,多分散系数0.23,超滤法(分子量50K,20000×g,10min)测定包封率89.7%;HPLC法测定药物浓度为3.6mg/ml。
实施例10
一种瑞德西韦改性脂质体组合物混悬液,其处方组成如下:
制备工艺:称取卵磷脂、TPGS,加注射用水50ml,高剪切10000rpm×5min,16000rpm×5min。加入处方量瑞德西韦,然后45℃高剪切16000rpm×5min、超声,经高压匀质950bar5次,0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径296nm,多分散系数0.43,超滤法(分子量50K,20000×g,10min)测定包封率93.7%;HPLC法测定药物浓度为3.7mg/ml。
实施例11
瑞德西韦改性脂质体组合物的冻干制剂及其复溶
一种瑞德西韦改性脂质体组合物的冻干制剂,其原料组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、TPGS于茄形瓶中,加入30mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液100mL进行水化,然后超声分散,形成含有脂质体组合物的混合物。再加入处方量甘露醇,充分溶解,经高压匀质800bar 3次,再经0.2μm聚醚砜滤器过滤,即得瑞德西韦改性脂质体组合物混悬液(HPLC法测定药物浓度为3.6mg/ml),将其放入冷冻干燥机,a)预冻阶段:板层-45℃,保温10h;b)升华干燥:板层在1h逐渐升温至-40℃,真空度150mTor,保温15h;c)解析干燥:板层在6h内逐渐升温至-5℃,真空度150mTor,保温4h,即得注射用瑞德西韦。加注射用水复溶,复溶时间为25秒,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径246nm,多分散系数0.32,超滤法(分子量50K,20000×g,10min)测定包封率91.8%。
对比例C1
一种瑞德西韦脂质体组合物混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、胆固醇于茄形瓶中,加入5mL乙醇,超声使脂质体材料和药物完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在45℃进行水化,然后超声分散,形成含有脂质体组合物的混合物。经0.2μm聚醚砜滤器过滤,即得瑞德西韦脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径220nm,多分散系数0.03,超滤法(分子量50K,20000×g,10min)测定包封率77.6%;HPLC法测定药物浓度为3.1mg/ml。
对比例C2
一种瑞德西韦改性脂质体组合物混悬液,其原料组成如下:
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制备工艺:称取处方量瑞德西韦、卵磷脂、胆固醇于茄形瓶中,加入30mL无水乙醇,超声使上述物料完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液100mL进行水化,然后超声分散,形成含有脂质体组合物的混合物。经高压匀质800bar 3次,再经0.2μm聚醚砜滤器过滤,即得瑞德西韦脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径183nm,多分散系数0.10;超滤法(分子量50K,20000×g,10min)测定包封率82.7%;HPLC法测定药物浓度为1.2mg/ml。说明载药量明显低于前述实施例1~11的样品。
对比例C3
一种瑞德西韦脂质体混悬液,其处方组成如下:
制备工艺:称取处方量瑞德西韦、卵磷脂、吐温80于茄形瓶中,加入2mL乙醇,超声使脂质体材料和药物完全溶解,以减压蒸发的方式除去乙醇。加入磷酸盐缓冲液5mL在45℃进行水化,然后超声分散,形成含有脂质体组合物的混合物。经400nm薄膜挤出机挤出,0.2μm聚醚砜滤器过滤,即得瑞德西韦脂质体组合物混悬液,激光粒度仪(380ZLS,NICOMP)测定粒径,平均粒径147nm,多分散系数0.12;超滤法(分子量50K,20000×g,10min)测定包封率89.5%;HPLC法测定药物浓度为0.80mg/ml。说明载药量明显低于前述实施例1~11的样品。
性能测试例
在本实施例中,将实施例1~10和对比实施例C1制得的瑞德西韦脂质体组合物混悬液置于4℃±2℃冷藏保存放置后测定粒度分布、包封率、药物浓度,并与0天相比较。还考察了实施例11的瑞德西韦改性脂质体冻干制剂于加速条件(30℃±2℃,60%RH)放置后,复溶后测定粒度分布、包封率,并与0月相比较。
结果如下表1~2所示,可见,与对比实施例C1~C3所制得的普通脂质体组合物相比,实施例1~10所制得的瑞德西韦改性脂质体组合物粒径、包封率和药物浓度的稳定性更好。如表2所示,实施例11的瑞德西韦改性脂质体组合物的冻干制剂则于加速条件(30℃±2℃,65%RH±5%RH)放置6个月后,与0月相比,复溶后粒径和包封率均无明显变化,说明本申请方法制备的瑞德西韦改性脂质体组合物的稳定性良好。
表1瑞德西韦脂质体组合物混悬液置于冷藏(4℃±2℃)保存放置后各指标情况
表2瑞德西韦脂质体组合物的冻干制剂于加速(30℃±2℃,65%RH±5%RH)放置后各指标情况
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种瑞德西韦改性脂质体组合物,其特征在于,所述的组合物包括:
(i)活性成分,所述活性成分为式I所示的瑞德西韦或其药学上可接受的盐;
(ii)脂质体材料;和
(iii)稳定剂,所述的稳定剂选自下组:维生素E聚乙二醇琥珀酸酯、聚氧乙烯(35)蓖麻油、15-羟基硬脂酸聚乙二醇酯,或其组合;
其中,所述的活性成分与脂质体材料的质量比为(1±0.2):5~(1±0.2):20;
所述的活性成分与稳定剂的质量比为(1±0.2):0.5~(1±0.2):20;
按重量比计,所述的活性成分0.5%~10%;脂质体材料30%~74%;稳定剂为18%~65%。
2.如权利要求1所述的组合物,其特征在于,所述的活性成分与脂质体材料的重量比(1±0.2):5~(1±0.2):15。
3.如权利要求1所述的组合物,其特征在于,所述的活性成分与稳定剂的质量比为(1±0.2):0.5~(1±0.2):15。
4.如权利要求1所述的组合物,其特征在于,所述的瑞德西韦改性脂质体的粒度分布为90~300nm;多分散系数为0.01~0.50。
5.如权利要求1所述的组合物,其特征在于,所述的组合物中,所述的瑞德西韦或其药学上可接受的盐的载药量为0.5~10wt%;较佳地为3~8wt%。
6.如权利要求1所述的组合物,其特征在于,所述的组合物的pH为4~9。
7.如权利要求1所述的组合物,其特征在于,所述的脂质体材料选自下组:蛋黄卵磷脂、大豆磷脂、氢化磷脂酰胆碱、二棕榈酰磷脂酰胆碱、胆固醇,或其组合。
8.一种权利要求1所述的组合物的制备方法,其特征在于,包括如下步骤:
a)提供第一混合物,所述的第一混合物中含有权利要求1中所述的(i)、(ii)、(iii)、惰性溶剂以及任选地pH调节剂;
b)对所述的第一混合物进行处理,形成含有脂质体组合物的第二混合物;
c)对所述的第二混合物进行后处理,得到含有权利要求1所述的组合物的混悬液。
9.如权利要求8所述的方法,其特征在于,在步骤(b)中,所述的处理包括:
(Z1)减压蒸发去除所述第一混合物中的惰性溶剂,加入载体水化后,经超声分散形成含有脂质体组合物的第二混合物;和/或
(Z2)对所述的第一混合物进行高速剪切,形成含有脂质体组合物的第二混合物。
10.一种如权利要求1所述的瑞德西韦改性脂质体组合物的冻干制剂的制备方法,其特征在于,冻干过程包括以下步骤:
(d)预冻阶段:将权利要求8-9获得的所述瑞德西韦改性脂质体组合物混悬液分装于制剂瓶中,并置于-55~-30℃,保温2~12h;
(e)升华阶段:在1h内逐渐升温至-50~-25℃,真空度为50~200mTor,保温4~20h;
(f)解析干燥:在6h内逐渐升温至-20~5℃,真空度为50~200mTor,保温1~6h,即得到所述瑞德西韦改性脂质体组合物的冻干制剂。
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