CN116763718A - 一种紫杉醇纳米晶温敏凝胶及其制备方法和其应用 - Google Patents
一种紫杉醇纳米晶温敏凝胶及其制备方法和其应用 Download PDFInfo
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- CN116763718A CN116763718A CN202310470573.XA CN202310470573A CN116763718A CN 116763718 A CN116763718 A CN 116763718A CN 202310470573 A CN202310470573 A CN 202310470573A CN 116763718 A CN116763718 A CN 116763718A
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Abstract
本发明涉及一种紫杉醇纳米晶温敏凝胶,以重量百分比计,所述的温敏凝胶中含有1‑30%的紫杉醇纳米晶混悬液、1‑30%的凝胶基质和0.1‑10%的生物粘附剂,其中,所述凝胶基质选自泊洛沙姆、聚N-异丙基丙烯酰胺、壳聚糖、β‑甘油磷酸钠、甲基纤维素、羟丙甲纤维素、PLGA‑PEG‑PLGA中的任一种或其组合,所述生物粘附剂选自甲基纤维素、羟丙甲纤维素、卡波姆、羧甲纤维素、明胶的任一种或其组合,紫杉醇纳米晶温敏凝胶的粘附力≥800gf*sec,紫杉醇纳米晶温敏凝胶的凝胶强度≥180g*cm。本发明的紫杉醇纳米晶温敏凝胶用于肿瘤术后局部靶向治疗,具有凝胶粘弹性更好、长效缓释、靶向治疗、安全有效等优点,有效降低肿瘤复发及转移风险。
Description
技术领域
本发明属于医药技术领域,具体涉及一种紫杉醇纳米晶温敏凝胶及其制备方法和其应用。
背景技术
恶性肿瘤成为威胁人类生命健康的严重疾病,其发病率呈现逐年增高趋势。全球癌症数据库2020年度报告显示,全球2020年新发癌症病例1929万例,死亡996万例。中国新发癌症病例457万例,死亡300万例,中国新发癌症人数位居全球第一。肿瘤切除手术业已成为多数早期或中期局部原发性肿瘤的首选治疗方法,并在一定程度上解除癌症患者遭受癌症带来的痛苦,但法用于体内深部肿瘤及扩散肿瘤,且存在肿瘤术后残留以及残留的肿瘤细胞/组织的恶化、复发、转移等技术难题。肿瘤根治术后的肿瘤转移是肿瘤治疗中的关键性难题。患者术后通常需要接受化疗和/或放疗,但放疗和化疗存在选择性低、副作用大、大剂量致死、呕吐、恶心等严重不良反应。
紫杉醇注射液(PTX)聚氧乙烯蓖麻油和无水乙醇制备而成,并被临床广泛用于治疗乳腺癌、卵巢癌、头癌、颈部癌、肺癌等病症。但聚氧乙烯蓖麻油易引起严重的过敏反应,需在给药前给予患者抗过敏预处理(如患者被动接受大剂量激素)而出现不良反应。白蛋白结合的紫杉醇注射液无须抗过敏治疗,但存在感觉神经病变发生率较高风险,并增加了患者治疗的经济负担和国家医保负担。为此,亟需开发安全有效、有效防止术后局部肿瘤复发及转移的抗肿瘤药物,以满足临床需求。
发明内容
本发明的目的在于提供一种紫杉醇纳米晶温敏凝胶,以重量百分比计,所述的温敏凝胶中含有1-30%的紫杉醇纳米晶混悬液、1-30%的凝胶基质和0.1-10%的生物粘附剂,其中,所述凝胶基质选自泊洛沙姆、聚N-异丙基丙烯酰胺、壳聚糖、β-甘油磷酸钠、甲基纤维素、羟丙甲纤维素、PLGA-PEG-PLGA中的任一种或其组合,所述生物粘附剂选自甲基纤维素、羟丙甲纤维素、卡波姆、羧甲纤维素、明胶的任一种或其组合,紫杉醇纳米晶温敏凝胶的粘附力≥800gf*sec,紫杉醇纳米晶温敏凝胶的凝胶强度≥180g*cm。
本发明的优选技术方案中,以重量百分比计,所述的紫杉醇纳米晶混悬液中含有紫杉醇1-10%、空间保护剂0.1-1%、电荷稳定剂0.1-1%和分散介质,其中,所述的空间保护剂选自HPMC E5、HPMC E3、HPMC E6、HPMC E4M、HPMC K4M、泊洛沙姆188、泊洛沙姆407、聚乙烯吡咯烷酮PVP K12、PVP K17、PVP K30、PVA、吐温80、吐温20、羧甲基纤维素钠、甘油、癸基葡糖苷、聚乙二醇琥珀酸盐(TPGS)的任一种或其组合,所述电荷稳定剂选自十二烷基硫酸钠(SDS)、多库酯钠、卵磷脂、大豆磷脂的任一种或其组合,所述分散介质选自水、聚乙二醇、甘油、大豆油、玉米油、茶油、棉籽油的任一种或其组合。
本发明的优选技术方案中,所述紫杉醇纳米晶的粒径≤500nm,优选≤400nm,更优选≤350nm。
本发明的优选技术方案中,以重量百分比计,紫杉醇纳米晶混悬液中含有紫杉醇1-10%、TPGS 0.1-1%和SDS 0.1-1%,分散介质为水。
本发明的优选技术方案中,以重量百分比计,紫杉醇纳米晶混悬液中含有1-5.0%的紫杉醇、0.2-0.5%的TPGS、0.2-0.5%的SDS,分散介质为水。
本发明的优选技术方案中,以重量百分比计,紫杉醇纳米晶混悬液中含有5.0%的紫杉醇、0.2%的TPGS、0.2%的SDS,分散介质为水。
本发明的优选技术方案中,以重量百分比计,温敏凝胶中含有10-20%的紫杉醇纳米晶混悬液、1-10%的壳聚糖、5-10%的β-甘油磷酸钠和0.1-0.5%的明胶。
本发明的优选技术方案中,以重量百分比计,温敏凝胶中含有20%的紫杉醇纳米晶混悬液、1.8%的壳聚糖、10%的β-甘油磷酸钠和0.4%的明胶。
本发明的优选技术方案中,壳聚糖的脱乙酰度不低于90%,优选不低于95%。
本发明的优选技术方案中,所述的温敏凝胶中任选地含有其他药学上可接受的载体。
本发明的优选技术方案中,所述的其他药学上可接受的载体任选地含有pH调节剂、防腐剂、分散介质的任一种或其组合。
本发明的优选技术方案中,所述pH调节剂选自盐酸、硫酸、硝酸、山梨酸、醋酸、草酸、琥珀酸、甲酸、乙酸、丁酸、丙二酸、丁二酸、己二酸、丙酮酸、谷氨酸、衣康酸、抗坏血酸、延胡索酸、α-酮戊二酸、果酸、氢氧化钠、氢氧化钾、氢氧化铵、碳酸钠、碳酸钾、碳酸氢钠、磷酸氢二钾、磷酸二氢钾、磷酸氢二胺、磷酸二氢胺、柠檬酸、柠檬酸钾、柠檬酸钠、苹果酸、苹果酸钠、苹果酸钾、磷酸、磷酸氢二钠、磷酸二氢钠、单乙醇胺、二乙醇胺、三乙醇胺、乳酸、乳酸钠、乳酸钾、丙酸、丙酸钠、丙酸钾、酒石酸、酒石酸钠、酒石酸钾、富马酸钠、富马酸钾、富马酸的任一种或其组合。
本发明的优选技术方案中,所述防腐剂选自苯氧乙醇、尼泊金甲酯丙酯、甲基异噻唑啉酮、羟苯甲酯、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲酸、苯甲酸钠、苯甲酸钾、山梨酸、山梨酸钾、山梨酸钠、对羟苯甲酸酯、焦亚硫酸钠、氯己定、柠檬酸、柠檬酸钠、柠檬酸钾、丁基羟基甲苯(BHT)、丁基羟基苯甲醚(BHA)、生育酚、乙二胺四乙酸、没食子酸丙酯、季铵化合物中的任一种或其组合。
本发明的优选技术方案中,所述分散介质选自水、聚乙二醇、甘油、大豆油、玉米油、茶油、棉籽油的任一种或其组合。
本发明的优选技术方案中,所述紫杉醇纳米晶温敏凝胶的粘附力≥850gf*sec。
本发明的优选技术方案中,所述紫杉醇纳米晶温敏凝胶的凝胶强度≥200g*cm。
本发明的优选技术方案中,所述紫杉醇纳米晶温敏凝胶pH6-8,优选为pH6.5-7.5。
本发明的目的在于提供一种纳米晶温敏凝胶的制备方法,以重量百分比计,所述的温敏凝胶中含有1-30%的紫杉醇纳米晶混悬液、1-30%的凝胶基质和0.1-10%的生物粘附剂,其中,所述凝胶基质选自泊洛沙姆、聚N-异丙基丙烯酰胺、壳聚糖、β-甘油磷酸钠、甲基纤维素、羟丙甲纤维素、PLGA-PEG-PLGA中的任一种或其组合,所述生物粘附剂选自甲基纤维素、羟丙甲纤维素、卡波姆、羧甲纤维素、明胶的任一种或其组合,紫杉醇纳米晶温敏凝胶的粘附力≥800gf*sec,紫杉醇纳米晶温敏凝胶的凝胶强度≥180g*cm,所述温敏凝胶的制备包括下述步骤:
1)在所需量的壳聚糖中加入所需量的分散介质,将其置于2-8℃溶胀,制得壳聚糖溶液;
2)将明胶:水按照2:8-10混合溶胀,制得明胶溶液,再按照明胶溶液:紫杉醇纳米晶混悬液的体积比为1:10-12缓慢加入紫杉醇纳米晶混悬液,均匀混合,制得紫杉醇纳米晶明胶混悬液;
3)在所需量的凝胶基质中加入所需量的分散介质,将其置于2-8℃溶胀,制得凝胶基质溶液;
4)在搅拌条件下,将制得的凝胶基质溶液和壳聚糖溶液,混合均匀后,再将紫杉醇纳米晶明胶混悬液逐步滴加入,调节pH6.5-7.5,即得。
本发明的优选技术方案中,以重量百分比计,所述的紫杉醇纳米晶混悬液中含有紫杉醇1-10%、空间保护剂0.1-1%、电荷稳定剂0.1-1%和分散介质,其中,所述的空间保护剂选自HPMC E5、HPMC E3、HPMC E6、HPMC E4M、HPMC K4M、泊洛沙姆188、泊洛沙姆407、聚乙烯吡咯烷酮PVP K12、PVP K17、PVP K30、PVA、吐温80、吐温20、羧甲基纤维素钠、甘油、癸基葡糖苷、聚乙二醇琥珀酸盐(TPGS)的任一种或其组合,所述电荷稳定剂选自十二烷基硫酸钠(SDS)、多库酯钠、卵磷脂、大豆磷脂的任一种或其组合,所述分散介质选自水、聚乙二醇、甘油、大豆油、玉米油、茶油、棉籽油的任一种或其组合。
本发明的优选技术方案中,所述紫杉醇纳米晶的粒径≤500nm,优选≤400nm,更优选≤350nm。
本发明的优选技术方案中,以重量百分比计,紫杉醇纳米晶混悬液中含有紫杉醇1-10%、TPGS 0.1-1%和SDS 0.1-1%,分散介质为水。
本发明的优选技术方案中,以重量百分比计,紫杉醇纳米晶混悬液中含有1-5.0%的紫杉醇、0.2-0.5%的TPGS、0.2-0.5%的SDS,分散介质为水。
本发明的优选技术方案中,以重量百分比计,紫杉醇纳米晶混悬液中含有5.0%的紫杉醇、0.2%的TPGS、0.2%的SDS,分散介质为水。
本发明的优选技术方案中,以重量百分比计,温敏凝胶中含有10-20%的紫杉醇纳米晶混悬液、1-10%的壳聚糖、5-10%的β-甘油磷酸钠和0.1-0.5%的明胶。
本发明的优选技术方案中,以重量百分比计,温敏凝胶中含有20%的紫杉醇纳米晶混悬液、1.8%的壳聚糖、10%的β-甘油磷酸钠和0.4%的明胶。
本发明的优选技术方案中,壳聚糖的脱乙酰度不低于90%,优选不低于95%。
本发明的优选技术方案中,所述紫杉醇纳米晶混悬液的制备包括下述步骤:称取所需量的紫杉醇、空间保护剂、电荷稳定剂和分散介质,将其均匀混合后,经超声均质、湿法研磨或高压均质的任一种或其组合,即得。
本发明的优选技术方案中,所述超声均质或高压均质的转速为10000-28000rpm,优选为13000-25000rpm,更优选为16000-22000rpm。
本发明的优选技术方案中,所述湿法研磨的初始研磨速度为800-2500rpm,优选为1000-2000rpm,更优选为1200-1800rpm。
本发明的优选技术方案中,湿法研磨的研磨速度增幅为100-1000rpm/min,优选为300-800rpm/min,更优选为500-700rpm/min。
本发明的优选技术方案中,湿法研磨的研磨速度为1500-4000rpm/min,优选为1800-3500rpm/min,更优选为2000-3000rpm/min。
本发明的优选技术方案中,所述均质或研磨时间为20min-72h,优选为40min-180min,更优选为60-150min。
本发明的优选技术方案中,所述的温敏凝胶中任选地含有其他药学上可接受的载体。
本发明的优选技术方案中,所述的其他药学上可接受的载体任选地含有pH调节剂、防腐剂、分散介质的任一种或其组合。
本发明的优选技术方案中,所述pH调节剂选自盐酸、硫酸、硝酸、山梨酸、醋酸、草酸、琥珀酸、甲酸、乙酸、丁酸、丙二酸、丁二酸、己二酸、丙酮酸、谷氨酸、衣康酸、抗坏血酸、延胡索酸、α-酮戊二酸、果酸、氢氧化钠、氢氧化钾、氢氧化铵、碳酸钠、碳酸钾、碳酸氢钠、磷酸氢二钾、磷酸二氢钾、磷酸氢二胺、磷酸二氢胺、柠檬酸、柠檬酸钾、柠檬酸钠、苹果酸、苹果酸钠、苹果酸钾、磷酸、磷酸氢二钠、磷酸二氢钠、单乙醇胺、二乙醇胺、三乙醇胺、乳酸、乳酸钠、乳酸钾、丙酸、丙酸钠、丙酸钾、酒石酸、酒石酸钠、酒石酸钾、富马酸钠、富马酸钾、富马酸的任一种或其组合。
本发明的优选技术方案中,所述防腐剂选自苯氧乙醇、尼泊金甲酯丙酯、甲基异噻唑啉酮、羟苯甲酯、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲酸、苯甲酸钠、苯甲酸钾、山梨酸、山梨酸钾、山梨酸钠、对羟苯甲酸酯、焦亚硫酸钠、氯己定、柠檬酸、柠檬酸钠、柠檬酸钾、丁基羟基甲苯(BHT)、丁基羟基苯甲醚(BHA)、生育酚、乙二胺四乙酸、没食子酸丙酯、季铵化合物中的任一种或其组合。
本发明的优选技术方案中,所述分散介质选自水、聚乙二醇、甘油、大豆油、玉米油、茶油、棉籽油的任一种或其组合。
本发明的优选技术方案中,所述紫杉醇纳米晶温敏凝胶的粘附力≥850gf*sec。
本发明的优选技术方案中,所述紫杉醇纳米晶温敏凝胶的凝胶强度≥200g*cm。
本发明的优选技术方案中,所述紫杉醇纳米晶温敏凝胶pH6-8,优选为pH6.5-7.5。
本发明的另一目的在于提供紫杉醇纳米晶或紫杉醇纳米晶温敏凝胶用于制备肿瘤术后局部靶向治疗或抑制肿瘤复发和/或肿瘤转移的药物中的应用。
本发明的优选技术方案中,所述肿瘤选自乳腺癌、卵巢癌、头癌、颈部癌、肺癌中的任一种或其并发症。
本发明的粒径、电位、多分散系数(PDI)的检测仪器为英国Malvern公司(Nano-ES90);采用透射电子显微镜(日本HitachiH-7650)检测纳米晶的形貌及粒径分布;球磨机为瑞士华尔宝机械有限公司的WAB AK71M-2WKF;高速剪切机(FM200A,FLUKO,德国);溶出仪为天大天发科技有限公司的ZRS-8G;超声乳化均质机为上海恒川机械有限公司的C25。
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
与现有技术相比,本发明具有下述有益的技术效果:
1、本发明科学筛选紫杉醇纳米晶及其温敏凝胶的组分及配比,制得的紫杉醇纳米晶粒径及粒径分布更优,温敏凝胶的粘附力和凝胶强度更利于局部靶向涂覆于术后伤口、凝胶的网状结构及高空隙率更利于载药、靶向长效缓释的凝胶制剂。本发明的温敏凝胶用于肿瘤术后部位的局部靶向给药,具有显著降低术后肿瘤复发或转移以及延长术后肿瘤复发或转移的时长等意想不到的技术效果,显著降低肿瘤术后患者的给药频率和注射痛苦及不良反应发生风险,并具有涂覆用药方便、患者用药依从性好、显著降低患者用药负担等优点,保障临床用药的安全有效性和经济性,让患者直接治疗获益。
2、本发明的制备方法具有操作简便、产率高、成本更优、适合工业化生产等优点。
附图说明
图1本发明紫杉醇纳米晶温敏凝胶的形貌观察;
图2本发明紫杉醇纳米晶温敏凝胶的粘附力和凝胶强度研究;
图3本发明紫杉醇纳米晶温敏凝胶的体外释放研究。
具体实施方式
以下对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
实施例1紫杉醇纳米晶温敏凝胶的制备
紫杉醇纳米晶及其温敏凝胶的组成:
温敏凝胶的制备包括下述步骤:
1、紫杉醇纳米晶混悬液的制备
1)称取0.2gTPGS和0.2gSDS,将其均匀混合后加入94.6g水中,再加入5g紫杉醇,3000rpm下高速剪切1min,制得紫杉醇剪切液;
2)将步骤1)制得的紫杉醇剪切液置于填充氧化锆珠(65%)的球磨机中湿法研磨,在1500rpm条件下球磨5min,2000rpm条件下球磨5min,2500rpm条件下球磨5min,3000rpm条件下球磨40min,制得紫杉醇纳米晶混悬液。
按照本发明的方法检测制得的紫杉醇纳米晶混悬液,紫杉醇纳米晶的粒径为314.6.5±1.05nm,pdI为0.342,Zeta电位为-25.5mv;
2、紫杉醇纳米晶温敏凝胶的制备
1)称取0.9g壳聚糖,将其溶胀于10ml水,制得壳聚糖溶液;
2)称取5gβ-甘油磷酸钠,在搅拌条件下,将其溶解于23ml水,制得β-甘油磷酸钠溶液,再将步骤1)制得的壳聚糖溶液与制得的β-甘油磷酸钠溶液均匀混合,制得壳聚糖β-甘油磷酸钠溶液;
3)在搅拌条件下,将0.2g明胶溶胀于0.9ml水,制得明胶溶液,再缓慢加入10g紫杉醇纳米晶混悬液,均匀混合,制得紫杉醇纳米晶明胶混悬液;
4)在搅拌条件下,将制得的紫杉醇纳米晶明胶混悬液逐步滴加入制得的壳聚糖β-甘油磷酸钠溶液,混合均匀后,以0.2mol/L NaOH溶液调节混合液pH6.5-7.5,即得。
紫杉醇纳米晶温敏凝胶置于37℃,呈半固体凝胶。
实施例2紫杉醇纳米晶温敏凝胶的制备
紫杉醇纳米晶及其温敏凝胶的组成:
温敏凝胶的制备包括下述步骤:
1、紫杉醇纳米晶混悬液的制备
1)称取1gTPGS和1gSDS,将其均匀混合后加入88g水中,再加入10g紫杉醇,3000rpm下高速剪切1分钟,制得紫杉醇剪切液;
2)将步骤1)制得的紫杉醇剪切液置于填充氧化锆珠(65%)的球磨机中湿法研磨,在1500rpm条件下球磨5min,2000rpm条件下球磨5min,2500rpm条件下球磨5min,3000rpm条件下球磨40min,制得紫杉醇纳米晶混悬液;
3)按照本发明所述的方法检测制得的紫杉醇纳米晶混悬液;
2、紫杉醇纳米晶温敏凝胶的制备
1)称取0.5g壳聚糖,将其溶胀于10ml水,制得壳聚糖溶液;
2)称取2.5gβ-甘油磷酸钠,在搅拌条件下,将其溶解于25.6ml水,制得β-甘油磷酸钠溶液;再将步骤1)制得的壳聚糖溶液与制得的β-甘油磷酸钠溶液均匀混合,制得壳聚糖β-甘油磷酸钠溶液;
3)在搅拌条件下,将0.5g明胶溶胀于0.9ml水,制得明胶溶液,再缓慢加入10g紫杉醇纳米晶混悬液,均匀混合,制得紫杉醇纳米晶明胶混悬液;
4)在搅拌条件下,将制得的紫杉醇纳米晶明胶混悬液逐步滴加入制得的壳聚糖β-甘油磷酸钠溶液,混合均匀后,以0.2mol/L NaOH溶液调节混合液pH6.5-7.5,即得;
紫杉醇纳米晶温敏凝胶置于37℃呈半固体凝胶。
实施例3紫杉醇纳米晶温敏凝胶的制备
紫杉醇纳米晶及其温敏凝胶的组成:
温敏凝胶的制备包括下述步骤:
1、紫杉醇纳米晶混悬液的制备
1)称取0.2gTPGS和0.2gSDS,将其均匀混合后加入98.8g水中,再加入1g紫杉醇,3000rpm下高速剪切1分钟,制得紫杉醇剪切液;
2)将步骤1)制得的紫杉醇剪切液置于填充氧化锆珠(65%)的球磨机中湿法研磨,在1500rpm条件下球磨5min,2000rpm条件下球磨5min,2500rpm条件下球磨5min,3000rpm条件下球磨40min,制得紫杉醇纳米晶混悬液;
3)按照本发明所述的方法检测制得的紫杉醇纳米晶混悬液;
2、紫杉醇纳米晶温敏凝胶的制备
1)称取5g壳聚糖,将其溶胀于9ml水,制得壳聚糖溶液;
2)称取5gβ-甘油磷酸钠,在搅拌条件下,将其溶解于20ml水,制得β-甘油磷酸钠溶液;再将步骤1)制得的壳聚糖溶液与制得的β-甘油磷酸钠溶液均匀混合,制得壳聚糖β-甘油磷酸钠溶液;
3)在搅拌条件下,将0.25g明胶溶胀于0.75ml水,制得明胶溶液,再缓慢加入10g紫杉醇纳米晶混悬液,均匀混合,制得紫杉醇纳米晶明胶混悬液;
4)在搅拌条件下,将制得的紫杉醇纳米晶明胶混悬液逐步滴加入制得的壳聚糖β-甘油磷酸钠溶液,混合均匀后,以0.2mol/L NaOH溶液调节混合液pH6.5-7,5,即得;
紫杉醇纳米晶温敏凝胶置于37℃呈半固体凝胶。
对比例1紫杉醇纳米晶温敏凝胶的制备
紫杉醇纳米晶及其温敏凝胶的组成:
温敏凝胶的制备包括下述步骤:
1、紫杉醇纳米晶混悬液的制备
1)称取1g PVP K30和0.5gSDS,将其加入93.5g水中,再加入5g紫杉醇,3000rpm下高速剪切1分钟,制得剪切混合液;
2)将步骤1)制得的剪切混合溶液置于填充氧化锆珠(65%)的球磨机中湿法研磨,在1500rpm条件下球磨5min,2000rpm条件下球磨5min,2500rpm条件下球磨5min,3000rpm条件下球磨40min,制得紫杉醇纳米晶混悬液;
3)按照本发明所述的方法检测制得的紫杉醇纳米晶混悬液;检测制得的紫杉醇纳米晶的粒径为361.5±1.15nm,pdI为0.135,Zeta电位为-32.5mv;
2、紫杉醇纳米晶温敏凝胶的制备
1)称取0.15g卡波姆974P,将其置于水中,再将其置于4℃溶胀,再加入所需量的泊洛沙姆407、泊洛沙姆188后,再将其置于4℃至溶胀完全;
2)加入步骤1)制得的紫杉醇纳米晶混悬液10g,混合均匀,即得,紫杉醇纳米晶温敏凝胶置于37℃呈半固体凝胶。
对比例2紫杉醇凝胶的制备
称取0.15g卡波姆974P,将其置于16.65g水中,再将其置于4℃溶胀,再加入9.5g的泊洛沙姆407、2g的泊洛沙姆188后,再将其置于4℃至溶胀完全,加入紫杉醇28.3mg,混合均匀,将其置于37℃下,即得。
对比例3空白凝胶的制备
称取0.15g卡波姆974P,将其置于16.65g水中,再将其置于4℃溶胀,再加入9.5g的泊洛沙姆407、2g的泊洛沙姆188后,再将其置于4℃至溶胀完全,混合均匀,即得。
试验例1本发明紫杉醇纳米晶凝胶的形貌研究
取实施例1和对比例1的紫杉醇纳米晶凝胶10ul,喷金处理,利用场发射扫描电镜(SEM)观察凝胶形貌,结果见图1。
与对比例1的紫杉醇温敏凝胶,实施例1的紫杉醇温敏凝胶呈现规律的三维网状结构,网状结构的孔径更大且孔隙率更高,具有更优的药物包载特性和长效缓释性能。
试验例2本发明紫杉醇纳米晶凝胶的粘附力考察
将实施例1和对比例1的紫杉醇纳米晶凝胶2g,采用质构仪检测其粘附性和凝胶强度。结果见图2。
实施例1紫杉醇纳米晶凝胶的粘附力(890.325gf*sec)和凝胶强度(201.26g*cm)均显著优于对比例1的粘附力(770.55gf*sec)和凝胶强度(164.25g*cm),利于术后局部涂覆靶向给药和长效缓释,显著降低术后局部肿瘤复发及转移。
试验例3本发明紫杉醇纳米晶温敏凝胶的体外释放实验
将1g的实施例1和对比例1的紫杉醇纳米晶凝胶分别置于10mL小瓶中,记录瓶子加凝胶的总重量。将装有凝胶的小瓶置于平衡恒温振荡器(37℃水浴)振荡20min。加入5mL预热至37℃的PBS(pH 7.4)作为释放介质,并将恒温振荡器设置为100rpm。每隔30分钟,取样,采用高效液相色谱法(HPLC)测定释放的紫杉醇含量,并用5mL新鲜PBS介质替换,记录小瓶和剩余水凝胶的总重量(WT)。构建凝胶释放曲线。结果见图3。
累积释放率(M):M=(W0-WT)/Wg×100%。
结果表明,实施例1紫杉醇纳米晶温敏凝胶具有显著优于对比例1的长效释放的优点,利于术后局部涂覆靶向给药和长效缓释,显著降低术后局部肿瘤复发及转移。
试验例4本发明紫杉醇纳米晶温敏凝胶抑制肿瘤术后局部肿瘤复发作用研究
用荧光素酶标记4T1-luc细胞,再将标记的4T1-luc细胞(1×106)皮下接种于雌性BALB/c小鼠(体重约14g)背部,接种5天后观察小鼠背部肿瘤块形成。当肿瘤体积达到约100mm3时,则试验小鼠造模成功。第9天手术切除肿瘤(肿瘤残留约10%)后,立即给予药物治疗。
将造模成功42只的雌性BALB/c试验小鼠随机分为7组,6只/组。空白组:将对比例3的空白凝胶涂覆在肿瘤切除后的残余组织上或周围;对照组1:将对比例2的紫杉醇凝胶涂覆在肿瘤切除后的残余组织上或周围,给药剂量20mg/kg(以紫杉醇计);对照组2:将PBS涂覆在肿瘤切除后的残余组织上或周围;对照组3:将紫杉醇注射液在第7天和第14天各静脉注射1次,给药剂量20mg/kg(以紫杉醇计);对照组4:紫杉醇溶液涂覆在肿瘤切除后的残余组织上或周围,给药剂量20mg/kg(以紫杉醇计);对照组5:将对比例1的紫杉醇纳米晶凝胶涂覆在肿瘤切除后的残余组织上或周围,给药剂量20mg/kg(以紫杉醇计);试验组:将实施例1的紫杉醇纳米晶凝胶涂覆在肿瘤切除后的残余组织上或周围,给药剂量20mg/kg(以紫杉醇计)。
检测肿瘤体积大小,当肿瘤体积超过50mm3时,证实肿瘤复发。
结果表明,从第9天开始,空白组、对照组1-4的肿瘤体积均逐步增长态势,第30天肿瘤体积均超过300nm,而对照组5和试验组的肿瘤体积基本检测不到,有效抑制了肿瘤复发。对照组5自30天之后开始检测到肿瘤体积增大,呈现肿瘤复发;而试验组具有显著的长效缓释,仅自第37天起呈现肿瘤复发,明显延长了肿瘤复发时间间隔。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (10)
1.一种紫杉醇纳米晶温敏凝胶,以重量百分比计,所述的温敏凝胶中含有1-30%的紫杉醇纳米晶混悬液、1-30%的凝胶基质和0.1-10%的生物粘附剂,其中,所述凝胶基质选自泊洛沙姆、聚N-异丙基丙烯酰胺、壳聚糖、β-甘油磷酸钠、甲基纤维素、羟丙甲纤维素、PLGA-PEG-PLGA中的任一种或其组合,所述生物粘附剂选自甲基纤维素、羟丙甲纤维素、卡波姆、羧甲纤维素、明胶的任一种或其组合,紫杉醇纳米晶温敏凝胶的粘附力≥800gf*sec,紫杉醇纳米晶温敏凝胶的凝胶强度≥180g*cm。
2.如权利要求1所述的温敏凝胶,以重量百分比计,所述的紫杉醇纳米晶混悬液中含有紫杉醇1-10%、空间保护剂0.1-1%、电荷稳定剂0.1-1%和分散介质,其中,所述的空间保护剂选自HPMC E5、HPMC E3、HPMC E6、HPMC E4M、HPMC K4M、泊洛沙姆188、泊洛沙姆407、聚乙烯吡咯烷酮PVP K12、PVP K17、PVP K30、PVA、吐温80、吐温20、羧甲基纤维素钠、甘油、癸基葡糖苷、聚乙二醇琥珀酸盐(TPGS)的任一种或其组合,所述电荷稳定剂选自十二烷基硫酸钠(SDS)、多库酯钠、卵磷脂、大豆磷脂的任一种或其组合,所述分散介质选自水、聚乙二醇、甘油、大豆油、玉米油、茶油、棉籽油的任一种或其组合。
3.如权利要求1-2任一项所述的温敏凝胶,所述紫杉醇纳米晶的粒径≤500nm,优选≤400nm,更优选≤350nm。
4.如权利要求1-3任一项所述的温敏凝胶,以重量百分比计,紫杉醇纳米晶混悬液中含有紫杉醇1-10%、TPGS 0.1-1%和SDS 0.1-1%,分散介质为水。
5.如权利要求1-4任一项所述的温敏凝胶,以重量百分比计,温敏凝胶中含有10-20%的紫杉醇纳米晶混悬液、1-10%的壳聚糖、5-10%的β-甘油磷酸钠和0.1-0.5%的明胶。
6.如权利要求1-5任一项所述的温敏凝胶,所述的温敏凝胶中任选地含有其他药学上可接受的载体,优选地,所述的其他药学上可接受的载体任选地含有pH调节剂、防腐剂、分散介质的任一种或其组合。
7.如权利要求1-6任一项所述的纳米晶温敏凝胶的制备方法,以重量百分比计,所述的温敏凝胶中含有1-30%的紫杉醇纳米晶混悬液、1-30%的凝胶基质和0.1-10%的生物粘附剂,其中,所述凝胶基质选自泊洛沙姆、聚N-异丙基丙烯酰胺、壳聚糖、β-甘油磷酸钠、甲基纤维素、羟丙甲纤维素、PLGA-PEG-PLGA中的任一种或其组合,所述生物粘附剂选自甲基纤维素、羟丙甲纤维素、卡波姆、羧甲纤维素、明胶的任一种或其组合,紫杉醇纳米晶温敏凝胶的粘附力≥800gf*sec,紫杉醇纳米晶温敏凝胶的凝胶强度≥180g*cm,所述温敏凝胶的制备包括下述步骤:
1)在所需量的壳聚糖中加入所需量的分散介质,将其置于2-8℃溶胀,
制得壳聚糖溶液;
2)将明胶:水按照2:8-10混合溶胀,制得明胶溶液,再按照明胶溶液:
紫杉醇纳米晶混悬液的体积比为1:10-12缓慢加入紫杉醇纳米晶混悬液,均匀混合,制得紫杉醇纳米晶明胶混悬液;
3)在所需量的凝胶基质中加入所需量的分散介质,将其置于2-8℃溶胀,制得凝胶基质溶液;
4)在搅拌条件下,将制得的凝胶基质溶液和壳聚糖溶液,混合均匀后,再将紫杉醇纳米晶明胶混悬液逐步滴加入,调节pH6.5-7.5,即得。
8.如权利要求7所述的制备方法,所述紫杉醇纳米晶混悬液的制备包括下述步骤:称取所需量的紫杉醇、空间保护剂、电荷稳定剂和分散介质,将其均匀混合后,经超声均质、湿法研磨或高压均质的任一种或其组合,即得。
9.如权利要求7-8任一项所述的制备方法,湿法研磨的研磨速度为1500-4000rpm/min,优选为1800-3500rpm/min,更优选为2000-3000rpm/min。
10.如权利要求1-6任一项所述的紫杉醇纳米晶或紫杉醇纳米晶温敏凝胶用于制备肿瘤术后局部靶向治疗或抑制肿瘤复发和/或肿瘤转移的药物中的应用。
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