CN113288873A - 一种喜树碱类似物固体分散体及其制备方法和应用 - Google Patents
一种喜树碱类似物固体分散体及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种喜树碱类似物固体分散体及其制备方法和应用,所述喜树碱类似物固体分散体由喜树碱类似物(I)、水溶性载体和功能性辅料制成,可采用旋转蒸发法、喷雾干燥法、热熔挤出法中的任意一种方法进行制备;经检测,喜树碱类似物由原晶型转变成无定型分散存在于固体分散体中,本发明制得的喜树碱类似物固体分散体解决了喜树碱类似物水溶性差的问题,提高了喜树碱类似物的生物利用度;
Description
技术领域
本发明涉及一种喜树碱类似物固体分散体及其制备方法和应用。
背景技术
全球上市药品中的40%属于难溶性药物,而处于研发阶段的难溶性候选药物占比更是高达90%。因此,增加难溶性药物的溶解度与溶出速度、进而提高其口服生物利用度已经成为药学领域最活跃的研究方向之一。难溶性药物经过口服使用后,在胃肠液中的溶出度较小、溶出的速率慢,吸收不完全导致生物利用度低,药物疗效发挥受到影响。
式(I)所示FL118是一种类似于喜树碱的半合成化合物,分子结构式为10,11-亚甲二氧基喜树碱,是美国研究者利用Survivin高通量筛选技术发现的一种小分子抗癌药,Survivin是凋亡抑制蛋白家族的新成员,主要调节细胞分裂和抑制细胞凋亡,其对肿瘤具有特异性,只表达于肿瘤和胚胎组织,并且与肿瘤细胞的分化增殖及浸润转移密切相关。前期研究已发现FL118对于人头颈癌(FaDu)、人结肠癌(SW620)和人肺癌(EKVX)等均有良好的抑制作用,能作用于产生耐药机制的多个靶点,能抑制多种抗凋亡蛋白;对多种耐药的肿瘤细胞的抑制效果明显高于其他抗癌药物,体内动物试验中的抗肿瘤效果也优于目前的临床药物,且在动物体内也体现较弱毒性,是非常有前景的候选化合物。
FL118为白色至淡黄色粉末,微溶于二氯甲烷、氯仿、乙腈、甲醇,不溶于水和乙醚。
固体分散体是指将药物以分子、无定型、微晶态等高度分散状态均匀分散在载体中形成的一种以固体形式存在的分散系统。作为一种药物制剂的中间体,固体分散体可以增加难溶性药物的溶出度和提高生物利用度、延缓药物释放、增加药物稳定性和液体药物固体化等用途。固体分散体通过将药物高度分散在水溶性载体材料中从而提高药物的溶出度。其中,载体材料发挥了重要作用:
(1)提高药物的溶解度:在溶出过程中,首先载体材料迅速溶解形成载体材料的溶液,随后对药物产生增溶作用,使药物快速溶出;(2)抑晶作用:药物与载体分子之间由于氢键、络合等作用,使药物晶核的形成和生长受到抑制,药物以无定形态存在于载体材料中,有利于药物的释放;(3)保证药物的高度分散性;(4)润湿性:水溶性载体材料的溶解可促进药物与水的接触、润湿,轻微搅拌即可形成极细的均匀混悬液,有利于药物的溶出。
发明内容
针对喜树碱类似物水溶性差、生物利用度低的问题,本发明提供一种喜树碱类似物固体分散体及其制备方法。经检测,喜树碱类似物由原晶型转变成无定型分散在固体分散体中,从而提高了喜树碱类似物的溶解度和生物利用度。
本发明的技术方案如下:
一种喜树碱类似物固体分散体,由如下重量百分数的原料制成:
喜树碱类似物1~15%、水溶性载体75~95%、功能性辅料0~10%;
所述喜树碱类似物、水溶性载体、功能性辅料合计100%;
所述喜树碱类似物为式(I)所示化合物:
所述水溶性载体为聚乙烯吡咯烷酮PVP k30;
所述功能性辅料为十二烷基硫酸钠。
优选的,所述喜树碱类似物固体分散体由如下重量百分数的原料制成:
喜树碱类似物1~10%、水溶性载体80~95%、功能性辅料1~10%。
本发明所述喜树碱类似物固体分散体的制备方法可采用旋转蒸发法、喷雾干燥法、热熔挤出法中的任意一种。
所述旋转蒸发法为:
按配方比例称取喜树碱类似物、水溶性载体以及功能性辅料,溶于有机溶剂,在30~70℃(优选50~70℃)下搅拌0.5~6h(优选1~3h),得到混合物溶液;将混合物溶液通过旋转蒸发仪去除溶剂,得到喜树碱类似物固体分散体薄膜;将喜树碱类似物固体分散体薄膜置于真空干燥箱中干燥后,经粉碎,过筛,即得喜树碱类似物固体分散体粉末;
所述有机溶剂选自丙酮、乙腈、二氯甲烷、三氯甲烷、甲醇、乙醇、四氢呋喃、异丙醇中的一种或两种以上任意比例的混合溶剂;优选乙腈、三氯甲烷、甲醇中的一种或两种以上任意比例的混合溶剂;
所述旋转蒸发仪去除溶剂的温度为25~75℃(优选45~70℃),旋转蒸发时间应大于10分钟;
所述真空干燥箱中干燥的温度为50℃,干燥时间为8~12h。
所述喷雾干燥法为:
按配方比例称取喜树碱类似物、水溶性载体以及功能性辅料,溶于有机溶剂,在30~70℃(优选50~70℃)下搅拌0.5~6h(优选1~3h),得到混合物溶液;将混合物溶液用喷雾干燥法进行干燥,收集粉末,即得喜树碱类似物固体分散体粉末;
所述有机溶剂选自丙酮、乙腈、二氯甲烷、三氯甲烷、甲醇、乙醇、四氢呋喃和异丙醇中的一种或两种以上任意比例的混合溶剂;优选乙腈、三氯甲烷、甲醇中的一种或两种以上任意比例的混合溶剂;
所述喷雾干燥法的参数为:入口温度55~75℃、出口温度35~55℃、雾化压力3~6kg/cm2、蠕动泵速度2~5mL/min;优选的参数为:入口温度60~70℃、出口温度40~50℃、雾化压力4~6kg/cm2、蠕动泵速度2~4mL/min。
所述热熔挤出法为:
按配方比例称取喜树碱类似物、水溶性载体以及功能性辅料,混合均匀后加入双螺杆热熔挤出机中,经过机器内热熔温度的处理,双螺杆挤压的推动,口模成型的加工,挤出物在室温(20~30℃)自然冷却后,成为条状固体分散体;经剪切、粉碎、过筛,即得喜树碱类似物固体分散体粉末;
所述热熔挤出法的参数为:热熔温度80~200℃,螺杆旋转速度15~300r/min;优选的参数为:热熔温度120~200℃,螺杆旋转速度20~150r/min。
本发明所述喜树碱类似物固体分散体呈粉末状,性质稳定、均一性好,根据产品研发所需要的剂型,通过添加适宜的赋形剂,还可制成片剂、胶囊剂、颗粒剂、散剂或混悬剂;所述赋形剂包括但不限于填充剂、润滑剂、助流剂、粘合剂和崩解剂。
本发明所述喜树碱类似物固体分散体可用于制备治疗肺癌、肛门癌、膀胱癌、乳腺癌、宫颈癌、卵巢癌、胰腺癌、小肠癌、胃癌、肝癌、结肠癌和头颈癌的药物。
本发明的有益效果在于:
本发明通过旋转蒸发法、喷雾干燥法或热熔挤出法中的任意一种方法,将喜树碱类似物与水溶性载体、功能性辅料相结合,使喜树碱类似物以无定型的状态均匀地分布在水溶性载体中,制得喜树碱类似物固体分散体,同时实现了制备工艺简便,成本低,用时短等技术优势。
喜树碱类似物原本在水中完全不溶,在本发明喜树碱类似物固体分散体中,喜树碱类似物与载体结合转变为无定型态后可大量溶解于水中,溶解度和溶出度大幅提高,同时生物利用度也大幅提升,使喜树碱类似物能在生物体内发挥出其应有的抗肿瘤作用。
附图说明
图1为本发明实施例3制备的喜树碱类似物固体分散体在蒸馏水中的溶出曲线。
图2为本发明实施例2制备的喜树碱类似物固体分散体以及其原料、载体、物理混合物的XRD扫描图。
具体实施方式
下面通过具体实施例进一步描述本发明,但本发明的保护范围并不仅限于此。
实施例1
本实施例的喜树碱类似物固体分散体主要原料由10%喜树碱类似物、80%PVPk30和10%十二烷基硫酸钠组成,其具体的制备工艺如下:
将41mg喜树碱类似物、320mg PVP k30和43mg十二烷基硫酸钠均匀混合溶解于30mL 20%丙酮-乙腈溶液(v/v)中,在50℃下充分搅拌3h,将混合液通过旋转蒸发仪在65℃下去除溶剂,得到喜树碱类似物固体分散体薄膜,将薄膜置于50℃的真空干燥箱中过夜干燥后,经粉碎,过80目筛,得到喜树碱类似物固体分散体粉末。
实施例2
本实施例的喜树碱类似物固体分散体主要原料由5%喜树碱类似物、90%PVPk30、和5%十二烷基硫酸钠组成,其具体的制备工艺如下:
将22mg喜树碱类似物、396mg PVP k30和21mg十二烷基硫酸钠均匀混合溶解于23mL 20%二氯甲烷-丙酮溶液(v/v)中,在50℃下充分搅拌3h,将混合液通过旋转蒸发仪在50℃下去除溶剂,得到喜树碱类似物固体分散体薄膜,将薄膜置于50℃的真空干燥箱中过夜干燥后,经粉碎,过80目筛,得到喜树碱类似物固体分散体粉末。
实施例3
本实施例的喜树碱类似物固体分散体主要原料由10%喜树碱类似物、80%PVPk30、和10%十二烷基硫酸钠组成,其具体的制备工艺如下:
将501mg喜树碱类似物、4.021g PVP k30和498mg十二烷基硫酸钠均匀混合溶解于300mL 20%丙酮-乙腈溶液(v/v)中,在50℃下充分搅拌3h,将混合物溶液用喷雾干燥法进行干燥,喷雾干燥参数设置为:入口温度70℃、出口温度50℃、雾化压力为4kg/cm2、蠕动泵速度为2mL/min,收集粉末,即得喜树碱类似物固体分散体粉末。
实施例4
本实施例的喜树碱类似物固体分散体主要原料由5%喜树碱类似物、90%PVP k30和5%十二烷基硫酸钠组成,其具体的制备工艺如下:
将252mg喜树碱类似物、4.518g PVP k30和250mg十二烷基硫酸钠均匀混合,设置双螺杆热熔挤出机的熔融温度为120~160℃,当所有实际温度达设置温度时,开始添加混合物料,并且缓慢启动螺杆,开始转速为20r/min,观察机器的压力和扭矩,如果压力和扭矩在正常范围内,将螺杆转速加快150r/min,经分段加热,混合,熔融,推挤的过程,熔融物由口模处呈条状物出来,在室温下冷却成固体,剪短、粉碎后得喜树碱类似物固体分散体。
实施例5
(一)溶解度实验
将过量的喜树碱类似物、实施例1-4所得的喜树碱类似物固体分散体分别放入10毫升蒸馏水中,在37℃,100r/min振荡摇床中孵育24小时。收集上清液离心并通过0.22μm的膜过滤器过滤,通过HPLC测定化合物浓度,其结果如表1所示。
表1
组别 | 饱和溶解度mg/ml |
喜树碱类似物 | 完全不溶 |
实施例1 | 5.23 |
实施例2 | 5.32 |
实施例3 | 5.28 |
实施例4 | 5.26 |
(二)溶出度实验
取实施例3喜树碱类似物固体分散体适量(约相当于化合物500mg),直接投入溶出杯中,照溶出度与释放度测定法(ChP2015版四部通则0931)第一法(篮法),以水900mL为溶出介质,转速为100r/min,溶出液温度为(37±0.5℃),经15,30,45,60,90,120,150,180min分别取溶液5mL,同时补充等体积的溶出介质,用0.22μm微孔滤膜滤过,通过HPLC测定药物浓度。
其结果如图1所示,喜树碱类似物固体分散体在水中前45分钟能快速溶出82.9%,后溶出速率减缓直至3h累计溶出度为97.7%。
(三)喜树碱类似物固体分散体表征
X射线衍射(XRD)分析:对本发明实施例2制备得到的喜树碱类似物固体分散体以及其原料、载体、物理混合物进行XRD分析。
图2中,(A)是喜树碱类似物的XRD扫描图,可以看到有多个特征衍射峰;(B)是载体PVP k30的XRD扫描图,无特征衍射峰;(C)是喜树碱类似物和载体PVP k30物理混合物的XRD扫描图,可以看仍存在多个喜树碱类似物的特征衍射峰,说明喜树碱类似物仍以晶型的形式存在;(D)是实施例2制备得到的喜树碱类似物固体分散体的XRD扫描图,无特征衍射峰,说明喜树碱类似物以无定型状态存在于固体分散体中。
Claims (8)
2.如权利要求1所述喜树碱类似物固体分散体,其特征在于,由如下重量百分数的原料制成:
喜树碱类似物1~10%、水溶性载体80~95%、功能性辅料1~10%。
3.如权利要求1所述喜树碱类似物固体分散体的制备方法,其特征在于,所述制备方法为旋转蒸发法、喷雾干燥法、热熔挤出法中的任意一种。
4.如权利要求3所述的制备方法,其特征在于,所述旋转蒸发法为:
按配方比例称取喜树碱类似物、水溶性载体以及功能性辅料,溶于有机溶剂,在30~70℃下搅拌0.5~6h,得到混合物溶液;将混合物溶液通过旋转蒸发仪去除溶剂,得到喜树碱类似物固体分散体薄膜;将喜树碱类似物固体分散体薄膜置于真空干燥箱中干燥后,经粉碎,过筛,即得喜树碱类似物固体分散体粉末;
所述有机溶剂选自丙酮、乙腈、二氯甲烷、三氯甲烷、甲醇、乙醇、四氢呋喃、异丙醇中的一种或两种以上任意比例的混合溶剂;
所述旋转蒸发仪去除溶剂的温度为25~75℃。
5.如权利要求3所述的制备方法,其特征在于,所述喷雾干燥法为:
按配方比例称取喜树碱类似物、水溶性载体以及功能性辅料,溶于有机溶剂,在30~70℃下搅拌0.5~6h,得到混合物溶液;将混合物溶液用喷雾干燥法进行干燥,收集粉末,即得喜树碱类似物固体分散体粉末;
所述有机溶剂选自丙酮、乙腈、二氯甲烷、三氯甲烷、甲醇、乙醇、四氢呋喃和异丙醇中的一种或两种以上任意比例的混合溶剂;
所述喷雾干燥法的参数为:入口温度55~75℃、出口温度35~55℃、雾化压力3~6kg/cm2、蠕动泵速度2~5mL/min。
6.如权利要求3所述的制备方法,其特征在于,所述热熔挤出法为:
按配方比例称取喜树碱类似物、水溶性载体以及功能性辅料,混合均匀后加入双螺杆热熔挤出机中,经过机器内热熔温度的处理,双螺杆挤压的推动,口模成型的加工,挤出物在室温自然冷却后,成为条状固体分散体;经剪切、粉碎、过筛,即得喜树碱类似物固体分散体粉末;
所述热熔挤出法的参数为:热熔温度80~200℃,螺杆旋转速度15~300r/min。
7.如权利要求1所述喜树碱类似物固体分散体在制备治疗肺癌、肛门癌、膀胱癌、乳腺癌、宫颈癌、卵巢癌、胰腺癌、小肠癌、胃癌、肝癌、结肠癌、头颈癌的药物中的应用。
8.一种药物制剂,所述药物制剂为片剂、胶囊剂、颗粒剂、散剂或混悬剂,其特征在于,由权利要求1所述喜树碱类似物固体分散体添加赋形剂制成,所述赋形剂选自填充剂、润滑剂、助流剂、粘合剂、崩解剂。
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CN1422618A (zh) * | 2002-12-12 | 2003-06-11 | 复旦大学 | 9-硝基喜树碱固体分散体及其制备方法 |
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