CN106110306A - 一种特立帕肽鼻腔给药脂质体制剂及其制备方法 - Google Patents
一种特立帕肽鼻腔给药脂质体制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种特立帕肽鼻腔给药脂质体制剂及其制备方法,属于药物制剂领域。一种特立帕肽鼻腔给药脂质体制剂,主要由特立帕肽0.01~0.5g、磷脂0.1~1.5g、胆固醇0.015~0.6g、DSPE‑PEG2000 0.015~0.2g、膜软化剂0.012~0.5g、稳定剂0.02~0.3g制成;所包封的药物为特立帕肽,脂质体的粒径可控在20~100nm,分布均匀,包封率高于90%,活性稳定在90%以上。该鼻腔给药脂质体制剂能够实现特立帕肽的非注射给药,并提高特立帕肽的生物利用度,降低其毒副作用,提高患者用药的顺应性。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种特立帕肽的鼻腔给药脂质体及其制备方法。
背景技术
特立帕肽是一种重组人甲状旁腺激素1-34(rhPTH1-34),可以促进骨形成,临床上用于治疗骨质疏松症。该药由美国礼来公司开发,2002年获得FDA批准上市。特立帕肽的给药方式一直以来都是注射给药,长期的注射给药,不仅增加了药物的毒副作用,使患者非常痛苦,而且很不方便,甚至可能出现不良反应如过敏、硬结、炎症等。因此,开发一种安全有效、应用方便的非注射给药特立帕肽制剂——特立帕肽鼻腔给药脂质体,具有非常重要的临床意义。
鼻腔黏膜中分布着丰富的静、动脉和毛细淋巴管,大量微小绒毛位于鼻腔呼吸区细胞表面,使得药物对鼻腔黏膜的穿透性较高;鼻腔内酶分布相对较少,药物的分解比胃肠道低,从而有利于药物的吸收并直接进入体内血液循环,避免肝脏首过作用;因此,鼻腔给药是多肽类药物非注射给药途径中最有发展前景的给药方式。
脂质体是一种类似生物膜结构的双分子层微小囊泡,具有生物膜特性和药物传输能力。药物包裹于脂质体内,可降低在组织中扩散而缓慢向血液中释放药物从而延长药物作用时间,有利于提高生物利用度;脂质体的内水相能保护多肽不受酶解的影响,从而提高药物的稳定性;制备脂质体用到的脂材毒性小,生物相容性好,没有免疫反应,从而减少不良反应。
鼻腔给药脂质体能够减少药物的鼻黏膜毒性和刺激性;持续释放被包封药物,有长效缓释作用;较强的生物黏附性能够减少药物被黏膜纤毛的清除,从而使药物较长时间保持有效血药浓度,提高生物利用度。
脂质体制备的传统方法有反相蒸发法、薄膜法、钙融合法、表面活性剂处理法及挤出容器法等,但通过这些方法制备的脂质体存在以下问题:包封率低、残留的有机溶剂或表面活性剂可能导致多肽药物活性的降低、难以实现产业化等,为此,新的脂质体制备方法已成为脂质体研究的热点。超临界溶液快速膨胀法(RESS)是美国人Matson D.W.于1987年发明的,因其具有无溶剂残留和操作温度不高等优点,特别适用于热敏性及不稳定性高的多肽制品。它的具体工艺流程为:超临界二氧化碳与溶剂溶解,经喷嘴的快速膨胀后,由于溶液在喷嘴中的膨胀导致温度快速下降,溶剂在高压釜内沉析,二氧化碳以气体状态通过过滤器排放。专家认为,这实际上是超临界溶剂和溶质的二元混合物在收敛性喷嘴中膨胀,当超临界溶液处于过饱和状态时,形成粒子沉析。
发明内容
本发明的目的在于提供一种特立帕肽鼻腔给药脂质体制剂及其制备方法,该鼻腔给药脂质体制剂能够实现特立帕肽的非注射给药,并提高特立帕肽的生物利用度,降低其毒副作用,提高患者用药的顺应性。
为实现上述目的,本发明采用以下技术方案:
一种特立帕肽鼻腔给药脂质体制剂,主要由特立帕肽0.01~0.5g、磷脂0.1~1.5g、胆固醇0.015~0.6g、DSPE-PEG2000 0.015~0.2g、脂质体膜调节剂0.012~0.5g、稳定剂0.02~0.3g制成;所包封的药物为特立帕肽,脂质体的粒径可控在20-100nm,分布均匀,包封率高于90%,活性稳定在90%以上。
所述磷脂选自大豆卵磷脂、蛋黄卵磷脂。
所述脂质体膜调节剂选自胆酸钠、去氧胆酸钠、Triton-100中的一种或多种。
优选地,脂质体膜调节剂为胆酸钠。
所述稳定剂选自磷脂酰甘油、磷脂酸、硬脂胺中的一种或多种。
一种特立帕肽鼻腔给药脂质体制剂,通过下列方法制得:
a)将特立帕肽、磷脂、胆固醇、DSPE-PEG2000和脂质体膜调节剂溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力、温度条件下预膨胀;以一定流速通过喷嘴快速喷射至超临界收集釜内的水相介质中,经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入稳定剂,制得鼻腔给药制剂。
所述预膨胀压力为15~30MPa,预膨胀温度为323~345K,所述超临界微乳液是以1~5L/min的喷射速度喷射至所述超临界收集釜内的水相介质中。
所述水相为磷酸盐缓冲溶液,pH值为5.5~7.5。
所述用于鼻腔给药的特立帕肽脂质体制剂中,特立帕肽的浓度为20-30%w/v(每mL鼻腔给药制剂中含特立帕肽200-300μg)。
所述鼻腔给药制剂为喷雾剂、滴鼻剂、粉雾剂。
本发明的特立帕肽脂质体是在脂质体基础上加入了脂质体膜调节剂,制备成了柔性纳米脂质体,不仅能提高脂质体的生物黏附性,延长药物在鼻黏膜的滞留时间,而且制剂的各种辅料对鼻黏膜的毒性较低。
CO2超临界法以超临界状态下的CO2代替有机溶剂,并能保证制备过程在低温下进行,既避免了与有机溶剂的接触,又能减少多肽药物活性的损失,是多肽类脂质体制备中较为理想的一种方法。
本发明制备的特立帕肽脂质体克服了传统脂质体制备的缺点,所制备脂质体的粒径可控在20~100nm,分布均匀,包封率高于90%,活性稳定在90%以上。
研究发现,脂质体的大小是影响脂质体在体内分布和停留时间的主要因素,脂质体的粒径越小,体内停留时间越长。通过本发明方法制备的特立帕肽脂质体颗粒小,粒径大小分布均匀,这是其在体内代谢率低、生物利用度高的因素之一。
附图说明
图1为鼻腔给药特立帕肽脂质体制剂体外释放曲线。
具体实施方式
以下实施例是对本发明的进一步说明,但绝不是对本发明范围的限制。下面参照实施例进一步详细阐述本发明,但是本领域技术人员应当理解,本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
实施例1
a)将特立帕肽、大豆卵磷脂、胆固醇、DSPE-PEG2000和胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(16MPa)、温度(335K)条件下预膨胀;以一定流速(3L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为5.5),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂酰甘油,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径65nm,球状,均匀,包封率93.4%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存180天,溶液均匀稳定无分层和变质现象。
实施例2
a)将特立帕肽、蛋黄卵磷脂、胆固醇、DSPE-PEG2000和去氧胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(20MPa)、温度(328K)条件下预膨胀;以一定流速(2.5L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为6.5),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂酸,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径35nm,球状,均匀,包封率94.5%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存180天,溶液均匀稳定无分层和变质现象。
实施例3
a)将特立帕肽、蛋黄卵磷脂、胆固醇、DSPE-PEG2000和去氧胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(25MPa)、温度(338K)条件下预膨胀;以一定流速(3.5L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为7.0),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入硬脂胺,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径50nm,球状,均匀,包封率95.6%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存185天,溶液均匀稳定无分层和变质现象。
实施例4
a)将特立帕肽、大豆卵磷脂、SM、胆固醇、DSPE-PEG2000和Triton-100溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(30MPa)、温度(330K)条件下预膨胀;以一定流速(4.0L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为7.5),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂酰甘油,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径45nm,球状,均匀,包封率90.5%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存176天,溶液均匀稳定无分层和变质现象。
实施例5
a)将特立帕肽、蛋黄卵磷脂、胆固醇、DSPE-PEG2000和胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(20MPa)、温度(325K)条件下预膨胀;以一定流速(3.5L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为6.8),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂酸,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径65nm,球状,均匀,包封率92.3%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存178天,溶液均匀稳定无分层和变质现象。
实施例6
a)将特立帕肽、蛋黄卵磷脂、胆固醇、DSPE-PEG2000和Triton-100溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(26MPa)、温度(345K)条件下预膨胀;以一定流速(1.0L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为6.0),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂酰甘油,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径80nm,球状,均匀,包封率93.1%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存185天,溶液均匀稳定无分层和变质现象。
实施例7
a)将特立帕肽、大豆卵磷脂、胆固醇、DSPE-PEG2000和去氧胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(16MPa)、温度(325K)条件下预膨胀;以一定流速(1.5L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为7.0),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂酰甘油,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径95nm,球状,均匀,包封率95.4%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存180天,溶液均匀稳定无分层和变质现象。
实施例8
a)将特立帕肽、蛋黄卵磷脂、胆固醇、DSPE-PEG2000和去氧胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(20MPa)、温度(330K)条件下预膨胀;以一定流速(2.0L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为5.5),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷脂胺,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径76nm,球状,均匀,包封率96.0%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存185天,溶液均匀稳定无分层和变质现象。
实施例9
a)将特立帕肽、大豆卵磷脂、胆固醇、DSPE-PEG2000和胆酸钠溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(20MPa)、温度(330K)条件下预膨胀;以一定流速(2.0L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为7.5),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷酸酰甘油,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径76nm,球状,均匀,包封率96.0%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存185天,溶液均匀稳定无分层和变质现象。
实施例10
a)将特立帕肽、蛋黄卵磷脂、胆固醇、DSPE-PEG2000和Triton-100溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力(20MPa)、温度(330K)条件下预膨胀;以一定流速(2.0L/min)通过喷嘴快速喷射至超临界收集釜内的磷酸盐缓冲溶液介质中(pH为6.5),经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入磷酸酰甘油,制得鼻腔给药制剂。
测定混悬液中包封药物载体脂质体平均粒径76nm,球状,均匀,包封率96.0%,常温下保存60天,溶液物理化学性质稳定,低温4℃下保存185天,溶液均匀稳定无分层和变质现象。
实施例11体外释放
取实施例1、3、5、8、10所制备的特立帕肽脂质体,加水溶解,制成5mL溶液,置透析袋中,放在装有50mL 0.2M的pH7.4磷酸盐缓冲液锥形瓶中,温度控制在(37±0.5)℃,以浆板法测定体外性能,转速为100r/min,设计取样时间为2、4、6、8、12、16、20、24h。每次取样5mL,同时补充同体积的PBS。释放液经0.22μm微孔滤膜滤过,取续滤液20μL进液相色谱仪,测定峰面积,代入标准曲线计算浓度,得出每阶段释药量。其色谱条件为:色谱柱KromasilC18(4.6mm×250mm,5μm),流动相为0.05mol/L氯化钾溶液(磷酸调节至pH4.5)-乙腈(75∶25),流速1.0mL/min;检测波长210nm。结果见图1。结果,特立帕肽脂质体体外长效释放完全。
Claims (10)
1.一种特立帕肽鼻腔给药脂质体制剂,其特征在于主要由特立帕肽0.01~0.5g、磷脂0.1~1.5g、胆固醇0.015~0.6g、DSPE-PEG2000 0.015~0.2g、脂质体膜调节剂0.012~0.5g、稳定剂0.02~0.3g制成;所包封的药物为特立帕肽,脂质体的粒径可控在20~100nm,分布均匀,包封率高于90%,活性稳定在90%以上。
2.根据权利要求1所述的特立帕肽鼻腔给药脂质体制剂,其特征在于,所述磷脂选自大豆卵磷脂、蛋黄卵磷脂。
3.根据权利要求1所述的特立帕肽鼻腔给药脂质体制剂,其特征在于,所述脂质体膜调节剂选自胆酸钠、去氧胆酸钠、Triton-100中的一种或多种。
4.根据权利要求3所述的脂质体膜调节剂,优选为胆酸钠。
5.根据权利要求1所述的特立帕肽鼻腔给药脂质体制剂,其特征在于,所述稳定剂选自磷脂酰甘油、磷脂酸、硬脂胺中的一种或多种。
6.一种如权利要求1所述的特立帕肽鼻腔给药脂质体制剂的制备方法,其特征在于,包括以下步骤:
a)将特立帕肽、磷脂、胆固醇、DSPE-PEG2000和脂质体膜调节剂溶解于超临界CO2/乙醇溶剂,并增溶一定量的蒸馏水形成超临界微乳液;
b)将所述超临界微乳液在设定的压力、温度条件下预膨胀;以一定流速通过喷嘴快速喷射至超临界收集釜内的水相介质中,经分散并沉析,形成脂质体混悬液;
c)将CO2持续通过超临界收集釜,溶解并除去脂质体混悬液中的残余乙醇,经转子计量计计量后排空,收集超临界收集釜内的纳米脂质体混悬液,即为特立帕肽柔性纳米脂质体;
d)将c步骤得到的特立帕肽柔性纳米脂质体混悬液中加入稳定剂,制得鼻腔给药制剂。
7.根据权利要求6所述的特立帕肽鼻腔给药脂质体制剂的制备方法,其特征在于,所述预膨胀压力为15~30MPa,预膨胀温度为323~345K,所述超临界微乳液是以1~5L/min的喷射速度喷射至所述超临界收集釜内的水相介质中。
8.根据权利要求6或7任一项所述的特立帕肽鼻腔给药脂质体制剂的制备方法,其特征在于,所述水相为磷酸盐缓冲溶液,pH值为5.5~7.5。
9.根据权利要求1所述的特立帕肽鼻腔给药脂质体制剂,其特征在于,所述用于鼻腔给药的特立帕肽脂质体制剂中,特立帕肽的浓度为20-30%w/v(每mL鼻腔给药制剂中含特立帕肽200-300μg)。
10.根据权利要求1所述的特立帕肽鼻腔给药脂质体制剂,其特征在于,所述鼻腔给药制剂为喷雾剂、滴鼻剂、粉雾剂。
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