CN106361702B - 一种硫酸或盐酸黄连素多囊脂质体及其制备方法 - Google Patents
一种硫酸或盐酸黄连素多囊脂质体及其制备方法 Download PDFInfo
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- CN106361702B CN106361702B CN201610960954.6A CN201610960954A CN106361702B CN 106361702 B CN106361702 B CN 106361702B CN 201610960954 A CN201610960954 A CN 201610960954A CN 106361702 B CN106361702 B CN 106361702B
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- Prior art keywords
- berberine
- multivesicular liposome
- concentration
- sulfuric acid
- hydrochloride
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- Medicinal Preparation (AREA)
Abstract
本发明公开了一种硫酸或盐酸黄连素多囊脂质体及其制备方法,通过将卵磷脂,胆固醇,油酸,三油酸甘油酯溶于混合溶剂中形成油相;将硫酸或盐酸黄连素溶于蔗糖溶液中形成内水相;再通过内水相与油相制备初乳;将初乳加入特定的混合溶液得到复乳;最终通过复乳得到多囊脂质体的过程制得了一种硫酸或盐酸黄连素包封率高、载药量大、缓释效果明显、药物释放浓度稳定、囊泡含量高、外形均匀的硫酸或盐酸黄连素多囊脂质体。
Description
技术领域
本发明涉及脂质体的技术领域,特别涉及盐酸或硫酸脂质体的技术领域。
背景技术
黄连素又称小檗碱(berberine),是传统中药黄连的有效成分,是一种异喹啉生物碱,在中国和印度已有3000余年的使用历史。可治疗由各种原因引起的腹泻。硫酸黄连素为黄连素的硫酸盐,特别适于兽用,在养殖业中用于敏感菌和密螺旋体感染引起的畜禽、仔猪红痢、黄痢、白痢、肠炎、水肿病、副伤寒等症,盐酸黄连素为黄连素的盐酸盐,更适于人体使用,其抗菌谱广,可用于治疗胃肠炎、细菌性痢疾、眼结膜炎、化脓性中耳炎等病症,同时还具有阻断α-受体,抗心律失常的作用。
硫酸黄连素或盐酸黄连素在动物或人体的肠道吸收均较困难,直接口服后血药浓度很低,若使用注射给药,又会出现药物维持时间短,需要频繁给药的问题,不方便人体使用,也不便于在养殖业中大量应用。
因此,寻找一种新的递药系统已成必然趋势。脂质体因为可以改变药物在体内的分布、代谢和吸收, 延长作用时间,增加疗效,降低毒副作用等得到了大量的研究。
常见的脂质体包括单室脂质体和多室脂质体,与普通的单室脂质体和多室脂质体不同,多囊脂质体(multivesicular liposome,MVL)具有不连续的药物溶液囊泡,具有更多的包封容积,当多囊脂质体中的某个囊泡破裂时,药物只从破裂囊泡释出,未破裂的囊泡仍可保持原状保存其中的药物,由此通过囊泡的不同时破裂,还可达到缓释和稳定药效的作用、大大减少给药次数。因此多囊脂质体的研制也得到了快速的发展,如中国专利CN102274183中公开了一种多囊脂质体制备方法与应用,通过中性磷脂、胆固醇、三酸甘油酯、负电荷磷脂、辅助乳化剂、渗透压调节剂及药物活性成分制得。中国专利申请CN102274182A中公开了一种含有艾塞那肽的多囊脂质体及其制备方法和应用,通过艾塞那肽、中性磷脂、胆固醇、三酸甘油酯、pH调节剂、渗透压调节剂、辅助乳化剂制备得到。
与上述产品不同,硫酸黄连素或盐酸黄连素在水中的溶解度高,采用普通多囊脂质体制备方法包封率低,多囊系统易被破坏,制剂过程中易出现复凝聚问题,无法得到稳定的终产品。
发明内容
本发明的目的在于提出一种可进行硫酸黄连素或盐酸黄连素包封、包封率高、载药量大、缓释效果明显、药物释放浓度稳定、囊泡含量高、外形均匀、成本较低的硫酸或盐酸多囊脂质体及其制备方法。
本发明的技术方案如下:
一种硫酸或盐酸多囊脂质体的制备方法,包括以下步骤:
(1)将卵磷脂,胆固醇,油酸,三油酸甘油酯溶于混合溶剂中形成油相;
(2)将硫酸或盐酸黄连素溶于蔗糖溶液中形成内水相;
(3)将内水相缓慢注入油相中,通过形成初乳;
(4)初乳注入混合溶液中形成外水相,制备得到复乳,所述混合溶液为L-赖氨酸、海藻酸钠和葡萄糖的混合水溶液;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到所述硫酸或盐酸黄连素多囊脂质体。
其优选的实施方案为:所述步骤(1)中所述混合溶剂为乙醚与氯仿的混合溶剂,其中乙醚与氯仿的体积比为0.5~1.5:1。
其另外的优选实施方案为:所述步骤(2)中所述蔗糖溶液浓度为5~7wt%。本发明中蔗糖溶液所起作用主要是调节渗透压。
其另外的优选实施方案为:所述油相与所述内水相的体积比为1:0.5~1.5。
本发明中制备复乳、初乳等环节的制备,采用常规方法即可,如均质、剪切、超声、射流、涡混、搅拌等方式。本发明一个具体实施方式中,使用均质技术。
优选实施方案为:所述步骤(3)中,通过均质制备初乳;进一步地,均质速率为10000~12000 r.min-1,时间为9 ~15min。
更进一步的优选为使用高速均质机进行该操作。
其另外的优选实施方案为:所述步骤(4)中所述混合溶液里L-赖氨酸的浓度为30~50 mmol.L-1,葡萄糖的浓度为5~7wt%,海藻酸钠的浓度为0.3~0.5wt%。
该优选实施方案更进一步的优选为:所述海藻酸钠的浓度为0.5wt%。
其另外的优选实施方案为:所述步骤(4)中,通过均质制备复乳;进一步地,均质的速率为9000~10000 r.min-1,时间为1~3min。
其另外的优选实施方案为:所述卵磷脂和胆固醇的质量和与所述硫酸或盐酸黄连素的质量比为4~10:1。
该优选实施方案更进一步的优选为:所述卵磷脂和胆固醇的质量和与所述硫酸或盐酸黄连素的质量比为8:1。
其另外的优选实施方案为:所述步骤(1)中所述卵磷脂与胆固醇的质量比为1~5:1,所述油酸的体积与油相总体积的体积比为1~5:75,所述三油酸甘油酯在油相中的浓度为40~70 mmol.L-1。
该优选实施方案更进一步的优选为:所述卵磷脂与胆固醇的质量比为2:1。所述三油酸甘油酯的浓度为70 mmol.L-1。
本发明另外的优选实施方案为:所述卵磷脂和胆固醇的质量和与所述硫酸或盐酸黄连素的质量比为8:1,所述卵磷脂与胆固醇的质量比为2:1,所述三油酸甘油酯的浓度为70 mmol.L-1,且所述海藻酸钠的浓度为0.5wt%。
在该优选实施方案下,制得的硫酸或盐酸黄连素多囊脂质体包封率达85.88%。
本发明进一步提出了一种硫酸或盐酸黄连素多囊脂质体,其可通过上述任一制备方法或其优选实施方案制备得到。
本发明在制备中使用了至少两种基础脂质,一种为两性的磷脂如卵磷脂,另一种为中性磷脂如三油酸甘油酯,其中中性磷脂可填充于脂质双分子层内的形成疏水间隙,稳定囊泡交叉处的连接,以形成不连续的非同心囊泡,因此为形成多囊脂质体的关键成分。
在现有技术中常通过加入负电荷磷脂的方法防止复乳凝集结块,如在油相中加入1,2-棕榈酰磷脂酰甘油(DPPG)等负电荷磷脂,但本发明中硫酸或盐酸黄连素为生物碱的强酸盐,使用负电荷磷脂无法得到稳定的复乳,因此为得到稳定的复乳,本发明首先采用了两种脂质,其后在油相中加入了油酸,其可以在囊泡表面形成疏水性薄膜,有效防止水溶性较强的硫酸或盐酸黄连素从囊泡内泄漏,因而达到提高包封率,增加缓释性能的作用,此外油酸在本体系内还具有增强膜稳定性的作用,同时可显著降低产品的材料成本。
此外,针对硫酸或盐酸黄连素的特殊性质,为了增强复乳稳定性,减少凝集问题,本发明进一步在外水相中加入了海藻酸钠,其除了具有乳化作用,及通过静电包覆囊泡,进一步防止水溶性硫酸或盐酸黄连素泄漏,从而提高多囊脂质体系统的稳定性和包封率,达到更好的缓释效果外,还可与油酸协同,作为复合的膜稳定剂增强复乳稳定性。
本发明具有以下有益效果:
(1)本发明制得的多囊脂质体可有效储存水溶性高的硫酸或盐酸黄连素;
(2)本发明采用两性磷脂如卵磷脂,中性磷脂如三油酸甘油酯,及胆固醇,形成多囊脂质体非同心囊泡结构,并采用油酸、海藻酸钠、L-赖氨酸作为复合膜稳定剂和辅助乳化剂,可以有效包封水溶性较强的硫酸黄连素,形成稳定的多囊脂质体;
(3)本发明采用膜稳定剂与辅助乳化剂的协同作用,优化制备工艺,有效防止硫酸或盐酸黄连素从囊泡系统中泄漏,且解决了复凝聚问题,可以制得包封率高、稳定性好、缓释效果明显的水溶性药物多囊脂质体系统;
(4)本发明选用的原材料成本相对较低,有效降低了产品的制备成本;
(5)本发明制得的硫酸或盐酸黄连素多囊脂质体包封率高,载药量大,药物缓释时间长,特别适于兽用;
(6)本发明制得的硫酸黄连素多囊脂质体外观良好、圆整光滑,囊泡数量多、大小均匀,缓释性能好、生物利用度高。
附图说明
图1为本发明的硫酸黄连素多囊脂质体的显微图片,放大倍数分别为图1-1:10×20倍,图1-2:10×50倍;
图2为本发明的硫酸黄连素多囊脂质体的72h累积释放率趋势图。
具体实施方式
以下通过实施例对本发明作进一步的详细说明,但不应将此理解为本发明的范围仅限于以下的实例。在不脱离本发明上述方法思想的情况下,根据本领域普通技术知识和惯用手段做出的各种替换或变更,均应包含在本发明的范围内。
本发明具体实施方式中使用到的仪器与试剂等信息如下:
FJ200S高速均质机(杭州奇威有限公司),TGL-16G型离心机(无锡瑞江分析仪器有限公司),722N可见分光分度计(上海精密仪器仪表有限公司),DF-101S集热式恒温加热磁力搅拌器(郑州恒岩仪器有限公司),JTN100-1干式吹氮仪(杭州聚同电子有限公司),奥林巴斯显微镜BX41(OLYMPUS, 日本),微量移液器(上海佳安分析仪器厂),透析袋(截流分子量8000~1.5×104,成都市科龙化工试剂厂),微孔滤膜(水性,0.45 mm成都市科龙化工试剂厂)。
黄连素(浙江四方生物科技有限公司,批号20160103,纯度98 %),无水乙醚(成都市科龙化工试剂厂),异丙醇(成都市科龙化工试剂厂),油酸(成都市科龙化工试剂厂),三油酸甘油酯(国药集团化学试剂有限公司),卵磷脂(成都市科龙化工试剂厂),胆固醇(成都市科龙化工试剂厂),蔗糖(广东光华科技股份有限公司),葡萄糖(成都市科龙化工试剂厂),吐温-80(天津市光复精细化工试剂厂),油酸钠(成都市科龙化工试剂厂),十二烷基硫酸钠(成都市科龙化工试剂厂),海藻酸钠(成都市科龙化工试剂厂),L-赖氨酸(国药集团化学试剂有限公司),氯仿、氯化钠等试剂均为分析纯。
下述实施例中包封率的测试方法为:精密量取制得的多囊脂质体的混悬溶液1mL与生理盐水等体积混合,于2000 r.min-1的速率下进行离心,取上清液1mL再加纯化水与乙醚混合,取水层溶液使用0.45μm的微孔滤膜过滤,取续滤液测定吸光度,包封率(encapsulation efficiency,EE)按以下公式计算:EE(%)=(W1-W2)/W1×100%,W1为总药量即投药量,W2为游离药物。
实施例1
(1)将质量为0.2g的卵磷脂,0.1g的胆固醇,0.1mL的油酸,0.5mL的三油酸甘油酯溶于由体积比为1:1的乙醚与氯仿形成的混合溶剂7.5mL中,得到油相;
(2)将质量为0.0375g的硫酸黄连素溶于浓度为5wt%的蔗糖溶液7.5mL中形成内水相;
(3)取与油相体积比为1:1的内水相缓慢注入油相中,通过高速均质机在12000r.min-1的速率下均质9min,得到初乳;
(4)量取4mL初乳快速倒入混合溶液中形成外水相,通过高速均质机在9500r.min-1的速率下均质1min,得到复乳,所述混合溶液中L-赖氨酸的浓度为40mmol.L-1、海藻酸钠的浓度为0.5wt%,葡萄糖的浓度为5wt%;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到硫酸黄连素多囊脂质体。
所得硫酸黄连素多囊脂质体颗粒大小均匀,圆整光滑,内部含有大量含水囊泡,如附图1所示;经测试,其包封率为85.88 %;将 0.9wt%的NaCl溶液作为释放介质测试其释放曲线如附图2所示,72h累积释放度为83.28%;
进一步对释放趋势图分别采用零级释放、一级释放、Highchi、 Retrer-Peppas、Weibull等模型进行拟合,从拟合结果可知所得硫酸黄连素多囊脂质体的体外释放符合Weibull方程。
实施例2
(1)将0.2g的卵磷脂,0.2g的胆固醇,0.5mL油酸,0.3mL三油酸甘油酯溶于由体积比为0.5:1的乙醚与氯仿形成的混合溶剂7.5mL中,得到油相;
(2)将质量为0.1g的硫酸黄连素溶于浓度为7wt%的蔗糖溶液3.75mL中形成内水相;
(3)取与油相体积比为0.5:1的内水相缓慢注入油相中,通过高速均质机在10000r.min-1的速率下均质15 min,得到初乳;
(4)量取5mL初乳快速倒入混合溶液中形成外水相,通过高速均质机在9000r.min-1的速率下均质3min,得到复乳,所述混合溶液中L-赖氨酸的浓度为30mmol.L-1、海藻酸钠的浓度为0.3wt%、葡萄糖的浓度为7wt%;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到硫酸黄连素多囊脂质体。
该硫酸黄连素多囊脂质体颗粒大小均匀,圆整光滑,内部含有大量含水囊泡。
实施例3
(1)将0.2g的卵磷脂,0.04g胆固醇,0.3mL油酸,0.4mL三油酸甘油酯溶于由体积比为1.5:1的乙醚与氯仿形成的混合溶剂7.5mL中,得到油相;
(2)将质量为0.05g的硫酸黄连素溶于浓度为6wt%的蔗糖溶液11.25mL中形成内水相;
(3)取与油相体积比为1.5:1的内水相缓慢注入油相中,通过高速均质机在11000r.min-1的速率下均质10 min,得到初乳;
(4)量取6mL初乳快速倒入混合溶液中形成外水相,通过高速均质机在10000r.min-1的速率下均质1min,得到复乳,所述混合溶液中L-赖氨酸的浓度为50mmol.L-1、海藻酸钠的浓度为0.4wt%、葡萄糖的浓度为6wt%;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到硫酸黄连素多囊脂质体。
该硫酸黄连素多囊脂质体颗粒大小均匀,圆整光滑,内部含有大量含水囊泡。
实施例4
(1)将质量为0.2g的卵磷脂,0.1g的胆固醇,0.1mL的油酸,0.5mL的三油酸甘油酯溶于由体积比为1:1的乙醚与氯仿形成的混合溶剂7.5mL中,得到油相;
(2)将质量为0.0375g的盐酸黄连素溶于浓度为5wt%的蔗糖溶液7.5mL中形成内水相;
(3)取与油相体积比为1:1的内水相缓慢注入油相中,通过高速均质机在12000r.min-1的速率下均质9min,得到初乳;
(4)量取4mL初乳快速倒入混合溶液中形成外水相,通过高速均质机在9500r.min-1的速率下均质1min,得到复乳,所述混合溶液中L-赖氨酸的浓度为40mmol.L-1、海藻酸钠的浓度为0.5wt%、葡萄糖的浓度为5wt%;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到盐酸黄连素多囊脂质体。
所得盐酸黄连素多囊脂质体颗粒大小均匀,圆整光滑,内部含有大量含水囊泡;经测试,其包封率为85.88 %;将 0.9wt%的NaCl溶液作为释放介质测试其释放性能可知其72h累积释放度为84.12%;
进一步对释放趋势图分别采用零级释放、一级释放、Highchi、 Retrer-Peppas、Weibull等模型进行拟合,从拟合结果可知所得盐酸黄连素多囊脂质体的体外释放符合Weibull方程。
实施例5
(1)将卵磷脂,胆固醇,油酸,三油酸甘油酯溶于由体积比为1:1的乙醚与氯仿形成的混合溶剂中,得到油相;
(2)将硫酸黄连素溶于浓度为5wt%的蔗糖溶液中形成内水相;
(3)取与油相体积比为1:1的内水相缓慢注入油相中,通过高速均质机在12000r.min-1的速率下均质9min,得到初乳;
(4)量取4mL初乳快速倒入混合溶液中形成外水相,通过高速均质机在9500r.min-1的速率下均质1min,得到复乳,所述混合溶液为L-赖氨酸、海藻酸钠和葡萄糖的混合水溶液,其中L-赖氨酸的浓度为40mmol.L-1、葡萄糖的浓度为5wt%;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到所述硫酸黄连素多囊脂质体;
其中药物硫酸黄连素与作为脂质的卵磷脂和胆固醇的总质量的比(药脂比),卵磷脂与胆固醇的质量比,油相中三油酸甘油酯的浓度,海藻酸钠的浓度按下表配制:
表1
由此得到1~7的硫酸黄连素多囊脂质体样品,所得样品均颗粒大小均匀,圆整光滑,内部含有大量含水囊泡,包封率测试结果如下:
表2
尽管这里参照本发明的解释性实施例对本发明进行了描述,上述实施例仅为本发明较佳的实施方式,本发明的实施方式并不受上述实施例的限制,应该理解,本领域技术人员可以设计出很多其他的修改和实施方式,这些修改和实施方式将落在本申请公开的原则范围和精神之内。
Claims (7)
1.一种硫酸或盐酸黄连素多囊脂质体的制备方法,其特征在于:包括以下步骤:
(1)将卵磷脂,胆固醇,油酸,三油酸甘油酯溶于混合溶剂中形成油相;
(2)将硫酸或盐酸黄连素溶于蔗糖溶液中形成内水相;
(3)将内水相缓慢注入油相中,通过均质形成初乳;
(4)初乳注入混合溶液中形成外水相,制备得到复乳,所述混合溶液为L-赖氨酸、海藻酸钠和葡萄糖的混合水溶液;
(5)向复乳中连续通气去除有机溶剂,直至复乳上层呈现半透明状,即得到所述硫酸或盐酸黄连素多囊脂质体;
步骤(1)中所述卵磷脂与胆固醇的质量比为1~5:1,油酸的体积与油相总体积的体积比为1~5:75,三油酸甘油酯在油相中的浓度为40~70mmol.L-1;
步骤(1)中所述卵磷脂与胆固醇的质量和步骤(2)中所述硫酸或盐酸黄连素的质量比为4~10:1;
步骤(4)中所述混合溶液中L-赖氨酸的浓度为30~50mmol.L-1,葡萄糖的浓度为5~7wt%,海藻酸钠的浓度为0.3~0.5wt%。
2.根据权利要求1所述的硫酸或盐酸黄连素多囊脂质体的制备方法,其特征在于:所述步骤(1)中所述混合溶剂为乙醚与氯仿的混合溶剂,其中乙醚与氯仿的体积比为0.5~1.5:1。
3.根据权利要求1所述的硫酸或盐酸黄连素多囊脂质体的制备方法,其特征在于:所述步骤(2)中所述蔗糖溶液浓度为5~7wt%。
4.根据权利要求1所述的硫酸或盐酸黄连素多囊脂质体的制备方法,其特征在于:所述油相与所述内水相的体积比为1:0.5~1.5。
5.根据权利要求1所述的硫酸或盐酸黄连素多囊脂质体的制备方法,其特征在于:所述步骤(3)中,通过均质制备初乳;所述均质速率为10000~12000r.min-1,时间为9~15min。
6.根据权利要求1所述的硫酸或盐酸黄连素多囊脂质体的制备方法,其特征在于:所述步骤(4)中,通过均质制备复乳;所述均质的速率为9000~10000r.min-1,时间为1~3min。
7.一种硫酸或盐酸黄连素多囊脂质体,其特征在于:所述硫酸或盐酸黄连素多囊脂质体通过上述1~6中任一项所述的制备方法制备得到。
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