CN113149023B - 一种介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法 - Google Patents
一种介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法 Download PDFInfo
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- CN113149023B CN113149023B CN202110267492.0A CN202110267492A CN113149023B CN 113149023 B CN113149023 B CN 113149023B CN 202110267492 A CN202110267492 A CN 202110267492A CN 113149023 B CN113149023 B CN 113149023B
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Abstract
本发明公开一种介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法,通过模板法制备介孔二氧化硅纳米颗粒,然后将柠檬酸共价接到介孔二氧化硅上,最后通过加热和真空蒸发制备介孔二氧化硅‑柠檬酸‑氨基酸低共熔体系;本发明通过将介孔二氧化硅纳米颗粒接上柠檬酸‑氨基酸形成低共熔体系,增大了介孔二氧化硅的分散性,本发明提供一种纳米颗粒经皮递送进入全身循环系统的新的药剂学策略,在长效循环纳米药物制备、经皮免疫治疗方面具有潜在的应用前景。
Description
技术领域
本发明属于医药领域,涉及一种介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法。
背景技术
许多市售产品,包括食品,药品,化妆品和纺织品,已经包含纳米颗粒作为活性剂,载体或添加剂。目前在包括材料科学以及生物医学研究在内的多个领域中探索纳米颗粒。(1)在皮肤病学和美容学中,纳米粒子有望成为重要的工具,可将药物更有效和选择性地靶向皮肤区域和目标细胞群。(2)但是,到目前为止,人们对纳米粒子通过人体屏障的原理以及细胞对粒子的吸收机理及其与生物过程的相互作用知之甚少。
经皮药物传递系统(TDDS)是指皮肤表面给药,使药物以恒定的速率或接近恒定速率通过皮肤,进入血液循环产生全身或局部治疗作用的途径。纳米颗粒的经皮给药平台的建立将会给纳米颗粒载药进入体内提供一种新型给药途径。目前的纳米颗粒经皮给药研究仅仅局限于纳米颗粒难以穿过角质层,只有部分纳米颗粒集中在毛囊释放药物,达到局部治疗的作用。二氧化硅纳米颗粒由于其特殊的性能(如耐磨性,化学惰性和高热稳定性)而具有多种工业应用。此外,由于二氧化硅颗粒具有可控载药的孔道结构、吸附能力强、表面可功能化的能力,因此二氧化硅纳米颗粒作为药物模型载体是可行的。
绿色溶剂的开发一直是绿色化学研究的热点之一,低共熔溶剂(deep eutecticsolvents,DES)展现出了无毒、可生物降解、制备简单、价格低廉等突出特点,还兼具离子液体具有的低挥发性、热稳定性和可设计性,这些优点使得DES在许多研究领域被广泛研究。DES本质上是一种混合物,通过2种或多种不同熔点的固体化合物按一定比例混合后形成,不同化合物之间会形成氢键作用力、范德华力和π-π作用力等,使得晶格能下降,晶格结构破坏,化合物的熔点降低的共熔现象。
传统的纳米颗粒通常在毛囊吸收,无法跨越角质层,因此,其通常被用作增加药物皮肤滞留量,发挥局部治疗的作用。
发明内容
本发明提供一种介孔二氧化硅纳米颗粒经皮递送的低共熔体系的制备方法,通过介孔二氧化硅共价连接柠檬酸,然后与氨基酸通过氢键作用形成低共熔体系,该体系中的介孔二氧化硅纳米颗粒不会聚集,能充分增大介孔二氧化硅纳米颗粒的溶解性,并成功透过皮肤。
本发明提供一种介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法,具体步骤如下:
将1.0g介孔二氧化硅纳米颗粒(MSNs)加入到50mL甲苯中,搅拌使其分散均匀,然后逐滴加入1.0mL的3-氨丙基三乙氧基硅烷(APTES),使其在120℃下回流24小时,反应结束后,分别用乙醇和水洗涤三次,离心分离并冷冻干燥得到氨基化修饰的二氧化硅纳米粒子(MSNs-NH2);
称取2-吗啉乙磺酸(MES)0.9762g,加入水50mL,再称取柠檬酸(CA)1g加到MES中,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)1g和N-羟基琥珀酰亚胺(NHS)800mg,活化1h,加入400mg氨基化修饰的二氧化硅纳米粒子(MSNs-NH2)反应24小时,13500rpm离心分离得到沉淀MSNs-CA,按照MSNs-CA:Lys=2.5wt%的比例称取氨基酸(AA)的量,将二者混合,再按照氨基酸与水的质量体积比g:mL为1:0.25加入H2O,混合物加热到90℃,保温至溶液澄清时,将溶液在55℃下旋蒸得到粘稠性液体即为介孔二氧化硅纳米颗粒经皮递送的低共熔体系MSNs-CA-AA,最后装入样品管,将其放于干燥器中干燥备用,防止长期吸水降低皮肤渗透能力从而影响后续实验,用时直接用滴管吸取即可。
所述介孔二氧化硅纳米颗粒的粒径为50-100nm,形貌为球状,有明显孔道结构,介孔二氧化硅纳米颗粒可以市场购买得到或者通过常规方法制备得到。
所述氨基酸(AA)为丙氨酸(Ala)、精氨酸(Arg)、天冬氨酸(Asp)、半胱氨酸(Cys)、谷氨酰胺(Gln)、谷氨酸(Glu)、甘氨酸(Gly)、天冬酰胺(Asn)、赖氨酸(Lys)、甲硫氨酸(Met)、苏氨酸(Thr)、缬氨酸(Val),上述氨基酸是通过汉森溶解度参数(HSP)指标来评估制得的DES与皮肤的溶解度差异,从而筛选渗透效果更好的氨基酸,汉森溶解度参数(HSP)是评价分子间色散力δD、极性力δP和氢键相互作用力δH的作用能力,HSP通过计算机分析,采用materials studio软件,绘制所制备20种氨基酸-柠檬酸低共熔体系的3D分子结构并通过Dmol3模块建立模拟盒子计算电势分布,用Forcite模块进行几何优化和动力学计算(NPT,100ps),计算得到20种氨基酸-柠檬酸低共熔体系的溶解度参数,并与皮肤的溶解度参数(δD=17.6,δP=13.5,δH=10.2)进行对比,筛选出与皮肤溶解度参数相近的DES对应的氨基酸。
本发明在Franz扩散池中进行皮肤渗透实验,使用皮肤为大鼠背部皮肤,取介孔二氧化硅纳米颗粒经皮递送的低共熔体系MSNs-CA-AA 1mL放于供给室作实验组,25mgMSNs-NH2溶于1mL水作对照组,扩散池配备搅拌系统,并使温度控制在37℃,受体室加入双抗抑菌剂,24h后取受体室的液体17400rpm、30min高速离心,取沉淀替换成水溶液再次高速离心,最后分散在0.5ml水中,利用透射电镜TEM和EDS能谱检测到二氧化硅纳米颗粒的存在,用载荧光染料FITC的介孔二氧化硅纳米颗粒进行皮肤的渗透性实验,荧光材料透过了皮肤,相比空白组的表现更好。
介孔二氧化硅纳米颗粒具有优秀的物理化学性质,如可控的尺寸、成分、形貌、多孔结构和孔隙大小,易于表面化学修饰和良好的分散性,高客体分子装载量和良好的生物相容性(包括血液内循环特性),并且结构稳定可以保护客体分子不受破坏等,因此用介孔二氧化硅纳米颗粒做药物载体是一个不错的选择。本发明用一种新的方式把介孔二氧化硅高度分散在低共熔体系里来考察二氧化硅透过皮肤的能力,考察皮肤渗透能力的实验最常用的方法就是利用Franz扩散池,分析扩散池受体室的药物含量来评价其渗透能力,为了更加确定二氧化硅纳米粒透过了皮肤,本发明借助透射电镜和能谱检测到了二氧化硅纳米颗粒的存在。
本发明的有益效果:
本发明通过介孔二氧化硅纳米颗粒共价连接柠檬酸,再与氨基酸通过氢键作用形成低共熔体系,增大了介孔二氧化硅的分散性,提供了一种纳米颗粒经皮递送进入全身循环系统的新的药剂学策略,在长效循环纳米药物制备、经皮免疫治疗方面具有潜在的应用前景。
相较传统纳米颗粒的口服、注射、吸入等用药途径,本发明纳米颗粒经皮吸收的平台建立具有更加安全,可控,药物生物利用度提高,病人顺应性提高,长期治疗等优势。目前尚未有纳米颗粒经皮递送的研究,本发明提供了一种固体纳米颗粒经皮递送进入全身循环系统的新的药剂学策略,在长效循环纳米药物制备、经皮免疫治疗方面具有潜在的应用前景。
附图说明
图1实施例1的DES的3D结构图;
图2实施例1的DES的HSP计算结果图;
图3实施例1的DES的HSP筛选图;
图4实施例2的介孔二氧化硅纳米颗粒的透射电镜(TEM)图;
图5实施例2的MSN,MSNs-NH2,MSNs-CA的红外光谱图;
图6实施例3的MSNs(FITC)-CA-Lys的荧光染料24h的累积渗透量;
图7实施例3的MSNs-CA-Lys的扩散池受体室TEM图;
图8实施例3的MSNs-CA-Lys的扩散池受体室的EDS能谱图。
具体实施方式
下面通过具体实施例和附图进一步阐述本发明的实质特点,但本发明的保护范围绝非仅局限于实施例。实施例中未特别说明的,均是本领域常规试剂、方法。
实施例1
汉森溶解度参数是一种评价物质皮肤渗透能力的方法,汉森溶解度参数(HSP)是评价分子间色散力δD、极性力δP和氢键相互作用力δH的作用能力,一般认为,某物质的溶解度参数越接近皮肤的溶解度参数,会具有更好的皮肤渗透能力,因此可以用这一项指标来筛选出效果更好的DES。
汉森溶解度参数(HSP)通过计算机分析,采用materials studio软件,绘制所制备20种氨基酸-柠檬酸低共熔体系的3D分子结构,如图1所示;并通过Dmol3模块建立模拟盒子计算电势分布,选择的力场为Universal,设置初始密度为1,用Forcite模块进行几何优化和动力学计算(NPT,100ps),如图2所示,计算得到20种氨基酸-柠檬酸低共熔体系的溶解度参数,并与皮肤的溶解度参数(δD=17.6,δP=13.5,δH=10.2)进行对比,筛选出与皮肤溶解度参数相近的DES,一般认为皮肤溶解度参数方程4(δD-17.6)2+(δP-13.5)2+(δH-10.2)2=R2中R<4.3是皮肤渗透效果更好的条件,通过δes 2=δP 2+δH 2变形得到符合条件的溶解度参数方程:4(δD-17.6)2+(δes-16.92)2=4.32,如图3所示深色区域中的DES为更接近皮肤的溶解度参数值,最后得到皮肤渗透效果更好的12种DES为:Gly-CA、Ala-CA、Val-CA、Met-CA、Cys-CA、Asn-CA、Thr-CA、Arg-CA、Gln-CA、Glu-CA、Lys-CA、Asp-CA,如图2所示深色部分,继而可以推断出,还可以选择如丙氨酸(Ala)、精氨酸(Arg)、天冬氨酸(Asp)、半胱氨酸(Cys)、谷氨酰胺(Gln)、谷氨酸(Glu)、甘氨酸(Gly)、天冬酰胺(Asn)、甲硫氨酸(Met)、苏氨酸(Thr)、缬氨酸(Val)等氨基酸制备低共溶体系。
实施例2
一种介孔二氧化硅-柠檬酸-氨基酸低共熔体系的制备方法,本实施例选择赖氨酸制备低共溶体系,具体过程如下:
(1)将16g氯化三甲基十六烷基铵(CTAC)溶解于100mL去离子水中,加热到95℃,搅拌溶解,然后加入0.5mL三乙醇胺(TEA),继续搅拌1小时,接着逐滴加入12mL正硅酸乙酯(TEOS),继续反应1小时,直至产生白色悬浮液,于13500rpm离心分离,得到沉淀即为二氧化硅纳米粒子;
(2)步骤(1)的沉淀于盐酸/甲醇的混合溶液(1:4体积比)中回流6小时,再离心分离,得到沉淀,重复以上回流操作三次,即可去除模板剂CTAC,最后得到的沉淀用乙醇和去离子水分别洗三次,离心并冷冻干燥得到介孔二氧化硅纳米粒子(MSNs);
(3)将1.0g MSNs加入到50mL甲苯中,搅拌使其分散均匀,然后逐滴加入1.0mL的3-氨丙基三乙氧基硅烷(APTES),使其在120℃下回流24小时,反应结束后,分别用乙醇和水洗涤三次,离心分离并冷冻干燥得到氨基化修饰的二氧化硅纳米粒子(MSNs-NH2);
(4)称取2-吗啉乙磺酸(MES)0.9762g,加入水50mL,再称取柠檬酸(CA)1g加到MES中,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)1g和N-羟基琥珀酰亚胺(NHS)800mg,活化1h,加入400mg步骤(3)制备的MSNs-NH2反应24小时,13500rpm离心分离得到沉淀MSNs-CA,按照MSNs-CA:Lys=2.5wt%的比例称取赖氨酸(Lys)的量,将二者混合,再按照赖氨酸与水的质量体积比g:mL为1:0.25加入H2O,分别是50mg MSNs-CA、2g的赖氨酸和0.5mL的水,混合物加热至90℃,保温待溶液澄清时,将溶液在55℃下旋蒸得到1mL粘稠性液体MSNs-CA-Lys,得到的MSNs-CA-Lys通过粘度仪测其粘度为625.4mPa·s,最后装入样品管,将其放于干燥器中干燥备用,防止长期吸水降低皮肤渗透能力从而影响后续实验,用时直接用滴管吸取即可。
表征:
(1)透射电镜TEM测定:
TEM检测设置参数:电子枪:LaB6(六硼化镧)点分辨率:0.23nm线分辨率:0.14nm加速电压:200kV束斑尺寸:1.0~25nm放大倍数(高倍):2000~1500000放大倍数(低倍):50~6000倾斜角:±35°,能谱仪技术指标:能谱仪能量分辨率(MnK):优于136eV分析元素:5B~92U。
实验处理与结果分析:将本实施例步骤(2)得到的介孔二氧化硅纳米粒子(MSNs)在水中超声分散,然后取少许液体经制样—合轴—拍形貌对纳米颗粒分析,如图4所示,二氧化硅纳米颗粒为球状,粒径在50-100nm之间,颗粒有明显的孔道结构;实施例最后得到的低共溶体系的TEM图与图4一致,都可以看到球状二氧化硅和孔道结构。
(2)傅里叶红外光谱测定:
通过干燥KBr压片法测定MSN,MSNs-NH2,MSNs-CA的傅里叶红外光谱。
实验结果分析:如图5所示,MSN的特征吸收峰有3429cm-1OH峰,1093cm-1和798cm-1的Si-O-Si峰,964cm-1的Si-O峰;MSNs-NH2的特征吸收峰有3625cm-1的NH2峰,1562cm-1的N-H峰;MSNs-CA的特征吸收峰有1633cm-1的酰胺I带,1575cm-1的酰胺II带,1396cm-1的酰胺III带。
实施例3
制备装载异硫氰酸荧光素的MSNs-CA-Lys,考察MSN-CA-Lys的透皮能力,具体步骤如下:
(1)将16g氯化三甲基十六烷基铵(CTAC)溶解于100mL去离子水中,加热到95℃,搅拌溶解,加入溶解于3mL乙醇溶液的10mg FITC荧光染料,然后加入0.5mL三乙醇胺(TEA),继续搅拌1小时,接着逐滴加入12mL正硅酸乙酯(TEOS),继续反应1小时,直至产生白色悬浮液,于13500rpm离心分离,得到沉淀即为二氧化硅纳米粒子;
(2)步骤(1)的沉淀于盐酸/甲醇的混合溶液(1:4体积比)中回流6小时,再离心分离,得到沉淀,重复以上回流操作三次,即可去除模板剂CTAC,最后得到的沉淀用乙醇和去离子水分别洗三次,离心并冷冻干燥得到介孔二氧化硅纳米粒子(MSNs(FITC));
(3)将1.0g MSNs(FITC)加入到50mL甲苯中,搅拌使其分散均匀,然后逐滴加入1.0mL的3-氨丙基三乙氧基硅烷(APTES),使其在120℃下回流24小时,反应结束后,分别用乙醇和水洗涤三次,离心分离并冷冻干燥得到氨基化修饰的二氧化硅纳米粒子(MSNs(FITC)-NH2);
(4)称取2-吗啉乙磺酸(MES)0.9762g,加入水50ml,再称取柠檬酸(CA)1g加到MES中,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)1g和N-羟基琥珀酰亚胺(NHS)800mg,活化1h,加入400mg MSNs(FITC)-NH2反应24小时,13500rpm离心分离得到沉淀MSNs(FITC)-CA,按照MSNs(FITC)-CA:Lys=2.5wt%的比例称取氨基酸(AA)的量,将二者混合,再按照赖氨酸与水的质量体积比g:mL为1:0.25加入H2O,分别是50mg MSNs(FITC)-CA、2g的赖氨酸和0.5mL的水,混合物加热至90℃,保温待溶液澄清时,将溶液在55℃下旋蒸得到1mL粘稠性液体MSNs(FITC)-CA-Lys,得到的MSNs(FITC)-CA-Lys通过粘度仪测其粘度为625.4mPa·s,最后装入样品管,将其放于干燥器中干燥备用,防止长期吸水降低皮肤渗透能力从而影响后续实验,用时直接用滴管吸取即可。
Franz扩散池渗透实验:
(1)使用皮肤为大鼠背部皮肤,直接取保存在干燥器中的MSNs(FITC)-CA-Lys 1mL放于供给室作实验组,取25mgMSNs(FITC)-NH2溶于1mL水作对照组,扩散池配备搅拌系统,并使温度控制在37℃,受体室中加入双抗抑菌剂(青链霉素混合液100X,含青霉素10000u/mL,含链霉素10000ug/mL,下同)和PBS缓冲液,超净台紫外灯下进行透皮实验,加入MSNs(FITC)-CA-Lys后计时,取样时间点为1h,2h,4h,6h,8h,10h,12h,24h,每次从受体室取2mL液体后,再排出受体室的气泡并补加2mLPBS缓冲液继续进行渗透实验,最后通过荧光分光光度计在488nm激发波长和515nm左右发射波长下测定每个时间点的染料浓度,并绘制药物经皮释放曲线,如图6所示,由于在制备介孔二氧化硅的初期就加入了FITC,所以FITC不易从纳米颗粒中泄漏出来,这样一旦测出了荧光就代表了有二氧化硅的存在,从实验组的累积释放量也可看出渗透效果显著;
(2)使用皮肤为大鼠背部皮肤,直接取保存在干燥器中的MSNs-CA-Lys 1mL放于供给室作实验组,取25mgMSNs-NH2溶于1mL水作对照组,扩散池配备搅拌系统,并使温度控制在37℃,受体室中加入双抗抑菌剂和PBS缓冲液,在超净台紫外灯下透皮24h后,取受体室的液体17400rpm、30min高速离心,取沉淀替换成水溶液再次高速离心最后分散在0.5mL水中,如图7所示,透射电镜(TEM)观察到了实验组二氧化硅纳米颗粒的存在,图8,通过EDS能谱核查了样品中的Si元素,O元素,C元素是典型二氧化硅纳米颗粒的元素分布,且有着介孔二氧化硅纳米颗粒的球形孔道特征,而对照组没有检测到颗粒,说明在离体环境下,低共溶体系MSNs-CA-Lys中的介孔二氧化硅纳米颗粒通过了皮肤屏障,成功穿过整个皮肤层。
采用实施例1筛选出的透皮效果好的11种其他DES,采用上述方法制备并检测,可以得到与上述相同的结果,表明:MSN能通过连接DES的方式“拖拽”二氧化硅纳米粒跨过完整的皮肤。
本发明将氨基修饰的介孔二氧化硅纳米颗粒(MSN-NH2)通过共价连接“绑到”柠檬酸上,并与氨基酸反应,制备了介孔二氧化硅-柠檬酸-氨基酸的低共熔体系,使MSN高度分散在DES内部,通过Franz扩散池实验,荧光分光光度计、透射电镜与能谱来综合分析介孔二氧化硅-柠檬酸-氨基酸低共熔体系透过皮肤的能力。
目前尚未有固体纳米颗粒经皮递送的研究,本发明提供了一种固体纳米颗粒经皮递送进入全身循环系统的新的药剂学策略,在长效循环纳米药物制备、经皮免疫治疗方面具有潜在的应用前景。
Claims (3)
1.一种介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法,其特征在于,具体步骤如下:
将1.0g介孔二氧化硅纳米颗粒加入到50mL甲苯中,搅拌分散均匀,逐滴加入1.0mL的3-氨丙基三乙氧基硅烷,在120℃下回流24小时,反应结束后,分别用乙醇和水洗涤三次,离心分离并冷冻干燥得到氨基化修饰的二氧化硅纳米粒子;取2-吗啉乙磺酸0.9762g,加入水50mL,加入柠檬酸1g,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐1g和N-羟基琥珀酰亚胺800mg,活化1h,加入400mg 氨基化修饰的二氧化硅纳米粒子,反应24小时,13500rpm离心分离得到沉淀MSNs-CA,按照MSNs-CA:氨基酸质量比为2.5%的比例,称取氨基酸,将二者混合,再按照氨基酸与水的质量体积比g:mL为1:0.25加入H2O,混合物加热到90℃,保温至溶液澄清,将溶液在55℃下旋蒸得到粘稠性液体即为介孔二氧化硅纳米颗粒经皮递送低共熔体系。
2.根据权利要求1所述介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法,其特征在于,介孔二氧化硅纳米颗粒的粒径为50-100nm,形貌为球状,有孔道结构,介孔二氧化硅纳米颗粒市场购买得到或者通过常规方法制备得到。
3.根据权利要求1所述介孔二氧化硅纳米颗粒经皮递送低共熔体系制备方法,其特征在于,氨基酸为丙氨酸、精氨酸、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、天冬酰胺、赖氨酸、甲硫氨酸、苏氨酸或缬氨酸。
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