CN115024989B - 用分子马达囊泡包裹姜黄素或四氢姜黄素的脂质体-分子马达稳定剂溶液及制备方法和应用 - Google Patents
用分子马达囊泡包裹姜黄素或四氢姜黄素的脂质体-分子马达稳定剂溶液及制备方法和应用 Download PDFInfo
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- Medicinal Preparation (AREA)
Abstract
本申请涉及生物材料技术领域,具体涉及用分子马达囊泡包裹姜黄素或四氢姜黄素的脂质体‑分子马达稳定剂溶液及制备方法和应用。该脂质体主要由在膜泡上带有分子马达的脂质双分子层囊泡包裹姜黄素/四氢姜黄素而成,可以在液态或半固态体系中稳定存在,有效提高姜黄素/四氢姜黄素的氧化稳定性、体系稳定性和生物利用度,降低细胞毒性,还可以用水以任意比直接配制,有效提升了姜黄素/四氢姜黄素的使用便利性,能够较好地在化妆品、护肤品、食品、保健品、药品中应用。
Description
技术领域
本申请涉及生物材料技术领域,具体涉及用分子马达囊泡包裹姜黄素或四氢姜黄素的脂质体-分子马达稳定剂溶液及制备方法和应用。
背景技术
姜黄素是一种天然化合物,是从姜科、天南星科中的一些植物的根茎中提取的一种二酮类化合物,化学式为C21H20O6,具有良好的抗炎和抗癌特性。四氢姜黄素(Tetrahydrocurcumin,简称THC)作为姜黄素在生物体内产生的活跃和主要的代谢产物,由姜黄素氢化而来,能有效改善姜黄素化学稳定性差的问题。四氢姜黄素不仅能有效抑制酪氨酸酶的活性,还能有效抑制氧自由基的生成并能清除已经形成的自由基,具有明显的美白祛斑、抗氧化、抗炎、抗肿瘤、抗抗动脉粥样硬化等效果,被广泛应用于日化、食品、医药等行业中。
目前,虽然四氢姜黄素的化学稳定性得以有效改善,但其水溶性和生物利用度仍然较低,在开发和应用上有一定程度上的限制。为此,人们采用磷脂类对四氢姜黄素包裹为脂质体,但该脂质体大多在液态环境中稳定性较差,难以有效发挥其效果。
发明内容
本申请提供用分子马达囊泡包裹姜黄素的脂质体-分子马达稳定剂溶液及制备方法和应用,该脂质体主要由在膜泡上带有分子马达的脂质双分子层囊泡包裹姜黄素/四氢姜黄素而成,可以在液态或半固态体系中稳定存在,有效提高姜黄素/四氢姜黄素的氧化稳定性、体系稳定性和生物利用度,降低细胞毒性,其还可以用水以任意比例直接配制所需要浓度,有效提升了姜黄素/四氢姜黄素的使用便利性,有助于姜黄素/四氢姜黄素的效果得以有效发挥,能够较好地在化妆品、护肤品、食品、保健品、药品中应用。
第一方面,本申请提供一种用分子马达囊泡包裹姜黄素的脂质体-分子马达稳定剂溶液,包括以下重量百分比的原料:姜黄素/四氢姜黄素0.01-60%,分子马达0.01-80%,增塑剂0.01-20%,静电保护剂0-20%。
分子马达是ATP合成酶,是一类跨膜蛋白质,利用跨膜电化学梯度催化合成ATP的膜蛋白复合物家族,ATP合成酶在细胞内催化能源物质ATP的合成,是支持光合作用与呼吸作用的关键结构,在呼吸或光合作用过程中通过电子传递链释放的能量先转换为跨膜质子(H+)梯差,之后质子流顺质子梯差通过ATP合成酶可以使ADP+Pi合成ATP。F1Fo-ATPase的能量转换效率非常高,作为天然存在的纳米尺度能量转换装置,ATP合成酶的催化过程是可逆的,既可水解ATP,也能合成ATP。
本申请的脂质体主要由分子马达囊泡包裹姜黄素/四氢姜黄素而成,带有天然脂质膜泡,在增塑剂和静电保护剂的作用下,其在胞外溶液中仍具有较高的ATP合成酶活性,有助于降低姜黄素/四氢姜黄素的入胞难度,进而提高姜黄素/四氢姜黄素的生物利用度。
相对于磷脂类包裹的脂质体,本申请的脂质体还能促使姜黄素/四氢姜黄素在细胞内缓慢持续地发挥功效,从而在一定程度上能降低姜黄素/四氢姜黄素的细胞毒性,具有更高的使用安全性。
在此基础上,分子马达囊泡包裹在外能避免姜黄素/四氢姜黄素与其他物质直接接触,从而对姜黄素/四氢姜黄素起到良好的防护作用,在一定程度上能增加姜黄素/四氢姜黄素的氧化稳定性。
另外,被分子马达的磷脂包裹后,脂质体与水的相容性更好,姜黄素/四氢姜黄素以被包裹在内能更好地分散在液态或半固态体系中并稳定存在,有效提高姜黄素/四氢姜黄素的水溶性,进而提升了四氢姜黄素的使用便利性。同时,由分子马达囊泡包裹姜黄素/四氢姜黄素脂质体的组合物能以溶液或半固体形式保持长期稳定的物性状态,能够长期贮存。
优选的,所述增塑剂为胆甾醇、7-脱氢胆甾醇、二氢胆甾醇、磷脂酰胆碱、甘油磷酸胆碱、氢化磷脂酰胆碱、聚乙烯醇、甘油磷酸肌醇胆碱盐、胆甾醇/辛基十二烷醇月桂酰谷氨酸酯、胆甾醇聚醚、二氢胆甾醇丁酸酯、二氢胆甾醇聚醚、C10-30酸胆甾醇/羊毛甾醇混合酯、胆甾醇/山嵛醇/辛基十二烷醇月桂酰谷氨酸酯中的一种或多种的混合物。
优选的,所述静电保护剂为精氨酸、赖氨酸、谷氨酸、天冬氨酸、阳离子淀粉、阳离子瓜尔胶和聚季铵盐中的一种或多种的混合物。
第二方面,本申请提供一种脂质体-分子马达稳定剂溶液的制备方法,包括以下步骤:
将姜黄素/四氢姜黄素分散为姜黄素/四氢姜黄素溶液;
取分子马达,加入增塑剂、静电保护剂和其它加工助剂,制成分子马达溶液;
将姜黄素/四氢姜黄素溶液加入到分子马达溶液中,通过均质或超声进行包覆处理,即得脂质体溶液。
本申请先将姜黄素/四氢姜黄素以及分子马达分散为对应的溶液,有助于分子马达与姜黄素/四氢姜黄素均匀分散,在通过均质或超声的方式,使得分子马达在姜黄素/四氢姜黄素周围存形成一层脂质囊泡,由此实现姜黄素/四氢姜黄素的包覆处理,具有操作简单、包覆效果优异的特点。
第三方面,本申请提供的脂质体能被广泛应用于化妆品、护肤品、食品、保健品、药品中。
第四方面,本申请提供一种脂质体组合物,包括以下重量百分比的原料:所述脂质体30-96%,分子马达稳定剂0-60%,抗氧化剂0.01-10%,抗菌剂0.05-10%,络合剂0.01-5%。
本申请的脂质体组合物中,将脂质体与上述设定量的加工助剂进行配伍,可以形成一个组分均一稳定的液态或半固态体系,使脂质体能更为稳定地存在于液态或半固态系统中,进一步提高姜黄素/四氢姜黄素的生物利用度。此外,该脂质体组合物同样可以用水以任意比例直接配制所需要浓度,进而能进一步提升四氢姜黄素的使用便利性。
优选的,所述分子马达稳定剂为海藻糖、赤鲜糖、甘露醇、山梨醇、蔗糖、乳糖和葡萄糖中的一种或多种的混合物与甘油混合而成。
优选的,所述抗氧化剂为D-异抗坏血酸钠、VC、ɑ-硫辛酸、VE和β胡萝卜素中的一种或多种的混合物。
优选的,所述抗菌剂为对羟基苯乙酮、辛酰羟肟酸、丹皮酚和辛甘醇中的一种或多种的混合物。
通过采用上述技术方案,上述抗菌剂均为无防腐剂的抗菌抑菌试剂,其能有效降低脂质体组合物的生物安全性。
优选的,所述络合剂为EDTA和植酸中的一种。
综上所述,本申请具有以下有益效果:
1、本申请的脂质体用分子马达囊泡包裹姜黄素/四氢姜黄素,可以在液态或半固态体系中稳定存在,有效提高姜黄素/四氢姜黄素的氧化稳定性、体系稳定性和生物利用度,降低细胞毒性,还可以用水以任意比例直接配制所需要浓度,有效提升了姜黄素/四氢姜黄素的使用便利性,有助于姜黄素/四氢姜黄素的效果得以有效发挥。
2、本申请的脂质体组合物将脂质体与设定量的加工助剂进行配伍,可以形成一个组分均一稳定的液态或半固态体系,使脂质体能更为稳定地存在于液态或半固态系统中,还能进一步提升四氢姜黄素的使用便利性。
附图说明
图1是四氢姜黄素以及本申请实施例1a的不同浓度的脂质体对HepG-2细胞的抑制率折线图;
图2是四氢姜黄素以及本申请实施例1a的不同浓度的脂质体对A549细胞的抑制率折线图;
图3是四氢姜黄素以及本申请实施例1a的不同浓度的脂质体对MCF-7细胞的抑制率折线图;
图4是本申请空白对照组、四氢姜黄素组和脂质体组(实施例1a)的透皮荧光显色效果图;
其中,A为空白对照组,B为四氢姜黄素组,C为脂质体组;
图5是本申请空白对照组、空白分子马达组、四氢姜黄素和脂质体组(实施例1a)的入胞荧光显色效果图;其中,A为空白对照组,B为空白分子马达组,C为四氢姜黄素组,D为脂质体组;
图6是图5的局部放大图;
图7是单组分的四氢姜黄素以及本申请实施例1a脂质体组合物的DPPH抗氧化能力及L-酪氨酸酶抑制能力对比的柱形图。
具体实施方式
原料来源
分子马达:采用自制,其制备方法包括以下步骤:
1)取嗜热栖热菌(ATCC33923)接种至培养基,培养温度控制在60℃-80℃,培养5-7天,5000×g离心,收集菌体。
其中,培养基的制备方法,包括以下步骤:按下列称取各配料:K2HPO4·3H2O 0.1g,KH2PO41.0g,MgCl20.8g,CaCl20.1g,NaCl 1.0g,醋酸钠2.2g,琥珀酸钠1.5g,酵母膏3.0g,NaHCO30.5g,麦芽汁0.3g,蛋白胨1.5g(OXOID),牛肉汤0.2g,甘露醇0.3g,微量元素1.0mL【微量元素成分:FeC12·4H201.8g;CoCl2·6H200.25g;NiCl2·6H200.01g;CuCl2·2H200.05g,MnCl2·4H200.07g;ZnCl20.1g,B3PO40.5g,Na2SeO3·5H2O 0.01g,(NH4)6Mo7O4·4H2O 0.02g,纯化水定容至1.0L】,维生素液1.0mL【维生素液成分:生物素0.1g(进口分装),核黄素0.05g,盐酸硫胺素(Thiamine dichloride)0.3g,泛酸钙(Ca-panthothenate)0.1g,叶酸0.05g,维生素B12(VitaminB12)0.05g,烟酰胺0.2g,谷氨酰氨0.1g,盐酸吡哆醇(ryridoxoltum Hydrochlor1de,Fluka)0.2g,氯化胆碱0.05g,纯化水定容至1.0L】;调节pH为8.0,高压灭菌锅121℃灭菌30分钟。
2)分子马达囊泡的提取制备:菌体样品用TS缓冲液【50mM,Tricine(三(羟甲基)甲基甘氨酸,Amresco进口分装),pH8.0,0.25M蔗糖;5M MgC1】洗涤一次,然后再加入15mL TS缓冲液,悬浮后,加入1mg/mL的溶菌酶(sigma分装),在冰中孵育30分钟,超声(20%振幅,Cole Parmer CPX 600超声仪13#探头,昆山市超声仪器公司KQ218型超声仪)10分钟,25,000×g离心30分钟,保留上清,再将上清在4℃,180,000×g下超速离心分离,得到含有F1FO-ATP酶脂质囊泡的复合体,即为分子马达。
本申请涉及的其他原料均采用市售产品,以下结合附图、实施例和对比例对本申请作进一步详细说明。
实施例
实施例1a
一种用分子马达囊泡包裹四氢姜黄素的脂质体-分子马达稳定剂溶液,其制备方法包括以下步骤:
①、四氢姜黄素溶液的制备
用体积浓度为30-60%(本实施例中优选50%)的乙醇将四氢姜黄素10g分散为四氢姜黄素溶液,乙醇的添加量可根据四氢姜黄素的分散效果加以调整,本实施例中乙醇的添加量为四氢姜黄素重量的5倍;
②、分子马达溶液的制备
称取分子马达45.20g,加入分子马达稳定剂(甘油16.95g和海藻糖11.30g)、增塑剂(胆甾醇5.65g)、静电保护剂(精氨酸2.26g和赖氨酸3.39g),混合均匀后制得分子马达溶液;
③、包覆处理
将步骤①制得的四氢姜黄素溶液加入到步骤②制得的分子马达溶液中,在30-80MPa(本实施例中优选50MPa的高压条件)的高压条件下均质进行包覆处理,真空去除多余的乙醇,收获脂质体-分子马达稳定剂溶液。
上述脂质体对应的脂质体组合物,其制备方法包括以下步骤:
往上述收获的脂质体-分子马达稳定剂溶液中加入D-异抗坏血酸钠2.26g、对羟基苯乙酮1.13g和EDTA0.56g,混合均匀后制得100g脂质体组合物。
性能检测
将实施例1a制得的脂质体以及四氢姜黄素作为试样,进行如下性能测试。
一、粒径、电位及酸碱稳定性试验:
试验方法:采用PMX ZetaView纳米颗粒跟踪分析仪对样品直接测定。
1.1、在HAc-Buffer(pH 5.5)缓冲体系下:脂质体的粒径为206.7nm,Zeta电位-5.07mV;而四氢姜黄素的Zeta电位-0.81mV。
1.2、在PBS-Buffer(pH 7.2)缓冲体系下:脂质体的粒径为257.5nm,Zeta电位-8.49mV;而四氢姜黄素的Zeta电位-1.12mV。
1.3、在碳酸-Buffer(pH 9.6)缓冲体系下:脂质体粒径为283.4nm,Zeta电位-12.2mV;而四氢姜黄素的Zeta电位-2.70mV。
由此可见,本申请制得的脂质体比四氢姜黄素具有更大的负电位,说明该脂质体在上述三种缓冲体系中均具有优异的酸碱稳定性。
二、细胞MTT试验(包裹与未包裹的四氢姜黄素的肿瘤抑制率)
MTT试验方法:样品直接用纯化水溶解;配制成最高浓度(饱和溶液),再10倍稀释。将细胞培养2-3天后,每孔加MTT溶液(5mg/mL)20μL.继续孵育3h,小心吸去孔内培养基,对于悬浮细胞需要离心后再吸弃孔内培养基。每孔加100μLDMSO(或异丙醇),振荡10min,使结晶物充分溶解,选择490nm波长,以630nm为参比波长,在酶标仪上测定各孔光吸收值。
经试验,四氢姜黄素组以及脂质体组在不同浓度下对HepG-2细胞(肝癌细胞)、A459细胞(人肺癌细胞)和MCF-7细胞(人乳腺癌细胞)的抑制率参见图1-3。其中,本实施例的脂质体(浓度为80μmol/L)对HepG-2细胞的抑制率达81.5%(四氢姜黄素为46.2%),对A459细胞的抑制率达82.3%(四氢姜黄素为70.0%),对MCF-7细胞的抑制率达64.5%(四氢姜黄素为42.0%);可见本申请的脂质体能够有效提高四氢姜黄素的肿瘤抑制率。
三、透皮效果试验
选取乳猪皮作为测试模型,选取乳猪皮-Franz cell扩散池体系为测试体系,采用TK-12D型透皮扩散试验仪进行试验,具体试验方法为:
(1)向接收室中加入接收液:用移液枪吸取6.0mL接收液(生理盐水溶液)注入接收室,并将配套的磁力搅拌子放置于接收室内。
(2)测试模型的组装与固定:将乳猪皮固定于Franz cell扩散池的扩散室和接收室之间,乳猪皮角质层朝向扩散室,真皮层朝向接收室。固定好乳猪皮后,根据取样管的液体高度,在取样管中用移液枪补加1mL接收液(生理盐水溶液),使乳猪皮真皮层与接收液紧密接触,接收液总体积为7mL。
(3)将Franz cell扩散池固定于透皮吸收扩散仪中,开启电磁搅拌器以300rpm的速度搅拌,保持(37±1)℃恒温水浴,并确保水浴夹层无气泡。
(4)上样:待扩散仪水浴温度恒定后进行上样处理,用移液枪吸取500μL样品添加至乳猪皮表面并涂抹均匀。
(5)接收池样本采集:于24h后分别将空白对照组、四氢姜黄素组和脂质体组的猪皮保存于-80℃。
(6)进行常规的冰冻切片流程,并利用荧光显微镜进行拍照。
经试验,空白对照组、姜黄素组和脂质体组的透皮效果参见图4-6,同时对比姜黄素和本申请的脂质体测试透皮能力,24小时后,与空白对照组相比,姜黄素组和脂质体组在皮肤表面均有大量的绿色荧光;其中,姜黄素组的荧光达到基底层和棘层交界处(未能渗透到真皮层);脂质体组的荧光均已穿过基底层达到并完整地覆盖了真皮层。由此可见,与姜黄素组相比,本申请的脂质体的渗透可以到达真皮层,具有促渗作用。
三、入胞效果试验试验方法:取HaCat细胞,加入RPMI-1640细胞培养液,参照上述本实施例1a中MTT试验中的细胞培养方法培养细胞生长至对数期,分别在细胞培养液中加入1μg/mL的各组分(对照组的有效成分剂量相当),将空白对照组、空白分子马达组、四氢姜黄素组和脂质体这四组与细胞共同孵育,在37℃下细胞孵育2小时,在倒置荧光显微镜下观察入胞效果。
经试验,空白对照和空白马达都没有荧光;普通四氢姜黄素荧光弱,多在细胞表面;通过包裹可以看见大大提高了四氢姜黄素的细胞吸收(参见图5和图6)。
四、功效能力(数据)对比试验试验方法:DPPH采用T/SHRH 006-2018化妆品-自由基(DPPH)清除实验方法。酪氨酸酶采用T/GDCA006-2021化妆品原料对酪氨酸酶活性抑制试验方法(体外法)进行试验。
经试验,相较于四氢姜黄素,本实施例1a制得的脂质体组合物对DPPH清除能力和酪氨酸酶抑制能力均显著提升(参见图7)。其中,通过DPPH清除能力的IC50%对比发现,DPPH清除能力效率提升了1.8倍;通过L-酪氨酸酶的IC50%对比发现,L-酪氨酸酶抑制效率提升了5.0倍。
实施例1b-1f
实施例1b-1f是在实施例1a的方法基础上,对脂质体组合物的原料用量进行调整,具体调整情况参见下表一。
表一实施例1a-1f的脂质体组合物的原料用量表(单位:g)
性能检测
将实施例1a-1f的脂质体组合物进行组分稳定性试验,将实施例1b-1e的脂质体进行上述细胞MTT实验和功效能力试验,测试结果参见下表二。
其中,组分稳定性试验的方法如下:将试样分散在PBS-Buffer(pH 7.2)缓冲体系中,试样与缓冲体系的重量比为1:5,放置于温度为36±0.5℃、湿度为60%的试验环境中,考察12周,观察试样是否出现变色和沉淀。
本申请的组分稳定性分为优、优良、良好、一般、差五个等级。“优”表示试样未出现变色和沉淀;“优良”表示试样出现微小变色且几乎不出现沉淀;“良好”表示试样出现不明显变色和少量沉淀(沉淀量占脂质体组合物的<0.1wt%);“一般”表示试样出现明显变色或较多沉淀(沉淀量占脂质体组合物的<0.5wt%);“差”表示试样同时出现明显变色和较多沉淀(沉淀量占脂质体组合物的≥0.5wt%)。
表二实施例1a-1f的性能检测结果
实施例 | 1a | 1b | 1c | 1d | 1e | 1f |
组分稳定性 | 优 | 良好 | 优良 | 优良 | 优良 | 优良 |
HepG-2细胞抑制率/% | 81.5 | 69.1 | 78.5 | 73.1 | 80.0 | 77.6 |
A459细胞抑制率/% | 82.3 | 73.8 | 79.0 | 76.6 | 79.1 | 78.2 |
MCF-7细胞抑制率/% | 64.5 | 49.5 | 56.9 | 53.0 | 60.2 | 56.1 |
DPPH清除能力提升倍数 | 1.8 | 1.1 | 1.5 | 1.2 | 1.6 | 1.5 |
L-酪氨酸酶抑制倍数 | 5.0 | 3.4 | 4.2 | 4.0 | 4.6 | 4.1 |
结合表二的检测结果可知,本申请实施例1a的稳定性更好,肿瘤抑制率更高,DPPH抗氧化能力及L-酪氨酸酶抑制能力更为优异,因此本申请将实施例1a制得的脂质体组合物作为进一步的优选。
实施例2a-2c
实施例2a-2c在实施例1a的组分基础上,对制备方法进行调整。
实施例2a与实施例1a的区别之处在于,实施例2a的步骤③中,四氢姜黄素溶液加入到分子马达溶液中后超声0.5-3h(本实施例的超声时间优选为1h),随后减压浓缩回收乙醇。
实施例2b与实施例1a的区别之处在于,实施例2b的步骤①中,用体积浓度为10-30%(本实施例中优选20%)的甲醇溶解四氢姜黄素。
实施例2c与实施例1a的区别之处在于,实施例2b的步骤①中,用体积浓度为10-30%(本实施例中优选20%)的甲醇溶解四氢姜黄素,步骤③中,四氢姜黄素溶液加入到分子马达溶液中后超声0.5-3h(本实施例的超声时间优选为1h),随后减压浓缩回收乙醇。
性能检测
将实施例2a-2c的脂质体和脂质体组合物对应进行如上性能测试,测试结果参见下表三。
表三实施例1a、2a-2c的性能检测结果
实施例 | 1a | 2a | 2b | 2c |
组分稳定性 | 优 | 优 | 优良 | 优 |
HepG-2细胞抑制率/% | 81.5 | 82.7 | 80.8 | 81.4 |
A459细胞抑制率/% | 82.3 | 84.0 | 81.2 | 82.0 |
MCF-7细胞抑制率/% | 64.5 | 68.1 | 63.6 | 64.0 |
DPPH清除能力提升倍数 | 1.8 | 2.0 | 1.7 | 1.8 |
L-酪氨酸酶抑制倍数 | 5.0 | 5.5 | 4.8 | 5.0 |
结合表三的检测结果可知,本申请实施例2a的稳定性更好,肿瘤抑制率更高,DPPH抗氧化能力及L-酪氨酸酶抑制能力更为优异,因此本申请将实施例2a制得的脂质体组合物作为进一步的优选。
实施例3a
本实施例在实施例2a的方法和组分配比基础上,将四氢姜黄素替换为姜黄素。其值得的脂质体组合物按上述性能测试方法进行试验,组分稳定性、肿瘤抑制率、DPPH抗氧化能力及L-酪氨酸酶抑制能力均略低于实施例2a,这可能是由于姜黄素自身的化学稳定性相对较差,但其功效相较于单一组分的姜黄素能够有明显提高,因此其值得的脂质体组合物同样在本申请的保护范围内。
实施例4a-4e
本申请脂质体组合物中的分子马达稳定剂可以为海藻糖、赤鲜糖、甘露醇、山梨醇、蔗糖、乳糖和葡萄糖中的一种或多种的混合物与甘油混合而成,为此,申请人选取其中几种方案进行以下实施例4a-4e试验,其在实施例2a的方法和组分配比基础上,对分子马达稳定性的种类进行调整,该具体调整情况参见下表四。
表四实施例2a、4a-4e的分子马达稳定剂调整表(单位:g)
性能检测
将实施例4a-4e的脂质体和脂质体组合物对应进行如上性能测试,测试结果参见下表五。
表五实施例2a、4a-4e的性能检测结果
实施例 | 2a | 4a | 4b | 4c | 4d | 4e |
组分稳定性 | 优 | 优良 | 优良 | 优良 | 良好 | 优良 |
HepG-2细胞抑制率/% | 82.7 | 80.7 | 71.0 | 78.6 | 75.0 | 81.9 |
A459细胞抑制率/% | 84.0 | 81.5 | 72.6 | 79.5 | 78.1 | 83.4 |
MCF-7细胞抑制率/% | 68.1 | 64.0 | 55.5 | 63.8 | 61.0 | 66.5 |
DPPH清除能力提升倍数 | 2.0 | 1.8 | 1.3 | 1.7 | 1.5 | 1.9 |
L-酪氨酸酶抑制倍数 | 5.5 | 5.1 | 4.1 | 5.0 | 4.8 | 5.3 |
结合表五的检测结果可知,本申请实施例2a的稳定性更好,肿瘤抑制率更高,DPPH抗氧化能力及L-酪氨酸酶抑制能力更为优异,因此本申请优选甘油与海藻糖混合制得的分子马达稳定剂,其中进一步优选甘油与海藻糖的质量比为3:2。
实施例5a-5d
本申请脂质体组合物中的增塑剂可以为胆甾醇、7-脱氢胆甾醇、二氢胆甾醇、磷脂酰胆碱、甘油磷酸胆碱、氢化磷脂酰胆碱、聚乙烯醇、甘油磷酸肌醇胆碱盐、胆甾醇/辛基十二烷醇月桂酰谷氨酸酯、胆甾醇聚醚、二氢胆甾醇丁酸酯、二氢胆甾醇聚醚、C10-30酸胆甾醇/羊毛甾醇混合酯、胆甾醇/山嵛醇/辛基十二烷醇月桂酰谷氨酸酯中的一种或多种的混合物。为此,申请人选取其中几种方案进行以下实施例5a-5e试验,其在实施例2a的方法和组分配比基础上,对增塑剂的种类进行调整,具体调整情况参见下表六。
表六实施例2a、5a-5e的增塑剂调整表(单位:g)
性能检测
将实施例5a-5e的脂质体和脂质体组合物对应进行如上性能测试,其稳定性,肿瘤抑制率,DPPH抗氧化能力及L-酪氨酸酶抑制能力与实施例2a相近,可见上述增塑剂均可较好地应用于本申请中。
实施例6a-6d
本申请脂质体组合物中的静电保护剂可以为精氨酸、赖氨酸、谷氨酸、天冬氨酸、阳离子淀粉、阳离子瓜尔胶、聚季铵盐中的一种或多种的混合物。为此,申请人选取其中几种方案进行以下实施例6a-6d试验,其在实施例2a的方法和组分配比基础上,对静电保护剂的种类进行调整,具体调整情况参见下表七。
表七实施例2a、6a-6d的静电保护剂调整表(单位:g)
性能检测
将实施例6a-6d的脂质体和脂质体组合物对应进行如上性能测试,测试结果参见下表八。
表八实施例2a、6a-6d的性能检测结果
实施例 | 2a | 6a | 6b | 6c | 6d |
组合稳定性 | 优 | 优良 | 良好 | 优良 | 良好 |
HepG-2细胞抑制率/% | 82.7 | 80.7 | 73.8 | 78.6 | 77.0 |
A459细胞抑制率/% | 84.0 | 82.5 | 76.5 | 80.9 | 78.9 |
MCF-7细胞抑制率/% | 68.1 | 66.7 | 61.3 | 64.5 | 63.0 |
DPPH清除能力提升倍数 | 2.0 | 1.7 | 1.3 | 1.6 | 1.4 |
L-酪氨酸酶抑制倍数 | 5.5 | 5.1 | 4.6 | 5.0 | 4.7 |
结合表九的检测结果可知,本申请实施例2a的稳定性更好,肿瘤抑制率更高,DPPH抗氧化能力及L-酪氨酸酶抑制能力更为优异,因此本申请的静电保护剂进一步优选精氨酸与赖氨酸的混合物。
实施例7a-7d
本申请脂质体组合物中的抗氧化剂为D-异抗坏血酸钠、VC、VE、ɑ-硫辛酸和β胡萝卜素中的一种或多种的混合物。为此,申请人选取其中几种方案进行以下实施例7a-7d试验,其在实施例2a的方法和组分配比基础上,对抗氧化剂的种类进行调整,具体调整情况参见下表九。
表九实施例2a、7a-7d的抗氧化剂调整表(单位:g)
性能检测
将实施例7a-7d的脂质体和脂质体组合物对应进行如上性能测试,测试结果参见下表十。
表十实施例2a、7a-7d的性能检测结果
实施例 | 2a | 7a | 7b | 7c | 7d |
组分稳定性 | 优 | 优良 | 优良 | 优良 | 优良 |
HepG-2细胞抑制率/% | 82.7 | 81.9 | 82.2 | 82.0 | 82.5 |
A459细胞抑制率/% | 84.0 | 82.7 | 83.1 | 82.9 | 83.6 |
MCF-7细胞抑制率/% | 68.1 | 67.0 | 67.6 | 66.8 | 67.9 |
DPPH清除能力提升倍数 | 2.0 | 1.8 | 1.8 | 1.8 | 1.9 |
L-酪氨酸酶抑制倍数 | 5.5 | 5.2 | 5.3 | 5.3 | 5.3 |
结合表十一的检测结果可知,本申请实施例2a的稳定性更好,肿瘤抑制率更高,DPPH抗氧化能力及L-酪氨酸酶抑制能力更为优异,因此本申请的抗氧化剂进一步优选D-异抗坏血酸钠。
实施例8a-8d
本申请脂质体组合物中的抗菌剂为对羟基苯乙酮、辛酰羟肟酸、丹皮酚和辛甘醇中的一种或多种的混合物。为此,申请人选取其中几种方案进行以下实施例8a-8d试验,其在实施例2a的方法和组分配比基础上,对抗氧化剂的种类进行调整,具体调整情况参见下表十一。
表十一实施例2a、8a-8d的抗菌剂调整表(单位:g)
性能检测
将实施例8a-8d的脂质体和脂质体组合物对应进行如上性能测试,经测试,实施例8a-8d的性能测试结果与实施例2a的相近,可见上述抗菌剂均可在本申请的脂质体组合物中进行使用。
实施例9a
本实施例在实施例2a的方法和组分配比基础上,将络合剂EDTA替换为植酸。其值得的脂质体组合物按上述性能测试方法进行试验,其稳定性,肿瘤抑制率,DPPH抗氧化能力及L-酪氨酸酶抑制能力与实施例2a相近,因植酸的温和性更好,因此进一步优选植酸作为络合剂的脂质体组合物。
综上,本申请的脂质体组合物用分子马达囊泡包裹姜黄素/四氢姜黄素,有效提高了姜黄素/四氢姜黄素的水溶性、氧化稳定性和生物利用度,降低了姜黄素/四氢姜黄素的细胞毒性,使姜黄素/四氢姜黄素的效果得以有效发挥。
本具体实施例仅仅是对本申请的解释,其并不是对本申请的限制,本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改,但只要在本申请的权利要求范围内都受到专利法的保护。
Claims (8)
1.一种用分子马达囊泡包裹姜黄素或四氢姜黄素的脂质体-分子马达稳定剂溶液,其特征在于,所述脂质体包括以下重量百分比的原料:姜黄素/四氢姜黄素0.01-60%,分子马达0.01-80%,增塑剂0.01-20%,静电保护剂为8.33%;所述分子马达来源于嗜热栖热菌;所述分子马达稳定剂的重量占脂质体-分子马达稳定剂溶液的29.41%;
所述脂质体-分子马达稳定剂溶液的制备方法,包括以下步骤:
将姜黄素/四氢姜黄素用乙醇或甲醇分散为姜黄素/四氢姜黄素溶液;
取分子马达,加入分子马达稳定剂、增塑剂和静电保护剂,制成分子马达溶液;所述分子马达稳定剂为甘油与海藻糖的混合物;
将姜黄素/四氢姜黄素溶液加入到分子马达溶液中,通过均质或超声进行包覆处理,真空除去多余的乙醇或甲醇,即得脂质体-分子马达稳定剂溶液备用。
2.根据权利要求1所述的脂质体-分子马达稳定剂溶液,其特征在于:所述增塑剂为胆甾醇、7-脱氢胆甾醇、二氢胆甾醇、磷脂酰胆碱、甘油磷酸胆碱、氢化磷脂酰胆碱、聚乙烯醇、甘油磷酸肌醇胆碱盐、胆甾醇/辛基十二烷醇月桂酰谷氨酸酯、胆甾醇聚醚、二氢胆甾醇丁酸酯、二氢胆甾醇聚醚、C10-30 酸胆甾醇/羊毛甾醇混合酯、胆甾醇/山嵛醇/辛基十二烷醇月桂酰谷氨酸酯中的一种或多种的混合物。
3.根据权利要求1所述的脂质体-分子马达稳定剂溶液,其特征在于:所述静电保护剂为精氨酸、赖氨酸、谷氨酸、天冬氨酸、阳离子淀粉、阳离子瓜尔胶和聚季铵盐中的一种或多种的混合物。
4.权利要求1-3任一项所述的脂质体-分子马达稳定剂溶液在制备化妆品、护肤品、药品中的应用。
5.一种脂质体组合物,其特征在于,包括以下重量百分比的原料:如权利要求1-3任一项所述的脂质体-分子马达稳定剂溶液96.05%,抗氧化剂0.01-10%,抗菌剂0.05-10%,络合剂0.01-5%。
6.根据权利要求5所述的脂质体组合物,其特征在于:所述抗氧化剂为D-异抗坏血酸钠、VC、VE、ɑ-硫辛酸和β胡萝卜素中的一种或多种的混合物。
7.根据权利要求5所述的脂质体组合物,其特征在于:所述抗菌剂为对羟基苯乙酮、辛酰羟肟酸、丹皮酚和辛甘醇中的一种或多种的混合物。
8.根据权利要求5所述的脂质体组合物,其特征在于:所述络合剂为EDTA或植酸。
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