CN112245571A - 一种用于乌发的脂质体制剂及其制备方法 - Google Patents
一种用于乌发的脂质体制剂及其制备方法 Download PDFInfo
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- CN112245571A CN112245571A CN202010972969.0A CN202010972969A CN112245571A CN 112245571 A CN112245571 A CN 112245571A CN 202010972969 A CN202010972969 A CN 202010972969A CN 112245571 A CN112245571 A CN 112245571A
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- Prior art keywords
- liposome
- hair
- preparation
- solution
- melanin
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Abstract
本发明涉及一种用于乌发的脂质体制剂及其制备方法,将黑色素、微量元素、恢复黑色素正常代谢的蛋白多肽成分、增强或修复毛囊基因的核酸成分、抗氧化相关基因和/或有益毛囊健康的细胞因子等高效制备成脂质体。采用脂质体包封蛋白质DNA等功效性生物大分子,可极大的提高其透皮吸收效率,有效促进毛囊黑色素正常代谢,维护头皮毛囊健康,促进白发转黑;有效成分尤其是生物大分子,被脂质体包裹后,透皮吸收效果和常温保存稳定性得到很大提高,还可在皮肤表皮层蓄积,起到长效缓释作用,提升局部药物浓度,增强治疗作用;该脂质体与人体内天然微囊的大小和结构类似,有亲毛囊特性,靶向毛囊、起到促进乌发、维护头皮健康的作用。
Description
技术领域
本发明属于医药技术领域,尤其涉及一种用于乌发的脂质体制剂及其制备方法。
背景技术
随着年龄增长,人体发生生理性衰老,头发由黑变白是一种自然衰老特征。但是,受到环境污染和工作、生活压力影响,白发发生比例逐渐上升,并且明显年轻化。过早出现的白发等毛发疾病严重影响个人形象以及社交活动。
白发因毛囊黑素细胞的黑色素生成与色素沉着出现障碍,与营养、遗传、不良生活习惯、情绪、环境等多种因素有关。现代医学目前能确认的白发的主要病变机制为毛囊黑素细胞增殖受到抑制,细胞内的酪氨酸酶活性降低,导致黑色素合成减少,从而产生白发。另外,维生素矿物质等营养成分缺乏,紫外线照射、不当饮食、烫染药剂频繁使用等诸多因素在头皮中产生过量活性氧(ROS),损伤DNA、蛋白质和脂质等功效性生物大分子,引起黑色素合成代谢功能障碍,导致白发症状。西医目前对本病尚无特效疗法,中医方剂虽然较多,但没有从毛囊黑素细胞的正常代谢、毛囊健康以及抗氧化应激衰老的角度去解决问题,所以效果并不显著。
因为治疗方法缺失,绝大多数患者不得不反复使用化学药剂染发。而目前市场上销售的大多为苯胺类染发剂,具有致敏性。轻者头皮出现红斑,瘙痒、灼热,重者引发全身症状。经常使用染发剂,其中的强氧化剂会造成头皮出现严重的氧化应激性衰老,破坏头发的保护层、损伤头皮和毛囊,导致发质变脆弱、大量白发出现,同时也增加了患癌的风险。
人的皮肤由表皮、真皮和皮下脂肪构成。表皮最外层是由数层角化细胞组成的角质层,能防止绝大部分微生物和有害物质的入侵,对人体起到保护作用。但也是阻碍美容产品中有效成分吸收的主要障碍。透皮给药是将药物涂抹或敷贴于皮肤表面的给药方法。相比于口服或注射给药途径,透皮给药能避免胃肠道刺激,局部给药降低药物毒副作用,提高安全性与疗效。但是,由于皮肤角质层的存在,大多数药物无法直接被人体吸收,达不到有效的渗透速率和渗透量,所以使用合适的方法提高药物的透皮量成为关键。脂质体是磷脂双分子膜包封水相形成的球型载体,结构与人体细胞膜类似,因此易与细胞膜融合,从而将内部包裹的组分送入细胞内部,极大的提高其内含物的组织穿透性能。蛋白质、DNA、维生素、矿物质等经脂质体包裹后,与游离状态相比,透皮吸收比例显著提高。脂质体可经毛囊途径快速进入真皮层,通过毛干周围的内根鞘细胞将包裹的有效成分迅速扩散到整个毛囊,从而发挥功效。脂质体应用于皮肤时,不仅可促进内容物穿透角质层,还可在表皮层和真皮层蓄积,长效缓释,提高局部药物浓度,极大的增强对患处的治疗作用,减少对其他无关区域的副作用。将DNA等遗传物质包裹于脂质体中,局部应用在人皮肤上,可成功转染皮肤上生长期的毛囊细胞。转染的基因可以选择性进入毛母质细胞,转录表达,进而影响毛囊的生物学性状,起到增强和修复的作用。
发明内容
本发明的目的在于,提供一种用于乌发的脂质体制剂及其制备方法,本发明将黑色素,黑色素代谢相关多肽,抗氧化相关基因、有益毛囊健康的细胞因子等高效制备成脂质体,生物大分子被脂质体包裹后,透皮吸收效果和常温保存稳定性得到很大提高,还可起到长效缓释作用,提升局部药物浓度,增强治疗作用,靶向毛囊、起到促进白发变黑、维护头皮健康的作用。
本发明是通过以下技术方案来实现的:
本发明提供了一种用于乌发的脂质体,其包括以下组分:脂质体成膜材料,质量百分比浓度为2%~12%;黑色素,质量百分比浓度为1%~5%;抗氧化剂,质量百分比浓度为0~5%。优选的,所述脂质体成膜材料包括磷脂、胆固醇,所述磷脂与胆固醇的质量比为9-10:0-2;所述磷脂包括大豆磷脂、二月桂酰卵磷脂、二肉豆蔻酰卵磷脂、二棕榈酰卵磷脂、二硬脂酰卵磷脂、二硬脂酰卵磷脂、蛋黄卵磷脂、氢化豆磷脂、二油酰基卵磷脂、二月桂酰磷脂酰甘油、二棕榈脂酰甘油、二硬脂酰磷脂酰甘油、二油酰磷脂酰甘油和二肉豆蔻酰磷脂酸中的一种或几种。优选的,所述抗氧化剂包括花青素、白藜芦醇、维生素A、维生素C、维生素E、类胡萝卜素等成分中的一种或几种。
作为发明的进一步说明:该用于乌发的脂质体还包括微量元素,所述微量元素包括铜、铁、锌、硒、镁及钙盐或有机酸盐的一种或一种以上,所述微量元素在制剂中的浓度:Cu:10~20μmol/L,Fe:15~35μmol/L,Zn:10~20μmol/L,Se:0.5~1.5μmol/L,Mg:0.5~1mmol/L,Ca:1.5~2mmol/L。
作为发明的进一步说明:该用于乌发的脂质体还包括:恢复黑色素正常代谢的蛋白多肽成分,质量百分比浓度为0.001%~1%;所述蛋白多肽包括α-黑素细胞刺激素、内皮素-1或铜肽中的一种或者一种以上。
作为发明的进一步说明:该用于乌发的脂质体还包括:增强或修复毛囊基因的核酸成分,质量百分比浓度为0~0.05%。优选的,所述增强或修复毛囊基因的核酸成分,包含酪氨酸酶、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽过氧化物酶的编码基因中的一种或者一种以上;所述核酸类型可为质粒DNA、siRNA、shRNA、microRNA、反义RNA或寡聚核苷酸。
作为发明的进一步说明:该用于乌发的脂质体还包括细胞因子成分,所述细胞因子成分为源自脐带干细胞、脂肪干细胞、成纤维细胞中的一种或者多种,质量百分比浓度为0.01~0.1%;或者所述细胞因子成分为成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、角质细胞生长因子中的一种或者多种,质量百分比浓度为0.0001~0.01%。
作为发明的进一步说明:该用于乌发的脂质体:还包括透皮吸收促进剂,质量百分比浓度为0~0.05%;所述透皮吸收促进剂包括促渗肽TAT、R9、R11、Pep-1、SPACE、TD-1以及Penetratin中的一种或几种。
另一方面,本发明还提供了所述的用于乌发的脂质体的制备方法,其包括以下步骤:
步骤a:水相的制备
溶液A的制备:称取黑色素、氨基酸和微量元素,加入蒸馏水中搅拌5-20min,加热溶解,过滤,加水补足体积;所述黑色素与氨基酸的质量比为1g:1-3g,所述氨基酸为L-精氨酸、DL-精氨酸或DL-组氨酸中的一种或一种以上;
溶液B的制备:称取适量蛋白多肽成分,加生理盐水搅拌混匀,配置成溶液;
溶液C的制备:构建酪氨酸酶、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)或谷胱甘肽过氧化物酶重组质粒,转化到大肠杆菌中进行大量扩增,收集质粒,溶于无菌的超纯水中,配制成溶液;
溶液D的制备:培养脐带干细胞、脂肪干细胞或成纤维细胞,收集上清液,通过超滤浓缩技术富集细胞因子复合物,配制成溶液;或将市售成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、角质细胞生长因子中的一种或者多种,用无菌注射用水或生理盐水搅拌溶解;
步骤b:油相的制备:
将磷脂、胆固醇加入到无水乙醇中,在45-60℃条件下溶解,将溶解后的溶液进行旋转蒸发,使其形成均匀的脂质体膜;所述的无水乙醇的用量是磷脂、胆固醇总质量的4-6倍;或直接使用市售的磷脂脂质体膜;
步骤c:脂质体的制备:
将步骤a中的溶液A、溶液B、溶液C和/或溶液D加入到步骤b中的脂质体膜中,再加入抗氧化剂混合搅拌,直至脂质体膜完全溶解,得到乳浊液,然后将A、B、C和/或D的乳浊液在30-45℃的水浴条件下搅拌20-40min得混悬液,混悬液在35-40℃水浴条件下超声处理10-30min,得粗制脂质体;然后加入透皮吸收促进剂,进行均质处理,即得到精制脂质体混悬液;
步骤d:脂质体制剂的制备:
将所得的精制脂质体混悬液灌装于容器中,再向容器中依次冲入CO2和N2,即得脂质体喷雾剂;
或将所得的精制脂质体混悬液,加入冻干保护剂,冻干,得脂质体冻干粉成品;所述冻干保护剂为海藻糖、乳糖、蔗糖、麦芽糖、甘露醇、脯氨酸和甘氨酸中的一种或几种;将所得的精制脂质体冻干粉成品制备成脂质体喷雾剂、脂质体凝胶、脂质体搽剂、脂质体乳剂。
更优选的,步骤c中,所述均质过程中的压力控制在40~300Mpa范围内,匀质次数为3~15次。
当代社会生存压力大,白发人群年轻化趋势日益明显,白发的治疗逐渐成为一个不容忽视的问题。但目前并没有疗效明确的药物。市面常见的多为中药复方,没有准确针对白发病因,见效慢,长期服用不方便且为全身给药,可能对人体造成危害。目前,除了化学药剂和中医治疗,生物制剂也有了很多研究,其药效显著,但应用较少。乌发效果明确的生物制剂主要有α-黑素细胞刺激素(α-MSH),内皮素-1(ET-1)等。其中α-MSH对黑素细胞有广泛的刺激效应,可刺激黑素细胞的分裂,提高酪氨酸酶活性。还能促进黑素细胞树突生长,帮助黑色素转移和扩散。针对氧化应激所致白发,超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽过氧化物酶等都有清除氧自由基,保护细胞和组织免受氧化损伤的作用。此外维生素C、维生素E、胡萝卜素、花青素、白藜芦醇等抗氧化剂也能起到很好的保护作用,提高毛囊干细胞增殖活力,维持其正常代谢。本发明将生物大分子有效成分与脂质体结合,靶向递送毛囊,可以最大限度的降低副作用,提高黑发效果。
本发明的各成分功效与分析:
黑色素(melanin)是一种广泛存在于动植物和微生物中的非均质的类多酚聚合体。自然界的黑色素主要可以分为三类,一类是真黑色素,呈棕黑色;一类称为脱黑素,呈红黄色等较浅的颜色;还有一类称为异黑素,呈黑色。这三类色素不溶于酸性溶液,微溶于水,不溶于常见有机溶剂,可溶于碱性溶液;黑色素具有很多独特的功能特性,不仅能作为一类光保护剂、抗辐射剂、螯合剂、生物抗氧化剂和免疫促进剂,而且还可作为一类生物半导体材料。近年来的研究还发现,黑色素具有抗蛇毒、抗癌、抑制艾滋病毒复制、治疗帕金森症等作用,在医药、化妆品、食品、电子等领域有着广泛的应用前景。
微量元素是头发的基本成分,头发中微量元素的含量是血液中的10-1000倍,人体必须摄取足够的矿物质及微量元素如铜、铁、锌、钙等防治白发的产生。铜为体内多种重要酶系的成分,能够促进铁的吸收和利用,维持中枢神经系统的功能。缺铜时人体内各种血管与骨骼的脆性增加、脑组织萎缩,还可以引起白癜风及少白头等黑色素丢失症。所述微量元素为盐或有机酸盐,比如硫酸亚铁、硫酸铜、硫酸锌、葡萄糖酸铜等。
蛋白多肽的成分功效分析:
内皮素(ET)是由21个氨基酸组成的活性多肽,目前发现人和哺乳动物体内有ET-1、ET-2和ET-3。内皮素不仅有强烈缩血管,加强心肌、平滑肌收缩和促进神经内分泌功能,而且还是一类强大的促分化剂和细胞生长因子,具有促进细胞有丝分裂的性质。ET的3个异构肽在生物活性上有一定程度的差异,ET-1最强,ET-3最弱。ET-1是迄今公认最强的缩血管物质,维持生理条件下血管的舒缩功能,同时ET-1也参与多种疾病病理机制的调节,在高血压、肺动脉高压、冠心病、脑卒中和肺纤维化中具有重要的作用。
铜肽的英文名为copper peptide,是甘氨酰组氨酰赖氨酸三肽(GHK)与铜的络合物,其水溶液呈蓝色,所以又称为蓝铜肽、铜胜肽或者三胜肽-铜。铜肽的功能主要包括:有效促进胶原蛋白的产生,增加血管生长和抗氧化能力,并刺激葡糖胺聚糖产生,帮助皮肤恢复自我修补的能力;促使上皮细胞的生长和分化,从而加快创面的愈合;作为组织重塑的激活剂,还可促使神经细胞、免疫相关细胞和肾小球细胞的生长、分裂和分化,刺激表皮干细胞标记物整合素、p63的产生。
α-黑素细胞刺激素(α-MSH)是神经内分泌激素黑素细胞刺激素中的一种,主要存在于下丘脑垂体及多种外周组织;近来研究发现,α-MSH除能刺激黑素细胞增殖分化及促进黑素形成,使皮肤和毛发颜色变深外,还具有抗菌、抗炎、退热、调节神经内分泌及保护心血管功能等作用。α-MSH作为一种内源性活性物质,其水溶性高、性质稳定,而其受体广泛分布于机体内,因此不论在中枢神经或外周器官使用α-MSH,均能通过其受体发挥药理效应。另外在动物实验中已证明,α-MSH毒性低,作用持久,其疗效可被精确调节,且反复使用后无耐受。此外,α-MSH安全性较高,临床研究表明其不会引发任何严重不良反应,故而极具开发前景。
穿膜肽(促渗肽)的成分功效分析:
近年来发现有一些小分子的多肽可以介导外源物质穿过细胞膜,这种小分子多肽被称之为细胞穿膜肽(CPP)。人们对肽在药物转运方面的研究最初主要集中于富含碱性氨基酸的细胞穿膜肽,如人免疫缺陷病毒反式激活蛋白TAT、PEP-1等,这些穿膜肽本身可以穿过人或动物的皮肤,部分穿膜肽还可以通过与蛋白共价链接的方式携带蛋白穿过皮肤或生物膜。现在研究最多、应用范围最广的细胞穿膜肽来源于人免疫缺陷病毒I型(HIV-1)的转录激活因子(TAT)。不管是单独的TAT穿膜肽,或者是携带其他大分子物质如蛋白质、寡聚核苷酸或脂质体等,在穿膜时都可以表现出较高的穿膜活性。穿膜肽能够与基因、多肽和蛋白质等生物大分子自组装形成复合物,并将生物大分子递送至细胞内或携载其穿透生物膜屏障。
增强或修复毛囊基因的核酸成分功效分析:
酪氨酸酶是黑色素形成过程的限速酶,含529个氨基酸残基,是一种含铜酶,能被紫外线照射活化,催化酪氨酸氧化聚合等一系列生化反应,生成黑色素。该酶活性大小决定着黑色素形成的数量,故通过调控其活性可以调控黑色素的生成量。
超氧化物歧化酶(SOD)是生物体系中抗氧化酶系的重要组成成员,广泛分布在微生物、植物和动物体内。
谷胱甘肽过氧化物酶(GSH-Px)是机体内广泛存在的一种重要的过氧化物分解酶。GSH-Px的活性中心是硒半胱氨酸,其活力大小可以反映机体硒水平。硒是GSH-Px酶系的组成成分,它能催化GSH变为GSSG,使有毒的过氧化物还原成无毒的羟基化合物,从而保护细胞膜的结构及功能不受过氧化物的干扰及损害。GSH-Px主要包括4种:分别为胞浆GSH-Px、血浆GSH-Px、磷脂氢过氧化物GSH-Px及胃肠道专属性GSH-Px。
过氧化氢酶(CAT)是抗氧化酵素系统的重要一员,又被称为触酶,是以铁卟啉为辅基的结合酶。过氧化氢酶的生物功能是在细胞中促进过氧化氢分解,使其不会进一步产生毒性很大的氢氧自由基,从而保护抗氧化酵素系统的功能作用,对于人体的生长发育和代谢活动亦具有重要意义。
细胞因子的成分功效分析:
细胞因子是免疫原、丝裂原或其他刺激剂诱导多种细胞产生的低分子量可溶性蛋白质,具有调节固有免疫和适应性免疫、促进血细胞生成和细胞生长以及损伤组织修复等多种功能。细胞因子可被分为白细胞介素、干扰素、肿瘤坏死因子超家族、集落刺激因子、趋化因子、生长因子等,众多细胞因子在体内通过旁分泌、自分泌或内分泌等方式发挥作用,具有多效性、重叠性、拮抗性、协同性等多种生理特性,形成了十分复杂的细胞因子调节网络,参与人体多种重要的生理功能,细胞因子能够激活内源干细胞,促进干细胞增殖分裂,补充代替皮肤的衰老死亡细胞,修复损伤的组织,使皮肤重新饱满,增加皮肤弹性,消除皱纹。
成纤维细胞生长因子(FGFs)是参与血管生成、伤口愈合、胚胎发育及各种内分泌信号转导通路的一类生长因子。FGFs是肝素结合蛋白,与细胞表面相关硫酸乙酰肝素蛋白多糖(HSPG)相互作用,该蛋白多糖已被证明是FGF信号转导必不可少的。FGFs在多种组织和细胞增殖分化过程中起到关键作用。其功能强大,具有深层修复作用,在现代临床医学及外科手术和美容手术中发挥着不可估量的巨大作用。
人表皮生长因子(hEGF)是由53个氨基酸组成的小分子多肽,分子量约为6000道尔顿,等电点约为4.6,分子内有三对二硫键,因而对酸、碱、热等理化因素均较稳定。hEGF具有广泛的生物学效应,能极强地促进各种表皮组织生长,在医学上已用于烧烫伤、溃疡、各类创伤以及角膜损伤等的治疗。EGF还能促进正常表皮细胞的新陈代谢,添加到美容护肤品中可以达到美白、抗皱、延缓衰老的作用。重组人表皮生长因子在化妆品中应用具有很好的安全性。临床实验发现重组人表皮生长因子虽然能很快诱导皮肤细胞中多角形细胞增殖,但经过一段时间后便达到生理平衡,细胞不再无限增殖,即表皮生长因子具有使皮肤细胞更新又不导致细胞畸型的特性。
血管内皮生长因子(VEGF),又称血管通透因子(VPF),是一种高度特异性的促血管内皮细胞生长因子,具有促进血管通透性增加、细胞外基质变性、血管内皮细胞迁移、增殖和血管形成等作用。
角质细胞生长因子(KGF-2)是一种碱性蛋白生长因子,能特异刺激上皮细胞的新陈代谢等生理过程,包括细胞的再生、分化和迁移等。角质细胞因子又称FGF-10,是成纤维细胞生长因子(FGF)大家族中较晚被成功克隆的成员,也是人类基因组计划的一个商业化成果。它是人机体内自然存在的一种具有活性的可溶性蛋白质,由194个氨基酸编码组成,成熟KGF有163个氨基酸残基,其N端有一个糖基化位点在人体内主要由皮下组织分泌,并特异性的结合到上皮细胞表面的特异受体,经过复杂的信号传递过程,启动上皮细胞内参与分裂生长的基因表达,从而刺激上皮组织的新陈代谢。角质细胞生长因子中的KGF-2有以下的优点:①组织特异性强,稳定,安全性好。②对新生或老化的上皮细胞均有刺激生长分裂作用。而其他如TGF等虽然也能促表皮组织生长,但组织特异性弱,对已老化的组织没有任何作用;③具有明显的除疤痕和抗辐射损伤的作用。其他因子(包括KGF-1和TGF)效果不理想;④独特的育发生发作用。裸鼠实验证实KGF-2可促进毛囊发育和毛发生长,而用其他生长因子则未观察到相应结果。
本发明具有以下有益的技术效果:
1、本发明将黑色素、微量元素、恢复黑色素正常代谢的蛋白多肽成分、增强或修复毛囊基因的核酸成分、抗氧化相关基因和/或有益毛囊健康的细胞因子等高效制备成脂质体。采用脂质体包封蛋白质DNA等功效性生物大分子,可极大的提高其透皮吸收效率,有效促进毛囊黑色素正常代谢,维护头皮毛囊健康,促进白发转黑;有效成分尤其是生物大分子,被脂质体包裹后,透皮吸收效果和常温保存稳定性得到很大提高,还可在皮肤表皮层蓄积,起到长效缓释作用,提升局部药物浓度,增强治疗作用;该脂质体与人体内天然微囊的大小和结构类似,有亲毛囊特性,靶向毛囊、起到促进白发转黑、维护头皮健康的作用。
2、本发明主要解决两个技术问题:一,增加头皮对治疗产品的吸收率和药物成分靶向性,前者主要是利用脂质体强大的透皮吸收能力转导有效成分突破角质层来实现,后者则是脂质体亲毛囊属性的体现;二,解决白发问题,脂质体是基因转染的良好载体,可以将乌发相关基因,特异性载入毛母质细胞和毛囊干细胞,还可以利用其包裹黑发相关细胞因子/维生素/矿物质等关键成分,多个靶点共同作用,达到恢复毛囊健康颜色的目的。黑色素是一类结构复杂的生物大分子色素的总称,在正常毛发中存在生成、转运、释放三个阶段,其中任何一个出现障碍都会导致白发。除了提高黑色素生成的关键酶——酪氨酸酶的活性、促进黑色素生成,直接补充黑色素也是一种可行的办法。且随着年龄增长,普遍出现的衰老性白发以及频繁染发导致的白发多与氧化应激有关,因此增强毛囊部位清除氧自由基的能力也很关键。另外,白发症状可由维生素缺乏导致,如维生素B6/B12;同时白发患者常缺乏Cu2+、Fe2+、Zn2+等矿物质。
3、本发明中溶液A、溶液B、溶液C和/或溶液D四类组分别以脂质体包裹,可以根据白发的病因、病情严重程度和治疗阶段调整应用比例,以便达到最佳治疗效果。作为水相的溶液可以是溶液A、溶液B、溶液C、溶液D四类液体中的一种,也可以多种成分的混合。所述乌发类蛋白多肽类成分可以为α-黑素细胞刺激素(α-MSH),内皮素-1(ET-1),铜肽中的一种或者混合。抗氧化相关基因可包括酪氨酸酶,超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽过氧化物酶等。核酸类型可为质粒DNA,siRNA,shRNA,microRNA,反义RNA和寡聚核苷酸。所述维护头皮健康的细胞因子成分可使用源自脐带干细胞、脂肪干细胞、成纤维细胞中的一种或者多种分泌的细胞因子复合物,也可以使用成分明确的生长因子,如表皮生长因子、血管内皮生长因子、角质细胞生长因子等中的一种或者多种混合。
4、本发明的脂质体可以是液体制剂或固体制剂,还可以根据情况制成喷雾剂,喷雾剂是指不含抛射剂,借助于手动泵的压力将液体喷射成雾状的制剂,相比其他剂型而言,喷雾携带使用方便,雾状直接喷洒于头发和头皮,不需用手涂抹,不粘手,同时可以减少损失。
附图说明
下面结合附图对本发明作进一步的说明:
图1为本发明实施例所得脂质体的粒径分布图;
图2为本发明实施例制备脂质体的透射电镜图;
图3为本发明实施例所得脂质体透皮吸收效果图。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点,下面结合附图和具体实施例对本发明进行详细描述。需要说明的是,在不冲突的情况下,本申请的实施例及实施例中的特征可以相互组合。除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
实施例1:
该实施例提供一种促进头皮健康、并能使白发变黑的脂质体乌发喷剂。所述脂质体乌发喷剂包括下表中所述的重量份比的成分:
表1实施例1的脂质体乌发喷剂的配方
成分 | 百分比含量 |
磷脂/胆固醇 | 3.5% |
黑色素 | 2% |
铜肽 | 0.01% |
超氧化物歧化酶重组质粒 | 0.001% |
表皮生长因子 | 0.001% |
碱性成纤维细胞生长因子 | 0.001% |
花青素 | 2% |
促渗肽TAT | 0.001% |
该实施例提供的脂质体乌发喷剂的制备方法如下:
1.磷脂脂质体膜的制备
将质量比为10:1的蛋黄卵磷脂和胆固醇加入到4-6倍量的无水乙醇中,在45-60℃条件下溶解,将溶解后的溶液进行旋转蒸发,使其形成均匀的薄膜;或直接使用市售的磷脂脂质体膜(Pro-LipoTM Neo,Lucas Meyer Cosmetics公司)。
2.水相的制备
溶液A的制备:称取5g水溶性黑色素和10g L-精氨酸,加入蒸馏水中搅拌5-20min,加热溶解,过滤,加水补足100mL体积,黑色素终浓度5%;
溶液B的制备:称取25mg铜肽,加入50ml生理盐水搅拌混匀,配置为0.05%的溶液。
溶液C的制备:称取2.5mg超氧化物歧化酶重组质粒,加入50ml超纯水搅拌混匀,配置为0.005%的溶液。
溶液D的制备:称取2.5mg表皮生长因子、2.5mg碱性成纤维细胞生长因子,加50ml生理盐水溶解,配置为0.01%的溶液。
3.脂质体的制备:
分别以溶液A、溶液B、溶液C、溶液D为水相,按3.5%的重量比称取磷脂脂质体膜,每种溶液单独制备脂质体。具体过程为:将水相以4%V/min的速度缓慢注入磷脂中,同时以900rpm/min的速度搅拌,完成后继续搅拌20min,然后进行均质处理,即得到脂质体溶液。根据使用水相的不同,分别得到脂质体A液,脂质体B液,脂质体C液,脂质体D液。
取脂质体A液40ml,脂质体B液20ml,脂质体C液20ml,脂质体D液20ml,加入1mg促渗肽TAT和2g花青素混合均匀,灌装于喷剂专用瓶中,即得到具有乌发作用的脂质体喷剂。用超滤离心法测定脂质体的包封率,透射电镜观察脂质体的形态,粒度分析仪检测脂质体的粒径分布和Zeta电位。
放置稳定性考察:脂质体乌发喷剂使用的脂质体A液,脂质体B液,脂质体C液,脂质体D液均于25℃放置3个月,用超滤离心法测定脂质体的包封率,粒度分析仪检测脂质体的粒径分布。
表2本实施例1所含各脂质体溶液组分的包封率
图1为脂质体乌发喷剂的粒径分布,平均粒径272.3nm,zeta电位-19.71mv。
图2为透射电镜下脂质体乌发喷剂的形态。
实验结果:脂质体乌发喷剂最初粒径分布在120-650nm,无聚集沉淀现象,各组分包封率均在85%以上。25℃放置3个月后,粒径分布仍然在120-650nm,无聚集沉淀现象,各组分包封率仍为85%以上,证明脂质体乌发喷剂放置过程中包封的各种有效成分无明显渗漏,稳定性好,包封率高。
本实施例提供的脂质体乌发喷剂经50个35岁到47岁的白发患者试用,45天后,76%出现白发发根处转黑的现象。
实施例2
该实施例提供一种促进头皮健康、并能使头发变黑的脂质体乌发喷剂。所述脂质体乌发喷剂包括下表中所述的重量份比的成分:
表3实施例2的脂质体乌发喷剂的配方
成分 | 具体含量 |
磷脂 | 3.5% |
黑色素 | 4% |
铜肽 | 0.01% |
过氧化氢酶重组质粒 | 0.001% |
表皮生长因子 | 0.001% |
碱性成纤维细胞生长因子 | 0.001% |
维生素C | 2% |
促渗肽TAT | 0.001% |
该实施例提供的脂质体乌发喷剂的制备方法如下:
1.磷脂脂质体膜的制备
将蛋黄卵磷脂加入到4-6倍量的无水乙醇中,在45-60℃条件下溶解,将溶解后的溶液进行旋转蒸发,使其形成均匀的薄膜;
2.水相的制备
溶液A的制备:称取10g水溶性黑色素和10gL-精氨酸,加入蒸馏水中搅拌5-20min,加热溶解,过滤,加水补足100mL,黑色素终浓度10%。
溶液B的制备:称取25mg铜肽,加入50ml生理盐水搅拌混匀,配置为0.05%的溶液。
溶液C的制备:称取2.5mg过氧化氢酶重组质粒,加入50ml超纯水搅拌混匀,配置为0.005%的溶液。
溶液D的制备:称取2.5mg表皮生长因子、2.5mg碱性成纤维细胞生长因子,加50ml生理盐水溶解,配置为0.01%的溶液。
3.脂质体的制备:
分别以溶液A、溶液B、溶液C、溶液D为水相,按3.5%的重量比称取磷脂脂质体膜(不含胆固醇),每种溶液单独制备脂质体。具体过程为:将水相以4%V/min的速度缓慢注入磷脂中,同时以900rpm/min的速度搅拌,完成后继续搅拌20min,然后进行均质处理,即得到脂质体溶液。根据使用水相的不同,分别得到脂质体A液,脂质体B液,脂质体C液,脂质体D液。
取脂质体A液40ml,脂质体B液20ml,脂质体C液20ml,脂质体D液20ml,加入1mg促渗肽TAT和2g维生素C混合均匀,灌装于喷剂专用瓶中,即得到具有乌发作用的脂质体喷剂。用超滤离心法测定脂质体的包封率,透射电镜观察脂质体的形态,粒度分析仪检测脂质体的粒径分布和Zeta电位。
放置稳定性考察:同实施例1。
表4本实施例所含各脂质体溶液组分的包封率
实验结果:脂质体乌发喷剂最初粒径分布在100-700nm,无聚集现象,各组分包封率均在82%以上。25℃放置3个月后,粒径分布仍然在100-700nm,无聚集现象,各组分包封率均在82%以上。证明脂质体乌发喷剂放置过程中包封的有效成分无明显渗漏。稳定性好,包封率高。
对比实施例1和2制备的脂质体可知,制备过程中加入或不加入胆固醇所得的脂质体,其粒径大小及分布、外观、稳定性均相似。
本实施例提供的脂质体乌发喷剂经50个30岁到45岁的白发患者试用,45天后,81%出现白发发根处转黑的现象。
实施例3:
分别按下表处方进行脂质体乌发喷剂的制备。
表5实施例3中的脂质体乌发喷剂的配方
制备方法:
步骤a:水相的制备
溶液A的制备:称取黑色素、氨基酸和微量元素,加入蒸馏水中搅拌5-20min,加热溶解,过滤,加水补足体积;所述黑色素与氨基酸的质量比为1g:1-3g,所述氨基酸为L-精氨酸、DL-精氨酸或DL-组氨酸中的一种或一种以上;其中,处方1中的微量元素加入量:硫酸亚铁15μmol/L、硫酸锌20μmol/L;处方2中的微量元素加入量:葡萄糖酸铜10-20μmol/L;处方3中的微量元素加入量:葡萄糖酸锌10-20μmol/L;处方4-5未加入微量元素。
溶液B的制备:称取适量蛋白多肽成分,加生理盐水搅拌混匀,配置成溶液;所述蛋白多肽包括α-黑素细胞刺激素、内皮素-1或铜肽中的一种或者一种以上。
溶液C的制备:构建酪氨酸酶、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)或谷胱甘肽过氧化物酶重组质粒,转化到大肠杆菌中进行大量扩增,收集质粒,溶于无菌的超纯水中,配制成溶液;
溶液D的制备:培养脐带干细胞、脂肪干细胞或成纤维细胞,收集上清液,通过超滤浓缩技术富集细胞因子复合物,配制成溶液;或将市售成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、角质细胞生长因子中的一种或者多种,用无菌注射用水或生理盐水搅拌溶解;
步骤b:油相的制备:
将磷脂、胆固醇加入到无水乙醇中,在45-60℃条件下溶解,将溶解后的溶液进行旋转蒸发,使其形成均匀的薄膜;所述的无水乙醇的用量是磷脂、胆固醇总质量的4-6倍;或直接使用市售的磷脂脂质体膜(Pro-LipoTM Neo,Lucas Meyer Cosmetics公司)。
步骤c:脂质体的制备:
将步骤a中的溶液A、溶液B、溶液C和/或溶液D加入到步骤b中的薄膜中,再加入抗氧化剂混合搅拌,直至薄膜完全溶解,得到乳浊液,然后将A、B、C和/或D的乳浊液在30-45℃的水浴条件下搅拌20-40min得混悬液,混悬液在35-40℃水浴条件下超声处理10-30min,得粗制脂质体;然后加入透皮吸收促进剂,进行均质处理,即得到精制脂质体混悬液;
步骤d:脂质体制剂的制备:
将所得的精制脂质体混悬液灌装于容器中,再向容器中依次冲入CO2和N2,即得脂质体喷雾剂;
用超滤离心法测定脂质体的包封率,透射电镜观察脂质体的形态,粒度分析仪检测脂质体的粒径分布和Zeta电位。
放置稳定性考察:同实施例1。
其中,源自人脐带干细胞、脂肪干细胞、成纤维细胞的细胞因子复合物的制备方法:
1)细胞的原代分离:临床来源新鲜人体组织(脐带/脂肪/包皮),通过酶消化法获得细胞悬液(脐带干细胞/脂肪干细胞/成纤维细胞),正常接种,传代培养;
2)扩大培养:步骤1)所得细胞用细胞工厂进行扩大培养,收集足够数量的细胞;
3)细胞因子复合物的获取:细胞正常培养3~5d,收集上清,用0.22μm滤器过滤,除去细胞碎片及其他较大粒径的颗粒,用超滤浓缩技术对收集到的条件培养基进行浓缩,即得到细胞因子复合物。
实验结果:脂质体乌发喷剂最初粒径分布在100-700nm,无聚集现象,各组分包封率均在85%以上。25℃放置3个月后,粒径分布仍然在100-700nm,无聚集现象,各组分包封率均在85%以上。证明脂质体乌发喷剂放置过程中包封的有效成分无明显渗漏。稳定性好,包封率高。
实施例4:
本发明的实施方案利用昆明小鼠皮肤观察实施例1所得脂质体乌发喷剂的透皮吸收情况。
小鼠皮肤的处理:将昆明小鼠用4%水合氯醛腹腔麻醉后(0.1ml/10g),用电动剃刀小心剃去背部毛发,脱毛膏处理残留毛发,露出皮肤,第二天处死,取下已去毛的皮肤,剔除皮下脂肪,保鲜膜包裹,4度保存备用。
透皮实验:准备好的离体鼠皮制成直径30mm的皮肤样本,置于Franz扩散池上,表皮面向供给池,接受池开口直径20mm,接受液为生理盐水。脂质体乌发喷剂加入供给池,作用1h后,取下待测皮肤。生理盐水漂洗3次,滤纸吸干表面水分,切下中心5×5mm2的皮肤,用OTC包埋剂于-20℃包埋,立即用于制作冰冻切片,厚度15μm。通过激光共聚焦观察脂质体在皮肤各层的分布。
图3是本实施例提供的脂质体乌发喷剂的透皮吸收过程。如图所示,由于包封有效成分的脂质体膜与人体细胞膜结构及成分接近,经由脂质融合作用,完整的脂质体可以顺利透过角质层,将其所包裹的有效成分直接导入皮肤发挥作用。脂质体无毒无免疫原性,可在生物体内安全蓄积,因此可起到控释作用,使局部药物浓度长时间恒定维持在有效作用范围内,减少副作用。同时因脂质体具有毛囊靶向性,可以提高基因、多肽等有效成分在毛囊的作用浓度,从而针对性的治疗白发。
最后应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或等同替换,而不脱离本发明技术方案的精神和范围。
Claims (10)
1.一种用于乌发的脂质体,其特征在于包括以下组分:脂质体成膜材料,质量百分比浓度为2%~12%;黑色素,质量百分比浓度为1%~5%;抗氧化剂,质量百分比浓度为0~5%。
2.根据权利要求1所述的用于乌发的脂质体,其特征在于:还包括微量元素,所述微量元素包括铜、铁、锌、硒、镁及钙的盐或有机酸盐一种或一种以上,所述微量元素在制剂中的浓度:Cu:10~20μmol/L,Fe:15~35μmol/L,Zn:10~20μmol/L,Se:0.5~1.5μmol/L,Mg:0.5~1mmol/L,Ca:1.5~2mmol/L;所述抗氧化剂包括花青素、白藜芦醇、维生素A、维生素C、维生素E、类胡萝卜素等成分中的一种或几种。
3.根据权利要求1所述的用于乌发的脂质体,其特征在于:所述脂质体成膜材料包括磷脂、胆固醇,所述磷脂与胆固醇的质量比为9-10:0-2;所述磷脂包括大豆磷脂、二月桂酰卵磷脂、二肉豆蔻酰卵磷脂、二棕榈酰卵磷脂、二硬脂酰卵磷脂、二硬脂酰卵磷脂、蛋黄卵磷脂、氢化豆磷脂、二油酰基卵磷脂、二月桂酰磷脂酰甘油、二棕榈脂酰甘油、二硬脂酰磷脂酰甘油、二油酰磷脂酰甘油和二肉豆蔻酰磷脂酸中的一种或几种。
4.根据权利要求1所述的用于乌发的脂质体,其特征在于:还包括恢复黑色素正常代谢的蛋白多肽成分,质量百分比浓度为0.001%~1%;所述蛋白多肽包括α-黑素细胞刺激素、内皮素-1或铜肽中的一种或者一种以上。
5.根据权利要求1所述的用于乌发的脂质体,其特征在于:还包括增强或修复毛囊基因的核酸成分,质量百分比浓度为0~0.05%;所述增强或修复毛囊基因的核酸成分,包含酪氨酸酶、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽过氧化物酶的编码基因中的一种或者一种以上;所述核酸类型可为质粒DNA、siRNA、shRNA、microRNA、反义RNA或寡聚核苷酸。
6.根据权利要求1所述的用于乌发的脂质体,其特征在于:还包括细胞因子成分,所述细胞因子成分为源自脐带干细胞、脂肪干细胞、成纤维细胞中的一种或者多种,质量百分比浓度为0.01~0.1%。
7.根据权利要求1所述的用于乌发的脂质体,其特征在于:还包括细胞因子成分,所述细胞因子成分为成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、角质细胞生长因子中的一种或者多种,质量百分比浓度为0.0001~0.01%。
8.根据权利要求1所述的用于乌发的脂质体,其特征在于:还包括透皮吸收促进剂,所述透皮吸收促进剂包括促渗肽TAT、R9、R11、Pep-1、SPACE、TD-1以及Penetratin中的一种或几种,所述透皮吸收促进剂在制剂中的浓度0~0.05%。
9.根据权利要求1-8任一所述的用于乌发的脂质体的制备方法,其特征在于包括以下步骤:
步骤a:水相的制备
溶液A的制备:称取黑色素、氨基酸和微量元素,加入蒸馏水中搅拌5-20min,加热溶解,过滤,加水补足体积;所述黑色素与氨基酸的质量比为1g:1-3g,所述氨基酸为L-精氨酸、DL-精氨酸或DL-组氨酸中的一种或一种以上;
溶液B的制备:称取适量蛋白多肽成分,加生理盐水搅拌混匀,配置成溶液;
溶液C的制备:构建酪氨酸酶、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)或谷胱甘肽过氧化物酶重组质粒,转化到大肠杆菌中进行大量扩增,收集质粒,溶于无菌的超纯水中,配制成溶液;
溶液D的制备:培养人源脐带干细胞、脂肪干细胞或成纤维细胞,收集上清液,通过超滤浓缩技术富集细胞因子复合物,配制成溶液;或将市售成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、角质细胞生长因子中的一种或者多种,用无菌注射用水或生理盐水搅拌溶解;
步骤b:油相的制备:
将磷脂、胆固醇加入到无水乙醇中,在45-60℃条件下溶解,将溶解后的溶液进行旋转蒸发,使其形成均匀的磷脂脂质体膜;所述的无水乙醇的用量是磷脂、胆固醇总质量的4-6倍;或直接使用市售的磷脂脂质体膜;
步骤c:脂质体的制备:
将步骤a中的溶液A、溶液B、溶液C和/或溶液D分别加入到步骤b中的磷脂脂质体膜中,再加入抗氧化剂混合搅拌,直至薄膜完全溶解,得到乳浊液,然后将A、B、C和/或D的乳浊液在30-45℃的水浴条件下搅拌20-40min得混悬液,混悬液在35-40℃水浴条件下超声处理10-30min,得粗制脂质体;然后加入透皮吸收促进剂,进行均质处理,即得到精制脂质体混悬液;
步骤d:脂质体制剂的制备:
将所得的精制脂质体混悬液灌装于容器中,再向容器中依次冲入CO2和N2,即得脂质体喷雾剂;
或将所得的精制脂质体混悬液,加入冻干保护剂,冻干,得脂质体冻干粉成品;所述冻干保护剂为海藻糖、乳糖、蔗糖、麦芽糖、甘露醇、脯氨酸和甘氨酸中的一种或几种;将所得的精制脂质体冻干粉成品再制备成脂质体喷雾剂、脂质体凝胶、脂质体搽剂、脂质体乳剂。
10.根据权利要求9所述的用于乌发的脂质体的制备方法,其特征在于:步骤c中,所述均质过程中的压力控制在40~300Mpa范围内,匀质次数为3~15次。
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