CN113226293B - 利用壳聚糖涂覆的纳米胶囊及其用途 - Google Patents
利用壳聚糖涂覆的纳米胶囊及其用途 Download PDFInfo
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- CN113226293B CN113226293B CN201980085253.4A CN201980085253A CN113226293B CN 113226293 B CN113226293 B CN 113226293B CN 201980085253 A CN201980085253 A CN 201980085253A CN 113226293 B CN113226293 B CN 113226293B
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Abstract
本发明涉及涂覆有壳聚糖的纳米胶囊及其用途,确立了制备具有优异的稳定性且粒子大小为500nm以下、或300nm,尤其是100nm以下的纳米胶囊的方法,并通过将难溶性药物载入由此制备的纳米胶囊,确认了包含药物的纳米胶囊具有优异的皮肤渗透率以及基于此的向皮肤的药物递送和基于药物的功效。并且,通过口服给药所制备的纳米胶囊确认体内有效成分的生物利用率得以提高,可期待利用本发明的涂覆有壳聚糖的纳米胶囊开发出一种能使医药领域、化妆品行业、食品产业等中的难溶性药物或有效物质向人体、家畜及宠物等动物的递送效率显著提高的优异的递送系统。
Description
技术领域
本发明涉及一种利用壳聚糖涂覆的纳米胶囊及其用途,更详细地,涉及一种利用壳聚糖涂覆含普兰尼克的纳米粒子的纳米胶囊及其用途。
背景技术
纳米粒子(nanoparticles)是指大小一般大于原子且小于细胞,直径在1~1000nm范围内的粒子形态的物质,其为一种利用随着纳米粒子的大小减小而产生的表面积增加效果或渗透效果创造出新的应用领域的材料。尤其,在利用电磁特性的电子部件领域、利用药物吸收性质的医药和化妆品领域以及光催化剂或燃料电池领域等领域中的应用大大增加。
通常,纳米粒子可利用诸如金(gold)、氧化锡(tin oxide)、白蛋白(albu min)等聚合物(polymeric material)之类的非活性物质来制备,与具有较大直径的粒子相比,将这些水平的粒子应用于生物系统时,具有通过膜的渗透性增加、光学活化、对分子水平上的凝集现象的调节等物理、化学及生物上明显不同的特性。
纳米胶囊是纳米大小的空心球形的胶囊,可在纳米胶囊的空心内部装入各种物质。脂质体是具有代表性的纳米胶囊之一,具有两性性质的磷脂等以两层形成的球体形态存在,由于可将水溶性药物包含在空隙中,因此用于药物递送等。然而,此类脂质体具有结构不稳定且渗透度低的缺点,因此仅应用于有限的领域中。因此,已经以多种方式尝增加空心胶囊的稳定性和渗透度,其结果诞生了利用高分子制备的纳米胶囊。
在医药领域中,目前正在进行着许多利用包含各种药物的纳米递送体向细胞中递送药物来表达药物功效的研究。作为具有代表性的药物递送体,首先,脂质体(liposome)是由磷脂组成的递送体,亲油性和亲水性药物均可包含于其中,且其作为生物相容性物质无毒,并且,具有能够对粒子表面进行改性以适应目的的优点,但存在如下缺点,即在肝脏或脾脏细胞中被网状内皮系统(reti culoendothelial system)捕获,并迅速从血液中清除或粒子被破坏而导致到达靶标的量少,因此,还以在脂质体表面修饰聚乙二醇(polyethylene glycol,PEG)来增加体内血中的停留时间或应用各种抗体或配体以增加靶向性的方式进行使用。胶束(micelle)是由亲水性和疏水性链组成的共聚合物构成的递送体,在水溶液中,疏水部分聚集在中心形成球形,正在进行通常在中心加入难溶性药物来增加溶解度和生物利用率的研究(权赫灿,2010).
在化妆品行业中,开发美白、抗皱、抗氧化及抗老化等功能性化妆品的新材料的同时,实际应用于皮肤时提高经皮吸收率的技术是一项重要的课题。这是因为有效成分因作为屏障的皮肤而不能吸收,即使是具有非常优秀的功效的成分,应用于皮肤时也无法发挥其效果。因此,化妆品行业的最大的关心点在于能否在不刺激皮肤的情况下促进其吸收有效成分并发挥最大效果。为此,提出了许多促进吸收有效成分的方法,目前也正在积极进行从局部作用(topical effect)到全身作用(systemic effect)等的研究,通过这些研究确认了有效成分大小在500nm以下且水包油(oil in water,O/W)剂型时,更易于皮肤渗透(金银珠等,2010)。
最近,在经皮吸收促进方法中,研究最多的方法是剂型促透法,大致可分为五种。第一种是pH敏感性高分子水凝胶。其为通过制备具有pH敏感性的高分子水凝胶来将对外部环境下不稳定的活性物质稳定地保存在化妆品剂型中,并涂抹于皮肤时通过快速释放能够被皮肤吸收的系统。第二种是高分子胶束,其中,亲水性高分子和疏水性高分子以嵌段共聚物的形式结合,以将疏水性活性成分有效地分散在水溶液中。第三种是纳米乳液,其特征在于,其为粒子大小为100~500nm的乳液之一,但其与普通乳液不同,没有粒子之间聚集或聚结现象,因此在低粘度条件下也长期保持稳定性。第四种是脂质体,它是由结构类似于细胞膜或角质层的细胞间脂质的脂质双层组成,通过与细胞膜融合,可以有效地将活性成分输送到细胞内的结构。第五种是醇质体和弹性脂质体,作为为了相比于脂质体提高皮肤渗透率而提出的方法,其为以使膜更柔软且易于变形的状态制备的制剂,(Chung,J.Y.等,2014)。
食品产业中的纳米粒子主要制成粒子或胶囊的形式,其具有保护营养成分免受光、氧、水分和温度等外界因素的影响,减少损失,增加有用性,增加生理活性,增加稳定性,调节靶点等的优点,因此可以以各种方式应用于未来的高附加值食品等中。与传统食品材料相比,应用纳米技术的食品材料体积减小、表面积增加,因此提高了粒子和胶囊的渗透性和滞留时间,有望增加体内吸收和利用,并且,可提高溶解度和分散性(dispersibility),利用于体内细胞时,具有可通过很难渗透的细胞的脂质双层膜的潜力,因此可期待功能性物质的有效利用(金世勋等,2014)。
为此,本发明人在开发向人体递送生理有效物质的系统的过程中,确立了一种制备粒子大小为500nm以下,尤其是200nm以下且稳定性优异的纳米胶囊的方法,并通过将难溶性药物载入由此制备的纳米胶囊,确认了包含药物的纳米胶囊的优异的皮肤渗透率以及基于此的向皮肤的药物递送和基于药物的功效。并且,确认了通过口服给药所制备的纳米胶囊的体内有效成分的生物利用率增加,从而完成了本发明。
在作为现有技术的韩国授权专利第1698809号中,记载了由难溶性药物、普兰尼克和壳聚糖组成的多层纳米粒子,但含药物的第一核中进一步含有二醇类化合物,包含泊洛沙姆的第二核中进一步含有聚氧醚类化合物或聚氧蓖麻油类化合物,因此其组成与本发明的仅由难溶性药物和普兰尼克组成的纳米粒子不同。并且,韩国授权专利第1748127号中记载了对包含药物和普兰尼克(泊洛沙姆)的纳米粒子利用壳聚糖进行涂覆的纳米粒子,但它是对药物中含普兰尼克和聚乳酸-羟基乙酸共聚物(PLGA)的纳米粒子利用壳聚糖进行涂覆的纳米粒子,其组成与本发明的对仅由药物和普兰尼克组成的纳米粒子利用壳聚糖进行涂覆的纳米胶囊具有差异,并且,未记载本发明的纳米胶囊的优异的皮肤渗透效果。
非专利文献(Escobar-Chavesz,J.J.,et al.,(2006))中记载了普兰尼克凝胶的药学剂型和纳米粒子、温度反应性和皮肤递送,并记载了壳聚糖的皮肤渗透效果,但并未记载本发明的利用壳聚糖涂覆含药物和普兰尼克的纳米粒子的纳米胶囊以及其皮肤渗透率增加效果。
发明内容
发明要解决的问题
本发明的目的在于提供涂覆有壳聚糖的纳米胶囊及其制备方法。
并且,本发明的目的在于提供含有所述纳米胶囊的各种用途的组合物。
用于解决问题的手段
本发明涉及一种含活性剂和普兰尼克的纳米粒子涂覆有壳聚糖的纳米胶囊。
所述纳米胶囊可通过如下步骤制备:第一步骤,将活性剂和普兰尼克溶于有机溶剂并在常温下通过反应制备反应溶液;第二步骤,将所述第一步骤的反应溶液滴入蒸馏水中,并持续搅拌,通过自然蒸发除去反应溶液的有机溶剂来制备纳米粒子;以及第三步骤,在所述第二步骤的纳米粒子中加入壳聚糖来涂覆壳聚糖。
以100重量份的普兰尼克为基准,所述活性剂可以为0重量份~20重量份,但不包括0。
所述活性剂可以为选自由抗癌剂、免疫抑制剂、抗氧化剂、抗炎剂、抗皱剂、防脱发剂、伤口愈合剂、皮肤美白剂、营养补充剂、免疫抗原、蛋白质疗剂、血管再生剂、抗真菌剂、抗生素、抗病毒剂、镇静剂、镇痛剂、抗老化剂、抗皱剂、皮肤美白剂、皮肤脱色剂、紫外线阻隔剂、染料、着色剂、除臭剂及芳香剂组成的组中的一种以上。
所述活性剂可以是脂溶性或难溶性药物,其可以是选自由所述脂溶性或难溶性抗癌剂(紫杉醇(paclitaxel)、多西他赛(docetaxel)、汉防己甲素(tetradr ine));所述脂溶性或难溶性免疫抑制剂(环孢素A(cyclosporin A)、地塞米松(dexamethasone));所述脂溶性或难溶性抗氧化剂(生育酚乙酸酯(tocopheryl acetate)、虾青素(astaxanthin)、姜黄素(curcumin)、抗坏血酸-棕榈酸酯(ascorbyl palmitate));所述脂溶性或难溶性抗炎剂(右泛醇(dexpanthenol)、咖啡酸苯乙酯(caffeic acid phenethyl ester;CAPE));所述脂溶性或难溶性抗皱剂(视黄醇乙酸酯(retinyl palmitate));所述脂溶性或难溶性防脱发剂(米诺地尔(minoxidil)、非那雄胺(finasteride));所述脂溶性或难溶性伤口愈合剂(积雪草(centella asiatica)提取物、β-谷甾醇);所述脂溶性或难溶性皮肤美白剂(抗坏血酸四异棕榈酸酯(ascorbyl tetraisopalmitate));所述脂溶性或难溶性营养补充剂(胶原三肽(tripeptide collagen))组成的组中的一种以上。
所述活性剂可以为水溶性药物,其可以是选自由所述水溶性抗癌剂(多柔比星(doxorubicin));所述水溶性抗炎剂(磷脂酶A2(phospholipase A2;PLA2));所述水溶性免疫抗原(卵白蛋白(ovalbumin));所述水溶性蛋白质疗剂(牛血清白蛋白(bovine serumalbumin));所述水溶性伤口愈合剂(碱性成纤维细胞生长因子(b-FGF));所述水溶性血管再生剂(血管内皮生长因子(vascular endothelial growth factor;VEGF))组成的组中的一种以上。
所述普兰尼克可以为选自由普兰尼克L35、普兰尼克L43、普兰尼克L44、普兰尼克L64、普兰尼克F68、普兰尼克P84、普兰尼克P85、普兰尼克F87、普兰尼克F88、普兰尼克F98、普兰尼克P103、普兰尼克P104、普兰尼克P105、普兰尼克F108、普兰尼克P123和普兰尼克F127组成的组中的一种以上。
所述纳米粒子在32.5~37℃的温度下粒子大小可以为5~80nm。优选为5~50nm。
所述壳聚糖可以是分子量为3~100kDa的壳聚糖。
以100重量份的普兰尼克为基准,可包含0.001~200重量份的所述壳聚糖。
所述纳米胶囊在32.5~37℃的温度下粒子大小可以为700nm以下。优选地,在32.5~37℃的温度下粒子大小可以为30~500nm。更优选为30~300nm,最优选为30~100nm。
所述第一步骤的有机溶剂可以为选自由丙酮、二甲基亚砜(dimethyl sulfoxide,DMSO)、乙醇、乙腈(acetonitrile)、四氢呋喃(tetrahydrofuran)、氯仿(chloroform)和二氯甲烷(dichloromethane)组成的组中的一种。
以所述第一步骤的有机溶剂体积为基准,所述第二步骤的蒸馏水可使用所述第一步骤的有机溶剂体积的4倍。
相对于单独处理活性剂,所述纳米胶囊的皮肤渗透率可以增加2倍以上,优选为5倍以上,更优选为10倍以上,进一步优选为14倍以上。
并且,本发明涉及含有所述纳米胶囊的药物递送系统、化妆品材料组合物、保健功能食品组合物、医疗设备用组合物及生活用品用组合物。
下面,详细说明本发明。
本发明涉及涂覆有壳聚糖的纳米胶囊,具体地涉及在活性剂和普兰尼克组成的纳米粒子涂覆有壳聚糖的纳米胶囊。
在本发明中,“纳米胶囊”是纳米大小的空心的球形胶囊,可在空心的纳米胶囊中载入各种物质,如活性剂。
可利用本领域公知的制备方法来制备本发明的纳米胶囊。优选地可利用纳米沉淀法和膜重分散法,更优选为纳米沉淀法。
最优选地,所述纳米胶囊可通过如下步骤制备:第一步骤,将活性剂和普兰尼克溶于有机溶剂并在常温下通过反应制备反应溶液;第二步骤,将所述第一步骤的反应溶液滴入蒸馏水中,并持续搅拌,通过自然蒸发除去反应溶液的有机溶剂来制备纳米粒子;以及第三步骤,在所述第二步骤的纳米粒子中加入壳聚糖来涂覆壳聚糖。
所述第一步骤的有机溶剂为选自由丙酮、二甲基亚砜、乙醇、乙腈、四氢呋喃、氯仿及二氯甲烷组成的组中的一种以上,但并不限定于此。优选为,选自由丙酮、四氢呋喃、乙醇及乙腈组成的组中的一种以上,更优选丙酮。
所述第二步骤的蒸馏水可以使用所述第一步骤的有机溶剂体积的2~10倍。优选地,使用2~5倍,更优选地,使用4倍。基于小于有机溶剂的体积,在使用小于机溶剂的体积2倍的所述蒸馏水的情况下,可能会发生部分沉淀,在大于10倍的情况下,壳聚糖涂覆不稳定或纳米胶囊的浓度被稀释,导致需要添加浓缩工序而不佳。
所述活性剂是具有水溶性和脂溶性特性的有效物质,可为选自由抗癌剂、免疫抑制剂、抗氧化剂、抗炎剂、抗皱剂、防脱发剂、伤口愈合剂、皮肤美白剂、营养补充剂、免疫抗原、蛋白质疗剂、血管再生剂、抗真菌剂、抗生素、抗病毒剂、镇静剂、镇痛剂、抗老化剂、抗皱剂、皮肤美白剂、皮肤脱色剂、紫外线阻隔剂、染料、着色剂、除臭剂和芳香剂等组成的组中的一种以上,但并不限定于此。
以100重量份的普兰尼克为基准,可包含使活性剂具有功效和效果的最低重量份至20重量份的所述活性剂,即0重量份~20重量份,但不为0。优选地,包含0重量份至10重量份(不为0)。在所述活性剂大于20重量份的情况下,纳米粒子的大小变得过大,或者纳米粒子不含所有活性剂,不能准确的递送有效量的活性剂,因此不佳。
在本发明中,“普兰尼克”为亲水性高分子,具有温度敏感性性质,存在具有各种亲水亲油平衡值(hydrophile-lipophile balance,HLB)的衍生物。所述普兰尼克可以为选自由亲水亲油平衡值为8~29的普兰尼克,例如,可为选自由普兰尼克L35、普兰尼克L43、普兰尼克L44、普兰尼克L64、普兰尼克F68、普兰尼克P84、普兰尼克P85、普兰尼克F87、普兰尼克F88、普兰尼克F98、普兰尼克P103、普兰尼克P104、普兰尼克P105、普兰尼克F108、普兰尼克P123及普兰尼克F127组成的组中的一种以上,优选地,选自由亲水亲油平衡值为15~29的普兰尼克,例如,可为选自由普兰尼克L35、普兰尼克L44、普兰尼克L64、普兰尼克F68、普兰尼克P85、普兰尼克F87、普兰尼克F88、普兰尼克F98、普兰尼克P105、普兰尼克F108及普兰尼克F127组成的组中的一种以上。但并不限定于此。
所述纳米粒子为由活性剂和普兰尼克组成的纳米粒子,由于温度敏感性,纳米粒子的大小可根据测定温度而不同。具体地,温度越低粒子大小可能越大。
所述纳米粒子在32.5~37℃的温度下粒子大小可以为5~80nm。优选为5~50nm。
在本发明中,“壳聚糖”是甲壳素通过部分脱乙酰化形成的多糖,是一种无毒,具有高的生物相容性和生物降解性的高分子,具有亲水性高且黏膜粘附性高的性质。壳聚糖在酸性环境下溶解度高并倾向于带正电荷,因此具有容易附着在粘膜等的性质,并具有抗菌性和止血效果。所述壳聚糖通常对乙酸、乳酸等酸性溶液具有高溶解度。在溶于所述酸性溶液的壳聚糖的情况下,应用于人体时可诱发皮肤刺激或因体内pH的变化引起的障碍等。
与此相反,本发明的所述壳聚糖易溶于水,可以克服使用溶于酸性溶液的壳聚糖时出现的问题点。所述壳聚糖的分子量可以为3~100kDa。优选为3~20kDa,更优选为3~10kDa。在所述壳聚糖的分子量大于100kDa的情况下,对水的溶解度低,因此不佳。
以100重量份的普兰尼克为基准,可包含200重量份以下的所述壳聚糖。优选为0.001~200重量份,更优选为0.001~100重量份。若包含小于0.001重量份的壳聚糖,则纳米粒子的表面没有被壳聚糖充分涂覆,因此可能难以表现出带正电荷的表面电荷,若包含大于200重量份的壳聚糖,则由于纳米胶囊的大小变得过大或可能发生部分沉淀,因此不佳。
所述纳米胶囊具有温度敏感性,温度越低粒子大小可能越大。所述纳米胶囊在10℃的温度下粒子大小为1000nm以下,在大于10℃的温度下粒子大小变小。
优选地,所述纳米胶囊在32.5~37℃的温度下粒子大小为700nm,更优选地,在32.5~37℃的温度下粒子大小为30~500nm,进一步优选地,粒子大小为30~300nm,最优选地,粒子大小为30~100nm。若所述纳米胶囊的粒子大小大于700nm,则应用于皮肤时皮肤渗透效果低,因此不佳。
所述纳米胶囊可在空心的内部装入各种活性剂。并且,由于所述纳米胶囊的温度敏感性质,因此在低温下,纳米胶囊可溶胀(swelling),使得活性剂渗入组成纳米胶囊的普兰尼克物质之间,由此脂溶性和水溶性活性剂均可包含于其中。
所述纳米胶囊的表面涂覆有壳聚糖,因此纳米胶囊的表面电荷可带正电荷以增加皮肤渗透率和黏膜粘附性。
涂覆有壳聚糖的纳米胶囊的皮肤渗透率显著高于未涂覆壳聚糖的高分子胶囊(PluNC),且可比商业上使用最多的脂质体(Liposome)剂型增加6倍以上,与单独处理包含在纳米胶囊中的活性剂的情况相比,可增加2倍以上,优选为5倍以上,更优选为10倍以上,进一步优选为14倍以上。
所述纳米胶囊是由组成纳米粒子的普兰尼克与涂覆于纳米粒子表面的壳聚糖之间的物理结合来形成,与利用通过普兰尼克与壳聚糖的化学键合制备的普兰尼克-壳聚糖聚合物来制备的纳米粒子不同,无需额外的聚合物制备工序,不必考虑因用于制备聚合物的结合剂而引起的毒性。
并且,本发明涉及含有所述纳米胶囊的药物递送系统。
在本发明中,“药物递送系统”是将具有治疗功效的药物递送到体内需要的部位的系统,向需要药物的组织以具有递送效率且有效地递送所需量及药物,可理解为药物组合物、药物处方、配合方法或药物制剂。
所述药物递送系统可以是包含具有治疗功效的药物的纳米胶囊。
所述药物可以为选自由抗癌剂、免疫抑制剂、抗氧化剂、抗炎剂、抗皱剂、防脱发剂、伤口愈合剂、皮肤美白剂、营养补充剂、免疫抗原、蛋白质疗剂、血管再生剂、抗真菌剂、抗生素、抗病毒剂、镇静剂、镇痛剂、抗老化剂、抗皱剂、皮肤美白剂、皮肤脱色剂、紫外线阻隔剂、染料、着色剂、除臭剂及芳香剂等组成的组中的一种以上,但并不限定于此。
所述抗真菌剂可以是多烯(polyene)类,如两性霉素B(amphotericin B)、制霉菌素(nystatin,fungicidin)等;唑类(azole),如酮康唑(ketoconazole)、伊曲康唑(itraconazole)等;丙烯胺类(allylamine),如布替萘芬(butenafine)、特比萘芬(terbinafine)、萘替芬(naftifine)等;棘白菌素类(echinocandin),如阿尼芬净(anidulafungin)、卡泊芬净(caspofungin)等;其他抗真菌剂,如橙酮(aurones)、苯甲酸(benzoic acid)、环吡酮(ciclopirox)、氟胞嘧啶(flucytosine)、灰黄霉素(griseofulvine)等,但并不限定于此。
所述抗生素为青霉素类(penicillin)、头孢菌素类(cephalosporin)、多粘菌素(polymyxin)、磺胺(sulfonamide)、喹啉类(quinoline)、利福平(rifampicin)、氨基糖苷类(aminoglycoside)、大环内酯类(macrolide)及四环素类(tetracycline)等,但并不限定于此。
所述抗病毒剂可以是抗流感病毒(anti-influenza virus)剂,如金刚烷胺(amantadine)、金刚乙胺(rimantadine)、奥司他韦(oseltamivir)、扎那米韦(zanamivir)等;抗疱疹病毒(anti-herpes virus)剂,如阿糖腺苷(vidarabine)、阿昔洛韦(acyclovir)、膦甲酸钠(foscarnet)等;抗乙型肝炎病毒(anti-hepatitis B virus)剂,如拉米夫定(lamivudine)、恩替卡韦(entecavir)、泰诺福韦(tenofovir)等;抗HIV剂,如齐多夫定(zidovudine)、去羟肌苷(didanosine)、扎西他滨(zalcitabine)、依法韦仑(efavirenz)、利匹韦林(rilpivirine)、沙奎那韦(saquinavir)、利托那韦(ritonavir)、拉替拉韦(raltegravir)、埃替拉韦(elvitegravir)、杜鲁特韦(dolutegravir)及恩夫韦肽(enfuvirtide)等,但并不限定于此。
所述镇静剂可以是唑吡坦(zolpidem)、地西泮(diazepam)、吗啡(morphine)等,但并不限定于此。
所述镇痛剂可以是对乙酰氨基酚(acetaminophen)系列、非甾体抗炎药(nonsteroidal antiinflammatory drugs)系列、吗啡(morphine)、芬太尼(fentanyl)、羟考酮(oxycodone)、氢吗啡酮(hydromorphone)等,但并不限定于此。
所述伤口愈合剂可以是积雪草(centella asiatica)、胶原(collagen)、表皮生长因子(epithelial growth factor,EGF)等,但并不限定于此。
所述抗炎剂可以是美洛昔康(meloxicam)、水飞蓟宾(silibinin)、吲哚美辛(indomethacin)、蜂胶(propolis)、咖啡酸苯乙酯(caffeic acid phenethyl ester)等,但并不限定于此。
所述抗癌剂可以为紫杉醇(paclitaxel)、雌激素(estrogen)、多柔比星(doxorubicin)、5-氟尿嘧啶(5-fluoro uracil)、洛匹那韦(lopinavir)、尼美舒利(nimusulide)、黄体酮(progesterone)、瑞格列奈(repaglinide)、四环素(tetracycline)、全反式维甲酸(all-trans retinoic acid)、木樨草素(luteoline)、血管内皮生长因子受体抑制剂(vascular endothelial growth factor receptor(VEGFR)inhibitor)、Wnt/β-连环蛋白调节剂(Wnt/β-catenin modulator)、刺猬抑制剂(hedgehog inhibitor)、PI3K/Akt/mTOR调节剂等,但并不限定于此。
所述免疫抑制剂可以为环孢素A(cyclosporin A)、他克莫司(tacrolimus)、甲氨蝶呤(methotrexate)、雷帕霉素(rapamycin)、西罗莫司(sirolimus)等,但并不限定于此。
所述防脱发剂可以为具有抑制脱发或促进毛发生长效果的物质,如非那雄胺(finasteride)、米诺地尔(minoxidil)、环孢素A(cyclosporin A),也可以为天然防脱发剂、如薏苡仁(Coicis semen)提取物、覆盆子(Rubus coreanus)提取物、甘草(Glycyrrhizaradix)提取物、侧柏(Thuja orientalis)提取物、当归(Angelical radix)提取物、山茱萸(Cornus officinalis)提取物等具有毛发生长促进作用的肽,但并不限定于此。
所述活性剂可以是脂溶性或难溶性药物,其可为选自由所述脂溶性或难溶性抗癌剂(紫杉醇、多西他赛、汉防己甲素);所述脂溶性或难溶性免疫抑制剂(环孢素A、地塞米松);所述脂溶性或难溶性抗氧化剂(生育酚乙酸酯、虾青素、姜黄素、抗坏血酸-棕榈酸酯);所述脂溶性或难溶性抗炎剂(右泛醇、咖啡酸苯乙酯);所述脂溶性或难溶性抗皱剂(视黄醇棕榈酸酯(retinyl palmitate));所述脂溶性或难溶性防脱发剂(米诺地尔、非那雄胺);所述脂溶性或难溶性伤口愈合剂(积雪草提取物、β-谷甾醇);所述脂溶性或难溶性皮肤美白剂(抗坏血酸四异棕榈酸酯);所述脂溶性或难溶性营养补充剂(胶原三肽)组成的组中的一种以上。
所述活性剂可以是水溶性药物,其可以是选自由所述水溶性抗癌剂(多柔比星);所述水溶性抗炎剂(磷脂酶A2);所述水溶性免疫抗原(卵白蛋白);所述水溶性蛋白质疗剂(牛血清白蛋白);所述水溶性伤口愈合剂(碱性成纤维细胞生长因子);所述水溶性血管再生剂(血管内皮生长因子)组成的组中的一种以上。
所述药物递送系统可包含所述纳米胶囊和药学上可接受的赋形剂。
所述药物递送系统可以按照常规方法分别制成:口服型剂型,散剂、颗粒剂、片剂、胶囊剂、悬浮液、乳剂、糖浆剂、气雾剂等;外用剂;栓剂和无菌注射液形式。作为可包含在所述药学组合物中的载体、赋形剂和稀释剂可列举:乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油。在进行制剂化的情况下,使用常用的填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等稀释剂或赋形剂配制而成。用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这些固体制剂在所述纳米胶囊中混入至少一种赋形剂来制成,例如淀粉、碳酸钙、蔗糖或乳糖、明胶。并且,除了简单的赋形剂之外,还使用硬脂酸镁、滑石等润滑剂。用于口服给药的液体制剂有悬浮剂、内服液剂、乳剂、糖浆等,除了作为常用的简单的稀释剂的水、液体石蜡之外,还可包括各种赋形剂,例如,润湿剂、甜味剂、芳香剂、保存剂等。用于肠胃外给药的制剂包括无菌水溶液、非水性溶剂、悬浮剂、乳剂、冷冻干燥剂、栓剂。非水性溶剂、悬浮剂可使用丙二醇、聚乙二醇、橄榄油等植物油、油酸乙酯等可注射的酯等。作为栓剂的基质,可以使用半合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)61、可可脂、月桂酸甘油酯、甘油明胶等。
并且,对剂型没有特别限制,可以作为具有选自软膏剂、乳液、喷雾剂、贴剂、霜剂、凝胶剂和胶质体中的一种剂型的皮肤外用剂使用。增加经皮吸收的制剂,例如但不限于,可包括二甲基亚砜、二甲基乙酰胺、二甲基甲酰胺、表面活性剂、醇、丙酮、丙二醇或聚乙二醇。涂抹频率可根据受治疗对象的年龄、性别、体重、需治疗的特定疾病或病理状态、疾病或病理状态的严重程度、给药途径及根据开药人员的判断而有很大差异,建议涂抹频率为每月至每天10次,优选为每周至每天4次,更优选为每周3次至每天3次,进一步优选为每天1次至2次。
本发明的药物递送系统可以通过多种途径施用于小鼠、家畜、人、宠物等哺乳动物。可以设想任何给药方式,例如,口服、直肠或静脉内、肌肉内、皮下、皮肤、子宫内硬膜或脑血管内注射。优选为皮肤给药。
本发明还涉及包含所述纳米胶囊的化妆品材料组合物。
所述纳米胶囊可包含美白、抗皱、抗氧化、抗老化、抗炎症、阻隔紫外线等功能性化妆品材料。
所述美白功能性材料可以是构树提取物、熊果苷(arbutin)、乙基抗坏血酸醚(ethyl ascorbyl ether)、油溶性甘草提取物、抗坏血酸葡糖苷(ascorbyl glucoside)、烟酰胺(niacinamide)、α-红没药醇(α-bisabolol)及抗坏血酸四异棕榈酸酯(ascorbyltetraisopalmitate)等,但并不限定于此。
所述抗皱功能性材料可以是维生素A、维生素A衍生物(视黄醇棕榈酸酯、视黄醇乙酸酯等)、腺苷、聚乙氧基化视黄酰胺等,但并不限定于此。
所述抗氧化功能性材料可以是维生素A、维生素A衍生物、维生素E、维生素E衍生物、胡萝卜素(carotene)、番茄红素(lycopene)、叶黄素(lutein)、辅酶Q10、虾青素等,但并不限定于此。
所述化妆品材料组合物可包含所述纳米胶囊及化妆品领域常用的辅助剂,例如,亲水性或亲油性胶凝剂、亲水性或亲油性活性剂、保存剂、抗氧化剂、溶剂、芳香剂、填充剂、阻隔剂、颜料、除味剂或染料。
所述辅助剂的量是本领域常用的量,在任何情况下辅助剂及其比例可在对本发明的化妆品材料组合物的优选性质不产生不利的影响的前体下进行选择。
所述化妆品材料组合物可以由选自由乳液、柔肤水、爽肤水、安瓿,收敛剂、乳霜、粉底、精华、膜、面膜、肥皂、沐浴露、洁面泡沫、洗发水、护发素、焗油膏、发油、身体油及身体乳液组成的组中的一种以上的剂型,但并不限定于此。
所述化妆品材料组合物可以每天使用,并且,也可以无限期使用,优选地,可以根据年龄、皮肤状况或皮肤类型调整使用量、使用次数和使用期限。
并且,本发明涉及包含所述纳米胶囊的保健功能食品组合物。
所述纳米胶囊可包含保健功能食品材料。
所述保健功能食品材料可以是维生素、矿物质、益生菌、生物活性肽、抗氧化剂、植物甾醇、植物提取物、辅酶Q10、欧米加-3、虾青素等。优选地,可以是胶原三肽、红参油、虾青素、欧米加-3,但并不限定于此。
所述保健功能食品组合物可包含所述纳米胶囊和食品学上可接受的食品辅助剂。
本发明的保健功能食品组合物可包括片剂、胶囊剂、丸剂或液剂等形式,可添加本发明的纳米胶囊的食品可包括:例如各种食品类、饮料、口香糖、茶、维生素复合物和健康功能性食品类等。
本发明的另一方面提供一种包含本发明的纳米胶囊的医疗设备。
所述医疗设备可以是填料、伤口敷料、骨修复剂、植入物涂层剂、栓塞治疗辅助剂、诊断剂等。
本发明的再一方面提供一种包含本发明的纳米胶囊的生活用品用组合物。
所述生活用品用组合物可以是染色剂、着色剂、除臭剂、芳香剂等,但并不限定于此。
发明的效果
本发明涉及涂覆有壳聚糖的纳米胶囊及其用途,确立了制备具有优异的稳定性且粒子大小为500nm以下、尤其是200nm以下的纳米胶囊的方法,并通过将难溶性药物载入由此制备的纳米胶囊,确认了包含药物的纳米胶囊具有优异的皮肤渗透率以及基于此的向皮肤的递送药物和基于药物的功效。并且,确认了通过口服给药所制备的纳米胶囊的体内有效成分的生物利用率增加。
由此,可期待利用本发明的涂覆有壳聚糖的纳米胶囊开发出一种能使医药领域、化妆品行业、食品产业等中的难溶性药物或有效物质向人体、家畜及宠物等动物的递送效率显著提高的优异的递送系统。
附图说明
图1示出根据普兰尼克的种类和温度确认制备的纳米粒子的大小的结果。
图2为根据普兰尼克种类分析壳聚糖纳米胶囊的特性的结果,(a)部分示出纳米胶囊的形状,(b)部分示出纳米胶囊的大小,(c)部分示出纳米胶囊的多分散性,(d)部分示出纳米胶囊的表面电荷。
图3为根据壳聚糖的分子量分析所制备的涂覆有壳聚糖的纳米胶囊的特性的结果,(a)部分示出纳米胶囊的大小,(b)部分示出纳米胶囊的多分散性,(c)部分示出纳米胶囊的表面电荷,(d)部分为确认示出纳米胶囊的形态的结果。
图4为根据溶剂种类分析壳聚糖纳米胶囊的特性的结果,(a)部分示出纳米胶囊的大小,(b)部分示出纳米胶囊的多分散性,(c)部分示出纳米胶囊的表面电荷。
图5为根据本发明的包含药物的涂覆有壳聚糖的纳米胶囊的制备方法确认粒子大小的结果。
图6为利用纳米沉淀法制备本发明的包含药物的涂覆有壳聚糖的纳米胶囊时,根据溶剂和蒸馏水的混合比例来确认纳米胶囊的粒子大小的结果。
图7为确认本发明的涂覆有壳聚糖的纳米胶囊是否有细胞毒性的结果。
图8为根据包含紫杉醇和多西他赛的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果,(a)部分示出纳米胶囊的大小,(b)部分示出纳米胶囊的多分散性,(c)部分示出纳米胶囊的表面电荷。
图9为根据包含环孢素A((a)部分)和地塞米松((b)部分)的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果,分别示出纳米胶囊的大小、多分散性、表面电荷。
图10为根据包含视黄醇棕榈酸酯((a)部分)和生育酚乙酸酯((b)部分)的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果,分别示出纳米胶囊的大小、多分散性、表面电荷。
图11为根据包含米诺地尔((a)部分)和非那雄胺((b)部分)的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果,分别示出纳米胶囊的大小、多分散性、表面电荷。
图12为示出根据温度的纳米胶囊的大小和分散度特性。
图13为根据包含多柔比星(doxorubicin)的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果。
图14为根据包含卵清蛋白(Ovalbumin)的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果。
图15为根据包含牛血清白蛋白的涂覆有壳聚糖的纳米胶囊的药物载入量分析特性的结果。
图16为确认是否产生含有环孢素A(CsA@ChiNC)、尼罗红(Nile red@ChiNC)或芘(pyrene@ChiNC)的涂覆有壳聚糖的纳米胶囊的沉淀物的结果。
图17为示出载有药物(CsA和RP)的壳聚糖纳米胶囊冷冻前后的特性的结果。
图18为示出根据壳聚糖种类的药物皮肤渗透的结果。
图19为确认本发明的含有药物(尼罗红)的涂覆有壳聚糖的纳米胶囊的皮肤渗透率的结果。
图20为确认本发明的含有药物(尼罗红)的涂覆有壳聚糖的纳米胶囊向皮肤内的药物递送效果的结果。
图21为根据本发明的含有药物(环孢素A,CsA)的涂覆有壳聚糖的纳米胶囊向皮肤内的药物递送来确认毛发生长功效的结果。
具体实施方式
下面,详细说明本发明的优选实施例。但是本发明不限于这里描述的实施例并且还可以以其他形式实现。其是为了使在这里提及的内容更彻底和完整,并向本领域技术人员充分传达本发明的构思。
实施例1.制备涂覆有壳聚糖的纳米胶囊
实施例1-1.优化根据普兰尼克种类的纳米粒子制备
普兰尼克(pluronic,poloxamer)是一种由亲水性高分子的聚(环氧乙烷)(poly(ethylene oxide),PEO)和疏水性高分子的聚(环氧丙烷)(poly(propylene oxide),PPO)组成的非离子型的PEO-PPO-PEO三嵌段共聚物,是具有代表性的温度敏感性高分子,其具有随温度升高而可逆地改变内部结构的独特特性。根据普兰尼克的聚(环氧乙烷)和聚(环氧丙烷)的添加摩尔数,存在具有各种亲水亲油平衡值的普兰尼克衍生物,当使用普兰尼克制备纳米粒子时,普兰尼克的亲水亲油平衡值可对粒子大小产生影响。为此,确认了根据普兰尼克种类的纳米粒子的大小。
使用亲水亲油平衡值2~29的普兰尼克制备了纳米粒子。具体而言,通过将20mg的普兰尼克溶于1ml的丙酮来制备了反应溶液。将制备好的反应溶液缓慢滴入以530rpm进行搅拌的4ml的三重蒸馏水后,在常温下分别反应12小时以上,并自然蒸发除去丙酮,制备了由普兰尼克组成的纳米粒子。使用粒度分析仪(Zetasizer,Nono-Zs,Malvern)和透射电子显微镜(transmission electron microscopy)分析制备的纳米粒子的大小,其结果如图1所示。
如图1所示,在由普兰尼克F127组成的纳米粒子的情况下,在25℃的温度下形成200nm以下的纳米粒子,在32.5~37℃的温度下形成小至5nm、大至80nm的纳米粒子,可形成平均50nm的纳米粒子。在普兰尼克F68的情况下,在25℃的温度下具有300nm以下的粒子大小,在32.5~37℃的温度下具有200nm以下的粒子大小。
并且,除了普兰尼克F127和普兰尼克F68之外,在由亲水亲油平衡值2~29的普兰尼克组成的纳米粒子的情况下,确认在32.5~37℃的温度下制得大小为200nm以下的纳米粒子。
如上所述,确认了通过使用普兰尼克可根据温度调节粒子大小,为了将下述纳米胶囊的大小制备成100nm以下,通过使用亲水亲油平衡值2~29的普兰尼克,将纳米粒子的大小优化为5~80nm的大小,优选为5~50nm的大小。
实施例1-2.优化根据普兰尼克种类的纳米胶囊制备
为了确认根据普兰尼克种类的纳米胶囊制备优化条件,通过使用对应于下述表1中的亲水亲油平衡值2~29的普兰尼克来制备了纳米粒子,并用壳聚糖进行涂覆来制备了纳米胶囊。
具体而言,将每20mg的普兰尼克溶于1ml的丙酮后,在常温下搅拌2小时。随后,通过将高分子溶液缓慢滴入以400rpm进行搅拌(stirring)的4ml的三重蒸馏水(去离子水(deionized water))来制备高分子纳米粒子后,在通风橱中去除丙酮约6小时。最后,向每个高分子纳米粒子中加入脱乙酰化为90%、分子量为10kDa的20mg的壳聚糖,并在常温下搅拌2小时来制备了壳聚糖纳米胶囊。使用电泳光散射分光光度计(electrophoretic lightscattering spectrophoto meter)(ELS-Z2,Otsuka)设备分析了根据不同普兰尼克种类制备的壳聚糖纳米胶囊(ChiNC)的大小、分散度和表面电荷,其结果如图2所示。
[表1]
普兰尼克 | 分子量(Da) | 亲水亲油平衡值值(HLB value) |
F68(P188) | 8400 | 29 |
F127(P407) | 12600 | 22 |
L35 | 1900 | 19 |
P123 | 5750 | 8 |
L81 | 2750 | 2 |
如图2所示,在所有普兰尼克种类中,使用具有不同亲水亲油平衡值指数的五种普兰尼克(F127、P123、P188、L35、L81)并通过纳米沉淀法(nanopr ecipitation)稳定地制备了壳聚糖纳米胶囊(ChiNC)而没有产生沉淀。
使用F127和P123制备的壳聚糖纳米胶囊在32.5~37℃的温度下大小为30nm至80nm,大小平均为60nm左右,稳定地形成了100nm以下的壳聚糖纳米胶囊。使用P188、L35制备的壳聚糖纳米胶囊大小为209nm至688nm,平均500nm,使用L81制备的壳聚糖纳米胶囊大小最大显示出1.4μm的大小。就分散性而言,使用F127、P123、P188、L35制备的壳聚糖纳米胶囊为0.3以下,大体显示出单分散性,相比之下,使用L81制备的壳聚糖纳米胶囊具有微米大小且具有相对大的分散度。就表面电荷而言,壳聚糖稳定地涂覆在普兰尼克胶囊表面,平均为+20mV左右。
基于这些结果可知,为了根据普兰尼克种类的优化壳聚糖纳米胶囊剂型,亲水亲油平衡值为8至29的普兰尼克种类均合适,根据普兰尼克种类和温度,可形成壳聚糖纳米胶囊的大小为700nm以下、30~500nm、30~300nm或30~100nm。
并且,确认了在亲水亲油平衡值指数为8以下的情况下,虽不是纳米级大小,但可制备微米的胶囊,由此确认了根据局部应用等需要,可制备具有纳米和微米大小的壳聚糖胶囊。
实施例1-3.优化根据壳聚糖分子量的壳聚糖纳米胶囊制备
基于所述实施例1-1和实施例1-2的结果,根据普兰尼克条件确立了根据各种壳聚糖(3~100kDa)的壳聚糖纳米胶囊制备优化条件。
当制备本发明的涂覆有壳聚糖的纳米胶囊时,使用了美国食品药品监督管理局批准的作为生物相容性物质的普兰尼克F127(pluronic F127,poloxamer 407),并利用纳米沉淀法制备了涂覆有壳聚糖的纳米胶囊。具体而言,通过将20mg的普兰尼克F127溶于1ml的丙酮来制备了反应溶液。将制备好的反应溶液缓慢滴入以530rpm进行搅拌的4ml的三重蒸馏水后,在常温下反应12小时以上,自然蒸发除去丙酮,获得了由普兰尼克组成的纳米粒子(PluNC)。在获得的PluNC中加入壳聚糖并在常温下混合1小时以上,制备了本发明的涂覆有壳聚糖的纳米胶囊(ChiNC)。此时,使用分子量为3kDa、10kDa、20kDa、50kDa、100kDa的壳聚糖,对PluNC进行涂覆,利用粒度分析仪(Zetasizer,Nono-Zs,Malvern)和透射电子显微镜(transmission electron microscopy)分析了根据不同壳聚糖的分子量制备的ChiNC的形态、大小、多分散性指数(polydispersity index,PDI)和表面电荷,其结果如图3所示。
相对于普兰尼克混合0.001~200重量份的壳聚糖来制备了壳聚糖纳米胶囊。此时,若壳聚糖小于0.001重量份,则纳米粒子的表面不能被壳聚糖充分涂覆,因此难以表现出带正电荷的表面电荷,若壳聚糖大于200重量份,则纳米胶囊的大小变得过大或部分发生了沉淀。在随后的实验中混合了与普朗尼克重量相同的壳聚糖。
在图3中,如(a)部分所示,就粒子大小而言,确认了使用分子量为20kDa以下的壳聚糖涂覆的ChiNC(ChiNC 3K、ChiNC 10K、ChiNC 20K)形成了100nm以下的壳聚糖纳米粒子,使用分子量为50kDa和100kDa的壳聚糖涂覆的ChiNC(ChiNC 50K、ChiNC 100K)形成约200nm的大小。如(b)部分所示,就多分散性而言,确认使用分子量为20kDa以下的壳聚糖涂覆的ChiNC(ChiN C 3K、ChiNC 10K、ChiNC 20K)分散度为0.2以下,使用分子量为50kDa和100kDa的壳聚糖涂覆的ChiNC(ChiNC 50K。ChiNC 100K)分散值为0.2~0.3左右,如(c)部分所示,就表面电荷而言,确认了未涂覆壳聚糖的PluNC自身表面电荷值呈??5mV左右的负电荷,相反,在涂覆壳聚糖的情况下,确认了与壳聚糖的分子量无关地,均带正电荷。并且,如(d)所示,观察纳米胶囊的形态的结果,确认了纳米胶囊呈球形结构,随着壳聚糖的分子量变大纳米胶囊的大小也变大。
虽然在本说明书中没有示出,但是在使用分子量大于100kDa的壳聚糖的情况下,确认了必须将壳聚糖溶解在乙酸中来进行涂覆,在将壳聚糖溶解在乙酸时发生沉淀,导致剂型稳定性下降。
由此可知,就本发明的涂覆有壳聚糖的纳米胶囊而言,可知通过所述制备方法能将壳聚糖稳定地涂覆在由普兰尼克组成的纳米粒子表面,根据涂覆的壳聚糖的分子量可对纳米胶囊的大小和分散性产生影响。进而确认,在壳聚糖的分子量为3~20kDa的情况下,可以制备出大小较小、均匀且能确保剂型稳定性的纳米胶囊。
实施例1-4.优化根据溶剂的壳聚糖纳米胶囊制备
在壳聚糖纳米胶囊制备工艺中,对根据溶剂的壳聚糖纳米胶囊制备工艺进行了优化。
作为溶剂选择丙酮(acetone;ACE)、乙醇(ethanol;ETH)、四氢呋喃(tetrahydrofuran;THF)、氯仿(chloroform;CHL)和二氯甲烷(dichloromethane;DCM)进行了评价。由此,确立了可根据溶剂溶解度载入不同的各种药物(活性剂)的平台。
首先,根据纳米沉淀法(Nanoprecipitaion)将20mg的普兰尼克F127溶于1ml的丙酮、乙醇、四氢呋喃后反应2小时。随后,将反应溶液缓慢滴入以400rpm进行搅拌的4ml的三重蒸馏水(去离子水(deionized water))中制备高分子纳米胶囊后,在通风橱中去除溶剂约6小时。最后,将20mg的壳聚糖(脱乙酰化为90%、分子量为10kDa)加入各个高分子纳米胶囊中,在常温下搅拌2小时来制备了壳聚糖纳米胶囊。
氯仿使用了单乳液(Single emulsion)法。将20mg的普兰尼克F127溶于1ml的氯仿后,反应了2小时。随后,将反应溶液缓慢滴入以400rpm进行搅拌的4ml的三重蒸馏水(去离子水)中制备高分子纳米胶囊后,利用均质机(homog enizer)进行分散后,通过2小时的真空干燥(vacuum drying)去除了溶剂。最后,将20mg的壳聚糖(脱乙酰化为90%、分子量为10kDa)分别加入各个高分子纳米胶囊中,在常温下搅拌2小时来制备了壳聚糖纳米胶囊。
使用电泳光散射分光光度计(ELS-Z2,Otsuka)设备分析了根据所述纳米沉淀法和单乳液法的分子量为10kDa的壳聚糖涂覆纳米胶囊(ChiNC 10K)的大小、分散度和表面电荷。
如图4所示,使用作为水混溶性(water miscibility)高的有机溶剂的丙酮、乙醇、四氢呋喃的纳米沉淀法制备的壳聚糖纳米胶囊(ChiNC 10K)均具有60nm左右的大小。并且,多分散性(PDI:polydispersity)也为0.3以下,从而显示出单分散性。
相比之下,使用作为水混溶性低的有机溶剂的氯仿的单乳液法制备的壳聚糖纳米胶囊(ChiNC 10K)具有750nm左右的大小(在二氯甲烷中也相同),多分散性(PDI:polydispersity)也大于使用所述丙酮、乙醇、四氢呋喃的纳米沉淀法制备的壳聚糖纳米胶囊。但在所有壳聚糖纳米胶囊组中的表面电荷为20mV左右,因此确认了可在各种溶剂和工艺中稳定地制备涂覆有壳聚糖的高分子胶囊,即壳聚糖纳米胶囊。
实施例1-5.确立含有药物的纳米胶囊的制备方法
作为含药物的涂覆有壳聚糖的纳米胶囊的制备方法使用了纳米沉淀法和膜重分散法(membrane resuspension),并确认了根据每个制备方法制备的纳米胶囊的特性,药物使用了作为难溶性物质的环孢素A(cyclosporine,以下称为CsA)。
膜重分散法(membrane resuspension)如下:将0.2mg(2重量百分比)或0.6mg(6重量百分比)的环孢素A和10mg的普兰尼克F126加入1ml的丙酮,在常温下搅拌2小时来制备了反应溶液。将制备的反应溶液在通风橱(fume hood)中放置2小时,使丙酮挥发,以形成膜。在所形成的膜上添加5ml的三重蒸馏水并搅拌30分钟以上,添加以与普兰尼克相同重量的10kDa的壳聚糖后,通过搅拌制备了纳米胶囊。
作为另一方法的纳米沉淀法如下:将0.2mg或0.6mg的环孢素A和10mg的普兰尼克F126加入1ml的丙酮,在常温下搅拌2小时制备了反应溶液。将制备好的反应溶液缓慢滴入以530rpm进行搅拌的4ml的三重蒸馏水,并在通风橱中搅拌4小时以上,以自然蒸发丙酮。在去除丙酮的含有由普兰尼克组成的纳米粒子的三重蒸馏水中添加与普兰尼克相同重量的10kDa的壳聚糖后,通过搅拌制备了纳米胶囊。使用粒度分析仪和透射电子显微镜测定了通过所述制备方法制备的纳米胶囊的粒子大小,其结果如图5所示。
如图5所示,确认在不含环孢素A的纳米胶囊的情况下,通过纳米沉淀法制备的纳米胶囊大小是通过膜重分散法制备的纳米胶囊大小的2倍左右,就含环孢素A的纳米胶囊而言,通过膜重分散法制备时,根据不同环孢素A的含量所制备的纳米胶囊的粒子大小差异较大,在环孢素A的含量为6重量百分比的情况下,部分纳米胶囊发生聚集,相反,与膜重分散法相比,通过纳米沉淀法制备的含环孢素A的纳米胶囊根据环孢素A的含量的粒子大小的差异并不大,从而可制备具有稳定的大小范围的纳米胶囊,并确认纳米胶囊不发生凝集(aggregation),环孢素A的含量为2重量百分比时,所制备的粒子的大小为100nm以下,含6重量百分比的环孢素A时,所制备的粒子的大小为200nm以下。
由此可知,为了提高本发明的包含药物的涂覆有壳聚糖的纳米胶囊的剂型的稳定性,优选使用纳米沉淀法。
实施例1-6.确认纳米沉淀法中溶剂和蒸馏水的比例
在所述实施例1-5的纳米沉淀法过程中,确认了根据作为反应溶液的溶剂的丙酮和用于制备纳米粒子的三重蒸馏水的不同混合比例的制备的纳米胶囊的大小。
以与所述实施例1-5的纳米沉淀法相同的方法制备,但将药物的含量设置为6重量百分比、将丙酮和蒸馏水的混合比例设置成丙酮:蒸馏水为1:5或1:4,由此制备含药物的涂覆有壳聚糖的纳米胶囊并分析了粒子大小,其结果如图6所示。此时,分析了使用壳聚糖涂覆前后的纳米胶囊的大小。
如图6所示,在丙酮与蒸馏水的混合比例为1:4的情况下,与混合比例为1:5时相比,确认壳聚糖涂覆前后的壳聚糖纳米胶囊的大小均形成为100nm以下。
由此可知,在利用纳米沉淀法制备本发明的含药物的涂覆有壳聚糖的纳米胶囊的情况下,当溶剂和蒸馏水比例为1:4时,可制备稳定大小的纳米胶囊。
虽然在本说明书中没有示出,但可知,在二甲基亚砜、乙醇、乙腈、四氢呋喃、氯仿和二氯甲烷溶剂中,当溶剂和蒸馏水的比例为1:4时,可制备出稳定大小的纳米胶囊(参照实施例1-4)。
实施例2.确认涂覆有壳聚糖的纳米胶囊的细胞毒性
确认了在所述实施例1-3中制备的涂覆有壳聚糖的纳米胶囊(ChiNC)是否诱发细胞毒性。
将NIH3T3细胞以每孔10000个接种于96孔板后,培养8~12小时。随后,将在所述实施例1-3中制备的PluNC或ChiNC分别以使浓度成为10μg/ml、20μg/ml、50μg/ml、100μg/ml的方式进行处理,培养24小时后,基于CCK8(cell counting kit-8)和厂商提供的说明书确认了细胞存活率,其结果如图7所示。此时,以未进行任何处理的NIH3T3细胞为对照组(control),以对照组的细胞存活率为100%,分析了针对各个处理组的细胞存活率。
如图7所示,确认PluNC或所有ChiNC在所有浓度下示出90%细胞存活率。
由此可知,本发明的涂覆有壳聚糖的纳米胶囊是不引起细胞毒性的具有优异的生物相容性的物质。
实施例3.确立含难溶性(脂溶性)活性剂的涂覆有壳聚糖的纳米胶囊制备条件
在本发明中,确立了包含活性剂中具有脂溶性特性的抗癌剂(紫杉醇、多西他赛)、抗炎剂(地塞米松)、免疫抑制剂(环孢素A)、抗氧化剂(生育酚乙酸酯)、抗皱剂(视黄醇棕榈酸酯)、防脱发剂(米诺地尔、非那雄胺)、抗老化剂(生育酚乙酸酯、视黄醇棕榈酸酯)的涂覆有壳聚糖的纳米胶囊制备条件。
将多西他赛、紫杉醇、地塞米松、生育酚乙酸酯、环孢素A、视黄醇棕榈酸酯分别溶于1ml的丙酮后,将反应溶液溶于20mg的普兰尼克F127并反应2小时。随后,将反应溶液缓慢滴入以400rpm进行搅拌的4ml的三重蒸馏水(去离子水),以制备药物载入高分子纳米胶囊后,在通风橱中去除丙酮约6小时。最后,将20mg的壳聚糖(脱乙酰化为90%、分子量为10kDa)加入各个高分子纳米胶囊中,在常温下搅拌2小时来制备了药物载入壳聚糖纳米胶囊。最后,为了去除未载入的药物进行了超滤(ultrafiltration)(Amicon Ultra-15filter)。
另一方面,将非那雄胺、米诺地尔、生育酚乙酸酯、视黄醇棕榈酸酯分别溶于1ml的乙醇后,将反应溶液溶于20mg的普兰尼克F127并反应2小时。随后,将反应溶液缓慢滴入以400rpm进行搅拌的4ml的三重蒸馏水(去离子水),以制备药物载入高分子纳米胶囊后,在通风橱中去除乙醇约6小时。最后,将20mg的壳聚糖(脱乙酰化为90%、分子量为10kDa)加入各个高分子纳米胶囊中,在常温下搅拌2小时来制备了药物载入壳聚糖纳米胶囊。最后,为了去除未载入的药物进行了超滤(Amicon Ultra-15filter)。
利用电泳光散射分光光度计(ELS-Z2,Otsuka)设备分析了所制备的载入有药物的ChiNC 10K的大小、分散度和表面电荷。
实施例3-1.制备含紫杉醇(paclitaxel)和多西他赛(docetaxel)的涂覆有壳聚糖
的纳米胶囊
如图8所示,可制备载入有紫杉醇(PTX)的纳米胶囊,直到加载至载入量(0.1重量百分比),对载入前后的大小、分散度、表面电荷没有产生影响。而在0.2重量百分比下,纳米胶囊的直径达3μm,但没有产生沉淀,因此确认可以制备可局部使用的壳聚糖微胶囊。但是,在0.5重量百分比下,产生部分沉淀。
在多西他赛(DOC)的情况下,确认了直至2重量百分比可向壳聚糖纳米胶囊进行稳定地载入。并且,确认了直至3重量百分比为不生成沉淀物的剂型制备条件,由此确认了可制备载入有抗癌剂的壳聚糖纳米胶囊和壳聚糖微胶囊。
实施例3-2.制备含环孢素A(CyclosporinA)和地塞米松(dexamethason
e)的涂覆
有壳聚糖的纳米胶囊
如图9所示,在环孢素A的情况下,确认了直至5重量百分比,能够稳定地载入壳聚糖纳米胶囊中。并且,确认了直至10重量百分比为不生成沉淀物的剂型制备条件。当载入量为5重量百分比时,形成了壳聚糖纳米胶囊,而考虑到使用稍大的壳聚糖纳米胶囊进行局部治疗时,确认了可载入至10重量百分比。并且,对温度敏感性进行评价的结果而言,在10℃的温度下,粒子大小为700nm以上,在32.5℃或37℃的温度下,粒子大小为100nm以下(30~100nm)。
在地塞米松(DEX)的情况下,直至3重量百分比,能够以最优的方式进行载入,直至5重量百分比未产生沉淀物,因此确认可制备900nm大小的大的壳聚糖纳米胶囊。
实施例3-3.制备含视黄醇棕榈酸酯(Retinyl palmitate)和生育酚乙酸酯
(tocopherylacetate)的涂覆有壳聚糖的纳米胶囊
如图10所示,在视黄醇棕榈酸酯(RP)的情况下,确认了直至5重量百分比,能够稳定地载入壳聚糖纳米胶囊中。并且,当载入量为10重量百分比时,壳聚糖纳米胶囊的大小为100nm左右,但分散度和表面电荷几乎相似,从而能够稳定地制备出,且不会产生沉淀。
如下述表2所示,在将视黄醇棕榈酸酯用作活性剂的情况下,载入直至20重量百分比时,大小虽增加,但分散度和表面电荷几乎没有差异,因此确认可以以20重量百分比的高浓度进行载入。
[表2]
在生育酚乙酸酯(TA)的情况下,直至2重量百分比,能够以最优的方式进行载入,直至5重量百分比不发生沉淀,因此可制备90nm大小的壳聚糖纳米胶囊。
实施例3-4.制备含米诺地尔(Minoxidil)和非那雄胺(Finasteride)的涂覆有壳
聚糖的纳米胶囊
如图11所示,在米诺地尔(MX)的情况下,确认直至载入5重量百分比,对载入前的壳聚糖纳米胶囊的大小、分散度、表面电荷没有显著影响,可以以最优地方式稳定载入壳聚糖纳米胶囊中。
并且,在非那雄胺(FS)的情况下,直至0.1重量百分比,能够以最优的方式进行载入,直至2重量百分比不产生沉淀,因此可制备4μm大小的壳聚糖微胶囊。并且,当载入5重量百分比时,确认分散度和表面电荷与载入前的壳聚糖纳米胶囊具有显著差异,因此,优选地,直到0.1重量百分比为最优的载入条件,但目的为通过制备微胶囊用于局部递送的情况下,最多可载入至2重量百分比。
如上所述,对于难溶性(脂溶性)活性剂,在0.1重量百分比至20重量百分比范围内确立了100nm以下的涂覆有壳聚糖的纳米胶囊的制备条件,由此,可确立汉防己甲素(tetradrine)、虾青素(astaxanthin)、姜黄素(curcumin)、抗坏血酸-棕榈酸酯(ascorbylpalmitate)、咖啡酸苯乙酯(caffeic acid phenethyl ester;CAPE)、积雪草(centellaasiatica)、β-谷甾醇、抗坏血酸四异棕榈酸酯(ascorbyl tetraisopalmitate)、胶原三肽(tripeptide collagen)等活性剂的壳聚糖涂覆纳米胶囊优化条件。
实施例4.确立含水溶性活性剂的涂覆有壳聚糖的纳米胶囊制备条件
在本发明中,确立了包含活性剂中具有水溶性特性的抗癌剂(多柔比星)、免疫抗原(卵白蛋白)、蛋白质治疗剂药物(牛血清白蛋白)的涂覆有壳聚糖的纳米胶囊制备条件。
将20mg普兰尼克F127溶于1ml的丙酮并反应2小时。随后,将反应溶液缓慢滴入以400rpm进行搅拌的4ml的三重蒸馏水(去离子水),以制备药物载入高分子纳米粒子后,在通风橱中去除丙酮6小时。将20mg的壳聚糖(脱乙酰化为90%、分子量为10kDa)加入各个高分子纳米粒子中并在常温下搅拌2小时来制备了药物载入壳聚糖纳米胶囊。
向制备的壳聚糖纳米胶囊中添加水溶性药物(多柔比星、牛血清白蛋白、卵白蛋白)后,以能够在4℃的温度下进行载入的方式保管2小时。通过超滤(Amicon Ultra-15filter)去除未被载入的药物后,对载入条件进行了优化。
利用吸光度(480nm)测定了未被载入的多柔比星,而对牛血清白蛋白和卵白蛋白,则是通过考马斯亮蓝法(Coomassie blue assay)在吸光度(580nm)下进行了测定。
利用电泳光散射分光光度计(ELS-Z2,Otsuka)设备分析了载入水溶性药物的壳聚糖纳米胶囊(ChiNC 10K)的大小、分散度和表面电荷。
实施例4-1.制备含多柔比星(doxorubicin)的涂覆有壳聚糖的纳米胶囊
与将脂溶性药物载入壳聚糖纳米胶囊中的方法不同,对水溶性药物而言,如图12所示,利用壳聚糖纳米胶囊的温度敏感性特性(在4℃的温度下大小变大至1μm并发生体积膨胀(volume expansion))在低温(4℃)下进行了加载。
如图13所示,在载入多柔比星(DOX)的壳聚糖纳米胶囊的情况下,大小、分散度、表面电荷均几乎类似,尤其,确认了直至10重量百分比可以稳定地进行加载,虽然在图13中未示出,直至20重量百分比,也可形成微胶囊。
通过吸光度分析法确认的结果,确认最优加载量为6重量百分比。
实施例4-2.制备含卵白蛋白(Ovalbumin)的涂覆有壳聚糖的纳米胶囊
如图14所示,就载入卵白蛋白(OVA)的壳聚糖纳米胶囊而言,确认直至5重量百分比,其大小、分散度、表面电荷类似,并且可以稳定地进行加载而不会产生沉淀物。通过吸光度分析法确认的结果,确认最优加载量为3重量百分比。
实施例4-3.制备含牛血清白蛋白(bovine
serum
albumin,BSA)的涂覆有壳聚糖
的纳米胶囊
如图15所示,就加载作为各种蛋白质治疗剂模型药物的牛血清白蛋白(67kDa)的壳聚糖纳米胶囊而言,确认直至5重量百分比,其大小、分散度、表面电荷类似,并且可以稳定地进行加载而不会产生沉淀物。通过吸光度分析法确认的结果,确认最优加载量为4重量百分比。
如上所述,对于水溶性活性剂,在0.1重量百分比至20重量百分比范围内确立了100nm以下的涂覆有壳聚糖的纳米胶囊的制备条件,由此,可确立磷脂酶A2(phospholipaseA2;PLA2)、碱性成纤维细胞生长因子(Basic FibroblastGrowth Factor;b-FGF)、血管内皮生长因子(vascular endothelial growth fact or;VEGF)等活性剂的壳聚糖涂覆纳米胶囊优化条件。
实施例5.确立含药物的涂覆有壳聚糖的纳米胶囊剂型稳定性
实施例5-1.含药物的涂覆有壳聚糖的纳米胶囊剂型稳定性
基于在所述实施例4中确立的含药物的涂覆有壳聚糖的纳米胶囊的制备方法和条件,制备了本发明的含药物的涂覆有壳聚糖的纳米胶囊,将作为难溶性药物的环孢素A(CsA)和通常用作模型难溶性药物的尼罗红(Nile red)和芘(Pyrene)用作了药物。
将0.2mg或0.5mg的环孢素A、尼罗红或芘和10mg的普兰尼克F126加入1ml的丙酮并在常温下搅拌2小时,从而制备了反应溶液。将制备好的反应溶液缓慢滴入以530rpm进行搅拌的4ml的三重蒸馏水,并在通风橱中搅拌4小时以上,以蒸发丙酮。在去除丙酮的含有由普兰尼克组成的纳米粒子的三重蒸馏水中添加与普兰尼克相同重量的10kDa的壳聚糖后,通过搅拌制备了包含各种药物的涂覆有壳聚糖的纳米胶囊(分别称为CsA@ChiNC、Nile red@ChiNC、Pyr ene@ChiNC),将制备的CsA@ChiNC、Nile red@ChiNC、Pyrene@ChiNC置于常温下观察是否有沉淀产生,以确认稳定性,其结果如图16所示。
如图16所示,确认CsA@ChiNC、Nile red@ChiNC、Pyrene@ChiNC均未产生沉淀。
由此可知,本发明的含药物的涂覆有壳聚糖的纳米胶囊在剂型上是稳定的。
实施例5-2.含药物的涂覆有壳聚糖的纳米胶囊的冷冻干燥稳定性
为了评估壳聚糖纳米胶囊剂型的稳定性,进行了三重蒸馏水和磷酸盐缓冲液(PBS)中的稳定性评估和冷冻干燥前后的稳定性评估。
如图17所示,评估加载环孢素A和视黄醇棕榈酸酯(RP)的壳聚糖纳米胶囊在37℃、100rpm条件下的稳定性的结果,其结果为:在4周的时间里,在蒸馏水和磷酸盐缓冲液中均具有类似大小,从而确认了可以很好地保持稳定性。
并且,通过观察到冷冻干燥前(Before FD or B.F:before freeze-drying)和冷冻干燥后(After FD or A.F:after freeze-drying)的壳聚糖纳米胶囊没有大小变化且没有产生沉淀物,由此确认了其稳定性优秀,尤其,在冷冻干燥过程中,确认了即使没有冷冻保护剂(cryoprotectants),也容易冷冻干燥再分散。
实施例6.确认含药物的涂覆有壳聚糖的纳米胶囊的经皮递送效果
药物或有效成分的经皮递送剂型的开发是在制药和化妆品行业中备受关注的领域。为此,确认了本发明的含药物的涂覆有壳聚糖的纳米胶囊的皮肤渗透率及基于此的药物递送功效。
实施例6-1.使用Franz扩散池系统(Franz Diffusion Cell system)的、为进行皮
肤渗透优化的壳聚糖种类优化
在实施例1-3中确认了,分子量为20kDa以下的壳聚糖涂覆的ChiNC(Chi NC 3K、ChiNC 10K、ChiNC 20K)稳定地形成了100nm以下的壳聚糖纳米粒子,其中,为了确立再皮肤渗透率方面最优的壳聚糖纳米胶囊,使用了Franz扩散池系统。
Franz扩散池系统如下:将含药物的剂型施加到供体室(donor chamber),并用磷酸盐缓冲液(phosphate buffered saline,PBS)等生理盐水填充受体室(receptorchamber),供体室和受体室之间固定渗透层(如渗透膜、动物皮肤或细胞培养皮肤等)后,可通过在供体室测量通过渗透层渗透到受体室的药物的量来测量皮肤渗透度等。
向Franz扩散池系统的受体室中加入5ml的磷酸盐缓冲液(pH 7.4且含0.05%的聚山梨醇酯80(polysorbate 80))后,受体室与供体室之间用1.5×1.5cm大小的人体尸体皮肤(human cadaver skin)覆盖固定,将每个样品放入了Franz池(Franz cell)的供体(donor)部分。将受体室的条件调至37℃、600rpm,采样时间(sampling time)为0.5小时、1小时、2小时、4小时、8小时、12小时、18小时、24小时,每次收集500μl,使用高效液相色谱(HPLC)测量不同时间的通过皮肤渗透的药物的量,如图18所示。
如图18所示,就环孢素A而言,在使用10kDa的壳聚糖制备的壳聚糖纳米胶囊(ChiNC 10K)中示出最优的皮肤渗透率。其与使用3kDa的壳聚糖相比,具有统计学上的显着差异,评估其原因是因为ChiNC 10K具有比ChiNC 3K更高的表面电荷(如图3所示)。
与未涂覆壳聚糖的高分子胶囊(PluNC)相比,使用10kDa的壳聚糖制备的壳聚糖纳米胶囊(ChiNC 10K)的皮肤渗透率显著增加,皮肤渗透率比商业上使用最多的脂质体(Liposome)剂型高6倍以上。
将视黄醇棕榈酸酯用作药物来进行评估的结果,相对于作为对照组的仅用视黄醇棕榈酸酯自身进行实验时,在作为最优条件的ChiNC 10K中显示出14倍以上的皮肤渗透率,从而得出使用10kDa的壳聚糖时可提高药物的皮肤渗透率的结果。
实施例6-2.使用Franz扩散池系统的壳聚糖涂覆纳米胶囊的皮肤渗透率确认
以与实施例6-1相同的方法,在Franz扩散池系统下确认了纳米胶囊、壳聚糖涂覆纳米胶囊的皮肤渗透率。
将含2重量百分比的尼罗红的涂覆有壳聚糖的纳米胶囊(Nile red@ChiNC)加入到供体室,以使浓度为以2mg/ml。此时,作为对照组仅处理尼罗红(Nile red)、处理含尼罗红的未涂覆壳聚糖的纳米胶囊(Nile red@PluNC)。将受体室的条件调至37℃、600rpm,并在0.5小时、1小时、2小时、3小时、8小时、12小时、24小时时,每次从受体室取500μl的样品,并测量了不同时间样品的荧光来测量皮肤透光率,结果如图19所示。
如图19所示,确认在单独处理尼罗红的情况下,几乎没有发生皮肤渗透,相反,在使用Nile red@PluNC和Nile red@ChiNC的情况下,皮肤渗透率增加,尤其,与Nile red@PluNC相比,Nile red@ChiNC的皮肤渗透率增加了4倍以上。
由此可知,本发明的含药物的涂覆有壳聚糖的纳米胶囊的皮肤渗透率优异。
实施例7.使用动物模型的经皮递送确认
实施例7-1.动物模型中利用涂覆有壳聚糖的纳米胶囊的尼罗红经皮递送
将基于实施例4制备的含2重量百分比的尼罗红的涂覆有壳聚糖的纳米胶囊(Nilered@ChiNC)制备成浓度为2mg/ml,在脱毛小鼠背部每天每次涂抹300μl并涂抹5天。之后,取背部皮肤并用10%的中性福尔马林溶液固定12小时,将固定的皮肤与最适切割温度(Optimal Cutting Temperature,OCT)包埋剂混合并在液氮和-20℃以下的温度下冷冻后,使用冷冻切片(cryosection)装置切成20μm的厚度并附着在载玻片上以获得皮肤组织样品。将获得的皮肤组织样品用三重蒸馏水清洗后利用荧光显微镜观察尼罗红的皮肤中的分布情况,其结果如图20所示。
如图20所示,确认在涂抹Nile red@ChiNC的情况下,皮肤组织中存在尼罗红。
由此可知,本发明的含药物的涂覆有壳聚糖的纳米胶囊可通过皮肤递送药物。
实施例7-2.通过经皮递送确认药物的功效表达
环孢素A用于治疗银屑病和特应性,据报道还有生发作用,但由于环孢素A疏水性性质高,不溶于水溶液,因此递送至皮肤内时存在限制。因此,为了使环孢素A溶解,用丙酮等有机溶剂溶解后在进行涂抹,但就有机溶剂而言,涂抹于皮肤时可能会引起皮肤刺激和皮肤屏障损伤。
为此,能够以不会刺激和损伤皮肤的方式有效地将环孢菌素A渗透到皮肤中来增加生发功效,由此可在脱发治疗中获得极好的效果,因此,通过使用本发明的含药物的涂覆有壳聚糖的纳米胶囊确认了环孢素A的经皮递送和基于此的生发效果。
为了生发实验,根据食品药品安全部的指南,去除了7周龄的C57B/6雌性小鼠的背毛。将其分为:对去除背毛的小鼠处理生理盐水的对照组(CTL)、溶于丙酮的环孢素A处理组(CsA)、和实施例4中制备的含5重量百分比的环孢素A的涂覆有壳聚糖的纳米胶囊处理组(CsA@ChiNC),并每个试样每周涂抹5天(每次涂抹时,以使环孢素A的量为50mg/kg的方式进行涂抹),用肉眼确认生发效果,其结果如图21所示。
如图21所示,在溶于丙酮的环孢素A单独处理组中,在显示出生发最佳效果的第四周,5只中的5只都确认了生发,相反,在对照组(CTL)中,观察到的自然生发小于5%。在环孢素A单独处理组的情况下,预期皮肤的组织和屏障因溶解环孢素A的丙酮而受损,从而使环孢素A的药物渗透到皮肤中。
在CsA@ChiNC处理组中,确认5只中的4只发生生发,与环孢素A单独处理组相比,其功效具有80%以上的生发功效。
进而,取所述各个处理组的小鼠背部皮肤观察了毛囊的数量和大小,其结果如图21的(b)部分和(c)部分所示。
如图21的(b)部分和(c)部分所示,确认溶于丙酮的环孢素A单独处理组(D)和CsA@ChiNC(C)处理组中的毛囊数量和大小类似。
通过所述结果,可确认本发明的含药物的涂覆有壳聚糖的纳米胶囊具有优异的皮肤渗透率和向皮肤内的药物递送效率,可作为将难溶性药物递送到人类和动物体内的平台技术。
实施例8.通过纳米胶囊的口服给药的体内有效成分的生物利用率增加确认
为了进行浸渍有环孢素A药物的纳米胶囊的口服实验,使用了雄性SD大鼠(MaleSprague-Dawley rat)(200~250g)。使用灌胃针(feeding needle)将加载有5重量百分比的环孢素A的纳米胶囊(1ml的纯净水,50mg/㎏)进行了给药。之后,在2小时、4小时、6小时、8小时、12小时、24小时时分别取血液,并用高效液相色谱进行了定量分析。
实验结果确认,与未涂覆壳聚糖的纳米胶囊相比,壳聚糖纳米胶囊组中的血液中环孢素A的半衰期和生物利用率增加。
并且,以与所述实施例7相同的方法,为了生发实验,根据食品药品安全部的指南,去除了7周龄的黑色C57B/6雌性C57B/6小鼠的背毛后,以与如上所述的方法相同的方法,用环孢素A和CsA@ChiNC溶液每周3次口服给药,根据持续4周口服给药的结果,确认了与环孢素A口服给药组相比,口服给药CsA@ChiNC溶液的小鼠组的生发功效进一步提高。这被认为是因为壳聚糖纳米胶囊提高了体内吸收率,使用本发明的壳聚糖纳米胶囊的药物递送系统具有优异的药物递送效果。
Claims (12)
1.一种纳米胶囊,其特征在于,在含活性剂和普兰尼克的纳米粒子上涂覆壳聚糖,
所述纳米胶囊在32.5~37℃的温度下粒子大小为30~100nm,
所述活性剂为选自紫杉醇(paclitaxel)、多西他赛(docetaxel)、汉防己甲素(tetradrine)、环孢素A(cyclosporin A)、地塞米松(dexamethasone)、生育酚乙酸酯(tocopheryl acetate)、虾青素(astaxanthin)、姜黄素(curcumin)、抗坏血酸-棕榈酸酯(ascorbyl palmitate)、咖啡酸苯乙酯(caffeic acid phenethyl ester;CAPE)、视黄醇乙酸酯(retinyl palmitate)、米诺地尔(minoxidil)、非那雄胺(finasteride)、积雪草(centella asiatica)、β-谷甾醇、抗坏血酸四异棕榈酸酯(ascorbyltetraisopalmitate)、胶原三肽(tripeptide collagen)、多柔比星(doxorubicin)、磷脂酶A2(phospholipase A2;PLA2)、卵白蛋白(ovalbumin)、牛血清白蛋白(bovine serumalbumin)、碱性成纤维细胞生长因子(b-FGF)及血管内皮生长因子(vascular endothelialgrowth factor;VEGF)中的一种以上,
所述普兰尼克为选自由普兰尼克L43、普兰尼克L44、普兰尼克L64、普兰尼克P84、普兰尼克P85、普兰尼克F87、普兰尼克F88、普兰尼克F98、普兰尼克P103、普兰尼克P104、普兰尼克P105、普兰尼克F108、普兰尼克P123及普兰尼克F127组成的组中的一种以上,并且所述普兰尼克为亲水亲油平衡值为8~29的普兰尼克,
所述壳聚糖的分子量为3~20kDa,
并且,所述纳米胶囊根据如下的纳米沉淀法的步骤制备:
第一步骤,将活性剂和普兰尼克溶于有机溶剂并在常温下通过反应制备反应溶液;
第二步骤,将所述第一步骤的反应溶液滴入以400rpm或530rpm进行搅拌的蒸馏水中,并持续搅拌,通过自然蒸发除去反应溶液的有机溶剂来制备粒子大小为5~50nm的纳米粒子;以及
第三步骤,在包括所述第二步骤的纳米粒子的蒸馏水中加入分子量为3~20kDa的壳聚糖来涂覆壳聚糖,
其中,所述壳聚糖通过与普兰尼克纳米粒子的物理结合而涂覆于纳米粒子。
2.根据权利要求1所述的纳米胶囊,其特征在于,以100重量份的普兰尼克为基准,所述活性剂为0重量份~20重量份,但不包括0重量份。
3.根据权利要求1所述的纳米胶囊,其特征在于,以100重量份的普兰尼克为基准,所述壳聚糖为0.001重量份~200重量份。
4.根据权利要求1所述的纳米胶囊,其特征在于,所述第一步骤的有机溶剂为选自由丙酮、乙醇、乙腈及四氢呋喃组成的组中的一种以上。
5.根据权利要求1所述的纳米胶囊,其特征在于,以第一步骤的有机溶剂的体积为基准,所述第二步骤的蒸馏水为所述有机溶剂的体积的4倍。
6.根据权利要求1所述的纳米胶囊,其特征在于,相对于单独处理活性剂,所述纳米胶囊的皮肤渗透率增加2倍以上。
7.一种包含根据权利要求1所述的纳米胶囊的药物递送系统。
8.根据权利要求7所述的包含纳米胶囊的药物递送系统,其特征在于,所述药物递送系统为皮肤外用剂或口服给药制剂。
9.一种包含根据权利要求1所述的纳米胶囊的化妆品材料组合物。
10.一种包含根据权利要求1所述的纳米胶囊的保健功能食品组合物。
11.一种包含根据权利要求1所述的纳米胶囊的医疗设备用组合物。
12.一种包含根据权利要求1所述的纳米胶囊的生活用品用组合物。
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