CN116650402A - 一种促进创面修复的纳米凝胶及其制备方法 - Google Patents
一种促进创面修复的纳米凝胶及其制备方法 Download PDFInfo
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- CN116650402A CN116650402A CN202310514828.8A CN202310514828A CN116650402A CN 116650402 A CN116650402 A CN 116650402A CN 202310514828 A CN202310514828 A CN 202310514828A CN 116650402 A CN116650402 A CN 116650402A
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- verteporfin
- polylactic acid
- nanogel
- hyaluronic acid
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- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Materials For Medical Uses (AREA)
Abstract
本发明公开了一种促进创面修复的纳米凝胶及其制备方法。本发明的纳米凝胶是将维替泊芬包载于聚乳酸纳米颗粒中,混合透明质酸凝胶制备得到纳米凝胶。通过纳米凝胶涂抹于创面表面,不仅有利于创面愈合,还能增强维替泊芬在创面上的应用,减少创面疤痕形成。
Description
技术领域
本发明属于生物医药领域,具体涉及一种促进创面修复的纳米凝胶及其制备方法。
背景技术
皮肤是人体自我保护的屏障。皮肤损伤后会出现伤口或创面并导致感染,创面不良愈合会产生大量疤痕等病理性严重纤维化组织,不仅导致患者活动受限、身体畸形,也会对其心理造成重大影响。因此,创面愈合与疤痕防治已成为不容忽视的社会问题,也是现代皮肤损伤修复的两大焦点。在成人中,伤口愈合的目的是迅速恢复皮肤的屏障功能,但会导致疤痕。而创面的少疤痕再生性愈合是未来的方向。研究证明,在创面中破坏成纤维细胞的YAP机械传导,通过减少YAP表达和入核效率影响细胞纤维化水平,能够实现创面少疤痕甚至是无疤痕愈合。
纳米凝胶具有较小的粒径,其内部具有三维网状结构,可将药物包封于其内部,保护药物免受外界环境破坏,并实现稳定释放。
因此制备一种有效的促进创面愈合,减少疤痕形成的纳米凝胶是本领域亟待解决的问题。
发明内容
为弥补现有技术的不足,本发明提供了一种维替泊芬-聚乳酸纳米凝胶及其制备方法。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面提供了一种促进创面修复的纳米凝胶的制备方法,所述方法包括:
(1)将维替泊芬与聚乳酸混合溶解;
(2)加入透明质酸,得到维替泊芬-聚乳酸纳米凝胶。
进一步,步骤(1)中维替泊芬与聚乳酸于有机溶剂中溶解。
进一步,所述有机溶剂包括丙酮、二氯甲烷、乙酸乙酯。
进一步,所述有机溶剂选自丙酮。
进一步,维替泊芬与聚乳酸的质量比为1:(5-6)。
进一步,维替泊芬的浓度为0.01-2mg/mL。
进一步,维替泊芬的浓度为1-2mg/mL。
进一步,聚乳酸的浓度为1-20mg/mL。
进一步,聚乳酸的浓度为6-10mg/mL。
进一步,步骤(1)还包括将维替泊芬与聚乳酸的溶解液加入到乙醇溶液。进一步,采用逐滴加入的方式将维替泊芬与聚乳酸的溶解液加入到乙醇溶液。
进一步,乙醇的体积比例为10%-50%。
进一步,乙醇的体积比例为20%-30%。
进一步,加入到乙醇溶液后还包括搅拌的步骤。
进一步,搅拌的时间为1-5小时。
进一步,搅拌的时间为3-4小时。
进一步,步骤(1)还包括去除溶液中的有机相。
进一步,通过减压去除溶液中的有机相。
进一步,步骤(2)包括分两次加入透明质酸。
进一步,第一次加入透明质酸后进行搅拌。
进一步,搅拌的时间为2-5小时。
进一步,搅拌后通过超声制备成包载有维替泊芬的聚乳酸纳米颗粒。
进一步,所述透明质酸的浓度为0.1%-0.5%。
进一步,步骤(2)第二次加入透明质酸后搅拌水化。
进一步,所述透明质酸的浓度为2%-8%。
进一步,步骤(2)中的透明质酸包括透明质酸及其盐或其衍生物。
进一步,所述透明质酸选自透明质酸盐。
进一步,所述透明质酸盐包括透明质酸钠、透明质酸钾、透明质酸锌。
进一步,所述透明质酸盐选自透明质酸钠。
进一步,所述透明质酸钠的分子量为40000-1000000。
本发明的第二方面提供了一种用于促进创面修复的纳米凝胶,所述纳米凝胶包括维替泊芬、聚乳酸和透明质酸。
进一步,所述纳米凝胶由本发明第一方面所述的方法制备而成。
进一步,所述纳米凝胶颗粒大小为200-1000nm。
进一步,所述纳米凝胶颗粒大小为200-500nm。
进一步,所述纳米凝胶通过抑制组织中YAP的表达量促进创面修复。
进一步,所述纳米凝胶通过抑制胶原增殖和/或调控胶原比例促进创面修复。
本发明的第三方面提供了本发明第二方面所述的纳米凝胶在制备促进创面修复的药物中的应用。
进一步,所述药物还包括药学上可接受的载体和/或辅料。
本发明的优点和有益效果:
本发明提供的维替泊芬-聚乳酸纳米凝胶,将维替泊芬包载于聚乳酸纳米颗粒中,混合透明质酸凝胶制备得到纳米凝胶。通过纳米凝胶涂抹于创面表面,不仅有利于创面愈合,还能增强维替泊芬在创面上的应用,减少创面疤痕形成。
附图说明
图1是维替泊芬-聚乳酸纳米凝胶的透射电镜结果图;
图2是维替泊芬-聚乳酸纳米凝胶促进鼠创面愈合结果图;
图3是维替泊芬-聚乳酸纳米凝胶抑制YAP表达结果图,其中,3A是空白组YAP表达结果图,3B是纳米凝胶组YAP表达结果图;
图4是维替泊芬-聚乳酸纳米凝胶的扫描电镜结果图;
图5是维替泊芬-聚乳酸纳米凝胶在兔耳模型中减少疤痕形成的结果图,其中,5A是术后15天减少疤痕形成的结果图;5B是术后30天减少疤痕形成的结果图;
图6是维替泊芬-聚乳酸纳米凝胶抑制胶原增殖和调控胶原比例的效果图,其中,6A是纳米凝胶组Masson染色结果图,6B是空白组Masson染色结果图,6C是纳米凝胶组天狼星红染色结果图,6D是空白组天狼星红染色结果图。
具体实施方式
下文提供了本说明书中使用的一些术语的定义。除非另有说明,本文中使用的所有技术和科学用语通常具有和本发明所属领域的普通技术人员通常理解的意思相同的意思。
本发明提供了一种促进创面修复的纳米凝胶的制备方法,所述方法包括:
(1)将维替泊芬与聚乳酸混合溶解;
(2)加入透明质酸,得到维替泊芬-聚乳酸纳米凝胶。
维替泊芬,其化学名为9-甲基(I)和13-甲基(II)反式-(±)-18-乙烯-4,4a-二氢-3,4-双(甲酯基)-4a,8,14,19-四甲基-23H,25H-苯卟啉-9,13-二丙酯,分子式为C41H42N4O8,分子量为718.79。
在本发明中,创面修复是指正常皮肤(组织)在外界致伤因子如外科手术、外力、热、电流、化学物质、低温以及机体内在因素如局部血液供应障碍等作用下所导致的损害。常伴有皮肤完整性的破坏以及一定量正常组织的丢失,同时,皮肤的正常功能受损。创面也称为伤口或者创伤。创面修复即伤口修复。本发明的创面修复包括促进创面愈合和减少创面疤痕形成。
在本发明中,纳米凝胶意指当量直径为约几纳米至1000nm的任何形状的聚合物凝胶颗粒。纳米凝胶描述了相互连接的局部的网络结构,以及适当描述了聚合物凝胶颗粒的物理尺寸。纳米凝胶通常在制备它们的溶剂中是可溶的,并且纳米凝胶还可以根据其制造中所使用的单体按需要制备并可溶于各种液体。然而,纳米凝胶还可以在不存在溶剂(大量)的情况下制备,然后溶解于适当的溶剂或单体组合物中。
在本发明中,聚乳酸或聚丙交酯或PLA是可互换使用的,并且指的是包括得自乳酸的重复单元的聚(乳酸)聚合物。聚乳酸包括四种在形态学上不同的聚乳酸聚合物中的任一种或多种:D-聚乳酸、L-聚乳酸、D,L-聚乳酸和内消旋聚乳酸。D-聚乳酸和L-聚乳酸分别为右旋聚乳酸和左旋聚乳酸,并且它们二者均是光学活性聚合物,当光矢量透过该聚合物时它们使光矢量旋转。D,L-聚乳酸为外消旋聚合物,即具有明确的D-聚乳酸单元和L-聚乳酸单元构象的D-聚乳酸和L-聚乳酸的共聚物。内消旋聚乳酸为D-聚乳酸和L-聚乳酸的无规共聚物。
本发明的聚乳酸也包括含乳酸的共聚物。也可使用除了乳酸之外的共聚组分并且其包含二羧酸、多羟基醇、羟基羧酸、内酯、或者具有两个或更多个各自能够形成酯键的官能团的类似物。这些例如聚酯、聚醚、聚碳酸酯、或者在分子中具有两个或更多个未反应的官能团的类似物。所述羟基羧酸可选自包括如下的列表:羟基乙酸、羟基丁酸、羟基缬草酸、羟基戊酸、羟基己酸、和羟基庚酸。
本发明的聚乳酸可以根据现有技术已知的任何方法制备。所述聚乳酸可通过选自如下的具有所需结构的原材料的开环聚合而制备:丙交酯,其为乳酸的环状二聚体;乙交酯,其为羟基乙酸的环状二聚体;和己内酯等。丙交酯包含:L-丙交酯,其为L乳酸的环状二聚体;D-丙交酯,其为D-乳酸的环状二聚体;内消旋-丙交酯,其为D-乳酸和L乳酸的环状二聚体;和DL-丙交酯,其为D-丙交酯和L-丙交酯的外消旋体。由内消旋-丙交酯制成的无规共聚物导致被称作聚(内消旋-丙交酯)(PmesoLA)的无规立构的主要结构并且是无定形的。由等摩尔量的D-丙交酯和L-丙交酯制成的无规光学共聚物被称作聚-DL-丙交酯(PDLLA)或者聚(外消旋-丙交酯)并且也是无定形的。L-丙交酯或L-L-丙交酯指的是(S,S)-丙交酯并且是两乳酸S对映异构体的环状二酯。D-丙交酯或D-D-丙交酯指的是(R,R)-丙交酯并且是两乳酸R对映异构体的环状二酯。
步骤(1)中维替泊芬与聚乳酸于有机溶剂中溶解。
在本发明中,有机溶剂包括但不限于甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、丙酮、甲乙酮、1,2-二甲氧基乙烷、乙腈、己烷、甲苯、乙醚、氯仿、乙酸乙酯、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺、二甲亚砜、乙酸、甲酸。
在本发明的实施方案中,有机溶剂包括丙酮、二氯甲烷、乙酸乙酯。
在本发明的具体实施方案中,有机溶剂选自丙酮。
步骤(1)还包括将维替泊芬与聚乳酸的溶解液加入到乙醇溶液。
所述维替泊芬与聚乳酸的溶解液加入到乙醇溶液的方式包括逐滴加入、一次性加入。
在本发明的具体实施方案中,采用逐滴加入的方式将维替泊芬与聚乳酸的溶解液加入到乙醇溶液。
所述乙醇的体积比例为10%-50%v/v,例如10%v/v、20%v/v、30%v/v、40%v/v、50%v/v以及上述任意两点之间的体积比例;优选的体积比例为20%-30%v/v,例如,在本发明中,当维替泊芬与聚乳酸的质量比为1:6时,乙醇的体积比例为20%;当维替泊芬与聚乳酸的质量比为1:5时,乙醇的体积比例为30%。
加入乙醇溶液后还包括搅拌的步骤。
搅拌的时间为1-5小时或更长时间,例如可以是1小时、2小时、3小时、4小时、5小时,优选3小时或4小时,在本发明中,当乙醇的体积比例为20%时,搅拌时间为4小时,乙醇的体积比例为30%时,搅拌的时间为3小时。
步骤(2)包括分两次加入透明质酸。
第一次加入透明质酸后进行搅拌,搅拌的时间为2-5小时。
搅拌的时间例如可以是2小时、3小时、4小时、5小时,在本发明中,当加入的透明质酸为8mg,分子量40000时,搅拌的时间为2小时,当加入10mg透明质酸,分子量为1000000时,搅拌5小时。
步骤(2)所述的透明质酸包括透明质酸及其盐或其衍生物,即透明质酸还包括透明质酸盐、透明质酸衍生物。
在本发明中,透明质酸也称为透明质烷或HA,是一种天然和直链的碳水化合物聚合物,其属于非硫酸化的氨基多糖类。它是由β-1,3-N-乙酰基葡萄糖胺和β-1,4-葡萄糖醛酸的重复二糖单元组成。透明质酸存在于透明软骨、滑膜关节滑液以及真皮或表皮的皮肤组织中。透明质酸可从包括脊椎动物的结缔组织的天然组织中、从人类脐带以及从鸡冠中提取。
透明质酸衍生物是指透明质酸的全部衍生物,其包括诸如胺基、醛基、乙烯基、硫醇基、烯丙氧基、N-琥珀酰亚胺基-3-(2-吡啶二硫基)丙酸盐(SPDP)和N-羟基琥珀酰亚胺(NHS)的取代基,导入到透明质酸的基本骨架结构等。透明质酸的衍生物的例子包括HA-二氨基丁烷、HA-己二胺、HA-醛、HA-己二酸二酰肼(HA-ADH)、HA-2-氨乙基甲基丙烯酸酯盐酸盐、HA-精胺、HA-亚精胺、HA-SPDP、HA-NHS。
透明质酸盐包括透明质酸钠、透明质酸钾、透明质酸锌、透明质酸钙、透明质酸镁、或者透明质酸铵。
在本发明的实施方案中,透明质酸选自透明质酸盐。
在本发明的具体实施方案中,透明质酸盐选自透明质酸钠。
本发明的透明质酸钠例如分子量(MW)在10000至1000000Da范围内、优选MW在30000至1000000Da范围内、最优选MW在40000至1000000Da范围内的透明质酸钠。
本发明提供了一种用于促进创面修复的纳米凝胶,所述纳米凝胶包括维替泊芬、聚乳酸和透明质酸。
所述纳米凝胶由上述方法制备而成。
所述纳米凝胶颗粒大小为200-1000nm。
优选的,所述纳米凝胶颗粒大小为200-500nm。
在本发明中,纳米凝胶颗粒大小一般指纳米凝胶的直径,直径涵盖了宽的含义。例如,相对于具有圆形横截面的部件,术语直径具有常规含义并且是指通过圆形中心连接圆周上两点的直线。本发明所用直径是指横截面的特征直径。
所述纳米凝胶通过抑制组织中YAP的表达量促进创面修复。
在本发明中,YAP包括野生型、突变型或其片段。该术语涵盖全长,未加工的YAP,源自细胞中加工的任何形式的YAP,以及YAP的天然发生变体(例如剪接变体或等位变体)。该术语涵盖例如人的YAP以及来自任何其它脊椎动物来源,包括哺乳动物,诸如灵长动物和啮齿动物(例如小鼠和大鼠)的YAP,基因ID:10413。
所述纳米凝胶通过抑制胶原增殖和/或调控胶原比例促进创面修复。
在本发明中,纳米凝胶可以有效的减少组织中胶原生成量,有效的增强组织中III型胶原的生成比例。
在本发明中,纳米凝胶还可以包括促进创面修复的IGF、bFGF、EGF及GMCSF的成长因子或P物质(Substance-P)。
还可以包括促进创面修复的胶原蛋白(Collagen)、糖胺(Glycosaminoglycanes)、纤维连接蛋白(Fibronectin)或其混合物组成的群中的细胞间质(ECM)。
还可以包括促进创面修复的所甲基纤维素(Carboxymethyl cellulose)、海藻酸钠(Alginate)、壳聚糖(Chitosan)、聚己内酯(Poly(e-caprolactone))、聚乙醇酸(Poly(glycolicacid))、羟基磷灰石(Hydroxyapatite)、磷酸三钙(Tricalcium phosphate)的生物材料,或由其混合物的生物材料(Biomaterials)。
还可以包括细胞,细胞传送到人体适用部位用于促进创面修复等。所述细胞可以为例如皮肤角质细胞、成纤维细胞、色素细胞、骨髓间充质干细胞、间质干细胞、造血干细胞、骨髓细胞、神经细胞、上皮细胞或其混合物。
在本发明中,纳米凝胶可以例如应用到皮肤或伤口上。可以例如包括经口、直肠、经粘膜或肠内施用;肠胃外递送,包括肌内、皮下、静脉内、髓内注射,以及鞘内、直接心室内、腹膜内、鼻内或眼内注射,以及直接涂抹。在这点上应指出,为了施用纳米凝胶,不需要手术操作。
在本发明的实施方案中,纳米凝胶直接涂抹于创面表面。
本发明提供了所述的纳米凝胶在制备促进创面修复的药物中的应用。
所述药物还包括药学上可接受的载体和/或辅料。
在本发明中,药学上可接受的是指那些在合理的医学判断范围内适合与人类和动物的组织接触而没有过多毒性、刺激性、过敏反应或其他与合理的利益/风险比相称的问题并发症的化合物、材料、组合物和/或剂型。药学上可接受的载体和/或辅料是指这样的载体和/或辅料,其并不引起对生物体的显著刺激,并且并不废除所给予化合物的生物活性和性质。
药学上可接受的载体和/或辅料在Remington's Pharmaceutical Sciences(19thed.,1995)中有详细的记载,包括但不限于稀释剂、粘合剂、表面活性剂、致湿剂、吸附载体、润滑剂、填充剂、崩解剂。在这种药物中可以使用的制剂可以是其原始化合物本身的形式或任选地使用其药物学可接受的盐的形式,如此配制的药物根据需要可选择本领域技术人员已知的任何适当的方式把药物进行给药。使用药物时,是将安全有效量的本发明的药物施用于哺乳动物。
其中,稀释剂包括但不限于乳糖、氯化钠、葡萄糖、尿素、淀粉、水。
粘合剂包括但不限于淀粉、预胶化淀粉、糊精、麦芽糖糊精、蔗糖、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素、乙基纤维素、聚乙烯醇、聚乙二醇、聚乙烯比咯烷酮、海藻酸及海藻酸盐、黄原胶、羟丙基纤维素和羟丙基甲基纤维素。
表面活性剂包括但不限于聚氧化乙烯山梨聚糖脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘油酯、十六烷醇。
致湿剂包括但不限于甘油、淀粉。
吸附载体包括但不限于淀粉、乳糖、斑脱土、硅胶、高岭土和皂粘土。
润滑剂包括但不限于硬脂酸锌、单硬脂酸甘油酯、聚乙二醇、滑石粉、硬脂酸钙和镁、聚乙二醇、硼酸粉末、氢化植物油、硬脂富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁。
填充剂包括但不限于甘露醇(粒状或粉状)、木糖醇、山梨醇、麦芽糖、赤藓糖、微晶纤维素、聚合糖、偶合糖、葡萄糖、乳糖、蔗糖、糊精、淀粉、海藻酸钠、海带多糖粉末、琼脂粉末、碳酸钙和碳酸氢钠。
崩解剂包括但不限于交联乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基甲基、交联羧甲基纤维素钠、大豆多糖。
有效量是指足以诱导期望的生物、药物、或治疗结果的量。所述结果可以是疾病或障碍或病症的体征、症状、或起因的缓和,或生物系统的任何其它期望的改变。在本发明中,所述结果将涉及全部或部分地促进和/或改善伤口愈合,包括伤口愈合和伤口闭合的速率,以及减少疤痕的全部或部分地减少。其它益处包括肿胀、发炎等。
本发明所述的药物的适合的给药剂量根据制剂化方法、给药方式、患者的年龄、体重、性别、病态、饮食、给药时间、给药途径、排泄速度及反应灵敏性之类的因素而可以进行多种处方,熟练的医生通常能够容易地决定处方及处方对所希望的治疗或预防有效的给药剂量。
本发明的药物以乳膏、贴剂或膜的形式提供。
哺乳动物包括但不限于人、狗、猫、兔、鼠、马、牛、猴和猪。
下面结合具体实施例进一步阐述此发明。应理解的是,在此描述的特定实施方式通过举例的方式来表示,并不作为对本发明的限制。在不偏离本发明范围的情况下,本发明的主要特征可以用于各种实施方式。
实施例1维替泊芬-聚乳酸纳米凝胶促进创面愈合
1)将10mg维替泊芬和60mg聚乳酸共同溶解于1mL丙酮后,逐滴加入到10mL乙醇水溶液(乙醇体积比例为20%),搅拌4小时,获得溶液a。
2)将获得的溶液a在常温条件下减压除去溶液中的有机相,得到体积约为8mL的溶液b。
3)在获得的溶液b加入8mg透明质酸钠(分子量40000),充分搅拌2小时后,超声制备成包载有维替泊芬的聚乳酸纳米颗粒,得到溶液c。当透明质酸在低于0.1%或高于0.5%时得到的聚乳酸纳米颗粒稳定性不如在0.1%~0.5%时的效果好。
4)将获得的溶液c中再加入160mg透明质酸钠(分子量40000),充分搅拌水化,得到所述的维替泊芬-聚乳酸纳米凝胶。
维替泊芬-聚乳酸纳米凝胶的透射电镜图显示,包载维替泊芬的聚乳酸纳米颗粒大小约为200nm,且分布于透明质酸网状结构中(图1)。将制得的纳米凝胶涂抹于大鼠创面上发现,创面愈合速度较对照组明显加快(图2)。将大鼠创面样品进行免疫荧光检测发现,组织中YAP表达量明显抑制(图3)。因此,所制备的维替泊芬-聚乳酸纳米凝胶可以加速创面愈合。
实施例2维替泊芬-聚乳酸纳米凝胶减少疤痕形成
1)将20mg维替泊芬和100mg聚乳酸共同溶解于1mL丙酮后,逐滴加入到10mL乙醇水溶液(乙醇体积比例为30%),搅拌3小时,获得溶液a。
2)将获得的溶液a在常温条件下减压除去溶液中的有机相,得到体积约为8mL的溶液b。
3)在获得的溶液b加入10mg透明质酸(分子量1000000),充分搅拌5小时后,超声制备成包载有维替泊芬的聚乳酸纳米颗粒,得到溶液c。
4)将获得的溶液c中再加入80mg透明质酸钠(分子量100000),充分搅拌水化,得到所述的维替泊芬-聚乳酸纳米凝胶。当透明质酸在低于2%或高于8%时得到的纳米凝胶不如在2-8%时的效果好。
维替泊芬-聚乳酸纳米凝胶的扫描电镜图显示,包载维替泊芬的聚乳酸纳米颗粒大小约为500nm,且分布于透明质酸网状结构,呈明显的凝胶结构(图4)。将制得的纳米凝胶涂抹于兔耳创面上,术后15天创面都愈合,一个月后取样进行观察发现,纳米凝胶可以有效的减少疤痕形成(图5)。将兔耳样品进行组织学分析,Masson染色结果证实纳米凝胶可以有效的减少组织中胶原生成量,天狼星红染色结果证实纳米凝胶可以有效的增强组织中III型胶原的生成比例(图6)。因此,所制备的维替泊芬-聚乳酸纳米凝胶可以有效减少创面愈合时的疤痕生成。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (10)
1.一种促进创面修复的纳米凝胶的制备方法,其特征在于,所述方法包括:
(1)将维替泊芬与聚乳酸混合溶解;
(2)加入透明质酸,得到维替泊芬-聚乳酸纳米凝胶。
2.根据权利要求1所述的方法,其特征在于,步骤(1)中维替泊芬与聚乳酸于有机溶剂中溶解;
优选的,所述有机溶剂包括丙酮、二氯甲烷、乙酸乙酯;
优选的,所述有机溶剂选自丙酮;
优选的,维替泊芬与聚乳酸的质量比为1:(5-6);
优选的,维替泊芬的浓度为0.01-2mg/mL;
优选的,维替泊芬的浓度为1-2mg/mL;
优选的,聚乳酸的浓度为1-20mg/mL;
优选的,聚乳酸的浓度为6-10mg/mL。
3.根据权利要求1所述的方法,其特征在于,步骤(1)还包括将维替泊芬与聚乳酸的溶解液加入到乙醇溶液;
优选的,采用逐滴加入的方式将维替泊芬与聚乳酸的溶解液加入到乙醇溶液;
优选的,乙醇的体积比例为10%-50%;
优选的,乙醇的体积比例为20%-30%;
优选的,加入到乙醇溶液后还包括搅拌的步骤;
优选的,搅拌的时间为1-5小时;
优选的,搅拌的时间为3-4小时。
4.根据权利要求1所述的方法,其特征在于,步骤(1)还包括去除溶液中的有机相;
优选的,通过减压去除溶液中的有机相。
5.根据权利要求1所述的方法,其特征在于,步骤(2)包括分两次加入透明质酸;
优选的,第一次加入透明质酸后进行搅拌;
优选的,搅拌的时间为2-5小时;
优选的,搅拌后通过超声制备成包载有维替泊芬的聚乳酸纳米颗粒;
优选的,所述透明质酸的浓度为0.1%-0.5%。
6.根据权利要求1所述的方法,其特征在于,步骤(2)第二次加入透明质酸后搅拌水化;
优选的,所述透明质酸的浓度为2%-8%。
7.根据权利要求1所述的方法,其特征在于,步骤(2)中的透明质酸包括透明质酸及其盐或其衍生物;
优选的,所述透明质酸选自透明质酸盐;
优选的,所述透明质酸盐包括透明质酸钠、透明质酸钾、透明质酸锌;
优选的,所述透明质酸盐选自透明质酸钠;
优选的,所述透明质酸钠的分子量为40000-1000000;
优选的,所述创面修复包括促进创面愈合和减少创面疤痕形成。
8.一种用于促进创面修复的纳米凝胶,其特征在于,所述纳米凝胶包括维替泊芬、聚乳酸和透明质酸;
优选的,所述纳米凝胶由权利要求1-7任一项所述的方法制备而成;
优选的,所述纳米凝胶颗粒大小为200-1000nm;
优选的,所述纳米凝胶颗粒大小为200-500nm;
优选的,所述纳米凝胶通过抑制组织中YAP的表达量促进创面修复;
优选的,所述纳米凝胶通过抑制胶原增殖和/或调控胶原比例促进创面修复。
9.权利要求8所述的纳米凝胶在制备促进创面修复的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述药物还包括药学上可接受的载体和/或辅料。
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