CN114524950B - 一种疏水药物载体水凝胶及其制备方法和应用 - Google Patents
一种疏水药物载体水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于高分子材料制备领域,涉及一种疏水药物载体水凝胶及其制备方法和应用,包括:在单‑6‑脱氧‑乙二胺基‑β‑环糊精溶液中加入胶原蛋白,溶解后,降温,与4,5‑脱水‑6(n‑乙酰葡糖胺)‑氧化透明质酸溶液混合,混合均匀,脱气,倒入模具,静置,即得。本发明提供的载药水凝胶,在酶的作用下胶原蛋白和透明质酸分解生成小分子产物,而透明质酸属于酸性粘多糖,胶原蛋白属于蛋白质,二者在人体中相应酶的存在下能被人体降解吸收。
Description
技术领域
本发明属于高分子材料制备技术领域,具体涉及一种疏水药物水凝胶载体及其制备方法和应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
药物载体,是指能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系。在药物载体中,来源于动、植物及微生物的生物高分子,因其良好的生物相容性、可生物降解及可再生性,成为一类重要的药物载体材料。
药物控制释放体系可提高药物的利用率、安全性和有效性,从而可减少给药频率,减轻病人的痛苦,因此受到广泛的关注。其中,化学控制药物释放体系可分为两种:混合药膜可生物降解体系和可生物降解大分子药物体系。在混合药膜体系中,药物分散在可生物降解高分子材料中,药物在高分子载体中难以扩散,只有在外层高分子降解后药物才能从载体中释放出来。在可生物降解大分子药物体系中,药物与高分子载体或药物分子之间是以化学键的形式相连,药物的释放必须通过水解或酶解来进行。
有研究公开了一种壳聚糖-银纳米复合基季铵盐协同抗菌水凝胶,这是一种具有抗菌活性的水凝胶,用于治疗烧伤创面。先制备氧化葡聚糖(ODex)和己二酰肼接枝透明质酸(HA-ADH),再与季铵盐壳聚糖(HACC)和银纳米颗粒混合制备Ag@ODex/HA-ADH/HACC水凝胶。壳聚糖具有大量的胺基等亲水基团,极大地提高了溶胀率。AgNPs与HACC协同抗菌,水凝胶具有良好的抗菌、抗炎、促愈合作用,葡聚糖和透明质酸是全天然生物材料,具有良好的生物相容性,可促进细胞增殖,但无论以何种暴露途径,纳米银都会导致各器官和组织中银元素水平的显著上升,且蓄积可长达数月,并因此造成明显的肝、肾毒性和免疫毒性。
专利202110679090.1公开了一种促进创面愈合的可吸收水凝胶组合物。聚乙二醇(PEG)、聚己内酯(PCL)在催化剂作用下,进行开环聚合反应得到PCEC共聚物,将PCEC共聚物、龙血素A溶于四氢呋喃,旋转蒸发有四氢呋喃,生成聚合物/药物基质薄膜,得到PCECA可降解水凝胶。PCEC水凝胶是通过开环聚合法合成的三嵌段聚合物溶解而成,这种水凝胶无毒并且有良好的生物相容性,同时与包封的药物小分子之间形成氢键或者静电作用力,因此可以很好地应用于体内外药物以及小分子的输送。
专利202010587569.8公开了一种用于治疗全层烧伤创面的水凝胶。先将N-异丙基丙烯酰胺单体和聚乙二醇单体采用RAFT聚合法合成共聚物,反应过程中甲叉双丙烯酰胺做交联剂、过硫酸铵做引发剂和二硫代氨基甲酸酯做催化剂;然后将所得共聚物中的活性酯与多巴胺基团进行置换,向聚合物中引入多巴胺基团;再向其中加入巯基乙胺进行化学接枝反应;最后将环孢素A和银纳米颗粒负载到所得物中即可得到水凝胶材料。该水凝胶用于治疗全层烧伤创面,使得烧伤创面可以得到快速愈合,其具有生物组织粘合性、温敏性和抗菌性。但频繁换药会造成二次伤害,增加感染风险,加大伤者痛苦。
有研究还公开了一种新型光交联鱼胶原蛋白肽-透明质酸水凝胶。用肽粉和甲基丙烯酸酐反应,用碳酸氢钠调节pH值,透析后冻干后得到胶原蛋白肽-甲基丙烯酸;用相同的方法合成透明质酸-甲基丙烯酸。用光交联剂I2959交联二者得到新型光交联鱼胶原蛋白肽-透明质酸水凝胶。水凝胶降解较慢,具有早期稳定性,但并未提及其应用于药物递送方面的应用。
当前,药剂学的发展已进入新时代,新型药物剂型正在朝着控释缓释方向发展,以便更好地控制药量、提高利用率和降低毒副作用,既有效治疗疾病又减轻患者痛苦。但目前适用于疏水药物的水凝胶的性能仍有缺陷,例如药物缓释时间短、水凝胶分解产物不能很好地被人体吸收,不能很好地满足患者的需求。
发明内容
针对上述不足,本发明提供了一种可吸收药物缓释水凝胶载体及其制备方法和应用。该水凝胶主要是由单-6-脱氧-乙二胺基-β-环糊精(β-CD-6-E)、4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸(ΔHA-CHO)与胶原蛋白交联形成。由于环糊精内腔疏水、外缘亲水,β-环糊精分子大小合适的空腔可与疏水性药物发生非共价结合,从而实现对高疏水性药物的负载,人体内的酶能降解环糊精多糖,从而将环糊精结合的药物释放出来,达到给药的目的。胶原蛋白与透明质酸在体内酶的作用下,逐渐发生降解,不仅能给伤口创造湿润、无菌的环境,降解产物还能够作为伤口修复的原料被人体使用,由于胶原蛋白与透明质酸交联成的网络,分解环糊精分子的酶不能立即与环糊精分子接触,延长了给药时间,实现长期给药。
为实现上述技术目的,本发明采用如下技术方案:
本发明的第一个方面,提供了一种疏水药物载体水凝胶的制备方法,包括:
在单-6-脱氧-乙二胺基-β-环糊精溶液中加入胶原蛋白,溶解后,降温,与4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合,混合均匀,脱气,倒入模具,静置,即得。
本发明的第二个方面,提供了上述的方法制备的疏水药物载体水凝胶。
本发明的第三个方面,提供了一种载药水凝胶的制备方法,包括:
向单-6-脱氧-乙二胺基-β-环糊精溶液中滴加药物的乙醇溶液,滴加完毕后,降温;再加入胶原蛋白,溶解后;与4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合,混合均匀,脱气,倒入模具,静置,即得。
本发明的第四个方面,提供了上述的方法制备的载药水凝胶。
本发明的第五个方面,提供了上述的疏水药物载体水凝胶,或,载药水凝胶在制备缓释药物中的应用。
本发明的有益效果在于:
(1)上述技术方案提供的载药水凝胶,在酶的作用下胶原蛋白和透明质酸分解生成小分子产物,而透明质酸属于酸性粘多糖,胶原蛋白属于蛋白质,二者在人体中相应酶的存在下能被人体降解吸收;
(2)上述技术方案提供的载药水凝胶,胶原蛋白能够起到保湿作用,透明质酸有着补水的效果,二者不但为伤口提供湿润的环境,而且能够阻隔外界的灰尘与细菌,有利于伤口恢复;
(3)上述技术方案提供的水凝胶内部含有环糊精分子,由于环糊精空腔可以与疏水性药物进行主客体作用,从而实现对疏水性药物的负载,该药物负载比较稳定,不受水凝胶的溶胀的影响;
(4)上述技术方案提供的水凝胶对疏水药物的负载量取决于水凝胶中环糊精的含量,可以通过调节环糊精的用量来控制水凝胶的载药量。
(5)上述技术方案提供的载药水凝胶,只有在酶的作用下环糊精分解才能释放出药物,而环糊精属于多糖,人体中酶的存在下可以降解吸收,因此具有良好的实际应用之价值。
(6)本申请的操作方法简单、成本低、具有普适性,易于规模化生产。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1:实施例1制备的水凝胶G1冷冻干燥后的SEM照片;
图2:实施例1~3制备的载药(姜黄素)水凝胶含有不同含量的α-淀粉酶、胶原蛋白酶、透明质酸酶的PBS溶液中药物释放曲线图;
图3:实施例1制备的水凝胶的吸水率。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本发明使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
本发明的第一个方面,提供一种可吸收药物缓释水凝胶载体的制备方法,包括以下步骤:在单-6-脱氧-乙二胺基-β-环糊精(β-CD-6-E)的PBS溶液(pH=7.4)中加入胶原蛋白,搅拌溶解,降温至2~8℃,然后与2~8℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸(ΔHA-CHO)的PBS溶液(pH=7.4)混合,快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得水凝胶。
在一些实施例中,单-6-脱氧-乙二胺基-β-环糊精(β-CD-6-E)的结构示意图如下所示:
在一些实施例中,β-CD-6-E在PBS中的浓度为0.6mg/mL;
胶原蛋白选择I型胶原蛋白,该胶原蛋白的伯氨基含量0..508mmol/g;
β-CD-6-E与I型胶原蛋白投料的质量比为1:20~1:9;
ΔHA-CHO的结构示意图如下所示:
在一些实施例中,ΔHA-CHO的大小为5~100kDa,醛基取代度为20%;更优选ΔHA-CHO的大小为50kDa;
在一些实施例中,ΔHA-CHO的加入量为-CHO与-NH2的摩尔比为1:1;
4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸(ΔHA-CHO)的制备方法按照文献(Buffa R,et al.Conjugates of modified hyaluronic acidwith amino compounds for biomedical applications[J].Carbohydrate Polymers,2018,189:273-279.)所述,并以全文的方式引入本发明中,制备方法如下:
透明质酸用离子交换树脂转化为酸性,冷冻干燥分离后,在无水二甲基亚砜中溶解一夜,形成1%的溶液。缓慢加入0.7等量的戴斯-马丁试剂,室温下搅拌24小时,然后用去等体积的离子水稀释,透析后得到HA-CHO。在3%的HA-CHO溶液中加入70mL二甲基亚砜和5当量的N,N-二异丙基乙胺。混合物在40℃下搅拌72h。用异丙醇/正己烷混合液(体积比5:2)沉淀分离产物,真空干燥得到白色粉末即为ΔHA-CHO。
本发明的第二个方面,提供一种上述水凝胶的载药水凝胶。
本发明的第三个方面,提供上述负载药物的水凝胶的制备方法,其制备方法包括:单-6-脱氧-乙二胺基-β-环糊精(β-CD-6-E)溶于PBS溶液中,搅拌下滴加药物的乙醇溶液,滴加完毕继续搅拌10分钟,降温至2~8℃,再加入胶原蛋白,搅拌5min,然后与2~8℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸(ΔHA-CHO)的PBS溶液混合,搅拌2~3min,适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得载药水凝胶。
在一些实施例中,上述载药水凝胶的制备方法中,药物为抗菌、消炎、促进伤口愈合、治疗烧伤等皮肤疾病的疏水性药物,包括但不限于苯酚、丁香酚、茶多酚、黄柏酮和姜黄素等;
在一些实施例中,上述载药水凝胶的制备方法中,药物在乙醇中的浓度为0.03~0.10g/mL;
在一些实施例中,上述载药水凝胶的制备方法中,药物的加入量为体系中环糊精基团摩尔量的80%~90%;
本发明的第四个方面,提供该可吸收药物缓释水凝胶作为药物载体的应用。
本发明的第五个方面,提供一种药物缓释的方法,所述方法包括施用上述载药水凝胶,并在多种酶作用下,环糊精、透明质酸、胶原蛋白分别分解,将药物释放出来,达到缓慢给药的目的。
其中,所述酶包括能够用于降解环糊精的酶,如α-淀粉酶;能够用于降解透明质酸的酶,如透明质酸酶;能够用于降解胶原蛋白的酶,如胶原蛋白酶。
本发明的第六个方面,提供该水凝胶或载药水凝胶的其它存储方式,可以将水凝胶或载药水凝胶进行冷冻干燥,得到相应的海绵材料,该海绵材料在PBS溶液中浸泡,又可重新得到水凝胶或载药水凝胶。
下面结合具体的实施例,对本发明做进一步的详细说明,应该指出,所述具体实施例是对本发明的解释而不是限定。
实施例1
水凝胶的制备:将0.06g单-6-脱氧-乙二胺基-β-环糊精溶于100mL PBS溶液(pH=7.4)中,加入1g胶原蛋白,搅拌溶解,降温至4℃,然后与4℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合(1.06g 4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶于100mL PBS中),快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得水凝胶G1。
载药水凝胶的制备:将0.06g单-6-脱氧-乙二胺基-β-环糊精溶于100mL PBS溶液中,搅拌下滴加姜黄素的乙醇溶液(0.0159g姜黄素溶于1mL乙醇中),滴加完毕继续搅拌10分钟,降温至4℃,再加入1g胶原蛋白,搅拌5min,然后与4℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合(1.06g 4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶于100mL PBS中),快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得载药水凝胶GR1。
实施例2
水凝胶的制备:将0.06g单-6-脱氧-乙二胺基-β-环糊精溶于100mL PBS溶液(pH=7.4)中,加入0.8g胶原蛋白,搅拌溶解,降温至4℃,然后与4℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合(0.866g 4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶于100mL PBS中),快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得水凝胶G2。
载药水凝胶的制备:将0.06g单-6-脱氧-乙二胺基-β-环糊精溶于100mL PBS溶液中,搅拌下滴加姜黄素的乙醇溶液(0.0159g姜黄素溶于1mL乙醇中),滴加完毕继续搅拌10分钟,降温至4℃,再加入0.8g胶原蛋白,搅拌5min,然后与4℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合(0.866g 4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶于100mL PBS中),快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得载药水凝胶GR2。
实施例3
水凝胶的制备:将0.06g单-6-脱氧-乙二胺基-β-环糊精溶于100mL PBS溶液(pH=7.4)中,加入0.5g胶原蛋白,搅拌溶解,降温至4℃,然后与4℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合(0.578g 4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶于100mL PBS中),快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得水凝胶G3。
载药水凝胶的制备:将0.06g单-6-脱氧-乙二胺基-β-环糊精溶于100mL PBS溶液中,搅拌下滴加姜黄素的乙醇溶液(0.0159g姜黄素溶于1mL乙醇中),滴加完毕继续搅拌10分钟,降温至4℃,再加入0.5g胶原蛋白,搅拌5min,然后与4℃的4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合(0.578g 4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶于100mL PBS中),快速搅拌均匀(约2~3min),适当减压去除溶解的气体,倒入模具,常温下静置24~48小时,得载药水凝胶GR3。
分析与说明
以下方法用于所有实施例,除非另外说明
破裂强度:采用质构仪测试(美国Brookfield公司CT3质构分析仪),将凝胶裁成直径12mm、高10mm的圆柱体,采用直径12mm的探头逐渐加压,记录凝胶破碎时的压力,进而计算出破裂强度;
载药水凝胶的体外释放:将载有药物的水凝胶分别浸没在含有不同种类的酶的PBS(pH=7.4)溶液中,置于转速为35r/min的摇床上,调节温度至37℃,每隔24h,取出2mL含释放药物的溶液,同时加入2mL不含药物的溶液,溶液中的药物含量可以通过紫外-可见分光光度计于特定波长处测得,根据标准曲线计算药物的累计释放量;
水凝胶的吸水率:将水凝胶冷冻干燥,称重,标记初始干重质量m0。将冻干后的样品浸泡在去离子水中,在温度37℃下,每隔一段时间,用吸水纸吸掉水凝胶表面的水分,电子分析天平进行称重,标记为mt。每次测量之后水凝胶浸泡在新去离子水中,每组做5个平行样本。
水凝胶的吸水率记为W,W(%)=(mt-m0)/m0×100%
实施例1-3制备的水凝胶的破裂强度如表1所示,因为水凝胶的破裂强度顺序为G3<G2<G1,样品的交联度顺序为G3<G2<G1,这说明破裂强度与交联度一致,在固含量近似的基础上,凝胶的强度主要是由凝胶中聚合物的交联度所控制的。整体上实施例1-3制备的水凝胶均表现出良好的破裂强度,这是因为所是胶原蛋白和透明质酸均为多官能度的,交联效果较好。
表1.实施例1-3制备的水凝胶的性能
冻干后的水凝胶的SEM图片(图1)显示样品呈现出疏松多孔的结构,形似海绵,有较高的空隙率,吸水性能良好,该样品的原料中,胶原蛋白与透明质酸同时存在,使得该水凝胶具有良好的保水性能。
图2为水凝胶在含有不同含量的α-淀粉酶、胶原蛋白酶、透明质酸酶的PBS溶液中药物释放曲线图。由图2可知,在不含α-淀粉酶的PBS溶液中,水凝胶负载的药物几乎没有释放。在含有α-淀粉酶的PBS溶液中,随着时间变化只有少量药物释放出来。在含有α-淀粉酶、胶原蛋白酶、透明质酸酶的PBS溶液中,药物随着时间变化逐渐释放出来,在8~10天时药物释放量能够达到90%。这是因为环糊精包覆的药物不会随着水凝胶的溶胀而释放,而在酶的作用下环糊精分子(多糖)降解,内部的空腔被破坏破坏,药物释放出来;与此同时,大量的载药环糊精分子被包埋在胶原蛋白和透明质酸形成的网络中,通过相应的酶破坏网络结构,使环糊精分子裸露出来,才能进一步降解环糊精,释放药物。这说明该发明所制备的水凝胶药物释放稳定且缓慢,只有在多种酶的作用下药物才会得到充分释放,随着时间的不断延长逐渐被人体中的酶所降解吸收,从而达到了药物缓释的目的。
图3为不同组分水凝胶冷冻干燥后干胶在37℃去离子水中的吸水率,由图3可知,初期水凝胶的吸水速度相对较快,后期逐渐变缓,最后达到平衡,透明质酸和胶原蛋白含量不同的水凝胶都可在2h内达到溶胀平衡。G1水凝胶达平衡时的吸水率为873%;G2水凝胶达平衡时的吸水率为1230%;G3水凝胶达平衡时的吸水率为1797%。由图3可知,随着原水凝胶中固含量的增高,达到平衡时的最大吸水率降低。
最后应该说明的是,以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (11)
1.一种疏水药物载体水凝胶的制备方法,其特征在于,包括:
在单-6-脱氧-乙二胺基-β-环糊精溶液中加入胶原蛋白,溶解后,降温,与4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合,混合均匀,脱气,倒入模具,静置,即得;
所述胶原蛋白为I型胶原蛋白。
2.如权利要求1所述的疏水药物载体水凝胶的制备方法,其特征在于,所述单-6-脱氧-乙二胺基-β-环糊精与I型胶原蛋白投料的质量比为1:20~1:9。
3.如权利要求1所述的疏水药物载体水凝胶的制备方法,其特征在于,4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸的加入量为-CHO与-NH2的摩尔比为1~1.5:1~1.5。
4.如权利要求1所述的疏水药物载体水凝胶的制备方法,其特征在于,所述单-6-脱氧-乙二胺基-β-环糊精溶液的浓度为0.6~0.8mg/mL,所述溶剂为PBS溶液。
5.如权利要求1所述的疏水药物载体水凝胶的制备方法,其特征在于,所述胶原蛋白的伯氨基含量0.508~0.6mmol/g;
或,所述4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸的分子量为5~100kDa,醛基取代度为20%。
6.如权利要求1所述的疏水药物载体水凝胶的制备方法,其特征在于,所述4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸的分子量为50kDa。
7.如权利要求1-6任一项所述的方法制备的疏水药物载体水凝胶。
8.一种载药水凝胶的制备方法,其特征在于,包括:
向单-6-脱氧-乙二胺基-β-环糊精溶液中滴加药物的乙醇溶液,滴加完毕后,降温;再加入胶原蛋白,溶解后;与4,5-脱水-6(n-乙酰葡糖胺)-氧化透明质酸溶液混合,混合均匀,脱气,倒入模具,静置,即得;
所述胶原蛋白为I型胶原蛋白。
9.如权利要求8所述载药水凝胶的制备方法,其特征在于,所述药物为苯酚、丁香酚、茶多酚、黄柏酮或姜黄素。
10.权利要求8或9所述的方法制备的载药水凝胶。
11.权利要求7所述的疏水药物载体水凝胶,或,权利要求10所述的载药水凝胶在制备缓释药物中的应用。
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