CN114099710A - 一种促进活性物质皮肤滞留的透明质酸-环糊精纳米载体 - Google Patents
一种促进活性物质皮肤滞留的透明质酸-环糊精纳米载体 Download PDFInfo
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- CN114099710A CN114099710A CN202111514430.1A CN202111514430A CN114099710A CN 114099710 A CN114099710 A CN 114099710A CN 202111514430 A CN202111514430 A CN 202111514430A CN 114099710 A CN114099710 A CN 114099710A
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Abstract
本发明涉及一种促进活性物质不同层次皮肤储留的透明质酸‑环糊精纳米载体的制备方法。一种透明质酸‑环糊精纳米载体，其特征在于所述的纳米载体为透明质酸和环糊精或环糊精衍生物通过共价键结合形成的聚合物。环糊精可以形成活性物质的储库，另一方面透明质酸作为靶头，与皮肤细胞中的受体结合，可以增加共聚物的皮肤渗透性和靶向性。将共聚物与活性成分溶于溶剂中，可以自组装形成载药纳米载体，促进活性物质在皮肤中的渗透，同时利用HA的受体结合能力，使其停留在皮肤中缓慢释放活性成分，增加活性成分在角质层与真皮层中的储留。
Description
技术领域：
本发明属于经皮给药载体领域，具体涉及一种促进活性物质皮肤储留的透明质酸-环糊精纳米载体的制备方法。
背景技术：
经皮给药系统(Transdermal Drug Delivery Systems,TDDS)是使药物通过皮肤进入体循环或者皮肤内部发生作用，其给药方式存在着许多优势。与透皮给药系统(发挥全身作用的药物制剂)不同的是，治疗局部皮肤疾病的药物，如治疗皮肤癣的抗真菌类药物，希望其可以更多的进入角质层，并储留于角质层中发挥抗真菌的作用，并且药物尽可能少的进入真皮，被毛细血管吸收进入全身血液循环，从而减少的全身副作用的产生；对于作用于皮肤不同层次的化妆品中功效成分，如保湿剂则可能希望药物在角质层中储留发挥保湿作用，美白成分则作用于基底层中的黑色素细胞，营养和抗皱类成分则尽可能的停留于真皮中。目前大多关于经皮给药的研究更多的是关注发挥全身作用的药物制剂，如何采用新技术或新剂型促进药物的透皮吸收；但对于研究药物在皮肤不同层次中的储留情况以及如何促进药物在皮肤不同层次的滞留技术，则少有研究。
透明质酸(HyaluronicAcid,HA)又称玻尿酸，是由D-葡萄糖醛酸及N-乙酰葡糖胺组成的双糖单位的糖胺聚糖。基于HA独特的物理化学性质，其具有可降解性、粘弹性、保湿性、良好的生物相容性和皮肤渗透性。HA通过对角质层和真皮层的水合作用及与脂质和角蛋白的相互作用提高HA分子以及活性物质的跨膜吸收，通过对皮肤中受体的特异性粘附增加活性物质在皮肤中的积累。虽然HA有很多优点，但其对碱、酸、高温及酶等因素敏感，稳定性一般，易降解。这些因素限制了HA的应用。为了克服这些缺点，可以对HA的羟基、羧基和N-乙酰基进行相关化学修饰。这为HA提供了一系列新的优异性能，例如稳定性、流变特性、机械强度、抗酶降解等，也为开发具有更长的药物保留时间的载药系统提供了可能。
环糊精(Cyclodextrin，CD)，是一种环状结构的低聚糖，由6～8个吡喃葡萄糖单元组成。吡喃葡萄糖的椅式构象使CD分子具有中心腔的截圆锥形状，赋予CD外表面亲水、内表面疏水的特征。由于其特殊的空腔结构，CD能够捕获具有一定尺寸大小的疏水性分子，通过某些非共价键作用力如范德华力与氢键，从而与疏水性分子形成相应包合物，可以显著增加难溶性药物的溶解性、稳定性。
基于此，针对HA的性能，采用化学合成接枝的方式复合环糊精形成一种新型的经皮递送载体，用于增加活性物质在不同皮层中的定向给药。
发明内容：
本发明提供一种疗效确切、制备方法简单、适合大规模工业化生产的能够促进活性物质皮肤滞留的透明质酸-环糊精纳米载体的制备方法。
本发明的技术方案为：
一种透明质酸-环糊精纳米载体，其特征在于所述的纳米载体为透明质酸和环糊精或环糊精衍生物通过共价键结合形成的聚合物。
所述纳米载体,其特征在于透明质酸的相对分子量包括＜10K DA，10K～1000KDA，＞1000K DA。
所述纳米载体，环糊精包括α-环糊精、β-环糊精、γ-环糊精，β-环糊精衍生物包括单(6-氨基-6-去氧)-β-环糊精、单(6-乙二氨基-6-去氧)-β-环糊精、单(6-己二氨基-6-去氧)-β-环糊精、磺烷基醚环糊精衍生物(例如磺丁基醚-β-环糊精等)、烷基醚环糊精衍生物(例如，甲基、乙基和丙基醚环糊精等)硫烷基醚环糊精衍生物、羟烷基环糊精衍生物(例如，羟乙基和羟丙基醚环糊精等)、羧化环糊精衍生物、磺酸化环糊精衍生物等以及多官能团环糊精衍生物(例如葡萄糖-环糊精、麦芽糖-环糊精、麦芽三糖-环糊精、磺烷基醚-烷基醚环糊精衍生物)。
所述的纳米载体，其特征在于所述的纳米载体为如下结构的任意一种：
其中，m，i为聚合度，接枝率为24.78±0.37％，透明质酸平均分子量5K～1770K。
所述纳米载体的制备方法，其特征在于包括下述步骤：将透明质酸溶解在溶剂中，加入催化剂进行活化，并加入环糊精或其衍生物溶液，混合，结束后透析冷冻干燥形成所述的透明质酸-环糊精纳米载体。
所述的方法，其特征在于催化剂包括羧基或羟基活化剂；混合步骤包括超声波处理和物理搅拌中的至少一种；透明质酸与环糊精的摩尔比例为5:1-1:5。
所述的方法，其特征在于所述的催化剂为N-羟基琥珀酰亚胺磺酸钠盐或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
纳米载体在制备经皮给药系统中的应用，其特征在于所述，所述的应用通过纳米载体携载活性物质实现。
所述的应用，其特征在于：
相对分子量＜10K DA的透明质酸制得的透明质酸-环糊精纳米载体被用以携载需要在真皮层中储留的生物活性物质，生物活性物质包括烟酰胺、传明酸、光果甘草、谷胱甘肽视黄醇、玻色因；
相对分子量10K～1000K DA的透明质酸制得的透明质酸-环糊精纳米载体被用以携载需要在角质层中储留生物活性物质，生物活性物质包括聚谷氨酸，治疗皮肤癣或细菌感染的抗真菌或细菌的药物；
相对分子量＞1000K DA的透明质酸制得的透明质酸-环糊精纳米载体被用以携载需要覆盖在皮肤表面、不进入皮肤中、易于清洗的生物活性物质，生物活性物质包括硫醚抗生素、乳酸细菌素、滑瓜蟾素、防御素、天蚕素、贻贝素、线肽素、蝎血素、蜂毒素、银离子、纳米银、氧化铁、氧化铝、氧化锌、二氧化钛、纳米氧化锌、纳米二氧化钛、高岭土、滑石粉。
具体而言：
透明质酸-环糊精，其结构通式为
其中，m，i为聚合度，接枝率为24.78±0.37％，透明质酸平均分子量5K～1770K。
一种促进活性物质皮肤滞留的透明质酸-环糊精纳米载体的制备方法，其特征在于将至少一种相对分子量的透明质酸溶解在溶剂中，依次加入N-羟基琥珀酰亚胺磺酸钠盐(NHS)及1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)进行活化，并加入一定比例的至少一种β-环糊精衍生物溶液，混合一定时间，结束后透析冷冻干燥形成所述接枝共聚物。
透明质酸的相对分子量包括＜10KDA，10K～1000K DA，＞1000KDA。
一种β-环糊精衍生物包括单(6-氨基-6-去氧)-β-环糊精、单(6-乙二氨基-6-去氧)-β-环糊精、单(6-己二氨基-6-去氧)-β-环糊精，磺丁基醚-β-环糊精，甲基醚环糊精、乙基醚环糊精、丙基醚环糊精，羟乙基醚环糊精、羟丙基醚环糊精，葡萄糖-环糊精、麦芽糖-环糊精、麦芽三糖-环糊精。
进一步地，透明质酸与环糊精的摩尔比例为5:1-1:5。
进一步地，混合步骤包括超声波处理和物理搅拌中的至少一种。
进一步地，混合时间为24～72h。
反应方程式如下：
(1)HA-单(6-氨基-6-去氧)-β-环糊精接枝共聚物的合成路线
(2)HA-单(6-乙二氨基-6-去氧)-β-环糊精接枝共聚物的合成路线
(3)HA-单(6-己二氨基-6-去氧)-β-环糊精接枝共聚物的合成路线
其中，n，m，i为聚合度。
作用原理
本发明所述的促进活性物质皮肤滞留的透明质酸-环糊精纳米载体，通过将原料进行适合的重量配比，使得各种原料成分协同作用，并将至少一种环糊精衍生物接枝在低分子量HA主链上，得到一种像CD能包合药物的同时又能具有HA优良透皮特性的共轭聚多糖分子(HACD)。一方面利用透明质酸具有良好的皮肤渗透性；另一方面，环糊精可以形成储库。将HACD与活性成分投入溶剂中，可以自组装形成载药纳米载体，利用HA的受体结合作用，使其停留在皮肤外或皮肤中缓慢释放活性成分，增加活性成分在角质层外、角质层中与真皮层中的储留。
有益效果
(1)利用HA和CD可以发生酯化反应的特点，将两者结合在一起，故CD可以与任意分子量的HA结合形成HACD共聚物。
(2)根据不同分子量HA对皮肤水合作用程度不同的原理，可以实现共聚物在角质外层、角质层或真皮层的定向渗透和储留，即低相对分子质量的HA(＜10K)与CD形成的共聚物可以定向于真皮层的储留，可负载需要在真皮层中发挥作用的活性物质；相对分子质量10K～100K DA的HA与CD形成的共聚物可以定向于角质层的储留，而相对分子质量100K～1000K DA的HA与CD形成的共聚物在角质层中的储留优势更加明显，可负载需要在角质层中发挥作用的活性物质；大于1000K DA相对分子质量的HA与CD形成的共聚物则将药物阻隔在角质层外，可负载需要停留在皮肤表面发挥作用的物质，易于清洗、减小安全隐患。
附图说明：
图1透明质酸、环糊精、接枝共聚物的核磁共振氢谱1H-NMR；
图2透明质酸、环糊精、接枝共聚物的红外光谱图；
图3各给药组在角质层(A)及真皮层(B)中的丹皮酚滞留量
图4给药前后AD模型小鼠的皮炎大体情况(A.空白组，B.模型组，C.PAE，D.HA+PAE，E.CD+PAE，F.HACD-PAE)；
图5给药前后AD模型小鼠的皮炎评分。
具体实施方式：
下面通过具体实施例，对本发明作进一步说明，但本发明并不局限于此。
实施例
实施例1提供一种促进活性物质皮肤滞留的透明质酸-环糊精纳米载体的制备方法；实施例2、实施例3提供透明质酸-环糊精纳米载体的相关应用。
实施例1
一种所述促进活性物质皮肤滞留的透明质酸-环糊精接枝共聚物的制备方法。具体步骤为，将4g 5K分子量HA加入500ml pH 7.4PBS溶液中，搅拌溶解，依次加入8g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、8.6g N-羟基琥珀酰亚胺磺酸钠、5g单(6-氨基-6-去氧)-β-环糊精，继续搅拌反应48h。反应结束后转入透析袋中用去离子水透析冷冻干燥即可得所述的接枝共聚物。
进一步地，所述活性药物为丹皮酚(PAE)。
进一步地，提供一种促进活性物质皮肤滞留的搭载活性物质的透明质酸-环糊精纳米胶束的制备方法。具体步骤为，将接枝共聚物溶于pH 7.4PBS缓冲液中形成20mg/ml溶液，缓慢加入丹皮酚溶液，搅拌反应24h后将所述溶液进行旋转蒸发除去挥发性溶剂、冷冻干燥，即得所述的促进丹皮酚皮肤滞留的丹皮酚-透明质酸-环糊精纳米胶束。
1.结构表征
1.1核磁共振氢谱1H-NMR表征
分别取适量接枝共聚物(HACD)，透明质酸(HA),单(6-氨基-6-去氧)-β-环糊精(PMMABCD)溶于D2O中，终浓度约10mg/mL，采用1H-NMR法测定HACD接枝物的结构，实验结果如图1所示。HACD的结构式如下。
通过与未修饰的HA的谱图进行比较，在5.1ppm左右看出HACD主体大分子的谱图上新出现了PMMABCD七元环C-1位叔碳上氢的特征峰，在2.91ppm附近出现新的特征峰位，且出现了PMMABCD与HA的共同峰位，证明HA与PMMABCD成功接枝。
1.2红外光谱FT-IR表征
分别取HA，PMMABCD和HACD粉末适量，KBr混合压片后经红外光谱仪测定4000到400cm-1处的红外吸收，实验结果如图2所示。
图谱中，HA的特征峰主要有3405.5cm-1处的O-H伸缩振动峰，由于分子间氢键作用而使得峰信号强而宽，611.5cm-1处是HA上酰胺键N-H振动峰，而1410.7cm-1为C-N伸缩振动及部分NH弯曲振动，1043.1cm-1周围的峰是环状醚C-O-C及伯醇的C-O伸缩振动，最重要的特征峰是1617.8cm-1处归属于HA中羧酸盐中羰基的伸缩振动峰；PMMABCD谱图中，3377.6cm-1和1639.3cm-1分别为的O-H伸缩振动峰和弯曲振动峰，2927.3cm-1处为CH/CH2的C-H伸缩振动峰，1368.3cm-1是甲基的面内弯曲特征峰，1157.8cm-1、1081.5cm-1归属于环状醚的C-O伸缩振动，而945.3cm-1、853.8cm-1是PMMABCD结构中的骨架伸缩振动和糖苷键的特征峰。相较于HA和PMMABCD，接枝物HACD除了他们各自的关键特征峰之外，可以明显的看到HA在1617.8cm-1处的羧酸盐羰基特征峰移动至1649.3cm-1，增加了31.5cm-1，这是由于PMMABCD接枝后使得酰胺羰基峰向高频方向移动，表明PMMABCD成功接枝到了HA聚合物上。
1.3粒径、PDI、Zeta电位的表征
将10mg搭载了丹皮酚的透明质酸-环糊精纳米胶束(HACD-PAE)溶于10mL超纯水中，采用Malvern Zetasizer粒度测定仪测定HACD-PAE的粒径、PDI和Zeta电位，实验结果如表1所示。
表1搭载丹皮酚的透明质酸-环糊精纳米胶束的粒径、PDI、Zeta
结果显示HACD-PAE粒径为177.8±9.19nm，PDI为0.241±0.019，说明纳米粒的粒径均一，Zeta电位为-12.90±0.55mV。表明基于CD的包和作用，PAE能够被HACD识别并且包合形成HACD-PAE，其形成的原因可能归因于HA的亲水作用以及PAE与CD的疏水作用，在水溶液中由于亲疏水作用力自组装形成纳米粒子。
2.滞留实验
采用Franz扩散池法研究上述所得HACD-PAE的皮肤不同皮层的滞留情况，切割鼠皮并固定在扩散池上。真皮一侧与接收液接触，角质层面向供给池。磁力搅拌速度为400r/min，水浴温度为(32±0.5)℃。供给池加入生理盐水溶液6.5mL，接收池分别加入含有300μg丹皮酚的丹皮酚混悬液，即对照组(PAE组)、5K Da HA与PAE的物理混合物(HA+PAE组)、CD与PAE的物理混合物(CD+PAE组)及丹皮酚-接枝共聚物(HACD-PAE组)300μL，分别于1h、4h、8h、12h后通过HPLC计算角质层(图A)和真皮层(图B)中丹皮酚的含量，实验结果如图3所示。
结果显示，在12h时丹皮酚-接枝共聚物在角质层与真皮层中对丹皮酚有显著性促进储留的作用，储留的丹皮酚的量分别为对照组1.52倍，1.76倍。
此外，采用Franz扩散池法还比较了不同相对分子质量的HA与CD的接枝共聚物的不同皮层的滞留情况。即比较42K、340K、920K、1770K Da的HA与CD的接枝共聚物包裹丹皮酚的实验组(HACD-PAE组)与对照组(PAE组)在12h时的角质层和真皮层中丹皮酚的含量。对比发现，42K的HACD-PAE组在角质层中较真皮层中对丹皮酚有显著性促进储留的作用，储留的丹皮酚的量分别为对照组的1.66、0.92倍。340K、920K的HACD-PAE组在角质层中对丹皮酚均有显著性促进储留的作用，储留的丹皮酚的量分别为对照组3.35和2.24倍；在真皮层中丹皮酚的储留量分别为对照组的1.78和0.64倍。较高相对分子量HA(1770K)的HACD-PAE组中，角质层与真皮层中均检测不到PAE。表明高相对分子质量的HA(1770K)不利于丹皮酚在皮肤中的滞留；低相对分子质量的HA(5K)更利于丹皮酚在真皮层中的储留；在中相对分子质量的HA(42K、340K、920K)中，340K、920K相对分子质量的HA在角质层中的储留优势更加明显。
3.药效试验
特应性皮炎(Atopic Dermatitis)是一种常见的炎症性皮肤病。特应性皮炎的特征是剧烈瘙痒且反复发作、皮肤干燥、红斑、丘疹也伴随出现。丹皮酚来源于中药中的牡丹皮,已用于治疗炎症和免疫疾病。由于其众多的药理作用,包括抗氧化、抗炎、抗癌、凋亡诱导和抗糖尿病作用。一些动物模型和细胞实验报道了丹皮酚可以减轻小鼠模型的银屑病样病变并减轻炎症反应。基于此，评估丹皮酚-接枝共聚物对于AD模型小鼠的治疗效果。
利用丙酮和橄榄油以3:1比例配制成基础液，然后利用DNFB和基础液配制1％和0.2％的DNFB致敏药物，造模的第1d前一天(第0天)剔除背部毛发(4cm2/只)，之后利用浓度为1％的DNFB药物对小鼠背部皮肤(200μL)以及右耳(20μL)进行涂抹致敏，3天后利用浓度为0.2％的DNFB溶液涂抹小鼠背部皮肤及右耳诱发特应性皮炎，每周三次，持续三周，空白组小鼠涂抹等量的基础液。第三周造模结束后开始涂抹给药，持续7天，每天三次，(背部200μL，耳部20μL)给药分组如表2所示。给药前后AD模型小鼠的皮炎大体情况如(图4)及评分(图5)如所示。
表2给药分组
结果显示，鼠背部、耳涂抹1％DNFB 3天后，皮肤出现红斑、水肿和鳞屑，改为0.2％DNCB涂抹后，随着用药时间的延长逐渐出现糜烂、出血、结痂和干燥，与AD的临床表现相似。第四周给予PAE各组后，小鼠的皮炎状况逐渐好转，至实验结束时(第28天)，实验组四组即PAE、HA+PAE、CD+PAE与HACD-PAE组皮肤状态与模型组相比均有好转，HACD-PAE制剂组表现最为显著。
实施例2
根据实施例1所述的透明质酸-环糊精纳米载体的制备方法，制得92K Da的HACD，搭载抗真菌药物酮康唑(KC)制得透明质酸相对分子量为92K Da的HACD-KC。采用Franz扩散池法研究上述所得的搭载活性物质的透明质酸-环糊精纳米载体的皮肤不同皮层的滞留情况。
切割鼠皮并固定在扩散池上，真皮一侧与接收液接触，角质层面向供给池。磁力搅拌速度为400r/min，水浴温度为(32±0.5)℃。供给池加入乙醇生理盐水溶液6.5mL，接收池加入含有500μg酮康唑的酮康唑混悬液，即对照组1(KC组)及酮康唑-接枝共聚物(HACD-KC组)1mL，分别于6h后通过HPLC计算角质层和真皮层中酮康唑的含量。
结果显示，在6h时酮康唑-接枝共聚物在角质层中对酮康唑有显著性促进储留的作用，在真皮层中有微量的储留，储留的酮康唑的量分别为对照组1.56倍，0.86倍。
实施例3
根据实施例1所述的透明质酸-环糊精纳米载体的制备方法，制得1770K Da的HACD，搭载纳米银离子，制得透明质酸相对分子量为1770KDa的HACD-Ag+。采用Franz扩散池法研究上述所得的搭载活性物质的透明质酸-环糊精纳米载体的皮肤不同皮层的滞留情况。
切割鼠皮并固定在扩散池上，真皮一侧与接收液接触，角质层面向供给池。磁力搅拌速度为400r/min，水浴温度为(32±0.5)℃。供给池加入乙醇PBS溶液6.5mL，接收池加入含有5μg纳米银离子的混悬液，即对照组2(Ag+组)及纳米银-接枝共聚物(HACD-Ag+组)100μL分别于6h后通过MS计算角质层和真皮层中银的含量。
结果显示，在6h时角质层和真皮层中均未检测到银的存在。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。
Claims (8)
1.一种透明质酸-环糊精纳米载体，其特征在于所述的纳米载体为透明质酸和环糊精或环糊精衍生物通过共价键结合形成的聚合物。
2.根据权利要求1 所述纳米载体, 其特征在于透明质酸的相对分子量包括＜10K DA，10K~1000K DA，＞1000K DA。
3.根据权利要求1 所述纳米载体，环糊精包括α-环糊精、β-环糊精、γ-环糊精，β-环糊精衍生物包括单（6-氨基-6-去氧）-β-环糊精、单（6-乙二氨基-6-去氧）-β-环糊精、单（6-己二氨基-6-去氧）-β-环糊精、磺烷基醚环糊精衍生物包括磺丁基醚-β-环糊精，烷基醚环糊精衍生物包括甲基、乙基和丙基醚环糊精，硫烷基醚环糊精衍生物，羟烷基环糊精衍生物包括羟乙基和羟丙基醚环糊精，羧化环糊精衍生物，磺酸化环糊精衍生物以及多官能团环糊精衍生物包括葡萄糖-环糊精、麦芽糖-环糊精、麦芽三糖-环糊精、磺烷基醚-烷基醚环糊精衍生物。
4.根据权利要求 1-3任意一项所述纳米载体的制备方法，其特征在于包括下述步骤：将透明质酸溶解在溶剂中，加入催化剂进行活化，并加入环糊精或其衍生物溶液，混合，结束后透析冷冻干燥形成所述的透明质酸-环糊精纳米载体。
5.根据权利要求 4所述的方法，其特征在于催化剂包括羧基或羟基活化剂；混合步骤包括超声波处理和物理搅拌中的至少一种；透明质酸与环糊精的摩尔比例为5:1-1:5。
6.根据权利要求5所述的方法，其特征在于所述的催化剂为N-羟基琥珀酰亚胺磺酸钠盐或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
7.根据权利要求 1-3纳米载体在制备经皮给药系统中的应用，其特征在于，所述的应用通过纳米载体携载活性物质实现。
8.根据权利要求7所述的应用，其特征在于：
相对分子量＜10K DA的透明质酸制得的透明质酸-环糊精纳米载体被用以携载需要在真皮层中储留的生物活性物质，生物活性物质包括烟酰胺、传明酸、光果甘草、谷胱甘肽视黄醇、玻色因；
相对分子量10K~1000K DA的透明质酸制得的透明质酸-环糊精纳米载体被用以携载需要在角质层中储留生物活性物质，生物活性物质包括聚谷氨酸，治疗皮肤癣或细菌感染的抗真菌或细菌的药物；
相对分子量＞1000K DA的透明质酸制得的透明质酸-环糊精纳米载体被用以携载需要覆盖在皮肤表面、不进入皮肤中、易于清洗的生物活性物质，生物活性物质包括抗菌肽、银离子、纳米银、氧化铁、氧化铝、氧化锌、二氧化钛、纳米氧化锌、纳米二氧化钛、高岭土、滑石粉，其中抗菌肽包括硫醚抗生素、乳酸细菌素、滑瓜蟾素、防御素、天蚕素、贻贝素、线肽素、蝎血素、蜂毒素。
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