乙酰氨基阿维菌素混合胶束的制备、表征及体外透皮性能研究

doi:10.16431/j.cnki.1671-7236.2025.04.038

摘要/Abstract

摘要： 【目的】制备一种可用于透皮给药的乙酰氨基阿维菌素混合胶束(eprinomectin mixed micelles，EPR-MMs)。【方法】采用薄膜分散法，以聚氧乙烯氢化蓖麻油40和壬基酚聚氧乙烯醚40为载体材料制备EPR-MMs，通过单因素法考察EPR-MMs的粒径、多分散性指数(PDI)、包封率、载药量以及稳定性等指标，并对表面活性剂比、药辅比、水化转速以及水化时间等参数进行筛选和优化，确立最佳处方和工艺参数。采用芘荧光探针法测定EPR-MMs的临界胶束浓度(CMC)，通过透射电镜和傅立叶变换红外光谱(FT-IR)分析对其微观结构进行表征；以市售浇泼剂作为对照，采用改良的Franz扩散池考察EPR-MMs的体外透皮性能。【结果】试验筛选出的EPR-MMs最佳工艺处方为：表面活性剂比为20∶1、药辅比为1∶9、水化转速为1 200 r/min、水化时间为4 h。以筛选的最佳工艺条件制备的EPR-MMs临界胶束浓度为11.596 μg/mL，其在透射电镜下为类球形，粒径大小适宜，形态良好。通过FT-IR分析证实药物被包载在胶束中。稳定性研究表明制备的EPR-MMs在室温下放置7 d稳定性良好。体外透皮结果显示，EPR-MMs单位面积透皮累积渗透量为44.26 μg/cm²，约为浇泼剂的3.82倍，渗透速率为浇泼剂的3.90倍。【结论】试验成功制备了稳定且粒径适宜的EPR-MMs，并通过多项表征方法验证了其理化性质，表现出良好的体外释药特性，相较于市售浇泼剂具有更高的透皮速率和渗透量。

关键词: 乙酰氨基阿维菌素(EPR); 混合胶束; 透皮给药

Abstract: 【Objective】 The aim of this study was to prepare a kind of eprinomectin mixed micelle (EPR-MMs) which could be used for transdermal adminstration.【Method】 EPR-MMs were prepared by membrane hydration method using PEG-40 hydrogenated castor oi and nonyl phenol polyoxyethylene ether 40 as carriers.The particle size,polydispersity index (PDI),encapsulation efficiency,loading efficiency,and stability of EPR-MMs were evaluated through single-factor examination.Parameters such as the surfactant ratio,drug surfactant ratio,hydration rotation speed,and hydration time were screened and optimized to establish the best prescription and process parameters.The critical micelle concentration (CMC) was determined using the pyrene fluorescence probe method.The microstructure was characterized by transmission electron microscopy and Fourier transform infrared spectroscopy (FT-IR).The in vitro transdermal properties of EPR-MMs were investigated by using Franz diffusion cell,with a commercial pour-on agent as the control.【Result】 The optimum process prescription of EPR-MMs was as follows:Surfactant ratio was 20∶1,drug and surfactant ratio was 1∶9,hydration speed was 1 200 r/min and hydration time was 4 h.The CMC of EPR-MMs prepared under the optimal screening conditions was 11.596 μg/mL.EPR-MMs was spheroid under transmission electron microscope,with suitable particle size and good morphology.FT-IR analysis confirmed that the drug was encapsulated in the micelle.Stability studies showed that the prepared EPR-MMs had good stability when placed at room temperature for 7 d.In vitro permeation results demonstrated that the cumulative permeation amount per unit area of EPR-MMs was 44.26 μg/cm²,which was about 3.82 times that of the pour-on,and the penetration rate was 3.90 times that of the pour-on. 【Conclusion】 The stable EPR-MMs with suitable particle size was successfully prepared,and its physicochemical properties were verified by multiple characterization methods,showing good in vitro release characteristics,and higher transdermal rate and permeability than the commercial pour-on.

Key words: eprinomectin (EPR); mixed micelles; transdermal adminstration

中图分类号:

S859.79⁺5

冒玉娟, 张红袖, 陈未, 于生兰, 郭刘娜, 高洁. 乙酰氨基阿维菌素混合胶束的制备、表征及体外透皮性能研究[J]. 中国畜牧兽医, 2025, 52(4): 1862-1872.

MAO Yujuan, ZHANG Hongxiu, CHEN Wei, YU Shenglan, GUO Liuna, GAO Jie. Preparation,Characterization and in vitro Transdermal Properties of Eprinomectin Mixed Micelles[J]. China Animal Husbandry and Veterinary Medicine, 2025, 52(4): 1862-1872.

参考文献

[1] SHOOP W L,EGERTON J R,EARY C H,et al.Eprinomectin:A novel avermectin for use as a topical endectocide for cattle[J].International Journal for Parasitology,1996,26(11):1237-1242.
[2] DO NASCIMENTO C G,BRAGAGLIA G,TOMA S B,et al.Injectable eprinomectin for cattle:Tick efficacy and pharmacokinetics[J].Journal of Veterinary Pharmacology and Therapeutics,2020,43(2):171-178.
[3] HAMEL D,KUNKLE B N,LIEBSTEIN M,et al.Eprinomectin 5% w/v extended-release injection for the treatment of larval and/or adult Bunostomum phlebotomum,Haemonchus contortus,H.placei, Nematodirus helvetianus,Oesophagostomum radiatum,and Trichostrongylus colubriformis infections in cattle[J].Parasitology Research,2022,121(7):2173-2178.
[4] HAMEL D,VISSER M,MAYR S,et al.Eprinomectin pour-on:Prevention of gastrointestinal and pulmonary nematode infections in sheep[J].Veterinary Parasitology,2018,264:42-46.
[5] TERMATZIDOU S A,ARSENOPOULOS K,SIACHOS N,et al.Anthelmintic activity of injectable eprinomectin (Eprecis^® 20 mg/mL) in naturally infected dairy sheep[J].Veterinary Parasitology,2019,266:7-11.
[6] HAMEL D,BOSCO A,RINALDI L,et al.Eprinomectin pour-on (EPRINEX^® Pour-on,Merial):Efficacy against gastrointestinal and pulmonary nematodes and pharmacokinetics in sheep[J].BMC Veterinary Research,2017,13(1):148.
[7] AVCIOGLU H,BALKAYA I.Efficacy of eprinomectin against Toxocara vitulorum in calves[J].Tropical Animal Health and Production,2011,43(2):283-286.
[8] 李铉焕,吕慧侠,诸吕锋.纳米制剂在透皮药物递送系统中的应用研究进展[J].药学进展,2023,47(7):504-518.LI X H,LYU H X,ZHU L F.Research progress in the application of nanoformulations in transdermal drug delivery systems[J].Progress in Pharmaceutical Scineces,2023,47(7):504-518.(in Chinese)
[9] 张兆欣,颜航,李宏全,等.新型药物递送系统在兽药制剂领域的研究进展[J].中国兽药杂志,2023,57(3):59-72.ZHANG Z X,YAN H,LI H Q,et al.Research progress in novel drug delivery systems for veterinary pharmaceuticals[J]. Chinese Journal of Veterinary Drug,2023,57(3):59-72.(in Chinese)
[10] SABBAGH F,KIM B S.Recent advances in polymeric transdermal drug delivery systems[J].Journal of Controlled Release,2022,341:132-146.
[11] MUNIR M,ZAMAN M,WAQAR M A,et al.A comprehensive review on transethosomes as a novel vesicular approach for drug delivery through transdermal route[J].Journal of Liposome Research,2024,34(1):203-218.
[12] MAKHMALZADE B S,CHAVOSHY F.Polymeric micelles as cutaneous drug delivery system in normal skin and dermatological disorders[J].Journal of Advanced Pharmaceutical Technology&Research,2018,9(1):2-8.
[13] NEWTON S J.Chemical penetration enhancers[J].International Journal of Pharmaceutical Compounding,2013,17(5):370-374.
[14] 廖朗坤.难溶性药物缓释微针的设计和评价[D].广州:广东药科大学,2021.LIAO L K.Design and evaluation of microneedles for sustained release of water-insoluble drugs[D].Guangzhou:Guangdong Pharmaceutical University,2021.(in Chinese)
[15] ROSTANG A,DEVOS J,CHARTIER C.Review of the eprinomectin effective doses required for dairy goats:Where do we go from here?[J].Veterinary Parasitology,2020,277:108992.
[16] 冒玉娟,沈雁,张乐,等.乙酰氨基阿维菌素乳剂凝胶的制备及透皮给药特性评价[J].黑龙江畜牧兽医,2019,15:138-141.MAO Y J,SHEN Y,ZHANG L,et al.Preparation of acetylamamectin emulsion gel and evaluation of transdermal drug delivery characteristics[J].Heilongjiang Animal Science and Veterinary Medicine,2019,15:138-141.(in Chinese)
[17] 耿响,刘希望,杨亚军,等.乙酰氨基阿维菌素缓释注射剂中乙酰氨基阿维菌素含量与有关物质HPLC检测方法的建立[J].中国畜牧兽医,2021,48(12):4681-4689.GENG X,LIU X W,YANG Y J,et al.Establishment of HPLC method for determination of eprinomectin and related substances in eprinomectin sustained-release injection[J].China Animal Husbandry&Veterinary Medicine,2021,48(12):4681-4689.(in Chinese)
[18] 赵小义,冯华,朱钰叶.洛匹那韦混合胶束的制备与大鼠口服生物利用度研究[J].沈阳药科大学学报,2022,39(7):773-779.ZHAO X Y,FENG H,ZHU Y Y.Preparation of lopinavir mixed micelles and study on oral bioavailability in rats[J].Journal of Shenyang Pharmaceutical University,2022,39(7):773-779.(in Chinese)
[19] 张欣欣,许洁,蒋岩,等.依托泊苷纳米混合胶束的制备及其理化性质[J].河北科技大学学报,2021,42(4):389-399.ZHANG X X,XU J,JIANG Y,et al.Preparation and evaluation of physicochemical properties of etoposide nano-mixed micelles[J].Journal of Hebei University of Science and Technology,2021,42(4):389-399.(in Chinese)
[20] ROSEN M J,ZHOU Q.Surfactant-surfactant interactions in mixed monolayer and mixed micelle formation[J].Langmuir,2001,17(12):3532-3537.
[21] CAGEL M,TESAN F C,BERNABEU E,et al.Polymeric mixed micelles as nanomedicines:Achievements and perspectives[J].European Journal of Pharmaceutics and Biopharmaceutics,2017,113:211-228.
[22] 郑婷.乙酰氨基阿维菌素/PLGA缓释微球的研究[D].石家庄:河北科技大学,2012.ZHENG T.Study of sustained-release eprinomectin loaded PLGA microspheres[D].Shijiazhuang:Hebei University of Science and Technology,2012.(in Chinese)
[23] GERARDOS A M,BALAFOUTI A,PISPAS S.Mixed copolymer micelles for nanomedicine[J].International Journal of Nanomanufacturing,2023,3(15):233-247.
[24] LE GUYADER G,DO B,RIETVELD I B,et al.Mixed polymeric micelles for rapamycin skin delivery[J].Pharmaceutics,2022,14(3):569.
[25] STANVHEVA R,PAUNOVA-KRASTEVA T,TOPOUZOVA-HRISTOVA T,et al.Ciprofloxacin-loaded mixed polymeric micelles as antibiofilm agents[J].Pharmaceutics,2023,15(4):1147.
[26] AHMED S,KASSEM M A,SAYED S.Co-polymer mixed micelles enhanced transdermal transport of lornoxicam:In vitro characterization,and in vivo assessment of anti-inflammatory effect and antinociceptive activity[J].Journal of Drug Delivery Science and Technology,2021,62:102365.
[27] YASSIN A E B,MASSADEH S,ALSHWAIMI A A,et al.Tween 80-based self-assembled mixed micelles boost valsartan transdermal delivery[J].Pharmaceuticals (Basel),2023,17(1):19.
[28] FUKUTA T,OSHIMA Y,MICHIUE K,et al.Non-invasive delivery of biological macromolecular drugs into the skin by iontophoresis and its application to psoriasis treatment[J].Journal of Controlled Release,2020,323:323-332.
[29] HONG Y,YU H,WANG L,et al.Transdermal insulin delivery and microneedles-based minimally invasive delivery systems[J].Current Pharmaceutical Design,2022,28(39):3175-3193.
[30] GAIKWAD S S,ZANJE A L,SOMWANSHI J D.Advancements in transdermal drug delivery:A comprehensive review of physical penetration enhancement techniques[J].International Journal of Pharmaceutics,2024,652:123856.