马来酸阿塞那平微乳凝胶剂的制备及经鼻入脑的靶向性研究  

Preparation and brain targeting via nasal route of asenapine maleate microemulsion gel

作　　者：张水杰 童晓云 曾媛 雷刚 ZHANG Shuijie;TONG Xiaoyun;ZENG Yuan;LEI Gang(Department of Neurology,Wuhan University of Science and Technology Affiliated Tianyou Hospital,Wuhan 430064,China;Department of Pharmacy,Central Hospital of Central Theater of the PLA,Wuhan 430019,China)

机构地区：[1]武汉科技大学附属天佑医院神经内科,武汉430064 [2]中部战区总医院药剂科,武汉430019

出　　处：《中国药师》2024年第2期199-208,共10页China Pharmacist

摘　　要：目的 制备马来酸阿塞那平微乳凝胶剂(ASPM-Emulgel),并通过鼻腔给药评价其脑靶向性。方法 根据马来酸阿塞那平(ASPM)在不同种类油、乳化剂和助乳化剂中的平衡溶解度以及辅料相容性结果确定马来酸阿塞那平微乳(ASPMEmul)的处方组成及用量,并以卡波姆940作为凝胶基质将ASPM-Emul制备成凝胶剂;考察ASPM-Emul的粒径分布及微观形态,通过Franz扩散池法比较ASPM-Emul与ASPM-Emulgel的体外释放速率以及在羊鼻黏膜的渗透性;采用在体蟾蜍上颚模型法考察ASPM-Emulgel的鼻腔纤毛毒性;评价ASPM-Emulgel经大鼠鼻腔∶给∶药的脑靶向性。结果根据平衡溶解度和相容性结果,选择单亚油酸甘油酯、吐温80和二乙二醇单乙基醚分别作为ASPM-Emul的油相、乳化剂和助乳化剂,配比为4为淡蓝色半透明状微乳液,粒径为(73.6±7.4)nm,在透射电镜下可观察到微乳呈规则球形,均匀分散;体外释放及渗透结果显示,ASPM-Emul的释药速率较快,ASPMEmulgel释药速率持续平缓,但两者在羊鼻黏膜中的渗透率基本一致;ASPM-Emul和ASPM-Emulgel对蟾蜍鼻腔纤毛无明显毒性;与尾静脉ASPM组相比,ASPM-Emul和ASPM-Emulgel经鼻腔给药后在大脑中的药物含量显著增高,均表现出明显的脑靶向性,且ASPM-Emulgel的脑靶向效率更高。结论 将ASPM制备成微乳凝胶剂,经鼻腔给药后可以显著提高药物的脑靶向性,有望提高马来酸阿塞那平的临床治疗效果。Objective To prepare asenapine maleate microemulsion gel(ASPMEmulgel) and evaluate its brain targeting by nasal administration.Methods The prescription composition and dosage of asenapine maleate microemulsion(ASPM-Emul) was determined according to the equilibrium solubility of asenapine maleate(ASPM) in different oils,emulsifiers,co-emulsifiers and the compatibility results of excipients,and ASPM-Emul was prepared into a gel with carbomer 940 as the gel matrix.The particle size distribution and micro structure of ASPM-Emul were investigated.The in vitro release rates and permeability in sheep nasal mucosa of ASPM-Emul and ASPM Emulgel were compared using the Franz diffusion cell method.The nasal ciliary toxicity of ASPM-Emulgel was investigated using the in vivo toad maxillary model method.Brain targeting of ASPM-Emulgel by nasal administration in rats was evaluated.Results According to the results of equilibrium solubility and compatibility,Maisine 35-1,Tween 80 and Transcutol P were selected as the oil phase,emulsifier and coemulsifier of ASPM-Emul,respectively,with the ratio of 4:4:2.ASPM-Emul was a light blue semi-transparent microemulsion with a particle size of(73.6±7.4) nm.The microemulsion was regularly spherical and uniformly dispersed under transmission electron microscopy.The results of in vitro release and permeation showed that the release rate of ASPM-Emul was relatively fast,while the release rate of ASPM-Emulgel remained stable.However,the permeability of the two formulations in sheep nasal mucosa was basically similar.ASPM-Emul and ASPMEmulgel showed no significant toxicity to nasal cilia of toad.Compared with the tail vein ASPM group,the drug content in the brain of ASPM-Emul and ASPM-Emulgel significantly increased after nasal administration,both exhibiting significant brain targeting,and the drug targeting efficiency(DTE) of ASPM-Emulgel was higher.Conclusion The preparation of ASPM into microemulsion gel can significantly improve the brain targeting after nasal administration,and is expecte

关 键 词：马来酸阿塞那平 微乳凝胶剂 鼻腔给药 脑靶向性 Franz扩散池法 

分 类 号：R943[医药卫生—药剂学]