Transformation of Hydrophilic Drug into Oil-Miscible Ionic Liquids for Transdermal Drug Delivery
Transformation of Hydrophilic Drug into Oil-Miscible Ionic Liquids for Transdermal Drug Delivery
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亲水性药物转化为油混溶性离子液体用于透皮给药
DOI：
10.1021/acsami.2c15636
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发表时间：
2022
影响因子：
9.5
通讯作者：
Goto Masahiro
中科院分区：
文献类型：
--
作者：
Md Moshikur Rahman;Shimul Islam Md;Uddin Shihab;Wakabayashi Rie;Moniruzzaman Muhammad;Goto Masahiro
由于亲水性药物渗透皮肤的能力较差，其透皮递送仍然具有挑战性；如果不添加化学渗透促进剂或共溶剂，用油介质配制是很困难的。在此，我们合成了 12 种油混溶性离子液体 (IL) 药物，包括利多卡因、丙咪嗪和左旋咪唑 (Lev) 盐酸盐，并以脂肪酸渗透促进剂（即月桂酸根、油酸根、亚油酸根和硬脂酸根）作为抗衡离子。进行了一系列体外和体内研究来研究透皮药物制剂的效力和递送能力。所有合成的化合物均与药学上可接受的溶剂/试剂（即乙醇、N-甲基吡咯烷酮、吐温20和肉豆蔻酸异丙酯（IPM））自由混溶。体外渗透研究表明，基于油酸盐的Lev制剂的皮肤渗透能力比Lev盐高2.6倍，并且与含月桂酸盐、亚油酸盐和硬脂酸盐的样品相比也具有优异的能力。小鼠体内透皮给药后，Lev-IL的血浆峰浓度、消除半衰期和血浆浓度曲线下面积值分别比Lev盐高4.6、2.9和5.4倍。此外，体外皮肤刺激和体内组织学研究表明，与传统的离子液体载体相比，Lev-IL具有优异的生物相容性。结果表明，油混溶性 IL 药物为设计有效的透皮给药系统提供了一种简单且可扩展的策略。
The transdermal delivery of hydrophilic drugs remains challenging owing to their poor ability to permeate the skin; formulation with oil media is difficult without adding chemical permeation enhancers or co-solvents. Herein, we synthesized 12 oil-miscible ionic liquid (IL) drugs comprising lidocaine-, imipramine-, and levamisole (Lev)-hydrochloride with fatty acid permeation enhancers, i.e., laurate, oleate, linoleate, and stearate as counterions. A set ofin vitroandin vivostudies was performed to investigate the potency and deliverability of the transdermal drug formulations. All of the synthesized compounds were freely miscible with pharmaceutically acceptable solvents/agents (i.e., ethanol,N-methyl pyrrolidone, Tween 20, and isopropyl myristate (IPM)).In vitropermeation studies revealed that the oleate-based Lev formulation had 2.6-fold higher skin permeation capability than the Lev salts and also superior ability compared with the laurate-, linoleate-, and stearate-containing samples. Uponin vivotransdermal administration to mice, the peak plasma concentration, elimination half-life, and area under the plasma concentration curve values of Lev-IL were 4.6-, 2.9-, and 5.4-fold higher, respectively, than those of the Lev salt. Furthermore,in vitroskin irritation andin vivohistological studies have demonstrated that Lev-IL has excellent biocompatibility compared with a conventional ionic liquid-based carrier. The results indicate that oil-miscible IL-based drugs provide a simple and scalable strategy for the design of effective transdermal drug delivery systems.