A Novel Drug Delivery Carrier Comprised of Nimodipine Drug Solution and a Nanoemulsion: Preparation, Characterization, in vitro, and in vivo Studies

Saixu Huang, 1–3,* Zhiyong Huang, 1–3,* Zhiqin Fu, 3,* Yamin Shi, 3, 4 Qi Dai, 1, 2 Shuyan Tang, 3 Yongwei Gu, 3 Youfa Xu, 3 Jianming Chen, 3, 4 Xin Wu, 3 Fuzheng Ren 1, 2 1Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China; 2Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Shanghai Weier Biological Medicine Science and Technology Co. Ltd., Shanghai, People’s Republic of China; 4Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fuzheng RenSchool of Pharmacy, East China University of Science and Technology, No. 130, Meilong Road, Shanghai 200237, People’s Republic of ChinaTel/Fax +86 21 6425 3255Email fzren@ecust.edu.cnXin WuShanghai Weier Biological Medicine Science and Technology Co. Ltd., No. 358, Tian Chen Road, Shanghai 201799, People’s Republic of ChinaTel/Fax +86 21 3119 8947Email xinwu007@126.comPurpose: Nimodipine (NIMO) is used clinically to treat ischemic damage resulting from subarachnoid hemorrhage. However, clinical application of NIMO is limited by poor aqueous solubility and low safety. To overcome these limitations, a novel two-vial NIMO-loaded nanoemulsion (NIMO-TNE) was designed in this study.Methods: NIMO-TNE was prepared by mixing a nimodipine-polyethylene glycol 400 (NIMO-PEG400) solution and a commercially available 20% injectable blank nanoemulsion (BNE). Drug distribution in NIMO-TNE, physical stability, and dilution stability were evaluated in vitro, and pharmacokinetics and pharmacodynamics were evaluated in vivo. Safety was assessed using the hemolysis test and the intravenous irritation test, and acute toxicity of NIMO-TNE was compared with that of commercial Nimotop injection.Results: Drug loading (DL) in NIMO-TNE was enhanced 5-fold compared with that in Nimotop injection. The mean particle size of NIMO-TNE was 241.53 ± 1.48 nm. NIMO-TNE and NIMO-TNE diluted in 5% glucose injection and 0.9% sodium chloride was stable for a sufficient duration to allow for clinical use. In addition, NIMO-TNE exhibited a similar pharmacokinetic profile and similar brain ischemia reduction in a rat middle cerebral artery occlusion (MCAO) model compared to Nimotop injection. Furthermore, NIMO-TNE did not induce hemolysis at 37°C, and NIMO-TNE induced less intravenous irritation than Nimotop injection. Moreover, NIMO-TNE could be injected at a 23-fold higher dose than the LD 50 of Nimotop injection with no obvious toxicity or side effects.Conclusion: NIMO-TNE is a promising formulation suitable for intravenous injection, is easy to prepare, and exhibits excellent safety.Keywords: nimodipine, nanoemulsion, pharmacokinetics, MCAO, LD50