Development of Remimazolam-Encapsulated Liposomes for Intranasal Administration

Objectives: Remimazolam, a new intravenous benzodiazepine drug, differs from commonly used midazolam, and is characterized by rapid metabolism and rapid recovery. It is ineffective when administered orally because of more rapid metabolism in the digestive tract, but it was reported to be effective when administered intranasally, but it is not suitable for intranasal administration due to its irritating effects. Therefore, we considered that it would be effective to encapsulate it in liposomes for intranasal administration. Liposomes have been developed as vesicles encapsulating various kinds of drugs to serve as a medical drug-delivery system. We previously developed liposome-encapsulating midazolam for oral administration. Thus, in the present study we developed remimazolam-encapsulated liposomes and evaluated their remimazolam-encapsulating efficiency.
Methods: Firstly, a standard curve was prepared to measure the concentration of remimazolam. Diazepam as the internal standard was added to remimazolam for analyzing by high-performance liquid chromatography (HPLC). Secondly, as a pretreatment for preparing liposomes, remimazolam was extracted from commercially available remimazolam besylate products by liquid-liquid extraction. Then, L-alpha-phosphatidylcholine, cholesterol, dimyristoyl-phosphatidylcholine, and remimazolam were mixed, and each mixture solution was evaporated using an evaporater at a bath temperature to prepare a lipid film. The lipid film of their mixture was suspended, resulting in the production of remimazolam-encapsulated liposomes. The capacity of liposomes to encapsulate remimazolam (encapsulation efficiency) were evaluated by measuring the remimazolam concenration using HPLC.
Results: A stable standard curve was prepared. The recovery rate of remimazolam in liquid-liquid extraction was over 95.0%. The encapsulation efficiency in produced remimazolam-encapsulated liposomes was 42.5±2.7%.
Conclusions: We were able to prepare remimazolam-encapsulated liposomes at a stable encapsulation efficiency. Next, we plan to evaluate the pharmacokinetics and bioavailability of liposome-encapsulating remimazolam when administred intranasally to animals.