Dose Membrane Composition of Midazolam-encapsulated Liposome Influence on Its Pharmacokinetics?

Objectives: The oral administration of midazolam has often been used for sedation in pediatric patients or those with disabilities. Liposomes have been developed as vesicles encapsulating various kinds of drug to serve as a medical drug-delivery system. We previously developed midazolam-encapsulating liposomes for oral administration, and reported that when miniaturized midazolam-encapsulated liposomes (MML) are orally administered, the bioavailability of MML is higher than that of midazolam solution. On the other hand, various lipid materials are used for making liposome membrane, and membrane composition is known to influence on properties of liposome. Thus, in the present study we produced two types of MML, using different lipid materials, and evaluated the pharmacokinetics of each MML following oral administration in rabbits.
Methods: L-alpha-phosphatidylcholine, cholesterol, and midazolam were mixed, and dipalmitoylphosphatidic acid (DPPA) or dimyristoylphosphatidylcholine (DMPC) was added to them. A lipid film of their mixture was suspended and briefly sonicated in a water bath, and finally used a sonic vibrator with ultrasonic waves to produce two types of MML: DPPA-MML and DMPC-MML. After being approved by the Animal Care and Use Committee, we conducted experiments using male New Zealand white rabbits. Each MML was orally administered at the same dose of 2 mg/kg, and blood samples were collected until 4 hours after the administration. Blood midazolam concentrations of the samples were measured using HPLC, and analyzed using two-way ANOVA followed by Turkey’s or Sidak’s multiple comparisons test.
Results: Blood midazolam concentration in rabbits administered DMPC-MML was significantly higher than that in rabbits administered DPPA-MML.
Conclusions: The result of the present study indicates that membrane composition of midazolam-encapsulated liposome influences on its pharmacokinetics of midazolam following oral administration.