| Summary: | 博士 === 國立陽明大學 === 傳統醫藥研究所 === 103 === Lipid nanoparticles are commonly used in drug delivery and have the potential to improve the oral absorption of poorly soluble drugs and chemotherapeutic drugs for targeted delivery. However, most previous studies of lipid nanoparticles were still in the initial stages, and a full pharmacokinetic assessment was not completed. In this study, we evaluated the pharmacokinetic properties of lipid nanoparticles (including liposomes, ethosomes and nanodroplets), encapsulated botanical drugs and chemotherapy drugs. This study was divided into three experiments.
Silymarin is extracted from milk thistle, one of the most useful herbal medicines, has been widely used for its hepatoprotective effects. However, its therapeutic effects are limited by its poor oral bioavailability, low solubility and poor permeability across intestinal epithelia. The aim of this study was to prepare silymarin formulations (silymarin is entrapped in the liposome and ethosome, where the formulations are referred to as LSM and ESM, respectively) to improve the oral bioavailability of silymarin and to evaluate its tissue distribution using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) in free-moving rats. Silibinin is the major active constituent of silymarin, which is the main target to be analyzed. A rapid, sensitive, and repeatable HPLC-MS/MS method was developed and validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study the pharmacokinetics and tissue distribution of silymarin in the rats. The size, zeta potential and drug release of the formulations were characterized. The mean particle size and zeta potential of LSM and ESM were approximately 300 nm and -30 mV, respectively. The pharmacokinetic results demonstrated that LSM and ESM had a high area under the concentration-time curve (AUC), high the peak plasma concentration of a drug after administration (Cmax) and low clearance (CL) compared with silymarin (free form). Furthermore, the bioavailability of silymarin was significantly increased by LSM and ESM (up to 7.5-fold and 2.2-fold, respectively). In distribution studies, LSM and ESM were found mainly in the lung, spleen and liver. These formulations could significantly increase the silymarin levels in these organs, and they may be more efficiently distributed to organs than silymarin alone, thereby supporting therapeutic bioactive properties in the body.
The bubble formulations have both diagnostic and therapeutic applications. However, research on nanobubbles and nanodroplets remains in the initial stages. In this study, a nanodroplets formulation was prepared and loaded quercetin, to observe its pharmacokinetic properties and ultrasonic bioimaging of specific sites, namely, the abdominal vein and bladder. Four parallel groups were designed to investigate the effects of ultrasound and nanodroplets on the pharmacokinetics of quercetin. These groups were quercetin alone, quercetin triggered with ultrasound (quercetin+U), quercetin encapsulated in nanodroplets (N+Q), and N+Q triggered with ultrasound (N+Q+U). Spherical vesicles, with a mean diameter of 280 nm, were formed, and quercetin was completely encapsulated within these vesicles. In vivo ultrasonic imaging confirmed that the nanodroplets could be treated by ultrasound. The results indicate that the initial 5 min serum concentration (C5 min), AUC, elimination half-life (t1/2) and Cl of quercetin were significantly enhanced by the treatment of nanodroplets with or without ultrasound.
The nanodroplets treated with ultrasound can be used to enhance drug penetrate into brain and increased treatment. In the study, we prepared a nanodroplet formulation and loaded with 5-fluorouracil (5-FU) to investigate the pharmacokinetic of protein unbound 5-FU in rat blood and brain by simultaneous multiple microdialysis technique. This sensitive and repeatable HPLC-UV (high performance liquid chromatography-ultraviolet) method was developed and validated, and the established method was applied to measure the pharmacokinetics of unbound 5-FU in the rat’s blood and brain The properties of the formulations were evaluated, such as particle size, zeta potential, encapsulation percentage, and transmission electron microscope (TEM). The pharmacokinetic study was divided into four groups of group 1: 5-FU (50 mg/kg, i.v.) alone. Group 2: 5-FU+U; 5-FU (50 mg/kg, i.v.) triggered with ultrasound for 2 min. Group 3: N+5-FU; nanodroplets-encapsulated 5-FU formulation of 5-FU (50 mg/kg, i.v.). Group 4: N+5-FU+U; nanodroplets-encapsulated 5-FU formulation of 5-FU (50 mg/kg, i.v.) triggered with ultrasound for 2 min. The N+5-FU presented circle shape and the mean particle size and zeta potential was about 280 nm and -35 mV, respectively. The results of pharmacokinetics showed successfully enhanced 5-FU levels in the brain and its reduced concentration in the blood, thus improving its therapeutic effectiveness in treating brain disease.
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