Improved Oral Bioavailability of Total Flavonoids of Dracocephalum moldavica via Composite Phospholipid Liposomes: Preparation, in-vitro Drug Release and Pharmacokinetics in Rats.

BACKGROUND: Dracocephalum moldavica L is a traditional Uygur medicine for centuries, total flavonoids extracted from Dracocephalum moldavica are the major active ingredients of herbs, which possesses significant medicinal values to treat coronart disease and hypertension, due to the glycosyl group on the ring, total flavonoids of Dracocephalum moldavica has low hydrophilic and poorly absorbed after oral administration, so one way is the formulation of poorly water soluble and permeabledrugs with lipids containing formulations such as Composite phospholipid liposomes to improve the absorption profile of drug.

OBJECTIVES: To prepare composite phospholipid liposome (CPL) encapsulatetotal flavonoids extract from Dracocephalum moldavica (TFDM), determine its physicochemical properties, investigate its in-vitro release and evaluate the pharmacokinetics in Sprague-Dawley (SD) rats to increase the bioavailability of TFDM-CPL.

MATERIAL AND METHODS: The TFDMCPL was prepared by the method of ammonium sulfate transmembrane gradients. The CPL and TFDM were separated by Sephadex-G50 chromatography. The concentration of TFDM in the CPL was detected by HPLC, then the entrapment efficiency (EE) was evaluated. And the shape, particle size, zeta potential, drug release in vitro of TFDMCPL were investigated, and the pharmacokinetics was evaluated by rat jugular vein intubation tube in SD rats.

RESULTS: The EE of TFDM was 84.17±2.2%, mean size of TFDMCPL was 136.2±3.7nm, polymey disperse index (PDI) was 0.158±0.015 and zeta potential was -19.8±1.2mV. TFDM-CPLwere found to enhance the release of drugs more effectively than TFDM based on the in vitro model and Following oral administration of TFDM, the plasma exposures of TFDM-CPL was significantly extended, and the mean concentration of TFDM-CPL was significantly higher compared to TFDM-solution. TheCmax, t1/2, AUC0-12 h values of TFDM for group of TFDM-CPL were siginificantly increased.

CONCLUSION: The method of ammonium sulfate transmembrane gradients is suitable for preparingTFDM-CPL. And TFDM-CPL have potential to be used to improve the bioavailability of poorly soluble drugs after oral administration.

SUMMARY: For the first time, composite phospholipid liposomes (CPL) containing total flavonoids of Dracocephalum moldavica (TFDM) were developed by method of ammonium sulfate transmembrane gradients.The TFDM-CPL was a significant improvement in bioavailability compared to the TFDM-solution, with a 10-fold increase in relative bioavailability in vivo.The TFDM-CPL was still stable during storage at 4oC for 6 months. Abbreviations Used: CPL: composite phospholipid liposome.; TFDM: Total Flavonoids Extract from Dracocephalum moldavica; SD:Sprague-Dawley; EE:entrapment efficiency; PDI: polymey disperse index; TFDM-CPL: Total flavonoid extract from Dracocephalum moldavica - composite phospholipid liposome; DM: Dracocephalum moldavica L.; SPC: Soybean phospholipid; HSPC: Hydrogenated soya phosphatide; PBS: phosphate buffered saline; HPLC: high performance liquid chromatography; TEM: transmission electron microscopy; CMC-Na: Carboxy Methyl Cellulose-Natrium; AUC: area under the curve.