Study on Integrated Pharmacokinetics of the Component-Based Chinese Medicine of Ginkgo biloba Leaves Based on Nanocrystalline Solid Dispersion Technology.

Background: To improve the dissolution and bioavailability of the component-based Chinese medicine of Ginkgo biloba leaves (GBCCM), a novel nanocrystalline solid dispersion of GBCCM (GBCCM NC-SD) was first prepared. Methods: GBCCM mainly containing high pure flavonoid aglycones (FAs) and terpenoid lactones (TLs) was used as the model drug. PVP K30 and SDS were used as solubilizers, combined stabilizers and carriers, and GBCCM NC-SD was prepared by high-pressure homogenization combined with freeze-dryer. Morphology and crystal characteristic of GBCCM NC-SD were analyzed. The dissolution and bioavailability evaluation were performed to investigate the feasibility of GBCCM NC-SD by in vitro dissolution and in vivo integrated pharmacokinetic models. Results: After homogenizing for 30 cycles under the pressure of 650 bar and freeze-drying, GBCCM NC-SD with uniform quality would be obtained. The particle size, PDI and zeta potential were found to be 335.9 ± 32.8 nm, 0.29 ± 0.02 and -28.4 ± 0.7 mV respectively. Based on charged aerosol detector (CAD) technology, a new chromatographic method for simultaneous detection of eight components in GBCCM was developed. In vitro drug release study showed that the cumulative dissolution of FAs and TLs in GBCCM NC-SD increased from 12.77% to 52.92% (P < 0.01) and 90.91% to 99.21% (P < 0.05) respectively. In comparison with physical mixture of GBCCM and stabilizer (PM), the integrated pharmacokinetics AUC0-t of FAs and TLs in GBCCM NC-SD were significantly increased (P < 0.05), and the T1/2 of TLs was also significantly prolonged (P < 0.05). Conclusion: This study demonstrated that novel GBCCM NC-SD was prepared using Polyvinylpyrrolidone K30 (PVP K30) and Sodium dodecyl sulfate (SDS) as a synergetic stabilizer and also provided a feasible way to improve the dissolution and oral bioavailability of poorly soluble candidate antihypertensive drugs.

Preparation of Icaritin-Loaded mPEG-PLA Micelles and Evaluation on Ischemic Brain Injury.

Icaritin is an active ingredient derived from the plant Herba Epimedium, which exhibits various pharmacological and biological activities. However, icaritin has solubility in water of less than 1.0 µg/ml and the low aqueous solubility hampered its use as a therapeutic agent. In this work, as shown in Scheme 1, we synthesized a series of mPEG-PLA (Methyl poly (ethylene glycol)-Polylactic acid) with different hydrophilic and hydrophobic segment ratios via ring-opening polymerization and prepared mPEG-PLA/icaritin micelles by solid dispersion method to improve the solubility of icaritin. After studying the particle size, zeta potential, encapsulation efficiency and drug loading efficiency, mPEG2000-PLA50(hydrophilic/hydrophobic segment ratio = 5:6) was selected for subsequent experiment, including single factor experiments and orthogonal experiments for optimizing mPEG-PLA (5:6)/icaritin micelles preparation. The particle size and zeta potential of the mPEG-PLA (5:6)/icaritin micelles were about (64.25 ± 0.21) nm and (-1.37 ± 0.31) mV, the encapsulation efficiency (EE) and drug loading efficiency (DL) were 83.96% and 9.33%, the critical micelle concentration was about 2.24 µg/ml and the solubility about 2.0 mg/ml in water. In vivo studies have shown that mPEG-PLA (5:6)/icaritin micelles have a longer circulation time in plasma and have a distribution in the brain of mice. The pharmacodynamic results indicated that pretreatment with mPEG-PLA (5:6)/icaritin micelles can decrease neurological deficit score, diminish the infarct volume and brain edema. These results suggested that mPEG-PLA (5:6)/icaritin micelles have a good advantage to improve the bioavailability of icaritin, potentially to be a neuroprotectant for ischemic brain injury.