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

Hongbao Liang,1– 3,&ast; Chenghong Sun,2,3,&ast; Zhong Feng,2– 4 Xianzhen Wang,2 Lingpeng Kong,2,3 Feng Zhu,2,3 Jingchun Yao,2,3 Xiaomei Yuan,3 Zhong Liu,2,3 Guimin Zhang,2,3 Feng Li1 1School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Center for Drug Safety Evaluation, Shandong New Time Pharmaceutical Co., Ltd., Linyi, People’s Republic of China; 3State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi, People’s Republic of China; 4School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Li, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan, 250355, People’s Republic of China, Tel +86 139 6914 1796, Email 13969141796@163.com Guimin Zhang, Lunan Pharmaceutical Group Co., Ltd., State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, No. 209 Hongqi Road, Linyi, 276006, People’s Republic of China, Tel +86 539-5019206, Email lunanzhangguimin@yeah.netBackground: 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.Keywords: Ginkgo biloba, flavonoid aglycones, terpenoid lactones, nanocrystalline solid dispersion, integrated pharmacokinetics, charged aerosol detector