As previously reported (Horii C., et al., Shoyakugaku Zasshi, 68 (1), 9-12 (2014), Shoyakugaku Zasshi, 69 (2), 59-65 (2015), Shoyakugaku Zasshi, 68 (2), 65-69 (2014), Shoyakugaku Zasshi, 73 (2), 73-83 (2019), and Shoyakugaku Zasshi, 74 (1), 46-57 (2020)), we investigated the bioequivalence of the decoctions and extract preparations of Kakkonto, Shoseiryuto and Hachimijiogan, demonstrating that some components may serve as marker compounds for the evaluation of bioequivalence. Of them, ephedrine and pseudoephedrine contained in the Ephedra Herba might serve as the most effective marker compounds for examining the bioequivalence between the decoction and the extract preparation in an increased number of subjects.

The present study examined the bioequivalence between the decoction and the extract preparation of Kakkonto by comparing the plasma concentrations of the components of the decoction of Kakkonto and Kracie Kakkonto extract fine granules, prepared with the same crude drug, as test and control drugs, respectively, after administration to 20 human subjects. As a result, the decoction and the extract preparation showed no significant difference in the plasma concentrations, maximum plasma concentrations (C_max), or areas under the plasma concentration versus time curve (AUC_24 h) at any blood sampling time. As the 90% confidence interval of the difference in the mean logarithmic values of the C_max and AUC_24 h of ephedrine and pseudoephedrine between the decoction and the extract preparation were within the range of log (0.80) to log (1.25) (criterion for bioequivalence), a statistical power (1-β) was employed. As a result, the C_max and AUC_24 h in ephedrine and pseudoephedrine had sufficient power (more than 80%), suggesting that the bioequivalence of the decoction and extract preparation of Kakkonto can be evaluated using ephedrine and pseudoephedrine as marker compounds.

To promote the effective utilization and quality control of single crude drug extract products, the “Application guidance for OTC of (non-Kampo) single crude drug extract products” was published by the Ministry of Health, Labour and Welfare of Japan in December 2015. For further expansion of this guidance, we previously reported the standardization of three single crude drug extracts, which were listed in Non-JP Crude Drug Standards (Non-JPS) 2018. In this study, we report the designed and verified methods for the identification tests and assay of six single crude drug extracts, i.e. Ginseng Extract (1), Red Ginseng Extract (2), Polygala Root Extract (3), Bupleurum Root Extract (4), Peony Root Extract (5), and Citrus Unshiu Peel Extract (6), which were newly listed in Non-JPS 2022, published in March 2022.

Ginsenoside Rg₁ was selected as the marker compound (MC) of 1 and 2 for the identification test by TLC, and ginsenoside Rg₁ and ginsenoside Rb₁ were selected as the MCs of 1 and 2 for the assay by HPLC. Tenuifolin and 3,6’-di-O-sinapoylsucrose were selected as the MCs of 3 for the identification test by TLC and the assay by HPLC, respectively. Saikosaponins a and c were selected as the MCs of 4 for the identification test by TLC. Saikosaponin b₂ was selected as the MC of 4 for the assay using HPLC. Paeoniflorin was selected as the MC of 5 for the identification test using TLC and the assay using HPLC. Hesperidin and narirutin were selected as the MCs of 6 for the identification test using HPLC and hesperidin was selected as the MC of 6 for the assay using HPLC.

The survey on the variety, amount and producing countries of crude drugs for medicinal use was conducted among member companies belonging to Japan Kampo Medicines Manufacturers Association in fiscal 2019 and 2020. The results showed that total amount of use and number of items of crude drugs were 27,240 tons of 273 items in 2019, and 27,997 tons of 276 items in 2020, respectively. Comparing production ratios among countries, Japan, China and the other countries produced 9.9%, 83.8% and 6.3% of the total amount used in 2019, respectively. Similarly, each ratio turned to 10.3%, 82.7% and 7.0% in 2020.