著者

内山 奈穂子 鎌倉 浩之 政田 さやか 辻本 恭 細江 潤子 徳本 廣子 丸山 卓郎 合田 幸広 袴塚 高志

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

pp.17-00136, (Released:2017-07-19)

参考文献数

14

被引用文献数

2

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In January 2017, counterfeits of the hepatitis C drug 'HARVONI® Combination Tablets' (HARVONI®) were found at a pharmacy chain through unlicensed suppliers in Japan. A total of five lots of counterfeit HARVONI® (samples 1-5) bottles were found, and the ingredients of the bottles were all in tablet form. Among them, two differently shaped tablets were present in two of the bottles (categorized as samples 2A, 2B, 4A, and 4B). We analyzed the total of seven samples by high-resolution LC-MS, GC-MS and NMR. In samples 2A, 3 and 4B, sofosbuvir, the active component of another hepatitis C drug, SOVARDI® Tablets 400 mg (SOVARDI®), was detected. In sample 4A, sofosbuvir and ledipasvir, the active components of HARVONI®, were found. A direct comparison of the four samples and genuine products showed that three samples (2A, 3, 4B) are apparently SOVARDI® and that sample 2A is HARVONI®. In samples 1 and 5, several vitamins but none of the active compounds usually found in HARVONI® (i.e., sofosbuvir and ledipasvir) were detected. Our additional investigation indicates that these two samples are likely to be a commercial vitamin supplement distributed in Japan. Sample 2B, looked entirely different from HARVONI® and contained several herbal constitutents (such as ephedrine and glycyrrhizin) that are used in Japanese Kampo formulations. A further analysis indicated that sample 2B is likely to be a Kampo extract tablet of Shoseiryuto which is distributed in Japan. Considering this case, it is important to be vigilant to prevent a recurrence of distribution of counterfeit drugs.

著者

堀井 周文 小此木 明 高橋 隆二 鎌倉 浩之 袴塚 高志 合田 幸広

出版者

一般社団法人 日本生薬学会

雑誌

生薬学雑誌 (ISSN:13499114)

巻号頁・発行日

vol.74, no.1, pp.46-57, 2020-02-20 (Released:2021-03-11)

参考文献数

29

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Our previous studies [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)], in which bioequivalence between the Kakkonto /Shoseiryuto decoction and its extract preparation was evaluated, revealed that some components can be marker compounds for bioequivalence but not others. In this study, we selected Hachimijiogan containing benzoylmesaconine, benzoylhypaconine, and 14-anisoylaconine specified as marker compounds by the Japanese Pharmacopoeia for quantification for quality control, and evaluated these components as possible marker compounds for bioequivalence.Six healthy adult males were randomly divided into two groups, and an oral administration crossover study was performed. Changes in the plasma concentrations of 10 components (benzoylmesaconine, benzoylhypaconine, 14-anisoylaconine, alisol A, alisol A monoacetate, alisol B, alisol B monoacetate, loganin, morroniside, and paeoniflorin) were evaluated. As a result, the plasma concentration of each component in both the decoction and extract preparation varied among blood collection sites. A t-test revealed a significant difference (p<0.01) in the plasma concentration of benzoylhypaconine 4 h after administration, a significant difference (p<0.05) in the plasma concentration of alisol A monoacetate 1 h after administration, and a significant difference (p<0.05) in the plasma concentration of loganin 4 h after administration, for the decoction and the extract. However, significant differences in the plasma concentrations of other constituents were not noted for the decoction and extract.Alisol B and alisol B monoacetate could not be quantified due to an inadequate SN ratio (SN rate 10 or more). Analysis of variance for 8 components after excluding alisol B and alisol B monoacetate showed a significant difference (p<0.05) in the area under the blood concentration-time curve (AUC0-8) for benzoylmesaconine in the subjects’ neck. The preparation, time and subjects did not differ significantly as a factor, so the statistical power (1-β) was calculated (except for alisol B and alisol B). Both the peak plasma concentration (Cmax) and AUC0-8 values for all 8 components had inadequate (< 80%) statistical powers (1-β).Next, the number of subjects needed to achieve sufficient statistical power was estimated based on the obtained results. The statistical powers of both Cmax and AUC0-8 were adequate (≧ 80%) when the number of subjects (1 group) was ≧ 24 (1 group) for benzoylmesaconine, ≧ 25 for 14-anisoylaconine, and ≧ 24 for alisol A. On the other hand, the statistical power was inadequate even when the number of subjects was 61 (1 group) for benzoylhypaconine, alisol A monoacetate, loganin, paeoniflorin, or morroniside.The contents of alisols have been reported to vary in Alisma Tuber. Considering conversion due to metabolism, alisol A is also difficult to use as a marker compound. Therefore, in this prescription, benzoylmesaconine and 14-anisoylaconine may be appropriate marker compounds.

著者

袴塚 高志 鎌倉 浩之 渡辺 淳子 香取 征典 松本 和弘 石丸 順之 諸田 隆 合田 幸広

出版者

一般社団法人 日本生薬学会

雑誌

生薬学雑誌 (ISSN:13499114)

巻号頁・発行日

vol.74, no.2, pp.89-97, 2020-08-20 (Released:2021-09-08)

参考文献数

7

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Dry extract preparations of Kampo medicines for prescription were approved for use approximately 40 years ago in Japan. Presently, most Kampo medicines are prepared in the form of granules with a few being prepared as tablets or capsules. Granule formulations are generally unsuitable for the elderly due to their bulky nature. Although patients and Kampo manufacturers have expressed a need for the introduction of more acceptable granule alternatives, their introduction has been a challenge due to the lack of guidelines based on bioequivalence evaluations for medicines that include multiple chemical components. For resolving this issue, the researchers at the National Institute of Health Sciences initiated a study in 2009 funded by the Ministry of Health, Labour and Welfare. Several ingredients in Kampo extract products and corresponding standard decoctions were detectable and measurable in human plasma, and some compounds have been reported to be promising candidates for application in bioequivalence evaluations of Kampo formulations. The purpose of the present study was to investigate the potential to assess bioequivalence between kakkonto extract granules and tablets on the basis of the “Guidelines for Bioequivalence Testing of Generic Drugs (partial revision, PFSB/ELD Notification No. 0229010 dated February 29, 2012).”We investigated the pharmacokinetics of ephedrine and pseudoephedrine, which are ingredients derived from Ephedra Herba in kakkonto formulations, following the oral administration of kakkonto extract granules (one pack) and kakkonto extract tablets (eight tablets). The study was conducted as a two-group, two-period, and open-label crossover study in healthy Japanese volunteers. The plasma concentrations of ephedrine and pseudoephedrine following the administration of the drugs were measured using liquid chromatography with tandem mass spectrometry. Subsequently, we calculated their pharmacokinetic parameters and evaluated their bioequivalence. Analysis of variance using the area under the plasma concentration time curve (AUC) and the maximum plasma concentration (Cmax) of both ingredients revealed that while AUC indicated bioequivalence, Cmax values were significantly different. Plasma concentration levels in both formulations were similar in most volunteers and differed among some volunteers, which was attributed to a high number of tablets per dose as opposed to intra-individual variation. We concluded that ephedrine and pseudoephedrine in kakkonto extracts are good marker compounds for the evaluation of bioequivalence in different forms of kakkonto products. Our results suggest that the marker compounds exhibiting similarity in pharmacokinetic parameters following the administration of Kampo extract granules and the corresponding standard decoction could be applied as markers for the evaluation of bioequivalence between already-approved Kampo extract granules and novel Kampo products based on the same extract as that of granules.