Xiaochaihu

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This entry is adapted from the peer-reviewed paper 10.3390/separations8110199

Xiaochaihu (XCH) is a classic Chinese medicine formula. XCH tablet, XCH granule, XCH capsule, and XCH effervescent tablet are included in the Chinese Pharmacopoeia.

Xiaochaihu (XCH) formula preparations quality control standard

1. Introduction to XCH Formula

Xiaochaihu (XCH) formula, which was created by Zhang Zhongjing in the East Han Dynasty, is capable of inducing sweat to dispel heat, channeling the liver, regulating the spleen, soothing the stomach ^[1], etc. Traditionally, the recipe is composed of Bupleuri Radix , Scutellariae Radix , Ginseng Radix Et Rhizoma ( Ginseng Radix ), Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle ( Glycyrrhizae Radix ), Zingiberis Rhizoma Recens , Jujubae Fructus , and Pinelliae Rhizoma ^[2]. According to the principle of JUN-CHEN-ZUO-SHI (emperor-minister-assistant-courier in English), in this formula, Bupleuri Radix is JUN, Scutellariae Radix is CHEN, Glycyrrhizae Radix is SHI, and the others are ZUO. Modern research has verified that XCH has anti-inflammatory ^[3] and antitumor ^[4] functions and regulates the endocrine system ^[5]. Clinically, the formula is applied to treat various diseases of the respiratory system ^[6], digestive system ^[7], urogenital system ^[8], immune system ^[9], circulatory system ^[10], etc. The mechanism of XCH acting on the human body can be preliminarily explored by means of liquid chromatography-mass spectrometry, network pharmacology, and animal experiments. For fever, the widest application of XCH, potential antipyretic mechanism includes the reduction of inflammation level, inhibition of endogenous pyrogen and COX-2 ^[11]. Some active ingredients of XCH including quercetin, baicalein, and hanbaicalein can significantly inhibit the growth of hepatocellular carcinoma and induce apoptosis of hepatocellular carcinoma cells ^[12]. In recent years, many novel applications have been reported, including the prevention and treatment of methicillin-resistant Staphylococcus aureus ^[13], syncytial virus, and adenovirus ^[14], as well as the inhibition of influenza A virus ^[15], etc. For the period from 2000 to 2020, an overall trend of a steady rise in the numbers of publications in the field of XCH could be found. In the database of www.cnki.net , the number has grown annually and ranged from about 150 to nearly 400 works ^[16].

2. Formula Differences of Existing XCH Preparations

Capsules, granules, pills, tablets, and other XCH preparations are all on the Chinese domestic market. Among those, XCH tablets, XCH effervescent tablets, XCH capsules, and XCH granules were included in the 2020 edition of the Chinese Pharmacopoeia ^[17]. The Pharmaceuticals and Medical Devices Agency in Japan ^[18] has published more than 10 kinds of XCH preparations, which are mainly granules or tablets. The Japanese Pharmacopoeia includes two different specifications of the Shosaikoto extract ^[19]. In Korea, Soshiho-Tang is widely used as a classic recommendation, which is mainly sold in granules ^[20].

The raw materials of the Japanese XCH preparations are Pinelliae Rhizoma, Ginseng Radix, Bupleuri Radix, Scutellariae Radix, Glycyrrhizae Radix, Zingiberis Rhizoma Recens, and Jujubae Fructus. However, the main XCH preparations on the Chinese market use Pinelliae Rhizoma Praeparatum Cum Zingibere Et Alumine (Jiangbanxia), Codonopsis Radix, Bupleuri Radix, Scutellariae Radix, Glycyrrhizae Radix, Zingiberis Rhizoma Recens, and Jujubae Fructus as raw materials. Table 1 shows four XCH preparations that are listed in the Chinese Pharmacopoeia. The JUN material Bupleuri Radix is the highest in mass ratio among the four dosage forms included in Chinese Pharmacopoeia, accounting for approximately 30%. The raw material mass ratio of XCH tablets and XCH capsules is exactly the same, and the mass ratio of Jiangbanxia is higher than those of XCH effervescent tablets and XCH granules. Regarding the materials of Japanese XCH preparations, the mass ratio of Pinelliae Rhizoma is lower than that of Bupleuri Radix but higher than that of any other herb. The mass ratio values of Glycyrrhizae Radix and Zingiberis Rhizoma Recens are both lower than 10%.

Table 1. Formula amount of raw materials, their mass ratio and preparation amount in different XCH preparations in pharmacopoeias.

Raw Materials	XCH Tablets & XCH Capsules		XCH Effervescent Tablets		XCH Granules		Shosaikoto Extract (Japanese)
—	Amount (g)	Mass Ratio (%)	Amount (g)	Mass Ratio (%)	Amount (g)	Mass Ratio (%)	Amount (g)	Mass Ratio (%)	Amount (g)	Mass Ratio (%)
Bupleuri Radix	445	29.6	1550	31.0	150	31.0	7	29.2	6	26.1
Jiangbanxia	222	14.8	575	11.5	56	11.5	-	-	-	-
Pinelliae Rhizoma	-	-	-	-	-	-	5	20.8	5	21.7
Scutellariae Radix	167	11.1	575	11.5	56	11.5	3	12.5	3	13.0
Codonopsis Radix	167	11.1	575	11.5	56	11.5	-	-	-	-
Ginseng Radix	-	-	-	-	-	-	3	12.5	3	13.0
Glycyrrhizae Radix	167	11.1	575	11.5	56	11.5	2	8.33	2	8.70
Zingiberis Rhizoma Recens	167	11.1	575	11.5	56	11.5	1	4.17	1	4.35
Jujubae Fructus	167	11.1	575	11.5	56	11.5	3	12.5	3	13.0
Preparation amount	XCH tablets: 1000 tablets, 0.4 g each; XCH capsules: 1000 capsules, 0.4 g each;		XCH effervescent tablets: 1000 tablets, 2.5 g each		XCH granules: 1000 g (combined with sucrose); 400 g (combined with mannitol); 250 g (combined with lactose)		Not specified

Pinelliae Rhizoma can cause adverse reactions, such as mucosal irritation ^[21], hepatorenal toxicity ^[22], and pregnancy toxicity ^[23]^[24]. It has been reported that the needle crystals of calcium oxalate and its lectin protein contained in Pinelliae Rhizoma are the main irritant toxic substances ^[25]^[26]. In China, there is a long history to use Zingiberis Rhizoma Recens to alleviate the toxicity of Pinellia ternata. The processing standards for preparing Jiangbanxia have been established ^[27]. Therefore, the use of Jiangbanxia in XCH preparations in China is conducive to improving drug safety ^[28].

Table 1 compared the amount and mass ratio of raw materials in different XCH preparations which were included in the Chinese and Japanese Pharmacopoeia ^[17]^[19]. By having materials divided by the total weight, the mass ratios are calculated and listed.

2. Prospect on the Development Direction of Quality Control of XCH Preparations

2.1. Improvement in the Specificity of Quality Testing

According to Chinese Pharmacopoeia, Glycyrrhizae Radix, Bupleuri Radix and Codonopsis Radix are used as TLC reference materials, and baicalin is used as a TLC reference substance in qualitative identification. However, less attention has been given to Zingiberis Rhizoma Recens, Jujubae Fructus, and Jiangbanxia. The specific components of Jiangbanxia and Jujubae Fructus are not quantitatively analyzed in literature. Recently, guanosine, uridine, hypoxanthine and several other components were analyzed ^[29], which do not especially belong to Jiangbanxia, but it still suggests a way to improve the specificity of HPLC detection by detecting these compositions with strong polarity.

It is essential to distinguish the authenticity of Bupleuri Radix. There are 36 species, 17 varieties, and seven forms distributed all over China ^[30]. Among them, Bupleurum marginatum var. stenophyllum and even poisonous Bupleurum longiradiatum are common varieties that are all easy to mix up ^[31]. To confirm whether or not Bupleurum marginatum var. stenophyllum had been added, Liu et al. using the retention time and peak area of the specific ion detected in the mass spectrum as standards ^[32]. Liang et al. tried to establish near-infrared spectrum models to distinguish products of different factories, which provided a practical technology for low-cost and rapid detection ^[33]. Lai et al. used a polymerase chain reaction (PCR) method based on the site specificity of the Internal Transcribed Spacer (ITS) sequence to identify Bupleurum marginatum var. stenophyllum from Bupleurum chinense DC ^[34]. These new technologies provide ideas for improving the specificity of analytical methods. Bupleurum scorzonerifolium Willd and Bupleurum chinense DC are both included in the Chinese Pharmacopoeia, but National Institutes for Food and Drug Control can provide only the reference material of Bupleurum chinense DC. Hence, the lack of reference material of Bupleurum scorzonerifolium Willd is a problem for quality control of Bupleuri Radix.

2.2. Setting Reasonable Content Range of Index Components from Bupleuri Radix

Bupleuri Radix is the JUN of XCH formula. Thus far, qualitative identification using the reference material of Bupleuri Radix was adopted in Chinese Pharmacopoeia. However, considering drug safety and efficacy, the contents of saikosaponins should be controlled in specific ranges. Studies have indicated that saikosaponins are important active ingredients of Bupleuri Radix, which has antipyretic, anti-inflammatory and antitumor activities. Therefore, it is necessary to set up lower limits for their contents ^[35]^[36]. Moreover, some reference materials have reported that Bupleuri Radix has a certain degree of toxicity when taken in a large dose for a long period of time, and its toxic side effects are often caused by its saponins and volatile substances, which mainly affect the liver ^[37]. Therefore, from the perspective of drug safety, it is necessary to set up upper limits for saikosaponins. At present, the upper and lower limits of the saikosaponin B2 content are set up in the Japanese Pharmacopoeia, which is worth referencing. When setting up the lower limit, companies can consider collecting big data from clinical practice. Accordingly, the needs of drug quality control indicators can be taken into consideration, such as drug interactions and medications for special populations.

2.3. Strengthening the Standard of Limited Detected Items

In recent years, great progress in the control of heavy metals, pesticides, and biological toxins in Chinese medicines and extracts was achieved. The Chinese Pharmacopoeia has specially listed items General Principle for Inspection of Crude Drugs and Decoction Pieces and Guidelines for Establishment of Limit for Harmful Residue of Traditional Chinese Medicine, which have provided guidance for controlling heavy metals, pesticides and biological toxins for medicinal materials. The Chinese Pharmacopoeia stipulates that Jujubae Fructus needs to be tested for aflatoxin, Glycyrrhizae Radix needs to be tested for heavy metals, harmful elements and pesticide residues, and Codonopsis Radix needs to be tested for sulfur dioxide residues, all of which help to guarantee the safety of XCH preparations. However, the current guidelines for XCH preparations still require more relevant limiting items for heavy metals, pesticides and biological toxins, and other toxic ingredients. The Japanese Pharmacopoeia stipulates the limits of heavy metals and arsenic in XCH preparations. It takes the increase in heavy metals during the production process into account, which is more rigorous and improves the level of quality control.

Therefore, from the perspective of drug safety, XCH preparations require an upper limit for the amounts of certain active ingredients, heavy metals, pesticides, biotoxins, and other toxic components. Similar quality control problems exist for many other Chinese medicines. Therefore, the development direction of quality control presented in this work can also be referenced for that of other Chinese medicines.

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