Quality Control for Traditional Medicines - Chinese Crude Drugs

Tu Pengfei (屠鵬飛)

(Professor, Department of Natural Medicines, Peking University School of Pharmaceutical Sciences, Associate Dean, Institute of Innovative Medicines, Peking University, China)

Distinguished guests, ladies and gentlemen, I am very happy to meet many of my old friends today. I would also like to thank Chinese Pharmaceutical Association for providing me with such a good opportunity to communicate with Chinese and European friends. The topic of my report today is the quality standard of Chinese crude drugs and the development ideas. Director Ma introduced the relevant situation of the quality standards of Chinese patent medicines.

My report is divided into the following sections: an overview, the production quality control of Chinese crude drugs, work ideas of Chinese herbal medicines quality standards research and development, quality standards status and development ideas of Chinese crude drug in Chinese Pharmacopoeia, and finally introducing the technique for efficient analysis of complex systems of Chinese materia medica.

lNTRODUCTlON

As Director Ma introduced before, Chinese crude drugs are very important to us. They are raw material for Chinese decoction pieces and Chinese patent medicines. Therefore, if the source is not good, things will be difficult to do at later stage. The quality control is very complicated for Chinese crude drugs.

First of all, the source of Chinese crude drugs is very complicated. We have many origins of Chinese crude drugs. For example, there are 3 kinds of Radix et Rhizoma Rhei, which are Rheum palmatum L., Rheum Tanguticum, Rheum Officinale.

In addition, there are many cases that have the same name for different drugs and same drugs with different names. Due to large region in China, the medication habits vary from place to place. For example, many medicines in Guangdong may be different from other places. The same name may refer to different drugs in Guangdong and Guangxi region. Chinese crude drug is a natural resource that is naturally long and is greatly affected by various environmental factors. It is difficult to control Chinese medicine. In addition, the chemical compositions of traditional Chinese medicines are very complicated, and the functions and indications are also very extensive. At the same time, the production process of Chinese medicines is very complicated. From cultivation to harvesting and processing, it is very difficult to control. How can we establish a quality control method for Chinese medicines, which can effectively guarantee us? The consistency of Chinese medicine quality, clinical effectiveness and its safety, are very important work of quality standards.

QUALlTY CONTROL OF CHlNESE CRUDE DRUGS PRODUCTlON

I will introduce the quality control of Chinese crude drugs production. Actually, for Chinese materia medica, the quality is based on the production of it. Whether it is Chinese crude drugs, Chinese decoction pieces, or Chinese patent medicines, the quality is based on the production, not on standard tests. Only good medicinal materials standards play a role in quality checking. Therefore, we must formulate standard operating specifications and formulate SOP. Everyone will produce according to SOP, and Chinese medicinal materials can guarantee the quality.

From the choice of planting base, we must choose feasible planting area, feasible soil and ecological environment. We need accurate base of seeds, and choose some excellent seeds. Many Chinese crude drugs grow wildly, and may undergo some variations.

A standard operation specification should be formulated for field planting, planting techniques, including land preparation, irrigation, fertilization, pest control, etc.

Nowadays, the cultivation of Chinese crude drugs has shortened the number of years. For example, the growth of wild Radix et Rhizoma Rhei generally needs 8 or 9 years, and can be used for medical purpose after more than 10 years. Now we are planting Radix et Rhizoma Rhei for 2 years, or even 1 year. Last time I went to Sichuan, seeing that many Radix et Rhizoma Rhei grow only 1 year, and they look very light in color of the roots. It shows the quantity of the active ingredient content is very low. Harvesting time and harvesting methods have a great impact on the quality of Chinese crude drugs.

Processing is also very important. Now many materia medicines occurred mildews in the processing, and the contents of mycotoxins are far exceeding the standard.

For the testing of good quality Chinese crude drugs, such procedures could guarantee the high-quality Chinese crude drugs.

First of all, the research object that we are facing and the quality control is Chinese crude drugs. In fact, we have a very important work in the chemical composition research, including its chemical composition and active ingredients. Based on the clear chemical composition, we can identify the chromatogram, feature map, and establish fingerprint maps, the content of effective main components, plus traditional trait identification, powder microscopic identification. All of these form the identification of Chinese crude drugs to ensure the correctness of the Chinese crude drugs.

Fingerprint and main active ingredient are mainly to evaluate its quality. Some traditional inspection and modern inspections, including moisture, total ash, heavy metals and harmful elements, pesticide residues, sulfur dioxide residues, mycotoxins, as well as some of the toxic and harmful substances in the drugs are performed to ensure our safety.

Chinese Pharmacopoeia formulates the standards in accordance with this working principle. Personally, I think that the most important thing is to identify the true and false. Secondly, we will conduct inspection to ensure safety and high-quality drugs for people. Finally, fingerprint map and content determination are used to evaluate the quality of drugs. Our system includes name, source, trait identification, microscopic identification, chromatographic identification, fingerprints and characteristic maps, content determination, as well as nature, flavor, channel tropism, actions, indication, dosage, notes. This is the system of quality standard of Chinese crude drugs in Chinese Pharmacopoeia.

DEVELOPMENT OF CHlNESE CRUDE DRUGS QUALTY STANDARDS lN CHlNESE PHARMACOPOElA

The following is an brief introduction to the development of Chinese crude drugs quality standards in Chinese Pharmacopoeia.

The identification of Chinese crude herbs is a very important task. For example, a kilogram of Stigma Croci is worth about 20,000 - 30,000 yuan, but some fake things exist in the market. Stigma Croci has characteristics with wavy carvings on it, which cannot be made artificially. The traits are easy to identify. For example, Cortex Eucommiae and genuine Cordyceps are wrapped in the head of the worm below with fungus. Chinese Pharmacopoeia has collected the identification of old and new Chinese crude drugs.

Rhizoma Coptidis is easy to identify by cell distribution through microscopic identification. 78% of Chinese crude drugs have been microscopically identified, and we aim to have microscopic identification of all Chinese crude drugs.

TLC identification

The names that may be used in the pharmacopoeia may not be the same. TLC identification is also very simple and very useful. The visibility of the thin layer is very strong. Most of the medicinal materials of Chinese Pharmacopoeia have been microscopically identified. Microscopic identification is now mostly performed with a control. The price of the control product is very expensive. It is a pity to use it for microscopic identification. At the same time, the characteristics of the control are not strong enough. The control extract preparation price is very cheap, and we can package the control extract preparation, one piece per time, in which way a lot of cost can be saved. The TIC map can be attached to the manual, and it is very simple to use this map to identify it. We will gradually identify the Chinese crude drugs with controls in Chinese Pharmacopoeia.

For the control extract, the feature of Rhizoma Coptidis is very obvious. The identification of Radix Bupleuri can be performed for different species, with good accuracy.

Feature map

The research has developed rapidly in these years. What is the difference between the feature map and the fingerprint map? Fingerprint is mainly for all chromatographic combinations, feature maps that we select some characteristic chromatographic combinations, which is mainly for identification, fingerprint can evaluate its pros and cons, the feature map is mainly used for identification, which has characteristics of high resolution and rich information. At the same time, we can also make some regulations on it. and implement a semi-quantitative method, due to some valuable herbs, and confusing herbs easily, there are also Chinese herbal extracts, and now formula granules, including proprietary Chinese medicines, which can be used. This is a very good method.

Case study on the characteristic map of Chinese eaglewood. Agarwood is a very expensive medicinal material, also a spice, and a handicraft. The price of a good agarwood is from 10 thousand to 20 thousand, one kilogram to sell, so how much is a kilogram to sell? The price is very expensive. There are many inferior things on the market. The characteristic map study of Chinese eaglewood is very meaningful for identifying Chinese eaglewood.

The chemical composition inside the Chinese eaglewood is a very characteristic chemical composition. This ingredient is only Chinese eaglewood, in addition, there are some in the herbs. Others basically do not have this ingredient.

We study the Chinese eaglewood fingerprint map, and find that as long as it is true fingerprints map, it is basically similar. We choose a characteristic fingerprint, and compare the end of feature as its characteristic map, thereby formulating Chinese eaglewood characteristic map, which is received the 2015 edition of Pharmacopoeia. In this case, there are many fake agarwood on the market. If you take this method, you will know which one is fake. Many of them sold are fake.

This is what Director Ma does, because the identification of these animal gums is very difficult, including the use of DNA, PCR for identification, which is not identified, Director Ma team have been explored and used CMS for identification, and judge the inside characteristics, on the one hand, it can be quantified, on the other hand, it can be accurately oriented and qualitative, it can identify inside well in this way, like gelatin, yellow gelatin, new gelatin, tortoise gum, and so on, which can be accurately identified, this is a very good highlight of the 2015 edition of Chinese Pharmacopoeia.

There are other biological identifications, including DNAPCR, which is actually very meaningful to identify animal drugs. In the following 2010 edition of Pharmacopoeia, basically most animal drugs were identified by PCR. In addition, we used DNA for identification before, and there are DNA barcodes in it, although DNA barcode does not contain herbs, we have developed the barcode guidelines in the 2015 version. Later, we will use DNA barcode identification methods for some valuable drugs and easy-to-mix drugs. In addition, it includes protein gelatin, quickly identification of some Chinese medicines. we will all go to research.

Examination to ensure safety

In the previous statement, we talked about our examination mainly including some impurities, foreign matter, heavy metals, harmful elements, pesticide residues, fungal bacteria, sulfur dioxide residues, endogenous new toxic and hazardous substances. I am going to propose it here, we discuss issues with European friends and European counterparts. What kind of question do I want to ask? The examination costs of these heavy metal harmful elements, and pesticide residues, are very high. If you go to the test every time, the cost of medicine test is very high, although the amount of a batch of herbs is small, especially the European counterparts bought medicines from China, which is a small amount, and the cost of test is very high, I personally think that Chinese medicines that we eat daily, like the food that we eat daily, which is very small. We eat 10 grams Chinese medicines every day, and 20 grams is unbelievable, but we drink water and eat food every day are so much. Compared with our food, these heavy metals, harmful elements and pesticides that are left in Chinese medicines are neglected. It is equivalent to a number after the decimal point, spending so much money behind this decimal point, whether is necessary or not? I have been thinking about this problem. The amount of different Chinese medicines intake is different, and at the same time, our medication time is different. We should make different limits based on the daily intake and dosage of this drug, instead of directly negating. In addition, we need to study some highly sensitive detection methods, including monoclonal antibodies, chemical reactions. This can save us costs, and the quality standards must be economical and affordable.

The Chinese crude drugs in Chinese Pharmacopoeia now contains some characteristic maps, and do not contain fingerprints map yet. In addition, Chinese crude drugs standard received a part of the determination of multi-component content. I think our work in the future, which for some valuable medicinal materials, commonly used medicinal materials, such a quality control method that gradually collect some fingerprints map and add determination of multi-component content should be used. Our 2020 Pharmacopoeia, We have now selected 50 varieties, large and medium medicinal materials, commonly used medicinal materials, and we are ready to establish detection method of fingerprint map and establish determination of multi-component content, such as palm leaf rhubarb I just talked about, three types.

Determination of multi-component content of traditional Chinese medicine, there is no problem in the actual measurement method, spectral method is very fast, the reference substance lack of problems, this is a very important work, we use a table for multi test, conduct control and content determination by controlling extract, it is very good, and Ginkgo biloba was first adopted.

If the control extract is used for comparison, it can be made into a single package, once every time, with high accuracy and convenience. At the same time, the extract is controled and the fingerprint map is attached to the specification. After doing it well, there is a comparison when you used it, including the new drug we are doing now. I hope that we can provide a control extract when we make a new drug.

For example, we used the control extract as a control, multi-component content determination, and compared with different methods, we compared and then use the external standard method, use the control extract control, and use the quantitative nuclear magnetics, which is very good method in the future.

High-efficiency analysis technology of traditional Chinese medicine complex system

As our Chinese crude drugs ingredients are very complicated, how can we analyze such a complex system? Including quality consistency, analytical techniques, analytical methods, which are important, we started with the fine sample, and now if everyone is going to extract it, the extraction is inconsistent. We are now using a high-pressure system such as high efficiency anisotropy, directly pressed into pieces and put directly into, once you put in it, it is done. It is very fast, and the sample amount is very small, only 2 or 3 milligrams can be achieved. In addition, we use the spectrum method, including multi-dimensional spectrum, which greatly improves our resolution, mass spectrometry, database mechanism solve the problem of efficient analysis of complex systems of traditional Chinese medicine.

This is our traditional Chinese medicine, Cistanche, ordinary CMS has compounds of it, you can do it in a few minutes, we analyzed that each sample could not be retained on LP18 and could not be separated. If we specifically focused on blood-thirsty things before, then we can separate the previous things, and can detect hundreds of ingredients at once, which greatly enhances our analytical effectiveness.

In addition, we use mass spectrometry technology, for safflower, traditional Chinese medicine safflower, which the main ingredient is flavonoids, we use mass spectrometry diagnostic ion to extract from safflower, and identify 137 individual metabolites and 19 compounds from inside, and we quantify and semi-quantify these compounds. Now mass spectrometry is developing very fastly, for example, in vivo, identify metabolites in the body, and a total of 286 individual metabolites were identified, infer metabolic pathways of metabolites in the body. Through the establishment of efficient analysis methods for complex systems, which can provide many good methods for our pharmacopoeia, whether it is Chinese crude drugs, Chinese herbal medicines and future quality control of Chinese patent medicines. These are some prospective study. Those are my brief introduction, thank you all!