Where is the way for steroid hormone medicine?

■ Yang Shunkai

In recent years, the rise of core intermediates of steroid hormone drugs provided by biotransformation technology has changed the position of saponin and diene in the traditional production process and market of steroid hormones, and has triggered dominoes in environmental protection and upstream and downstream industries. phenomenon.

In view of the structural adjustment during the transformation period of my country's steroid hormone pharmaceutical industry, it is very necessary to explore the industrial development issues in which the industrial chain is closely linked to the market and application.

Industry status

In 2006, the global sales of steroid hormone drugs reached 40 billion U.S. dollars, accounting for about 10% of the world's total pharmaceutical products; in 2009, my country’s total export of steroid hormone raw materials and intermediates was 743.25 tons, worth 370 million U.S. dollars; 2013 The annual export volume has increased to 1,000 tons, with a value of nearly 800 million US dollars. It can be said that in the past 20 years, relying on the resources of diosgenin, my country has made significant contributions to the development of the global steroid hormone industry as a role in the global supply chain of low-end steroid hormone products.

At present, the global steroid hormone drugs are produced by semi-synthetic processes. The total market share is equivalent to 6,000 tons of diosgenin per year. The composition is as follows: diosgenin 50%, 4-androstenedione (4ad) 20%, bean Sterol 10%, hemp saponin 10%, and other semi-synthetic raw materials 10%.

For a long period of time, my country has had certain characteristics of the steroid hormone industry, and the chemical synthesis technology is almost the same as the international level, but the steroid transformation microbial engineering is difficult to be satisfactory and has been at a disadvantage. In recent years, my country has begun to export a certain amount of dexamethasone, betamethasone, methylprednisolone and other medium and high-grade glucocorticoid raw materials, which caused Pfizer to directly import some raw materials from my country and stopped the local raw materials. production line.

Diversified development path

In view of this, the semi-synthetic raw materials of my country's steroid hormone industry should be diversified. Diosgenin-diene compounds should be organized rationally, that is, the planting scale of yellow ginger is controlled at 20,000 hectares per year, which can produce 2,000 tons of diosgenin levels to ensure that old enterprises with good coastal technology continue to use diosgenin-diene. It will continue to occupy the domestic and foreign markets, give full play to its advantages, and gain the right to speak.

The existing plant steroid resources to be developed on a large scale in my country include 500 tons of sisal saponin; 100 tons of sesame saponin; the yield of synthetic dexamethasone using sesame saponin reaches 15.3%, and synthetic betamethasone is harvested The rate reached 11.2%. These preliminary research results based on the development of local steroidal plant resources indicate that my country has become a country where three semi-synthetic raw materials can be used in the world, namely, diosgenin, hemp saponin and sisal saponin to develop and produce steroid hormone drugs. . It is said that the uniquely developed sisal saponin in our country is a semi-synthetic raw material of very innovative value and rich in resources.

In recent years, Chinese companies have invested in plant sterol fermentation projects to produce 4ad with a capacity of 1,000 tons, and it is imperative to replace diosgenin to extend the industrial chain. Representative companies include Baoding Beirui Biotechnology, Shandong Heze Runxin (Saito) Company, Zhejiang Qianjiang Biochemical, etc., and have begun to develop 9a-oh-ad (the best intermediate for the production of halogen-containing glucocorticoids) to extend the industry chain The focus should be on the production and export of the four basic glucocorticoids and their intermediate products. Diene manufacturer.

It is understandable that enterprises develop new products as technical reserves. However, it should be noted that the current 4ad fermentation production of raw material phytosterols and fermentation strains in my country rely on imports and introduction, so the risk of project development increases.

In 2013, the import price of phytosterols was 22~26 US dollars/kg. Once the cost of 16-DPA raw materials increases, it is easy to cause losses; in addition, the steroid fermentation project belongs to the prokaryotic microbial actinomycete mycobacterial fermentation process. Process robustness is poor, not as robust as yeast and fungal fermentation processes, so the risk of steroidal bioengineering is self-evident, especially companies that are new to this industry lack microbiology professionals Time should be more careful to intervene.

Based on local scientific development

      The steroid hormone industry, established on the basis of natural steroidal biological resources, has a high degree of integration of semi-synthetic technology, integrating multi-step chemical synthesis and key biological transformation methods. After more than half a century of development, steroid hormone drugs have become the second largest drug category after antibiotics, and they are showing a trend of development with the times.

However, for a long time, the production of steroid hormones in my country has relied on a single semi-synthetic raw material-diosgenin. This causes technical and economic problems for the synthesis of different types of steroid hormone drugs. The industry has always believed that the important intermediate diene (c-21 steroid) produced by the chemical method of diosgenin has the best technical and economic efficiency for the manufacture of glucocorticoids, and it occupies a large share of this type of drug ( 70%).

In the past few years, domestic companies used diosgenin-diene compounds to produce 4ad in exchange for a large amount of foreign exchange through chemical methods, which is very uneconomical in terms of resource utilization. It is no wonder that European and American companies have successfully developed phytosterol fermentation to produce 4ad on an industrial scale since the 1980s, and are willing to exchange 2kg4ad for 1kg of diene in my country. This is why my country has become a major player in the global low-end supply chain of steroid hormones and their intermediates since the 1990s. The serious consequence is that my country's wild yam plant resources are quickly exhausted.

At the same time, the disorder of the market economy has led to the blind development of yam plantation across the country. The excessive planting of turmeric has caused the price of yam saponin to drop to a low (140,000 yuan/ton); especially the "chromium" in the processing of diene. The environmental protection problem of "pollution" has yet to be resolved.

Since 2011, there has been a shortage of diosgenin products in the market, so the price of diosgenin-diene has risen one after another. By the end of 2013, the price of diosgenin reached 1 million yuan/ton; the diene product was 1300~1400 yuan/kg. Many domestic companies have invested in the plant sterol project to produce 4ad.

By the autumn of 2014, the price of yam saponin had dropped to more than 800,000 yuan/ton. This indicates that domestically produced 4ad has begun to replace some diosgenin-diene compounds as raw materials for the synthesis of steroid hormones and their intermediates. According to estimates, if 4ad is used to replace the equivalent of 500-600 tons/year of diene produced by diosgenin based on the diene compound of 1,000 yuan/kg, the 4ad industry in my country will have a commercial value of 100 million to 200 million US dollars. value.

How many 4ads are actually produced every year in my country? This is still a question of uncertainty. Diene is mostly dependent on imports due to the restriction of plant sterol raw materials. In addition, my country's steroid fermentation microbial engineering is inherently weak, and it is difficult to say whether it can be as expected. The reliable development model is still based on the in-depth development of local steroidal biological resources to truly realize the diversification of semi-synthetic raw materials for the steroid industry in my country.

(The author is a researcher at Chengdu Institute of Biology, Chinese Academy of Sciences)

"China Science News" (2015-03-10 7th edition biology)