Summary
Borneol, called borneol in ancient times, is an important medicine for resuscitation, heat clearing and pain relieving. It is widely used in traditional Chinese patent medicines and simple preparations. The ancient Longnao (Longnao resin oil, hereinafter referred to as plum blossom ice), originated in Padang, Sumatra, Indonesia. Its ingredients are almost entirely right-handed Longnao (containing small amounts of huperzine, β - elemene, caryophyllene, Longnao ketone, and cocaine diol). Longnao fragrant tree has a narrow distribution and slow growth, and the price of the produced ice flakes is high, with a price of over 50000 yuan per kilogram, which does not have universal application value.
During the Republic of China period, the technology of synthesizing borneol using turpentine or camphor as the main raw material through chemical methods emerged. Due to its low price, large supply, and coinciding with the establishment and improvement of the Pharmacopoeia of the People's Republic of China (hereinafter referred to as the "Chinese Pharmacopoeia"), synthetic borneol was long named "borneol" until the 2000 edition of the Pharmacopoeia corrected it to "borneol (synthetic dragon brain)". In fact, synthetic borneol contains 45% impurities (isoborneol) and is a racemic form of levonorborneol and dextronorborneol, which means that only about 22.5% of the components in synthetic borneol are similar to those in plum blossom borneol, posing significant safety and efficacy risks. Due to the limited technological conditions at that time, no pharmacological or toxicological experiments were conducted to synthesize borneol instead of plum blossom borneol.
In 1987, China discovered a chemical type of camphor tree rich in right-handed borneol - camphora camphora. Fresh branches and leaves of camphora camphora can be distilled and cooled to obtain natural borneol similar to "plum blossom borneol". Due to the low price of natural borneol produced by this method and the fact that right-handed borneol can reach over 99%, this type of borneol is recorded as natural borneol (right-handed borneol) in the Chinese Pharmacopoeia from 2005 to 2020. Although natural ice flakes are not the ancient plum blossom ice flakes, they are superior to synthetic ice flakes in terms of preparation technology, safety and effectiveness, and ecological protection. Therefore, strong support should be given from a policy perspective.
This report summarizes the sources, ingredients and activities, safety, pharmacokinetics, resource status, usage, approval numbers, and other aspects of three types of ice flakes. It is found that:
1、 Plum blossom ice flakes are ancient ice flakes, synthetic ice flakes are substitutes for the Republic of China, and natural ice flakes are substitutes discovered in modern times
In ancient times, ice flakes were always known as "dragon brain fragrance" until the Ming Dynasty's "Bencao Mengqi" began using the name "ice flakes". Later generations, "Bencao" used ice flakes as an annotation for dragon brain fragrance, indicating that the market's understanding of the name "ice flakes" had surpassed that of dragon brain fragrance. Starting from "Bencao Congxin" in later generations, the name of Longnao Xiang was replaced by the name of ice flakes. The ice flakes used in ancient times were Longnaoxiang (resin oil of Longnaoxiang tree), which originated in Padang, Sumatra, Indonesia. Its composition is almost entirely right-handed Longnao (containing small amounts of gibberellin, β - elemene, caryophyllene, Longnaoxiang ketone, and cocaine diol). Although synthetic and natural ice flakes are both substitutes for Longnao fragrance, the right-handed Longnao content of natural ice flakes can also reach over 99%, which is relatively closer to Longnao fragrance. The main component of synthetic borneol is racemic camptothecin, which differs significantly from the composition of camptothecin. Traditionally, using natural ice flakes is in line with medicinal traditions.
2、 Synthetic borneol does not meet the definition of traditional Chinese medicine resources and should not be used as a Chinese medicinal herb
Article 32 of the Implementation Regulations of the Drug Administration Law of the People's Republic of China (Revised Draft for Comments) defines traditional Chinese medicine resources as those derived from animals, plants, and minerals, and generally does not include substances derived from genetically modified animals and plants, as well as substances modified chemically. Natural borneol meets the definition of traditional Chinese medicine resources mentioned above and should belong to the category of Chinese medicinal materials. However, synthetic borneol is a mixture obtained by chemical modification of turpentine, which does not meet the definition of traditional Chinese medicine resources mentioned above.
Synthetic borneol is used as an additive in the production of chemical drugs and belongs to the category of chemical raw materials. The historical reasons that led to the inclusion of synthetic borneol as a genuine product in the Pharmacopoeia of the People's Republic of China (1963-2005 edition) should be due to insufficient understanding and research. In history, there have been incidents of drug harm caused by incorrect sources, such as the mistaken use of Houttuynia cordata as Houttuynia cordata. Modern research has shown that synthetic borneol contains less than 30% right-handed borneol and 45% impurities (such as iso borneol). Zhang Boli, Li Lianda, and others believe that iso borneol is the main component causing adverse reactions such as ulcers. If synthetic borneol continues to be used as genuine borneol, there will be regulatory risks.
3、 Plum blossom ice flakes have similar components to natural ice flakes, with only 22.5% of synthetic ice flakes having similar components to plum blossom ice flakes
Three types of borneol ingredients and activities: almost all of the plum blossom borneol is right-handed borneol, the main component of natural borneol is right-handed borneol, the main component of synthetic borneol is borneol, and the content of alloborneol does not exceed 45%. Natural borneol is the closest to plum blossom borneol in terms of composition, with a similarity rate of over 99% for high-purity samples. Synthetic borneol contains 45% impurities (such as isoborneol), and is a racemic form of levo - and right-handed borneol. Therefore, approximately 22.5% of the components in synthetic borneol are similar to plum blossom borneol.
4、 Most research data shows that natural borneol is safer than synthetic borneol
The acute toxicity study of natural and synthetic borneol found that the LD50 values of the two types of borneol administered orally to mice were 2.72 and 3.00g • kg-1, respectively. The toxicity of isoborneol was greater than that of borneol, while the toxicity of synthetic borneol was between the two. The maximum non-toxic reaction doses of natural and synthetic borneol in mice are 0.68 and 0.75g • kg-1, respectively. From the current literature, most studies believe that natural borneol is safer than synthetic borneol, with right-handed borneol having the highest safety. Due to the possible impurities of camphor in different natural ice flakes, there may be differences in toxicological results caused by camphor.
5、 Isoborneol in synthetic borneol can be converted into camphor in the air, leading to increased toxicity
Both sealed and exposed synthetic ice flakes have a tendency to convert to camphor, with a stronger trend observed for those stored in air. However, there is no literature reporting whether natural ice flakes are converted to camphor during storage. Borneol can also be converted into camphor in animal bodies, and compared to camphora, allocamphora is more easily converted into camphor.
6、 From the perspective of resource utilization, the planting technology of natural borneol raw plants is mature, there are no obstacles to reproduction, and the supply is sustainable and stable
At present, China has abundant resources for extracting right-handed borneol. The Chinese Pharmacopoeia (2020 edition) stipulates that natural borneol comes from the Cinnamomum camphora (L.) Presl plant in the Lauraceae family. The "natural right-handed borneol" included in the 2010 edition of the Guangdong Provincial Chinese Medicinal Materials Standards is Cinnamomum burmannii (C. G. et Th. Nees) Bl., a plant in the Lauraceae family. These two natural sources of ice flakes grow rapidly and have no obstacles to reproduction. They are both native biological species in China and do not pose any ecological security issues. They are ice flake medicinal resources that can be quickly promoted and planted. Natural ice flakes are extracted and processed from fresh branches and leaves of the camphor plant in the camphor family. After the camphor tree grows, new branches and leaves can grow every year. Reasonable harvesting planning can achieve sustainable supply of medicinal resources.
7、 In terms of preparation methods, the quality of natural borneol medicinal materials is more stable
Synthetic borneol is chemically synthesized using raw materials such as turpentine, but it cannot solve the problem of producing isomers during the synthesis process, and cannot control the left-handed and right-handed conformations of camptothecin. Therefore, the chemically synthesized camptothecin must contain about 45% heterocamptothecin impurities, and camptothecin is also a racemic form of left-handed and right-handed camptothecin. Natural borneol is mainly produced by distillation cooling method, and the composition of right-handed borneol in natural borneol is over 96%. From the perspective of preparation methods, the quality of natural borneol medicinal materials is more stable.
To sum up, it is recommended to gradually resume the use of natural borneol, and release the use of natural borneol in traditional Chinese patent medicines and simple preparations feeding by steps and categories: traditional Chinese patent medicines and simple preparations derived from ancient classic famous prescriptions can directly replace the prescription feeding with natural borneol, traditional Chinese patent medicines and simple preparations new drugs developed through strict clinical experiments should be replaced after more research, and traditional Chinese patent medicines and simple preparations varieties upgraded from local standards to national standards should be replaced after pharmaceutical research data are supplemented. Medical institutions and pharmacies can provide two options: synthetic ice flakes and natural ice flakes. Prescriptions containing ice flakes can be paid for synthetic ice flakes or natural ice flakes, which can be chosen by physicians and patients themselves.
