ABSTRACT Concentrated herbal extract powders (colloquially referred to as granules) offer patients a convenient, customized option for Chinese

medicinal therapy, and their widespread use has impacted practitioners worldwide. In Asia, the prominence of granule extracts has given rise to a number of new trends in terms of formula composition and dosage. Despite the widespread use of granules in the West, many practitioners have not been exposed to these modern strategies and consequently remain uncertain about how to dose and formulate prescriptions that are filled in granular form. This article offers a brief survey of some of the emerging clinical approaches seen in Asia, and explores the key issues surrounding granule prescription with regard to dosage, formulation, and issues with minerals, gelatins, and other problematic medicinals. Maximizing the Clinical Efficacy of Granule Preparations: Understanding Dosage, Regional Trends, and Unforeseen Challenges The development of concentrated herbal extract powders, commonly known as granules, has had a major impact on the field of Chinese medicine. The consistent and easily quantifiable nature of granule extracts makes them well-suited to evidence based medical research, while the portability and convenience of granules dramatically increases patient compliance. Granule formulas can be extensively customized and deliver a comparable level of potency to raw herb decoctions, but granules have a longer shelf life and require less space and preparation than their raw counterparts. Most practitioners appreciate the degree to which these important factors affect our day-to-day clinical practice, but few practitioners are aware of the larger trends surrounding the use of granules in Asia. While granule use has produced a number of new approaches to prescription formulation and dosage in Asia, these clinically essential developments are only just now beginning to be appreciated in Western countries. 1. The Development of Granule Extracts The technology for producing the granule extracts in use today was originally pioneered in Japan. From Japan, the technology spread initially to Taiwan, Hong Kong, and South Korea; in recent years, the use and production of granules has taken off in mainland China as well. Although the technology used in manufacturing is similar in each locale, regional medical styles have given rise to distinct patterns of use in each country. In particular, Taiwan has been greatly impacted by the arrival of granule extracts; arguably the most distinctive regional characteristic of Chinese medicine in Taiwan is the extremely sophisticated and unique method of granule use seen there.[1] The process of manufacturing granules is essentially an industrial-scale reproduction of a traditional water decoction. Bulk herbs are purchased by the ton by large herbal pharmaceutical companies, which typically manufacture both single herb extracts as well as classical formulas. Large granule manufacturing companies generally have analytical labs where the raw materials are first screened for heavy metals or pesticide residues. Correct species identification is typically ensured by the use of liquid chromatography and micro-

scopic examination, and some companies even employ botanists and other specialists to help with the screening process. Production is typically followed by testing the levels of various marker chemicals to ensure consistent minimum standards of potency in the finished product. The manufacturing process itself is relatively straightforward, although many companies have trade secrets and minor variations in the process. Typically, medicinals are decocted in purified water and the decoction is then drained into a container that reduces the liquid by slowly evaporating the decoction at a low temperature. The concentrated decoction is then sprayed as a mist into a large container that bears a faint resemblance to a clothes dryer- this machine sprays the concentrated decoction into a regulated flow of dry powder, which serves as an excipient for the liquid concentrate. The excipient powder is typically a starch such as corn starch or potato starch, though some companies use the ground herb itself as an excipient in single herb extracts. A uniform powder is produced by mixing the liquid concentrate with the dry excipient; this allows the final powder to flow freely with minimal clumping and also extends its shelf life considerably. For classical formulas, the individual medicinals are first prepared according to the demands of the original prescription; for example, some medicinals must be first stir-fried with honey while others must be dry-fried, etc. The classical ratios and preparation methods are preserved, and the formula is cooked with all the medicinals together to preserve any potential chemical interactions that may result from their combination in the cooking process. The final chemical profile of a formula that is cooked together is said to differ from the same formula that is built from scratch by adding concentrated powders together, and many practitioners prefer to use these whole formulas rather than building formulas from scratch based on concentrated singles alone. Single herb extracts are relatively straightforward, although there are a number of issues that can ultimately affect their clinical use. Singles are typically made by the same process as complete formulas, but many singles use the ground raw medicinal itself as an excipient rather than starch. Although most plant-based single herb extracts are manufactured by producing a concentrated water decoction, it is worth noting that many minerals and gelatins are not decocted or concentrated; rather, they are simply a very finely powdered version of the crude drug. This feature affects some issues of dosage and safety, which are explored in more detail below. 2. Regional Styles The form that medicinals are administered in varies from region to region in Asia. Granules are generally more prominent in Japan and Taiwan, while decoctions made in smaller extraction machines are more prominent in China and Korea. Granule powders, raw home decoctions, and small extraction machines are seen in all of these countries, but their prevalence of use varies considerably. For example, granules are the only form of herbs that are covered by the national insurance system in Taiwan; thus, granule powders are used more frequently than other forms due to patient convenience and expense, and granules are widely stocked in local pharmacies. By contrast, granules are rarely seen in

mainland Chinese pharmacies, though many larger Chinese pharmacies have extraction machines that package the decoction in plastic retort pouches (a heat-sealed durable plastic container that travels well and stores well). In Japan, herbal medicine is restricted to prescription by licensed biomedical physicians. The herbal formulas used are mostly pre-Song Dynasty prescriptions (formulas created prior to 960 CE), and these classical formulas are generally prescribed without modifications. The development of Kampo in Japan arose through the work of contemporary physicians with a great mastery of traditional theory and pathomechanisms, and the assessment of biomedical diseases through the lens of traditional theory has provided Japanese practitioners with an advanced method of prescribing classical formulas based on modern disease categories. However, the Japanese method of using medicinals has branched considerably from the Chinese prescribing techniques familiar to most Westerners, and true application of Kampo therapies requires a depth of study that is well beyond the scope of this paper and the experience of this author. In mainland China, granules are not used as commonly as home decoctions or decoctions prepared by pharmacies. Many pharmacies and hospitals use extraction machines that are similar to large pressure cookers; the extraction machine cooks 320 packs of the customized decoction, which is then pumped into a paired packaging machine that dispenses the liquid in vacuum-sealed plastic retort packages. The widespread use of this technology in mainland China and Korea has caused granule powders to be less dominant in the marketplace in these areas. Most Chinese hospitals only stock granules in the form of single extracts; whole formulas are less commonly used and are rarely combined together. In Taiwan, granules dominate the market, owing largely to their convenience and integration with the national insurance system. All major hospitals and clinics use granules, and large institutions purchase granules in bulk direct from the manufacturers. However, the most striking feature of Taiwanese prescriptions is the tendency for practitioners to compound entire formulas together. Generally, a prescription is made by taking a base formula and augmenting it with single herb additions; however, it is extremely common for practitioners to prescribe several whole formulas together, often complemented with single herb additions. When compounding whole formulas, the ratio and principles of the individual formulas becomes extremely important and whole formulas are often added as though they were an additional single herb. This method of use requires a strong mastery of formula ingredients and principles, and can appear paradoxical to practitioners unversed in the Taiwanese prescribing system. Because the Taiwanese system of using granules is well-developed and highly relevant to the general prescribing methods used in Western countries, the issues and approaches seen in Taiwan form a major aspect of this article. 2. Issues Surrounding the Clinical Use of Granules One of the key issues surrounding the use of granules is dosage. Practitioners should understand how to correlate the doses of raw herbal products with prepared concentrates, but sadly this information is often absent from the product labels for granules and other

concentrated products sold in Western nations. As an example, Taiwanese granules make up the majority of granule products on the US domestic market; although the labels on the Taiwanese version of these products clearly express the precise mathematical relationship of the powder to the crude drugs, this important data is omitted from the exact same products when they are sold in the US. Inadequate practitioner education on granule dosage, as well as an insufficient demand for transparency on the part of the practitioners who prescribe these medicines, has resulted in an unacceptable lack of practitioner clarity regarding the actual quantity of medicine that is prescribed on a daily basis. Indeed, very few practitioners are aware that the extraction ratio is often different for every individual product, and the vast majority of practitioners dispense these products without any accurate means of estimating the actual dosage of crude drugs that is delivered in any given dose. The extraction ratio for any given product has a considerable range of variation. Most granule products made in Taiwan vary between a 4:1 extraction ratio and a 6:1 extraction ratio, although some products such as gelatins and minerals are not concentrated at all. Furthermore, some products vary significantly from company to company. As mentioned above, there is always precise information available on the extraction ratio of any particular product, but nearly all of the companies remove the extraction ratio information from their domestic labels when exporting to the US market. For example, the Taiwanese label will often say something like: one gram of granule extract contains 0.6 g of huang bai (Phellodendri Cortex) concentrate (equivalent to 4.2 g of crude drug yielding 0.6 g of extract, for a 7:1 concentration), mixed with 0.4 g of powdered raw huang bai (Phellodendri Cortex), yielding a final extraction ratio of 4.6:1. The US label of the exact same product typically just reads proprietary blend of huang bai (Phellodendri Cortex) extract and powder, 1 g. This non-transparent labeling protects the interests of the pharmaceutical manufacturers at the expense of the practitioners, who are left without any precise data to correlate their dose conversion process. If problems arise, many practitioners are so poorly informed about the actual dosage dispensed that they have little legal defense and appear irresponsible in the eyes of the mainstream scientific community. (It should be noted that the granule products used in research are generally commissioned by hospitals so that they are customized and produced in a single lot; this allows for administration of exactly the same product throughout the duration of the study. Thus, there is no variation from different batches of natural products, and reference samples from the same lot can be stored and assessed as needed.) It is generally common for practitioners to prescribe granules based on an average extraction ratio of 5:1. This means that five grams of crude drug is concentrated into one gram of finished powder. Although this is a useful guideline, the precise extraction ratio varies for each product. Products with more water soluble constituents yield a lower extraction ratio, while products with fewer water soluble constituents will naturally yield a higher extraction ratio. Furthermore, inefficient extraction technology will require more crude material to produce one gram of extract, while better extraction technology will be able to produce one gram of extract from a smaller quantity of crude drug; however, this difference will actually make the concentration ratio (crude:extract) appear higher in the product created with poor equipment. Although the 5:1 rule of thumb is quite useful clinically,

it is actually a misconception to think that most of the products on the market are standardized to the exact same level. Because dosage is such a challenging issue with regards to raw conversion rates, it is worth taking note of the dosage standards seen in Asia. Even though dosing habits generally vary from region to region to begin with, the widespread use of granules in Taiwan provides a particularly insightful look into the issue of appropriate granule dosage. The national health insurance of Taiwan pays for granule doses of up to 6.0 g per dose, which are typically given TID (18g/day). Some individual practitioners dose as high as 6.0 g QID (24g/day) in acute situations, but the vast majority of prescriptions hover around 6.0 g TID (18g/day). For children or mild cases, the daily dose is typically around 4.0 g TID (12g/day). In an 18-gram total daily dose, the main formula often accounts for 1215 grams, while single herb additions are generally used at a dose of 13 grams each per day. These dose ranges come from my experiences observing multiple doctors in several different departments of Chinese medicine at Chang Gung Memorial Hospital in Taiwan; although my personal experiences may fail to encapsulate all of the islands trends, these dose ranges are widely regarded as typical. Since the government puts a cap on the quantity of granules that can be dispensed per dose in Taiwan, the ratio of medicinals within the 6.0 gram TID dose becomes important. Indiscriminately using medicinals that are weak by weight can affect the desired overall potency. For example, mild medicinals such as yi yi ren (Coicis Semen) or shan yao (Dioscoreae Rhizoma) pose a problem, since effective doses of these comparatively mild medicinals can easily throw off the ratio of the formula. If 30 grams of yi yi ren (Coicis Semen) is included in a decoction, the overall dose of the other medicinals given is unaffected. However, if the equivalent of 30 grams of yi yi ren is given in a granule prescription, up to a third of the total daily dose of 18 grams of granule powder may be taken up by the yi yi ren alone; thus, comparatively weak medicinals take up a disproportionate amount of space and dilute the more potent medicinals in the prescription. Another issue affecting the dosage of granules revolves around mineral and gelatin products, which are not concentrated. In the case of gelatins, the chief concern is that their comparatively low potency by weight can dilute the stronger elements of the formula. This is the same problem as the yi yi ren (Coicis Semen) example above; if 10 grams of gelatin is given daily in a raw prescription, giving the same 10 grams of gelatin in a granule form could take up more than half of the daily 18-gram dose. Minerals are particularly problematic. For example, the formula ma xing shi gan tang (Ephedra, Apricot Kernel, Gypsum, and Licorice Decoction) is made by decocting around 1530 grams of gypsum with apricot kernel, ephedra, and licorice. If the premade granule version of this formula is given, the medicinals will be decocted together at the factory and the end product will be similar to the end product achieved in a home decoction. However, if the four ingredients are mixed from scratch based on single herb extracts, their ratio is entirely different. Because gypsum is a mineral that cannot be concentrated, the granule form of gypsum on its own is simply the finely ground crude

mineral. Since gypsum is not particularly water soluble, the patient ingests a relatively minor amount of the actual mineral when taking it in a decoction, even if 30 grams or more is used in the decoction. However, the patient ingests a larger quantity of the mineral when swallowing it as a straight granule powder. With a generally safe mineral like shi gao (Gypsum), this issue is an unresolved dosing issue alone. Yet with a medicinal like dai zhe shi (Haematitum), which contains trace amounts of arsenic, ingesting the straight powder may actually pose toxicity issues that are minimized when the mineral is decocted. [2] While the numerous issues surrounding minerals, gelatins, and weak medicinals are widely recognized, perfect solutions remain elusive. Although it is challenging to find solutions for all of the issues that arise when switching from traditional decoction-based prescribing techniques to granule powders, it is obvious that granule powders represent a key step in the future of Chinese medicine. Affordable, portable, flexible, and potent, granules provide an excellent alternative at a time when few patients have the dedication to cook raw herbs at home. Yet the increasingly widespread use of granules in the West requires increased awareness of critical issues such as appropriate dosage. Assimilating only the technological developments in our field is not enough; we must also strive to assimilate the wider range of knowledge and experience that our Asian colleagues have accumulated through their use of these new approaches. References: [1] Dr. Feng Ye, MD/CMD. Ongoing personal communication, 20032006. The coauthor of the groundbreaking Practical Dictionary of Chinese Medicine and the leading authority guiding the exceptional English-language Shang Han Lun by Paradigm Publications, Dr. Feng is widely regarded by his peers as one of the greatest thinkers in the world of Chinese medicine today. While the content of this article is derived from a synthesis of dozens of conversations with a variety of Taiwanese doctors at Chang Gung Memorial Hospital in Taiwan, Dr. Feng was an inspirational source and a fountain of knowledge for much of the information. [2] Dr. Chang Hen-Hong, MD/CMD, Vice-Superintendent of the Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital. Personal communication, 2005. Dr. Chang is an internationally renowned leader in the field of Chinese medicine, and he heads up the TCM department of one of the most sophisticated hospitals for integrative medicine in the world today. His invaluable experience contributed significantly to the discussions on dosage and other challenging issues. At present, no texts exist that adequately discuss the issues of modern granule use, even in the Chinese world. As a result, many people learn by observing their teachers and by discussing clinical approaches and outcomes. To learn more about these issues, I pursued the topic with many individuals and visited a number of factories. In the process, I learned a great deal from Andy Ellis, Xie Jia-Rong, and many others. (Originally published in the 2008 Thieme Almanac, published by Thieme International.) Article written by Eric Brand.