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Selective Metabolite Compound Drug Technology

SMCD

Oral Bioavailability Enhancement Technology

OBET

Selective Metabolite Compound Drug (SMCD) Platform

Selective metabolite compound product (SMCD) is a novel new drug discovery platform by means of identifying botanical drug metabolites in the body to develop new drug. The therapeutic value of traditional Chinese medicine has been widely recognized worldwide, however, it is still very difficult to emerge into the western mainstream drug market because traditional Chinese medicine is often a multi-component product without clear chemical composition and efficacy. Due to traditional Chinese medicine chemical composition of the highly complex nature, traditional Chinese medicine is not considered as the mainstream of modern Western medicine.

Panagin’s proprietary Selected Metabolite Compound Drug (SMCD) technology is a novel drug discovery platform based on the findings that –

  • 99% of ingredients in TCMs cannot be traced in blood after digestion, and those that can be traced are most likely to be responsible for the efficacy.

  • Many active components of TCM traceable in the blood are metabolites, modified and activated in the body through body’s metabolic system, including intestinal and liver metabolic systems. They have their chemical structures changed either before absorption in the intestine or after absorption in the liver, or both. Therefore, tracing the metabolites of TCM in the blood may lead to discovery of new drugs.

Theoretical basis of SMCD has the following principles: (a) currently, study of proprietary Chinese medicine is more focused on the role of the combination of herbs and the proportion of each component, as well as the claimed clinical efficacy, rather than indentifying active ingredients and their levels. The rational combination of the components can enhance the efficacy and reduce the side effects. Therefore, SMCD, a multi-compound drug, is an optimized combination of several identified active constituents with a clear mechanism of pharmacology. The synergistic actions of the combination fully play its multi-target, multi-pharmacological action of the mechanism, and its potency. (b) SMCD concept requires the active ingredients must have a clear chemical structure, can be more readily chemically identified and quantified as well as the drug product is of consistently good quality with adequate in-process control and cGMP compliance. (c) SMCD requires that the standard pharmacokinetics study of principal active ingredient can substantiate its absorption, distribution and metabolism regarding systemic exposure. In addition, advanced analytical technologies can be applied for indentifying individual active ingredient and well characterizing its biological activity, and further interpreting the relationship between function target and each active ingredient. So that can ensure the drug product is indeed "safety, efficacy, quality and potency". (d) "clinically proven efficacy is the clincher", SMCD propose to completely change the traditional Chinese medicine drug discovery process that previously regulatory approaches are more interest in preclinical studies other than human clinical studies. Clinical trials of new drugs will be focused and centered in traditional Chinese medicine drug discovery.

How can traditional Chinese medicine paradigm as an integrative and systematic therapy and the concept of combination of herbal formula be adopted to the development and modernization of Chinese herbal medicine today, it is a challenge yet to be faced. The reason is that traditional Chinese medicine including patent Chinese medicine itself, has many inherent problems, such as complex nature of composition, the active constituents not identified and quantified as well as not consistently good quality, its biological activity not well characterized, and standard pharmacokinetic measurements, such as absorption, distribution, metabolism and excretion, for active constituents may be infeasible due to the complexity of the botanical drug. The existence of these problems has greatly hampered the traditional Chinese medicine to the world. The modernization of traditional Chinese medicine should first solve the important issues and challenges.

In other words, SMCD Platform considers the body as a biological filter and converter-activator, which eliminates 99% of useless components in TCM, and then chemically converts those left into an active form. SMCD Platform traces and collects those metabolic compounds as new drug candidates. New drug developed using this approach is often a multi-compound drug which is much simpler than the original TCM formula. SMCD can be equal to, or even more efficacious and safer than the original TCM formula. SMCD is controllable in quality and compliable to GMP requirements because all the components in an SMCD are identified and characterized. SMCD might also lead to discovery of single-molecular entity drugs.

SMCD Platform is a valid approach to developing new drugs from the wealth of TCM formulae library. Key components of the SMCD technology have been filed for patent in 2004.

Oral Bioavailability Enhancement Technology OBET Platform

Oral intake is the most commonly adopted drug delivery route and almost the only route for TCMs. Absorption of medicinal ingredients into blood after oral intake is subject to many factors, such as chemical properties of the ingredients, solubility and dissolving speed, PH level and other conditions in various parts of the gastric-intestinal tract, bowel movement and emptying speed of the stomach, etc. Many natural medicinal ingredients, such as saponin and flavone families, which together account for 90% of TCM ingredients, have very low efficiency in entering blood after oral intake. It has been found that these ingredients, mostly hydrophilic, are quickly hydrolyzed and structurally modified into liposolubles under the influence of gastric acid and enzymes. Except very few metabolites processed and further converted by bacteria in the digestive tract, the majority of these liposolubles are precipitated in the gastric-intestinal fluid environment and eventually discharged from the body. Take ginsenosides, which are mostly sapoginins, for example. Bioavailability of Rb1, Rh2 and Rg1 are 1%, 3.4% and 1.9% respectively. Shenyi Capsule, a TCM extract product with ginsenoside Rg3 as its main active ingredient, was approved by Chinese SFDA in 2000 even though Rg3 level is too low to be measurable in blood.

An ideal solution to the bioavailability problem of many TCM ingredients is protection of the ingredients in their intact molecular form from effects of gastric-intestinal fluids and increasing stomach absorption as opposed to intestine absorption. Advancing absorption in the upper digestive tract minimizes the ingredients’ contact with digestive fluids and prevents the modification of the ingredients into medicinally inactive substances.

OBET includes a series of organic solvents and conditioning processes to increase the stability of ingredients in the gastric acid environment. Dosage forms designed with OBET ensure ingredients to be absorbed into blood in their intact molecular forms and primarily in the stomach rather than in the intestines. The result is a much higher bioavailability of ingredients in their medicinally active form and greatly enhancement of the pharmacological effects. Key OBET techniques have already been applied for patent.