Pharmaceutical Platform Technology for the Development of Natural Products

Abstract

The present invention provides a set of in vitro and in silico methodologies for predicting in vivo pharmacokinetics and pharmacodynamics of multiple components; the methodologies comprise mathematical models for solving multiple unknowns which are linearly independent and / or interacting with each other. The present invention can be applied to develop phytomedicines which contain multiple active ingredients without prior identification, isolation and purification of these components.

Description

[0001]This application is a Continuation-in-part of International App'l No. PCT / IB2008 / 001401, filed Mar. 31, 2008, which claims benefit of U.S. Ser. No. 60 / 909,018, filed Mar. 30, 2007. The entire content and disclosure of the preceding applications are incorporated by reference into this application.[0002]Throughout this application, various references are referred to and disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.BACKGROUND OF THE INVENTION[0003]Natural products have been used by the human civilization for thousands of years. Their medicinal values have been recorded throughout history. Since the advancement of pharmacology, clinical pharmacology, pharmacognosy and analytical chemistry, the active components in a natural substance were beginning to be unveiled. A good example is the discovery of acetylsalicylic acid in willow bark. Bay...

AI Technical Summary

Problems solved by technology

Although combinatorial techniques have succeeded as methods of optimizing structures, no de novo combinatorial compound approved as a drug has been identified on or before 2002.

The complexity of this area of research has been the major obstacle in natural medicine development (Williamson, 2001).

However, the activity of these ginsenosides is low and their bioavailability after oral administration is minuscule.

This approach is extremely unsuitable for the development of nature products.

For the longest time, Panax ginseng was thought to be an expensive “junk” because it has no apparent active ingredients.

However, it is difficult to substantiate the actual in vivo activity of rutin, simply because this substance is not detected in the blood stream (Hollman et al., 1997).

In pharmaceutical science terms, compounds like ligustilide lacks drug-like properties for oral administration.

Since there are permutations in arriving at the actives of an herbal extract, the complexity of delineating pharmacokinetic profiles for multi-components does appear to be prohibitive.

The advance of analytical technology may complicate this approach because the nature of components present in plasma will be different from that of the product and the number of components present could exceed that of the product because the number of potential metabolites formed could be daunting.

One could argue that only the major components needed be standardized; however, this assumption is clearly flawed because potent components present in minute quantities may be missed.

Among other shortcomings, this approach to discover biologically active components does not permit optimization of ratio and dosage of biologically active components.

While individual herbs contain mixtures of compounds, there was no attempt to address the effects of potential variability within each herb on the pharmacological outcome of the formula.

However, the active components identified using these methodologies were restricted to activity only; there was no attempt to investigate the “drug-like” properties of active components.

In the absence of an understanding of the number of components / precursors involved and their respective drug-like properties, it would be close to impossible to determine these intricate interactions in the body.

This limitation has restricted the evaluation of interactions, including synergism and antagonism.

Pharmaceutical technologies for drug discovery have not been employed extensively in the development of natural products.

However, there is no study on using physiologically based pharmacokinetic and / or pharmacodynamic models to predict the time course of active ingredients of an herbal extract in the body, nor are there any studies using the same approach to quantify the time course of a response.

No in silico methods to-date employed for drug discovery have been applied to predict pharmacokinetic and pharmacodynamic interaction of active components and their metabolites after administration of an herbal extract.

Therefore, it is not known whether the standardized ingredients are of the right amount or the appropriate ratios.

The reason is that some of these ingredients are not actually absorbed; therefore lacking “drug-like” properties.

This technology, however, has two problems: 1. it does not provide an estimate of the pharmacokinetics of ingredients and therefore, concentration-time profiles at the site of action; and 2. the cell membranes are susceptible to rupture when they are incubated with certain herbal extracts such as St.

While the technology may be useful for standardizing active components, however, these so-called active components have not been subjected to vigorous testing for in vivo testing.

In other words this technology does not provide information on the “drug-like” properties of these components.

In short, there is no method available to adequately mine the physiologically active components of an herbal substance.

It is believed, however, (while rarely demonstrated directly by experiment) that these individual ingredients, when taken together, may mutually reinforce each other synergistically.

However, existing technology does not allow stringent quality control because there have been no success in elucidating the activity of these ingredients as a group.

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