Chemistry: analytical and immunological testing – Peptide – protein or amino acid
Reexamination Certificate
2001-09-21
2004-10-19
Gakh, Yelena G. (Department: 1743)
Chemistry: analytical and immunological testing
Peptide, protein or amino acid
C436S173000
Reexamination Certificate
active
06806090
ABSTRACT:
The present invention relates to the use of NMR spectroscopy and biological profiling, in combination with computer-based statistical procedures, in the standardisation and quality control of medicinal plant materials.
Many societies around the world have developed, through the centuries, a system of traditional medicine relying largely on the use of plants and herbs as therapeutic substances. As used herein, the term “plant” encompasses plants, including herbs, and fungi.
In recent years there has been a significant growth of interest amongst the general public in the direct use of plants and plant extracts as health modifying agents, for instance
Panax ginseng, Allium sativum
(garlic),
Ginkgo biloba, Hypericum perforatum
(St John's wort),
Echinacea angustifolia
and
Aloe vera
. These are currently available on the market as herbal products and dietary supplements and annual sales of these products worldwide currently run to tens of billions of dollars. In spite of this marketing potential the mainstream pharmaceutical industry has not so far directed its attention to the development of medicinal products derived from plants. This is due in part to problems associated with the complex nature and inherent non-uniformity of plant materials, including the lack of an established system by which drug regulatory approval for such products can be secured.
The materials used in herbal and plant based medicine are usually whole plants, parts of plants or extracts of plants or fungi. Since plant and fungal materials contain many different chemical components the materials are, by definition, complex mixtures. This makes it very difficult to standardize and control the quality of the materials. Many of the remedies employed in traditional Chinese medicine and Ayurvedic medicine mentioned above are mixtures of two or more plant-based components. They are therefore effectively mixtures of mixtures and thus even more difficult to analyse than herbal remedies based on a single plant material. Furthermore, the recipes and methods of manufacture used for such remedies frequently remain undisclosed. These factors make it very difficult to ensure that two samples of a given remedy, obtained from disparate sources and ostensibly identical, do in fact contain the same mixture of ingredients. This problem, which leads to difficulties in controlling the quality of such materials, has so far limited the acceptability of Eastern herbal remedies to Western herbal practitioners.
The plants used in the practice of herbal medicine are frequently unavailable locally and therefore need to be obtained from sources which are remote from the end user. However, the supply of such plants from remote locations can be erratic and inaccurate, particularly because no detailed monographs including identity and quality standards exist for many such plants. The complex mixture of ingredients found in medicinal plants will in any event vary widely in type and concentration depending on many factors including the botanical origin, the location where the plant is grown, the time of year when the plant is harvested, the conditions under which the material is stored and processed and the extraction procedure used. When these plants are in turn mixed with other plants, for instance according to traditional Chinese herbal recipes, there is considerable scope for variability in the resulting product.
It is virtually impossible at present to provide any assurance that samples of a given plant material obtained from disparate sources will possess a uniform identity and biological activity. The present invention addresses this problem by providing a means of standardising a medicinal plant material. The approach takes account of the totality of the components of the plant material without demanding any inquiry into the intrinsic nature of either the components themselves or the plant's biochemistry. It involves interrogating the consistency of a plant material on both a chemical level and a biological level.
Thus the process of the present invention provides a means of defining a standard for a given medicinal plant material on the basis of a known sample of the material which possesses the particular property desired for the standard. A specification for the standard is established by submitting the known sample to (a) a combination of NMR spectroscopy and a computer-based pattern recognition technique and (b) one or more biological profiling techniques, and defining the results thus obtained as the standard specification. Subsequent “candidate” samples of the said plant material can then be tested for compliance with the standard. They can be accepted or rejected depending on whether they give analytical results which fall within or outside either part or all of the established specification.
The present invention accordingly provides a process for establishing a standard specification for a medicinal plant material, the process comprising:
(i) preparing a test solution or test extract of a sample of the medicinal plant material which is known to possess the or each property desired for the standard;
(ii) submitting the said solution or extract to two or more analytical methods including (a) a combination of NMR spectroscopy and a computer-based pattern recognition technique, and (b) one or more biological profiling techniques;
(iii) obtaining results from the analytical methods used in step (ii); and
(iv) defining a standard specification for the said plant material on the basis of the results obtained in step (iii).
The standard specification resulting from step (iv) is thus based on the results of NMR spectroscopy and computer-based pattern recognition as well as on the results of one or more biological profiling techniques. However, when candidate samples of the medicinal plant material are tested for compliance with the standard they need not all be submitted to both the NMR spectroscopic analysis and the biological profiling. Rather, all candidate samples are submitted to NMR spectroscopy and pattern recognition whilst only selected candidate samples, for instance taken periodically from batches of the medicinal plant material, are tested for compliance with the biological profiling aspect of the standard specification. The purpose of this is to rely principally on the analytical method which is best suited to convenient and fast operation on a high-throughput scale. This is the NMR spectroscopic and pattern recognition analysis. The biological techniques are typically used on a random basis for validation and reinforcement of the decisions being made to accept or reject the candidate samples on the basis of the NMR spectroscopic and pattern recognition results.
Accordingly the invention further provides a process for providing a sample of a medicinal plant material, which sample complies with a previously defined standard specification for that plant material, the process comprising:
(i′) preparing a test solution or test extract of a candidate sample of the medicinal plant material;
(ii′) submitting the said solution or extract to analysis by a combination of NMR spectroscopy and a computer-based pattern recognition technique;
(iii′) obtaining results from the analysis of step (ii′); and
(iv′) selecting the candidate sample if the results obtained in step (iii′) comply with the standard specification for the said material established in step (iv) of the process above.
This process is conveniently carried out on a high-throughput batch scale. Candidate samples are taken from batches of the same plant material and submitted to steps (i′) to (iv′). When the candidate sample is selected for submission to biological profiling in addition to the NMR spectroscopic and pattern recognition analysis the above step (iv′) is replaced by the following steps:
(iv′a) submitting the solution or extract prepared in step (i′) to one or more biological profiling techniques;
(iv′b) obtaining results from the or each technique used in step (iv′a)
Dunn Michael John
Holmes Elaine
Hylands Peter John
Nicholson Jeremy Kirk
Gakh Yelena G.
Nixon & Vanderhye P.C.
Oxford Natural Products PLC
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