Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2002-02-14
2004-01-13
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C424S773000, C424S777000, C514S861000, C514S863000, C514S885000, C514S886000, C514S887000
Reexamination Certificate
active
06676975
ABSTRACT:
The invention relates to materials derived from traditional Chinese herbs and to pharmaceutical compositions containing them which are useful in the treatment of atopic disease, in particular atopic eczema, and in treatment of other skin disorders such as non-atopic eczema and psoriasis.
It is to be understood that by the term Chinese herb is meant any herb which is used by traditional medicine practitioners, usually, but not exclusively, Chinese.
Practitioners of traditional Chinese medicine treat diseases using a system of anatomy and diagnosis totally different from that used in the west. The remedies prescribed are usually a plurality of Chinese herbs which are prepared for administration by the traditional method of decoction i.e. boiling the herbs in water. The herbs are removed and the water maintained for oral, parenteral or topical administration to the patient as appropriate.
Prescriptions for use in this kind of therapy may call for the use of ten or more herbs in combination and traditional Chinese medicine teaches that all of the herbs are necessary to achieve a balanced prescription. A prescription is seen as a balanced whole containing the hierarchy of herbs to which are attributed different functions in treating different manifestations and symptoms of disease.
The identification of herbs which have acceptable clinical activity for any particular human disease while, at the same time having low toxicity, has been made by observation and trial and error over very many years. In some cases prescriptions of traditional Chinese herbs can effectively treat diseases which are not well served by Western monotherapy.
Diseases which appear to respond to the use of a plurality of Chinese herbs are those where there is obscure and complex causality. A particular example is atopic eczema, in which there is chronic inflammation of the skin which is initiated and maintained by a number of different mediators, only some of which are known. Some are related to antigen-antibody reactions. Many others are suspected but not yet defined. Single therapeutic agents like non-steroidal anti-inflammatory drugs which interact with specific inflammatory mediators such as prostaglandins are ineffective in severe atopic eczema. On the other hand corticosteroids have multiple pharmacodynamic actions and are effective in eczema. It appears therefore that the treatment of severe atopic eczema requires a simultaneous attack on a number of pathological lesions, probably related to the immune process in cells and body fluids. While corticosteroids and some immune suppressants have the required broad spectrum of activity for such an attack, their use is limited because of their toxicity. Traditional Chinese herbal remedies known for the treatment of eczema would seem to possess the necessary activity of corticosteroids and immune suppressants but not their toxicity.
A prescription of the Chinese herbs with one selected from each of the following herbs and their Pin yin equivalents or designated by their Materia Medica names:—Radix Ledebouriella, Fructus Tribuli, Herba Potentilla chinensis, Caulis Clematis armandii, Radix Rehmannia, Radix Glycyrrhiza, Radix Paeonia rubra, Cortex Dictamni radicis, Herba Lopatheri and Spika Schizonepetae has been used to effectively treat atopic eczema and psoriasis. The clinical efficacy of such a prescription in children with atopic eczema is described by Sheehan et al in British Journal of Dermatology (1992) 126 pp 179-184 and in adults, again by Sheehan et al, in The Lancet (1992) July 4th pp 13-17. A particular method for preparing an extract of those same 10 herbs for use in treating atopic eczema and other inflammatory diseases of the skin is described in GB-A-2254783.
While a decoction of the above-described 10 herbs is known to be effective, the use of a complex prescription containing a plurality of herbs is expensive and it is therefore desirable to simplify the prescription if this can be done without compromising activity and/or safety. It would also be preferable to limit any prescription to herbs which might be grown in the UK or Europe rather than relying on import from China. Thus many attempts have been made to identify the active principle or principles in prescriptions of traditional Chinese medicines. In the case of eczema however this has proved difficult because hitherto there has been no validated animal or in vitro model for the disease which could be used to identify clinical activity in fractions or pure substances prepared from the crude herbs.
Now however an in vitro assay has been developed which appears to be predictive of clinical efficacy in atopic eczema and other atopic diseases and this has allowed the present inventors to detect active components in freeze-dried decoctions (hereinafter referred to as PSE222) of the 10 herbs listed above.
Although traditional Chinese wisdom dictates that a plurality of herbs is required, the use of this in vitro method and confirmation by in vivo clinical experiments has shown that the desired clinical effect can be reproduced by a subset of the 10 herbs and by individual components within them. Furthermore, the method has also permitted identification of components in PSE222 which may initiate worsening of the atopic condition and which it is desirable to remove from any extract for pharmaceutical use.
The in vitro test for efficacy is based on the observation that in atopic disease and in particular atopic eczema, skin cells and monocytes from human peripheral blood express a cell surface marker antigen CD23 and that the expression of CD23 is inhibited or reduced on successful treatment of the eczema. (see Takigawa et al, Clin. Exp. Immunol. (1991) 84 pp 275-282). CD23 expression can also be induced in vitro in human monocytes by exposure to the cytokine interleukin 4 (IL4) and in parallel with the in vivo situation described by Takigawa above the induction is inhibited by compounds known to be useful in atopic disease. These observations therefore provide the basis for a simple in vitro assay in which monocytes prepared from human peripheral blood are brought into contact simultaneously with IL4 and the active agent to be tested. The amount of CD23 expression is measured using labelled monoclonal antibodies to CD23 and any effect expressed as a percentage inhibition of CD23 expression compared to a control in which saline or a placebo preparation of herbs replaces the test material. That significant inhibition of CD23 expression in this in vitro test is predictive of clinical efficacy is demonstrated by the fact that the extract PSE222, prepared from the 10 herbs listed above which have been successfully used clinically for atopic eczema, shows an inhibition of CD23 expression in the assay of 50 to 60%.
Using the above assay the present inventors have identified components in PSE222 suitable for clinical use in atopic disease generally and also in the treatment of particular skin diseases such as non-atopic eczema and psoriasis.
Thus in accordance with a first aspect of the invention there is provided a material suitable for the treatment of atopic disease, non-atopic eczema or psoriasis which can be extracted from a freeze-dried decoction of a mixture comprising the following Chinese herbs:
Radix Ledebouriella
Fructus Tribuli
Herba Potentilla chinensis
Caulis Clematis armandii
Radix Rehmannia
Radix Glycyrrhiza
Radix Paeonia rubra
Cortex Dictamni radicis
Herba Lopatheri
Spika Schizonepetae
said material comprising one or more of those components present in the freeze-dried decoction which run with Rf values in the ranges 0.00 to 0.100, 0.167 to 0.300, 0.400 to 0.533, 0.700 to 0.833 or 0.900 to 0.967 if said freeze-dried decoction is diluted in aqueous solution and subjected to chromatography on a Whatman 2 cms×55 cms×3 mm cellulose strip for 10 hours using a solvent mixture of butanol, ethanol and water in the proportions 4:1:1.
Preferably said material comprises one or more of those components present in the freeze-dried decoction which run with Rf values in the range 0.00 to 0.10
Brostoff Jonathan
Latchman Yvette
Whittle Brian Anthony
Bacon & Thomas
Phytotech Limited
Tate Christopher R.
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