Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2001-02-23
2003-04-22
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C514S861000, C514S863000
Reexamination Certificate
active
06551626
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns a pharmaceutical composition based on petasites extract without hepatotoxic, carcinogenic, cytostatic and/or mutagenic effect, as well as its use and a method for its production.
Petasites extracts are isolated from the roots of the butterbur and have a spasmolytic and analgesic effect. This effect of butterbur was already known to Hippocrates, Galen and Paracelsus. The pharmaceutical preparations from petasites extract used now are viscous extracts from Rhizoma Petasites, i.e., extracts from the rootstock of the butterbur, which have an unpleasant, bitter taste, are not readily resorbable and thus have a slightly delayed pharmaceutical effect following administration.
The butterbur also contains eremophilane and pyrrolizidine alkaloids, in addition to other sesquiterpenes. The pyrrolizidine basic structure is common to the pyrrolizidine alkaloids. They are distributed worldwide in higher plants. Pyrrolizidine alkaloids and their N-oxides are found in the genus Petasites, among others. The pyrrolizidine alkaloids contained in the plant parts of the genus Petasites are characterized by significant hepatotoxic, carcinogenic and mutagenic, but also cytostatic properties. The toxicity of the pyrrolizidine alkaloids is connected with specific structural groups that have the following structural features:
double bonds in the 1,2-position of the pyrrolizidine ring,
esterifications of at least the primary hydroxymethyl group with a C
5
or C
6
carboxylic acid,
branching of the alkyl side chain with at least one of the necinic acids.
The cyclic diesters have the highest toxicity and carcinogenicity. The pyrrolizidine alkaloids are quickly resorbed after peroral intake, their N-oxides only after reduction by intestinal flora. On metabolism in the liver, the pyrrolizidine alkaloids are converted to very toxic pyrrole derivatives by oxidases with mixed functionality. These are very reactive and, under physiological conditions, alkylate the nucleophilic groups of DNA, like amino, thiol and hydroxy groups.
Pyrrolizidine alkaloid-containing medicinal plants have long been used in phytotherapy as natural drugs. Since the Federal Health Office (BGA) has classified all medicinal plants and their preparations containing toxic pyrrolizidine alkaloids as health hazards and potentially carcinogenic, intensive work was conducted to produce pharmaceutical petasites extracts that have a significantly reduced content of pyrrolizidine alkaloids.
Thus, methods are described in DE 39 10 831, DE 41 11 141, DE 41 41 749, with which the content of pyrrolizidine alkaloids in the extract can be reduced to less than 5 ppm, in the best case even below 0.1 ppm, but a truly pyrrolizidine alkaloid-free petasites extract cannot be obtained according to these methods.
The task of the present invention is to produce petasites extracts without hepatotoxic, carcinogenic, cytostatic and/or mutagenic effect.
Another task of the invention is to provide a method for production of petasites extracts without hepatotoxic, carcinogenic, cytostatic and/or mutagenic effect.
SUMMARY OF THE INVENTION
Another task of the invention is to produce petasites preparations without hepatotoxic, carcinogenic, cytostatic and/or mutagenic effect with a rapid and/or improved action.
The task of the present invention is solved by a pharmaceutical composition based on petasites extract in which the petasites extract is recovered from the plant and/or plant parts of the genus Petasites, the petasites extract is free of pyrrolizidine alkaloids, and in which magnesium and/or other pharmaceutically and/or physiologically active substances are optionally added to this pharmaceutical composition.
The task of the invention related to the process is solved by an extraction method in which the crude extract is subjected to subsequent final treatment in an aqueous medium with a pH value <7, preferably ≦4.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Petasites extract in the prior art has thus far been recovered from the rootstock of butterbur. It has now proven advantageous to recover the extract from plants and/or plant parts of
Petasites hybridus, Petasites albus, Petasites japonicus, Petasites paradoxus
and/or
Petasites spurius,
in which the underground plant parts are preferably used to produce the extract. Use of not only the underground plant parts to produce the extract, but also other plant parts has the advantage that a significantly higher yield of petasites extract is obtained, from to the entire plant.
In addition to the already known destraction methods with supercritical CO
2
, as described, for example, in EP 0 392 504 and EP 0 547 465, petasites extracts according to the invention can also be produced with other destraction agents. Because of the temperature sensitivity of the natural extracts, solvents are chosen that can be converted to the supercritical state at temperatures below 100° C., preferably at ≦50° C., and have sufficient solvent capacity for lipophilic petasites active principles. Appropriate gases include ethylene (critical temperature 9.95° C.) and ethane (critical temperature 32.25° C.). Appropriate conditions for destraction of petasin from butterbur plant parts with ethylene and ethane lie at pressures of 1-50 MPa, preferably 8-30 MPa, and temperatures of 10-50° C. The crude petasites extracts recovered according to these methods contain up to 30% water, depending on the degree of preliminary drying of the initial material, which must then be separated. The crude extract can optionally be treated with a one- to ten-fold quantity of water, preferably with a pH value ≦7, and then dried by usual methods.
It was found that, in the ordinary destraction process, especially during destraction of petasites with supercritical CO
2
, the water content in the overall system plays a decisive role in separation of pyrrolizidine alkaloids. Deliberate enrichment of the extracted product with water before destraction leads to extracts with increased water contents of up to 50%, which exhibit better and more rapid phase separation and already yield extracts with significantly lower pyrrolizidine content right after separation of the aqueous phase. The extracted product for this purpose is brought to a total moisture content of 10-40 wt. %, preferably 15-30 wt. %., and especially 20-25 wt. %, before destraction by addition of water.
As an alternative, good alkaloid depletion can also be achieved by forcing water into the compressed solvent-extract mixture in the separator region of the extraction unit. For this purpose, about 10-50 wt. % water, from the amount of extract being separated, is forced into the separator device of the extraction unit before decompression of the solvent-extract mixture, and then decompressed. The extracts so obtained have pyrrolizidine alkaloid contents below 0.1 ppm after separation of the aqueous phase.
It has now also been surprisingly demonstrated that suitable crude extracts of petasites can also be obtained by extraction under subcritical conditions with gases liquefied under high pressure, instead of destraction with gases in the supercritical state.
Pressure-liquefied propane gas has proven to be particularly suitable for petasites extraction under subcritical conditions. Propane (critical temperature 97° C.) can be liquefied at room temperature under high pressure (critical pressure about 42 MPa). Ground petasites plant material is subjected to solid extraction with liquefied propane gas according to the usual methods in appropriate autoclave reactors. Here again, the deliberate enrichment of the extracted product with up to 40 wt. % water can be used to advantage for improved pyrrolizidine alkaloid separation, as well as subsequent forcing of water into the compressed propane-extract mixture.
The propane extraction method can be run in the temperature range from 15-40° C., preferably 20-30° C., and especially at room temperature. The employed extraction pressures lie in the range from 5 to 20 MPa, preferably 10 to 15 MPa
Koch Volkmar
Rittinghausen Reiner
Reed Smith LLP
Tate Christopher R.
Weber & Weber GmbH & Co. KG
Wolfson Michael I.
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