Stable extract of Hypericum perforatum L.,process for...

Details Stable extract of Hypericum perforatum L.,process for... Stable extract of Hypericum perforatum L.,process for...

1998-05-14

2001-08-28

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

Reexamination Certificate

active

06280736

ABSTRACT:

It is proved by pharmacological and clinical trials that extracts of St. John's wort (extracts of Hypericum) can be successfully used in case of light to moderately severe depressions. The mild anti-depressive overall effect could not be exactly assigned to one or several components; cf J. Hölzl, S. Sattler and H. Schütt, Johanniskraut: Eine Alternative zu synthetischen Antidepressiva (St. Johns wort: an alternative to synthetic antidepressants),
Pharmazeutische Zeitung
, No. 46, 139. Jahrgang, 17. November 1994, pages 3959-3977. However, recently there are stronger hints that Hyperforin provides a considerable contribution to achieve effectiveness (EP-A-0 599 307).
The crude herbal drug consists of the aerial parts of
Hypericum perforatum L
. The components of
Hypericum perforatum L
. are among others Hypericin and Hyperforin; cf. J. Hölzl et al., see above.
The preparation of extracts of Hypericum with an enriched content of Hypericin is described in DE-PS- 1 569 849 as well as in S. Niesel and H. Schilcher in
Arch. Pharm
., Vol. 323 (1990), page 755.
From R. Berghöfer and J. Hölzl,
Deutsche Apothekerzeitung
, Vol. 126, No. 47 (1986) pages 2569-2573, it is known that Hyperforin in extracts from stored crude herbal drugs is already completely degraded after one week whilst it should be more stable in the extract of fresh plants. These authors assume that fresh plants contain a stabilizer for Hyperforin.
J. Hölzl et al.,
Planta Med
., Vol. 55 (1989) pages 601-602 report about Hypericum oil and assume a correlation between the concentration of Hypericin and the peroxide value. Hypericum oil products exposed to the sun light show different peroxide values. But according to J. Hölzl et al., there is no relation between the peroxide value and the concentration of Hypericin.
P. Maisenbacher and K.-A. Kovar report in
Planta Med
., Vol. 58, (1992), pages 351 to 354 about the stability of Hypericum oil. This oil also contained Hyperforin which was degraded within a few weeks.
From EP-A- 0 599 307 (corresponding to DE-OS 4 239 959) extracts of Hypericum and processes for its preparation are known which contain as less as possible Hypericin and similar photosensitising compounds but nevertheless show the effectivity that was formerly thought to result from Hypericin. The effectivity can be explained by the presence of Hyperforin.
Furthermore, it is known to prepare Hypericum oil (oil of St. John's wort; Oleum hyperici) by extraction of crushed (mashed) fresh flowers of St. John's wort with a fatty oil such as olive oil, soya-bean oil, wheat germ oil or sunflower seed oil. Hypericum oil contains variable amounts of Hyperforin and is useful for the topical treatment of wounds, in particular burns and abrasion; cf. P. Maisenbacher and K.-A. Kovar,
Planta Med
., Vol. 58 (1992), pages 351-354 and J. Hölzl, L. Demisch and S. Stock,
Planta Med
., Vol. 55 (1989), pages 601-602.
As well in the drug as in conventional extracts of Hypericum the content of Hyperforin decreases dramatically until the disappearance of the substance within a few months on conventional storage; cf Ph.D. thesis of P. Maisenbacher, Tübingen 1991 and the Ph.D. thesis of R. Berghöfer, Marburg /L. 1987. In earlier experiments with oily extracts of Hypericum the stability of compositions containing Hyperforin could only be improved in a better way by storage under Argon; cf. Ph.D. thesis of P. Maisenbacher, see above. A stabilisation with anti-oxidants such as butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA) was not achieved in these extracts. Moreover, conventional anti-oxidants such as Oxynex LM and Oxynex 2004 do also not improve the stability. In case of Hypericum oil the best stability is achieved (according to P. Maisenbacher's Ph.D. thesis) by use of octyldodecanol (Eutanol G) as an extraction agent.; cf see P. Maisenbacher's Ph.D. thesis, pages 151-154.
Extracts of Hypericum containing Hyperforin can be prepared with pharmaceutically conventional inorganic or organic solvents or mixtures thereof (P. List and P. C. Schmidt, Technologie pflanzlicher Arzneizubereitungen, Wissensch. Verlagsgesellschaft mbH, Stuttgart, 1984).
Conventional aqueous ethanolic extracts of Hypericum and finished pharmaceutical compositions prepared thereof usually contain less than about 1% Hyperforin (based on the extract). After the storage the value obviously decreases and moves towards zero depending on the individual storage conditions. One assumes that processes of oxidation are responsible for the degradation of the Hyperforin in the crude herbal drug and the extract.
The technical problem of the present invention is to provide improved Hyperforin-containing stabilized extracts of
Hypericum perforatum L
. (St. John's wort) in which the Hyperforin remains stable over a long period of time. It is a further technical problem of the invention to provide a process for the preparation of these stabilized extracts as well as to provide pharmaceutical compositions containing these stabilized extracts in which the Hyperforin content also remains stable.
According to the present invention these technical problems are solved by extracts according to claims
1
to
8
, by the process according to claims
9
to
21
as well as by the pharmaceutical composition according to claim
22
.
The present invention is based inter alia on the unexpected result that an extract of Hypericum with certain anti-oxidant and/or oxygen binding stabilizers or reducing agents, which are able to degrade oxidants such as radicals, peroxides, atmospheric oxygen etc. and/or to inhibit the degradation of Hyperforin, and optionally carrying out the extraction under inert gas such as nitrogen and/or exclusion of light and/or with a solvent with a highly reduced oxygen content, is essentially longer stable than an untreated extract of Hypericum. This extract can be derived contrary to the obsevations made by R. Berghöfer and J. Hölzl (see above) from a dried and stored crude herbal drug.
A solvent with a highly reduced oxygen content can be prepared by physical treatment such as rinsing with an inert gas such as nitrogen. In case the extract of Hypericum is preserved or stabilized according to the present invention, in particular by addition of an anti-oxidant and preferably by exclusion of light and atmospheric oxygen, then the Hyperforin in this extract remains essentially stable for a long time. The protection against light and atmospheric oxygen can also be achieved by a corresponding pharmaceutical formulation. In a preferred embodiment of the process of the present invention for the preparation of the stabilized extracts the fresh or preferably dried drug of St. John's wort is extracted with aqueous methanol or ethanol, the oxygen content of which was highly reduced by physical treatment. To the extract solution an anti-oxidant agent as a stabilizer is added and dissolved therein because of possibly present oxidants. Further examples for preferred solvents for the extraction of St. John's wort comprise the group of alkanes with low boiling points having about 5 to 8 carbon atoms such as pentanes, hexanes and heptanes, in particular n-heptane, and liquid or supercritical carbon dioxide The term “aqueous methanol or ethanol” denotes methanol or ethanol having a water content of preferably up to about 40% by volume.
Particular examples for preferred anti-oxidant stabilizers or anti-oxidant agents are pharmacologically acceptable substances, able to inhibit the degradation of Hyperforin and/or to reduce oxidants in the extract or the pharmaceutical composition. Particular examples are substances selected from the group of organic thiol compounds, such as cysteine and glutathione, as well as ascorbic acid and derivates thereof such as the fatty acid esters of ascorbic acid, such as the myristate, palmitate and stearate.
The anti-oxidant stabilizers are added to the extract solution of Hypericum in an amount sufficient to stabilize the Hyperforin. In general concentrations from 0.01 to 5% anti-oxidant stabilizer based o

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