Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
2000-02-18
2001-06-05
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
Reexamination Certificate
active
06241988
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 and E. Steinegger and R. Hänsel, Pharmakognosie, 5
th
edition 1992, pages 672-674, Springer Verlag. 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 primary extracts of the crude herbal drug of St. John's wort (see examples 1-3) are known. These primary extracts are obtained by simply extracting the crude herbal drug with 96% and 60% aqueous ethanol, respectively without any precautionary measures and without any additions.
In example 1 the Hyperforin content of the [fresh] primary extract is stated to be 6.3%. In the two other examples no Hyperforin content is stated at all. We have found that such Hyperforin extracts are extremely unstable; see description, example 5, Table I. The primary extract obtained according to example 1 (comparison) by extraction of the drug with 70% aqueous ethanol contains after 13 weeks no longer any detectable amounts 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. On pages 154-155 Maisenbacher describes historical methods of preparation. The crude herbal drug is extracted with hot plant oil, sometimes under the addition of oil of turpentine. Also in this case Maisenbacher observed degradation, in particular under the influence of water. On pages 158-166 Maisenbacher describes the conditions for an optimal process of preparation. The following instructions are particularly revealing: water has to be kept out; Eutanol G should be used as extraction agent; conventional anti-oxidants provide now protection against oxidation. After an induction period of 3 weeks a steady degradation of the Hyperforines began for the olive oil extract; cf. FIGS. 7-10. Despite rinsing with inert gas a complete degradation occurred after 3 months; cf. page 160. The oil prepared by the use of Eutanol G is stable for half a year at ambient temperature under argon. At 30° C. slow degradation occurs; cf. page 161.
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 Hyperforin-containing stabilized extracts of Hypericum perforatum L. (St John's wort) in which the Hyperforin remains stable. 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 and reducing agents, which are able to degrade oxidants such as radicals, peroxides, atmospheric oxygen etc. in the extract 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 more 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 optionally by exclusion of light and atmospheric oxygen, then the Hyperforin in this extract remains essentially stable. 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 extract the fresh or preferably dried drug of St. John's wort is extracted with aqueous ethanol,
Erdelmeier Clemens
Grethlein Eckhart
Lang Friedrich
Oschmann Rainer
Stumpf Karl-Heinz
Dr. Willmar Schwabe GmbH & Co.
McDonnell & Boehnen Hulbert & Berghoff
Sarussi Steven J.
Witz Jean C.
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