Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1999-04-15
2001-05-29
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C514S732000, C514S738000
Reexamination Certificate
active
06238671
ABSTRACT:
The present invention relates to a process for the gentle recovery of extract fractions of Hypericum (St. John's wort) having a high portion of active and/or standard substances, pharmaceutical preparations containing the same and their use for the therapy of depression.
St. John's wort,
Hypericum perforatum
L., is a plant drug which has been used for a long time for treating psychovegetative disorders (Daunderer, “Klinische Toxikologie”, 81, Suppl. March 1994). In addition,
Hypericum perforatum
is used to treat photosensitive dermatoses, functional and arteriosclerotic depression, conditions after
Commotio cerebri
and
Commotio spinalis
(Roth, Daunderer “Giftliste” (List of Toxic Substances), 60, Suppl. October 1994).
Oleum hyperici
is used to treat burns and wounds. The antimicrobial activity of hypericum against staphylococci and streptococci (Roth, Daunderer, see above) or viruses (EP-A-0 256 452) is also known. The dried leaves collected just before or during bloom or aqueous or alcoholic—especially ethanolic—full extracts or full dry extracts are used as a drug, for example Helarium® Hypericum.
In detail, about fifteen active ingredients have been isolated from hypericum, the most important of which are hypericin, pseudohypericin, hyperforin, a prenylated phloroglucin, adhyperforin and hyperosid.
So far, the anti-depressive effect has been attributed to hypericin as the active ingredient which determines effectiveness (cf. Roth, Daunderer as above; Daunderer, as above). It was assumed that the mechanism of action is based on the inhibition of MAO (monoamino oxidase) or COMT (catechol-O-methyl transferase). Since no such effect was confirmed upon administration of free hypericin, a dispute has arisen in literature whether the effect may not be due to hyperforin as an additional active ingredient after all (cf. EP-A-0 599 307, for example).
So far, full dry extracts of hypericum and a dry extract enriched in hyperforin and produced according to the process of EP-A-0 599 307 have been available commercially. With regard to effect, all these preparations are equivalent to tricyclic anti-depressive drugs, but have considerably reduced side effects, especially with regard to tolerance, reaction speed, fatigue and the ability to drive. In comparison with tricyclic anti-depressive drugs, they therefore constitute a far more easily tolerable therapeutic agent with the same effect. Patient compliance with this product is far better.
Hypericum extracts containing hypericin and/or hyperforin or the relevant dry extracts may be prepared by various known work-up processes and drying methods. As a rule, such processes start from the full extract the composition of which is determined by the selected starting material. Control of the content of the substance is therefore determined by the selection of suitable plants or the work-up method, e.g. the selection of the extractant, since hyperforin is very sensitive and decomposes easily. Hypericin as a pure substance is obtained in accordance with DE-B-15 69 849, for example.
Unfortunately, it is not possible with prior art processes such as pure solvent extraction (DE-B-15 69 849, or DE-C-39 35 772) and two-stage extraction (EP-A-0 599 307) to recover extracts containing hypericin and/or hyperforin with a defined and adjustable content of active ingredient. Especially in order to prepare hypericin-containing extracts, the method of lipophilic extraction is used. These lipophilic extracts can be recovered by using suitable solvents (methanol, acetone, methyl ethyl ketone). In order to recover hyperforin-containing extracts, it is possible to first prepare aqueous or hydrophilic extracts which are then washed with lipophilic solvents such as DMSO or dioxane or subjected to a lipophilic solids extraction, for example on PVP or active carbon (EP-A-0 599 397 or EP-A-0 702 957).
It is a disadvantage of these processes that the more lipophilic solvent must be replaced by a solvent which is suitable for pharmaceutical applications and the recovery of the extract requires a two-stage process. In addition, varying ingredient spectres result from the variance of the plants with regard to the content of the active ingredients which may not be controlled freely, but depend on the total content of active ingredients. When preparing dry extracts according to the prior art, it is therefore not possible to control the active ingredients. This would only be permitted by selecting an additional solvent or selecting the starting plant material accordingly.
In case of the well-known simple ethanolic dry full extracts which are prepared by means of spray drying and conventional vacuum drying, it is not possible either to influence the spectrum of the contents, because the dry extract or the dry extract preparation contains all the original ingredients extracted beforehand. Controlling the spectrum of active ingredients is only possible by selecting suitable plants.
Therefore, it was the object of the invention to develop a simple and gentle extraction process, which may be controlled with regard to the content of the active ingredients (hypericin and/or hyperforin) and permits the preparation of extracts the hyperforin and hypericin contents of which are clearly defined and adjustable.
This object is solved by a process for recovering extract fractions of
Hypericum perforatum
L. comprising
a) preparing an aqueous ethanolic extract of
Hypericum perforatum
L. by known methods,
b) concentrating the extract to a predetermined degree and
c) separating the precipitate obtained in step b) from the supernatant,
steps b) and c) being repeated at least once with any supernatant from step c).
The extractant for recovery of the aqueous ethanolic extract in step a) has an ethanol content of at least 40% by volume, preferably 60 to 90% by volume and most preferably 80% by volume.
Preferably, steps b) and c) are repeated at least once, more preferably twice to four times and most preferably twice. As a result, at least 2, preferably 2 to 4 or 5 and most preferably 3 or 4 extract fractions are obtained, the higher number of extract fractions being obtained, if the concentration in step b) in the last series of steps b)/c) is not carried out to 100% so that a (residual) supernatant is obtained in addition to the precipitate.
In a preferred embodiment, the process comprises an additional step d) wherein the precipitate obtained in step c) is redissolved. Redissolution is preferably carried out in a water/ethanol mixture having a higher ethanol content than the original extractant, for example a mixing ratio of ethanol/water from 95 to 50/5 to 50, more preferably 90 to 80/20 to 10 (v/v). To refine the separation, the redissolved precipitates may once again be subjected to one or several series of steps b) to d) and thus refractionated.
Preferably, precipitates or fractions are recovered which have degrees of concentration (calculated as amount of redistillation product (g): starting amount (g)) of 0 to 40-50%, 40-50 to 60-75% and 60-75 to 100%. If a finer separation is desired, it goes without saying that additional fractions corresponding to degrees of concentration of 0-40%, 40-50%, 50-65%, 65-75% and 75-85% may be collected. Additional separation steps are also feasible.
Owing to its more lipophilic character, hyperforin first precipitates at degrees of concentration of approx. 50% upon thickening by evaporation or concentration while hypericin as the more hydrophilic substance remains in solution up to a degree of concentration of approx. 50%. Above degrees of concentration of approx. 50%, the hypericin content of the precipitate rises significantly, and fractions in the precipitate enriched in hypericin in comparison with the full extract are obtained at degrees of concentration of 80 to 85%. In comparison, the precipitate initially obtained is enriched in hyperforin in comparison with the full extract.
Therefore, it is possible to obtain drugs enriched or depleted in hyperforin and hypericin, respectively, by selecting the pertinent degrees of concen
Bionorica Arzneimittel GmbH
Ratner & Prestia
Tate Christopher R.
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