Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from hypericum
Reexamination Certificate
2000-11-30
2002-08-06
Lilling, Herbert J. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from hypericum
Reexamination Certificate
active
06428820
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for preparing an extract of
Hypericum perforatum
(St. Johns wort) by fractioning water-alcohol, alcohol, or acetone extracts of the plant with esters of water-immiscible C
1
-C
5
alcohols. The invention also relates to formulations containing the extract.
BACKGROUND OF THE INVENTION
Flowering tops of
Hypericum perforatum
contain a number of classes of structurally different substances that can act directly or indirectly on the central nervous system.
Hypericum perforatum
is known to contain active compounds such as hypericin, hyperforin, and dimeric flavones that exert antidepressive and anxiolytic activities on animals and humans. The mechanisms of action of these compounds are different and include for example anti-MAO action, action on serotonin release, and activity on benzodiazepine receptors.
The activity of hypericin has been extensively discussed in the literature and includes conflicting reports on the activity of hypericin. The controversial antidepressive activity of hypericin, however, was recently confirmed in pharmacological models in vivo. It has been proven that hypericin is active when administered in the presence of dimeric procyanidins contained in the extracts of
Hypericum perforatum
(45
th
Annual Congress of the Society for Medicinal Plant Research, Sep. 7th-12th, 1997, Regensburg, Germany, V. Butterwecke et al., Abstract No. 011).
Hyperforin has recently been the subject of numerous studies that have established its role as antidepressant. Studies carried out by the Applicant have proven that hyperforin has serotonin-mimetic activity.
Other components of
Hypericum perforatum
that are considered important are dimeric flavones derived from apigenin which are considered to be natural benzodiazepines, as reported in “Naturally Occurring Benzodiazepines Structure, Distribution and Function”, I. lzquierdo and J. Medicine Eds., 1993, page 33.
These components, and particularly hyperforin, are not stable under typical extraction conditions and storage conditions. WO 97/13489 (Schwabe) discloses that the hyperforin content of a water-alcohol extract of St.-John's-wort falls to almost zero after only a few weeks. According to WO 97/13489, in order to obtain stable extracts with a constant hyperforin content it is necessary to perform the extraction, purification and storage in the presence of antioxidants such as vitamin C and the esters thereof, sulfurated amino acids, and the like.
EP 0599307 (Schwabe) discloses the removal of hypericin, responsible for undesired photo-sensitizing effects, by means of polyvinylpyrrolidone and other chemicals.
The patent describes extracts obtained without using antioxidants and having a hyperforin content of at least 5%.
Comparative pharmacological and clinical data between conventional methanolic extracts or extracts prepared according to the monograph of Commission E with the extracts prepared according to EP 0599307 and WO 97/13489 are not available. It is recognized, however, that conventional extract of
Hypericum perforatum
contain large amounts of flavonoids, which are potent radical scavengers and therefore natural stabilizing agents for easy-to-oxidize substances, together with other substances which can significantly contribute to the activity of the extract.
SUMMARY OF THE INVENTION
The invention relates to a method of preparing stable extracts of
Hypericum perforatum.
The method includes the steps of extracting flowering tops of
Hypericum perforatum
with alcohol or acetone solvent to provide a first extract solution; filtering the first extract solution; concentrating the first extract solution to provide a concentrate; diluting the concentrate with a water or a water-alcohol solvent to provide an aqueous solution; extracting the aqueous solution with one or more aliphatic ester solvents to provide an ester extract; filtering the ester extract; and g) evaporating the solvents from the ester extract to provide a stable extract of
Hypericum perforatum.
The method may further include the step of solubilizing the stable extract of
Hypericum perforatum
in a solvent comprising an acid in aqueous ethanol to provide an aqueous ethanol solution and evaporating the solvents from the aqueous ethanol solution at a temperature of less than 40° C. The organic acid may be citric acid, malic acid, acetylaspartic acid, phosphoric acid, or a mixture thereof. The aqueous ethanol solution may be 95 percent ethanol.
The alcohol or acetone solvent used in step (a) may be one or more of methanol or ethanol or it may be acetone. The ratio of the weight of the flowering tops to the alcohol or acetone solvent in step (a) may be from 1:2 to 1:20.
The concentrate in step (d) may be diluted with an equal volume of water or water-alcohol solvent. The concentrate may be diluted with a water-alcohol solvent having an alcohol to water volume ratio of from 1:2 to 1:5. The water-alcohol solution in step (d) may contain one or more of methanol or ethanol
The volume ratio of the aqueous solution to the one or more aliphatic ester solvents in step (e) may be from 1:0.5 to 1:2. The aliphatic ester solvent in step (e) may be ethyl acetate, methyl acetate, butyl acetate, or mixtures thereof. The aliphatic ester solvent may be ethyl acetate.
The invention also relates to an extract of
Hypericum perforatum
obtained by the process of the invention. The extract may have an IC
50
for inhibition of serotonin uptake of less than 0.32 &mgr;g/ml or an IC
50
for inhibition of dopamine uptake of less than 2.72 &mgr;g/ml. The hyperforin content of the extract may be from 10 to 50 percent by weight of the extract, the total hypericin content of the extract may be greater than 0.5 percent by weight of the extract, and dimeric flavones content of the extract may be from 1 to 2 percent by weight. In another embodiment the hyperforin content is from 10 to 50 percent by weight of the extract, the total hypericin content is from 0.5 to 1.2 percent by weight of the extract, and dimeric flavones content is from 1 to 2 percent by weight.
The invention also relates to pharmaceutical compositions containing the extract of
Hypericum perforatum
prepared by the process of the invention and a pharmaceutically acceptable excipient or carrier. The pharmaceutical composition may be formulated to be a ready-to-use solution, a soft-gelatin capsule, a hard-gelatin capsule, a tablet, or a controlled-release tablet. When the pharmaceutical composition is formulated to be a ready-to-use solution, a soft-gelatin capsule, a hard-gelatin capsule, or a tablet and the extract of
Hypericum perforatum
may be present in an amount of from 10 to 100 mg. When the pharmaceutical composition is formulated to be a controlled-release tablet and the extract of
Hypericum perforatum
may be present in an amount of from 10 to 300 mg.
The invention further relates to a method of treating or preventing depression and anxiety in humans and animals by administering to a human or animal a therapeutically effective amount of the extract prepared by the process of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has now been found that stable, highly active extracts of
Hypericum perforatum,
containing the main compounds responsible for pharmacological activity, in particular hypericin, hyperforin, flavonoids, and xanthones, can be prepared by a process that comprises:
a) extracting the flowering tops of
Hypericum perforatum
with alcohol or acetone;
b) filtering the extracts and concentrating the extract;
c) diluting the concentrate from step (b) with water or a water/alcohol mixture;
d) extracting the aqueous mixture from step (c) with aliphatic esters;
e) filtering and evaporating the ester extracts from step (d) to dryness; and, optionally,
f) solubilizing the dry residue from (e) in a solution of an organic acid in aqueous ethanol and evaporating the solvent at a temperature below 40° C.
Preferably the first extraction (step a) is carried out with methanol or ethanol; a weight/volume ratio for t
Bombardelli Ezio
Gabetta Bruno
Morazzoni Paolo
Indena S.p.A.
Lilling Herbert J.
Pennie & Edmonds LLP
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