Method For The Production of Extracts Rich in Beta-Aescin EP 0298148 A1

Method for the production of extracts rich in beta-aescin
EP 0298148 A1
ABSTRACT
Horse chestnut extracts with a particularly high beta -aescin content are obtained by using fresh, deep-frozen
chestnuts and extracting these, after thawing and comminution, with water as extractant.
DESCRIPTION translated from German
1. The therapeutic effect of numerous veins preparations is rated according to their Aescingehalt. This active
ingredient in the fruits or seeds of the horse chestnut (Aesculus hippocastanum L.) contained is a complex
mixture nahverwandter triterpene glycosides, which may exist in isomeric forms (J. Wagner et alk, Arzneim.Forsch. 20, 205 (1970). How we now know, is one of these isomers is the genuine form it has made under
the name of -aescin in the literature (The Merck Index, No. 3640, Tenth Edition (1983). Because of the
isomeric Aescinformen the beta-aescin the strongest pharmacological activity (H. Hampel et al., Arzneim.Forsch. 20, 209 (1970)), has this isomer preferably used in Aescinprparaten.
2. Due to the significant therapeutic significance of these preparations there has been no lack of attempts, the
long-known method for obtaining this active compound s to improve. In this case, the crushed seeds of the
fresh Rakastanie are first extracted with aqueous alcohols and then recovered from the extract, the aescin.
3. Of crucial importance is the Aescingehalt in the seed material, especially the content of betaescin. According to studies by H. Friedrich and E. Zeruhn (Arch. Pharmacy 304, 347 (1971)) is subject to
Aescingehalt of seeds of various trees Aesculus hippocastanum L. kind of significant fluctuations. As could
be found after exhaustive extraction of freeze-dried powdered seed material, it lies with the individuals
between 1.8% and 7.99%, on average, at 3.9%. Similar results are 27 33204 "Method for the isolation of
aescin from horse chestnut fruits of" notified also in the DE-PS. This refers to the fact that the dried "fruits"
(meaning seeds) contain 3.5% to 5.5% Gesamtaescin, the proportion of the isomeric form of alpha-aescin of
less than 20% for fresh chestnuts to 50% in elderly may increase fruit. This means that the proportion of the
isomeric form of beta-escin of more than 80% can decrease with longer stored fruit with fresh chestnuts to
50%.
In a detailed study of the industrial production of aescinreichen Rokastanienextrakten U. Bogs and D.
Report Bremer (Pharmacy 26, 410 (1971)) that you can win an extract of air-dried, crushed horse chestnut
seeds purified by percolation with 70% ethanol, which, on the drug used in relation containing 1.5% escin.
4. For the isolation of aescin from the Rokastaniensamenextrakten various methods have been developed
(literature review in J. Wagner and J. Bosse, Hoppe-Seyler's Ztschr Physiol Chem 320, 27 (1960)...). In the
specific case of the recovery of beta-escin one takes advantage of the low water solubility of the free acid
form of beta-escin. This is achieved by adjusting the already at almost neutral Rokastaniensamenextraktes
to pH values 3, for example, by the addition of appropriately strong acids `the. By treatment with a strongly
acidic ion exchanger In the GDR PS 11178 "process for the recovery of crystallized saponins (aescin) from
the seeds of the horse chestnut" was a methanolic-aqueous Ansurern Rokastaniensamenextraktes
crystallized escin in a yield of about 2.5% (based on the drug) obtained. According to W. Winkler and P. Patt
(Science 47, 83 (1960)) crystalline aescin falls after treatment with aqueous methanolic
Rokastaniensamenextrakte ion exchanger in a yield of about 2% (based on the drug) to. Later reports
Kamphius G., P. Patt and W. Winkler (Austrian Apoth.-Zeitung. 24, 535 (1970)) of an average yield of 1.5%
aescin crystallized.
5. In general, the technical Aescinproduktion is performed using the following process steps:
1 air / heat drying of pre-shredded chestnuts; 2. More crushing of chestnuts and extraction with 40-70%
alcohol (methanol or ethanol); 3. Isolation of Gesamtaescin (acid precipitation, ion exchange or

distribution); 4. Separation of alpha-aescin fraction and extraction of beta-escin trade specification.
6. Although it has been known that horse chestnut seeds contain an average of 4% aescin, and in the fresh
condition the drug is present more than 80% of them in the beta-form, no production has so far been
described that a substantial recovery of this genuine, so originally in fresh horse chestnut seeds existing
beta-aescin possible.
7. Surprisingly, it has now been found that the crushed chestnuts material can with water extract exhaustive as
solvent and subsequently isolated from the extract aescin - corresponds to the beta-escin trade specification
when used for extracting fresh frozen chestnuts - without separation of alpha-aescin share be. The fresh
chestnuts are frozen immediately after harvest and let ish store in this form good and transport. After
thawing, the seeds are crushed, cut for example to increase the extraction surface into thin slices, and then
extracted with water with agitation or circulation of the extraction water. The duration of the extraction stage,
in the meanwhile, the aescin is almost completely removed from the frozen and thawed chopped
Kastaniengewebsmaterial through the water, depends in part on the variety of chestnut, the degree of
comminution and the extraction temperature, and can be 3 - 50 hours. By extraction sample of each
material, the optimum time for this extraction step can be easily determined. From the resulting filtered or
centrifuged extract the dissolved aescin is immediately precipitated and this so worked up in the usual
manner by recrystallization of purified active substance by acidification.
8. Although the freezing and preservation of plant material has been known for a long time, it has not so far
used in the chestnut seeds. Also was not foreseeable that it will be possible by quick-freezing, after thawing,
the aescin in place with alcohol or with aqueous hard alcohol or other water-miscible polar organic solvents
alone now with water extract as extractant from the seed material, with better yield than before with the
organic extractants.
9. The process principle "deep freezing of chestnuts and extraction with water" invention results compared with
the state of the art in several respects to technical and economic progress:
o
1.) The dry chestnuts, which is connected with a partial isomerization of beta-escin to commercially
worthless alpha-aescin is eliminated.
2. The deep-freezing storage of fresh chestnut is a storage technology, in which the isomerization
of the aescin is prevented during storage, so that the work-up of the harvested chestnut can now
be carried as required.
10. On an industrial scale extraction of thawed frozen chestnut material with water brings the danger of a
possible development of microorganisms with it, especially since the chestnut also contain low molecular
weight sugars and various nutrients for fermentation, particularly at extraction temperatures of 20 - can
easily occur 40 C ,
11. By such fermentation, it could lead to an uncontrolled lowering of the otherwise near-neutral (5.5 - 6.5) pH
come, coupled with confusing degradation reactions and Isomerisiergefahr for genuine aescin. Therefore, it
is recommended that the extraction water add a small amount of the bacteria or yeast growth inhibiting agent
or to treat almost thawed whole chestnuts externally with a commercial disinfectant to reduce the basic
germs, what then cut the chestnuts quickly slice and the exhaustive extraction are subjected to the water. If
longer extraction times are provided but should the extraction water containing the disinfectant. As such a
fermentation-preventing agent to the extraction water can, inter alia, small amounts of phenol or Nipagin as
well as lower alcohols such as methanol, ethanol or isopropanol in an amount which safely prevents the
development of bacteria or yeast during the extraction period may be added. % 20 vol .- certainly the case at the lower alcohols, this is known to be at a concentration of 14.
Example 1
12. 10,000 kg fresh whole chestnuts are frozen and then stored. The thawed chestnuts that are usually located
in jute bags are batch in about 30 minutes in a 1% aqueous solution of the commercial disinfectant "Perform
New" from Schlke & Mary Gmbh - containing potassium peroxy, sodium benzoate and tartaric acid dipped. After draining the chestnuts cut into thin slices about 3 mm thickness using a meat slicer and
entered into 40,000 l initial charge of water. After 5 hours of extraction pumping the tincture is taken off, free
agent by centrifugation, suspended particles and immediately after that at about 45 C and addition of
sulfuric acid to a pH value of 2.5 - 2.8 aescin like this. After sitting overnight, the clear supernatant was
removed, filtered and the remaining Aescinsuspension and the filter cake was dried. The filter cake is
dissolved with stirring in methanol, the solution treated with activated carbon for decoloration, for example,
and the solvent removed to dryness.
Yield:
13. 178 kg aescin, ds 1.78%, based on fresh chestnuts and about 3.6% based on dry matter chestnut
Quality:
14. Corresponds to the beta-escin trade specification, ie, the aescin consists to 88.1% of beta-escin.
Example 2
15. 10,000 kg fresh whole chestnuts are stored frozen. After thawing, they are crushed (eg, roller mill, roller
spacing 10 mm) and entered into 8,000 liters of water to which a disinfectant methanol was added so that,
taking into account the water content of the chestnut, a methanol concentration of 15% (v / v) results. Under
pumping is extracted for 36 hours, the tincture withdrawn and filtered. The aforementioned extraction
process is then repeated twice with 8,000 liters of water containing 15% methanol.
16. 2.8 (addition of sulfuric acid) aescin like - from the combined tinctures is at about 40 C and pH 2.5. The
overnight deposited precipitate suspension is filtered. The moist filter cake is dissolved with stirring and
addition of isopropanol, treated with eg activated carbon to decolorize, filtered and the solvent evaporated to
dryness.
Yield:
17. 196 kg aescin, ds 1.96%, based on fresh chestnuts and about 3.9% based on dry matter chestnut
Quality:
18. Corresponds to the beta-escin trade specification and consists of 88.6% of beta-escin.
CLAIMS(3) translated from German
1. A process for the production of -aescinreichen extracts by extracting crushed chestnut seeds and
precipitating the aescin by acidification of the extract,characterized in that one uses fresh frozen horse
chestnut seeds, which are then extracted after thawing and grinding with water.
2. The method according to claim 1, characterized in that the extracting agent water to prevent microbial
growth during the extraction disinfectant may be added.
3. The method according to claim 2, characterized in that are used as disinfectants, lower alcohols, in
particular methanol or ethanol, in an amount up to 20 vol .-%.
a. 3.) eliminates the handling of large amounts of alcohol mixtures, so that recovery of the alcohol,
health precautions and protective devices are not required, and only in the final cleaning of aescin,
where the quantities to be processed are reduced to about one-hundredth, alcohol or used comes.
b. 4) Water is the most cost effective and least harmful solvents for extraction.
c.
5.) The step of separating alpha-aescin is omitted.
d. 6.) The yield of beta-escin is substantially increased.

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Method for the production of extracts rich in beta-aescin

alcohol (methanol or ethanol); 3. Isolation of Gesamtaescin (acid precipitation, ion exchange or

5.) The step of separating alpha-aescin is omitted.

d. 6.) The yield of beta-escin is substantially increased.

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