Note: Descriptions are shown in the official language in which they were submitted.
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Flavonolignan Preparations, especially Silymarin
Preparations
DESCRIPTION
The invention relates to flavonolignan preparations,
especially silymarin preparations, which dissolve more
easily than do pure flavonoids or pure silymarin, i.e.,
which have an especially improved release rate and
subsequently improved absorption and bio-availability in
animal or human bodies; to medicines containing these that
are used for the treatment and prevention of liver
ailments; and to a process for manufacturing the
preparations.
Among the medicines used for the treatment and prevention
of liver ailments, those based on milk thistle extracts
(Carduus extracts) are playing an ever more significant
role. An effective component of the milk thistle extract
preparation is silymarin, which consists of the four
flavonoid isomers (flavonolignan isomers), silibinin,
isosilibinin, silicristin, and silidianin. Since silymarin,
or flavonoids, in water are only minimally soluble (the
solubility of pure silymarin in a pH 6.9 buffer lies at ca.
0.08 mg/ml), all of these medicines have the problem that
their absorption, and thereby their bio-availability, in
human or animal bodies, is often only unsatisfactorily low.
Furthermore, the flavonoid isomers tend to form
agglomerates that do not dissolve easily with many of the
common galenic inactive ingredients. In order to improve
the water solubility, attempts have already been made to
convert, with special chemical agents, the flavonoid
isomers of silymarin into derivatives (adducts, complex
compounds, ester inclusion compounds) that exhibit better
water solubility and a higher release rate. A basic
disadvantage of these derivatives is the fact that, in
principle, one is dealing with new active substances, and
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the agents coupled to the flavonoid isomers can often cause
undesirable physiological side effects and/or also impair
the effectiveness of the flavonoid isomers. These
disadvantages in many ways outweigh the advantage of the
improved water solubility. Basically, a biopharmaceutical
influence of the absorption and bio-availability via the
optimization of the pharmaceutical composition is always
preferable.
Another method of improving the dissolution reaction,
release rate, and bio-availability is described in the
publication EP 0 722 719. Accordingly, the flavonoid
isomers are dissolved with pharmaceutically acceptable
carrier materials and wetting agents in an aqueous
alcoholic medium, and this solution is concentrated,
filtered, vacuum-dried, and pulverized to form a co-
precipitate. The silymarin co-precipitates resulting from
this method exhibit a significantly higher release rate (of
95 - 100 %) and bio-availability when compared to the pure
active substance, and they are very easily absorbed into
human or animal bodies and develop the desired and expected
physiological effect. This manufacturing process is,
however, technically very complex and results in relatively
high costs, above all caused by the fact that (1) several
inactive ingredients are needed, that (2) solvents are used
that must later be removed, that (3) grinding is necessary,
and that (4) the active substance is exposed to thermal
stress. Heating the initial solution to the boiling point
results in the disadvantage that under such thermal stress,
the probability of chemical alterations is increased.
A very similar solution to the problem has also already
been described in DE 27 19 581 A1. In the process shown
there, the active substance polyhydoxyphenl-chromanone
taken from Silybum marianum is dissolved together with
polyvinylpyrrolidone in an aqueous-organic solvent, and
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this solution is lyophylized, wherein a surface-active
substance can be added.
A process for manufacturing a plant extract preparation, in
which one expressly abstains from drying and grinding, is
already known from EP 0 496 705. This publication
recommends the manufacturing of a mass made from a liquid
partial- or full-extract of fresh and/or dried
plant(particles) and at least one carrier material, e.g.,
polyethylene glycol or polysorbate, in a mass ratio between
20:1 and 200:1. In the list of plants that may be used for
the plant extract, Silybum marianum or Carduus or milk
thistle are not listed, however; and the problem of the
poor dissolution, the release rate, and the bio-
availability of flavonoids is also nowhere touched upon in
this publication. Furthermore, the crude or primary plant
extract described therein still basically contains
significant residues of the solvents) used for its
manufacture; and also, following the final concentration,
the end product that is to be made into capsules still
contains solvent residues. In the end, none of the
manufactured preparations described therein contains the
plant extract in a completely or even largely dissolved
form.
The object of the present invention is therefore the
preparation of a silymarin preparation in which the
flavonoid isomers are left largely in their natural state,
i.e., especially do not exist bonded to other chemical
substances; and exhibit a high silymarin release rate,
i.e., a very good silymarin dissolution behavior and
thereby the prerequisite for a good absorption and high
bio-availability of the flavonoid isomers in human or
animal bodies. The inactive ingredients necessary for the
preparation should be completely physiologically harmless
and substantially limited in number, i.e., the least
possible number of different inactive ingredients. should be
used.
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A solution for this object lies in the preparation of
flavonolignan or silymarin preparations of the initially
described type, which consist exclusively, or almost
exclusively,. of an almost or completely homogenous liquid
mixture of dry milk thistle extract (Carduus extract) with
high silymarin content in polyethylene glycol (PEG) -
without using additional carrier materials. Surprisingly,
it was namely discovered that as sole solvent for the dry
milk thistle extract, PEG results in the technically
simplest method for obtaining a milk thistle extract that
exhibits a practically equally good dissolution behavior as
do the co-precipitates described in EP 0 722 719 A1 and the
tested and evaluated medicines found in the publication by
H.-U. Schulz et. al., "Untersuchungen zum
Freisetzungsverhalten and zur Bioaquivalenz von Silymarin-
Praparaten" (Investigations of the Release Rate Behavior
and Bioequivalence of Silymarin Preparations), Arzneim.-
Forsch./Drug Res. 45(I), No. 1, 1995.
The preparation according to the invention has the
advantage that it disperses very well in water and that it
releases the active substance silymarin at a comparatively
high rate. The established values for the in-vitro release
rate are at least equivalent to those of co-precipitate
preparations (see Table 2). In contrast to this known
preparation, the preparation according to the invention
can, however, be manufactured with considerably less
technical effort and more reasonable expense. In
particular, there is an elimination of the grinding and
those manufacturing steps that use special solvents that
must later be removed and disposed of, or reprocessed, as
waste.
The preferred forms of polyethylene glycol used are PEG
200, PEG 300, PEG 400, or PEG 600.
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In a preferred variation of the preparation according to
the invention, the ratio of dry milk thistle extract to
polyethylene glycol (PEG) lies in the range between 1:10
and 1:1.5, preferably between 1:5 and 1:2. This preparation
exhibits an extraordinarily good dissolution, both in
comparison to the values named in EP 0 722 719, as well as
to the values of diverse silymarin preparations mentioned
in the publication by H.-U. Schulz et. al., "Untersuchungen
zum Freisetzungsverhalten and zur Bioaquivalenz von
Silymarin-Praparaten", Arzneim.-Forsch./Drug Res. 45(I),
No. 1, 1995. A preparation with these kinds of
extraordinarily good characteristics contains the dry milk
thistle extract (Carduus extract) in polyethylene glycol
400 in a mass ratio of 1:3.
Depending upon the ratio of extract to solvent, either a
clear, colored extract solution is present, or a suspension
in which the extract is largely dissolved.
The preparation according to the invention can contain
additives of pharmaceutically commonly accepted inactive
ingredients and co-solvents. The addition of co-solvents is
particularly advantageous if the preparation is intended
for manufacture as soft gelatine capsules. Propylene
glycol, anhydrous glycerin or glycerin 85 % may be used as
co-solvents. Preferred co-solvents are glycerin or
propylene glycol.
Further additives, e.g., surfactants, especially
polysorbate 80 (Tween 80), can also be added.
For the manufacture of the preparations according to the
invention, a process is recommended that is characterized
by the number and sequence of the following procedural
steps:
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(a) Heating of liquid polyethylene glycol, preferably to
ca. 50 °C,
(b) Mixing a conventionally obtained dry milk thistle
extract into the heated solution, and intensive
homogenization,
(c) Addition of co-solvents and/or inactive ingredients,
(d) Homogenization with intensive stirring until an almost
completely or completely homogenized liquid mixture has
been obtained,
wherein method steps (a), (b), and (d) are necessary, while
method step (c) is performed only when required, i.e., when
the addition of co-solvents and/or inactive ingredients is
necessary, and is omitted when the preparations are free of
co-solvents and inactive ingredients.
The data of a preferred preparation according to the
invention are listed below:
dry milk thistle extract approx. 25 weight
with high silymarin content
(ca. 80 % m/m)
liquid polyethylene glycol approx. 60 weight
if necessary, polysorbate 80 approx. 5 weight o
(Tween 80)
if necessary, glycerin or approx. 15 weight o
propylene glycol
whereby the o by weight given always relates to the total
weight of dry milk thistle extract and polyethylene glycol.
The preparation according to the invention is especially
suitable for filling into gelatin capsules, preferably soft
gelatin capsules, manufactured from normal gelatin or
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succinylated gelatin. For this purpose, it is recommended
that the preparation be manufactured according to the
presently described method with the addition of co-solvents
and inactive ingredients.
The invention is explained in more detail in the following,
by using manufacturing examples and in-vitro test results.
Example 1: Manufacture of a milk thistle extract-
polyethylene glycol preparation
A dry extract with a silymarin content of ca. 80 0
(photometric assay) is manufactured from milk thistle
fruits (Cardui mariae fructus) according to a conventional
method. This extract is stirred into polyethylene glycol
400, which has been heated to ca. 50 °C for this purpose.
This mixture is intensively homogenized until a
homogeneous, liquid mixture is obtained, i.e, according to
experience, about 5 minutes.
Example 2: Manufacture of a milk thistle extract-
polyethylene glycol preparation for filling into
soft gelatin capsules
A dry extract with a silymarin content of ca. 80 0
(photometric assay) is manufactured from milk thistle
fruits (Cardui mariae fructus) according to conventional
methods. This extract is stirred into polyethylene glycol
400, which has been heated to ca. 50 °C for this purpose.
This mixture is intensively homogenized until a
homogeneous, liquid mixture has been obtained. Anhydrous
glycerin and, if necessary, other additions, such as,
polysorbate 80, are added to this mixture. Finally, it is
further homogenized (ca. 1 min.). The liquid mixture so
obtained can, when constantly stirred, be filled directly
into soft gelatin capsules.
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Example 3: Testing of the silymarin release rate of milk
thistle extract-polyethylene glycol preparations
The active substance release of the milk thistle extract-
polyethylene glycol preparations produced according to
Examples 1 and 2 were tested in a release apparatus
(standard conditions, Paddle model, according to DAB 10,
900 ml:. phosphate buffer pH 7.5 according to DAB 10). On
the basis of the minimal solubility of the active
substance, 1/ of the normal single dosage, corresponding to
ca. 35 mg. silymarin, was used. The quantitative
determination of the dissolved silymarin amount was
performed photometrically (photometer of manufacturer
Perkin Elmer, type Lambda 14) at 288 nm (calculation of the
concentration by means of comparison with correspondingly
produced comparative solutions). The results are presented
in the following Table 1.
Silymarin-polyethylene glycol Released portion (in o) of
preparations the utilized amount of
silymarin after 60 minutes
(photometrically determined
at 288 nm)
according to Example 1 98.3
according to Example 2 83.2
The rapid and most complete dissolution or release possible
guarantees good absorption and high bio-availability of the
active substance.
Table 2:
Release of silymarin from milk thistle extract preparations
(silymarin content ca. 80 o m/m) in 900 ml. phosphate
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buffer pH 7.4 R according to DAB 10, photometric
determination. Total weight of extract 43.9 mg./release
container, corresponding to 1/ of the normal single dosage.
Preparation Released Portion of
Silymarin (o)
after 60 Minutes
Liquid mixture according to the 98.3
invention made from milk thistle
extract and PEG 400/polysorbate 80
Ground co-precipitate, produced 85.0
analogous EP 0722719A1; particle
size 99 0 < 40 ~m
Commercial medicine, containing 84.0
milk thistle extract
