U.S. patent application number 10/262703 was filed with the patent office on 2003-02-13 for composition for treating chronic venous insufficiencies using an extract of red vine leaves.
This patent application is currently assigned to Boehringer Ingelheim Internationl GmbH. Invention is credited to Esperester, Anke, Frey, Hans W., Vix, Jean-Michel.
Application Number | 20030031739 10/262703 |
Document ID | / |
Family ID | 22577208 |
Filed Date | 2003-02-13 |
United States Patent
Application |
20030031739 |
Kind Code |
A1 |
Esperester, Anke ; et
al. |
February 13, 2003 |
Composition for treating chronic venous insufficiencies using an
extract of red vine leaves
Abstract
The invention relates to a dietary supplement consisting of an
aqueous extract of red vine leaves and an acceptable carrier which
prevents and reduces the discomfort relating to mild-to-moderate
chronic venous insufficiency of the legs.
Inventors: |
Esperester, Anke; (Mainz,
DE) ; Frey, Hans W.; (Ockenheim, DE) ; Vix,
Jean-Michel; (Weisbaden, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Internationl
GmbH
Binger Strasse 173
Ingelheim
DE
55216
|
Family ID: |
22577208 |
Appl. No.: |
10/262703 |
Filed: |
October 2, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10262703 |
Oct 2, 2002 |
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09691003 |
Oct 18, 2000 |
|
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6485727 |
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60160518 |
Oct 20, 1999 |
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Current U.S.
Class: |
424/774 |
Current CPC
Class: |
A23L 33/105 20160801;
A61P 9/14 20180101; A61P 43/00 20180101; A23V 2002/00 20130101;
A61K 36/87 20130101; A61P 7/00 20180101; A61P 9/00 20180101; Y10S
514/929 20130101; A23V 2002/00 20130101; A23V 2250/2116 20130101;
A23V 2002/00 20130101; A23V 2250/2116 20130101; A23V 2200/326
20130101 |
Class at
Publication: |
424/774 |
International
Class: |
A61K 035/78 |
Claims
What is claimed is:
1. An improved dietary supplement composition which comprises an
active principle for preventing or treating the discomfort
associated with mild-to-moderate chronic venous insufficiency of
the lower extremities; and a pharmaceutically, cosmetically or
dietetically acceptable carrier, the improvement wherein is that
said active principle consists essentially of an aqueous extract of
red vine leaves.
2. The dietary supplement composition according to claim 1, wherein
the aqueous extract of red vine leaves is obtainable by a method
comprising the steps of: (a) collecting red vine leaves at a point
of time when the content in flavonoids has reached an optimum; (b)
drying and crushing the leaves; (c) cutting the leaves to pieces;
(d) extracting the leaves with water at elevated temperatures for 6
to 10 hours; and (e) optionally concentrating the obtained
extract.
3. The dietary supplement according to claim 2 wherein the leaves
in step (d) are extracted with water at temperatures from
60.degree. to 80.degree. C.
Description
RELATED APPLICATION DATA
[0001] This application is a divisional of U.S. patent application
Ser. No. 09/691,003, filed Oct. 18, 2000, which claims, as does the
present application, priority benefit to U.S. Provisional
Application serial No. 60/160,518 filed Oct. 20, 1999, the
disclosures of all of which are incorporated by reference in their
entirety.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to a dietary supplement, and
more particularly, to a dietary supplement for preventing or
alleviating the discomfort associated with mild-to-moderate chronic
venous insufficiency of the lower extremities.
BACKGROUND OF THE INVENTION
[0003] Presently, there are millions of people around the world who
suffer from mild-to-moderate chronic venous insufficiency of the
legs. This common condition is characterised by an inadequacy of
the venous circulation to return blood from the legs to the heart.
The lack of adequate venous return results in venous stasis and an
increased pressure within the venous circulation, promoting the
development of oedema and tissular water retention.
[0004] Chronic venous insufficiency (CVI) is a functional disorder
caused by persistent inadequacy of the venous return and is
characterised clinically by oedema, skin changes and subjective
complaints such as tired, heavy legs, pain or tingling sensations,
which are typically amplified by standing upright and by high
ambient temperatures. This dysfunction may be a source of major
distress with a significant negative impact on the patient's
overall well-being and quality of life. Early stages (grade I) are
characterised by coronal phlebectasia paraplantaris, subfascial
congestion and oedema; grade II CVI is associated with low-grade
skin changes, eczema and lipodermatosclerosis. If untreated, grades
I and II often progress to an advanced stage characterised by
recurrent venous leg ulcers (grade III). The distress caused by the
symptoms, even when relatively mild initially, and the risk of
later complications call for appropriate supportive and preventive
measures to be initiated in the early stages of CVI.
[0005] Although some patients, even at early stages, might require
surgery (sclerotherapy and variceal surgery), the use of
compression stockings with or without additional physiotherapy is
the most common treatment approach. The effect of compression is
merely mechanical, i.e. this approach does not affect or correct
the related biological dysfunction (capillary fragility in
particular). Furthermore, the treatment with compression stockings
often lacks compliance because of cosmetic concerns and the overall
inconvenience of the compressive stockings, in the summer in
particular. Therefore there is an urgent need for alternative
approaches that are effective, well-tolerated and more
convenient.
BRIEF DESCRIPTION OF THE INVENTION
[0006] Surprisingly, it has been found that an aqueous extract of
red vine leaves can be used for the preparation of a dietary
supplement for the prevention and treatment of the discomfort
associated with mild-to-moderate chronic venous insufficiency of
the lower extremities.
[0007] The present invention therefore relates to a method for
preventing and/or alleviating the discomfort associated with
mild-to-moderate chronic venous insufficiency of the lower
extremities, which method comprises administering a dietary
supplement containing an aqueous extract of red vine leaves.
[0008] Another aspect of the present invention is a dietary
supplement composition which comprises an active principle being
capable of preventing and/or treating the discomfort associated
with mild-to-moderate chronic venous insufficiency of the lower
extremities and an pharmaceutically, cosmetically or dietetically
acceptable carrier, the improvement wherein is that said active
principle essentially consists of an aqueous extract of red vine
leaves.
[0009] The dietary supplement composition of the present invention
preferably consists of herbal ingredients derived by an aqueous
extraction from red vine leaves (folia vitis viniferae; Extractum
Vitis viniferae e folium spissum et siccum) and an acceptable
carrier. This extract contains flavon(ol)-glycosides, -glucuronides
and flavonoids, with quercetin-3-O-.beta.-D-glucuronide and
isoquercitrin (quercetin-3-O-.beta.-glucoside) as its main active
ingredients. The range of their pharmacological actions has not yet
been fully elucidated, but in-vitro studies indicate that they have
antioxidant and anti-inflammatory properties and that they inhibit
platelet aggregation and hyaluronidase and reduce oedema, possibly
by reducing capillary permeability. Preclinical in-vivo experiments
demonstrated anti-inflammatory and capillary wall thickening
effects.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In a preferred embodiment, the dietary supplement is in a
form suitable for oral administration, in particular in a solid
dosage form, i.e. a capsule or tablet, that consists of 20 to 60%
of aqueous red vine leaf extract with a high flavonoid content of
2-15%. Another preferred dosage form is that of drops containing 3
to 90% of extract. Further suitable administration forms may be
coated tablets, syrups, or the like.
[0011] With the foregoing in mind, it is a primary object of the
present invention to provide a dietary supplement for preventing
and alleviating the discomfort associated with mild-to-moderate
chronic venous insufficiency of the lower extremities.
[0012] It is a further object of the present invention to provide a
dietary supplement for preventing and/or alleviating the discomfort
associated with mild-to-moderate chronic venous insufficiency of
the lower extremities comprising herbal ingredients, wherein the
dietary supplement is manufactured pursuant to a controlled process
that preserves the herbal curing qualities of the ingredients.
[0013] It is still a further object of the present invention to
provide a dietary supplement which is effective in preventing
and/or alleviating the discomfort associated with mild-to-moderate
chronic venous insufficiency of the lower extremities.
[0014] It is still a further object of the present invention to
provide a dietary supplement for preventing and/or alleviating the
discomfort associated with mild-to-moderate chronic venous
insufficiency of the lower extremities comprising herbal
ingredients and having minimal or no side effects and thus being
safe for internal consumption.
[0015] A fundamental part of the present invention is the
preparation of a supplement for oral administration containing an
aqueous extract prepared from dried red vine leaves. The latter is
characterised by a high content of 2 to 20%, preferably 2 to 10% of
biologically active flavonoids.
[0016] In order that this invention be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustrating embodiments of this invention, and are not
to be construed as limiting the scope of the invention in any
way.
[0017] The examples which follow are illustrative and, as
recognized by one skilled in the art, particular conditions could
be modified as needed for individual compositions. Materials used
in tests below are either commercially available or easily prepared
from commercially available materials by those skilled in the
art.
[0018] The basis of the supplement is the aqueous extract of red
vine leaves (foliae vitis viniferae L.). The starting material for
the preparation of the extract are red vine leaves collected at a
point of time where the content in flavonoids has reached an
optimum. This is usually the case around the harvesting time of the
grapes. The leaves are carefully dried and crushed. For extraction
the leaves are cut to pieces of preferably 5 to 10 mm. To achieve a
high content in flavonoids the extraction is done at elevated
temperature, preferably at a temperature in the range of 60.degree.
to 80.degree. C., over a time of at least 6 up to 10 hours. The
preferred method is that of an exhaustive percolation.
[0019] The so-called fluid extract obtained in the course of the
extraction may be directly used in the preparation of liquid dosage
forms. In order to get a more concentrated extract preferably at
least part of the solvent is removed by use of a suitable
evaporator. The thick extract obtained in this step may again be
directly used in the manufacturing of liquid dosage forms. For the
preparation of solid dosage forms the thick extract is dried, for
instance by use of a vacuum drying oven or a vacuum drying
conveyer. Carriers or excipients may be added during drying to
facilitate further processing of the extract. Such carriers or
excipients may be silicon dioxide, maltodextrine, glucose syrup,
cellulose and others.
[0020] The supplement for oral administration is manufactured using
usual techniques applied in the food industry or in the
pharmaceutical industry. Preferred administration forms are
tablets, including coated tablets or capsules. But also liquid
preparations, preferably drops, may be chosen.
[0021] To prevent and/or alleviate the discomfort of
mild-to-moderate chronic venous insufficiency of the lower
extremities, the dietary supplement should be taken in dosages
corresponding to 80-1000 mg of extract, preferably 300-800 mg, in
particular 350-750 mg daily. The total amount of extract may be
divided up in 1 to 3 capsules or tablets a day (or an equivalent
dose by means of a liquid form). The daily dose should be taken at
once, preferably in the morning.
[0022] Impressive improvement of the symptoms can be expected
within 6 weeks of continuous use. The optimum effect is maintained
or amplified on longer use.
[0023] In order to verify the effectiveness, safety and
tolerability of the dietary supplement of the present invention, a
randomised, placebo-controlled, double-blind parallel-group study
was conducted in a large and representative sample of patients with
evidence of mild-to-moderate chronic venous insufficiency of the
lower extremities. This study was carried out in accordance with
the Declaration of Helsinki and the Principles of Good Clinical
Practice. The results are set forth below:
[0024] Objective--To assess the efficacy and safety of once-daily
doses of 360 and 720 mg red vine leaf extract (RVLE) compared to
placebo in patients with grade I and incipient grade II chronic
venous insufficiency (CVI).
[0025] Design--A 12-week, randomised, double-blind,
placebo-controlled, parallel-group, multi-center study.
[0026] Patients--Male and female outpatients between 25 and 75
years of age with grade I and grade II CVI (i.e. without extensive
trophic changes), without further significant medical conditions
and not treated with compression stockings, diuretics or other
drugs affecting fluid balance.
[0027] Intervention--Patients were randomly assigned to a
double-blind treatment with placebo, 360 mg RVLE or 720 mg RVLE
once daily for 12 weeks, preceded and followed by a single-blind
2-week placebo treatment for baseline run-in and end-of-trial
washout, respectively. Study criteria were evaluated at baseline,
after 6 and 12 weeks of treatment and 2 weeks after discontinuation
of treatment.
[0028] Outcome Measures--Primary outcome measure: Change in lower
leg volume, as determined by water displacement plethysmography.
Secondary outcome measures: Change in ankle and calf circumference;
change in intensity of key symptoms ("tired, heavy legs", "feeling
of tenseness", "tingling sensation", and "tenderness/pain")
compared to baseline.
[0029] Results--Of the 260 patients enrolled and randomised, 219
completed the study in accordance with the protocol. In the
intention-to-treat analysis (N=257), the mean (.+-.SD) lower leg
volume of the patients treated with placebo (N=87) increased by
15.2.+-.90.1 g (displaced water mass) compared to baseline after 6
weeks of treatment and by 33.7.+-.96.1 g compared to baseline after
12 weeks of treatment. In patients treated with RVLE according to
this invention, however, lower leg volume decreased and, after 12
weeks of treatment, the difference in mean lower leg volume between
the active treatment groups and the placebo group was -75.9 g (95%
CI: -106.1 to 45.8 g) for the 360-mg RVLE group (N=86) and -99.9 g
(95% CI: -130.3 to -69.6 g) for the 720-mg RVLE group (N=84). The
changes in calf circumference showed a similar pattern; in patients
treated with RVLE, both the higher dose (720 mg) and, to a lesser
extent, the lower dose (360 mg) resulted in a clear reduction in
circumference over time, whereas, in patients treated with the
placebo, the circumferences remained largely unchanged (95% CI of
the estimated treatment effects vs. placebo after 12 weeks: -1.4.0
to -0.56 cm for 360 mg RVLE and -1.73 to -0.88 cm for 720 mg RVLE).
The reductions in ankle circumference were qualitatively similar
but quantitatively less marked.
[0030] There was a clear improvement in key CVI symptoms at 6 weeks
with all treatments, but a further improvement at week 12 was seen
only in the active treatment groups; at 12 weeks, the changes
compared to baseline were significantly greater (p<0.001) in
both active treatment groups than in the placebo group. The
treatments were well tolerated. Adverse events were rare and
usually mild. Two AEs during treatment with the placebo led to
hospitalisation. Three further patients were withdrawn because of
AEs which occurred during treatment with the placebo.
[0031] Conclusion
[0032] Once-daily doses of 360 and 720 mg RVLE appeared safe and
effective in the treatment of mild CVI, reducing lower leg oedema
and circumference whilst improving key CVI-related symptoms. The
extent of oedema reduction is at least equivalent to that reported
for compression stockings and/or other oedema-reducing agents. The
higher dose was as well tolerated as the lower dose but resulted in
a slightly greater and more sustained improvement.
[0033] It will be readily apparent to those skilled in the art that
various changes and modifications of an obvious nature may be made
without departing from the spirit of the invention, and all such
changes and modifications of an obvious nature may be made without
departing from the spirit of the invention, and all such changes
and modifications are considered to fall within the scope of the
invention, as defined by the claims as defined. While the
composition of the present invention has been set forth in what is
believed to be preferred embodiments, it is recognised that
departures may be made within the spirit and scope of the following
claims which, therefore, should not be limited except within the
doctrine of equivalents.
* * * * *