U.S. patent application number 13/782391 was filed with the patent office on 2013-09-26 for compounds and mixtures influencing inflammatory states.
This patent application is currently assigned to Symrise AG. The applicant listed for this patent is SYMRISE AG. Invention is credited to Maria Blings, Marcus Gotz, Jakob Ley, Katharina Reichelt, Veronika Somoza, Jessica Walker, Joel Michael Walker.
Application Number | 20130251730 13/782391 |
Document ID | / |
Family ID | 47630214 |
Filed Date | 2013-09-26 |
United States Patent
Application |
20130251730 |
Kind Code |
A1 |
Ley; Jakob ; et al. |
September 26, 2013 |
Compounds and Mixtures Influencing Inflammatory States
Abstract
Suggested is a compound of the formula (X) ##STR00001## or any
salt of a compound of the formula (X) or any mixture containing or
consisting of two or more different compounds of the formula (X),
two or more different salts of compounds of the formula (X) or one
or more different compounds of the formula (X) and one or more
different salts of compounds of the formula (X), wherein for R1, R2
and R3 independently of one another in every compound of the
formula (X) the following applies: R1 means hydrogen or methyl, R2
means an organic residue with 5 carbon atoms and one oxygen atom or
none and R3 means an organic residue with 10 carbon atoms and one
or more oxygen atoms, or R1 and R2 together with the carbon atoms
in positions 4 and 5 and the oxygen atom bound to the carbon atom
in position 4 form a ring and comprise 5 carbon atoms and one
oxygen atom or none, and R3 means an organic residue with 10 carbon
atoms and one or more oxygen atoms, for use in a method for the
prophylaxis and/or treatment of inflammation.
Inventors: |
Ley; Jakob; (Holzminden,
DE) ; Reichelt; Katharina; (Holzminden, DE) ;
Gotz; Marcus; (Oberweser, DE) ; Blings; Maria;
(Holzminden, DE) ; Somoza; Veronika; (Weidling,
AT) ; Walker; Jessica; (Vienna, AT) ; Walker;
Joel Michael; (Vienna, AT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYMRISE AG |
Holzminden |
|
DE |
|
|
Assignee: |
Symrise AG
Holzminden
DE
|
Family ID: |
47630214 |
Appl. No.: |
13/782391 |
Filed: |
March 1, 2013 |
Current U.S.
Class: |
424/158.1 ;
424/93.4; 514/150; 514/171; 514/249; 514/263.2; 514/456; 514/568;
514/635; 549/399; 549/403; 562/463 |
Current CPC
Class: |
A61K 2800/10 20130101;
A61K 8/365 20130101; A23L 33/105 20160801; A61P 17/00 20180101;
C07C 65/40 20130101; A61K 31/192 20130101; A61K 31/353 20130101;
A61K 45/06 20130101; A61K 31/352 20130101; C07D 311/32 20130101;
A61K 8/498 20130101; A61P 1/00 20180101; A61P 29/00 20180101; C07D
311/58 20130101; A61Q 19/00 20130101; A61K 31/353 20130101; A61K
2300/00 20130101; A61K 31/192 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/158.1 ;
562/463; 514/568; 549/399; 514/456; 549/403; 424/93.4; 514/171;
514/150; 514/249; 514/263.2; 514/635 |
International
Class: |
A61K 31/192 20060101
A61K031/192; C07D 311/58 20060101 C07D311/58; A23L 1/30 20060101
A23L001/30; C07D 311/32 20060101 C07D311/32; A61K 45/06 20060101
A61K045/06; C07C 65/40 20060101 C07C065/40; A61K 31/353 20060101
A61K031/353 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 2, 2012 |
EP |
12157903.1 |
Feb 5, 2013 |
EP |
13154023.9 |
Claims
1-30. (canceled)
31. A compound of the formula (X) ##STR00010## or any salt of a
compound of the formula (X) or any mixture containing or consisting
of two or more different compounds of the formula (X), two or more
different salts of compounds of the formula (X) or one or more
different compounds of the formula (X) and one or more different
salts of compounds of the formula (X), wherein for R1, R2 and R3
independently of one another in every compound of the formula (X)
the following applies: R1 is hydrogen or methyl, R2 is an organic
residue with 5 carbon atoms and one oxygen atom or none and R3 is
an organic residue with 10 carbon atoms and one or more oxygen
atoms, or R1 and R2 together with the carbon atoms in positions 4
and 5 and the oxygen atom bound to the carbon atom in position 4
form a ring and comprise 5 carbon atoms and one oxygen atom or
none, and R3 is an organic residue with 10 carbon atoms and one or
more oxygen atoms.
32. The compound, salt or mixture according to claim 31, wherein
for the groups R1, R2 and R3 in the compound of the formula (X) or
independently of one another in one, several or all, preferably
all, compound(s) of the formula (X) the following applies: R3 is
##STR00011## wherein the dotted line which links the carbon atoms
designated as B and C denotes a single bond or a double bond is
present between these carbon atoms, and the dotted line which links
the carbon atoms designated as E and G means an individual double
bond, which is positioned either between the carbon atoms
designated as F and G or between the carbon atoms designated as E
and F, R7 for the case where the double bond is positioned between
the carbon atoms designated as E and F, is a hydroxy group or, for
the case where the double bond is positioned between the carbon
atoms designated as F and G, is absent, R5 and R6 is a hydrogen
atom and a hydroxy group or together are an oxygen atom, the dashed
line marks the bond which links R3 with the carbon atom in position
3; R1 is hydrogen or methyl and R2 is ##STR00012## wherein R4 is
hydrogen or a hydroxy group and the dashed line marks the bond
which links R2 with the carbon atom in position 5 or R1 and R2
together is ##STR00013## wherein the dashed line (a) marks the bond
which links the tertiary carbon atom with the oxygen atom bound to
the carbon atom in position 4 and the dashed line (b) marks the
bond which links the secondary carbon atom with the carbon atom in
position 5.
33. The compound, salt or mixture of claim 31, wherein one, several
or all compound(s) of the formula (X) is selected or are each
selected independently of one another from the group consisting of
the following compounds (1) to (10): ##STR00014## ##STR00015##
34. The mixture of claim 31, containing or consisting of two or
more different compounds of the formula (X), preferably of two,
three, four, five, six, seven, eight, nine or ten different
compounds of the formula (X).
35. The mixture of claim 33, containing or consisting of two or
more different compounds of the formula (X) selected from the group
consisting of the compounds (1) to (10).
36. A Mixture comprising a compound of the formula (X) or a salt of
the formula (X) to claim 31, additionally comprising a
hydroxyflavone of the formula (Y) ##STR00016## or a salt of a
hydroxyflavone of the formula (Y) or a mixture containing or
consisting of two or more different hydroxyflavones of the formula
(Y), two or more different salts of hydroxyflavones of the formula
(Y) or one or more different hydroxyflavones of the formula (Y) and
one or more different salts of hydroxyflavones of the formula (Y),
wherein for Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8 and Q9 independently of
one another in each hydroxyflavone of the formula (Y) the following
applies: Q1 to Q9 independently of one another is hydrogen atoms,
hydroxy groups, methyl, ethyl, 1-propyl, methoxy, ethoxy,
1-propyloxy or 2-propyloxy groups, with the proviso that at least
one of the residues Q1 to Q9 represents a hydroxy group.
37. The mixture of claim 36, wherein the following applies: Q2, Q4,
Q5, Q8 and Q9 represent hydrogen atoms, Q1, Q3 and Q6 independently
of one another are hydrogen atoms, hydroxy or methoxy groups, with
the proviso that at least one of the residues Q1 and Q3 represents
a hydroxy group and Q7 represents a hydroxy group.
38. The mixture of claim 36, containing one, several or all
compounds of the formula (Y) selected from the group consisting of
homoeriodictyol, sterubin, eriodictyol, hesperetin, chrysoeriol and
luteolin, preferably comprising homoeriodictyol.
39. The mixture of claim 36, wherein the proportion of the total
quantity of compounds of the formula (X) and salts of compounds of
the formula (X) in the mixture, based on the total weight of the
mixture, is 1 to 99 wt. %, and/or the proportion of the total
quantity of compounds of the formula (Y) and salts of compounds of
the formula (Y) in the mixture, based on the total weight of the
mixture, is 1 to 99 wt. %.
40. The mixture of claim 36, wherein the proportion of the total
quantity of compounds of the formula (X), compounds of the formula
(Y), salts of compounds of the formula (X) and salts of compounds
of the formula (Y) in the mixture, based on the total weight of the
mixture, is 0.0001 to 100 wt. %.
41. The mixture of claim 36, wherein the mixture comprises a plant
extract or consists thereof, and the proportion of the total
quantity of compounds of the formula (X) and salts of compounds of
the formula (X) in the mixture, based on the total weight of the
mixture, is preferably 0.1 to 100 wt. %.
42. The mixture of claim 36, wherein the plant extract is an
extract from Eriodictyon ssp.
43. The mixture of claim 36, wherein the ratio of the total
quantity of compounds of the formula (X) and salts of compounds of
the formula (X) to the total quantity of compounds of the formula
(Y) and salts of compounds of the formula (Y) lies in the range
from 0.00001:1 to 1:0.00001 based on the weight.
44. A preparation comprising a compound, a salt or a mixture as
defined in claim 31, for the prophylaxis and/or treatment of
inflammation. in particular of inflammation of the skin.
45. The preparation of claim 44, which is a food or enjoyment
preparation, a pharmaceutical preparation, a cosmetic preparation
or a dermatological preparation.
46. The preparation of claim 44, additionally containing one or
more further components selected from the group consisting of
probiotic bacteria, prebiotics, synbiotics, ballast substances,
whey proteins, soya proteins, minerals, tocopherols, vanilla,
vanilla extracts, omega-3 fatty acids, citrus, apple, grape seed,
green tea, rosemary, tarragon, thyme, horseradish and mace
extracts, tannins, tomato, melon and rosehip extracts,
beta-carotene; aubergines, rhubarb, red onions, red cabbage, black
carrot, superfruits, in particular acai, noni, goji, pomegranate,
mangosteen, currants, strawberries, aronia, blueberries and/or
elderberries, preferably in the form of dried fruit, extracts or
fruit preparations; soya isoflavones, nonsteroidal antiinflammatory
drugs, antibiotics, budesonide, systemically active steroids,
sulfasalazine, azathioprine/6-mercaptopurine, methotrexate,
anti-TNF-alpha antibodies, bisabolol, sodium lauryl-sulphate,
chlorhexidine, metal fluorides, organic and inorganic fluorides,
flavourings, essential oils, cooling active substances, in
particular menthol, extracts of pure substances from eucalyptus,
thyme, wintergreen, spearmint and peppermint.
47. The preparation of claim 44, for the treatment of animal or
human skin which requires a treatment with anti-inflammatory active
substances.
48. A method for the prophylaxis and/or treatment of inflammation
comprising administering a compound or salt of formula (X) or
mixture according to claim 31.
49. The method of claim 48 for at least one of a) prophylaxis
and/or treatment of inflammation of the skin, b) reducing the
release of TNF-alpha, c) reducing the release of an interleukin, d)
reducing the release of a prostaglandin, or e) reducing the release
of interferon-gamma and/or NF-.kappa.B.
50. The method of claim 49, wherein the method for the prophylaxis
and/or treatment of inflammation is or comprises (a) a method for
the prophylaxis and/or treatment of chronic inflammatory diseases
and/or (b) a method for strengthening damaged or undamaged skin,
and/or (c) a method for reducing tissue damage, and/or (d) a method
for recreating a normal cellular composition in the intestine,
and/or (e) a method for recreating or stabilizing the function of
skin.
51. A process for obtaining the mixture of claim 36 comprising the
following steps: (a) extraction of plant material from Eriodictyon
ssp., preferably from Eriodictyon califormicum and/or Eriodictyon
angustifolium, so that a mixture is formed which contains compounds
of the formula (X), optionally compounds of the formula (Y) and
other extracted compounds, and (b) concentration of extracted
compounds of the formula (X) and/or salts of the extracted
compounds of the formula (X) and optionally compounds of the
formula (Y) and/or salts of the extracted compounds of the formula
(Y) in the mixture by partial or complete removal of other
extracted compounds and optionally removal of extractants and/or
solvents.
52. The process of claim 51, wherein the proportion of the total
quantity of compounds of the formula (X) and salts of compounds of
the formula (X) in the mixture based on the total weight of the
mixture is 0.1 to 100 wt. %.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] The present invention belongs to the area pharmaceutical and
cosmetic compositions and refers to novel compounds, mixtures and
preparations comprising new compounds with excellent
anti-inflammatory properties.
[0003] 2. State of the Art
[0004] There is a constant need to provide inflammation-inhibiting
substances for the protection of cells or tissues (of people and
animals), in particular of the skin, above all for use in cosmetic
preparations, pharmaceutical preparations, foodstuffs or
semi-luxury products. In particular there is a constant need to
find new substances with anti-inflammatory activity, which support
the natural defence mechanisms against inflammation in
physiological systems (of people and animals). In this respect,
there is particularly great interest in substances from natural
extracts. Particularly attractive for use in foods are plants or
parts or extracts of plants, which have a long history of edible
consumption.
[0005] In the context of the present text, the term "skin"
comprises not only the (human or animal) skin in the usual sense,
but rather cell layers in general which cover internal and/or
external surfaces on/in the human or animal body. Accordingly, in
the context of the present text, the term "skin" comprises surface
and glandular epithelia, i.e. in particular also mucous membranes,
e.g. the oral mucosa, the gastric mucosa and the intestinal mucosa.
As barrier organs of the (human) body, the mucous membranes are
exposed to external influences to a particular extent. They line
the various body cavities which are either in contact with the
external environment (e.g. mouth and throat) or the internal organs
of a body (e.g. intestinal lumen).
[0006] Many intrinsic factors (e.g. genetic predisposition) and
extrinsic factors (e.g. damage to the skin barrier, influence of UV
light, skin-irritant or allergy-triggering substances) can lead to
skin irritation or dysfunctions of the skin.
[0007] In the context of the present text "skin irritation" is
understood to mean any change in the skin, which triggers
indisposition ("sensorial malaise"), and/or is characterized by
symptoms of dry, reddened and/or inflamed skin. The term "sensorial
malaise" also includes states which are associated with pruritus or
pains.
[0008] Skin irritation can include the following skin conditions:
sensitive skin, for example sensitive scalp, easily damaged skin,
atopic skin (atopy) and irritated or inflamed skin, which can
appear in the form of skin reddening (erythema).
[0009] Skin irritation can in particular also concern or comprise
[0010] irritation of the mucous membranes in the oral cavity, for
example periodontitis and gingivitis (as described in detail
below), [0011] irritation and infections of the airways, for
example rhinosinusitis (common cold), sinusitis and
pharyngitis/tonsillitis, and [0012] irritation of the
gastrointestinal tract.
[0013] The problem of sensitive skin affects a growing number of
adults and children. It is believed that a proportion of up to 50%
of the population have sensitive skin (see L. Misery et al., Ann.
Dermatol. Venereol. 2005, 132, 425-429). Sensitive skin describes
skin which has a decreased threshold for irritant substances, and
also hyper-reactive, intolerant and also atopic skin. In the case
of people with sensitive or easily damaged skin, the so-called
"stinging" (Engl. "to sting"=burn, stab, be painful) can be
observed. Typical symptoms which are associated with "stinging" or
"sensitive skin" in general are skin reddening, tingling, feelings
of tension and burning of the skin and pruritus. They can be
triggered by certain ambient influences, e.g. massage, influence of
surfactants, weather (heat, cold, dryness or high atmospheric
humidity), thermal or UV radiation (e.g. emanating from the sun) or
even by psychological stress.
[0014] Sensitive scalp is also characterized by skin reddening,
tingling, burning and stinging. Triggers are for example soap,
shampoos or other hair care products, surfactants, water with a
high calcium carbonate content and/or (mechanical) stress. Erythema
and hyperseborrhoea (excessive sebaceous secretion) of the scalp
and dandruff are often accompanied by the said symptoms.
[0015] Atopy (atopic syndrome) is observed (with a rising trend) in
ca. 10-20% of the population in industrialized countries. This is a
hypersensitivity of the skin to substances from the environment
with an increased tendency to development of hypersensitivity
reactions of the immediate type (allergies) towards substances from
the natural environment. It is believed that atopy has genetic
causes. Atopy can appear as atopic dermatitis. In this case, the
skin barrier is damaged, and the skin is often inflamed and
itches.
[0016] Periodontitis (as an example of an inflammatory reaction of
the gums or the oral mucosa) is an inflammation of the periodontium
(dental periosteum), i.e. the tissue which surrounds and supports
the teeth. The periodontium consists of various tissues: gingival
epithelium (gingiva; gum), connective tissue of the gingiva, dental
periosteum (periodontium, desmodontium), dental cement and
surrounding alveolar bone. The dental periosteum lies between the
surface of the root and the alveolar bone and is a cell-rich
connective tissue which holds the teeth in the osseous tooth
socket, the alveolus. 53 to 74% of the periodontal gap consists of
collagen and oxytalan fibre bundles. Periodontal fibres which are
present in the dental cement and in the alveolar bone hold the
tooth in the alveolar bone. The main characteristics of
periodontitis comprise inflammation of the gum, loss of stability,
formation of pockets in the dental periosteum and degradation of
the alveolar bone.
[0017] The main cause of periodontitis is plaque. This consists of
certain components of the saliva, food residues and bacteria and
degradation products thereof. This specific form of infectious
disease is in most cases caused by Porphyromonas gingivalis,
Bacteroides forsythus and Actinobacillus actinomycetemcomitans. The
continuous release of bacterial toxins, in particular
lipopolysaccharide (LPS), leads to a non-specific immune defence
reaction. LPS-stimulated macrophages release prostaglandin E2
(PGE2) and pro-inflammatory mediators, such as for example
interleukins (e.g. IL-1 beta) and TNF-alpha, in the affected tissue
of the patient. The pro-inflammatory mediators trigger the release
of further PGE2s and matrix-destroying metalloproteinases (matrix
metalloproteinases, MMPs) from the invasive fibroblasts, which
destroy the extracellular matrix of the surrounding connective
tissue. This in turn allows bacteria which are actually in contact
with the exposed gum to penetrate deeper into the underlying
connective tissue and there to drive the inflammatory process
further, so that eventually the junction between the top layer of
the epithelium and the root is lost. As a result a pocket in the
gum is formed. The body's reaction to this is an inflammation of
the gum and the dental periosteum with damage to the alveolar bone.
In the final stage of periodontitis, the person affected is at risk
of tooth loss.
[0018] However, in addition to bacteria, chemical or mechanical
damage can also cause irritation or inflammatory reactions of the
gum or the oral mucosa. Pro-inflammatory mediators, in particular
interleukins such as IL-1 alpha and PGE2, are released in this
process.
[0019] Irritation and infections of the airways affect the
respiratory tract (of people or animals). The respiratory tract is
subdivided into three sections: [0020] (i) the upper airways, incl.
nose and paranasal sinuses and pharynx, [0021] (ii) the lower
airways with larynx and trachea and [0022] (iii) the lungs with
bronchi, bronchioles, pulmonary alveoli, etc.
[0023] "Irritation and infections of the upper airways" designate
in particular an acute infection, which affects the upper airways,
nose, sinus, pharynx and/or larynx. In the United States of
America, ca. one billion acute diseases of the upper airways are
recorded each year. Irritation and infections of the upper airways
include rhinosinusitis (common cold), sinusitis,
pharyngitis/tonsillitis, laryngitis and sometimes bronchitis. The
symptoms of these infections often include swelling of the nasal
mucosae, cough, nasal catarrh, sore throat, fever, sneezing and
pressure sensation. The symptoms as a rule start 1 to 3 days after
contact with pathogenic germs, mostly viruses. The symptoms
typically cease in 7 to 10 days, but can also persist for
longer.
[0024] A commonly occurring (airway) infection is pharyngitis.
Pharyngitis is in most cases a painful inflammation of the pharynx
and is thus commonly also described as sore throat. Inflammation of
the tonsils, tonsil inflammation or tonsillitis can arise at the
same time.
[0025] For infections of the upper airways there are essentially
three therapeutic approaches: symptomatic, remedial and preventive.
Symptomatic therapy aims to alleviate symptoms and pain. Remedial
therapies are intended to treat the pharyngitis by preventing its
spreading and accelerate the healing process. Preventive therapy is
intended to prevent the outbreak of an infection.
[0026] Remedial therapies are most effective against bacterial
infections, e.g. streptococci. Many preventive therapies are also
remedial.
[0027] With viral infections, the recovery from a pharyngeal
inflammation as a rule occurs spontaneously within a few days.
Hence the favourite method is symptomatic therapy.
[0028] Various non-antibiotic therapies for throat inflammation
have been tested in controlled studies. Analgesic therapies are
among the most effective here.
[0029] The symptomatic therapies for infections of the upper
airways include: formulations whose purpose is to act remedially or
symptomatically and which can present in the following forms:
[0030] solid galenical forms (such as for example tablets (with and
without coating, with and without modified release), sugar-coated
tablets (with and without coating, with and without modified
release), capsules (soft or hard gelatine capsules with and without
modified release), granules (with and without modified release),
powders (with and without modified release), suppositories (with
and without coating, with and without modified release), lozenges
and chewing gums), [0031] liquid forms (such as for example
solutions, suspensions, emulsions, syrups (colloquially cough
syrup), mouthwashes, gargle solutions, throat sprays or nasal
sprays, nasal drops, nasal rinse solutions, nasal powders, nasal
ointments or ear drops, ear sprays, ear rinse solutions, ear
powders and aural tampons), [0032] semisolid forms (such as for
example hydrophobic ointments including for example: hydrocarbon
gels, lipogels, silicone gels, oleogels and water-absorbing
ointments including for example absorption bases, hydrophilic
ointments, hydrophilic gels (hydrogels) or pastes, [0033] Inhalants
(such as for example compressed gas dispenser inhalers, powder
inhalers, inhalers with atomisers, and inhalation concentrates for
inhalation), and [0034] active substance-containing plasters or
other therapeutic systems.
[0035] The gastrointestinal tract (also called digestive tract) is
the system of internal organs which take up and digest the food, in
order to absorb nutrient substances therefrom, to obtain energy and
to excrete the food components remaining. Accordingly, the main
functions of the digestive tract are food uptake, digestion,
absorption and excretion.
[0036] The upper digestive tract consists of the mouth, pharynx,
oesophagus and stomach. The mouth contains the oral mucosae, which
contain the openings of the saliva glands, the tongue and the
teeth. Behind the mouth lies the pharynx, which leads to a hollow
muscular tube, the oesophagus, which in turn leads into the
stomach. The small intestine is joined to the stomach. The lower
digestive tract consists of the intestines and the anus. The
intestines consist of the intestine, the small intestine, which
consists of three parts, duodenum, jejunum and ileum, the large
intestine, which also consists of three sections, caecum with
vermiform appendix (blind gut), the colon (rising colon, transverse
colon and descending colon) and the rectum.
[0037] The commonest inflammatory conditions of the digestive
tracts include gastro-oesophageal reflux diseases, heartburn and
gastric ulcers. The therapy usually includes firstly reduction of
the symptoms and reduction of the inflammation in the tissue and
secondly longer-term therapies in order to prevent reappearance of
the symptoms.
[0038] Other inflammatory diseases of the digestive system, inter
alia, are milder inflammatory diseases such as irritable bowel
syndrome (IBS) and inflammatory diseases of unknown aetiology and
chronic inflammatory intestinal diseases (IBD), such as for example
chronic colitis (ulcerative colitis).
[0039] There is a particularly great need for suitable applications
for the prevention or treatment of chronic inflammatory intestinal
diseases, in particular chronic colitis (ulcerative colitis).
[0040] Chronic inflammation can appear as a cause of various
diseases and living conditions. It can be associated with the most
diverse conditions such as arthritis, some types of cancer,
colitis, diabetes mellitus, coronary heart disease, obesity,
Alzheimer's disease and immune dysfunction.
[0041] There are essentially two enzymatic pathways for regulating
inflammation. The lipoxygenase pathway (5-LOX) results in the
production of leukotrienes, which have a pro-inflammatory action.
The second pathway is the cyclooxygenase pathway (COX-1 and COX-2).
A high level of COX-2 indicates inflammation. Further inflammation
markers are tumour necrosis factor (TNF-.alpha.), nuclear factor
.kappa.B (NF-.kappa.B), interleukin-6 (IL-6), interleukin-17
(IL-17) and interleukin-1-.beta. (IL1.beta.). The enzymes,
cytokines and metabolites thereof increase the production of
prostaglandins and leukotrienes, which function as intercellular
mediators, and are connected with the inflammatory process.
Regulation of the enzymes LOX-5 and COX-2 in particular can have a
positive effect in the development/suppression of inflammation.
[0042] A diet which is based on much sugar and starch, and fat and
trans fatty acids, has a direct connection with chronic
inflammation. Oxidation of multiply unsaturated fats and fatty
acids in vitro and in vivo leads to the formation of reactive
oxygen species (radicals), and to the form ation of nitrogen
oxides. These compounds can initiate and/or promote the first phase
of an inflammatory process. Damage to the DNA can result from
this.
[0043] Over its whole length, particularly in the region of the
intestine, the gastrointestinal tract is susceptible to
inflammation, hence it is very important to inhibit corresponding
processes and to prevent inflammation. Without treatment, harmful
processes can lead to irritation, acute and chronic inflammation,
and onwards to cancer.
[0044] Chronic inflammatory diseases of the digestive tract mucosa
represent a considerable health political problem. Younger people
in particular are falling ill, whose whole lifestyle is severely
affected thereby, and who have to rely on medical care throughout
their life. The aetiology/pathogenesis of the chronic inflammatory
diseases of the digestive tract is not completely clear. However,
it is believed to be a cause of the onset of a disorder of the
intestinal barrier.
[0045] Ulcerative colitis and Crohn's disease are inflammations of
the intestine, which exhibit characteristic accompanying symptoms
such as diarrhoea, blood in stools, abdominal pains and cramps, and
weight loss. At the same time, the intestinal mucosa appears red
and swollen and often bleeds on the slightest touch.
[0046] The epithelial cells of the mucosa represent the cell layer
closest to the surface. The intestinal epithelial cells constitute
the greatest contact area of the body with the outside world. They
absorb food and at the same time prevent the penetration of
pathogenic organisms. The latter is promoted by chronic
physiological inflammation. This is subject to a range of control
and regulatory mechanisms in order to avoid on one hand the
penetration of pathogenic germs and on the other hand damage due to
the inflammatory mediators themselves. For this, the epithelial
cells interact with the cells of the mucosa-associated immune
system.
[0047] Intestinal epithelial cells possibly have an important role
in the pathogenesis of chronic inflammatory intestinal diseases.
The main model for the onset of chronic inflammatory intestinal
diseases describes the following scenario: a defect in the
structural integrity of the intestinal epithelium leads to an
invasion of antigens from the intestinal lumen. In genetically
predisposed patients, this process can trigger a chronic
inflammation through activation of the mucosa-associated lymphatic
tissue. A disorder of the cell-cell contact due to genetic
modification of the N-adherin or keratin 8 triggers a chronic
intestinal inflammation. Epithelial cells possess a large number of
receptors for signal uptake. These in particular include receptors
for the recognition of bacterial motifs, so-called pattern
recognition receptors.
[0048] One such recognition receptor for bacterial motifs is the
so-called NOD2/CARD15 protein. NOD2/CARD15 is a member of the
NBS-LRR protein family (for nucleotide-binding site and
leucine-rich repeat), the members whereof all play a part in the
intracellular recognition of microbes and components thereof and
which also include for example Apaf-1 and CARD4/NOD1, which
possibly also can play a part in certain patients. When bacterial
components bind to NOD2/CARD15, this normally leads to activation
of the pro-inflammatory transcription factor NF-.kappa.B.
[0049] Adherent E. coli strains have been found in ulcerations in
patients with Crohn's disease. In general, in patients with IBD or
IBS, considerably more bacteria are directly adjacent to the
intestinal epithelial cells than in the normal mucosa, which is
protected from contact with bacteria by a mucus layer. This
observation supports the hypothesis of the importance of bacterial
translocation in the pathogenesis of IBD.
[0050] The currently available therapies for the treatment of
Crohn's disease and ulcerative colitis can alleviate, but not cure,
the disease symptoms. Most therapies end with a resistance to the
antibiotic and surgical intervention.
[0051] In Biosci. BioTech. Biochem Japan, 67(9) S. 2038-2041 (2003)
Makabe et al. showed that compound from Myrsine sequinii, in
particularly myrsonic acids have some anti-inflammatory properties.
However, performance differed seriously between the various species
and the document is silent with respect to the activity of the
compounds in view of the broad range of different inflammation
parameters.
[0052] JP 2007/077122 describes the use of plant proanthocyanidins,
for example from apple, pear, apricot, grape, guava, hops, barley
or adzuki bean for the prevention of intestinal inflammation,
especially in the case of ulcerative colitis. The recommended daily
intake is 100 to 2500 mg apple extract or corresponding quantities
of apple proanthocyanidins. The effect of the apple
proanthocyanidins was confirmed in mice with acute ulcerative
colitis caused by dextran sulphate (DSS, 2.5%) over a period of 20
days.
[0053] Models of the DSS-induced colitis (acute or chronic) are
rapid, simple to perform, well reproducible and inexpensive. They
enable the real-time study of the inflammatory process from onset
up to remission and are thus very suitable for studies of
epithelial regeneration and wound healing and for drug
screening.
[0054] The S3 Guideline "Diagnosis and Therapy of Crohn's disease"
summarizes the results (on the treatment of the aforesaid diseases)
of an evidence-based consensus conference of the German Society for
Digestive and Metabolic Diseases with the competence field Chronic
inflammatory intestinal diseases (Z Gastroenterol 2008; 46:
1094-1146). For the therapy of such diseases, inter alia
budesonide, systemically active steroids, sulfasalazine,
azathioprine/6-mercaptopurine, methotrexate and anti-TNF-alpha
antibodies have until now been used.
[0055] Overall, however, there is still a need for suitable uses
for the prophylaxis and/or treatment of inflammation.
SUMMARY OF THE INVENTION
[0056] Object of the present invention is a compound of the formula
(X)
##STR00002##
or any salt of a compound of the formula (X) or any mixture
containing or consisting of two or more different compounds of the
formula (X), two or more different salts of compounds of the
formula (X) or one or more different compounds of the formula (X)
and one or more different salts of compounds of the formula (X),
wherein for [0057] R1, R2 and R3 independently of one another in
every compound of the formula (X) the following applies: [0058] R1
means hydrogen or methyl, [0059] R2 means an organic residue with 5
carbon atoms and one oxygen atom or none and [0060] R3 means an
organic residue with 10 carbon atoms and one or more oxygen atoms,
[0061] or [0062] R1 and R2 together with the carbon atoms in
positions 4 and 5 and the oxygen atom bound to the carbon atom in
position 4 form a ring and comprise 5 carbon atoms and one oxygen
atom or none, and [0063] R3 means an organic residue with 10 carbon
atoms and one or more oxygen atoms, for use in a method for the
prophylaxis and/or treatment of inflammation, in particular of
inflammation of the (human or animal) skin, in particular in a
method [0064] for reducing the release of TNF-alpha, and/or [0065]
for reducing the release of an interleukin, preferably of IL-1,
IL-6 and/or IL-8, and/or [0066] for reducing the release of a
prostaglandin, preferably of PGE2, and/or [0067] for reducing the
release of interferon-gamma and/or NF-.kappa.B, particularly
preferably in a method [0068] for reducing the release of
TNF-alpha, and/or [0069] for reducing the release of an
interleukin, preferably of IL-1, IL-6 and/or IL-8, and/or [0070]
for reducing the release of a prostaglandin, preferably of
PGE2.
[0071] Essentially therefore, the present invention relates to the
aforementioned compounds, salts or mixtures thereof as
anti-inflammatory active substances.
[0072] For the term "skin", the aforesaid respectively applies. The
skin to be treated according to the invention is thus preferably
human or animal external skin (in the conventional sense) and/or a
mucous membrane, in particular the oral mucosa, the gastric mucosa
and/or the intestinal mucosa, in particular for the prophylaxis
and/or treatment of one or more of the diseases or symptoms
described above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0073] The present invention will be explained in greater detail
with reference to the accompanying drawings in which
[0074] FIGS. 1a and 1b are chromatograms of the invention according
to Example 4,
[0075] FIG. 2a is a graph showing test results of the invention
according to Example 1,
[0076] FIG. 2b is a graph showing test results of the invention
according to Example 4,
[0077] FIG. 3a is a graph showing test results of the invention
according to Example 1,
[0078] FIGS. 3b and 3c are graphs showing test results of the
invention according to Example 4,
[0079] FIG. 3d is a graph showing test results of the invention
according to Example 2, and
[0080] FIG. 3e is a graph showing test results of the invention
according to Example 3.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0081] Preferably the method for the prophylaxis and/or treatment
of inflammation is [0082] (a) a method for the prophylaxis and/or
treatment of chronic inflammatory diseases, in particular
intestinal diseases, and/or [0083] (b) a method for strengthening
damaged or undamaged skin, in particular mucosa, and/or [0084] (c)
a method for reducing tissue damage, in particular tissue damage in
the intestine, and/or [0085] (d) a method for recreating a normal
cellular composition in the intestine, and/or [0086] (e) a method
for recreating or stabilizing the function of skin, in particular
of mucosa.
Preferred Compounds of Formula X
[0087] Particularly advantageous and therefore preferred according
to the invention is a use as described above, wherein for the
groups R1, R2 and R3 in the compound of the formula (X) or
independently of one another in one, several or all, preferably
all, compound(s) of the formula (X) the following applies: [0088]
R3 means
[0088] ##STR00003## wherein the dotted line which links the carbon
atoms designated as B and C means that a single bond or a double
bond is present between these carbon atoms, and the dotted line
which links the carbon atoms designated as E and G means an
individual double bond, which is positioned either between the
carbon atoms designated as F and G or between the carbon atoms
designated as E and F, [0089] R7, for the case where the double
bond is positioned between the carbon atoms designated as E and F,
means a hydroxy group or, for the case where the double bond is
positioned between the carbon atoms designated as F and G, is
absent, [0090] R5 and R6 mean a hydrogen atom and a hydroxy group
or together mean an oxygen atom, the dashed line marks the bond
which links R3 with the carbon atom in position 3; [0091] R1 means
hydrogen or methyl and [0092] R2 means
[0092] ##STR00004## wherein R4 means hydrogen or a hydroxy group
and the dashed line marks the bond which links R2 with the carbon
atom in position 5 or [0093] R1 and R2 together mean
[0093] ##STR00005## wherein the dashed line (a) marks the bond
which links the tertiary carbon atom with the oxygen atom bound to
the carbon atom in position 4 and the dashed line (b) marks the
bond which links the secondary carbon atom with the carbon atom in
position 5.
[0094] Particularly preferable is a use according to the invention
(as described above), wherein one, several or all compound(s) of
the formula (X) is selected or are each selected independently of
one another from the group consisting of the following compounds
(1) to (10):
##STR00006## ##STR00007## [0095] Erionic acid A corresponds to:
4-hydroxy-3-((E)-7-hydroxy-3,7-dimethyl-4-oxo-oct-5-enyl)-5-((E)-4-hydrox-
y-3-methyl-but-2-enyl)-benzoic acid (1) [0096] Erionic acid B
corresponds to:
3-hydroxy-8-((E)-7-hydroxy-3,7-dimethyl-4-oxo-oct-5-enyl)-2,2-dimethy-
l-chroman-6-carboxylic acid (2) [0097] Erionic acid C corresponds
to:
3-(3,7-dimethyl-4-oxo-oct-6-enyl)-4-hydroxy-5-((E)-4-hydroxy-3-methyl-but-
-2-enyl)-benzoic acid (3) [0098] Erionic acid D corresponds to:
8-((E)-3,7-dimethyl-4-oxo-oct-5-enyl)-3-hydroxy-2,2-dimethyl-chroman-6-ca-
rboxylic acid (4) [0099] Erionic acid E corresponds to:
4-hydroxy-3-((E)-7-hydroxy-3,7-dimethyl-4-oxo-oct-5-enyl)-5-(3-methyl-but-
-2-enyl)-benzoic acid (5) [0100] Erionic acid F corresponds to:
3-(3,7-dimethyl-4-oxo-oct-6-enyl)-4-hydroxy-5-(3-methyl-but-2-enyl)-benzo-
ic acid (6) [0101] Eriolic acid A corresponds to:
3-((E)-4-hydroxy-3,7-dimethyl-octa-2,6-dienyl)-5-((E)-4-hydroxy-3-methyl--
but-2-enyl)-4-methoxy-benzoic acid (7) [0102] Eriolic acid B
corresponds to:
4-hydroxy-3-((E)-4-hydroxy-3,7-dimethyl-octa-2,6-dienyl)-5-(3-methyl--
but-2-enyl)-benzoic acid (8) [0103] Eriolic acid C corresponds to:
4-hydroxy-3-((E)-4-hydroxy-3,7-dimethyl-octa-2,6-dienyl)-5-((E)-4-hydroxy-
-3-methyl-but-2-enyl)-benzoic acid (9) and [0104] Eriolic acid D
corresponds to:
3-((E)-4-hydroxy-3,7-dimethyl-octa-2,6-dienyl)-4-methoxy-5-(3-methyl-but--
2-enyl)-benzoic acid (10).
[0105] The benzoic acids of the formula (X) to be used according to
the invention can contain one or more asymmetric carbon atoms.
These can each be present in the (R) or (S) configuration. These
stereoisomers can be present as enantiomers, diastereomers or
epimers, in particular as (R), (S), (R,R), (R,S), (S,R) or
(S,S)-configured compounds or as any mixture of these compounds,
for example as a racemate, or also as any mixture of the
corresponding diastereomers.
[0106] Particularly preferable according to the invention is a
mixture (as described above), containing or consisting of two or
more different compounds of the formula (X), preferably of two,
three, four, five, six, seven, eight, nine or ten different
compounds of the formula (X), preferably selected from the group
consisting of the compounds (1) to (10).
Herba Santa
[0107] The aforementioned compounds (7) and (9) are two
commercially available compounds (for example supplied by the firm
Ambinter) identified in Herba Santa. However no references to an
anti-inflammatory action of these compounds are known in the state
of the art. It was particularly surprising that the compounds of
the formula (X) from Herba Santa to be used according to the
invention are particularly well suited for use as anti-inflammatory
active substances.
[0108] Herba Santa (also Yerba Santa, mountain balm) in general
designates Eriodictyon ssp., in particular Eriodictyon californicum
(H. & A.) Torr and Eriodictyon angustifolium (from the
Hydrophyllaceae family). Herba Santa foliage has already long been
used as a medicinal plant on account of its medicinal action.
Traditionally, the plants, which were originally found in Mexico
and the west of the USA, were used by American indigenous
inhabitants and later by Spanish settlers (Heinsen, 1972; Munz,
1973; Barrett and Gifford, 1933; Immel, 2006). The antibacterial
action of extracts from Eriodictyon californicum was described by
Salle et al. in 1951 (Arch. Biochem. Biophys. 1951, 32, 121-123).
The main substances contained in Eriodictyon sp. include various
flavanones, inter alia homo-eriodictyol, hesperetin, sterubin,
chrysoeriol and luteolin (Hadleyy and Gisvold, 1942; Ley et al., J.
Agric. Food Chem., 2005). The different biological actions of Herba
Santa were previously mainly attributed to the flavanones
contained, the composition and structures whereof had already been
studied. Scarcely anything is so far known in the literature
concerning the properties of the components from Herba Santa which
do not have a flavanoid structure. In particular, nothing is known
concerning an antiinflammatory action of the compounds to be used
according to the invention. The compounds (1) to (10) also
occurring in various Eriodictyon sp. were only recently described
for the first time. Their capabilities as antioxidants are
presented in DE 10 2009 020729 A1. However, nothing was hitherto
known concerning (additional) anti-inflammatory properties.
Hydroxyflavones
[0109] Particularly preferable according to the invention is a
mixture for use in a method for the prophylaxis and/or treatment of
inflammation (as described above), comprising a compound of the
formula (X), a salt of the formula (X) or a mixture thereof (as
respectively described above) and additionally [0110] a
hydroxyflavone of the formula (Y)
[0110] ##STR00008## [0111] or a salt of a hydroxyflavone of the
formula (Y) [0112] or a mixture containing or consisting of two or
more different hydroxyflavones of the formula (Y), two or more
different salts of hydroxyflavones of the formula (Y) or one or
more different hydroxyflavones of the formula (Y) and one or more
different salts of hydroxyflavones of the formula (Y), wherein for
Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8 and Q9 independently of one another
in each hydroxyflavone of the formula (Y) the following applies: Q1
to Q9 independently of one another mean hydrogen atoms, hydroxy
groups, methyl, ethyl, 1-propyl, methoxy, ethoxy, 1-propyloxy or
2-propyloxy groups, with the proviso that at least one of the
residues Q1 to Q9 represents a hydroxy group, and wherein
preferably the following applies: Q2, Q4, Q5, Q8 and Q9 represent
hydrogen atoms, Q1, Q3 and Q6 independently of one another mean
hydrogen atoms, hydroxy or methoxy groups, with the proviso that at
least one of the residues Q1 and Q3 represents a hydroxy group, and
Q7 represents a hydroxy group.
[0113] The hydroxyflavones of the formula (Y) can be present as
mono- or (in the case of several hydroxy groups) multivalent
anions, wherein as counter-cations the singly positively charged
cations of the first main and transition group, the ammonium ion, a
trialkylammonium ion, the divalently charged cations of the second
main and transition group, and the trivalent cations of the
3.sup.rd main and transition group, preferably, Na.sup.+, K.sup.+,
NH.sub.4.sup.+, Ca.sup.2+, Al.sup.3+ and Zn.sup.2+, are used.
[0114] The hydroxyflavones of the formula (Y) can be present as
(2S) or (2R) enantiomers or as a mixture of both. Preferably the
hydroxyflavones of the formula (Y) are present as the (2S)
enantiomer or as a mixture enriched in (2S) enantiomer.
[0115] Without thereby limiting the invention, the following
compounds may be mentioned by way of example:
2-(4-hydroxyphenyl)-5,7-dihydroxychroman-4-one (naringenin),
2-(3,4-dihydroxyphenyl)-5,7-di hydroxychroman-4-one (eriodictyol),
2-(3,4-di hydroxyphenyl)-5-hydroxy-7-methoxychroman-4-one
(eriodictyol 7-methyl ether),
2-(3,4-dihydroxyphenyl)-7-hydroxy-5-methoxychroman-4-one
(eriodictyol 5-methyl ether),
2-(4-hydroxy-3-methoxyphenyl)-5,7-dihydroxychroman-4-one
(homoeriodictyol) and
2-(3-hydroxy-4-methoxyphenyl)-5,7-dihydroxychroman-4-one
(hesperetin), (2S) or (2R) enantiomers thereof or mixtures thereof,
and mono- or multivalent phenolate salts thereof with Na.sup.+,
K.sup.+, NH.sub.4.sup.+, Ca.sup.2+, Mg.sup.2+ or Al.sup.3+ as
counter-cations.
[0116] The structures of preferred examples of hydroxyflavones of
the formula (Y) are shown below (see compounds (11) to (16)):
##STR00009##
[0117] Particularly preferable is a mixture (as described above)
comprising one, several or all compounds of the formula (Y)
selected from the group consisting of homoeriodictyol, sterubin,
eriodictyol, hesperetin, chrysoeriol and luteolin.
[0118] Particularly preferably, such a mixture contains at least
homoeriodictyol as a compound of the formula (Y).
Mixtures
[0119] According to a preferable embodiment of the present
invention, a mixture (as described above) is provided for the use,
wherein [0120] the proportion of the total quantity of compounds of
the formula (X) and salts of compounds of the formula (X) in the
mixture, based on the total weight of the mixture, is 1 to 99 wt.
%, preferably 10 to 99 wt. %, particularly preferably 20 to 80 wt.
%, and/or [0121] the proportion of the total quantity of compounds
of the formula (Y) and salts of compounds of the formula (Y) in the
mixture, based on the total weight of the mixture, is 1 to 99 wt.
%, preferably 10 to 99 wt. %, particularly preferably 20 to 80 wt.
%, wherein preferably the proportion of the total quantity of
compounds of the formula (X), compounds of the formula (Y), salts
of compounds of the formula (X) and salts of compounds of the
formula (Y) in the mixture, based on the total weight of the
mixture, is 0.0001 to 100 wt. %, preferably 0.001 to 100 wt. %,
particularly preferably 0.1 to 90 wt. %, more preferably 1 to 90
wt. %. According to an especially preferred embodiment, the
proportion is 10 to 90 wt. %, in particular 25 to 90 wt. %
(preferably up to 100 wt. %), more preferably 45 to 90 wt. %
(preferably up to 100 wt. %).
[0122] Surprisingly, in our own studies it was found that certain
extracts prepared from Herba Santa foliage or fractions therefrom
are particularly suitable for treating inflammatory processes, for
example with inflammation in the gastrointestinal tract or
gingivitis, and/or preventing these. Hence, according to a further
aspect of the present invention, a mixture is stated for the use
described according to the invention, wherein the mixture comprises
a plant extract or consists thereof, preferably an extract from
Eriodictyon ssp., particularly preferably an extract from
Eriodictyon californicum and/or Eriodictyon angustifolium, wherein
the proportion of the total quantity of compounds of the formula
(X) and salts of compounds of the formula (X) in the mixture, based
on the total weight of the mixture, is preferably 0.1 to 100 wt. %,
more preferably 1 to 100 wt. %, particularly preferably 10 to 100
wt. %, and more preferably from 10 to 90 wt. %.
[0123] Particularly preferably, the ratio of the total quantity of
compounds of the formula (X) and salts of compounds of the formula
(X) to the total quantity of compounds of the formula (Y) and salts
of compounds of the formula (Y) in a mixture described herein
usable according to the invention lies in the range from 0.00001:1
to 1:0.00001, in particular in the range from 0.0001:1 to 1:0.0001,
preferably in the range from 0.001:1 to 1:0.001, preferably in the
range from 0.01:1 to 1:0.01, particularly preferably in the range
from 0.1:1 to 1:0.1, and more preferably in the range from 0.5:1 to
1:0.5, each based on the weight.
[0124] According to a preferable embodiment of the present
invention, a mixture described herein comprises as compounds of the
formula (Y) homoeriodictyol and sterubin or salt(s) thereof. Here,
as regards preferable quantity data and ratios, the aforesaid
respectively applies.
[0125] In a preferable embodiment of such a mixture, the mixture
contains a total quantity of homoeriodictyol and sterubin (and/or
salts thereof) which is greater than the total quantity of
compounds of the formula (X) (and optionally salts thereof).
Preparations
[0126] The present invention also relates to preparations, in
particular preparations used for food or enjoyment, pharmaceutical
preparations, cosmetic preparations or dermatological preparations
for use in a method for the prophylaxis and/or treatment of
inflammation, comprising a compound, a salt or a mixture as defined
above, for use in a method for the prophylaxis and/or treatment of
inflammation.
[0127] Preferably these are preparations for the prophylaxis and/or
treatment of inflammation of the skin (as described above), in
particular in a method [0128] for reducing the release of
TNF-alpha, and/or [0129] for reducing the release of an
interleukin, preferably of IL-1, IL-6 and/or IL-8, and/or [0130]
for reducing the release of a prostaglandin, preferably of PGE2,
and/or [0131] for reducing the release of interferon-gamma and/or
NF-.kappa.B, particularly preferably in a method [0132] for
reducing the release of TNF-alpha, and/or [0133] for reducing the
release of an interleukin, preferably of IL-1, IL-6 and/or IL-8,
and/or [0134] for reducing the release of a prostaglandin,
preferably of PGE2.
[0135] Preferably here this is also [0136] (a) a method for the
prophylaxis and/or treatment of chronic inflammatory diseases, in
particular intestinal diseases, and/or [0137] (b) a method for
strengthening damaged or undamaged skin, in particular mucosa,
and/or [0138] (c) a method for reducing tissue damage, in
particular tissue damage in the intestine, and/or [0139] (d) a
method for recreating a normal cellular composition in the
intestine, and/or [0140] (e) a method for recreating or stabilizing
the function of skin, in particular of mucosa.
[0141] Moreover, the aforesaid also respectively applies, in
particular as regards the contained compounds of the formula (X) or
salts thereof and the optionally contained compounds of the formula
(Y) or salts thereof.
[0142] Preferably a preparation described above contains a mixture
preferred according to the invention (as described above).
Preparation of the Mixtures
[0143] A mixture according to the invention or a mixture usable
according to the invention, preferably a mixture described above as
preferable, is preferably producible by a method with the following
steps: [0144] (a) Extraction of plant material from Eriodictyon
ssp., preferably from Eriodictyon californicum and/or Eriodictyon
angustifolium, so that a mixture is formed which contains compounds
of the formula (X), optionally compounds of the formula (Y) and
other extracted compounds, and [0145] (b) Concentration of
extracted compounds of the formula (X) and/or salts of the
extracted compounds of the formula (X) and optionally compounds of
the formula (Y) and/or salts of the extracted compounds of the
formula (Y) in the mixture by partial or complete removal of other
extracted compounds and optionally removal of extractants and/or
solvents, preferably so that the proportion of the total quantity
of compounds of the formula (X) and salts of compounds of the
formula (X) in the mixture based on the total weight of the mixture
is 0.1 to 100 wt. %, more preferably 1 to 100 wt. %, particularly
preferably 10 to 100 wt. %, more preferably from 10 to 90 wt.
%.
[0146] Preferably the plant material here is selected from the
group consisting of: [0147] Eriodictyon altissimum P. V.
Wells--Indian Knob mountain balm [0148] Eriodictyon angustifolium
Nutt.--Narrow-leaved Yerba Santa [0149] Eriodictyon californicum
(Hook. & Arm.) Torr.--California Yerba Santa [0150] Eriodictyon
capitatum Eastw.--Lompoc Yerba Santa [0151] Eriodictyon
crassifolium Benth.--Thick-Leaved Yerba Santa [0152] Eriodictyon
tomentosum Benth [0153] Eriodictyon traskiae and [0154] Eriodictyon
trichocalyx (Syn.: Eriodictyon lanatum (Brand) Abrams)--Hairy Yerba
Santa
[0155] According to a preferable aspect of the present invention, a
mixture described herein or a preparation described herein
comprises or consists of an appropriately concentrated extract from
Herba santa, preferably from plant material as described above.
[0156] In the context of the present invention, an extract from
fresh or dried Herba Santa plants or plant parts is preferable,
particularly preferably from plants or plant parts with a solids
content of 90 wt. % or more. Particularly preferably, the extract
is from above-ground plant parts, in particular from leaves, buds,
stems, bark, flowers and/or fruit of E. angustifolium or E.
californicum.
[0157] Extracts from Herba Santa foliage (as described above) can
be obtained by extraction methods known per se from the fresh or
dried foliage of the plants. These for example include maceration
or percolation. As the extraction medium, for example water and
ethanol or mixtures thereof can be used. Instead of ethanol,
methanol and other water-soluble solvents can also be used.
Likewise, ethyl acetate can be used as a solvent. Selection of the
temperature and mechanical disintegration of the fruit can promote
the extraction. According to the state of the art, the mechanical
disintegration of the dried foliage e.g. with stirrers,
homogenizers or ultrasound is also advisable. Further, other
extraction-promoting substances, such as acids, bases and enzymes,
can be used.
[0158] In the context of the present text, the term "Herba Santa
foliage" in particular comprises leaves, buds, bark, flowers, fruit
and stems of Eriodictyon angustifolium, E. californicum, E.
trichocalyx, E. traskiae, and E. crassifolium.
[0159] The identification and quantification of flavones and
bisprenylated benzoic acid derivatives in different Eriodictyon sp.
can be effected by means of RP-HPLC-UV/Vis and RP-HPLC-MS/MS after
the methanolic extraction, as performed in the context of our own
studies. The flavonoid contents, or contents of bisprenylated
benzoic acid derivatives can be determined by means of external
calibration with use of standard substances. The appended FIGS. 1 a
and 1 b respectively show by way of example the flavonoid or
erionic/eriolic acid profile of extracts studied (FIG. 1a: LC-MS
chromatogram of the flavonoid fraction from Eriodictyon
angustifolium extract; FIG. 1b: LC-MS chromatogram of the erionic
acid fraction from Eriodictyon angustifolium extract; each after
fractionation over Sephadex LH-20).
[0160] In the light of the above explanations, a preparation
according to the invention or a mixture according to the invention
(as respectively described above) preferably comprises or consists
of (i) Herba Santa foliage, (ii) an optionally concentrated extract
prepared therefrom or (iii) a fraction thereof.
Additives for the Mixtures
[0161] In the mixtures or preparations according to the invention,
as well as the components described above, one or more further
substances can be contained. Preferably one or more (further)
substances which are suitable for influencing inflammatory states
of the skin, in particular for prophylactic and/or therapeutic uses
as described above, are contained. Furthermore, one or more
substances for the treatment of a deficiency phenomenon arising
during inflammation of the skin (in particular a deficiency of
potassium, sodium, iron, calcium, vitamin D and/or folic acid) can
be contained.
[0162] In the mixtures or preparations according to the invention,
one or more further components selected from the following group
are preferably (also) contained: probiotic bacteria (e.g.
lactobacilli, bifidobacteria and enterococci), prebiotics (e.g.
inulin and fructooligosaccharides), synbiotics (pro- and
prebiotics), ballast substances (e.g. cellulose, starch, resistant
starch and fibres, such as for example apple fibres), whey
proteins, soya proteins, minerals (in particular Ca, Mg, with a
combination of Ca, Mg and inulin being particularly preferable),
tocopherols (e.g. vitamin E, vitamin E acetate), vanilla, vanilla
extracts, omega-3 fatty acids (preferably fish oil), citrus, apple,
grape seed, green tea, rosemary, tarragon, thyme, horseradish and
mace extracts, tannins, tomato, melon and rose hip extracts (in
particular lycopene-containing extracts), betacarotene; aubergines,
rhubarb, red onions, red cabbage, black carrot, superfruits, in
particular agai, noni, goji, pomegranate, mangosteen, currrants,
strawberries, aronia, blueberries and/or elderberries, preferably
in the form of dried fruit, extracts or fruit preparations; soya
isoflavones, nonsteroidal antiinflammatory drugs, antibiotics,
budesonide, systemically active steroids, sulfasalazine,
azathioprine/6-mercaptopurine, methotrexate, anti-TNF-alpha
antibodies, bisabolol, sodium laurylsulphate, chlorhexidine, metal
fluorides (e.g. aluminium and tin fluoride), organic and inorganic
fluorides, flavourings, essential oils, cooling active substances,
in particular menthol, extracts or pure substances from eucalyptus,
thyme, wintergreen, spearmint and peppermint.
Final Preparations for Customers
[0163] Preparations according to the invention (in particular the
preparations designated above as preferable) are preferably
selected from the group consisting of: [0164] Fruit
juice-containing drinks; vegetable juice-containing drinks; bakery
products; confectionery; snacks; instant products; soups; sauces;
spice mixtures; ice cream; fruit preparations; desserts; dairy
products; soya products; cereals; food supplements, medicinal
products and pharmaceutical products. [0165] Fruit juice-containing
drinks here are in particular fruit juices and smoothies (whole
fruit drinks). Vegetable juice-containing drinks are in particular
juices of red beet and black carrot. [0166] Bakery products are in
particular cakes, waffles and biscuits. [0167] Confectionery is in
particular lozenges and chewing gums, fruit gums, chewing sweets,
(breath freshening) sweets, boiled sweets, hard caramels, chocolate
creams, sweets and chocolate. [0168] Instant products are in
particular instant meals and other instant products, e.g. drink
powders and granules. [0169] Fruit preparations are in particular
jams, preserves and fruit sauces. [0170] Desserts are in particular
puddings and jellies. [0171] Dairy products comprise in particular
quark, yoghurt, milk drinks and whey preparations. [0172] Cereals
are in particular cornflakes, muesli and muesli bars. [0173]
Further preferable preparations, in particular food supplements,
medicinal products and pharmaceutical products, are [0174] Solid
galenical forms (such as for example tablets (with and without
coating, with and without modified release), sugar-coated tablets
(with and without coating, with and without modified release),
capsules (soft or hard gelatine capsules with and without modified
release) granules (with and without modified release), powders
(with and without modified release), suppositories (with and
without coating, with and without modified release), lozenges and
chewing gums), [0175] Liquid forms (such as for example solutions,
suspensions, emulsions, syrups (colloquially cough syrup),
mouthwashes, gargle solutions, throat sprays or nasal sprays, nasal
drops, nasal rinse solutions, nasal powders, nasal ointments or ear
drops, ear sprays, ear rinse solutions, ear powders and aural
tampons), [0176] Semisolid forms (such as for example hydrophobic
ointments including for example: hydrocarbon gels, lipogels,
silicone gels, oleogels and water-absorbing ointments including for
example absorption bases, hydrophilic ointments, hydrophilic gels
(hydrogels) or pastes, [0177] Inhalants (such as for example
compressed gas dispenser inhalers, powder inhalers, inhalers with
atomisers, and inhalation concentrates for inhalation), [0178]
Active substance-containing plasters or other therapeutic systems
and [0179] Cosmetic and/or dermatological preparations, which
(except for the substances to be used according to the invention)
are constituted as usual and are used for cosmetic, in particular
dermatological sun protection, for the treatment, care and
cleansing of the skin and/or the hair or as a make-up product in
decorative cosmetics. Accordingly, such preparations can be present
as for example cleaning agents such as for example soap, syndet,
liquid wash, shower and bath preparation, skin care agents such as
for example emulsion (as solution, dispersion, suspension; cream,
lotion or milk depending on production method and ingredients of
the type W/O, O/W or multiple emulsion, PIT emulsion, emulsion
foam, micro- or nanoemulsion, Pickering emulsion), ointment, paste,
gel (including hydro-, hydrodispersion- and oleogel), alcoholic or
aqueous/alcoholic solution, oil, toner, balsam, serum, powder,
wipe, Eau de Toilette, Eau de Cologne, perfume, wax, including the
presentation as stick, roll-on, (pump-)spray, aerosol (foaming,
non-foaming or after-foaming), skin care products (as described
above), as foot care products (including keratolytic agents and
deodorants), as insect repellents, as sunscreen agents, as
self-tanning agents and/or aftersun preparations, skin care
products as shaving products or after-shave, as depilatory agents,
as hair care products such as for example shampoo (including
shampoo for normal hair, for greasy hair, for dry, stressed
(damaged) hair, 2-in-1 shampoo, antidandruff shampoo, baby shampoo,
shampoo for dry scalp, shampoo concentrate), conditioner, hair
mask, hair lotion, hair conditioner, hair cream, pomade, permanent
wave and fixing agents, hair straighteners (straighteners,
relaxers), hair setting lotions, styling aids (e.g. gel or wax);
bleaching agents, hair dyes such as for example temporary, direct
and semipermanent hair dyes, permanent hair dyes), skin care
products as decorative toiletry products, such as for example nail
care products (nail varnish and nail varnish remover), decorative
cosmetics (e.g. powder, eyeshadow, eye pencil, lipstick), skin care
products as deodorant and/or antiperspirant; mouthwash and oral
waterjet, and [0180] Oral care products (e.g. toothpaste, tooth
cream, tooth gel, tooth powder, tooth cleaning fluid or foam,
mouthwash, tooth cream and mouthwash as 2-in-1 product, mouth
spray, dental floss or dental care chewing gum). Such oral or
dental care products as a rule contain abrasive systems (abrasive
or polishing ingredients), such as silicates, calcium carbonate,
calcium phosphate, aluminium oxide and/or hydroxyapatite,
surfactant substances, e.g. sodium laurylsulphate, sodium
laurylsarcosinate and/or cocamidopropyl betaine, humectants such as
glycerol and/or sorbitol, thickeners, e.g. carboxymethylcelluloses,
polyethylene glycols, carrageenan and/or Laponite.RTM., sweeteners
such as saccharin, flavour/taste correctants for unpleasant taste
sensations, taste-modulating substances (e.g. inositol phosphate,
nucleotides, e.g. guanosine monophosphate, adenosine monophosphate
or other substances, e.g. sodium glutamate or 2-phenoxypropionic
acid), cooling active substances, e.g. menthol derivatives (e.g.
L-menthyl lactate, L-menthyl alkyl carbonates, menthone ketals),
icilin and icilin derivatives, stabilizers and active substances,
e.g. sodium fluoride, sodium monofluorophosphate, tin difluoride,
quaternary ammonium fluorides, zinc citrate, zinc sulphate, tin
pyrophosphate, tin dichloride, mixtures of various pyrophosphates,
triclosan, cetylpyridinium chloride, aluminium lactate, potassium
citrate, potassium nitrate, potassium chloride, strontium chloride,
hydrogen peroxide, flavourings, sodium bicarbonate and/or odour
correctants, and [0181] Chewing gums or dental care gums consisting
of a chewing gum base containing elastomers, e.g. polyvinyl
acetates (PVA), polyethylenes, (low or medium molecular weight)
polyisobutenes (PIB), polybutadienes, isobutene-isoprene
copolymers, polyvinyl ethyl ethers (PVE), polyvinyl butyl ethers,
copolymers of vinyl esters and vinyl ethers, styrene/butadiene
copolymers (SBR) or vinyl elastomers, e.g. based on vinyl
acetate/vinyl laurate, vinyl acetate/vinyl stearate or
ethylene/vinyl acetate, and mixtures of the said elastomers such as
for example described in EP 0 242 325, U.S. Pat. No. 4,518,615,
U.S. Pat. No. 5,093,136, U.S. Pat. No. 5,266,336 U.S. Pat. No.
5,601,858 or U.S. Pat. No. 6,986,709. In addition, chewing gum
bases contain further ingredients, e.g. (mineral) fillers (e.g.
calcium carbonate, titanium dioxide, silicon dioxide, talc,
aluminium oxide, dicalcium phosphate, tricalcium phosphate,
magnesium hydroxide and mixtures thereof, plasticizers (e.g.
lanolin, stearic acid, sodium stearate, ethyl acetate, diacetin
(glycerol diacetate), triacetin (glycerol triacetate) and triethyl
citrate), emulsifiers (e.g. phosphatides, such as lecithin and mono
and diglycerides of fatty acids, e.g. glycerol monostearate),
antioxidants, waxes (e.g. paraffin waxes, candelilla waxes,
carnauba wax, microcrystalline waxes and polyethylene waxes), fats
or fatty oils (e.g. hardened (hydrogenated) plant or animal fats)
and mono, di- or triglycerides.
[0182] Preferable preparations according to the invention used for
food or enjoyment are:
[0183] Confectionery such as for example lozenges and chewing gums,
fruit gums, chewing sweets, (breath freshening) sweets, boiled
sweets, hard caramels, chocolate creams, sweets and chocolate,
bakery products such as cakes, waffles and biscuits, snacks,
instant meals and other instant products (drink powders and
granules), ice cream, fruit preparations (jams, preserves and fruit
sauces), desserts (puddings, jellies), dairy products (quark,
yoghurts, probiotic yoghurts, milk drinks, whey preparations) and
cereals (cornflakes, muesli and muesli bars).
[0184] Especially preferred preparations according to the invention
used for food or enjoyment are fruit gums, fruit preparations
(jams, preserves and fruit sauces), dairy products (quark,
yoghurts, probiotic yoghurts, milk drinks, whey preparations) and
cereals (cornflakes, muesli and muesli bars), wherein in turn the
dairy products yoghurts, probiotic yoghurts and milk drinks are
most preferred.
Additives for the Preparations
[0185] As further components for preparations according to the
invention used in particular for food or enjoyment, normal primary,
auxiliary and additive substances for food or luxury consumables
can be used, e.g. water, mixtures of fresh or processed, plant or
animal primary or raw substances (e.g. raw, roast, dried,
fermented, smoked and/or boiled meat, bones, cartilage, fish,
vegetables, fruit, spices, nuts, vegetable or fruit juices or
pastes or mixtures thereof), digestible or non-digestible
carbohydrates (e.g. amylose, amylopectin, inulin, xylans,
cellulose), natural or hardened fats (e.g. tallow, lard, palm fat,
coconut fat, hardened plant fat), oils (e.g. sunflower oil, peanut
oil, maize oil, olive oil, fish oil, soya oil, sesame oil), fatty
acids or salts thereof (e.g. potassium stearate), proteinogenic or
non-proteinogenic amino acids and related compounds (e.g.
.gamma.-amino-butyric acid, taurine), peptides (e.g. glutathione),
native or processed proteins (e.g. gelatine), enzymes (e.g.
peptidases), nucleic acids, nucleotides, taste correctants for
unpleasant taste sensations, further taste modulators for further,
as a rule not unpleasant taste sensations, other taste-modulating
substances (e.g. inositol phosphate, nucleotides such as guanosine
monophosphate, adenosine monophosphate or other substances such as
sodium glutamate or 2-phenoxypropionic acid), emulsifiers (e.g.
lecithins, diacylglycerols, gum Arabic), stabilizers (e.g.
carrageenan, alginate), preservatives (e.g. benzoic acid, sorbic
acid), antioxidants (e.g. tocopherol, ascorbic acid), chelators
(e.g. citric acid), organic or inorganic acidulants (e.g. malic
acid, acetic acid, citric acid, tartaric acid, phosphoric acid),
bitter substances (e.g. quinine, caffeine, limonin, amarogentin,
humolone, lupolone, catechins, tannins), mineral salts (e.g. sodium
chloride, potassium chloride, magnesium chloride, sodium
phosphate), substances preventing enzymatic browning (e.g.
sulphite, ascorbic acid), essential oils, plant extracts, natural
or synthetic dyes or pigments (e.g. carotenoids, flavonoids,
anthocyans, chlorophyll and derivatives thereof), spices,
trigeminally active substances or plant extracts, containing such
trigeminally active substances, cooling active substances such as
for example menthol, menthol derivatives (e.g. L-menthol, L-menthyl
lactate, L-menthyl glutarate, L-menthyl succinate) or cubebol,
synthetic, natural or nature-identical flavourings or aromatic
substances and odour correcta nts.
[0186] Preparations according to the invention, used in particular
for food or enjoyment can additionally contain one or more taste
correctants, preferably selected from the following list:
nucleotides (e.g. adenosine 5'-monophosphate, cytidine
5'-monophosphate) or pharmaceutically acceptable salts thereof,
lactisols, sodium salts (e.g. sodium chloride, sodium lactate,
sodium citrate, sodium acetate, sodium gluconate), further
hydroxy-flavanones (e.g. eriodictyol, homoeriodictyol or sodium
salts thereof), in particular according to US 2002/0188019,
hydroxybenzamides as per DE 10 2004 041 496 (e.g.
2,4-dihydroxybenzoic acid vanillylamide, 2,4-dihydroxybenzoic acid
N-(4-hydroxy-3-methoxybenzyl)amide, 2,4,6-trihydroxybenzoic acid
N-(4-hydroxy-3-methoxybenzyl)-amide, 2-hydroxybenzoic acid
N-4-(hydroxy-3-methoxybenzyl)amide, 4-hydroxybenzoic acid
N-(4-hydroxy-3-methoxybenzyl)amide, 2,4-dihydroxybenzoic acid
N-(4-hydroxy-3-methoxybenzyl)amide monosodium salt,
2,4-dihydroxybenzoic acid
N-2-(4-hydroxy-3-methoxyphenyl)ethylamide, 2,4-dihydroxybenzoic
acid N-(4-hydroxy-3-ethoxybenzyl)-amide, 2,4-dihydroxybenzoic acid
N-(3,4-dihydroxybenzyl)amide and
2-hydroxy-5-methoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]amide
(aduncamide), 4-hydroxybenzoic acid vanillylamide), bitter-masking
hydroxydeoxybenzoins according to WO 2006/106023 and the documents
based thereon (Symrise) (e.g.
2-(4-hydroxy-3-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)ethanone,
1-(2,4-dihydroxyphenyl)-2-(4-hydroxy-3-methoxy-phenyl)ethanone,
1-(2-hydroxy-4-methoxyphe-nyl)-2-(4-hydroxy-3-methoxyphenyl)ethanone),
amino acids (e.g. gamma-aminobutyric acid as per WO 2005/096841 for
reduction or masking of an unpleasant taste sensation such as
bitterness), malic acid glycosides as per WO 2006/003107,
salty-tasting mixtures as per WO 2007/045566, diacetyl trimers as
per WO 2006/058893, divanillin, mixtures of whey proteins with
lecithins and/or bitter-masking substances such as gingerdiones
according to WO 2007/003527.
[0187] Preparations according to the invention used in particular
for food or enjoyment can additionally contain one or more
alkamides, preferably selected from the group consisting of:
2E,4E-decadienoic acid N-isobutylamide (pellitorin),
2E,4Z-decadienoic acid N-isobutylamide (cispellitorin),
2Z,4Z-decadienoic acid N-isobutylamide, 2Z,4E-decadienoic acid
N-isobutylamide, 2E,4E-decadienoic acid
N-([2S]-2-methylbutyl)amide, 2E,4E-decadienoic acid
N-([2S]-2-methylbutylamide, 2E,4E-decadienoic acid
N-([2R]-2-methylbutylamide), 2E,4Z-decadienoic acid
N-(2-methylbutyl)amide, 2E,4E-decadienoic acid N-piperide
(achilleamide), 2E,4E-decadienoic acid N-piperide (sarmentin),
2E-decenoic acid N-isobutylamide, 3E-decenoic acid N-isobutylamide,
3E-nonenoic acid N-isobutylamide, 2E,6Z,8E-decatrienoic acid
N-isobutylamide (spilanthol), 2E,6Z,8E-decatrienoic acid
N-([2S]-2-methylbutyl)amide (homospilanthol), 2E,6Z,8E-decatrienoic
acid N-([2R]-2-methylbutyl)amide, 2E-decen-4-ynic acid
N-isobutylamide, 2Z-decen-4-ynic acid N-isobutylamide,
sanshoole.
[0188] Preparations according to the invention, used in particular
for prophylaxis and supplementation of food and for the therapy of
disease states and for toiletries can preferably contain substances
or combinations of substances from the following groups.
[0189] Fillers (e.g. cellulose, calcium carbonate), free-flow and
anticaking agents (e.g. talc, magnesium stearate), coatings (e.g.
polyvinyl acetate phthalate, hydroxypropyl-methylcellulose
phthalate), disintegrants (e.g. starch, crosslinked
polyvinylpyrrolidone), plasticizers (e.g. triethyl citrate, dibutyl
phthalate) substances for granulation (lactose, gelatine),
retardation (e.g. poly(meth)acrylic acid
methyl/ethyl/2-trimethylaminoethyl ester copolymers in dispersion,
vinyl acetate/crotonic acid copolymers) and compacting (e.g.
microcrystalline cellulose, lactose), solvent, suspension or
dispersion agents (e.g. water, ethanol), emulsifiers (e.g. cetyl
alcohol, lecithin), substances for modification of the rheological
properties (silicon dioxide, sodium alginate), substances for
microbial stabilization (e.g. benzalkonium chloride, potassium
sorbate), preservatives and antioxidants (e.g. DL-alpha-tocopherol,
ascorbic acid), substances for modification of the pH (lactic acid,
citric acid), propellant or inert gases (e.g. fluorinated
chlorohydrocarbons, carbon dioxide), colorants (iron oxides,
titanium dioxide), ointment bases (e.g. paraffins, beeswax), inter
alia as described in the technical literature (e.g. Schmidt,
Christin. Active and Auxiliary Substances for Individual and Bulk
Formulation, and Large-scale Manufacture. 1999; Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart or Bauer, Fromming Fuhrer.
Textbook of Pharmaceutical Technology. 8.sup.th Edition, 2006.
Wissenschaftliche Verlagsgesellschaft mbH Stuttgart).
[0190] Depending on the embodiment according to the invention and
desired purpose, mixtures according to the invention (as described
above) can also contain one or more of the components mentioned
above in connection with preparations according to the
invention.
INDUSTRIAL APPLICATION
[0191] A further aspect of the present invention relates to a
compound, a salt, a mixture or a preparation, as respectively
described or defined above, for use in a method for the treatment
of animal or human skin which requires treatment with
anti-inflammatory active substances. Regarding the selection of the
compounds or the salts and the preferable composition of the
mixtures and preparations, the aforesaid respectively applies.
[0192] The compounds (1) to (16) described herein advantageously
possess a particularly strong anti-inflammatory action. The
compounds (1) to (16) are advantageously suitable for supporting
the natural defence mechanisms against inflammatory processes in
physiological systems (of people and animals). Further, these
compounds advantageously occur in plants with a long edible
consumption history (e.g. Herba Santa) owing to which they are
particularly suitable for use in foods.
[0193] Particularly advantageous according to the invention
therefore is a mixture or a preparation as described above, where
this comprises one, two, three, four, five, six, seven, eight, nine
or all compounds (1) to (10) and also one, two, three, four, five
or all compounds (11) to (16) or consists thereof. Particularly
preferable here is a mixture or a preparation, which comprises all
of the compound (1) to (16) or consists thereof.
[0194] Such a mixture or preparation wherein one, several or all
compounds of the group of the compounds (1) to (16) are components
of a plant extract, preferably an extract from eriodictyon ssp.,
particularly preferably an extract from eriodictyon californicum
and/or eriodictyon angustifolium, is particularly preferable.
[0195] It was particularly surprising that the compounds of the
formula (X) to be used according to the invention or salts thereof
can mediate or possess strong anti-inflammatory effects. Compounds,
salts, mixtures and preparations according to the invention (as
respectively described above) are advantageously capable of
positively influencing inflammatory parameters in monocytes. In
cell models wherein irritated and inflammatory phenomena of the
mucous membranes, especially of gingiva and the gastrointestinal
tract, are simulated, these exhibit an anti-inflammatory action. In
particular, the following inflammatory parameters are positively
influenced according to the invention: PGE2, IL-1, TNF, IL-6 and IL
8, in particular PGE2. Appropriate experiments on this were
performed as described in TS1 (see below, "Example TS: Test
study"). Thus for example from a concentration of 1 .mu.g/ml,
eriol-/erion-containing fractions already exhibit a highly
significant action on some of the abovementioned parameters.
Concentrations of 10 .mu.g/ml and more are particularly suitable. A
total extract from Herba Santa foliage which contains compounds
usable according to the invention or individual extracts therefrom
for example exhibits significant effects on individual parameters
from a concentration of 1 .mu.g/ml and highly significant effects
up to 250 .mu.g/ml.
[0196] For salts of compounds of the formula (X) usable according
to the invention, that stated further above respectively applies as
regards the preferable meanings of the residues. The carboxylic
acid group which is bound to the carbon atom in position 1
(according to the numbering shown in formula (X)) is then present
deprotonated. In addition, one or more hydroxy groups (if present)
are optionally also present deprotonated. Here, as well as the
deprotonated compound(s) of the formula (X), a corresponding
quantity of counter-cations are present, where these are preferably
selected from the group consisting of: singly positively charged
cations of the first main and transition group, ammonium ions,
trialkylammonium ions, doubly positively charged cations of the
second main and transition group and triply positively charged
cations of the third main and transition group, and mixtures
thereof. The maximum degree of deprotonation of a compound of the
formula (X) on which such as salt is based is found from the
carboxyl group and the hydroxy groups of this compound lying
adjacent thereto. In turn, from the number of deprotonated groups,
the corresponding number of counter-cations is obtained (depending
on their charge). Thus for example for a compound of the formula
(X) with one carboxyl and one hydroxy group on which such as salt
is based, it is found that with complete deprotonation of the
groups a doubly negatively charged anion is present, from which in
turn the number of positive charges is found (here: two), which
must be provided by the countercation(s). Particularly preferably,
these counter-cations are cations selected from the group
consisting of Na.sup.+, K.sup.+, NH.sub.4.sup.+, Ca.sup.2+,
Mg.sup.2+, Al.sup.3+ and Zn.sup.2+.
[0197] Particularly preferable therefore is a salt of a compound of
the formula (X) or a mixture (as respectively described above)
containing or consisting of [0198] one, two or more different salts
of compounds of the formula (X), preferably of compounds of the
formula (X) previously designated as preferable, and optionally
[0199] one, two or more different salts of compounds of the formula
(Y), preferably of compounds of the formula (Y) previously
designated as preferable, or [0200] one or more different compounds
of the formula (X) and/or one or more different salts of compounds
of the formula (X), and optionally [0201] one or more different
compounds of the formula (Y) and/or one or more different salts of
compounds of the formula (Y), wherein the counter-cation(s) of one,
several or all of the salts of compounds of the formula (X) and/or
compounds of the formula (Y) is or are selected from the group
consisting of Na.sup.+, K.sup.+, NH.sub.4.sup.+, Ca.sup.2+,
Mg.sup.2+, Al.sup.3+ and Zn.sup.2+.
[0202] As aforesaid, one, several or all of the compounds of the
formula (X) or salts of compounds of the formula (X) to be used
according to the invention, and optionally one, several or all of
the compounds of the formula (Y) or salts of compounds of the
formula (Y) can also be used in the form of plant extracts, in
particular in the form of extracts from Eriodictyon ssp., in
particular from Eriodictyon californicum and/or Eriodictyon
angustifolium, optionally after treatment with a base for
conversion of the compound(s) of the formula (X) or (Y) into a
salt.
[0203] Preferably the dried plant parts (see above) used in the
context of the present invention e.g. fresh or dried roots, root
bark, tubers, onions, other under- or aboveground storage organs,
accessory fruit, fruit, seeds, bark, wood, pulp, bast, stems,
stalks, leaves or flower [parts], preferably the stems, stalks,
leaves and flower [parts], preferably in comminuted form, are
extracted with a solvent suitable for food and luxury consumables
at temperatures in the range between the freezing point and the
boiling point of the particular solvent or solvent mixture, then
filtered and the filtrate wholly or partially concentrated,
preferably by distillation, or freeze- or spray-drying. The crude
product thus obtained can then be still further worked up, for
example back-extracted, purified via distribution, absorption,
exclusion, affinity or ion chromatography, distilled, sublimed,
purified with adsorbents such as activated charcoal, bentonite,
diatomaceous earth, etc., treated enzymatically (e.g. with
glycosidases to increase yield of non-sugar-containing molecules),
with acid (e.g. under pressure), with suitable basic solutions e.g.
of hydroxides, carbonates or hydrogen carbonates of sodium,
potassium, calcium, magnesium and zinc, with acidic ion exchangers
or with steam, as a rule at pressures from 0.01 mbar to 100 bar,
preferably at 1 mbar to 20 bar, treated with an auxiliary and
carrier substance and optionally dried (e.g. spray dried) and/or
taken up in a solvent suitable for food and luxury consumables
and/or for cosmetic and dermatological uses.
[0204] Suitable solvents for the extraction are in particular
water, ethanol, methanol, propylene glycol, glycerine, acetone,
dichloromethane, ethyl acetate, diethyl ether, hexane, heptane,
triacetin, plant oils or fats, supercritical carbon dioxide and
mixtures thereof.
[0205] Preferable auxiliary or carrier substances are maltodextrin,
starch, natural or synthetic polysaccharides and/or plant gums such
as modified starches or gum Arabic, colouring agents, e.g.
permitted food dyes, colouring plant extracts, stabilizers,
preservatives, antioxidants and viscosity-modifying substances.
[0206] Particularly preferable is a mixture according to the
invention (as described above), wherein the mixture comprises a
plant extract or consists thereof, preferably an extract from
Eriodictyon ssp., particularly preferably an extract from
Eriodictyon californicum and/or Eriodictyon angustifolium. A
mixture preferred according to the invention or a mixture
preferably to be used according to the invention (as described
above) according to one embodiment of the present invention
particularly preferably comprises or consists of (1.) an extract
from Eriodictyon californicum, (2.) an extract from Eriodictyon
angustifolium or (3.) an extract from Eriodictyon californicum and
Eriodictyon angustifolium, i.e. an extract from plants or plant
parts from both Eriodictyon californicum and also Eriodictyon
angustifolium, or (4.) a mixture of an extract from Eriodictyon
californicum and an extract from Eriodictyon angustifolium.
[0207] Particularly preferably, a mixture according to the
invention or a mixture preferably to be used according to the
invention (as respectively described above) consists of an extract
from Eriodictyon ssp., particularly preferably of an extract from
Eriodictyon californicum and/or Eriodictyon angustifolium. The
production of a plant extract from Eriodictyon californicum and/or
Eriodictyon angustifolium is described later herein.
[0208] As described above, one aspect of the present invention
relates in particular to a preparation used for food or enjoyment,
in particular a food, luxury consumable or drink, or a cosmetic or
dermatological preparation, in particular a preparation suitable
for the treatment, protection and/or care of the skin, nails and/or
hair and of the oral cavity (in particular of the gingiva and the
teeth), or a pharmaceutical preparation, for the treatment of
inflammatory states of the body of warm-blooded animals. As regards
the composition of such a preparation, reference is essentially
made to the above explanations.
[0209] According to a preferable embodiment of the present
invention, the proportion of the total quantity of compounds of the
formula (X) and (optionally) compounds of the formula (Y) and salts
thereof in the preparation lies in the range from 0.0001 to 30 wt.
%, preferably in the range from 0.001 to 20 wt. %, particularly
preferably in the range from 0.001 to 5 wt. %, based on the total
weight of the preparation.
[0210] Preparations according to the invention, in particular
preparations according to the invention used for food or enjoyment,
in the context of the present invention can in particular be
embodied as compositions suitable for consumption (as described
below). The preparations used for food or enjoyment in the sense of
the present invention can also be used as semifinished goods for
the production of further preparations used for food or
enjoyment.
[0211] The preparations according to the invention used for food or
enjoyment and corresponding semifinished goods and preparations or
compositions suitable for consumption are as a rule products which
are intended to be introduced into the human oral cavity, to remain
there for a certain time and then either be consumed (e.g.
ready-to-eat foods, see below) or removed again from the oral
cavity (e.g. chewing gums). Thus these products include all
articles or substances which are intended to be ingested by people,
in the processed, partially processed or unprocessed state. In
particular, compositions suitable for consumption are articles
which products which are added to foods during the production,
processing or modification thereof and are intended to be
introduced into the human oral cavity, in particular with the said
food. Accordingly, such compositions can in turn be contained in
(further) ready-to-use or ready-to-eat preparations used for food
or enjoyment (in the context of the present text, ready-to-use or
ready-to-eat preparations used for food or enjoyment are in
particular foods, especially ready-to-eat foods (see below)). In
addition, such compositions can be a component of a semifinished
product which optionally can in turn be used for the production of
ready-to-use or ready-to-eat preparations used for food or
enjoyment.
[0212] Preparations used for food or enjoyment in the sense of the
present invention are in particular ready-to-use or ready-to-eat
preparations, in particular foods, especially ready-to-eat foods,
e.g. bakery products (e.g. bread, dry biscuits, cakes, other
pastries), confectionery (e.g. chocolates, chocolate bar products,
other products in bars, fruit gum, hard and soft caramels, chewing
gum), alcoholic or non-alcoholic drinks (e.g. coffee, tea, wine,
wine-containing drinks, beer, beer-containing drinks, liqueurs,
spirits, brandies, fruit-containing soft drinks, isotonic drinks,
refreshment drinks, nectars, fruit and vegetable juices, fruit or
vegetable juice preparations), instant drinks (e.g. instant cocoa
drinks, instant tea drinks, instant coffee drinks), meat products
(e.g. ham, fresh sausage or raw sausage preparations, spiced or
marinated fresh or pickled meat products), eggs or egg products
(dried egg, egg white, egg yolk), cereal products (e.g. breakfast
cereals, muesli bars, prefermented prepared rice products), dairy
products (e.g. milk drinks, milk-based ice cream, yoghurt, kefir,
cream cheese, soft cheese, hard cheese, dried milk powder, whey,
butter, buttermilk, partially or fully hydrolyzed milk
protein-containing products), products from soya protein or other
soya bean fractions (e.g. soya milk and products prepared
therefrom, soya lecithin-containing preparations, fermented
products such as tofu or tempe or products prepared therefrom, soya
sauces), fruit preparations (e.g. preserves, fruitflavoured ice
cream, fruit sauces, fruit fillings), vegetable preparations (e.g.
ketchup, sauces, dried vegetables, deep-frozen vegetables,
prefermented vegetables, vegetables marinated in vinegar, preserved
vegetables), nibbles (e.g. baked or fried potato crisps or potato
dough products, bread dough products, maize- or peanut-based
extruded products), fat and oil-based products or emulsions thereof
(e.g. mayonnaise, remoulade, dressings, spice preparations), other
ready-to-serve meals and soups (e.g. dried soups, instant soups,
prefermented soups), spices, spice mixtures and in particular
seasonings), which are for example used in the snacks field.
[0213] Preferable carrier substances contained in such (preferably
spray dried) compositions according to the invention are silicon
dioxide (silicic acid, silica gel), carbohydrates and/or
carbohydrate polymers (polysaccharides), cyclodextrins, starches,
degraded starches (starch hydrolyzates), chemically or physically
modified starches, modified celluloses, gum Arabic, ghatti gum,
tragacanth, karaya, carrageenan, guar gum, carob flour, alginates,
pectin, inulin or xanthan gum.
[0214] Preferable starch hydrolysates are maltodextrins and
dextrins, where here again maltodextrins with DE values in the
range 5 to 20 are particularly preferable. Here it is unimportant
what plant originally provided the starch for the production of the
starch hydrolyzates. Maize-based starches and starches from
tapioca, rice, wheat or potatoes in particular are suitable and
readily available. Here previously described carrier substances
(e.g. silicon dioxide) can advantageously function as free-flow
agents.
[0215] The preparations according to the invention, which as well
as one or more compounds of the formula (X) and/or salts thereof or
a suitable mixture also contain one or more solid carrier
substances can for example be produced by mechanical mixing
processes, wherein at the same time a comminution of the particles
can take place, or by means of spray-drying. As described above,
compositions according to the invention which contain solid carrier
substances and are produced by means of spray-drying are
preferable; concerning the spray-drying, reference is made to U.S.
Pat. No. 3,159,585, U.S. Pat. No. 3,971,852, U.S. Pat. No.
4,532,145 or U.S. Pat. No. 5,124,162.
[0216] Preferable preparations containing carrier substances (as
described above) which have been produced by means of spray-drying
preferably have a mean particle size in the range from 30 to 300
.mu.m and preferably a residual moisture content of 5 wt. % or
less.
[0217] According to one embodiment of the present invention, the
weight ratio of the total mass of compounds of the formula (X) and
optionally of the formula (Y) and salts thereof in a preparation
described herein containing one or more (suitable for consumption,
solid) carrier substances (as described above) to the total mass of
(suitable for consumption, solid) carrier substances preferably
lies in the range from 1:10 to 1:100000, preferably in the range
from 1:50 (preferably from 1:100) to 1:20000, particularly
preferably in the range from 1:100 (preferably from 1:1000) to
1:5000, based on the dry mass of the preparation.
[0218] In a preparation (as described above) containing one or more
(suitable for consumption, solid) carrier substances (as described
above), the proportion of the total quantity of compounds of the
formula (X) and optionally of the formula (Y), salts thereof and
(suitable for consumption, solid) carrier substances, based on the
total weight of the preparation, preferably lies in the range from
70 to 100 wt. %, preferably in the range from 85 to 100 wt. %.
[0219] The preparations according to the invention used for food or
enjoyment, as well as normally used animal or plant raw materials,
can additionally contain water, squalane or squalene, natural oils
(e.g. olive oil, sunflower oil, soya oil, peanut oil, rape oil,
almond oil, palm oil, coconut oil, palm nut oil, borage seed oil
and more of the like), natural ester oils (e.g. jojoba oil), fats,
waxes and other natural fatty substances, carbohydrates, for
example glucose, sucrose or lactose, sweeteners, for example
aspartame, cyclamate, saccharin, xylitol or sorbitol, bitter
substances, for example caffeine or quinine, bitterness-suppressing
substances, for example lactisol, flavour-intensifying substances,
for example sodium glutamate or inositol phosphate, amino acids,
for example glycine, alanine, leucine, isoleucine, valine, proline,
lysine, asparagine, aspartic acid, glutamine, glutamic acid,
tryptophan, phenylalanine, tyrosine, threonine, serine, cystine,
cysteine, methionine, hydroxyproline, arginine or histidine,
peptides, proteins, enzymes, fruit acids, preferably lactic acid,
malic acid or citric acid, as well as emulsifiers, which can
advantageously be selected from the group of the ionic, nonionic,
polymeric, phosphatecontaining and zwitterionic emulsifiers, and in
particular one or more thickeners, which can advantageously be
selected from the group of the polysaccharides or derivatives
thereof, e.g. hyaluronic acid, guar gum, carob flour, xanthan gum
or allulose derivatives, and natural, nature-identical or synthetic
aromas and salts, for example sodium chloride or potassium
chloride.
[0220] The cosmetic and dermatological preparations according to
the invention can contain cosmetic auxiliary agents and/or
additives such as are normally used in such preparations, e.g.
sunscreens (e.g. organic or inorganic light filter substances,
preferably micropigments), preservatives, bactericides, fungicides,
virucides, cooling active substances, plant extracts,
inflammation-inhibiting active substances, wound healing
accelerating substances (e.g. chitin or chitosan and derivatives
thereof), film-forming substances (e.g. polyvinylpyrrolidones or
chitosan or derivatives thereof), common antioxidants, vitamins
(e.g. vitamin C and derivatives, tocopherols and derivatives,
vitamin A and derivatives), 2-hydroxycarboxylic acids (e.g. citric
acid, malic acid, L-, D-, or dl-lactic acid), skin lighteners (e.g.
kojic acid, hydroquinone or arbutin), skin colorants (e.g. walnut
extracts or dihydroxyacetone), perfumes, substances for prevention
of foaming, colorants, pigments which have a colorant action,
thickeners, surfactant substances, emulsifiers, plasticizing,
moistening and/or humectant substances (e.g. glycerine or urea),
fats, oils, unsaturated fatty acids or derivatives thereof (e.g.
linolic acid, alpha-linolenic acid, gammalinolenic acid or
arachidonic acid and their respective natural or synthetic esters),
waxes or other normal components of a cosmetic or dermatological
formulation such as alcohols, polyols, polymers, foam stabilizers,
electrolytes, organic solvents, silicone derivatives or chelating
agents (e.g. ethylendiaminetetraacetic acid and derivatives).
[0221] The particular quantities to be used can easily be
determined by those skilled in the art by simple testing, depending
on the nature of the particular product.
[0222] Preferably preparations according to the invention (as
described above) additionally contain one or more antioxidants,
where the antioxidant or antioxidants is/are not a compound or
compounds of the formula (X) or a salt thereof. In particular, as
such antioxidants, all antioxidants suitable or usual for the
respective use can be used. The antioxidant or antioxidants is or
are preferably selected from the group consisting of amino acids
(e.g. glycine, histidine, 3,4-dihydroxyphenylalanine, tyrosine,
tryptophan) and derivatives thereof, imidazoles (e.g. urocanic
acid) and derivatives thereof, peptides (D,L-carnosine,
D-carnosine, L-carnosine, anserine) and derivatives thereof,
carotenoids, carotenes (e.g. beta-carotene, alpha-carotene,
lycopene) and derivatives thereof, chlorogenic acid and derivatives
thereof, lipoic acid and derivatives thereof, aurothioglucose,
propylthiouracil and other thiols (e.g. thioredoxin, glutathione,
cysteine, cystine, cystamine and glycosyl and N-acyl derivatives
thereof or alkyl esters thereof) and salts thereof, dilauryl
thiodipropionate, distearyl thiodipropionate, thiodipropionic acid
and derivatives thereof and phenolic acid amides of phenolic
benzylamines (e.g. homovanillic acid, 3,4-dihydroxyphenylacetic
acid, ferulic acid, sinapinic acid, caffeic acid, dihydroferulic
acid, dihydrocaffeic acid, vanillomandelic acid- or
3,4-dihydroxymandelic acid amides of 3,4-dihydroxybenzyl,
2,3,4-trihydroxybenzyl- or 3,4,5-trihydroxybenzyl-amine), catechol
oximes or catechol oxime ethers (e.g. 3,4-dihydroxybenzaldoxime or
3,4-dihydroxybenzaldehyde Oethyloxime), also (metal) chelators
(e.g. 2-hydroxyfatty acids, phytic acid, lactoferrin), humic acid,
bile acids, bile extracts, bilirubin, biliverdin, folic acid and
derivatives thereof, ubiquinone and ubiquinol and derivatives
thereof, vitamin C and derivatives thereof (e.g. ascorbyl
palmitate, magnesium ascorbyl phosphate, ascorbyl acetate),
tocopherols and derivatives (e.g. alphatocopherol, vitamin E
acetate), vitamin A and derivatives (e.g. vitamin A palmitate),
rutinic acid and derivatives thereof, flavonoids (e.g. quercetin,
alpha-glucosylrutin) and derivatives thereof, phenolic acids (e.g.
gallic acid, ferulic acid) and derivatives thereof (e.g. gallic
acid propyl ester, ethyl ester and octyl ester),
furfurylideneglucitol, dibutylhydroxytoluene, butylhydroxyanisole,
uric acid and derivatives thereof, mannose and derivatives thereof,
zinc and derivatives thereof (e.g. ZnO, ZnSO.sub.4), selenium and
derivatives thereof (e.g. selenomethionine), stilbene and
derivatives thereof (e.g. stilbene oxide, resveratrol) and the
derivatives of these named (active) substances suitable in the
context of the present invention.
[0223] Furthermore, a preparation according to the invention (as
described above), in particular a cosmetic or dermatological
preparation according to the invention, can include one or more
UV-A and/or UV-B filter substances. The filter substance or
substances here are preferably selected from the group consisting
of 3-benzylidenecamphor derivatives (e.g.
3-(4-methylbenzylidene)-dl-camphor), aminobenzoic acid derivatives
(e.g. 4-(N,N-dimethylamino)benzoic acid 2-ethylhexyl ester or
menthyl anthranilate), 4-methoxycinnamates (e.g. 2-ethylhexyl
p-methoxycinnamate or isoamyl p-methoxycinnamate), benzophenones
(e.g. 2-hydroxy-4-methoxybenzophenone), singly or multiply
sulphonated UV filters [e.g. 2-phenylbenzimidazol-5-sulphonic acid,
sulisobenzone or
1,4-bis(benzimidazolyl)benzene-4,4',6,6'-tetrasulphonic acid or
3,3'-(1,4-phenylene-dimethylidene)-bis(7,7-dimethyl-2-oxo-bicyclo[2,2,1]h-
eptane-1-methanesulphonic acid) and salts thereof], salicylates
(e.g. 2-ethylhexyl salicylate or homomethyl salicylate), triazines
{e.g.
2,4-bis-[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-t-
riazine,
4,4'-([6-([(1,1-dimethylethyl)aminocarbonyl]phenylamino)-1,3,5-tr-
iazin-2,4-diyl]-diimino)bisbenzoic acid bis-(2-ethylhexyl) ester)},
2-cyanopropenoic acid derivatives (e.g. 2-ethylhexyl
2-cyano-3,3-diphenyl-2-propenoate, dibenzoyl derivatives (e.g.
4-tert-butyl-4'-methoxydibenzoylmethane), polymerbound UV filters
(e.g. polymers of N-[2-(or
4)-(2-oxo-3-bornylidene)methyl]benzylacrylamide) or pigments (e.g.
titanium dioxides, zirconium dioxides, iron oxides, silicon
dioxides, manganese oxides, aluminium oxides, cerium oxides or zinc
oxides). Such a preparation according to the invention is
preferably a sunscreen for skin and/or hair.
[0224] Accordingly, the present invention particularly preferably
relates to a preparation according to the invention (as described
above) additionally comprising [0225] (II) one or more
antioxidants, wherein the antioxidant or antioxidants is or are not
a compound(s) of the formula (x) or a salt thereof and is or are
preferably selected from the group consisting of beta-carotene,
lycopene, chlorogenic acid, 2-hydroxy fatty acids, bilirubin, folic
acid, ubiquinone, ubiquinol, vitamin C and derivatives thereof, in
particular ascorbyl palmitate, magnesium ascorbyl phosphate and
ascorbyl acetate; tocopherols and derivatives thereof, in
particular alpha-tocopherol and vitamin E acetate; vitamin A and
derivatives thereof, in particular vitamin A palmitate; rutinic
acid, quercetin, ferulic acid, dibutylhydroxytoluene,
butylhydroxyanisole and uric acid, and/or [0226] (III) one or more
UV-A and/or UV-B filter substances, where one, several or all of
the UV-A and/or UV-B filter substances is or are preferably
selected from the group consisting of
3-(4-methylbenzylidene)-dl-camphor, menthyl anthranilate,
2-ethylhexyl p-methoxycinnamate, isoamyl p-methoxycinnamate,
2-hydroxy-4-methoxy-benzophenone, 2-phenylbenzimidazol-5-sulphonic
acid and salts thereof,
1,4-bis(benzimidazolyl)benzene-4,4',6,6'-tetrasulphonic acid and
salts thereof, 2-ethylhexyl salicylate, homomenthyl salicylate,
2,4-bis-[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-t-
riazine,
4,4'-([6-([(1,1-dimethylethyl)-amino-carbonyl]phenylamino)-1,3,5--
triazin-2,4-diyl]diimino)bisbenzoic acid bis-(2-ethylhexyl) ester),
2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate,
4-tert-butyl-4'-methoxydibenzoylmethane, titanium dioxide, silicon
dioxide and zinc oxide.
[0227] Particularly preferable is such a preparation according to
the invention, wherein [0228] the proportion of the total quantity
of component (II) in the preparation, based on the total weight of
the preparation, is 0.0001 to 30 wt. %, preferably 0.001 to 20 wt.
%, particularly preferably 0.001 to 5 wt. %, and/or [0229] the
proportion of the total quantity of component (Ill) in the
preparation, based on the total weight of the preparation, is 0.1
to 30 wt. %, preferably 0.5 to 10 wt. %.
[0230] The (pharmaceutical) preparations in the sense of the
present invention used for the treatment of inflammatory states of
warm-blooded animals can also be used as semifinished goods for the
production of further pharmaceutical preparations used for the
treatment of inflammatory states of warm-blooded animals.
[0231] The pharmaceutical preparations according to the invention
used for the treatment of inflammatory states of warm-blooded
animals, and corresponding semifinished goods are as a rule
products which are intended to be introduced into the body of
warm-blooded animals or used on the body of warm-blooded
animals.
[0232] The pharmaceutical preparations according to the invention
used for the treatment of inflammatory states of warm-blooded
animals in the sense of the present invention are preferably
ready-to-use preparations, in particular medicaments and medicinal
products, preferably in the following forms: solid galenical forms
(such as for example tablets (with and without coating, with and
without modified release), sugar-coated tablets (with and without
coating, with and without modified release), capsules (soft or hard
gelatine capsules with and without modified release) granules (with
and without modified release), powders (with and without modified
release), suppositories (with and without coating, with and without
modified release) lozenges and chewing gums), and liquid forms
(such as for example solutions, suspensions, emulsions, syrups
(colloquially cough syrup), mouthwashes, gargle solutions, throat
sprays or nasal sprays, nasal drops, nasal rinse solutions, nasal
powders, nasal ointments or ear drops, ear sprays, ear rinse
solutions, ear powders and aural tampons), and semisolid forms
(such as for example hydrophobic ointments including for example:
hydrocarbon gels, lipogels, silicone gels, oleogels and
water-absorbing ointments including for example absorption bases,
hydrophilic ointments, hydrophilic gels (hydrogels) or pastes, and
inhalants (such as for example compressed gas dispenser inhalers,
powder inhalers, inhalers with atomisers, and inhalation
concentrates for the preparation of inhalations), and active
substance-containing plasters or other therapeutic systems.
[0233] The pharmaceutical preparations according to the invention
can contain (further) pharmaceutical auxiliary and/or additive
substances, such as are normally used in such preparations, e.g.
active substances from the group of the non-steroidal
anti-inflammatories, antibiotics, systemically active steroids,
anti-TNF-alpha antibodies or other biotechnologically produced
active substances and/or pure substances such as budesonide,
sulfasalazine, azathioprine/6-mercaptopurine or methotrexate. And
for example fillers (e.g. cellulose, calcium carbonate), free-flow
and anticaking agents (e.g. talc, magnesium stearate), coatings
(e.g. polyvinyl acetate phthalate, hydroxypropyl-methylcellulose
phthalate), disintegrants (e.g. starch, crosslinked
polyvinylpyrrolidone), plasticizers (e.g. triethyl citrate, dibutyl
phthalate) substances for granulation (lactose, gelatine),
retardation (e.g. poly(meth)acrylic acid
methyl/ethyl/2-trimethylaminoethyl ester copolymers in dispersion,
vinyl acetate/crotonic acid copolymers) and compacting (e.g.
microcrystalline cellulose, lactose), solvent, suspension or
dispersion agents (e.g. water, ethanol), emulsifiers (e.g. cetyl
alcohol, lecithin), substances for modification of the rheological
properties (silicon dioxide, sodium alginate), substances for
microbial stabilization (e.g. benzalkonium chloride, potassium
sorbate), preservatives and antioxidants (e.g. DL-alpha-tocopherol,
ascorbic acid), substances for modification of the pH (lactic acid,
citric acid), propellant or inert gases (e.g. fluorinated
chlorohydrocarbons, carbon dioxide), colorants (iron oxides,
titanium dioxide), ointment bases (e.g. paraffins, beeswax), inter
alia as described in the technical literature (e.g. Schmidt,
Christin. Active and Auxiliary Substances for Individual and Bulk
Formulation, and Large-scale Manufacture. 1999; Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart or Bauer, Fromming Fuhrer.
Textbook of Pharmaceutical Technology. 8.sup.th Edition, 2006.
Wissenschaftliche Verlagsgesellschaft mbH Stuttgart).
[0234] The particular quantities to be used can easily be
determined by those skilled in the art by simple testing, depending
on the nature of the particular product.
[0235] According to one aspect of the present invention, a
preparation according to the invention wherein the proportion of
the total quantity of compounds of the formula (X) and optionally
of the formula (Y) and salts thereof in the preparation lies in the
range from 0.0001 to 30 wt. %, preferably in the range from 0.001
to 20 wt. %, and particularly preferably in the range from 0.001 to
5 wt. %, based on the total weight of the preparation, is
preferable.
[0236] (Further) preferable methods for the production of a
preferable mixture or preparation according to the invention (as
described above) are described below.
[0237] Such a method preferably comprises the steps [0238] (a)
extraction of plant material (as described above), preferably as
described above as preferable, and [0239] (b) concentration of
extracted compounds of the formula (X) and optionally additionally
of the formula (Y) and/or salts thereof (as described above) by
partial or complete removal of other extracted compounds and
optionally removal of extractants and/or solvents, preferably so
that the proportion of the total quantity of compounds of the
formula (X) and optionally (Y) and salts thereof in the mixture
obtained, based on the total weight of the mixture, is 0.0001,
preferably 15 to 100 wt. %, preferably 25 to 90 wt. % (preferably
100 wt. %), and particularly preferably 45 to 85 wt. % (preferably
100 wt. %).
[0240] For example, a mixture or preparation according to the
invention (as described above) can also be produced by a method
according to the invention (as described above), wherein the method
is carried out following the method described in the publication in
WO2004041804 (for the obtention of a crude extract from Eriodictyon
californicum and/or Eriodictyon angustifolium).
[0241] The steps of such a method according to the invention
(partly based on the method according to WO2004041804) are briefly
summarized below: [0242] (a) Plant material from Eriodictyon
californicum and/or Eriodictyon angustifolium is singly or multiply
extracted with a non-water-miscible extractant (optionally with
heating up to the relevant boiling point). [0243] (b) The crude
extract thus obtained (containing compounds of the formula X and/or
of the formula Y to be used according to the invention and other
extracted compounds such as for example rosmarinic acid) is
separated from the plant material. [0244] (c) The crude extract
(containing compounds of the formula X and/or of the formula Y to
be used according to the invention and other extracted compounds
such as for example rosmarinic acid) is preferably concentrated and
interim stocked. [0245] (d) Precipitated solids (waxes) are
optionally removed. [0246] (e) The (optionally dewaxed) crude
extract (containing compounds of the formula (X) and optionally of
the formula (Y) to be used according to the invention and other
extracted compounds such as for example rosmarinic acid) is
optionally treated with activated charcoal and separated from the
solid.
[0247] Through the following further steps, the compounds of the
formula (X) and optionally of the formula (Y) to be used according
to the invention can be further concentrated in the organic phase:
[0248] (f) (Preferably complete) removal of the organic solvent of
the organic phase by evaporative or permeative methods. [0249] (g)
Taking up of the residue (comprising compounds of the formula (X)
and optionally of the formula (Y) to be used according to the
invention) in methanol. [0250] (h) Removal of the
methanol-insoluble components of the mixture (comprising compounds
of the formula (X) and optionally of the formula (Y) to be used
according to the invention and other extracted compounds) by
filtration.
[0251] In the mixture present according to this method after step
e), the proportion of the total quantity of compounds of the
formula (X) and optionally of the formula (Y) and salts thereof,
based on the dry mass of the mixture (j), according to a preferable
embodiment of the present invention lies in the range from 1 to 35
wt. %, preferably in the range from 20 to 35 wt. %.
[0252] In the mixture (h) present according to this method
according to the invention after step h), the proportion of the
total quantity of compounds of the formula (X) and optionally of
the formula (Y) and salts thereof, based on the dry mass of the
mixture (h), preferably lies in the range from 40 to 100 wt. %,
preferably in the range from 45 to 85 wt. %.
[0253] The mixtures (e) and (h) and the mixtures present after the
steps f) and g), in particular mixture (h), can each be mixtures
according to the invention (as described above).
[0254] Evaporative or pervaporative methods can for example be
distillation, sublimation, steam distillation, freeze drying,
pervaporative membrane methods or spray-drying, and particular
appropriate auxiliary and/or carrier substances can be added
thereto.
[0255] According to an alternative embodiment of a method according
to the invention for the production of a mixture as described
above, a methanolic crude extract is obtained from Eriodictyon
ssp., preferably Eriodictyon californicum and/or Eriodictyon
angustifolium, which contains extracted compounds of the formula
(X) and optionally of the formula (Y) and other extracted compounds
(in particular rosmarinic acid). Herein also, the extracted
compounds of the formula (X) and optionally of the formula (Y)
and/or salts of these extracted compounds in the mixture are
concentrated by partial or complete removal of other extracted
compounds and optionally removal of extractants and/or solvents
(each time preferably analogously to the previously described
method design), so that the proportion of the total quantity of
compounds of the formula (X) and optionally of the formula (Y) and
salts thereof in the mixture, based on the dry mass of the mixture,
for example preferably lies in the range from 40 to 100 wt. %,
particularly preferably 45 to 85 wt. %.
[0256] Such concentration is preferably attained by FCPC (Fast
Centrifugal Partition Chromatography, Guido F. Pauli, Samuel M.
Pro, J. Brent Friesen Countercurrent Separation of Natural Products
J. Nat. Prod. 2008, 71, 1489-1508) and/or HTLC (High Temperature
Liquid Chromatography; WO2006111476) and/or preparative HPLC (High
Pressure Liquid Chromatography).
[0257] According to a preferable embodiment of the present
invention, the extracts or mixtures described herein are
incorporated in the form of emulsions into liposomes, for example
starting from phosphatidylcholine, into microspheres, into
nanospheres or also into capsules, granules or extrudates, for
example of starch, starch derivates, cellulose or cellulose
derivates (for example hydroxypropylcellulose), other
polysaccharides (for example alginates), natural fats, natural
waxes (for example beeswax, carnauba wax) or of proteins, for
example gelatine.
[0258] In connection with the present invention, a prophylactic
and/or therapeutic method as described above, with the following
step, is also described:
[0259] Contacting of (human or animal) tissue and/or of the (human
or animal) cells with an inflammation-inhibiting effective quantity
of a compound of the formula (X), a salt of a compound of the
formula (X), an above-described mixture, in particular of a mixture
which additionally comprises a compound of the formula (Y) and/or a
salt thereof, as respectively described above, or of a preparation
as described above.
[0260] The contacting of the tissue or the cells with one or more
compounds of the formula (X) and optionally additionally one or
more compounds of the formula (Y) and/or salts thereof or a mixture
or preparation according to the invention (as respectively
described above) here--depending on the tissue to be treated or the
cells to be treated--can also be effected by external (e.g.
topical) or internal use (e.g. oral application).
[0261] The following examples serve to clarify the invention,
without thereby restricting this.
EXAMPLES
Preparation Examples
Example 1
Production of a Methanolic Extract from Eriodictyon
angustifolium
[0262] Boiling water was poured over 500 g of dried leaves of
Eriodictyon angustifolium and stirred for one hour in order to
swell the plant material and prepare it for the further extraction.
The plant material was filtered off, dried and extracted twice with
2.01 methanol each time at room temperature for one hour with
stirring. The methanolic extract was filtered off, dried under
vacuum and stored overnight in the high vacuum drying oven to
remove residual solvent. The extraction yielded 84.53 g of dark
green extract.
Example 2
Isolation of the Individual Compounds from Eriodictyon
angustifolium by Means of FCPC
[0263] The methanolic extract of E. angustifolium according to
Example 1 was separated and fractionated by means of FCPC using a
two-phase solvent system (heptane/ethyl acetate/methanol/water
5:4:4:5). As well as flavones described in the literature, four
compounds of the formula (X) could be isolated. Structure
elucidation was effected by means of one- and two-dimensional NMR
experiments. The retention times are shown in Table 1, the FCPC
conditions in Table 2 and analytical data in Tables 3a and 3b.
TABLE-US-00001 TABLE 1 Retention time for various Erionic acids
Molecular weight Retention time Compound [g/mol] [min] Erionic acid
F (6) 358 17.0-19.0 (ascending) Erionic acid C (3) 374 64.0-69.0
(ascending) Erionic acid A (1) 390 52.0-54.0 (descending) Erionic
acid B (2) 390 55.0-56.0 (descending)
TABLE-US-00002 TABLE 2 FCPC conditions FCPC bench scale FCPC model,
version A (Kromaton Technologies, Angers, France) Rotor 200 ml
(semi-preparative) Injector Kronlab High Speed Valve (Kronlab
Chromatography Technology, Dinslaken) Injection loop 10 ml Pumps
Knauer HPLC pump 64 (Knauer Berlin) Pulse damper Type 55073
(BESTA-Technik, Wilhelmsfeld) Detector ELSD SEDEX 75 Light
scattering detector (S.E.D.E.R.E, Alfortville, Cedex, France)
Fraction collector Labocol Vario 2000 (Labomatic, Weil am Rhein)
Software PrepCon (SCPA GmbH, Weye-Leeste); Version 5.03.009, SCPA
GmbH 2003 Solvent system upper phase: heptane/ethyl acetate (5/4)
lower phase: methanol/water (4/5) Ascending mode methanol/water as
stationary phase Descending mode heptane/ethyl acetate as
stationary phase Stock solution 60 mg/10 ml stationary/mobile Phase
(1:1) Flow rate 8 ml/min (ascending mode) 10 ml/min (descending
mode) Fractionation 40 fractions of 8 ml (ascending mode) 30
fractions of 10 ml (descending mode)
TABLE-US-00003 TABLE 3a Analytical data Erionic acid F (6) Erionic
acid C (3) (400 MHz, CH3OD) (400 MHz, CH3OD) Pos. .delta..sub.c,
mult. .delta..sub.H (J in Hz) .delta..sub.c, mult. .delta..sub.H (J
in Hz) 1 123.2 n.d. 2 130.8 7.63, d (2.1) 131.1.sup.a 6.92, s 3
129.4 130.3 4 158.4 158.4 5 129.4 125.6 6 130.5 7.71, d (2.1)
130.8.sup.a 6.92, s 7 170.8 171.1 8 29.0 2.61, m 29.2 2.59, m 9
33.8 1.95, m 33.9 1.95, m 1.61, m 1.61, m 10 46.2 2.65, m 46.5
2.66, m 9 33.8 1.95, m 33.9 1.95, m 1.61, m 1.61, m 11 216.1 217.4
12 44.5 3.18, m 42.2 3.19, m 13 117.2 5.23, dd (7.1, 7.1) 117.5
5.24, m 14 136.7 136.8 15 25.9 1.77, s.sup.a 25.9 1.72, s 16 16.9
1.12, d (7.0) 16.9 1.12, d (7.0) 17 17.9.sup.a 1.72, s.sup.a 18.3
1.61, s 18 29.4 3.33, d (7.3) 29.2 3.40, d (7.4) 19 123.0 5.32, dd
(7.3, 7.3) 124.2 5.61, dd (7.4, 7.4) 20 134.2 137.8 21 26.0 1.72,
s.sup.b 69.1 3.99, s 22 18.1.sup.a 1.60, s.sup.b 13.9 1.76, s
.sup.a,binterchangeable signals
TABLE-US-00004 TABLE 3b Analytical data Erionic acid A (1) Erionic
acid B (2) (400 MHz, DMSO) (600 MHz, CH.sub.3OD) .delta..sub.c,
mult. .delta..sub.H (J in Hz) .delta..sub.c, mult. .delta..sub.H (J
in Hz) 1 127.7.sup.a 130.3.sup.a 2 128.7.sup.b 7.52, s 130.4.sup.a
7.57, d (2.1) 3 128.3.sup.a 129.6.sup.a 4 156.5 155.0.sup.b 5 121.0
131.4.sup.a 6 128.9.sup.b 7.52, s 130.4.sup.a 7.56, d (2.1) 7 169.1
170.2 8 27.4 2.55, m 28.9 2.58, m 9 32.6 1.83, m 34.6 1.96, m 1.51,
m 1.61, m 10 42.7 2.85, ddq 44.4 2.86, ddq (6.8, 6.8, 6.8) (6.8,
6.8, 6.9) 11 203.4 207.0 12 123.8 6.27, d (15.8) 125.6 6.29, d
(15.8) 13 154.3 6.83, d (15.8) 154.9.sup.b 6.83, d (15.8) 14 69.1
71.2 15 29.0 1.22, s.sup.a 29.3 1.30, s.sup.a 16 16.2 1.07, d (6.9)
16.8 1.13, d (6.9) 17 29.0 1.23, s.sup.a 29.3 1.29, s.sup.a 18 27.6
3.33, d (7.3) 32.4 3.02, dd (5.4, 16.5) 2.74, dd (7.8, 16.5) 19
120.8 5.50, dd (7.3, 7.3) 70.5 3.75, dd (7.8, 5.4) 20 136.2 78.4 21
66.1 3.83, s 24.3.sup.c 1.36, s.sup.a 22 13.1 1.65, s 21.0.sup.c
1.25, s.sup.a .sup.a,binterchangeable signals
Example 3
Isolation of the Individual Compounds from Eriodictyon
angustifolium by Means of High Temperature Liquid Chromatography
(HTLC)
[0264] The methanolic extract of E. angustifolium according to
Example 1 was separated and fractionated by means of HTLC using a
polymer-based semi-preparative column with water-ethanol gradients
under isothermal conditions (120.degree. C.). In addition to
flavones described in the literature, four substances could be
isolated. The results are shown in Table 4, the HTLC conditions in
Table 5 and analytical data in Tables 6.
TABLE-US-00005 TABLE 4 Retention time for various Erionic acids
Molecular weight Retention time Compound [g/mol] [min] Erionic acid
C (3) 374 14.5-15.3 Erionic acid D (4) 374 15.4-16.5 Erionic acid E
(5) 374 17.0-17.7 Erionic acid F (6) 358 22.0-23.0
TABLE-US-00006 TABLE 5 HTLC conditions Pumps 2 SunChrom HPLC pumps
SunFlow 100 (SunChrom, Friedrichsdorf, Germany) Injector 100 .mu.l
loop; Midas, Spark, A J Emmen, The Netherlands HPLC oven
Polaratherm Series 9000 (Selerity Technologies Inc., Salt Lake
City, USA) Detectors Light scattering detector (ELSD) Sedex 85
LT-ELSD (Sedere, Alfortville, Cedex, France); Diode array detector
(DAD) SunChrom SpectraFlow, wavelengths 200-400 nm (SunChrom,
Friedrichsdorf, Germany) Column Hamilton PRP-1 reversed phase; 250
.times. 10 mm semi-preparative; 10 .mu.m particle size (Hamilton,
Bonaduz, Switzerland) Flow rate 3 ml/min Fraction collector Labocol
Vario 2000 (Labomatic, Weil am Rhein) Software PrepCon (SCPA GmbH,
Weye-Leeste); Version 5.03.009, SCPA GmbH 2003 Stock solution 400
mg/ml E. angustifolium extract (Y) in ethanol/water (1:1) Injection
volume 100 .mu.l Column Hamilton PRP-1 250 .times. 10 mm
Temperature 120.degree. C. isothermal Eluent A: water C: ethanol
Gradient 0 min: 100% A 0% C 30 min: 50% A 50% C 50 min: 0% A 100% C
60 min: 0% A 100% C Detection ELSD (3.5 bar N2, 45.degree. C., gain
6); DAD 210 nm, 250 nm, 280 nm, 320 nm
[0265] The following analytical data for erionic acid C (3) and
erionic acid F (6) correspond to those stated in Example 2.
TABLE-US-00007 TABLE 6 Analytical data Erionic acid D (4) Erionic
acid E (5) (400 MHz, CH3OD) (400 MHz, CH.sub.3OD) Pos.
.delta..sub.c, mult. .delta..sub.H (J in Hz) .delta..sub.c, mult.
.delta..sub.H (J in Hz) 1 130.6.sup.a 123.3 2 130.6.sup.a 7.60, d
(2.2) 131.0.sup.a 7.60, d (2.2) 3 130.6.sup.a 130.3 4 156.2 158.1 5
120.9/120.8 128.9 6 131.3 7.61, d (2.2) 130.8.sup.a 7.63, d (2.2) 7
171.0 171.5 8 28.9/28.8 2.56, m 29.3 2.62, m 9 34.0/34.0 1.94, m
34.4 1.97, m 1.60, m 1.63, m 10 46.3/46.3 2.63, m 44.5 2.89, ddq
(6.9, 6.9, 6.9) 11 215.6/215.5 207.1 12 41.9 3.17, m 125.8 6.34, d
(15.9) 13 117.3 5.23, m 155.5 6.88, d (15.9) 14 136.6 71.2 15 25.9
1.72, s 29.3 1.31, s 16 16.7 1.11, d (6.9) 17.2 1.15, d (7.0) 17
18.3 1.60, s 29.3 1.31, s 18 32.2 3.05/3.06, dd/dd 29.7 3.31
(masked by (16.7, 5.2) solvents), 2.76, dd (16.6, 7.2) 19 70.0/70.0
3.78, m 123.4 5.33, dd (7.4, 7.4) 20 79.1/79.1 134.5 21 .sup.
26.1/26.0.sup.b 1.37/1.36.sup.a 26.2 1.77, s 22 .sup.
21.6/21.3.sup.b 1.30/1.29.sup.a 18.0 1.71, s
.sup.a,binterchangeable signals
Example 4
Production of a Extract of Erionic Acid from E. angustifolium by
Means of Gel Permeation Chromatography
[0266] From 0.5 g of the methanolic extract of E. angustifolium
according to Example 1, the flavanones were removed with a flow
rate of 2.5 ml/min over a Sephadex-LH 20 column. After evaporation
an extract ("FF") rich in flavonoids was obtained. The remaining
part was dried under vacuum and stored overnight in the high vacuum
drying oven to remove residual solvent. The flavonoidfree dry
extract thus obtained had a content of 46% of benzoic acid
derivatives to be used according to the invention.
Gel Permeation Chromatography Conditions
[0267] Stock solution: 0.5 g/20 ml methanol [0268] Column: Kronlab
3.5.times.60 cm [0269] Column material: Sephadex LH-20 [0270]
Solvent: Methanol [0271] Flow rate: 2.5 ml/min [0272] Detection
(UV): 210 nm
[0273] FIG. 1 shows typical LC-MS chromatograms (a) of the extract
rich in erionic acid thus obtained and (b) of the extract rich in
flavonoids respectively.
Example 5
Production of a Methanolic Extract from Eriodictyon
californicum
[0274] Boiling water was poured over 150 g of dried leaves of
Eriodictyon californicum and stirred for one hour in order to swell
the plant material and prepare it for the further extraction. The
plant material was filtered off, dried and extracted twice with 1.5
l of methanol each time at room temperature for one hour with
stirring. The extract was filtered, dried under vacuum and stored
overnight in the high vacuum drying oven to remove residual
solvent. The extraction yielded 32.65 g of dark green extract.
Example 6
Isolation Of the Individual Compounds from Eriodictyon californicum
by Means of HTLC
[0275] The methanolic extract of E. californicum according to
Example 5 was separated and fractionated by means of HTLC using a
polymer-based semi-preparative column with water-ethanol gradients
under isothermal conditions (120.degree. C.). In addition to
flavones known from the literature, four compounds of the formula
(X) could be isolated. The results are shown in Table 7, the HTLC
conditions in Table 8 and analytical data in Tables 9a and 9b.
TABLE-US-00008 TABLE 7 Retention time for various Eriolic acids
Molecular weight Retention time Compound [g/mol] [min] Eriolic acid
A (7) 388 15.0-16.5 Eriolic acid B (8) 358 21.0-22.9 Eriolic acid C
(9) 374 13.5-14.8 Eriolic acid D (10) 372 20.0-21.0
TABLE-US-00009 TABLE 8 HTLC conditions Pumps 2 SunChrom HPLC pumps
SunFlow 100 (SunChrom, Friedrichsdorf, Germany) Injector 100 .mu.l
loop; Midas, Spark, A J Emmen, The Netherlands HPLC oven
Polaratherm Series 9000 (Selerity Technologies Inc., Salt Lake
City, USA) Detectors Light scattering detector (ELSD) Sedex 85
LT-ELSD (Sedere, Alfortville, Cedex, France); Diode array detector
(DAD) SunChrom SpectraFlow, wavelengths 200-400 nm (SunChrom,
Friedrichsdorf, Germany) Column Hamilton PRP-1 reversed phase; 250
.times. 10 mm semi-preparative; 10 .mu.m particle size (Hamilton,
Bonaduz, Switzerland) Flow rate 3 ml/min Fraction collector Labocol
Vario 2000 (Labomatic, Weil am Rhein) Software PrepCon (SCPA GmbH,
Weye-Leeste); Version 5.03.009, SCPA GmbH 2003 Stock solution 300
mg/ml E. californicum extract (Y) in ethanol/water (1:1) Injection
volume 100 .mu.l Column Hamilton PRP-1 250 .times. 10 mm
Temperature 120.degree. C. isothermal Eluent A: water C: ethanol
Gradient 0 min: 100% A 0% C 30 min: 50% A 50% C 50 min: 0% A 100% C
60 min: 0% A 100% C Detection ELSD (3.5 bar N2, 45.degree. C., gain
6); DAD 210 nm, 250 nm, 280 nm, 320 nm
TABLE-US-00010 TABLE 9a Analytical data Eriolic acid A (7) Eriolic
acid B (8) (400 MHz, CH3OD) (400 MHz, CH.sub.3OD) Pos.
.delta..sub.c, mult. .delta..sub.H (J in Hz) .delta..sub.c, mult.
.delta..sub.H (J in Hz) 1 129.6 123.1 2 131.0 7.72, s 130.3 7.64, d
(2.2) 3 135.7 128.8 4 161.4 158.2 5 135.7 129.2 6 130.9 7.72, s
130.3 7.63, d (2.2) 7 170.6 170.9 8 28.8.sup.b 3.43, d (7.1) 29.0
3.38, d (7.4) 9 125.5 5.50, dd (7.2, 7.2) 124.9 5.50, dd (7.4, 7.4)
10 139.6 139.6 11 78.6 3.98, dd (7.0, 7.0) 78.7 3.99, dd (7.0, 7.0)
12 34.8 2.26, dd (7.0, 7.0) 34.8 2.26, dd (7.0, 7.0) 13 121.7 5.07,
dd (7.0, 7.0) 121.7 5.08, dd (7.0, 7.0) 14 134.0 134.0 15 26.0
1.63, s 26.0 1.64, s 16 11.8 1.74, s 11.6 1.72, s 17 18.0 1.60, s
17.9.sup.a 1.59, s 18 28.9.sup.a 3.45, d (7.1) 29.4 3.33, d (7.1)
19 124.5 5.57, dd (7.3, 7.3) 123.0 5.32, dd (7.3, 7.3) 20 137.5
134.1 21 68.7 3.98, s 26.0 1.76, s 22 13.9 1.78, s 18.0.sup.a 1.72,
s 23 61.6 .sup.a,b interchangeable signals
TABLE-US-00011 TABLE 9b Analytical data Eriolic acid C (9) Eriolic
acid D (10) (400 MHz, CH3OD) (400 MHz, CH.sub.3OD) Pos.
.delta..sub.c, mult. .delta..sub.H (J in Hz) .delta..sub.c mult.
.delta..sub.H (J in Hz) 1 123.4 128.4 2 130.4 7.65, s 130.8 7.71, d
(2.2) 3 128.8 135.5 4 158.1 161.3 5 128.8 136.1 6 130.4 7.65, s
130.8 7.70, d (2.2) 7 171.1 170.7 8 29.1.sup.a 3.38, d (7.2) 28.8
3.43, d (7.3) 9 124.7 5.55, dd (7.4, 7.4) 125.5 5.50, dd (7.2, 7.2)
10 139.6 139.5 11 78.6 3.99, dd (7.1, 7.1) 78.6 3.98, dd (7.0, 7.0)
12 34.8 2.26, dd (7.1, 7.1) 34.8 2.26, dd (7.0, 7.0) 13 121.6 5.09,
dd (7.1, 7.1) 121.6 5.06, dd (7.0, 7.0) 14 134.0 133.9 15 26.0
1.64, s 26.0.sup.a 1.63, s 16 11.6 1.72, s 11.7 1.74, s 17 18.0
1.60, s 18.0.sup.b 1.59, s 18 28.9.sup.a 3.40, d (7.4) 29.2 3.38, d
(7.3) 19 124.1 5.61, dd (7.4, 7.4) 123.7 5.28, dd (7.3, 7.3) 20
137.4 133.9 21 68.8 3.99, s 25.9.sup.a 1.75, s 22 13.8 1.76, s
17.9.sup.b 1.74, s 23 61.5 3.76, s .sup.a,binterchangeable
signals
Example 7
Production of a Concentrated Extract from Eriodictyon californicum
by Means of Precipitation
[0276] 5.0 g of an extract of E. californicum prepared analogously
to Example 5 were dissolved in 100 ml ethyl acetate. By addition of
10 ml of 3% sodium hydroxide solution with stirring, the
homoeriodictyol contained was precipitated out. The remaining
solution was dried over sodium sulphate and concentrated. The
sterubin also contained in the extract was precipitated out by
storage of the extract in the refrigerator for 12 hours. After
filtration, the filtrate was dried under vacuum and stored
overnight in the high vacuum drying oven to remove residual
solvent. The flavonoid-depleted dry extract thus obtained contained
benzoic acid derivatives to be used according to the invention in a
proportion of 50%.
Example 8
Production of a Concentrated Extract from E. californicum by Means
of Gel Permeation Chromatography
[0277] From 0.5 g of the methanolic extract of E. californicum
according to Example 5, the flavanoids were removed with a flow
rate of 2.5 ml/min over a Sephadex-LH 20 column, and the remaining
extract dried under vacuum and stored overnight in the high vacuum
drying oven to remove residual solvent. The purified dry extract
thus obtained had a content of the benzoic acid derivates to be
used according to the invention of 75%. [0278] Stock solution: 0.5
g/20 ml methanol [0279] Column: Kronlab 3.5.times.60 cm [0280]
Column material: Sephadex LH-20 [0281] Solvent: Methanol [0282]
Flow rate: 2.5 ml/min [0283] Detection (UV): 210 nm
Example 9
Production of a Concentrated Extract by Means of Gel Permeation
Chromatography
[0284] An extract prepared according to WO2004041804 which had
already been depleted of homoeriodictyol and sterubin by the method
described therein was fractionated over a Sephadex LH-20 column
analogously to Example 4 to remove the residual flavonoids, dried
under vacuum and stored overnight in the high vacuum drying oven to
remove residual solvent. The flavanoidfree dry extract thus
obtained had a content of the benzoic acid derivatives to be used
according to the invention of 62%.
Formulation Examples
[0285] The following tables show formulation examples comprising
the products of the present invention.
TABLE-US-00012 TABLE I Low-fat yoghurt, sweetened (Amounts in %
b.w.) Ingredient A B C Sucrose 10 8 6 Tagatose -- -- 0.5 Fructose
-- -- 0.05 Hesperetin -- 0.1 0.005 Phloretin -- -- 0.005 Strawberry
flavour -- 0.25 -- Peach flavour 0.3 -- 0.4 Herba Santa extract (E.
angustifolium) 0.4 0.4 as per Example 1 (10% in ethanol)
Concentrated Herba Santa extract (E. angustifolium) 0.1 as per Ex.
4 (10% in ethanol) Yoghurt, 0.1% fat Ad 100
TABLE-US-00013 TABLE II Low fat yoghurt, reduced sugar (amounts in
% b.w.) Ingredient A B C D Tagatose 0.482 0.482 0.482 Sucralose
0.003 0.003 0.003 Aspartame 0.00 0.00 0.00 Acesulfam K 0.01 0.01
0.01 Rebaudioside A 0.00 Rubus suavissimus extract 0.00 Hesperetin
0.01 0.00 0.00 Phloretin -- -- 0.00 0.00 Strawberry flavour -- 0.2
-- 0.2 Raspberry flavour 0.3 -- 0.4 Herba Santa extract (E.
californicum) 0.3 0.4 as per Ex. 5 (10% in ethanol) Concentrated
Herba Santa 0.1% 0.1% extract (E. californicum) as per Ex. 8 (10%
in ethanol) Yoghurt, 0.1% fat Ad 100
TABLE-US-00014 TABLE III Low fat yoghurt drink, sweetened (amounts
in % b.w.) Ingredient A B C Sucrose 7 4 5 Tagatose -- -- 0.5
Fructose -- -- 0.05 Hesperetin -- 0.1 0.005 Phloretin -- -- 0.005
Strawberry flavour -- 0.15 -- Red fruit flavour 0.2 -- 0.25
Colouring food: fruit juice 5 5 5 Herba Santa extract 0.35 0.2 (E.
angustifolium) as per Example 1 (10% in ethanol) Concentrated Herba
Santa 0.15 extract (E. angustifolium) as per Ex. 4 (10% in ethanol)
Yoghurt, 0.1% fat 60 60 60 Water Ad 100
TABLE-US-00015 TABLE IV Sugar-free hard caramels (amounts in %
b.w.) Ingredient A B Palatinit, type M Ad 100 Water 24.82 24.82
Peppermint flavour 0.15 0.05 Hesperetin 0.10 Trans-pellitorin (10%
in ethanol) 0.01 Herba Santa extract 0.1 (E. angustifolium) as per
Ex. 1 (10% in ethanol) Concentrated Herba Santa 0.05 extract (E.
angustifolium) as per Ex. 4 (10% in ethanol)
[0286] Palatinit was mixed with water and the mixture was melted at
165.degree. C. then cooled to 115.degree. C. Flavouring and extract
produced according to the invention, and trans-pellitorin in case A
and hesperetin in case B, were added, and after thorough mixing
poured into moulds, and after solidification were removed from the
foil and then individually packed.
TABLE-US-00016 TABLE V Black, green or herb tea (amounts in % b.w.)
Ingredient A B C D E Black tea (Ceylon) leaves 99.4 -- -- -- --
Green tea (China), leaves -- 99.2 -- -- -- Mate tea (Peru), leaves
-- -- 99.5 -- Rooibos tea (South Africa), leaves -- -- -- 99.6 --
Honeybush tea (South Africa), leaves -- -- -- -- 99.6 Herba Santa
extract 0.3 0.8 -- 0.4 0.2 (E. angustifolium) as per Ex. 1 Herba
Santa extract 0.3 -- 0.5 -- 0.2 (E. californicum) as per Ex. 5
TABLE-US-00017 TABLE VI Soya drink Ingredient A B C Sucrose 5 5 3.5
Tagatose -- -- 0.5 Fructose -- -- 0.05 Hesperetin -- -- 0.005
Phloretin -- -- 0.005 Chocolate flavour -- 0.15 -- Vanilla flavour
0.1 -- 0.1 Herba Santa extract 0.08 0.1 (E. angustifolium) as per
Example 1 (10% in ethanol) Concentrated Herba Santa 0.05 extract
(E. californicum) as per Ex. 8 (10% in ethanol) Unsweetened soya
milk base Ad 100
TABLE-US-00018 TABLE VII Fruity muesli bars (amounts in % b.w.)
Ingredients A Saccharose 15.992 Glucose syrup 14.0 Sorbitol P300
5.0 Plant fat 5.0 Water 3.0 Rolled oats 7.3 Oat flakes 7.0
Cornflakes 4.5 Rice crispies 15.0 Currants 3 Dried blueberries 20
Citric acid powder 0.2 Concentrated Herba Santa extract as per Ex.
4 0.008
TABLE-US-00019 TABLE VIII Chewing gum for bad breath (amounts in %
b.w.) Ingredients A B C D Chewing gum base 21.00 21.00 21.00 21.00
Glucose syrup 16.80 16.80 16.50 16.50 Glycerine 0.50 0.50 0.50 0.50
Sugar powder 60.00 60.00 60.40 60.40 Spearmint flavour 1.50 1.50
1.50 1.50 Herba Santa extract (E. angustifolium) 0.2 as per Ex. 1
10% in ethanol Herba Santa extract (E. californicum) 0.2 as per Ex.
5 10% in ethanol Concentrated extract from E. angustifolium 0.1 as
per Ex. 4 - 10% in ethanol Concentrated extract from E.
californicum 0.1 as per Ex. 7 - 10% in ethanol
TABLE-US-00020 TABLE IX Sugar-free chewing gum for bad breath
(amounts in % b.w.) Ingredients A B C D Chewing gum base 30.00
30.00 30.00 30.00 Sorbitol, powder 38.25 38.25 38.40 38.40
Palatinit 9.50 9.50 9.50 9.50 Xylitol 2.00 2.00 2.00 2.00 Mannitol
3.00 3.00 3.00 3.00 Aspartame 0.10 0.10 0.10 0.10 Acesulfam K 0.10
0.10 0.10 0.10 Emulgum/emulsifier 0.30 0.30 0.30 0.30 Sorbitol 70%,
in water 14.00 14.00 14.00 14.00 Glycerine 1.00 1.00 1.00 1.00
Cinnamon/menthol flavour 1.50 1.50 1.50 1.50 Herba Santa extract
(E. angustifolium) 0.25 as per Ex. 1 - 10% in ethanol Herba Santa
extract (E. californicum) 0.2 as per Ex. 5 - 10% in ethanol
Concentrated extract from E. angustifolium 0.1 as per Ex. 4 - 10%
in ethanol Concentrated extract from E. californicum 0.1 as per Ex.
7 - 10% in ethanol
TABLE-US-00021 TABLE X Ready-to-use mouthwash solution with
fluoride for bad breath (amounts in % b.w.) Ingredients A B C
Ethanol 7.00 7.00 7.00 Glycerine 12.00 12.00 12.00 Na fluoride 0.05
0.05 0.05 Pluronic F-127 .RTM. (BASF, 1.40 1.40 1.40 surface-active
substance) Na phosphate buffer pH 7.0 1.10 1.10 1.10 Sorbic acid
0.20 0.20 0.20 Na saccharinate 0.10 0.10 0.10 Cinnamon/menthol
flavour 0.15 0.15 0.15 Herba Santa extract (E. angustifolium) 0.3
as per Ex. 1 10% in ethanol Herba Santa extract (E. californicum)
0.3 as per Ex. 5 10% in ethanol Concentrated extract from E.
angustifolium 0.08 as per Ex. 4 10% in ethanol Colorant 0.01 0.01
0.01 Dist. water Ad 100
TABLE-US-00022 TABLE XI Mouthwash solution (concentrate) for bad
breath (amounts in % b.w.) Ingredients A B C Ethanol, 95% 80.00
80.00 80.00 Na cyclamate 0.15 0.15 0.15 Eucalyptus/wintergreen
flavour 3.50 3.50 3.50 Colorant 0.01 0.01 0.01 Herba Santa extract
0.50 (E. angustifolium) as per Ex. 1 Concentrated extract from 0.1
E. angustifolium as per Ex. 4 Concentrated extract from 0.1 E.
californicum as per Ex. 7 Demin. water Ad 100
TABLE-US-00023 TABLE XII Mouthwash solution with fluoride for bad
breath (amounts in % b.w.) Ingredient INCI A Ethyl alcohol Ethyl
alcohol 10.00 Cremophor CO 40 Cremophor CO 40 (PEG 1.00 40
hydrogenated castor oil) Benzoic acid Benzoic acid 0.12 Aroma (PF1,
PF2, PF3 or PF4) Flavour 0.25 Demin. water Water (deionized) 83.28
Sorbitol 70% Sorbitol 70% 5.00 Sodium saccharin Sodium saccharin
450 0.07 Sodium fluoride Sodium fluoride 0.18 Herba Santa extract
(E. angustifolium) 0.10 as per Ex. 1 (10% in ethanol)
TABLE-US-00024 TABLE XIII Toothpaste (amounts in % b.w.) Ingredient
INCI A Demin. water Water (deionized) 26.31 Sorbitol 70% Sorbitol
70% 70.0 Solbrol M (Na salt) Solbrol M (Sodium salt) 0.15
(methylparaben) Trisodium phosphate Trisodium phosphate 0.10
Saccharin Saccharin 0.20 Sodium Sodium monofluorophosphate 1.14
monofluorophosphate PEG 1500 PEG 1500 5.00 Sident 9 (abrasive
silica gel) Sident 9 (abrasive silica) 10.00 Sident 22 S
(thickener) Sident 22 S (thickening silica) 8.00 Sodium Sodium
carboxymethylcellulose 1.10 carboxymethylcellulose Titanium (IV)
oxide Titanium (IV) oxide 0.50 Sodium laurylsulphate (SLS) Sodium
laurylsulphate (SLS) 1.50 Aroma (PF1, PF2, PF3 or PF4) Flavour 1.00
Concentrated Herba Santa extract (E. californicum) 0.40 as per Ex.
7 (10% in ethanol)
TABLE-US-00025 TABLE XIV Anti-plaque toothpaste (amounts in % b.w.)
Ingredient A B Carrageenan 0.90 0.90 Glycerol 15.00 15.00 Sorbitol
70%, in water 25.00 25.00 PEG 1000 3.00 3.00 Na fluoride 0.24 0.24
Tetrapotassium diphosphate 4.50 4.50 Tetrasodium diphosphate 1.50
1.50 Na saccharinate 0.40 0.40 Precipit. silica gel 20.00 20.00
Titanium dioxide 1.00 1.00 Triclosan 0.30 0.30 PHB methyl ester
0.10 0.10 Spearmint flavour (containing 1.00 1.20 60 wt. %
L-carvone and 25 wt. % L-menthol) Concentrated Herba Santa 0.30 --
extract (E. californicum) as per Ex. 7 (10% in ethanol) Herba Santa
extract -- 0.50 (E. californicum) as per Ex. 1 (10% in ethanol)
Sodium dodecylsulphate 1.30 1.30 Demin. water Ad 100
TABLE-US-00026 TABLE XV Tooth cream for pain-sensitive teeth
(amounts in % b.w.) Ingredient A B Na carboxymethylcellulose 0.70
0.70 Xanthan gum 0.50 0.50 Glycerol 15.00 15.00 Sorbitol 70%, in
water 12.00 12.00 Potassium nitrate 5.00 5.00 Sodium
monofluorophosphate 0.80 0.80 PHB methyl ester 0.15 0.15 PHB propyl
ester 0.05 0.05 Na saccharinate 0.20 0.20 Flavour (PF1, PF2, PF3 or
PF4) 1.00 1.00 Herba Santa extract (E. angustifolium) 0.50 -- as
per Ex. 1 (10% in ethanol) Herba Santa extract (E. californicum) --
0.25 as per Ex. 5 (10% in ethanol) Ca carbonate 35.00 35.00 Silicon
dioxide 1.00 1.00 Sodium dodecylsulphate (SDS) 1.50 1.50 Demin.
water Ad 100
TABLE-US-00027 TABLE XVI Gelatine capsules for bad breath for
direct consumption (amounts in % b.w.) Ingredients A B C Gelatine
casing Glycerine 2.014 2.014 2.014 Gelatine 240 Bloom 7.91 7.91
7.91 Sucralose 0.065 0.065 0.065 Allura Red 0.006 0.006 0.006
Brilliant Blue 0.005 0.005 0.005 Core filling Plant oil
triglycerides 82.00 74.00 60.00 Flavour B 7.9 15.50 29.5 Herba
Santa extract 0.10 0.50 -- (E. angustifolium) as per Ex. 1 (10% in
ethanol) Herba Santa extract 0.10 -- 0.50 (E. californicum) as per
Ex. 5 (10% in ethanol)
[0287] Flavour B had the following composition (data in weight %):
0.1% neotame (powder), 0.05% aspartame, 29.3% peppermint oil
(Avensis), 29.3% peppermint oil (Piperita; Willamette), 2.97%
sucralose, 2.28% triacetin, 5.4% diethyl tartrate, 12.1% peppermint
oil (Yakima), 0.7% ethanol, 3.36% 2-hydroxyethyl menthyl carbonate,
3.0% 2-hydroxypropyl menthyl carbonate, 0.27% vanillin, 5.5%
D-limonene, 5.67% L-menthyl acetate.
[0288] The gelatine capsule, which is suitable for direct
consumption, has a diameter of 5 mm; the weight ratio between core
and casing material is about 90:10. The capsules open in the mouth
in less than 10 secs, and dissolve completely within 50 secs.
TABLE-US-00028 TABLE XVII Syndet - soap-free cleansing bar (amounts
in % b.w.) Ingredient INCI A B Zetesap 813 A Disodium lauryl
sulpho- 92.0 91.9 succinate, sodium lauryl sulphate, corn starch,
cetearyl alcohol, paraffin, titanium dioxide Amphotensid GB 2009
Disodium cocoamphodiacetate 6.0 6.0 Allantoin Allantoin 1.0 1.0
Perfume oil P2, Fragrance 1.0 -- P4, P6 or P7 Perfume oil P1,
Fragrance -- 1.0 P3 or P5 Herba Santa extract (E. angustifolium)
0.5 -- as per Example 1 (10% in EtoH) Concentrated Herba Santa
extract (E. angustifolium) -- 0.1 as per Example 4 (10% in
ethanol)
TABLE-US-00029 TABLE XVIII Soap bar (amounts in % b.w.) Ingredient
INCI A B Demin. water Water 2.5 2.5 Soap base mix Sodium
tallowates/ 95.5 95.8 palmitates Titanium dioxide Titanium dioxide
1.0 1.0 Perfume oil P2, Fragrance 0.8 -- P4, P6 or P7 Perfume oil
P1, Fragrance -- 0.5 P3 or P5 Concentrated Herba Santa extract (E.
angustifolium) 0.2 -- as per Example 4 (10% in ethanol)
Concentrated Herba Santa extract (E. californicum) -- 0.2 as per
Example 7 (10% in ethanol)
TABLE-US-00030 TABLE XIX Antimicrobial soap bar (amounts in % b.w.)
Ingredients A B Sodium soap from tallow 60.0 60.0 Sodium soap from
palm oil 27.0 27.0 Glycerol 2.0 2.0 Sodium chloride 0.5 0.5
1-hydroxyethane-1,1-diphosphoric 0.3 0.3 acid, tetrasodium salt
Alpha-tocopherol 0.1 0.1 Pigment yellow 1 0.02 0.02 Water Ad 100
Perfume oil P2, P4, P6 or P7 3.0 -- Perfume oil P1, P3 or P5 -- 3.0
Herba Santa extract (E.) 0.5 as per Example 1 (10% in ethanol)
Concentrated Herba Santa extract (E. angustifolium) -- 0.2 as per
Example 7 (10% in ethanol)
TABLE-US-00031 TABLE XX Liquid soap (amounts in % b.w.) Ingredient
INCI A B Tagat O 2 PEG-20 Glyceryl oleate 2.5 2.5 Coconut fatty
acid Cocamide DEA 5.0 5.0 diethanolamide Abil B 8842 Cyclomethicone
0.5 0.5 Sodium laurylether Sodium laureth sulphate 35.0 35.0
sulphate, 28% Tego-betaine L7 Cocamidopropyl betaine 5.0 5.0 Soap,
25% Coconut acid, potassium 20.0 20.0 salt, potassium oleate Water
Water Ad 100 Preservative DMDM hydantoin Perfume oil P2, Fragrance
0.4 -- P4, P6 or P7 Perfume oil P1, Fragrance -- 0.4 P3 or P5
Concentrated Herba Santa extract (E. angustifolium) 0.4 0.3 as per
Ex. 4 (10% in ethanol)
TABLE-US-00032 TABLE XXI Liquid soap (Syndet) (amounts in % b.w.)
Ingredients INCI A B Elfan OS 46 Sodium olefin C14-C16 35.5 35.5
sulphonate Armoteric LB Lauryl betaine 8.0 8.0 Elfan SG 10.0 10.0
Elfacos GT 282 L Talloweth-60 myristyl glycol 3.0 3.0 PCL-Liquid
100 cetearyl ethylhexanoate 4.0 4.0 Water water Ad 100 Perfume oil
P2, Fragrance 0.4 -- P4, P6 or P7 Perfume oil P1, Fragrance -- 0.4
P3 or P5 Herba Santa extract (E. angustifolium) 0.5 as per Ex. 1
(10% in ethanol) Herba Santa extract (E. californicum) 0.3 as per
Ex. 5 (10% in ethanol)
TABLE-US-00033 TABLE XXII Shampoo Ingredients A B Sodium lauryl
ether sulphate 12 12 (e.g. Texapon NSO) Cocamidopropylbetaine (e.g.
Dehyton K) 2 2 Sodium chloride 1.4 1.4 Citric acid 1.3 1.3
Phenoxyethanol, methyl, ethyl, 0.5 0.5 butyl and propylparaben
Perfume oil P2, P4, P6 or P7 0.3 -- Perfume oil P1, P3 or P5 -- 0.3
Herba Santa extract (E. californicum) 0.25 -- as per Ex. 5 (10% in
ethanol) Herba Santa extract (E. californicum) 0.15 as per Ex. 7
(10% in ethanol) Water Ad 100
TABLE-US-00034 TABLE XXIII 2 in 1 - Shampoo (all amounts in % b.w.)
Ingredients INCI A B Demineralized water Water Ad 100 Plantacare PS
10 Sodium laureth sulphate, 20.0 20.0 lauryl glucoside Euperlan PK
771 Glycol distearate, 6.0 6.0 sodium lauryl sul- phate, cocamide
MEA, laureth-10 Dragocid liquid Phenoxyethanol, methyl- 0.5 0.5
paraben, ethylparaben, butylparaben, propylparaben, isobutylparaben
Sodium chloride Sodium chloride 1.4 1.4 Citric acid monohydrate
Citric acid 0.1 0.1 (crystalline) Perfume oil P2, Fragrance 0.5 --
P4, P6 or P7 Perfume oil P1, Fragrance -- 0.5 P3 or P5 Concentrated
Herba Santa extract (E. angustifolium) 0.15 -- as per Ex. 4 (10% in
ethanol) Herba Santa extract (E. californicum) -- 0.15 as per Ex. 8
(10% in ethanol)
TABLE-US-00035 TABLE XXIV Anti-dandruff shampoo (all amounts in %
b.w.) Ingredients INCI A B Climbazole Climbazole 0.50 0.50
Phenoxyethanol, Phenoxyethanol, methylparaben, 0.70 0.70
methylparaben, ethylparaben, butylparaben, Ethylparaben,
propylparaben, isobutylparaben Butylparaben, Propylparaben,
Isobutylparaben Herba Santa extract (E. angustifolium) 0.60 -- as
per Ex. 1 (10% in ethanol) Concentrated Herba Santa extract (E.
angustifolium) -- 0.40 as per Ex. 4 (10% in ethanol) Sodium laureth
sulphate Sodium laureth sulphate 37.00 37.00 Cocamidopropyl betaine
Cocamidopropyl betaine 8.00 8.00 PEG-6 PEG-6 caprylic/capric
glycerides 2.50 2.50 Laureth -2 Laureth-2 2.00 2.00 Thyme extract
Water (aqua), glycerol, 0.50 0.50 Thymus vulgaris (thyme),
flower/leaf extract Rosemary extract Rosmarinus officinalis 0.50
0.50 (rosemary) leaf water, water (aqua), butylene glycol,
pentylene glycol Bisabolol Bisabolol 0.10 0.10 Panthenol Panthenol
0.50 0.50 Perfume oil P2, Fragrance 0.50 -- P4, P6 or P7 Perfume
oil P1, Fragrance -- 0.50 P3 or P5 Water Water (aqua) 46.30 46.30
Polyquaternium-10 Polyquaternium-10 0.40 0.40
TABLE-US-00036 TABLE XXV Shower gel (amounts in % b.w.) Ingredients
INCI A B Demin. water Water Ad 100 Plantacare PS 10 Sodium laureth
sulphate, 20.0 20.0 lauryl glucoside Dragocid Liquid
Phenoxyethanol, 0.5 0.5 methylparaben, ethylparaben, butylparaben,
propylparaben, isobutylparaben Sodium chloride Sodium chloride 1.4
1.4 Citric acid monohydrate Citric acid 1.3 1.3 (crystalline)
Perfume oil P2, Fragrance 0.6 -- P4, P6 or P7 Perfume oil P1,
Fragrance -- 0.6 P3 or P5 Herba Santa extract (E. angustifolium)
0.1 as per Example 1 (10% in ethanol) Concentrated Herba Santa
extract (E. angustifolium) 0.05 as per Example 4 (10% in
ethanol)
TABLE-US-00037 TABLE XXVI Shaving foam (amounts in % b.w.)
Ingredients A B Demin. water 77.2 77.22 Triethanolamine 4.0 4.0
Edenor L2 SM (stearic acid, 5.3 5.3 palmitic acid) (Cognis)
Laureth-23 3.0 3.0 Stearyl alcohol 0.5 0.5 Euxyl .RTM. K220
(methylisothiazolinone, 0.8 0.8 ethylhexylglycerol) Sodium lauryl
sulphate 3.0 3.0 Extrapone seaweed/alga (water, 1.0 1.0 propylene
glycol, potassium iodide, Fucus Vesiculosus Extract) Dragosantol
(bisabolol, farnesol) 0.1 0.1 Perfume oil P2, P4, P6 or P7 1.0 --
Perfume oil P1, P3 or P5 -- 1 Herba Santa extract (E. californicum)
0.1 -- as per Example 5 (10% in EtOH) Concentrated Herba Santa
extract as -- 0.08 per Example 8 (10% in ethanol) Propane, butane
4.2 bar 4.0 4.0
TABLE-US-00038 TABLE XXVII Aftershave (amounts in % b.w.)
Ingredients INCI A B SymSol .RTM. PF-3 Water (aqua), pentylene 3.00
3.00 glycol, sodium lauryl sulphoacetate, sodium oleoyl
sarcosinate, so- dium chloride, disodium sulphoacetate, sodium
oleate, sodium sulphate SymSitive .RTM. 1609 Pentylene glycol, 1.00
1.00 4-t-butylcyclo-hexanol Frescolat .RTM. ML Menthyl lactate 0.30
0.30 Glycerol 99.5 P. Glycerol 5.00 5.00 Water Water (aqua) Ad 100
Extrapone .RTM. Glacier Glycerol, Water (aqua) 1.00 1.00 Water GW
SymCalmin .RTM. Butylene glycol, pentylene 0.50 0.50 glycol,
hydroxyphenyl propamidobenzoic acid Dragosine .RTM. Carnosine 0.10
0.10 Hydrolite .RTM. 5 Pentylene glycol 5.00 5.00 Ethanol 96%
Alcohol denat. 5.00 5.00 Colour pigment Colour pigment 0.05 0.05
Perfume oil P2, P4, Perfume 0.15 -- P6 or P7 Perfume oil P1, P3
Perfume -- 0.15 or P5 Herba Santa extract (E. angustifolium) 0.15
-- as per Example 1 (10% in ethanol) Concentrated Herba Santa
extract (E. angustifolium) -- 0.08 as per Example 4 (10% in
ethanol)
TABLE-US-00039 TABLE XXVIII Deodorant formulation (Roll-on gel)
(amounts in % b.w.) Ingredients A B 1,3-Butylene glycol 2.00 2.00
PEG-40-hydrogen. castor oil 2.00 2.00 Hydroxyethylcellulose 0.50
0.50 Preservative (phenoxyethanol) 0.30 0.30 Perfume oil P2, P4, P6
or P7 0.30 -- Perfume oil P1, P3 or P5 -- 0.30 Herba Santa extract
(E. angustifolium) 0.30 -- as per Example 1 (10% in EtoH)
Concentrated Herba Santa extract (E. angustifolium) -- 0.10 as per
Example 4 (10% in ethanol) Water Ad 100
TABLE-US-00040 TABLE XXIX Deodorant stick (amounts in % b.w.)
Weight Weight Ingredients % % Sodium stearate 8.00 8.00 PPG-3
myristyl ether 70.00 70.00 1,2-propylene glycol 10.00 10.00
1,1-dimethyl-3-phenylpropanol 0.20 0.25 2-butyloctanoic acid 0.20
0.20 Perfume oil P2, P4, P6 or P7 0.60 -- Perfume oil P1, P3 or P5
-- 0.60 Herba Santa extract (E. angustifolium) 0.30 -- as per
Example 1 (10% in ethanol) Concentrated Herba Santa extract (E.
californicum) -- 0.20 as per Example 7 (10% in ethanol) Water Ad
100
TABLE-US-00041 TABLE XXX Antiperspirants (amounts in % b.w.)
Ingredients A B Reach AZP-908 SUF 24.00 22.00 Cyclomethicone
(pentamer) Ad 100 Polydecene (Silkflo 364 NF) 17.50 20.00 Neo
Heliopan OS (ethylhexyl salicylate) 2.50 1.00 L-menthyl lactate
(Frescolate ML) 0.25 -- Polyethylene 3.00 3.00 Hydrogen. castor oil
2.00 2.00 Promyristyl PM-3 7.00 7.00 PEG-8 distearate 3.00 3.00
Silicon dioxide (Cab-O-Sil M-5) 1.00 1.00 Stearyl alcohol 15.00
10.00 Octyldodecanol -- 8.00 Perfume oil P2, P4, P6 or P7 0.80 --
Perfume oil P1, P3 or P5 -- 0.80 Herba Santa extract (E.
angustifolium) 0.30 -- as per Example 1 (10% in ethanol)
Concentrated Herba Santa extract (E. angustifolium) -- 0.30 as per
Example 4 (10% in ethanol)
TABLE-US-00042 TABLE XXXI O/W lotion (amounts in % b.w.)
Ingredients INCI A B Paraffin oil Paraffin oil 5.00 5.00 Isopropyl
palmitate Isopropyl palmitate 5.00 5.00 Cetyl alcohol Cetyl alcohol
2.00 2.00 Beeswax Beeswax 2.00 2.00 Ceteareth-20 Ceteareth-20 2.00
2.00 PEG-20 glyceryl PEG-20 glyceryl 1.50 1.50 stearate stearate
Glycerol Glycerol 3.00 3.00 Perfume oil P2, Perfume 0.30 -- P4, P6
or P7 Perfume oil P1, Perfume -- 0.30 P3 or P5 Herba Santa extract
(E. californicum) 0.25 -- as per Example 5 (10% in ethanol)
Concentrated Herba Santa extract (E. californicum) -- 0.10 as per
Example 7 (10% in ethanol) Methylparaben Methylparabens 0.30 0.30
Water Water Ad 100
TABLE-US-00043 TABLE XXXII Body lotion (amounts in % b.w.)
Ingredients INCI A B Cetearyl alcohol Cetearyl alcohol 2.00 2.00
Ethylhexyl isononanoate Ethylhexyl isononanoate 5.00 5.00 Cetearyl
ethylhexanoate, Cetearyl ethylhexanoate, 3.00 3.00 isopropyl
myristate isopropyl myristate Glyceryl oleate citrate, Glyceryl
oleate citrate, 4.00 4.00 caprylic/capric triglyceride
caprylic/capric triglyceride Water Water (aqua) 79.50 79.50
Carbomer Carbomer 0.30 0.30 Sodium benzoate Sodium benzoate 0.10
0.10 Propylene glycol Propylene glycol 5.00 5.00 Triethylene
glycol, Triethylene glycol, imida- 0.30 0.30 imidazolidinylurea,
zolidinylurea, methylpara- methylparaben, ben, propylparaben, dehy-
propylparaben, dehy- droacetic acid droacetic acid Sodium hydroxide
Sodium hydroxide 30% 0.30 0.30 Soln. (30%) solution Perfume oil P2,
P4, Perfume 0.30 -- P6 or P7 Perfume oil P1, P3 or P5 Perfume --
0.30 Herba Santa extract (E. angustifolium) as per 0.10 -- Example
1 (10% in ethanol) Herba Santa extract (E. californicum) as per --
0.10 Example 5 (10% in ethanol)
TABLE-US-00044 TABLE XXXIII Hand and body cream (amounts in % b.w.)
Ingredients INCI A B Dracorin .RTM. GOC Glyceryl oleate citrate,
2.00 2.00 caprylic/capric triglycerides PCL-Solid Stearyl
heptanoate, stearyl 2.50 2.50 caprylate Lanette .RTM. O Cetearyl
alcohol 1.50 1.50 Cutina .RTM. GMS-V Glyceryl stearate 1.00 1.00
Dragoxat .RTM. 89 Ethylhexyl isononanoate 3.00 3.00 PCL-Liquid 100
Cetearyl ethylhexanoate 7.00 7.00 Isodragol .RTM. Triisononanoin
4.00 4.00 Xiameter .RTM. PMX-0345 Cyclopentasiloxane (and) 0.50
0.50 Cyclosiloxane cyclohexasiloxane Water Water (aqua) Ad 100
Carbopol .RTM. Ultrez 21 Acrylates/C10-30 alkyl acry- 0.20 0.20
late crosspolymer Keltrol .RTM. CG-RD Xanthan gum 0.10 0.10
Glycerol 85 P. Glycerol 3.00 3.00 DragoBetaGlucan Water (aqua),
butylene 1.50 1.50 glycol, glycerol, Avena sa- tiva (oat) kernel
extract Potassium sorbate Potassium sorbate 0.10 0.10 euxyl .RTM.
K300 Methyl, butyl, ethyl, propyl, 0.80 0.80 isobutylparaben,
phenoxyethanol. Sodium hydroxide Sodium hydroxide 0.50 0.50 10%
solution Perfume oil P2, Perfume 0.20 -- P4, P6 or P7 Perfume oil
P1, Perfume -- 0.20 P3 or P5 Herba Santa extract (E. angustifolium)
as per 0.20 -- Example 1 (10% in ethanol) Concentrated Herba Santa
extract (E. angustifolium) -- 0.15 as per Example 4 (10% in
ethanol)
TABLE-US-00045 TABLE XXXIV Face cream (amounts in % b.w.) Weight
Weight Ingredients INCI % % Emulsiphos .RTM. Potassium cetyl 1.50
1.50 phosphate, hydrogenated palm glycerides Cutina .RTM. GMS-V
Glyceryl stearate 1.70 1.70 Lanette .RTM. O Cetearyl alcohol 3.00
3.00 Tegosoft .RTM. MM Myristyl myristate 1.00 1.00 PCL-Liquid 100
Cetearyl ethylhexanoate 1.00 1.00 Isodragol .RTM. Triisononanoin
3.00 3.00 Dragoxat .RTM. 89 Ethylhexyl isononanoate 4.00 4.00
Avocado oil Persea gratissima 3.00 3.00 (avocado) oil Abil .RTM.
350 Dimethicone 0.50 0.50 Covi-ox .RTM. T-70 Tocopherol 0.10 0.10
Edeta .RTM. BD Disodium EDTA 0.10 0.10 Carbopol .RTM.
Acrylates/C10-30 alkyl 0.30 0.30 Ultrez 21 acrylate crosspolymer
Keltrol .RTM. CG-RD Xanthan gum 0.15 0.15 Water Water (aqua) Ad 100
Glycerol 99.5 P. Glycerol 4.00 4.00 Propylene glycol- Propylene
glycol 3.00 3.00 1,2 99 P GC Euxyl .RTM. K712 Sodium benzoate, 0.80
0.80 potassium sorbate SymMatrix .RTM. Maltodextrin, 0.50 0.50
Rubus fruticosus (blackberry) leaf extract Sodium hydroxide Sodium
hydroxide 0.50 0.50 10% solution Perfume oil P2, Perfume 0.30 --
P4, P6 or P7 Perfume oil P1, Perfume -- 0.30 P3 or P5 Concentrated
Herba Santa extract (E. angustifolium) 0.10 -- as per Example 4
(10% in ethanol) Concentrated Herba Santa extract (E. californicum)
-- 0.10 as per Example 8 (10% in ethanol)
TABLE-US-00046 TABLE XXXV Anti-wrinkle cream (amounts in % b.w.)
Ingredients A B Glyceryl stearate citrate 1.00 1.00 Glyceryl
laurate 1.00 1.00 Cetearyl alcohol, 2.00 2.00 Myristyl myristate
1.00 1.00 Cetearyl ethylhexanoate 4.00 4.00 Mineral oil 4.00 4.00
Cyclopentasiloxane, cyclohexasiloxane 0.50 0.50 Acrylate/C10-30
alkylarylate crosspolymer 0.20 0.20 Preservative (phenoxyethanol)
1.00 1.00 Water Ad 100 Xanthan gum 0.10 0.10 1,2-hexanediol 2.00
2.00 Sodium hydroxide 10% soln. 0.10 0.10 Narcissus Tazetta extract
1.00 1.00 Perfume oil P2, P4, P6 or P7 0.30 -- Perfume oil P1, P3
or P5 -- 0.30 Concentrated Herba Santa extract (E. angustifolium)
0.10 -- as per Example 4 (10% in ethanol) Concentrated Herba Santa
extract (E. californicum) -- 0.10 as per Example 8 (10% in
ethanol)
TABLE-US-00047 TABLE XXXVI Washing and cleansing gel (amounts in %
b.w.) Ingredient INCI A B Water Water (aqua) Ad 100 Pionier .RTM.
NP 37 G Sodium carbomer 1.50 1.50 SymSol .RTM. PF-3 Water (aqua),
pentylene glycol, 5.00 5.00 sodium lauryl sulphoacetate, sodium
oleoyl sarcosinate, sodium chloride, disodium sulphoacetate, sodium
oleate, sodium sulphate Hydroviton .RTM. 24 Water (aqua), pentylene
glycol, 1.00 1.00 glycerol, sodium lactate, lactic acid, serine,
urea, sorbitol, sodium chloride, allantoin Extrapone .RTM. Silk GW
Water (aqua), glycerol, 1.00 1.00 hydrolyzed silk Hydrolite .RTM. 5
Pentylene glycol 4.00 4.00 Preservative Phenoxyethanol Actipearls
Red Star # Water (aqua), propylene glycol, 1.00 1.00 DH10402/6
algin, gellan gum, xanthan gum, calcium chloride, CI 12490 (Pigment
Red 5), mica (CI 77019), titanium dioxide (CI 77891) Perfume oil
P2, Perfume 0.50 -- P4, P6 or P7 Perfume oil P1, Perfume -- 0.50 P3
or P5 Herba Santa extract (E. angustifolium) 0.2 -- as per Example
1 (10% in ethanol) Concentrated Herba Santa extract (E.
californicum) -- 0.25 as per Example 7 (10% in ethanol)
TABLE-US-00048 TABLE XXXVII Sunscreen spray (amounts in % b.w.)
Ingredient INCI A B Demineralized water Water (aqua) 69.40 69.40
Glycerol Glycerol 4.00 4.00 1,3 Butylene glycol Butylene glycol
5.00 5.00 D-Panthenol Panthenol 0.50 0.50 Lara Care A-200
Galactoarabinan 0.25 0.25 Baysilon oil M 10 Dimethicone 1.00 1.00
Edeta BD Disodium EDTA 0.10 0.10 Copherol 1250 Tocopheryl acetate
0.50 0.50 Cetiol OE Dicaprylyl ether 3.00 3.00 Neo Heliopan .RTM.
HMS Homosalate 5.00 5.00 Neo Heliopan .RTM. AV Ethylhexyl 6.00 6.00
methoxycinnamate Neo Heliopan .RTM. 357 Butyl methoxydibenzoyl-
1.00 1.00 methane Corapan TQ Diethylhexyl naphthalate 2.00 2.00
Alpha Bisabolol Bisabolol 0.10 0.10 Pemulen TR-2 Acrylates/C10-30
alkyl 0.25 0.25 acrylate crosspolymer Phenoxyethanol Phenoxyethanol
0.70 0.70 Solbrol M Methylparaben 0.20 0.20 Solbrol P Propylparaben
0.10 0.10 NaOH, 10% Sodium hydroxide 0.60 0.60 Perfume oil P2, P4,
P6 Fragrance 0.20 -- or P7 Perfume oil P1, P3 or Fragrance -- 0.20
P5 Concentrated Herba Santa extract (E. californicum) 0.10 -- as
per Example 8 (10% in ethanol) Concentrated Herba Santa extract (E.
angustifolium) -- 0.10 as per Example 4 (10% in ethanol)
TABLE-US-00049 TABLE XXVIII Sunscreen milk (W/O) (amount in % b.w.)
Ingredients INCI A B Dehymuls PGPH Polyglyceryl-2 dipoly- 3.00 3.00
hydroxystearate Beeswax 8100 Beeswax 1.00 1.00 Monomuls 90-0-18
Glyceryl oleate 1.00 1.00 Zinc stearate Zinc stearate 1.00 1.00
Cetiol SN Cetearyl isononanoate 5.00 5.00 Cetiol OE Dicaprylyl
ether 5.00 5.00 Tegosoft TN C12-15 alkyl benzoate 4.00 4.00 Vitamin
E Tocopherol 0.50 0.50 Neo Heliopan .RTM. OS Ethylhexyl salicylate
5.00 5.00 Neo Heliopan .RTM. AV Ethylhexyl methoxycinnamate 7.50
7.50 Uvinul .RTM. T150 Ethylhexyl triazone 1.50 1.50 Demin. water
Water (aqua) Ad 100 Trilon BD Disodium EDTA 0.10 0.10 Glycerol
Glycerol 5.00 5.00 Solbrol M Methylparaben 0.20 0.20 Phenoxyethanol
Phenoxyethanol 0.70 0.70 Solbrol P Propylparaben 0.10 0.10 Neo
Heliopan .RTM. AP 10% Disodium phenyl 15.00 15.00 solution,
neutralized dibenzimidazole with NaOH tetrasulphonate Perfume oil
P2, P4, P6 or Perfume 0.25 -- P7 Perfume oil P1, P3 or P5 Perfume
-- 0.25 Herba Santa extract (E. angustifolium) 0.15 -- as per
Example 1 (10% in ethanol) Concentrated Herba Santa extract (E.
angustifolium) -- 0.1 as per Example 4 (10% in ethanol) Alpha
bisabolol Bisabolol 0.10 0.10
TABLE-US-00050 TABLE XXXIX After-Sun Gel (amounts in % b.w.)
Ingredients INCI A B SymSol .RTM. PF-3 Water (aqua), pentylene
3.000 3.000 glycol, sodium lauryl sulphoacetate, sodium oleoyl
sarcosinate, sodium chloride, disodium sulphoacetate, sodium
oleate, sodium sulphate Glycerol 99.5 P. Glycerol 5.000 5.000
SymHelios .RTM. 1031 Benzylidene dimethoxy- 0.100 0.100
dimethylindanone Water Water (aqua) q.s.p. 100 q.s.p. 100 Pemulen
.RTM. TR-2 Acrylates/C10-30 alkyl 1.000 1.000 acrylate crosspolymer
D-Panthenol 75 W Panthenol 0.500 0.500 SymFinity .RTM. 1298
Echinacea Purpurea 0.100 0.100 extract Extrapone .RTM. Water
(aqua), glycerol, 1.000 1.000 Pearl GW hydrolyzed pearl, xanthan
gum Sodium hydroxide Sodium hydroxide 2.500 2.500 10% soln.
Preservatives Methyl, butyl, ethyl, 1.000 1.000 propylparaben,
phenoxyethanol Ethanol 96% Alcohol denat. 15.000 15.000 Perfume oil
P2, Perfume 0.20 -- P4, P6 or P7 Perfume oil P1, Perfume -- 0.20 P3
or P5 Herba Santa extract (E. angustifolium) 0.1 -- as per Example
1 (10% in ethanol) Concentrated Herba Santa extract -- 0.05 (E.
angustifolium) as per Example 4 (10% in ethanol)
TABLE-US-00051 TABLE XXXX After-sun lotion (amounts in % b.w.)
Ingredients A B Acrylat/C10-30 alkyl acrylate crosspolymer 0.4 0.4
Cetearyl ethylhexanoate 15.0 15.0 Bisabolol 0.2 0.2 Tocopheryl
acetate 1.0 1.0 Panthenol 1.0 1.0 Alcohol 15.0 15.0 Glycerol 3.0
3.0 Perfume oil P2, P4, P6 or P7 0.30 -- Perfume oil P1, P3 or P5
-- 0.30 Herba Santa extract (E. angustifolium) 0.25 -- as per
Example 1 (10% in ethanol) Concentrated Herba Santa extract (E.
angustifolium) -- 0.15 as per Example 4 (10% in ethanol) Pentylene
glycol 4.0 4.0 Preservatives (methyl, butyl, ethyl, 1.0 1.0
propylparaben, phenoxyethanol) Demin. water Ad 100 Triethanolamine
0.2 0.2
TABLE-US-00052 TABLE XXXXI Solution for wet wipes (amounts in %
b.w.) Ingredients INCI A B SymSol .RTM. PF-3 Water (aqua),
pentylene 2.00 2.00 glycol, sodium lauryl sulphoacetate, sodium
oleoyl sarcosinate, sodium chloride, disodium sulphoacetate, sodium
oleate, sodium sulphate Dragosantol .RTM. 100 Bisabolol 0.10 0.10
Glycerol 99.5 P. Glycerol 5.00 5.00 Water Water (aqua) Ad 100
Hydrolite .RTM. 5 Pentylene glycol 5.00 5.00 Preservative
Phenoxyethanol D-Panthenol 75 W Panthenol 0.80 0.80 DragoCalm .RTM.
Water (aqua), glycerol, 1.00 1.00 Avena sativa (oat) kernel extract
Hamamelis Distillate Hamamelis virginiana 1.0 1.00 (witch hazel)
water, water (aqua), alcohol Allplant Essence .RTM. Org. Rose
Pelargonium graveolens 1.00 1.00 Geranium P flower/leaf/stem water
Perfume oil P2, P4, P6 or P7 Perfume 0.10 -- Perfume oil P1, P3 or
P5 Perfume -- 0.10 Herba Santa extract as per Example 1 0.30 -- (E.
angustifolium) (10% in ethanol) Concentrated Herba Santa extract
(E. californicum) -- 0.20 as per Example 8 (10% in ethanol)
Test Studies
Example TS1
Test Study Anti-Inflammatory Action in LPS-Induced Human
Monocytes
[0289] The anti-inflammatory test was performed in a cell culture
system using human monocytes. Human monocytes are one of the main
cell types which are involved in inflammatory processes in tissues;
they are the cells which are mainly influenced by the
lipopolysaccharides (LPS) produced by gram-negative bacteria.
Further, they represent the first step in the cascade of the
inflammatory reactions, in that they release various cytokines,
e.g. interleukin-1beta, interleukin-6, interleukin-8 and tumour
necrosis factor alpha (TNF.alpha.), but also other inflammation
parameters (e.g. prostaglandin E2). The parameters measured here
are recognized inflammation mediators. The use of primary human
monocytes enables a realistic portrayal of the pathophysiological
situation.
[0290] For the experiments, human primary monocytes were sown into
24-well plates (ca. 500,000 cells/ml in 1 ml). The cell viability
was determined by means of the AlamarBlue method or by measurement
of the intracellular ATP level.
[0291] The cells were incubated with the stimulus (LPS) for 24 hrs.
Solutions of the Herba Santa extract according to Example 1 and an
extract rich in erionic acid according to Example 4 were added 30
mins before the treatment with LPS. After 24 hrs, the supernatant
was removed, centrifuged and investigated according to the
operating instructions of the particular manufacturer of the
immunoassay used. The results are shown in FIG. 2a (Herba Santa
extract according to Example 1) and FIG. 2b (extract rich in
erionic acid according to Example 4).
[0292] Adding of the Herba Santa extract according to Example 1 to
cells treated with LBS led to a serious reduction of the determined
inflammation markers. The effect using the extract rich in erionic
acid according to Example 4 were even more significant.
Example TS2
Anti-Inflammatory Action in Human Gingival Fibroblastic Cells
(HGF-1)
[0293] Human gingival fibroblastic cells (HGF-1) were sowed out in
24-well plates with 15,000 cells per well and cultivated for 3 to 5
days. DNEM containing 10% FBS, 1% penicillin/streptomycin and 4%
glutamine was used as the medium. For determination of the
anti-inflammatory action the cells were incubated with 10 .mu.g/ml
PG-LPS for 6 and 9 hrs. Subsequently, the release of IL-6 and IL-8
per magnetic bead was determined (Procarta, Affimetrix) using a
MAGPIX equipment (Merck-Millipore) and analysed using the Milliplex
software (Merck Millipore). In each case 4 samples with two
technical replicates were measured. In addition to this control the
cells were co-incubated with [0294] (a) 10 .mu.g/ml PG-LPS and also
with [0295] (b) solutions of the Herba Santa extract according to
Example 1 (HS, containing 21.7% HED, 0.1 .mu.M, 1 .mu.M and 10
.mu.M calculated on HED); [0296] (c) the flavonoid fraction ("FF")
obtained as a by-product according to Example 4 (containg 41.5%
HED, 0,1 .mu.M, 1 .mu.M and 10 .mu.M calculated on HED); [0297] (d)
the extract rich in erionic acid ("ES") according to Example 4 or
isolated erionic acid B (according to Example 2) and [0298] (e)
erionic acid C according to Example 3 (each 0,1 .mu.M, 1 .mu.M and
10 .mu.M).
[0299] After incubation the cell culture medium was transferred
into an Eppendorf reaction vessel and at 4.degree. C. for 10 min
subjected to centrifugation (1000.times.g) in order to separate the
cell depris. The upper layer was stored at -80.degree. C. until the
analysis started. The results of the release of IL-6 and
[0300] IL-8 after 6 and 9 hrs are shown in FIGS. 3a to 3e. In some
of the tested concentrations and after certain times of treatment
adding of the Herba Santa extract according to Example 1 also led
to a reduction of IL-6 and IL-8 release (FIG. 3a). Adding of the
extracts FF and ES led to a significant reduction in IL release
(FIGS. 3b, 3c); the same is true for the addition of erionic acid B
(FIG. 3d). The most significant reduction could be shown for
erinoic acid C (FIG. 3e): at higher concentration the release of
IL-6 and IL-8 was almost completely inhibited.
[0301] In the following Tables 3a to 3e the asterisks mean:
*p<0,05, **p<0,01, ***p<0,001.
TABLE-US-00053 TABLE 3a Release of IL-6 and IL-8 by HGF-1 cells
after stimulation with 10 .mu.g/ml PG-LPS or respectively
co-incubation with Herba Santa extract of Example 1 (HS,
concentration calculated on contained Homoeriodictyol, HED) IL-6
IL-8 IL-6 Standard IL-8 Standard Test Compound T/C [%] Deviation
T/C [%] Deviation 10 .mu.g/ml LPS control - 6 h 100.00 35.66 98.91
9.06 10 .mu.g/ml LPS + 0.1 .mu.M HED in HS - 6 h 74.54 18.31
117.33* 9.78 10 .mu.g/ml LPS + 1 .mu.M HED in HS - 6 h 61.90**
13.48 120.57 34.88 10 .mu.g/ml LPS + 10 .mu.M HED in HS - 6 h
47.97** 15.55 131.33** 37.98 10 .mu.g/ml LPS-control - 9 h 100.00
10.50 100.00 13.67 10 .mu.g/ml LPS + 0.1 .mu.M HED in HS - 9 h
127.27 56.92 101.45 15.92 10 .mu.g/ml LPS + 1 .mu.M HED in HS - 9 h
127.80* 26.77 139.93* 33.49 10 .mu.g/ml LPS + 10 .mu.M HED in HS -
9 h 73.12 20.93 62.92*** 8.38
TABLE-US-00054 TABLE 3b Release of IL-6 and IL-8 by HGF-1 cells
after stimulation with 10 .mu.g/ml PG- LPS or respectively
co-incubation with the flavonoid extract (FF) of Example 4 IL-6
IL-8 IL-6 Standard IL-8 Standard Test Compound T/C [%] Deviation
T/C [%] Deviation 10 .mu.g/ml LPS-Control - 6 h 100.00 35.66 98.91
9.06 10 .mu.g/ml LPS + 0.1 .mu.M HED in FF - 6 h 56.58** 12.39
79.04 51.34 10 .mu.g/ml LPS + 1 .mu.M HED in FF - 6 h 32.93*** 9.55
40.99*** 7.95 10 .mu.g/ml LPS + 10 .mu.M HED in flavonoid 63.65*
12.09 41.76*** 9.50 fraction - 6 h 10 .mu.g/ml LPS-Control - 9 h
100.00 10.50 100.00 13.67 10 .mu.g/ml LPS + 0.1 .mu.M HED in FF - 9
h 60.87** 22.17 46.73*** 16.38 10 .mu.g/ml LPS + 1 .mu.M HED in FF
- 9 h 55.88* 36.35 38.73*** 36.35 10 .mu.g/ml LPS + 10 .mu.M HED in
FF - 9 h 57.15*** 24.38 57.23*** 18.80
TABLE-US-00055 TABLE 3c Release of IL-6 and IL-8 by HGF-1 cells
after stimulation with 10 .mu.g/ml PG-LPS or respectively
co-incubation with the extract rich in erionic acid (ES) of Example
4 IL-6 IL-8 IL-6 Standard IL-8 Standard Test Compound T/C [%]
Deviation T/C [%] Deviation 10 .mu.g/ml LPS-Control - 6 h 100.00
35.66 98.91 9.06 10 .mu.g/ml LPS + 1 .mu.g/ml ES - 6 h 101.00 5.25
117.56 25.82 10 .mu.g/ml LPS + 10 .mu.g/ml ES - 6 h 69.31* 14.01
68.29** 13.30 10 .mu.g/ml LPS + 100 .mu.g/ml ES - 6 h 67.24* 13.42
50.18** 11.27 10 .mu.g/ml LPS-Control - 9 h 100.00 10.50 100.00
13.67 10 .mu.g/ml LPS + 1 .mu.g/ml ES - 9 h 38.86*** 11.18 67.36*
25.84 10 .mu.g/ml LPS + 10 .mu.g/ml ES - 9 h 46.62** 13.47 78.74
16.33 10 .mu.g/ml LPS + 100 .mu.g/ml ES - 9 h 42.00*** 13.20
21.99*** 5.38
TABLE-US-00056 TABLE 3d Release of IL-6 and IL-8 by HGF-1 cells
after stimulation with 10 .mu.g/ml PG-LPS or respectively
co-incubation with the erionic acid B of Example 2 IL-6 IL-8 IL-6
Standard IL-8 Standard Test Compound T/C [%] Deviation T/C [%]
Deviation 10 .mu.g/ml LPS-Control - 6 h 100.00 35.66 98.91 9.06 10
.mu.g/ml LPS + 1 .mu.g/ml erionic acid B - 6 h 61.93* 19.98 79.91
14.03 10 .mu.g/ml LPS + 10 .mu.g/ml erionic acid B - 6 h 102.30
2.56 134.54** 19.89 10 .mu.g/ml LPS + 100 .mu.g/ml erionic acid B -
6 h 41.30** 5.29 46.30** 19.81 10 .mu.g/ml LPS-Control - 9 h 100.00
10.50 100.00 13.67 10 .mu.g/ml LPS + 1 .mu.g/ml erionic acid B - 9
h 77.51* 13.53 77.33 49.22 10 .mu.g/ml LPS + 10 .mu.g/ml erionic
acid B - 9 h 61.47*** 10.05 71.35 28.24 10 .mu.g/ml LPS + 100
.mu.g/ml erionic acid B - 9 h 102.74 25.02 116.34 40.91
TABLE-US-00057 TABLE 3e Release of IL-6 and IL-8 by HGF-1 cells
after stimulation with 10 .mu.g/ml PG-LPS or respectively
co-incubation with the erionic acid C of Example 3 IL-6 IL-8 IL-6
Standard IL-8 Standard Test Compound T/C [%] Deviation T/C [%]
Deviation 10 .mu.g/ml LPS-Control - 6 h 100.00 35.66 98.91 9.06 10
.mu.g/ml LPS + 1 .mu.g/ml erionic acid C - 6 h 76.66 22.32 94.59
23.76 10 .mu.g/ml LPS + 10 .mu.g/ml erionic acid C - 6 h 65.22*
32.24 62.47* 25.75 10 .mu.g/ml LPS + 100 .mu.g/ml erionic acid C -
6 h 5.11*** 3.41 0.67*** 0.64 10 .mu.g/ml LPS-Control - 9 h 100.00
10.50 100.00 13.67 10 .mu.g/ml LPS + 1 .mu.g/ml erionic acid C - 9
h 53.26** 22.53 39.13*** 13.83 10 .mu.g/ml LPS + 10 .mu.g/ml
erionic acid C - 9 h 56.22*** 15.62 39.00*** 13.38 10 .mu.g/ml LPS
+ 100 .mu.g/ml erionic acid C - 9 h 7.67*** 6.85 1.49*** 1.83
* * * * *