U.S. patent application number 12/417111 was filed with the patent office on 2009-07-23 for herbal compositions for the treatment of mucosal lesions.
This patent application is currently assigned to Herbal Synthesis Corporation. Invention is credited to Mina Fran, William Z. Levine, Aron J. Saffer.
Application Number | 20090186104 12/417111 |
Document ID | / |
Family ID | 11075430 |
Filed Date | 2009-07-23 |
United States Patent
Application |
20090186104 |
Kind Code |
A1 |
Levine; William Z. ; et
al. |
July 23, 2009 |
HERBAL COMPOSITIONS FOR THE TREATMENT OF MUCOSAL LESIONS
Abstract
The present invention provides therapeutic compositions
comprising extracts of the plant species Echinacea purpurea and
Sambucus nigra and the extract(s) of at least one further plant
selected from the group consisting of Hypericum perforatum,
Commiphora molmol and Centella asiatica. The compositions of the
invention are of particular utility in the management of
inflammatory mucosal diseases of both viral and non-viral
origin.
Inventors: |
Levine; William Z.;
(Jerusalem, IL) ; Saffer; Aron J.; (Beit Shemesh,
IL) ; Fran; Mina; (Jerusalem, IL) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
Herbal Synthesis
Corporation
Jerusalem
IL
|
Family ID: |
11075430 |
Appl. No.: |
12/417111 |
Filed: |
April 2, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10478718 |
Nov 24, 2003 |
|
|
|
PCT/IL02/00402 |
May 22, 2002 |
|
|
|
12417111 |
|
|
|
|
Current U.S.
Class: |
424/729 ;
424/737 |
Current CPC
Class: |
A61P 31/00 20180101;
A61P 17/02 20180101; A61P 17/00 20180101; A61P 29/00 20180101; A61K
36/28 20130101; A61K 36/328 20130101; A61P 1/00 20180101; A61K
45/06 20130101; A61K 9/006 20130101; A61P 43/00 20180101; A61P
31/12 20180101; A61K 9/0031 20130101; A61K 36/23 20130101; A61K
36/38 20130101; A61K 36/185 20130101; A61K 36/35 20130101; A61K
36/23 20130101; A61K 2300/00 20130101; A61K 36/28 20130101; A61K
2300/00 20130101; A61K 36/328 20130101; A61K 2300/00 20130101; A61K
36/35 20130101; A61K 2300/00 20130101; A61K 36/38 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/729 ;
424/737 |
International
Class: |
A61K 36/28 20060101
A61K036/28; A61K 36/82 20060101 A61K036/82; A61P 17/00 20060101
A61P017/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 23, 2001 |
IL |
143318 |
Claims
1. A therapeutic composition comprising extracts of the plant
species Echinacea purpurea, Sambucus nigra and Centella
asiatica.
2. A therapeutic composition according to claim 1 for use in the
treatment of diseases of the oral mucosa.
3. A therapeutic composition according to claim 1 for use in the
treatment of diseases of the anal mucosa.
4. A therapeutic composition according to claim 1, further
comprising extracts of plants selected from the group consisting of
Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix
alba, Calendula officinalis, Usnea barbata, Ligusticum
porterii-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium
myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis
and Krameria triandra.
5. A therapeutic composition according to claim 4, wherein the
disease of the oral mucosa to be treated is selected from the group
consisting of periodontal disease, gingivitis, aphthous ulceration,
mechanical trauma, thermal trauma, lichen planus, bullous
pemphigoid, pemphigus vulgaris and dermatitis herpetiformis,
angular chelitis and recurrent herpes.
6. A therapeutic composition according to claim 5, wherein the
disease of the anal mucosa to be treated is selected from the group
consisting of anal fissures, hemorrhoids and non-specific
irritation.
7. A therapeutic composition according to claim 1 for the
inhibition of one or more matrix metalloproteinases.
8. A therapeutic composition according to claim 7, wherein the one
or more matrix metalloproteinases to be inhibited are selected from
the group consisting of matrix metalloproteinases 1-9.
9. A therapeutic composition according to claim 8, wherein the
matrix metalloproteinases that are inhibited are of matrix
metalloproteinases of subclasses 1, 2, 8 and 9.
10. A therapeutic composition according to claim 9, wherein the
matrix metalloproteinase that is inhibited is of subclass 2.
11. A therapeutic composition according to claim 10 for use in the
treatment of a disease of the oral mucosa selected from the group
consisting of periodontal disease and aphthous ulceration.
12. A therapeutic composition according to claim 2, wherein the
disease of the oral mucosa to be treated is selected from the group
consisting of periodontal disease, gingivitis, aphthous ulceration,
mechanical trauma, thermal trauma, lichen planus, bullous
pemphigoid, pemphigus vulgaris, dermatitis herpetiformis, angular
chelitis and recurrent herpes.
13. A therapeutic composition according to claim 3, wherein the
disease of the anal mucosa to be treated is selected from the group
consisting of anal fissures, hemorrhoids and non-specific
irritation.
Description
CROSS RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/478,718 filed Nov. 24, 2003, which is a
U.S. national phase of international application PCT/IL02/00402,
filed in English on 22 May 2002, which designated the US.
PCT/IL02/00402 claims priority to IL Application No. 143318, filed
23 May 2001. The entire contents of these applications are
incorporated herein by reference
FIELD OF THE INVENTION
[0002] The present invention relates to herbal compositions useful
for the treatment of mucosal lesions. Although primarily intended
for oral use the composition may also be used on the labial,
genital and other mucosal surfaces, as well as on the skin.
BACKGROUND OF THE INVENTION
[0003] Historically, the plant world has been the most important
source of medicinal agents for the treatment of human and animal
disease, and for use as preventative agents in maintaining good
health. However, for at least the last 150 years, Western medicine
has been dominated by synthetic and/or highly purified chemical
agents.
[0004] It is now being increasingly recognized, however, that plant
extracts may be highly effective agents for the prevention and
treatment of disease. This is particularly true when one considers
the low toxicity and greatly reduced incidence of adverse effects
associated with plant-based medicines as compared with many
synthetic or highly purified drugs. In addition, as the plant
possesses a large number of pharmaceutically active agents,
extracts obtained therefrom exert their activities on a variety of
physiologic processes, increasing the range of the desired
therapeutic effect.
[0005] Although traditional reference sources of herbal medicine
are valuable guides to the safe and effective use of plant
extracts, the appropriate selection and combination of extracted
material is still a major challenge to the development of new,
highly effective herbal medicines. The scale of this challenge may
be more clearly appreciated when it is realized that there are
approximately 750,000 species of flowering plants on earth, only
very few of which have been scientifically studied for their
potential therapeutic value.
[0006] Oral diseases constitute a diverse group of conditions that
are responsible for much human suffering. In addition to diseases
of the hard tissues of the oral cavity (e.g. dental caries), there
are many different pathological conditions affecting the oral
mucosa and periodontal tissues. This group includes the commonly
found conditions such as gingivitis, periodontal disease, aphthous
ulceration and Herpes simplex lesions, as well as the oral
manifestations of the less common vesicular-bullous conditions such
as bullous pemphigoid, pemphigus, erytheme multiforme and lichen
planus, as well as other autoimmune conditions.
[0007] The significance of host-related factors in the pathogenesis
of conditions such as periodontal disease is being increasingly
recognized. Far from being a passive recipient of pathogenic agents
released by plaque bacteria, the host tissues themselves (including
the biochemical and immunological factors contained therein) are
now known to make an active contribution to disease initiation and
progression. One group of host factors which have recently received
some attention in relation to the pathogenesis of periodontal
disease is the group consisting of various tissue-destroying and
tissue-remodelling enzymes. Of particular interest is the large
group of matrix metalloproteinases (Page, R. C. (1999) J.
Periodont. Res. 34: 331-339). It is now believed that certain,
defined, metalloproteinases such as matrix metalloproteinases 1-9
are of particular importance for the development and progression of
periodontal disease.
[0008] Although many pharmaceutical agents have been used in the
management of mucosal lesions, many of these have been relatively
ineffective, while some (in particular, the systemic regimes) are
associated with unacceptable adverse effects. There thus exists a
need for new, efficacious and safe modes of treatment for many of
the aforementioned mucosal diseases. There is a particular need for
a safe, effective topical treatment.
[0009] It is a purpose of the present invention to respond to the
aforementioned need by providing plant-based compositions for the
treatment of mucosal diseases.
[0010] It is another purpose of the invention to provide
plant-based anti-viral compositions for use in the treatment of
oral and genital lesions.
[0011] It is a further purpose of the invention to provide
compositions for the treatment of mucosal diseases having higher
efficacy and more rapid onset than compositions previously known in
the art.
[0012] It is a still further purpose of the invention to provide
compositions having lower toxicity and incidence of adverse effects
than pharmaceutical compositions for the treatment of mucosal
diseases that have been previously described in the art.
[0013] Further objects and advantages of the present invention will
become apparent as the description proceeds.
SUMMARY OF THE INVENTION
[0014] It has now been unexpectedly found that certain compositions
comprising particular combinations of plant extracts are highly
effective in the treatment of certain mucosal lesions, particularly
those of the oral, anal and genital mucosa, as well as in the
treatment of certain skin lesions. It is to be noted that the
compositions, medicaments and treatment methods of the present
invention which will presently be disclosed, described and
exemplified, have been unexpectedly found to cause a dramatic
improvement in two significant clinical parameters associated with
the mucosal and skin lesions being treated thereby. Firstly, it has
been surprisingly found that said compositions, medicaments and
treatment methods lead to unexpectedly rapid resolution of the
mucosal and skin lesions that are being treated. Secondly, the
compositions, medicaments and treatment methods of the present
invention have also been surprisingly found to cause a dramatic
reduction of the pain associated with the mucosal and skin lesions
being treated thereby.
[0015] The present invention is primarily directed to a therapeutic
composition comprising extracts of the plant species Echinacea
purpurea and Sambucus nigra and the extract(s) of at least one
further plant selected from the group consisting of Hypericum
perforatum, Commiphora molmol and Centella asiatica.
[0016] In one preferred embodiment of the therapeutic composition
of the present invention, the extract(s) of the at least one
further plant are extracts of the plant species Hypericum
perforatum and Commiphora molmol.
[0017] While it is not intended that the use of the composition of
the abovementioned preferred embodiment of the composition of the
invention be bound to, or limited by any particular theory
regarding its chemical or pharmacological mode of action, the
present invention is particular directed to an anti-viral
composition comprising extracts of the plant species Echinacea
purpurea, Sambucus nigra, Hypericum perforatum and Commiphora
molmol.
[0018] In a preferred embodiment of the invention, the
above-mentioned anti-viral composition further comprises extracts
of plants selected from the group consisting of Uncaria tomentosa,
Thymus vulgaris, Matricaria recutita, Salix alba, Calendula
officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria
procumbens, Camellia sinensis, Vaccinium myrtillus, Melissa
officinalis, Allium sativum, Camellia sinensis and Krameria
triandra.
[0019] In a particularly preferred embodiment of the invention, the
above-mentioned anti-viral composition comprises extracts of the
plant species Echinacea purpurea, Sambucus nigra, Hypericum
perforatum, Commiphora molmol and Uncaria tomentosa.
[0020] The present invention also provides a therapeutic
composition comprising extracts of the plant species Echinacea
purpurea and Sambucus nigra together with an extract of the plant
species Centella asiatica.
[0021] In a preferred embodiment of the invention, the immediately
preceding therapeutic composition is intended for use in the
treatment of diseases of the oral mucosa. In a more preferred
embodiment of the invention, said therapeutic composition is
intended for use in the treatment of an oral mucosal disease
selected from the group consisting of periodontal disease,
gingivitis, aphthous ulceration, mechanical trauma, thermal trauma,
lichen planus, bullous pemphigoid, pemphigus vulgaris, dermatitis
herpetiformis, angular chelitis and recurrent herpes.
[0022] In a further preferred embodiment, the above therapeutic
composition is intended for use in the treatment of skin lesions.
In one preferred embodiment of the invention, said therapeutic
composition is intended for use in the treatment of dermal trauma.
In another preferred embodiment, the therapeutic composition is
intended for use in the treatment of insect bites and other local,
superficial irritations.
[0023] In a still further preferred embodiment of the invention,
the above therapeutic composition is intended for use in the
treatment of anal lesions. In a more preferred embodiment of the
invention, said therapeutic composition is intended for use in the
treatment of an anal lesion associated with a condition selected
from the group consisting of anal fissures, hemorrhoids and
non-specific irritation.
[0024] While it is not intended that the mechanism of action of the
therapeutic composition for treating mucosal diseases that is
disclosed immediately hereinabove be bound to any particular
pharmacological or pathophysiological mechanism or mechanisms, it
is believed that said composition exerts at least some of its
desired effects by inhibiting one or more matrix metalloproteinase
(MMP) enzymes that are present in the oral mucosal and periodontal
tissues, and/or by increasing collagen production at or close to
the mucosal site to which said composition is applied. In
particular, it is believed that said therapeutic compositions may
exert at least some of their desired effects by the specific
inhibition of certain specific enzymes of the MMP group. More
specifically, it is believed that the therapeutic compositions of
the present invention are specific inhibitors of MMP subclasses
1-9, still more specifically of subclasses 1, 2, 8 and 9.
[0025] Thus, the invention is also directed to a therapeutic
composition comprising extracts of the plant species Echinacea
purpurea, Sambucus nigra and Centella asiatica described
hereinabove, for the inhibition of one or more matrix
metalloproteinases.
[0026] It is to be noted that the term "inhibition of one or more
matrix metalloproteinases" as used immediately hereinabove and
hereinabove is intended to convey the meaning of the inhibition of
the activity of these enzymes on their substrates.
[0027] In a preferred embodiment of this aspect of the invention,
the one or more matrix metalloproteinases to be inhibited are
selected from the group consisting of matrix metalloproteinases
1-9. In a more preferred embodiment, said one or more matrix
metalloproteinases are selected from the group consisting matrix
metalloproteinases 1, 2, 8 and 9. Still more preferably, the matrix
metalloproteinase to be inhibited is matrix metalloproteinase 2. In
a still further preferred embodiment of this aspect of the present
invention, the matrix metalloproteinase-inhibiting therapeutic
compositions described immediately hereinabove are intended for use
in the treatment of a disease of the oral mucosa selected from the
group consisting of periodontal disease and aphthous
ulceration.
[0028] In a further preferred embodiment of the invention, the
aforementioned therapeutic compositions for treating conditions of
the oral or anal mucosal tissues, as well as the aforementioned
therapeutic compositions for inhibiting matrix metalloproteinases
further comprise extracts of plants selected from the group
consisting of Uncaria tomentosa, Thymus vulgaris, Matricaria
recutita, Salix alba, Calendula officinalis, Usnea barbata,
LigustLicum porterii-osha, Gaultheria procumbens, Camellia
sinensis, Vaccinium myrtlillus, Melissa officinalis, Allium
satlivum, Camellia sinensis and Krameria triandra.
[0029] In another aspect, the present invention is directed to the
use of a combination of extracts of the plant species Echinacea
purpurea and Sambucus nigra and of at least one further plant
species selected from the group consisting of Hypericum perforatum,
Commiphora molmol and Centella asiatica in the preparation of a
medicament.
[0030] In one preferred embodiment, the invention is directed to
the use of the combination of plant extracts described immediately
hereinabove in the preparation of a medicament, wherein said
extracts of at least one further plant are extracts of Hypericum
perforatum and Commiphora molmol. Preferably, this combination of
plant extracts is used in the preparation of an anti-viral
medicament.
[0031] In a further preferred embodiment, the present invention is
directed to the use of extracts of plants selected from the group
consisting of Uncaria tomentosa, Thymus vulgaris, Matricaria
recutita, Salix alba, Calendula officinalis, Usnea barbata,
Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis,
Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia
sinensis and Krameria triandra, in addition to the extracts
mentioned hereinabove, in the preparation of an anti-viral
medicament.
[0032] In a particularly preferred embodiment the present invention
is directed to the use of a combination of extracts of the plant
species Echinacea purpurea, Sambucus nigra, Hypericum perforatum,
Commiphora molmol and Uncaria tomentosa in the preparation of an
anti-viral medicament.
[0033] The present invention also provides for the use of the above
combination of plant extracts in the preparation of a medicament,
said extract of at least one further plant being an extract of
Centella asiatica. Preferably, this combination of plant extracts
is used in the preparation of a medicament for the treatment of a
disease of the oral mucosa. In one embodiment of the invention,
said disease of the oral mucosa is selected from the group
consisting of periodontal disease, gingivitis, aphthous ulceration,
mechanical trauma, thermal trauma, lichen planus, bullous
pemphigoid, pemphigus vulgaris, dermatitis herpetiformis, angular
chelitis and recurrent herpes.
[0034] In another preferred embodiment, the invention also provides
for the use of the above combination of plant extracts in the
preparation of a medicament for the treatment of a skin lesion. In
one preferred embodiment, the skin lesion to be treated is a lesion
arising from dermal trauma. In a further preferred embodiment, the
skin lesion to be treated is an insect bite.
[0035] In another preferred embodiment of the invention, the
abovementioned combination of plant extracts is used in the
preparation of a medicament for the treatment of a disease of the
anal mucosa. In one embodiment of the invention, said disease of
the anal mucosa is selected from the group consisting of anal
fissures, hemorrhoids and non-specific irritation.
[0036] In another aspect the invention provides for the use of a
combination of extracts of the plant species Echinacea purpurea,
Sambucus nigra and Centella asiatica in the preparation of a
medicament for inhibiting one or more matrix metalloproteinases.
Preferably, said matrix metalloproteinases are selected from the
group consisting of matrix metalloproteinases 1 to 9. Most
preferably, the one or more matrix metalloproteinases to be
inhibited are selected from the group consisting of matrix
metalloproteinases 1, 2, 8 and 9. In a preferred embodiment, the
abovementioned metalloproteinase-inhibiting medicament is used to
treat a disease of the oral mucosa selected from the group
consisting of periodontal disease and aphthous ulceration.
[0037] In a further preferred embodiment, the invention is directed
to the use of the above combination of plant extracts in
combination with further extracts of plants selected from the group
consisting of Uncaria tomentosa, Thymus vulgaris, Matricaria
recutita, Salix alba, Calendula officinalis, Usnea barbata,
Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis,
Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia
sinensis and Krameria triandra, in the preparation of medicaments
for the treatment of a diseases of the oral and/or anal mucosal
tissues, and in the preparation of medicaments for inhibiting the
abovementioned one or more matrix metalloproteinases.
[0038] In another aspect, the present invention is directed to a
combination of extracts of the plant species Echinacea purpurea and
Sambucus nigra and of at least one further plant species selected
from the group consisting of Hypericum perforatum, Commiphora
molmol and Centella asiatica for use as a medicament.
[0039] In a preferred embodiment, the invention is directed to a
combination of extracts as disclosed immediately hereinabove,
wherein the extracts of the at least one further plant are extracts
of Hypericum perforatum and Commiphora molmol. In a preferred
embodiment, the invention is directed to said combination of
extracts for use as an anti-viral medicament. In a further
preferred embodiment, said combination of extracts is further
supplemented by extracts of one or more plants selected from the
group consisting of Uncaria tomentosa, Thymus vulgaris, Matricaria
recutita, Salix alba, Calendula officinalis, Usnea barbata,
Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis,
Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia
sinensis and Krameria triandra.
[0040] In a particularly preferred embodiment, the invention is
directed to a combination of extracts of the plant species
Echinacea purpurea, Sambucus nigra, Hypericum perforatum,
Commiphora molmol and Uncaria tomentosa for use as an anti-viral
medicament.
[0041] The invention also provides a combination of plant extracts
as disclosed hereinabove for use as a medicament, said extract of
the at least one further plant being an extract of Centella
asiatica. Preferably, this combination of extracts is provided for
use as a medicament for the treatment of diseases of the oral
mucosa. While said combination of plant extracts may be used as a
medicament for the treatment of many different conditions of the
oral mucosa, in a preferred embodiment, the disease to be treated
is selected from the group consisting of periodontal disease,
gingivitis, aphthous ulceration, mechanical trauma, thermal trauma,
lichen planus, bullous pemphigoid, pemphigus vulgaris, dermatitis
herpetiformis, angular chelitis and recurrent herpes. In another
preferred embodiment, the combination of plant extracts is provided
for use as a medicament for the treatment of skin lesions. In one
preferred embodiment, the skin lesions are lesions arising from
dermal trauma. In another preferred embodiment, the skin lesions
are insect bites. In yet another preferred embodiment, the
aforementioned combination of extracts is provided for use as a
medicament for the treatment of diseases of the anal mucosa. While
said combination of plant extracts may be used as a medicament for
the treatment of many different conditions of the anal mucosa, in a
preferred embodiment, the disease to be treated is selected from
the group consisting of anal fissures, hemorrhoids and non-specific
irritation.
[0042] In another aspect, the above-described combination of
extracts is used as a medicament for inhibiting one or more matrix
metalloproteinases. Preferably, the one or more matrix
metalloproteinases are selected from the group consisting of matrix
metalloproteinases 1 to 9. More preferably, said metalloproteinases
are selected from the group consisting of matrix metalloproteinases
1, 2, 8 and 9. In a preferred embodiment, the abovementioned
combination of extracts for inhibiting metalloproteinases is used
in the treatment of a disease of the oral mucosa selected from the
group consisting of periodontal disease and aphthous
ulceration.
[0043] In yet another embodiment of the invention, the plant
extracts used in the aforementioned combination of extracts are
further supplemented by extracts of plants selected from the group
consisting of Uncaria tomentosa, Thymus vulgaris, Matricaria
recutita, Salix alba, Calendula officinalis, Usnea barbata,
Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis,
Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia
sinensis and Krameria triandra.
[0044] The present invention also encompasses a method of treatment
of mucosal and/or skin lesions comprising the application of a
therapeutically-effective amount of a mixture of extracts of the
plant species Echinacea purpurea and Sambucus nigra and the
extract(s) of at least one further plant selected from the group
consisting of Hypericum perforatum, Commiphora molmol and Centella
asiatica to the mucosal lesions and surrounding tissue of a subject
in need of such treatment. In a preferred embodiment of this method
of treatment, said extracts of at least one further plant are
extracts of Hypericum perforatum and Commiphora molmol. In a
preferred embodiment, the lesions to be treated by this method of
treatment are viral lesions.
[0045] In a further preferred embodiment, the present invention
also provides a method of treatment of viral lesions as described
hereinabove, wherein the aforementioned plant extracts are
supplemented by extracts of plants selected from the group
consisting of Uncaria tomentosa, Thymus vulgaris, Matricaria
recutita, Salix alba, Calendula officinalis, Usnea barbata,
Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis,
Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia
sinensis and Krameria triandra.
[0046] In a particularly preferred embodiment, the present
invention provides a method of treatment of mucosal and/or skin
lesions of viral origin comprising the application of a
therapeutically-effective amount of a mixture of extracts of the
plant species Echinacea purpurea, Sambucus nigra, Hypericum
perforatum, Commiphora molmol and Uncaria tomentosa.
[0047] In another preferred embodiment of the method of the
invention, the extract of the at least one further plant is an
extract of Centella asiatica. In one preferred embodiment of this
aspect of the invention, the lesions to be treated are oral lesions
associated with a disease selected from the group consisting of
periodontal disease, gingivitis, aphthous ulceration, mechanical
trauma, thermal trauma, lichen planus, bullous pemphigoid,
pemphigus vulgaris, dermatitis herpetiformis, angular chelitis and
recurrent herpes. In another preferred embodiment, the lesions to
be treated are skin lesions. In one more preferred embodiment, the
skin lesions to be treated are lesions arising from dermal trauma.
In a further preferred embodiment, the lesions are insect bites. In
another preferred embodiment of this aspect of the invention, the
lesions to be treated are anal lesions associated with a disease
selected from the group consisting of anal fissures, hemorrhoids
and non-specific irritation.
[0048] In a further aspect, the present invention is directed to a
method of inhibiting one or more matrix metalloproteinases in
mucosal and/or skin lesions of a subject in need of such treatment,
comprising the application of a therapeutically-effective amount of
a mixture of extracts of the plant species Echinacea purpurea,
Sambucus nigra and Centella asiatica to said mucosal and/or skin
lesions and surrounding tissue. Preferably, the one or more matrix
metalloproteinases are selected from the group consisting of matrix
metalloproteinases 1 to 9. More preferably, the one or more matrix
metalloproteinases are selected from the group consisting of matrix
metalloproteinases 1, 2, 8 and 9. In a preferred embodiment of this
aspect of the invention, the aforementioned inhibition of the one
or more matrix metalloproteinases is used in the treatment of
periodontal disease. In another preferred embodiment, the
inhibition of the one or more matrix metalloproteinases is used in
the treatment of aphthous ulceration.
[0049] In each of the above-described methods, the mixture of plant
extracts used may further comprise extracts of plants selected from
the group consisting of Gotu kola, Uncaria tomentosa, Thymus
vulgaris, Matricaria recutita, Salix alba, Calendula officinalis,
Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens,
Camellia sinensis, Vaccinium myrtillus, Melissa officinalis, Allium
sativum, Camellia sinensis and Krameria triandra.
[0050] In one preferred embodiment of the invention, the anti-viral
compositions, medicaments and treatment methods are used in the
treatment or management of viral lesions of the oral cavity.
[0051] In another preferred embodiment of the invention, the
anti-viral compositions, medicaments and treatment methods are used
in the treatment or management of perioral lesions of viral
origin.
[0052] In yet another preferred embodiment of the invention, the
anti-viral compositions, medicaments and treatment methods are used
in the treatment or management of genital lesions of viral
origin.
[0053] In yet another preferred embodiment of the invention, the
anti-viral compositions, medicaments and treatment methods are used
in the treatment or management of viral lesions caused by the
Herpes simplex virus.
[0054] In yet another preferred embodiment of the invention, the
anti-viral compositions, medicaments and treatment methods are used
in the treatment or management of viral lesions of the skin.
[0055] In another aspect, the present invention also encompasses a
method for inhibiting one or more matrix metalloproteinases in
vitro, comprising contacting an effective amount of a mixture of
extracts of the plant species Echinacea purpurea, Sambucus nigra
and Centella asiatica with said one or more matrix
metalloproteinases. In one embodiment of this aspect of the
invention, the one or more matrix metalloproteinases to be
inhibited are selected from the group consisting of matrix
metalloproteinases 1 to 9. In another embodiment, the one or more
matrix metalloproteinases to be inhibited are selected from the
group consisting of matrix metalloproteinases 1, 2, 8 and 9.
[0056] All the above and other characteristics and advantages of
the present invention will be further understood from the following
illustrative and non-limitative examples of preferred embodiments
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0057] FIG. 1 graphically illustrates the reduction in
ulcer-associated pain following treatment with an herbal
composition of the invention.
[0058] FIG. 2 shows a typical gelatin zymogram indicating the
inhibitory effects of composition of the invention on the activity
of a mixture of matrix metalloproteinases.
[0059] FIG. 3 graphically illustrates the reduction in insect
bite-associated pain and irritation following treatment with an
herbal composition of the invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0060] The compositions and medicaments of the present invention
are based on mixtures of plant extracts. It is to be noted that the
term "extract" is used herein to include all of the many types of
preparations containing some or all of the active ingredients found
in the relevant plants. Thus the extracts may be produced by cold
extraction techniques using a variety of different extraction
solvents including, but not limited to, water, fatty solvents (such
as olive oil), and alcoholic solvents (e.g. 70% ethanol). Cold
extraction techniques are usefully applied to softer parts of the
plant such as leaves and flowers, or in cases wherein the desired
active components of the plant are heat labile. Alternatively, the
aforementioned solvents may be used to produce extracts of the
desired plants by a hot extraction technique, wherein said solvents
are heated to a high temperature, the precise value of said
temperature being dependent on the properties of the chosen
solvent, and maintained at that temperature throughout the
extraction process. Hot extraction techniques are more commonly
applied to the harder, tougher parts of the plant, such as bark,
woody branches and larger roots. In some cases, sequential
extractions need to be performed in more than one solvent, and at
different temperatures.
[0061] Standard procedures for producing plant extracts (including
hot extraction, cold extraction and other techniques) are described
in many publications including "Medicinal plants: a field guide to
the medicinal plants of the Land of Israel (in Hebrew), author: N.
Krispil, Har Gilo, Israel, 1986" and "Making plant medicine,
author: R. Cech, pub. by Horizon Herbs, 2000".
[0062] Compositions and medicaments containing mixtures of extracts
of different plant species, such as those of the present invention
may be prepared using different ratios of each extract. For
example, the antiviral medicaments and compositions of the present
invention preferably comprise extracts of Echinacea purpurea,
Sambucus nigra, Commiphora molmol and Hypericum perforatum in the
following range of weight ratios: [0063] 2-6:2-4: 3-6:2-6
[0064] More preferably, these components are present in the weight
ratio of 4:3:5:4.
[0065] Similarly, the compositions of the invention used to treat
mucosal diseases preferably comprise extracts of Centella asiatica,
Echinacea purpurea and Sambucus nigra in the following range of
weight ratios:
0.5-3:0.5-3:2:15
[0066] More preferably, these extracts are present in the weight
ratio of 1.5:1.5:7
[0067] In order to treat a patient with a therapeutic composition
or medicament containing a mixture of herbal extracts as described
hereinabove, it is necessary to administer said composition or said
medicament in a therapeutically-effective amount, that is, in an
amount that will provide a concentration of the herbal extracts at
the treatment site that is capable of exerting the desired
therapeutic effect. It has been found, in general terms, that the
compositions and medicaments of the present invention need to be
administered in amounts such that, typically, each topical dose
contains between 0.1 mg and 10 mg (dry weight) of each herbal
extract, the precise values depending on the particular combination
of extracts used, and on the mode of topical delivery. Thus, in the
case of the therapeutic composition of the present invention that
is used in the treatment of mucosal lesions, the weights of the
original plant material used to prepare a controlled-release
delivery device (as described in Example 2, hereinbelow) are:
Centella asiatica 1.6 mg Echinacea purpurea 1.6 mg Sambucus nigra
7.56 mg
[0068] In the case of compositions and medicaments intended
primarily for topical use (such as those of the present invention),
it is necessary to administer said compositions and medicaments for
periods of time that are sufficient to allow optimal contact of the
therapeutically effective amounts of the herbal extracts with the
lesions to be treated. When the compositions and medicaments are to
be given by incorporation into a controlled-release intra-oral
device (as described in Example 2 hereinbelow), said device needs
to remain in contact with the lesion to be treated for a period of
between 1 and 5 hours. This treatment may be repeated up to 5 times
each day, as required, and as determined by a competent
clinician.
[0069] Mouthwashes containing the compositions and medicaments of
the present invention should be taken in quantities of between 5 ml
and 15 ml and allowed to remain in contact with the lesions to be
treated for periods of between 30 seconds and one minute. This
treatment regime may be repeated up to 5 times per day.
[0070] Lozenges, pastilles, candies and other solid, soluble
formulations are to be placed in the mouth, if possible in close
proximity to the lesions to be treated, and allowed to dissolve at
the natural rate determined by the additives present in said
formulations.
[0071] The compositions and medicaments of the present invention as
disclosed hereinabove and exemplified hereinabove may be prepared
and delivered in a number of different forms.
[0072] In a preferred embodiment of the invention, medicaments and
compositions are intended for topical application at the site of
the mucosal lesion. Dosage forms suitable for topical application
to mucosal surfaces include ointments, pastes, lotions, creams,
mouthwashes, lozenges, candies, chewing gums, solutions, gels and
sprays. Thus, in addition to the active ingredients, the
compositions of the present invention may also contain excipients
such as zinc, zinc oxide, silicones, calcium silicate, aluminum
hydroxide, polyethylene glycols, fats of animal or vegetable
origin, oils, waxes gums, starch and cellulose or cellulose
derivatives.
[0073] In other embodiments of the invention, compositions for
vaginal administration or for anal administration may be prepared
by mixing the active plant-derived components with suitable
non-toxic, non-irritating carriers such as suppository wax,
polyethylene glycol or cocoa butter.
[0074] In a preferred embodiment of the invention, the compositions
and medicaments are administered by means of a localized delivery
system that allows topical release of the active constituents of
said compositions and medicaments. Any suitable local delivery
device may be used to administer the compositions and medicaments
to the mucosal surface. However, in a particularly preferred
embodiment of the invention the local delivery device is a slow
release device such as illustrated hereinbelow in Example 2.
[0075] The following examples are provided for illustrative
purposes and in order to more particularly explain and describe the
present invention. The present invention, however, is not limited
to the particular embodiments disclosed in the examples.
Example 1
Effect of the Anti-Viral Composition on the Formation of Viral
Plaques In Vitro
Method:
[0076] The antiviral composition was prepared as follows: 2 ml of a
1:1 hydroalcoholic extract of Echinacea purpurea was mixed with 7.5
ml of a 1:5 hydroalcoholic extract of Sambucus nigra, 8 ml of a 1:4
hydroalcoholic extract of Commiphora molmol , 10 ml of a 1:4
preparation of a hydroalcoholic extract of Uncaria tomentosa and 20
ml of a 1:10 hydroalcoholic extract of Hypericum perforatum. The
term "a 1:x hydroalcoholic extract" as used herein indicates that 1
gram of plant material was extracted with x volumes of the
alcoholic extraction medium. In the case of all of the plant
extracts used in the present example, the extraction medium was a
"hydroalcohol". For the present purposes, the term "hydroalcohol"
is defined as an aqueous solution of a lower alcohol. Preferably,
the lower alcohol used was ethanol, which was generally prepared as
a 50% solution. In some preparations, ethanol was prepared at a
different aqueous dilution within the range of 25-90% (v/v), with
respect to the ethanol. The weight ratio of E. purpurea:S. nigra:C.
molmol:U. tomentosa:H. perforatum in this mixture is 4:3:4:5:4. The
above-mentioned alcoholic extracts were purchased either from
Herbal Apothecary, Syston, Leicester, U.K. or from Analit Extracts
Ltd, M.P. Hefer 38100, Israel.
[0077] Disks of 3 MM filter paper (Whatman Inc.) (5 mm diameter)
were soaked in a solution of the compositions to be tested, and
placed on a semi-solid agar-containing culture medium covering a
monolayer of BSC-1 (green monkey kidney) cells infected with a
partially confluent dose of either Herpes simplex type 1 virus
(HSV-1) or Herpes simplex type 2 virus (HSV-2). Following 3-4 days
incubation at 37.degree. C., the cells were fixed with formaldehyde
(20% aqueous solution) and stained with crystal violet (0.1%
solution in 0.1M citric acid). The presence of a white color in the
central area of the culture indicated toxic damage of the cultured
cells due to the anti-viral compositions. Inhibition of viral
plaque formation indicated that the composition tested possesses
anti-viral activity.
[0078] Acyclovir (ACG), a known and commonly used drug against
herpes viruses, was included in the assay as a positive
control.
Results:
[0079] The results of a typical plaque assay are given below.
TABLE-US-00001 anti- anti- Extract Toxicity HSV1 HSV2 Virosyn 0-10
2-11 3-11 Hypericum 5 4-7 3-12 Uncaria 0 0-8 7-8 Note 1: Virosyn is
the herbal composition described hereinabove comprising extracts of
the following five plant species: Echinacea purpurea, Hypericum
perforatum, Commiphora molmol, Uncaria tomentosa and Sambucus
nigra. Note 2: The numerical results in the above table are the
diameters of the plaques (in mm) after treatment of the cell
cultures with the disks soaked with extracts. Each virus inhibition
or cell toxicity experiment was performed in triplicate. Note 3:
The toxicity of each extract was assessed by measuring the diameter
of the blue-stained plaque in the center of cell cultures that did
not receive virus.
[0080] The above results indicate that the herbal extract mixture
tested possess antiviral activity for both HSV1 and with minimal
toxicity to the cultured mammalian cells.
Example 2
Topical Slow-Release Device for Delivery of the Compositions to the
Oral Mucosa
[0081] This example demonstrates the preparation of a slow-release
device and the incorporation therein of a plant extract mixture
containing Centella, Echinacea and Sambucus.
[0082] The slow release device consists of a mixture of carbomer
(carbopol), hydroxypropyl cellulose and magnesium stearate blended
as described hereinbelow. Magnesium stearate is used as a
protective coating to reduce the solubility and adhesiveness of the
device.
[0083] The device is prepared as follows:
[0084] 1. The plant extract mixture is prepared by mixing 6 ml of a
1:4 hydroalcoholic extract of Centella asiatica with 1.5 ml of a
1:1 hydroalcoholic extract of Echinacea purpurea and 35 ml of a 1:5
hydroalcoholic extract of Sambucus nigra. The weight ratio of C.
asiatica:E. purpurea:S. nigra in this mixture is 15:15:70. The
hydroalcoholic extracts of Centella asiatica and Echinacea purpurea
were purchased from Herbal Apothecary, Syston, Leicester, U.K.,
while the hydroalcoholic extract of Sambucus nigra was purchased
from Analit Extracts Ltd., M.P. Hefer 38100, Israel. It is be noted
that the abovementioned extract values of the form 1:x indicate
that 1 g of the plant material was dissolved in x liters of
solvent. The term "hydroalcoholic extract" indicates that the plant
material was extracted using ethanol at concentrations of between
25% and 50% in water.
[0085] 2. The plant extract mixture is mixed with 2 g sucrose and
evaporated to dryness at 40.degree. C. The residue is dissolved in
2 ml water, a further small volume of water added, and the solution
lyophilized overnight.
[0086] 3. A mixture of the carbomer compound Carbopol.RTM. 934 P
(B.F. Goodrich, Cleveland, Ohio, USA) (2 g) and hydroxypropyl
cellulose (Klucel Type HF, Hercules BV, Rijswijk, Holland) (1 g) is
prepared by crushing the two components together.
[0087] 4. A 1 g aliquot of the carbomer-hydroxypropyl cellulose mix
(prepared in step 3.) is mixed together with 100 mg of the
lyophilized plant extract powder (prepared in step 2).
[0088] 5. Magnesium stearate (pharmaceutical grade, obtained from
Riedel-De Haen, Germany) (1 g) is mechanically mixed with 2 g of
the carbomer-hydroxypropyl cellulose mix.
[0089] 6. 14 mg of the magnesium stearate-polymer mix (step 5.) is
placed on the bottom of the plunger (13 mm diameter die
manufactured by Perkin-Elmer, U.K.) of a mechanical press (Spex
Industries, Mutuchen, N.J., USA) and overlaid with 70 mg of the
plant extract-polymer mix (step 4.). Pressure (10 tons force) is
applied for 30 seconds.
[0090] In addition to the active herbal ingredients, various
flavorings, excipients and colorings may be added in order to
modify the taste, consistency and color of the preparation.
[0091] The side of the device containing the herbal ingredients
(i.e. the side not containing the magnesium stearate) is applied
directly to the mucosal surface containing the lesion to be
treated. Alternatively, the mucosal surface may be pre-moistened
with water or saline before application of the device. Following
application, the device is held in place with gentle pressure for
approximately 10 seconds. After releasing the gentle pressure, the
device adheres to the mucosal tissue for a period of up to five
hours.
[0092] Depending on the mucosal lesion to be treated, the device
containing the herbal mixture described hereinabove may be used
several times per day (e.g. 3 times per day) for periods of between
two days and one month.
Example 3
Use of an Herbal Composition of the Invention to Reduce the Pain
Associated with Oral Mucosal Lesions
[0093] A convenient, non-random sample of 57 dental patients
presenting in a private dental clinic with painful oral ulcers of
either traumatic or aphthous origin were treated by applying to the
affected site a slow-release device containing a herbal composition
of the invention (as described in Example 2 hereinabove). The
device was left in place for a 24 hour period. The ulcer-associated
pain experienced by the patients was recorded and expressed on a
visual analog scale (S. Chrubasik et al. (2000) Am. J. Med. 109:
9-14), as depicted in FIG. 1. The clinical correlates of the pain
index values used in this scale are as follows: 0=no pain;
50=requires analgesic; 100=requires anesthetic. The highest
recorded pain index reported by an individual patient in this study
was 90.
[0094] It may be seen from these results that the patients
experienced an almost immediate decrease in pain (with a mean
decrease of greater than 50%). This decrease in pain levels
continued over the following 6 hours, achieving a mean pain
decrease of greater than 70%. The painful symptoms did not recur
following cessation of treatment.
Example 4
Effect of an Herbal Composition of the Invention on the Size of
Mucosal Lesions
[0095] Operating as in the study presented in Example 3, the effect
of the herbal composition used therein on the healing of the oral
ulceration experienced by the patients was determined by
quantification of lesion size using a Scion image analysis system.
Briefly, lesions were photographed and digitized using a digital
camera and associated Smartcard. The image files obtained thereby
were processed using the Photoshop software package (Adobe Systems
Inc.) running in Microsoft Windows ME on an IBM-compatible personal
computer. The periphery of each lesion was outlined and copied into
a new window of the NIH Image software package (National Institutes
of Health, Bethesda, Md.), where, following thresholding, the
lesion area was automatically calculated.
[0096] Results from a sequential study of 45 patients with oral
ulceration demonstrate that the treatment with the herbal
composition caused a mean 60% decrease in lesional size over a
24-36 hour period.
Example 5
Anticollagenase Activity of an Herbal Composition of the
Invention
Anticollagenase Testing:
Procedure:
[0097] Protease activity was assessed on gelatin zymograms. Twelve
percent polyacrylamide gels (0.75 mm thickness) were cast
containing 10% gelatin as a substrate for the collagenase enzymes,
which were applied to the gels under non-reducing conditions
without heating. The gels were run, soaked in 200 ml of 2% Triton
X-100 in distilled water on a gyratory shaker (0.5 hours,
20.degree. C.), and incubated in developing buffer (50 mM Tris [pH
8.0], 1 mM CaCl.sub.2), unless otherwise indicated, for 15 hours at
37.degree. C. The gels were examined following staining with
Coumassie blue. Protease activity shows up as clear bands
(indicative of cleavage of the gelatin substrate) on a blue
background. For inhibition studies, either specific protease
inhibitors (DFP (1 Mm), EDTA (5 Mm), BBI (10 mg/ml), phenylmethyl
sulfonyl fluoride (PMFS) (50 Mm) or tetracyclines (0.1 and 0.25
Mm)) or a composition comprising a mixture of Echinacea purpurea,
Sambucus nigra and Centella asiatica (prepared as described in
Example 2, hereinabove) were added to the developing buffer after
the run but before the gel was incubated in said developing buffer.
In the latter case, the herbal composition was added to the buffer
at a concentration of one volume composition to 50 volumes buffer.
To determine protease activity as a function of pH, samples were
run on zymograms and subsequently incubated in the appropriate
buffer (50 Mm citrate-phosphate buffer [pH 5], 50 Mm ADA buffer [pH
6 and 7], 50 Mm TRIS [pH 8 and 9] or 50 Mm CAPS [pH 10]),
containing 1 Mm CaCl.sub.2.
Results:
[0098] Preliminary findings have demonstrated strong inhibitory
effects of low concentrations of the herbal extracts on a cocktail
of proteases (containing high concentrations of matrix
metalloproteinases 2, 3, 8 and 9). These results demonstrate a
direct inhibitory effect of low doses of herbal extracts on common
metalloproteinases.
[0099] Representative results are shown in the gelatin zymogram
depicted in FIG. 2, in which active proteases are indicated as
white bands on a dark background. Line 1: 50 ng active
metalloproteases are clearly detectable. Line 2 demonstrates
definitive inhibition of the same metalloprotease cocktail present
in line 1 by a 1/50 dilution of the aforementioned herbal
composition.
Example 6
In Vivo Treatment of Gingival Inflammation Using an Herbal
Composition of the Invention
Effects on MMP Activity
[0100] This study forms part of a controlled double-blind
matched-sample (sixteen patients), three part clinical trial of the
use of a herbal composition of the invention in controlling
gingival inflammation 1, 4 and 7 days after placement of a
transmucosal adhesive patch containing a composition containing
Echinacea purpurea, Sambucus nigra and Centella asiatica (prepared
as described in Example 2, hereinabove).
[0101] In the control subjects, a placebo treatment comprising a
transmucosal adhesive patch containing food color was used.
[0102] Gingival Tissue removed during periodontal surgery was
immediately placed on ice and subsequently frozen and stored at -80
degrees C., prior to performing matrix metalloproteinase (MMP)
activity analysis thereon, as described hereinabove in Example 5.
The gingival samples are prepared for this analysis by homogenizing
the thawed tissue in PBS and centrifuging [100000 g.times.10
min].
[0103] The preliminary results obtained (data not shown)
demonstrate that bands were found in the areas consistent with MMP
2,9 which have been identified as proteases associated with
periodontal disease. Tissue samples taken from the experimental
sites showed no protease activity, indicating complete inhibition
by the herbal composition of the invention.
Example 7
In Vivo Effect of an Herbal Composition of the Invention on
Localized Irritation Following an Insect Bite
[0104] A subject having a painful insect bite on the skin overlying
the upper arm was treated for a period of 24 hours with an adhesive
patch comprising a composition containing Echinacea purpurea,
Sambucus nigra and Centella asiatica (prepared as described in
Example 2, hereinabove). The insect bite-associated pain
experienced by the patient was recorded and expressed on a visual
analog scale, as depicted in FIG. 3. The clinical correlates of the
pain index values used in this scale are as follows:
0=asymptomatic; 50=requires medication; 100=extreme localized
discomfort. The highest recorded pain index reported in this study
was 38.
[0105] It may be seen from these results that almost instantaneous
relief of the localized irritation was obtained.
Formulations
[0106] The following formulations comprising herbal compositions of
the invention are given for purposes of illustration and
exemplification only, and are not intended to limit the scope of
the invention in any way. Thus, both the concentration of active
ingredient within each formulation may be changed without removing
said formulation from the scope of the invention. Similarly, other
formulations comprising the herbal compositions claimed herein that
contain different carriers, diluents, excipients, colorings,
flavorings and other additives are still to be considered to be
within the scope of the present invention.
[0107] The term "Active ingredient" used in the following
formulation tables refers to any combination of herbal extracts
that are within the scope of the invention. The weight percentage
of the active ingredient is calculated in terms of the dry weight
of the herbal composition. Representative examples of such
combinations are:
[0108] A) composition comprising Echinacea purpurea, Hypericum
perforatum, Commiphora molmol , Uncaria tomentosa and Sambucus
nigra in a weight ratio of 4:4:4:5:3.
[0109] B) composition comprising Echinacea purpurea, Sambucus nigra
and Centella asiatica in a weight ratio of 15:70:15.
Formulation 1
TABLE-US-00002 [0110] Mouthwash Ingredient % by weight Active
ingredient 0.15 Glycerin, U.S.P 10.000 Ethanol, 190-proof, U.S.P
7.500 Flavor 0.040 Polyoxythylene (20) sorbitan 0.200
monoisostearate Sodium saccharin, N.P. 0.050 Boric acid, U.S.P
0.075 FD&C Green (1% solution) 0.045 Distilled water
balance
Formulation 2
TABLE-US-00003 [0111] Lozenge Ingredient % by weight Active
ingredient 0.25 Sorbitol 17.5 Mannitol 17.5 Starch 13.6 Sugar
substitute 1.2 Flavor 11.7 Color 0.1 Corn syrup Balance
Formulation 3
TABLE-US-00004 [0112] Chewing Gum Ingredient % by weight Active
ingredient 0.25 Gum base (30 parts Eastergum, 30.00 45 parts
Coumarone resin, 15 parts dry latex, 10 parts Paraffin wax) Sugar
50.00 Corn syrup 18.00 Citric acid 1.00 Flavor balance
Formulation 4
TABLE-US-00005 [0113] Toothpaste Ingredient % by weight Active
ingredient 0.5 Sorbitol 33.00 Saccharin 0.46 Silica 22.00 NaF 0.243
Glycerin 9.00 NaOH (50%) 0.20 Carbopol 0.20 Keltrol 0.60 TiO.sub.2
0.50 Sodium alkyl sulphate (28% 4.00 solution) PEG 6 3.00 FD&C
Blue# 1 (1% solution) 0.05 Flavor 1.1 Water Balance
[0114] While specific embodiments of the invention have been
described for the purpose of illustration, it will be understood
that the invention may be carried out in practice by skilled
persons with many modifications, variations and adaptations,
without departing from its spirit or exceeding the scope of the
claims.
* * * * *