Depends on what you try to do....there was a theraccine being tried, think
it was licensed out to SKB before SKB and Glaxo merged. However none have
be got to work yet and I think you are probably right on simply increasing
existing immune response. To work you have to generate one to something
new. However its not going to clear the neuron - it'll just do the
baseline of vaccines which is protect from disease at best.

There are some people looking at the transport systems. Ideas include
blocking the virus binding to the system somehow with a selective ligand
of some kind. The problem with shutting that system down itself is that
its almost certainly not going to be there just for virus transport....

Again some people are trying. There's some ideas floating round with
antisense molecules, interfering RNAs, even chemicals targetting
transcription site. The issue is usually selectivity.

Tim
--
When playing rugby, its not the winning that counts, but the taking apart
ICQ: 5178568

ok, here is something related:

( 21 of 118 )

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United States Patent Application 20040151789
Kind Code  A1
Levine, William Z. ;   et al.  August 5, 2004

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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.

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Inventors: Levine, William Z.; (Jerusalem, IL) ; Fer, Aron J.; (Beit
Shemesh, IL) ; Faran, Mina; (Jerusalem, IL)
Correspondence Name and Address:      NIXON & VANDERHYE, PC
1100 N GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
22201-4714
US

Serial No.:  478718
Series Code:  10
Filed:  November 24, 2003
PCT Filed:  May 22, 2002
PCT NO:  PCT/IL02/00402

U.S. Current Class: 424/729; 424/730; 424/737; 424/745; 424/748;
424/754; 424/764; 424/771
U.S. Class at Publication: 424/729; 424/730; 424/737; 424/748; 424/754;
424/764; 424/745; 424/771
Intern'l Class:  A61K 035/78

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Foreign Application Data

--------------------------------------------------------------------------------
Date Code Application Number
May 23, 2001 IL 143318

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Claims

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1. 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.

2. A therapeutic composition according to claim 1, wherein the extracts
of the at least one further plant are extracts of the plant species
Hypericum perforatum and Commiphora molmol.

3. A therapeutic composition according to claim 2 for use as an
anti-viral composition.

4. An anti-viral composition according to claim 3, 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. An anti-viral composition according to claim 4, wherein said
composition comprises extracts of the plant species Echinacea purpurea,
Sambucus nigra, Hypericum perforatum, Commiphora molmol and Uncaria
tomentosa.

6. An anti-viral composition according to claim 3 for use in the
treatment of oral lesions.

7. An anti-viral composition according to claim 3 for use in the
treatment of perioral lesions.

8. An antiviral composition according to claim 3 for use in the
treatment of genital lesions.

9. A therapeutic composition according to claim 1, wherein the extract
of at least one further plant is an extract of the plant species
Centella asiatica.

10. A therapeutic composition according to claim 9 for use in the
treatment of diseases of the oral mucosa.

11. A therapeutic composition according to claim 9 for use in the
treatment of diseases of the anal mucosa.

12. A therapeutic composition according to claim 10 or claim 11,
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.

13. A therapeutic composition according to claim 10, 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.

14. A therapeutic composition according to claim 11, wherein the
disease of the anal mucosa to be treated is selected from the group
consisting of anal fissures, hemorrhoids and non-specific irritation.

15. A therapeutic composition according to claim 9 for the inhibition
of one or more matrix metalloproteinases.

16. A therapeutic composition according to claim 15, wherein the one or
more matrix metalloproteinases to be inhibited are selected from the
group consisting of matrix metalloproteinases 1-9.

17. A therapeutic composition according to claim 16, wherein the matrix
metalloproteinases that are inhibited are of matrix metalloproteinases
of subclasses 1,2,8 and 9.

18. A therapeutic composition according to claim 17, wherein the matrix
metalloproteinase that is inhibited is of subclass 2.

19. A therapeutic composition according to any one of claims 15 to 18
for use in the treatment of a disease of the oral mucosa selected from
the group consisting of periodontal disease and aphthous ulceration.

20. 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.

21. Use of a combination of plant extracts according to claim 20,
wherein the extracts of the at least one further plant are extracts of
Hypericum perforatum and Commiphora molmol.

22. Use of a combination of plant extracts according to claim 21 in the
preparation of an anti-viral medicament.

23. Use according to claim 22, wherein the combination of plant
extracts is 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.

24. Use of a combination of plant extracts according to claim 23,
wherein said combination comprises extracts of the plant species
Echinacea purpurea, Sambucus nigra, Hypericum perforatum, Commiphora
molmol and Uncaria tomentosa.

25. Use of a combination of plant extracts according to claim 20,
wherein the extract of the at least one further plants is an extract of
Centella asiatica.

26. Use of a combination of plant extracts according to claim 25 in the
preparation of a medicament for the treatment of diseases of the oral
mucosa.

27. Use according to claim 26, 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.

28. Use of a combination of plant extracts according to claim 25 in the
preparation of a medicament for the treatment of diseases of the anal
mucosa.

29. Use according to claim 28, wherein the disease of the anal mucosa
to be treated is selected from the group consisting of anal fissures,
hemorrhoids and non-specific irritation.

30. Use according to claim 25 in the preparation of a medicament for
the inhibition of one or more matrix metalloproteinases.

31. Use according to claim 30, wherein the one or more matrix
metalloproteinases to be inhibited are selected from the group
consisting of matrix metalloproteinases 1 to 9.

32. Use according to claim 31, wherein the one or more matrix
metalloproteinases to be inhibited are selected from the group
consisting of matrix metalloproteinases 1,2,8 and 9.

33. Use according to any one of claims 30 to 32 in the preparation of a
medicament, wherein the inhibition of one or more metalloproteinases is
used to treat a disease of the oral mucosa selected from the group
consisting of periodontal disease and aphthous ulceration.

34. Use according to any one of claims 26, 28 and 30-33 wherein the
combination of plant extracts is further supplemented by 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.

35. 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.

36. A combination of extracts according to claim 35, wherein the
extracts of the at least one further plant are extracts of Hypericum
perforatum and Commiphora molmol.

37. A combination of extracts according to claim 36 for use as an
anti-viral medicament.

38. A combination of, extracts for use according to claim 37, wherein
said 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.

39. A combination of extracts for use according to claim 38, wherein
said combination comprises extracts of the plant species Echinacea
purpurea, Sambucus nigra, Hypericum perforatum, Commiphora molmol and
Uncaria tomentosa.

40. A combination of extracts for use according to claim 35, wherein
the extract of the at least one further plant is an extract of Centella
asiatica.

41. A combination of extracts according to claim 40 for use as a
medicament for the treatment of diseases of the oral mucosa.

42. A combination of extracts for use according to claim 41, 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.

43. A combination of extracts according to claim 40 for use as a
medicament for the treatment of diseases of the anal mucosa.

44. A combination of extracts for use according to claim 43, wherein
the disease of the anal mucosa to be treated is selected from the group
consisting of anal fissures, hemorrhoids and non-specific irritation.

45. A combination of extracts according to claim 40 for use as a
medicament for inhibiting one or more matrix metalloproteinases.

46. A combination of extracts for use according to claim 45, wherein
the one or more matrix metalloproteinases to be inhibited are selected
from the group consisting of matrix metalloproteinases 1 to 9.

47. A combination of extracts for use according to claim 46, wherein
the one or more matrix metalloproteinases to be inhibited are selected
from the group consisting of matrix metalloproteinases 1,2,8 and 9.

48. A combination of extracts as defined in claim 40 for use as a
medicament according to any one of claims 45 to 47, wherein said
medicament is used in the treatment of a disease of the oral mucosa
selected from the group consisting of periodontal disease and aphthous
ulceration.

49. A combination of extracts for use according to any one of claims
41,43 and 45-48, wherein said 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.

50. A method of treatment of mucosal 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.

51. A method of treatment according to claim 50, wherein the extracts
of at least one further plant are extracts of Hypericum perforatum and
Commiphora molmol.

52. A method of treatment according to claim 51, wherein the mucosal
lesions to be treated are viral lesions.

53. A method of treatment according to claim 52, wherein the viral
lesions are located in the oral cavity.

54. A method of treatment according to claim 52, wherein the viral
lesions are located in the perioral region.

55. A method of treatment according to claim 52, wherein the viral
lesions are located in the genital mucosa.

56. A method of treatment according to claim 52, wherein the viral
lesions are caused by Herpes simplex.

57. A method of treatment according to claim 52, wherein the mixture of
plant extracts 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.

58. A method of treatment according to claim 7, wherein the mixture of
plant extracts comprises extracts of the plant species Echinacea
purpurea, Sambucus nigra, Hypericum perforatum, Commiphora molmol and
Uncaria tomentosa.

59. A method of treatment according to claim 50, wherein the extract of
the at least one further plant is an extract of Centella asiatica.

60. A method of treatment according to claim 59, wherein the mucosal
lesions 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.

61. A method of treatment according to claim 59, wherein the mucosal
lesions are anal lesions associated with a disease selected from the
group consisting of anal fissures, hemorrhoids and non-specific
irritation.

62. 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.

63. A method according to claim 62, wherein the one or more matrix
metalloproteinases are selected from the group consisting of matrix
metalloproteinases 1 to 9.

64. A method according to claim 63, wherein the one or more matrix
metalloproteinases are selected from the group consisting of matrix
metalloproteinases 1,2,8 and 9.

65. A method according to any one of claims 62, 63 and 64, wherein the
inhibition of the one or more matrix metalloproteinases is used in the
treatment of periodontal disease.

66. A method according to any one of claims 62, 63 and 64, wherein the
inhibition of the one or more matrix metalloproteinases is used in the
treatment of aphthous ulceration.

67. A method according to any one of claims 59 to 66, wherein the
mixture of plant extracts further comprises 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.

68. 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.

69. A method according to claim 68, wherein the one or more matrix
metalloproteinases to be inhibited are selected from the group
consisting of matrix metalloproteinases 1 to 9.

70. A method according to claim 69, wherein the one or more matrix
metalloproteinases to be inhibited are selected from the group
consisting of matrix metalloproteinases 1,2,8 and 9.
--------------------------------------------------------------------------------

Description

--------------------------------------------------------------------------------

FIELD OF THE INVENTION

[0001] 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

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] It is another purpose of the invention to provide plant-based
anti-viral compositions for use in the treatment of oral and genital
lesions.

[0010] 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.

[0011] 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.

[0012] Further objects and advantages of the present invention will
become apparent as the description proceeds.

SUMMARY OF THE INVENTION

[0013] 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.

[0014] 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.

[0015] 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

[0016] 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 myrtilltus, 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 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.

[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:

2-6:2-4:3-6:2-6

[0063] More preferably, these components are present in the weight
ratio of 4:3:5:4.

[0064] 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

[0065] More preferably, these extracts are present in the weight ratio
of 1.5:1.5:7

[0066] 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:

[0067] Centella asiatica 1.6 mg

[0068] Echinacea purpurea 1.6 mg

[0069] Sambucus nigra 7.56 mg

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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

[0078] Method:

[0079] 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 abovementioned alcoholic extracts were purchased either
from Herbal Apothecary, Syston, Leicester, U.K. or from Analit Extracts
Ltd, M. P. Hefer 38100, Israel.

[0080] 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 0.1 M 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.

[0081] Acyclovir (ACG), a known and commonly used drug against herpes
viruses, was included in the assay as a positive control.

[0082] Results:

[0083] The results of a typical plaque assay are given below.

1 anti- Extract Toxicity HSV1 anti-HSV2 Virosyn 0-10 2-11 3-11
Hypericum 5 4-7 3-12 Uncaria 0 0-8 7-8

[0084] 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.

[0085] 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.

[0086] 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.

[0087] The above results indicate that the herbal extract mixture
tested possess antiviral activity for both HSV1 and HSV2 with minimal
toxicity to the cultured mammalian cells.

EXAMPLE 2

Topical slow-release Device for Delivery of the Compositions to the
Oral Mucosa

[0088] This example demonstrates the preparation of a slow-release
device and the incorporation therein of a plant extract mixture
containing Centella, Echinacea and Sambucus.

[0089] 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.

[0090] The device is prepared as follows:

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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).

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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

[0100] 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.

[0101] 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

[0102] 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.

[0103] 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

[0104] Anticollagenase Testing:

[0105] Procedure:

[0106] 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.

[0107] Results:

[0108] 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.

[0109] 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

[0110] 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). In the control subjects, a placebo treatment comprising a
transmucosal adhesive patch containing food color was used.

[0111] 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 [10000 g.times.10 min].

[0112] 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

[0113] 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.

[0114] It may be seen from these results that almost instantaneous
relief of the localized irritation was obtained.

Formulations

[0115] 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.

[0116] 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:

[0117] A) composition comprising Echinacea purpurea, Hypericum
perforatum, Commiphora molmol, Uncaria tomentosa and Sambucus nigra in
a weight ratio of 4:4:4:5:3.

[0118] B) composition comprising Echinacea purpurea, Sambucus nigra and
Centella asiatica in a weight ratio of 15:70:15.

2 Formulation 1 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

[0119]

3 Formulation 2 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

[0120]

4 Formulation 3 Chewing Gum Ingredient % by weight Active ingredient
0.25 Gum base (30 parts Eastergum, 45 30.00 parts Coumarone resin, 15
parts dry latex, 10 parts Paraffin wax) Sugar 50.00 Corn syrup 18.00
Citric acid 1.00 Flavor balance

[0121]

5 Formulation 4 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

[0122] 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.

* * * * *

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