Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF INVENTION
Topical Organic Acid Salt Compositions Suitable for Treating Infections
(This application is a continuation-in-part of US application serial number
12/466,615
filed May 15, 2009 whose contents are incorporated herein by reference.)
FIELD OF THE INVENTION
The present invention relates to non-aqueous topical compositions of low
molecular
weight, hydrophilic carboxylic acid salts and/or derivatives for treating toe
and finger
nail fungal infections (onychomycosis), as well as fungal infections of the
skin. Tinea
pedis (athlete's foot), Tinea unguium (nail infections), Tinea cruris (jock
itch), Tinea
corporis, Tinea versicolor and Tinea candidiasis, among others, are examples
of
onychomycosis and fungal infection. Each are caused by different types of
fungus
such as those of the gena Trichophyton, Epidermophyton, Microsporum and
Candida.
The present invention also relates to the use of the non-aqueous topical
compositions
for treating herpes infections.
BACKGROUND OF THE INVENTION
Fungal infection of the nails is one of the most common diseases of the nail-
bed or
plate. It is estimated that between 6 and 8 percent of the adult population is
affected
by such fungal infections to a varying degree. Fungal
infections of the nail
(onychomycosis) are often caused by dermatophytic fungi, most often by one of
Trichophyton mentagrophytes (also known as Trichophyton interdigitale) and
Trichophyton rubrum, although numerous other fungi are also known to cause
such
infections. Fungal infection of the skin such as Tinea pedis (athlete's foot),
Tinea cruris
(jock itch) and Tinea corporis are also commonly caused by T. rubrum and T.
mentagrophytes, among other fungi. T. mentagrophytes is generally easily
treated by
conventional over-the-counter (OTC) medications whereas T. rubrum is
significantly
more difficult to treat.
RECTIFIED SHEET (RULE 91.1)
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Herpes is an infection that is caused by a herpes simplex virus. Oral herpes
causes
cold sores around the mouth and face. Genital herpes affects the genitals,
buttocks or
anal area. Herpes has no cure and can only be controlled by powerful anti-
viral drugs.
A large number of pharmaceutical compositions for use in the topical treatment
of skin
and nail fungal infections have been described in the art. These topical
applications
include lotions, sprays, gels, ointments and powders containing a variety of
prescription
and non-prescription active ingredients.
United States Patent 6,080,744 describes cream-based topical treatments for
mycotic
infections consisting of a blend containing multiple active ingredients
including
ketaconazole, nystatin, miconazole nitrate, tolnaftate, clotrimazole,
undecenoic acid,
zinc undecenoate, propionic acid and sodium propionate. Optionally, the
compositions
may include additional active ingredients such as an antibacterial agent
(e.g.,
gentamicin) or an anti-inflammatory agent (e.g., dipropionate betamethasone).
However, the testing data only demonstrates activity against skin infections
and there is
no discussion of infections of the nail.
United States Patent 6,664,292 describes compositions for the treatment of
fungal
infections of the nail comprised of a lower alcohol, preferably methanol, and
a single,
lower carboxylic acid. The composition is extremely volatile, however, and
requires
special storage considerations in order to prevent the methanol from
evaporating.
United States Patent 4,824,865 describes compositions containing 2-
hydroxyoctanoic
acid, 2-ketooctanoic acid and C2 to C6 esters thereof in aqueous and non-
aqueous
formulations for the treatment of various skin infections. There is no
discussion of nail
infections and the acidic pH of the water-containing formulations would result
in
irritation to the user.
United States Patent 6,214,889 describes liquid and gel compositions for the
treatment
of adverse skin conditions consisting of one or more of potassium, sodium,
calcium or
cesium formate alone or in combination, preferably in concentrations of about
50% in
distilled water and an optional gelling agent. The composition of this
invention contains
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a very large amount of water and there is no teaching that it would be
effective against
nail infections.
United States Patent 6,921,529 describes a topical composition containing a
weak
organic acid dispersed in a non-biodegradeable polymeric matrix to form a
supersaturated hydrogel. The polymer is preferably a polyacrylate and the weak
organic acid is acetic or citric acid. Optionally, the use of other, known,
antimycotic
agents such as azole derivatives, undecylenic acid, tea tree oil (Melaleuca
altemifolia),
or salicyclic acid may be added to the hydrogel. By definition a hydrogel
contains a
large amount of water and the use of these acids would result in an irritation
to the end
user
Nettleship (Archives of Dermatology and Syphilology, 1950, 61(4), 669)
discusses the
use of a propionic acid-propionate-caprylate mixture in ointment or powder
form to treat
skin infections. Application of the ointment containing 12.3% sodium
propionate, 2.7%
propionic acid, 10% sodium caprylate and 5% zinc caprylate and subsequent
application of the powder containing 15% calcium propionate, 5% zinc
propionate, 5%
zinc caprylate and 0.25% propionic acid were required to effect treatment. In
addition,
there is no discussion of treatment of nail infections.
Brewer (Archives of Dermatology and Syphilology, 1950, 61(4), 681) discusses
the use
of "sopronol" (a mixture of 12.3% sodium propionate, 2.7% propionic acid and
10%
sodium caprylate) in powder or water-sotubte ointment to treat mild to severe
skin
infections. Ointment application to the skin and powder application to socks
and
footwear was required. Moreover, there is no discussion of treatment of nail
infections.
Sulzberger and Kanof (Archives of Dermatology and Syphilology, 1947, 55(3),
391)
discuss the use of "sopronol" (a mixture of 5% zinc propionate and 15% calcium
propionate) powder in comparison with other compositions for the prevention
and
treatment of skin infections of the feet. There is no discussion of the use of
these
compositions for treating nail infections.
Peck and Russ (Archives of Dermatology and Syphilology, 1947, 56(5), 601)
discuss
the use of an aqueous ointment containing 12.3% sodium propionate, 2.7%
propionic
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acid and 10% sodium caprylate to treat tinea infections of the scalp, rectum,
nails and
hands and feet. Treatment of the nails was cumbersome and arduous, requiring
grinding of the nails until pain was induced, application of the ointment and
alternating
filing of the nails and application of the ointment twice a day for several
months.
Mon et at (Agricultural and Biological Chemistry, 1987, 51(12) 3403) examined
the
activity of various saturated and unsaturated fatty acids against Pyricularia
otyzae and
Miscanthus sinensis and concluded C10 to C13 monocarboxylic fatty acids were
the
most active. However, there is no discussion of clinical treatment of skin and
nail
infections.
Kabara et at (Antimicrobial Agents and Chemotherapy, 1972, 2(1), 23) evaluated
the
activity in vitro of 15 saturated and unsaturated fatty acids against gram
positive and
gram negative bacteria. Lauric (C12) acid was found to be the most effective.
However, there was no discussion of clinical treatment of skin and nail
infections.
Garg and Muller (Mycoses, 1993, 36, 51) examined the in vitro antifungal
activity of
saturated and unsaturated C7 to C18 fatty acids against Trichophyton and
Microsporum
species that cause fungal infection. C7 to Cii saturated fatty acids were most
active
against fungi that cause skin infection. However, there was no discussion of
clinical
treatment of skin and nail infection.
While these teachings describe topical compositions for the treatment of
fungal
infections, most of these compositions have a high loading of active
ingredient, cause
undesirable side effects and require an invasive or long treatment regimen.
Further, fungal infections of nails (onychomycosis) are very difficult to
treat with topical
formulations because the fungus is often embedded deep within the nail and
nail bed.
This is due to the physiological make up of the nail which precludes proper
absorption
of the antifungal treatment. These factors can contribute to a treatment
regimen which
offers no guarantee of fungus eradication because of ineffectiveness or
noncompliance
with the administration guidelines.
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As a result, there remains a long-felt need for new, safe and inexpensive
compositions
for the effective treatment of fungal infections of both skin and nails, and
viral infections
of the skin.
SUMMARY OF THE INVENTION
The present invention relates to a non-toxic, topical antifungal composition
for the
treatment of fungal infections of the nails and skin. The active ingredients
of the
antifungal composition comprise a combination of low molecular weight,
hydrophilic
carboxylic acid salts or derivatives exhibiting a synergistic enhancement,
dissolved in a
non-aqueous, non-volatile polyhydric carrier. The composition can also contain
a nail-
penetrating agent to allow absorption of the composition into the nail. Since
the source
of onychomycosis can be traced to the nail bed, allowing the low molecular
weight,
hydrophilic carboxylic acid salts and/or derivatives to penetrate to the nail
bed results in
the most effective treatment of the fungal infection.
While the low molecular weight, hydrophilic carboxylic acids of the
composition
individually have each been previously known to demonstrate weak antifungal
activity, it
unexpectedly has been found that when they are used in combination, a
synergistic
enhancement and a potent effect is observed. Synergistic is defined as
providing more
than an additive effect of the combination. This still greater enhancement has
allowed
for a non-toxic, topical antifungal formulation with a lower amount of low
molecular
weight, hydrophilic carboxylic acid salts or derivatives than had been used in
the prior
art.
Thus, in one aspect of the invention there is provided a composition suitable
for the
topical treatment of a variety of fungal infections that may develop on the
skin and nails
comprising a combination of low molecular weight, hydrophilic organic acid
salts or
derivatives exhibiting a synergistic enhancement, dissolved in a non-aqueous,
non-
volatile polyhydric carrier.
In another aspect of the invention there is provided a composition comprising
a
combination of low molecular weight, hydrophilic organic acid salts or
derivatives
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exhibiting a synergistic enhancement and a penetrating agent, dissolved in a
non-
aqueous, non-volatile polyhydric carrier used to treat onychomycosis.
In another aspect of the invention there is provided a composition comprising
a
combination of low molecular weight organic acid salts or derivatives
exhibiting a
synergistic enhancement and a penetrating agent, dissolved in a non-aqueous,
non-
volatile polyhydric carrier used to treat fungal infection.
In a further aspect of the invention there is provided a method of treatment
using a
composition comprising a combination of low molecular weight, hydrophilic
carboxylic
acid salts or derivatives exhibiting a synergistic enhancement and a
penetrating agent,
dissolved in a non-aqueous, non-volatile polyhydric solvent.
In a further aspect of the invention there is provided a combination of low
molecular
weight, hydrophilic carboxylic acid salts or derivatives exhibiting a
synergistic
enhancement useful in treating onychomycosis and fungal infection.
In a further aspect of the invention there is provided a method of treating
skin and nails
using a combination of low molecular weight, hydrophilic carboxylic acid salts
or
derivatives exhibiting a synergistic enhancement at a lower concentration than
previously used.
In a further aspect of the invention there is provided a composition having an
increased
drug flux comprising a supersaturated concentration of low molecular weight,
hydrophilic organic acid salts or derivatives.
According to another aspect of the invention we have discovered unexpectedly
that the
invention is suitable for use for the treatment of genital herpes and
particularly herpes
cold sores
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MORE DETAILED DESCRIPTION OF ASPECTS OF THE INVENTION
According to another aspect of the invention there is provided a non-toxic,
topical
antifungal composition comprising a combination of at least three or more low
molecular weight, hydrophilic organic acid salts or derivatives exhibiting a
still greater
synergistic enhancement, dissolved in a carrier, wherein
the low molecular weight organic acid salts are selected from the group
consisting
of saturated and unsaturated, acyclic, branched and unbranched aliphatic
carboxylic acids wherein the longest carbon chain has eight carbons, and
aromatic
carboxylic acids containing less than ten carbon atoms;
to the carrier is
comprised of one or more non-aqueous, non-volatile polyhydric
solvents; and
wherein the combination of low molecular weight, hydrophilic organic acid
salts
and/or derivatives comprises between about 0.5% to about 50%, preferably to
about 30% and most preferably to about 10% by weight of the composition, and
no
is single acid
salt or derivative comprises more than about 75% by weight of the total
acid content.
According to another aspect of the invention the active ingredients of the
present
antifungal compositions are combinations of at least three or more low
molecular
weight, hydrophilic organic acid salts or derivatives. These low molecular
weight,
20 hydrophilic organic acids include both substituted and non-substituted
aliphatic
(saturated and unsaturated) and aromatic acids. Preferably, the carboxylic
acid has
less than 12, and more preferably less than ten carbons, with the longest
carbon chain
being eight carbon atoms in length and the aromatic carboxylic acid containing
less
than ten carbon atoms. The carboxylic acids used in the present invention can
be
25 substituted by
one or more functional groups, such as alkyl, alkenyl, alkynyl, halogen,
hydroxy, carbonyl, carboxylic acid, aldehyde, ester, amide, carbonate,
carbamate,
ether, amino, cyano, isocyano, oxy, oxo, thia, aza, azide, imine, nitro,
nitrate, nitroso,
nitrosooxy, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl,
sulfhydryl,
sulfonyl, phosphino. Each of the alkyl, alkenyl, alkynyl and amino groups may
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themselves be optionally substituted with one or more of the preceding
functional
groups.
Preferably, the carboxylic acids are selected from branched and unbranched
alkanoic
acids, hydroxyalkanoic acids, alkenoic acid, aromatic acids, and
hydroxpromatic acids.
Such organic acids include formic, acetic, propionic, butyric, valeric,
caproic, enanthic,
caprylic, lactic, tartaric, gluconic, benzoic, mandelic, salicylic, acrylic,
acetoacetic,
pyruvic, adipic, aldaric, fumaric, glutaric, maleic, sorbic, malic, malonic,
oxalic, succinic,
tartronic, citric, isocitric, aconitic, and carballylic acids, as well as
their further branched
and substituted derivatives.
The salts of the carboxylic acids most useful in the present invention are
preferably
metal salts. More preferably, the metal salts are selected from the usual
groups 1 and
2 metals and zinc. Groups 1 and 2 metal salts normally comprise lithium,
sodium
potassium, magnesium and calcium salts. Most preferably the metal salts used
in the
present invention are sodium, calcium and zinc.
Most preferred active ingredients for the composition of the present invention
are
sodium acetate, sodium formate, zinc propionate, calcium propionate and sodium
benzoate, and various combinations thereof. These compounds and other salts
and/or
derivatives can be grouped together in various amounts and in various numbers
and
provides substantially the same benefits, and groups of three, four or five
salts and/or
-- de riv.atives_may-be-chose Neve-the-benefits-of-the if mei
r.
It unexpectedly has been found that the compositions of the invention are most
potent
when the carrier system is non-aqueous. Non-aqueous in this case means low to
negligible water content, i.e. 5% and more preferably less than about 1% water
as
formulated based on the weight of the composition. The solvents used for the
present
compositions will preferably have a low to negligible water content. Thus, the
low
molecular weight, hydrophilic carboxylic acid salts or derivatives of the
present
compositions are dissolved in a non-aqueous, non-volatile polyhydric solvent.
Polyhydric in this case means containing more than one hydroxyl group.
Preferably,
the solvents include glycerine, diglycerol, ethylene glycol, propylene glycol,
low
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molecular weight polyglycols, such as polyethylene glycol or polypropylene
glycol with
molecular weight less than 500 gmol-1, among others, and their derivatives,
particularly
monoether and ester derivatives. More preferred as solvents are glycerine and
propylene glycol. Most preferred as a solvent is propylene glycol.
The compositions of the present invention can also comprise from between about
1%
to about 80% preferably between about 30% and about 80%, more preferably
between
about 50% to about 70% of a penetrating agent to allow the low molecular
weight,
hydrophilic carboxylic acid salts or derivatives to penetrate the nail itself
to ensure the
carboxylic acid salts or derivatives contact the source of the fungal
infection, usually the
nail bed. The penetrating agent may be selected from alcohols, preferably
lower
alkanols. More preferred alkanols are methanol, ethanol, n-propanol,
isopropanol, n-
butanol, sec-butanol and tert-butanol. Most preferred are isopropanol and
ethanol.
An optional gel-forming component may be incorporated in the compositions of
the
invention to produce a formulation suitable for application to bandages,
dressings and
the like. Preferred gel-forming ingredients are hydroxyl ethyl cellulose or a
fumed silica
(Aerosilq which may be used in non-aqueous solvents or carriers.
Two preferred compositions of the present invention comprise the combination
of
sodium acetate, sodium formate, zinc propionate, calcium propionate, and
sodium
benzoate or the above without sodium acetate in the non-aqueous, non-volatile
oolyhydric carrier propylene glycol, to which is added the penetrating agent
ethanol or
isopropanol. Glycerol may optionally be added to alter the viscosity of the
compositions
of the present invention.
The combination of low molecular weight, hydrophilic carboxylic acid salts
and/or
derivatives in the present compositions may be added to the carrier at a level
between
about 1% to about 50% total carboxylic acid salt or derivative content by
weight of the
composition. Preferably, the total combination of carboxylic acid salts or
derivatives is
between about 1% to about 30% by weight of the composition, and more
preferably the
total synergistic combination of carboxylic acid salts or derivatives is
between about 1%
to about 20% by weight of the composition. The distribution of the individual
carboxylic
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acid salts or derivatives within the total combination of carboxylic acid
salts or
derivatives is not limited, however. It is preferable that any one carboxylic
acid salt or
derivative does not comprise more than about 75% of the combination.
Preferably, the
individual carboxylic acid salts and/or derivatives are added to the carrier
at a level of
between about 1% to about 10% by weight of the total formulation.
The compositions of the present invention exhibit antifungal properties and
are
therefore useful in the topical treatment against fungi which cause
onychomycosis and
fungal infection such as tinea unguium, tinea pedis, tinea cruris, tinea
corporis, tinea
versicolor and tinea candidiasis. The fungi causing these tinea infections
include the
various species of Trichophyton, Epidermophyton, Microsporum and Candida. The
compositions of the present invention are particularly useful in treating
onychomycoses
caused by T. mentagrophytes (also known as T. interdigitale) and T. rubrum, in
particular T. rubrum.
As well as being applied directly to the infected area, compositions of the
invention can
also be pre-applied to bandages or other absorbent material, which is then
applied to
the infected area. Alternatively, the treated area can be wrapped in a bandage
or other
protective covering.
Further, the use of the compositions described herein as a medicament is
provided for
the topical treatment of cold sores, in one embodiment herpes cold sores.
Thus, in accordance with the invention, methods of treatment of onychomycosis
and
fungal infection have been provided wherein an effective amount of the
compositions
described herein is liberally applied to the infected area by applying by hand
or
painting. As well, the use of the compositions described herein for the
topical treatment
of onychomycosis and fungal infection has also been provided. Topical
treatment of
fungal infection may include, but not be limited to, application of a gel
formulation of the
compositions of the present invention to the skin with repeated, daily
application of the
gel formulation until eradication of the fungal infection is achieved, for
example
singularly or repeatedly. Topical treatment of onychomycosis may include, but
not be
limited to, painting the infected nail or nails with a liquid formulation of
the compositions
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of the present invention with repeated, daily application of the liquid
formulation until
eradication of the fungal infection is achieved, for example singularly or
repeatedly.
Optionally a bandage or dressing impregnated with a composition of the present
invention further can be applied to maintain a steady level of the antifungal
composition
at the treatment site. Other formulations of the compositions of the present
invention
that may be used to treat fungal infections of the skin and nails may include
creams,
lotions, ointments and the like.
Further, the use of the compositions described herein in the preparation of a
medicament for the topical treatment of onychomycosis and fungal infection is
also
provided.
Further, the use of the compositions of the invention in the preparation of a
medicament for the topical treatment of Candida infections is also provided.
Exemplary Formulations of the HerpeslAntifungal Compositions of the Invention
Formulation of the antifungal compositions of the present invention may be
prepared by
the methods known to the skilled person. Two
exemplary, but non-limiting,
formulations of the present invention, a liquid and a gel formulation, are
provided
below. In addition to these exemplary formulations, other topical
formulations,
prepared using methods known to the skilled person, may also be used for the
administration of the antifungal compositions of the present invention.
Example 1 ¨ Liquid Formulation
A preferred liquid formulation having low to negligible water content contains
the
following ingredients:
Ingredient cto by Wt.
Propylene glycol 72
Sodium benzoate 5
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Calcium propionate 5
Zinc propionate 5
Sodium formate 3
Glycerol 10
This formulation may be prepared by, among other methods, first warming the
propylene glycol and sequentially dissolving in it, the sodium benzoate,
calcium
propionate, zinc propionate and sodium formate. After dissolution of each of
the salts,
the glycerol is added, following which the mixture is cooled to room
temperature.
Example 2 ¨ Gel Formulation
A preferred gel formulation having low to negligible water content contains
the following
ingredients:
Ingredient % by Wt.
Propylene glycol 80
Sodium benzoate 5
Calcium propionate 5
Zinc propionate 5
Sodium formate 3
Hydroxy ethyl cellulose 2
This formulation may be prepared by, among other methods, first warming the
propylene glycol and sequentially dissolving in it the sodium benzoate,
calcium
propionate, zinc propionate and sodium formate. After dissolution of each of
the salts,
the hydroxy ethyl cellulose is slowly added to prevent agglomeration,
following which
the mixture is cooled to room temperature.
Use and Efficacy of the Antifungal Compositions of the Invention
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Example 3 ¨ Confirmation of the AntifunqaI Activity of the Antifunqal
Compositions ¨
Liquid Broth Assay
The antifungal activity of the present compositions was confirmed through in
vitro
testing using an antifungal microdilution method using Canadian Laboratory
Standards
Institute (CLSI) Reference Method 38-A2 with modifications as described below.
This
method is the gold standard used in measuring the antifungal susceptibility of
filamentous fungi that cause invasive infections. Fungal colonies are grown on
potato
glucose agar (PGA). One colony is picked and grown in Sabouraud glucose broth
(SGB) at 24 C for 3 days in the presence of test compound. Microdilution
trays are
incubated at 24 C, and are read after 5 days of culture. Turbidity in the
microdilution
wells is scored with the aid of a reading mirror and compared with that of the
growth
control. A numerical score from 0 to 4 is given to each well using the
following scale: 0
= optically clear or absence of growth, 1 = slight growth (25% of growth
control), 2 =
prominent reduction in growth (50% of growth control), 3 = slight reduction in
growth
IS (75% of growth control), 4 = no reduction in growth.
The turbidity scores (average of 3 tests) for T. rubrum and T. mentragrophytes
grown in
different concentrations (or dilutions) of test compounds for 5 days was as
follows:
Trichophyton rubrum
Purity (%) 0 0.625 1.25 2.5 5 10
Formulation of Ex. 1 4 0 0 0 0 0
1
- Carrier 4 4 - 4 4 2.67 1
Trichonhyton mentadrophytes
Purity (%) 0 0.625 1.25 2.5 5 10
Formulation of Ex. 1 4 -1 1 0.67 0 0
Carrier 4 4 _____ 4 4 3 2
The compositions of the current invention contain several carboxylic acid
salts as the
active ingredients. Individually, the preferred carboxylic acid salts of the
present
invention have antifungal activity against T. mentogrophytes and T. rubrum.
However,
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when combined the resultant antifungal activity is synergistic. In this case,
synergistic
is defined to mean more than additive.
Example 4 ¨ Demonstration of Synergistic Activity: Addition of Sodium Benzoate
to
Mixture of Zinc Propionate, Calcium Propionate and Sodium Formate
Using CLSI Reference Method 38-A2, activity against T. rubrum was examined
using
separately a mixture of zinc propionate (F9), calcium propionate (F10) and
sodium
formate (F12), sodium benzoate (F11) and a combination of zinc propionate,
calcium
propionate, sodium formate and sodium benzoate (N = negative growth; P =
positive
growth):
F9+F1O+F12 VS F11
0.25X_N N I N N N I N 14 N
' 01,z5)s N N
0.00X N N
N N L 74 N N N
0.015X P N
0.007 P N H N N N ____________ N _ N __
0.004X P '"* N N N NN
P0 004X P 0.007X P 0.015X N
0.08X N 0.125x N 0.25X 4
0
In this test, individually the combination of F9+F10+F12 showed negative
growth at
0.03 times the initial concentration and Eli showed negative growth at 0.03
times the
initial concentration. The combination of F9+F1O+F12+F11 showed a negative
growth
at 0.004 times the concentration of F9+F10+F12 and 0.004 times the
concentration of
F11 thus demonstrating that the combination of the four carboxylic acid salts
is
synergistic.
Example 5 ¨ Demonstration of Synergistic Activity: Addition of Zinc Propionate
to
Mixture of Calcium Propionate. Sodium Benzoate and Sodium Formate
Using the same protocol as in Example 4 activity against T. rubrum was
examined
using separately a mixture of calcium propionate (F10), sodium benzoate (F11)
and
sodium formate (F12), zinc propionate (F9) and combined a mixture of calcium
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propionate, sodium benzoate, sodium formate and zinc propionate (N = negative
growth; P = positive growth):
F10+F11+F12 VS F9
-
025X ., 14_ , _ 14 N N ___________ NN N N
.., .-
0 125X i4 tsi.õ _ N N _ N _ N
___________________________________ N . N NN N N .'
-
0.03X P P N _,.. N N .... N N N
,
---
' 0.01SX P P ,--.14: ,',. N N ' N N N
, -
......_ -
-&007X P
0.004x , J! i; P P N N N N
P 0 004X P 0.007X P 0.015X N
0.00X N 0.125X N 0.25X
_ _
In this test, individually the combination of F1O+F11+F12 showed negative
growth at
0.06 times the initial concentration and F9 showed negative growth at 0.03
times the
initial concentration. The combination of F10+F11+F12+F9 showed a negative
growth
at 0.015 times the concentration of F10+F11+F12 and at 0.007 times the
concentration
of F9 thus demonstrating that the combination of the four carboxylic acid
salts is
synergistic.
Example 6¨ Demonstration of Synergistic Activity: Addition of Sodium Formate
to a
Mixture of Zinc Propionate and Calcium Propionate
Using the same protocol as in Example 4 , activity against T. rubrum was
examined
using separately a mixture of zinc propionate (F9) and calcium propionate
(F10), and
sodium formate (F12) and a combined mixture of zinc propionate, calcium
propionate
and sodium formate (N = negative growth; P = positive growth):
F9+F10 VS F12
1 _______________________________________________________________________
025X N N N N N N N N
0.125X N N N N _ _ N _ N , N 1 N __ N
N - N N N N N
0.03X _ P _ N _ N N N N N N
-
0.015X P `,14,4i *, 73 N N N N N N
0.007X P P P P P N N N
0.004X P P _ P P _ P NN N _
0 P
0.004X P 0.007X P 0.015X P 0.03X WM N 0.125X N 025X .
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In this test, individually the combination of F9+F10 showed negative growth at
0.06
times the initial concentration and F12 showed negative growth at 0.06 times
the initial
concentration. The combination of F9+F10+F12 showed a negative growth at 0.015
times the concentration of F9+F10 and 0.004 times the concentration of F12
thus
demonstrating that the combination of the three carboxylic acid salts is
synergistic.
Example 7 ¨ Demonstration of Synergistic Activity: Addition of Sodium Acetate
to the
Liquid Formulation of Example 1 without Sodium Formate
Using the same protocol as in Example 4, activity against T. rubrum was
examined
using separately the liquid formulation of Example 1 without sodium formate
(F2), and
sodium acetate (F12) and the combined liquid formulation of Example 1 without
sodium
formate and sodium acetate (N = negative growth; P = positive growth):
______________________ F2 VS F14
0.25X N N N j N N N N N
0. 1 25X N N N NN N N N
0,06X N N N ____ N N N N
063X N __________ N NN N N N - N
NM. N
_____________________________________________ N N N
=
0.007X P P P __________________________ N N N
0.004X P p P P Nt: N
P 063X P ti 0208X 5X
In this test, individually the liquid formulation F2 showed negative growth at
0.015 times
the initial concentration and F14 showed negative growth at 0.125 times the
initial
concentration. The combination of F2+F14 showed a negative growth at 0.004
times
the concentration of F2 and 0.03 times the concentration of F14 thus
demonstrating
that the combination of the liquid formulation of Example 1 without sodium
formate and
sodium acetate is synergistic.
Example 8 ¨ Antifungal Activity Aoainst Candida
Using the broth assay of Example 3 the liquid formulation of Example 1 was
tested
against Candida albacans, Candida parapsilosis and Candida krusei. Against C.
albicans an MIC value of 0.63% of the liquid formulation of Example 1 was
determined.
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Against C. parapsilosis an MIC value of 0.63% of the liquid formulation of
Example 1
was determined. Against C. krusei an M1C value of 0.31% of the liquid
formulation of
Example 1 was determined.
Example 9 ¨ Penetrating Agent Action
To the liquid formulation of Example 1 was added isopropanol or ethanol so
that it
comprised 25, 33, 50, 66, 75 or 80% of the weight of the formulation. The new
formulations were applied to a human nail. The liquid formulation dried on the
nail
leaving no powdery residue indicating that the carboxylic acid salts were
rapidly
absorbed by the human nail.
Example 10 ¨ Treatment of Onychomvcosis and Fungal infection
In two individuals, each with fungal infections of the nail on all nails of
both feet, the
nails were first debrided to remove damaged nail material only. Following
debridement,
the liquid formulation of Example 1 was applied to each nail and the
surrounding skin
twice daily (morning and evening). Within two weeks, both individuals
perceived a
marked reduction in the sensation of irritation at the nails. Treatment was
continued for
eight weeks at which time cultures taken from one individual tested negative
for nail
fungus. Following cessation of treatment, reoccurrence of the infection was
not
reported by either individual. No irritation or other discomfort owing to the
application of
a composition of the invention was reported by either subject.
In two individuals, each with a fungal infection of the nail on a big toe, the
liquid
formulation of Example 1 was applied twice daily (morning and evening) for
eight
weeks at which time there was no evidence of infection. Prior to treatment the
nails
were not debrided. Following cessation of treatment, reoccurrence of the
infection was
not reported by either individual. No irritation or other discomfort owing to
the
application of a composition of the invention was reported by either subject.
One individual reported suffering from a fungal infection of the skin on the
top and
underside of the foot and between the toes. The gel formulation of Example 2
was
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applied twice daily to this area. Although treatment was continued for eight
weeks, the
subject reported that the redness and irritation had cleared within two days
One individual with fungal infections on the under arms and the back sides of
the
elbows was treated with the liquid formulation of Example 1 twice daily
(morning and
evening) for five days. Following cessation of treatment, both infections had
been
completely eradicated; no reoccurrence was reported. No irritation or other
discomfort
owing to the application of a composition of the invention was reported.
While the treatment of infected nails in the above examples relied upon an
eight-week
application period, this should not be taken as the minimum time required for
successful eradication of nail infections. An eight-week period was selected
based
upon the treatment periods generally indicated for fungal nail infections.
Minimum
effective treatment times using the present compositions may be determined in
a
formalized clinical trial program designed for such an outcome.
A synergistic enhancement by the low molecular weight, hydrophilic carboxylic
acid
salts or derivatives was observed in the treatment of fungal infections of the
skin. An
aqueous solution of calcium and sodium propionate (constituents of the known
antifungal agent Mycobane, which is commonly used as a food preservative) led
to an
initial clearing of fungal infections of the skin, however, the infections
reoccurred within
two weeks following cessation of treatment. In contrast, the infections were
eradicated
when _using _a_ _composition_ Pt the- present -invention- -containing- -
propionic- acid -and- -- ---
benzoic acid salts in propylene glycol, with an even greater synergistic
enhancement
observed through the addition of a third organic acid.
Example 11 ¨ Treatment of Herpes Simplex
An individual with medically confirmed genital Herpes treated himself with the
formulation described in example 1. The individual applied the formulation on
two
consecutive days to the effected area of the penis. On the day following the
first
application, the cold sore had mostly disappeared. Forty-eight hours following
the first
application, the herpes cold sore had completely disappeared.
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As many changes can be made to the provided examples without departing from
the
scope of the invention, it is intended that all material herein be interpreted
as illustrative
of the invention and not in a limiting sense.
