Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF DISSOLVING ANTIFUNGAL AGENT, AND COMPOSITIONS
WITH A HIGH CONCENTRATION OF ANTIFUNGAL AGENT, SUITABLE
FOR APPLICATION TO THE NAIL
TECHNICAL BACKGROUND
The present invention relates to the development
of a ternary solvent system comprising water that
allows substantial amounts of antifungal agents from
the class of the allylamines or from the class of the
morpholines to be dissolved. This invention allows
compositions to be prepared that are specifically
adapted to application to the nail, the latter possibly
being optionally perforated or pretreated chemically or
physically.
Pharmaceutical or dermatological compositions of
this kind are useful especially for the treatment, in
humans and animals, of onychomycoses, especially those
due to dermatophytes or to Candida.
PRIOR ART
Antifungal agents from the class of the
allylamines, especially terbinafine or naftifine, and
those from the class of the morpholines, especially
amorolfine, are promising compounds in antifungal
control. Their presumed or demonstrated mode of action
involves inhibition at the level of ergosterol, a
specific constituent of the wall of fungal cells,
especially via the inhibition of squalene epoxidase
("Terbinafine: Mode of action and properties of the
squalene epoxidase inhibition" British Journal of
Dermatology, Volume 126 Issue s39, pages 2-69 (February
1992); "Preclinical data and mode of action of
amorolfine", Dermatology, 1992, vol. 184, SUP1
(10 ref.), pp. 3-7).
Traditionally, antifungals have been administered
either topically or orally.
By the oral route, terbinafine administered at a
level of 250 mg/day for 6 months has proved to be
effective and of low toxicity in the treatment of
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onychomycoses due to Trichophyton rubrum. However,
treatment of this kind raises a problem of duration and
of cost, and sometimes has side-effects affecting the
digestive sphere, taste disorders or else transitory
skin eruptions (GUPTA A, LYNDE C, LAUZON G et al.
Cutaneous adverse effects associated with terbinafine
therapy: 10 case reports and a review of the
literature. Br J Dermatol, 1998, 138: 529-532).
By the topical route, transungual administration
represents an alternative solution to oral
administration for the treatment of onychomycoses.
However, the problem which arises in the case of
administration to the nail is to ensure the penetration
and spreading of the antifungal agents in the nail,
allowing therapeutically effective concentrations to be
attained in the nail and under the nail, in other words
in the nail bed.
The nail as such is composed essentially of
keratin, a fibrous protein which is indeed insoluble
yet which exhibits an affinity for water. Thus the nail
is considered to be hydrophilic in nature, which is to
say that it behaves as a hydrogel. Consequently, and
for transungual application, it would appear mandatory
to formulate the antifungal agent in water. Water,
however, has difficulties in its compatibility with the
aforementioned antifungal agents of interest,
especially terbinafine, which per se exhibit little
spreading ability into the nail, and, moreover, are
virtually insoluble in water.
Among all of the technical solutions proposed for
transungual formulations of antifungal agents in the
prior art, the solution used has been that of an
aqueous-alcoholic mixture with addition of polymers.
Alternatively, document EP 0 503 988 proposed
admixing the aqueous-alcoholic medium with hydrophilic
penetrants, which were hitherto known and used for
promoting the transcutaneous penetration of active
agents through the horny layer of the skin; this horny
layer is lipophilic in nature and behaves as a water
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barrier.
However, even in the presence of such hydrophilic
penetrants, the proportion of water in the compositions
described in document EP 0 503 988 is never greater
than 30% of the total weight of the composition.
There is therefore a need to find new formulations
for antifungal agents that allow improved spreading
through the nail of an effective amount of active
principle.
SUMMARY OF THE INVENTION
The present invention lies in the demonstration of
a ternary solvent system which comprises water and
which combines a capacity for substantial amounts of
antifungal agents of interest to be dissolved, the
possibility of a large amount of water, and a capacity
for effective spreading and effective penetration into
and through the keratinized ungual tablet of the nail.
By "large amount of water" is meant a total amount
of water in the composition of more than 30% by weight,
relative to the total weight of the composition.
More specifically, the present invention provides
a dermatological composition intended for the treatment
of onychomycoses, which takes the form of a solution
and comprises:
- first, an effective amount of at least one
antifungal agent;
- second, a solvent medium for said antifungal
agent (or agents) that is composed of a mixture
of water, at least one branched or straight
chain C2-C8 alkanol, and at least one glycol
that has free hydroxyl functions.
A composition of this kind is characterized in
that the total water represents more than 30% by
weight, relative to the total weight of the composition
(w/w), advantageously more than 33%, or even more than
35%, or, indeed, even more than 40%.
In the context of the invention, an "effective
amount" of at least one antifungal agent is a
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substantial amount of said agent in the composition. It
is obvious that the problem of solubility in the
solvent medium, more particularly in water, arises for
substantial amounts of this kind.
In practice, the substantial amount of antifungal
agent, as will be defined below, represents more than
5%, or even at least 8%, or, indeed, even at least 10%
(w/w) of the total composition. Hence it is possible to
envisage up to 15% or even 20% of this agent in the
composition.
It is of course possible to contemplate a mixture
of antifungal agents, possibly from different classes.
As already stated, the antifungal agents of
interest that are more particularly a target of the
present invention are those from the class of the
allylamines and from the class of the morpholines, the
class of the allylamines being preferred.
Within the class of the allylamines, mention may
be made, in particular, of terbinafine and its acid
salts, and naftifine and its acid salts. Among the acid
salts, preference will be given to terbinafine
hydrochloride and naftifine hydrochloride, the
respective formulae of which are as follows:
CH3
CH3 CH3
N - CH3
HCI
Terbinafine hydrochloride
CH3
N
.HCI
Naftifine hydrochloride
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Among the molecules from this class, preference is
given to terbinafine.
Alternatively, the antifungal agent may belong to
the class of the morpholines, especially amorphine and
5 its acid salts, for which similar problems of
solubility in water arise.
As indicated above, the invention is based on the
demonstration of a ternary solvent system comprising
water and exhibiting a synergy in the dissolution of
the antifungal agents of interest.
This system comprises:
- water, which is known to be a very poor solvent
of antifungal agents from the class of the
allylamines or from that of the morpholines;
- a short chain alcohol, and more specifically,
at least one branched or straight chain C2-C8
alkanol, these alcohols being known to be
solvents for antifungal agents from the class
of the allylamines or from that of the
morpholines;
- at least one glycol.
A very poor solvent is a solvent which allows
dissolution of not more than 1% (w/w) of the antifungal
agent from the class of the allylamines or from that of
the morpholines.
Hence, remarkably, the inventors have demonstrated
that this combination of three solvents comprising
water exhibits a synergy in the dissolution of the
antifungal agents of interest, thereby allowing the
amount of water in the mixture to be increased while at
the same time allowing the dissolution of substantial
amounts of antifungal agents.
As already stated, and remarkably, the total water
represents more than 30% by weight, relative to the
total weight of the composition (w/w), advantageously
more than 33%, or even more than 35% or, indeed, even
more than 40%. Consequently, the total water
advantageously represents more than a third of the
ternary solvent mixture.
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By total water is meant the amount of water
introduced as such into the composition, with the
addition of the amount of water originating from the
various solvents and/or excipients in the composition,
where they contain water.
On the other hand, the total water represents
advantageously less than 60%, or even less than 50%, of
the total composition.
The second entity in this ternary system is a
short chain alcohol, and more specifically at least one
branched or straight chain C2-C8 alkanol, preferably
ethanol, isopropanol and n-butanol. Ethanol is
particularly preferred. A mixture of different alcohols
may also be contemplated.
Lastly, this ternary solvent system comprises at
least one glycol. A glycol here is a compound which has
at least two hydroxyl functions. The invention relates
more particularly to glycols whose two hydroxyl
functions are free, which is to say that they are not
engaged in an ether or ester linkage. Such glycols
include, for example, propylene glycol, butylene
glycol, hexylene glycol, ethylene glycol and
polyethylene glycols. Propylene glycol is preferred. A
mixture of different glycols may also be contemplated.
Advantageously, the ternary solvent system
represents at least 60%, or even 70%, 80%, or, indeed,
even 90% (w/w) of the total composition.
Moreover, and advantageously, the proportion of
alcohol is greater than or equal to that of glycol.
Even more advantageously, the total proportion of
water is greater than that of glycol.
Generally speaking, a pharmaceutical or
dermatological composition according to the invention
takes the form of a solution. It may equally be
formulated as a lotion, spray, emulsion, foam or gel,
which advantageously is fluid.
The composition according to the invention may
also include at least one additive selected from the
group consisting of:
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- preservatives, such as phenylethyl alcohol,
benzyl alcohol and phenoxyethanol, parabens and
derivatives;
- antioxidants, such as butylated hydroxyanisole
(BHA), butylated hydroxytoluene (BHT), palmityl
ascorbate, alpha-tocopherol and/or its esters;
- dyes, fillers or pigments, such as the titanium
micas commonly used in the cosmetics field for
producing nail varnish;
- polymers capable of preventing the flow of the
composition before penetration, such as, for
example, alkylcellulose derivatives, especially
methylcelluloses, ethylcelluloses and hydroxy-
alkylcelluloses, such as those sold under the
name "KLUCEL";
- chelating agents such as disodium edetate
(EDTA) ;
- emollients such as cyclomethicone;
- antiseptics, especially acetic acid or
chlorhexidine.
The amounts of each of these additives are readily
determined by a person skilled in the art.
As already stated, a composition according to the
invention is particularly adapted for the treatment of
onychomycoses transungually. Hence it is intended for
application to the surface of the nail.
WORKING EXAMPLES
The invention and its attendant advantages will
emerge more clearly from the working examples which
follow. In no case, however, are these examples
limitative.
In these examples, the following compounds were
tested:
- antifungal agent = terbinafine hydrochloride
(terbinafine HC1);
- water = purified water;
- alcohol = ethanol;
- glycol = propylene glycol.
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1/ Demonstration of synergy of the ternary solvent
system for the dissolution of the antifungal agent:
Different solubility tests on terbinafine HC1 were
carried out in different solvent systems. The
solubility was both estimated visually by Method 1
below, then quantified by HPLC assay by Method 2 below.
Method 1: Dissolution of the terbinafine HC1
Terbinafine HC1 is weighed out accurately into a
20 ml flask and then the solvents are added. The flask
is subsequently placed, with magnetic stirring, in a
chamber thermostated at 20 C, for 16 h. If some of the
active ingredient has not dissolved, a further addition
of solvent is made. The flask is then placed again,
with magnetic stirring, in the thermostated chamber,
for 16 h, until dissolution is complete. If this is not
so, the preceding step is repeated.
Method 2: Quantification of the terbinafine by HPLC
PREPARATION OF SOLUTIONS:
Diluent:
Solvent Acetonitrile Ultrapure water
Volume 50 50
Stock solutions
Solution A (300 }gig/ml)
Weigh out precisely approximately 15 mg of
terbinafine HC1 into a 50 ml volumetric flask. Dissolve
in the diluent and make up to the volume with the same
solvent. Prepare the solution in duplicate (Al. A2)
Daughter solution (60 }gig/ml)
Dilute solution A to 1/5 in the diluent. Dilution
A1=>STD1, dilution A2=>STD2
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Standard range
The standard range is produced by varying the
injection volume of solution A, at an equivalent
concentration of 4 }gig/ml to 120 }gig/ml.
Sample solutions
2 tests per sample are prepared, of concentrations
from 40 }gig/ml to 100 }gig/ml.
OPERATING CONDITIONS
Eluent phase
Mixtures/solvents Acetonitrile Methanol Water Triethylamine
(ml) (ml) (ml) (ml)
Path A 99 0 0 1
Path B 0 100 0 0
Path C 0 0 99 1
Parameters of the chromatography system
Column: Sun Fire C18 4.6 x 100 mm 3.5 }gym,
fitted with a precolumn.
Column temperature: 30 C
Flow rate: 1.5 ml/min
Injected volume: 30 pl for the sample solutions
Analysis time: 10 min
Detection at: 285 ran
Gradient:
Time (min) Path A (%) Path B (%) Path C (%)
0 60 20 20
7 80 20 0
9 80 20 0
9.1 60 20 20
10 60 20 20
Chromatography system conformity test
Inject the control solution STD 6 times, and, on
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the peak of the assayed active ingredient, measure the
following parameters:
Parameter: Limit: Tolerance:
Retention time: approximately: +/- 1 min
5.73 min
Repeatability of areas: < 2% -
CV (s6/mean):
Peak symmetry: 0.8 to 1.4
Number of theoretical > 10 000/column
plates (mean) :
5 - Inject a blank sample (diluent) and check that
no peak of the blank sample interferes with the
terbinafine HC1.
- Inject solutions STD1 and STD2 and check that
the % deviation between the 2 controls is < 2%.
A/ Binary solvent system:
A-1/ Ethanol/propylene glycol
- In ethanol, the visual solubility of the
terbinafine HC1 is 19.7% w/w, confirmed at 18.09%
w/w by HPLC assay;
- In propylene glycol, the visual solubility of
the terbinafine HC1 is 8.9% w/w, confirmed at
10.3% w/w by HPLC assay;
- In a 50/50 ethanol/propylene glycol mixture, the
visual solubility of the terbinafine HC1 is 23.3%
w/w, confirmed at 20.4% w/w by HPLC assay.
In conclusion, although propylene glycol is not as
good a solvent of the terbinafine HC1 as is ethanol,
the solubility obtained in the binary mixture is
slightly greater than that obtained in ethanol. By
additive effect, the expected solubility of the
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terbinafine HC1 would have been of the order of 14%.
The fact that a solubility of the order of 20% is
measured demonstrates the existence of a synergy in the
dissolution of terbinafine HC1 between propylene glycol
and ethanol.
A-2/ Water/ethanol
In water, the visual solubility of the terbinafine
HC1 is 0.6% w/w.
In the case of a binary water/ethanol mixture
(50/50), the visual solubility of the terbinafine HC1
is 16.7% w/w, in other words below that obtained with
ethanol alone.
A-3/ Water/propylene glycol
In the case of a binary water/propylene glycol
mixture (50/50), the visual solubility of the
terbinafine HC1 drops to 2.2% w/w, i.e. slightly less
than that obtained with propylene glycol alone.
In conclusion, in the binary water/propylene
glycol and water/ethanol mixtures, the water lowers the
solubility of the terbinafine HC1 by comparison,
respectively, with the solubilities obtained in
propylene glycol and in ethanol.
B/ Ternary solvent system:
When 15% of water is introduced into a mixture
composed either of 70% of propylene glycol and 15% of
ethanol, or of 70% of ethanol and 15% of propylene
glycol, the visual solubility of the terbinafine HC1
goes up, surprisingly, and reaches 25.0% w/w and 25.2%
w/w, respectively.
In conclusion, and in contrast to any expectation,
the introduction of water (qs 100%) into a binary
propylene glycol/ethanol mixture (70/15 or 15/70)
increases, surprisingly, the solubility of the
terbinafine HC1, although water is a poor solvent per
se for terbinafine HC1. There is therefore a synergy,
in terms of dissolution, of terbinafine HC1 in a
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ternary propylene glycol/ethanol/water mixture.
In order to come close to optimal conditions for
transungual application, namely a large amount of water
in the pharmaceutical composition and an amount of
terbinafine HC1 of at least 10%, the amount of water
was then increased to 30% in the presence of equivalent
amounts of 35% of propylene glycol and 35% of ethanol.
Under these conditions, the visual solubility of
the terbinafine HC1 is then 18.5% w/w, i.e. well above
10%, a concentration determined as being optimum in
terms of the biological activity of the active
principle.
When the amount of water is increased to 33% in
the presence of equivalent amounts of propylene glycol
(33%) and ethanol (33%), the visual solubility of
terbinafine HC1 is 15.5% w/w, i.e. still above 10%.
In conclusion, it appears that water, which is
desirable for providing moisture to the nail in the
intended application, and hence promoting improved
spreading of the antifungal agent within the nail
matrix, makes it possible to increase the solubility of
terbinafine HC1, in spite of its poor solvency for this
antifungal agent. This increase in solubility is
dependent on the combination propylene glycol and
ethanol.
As already seen above, in a binary water/propylene
glycol or water/ethanol mixture, the water reduces the
solubility of the terbinafine HC1. Therefore, only the
combination of a ternary water/propylene glycol/ethanol
mixture makes it possible to increase the solubility of
terbinafine HC1. It has thus been shown that the
solubility of terbinafine HC1 is greater than 10% in a
ternary water/propylene glycol/ethanol mixture
containing at least 30% of water (Graph 1).
The solubility of terbinafine remains greater than
10% with 40% of water, with the proviso that the amount
of ethanol is at least greater than or equal to that of
the propylene glycol.
It has thus been possible to define the
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proportions of a ternary propylene glycol/ethanol/water
mixture that allow at least 10% of terbinafine HC1 to
be dissolved, and in which the total amount of water is
at least 30%, an amount of water necessary for
obtaining improved spreading of the terbinafine within
the nail matrix.
2/ Compositions based on the ternary solvent
system:
The ternary solvent system as defined allowed
various formulations to be produced, containing
substantial amounts of terbinafine HC1, with no
solubility problem. The examples below are given by way
of illustration, and are not at all limitative.
For each example, the formula is expressed as a
function of the percent of each ingredient used as sold
(1st column).
The formula is also expressed by taking account of
the water present in each ingredient. In this case, the
% corresponding to the ingredients are considered to
add up to 100% (2nd column).
The formulations are prepared by following procedure:
Step 1: Dissolve the hydroxytoluene in ethanol.
Step 2: When the Butylhydroxytoluene is fully
dissolved, add successively:
PROPYLENE GLYCOL
PURIFIED WATER
EDTA
Stirring until complete solubilization of EDTA.
Step 3: add terbinafine HCL mixture obtained in step 2.
Let stirring until complete solubilization.
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Example 1:
Ingredients (w/w) Formula Formula
(% per (% taking account
ingredient) of the water
present in each
ingredient)
Terbinafine HC1 10% 10%
Purified water 34.17% /
Total water (purified / 34.17 + (35.53 X
water + water present 0.05) = 35.95%
in the ingredients)
Propylene glycol 20.25% 20.25%
Ethanol 100% / 35.53 - (35.53 X
0.05) = 33.75%
Ethanol 95-96% 35.53% /
Butylated 0.04% 0.04%
hydroxytoluene
EDTA 0.01% 0.01%
The physical and chemical stabilities were
measured for 3 months at room temperature and at 40 C.
Physical stability:
Specifications at TO
Macroscopic appearance: clear, colourless solution
Microscopic appearance: absence of crystals of
terbinafine HC1
Time- T 1 month T 2 months T 3 months
Stability
conditions,
TA in line with in line with in line with
specifications specifications specifications
40 C in line with in line with in line with
specifications specifications specifications
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Chemical stability:
Time- T 1 month T 2 months T 3 months
Stability
conditions,
TA 99.6% 99.9% 96.4%
40 C 97.2% 100% 99.8%
Example 2:
Ingredients (w/w) Formula Formula
(% per (% taking account
ingredient) of the water
present in each
ingredient)
Terbinafine HC1 10% 10%
Purified water 33.67% /
5
Total water (purified / 33.67 + (35.53 X
water + water present 0.05) = 35.45%
in the ingredients)
Propylene glycol 20.25% 20.25%
Ethanol 100% / 35.53 - (35.53 X
0.05) = 33.75%
Ethanol 95-96% 35.53% /
Hydroxyethylcellulose 0.50% 0.50%
Butylated 0.04% 0.04%
hydroxytoluene
EDTA 0.01% 0.01%
The physical and chemical stabilities were
measured for 3 months at room temperature and at 40 C.
10 Physical stability:
Specifications at TO
Macroscopic appearance: clear, colourless,
slightly viscous solution
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Microscopic appearance: absence of crystals of
terbinafine HC1
Time- T 1 month T 2 months T 3 months
Stability
conditions,
TA in line with in line with in line with
specifications specifications specifications
40 C in line with in line with in line with
specifications specifications specifications
Chemical stability:
Time-> T 1 month T 2 months T 3 months
Stability
conditions,
TA 100.49% 97.24% 98.82%
40 C 100.1% 99.8% 100.1%
Example 3:
Ingredients (w/w) Formula Formula
(% per (% taking account
ingredient) of the water
present in each
ingredient)
Terbinafine HC1 10% 10%
Purified water 33.44% /
Total water (purified / 33.44 + (0.05 X
water + water present 31.88) = 35.03%
in the ingredients)
Propylene glycol 19.13% 19.13%
Ethanol 100% / 31.88 - (31.88 x
0.05) = 30.29%
Ethanol 95-96% 31.88% /
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Hydroxyethylcellulose 0.50% 0.50%
Butylated 0.04% 0.04%
hydroxytoluene
EDTA 0.01% 0.01%
Cyclomethicone 5% 5%
Example 4:
Ingredients (w/w) Formula Formula
(% per (% taking account
ingredient) of the water
present in each
ingredient)
Terbinafine HC1 10% 10%
Purified water 38.75% /
Total water (purified / 38.75 + (31.50 X
water + water present 0.05) = 40.32%
in the ingredients)
Propylene glycol 18.90% 18.90%
Ethanol 100% / 31.50 - (31.5 x
0.05) = 29.93%
Ethanol 95-96% 31.50% /
Hydroxyethylcellulose 0.30% 0.30%
Butylated 0.04% 0.04%
hydroxytoluene
EDTA 0.01% 0.01%
Acetic acid 0.50% 0.50%
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Example 5:
Ingredients (w/w) Formula Formula
(% per (% taking account
ingredient) of the water
present in each
ingredient)
Terbinafine HC1 10% 10%
Purified water 33.87% /
Total water (purified / 33.87 + (35.53 X
water + water present 0.05) = 35.65%
in the ingredients)
Propylene glycol 20.25% 20.25%
Ethanol 100% / 35.53 - (35.53 X
0.05) = 33.75%
Ethanol 95-96% 35.53% /
Hydroxyethylcellulose 0.30% 0.30%
Butylated 0.04% 0.04%
hydroxytoluene
EDTA 0.01% 0.01%
By using the ternary propylene glycol/ethanol/water
mixture in certain proportions, we have demonstrated
that it is possible to obtain a terbinafine HC1
solubility which is much greater than that obtained in
each solvent taken separately.
This ternary propylene glycol/ethanol/water mixture
therefore exhibits a synergistic effect in the
dissolution of terbinafine HC1 in the proportions used.
On the basis of this ternary propylene glycol/ethanol/-
water mixture, it was possible to produce stable
compositions containing a minimum of 30% of total
water, while permitting solubilization of a terbinafine
HC1 content of 10% w/w.
