Note: Descriptions are shown in the official language in which they were submitted.
~L17535~
The present invention relates to certain novel formulations of anti-
mycotic active compounds which may in themselves be known, which have a depot
action~ in spite of film formation, and a relatively high bioavailability of theactive compounds and thereby make short-term therapy possible.
Formulations of antimycotic derivatives for the treatment of mycoses
in humans, above all mycoses of the skin, have already been disclosed. Using
these formulations, a therapy period of > 21 days has been required for a com-
plete cure.
In order to shorten the period of therapy, a certain depot action and
a relatively high bioavailability of the active compounds are required, in par-
ticular to eliminate the germs and in order to achieve a mycological cure. The
known formulations are suitable for this only to a limited extent, because only
a small proportion of the available active compound is released in the liquid
volume at the site of infection. If a shortening of the period of therapy, for
example to one day and a single application, is to be achieved without a furtherincrease in the concentration of active compound, optimum bioavailability of the; active compound must be ensured.
According to the present invention we provide a formulation which com-
prises an antimycotically effective amount of an antimycotic compound and an in-ert pharmaceutical carrier containing a spreading agent, a solubilizing agent
and a fiber forming agent. In a preferred embodiment we provide a formulation ofan antimycotic active compound which comprises 2 to 10% of a spreading agent, 1
to 8% of a solubilising agent and, as a film-forming agent, a cellulose ether
(preferably hydroxypropylcellulose) which is soluble both in water and in organic
solvents. Any desired further formulation auxiliary or auxiliaries.
The formulations according to the present invention make possible
optimum release of the active compound and hence a therapy period which is
shortened to one day by high concentrations of the active compound being achieved.
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This effect is achieved by the presence of spreading-oils
and solubilising agents and by the addition of adherent
film-forming agents which allow the release of active
compounds to be increased up to ten-fold and the action
of the active compound thereby to be increased.
The formulations according to the invention, which
are elastic liquid plaster formulations, represent a new
application principle for dermal treatment of mycoses which,
in addition to being very effective in applying the active
compounds, provides, as a result of sealing the infection
site, protection against infection of the surrounding area.
The formulations according to the invention are particularly
suitable for the treatment of nail mycoses.
The formulations according to the invention can be
either a solution or a spray.
Active compounds which can be formulated in this
manner are any of the compounds having an antimyotic action,
in particular imidazole derivatives and triazole deriva-
tives. They are generally present in the agents accord-
ing to the invention in amounts of 0.05 - 1%, preferably
0.1-1%, by weight.
The active compounds with the following formulae
may be mentioned as preferred examples:
-,
~J ~
; (I) ~ C ~ clotri~.azole,
Cl
~ ~ .
::
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c,-~
(II)
trifonazole and
N
C ~ lombazole
CIII ) I C1
: Numerous. other azole derivatives h.aving an anti-
: mycotic action are known from DE-OS CGerman Published
Speclfication) 2,430,039. They can likewise be used
as active: compounds in the agents according to the inven-
; ~: : tion.
By spreading agents there are understood oilyliquids which are particularly readily distributed on
the skin. (R. Keymer, Pharm~ Ind. 32 (1970, page 77-
O ~page 81). The compounds which follow are particularlysuitable as spreading agents ~or the agents according to
the invention:~ ~
Si'l'ic'one''oi'ls of various. viscosities;
atty acid Qsters, such as ethyl stearate, di-n-butyl
~ ~ .
adip.ate, lauric acid hexyl ester, dipropylene glycol
: ~ pelargonate, esters of a branched fatty acid of medium
chain.length with saturated Cl6-Cl8-fatty alcohols~ iso-
propyl myristate, isopropyl paImitate, caprylic/capric
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acid esters of saturated fatty alcohols of C12-C18 chain
length, isopropyl stearate, oleic acid oleyl ester, oleic
acid decyl ester, ethyl oleate, lactic acid ethyl ester,
waxy fatty acid esters, such as synthesised duck uropygial
5 gland fat, dibutyl phthalateg adipic acid diisopropyl
ester and ester mixtures related to the latter;
Trigly-c _ des, such as caprylic/capric acid triglyceride,
triglyceride mixtures with vegetable fatty acids of C8-C12
O chain length or other specially selected naturally occur-
10 ring fatty acids, partial glyceride mixtures of saturated
or unsaturated fatty acids which optionally also contain
hydroxyl groups and monoglycerides of C8/C10-fatty acids,
Fatty alcoh'ols, such as isotridecyl alcohol, cetyl
stearyl alcohol and oleyl alcohol, and
15 F'atty''a ids, such as oleic acid.
' ~he compounds which follow are particularly suit-
able spreading~oils: isopropyl myristate, isopropyl
palmitate, isopropyl stearate, caprylic/capric acid esters
of saturated fatty alcohols of C12-C18 chain length, waxy
20 fatty acid esters, such as synthesised duck uropygial gland
fat, silicone oils, an isopropyl myristate/isopropyl
palmitate/isopropyl stearate mixture and coconut oil acid
isopropyl ester.
; Preferred suitable solubilising agents for use in
the formulations according to the present invention are:
; benzyl alcohol, 2-octyl-dodecanol, polyethylene glycols,
phthalates, adipates, propylene glycol, glycerol, di-
propylene and tripropylene glycol and waxes, and other
additives used in cosmetics.
3 Possible gel-forming and film-forming agents are
cellulose ethers which can dissolve or start to swell both
in water and in c.~ganic solvents and form a type of film
` after drying.
Hydroxypropylcellulose is particularly suitable.
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S354
Other suitable cellulose ethers are, for example,
methylcellulose, ethylcellulose and soluble starches.
Suitable solvents are water and any of the water- ~
miscible solvents. Possible solvents are, for example,
alkanols (such as ethanol and isopropyl alcohol), propyl-
ene glycol, Methylcellosolve, Cellosolve, esters,
morpholines, dioxane, dimethylsulphoxide, dimethyl-
formamide, tetrahydrofuran and cyclohexanone.
One or more solvents can be employed in the pre-
paration of the formulations ac.cording to the invention.
The auxiliaries which follow can, in`ter alia, beused as appropriate in practice to establish an optimum
formulation: glycerol~. viscous paraffin, highly liquid
paraffin,. triethanolamine, collagen, allantoin,
novantisolic acid and perfume oils.
Further auxiliaries which are suitable are:
(a) Sub.stances which, for example, can stabilise a sus-
pension, for example colloidal silicic acid or montmorillo-
nitesj
(b) Surface-act.i~e agents (including emulsifiers and
wetting agents), for example
l. anionic surface-active agents~ such as Na
lauryl sulphate, fatty alcohol ether-sulphates and the mono-
~. ethanolamine salts of mono-/di-alkyl polyglycol ether-
:~ 25 orthophosphates;
~ :~ 2. cationic surface-active agents, such as cetyl
.~ trimethylammonium chloride;
~: : 3. ampholytic surface~active agents, such as di-Na-
N-lauryl-~-iminodipropionate or lecithin; and
3 4.- non-anionic surface-active agents, for example
polyoxyethylated castor oil, polyoxJethylated sorbitane
monooleate~ sorbitane monostearate, cetyl alcohol, glycerol
monostearate, polyoxyethylene stearate and alkylphenol
polyglycol ethers,
(c) Stabilisers for preventing the chemical degradation
.
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which occurs in the case of some active compounds, such
as antioxidants, for example tocopherols and butyl-
hydroxyanisole; and
(d) Aqueous solutions which have been rendered acid can
be stabilised by the addition of preservatives which are
customary in cosmetics, for example p-hydroxybenzoic acid
esters, ~ '
The following Examples illustrate formulations
according to the present invention (in these Examples
"~.W," indicates the weight average molecular weight),
EXa'mp'l'e 1
Trifonazole 1,0 g
Benzyl alcohol 5.0 g
Hydroxypropylcellulose (M,W, 60,000~10,0 g
15 Isopropanol' to 100 ml
The individual components were mixed with one
another at room temperature and thereby dissolved, The
formulations. of Examples 2 to 8 were prepared in the same
way,
Example' 2
Trifonazole 0,1 g
Benzyl alcohol 5.0 g
Isopropyl myristate 6,o g
Hydroxypropylcellulose (M,W, 60,000~10,0 g
25 Isopropanol to 100 ml
Example 3
: Trifonazole 1,0 g
~ ~ Benzyl alcohol 4,0 g
: Isopropyl stearate 10,0 g
: 3 Hydroxypropylcellulose CM.W, 60,000) 12,0 g
~ Isopropanol to 100 ml
:: Examp'l`e' 4
Lombazole 1,0 g
1,2-Propylene glycol 1,0 g
~ 35 Isopropyl myristate 6.o g
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Hydroxypropylcellulose (M.W. 60,000) 10. 9
Isopropanol to 100 ml
Example 5
Lombazole 0.1 9
Benzyl alcohol 5.0 9
lsopropyl myristate 6.0 9
Hydroxypropylcellulose (M~Wo 60,000) 10.0 9
Isopropanol to 100 ml
~.
Clotrimazole 1.0 9
Benzyl alcohol 5.0 9
Isopropyl myristate 6.0 9
Hydroxypropylcellulose (M.W. 60,000) 10.0 9
15 Isopropanol to 100 ml
i ~
Lombazole 1.0 9
Benzyl alcohol 8.0 9
Isopropyl myristate/isopropyl s-tearate/
20 isopropyl palmitate 1.0 9
Hydroxypropylcellulose (M.W. 60,000) 10.0 9
Isopropanol to 100 ml
Example 8
Clotrimazole 1.0 9
25 Benzyl alcohol 5.0 9
Isopropyl myristate 6.0 9
Methylcellulose 10.0 9
Isopropanol to 100 ml
Example 9
Spra~y~sl
The active compound solutions prepared according to
Examples 1 to 8 coul~ also be processed to sprays. For
this purpose, for example, 60 to 90O of active compound
solution was mixed with 10 to 40O of a customary propel-
lant, for example N2, N20, C02, propane, butane or a
halogenated hydrocarbon.
;
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The following Example illustrates the activi-ty of
certain formulations according to the present invention.
Example A
Testing the activity of the formulations according to the
______________ ______=_______ _____________ __ ________
invention on Trichophyton-infected guineapigs.
______________________________________________
' Trichophyton-infected Pirbright white guineapigs
with an average weight of 600 9 were used as ~ test model
for a comparative examination of the activity of the
agents according to the invention. The backs of the -
animals were shaved with electric hair-clippers such,that
hair stubbie about 1/10 mm long remained.
Infection with Trichophyton mentagrophytes was
effected by lightly rubbing in a spore suspension of the
pathogen,, which had been initially germinated for 24 hours
in Sabouraud nutrient solution, over an approximately
2 x 2 cm area of the shaved back of the animals. 0.5 ml
of germ suspension, which contained 1 - 3 x 105 infec-
tious fungus particles, were applied per animal.
In the case of this mode of infection, the first
symptons of dermatophytosis show as reddening and scaling
of the skin 2-3 days after infection. In the case of
untreated animals, the dermatophytosis is most pronounced
about 1~ days after infection. Loss of hair in patches
and bloody integumentary defects within a phlogistically
changed, scaly edge zone.
The formulations to be tested were applied locally
once, on the 2nd day after infection, to the reddened
infection sites on the animals. In each case 0.5 ml of
the formulations (= 5 mg of active compound as 1o strength
formulation) was applied. The course of the infection was
evaluated daily up to the 20th day after infection.
The results are given in the following Table (in
which + = weak action, ++ = action, +++ = good action,
++*+ = very good action).
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Action on Trichophyton-
Agent_of Example infected guineapigs
++++
2 +++
3 +++
4 +~+
~ +
6 ++++
7 +++
8 +++
When formulations which contained water-insoluble polymers, for
example methacrylates, instead of cellulose ethcrs were used instead of the
formulations according to the invention, the mycosis was aggravated.
When formulations which, in addition to the active compound, contained
only water-soluble cellulose ethers and neither spreading agents nor solubilising
ag-nts were used, only a weak action was achieved.
