Note: Descriptions are shown in the official language in which they were submitted.
The present invention relates to certain novel antimycotic formula-
tions of antimycotic active compounds ~hich may in tllemselves be Xnown WhiCll
have a relatively good release of the active compoullds ancl tllereby m:l~e
short-term therapy possible.
Formulations of alltilllycotic ~Ic~rlv;l-tives for the treat:lllellt of mycos-
es in hummls above all mycoses of thc~ s1~in and of cllcallcous ap l-elld;lges, llave
already beell disclosed. llsillg those k`orlll~lla~iolls a ehcrnl)y period ot` 1-~ to
2l days hlls been re(lll:ired for a complete cllre.
ln order to shorten the perlo(l of theral~y ~or e~ ple in the case
of vaginal or buccal mycoses or dermatolllycoses a relatively good release of
the active compounds in an aqueous medium is required in particular to eli-
minate the germs and in order to achieve a mycologically certain cure~ The
known formulations are suitable for this only to a limited e~tent 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 e~cample to one day and a single application is to be achieved
ith or ~ithout a further increase in the concelltration of active compoulld~
optimum bioavailabill-ty of tlle active compoulld must be ensllred.
Accordillg to tlle present inve;ltio~ e provide an ;ntimycotic formu-
lation ~hich coDlprises an antilllycotically effective amollllt of a compoulld ~ to
5% of benzyl alcollol anl ~5 to ~O!li of a spren(ling agent~ Tlle formulation
may also contaill furtller formulatioll au~ili;lries~
The formulatiolls of the presel~t in~Selltioll rele;lst tlle active com-
pound -to a higher degree and thereby ma~e it possille to shorten the periocl
of tllerapy to 1 day. This et`fect of better rele.lse of tile active compo~md
can be as
--1--
much as ten-fold.
Active ccmpounds which can be farmulated in this
manner are any oF the compounds having an antimycotic
action, in particular imidazole derivatives and triazole
derivatives. They are generally present in the agents
according to the invention in am~unts oF 0.05O to l~,
0.1 to 'IO~ by w~ight.
The active compounds wlth the following Formulae may
be mentioned as preFcrrecl ~amples:
~3
(I) ~G_Ç3 clotri}~ .ol-,
~Cl
~ C~
(II)
~rifon~Ol~ and
~ C ~ lolilbarrol~.
CIII ) ¦ Cl
~I-
Le A ~0 573
D6~
Numerous other azole derivatives having an anti-
mycotic action are known from DE-OS (German Published
Specification) 2,430,039. They can li~ewise be used
as active compounds in the agents according to the inven-
tion.
By spreading-agent~ there are understood oily liquids
wl-ich are particularly readily distributed on the s~in
[R. I(eymer, Pharm. Ind. 32 [1970~, 577-58l]. The compounds
which follow are partlcularly suitable as sprendin~ agents
t`or the agents according to the~ invention:
Sllicone olls of various viscosities;
-
Fatty acid esters, such as ethyl stearate, di-n-butyl
. .
adipate3 lauric acid he~yl ester, dipropylene glycol
pelargonate, esters of a branched fatty acid of medium
chain length with saturated C16-C18-fatty alcohols, iso-
propyl myristate, isopropyl palmitate, caprylic/capric
acid esters of saturated fatty alcohols of C12-C18 chain
length, isopropyl stearate, oleic acid oleyl esterS oleic
acid decyl ester, ethyl oleate, lactic acid ethyl ester,
waxy fatty acid esters, such as synthesised duck uropygial
gland fat, dibutyl phthalate, adipic acid diisopropyl
ester and ester mixtures related to the latter;
rides, such as caprylic/capric acid triglyceride,
triglyceride mi~tures with vegetable fatty acids of C8-C12
chain length or other specially selected naturally occur-
ring fatty acids, partial glyceride mi~tures of saturated
or unsaturated fatty acids which optionally also contain
hydro~yl groups and monoglycerides of C8/C10- fatty acids;
Fatty alcohols, such as isotridecyl alcohol, 2-octyl-
dodecanol, cetyl stearyl alcnhol and oleyl alcohnl; andFatty acids, such as oleic acid.
The compounds which follow are particularly suitable
spreading-oils: isopropyl myristate, isopropyl palmitate,
caprylic/capric acid ester~ of saturated fatty alcnhols of
C12-Cl~ chain length 3 wa~y fatty acid esters ~such as
Le_A 20 573
6~
- 4 -
synthesised duck uropygial gland fat), silicone oils and
an isopropyl myristate/isopropyl stearate/isopropyl
palmitate mixture.
The Following other auxiliaries and/or formulation
base auxiliaries can be used in the preparation of the
agents according to th~ invention.
"Glyceryl stearates"t a mixture oil-:in-water cream
of mono- and di-glycerides of base~ not self-
palmitic acid and stearic acid ~mulc3i~ying
10 Colloidally clisperse mi~ture oil~in-watcr emulsion
oF cetyl stearyl alcohol and base, self`-
sodium cctyl-stearyl sulphate emulslfying
Esters of a branched fatty acid oil component with a
15 wi-th saturated C16-C18~fatty pronounced hydro-
alcohols phooic effect for
sl<in-protection
products
20 Cetyl palmitate artificial spermaceti,
consistency for
creams, ointments,
emulsions
Polyethylene stearate non-ionic hydrophilic
emulsifier
Cetyl stearyl alcohol o~y- non-ionic oil-in-water
ethylated with about 1'~ mol emulsifier
of ethylene n~ide
30 Cetyl stearyl ~lcohol ~y- non-ionic oil-in-wate~
ethylated with about 30 mol emulsifier
of ethylene o~ide
e A 20 573
sorbitane and glycerol fatty non ionic emulsifier
acid ester
Slightly crosslinked poly- sweller, thic~ener and
acrylic acid of stabiliser
extremely high molecular
weight
Furthermore, the following formulat.ion au~iliarias
can also be used: glyccrol, viscous paraffin, highly
liguid parafFin, triethanolanline, co.llagen, allantoil-,
novant.isolic acicl and perfumc oils.
Further compounds which are suitable au~iliaries are:
(a) Substances which, for e~ample, can stabilise a sus-
pension, for e~ample colloidal silicic acid or montmorillo-
nites;
(b) Surface-active agents (including emulsifiers and
wetting agents), for example
.1. anionic surface-active agents, such as Na lauryl
sulphate, fatty alcohol ether-sulphates and the mono-
ethanolamine salts of mono-/di-alkyl polyglycol ether-
orthophosphates;
2. cationic surface-active agents, such as cetyl tri-
methylammonium chloride;
3. ampholytic surface-active agents, such as di-Na-N-
lauryl-~-iminodipropionate or lecithin; and
4. non~anionic surface-active agents, for example
polyo~yethylated-castor oil, polyo~yathylated sorbitanr
mono-oleate, sorbitane monost~srate, cetyl alcohol/
glycerol monostearate, polyoxyethylene stearate and alkyl-
phenol polyglycol ethers;
(c) Stabilisers for preventing the chemical degradation
which occurs in the case of so,ne aCti~f~ cor..~ounds, such
as antio.~idants, for e~ample tocopherols and butyl-
hydroxyanisole; and
(d) Pl~sticisers, for e~ample propylene glycol, glycerol,
Le A 20 573
dipropylene and tripropylene glycol, triethanolamine, and
waxes.
Possible gel-forming agents which may be used as
auxiliaries are macromolecular compounds which can be
dissolved or partially swollen both in water and in organic
solvents and Form a type of film after drying.
If the macrornolecular auxlliaries are classified
C~<eipert et al., Die Pharma~ie 2~, 145-lR3 (l973~, ionic
macromolecules in salt ~`orm are used above a;ll. rhes~
are, inter alia, sodlum carbo~ymcthylcellulose, poly-
acrylic acid, polymethacrylic acid and salts thereof,
sodium amylopectin semiglycolate, alginic acid and propyl-
ene glycol alginate as the sodium salt, gum arabic,
~anthan gum and guar gum~
Amphoteric macromolecules, such as protein deriva-
tives, for example gelatin, are just as suitable as non-
ionic polymers, for example methylcellulose, hydroxy-
propylcellulose and soluble starches, which fulfil the
above requirements.
Suitable solvents which may be present in the formula-
tions of the present invention are water and any of the
water-mixcible solvents. Possible solvents are, for
e~ample, alkanols (such as ethanol and isopropyl alcohol),
propylene glycol, methylcellosolve, cellosolve, esters,
morpholines, dioxane~ dimethylsulpho~ide, dimethylformamide,
tetrahydrofuran and cyclohe~anone.
One or more solvents can be employed in the pre-
paration of the formulations accordiny to the present
invention.
The following E~amples I to IS illustrate formulations
according to the present :invention.
Example ~ Emulsion, oil-in-water.
Phase I
"Glyceryl stearates" (mi~ture of mono- and
di-clycerides of palmitic and stearic acid) 8 .00 9
Le A 20 573
2-Octyldodecanol 10.00 g
Cetyl stearyl a].cohol oxyethylated
with about 12 mol. of ethylene o~cide1.50 g
Cetyl stearyl alcohol o~ye-thylatecl
Witil about 30 mol. of etllylellc o~;;ide l~5n ~
I~araffin, viscous 6.()n g
.1,2~ ropylclle glyco:l 5.0() g
Capry:lic/cal)ric ac:icl t~ glYcc~ :i.cle ~.0() g
Tllc mi~t-lre is stlrrccl, and meltcd at 70C.
Pllase II
Water, demilleralisecl 5S.OO g
Phase III
Clotrimazole, 1.00 g
dissolved in benzyl alcohol .00 g
Phase I, which had been warmed to 70C, was aclded "~ith stirring,
to Phase II, ~Yhich had been warmcd ~o 75C. The mi~ture ~as allow2d to cool
slowly to 40C, phase III was added and the mi~ture was c.ooled to room temp-
erature, ~Yith stirring. The crude emulsion ~Yas holllogenisecl at 20 to '5C in
a high-pressure homogeniser~
~0 Examples 2 to 6 an(l 12 to 15 are pr-cessed :in all alr.llogolls maoller.
Emulsioll, oil-in-~Yater
~icrollisecl ~rifolln~ole I ~ on
"Glyceryl steara~es", m.i~ture o:~ mollo-allcl .I.i-g~lycericles
of palmitic alld stearic ncid '1.OO g
etyl stearyl alcollol o~yethyl;ltecl~Yitll abollt l' mol.
o~ ethylelle o~ide 3 00 g
2-Octyldodecanol 10.00 g
--7--
Viscous paraffin
5.00
Benzyl alcohol
Demineralised wa~er
to 100 ml
-7a_
-- 8 --
Example 3 Emulsion, oil-in-water
Micronised trifonazole l.OO g
"Glyceryl stearates", mixture of mono- and
di-glycerides of palmitic and stear.ic acid 9.00 9
Cetyl stearyl alcohol o~yethylated with
about 12 mol. o~ ethylene oxide3.00 g
2-Octyldodecanol IO.OO g
Benzyl alcohol 5.00 9
Isopropyl myr.;state 5 00 9
.lO Demineralised ~vater to lOO ml
Exan~ ~4 Cream, soft consistency, oil-in-water
Micronised clotrimazole I.OO g
"Glyceryl stearates", mixture of mono- and
dl-glycerides of palmitic and stearic acid 4.00 9
15 Cetyl palmitate 4.00 9
Cetyl stearyl alcohol oxyethylated with
about 12 mol. of ethylene.oxide1~00 g
Cetyl stearyl alcohol oxyethylated with
about 30 mol of ethylene oxide1~00 g
20 Isopropyl myristate/isopropyl palmitate,
isopropyl stearate mixture 5.00 9
Slightly crosslinked polyacrylic acid of
extremely high M.W. o 50 g
45O strength sodium hydroxide 0.11 g
25 Glycerol 3.00 9
Ben~yl alcohol 3.00 g
Demineralised water to lOO ml
~ Cream, soft consistency, oil-in-wster
~licronised clotrima~sIe l.OO g
l'Glyceryl stearates", mi~ture of mono- and
di-glycerides of palmitic and stearic acid 4.00 g
Cetyl palmitate 4.00 g
35 Cetyl stearyl alcohol o~yethylated with
Le A 20 573
.
about 12 mol. of ethylene oxide 1.00 9
Cetyl stearyl alcohol oxyethylated with
about 30 mol. of ethylene oxide l.00 9
Isopropyl myristate/isopropyl palmitate/
isopropyl stearate mi~ture 5.00 9
Slightly crosslinl<ed polyacrylic acid of
extremely high molecular weight 0.50 9
45O strength sodium hydro~ide 0.11 9
Glycerol 3.00 9
Ben~y:l alcohol ~.00 9
Demineralised water to 100 ml
Exall!ple 6 Cresm, soft consistency, oil-in-water
Micronised trifonazole 1.00 g
"Glyceryl stearates", mixture of mono- and
15 di-glycerides of palmitic and stearic acid '~.00 9
Cetyl palmitate 4.00 9
Cetyl stearyl alcohol oxyethylated with
about 12 mol. of ethylene o~ide 1.00 9
Cetyl stearyl alcohol oxyethylated with
about 30 mol~ of ethylene oxide 1.00 g
Isopropyl myristate/isopropyl palmitate/'
isopropyl stearate mixture 5.00 9
Slightly crosslinked polyacrylic acid of
extremely high molecular weight 0.50 g
45~0 strength sodium hydroxide 0.11 9
Glycerol 3.00 9
Benzyl alcohol 3.00 9
Demineralised water to 100 ml
Example 7 Emulsion, non-greasy, oil-in-water
Phase I
ûleic acid decyl Pster ~.5n 9
Isopropyl myristate ~.50 9
Paraffin, highly liqwid 4.00 9
Polyethylene stearate 0.90 9
35 Sorbitane and glycerol fatty acid esters 0.60 9
Le A 20 573
-- 10 -
The mixture is stirred and melted, at 70C for 10
minutes.
Phase II
Water, demineralised 50.00 9
Allantoin 0.10 9
Carbopol mucus
Alcohol, denat~red 10~00 o
Carbopol 934 (slighly crosslinked
polyacrylic acicl) 0.70 ~
~o Water, demineralised 2_.945 9
A disperslon was obtained with a "Turra~" and the
dispersion was allowed to swell for 2 hours and then
neutralised with 0.155 9 of 45~ strength sodium nydro~ide
solution.
Phase I, which had been warmed to 70C, was added,
with stirring, to phase II, which had been heated to 75C,
and the mixture was cooled to 45C. The carbopol mucus
was stirred in at 45C and cooled further to 40C.
l.00 9 of collagen was added at 40C and cooled to 25C.
Then l~0 9 of lomba~ole was dissolved in 3.0 9 of ben7yl
alcohol and the solution was added to phase I and II.
0.600 9 of perfume was then added and the crude
emulsion was homogenised, with stirring, in a high-
pressure homogeniser at 20C to 25GC.
Examples 8, 9, 10 and 11 were processed in an
analogous manner.
Example 3 Emulsion, non-greasy, oil-ln-water
~licronised lamba7ole 0.10 9
Oleic acid decyl ester 2.50 9
30 Isopropyl myristate 2.50 9
Highly liquid paraffin 4.00 9
Polyethylene stearate 0.90 9
Sorbitane and glycerol fatty acid esters 0.60 9
35 Allantoin û.10 9
Le A 20 573
45O strength sodiuln hydroxide 0.155 9
Slightly crosslinked polyacrylic acid of
extremely high molecular weight0.70 9
Collagen l.G0 9
Benzyl alcohol 3.ûO g
Ethanol lO.00 9
Perfume oil 0.63 g
Demi.nerallsed water to lno ml
E~ample 9 Emulslon, non-greasy~ oll-.in-water
10 ~llcronised lombazole O.û5 g
Oleic acld decyl ester 7. sn 9
Isopropyl myristflte 2.50 9
Highly liquld paraffin 4.00 9
Polyethylene stearate 0.90 9
15 Sorbitane and glycerol fatty acid esters 0.60 9
Allantoin 0.10 9
Slightly crosslinked polyacrylic acid
of extremely high molecular weight 0.70 9
45O strength sodium hydroxiden. 155 9
20 Collagen 1.00 9
Benzyl alcohol 3.00 9
Ethanol 10.00 9
Perfume oil 0.60 9
Demlneralised water to lO0 ml
Example 10 Emulsion, non~greasy, oil-in-water
Micronised trifonazole 0.10 9
Oleic acid decyl ester 2.50 9
Isopropyl myristate 7.50 9
Highly liquid paraffin 4.00 9
30 Polyethylene stearate 0,90 9
Sorbitane and glycerol fatty acld esters 0.60 9
Allantoin 0.10 9
45O strength sodium hydroxide0.155 9
Slightly crosslinked polyacrylic acid
35 of extremely high molecular weight 0.70 g
Le A 20 573
- 12 -
Collagen 1.00 9
Benzyl alcohol 3.00 9
Ethanol 10.00 g
Perfume oil 3.60 9
Deminerali~ed water to lO0 ml
Example l1 Emulsion, non-greasy, oil-in-water
Micronised triFonazole 0 05 9
Oleic acicl decyl estcr 2.50 y
Isopropyl myrlstatc 2.50 ~
10 Highly liquid paraffln !1,00 9
Polyethylene stearate 0 90 9
Sorbitane and glycerol fatty acid esters 0.60 9
Allantoin 0.10 9
45O strength sodium hydroxide0.155 g
15 Slightly crosslinked polyacrylic acid of
extremely high molecular weight0.70 9
Collagen 1.00 9
Benzyl alcohol 3.00 9
Ethanol 10.00 9
20 Perfume oil 0.60 9
Demineralised water to 100 ml
Example 12 Cream, soft consistency, oil-in-water
Micronised trifonazole 0.10 9
"Glyceryl stearates", mixture of mono- and
25 di-glycerides of palmitic and staaric acid 4.00 9
Cetyl palmitate 4.00 9
Cetyl stearyl alcohol, oxyethylated with
about 12 mol. oF ethylene oxide1.00 9
Cetyl stearyl alcohol, oxyethylated with
about 30 mol.~ of ethylene oxide1 00 9
Isopropyl myristate/isop~pyl palmitàte~
isopropyl stea~ate mixture 5.00 9
Slightly crosslinked polyacrylic acid
of extremely high molecular weight 0.50 9
45~0 strength sodium hydroxide0.11 9
Le A 20 573
- 13 -
Glycerol 3 oo g
Benzyl alcohol 3.00 g
Demineralised water to 100 ml
Example 13 Cream, soft consistency, oil-in-water
..... _ .. .
5 Micronised trifonazole 0.05 g
"Glyceryl stearates", mi.~ture of mono- and
di-glycerides of palmitic and stearic acid ll 00 ;
Cetyl palmitate 4~0 --s
Cety:L stearyl alcohol o~yethyllted with
10 about 12 mol O.t' ethylene o~ide l.PO g
Cetyl stearyl alcohol o~yethylated with
about 30 mol of ethylene oxide 1.00 g
Isopropyl myristate/isopropyl palmitate,
isopropyl stearate mi~ture ~00 g
15 Slightly crosslinked polyacrylic acid
of extremely high molecular weight 0 50 g
45% strength sodium hydroxide 0.11 g
Glycerol 3.00 g
Benzyl alcohol 3.00 g
20 Demineralised water to 100 ml
Example 14 Cream, soft eonsistency, oil-in-water
Lombazole 1.00 g
"Glyceryl stearates", mixture of mono-and
di-glycerides of palmitic and stearic acid 4 00 g
25 Na stearate 16~0Q g
Cetyl stearyl alcohol o~yethylar~d with
about 12 mol of ethylene o~ide 3 00 g
Benzyl alcohol 3.50 ~
2-Octyldodeeanol 2~50 g
30 Coeonut oil acid isopropyl e~ter (Isc~rcpyl n~-rist~e/ 2 5~ g
isopropyl pa~nitate/iso~r~pyl ste~atell~iYt~
paraffin, highly llquld` 3.00 g
~ater~ demineralised to 100.00 ml
Exam~le- 15 (transparent cream in gel form)
Le A 20 573
- 14 -
Clotrimazole 1.00 9
Cetyl stearyl alcohol oxye-thylated with
about 30 mols of ethylene oxide14.00 ~
Coconut oil acid isopropyl ester20.00 y
2-Octyldodecanol 5.00 y
Benzyl alcohol 3.00 y
Water, demineraliseclto lO0.00 ml
The following E~ampLe illustratas the activlty of
certaln formu.Lations accorclin~ to the prascr1t lnvcl-tion.
I0 lestin~ t_e s___vitv oF the formulations acc_rd ng to tha
invention on Trichophyton-infacted yuineaeigs.
_______~______~__.___ _____________ _____ _ _,
Trichophyton-inFected Pirbright white guineapiys with
an average weight oF 600 9 were used as a test model for a
comparative examination of the activity of the formulations
according to the invention. The backs of the animals ~ere
shaved with electric hair-clippers such that hair stubble
about 1/lO mm long remained.
Infection of Trichophyton mentagrophytes was effected
by lightly rubbing in a spore suSpenSiQn 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 ~ 105 infectious fungus
particles, were applied per animal.
In the case of this mode of infection, the first
symptoms of dermatophytosis showed as reddening and scaling
of the sl<in ~-3 days after infection. In the case of un-
treated animals, the dermatophytosis wss most pronounced
about 14 days ar`ter infection: los~ of hair in patches
and bloody integumentary defocts within a phloyistically
changed, scaly edge ~one.
The formulation~ to be tested were applied locally
once, on the 2nd day after infection, to the reddened
infection.sitPs on the animals and were rubbed lightly with
a horn spatula. In each case 0.5 ml of the formulations
Le ~ 20 573
~= 5 mg of active compound as 1% strength formu1ation) was appliecd. The
course of the infectioil was evaluated da:ily up to the 30th day after infec-
ti.on.
The test rcsults can be seell from the -t~ble belo~.
~ent of ex~ Act:ion on Tr:icl~Qphyton-in~ected
U~ ig~;
4**1~
2 ****
3 ****
'I
****
6 ****
7 ****
****
9 ****
1 0
1 1
12 ***
13
2n l~ ****
****
****: very goocl actlo
*** : goo~l ~ctio
** : actioll
* : Sligllt ~ICtiOIl
O : 110 actioll
l~llell insteacl of the formulatloll~ according to the invelltioll, form-l-
-15-
lations which contained no benzyl alcohol and no spreading agent ~ere used,
an effect which corresponded to that of tile formulations according to the
invention was achieved only after three appllcations.
