AGENTS ANTIMYCOSIQUES POUR DES TRAITEMENTS GYNECOLOGIQUES EN UNE SEULE DOSE

ANTIMYCOTIC AGENTS FOR SINGLE GYNAECOLOGICAL TREATMENT

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
* * *
The invention relates to antimycotic agents
containing azole derivatives, such as clotrimazole,
bifonazole, or lombazole, with the active compounds having
a mean particle diameter of 4 to 20 µm ? 10 %, preferably
5 µm ? 10 %. The antimycotic agents of the invention
provide greater bioavailability, thus making possible single
dosage adminstration in gynaecological treatment.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An antimycotic agent with greater bioavailability of
the active ingredient which comprises as active ingredient 1 to
10% of one or more antimycotically effective azole compounds or
pharmaceutically acceptable salts thereof, in admixture with one
or more pharmaceutically acceptable formulation auxiliaries, with
a pharmaceutically acceptable acid or with a pharmaceutically
acceptable buffer system, wherein the active ingredient is present
in the form of particles whose mean size is 5 µm + 10%.
2. An antimycotic agent according to claim 1 wherein there
is present a pharmaceutically acceptable acid or a pharmaceutically
acceptable buffer system comprising an organic acid and/or its
salt.
3. An antimycotic agent according to claim 1 which contains,
as active ingredient, clotrimazole of the formula
<IMG>
4. An antimycotic agent according to claim 1 which contains,
as active ingredient, bifonazole of the formula

<IMG>
5. An antimycotic agent according to claim 1 which contains,
as active ingredient, lombazole of the formula
<IMG>
6. An antimycotic agent according to claim 1 or 2, which
is in the form of a cream.
7. A antimycotic agent according to claim 3, 4 or 5, which
is in the form of a cream.
8. An antimycotic agent according to claim 1 or 2,
characterised in that it is a spray.
9. An antimycotic agent according to claim 3, 4 or 5,
characterised in that it is a spray.
10. An antimycotic agent according to claim 1 or 2, wherein
the active ingredient is present in a suspended form.
11. An antimycotic agent according to claim 3, 4 or 5,
wherein the active ingredient is present in a suspended form.
11

12. A process for preparing an antimycotic agent according
to claim 1 which comprises admixing an antimycotically effective
azole compound or a pharmaceutically acceptable salt thereof with
one or more pharmaceutically acceptable formulation auxiliaries,
with a pharmaceutically acceptable acid or with a pharmaceutically
acceptable buffer system, the azole compound or salt thereof being
in the form of particles whose mean size is 5µm ? 10% and being
present in an amount of 1 to 10%, at a temperature between room
temperature and 70°C.
13. A process according to claim 12 wherein the azole
compound or salt thereof is subjected to comminution to obtain the
required particle size, prior to admixture with other ingre-
dients.
12

Description

2904~i
The present invention relates to novel formula-
tions of the known ant;mycot;c azole der;vat;ves, which
exh;b;t greater b;oavai~ability of the active compounds
and thus make poss;ble gynaecolog;caL treatment which need
only be administered once.
Numerous formulat;ons of ant;mycotic azole deriva-
tives have already been disclosed for the treatment of
vaginal infections with fungi. Using these formulations, 14
to 3 days of therapy are required for complete elimination
of vaginal infection. This is attributable to, inter alia,
the active compounds contained in the customary vaginal
formulations being only partly soluble ;n aqueous media.
In order to shorten the duration of therapy, it
is necessary, particularly for the elimination of the
organisms in the vag;nal d;scharge~ to have a certain
depot effect and a greater b;oava;lab;l;ty of the active
compounds. The known formulations are suitable for this
only to a restr;cted extent because only a small port;on
of the available supply of active compound dissolves in
the volume of fluid in the vagina. If the intention is
now to achieve a shortening of the duration of therapy,
for example to one day with a single administration, by
further increasing the concentrat;on of active compound,
care must be taken that the bioavailability of the active
compound is opt;mal~
It has now been found that those types of cream,
foam or spray formulat;ons of ant;mycot;c a~ole deriva-
tlves, wh;ch contain the active compound ;n a very finely
ground form, preferably in part;cle s;zes with a mean
~(~/c~ t-~s~
particle diameter of 5 ~ + 10%, the customary formulat-
ing auxiliaries and/or an acid andlor a buffer system
comprising an organic acid and/or its salts, exhibit
opt;mal release of the active compound and thus make
possible a duration of therapy shortened to a single
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administration.
Active compounds which can be formulated in this
manner are all derivatives having antimycotic activity, in
particular imidazole and triazole derivatives. They are present
in the agents according to the invention in amounts of from 1%
to 10%, preferably from 5 to 10%.
The compounds of the formulae given below may be
mentioned as examples:
I ~ C ~ clotrimazole
~ N
II ~ ~ CH ~ bifonazole
1~
~3
III ~ ~ f ~ lombazole
cN ~
Numerous other azole derivatives having anti-
mycotic activity have been disclosed in DE-OS (German Published
Specification) 2,430,039. They can likewise be used as active
compounds in the agents according to the invention.

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The present invention is therefore directed to an
antimycotic agent with greater bioavailability of the active
ingredient which comprises as 1 to 10% of one or more antimy-
cotically effective azole compounds or pharmaceutically accept-
able salts thereof, in admixture with one or more pharmaceutically
acceptable formulation auxiliaries, with a pharmaceutically
acceptable acid or with a pharmaceutically acceptable buffer
system, wherein the active ingredient is present in the form
of particles whose size is 5 ~m 1 10%.
In particular, it has been found that those types of
vaginal cream or spray formulations which contain the active
compound in a very finely ground form, that is to
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say in particle sizes 5 m~ + 10X, or contain the compound
of the formula II, and which also contain lactic acid and
calc;um acetate, or of the formulae I and III, and ~hich
also contain primary or tertiary sodium citrate, release
the active compound so optimally that a single administra-
tion can be brought to cure vaginal mycoses, for example
those caused by cand;da spec;es and torulops;s species.
These types of formulat;ons are sat;sfactor;ly tolerated.
Moreover, other buffer systems and/or the acids
or the acidic salts alone affect the formulations in the
indicated favourabLe manner. These may be as follcws:
citric acid / primary Na citrate / tertiary Na citrate
lactic acid / Na lactate
DL tartaric acid / K Na tartrate
adipic acid
ascorbic acid / 1/2 Na salt or Na salt of ethylenedi-
aminetetraacetic acid
fumaric acid
glyco/
glyc^r^lL buffer
potassium hydrogen phthalate buffer
tartrate buffer tKHC2H406)
phosphate buffer
ln this context, the customary formulating auxi-
liaries are understood to include those given belo~.
In the first place, spreading agents or o~ls are
suitable.
Silicone oils of various viscosities.
Fatty acid esters, such as ethyl stearate, di-n-butyl
adipate, hexyl laurate, dipropylene glycol pelargonate,
esters of a branched fatty acid of medium chain length
~ith saturated C16~C18 fatty alcohols, isopropyl
myristate, isopropyl palmitate, caprylic/capric esters of
saturated fatty alcohols of cha;n length C12-C18,
isopropyl stearate, oleyl oleate, decyl oleate, ethyl
oleate, ~axy fatty acid esters, such as artificial duck
preen gland oil, dibutyl phthalate, diisopropyl adipate,
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ester m;xtures related to the latter, and others.
Triglycerides, such as caprylictcapric triglycerides,
triglyceride mixtures with vegetable fatty acids of chain
length C8-C12 or other specially selected natural fatty
acids, partial glyceride mixtures of saturated or unsatu-
rated fatty acids, which may possibly also contain hydrox-
yl groups, monoglycerides of C8-C10 fatty acids, and
others.
Fatty alcohols, such as isotridecyl alcohol, cetylstearyl
alcohol or oleyl alcohol.
Fatty acids, such as, for example, ole;c acid.
Particularly well suited spreading oils are the
following: isopropyl myristate, isopropyl pa~mitate,
caprylic/capric esters of saturated fatty alcohols of
chain length C12-C18, waxy fatty acid esters, such as
artificial duck preen gland oil, silicone o;ls, and mix-
tures of ;sopropyl myristate/isopropyl stearatetisopropyl
palmitate.
Glycerol, high-viscosity paraffin and low-viscos-
ity paraffin.
The following agents are suitable as emulsifiersfor the agents according to the invention:
Polyoxyethylene-sorbitan fatty acid esters,
colloidal disperse mixture of cetylstearyl alcohol and
sodium cetylstearyl sulphate, polyethylene stearate,
cetylstearyl alcohol etherified with about 12 mol of
ethylene oxide, cetylstearyl alcohol etherified with
about 30 mol of ethylene oxide, and C16-C18 fattY a
etherified with 25 mol of ethylene oxide, sorbitan and
glycerol fatty acid esters, ethoxylated castor oil, and
cetylstearyl alcohol w;th the addition of a non-ionic
emulsifier.
The following other auxiliaries and/or formulating
bases can be used for the preparation of the agents
according to the invention:
Surfactants tincluding emulsifiers and wetting agents),
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for example
1. anionic, such as Na lauryL suLphate, fatty aLcohoL
ether suLphates, and the monoethanoLamine saLt of mono-
aLkyL/dialkyl polyglycol ether orthophosphates;
2. cationic, such as cetyltrimethylammonium chloride;
3. ampholytic, such as di-N-Na N-lauryl ~-jminodipropjon-
ate or lecithin;
Example 1
Clotrimazole active compound,
10 micronised 5 ~ ~ 10X 10.00 g
Sorbitan fatty acid ester 2.00 9
Polyoxyethylene-sorbitan fatty acid ester 1.50 9
Artif;cial spermaceti 3.00 9
CetylstearyL aLcohoL 3.50 9
15 Isopropyl myristate 13.50 9
8enzyL aLcohoL 1.00 9
Dem;neraLised water 65.50 g
Phase I.
MeLt, stir and mix up to 70C the sorbitan fatty
acid ester and part quantities of the polyoxyethylene-
sorbitan fatty acid ester, artificial spermaceti, cetyl-
stearyL alcohol and isopropyl myristate.
Phase II.
Mix benzyl alcohol with water, boil and cool to
75C.
Slowly stir phase II into phase I and cool to
25C. Dissolve phase III, that is to say the remaining
quantity of polyoxyethylene-sorbitan fatty acid ester, in
water at 50C, cool to 25C, add micronised clotrima-
zole active compound, stir, suspend and add to phase I +II.
The process is carried out in an analogous manner
for Examples Z to 5.
Example 2
35 aifonazole active compound,
micronised 5 ~ ~ 10X 10.00 g
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Sorbitan fatty acid ester 2.00 9
Polyoxyethylene-sorbitan fatty acid ester 1.50 9
Artificial spermaceti 3.00 9
Cetylstearyl alcohol 3.50 9
5 Isopropyl myristate 13.50 9
Lactic acid 1.00 g
Ca lactate 0.50 g
8enzyl alcohol 1.00 g
Dem;neralised water 64.00 g
10 Example 3
Lombazole act;ve compound,
A micron;sed 5 ~ + 10% 10.00 9
Sorbitan fatty acid ester 2.00 9
Polyoxyethylene-sorbitan fatty acid ester 1.50 9
15 Artificial spermaceti 3 00 9
Cetylstearyl alcohol 6.00 9
Isopropyl myristate 13,50 9
Lactic acid 1.00 9
Tertiary Na citrate 1.00 g
20 aenzyl alcohol 1.00 g
Demineralised water 61.00 g
Example 4
Clotr;mazole active compound,
~m
m;cron;sed 5 ~ + 10X 10.00 9
25 Sorb;tan fatty ac;d ester 2.00 9
Polyoxyethylene-sorbitan fatty acid ester 1.50 9
Art;f;cial spermacet; 3.00 9
Cetylstearyl alcohol 3.50 9
Isopropyl myr;state 13.50 9
30 8enzyl alcohol 1.00 g
Primary Na c;trate 0.03 9
Demineral;sed water 65.47 g
Example 5
8ifonazole active compound,
35 micronised 5 ~ + 10X 5.00 9
Sorb;tan fatty acid ester 2.00 9
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Polyoxyethylene-sorbitan fatty acid ester 1.50 9
Art;f;cial spermacet; 3.00 g
Cetylstearyl alcohol 6.00 9
Isopropyl myr;state 13.50 9
5 Benzyl alcohol 1.00 9
~act;c ac;d 0.50 9
Calc;um lactate 0.25 9
Dem;neral;sed water 67.25 9
The for~ulations thus made up are filled into
10 applicators.
Example 6
Part A Clotrimazole active compound,
A m;cronised 5 ~ + 10X10.000 9
Anhydrous glycerol 1.000 9
Pr;mary Na citrate 0.025 9
Deminer~alised water 84.775 9
Solbrol M 0.150 9
Part B Cetylstearyl alcohol, with the
add;tion of non-ionic emulsifier 2.000 9
Sodium cetylstearyl sulphate1.000 9
Decyl oLeate 1.000 9
Solbrol~P o.o50 9
Heat part B to 60C and stir. For part A, dis-
solve Solbrol~M at 90C, cool to 60C, and add gly-
cerol and Na citrate. Stir part A into part B under
v~acuum, add clotr~mazole at 40C, suspend and cool to
25C. Fill into aluminium canisters: 9Z parts of emul-
sion and 8 parts of propellant gas 12/114 ~40:60).
The sprays thus prepared are admin1stered in the
upside down position. Volume of foam about 40-45 ml.
Test of the efficacy of the agents according to
the invention on guinea-p;gs infected w1th tr;chophyton.
::
The test model used by us to compare the efficacy
of the formulations according to the invention was
P~rbrigth~ ~h;te guinea-pigs, of mean weight ~00 9~ wh;ch
w~ere~infected ~;th trichophyton. The backs of th`e animals
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were sheared with an electric hair cutter such that the
stubble remaining was about 1/10 mm long. Infection ~ith
Trichophyton mentagrophytes was carried out by gently
rubbing into an area about 2 x 2 cm in size on the shorn
backs of the animals a suspension of spores of the patho-
gen which had been germinated in Sabouraud's nutrient
solution for 24 hours. 0.5 ml of suspension of organisms
which contained 1 - 3 x 105 ;nfectious fungal particles
was applied to each animal.
Using th;s mode of infection, the first symptoms
of dermatophytosis emerged 2-3 days after infection as
reddening and scal;ng of the skin. The dermatophytosis
;s maximally pronounced in untreated animals about 14 days
after infect;on: areas of hair loss and bleeding damage
to the ;ntegument with;n a scaly edge zone having inflam-
matory changes.
The formulations to be tested were applied once,
on the 2nd day after infection, topically to the reddened
site of infection on the animals, and gently rubbed in
using a horn spatula.
In each case, 0.5 9 of the formulations = 50 mg
of act;ve compound was appl;ed. The course of the infec-
tion was assessed da;ly up to the 20th day after ;nfec-
t;on.
The results of the tests are clear from the table
below.
Agent of Example Effect on gu;nea-pigs
_ _infected with tr;chophyton
x x x x
2 xxxx
3 xxxx
4 xxxx
xxxx
xxxx .
xxxx: very good effect
xxx: good effect
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~2Z9 !)~6
_ 9 _
xx: effect
x: ~eak effect
0: no effect
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