Note: Descriptions are shown in the official language in which they were submitted.
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The present invention reLates to novel antimycotic
agents in gel form, for the treatment of fungal infections
of the oral cavity, having a depot effect, good adhesion
properties and a relatively high bioavailabil;ty of the
active compounds and thus they make short-term therapy
possible.
Formulations of antimycotic compounds have already
been disclosed for the treatment of infections, primarily
by blastomycetes, sf the oral cavity. Using these formu-
lations, a 10 to 21-day therapy period is neGessary for
complete heal;ng.
In order to ach;eve a shortening of the durat;on
of therapy, a certain depot effect and a relatively high
bioavailability of the active compounds are necessary
especially in order to eliminate the organisms and achieve
mycolog;cal healing. The known formulations have only
restricted suitability for this purpose. ~f it is now
desired to achieve a shorten;ng of the duration of therapy
without a further increase in the concentration of the
Z0 active compound, care must ~e taken that the bioavailabil-
ity of the active compound is optimal.
Thus, formulations which~ on the one hand, have an
adequate adhesion after application to the oral mucosa
and, on the other hand, are able adequately to release ~he
active compound conta;ned in the formulat;on, even dis-
solved in saliva~ were requ;red.
It has now been found that formulations of anti-
mycotic active compounds which contain as the gel-forming
agent a celluLose ether, in particuiar hydroxypropylcel-
lulose, sodium alginate or propylene glycol alginate, andalso contain the customary formulating aux;liaries, pro-
duce optimal adhesion propert;es and optimal release of
the active compound and thus shorten the duration of ther-
apy because fung;cidal concentrations of the act;ve
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compound are reached. This effect is achieved by increasing th~e bioavail-
ability of the active compounds contained in the formulations, due to the
adhesion properties, and thus the release of the active compound into the sal-
iva can be increased.
In particular, it has been found that formulations of antimycotic
derivatives which contain the abovementioned gel-forming agents in addition
to linear high-molecular weight polysaccharides as stabilising gel-forming
agents significantly improve the stability of the formulations to heat and
thus the long-term storage stability. Formulations without the addition of
high-molecular weight polysaccharides are only stable up to 30C, phase separa-
tion occurring after a short time at above 30C, that is to say the gel
structure is irreversibly destroyed. Formulations which, in addition to the
gel-forming agents, also contain small amounts of a linear high-molecular
weight polysaccharide are stable up 50C and thus the storage stability of
formulations of this type is significantly increased.
The agents thus prepared also possess other unusual properties:
The viscosity is hardly affected by variations in temperature;
the adhesion properties of the formulation are improved.
The development of the flavour is improved and a pleasant sensa-
tion in the mouth is achieved.
Thus the present invention provides an antimycotic agent in gel
form for the treatment of fungal infections of the oral cavi~y, containing
an antimycotic azole compound and customary formulating auxiliaries, charac-
terised in that it contains 2.5% - 17.5% of a cellulose ether, sodium alginate,
propylene glycol alginate, polyacrylic acid or a salt thereof, polymeth-
acrylic acid or a salt thereof sodium amylopectin semiglycolate J gum arabic,
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guar gum or a protein derivative as gel-forming agent and 0.1 - 1.5% of a
biopolysaccharide as stabiliser and/or gel-forming agent.
In another aspect the invention provides a process for the pro-
duction of an antimycotic agent in gel form for the treatment of fungal in-
fections of the oral cavity, wherein there is added to a 1% solution of benzyl
alcohol in demineralised waterJ at about 60C under vigorous stirring, 2.5 -
17.5 % of a cellulose etherJ sodium alginate, propylene glycol alginate,
polyacrylic acid or a salt thereof, polymethacrylic acid or a salt thereof,
sodium a~ opectin semiglycolate, gum arabic, guar gum or a protein derivative
as gel-forming agent and 0.1 - 1.5% of a biopolysaccharide, the mixture is
cooled to about 30C, there is added 0.05 - 1% of an antimycotic azole com-
pound and the mixture cooled to room temperature.
The demineralised water can contain the usual formulation auxi-
liaries.
Active compounds which can be formulated in this manner are any
compounds having antimycotic activity, in particular imidazole and triazole
derivatives. They are present in the agents according to the invention in
amounts pref~rably of 0.05 - 1%, most preferably 0.1 1%.
The comp~ ds of the formulae below may be mentioned as examples:
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Cl~trimazole
~ l~ Cl
II ~--CP. ~3
II Bi f onazo le
L~1
~ I C1 Lomb a zoL e
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~o9~z~
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Nu~erous other azole clerivatives having antimycotic
activity are disclosed in DE-OS (German Published Specifi-
cation~ 2~430,039. They can likewise be used as active
compounds ;n the agents according to the invention.
Suitable gel-forming agents are those macromolecular compounds
which can dissolve or swell both in water and in organic solvents.
In this context, cellulose ethers, p.e. hydroxypropylcellulose,
may be particularly mentioned, 2.5 to 17.5 % of these being
re~uired. Especially suitable is hydroxypropylcellulose, having
1~ a molecular weight from 60 000 to 1000 000. Foll~wing a classi-
fication of macromolecul~ auxiliaries (Keipert et al., Die
Pharmazie 28, 145-183 (1973)), in particular, ionic macromolecules
in the form of their salts are used. These are, inter alia,
sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic
acids and their salts, sodium amylopectin semiglycolate,
alginic acid and propylene glycol alginate as the sodium salt,
gum arabic and guar gum.
Amphoter;c macromolecules, such as protein deriva-
tives, for example gelatin, are just as suitable as non-
;onic polymers, for example methylcellulose, hydroxypropyl-
cellulose and solubLe starches, ~hich fulfil the above
requirements.
Suitable gel-forming agents ~hich also have a
stabilising effect are long-chain linear high-molecular
~e;ght polysacchar;des having a molecular ~eight of more
than one mill;on. 0.1 - 1.5X of stab;lisers of this type
are requ;red.
Suitable solvents are water and all solvents mis-
cible with ~ater. Examples of suitable solvents are alka-
nols, such as ethanol and isopropyl alcohol, benzyl alco-
hol, propylene glycol etc~.
Gel comb;nation bases which have been found to be
particularly stable are those macromolecular compounds,
such as, for example, hydroxypropylcellulose ~molecular
weight 60,000 - 1,00U,000), with a linear high-molecular
weight polysaccharide tmolecular weight probably 2,000,000).
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A suitable biopolysaccharide in Xanthan Gum (Keltron,
Kelza of the firm Kelco.) It is th~ high molecular aarbo-
hydrate of the formula
CH,OH CH.Otl
_ OHo ~ n
c~orcH~ I
~1
~0~
COOCM3 ~ .~ N
COO~M~O Cl-, ~
CH, \~
which is formed during the fermentation of Xanthomonas
campestris.
The gels according to the invention are prepaxed in that
to a 1 ~ solution of benzyl alcohol in demineralised water,
which contains the usual formulation auxiliaries, there is
added at 60 C under vigorous stirring 2.5 - 17.5 % cellulose
ether as gel forming agent and 0.1 - 1.5 % biopolysaccharide,
~he mixture is cooled down to 30 C, there is added 0.05 -
1 %, preferably 0.1 - 1~ azole deriva~ive and the mixture
cooled down to room temperature.
1 kg benzyl alcohol, 0.1 kg saccharin and 0.01 kg prim.
sodium citrate are dissolved in 94.89 kg dimineralised
water and the solution warmed to 60 C.
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Under vigorous stirring 2.5 kg hydroxypropylcellulose
(m.w. 1 OOO OOO) and O.S kg biopolysaccharide are added
and the mixture cooled down to 30 C. 1 kg clotrimazole
is added under vigorous stirring and the mixtuxe cooled
down to room temperature.
In an analogous manner the gels of the following examples
are prep~red.
Example 2
~ifonazole active compound, micron. 1.00
10 Benzyl alcohol 1.00
Hydroxypropylcellulose (M.~. about 1,000,000) 2.5
Biopolysaccharide (M.W. about 2,000,000) 0.5
Sweetener 0.1
Aroma 0.2
15 Demieralised water ad 100
Example_
Lombazole active compound, micron. 1.00
6enzal aLcohol 1.00
Hydroxypropylcellulose ~M.W. 1,000,000) 2.5
20 Biopolysaccharide (M.W. about 2,000,000) 0.5
Sweetener 0.1
Aroma 0.25
Demineralised ~ater ad 100
Example 4
25 Clotrimazole act;ve compound, micron.1.00
8enzyl alcohol 1.00
Hydroxypropylcellulose ~M.W. 60,000)17.50
Biopolysaccharide (M.W. about 2,00D,000) 0.50
Sweetener 0~20
30 Demineralised ~ater ad 100
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