PREPARATION PHRAMACEUTIQUE A APPLICATION VAGINALE ET PROCEDE DE PREPARATION

PHARMACEUTICAL, VAGINAL APPLICABLE PREPARATION AND A PROCESS FOR ITS PREPARATION

Abrégé français

La préparation pharmaceutique, pour application vaginale, est caractérisée par le fait qu'elle renferme, subdivisés de façon homogène, au moins un poly(alcool vinylique) hydrosoluble, au moins un constituant A, choisi dans le groupe constitué d'agents hydratants, de dispersants et de tensioactifs non ioniques, ainsi que d'au moins un constituant actif B - pour le traitement topique de maladies transmissibles ou transmises sexuellement et (ou) d'affections vaginales -, et éventuellement un ou plusieurs agents auxiliaires; elle est aussi caractérisée par le fait qu'elle forme une pellicule d'une épaisseur de 0,05 à 0,5 mm, plus spécifiquement de 0,06 à 0,2 mm, et préférablement de 0,07 à 0,15 mm.

Abrégé anglais

The pharmaceutical, vaginal applicable
preparation is characterized in that it contains,
homogeneously sub-divided, at least one in water soluble
polyvinyl alcohol, at least one component A, selected from
the group consisting of wetting agents, non-ionic
surface active agents and dispersing agents, as well as at
least one active component B for the local treatment of
sexual transmissible or transmitted, respectively,
diseases, and/or for vaginal affections, and occasionally
one or more auxiliary agent(s), and in that it is in the
form of a film having a thickness of the layer of from
0.05 to 0.5 mm, especially from 0.06 to 0.2 mm,
preferably from 0.07 to 0.15 mm.

Revendications

11
Claims
1. A pharmaceutical, vaginal applicable
preparation, characterized in that it contains, homogeneously
sub-divided, at least one water soluble polyvinyl alcohol,
at least one component A, selected from the group
consisting of wetting agents, non-ionic surface active
agents and dispersing agents, as well as at least one
active component B, whereby this component B is active
for at least one of the local treatment of sexual
transmissible or transmitted, respectively, diseases, and
vaginal affections, and in that it is in the form of a
film having a thickness of the layer of from 0.05 to 0.5
mm.
2. The preparation according to claim 1,
characterized in that it contains one or more auxiliary
agent(s).
3. The preparation according to claim 1,
characterized in that the film has a thickness of the layer
from 0.06 to 0.2 mm.
4. The preparation according to claim 3,
characterized in that the film has a thickness of the layer
from 0.07 to 0.15 mm.
5. The preparation according to claim 1,
characterized in that the active component B is an active
component for the local treatment of bacterial or viral
infections, or an active component for the local treatment
of diseases caused by fungus or trichomonas, or an
active component for the treatment of vaginal mucosa
affections, whereby these active components are optionally
mixed with at least one nonoxynol.

12
6. The preparation according to claim 1,
characterized in that the component B is selected from the
group consisting of benzalkonium chloride, a neomycin, a
polymyxin, econazole, econazole nitrate, metronidazole,
miconazole, miconazole nitrate and a placenta extract.
7. The preparation according to claim 6,
characterized in that the neomycin is neomycin-B-sulfate
and that the polymyxin is polymyxin-B-sulfate.
8. The preparation according to claim 5,
characterized in that the nonoxynol has the formula
C9H19~ C6H4 ~ OCH2 CH2~ OH
wherein n is the integer 9 or 10.
9. The preparation according to claim 1,
characterized in that the component A is selected from
polyoxyethylene ethers of fatty alcohols, monovalent
alcohols, and polyvalent alcohols.
10. The preparation according to claim 1,
characterized in that the component A is selected from the
group consisting of lauryl alcohol, a nonoxynol,
propylene glycol and glycerin.
11. The preparation according to claim 10,
characterized in that the lauryl alcohol is Brij 30TM or
Brij 35TM and that the nonoxynol is nonoxynol-9 or
nonoxynol-10.
12. The preparation according to claim 1,
characterized in that the component A is a mixture of a
nonoxynol and glycerin.

13
13. The preparation according to claim 2,
characterized in that it contains from 50 to 70 % by weight
of a polyvinyl alcohol, from 15 to 35 % by weight of
nonoxynol, from 3 to 8 % by weight of glycerin, and up
to 15 % by weight of active component B, whereby the
total of all components, including the auxiliary agent(s),
gives always 100 % by weight.
14. The preparation according to claim 13,
characterized in that it contains from 55 to 65 % by
weight of a polyvinyl alcohol, from 20 to 30 % by weight
of nonoxynol, 5 % by weight of glycerin, and up to 15 %
by weight of active component B, whereby the total of
all components, including the auxiliary agent(s), gives
always 100 % by weight.
15. The preparation according to claim 2,
characterized in that the auxiliary agents are selected
from the group consisting of stabilizers, plasticizers,
buffers, antioxidants, perfumes and dyes, and in that
they are present always in active concentrations.
16. The preparation according to claim 1,
characterized in that the surface of the film is increased
by means of embossing.
17. A process for preparing a pharmaceutical,
vaginal applicable preparation, characterized in that at
least one water soluble polyvinyl alcohol, at least one
component A, selected from the group consisting of
wetting agents, non-ionic surface active agents and
dispersing agents, as well as at least one active component B,
whereby this component B is active for at least one of
the local treatment of sexual transmissible or transmitted,

14
respectively, diseases, and vaginal affections, are
mixed with water and are homogeneously sub-divided under
heating, and in that the so obtained mixture is poured
and in that finally the present solvents are removed.
18. The process according to claim 17,
characterized in that the mixture comprises one or more
auxiliary agent(s).
19. The process according to claim 17,
characterized in that the components are mixed with water
and at least one organic solvent.
20. The process according to claim 17,
characterized in that the heating is done to a temperature
of about 90°C.
21. The process according to claim 17,
characterized in that the active component B is an active
component for the local treatment of bacterial or viral
infections, or an active component for the local treatment
of diseases caused by fungus or trichomonas, or an
active component for the treatment of vaginal mucosa
affections, whereby these active components are optionally
mixed with at least one nonoxynol.
22. The process according to claim 17,
characterized in that the component B is selected from the
group consisting of benzalkonium chloride, a neomycin, a
polymyxin, econazole, econazole nitrate, metronidazole,
miconazole, miconazole nitrate and a placenta extract.
23. The process according to claim 22,
characterized in that the neomycin is neomycin-B-sulfate
and that the polymyxin is polymyxin-B-sulfate.

24. The process according to claim 21,
characterized in that the nonoxynol has the formula
C9H19~C6H4 ~ OCH2 CH2 ~ OH
wherein n is the integer 9 or 10.
25. The process according to claim 17,
characterized in that the component A is selected from
polyoxyethylene ethers of fatty alcohols, monovalent
alcohols, and polyvalent alcohols.
26. The process according to claim 17,
characterized in that the component A is selected from the
group consisting of lauryl alcohol, a nonoxynol,
propylene glycol and glycerin.
27. The process according to claim 26,
characterized in that the lauryl alcohol is Brij 30TM or
Brij 35TM and that the nonoxynol is nonoxynol-9 or
nonoxynol-10.
28. The process according to claim 17,
characterized in that the component A is a mixture of a
nonoxynol and glycerin.
29. The process according to claim 18,
characterized in that the mixing proportion is adjusted in
such a way, that the preparation contains from 50 to 70
% by weight of a polyvinyl alcohol, from 15 to 35 % by
weight of nonoxynol, from 3 to 8 % by weight of glycerin,
and up to 15 % by weight of active component B,
whereby the total of all components, including the
auxiliary agent(s), gives always 100 % by weight.

16
30. The process according to claim 18,
characterized in that the mixing proportion is adjusted in
such a way, that the preparation contains from 55 to 65
% by weight of a polyvinyl alcohol, from 20 to 30 % by
weight of nonoxynol, 5 % by weight of glycerin, and up
to 15 % by weight of active component B, whereby the
total of all components, including the auxiliary agent(s),
gives always 100 % by weight.
31. The process according to claim 18,
characterized in that the auxiliary agents are selected
from the group consisting of stabilizers, plasticizers,
buffers, antioxidants, perfumes and dyes, and in that
they are present always in active concentrations.
32. The process according to claim 17,
characterized in that the mixture is filtrated before it is
poured.
33. The process according to claim 17,
characterized in that the preparation is in the form of a
film having a thickness of the layer of from 0.05 to 0.5
mm.
34. The process according to claim 33,
characterized in that the film has a thickness of the layer
from 0.06 to 0.2 mm.
35. The process according to claim 34,
characterized in that the film has a thickness of the layer
from 0.07 to 0.15 mm.

17
36. The process according to claim 33,
characterized in that the surface of the film is increased
by means of embossing.

Description

.,~ 1 Z05~
Pharmaceutical. vaginal applicable preparation and a
process for its preparation
Field of the invention
The present invention is directed to a pharma-
ceutical, vaginal applicable preparation and to a pro-
cess for its preparation.
Background of the invention
For the pharmaceutical treatment of vaginal
diseases are used usually vaginal tablets, ointments,
gels, foams and ovuli. Each of these administrative
forms has advantages and disadvantages. From the disad-
vantages are mentioned: bad decomposition of the prepa-
ration, foreign body feeling, bad distribution of the
respective active component in the vaginal mucosa, com-
plicated dosage, for example by means of an applicator.A foam may cause an unpleasant feeling and thus may be
refused because of objective and/or subjective reasons.
Furthermore, it is known a so-called C-film for the pre-
vention of pregnancy.
Summary of the invention
It is an object of the present invention to
provide a new galenic form, i.e. a film for the propor-
tioned release of the active components for the local
treatment of sexual transmissible or transmitted,
respectively, diseases, and/or for vaginal affections.
This new galenic form shall distribute the active compo-
nents on the vaginal mucosa relatively quick, good and
uniform. In addition, also the stability of the active

2 20~ 5
compounds, which are present in the film, shall be in-
creased.
These objects are obtained in an excellent way
with the inventive preparation.
It is also an object of the present invention
to provide a process for preparing said inventive prepa-
ration.
The inventive pharmaceutical, vaginal appli-
cable preparation is characterized in that it contains,
homogeneously sub-divided, at least one in water soluble
polyvinyl alcohol, at least one component A, selected
from the group consisting of wetting agents, non-ionic
surface active agents and dispersing agents, as well as
at least one active component B for the local treatment
of sexual transmissible or transmitted, respectively,
diseases, and/or for vaginal affections, and occasio-
nally one or more auxiliary agent(s), and in that it is
in the form of a film having a thickness of the layer of
from 0.05 to 0.5 mm, especially from 0.06 to 0.2 mm,
preferably from 0.07 to 0.15 mm.
The inventive procress is characterized in
that at least one in water soluble polyvinyl alcohol, at
least one component A, selected from the group consis-
ting of wetting agents, non-ionic surface active agents
and dispersing agents, as well as at least one active
component B for the local treatment of sexual transmis-
sible or transmitted, respectively, diseases, and/or for
vaginal affections, and occasionally one or more auxi-
liary agent(s), are mixed with water, and occasionally
with at least one organic solvent, and are homogeneously
sub-divided under heating, for example to a temperature

4 ~ ~
of about 90~C, and in that the so obtained mixture is
poured and in that finally the present solvents are re-
moved.
Detailed description of the preferred
embodiments
Preferred embodiments of this invention are
defined in the dependent claims.
In the following part possible embodiments for
preparing said inventive preparation (film) are descri-
bed.
A in water soluble polyvinyl alcohol, forexample Poval 205 of the firm Kuraray Co. Ltd., Japan,
is mixed with at least one of said component A, for
example a mixture of at least one nonoxynol, such as
nonoxynols of the formula
CgHlg--C6H4---~OCH2CH2 t~ OH
wherein n is an integer, preferably 9 or 10,
and glycerin, and with water. This mixture is then hea-
ted, for example to a temperature of about 90~C. It is
preferred to filter the cooled solution, for example at
a temperature of about 50~C. If the active component B
and the optional auxiliary agents are soluble in water,
then they are dissolved in water and are added to the
mixture preferably before the filtration. If the active
component B and the optional auxiliary agents are not
soluble in water, then they are added to the mixture af-
ter said filtration, preferably under stirring, for
example in the form of a suspension or an emulsion, whe-
reby aqueous suspensions or aqueous emulsions are pre-

2~5~ 5
~_ 4
ferred. Water-in-oil microemulsions and oil-in-water
microemulsions are also applicable. It is also possible
to add an in water not soluble active component B and/or
auxiliary agent to the filtered mixture in solid form,
preferably under stirring, especially then when the sus-
pension becomes homogenized. It is also possible to add
the active component B and/or auxiliary agent, dissolved
in at least one organic solvent, to the mixture.
In this kind of addition no separation of the
phases between the organic solvent and water shall oc-
cur. If necessary for the corrosion protection of film
preparation devices the filmcasting solution may be buf-
fered.
Said filtration is carried out in order to re-
move impurities, which may occasionally be present, suchas water insoluble polymers of polyvinyl alcohol, dust
and further foreign substances. In the case of absolu-
tely pure and uniform products, the filtration can be
omitted. The filmcasting solution must be homogeneous.
Occasionally present air bubbles can be removed by lea-
ving the solution to rest or by treating under vacuum or
by performing a gentle agitation.
This filmcasting solution can now be processed
in many manners, in the conventional way, in order to
obtain a film.
According to a first method, the filmcasting
solution is batch poured into a tub which has the dimen-
sions desired. Then, the water and the occasionally pre-
sent organic solvents are removed by drying. The drying
can be carried out, for instance, by means of hot air,
coming from a suitable hair-dryer, or coming from a sui-

2~
, " ~.
table thermic lamp, for example an infra-red lamp. The
temperature used must be such that no component is che-
mically transformed, especially decomposed, by the in-
fluence of heat.
The film can now be subjected to an embossing,
thus increasing its surface and gripping capacity. The
film is finally cut and ancillary processed, for in-
stance packed into bags, and if necessary made sterile
by a suitable irratiation method.
According to a second method, the filmcasting
solution is processed continuously in a filmcasting de-
vice. Thereby the filmcasting solution is poured onto a
continuous tape through a slot nozzle. The film support
is usually a strip of chrome steel polished to obtain
high brightness. When pouring, the viscosity of the
filmcasting solution must be such as to flow still, but
not to stop.
The used viscosity depends among other things
on the type of machine. The continuous tape, coated with
the filmcasting solution, enters a drying tunnel, where
the water and the organic solvent, which is occasionally
present, are removed. The temperature in the drying tun-
nel must be such that no component is chemically trans-
formed, especially decomposed, by the influence of heat.
At the end o~ the drying tunnel, the film contains only
a few percents by weight of water, for example about 5 %
by weight of water. The desired film thickness can be
controlled and regulated by using a computer. If, when
starting, the film is too thin, then the slot nozzle is
automatically opened a little bit. On the contrary, if
the film is too thick, then the slot nozzle is closed a
little bit.

6 ,~ 4 ~ -
With regard to the embossing, cutting and type
of packaging, reference is made to the above correspon-
ding statements.
The component B for the local treatment of se-
xual transmissible or transmitted, respectively, di-
seases, and/or for vaginal affections is especially an
active component for the local treatment of bacterial or
viral infections, or an active component for the local
treatment of diseases caused by fungus or trichomonas.
Examples are: benzalkonium chloride, neomy-
cins, such as neomycin-B-sulfate, polymyxins, such as
polymyxin-B-sulfate, econazole, econazole nitrate,
metronidazole, miconazole and miconazole nitrate.
These and still further active compounds,
including a placenta extract, may be mixed with a non-
oxynol, for example a nonoxynol of the formula
CgH1g - C6H4 ( 0CH2CH2tn OH
wherein n is an integer, preferably 9 or 10.
Nonoxynol-9 and nonoxynol-10 are preferred, especially
then when these compounds fulfill the prescriptions ac-
cording to USP 22.
The inventive preparation is very easy to be
applied. It can, cut to the desired dimensions, for
example 5 x 5 cm, be introduced into the vagina by a
finger. A foreign body feeling, if any, is only felt in
the first minutes. By the influence of body heat and/or
due to secretions, which are present in the vagina, the
active component(s) contained in the film exhibit a bet-
ter and more homogenous actions, in comparison with
x~
.~ ,..,..

~_ 7
other, above all solid galenic forms. The pharmaceutical
effect to be obtained depends on the used combination of
active components.
The following examples shall illustrate the
present invention.
Example 1
Vaginal pre~aration aqainst bacterial
infections
A mixture of 4.53 kg of polyvinyl alcohol Po-
val 205rM of the firm Kuraray Co, Ltd., Japan, 360 g ofglycerin, 2.16 kg of nonoxynol-9 and 600 g of benzalko-
nium chloride was slowly warmed to a temperature of 90~C
in 17.35 kg of water under stirring. When all components
had dissolved the slightly cloudy solution was cooled
and filtered at a temperature of 50~C. The clear
filtrate was allowed to stand at a temperature of 45~C
during 30 minutes, whereupon in the mixture no air
bubbles were present. With this filmcasting solution was
prepared on a filmcasting machine a homogeneous film
with a thickness of 0,09 mm. The filmcasting solution
was poured at a temperature of 40~C to 50~C.

Example 2
Vaqinal Preparation against trichomonas
A mixture of 453 mg of polyvinyl alcohol Poval
205TMof the firm Kuraray Co, Ltd., Japan, 36 mg of
glycerin, 216 mg of nonoxynol-9 and 100 mg of
metronidazole was dissolved in 10 ml of water and heated
to a temperature of 90~C under stirring. The slightly
cloudy solution was cooled and filtered at a temperature
of 50~C. This filtrate was poured into a rectangular tub
(5 x 10 cm) and dried with a heat lamp (Biccatherm~M-
lamp). There was obtained a homogeneous film having a
thickness of 0.075 mm.
Example 3
Vaqinal Preparation for the control of fungus
A mixture of 3.01 kg of polyvinyl alcohol Po-
val 205 of the firm Kuraray Co, Ltd., Japan, 240 g of
glycerin and 1.0 kg of nonoxynol was slowly warmed to a
temperature of 90~C under stirring in 13.35 kg of water.
The slightly cloudy solution was cooled and filtered at
a temperature of 50OC. To this clear filtrate was added
under stirring a slurry of 400 g of finally grinded
econazole in 2.0 kg of water at a temperature of 35~C.
This mixture was slightly stirred at a temperature of
35~C during 30 minutes, whereupon in the mixture no more
air bubbles were present. With this filmcasting solution
was prepared a homogeneous film with a thickness of 0.07
mm on a filmcasting machine. The filmcasting solution
was poured at a temperature of 35~C.

Exam~le 4
According to the teachings of example 2 but
without said filtration a homogeneous film (8x8 cm) was
prepared with the following components:
Polyvinyl alcohol Poval 205 T~ 435 mg
Glycerin 35 mg
Brij 35TM (a product of the firm ICI)300 mg
Econazole nitrate 150 mg
920 mg
At no place this film was thicker than
0.120 mm.
Exam~le 5
According to the teachings of example 2 but
without said filtration a homogeneous film (5.3 x 6 cm)
was prepared with the following components:
Polyvinyl alcohol Poval 205TM 255 mg
Glycerin 20 mg
Brij 35TM (a product of the firm ICI) 50 mg
Metronidazole 100 mg
425 mg

Z~&~5
At no place this film was thicker than
0.120 mm.
While there are shown and described present
preferred embodiments of the invention, it is to be
distinctly understood that the invention is not limited
thereto, but may be otherwise variously embodied and
practiced within the scope of the following claims.