COMPRIMES VAGINAUX CONTRACEPTIFS ET METHODE DE PREPARATION

CONTRACEPTIVE VAGINAL TABLETS AND PROCESS FOR PREPARING THEM

Abrégé anglais

ABSTRACT
The invention relates to contraceptive vaginal tablets and to
a process for preparing them. The tablets of the invention have the
following composition: 0.2 to 3 parts by weight of boric acid, 10 to 20
parts by weight of tartaric acid, 1 to 2 parts by weight of vitamin K3-
sodium bisulfite adduct, 0.8 to 1.2 parts by weight of polyvinyl pyrrolidone,
2 to 5 parts by weight of magnesium stearate, 8 to 12 parts by weight of
carboxymethyl cellulose, 8 to 12 parts by weight of lactose and 50 to 65
parts by weight of microcrystalline cellulose. The vaginal tablets contain
preferably 5 to 10 mg of vitamin K3-sodium bisulfite adduct and have a
total weight of 500 mg. The tablets are prepared preferably in such a way
that the boric acid, the tartaric acid and the vitamin K3-sodium bisulfite
adduct, as well as the polyvinyl pyrrolidone, the magnesium stearate, the
carboxymethyl cellulose, the lactose and the microcrystalline cellulose are
homogenized separately to powder mixtures and thereafter the powder mixtures
are mixed and pressed to form tablets. The tablets should be wetted and
inserted into the back-vaginal fornix 10 minutes before the coitus.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Contraceptive vaginal tablets characterized in that
they contain:
0.2 to 15 parts by weight of boric acid,
10 to 100 parts by weight of tartaric acid,
1 to 10 parts by weight of vitamin K3-sodium bisulfite
adduct,
0.8 to 5 parts by weight of polyvinyl pyrrolidone,
2 to 15 parts by weight of magnesium stearate,
8 to 50 parts by weight of carboxymethyl cellulose,
8 to 12 parts by weight of lactose, and
50 to 320 parts by weight of microcrystalline cellulose.
2. Contraceptive vaginal tablets characterized in that
they contain:
0.2 to 3 parts by weight of boric acid,
10 to 20 parts by weight of tartaric acid,
1 to 2 parts by weight of vitamin K3-sodium bisulfite
adduct,
0.8 to 1.2 parts by weight of polyvinyl pyrrolidone,
2 to 5 parts by weight of magnesium stearate,
8 to 12 parts by weight of carboxymethyl cellulose,
8 to 12 parts by weight of lactose, and
50 to 65 parts by weight of microcrystalline cellulose.
3. A contraceptive vaginal tablet according to claim 1
which has the following composition:
boric acid about 5 parts by weight,
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tartaric acid about 50 parts by weight,
vitamin K3-sodium bisulfite adduct about 5 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 320 parts by weight.
4. A contraceptive vaginal tablet according to claim 1
which has the following composition:
boric acid about 15 parts by weight,
tartaric acid about 50 parts by weight.
vitamin K3-sodium bisulfite adduct about 5 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 310 parts by weight.
5. A contraceptive vaginal tablet according to claim 1
which has the following composition:
boric acid 1 part by weight,
tartaric acid about 100 parts by weight,
vitamin K3-sodium bisulfite adduct about 5 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
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carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 274 parts by weight.
6. A contraceptive vaginal tablet according to claim 1
which has the following composition:
boric acid about 1 part by weight,
tartaric acid about 50 parts by weight,
vitamin K3-sodium bisulfite adduct about 10 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 319 parts by weight.
7. A contraceptive vaginal tablet according to claim 1
which has the following composition:
boric acid about 5 parts by weight,
tartaric acid about 50 parts by weight,
vitamin K3-sodium bisulfite adduct about 10 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 315 parts by weight.
8. A contraceptive vaginal tablet according to claim 1
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which has the following composition:
boric acid about 15 parts by weight,
tartaric acid about 50 parts by weight,
vitamin K3-sodium bisulfite adduct about 10 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 305 parts by weight.
9. A contraceptive vaginal tablet according to claim 1
which has the following composition:
boric acid about 1 part by weight,
tartaric acid about 100 parts by weight,
vitamin K3-sodium bisulfite adduct about 10 parts by
weight,
polyvinyl pyrrolidone about 5 parts by weight,
magnesium stearate about 15 parts by weight,
carboxymethyl cellulose about 50 parts by weight,
lactose about 50 parts by weight,
microcrystalline cellulose about 269 parts by weight.
10. Process for preparing contraceptive vaginal tablets
characterized in that:
0.2 to 15 parts by weight of boric acid,
10 to 100 parts by weight of tartaric acid,
1 to 10 parts by weight of vitamin K3-sodium bisulfite
adduct,
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0.8 to 5 parts by weight of polyvinyl pyrrolidone,
2 to 15 parts by weight of magnesium stearate,
8 to 50 parts by weight of carboxymethyl cellulose,
8 to 12 parts by weight of lactose, and
50 to 320 parts by weight of microcrystalline cellulose
are homogenized and formed into tablets.
11. Process for preparing contraceptive vaginal tablets
characterized in that:
0.2 to 3 parts by weight of boric acid,
10 to 20 parts by weight of tartaric acid,
1 to 2 parts by weight of vitamin K3-sodium bisulfite
adduct,
0.8 to 1.2 parts by weight of polyvinyl pyrrolidone,
2 to 5 parts by weight of magnesium stearate,
8 to 12 parts by weight of carboxymethyl cellulose,
8 to 12 parts by weight of lactose and
50 to 65 parts by weight of microcrystalline cellulose
are homogenized and formed into tablets.
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Description

72S
The invention relates to contraceptive vaginal table-ts which are
free from hormones, and to a process for preparing them.
Apart from steriliza~ion, several methods are known for preventing
undesirable pregnancy. These include use of condoms, intrauterine instruments,
vaginal pessaries (mechanical instruments), hormonal preparations which
prevent the occurrence of the pregnancy and local spermicidal preparations which
are free from hormones.
All the known methods have, however, disadvantages which prevent
general application. It is known that not every conceptive age-group may use
preparations containing hormones. Certain persons, who could take these
preparations in view of their age, are prevented from employing them owing to
the side effects. From among the mechanical instruments the condom and the
vaginal pessary cause in certain cases uncomfortable feeling or require
preparation destroying the illusions. The intrauterine instruments are free
from these disadvantages, but not all persons may wear them, and members
of even the youngest age-group may not use them. A further disadvantage of
these instruments is that they may be ~nserted only by the physician. With
preparations which are free from hormones there is no contraindication relating
to age-group. These are rarely applied, however, per se since they are not
reliable enough.
The efficiency of the known contraceptive instruments and methods
is characterized by the so-called Pearl-index. This is a number which shows
how many from among 100 conceptive women using the instrument or method in
question, will become pregnant during a year. The Pearl-index of the
contraceptive instruments and methods is stated in the following Table.
-- 1 --

~Z~ 5
Table
vaginal irrigation 29.3-40.8
coitus interruptus 12-38
Ogino-Knaus rule 12-34.5
foam tablet 11.9-42.8
vaginal pellet 7.7-42.3
diaphragm 6.1-33.6
jelly 6.4-41
vaginal pessary 6.0-29
condom 6-28
intrauterine instrument 0.9-8
hormonal preparation 0-1.7
From the data of this Table it can be seen that only the
hormonal preparations possess the safety desired. The efficiency of the
preparations containing only chemical substances falls far behind that of
the hormonal preparations.
An aim of the present invention is to find a vaginal tablet which
is free from hormones, which possesses the same efficiency as the hormonal
preparations and does not show the disadvantages thereof, so that the tablet
may be used without any limitation of the age or the physical condition.
Vitamin K3 and the adduct thereof with sodium bisulfite are widely
used in the therapy e.g. for treating icterus occulsion, pre- and post-
operative treatment in cholemia, biliary fistula, ulcerative colitis, dysentery,
steatorrhea, sprue, celiac disease, hemophilia of the newborn, jaundice,
salicylism, purpura, thormbophenia, serum sickness, urticaria, haemoptoe. The
contraceptive effect of these compounds has not been previously disclosed.

47:2~
The therapeutic use ot boric acid and tartaric acid is
also known. The boric acid is used for rinsing cavities owing -to
its weak dlsinfectant effect, the tartaric acid is applied for
regulating the pH of the preparations due to its weak acidic
reaction.
It was surprisingly found that a preparation, which
corresponds to the above requirements, may be obtained when
0.2 to 15 parts by weight of boric acid, 10 to 100 parts by
weigh-t of tartaric acid, 1 to 10 parts by weight of vitamin K3-
sodium bisulfite adduct, 0.8 to 5 parts by weight of polyvinyl
pyrrolidone, 2 to 15 parts by weight of magnesium stearate,
8 to 50 parts by weight of carboxymethyl cellulose~ 8 to 12 parts
by weight of lactose, and 50 to 320 parts by weight of
microcrystalline cellulose are homogenized and formed into tablets.
In a preferred embodiment 0.2 to 3.0 parts by weight of boric
acid, 10.0 to 20 parts by weight of tartaric acid, 1 to 2 parts
by weight of vitamin K3-sodium bisulfite adduct, 0.8 to 1.2 parts
by weight of polyvinyl pyrrolidone, 2 to 5 parts by weight of
magnesium stearate, 8 to 12 parts by weight of carboxymethyl
cellulose, 8 to 12 parts by weight of lactose and 50 to 65 parts
by weight of microcrystalline cellulose are homogenized and
formed into tablets.
The tablets contain preferably 5 mg of vitamin K3-
sodium bisulfite adduct per tablet. A suitable tablet has a
total weight of about 500 mg.
The vaginal tablets of the invention should be wetted
before use and thereaEter inserted into the back-vaginal fornix.
Here the tablets disintegrate quickly owing to the moisture and
. .
,

~L2~2~
form a suspension. This suspension covers the cervix and
paralyzes the spermiums being thereon. The rest oE the
preparation may be removed by irrigation. The use oE -the tablets
does not cause discomfort; the tablets disintegrated in the
vagina do not have any noxious side effect.
Further details of the invention are shown in the
following Examples without any limitation thereto.
Example 1
Homogeneous powder mixture is prepared from 2.0 g of
powdered boric acid, 100.0 g of powdered tartaric acid and
100.0 g of microcrystalline

L4~ S
cellulose. Separately 10.0 g of vitamin K3-sodium bisulfite adduct, lO.0 g
of polyvinyl pyrrolidone ~Polyplasdon XL*~, 30.0 g of magnesium stearate
and 100.0 g of carboxymethyl cellulose are homogenized. The two powder
mixtures are mixed thereafter 648.0 g of microcrystalline cellulose are
admixed. lO00.0 g of the powder mixture are obtained~ from which 2000 tablets
each weighing 500 mg and having a diameter of 12 mm are pressed without edges.
Some proper~ies of the tablets so obtained are summarized as
follows:
abrasion hardness (ERWEKA-TAP):
after 5 minutes after 10 minutes
1.46% 3.02%
1.29% 2.86%
compression strength ~ERWEKA): 14.3 N
average height of the tablets: 4.52 mm
disintegration time ~flask method according to PA.Mg.VI):
9 to 10 minutes.
Example 2
Tablets are prepared according to the process described in Example
l with the ~ollowing composition:
boric acid 5.0 mg
tartaric acid 50.0 mg
vitamin K3-sodium bisulfite adduct5.0 mg
polyvinyl pyrrolidone 5.0 mg
magnesium stearate 15.0 mg
carboxymethyl cellulose 50.0 mg
lactose 50.0 mg
microcrystalline cellulose 320.0 mg
* Trade Mark 500.0 mg
-- 4 --

Example 3
Tablets are prepared according to the process described in Example 1
with the following composition:
boric acid 15.0 mg
tartaric acid 50.0 mg
vitamin K3-sodium bisulfite adduct 5.0 mg
polyvinyl pyrrolidone5.0 mg
magnesium stearate 15.0 mg
carboxymethyl cellulose50.0 mg
lactose 50.0 mg
microcrystalline cellulose 310.0 mg
500.0 mg
Example ~
Tablets are prepared according to the process descri.bed in
Example 1 with the following composition:
boric acid 1.0 mg
tartaric acid 100.0 mg
vitamin K3-sodium bisul~ite adduc~ 5.0 mg
polyvinyl pyrrolidone5.0 mg
magnesium stearate 15.0 mg
carboxymethyl cellulose50.0 mg
lactose 50.0 mg
microcrystalline cellulose 274.0 mg
500.0 mg

72~
Example 5
Tablets are prepared with the following composition:
boric acid 1.0 mg
tartaric acid 50.0 mg
vitamin K3-sodium bisulfite adduct 10.0 mg
polyvinyl pyrrolidone 5.0 mg
magnesium stearate 15.0 mg
carboxymethyl cellulose 50.0 mg
lactose 50.0 mg
lV microcrystalline cellulose319.0 mg
500.0 mg
Example 6
Tablets are prepared with the following composition:
boric acid 5.0 mg
tartaric acid 50.0 mg
vitamin K3-sodium bisulfite adduct 10.0 mg
polyvinyl pyrrolidone 5.0 mg
magnesium s~earate 15.0 mg
carboxymethyl cellulose 50.0 mg
lac~ose 50.0 mg
microcrystalline cellulose315.0 mg_
500.0 mg
Example 7
Tablets are prepared with the following composition:
boric acid 15.0 mg
tartaric acid '0.0 mg
vitamin K3-sodium bisulfite adduct 10.0 mg

~2~9~72~i
polyvinyl pyrrolidone 5.0 mg
magnesium stearate 15.0 mg
carboxymethyl cellulose50.0 mg
lactose 50.0 mg
microcrystalline cellulose305.0 mg
500.0 mg
Example 8
Tablets are prepared with the following composition:
boric acid 1.0 mg
tartaric acid 100.0 mg
vitamin K3-sodium bisulfite adduct 10.0 mg
polyvinyl pyrrolidone 5.0 mg
magnesium stearate 15.0 mg
lactose 50.0 mg
carboxymethyl cellulose50.0 mg
microcrystalline cellulose2~.0 mg
500.0 mg
The following in vitro and in vivo tests were performed with
the tablets of the invention.
In vitro test
Sperm obtained from 32 normo zoospermia persons was examined.
From the sperm 1 ml quantities containing 10 to lO0 millions of spermatozoa
were mixed with 1 ml suspension obtained from 1 tablet at +38C on a watch-
glass. The motion of the spermatozoa was observed. Partial immobilisation
began l minute after the mixing and became complete in 5 to lO minutes
depending on the vitality of the spermatozoa. The immobilized spermatozoa
became eosin binders, which indicates the cell death. This process is

irreversible. The spermatozoa could not be revived either by changing the
pH or by adding fresh serum or by other methods.
In vivo model test
The following test was carried out with women in their ovulation
period. Tablets prepared according to the invention were wetted by water and
thereafter inserted into the back-vaginal fornix. After 5 minutes the vagina
was exposed and each 2 ml of a sperm having a concentration of 160 to 240
millions spermatozoa/ml were injected onto the women's cervix. The exposing
instrument was removed and af~er 5 and 10 minutes repeated exposures were
performed thereafter the content of the vagina was examined.
According to the microscopic examinations the immobilization is
50% after 5 minutes, while 100% after 10 minutes.
In vivo application test
The tablets were used by women who were proved to be conceptive
and till the time of the examination protected themselves only by the Ogino-
Knaus rule. Among these women pregnancy occurred only in two cases during a
one year period. In view of this fact the tablets of the inventions have the
same efficiency as the intrauterine instruments ~the Pearl-index was 2).
The women examined were subjected to gynaecological examination every
two or three months so that any side effects on the vagina or damaging effect
on the mucous membrane would be determined. No such cases were found.
In view of the above described it can be stated that the vaginal tablets of
the invention are suitable for the modern contraception in every respect.