Prostaglandins and antigestagens for induction of labor and for abortion

A pharmaceutical composition containing a prostaglandin and an antigestagen is suitable for induction of labor and for abortion.

BACKGROUND OF THE INVENTION 
This invention relates to a combination product for combined use in the 
induction of labor or for abortion. 
To avert danger for the mother and/or child, it is sometimes necessary to 
induce labor artificially or to terminate a pregnancy before term. 
Surgical techniques and pharmacological methods are available for this 
purpose. 
A favorable pharmacological method is vaginal or intramuscular application 
of prostaglandins which, in the case of abortion, are taken in the first 
or second three-month period of pregnancy (Contraception 1983, Vol. 27, 
51-60 and Int. J. Gynaecol. Obstet. 1982, Vol. 20, 383-386. Advantages of 
prostaglandins include their simple administrability and their 
applicability for use over a long period of pregnancy. Disadvantages 
include acute side effects such as pain and nausea; moreover, the success 
rate in the case of abortion in advanced phases of pregnancy is not over 
90% even with a long period of prostaglandin treatment. 
Another possibility of terminating a pregnancy consists in the application 
of an antigestagen (Med. et Hyg. 1982, Vol 40, 2087-2093). Antigestagens 
are better tolerated than prostaglandins but have a greater latency and 
individual variability of onset of action in comparison with 
prostaglandins. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of this invention to provide a new composition 
and method for induction of labor or abortion, which significantly 
ameliorates these problems. 
Upon further study of the specification and appended claims, further 
objects and advantages of this invention will become apparent to those 
skilled in the art. 
These objects have been attained based in part on this finding, that the PG 
type and AG type disadvantages are avoided or significantly ameliorated if 
prostaglandins (PG) and antigestagens (AG) are used together for these 
purposes.

DETAILED DISCUSSION 
Surprisingly, the amounts by weight of prostaglandin and antigestagen can 
be greatly reduced in combined use in comparison with the usual amounts 
employed when they are used alone. Further surprising is the fact that the 
success rate of abortions or labor induction can even be increased as a 
result. The prostaglandin and antigestagen are advantageously used 
separately, simultaneously and/or sequentially. The weight ratio of 
prostaglandin to antigestagen is generally 1:20 to 1:6000, preferably 
1:100 to 1:500. 
These weight ratios are based on appropriate values for the two preferred 
active ingredients, i.e., sulprostone as the prostaglandin and 
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propiny 
l-4,9(10)-estradiene-3-one as the antigestagen. Corresponding weight ratios 
for any other ingredients can be readily determined using fully 
conventional techniques, e.g., involving differential potency studies 
using conventional protocols. 
Prostaglandins suitable for use according to the invention are all 
prostaglandins suitable for abortion or inducing labor. These are well 
known. They particularly include prostaglandins of the E and F types. 
There can be mentioned for example: prostaglandin E.sub.2, prostaglandin 
F.sub.2a, prostaglandin E derivatives, e.g., 
16-phenoxy-.omega.-17,18,19,20-tetranor-PGE.sub.2 -methylsulfonyl-amide 
(sulprostone), 16,16-dimethyl-trans-.DELTA. .sup.2 -PGE.sub.1 -methyl 
ester (Gemeprost), 9-deoxo-16,16-dimethyl-9-methylene-PGE.sub.2 
(Metenenprost), prostaglandin F derivatives, e.g. 15-methyl-PGF.sub.2 
.alpha.-methyl ester, 
(5Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prostad 
ienoic acid (DE-OS No. 29 50 027), 
(5Z,13E)-(9R,11R,15R)-11,15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetr 
anor-5,13-prostadienoic acid (DE-OS No. 31 26 924), 
(5Z,13E)-(9R,11R,15R)-11,15-dihydroxy-16,16-dimethyl-9-fluoro-5,13-prostad 
ienoic acid (DE-OS No. 31 26 924), 
(5Z,13E)-(9R,11R,15R)-9-bromo-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetra 
nor-5,13-prostadienoic acid (DE-OS No. 31 48 743), or 
(5Z,13E)-(9R,11R,15R)-9-bromo-11,15-dihydroxy-16,16-dimethyl-5,13-prostadi 
enoic acid (DE-OS 31 48 743), etc. 
This listing is exemplary only. Many other prostaglandins can be used. 
The prostaglandins can be used in amounts that are clearly lower than the 
generally normal amounts for abortion or induction of labor. The amount to 
be used according to the invention conventionally depends, inter alia, on 
the hormone level, the period of the pregnancy, etc., of the patient and 
the manner of application. Precise dosages can be routinely determined 
using conventional techniques in view of this disclosure. When sulprostone 
is used as the prostaglandin, as a rule 0.03 to 0.5 mg per day suffices. 
Application can, for example, be made locally, topically, enterally or 
parenterally. Upon intramuscular injection or intravenous infusion, for 
example, amounts of about 0.1 to 0.3 mg of sulprostone per day are 
satisfactory. Upon local application, for example extra-amniotically or 
intravaginally, about 0.03 to 0.5 mg of sulprostone per day is used. For 
topical application, transdermal systems, such as skin plasters, can be 
used. According to this invention, biologically equivalent amounts of 
other prostaglandins can be used instead of sulprostone. These 
bioavailability equivalent amounts can be determined routinely and 
conventionally, e.g., by performing differential potency studies using 
fully routine pharmacological protocols, e.g., W. Elger, Animal 
Reproduction Science 2 (1979), 133. 
The combined treatment with prostaglandin and antigestagen occurs as a rule 
over 1 to 4, preferably 1 to 2 days, during which time the prostaglandin 
and antigestagen can be applied preferably separately and simultaneously, 
or also separately and sequentially. The prostaglandin and antigestagen 
can also be combined in a single dosage unit. In sequential therapy, 
preferably, first the antigestagen is applied for 1 to 4 days and then the 
prostaglandin alone, or the prostaglandin and additional antigestagen 
together, over 24 hours. The application of the antigestagen for 1 or for 
4 days depends on the period of pregnancy and on the progesterone level. 
All compounds are suitable as antigestagens for this invention which have a 
strong affinity for the gestagen receptor (progesterone receptor) and yet 
show no progestational activity of their own, thus functioning as 
antigestagens. For example, the following steroids are suitable as such 
competitive progesterone antagonists: 
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propinyl 
-4,9(10)-estradien-3-one, 
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-18-methyl-17.alpha 
.-propinyl-4,9(10)-estradien-3-one, 
11.beta.-[4-N,N-dimethylamino)-phenyl]-17a.beta.-hydroxy-17a.alpha.-propiny 
l-D-homo-4,9(10),16-estratrien-3-one, (European patent application No. 
82400025.1--Publication No. 0 057 115); 
11.beta.-p-methoxyphenyl-17.beta.-hydroxy-17.alpha.-ethinyl-4,9(10)-estradi 
en-3-one (Steroids 37 (1981) 361-382), or 
11.beta.-(4-dimethylaminophenyl)-17.alpha.-hydroxy-17.beta.-(3-hydroxypropy 
l)-13.alpha.-methyl-4,9-gonadien-3-one. 
Also suitable for use in this invention are antigestagens which antagonize 
the effect of gestagens per se, i.e., operate by a route different from 
competing with the gestagen receptor. Suitable such antigestagens include 
the derivatives of trilostane (U.S. Pat. No. 4,160,027). 
The foregoing listing is exemplary only. Many other antigestagens can be 
used, e.g., as disclosed in Fertility and Sterility 40, 253 (1982), 
Steroids 37, 361 (1981). 
The antigestagens according to this invention are used in amounts that as a 
rule are also lower than the generally normal amounts for abortion or 
labor induction. In general, 10-200 mg of 
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propiny 
l-4,9(10)-estradien-3-one per day or a biologically equivalent amount of 
another antigestagen suffice. Precise dosages can be routinely determined 
using conventional techniques in view of this disclosure. The mentioned 
bioequivalent amounts can be determined conventionally and routinely, 
e.g., by performing differential potency studies using fully routine 
pharmacological protocols, e.g., Fertility and Sterility 40, 253 (1982), 
Steroids 37, 361 (1981). 
The antigestagens can, for example, be applied locally, topically, 
enterally or parenterally. 
For the preferred oral application of either component, tablets, coated 
tablets, capsules, pills, suspensions or solutions are suitable. These can 
be produced in the usual way using the admixtures and vehicles customary 
in galenicals, most notably those well known for formulations of PG and AG 
compounds. For local or topical application, for example, vaginal 
suppositories or transderamal systems such as skin plasters are suitable. 
A dosage unit generally contains about 10 to 200 mg of antigestagen. 
Suitable hosts are mammals including humans. Other than as indicated 
herein, administration will be analogous to that of the known active 
ingredients alone. 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. In the following 
example(s), all temperatures are set forth uncorrected in degrees Celsius; 
unless otherwise indicated, all parts and percentages are by weight. 
EXAMPLE 1 
Composition of a freeze-dried sulprostone formulation per ampoule 
______________________________________ 
0.1 mg Sulprostone 
5.0 mg Polyvinylpyrrolidone (K value = 15-18) 
1.95 mg Tris(hydroxymethyl)aminomethane hydrochloride 
(tremetamol.HCl) (from 1.5 mg tremetamol and 
1N hydrochloric acid) 
7.05 mg 
______________________________________ 
For dosage and application, the content of the ampoule is dissolved with 
isotonic saline solution for intramuscular injection or intravenous 
infusion for extra-amniotic application. 
Production of the dry substance 
Sulprostone is brought to solution by addition to an ice-cooled solution of 
polyvinylpyrrolidone and tremetamol in distilled water. The pH of the 
solution is adjusted to 5.0 by addition of 1N hydrochloric acid with 
strong cooling. Then the solution was filled to the required volume. After 
filtering with a membrane filter, the solution is dosed in ampoules. 
The solution is then frozen by immersion of the ampoules in an acetone/dry 
ice freezing mixture and immediately freeze-dried in a precooled 
freeze-dry unit for about 48 hours. After completion of the freeze-drying, 
the ampoules are immediately sealed. 
EXAMPLE 2 
Composition of a film with sulprostone for vaginal application 
______________________________________ 
0.1 mg Sulprostone 
19.6 mg Hydroxypropyl cellulose 
0.32 mg Polyoxyethylenepolyoxypropylene polymer 
(Pluronic F 68 .RTM.) 
20.02 mg 
______________________________________ 
The film has a length of 3 cm. 
EXAMPLE 3 
Composition of a film with sulprostone for buccal application 
______________________________________ 
0.3 mg Sulprostone 
9.16 mg Hydroxypropyl cellulose 
9.16 mg Cellulose fibers 
0.15 mg Polyoxyethylenepolyoxypropylene polymer 
(Pluronic F 68 .RTM.) 
18.77 mg 
______________________________________ 
The surface of the film is 1.2.times.1.2 cm. 
EXAMPLE 4 
Composition of a tablet with sulprostone for vaginal application 
______________________________________ 
0.1 mg Sulprostone 
238.9 mg Lactose 
110.0 mg microcrystalline cellulose 
1.0 mg Magnesium stearate 
350.0 mg 
______________________________________ 
EXAMPLE 5 
Composition of another tablet with 
11.beta.-[(4-N,N-Dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propiny 
l-4,9(10)-estradien-3-one for oral application 
______________________________________ 
10.0 mg 11.beta.-[(4-N,N--Dimethylamino)-phenyl]-17.beta.-hydroxy- 
17.alpha.-propinyl-4,9(10)-estradien-3-one 
140.5 
mg Lactose 
69.5 mg Corn starch 
2.5 mg Polyvinylpyrrolidone 25 
2.0 mg Aerosil 
0.5 mg Magnesium stearate 
225.0 
mg Total weight 
______________________________________ 
Pharmacological observations 
The prostaglandin sulprostone and the antigestagens 
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propiny 
l-4,9(10)-estradien-3-one (RU 38486) and 
11.beta.-(4-dimethylaminophenyl)-17.alpha.-hydroxy-17.beta.-(3-hydroxyprop 
yl)-13.alpha.-methyl-4,9-gonadien-3-one were selected as model substances 
for a pilot test on pregnant guinea pigs and rats. The dosages tested can 
be gathered from Table 1 and FIGS. 1 to 4. 
(1) Research on pregnant guinea pigs 
(1.1) Testing of the combination 
Description of the test 
Pregnant guinea pigs with a body weight of about 800 g were taken on the 
42nd day of pregnancy for the test (the second day of the vaginal opening 
in the mating season was counted as the first day of pregnancy). Pregnancy 
was checked by palpation before beginning of the test. The treatment took 
place with the selected test substances or the combination by daily 
injection on the 43rd and 44th day of pregnancy. For this purpose, the 
test substances were dissolved in benzyl benzoate+castor oil (ratio of the 
mixture in the case of sulprostone: 1+2; RU 38486: 2+4.5) and the daily 
dose was injected s.c. in a volume of 0.4 ml (sulprostone) or of 1.0 ml 
(RU 38486). The possible expulsion of the fetus was checked during and 
after treatment several times daily. On the 50th day of pregnancy, the 
animals were sacrified. The uteri were examined and the fetuses found. 
Results: 
The results of the tests for induction of abortion in pregnant guinea pigs 
with combined administration of antigestagen and prostaglandin are 
summarized in Table 1. 
TABLE 1 
______________________________________ 
Comparative examination of the abortive action of 
sulprostone (PG), RU-38.486 (competitive progesterone 
antagonist) and the combination of both substances in pregnant 
guinea pigs.) Treatment d43 and d44, autopsy on d50. 
n animals with abort./ 
Dose n total animals 
mg/d Sulpro- 
s.c. tone(S) RU-38.486 S-/RU - combination 
______________________________________ 
30.0 -- 4/9 0.03 mg Sulprostone 
10.0 -- 3/9 + 7/9 
3.0 -- 1/8 10.0 mg RU-38.486 
1.0 -- 0.03 mg Sulprostone 
0.3 10/10 + 4/8 
0.1 8/10 3.0 mg RU-38.486 
(2/10)* 
0.03 3/10 
0.01 0/9 
______________________________________ 
()* = `missed abortions`- 
Sulprostone: 
The abortifacient action of sulprostone was dependent on dosage. An 
abortion rate of 30% (=abortion in 3 out of 10 animals treated) was found 
in the case of a dose of 0.03 mg/d s.c. Expulsion of the embryos from the 
uterus occurred with this dose with a latency of about 1-2 days (see FIG. 
1). 
Antigestagens: 
With antigestagen RU 38486 a termination of an existing pregnancy with 30 
mg/d s.c. was to be obtained in 4 out of 9 animals treated. With a dose of 
10.0 mg/d the abortion rate was 3/9 animals treated. After 3.0 mg/d s.c. 
only 1 out of 8 animals treated aborted. The abortions occurred with 
latency of 4 to 7 days from the beginning of treatment (see FIG. 1). 
AG/PG combination: 
The combination of subabortive antigestagen doses (3.0 mg or 10.0 mg RU 
38486/d s.c.) with a marginally effective sulprostone dose of 0.03 mg/d 
s.c. led, in comparison with only antigestagen treatment, in each case to 
a clearly higher abortion rate and to a far faster induction of abortions. 
The interval of induction of abortion was also shorter than with only PG 
treatment, to the extent that the latter caused expulsion of the 
primordium at all (see table 1 and FIG. 1). 
1.2 Testing with sequential treatment 
Description of the test 
Pregnant guinea pigs with a body weight of about 800 g were taken on the 
42nd day of pregnancy for the tests (the second day of the vaginal opening 
in the mating season was counted as the first day of pregnancy). Pregnancy 
was checked by palpation before beginning of the test. The treatment took 
place with the selected antigestagens by daily injection on the 43rd and 
44th day of pregnancy. The prostaglandin was applied on the 45th day. For 
this purpose the antigestagen was dissolved in benzyl benzoate+castor oil 
(mixture ratio 2+4.5) and the daily dose injected subcutaneously in a 
volume of 1.0 ml. The sulprostrone was put in the galenical preparation of 
the Nalador.RTM. ampoule and injected subcutaneously. The possible 
expulsion of fetuses was checked during and after treatment several times 
daily. On the 50th day of pregnancy the animals were sacrificed. The uteri 
were inspected and the fetuses found. 
Results: 
The results of the tests for induction of abortion in pregnant guinea pigs 
in sequential application of antigestagen and prostaglandins are 
summarized in FIG. 2. 
Sulprostone: 
With a dose of 0.1 mg sulprostone/d s.c. an abortion rate of 50% (=abortion 
in 3 out of 6 animals treated) was found. Expulsion of embryos from the 
uterus occurred with this dose with a latency of about 6-24 hours (see 
FIG. 2). 
Antigestagens: 
With antigestagen RU 38486 a termination of an existing pregnancy with 10 
mg/c s.c. in 3 out of 9 animals treated was achieved. However, the 
abortion occurred only on the 48th or 49th day, i.e., with a latency of 5 
to 6 days from the beginning of treatment (see FIG. 2). 
AG/PG sequential treatment: 
With sequential administration of the above mentioned marginally effective 
AG and PG doses, termination of pregnancy in all guinea pigs (6/6 animals) 
occurred (see FIG. 2), in which the latency period was much shorter than 
with only PG treatment, to the extent that the latter was successful at 
all (median value: 4 hours versus12 to 24 hours). 
(2) Research on pregnant rats 
Description of test 
The tests were conducted on female Wistar rats of an in-house breed with a 
weight of about 200 g. After mating had occurred, the beginning of 
pregnancy was assured by determination of sperm in a vaginal smear. 
The day of determination of sperm is considered as day 1 of pregnancy (=dl 
p.c.). 
The antigestagens were dissolved in a benzyl benzoate-castor oil mixture 
(ratio 1+4). The vehicle volume per individual dose was 0.2 ml. The 
treatment was subcutaneous. 
The dosages selected can be gathered from FIG. 3. 
The prostaglandin sulprostone was dissolved in a mixture of ethanol+benzyl 
benzoate+castor oil (ratio 1+5+12). The vehicle volume of the selected 
individual dose of 0.1 mg was 0.2 ml. Sulprostone was applied 
subcutaneously. 
Pregnancy was checked by palpation before beginning of the test. Assignment 
of the pregnant animals to the various test groups was done randomly 
(n=6/group). With administration only of the antigestagens selected, the 
treatment took place by injection from d13-d15 of pregnancy. Groups, which 
were given a combined antigestagen/prostaglandin treatment, received, in 
addition, 2.times.0.1 mg sulprostone/animal s.c. on d15 p.c. 
Only sulprostone (2.times.0.1 mg/animal s.c. on d15 p.c.) was administered 
to another group. From d13-15 p.c. 0.2 ml of the benzyl benzoate-castor 
oil vehicle was applied daily to the control group. The rats were 
sacrificed on d17 p.c. and the uteri were examined for living and dead 
fetuses, retained placentas and empty nidation sites. The percentage of 
complete abortions (by definition: empty nidation site) was calculated per 
group. 
Results: 
The results of the tests for induction of abortion in pregnant rats are 
documented in FIGS. 3 and 4. 
Treatment with effective antigestagens led to induction of abortions in 
rats. However, there is a tendency to incomplete abortions, in part, the 
abortions go along with prolonged, continuous vaginal bleeding. (A 
corresponding behavior was observed in the first clinical research with 
RU-486 at the time of suppressed menstruation.) 
The percentage of complete abortions with 3-day s.c. administration of 3.0 
mg/d s.c. was 49.5% for the test substance 
11.beta.-(4-dimethylaminophenyl)-17.alpha.-hydroxy-17.beta.-(3-hydroxyprop 
yl)-13.alpha.-methyl-4,9-gonadien-3-one. After administration of 3.0 mg of 
RU-486/d s.c., the rate of complete abortions was 8.3%. Additional 
sulprostone administration of 2.times.0.1 mg/d s.c. on day 15 could 
clearly increase the abortive effectiveness of 
11.beta.-(4-dimethylaminophenyl)-17.alpha.-hydroxy-17.beta.-(3-hydroxyprop 
yl)-13.alpha.-methyl-4,9-gonadien-3-one and RU-486 (see FIGS. 3 and 4). 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.