Note: Descriptions are shown in the official language in which they were submitted.
z~
The invention relates to a novel phar~aceutical composition
which contains the pharmaceutically active compound 7~ -~2-[3-(3-chloro-
phenoxy)-2-hydroxy-propylthio]-3 ~ ,5 ~ -dihydroxycyclopent-1-yl~-hept-5-
enoic acid and a specific excipient or carrier therefor.
7~ -~2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-3 ~,5 ~-
dihydroxycyclopent-l-yl~-hept-5-enoic acid, which is a compound analogous
to prostaglandin, has achieved particular significance in veterinary
medicine. It is active in the sexual organs and thus participates in
sperm migration, ovulation, fertilization, nidation, luteolysis and
uterus contraction. This gives rise to very diverse applications and
indications, e.g., estrus induction, cycle synchronization, induction of
- labour, termination of undesired pregnancy, persistent corpus luteum,
healing of corpus-luteum-cysts and follicule-lutein-cysts, and chronic
endometritis, in very diverse species of animals, for example, cattle,
horses, pigs and sheep.
Because of its great zootechnical significance, the most impor-
tant of these indications is cycle synchronization, for which the targets
hitherto have mainly been cattle. In cattle, luteolytic action of
7 ~-~2[3-(3-chlorophenoy)-2-hydroxy-propylthio]-3~C,5 ~ -dihydroxycyclopent-
1-yl~-hept-5-enoic acid effects involution of the corpus luteum and the
~ compound i5 therefore active in the perlod of the 5th to the 16th day of
; the cycle. After this luteolysis, a follicle capable of ovulation forms
with great reliability and after 2 - 3 days estrus and ow lation take
place.
7 ~-{2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-3O~,5~ -
dihydroxycyclopent-l-yl}-hept-5-enoic acid already has the full desired
activity at a dosage which is many times less than that required with the
naturally oCcurring prostaglandin F2~. The very good tolerance which
exists at the same time is retained, even at considerable overdosages,
~! 30 which can be administered without side effects. Compositions containing
-- 1 -- ~
., ,
7~-~2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-3 ~,5 ~ -dihydroxycyclo-
pent-l-yl~-hept~5-enoic acid can be administered intramuscularly, sub-
cutaneously, intravenously, intrauterinely, intraperitonously. The
intramuscular administration is preferred.
7~-{2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-3~ ,5~-
dihydroxycyclopent-l-yl~-hept-5-enoic acid is known from German Offen-
legungsschrift 2,513,371. 7~-~2-[3-(3-chlorophenoxy)-2-hydroxy-propyl-
thio]-3 ~,5e~-dihydroxycyclopent-1-yl~-hept-5-enoic acid is a markedly
lipophilic substance which is virtually insoluble in water. It has been
found in the past that it is not possible significantly to improve the
solubility of 7~ 2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-3 ~,5 ~-
dihydroxycyclopent-l-yl~-hept-5-enoic acid in water, even by the addition
of very diverse surface-active agents. While an opaque solution of this
type can be administered intramuscularly without difficulty, there is a
very great danger that the solution then no longer contains the full
amount of active ingredient when it is used, since the lipophilic compound
7~-~2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-3~ 95 ~-dihydroxycyclo-
pent-l-y~hept-5-enoic acid can settle in very small droplets on the walls
of the vessel.
It is an object, therefore, of a broad aspect of this invention
to provide a novel composition containing 7~-~2-[3-(3-chlorophenoxy)-2-
hydroxy-propylthio]-3~ ,5 ~ -dihydroxycyclopent-l-yl~ hept-5-enoic acid in
which 7~-~2-[3(3 chlorophenoxy)-2-hydroxy-propylthio]-3 ~ ,5 ~-dihydroxy-
cyclopent-l-yl~hept-5-enoic acid is readily soluble and which enables a
composition to be prepared which is stable for a long period without
special storage conditions having to be maintained.
By a broad aspect of this invention, a pharmaceutical composition
is provided which consists essentially of 7~ -~2-[3-(3-chlorophenoxy)-2-
hydroxy-propylthio]-3 ~,5~ -dihydroxycyclopent-1-yl~-hept-5-enoic acid
and propane-1,2-diol.
By a variant thereof, the concentration of 7~-~2-[3-~3-chloro-
phenoxy)-2-hydroxy-propylthio]-3 ~,5 ~-dihydroxycyclopent-l-yl~hept 5-enoic
acid is between 0.0001 and 20 g/l.
Thus, it has ncw surprisingly been found that propane-1,2-diol
meets all of the requirements which are made of an excipient for a pharma-
ceutical composition, especially an injection solution, of 7~ -~2-[3-(3-
chlorophenoxy)-2-hydroxy-propylthio]-3 ~,5:~-dihydroxycyclopent-1-yl3hept-
5-enoic acid. It has been found that 7O~-~2-[3-(3-chlorophenoxy)-2-
hydroxy-propylthio]-3 ~,5 ~-dihydroxycyclopent-1-yl~hept-5-enoic acid is
very readily soluble in propane-1,2-diol, so that the desired completely
clear injection solution can be prepared without difficulty.
Moreoverg when propane-1,2-diol is used as the solvent, an
injection solution is obtained which,surprisingly, is stable for several
years without a special preservative having to be added and without
special storage conditions having to be maintained.
This characteristic of the solution of 70~-~2-[3-(3-chloro-
pheno~y)-2-hydroxy-propylthio]-3OC,5 ~-dihydroxycyclopent-1-yl~hept-5-
enoic acid in propane-1,2-diol is of extremely great importance precisely
in the case of its use in veterinary medicine, which in most cases has to
be carried out in the open air, since a possibility for storage under
special storage condltions does not usually exist.
The pharmaceutical solutions according to aspects of the inven-
tion are prepared, for example, by adding propane-1,2-diol to 7O~- 2-[3-
(3-chlorophenoxy)-2-hydroxy-propylthio]-3 ~,5~ -dihydroxycyclopent-l-yl~-
- hept-5-enoic acid under aseptic conditions, with protection against light
and with the exclusion of traces of water, and if necessary warming to
temperatures of up to 80C. and preferably of up to 50C., with stirring,
until a clear solution has formed. If necessary, the solution may be
cooled and/or may be made up to the desired volume with propane-1,2-diol,
with stirring.
4;~34
The concentrations of the pharmaceuti~al solutions of aspects
of this invention which can be prepared in this way are appropriately
between 0.0001 and 20 g/l, preferably be~ween 0.001 and 10 g/l and in
particular 7.5 g/l.
The pharmaceutical solutions of aspects of this invention can be
filled into ampoules or vials and each ampoule or vial can contain between
0.1 and 1000 mg oE 7~ -~2-[3-(3-chlorophenoxy)-2-hydroxy-propylthio]-
3~,5 d-dihydroxycyclopent-1-yl~-hept 5-enoic acid, depending on its size
and on the concentration of t'he solution.
Filling of this type is carried out under aseptic conditions,
with protection against light and with the substantially complete exclusion
of traces of water. For example, a vacuum is applied to the batch vessels
and the vessels are filled with an inert gas, appropriately nitrogen.
The clear,'homogeneous solution of 7~ -~2-[3-(3-chlorophenoxy)-
2-hydroxy-propylthio]-3 ~,5 ~-dihydroxycyclopent-1-yl~-hept-5-enoic acid
in propane-1,2-diol is sterile-filtered, likewise under an inert gas
atmosphere, preferably through a membrane filter with a pore width of
O.2~um. The solution is then filled into sterilized containers, again
under an inert gas atmosphere, and the containers are sealed under sterile
conditions.
These'novel pharmaceutical compositions of aspects of this inven-
tion are preEerably administered in a dosage of 0.001 to 1 mg per kg
weight of the species treated and in particular 0.005 to 0.1 mg per kg
weight of the species treated. The dosage depends on the species treated,
the mode of administration and the purpose of the treatment and can, there-
fore, also be above or below the values indicated above.
If, for example, it is deslred to utilize the estrus-synchronizing
action of 7~ -~2-[3-~3-chlorophenoxy)-2-hydroxy-propylthio]-3~C,SO~-
dihydroxycyclopent-l-yl}hept-5-enoic acid, it is particularly advantageous
to inject 0.1 mg to 20 mg, preferably 0.5 mg to 15 mg and in particular
-- 4 --
~L~L4Z4~
lo 5 mg to 10 mg of the active ing t intramuscularly into cattle (C~lS
or heifers). In case the phase of the cycle is unknown, the first injec-
tion is administered at any time that will suit and the following second
injection is administered lO to 12 days later. If the phase of the cycle is
known, however, it is advantageous to administer the effective dose by a
single injection between the 5th day and the 16th day of the cycle,
preferably between the 7th day and the 12th day of tne cycle. It is also
possible to inject several partial doses, optionally divided over a period
of several days. It is also possible to synchronize the estrus in other
useful animals, for example, in sheep, pigs, horses and dogs, by adminis-
tration of 7~-~2-[3-(3-chlorophenoxy~-2-hydroxy-propylthio]-3 ~,5~ -
dihydroxycyclopent-l-yl~-hept-5-enoic acid. The effective dose varies as
a function of the average body weight of the species treated and can be
determined without difficulty by those skilled in the art, with the aid
of the nominal values indicated above for cattle.
The following Example shows the preparation of a pharmaceutical
solution according to one aspect of this invention.
Example
280 g of propane-1,2-diol are added to 2.25 g of 7~ -~2-[3-(3-
chlorophenoxy)-2-hydroxy-propylthio]-3vC,5 ~ -dihydroxycyclopent-l-yl ~hept-
5-enoic acid, the mix~ure is warmed at 40-50C., with stirring, until a
solution forms. The solution is cooled to 20C. and made up to 311 g
with propane-1,2-diol.
,. I
- 5 -