Solution of luprostiol and 1,2,-propanediol and methods of preparation and use

A solution containing luprostial and 1,2-propanediol, characterized in that it contains luprostial in the form of its sodium salt in a solvent mixture comprising 50-90 percent by weight of 1,2-propanediol and 10-50 percent by weight of water, and has a pH between about 6 and 8.

BACKGROUND OF THE INVENTION 
This invention relates to an improved solution containing luprostiol and 
1,2-propanediol. 
Solutions of luprostiol 
(7.alpha.-(2-(3-(3-chlorophenoxy)hydroxypropylthio)-3.alpha., 
5.alpha.-dihydroxycyclopentyl)-5-heptenoic acid) in 1,2-propanediol are 
disclosed in Canadian Patent Specification No. 1,142,434. They are used in 
particular, as injection solutions in medical treatment of humans and, 
above all, in veterinary medicine, for luteolysis, for synchronizing 
estrus or for inducing labor, for example in the case of horses, cattle, 
pigs, sheet and goats. 
Disadvantages have been found in using the known solutions. In particular, 
problems are caused by the high viscosity, which renders drawing and 
injection considerably difficult, particularly at low temperatures such as 
prevail in the winter half-year, which is the principal season for 
practical use. Furthermore, solutions of the free acid luprostiol are 
unstable to a limited extent, since esters are formed from the acid and 
the solvent as the result of acid autocatalysis. 
OBJECTS OF THE INVENTION 
It is an object of this invention to avoid, or at least to mitigate, these 
disadvantages of the known Luprostiol solutions. 
Another object is to provide a luprostiol solution of low viscosity which 
is stable from the chemical and pharmaceutical aspects. 
Another object is to provide a Luprostiol solution which permits an 
adequately high concentration of active compound and for which the local 
tolerance is good. 
It is another object of the invention to provide a method of preparing a 
solution containing the sodium salt of luprostiol in a solvent mixture of 
50 to 90 percent by weight 1,2-propanediol and 10 to 50 percent by weight 
water. 
Another object of the invention is to provide a methodo for inducing labor 
in mammals. 
Another object of the invention is to provide a method for inducing 
luteolysis in mammals. 
Furthermore, another object of the invention is to provide a method for 
synchronizing estrus in mammals. 
Upon further study of the specific and appended claims, further objects and 
advantages of this invention will become apparent to those skilled in the 
art. 
SUMMARY OF THE INVENTION 
These objects are achieved by providing a solution containing luprostiol 
sodium salt dissolved in a solvent mixture comprising, based on the total 
solvent mixture, about 50-90 percent by weight 1,2-propanediol and 10-50 
percent by weight water, said solution having a pH of about 6-8. 
This improved solution is stable from the chemical and pharmaceutical 
aspects, is self-preserving and has a substantially lower viscosity than 
the known luprostiol solutions, so that, as far as viscosity is concerned, 
it can be handled with few if any problems at any temperature customary in 
practice. In addition, the local tolerance for the solution is better than 
that for conventional luprostiol solutions, 
The solution according to the invention preferably contains 0.1 to 100, 
preferably 1 to 10 and especially 3 to 8 mg of luprostiol sodium salt per 
ml. 
The solvent mixture contains 50 to 90, preferably 60 to 80 and especially 
65 to 75, per cent by weight of 1,2-propanediol and, accordingly, 10 to 
50, preferably 20 to 40 and especially 25 to 35, percent by weight of 
water. 
When the water content is higher than 50 percent, luprostiol or its sodium 
salt may precipitate. 
The pH of the solution is between about 6 and 8, preferably between 6.5 and 
75 and especially between 6.8 and 7.2. 
At pH values lower than 6 and higher than 8, the chemical and galenical 
stability as well as the compatibility of the solution will decrease. 
The invention also relates to a process for the preparation of a solution 
containing luprostiol and 1,2-propanediol, characterized in that 
luprostiol or preferably its sodium salt is dissolved in 1,2-propanediol 
and the concentration of the solution is then adjusted by the addition of 
water. If appropriate, additional 1,2-propanediol cn be added in order to 
obtain a solvent mixture which has the desired concentrations of 50-90 
percent by weight of 1,2-propanediol and 10-50 percent by weight of water. 
If necessary, the pH of the solution can be adjusted to the desired value 
of between about 6 and 8 by adding a basic sodium compound. 
Preferably, the solution of the invention is prepared by the following 
procedure: (1) a solution of approximately 12% of 13% luprostiol in 
1,2-propanediol is prepared; (2) the calculated amount of water and, if 
necessary, additional 1,2-propanediol are added to the solution; (3) if 
necessary, the pH of the solution is adjusted to within the desired range 
by adding sodium hydroxide solution; and (4) if necessary, addition 
1,2-propanediol is added to the solution to achieve the desired 
concentration of the solvent mixture components. 
This procedure avoids a precipitation of luprostiol or its sodium salt. 
Examples of basic sodium compounds which are also suitable instead of 
sodium hydroxide solution are sodium carbonate or bicarbonate, preferably 
in the form of their aqueous solutions. 
The operations described up to this point are preferably carried out at 
temperatures between 10.degree. and 80.degree. C., preferentially between 
20.degree. and 30.degree. C., and advantageously with stirring. 
The solution thus obtained is preferably subjected to sterile filtration 
under aseptic conditions and, if desired, under an inert gas, such as 
nitrogen, through a membrane filter having a pore width of 0.1 to 0.4 
.mu.m, preferably 0.2 .mu.m. The low viscosity of the solution enables it 
to be filtered more rapidly than the known solution of higher viscosity. 
Thus, the low viscosity provides a saving of time in the preparation, a 
briefer and hence smaller exposure of the active compound and a shorter 
time for the possible absorption of impurities. 
The resulting solution can be filled into ampules or injection vials, 
preferably under aseptic conditions and protected from light. The stock 
vessels can be evacuated and filled with an inert gas, such as nitrogen. 
Each ampule or injection vial can contain, for example, between 0.1 and 
1,000, preferably between 0.5 and 100, mg of active compound. 
The new solution can be used for medical treatment of mammals, including 
humans, for luteolysis, synchronizng estrus, and inducing labor. It is 
preferably administered parenterally as an injection solution, in 
particular by intramuscular or intravenous injection, but can also be 
administered orally, for example in the form of drops. It is preferably 
administered in a dosage of 0.001 to 1, in particular 0.005 to 0.1 mg of 
active compound per kg of body weight. The dosage depends on the species 
treated, the mode of administration and the purpose of treatment. The 
dosage can therefore also fall below or exceed the values indicated above. 
If it is desired, for example, to utilize the estrus synchronizing action 
of luprostiol, it is particularly advantageous to administer, for example 
to cattle (cows or heifers), 0.1 mg to 20 mg, preferably 0.5 mg to 15 mg 
and especially 1.5 mg to 10 mg, of the active compound by intramuscular 
injection. It is favorable to administer the effective dose by a single 
injection between the 7th day and the 12th day of the menstrual cycle, but 
is is also possible to inject part doses several times, and, if 
appropriate, distributed over several days. Estrus can be synchronized by 
administering luprostiol in the case of other animals too, for example in 
the case of dogs, horses, sheep and pigs. The effective dose then varies, 
depending on the average body weight of the species treated, and can be 
determined withoout difficulty by those skilled in the art with the aid of 
the guiding values indicated above for cattle. 
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 preceding text and the following examples, all temperatures are set 
forth uncorrected in degrees Celsius and all parts and percentages are by 
weight, unless otherwise indicated. 
EXAMPLE 1 
600 g of 1,2-propanediol and 298.8 g of water for injection purposes are 
added successively to 60.19 g of a 12.46 percent solution of luprostiol in 
1,2-propanediol, and the mixture is stirred until a clear solution is 
available. The pH of this solution is adjusted to a value of 7.0 with 16.7 
ml of 1 M sodium hydroxide solution. The solution is made up with 
1,2-propanediol to a final weight of 1,048 g= 1,000 ml, subjected to 
sterile filtration through a membrane filter under aseptic conditions and 
filled into 10 ml injection vials. One ml of this injection solution 
contains 7.5 mg of luprostiol. Viscosity: 14 mPas at 20.degree., 44 mPas 
at 0.degree.. (In comparison, a solution of 7.5 mg/ml of luprostiol in 
pure 1,2-propanediol has the following viscosity values: 61 MPas at 
20.degree., 257 MPas at 0.degree.). 
EXAMPLE 2 
650 g of 1,2-propanediol, 313.7 g of water for injection purposes and 6.7 
ml of 1 M sodium hydroxide solution are added, analogously to Example 1, 
to 23.47 g of a 12.78 percent solution of luprostiol in 1,2-propanediol, 
and the mixture is then made up with 1,2-propaediol to a final weight of 
1,045 g=1,000 ml. The solution, which has a pH of 7.0, is filtered under 
sterile conditions and filled into 10 ml injection vials. One ml of this 
injection solution contains 3.0 mg of luprostiol. 
EXAMPLE 3 
1,000 ml of an injection solution containing 7.5 mg/ml of luprostiol are 
obtained, analogously to Example 1, from 55.8 g of a 13.5 percent solution 
of luprostiol in 1,2-propanediol, 404.5 g of water for injection purposes, 
570.6 g of 1,2-propanediol and 16.1 g of 1 M sodium hydroxide solution. 
Viscosity: 10.1 mPas at 20.degree., 29.4 mPs at 0.degree.. 
The preceding examples can be repeated with similar success by substituting 
the 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.