RU2123336C1 - Prostaglandin-containing preparation for veterinary purpose - Google Patents

Abstract

FIELD: veterinary science. SUBSTANCE: invention relates to development and search of new veterinary preparations regulating reproductive function of agriculture animals and useful for veterinary gynecology. Preparation has a complex compound of cloprostenol with glycyrrhizic acid and tyrosine as an active component. EFFECT: decreased dosage and cost of preparation, decreased toxicity, enhanced effectiveness. 2 cl, 10 tbl, 13 ex

Description

 The invention relates to the field of veterinary medicine, namely to the development and search for new veterinary drugs that regulate the reproductive function of farm animals and suitable for use in veterinary gynecology.

 Currently, prostaglandin veterinary drugs are widely used in agriculture to synchronize hunting, treat obstetric and gynecological diseases in cows and heifers, to synchronize farrowing, prevent postpartum pathology and increase reproductive functions in sows (Tolstikov G.A., Miftanov N.S. , Lazareva D.N., Pomoynetsky V.D., Sidorov N.N. Prostaglandins and their analogues in reproduction of animals and humans. Tallinn, Institute for Advanced Studies of Teachers of the Estonian SSR MP, 1989, 400 pp.).

 The following prostaglandin preparations are known that are used in veterinary medicine to regulate reproductive function and treat gynecological diseases: Estrofan (Czech Republic), Enzaprost (Hungary), Estufalan (USSR).

The Hungarian drug Enzaprost contains 20 mg of prostaglandin F ₂ as an active ingredient.

The active principle of the Estrofan preparation is the sodium salt of cloprostenol (I), a structural analogue of prostaglandin F ₂ . A single dose of the drug contains 500 μg of the indicated prostaglandin.

 As a prototype, the drug Estufalan was used, developed at the Institute of Organic Chemistry, Scientific Center of the Russian Academy of Sciences (IOKh UTs RAS) (TU-10-07-232-86), which contains cloprostenol, citric acid, sodium citrate, phenol and distilled water.

 The main disadvantage of many prostaglandin drugs is the rapid metabolism of an active substance (ADV) (prostaglandin) in living tissues, which is a limitation on the use of these drugs in medicine and veterinary medicine. In addition, the active substances of these drugs - prostaglandins - are quite toxic substances.

So, the Hungarian drug Enzaprost can cause an increase in body temperature in animals (sows) by 0.5-1.0 ^o C, increased heart rate, respiration, anxiety, urination, etc. Synthetic modified prostaglandins also have high toxicity and low stability (Roberts SM, Scheinman F. Chemistry, Biochemistry and Pharmacological Activity of Prostanoids. New York: Pergamon Press, 1979, 407 p .; Azhgikhin I.S. Prostaglandins. M .: Medicine, 1978, 415 p.). Despite the low doses of the active substance, prostaglandin preparations are still expensive, due to the complex technology of their preparation, which requires multi-stage synthesis.

 The invention solves the problem of developing relatively cheap, effective low-toxic drugs for regulating the reproductive function of farm animals and treating obstetric and gynecological diseases. This is also associated with the intensification of reproduction of farm animals in the conditions of industrial animal husbandry, when synchronization of hunting, labor, increasing the yield (preservation) of young animals and other sanitary and veterinary measures are of great importance.

 Currently, successes in creating new drugs are associated not only with the search for new biologically active substances, but also largely with the development of new dosage forms with targeted delivery to the affected organ and controlled release of ADV (prostaglandin) (Tolstikov A.A., Baltina L.A. Murinov Yu.I., Davydova V.A., Tolstikova T.G., Bondarev A.I., Lazareva D.N. Complexes of β-glycyrrhizic acid with prostaglandins - a new class of uterotonic active substances. Journal., 1991, 65 (2), pp. 29-32).

 In the search for combined dosage forms of cloprostenol (I) to solubilize, reduce toxicity and enhance the biological effect, the authors found that triterpene glycoside - glycyrrhizic acid (HA) (II) - the active principle of licorice root (Glycyrrhiza glabra L) - is capable of forming molecular complexes with tyrosine (III) and prostaglandins (PG), in particular cloprostenol (I). These complexes are stable substances, soluble in aqueous media, with higher uterotonic activity and lower toxicity than the original PG.

 When creating a new formulation, it was taken into account that HA has a strengthening effect on exogenous hormones of the adrenal cortex, increases the activity of glutamine transaminase, and has anti-allergic and antidote effects; acts as a stimulant of nonspecific immunity against various infections (Tolstikov G.A., Schulz E.E., Baltina L.A., Tolstikova T.G. Licorice. Unused opportunities of public health in Russia. Chemistry for Sustainable Development, 1997, 5 ( 1), 57-73). Tyrosine (III) is an important intermediate in the peptide synthesis and synthesis of the hormone DOPA. The latter produces dopamine, which acts as a central mediator in the nervous system. In particular, from dopamine in the nerve endings and structures of the central nervous system (CNS), such as the hypothalamus, norepinephrine, a precursor to adrenaline, is produced.

 The problem is solved by using the drug “Clathiram” as an agent for regulating the reproductive function and treating obstetric-gynecological diseases of farm animals, containing the complex compound of cloprostenol (I) with glycyrrhizic acid (II) and tyrosine (III) as an active substance (ADV), the use of which allowed to reduce the dosage of valuable prostaglandin - cloprostenol (I) obtained as a result of multistage synthesis, 3 times in a single dose of the drug (1 ml contains 75.0 μg clrosros tenola) compared with the well-known veterinary drugs "Estrofan" and "Estufalan."

Таким образом, в состав препарата "Клатирам" входят клопростенол (0,10 - 0,20 мг), глицирризиновая кислота (0,8 - 1,5 мг), тирозин (0,10 - 0,15 мг), фенол (0,8 - 1,3 мг), хлористый натрий (12 - 20 мг), фосфорнокислый натрий однозамещенный (55 - 65 мг), фосфорнокислый натрий двузамещенный (30 - 35 мг), диметилсульфоксид (0,05 - 1,0 мл), этанол 96% (0,02 - 0,7 мл), вода дистиллированная до 2 мл.

Thus, the composition of the drug “Clathiram” includes cloprostenol (0.10 - 0.20 mg), glycyrrhizic acid (0.8 - 1.5 mg), tyrosine (0.10 - 0.15 mg), phenol (0 , 8 - 1.3 mg), sodium chloride (12 - 20 mg), sodium phosphate monosubstituted (55 - 65 mg), sodium phosphate disubstituted (30 - 35 mg), dimethyl sulfoxide (0.05 - 1.0 ml), ethanol 96% (0.02 - 0.7 ml), distilled water to 2 ml.

 Clathiram is 10 times less toxic than Estrofan and Estufalan. The drug is released in 2 ml ampoules with a content of cloprostenol of 150 μg or 75.0 μg in 1 ml.

 Clathiram "has powerful luteolytic and uterotropic effects that exceed the similar properties of imported (" Estrofan "," Enzaprost ") and domestic (" Estufalan ") analogues when used on animals at doses 5-100 times lower than accepted.

 "Clathyram" enhances the contractile function of the uterus (uterotropic effect). The uterotropic activity of the drug in vitro exceeds the similar effect of Estufalan by 35 times.

 When administered intramuscularly, “Clathiram” causes a regression of yellow bodies and luteal structures in female farm animals, accompanied by a decrease in progesterone secretion, growth and maturation of follicles (luteolytic effect), increased levels of estrogen in the blood, manifestation of estrus, hunting and subsequent ovulation of mature follicles.

 “Clathyram” is more effective than “Estrofan” when used as a luteolytic agent to synchronize hunting in cows with a prostaglandin (cloprostenol) content 100 times lower than in the reference preparation.

 "Clathyram" has a regulatory effect on labor (synchronization of farrowing in sows) similar to "Estufalan" when using the drug with a lower dose of the active substance (35 times), reduces the postpartum period in cows by 15 days compared to "Estrofan".

 “Clathyram” is more effective than “Estrofan” and “Estufalan” in the treatment of functional disorders of the ovaries in cows, during transplantation of embryos.

 "Clathyram" is suitable for use in veterinary gynecology as a tool for the treatment of acute and chronic endometritis in cows. The therapeutic effect of the drug is not inferior to Estrofan and Estufalan, and combinations with 5-nitrox and gentamicin are especially highly effective. The therapeutic dose of “Clathirama” is 3 times less than the dose of comparison drugs.

 Thus, the obtained results indicate the possibility of widespread use of the drug "Clathyram" in animal husbandry and veterinary medicine as a regulator of the reproductive function of farm animals and the treatment of obstetric and gynecological diseases.

 "Clathyram" is used to treat cows with luteal and follicular cysts, persistent corpus luteum, ovarian hypofunction; treatment and prevention of subinvolution of the uterus and endometritis in cows, synchronization of sexual hunting in cows and heifers and superovulation in donor cows; treatment and prevention of functional disorders of the ovaries, prevention of postpartum diseases, synchronization of farrowings in pigs.

 "Clathyram" is administered to animals intramuscularly, once, to cows after milking.

 In the treatment of functional ovarian disorders, “Clathyram” is administered to cows at a dose of 200 mg by ADV in combination with gonadotropin (per 1 animal). Cows with persistent corpus luteum "Clathyram" is administered at a dose of 150 μg by ADV, with hypofunction of the ovaries in cows, "Clathyram" is administered at a dose of 150 μg by ADV in combination with gonadotropin.

 To prevent postpartum subinvolution of the uterus and endometritis, “Clathyram” is administered to cows at a dose of 150 μg by ADV in combination with subcutaneous injection of oxytocin.

 For the treatment of cows with acute and chronic uterine subinvolution, postpartum or chronic endometritis, Clathyram is administered at a dose of 150 mcg with the simultaneous administration of ethnotropic, pathogenetic and symptomatic therapy.

 Synchronization of sexual hunting in cows and mature heifers is carried out on 6-15 days of the reproductive cycle by introducing "Clathiram" in a dose of 150 μg by ADV. Animals that come to the hunt after the administration of the drug are inseminated, and not come, they are subjected to clinical and gynecological examination.

 To prevent infertility in pigs, "Clathyram" is administered at a dose of 75.0 mcg by ADV in combination with gonadotropin.

 To synchronize polls in pigs and to prevent postpartum diseases in them, “Clathyram” is administered at a dose of 75.0 μg to sows not farrowing on 113-114 days of gestation.

Example 1. Obtaining the drug "Clathyram". 75.0 mg of cloprostenol (I) is dissolved in 1.6 ml of ethanol and 600 mg of glycyrrhizic acid, 37 mg of tyrosine and 100 mg of phenol in 40 ml of freshly distilled dimethyl sulfoxide are added to the solution. The mixture was diluted with phosphate buffer prepared from 8 g of NaCl, 32 g of NaH ₂ PO ₄ • 2H ₂ O and 12 g of Na ₂ HPO ₄ • 12H ₂ O to a volume of 1000 ml, filtered through a Millipor sterilizing filter and poured into ampoules of 2 ml The preparation contains 0.15 mg of cloprostenol in the form of a complex with 1.2 mg of glycyrrhizic acid and 0.08 mg of tyrosine, and also contains 0.09 ml of dimethyl sulfoxide, 0.05 ml of ethanol (96%), 1.1 mg of phenol, 16 0 mg of sodium chloride, 61.0 mg of sodium phosphate monosubstituted, 31.0 mg of sodium phosphate disubstituted, 1.84 ml of distilled water.

 Example 2. Determination of acute toxicity of the drug "Clathyram".

The acute toxicity of Clathiram was determined on white outbred mice with the intravenous route of administration. The toxicity parameters were calculated according to Litchfield and Wilconson. The LD _{50 of} Clathiram was 95.0 mg / kg, the LD _{50 of} Estufalan was 14.0 mg / kg.

 Thus, Clathiram is approximately 6 times less toxic than the reference drug.

 Example 3. The study of the uterotropic activity of the drug "Clathyram".

The uterotonic activity of Clathiram was studied in vitro on outbred rats by the Magnus method. Estufalan with a similar concentration of cloprostenol was used as the reference drug. A section of an isolated uterine horn was placed in a thermostatted (37 ^o C) Ringer-Locke solution (solution composition: NaCl - 9 g / L; KCl - 420 mg / L; NaHCO ₃ - 150 mg / L; CaCl ₂ - 240 mg / l; glucose - 1 g / l) and attached to the recorder. The uterotropic activity of the drugs was judged by the percentage increase in the amplitude of uterine contractions (inotropic effect) and by the percentage of increase in tone (tonotropic effect). The results of the experiments are presented in table. 1.

 From the table. 1 shows that the most effective is the molecular complex of the following composition: 1 PG • 4 HA • 1 tyrosine, called “Clathyram”.

The drug "Clathyram" with a concentration of PG 1 • 10 ^-12 g / ml is more than 3.5 times more active than the comparison drug "Estufalan" (1 • 10 ^-8 g / ml). Moreover, the complex 1 PG • 4 HA • 1 tyrosine with a concentration of PG 1 • 10 ^-16 g / ml has a noticeable uterotonic effect, while the Estufalan preparation containing PG in a concentration of 1 • 10 ^-12 g / ml, not active anymore. The discovered effect allowed us to reduce the dosage of cloprostenol in the Clathiram preparation 30 times lower than the accepted ones.

 Example 4. The use of the drug "Clathyram" to synchronize farrowing in sows.

 In the experimental and control groups were taken 10 sows with a gestation period of 113 days. The animals of the experimental group were injected intramuscularly with “Clathyram”, the control group remained intact (Table 2). In the experimental group, farrowing occurred after 24.38 ± 2.6 hours with a duration of 3.05 ± 0.42 hours, in the control group farrowing occurred only after 50.8 ± 5.1 hours.

 The data from a comparative study on the effect of the Clathiram and Estufalan preparations on the synchronization of farrowings are given in Table. 2.

 As can be seen from the data table. 2, the Clathiram preparation compares favorably with the Estufalan comparison drug, since 1/35 of the active principle of the indicated comparison preparations, cloprostenol, is sufficient to achieve physiological effects on sows compared to Estufalan and similar imported drugs (Estrofalan). The time of onset of farrowing with the introduction of a dose of Clathiram containing a dose of 5 mg cloprostenol is 24.38 ± 2.6 hours; Estufalan has a similar effect when it contains ADV 175 μg, and Estufalan is more active than Estrofan when administered in equal doses and more effective than Enzaprost (the dosage of Estufalan is approximately 113 times lower) (Estufalan TU-10-07-232-86). There was no statistically significant difference in the effectiveness of the doses calculated for cloprostenol in the Estufalan (175 mcg) and Clathyram (125-2.5 mcg) preparations.

 For farrowing synchronization, a dose of 5 μg of cloprostenol is economically viable and with a high margin of reliability.

 Example 5. The study of the effect of the drug "Clathyram" on the regulation of sexual function and treatment of obstetric and gynecological diseases.

 To study the effect of Clathiram on the regulation of sexual function and the treatment of obstetric and gynecological diseases, we tested 77 cows with functioning yellow bodies of the sexual cycle, luteic acids, persistent yellow bodies and pregnant animals with a gestational age of 2-5 months.

 Separately prepared preparations "Clathiram" with the content of cloprostenol 250, 175, 50.5, 2.5, 0.25, 0.0025 μg were administered in a volume of 2 ml. As a comparison drug, Estufalan was used in the dose taken (500 μg per cow) (Table 3). The results were taken into account by continuous clinical and gynecological examination of animals and their slaughter for 6-9 days after drug administration. It was established that “Clathyram” in doses of 250 to 50 μg of cloprostenol causes the resorption of functional corpus luteum. At a dose of 5 μg cloprostenol, a similar phenomenon is observed only in 20% of animals. Drugs with a lower concentration of cloprostenol (2.5 μg) do not cause clinical changes.

 Example 6. The effect of the drug "Clathyram" on the synchronization of hunting in heifers.

 The drug "Clathyram" was tested for synchronization of hunting in heifers. Selection of heifers for experience and control was carried out according to the method of analog groups. The experimental group was administered “Clathyram” with a concentration of cloprostenol 50 μg / 2 ml intramuscularly, the control group “Estrofan” in the recommended dose of 500 μg per cow (Table 4).

 The arrival of heifers into the hunt was determined by the presence of mucus, redness of the mucous membrane of the vagina and the "reflex of immobility". In addition, the condition of the ovaries was examined by palpation through the rectum.

 A total of 40 heifers were treated, 20 of them with Estrofan and 20 with Clathiram. The drugs were administered at the same time twice with an interval of 11 days. 48 hours after the second injection, rectal studies were performed in animals to identify the effect of luteolysis of the corpus luteum of the ovaries.

 As a result, it was found that after a single treatment with Clathiram, 17 heads (80%) of heifers came into the hunt, and after Estrofan - 12 goals (60%). Thus, the luteolytic effect of the introduction of the drug “Clathiram” is manifested at a higher level than that of “Estrofan”, and the dose of ADV in the drug “Clathiram” is 10 times less than in the comparison drug.

 Example 7. The effect of the drug "Clathyram" on the morphological and functional regression of the corpus luteum in cows (luteolytic effect).

 The experiments were carried out on 68 cows, divided into 3 groups. A test group of 18 cows was injected once intramuscularly with Clathiram (100 μg of ADV per cow) and the progesterone content in milk was examined 24, 48, 72 and 96 hours after Clathiram injection.

 The control group of 29 cows received a single intramuscular injection of 500 μg of Estufalan, and the second control group of 21 cows received a single intramuscular injection of 500 μg of Estrofan. In both control groups, the level of progesterone in milk was evaluated as in the experimental group.

 The progesterone content in milk was determined using the apparatus "Gama Muvek" company Yanma (Hungary).

 The results of the experiments are presented in table. 5.

 From the data table. Figure 5 shows that in the group of cows treated with Clathiram, regression of the corpus luteum is clearly expressed and is similar to the effect of the preparations Estufalan and Estrofan taken in a five-fold increased dose.

 Thus, the drug "Clathyram" with a single dose of 100 μg per cow shows a powerful luteolytic effect, which is detected by a decrease in the amount of progesterone in milk. The luteolytic effect of the drug is not inferior to the similar effect of the preparations of comparison "Estufalan" and "Estrofan" when administered in doses of 500 μg per cow.

 Example 8. The effect of the drug "Clathyram" on the postpartum period of cows with functional disorders of the ovaries.

 The effect of the Clathiram preparation on the reproductive function of cows with functional disorders of the ovaries (hypofunction, persistent corpus luteum, ovarian cyst) was studied. As a comparison drug used the drug "Estrofan". Under observation were 52 cows with a persistent corpus luteum of the ovaries. Of these, 27 cows in the experimental group and 25 in the control; 53 cows with ovarian hypofunction (28 experimental and 25 control animals); 14 animals with follicular cysts (8 in the experiment and 6 in the control). Experienced animals were injected with “Clathyram” at a dose of 100 μg ADV, and with control animals “Estrofan” at a dose of 500 μg ADV.

 Animals that came to the hunt were artificially inseminated by the visocervical method. Then, animals were monitored and examined for pregnancy for 60 days.

 Analysis of the test results showed that the postpartum period in the cows of the experimental groups was 46.6 days, and in the control - 62.1 days.

 Thus, the postpartum period decreased by 15.5 days.

 Example 9. The use of the drug "Clathyram" for the treatment of cows with persistent corpus luteum.

 The experiments were carried out on 71 cows, divided into 3 groups.

 An experimental group of 20 cows, which were injected once intramuscularly at 150 μg (ADV) "Clathirama". The progesterone content in milk was determined 24, 48, 72 and 96 hours after drug administration.

 A control group of 26 cows received 500 mcg (by ADV) of Estufan, and another control group of 25 cows received 500 mcg (by ADV) of Estrofan.

 The results of the experiments are presented in table. 6 show that 60% of cows showed estrus with Clathiram, 46.2% with Estufalan and 48% with Estrofan. Fertilization of cows in all three groups of the same insemination is approximately the same.

 Example 10. Treatment of acute (purulent) endometritis in cows with the drug "Clathyram".

We studied 125 cows, divided into 6 groups:
The 1st group of 8 cows was administered "Clathyram" (150 μg ADV) twice intramuscularly after 11 days.

 Group 2 of 11 cows, between the two administrations of Clathiram, 2 g of gentamicin was administered intrauterine after 48 hours

 The 3rd group of 14 cows, between two injections of “Clathiram” was administered intrauterine 5-nitrox (2 tablets).

 The 4th group of 18 cows was twice injected with 500 μg of Estrofan (intramuscularly) after 11 days.

 5th group of 24 cows, between two injections of Estrofan, gentamicin (2 g) was intrauterine injected after 48 hours

 The 6th group of 49 cows, between the injections of "Estrofan" was administered intrauterine 5-nitrox (2 tablets).

 The results of the experiments are presented in table. 7. The Clathiram and Estrofan preparations, when used in their pure form, showed the same effect: 62.5 and 61.1% of the cows were cured, respectively.

 With the introduction of both drugs in combination with gentamicin or 5-nitrox (intrauterine), the healing effect was higher, and the combination of Clathiram + 5-nitrox and Estrofan + 5-nitrox proved to be the most effective (cure reached 92.8 and 95.9 %, respectively), and only one cow out of 14 (7.2%) in the case of Clathiram and 2 out of 49 cows (4.1%) in the case of Estrofan got the disease in a chronic form.

 According to their influence on the independent and service period, “Clathyram” and “Estrofan” are also the same both individually and in combination with other drugs (gentamicin and 5-nitrox). Thus, “Clathyram” in a five-fold reduced dosage in comparison with the comparison drug “Estrofan” has the same effective therapeutic effect on acute endometritis in cows.

 Example 11. The treatment of chronic catarrhal endometritis in cows with the drug "Clathyram".

Studied 111 cows, divided into 4 groups:
The 1st group of 12 cows was administered 150 μg (according to ADV) of the Clathyram drug intramuscularly, twice, after 11 days.

 The 2nd group of 19 cows was injected intramuscularly with 5-nitrox (2 tablets) between two injections of Clathiram.

 The 3rd group of 44 cows was administered 500 μg of Estrofan intramuscularly, twice, after 11 days.

 The 4th group of 36 cows, between two injections of "Estrofan" was administered intramuscularly 5-nitrox in 2 tablets.

 As can be seen from the data table. 8, in the group of cows treated with Clathiram, the cure rate reached 58.3%, and with Estrofan the effect was 47.7%.

 When using both drugs in combination with 5-nitrox, the therapeutic effect was significantly higher, and the effectiveness of both drugs was approximately the same.

 In the treatment of acute and chronic catarrhal endometritis in cows, a high cure effect is observed when using Clathiram in combination with gentamicin or 5-nitrox 3 times after 48 hours between two injections of the drug (within 11 days). The effect of recovery is similar to the action of Estrofan in a similar combination.

 Example 12. The use of the drug "Clathyram" to synchronize heifice recipients during transplantation of embryos.

 Heifers were treated by intramuscular injection of Clathiram in 2 ml (150 μg ADV) with an interval of 10 days. After 48-72 hours, ovarian condition was monitored by rectogenital palpation, according to the reflex of immobility. Then heifers were selected by the presence of an actively functioning corpus luteum in the ovaries.

 Thawed embryos were injected on the 7th day after estrus by a non-surgical method. As a control, the drug Estrofan was used at a dose of 500 μg ADV.

 The test results are presented in table. nine.

 As can be seen from the data table. 9, the drug “Clathyram” is not inferior in biological activity to the imported drug “Estrofan” (synchronization of hunting in heifers). Moreover, the Clathiram preparation was more effective than Estrofan in embryo transplantation by 2.3 times.

 The high activity of the Clathiram preparation was confirmed by the radioimmunological method of studying the level of progesterone in the blood of animals.

 Example 13. The effect of the drug "Clathyram" on the contraction of the uterus in cows.

 We studied 74 cows, divided into 3 groups: an experimental group of 20 cows, which were injected intramuscularly with a dose of 100 μg (according to ADV) of the drug “Clathyram” 5 hours after delivery; the control group of 17 cows was treated with 500 mcg of Estufalan and the 2nd control group of 37 cows was left without treatment.

 Observations were made for the duration of the independent and service periods, placenta retention, and the occurrence of acute endometritis. The results of the experiments are presented in table. 10. As can be seen from the data table. 10, “Clathyram” prevents the development of acute endometritis in 12-15% of cows compared to controls similar to “Estrofan” and “Estufalan”. The reduction of the uterus after childbirth with the introduction of “Clathiram” is completed 8 days earlier than in the control, when treated with “Estrofan” - 9 days, “Estufalan” - 7 days earlier. There is a decrease in the independent and service periods when administering the drug compared with the control groups (treatment with Estufalan and Estrofan). Thus, "Clathyram" can be successfully used as a stimulator of uterine contractions after childbirth and as a means for the prevention of postpartum complications.

Claims (1)

1. Veterinary drug for the regulation of reproductive function and treatment of obstetric and gynecological diseases of farm animals, containing cloprostenol (prostaglandin) and the target additive phenol and distilled water as an active principle, characterized in that the active principle additionally contains tyrosine and glycyrrhizic acid in the following ratio components, mg:
Cloprostenol - 0.10 - 0.20
Glycyrrhizic acid - 0.8 - 1.5
Tyrosine - 0.10 - 0.15
Target Additive:
dry components - 100 - 120
liquid components, mm - 2
2. The drug according to claim 1, characterized in that the target additive contains dimethyl sulfoxide, ethanol (96%), sodium chloride, phenol, sodium phosphate, monosubstituted and disubstituted, distilled water in the following ratio, mg:
Phenol - 0.8 - 1.3
Sodium Chloride - 12 - 20
Monosubstituted sodium phosphate - 55 - 65
Sodium Phosphate Disubstituted - 30 - 35
Distilled water, ml - Up to 2
Dimethyl sulfoxide, ml - 0.05 - 1.00
Ethanol (96%), ml - 0.02 - 0.07 n

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