RU2390333C1 - Veterinary implanted retard drug for improving productivity of farm animals (versions) - Google Patents

Abstract

FIELD: medicine, veterinary science. ^ SUBSTANCE: invention refers to agents of veterinary medicine and can be used in fur farming and animal husbandry for improving young growth liveability and productivity of animals. A new veterinary implanted retard drug for improving productivity of farm animals contains active substances: melatonin or melatonin and ximedone, a biodegradable polymer base and processing aids; and said biodegradable polymer base is presented with interpolymer complexes of polymethacrylic acid and polyethylene glycol ("Ü"-1) or interpolymer complexes of polymethacrylic acid and polypropylene glycol ("Ü"-2) in a certain ratio. The processing aids are lactose or microcrystalline cellulose or their mixtures in the ratio (wt %) 50:50. Said "Ü"-1 or "Ü"-2 used as the polymer base allows introducing up to 25% of ximedone into a dosage form of said veterinary drugs that essentially improves their effect, and reducing their cost in 1.5-2 times in comparison with a prototype. ^ EFFECT: application of the veterinary drugs containing melatonin and "Ü"-1 or "Ü"-2 bases in fur farming with using an accelerated technology of mink farming ensures liveability of a mink livestock to the slaughter period with reducing farming time by 1,5-2 months and gain in fur production of the area exceeding the untreated animals by 15-20%. ^ 8 cl, 2 tbl, 38 ex

Description

The invention relates to veterinary medicine and can be used in fur farming and animal husbandry to improve the safety of young animals and animal productivity.

The progress of veterinary pharmacology is provided by the constant search and creation of new highly effective and safe drugs. It has been established that many environmental factors, such as unbalanced feeding, stresses of various etiologies, adversely affect the metabolism and immune system of animals. All this leads to a decrease in natural resistance and impaired reproductive ability (decrease in fertility, increase in embryonic mortality) of animals and, consequently, a decrease in their productivity. For example, in pigs killed during and after stress, gastric ulcers, atrophy of lymphoid tissue, and an increase in the size of the adrenal glands are found. The meat of such animals of low quality: pale, watery [Smirnov A.P., Pigalev S.A. The natural resistance of the organism of animals in conditions of no-leave content. Ministry of Agriculture of the USSR. - Saratov. - 1983. - 60]. In this regard, the development, research and production of pharmacological agents for the prevention and treatment of diseases associated with metabolic disorders, as well as means of stimulating the growth and productivity of animals, is an urgent area in veterinary medicine.

It is known to use synthetic hormonal preparations, such as testosterones, methylandrostenediol, etc., to increase the live weight gain of animals [Paducheva A. L., Hormonal preparations in animal husbandry. - M .: Rosselkhozizdat, 1979, 231]. It is also known the use of a synthetic peptide - thymogen as a means to increase the growth and preservation of young animals [Patent RU 2111756, publ. May 27, 1998; BI No. 15 (II h), p. 237, 1998]. It is also known to use selenopyran for the growth rate and preservation of the number of piglets by injecting subcutaneously or intramuscularly to newborn piglets of a prolonged form of selenopyran in a hydrophobic carrier at a dose of 14 mg of selenopyran per piglet [Patent RU 2157690, 20.10.2000].

Unfortunately, the well-known pharmacological preparations used at various stages of the technological process of raising animals are short-lived. There is a need to use them according to certain schemes during the entire period of growing animals, which leads to higher prices for agricultural products.

It is known to use synthetic melatonin for regulating the biological rhythm of animal vital processes [Patent AU 78305/81 06.1982]. It is also known to use veterinary implants for these purposes containing melatonin or related chemicals of the Indole class, a polymer carrier and a coating for the implant from a physiologically compatible polymer [US Pat. No. 4,882,137 of 11/21/1989]. These implants have a low level of prolongation of melatonin (less than 20 days), a multicomponent composition, the method of their manufacture is technologically complicated and multi-stage. More attractive are veterinary preparations developed in Russia, containing melatonin and a polymer base, contributing to the acceleration of hair maturation of fur animals [A.S. 1579489 USSR, MKI A01K 67/02; RU 2122787 dated 10.10.1998, IPC 6 A01K 67/02, A61K 31/51 // BI No. 9, 1999,]. But they are not without some significant drawbacks, namely, they contain a partially biodegradable polymer base, which leads to incomplete "release" of melatonin; in addition, these drugs are effective with the mandatory inclusion in the diet of digestible protein in the amount of 6-8 g per 100 kcal of feed.

It is known that a veterinary implantable preparation containing synthetic hormone of the pineal gland, melatonin on a polymer basis, obtained from ethyl cyanoacrylate [RU 2096044, MKI A61K 47/30 (A61K 47/30, 38:22), is known for growing fur animals. // BI No. 32, 1997]. The use of this drug in fur farming allows animals to be slaughtered 1.5-2 months earlier than the standard slaughter terms and get fur products with an area of 10-15% more than the standard.

Most preferred are prolonged-acting implantable veterinary preparations containing melatonin or melatonin with xymedon, a biodegradable polymer base and processing aids or plasticizer [RU 2219910 C2, 12/27/2003 - prototype]. Xymedon (1- (β-hydroxyethyl) -4,6-dimethyl-1,2-dihydro-2-hydroxypyrimidine) is a promising drug that has proven itself in the treatment of purulent-inflammatory postoperative complications [Patent RU 2019176, MKI A61K 31 / 505 // BI No. 60 1995; Patent RU 2063752, MKI A61K 31/505 // BI No. 20, 1996; Patent RU 2082402, MKI A61K 31/505 // BI No. 18, 1997]. By order of the Ministry of Health of the Russian Federation dated 07.12.93, No. 287, Xymedon is approved for use in medicine. Compared with drugs such as retabolil, methandrostenolone, levomizole, xymedon is a drug with a combined therapeutic effect, has no side effects, does not cause allergic reactions, does not have any hormonal activity and does not affect endocrine homeostasis. As the polymer base, water-soluble cellulose derivatives are used, preferably microcrystalline cellulose (MCC) with a polymerization degree of 150-200 using technological additives to give the composition the necessary physicomechanical and prolonging properties or biodegradable polymers based on ethyl cyanoacrylate (cyacrin-EO) using plasticizers . The introduction of the above drug to mink patients with viral plasmacytosis contributes to the course of the disease in the form of a sluggish subclinical infection without activating the autoimmune phase of the disease. This ensures the safety of the livestock of minks until the slaughter period, while reducing the time for their cultivation by 1.5-2 months earlier than standard terms and obtaining fur products with an area of 18-20% more compared to untreated animals. The claimed drugs can increase the nonspecific resistance of the organism and the safety of piglets in the postnatal period of development, to provide an increase in live weight by 20-50%.

It should be noted that the best results when using the prototype drug were obtained using polyethyl cyanoacrylate as the polymer base, which requires expensive cyacrine - EO according to TU 2435-353-00208947-2001 (the cost of 1 kg of this reagent is about 14,000 rubles), which leads to a rise in price of target products several times. In addition, the use of ethyl cyanoacrylate (cyacrine-EO) to obtain a polymer base provides a more technological mass for processing. However, in this case, the preservation of the necessary physicochemical characteristics of the drug samples is ensured only when Xymedon is added to the formulation in an amount of not more than 9%. An increase in the content of xymedon in the formulation leads to a liquefaction of the reaction mass and the inability to process it into final products.

Thus, the known implantable prototype drugs of prolonged action have the following disadvantages:

- the high cost of the preparations associated with the use of a polymer based on expensive ethyl cyanoacrylate (cyacrine-EO) as a polymer carrier, which leads to an increase in the cost of the preparations;

- the impossibility of introducing into the formulation of the drug the active substance Ximedon in an amount of more than 9 wt.%, which reduces the effectiveness of the drug.

The objective of the invention is a new implantable prolonged-action drugs for veterinary medicine based on synthetic melatonin, expanding the arsenal of known highly effective medicinal veterinary drugs, increasing the productivity of farm animals with their minimum consumption, having low cost and high economic efficiency.

The technical result - new, cheaper, cost-effective implantable veterinary drugs of prolonged action, increasing the productivity of farm animals with minimal consumption.

The technical result is achieved by using as a polymer base a promising composite polymer carrier - KPN-1 according to FSP 42-0354196501, which is an interpolymer complex of polymethacrylic acid and polyethylene glycol of equimolar composition, or KPN-2 according to TU 6-02-121-98, which is an interpolymer a complex of polymethacrylic acid and polypropylene glycol of equimolar composition. The cost of CPN-1 and CPN-2 is 10-12 times lower than the cost of cyacrine-EO. The use of interpolymer complexes in the formulation of drugs based on melatonin will allow at least 2 times to reduce the cost of veterinary drugs.

The interpolymer complexes used are the products of the intermolecular interaction of linear or rarely cross-linked polymethacrylic acid with polyethylene glycol or polypropylene glycol. Complexes are structures with regular sequences of hydrogen bonds separated by defects - polymer units that are not included in the complexation reaction. These complexes are not soluble in an acidic environment and decompose into water-soluble components in a neutral environment. The use of interpolymer complexes allows not only to provide a prolonging effect, but also to avoid multicomponent composition and reduce the amount of excipients.

It is known that KPN-1 and KPN-2 are used as carriers for uniform release of active substances into the gastrointestinal tract, in prolonged-release drugs with oral administration [Patent RU 2267321 of 05.25.2004; Patent RU 2267322 dated 05.25.2004; Patent RU 2267318 dated 05.25.2004; Patent RU 2172170 from 07.10.1999]. The use of CPN-1 and CPN-2 as polymer carriers in drugs implanted under the skin of animals has not been previously described in the literature.

Four compositions of a veterinary implant based on melatonin of the following composition are claimed (wt.%):

1. Melatonin 10-50 KPN-1 89.95-35 Technological Additives 0.05-15 2. Melatonin 5-25 Ximedon 5-25 KPN-1 89.95-35 Technological Additives 0.05-15 3. Melatonin 10-50 KPN-2 89.95-35 Technological Additives 0.05-15 4. Melatonin 5-25 Ximedon 5-25 KPN-2 89.95-35 Technological Additives 0.05-15

A distinctive feature of the claimed compositions of drugs of prolonged action is the use as a polymer carrier of composite polymer material KPN-1 or KPN-2.

The introduction of active substances below 5 wt.% Does not provide the expected effect, above 50 wt.% (Compositions 1, 3) and 25 wt.% (Compositions 2, 4) is not economically feasible.

The content of the polymer base below 35 wt.% And above 89.95 wt.% Does not provide the necessary prolonging properties of the drug. As technological additives, lactose or water-soluble cellulose derivatives are used, preferably microcrystalline cellulose. The introduction of technological additives can improve the physico-mechanical characteristics of the drug. Being pore-formers, these additives allow you to regulate the process of prolonged release of active substances.

The use of technological additives above 15 wt.% Leads to a violation of the strength characteristics of the drug, below 0.05 wt.% Does not provide the necessary physico-chemical characteristics of the composition.

The dosage form of the proposed compositions are cylindrical tablets weighing 0.040 ± 0.010 g with a diameter of 2.0-2.4 mm in brown (shades are not standardized). Preparation of the drug was carried out similarly [Patent RU 2267318 of 05.25.2004].

The use of the drug based on KPN-1 or KPN-2 in fur farming contributes to the safety of the livestock of minks until the slaughter period while reducing the time for their cultivation by 1.5-2 months earlier than standard times and to obtain fur products with an area of 15-20% more than untreated animals at a cost of 1.5-2 times lower than known.

The experiment showed that the implantation of model veterinary compositions containing only Xymedon and KPN-1 or KPN-2 as the active substance does not provide minks with accelerated maturation of the hairline of fur animals, weight gain and an increase in the area of skins. Fur ripening in experimental animals and their slaughter in this case occurred at the same time as in untreated mink preparations (Table 2).

To assess the effectiveness of the claimed veterinary drugs, the kinetics of the release ("release") of active substances from prototypes of the claimed drugs in a blood substitute solution (LIPC fluid) was studied similarly [Patent RU 2096044, MKI A61K 47/30 (A61K 47/30, 38: 22) // BI No. 32 of 1997]. The studied samples in an amount of 10 mg were placed in a 50 ml volumetric flask, 50 ml of LIPC liquid with a preservative was added, the flask was closed with a stopper and placed in a thermostat at a temperature of 37 ° C. Samples of 5 ml were taken on 2, 10, 20, 30, 40, 50, 60 days of the experiment. After sampling each sample, 5 ml of LIPC liquid with a preservative was added to a volumetric flask. The content of the active substance in the samples was determined by gas-liquid chromatography on a Waters chromatograph (LC / GPC-244) or any other model equipped with a UV spectrophotometric detector (wavelength 254 nm; sorbent - silica gel C _{18 with a} grain size of 5-18 μm; eluent - acetonitrile-water; temperature 25 ° C). The high efficiency of the proposed veterinary implantable drugs is confirmed by the following examples.

Example 1. The composition composition (wt.%): Melatonin - 10, CPN-1 - 89.95, lactose - 0.05 obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 2. The composition composition (wt.%): Melatonin - 10, CPN-1 - 89.95, microcrystalline cellulose - 0.05 obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 3. The composition composition (wt.%): Melatonin - 10, CPN-1 - 89.95, lactose - 0.025, microcrystalline cellulose - 0.025 obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 4. The composition composition (wt.%): Melatonin - 50, CPN-1 - 35, lactose - 7.5, microcrystalline cellulose - 7.5 obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 5. The composition composition (wt.%): Melatonin - 50, CPN-1 - 35, lactose - 15 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 6. The composition composition (wt.%): Melatonin - 25, CPN-1 - 69, lactose - 6 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 7. The composition composition (wt.%): Melatonin - 25, CPN-1 - 69, microcrystalline cellulose - 6 obtained in the same way [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 8. The composition composition (wt.%): Melatonin - 9, CPN-1 - 89.95, lactose - 1.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 9. The composition composition (wt.%): Melatonin - 9, CPN-1 - 89.95, microcrystalline cellulose - 1.05 was obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 10. The composition composition (wt.%): Melatonin - 60, CPN-1 - 37, microcrystalline cellulose - 3 obtained in the same way [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 11. The composition composition (wt.%): Melatonin - 10, CPN-2 - 89.95, lactose - 0.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 12. The composition composition (wt.%): Melatonin - 10, CPN-2 - 89.95, microcrystalline cellulose - 0.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

Example 13. The composition composition (wt.%): Melatonin - 10, CPN-2 - 89.95, lactose - 0.025, microcrystalline cellulose - 0.025 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 14. The composition composition (wt.%): Melatonin - 50, CPN-2 - 35 lactose - 7.5, microcrystalline cellulose - 7.5 was obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 15. The composition composition (wt.%): Melatonin - 50, CPN-2 - 35, lactose - 15 obtained in the same way [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 16. The composition composition (wt.%): Melatonin - 25, CPN-2 - 69, lactose - 6 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 17. The composition composition (wt.%): Melatonin - 25, CPN-2 - 69, microcrystalline cellulose - 6 obtained in the same way [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 18. The composition composition (wt.%): Melatonin - 9, CPN-2 - 89.95, lactose - 1.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 19. The composition composition (wt.%): Melatonin - 9, CPN-2 - 89.95, microcrystalline cellulose - 1.05 was obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 20. The composition composition (wt.%): Melatonin - 60, CPN-2 - 37, microcrystalline cellulose - 3 obtained in the same way [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 21. The composition composition (wt.%): Melatonin - 5, xymedon - 5, CPN-1 - 89.95, lactose - 0.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 22. The composition composition (wt.%): Melatonin - 5, xymedon - 5, CPN-1 - 89.95, microcrystalline cellulose - 0.05 obtained similarly [Patent RU 2267318 from 05.25.2004]. The kinetic data on the release of ADV in percent are shown in table 1.

Example 23. The composition composition (wt.%): Melatonin - 25, xymedon - 25, CPN-1 - 45, lactose - 5 was obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 24. The composition composition (wt.%): Melatonin - 12.5, xymedon - 12.5, CPN-1 - 49, lactose - 0.5, microcrystalline cellulose - 0.5 obtained similarly [Patent RU 2267318 from 25.05. 2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 25. The composition composition (wt.%): Melatonin - 3, xymedon - 3, CPN-1 - 89.95, lactose - 5.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 26. The composition composition (wt.%): Melatonin - 30, xymedon - 30, CPN-1 - 30, lactose - 10 was obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 27. The composition composition (wt.%): Melatonin - 5, xymedon - 5, CPN-2 - 89.95, lactose - 0.05 obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 28. The composition composition (wt.%): Melatonin - 5, xymedon - 5, CPN-2 - 89.95, microcrystalline cellulose - 0.05 was obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 29. The composition composition (wt.%): Melatonin - 25, xymedon - 25, CPN-2 - 45, lactose - 5 was obtained similarly [Patent RU 2267318 from 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 30. The composition composition (wt.%): Melatonin - 12.5, xymedon - 12.5, CPN-2 - 49, lactose - 0.5, microcrystalline cellulose - 0.5 obtained similarly [Patent RU 2267318 from 25.05. 2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 31. The composition composition (wt.%): Melatonin - 3, xymedon - 3, CPN-2 - 89.95, lactose - 5.05 obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 32. The composition composition (wt.%): Melatonin - 3, xymedon - 3, CPN-2 - 89.95, microcrystalline cellulose - 5.05 was obtained similarly [Patent RU 2267318 of 05.25.2004].

The kinetic data on the release of ADV in percent are shown in table 1.

Example 33. The composition composition (wt.%): Xymedon - 25, CPN-1 - 69, lactose - 6 obtained in the same way [Patent RU 2267318 from 05.25.2004].

Example 34. The composition composition (wt.%): Xymedon - 25, CPN-2 - 69, lactose - 6 obtained in the same way [Patent RU 2267318 from 05.25.2004].

Example 35. The composition composition (wt.%): Xymedon - 25, KPN-2 - 69, microcrystalline cellulose - 6 obtained in the same way [Patent RU 2267318 from 05.25.2004].

Example 36. The composition composition (wt.%): Xymedon - 25, KPN-2 - 69, microcrystalline cellulose - 6 obtained in the same way [Patent RU 267318 from 05.25.2004].

As can be seen from the data given in table 1, a biodegradable polymer base containing CPN-1 or CPN-2 with technological additives: lactose or microcrystalline cellulose or a mixture thereof, provides a fairly uniform "release" of melatonin and melatonin with xymedon in the inventive veterinary preparations , which determines their 100% "response" (examples 1-7, 11-17, 21-24, 27-30). In model samples (examples 33-36) that do not contain melatonin, the release of xymedon occurred much faster, the prolongation time was 30-40 days.

Example 37. Tests of prototypes of the claimed veterinary drugs in fur farming.

In order to study the effect of the developed prolonged-action veterinary preparations containing synthetic melatonin and xymedon on the mink organism, production tests of prototypes were carried out at the Koshchakovsky fur farm of the Pestrechinsky district of the Republic of Tatarstan.

For testing, 5 prototypes of the claimed veterinary products were manufactured (Table 2). In the experiment, 80 heads of mink of a standard color of 4 months of age were used, divided into experimental and control groups (animals not treated with preparations, Table 2).

The test preparations were implanted in a single dose (one granule) to each animal in the subcutaneous tissue of the area between the shoulder blades using an I-28 injection needle according to TU 64-1-3177-77 with a needle inner diameter of 2.6 mm. The injection site and the needle were sterilized with 70% alcohol. Young growth was treated in the period from June 25 to July 10. Side effects and complications when using the drug were not observed. At the site of implantation of the drug, inflammatory processes in the outer and inner layers of the skin and subcutaneous tissue were absent. A study of the dynamics of changes in live weight showed that the difference in the gain in live weight of animals of the experimental and control groups ranged from 15 to 20%. The animals of the experimental groups were killed September 22, 2007 - September 25, 07; animals of the control group - 09.11.07, Pushnina after dressing corresponded to GOST 7906. The test results are shown in table.2.

Thus, the presented results demonstrate the high efficiency of long-acting implantable veterinary preparations based on CPN-1 and CPN-2 for increasing the safety and productivity of farm animals.

Example 38. To assess the safety of the use of the claimed drugs in fur farming and animal husbandry, morphological studies of organs and tissues of minks exposed to prototypes of drugs were carried out.

Morphological studies were carried out in accordance with the methods [Rapoport Ya.L. Morphological basis of immunogenesis (immunomorphology) - Arch. patol., 1957, No. 2, pp. 3-19; Fontalin L.N. Immunological reactivity of lymphoid organs and stock. - L .: Medicine, 1967, 210 p .; Fridenshtein A.Ya., Chertkov I.L. Cellular immunity basics. - M .: Medicine, 1969, 256 p .; Bart I. The Spleen. Anatomy, physiology, pathology and clinic. Budapest: Acad. Hungarian Sciences, 1976, 264 p .; Petrov R.V. Immunology. - M .: Medicine, 1983, 367 p .; Avtandilov G.G., Yabluchansky N.I., Gubenko V.G. Systemic stereometry in the study of the pathological process. - M .: Medicine, 1981, 192 p .; Loyda Z. Gossrau R., Schiebler T. Histochemistry of enzymes. Laboratory methods. - M .: Mir, 1982, 272 p.].

Morphological, histochemical and histochemical studies were subjected to samples of tissues and organs of animals taken for research on the day of slaughter (end of experiment).

Liver. Histological changes in the liver of minks subjected to prolonged exposure to melatonin and xymedon were characterized by the development of the structural organization of the organ. Hepatocytes were distinguished by heterogeneity in the size and structure of the cytoplasm. The volume of hepatocyte nuclei was 154.37 ± 4.64 μm ³ , which significantly exceeded the average values of the volume of hepatocyte nuclei of the 2nd class and testified to their moderately expressed polyploidization. Enrichment of their chromatin, the presence of one, rarely several, nucleoli with an average volume of 4.10 ± 0.31 μm ³ and fairly high indices of the nucleolus-nuclear ratio - 0.027 also testified to an increase in the synthetic activity in the nuclear apparatus of hepatocytes. As a result of the protective effect of synthetic melatonin in hepatocytes, no manifestations of lipid peroxidation processes in the form of destructive processes causing the development of protein and lipoid dystrophy were detected. The bile ducts had a well-defined lumen. The mucous membrane of the bile ducts was represented by a single layer of prismatic epithelial cells, whose mitotic activity was not detected. Histochemical studies in the walls of the blood vessels of the liver did not reveal deposits of a chromotropic substance exhibiting metachromasia. No signs of disorganization of the connecting elements were noted in the walls of the vessels of the organ microcirculation. In the perivascular connective tissue of the vessels of the organ portal system, the presence of single lymphocytes was noted. In moderately blood-filled sinusoidal capillaries, single lymphocytes and macrophages were located.

Spleen. The spleen of experimental minks had a weakly expressed follicular structure. Small follicles were characterized by polymorphism with a predominance of compact forms. The average area of the lymph nodes was 106.21 ± 7.32 cu Germinal centers of nodules were weakly expressed and also differed in small sizes. The average area of germination centers was 23.12 ± 3.52 cu The cellular elements of the reactive centers of the nodules were represented by swollen reticular cells, small blasts, and medium lymphocytes. Mitotic activity in the cells of the germinal centers of the nodules was weak and was observed only in the form of single figures of mitosis. The bulk of the lymphoid tissue of the nodules was medium and small lymphocytes, most of which were concentrated on the periphery, close to the mantle zone of the nodules. The nuclei of these cells had a high optical density and were enriched in chromatin. The relatively narrow mantle zone of the lymph nodes was represented by sharply squeezed reticular fibers, reticular cells, small and medium lymphocytes. A marked increase in the presence of small lymphocytes near the thymus-dependent periarterial zone of nodules was noted. The sparseness of cellular elements in the marginal zone of nodules was the result of intensive migration of lymphocytes into the red pulp of an organ. Reticular cells, small, medium lymphocytes prevailed in the moderately blood-filled red pulp of the organ, macrophages and compact rarefied accumulations of plasmoblasts were found. An increase in the content of megakaryocytes was found, among which immature cell forms prevailed, which were distinguished by small size and roundness of the cytoplasm boundaries and weak nuclear segmentation. These changes indicated a sufficient level of blood filtration in the organ and high activity of the lymphoid-macrophage link in the cellular mechanism of the manifestation of the body's immune reactivity. This was also confirmed by the high activity of acid phosphatase in reticular cells, germinal centers of nodules, and especially in small lymphocytes located near the periarterial zone and around ellipsoid arterioles.

The kidneys. The kidneys of experimental mink exposed to the complex preparation had a developed structure of the cortical and medulla. The enlarged glomeruli were represented by a developed network of sharply blood-filled capillaries with a clearly defined line of the basement membrane. The nuclei of podocytes, endothelial mesanginal cells were distinguished by saturation with chromatin granules. A decrease in the content of juxtaglomerular and juxtavascular cells was noted. The nuclei of these cells were reduced in volume and became intensely basophilic, which reflected the whole process of reducing the biosynthesis of renin (vasoactive substances) in the organ. A compensatory reaction to these processes should be considered an increase in the volume and number of mesangial cells, which testified to the compensation of a deficiency in the synthesis of vasoactive substances. Most of the convoluted tubule epithelial cells had an intensely stained cytoplasm, without manifestations of protein, fatty degeneration. And it was not noted, in contrast to the control minks not treated with drugs, deposits of mucopolysaccharides in the walls of blood vessels. Therefore, the nature of the structural changes in the kidneys of sick minks indicates that the infectious process is suspended or delayed at the stage of the primary infection cycle, without activating the autoimmune phase of the disease.

Stomach. The mucous membrane of the stomach of experimental minks was characterized by the integrity of the foveolar and fossa epithelium, the cells of which were distinguished by a cylindrical shape. The noted changes in the state of the epithelial tissue of the gastric mucosa reflected a moderately expressed process of cell regeneration and biosynthesis of the protective factor by these cells. Exocrinocyte populations in the tubular glands were distinguished by their differentiation and multiplicity. In the majority of the nuclei of these cells, a low content of chromatin elements was noted, which indicated the completeness of cell differentiation. Elements of the stroma of the gastric mucosa were represented by small lymphoid cells, histiocytes, fibroblasts, fibrocytes, and poorly differentiated cells. The vascular system of the organ was distinguished by the development of capillaries, arterioles, venules and lymphatic vessels and their moderate filling and the absence of signs of disorganization of the elements of the connective tissue in their walls. Histochemical studies revealed a high level of succinate dehydrogenase activity in surface epithelial cells, the main and especially parietal exocrinocytes. Therefore, the state of the gastric mucosa of experimental minks was characterized by the preservation of cellular elements of the epithelial and connective tissue of the organ, a high level of synthetic and regenerative activity, and the production of digestive enzymes. It should be noted that there are no revealed violations in the vascular wall, as well as plasma cell infiltration of organ stroma elements, which are often found in the mucous membrane of control minks.

Thus, the detected structural changes in the parenchymal organs and the mucous membrane of the stomach of experimental minks indicate a significant reduction and even absence of manifestations of metabolic disturbances arising from the development of viral plasmacytosis. A sharp decrease in the severity of the plasma cell reaction was noted; the absence or mild manifestation of transcapillary metabolic disorders caused by the disorganization of the vascular walls and the deposition of immune complexes in them; the absence of a generalized nature of the cellular reactions of mesenchymal tissue, the weakening of mitotic activity in the cells of the lymph nodes of the spleen, and an increase in the migration mobility of immunocompetent cells, primarily thymus-dependent lymphocytes and macrophages. The noted changes are associated with the positive role of the studied prototypes in the regulation of synthetic processes occurring in cells.

The proposed drug formulations can be recommended as adaptogenic and stimulating agents that increase the non-specific resistance of the animal organism in the postnatal period of development.

In general, as a result of comparative histological studies of the organs and tissues of experimental minks implanted with the claimed preparations, no structural changes in the organs of animals were observed with healthy control animals.

Thus, in comparison with the known veterinary drugs based on melatonin, melatonin and xymedon, the proposed veterinary preparations have significant advantages:

1. The cost of the claimed drugs is significantly (1.5-2 times) lower than the cost of prototypes.

2. The use of veterinary products containing melatonin, based on KPN-1 or KPN-2 in fur farming using accelerated mink cultivation technology, contributes to the safety of the mink population until the slaughter period while reducing the time for their cultivation by 1.5-2 months and to obtain fur products with an area 15-20% more compared to untreated animals.

Industrial applicability. The inventive veterinary drugs can be used in fur farming, animal husbandry, veterinary medicine. The release of the first pilot batches is planned for the IV quarter. 2010 - I quarter 2011 OOO Scientific and Production Enterprise "Vetta-Service".

Table 1. The results of studying the kinetics of the release of melatonin in experimental samples with melatonin and xymedon. No. of Example The composition of the sample, wt.% The rate of release,% Test time, day 10 twenty thirty 40 fifty 60 one melatonin - 10; KPN-1 - 89.95; lactose - 0.05 13.1 32,5 48.8 69.8 89.5 one hundred 2 melatonin - 10; KPN-1 - 89.95; microcrystalline cellulose - 0.05 11.3 26,4 43.7 67.4 86.9 one hundred 3 melatonin - 10; KPN-1 - 89.95; lactose - 0.025; microcrystalline cellulose - 0.025 11.5 26.6 43.8 67.8 87.0 one hundred four melatonin - 50; KPN-1 - 35; lactose - 7.5, microcrystalline cellulose - 7.5 12,4 27.6 44,2 71,4 88.2 one hundred 5 melatonin - 50; KPN-1 - 35; lactose - 15 12.5 28.0 44,4 71.8 88.5 one hundred 6 melatonin - 25; KPN-1 - 69, lactose - 6 13, 31.7 52.1 70.8 93.2 one hundred 7 melatonin - 25; KPN-1 -69, microcrystalline cellulose - 6 14.3 37,2 50,2 88.4 94.2 one hundred 8 melatonin - 9; KPN-1 - 89.95; lactose - 1.05 12.9 28,2 69.8 88.7 one hundred 9 melatonin - 9; KPN-1 - 89.95; microcrystalline cellulose - 1.05 12.3 28.1 66.7 91.5 one hundred 10 melatonin - 60; KPN-1 - 37, microcrystalline cellulose - 3 14.6 41.9 62.0 78.6 86.5 95.8 eleven melatonin - 10; KPN-2 - 89.95; lactose - 0.05 13.0 27.8 47.2 70,4 88.1 one hundred 12 melatonin - 10; KPN-2 - 89.95; microcrystalline cellulose - 0.05 12.3 27.8 41.6 71.2 90.6 one hundred 13 melatonin - 10; KPN-2 - 89.95; lactose - 0.025; microcrystalline cellulose - 0.025 12.1 24.3 43,2 69.8 89.1 one hundred fourteen melatonin - 50; KPN-2 - 35; lactose - 7.5, microcrystalline cellulose - 7.5 12.1 24.9 44,2 68.9 88.5 one hundred fifteen melatonin - 50; KPN-2 - 35; lactose - 15 12.9 23.8 43.6 68.7 87.8 one hundred 16 melatonin - 25; KPN-2 - 69, lactose - 6 13,2 27.8 47.2 74,4 88.7 one hundred 17 melatonin - 25; KPN-2 - 69, microcrystalline cellulose - 6 13.8 27.1 462 70,4 88.1 one hundred eighteen melatonin - 9; KPN-2 - 89.95; lactose - 1.05 12.7 27.8 69.8 95.5 one hundred 19 melatonin - 9; KPN-2 - 89.95; microcrystalline cellulose - 1.05 12,4 28.3 66.6 97.6 one hundred twenty melatonin 60; KPN-2 - 37, microcrystalline cellulose - 3 15.6 49.9 62.0 78.6 84.1 92.6 21 melatonin - 5; Xymedon - 5, CPN-1 - 89.95; lactose - 0.05 12.1 32.9 46.8 69.3 88.5 one hundred 22 melatonin - 5; Xymedon - 5, CPN-1 - 89.95; microcrystalline cellulose - 0.05 13.1 32,5 46.7 69.8 89.5 one hundred 23 melatonin - 25; Xymedon - 25, KPN-1 - 45; lactose - 5 12.5 28.0 44,4 71.8 88.5 one hundred 24 melatonin - 12.5, xymedon - 12.5, CPN-1 - 49; lactose - 0.5 12.9 29.6 46,4 73.8 92.5 one hundred 25 melatonin - 3; Xymedon - 3, KPN-1 - 89.95; lactose - 5.05 12,4 28.1 66.6 92.6 one hundred 26 melatonin - 30; Xymedon - 30, KPN-1 - 30; lactose - 10 17.4 42.9 66.3 86.6 91.2 97.5 27 melatonin - 5; Xymedon - 5, KPN-2 - 89.95; lactose - 0.05 13.1 32,3 44.7 69.1 88.5 one hundred 28 melatonin - 5; Xymedon - 5, KPN-2 - 89.95; microcrystalline cellulose - 0.05 12.5 34.5 49.7 66.8 97.5 one hundred 29th melatonin - 25; Xymedon - 25, KPN-2 - 45; lactose - 5 13.7 32,5 46.7 65.8 94.5 one hundred thirty melatonin - 12.5; Xymedon - 12.5; KPN-2 - 49; lactose - 0.5 13.1 32,4 46.1 69.8 86.7 one hundred 31 melatonin - 3; Xymedon - 3, KPN-2 - 89.95; lactose - 5.05 12.1 25.1 60.6 88.6 one hundred 32 melatonin - 3; Xymedon - 3, KPN-2 - 89.95; microcrystalline cellulose - 5.05 11.9 28.1 69.6 98.6 one hundred 33 xymedon - 25, CPN-1 - 69, lactose - 6 31.6 78.8 96.8 one hundred 34 Xymedon - 25, KPN-2 - 69, lactose - 6 32,4 76,4 92.8 one hundred 35 Xymedon - 25, KPN-1 - 69, microcrystalline cellulose - 6 42.6 82,4 one hundred 36 Xymedon - 25, KPN-2 - 69, microcrystalline cellulose - 6 39.6 78.8 one hundred

Table 2. The test results of prototypes of veterinary drugs based on CPN-1 and CPN-2, containing melatonin and xymedon, on young mink. No. p / p The test prototype, composition, wt.% amount
beasts The timing
slaughter The workability of the samples,% The difference in the gain in live weight of the experimental and control animals,% The quality of skins according to GOST 7906 one Melatonin - 25, CPN-1 - 74, lactose - 1 fifteen 09/25 one hundred fifteen standard 2 Melatonin - 25, KPN-2 - 74 microcrystalline cellulose - 1 fifteen 09/25 one hundred eighteen standard 3 Melatonin - 12.5, Xymedon - 12.5, CPN-1 - 49, lactose - 1 fifteen 09/19 one hundred twenty standard four Melatonin - 12.5, Xymedon-12.5, KPN-2 - 49, microcrystalline cellulose - 1 fifteen 09/19 one hundred twenty standard 5 Xymedon - 25, CPN-1 - 74, lactose - 1 5 11/14 standard 6 control group of animals not treated with the drug twenty 11/14 standard

Claims (8)

1. A prolonged-acting veterinary implantable agent for increasing the productivity of farm animals, containing an active substance - melatonin, a biodegradable polymer base and technological additives, characterized in that an interpolymer complex of polymethacrylic acid and polyethylene glycol (KPN-1) is used as the biodegradable polymer base in the following the ratio of components, wt.%:
Melatonin 10-50 KPN-1 89.95-35 Technological Additives 0.05-15 2. The veterinary implantable agent according to claim 1, characterized in that lactose, or microcrystalline cellulose, or mixtures thereof in a ratio (wt.%) Of 50:50, are used as technological additives. 3. A long-acting implantable veterinary agent to increase the productivity of farm animals, containing actively active substances: melatonin and xymedon, a biodegradable polymer base and technological additives, characterized in that an interpolymer complex of polymethacrylic acid and polyethylene glycol (KPN-1) is used as a biodegradable polymer base in the following ratios of components, wt.%:
Melatonin 5-25 Ximedon 5-25 KPN-1 89.95-35 Technological Additives 0.05-15 4. The veterinary implantable agent according to claim 3, characterized in that lactose, or microcrystalline cellulose, or mixtures thereof in a ratio (wt.%) Of 50:50 are used as technological additives. 5. A prolonged-acting implantable veterinary agent to increase the productivity of farm animals, containing an active substance - melatonin, a biodegradable polymer base and processing aids, characterized in that an interpolymer complex of polymethacrylic acid and polypropylene glycol (KPN-2) is used as the biodegradable polymer base in the following the ratio of components, wt.%:
Melatonin 10-50 KPN-2 89.95-35 Technological Additives 0.05-15 6. The veterinary implantable agent according to claim 5, characterized in that lactose or microcrystalline cellulose or mixtures thereof in a ratio (wt.%) Of 50:50 are used as technological additives. 7. A prolonged-acting implantable veterinary product to increase the productivity of farm animals, containing active ingredients: melatonin and xymedon, a biodegradable polymer base and technological additives, characterized in that an interpolymer complex of polymethacrylic acid and polypropylene glycol (KPN-2) is used as a biodegradable polymer base in the following ratios of components, wt.%:
Melatonin 5-25 Ximedon 5-25 KPN-2 89.95-35 Technological Additives 0.05-15 8. The veterinary implantable agent according to claim 7, characterized in that lactose, or microcrystalline cellulose, or mixtures thereof in a ratio (wt.%) Of 50:50 are used as technological additives.