RU2730476C1 - Anti-inflammatory ointment for animals - Google Patents

Abstract

FIELD: veterinary science; cattle breeding.SUBSTANCE: invention refers to veterinary science and livestock farming, namely to veterinary pharmacy, and aims at treating inflammatory processes in animals. Anti-inflammatory ointment for animals includes ketoprofen, methylprednisolone aceponate, tocopherol acetate, beta-carotene, butylhydroxytoluene, dimethylsulphoxide, anhydrous lanolin and Vaseline. Components are used in claimed amounts.EFFECT: use of the invention provides local anti-inflammatory, analgesic, anti-edema and antioxidant action, and also allows to normalize local temperature in the focus of the inflammatory process, wherein said ointment has low toxicity, is easy to use and highly effective in treating local inflammatory processes in animals.1 cl, 6 dwg, 7 ex

Description

The technical field to which the invention relates

The invention relates to veterinary pharmacy, in particular, to anti-inflammatory ointments for animals and can be used in veterinary medicine and animal husbandry for the treatment of inflammatory processes in animals.

State of the art

A known composition is a dosage form of a non-steroidal anti-inflammatory agent ketoprofen for external use, which has anti-inflammatory and analgesic effects, containing ketoprofen as an active agent, and propylene glycol as auxiliary substances, water, cetyl alcohol, polyethylene oxide 1500 and glycerin. The composition is made in the form of an ointment and provides an increase in the bioavailability of ketoprofen and an increase in the pharmacological action. An essential distinguishing feature of the claimed invention is a combination of a solvent, a surfactant and basic components, which makes it possible to increase the release of the drug ketoprofen from the drug, namely, in the manufacture of this ointment, propylene glycol is used as a solvent, a surfactant is cetyl alcohol, the basic components are polyethylene oxide, glycerin and purified water with the following ratio of components, in g per 100 g of product: ketoprofen - 5.0, propylene glycol - 3.3, cetyl alcohol - 4.0, polyethylene oxide 1500 - 52.7, glycerin - 17.7, purified water - 17.3 ... (See patent RU No. 2404760, class A61K 31/192, A61K 31/12, A61K 47/10, A61K 47/30, A61K 47/02, A61R 29/00, publ. 27.11.2010)

The disadvantage of this composition is the absence in the composition of components that ensure the achievement of an antioxidant effect, as well as an insufficient anti-inflammatory effect.

Known anti-inflammatory ointment, including sulfonamide (streptocid), racemic camphor, petrolatum, rendered pork fat, additionally contains antioxidants - butylhydroxyanisole and butylhydroxytoluene. Sulfanilamide is included in the composition of the ointment in a micronized state, while not less than 90% of the particles have a size of up to 20 microns and not more than 10% of the particles have a size of up to 90 microns. The invention can be used as a pharmacological agent for external use, intended for local conservative treatment of cracks, shallow wounds in the stage of granulation, scratches on the skin, inflammation of the mucous membranes, edema, proctological diseases, in particular anal fissures, acute and chronic hemorrhoids, etc. (See patent RU No. 2493837, class A61K 31/125, A61K 31/63, A61K 31/355, A61K 47/44, A61R 17/00, publ. 09/27/2013).

The disadvantage of this ointment is a low anti-inflammatory effect, which is due to the absence of components from the number of non-steroidal anti-inflammatory drugs and / or steroid anti-inflammatory drugs in its composition.

The closest in technical essence and the achieved positive effect and adopted by the authors as a prototype is a remedy for the treatment of inflammation and injuries of the mammary gland in cows, containing ketoprofen as an active component, and as a base organosilicon glycerohydrogel of the composition:

Si (C3H7O3) 4⋅xC3H8O3⋅yH2O, where 3≤х≤10, 20≤y≤40 with a dynamic viscosity of 4.8-28.5 Pa (s (20 ± 0.5 ° C), at a ratio of components, wt ... %: ketoprofen - 2, organosilicon glycerohydrogel - the rest, and the agent is prepared by mechanical mixing of the components. The invention improves the effectiveness of treatment. (See patent RU No. 2356556, class A61K 33/00, A61K 31/192, A61K 47/30, A61P 15/00, A61P 31/04, publ. 27.05.2009).

The disadvantage of this agent is insufficient anti-inflammatory effect, which is associated with the presence in its composition of components only from the number of non-steroidal medicinal anti-inflammatory drugs and the absence of components from the number of steroid anti-inflammatory drugs and antioxidant effect, as well as a low rate of penetration of active substances into the affected tissues.

Brief description of drawings and other materials

FIG. 1 is an anti-inflammatory ointment for animals. Acute toxicity of anti-inflammatory ointment for animals, tab. 1.

FIG. 2, too, is a graphic representation of the acute toxicity for white mice of an anti-inflammatory ointment for animals, Fig. 1.

FIG. 3, too, is a graphic representation of the acute toxicity for white rats of an anti-inflammatory ointment for animals, Fig. 2.

FIG. 4, too, hematological and biochemical parameters of cows who received treatment for mastitis, table. 2.

FIG. 5, also, indicators of the quality of milk obtained from cows that were treated for mastitis, table. 3.

FIG. 6, too, the timing of recovery in cows that were treated for mastitis and the amount of disposed milk, table. 4.

Disclosure of invention

The objective of the invention is to develop an anti-inflammatory ointment for animals with a pronounced anti-inflammatory, analgesic and antioxidant effect, low toxicity, ease of use, high efficiency in the treatment of local inflammatory processes in animals.

The technical result, which can be achieved with the help of the present invention, is reduced to a pronounced local anti-inflammatory, analgesic, decongestant and antioxidant effect, as well as normalization of the local temperature in the focus of the inflammatory process, low toxicity, ease of use, high efficiency in the treatment of local inflammatory processes in animals ...

The technical result is achieved using an anti-inflammatory ointment for animals, including ketoprofen, while it additionally contains methylprednisolone aceponate, tocopherol acetate, beta-carotene, and dimethyl sulfoxide, anhydrous lanolin and petroleum jelly are used as an ointment base, and butyl hydroxy is used as an antioxidant for an ointment base , with the following ratio of components in wt. %:

Ketoprofen 2.5-4.5 methylprednisolone aceponate 0.09-0.11 tocopherol acetate 0.4-0.6 beta carotene 0.75-1.25 butylhydroxytoluene 0.4-0.6 dimethyl sulfoxide 10.0-15.0 lanolin anhydrous 25.0-23.0 petrolatum rest

Common to the claimed prototype is the presence of ketoprofen as an active ingredient in the composition. The difference from the closest analogue of the claimed anti-inflammatory ointment for animals is the presence of additional methylprednisolone aceponate, tocopherol acetate, beta-carotene, and dimethyl sulfoxide, which is due to the achievement of a higher anti-inflammatory and decongestant effect, the presence of antioxidant action and an increase in the rate of penetration of active substances into the focus of the inflammatory process, as well as the use of anhydrous lanolin and petroleum jelly as an ointment base, stabilized by the antioxidant butylhydroxytoluene, which prevents its oxidation, which makes it possible to carry out better and more efficient prevention and treatment of local inflammatory diseases in animals.

The claimed anti-inflammatory ointment for animals is a homogeneous white ointment with a weak yellowish tint, odorless, having a pronounced local anti-inflammatory effect, providing a local antioxidant, analgesic and decongestant effect, contributing to the normalization of the local temperature in the focus of inflammation, is convenient to use.

Inflammation is one of the typical defensive reactions to local damage inherent in all mammals, its classic external signs have been known since ancient times. The generalization of a large amount of new data made it possible to reach a qualitatively new level of understanding of inflammation as a universal pathological process underlying a large number of diseases (See I.D.Bespalova, N.V. Ryazantseva, V.V. Kalyuzhin, D.S. , Murashev B.Yu., Osikhov I.A. // Siberian Medical Journal (Irkutsk). - 2013. - T. 117. - No. 2. - S. 5-9.).

Inflammation is a universal biological defense mechanism in response to any damage. From the standpoint of immunopathophysiology, this is a protective reaction of the body, which is characterized by a sequential change of phases and is mediated by the participation of a whole range of cells, humoral factors. At the same time, the mobilization of phagocytic cells is accompanied by an inflammatory reaction of microvessels, protein systems of blood plasma and perivascular mesenzymal cells. Inflammation is a predominantly local process aimed at delimiting a pathological focus and is clinically accompanied by a number of signs - hyperemia, edema, pain and organ dysfunction (See Kashuba E.A., Chernetsova L.F., Kuzmenko M.Ya., Maksimova N. A. // Medical science and education of the Urals. - 2006. - T. 7. - No. 1 (40). - P. 29-30.).

Inflammation as the main, the main typical pathological process is a universal, genetically programmed for any phlogogenic effect of a different nature, a complex of reactions to damage (See MV Chereshneva, VA Chereshnev // Medical Immunology. - 2011. - V. 13. - No. 6. - S. 557-568.).

Non-steroidal anti-inflammatory drugs, the main indications for the appointment of which are inflammatory processes of various nature and localization, pain, fever, are among the drugs widely used in clinical practice (See Lazutina PP // International Veterinary Bulletin. - 2010. - No. 2. - S. 16-18.).

Ketoprofen is a non-steroidal anti-inflammatory agent of the family of propionic acid derivatives with analgesic, anti-inflammatory and antipyretic effects. It is a racemic mixture, among the components of which the S-isomer inhibits cyclooxygenase (See Sarzi-Puttini P., Atzeni F., Lanata L., Bagnasco M., Colombo M., Fisher F., Dimporzano M. // Russian Medical magazine. - 2012. - T. 20. - No. 5. - S. 259-264.).

Ketoprofen - Chemically and pharmacologically, is the next generation of ibuprofen. Ketoprofen was approved for use in the United States in 1986, and its soluble oral form in 2009. Thus, the experience of using ketoprofen is more than thirty years. Its action is subdivided into anti-inflammatory, analgesic and antipyretic, but all 3 effects are associated with inhibition of prostaglandin production due to non-selective inhibition of both types of cyclooxygenase. The main anti-inflammatory effect is associated with the blockade of cyclooxygenase-2, however, in a number of tissues, the inflammatory process is also mediated by cyclooxygenase-1. An increase in its activity is shown in the joints with rheumatoid arthritis and osteoarthritis, especially in the synovium, as well as with bursitis. The non-selectivity of ketoprofen in this case is an advantage in terms of the anti-inflammatory effect (See Taratukhin E.O. // Therapy. - 2017. - No. 7 (17). - S. 21-24.).

According to the chemical structure, ketoprofen (2RS) -2- (3-benzoylphenyl) propanoic acid is a derivative of arylpropionic acid, which has strong acidic properties, as well as high lipophilicity, which makes it easy for the drug to penetrate the blood-brain barrier. In the ketoprofen molecule, the carboxyl and benzene groups are in the anti-position with respect to the benzene ring. (See Belyatskaya A.V., Krasnyuk (Jr.) I.I., Krasnyuk I.I., Machikina T.E., Korosteleva Yu.A., Stepanova O.I., Kashlikova I.M., Skovpen Yu.V., Vorobyov A.N. // Development and registration of medicines. - 2017. - No. 2. - (19). - P. 102-107.)

Ketoprofen has found wide systemic use in inflammatory and degenerative diseases of the musculoskeletal drug (arthrosis, osteochondrosis, rheumatoid arthritis), relief of pain in the post-traumatic and postoperative period, sciatica, sciatica and renal colic, and is also often used in gynecological, dental and oncological practice. As an external agent, ketoprofen is used for painful inflammatory lesions of the skin and joints, for sports injuries of tendons, ligaments and muscles. In the form of solutions, ketoprofen is used in dentistry for the symptomatic treatment of inflammatory processes in the oral cavity, pharynx and larynx. (See Belyatskaya A.V., Krasnyuk (Jr.) I.I., Krasnyuk I.I., Machikina T.E., Korosteleva Yu.A., Stepanova O.I., Kashlikova I.M., Skovpen Yu.V., Vorobyov A.N. // Development and registration of medicines. - 2017. - No. 2. - (19). - P. 102-107.)

Considering the fact that oral administration of ketoprofen can have an ulcerogenic effect, the most commonly used dosage forms for external use (See Gubanov O.D., Vergeichik E.N., Gubanova L.B. // Bulletin of Voronezh State University. Series: Chemistry. Biology. Pharmacy. - 2009. - No. 2. - S. 161-164.).

Local glucocorticoid agents have a complex anti-inflammatory and immunomodulatory effect. They inhibit the production and release of factors such as cytokines, prostaglandins, and leukotrienes that are involved in inflammation. In addition, local glucocorticosteroids have a vasoconstrictor effect, reduce intracellular edema and tissue infiltration (See Levin Yu.G., Alekseeva A.A., Vishneva E.A., Efendieva K.E., Tomilova A.Yu. // Pediatric pharmacology. - 2014. - T. 11. - No. 5. - S. 52-58.).

Among the modern topical fourth-generation glucocorticoid drugs are methylprednisolone aceponate. Its high anti-inflammatory activity has been proven, and the peculiarities of the mechanism of action are in the activation of the prodrug in the inflammation focus due to enzymes - esterases, a high rate of penetration into the skin and a rapid onset of action due to its high lipophilicity and affinity to cell receptors - inflammatory effectors. Methylprednisolone aceponate is characterized by minimized penetration (0.27-2.5%) into the blood and complete rapid inactivation due to binding to glucuronic acid due to the compactness of the molecule. The high anti-inflammatory activity of methylprednisolone aceponate, which is determined by its special pharmacological properties, is combined with a minimal severity of adverse events (See Kungurov N.V., Kokhan M.M., Keniksfest Yu.V., Stukova E.I., Koryukina E.B. , Vedernikova S.V. // Bulletin of Dermatology and Venereology. - 2013. - No. 5. - P. 138-151.).

Methylprednisolone aceponate is an active non-halogenated synthetic glucocorticosteroid belonging to the 3rd activity class according to the European classification. Its molecule has a unique structure, which is responsible for its anti-inflammatory properties. The introduction of a methyl group at the C6 position determines the high activity of the drug, and the absence of fluorine and chlorine at the C6, C9 or C12 positions, typical for most strong glucocorticosteroids, minimizes local and systemic side effects. Double esterification (in positions C17 and C21) ensures optimal lipophilicity of the molecule, fast penetration through the epidermis and high concentration. A stable concentration of methylprednisolone aceponate is maintained throughout the day, which makes it possible to use it once a day. Due to the optimal lipophilicity, the concentration of methylprednisolone aceponate is maintained in the inflammatory focus during the day, while its depot is created (See Elisyutina O.G. // Inpatient technologies: Outpatient surgery. - 2014. - No. 3-4. - P. 56- 59.).

One of the most significant causes of pathological processes in the body that cause the development of many diseases is an excessive accumulation of oxygen free radicals, that is, oxidative stress. Due to the harmful effects of free radicals, the walls of blood vessels, membranes are damaged, lipids are oxidized. The concentration of free radicals increases due to a decrease in the natural antioxidant system (See Nikitina E.V., Romanova N.K. // Bulletin of the Kazan Technological University. - 2010. - No. 10. - P. 375-381.).

The bulk of inflammatory diseases are associated with the activation of the processes of free radical oxidation and lipid peroxidation both at the local level and at the level of the whole organism (See Melkonyan K.I., Bykov I.M., Pavlyuchenko I.I., Belkina N.V. . // Kuban Scientific Medical Bulletin. - 2009. - No. 3. - P. 74-78.).

Antioxid antami are substances of plant, animal origin, as well as synthetic, capable of inhibiting the development of free-radical oxidation processes during chemical interaction (See.Okunevich I.V., Sapronov N.S. // Reviews on clinical pharmacology and drug therapy. - 2004 . - T. 3. - No. 3. - S. 2-17.).

The practice of using antioxidant agents in the treatment of inflammatory diseases is known. The positive effect of the complex use of antioxidant drugs in order to correct the disorders of the antioxidant system caused by inflammatory diseases of the middle ear was revealed, which confirms the validity of the ideas about the general biological significance of the antioxidant system and the processes of free radical oxidation in the genesis of the formation of pathological conditions (See. Bakulina L.S. , Pluzhnikov N.N., Isaev A.V., Maltsev A.B., Zhdanova I.Yu. // Bulletin of Voronezh State University. Series: Chemistry. Biology. Pharmacy. - 2018. - No. 2. - P. 284 -291.).

Tocopherol is the most important link in the system of exogenous bioantioxidant defense of cellular and subcellular membrane phospholipids from peroxidation. It is not formed in the animal organism, but is a product of the biosynthesis of plant cells. Concentrating in the composition of membranes, vitamin E acts as their universal protector, regardless of the type of tissue. Tocopherols, being quenching antioxidants and acting as radical traps, are capable of transferring phenolic hydrogen to the peroxide radical (See N. Ermakova, N. Yarovan // Modern problems of science and education. - 2014. - No. 3. - P 721-726.].

According to the literature, α-tocopherol is involved in the antioxidant protection of serum lipoproteins, stabilizes the structure of cell membranes, destroys most active oxygen metabolites, and is able to activate genes involved in the induction and inhibition of apoptosis (See L.K. Khuzhakhmetova, D.L. // Natural sciences. - 2016. - No. 4 (57). - P. 72-78.).

It has now been convincingly shown that carotenoids have valuable specific properties that are not associated with A-vitamin activity. In living organisms, they act as photoprotectors and antioxidants, at the molecular and cellular level, they prevent transformations induced by oxidants, genotoxic substances, X-ray and UV radiation; maintain the stability of the genome and the resistance of the organism to mutagenesis and carcinogenesis. They increase the immunocompetence and contact interaction of cells, participate in the regulation of the expression of the connexin-43 gene. Promote economical consumption of antioxidant vitamins and enzymes, exhibit anti-stress properties [Kuzminova E.V. // Veterinary pathology. - 2007. - No. 3. - S. 226-228.].

It is known that the protective effect of natural carotenoids is associated with their ability to deactivate highly reactive free radicals of oxygen, xenobiotics and peroxides (See Voevodin Yu.E., Ulitko V.E., Lifanova S.P., Erisanova O.E. // Bulletin of Ulyanovskaya State Agricultural Academy. - 2014. - No. 1 (25). - S. 113-117.).

Carotenoids protect low-density lipids of cell membranes from oxidative stress induced by singlet oxygen, light quanta, radiolysis or oxidation in the presence of copper (See Shashkina M.Ya., Shashkin P.N., Sergeev A.V. // Russian Biotherapeutic Journal. - 2010. - No. 1. - Volume 9. - P. 77-86.).

Dimethyl sulfoxide belongs to the group of dermatotropic drugs. It has anti-inflammatory, analgesic, antimicrobial effects. When applied topically, it quickly and well penetrates biological membranes, including through the skin, mucous membranes, and the membrane of microbial cells. It also performs a transport function, providing deep penetration of other drugs through the skin (See Dyachkova L.V., Trukhacheva T.V., Zhebentyev A.I. // Pharmacy Bulletin. - 2012. - No. 1 (55). - P . 35-44.).

In the manufacture of soft dosage forms, two problems should be solved: the problem of choosing a base and the problem of choosing pharmacologically active substances that will determine the therapeutic effect (See Grigorieva U.A., Minyaeva O.A., Kupriyanova N.P. Education. - 2015. - No. 6. - S. 38-43.).

Despite the fact that the assortment of the considered ointment bases is quite diverse, nowadays, in the conditions of pharmacies, in the preparation of soft medicines, petroleum jelly is mainly used. Lanolin is also used and its undoubted advantage over other bases is that it is able to emulsify aqueous solutions (See Yarnykh TG, Garkavtseva OA // Scientific Bulletin of Belgorod State University. Series: Medicine. Pharmacy. - 2012. - No. 10-3 (129). - S. 16-22.).

Petroleum jelly is a mixture of solid and liquid hydrocarbons obtained from the fractional distillation of petroleum and is a white, viscous, sticky, oily, odorless substance. This substance is low-allergenic, softens and moisturizes the skin well due to the film-forming effect. By the severity of the occlusive effect, petroleum jelly is considered the "gold standard" in relation to other substances. The positive qualities of lanolin include high hygroscopicity and the ability to absorb water, which has a cooling and softening effect on the skin (See Arabian E.R., Sokolovsky E.V., Bakhtina S.M., Pchelintsev M.V. // Bulletin of Dermatology and venereology. - 2010. - No. 2. - S. 64-70.).

Since lanolin can be subject to oxidation to a certain extent, in the industrial production of ointment bases, an antioxidant such as hydroxytoluene is added to lanolin (See E.R. Arabiyskaya, E.V. Sokolovsky, S.M. Bakhtina, M.V. Pchelintsev / / Bulletin of Dermatology and Venereology. - 2010. - No. 2. - S. 64-70.).

The essence of obtaining an anti-inflammatory ointment for animals is as follows: the initial components in wt. %, namely ketoprofen - 2.5-4.5, methylprednisolone aceponate - 0.09-0.11, tocopherol acetate - 0.4-0.6, beta-carotene - 0.75-1.25, butylhydroxytoluene - 0.4-0.6, dimethyl sulfoxide 10.0-15.0, anhydrous lanolin - 25.0-23.0, petroleum jelly - the rest is mixed under aseptic conditions and packed. At the same time, initially ketoprofen, methylprednisolone aceponate, tocopherol acetate, beta-carotene and butylhydroxytoluene are dissolved in dimethyl sulfoxide, and then the resulting solution is slowly poured into melted and mixed until a homogeneous mass of anhydrous lanolin and petroleum jelly at its temperature of 40 ° C, with constant the resulting mixture until a homogeneous mass is formed.

Implementation of the invention

Examples of specific implementation of the preparation and testing of anti-inflammatory ointment for animals.

Example 1.

An anti-inflammatory ointment for animals is prepared by mixing the components under aseptic conditions with the following ratio of components in wt. %:

ketoprofen 1.5 methylprednisolone aceponate 0.08 tocopherol acetate 0.3 beta carotene 0.5 butylhydroxytoluene 0.3 dimethyl sulfoxide 7.5 lanolin anhydrous 26.0 petrolatum rest

The resulting ointment when applied to white laboratory rats, in which the inflammatory process was experimentally simulated by subcutaneous injection of turpentine oil, leads to a decrease in pain response to palpation, a decrease in irritation and itching, a decrease in edema and a decrease in local temperature in the area of inflammatory damage, and also has a positive effect on the dynamics of laboratory blood parameters, which is manifested in a decrease in the number of leukocytes in the blood for five days of treatment by 4.73 %% and a decrease in the erythrocyte sedimentation rate by 5.48% over the same period. The main symptoms of local inflammation (lameness, hyperemia, edema, changes in local temperature) disappeared on average by 7.26 ± 0.69 days of the treatment.

Example 2.

Carried out analogously to example 1, but take the following ratio of components in wt. %:

ketoprofen 2.5 methylprednisolone aceponate 0.09 tocopherol acetate 0,4 beta carotene 0.75 butylhydroxytoluene 0,4 dimethyl sulfoxide 10.0 lanolin anhydrous 25.0 petrolatum rest

The application of the obtained ointment to white laboratory rats led to a decrease in pain, irritation, edema and local hyperthermia in the area of the pathological process. When conducting laboratory analysis on the fifth day after the start of treatment, it was found that the number of leukocytes decreased by 7.21%, and the erythrocyte sedimentation rate decreased by 6.24%. The disappearance of the main symptoms of local inflammation, on average, was recorded at 5.39 ± 0.41 days.

Example 3.

Carried out analogously to example 1, but take the following ratio of components in wt. %:

ketoprofen 3.5 methylprednisolone aceponate 0.1 tocopherol acetate 0.5 beta carotene , 0 butylhydroxytoluene 0.5 dimethyl sulfoxide 12.5 lanolin anhydrous 24.0 petrolatum rest

Treatment of the inflammatory process in white laboratory rats using the obtained ointment helped to reduce pain, edema, irritation, hyperemia and hyperemia in the area of local inflammation. When examining the blood on the fifth day after the start of treatment, there is a decrease in the number of leukocytes and erythrocyte sedimentation rate by an average of 7.93% and 7.67%, respectively. The disappearance of the main symptoms of local inflammation was recorded on average at 4.90 ± 0.32 days.

Example 4.

Carried out analogously to example 1, but take the following ratio of components in wt%:

ketoprofen 4.5 methylprednisolone aceponate 0.11 tocopherol acetate 0.6 beta carotene 1.25 butylhydroxytoluene 0.6 dimethyl sulfoxide 15.0 lanolin anhydrous 23.0 petrolatum rest

When using the obtained ointment in the treatment of white laboratory rats, a decrease in the pain response, a decrease in the manifestation of irritation, edema and hyperemia within the boundaries of the topographic location of the affected tissues is noted. On the fifth day of therapy, the number of leukocytes in the blood and the erythrocyte sedimentation rate decreased by an average of 8.19% and 7.11%, respectively. The disappearance of the main symptoms of local inflammation, on average, was recorded at 5.02 ± 0.37 days.

Example 5.

Carried out analogously to example 1, but take the following ratio of components in wt. %:

ketoprofen 5.5 methylprednisolone aceponate 0.12 tocopherol acetate 0.7 beta carotene 1.5 butylhydroxytoluene 0.7 dimethyl sulfoxide 17.5 lanolin anhydrous 22.0 petrolatum rest

The resulting ointment was used to treat a local inflammatory process in white laboratory rats; as a result, a decrease in pain, edema, irritation, hyperemia and local temperature in the area of the inflammatory lesion was noted. For five days of the treatment, a decrease in the number of leukocytes and erythrocyte sedimentation rate by an average of 6.89% and 6.52%, respectively, was established. The disappearance of the main symptoms of local inflammation, on average, was recorded at 6.19 ± 0.54 days. In general, against the background of the positive dynamics of clinical indicators, as well as laboratory markers of inflammation in the blood, it can be noted that the result of using the ointment in this example showed less efficiency than in examples 2, 3 and 4, and the cost of the ointment also increased due to an increase in the consumption of active components.

Thus, examples 2, 3, 4 are the most optimal, since, as a result of the application of the ointment to white laboratory rats, a greater positive effect is obtained, consisting in a decrease in pain, irritation of edema and local hyperthermia in the area of localization of the inflammatory process, a decrease by the fifth day of the treatment with the use of ointment erythrocyte sedimentation rate - from 6.24% to 7.67% and the number of leukocytes in the blood from 7.21% to 8.19%, as well as the disappearance of the main symptoms of inflammation in the interval from 4.90 ± 0.32 days up to 5.39 ± 0.41 days, respectively. In the implementation of these examples, a positive effect of the use of the ointment on the main indicators of the clinical status of white laboratory rats and the course of the pathological process was noted.

Example 6.

To assess the anti-inflammatory ointment for animals for acute toxicity, take the following ratio of components in wt. %:

Ketoprofen 3.5 methylprednisolone aceponate 0.1 tocopherol acetate 0.5 beta carotene 1.0 butylhydroxytoluene 0.5 dimethyl sulfoxide 12.5 lanolin anhydrous 24.0 petrolatum rest

Studies to study the acute toxicity of anti-inflammatory ointment for animals are carried out on white laboratory mice and laboratory rats with a single intragastric administration, which allows determining lethal doses, classifying the ointment according to GOST 12.1.007-76 and attributing it to the 3rd hazard class "Substances moderately hazardous" ( fig. 1, 2, 3).

Example 7.

The effectiveness of anti-inflammatory ointment for animals was studied in cows according to example 3, which is the most effective, which includes the following ratio of components in wt. %: ketoprofen - 3.5, methylprednisolone aceponate - 0.1, tocopherol acetate - 0.5, beta-carotene - 1.0, butylhydroxytoluene - 0.5, dimethyl sulfoxide - 12.5, anhydrous lanolin - 24.0, petrolatum - the rest.

The essence of the experiment is that two groups of lacquering cows are used during the milking period of patients with catarrhal mastitis, which are divided, taking into account the principle of analogues, into two groups of 10 animals each. Mastitis is diagnosed during milking and confirmed by the reaction of milk with matotest. In the first group, the drug "Mastomycin" (LLC "Nita-Pharm", Russia) is used intercisternally into the affected lobe of the mammary gland, one syringe with a 10 ml dispenser with an interval of 12 hours until the disappearance of clinical signs. A similar treatment is carried out in the second group, but additionally externally on the affected lobe of the mammary gland twice a day, after milking, an anti-inflammatory ointment for animals is applied with a thin layer for five days and rubbed lightly. In a laboratory study of blood, markers of inflammation in cows are determined. The clinical condition of the animals is taken into account and a test express determination of mastitis is performed daily.

As a result of the studies conducted, it was found that at the onset of the disease, the number of leukocytes and the erythrocyte sedimentation rate (ESR) significantly exceeded physiological parameters (Fig. 4). Under the influence of the therapy, these indicators gradually decreased as the animals recovered. At the same time, in the second group the number of erythrocytes was statistically significantly higher than in the first group five days after the start of treatment by 28.8% and after ten days - by 29.3%, and the ESR after five days was significantly lower by 19.8 % and after ten days - higher by 17.4%, respectively.

The level of reduced glutathione in the blood of cows at the beginning of the experiment was significantly lower than the reference values, which may indicate a depression of the body's antioxidant defense system under the influence of the inflammatory process and in mastitis, in particular. This indicator increased with recovery in both groups, but in the first group five days after its start it was lower than in the second group by 8.33%, and after ten days it was significantly lower - by 12.0%. At the initial stage of the experiment, a high concentration of diene conjugates was recorded in the blood of cows, and the further dynamics of this product of lipid peroxidation was not the same in animals from the first and second groups. In the control, five days after the start of treatment, the values of this indicator increased by 16.9%, and in the second group they decreased by 3.51%. In general, in the first group, this indicator was higher than in the second five days after the start of treatment by 11.29%, and after ten days - by 10.00%. A similar dynamics was observed in relation to malondialdehyde (MDA), the level of which on the fifth day of the experiment was lower in the second group than in the control group by 7.25%, and on the tenth day - lower by 4.89%.

One of the most significant indicators in dairy farming is the quality of the products obtained, which is reflected in its price. Based on this, the definition of some indicators reflecting the commercial value of milk was carried out.

The amount of protein, fat and non-fat milk solids throughout the experiment did not change significantly, fluctuations did not exceed 2.5% (Fig. 6). The density of milk five days after the start of treatment in the second group did not go beyond the normative indicators of the current GOST, after ten days the indicators in all groups corresponded to the norm.

The acidity of milk at the onset of the disease was 12.3 ° T in the first group, and 12.7 ° T in the second. Subsequently, this indicator returned to normal as the animals recovered. In general, during the experiment, it normalized and on the tenth day was 17.5 ° T in the first group, 17.7 ° T in the second, and milk corresponded to GOST R 52054-2003. The most significant changes occurred in relation to the number of somatic cells in milk, which was sharply increased with the development of the inflammatory process. Subsequently, starting from the fifth day of the study, there was a gradual decrease in the number of somatic cells. So, in the first group on the fifth day, the decrease was 3.3 times, in the second - 4.1 times. Over the entire experimental period, the decrease in the number of somatic cells in the first group was 4.4 times from the initial indicators, and in the second - 5.4 times, respectively.

Clinical observation and the use of mastotests made it possible to establish that in the first group the disappearance of the main clinical signs occurred on average 1.63 days later than in the second group (Fig. 5). This was due to the high costs of treatment in control, since for each affected portion of the udder in these animals, an average of three more mastomycin dispenser syringes were spent. Also, due to the fact that milk received from cows with mastitis is not subject to food use, it was utilized. Statistical analysis revealed that in the first group, 539.7 liters of milk was utilized more than in the second.

Thus, the conducted studies allow us to conclude that in cows with mastitis, the use of a new anti-inflammatory ointment for animals can significantly increase the effectiveness of the standard therapeutic regimen and, at the same time, contributes to the normalization of the antioxidant status in animals.

The results of this experiment indicate that the use of anti-inflammatory ointment for animals is an effective way to treat inflammatory pathology. This happens due to the provision of a pronounced local anti-inflammatory, analgesic, decongestant and antioxidant effect.

The advantages of the proposed anti-inflammatory ointment for animals are that it contains in the complex ketoprofen, methylprednisolone aceponate, tocopherol acetate, beta-carotene and dimethyl sulfoxide, and as an ointment base, a mixture of anhydrous lanolin and petroleum jelly, stabilized by butylhydroxytoluene, which significantly increases its effectiveness.

The proposed invention has the following technical advantages in comparison with the prototype and other known technical solutions:

- increased anti-inflammatory action;

- the presence of an antioxidant effect;

- an increase in the speed and degree of penetration of the active substance into the focus of the inflammatory pathological process;

- increased anti-edema effect;

- complex action;

- economy in manufacture and use.

Claims (2)

An anti-inflammatory ointment for animals, including ketoprofen, characterized in that it additionally contains methylprednisolone aceponate, tocopherol acetate, beta-carotene, and dimethyl sulfoxide, and anhydrous lanolin and petroleum jelly, stabilized by an antioxidant, are used as an ointment base, which is used as butylhydroxytol the ratio of components in wt. %: ketoprofen 2.5-4.5 methylprednisolone aceponate 0.09-0.11 tocopherol acetate 0.4-0.6 beta carotene 0.75-1.25 butylhydroxytoluene 0.4-0.6 dimethyl sulfoxide 10.0-15.0 lanolin anhydrous 25.0-23.0 petrolatum rest

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