RU2563826C1 - Injection antibacterial pharmaceutical composition - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: composition comprises flunixin or one of its pharmaceutically acceptable salts, azithromycin in the form of dihydrate, citric acid and water for injections with the following ratio of ingredients (mg/ml): azithromycin dihydrate - 60.0-120.0, flunixin or one of its pharmaceutically acceptable salts - 38.0-50.0, citric acid - 0.01-1.0, water for injections - 1 ml.

EFFECT: composition is stable while storing, has a wide spectrum of antibacterial action when administered intramuscularly to animals, non-toxic, does not cause complications and side effects in use, contributes to speed up excretion of residual amounts of azithromycin and flunixin from the body and thereby enables to reduce the period of pre-slaughter animal management.

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Description

The invention relates to the field of veterinary medicine, namely to pharmaceuticals, and can be used to treat infections of bacterial etiology.

One of the main tasks of modern agriculture is the intensification of livestock production.

Livestock supply the population with high-value foodstuffs, and industry - with raw materials and valuable fertilizers. To increase the production of livestock products at the enterprise, the main criterion is a healthy population. However, diseases of farm animals, despite the undeniable achievements of domestic and foreign science in their diagnosis, treatment and prevention, continue to be one of the main reasons that impede the development of animal husbandry and cause significant economic damage.

The most important component of therapy is the fight against bacterial infections. The fight against these pathogens should be based on a specific immunization or chemoprophylaxis, but often the disease has to be treated, not prevented. With the timely detection of the disease and the immediate start of treatment with an effective antibiotic or chemotherapeutic agent in 85-90% of animals, a persistent improvement in the clinical picture is already observed within the first 24 hours.

As a rule, in the development of the disease, the etiotropic factor is the association of microorganisms that affect several organs and systems. In this regard, the most effective drugs are a wide spectrum of action. In this case, it is advisable to use injectable forms of drugs that have a number of advantages: increased bioavailability, speed of action, accuracy and ease of dosing of drugs, the ability to administer drugs to weakened animals with anorexia and dehydration.

Thus, the search for new, more effective injection drugs for the prevention and treatment of bacterial infections is of great theoretical and practical importance.

Known injection composition for the treatment of infections of bacterial etiology in animals based on azithromycin (see, for example, RU 2512683 C2, 04/10/2014).

The composition is suitable for intravenous, intramuscular, subcutaneous, intrauterine and intracisternal administration, however, since it contains only azithromycin as an active substance, its spectrum of action is limited by the spectrum of action of azithromycin.

Known injection composition for the treatment of infections of bacterial etiology in animals, containing azithromycin and doxycycline hydrochloride (see, for example, CN 102846649 A, 02.01.2013).

The following injection compositions are known for the treatment of infections of bacterial etiology in animals, comprising:

- flunixin and chloramphenicol (see, for example, MY 135791 A, 06/30/2008);

- flunixin and enrofloxacin (see, for example, EP 1875913 A1, 01/09/2008 or CN 102697784 A, 03/10/2012);

- flunixin, enrofloxacin, sulfadiazine, trimethoprim and dexamethasone (see, for example, CN 101829124 A, 09/15/2010);

- flunixin, enrofloxacin, trimethoprim, tylosin and sulfamethoxazole (see, for example, CN 102697784 A, 03.03.2010);

- flunixin and oxytetracycline (PL 335878 A1, 05.22.2000);

- flunixin or one of its pharmaceutically acceptable salts and florfenicol (RU 2512683 C2, 04/10/14).

All the above compositions have a wide spectrum of action, are stable during storage, have a prolonged action and a high therapeutic effect. However, all these medicines are manufactured abroad and are not available for the treatment of animals in Russia.

Closest to the claimed is an antibacterial injection pharmaceutical composition comprising flunixin, azithromycin in the form of a dihydrate and excipients (US 2005148519 A1, 07.07.2005).

This composition was also developed by a foreign - American - company, and as auxiliary substances it contains propylene glycol and stabilized glycerinformal, which are used to enhance the stability of the drug.

The task to which the claimed invention is directed is to create an effective storage stable domestic pharmaceutical composition based on flunixin or its salts and azithromycin for the treatment of animal diseases of bacterial etiology, suitable for parenteral administration and having a stimulating effect on the indicators of humoral immunity.

The problem is solved in that an injectable antibacterial composition is developed that contains flunixin or one of its pharmaceutically acceptable salts, azithromycin in the form of dihydrate, citric acid and water for injection in the following ratio of ingredients (mg / ml): azithromycin dihydrate - 60.0- 120.0, flunixin or one of its pharmaceutically acceptable salts - 38.0-50.0, citric acid - 0.01-1.0, water for injection - up to 1 ml.

The technical result obtained as a result of the implementation of the claimed invention is that the injectable pharmaceutical composition has a pronounced antimicrobial effect on both gram-negative and gram-positive microflora, while it effectively acts on both vegetative and spore forms of bacteria, it is harmless, allows you to effectively treat a wide range of diseases of bacterial etiology in animals in the absence of data on the causative agent of infection and its sensitivity to antibiotics does not possess allergenic properties, has a stimulating effect on the indicators of the humoral immune response and is stable during storage.

The addition of citric acid to the azithromycin + flunixin complex contributes to:

- restoration of hematological and biochemical parameters faster than in animals that received only the composition azithromycin + flunixin_ + water;

- accelerate the removal of residual amounts of azithromycin and flunixin from the body of calves and piglets;

- reducing the term pre-slaughter exposure.

According to the degree of exposure to the body, the claimed pharmaceutical composition refers to moderately hazardous substances (hazard class 3 according to GOST 12.1.007-76).

The invention is illustrated by the following examples, which, however, do not limit the scope of the claims of the applicant.

Example 1. Getting the drug

The drug is obtained by mixing the components. The mixing order of the components is not significant. The composition in one of the options for its implementation is as follows (mg / ml solution):

Azithromycin dihydrate 100.0 Flunixin meglumine 44.0 Lemon acid 0.5 Water for injections up to 1 ml

In appearance, the drug is a clear solution of light yellow color.

Example 2. The study of the pharmacokinetics of azithromycin and flunixin in the blood of calves and piglets after administration of the claimed pharmaceutical composition

The results of the study of the pharmacokinetics of azithromycin in the blood serum of piglets showed that after 0.05, 0.12 and 0.33 hours the field of application of the drug, the concentration of azithromycin in blood serum increases and reaches a maximum of 0.5 hours (about 828 ng / ml). In the future, there is a gradual decrease in the concentration of the component in the blood serum of calves, and after 96 hours it is about 5 ng / ml.

The maximum concentration of flunixin was detected 1 hour after the use of the drug and was about 966 ng / ml, then the concentration decreased, and after 96 hours it was about 9 ng / ml.

Example 3. The study of the pharmacokinetics of azithromycin and flunixin in the organs and tissues of calves and piglets after administration of the claimed pharmaceutical composition

All animals participating in the experiment were kept in standard farming conditions. The calves and piglets did not receive any chemotherapeutic drugs before and were clinically healthy. Animals were slaughtered for the purpose of selecting organs and tissues 30, 35, and 40 days after a single intramuscular injection of the claimed pharmaceutical composition in a dose of 1 ml per 20 kg of animal weight. After the preparation of tissue samples, solid-phase extraction of azithromycin and flunixin was performed and the samples were analyzed on a chromatograph. To conduct a qualitative and quantitative analysis of the obtained extracts, the calibration procedure of chromatographic data was used. The calibration procedure has the following goals: determining the retention time of the analyzed component for its subsequent identification (qualitative analysis of samples), determining the retention time of the internal standard and determining the analyte concentration using the calibration graph (quantitative analysis using the internal standard method).

According to the results, the highest concentrations of azithromycin are observed in the kidney, liver and injection sites (163.2: 127.3 and 126.1 ng / g, respectively) on day 30. On the 35th day, the concentration of azithromycin decreased in all organs and did not exceed 28.8 ng / g. Over time, the residual amounts of azithromycin decrease, and 40 days after the use of the drug, its content in the tissues does not exceed the limits of quantitative determination of the method.

In samples of organs and tissues of calves and piglets at all stages of the study, the content of flunixin in all organs was below the limit of quantification.

Example 3. Clinical studies

As a result of the studies, it was found that the claimed composition is particularly suitable for cattle and small cattle and pigs. The claimed injectable pharmaceutical composition was tested as a treatment for bacterial infections of the respiratory system in cattle and small cattle and pigs caused by Pasteurella haemolytica, Pasteurella multocida, Haemophilus somnus, for the treatment of necrobacteriosis in pigs, as well as for the treatment of infections caused by Pasteurella haemolytica, Paste , Actinobacillus pleuropneumoniae and Streptococcus suis, swine erysipelas, spirochetosis and mycoplasma infections, skin and soft tissue infections - erysipelas, impetigo, secondarily infected dermatoses; chlamydia, Lyme disease (borreliosis), diseases accompanied by fever, including gastrointestinal. The animals were divided into the following groups: a) a group of animals that received only azithromycin, b) a group of animals that received only flunixin, c) a group of animals that received azithromycin and flunixin at the same time, but in different compositions, d) a group of animals that received azithromycin and flunixin simultaneously as part of the proposed pharmaceutical composition. In this case, compositions containing flunixin in an amount from 38.0 to 50.0 mg / ml, azithromycin from 60.0 to 120 mg / ml and citric acid in an amount from 0.01 to 1.0 mg / ml were tested .

The pharmaceutical composition was administered to cattle and small cattle and pigs once a day intramuscularly at a dose of 1 ml per 20 kg of animal weight for 3-5 days in a row.

The maximum dose for the introduction of the claimed pharmaceutical composition at one point in the body was: cattle - 20 ml, small animals - 5-10 ml.

If the volume of the injected solution exceeded the above, it was administered to animals in several places.

As a result of clinical trials, a high degree of treatment efficiency was established for a group of animals treated with azithromycin and flunixin simultaneously in the composition of the proposed pharmaceutical composition, compared with groups that received only azithromycin or only flunixin, as well as with the group treated with azithromycin and flunixin simultaneously, but in different compositions .

With the above schemes for the administration of the drug, side effects and complications have not been established. In a small number of animals (<3%), swelling was observed at the injection site of the pharmaceutical composition, which quickly passed and did not require treatment.

Example 4. The dynamics of the hematological and biochemical parameters of blood of calves and piglets after intramuscular injection of the claimed composition

Under the experiment, 15 calves and 15 piglets were taken, which were divided into 3 groups:

- the first group of calves and piglets was administered at a therapeutic dose of 1.0 ml per 20 kg of the animal’s weight intramuscularly once a day for 3 days in a row an injectable antibacterial pharmaceutical composition consisting of: azithromycin - 100 mg / ml, meglumine flunixin - 44 mg / ml, water - up to 1 ml;

- the second group of calves and piglets was injected with the claimed injectable antibacterial pharmaceutical composition with the addition of citric acid in the same dose - 1.0 ml / 20 kg of animal weight once a day for 3 days;

- the third (control) group of calves and piglets was injected intramuscularly with saline for 3 days once a day at a dose of 1 ml / 20 kg of animal weight.

10 days after the last injection, hematological and biochemical studies were performed (see table).

Studies have shown that the blood picture (hematological and biochemical parameters) returned to the physiological level in the 2nd group of calves and piglets faster than in the 1st.

When studying the timing of the elimination of residual amounts of azithromycin and meglumine flunixin in the organs and tissues of piglets and calves after 3 times the injection of an injectable antibacterial pharmaceutical composition in a therapeutic dose (1.0 ml per 20 kg of animal weight) without the addition of citric acid (group 1) - residual amounts azithromycin in concentrations of the order of 3-7 ng / g was found in the liver and kidneys of piglets at 42 days, calves at 45 days after the last injection. Residual amounts of flunixin meglumine in concentrations of about 2-5 ng / g were found in the liver and kidneys of piglets on the 25th day, calves on the 30th day after the last injection.

In the 2nd group, where the claimed injectable antibacterial pharmaceutical composition was added with the addition of citric acid in the same therapeutic dose, the elimination of azithromycin and meglumine flunixin from internal organs was faster: in piglets, only trace amounts of the antibiotic were noted on day 40 (1-3 ng / g ), (on day 42, azithromycin was not found in the organs and tissues of piglets), and flunixin meglumine on day 21 was determined by trace amounts (1-2 ng / g); on day 23, meglumine flunixin was not detected. In calves, the content of azithromycin in the liver and kidneys at a level of 2-5 ng / g was recorded on day 40; residual antibiotic amounts were not found in these organs on day 45. Meglumine flunixin was detected on day 24 — trace amounts (1-2 ng / g), and meglumin flunixin was not detected on day 27.

Thus, the addition of citric acid to the macrolide-NSAID combination helps to restore hematological and biochemical parameters faster than in animals that received only the macrolide-NSAID combination, and also helps to accelerate the elimination of residual amounts of azithromycin and flunixin from the body of calves and piglets.

The acceleration of elimination of foreign substances from the body plays an important role in the treatment of infectious diseases and can reduce the time before slaughter exposure.

Tests have shown that the claimed pharmaceutical composition is stable for two years when stored at a temperature of from 5 ° C to 25 ° C in a dry place protected from direct sunlight.

As follows from the above data, the problem is solved — a pharmaceutical composition that is stable during storage was obtained, which has a wide spectrum of antibacterial effects when administered intramuscularly to animals, is non-toxic, does not cause complications and side effects, and helps to accelerate the excretion of residual amounts of azithromycin and flunixin and thereby reducing the time before slaughter exposure of animals.

Claims (1)

An injectable antibacterial pharmaceutical composition containing flunixin or one of its pharmaceutically acceptable salts, azithromycin in the form of a dihydrate, citric acid and water in the following ratio of ingredients (mg / ml):
Azithromycin in the form of dihydrate 60.0-120.0
Flunixin or one of it
pharmaceutically acceptable salts 38.0-50.0
Citric acid 0.01-1.0
Water for injection up to 1 ml