EA024164B1 - Pharmaceutical composition - Google Patents

Abstract

The invention relates to the filed of veterinary medicine, in particular, to preparations for treating bacterial infections in livestock, i.a. poultry. A pharmaceutical composition comprises the active antibacterial substances: fluoroquinolone or pharmaceutically acceptable salts thereof; trimethoprim, antibiotic of polymyxin group, or pharmaceutically acceptable salts thereof; adjuvants (preservatives, stabilizers, organic acids, water), and can further comprise functional additives: feeding indicators (food grade dyes) or sweeteners, with the following component ratio, wt.%: fluoroquinolone - 0.5-15.0, trimethoprim - 0.5-15.0, polymyxin - 0.5-15.0, preservative - 1.0-5.0, stabilizer - 0.1-5.0, organic acid - 5.0-35.0, functional additive - 0.01-5.0, water - the rest.

Description

The invention relates to the field of veterinary medicine and relates to the creation of a broad-spectrum antibacterial agent for oral administration intended for the treatment of farm animals, including poultry, for infections of bacterial etiology.

The use of antibacterial drugs in animal husbandry and poultry farming is an integral part of the technology of growing and ensuring a healthy livestock. In veterinary medicine, a wide range of antibacterial substances and their combinations are used to treat diseases of bacterial origin.

Combined drugs characterize the widest possible spectrum of action, mutually reinforcing antibacterial effect, which is especially important for generalized infections occurring in an acute form and require the fastest possible start of effective treatment, or in mixed infections, when microbial association pathogens have different sensitivity to antibacterial drugs; minimizing side effects by achieving a quicker and more complete clinical effect while administering two or more synergistically active components, preventing or slowing the development of resistance in microorganisms.

It is known that a wide range of antimicrobial activity of drugs is usually achieved by combining several drugs. Moreover, the combination of chemical structures in the composition allows to achieve their synergistic effect, which allows to reduce the dose of the drug and thereby reduce the risk of side effects or to obtain a drug with new useful properties.

Known pharmaceutical composition [1] containing trimethoprim, excipients and water, as well as active antibacterial substances in the form of sulfonamides (sulfadimidine, sulfathiazole).

The disadvantages of the known funds is the injection form of the drug, inappropriate for group use, as well as a combination with sulfonamides, the positive effect of which in this composition has not been confirmed in practice.

The closest to the proposed technical solution in terms of the set of essential features of the active antibacterial substances is a pharmaceutical composition [2] containing fluoroquinolone (ofloxacin), trimethoprim, excipients (including dexamethasone) and water for injection, in addition, containing sulfanilamide ( sulfonomethoxin). The described composition is injected.

The disadvantages of the above pharmaceutical composition include the fact that the synergism of trimethoprim with sulfonamides, which was observed ίη νίίτο, in clinical conditions was not confirmed, and the effect of the combined drugs is due mainly to the presence of trimethoprim. The introduction of sulfonamides into the composition in practice does not give the expected therapeutic effect, but enhances the toxic effect of the drug.

The disadvantages include the injection form of the drug, since the group application of injections is an uncomfortable and time-consuming process that can only be performed by qualified specialists in veterinary medicine.

The basis of the invention is the task of developing a new pharmaceutical composition with the widest possible spectrum of action, with a low level of toxicity, convenient to use, which would prevent the development of resistance of microorganisms, easily dissolve in water, maintain medicinal properties in hard water and, if necessary, allow you to control the process evaporating the composition when used in large livestock and poultry farms.

The technical result of the present invention is to create an optimal group composition of an antibacterial agent with a pronounced synergistic effect of the component composition of a composite compound having high efficiency against a wide range of bacterial infections, with an increased therapeutic effect at the cellular level (all components of a pharmaceutical composition in a microbial cell act on different levels of nucleic acid synthesis, provides potentiation of their action Ia), with a lower concentration of the active ingredients that is achieved by the combined action of all the essential features of the invention.

The problem is solved in that in a pharmaceutical composition containing active ingredients: fluoroquinolone or its pharmaceutically acceptable salts; trimethoprim, excipients and water; an antibiotic from the group of polymyxins or its pharmaceutically acceptable salts is additionally introduced; and auxiliary substances in the form of preservatives, stabilizers, organic acids, and also functional additives have been introduced: indicators of evaporation (food coloring), or sweeteners.

Analysis of the set of essential features showed that the active components have a synergistic effect, exhibit a pronounced antibacterial effect. This composition provides a wide range of antibacterial action, increasing the therapeutic effectiveness of the pharmaceutical composition, is sufficient to obtain a high therapeutic effect in the treatment of farm animals, including poultry. The indicated quantitative content of 1,024164 components is optimal from the point of view of the safety of taking the pharmaceutical composition, avoids possible side effects during treatment and allows to obtain a convenient soluble oral dosage form stable in hard water.

All drugs of the quinolone class, regardless of the presence or absence of fluorine in the molecule, are united by a single mechanism of action on the microbial cell: their main target is DNA gyrase, one of the key enzymes of the cell, determines the normal process of DNA biosynthesis and cell division. Therefore, this class of substances is often referred to by the general term - DNA gyrase inhibitors.

The introduction of fluoroquinolone (norfloxacin, ofloxacin, enrofloxacin, ciprofloxacin, danofloxacin) or its pharmaceutically acceptable salt in the composition in an amount of 0.5-15.0 wt.% Provides an optimal and balanced effect, since it allows you to dose the pharmaceutical composition depending on the amount of water, which gets the animal during treatment.

It is advisable to use trimethoprim as the active substance, which is a competitive inhibitor of dihydrofolate reductase and violates one of the stages of nucleic acid synthesis - the formation of tetrahydrofolate from dihydrofolate.

Trimethoprim acts on a wide range of microorganisms, including gram-positive and gram-negative bacteria, chlamydia, nocardia (actinomycetes), some mycobacteria and protozoa anaerobic bacteria. The spectrum of action against gram-negative bacteria of the drug includes Nastoribik ragatLisp / as. Nastorybik bisgsuk Sbgobas1sg Gsipbp et al., Kasbms Paa okhu! Oka et al., Ep1sgobas1sg s1oasas, 8sggaya tagsskssik, etc.

MusoBac1crst 1uBrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr, they are insensitive to trimethoprim.

The introduction of trimethoprim into the composition in an amount of 0.5-15.0 wt.% Provides the most optimal and balanced effect.

All polymyxins affect the cytoplasmic membrane of a bacterial cell by interacting with phospholipids. They bind to anionic sections of the membrane and resemble cationic detergents in the nature of their action. Damage to the bacterial membrane structure leads to a change in permeability for both intracellular and extracellular components.

The antibacterial activity of polymyxins (polymyxin B, polymyxin E (colistin), polymyxin M) extends only to the gram-negative microflora (see Table 1): EksysbSoya kr. HiDisigas, VgissPa kr., Rksibotopak asgidshoka, Asshs1obas1sg krr.

The activity of polymyxins against certain pathogenic bacteria: MIC (mg / l) and / or a qualitative assessment (K - resistance).

Table 1

Microorganism Colistina sulfate Colistina sulfate Polymyxin B sulfate 31arIu1ossoss aigeiz 64 (C) (IN) 64 (P) 31ger1ossoss rudepez 32 (C) 32 (P) 16 (P) Group 31ger1ossoss utyapz 32 (P) 32 (P) 32 (P) Ep1gossossiz 1aesa1 | 3 R R R Nayetor Zh1 of 1p11iepay 0.5-1.0 - 0,03 Jesse Jane 0.01-32 0.05-64 0,03 K1e3s1e11a 0.01-1.0 0.01-4.0 0.03-0.5 Joshogas (his spr. 0.03-32 0,5-P 0.03-16 Рgo (езр.р. R R R Zatope11a spr. 0.01-1.0 0.03-0.5 0.01-1.0 ZhdeNa spr. 0.01-1.0 0.1-0.25 0.01-1.0 Rezeybotopaz aegid! Pose 0.03-4.0 2.0-320.03-4.0 -

In many cases, polymyxins remain highly active antibiotics against bacteria that are resistant to most antimicrobials. Less activity is shown against anaerobes. Insensitive to the action of polymyxins, all types of Prgo1sik crr., 8sggya tagssksspk, gram (+) bacteria and many anaerobes, in particular Vas1sgo1bsk GgadShk. Acquired bacterial resistance develops slowly and is usually associated with a decrease in the permeability of bacterial cell membranes for polymyxins.

Polymyxins exhibit a synergistic effect with certain other antibacterial agents for certain pathogens. So, synergism with trimethoprim against §.tagsskssspk and others was discovered.

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The use of an antibiotic from the group of polymyxins in the composition in an amount of 0.5-15.0 wt.% Provides the widest possible spectrum of action and the optimal synergistic combination of components, the possibility of administering the composition 1 time per day, which greatly simplifies the treatment of animals that can be treated, and ensures high economic feasibility of using the composition in veterinary medicine.

The mechanism of the synergistic action of actively acting components (trimethoprim, fluoroquinolone, polymyxin) is that all components of the pharmaceutical composition in the microbial cell act at different levels of nucleic acid synthesis and provide potentiation of their action. This allows you to use lower concentrations of substances to obtain the optimal therapeutic effect.

Bacterial resistance to this composition is rare compared with that of other drugs.

The introduction of phenol and / or n-butanol and / or benzyl alcohol and / or nipagin and / or nipazole or their combinations in the amount of 1.0 to 5.0 wt.% As preservatives provided the optimum preservative effect .

It is known that the activity of fluoroquinolones in working solutions when using water of increased hardness, which is often found in farms in practice, significantly reduces the therapeutic effect of fluoroquinolone-based preparations.

Introduction to the composition of organic acids (citric, lactic, malic, ascorbic, succinic individually or in various combinations) in an amount of from 5.0 to 35.0 wt.% Promotes the complete dissolution of insoluble components of the composition, allows you to get a chemically stable liquid pharmaceutical dosage form composition, and ensures its further stability in working solutions, including hard water.

To prevent the catalytic effect of heavy metal ions in the feed, indirect sodium antioxidant edetate, and / or sodium thiosulfate, and / or Trilon B, and / or sodium metabisulfite, or combinations thereof, from 0, were introduced into the composition as stabilizers. 1 to 5.0 wt.%.

Introduction to the composition of functional additives allows the most effective use of drugs based on this pharmaceutical composition for various animal species, given their anatomical and physiological characteristics and conditions.

If necessary, mass treatment of poultry introducing into the composition a food coloring, in particular the blue patented V (food supplement E 131), or indigo carmine (food supplement E 132), or food coloring green (food supplement 8E142), or combinations thereof in an amount of 0.010 , 10 wt.% Allows you to visually control the uniformity of the distribution of the pharmaceutical composition in the water supply system, allows you to control the bird receiving a therapeutic dose of the drug and in time to avoid uneven receipt of a therapeutic dose, ensuring high treatment efficiency and economic benefits. Prevents excessive or insufficient use of the drug and related problems.

Introduction to the composition of sweeteners in an amount of from 0.5 to 5.0 wt.% Improves the palatability of the pharmaceutical composition, which is especially important when using preparations for pigs. Acesulfate K and / or aspartame and / or cyclamate and / or saccharin and / or thaumatin or combinations thereof were used as sweeteners.

The study of the chemical stability of the pharmaceutical composition and the compatibility of its components was carried out by studying their basic physical and chemical properties. For this, examples of dosage forms based on a pharmaceutical composition of various concentrations using various stabilizing substances were made. The optimal ratios of the components were determined at which the active substances are contained in the dispersed system in the form of true solutions.

Embodiments of the pharmaceutical composition of this invention are illustrated by the following examples of compositions (solutions were prepared by the volumetric weight method).

Example 1

The pharmaceutical composition in the following ratio, wt.%:

enrofloxacin trimethoprim colistin sulfate lactic acid trilon B p-butanol water

10.0

3.0

2.0

15.0

3.0

4.0 rest.

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Example 2

The pharmaceutical composition in the following ratio, wt.%:

norfloxacin trimethoprim polymyxin E lactic acid citric acid polyvinylpyrrolidone sodium edetate phenol blue patented V

10.0

5,0

5,0

10.0

5,0

3.0

1,0

0.5

0.5 rest water.

Example 3

The pharmaceutical composition in the following ratio, wt.%:

danofloxacin trimethoprim polymyxin E lactic acid ascorbic acid sodium gasoline alcohol metabisulf! t acetolsulfam water

2,5

3.0

2,5

12.0

2,5

1,0

1,0

2.0 rest.

The prepared examples of dosage formulations were tested for stability. Accelerated aging method has been applied to pharmaceutical compositions. The tests were carried out under the following storage conditions: temperature 37 ± 5 ° C, relative humidity 75 ± 5%, quality indicators were monitored after 0, 15, 30, 45, 60, 75 days. The results are presented in table. 2.

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table 2

The results of the stability study of examples of compositions of dosage forms of the pharmaceutical composition (claimed)

the luminosity of the obtained pharmaceutical compositions. Thus, the preparations are suitable for use within 2 years from the date of manufacture, based on the assumption that 30 days of research time with accelerated aging corresponds to 1 year of the present time.

Working solutions for evaporation were made from the obtained pharmaceutical compositions and tested for their stability in hard water. Enrofloxacin 10% solution was used as a comparison. Working solutions were prepared in concentrations: 1 ml per 1 liter of water and 10 ml per 1 liter of water. Hard water with a hardness index (5-10 ° W) was used for the study. The organoleptic qualities of the resulting solutions were evaluated after 0, 6, 12, 18, 24, 30 hours. The results are presented in table. 3.

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Table 3

The results of the study of the stability of working solutions

Indicator Name

Appearance

Transparency

The presence of mechanical impurities

The presence of sediment, opalescence

Norm Working solutions ‘Result, hours 0 6 12 eighteen 24 thirty Example No. 1 (1 ml per 1 liter) Example No. 2 (1 ml per 1 liter) + + + + + + Example No. 3 (1 ml per 1 liter) + + + + 4· + Enrofloxacin 10% (1 ml + + + + + + 1 l) + + + + + + Solution Example No. 1 (10 ml per 1 l) + + + + + + Example No. 2 (10 ml per 1 l) + + + + + + Example No. 3 (10 ml per 1 l) + + + + + + Enrofloxacin 10% (10 ml + + + + + + 1 l) Example No. 1 (1 ml per 1 liter) Example No. 2 (1 ml per 1 liter) + + + + + + Example No. 3 (1 ml per 1 liter) + + + + + + Enrofloxacin 10% (1 ml + 4 + + + 1 l) + + + + + + Transparent Example No. 1 (10 ml per 1 l) + + + + + + Example No. 2 (10 ml per 1 l) + + + + + + Example No. 3 (10 ml per 1 l) + + + + + Enrofloxacin 10% (10 ml + + - - - 1 l) Example No. 1 (1 ml per 1 liter) Example No. 2 (1 ml per 1 liter) + + + + + + Example No. 3 (1 ml per 1 liter) + + + + + + No visible Enrofloxacin 10% (1 ml + + + + + 4- 1 l) + + + + + + mechanical Example No. 1 (10 ml per 1 l) + + + + + particles Example No. 2 (10 ml per 1 l) + + + + + Example No. 3 (10 ml per 1 l) + + + + + + Enrofloxacin 10% (10 ml + + + + + + 1 l) Example No. 1 (1 ml per 1 liter) + + + + + + Example No. 2 (1 ml per 1 liter) + + + + + Are absent Example N93 (1 ml per 1 l) + + + + + + Enrofloxacin 10% (1 ml + + + + + + 1 l) + + + + + Example No. 1 (10 ml per 1 l) + + + + + + Example No. 2 (10 ml per 1 l) + + + + + Example No. 3 (10 ml per 1 l) + - - - - - Enrofloxacin 10% (10 ml 1 l)

Note: + matches, - doesn't match.

Based on the data obtained during the study, the high chemical stability of the obtained pharmaceutical compositions in hard water was established, the working solution of enrofloxacin 10% (10 ml / l) was unstable.

A study was conducted of the sensitivity of bacterial cultures, for example, the pharmaceutical composition of the claimed and various antibacterial substances by the disk diffusion method. The results are shown in table. 4.

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Table 4

The sensitivity of bacterial cultures of the pharmaceutical composition of the claimed and various antibacterial substances (disco-diffuse method)

No. p / p The name of the tank. of culture dedicated from cattle, pigs birds No. EZ Growth retardation (sensitivity) in mm. Pharmaceutical composition Enrofloxacin Trimethoprim one 51 ayy1ossoss aigeez 1404 30,0 29.0 6.0 2 31 ayu1ossoss aigeez 22.0 22.0 11.0 3 51 ayy1ossoss aigeez 35.0 33.0 6.0 4 31 ayu1ossoss aigeez 250 15.0 15.0 10.0 5 E. Co1g 240 18.0 15.0 6.0 (thirteen) 6 E. Con 194 26.0 13.0 6.0 7 E. Con 244 (one) 26.0 18.0 20,0 8 E. Con 240 (13 g) 19.0 17.0 6.0 nine Zatope11a spr. 240 (eighteen) 30,0 20,0 22.0 10 Zatope11a spr. 196 (12) 33.0 32,0 23.0

Dosage forms based on the claimed pharmaceutical composition have been tested in laboratory animals, cattle, pigs and poultry.

Toxicity studies were conducted in laboratory animals and it was found that the dosage forms are low toxic for animals (according to GOST 12.1.007-76 - hazard class IV, low-hazard substances) and do not exhibit sensitizing, embryotoxic, teratogenic and mutagenic effects in recommended doses.

Dosage forms obtained on the basis of the claimed pharmaceutical composition were used to treat farm animals, including poultry, for diseases of the respiratory and digestive organs, by drinking with water in working solutions. The results are shown in table. 5.

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Table 5

The effectiveness of the dosage form obtained on the basis of the claimed pharmaceutical composition for diseases of bacterial etiology in calves, piglets, poultry (chickens)

Indicators: quantity animals (including number of bird) The drug is based on the declared pharmaceutical composition dose. Enrofloxacin 10% 0.5 ml / 1 l drinking water 1.0 ml / 1 l drinking water 1.5 ml / 1 l drinking water 1.0 ml / 1 l drinking water Calves (treatment for 10 fifteen 12 10 bronchopneumonia) Duration treatment days 7.0 ± 0.5 4.0 ± 0.5 3.0 + 0.5 5.0 ± 0.5 Efficiency. % 88.3 96.4 96.6 1 93.3 Piglets (treatment with enteritis) fifteen fifteen fifteen fifteen Duration treatment days 7.5 ± 0.5 3.5 ± 0.5 3.0 ± 0.5 4,5 ± 0,5 Efficiency% 89.4 97.6 97.3 95.6 Chickens (treatment with enteritis) 26 thirty 25 28 Duration treatment days 6.5 ± 0.5 3.0 + 0.5 2.5 ± 0.5 5.0 ± 0.5 Efficiency. % 86.8 98.2 98.5 94.4

Thus, the pharmaceutical composition for oral administration, which embodies the proposed invention, is intended for use in agriculture, namely in veterinary medicine.

Dosage forms obtained on the basis of the claimed pharmaceutical composition, due to their qualitative and quantitative composition, have high therapeutic efficacy, provide effective treatment for diseases caused by sensitive microorganisms; the widest possible spectrum of antibacterial action; low toxicity; convenient to use; well soluble in water; retain medicinal properties in hard water; do not show tolerance when reused.

The use of functional additives allows the most efficient use of drugs based on the pharmaceutical composition for various types of target animals.

Information sources:

1. Patent I8 No. 4089949 for the invention Injection therapeutic composition, A61K 31/505; A61K 31/635; A61K 47/18; A61K 9/08, publ. 05/16/1978.

2. Patent СЫ No. 101053568 for the invention. Composition and processing technologies for sodium injection A61K 31/505; A61K 31/538; A61K 31/57; A61K 31/635; A61K 47/02, A61K 47/10; A61K 9/08; A61P 31/00; A61P 33/00, publ. 10/17/2007.

Claims (11)

CLAIM 1. A pharmaceutical composition containing active antibacterial agents, such as fluoroquinolone or its pharmaceutically acceptable salts, trimethoprim, auxiliary substances and water, characterized in that it additionally contains an antibiotic from the group of polymyxins or its pharmaceutically acceptable salts, auxiliary substances in the form of preservatives, stabilizers, organic acids and additionally contains functional additives to control the effectiveness of use in the following ratio of components ntov% wt./wt fluoroquinolone: 0,515,0;. trimethoprim: 0.5-15.0; polymyxin: 0.5-15.0; preservative: 1.0-5.0; stabilizer: 0.1-5.0; organic acid: 5.0-35.0; functional additive: 0.01-5.0; water: the rest. 2. The pharmaceutical composition according to claim 1, characterized in that it contains polymyxin or its pharmaceutically acceptable salts selected from the group consisting of polymyxin B, polymyxin E (colistin), polymyxin M. 3. The pharmaceutical composition according to claim 1, characterized in that the fluoroquinolone or its pharmaceutically acceptable salt is selected from the group consisting of norfloxacin, ofloxacin, enrofloxacin, - 8 024164 ciprofloxacin, danofloxacin. 4. The pharmaceutical composition according to claim 1, characterized in that it contains phenol, or n-butanol, or benzyl alcohol, or nipagin, or nipazol, or a combination thereof as preservatives. 5. The pharmaceutical composition according to claim 1, characterized in that it contains sodium edetate, or sodium thiosulfate, or Trilon B, or sodium metabisulfite, or combinations thereof, as stabilizers. 6. The pharmaceutical composition according to claim 1, characterized in that the organic acid contains citric acid, or lactic acid, or malic acid, or ascorbic acid, or succinic acid, or a combination thereof. 7. The pharmaceutical composition according to claim 1, characterized in that it is administered by oral route. 8. The pharmaceutical composition according to claim 1, characterized in that it is made stable in hard water. 9. The pharmaceutical composition according to claim 1, characterized in that functional additives are used in the form of feeding indicators or sweeteners. 10. The pharmaceutical composition according to p. food additive 8Е142) or their combination. 11. The pharmaceutical composition according to claim 1, characterized in that, as sweeteners, it contains acesulfate K, and / or aspartame, and / or cyclamate, and / or saccharin, and / or thaumatin, or combinations thereof.