JPH0140809B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel synergistic antimicrobial compositions. The resistance of pathogens to commercially available active ingredients has increased to a significant degree, with the result that some of the effective active ingredients that have been used for many years are no longer available. In addition to chromosomal resistance, the recently discovered "plasmid resistance" is responsible for this "resistance" phenomenon. The latter indicates the possibility of a pathogen directly transferring its plasmid resistance to individuals belonging to the same or other species as well. In this way polyresistant pathogens may be generated in a short period of time. The above facts make it more important to use active ingredients in combination. The interactions, antagonistic and synergistic effects, of active ingredients administered simultaneously have been known for a long time. Synergism refers to an increased effectiveness of the combination relative to the effectiveness of the components, and this effect is particularly important in cases of mixed infections. The present invention contains 5 to 50% by weight of primycin or its derivatives, and 95 to 50% by weight of primycin or its derivatives.
doxycycline or its derivatives and/or sisomicin
or a derivative thereof and an antimicrobial agent having synergistic action by mixing with an inert, solid or liquid, non-toxic pharmaceutically acceptable carrier and forming the mixture into a pharmaceutical composition. Regarding the composition. The synergistic pharmaceutical composition according to the invention has the following advantages. 1 By attacking the metabolism of pathogens at several points simultaneously, a killing effect is better achieved, and this effect is more effective than a “static” effect, which is simply the arrest of microbial evolution. more advantageous. 2. When attacking several metabolic pathways, resistance to the combination of active ingredients used does not occur at all, or only after a long period of time. 3. As a result of the synergistic action between the active ingredients, the amount of active ingredient can be significantly reduced, with the following benefits: a. In the case of long-term continuous administration, the toxicity of the ingredients reduces the effective amount introduced into the microorganism. By doing so, it will be significantly reduced. b In the case of some more expensive compositions, a reduction in the amount of active ingredient may also have economic benefits. A further advantage is that for certain active ingredient combinations not only is the extent of the minimum inhibitory concentration significantly reduced, but in many cases the spectrum of activity is also broadened. We now have Thermomonospora galeriensis
Primycin and its derivatives (Hungarian patent specification 153593) produced by fermentation from the strain 5
It has been found that amounts of ~50% by weight provide a synergistic effect with 95-50% by weight of Sisomicin and/or Doxycycline. Owing to the strong synergistic effect, the combination according to the invention is effective and has a broad spectrum of activity, so that it can be successfully used against multiresistant and potent pathogenic microorganisms that cause serious epidemics and diseases. They are particularly advantageously used in cases of mixed infections. The composition according to the invention may preferably contain primycin in the form of heterocolloidal primycin (UK Patent Specification 1512604). The composition according to the invention comprises as doxycycline derivative a doxycycline salt of an inorganic acid, preferably doxycycline hydrochloride or doxycycline hyclate. The composition according to the present invention as a sisomicin derivative has lower alkyl, hydroxy-
It may also include sisomicin or acid sisomicin salts substituted with lower alkyl, lower aminoalkyl or lower alkanoyl. As the sisomicin derivative, preferably N-methyl, N-hydroxyethyl, N-acetyl-sisomicin or sisomicin-hydrochloride can be used. The above-mentioned doxycycline and its derivatives (UK patent specification 845649) and the above-mentioned sisomicin and its derivatives (US patent specification 3907771 and Hungarian patent specification 170513) are known compounds. According to one preferred embodiment of the invention, primycin and sisomicin are used as active ingredients. According to another feature of the invention, primycin and doxycycline are used as active ingredients.
Derivatives of the antibiotics mentioned above may also be used in the compositions mentioned above. A preferred composition according to the invention comprises 30 to 35% by weight of primycin, 30 to 35% of the total active ingredient content.
% by weight of doxycycline or an equivalent amount of its hydrochloride and 30-35% by weight of sisomicin. The synergistic pharmaceutical compositions according to the invention may be solid compositions such as tablets, capsules, dragees, suppositories, semi-solid compositions such as ointments or liquid compositions such as injectable solutions, suspensions or emulsions. Can be formed into objects. The most advantageous forms are gels, ointments, talc, injectable solutions or suspensions and powders - ampoules.
Examples include solvent-ampule combinations. The composition can be administered orally, parenterally, rectally or topically (eg, as an ointment). The pharmaceutical composition may include pharmaceutically acceptable carriers such as magnesium carbonate, stearic acid, magnesium, starch, talc, water, etc. and optionally excipients such as fillers, disintegrants, lubricants, emulsifiers, etc. good. Compositions for oral administration may take the form of tablets, capsules or dragees. The synergistic compositions can also be used in veterinary therapy, for example as a powder mixture mixed into feed or as a solution mixed into an aqueous mixture fed to the animal. Compositions for parenteral use may take the form of aqueous solutions, emulsions or suspensions. For topical use, ointments, aqueous or oily emulsions or suspensions, or sprays may be employed. The composition used parenterally consists of sisomicin and doxycycline in a powder ampoule in the presence of sodium acetate, and in a solvent ampoule a heterocolloidal primycin and a surfactant, preferably a quaternary ammonium salt such as cetyl. It can be produced by adding trimethylammonium bromide. The contents of the solvent ampoule are poured into the powder ampoule immediately before use. After dissolution, a fully usable veterinary injection composition is obtained. A composition which can be administered parenterally is preferably prepared by mixing a hydroalcoholic solution of primycin with a suitable carrier (e.g. castor oil) and incorporating sisomicin and/or primycin into the resulting castor oil mixture after distilling off the alcohol and cooling. or prepared by suspending doxycycline. Ointments are prepared by uniformly dispersing the active ingredients in a conventional ointment, such as petrolatum. Biological (in vitro) compositions according to the invention
Activity is demonstrated in the following examples. The following internationally resistant and/or multiresistant human and/or animal pathogenic microorganisms were used in the course of the study: 1 Vibrio parahaemolyticus CCM.5938, 2 Pseudomonas acidovorans CCM.283, 3 Proteus vulgaris CCM. 1799, 4 Proteus mirabilis CCM.1944, 5 Shigella sonnei CCM.1373, 6 Salmonella typhimurim CCM.5445, 7 Salmonella cholerae-suis CCM.5438, (Inst.Pasteur Stamm), 8 Salmonella cholerae-suis CCM.5874, 9 Salmonella cholerae-suis subsp.
Kunzendorf.ccm.5967, 10 Escherichia Coli DSM.30038, Escherichia Coli ATTC 11775, Cyctitis, Pattern pathogens, 12 Escherichia Coli CCM.180, IySogenicus, COLIC, COLIC. Inogenicus, 13 Escherichia COLI CCM.5863, Haemolyticus, 14 Klebsiera Pneumoniae CCM.1848 , 15 Serratia Macerscens CCM.303, 16 Staphylococcus aureus CCM.885, 17 Staphylococcus aureus DSM.20231, 18 Staphylococcus aureus CCM.2317, human mastitis, 19 Staphylococcus aureus CCM.2326 human mastitis, 20 Staphylococcus aureus CCM. 2515
betahaemylysis, 21 Staphylococcus aureus CCM.2515 coagulase positive, 22 Streptococcus faecalis CCM.885, 23 Streptococcus sgalactiae CCM.5153, from milk of a cow with mastitis, 24 Streptococcus sgalactiae CCM.5534, from cow with mastitis From cow's milk, 25 Bacillus cereus CCM.2010, 26 Listeria monocytogenws CCM.5576, ATCC＝The American Type Culture
Collection, CCM＝Czechoslovac Collection of
Microorganisms, DSM＝Deutsche Sammlung fur
Mikroorganismen. Abbreviation: P = Purimycin sulfate S = Sisomicin sulfate D = Doxycycline sulfate μg/ml = Micrograms/milliliter MIC = Minimum inhibitory concentration 0 = No growth, complete inhibition of microorganisms ± = Slight growth ++ = Moderately Growth +++ = strong growth, no inhibition Tests were carried out on DIFCO broth medium at 37°C
The samples were evaluated after incubation for 24 and 48 hours, respectively. In Tables 1 to 1, Thermomonospora
It has been shown that the combination of primycin prepared from the fermentation broth of S. glariensis and sisomicin or doxycycline has a synergistic effect, and the synergistic effect increases the original activity by 30-40 times. Pharmaceutical compositions according to the invention may also contain other active ingredients, such as chemotherapeutic agents.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Control
contrast
MIC〓P〓0.5, S〓0.5, D〓1
MIC〓P〓0.5, S〓0.25, D〓0.
twenty five

[Table] Control

MIC〓P〓0.5, S〓0.25, MIC〓P〓
0.25, S〓0.25, D〓0.25
D〓0.25

[Table] Control
contrast
MIC〓P〓0.5, S〓50, D〓0.5
MIC〓P〓0.25, S〓1, D〓1

[Table] Control

MIC〓P〓0.25, S〓1, D MIC〓P
〓0.25, S〓0.75, D〓0.25
〓1

[Table] Control
contrast
MIC〓P〓25, S〓150, D〓0.5
MIC〓P〓50, S〓50, D〓0.5,

[Table] Control

MIC〓P〓50, S〓50, D〓 MIC〓P〓
＞200, S〓2.5, D〓150
0.5,

[Table] Control
contrast
MIC〓P〓150, S〓2.5, D〓2.5
MIC〓P〓150, S〓0.75, D〓5

[Table] Control

MIC〓P〓150, S〓0.75,
MIC〓P〓75, S〓0.75, D〓5

D〓5

[Table] Control
contrast
MIC〓P〓75, S〓2.5, D〓5
MIC〓P〓200, S〓2.5, D〓2.
Five

[Table] Control

MIC〓P〓200, S〓2.5,
MIC〓P〓200, S〓2.5, D〓5

D〓2.5

[Table] Control
contrast
MIC〓P＞200, S〓1, D〓5
MIC〓P〓200, S〓0.75, D〓
2.5

[Table] Control

MIC〓P〓200, S〓0.75,
MIC〓P〓200, S〓10, D〓25

D〓2.5
Further details of the invention are illustrated by the following examples, which are intended to be illustrative only and not limiting. Example 1 Composition of powder ampoule: Sisomicin 0.10 g Doxycycline, HCl 0.10 g Sodium acetate 0.533 g Composition of solvent ampoule: Primycin heterocolloid (active ingredient content): 0.1 g) 10.0 g Cetyltrimethylammonium bromide
A 0.5 mg composition is prepared as follows: Sisomicin, doxycycline and pre-powdered sodium acetate are homogenized, weighed into a powder ampoule and sealed (). Dissolve cetyltrimethylammonium bromide in heterocolloidal primycin, fill in a 10 ml ampoule, and seal (). Before use, the contents of the solvent ampoule are poured into the powder ampoule, which after dissolution is pressed into the breast area using a plastic needle. The composition thus produced can be administered in a two-chamber syringe by methods known per se.
syringe). Example 2 Sisomicin 0.10g Doxycycline, HCl 0.10g Primycin heterocolloid (active ingredient content: 0.1g) 10.00g Sodium acetate 0.97g Cetyltrimethylammonium bromide
A 0.5 mg composition is prepared as follows: Sodium acetate is dissolved in primycin heterocolloid, filled into powder ampoules and lyophilized by conventional means, and sisomicin and doxycycline are added to this lyophilized product. in dry form, and the powder ampoule is sealed with a rubber stopper in a known manner. The contents of the powder ampoule are dissolved in 10 ml of distilled water before use and pressed into the breast area with a plastic needle or by other means. Example 3 Primycin heterocolloid (alcoholic) (active ingredient content: 0.1 g) 10.00 g Castor oil 10.00 g Cholesterol 0.25 g Sisomicin 0.10 g Doxycycline, HCl 0.10 g A composition is prepared as follows: Primycin - Mixing the alcoholic solution of the heterocolloid with castor oil and distilling off the alcohol, preferably in vacuo. Cholesterol is dissolved in the castor oil-primycin mixture, preferably while warm. Dry sisomicin and doxycycline are conventionally suspended in the cooled castor oil and primicin mixture. The suspension thus obtained is filled into suitable plastic ampoules or aluminum tubes and fitted with plastic needles most suitable for the use. Example 4 Composition of powder ampoule Sisomicin 0.10 g Doxycycline 0.10 g Composition of solvent ampoule Primycin-heterocolloid (active ingredient content: 0.1 g) 10.0 g Cetyltrimethylammonium bromide
0.5 g Disodium hydrogen phosphate 0.1716 g Crystalline citric acid 0.7596 g The composition is prepared as follows: Doxycycline and Sisomicin are mixed together and sealed in an ampoule (). Cetyltrimethylammonium bromide, crystalline disodium hydrogen phosphate _{( Na2HPO4.12H2O} ) and citric acid were combined with primycin- _{heterocolloid ( C6H8O7 .}
Dissolve in H ₂ O), fill into ampoules and seal (). Example 5 Ointment Sisomicin 0.10g Doxycycline, HCl 0.10g Primycin 0.10g Polyethylene Glycol 400 4.85g Polyethylene Glycol 4000 4.85g A composition is prepared as follows: Sisomicin, doxycycline and Primycin powdered to smaller than 50μ. is used in the manufacture of ointments. Polyethylene glycol 400 and polyethylene glycol 4000 are mixed homogeneously and the active ingredient is mixed with a small portion of the homogenized excipient and in stages with the remainder of the excipient. The mixture is then filled into tubes. Example 6 Aerosol film former Sisomicin 0.10 g Doxycycline, HCl 0.10 g Primycin 0.10 g Polyvinylpyrrolidone 2.0 g Absolute ethanol 47.7 g Freon 11/12 5050 50.0 g The composition is prepared as follows: Drying and powdering Sisomicin, doxycycline, HCl, and primycin (less than 50μ) are placed in an aerosol container, then an anhydrous ethanolic solution of polyvinylpyrrolidone is added. The container is filled and sealed in a manner known per se. Example 7 Aerosol Tarxisomycin 0.10 g Doxycycline, HCl 0.10 g Primycin 0.10 g Isopropyl myristate 1.0 g Freon 11/12 5050 98.7 g The composition is prepared as follows: Pre-dried and powdered. Homogenize the Sisomicin (less than 50μ), Doxycycline, HCl, and Primycin and triturate with isopropyl myristate. Fill an aerosol container for each dose. The container is filled and sealed in a manner known per se. Example 8 Comparative study of primycin and primycin compositions in patients with mastitis Primycin and primycin compositions are tested in patients with clinically proven mastitis. . The test is performed using the thermographic method (colorimetric film).
set). Active ingredients commercially available in Hungary, such as Neomaticur and Mastalone, were used as comparison substances. Disease classification Simple catarrhal mastitis Acute infectious catarrhal mastitis Acute infectious catarrhal mastitis Suppurative mastitis with pyoma Treatment 1 Primycin 100 mg/breast 8 out of 15 cases recovered 2 Primycin composition Composition: Powdered ampoule Sisomicin (dry) 85 mg Doxycycline (dry) 100 mg Sodium acetate (anhydrous) 533 mg Prednisolone 10 mg Solvent ampoulpurimycin-heterocolloid (active ingredient content): 0.1 g) 20 ml Cetyltrimethylammonium bromide 1.0 mg Purimycin composition The drug proved effective in 14 out of 16 cases. In the remaining case, the animal died from pyoma formation, and the other case had chronic infectious catarrhal mastitis. The above results are confirmed by in vitro test results.

Claims (1)

[Scope of Claims] 1. primycin or a derivative thereof in an amount of 5 to 50% by weight relative to the total active ingredient content;
consisting of 95 to 50% by weight of doxycycline or a derivative thereof and/or sisomicin or a derivative thereof and an inert solid or liquid non-toxic drug carrier and optionally other excipients,
Antibacterial combination drug composition with synergistic action. 2. The antibacterial formulation composition according to claim 1, which comprises a pharmaceutical composition in the form of a film-forming agent of ointment, talc or aerosol. 3. Antimicrobial formulation composition according to claim 1, consisting of a composition in injectable form, preferably in the form of an injectable solution or suspension or a powder-solvent combination ampoule. 4. The antibacterial formulation composition according to claim 1, wherein the doxycycline derivative comprises an inorganic acid salt of doxycycline, preferably doxycycline hydrochloride or doxycycline hyclate. 5. The antimicrobial according to claim 1, wherein the sisomicin derivative includes sisomicin whose nitrogen atom is substituted with lower alkyl, hydroxy lower alkyl, lower aminoalkyl, or lower alkanoyl, or a sisomicin salt formed with an acid. Combination drug composition. 6 As the sisomicin derivative, N-methyl,
The antibacterial formulation composition according to claim 1, comprising N-hydroxyethyl, N-acetyl-sisomicin or sisomicin-hydrochloride. 7. The antibacterial combination composition according to claim 1, comprising primycin and sisomicin as the active ingredients. 8. The antimicrobial combination composition according to claim 1, which contains primycin and doxycycline as the active ingredients. 9. The antibacterial combination composition according to claim 1, comprising primycin, sisomicin and doxycycline as the active ingredients. 10 30 to 35% by weight with respect to the active ingredient content
of primycin, about 30% by weight of doxycycline or an equivalent amount of its hydrochloride and 30-35% by weight
The antibacterial formulation composition according to claim 9, comprising sisomicin. 11. The antibacterial formulation composition according to claims 1 to 10, which comprises the primycin component in the form of heterocolloidal primycin.