WO2012036585A1

WO2012036585A1 - Pharmaceutical composition with antimicrobial activity for parenteral administration and process for preparing same

Info

Publication number: WO2012036585A1
Application number: PCT/RU2011/000320
Authority: WO
Inventors: Виктор Львович ЛИМОНОВ; Константин Валентинович ГАЙДУЛЬ; Александр Валерьевич ДУШКИН
Original assignee: Limonov Viktor Lvovich
Priority date: 2010-09-13
Filing date: 2011-05-11
Publication date: 2012-03-22
Also published as: CN103096896A; AU2011302724C1; JP2013537190A; AU2011302724A1; BR112012023964A2; NZ598831A; CA2785228A1; AU2011302724B2; MX2012010535A; EA021874B1; EA201001449A1; WO2012036585A8

Abstract

The invention relates to pharmacology, medicine, veterinary medicine and to the pharmaceutical industry, in particular to a process for preparing original composite antimicrobial preparations for parenteral administration which have increased therapeutic effectiveness in the treatment of severe forms of infectious and inflammatory diseases. The proposed pharmaceutical compositions comprise, as active ingredient, beta-lactam antibiotics and highly disperse nanostructured silicon dioxide in ratios of from 10:1 to 75:1 by weight, respectively. The silicon dioxide particles present in the composition are the means of supplying the molecules of the antibiotics to the phagocytes, which makes it possible to increase, in a targeted manner, the concentration of the antimicrobial preparations in the areas of inflammation and to substantially neutralize the phenomenon of antibiotic resistance of microorganisms. The claimed process for preparing a pharmaceutical composition consists in mixing a beta-lactam antibiotic substance with highly disperse nanostructured silicon dioxide and is characterized in that the mixture of the above-mentioned substances in ratios of from 10:1 to 75:1 by weight, respectively, is subjected to mechanical processing by means of impact abrasion until the proportion by weight of the finely disperse fraction (< 5 µm) is increased to at least 25%. The resultant mixture is used for preparing injection solutions.

Description

PHARMACEUTICAL COMPOSITION OF ANTIMICROBIAL ACTION FOR PARENTERAL INTRODUCTION AND METHOD OF ITS

OBTAINING

The invention relates to antimicrobial pharmaceutical preparations and technologies for their preparation and can be used in medicine and veterinary medicine for the treatment of infectious and inflammatory diseases, as well as in the pharmaceutical industry for the production of medicines.

Currently, the successful treatment of most infectious and inflammatory diseases is based on the use of various antibacterial agents, including beta-lactam antibiotics.

Beta-lactams include drugs (natural and semisynthetic penicillins, cephalosporins, cefamycins, carbapenems and monobactams), which have a common fragment in the chemical structure of the beta-lactam ring, which determines the antimicrobial activity and a number of common properties of this group of drugs [1].

All beta-lactams have a wide spectrum of antimicrobial activity and high antimicrobial activity, however, the resistance of microorganisms to many of them develops relatively quickly due to their production of specific beta-lactamase enzymes (extended-spectrum beta-lactamases, class C chromosome beta-lactamases, etc. ) hydrolyzing the beta-lactam ring, which deprives these drugs of antibacterial properties and leads to the development of resistant strains of microorganisms [2].

In recent decades, specific beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam, etc.) have been created, based on the use of which a number of effective combined antibacterial beta-lactam drugs of the penicillin and cephalosporin series (amoxicillin / clavulanic acid, ampicillin / sulbacanum piperacillin / tazobactam, cefoperazone / sulbactam, etc.), which are characterized by increased resistance to beta-lactamases and more pronounced antibacterial activity [2, 3].

However, it should be noted that many of these "inhibitor-protected" drugs were not effective enough, since at a high level production by pathogenic microorganisms beta-lactamases, the above inhibitors do not completely protect antibiotics from hydrolysis.

The carbapenems that are resistant to many beta-lactamases also do not completely solve the problem of microbial resistance to these antibiotics, since their widespread use for the treatment of severe infections leads to the formation of multi-resistant P. aeruginosa strains [3].

In addition, it must be emphasized that, often, the clinical inefficiency (or low efficiency) of beta-lactams in infections caused by various microorganisms is associated not only with the negative effect of beta-lactamases, but also with the limited ability of these drugs to concentrate locally in the focus of infectious inflammation and penetrate into macrophages, in which the phagocytosed pathogens of many infectious and inflammatory diseases are deposited and from the severity of their functional state, which The level of antimicrobial resistance depends on the degree of measure [4, 5].

In recent years, it was found that the use of a variety of nanoparticles as carriers for the delivery of various antibiotics (including beta-lactams) into bacteria and macrophages, in order to increase their concentration in the area of infectious inflammation, and, accordingly, in order to enhance their antimicrobial properties, as well as to stimulate the functional activity of phagocytes (neutrophils and macrophages) and their additional recruitment into infected tissues, is a promising direction in the development of a modern experiment hydrochloric pharmacology and clinical medicine [6, 7, 8, 9, 10, 11, 12].

The essence of the invention lies in the fact that in order to enhance the therapeutic efficacy of beta-lactams, it is proposed to use SiCte (silicon dioxide) nanoparticles, which, differing in pharmacologically advantageous properties of biocompatibility, biodistribution, biodegradation and low toxicity (regardless of the severity of the structure's porosity), can serve as carrier of antibiotics for intracellular delivery to macrophages, which are concentrated in the foci of inflammation observed in the lungs, liver, kidney x, spleen, lymph nodes, heart, skin, bladder and other organs of mammals (i.e., significantly increase the concentration of antibiotics in infected areas), and to stimulate antimicrobial activity of these cells of the immune system, thereby significantly enhancing the therapeutic effect of antimicrobials in the treatment of infectious and inflammatory diseases [13, 14, 15, 16, 17, 18, 19, 20, 21].

The invention solves the problem of creating a pharmaceutical composition of antimicrobial action for injection based on the use of antibiotics from the group of beta-lactams and nanoparticles of silicon dioxide, which has increased therapeutic efficacy (compared with conventional beta-lactams, which are considered as a prototype in this invention) in the treatment of infectious inflammatory diseases.

The problem is solved in that a pharmaceutical composition of antimicrobial action for injection is proposed, which contains a beta-lactam antibiotic and highly dispersed nanostructured silicon dioxide in a weight ratio of (10-75): 1.

The problem is also solved by the fact that the proposed method for producing a pharmaceutical composition of antimicrobial action for injection, comprising mixing beta-lactam antibiotics with other components, according to which a beta-lactam antibiotic in powder form is mixed with highly dispersed nanostructured silicon dioxide powder in a weight ratio of (10 -75): 1, and the resulting mixture is machined by impact-abrasion.

The therapeutic efficacy of the proposed pharmaceutical composition is enhanced if the resulting mixture is machined by impact-abrasion such that the proportion of highly dispersed nanostructured silicon dioxide particles having a size of not more than 5 μm is at least 25%.

For the preparation of the pharmaceutical composition, imported beta-lactam antibiotics were used, provided by the Russian pharmaceutical company ABOLmed LLC (penicillins: carbenicillin; cephalosporins: cefazolin, cefuroxime, cefotaxime, ceftriaxone, cefopezzone, cefenfexfam; cefefexfon; cefefexfon; cefcefimzone; cefzefzone; cefzefzone; meropenem; monobactam: aztreonam). As a highly dispersed nanostructured silicon dioxide (hereinafter: BHS1O2), the drug “Polysorb” (pharmacological group: enterosorbing agent; active substance: silicon dioxide) was used colloidal), produced by the Russian company Polisorb CJSC, consisting of round-shaped silicon dioxide nanoparticles (size 5-20 nm), combined into aggregates (irregularly shaped microparticles) with sizes <90 μm (registration 001140 / 01-100908). A similar drug is produced by the Ukrainian company ZAO Biofarma under the trade name Silix [12].

The composition composition is based on the phenomenon of reversible sorption of beta-lactam molecules by nano- and micro-sized particles of BHSi02, as well as a decrease in the size of BHS1O2 microparticles upon mechanical activation of its mixtures with beta-lactam substances by intense impact-abrasion mechanical stresses.

The inventive method for producing the above pharmaceutical composition by mechanically activating a powder mixture of a beta-lactam antibiotic and BHS1O2 by intensive shock-abrasion action makes it possible to increase the proportion of finely dispersed (less than 5 μm) particles of BHS1O2 on which beta-lactam molecules are adsorbed and which are phagocytized mainly by macrophages [10,19].

For this, a mixture of the above substances in a weight ratio of beta-lactam antibiotic: BHS1O2 equal to (10-75): 1 is subjected to mechanical activation by impact-abrasion until the weight fraction of the finely dispersed fraction is increased to no less than 25%.

The particle size distribution of the aqueous suspension of the composition using the example of a ceftriaxone: BHS1O2 mixture equal to 30: 1 by weight, measured on a Micro-Sizer 201 laser granulometer, is shown in Fig. 1 and Fig. 2.

As can be seen from Figures 1 and 2, two-hour mechanical activation of the studied composition leads to an increase in the weight fraction of its finely dispersed fraction (particles <5 μm in size), which is at least 25%.

Injectable colloidal solutions for parenteral administration (by dilution by any known method adopted for beta-lactams), consisting of finely dispersed particles of BHS1O2 with molecules of one or another beta-lactam, reversibly sorbed on their surface, are prepared from the obtained powder composition.

Table 1 shows the data (obtained by high performance liquid chromatography - HPLC) on the degree of sorption of various beta-lactam antibiotics on BHS1O2 particles after mechanical activation of the antibiotic: BHS1O2 composition in a weight ratio of 30: 1, which suggests that highly dispersed nanostructured silicon dioxide can be used for parenteral administration of antimicrobial and other drugs that can be adsorbed onto nanoparticles and microparticles of this inorganic substance for delivery to areas of inflammation, tumor growth, regeneration, healing, scarring, etc., i.e. in areas of increased presence of macrophages, with the goal of deliberately increasing the local (including intracellular) concentration of the pharmaceutical product and, accordingly, enhancing the therapeutic effect.

Table 1

The degree of sorption of beta-lactams by particles BHSi0 ₂ *

fine nanostructured silicon dioxide _; * * - mechanical activation

Introduction to the proposed composition of highly dispersed nanostructured silicon dioxide in ratios of beta-lactam: BHS1O2 from 10: 1 to 75: 1 weight, respectively, is determined by a combination of two factors: 1) with an increase in the BHS1O2 content of more than 10% of the composition weight in laboratory animals, the phenomena of blockade of small capillaries in parenchymal organs are observed; 2) with a decrease in the BHS1O2 content below 1% by weight of the composition, its therapeutic effectiveness (in particular, in the treatment of bacterial sepsis in mice) does not actually differ from the basic effectiveness of the initial antibiotic.

To obtain the compositions, a mechanochemical approach was used, which consists in processing a mixture of solid components by intense mechanical stresses - pressure and shear deformations, which are realized mainly in various types of mills that carry out impact-abrasive effects on substances. A mixture of a solid substance of a beta-lactam antibiotic and highly dispersed nanostructured silicon dioxide, taken predominantly in ratios of 10: 1 to 75: 1 by weight, is subjected to mechanical activation in ball mills. The method used to obtain mixtures allows one to significantly avoid chemical decomposition, achieve complete homogeneity of the powder components in comparison with the preparation of mixtures by simple mixing of the components, or by evaporation of their solutions, and, as a result, determines the high pharmacological activity of the pharmaceutical composition.

As a quantitative criterion for the minimum required dose of mechanical stress, it is convenient to use the method of granulometry of the suspension of the resulting composition. In this case, it is necessary that the mass fraction of particles with a size of not more than 5 μm is at least 25%. On the other hand, it is necessary to avoid excessive machining, which leads to the chemical decomposition of beta-lactams, the degree of which is controlled by known analytical methods, such as HPLC.

The mechanical processing of powdered mixtures is carried out in rotary, vibration or planetary mills. As grinding media can be used balls, rods, etc.

Pharmacological tests of the obtained compositions in laboratory animals (mice) showed that the claimed compositions prepared by the claimed method have significantly increased therapeutic efficacy in the treatment of bacterial sepsis caused by Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, compared with the original antibiotics.

Thus, the use of the claimed pharmaceutical compositions and the method for their preparation provides the following advantages:

1) a clinically significant increase in the effectiveness and quality of antimicrobial therapy of moderate to severe and severe infectious and inflammatory diseases, a decrease in mortality;

2) environmental safety, waste-free and low-cost pharmaceutical production technology.

The invention is illustrated by the following examples.

Example 1. Obtaining a solid composition beta-lactam antibiotic is a highly dispersed nanostructured silicon dioxide.

A mixture of beta-lactam antibiotic and BHSi0 ₂ in weight ratios of 10: 1, 20: 1; 30: 1 and 40: 1 by weight are processed for 1, 2 and 4 hours in a rotary ball mill. The data on the particle size distribution of aqueous suspensions of the obtained compositions and the HPLC analysis of the content of antibiotics in them (in% of the initial substance) are given in table. 2.

table 2

Granulometric composition of aqueous suspensions and antibiotic content in various compositions

Composition, Size and% of particle content Content time m / a * BHSi0 ₂ ** antibiotic

% <3% <5% <10 (%) μm μm μm

Original BHSi0 ₂ 0.5 5.3 25.7 -

Cefotaxime: VN8Yu ₂ (10: 1), 13.4 30.4 57.3 89 m / a 1 hour

Cefotaxime: HSE ₂ (20: 1), m / a 16.6 33.9 59.1 95

1 hour

Cefotaxime: BHSiO ₂ (40: l), m / a 13.1 27.7 47.9 97

1 hour

Cefotaxime: BH8U ₂ (30: 1), 14.7 30.6 54.1 99 m / a 2 hours

Cefuroxime: BH8U (30: 1), m / a 22.6 35.2 50.2 97

2 hours

Ceftazidime: BH8 ₂ (30: 1), m / a 14.3 25.3 37.0 98

2 hours Ceftazidime: BH8Yu ₂ (30: 1), m / a 23.8 38.9 56.2 96 4 hours

Cepepime: BHSiO ₂ (30: l), 23.8 38.8 57.7 92

m / a 2 hours

Ceftriaxone: BH8U ₂ (30: 1), 24.2 43.9 66.2 97

m / a 1 hour

Ceftriaxone: BH8U ₂ (30: 1), 19.4 34.5 52.4 99 m / a 2 hours

Ceftriaxone: BH8U ₂ (30: 1), 14.5 26.4 41.7 95

m / a 4 hours

Ceftriaxone: BH8Yu ₂ (40: 1), m / a 23.4 41.2 59.1 98

1 hour

A3TpeoHaM: BHSi0 ₂ (30: 1), 21.7 39.4 53.6 97

m / a 2 hours

Meropenem: BHSiO ₂ (30: l), 19.1 32.9 47.3 98

m / a 2 hours

Aztreonam: BHSi0 ₂ (30: 1), 19.8 31.1 49.5 97

m / a 2 hours

Carbenicillin: BHSiO ₂ (30: l), 22.3 38.9 51.4 96 m / a 2 hours

- mechanical activation; ** - highly dispersed nanostructured silicon dioxide

As can be seen from table 2, the selected conditions for obtaining the proposed composition can increase to the required value (at least 25% of the total weight) the fraction of the finely dispersed fraction of BHSi0 ₂ (particle size less than 5 microns) and thus avoid chemical decomposition of the antibiotic.

Example 2. Determination of therapeutic efficacy of antimicrobial agents and pharmaceutical compositions

We studied beta-lactam antibiotics (cefazolin, cefuroxime, cefotaxime, ceftriaxone, cefoperazone, cefoperazone / sulbactam, ceftazidime, cefepime, cefoxitin, aztreone, meropenem, carbenicillin), and they were mixed for 2 hours. in weight ratios of 30: 1, respectively (cefazolin / in South, cefuroxime / BHSiCh, cefotaxime / VNB g, ceftriaxone / VNBYug cefoperazone / VNBYug, cefoperazone / sul Bacto / VN8YU _2, ceftazidime / VNB g, cefepime / VN8YU _2, cefoxitin / Vn8yu ₂ , aztreonam / vn8yu ₂ , meropenem / vn8yu ₂ , carbenicillin BHSi0 ₂ ).

Experimental models were used to determine the therapeutic efficacy of beta-lactams and their pharmaceutical compositions with BHSi0 ₂ sepsis and the method of statistical processing of the obtained results (χ) according to [22, 23].

Microorganisms: Staphylococcus aureus (ATCC N ° 25923 F-49), Escherichia coli (ATCC JYQ25922 F-50), Pseudomonas aeruginosa (ATCC 27853 F-51).

Animals: experiments were performed on hybrid mice (CBA x

C ^ Black / eiCBF _! in accordance with the "Rules for the Use of Experimental Animals" (Appendix to the order of the Ministry of Health of the USSR of 08.08. 1977, J 755).

Experimental sepsis models

Suspension of daily culture was administered intravenously in a volume of 0.8 ml

Pseudomonas aeruginosa at a dose of 5x10 CFU / mouse or a suspension of a daily culture of Staphylococcus aureus at a dose of 10 ¹⁰ CFU / mouse or a suspension of a daily culture of Escherichia coli at a dose of 8x10 ⁸ CFU / mpp. The control group was administered physical. solution (0.9% sodium chloride solution) in a volume of 0.8 ml. A day after infection, antibiotics and various pharmaceutical compositions (antibiotic / BH8 ₂ ) at a dose of 100 mg / kg diluted in 0.25 ml of physiological saline were injected intravenously daily for 3 days once a day. The control group of mppey was injected with saline in a volume of 0.25 ml according to the same scheme.

The effectiveness of antibiotic therapy was assessed by the number of survivors of the disease on the 7th day after infection [22, 23].

The obtained data, presented in table 3, reflect the results of three independent experiments (at least 30 experimental animals were used in total for the study of each drug).

Table 3

Therapeutic efficacy of antimicrobial therapy

bacterial sepsis

Antibiotics under study. Survival of mice on the 7th day after

and compositions * infection * * X2

Staphylococcus Escherichia Pseudomonas

aureus coli aeruginosa

Fiz. solution (control) 0% (0/30) 0% (0/30) 0% (0/30) -

Cefazolin 37.5% (12/32) - - *** P <0.01

Cefazolin / BH8U ₂ 83.9% (26/31) - -

Cefuroxime 40.0% (14/35) 43.7% (14/32) - P <0.01

Cefuroxime / BH8U ₂ 84.4% (27/32) 81.2% (26/32) - Cefotaxime 40.0% (12/30) 43.3% (13/30) - P <0.01

Cefotaxime / VNB g 86.7% (26/30) 83.3% (25/30) -

Ceftriaxone 46.7% (14/30) 41.9% (13/31) - P <0.01

Ceftriaxone / BH8U ₂ 90.0% (27/30) 87.5% (28/32) -

Cefoperazone - 45.2% (14/31) 40.0% (12/30) P <0.01

Cefoperazone / VSHYug - 90.0% (27/30) 80.6% (25/31)

Ceftazidime - 38.7% (15/31) 43.3% (13/30) P <0.01

Ceftazidime / BHSiC - 84.8% (28/33) 86.7% (26/30)

Cepepim 46.7% (14/30) 43.7% (14/32) 46.7% (14/30) P <0.01

Cepepime / VSHYug 90.0% (27/30) 85.3% (29/34) 90.3% (28/31)

Cefoxitin 35.2% (15/34) 46.7% (14/30) - P <0.01

Cefoxitin / BHSiCh 87.5% (28/32) 83.3% (25/30) -

Aztreonam - 77.5% (31/40) 74.4% (32/43) P <0.01

A3TpeoHaM / BHSi0 ₂ - 95.0% (38/40) 95.2% (40/42)

Meropenem 73.3% (22/30) 78.0% (32/41) 73.8% (31/42) P <0.01

MeponeHeM / BHSi0 ₂ 90.6% (29/32) 95.0% (38/40) 95.1% (39/41)

Carbenicillin 46.7% (14/30) 43.3% (13/30) 43.3% (13/30) P <0.01

Carbenicillin / VNZYug 83.3% (25/30) 86.7% (26/30) 90.0% (27/30)

Cefoperazone / sulbactam 56.7% (17/30) 58.1% (18/31) 59.3% (19/32) P <0.01

Cefoperazone / sulbactam / 86.7% (26/30) 93.3% (28/30) 93.5% (29/31)

BHSi0 ₂

* - mixtures that were mechanically activated for 2 hours - beta-lactam antibiotic: highly dispersed nanostructured silica (BHSi0 ₂ ) in a weight ratio of 30: 1.

** - in% and in absolute values (number of survivors / number of infected).

*** - experiments were not carried out, due to the relatively low sensitivity of microorganisms to the initial antibiotics.

As can be seen from table 3, all the proposed pharmaceutical compositions of antimicrobial action (beta-lactam / BHSi0 ₂₎ have significantly increased therapeutic efficacy (1.2 - 2 times), compared with conventional beta-lactams, in the treatment of sepsis in experimental animals, caused by Pseudomonas aeruginosa, Staphylococcus aureus or Escherichia coli. This is especially true for compositions in which antibiotics from the group of cephalosporins, cefamycins and penicillins act as beta-lactam.

Literature

Antibacterial drugs. Methods of standardization of drugs. - M .: OJSC "Publishing house" Medicine ", 2004. - 944 p.

Mashkovsky M.D. // Medicines: Volume 2. - 14th ed. M.: Publishing House New Wave LLC, 2001. - 608 p.

RF patent J ° 2377985 IPC A61KZ 1/43

Rational antimicrobial pharmacotherapy // Guide for practitioners. Under the general editorship of V.P. Yakovlev, S.V. Yakovlev. - M .: Litterra, 2003 .-- 1008 p.

Mayansky A.N. // Microbiology for doctors (essays on pathogenetic microbiology). - Nizhny Novgorod: Publishing House of the Nizhny Novgorod State Medical Academy, 1999. - 400 p.

Abeylath S.C., Turos E. Drag delivery approaches to overcome bacterial resistance to β-lactam antibiotics // Expert Opinion on Drug Delivery. - 2008 .-- Vol.5. - P.931-949. Bastus N.G., Sanchez-Tillo E., Pujals S. et al. Peptides conjugated to gold nanoparticles induce macrophage activation // Molecular Immunology. - 2009. - Vol. 46. - P.743-748.

Pinto-Alphandary H., Andremont A., Couvreur P. Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications // International Journal of Antimicrobial Agents. - 2000. - Vol.13. - P.155-168.

Ulbrich W., Lamprech A. Targeted drug-delivery approaches by nanoparticulate carriers in the therapy of inflammatory diseases // Journal Royal Society Interface. - 2010 .-- Vol. 7, Suppl. 1.- P.S55-S66.

Gulyaev A.E., Ermekbaeva B.A., Kivman G.Ya. and other Nanoparticles as a vector of directional transport of antibiotics (review) // Chemical and Pharmaceutical Journal. - 1998. - jV ° 3. - C.3-6.

Rosemary M.J., MacLaren I., Pradeep T. Investigation of antibacterial properties of ciprofloxacin @ Si02. // Langmuir. - 2006. - Vol.22. - P.10125-10129.

Rai A., Prabhune A., Perry C.C. Antibiotic mediated synthesis of gold nanoparticles with potent antimicrobial activity and their application in antimicrobial coatings // Journal of Materials Chemistry. - 2010 .-- Vol.20. - P.6789-6798.

Park JH., Gu L., Maltzahn G. et al. Biodegradable luminescent porous silicon nanoparticles for in vivo applications // Nature Materials. - 2009. - Vol.8. - P.331-336. 14. Pernis B. Silica and the immune system // Acta Biomed. - 2005 .-- Vol. 76, Suppl. 2.- P.38-44.

15. Tasciotti E., Liu X., Bhavane R. Et et al. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications // Nature Nanotechnology. - 2008 .-- Vol.3. - P.151-157.

16. Seleem M.N., Munusamy P., Ranjan A et al. Silica-antibiotic hybrid nanoparticles for targeting intracellular pathogens // Antimicrobial Agents and Chemotherapy. - 2009. - Vol. 53. - P. 4270-4274.

17. Medical chemistry and clinical use of silicon dioxide // Edited by Academician of NAS of Ukraine A.A. Chuyko. - Kiev: “Naukova Dumka”, 2003.

- 416 p.

18. Chuiko A., Pentyuk A., Shtat'ko E., Chuiko N. Medical aspects of application of highly disperse amorphous silica // Surface Chemistry in Biomedical and Environmental Science. Edited by J.P. Blitz and V. Gun'ko.II. Mathematics, Physics and Chemistry. - 2006 .-- Vol.228. - P.191-204.

19. Lucarelli M., Gatti A.M., Savarino G. et al. Innate defense functions of macrophages can be biased by nano-sized ceramic and metallic particles // European Cytokine Network. - 2004 .-- Vol.15. - P.339-346.

20. Zolnik B.S., Gonzalez-Fernandez A., Sadrieh N., Dobrovolskaia V. Minireview:

Nanoparticles and the immune system // Endocrinology. - 2010 .-- Vol. 151. - P.458-

465.

21. Pyatayev H.A., Belyaev A.H., Romanov M.D., Kotlov I.S. // Directional cell-associated drug transport. - Saransk .: Publishing House of Mordovia University, 2007. - 140 p.

22. Eckhardt C, Fickweiler K., Schaumann R. et al. Therapeutic efficacy of moxifloxacin in a murine model of severe systemic mixed infection with E. coli and B.fragilis II

Anaerobe - 2003. - Vol. 9. - P.157-160.

23. Schaumann R., Blatz R., Beer J. et al. Effect of moxifloxacin versus imipenem / cilastatin treatment on the mortality of mice infected intravenously with different strains of Bacteroides fragilis and Escherichia colt II Journal of Antimicrobial

Chemotherapy. - 2004 .-- Vol. 53. - P.318-324.

Claims

Claim

1. A pharmaceutical composition of antimicrobial action for parenteral administration containing a beta-lactam antibiotic as a therapeutic substance, characterized in that it is in the form of a powder for injection and contains highly dispersed nanostructured silicon dioxide in a weight ratio of beta-lactam antibiotic: highly dispersed nanostructured silicon dioxide equal to (10-75): 1.

2. The composition according to claim 1, characterized in that the proportion of highly dispersed nanostructured silicon dioxide particles having a size of not more than 5 μm is at least 25%.

3. A method of obtaining a pharmaceutical composition of antimicrobial activity for parenteral administration, comprising mixing a beta-lactam antibiotic with other components, characterized in that the beta-lactam antibiotic in powder form is mixed with powdered highly dispersed nanostructured silicon dioxide in a weight ratio of beta-lactam antibiotic: highly dispersed nanostructured silicon dioxide, equal to (10-75): 1, and the resulting mixture is subjected to mechanical treatment by impact abrasion .

4. The method according to p. 3, characterized in that the resulting mixture is subjected to mechanical processing by impact-abrasion such that the proportion of particles of highly dispersed nanostructured silicon dioxide having a size of not more than 5 μm is at least 25%.