AU2011302724B2

AU2011302724B2 - Pharmaceutical composition with antimicrobial activity for parenteral administration and process for preparing same

Info

Publication number: AU2011302724B2
Application number: AU2011302724A
Authority: AU
Inventors: Aleksandr Valerevich Dushkin; Konstantin Valentinovich Gaidul; Viktor Lvovich Limonov
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-09-13
Filing date: 2011-05-11
Publication date: 2012-06-28
Anticipated expiration: 2031-05-11
Also published as: CN103096896A; AU2011302724C1; JP2013537190A; AU2011302724A1; BR112012023964A2; NZ598831A; CA2785228A1; MX2012010535A; EA021874B1; EA201001449A1; WO2012036585A1; 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 ADMINISTRATION, PROCESS OF PRODUCING THE SAME This invention is related to antimicrobial pharmaceutical preparations and to related 5 methods of production. In particular, the present invention has application in medicine and veterinary science for treating contagious and inflammatory diseases, as well as in the pharmaceutical industry for the manufacture of medicinal products. Currently most successful contagious and inflammatory disease therapy is based on usage 10 of different anti-infectives, including beta-lactam antibiotics. Beta-lactam preparations (natural and semisynthetic penicillins, cephalosporins, cephamycins, carbapenems and monobactams) have a beta-lactam ring as a common chemical structure, which determines both the antimicrobial activity and a series of 15 common properties of this drug preparation group [I1]. All beta-lactams possess a wide antimicrobial spectrum and a high level of antimicrobial activity, but many of them result in fast developing microbial resistance, because of the specific way in which the fermentation production is undertaken - for example, beta 20 lactamase (such as extended spectrum beta-lactamase, chromosomal beta-lactamase class C, etc.), which hydrolyze the beta-lactam ring. This is what deprives these preparations of their prolonged antibacterial properties and leads to the development of microbe resistant strains [2]. 25 In the past decades there have been created specific beta-lactamase inhibitors (such as clavulanic acid, sulbactam, tazobactam, etc.) and on this basis there has been developed an entire range of effective combined antibacterial beta-lactam preparations including those from the penicillin and cephalosporin family (such as amoxicillin/clavulanic acid, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, etc.) which are 30 noted because of their increased persistence to beta-lactamase as well as their more apparent antibacterial activity [2, 3]. - 1- Nevertheless, many of these "inhibitor screened" preparations appear to be insufficiently effective due to high beta-lactamase production by germs, and hence the inhibitors cannot fully protect the antibiotics from hydrolysis. 5 The carbapenems, which are resistant to many beta-lactamase actions, cannot entirely solve the microbial resistance to these problems. This is because the application of different methods for treating serious infections may lead to the formation of multiply resistant P. Aeruginosa strains [3]. 10 In addition, the ineffectiveness (or low effectiveness) of clinical betalactam in the case of infections induced by different microbes is associated not only with negative beta lactamase activity, but also with these preparations being limited in their ability to provide a localised concentration at contagious inflammation locus and macrophage penetration, where many contagious and inflammatory disease activators are deposited. The 15 antimicrobial resistance level therefore depends on the functional intensity of therapeutic activity at the localized site of infection [4, 5]. In the last few years it has been discovered that the use of different nanoparticles as a dosing vehicle for the delivery of different antibiotics (as well as betalactam) inside the 20 bacteria and macrophages to increase their concentration at the contagious inflammation area, and to increase their antimicrobial properties, as well as for the activation of phagocytes (such as neutrophils and macrophages) and their additional recruitment to infected tissues, is a very challenging task for modern experimental pharmacology and clinical medicine [6, 7, 8, 9, 10, 11, 12]. 25 In one aspect of the present invention, there is provided a method for increasing the therapeutic effectiveness of betalactam by using SiO 2 (silica dioxide) nanoparticles. Such nanoparticles have a different pharmacological biocompatibility, biodistribution, biodegradation and low toxicity properties (independent from the looseness of the structure 30 intensity of betalactam) relative to other previous attempted solutions. In addition, such nanoparticles can serve as antibiotic carriers for endocellular macrophage delivery, which facilitates concentration at the inflammatory tissues of the lungs, liver, kidneys, absorbent glands, heart, skin, bladder and other mammal organs. This considerably increases -2antibiotic concentration in infected areas and also initiates immune system cells to undertake antimicrobial activity. This helps to increase the therapeutic germicide effect during treatment of contagious inflammatory diseases [13, 14, 15, 16, 17, 18, 19, 20, 21]. 5 The present invention solves the problem of creating an antimicrobial pharmaceutical composition that is suitable for injection. This is achieved by using betalactam and silica dioxide nanoparticle with antibiotics which thereby possesses a higher therapeutic effectiveness (compared to standard betalactam) for treatment of contagious and inflammatory diseases. 10 In one embodiment of the present invention, there is provided an antimicrobial pharmaceutical composition suitable for injection, wherein the composition contains a betalactam antibiotic and finely dispersed nanostructured silica dioxide w/w (10-75) : 1. 15 In another embodiment of the present invention, there is provided a production process for obtaining the antimicrobial pharmaceutical composition by mixing a betalactam antibiotic with other components. The betalactam antibiotic powder is mixed with the finely dispersed nanostructured silica dioxide powder w/w (10-75) : 1. The procured mixture is machined by an impact abrasive method. 20 The therapeutic effectiveness of the proposed pharmaceutical composition will increase if the obtained mixture is machined by an abrasive method in a way such that the finely dispersed nanostructured silica dioxide particles of 5 microns in size are no less than 25% of the composition. 25 To prepare the pharmaceutical composition, antibiotics were provided by the Russian pharmacological company LLC "ABOLmed" (penicillins: carbenicillin; cephalosporins: cefazolin, cefuroxime, cefotaxime, ceftriaxone, cefoperazone, ceftazidime, cefoperazone/sulbactam, cefepime; cephamycims: cefoxin; carbapenems: meropenem; 30 monobactams: aztreonam). As a finely dispersed nanostructured silica dioxide (hereafter referred to as BHSiO 2 ) was used "Polysorb" drug (pharmacological group: enterosorbing solution; active substance: colloidal silica dioxide), produced by Russian company CJSC "Polysorb", containing round shaped silica dioxide nanoparticles (dimension 5-20 nm) -3combined into aggregates (irregular microparticles) with dimension < 90 micron (registration number # 001140/01-100908). Similar preparations are also produced by the Ukrainian company CJSC "Biopharma" with a trade name "Silics" [12]. 5 The composition formulation used convertible betalactam molecules and nano- as well as micro BHSiO 2 particles via a sorption process, together with BHSiO 2 particles undergoing reduction during the mixture with betalactam substances by an impact abrasive mechanization process. 10 The stated production process of the pharmaceutical composition by treating betalactam antibiotic powder mixture and BHSiO 2 with mechanical activation and an intensive impact abrasive operation allows for an increase in the amount of finely divided BHSi02 particles (less than 5 microns) on which betalactam molecules are adsorbed and which are phagocyted by macrophages [10,19]. 15 To achieve this goal the mixture of the materials was undertaken in a weight rating, whereby betalactam antibiotic: BHSiO2 equals (10-75) : 1, is exposed to an intensive impact abrasive mechanical activation process until the finely divided fraction weight rating is increased up to 25% of the total of the composition. 20 The data from an aqueous slurry fractional makeup in terms of ceftriaxone: BHSiO2 equals 30 : 1, by weight, as measured by a laser granulometer Micro-Sizer 201 This is shown in figures 1 and 2. 25 As can be seen in figures 1 and 2, the composition, when analyzed for two hours of mechanical activation, leads to a weight rating increase of the finely dispersed fraction (i.e. particles of a dimension < 5 micron). This fraction contains not less than 25% of the total of the composition. 30 An injectable solution for parenteral administration can also be prepared by dissolving the composition by any means appropriate for betalactam, as known to the skilled person. The resulting solution is composed of finely dispersed BHSiO2 particles with adsorbed betalactan molecules on its surface. -4- Table #1 contains data (produced by high performance liquid chromatography method HPLC) showing different betalactam antibiotic sorption rate on BHSiO2 particles after mechanical activation of the antibiotic composition : BHSiO2, equaling 30 : 1. This 5 indicates that the finely dispersed nanostructured silica dioxide can be used for parenteral administration as a dosing vehicle for antibiotics and other pharmacons which are capable of sorbing on the nano- and microparticles of BHSiO2to facilitate delivery to inflammation areas, tumor growth areas, regeneration areas, cicatrization areas, scaring areas, etc. Hence, delivery of the composition into areas with increased macrophage presence is facilitated in 10 order to increase localized concentration (as well as cellicolous) of the pharmaceutical composition and its therapeutic effect. Table #1 15 Betalactam sorption rate by BHSiO2* particles Composition formulation, Sorbed antibiotic q-ty : BHSiO2 q-ty, m/a time** mg (weight %) Cefazolin:BHSiO2 (30:1), 8,1 mg :16,7 mg (48%) m/a 2 hours Ceftriaxone:BHSiO2 (30:1), 14,5 mg :16,7 mg (85%) m/a 2 hours Cefotaxime:BHSiO2 (30:1), 9,4 mg :16,7 mg (55%) m/a 2 hours Cefuroxime:BHSiO2 (30:1), 7,4 mg :16,7 mg (44%) m/a 2 hours Cefepime:BHSiO2 (30:1), 16,1 mg: 16,7 mg (96%) m/a 2 maca Cefoperazone:BHSiO2 (30:1), 12,2 mg :16,7 mg (73%) m/a 2 hours Cefoperazone/sulbactam: BHSiO2 13,9 mg :16,7 mg (83%) (30:1), m/a 2 hours -5- Ceftazidime:BHSiO2 (30:1), 9,6 mg :16,7 mg (53%) m/a 2 hours Cefoxotin:BHS1O2 (30:1), 8,5 mg :16,7 mg (51%) m/a 2 hours Meropenem:BIISiO2 (30:1), 10,6 mg :16,7 mg (63%) m/a 2 hours Aztreonam:BHSiO2 (30:1), 9, 7 mg :16,7 mg (58%) m/a 2 hours Carbenicillin:BHSiO2 (30:1), 11,2 mg: 16,7 mg (67%) m/a 2 hours * - finely dispersed nanostructured silica dioxide **- mechanical activation Increasing the ratio of finely dispersed nanostructured silica dioxide to betalactam BHSiO2 from 10:1 to 75:1 in terms of weight is determined by the combination of 2 5 factors: 1) when the weight of BHSiO2 is increased more than 10%, studies of laboratory animals indicate small capillary tube blockage by solid / viscous material; 2) when the weight of BHSiO2 is decreased more than 1%, studies in mice with bacterial sepsis indicate that therapeutic efficiency reduces to the same as the initial antibiotic efficiency. 10 To produce the composition, a mechano-chemical method was used, in which the solid components were mixed by an intensive mechanical impact - pressure and shearing deformation, performed in a mill. The mixture of the solid betalactam antibiotic substance and the finely dispersed nanostructured silica dioxide was undertaken in the ratio of from 10:1 to 75:1 by weight. These ingredients were exposed to a bead mills mechanical 15 activation. The method avoids chemical degradation and achieves powdered components with full homogeneity in comparison with making the mixture by a simple mixing process, or by evaporating solutions. As a consequence the method disclosed herein results in a high pharmacological activity of the pharmaceutical composition. 20 As a quantitative criterion of the minimum necessary mechanical impact dose, it is recommended to use the granulometry method for the composition. It is necessary that the mass fraction of the particles less than 5 micron is more than 25%. On the other hand, it is necessary to avoid excessive mechanical processing which can cause betalactam chemical degradation, which level can be controlled by known analytical methods, such as HPLC. -6- Powder mixture mechanical processing is performed in rotary, vibrational and planetary mills. As grinding bodies the person skilled in the art can use balls, cores, etc. 5 Laboratory animals (mice) were used for pharmacological tests of the compositions and showed that the present compositions prepared by the present method have a higher therapeutic efficiency, for example, while treating bacterial sepsis provoked by Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, compared to standard antibiotics. 10 In such manner, using the present pharmaceutical compositions and their production processes provides the following advantages: 1) Clinically significant increase of the effectiveness and quality of the antimicrobial therapy of semi-acute and acute infection inflammatory diseases, and death rate 15 reduction; 2) Ecological safety, lack of wastes and low price of the pharmaceutical production technology. The present invention is illustrated by the examples listed below. 20 Example #1. Solid composition production: betalactam antibiotic - finely dispersed nanostructured silica dioxide. A mixture of the betalactam antibiotic and BHSiO2 in a weight ratio of 10:1, 20:1; 30:1 25 and 40:1 were processed in an orbicular rotary mill for 1, 2 and 4 hours. The data of the water suspension granulometric composition as well as HPLC analysis of the antibiotic content (in % from the initial substance) are listed in table #2. 30 -7- Table #2 Water suspensions granulometric composition and antibiotics content in different composition variations 5 Composition content, Dimension and content % of Antibiotic time m/a* BHSiO 2 particles** content %<3 %<5 %<10 (%) micron micron micron Initial BHSiO 2 0,5 5,3 25,7 Cefotaxime:BHSiO 2 (10:1). 13,4 30,4 57,3 89 m/a 1 hour Cefotaxime:BHSiO 2 (20:1), m/a 16,6 33,9 59,1 95 1 hour Cefotaxime: BHSiO 2 (40:1), m/a 13,1 27,7 47,9 97 1 hour Cefotaxime:BHSiO 2 (30:1), 14,7 30,6 54,1 99 m/a 2 hours Cefuroxime:BHSiO 2 (30:1), m/a 22,6 35,2 50,2 97 2 hours Ceftazidime:BHSiO 2 (30:1), rn/a 14,3 25,3 37,0 98 2 hours Ceftazidime:BHSiO 2 (30:1), m/a 23,8 38,9 56,2 96 4 hours Cefepime: BHSiO 2 (30:1), 23,8 38,8 57,7 92 m/a 2 hours Ceftriaxone:BHSiO 2 (30:1), m/a 24,2 43,9 66,2 97 1 hour Ceftriaxone:BHSiO 2 (30:1), 19,4 34,5 52,4 99 m/a 2 hours Ceftriaxone:BHSiO 2 (30:1), m/a 14,5 26,4 41,7 95 4 hours -8- Ceftriaxone:BHSiO 2 (40:1), m/a 23,4 41,2 59,1 98 1 hour Aztreonam:BHSiO 2 (30:1), 21,7 39,4 53,6 97 m/a 2 hours Meropenem: BHSiO 2 (30:1), 19,1 32,9 47,3 98 m/a 2 hours Aztreonam: BHSiO 2 (30:1), 19,8 31,1 49,5 97 m/a 2 hours Carbenicillin: BHSiO 2 (30:1), 22,3 38,9 51,4 96 m/a 2 hours * - finely dispersed nanostructured silica dioxide **- mechanical activation Table #2 indicates that the chosen conditions of the composition production afford an increase until a certain value (not less than 25% of the total weight), being the part of the 5 finely dispersed BHSiO 2 fraction (particles of a size less than 5 micron). The process also avoids antibiotic chemical degradation. Example #2. Determination of the therapeutic efficiency of antimicrobial preparations and pharmaceutical compositions. 10 There has been research of betalactam antibiotics (Cefazolin, Cefuroxime, Cefotaxime, Ceftriaxone, Cefoperazone, Cefoperazone/sulbactam, Ceftazidime, Cefepime, Cefoxitin, Aztreonam, Meropenem, Carbenicillin) and their compositions mechanized for 2 hours and composed of antibiotic/ BHSiO 2 in a weight ratio of 30:1, consequently (Cefazolin/ 15 BHSiO 2 , Cefuroxime/ BHSiO 2 , Cefotaxime/ BHSiO 2 , Ceftriaxone/ BHSiO 2 , Cefoperazone/ BHSiO 2 , Cefoperazone/sulbactam/ BHSiO 2 , Ceftazidime/ BHSiO 2 , Cefepime/ BHSiO 2 , Cefoxitin/ BHSiO 2 , Aztreonarn/ BHSiO 2 , Meropenem/ BHSiO 2 , Carbenicillin/ BHSiO 2 ). 20 To determine the therapeutic efficiency of betalactam and pharmaceutical compositions including BHSiO 2 , an experimental sepsis model was used together with a statistical processing method of the received data ( Z) according to [22, 23]. -9- Microorganisms: Staphylococcus aureus (ATCC N2 25923 F-49), Escherichia coli (ATCC N225922 F-50), Pseudomonas aeruginosa (ATCC X27853 F-51) were used. Animals: for the experiments hybrid mice were used (CBA x Cs 7 Black/6)CBF1 according 5 to the "Regulations for test animals use" (USSR Ministry of health order supplement #755 from 12.08. 1977). Experimental sepsis models: 10 Mice were injected with 0,8ml of Pseudomonas aeruginosa daily culture suspension with a dosage of 5x10 8 CFU/mouse or Staphylococcus aureus daily culture suspension with a dosage of 1010 CFU/mouse or Escherichia coli daily culture suspension with a dosage of 8x108 CFU/mouse. The control group was injected with 0,8ml of normal saline solution (0,9% sodium chloride solution). One day after being infected the test mice (during 3 days) 15 were intravenously injected each day with 100mg/kg of antibiotics or different pharmaceutical compositions (antibiotic/ BHSiO 2 ) watered down with 0,25ml of normal saline solution. The control group of mice was injected using the same scheme with normal saline solution 0,25mg. 20 Antibacterial therapy efficiency was evaluated based on the quantity of the surviving animals on the 7th day after being infected [22, 23]. The received data shown in table #3 reflect the results of 3 independent experiments (for each preparation not less than 30 test animals in total were used). 25 30 -10- Table #3 Bacterial sepsis antimicrobial therapy efficiency Tested antibiotics and Mice survival rate on the 7 th day of infection** compositions* Staphylococcus Escherichia Pseudomonas X2 aureus coli aeruginosa Normal saline solution 0% (0/30) 0% (0/30) 0% (0/30) (control) Cefazolin 37,5% (12/32) - - P<0,01 Cefazolin/BHSiO 2 83,9% (26/31) - Cefuroxime 40,0% (14/35) 43,7% (14/32) - P<0,01 Cefuroxime/BHSiO 2 84,4% (27/32) 81,2% (26/32) Cefotaxime 40,0 % (12/30) 43,3% (13/30) - P<0,01 Cefotaxime/BHSiO 2 86,7% (26/30) 83,3% (25/30) Cefiriaxone 46,7% (14/30) 41,9% (13/31) - P<0,01 Ceftriaxone/BHSiO 2 90,0% (27/30) 87,5% (28/32) Cefoperazone - 45,2% (14/31) 40,0% (12/30) P<0,01 Cefoperazone/BHSiO 2 - 90,0% (27/30) 80,6% (25/31) Ceftazidime - 38,7% (15/31) 43,3% (13/30) P<0,01 Ceftazidime/BHSiO 2 - 84,8% (28/33) 86,7% (26/30) Cefepime 46,7% (14/30) 43,7% (14/32) 46,7% (14/30) P<0,01 Cefepime/BHSiO 2 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/BHSiO 2 87,5% (28/32) 83,3% (25/30) Aztreonam - 77,5% (31/40) 74,4% (32/43) P<0,01 Aztreonam/BHSiO 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 Meropenem/BHSiO 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 /BHSiO 2 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) BHSiO 2 - 11 - *- mixtures composed of betalactam antibiotic:finely dispersed nanostructured silica dioxide (BHSiO 2 ) in a weight ratio of 30: 1 **- survival rate/infected animals rate measured in % and absolute values ***- tests were not conducted because microorganisms had relatively low-grade sensitivity to initial 5 antibiotics Table #3 shows that all tested antimicrobial pharmaceutical compositions (betalactsm/BHSiO 2 ) possess an increased therapeutic efficiency (1,2 - 2 times higher) compared to simple betalactam in the case of lab animal sepsis treatment, provoked by 10 Pseudomonas aeruginosa, Staphylococcus aureus or Escherichia coli. These results involve compositions with cefalosporins, cefamicyns and penicillins used as betalactam. Throughout this specification and the claims, unless the context requires otherwise, the word "comprise" and its variations, such as "comprises" and "comprising", will be 15 understood to imply the inclusion of a stated integer or step or group of integers but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that prior art forms part of the common 20 general knowledge in Australia. - 12 - Used litera ure 1. Antibacterial pharmacons. Preparations standartization methods. - M.: JSC «Medicine Publishing , 2004. - 944 p. 5 2. M.D. Mashkovsky // Pharmacons: Tome 2. - 146 edition. M.: LLC <Novaya Volna Publishing , 2001. - 608 p. 3. Patent RU # 2377985 MPK A61K31/43 4. Rational antibacterial pharmacopeias // Practicians' Guidance. Under the general editorship of V.P. Yakovlev, S.V. Yakovlev. -- M.: Litterra, 2003. - 1008 p. 10 5. A.M. Mayansky // Microbiology for physitians (patogenetic microbiology essays). Nizhny Novgorod: Nizhny Novgorod State Vedical Academy Publishing, 1999. - 400 p. 6. Abeylath S.C., Turos E. Drug delivery approaches to overcome bacterial resistance to p-lactam antibiotics // Expert Opinion on Dru Delivery. - 2008. - Vol.5. - P.931-949. 15 7. Bastus N.G., Sanchez-Tillo E., Pujals S. et al. Peptides conjugated to gold nanopar ticles induce macrophage activation // Molecular Immunology. - 2009. - Vol.46. P.743-748. 8. Pinto-Alphandary H., Andremont A., Couvreur P. Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications // International Journal of 20 Antimicrobial Agents. - 2000. - Vol.13. - P.155-168. 9. 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. 10. A.E. Guliaev, B.A. Ermekbaeva, G.Y. Kivman and etc. Nanoparticles as targeted 25 antibiotic transport (review) // Chemical and pharmaceutical magazine. - 1998. - N3. P.3-6. 11. Rosemary M.J., MacLaren I., Pradeep T. Investigation of antibacterial properties of ciprofloxacin@Si02. // Langmuir. - 2006. - Vol.22. - P.10125-10129. 12. Rai A., Prabhune A., Perry C.C. Antibiotic riediated synthesis of gold nanoparticles 30 with potent antimicrobial activity and their application in antimicrobial coatings // Journal of Materials Chemistry. - 2010. - Vol.20. - P.6789-6798. 13. Park J-H., Gu L., Maltzahn G. et al. Bi degradable luminescent porous silica nanoparticles for in vivo applications // Nature Materials. - 2009. - Vol.8. - P.331-336. - 13 - 14. Pernis B. 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P.38-44. 15. Tasciotti E., Liu X., Bhavane R. Et et al. Mesoporous silica particles as a multistage delivery system for imaging and therapeutic applications // Nature Nanotechnology. 5 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. Clinical chemistry and silica dioxide clinical use // Edited by NAS of Ukrane 10 academician F.F. 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. 15 19. Lucarelli M., Gatti A.M., Savarino G. et al. Innate defence 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 20 465. 21. N.A. Piataev, F.N. Beliaev, M.D. Romanov, I.S. Kotlov // Pharmacons directed celll assosiated transport. - Saransk: Mordovia University Publishing, 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 Bfragilis // 25 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 Bacteroidesfragilis and Escherichia coli / Journal of Antimicrobial Chemotherapy. - 2004. - Vol.53. - P.318-324. 30 - 14 -

Claims

1. An antimicrobial pharmaceutical composition comprising a betalactam antibiotic and a finely dispersed nanostructured silica dioxide, wherein the composition is 5 formulated for parenteral administration, and wherein the betalactam antibiotic and the finely dispersed nanostructured silica dioxide are present in the composition in a weight ratio of (10-75):1.

2. The composition according to claim 1, wherein the finely dispersed nanostructured silica dioxide is substantially present in particles measuring less than 5 10 microns.

3. The composition according to claim 1 or claim 2, wherein the finely dispersed nanostructured silica dioxide comprises not less than 25% of the total weight of the composition.

4. Use of a betalactam antibiotic and a finely dispersed nanostructured silica 15 dioxide in the manufacture of a medicament for the treatment of a disease, wherein the medicament is formulated for parenteral administration, and wherein the betalactam antibiotic and the finely dispersed nanostructured silica dioxide are present in the medicament in a weight ratio of (10-75):1.

5. The use according to claim 4, wherein the finely dispersed nanostructured 20 silica dioxide is substantially present in particles measuring less than 5 microns.

6. The use according to claim 4 or claim 5, wherein the finely dispersed nanostructured silica dioxide comprises not less than 25% of the total weight of the composition.

7. A process for the manufacture of an antimicrobial pharmaceutical 25 composition, wherein the composition is formulated for parenteral administration, wherein the process comprises mixing betalactam antibiotic with finely dispersed nanostructured silica dioxide in a weight ratio of (10-75):1, and subjecting the mixture to a mechanized impact abrasive action.

8. The process according to claim 7, wherein the finely dispersed 30 nanostructured silica dioxide is substantially present in particles measuring less than 5 microns. - 15 -

9. The process according to claim 7 or claim 8, wherein the finely dispersed nanostructured silica dioxide comprises not less than 25% of the total weight of the composition.

10. An antimicrobial pharmaceutical composition according to any one of 5 claims 1 to 3 when used for parenteral administration.

11. A method for preventing or treating a disease in a subject, wherein the method comprises administering to the subject the composition according to any one of claims 1 to 3 or 10, or a composition produced by the process according to any one of claims 7 to 9. 10

12. The method according to claim 11, wherein the subject is a human.

13. An antimicrobial pharmaceutical composition substantially as herein disclosed.

14. Use of a betalactam antibiotic and a finely dispersed nanostructured silica dioxide in the manufacture of a medicament for the treatment of a disease substantially as 15 herein disclosed.

15. A process for the manufacture of an antimicrobial pharmaceutical composition substantially as herein disclosed.

16. A method for preventing or treating a disease in a subject substantially as herein disclosed. -16-