AU2011302724A1 - Pharmaceutical composition with antimicrobial activity for parenteral administration and process for preparing same - Google Patents

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 belongs to antimicrobial pharmaceutical preparations and their production 5 technologies. It can be used in medicine and veterinary science for treating contagious and inflammatory diseases, as well as in pharmaceutical industry for medicinal products manufacturing. Currently most contagious and inflammatory diseases successful therapy is based on usage 10 of different anti-infectives, including beta-lactam antibiotics. Beta-lactam are preparations (natural and semisynthetic penicillins, cephalosporins, cephamycins, carbapenems and monobactams) with a beta-lactam ring as a chemical structure common fragment, which determines the antimicrobial activity and a series of 15 common properties of this drug preparation group [1]. All beta-lactam possess a wide antimicrobial spectrum and a high level of antimicrobial activity, but many of them have a fast developing microbial resistance, because of their specific ferments production - beta-lactamase (extended spectrum beta-lactamase, 20 chromosomal beta-lactamase class C, etc.), which hydrolyze the beta-lactam ring. This is what deprives these preparation of their antibacterial properties and leads to microbe resistant strains development [2]. In the past decades there have been created specific beta-lactamase inhibitors (clavulanic 25 acid, sulbactam, tazobactam and etc.) and on their basis there has been developed an entire range of effective combined antibacterial beta-lactam preparations of penicillin and cephalosporin family (amoxicillin/clavulanic acid, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam and etc.) which are noted because of their increased persistence to beta-lactamase as well as their more apparent antibacterial activity 30 [2, 3]. - 1- Nevertheless it ought to be remarked that many of these "inhibitor screened" preparations appeared to be insufficiently effective because in case of high beta-lactamase production by germs the inhibitors cannot fully protect the antibiotics from hydrolysis. 5 The carbapenems which are resistant to many beta-lactamase action cannot entirely solve the microbial resistance to the mentioned antibiotics problem. It happens because many application ways for treating serious infections lead to forming of multiply P. Aeruginosa resistant strains [3]. 10 Besides, frequently the clinical betalactam ineffectiveness (or their low effectiveness) in case of infections induced by different microbes is associated not only with the negative beta-lactamase activity, but also with these preparations limited ability of local concentration at contagious inflammation locus and macrophage penetration, where many contagious and inflammatory diseases' activators are deposited. The antimicrobial 15 resistance level depends on their functional status intensity [4, 5]. In the last few years it has been discovered that the use of different nanoparticles as dosing vehicle for different antibiotics delivery (as well as betalactam) inside the bacteria and macrophages to increase their concentration at the contagious inflammation area and to 20 increase their antimicrobial properties as well as phagocytes (neutrophils and macrophages) functional activity stimulation and their additional recruitment to infected tissues, is a very challenging trend for modem experimental pharmacology and clinical medicine [6, 7, 8, 9, 10, 11, 12]. 25 Here is the character of the mentioned invention. To increase the betalactam therapeutic effectiveness it is suggested to use the SiO 2 (silica dioxide) nanoparticles, which have different pharmacologically beneficial biocompatibility, biodistribution, biodegradation and low toxicity properties (independent from looseness of the structure intensity), can serve as antibiotics carrier for endocellular macrophage delivery, which are concentrated at 30 the inflammatory tissues of lungs, liver, kidneys, lien, absorbent glands, heart, skin, bladder and other mammal organs (i.e. considerably increase antibiotics concentration in the infected areas), and also initiate the immune system cells antimicrobial activity. This -2will help to authentically increase the germicides therapeutic effect during contagious inflammatory diseases treatment [13, 14, 15, 16, 17, 18, 19, 20, 21]. The mentioned invention solves the issue of creating an antimicrobial action 5 pharmaceutical composition for injections on basis of using betalactam and silica dioxide nanoparticles antibiotics which possesses a higher therapeutic effectiveness (comparing to the standard betalactam which are considered as a basis for this invention) for contagious and inflammatory diseases treatment. 10 To solve the assigned task it is suggested to use an antimicrobial action pharmaceutical composition for injections, which contains a betalactam antibiotic and finely dispersed nanostructured silica dioxide w/w (10-75) : 1. The production process suggested to solve the assigned task is to obtain the antimicrobial 15 action pharmaceutical composition for injections by mixing the betalactam antibiotics 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 impact abrasive method. 20 The therapeutic effectiveness of the proposed pharmaceutical composition will increase if the obtained mixture is machined by abrasive method in a way that the part of finely dispersed nanostructured silica dioxide particles of 5 microns would be no less than 25%. To prepare the mentioned pharmaceutical composition, were used foreign production 25 antibiotics provided by Russian pharmacological company LLC "ABOLmed" (penicillins: carbenicillin; cephalosporins: cefazolin. cefuroxime, cefotaxime, ceftriaxone, cefoperazone, ceftazidime, cefoperazone/sulbactam, cefepime; cephamycims: cefoxin; carbapenems: meropenem; monobactams: aztreonam). As a finely dispersed nanostructured silica dioxide (hereafter referred to as BHSiO 2 ) was used "Polysorb" drug 30 (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) combined into aggregates (irregular microparticles) with dimension < 90 micron (registration number # 001140/01-100908). There is s similar - 3 preparation produced by Ukrainian company CJSC "Biopharma" with a trade name "Silics" [12]. The composition formulation choice was based on convertible betalactam molecules and 5 nano- as well as micro BHSiO 2 particles sorption process, together with BHSiO 2 particles reduction during its' mixtures mechanical activation with betalactam substances by impact abrasive mechanization process. The stated production process of the previously mentioned pharmaceutical composition by 10 betalactam antibiotic powder mixture and BHSiO 2 mechanical activation with intensive impact abrasive operations allow to increase the finely divided BHSiO 2 particles (less than 5 micron) on which betalactam molecules are adsorbed and which are mostly phagocyted by macrophages [10,19]. 15 To achieve this goal the mixture of the stated above materials in weight rating, betalactam antibiotic: BHSiO2 equal (10-75) : 1, is exposed to intensive impact abrasive mechanical activation process until the finely divided fraction weight rating is increased up to 25%. The data from the aqueous slurry fractional makeup in terms of ceftriaxone: BHSiO2 equal 20 30 : 1, by the weight, measured by a laser granulometer Micro-Sizer 20lis shown in picture 1 and 2. As you may see in pictures 1 and 2. the two hours analyzed composition mechanical activation leads to weight rating increase of its finely dispersed fraction (particles 25 dimension < 5 micron) which contains not less than 25%. From the received powder like composition you can prepare an injection sol for parenteral insertion (water it down by any means appropriate for betalactam), composed of finely dispersed BHSiO2 particles with inversibly sorbed any betalactan molecules on its surface. 30 The table #1 contains data (received by high performance liquid chromatography method HPLC) about different betalactam antibiotics sorption rate on BHSiO2 particles after mechanical activation of antibiotic composition : BHSiO2, equal 30 : 1, which shows us -4that 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 this inanimate matter to make its' delivery to the inflammation areas, tumor growth areas, regeneration areas, cicatrization areas, scaring 5 areas and etc. That means make the delivery into the areas with increased macrophages presence to purposefully increase local concentration (as well as cellicolous) the pharmaceutical concentration and its therapeutic effect. Table #1 10 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 qaca 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 Ceftazidime:BHSiO2 (30:1), 9,6 mg :16,7 mg (53%) m/a 2 hours Cefoxotin:BHSiO2 (30:1), 8,5 mg :16,7 mg (5 1%) m/a 2 hours -5 - Meropenem:BHSiO2 (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 Introducing of the finely dispersed nanostructured silica dioxide equal betalactam BHSiO2 from 10:1 to 75:1 regarding its' weight is determined by the combination of 2 5 factors: 1) during BHSiO2 more than 10% increase from the composition weight in case of laboratory animals, they suffer from the small capillary tube blockage of solid viscus; 2) in case of BHSiO2 content decrease for more than 1% of the composition weight (in particular during the mice treatment of bacterial sepsis) it's therapeutic efficiency doesn't differ from the initial antibiotic basic efficiency. 10 To receive the composition mechanochemical method was used, which comprehends the solid components mixture processing by intensive mechanical impacts - pressure and shearing deformations, mostly realized in different kind of mills which perform impact abrasing actions on the substances. The mixture of the solid betalactam antibiotic 15 substance and finely dispersed nanostructured silica dioxide taken in the ratio from 10:1 to 75:1 by weight, are exposed to bead mills mechanical activation. The used mixture preparation method helps in a certain way to avoid chemical degradation and achieve powder components full homogeneity in comparison with making the mixture by a simple components mixing, or evaporating their solutions, and as consequence causes a high 20 pharmacological activity of pharmaceutical composition. As a quantitative criterion of the minimum necessary mechanical impact dose it is comfortable to use the granulometry method of the composition suspension. It is necessary that the mass fraction of the particles less than 5 micron was more than 25%. On the other 25 hand it is necessary to avoid the excessive mechanical processing which can cause betalactam chemical degradation which level can be controlled by the known analytical methods, such as HPLC. -6- Powder mixtures mechanical processing is performed in rotary, vibrational and planetary mills. As grinding bodies you can use balls, cores and etc. Laboratory animals (mice) pharmacological tests of the compositions showed, that the 5 mentioned compositions prepared by the mentioned method have a higher therapeutic efficiency while treating bacterial sepsis, provoked by Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, comparing to the initial antibiotics. In such manner, using the mentioned pharmaceutical compositions and their production 10 process provide the stated below advantages: 1) Clinically significant increase of the effectiveness and quality of the antimicrobial therapy of semi-acute and acute infection inflammatory diseases, death rate reduction; 2) Ecological safety, lack of wastes and low price of pharmaceutical production 15 technology. The offered invention is illustrated by examples listed below. Example #1. Solid composition production: betalactam antibiotic - finely dispersed nanostructured silica dioxide. 20 The mixture of the betalactam antibiotic and BHSiO2 in weight ratio 10:1, 20:1; 30:1 and 40:1 are being 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 the table #2. -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 As you can see from table #2 the chosen conditions of the composition production afford to increase until a certain value (not less than 25% from the total weight) the part of the 5 finely dispersed BHSiO 2 fraction (particles size less than 5 micron) and to avoid the antibiotic chemical degradation. Example #2. Determination of the therapeutic efficiency of antimicrobial preparations and pharmaceutical compositions. 10 There has been a 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 a miture antibiotic/ BHSiO 2 in weight ratio 30:1, consequently (Cefazolin/ 15 BHSiO 2 , Cefuroxime/ BHSiO 2 , Cefotaxime/ BHSiO 2 , Ceftriaxone/ BHSiO 2 , Cefoperazone/ BHSi0 2 , Cefoperazone/sulbactam/ BHSi0 2 , Ceftazidime/ BHSi0 2 , Cefepime/ BHSiO 2 , Cefoxitin/ BHSiO 2 , Aztreonam/ BHSiO 2 , Meropenem/ BHSiO 2 , Carbenicillin/ BHSiO 2 ). 20 To determine therapeutic efficiency of betalactam and their pharmaceutical compositions including BHSiO 2 , we used experimental sepsis models and a statistical processing method of the received data ( X 2 ) according to [22, 23]. -9- Microorganisms: Staphylococcus aureus (ATCC No 25923 F-49), Escherichia coli (ATCC N225922 F-50), Pseudomonas aeruginosa (ATCC N227853 F-51). Animals: for the experiments we used hybrid mice (CBA x Cs 7 Black/ 6 )CBF1 according to 5 the "Regulations for test animals use" (USSR Ministry of health order supplement #755 from 12.08. 1977). Experimental sepsis models: 10 The mice have been injected 0,8ml of Pseudomonas aeruginosa daily culture suspension with a dosage 5x10 8 CFU/mouse or Staphylococcus aureus daily culture suspension with a dosage 1010 CFU/mouse or Escherichia coli daily culture suspension with a dosage 8x10 8 CFU/mouse. The control group has been injected with 0,8m] of normal saline solution 15 (0,9% sodium chloride solution). In a day after being infected the test mice have been daily (during 3 days) intravenous injected 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 has been injected using the same scheme with normal saline solution 0,25mg. 20 Antibacterial therapy efficiency was evaluated basing 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 25 each preparation research were used not less than 30 test animals in total). - 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 coil 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) Ceftriaxone 46,7% (14/30) 41,9% (13/31) - P<0,01 Ceftriaxone/BHSiO2 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 weight ratio 30:1 * survival rate/infected animals rate measured in % and absolute values ***- tests were not conducted because microorganisms relatively low-grade sensitivity to initial antibiotics 5 As you may see in Table #3 all suggested antimicrobial action pharmaceutical compositions (betalactsm/BHSiO 2 ) definitely possess an increased therapeutic efficiency (1,2 - 2 times higher) comparing to simple betalactam in case of lab animals sepsis treatment, provoked by Pseudomonas aeruginosa, Staphylococcus aureus or Escherichia 10 coli. These results mostly concern compositions with cefalosporins, cefamicyns and penicillins used as betalactam. - 12- Used literature 1. Antibacterial pharmacons. Preparations standartization methods. - M.: JSC Medicine Publishing , 2004. - 944 p. 5 2. M.D. Mashkovsky // Pharmacons: Tome 2. - 14t 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 Medical 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 Drug Delivery. - 2008. - Vol.5. - P.931-949. 15 7. Bastus N.G., Sanchez-Tillo E., Pujals S. et al. 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Claims (4)

1. Antimicrobial pharmaceutical composition for parenteral administration containing betalactam antibiotic as therapeutic agent. Its' main difference is that it is made as 5 an injections preparation powder and contains finely betalactam antibiotic and dispersed nanostructured silica dioxide in weight ratio (10-75):1.

2. The composition according to claim 1. is different by its' finely dispersed nanostructured silica dioxide particles (their dimension is less than 5 micron) portion, which is not less than 25%. 10

3. The production process of the antimicrobial pharmaceutical composition for parenteral administration includes mixing betalactam antibiotic with other components is noted by the fact that powder like betalactam antibiotic is mixed with powder like finely dispersed nanostructured silica dioxide in weight ratio (10 75):1. The received mixture is mechanized impact abrasive actions. 15

4. The production process according to claim 3, different by mechanized impact abrasive actions, makes the finely dispersed nanostructured silica dioxide particles quantity (with less than 5 micron dimension) not less than 25%. - 15-