Patent Abstract:
there is proposed herein a process for production of composite antimicrobial preparations for parenteral administration , featuring a higher therapeutic efficiency in case of grave infection and inflammatory diseases . the proposed compositions include an active agent being fosfomycin and finely dispersed nanostructured silica dioxide , with a weight ratio from 10 : 1 to 75 : 1 respectively . the mentioned production process includes mixing fosfomycin with finely dispersed nanostructured silica dioxide . its main difference is that the mixture of aforementioned substances with the mentioned weight ratio is exposed to mechanical processing by blow impact and abrasive actions until a portion of the fine powder fraction with particles smaller than 5 micrometers , contained in the mixture , increases to at least 25 %. the so obtained mixture is used for injection preparations .

Detailed Description:
as a main point of this invention , it is suggested to use sio 2 ( silica dioxide ) nano - particles which having pharmacologically profitable qualities of biocompatibility , biodistribution , biodegradation and low toxicity ( not depending on the structure porosis intensity rate ), are capable of serving as antibiotics endocellular delivery agents into macrophages in case of parenteral administration . these macrophages are concentrated in the areas of inflammation which can be seen in lungs , liver , kidneys , lien , lymph glands , heart , skin , urinary bladder and other organs of the mammals ( i . e . considerably increase antibiotic concentration in the infected areas ) as well as stimulate the antimicrobial activity of those immune system cells . this will lead to antimicrobial preparations therapeutic efficiency in case of contagious and inflammatory diseases treatment [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. the mentioned invention solves the issue of creating an antimicrobial and anti - inflammatory action pharmaceutical composition for injections on basis of using fosfomycin and silica dioxide nano - particles , which possess an increases therapeutic efficiency ( comparing to the initial fosfomycin , which is considered as the prototype of the mentioned invention ) in case of contagious and inflammatory diseases treatment . to solve the assigned task it is suggested to use an antimicrobial and anti - inflammatory action pharmaceutical composition for parenteral administration , which contains fosfomycin injection powder as therapeutic substance as well as finely dispersed nanostructured silica dioxide with a weight ratio — fosfomycin : finely dispersed nanostructured silica dioxide w / w ( 10 - 70 ): 1 . the portion of the finely dispersed nanostructured silica dioxide with the dimension ≦ 5 micron is not less than 25 %. to solve the assigned task it is also suggested to use an antimicrobial and anti - inflammatory action pharmaceutical composition for parenteral administration , produced by mixing fosfomycin with other components , i . e . mixing fosfomycin injection powder as therapeutic substance with finely dispersed nanostructured silica dioxide with a weight ratio — fosfomycin : finely dispersed nanostructured silica dioxide w / w ( 10 - 70 ): 1 . the received mixture is being mechanized by impact and abrasive actions . the received mixture is being mechanized by impact and abrasive actions to make the portion of the finely dispersed nanostructured silica dioxide with the dimension ≦ 5 micron not less than 25 %. therapeutic efficiency of the proposed pharmaceutical composition will increase , if it the received mixture is being mechanized by impact and abrasive actions to make the portion of the finely dispersed nanostructured silica dioxide with the dimension ≦ 5 micron not less than 25 %. to prepare the mentioned pharmaceutical composition , we used fosfomycin ( parenteral administration form ) produced by a spanish company “ ercros ”. as a finely dispersed nanopatterned 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 ) combined into aggregates ( irregular microparticles ) with dimension ≦ 90 micron ( registration number no 001140 / 01 - 100908 ). there is s similar preparation produced by ukrainian company cjsc “ biopharma ” with a trade name “ silics ” [ 24 ]. the composition formulation choice was based on convertible betalactam molecules and nano - as well as micro bhsio 2 particles sorption process , together with bhsio 2 particles reduction during its &# 39 ; mixtures mechanical activation with fosfomycin substances by impact abrasive mechanization process . the stated production process of the previously mentioned pharmaceutical composition by fosfomycin powder mixture and bhsio2 mechanical activation with intensive impact abrasive operations allows to increase the finely dispersed bhsio2 particles ( less than 5 micron ) on which fosfomycin molecules are adsorbed and which are mostly phagocyted by macrophages [ 28 ]. to achieve this goal the mixture of the stated above materials in weight rating , fosfomycin : bhsio 2 w / w ( 10 - 75 ): 1 , is exposed to intensive impact abrasive mechanical activation process until the finely divided fraction weight rating is increased up to 25 %. from the received powder like composition you can prepare an injection sol for parenteral insertion ( water it down by any means appropriate for fosfomycin ), composed of finely dispersed bhsio 2 particles with inversibly sorbed any fosfomycin molecules on its surface . introducing of the finely dispersed nanostructured silica dioxide equal fosfomycin : bhsio 2 from 10 : 1 to 75 : 1 regarding its &# 39 ; weight is determined by the combination of 2 factors : 1 ) during bhsio 2 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 bhsio 2 content decrease for more than 1 % of the composition weight ( in particular during the mice treatment of bacterial sepsis ) it &# 39 ; s therapeutic efficiency doesn &# 39 ; t differ from the initial antibiotic basic efficiency . 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 abrasive actions on the substances . the mixture of the solid fosfomycin 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 pharmacologic 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 %. 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 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 fosfomycin . in such manner , using the mentioned pharmacological compositions and their production 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 pharmacological production technology . the mixture of fosfomicin and bhsio 2 in weight ratio 10 : 1 , 30 : 1 and 50 : 1 is being processed for 1 , 2 or 4 hours in a rotary mill . in table no 1 you will see the granulometric composition data for the water suspensions of the received compositions variations ( micro - sizer 201 laser granulometer was used ) as well as helc analysis results which show their antibiotics content ( in % from the initial substance ) and fosfomicin sorption degree ( in %) by bhsio 2 particles , as can be seen from table no 1 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 finely dispersed bhsio 2 fraction ( particles size less than 5 micron ) and to avoid the antibiotic chemical degradation . there has been a research of fosfomycin mechanized for 2 hours and composed of a mixture antibiotic / bhsio 2 in weight ratio 30 : 1 and 50 : 1 respectively . to determine therapeutic efficiency of fosfamicin and their pharmaceutical compositions including bhsio 2 , we used experimental sepsis models and a statistical processing methos of the received data ( χ 2 ) according to [ 29 , 30 ]. microorganisms : staphylococcus aureus ( atcc no 25923 f - 49 ), escherichia coli ( atcc no 25922 f - 50 ), pseudomonas aeruginosa ( atcc n227853 f - 51 ). animals : for the experiments we used hybrid mice ( cba × c 57 black / 6 ) cbf 1 according to the “ regulations for test animals use ” ( ussr ministry of health order supplement no 755 from 12 . 08 . 1977 ). the mice have been injected 0 . 8 ml of pseudomonas aeruginosa daily culture suspension with a dosage 5 × 10 8 cfu / mouse or staphylococcus aureus daily culture suspension with a dosage 10 10 cfu / mouse or escherichia coli daily culture suspension with a dosage 8 × 10 8 cfu / mouse . the control group has been injected with 0 . 8 ml of normal saline solution ( 0 . 9 % sodium chloride solution ). in a day after being infected the test mice have been daily ( during 3 days ) intravenous injected with 100 mg / kg of antibiotics or different pharmaceutical compositions ( antibiotic / bhsio 2 ) watered down with 0 . 25 ml of normal saline solution . the control group of mice has been injected using the same scheme with normal saline solution 0 . 25 mg . antimicrobial therapy efficiency has been estimated basing on the q - ty of the living mice on the 7 th day of the experiment [ 29 , 30 ]. the obtained data stated in table no 2 reflect the results of 3 independent experiments conducted for each test group . mice survival rate on the 7 th day of infection * as can be seen from table no 2 the suggested antimicrobial and anti - inflammatory action pharmaceutical composition ( fosfomycin / bhsio 2 ) definitely possess an increased therapeutic efficiency ( 2 times higher ) comparing to simple fosfomycin in case of lab animals sepsis treatment , provoked by pseudomonas aeruginosa , staphylococcus aureus or escherichia coli . it is known that in case of sepsis the quantity of peripheral blood leucocytes can determine the activity of the inflammatory process [ 31 ]. we have studied the leukocytes quantity of the mice that have survived until the day 7 after sepsis induction , according to the method described above . the obtained data are shown in table no 3 . survived until day 7 after being infected with pseudomonas aeruginosa as may be seen from table no 3 the proposed pharmaceutical composition ( fosfomycin / bhsio 2 ) an authentically expressed anti - 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