Patent Application: US-201113390151-A

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 active agents being betalactam antibiotics and finely dispersed nanostructured silica dioxide with a weight ratio from 10 : 1 to 75 : 1 respectively . the silica dioxide particles are antibiotic molecules delivery agents into the phagocytes , which allows increasing the antimicrobial preparations concentration at inflammation areas and considerably decrease microorganisms antibiotic resistance . the mentioned production process includes mixing betalactam antibiotic with finely dispersed nanostructured silica dioxide . its main difference is that the mentioned substances mixture with a weight ratio from 10 : 1 to 75 : 1 respectively is exposed to mechanical processing by impact and abrasive actions until a proportion of the fine powder fraction with particles smaller than 5 micrometers increases to at least 25 %. the so obtained mixture is used for injection preparations .

Description:
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 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 will 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 pharmaceutical composition for injections on basis of using betalactam and silica dioxide nanoparticles antibiotics which possess a higher therapeutic effectiveness ( comparing to the standard betalactam which are considered as a basis for this invention ) for contagious and inflammatory diseases treatment . 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 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 . 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 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 ( 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 preparation produced by ukrainian company cjsc “ biopharma ” with a trade name “ silics ” [ 12 ]. 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 betalactam substances by impact abrasive mechanization process . the stated production process of the previously mentioned pharmaceutical composition by 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 ]. to achieve this goal the mixture of the stated above materials in weight rating , betalactam antibiotic : bhsio 2 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 : bhsio 2 equal 30 : 1 , by the weight , measured by a laser granulometer micro - sizer 201is shown in picture 1 and 2 . as can be seen from fig1 and 2 , the two hours analyzed composition mechanical activation leads to weight rating increase of its finely dispersed fraction ( particles dimension & lt ; 5 micron ) which contains not less than 25 %. from the received powder - like composition , one you can prepare an injection solution for parenteral insertion ( water it down by any means appropriate for betalactam ), composed of finely dispersed bhsio 2 particles with inversibly sorbed any betalactan molecules on its surface . table 1 contains data ( received by high performance liquid chromatography method — hplc ) about different betalactam antibiotics sorption rate on bhsio 2 particles after mechanical activation of antibiotic composition : bhsio 2 , equal 30 : 1 , which shows 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 this inanimate matter for delivery thereof to the inflammation areas , tumor growth areas , regeneration areas , cicatrization areas , scaring areas , etc ., i . e . into the areas with increased macrophages presence to purposefully increase the local concentration ( as well as cellicolous ) the pharmaceutical concentration and its therapeutic effect . introducing of the finely dispersed nanostructured silica dioxide equal betalactam : 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 abrasing actions on the substances . the mixture of the solid betalactam antibiotic 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 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 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 . 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 antibiotics . in such manner , using the mentioned pharmaceutical 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 pharmaceutical production technology . example 1 . solid composition production : betalactam antibiotic — finely dispersed nanostructured silica dioxide . the mixture of the betalactam antibiotic and bhsio 2 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 table 22 . as can be seen 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 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 . 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 mixture antibiotic / bhsio 2 in weight ratio 30 : 1 , consequently ( cefazolin / 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 , aztreonam / bhsio 2 , meropenem / bhsio 2 , carbenicillin / bhsio 2 ). 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 ( χ 2 ) according to [ 22 , 23 ]. microorganisms : staphylococcus aureus ( atcc 25923 f - 49 ), escherichia coli ( atcc 25922 f - 50 ), pseudomonas aeruginosa ( atcc 27853 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 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 of 10 10 cfu / mouse or escherichia coli daily culture suspension with a dosage of 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 . antibacterial therapy efficiency was evaluated basing on the quantity of the surviving animals on the 7th day after being infected [ 22 , 23 ]. the obtained data shown in table 3 reflect the results of 3 independent experiments ( for each preparation research were used not less than 30 test animals in total ). mice survival rate on the 7 th day of infection ** * mixtures composed of betalactam antibiotic : finely dispersed nanostructured silica dioxide ( bhsio 2 ) in weight ratio 30 : 1 *** tests were not conducted because microorganisms relatively low - 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