Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• 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.
• 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].
• 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].
• beta-lactamase inhibitors clavulanic acid, sulbactam, tazobactam, etc.
• 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.
• beta-lactamase inhibitors clavulanic acid, sulbactam, tazobactam, etc.
• 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].
• 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].
• 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.
• a pharmaceutical composition of antimicrobial action for injection 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 ⁇ m is at least 25%.
• 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).
• BHS1O2 nanostructured silicon dioxide
• the drug “Polysorb” pharmaceutical group: enterosorbing agent; active substance: silicon dioxide
• Polisorb CJSC complex organic compound
• a similar drug is produced by the Ukrainian company ZAO Biofarma under the trade name Silix [12].
• 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 ⁇ m) particles of BHS1O2 on which beta-lactam molecules are adsorbed and which are phagocytized mainly by macrophages [10,19].
• 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%.
• Fig. 1 and Fig. 2 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.
• 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.
• 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.
• 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.
• the mechanical processing of powdered mixtures is carried out in rotary, vibration or planetary mills.
• grinding media can be used balls, rods, etc.
• 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.
• 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.
• Granulometric composition of aqueous suspensions and antibiotic content in various compositions are provided.
• A3TpeoHaM BHSi0 2 (30: 1), 21.7 39.4 53.6 97
• 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.
• beta-lactam antibiotics cefazolin, cefuroxime, cefotaxime, ceftriaxone, cefoperazone, cefoperazone / sulbactam, ceftazidime, cefepime, cefoxitin, aztreone, meropenem, carbenicillin
• Microorganisms Staphylococcus aureus (ATCC N ° 25923 F-49), Escherichia coli (ATCC JYQ25922 F-50), Pseudomonas aeruginosa (ATCC 27853 F-51).
• 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.
• antibiotics and various pharmaceutical compositions 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.
• MeponeHeM / BHSi0 2 90.6% (29/32) 95.0% (38/40) 95.1% (39/41)
• beta-lactam antibiotic highly dispersed nanostructured silica (BHSi0 2 ) in a weight ratio of 30: 1.
• Rational antimicrobial pharmacotherapy // Guide for practitioners. Under the general editorship of V.P. Yakovlev, S.V. Yakovlev. - M .: Litterra, 2003 .-- 1008 p.

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• Dermatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Inorganic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2010
  • 2010-09-13 EA EA201001449A patent/EA021874B1/ru not_active IP Right Cessation
• 2011
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