Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its production process (variations)

Abstract

The proposed compositions and methods for preparation thereof relate to pharmacology, medicine, veterinary science and pharmaceutical industry. The compositions can be used for preparing infusion solutions of antimicrobial (antibacterial and antifungal) preparations increasing therapeutic efficiency thereof. The compositions include nanostructured colloidal silica and are efficient when treating overwhelming sepsis of tested animals. The pharmaceutical compositions have a proven and significant clinically important potentiating impact on therapeutic efficiency of the infusion solution, when treating inflammatory diseases, in comparison with traditional solvents.

Claims

1. A method of making an injection pharmaceutical composition soluble in water, said method comprising the steps of: (a) preparing a powder composition consisting of sodium chloride in a powder form and powdered silica nanoparticles having an average diameter of from 7-40 nm joined into microparticles having a size of less than 100 μm, wherein said sodium chloride and said powdered silica are present in said powder composition in a weight ratio of 4.5:1 to 4.5:5 or 9:1 to 9:5, and further wherein said powder composition has a mass fraction; (b) subjecting said powder composition to intensive mechanical impact and abrasive action, so that at least 35% of said silica microparticles are reduced to dimensions not exceeding 5 micrometers, thereby increasing said mass fraction of said powder composition and producing a mechano-chemical activated powder composition; c) selecting a single dose of a dry powder of a pharmaceutical agent soluble in water for injection, and dissolving said single dose in 10 ml of water, thereby obtaining a pharmaceutical solution; d) mixing said pharmaceutical solution of step (c) with said mechano-chemical activated power composition of step (b), thereby obtaining a suspension; e) shaking said suspension for 2-3 minutes to provide an injection pharmaceutical composition; and f) further dissolving said injection pharmaceutical composition in 50 to 200 ml of a 0.45% or 0.9% aqueous solution of sodium chloride, thereby obtaining a ready to use injection pharmaceutical composition.

Description

DETAIL DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

(1) While the invention may be susceptible to embodiment in different forms, there are described in detail herein below, specific embodiments of the present invention, with the understanding that the instant disclosure is to be considered an exemplification of the principles of the invention, and is not intended to limit the invention to that as described herein.

(2) The present invention is illustrated by examples listed below.

Example 1

(3) Solid Composition Production NaCl:Colloidal Silica.

(4) A mixture of sodium chloride and colloidal silica in weight ratios of 4,5:1, 4,5:2, 4,5:5, 9:1, 9:2, and 9:5 is treated for 1, or 2, or 4 hours in a drum rotary mill.

(5) Analysis of the granulometric content of water suspensions of initial colloidal silica particles, as well different variations of compositions with NaCl, was conducted on a laser analyzer of particle dimensions Microsizer-201a produced by <<VA Instalt>>, Russia. Powder, being analyzed, in an amount of from 1 g to 5 g was placed into a sample preparation module (a cuvet having a liquid volume of 150 cm.sup.3) in a quantity sufficient for achieving 70-75% of optical transmission through the cuvet. After passing 1-2 minutes, a measurement was conducted with a simultaneous treatment of the suspension for destruction of agglomerations. The measurement data were processed according to a computer program embedded into the analyzer. The obtained measurement results were presented in the form of hystograms for weight distribution by particle dimensions.

(6) For determining the number of antimicrobial preparations sorbed by colloidal silica particles, 0.5 g antibiotic substance (by active matter) was dissolved in 5 cm.sup.3 water for injections. Thereafter, the known quantity of dry compositions NaCl:Colloidal silica suspended in the fresh antibiotic solution, the obtained suspension was centrifuges within 30 minutes at a speed of 12000 rpm, the supernatant liquid was poured carefully out, the residual matter of Colloidal silica was suspended again in the same quantity of water for injections. The concentration of antibiotic desorbing into the aqueous phase was determined by the HPLC method. Thereafter, the procedure of subsidence and suspending was repeated. The quantity of absorbed antibiotic was calculated based on the total antibiotic quantity desorbed from colloidal silica residual.

(7) Data obtained for the granulometric composition and sorption rate are shown in Table 1 below. As it follows from the obtained data, the chosen conditions for producing the inventive composition allow for: —increasing a proportion of the fine powder fraction (with a particles' dimensions not exceeding 5 micrometers) of colloidal silica at least twofold, and—attaining a binding degree of molecules of antimicrobial preparations by colloidal silica particles of at least 40%.

(8) TABLE-US-00001 TABLE 1 Granulometric data of water suspensions of composition and solution of antimicrobial preparations produced on the basis of the composition application; the preparations' sorption rate by colloidal silica particles Dimension and Antimicrobial Composition content content % of preparation and contents of colloidal silica sorption antimicrobial preparations particles rate by colloidal solutions % ≦5 um silica particles (%) Initial Colloidal silica 15.2 — NaCl:Colloidal silica 38.5 — (4.5:1; mechanical activation 1 hour ) NaCl:Colloidal silica 41.3 — (4.5:2; mechanical activation 2 hours) NaCl:Colloidal silica 39.2 — (4.5:5; mechanical activation 4 hours) NaCl:Colloidal silica 37.7 — (9:1; mechanical activation 1 hour) NaCl:Colloidal silica 43.9 — (9:2; mechanical activation 2 hours) NaCl:Colloidal silica 35.8 — (9:5; mechanical activation 4 hours) Ceftriaxone/NaCl:Colloidal 43.5 45.3 silica (4.5:1; mechanical activation 1 hour) Ceftriaxone/NaCl:Colloidal silica 45.4 47.8 (4.5:2; mechanical activation 2 hours) Ceftriaxone/NaCl:Colloidal silica 42.1 49.5 (4.5:5; mechanical activation 4 hours) Cefotaxime/NaCl:Colloidal silica 37.8 41.6 (9:1; mechanical activation 1 hour) Cefotaxime/NaCl:Colloidal silica 41.2 51.4 (9:2; mechanical activation 2 hours) Ceftazidime/NaCl:Colloidal silica 36.7 46.3 (9:5; mechanical activation 2 hours) Cefepime/NaCl:Colloidal silica 38.3 44.5 (9:2; mechanical activation 2 hours) Amikacin sulfate/NaCl:Colloidal 40.2 43.7 silica (9:2; mechanical activation 2 hours) Azithromycin/NaCl:Colloidal 39.1 51.9 silica (9:2; mechanical activation 2 hours) Vancomycin/NaCl:Colloidal 42.9 50.6 silica (9:5; mechanical activation 2 hours) Meropenem/NaCl:Colloidal silica 36.7 43.9 (9:2; mechanical activation 2 hours) Voriconazole/NaCl:Colloidal 37.5 41.7 silica (9:2; mechanical activation 2 hours) Capreomycin/NaCl:Colloidal 40.1 49.9 silica (9:5; mechanical activation 2 hours)

Example 2

(9) Obtaining Solid Composition.

(10) Dextrose:Colloidal silica. A mixture of dextrose and colloidal silica in weight ratios of 20:1, 20:2, 20:5, 50:1, 50:2, and 50:5 is treated for 1, or 2, or 4 hours in a drum rotary mill.

(11) Measurements of the granulometric content of water suspensions including colloidal silica and measurements of a sorption rate of antibiotics were performed following the methods described above in Example 1. Data obtained from the measurements are shown in Table 2. It follows from the data that the claimed method for preparation of the inventive composition also allows for: at least a double increase of a proportion of the fine powder fraction (having particles with dimensions not exceeding 5 micrometers) of colloidal silica and attaining the binding degree of antimicrobial preparations molecules by colloidal silica particles of at least 40%.

(12) TABLE-US-00002 TABLE 2 Granulometric data of water suspensions of composition and solutions of antimicrobial preparations produced on the basis of the composition application; the preparations' sorption rate by colloidal silica particles Dimension Antimicrobial and content preparation % of colloidal sorption silica rate by Composition content and contents of particles colloidal silica antimicrobial preparations solutions % ≦5 um particles (%) Initial Colloidal silica 15.2 — Dextrose:Colloidal silica 39.1 — (20:1; mechanical activation 1 hour) Dextrose:Colloidal silica 42.3 — (20:2; mechanical activation 2 hours) Dextrose:Colloidal silica 41.2 — (20:5; mechanical activation 4 hours) Dextrose:Colloidal silica 42.7 — (50:1; mechanical activation 1 hour) Dextrose:Colloidal silica 39.9 — (50:2; mechanical activation 2 hours) Dextrose:Colloidal silica 40.7 — (50:5; mechanical activation 4 hours) Ceftriaxone/Dextrose:Colloidal silica 43.5 41.3 (20:1; mechanical activation 1 hour) Ceftriaxone/Dextrose:Colloidal silica 48.4 47.8 (20:2; mechanical activation 2 hours) Ceftriaxone/Dextrose:Colloidal silica 42.1 51.5 (20:5; mechanical activation 4 hours) Cefotaxime/Dextrose:Colloidal silica 41.8 40.6 (50:1; mechanical activation 1 hour) Cefotaxime/Dextrose:Colloidal silica 44.2 51.4 (50:2; mechanical activation 2 hours) Cefotaxime/Dextrose:Colloidal silica 46.7 66.3 (50:5; mechanical activation 4 hours) Ceftazidime/Dextrose:Colloidal silica 37.9 47.8 (50:2; mechanical activation 2 hours) Cefepime/Dextrose:Colloidal silica 42.1 44.9 (50:2; mechanical activation 2 hours) Azithromycin/Dextrose:Colloidal 41.8 55.7 silica (50:2; mechanical activation 2 hours) Vancomycin/Dextrose:Colloidal silica 36.9 50.9 (50:5; mechanical activation 2 hours) Meropenem/Dextrose:Colloidal silica 40.5 78.5 (50:2; mechanical activation 2 hours) Voriconazole/Dextrose:Colloidal 35.1 47.1 silica (50:2; mechanical activation 2 hours) Amikacin sulfate/Dextrose:Colloidal 43.6 52.3 silica (50:2; mechanical activation 2 hours)

Example 3

(13) Determination of Therapeutic Efficiency of Antimicrobial Preparations, Wherein Solutions of the Antimicrobial Preparations for Intravenous Injection are Prepared Based on the Inventive Pharmaceutical Composition.

(14) Research was carried out for beta-lactam antibiotics (amoxycillin+clavulanate, cefotaxime, ceftriaxone, cefoperazone+sulbactam, ceftazidime, cefepime, aztreonam, meropenem), of macrolides (azithromycin), of aminoglycosides (amikacin sulfate), of glycopeptides (vancomycin), of antifungal agent (voriconazole), as well as of fosfomycin.

(15) Determination of therapeutic efficiency of antimicrobial agents was done on experimental models of sepsis and methods for statistical treatment of the obtained results (χ.sup.2) according to [R19 and R20].

(16) Microgerms. Staphylococcus aureus (ATCC No 25923 F-49), Escherichia coli (ATCC No25922 F-50), Pseudomonas aeruginosa (ATCC No 27853 F-51), Candida albicans (ATCC No 24433).

(17) Animals. The experiments were carried out on hybrid mice (CBA×C.sub.57Black/.sub.6)CBF.sub.1 according to the “Regulations for test animals use” (USSR Ministry of health, order supplement No 755 from Dec. 8, 1977).

(18) Experimental sepsis models. Tested mice were injected intravenously 0.8 ml of P. aeruginosa daily culture suspension with a dosage 5×10.sup.8 CFU/mouse or S. aureus daily culture suspension with a dosage 10.sup.10 CFU/mouse or E. coli daily culture suspension with a dosage 8×10.sup.8 CFU/mouse or Candida albicans daily culture suspension with a dosage 10.sup.10 CFU/mouse. Mice of a control group were injected the 0.9% solution of NaCl or 5% dextrose solution in the volume of 0.8 ml.

(19) In a day after being infected, during 3 days, the tested mice were daily intravenously injected with the indicated above antimicrobial preparations, dissolved in 0.9% solution of NaCl or in 5% dextrose solution, as well as their solutions prepared based on the pharmaceutical composition (as described hereinabove).

(20) All beta-lactams were injected daily in the amount of 0.2 mg/mouse, amikacin sulfate in the amount of 2 mg/mouse daily, vancomycin in the amount of 1 mg/mouse daily, fosfomycin in the amount of 2 mg/mouse daily, and voriconazole in the amount of 0.1 mg/mouse contained in 0.5 ml of solution. Following the same order, the control group was injected with 0.9% NaCl solution or 5% dextrose solution, as well as water solutions of the pharmaceutical composition in the volume of 0.5 ml.

(21) The antibacterial therapy efficiency was evaluated based on the number of surviving mice on the seventh day after being infected [R19, R20].

(22) The obtained data shown in Tables 3 and 4 reflect the results of three independent experiments (at least 30 test animals were used for research of each inventive pharmaceutical preparation).

(23) TABLE-US-00003 TABLE 3 Bacterial sepsis antimicrobial therapy efficiency (the preparation solutions have been prepared on the basis of composition NaCl:Colloidal silica) Mice survival rate on the 7th day of infection * P. Candida Tested antibiotics S. aureus E. coli aeruginosa albicans χ2 0.9% NaCl solution   0%   0%   0%   0% —  (0/31)  (0/30)  (0/32)  (0/30) Solution NaCl:   0%   0%   0%   0% — Colloidal silica  (0/30)  (0/34)  (0/32)  (0/31) (9:2; mechanical activation 2 hours) Amoxycillin + 40.0% 41.9% —  —** P < clavulanate/0.9% (12/30) (13/31) 0.01 NaCl solution Amoxycillin + 83.9% 83.3% — — clavulanate/NaCl: (26/31) (25/30) Colloidal silica (9:2; mechanical activation 2 hours) Cefotaxime/0.9% 43.7% 37.5% — — P < NaCl solution (14/32) (12/32) 0.01 Cefotaxime/NaCl: 81.2% 86.7% — — Colloidal silica (9:2; (26/32) (26/30) mechanical activation 2 hours) Cefoperazone + 43.3% 59.3% 46.6% — P < sulbactam/0.9% (13/30) (19/32) (14/30) 0.01 NaCl solution Cefoperazone + 80.6% 93.5% 93.3% — sulbactam/NaCl: (25/31) (29/31) (28/30) Colloidal silica (9:2; mechanical activation 2 hours) Ceftazidime/0.9% 38.7% 48.4% 46.7% — P < NaCl solution (12/31) (15/31) (14/30) 0.01 Ceftazidime/NaCl: 78.1% 90.6% 87.0% — Colloidal silica (9:2; (25/32) (29/32) (27/31) mechanical activation 2 hours) Cefepime/0.9% 46.7% 58.1% 51.6% — P < NaCl solution (14/30) (18/31) (16/31) 0.01 Cefepime/NaCl: 83.3% 93.3% 90.0% — Colloidal silica (9:2; (25/30) (28/30) (27/30) mechanical activation 2 hours) Aztreonam/0.9% — 70.0% 67.7% — P < NaCl solution (21/30) (21/31) 0.01 Aztreonam/NaCl: — 93.9% 90.3% — Colloidal silica (31/33) (28/31) (9:2; mechanical activation 2 hours) Meropenem/0.9% 70.9% 73.8% 71.8% — P < NaCl solution (22/31) (31/42) (23/32) 0.01 Meropenem/NaCl: 90.9% 95.2% 94.1% — Colloidal silica (9:2; (30/33) (40/42) (32/34) mechanical activation 2 hours) Azithromycin/0.9% 43.3% — — — P < NaCl solution (13/30) 0.01 Azithromycin/NaCl: 90.0% — — — Colloidal silica (9:2; (27/30) mechanical activation 2 hours) Vancomycin/0.9% 71.4% — — — P < NaCl solution (30/42) 0.01 Vancomycin/NaCl: 97.5% — — — Colloidal silica (9:2; (39/40) mechanical activation 2 hours) Amikacin sulfate/ — 48.3% — — P < 0.9% NaCl solution (15/31) 0.01 Amikacin sulfate/ — 86.6% — — NaCl:Colloidal silica (26/30) (9:2; mechanical activation 2 hours) Fosfomycin/0.9% 36.7% 43.3 % 30.0% — P < NaCl solution (11/30) (13/30) (9/30) 0.01 Fosfomycin/NaCl: 83.3% 86.7% 61.3% — Colloidal silica (9:2; (25/30) (26/30) (19/31) mechanical activation 2 hours) Voriconazole/0.9% — — — 45.1% P < NaCl solution (14/31) 0.01 Voriconazole/NaCl: — — — 90.3% Colloidal silica (9:2; (28/31) mechanical activation 2 hours) * in % and absolute values (survival rate/infected animals). **tests were not conducted

(24) TABLE-US-00004 TABLE 4 Bacterial sepsis antimicrobial therapy efficiency (the preparation solutions have been prepared on the basis of composition Dextrose:Colloidal silica) Mice survival rate on the 7th day of infection * P. Candida Tested antibiotics S. aureus E. coli aeruginosa albicans χ2 5% dextrose solution   0%   0%   0%   0% —  (0/31)  (0/30)  (0/32)  (0/30) Solution   0%   0%   0%   0% — Dextrose:Colloidal silica  (0/30)  (0/31)  (0/30)  (0/30) (50:2; mechanical activation 2 hours) Ceftriaxone/5% dextrose 40.6% 45.2% —  —** P < solution (13/32) (14/31) 0.01 Ceftriaxone/ 83.9% 90.0% — — Dextrose:Colloidal silica (26/31) (27/30) (50:2; mechanical activation 2 hours) Cefotaxime/5% dextrose 42.8% 43.7% — — P < solution (15/35) (14/32) 0.01 Cefotaxime/ 84.4% 81.2% — — Dextrose:Colloidal silica (27/32) (26/32) (50:2; mechanical activation 2 hours) Ceftazidime/5% dextrose 40.0 % 53.3% 46.8% — P < solution (12/30) (16/30) (15/32) 0.01 Ceftazidime/ 86.7% 93.3% 87.0% — Dextrose:Colloidal silica (26/30) (28/30) (27/31) (50:2; mechanical activation 2 hours) Cefepime/5% dextrose 56.7% 54.4% 50.0% — P < solution (17/30) (17/31) (15/30) 0.01 Cefepime/ 90.0% 93.7% 93.5% — Dextrose:Colloidal silica (27/30) (30/32) (29/31) (50:2; mechanical activation 2 hours) Azithromycin/ 5% 43.3% — — — P < dextrose solution (13/30) 0.01 Azithromycin/ 80.6% — — — Dextrose:Colloidal silica (25/31) (50:2; mechanical activation 2 hours) Vancomycin/5% dextrose 77.5% — — — P < solution (31/40) 0.01 Vancomycin/ 95.0% — — — Dextrose:Colloidal silica (38/40) (50:2; mechanical activation 2 hours) Meropenem/5% dextrose 73.8% 78.0% 74.4% — P < solution (31/42) (32/41) (32/43) 0.01 Meropenem/ 95.1% 95.0% 95.2% — Dextrose:Colloidal silica (39/41) (38/40) (40/42) (50:2; mechanical activation 2 hours) Amikacin sulfate/5% — 46.7% — — P < dextrose solution (14/30) 0.01 Amikacin sulfate/ — 83.3% — — Dextrose:Colloidal silica (25/30) (50:2; mechanical activation 2 hours) Fosfomycin/5% dextrose 43.7% 46.7% 35.2% — P < solution (14/32) (14/30) (15/34) 0.01 Fosfomycin/ 87.5% 90.0% 85.3% — Dextrose:Colloidal silica (28/32) (27/30) (29/34) (50:2; mechanical activation 2 hours) Voriconazole/ 5% — — — 46.7% P < dextrose solution (14/30) 0.01 Voriconazole/ — — — 93.5% Dextrose:Colloidal silica (29/31) (50:2; mechanical activation 2 hours) * in % and absolute values (survival rate/infected animals). **tests were not conducted

(25) As it can be seen from Tables 3 and 4, all the inventive pharmaceutical compositions for preparing injections in all of the tested antimicrobial preparations containing the finely dispersed powder of nanostructured colloidal silica, fairly increase their therapeutic efficiency when treating overwhelming sepsis of tested animals, provoked by Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans.

(26) Therefore, following the obtained data, a conclusion can be made that the inventive pharmaceutical compositions for preparing solutions of antibacterial and antifungal preparations for intravenous infusions (NaCl: Colloidal silica and Dextrose: Colloidal silica) have a significant clinically important potentiating impact on therapeutic efficiency thereof, when treating malignant contagious and inflammatory diseases, in comparison with traditional solvents (prototypes of the invention).

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