NZ601748B - Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its' production process - Google Patents

Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its' production process Download PDF

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NZ601748B
NZ601748B NZ601748A NZ60174812A NZ601748B NZ 601748 B NZ601748 B NZ 601748B NZ 601748 A NZ601748 A NZ 601748A NZ 60174812 A NZ60174812 A NZ 60174812A NZ 601748 B NZ601748 B NZ 601748B
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New Zealand
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colloidal silica
dextrose
composition
sodium chloride
present
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NZ601748A
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NZ601748A (en
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Aleksandr Valerevich Dushkin
Konstantin Valentinovich Gaidul
Viktor Lvovich Limonov
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Viktor Lvovich Limonov
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Priority claimed from RU2011147170/15A external-priority patent/RU2476206C1/en
Application filed by Viktor Lvovich Limonov filed Critical Viktor Lvovich Limonov
Publication of NZ601748A publication Critical patent/NZ601748A/en
Publication of NZ601748B publication Critical patent/NZ601748B/en

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/546—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 containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • A61K9/143—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 with 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
    • A61K9/14—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
    • A61K9/145—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 with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • 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
    • 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
    • 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
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Patent 601748 Disclosed herein is an antimicrobial pharmaceutical composition comprising: an antibiotic; sodium chloride or dextrose; and colloidal silica wherein, if the composition comprises sodium chloride, the sodium chloride and the colloidal silica are present in the composition in a weight ratio of (4.5-9):(1-5), and wherein, if the composition comprises dextrose, the dextrose and the colloidal silica are present in the composition in a weight ratio of (20 to 50):(1-5). Said compositions are useful in the treatment of infectious diseases. Also disclosed is a process of the preparation of such compositions. weight ratio of (4.5-9):(1-5), and wherein, if the composition comprises dextrose, the dextrose and the colloidal silica are present in the composition in a weight ratio of (20 to 50):(1-5). Said compositions are useful in the treatment of infectious diseases. Also disclosed is a process of the preparation of such compositions.

Description

1.3 NEW ZEALAND Patents Act 1953 Patents Form No. 5 COMPLETE SPECIFICATION Title: ' CEUTICAL COMPOSITION FOR THE PREPARATION OF INFUSION SOLUTIONS OF ANTIMICROBIAL ATIONS, ITS' PRODUCTION PROCESS I, Viktor Lvovich Limonov, of ulitsa Rashchupkina, 10, kv. 62, , 121374, Russian Federation (Russian), do hereby declare the invention for which I pray that a patent may be granted to me and the method by which it is to be performed, to be particularly described in and by the following statement.
INTELLECTUAL PROPERTY OFFlCE or NZ, 1 0 AUG 2012 P:\CommonWord97\36501~37000\36934LIM\20120806 lPO - File Applicationdoc ed at IPONZ on 26 r 2012 PHARMACEUTICAL ITION FOR THE ATION OF INFUSION SOLUTIONS OF ANTIMICROBIAL PREPARATIONS, ITS’ PRODUCTION PROCESS This invention encompasses pharmaceutical preparations, including preparations of antimicrobial ceuticals, as well as methods for the preparation of pharmaceutical compositions. The compositions and preparations may be used in medicine and veterinary medicine, for e, to treat contagious and inflammatory diseases of different aetiologies.
Traditionally, for many decades in the clinical practice of preparing antimicrobial (antibacterial and ngal) preparations for intravenous injection and infusion, the most commonly used ingredients have been water, a 0,9% solution of sodium chloride, and a 5% solution of dextrose (glucose). Less ntly, a 0,45% solution of sodium chloride has been used. In addition, 2% and 10% solutions of dextrose, Ringer's solution, lactated Ringer's solution, solutions of potassium de and sodium chloride has been used, which by themselves, have no antimicrobial action and do not have a potentiating action for the therapeutic efficiency of antimicrobial ceuticals [1].
Taking into account that many clinically significant microbial strains have now acquired resistance to many crobial preparations, the development of new approaches to increase antimicrobial activity and improve clinical efficiency is an urgent requirement in modern experimental pharmacology and practical medicine.
Recently, it has been discovered that the use of various nanoparticles as carriers for the delivery of different antibiotics directly to immune system cells (such as macrophages) can provide for the protection of organisms against infectious agents. This approach involves an se in the intracellular concentration of these preparations and accordingly an increase in antimicrobial ties. This is an important aspect with regard to treating persistent microorganisms such as clamydias, mycoplasmas, and mycobacteria, as well as for the stimulation of the antibacterial activity of macrophages and their recruitment into the infected tissues. This is a very promising development in new pharmaceutical technologies for antibiotic-based therapies [2, 3, 4, 5, 6, 7, 8, 9].
One aspect of the present invention is the use of pharmaceutical compositions for preparing infusion ons from pulverized injectable forms of antimicrobial preparation.
This is achieved on the basis of using sodium chloride, dextrose and dal silica having a potentiating action on the therapeutic efficiency of antibacterial and antifungal preparations in Received at IPONZ on 26 r 2012 ison with traditional solvents (such as water for injection, a 0,9% solution of sodium de, a 5% solution of dextrose, Ringer's solution and ).
The present invention results in the intensification of the eutic ency of parenteral forms of antibacterial and antifungal preparations on the basis of using nanoparticles and microparticles of colloidal silica.
Various nanoparticles and microparticles of dal silica differ depending upon their properties of biocompatibility, biodistribution, biodegradation and low toxicity. During parenteral administration, they are able to serve as a carrier of antibiotics for intracellular delivery to macrophages. The concentration of antibiotics is thereby increased in inflamed tissues such as in the lungs, liver, kidneys, spleen, lymph nodes, heart, skin, bladder and other organs. In addition, the antimicrobial activity of cells of the immune system is also increased (particularly by stimulating nitric oxide tion, and activating phagocytosis), thereby icantly increasing the therapeutic effect of antibacterial and antifungal ceuticals [10, 11, 12, 13, 14, 15, 16, 17].
The present invention therefore overcomes problems in the prior art by creating pharmaceutical compositions for the preparation of infusion solutions of antibacterial and antifungal preparations.
In one aspect of the present invention, there is provided a pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations soluble in sterile water for ions, preferably comprising a 0,45% or 0,9% solution of sodium chloride, in powder form, and further comprising sodium chloride and colloidal silica at a weight ratio of 4,5 or 9 : (1-5), tively.
Production of this pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations is also disclosed . Such production includes, for example, mixing sodium chloride with other components, wherein powdered sodium chloride is mixed with powder-like colloidal silica at a weight ratio of 4,5 or 9 : (1-5), respectively , and the derived mixture is then machined by means of an ing and/or rubbing influence until the mass fraction of finely-dispersed (equal to or less than 5 micron) les of colloidal silica is increased at least two-fold.
For the preparation of infusion solutions, a single dose of dry powder of an antimicrobial preparation (soluble in water for injection) is most preferred. Typically, this is clearly indicated to the skilled person in the manufacturer’s instructions, whereby the preparation is dissolved in 10 ml of water for injection, after which the whole volume of the derived solution is transferred into a vial with the dry powder of the pharmaceutical Received at IPONZ on 26 October 2012 composition indicated above. In addition, the composition is intensively shaken for 2 or 3 minutes, after which the resulting sion (consisting of the solution of the antimicrobial preparation and the pharmaceutical composition) is further ved in, for example, 50 or 100 or 200 ml of a 0,45% or 0,9% solution of sodium de (depending on the composition contents). The ation may then be ed intravenously as an infusion according to the requirements indicated in the antimicrobial preparation prescribing information.
In a second aspect of the present invention, there is a provided a pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations soluble in sterile water for ions, preferably comprising a 2% or 5% dextrose solution, in powder form, and further comprising dextrose and colloidal silica at a weight ratio of 20 or 50 : (1-5), respectively.
Production of this pharmaceutical composition for the preparation of infusion ons of antimicrobial preparations is also disclosed herein. Such production includes, for example, mixing of dextrose with other components, wherein powdered dextrose is mixed with powder-like colloidal silica at a weight ratio of dextrose to colloidal silica of 20 or 50 : (1-5), respectively. The resulting mixture is then ed by means of an impacting and/or rubbing influence until the mass fraction of finely-dispersed (equal to or less than 5 micron) particles of colloidal silica is increased at least two-fold.
For the ation of infusion solutions, a single dose of dry powder of an antimicrobial preparation (soluble in water for injection) is most preferred. Typically, this is clearly indicated to the skilled person in the manufacturer’s instructions, whereby the preparation is dissolved in 10 ml of water for injection, after which the whole volume of the derived solution is erred into a vial with the dry powder of the pharmaceutical composition indicated above. In addition, the ition is intensively shaken for 2 or 3 s, after which the resulting suspension (consisting of the solution of the antimicrobial preparation and the pharmaceutical ition) is further dissolved in, for example, 50 or 100 or 200 ml of 2% or 5% dextrose solution (depending on the composition contents). The formulation may then be injected intravenously as an infusion according to the requirements indicated in the antimicrobial ation prescribing information.
The therapeutic efficiency of crobial preparations when using the pharmaceutical compositions disclosed herein is increased if the obtained mix (sodium chloride + colloidal silica or dextrose + colloidal silica) is machined by means of an impacting and/or rubbing influence so that the contents of colloidal silica particles have a size of ≤5 um and acoount forat least 35% of the total amount of the formulation.
Received at IPONZ on 26 October 2012 For the preparation of pharmaceutical itions, the present ors used a crystalline powder of sodium de and dextrose ed by «ABOLmed» LLC, along with the following antimicrobial preparations: amoxycillin+clavulanate, aztreonam, xime, ceftriaxone, ceftazidime, cefoperazone+sulbactam, cefepime, meropenem, amikacin sulfate, omycin, ycin, capreomycin, fosfomycin and voriconazole. As a source of colloidal silica, the present inventors used L 200 (generic name: colloidal silica) produced by «Evonik Degussa ation» (Germany) consisting of a round shape of nonporous silica nanoparticles (with an average diameter of 7-40 nm) joined into non-regular microparticles with a size of < 100 um.
The choice of the composition formulation is based on the phenomenon of reciprocal sorption of the antibacterial and antifungal preparations by nanoparticles and microparticles of colloidal silica, and the se in the dimensions of the colloidal silica microparticles in the case of mechanical activation of the crystalline powders of sodium chloride and dextrose by means of an intensive mechanical and/or rubbing impact.
The use of the colloidal silica according to the provided weight ratio was defined experimentally on laboratory mice following assessment of the maximum therapeutic efficiency of the antimicrobial preparations with the minimum probability of side effects.
The production of pharmaceutical compositions indicated above by means of mechanical activation of a powdered blend of sodium chloride or dextrose with colloidal silica by an intensive mechanical and/or rubbing impact allows for comparison with other known means of increasing the proportion of finely dispersed colloidal silica particles with a size ≤ 5 um [18].
For this purpose, a blend of agents (sodium chloride + colloidal silica or dextrose + dal silica) were subjected to mechanical activation by means of an intensive ical and/or rubbing impact until the weight ratio of the colloidal silica fine powder fraction (being ≤ 5 um) was increased at least two-fold.
The obtained compositions may be used for the production of infusion solutions ting of colloidal silica fine particles with various crobial preparations inversely adsorbed on their surface, and soluble in sterile water for injections.
To obtain the compositions, the inventors used a mechanochemical approach consisting of ent of the blend of solid ingredients by an intensive mechanical impact, that is, pressure and shearing using various grinders causing an impacting and/or rubbing influence on the ingredients. The mechanical activation was ed using drum mills. This method allows for the achievement of full homogenicity of the powdered components when Received at IPONZ on 26 October 2012 compared with ing blends by a simple mixing of components, or by vaporisation of their ons. As a result, the present methodology provides for a high pharmacological activity of the pharmaceutical compositions of the invention.
As a quantitative criterion of the minimally required dose of mechanical action it is ient to use the method of granulometry. Herein it is necessary that the weight content of the colloidal silica particles not exceeding 5 um as measured by means of laser photometry, should increase at least ld. The mechanical treatment of powder nds is performed in rotary, vibratory or planetary mills. As grinding media it is possible to use balls, pivots, etc.
The pharmacological trials of the ed compositions on laboratory rodents (mice) have shown that the t compositions produced as herein disclosed have a specific potentiating action on the therapeutic efficiency of antimicrobial (antibacterial and antifungal) preparations, for example, when treating bacterial sepsis induced by lococcus aureus, Escherichia coli and Pseudomonas aeruginosa, as well as mycotic sepsis induced by Candida albicans, in comparison with the prior art solvents of antimicrobial medications.
Therefore, the use of the present pharmaceutical compositions and their production ses provides for the following advantages: 1) A clinically significant increase in the efficiency and quality of antimicrobial therapy of malignant contagious and inflammatory diseases, and a mortality decrease; and 2) Ecological safety, efficiency and low-cost technology of pharmaceutical production.
The present invention is illustrated by the examples listed below.
Example 1. Solid composition production of NaCl : colloidal silica.
A blend of sodium chloride and colloidal silica in weight ratios 4,5:1, 4,5:2, 4,5:5, 9:1, 9:2 and 9:5 was treated for 1, 2 or 4 hours in a drum rotary mill.
Analysis of the granulometric t of colloidal silica, as well different itions with NaCl, was performed on a laser analyzer in order to assess particle dimensions, using a Microsizer-201а produced by «VA Instalt», . From 1g to 5g of the powder was placed into the sample preparation module (with a liquid volume of 150 sm³) in a ty ient for achieving 70-75 % optical transmission through the cuvet. Measuring was performed after delaying for one or two minutes between samples. In addition, a simultaneous / duplicate suspension was also ed. Analysis was performed according to Received at IPONZ on 26 October 2012 the program provided with the analyzer. The s were prepared in the form of hystograms of weight distribution versus particle dimensions.
For defining the number of antimicrobial preparations sorbed by colloidal silica particles, 0,5g antibiotic substance (by active matter) was dissolved in 5 sm3 water for injections. Thereafter, the NaCl : Colloidal silica suspended in fresh antibiotic solution was fuged for 30 minutes at a speed of 12000 rpm. The supernatant liquid was then poured carefully, and the residual Colloidal silica was suspended again in the same ty of water for injections. The concentration of antibiotic desorbing into the aqueous phase was defined using HPLC. Thereafter, the procedure was repeated. The quantity of the sorbed antibiotic was calculated from the total antibiotic quantity desorbing from the colloidal silica al matter.
The results of the granulometric composition and sorption rate are shown in Table 1. ing from the results, the chosen ions of producing the present composition allow for increasing the tion of the colloidal silica fine powder fraction (with particle size ≤ 5 um) at least two-fold. This allows for binding of antimicrobial preparations by colloidal silica to increase at least by 40%.
Table 1.
Granulometric data of water suspensions of compositions and solutions of antimicrobial preparations; and the sorption rate of the preparations by colloidal silica particles Composition t and contents of Dimension and content % Antimicrobial crobial preparation solutions of colloidal silica particles preparation on % ≤5 um rate by colloidal silica particles (%) Initial Colloidal silica 15,2 - NaCl: Colloidal silica 38,5 - ; ical 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 silica 43,5 45,3 (4,5:1; mechanical activation 1 hour) Received at IPONZ on 26 r 2012 Ceftriaxone/NaCl: Colloidal silica 45,4 47,8 (4,5:2; mechanical activation 2 hours) Ceftriaxone/NaCl: Colloidal silica 42,1 49,5 ; 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) idime/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 silica 40,2 43,7 (9:2; ical activation 2 hours) Azithromycin/NaCl: Colloidal silica 39,1 51,9 (9:2; mechanical activation 2 hours) Vancomycin/NaCl: Colloidal silica 42,9 50,6 (9:5; mechanical activation 2 hours) Meropenem/NaCl: Colloidal silica 36,7 43,9 (9:2; mechanical activation 2 hours) Voriconazole/NaCl: Colloidal silica 37,5 41,7 (9:2; mechanical activation 2 hours) Capreomycin/NaCl: Colloidal silica 40,1 49,9 (9:5; mechanical activation 2 hours) Example 2. Solid composition production Dextrose:Colloidal silica. A blend of dextrose and colloidal silica in weight ratios of :1, 20:2, 20:5, 50:1, 50:2 and 50:5 was treated for 1, 2 or 4 hours in a drum rotary mill. ement of the granulometric content of the colloidal silica and antibiotic blend sorption rate was performed following the methods described in example 1. The results are shown in Table 2. It follows from the s that the method of preparation of the t compositions allows for increasing at least two-fold the proportion of the dal silica fine powder fraction (with particle size ≤ 5 um) and thereby ing an increase in the degree of binding of antimicrobial preparations molecules by colloidal silica particles by at least 40%.
Received at IPONZ on 26 October 2012 Table 2.
Granulometric data of water suspensions of compositions and solutions of crobial preparations; and the sorption rate ofteh preparations by colloidal silica particles Composition content and ts of Dimension and content crobial antimicrobial preparation solutions % of colloidal silica preparation sorption particles rate by colloidal silica % ≤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 tion 4 hours) Ceftriaxone/Dextrose:Colloidal silica 43,5 41,3 (20:1; mechanical tion 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 silica 41,8 55,7 (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 silica 35,1 47,1 (50:2; ical activation 2 hours) Amikacin e/Dextrose:Colloidal 43,6 52,3 silica (50:2; mechanical activation 2 hours) Received at IPONZ on 26 October 2012 e 3. Determination of the therapeutic efficiency of antimicrobial preparation solutions (for intravenous injection) Beta-lactam antibiotics such as amoxycillin+clavulanate, cefotaxime, ceftriaxone, razone+sulbactam, ceftazidime, cefepime, nam, meropenem, macrolides (azithromycin), aminoglycosides (amikacin sulfate), glycopeptides (vancomycin), antifungal agents (voriconazole), and in particular fosfomycin have been examined in the past.
To ine the therapeutic efficiency of antimicrobial agents the present inventors used experimental models of sepsis and made a statistical ent of the results ( χ2) according to [19, 20].
Microgerms: Staphylococcus aureus (ATCC № 25923 F-49), Escherichia coli (АТСС №25922F-50), monas aeruginosa (ATCC №27853 F-51), Candida albicans (ATCC № 24433).
Animals: the experiments were carried out on hybrid mice (CBA x C57Black/6)CBF1 according to the «Regulations for test animals use» (USSR Ministry of health order supplement № 755 from 12.08. 1977).
Experimental sepsis models Mice were injected intravenously with 0,8ml of P. aeruginosa as a daily culture suspension with a dosage of 5х108 CFU/mouse, or with S. aureus as a daily culture suspension with a dosage of 1010 CFU/mouse, or with Е. coli as a daily culture sion with a dosage of 8х108 CFU/mouse, or with Candida albicans as a daily culture suspension with a dosage of 1010 CFU/mouse. The control group of mice was ed with a 0,9% solution of NaCl or a 5% dextrose solution at a volume of 0,8 ml.
A day after being infected, test mice were injected intravenously each day for 3 days with the germicides indicated above, dissolved in a 0,9% solution of NaCl or in a 5% dextrose on. In addition, solutions of the pharmaceutical compositions (as described hereabove) were used.
All beta-lactams were injected daily at the amount of 0,2 mg/mouse. Amikacin sulfate was injected at the amount of 2 mg/mouse daily. Vancomycin was injected at the amount of 1 mg/mouse daily. Fosfomycin was injected at the amount of 2 mg/mouse daily. Voriconazole was injected at the amount of 0,1 mg/mouse daily. All ions made with 0,5 ml of solution. Following the same , the control group was injected with 0,9% NaCl solution or with 5% dextrose solution, as well as water solutions of the pharmaceutical compositions at a volume of 0,5 ml.
Received at IPONZ on 26 October 2012 The results were evaluated on the basis of the number of surviving mice on the seventh day after being infected [19, 20].
The results are shown in tables 3 and 4, reflecting the results of three independent experiments (for each preparation at least 30 test animals were used).
Table 3. ial sepsis antimicrobial therapy efficiency (the preparation solutions were prepared on the basis of NaCl:Colloidal silica compositions) Tested antibiotics Mice survival rate on the 7th day of ion * S. аureus E. coli P. aeruginosa a χ2 albicans 0,9% NaCl solution 0% 0% 0% 0% - (0/31) (0/30) (0/32) (0/30) Solution NaCl:Colloidal silica 0% 0% 0% 0% - (9:2; mechanical activation 2 (0/30) (0/34) (0/32) (0/31) hours) Amoxycillin+clavulanate/ 40,0% 41,9% - -** Р<0,01 0,9% NaCl on (12/30) ) Amoxycillin+clavulanate/ 83,9% 83,3% - - NaCl:Colloidal silica (26/31) (25/30) (9:2; mechanical activation 2 hours) Cefotaxime/0,9% NaCl 43,7% 37,5% - - Р<0,01 solution (14/32) (12/32) Cefotaxime/NaCl: Colloidal 81,2% 86,7% - - silica (9:2; mechanical (26/32) ) activation 2 hours) Cefoperazone+sulbactam / 43,3% 59,3% 46,6% (14/30) - Р<0,01 0,9% NaCl solution (13/30) (19/32) Cefoperazone+sulbactam / 80,6% 93,5% 93,3% (28/30) - NaCl:Colloidal silica (25/31) (29/31) (9:2; ical activation 2 hours) Ceftazidime/0,9% NaCl 38,7% 48,4% 46,7% (14/30) - Р<0,01 solution (12/31) (15/31) Ceftazidime/NaCl: Colloidal 78,1% 90,6% 87,0% - silica (9:2; mechanical (25/32) (29/32) (27/31) activation 2 hours) me/0,9% NaCl solution 46,7% 58,1% 51,6% (16/31) - Р<0,01 (14/30) (18/31) Cefepime/NaCl:Colloidal 83,3% 93,3% 90,0% (27/30) - silica (9:2; mechanical (25/30) ) activation 2 hours) nam/0,9% NaCl - 70,0% 67,7% (21/31) - Р<0,01 solution (21/30) Aztreonam/NaCl:Colloidal - 93,9% 90,3% (28/31) - silica (9:2; mechanical (31/33) activation 2 hours) Meropenem/0,9% NaCl 70,9% 73,8% 71,8% (23/32) - Р<0,01 solution (22/31) (31/42) Received at IPONZ on 26 October 2012 Meropenem/NaCl:Colloidal 90,9% 95,2% 94,1% (32/34) - silica (9:2; mechanical (30/33) (40/42) activation 2 hours) Azithromycin/0,9% NaCl 43,3% - - - Р<0,01 solution (13/30) Azithromycin/NaCl: 90,0% - - - Colloidal silica (9:2; (27/30) ical activation 2 hours) Vancomycin/0,9% NaCl 71,4% - - - Р<0,01 solution ) Vancomycin/NaCl: Colloidal 97,5% - - - silica (9:2; mechanical (39/40) activation 2 hours) Amikacin sulfate/0,9% NaCl - 48,3% - - Р<0,01 solution (15/31) Amikacin sulfate/ NaCl: - 86,6% - - Colloidal silica ) (9:2; mechanical activation 2 hours) Fosfomycin/0,9% NaCl 36,7% 43,3 % 30,0% - Р<0,01 solution (11/30) (13/30) (9/30) Fosfomycin/NaCl: Colloidal 83,3% 86,7% 61,3% - silica (9:2; ical (25/30) (26/30) (19/31) activation 2 hours) Voriconazole/0,9% NaCl - - - 45,1% Р<0,01 solution (14/31) Voriconazole/NaCl: Colloidal - - - 90,3% silica (9:2; mechanical (28/31) tion 2 hours) *- in % and te values (survival rate/infected animals). ** - tests were not conducted Table 4.
Bacterial sepsis antimicrobial therapy efficiency (the preparation solutions were prepared on the basis of Dextrose:Colloidal silica compositions) Tested antibiotics Mice survival rate on the 7th day of ion * S. аureus E. coli P. aeruginosa Candida χ2 albicans % dextrose solution 0% 0% 0% 0% - (0/31) (0/30) (0/32) (0/30) Solution Dextrose:Colloidal 0% 0% 0% 0% - silica (50:2; mechanical (0/30) (0/31) (0/30) (0/30) activation 2 hours) Ceftriaxone/ 5% dextrose 40,6% 45,2% - -** Р<0,01 solution (13/32) (14/31) axone/ 83,9% 90,0% - - Dextrose:Colloidal silica (26/31) (27/30) (50:2; mechanical tion 2 hours) Cefotaxime/ 5% dextrose 42,8% 43,7% - - Р<0,01 ed at IPONZ on 26 October 2012 solution ) (14/32) 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% - Р<0,01 on (12/30) (16/30) (15/32) Ceftazidime/ 86,7% 93,3% 87,0% - se:Colloidal silica ) ) (27/31) (50:2; mechanical activation 2 hours) Cefepime/ 5% se 56,7% 54,4% 50,0% - Р<0,01 solution (17/30) (17/31) (15/30) me/ Dextrose:Colloidal 90,0% 93,7% 93,5% - silica (27/30) (30/32) (29/31) (50:2; mechanical activation 2 hours) Azithromycin/ 5% dextrose 43,3% - - - Р<0,01 solution (13/30) Azithromycin/ 80,6% - - - Dextrose:Colloidal silica (25/31) (50:2; mechanical activation 2 hours) Vancomycin/ 5% dextrose 77,5% - - - Р<0,01 solution (31/40) Vancomycin/ 95,0% - - - Dextrose:Colloidal silica (38/40) (50:2; mechanical activation 2 hours) Meropenem/ 5% dextrose 73,8% 78,0% 74,4% (32/43) - Р<0,01 solution (31/42) (32/41) Meropenem/ 95,1% 95,0% 95,2% (40/42) - Dextrose:Colloidal silica (39/41) (38/40) (50:2; mechanical activation 2 hours) Amikacin sulfate/ 5% - 46,7% - - Р<0,01 dextrose solution (14/30) Amikacin sulfate/ - 83,3% - - Dextrose:Colloidal silica (25/30) (50:2; mechanical activation 2 hours) Fosfomycin/ 5% dextrose 43,7% 46,7% 35,2% (15/34) - Р<0,01 solution (14/32) (14/30) Fosfomycin/ 87,5% 90,0% 85,3% ) - Dextrose:Colloidal silica (28/32) (27/30) (50:2; mechanical activation 2 hours) Voriconazole/ 5% dextrose - - - 46,7% Р<0,01 solution (14/30) Voriconazole/ - - - 93,5% Dextrose:Colloidal silica ) (50:2; mechanical activation 2 hours) *- in % and absolute values (survival rate/infected animals). ** - tests were not conducted Received at IPONZ on 26 October 2012 As can be seen from Tables 3 and 4, all of the pharmaceutical compositions sed therapeutic efficiency when treating sepsis of test s initiated by Staphylococcus аureus, Escherichia coli, Pseudomonas nosa and Candida albicans.
Therefore, the present pharmaceutical compositions for preparing solutions of antibacterial and antifungal preparations for intravenous infusions (NaCl:Colloidal silica and Dextrose: dal silica ) have a significant potentiating action when treating contagious and inflammatory diseases, in comparison with traditional solvents.
Received at IPONZ on 26 October 2012 Used literature 1. Kucers’ The use of antibiotics// By M.L.Grauson, S.M.Crowe, J.S.McCarthy et al. 6th ed, 2 vols, 3000 pp. , UK, Hodder Education/ASM Press, 2010. 2. Abeylath S.C., Turos E. Drug delivery approaches to overcome bacterial resistance to m antibiotics // Expert Opinion on Drug Delivery. – 2008. – Vol.5. - P.931-949. 3. Bastus N.G., Sanchez-Tillo E., Pujals S. et al. Peptides conjugated to gold nanoparticles induce macrophage activation // Molecular Immunology. – 2009. – Vol.46. – P.743-748. 4. Pinto-Alphandary H., ont A., Couvreur P. Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications // International Journal of Antimicrobial Agents. – 2000. – Vol.13. – P.155-168.
. Ulbrich W., Lamprech A. Targeted drug-delivery approaches by nanoparticulate rs in the therapy of inflammatory diseases // l Royal y Interface. – 2010. – Vol.7, Suppl. 1. – P.S55-S66. 6. ry M.J., MacLaren I., Pradeep T. Investigation of antibacterial properties of ciprofloxacin@SiO2. // ir. – 2006. – Vol.22. – P.10125-10129. 7. Rai A., Prabhune A., Perry C.C. Antibiotic mediated synthesis of gold nanoparticles with potent antimicrobial activity and their ation in antimicrobial coatings // Journal of als Chemistry. – 2010. – Vol.20. – P.6789-6798. 8. Zolnik B.S., Gonzalez-Fernandez A., Sadrieh N., Dobrovolskaia V. Minireview: Nanoparticles and the immune system // Endocrinology. – 2010. – Vol.151. – P.458-465. 9. Pinto-Alphandary H., Balland O., Laurent M. et al. Intracellular visualization of ampicillin-loaded nanoparticles in peritoneal macrophages infected in vitro with Salmonella typhimurium // Pharmaceutical ch. – 1994. – Vol.11. – P.38-46.
. Park J-H., Gu L., Maltzahn G. et al. Biodegradable luminescent porous silicon nanoparticles for in vivo ations // Nature Materials. – 2009. – Vol.8. – P.331-336. 11. Hetrick E.M., Shin J.H., Stasko N.A. et al. Bactericidal efficacy of nitric oxide-releasing silica nanoparticles// ACS Nano. – 2008. – Vol.2. – P.235-246. 12. Pernis B. Silica and the immune system // Acta Biomed. – 2005. – Vol.76, Suppl. 2.- 13. Tasciotti E., Liu X., Bhavane R. Et et al. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications // Nature Nanotechnology. – 2008. – Vol.3. – P.151-157. ed at IPONZ on 26 October 2012 14. Seleem M.N., Munusamy P., Ranjan A et al. Silica-antibiotic hybrid nanoparticles for targeting intracellular pathogens // Antimicrobial Agents and Chemotherapy. – 2009. – Vol.53. – P.4270-4274.
. Chuiko A., Pentyuk A., Shtat’ko E., Chuiko N. l aspects of application of highly disperse amorphous silica // Surface Chemistry in Biomedical and Environmental Science.
Edited by J.P.Blitz and V. Gun’ko.II. Mathematics, Physics and Chemistry. –2006. – Vol.228. – P.191-204. 16. Waters K.M., Masiello L.M., Zangar R.C. et al. Macrophage responses to silica nanoparticles are highly conserved across le sizes // Toxicological Sciences. – 2009.
– Vol.107. – P. 553-569. 17. Lucarelli M., Gatti A.M., Savarino G. et al. Innate defence functions of macrophages can be biased by nano-sized ceramic and metallic particles // European Cytokine Network. – 2004. – Vol.15. – P.339-346. 18. Hamilton R.F., Thakur S.A., r J.K., Holian A. MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice // Journal Biological Chemistry. – 2006. – Vol.281. – P. 34218-34226. 19. Eckhardt С., Fickweiler K., ann R. et al. Therapeutic efficacy of moxifloxacin in a murine model of severe systemic mixed infection with E.coli and B.fragilis // Anaerobe. - 2003. - Vol.9. - P.157-160.
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Received at IPONZ on 26 October 2012

Claims (13)

Claims
1. An antimicrobial pharmaceutical composition comprising: (a) an antibiotic; (b) sodium chloride or dextrose; and (c) colloidal silica n, if the ition comprises sodium chloride, the sodium chloride and the colloidal silica are present in the composition in a weight ratio of (4.5-9) : (1-5), and wherein, if the composition comprises dextrose, the dextrose and the colloidal silica are present in the ition in a weight ratio of (20 to 50) : (1-5).
2. The composition according to claim 1, wherein at least some of the colloidal silica is present in particles measuring equal to or less than 5 microns.
3. The composition according to claim 1 or 2, wherein the composition is formulated for parenteral administration.
4. Use of: (a) an antibiotic; (b) sodium chloride or dextrose; and (c) colloidal silica in the manufacture of a medicament for the treatment of an infectious e n, if the medicament comprises sodium chloride, the sodium chloride and the colloidal silica are t in the medicament in a weight ratio of (4.5-9) : (1-5), and wherein, if the medicament comprises dextrose, the dextrose and the colloidal silica are present in the medicament in a weight ratio of (20 to 50) : (1-5).
5. The use according to claim 4 , n at least some of the colloidal silica is present in particles measuring equal to or less than 5 microns.
6. The use according to claim 4 or 5, wherein the medicament is ated for parenteral administration.
7. A process for the manufacture of an antimicrobial pharmaceutical composition, wherein the process comprises (a) mixing an antibiotic with either sodium chloride or dextrose, and colloidal silica Received at IPONZ on 26 r 2012 wherein, if the composition comprises sodium chloride, the sodium chloride and the colloidal silica are present in the composition in a weight ratio of (4.5-9) : (1-5), and wherein, if the composition comprises dextrose, the dextrose and the colloidal silica are present in the composition in a weight ratio of (20 to 50) : (1-5), and (b) subjecting the mixture to a mechanized ing, abrasive and/or rubbing action.
8. The process according to claim 7 , wherein at least some of the dal silica is present in les measuring equal to or less than 5 microns.
9. The process according to claim 7 or 8, wherein the composition is ated for parenteral administration.
10. The process according to any one of claims 7 to 9 , wherein the amount of colloidal silica present in particles measuring equal to or less than 5 micron is increased at least two-fold by the mechanized impacting, abrasive and/or g action.
11. An antimicrobial pharmaceutical composition substantially as herein disclosed , with reference to any one or more of the examples, excluding comparative examples.
12. Use of an antibiotic, sodium chloride or dextrose, and colloidal silica in the manufacture of a medicament for the ent of a disease ntially as herein disclosed, with reference to any one or more of the examples, excluding comparative examples.
13. A process for the manufacture of an antimicrobial ceutical composition substantially as herein disclosed, with reference to any one or more of the examples, excluding comparative examples.
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