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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
  • A01N59/16—Heavy metals; Compounds thereof
• • 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
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/38—Silver; Compounds thereof
• • 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
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • 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

Definitions

• the present invention relates to an antimicrobial composition having antimicrobial properties and activity towards, inter alia, tuberculosis (TB), malaria and cancer. More particularly, but not exclusively, the present invention relates to an antimicrobial composition useful in the treatment and prevention of infections, diseases and/or disorders. The present invention further relates to processes for preparing the antimicrobial composition and the use of the said composition in the manufacture of antimicrobial preparations for the treatment and/or prevention of infections, diseases and/or disorders.
• TB tuberculosis
• the word “aggregation” denotes a plurality of silver particles (atoms, molecules, or macromolecules) loosely bound together via weak intermolecular van der Waals forces.
• the word “aggregation” is also understood to denote a plurality of silver particles (atoms, molecules, or macromolecules) which are loosely bound together to form one or more weak, friable, crystalline silver structures.
• antibacterial as referred to herein is understood to encompass antibacterial, antifungal, antiprotozoal and antiviral properties.
• pathogenic microorganisms may be eukaryotic or prokaryotic and may include bacteria, fungi, archaea, protista, protazoa, algae, parasites, yeasts and viruses. Summary of the Invention
• the present invention provides an antimicrobial composition including at least one or more friable aggregation(s) of silver particles in a liquid medium, wherein the concentration of the composition is from 40 ppm up to, and including, 500 000 ppm of silver.
• the invention provides for the silver particles to be elemental silver (Ag) particles.
• the silver particles which in combination form the aggregations, have a particle size of 1 x 10 *9 m (1 nm) to 100 x 10 *9 m in diameter, both values inclusive. It will be appreciated that the particle size of each silver particle included in the aggregation(s) does not have to be identical, such that the plurality of silver particles may demonstrate a variety of particle sizes ranging from 1 x 10 "9 m to 100 x 10 ⁇ 9 m in diameter.
• the invention provides for the aggregations to be friable and to include a plurality of loosely bound silver particles. As mentioned herein before, the plurality of silver particles are loosely bound together via weak intermolecular van der Waals forces. Furthermore, in terms of the invention, the silver particles are loosely bound together to form one or more weak, friable, crystalline silver structures.
• the one or more aggregations of silver particles are 100 x 10 "9 m to 10 000 x 10 "9 m in diameter, both values inclusive.
• the friable aggregations fracture or dissociate under the influence of weak mechanical forces to form a plurality of smaller silver aggregations which are 10 x10 "9 m to 100 x 10 *9 m in diameter (both values inclusive) and/or to form a plurality of silver particles which are 10 x10 "9 m to 100 x 10 "9 m in diameter (again, both values being inclusive).
• the friable aggregations fracture or dissociate under the influence of weak mechanical forces which forces include, but are not limited to, rubbing, peristalsis, friction, vibration, mechanical movement, sonication or a combination of one or more thereof.
• the present composition contemplates concentrations of 40 ppm to 500 000 ppm of silver, both values inclusive. In one embodiment of the invention, the preferred concentration of the composition is 1 000 ppm to 10 000 ppm of silver, both values inclusive.
• the surface area of silver in any given composition is directly proportional to its subsequent activity and efficacy as an antimicrobial agent. Particle surface area per unit volume of liquid medium increases as the concentration of silver particles increases. Furthermore, particle surface area per gram of silver increases as the particle size decreases. Thus high surface areas will give high antimicrobial activity and low surface areas will give correspondingly lower activity.
• the silver aggregations have a surface area of 0.5 cm 2 /ml at lOOppm to 540 cm 2 /ml at 100000 ppm. It will be appreciated that the surface area pertaining to each silver particle included in the aggregation(s) does not have to be identical, such that the aggregations may demonstrate surface areas ranging from 0.5 cm 2 /ml to 540 cm 2 /ml for a range of concentrations from 100 to 100000 ppm. Thus, it will be appreciated that high particle surface area per unit volume of liquid medium is achieved by increasing the concentration of the silver particles, which in turn form the aggregations present in the antimicrobial composition, to 40 ppm of silver or higher.
• the liquid medium referred to herein above is water, preferably distilled water.
• the liquid medium may be deionised or demineralised water.
• the liquid medium may be any suitable organic medium, for instance, a suitable alcohol or oil.
• the antimicrobial composition as described herein contains a higher concentration of silver in comparison to silver products of the type known and described in the art, thereby providing strong antimicrobial activity whilst avoiding the need to administer large volumetric dosages of the composition which large dosages are, as is discussed above, most undesirable owing to the associated adverse side effects of the prior art silver products. Accordingly, the Inventor has found that, at the high concentrations of silver disclosed herein, no adverse toxicity has been observed.
• ionic silver compounds particularly with reference to silver antibiotic products of the type known in the art, have reduced activity upon being administered, since these compounds react with bodily fluids and electrolytes such as chloride in the stomach to form less soluble silver compounds, such as silver chloride.
• the present composition contemplates the inclusion/presence of no anionic species other than hydroxyl ions.
• the bond strength between the silver particles, which silver particles in combination form the aggregations is such that the fracturing of the aggregations, under the action of weak mechanical forces, to generate new sites on the surface of the silver particles is not instantaneous and can take place over a period of time.
• said silver deposits do not form an adherent or coherent mass or plate on the cathode.
• further deposits of silver are formed on the surface of the deposits, already formed.
• the silver particles form aggregations which are then removed from the cathode by various methods, including sweeping or brushing techniques of the type known in the art.
• an antimicrobial preparation for use in the treatment of infections, diseases and/or disorders, comprising a therapeutically effective amount of the antimicrobial composition, as described and identified herein, in combination with one or more suitable/acceptable excipients, additives or carriers.
• treatment of infection, diseases and/or disorders is intended to be understood as covering prophylactic, alleviating and curative interventions.
• the antimicrobial composition and/or antimicrobial preparation aids, supports, augments and accelerates the healing processes for, inter alia, wounds and invasive trauma.
• the term "effective amount” refers to that amount of antimicrobial composition that is required to provide therapeutic benefit.
• the present invention is not limited by the nature or scope of the therapeutic benefit provided. The degree of benefit may depend on a number of factors, inter alia, the severity of the infection, disease and/or disorder and the immune status of the individual.
• the excipients, additives and carriers may include, but are not limited to including, proteins, peptides, amino acids, lipids, carbohydrates (e.g.
• sugars including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars, polysaccharides or sugar polymers), mineral oils and the like, which can be present singly or in combination.
• the antimicrobial preparation to possess activity towards cancer cells.
• the present invention provides a method of treating a patient suffering from an infection, disease and/or disorder comprising the step of administering to such patient a therapeutically effective amount of the antimicrobial composition, as described and identified herein, or an antimicrobial preparation, as described and identified herein.
• the invention further provides for the use of the antimicrobial composition, as described and identified herein, for the treatment, diagnosis and/or prevention of diseases and/or disorders.
• one or more agents may be used in combination with the present antimicrobial composition.
• the invention also contemplates the use of nutritional agents in combination with the antimicrobial composition of the present invention.
• nutritional agents include, but are not limited to, nutrients, nutriceuticals, minerals, vitamins, amino acids and essential fats.
• Non-limiting examples of the agents contemplated for use with the antimicrobial composition of the present invention include acne preparations such as isotretinoin, benzoyl peroxide, salicylic acid and tetracycline; anesthetics for topical administration such as dibucaine, lidocaine, benzocaine, tetracacine, deperodon and pramoxine hydrochloride; anti-inflammatory agents such as betamethasone benzoate, betamethasone valerate, desonide, fluocinolone acetonide, halcinonide, hydrocortisone; antiperspirants; antipruritic and external analgesic agents such as camphor, menthol, salicylic acid, methylsalicylate; cleansing agents; pigmenting agents; anabolic steroids for building up tissues under wound healing such as methandienone; proteolytic agents for the decomposition of fibrin such as trypsin; vasodilating substances for improving the flow of blood during wound healing such as tol
• administration methods which may be used in accordance with embodiments of the present invention include oral administration, injection, topical administration, intravenous administration, rectal administration, transdermal administration, ophthalmic administration, lymphatic administration and nasal administration.
• the antimicrobial composition and/or antimicrobial preparation can be applied using gloved hands or by an applicator. Likewise, the composition and/or antimicrobial preparation can be applied to the surface of a dressing, which can then be applied topically.
• Topical administration can be carried out using, inter alia, sprays, mists, lotions, creams, ointments, or gels which are formulated to include the antimicrobial composition and/or antimicrobial preparation of the present invention.
• Submersion of the diseased or otherwise infected tissue is also an acceptable means of topical administration.
• Ophthalmic infections can be treated using standard procedures in the art, such as by pulling down the lower eyelid to form a pocket and applying the antimicrobial composition and/or antimicrobial preparation thereto.
• infections of the mouth can be treated by applying the antimicrobial composition and/or antimicrobial preparation with a sponge applicator or a toothbrush.
• the mode of administration can be dependent on the disease or infection being treated and the formulated potency of the composition.
• antimicrobial composition and/or antimicrobial preparation of the present invention can be administered for clinical use in humans and for veterinary use, such as with domestic animals, in manners known in the art and similar to other therapeutic agents.
• the present antimicrobial composition and/or antimicrobial preparation may be administered for horticulture as well as agriculture use. It is further envisaged that the present antimicrobial composition and/or antimicrobial preparation may be administered for the treatment of raw materials including, but not limited to, food and water.
• antimicrobial composition and/or antimicrobial preparation of the present invention can be incorporated with other ingredients to form a variety of products for administration, as detailed herein below.
• the antimicrobial composition and/or antimicrobial preparation may be made up in any suitable dosage formulation and may be prepared by conventional techniques.
• the dosage formulation comprises tablets, capsules, caplets, syrups, beverages, powders, granulates, lozenges or the like.
• the formulation may contain any suitable excipients such as fillers, lubricants, disintegrants, taste masking agents and the like.
• the antimicrobial composition and/or antimicrobial preparation of the present invention may be used in cosmetics and personal care products to make said products resistant to antimicrobial contamination.
• Non-limiting examples thereof include creams, ointments, sunscreens, mouth rinses, toothpastes, dental flosses, gels, moisturizers, foams, powders, liquid and powder makeup foundations, powder and cream blushes, lipsticks and lip-glosses, lip pencils, mascaras, eye liners, eye shadows, perfumes, colognes, deodorants, toners, wipes for skin application, dermal patches, shaving creams, shampoos, conditioners and various hair treatments like mousses and sprays.
• the antimicrobial composition and/or antimicrobial preparation may be incorporated in aerosols and sprays for topical or inhalation application.
• antimicrobial composition and/or antimicrobial preparation may be used in or applied to, inter alia, bandage dressings, sponges, surgical and examination gloves, combs, brushes, cotton swabs, razors and toothbrushes.
• the antimicrobial composition of the present invention may be incorporated into medical devices including, but not limited to medical implants and wound care devices and can be used to impart antiseptic and disinfectant properties to medical appliances and utensils.
• the antimicrobial composition may be used in applications to sterilize surfaces.
• Medical implants include, but are not limited to, urinary and intravascular catheters, dialysis shunts, wound drain tubes, endotracheal breathing tubes, skin sutures, vascular grafts and implantable meshes, intraocular devices and heart valves.
• the composition of the invention can also be used in, inter alia, bone prostheses and reconstructive orthopaedic surgery.
• Wound care devices include, but are not limited to, general wound dressings, non-adherent dressings, burn dressings, biological graft materials, tape closures and dressings and surgical drapes.
• the appropriate dosage of the antimicrobial composition, antimicrobial preparation and/or formulation of the present invention, as indentified herein, will depend on, inter alia, the type of infection, disease or disorder to be treated, as is defined herein below; the severity and course of the infection; whether the antimicrobial composition, antimicrobial preparation and/or formulation is administered for therapeutic or preventive purposes; previous therapy and the patient's clinical history and response to the composition.
• the antimicrobial composition, antimicrobial preparation and/or formulation of the present invention is/are suitably administered to a patient at one time or over a series of treatments.
• the administration can occur one or more times daily for a period of 1 day to 360 days. In another embodiment, the administration can occur one or more times daily for a period of 1 to 7 days. In another embodiment, the administration can occur one or more times for a period of 4 hours to 24 hours. In a further embodiment of the invention, single administration will suffice.
• the disease symptoms and parameters for assessing improvement and the progress of the therapy can be readily monitored by conventional methods and assays known to the physician or other persons of skill in the art.
• the amount of antimicrobial composition, antimicrobial preparation and/or formulation may not be as important, but rather, the concentration thereof and the frequency of administration may be more significant.
• the present invention relates to methods of treating (including prophylactically treating) viral infections, bacterial infections, fungal infections, parasitic infections and/or cancer.
• the invention is envisaged to have a regenerative effect on damaged tissue thereby facilitating and expediting the healing process.
• viral infections which may be treated using the methods and/or composition, preparation and/or formulation of the present invention include, without limitation, HIV/AIDS infection, herpes virus infection, viral dysentery, flu, bronchitis, pneumonia, measles, rubella, chickenpox, mumps, polio, rabies, sinusitis, tonsillitis, mononucleosis, ebola, respiratory syncytial virus, croup, SARS, dengue fever, yellow fever, lassa fever, arena virus, bunyavirus, filovirus, flavivirus, hantavirus, rotavirus, viral meningitis, H5N1 virus (bird flu), arbovirus, parainfluenza, smallpox, epstein-barr virus, dengue hemorrhagic fever, cytomegalovirus, infant cytomegalic virus, progressive multifocal leukoencephalopathy, viral gastroenteritis, hepatitis, cold sores, meningitis,
• bacterial infections which can be treated and prevented using the methods and/or composition, preparation and/or formulation of the present invention include, without limitation, tuberculosis, cholera, syphilis, bacterial pneumonia, Escherichia coli (e. coli) infections, Candida infection, RSA methicillin resistant Staphylococcus aureus (S. aureus) infection - strain ATCC #43300, vancomycin resistant Enterococcus faecalis (E. faecalis) infection - strain #1061 , salmonella enteritidis (S. enteritidis) infection - strain ATCC #13076, Clostridium difficile (C.
• fungal infection which can be treated and prevented using the methods and/or composition, preparation and/or formulation of the present invention include, without limitation, thrush, candidiasis, cryptococcosis, histoplasmosis, blastomycosis, aspergillosis, coccidioidomycosis, paracoccidiomycosis, sporotrichosis, zygomycosis, chromoblastomycosis, lobomycosis, mycetoma, onychomycosis, piedra pityriasis versicolor, tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea favosa, tinea nigra, tinea pedis, otomycosis, phaeohyphomycos
• the present invention also provides methods for treating cancerous tissue in a subject.
• the present invention has been shown to be effective in reducing the size of and even eliminating cancerous tumors.
• the types of cancers which can be treated using the methods of the present invention include, without limitation, melanomas of the skin, lung and/or bronchus cancers, colon and rectum cancers, urinary bladder cancer, pancreatic cancer, ovarian cancer, thyroid cancer, stomach cancer, brain cancer, cervical cancer, testicular cancer, lymphomas, breast cancer, prostate cancer, cancers of the blood, cancer of the bones and joints, and the like.
• the invention contemplates methods for treating cancerous tissue in a subject in conjunction with chemotherapies and radiothereapies.
• the present invention further provides methods for treating respiratory diseases in a subject including, but not limited to, asthma, Tuberculosis (TB) and pulmonary fibrosis.
• respiratory diseases including, but not limited to, asthma, Tuberculosis (TB) and pulmonary fibrosis.
• Figure 1A is a graph depicting particle size distribution of the silver aggregations of the present invention measured at 15 minute intervals in accordance with the analysis conducted in Example (ii);
• Figure 1C shows photographs depicting a comparative analysis to demonstrate the efficacy of the friable silver aggregations as antimicrobial agents when compared to a commercial silver colloid product
• Figure 7 is a photograph depicting the results of a disk diffusion test to compare the silver aggregations employed in Example (iii) and the silver aggregation employed in Example (iv) in their activity against S, enteritidis wherein PBS Tween was the negative control;
• Figure 8 is a photograph depicting the results of a disk diffusion test using S. enteritidis grown on Mueller-Hinton agar wherein the silver aggregations were used at 1.0 and 5.0 % w/v;
• Figure 9 is a graph depicting a biocide challenge assay against S. enteritidis;
• Figure 10 is a photograph depicting the results of a biocide challenge assay showing the effects on S. enteritidis after 20 minutes of contact with the silver aggregations.
• the plates show the effect of the silver aggregations at 1.0% w/v (far left) and 0.1 w/v (middle).
• the control plate on the far right illustrates the growth of S. enteritidis without the addition of the silver aggregations of the present invention
• Figure 13 is a graph depicting the results of a test patient's white blood cell (WBC) count whilst receiving treatment comprising 3 ml of Formulation A, three times per day;
• WBC white blood cell
• the current to the electrolytic cell can be adjusted by varying the voltage, by moving the anode and cathode closer or further apart or by increasing the number of plates.
• the current density was set in the range of 0.0008 to 0.002 amps/sq cm.
• a desired current of 4 to 10 amps is employed.
• the anode employed comprises fine silver sheets having a purity of 99.9% or higher.
• Silver sheets were sized according to a 250 mm x 250 mm square dimension. Depending on the nature (for instance, the geometry) of the silver employed, the size thereof will be manipulated to complement the apparatus employed.
• the silver sheets were suspended from current-carrying rods or clips and were arranged in parallel connection to the voltage source. Both sides of the silver sheet can be active during electrolysis.
• multiple anodes may be arranged within the electrolytic cell.
• the cathode employed may comprise an inert conducting material.
• the cathode employed is in the form of stainless steel. However, it will be appreciated that any other suitable inert material can be employed, for instance, carbon.
• the cathode may comprise silver.
• the dimensions of the cathode were similar to those provided for the dimensions of the anode.
• the one or more cathodes were suspended within the electrolytic cell so as to alternate with the anodes.
• the cathodes were suspended from current-carrying rods or clips and were arranged in parallel connection to the voltage source.
• multiple cathodes may be arranged within the electrolytic cell.
• the loose particulate deposit was removed from the cathode, either by way of being swept, brushed or otherwise removed there from and collected.
• the collected product comprised aggregations of silver particles, said aggregations being 100 x 10 "9 m to 10000 x 10 "9 m in size as measured by Dynamic Light Scattering analysis (DLS).
• the resulting aggregations were friable to the touch and when applied wet as a drop to an absorbent surface showed a cortex or corona displaced from the centre, indicating the ease with which the aggregations fracture to smaller entities.
• the aggregations were preferably kept wet although they may be dried for alternative use such as blends with petroleum products, e.g. Vaseline, to produce creams and ointments.
• petroleum products e.g. Vaseline
• a cream can be prepared by blending 1 g of the silver aggregation, in dry form, (as mentioned in Example (i)(a) herein above) with 10 g of petroleum jelly to produce an ointment or cream. This may then be applied topically or applied to a bandage, plaster, etc.;
• Said silver aggregation in dry form, can be blended with a setting resin plastic gel and applied to a prosthesis or device as a thin film to become integral with the device.
• a setting resin plastic gel for example, 1 g of the antimicrobial composition, in dry form, is blended with 10 g of silicone paste. The resulting formulation is then applied to a plastic medical tube and is allowed to set to form a thin coating;
• the antimicrobial composition presented as a dry material in dry form, can be tabletted at 0.01 g per tablet in an inert carrier of the type known in the art;
• the antimicrobial composition either presented as a wet or dry material where appropriate, can be blended to form creams, emulsions, etc. Analyses of the properties of the antimicrobial composition
• Table B Surface area values obtained for the silver aggregation, in dry form
• a factor of 10% (100:1 ) of the above value is considered conservative, especially when it is appreciated that the initial silver aggregations of Formulation A prior to agitation are shown by DLS to have diameters averaging 4000 d nm and above, which would further augment the potential increase in surface area on fracturing.
• Table C Surface area values at varying silver concentrations of Formulation A following the influence of mechanical agitation
• Formulation A has a surface area of 5400 cm 2 /ml following mechanical agitation when compared to the highest value of 104.7 cm 2 /ml for a commercial silver colloid, as is indicated in Table A presented herein before. This demonstrates a greater than 50 times increase in surface area. Further potential fracturing up to 100% gives an increase of 500 times in surface area.
• a 1000 ppm stock solution of the antimicrobial composition was prepared by 10:1 dilution of Formulation A.
• Record 6 in Figure 1 A indicates that the silver aggregations below 1000 nm in the aliquot have an initial size of 400 nm. After sonication for 15 minutes (Record 7), the silver aggregations have started to fracture/dissociate with diminution of the 400 nm peak and the formation of smaller silver particulates around 80 nm. After further sonication (Records 8 and 9), a further size reduction at 400 nm and further fracturing from 80 nm down to 40 - 50 nm is observed. This collectively demonstrates the fracturing of the silver aggregations at 400 nm into silver particulates at 40 to 50 nm.
• Figure 1 B is a pre-sonication photograph showing the typical range of aggregation sizes and geometries of the friable silver aggregations under an optical magnification of x400.
• a 10 ppm commercial silver colloid product was employed for purposes of the comparative evalution.
• a laboratory produced stock solution of the aforesaid microbial culture was used to dose the aliquots, as indicated in Table D below. pH and salinity were adjusted for test samples 7 to 12 to correspond qualitatively to conditions that can exist in ambient bodily fluids such as the stomach (typically a pH of 2 to 4). Individual 0.1 ml samples were drawn from the aforesaid prepared solutions and striped down petri dishes, pre-prepared with nutrient agar.
• the bacterial strains used in the study were:
• MRSA Methicillin-resistant Staphylococcus aureus
• a stock suspension of the silver aggregations was prepared (20% w/v in sterile phosphate- buffered saline with 0.1% v/v Tween; Sigma-Aldrich Ltd, UK).
• Figure 5 demonstrates the effects of a streak of the silver aggregations (20.0% w/v) on the growth of MRSA. Similar results were observed with £ coli and P. aeruginosa (photographs not shown). Table 1 : Mean diameters (with standard errors) of the zones of inhibition for each of the bacterial species and dilutions of the silver aggregations tested
• Example (i)(a) above 0.5 g of the silver aggregations, as prepared in Example (i)(a) above, was provided in dry form.
• the bacterial species used in the study were:
• Clostridium difficile an anaerobic bacteria, American Type Cell Collection (ATCC) #9689; 2) Vancomycin-resistant Enterococcus faecalis (#1061 ), an aerobe, obtained from the strain collection of Professor C. Dowson, Dept of Biology, University of Warwick; and
• a stock suspension of the silver aggregations was prepared (10% w/v in sterile phosphate- buffered saline with 0.1% v/v Tween; Sigma-Aldrich Ltd, UK).
• Anaerobic conditions for incubation were achieved using the AnaeroGen Compact system from Oxoid.
• the system consists of a plastic pouch and a paper gas-generating sachet.
• the paper sachet contains ascorbic acid and activated carbon which react on contact with air. Oxygen is rapidly absorbed and carbon dioxide is produced.
• the AnaeroGen Compact sachet reduces the oxygen content in the pouch to below 1.0% within 30 minutes.
• the resulting carbon dioxide content is between 8.0% and 14.0% depending on how many plates are placed in the pouch.
• Example (i)(a) above The silver aggregations as prepared in accordance with Example (i)(a) above were tested at 5.0 and 1.0% w/v using the disk diffusion method under anaerobic conditions using a blood anaerobe agar (Table 2). C. difficile was inhibited by the aggregations at both dilutions tested. The zones of inhibition were accompanied with zones of haemolysis (clearing of the blood agar) of identical size.
• Table 2 Mean diameters (with standard errors) of the zones of inhibition for each of the bacterial species and dilutions of the silver aggregations tested
• Oxoid ' Iso-Sensitest Agar' was developed specifically for antimicrobial susceptibility tests. Its formulation was carefully constructed to give a reproducible, semi-defined medium in which the undefined components were kept to a minimal level. However, it allows the growth of the majority of microorganisms without further supplementation.
• Agar 8.0 Mueller-Hinton Agar is an antimicrobial susceptibility-testing medium that may be used in internationally recognised standard procedures having a pH of 7.3 ⁇ 0.1.
• Filter paper 1 represents a colloidal silver 10 ppm solution applied to test filter paper.
• Filter paper 2 represents the antimicrobial composition of the present invention, as prepared in accordance with Formulation A, at 100 times dilution applied to test filter paper.
• Filter paper 3 represents the antimicrobial composition of the present invention, as prepared in accordance with Formulation A, at 10 times dilution.
• Filter paper 4 represents the antimicrobial composition of the present invention, as prepared in accordance with Formulation A, at no dilution and filter paper 5 represents a blank control.
• the zone of bacterial inhibition is an indicator of bacterial growth inhibition efficacy.
• this solution is to be taken three to four times a day, approximately 5 minutes before meals.

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