IMPROVED PATHOGEN INHIBITOR

Abstract

A formulation of a pathogen inhibitor or probiotic as a slurry concentrate of a hydrated metal oxide for applications in agriculture, aquaculture, and as an anti antibiotic in which the bioactivity, when applied by dilution, is controlled by a precursor of Reactive Oxygen Species, and the release rate is controlled by the particle size. The invention may include a means whereby the precursor concentration may be controlled to meet the requirements of the ecosystem, from the maintenance of an aerobic system, to killing pathogenic, anaerobic microbes, or producing sterile ecosystems. In addition, the metal oxide may be selected to provide essential nutrients for growth of the agricultural or aquacultural products.

Claims

1. An agricultural spray comprising a formulation adapted for use in agricultural applications, the formulation comprising; a slurry comprising particles and a fluid, in which the particles include a uniform distribution of magnesium hydroxide and magnesium peroxide with a relative molar ratio that is formulated to provide sufficient alkali and reactive oxygen species such that an ecosystem is promoted; providing magnesium to the plant as a fertilizer, when diluted and sprayed onto the leaves of a plant as a folia spray; and wherein at least one of the magnesium hydroxide and the magnesium peroxide make up at least 30% by weight of the formulation.

2. The agricultural spray as claimed in claim 1, wherein the particles include a pathogen inhibitor.

3. The agricultural spray of claim 1, wherein the particles are of a particle size distribution in the range of about 0.3-100 microns.

4. The agricultural spray of claim 3, wherein the particle size distribution includes a mean particle size of between 10-20 microns.

5. The agricultural spray of claim 4, wherein the content of solids is at least 35% by weight, and preferably 60% by weight.

6. The agricultural spray of claim 5, wherein the formulation is diluted to 2% for at least one of spraying and dosing.

7. The agricultural spray of claim 6, wherein the magnesium hydroxide content is at least 50% by weight.

8. The agricultural spray of claim 7, wherein the combined magnesium hydroxide and calcium carbonate content is at least 80% by weight, and the calcium to magnesium ratio on a molar basis is at least 35%.

9. The agricultural spray of claim 1, wherein the promoted ecosystem is a healthy ecosystem.

10. The agricultural spray of claim 9, wherein the magnesium peroxide to promote the healthy ecosystem is formed in the slurry by adding at least one precursor to generate the magnesium peroxide.

11. The agricultural spray of claim 10, wherein the at least one precursor is a reactive precursor comprising hydrogen peroxide.

12. The agricultural spray of claim 1, wherein the magnesium peroxide to magnesium hydroxide content on a molar basis is determined by the requirement of maintaining the health of the respective ecosystem, including the presence or potential presence of pathogenic microbes that would otherwise induce necrosis of the host unless the formulation was applied.

13. A method of applying the agricultural spray of claim 1, wherein a dose rate of a concentrate is at least 3 kg/Ha per application, and the time between applications is determined solely by the loss of coverage of a powder on the leaf.

14. The agricultural spray of claim 1, in which the magnesium peroxide is formed in the process of manufacture of the slurry, without the need for specific addition of compounds that produce magnesium peroxide, and wherein the magnesium peroxide to magnesium hydroxide content on a molar basis is determined by the requirement of maintaining the health of the respective ecosystem, including the presence or potential presence of pathogenic microbes that would otherwise induce necrosis of the host unless the formulation was applied.

15. The agricultural spray of claim 1, wherein the magnesium peroxide does not meet the requirements of claim 12 and wherein additional magnesium peroxide is added to the formulation, or formed by the addition of precursors such as hydrogen peroxide.

16. The agricultural spray of claim 1, wherein the fluid comprises water.

17. A formulation for producing a pathogen inhibitor concentrate formulation, wherein the formulation comprises a mixture of particles and fluid in a slurry, in which the particles include a uniform distribution of magnesium hydroxide, calcium carbonate and magnesium peroxide with a relative molar ratio that is formulated to provide sufficient alkali and reactive oxygen species to maintain a healthy ecosystem, and to provide magnesium and calcium to fish as a food, when diluted and dosed into the fluid, in which at least one of the magnesium hydroxide and the magnesium peroxide make up at least 30% by weight of the formulation.

18. A formulation for a topical ointment, wherein the formulation comprises a mixture of particles, fluid and viscosity modifiers and stabilizers, in which the particles include a uniform distribution of magnesium hydroxide and magnesium peroxide with a relative molar ratio that is formulated to provide alkali and reactive oxygen species to maintain a healthy ecosystem, in which at least one of the magnesium hydroxide and the magnesium peroxide make up at least 30% by weight of the formulation.

19. A bandage formulation comprising particles, fluid and setting agents, in which the particles comprise a uniform distribution of magnesium hydroxide and magnesium peroxide with a relative molar ratio that is formulated to provide alkali and reactive oxygen species to substantially inhibit migration of a pathogen through a bandage, in which at least one of the magnesium hydroxide and the magnesium peroxide make up at least 30% by weight of the formulation.

20. The formulation of claim 17, wherein the fluid comprises water.

Description

DETAILED DESCRIPTION

[0043] Embodiments of the disclosure will be better understood and readily apparent to one of ordinary skill in the art from the following written description, by way of example only.

[0044] Preferred embodiments of the disclosure will now be described with reference to the non-limiting examples. The disclosure is related to a slurry of solids in water, which is a concentrate which is diluted for spraying or dosing. The solids comprise a hydrated metal oxide and one or more precursors for the generation of ROS.

[0045] The preferred product is stable, 60% solids slurry as a concentrate, with a particle size distribution preferably between 0.3 and 100 microns in which the ROS precursors are uniformly distributed in each particle. The viscosity of the concentrate should be less than 250 cP, and preferably less than 100 cP to allow for use in dosing systems, and for storage and transport. The formation of a gel, and syneresis, should be minimized. The resistance of the gel that does form should be low, so that the product can be readily fluidized by stirring. The production of magnesium hydroxide slurry with these properties is described by Sceats and Vincent in WO 2015/058236 A1 (incorporated herein by reference). An object of this disclosure is to optimize the bioactivity of such slurries.

[0046] The primary basis for the examples are that the ROS precursors in the particles can be intrinsic precursors formed during the preparation of the oxide and the hydration of the oxide to form the slurry, and, in addition, precursors formed by synthetic precursors using a reagent added during this slurry preparation process. It will be apparent to a person skilled in the art that the control of the ROS precursor concentration in the particles is desirable, given the sensitivity of the ecosystems described above to ROS. Such a control during manufacturing may produce a slurry that has a specified redox potential to achieve a mild bioactivity, and which the ROS concentration is used to sustain an existing aerobic environment, or a slurry with an intermediate bioactivity in which the ROS is sufficiently high that pathogenic, anaerobic microbes are killed, but aerobic bacteria that provide positive synergy to the ecosystem are not adversely impacted, or a slurry that has a very high ROS concentration that kills all the microbes in the ecosystem, and which produces a sterile surface. Users of these products can determine the impact they wish to have, ranging from a preventative measure that sustains an ecosystem, to a high impact measure, which combats pathogenic colonies that have taken control of the ecosystems, and which may already have induced infection and possible necrosis to the host organism. In the case of magnesium, the dosage of magnesium for fertilization can, therefore, be independently controlled. This flexibility is an important feature of the present disclosure.

[0047] Another basis for the examples is the controlled release of the ROS into the ecosystem. Controlled release is a known art in pharmaceuticals in which an active compound, generally uniformly distributed into a particle, is released as the particle is slowly dissolved. The particle size distribution can be used to produce the desired response. Dissolution occurs from the external surface at a constant rate (in m/s), for particles having the same surface area. Thus large particles can provide a source of ROS over an extended period of time, as all the particles gradually dissolve. Magnesium hydroxide is relatively insoluble in water, and is gradually dissolved because it is a source of alkali, and is therefore consumed at a rate that depends on the difference of the pH of the ecosystem compared to the intrinsic pH of magnesium hydroxide, of 10.4. The product user can specify the duration required for the generation of ROS through specification of the particle size distribution and the particle surface area. This capability does not exist for nanoparticles.

[0048] Consider firstly the production of ROS from intrinsic precursors, for the case of a magnesium hydroxide slurry. The prior art shows that a slurry produced from conventional caustic magnesia produces a transient biocidal impact, and this arises from the low density of ROS precursors because of the low density of defects on the large stable surfaces of the magnesia. The primary indicator of the density of defects is the specific surface area by volume of the particles, SSAv. Thus an SSAv of 400 m.sup.2/cm.sup.3 in the magnesia will have a higher precursor density than magnesia with an SSAv of 10 m.sup.2/cm.sup.3. The SSAv of magnesia can be controlled by sintering of the magnesia, which causes the micropores of the particles to collapse to form mesopores as the surface energy is reduced, and it is the reduction of the surface energy that eliminates the crystal defects that generate ROS during hydration. The highest ROS will be generated from the highest SSA materials, and there are a number of production processes that can be used to produce high surface area magnesia. One such process is described by Sceats and Horley, in WO 2007/112496 (incorporated herein by reference), using flash calcination of magnesite in an indirectly heated reactor in which the external heating gas flows in a counterflow to the calcining particles. Sintering of those particles at a high temperature, in steam or CO.sub.2, can be used to produce the desired SSAv. The particle size distribution can be controlled during the grinding process, either pre- or post-calcination, or as part of a hydration process during wet grinding of magnesia.

[0049] Consider secondly, the synthesis of the ROS precursors. It is desirable that the reaction takes place homogeneously within the particle in such a way that the active species is formed uniformly with the magnesia particle. In the case where magnesium peroxide is the active compound, hydrogen peroxide can be used to react with magnesia to form magnesium peroxide in an exothermic reaction. This process is a known art, and produces, if allowed to go to completion, particles that are about 30% magnesium peroxide by weight. The magnesium peroxide is stable below 100° C., above which it begins to decompose to give oxygen, and the reaction is generally carried out at 50° C. The synthesis route is not prescribed in this disclosure. Production may take place as a gas phase reaction, or in the slurry. For high surface area magnesia, the preferred process is a gas phase process on the very high porosity magnesia particles at a temperature and pressure such that the homogeneous material is produced. Alternatively, in a wet grinding process using large magnesium oxide granules, the hydrogen peroxide may be added to the water and reacts with the particles as they are ground and hydrated, or is added in a subsequent synthetic process. Generally, the hydrogen peroxide is dosed into the system to give the desired concentration of ROS precursors in the particle, including the intrinsic ROS.

[0050] Another approach to control the precursors is to heat a powder containing excess magnesium peroxide to about 150° C., for a controlled time, to decompose the peroxide sufficiently to achieve the desired activity. Alternatively, a slurry of such material can be heated to about 70° C. for a period of time. In both cases, the excess peroxide forms oxygen gas. Heating can be used be adjust the activity of any powder or slurry to meet the requirements of the application.

[0051] For applications in aquaculture, the size distribution of the particles is important. Small particles, typically less than 5 microns, are buoyed by Brownian motion, move with currents, and drift slowly downwards under the force of gravity. Larger particles fall quickly to the base of the pen. The residence time of a particle in each of the ecosystems depends on the particle size. The particle size distribution, such a fine or coarse grade, can be optimized for delivery of ROS and alkali to each system as required. In addition, the growth of fish is determined by the calcium content of the ingested food, and the particles can be processed from dolomite as a feedstock to produce a particle in which the degree of calcination of the magnesium site and the calcium site is controlled to selectively remove CO.sub.2 from the magnesium oxide site to form a material semidolime MgO.CaCO.sub.3. When processed to a slurry with the desired ROS levels, the product has both magnesium and calcium as nutrients for the growth of the fish. The stock in the pond benefits from the nutrients, as well as from living in the water and pond base ecosystems that are healthy and aerobic.

[0052] The pathogen inhibitor activity of the slurry has been established using in vitro measurements and in preliminary crop trials. For in vitro studies, the slurry is diluted to 2% by the addition of water, and is sprayed into a prepared Petri dish in which a dot of the fungus, bacteria, or virus strain under test has been incubated and grown over 24 hours. The rate of growth of the radius is measured over a period, and the biocidal impact is measured by the extent that the ring growth rate has been suppressed. Studies were completed on a number of fungi, and a broad spectrum antifungal impact was observed, and is comparable to commercial fungicides.

[0053] For preliminary crop trials, a number of crops such as grapes, avocados and bananas exhibiting fungal outbreaks were sprayed with the diluted slurry, and the biocidal impact measured by the healthiness of the crop, especially with regard to the presence of fungi, compared to a field that was not sprayed. On inspection, after 7 days, the fungi were not observable on the sprayed area. It was noted that the powder had a strong adherence to leaves, and that the leaf appearance had improved indicating that the magnesium was being adsorbed into the plant and promoting greater photosynthesis. Such leaf characteristics include the color and leaf thickness.

[0054] In trials of insecticide response, a sample of insect ridden wheat was dusted with magnesium oxide powder. After several days, the insect count had decreased considerably, and with a response that was similar to dehydrated diatomaceous earth.

[0055] The slurry described herein is not generally deployed as a pathogen inhibitor at 60% solids. It is a concentrate that is used to make pathogen inhibitors for different applications. The means of application of pathogen inhibitors in agriculture is preferably through a sprinkling system to avoid losses to the crop from wind. A common means is to use a slurry of the materials, which is diluted by the spray water to about 2%. This foliar spray approach has wide industry acceptance. In that case, a material based on magnesium hydroxide has an added benefit of providing a source of magnesium, which is an essential nutrient for photosynthesis. A spray should preferably have particles that are less than 100 microns, and preferably 25 microns, diameter to avoid blockage of the nozzle. The use of a spray may also be applicable for medical applications. However, in that area, there is also an application for the incorporation of the material in a mask to reduce infection from airborne microbes, or a wipe to remove microbes from surfaces.

[0056] In another application, the slurry should be mixed with existing biocides as adjuvants. This includes conventional water soluble biocides, typically molecular, which adsorb onto the particle to deliver a desired biocide activity. The formation of emulsions with oils that contain oil soluble adjuvants is another such application.

[0057] In a further embodiment, the aforementioned slurry may be mixed with other compounds to form a topical cream for the treatment of wound dressings. Preferably, the water component of the abovementioned slurry may further incorporate a standard topical cream with additives including sorbolene.

[0058] In a further embodiment, the slurry may be applied to a wound dressing wherein a medical bandage is soaked for at least 10 minutes in a solution or formulation comprising the aforementioned slurry. The bandage then preferably takes on some of the pathogen inhibitor qualities of the slurry.

[0059] In this specification, the word “comprising” is to be understood in its “open” sense, that is, in the sense of “including,” and thus not limited to its “closed” sense, that is the sense of “consisting only of” A corresponding meaning is to be attributed to the corresponding words “comprise,” “comprised” and “comprises” where they appear.

[0060] While particular embodiments of the present invention have been described, it will be evident to those skilled in the art that the present invention may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiments and examples are therefore to be considered in all respects as illustrative and not restrictive, with all changes that come within the meaning and range of equivalency therefore intended to be embraced therein. It will further be understood that any reference herein to known prior art does not, unless the contrary indication appears, constitute an admission that such prior art is commonly known by those skilled in the art to which the invention relates.

[0061] Although embodiments of the invention have been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms, in keeping with the broad principles and the spirit of the invention described herein.