NL2030858B1 - Sprayable composition and use thereof in the treatment and prevention of epithelial infections in animals - Google Patents
Sprayable composition and use thereof in the treatment and prevention of epithelial infections in animals Download PDFInfo
- Publication number
- NL2030858B1 NL2030858B1 NL2030858A NL2030858A NL2030858B1 NL 2030858 B1 NL2030858 B1 NL 2030858B1 NL 2030858 A NL2030858 A NL 2030858A NL 2030858 A NL2030858 A NL 2030858A NL 2030858 B1 NL2030858 B1 NL 2030858B1
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- NL
- Netherlands
- Prior art keywords
- copper
- composition
- zinc
- composition according
- chelates
- Prior art date
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Classifications
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- 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
- A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
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- A—HUMAN NECESSITIES
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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Abstract
Provided herein are sprayable compositions comprising one or more synthetic resins and micronized copper and zinc chelates. More particularly, the compositions comprise micronized copper and zinc chelates, and synthetic resins suspended in the same or a distinct liquid. Provided herein is also a method for preparing the sprayable compositions. Also provided herein is the use of said composition for the treatment of an epithelial infection in an animal.
Description
SPRAYABLE COMPOSITION AND USE THEREOF IN THE TREATMENT AND PREVENTION OF
EPITHELIAL INFECTIONS IN ANIMALS
The present inventions relates to sprayable formulation for the treatment and prevention of infections of epithelia in animals.
Farm animals such as swine, sheep, goats, horses, and cattle are prone to infectious diseases of the skin, such as exudative epidermitis, digital dermatitis {hairy hoof warts}, hoof rot (interdigital phlegmon), stable hoof rot (interdigital dermatitis), Digital Dermatitis, also known as “Papillomatous digital dermatitis" (PDD) or foot rot, and udder cleft dermatitis. Farm animals are also susceptible to non-infectious diseases such as navel infections and secondary wound infections by opportunistic pathogens after for example castration, tail clipping, or tail or ear biting. These conditions cause stress to the animals and can affect weight gain, reproductive rates, and in the case of sheep, wool production. Skin disease in a swine herd can cause a significant decrease in growth rate and feed efficiency. Hoof ailments in milk cattle may result in reduced milk production, reduced fertility, and increased risk of mastitis. Furthermore, skin ailments demand much more work and more treatment costs often leading to premature removal of the affected animals.
The infected animals are preferably separated away from the herd as soon as possible to prevent the infection from spreading. Current treatment consists in cleaning the foot thoroughly, clipping the hoof with subsequent treatment with an antimicrobial product. Infectious diseases of the hoof can be prevented and treated by utilizing a foot bath or footwrap with zinc sulfate and copper sulfate, but also other germicides such as hydrogen peroxide, or even an antibiotic can be used.
There is a continuous need for improved treatments effective against hoof infections, in particular foot rot, stable foot rot, and PDD, that is affordable, that is convenient to apply and that has a prolonged effect. One or more of these needs are met by the present invention.
Present inventors have developed a formulation, more particularly sprayable formulation, comprising a synthetic resin and micronized copper and zinc chelates. Present inventors have found that when applying such formulation to an area of infection or susceptible to infection in the skin or hoof of an animal, such formulation will not be easily rinsed off with water. Moreover, to their surprise, present inventors found that the micronized copper and zinc chelates were only gradually released (i.e. no burst release} from the formulation as taught herein to the area of infection or susceptible to infection, such as to the epithelial cells of the lesion site. Accordingly, the formulation as taught herein allows a prolonged antimicrobial, antifungal and/or anti-inflammatory activity of the formulation, as well as allowing a better stimulation of formation of new blood vessels (angiogenesis), skin regeneration and re-epithelialization, compared to a formulation comprising micronized copper and zinc chelates in the absence of a synthetic resin.
In addition, the sprayable formulation as taught herein also allows to keep any dirt or other contaminants out of the area of infection or susceptible to infection. Accordingly, the sprayable formulation as taught herein also makes the application of a bandage over the area of infection or susceptible to infection superfluous, thereby making the treatment faster and more convenient, reducing the stress on the treated animal. Finally, the use of the formulation according to the invention also avoids (i} additional stress on the treated animal caused by the use of bandages, such as by the removal of bandage, (ii) the risk of forgetting to remove the bandage, which may lead to new wounding and infections, and (iii) the risk of any bandages ending up in the manure of the animals.
Accordingly, a first aspect provides a sprayable composition comprising one or more synthetic resins and micronized copper and zinc chelates. In particular embodiments, said composition comprises from 5.0 to 15.0% (w/w) of one or more synthetic resins and from 0.6 to 35.0% (w/w) of micronized copper and zinc chelates. The amount of from 0.6 to 35.0% (w/w) of micronized copper and zinc chelates refers to the total amount of the micronized copper chelates and the micronized zinc chelates present in the sprayable composition as taught herein,
In particular embodiments, the one or more synthetic resins are selected from the group consisting of an acrylic resin, a polyacrylic resin, glycerol phthalate, abietic acid glycerol, an amine-aldehyde resin, a maleic anhydride modified resin, a phenol modified resin, and a mixture thereof, preferably said resin is an acrylic resin.
In a particular embodiment of the compositions provided herein, the micronized copper and zinc chelates comprised in the compositions envisaged herein are dialkalimetal salts of copper(EDTA) and zinc(EDTA), preferably disodium salts of copper(EDTA) and zinc(EDTA).
In particular embodiments, the compositions as taught herein comprise the micronized copper and zinc chelates suspended in a non-aqueous suspension liquid, wherein the amount of copper and zinc chelate in said non-aqueous suspension liquid ranges from 1.0 to 50.0 % (w/w) and less than 5.0% (w/v) of said copper and zinc chelates are dissolved in said non-aqueous suspension liquid.
In specific embodiments, the non-aqueous suspension liquid for said micronized copper and zinc chelates is selected from the group consisting of propanol, isopropanol, butanol, isobutanol, and a mixture thereof, preferably isopropanol. In more specific embodiments, such compositions comprise from 45.0 to 85.0% (w/w) of said non-aqueous suspension liquid comprising said micronized copper and zinc chelates.
In particular embodiments, the composition envisaged herein further comprises a solvent for said one or more synthetic resins. In particular embodiments the solvent is selected from the group consisting of an organic ester, a hydrocarbon, an alcohol, a ketone, an organic ether, an organic oxide, an aromatic hydrocarbon, a chlorinated aliphatic hydrocarbon, a chlorofluorinated hydrocarbon, and a mixture thereof, preferably ethyl acetate or isopropanol.
In particular embodiments, the composition comprises from 55.0 to 75.0% (w/w) of non-aqueous suspension liquid comprising copper and/or zinc chelates, from 7.0 to 12.0% (w/w) of one or more resins and from 20.0 to 35.0% (w/w) of solvent for said one or more synthetic resins.
The invention also provides the compositions as described herein for use in the treatment or prevention of an epithelial infection in an animal. In particular embodiments the epithelial infection is a bacterial infection of epithelial cells in an animal or a condition related to a bacterial infection of epithelial cells in an animal.. In particular embodiments, the composition is for use in the treatment or prevention of a skin condition selected from the group consisting of exudative epidermitis, digital dermatitis, hoof rot, interdigital dermatitis and udder cleft dermatitis, preferably digital dermatitis, hoof rot or interdigital dermatitis.
The invention also provides a composition for use in a spray can comprising from 50.0 to 70.0% (w/w) of the composition as described herein; and from 30.0 to 50.0% (w/w) of a gas propellant.
Also provided is a spray can comprising a gas propellant and a sprayable composition as described herein or the composition as described herein.
Figure 1 illustrates the copper content of swabs of claws taken at different time points after the administration of a composition according to an embodiment of the invention. Figure legend: na; after washing.
As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.
The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass “consisting of” and “consisting essentially of”, which enjoy well-established meanings in patent terminology.
The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.
The terms “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, are meant to encompass variations of and from the specified value, such as variations of +/-10% or less, preferably +/-5% or less, more preferably +/-1% or less, and still more preferably +/-0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. it is to be understood that the value to which the modifier “about” refers is itself also specifically, and preferably, disclosed.
Whereas the terms “one or more” or “at least one”, such as one or more members or at least one member of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any 23, 24, 25, 26 or >7 etc. of said members, and up to all said members. In another example, “one or more” or “at least one” may refer to 1, 2, 3, 4, 5, 6, 7 or more.
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.
Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. All documents cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents herein specifically referred to are incorporated by reference.
Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the invention. When specific terms are defined in connection with a particular aspect of the invention or a particular embodiment of the invention, such connotation is meant to apply throughout this specification, i.e, also in the context of other aspects or embodiments of the invention, unless otherwise defined.
In the following passages, different aspects or embodiments of the invention are defined in more 5 detail. Each aspect or embodiment so defined may be combined with any other aspect(s} or embodiment(s) unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Reference throughout this specification to “one embodiment”, “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination.
Present inventors have developed a formulation capable of shielding an area of infection or susceptible to infection from external elements that are harmful to said area, such as dirt and water, while at the same time providing long-term antimicrobial activity. More particularly, present inventors have developed a sprayable formulation, comprising a synthetic resin and micronized copper and zinc chelates, capable of forming a flexible film in situ. Present inventors found that the presence of one or more resins in the formulation does not affect the antimicrobial activity of the micronized copper and zinc chelates. Even more, unexpectedly, the formulation as taught herein leads to a slow release of the micronized copper and zinc chelates to the area of infection or susceptible to infection, such as to the epithelial cells of a lesion site in the skin or hoof of an animal, thereby resulting in a prolonged antimicrobial effect and a prolonged skin regenerating effect, such as when compared to formulations comprising micronized copper and zinc chelates, but no resins.
The sprayable formulation as taught herein also makes the application of a bandage over the lesion site superfluous, thereby making the treatment of the area of infection or susceptible to infection in the animal faster and more convenient, reducing the stress on the treated animal (including the stress caused by removal of the bandage) and eliminating the risk of any bandages ending up in the manure of the animals.
Composition
Accordingly, a first aspect provides a sprayable composition comprising one or more synthetic resins and micronized copper and zinc chelates.
The term “sprayable” as used herein means that they can be administered using a suitable spraying device. For example, the viscosity can be sufficiently low, e.g. below 10 mPa.s. In particular embodiments, the sprayable composition comprises less than 50% (w/w) of solids.
In particular embodiments, the one or more synthetic resins are selected from the group consisting of an acrylic resin, a polyacrylic resin, glycerol phthalate, abietic acid glycerol, an amine-aldehyde resin, a maleic anhydride modified resin, a phenol modified resin, and a mixture thereof,
Preferably, the one or more synthetic resins comprise, consist essentially of or consist of an acrylic resin. Even more preferably, the one or more synthetic resins comprise, consist essentially of or consist of rubber modified thermoplastic resin derived from at least one vinyl aromatic monomer, at least one monoethylenically unsaturated nitrile monomer, and at least one monomer selected from the group consisting of {CI-Cl,} alkyl- and aryl- (meth) acrylate monomers.
In particular embodiments, said composition comprises from 5.0 to 30% (w/w); from 5.0 to 25% (w/w), from 5.0 to 20% (w/w) or from 5.0 to 15.0% (w/w) of one or more synthetic resins. In particular embodiments the concentration of synthetic resins is from 7.0 to 12.0% (w/w), in further embodiments, the concentration of synthetic resins is from 8.0 to 10.0% (w/w), such as 9.0% (w/w) of the composition.
In particular embodiments, said composition comprises a solvent, preferably a volatile solvent, for said synthetic resins. Preferably, the solvent is a skin-tolerable solvent e.g. non-toxic, causing no irritation or allergic reactions for the animal to be treated and is also not toxic for the user when inhaled. The solvent evaporates easily leaving behind the synthetic resin(s) on the area of interest.
The term “evaporative” or “volatile” as used herein refers to a liquid having a vapor pressure higher than the vapor pressure of water at a temperature of about 25°C.
In particular embodiments, said solvent for said one or more synthetic resins is selected from the group consisting of an organic ester (such as ethyl acetate), a hydrocarbon (such as an isobutene), an alcohol (such as ethanol), a ketone (such as acetone}, an organic ether, an organic oxide (such as ethylene oxide}, an aromatic hydrocarbon (such as toluene), a chlorinated aliphatic hydrocarbon
{such as methylene chloride or chloroform), a chlorofluorinated hydrocarbons (such as dichloro- difluoro-methane) and a mixture thereof. Preferably, said solvent for said one or more synthetic resins, such as acrylic resin, is ethyl acetate. The solvent component is typically selected based on its abilities to produce a desired drying rate and viscosity of the sprayable composition and the ability not to affect the suspension of copper and zinc chelates in the composition.
In particular embodiments, strong nonpolar solvents are used, preferably ethyl acetate or isopropanol.
In particular embodiments, where said solvent is different from the suspension liquid of the chelate solution, said composition comprises from 20.0 to 35.0% (w/w) of said solvent for said one or more synthetic resins. In further particular embodiments, said composition comprises from 25.0 to 30.0% (w/w) of said solvent, more particularly from 26.0 to 28.0% (w/w), such as 27.0% of said solvent.
In particular embodiments, where said solvent is the same as the suspension liquid of the chelate solution, said composition comprises from 20.0 to 72.0% (w/w), from 20.0 to 65% (w/w), from 20.0 to 50.0% (w/w), from 20.0 to 45.0% (w/w), from 20.0 to 40.0% (w/w) or from 20.0 to 35.0% (w/w) of said solvent for said one or more synthetic resins. In further particular embodiments, said composition comprises from 25.0 to 30.0% (w/w) of said solvent, more particularly from 26.0 to 28.0% (w/w), such as 27.0% (w/w) of said solvent.
The composition also comprises micronized copper and zinc chelates. The micronized copper and zinc chelates may be suspended in a non-aqueous suspension liquid prior to incorporating them into the sprayable composition as taught herein, such that less than 5.0% {w/v} of said copper and zinc chelates are dissolved in said non-aqueous suspension liquid. In particular embodiments, the copper and zinc chelates are EDTA chelates of copper and zinc, in particular the salts of EDTA chelates of copper and zinc. Of interest are the dialkalimetal salts of copper[EDTA}* and of Zn[EDTA}*. Of further interest are the disodium salts of copper(EDTA) and of Zn(EDTA) complex. These salts may also be referred to as copper and zinc disodium ethylenediaminetetraacetic acid or ethylenediaminetetraacetate-copper- and zinc-sodium complex.
The disodium salts of copperlEDTA]? and of Zn[EDTA}® in particular are attractive due to their effectiveness, thereby reducing amount of copper and zinc to be administered, and reducing concomitant side effects.
The amount of chelate in the composition of the invention may depend on the envisaged application. For instance, the concentration may be higher for therapeutic applications than for prophylactic applications, though it is envisaged that the same concentration may also be suitable for both prophylactic and therapeutic use.
In particular embodiments, the composition envisaged herein comprises from 0.6 to 50.0% (w/w), from 1.0 to 50.0% (w/w), from 1.0 to 45.0% (w/w), from 1.0 to 40.0% {w/w}, preferably from 0.6 to 35.0% (w/w) or from 1.0 to 35.0% (w/w), such as from 3.0 to 35.0% (w/w) or from 5.0 to 35.0%(w/w), more preferably from 5.0 to 30.0% (w/w), even more preferably from 10.0 to 25% (w/w) or from 15.0 to 25.0% (w/w) of micronized copper and zinc chelates. The sprayable composition as taught herein may be further diluted, such as a 3 to 2 dilution, with a gas propellant when being incorporated into a spray can, thereby also resulting in lower concentrations of micronized copper and zinc chelates in the spray can.
The copper and zinc chelates may be present in the composition in a copper chelate: zinc chelate molar ratio that is in the range of about 2 : 1 to about 1: 2, or about 1.5 : 1 to about 1 : 1.5, the molar ratio between these chelates preferably being about 1: 1.
The micronized zinc or copper chelates are present in the composition envisaged herein as microparticles. In one embodiment, the mean surface weighed diameter is in the range of 0.5 to 10.0 um, or 1.0 to 5.0 um, or 2.0 to 4.0 um, or preferably 2.2 to 2.8 um. Or the mean volume weighed diameter is in the range of 1.0 to 10.0 um, or 2.0 to 5.0 um, or 3.0 to 5.0 um, or 3.5 to 4.0 um, The size or diameter of the microparticles can be determined as an equivalent spherical diameter via techniques such as Dynamic Light Scattering. Microparticles of the copper and zinc chelates provide the advantage that they can be sprayed. Indeed, providing the chelates as microparticles may allow for obtaining compositions having a high chelate content, which still have a suitable viscosity for spraying. Moreover, the ratio between surface and content is such that the particle will easily dissolve in the wound fluid.
In particular embodiments, the microparticles have a size of about 4.0 um. The effectiveness of these microparticles results in less of the salts having to be administered with fewer concomitant side effects.
The span of the microparticle distribution may be in the range of about 50 to about 0.1, preferably in the range of about 3 to about 0.1, in particular about 3 to about 1, or about 2 to about 1, and more preferably about 1.5 to about 1.7.
The particles of the chelates are preferably present as a monomodal distribution.
Each of the copper and zinc chelates in micronized form can be prepared separately or they can be prepared in combination. When prepared separately, the micronized powders or micronized dispersions can be mixed subsequently. Also end formulations or intermediate formulations with only copper chelate and zinc chelate can be prepared and subsequently mixed.
The copper and zinc chelates in micronized form can be prepared using techniques known in the art.
Such methods include milling, bashing and grinding. The mechanical means applied to reduce the effective average effective particle size can include a ball mill, an attritor/attrition mili, a vibratory mill, a planetary mill, media mills, such as a sand mill and a bead mill.
The micronized copper and zinc chelates can also be prepared by wet milling of the starting copper and zinc chelates as a dispersion in a suitable liquid medium in which they are essentially insoluble, for example in any of the skin-tolerable non-aqueous liquids mentioned herein.
A bead mill can be used with ceramic or metal beads. The milling can be done in a one step or multistep procedure, where in the latter instance different mills and/or beads can be used.
Prior to milling, the particle size of the material may be reduced first reduced to a particular size, e.g. a size of less than about 100.0 um, which after sieving may be processed further.
In particular embodiments, said composition comprises said copper and zinc chelates suspended in a non-aqueous suspension liquid and the composition of the invention is a mixture of a suspension liquid comprising micronized copper and zinc chelates (suspension liquid) and a solvent comprising one or more resins. In particular embodiments, the suspension liquid serves as a carrier fluid and evaporates easily leaving behind the particles on the area of interest. In particular embodiments, the suspension liquid is a skin-tolerable liquid e.g. non-toxic, causing no irritation or allergic reactions. In particular embodiments the liquid is evaporative (volatile) and skin-compatible. In particular embodiments, the suspension liquid allows suspending the chelates in the form of micronized particles.
The suspension liquid in which the micronized particles can be suspended is selected such that substantially none of the copper or zinc chelate dissolves, the term substantially none meaning that no or a small amount of the copper and zinc chelates present in the formulation dissolves, e.g. less than 5.0%, or less than 2.0 %, or less than 1.0 % (each % being w/v). Said liquid is non-agueous, although minor amounts of water, e.g. less than 5.0 %, or less than 2.0 %, or less than 1.0 % (each w/v} can be present.
Exemplary evaporative liquids that can be used include alcohols, in particular alkanols such a propanol, isopropanol, butanol, isobutanol, including mixtures thereof. They may contain small amounts of water, i.e. such amounts of water that do not cause the micronized particles to dissolve.
In particular embodiments, the liquid comprises less than 20.0% (w/w) water, more preferably less than 10.0% (w/w) water, most preferably less than 5.0% (w/w) water.
Preferably, the suspension liquid for said micronized copper and zinc chelates is isopropanol.
In particular embodiments, the composition envisaged herein comprises from 45.0 to 85.0% (w/w) of said non-aqueous suspension liquid comprising said micronized copper and zinc chelates, or in other words, from 45.0 to 85.0% (w/w) of non-aqueous suspension liquid and micronized copper and zinc chelates. The final concentration of micronized copper and zinc chelates within the sprayable composition as taught herein is as described elsewhere in the present specification. In further particular embodiments, said composition comprises from 55.0 to 75.0% (w/w) of said non- aqueous suspension liquid comprising said micronized copper and zinc chelates. Preferably, the composition of the invention comprises from 60.0 to 70.0% (w/w}, more preferably from 60.0 to 65.0% (w/w) of said non-aqueous suspension liquid comprising said micronized copper and zinc chelates, such as 62.0, 63.0% or 64.0% (w/w). In these embodiments, the solvent for the synthetic resin(s) is preferably present in about 15.0-40.0% (w/w), such as from 20.0 to 35.0% (w/w), more particularly from 25.0 to 30.0% (w/w), such as 26.0% (w/w), 27.0% (w/w), 28.0% (w/w) or 29.0% {w/w}. The resin is preferably present from 5.0 to 15.0% (w/w), preferably from 7.0 to 12.0% (w/w), such as 8.0% (w/w), 9.0% (w/w), 10.0% (w/w) or 11.0% (w/w).
In particular embodiments, the chelate containing evaporative fluid (i.e. non-aqueous suspension liquid comprising micronized copper and zinc chelates), the solvent for the synthetic resin(s) and the one or more resin{s) are present in the sprayable composition as taught herein at about 64.0 (w/w), 27.0 (w/w), 9.0% (w/w), respectively.
In these embodiments, the amount of micronized copper and zinc chelates in the non-aqueous suspension liquid can range from 1.0 to 50.0% (w/w), preferably from 3.0 to 50.0% (w/w), more preferably from 5.0 to 50.0% (w/w)or from 5.0 to 40.0% (w/w). In further particular embodiments the amount of copper and zinc chelate in the non-aqueous suspension liquid ranges from 10.0 to 40.0% (w/w), preferably from 20.0 to 40.0% (w/w). In further particular embodiments the concentration of chelate in the non-aqueous suspension liquid is about 30.0% (w/w).
In particular embodiments, the evaporative liquid that is used to suspend the copper and zinc chelates (i.e. non-aqueous suspension liquid) is the same as the solvent used for the one or more synthetic resins, but this need not be the case. Where the same solvent is used, the synthetic resins may be combined directly with the copper and zinc chelates as described herein below. In these embodiments, the total amount of solvent used may be lower, such as from 20.0 to 50.0% (w/w) or from 20.0 to 35.0% (w/w).
In particular embodiments, the composition envisaged herein comprises from 20.0 to 70.0% (w/w), from 25.0 to 70.0% (w/w), from 30.0 to 70.0% (w/w), from 35.0 to 70.0% (w/w), from 35.0 to 65.0%
(w/w), from 35.0 to 60.0% (w/w), from 20.0 to 50.0% (w/w), from 20.0 to 35.0% (w/w), from 40.0 to 50.0% (w/w) of non-aqueous suspension liquid.
The formulations envisaged herein may further contain other therapeutically active ingredients such as antibiotics, including antibacterials and antifungals. In particular embodiments however, the compositions do not comprise antibiotics, more particularly they do not comprise specific antibiotics. Indeed, it was found that the compositions described herein are surprisingly effective for the treatment of epithelial infections, without requiring the addition of antibiotics.
In particular embodiments the formulations of the present invention comprise copper and zinc chelates as the only chelates present in the formulation. In further particular embodiments the formulation comprises copper zinc disodium EDTA as the only active ingredient.
In particular embodiments, the composition envisaged herein comprises from 55.0 to 70.0 % (w/w) of a composition comprising from 1.0 to 50.0% (w/w) or from 2.0 to 50.0% {w/w}, preferably from 10.0 to 40.0% (w/w) of micronized copper and zinc chelates suspended in a non-aqueous suspension liquid, such as isopropanol, and wherein less than 5.0% (w/v) of said copper and zinc chelates are dissolved in said non-aqueous suspension liquid; from 1.0 to 20.0% (w/w), preferably from 5.0 to 15.0% (w/w) of one or more synthetic resins, such as acrylic resin; and from 25.0 to 35.0% (w/w), preferably around 27.0% (w/w), of ethyl acetate.
The formulations for use in the invention may further contain adjuvants, such as preservatives, stabilizing agents, emulsifying agents, anti-foaming agents, anti-agglomeration agents, etc.
In particular embodiments, the composition as envisaged herein comprises one or more silicates, such as Bentone gel®. In certain embodiments, the composition as envisaged herein comprises from 0.1 % (w/w) to 2.0 % (w/w) of silicates.
The composition as envisaged herein may also contain ingredients that improve the spraying characteristics of the formulations or the color. The addition of dyes to the composition may facilitate the identification of the areas on the skin which have been treated with the composition.
Suitable dyes for use in the composition include but are not limited to Brilliant blue FCF, Patent blue
V, and curcumin. In certain embodiments, the composition as envisaged herein comprises from 0.01 % (w/w) to 1.0 % (w/w) of dyes, more particularly from 0.05 % (w/w) to 0.5 % (w/w).
Method of production
A further aspect provides a method of preparing a sprayable composition as envisaged herein, comprising admixing one or more synthetic resins and micronized copper and zinc chelates.
In particular embodiments, the method comprises, prior to admixing said one or more synthetic resins and micronized copper and zinc chelates, a step of suspending the micronized copper and zinc chelates in a non-aqueous suspension liquid, such that the total amount of copper and zinc chelate in said suspension ranges from 1.0 to 50.0 % (w/w); and less than 5.0% (w/v) of said copper and zinc chelates are dissolved in said liquid. In particular embodiments, the liquid is isopropanol. In particular embodiments the method further comprises, prior to admixing the step of dissolving the synthetic resin, preferably an acryl resin, in a solvent, preferably a solvent selected from the group comprising an organic ester, a hydrocarbon, an alcohol, a ketone, an organic ether, an organic oxide, an aromatic hydrocarbon, a chlorinated aliphatic hydrocarbon, a chlorofluorinated hydrocarbon, and a mixture thereof, even more preferably said solvent is ethyl acetate or isopropanol. In these embodiments, the solvent used for the synthetic resin may be the same or different from the liquid used for the preparation of the chelate suspension. In alternative embodiments of the methods of the invention, the solvent used for the synthetic resin is dissolved in the liquid prior to suspension of the chelates therein. In these embodiments, the solvent used for the synthetic resin is the liquid used for the preparation of the chelate suspension.
Treatment and prevention
A further aspect provides use of the sprayable composition as taught herein in the treatment and prevention of an epithelial infection (i.e. infections of epithelial cells) in an animal, and optionally conditions associated with or resulting from such infections. Also provided are the compositions as described herein for use in the treatment of infection of epithelial cells of animals, and conditions associated with or resulting from such infections, preferably wherein the infections are or include bacterial infections.
The term “infection of epithelial cells of animals” or "epithelial infection in an animal”, as used herein, refers to infections of any epithelial cell, but more particularly the skin and the hooves of animals, In particular embodiments, the infections are or include bacterial infections. These infections or skin conditions include but are not limited to the infections described above, in particular greasy pig disease (exudative epidermitis), porcine cutaneous spirochetosis, porcine necrotic ear syndrome, hairy hoof warts (digital dermatitis), hoof rot (interdigital phlegmon), stable hoof rot (interdigital dermatitis), and udder cleft dermatitis. Preferably, the epithelial infection (or skin condition) is digitalis dermatitis, hoof rot or interdigital dermatitis. The infection may also be in the context of a non-infectious disease such as navel infections and secondary wound infections by opportunistic pathogens after for example castration, tail clipping, or tail or ear biting. The term is also meant to cover conditions associated with or resulting from epithelial cell infections, in particular irritation (including reddening, swelling and other phenomena), pain, inflammation, more in particular skin inflammation. In particular embodiments, the “conditions related to epithelial cell infections” include reduced growth, reduced reproductive rates, and in the case of sheep, reduced wool production, less milk production, increased risk of mastitis, as well as those conditions further mentioned herein. The conditions may be acute as well as chronic.
In particular embodiments, the epithelial infection is a bacterial infection of epithelial cells in an animal or a condition related to a bacterial infection of epithelial cells in an animal. The compositions envisaged herein are in particular suitable for use in the treatment and prevention of bacterial dermatoses, such as Greasy pig disease, porcine necrotic ear syndrome, porcine cutaneous spirochetosis, Mortellaro's Disease (digital dermatitis), hoof rot, including inflammatory conditions associated therewith. It was further found that the compositions described herein are surprisingly effective for use in the treatment and prevention of udder cleft dermatitis, including inflammatory conditions associated therewith. In particular embodiments, the compositions envisaged herein are used for the treatment of M1 (early stage) and/or M2 (ulcerative stage) lesions on the skin or in the hoof.
The compositions envisaged herein are in particular suitable for use in the treatment and prevention of infections of the areas of the animals which are often in contact with dirt, such as the hoofs, legs, navel and udder, and that typically require the use of a bandage to avoid the area coming into contact with dirt. Accordingly, in particular embodiments, the composition envisaged herein is used for the treatment or prevention of an infection selected from the group consisting of digital dermatitis, hoof rot and interdigital dermatitis. The compositions are also of particular interest for the use in the treatment and/or prevention of epithelial infections on parts of the animal body which are not easily bandaged, such as, but not limited to, the udders.
The compositions are envisaged both for prophylactic and therapeutic use. Where the use is prophylactic, the animal is particularly an animal which is susceptible to an epithelial cell infection.
This can be as a result of a specific event, e.g. a wound or due to the nature of its living environment.
Although the compositions envisaged herein may be applied on any (ungulate) animal, the application on farm animals such as sheep, goats, horses, pigs and cattle is particularly envisaged.
In particular embodiments, the application method envisaged herein is by spraying the composition on the skin, more particularly the area of infection or susceptible to infection. In further particular embodiment, the area of infection is characterized by signs of inflammation. In further particular embodiments, the compositions are sprayed directly onto lesions present on the skin.
The compositions envisaged herein are typically provided as sprayable compositions, meaning that they can be administered using a suitable spraying device. For example the viscosity will be sufficiently low, e.g. below 10 mPa.s. Accordingly, provided herein are sprays for liquid compositions comprising the compositions envisaged herein.
In any given case, the quantity of the formulations of zinc and copper chelate administered to the animal to be treated, and therefore also the quantity of the zinc and copper chelate active ingredients therein, will be adjusted in accordance with the purpose to be attained (prevention or therapy), the nature of the subject, the condition under consideration as well as the severity of the condition, the type of the formulation concerned, and any other relevant facts that may modify the activity of the zinc and copper chelate or the response of the subject, as is well known by those skilled in the art.
The formulations of the invention may be administered once daily or multiple times daily, for example two, three, or four times per day. As the compositions of the inventions allow for a prolonged prophylactic and/or therapeutic effect, the frequency of application can be reduced compared to other products. in particular embodiments, at least two administrations are envisaged within a time period of one week. In further particular embodiments, two administrations are envisaged separated by 2 days (i.e. day 0 and day 3). In further particular embodiments, three administrations are envisaged separated by 2 or 3 days (i.e. day 0, day 3 and day 7). Alternatively daily applications or an application every other day for a period of four weeks can also be envisaged.
In further particular embodiments the methods involve spraying the infected hoof. In certain embodiments, one or more daily administrations are envisaged per day, during a period of at least one week, at least 10 days, or at least two weeks. In further additional embodiments, one daily administration is envisaged per day, during a period of at least 4 weeks.
In particular embodiments, the methods envisaged herein attain a reduction of inflammation within 10 days after the first treatment.
In particular embodiments, the area of infection or susceptible to infection is not treated with an antibiotic prior to administering the composition as envisaged herein.
In particular embodiments, after administration, the composition as envisaged herein will dry on the skin or hoof of the animal when contacted with air, preferably in less than 90 seconds, less than 60 seconds, more preferably less than 30 seconds, resulting in a flexible film on the skin or hoof.
Spraying device/ spray can
The formulations for use in the invention can be administered by various devices, which may be sterile or non-sterile. Such devices comprise multi-dose or unit-dose containers or unit-dose sprays or any other container, including glass bottles with a spray device and spraying cans with or without the use of propellants. In the latter instance the sprayable formulations may comprise from 5.0 to 80.0% (w/w), in particular from 10.0 to 80.0 % (w/w)of a propellant. In further embodiments, the formulations may contain from 10.0 to 70.0% (w/w), or from 20.0 to 60.0% {w/w}, of a propellant.
Propellants can be liquefied gas propellants or compressed gas propellants. Liquified propellants that can be used are hydrocarbons with a boiling point below room temperature such as Cia hydrocarbons, in particular propane or butane, dimethylether or chlorofluorocarbons. Alternative propellants include but are not limited to compressed gas propellants such as compressed air and
Nitrogen. The propellant produces a pressure in the container such that upon usage it expels the formulation out of the container. In particular embodiments, the propellant is LPG with various components.
Accordingly, also provided herein is a spray device, such as a spray can, comprising a gas propellant and a sprayable composition as envisaged herein.
In particular embodiments, the gas propellant is dimethylether.
In particular embodiments, the spray device, such as a spray can comprises from 50.0 to 70.0% {w/w}, such as 60.0% (w/w) of the sprayable composition as taught herein and from 30.0 to 50.0% (w/w), such as 40.0{w/w), of a gas propellant. Accordingly, a further aspect provided herein is a sprayable composition for a spray can comprising between from 50.0 and to 70.0% (w/w) of the composition as taught herein; and between from 30.0 and to 50.0% (w/w) of a gas propellant.
Using a spraying device significantly facilitates the application of the formulation as envisaged herein on the area of the skin or hoof to be treated.
The person skilled in the art will understand that the embodiments for the sprayable composition as taught herein can also be applied to the methods as described herein, and vice versa.
The following examples are meant to illustrate the present invention and should not be construed as a limitation of its scope.
A. Composition
An exemplary formulation 1 of a sprayable formulation according to a particular embodiment of the present invention comprises 64.0 % (w/w) of a copper and zinc chelates suspension, 9.0% (w/w) of acryl resin and 27.0 % (w/w) of ethyl acetate (as a solvent for the resin}. The copper and zinc are in the form of copper disodium ethylenediaminetetraacetic acid (EDTA) and zinc disodium EDTA, respectively. The chelate suspension (including excipients such as propellants) comprises about 5.0 % (w/w) of each chelate, hence, in total, the chelate suspension comprises about 10.0% (w/w) of copper and zinc chelates.
Formulation 1 further comprises a number of excipients. Isopropyl alcohol is used as a carrier liquid for the copper and zinc cations, and colloidal anhydrous silica is used as a rheological additive.
Butane and propane are used as propellants. Formulation 1 further comprises a number of dyes:
Brilliant blue FCF, Patent blue V, and curcumin. The dyes provide a clear indication of the treated area of the skin.
Formulation 1 is filled in a spray can in a ratio of about 60.0% (w/w) to 40.0% {w/w} dimethylether (i.e. a ratio of 3:2), resulting in a quickly drying thin even layer when sprayed on paper.
Formulation 1 was used for the treatment of digital dermatitis in a number of trials on cattle, as discussed below.
B. Testing the sprayable bandage- Dry stable
Two cows kept in a dry stable and diagnosed with digital dermatitis were treated with formulation 1 described above, in the box or at the feeding fence.
On day 0, the claws of the infected animals were sprayed with formulation 1. The formulation did not drip off and dried quickly, no specific odor was observed in the stable. A first swab was taken immediately after spraying from the site where formulation 1 was sprayed (“0 hours”).
Asecond swab was taken 5 hours later (“5 hours”) from the same site. Then, a swab was taken from that site 24 hours after application of formulation 1 (i.e. “24 hours pre-washing”). Directly after this swab, the leg of the cow was washed with water by spraying using a water hose. Then, a new swab was taken (i.e. “24 hours after-washing”) from the same site as in the pre-washing condition. Finally,
a swab was taken 72 hours after spraying of formulation 1 (“72 hours”). It is noted that the 72 hour- sample of cow 1 was taken from a non-washed leg sprayed with formulation 1.
All collected swabs were stored and the copper content of these samples was analysed using Atomic
Emission Spectroscopy (AES) analysis. After 3 days (72 hours), the copper was still measurable (see
Figure 1).
C. Treatment of digital dermatitis (DD) 22 cows with digital dermatitis (DD) in a stable representing a commercial dairy farm stable, which is typically characterized by some manure on the flooring of the stable (i.e. “wet stable”) were treated with formulation 1.
After 3 (Table 1} or 10 (Table 2) days, the sprayable bandage was checked (green color}, swab samples were taken and the amounts of copper and zinc were measured. Some animals received a retreatment with formulation 1 on day 3. Accordingly, for the animals receiving retreatment on day 3, the swab sample taken at “day 10”, is taken 7 days after the retreatment on day 3. After 10 days 64% (14 out of 22) of the cows showed measurable copper present on the hoof. As can be seen in
Table 2, there were still measurable amounts of copper and zinc in cows with or without retreatment with formulation 1 on day 3.
Table 1: Determination of copper and zinc on hoofs of 3 different cows (after 3 days)
Tower Jes
Cow 1 treated with | 3.59 4.05 es
Cow 2 treated with | 0.4 0.59 es 7
Cow 3 treated with | 16.98 34.16 formulation 1
Table 2 {after a total of 10 days of treatment (with or without retreatment on day 3))
Treatment on | Green Retreatment with | Copper Zinc (mg/L) day0 color formulation 1 on | {mg/L) day3
Abbreviations: N: no; Y: yes 23 cow hoofs maintained in a wet environment were treated on day 0, and optionally retreated on day 3, with the composition of formulation 1. The effect on the digital dermatitis is demonstrated in
Table 3. In 62% of the treated cows, treatment with formulation 1 resulted in a beneficial effect (i.e. healing or improvement of all non-MO at start} on the digital dermatitis.
Table 3. Transition matrix
Day 10
MO mi M2 OMS OM4 mal a
EE ww ve oo
EE
*no healing or even worsening **improvement
***no change ****healing
MO: normal intact skin
M1: small digital dermatitis lesion
M2: large digital dermatitis lesion
M3: scrab/crust healing phase
M4: chronic subcutaneous reservoir
M4.1 chronic with small digital dermatitis lesion
Claims (15)
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RU2764178C1 (en) * | 2020-10-08 | 2022-01-14 | Людмила Александровна Тихонова | Aqueous bactericidal composition for preventing and/or treating infectious diseases of hooves in animals and method for use thereof |
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US20100137451A1 (en) * | 2008-11-28 | 2010-06-03 | Agrochem, Inc. | Compositions and methods for treating hoof diseases |
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WO2021023885A1 (en) * | 2019-08-08 | 2021-02-11 | Cambridge Enterprise Limited | Liquid dressing compositions and their uses |
RU2764178C1 (en) * | 2020-10-08 | 2022-01-14 | Людмила Александровна Тихонова | Aqueous bactericidal composition for preventing and/or treating infectious diseases of hooves in animals and method for use thereof |
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