TECHNICAL FIELD

The present invention relates to a stabilised solution or formulation of hypohalous acid, such as hypochlorous acid (HOCI), packaged in a double-compartment packaging of the type used to deliver fluids under pressure. More specifically, the invention relates to a stabilised solution or formulation of hypohalous acid packaged in a non-aspirating dispenser that comprises a pressure-resisting external container having a flexible container of variable volume therein enclosing the stabilised solutions or formulations (a liquid or a thixotropic gel), and comprising a pressurised gas that is capable of exerting pressure on said flexible container of variable volume and forcing said stabilised solutions or formulations out of said flexible container of variable volume in a steady stream upon pressing an actuator that is operatively connected to an ejection valve. The flexible container of variable volume is free of propellants and does not produce an aerosol. By pressing the actuator, the user can dispense the liquid or gel to a desired surface, in the form of droplets that are free of air or a gas therein. The invention finds use for cleaning and/or disinfecting surfaces, food such as fruit, vegetables, crops, cut flowers or mammalian tissues (including wounds).

BACKGROUND

In many industrial sectors and notably in those of medicines and cosmetic products, it is necessary to deliver under pressure, fluids and principally liquids containing medicinal substances or cosmetics, or products consisting of natural products possibly modified or adapted, thus permitting utilisation of these fluids. For example, isotonic sea water, which finds applications for the washing of the nasal cavities, is one of these fluids.

Typical spray bottles or containers dispense liquids or foams via a mechanical trigger that requires continual pumping thereof to dispense a sprayed product. Since very small amounts of product are dispensed with each pump, numerous pumps are required to adequately cover a surface. The same often exhausts the user and becomes an ergonomic issue as spraying numerous surfaces, articles, etc., may require a person to take a break or rest.

Moreover, various dispensers, such as a spray bottle, eject a fluid via aspiration such that an aerosol mist is formed. These dispensers are undesirable in sterile situations as the air drawn in by the aspirator may come from a contaminated environment. Moreover, the aerosol droplets are small and therefore subject to being transported to an adjacent sterile environment and contaminating the same.

Various other dispensers contain a sprayable liquid in association with propellants such as volatile hydrocarbons, e.g. butane, propane, or fluorocarbon gases that can pose flammable or toxic problems. In some other cases, the liquid or gel to be dispensed cannot be put in contact with the propellant, as the two fluids are not chemically compatible.

U.S. Patents No. 4,387,833, 4,423,829, 5,927,551 and 4,964,540 describe devices that can be operated in all positions and also in the inverted position. With them the fluid is delivered, not by the action of a propellant gas, but under the action of a mechanical constraint, which is exerted on a container that has the shape of a pouch or flexible receptacle of variable volume; this container generally has a cylindrical shape, is equipped with longitudinal pleats, and is filled with the fluid to be delivered.

Still in the case of the devices disclosed in the aforementioned U.S. Patents, the mechanical constraint, under the action of which the liquid contained within the container of variable volume is delivered under pressure, is exerted by a cylindrical sleeve of elastic material, especially rubber with particular elastic properties, which envelops the container in the form of a pouch or flexible receptacle and whose diameter is slightly larger than the diameter of the container of variable volume when the latter is empty.

The sleeve in question is then put into place and the fluid to be delivered is introduced under pressure into the container which expands against the opposite action of the elastic sleeve of which the compression force exerted on the container increases with the expansion of said container due to the filling with the fluid to be delivered. The container in the form of a pouch or flexible receptacle is equipped with an actuator that allows the activation of a valve for the delivery of the fluid, the whole being arranged inside a classic container or reservoir of the type used in the aerosol industry, notably in cosmetics or personal care products.

These devices, which are very robust, have always given complete satisfaction to users but are penalised by their manufacturing cost due to the price of the rubber sleeve that is part of their constitution.

Other devices of the type in question exist, wherein a flexible container of variable volume, intended to be filled with the fluid to be delivered, and also equipped with an actuator adapted to activate a valve to permit the fluid under pressure to be delivered, is located inside an external container capable of resisting elevated pressures, notably in excess of 20 bars; this pressure-resisting external container is filled with a neutral gas under pressure, the empty flexible container of variable volume being in place and then the latter is filled with the fluid to be delivered, this fluid being introduced under a pressure which is sufficient to overcome the pressure exerted on the container by the neutral gas with which the pressure-resisting external container is filled, which consequently further increases the pressure of the neutral gas.

In the case of these devices, the constraint exerted on the internal flexible container of variable volume, and under the action of which the pressurised fluid can be delivered, is therefore of a pneumatic nature.

These devices have not known a success comparable to those disclosed above, notably due to their fragility in case of impact or fall, in particular at the level of the connection between the container of variable volume and the actuator, whose operation allows the product under pressure to be delivered.

U.S. Patent Application 2008/0272145 discloses a device that comprises a container of variable volume in the form or shape of a pouch or flexible receptacle of generally cylindrical shape with longitudinal pleats containing the fluid under pressure to be delivered and equipped with an actuator permitting to open a valve to enable the aforementioned fluid to be delivered, the whole being located inside an external container capable of resisting an elevated internal pressure which is notably superior to 20 bars, the internal volume of the latter container comprises, between its wall and the container of variable volume being filled with the fluid to be delivered, a neutral gas under a pressure sufficient to exert on the container of variable volume a pneumatic constraint sufficient to allow the delivery of the therein contained fluid when the aforementioned valve permitting said delivery is operated by the aforementioned actuator. According to a particular embodiment, the container of variable volume containing the fluid to be delivered and the external pressure-resisting container are both made of transparent materials (e.g. polyethylene terephthalate or PET), allowing the user to see the fluid and to determine at every moment the state of filling of the device as well as any alteration of the fluid which could lead to a change in the aspect of the same (colouring, separation of phases, etc.).

The Patent Application further teaches that the container of variable volume containing the fluid to be delivered and the external pressure-resisting container may be realised using laminated materials wherein at least one of the constitutive layers confers to the laminate sufficient mechanical resistance, while another layer may confer the properties of a barrier to gas, in particular to oxygen, nitrogen and/or carbon dioxide, and/or while another layer may still confer the properties of chemical resistance to the product to be delivered. A layer adapted to confer good mechanical resistance may, for example, be constituted of polyethylene terephthalate or PET. A layer adapted to confer good gas barrier properties may, for example, be realized in Nylon, especially Nylon MXD6, or in ethylene vinyl alcohol resin (or EVOH). A layer adapted to confer good properties of chemical resistance may also, for example, be constituted in polyethylene terephthalate.

Accordingly, the container of variable volume containing the fluid to be delivered may be constituted either by using a laminate of the type PET/Nylon/PET, that is to say comprising an external layer of polyethylene terephthalate, an intermediate layer of Nylon and an internal layer, that is to say a layer intended to be in contact with the fluid to be delivered, also of polyethylene terephthalate; or by using a laminate of the type PET/EVOH/PET. The pressure-resisting external container may be advantageously realised in the same material. However, bearing in mind that the material constituting this container is not in contact with the fluid to be delivered, it is possible to use a bi-layer laminate, for example in polyethylene terephthalate and Nylon. A material of this type, which does not comprise an internal layer conferring chemical resistance, may also be employed for the constitution of the container of variable volume containing the fluid to be delivered, provided that the fluid to be delivered is chemically compatible with the other layers.

In a subsequent document from the same inventors (U.S. Patent No. 8,752,731), a method for producing a device for dispensing fluid product under pressure, an apparatus for implementing the production method, and a device for dispensing a pressurised fluid product are disclosed. In particular, the latter comprises: a valve equipped with a stem, being suitable for dispensing the pressurised fluid product to outside when the stem is in the actuation position; an internal reservoir with a variable volume, a deformable side wall and a dispensing opening; an external container, made of thermoplastic rigid polymer; an attachment sleeve made of thermoplastic polymer, sealingly attached to the internal reservoir, and also welded to the external container.

The internal reservoir and the valve are placed in the external container so that the axis A of the internal reservoir and the axis B of the external container are coaxial. The external container and the internal reservoir then delimit between them an internal volume in which a pressurised gas is placed. The gas may be at least one of, or a mixture of, the gases selected from the group air, nitrogen, argon, carbon dioxide or another gas. Provision is made for the external container to form a barrier to the gas and to offer a chemical resistance to the gas and a mechanical resistance to a pressure higher than 20 bar. In particular, the external container is made of thermoplastic polymer, such as polyethylene terephthalate (PET) or polyethylene naphthalate (PEN), advantageously transparent, used alone or in the form of a mixture, in order to be able to soften under the action of heat and harden when cooling, in order to form a barrier to the gas and to offer the chemical resistance and mechanical resistance to pressure.

Based on the information provided above, it seems clear that general knowledge supports the use of polyethylene terephthalate (PET) as a layer with not only good mechanical resistance, but also reasonably good gas barrier properties. PET is known to exhibit very low gas permeation compared with most polymers such as polystyrene, polyethylene and polypropylene (Fernandez-Menendez et al., Polymer Testing 90 (2020) 106729); in addition, PET bottles are widely used as containers for carbonated liquids (e.g. carbonated water, soft drinks, beer, etc.).

WO 2012/129161 is also in support to the above, as it discloses a stabilised solution or formulation packaged in a container for storage or sale, comprising hypochlorous acid and a stabilising amount of dissolved inorganic carbon (DIC) incorporated in the form of a bicarbonate or carbonate of an alkali or alkaline earth metal, wherein the solution or formulation has an available free chlorine (AFC) content of from about 10 to about 10,000 parts per million, a pH of from about 4.0 to 7.0, a DIC-to-AFC molar ratio of from 5:1 to 1 :5, and wherein the container is minimally permeable to CO2 or O2. In particular, Figure 6 in WO 2012/129161 shows the results of an extended stability study of HOCI produced by electrochemical treatment of a NaHCOs-enriched NaCI solution at pH 5.4, bottled in a polyethylene terephthalate (PET) container and stored at room temperature.

The method disclosed in WO 2012/129161 for obtaining the stabilised solution or formulation involves incorporating the DIC (e.g., in the form of carbonate or bicarbonate) by adding it to an electrolyte for electrochemical treatment, or incorporating the DIC (e.g., in the form of carbonate or bicarbonate) by directly adding it to an electrolysed solution comprising hypohalous acid (e.g., HOCI). More in detail, WO 2012/129161 teaches that the stabilised hypochlorous acid solutions (e.g., solutions of greater than 90%, 95%, or 97% HOCI) may be obtained by electrolysis of a saline solution as described in U.S. Patent 7,276,255 or can be prepared by any suitable method or apparatus by incorporating the bicarbonate or carbonate into the dry electrolyte or the solution for electrolysis. The carbonate or bicarbonate can be added to the dry electrolyte in accordance with the desired AFC content of the resulting solution. Hypochlorous acid solutions may be prepared by passing saline solution containing the carbonate/bicarbonate over coated titanium electrodes separated by a semi-permeable ceramic membrane at a current of about 6 to 9 Amps. Electrochemical treatment of saline is described, for example, in U.S. Patent 7,303,660, U.S. Patent 7,828,942, and U.S. Patent 7,897,023. In some embodiments, the bicarbonates or carbonates are added prior to the formation of hypohalous acid (e.g., prior to the electrochemical treatment), and in other embodiments, the bicarbonates or carbonates are added to the solution after formation of hypohalous acid. For example, the bicarbonate(s) or carbonate(s) may be added to the precursor solution, the electrolyte, and/or the end solution.

When dissolved in water, a bicarbonate or carbonate of an alkali or alkaline earth metal imparts an alkaline pH to the solution. It will therefore be apparent to those skilled in the art that, in order to obtain a stabilised solution or formulation comprising hypochlorous acid and a stabilising amount of dissolved inorganic carbon (DIC) incorporated in the form of a bicarbonate or carbonate of an alkali or alkaline earth metal, and having a pH of from about 4.0 to 7.0, a particular electrolysis apparatus is required, comprising one or more electrolytic cells, each of which comprises an anode, a cathode and a separator (diaphragm or membrane) capable of avoiding mixing between the solution treated at the anode and the one treated at the cathode. When subjected to electrolytic treatment on the anode side of the just described electrolytic cell, the saline solution (i.e., a solution containing an alkali or alkaline earth halogenide) entering the cell is converted into a solution containing the corresponding hypohalous acid. If the saline solution originally has an alkaline pH (due to the presence of a bicarbonate or carbonate of an alkaline or alkaline earth metal), depending on the residence time of the solution in the electrolytic cell and the electric current used, the electrolytic treatment on the anode side of the electrolytic cell above described may allow to lower the solution pH up to acidic values (i.e. lower than 7), and thus to obtain a solution or formulation with the characteristics described by Panicheva et al. (WO 2012/129161). Unfortunately, this can only be obtained by using an electrolysis apparatus in which the anode and cathode compartments are kept separated by using a diaphragm or a membrane.

Based on the above, there is still an unmet need for a simple way to prepare a hypohalous acid solution that has a high AFC content, has sufficient stability and/or other properties required to be commercially useful in medical and other commercial settings, and is not irritating or harmful to humans. The claimed invention meets these and other objectives. Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention, as it existed before the priority date of each claim of this specification.

SUMMARY OF THE INVENTION

The present invention relates to a stabilised hypohalous acid solution or formulation thereof, conveniently packaged for sale in a double-compartment packaging of the type used to deliver fluids under pressure. The invention further relates to methods of use for disinfecting mammalian tissue, including wounds and burns, disinfecting or cleansing hard surfaces, treating (e.g., preserving and/or disinfecting) food products or cut flowers, among other uses.

More specifically, the invention relates to a stabilised solution or formulation of hypohalous acid packaged in a non-aspirating dispenser that comprises a pressure- resisting external container having a flexible container of variable volume therein enclosing the stabilised solution or formulation (a liquid or a thixotropic gel), and comprising a pressurised gas that is capable of exerting pressure on said flexible container of variable volume and forcing said stabilised solution or formulation out of said flexible container of variable volume in a steady stream upon pressing an actuator that is operatively connected to an ejection valve. The flexible container of variable volume is free of propellants and does not produce an aerosol. By pressing the actuator, the user can dispense the liquid or gel to a desired surface, in the form of droplets that are free of air or a gas therein. The invention finds use for cleaning and/or disinfecting surfaces, food such as fruit, vegetables, crops, cut flowers or mammalian tissues (including wounds).

In a first aspect, the invention provides a stabilised solution or formulation comprising an antimicrobial solution, for example hypochlorous acid, wherein the solution or formulation has an available free chlorine (AFC) content of from about 10 to about 10,000 parts per million, a pH of from about 3.0 to 7.0, and is packaged in a double compartment packaging of the type used to deliver fluids under pressure. The flexible container of variable volume containing the fluid to be delivered is in the form or shape of a pouch or flexible receptacle and is equipped with an actuator that allows the activation of a valve for the delivery of the fluid, the whole being located inside a pressure-resisting external container or reservoir of the type used in the aerosol industry, notably in cosmetics or personal care products. The internal volume of the pressure-resisting external container comprises, between its wall and the flexible container of variable volume being filled with the fluid to be delivered, a neutral gas under a pressure sufficient to exert on the flexible container of variable volume a pneumatic constraint sufficient to allow the delivery of the therein contained fluid when the aforementioned valve permitting said delivery is operated by the aforementioned actuator.

In a further aspect, the present invention provides a method for disinfecting or treating a mammalian tissue, the method comprising applying the solution or formulation to a mammalian tissue in need of disinfection or treatment.

In another aspect, the present invention provides a method for disinfecting or cleansing a hard surface comprising applying the solution or formulation according to the first aspect of the invention to the hard surface, and optionally, wherein the hard surface comprises porcelain, glass, steel, iron, ceramic or polymeric material.

In a further aspect, the present invention provides a method of treating a food product comprising applying the solution or formulation according to the first aspect of the invention to the food product.

Also disclosed herein is a stabilised hypohalous acid solution. The solution may have an available free chlorine (AFC) content of from about 10 to about 10,000 parts per million, and a pH of from about 3.0 to about 7.0. For example, in certain embodiments, the solution has a pH of from about 6.1 to about 6.75. In certain embodiments, the solution contains hypochlorous acid, and is prepared by electrolysis of saline. The solution is stabilised, as determined by its limited change in pH and/or AFC over time, for at least one month, but in various embodiments, the solution is stabilised for at least six months, at least one year, or more.

In certain embodiments, the solution comprises HOCI produced by electrolysis of saline, and the solution may have an AFC content of from about 100 to about 500 parts per million, a pH in the range of about 3.0 to about 7.0, and a salinity of from about 0.02% to about 1.0%. In certain embodiments, the HOCI solution is formulated as a hydrogel.

Also disclosed herein is a method for preparing a stabilised hypohalous acid solution packaged in a double-compartment packaging of the type used to deliver fluids under pressure. The method involves assembling a device of the type used in the aerosol industry, notably in cosmetics or personal care products; in particular, the device is a double-compartment packaging. For example, as schematised in Figure 1, an aluminium or tinplate can (pressure-resisting external container) is closed by a valve on which a flexible container of variable volume (e.g., a multilayer film bag) and containing the product to be dispensed is affixed or welded. The propellant (liquid or compressed gas) is contained inside the pressure-resisting external container and outside the flexible container of variable volume, and squeezes the flexible container of variable volume to release the product through the valve. This solution makes it possible to dispense the product in whatever position the double-compartment packaging is held.

Other aspects and embodiments of the invention will be apparent from the following detailed description of the invention.

DESCRIPTION OF THE FIGURES

Figure 1 schematises the assembly procedure for a device of the type used in the aerosol industry, notably in cosmetics or personal care products; in particular, the device is a double-compartment packaging. As shown, the assembly procedure involves several steps: 1A placing a bag with affixed valve inside a container, 1B gassing (air/nitrogen) followed by crimping of the valve into the container, 1C filling the product into the bag, 1 D positioning of actuator and cap.

Figure 2 shows the relative percentage of the HOCI and NaOCI species present in a free chlorine aqueous solution at a temperature of 20 °C and 0.1 M ionic strength, as a function of pH (Dissociation of hypochlorous acid, in White’s Handbook of Chlorination and Alternative Disinfectants (5 ^th edition), Black & Veatch Corporation, 2010).

Figures 3A and 3B show the change in AFC and pH over storage time of packaged aqueous solutions of free chlorine (produced by electrochemical treatment of a NaCI solution), whose pH was initially adjusted to about 7 with hydrochloric acid; different double-compartment packaging of the type used to deliver fluids under pressure were filled with aliquots of the same solution, stored at 40°C to accelerate the deterioration of the solution, and kept unopened until measurement. Aluminium cans and flexible PET pouches equipped with a valve and an aluminium mounting cap were used; nitrogen gas was used as the propellant. The data shown are averages of three values; also shown is the linear regression (solid line) with 95% prediction intervals (broken lines).

Figures 4A and 4B show the change in AFC and pH over storage time of packaged aqueous solutions of free chlorine (produced by electrochemical treatment of a NaCI solution), whose pH was initially adjusted to about 7 with hydrochloric acid; different double-compartment packaging of the type used to deliver fluids under pressure were filled with aliquots of the same solution, stored at 40°C to accelerate the deterioration of the solution, and kept unopened until measurement. Aluminium cans and flexible PET pouches equipped with a valve and an aluminium mounting cap were used; however, this time gaseous carbon dioxide was used as the propellant. The data shown are averages of three values, along with the non-linear regression (solid line) with 95% prediction intervals (broken lines). DETAILED DESCRIPTION

The present invention relates to a stabilised solution or formulation of hypohalous acid packaged in a non-aspirating dispenser that comprises a pressure-resisting external container having a flexible container of variable volume therein enclosing the stabilised solution or formulation (a liquid or a thixotropic gel), and comprising a pressurised gas that is capable of exerting pressure on said flexible container of variable volume and forcing said stabilised solution or formulation out of said flexible container of variable volume in a steady stream upon pressing an actuator that is operatively connected to an ejection valve. The flexible container of variable volume is free of propellants and does not produce an aerosol. By pressing the actuator, the user can dispense the liquid or gel to a desired surface, in the form of droplets that are free of air or a gas therein. The invention finds use for cleaning and/or disinfecting surfaces, food such as fruit, vegetables, crops, cut flowers or mammalian tissues (including wounds).

In a first aspect, the invention provides a stabilised solution or formulation comprising hypohalous acid, wherein the solution or formulation has an available free halide (AFC) content of from about 10 to about 10,000 parts per million, a pH of from about 3.0 to 7.0, and is packaged in a double-compartment packaging of the type used in the aerosol industry, notably in cosmetics or personal care products. An aluminium or tinplate can (pressure-resisting external container) is closed by a valve on which a flexible container of variable volume (e.g., a multilayer film bag) and containing the product to be dispensed is affixed or welded. The propellant (liquid or compressed gas) is contained inside the pressure-resisting external container, outside the flexible container of variable volume, and squeezes the flexible container of variable volume to release the product through the valve. This solution makes it possible to dispense the product in whatever position the double-compartment packaging is held.

The flexible container of variable volume containing the fluid to be delivered is in the form or shape of a pouch or flexible receptacle and is equipped with an actuator that allows the activation of a valve for the delivery of the fluid, the whole being located inside a pressure-resisting external container (e.g., an aluminium or tinplate can). The internal volume of the pressure-resisting external container comprises, between its wall and the flexible container of variable volume being filled with the fluid to be delivered, a neutral gas under a pressure sufficient to exert on the flexible container of variable volume a pneumatic constraint sufficient to allow the delivery of the therein contained fluid when the aforementioned valve permitting said delivery is operated by the aforementioned actuator.

The pressure-resisting external container is preferably capable of resisting an elevated internal pressure, which is notably higher than 5 bars, preferably higher than 8 bars, more preferably higher than 12 bars and possibly even capable of supporting pressures in excess of 20 bars.

According to a particular embodiment, the flexible container of variable volume containing the fluid to be delivered and the pressure-resisting external container are both made of transparent materials, allowing the user to see the fluid to be delivered and determine at every moment the state of filling of the device.

In a preferred embodiment, the flexible container of variable volume containing the fluid to be delivered is made in polyethylene terephthalate (PET); this material not only exhibits good mechanical resistance, but also reasonably good gas barrier properties. In particular, PET exhibits very low gas permeation compared with most polymers such as polystyrene, polyethylene and polypropylene (Fernandez-Menendez et al., Polymer Testing 90 (2020) 106729); for this reason, PET bottles are widely used as containers for carbonated liquids (e.g. carbonated water, soft drinks, beer, etc.).

The propellant (liquid or compressed gas) may be at least one of, or a mixture of, the gases selected from the group air, nitrogen, argon, carbon dioxide or another gas. The gas is inserted in the volume delimited by the internal wall of the pressure-resisting external container and the external wall of the flexible container of variable volume being filled with the fluid to be delivered, in any appropriate form, particularly gaseous or dissolved in an appropriate liquid or solid medium, the release of the dissolved gas in the liquid or solid medium making it possible to maintain a constant pressure in the internal volume delimited by the internal wall of the pressure-resisting external container and the external wall of the flexible container of variable volume being filled with the fluid to be delivered.

While the solution or formulation comprising hypohalous acid may be produced chemically in accordance with some embodiments (e.g., by acidification of hypohalite), the hypohalous acid may also be produced electrochemically. The hypohalite solution may be generated by electrolysis of a halide salt, such as sodium chloride, and may comprise a mixture of oxidising species such as predominantly sodium hypochlorite and hypochlorous acid. Hypochlorous acid and hypochlorite are in equilibrium and the position of the equilibrium is determined predominantly by the pH (that is, pH affects the concentration of each component). An electrolysed sodium chloride solution with a pH of 8.8 to 10.0 has a purity of about > 95% sodium hypochlorite (see Figure 2); by reducing the pH to less alkaline values, the available free chlorine content can be converted into the more effective hypochlorous acid form. Thus, the pH-adjusted solution may have a pH of from about 4.0 to about 7.5, but in certain embodiments has a pH of from about 4.4 to about 6.75, or a pH of from about 5 to about 6.75, or a pH of from about 5.4 to about 6.4, or a pH of from about 6.0 to about 6.4. At a pH lower than 6.2 the solution will contain mostly (< 95%) hypochlorous acid with respect to hypochlorite (see Figure 2).

To reduce the pH of a hypohalite solution having originally an alkaline pH (e.g. a pH comprised between 8.8 to 10.0) and convert the hypohalite into the more effective hypohalous acid form, any suitable acid that does not react with the hypohalite can be used; for example, the following acids may be considered: hydrochloric acid (HCI), sulphuric acid (H2SO4), chloric acid (HCIO3), perchloric acid (HCIO4), nitric acid (HNO3), phosphoric acid (H3PO4), acetic acid (CH3COOH), carbonic acid (H2CO3), boric acid (H3BO3).

While the final solution may comprise or consist essentially of hypochlorous acid as the active agent, in some embodiments it may contain other hypohalous acids (e.g., HOBr, or mixture thereof). In some embodiments, the solution contains other oxidising or radical producing species such as a hypohalite (e.g., hypochlorite), hydroxide, H2O2 and O3, among others.

The biocidal activity of the solution can be expressed in terms of available free chlorine or AFC. While the invention is applicable to an AFC range of from about 10 to about 10,000 ppm (or to about 5,000 ppm), in certain embodiments, the solution has a relatively high AFC content and is suitable for use with mammalian tissues or agricultural products. For example, the solution may have an AFC content of from about 100 to 1,000 ppm, or 100 to 500 ppm, or about 150 to about 250 ppm. Other AFC levels may be employed and may be selected based upon the intended application. For example, without any limitation, for surface disinfection the AFC may be in the range of about 140 to about 2,000 ppm, or about 400 to about 1 ,000 ppm.

Also disclosed herein is a method for preparing a stabilised hypohalous acid solution packaged in a container of variable volume of the type used to deliver fluids under pressure. The method involves introducing an empty flexible container of variable volume, having the form or shape of a pouch or flexible receptacle and equipped with a mounting cup also comprising a gasket, into a pressure-resisting external container. After positioning the mounting cup comprising the gasket on the edge of the opening of the pressure-resisting external container, the mounting cup is crimped on the external edge of the opening of the pressure-resisting external container. In the volume comprised between the wall of the pressure-resisting external container and the external surface of the internal flexible container of variable volume, a neutral gas under pressure is introduced in a quantity sufficient for bringing the pressure to a value preferably comprised between about 1.5 bars and about 6 bars, the precise value of the said pressure being chosen in accordance with the nature of the fluid to be delivered and the final application. Further details about the assembly of the just described device can be found in U.S. Patent 2008/0272145, which is hereby incorporated by reference in its entirety. In view of introducing the neutral gas, one may proceed using a suitable tool, for example an under the cup gasser crimper of the type marketed by the company Pamasol Willi Mader AG, DriesbOelstrasse 2, CFI-8808 Pfaffikon, SZ Switzerland under the name "Tete UTC" (i.e. “UTC Head”). This tool ensures the tightness at the level of the upper surface of the pressure-resisting external container and lifts slightly the mounting cup, using a connection by vacuum to pull by aspiration the mounting cup into a seat, and to permit the introduction under pressure of a neutral gas or of compressed air. Once the gas has been introduced, the mounting cup is pressed against the external edge of the opening of the pressure-resisting external container, then a crimping is made between the mounting cup and the pressure-resisting external container. During this operation, a pressure is maintained by the head to compress the gasket included within the mounting cup and therefore ensure a good tightness between the mounting cup and the pressure-resisting external container. The internal flexible container of variable volume is then filled with the fluid intended to be delivered under pressure. In this respect, it is possible to have recourse to a so-called metering unit, for instance that which is marketed by the company Pamasol Willi Mader AG, Driesbiielstrasse 2, CH-8808 Pfaffikon, SZ Switzerland under the name "Remplisseur volumetrique sous pression" (i.e. “Volumetric pressure filling machine”). This quantity determining unit generally comprises a device for volumetric quantity determination under high pressure and a filling nozzle. Once the mounting cap is crimped on the pressure-resisting external container, the whole is positioned under the filling nozzle, which is part of the metering unit, and the nozzle is operated to come down and to ensure tightness on the mounting cup. The fluid is introduced under pressure through the valve in order to fill the internal flexible container.

The authors of the present invention have surprisingly discovered that it is possible to obtain a stabilised hypohalous acid solution packaged in a double-compartment packaging of the type used in the aerosol industry, notably in cosmetics or personal care products, simply by selecting an internal flexible container (of variable volume, to contain the fluid to be delivered) made in polyethylene terephthalate (PET) and using carbon dioxide as the propellant. Without being bound by theory, carbon dioxide is able to slowly permeate through the minimally permeable PET layer of the flexible container, and to dissolve in the solution therein contained. The solution thus becomes progressively more stable, the stabilising effect being due, at least in part, to the free radical scavenging ability of dissolved inorganic carbon (which generally includes carbonates, bicarbonates, carbonic acid and dissolved CO2) to thereby slow down the decomposition of the hypohalous acid.

If the solution inserted in the internal flexible container has originally an alkaline pH, a larger amount of carbon dioxide will be required to stabilise the hypohalous acid. However, the pH of the solution can also be reduced prior to packaging by adding acid, as previously discussed. In such a case, the diffusion of carbon dioxide through the PET layer of the flexible container will take place anyway, thus providing the stabilising effect.

While the hypohalous acid solution may be in the form of a liquid, the solution may take the form of a cream, gel (e.g. silicate-based gel), and/or foam by the addition of conventional ingredients known in the art. For example, topical formulations of electrochemical solutions are disclosed in US 2005/0196462, which is hereby incorporated by reference in its entirety. In these embodiments, the formulation is better contained around the application site by limiting solution run-off. Further, convenient applicators for creams, foams, and the like are known, and may be used in accordance with the present invention. Since the solutions of the invention provide the potential for low conductivity, even with relatively high AFC content, and at “skin- friendly” pH levels, the solutions of the invention are particularly suitable for hydrogel formulations.

In certain embodiments employing hydrogel formulations, the composition has an AFC content of greater than about 150 ppm, greater than about 200 ppm, greater than about 250 ppm, greater than about 300 ppm, or greater than about 400 ppm. Further, the formulation may have a conductivity of from about 0.3 mS/cm to about 12 mS/cm, such as from about 0.5 mS/cm to about 10 mS/cm in some embodiments. Further, hydrogel formulations in some embodiments have a pH of from about 5 to about 7, or from about 6 to about 6.5 in other embodiments. The hydrogels may be prepared from silicate- based carriers, such as sodium magnesium fluorosilicate (e.g., from about 0.5% to about 5%), and may employ an additional buffer for targeting the pH. An exemplary buffer is phosphoric acid.

The hypohalous acid solution of the invention may also be hypertonic, hypotonic, or isotonic with respect to physiological fluids (blood, plasma, tears, etc.). Alternatively, the solution may contain varying levels of salinity, such as from 0.01 to about 2.0%. Generally, the solution contains from about 0.02% to about 0.9% w/v NaCI when intended for use in medicine. In some embodiments, the solution may be a normal saline solution (about 0.91% w/v NaCI). In some embodiments, the solution may contain from about 0.01 to 2.0% w/v of one or more salts, such as a halide salt, e.g. NaCI, KCI, or a mixture of salts or halide salts. The salt or halide salt may be a salt of an alkali metal or alkaline earth metal, such as sodium, potassium, calcium, or magnesium. In certain embodiments, the electrolysed solution is generated using a mixture of physiologically balanced salts, as disclosed in U.S. Patent 6,426,066, which is hereby incorporated by reference in its entirety. Such salts may include potassium halides (e.g., KCI) and magnesium halides (e.g., MgCh).

Still other aspects of the invention provide methods of disinfecting or cleansing a mammalian tissue, such as a wound or burn, or disinfecting or cleansing a hard surface, or for treating or preserving a food product or cut flowers. Due to the stability of the hypohalous acid solutions, such methods need not be performed proximately to the production of the biocidal solution, and the solution may be prepared well in advance of its use.

The solutions and formulations of the invention may be used as sterilising, disinfecting and biocidal solutions for human and animal care. The solutions are non-hazardous, non-irritating, non-sensitising to the skin, non-irritating to the eyes, not harmful if swallowed, and show no evidence of mutagenic activity. For example, the method of the invention provides for moistening, lubricating, irrigating, cleaning, deodorising, disinfecting, or debriding a wound by rinsing, washing or immersing the wound, with or in, the stabilised hypohalous acid solutions, or by applying the solution to the wound and/or wound dressing. The wound may or may not be infected, and thus the method of the invention is useful for treating infected wounds and useful for preventing infection of uninfected wounds.

In one aspect, the invention provides a convenient means for wound care and management and may be used in combination with the apparatus and methods described in U.S. 2010/030132, which is hereby incorporated by reference in its entirety. For example, the method may comprise supplying the stabilised solution to a wound site by one or more of soak, scrub, pulsed lavage, hydrosurgery, and ultrasound to effectively debride and disinfect a wound or tissue. The solution may be delivered before, during and/or after negative pressure wound therapy to promote proper wound healing physiology. In these embodiments, the method may employ a wound dressing for coordinating debridement by infusion of hypochlorous acid with negative pressure therapy. Thus, the invention may be used in combination with a wound treatment apparatus and/or wound dressing.

For example, in certain embodiments, the invention allows for an initial stabilised hypochlorous acid solution soak and/or scrub to both debride and disinfect the wound or tissue, followed by the application of negative pressure to the wound or tissue using the stabilised hypochlorous acid solution as an irrigating agent to control wound bioburden, remove excess exudate, and promote formation of granulation tissue. Optionally, the method also involves seamless transition to the stabilised hypohalous acid solution infusion (e.g., active or passive infusion without negative pressure). Such seamless transition can be effected via a wound dressing which allows for controlled infusion of stabilised hypochlorous acid solution with controlled vacuum source. In these embodiments, continued cell proliferation and regeneration continues without disruption of the wound bed, once the endpoints of negative pressure therapy have been obtained.

In certain embodiments of the invention, the wound needing care is a stage l-IV pressure ulcer, stasis ulcer, diabetic ulcer, post-surgical wound, burn, cut, abrasion, or a minor irritation of the skin. In certain embodiments, the wound is rinsed, washed, or immersed in the solution periodically over at least two weeks, but treatment may continue periodically for over about 4 weeks, about 9 weeks, or more. The wound, in some embodiments, is rinsed with the solution at least once a week, but may be treated with the solution at least twice a week, or more frequently.

In some embodiments, the invention provides a method for treating an infected or colonised wound, tissue, surgical cavity, or bone, and a method for reducing wound bioburden. The treatment solution in accordance with the invention, as already described, is generally effective for killing or inactivating a broad spectrum of bacterial, fungal, and viral pathogens, including S. aureus, P. aeruginosa, E. coli, Enterococcus spp., C. difficile, and Candida spp.. The solution does not produce resistant species, making the methods desirable over the delivery of traditional antibiotics.

In another aspect, the solution of the invention is particularly suitable for use in conjunction with stem cell and growth factor therapy, including the use of genetically engineered cells and engineered tissue and allografts and organs for transplant in various treatments. Using the stabilised hypohalous acid solution of the invention to disinfect tissue before, during or after addition of cells or growth factors, maintains the viability of the cells and integrity of the growth factors, while killing the unwanted microbes.

In certain embodiments, the solution or formulation thereof is applied for the control of inflammation, including an inflammatory reaction or hyper-inflammation of the skin. For example, the solution or formulation thereof may be applied for use in a method as described in U.S. 2007/0196357 or U.S. 2010/0285151, which are hereby incorporated by reference. In certain embodiments, the solution or composition of the invention is applied (e.g., to an affected area) for treatment of a patient having a dermatosis, atopic dermatitis, skin allergy, rosacea, psoriasis, or acne, among others. In such embodiments, the solution may be formulated as a hydrogel, for example, as described elsewhere herein.

In certain embodiments, this invention is advantageously used against microbes on surfaces because of its fast activity against bacterial spores, fungi, and other resistant microorganisms. Because of its effectiveness and the speed at which it acts, the invention meets a substantial public health need, and one that is not adequately addressed by current commonly used antimicrobial agents. Accordingly, application of the solution to various surfaces and materials is useful to control microbial contamination, not only for the care and management of wounds, but for disinfecting hard surfaces such as medical or dental equipment, preserving and decontaminating food products, water treatment, as well as other industrial and agricultural applications. In certain embodiments, the solution or composition of the invention is applied to crops (pre- or post-harvest) or cut flowers for their preservation and/or for improving the overall quality of the product. In some embodiments, the solution is potassium based and has one or more utilities (e.g., methods of use) as disclosed in PCT/US2011/43590, which is hereby incorporated by reference in its entirety.

Killing, inactivating, or otherwise reducing the active population of bacterial spores and fungi on surfaces is particularly difficult. Bacterial spores have a unique chemical composition of spore layers that make them more resistant than vegetative bacteria to the antimicrobial effects of chemical and physical agents. Likewise, the unique chemical composition of fungal cells, especially mould spores, makes them more resistant to chemical and physical agents than other microorganisms. This resistance can be particularly troublesome when the spores or fungi are located on surfaces such as food, food contact sites, ware, hospitals and veterinary facilities, surgical implements, and hospital and surgical linens and garments.

Control of the mould Chaetomium funicola, and of bacterial spore-forming microorganisms of the Bacillus species, can be especially important during food packaging, particularly during cold or hot aseptic filling of food and beverage products. Microorganisms of the Bacillus species include Bacillus cereus, Bacillus mycoides, Bacillus subtilis, Bacillus anthracis, and Bacillus thuringiensis. These latter microorganisms share many phenotypical properties, have a high level of chromosomal sequence similarity, and are known enterotoxin producers. Bacillus cereus is one of the most problematic because it has been identified as possessing increased resistance to germicidal chemicals used to decontaminate environmental surfaces.

As used herein, the term “surface” refers to both hard and soft surfaces and includes, but are not limited to, tile grout, plaster, drywall, ceramic, cement, clay, bricks, stucco, plastic, wallpaper, fabric, tiles, cement and vinyl flooring, heating and/or cooling fins, filters, vanes, baffles, vents, crevices in walls or ceilings, paper and wood products such as lumber, paper, and cardboard, woven products such as blankets, clothing, carpets, drapery and the like. The term surface also includes human surfaces, animal surfaces, military equipment, transportation equipment, children’s items, plant surfaces, seeds, outdoor surfaces, soft surfaces, air, wounds, and medical instruments, and the like.

EXAMPLES

Example 1 : Solutions of free chlorine packaged using nitrogen aas as the propellant

Figures 3A and 3B show averages of three AFC and pH measurements for aqueous solutions of free chlorine (AFC * 380 ppm, initial pH » 9.8) produced by electrochemical treatment of a diluted saline, pH-adjusted to about 7 with hydrochloric acid. Different double-compartment packaging of the type used to deliver fluids under pressure were filled with aliquots of the same solution, stored at 40°C to accelerate the deterioration of the solution, and kept unopened until measurement. The solution should be stored at 25°C or at 20°C or less for greater stability; however, for stability testing, accelerated tests can be performed by storing the solution at a higher temperature, and the shelf- life predicted from accelerated data by extrapolation. For example, storing the solution at 15 °C above normal storage conditions (storage conditions for Australia are considered to be the temperatures of 25 - 30 °C), a time period of 3 months gives a possible shelf-life prediction of 18 months (TGA instructions for disinfectant testing, version 2.1, March 2020 - Australian Government, Department of Health, Therapeutic Goods Administration). Aluminium cans and flexible PET pouches equipped with an aluminium mounting cap and a valve were used; nitrogen gas was used as the propellant. Although the AFC content remained relatively stable over time, showing a reduction of about 50% in just over two months, the pH of the solution dropped sharply in less than a month, becoming even more acidic in the long run.

Example 2: Stabilised solutions of free chlorine packaged using gaseous carbon dioxide as the propellant

In an attempt to stabilise the solution, an aqueous solution of free chlorine (AFC * 380 ppm, initial pH ^» 9.8) was produced by electrochemical treatment of a diluted saline and then pH-adjusted to about 7 with hydrochloric acid. Different double-compartment packaging of the type used to deliver fluids under pressure were filled with aliquots of the same solution, stored at 40°C to accelerate the deterioration of the solution, and kept unopened until measurement. Aluminium cans and flexible PET pouches equipped with an aluminium mounting cap and a valve were used; however, this time gaseous carbon dioxide was used as the propellant.

Figures 4A and 4B show averages of three AFC and pH measurements as a function of time; also shown is the non-linear regression (solid line) with 95% prediction intervals (broken lines). The results clearly show how solutions packaged in double compartment packaging of the type used to deliver fluids under pressure are more stable over time when pressurised with carbon dioxide, not only as regards their AFC content (more than 80 days were required to see a 50% reduction) but above all as regards the change in pH. This surprising result is attributable to the propellant, which appears to be able to slowly permeate through the minimally permeable PET layer of the flexible PET pouch, and to dissolve in the solution therein contained. The solution thus becomes progressively more stable, the stabilising effect being due, at least in part, to the free radical scavenging ability of dissolved inorganic carbon (which generally includes carbonates, bicarbonates, carbonic acid and dissolved CO2) to thereby slow down the decomposition of the hypohalous acid. All references cited herein are incorporated by reference in their entireties.